U.S. patent application number 10/205600 was filed with the patent office on 2003-05-22 for novel compounds and compositions as protease inhibitors.
This patent application is currently assigned to AXYS PHARMACEUTICALS, INC.. Invention is credited to Bryant, Clifford M., Bunin, Barry A., Kraynack, Erica A., Patterson, John W..
Application Number | 20030096796 10/205600 |
Document ID | / |
Family ID | 22414780 |
Filed Date | 2003-05-22 |
United States Patent
Application |
20030096796 |
Kind Code |
A1 |
Bryant, Clifford M. ; et
al. |
May 22, 2003 |
Novel compounds and compositions as protease inhibitors
Abstract
The present invention relates to novel N-cyanomethyl amides
which are cysteine protease inhibitors, the pharmaceutically
acceptable salts and N-oxides thereof, their uses as therapeutic
agents and the methods of their making.
Inventors: |
Bryant, Clifford M.;
(Millbrae, CA) ; Bunin, Barry A.; (San Bruno,
CA) ; Kraynack, Erica A.; (Oakland, CA) ;
Patterson, John W.; (Mountain View, CA) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
AXYS PHARMACEUTICALS, INC.
SO. SAN FRANCISCO
CA
|
Family ID: |
22414780 |
Appl. No.: |
10/205600 |
Filed: |
July 24, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10205600 |
Jul 24, 2002 |
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09526090 |
Mar 15, 2000 |
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6455502 |
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60124420 |
Mar 15, 1999 |
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Current U.S.
Class: |
514/112 ;
514/519; 514/528; 558/168; 558/436; 558/445 |
Current CPC
Class: |
C07D 239/28 20130101;
C07D 295/155 20130101; C07C 255/29 20130101; C07C 317/50 20130101;
C07D 295/215 20130101; C07D 277/56 20130101; C07C 323/62 20130101;
A61P 25/28 20180101; C07D 211/60 20130101; C07D 277/42 20130101;
A61P 3/10 20180101; C07D 213/70 20130101; C07D 277/30 20130101;
C07C 255/24 20130101; C07C 2601/14 20170501; C07C 255/60 20130101;
C07D 333/38 20130101; C07C 271/22 20130101; C07D 307/68 20130101;
C07D 417/04 20130101; C07D 417/12 20130101; C07C 323/60 20130101;
A61P 9/10 20180101; A61P 11/00 20180101; A61P 21/04 20180101; C07C
275/24 20130101; A61P 19/02 20180101; A61P 25/00 20180101; A61P
37/00 20180101; A61P 35/00 20180101; C07C 311/06 20130101; A61P
9/00 20180101; A61P 33/00 20180101; C07B 2200/07 20130101; C07D
213/81 20130101; C07D 333/20 20130101; A61P 37/08 20180101; A61P
43/00 20180101; C07D 209/06 20130101; C07D 209/26 20130101; A61P
37/02 20180101; C07D 207/16 20130101; A61P 19/10 20180101; A61P
17/00 20180101; A61P 11/06 20180101; A61P 5/14 20180101; A61P 27/02
20180101; C07C 311/09 20130101; C07D 209/52 20130101; C07D 213/82
20130101; A61P 29/00 20180101; A61P 17/02 20180101; C07D 233/26
20130101 |
Class at
Publication: |
514/112 ;
514/519; 514/528; 558/445; 558/436; 558/168 |
International
Class: |
A61K 031/66; A61K
031/275; C07F 009/10; C07C 255/27 |
Claims
We claim:
1. A compound of Formula (I): 40in which: R.sup.1 is a group, of
Formula (a) or (b): 41 wherein: X.sup.1 and X.sup.2 independently
are --C(O)-- or --CH.sub.2S(O).sub.2--; R.sup.5 and R.sup.6 are
hydrogen or (C.sub.1-6)alkyl; R.sup.7 and R.sup.8 are hydrogen or
(C.sub.1-6)alkyl or as defined below; R.sup.9 and R.sup.10
independently are (i) (C.sub.1-6)alkyl optionally substituted with
cyano, halo or nitro or (ii) a group selected from
--X.sup.3NR.sup.12R.sup.12, --X.sup.3NR.sup.12C(O)O- R.sup.12,
--X.sup.3NR.sup.12C(O)NR.sup.12R.sup.12, --X.sup.3NR.sup.12C(NR.-
sup.12)NR.sup.12R.sup.12, --X.sup.3OR.sup.12, --X.sup.3SR.sup.12,
--X.sup.3C(O)OR.sup.12, --X.sup.3C(O)NR.sup.12R.sup.12,
--X.sup.3S(O).sub.2NR.sup.12R.sup.12,
--X.sup.3P(O)(OR.sup.12)OR.sup.12,
--X.sup.3OP(O)(OR.sup.12)OR.sup.12, --X.sup.3NR.sup.12C(O)R.sup.13,
--X.sup.3S(O)R.sup.13, --X.sup.3S(O).sub.2R.sup.13,
--X.sup.3C(O)R.sup.13, --X.sup.3C(O)R.sup.14,
--X.sup.3C(O)OR.sup.14, --X.sup.3OC(O)R.sup.14,
--X.sup.3NR.sup.15C(O)R.sup.14, --X.sup.3NR.sup.15C(O)OR.sup.14,
--X.sup.3C(O)NR.sup.14R.sup.15,
--X.sup.3S(O).sub.2NR.sup.14R.sup.15,
--X.sup.3NR.sup.15C(O)NR.sup.14R.su- p.15,
--X.sup.3NR.sup.15C(NR.sup.15)NR.sup.14R.sup.15,
--X.sup.4SR.sup.14--X.sup.4S(O)R.sup.14,
--X.sup.4S(O).sub.2R.sup.14, --X.sup.4OR.sup.14, or
--X.sup.4NR.sup.14R.sup.15, wherein X.sup.3 is (C.sub.1-6)alkylene,
X.sup.4 is a bond or (C.sub.1-6)alkylene, R.sup.12 at each
occurrence independently is hydrogen, (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.13 is (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.14 is
(C.sub.3-12)cycloalkyl(C.s- ub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloa- ryl(C.sub.0-6)alkyl and R.sup.15 is
hydrogen or (C.sub.1-6)alkyl, and wherein within R.sup.14 said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.4NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.4 is
a bond or (C.sub.1-6)alkylene, R.sup.16 is hydrogen or
(C.sub.1-6)alkyl and R.sup.17 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, or (iii) a group
selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl and
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.4NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.4,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.9
and/or R.sup.10 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.4)OR.sup.12,
--X.sup.4OP(O)(OR.sup.12)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above, or R.sup.9
taken together with R.sup.7 and/or R.sup.10 taken together with
R.sup.8 form trimethylene, tetramethylene or
phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo
or methylene; and R.sup.11 is --X.sup.5X.sup.6R.sup.18, wherein
X.sup.5 is --C(O)--, --C(O)C(O)-- or --S(O).sub.2--, X.sup.6 is a
bond, --O-- or --NR.sup.19--, wherein R.sup.19 is hydrogen or
(C.sub.1-6)alkyl, and R.sup.18 is (i) (C.sub.1-10)alkyl optionally
substituted by cyano, halo, nitro, --NR.sup.12R.sup.12,
--NR.sup.12C(O)OR.sup.12, --NR.sup.12C(O)NR.sup.12R.- sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.12, --OR.sup.12, --SR.sup.12,
--C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.20,
--SR.sup.20, --S(O)R.sup.20, --S(O).sub.2R.sup.20, --C(O)R.sup.20,
--C(O)OR.sup.20, --C(O)NR.sup.20R.sup.21, --NR.sup.20R.sup.21,
--NR.sup.21C(O)R.sup.20, --NR.sup.21C(O)OR.sup.20,
--NR.sup.21C(O)NR.sup.20R.sup.21 or
--NR.sup.21C(NR.sup.21)NR.sup.20R.sup.21, wherein R.sup.12 and
R.sup.13 are as defined above, R.sup.20 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)bicycloaryl(C.s- ub.0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl and R.sup.21 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl, or (ii)
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-6)alkyl, (C.sub.9-12)bicycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl or (iii)
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.- 0-6)alkyl,
phenyl(C.sub.0-6)alkyl or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl- ,
wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is
substituted by --X.sup.4OR.sup.22, --X.sup.4SR.sup.22,
--X.sup.4S(O)R.sup.22, --X.sup.4S(O).sub.2R.sup.22,
--X.sup.4C(O)R.sup.22, --X.sup.4C(O)OR.sup.22,
--X.sup.4C(O)NR.sup.22R.su- p.23, --X.sup.4NR.sup.22R.sup.23,
--X.sup.4NR.sup.23C(O)R.sup.22, --X.sup.4NR.sup.23C(O)OR.sup.22,
--X.sup.4NR.sup.23C(O)NR.sup.22R.sup.23 or
--X.sup.4NR.sup.23C(NR.sup.23)NR.sup.22R.sup.23, wherein X.sup.4 is
as defined above, R.sup.22 is
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl and R.sup.23 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl; wherein
within R.sup.11 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above; R.sup.2 is
hydrogen or (C.sub.1-6)alkyl or as defined below; R.sup.3 is
hydrogen, (C.sub.1-6)alkyl or as defined below; and R.sup.4 is (i)
hydrogen or (C.sub.1-6)alkyl, wherein said alkyl is optionally
substituted with cyano, halo, nitro, --NR.sup.12R.sup.12,
--NR.sup.12C(O)OR.sup.12, --NR.sup.12C(O)NR.sup.12R.sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.1- 2, --OR.sup.12,
--SR.sup.12, --C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.14,
--SR.sup.14, --S(O)R.sup.14, --S(O).sub.2R.sup.14, --C(O)R.sup.14,
--C(O)OR.sup.14, --OC(O)R.sup.14, --NR.sup.14R.sup.15,
--NR.sup.15C(O)R.sup.14, --NR.sup.15C(O)OR.sup.14,
--C(O)NR.sup.14R.sup.15, --S(O).sub.2NR.sup.14R.sup.15,
--NR.sup.15C(O)NR.sup.14R.sup.15 or
--NR.sup.15C(NR.sup.15)NR.sup.14R.sup.15, wherein R.sup.12,
R.sup.13, R.sup.14 and R.sup.15 are as defined above, or (ii) a
group selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-2)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.sub-
.0-6)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-6)alkyl and
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.1- 7,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.sup.17 or
--X.sup.4NR.sup.17C(NR.sup.17)- NR.sup.16R.sup.17, wherein X.sup.4,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.9
and/or R.sup.10 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above, or R.sup.4 and
R.sup.2 taken together form trimethylene, tetramethylene or
phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo
or methylene, or R.sup.4 and R.sup.3 together with the carbon atom
to which both R.sup.4 and R.sup.3 are attached form
(C.sub.3-8)cycloalkylene or (C.sub.3-8)heterocycloalkyl- ene; and
the N-oxide derivatives, prodrug derivatives, protected
derivatives, individual isomers and mixtures of isomers; and the
pharmaceutically acceptable salts thereof.
2. The compound of claim 1 in which: R.sup.1 is a group of Formula
(a) wherein within Formula (a): X.sup.1 is --C(O)--; R.sup.5 is
hydrogen or (C.sub.1-6)alkyl; R.sup.7 is hydrogen or methyl;
R.sup.9 is (i) (C.sub.1-6)alkyl optionally substituted with
--OR.sup.14, --SR.sup.14, --S(O)R.sup.14, --S(O).sub.2R.sup.14,
--C(O)R.sup.14, --C(O)OR.sup.14, --OC(O)R.sup.14,
--NR.sup.14R.sup.15, --R.sup.15C(O)R.sup.14,
--NR.sup.15C(O)OR.sup.14, --C(O)NR.sup.14R.sup.15,
--S(O).sub.2NR.sup.14R.sup.15, --NR.sup.5C(O)NR.sup.14R.sup.15 or
--NR.sup.15C(NR.sup.15)NR.sup.14R.sup.15, wherein R.sup.14 is
(C.sub.3-10)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-10)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-10)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-10)aryl(C.su-
b.0-6)alkyl, (C.sub.9-10)polycycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-10)polycycloaryl(C.sub.0-6)alkyl and R.sup.15 is
hydrogen or (C.sub.1-6)alkyl, and wherein within R.sup.14 said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.3OR.sup.16, --X.sup.3SR.sup.16,
--X.sup.3S(O)R.sup.16, --X.sup.3S(O).sub.2R.sup.16,
--X.sup.3C(O)R.sup.16, --X.sup.3C(O)OR.sup.16,
--X.sup.3OC(O)R.sup.16, --X.sup.3NR.sup.16R.sup.1- 7,
--X.sup.3NR.sup.17C(O)R.sup.16, --X.sup.3NR.sup.17C(O)OR.sup.16,
--X.sup.3C(O)NR.sup.16R.sup.17,
--X.sup.3S(O).sub.2NR.sup.16R.sup.17,
--X.sup.3NR.sup.17C(O)NR.sup.16R.sup.17 or
--X.sup.3NR.sup.17C(NR.sup.17)- NR.sup.16R.sup.17, wherein X.sup.3
is a bond or (C.sub.1-6)alkylene, R.sup.16 is hydrogen or
(C.sub.1-6)alkyl and R.sup.17 is
(C.sub.3-10)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-10)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-10)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-10)aryl(C.su-
b.0-6)alkyl, (C.sub.9-10)polycycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-10)polycycloaryl(C.sub.0-6)alkyl, or (ii) a group
selected from (C.sub.3-10)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-10)cycloalkyl- (C.sub.0-6)alkyl,
(C.sub.6-10)aryl(C.sub.0-6)alkyl,
hetero(C.sub.5-10)aryl(C.sub.0-6)alkyl,
(C.sub.9-10)polycycloaryl(C.sub.0- -6)alkyl and
hetero(C.sub.8-10)polycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.3OR.sup.16, --X.sup.3SR.sup.16,
--X.sup.3S(O)R.sup.16, --X.sup.3S(O).sub.2R.sup.16,
--X.sup.3C(O)R.sup.16, --X.sup.3C(O)OR.sup.16,
--X.sup.3OC(O)R.sup.16, --X.sup.3NR.sup.16R.sup.17,
--X.sup.3NR.sup.17C(O)R.sup.16, --X.sup.3NR.sup.17C(O)OR.sup.16,
--X.sup.3C(O)NR.sup.16R.sup.17,
--X.sup.3S(O).sub.2NR.sup.16R.sup.17,
--X.sup.3NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.3NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.3,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.9
any alicyclic or aromatic ring system present may be substituted
further by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.3NR.sup.12R.sup.12, --X.sup.3NR.sup.12C(O)OR.sup.12,
--X.sup.3NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.3NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.3OR.sup.12, --X.sup.3SR.sup.12, --X.sup.3C(O)OR.sup.12,
--X.sup.3C(O)NR.sup.12R.sup.12,
--X.sup.3S(O).sub.2NR.sup.12R.sup.12,
--X.sup.3P(O)(OR.sup.3)OR.sup.12,
--X.sup.3OP(O)(OR.sup.3)OR.sup.12, --X.sup.3OC(O)R.sup.13,
--X.sup.3NR.sup.12C(O)R.sup.13, --X.sup.3S(O)R.sup.13,
--X.sup.3S(O).sub.2R.sup.13 and --X.sup.3C(O)R.sup.13, wherein
X.sup.3 is as defined above, R.sup.12 at each occurrence
independently is hydrogen, (C.sub.1-6)alkyl or halo-substituted
(C.sub.1-3)alkyl and R.sup.13 is (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl; and R.sup.11 is
--X.sup.4X.sup.5R.sup.18, wherein X.sup.4 is --C(O)-- or
--S(O).sub.2--, X.sup.5 is a bond, --O-- or --NR.sup.19--, wherein
R.sup.19 is hydrogen or (C.sub.1-6)alkyl, and R.sup.18 is (i)
(C.sub.1-10)alkyl or (ii) (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl or hetero(C.sub.5-12)aryl(C.-
sub.0-6)alkyl or (iii) (C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl, wherein said cycloalkyl,
heterocycloalkyl, phenyl or heteroaryl is substituted by
--X.sup.9OR.sup.24,--X.sup.9C(O)R.sup.24, --X.sup.9C(O)OR.sup.24,
--X.sup.9C(O)NR.sup.24R.sup.25, --X.sup.9NR.sup.24R.sup.25,
--X.sup.9NR.sup.25C(O)R.sup.24, --X.sup.9NR.sup.25C(O)OR.sup.24,
--X.sup.9NR.sup.25C(O)NR.sup.24R.sup.25 or
--X.sup.9NR.sup.25C(NR.sup.25)- NR.sup.24R.sup.25, wherein X.sup.9
is a bond or (C.sub.1-6)alkylene, R.sup.24 is
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl and R.sup.25 is hydrogen
or (C.sub.1-6)alkyl, wherein within R.sup.11 any alicyclic or
aromatic ring system present may be substituted further by 1 to 5
substituents independently selected from (C.sub.1-6)alkyl, halo,
halo-substituted (C.sub.1-4)alkyl, --OR.sup.12, --X.sup.3SR.sup.12,
--C(O)OR.sup.12 and --X.sup.3NR.sup.12C(O)OR.sup.12, wherein
X.sup.3 is a bond or (C.sub.1-6)alkylene and R.sup.14 is hydrogen
or (C.sub.1-6)alkyl; R.sup.2 is hydrogen; R.sup.3 is hydrogen or
(C.sub.1-4)alkyl or taken with R.sup.4 together with the carbon
atom to which both R.sup.3 and R.sup.4 are attached forms
(C.sub.3-8)cycloalkylene; and R.sup.4 is hydrogen or as defined
above; and the N-oxide derivatives, prodrug derivatives, protected
derivatives, individual isomers and mixtures of isomers; and the
pharmaceutically acceptable salts thereof.
3. The compound of claim 2 in which: R.sup.1 is a group of Formula
(a) wherein within Formula (a): R.sup.5 and R.sup.7 both are
hydrogen; R.sup.9 is (i) (C.sub.1-6)alkyl optionally substituted
with --OR.sup.14 or --SR.sup.14, wherein R.sup.14 is
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl- , phenyl(C.sub.0-6)alkyl,
biphenylyl(C.sub.0-6)alkyl or
hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl, or (ii) a group selected
from (C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl,
biphenylyl(C.sub.0-6)alkyl or
hetero(C.sub.5-10)aryl(C.sub.0-6)alkyl; wherein within R.sup.9 any
alicyclic or aromatic ring system present may be substituted
further by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.3NR.sup.12R.sup.12, --X.sup.3NR.sup.12C(O)OR.sup.12,
--X.sup.3NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.3NR.sup.12C(NR.sup.12)NR.sup.12R.sup.12,
--X.sup.3OR.sup.12, --X.sup.3SR.sup.12, --X.sup.3C(O)OR.sup.12,
--X.sup.3C(O)NR.sup.12R.sup.1- 2,
--X.sup.3S(O).sub.2NR.sup.12R.sup.12,
--X.sup.3P(O)(OR.sup.3)OR.sup.12,
--X.sup.3OP(O)(OR.sup.3)OR.sup.12, --X.sup.3OC(O)R.sup.13,
--X.sup.3OC(O)R.sup.13, --X.sup.3NR.sup.12C(O)R.sup.13,
--X.sup.3S(O)R.sup.13, --X.sup.3S(O).sub.2R.sup.13 and
--X.sup.3C(O)R.sup.13, wherein X.sup.3 is a bond or
(C.sub.1-6)alkylene, R.sup.12 at each occurrence independently is
hydrogen, (C.sub.1-3)alkyl or halo-substituted (C.sub.1-3)alkyl and
R.sup.13 is (C.sub.1-3)alkyl or halo-substituted (C.sub.1-3)alkyl;
and R.sup.11 is --X.sup.4X.sup.5R.sup.18, wherein X.sup.4 is
--C(O)--, X.sup.5 is a bond and R.sup.18 is (i)
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl or (ii)
phenyl(C.sub.0-6)alkyl or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl,
wherein said phenyl or heteroaryl is substituted by
--X.sup.9OR.sup.24, --X.sup.9C(O)R.sup.24, --X.sup.9C(O)OR.sup.24,
--X.sup.9C(O)NR.sup.24R.su- p.25, --X.sup.9NR.sup.24R.sup.25,
--X.sup.9NR.sup.25C(O)R.sup.24, --X.sup.9NR.sup.25C(O)OR.sup.24,
--X.sup.9NR.sup.25C(O)NR.sup.24R.sup.25 or
--X.sup.9NR.sup.25C(NR.sup.25)NR.sup.24R.sup.25, wherein X.sup.9 is
a bond or (C.sub.1-6)alkylene, R.sup.24 is phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl and R.sup.25 is hydrogen
or (C.sub.1-6)alkyl, wherein within R.sup.11 any aromatic ring
system present may be substituted further by 1 to 5 substituents
independently selected from (C.sub.1-6)alkyl, halo,
halo-substituted (C.sub.1-4)alkyl, --OR.sup.12, --X.sup.3SR.sup.12,
--C(O)OR.sup.12 and --X.sup.3NR.sup.12C(O)OR.sup.12 wherein X.sup.3
is a bond or (C.sub.1-6)alkylene and R.sup.12 is hydrogen or
(C.sub.1-6)alkyl; and R.sup.3 and R.sup.4 are both hydrogen; and
the N-oxide derivatives, prodrug derivatives, protected
derivatives, individual isomers and mixtures of isomers; and the
pharmaceutically acceptable salts thereof; and the N-oxide
derivatives, prodrug derivatives, protected derivatives, individual
isomers and mixtures of isomers; and the pharmaceutically
acceptable salts thereof.
4. The compound of claim 3 in which within Formula (a) R.sup.9 is
cyclohexylmethyl, wherein said cyclohexyl may be substituted by 1
to 5 radicals independently selected from (C.sub.1-4)alkyl,
(C.sub.1-6)alkylidene or --X.sup.3OC(O)R.sup.13, or
phenylmethylsulfanylmethyl or phenylsulfanylethyl, wherein said
phenyl may be substituted by 1 to 5 radicals independently selected
from (C.sub.1-4)alkyl, cyano, halo, halo-substituted
(C.sub.1-4)alkyl, nitro, --OR.sup.12, --SR.sup.12 and
--C(O)OR.sup.12, wherein R.sup.12 is hydrogen, (C.sub.1-3)alkyl or
halo-substituted (C.sub.1-3)alkyl and R.sup.13 is (C.sub.1-6)alkyl
or halo-substituted (C.sub.1-3)alkyl; and R.sup.11 is benzoyl,
furylcarbonyl, phenyloxybenzoyl, pyridylthienylcarbonyl,
benzoylbenzoyl, thienylcarbonyl, morpholinylcarbonyl,
phenyluriedobenzoyl, cyclohexenylcarbonyl or piperazinylcarbonyl,
wherein within R.sup.11 any aromatic ring system present may be
substituted further by 1 to 2 substituents independently selected
from (C.sub.1-6)alkyl, tert-butoxycarbonylamino,
tert-butoxycarbonylaminomethyl, bromo, chloro, ethoxy, fluoro,
hydroxy, methoxy and methylsulfanyl; and the N-oxide derivatives,
prodrug derivatives, protected derivatives, individual isomers and
mixtures of isomers; and the pharmaceutically acceptable salts
thereof.
5. The compound of claim 4 in which within Formula (a), R.sup.9 is
a group having the following formula: 42in which q is 0 to 5 and
R.sup.26 at each occurrence is independently selected from
(C.sub.1-4)alkyl, cyano, halo, halo-substituted (C.sub.1-4)alkyl,
nitro, --OR.sup.12, --SR.sup.12 and --C(O)OR.sup.12, wherein
R.sup.12 is hydrogen, (C.sub.1-3)alkyl or halo-substituted
(C.sub.1-3)alkyl and R.sup.13 is (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl; and the N-oxide derivatives,
prodrug derivatives, protected derivatives, individual isomers and
mixtures of isomers; and the pharmaceutically acceptable salts
thereof.
6. The compound of claim 3 in which within Formula (a), R.sup.9 is
benzylsulfanylmethyl, 2-bromobenzylsulfanylmethyl,
2-chlorobenzylsulfanyl, 2-(2-chlorophenylsulfanyl)ethyl,
cyclohexyl, 4-ethylidenecyclohexyl, 2-iodobenzylsulfanylmethyl,
2-methylbenzylsulfanylmethyl,
3-methyl-3-trifluorocarbonyloxycyclohexylme- thyl,
4-methylenecyclohexylmethyl or 2-nitrobenzylsulfanylmethyl and
R.sup.11 is 4-tert-butoxycarbonylaminobenzoyl,
3-tert-butoxycarbonylamino- methylbenzoyl,
2-(3,5-dimethoxyphenyl)thiazol-4-ylcarbonyl, fur-3-ylcarbonyl,
4-methoxybenzoyl, 3-methylbenzoyl, 3-phenoxybenzoyl,
5-pyrid-2-ylthien-2-ylcarbonyl, 3-benzoylbenzoyl, 4-methylbenzoyl,
thien-2-ylcarbonyl, morpholin-4-ylcarbonyl,
5-bromothien-2-ylcarbonyl, 5-chlorothien-2-ylcarbonyl,
5-methylthien-2-ylcarbonyl,
2-(2-chloro-6-methylphenyl)ureidobenzoyl,
cyclohexyl-1-en-1-ylcarbonyl, 3-ethoxybenzoyl, 3-fluorobenzoyl,
4-fluorobenzoyl and piperidin-1-ylcarbonyl; and the N-oxide
derivatives, prodrug derivatives, protected derivatives, individual
isomers and mixtures of isomers; and the pharmaceutically
acceptable salts thereof.
7. The compound of claim 6 selected from a group consisting of:
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)-4-hydroxybenzamide;
N-[2-(2-bromobenzylsulfanyl)-1R-cyanomethylcarbamoylethyl]benzamide;
N-[1R-cyanomethylcarbamoyl-2-(2-iodobenzylsulfanyl)ethyl]benzamide;
N-[1R-cyanomethylcarbamoyl-2-(2-cyanobenzylsulfanyl
)ethyl]morpholine-4-carboxamide;
N-[3-(2-chlorophenylsulfanyl)-1R-cyanome-
thylcarbamoylpropyl]benzamide;
N-[1R-cyanomethylcarbamoyl-2-(2-nitrobenzyl-
sulfanyl)ethyl]morpholine-4-carboxamide
N-[1R-cyanomethylcarbamoyl-2-(2-me-
thylbenzylsulfanyl)ethyl]morpholine-4-carboxamide; and
N-[1R-cyanomethylcarbamoyl-2-(2-methylbenzylsulfanyl)ethyl]benzamide;
and the N-oxide derivatives, prodrug derivatives, protected
derivatives, individual isomers and mixtures of isomers; and the
pharmaceutically acceptable salts thereof.
8. A pharmaceutical composition comprising a compound of claim 1,
or a N-oxide derivative, prodrug derivative, individual isomer,
mixture of isomers, or a pharmaceutically acceptable salt thereof
in admixture with one or more suitable excipients.
9. A method of treating a disease in an animal in which cysteine
protease activity contributes to the pathology and/or
symptomatology of the disease, which method comprises administering
to the animal a therapeutically effective amount of compound of
claim 1; or a N-oxide derivative, prodrug derivative, individual
isomer or mixture of isomers or a pharmaceutically acceptable salt
thereof.
10. The method of claim 9 in which the cysteine protease is
cathepsin S.
11. The method of claim 10 in which the disease is an autoimmune
disorder, allergic disorder, allogeneic immune response, a disorder
involving excessive elastolysis, cardiovascular disorders or a
disorder involving fibril formation.
12. The method of claim 11 in which the disorder is selected from
juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris,
Graves' disease, myasthenia gravis, systemic lupus erythemotasus,
rheumatoid arthritis, Hashimoto's thyroiditis, asthma, organ
transplant or tissue graft rejections, chronic obstructive
pulmonary disease, bronchiolitis, excessive airway elastolysis in
asthma and bronchitis, pneumonities, plaque rupture, atheroma and
systemic amyloidosis.
13. A compound according to claim 1 in which R.sup.1 is a group of
formula (a) wherein X.sup.1 is --CH.sub.2S(O).sub.2--; and the
N-oxide derivatives, prodrug derivatives, protected derivatives,
individual isomers and mixtures of isomers; and the
pharmaceutically acceptable salts thereof.
14. A compound of Formula (II): 43wherein: R.sup.2 is hydrogen or
(C.sub.1-6)alkyl or as defined below; R.sup.3 is hydrogen,
(C.sub.1-6)alkyl or as defined below; R.sup.4 is (i) hydrogen or
(C.sub.1-6)alkyl, wherein said alkyl optionally is substituted with
cyano, halo, nitro, --NR.sup.12R.sup.12, --NR.sup.12C(O)OR.sup.12,
--NR.sup.12C(O)NR.sup.12R.sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.1- 2, --OR.sup.12,
--SR.sup.12, --C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.14,
--SR.sup.14, --S(O)R.sup.14, --S(O).sub.2R.sup.14, --C(O)R.sup.14,
--C(O)OR.sup.14, --OC(O)R.sup.14, --NR.sup.14R.sup.15,
--NR.sup.15C(O)R.sup.14, --NR.sup.15C(O)OR.sup.14,
--C(O)NR.sup.14R.sup.15, --S(O).sub.2NR.sup.14R.sup.15,
--NR.sup.15C(O)NR.sup.14R.sup.15 or
NR.sup.15C(NR.sup.15)NR.sup.14R.sup.15, wherein R.sup.12 at each
occurrence independently is hydrogen, (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.13 is (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.14 is
(C.sub.3-12)cycloalkyl(C.s- ub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloa- ryl(C.sub.0-6)alkyl and R.sup.15 is
hydrogen or (C.sub.1-6)alkyl, and wherein within R.sup.14 said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.4NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.4 is
a bond or (C.sub.1-6)alkylene, R.sup.16 is hydrogen or
(C.sub.1-6)alkyl and R.sup.17 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, or (ii) a group
selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl and
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.4NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.4,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.4
any alicyclic or aromatic ring system present may be substituted
further by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above, or R.sup.4 and
R.sup.2 taken together form trimethylene, tetramethylene or
phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo
or methylene, or R.sup.4 and R.sup.3 together with the carbon atom
to which both R.sup.4 and R.sup.3 are attached form
(C.sub.3-8)cycloalkylene or (C.sub.3-8)heterocycloalkyl- ene;
R.sup.5 is hydrogen or (C.sub.1-6)alkyl; R.sup.7 is hydrogen or
(C.sub.1-6)alkyl; R.sup.9 is (C.sub.6-12)aryl(C.sub.1-6)alkyl,
hetero(C.sub.5-12)aryl(C.sub.1-6)alkyl, --X.sup.4OR.sup.14,
--X.sup.4SR.sup.14, --X.sup.4S(O)R.sup.14,
--X.sup.4S(O).sub.2R.sup.14 or --X.sup.4NR.sup.14R.sup.15, wherein
X.sup.4, R.sup.14 and R.sup.15 are as defined above and wherein
within R.sup.9 said aryl or heteroaryl ring optionally is
substituted by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, cyano, halo, halo-substituted (C.sub.1-4)alkyl,
nitro, --X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)R.sup.12,
--X.sup.4C(O)OR.sup.12, --X.sup.4C(O)NR.sup.12R.su- p.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.- 12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13, wherein X.sup.4, R.sup.12 and R.sup.13
are as defined above; and R.sup.11 is --X.sup.5X.sup.6R.sup.18,
wherein X.sup.5 is --C(O)--, --C(O)C(O)-- or --S(O).sub.2--,
X.sup.6 is a bond, --O-- or --NR.sup.19--, wherein R.sup.19 is
hydrogen or (C.sub.1-6)alkyl, and R.sup.18 is (i) (C.sub.1-10)alkyl
optionally substituted by cyano, halo, nitro, --NR.sup.12R.sup.12,
--NR.sup.12C(O)OR.sup.12, --NR.sup.12C(O)NR.sup.12R.sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.1- 2, --OR.sup.12,
--SR.sup.12, --C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.20,
--SR.sup.20, --S(O)R.sup.20, --S(O).sub.2R.sup.20, --C(O)R.sup.20,
--C(O)OR.sup.20, --C(O)NR.sup.20R.sup.21, --NR.sup.20R.sup.21,
--NR.sup.21C(O)R.sup.20, --NR.sup.21C(O)OR.sup.20,
--NR.sup.21C(O)NR.sup.20R.sup.21 or
--NR.sup.21C(NR.sup.21)NR.sup.20R.sup.21, wherein R.sup.12 and
R.sup.13 are as defined above, R.sup.20 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)bicycloaryl(C.s- ub.0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl and R.sup.21 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl, or (ii)
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-6)alkyl, (C.sub.9-12)bicycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl or (iii)
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.- 0-6)alkyl,
phenyl(C.sub.0-6)alkyl or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl- ,
wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is
substituted by --X.sup.4OR.sup.22, --X.sup.4SR.sup.22,
--X.sup.4S(O)R.sup.22, --X.sup.4S(O).sub.2R.sup.22,
--X.sup.4C(O)R.sup.22, --X.sup.4C(O)OR.sup.22,
--X.sup.4C(O)NR.sup.22R.su- p.23, --X.sup.4NR.sup.22R.sup.23,
--X.sup.4NR.sup.23C(O)R.sup.22, --X.sup.4NR.sup.23C(O)OR.sup.22,
--X.sup.4NR.sup.23C(O)NR.sup.22R.sup.23 or
--X.sup.4NR.sup.23C(NR.sup.23)NR.sup.22R.sup.23, wherein X.sup.4 is
as defined above, R.sup.22 is
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl and R.sup.23 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl; wherein
within R.sup.11 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above; and the
N-oxide derivatives, prodrug derivatives, protected derivatives,
individual isomers and mixtures of isomers; and the
pharmaceutically acceptable salts thereof.
15. The compound of claim 14 in which: R.sup.2 is hydrogen; R.sup.3
is hydrogen, methyl or taken with R.sup.4 together with the carbon
atom to which both R.sup.3 and R.sup.4 are attached forms
(C.sub.3-8)cycloalkylen- e; R.sup.4 is hydrogen, methyl or as
defined above; R.sup.5 is hydrogen or (C.sub.1-6)alkyl; R.sup.7 is
hydrogen or methyl; R.sup.9 represents
(C.sub.6-12)aryl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl, --X.sup.4OR.sup.14,
--X.sup.4SR.sup.14, --X.sup.4S(O)R.sup.14 or
--X.sup.4NR.sup.14R.sup.15, wherein X.sup.4 is a bond or
(C.sub.1-6)alkylene, R.sup.14 is (C.sub.6-12)aryl(C.sub.0-6)alkyl
or hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl and R.sup.15 is hydrogen
or (C.sub.1-6)alkyl, and wherein within R.sup.9 said aryl or
heteroaryl ring optionally is substituted by 1 to 5 radicals
independently selected from (C.sub.1-6)alkyl, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4OR.sup.12,
--X.sup.4C(O)R.sup.12, --X.sup.4SR.sup.12, wherein X.sup.4 is a
bond or (C.sub.1-6)alkylene, R.sup.12 at each occurrence
independently is hydrogen, (C.sub.1-6)alkyl or halo-substituted
(C.sub.1-3)alkyl, and R.sup.13 is (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl; and R.sup.11 is
--X.sup.4X.sup.5R.sup.18, wherein X.sup.4 is --C(O)-- or
--S(O).sub.2--, X.sup.5 is a bond, --O-- or --NR.sup.19--, wherein
R.sup.19 is hydrogen or (C.sub.1-6)alkyl, and R.sup.18 is (i)
(C.sub.1-10)alkyl or (ii) (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl or hetero(C.sub.5-12)aryl(C.-
sub.0-6)alkyl or (iii) (C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl, wherein said cycloalkyl,
heterocycloalkyl, phenyl or heteroaryl is substituted by
--X.sup.9OR.sup.24, --X.sup.9C(O)R.sup.24, --X.sup.9C(O)OR.sup.24,
--X.sup.9C(O)NR.sup.24R.sup.25, --X.sup.9NR.sup.24R.sup.25,
--X.sup.9NR.sup.25C(O)R.sup.24, --X.sup.9NR.sup.25C(O)OR.sup.24,
--X.sup.9NR.sup.25C(O)NR.sup.24R.sup.25 or
--X.sup.9NR.sup.25C(NR.sup.25)- NR.sup.24R.sup.25, wherein X.sup.9
is a bond or (C.sub.1-6)alkylene, R.sup.24 is
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl and R.sup.25 is hydrogen
or (C.sub.1-6)alkyl, wherein within R.sup.11 any alicyclic or
aromatic ring system present may be substituted further by 1 to 5
substituents independently selected from (C.sub.1-6)alkyl, halo,
halo-substituted (C.sub.1-4)alkyl, --OR.sup.12, --X.sup.3SR.sup.12,
--C(O)OR.sup.12 and --X.sup.3NR.sup.12C(O)OR.sup.12, wherein
X.sup.3 is a bond or (C.sub.1-6)alkylene and R.sup.14 is hydrogen
or (C.sub.1-6)alkyl; and the N-oxide derivatives, prodrug
derivatives, protected derivatives, individual isomers and mixtures
of isomers; and the pharmaceutically acceptable salts thereof.
16. The compound of claim 15 in which: R.sup.3, R.sup.4, R.sup.5
and R.sup.7 each are hydrogen; R.sup.9 represents benzyl,
benzyloxymethyl, benzylsulfanylethyl, benzylsulfanylmethyl,
benzylsulfinylmethyl, indolylmethyl, naphthylmethyl, phenethyl,
phenoxyethyl, phenylamino, pyridylmethyl, pyridylsulfanylethyl,
phenylsulfanylethyl, thiazolyl or thienyl, wherein within R.sup.9
the aromatic ring may be substituted further by 1 to 5 radicals
independently selected from (C.sub.1-6)alkyl, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4OR.sup.12,
--X.sup.4C(O)R.sup.12, --X.sup.4SR.sup.12, wherein X.sup.4 is a
bond or (C.sub.1-6)alkylene, R.sup.12 at each occurrence
independently is hydrogen, (C.sub.1-6)alkyl or halo-substituted
(C.sub.1-3)alkyl, and R.sup.13 is (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl; and R.sup.11 is
--X.sup.4X.sup.5R.sup.18, wherein X.sup.4 is --C(O)--, X.sup.5 is a
bond and R.sup.18 is (i) (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl or (ii)
phenyl(C.sub.0-6)alkyl or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl,
wherein said phenyl or heteroaryl is substituted by
--X.sup.9OR.sup.24, --X.sup.9C(O)R.sup.24, --X.sup.9C(O)OR.sup.24,
--X.sup.9C(O)NR.sup.24R.su- p.25, --X.sup.9NR.sup.24R.sup.25,
--X.sup.9NR.sup.25C(O)R.sup.24, --X.sup.9NR.sup.25C(O)OR.sup.24,
--X.sup.9NR.sup.25C(O)NR.sup.24R.sup.25 or
--X.sup.9NR.sup.25C(NR.sup.25)NR.sup.24R.sup.25, wherein X.sup.9 is
a bond or (C.sub.1-6)alkylene, R.sup.24 is phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl and R.sup.25 is hydrogen
or (C.sub.1-6)alkyl, wherein within R.sup.11 any aromatic ring
system present may be substituted further by 1 to 5 substituents
independently selected from (C.sub.1-6)alkyl, halo,
halo-substituted (C.sub.1-4)alkyl, --OR.sup.12, --X.sup.3SR.sup.12,
--C(O)OR.sup.12 and --X.sup.3NR.sup.12C(O)OR.sup.12 wherein X.sup.3
is a bond or (C.sub.1-6)alkylene and R.sup.12 is hydrogen or
(C.sub.1-6)alkyl; and the N-oxide derivatives, prodrug derivatives,
protected derivatives, individual isomers and mixtures of isomers;
and the pharmaceutically acceptable salts thereof.
17. The compound of claim 16 in which R.sup.9 is a group having the
following formula: 44in which q is 0 to 5 and R.sup.26 at each
occurrence is independently selected from (C.sub.1-4)alkyl, cyano,
halo, halo-substituted (C.sub.1-4)alkyl, nitro, --OR.sup.12,
--SR.sup.12 and --C(O)OR.sup.12, wherein R.sup.12 is hydrogen,
(C.sub.1-3)alkyl or halo-substituted (C.sub.1-3)alkyl and R.sup.13
is (C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl; and the
N-oxide derivatives, prodrug derivatives, protected derivatives,
individual isomers and mixtures of isomers; and the
pharmaceutically acceptable salts thereof.
18. The compound of claim 17 in which R.sup.9 is 4-aminobenzyl,
benzyl, benzyloxymethyl, 2-benzylsulfanylethyl,
benzylsulfanylmethyl, 2-bromobenzylsulfanylmethyl,
4-tert-butylbenzylsulfanylmethyl, 2-chlorobenzyl, 4-chlorobenzyl,
2-chlorobenzylsulfanylmethyl, 4-chlorobenzylsulfanylmethyl,
2-(2-chlorophenylsulfanyl)ethyl, 4-cyanobenzyl,
3,4-dichlorobenzylsulfanylmethyl, 1,6-dichlorobenzyl,
3,5-dimethylbenzylsulfanylmethyl, 2-fluorobenzyl, 4-fluorobenzyl,
2-fluorobenzylsulfanylmethyl, 1-formylindol-3-ylmethyl,
indol-3-ylmethyl, 2-iodobenzylsulfanylmethyl,
2-methylbenzylsulfanylmethyl, 3-methylbenzylsulfanylmethyl,
3-methylbenzylsulfanylmethyl, 4-methylbenzylsulfanylmethyl,
2-(2-methylphenylsulfanyl)ethyl, 4-methoxybenzyl,
4-methoxybenzylsulfanylmethyl, 4-methoxybenzylsulfinylme- thyl,
naphth-2-ylmethyl, naphth-2-ylmethylsulfanylmethyl, 3-nitrobenzyl,
1-nitrobenzylsulfanylmethyl, 2-nitrobenzylsulfanylmethyl,
3-nitrobenzylsulfanylmethyl, 4-nitrobenzylsulfanylmethyl,
4-nitrobenzyl, pentafluorobenzylsulfanylmethyl, phenylamino,
phenethyl, phenethyloxy, 2-phenoxyethyl, 2-phenoxyethyl
2-phenylsulfanylethyl, pyrid-4-ylmethyl,
pyrid-2-ylmethylsulfanylmethyl, pyrid-3-ylmethylsulfanylmethyl,
pyrid-4-ylmethylsulfanylmethyl, 2-pyrid-2-ylsulfanylethyl,
2-pyrid-4-ylsulfanylethyl, thiazol-5-yl, thien-2-ylmethyl,
4-trifluoromethylbenzylsulfanylmethyl,
3-trifluoromethylbenzylsulfanylmet- hyl,
3-trifluoromethoxybenzylsulfanylmethyl,
4-trifluoromethoxybenzylsulfa- nylmethyl or
4-trifluorosulfanylbenzylsulfanylmethyl; and the N-oxide
derivatives, prodrug derivatives, protected derivatives, individual
isomers and mixtures of isomers; and the pharmaceutically
acceptable salts thereof.
19. The compound of claim 18 which is selected a group from
consisting of:
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)-4-hydroxybenzamide;
N-[2-(2-bromobenzylsulfanyl)-1R-cyanomethylcarbamoylethyl]benzamide;
N-[1R-cyanomethylcarbamoyl-2-(2-iodobenzylsulfanyl)ethyl]benzamide;
N-[1R-cyanomethylcarbamoyl-2-(2-cyanobenzylsulfanyl)ethyl]morpholine-4-ca-
rboxamide;
N-[3-(2-chlorophenylsulfanyl)-1R-cyanomethylcarbamoylpropyl]ben-
zamide;
N-[1R-cyanomethylcarbamoyl-2-(2-nitrobenzylsulfanyl)ethyl]morpholi-
ne-4-carboxamide
N-[1R-cyanomethylcarbamoyl-2-(2-methylbenzylsulfanyl)ethy-
l]morpholine-4-carboxamide; and
N-[1R-cyanomethylcarbamoyl-2-(2-methylbenz-
ylsulfanyl)ethyl]benzamide; and the N-oxide derivatives, prodrug
derivatives, protected derivatives, individual isomers and mixtures
of isomers; and the pharmaceutically acceptable salts thereof.
20. A method of treating a disease in an animal in which cathepsin
S activity contributes to the pathology and/or symptomatology of
the disease, which method comprising administering to the animal a
therapeutically effective amount of a compound of Formula (I): 45in
which: R.sup.1 is a group of Formula (a) or (b): 46 wherein:
X.sup.1 and X.sup.2 independently are --C(O)-- or
--CH.sub.2S(O).sub.2--; R.sup.5 and R.sup.6 are hydrogen or
(C.sub.1-6)alkyl; R.sup.7 and R.sup.8 are hydrogen or
(C.sub.1-6)alkyl or as defined below; R.sup.9 and R.sup.10
independently are (i) (C.sub.1-6)alkyl optionally substituted with
cyano, halo or nitro or (ii) a group selected from
--X.sup.3NR.sup.12R.sup.12, --X.sup.3NR.sup.12C(O)OR.sup.12,
--X.sup.3NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.3NR.sup.12C(NR.sup.12)NR.sup.12R.sup.12,
--X.sup.3OR.sup.12, --X.sup.3SR.sup.12, --X.sup.3C(O)OR.sup.12,
--X.sup.3C(O)NR.sup.12R.sup.1- 2,
--X.sup.3S(O).sub.2NR.sup.12R.sup.12,
--X.sup.3P(O)(OR.sup.12)OR.sup.12- ,
--X.sup.3OP(O)(OR.sup.12)OR.sup.12, --X.sup.3NR.sup.12C(O)R.sup.13,
--X.sup.3S(O)R.sup.13, --X.sup.3S(O).sub.2R.sup.13,
--X.sup.3C(O)R.sup.13, --X.sup.3C(O)R.sup.14,
--X.sup.3C(O)OR.sup.14, --X.sup.3OC(O)R.sup.14,
--X.sup.3NR.sup.15C(O)R.sup.14, --X.sup.3NR.sup.15C(O)OR.sup.14,
--X.sup.3C(O)NR.sup.14R.sup.15,
--X.sup.3S(O).sub.2NR.sup.14R.sup.15,
--X.sup.3NR.sup.15C(O)NR.sup.14R.su- p.15,
--X.sup.3NR.sup.15C(NR.sup.15)NR.sup.14R.sup.15,
--X.sup.4SR.sup.14--X.sup.4S(O)R.sup.14,
--X.sup.4S(O).sub.2R.sup.14, --X.sup.4OR.sup.14, or
--X.sup.4NR.sup.14R.sup.15, wherein X.sup.3 is (C.sub.1-6)alkylene,
X.sup.4 is a bond or (C.sub.1-6)alkylene, R.sup.12 at each
occurrence independently is hydrogen, (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.13 is (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.14 is
(C.sub.3-12)cycloalkyl(C.s- ub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloa- ryl(C.sub.0-6)alkyl and R.sup.15 is
hydrogen or (C.sub.1-6)alkyl, and wherein within R.sup.14 said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.4NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.4 is
a bond or (C.sub.1-6)alkylene, R.sup.16 is hydrogen or
(C.sub.1-6)alkyl and R.sup.17 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, or (iii) a group
selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl and
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.4NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.4,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.9
and/or R.sup.10 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.4)OR.sup.12,
--X.sup.4OP(O)(OR.sup.12)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above, or R.sup.9
taken together with R.sup.7 and/or R.sup.10 taken together with
R.sup.8 form trimethylene, tetramethylene or
phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo
or methylene; and R.sup.11 is --X.sup.5X.sup.6R.sup.18, wherein
X.sup.5 is --C(O)--, --C(O)C(O)-- or --S(O).sub.2--, X.sup.6 is a
bond, --O-- or --NR.sup.19--, wherein R.sup.19 is hydrogen or
(C.sub.1-6)alkyl, and R.sup.18 is (i) (C.sub.1-10)alkyl optionally
substituted by cyano, halo, nitro, --NR.sup.12R.sup.12,
--NR.sup.12C(O)OR.sup.12, --NR.sup.12C(O)NR.sup.12R.- sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.12, --OR.sup.12, --SR.sup.12,
--C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.20,
--SR.sup.20, --S(O)R.sup.20, --S(O).sub.2R.sup.20, --C(O)R.sup.20,
--C(O)OR.sup.20, --C(O)NR.sup.20R.sup.21, --NR.sup.20R.sup.21,
--NR.sup.21C(O)R.sup.20, --NR.sup.21C(O)OR.sup.20,
--NR.sup.21C(O)NR.sup.20R.sup.21 or
--NR.sup.21C(NR.sup.21)NR.sup.20R.sup.21, wherein R.sup.12 and
R.sup.13 are as defined above, R.sup.20 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)bicycloaryl(C.s- ub.0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl and R.sup.21 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl, or (ii)
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-6)alkyl, (C.sub.9-12)bicycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl or (iii)
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.- 0-6)alkyl,
phenyl(C.sub.0-6)alkyl or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl- ,
wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is
substituted by --X.sup.4OR.sup.22, --X.sup.4SR.sup.22,
--X.sup.4S(O)R.sup.22, --X.sup.4S(O).sub.2R.sup.22,
--X.sup.4C(O)R.sup.22, --X.sup.4C(O)OR.sup.22,
--X.sup.4C(O)NR.sup.22R.su- p.23, --X.sup.4NR.sup.22R.sup.23,
--X.sup.4NR.sup.23C(O)R.sup.22, --X.sup.4NR.sup.23C(O)OR.sup.22,
--X.sup.4NR.sup.23C(O)NR.sup.22R.sup.23 or
--X.sup.4NR.sup.23C(NR.sup.23)NR.sup.22R.sup.23, wherein X.sup.4 is
as defined above, R.sup.22 is
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl and R.sup.23 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl; wherein
within R.sup.11 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR.s- up.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above; R.sup.2 is
hydrogen or (C.sub.1-6)alkyl or as defined below; R.sup.3 is
hydrogen, (C.sub.1-6)alkyl or as defined below; and R.sup.4 is (i)
hydrogen or (C.sub.1-6)alkyl, wherein said alkyl is optionally
substituted with cyano, halo, nitro, --NR.sup.12R.sup.12,
--NR.sup.12C(O)OR.sup.12, --NR.sup.12C(O)NR.sup.12R.sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.1- 2, --OR.sup.12,
--SR.sup.12, --C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.14,
--SR.sup.14, --S(O)R.sup.14, --S(O).sub.2R.sup.14, --C(O)R.sup.14,
--C(O)OR.sup.14, --OC(O)R.sup.14, --NR.sup.14R.sup.15,
--NR.sup.15C(O)R.sup.14, --NR.sup.15C(O)OR.sup.14,
--C(O)NR.sup.14R.sup.15, --S(O).sub.2NR.sup.14R.sup.15,
--NR.sup.15C(O)NR.sup.14R.sup.15 or
--NR.sup.15C(NR.sup.15)NR.sup.14R.sup.15, wherein R.sup.12,
R.sup.13, R.sup.14 and R.sup.15 are as defined above, or (ii) a
group selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-6)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-6)alkyl and
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.1- 7,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.sup.17 or
--X.sup.4NR.sup.17C(NR.sup.17)- NR.sup.16R.sup.17, wherein X.sup.4,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.9
and/or R.sup.10 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above, or R.sup.4 and
R.sup.2 taken together form trimethylene, tetramethylene or
phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo
or methylene, or R.sup.4 and R.sup.3 together with the carbon atom
to which both R.sup.4 and R.sup.3 are attached form
(C.sub.3-8)cycloalkylene or (C.sub.3-8)heterocycloalkyl- ene; or an
N-oxide derivative, prodrug derivative, individual isomer and
mixtures of isomers; or a pharmaceutically acceptable salt thereof,
but excluding compounds of the formula 47in which R.sup.3 and
R.sup.4 are each hydrogen or (C.sub.1-6)alkyl, or together with the
carbon atom to which they are both attached form
(C.sub.3-5)cycloalkylene; R.sup.5 is hydrogen or (C.sub.1-6)alkyl;
R.sup.9 is (C.sub.6-12)aryl(C.sub.1-6)alkyl- ,
hetero(C.sub.5-12)aryl(C.sub.1-6)alkyl, (C.sub.4-5)alkyl or
cyclohexylmethyl; and R.sup.11 is C(O)R.sup.18 wherein R.sup.18 is
hetero(C.sub.3-12)cycloalkyl, (C.sub.6-12)aryl(C.sub.0-6)alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl.
21. The use of a compound of Formula (I): 48in which: R.sup.1 is a
group of Formula (a) or (b): 49 wherein: X.sup.1 and X.sup.2
independently are --C(O)-- or --CH.sub.2S(O).sub.2--; R.sup.5 and
R.sup.6 are hydrogen or (C.sub.1-6)alkyl; R.sup.7 and R.sup.8 are
hydrogen or (C.sub.1-6)alkyl or as defined below; R.sup.9 and
R.sup.10 independently are (i) (C.sub.1-6)alkyl optionally
substituted with cyano, halo or nitro or (ii) a group selected from
--X.sup.3NR.sup.12R.sup.12, --X.sup.3NR.sup.12C(O)O- R.sup.12,
--X.sup.3NR.sup.12C(O)NR.sup.12R.sup.12, --X.sup.3NR.sup.12C(NR.-
sup.12)NR.sup.12R.sup.12, --X.sup.3OR.sup.12, --X.sup.3SR.sup.12,
--X.sup.3C(O)OR.sup.12, --X.sup.3C(O)NR.sup.12R.sup.12,
--X.sup.3S(O).sub.2NR.sup.12R.sup.12,
--X.sup.3P(O)(OR.sup.12)OR.sup.12,
--X.sup.3OP(O)(OR.sup.12)OR.sup.12, --X.sup.3NR.sup.12C(O)R.sup.13,
--X.sup.3S(O)R.sup.13, --X.sup.3S(O).sub.2R.sup.13,
--X.sup.3C(O)R.sup.13, --X.sup.3C(O)R.sup.14,
--X.sup.3C(O)OR.sup.14, --X.sup.3OC(O)R.sup.14,
--X.sup.3NR.sup.15C(O)R.sup.14, --X.sup.3NR.sup.15C(O)OR.sup.14,
--X.sup.3C(O)NR.sup.14R.sup.15,
--X.sup.3S(O).sub.2NR.sup.14R.sup.15,
--X.sup.3NR.sup.15C(O)NR.sup.14R.su- p.15,
--X.sup.3NR.sup.15C(NR.sup.15)NR.sup.14R.sup.15, --X.sup.4SR.sup.14
--X.sup.4S(O)R.sup.14, --X.sup.4S(O).sub.2R.sup.14,
--X.sup.4OR.sup.14, or --X.sup.4NR.sup.14R.sup.15, wherein X.sup.3
is (C.sub.1-6)alkylene, X.sup.4 is a bond or (C.sub.1-6)alkylene,
R.sup.12 at each occurrence independently is hydrogen,
(C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl, R.sup.13 is
(C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl, R.sup.14 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl and R.sup.15 is
hydrogen or (C.sub.1-6)alkyl, and wherein within R.sup.14 said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.4NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.4 is
a bond or (C.sub.1-6)alkylene, R.sup.16 is hydrogen or
(C.sub.1-6)alkyl and R.sup.17 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, or (iii) a group
selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl and
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.4NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.4,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.9
and/or R.sup.10 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.4)OR.sup.12,
--X.sup.4OP(O)(OR.sup.12)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above, or R.sup.9
taken together with R.sup.7 and/or R.sup.10 taken together with
R.sup.8 form trimethylene, tetramethylene or
phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo
or methylene; and R.sup.11 is --X.sup.5X.sup.6R.sup.18, wherein
X.sup.5 is --C(O)--, --C(O)C(O)-- or --S(O).sub.2--, X.sup.6 is a
bond, --O-- or --NR.sup.19--, wherein R.sup.19 is hydrogen or
(C.sub.1-6)alkyl, and R.sup.18 is (i) (C.sub.1-10)alkyl optionally
substituted by cyano, halo, nitro, --NR.sup.12R.sup.12,
--NR.sup.12C(O)OR.sup.12, --NR.sup.12C(O)NR.sup.12R.- sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.12, --OR.sup.12, --SR.sup.12,
C(O)OR.sup.12, C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.20,
--SR.sup.20, --S(O)R.sup.20, --S(O).sub.2R.sup.20, --C(O)R.sup.20,
--C(O)OR.sup.20, --C(O)NR.sup.20R.sup.21, --NR.sup.20R.sup.21,
--NR.sup.21C(O)R.sup.20, --NR.sup.21C(O)OR.sup.20,
--NR.sup.21C(O)NR.sup.20R.sup.21 or
--NR.sup.21C(NR.sup.21)NR.sup.20R.sup.21, wherein R.sup.12 and
R.sup.13 are as defined above, R.sup.20 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)bicycloaryl(C.s- ub.0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl and R.sup.21 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl, or (ii)
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-6)alkyl, (C.sub.9-12)bicycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl or (iii)
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.- 0-6)alkyl,
phenyl(C.sub.0-6)alkyl or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl- ,
wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is
substituted by --X.sup.4OR.sup.22, --X.sup.4SR.sup.22,
--X.sup.4S(O)R.sup.22, --X.sup.4S(O).sub.2R.sup.22,
--X.sup.4C(O)R.sup.22, --X.sup.4C(O)OR.sup.22,
--X.sup.4C(O)NR.sup.22R.su- p.23, --X.sup.4NR.sup.22R.sup.23,
--X.sup.4NR.sup.23C(O)R.sup.22, --X.sup.4NR.sup.23C(O)OR.sup.22,
--X.sup.4NR.sup.23C(O)NR.sup.22R.sup.23 or
--X.sup.4NR.sup.23C(NR.sup.23)NR.sup.22R.sup.23, wherein X.sup.4 is
as defined above, R.sup.22 is
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl and R.sup.23 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl; wherein
within R.sup.11 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above; R.sup.2 is
hydrogen or (C.sub.1-6)alkyl or as defined below; R.sup.3 is
hydrogen, (C.sub.1-6)alkyl or as defined below; and R.sup.4 is (i)
hydrogen or (C.sub.1-6)alkyl, wherein said alkyl is optionally
substituted with cyano, halo, nitro, --NR.sup.12R.sup.12,
--NR.sup.12C(O)OR.sup.12, --NR.sup.12C(O)NR.sup.12R.sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.1- 2, --OR.sup.12,
--SR.sup.12, --C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.14,
--SR.sup.14, --S(O)R.sup.14, --S(O).sub.2R.sup.14, --C(O)R.sup.14,
--C(O)OR.sup.14, --OC(O)R.sup.14, --NR.sup.14R.sup.15,
--NR.sup.15C(O)R.sup.14, --NR.sup.15C(O)OR.sup.14,
--C(O)NR.sup.14R.sup.15, --S(O).sub.2NR.sup.14R.sup.15,
--NR.sup.15C(O)NR.sup.14R.sup.15 or
--NR.sup.15C(NR.sup.15)NR.sup.14R.sup.15, wherein R.sup.12,
R.sup.13, R.sup.14 and R.sup.15 are as defined above, or (ii) a
group selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-6)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-6)alkyl and
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.1- 7,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.sup.17 or
--X.sup.4NR.sup.17C(NR.sup.17)- NR.sup.16R.sup.17, wherein X.sup.4,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.9
and/or R.sup.10 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above, or R.sup.4 and
R.sup.2 taken together form trimethylene, tetramethylene or
phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo
or methylene, or R.sup.4 and R.sup.3 together with the carbon atom
to which both R.sup.4 and R.sup.3 are attached form
(C.sub.3-8)cycloalkylene or (C.sub.3-8)heterocycloalkyl- ene; or an
N-oxide derivative, prodrug derivative, individual isomer and
mixtures of isomers; or a pharmaceutically acceptable salt thereof,
but excluding compounds of the formula 50in which R.sup.3 and
R.sup.4 are each hydrogen or (C.sub.1-6)alkyl, or together with the
carbon atom to which they are both attached form
(C.sub.3-5)cycloalkylene; R.sup.5 is hydrogen or (C.sub.1-6)alkyl;
R.sup.9 is (C.sub.6-12)aryl(C.sub.1-6)alkyl- ,
hetero(C.sub.5-12)aryl(C.sub.1-6)alkyl, (C.sub.4-5)alkyl or
cyclohexylmethyl; and R.sup.11 is C(O)R.sup.18 wherein R.sup.18 is
hetero(C.sub.3-12)cycloalkyl, (C.sub.6-12)aryl(C.sub.0-6)alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl, in the manufacture of a
medicament for treating a disease in an animal in which cathepsin S
activity contributes to the pathology and/or symptomatology of the
disease.
22. A process for preparing a compound of Formula I: 51in which:
R.sup.1 is a group of Formula (a) or (b): 52 wherein: X.sup.1 and
X.sup.2 independently are --C(O)-- or --CH.sub.2S(O).sub.2--;
R.sup.5 and R.sup.6 are hydrogen or (C.sub.1-6)alkyl; R.sup.7 and
R.sup.8 are hydrogen or (C.sub.1-6)alkyl or as defined below;
R.sup.9 and R.sup.10 independently are (i) (C.sub.1-6)alkyl
optionally substituted with cyano, halo, nitro,
--NR.sup.12R.sup.12, --NR.sup.12C(O)OR.sup.12,
--NR.sup.12C(O)NR.sup.12R.- sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.12, --OR.sup.12, --SR.sup.12,
--C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.14,
--SR.sup.14, --S(O).sub.2R.sup.14, --C(O)R.sup.14, --C(O)OR.sup.14,
--OC(O)R.sup.14, --NR.sup.14R.sup.15, --NR.sup.15C(O)R.sup.14,
--NR.sup.15C(O)OR.sup.14, --C(O)NR.sup.14R.sup.15,
--S(O).sub.2NR.sup.14R.sup.15, --NR.sup.15C(O)NR.sup.14R.sup.15 or
--NR.sup.15C(NR.sup.15)NR.sup.14R.sup- .15, wherein R.sup.12 at
each occurrence independently is hydrogen, (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.13 is (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.14 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-6)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl and R.sup.15 is
hydrogen or (C.sub.1-6)alkyl, and wherein within R.sup.14 said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.3OR.sup.16, --X.sup.3SR.sup.16,
--X.sup.3S(O)R.sup.16, --X.sup.3S(O).sub.2R.sup.16,
--X.sup.3C(O)R.sup.16, --X.sup.3C(O)OR.sup.16,
--X.sup.3OC(O)R.sup.16, --X.sup.3NR.sup.16R.sup.1- 7,
--X.sup.3NR.sup.17C(O)R.sup.16, --X.sup.3NR.sup.17C(O)OR.sup.16,
--X.sup.3C(O)NR.sup.16R.sup.17,
--X.sup.3S(O).sub.2NR.sup.16R.sup.17,
--X.sup.3NR.sup.17C(O)NR.sup.16R.sup.17 or
--X.sup.3NR.sup.17C(NR.sup.17)- NR.sup.16R.sup.17, wherein X.sup.3
is a bond or (C.sub.1-6)alkylene, R.sup.16 is hydrogen or
(C.sub.1-6)alkyl and R.sup.17 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-6)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, or (ii) a group
selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl- (C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C.sub.0- -6)alkyl and
hetero(C.sub.8-12)poycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.3OR.sup.16, --X.sup.3SR.sup.16,
--X.sup.3S(O)R.sup.16, --X.sup.3S(O).sub.2R.sup.16,
--X.sup.3C(O)R.sup.16, --X.sup.3C(O)OR.sup.16,
--X.sup.3OC(O)R.sup.16, --X.sup.3NR.sup.16R.sup.17,
--X.sup.3NR.sup.17C(O)R.sup.16, --X.sup.3NR.sup.17C(O)OR.sup.16,
--X.sup.3C(O)NR.sup.16R.sup.17,
--X.sup.3S(O).sub.2NR.sup.16R.sup.17,
--X.sup.3NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.3NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.3,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.9
and/or R.sup.10 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.3NR.sup.12R.sup.12, --X.sup.3NR.sup.12C(O)OR.sup.12,
--X.sup.3NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.3NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.3OR.sup.12, --X.sup.3SR.sup.12, --X.sup.3C(O)OR.sup.12,
--X.sup.3C(O)NR.sup.12R.sup.12,
--X.sup.3S(O).sub.2NR.sup.12R.sup.12,
--X.sup.3P(O)(OR.sup.3)OR.sup.12,
--X.sup.3OP(O)(OR.sup.3)OR.sup.12, --X.sup.3OC(O)R.sup.13,
--X.sup.3NR.sup.12C(O)R.sup.13, --X.sup.3S(O)R.sup.13,
--X.sup.3S(O).sub.2R.sup.13 and --X.sup.3C(O)R.sup.13, wherein
X.sup.3, R.sup.12 and R.sup.13 are as defined above, or R.sup.9
taken together with R.sup.7 and/or R.sup.10 taken together with
R.sup.8 form trimethylene, tetramethylene or
phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo
or methylene; and R.sup.11 is --X.sup.4X.sup.5R.sup.18, wherein
X.sup.4 is --C(O)--, --C(O)C(O)-- or --S(O).sub.2--, X.sup.5 is a
bond, --O-- or --NR.sup.19--, wherein R.sup.19 is hydrogen or
(C.sub.1-6)alkyl, and R.sup.18 is (i)(C.sub.1-10)alkyl optionally
substituted by cyano, halo, nitro, --NR.sup.12R.sup.12,
--NR.sup.12C(O)OR.sup.12, --NR.sup.12C(O)NR.sup.12R.- sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.12, --OR.sup.12, --SR.sup.12,
--C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.20,
--SR.sup.20, --S(O)R.sup.20, --S(O).sub.2R.sup.20, --C(O)R.sup.20,
--C(O)OR.sup.20, --C(O)NR.sup.20R.sup.21, --NR.sup.20R.sup.21,
--NR.sup.21C(O)R.sup.20, --NR.sup.21C(O)OR.sup.20,
--NR.sup.21C(O)NR.sup.20R.sup.21 or
--NR.sup.21C(NR.sup.21)NR.sup.20R.sup.21, wherein R.sup.12 and
R.sup.13 are as defined above, R.sup.20 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)bicycloaryl(C.s- ub.0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl and R.sup.21 at each
occurence independently is hydrogen or (C.sub.1-6)alkyl, or
(ii)(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(- C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(-
C.sub.0-6)alkyl, (C.sub.9-12)bicycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl or
(iii)(C.sub.3-6)cycloalk- yl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.0-6alkyl, phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl, wherein said cycloalkyl,
heterocycloalkyl, phenyl or hetroaryl is substituted by
--X.sup.3OR.sup.22, --X.sup.3SR.sup.22, --X.sup.3S(O)R.sup.22,
--X.sup.3S(O).sub.2R.sup.22, --X.sup.3C(O)R.sup.22,
--X.sup.3C(O)OR.sup.22, --X.sup.3C(O)NR.sup.22R.sup.23,
--X.sup.3NR.sup.22R.sup.23, --X.sup.3NR.sup.23C(O)R.sup.22,
--X.sup.3NR.sup.23C(O)OR.sup.22,
--X.sup.3NR.sup.23C(O)NR.sup.22R.sup.23 or
--X.sup.3NR.sup.23C(NR.sup.23)NR.sup.22R.sup.23, wherein X.sup.3 is
as defined above, R.sup.22 is
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl and R.sup.23 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl; wherein
within R.sup.11 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.3NR.sup.12R.sup.12, --X.sup.3NR.sup.12C(O)OR.sup.12,
--X.sup.3NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.3NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.3OR.sup.12, --X.sup.3SR.sup.12, --X.sup.3C(O)OR.sup.12,
--X.sup.3C(O)NR.sup.12R.sup.12,
--X.sup.3S(O).sub.2NR.sup.12R.sup.12,
--X.sup.3P(O)(OR.sup.3)OR.sup.12,
--X.sup.3OP(O)(OR.sup.3)OR.sup.12, --X.sup.3OC(O)R.sup.13,
--X.sup.3NR.sup.12C(O)R.sup.13, --X.sup.3S(O)R.sup.13,
--X.sup.3S(O).sub.2R.sup.13 and --X.sup.3C(O)R.sup.13, wherein
X.sup.3, R.sup.12 and R.sup.13 are as defined above; R.sup.2 is
hydrogen or (C.sub.1-6)alkyl or as defined below; R.sup.3 is
hydrogen, (C.sub.1-6)alkyl or as defined below; and R.sup.4 is (i)
hydrogen or (C.sub.1-6)alkyl, wherein said alkyl is optionally
substituted with cyano, halo, nitro, --NR.sup.12R.sup.12,
--NR.sup.12C(O)OR.sup.12, --NR.sup.12C(O)NR.sup.12R.sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.1- 2, --OR.sup.12,
--SR.sup.12, --C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.14,
--SR.sup.14, --S(O)R.sup.14, --S(O).sub.2R.sup.14, --C(O)R.sup.14,
--C(O)OR.sup.14, --OC(O)R.sup.14, --NR.sup.14R.sup.15,
--NR.sup.15C(O)R.sup.14, --NR.sup.15C(O)OR.sup.14,
--C(O)NR.sup.14R.sup.15, --S(O).sub.2NR.sup.14R.sup.15,
--NR.sup.15C(O)NR.sup.14R.sup.15 or
--NR.sup.15C(NR.sup.15)NR.sup.14R.sup.15, wherein R.sup.12,
R.sup.13, R.sup.14 and R.sup.15 are as defined above, or (ii) a
group selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-6)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-6)alkyl and
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.3OR.sup.16, --X.sup.3SR.sup.16,
--X.sup.3S(O)R.sup.16, --X.sup.3S(O).sub.2R.sup.16,
--X.sup.3C(O)R.sup.16, --X.sup.3C(O)OR.sup.16,
--X.sup.3OC(O)R.sup.16, --X.sup.3NR.sup.16R.sup.1- 7,
--X.sup.3NR.sup.17C(O)R.sup.16, --X.sup.3NR.sup.17C(O)OR.sup.16,
--X.sup.3C(O)NR.sup.16R.sup.17,
--X.sup.3S(O).sub.2NR.sup.16R.sup.17,
--X.sup.3NR.sup.17C(O)NR.sup.16R.sup.17 or
--X.sup.3NR.sup.17C(NR.sup.17)- NR.sup.16R.sup.17, wherein X.sup.3,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.9
and/or R.sup.10 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.3NR.sup.12R.sup.12, --X.sup.3NR.sup.12C(O)OR.sup.12,
--X.sup.3NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.3NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.3OR.sup.12, --X.sup.3SR.sup.12, --X.sup.3C(O)OR.sup.12,
--X.sup.3C(O)NR.sup.12R.sup.12,
--X.sup.3S(O).sub.2NR.sup.12R.sup.12,
--X.sup.3P(O)(OR.sup.3)OR.sup.12,
--X.sup.3OP(O)(OR.sup.3)OR.sup.12, --X.sup.3OC(O)R.sup.13,
--X.sup.3NR.sup.12C(O)R.sup.13, --X.sup.3S(O)R.sup.13,
--X.sup.3S(O).sub.2R.sup.13 and --X.sup.3C(O)R.sup.13, wherein
X.sup.3, R.sup.12 and R.sup.13 are as defined above, or R.sup.4 and
R.sup.2 taken together form trimethylene, tetramethylene or
phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo
or methylene, or R.sup.4 and R.sup.3 together with the carbon atom
to which both R.sup.4 and R.sup.3 are attached form
(C.sub.3-8)cycloalkylene or (C.sub.3-8)heterocycloalkyl- ene; and
the N-oxide derivatives, prodrug derivatives, protected
derivatives, individual isomers and mixtures of isomers; and the
pharmaceutically acceptable salts thereof; which process comprises:
(A) reacting a compound of Formula 2: 53 or a protected derivative
thereof, with a compound of the formula R.sup.1OY, or a protected
derivative thereof, in which Y is hydrogen or
2,5-dioxopyrrolidin-1-yl and each R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are as defined above; or (B) reacting a compound of Formula
3: 54 or a protected derivative thereof, with ammonia to provide a
corresponding amide and then reacting the amide with
trifluoroacetic anhydride, in which each R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are as defined above; (C) optionally deprotecting a
protected derivative of a compound of Formula I to provide a
corresponding unprotected derivative; (D) optionally converting a
compound of Formula I into a pharmaceutically acceptable salt; (E)
optionally converting a salt form of a compound of Formula I to
non-salt form; (F) optionally converting an unoxidized form of a
compound of Formula I into a pharmaceutically acceptable N-oxide;
(G) optionally converting an N-oxide form of a compound of Formula
I its unoxidized form; (H) optionally converting a non-derivatized
compound of Formula I into a pharmaceutically prodrug derivative;
and (I) optionally converting a prodrug derivative of a compound of
Formula I to its non-derivatized form.
Description
This application claims the benefit under U.S.C. Sec 119 (e)(1) of
prior filed U.S. Provisional Application No. 60/124,420 filed Mar.
15, 1999.
THE INVENTION
[0001] This application relates to compounds and compositions for
treating diseases associated with cysteine protease activity,
particularly diseases associated with activity of cathepsins B, K,
L or S.
DESCRIPTION OF THE FIELD
[0002] Cysteine proteases represent a class of peptidases
characterized by the presence of a cysteine residue in the
catalytic site of the enzyme. Cysteine proteases are associated
with the normal degradation and processing of proteins. The
aberrant activity of cysteine proteases, e.g., as a result of
increase expression or enhanced activation, however, may have
pathological consequences. In this regard, certain cysteine
proteases are associated with a number of disease states, including
arthritis, muscular dystrophy, inflammation, tumor invasion,
glomerulonephritis, malaria, periodontal disease, metachromatic
leukodystrophy and others. For example, increased cathepsin B
levels and redistribution of the enzyme are found in tumors; thus,
suggesting a role for the enzyme in tumor invasion and metastasis.
In addition, aberrant cathepsin B activity is implicated in such
disease states as rheumatoid arthritis, osteo arthritis,
pneumocystis carinii, acute pancreatitis, inflammatory airway
disease and bone and joint disorders.
[0003] The prominent expression of cathepsin K in osteoclasts and
osteoclast-related multinucleated cells and its high collagenolytic
activity suggest that the enzyme is involved in
ososteoclast-mediated bone resorption and, hence, in bone
abnormalities such as occurs in osteoporosis. In addition,
cathepsin K expression in the lung and its elastinolytic activity
suggest that the enzyme plays a role in pulmonary disorders as
well.
[0004] Cathepsin L is implicated in normal lysosomal proteolysis as
well as several disease states, including, but not limited to,
metastasis of melanomas. Cathepsin S is implicated in Alzheimer's
disease and certain autoimrnune disorders, including, but not
limited to juvenile onset diabetes, multiple sclerosis, pemphigus
vulgaris, Graves' disease, myasthenia gravis, systemic lupus
erythemotasus, rheumatoid arthritis and Hashimoto's thyroiditis;
allergic disorders, including, but not limited to asthma; and
allogeneic immune responses, including, but not limited to,
rejection of organ transplants or tissue grafts.
[0005] In view of the number of diseases wherein it is recognized
that an increase in cysteine protease activity contributes to the
pathology and/or symptomatology of the disease, molecules which are
shown to inhibit the activity of this class of enzymes, in
particular molecules which are inhibitors of cathepsins B, K, L
and/or S, will be useful as therapeutic agents.
SUMMARY OF THE INVENTION
[0006] In one particular embodiment, the present invention relates
to compounds of Formula (I): 1
[0007] in which:
[0008] R.sup.1 is a group of Formula (a) or (b): 2
[0009] wherein:
[0010] X.sup.1 and X.sup.2 independently are --C(O)-- or
--CH.sub.2S(O).sub.2--;
[0011] R.sup.5 and R.sup.6 are hydrogen or (C.sub.1-6)alkyl;
[0012] R.sup.7 and R.sup.8 are hydrogen or (C.sub.1-6)alkyl or as
defined below;
[0013] R.sup.9 and R.sup.10 independently are (i) (C.sub.1-6)alkyl
optionally substituted with cyano, halo or nitro or (ii) a group
selected from --X.sup.3NR.sup.12R.sup.12,
--X.sup.3NR.sup.12C(O)OR.sup.12,
--X.sup.3NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.3NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.3OR.sup.12, --X.sup.3SR.sup.12, --X.sup.3C(O)OR.sup.12,
--X.sup.3C(O)NR.sup.12R.sup.12,
--X.sup.3S(O).sub.2NR.sup.12R.sup.12,
--X.sup.3P(O)(OR.sup.12)OR.sup.12,
--X.sup.3OP(O)(OR.sup.12)OR.sup.12, --X.sup.3NR.sup.12C(O)R.sup.13,
--X.sup.3S(O)R.sup.13, --X.sup.3S(O).sub.2R.sup.13,
--X.sup.3C(O)R.sup.13, --X.sup.3C(O)R.sup.14,
--X.sup.3C(O)OR.sup.14, --X.sup.3OC(O)R.sup.14,
--X.sup.3NR.sup.15C(O)R.sup.14, --X.sup.3NR.sup.15C(O)OR.sup.14,
--X.sup.3C(O)NR.sup.14R.sup.15,
--X.sup.3S(O).sub.2NR.sup.14R.sup.15,
--X.sup.3NR.sup.15C(O)NR.sup.14R.su- p.15,
--X.sup.3NR.sup.15C(NR.sup.15)NR.sup.14R.sup.15,
--X.sup.4SR.sup.14, --X.sup.4S(O)R.sup.14,
--X.sup.4S(O).sub.2R.sup.14, --X.sup.4OR.sup.14, or
--X.sup.4NR.sup.14R.sup.15, wherein X.sup.3 is (C.sub.1-6)alkylene,
X.sup.4 is a bond or (C.sub.1-6)alkylene, R.sup.12 at each
occurrence independently is hydrogen, (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.13 is (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.14 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl and R.sup.15 is
hydrogen or (C.sub.1-6)alkyl, and wherein within R.sup.14 said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O).sub.2R.sup.16,
--X.sup.4NR.sup.17C(O)OR.sup.16, --X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.4NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.4 is
a bond or (C.sub.1-6)alkylene, R.sup.16 is hydrogen or
(C.sub.1-6)alkyl and R.sup.17 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, or (iii) a group
selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)ary(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C.- sub.0-6)alkyl and
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.1- 7,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.sup.17 or
--X.sup.4NR.sup.17C(NR.sup.17)- NR.sup.16R.sup.17, wherein X.sup.4,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.9
and/or R.sup.10 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.4)OR.sup.12,
--X.sup.4OP(O)(OR.sup.12)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above, or
[0014] R.sup.9 taken together with R.sup.7 and/or R.sup.10 taken
together with R.sup.8 form trimethylene, tetramethylene or
phenylene-1,2-dimethyle- ne, optionally substituted with hydroxy,
oxo or methylene; and
[0015] R.sup.11 is --X.sup.5X.sup.6R.sup.18, wherein X.sup.5 is
--C(O)--, --C(O)C(O)-- or --S(O).sub.2--, X.sup.6 is a bond, --O--
or --NR.sup.19--, wherein R.sup.19 is hydrogen or (C.sub.1-6)alkyl,
and R.sup.18 is (i) (C.sub.1-10)alkyl optionally substituted by
cyano, halo, nitro, --NR.sup.12R.sup.12, --NR.sup.12C(O)OR.sup.12,
--NR.sup.12C(O)NR.sup.12R.sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.1- 2, --OR.sup.12,
--SR.sup.12; --C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.20,
--SR.sup.20, --S(O)R.sup.20, --S(O).sub.2R.sup.20, --C(O)R.sup.20,
--C(O)OR.sup.20, --C(O)NR.sup.20R.sup.21, --NR.sup.20R.sup.21,
--NR.sup.21C(O)R.sup.20, --NR.sup.21C(O)OR.sup.20,
--NR.sup.21C(O)NR.sup.20R.sup.21 or
--NR.sup.21C(NR.sup.21)NR.sup.20R.sup.21, wherein R.sup.12 and
R.sup.13 are as defined above, R.sup.20 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alky
(C.sub.9-12)bicycloaryl(C.sub- .0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl and R.sup.21 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl, or (ii)
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-6)alkyl, (C.sub.9-12)bicycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl or (iii)
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.- 0-6)alkyl,
phenyl(C.sub.0-6)alkyl or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl- ,
wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is
substituted by --X.sup.4OR.sup.22, --X.sup.4SR.sup.22,
--X.sup.4S(O)R.sup.22, --X.sup.4S(O).sub.2R.sup.22,
--X.sup.4C(O)R.sup.22, --X.sup.4C(O)OR.sup.22,
--X.sup.4C(O)NR.sup.22R.su- p.23, --X.sup.4NR.sup.22R.sup.23,
--X.sup.4NR.sup.23C(O)R.sup.22, --X.sup.4NR.sup.23C(O)OR.sup.22,
--X.sup.4NR.sup.23C(O)NR.sup.22R.sup.23 or
--X.sup.4NR.sup.23C(NR.sup.23)NR.sup.22R.sup.23, wherein X.sup.4 is
as defined above, R.sup.22 is
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl and R.sup.23 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl; wherein
within R.sup.11 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above;
[0016] R.sup.2 is hydrogen or (C.sub.1-6)alkyl or as defined
below;
[0017] R.sup.3 is hydrogen, (C.sub.1-6)alkyl or as defined below;
and
[0018] R.sup.4 is (i) hydrogen or (C.sub.1-6)alkyl, wherein said
alkyl is optionally substituted with cyano, halo, nitro,
--NR.sup.12R.sup.12, --NR.sup.12C(O)OR.sup.12,
--NR.sup.12C(O)NR.sup.12R.sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.12, --OR.sup.12, --SR.sup.12,
--C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.14,
--SR.sup.14, --S(O)R.sup.14, --S(O).sub.2R.sup.14, --C(O)R.sup.14,
--C(O)OR.sup.14, --OC(O)R.sup.14, --NR.sup.14R.sup.15,
--NR.sup.15C(O)R.sup.14, --NR.sup.15C(O)OR.sup.14,
--C(O)NR.sup.14R.sup.15, --S(O).sub.2NR.sup.14R.sup.15,
--NR.sup.15C(O)NR.sup.14R.sup.15 or
--NR.sup.15C(NR.sup.15)NR.sup.14R.sup- .15, wherein R.sup.12,
R.sup.13, R.sup.14 and R.sup.15 are as defined above, or (ii) a
group selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alk- yl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0- -6)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl, (C.sub.9-12)polycycloary-
l(C.sub.0-6)alkyl and
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)R.sup.16,
--X.sup.4NR.sup.17(CO)OR.sup.16R.sup.17,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.4NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.4,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.9
and/or R.sup.10 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above, or
[0019] R.sup.4 and R.sup.2 taken together form trimethylene,
tetramethylene or phenylene-1,2-dimethylene, optionally substituted
with hydroxy, oxo or methylene, or
[0020] R.sup.4 and R.sup.3 together with the carbon atom to which
both R.sup.4 and R.sup.3 are attached form (C.sub.3-8)cycloalkylene
or (C.sub.3-8)heterocycloalkylene; and the N-oxide derivatives,
prodrug derivatives, protected derivatives, individual isomers and
mixtures of isomers; and the pharmaceutically acceptable salts
thereof.
[0021] In another particular embodiment, this invention relates to
compounds of Formula (II): 3
[0022] wherein:
[0023] R.sup.2 is hydrogen or (C.sub.1-6)alkyl or as defined
below;
[0024] R.sup.3 is hydrogen, (C.sub.1-6)alkyl or as defined
below;
[0025] R.sup.4 is (i) hydrogen or (C.sub.1-6)alkyl, wherein said
alkyl optionally is substituted with cyano, halo, nitro,
--NR.sup.12R.sup.12, --NR.sup.12C(O)OR.sup.12,
--NR.sup.12C(O)NR.sup.12R.sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.12, --OR.sup.12, --SR.sup.12,
--C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NNR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.14,
--SR.sup.14, --S(O)R.sup.14, --S(O).sub.2R.sup.14, --C(O)R.sup.14,
--C(O)OR.sup.14, --OC(O)R.sup.14, --NR.sup.14R.sup.15,
--NR.sup.15C(O)R.sup.14, --NR.sup.15C(O)OR.sup.14,
--C(O)NR.sup.14R.sup.15, --S(O).sub.2NR.sup.14R.sup.15,
--NR.sup.15C(O)NR.sup.14R.sup.15 or
--NR.sup.15C(NR.sup.15)NR.sup.14R.sup- .15, wherein R.sup.12 at
each occurrence independently is hydrogen, (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.13 is (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.14 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-6)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl and R.sup.15 is
hydrogen or (C.sub.1-6)alkyl, and wherein within R.sup.14 said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.1- 7,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sub.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sub.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.sup.17 or
--X.sup.4NR.sup.17C(NR.sup.17)- NR.sup.16R.sup.17, wherein X.sup.4
is a bond or (C.sub.1-6)alkylene, R.sup.16 is hydrogen or
(C.sub.1-6)alkyl and R.sup.17 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-6)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, or (ii) a group
selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl- (C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C.sub.0- -6)alkyl and
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sub.16,
--X.sup.4OC(O)R.sub.16, --X.sup.4NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
X.sup.4C(O)NR.sup.16R.sup.17, --X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.4NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.4,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.4
any alicyclic or aromatic ring system present may be substituted
further by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12--X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above, or
[0026] R.sup.4 and R.sup.2 taken together form trimethylene,
tetramethylene or phenylene-1,2-dimethylene, optionally substituted
with hydroxy, oxo or methylene, or
[0027] R.sup.4 and R.sup.3 together with the carbon atom to which
both R.sup.4 and R.sup.3 are attached form (C.sub.3-8)cycloalkylene
or (C.sub.3-8)heterocycloalkylene;
[0028] R.sup.5 is hydrogen or (C.sub.1-6)alkyl;
[0029] R.sup.7 is hydrogen or (C.sub.1-6)alkyl;
[0030] R.sup.9 is (C.sub.6-12)aryl(C.sub.1-6)alkyl,
hetero(C.sub.5-12)aryl(C.sub.1-6)alkyl, --X.sup.4OR.sup.4,
--X.sup.4SR.sup.14, --X.sup.4S(O)R.sup.14,
--X.sup.4S(O).sub.2R.sup.14 or X.sup.4NR.sup.14R.sup.15, wherein
X.sup.4, R.sup.14 and R.sup.15 are as defined above and wherein
within R.sup.9 said aryl or heteroaryl ring optionally is
substituted by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, cyano, halo, halo-substituted (C.sub.1-4)alkyl,
nitro, --X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)R.sup.12,
--X.sup.4C(O)OR.sup.12, --X.sup.4C(O)NR.sup.12R.su- p.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.- 12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13, wherein X.sup.4, R.sup.12 and R.sup.13
are as defined above; and
[0031] R.sup.11 is --X.sup.5X.sup.6R.sup.18, wherein X.sup.5 is
--C(O)--, --C(O)C(O)-- or --S(O).sub.2--, X.sup.6 is a bond, --O--
or --NR.sup.19--, wherein R.sup.19 is hydrogen or (C.sub.1-6)alkyl,
and R.sup.18 is (i) (C.sub.1-10)alkyl optionally substituted by
cyano, halo, nitro, --NR.sup.12R.sup.12, --NR.sup.12C(O)OR.sup.12,
--NR.sup.12C(O)NR.sup.12R.sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.1- 2, --OR.sup.12,
--SR.sup.12, --C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.20,
--SR.sup.20, --S(O)R.sup.20, --S(O).sub.2R.sup.20, --C(O)R.sup.20,
--C(O)OR.sup.20, --C(O)NR.sup.20OR.sup.21, --NR.sup.20R.sup.21,
--NR.sup.21C(O)R.sup.20, --NR.sup.21C(O)OR.sup.20,
--NR.sup.21C(O)NR.sup.20R.sup.21 or
--NR.sup.21C(NR.sup.21)NR.sup.20R.sup.21, wherein R.sup.12 and
R.sup.13 are as defined above, R.sup.20 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)bicycloaryl(C.s- ub.0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl and R.sup.21 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl, or (ii)
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-6)alkyl, (C.sub.9-12)bicycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl or (iii)
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.- 0-6)alkyl,
phenyl(C.sub.0-6)alkyl or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl- ,
wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is
substituted by --X.sup.4OR.sup.22, --X.sup.4SR.sup.22,
--X.sup.4S(O)R.sup.22, --X.sup.4S(O).sub.2R.sup.22,
--X.sup.4C(O)R.sup.22, --X.sup.4C(O)OR.sup.22,
--X.sup.4C(O)NR.sup.22R.su- p.23, --X.sup.4N.sup.22R.sup.23,
--X.sup.4NR.sup.23C(O)R.sup.22, --X.sup.4NR.sup.23C(O)OR.sup.22,
--X.sup.4NR.sup.23C(O)NR.sup.22R.sup.23 or
--X.sup.4NR.sup.23C(NR.sup.23)NR.sup.22R.sup.23, wherein X.sup.4 is
as defined above, R.sup.22 is
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl and R.sup.23 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl; wherein
within R.sup.11 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --SR.sup.12; --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above; and the
N-oxide derivatives, prodrug derivatives, protected derivatives,
individual isomers and mixtures of isomers; and the
pharsnaceutically acceptable salts thereof.
[0032] In another particular embodiment, the present invention
relates to a pharmaceutical composition which contains a compound
of Formula I or a N-oxide derivative, prodrug derivative,
individual isomer or mixture of isomers or a pharmaceutically
acceptable salt thereof in admixture with one or more suitable
excipients.
[0033] In another particular embodiment, the present invention
relates to a method of treating a disease in an animal in which
inhibition of a cysteine protease can prevent, inhibit or
ameliorate the pathology and/or symptomatology of the disease,
which method comprises administering to the animal a
therapeutically effective amount of compound of Formula I or a
N-oxide derivative, prodrug derivative, individual isomer or
mixture of isomers or a pharmaceutically acceptable salt
thereof.
[0034] In another particular embodiment, the present invention
relates processes for preparing compounds of Formula I and the
N-oxide derivatives, prodrug derivative, protected derivatives,
individual isomers and mixtures of isomers, and the
pharmaceutically acceptable salts thereof as set forth in "Detailed
Description of the Invention".
[0035] In another particular embodiment, the present invention
relates a compound of Formula (III): 4
[0036] in which:
[0037] R.sup.1 is a group of Formula (a) or (b): 5
[0038] wherein:
[0039] X.sup.1 and X.sup.3 independently are --C(O)-- or
--S(O).sub.2--,
[0040] X.sup.2 is --CR.sup.8R.sup.9--, --CH.sub.2CR.sup.8R.sup.9--
or --CR.sup.8R.sup.9CH.sub.2-- and X.sup.4 is --CHR.sup.10--,
--CH.sub.2CHR.sup.10 -- or -CHR.sup.10CH.sub.2--, wherein:
[0041] R.sup.8 is hydrogen or (C.sub.1-6)alkyl,
[0042] R.sup.9 is (i) (C.sub.1-6)alkyl or
halo-substituted(C.sub.1-6)alkyl optionally substituted with
--OR.sup.11, --SR.sup.11, --S(O)R.sup.11, --S(O).sub.2R.sup.11,
--C(O)R.sup.11, --C(O)OR.sup.11, --NR.sup.11R.sup.12,
--NR.sup.12C(O)OR.sup.11, --C(O)NR.sup.11R.sup.12,
--S(O).sub.2NR.sup.11R.sup.12, --NR.sup.12C(O)NR.sup.11R.sup.12 or
--NR.sup.12C(NR.sup.12)NR.sup.11R.sup.12, wherein R.sup.11 is
hydrogen, (C.sub.1-6)alkyl, (C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)- alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl and R.sup.12 is hydrogen or
(C.sub.1-6)alkyl, or (ii) (C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.3-12)cycloalky)(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-3)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-3)alkyl optionally
substituted with --R.sup.13, --X.sup.5OR.sup.13,
--X.sup.5SR.sup.13, --S(O)R.sup.13, --S(O).sub.2R.sup.13,
--C(O)R.sup.13, --C(O)OR.sup.13, --X.sup.5NR.sup.13R.sup.14,
--X.sup.5NR.sup.14C(O)OR.sup- .13, --C(O)NR.sup.13R.sup.14,
--S(O).sub.2NR.sup.13R.sup.14, --NR.sup.14C(O)NR.sup.13R.sup.14 or
--NR.sup.14C(NR.sup.14)NR.sup.13R.sup- .14, wherein X.sup.5 is a
bond or methylene, R.sup.13 is
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-3)alkyl, (C.sub.9-12)polycycloarlyl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-3)alkyl and R.sup.14 is
hydrogen or (C.sub.1-6)alkyl, or (iii) together with R.sup.5 when
X.sup.2 is --CHR.sup.9-- forms trimethylene, tetramethylene or
phenylene-1,2-dimethylene, optionally substituted with 1 to 2 of
hydroxy, oxo, (C.sub.1-4)alkyl or methylene; wherein any 1 to 3
annular atoms of any aromatic ring with available valences
comprising R.sup.9 are optionally independently substituted with
halo, nitro, cyano, (C.sub.1-6)alkyl,
halo-substituted(C.sub.1-6)alkyl, --OR.sup.15, --C(O)R.sup.15,
--C(O)OR.sup.15, --C(O)NR.sup.15R.sup.15,
--S(O).sub.2NR.sup.15R.sup.15, --X.sup.5NR.sup.15R.sup.15,
--X.sup.5NR.sup.15C(O)OR.sup.15,
--X.sup.5NR.sup.15C(O)NR.sup.15R.sup.15, or
--X.sup.5NR.sup.15C(NR.sup.15NR.sup.15R.sup.15, wherein X.sup.5 is
as defined above and each R.sup.15 independently is hydrogen or
(C.sub.1-6)alkyl, and
[0043] R.sup.10 is hydrogen or (C.sub.1-4)alkyl;
[0044] R.sup.5 and R.sup.7 are independently hydrogen,
(C.sub.1-6)alkyl or as defined above; and
[0045] R.sup.6 is --X.sup.6X.sup.7R.sup.16, wherein X.sup.6 is
--C(O)-- or --S(O).sub.2--, X.sup.7 is a bond, --O-- or
--NR.sup.17--, wherein R.sup.17 is hydrogen or (C.sub.1-6)alkyl,
and R.sup.16 is (i) (C.sub.1-6)alkyl or
halo-substituted(C.sub.1-6)alkyl optionally substituted with
--OR.sup.11, --SR.sup.11, --S(O)R.sup.11, --S(O).sub.2R.sup.11,
--C(O)R.sup.11, --C(O)OR.sup.11, --NR.sup.11R.sup.12,
--NR.sup.12C(O)OR.sup.11, --C(O)NR.sup.11R.sup.12,
--NR.sup.12C(O)NR.sup.11R.sup.12 or
--NR.sup.12C(NR.sup.12)NR.sup.11R.sup- .12, wherein R.sup.11 and
R.sup.12 are as defined above, or (ii)
(C.sub.3-6)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.- 0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl, hetero(C.sub.5-12)aryl(C.sub.-
0-3)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-3)alkyl optionally
substituted with 1 to 2 of --R.sup.13, --X.sup.5OR.sup.13,
--X.sup.5SR.sup.13, --S(O)R.sup.13, --S(O).sub.2R.sup.13,
--C(O)OR.sup.13, --X.sup.5NR.sup.13R.sup.14,
--X.sup.5NR.sup.14C(O)OR.sup.13, --C(O)NR.sup.13R.sup.14,
--NR.sup.14C(O)NR.sup.13R.sup.14 or
--NR.sup.14C(NR.sup.14)NR.sup.13R.sup.14, wherein X.sup.5, R.sup.13
and R.sup.14 are as defined above; wherein any 1 to 3 annular atoms
of any aromatic ring with available valences comprising R.sup.16
optionally independently are substituted with halo, nitro, cyano,
(C.sub.1-6)alkyl, halo-substituted(C.sub.1-6)alkyl, --OR.sup.15,
--C(O)R.sup.15, --C(O)OR.sup.15, --C(O)NR.sup.15R.sup.15,
--S(O).sub.2NR.sup.15R.sup.15, --X.sup.5NR.sup.15R.sup.15,
--X.sup.5NR.sup.15C(O)OR.sup.15,
--X.sup.5NR.sup.15C(O)NR.sup.15R.sup.15 or
--X.sup.5NR.sup.15C(NR.sup.15)- NR.sup.15R.sup.15, wherein X.sup.5
and R.sup.15 are as defined above;
[0046] R.sup.2 is hydrogen or (C.sub.1-6)alkyl or as defined
below;
[0047] R.sup.3 is hydrogen, (C.sub.1-10)alkyl or as defined below;
and
[0048] R.sup.4 is (i) hydrogen, (ii) (C.sub.1-6)alkyl or
halo-substituted(C.sub.1-6)alkyl optionally substituted with
--OR.sup.11, --SR.sup.11, --S(O)R.sup.11, --S(O).sub.2R.sup.11,
--C(O)R.sup.11, --C(O)OR.sup.11, --NR.sup.11R.sup.12,
--NR.sup.12C(O)OR.sup.11, --C(O)NR.sup.11R.sup.12,
--NR.sup.12C(O)NR.sup.11R.sup.12 or
--NR.sup.12C(NR.sup.12)NR.sup.11R.sup.12, wherein R.sup.11 and
R.sup.12 are as defined above, or (iii)
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-3)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-3)alkyl optionally
substituted with --R.sup.13, --X.sup.5OR.sup.13,
--X.sup.5SR.sup.13, --S(O)R.sup.13, --S(O).sub.2R.sup.13,
--C(O)OR.sup.13, --X.sup.5NR.sup.13R.sup.14,
--X.sup.5NR.sup.14C(O)OR.sup- .13, --C(O)NR.sup.13R.sup.14,
--NR.sup.14C(O)NR.sup.13R.sup.14 or
NR.sup.14C(NR.sup.14)NR.sup.13R.sup.14, wherein X.sup.5, R.sup.13
and R.sup.14 are as defined above or (iv) together with R.sup.2
forms trimethylene, tetramethylene or phenylene-1,2-dimethylene,
optionally substituted with hydroxy, oxo, (C.sub.1-4)alkyl or
methylene or (v) together with R.sup.3 forms ethylene, trimethylene
or tetramethylene; wherein any 1 to 3 annular atoms of any aromatic
ring with available valences comprising R.sup.4 optionally
independently are substituted with halo, nitro, cyano,
(C.sub.1-6)alkyl, halo-substituted(C.sub.1-6)alkyl, --OR.sup.15,
--C(O)R.sup.15, --C(O)OR.sup.15, --C(O)NR.sup.15R.sup.15,
--S(O).sub.2NR.sup.15R.sup.15, --X.sup.5NR.sup.15R.sup.15,
--X.sup.5NR.sup.15C(O)OR.sup.15,
--X.sup.5NR.sup.15C(O)NR.sup.15R.sup.15 or
--X.sup.5NR.sup.15C(NR.sup.15)NR.sup.15R.sup.15, wherein X.sup.5
and R.sup.15 are as defined above; and the N-oxide derivatives,
prodrug derivatives, protected derivatives, individual isomers and
mixtures of isomers; and the pharmaceutically acceptable salts
thereof.
[0049] In another particular embodiment, the present invention
relates to a method of treating a disease in an animal in which
cathepsin S activity contributes to the pathology and/or
symptomatology of the disease, which method comprising
administering to the animal a therapeutically effective amount of a
compound of Formula (I): 6
[0050] in which:
[0051] R.sup.1 is a group of Formula (a) or (b): 7
[0052] wherein:
[0053] X.sup.1 and X.sup.2 independently are --C(O)-- or
--CH.sub.2S(O).sub.2--;
[0054] R.sup.5 and R.sup.6 are hydrogen or (C.sub.1-6)alkyl;
[0055] R.sup.7 and R.sup.8 are hydrogen or (C.sub.1-6)alkyl or as
defined below;
[0056] R.sup.9 and R.sup.10 independently are (i) (C.sub.1-6)alkyl
optionally substituted with cyano, halo or nitro or (ii) a group
selected from --X.sup.3NR.sup.12R.sup.12,
--X.sup.3NR.sup.12C(O)OR.sup.12,
--X.sup.3NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.3NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.3OR.sup.12, --X.sup.3SR.sup.12, --X.sup.3C(O)OR.sup.12,
--X.sup.3C(O)NR.sup.12R.sup.12,
--X.sup.3S(O).sub.2NR.sup.12R.sup.12,
--X.sup.3P(O)(OR.sup.12)OR.sup.12,
--X.sup.3OP(O)(OR.sup.12)OR.sup.12, --X.sup.3NR.sup.12C(O)R.sup.13,
--X.sup.3S(O)R.sup.13, --X.sup.3S(O).sub.2R.sup.13,
--X.sup.3C(O)R.sup.13, --X.sup.3C(O)R.sup.14,
--X.sup.3C(O)OR.sup.14, --X.sup.3OC(O)R.sup.14,
--X.sup.3NR.sup.15C(O)R.sup.14, --X.sup.3NR.sup.15C(O)OR.sup.14,
--X.sup.3C(O)NR.sup.14R.sup.15,
--X.sup.3S(O).sub.2NR.sup.14R.sup.15,
--X.sup.3NR.sup.15C(O)NR.sup.14R.su- p.15,
--X.sup.3NR.sup.15C(NR.sup.15)NR.sup.14R.sup.15, --X.sup.4SR.sup.14
--X.sup.4S(O)R.sup.14, --X.sup.4S(O).sub.2R.sup.14,
--X.sup.4OR.sup.14, or --X.sup.4NR.sup.14R.sup.15, wherein X.sup.3
is (C.sub.1-6)alkylene, X.sup.4 is a bond or (C.sub.1-6)alkylene,
R.sup.12 at each occurrence independently is hydrogen,
(C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl, R.sup.13 is
(C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl, R.sup.14 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl and R.sup.15 is
hydrogen or (C.sub.1-6)alkyl, and wherein within R.sup.14 said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.4NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.4 is
a bond or (C.sub.1-6)alkylene, R.sup.16 is hydrogen or
(C.sub.1-6)alkyl and R.sup.17 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, or (iii) a group
selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl and
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.17,
X.sup.4NR.sup.17C(O)R.sup.16, X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.4NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.4,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.9
and/or R.sup.10 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.4)OR.sup.12,
--X.sup.4OP(O)(OR.sup.12)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above, or
[0057] R.sup.9 taken together with R.sup.7 and/or R.sup.10 taken
together with R.sup.8 form trimethylene, tetramethylene or
phenylene-1,2-dimethyle- ne, optionally substituted with hydroxy,
oxo or methylene; and
[0058] R.sup.11 is --X.sup.5X.sup.6R.sup.18, wherein X.sup.5 is
--C(O)--, --C(O)C(O)-- or --S(O).sub.2--, X.sup.6 is a bond, --O--
or --NR.sup.19--, wherein R.sup.19 is hydrogen or (C.sub.1-6)alkyl,
and R.sup.18 is (i) (C.sub.1-10)alkyl optionally substituted by
cyano, halo, nitro, --NR.sup.12R.sup.12, --NR.sup.12C(O)OR.sup.12,
--NR.sup.12C(O)NR.sup.12R.sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.1- 2, --OR.sup.12,
--SR.sup.12, --C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.20,
--SR.sup.20, --S(O)R.sup.20, --S(O).sub.2R.sup.20, --C(O)R.sup.20,
--C(O)OR.sup.20, --C(O)NR.sup.20R.sup.21, --NR.sup.20R.sup.21,
--NR.sup.21C(O)R.sup.20, --NR.sup.21C(O)OR.sup.20,
--NR.sup.21C(O)NR.sup.20R.sup.21 or
--NR.sup.21C(NR.sup.21)NR.sup.20R.sup.21, wherein R.sup.12 and
R.sup.13 are as defined above, R.sup.20 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)bicycloaryl(C.s- ub.0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl and R.sup.21 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl, or (ii)
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-6)alkyl, (C.sub.9-12)bicycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl or (iii)
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.- 0-6)alkyl, phenyl
(C.sub.0-6)alkyl or hetero(C.sub.5-6)aryl(C.sub.0-6)alky- l,
wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is
substituted by --X.sup.4OR.sup.22, --X.sup.4SR.sup.22,
--X.sup.4S(O)R.sup.22, --X.sup.4S(O).sub.2R.sup.22,
--X.sup.4C(O)R.sup.22, --X.sup.4C(O)OR.sup.22,
--X.sup.4C(O)NR.sup.22R.su- p.23, --X.sup.4NR.sup.22R.sup.23,
--X.sup.4NR.sup.23C(O)R.sup.22, --X.sup.4NR.sup.23C(O)OR.sup.22,
--X.sup.4NR.sup.23C(O)NR.sup.22R.sup.23 or
--X.sup.4NR.sup.23C(NR.sup.23)NR.sup.22R.sup.23, wherein X.sup.4 is
as defined above, R.sup.22 is
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl and R.sup.23 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl; wherein
within R.sup.11 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above;
[0059] R.sup.2 is hydrogen or (C.sub.1-6)alkyl or as defined
below;
[0060] R.sup.3 is hydrogen, (C.sub.1-6)alkyl or as defined below;
and
[0061] R.sup.4 is (i) hydrogen or (C.sub.1-6)alkyl, wherein said
alkyl is optionally substituted with cyano, halo, nitro,
--NR.sup.12R.sup.12, --NR.sup.12C(O)OR.sup.12,
--NR.sup.12C(O)NR.sup.12R.sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.12, --OR.sup.12, --SR.sup.12,
--C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.14,
--SR.sup.14, --S(O)R.sup.14, --S(O).sub.2R.sup.14, --C(O)R.sup.14,
--C(O)OR.sup.14, --OC(O)R.sup.14, --NR.sup.14R.sup.15,
--NR.sup.15C(O)R.sup.14, --NR.sup.15C(O)OR.sup.14,
--C(O)NR.sup.14R.sup.15, --S(O).sub.2NR.sup.14R.sup.15,
--NR.sup.15C(O)NR.sup.14R.sup.15 or
--NR.sup.15C(NR.sup.15)NR.sup.14R.sup- .15, wherein R.sup.12,
R.sup.13, R.sup.14 and R.sup.15 are as defined above, or (ii) a
group selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alk- yl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0- -6)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl, (C.sub.9-12)polycycloary-
l(C.sub.0-6)alkyl and
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.4NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.4,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.9
and/or R.sup.10 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)R.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.2C(NR.sup.12)NR.- sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above, or
[0062] R.sup.4 and R.sup.2 taken together form trimethylene,
tetramethylene or phenylene-1,2-dimethylene, optionally substituted
with hydroxy, oxo or methylene, or
[0063] R.sup.4 and R.sup.3 together with the carbon atom to which
both R.sup.4 and R.sup.3 are attached form (C.sub.3-8)cycloalkylene
or (C.sub.3-8)heterocycloalkylene; or an N-oxide derivative,
prodrug derivative, individual isomer and mixtures of isomers; or a
pharmaceutically acceptable salt thereof, but excluding compounds
of the formula 8
[0064] in which R.sup.3 and R.sup.4 are each hydrogen or
(C.sub.1-6)alkyl, or together with the carbon atom to which they
are both attached form (C.sub.3-5)cycloalkylene; R.sup.5 is
hydrogen or (C.sub.1-6)alkyl; R.sup.9 is (C.sub.6-12)aryl
(C.sub.1-6)alkyl, hetero(C.sub.5-12)aryl(C.su- b.1-6)alkyl,
(C.sub.4-5)alkyl or cyclohexylmethyl; and R.sup.11 is C(O)R.sup.18
wherein R.sup.18 is hetero(C.sub.3-12)cycloalkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alky- l.
[0065] In another particular embodiment, the present invention
relates to the use of a compound of Formula (I): 9
[0066] in which:
[0067] R.sup.1 is a group of Formula (a) or (b): 10
[0068] wherein:
[0069] X.sup.1 and X.sup.2 independently are --C(O)-- or
--CH.sub.2S(O).sub.2--;
[0070] R.sup.5 and R.sup.6 are hydrogen or (C.sub.1-6)alkyl;
[0071] R.sup.7 and R.sup.8 are hydrogen or (C.sub.1-6)alkyl or as
defined below;
[0072] R.sup.9 and R.sup.10 independently are (i) (C.sub.1-6)alkyl
optionally substituted with cyano, halo or nitro or (ii) a group
selected from --X.sup.3NR.sup.12R.sup.12,
--X.sup.3NR.sup.12C(O)OR.sup.12,
--X.sup.3NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.3NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.3OR.sup.12, --X.sup.3SR.sup.12, --X.sup.3C(O)OR.sup.12,
--X.sup.3C(O)NR.sup.12R.sup.12,
--X.sup.3S(O).sub.2NR.sup.12R.sup.12,
--X.sup.3P(O)(OR.sup.12)OR.sup.12,
--X.sup.3OP(O)(OR.sup.12)OR.sup.12, --X.sup.3NR.sup.12C(O)R.sup.13,
--X.sup.3S(O)R.sup.13, --X.sup.3S(O).sub.2R.sup.13,
--X.sup.3C(O)R.sup.13, --X.sup.3C(O)R.sup.14,
--X.sup.3C(O)OR.sup.14, --X.sup.3OC(O)R.sup.14,
--X.sup.3NR.sup.15C(O)R.sup.14, --X.sup.3NR.sup.15C(O)OR.sup.14,
--X.sup.3C(O)NR.sup.14R.sup.15,
--X.sup.3S(O).sub.2NR.sup.14R.sup.15,
--X.sup.3NR.sup.15C(O)NR.sup.14R.su- p.15,
--X.sup.3NR.sup.15C(NR.sup.15)NR.sup.14R.sup.15,
--X.sup.4SR.sup.14, --X.sup.4S(O)R.sup.14,
--X.sup.4S(O).sub.2R.sup.14, --X.sup.4OR.sup.14, or
--X.sup.4NR.sup.14R.sup.15, wherein X.sup.3 is (C.sub.1-6)alkylene,
X.sup.4 is a bond or (C.sub.1-6)alkylene, R.sup.12 at each
occurrence independently is hydrogen, (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.13 is (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.14 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl and R.sup.15 is
hydrogen or (C.sub.1-6)alkyl, and wherein within R.sup.14 said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.4NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.4 is
a bond or (C.sub.1-6)alkylene, R.sup.16 is hydrogen or
(C.sub.1-6)alkyl and R.sup.17 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, or (iii) a group
selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl and
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.4NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.4,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.9
and/or R.sup.10 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.4)OR.sup.12,
--X.sup.4OP(O)(OR.sup.12)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above, or
[0073] R.sup.9 taken together with R.sup.7 and/or R.sup.10 taken
together with R.sup.8 form trimethylene, tetramethylene or
phenylene-1,2-dimethyle- ne, optionally substituted with hydroxy,
oxo or methylene; and
[0074] R.sup.11 is --X.sup.5X.sup.6R.sup.18, wherein X.sup.5 is
--C(O)--, --C(O)C(O)-- or --S(O).sub.2--, X.sup.6 is a bond, --O--
or --NR.sup.19--, wherein R.sup.19 is hydrogen or (C.sub.1-6)alkyl,
and R.sup.18 is (i) (C.sub.1-10)alkyl optionally substituted by
cyano, halo, nitro, --NR.sup.12R.sup.12, --NR.sup.12C(O)OR.sup.12,
--NR.sup.12C(O)NR.sup.12R.sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.1- 2, --OR.sup.12,
--SR.sup.12, --C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.20,
--SR.sup.20, --S(O)R.sup.20, --S(O).sub.2R.sup.20, --C(O)R.sup.20,
--C(O)OR.sup.20, --C(O)NR.sup.20R.sup.21, --NR.sup.20R.sup.21,
--NR.sup.21C(O)R.sup.20, --NR.sup.21C(O)OR.sup.20,
--NR.sup.21C(O)NR.sup.20R.sup.21 or
--NR.sup.21C(NR.sup.21)NR.sup.20R.sup.21, wherein R.sup.12 and
R.sup.13 are as defined above, R.sup.20 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)bicycloaryl(C.s- ub.0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl and R.sup.21 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl, or (ii)
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-6)alkyl, (C.sub.9-12)bicycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-6)alkyl or (iii)
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.- 0-6)alkyl,
phenyl(C.sub.0-6)alkyl or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl- ,
wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is
substituted by --X.sup.4OR.sup.22, --X.sup.4SR.sup.22,
--X.sup.4S(O)R.sup.22, --X.sup.4S(O).sub.2R.sup.22,
--X.sup.4C(O)R.sup.22, --X.sup.4C(O)OR.sup.22,
--X.sup.4C(O)NR.sup.22R.su- p.23, --X.sup.4NR.sup.22R.sup.23,
--X.sup.4NR.sup.23C(O)R.sup.22, --X.sup.4NR.sup.23C(O)OR.sup.22,
--X.sup.4NR.sup.23C(O)NR.sup.22R.sup.23 or
--X.sup.4NR.sup.23C(NR.sup.23)NR.sup.22R.sup.23, wherein X.sup.4 is
as defined above, R.sup.22 is
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl and R.sup.23 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl; wherein
within R.sup.11 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above;
[0075] R.sup.2 is hydrogen or (C.sub.1-6)alkyl or as defined
below;
[0076] R.sup.3 is hydrogen, (C.sub.1-6)alkyl or as defined below;
and
[0077] R.sup.4 is (i) hydrogen or (C.sub.1-6)alkyl, wherein said
alkyl is optionally substituted with cyano, halo, nitro,
--NR.sup.12R.sup.12, --NR.sup.12C(O)OR.sup.12,
--NR.sup.12C(O)NR.sup.12R.sup.12,
--NR.sup.12C(NR.sup.12)NR.sup.12R.sup.12, --OR.sup.12, --SR.sup.12,
--C(O)OR.sup.12, --C(O)NR.sup.12R.sup.12,
--S(O).sub.2NR.sup.12R.sup.12, --P(O)(OR.sup.12)OR.sup.12,
--OP(O)(OR.sup.12)OR.sup.12, --NR.sup.12C(O)R.sup.13,
--S(O)R.sup.13, --S(O).sub.2R.sup.13, --C(O)R.sup.13, --OR.sup.14,
--SR.sup.14, --S(O)R.sup.14, --S(O).sub.2R.sup.14, --C(O)R.sup.14,
--C(O)OR.sup.14, --OC(O)R.sup.14, --NR.sup.14R.sup.15,
--NR.sup.15C(O)R.sup.14, --NR.sup.15C(O)R.sup.14,
--C(O)NR.sup.14R.sup.15, --S(O).sub.2NR.sup.14R.sup.15,
--NR.sup.15C(O)NR.sup.14R.sup.15 or
--NR.sup.15C(NR.sup.15)NR.sup.14R.sup- .15, wherein R.sup.12,
R.sup.13, R.sup.14 and R.sup.15 are as defined above, or (ii) a
group selected from (C.sub.3-12)cycloalkyl(C.sub.0-6)alk- yl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0- -6)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl, (C.sub.9-12)polycycloary-
l(C.sub.0-6)alkyl and
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.4OR.sup.16, --X.sup.4SR.sup.16,
--X.sup.4S(O)R.sup.16, --X.sup.4S(O).sub.2R.sup.16,
--X.sup.4C(O)R.sup.16, --X.sup.4C(O)OR.sup.16,
--X.sup.4OC(O)R.sup.16, --X.sup.4NR.sup.16R.sup.17,
X.sup.4NR.sup.17C(O)R.sup.16, --X.sup.4NR.sup.17C(O)OR.sup.16,
--X.sup.4C(O)NR.sup.16R.sup.17,
--X.sup.4S(O).sub.2NR.sup.16R.sup.17,
--X.sup.4R.sup.17C(O)NR.sup.16R.sup- .17 or
--X.sup.4NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.4,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.9
and/or R.sup.10 any alicyclic or aromatic ring system present may
be substituted further by 1 to 5 radicals independently selected
from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4NR.sup.12C(O)OR.sup.12,
--X.sup.4NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.4N.sup.12C(NR.sup.12)NR.- sup.12R.sup.12,
--X.sup.4OR.sup.12, --X.sup.4SR.sup.12, --X.sup.4C(O)OR.sup.12,
--X.sup.4C(O)NR.sup.12R.sup.12,
--X.sup.4S(O).sub.2NR.sup.12R.sup.12,
--X.sup.4P(O)(OR.sup.3)OR.sup.12,
--X.sup.4OP(O)(OR.sup.3)OR.sup.12, --X.sup.4OC(O)R.sup.13,
--X.sup.4NR.sup.12C(O)R.sup.13, --X.sup.4S(O)R.sup.13,
--X.sup.4S(O).sub.2R.sup.13 and --X.sup.4C(O)R.sup.13, wherein
X.sup.4, R.sup.12 and R.sup.13 are as defined above, or
[0078] R.sup.4 and R.sup.2 taken together formn trimethylene,
tetramethylene or phenylene-1,2-dimethylene, optionally substituted
with hydroxy, oxo or methylene, or
[0079] R.sup.4 and R.sup.3 together with the carbon atom to which
both R.sup.4 and R.sup.3 are attached form (C.sub.3-8)cycloalkylene
or (C.sub.3-8)heterocycloalkylene; or an N-oxide derivative,
prodrug derivative, individual isomer and mixtures of isomers; or a
pharmaceutically acceptable salt thereof, but excluding compounds
of the formula 11
[0080] in which R.sup.3 and R.sup.4 are each hydrogen or
(C.sub.1-6)alkyl, or together with the carbon atom to which they
are both attached form (C.sub.3-5)cycloalkylene; R.sup.5 is
hydrogen or (C.sub.1-6)alkyl; R.sup.9 is
(C.sub.6-12)aryl(C.sub.1-6)alkyl, hetero(C.sub.5-12)aryl(C.sub-
.1-6)alkyl, (C.sub.4-5)alkyl or cyclohexylmethyl; and R.sup.11 is
C(O)R.sup.18 wherein R.sup.18 is hetero(C.sub.3-12)cycloalkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alky- l, in the manufacture of a
medicament for treating a disease in an animal in which cathepsin S
activity contributes to the pathology and/or symptomatology of the
disease.
[0081] In another particular embodiment, the present invention
relates to a method of treating a disease in an animal in which
cathepsin S activity contributes to the pathology and/or
symptomatology of the disease, which method comprising
administering to the animal a therapeutically effective amount of a
compound of Formula (III): 12
[0082] in which:
[0083] R.sup.1 is a group of Formula (a) or (b): 13
[0084] wherein:
[0085] X.sup.1 and X.sup.3 independently are --C(O)-- or
--S(O).sub.2--,
[0086] X.sup.2 is --CR.sup.8R.sup.9, --CH.sub.2CR.sup.8R.sup.9-- or
--CR.sup.8R.sup.9CH.sub.2-- and X.sup.4 is --CHR.sup.10--,
--CH.sub.2CHR.sup.10-- or --CHR.sup.10CH.sub.2--, wherein:
[0087] R.sup.8 is hydrogen or (C.sub.1-6)alkyl,
[0088] R.sup.9 is (i) (C.sub.1-6)alkyl or
halo-substituted(C.sub.1-6)alkyl optionally substituted with
--OR.sup.11, --SR.sup.11, --S(O)R.sup.11, --S(O).sub.2R.sup.11,
--C(O)R.sup.11, --C(O)OR.sup.11, --NR.sup.11R.sup.12,
--NR.sup.12C(O)OR.sup.11, --C(O)NR.sup.11R.sup.12,
--S(O).sub.2NR.sup.11R.sup.12, --NR.sup.12C(O)NR.sup.11R.sup.12 or
--NR.sup.12C(NR.sup.12)NR.sup.11R.sup.12, wherein R.sup.11 is
hydrogen, (C.sub.1-6)alkyl, (C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)- alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl and R.sup.12 is hydrogen or
(C.sub.1-6)alkyl, or (ii) (C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-3)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-3)alkyl optionally
substituted with --R.sup.13, --X.sup.5OR.sup.13,
--X.sup.5SR.sup.13, --S(O)R.sup.13, --S(O).sub.2R.sup.13,
--C(O)R.sup.13, --C(O)OR.sup.13, --X.sup.5NR.sup.13R.sup.14,
--X.sup.5NR.sup.14C(O)R.sup.- 13, --C(O)NR.sup.13R.sup.14,
--S(O).sub.2NR.sup.13R.sup.14, --NR.sup.14C(O)NR.sup.13R.sup.14 or
--NR.sup.14C(NR.sup.14)NR.sup.13R.sup- .14, wherein X.sup.5 is a
bond or methylene, R.sup.13 is
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-3)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-3)alkyl and R.sup.14 is
hydrogen or (C.sub.1-6)alkyl, or (iii) together with R.sup.5 when
X.sup.2 is --CHR.sup.9-- forms trimethylene, tetramethylene or
phenylene-1,2-dimethylene, optionally substituted with 1 to 2 of
hydroxy, oxo, (C.sub.1-4)alkyl or methylene; wherein any 1 to 3
annular atoms of any aromatic ring with available valences
comprising R.sup.9 are optionally independently substituted with
halo, nitro, cyano, (C.sub.1-6)alkyl,
halo-substituted(C.sub.1-6)alkyl, --OR.sup.15, --C(O)R.sup.15,
--C(O)OR.sup.15, --C(O)NR.sup.15R.sup.15,
--S(O).sub.2NR.sup.15R.sup.15, --X.sup.5NR.sup.15R.sup.15,
--X.sup.5NR.sup.15C(O)OR.sup.15,
--X.sup.5NR.sup.15C(O)NR.sup.15R.sup.15 or
--X.sup.5NR.sup.15C(NR.sup.15NR.sup.15R.sup.15, wherein X.sup.5 is
as defined above and each R.sup.15 independently is hydrogen or
(C.sub.1-6)alkyl, and
[0089] R.sup.10 is hydrogen or (C.sub.1-4)alkyl;
[0090] R.sup.5 and R.sup.7 are independently hydrogen,
(C.sub.1-6)alkyl or as defined above; and
[0091] R.sup.6 is --X.sup.6X.sup.7R.sup.16, wherein X.sup.6 is
--C(O)-- or --S(O).sub.2--, X.sup.7 is a bond, --O-- or
--NR.sup.17--, wherein R.sup.17 is hydrogen or (C.sub.1-6)alkyl,
and R.sup.16 is (i) (C.sub.1-6)alkyl or
halo-substituted(C.sub.1-6)alkyl optionally substituted with
--OR.sup.11, --SR.sup.11, --S(O)R.sup.11, --S(O).sub.2R.sup.11,
--C(O)R.sup.11, --C(O)OR.sup.11, --NR.sup.12,
--NR.sup.12C(O)OR.sup.11, --C(O)NR.sup.11R.sup.12,
--NR.sup.12C(O)NR.sup.11R.sup.12 or
--NR.sup.12C(NR.sup.12)NR.sup.11R.sup- .12, wherein R.sup.11 and
R.sup.12 are as defined above, or (ii)
(C.sub.3-6)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.- 0-3)alkyl,
(C6-12)aryl(C.sub.0-3)alkyl, hetero(C.sub.5-12)aryl(C.sub.0-3)a-
lkyl, (C.sub.9-12)polycycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)polyc- ycloaryl(C.sub.0-3)alkyl optionally
substituted with 1 to 2 of --R.sup.13, --X.sup.5OR.sup.13,
--X.sup.5SR.sup.13, --S(O)R.sup.13, --S(O).sub.2R.sup.13,
--C(O)OR.sup.13, --X.sup.5NR.sup.13R.sup.14,
--X.sup.5NR.sup.14C(O)OR.sup.13, --C(O)NR.sup.13R.sup.14,
--NR.sup.14C(O)NR.sup.13R.sup.14 or
--NR.sup.14C(NR.sup.14)NR.sup.13R.sup- .14, wherein X.sup.5,
R.sup.13 and R.sup.14 are as defined above; wherein any 1 to 3
annular atoms of any aromatic ring with available valences
comprising R.sup.16 optionally independently are substituted with
halo, nitro, cyano, (C.sub.1-6)alkyl,
halo-substituted(C.sub.1-6)alkyl, --OR.sup.15, --C(O)R.sup.15,
--C(O)OR.sup.15, --C(O)NR.sup.15R.sup.15,
--S(O).sub.2NR.sup.15R.sup.15, --X.sup.5NR.sup.15R.sup.15,
--X.sup.5NR.sup.15C(O)OR.sup.15,
--X.sup.5NR.sup.15C(O)NR.sup.15R.sup.15 or
--X.sup.5NR.sup.15C(NR.sup.15)NR.sup.15R.sup.15, wherein X.sup.5
and R.sup.15 are as defined above;
[0092] R.sup.2 is hydrogen or (C.sub.1-6)alkyl or as defined
below;
[0093] R.sup.3 is hydrogen, (C.sub.1-10)alkyl or as defined below;
and
[0094] R.sup.4 is (i) hydrogen, (ii) (C.sub.1-6)alkyl or
halo-substituted(C.sub.1-6)alkyl optionally substituted with
--OR.sup.11, --SR.sup.11, --S(O)R.sup.11, --S(O).sub.2R.sup.11,
--C(O)R.sup.11, --C(O)OR.sup.11, --NR.sup.11R.sup.12,
--NR.sup.11C(O)OR.sup.11, --C(O)NR.sup.11R.sup.12,
--NR.sup.12C(O)NR.sup.11R.sup.12 or
--NR.sup.12C(NR.sup.12)NR.sup.11R.sup.12, wherein R.sup.11 and
R.sup.12 are as defined above, or (iii)
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-3)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-3)alkyl optionally
substituted with --R.sup.13, --X.sup.5OR.sup.13,
--X.sup.5SR.sup.13, --S(O)R.sup.13, --S(O).sub.2R.sup.13,
--C(O)OR.sup.13, --X.sup.5NR.sup.13R.sup.14,
--X.sup.5NR.sup.14C(O)OR.sup- .13, --C(O)NR.sup.13R.sup.14,
--NR.sup.14C(O)NR.sup.13R.sup.14 or
--NR.sup.14C(NR.sup.14)NR.sup.13R.sup.14, wherein X.sup.5, R.sup.13
and R.sup.14 are as defined above or (iv) together with R.sup.2
forms trimethylene, tetramethylene or phenylene-1,2-dimethylene,
optionally substituted with hydroxy, oxo, (C.sub.1-4)alkyl or
methylene or (v) together with R.sup.3 forms ethylene, trimethylene
or tetramethylene; wherein any 1 to 3 annular atoms of any aromatic
ring with available valences comprising R.sup.4 optionally
independently are substituted with halo, nitro, cyano,
(C.sub.1-6)alkyl, halo-substituted(C.sub.1-6)alkyl, --OR.sup.15,
--C(O)R.sup.15, --C(O)OR.sup.15, --C(O)NR.sup.15R.sup.15,
--S(O).sub.2NR.sup.15R.sup.15, --X.sup.5NR.sup.15R.sup.15,
--X.sup.5NR.sup.15C(O)OR.sup.15,
--X.sup.5NR.sup.15C(O)NR.sup.15R.sup.15 or
--X.sup.5NR.sup.15C(NR.sup.15)NR.sup.15R.sup.15, wherein X.sup.5
and R.sup.15 are as defined above; or an N-oxide derivative,
prodrug derivative, individual isomer and mixtures of isomers; or a
pharmaceutically acceptable salt thereof, but excluding compounds
of the formula 14
[0095] in which R.sup.3 and R.sup.4 are each hydrogen or
(C.sub.1-6)alkyl, or together with the carbon atom to which they
are both attached form (C.sub.3-5)cycloalkylene; R.sup.5 is
hydrogen or (C.sub.1-6)alkyl; R.sup.9 is
(C.sub.6-12)aryl(C.sub.1-6)alkyl, hetero(C.sub.5-12)aryl(C.sub-
.1-6)alkyl, (C.sub.4-5)alkyl or cyclohexylmethyl; and R.sup.11 is
C(O)R.sup.18 wherein R.sup.18 is hetero(C.sub.3-12)cycloalkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alky- l.
[0096] In another particular embodiment, the present invention
relates to the use of a compound of Formula (III): 15
[0097] in which:
[0098] R.sup.1 is a group of Formula (a) or (b): 16
[0099] wherein:
[0100] X.sup.1 and X.sup.3 independently are --C(O)-- or
--S(O).sub.2--,
[0101] X.sup.2 is --CR.sup.8R.sup.9--, --CH.sub.2CR.sup.8R.sup.9--
or --CR.sup.8R.sup.9CH.sub.2-- and X.sup.4 is --CHR.sup.10--,
--CH.sub.2CHR.sup.10--or --CHR.sup.10CH.sub.2--, wherein:
[0102] R.sup.8 is hydrogen or (C.sub.1-6)alkyl,
[0103] R.sup.9is (i) (C.sub.1-6)alkyl or
halo-substituted(C.sub.1-6)alkyl optionally substituted with
--OR.sup.11, --SR.sup.11, --S(O)R.sup.11, --S(O).sub.2R.sup.11,
--C(O)R.sup.11, --C(O)OR.sup.11, --NR.sup.11R.sup.12,
--NR.sup.12C(O)OR.sup.11, --C(O)NR.sup.11R.sup.12,
--S(O).sub.2NR.sup.11R.sup.12, --NR.sup.12C(O)NR.sup.11R.sup.12 or
--NR.sup.12C(NR.sup.12)NR.sup.11R.sup.12, wherein R.sup.11 is
hydrogen, (C.sub.1-6)alkyl, (C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)- alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl and R.sup.12 is hydrogen or
(C.sub.1-6)alkyl, or (ii) (C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.3-12)cycIoaIkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-3)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-3)alkyl optionally
substituted with --R.sup.13, --X.sup.5OR.sup.13,
--X.sup.5SR.sup.13, --S(O)R.sup.13, --S(O).sub.2R.sup.13,
--C(O)R.sup.13, --C(O)OR.sup.13, --X.sup.5NR.sup.13R.sup.14,
--X.sup.5NR.sup.14C(O)OR.sup- .13, --C(O)NR.sup.13R.sup.14,
--S(O).sub.2NR.sup.13R.sup.14, --NR.sup.14C(O)NR.sup.13R.sup.14 or
--NR.sup.4C(NR.sup.14)NR.sup.13R.sup.- 14, wherein X.sup.5 is a
bond or methylene, R.sup.13 is
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-3)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-3)alkyl and R.sup.14 is
hydrogen or (C.sub.1-6)alkyl, or (iii) together with R.sup.5 when
X.sup.2 is --CHR.sup.9-- forms trimethylene, tetramethylene or
phenylene-1,2-dimethylene, optionally substituted with 1 to 2 of
hydroxy, oxo, (C.sub.1-4)alkyl or methylene; wherein any 1 to 3
annular atoms of any aromatic ring with available valences
comprising R.sup.9 are optionally independently substituted with
halo, nitro, cyano, (C.sub.1-6)alkyl,
halo-substituted(C.sub.1-6)alkyl, --OR.sup.15, --C(O)R.sup.15,
--C(O)OR.sup.15, --C(O)NR.sup.15R.sup.15,
--S(O).sub.2NR.sup.15R.sup.15, --X.sup.5NR.sup.15R.sup.15,
--X.sup.5NR.sup.15C(O)OR.sup.15,
--X.sup.5NR.sup.15C(O)NR.sup.15R.sup.15 or
--X.sup.5NR.sup.15C(NR.sup.15NR.sup.15R.sup.15, wherein X.sup.5 is
as defined above and each R.sup.15 independently is hydrogen or
(C.sub.1-6)alkyl, and
[0104] R.sup.10 is hydrogen or (C.sub.1-4)alkyl;
[0105] R.sup.5 and R.sup.7 are independently hydrogen,
(C.sub.1-6)alkyl or as defined above; and
[0106] R.sup.6 is --X.sup.6X.sup.7R.sup.16, wherein X.sup.6 is
--C(O)-- or --S(O).sub.2--, X.sup.7 is a bond, --O-- or
--NR.sup.17--, wherein R.sup.17 is hydrogen or (C.sub.1-6)alkyl,
and R.sup.16 is (i) (C.sub.1-6)alkyl or
halo-substituted(C.sub.1-6)alkyl optionally substituted with
--OR.sup.11, --SR.sup.11, --S(O)R.sup.11, --S(O).sub.2R.sup.11,
--C(O)R.sup.11, --C(O)OR.sup.11, --NR.sup.11R.sup.12,
--NR.sup.12C(O)OR.sup.11, --C(O)NR.sup.11R.sup.12,
--NR.sup.12C(O)NR.sup.11R.sup.12 or
--NR.sup.12C(NR.sup.12)NR.sup.11R.sup- .12, wherein R.sup.11 and
R.sup.12 are as defined above, or (ii)
(C.sub.3-6)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.- 0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl, hetero(C.sub.5-12)aryl(C.sub.-
0-3)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-3)alkyl optionally
substituted with 1 to 2 of --R.sup.13, --X.sup.5OR.sup.13,
--X.sup.5SR.sup.13, --S(O)R.sup.13, --S(O).sub.2R.sup.13,
--C(O)OR.sup.13, --X.sup.5NR.sup.13R.sup.14,
--X.sup.5NR.sup.14C(O)OR.sup.13, --C(O)NR.sup.13R.sup.14,
--NR.sup.14C(O)NR.sup.13R.sup.14 or
--NR.sup.14C(NR.sup.14)NR.sup.13R.sup.14, wherein X.sup.5, R.sup.13
and R.sup.14 are as defined above; wherein any 1 to 3 annular atoms
of any aromatic ring with available valences comprising R.sup.16
optionally independently are substituted with halo, nitro, cyano,
(C.sub.1-6)alkyl, halo-substituted(C.sub.1-6)alkyl, --OR.sup.15,
--C(O)R.sup.15, --C(O)OR.sup.15, --C(O)NR.sup.15R.sup.15,
--S(O).sub.2NR.sup.15R.sup.15, --X.sup.5NR.sup.15R.sup.15,
--X.sup.5NR.sup.15C(O)OR.sup.15,
X.sup.5NR.sup.15C(O)NR.sup.15R.sup.15 or
--X.sup.5NR.sup.15C(NR.sup.15)NR- .sup.15R.sup.15, wherein X.sup.5
and R.sup.15 are as defined above;
[0107] R.sup.2 is hydrogen or (C.sub.1-6)alkyl or as defined
below;
[0108] R.sup.3 is hydrogen, (C.sub.1-10)alkyl or as defined below;
and
[0109] R.sup.4 is (i) hydrogen, (ii) (C.sub.1-6)alkyl or
halo-substituted(C.sub.1-6)alkyl optionally substituted with
--OR.sup.11, --SR.sup.11, --S(O)R.sup.11, --S(O).sub.2R.sup.11,
--C(O)R.sup.11, --C(O)OR.sup.11, --NR.sup.11R.sup.12,
--NR.sup.12C(O)OR.sup.11, --C(O)NR.sup.11R.sup.12,
--NR.sup.12C(O)NR.sup.11R.sup.12 or
--NR.sup.12C(NR.sup.12)NR.sup.11R.sup.12, wherein R.sup.11 and
R.sup.12 are as defined above, or (iii)
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-3)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-3)alkyl optionally
substituted with --R.sup.13, --X.sup.5OR.sup.13,
--X.sup.5SR.sup.13, --S(O)R.sup.13, --S(O).sub.2R.sup.13,
--C(O)OR.sup.13, --X.sup.5NR.sup.13R.sup.14,
--X.sup.5NR.sup.14C(O)OR.sup- .13, --C(O)NR.sup.13R.sup.14,
--NR.sup.14C(O)NR.sup.13R.sup.14 or
--NR.sup.14C(NR.sup.14)NR.sup.13R.sup.14, wherein X.sup.5, R.sup.13
and R.sup.14 are as defined above or (iv) together with R.sup.2
forms trimethylene, tetramethylene or phenylene-1,2-dimethylene,
optionally substituted with hydroxy, oxo, (C.sub.1-4)alkyl or
methylene or (v) together with R.sup.3 forms ethylene, trimethylene
or tetramethylene; wherein any 1 to 3 annular atoms of any aromatic
ring with available valences comprising R.sup.4 optionally
independently are substituted with halo, nitro, cyano,
C.sub.1-6)alkyl, halo-substituted(C.sub.1-6)alkyl, --OR.sup.15,
--C(O)R.sup.15, --C(O)OR.sup.15, --C(O)NR.sup.15R.sup.15,
--S(O).sub.2NR.sup.15R.sup.15, --X.sup.5NR.sup.15R.sup.15,
--X.sup.5NR.sup.15C(O)OR.sup.15,
--X.sup.5NR.sup.15C(O)NR.sup.15R.sup.15 or
--X.sup.5NR.sup.15C(NR.sup.15)NR.sup.15R.sup.15, wherein X.sup.5
and R.sup.15 are as defined above; or an N-oxide derivative,
prodrug derivative, individual isomer and mixtures of isomers; or a
pharmaceutically acceptable salt thereof, but excluding compounds
of the formula 17
[0110] in which R.sup.3 and R.sup.4 are each hydrogen or
(C.sub.1-6)alkyl, or together with the carbon atom to which they
are both attached form (C.sub.3-8)cycloalkylene; R.sup.5 is
hydrogen or (C.sub.1-6)alkyl; R.sup.9 is
(C.sub.6-12)aryl(C.sub.1-6)alkyl, hetero(C.sub.5-12)aryl(C.sub-
.1-6)alkyl, (C.sub.4-5)alkyl or cyclohexylmethyl; and R.sup.11 is
C(O)R.sup.18 wherein R.sup.18 is hetero(C.sub.3-12)cycloalkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alky- l, in the manufacture of a
medicament for treating a disease in an animal in which cathepsin S
activity contributes to the pathology and/or symptomatology of the
disease.
DETAILED DESCRIPTION OF THE INVENTION
[0111] Definitions
[0112] Unless otherwise stated, the following terms used in the
specification and claims are defined for the purposes of this
Application and have the meanings given this Section:
[0113] "Alicyclic" means a moiety characterized by arrangement of
the carbon atoms in closed non-aromatic ring structures having
properties resembling those of aliphatics and may be saturated or
partially unsaturated with two or more double or triple bonds.
[0114] "Aliphatic" means a moiety characterized by straight or
branched chain arrangement of the constituent carbon atoms and may
be saturated or partially unsaturated with two or more double or
triple bonds.
[0115] "Alkyl" indicated alone means a straight or branched,
saturated or unsaturated aliphatic radical having the number of
carbon atoms indicated (e.g., (C.sub.1-6)alkyl includes methyl,
ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,
vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl,
3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the
like). Alkyl indicated as part of a larger radical (e.g., as in
arylalkyl) means a straight or branched, saturated or unsaturated
aliphatic divalent radical having the number of atoms indicated or
when 0 atoms are indicated means a bond (e.g., (C.sub.0-3)alkyl of
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl means a bond, methylene,
ethylene, trimethylene, 1-methylethylene, or the like).
[0116] "Alkylene", unless indicated otherwise, means a straight or
branched, saturated or unsaturated, aliphatic, divalent radical
having the number of carbon atoms indicated (e.g.
(C.sub.1-6)alkylene includes methylene (--CH.sub.2--), ethylene
(--CH.sub.2CH.sub.2--), trimethylene
(--CH.sub.2CH.sub.2CH.sub.2--), 2-methyltrimethylene
(--CH.sub.2CH(CH.sub.3)CH.sub.2--), tetramethylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), 2-butenylene
(--CH.sub.2CH.dbd.CHCH.sub.2--), 2-methyltetramethylene
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.2--), pentamethylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) and the like). For
example, the instance wherein R.sup.5 is hydrogen and R.sup.9 taken
together with R.sup.7 formns optionally substituted trimethylene is
illustrated by the following: 18
[0117] in which R is an optional hydroxy or oxo group and X.sup.1
and R.sup.11 are as defined in the Summary of the Invention.
[0118] "Alkylidene" means a straight or branched saturated or
unsaturated, aliphatic, divalent radical having the number of
carbon atoms indicated (e.g. (C.sub.1-6)alkylidene includes
methylene (CH.sub.2), ethylidene (CHCH.sub.3), isopropylidene
(C(CH.sub.3).sub.2), propylidene (CHCH.sub.2CH.sub.3), allylidene
(CHCHCH.sub.2), and the like).
[0119] "Amino" means the radical --NH.sub.2. Unless indicated
otherwise, the compounds of the invention containing amino moieties
include protected derivatives thereof. Suitable protecting groups
for amino moieties include acetyl, tert-butoxycarbonyl,
benzyloxycarbonyl, and the like.
[0120] "Animal" includes humans, non-human mammals (e.g., dogs,
cats, rabbits, cattle, horses, sheep, goats, swine, deer, etc.) and
non-mammals (e.g., birds, etc.).
[0121] "Aryl" means a monocyclic or bicyclic ring assembly (fused
or linked by a single bond) containing the total number of ring
carbon atoms indicated, wherein each ring is comprised of 6 ring
carbon atoms and is aromatic or when fused with a second ring forms
an aromatic ring assembly. For example, (C.sub.6-12)aryl includes
phenyl, naphthyl and biphenylyl.
[0122] "Aromatic" means a moiety wherein the constituent atoms make
up an unsaturated ring system, all atoms in the ring system are sp2
hybridized and the total number of pi electrons is equal to
4n+2.
[0123] "Carbamoyl" means the radical --C(O)NH.sub.2. Unless
indicated otherwise, the compounds of the invention containing
carbamoyl moieties include protected derivatives thereof. Suitable
protecting groups for carbamoyl moieties include acetyl,
lert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the
unprotected and protected derivatives fall within the scope of the
invention.
[0124] "Carboxy" means the radical --C(O)OH. Unless indicated
otherwise, the compounds of the invention containing carboxy
moieties include protected derivatives thereof. Suitable protecting
groups for carboxy moieties include benzyl, tert-butyl, and the
like.
[0125] "Cycloalkyl" means a saturated or partially unsaturated,
monocyclic ring, bicyclic ring assembly (directly linked by a
single bond or fused) or bridged polycyclic ring assembly
containing the number of annular carbon atoms indicated, and any
carbocyclic ketone, thioketone or ininoketone derivative thereof
(e.g., (C.sub.3-12)cycloalkyl includes cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl,
bicyclohexylyl, cyclopentylcyclohexyl, bicyclo[2.2.2]octyl,
adamantan-1-yl, decahydronaphthalenyl, oxocyclohexyl,
dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1- -yl,
etc.).
[0126] "Cycloalkylene" means a saturated or partially unsaturated,
monocyclic ring or bridged polycyclic ring assembly containing the
number of annular carbon atoms indicated, and any carbocyclic
ketone, thioketone or iminoketone derivative thereof. For example,
the instance wherein R.sup.9 and R.sup.5 together with the carbon
atom to which both R.sup.9 and R.sup.5 are attached form
(C.sub.3-8)cycloalkylene" includes, but is not limited to, the
following: 19
[0127] in which X.sup.1 and R.sup.7 are as defined in the Summary
of the Invention.
[0128] "Disease" specifically includes any unhealthy condition of
an animal or part thereof and includes an unhealthy condition which
may be caused by, or incident to, medical or veterinary therapy
applied to that animal, i.e., the "side effects" of such
therapy.
[0129] "Guanidino" means the radical --NHC(NH)NH.sub.2. Unless
indicated otherwise, the compounds of the invention containing
guanidino moieties include protected derivatives thereof. Suitable
protecting groups for amino moieties include acetyl,
terl-butoxycarbonyl, benzyloxycarbonyl, and the like.
[0130] "Halo" means fluoro, chloro, bromo or iodo.
[0131] "Halo-substituted alkyl", as a group or part of a group,
means "alkyl" substituted by one or more "halo" atoms, as such
terms are defined in this Application. Halo-substituted alkyl
includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the
like (e.g. halo-substituted (C.sub.1-3)alkyl includes chloromethyl,
dicloromethyl, difluoromethyl, trifluromethyl,
2,2,2-trifluoroethyl, perfluoroethyl,
2,2,2-trifluoro-1,1-dichloroethyl, and the like).
[0132] "Heteroaryl" means aryl, as defined in this Application,
provided that one or more of the ring member carbon atoms
indicated, is replaced by heteroatom moiety selected from --N,
--NR--, --O-- or --S--, wherein R is hydrogen, (C.sub.1-6)alkyl or
a protecting group, and each ring contained therein is comprised of
5 to 6 ring member atoms. For example, hetero(C.sub.5-12)aryl as
used in this Application includes benzofuryl, benzooxazolyl,
benzothiazolyl, [2,4']bipyridinylyl, carbazolyl, carbolinyl,
chromenyl, cinnolinyl, furazanyl, furyl, imidazolyl, indazolyl,
indolyl, indolizinyl, isobenzofuryl, isochromenyl, isooxazolyl,
isoquinolyl, isothiazolyl, naphthyridinyl, oxazolyl, perimidinyl,
2-phenylpyridyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl,
pyradazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolizinyl,
pyrrolidinyl, pyrrolyl, pyranyl, quinazolinyl, quinolizinyl,
quinolyl, quinoxalinyl, tetrazolyl, thiazolyl,
4-thiazol-4-ylphenyl, thienyl, xanthenyl, and the like. Suitable
protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl,
benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like.
[0133] "Heterocycloalkyl" means cycloalkyl, as defined herein,
provided that one or more of the ring member carbon atoms indicated
is replaced by heteroatom moiety selected from --N, --NR--, --O--,
--S-- or --S(O).sub.2, wherein R is hydrogen, (C.sub.1-6)alkyl or a
protecting group, and any carbocyclic ketone, thioketone or
iminoketone derivative thereof (e.g. the term
hetero(C.sub.5-12)cycloalkyl includes [1,4']bipiperidinylyl,
dihydrooxazolyl, morpholinyl, 1-morpholin-4-ylpiperidinyl,
piperazinyl, piperidyl, pirazolidinyl, pirazolinyl, pyrrolinyl,
pyrrolidinyl, quinuclidinyl, and the like). Suitable protecting
groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl,
4-methoxybenzyl, 2-nitrobenzyl, and the like. For example, a
compound of Formula I wherein R.sup.1 is piperidin-4-ylcarbonyl may
exist as either the unprotected or a protected derivative, e.g.
wherein R.sup.1 is 1-tert-butoxycarbonylpiperidin-4-ylca- rbonyl,
and both the unprotected and protected derivatives fall within the
scope of the invention.
[0134] "Heterocycloalkylene" means cycloalkylene, as defined in
this Application, provided that one or more of the ring member
carbon atoms indicated, is replaced by heteroatom moiety selected
from --N--, --NR--, --O--, --S-- or --S(O).sub.2--, wherein R is
hydrogen or (C.sub.1-6)alkyl. For example, the instance wherein
R.sup.3 and R.sup.4 together with the carbon atom to which both
R.sup.3 and R.sup.4 are attached form
hetero(C.sub.3-8)cycloalkylene" includes, but is not limited to,
the following: 20
[0135] in which R is hydrogen, C.sub.1-6)alkyl or a protecting
group and R.sup.2 is as defined in the Summary of the
Invention.
[0136] "Heteropolycycloaryl" means polycycloaryl, as defined
herein, except one or more of the annular carbon atoms indicated
are replaced by a heteroatom moiety selected from --N, --NR--,
--O--, --S-- or --S(O).sub.2--, wherein R is hydrogen,
(C.sub.1-6)alkyl or a protecting group, and any carbocyclic ketone,
thioketone or iminoketone derivative thereof (e g.,
hetero(C.sub.8-12)polycycloaryl includes 3,4-dihydro-2H-quinolinyl,
5,6,7,8-tetrahydroquinolinyl, 3,4-dihydro-2H-[1,8]naphthyridinyl,
morpholinylpyridyl, piperidinylphenyl,
1,2,3,4,5,6-hexahydro-[2,2']bipyridinylyl,
2,4-dioxo-3,4-dihydro-2H-quinazolinyl,
3-oxo-2,3-dihydrobenzo[1,4]oxaziny- l, etc.).
[0137] "Heteroatom moiety" includes --N, --NR--, --O--, --S-- or
--S(O).sub.2--, wherein R is hydrogen, (C.sub.1-6)alkyl or a
protecting group.
[0138] "Hydroxy" means the radical --OH. Unless indicated
otherwise, the compounds of the invention containing hydroxy
radicals include protected derivatives thereof. Suitable protecting
groups for hydroxy moieties include benzyl and the like. For
example, a compound of Formula I wherein the R.sup.9 contains a
hydroxy moiety exist as either the unprotected or a protected
derivative, e.g., wherein R.sup.9 is benzyloxybenzyl, and both the
unprotected and protected derivatives fall within the scope of the
invention.
[0139] "Iminoketone derivative" means a derivative containing the
moiety --C(NR)--, wherein R is hydrogen or (C.sub.1-6)alkyl.
[0140] "Isomers" mean compounds of Formula I having identical
molecular formulae but differ in the nature or sequence of bonding
of their atoms or in the arrangement of their atoms in space.
Isomers that differ in the arrangement of their atoms in space are
termed "stereo isomers". Stereo isomers that are not mirror images
of one another are termed "diastereomers" and stereo isomers that
are nonsuperimposable mirror images are termed "enantiomers" or
sometimes "optical isomers". A carbon atom bonded to four
nonidentical substituents is termed a "chiral center". A compound
with one chiral center has two enantiomeric forms of opposite
chirality is termed a "racemic mixture". A compound that has more
than one chiral center has 2.sup.n-1 enantiomeric pairs, where n is
the number of chiral centers. Compounds with more than one chiral
center may exist as ether an individual diastereomer or as a
mixture of diastereomers, termed a "diastereomeric mixture". When
one chiral center is present a stereoisomer may be characterized by
the absolute configuration of that chiral center. Absolute
configuration refers to the arrangement in space of the
substituents attached to the chiral center. Enantiomers are
characterized by the absolute configuration of their chiral centers
and described by the R- and S-sequencing rules of Cahn, Ingold and
Prelog. Conventions for stereochemical nomenclature, methods for
the determination of stereochemustry and the separation of stereo
isomers are well known in the art (e.g., see "Advanced Organic
Chemistry", 3rd edition, March, Jerry, John Wiley & Sons, New
York, 1985). It is understood that the names and illustration used
in this Application to describe compounds of Formula I are meant to
be encompassed all possible stereo isomers. Thus, for example, the
name 1-(1-cyano-1-methylethylcarbamoyl)-3-methylbutylcarbamate is
meant to include
1S-(1-cyano-1-methylethylcarbamoyl)-3-methylbutylcarbamate and
1R-(1-cyano-1-methylethylcarbamoyl)-3-methylbutylcarbamate and any
mixture, racemic or otherwise, thereof.
[0141] "Ketone derivative" means a derivative containing the moiety
--C(O)--.
[0142] "Methylene" means the divalent radical --CH.sub.2-- or
CH.sub.2, wherein its free valances can be attached to different
atoms or the same atom. For example, the instance wherein R.sup.9
together with R.sup.7 forms trimethylene substituted methylene
includes the following: 21
[0143] in which X.sup.1 and R.sup.11 are as defined in the Summary
of the invention, and may be referred to as 2,2-methylene and
1,2-methylene, respectively.
[0144] "Nitro" means the radical --NO.sub.2.
[0145] "Optional" or "optionally" means that the subsequently
described event or circumstance may or may not occur, and that the
description includes instances where the event or circumstance
occurs and instances in which it does not. For example, the phrase
"any 1 to 3 annular atoms of any aromatic ring with available
valences comprising R.sup.6 optionally independently is
substituted" means that the aromatic ring referred to may or may
not be substituted in order to fall within the scope of the
invention.
[0146] "N-oxide derivatives" means a derivatives of compound of
Formula I in which nitrogens are in an oxidized state (i.e.,
O.rarw.N) and which possess the desired pharmacological
activity.
[0147] "Oxo" means the radical O.
[0148] "Pathology" of a disease means the essential nature, causes
and development of the disease as well as the structural and
functional changes that result from the disease processes.
[0149] "Pharmaceutically acceptable" means that which is useful in
preparing a pharmaceutical composition that is generally safe,
non-toxic and neither biologically nor otherwise undesirable and
includes that which is acceptable for veterinary use as well as
human pharmaceutical use.
[0150] "Pharmaceutically acceptable salts" means salts of compounds
of Formula I which are pharmaceutically acceptable, as defined
above, and which possess the desired pharmacological activity. Such
salts include acid addition salts formed with inorganic acids such
as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; or with organic acids such as acetic
acid, propionic acid, hexanoic acid, heptanoic acid,
cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic
acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric
acid, tartatic acid, citric acid, benzoic acid,
o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
p-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2.2.2]oct-2- -ene-1-carboxylic acid, glucoheptonic
acid, 4,4'-methylenebis(3-hydroxy-2-- ene-1-carboxylic acid),
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid
and the like.
[0151] Pharmaceutically acceptable salts also include base addition
salts which may be formed when acidic protons present are capable
of reacting with inorganic or organic bases. Acceptable inorganic
bases include sodium hydroxide, sodium carbonate, potassium
hydroxide, ammonium hydroxide, aluminum hydroxide and calcium
hydroxide. Acceptable organic bases include ethanolamine,
diethanolamine, triethanolamine, tromethamine, N-methylglucamine
and the like. p1 "Phenylene-1,2-dimethyle- ne" means the divalent
radical --CH.sub.2C.sub.6H.sub.4CH.sub.2--, wherein the methylene
moieties are attached at the 1- and 2-positions of the phenylene
moiety. For example, a group of Formula (a), wherein R.sup.9
together with R.sup.7 form optionally substituted
phenylene-1,2-dimethyle- ne is illustrated by the following
formula: 22
[0152] in which R is an optional hydroxy or (C.sub.1-4)alkyl group
and X.sup.1 and R.sup.11 are as defined in the Summary of the
Invention.
[0153] "Polycycloaryl" means a bicyclic ring assembly (directly
linked by a single bond or fused) containing the number of ring
member carbon atoms indicated, wherein at least one, but not all,
of the fused rings comprising the radical is aromatic, and any
carbocyclic ketone, thioketone or iminoketone derivative thereof
(e.g., (C.sub.9-12)polycycloaryl includes indanyl, indenyl,
1,2,3,4-tetrahydronaphthalenyl, 1,2-dihydronaphthalenyl,
cyclohexylphenyl, phenylcyclohexyl,
2,4-dioxo-1,2,3,4-tetrahydronaphthale- nyl, and the like).
[0154] "Prodrug" means a compound which is convertible in vivo by
metabolic means (e.g. by hydrolysis) to a compound of Formula (I).
For example an ester of a compound of Formula (I) containing a
hydroxy group may be convertible by hydrolysis in vivo to the
parent molecule. Alternatively an ester of a compound of Formula
(I) containing a carboxy group may be convertible by hydrolysis in
vivo to the parent molecule. Suitable esters of compounds of
Formula (I) containing a hydroxy group, are for example acetates,
citrates, lactates, tartrates, malonates, oxalates, salicylates,
propionates, succinates, fumarates, maleates,
methylene-bis-b-hydroxynaphthoates, gentisates, isethionates,
di-p-toluoyltartrates, methanesulphonates, ethanesulphonates,
benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and
quinates. Suitable esters of compounds of Formula (I) containing a
carboxy group, are for example those described by F. J. Leinweber,
Drug Metab. Res., 1987, 18, page 379. An especially useful class of
esters of compounds of Formula (I) containing a hydroxy group, may
be formed from acid moieties selected from those described by
Bundgaard et. al., J. Med. Chem., 1989, 32 , page 2503-2507, and
include substituted (aminomethyl)-benzoates, for example,
dialkylamino-methylbenzoates in which the two alkyl groups may be
joined together and/or interrupted by an oxygen atom or by an
optionally substituted nitrogen atom, e.g. an alkylated nitrogen
atom, more especially (morpholino-methyl)benzoates, e.g. 3- or
4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)ben-
zoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.
[0155] "Protected derivatives" means derivatives of compounds of
Formula I in which a reactive site or sites are blocked with
protecting groups. Protected derivatives of compounds of Formula I
are useful in the preparation of compounds of Formula I or in
themselves may be active cysteine protease inhibitors. A
comprehensive list of suitable protecting groups can be found in T.
W. Greene, Protecting Groups in Organic Synthesis, John Wiley &
Sons, Inc. 1981.
[0156] "Therapeutically effective amount" means that amount which,
when administered to an animal for treating a disease, is
sufficient to effect such treatment for the disease.
[0157] "Thioketone derivative" means a derivative containing the
moiety --C(S)--.
[0158] "Treatment" or "treating" means any administration of a
compound of the present invention and includes:
[0159] (1) preventing the disease from occurring in an animal which
may be predisposed to the disease but does not yet experience or
display the pathology or symptomatology of the disease,
[0160] (2) inhibiting the disease in an animal that is experiencing
or displaying the pathology or symptomatology of the diseased
(i.e., arresting further development of the pathology and/or
symptomatology), or
[0161] (3) ameliorating the disease in an animal that is
experiencing or displaying the pathology or symptomatology of the
diseased (i.e., reversing the pathology and/or symptomatology).
[0162] "Ureido" means the radical --NHC(O)NH.sub.2. Unless
indicated otherwise, the compounds of the invention containing
ureido moieties include protected derivatives thereof. Suitable
protecting groups for ureido moieties include acetyl,
tert-butoxycarbonyl, benzyloxycarbonyl, and the like. For example,
a compound of Formula I wherein the R.sup.9 contains an ureido
moiety may exist as either the unprotected or a protected
derivative and the like, and both the unprotected and protected
derivatives fall within the scope of the invention.
[0163] Presently Preferred Embodiments
[0164] While the broadest definition of the invention is set forth
in the Summary of the Invention, certain aspects of the invention
are preferred. Preferred are compounds of Formula I in which:
[0165] R.sup.1 represents a group of Formula (a) wherein within
Formula (a):
[0166] X.sup.1 is --C(O)--;
[0167] R.sup.5 represents hydrogen or (C.sub.1-6)alkyl, preferably
hydrogen;
[0168] R.sup.7 represents hydrogen or methyl, preferably
hydrogen,
[0169] R.sup.9 represents (i) (C.sub.1-6)alkyl optionally
substituted with --OR.sup.14, --SR.sup.14, --S(O)R.sup.14,
--S(O).sub.2R.sup.14, --C(O)R.sup.14, --C(O)OR.sup.14,
--OC(O)R.sup.14, --NR.sup.14R.sup.15, --NR.sup.15C(O)R.sup.14,
--NR.sup.15C(O)OR.sup.14, --C(O)NR.sup.14R.sup.15,
--S(O).sub.2NR.sup.14R.sup.15, --NR.sup.15C(O)NR.sup.14R.sup.15 or
--NR.sup.15C(NR.sup.15)NR.sup.14R.sup- .15, wherein R.sup.14 is
(C.sub.3-10)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-10)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-10)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-10)aryl(C.sub.0-6)alkyl,
(C.sub.9-10)polycycloaryl(C- .sub.0-6)alkyl or
hetero(C.sub.8-10)polycycloaryl(C.sub.0-6)alkyl and R.sup.15 is
hydrogen or (C.sub.1-6)alkyl, and wherein within R.sup.14 said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.3OR.sup.16, --X.sup.3SR.sup.16,
--X.sup.3S(O)R.sup.16, --X.sup.3S(O).sub.2R.sup.16,
--X.sup.3C(O)R.sup.16, --X.sup.3C(O)OR.sup.16,
--X.sup.3OC(O)R.sup.16, --X.sup.3NR.sup.16R.sup.17,
--X.sup.3NR.sup.17C(O)R.sup.16, --X.sup.3NR.sup.17C(O)OR.sup.16,
--X.sup.3C(O)NR.sup.16R.sup.17,
--X.sup.3S(O).sub.2NR.sup.16R.sup.17,
--X.sup.3NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.3NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.3 is
a bond or (C.sub.1-6)alkylene, R.sup.16 is hydrogen or
(C.sub.1-6)alkyl and R.sup.17 is
(C.sub.3-10)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-10)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-10)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-10)aryl(C.sub.0-6)alkyl,
(C.sub.9-10)polycycloaryl(C- .sub.0-6)alkyl or
hetero(C.sub.8-10)polycycloaryl(C.sub.0-6)alkyl, or (ii) a group
selected from (C.sub.3-10)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-10)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-0)aryl(C.sub.0-6)a- lkyl,
hetero(C.sub.5-10)aryl(C.sub.0-6)alkyl,
(C.sub.9-10)polycycloaryl(C.- sub.0-6)alkyl and
hetero(C.sub.8-10)polycycloaryl(C.sub.0-6)alkyl, wherein said
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.16, --X.sup.3OR.sup.16, --X.sup.3SR.sup.16,
--X.sup.3S(O)R.sup.16, --X.sup.3S(O).sub.2R.sup.16,
--X.sup.3C(O)R.sup.16, --X.sup.3C(O)OR.sup.16,
--X.sup.3OC(O)R.sup.16, --X.sup.3NR.sup.16R.sup.17,
--X.sup.3NR.sup.17C(O)R.sup.16, --X.sup.3NR.sup.17C(O)OR.sup.16,
--X.sup.3C(O)NR.sup.16R.sup.17,
--X.sup.3S(O).sub.2NR.sup.16R.sup.17,
--X.sup.3NR.sup.17C(O)NR.sup.16R.su- p.17 or
--X.sup.3NR.sup.17C(NR.sup.17)NR.sup.16R.sup.17, wherein X.sup.3,
R.sup.16 and R.sup.17 are as defined above; wherein within R.sup.9
any alicyclic or aromatic ring system present may be substituted
further by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.3NR.sup.12R.sup.12, --X.sup.3NR.sup.12C(O)OR.sup.12,
--X.sup.3NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.3NR.sup.12C(NR.sup.12)NR- .sup.12R.sup.12,
--X.sup.3OR.sup.12, --X.sup.3SR.sup.12, --X.sup.3C(O)OR.sup.12,
--X.sup.3C(O)NR.sup.12R.sup.12,
--X.sup.3S(O).sub.2NR.sup.12R.sup.12,
--X.sup.3P(O)(OR.sup.3)OR.sup.12,
--X.sup.3OP(O)(OR.sup.3)OR.sup.12, --X.sup.3OC(O)R.sup.13,
--X.sup.3NR.sup.12C(O)R.sup.13, --X.sup.3S(O)R.sup.13,
--X.sup.3S(O).sub.2R.sup.13 and --X.sup.3C(O)R.sup.13, wherein
X.sup.3 is as defined above, R.sup.12 at each occurrence
independently is hydrogen, (C.sub.1-6)alkyl or halo-substituted
(C.sub.1-3)alkyl and R.sup.13 is (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl; and
[0170] R.sup.11 represents --X.sup.4X.sup.5R.sup.18, wherein
X.sup.4 is --C(O)-- or --S(O).sub.2--, X.sup.5 is a bond, --O-- or
--NR.sup.19--, wherein R.sup.19 is hydrogen or (C.sub.1-6)alkyl,
and R.sup.18 is (i) (C.sub.1-10)alkyl or (ii)
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl or (iii)
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.- 0-6)alkyl,
phenyl(C.sub.0-6)alkyl or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl- ,
wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is
substituted by --X.sup.9OR.sup.24, --X.sup.9C(O)R.sup.24,
--X.sup.9C(O)OR.sup.24, --X.sup.9C(O)NR.sup.24R.sup.25,
--X.sup.9NR.sup.24R.sup.25, X.sup.9NR.sup.25C(O)R.sup.24,
--X.sup.9NR.sup.25C(O)OR.sup.24,
--X.sup.9NR.sup.25C(O)NR.sup.24R.sup.25 or
--X.sup.9NR.sup.25C(NR.sup.25)NR.sup.24R.sup.25, wherein X.sup.9 is
a bond or (C.sub.1-6)alkylene, R.sup.24 is
(C.sub.3-6)cycloalkyl(C.sub.0-6)- alkyl,
hetero(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl and R.sup.25 is hydrogen
or (C.sub.1-6)alkyl, wherein within R.sup.11 any alicyclic or
aromatic ring system present may be substituted further by 1 to 5
substituents independently selected from (C.sub.1-6)alkyl, halo,
halo-substituted (C.sub.1-4)alkyl, --OR.sup.12, --X.sup.3SR.sup.12,
--C(O)OR.sup.12 and --X.sup.3NR.sup.12C(O)OR.sup.12, wherein
X.sup.3 is a bond or (C.sub.1-6)alkylene and R.sup.14 is hydrogen
or (C.sub.1-6)alkyl.
[0171] Within Formula (a), R.sup.11 particularly represents
--X.sup.4X.sup.5R.sup.18, wherein X.sup.4 is --C(O)--, X.sup.5 is a
bond and R.sup.18 is (i) (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl or (ii)
phenyl(C.sub.0-6)alkyl or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl,
wherein said phenyl or heteroaryl is substituted by
--X.sup.9OR.sup.24,--X.sup.9C- (O)R.sup.24, --X.sup.9C(O)OR.sup.24,
--X.sup.9C(O)NR.sup.24R.sup.25, --X.sup.9NR.sup.24R.sup.25,
--X.sup.9NR.sup.25C(O)R.sup.24, --X.sup.9NR.sup.25C(O)OR.sup.24,
--X.sup.9NR.sup.25C(O)NR.sup.24R.sup.25 or
--X.sup.9NR.sup.25C(NR.sup.25)NR.sup.24R.sup.25,wherein X.sup.9 is
a bond or (C.sub.1-6)alkylene, R.sup.24 is phenyl(C.sub.0-6)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl and R.sup.25 is hydrogen
or (C.sub.1-6)alkyl, wherein within R.sup.11 any aromatic ring
system present may be substituted further by 1 to 5 substituents
independently selected from (C.sub.1-6)alkyl, halo,
halo-substituted (C.sub.1-4)alkyl, --OR.sup.12, --X.sup.3SR.sup.12,
--C(O)OR.sup.12 and --X.sup.3NR.sup.12C(O)OR.sup.12 wherein X.sup.3
is a bond or (C.sub.1-6)alkylene and R.sup.12 is hydrogen or
(C.sub.1-6)alkyl.
[0172] Within Formula (a), R.sup.11 more particularly represents
benzoyl, furylcarbonyl, phenyloxybenzoyl, pyridylthienylcarbonyl,
benzoylbenzoyl, thienylcarbonyl, morpholinylcarbonyl,
phenyluriedobenzoyl, cyclohexenylcarbonyl or piperazinylcarbonyl,
wherein within R.sup.11 any aromatic ring system present may be
substituted further by 1 to 2 substituents independently selected
from (C.sub.1-6)alkyl, tert-butoxycarbonylamino,
tert-butoxycarbonylaminomethyl, bromo, chloro, ethoxy, fluoro,
hydroxy, methoxy and methylsulfanyl.
[0173] Within Formula (a), R.sup.9 particularly represents (i)
(C.sub.1-6)alkyl optionally substituted with --OR.sup.14 or
--SR.sup.14, wherein R.sup.14 is
(C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl,
biphenylyl(C.sub.0-6)alkyl or
hetero(C.sub.5-6)aryl(C.sub.0-6)alkyl, or (ii) a group selected
from (C.sub.3-6)cycloalkyl(C.sub.0-6)alkyl, phenyl(C.sub.0-6)alkyl,
biphenylyl(C.sub.0-6)alkyl or
hetero(C.sub.5-10)aryl(C.sub.0-6)alkyl; wherein within R.sup.9 any
alicyclic or aromatic ring system present may be substituted
further by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.3NR.sup.12R.sup.12, --X.sup.3NR.sup.12C(O)OR.sup.12,
--X.sup.3NR.sup.12C(O)NR.sup.12R.sup.12,
--X.sup.3NR.sup.12C(NR.sup.12)NR.sup.12R.sup.12,
--X.sup.3OR.sup.12, --X.sup.3SR.sup.12, --X.sup.3C(O)OR.sup.12,
--X.sup.3C(O)NR.sup.12R.sup.1- 2,
--X.sup.3S(O).sub.2NR.sup.12R.sup.12,
X.sup.3P(O)(OR.sup.3)OR.sup.12, --X.sup.3OP(O)(OR.sup.3)OR.sup.12,
--X.sup.3OC(O)R.sup.13, --X.sup.3OC(O)R.sup.13,
--X.sup.3NR.sup.12C(O)R.sup.13, --X.sup.3S(O)R.sup.13,
--X.sup.3S(O).sub.2R.sup.13 and --X.sup.3C(O)R.sup.13, wherein
X.sup.3 is a bond or (C.sub.1-6)alkylene, R.sup.12 at each
occurrence independently is hydrogen, (C.sub.1-3)alkyl or
halo-substituted (C.sub.1-3)alkyl and R.sup.13 is (C.sub.1-3)alkyl
or halo-substituted (C.sub.1-3)alkyl.
[0174] Within Formula (a), R.sup.9 more particularly represents
cyclohexylmethyl, wherein said cyclohexyl may be substituted by 1
to 5 radicals independently selected from (C.sub.1-4)alkyl,
(C.sub.1-6)alkylidene or --X.sup.3OC(O)R.sup.13, or
phenylmethylsulfanylmethyl or phenylsulfanylethyl, wherein said
phenyl may be substituted by 1 to 5 radicals independently selected
from (C.sub.1-4)alkyl, cyano, halo, halo-substituted
(C.sub.1-4)alkyl, nitro, --OR.sup.12, --SR.sup.12 and
--C(O)OR.sup.12, wherein R.sup.12 is hydrogen, (C.sub.1-3)alkyl or
halo-substituted (C.sub.1-3)alkyl and R.sup.13 is (C.sub.1-6)alkyl
or halo-substituted (C.sub.1-3)alkyl.
[0175] Within Formula (a), R.sup.9 more particularly presents a
group having the following formula: 23
[0176] in which q is 0 to 5 and R.sup.26 at each occurrence is
independently selected from (C.sub.1-4)alkyl, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro, --OR.sup.12, --SR.sup.12
and --C(O)OR.sup.12, wherein R.sup.12 is hydrogen, (C.sub.1-3)alkyl
or halo-substituted (C.sub.1-3)alkyl and R.sup.13 is
(C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl.
[0177] Within Formula (a), R.sup.9 preferably represents
benzylsulfanylmethyl, 2-bromobenzylsulfanylmethyl,
2-chlorobenzylsulfanyl, 2-(2-chlorophenylsulfanyl)ethyl,
cyclohexyl, 4-ethylidenecyclohexyl, 2-iodobenzylsulfanylmethyl,
2-methylbenzylsulfanylmethyl,
3-methyl-3-trifluorocarbonyloxycyclohexylme- thyl,
4-methylenecyclohexylmethyl or 2-nitrobenzylsulfanylmethyl.
[0178] R.sup.2 preferably represents hydrogen;
[0179] R.sup.3 preferably is hydrogen or (C.sub.1-4)alkyl,
typically hydrogen, or taken with R.sup.4 together with the carbon
atom to which both R.sup.3 and R.sup.4 are attached form
(C.sub.3-8)cycloalkylcne (e.g. cyclopropylene or
cyclohexylene).
[0180] R.sup.4 preferably is hydrogen or taken with R.sup.3
together with the carbon atom to which both R.sup.3 and R.sup.4 are
attached form (C.sub.3-8)cycloalkylene (e.g. cyclopropylene or
cyclohexylene).
[0181] Compounds of Formula II specifically include those in which
R.sup.9 represents (C.sub.6-12)aryl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)aryl(C.sub- .0-6)alkyl, --X.sup.4OR.sup.14,
--X.sup.4SR.sup.14, --X.sup.4S(O)R.sup.14 or
--X.sup.4NR.sup.14R.sup.15, wherein X.sup.4 is a bond or
(C.sub.1-6)alkylene, R.sup.14 is (C.sub.6-12)aryl(C.sub.0-6)alkyl
or hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl and R.sup.15 is hydrogen
or (C.sub.1-6)alkyl, and wherein within R.sup.9 said aryl or
heteroaryl ring optionally is substituted by 1 to 5 radicals
independently selected from (C.sub.1-6)alkyl, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.12R.sup.12, --X.sup.4OR.sup.12,
--X.sup.4C(O)R.sup.12, --X.sup.4SR.sup.12, wherein X.sup.4 is a
bond or (C.sub.1-6)alkylene, R.sup.12 at each occurrence
independently is hydrogen, (C.sub.1-6)alkyl or halo-substituted
(C.sub.1-3)alkyl, and R.sup.13 is (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl.
[0182] Compounds of Formula II particularly include those in which
R.sup.9 represents benzyl, benzyloxymethyl, benzylsulfanylethyl,
benzylsulfanylmethyl, benzylsulfinylmethyl, indolylmethyl,
naphthylmethyl, phenethyl, phenoxyethyl, phenylamino,
pyridylmethyl, pyridylsulfanylethyl, phenylsulfanylethyl, thiazolyl
or thienyl, wherein within R.sup.9 the aromatic ring may be
substituted further by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, cyano, halo, halo-substituted (C.sub.1-4)alkyl,
nitro, --X.sup.4NR.sup.12R.sup.12, --X.sup.4OR.sup.12,
--X.sup.4C(O)R.sup.12, --X.sup.4SR.sup.12, wherein X.sup.4 is a
bond or (C.sub.1-6)alkylene, R.sup.12 at each occurrence
independently is hydrogen, (C.sub.1-6)alkyl or halo-substituted
(C.sub.1-3)alkyl, and R.sup.13 is (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl.
[0183] Compounds of Formula II more particularly include those in
which R.sup.9 represents 4-aminobenzyl, benzyl, benzyloxymethyl,
2-benzylsulfanylethyl, benzylsulfanylmethyl,
2-bromobenzylsulfanylmethyl, 4-tert-butylbenzylsulfanylmethyl,
2-chlorobenzyl, 4-chlorobenzyl, 2-chlorobenzylsulfanylmethyl,
4-chlorobenzylsulfanylmethyl, 2-(2-chlorophenylsulfanyl)ethyl,
4-cyanobenzyl, 3,4-dichlorobenzylsulfany- lmethyl,
1,6-dichlorobenzyl, 3,5-dimethylbenzylsulfanylmethyl,
2-fluorobenzyl, 4-fluorobenzyl, 2-fluorobenzylsulfanylmethyl,
1-formylindol-3-ylmethyl, indol-3-ylmethyl,
2-iodobenzylsulfanylmethyl, 2-methylbenzylsulfanylmethyl,
3-methylbenzylsulfanylmethyl, 3-methylbenzylsulfanylmethyl,
4-methylbenzylsulfanylmethyl, 2-(2-methylphenylsulfanyl)ethyl,
4-methoxybenzyl, 4-methoxybenzylsulfanyl- methyl,
4-methoxybenzylsulfinylmethyl, naphth-2-ylmethyl,
naphth-2-ylmethylsulfanylmethyl, 3-nitrobenzyl,
1-nitrobenzylsulfanylmeth- yl, 2-nitrobenzylsulfanylmethyl,
3-nitrobenzylsulfanylmethyl, 4-nitrobenzylsulfanylmethyl,
4-nitrobenzyl, pentafluorobenzylsulfanylmeth- yl, phenylamino,
phenethyl, phenethyloxy, 2-phenoxyethyl, 2-phenoxyethyl
2-phenylsulfanylethyl, pyrid-4-ylmethyl,
pyrid-2-ylmethylsulfanylmethyl, pyrid-3-ylmethylsulfanylmethyl,
pyrid-4-ylmethylsulfanylmethyl, 2-pyrid-2-ylsulfanylethyl,
2-pyrid-4-ylsulfanylethyl, thiazol-5-yl, thien-2-ylmethyl,
4-trifluoromethylbenzylsulfanylmethyl,
3-trifluoromethylbenzylsulfanylmethyl,
3-trifluoromethoxybenzylsulfanylme- thyl,
4-trifluoromethoxybenzylsulfanylmethyl or
4-trifluorosulfanylbenzyls- ulfanylmethyl,
[0184] Reference to the preferred embodiments set forth above is
meant to include all combinations of particular and preferred
groups.
[0185] Further preferred are compounds of Formula I selected froma
group consisting of:
[0186]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)-4-hydroxybenzamid-
e;
[0187]
N-[2-(2-bromobenzylsulfanyl)-1R-cyanomethylcarbamoylethyl]benzamide-
;
[0188]
N-[1R-cyanomethylcarbamoyl-2-(2-iodobenzylsulfanyl)ethyl]benzamide;
[0189]
N-[1R-cyanomethylcarbamoyl-2-(2-cyanobenzylsulfanyl)ethyl]morpholin-
e-4-carboxamide;
[0190]
N-[3-(2-chlorophenylsulfanyl)-1R-cyanomethylcarbamoylpropyl]benzami-
de;
[0191]
N-[1R-cyanomethylcarbamoyl-2-(2-nitrobenzylsulfanyl)ethyl]morpholin-
e-4-carboxamide
[0192]
N-[1R-cyanomethylcarbamoyl-2-(2-methylbenzylsulfanyl)ethyl]morpholi-
ne-4-carboxamide; and
[0193]
N-[1R-cyanomethylcarbamoyl-2-(2-methylbenzylsulfanyl)ethyl]benzamid-
e.
[0194] Pharmacology and Utility
[0195] The compounds of the invention are cysteine protease
inhibitors, in particular the compounds of the invention inhibit
the activity of cathepsins B, L, K and/or S and, as such, are
useful for treating diseases in which cathepsin B, L, K and/or S
activity contributes to the pathology and/or symptomatology of the
disease. For example, the compounds of the invention are useful in
treating tumor invasion and metastasis, in particular as
anti-angiogenic agents, rheumatoid arthritis, osteo arthritis,
pneumocystis carinii, acute pancreatitis, inflammatory airway
disease and bone and joint disorders. Furthermore, the compounds of
the invention are useful in treating bone resorption disorders,
e.g., osteoporosis. The compounds of the invention also are useful
in treating autoimmune disorders, including, but not limited to
juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris,
Graves' disease, myasthenia gravis, systemic lupus erythemotasus,
rheumatoid arthritis and Hashimoto's thyroiditis, allergic
disorders, including, but not limited to asthma, and allogeneic
immune responses, including, but not limited to, organ transplants
or tissue grafts.
[0196] The cysteine protease inhibitory activities of the compounds
of the invention can be determined by methods known to those of
ordinary skill in the art. Suitable in vitro assays for measuring
protease activity and the inhibition thereof by test compounds are
known. Typically, the assay measures protease induced hydrolysis of
a peptide based substrate. Details of assays for measuring protease
inhibitory activity are set forth in Examples 10, 11, 12 and 13,
infra.
[0197] Nomenclature
[0198] The compounds of Formula I and the intermediates and
starting materials used in their preparation are named in
accordance with IUPAC rules of nomenclature in which the
characteristic groups have decreasing priority for citation as the
principle group as follows: acids, esters, amides and amidines. For
example, a compound of Formula I in which R.sup.1 is a group of
Formula (a), wherein X.sup.1 is carbonyl, R.sup.5 and R.sup.7 are
each hydrogen, R.sup.9 is benzyl and R.sup.11 is
tert-butoxycarbonyl and R.sup.2, R.sup.3 and R.sup.4 are each
hydrogen; that is, a compound having the following structure:
24
[0199] is named tert-butyl
1S-cyanomethylcarbamoyl-2-phenylethylcarbamate and a compound of
Formula I in which R.sup.1 is a group of Formula (a), wherein
X.sup.1 is carbonyl, R.sup.5 and R.sup.7 are each hydrogen, R.sup.9
is cyclohexylmethyl and R.sup.11 is morpholin-4-ylcarbonyl and
R.sup.2, R.sup.3 and R.sup.4 are each hydrogen; that is, a compound
having the following structure: 25
[0200] is named
N-(1S-Cyanomethylcarbamoyl-2-cyclohexylethyl)morpholine4-c-
arboxamide.
[0201] Administration and Pharmaceutical Compositions
[0202] In general, compounds of Formula I will be administered in
therapeutically effective amounts via any of the usual and
acceptable modes known in the art, either singly or in combination
with another therapeutic agent. A therapeutically effective amount
may vary widely depending on the severity of the disease, the age
and relative health of the subject, the potency of the compound
used and other factors. For example, therapeutically effective
amounts of a compound of Formula I may range from 0.1 micrograms
per kilogram body weight (.mu.g/kg) per day to 10 milligram per
kilogram body weight (mg/kg) per day, typically 1 .mu.g/kg/day to 1
mg/kg/day. Therefore, a therapeutically effective amount for a 80
kg human patient may range from 10 .mu.g/day to 100 mg/day,
typically 0.1 mg/day to 10 mg/day. In general, one of ordinary
skill in the art, acting in reliance upon personal knowledge and
the disclosure of this Application, will be able to ascertain a
therapeutically effective amount of a compound of Formula I for
treating a given disease.
[0203] The compounds of Formula I can be administered as
pharmaceutical compositions by one of the following routes: oral,
systemic (e.g., transdermal, intranasal or by suppository) or
parenteral (e.g., intramuscular, intravenous or subcutaneous).
Compositions can take the form of tablets, pills, capsules,
semisolids, powders, sustained release formulations, solutions,
suspensions, elixirs, aerosols, or any other appropriate
composition and are comprised of, in general, a compound of Formula
I in combination with at least one pharmaceutically acceptable
excipient. Acceptable excipients are non-toxic, aid administration,
and do not adversely affect the therapeutic benefit of the active
ingredient. Such excipient may be any solid, liquid, semisolid or,
in the case of an aerosol composition, gaseous excipient that is
generally available to one of skill in the art.
[0204] Solid pharmaceutical excipients include starch, cellulose,
talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,
silica gel, magnesium stearate, sodium stearate, glycerol
monostearate, sodium chloride, dried skim milk, and the like.
Liquid and semisolid excipients may be selected from water,
ethanol, glycerol, propylene glycol and various oils, including
those of petroleum, animal, vegetable or synthetic origin (e.g.,
peanut oil, soybean oil, mineral oil, sesame oil, etc.). Preferred
liquid carriers, particularly for injectable solutions, include
water, saline, aqueous dextrose and glycols.
[0205] The amount of a compound of Formula I in the composition may
vary widely depending upon the type of formulation, size of a unit
dosage, kind of excipients and other factors known to those of
skill in the art of pharmaceutical sciences. In general, a
composition of a compound of Formula I for treating a given disease
will comprise from 0.01%w to 10%w, preferably 0.3%w to 1%w, of
active ingredient with the remainder being the excipient or
excipients. Preferably the pharmaceutical composition is
administered in a single unit dosage form for continuous treatment
or in a single unit dosage form ad libitum when relief of symptoms
is specifically required. Representative pharmaceutical
formulations containing a compound of Formula I are described in
Example 15.
[0206] Chemistry
[0207] Processes for Making Compounds of Formula I
[0208] Compounds of Formula I can be prepared by proceeding as in
the following Scheme 1: 26
[0209] in which Y is hydrogen or an activating group (e.g.,
2,5-dioxopyrrolidin-1-yl (NBS), and the like) and each R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are as defined in the Summary of the
Invention.
[0210] Compounds of Formula I can be prepared by reacting a
compound of Formula 2, or a protected derivative thereof, with a
compound of the formula R.sup.1OY, or a protected derivative
thereof, and then optionally deprotecting. The reaction is carried
out in the presence of a suitable acylation catalyst (e.g.,
triethylamine) and in a suitable solvent (e.g., acetonitrile,
N,N-dimethylformamide (DMF), methylene chloride, or any suitable
combination thereof) at 10 to 30.degree. C., preferably at about
25.degree. C., and requires 24 to 30 hours to complete. When Y is
hydrogen the reaction can be effected in the presence of a suitable
coupling agent (e.g.,
benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate
(PyBOP.RTM.), 1-(3-dimethylaminopropyl)-3-ethylcarbod- iimide
hydrochloride (EDC), O-benzotri
azol-1-yl-N,N,N',N'-tetramethyluron- ium hexafluorophosphate
(HBTU), 1,3-dicyclohexylcarbodiimide (DCC), or the like) and base
(e.g., N,N-diisopropylethylarine, triethylarmine, or the like) and
requires 2 to 15 hours to complete. Alternatively, when Y is
hydrogen the reaction can be carried out by treating the compound
of formula R.sup.1OH with N-methylmorpholine and isobutyl
chloroformate in a suitable solvent (e.g., THF, or the like) at
between 0 and 5.degree. C. for 30 minutes to an hour and then
introducing the compound of Formula 2 to the reaction mixture and
allowing the reaction to proceed for 12 to 15 hours.
[0211] Deprotection can be effected by any means which removes the
protecting group and gives the desired product in reasonable yield.
A detailed description of the techniques applicable to the creation
of protecting groups and their removal can be found in T. W.
Greene, Protecting Groups in Organic Synthesis, John Wiley &
Sons, Inc. 1981. A detailed description of the preparation of a
compound of Formula I according to Scheme 1 is set forth in
Examples 4, 5, 6 and 8, infra.
[0212] Alternatively, compounds of Formula I can be prepared by
reacting a compound of Formula 2 with a compound of the formula
R.sup.1-SS, wherein SS is a suitable solid support (e.g.,
thiophenol resin, or the like). The reaction can be carried out in
the presence of a suitable acylation catalyst (e.g.,
4-dimethylaminopyridine, or the like) and in a suitable solvent
(e.g., dry pyrimidine, or the like) and requires 60 to 70 hours to
complete.
[0213] Compounds of Formula I can be prepared by proceeding as in
the following reaction Scheme 2: 27
[0214] in which each R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as
defined in the Summary of the Invention.
[0215] Compounds of Formula I can be prepared by treating a
compound of Formula 3, or a protected derivative thereof, with
ammonia to provide a corresponding amide, then reacting the amide
with a suitable dehydrating agent (e.g., trifluoroacetic anhydride,
cyanuric chloride, thionyl chloride, phosphonyl chloride, and the
like) and optionally deprotecting. The reaction with the ammonia is
carried out in a suitable solvent (e.g., methanol) at between 0 and
5.degree. C. and requires 6 to 10 days to complete. The reaction
with the dehydrating agent is carried out in the presence of a
suitable base (e.g, triethylamine) and in a suitable solvent (e.g.,
tetrahydrofuran (THF), and the like) at between 0 and 50.degree. C.
and requires 1 to 2 hours to complete. A detailed description of
the preparation of a compound of Formula I according to Scheme 2 is
set forth in Examples 7 and 8, infra. Additional Processes for
Preparing Compounds of Formula I:
[0216] A compound of Formula I can be prepared as a
pharmaceutically acceptable acid addition salt by reacting the free
base form of the compound with a pharmaceutically acceptable
inorganic or organic acid. Alternatively, a pharmaceutically
acceptable base addition salt of a compound of Formula I can be
prepared by reacting the free acid form of the compound with a
pharmaceutically acceptable inorganic or organic base. Inorganic
and organic acids and bases suitable for the preparation of the
pharmaceutically acceptable salts of compounds of Formula I are set
forth in the definitions section of this application.
Alternatively, the salt forms of the compounds of Formula I can be
prepared using salts of the starting materials or
intermediates.
[0217] The free acid or free base forms of the compounds of Formula
I can be prepared from the corresponding base addition salt or acid
addition salt form. For example, a compound of Formula I in an acid
addition salt form can be converted to the corresponding free base
by treating with a suitable base (e.g., ammonium hydroxide
solution, sodium hydroxide, etc.). A compound of Formula I in a
base addition salt form can be converted to the corresponding free
acid by treating with a suitable acid (e.g., hydrochloric acid,
etc).
[0218] The N-oxides of compounds of Formula I can be prepared by
methods known to those of ordinary skill in the art. For example,
N-oxides can be prepared by treating an unoxidized form of the
compound of Formula I with an oxidizing agent (e.g.,
trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic
acid, meta-chloroperoxybenzoic acid, etc.) in a suitable inert
organic solvent (e.g., a halogenated hydrocarbon such as methylene
chloride) at approximately 0.degree. C. Alternatively, the N-oxides
of the compounds of Formula I can be prepared from the N-oxide of
an appropriate starting material.
[0219] Compounds of Formula I in unoxidized form can be prepared
from N-oxides of compounds of Formula I by treating with a reducing
agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium
borohydride, sodium borohydride, phosphorus trichloride,
tribromide, etc.) in an suitable inert organic solvent (e.g.,
acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80.degree.
C.
[0220] Prodrug derivatives of the compounds of Formula I can be
prepared by methods known to those of ordinary skill in the art
(e.g., for further details see Saulnier et al.(1994), Bioorganic
and Medicinal Chemistry Letters. 4:1985). For example, appropriate
prodrugs can be prepared by reacting a non-derivatized compound of
Formula I with a suitable carbamylating agent (e.g.,
1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate,
etc.).
[0221] Protected derivatives of the compounds of Formula I can be
made by means known to those of ordinary skill in the art. A
detailed description of the techniques applicable to the creation
of protecting groups and their removal can be found in T. W.
Greene, Protecting Groups in Organic Synthesis, John Wiley &
Sons, Inc. 1981.
[0222] Compounds of Formula I can be prepared as their individual
stereo isomers by reacting a racemic mixture of the compound with
an optically active resolving agent to form a pair of
diastereoisomeric compounds, separating the diastereomers and
recovering the optically pure enantiomer. While resolution of
enantiomers can be carried out using covalent diasteromeric
derivatives of compounds of Formula I, dissociable complexes are
preferred (e.g., crystalline diastereoisomeric salts).
Diastereomers have distinct physical properties (e.g., melting
points, boiling points, solubilities, reactivity, etc.) and can be
readily separated by taking advantage of these dissimilarities. The
diastereomers can be separated by chromatography or, preferably, by
separation/resolution techniques based upon differences in
solubility. The optically pure enantiomer is then recovered, along
with the resolving agent, by any practical means that would not
result in racemization. A more detailed description of the
techniques applicable to the resolution of stereo isomers of
compounds from their racemic mixture can be found in Jean Jacques
Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and
Resolutions, Honh Wiley & Sons, Inc. (1981).
[0223] In summary, an aspect of the invention is a process for
preparing a compound of Formula I, which process comprises:
[0224] (A) reacting a compound of Formula 2: 28
[0225] or a protected derivative thereof with a compound of the
formula R.sup.1OY, or a protected derivative thereof, in which Y is
hydrogen or an activating group and each R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are as defined in the Summary of the Invention; or
[0226] (B) reacting a compound of Formula 3: 29
[0227] with ammonia to provide a corresponding amide and then
reacting the amide with trifluoroacetic anhydride, in which each
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined in the Summary
of the Invention
[0228] (C) optionally deprotecting a protected derivative of a
compound of Formula I to provide a corresponding unprotected
derivative;
[0229] (D) optionally converting a compound of Formula I into a
pharmaceutically acceptable salt;
[0230] (E) optionally converting a salt form of a compound of
Formula I to non-salt form;
[0231] (F) optionally converting an unoxidized form of a compound
of Formula I into a pharmaceutically acceptable N-oxide;
[0232] (G) optionally converting an N-oxide form of a compound of
Formula I its unoxidized form;
[0233] (H) optionally converting a non-derivatized compound of
Formula I into a pharmaceutically prodrug derivative; and
[0234] (I) optionally converting a prodrug derivative of a compound
of Formula I to its non-derivatized form. Processes for Preparing
Intermediates:
[0235] Compounds of Formula 2 can be prepared by reacting a
compound of Formula 4: 30
[0236] in which R.sup.19 is an amino protecting group and each
R.sup.2, R.sup.3 and R.sup.4 are as defined in the Summary of the
Invention, with thionyl chloride and then deprotecting. The
reaction with the thionyl chloride is carried out in the presence
of a suitable base (e.g, triethylaamine) and in a suitable solvent
(e.g, Do) at between 0 and 5.degree. C. and requires 30 minutes to
an hour to complete. Alternatively, compounds of Formula 2 can be
prepared by reacting a compound of Formula 4 with trifluoroacetic
anhydride. The deprotection can be effected by any means which
removes the protecting group and gives the desired product in
reasonable yield. A detailed description of the preparation of a
compound of Formula 2 according to above-described procedure is set
forth in Example 1, infra.
[0237] Compounds of Formula 4 can be prepared by treating a
corresponding alkanoyl halide with ammonia. The treatment is
carried out in a suitable solvent (e.g., dichloromethane, 5%
aqueous sodium carbonate, and the like, or any suitable combination
thereof) at 10 to 30.degree. C. and requires 30 minutes to an hour
to complete. The alkanoyl halide intermediates can be prepared from
the corresponding alkanoic acid by treating with thionyl chloride
in a suitable solvent (e.g., dichloromethane) under nitrogen for 30
minutes to an hour. A detailed description of the preparation of a
compound of Formula 2 according to the above-described procedures
is set forth in Example 1, infra.
[0238] Compounds of the formula R.sup.1-SS can be prepared by
reacting a compound of Formula 5(a) or 5(b): 31
[0239] in which R.sup.19 is an amino protecting group (e.g.,
tert-butoxycarbonyl, fluoren-9-ylmethoxycarbonyl, or the like) and
each X.sup.1, X.sup.2, X.sup.3, R.sup.5 and R.sup.7 are as defined
for Formula I in the Summmary of the Invention, with a suitable
solid support resin (e.g, Wang (4-benzyloxybenzyl alcohol) resin,
thiophenol resin, or the like), deprotecting to provide,
respectively, a compound of Formula 6(a) or 6(b): 32
[0240] in which SS is a solid support and then reacting the
compound of Formula 6(a) or 6(b) with a compound of the formula
R.sup.6OH (e.g., benzoic acid, indole-5-carboxylic acid,
methanesulfonic acid, or the like).
[0241] The reaction between the compound of Formula 5(a) or 5(b)
and the resin is carried out in the presence of a suitable coupling
agent (e.g., benzotriazole-1-yloxytrispyrrolidinophosphonium
hexafluorophosphate (e.g., diisopropylcarbodiimide (DIC),
PyBOP.RTM., EDC, HBTU, DCC, or the like) and acylation catalyst
(e.g., NN-diisopropylethylaamine, triethylaamine,
4-dimethylaminopyridine, 1-hydroxybenzotriazole hydrate, or the
like) in a suitable solvent (e.g., methylene chloride, DMF, or the
like) and requires approximately 3 to 20 hours to complete.
Deprotection can be effected by any means which removes the
protecting group and gives the desired product in reasonable yield.
The reaction between the compound of Formula 6(a) or 6(b) is
carried out with a suitable coupling agent and acylation catalyst.
A detailed description of the preparation of a compound of the
formula R.sup.1-SS according to the above-described procedures is
set forth in Examples 2(A-C) and 4(A-C), infra.
[0242] Compounds of the formula R.sup.1OH can be prepared by
treating a compound of formula R.sup.1-SS with a suitable acid
(e.g., trifluoroacetic acid, or the like) in a suitable solvent
(e.g, methylene chloride, or the like). Alternatively, compounds of
the formula R.sup.1OH in which X.sup.1 is --C(O)--and X.sup.2 is
--CHR.sup.9-- can be prepared by alkylating an organometallic
compound of Formula 7(a) or 7(b): 33
[0243] with a compound of the formula R.sup.9L, in which L is a
leaving group and each X.sup.3, X.sup.4, R.sup.5, R.sup.6, R.sup.7
and R.sup.9 are as defined for Formula I in the Summary of the
Invention, and then converting the resulting ethyl ester to the
corresponding acid. The alkylation is carried out in a suitable
solvent (e.g., THF) at -78.degree. C. to 0.degree. C. and requires
1 to 2 hours to complete. Conversion the acid can be effected by
treating the ester with lithium hydroxide for approximately 15
hours. The organometallic compound is generated by treating a
corresponding organo compound with an appropriate base (e.g.,
N,N-diisopropylethylamine, triethylamine, and the like) and
n-butyllithium or tert-butyllithium at -80 to -70.degree. C.,
preferably at about -78.degree. C., for approximately 30 minutes to
an hour. A detailed description of the preparation of a compound of
the formula R.sup.1OH according to the above-described procedures
is set forth in Example 3, infra. Examples:
Reference 1
Lithium 2S-amino-3-cyclohexylpropionate
[0244] A solution of methyl 2S-amino-3-cyclohexylpropionate
hydrochloride (8.03 mmol, 1 eq) in dichloromethane (80 mL) and
saturated NaHCO.sub.3 solution (80 mL) was cooled to 0.degree. C.
and then the organic layer was treated with a solution of 1.93 M
phosgene in toluene (8.3 mL, 2 eq). The mixture was stirred for 10
minutes and then the aqueous was separated and extracted with
dichloromethane (3.times.27 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated. A portion of
the residue (767 .mu.M, 1.0 eq) was stirred under nitrogen together
with morpholine (767 .mu.M, 1.0 eq) in, dry THF (1 mL) for 12
hours. The mixture was concentrated in vacuo and the residue
dissolved in ethyl acetate (1 mL). The solution was washed with
water (3.times.1 mL), dried over sodium sulfate and concentrated.
The residue was dissolved in methanol (2 mL) and water (37 .mu.L)
and the solution was treated with lithium hydroxide monohydrate (19
mg, 1.05 eq) and then stirred for 12 hours. The solution was
adjusted to pH 11 with additional lithium hydroxide monohydrate,
heated at 60.degree. C. for 4 hours and then the concentrated in
vacuo to provide lithium 2S-morpholin-4-ylcarbonylamino-3-
-cyclohexylpropionate.
[0245] Proceeding as in Reference 1 provided the following
compounds:
[0246] lithium
2S-piperidin-1-ylcarbonylamino-3-cyclohexylpropionate;
[0247] lithium
2S-(4-tert-butoxycarbonylpiperazin-1-ylcarbonylamino)-3-cyc-
lohexylpropionate;
[0248] lithium
2S-(4-benzylpiperazin-1-ylcarbonylamino)-3-cyclohexylpropio-
nate;
[0249] lithium
2S-(4-ethoxycarbonylpiperazin-1-ylcarbonylamino)-3-cyclohex-
ylpropionate;
[0250] lithium
2S-(4-fur-2-ylcarbonylpiperazin-1-ylcarbonylamino)-3-cycloh-
exylpropionate;
Reference 2
3-Cyclohexyl-2S-(3-methoxybenzyloxycarbonylamino)propionic acid
[0251] A mixture of 2S-amino-3-cyclohexylpropionic acid (2.95 mmol,
1.0 eq) and sodium hydroxide (5.9 mmol, 2 eq) in a 1:1 mixture of
THF/water (14 mL) was treated with 3-methoxybenzyloxyformyl
chloride (2.95 mmol, 1.0 eq), stirred for 3 hours and then treated
with N,N-diethyl ethylenediamine (2.95 mmol, 1.0 eq). The mixture
was stirred for approximately 12 hours, adjusted to pH 2 with 1M
hydrochloric acid solution (13 mL) and then extracted with ethyl
acetate (2.times.9 mL). The extract was washed with 1M hydrochloric
acid solution (6 mL), dried over sodium sulfate and concentrated to
provide 3-cyclohexyl-2S-(3-methox-
ybenzyloxycarbonylamino)propionic acid as a yellow oil.
EXAMPLE 1
tert-Butyl 1S-cyanomethylcarbamoyl-2-phenylethylcarbamate (Compound
1)
[0252] 34
[0253] A mixture comprised of
2S-tert-butoxycarbonylamino-3-phenylpropioni- c acid (28.9 g, 0.109
mol), aminoacetonitrile hydrochloride (10.1 g, 0.109 mol),
triethylamine (61 mL, 0.436 mol), DMF (40 mL) and acetonitrile (360
mL) was stirred at room temperature for 27 hours. The mixture was
filtered, concentrated to a volume of 100 mL and poured into ice
water (1000 mL). The mixture was stirred until a precipitate had
formed. The precipitate was collected, washed with water and dried.
The dry product was recrystallized from 55% ethanol/water (80 mL).
The crystals were collected and recrystallized from 65%
ethanol/water (70 mL). The crystals were collected and dried to
provide tert-butyl 1S-cyanomethylcarbamoyl-2-- phenylethylcarbamate
(20.3 g, 0.067 mol) as white needles; .sup.1H NMR: .delta.1.39 (s,
9H), .delta.3.06 (d, 2H, J=7 Hz), .delta.4.08 (m, 2H), .delta.4.34
(dd, 1H, J=13, 7 Hz), .delta.4.97 (d, 1H, J=8 Hz), .delta.6.59 (m,
1H), .delta.7.23 (m, 5H); ES-MS m/z 304 (MH+).
[0254] Proceeding as in Example 1 provided the following compounds
of Formula I:
[0255] benzyl
5S-tert-butoxycarbonylamino-5-cyanomethylcarbamoylpentylcarb- amate
(Compound 2); .sup.1H NMR: .delta.1.37 (m, 15 H), .delta.1.63 (m,
1H), .delta.1.78 (m, 1H), .delta.3.14 (dd, 2H, J=13, 6 Hz),
.delta.4.07 (m, 2H), .delta.5.06 (s, 2H), .delta.5.42 (br s, 1H),
.delta.7.32 (m, 5H) .delta.7.48 (br s, 1H); ES-MS m/z 419
(MH+);
[0256] cyclohexyl
3S-tert-butoxvcarbonylamino-N-cyanomethylsuccinamate (Compound 3);
.sup.1H NMR: .delta.1.35 (m, 17 H), .delta.1.72 (m, 1H),
.delta.1.83 (m, 1H), .delta.2.66 (dd, 1H, J=18, 7 Hz) .delta.2.96
(dd, 1H, J=18, 5 Hz), .delta.4.15 (dd, 2H, J=6, 2 Hz), .delta.4 50
(m, 1H), .delta.4.77 (m, 1H), .delta.5 64 (br s, 1H), .delta.7.11
(br s, 1H); ES-MS m/z 354 (MH+);
[0257] tert-butyl
1S-cyanomethylcarbamoyl-2-(1-formyl-1H-indol-3-yl)ethylc- arbamate
(Compound 4); .sup.1H NMR: .delta.1.44 (s, 9H), .delta.3.23 (m,
2H), .delta.4.08 (m, 2H), .delta.4.46 (m, 1H), .delta.4.95 (br s,
1H), .delta.7.38 (m, 4H), .delta.7.62 (br s, 1H); ES-MS m/z 371
(MH+);
[0258] tert-butyl
2-(3-benzyloxymethyl-3H-imidazol-4-yl)-1S-cyanomethylcar-
bamoylethylcarbamate (Compound 5); .sup.1H NMR: .delta.1.39 (s,
9H), .delta.3.09 (d, 2H, J=7 Hz), .delta.4.00 (d, 2H, J=6 Hz),
.delta.4.42 (m, 1H), .delta.4.45 (s, 2H), .delta.5.29 (m, 2H),
.delta.5.58 (br d, 1H, J=8 Hz), .delta.6.79 (s, 1H), .delta.7.29
(m, 1H), .delta.7.49 (s, 1H), .delta.7.93 (br s); ES-MS m/z 414
(MH+);
[0259] tert-butyl
2-(4-benzyloxyphenyl)-1S-cyanomethylcarbamoylethylcarbam- ate
(Compound 6); .sup.1H NMR: .delta.1.40 (s, 9H), .delta.3.01 (t, 2H,
J=6 Hz), .delta.4.07 (t, 2H, J=6 Hz .delta.4.29 (m, 1H),
.delta.4.90 (br s, 1H), .delta.5.02 (s, 2H), .delta.6.40 (br s,
1H), .delta.6.92 (d, 2H, J=8 Hz), .delta.7.09 (d, 2H, J=8 Hz),
.delta.7.37 (m, 5H); ES-MS m/z 410 (NH+); and
[0260] tert-butyl
1S-cyanomethylcarbamoyl-2-cyclohexylethylcarbamate (Compound 7);
.sup.1H NMR: .delta.0.94 (m, 2H), .delta.1.20 (m, 3H), .delta.1.44
(m, 11H), .delta.1.71 (m, 6H), .delta.4.15 (m, 2H), .delta.4.30 (m,
1H), .delta.4.87 (br s, 1H), .delta.7.04 (br s); ES-MS mnz 210
(M-BuCO.sub.2).
EXAMPLE 2
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)benzamide
(Compound 8)
[0261] 35
[0262] A mixture comprised of
2R-benzoylamino-3-benzylsulfanylpropionic acid (0.508 g, 1.61
mmol), aminoacetonitrile hydrochloride (0.149 g, 1.61 mmol),
PyBOP.RTM. (0.838 g, 1.61 mmol), N,N-diisopropylethylamine (0.84
mL, 4.83 mmol) and DMF (10 mL) was stirred at room temperature for
2.5 hours. The mixture was concentrated and the residue was taken
up into dichloromethane. The dichloromethane mixture was washed
with 1N hydrochloric acid, water and aqueous sodium bicarbonate,
dried (MgSO.sub.4), filtered and concentrated. Product was purified
from the residue by silica gel chromatography using 5% methanol in
dichloromethane to provide
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoyl)ethyl)benzamide (541
mg, 1.53 mmol) as an oil. MS: m/e 353.8 (theory 353.1); Proton NMR
Spectrum (DMSO-d.sub.6): .delta.8.85 (t, 1H), .delta.8.75 (d, 1H),
.delta.7.99 (d, 2H), 7.5 (m, 3H), .delta.7.3 (m, 5H) .delta.4.7 (m,
1H), .delta.4.15 (d, 2H), .delta.3.75 (s, 2H), .delta.2.8 (m, 2H)
ppm.
[0263] Proceeding as in Example 2 provided the following compounds
of Formula I:
[0264]
N-[1R-cyanomethylcarbamoyl-2-(4-methylbenzylthioethyl)]benzamide(Co-
mpound 9); MS: m/e 367.9 (theory 367.1); NMR Spectrum
(DMSO-d.sub.6): .delta.8.82 (t, 1H), .delta.8.69 (d, 1H),
.delta.7.88 (d, 2H), .delta.7.5 (m, 3H), .delta.7.16 (d, 2H),
.delta.7.08 (d, 2H), .delta.4.7 (m, 1H), .delta.4.2 (d, 2H),
.delta.3.7 (s, 2H), .delta.2.75 (m, 2H), .delta.2.1 (s, 3H)
ppm;
[0265]
N-[1R-cyanomethylcarbamoyl)-2-(4-methoxybenzylthioethyl)]benzamide(-
Compound 10); MS: m/e 383.9 (theory 383.1); NMR Spectrum
(DMSO-d.sub.6): .delta.8.8 (t, 1H) .delta.8.65 (d, 1H) .delta.7.9
(d, 2H), .delta.7.5 (m, 3H), .delta.7.25 (d, 2H), .delta.6.8 (d,
2H), .delta.4.7 (m, 1H) .delta.4.2 (d, 2H), .delta.3.7 (s, 3H),
.delta.3.3 (s, 2H), .delta.2.8 (m, 2H) ppm;
[0266] N-[2-benzyloxy-1S-cyanomethylcarbamoylethyl]benzamide
(Compound 11); MS: m/e 337.8 (theory 337.1); NMR Spectrum
(DMSO-d.sub.6): .delta.8.82 (t, 1H) .delta.8.67 (d, J=7.8 Hz, 1H)
.delta.7.91 (d, J=7 Hz, 2H), .delta.7.5(m, 3H), .delta.7.3 (m, 5H),
.delta.4.8 (m, 1H) .delta.4.54 (s, 2H), .delta.4.17 (d, 2H),
.delta.3.7 (m, 2H) ppm;
[0267] benzyl 1-cyanomethylcarbamoyl-3-methylthiopropylcarbamate
(Compound 12); MS: m/e 321.8 (theory 321.1); NMR Spectrum
(DMSO-d.sub.6): .delta.8.7 (t, 1H) .delta.7.6 (d, 1H) .delta.7.3
(m, 5H), .delta.5.0 (q, 2H), .delta.4.1 (m, 3H), .delta.3.3 (d,
2H), .delta.2.4 (m, 2H), .delta.1.9 (s, 3H) ppm;
[0268] N-[1S-cyanomethylcarbamoyl-3-methylthiopropyl]benzamide
(Compound 13); MS: m/e 291.7 (theory 291.1); NMR Spectrum
(DMSO-d.sub.6): .delta.8.7 (t, J=5.6 Hz, 1H), .delta.8.6 (d, J=7.7
Hz, 1H), .delta.7.9 (m, 2H), .delta.7.5 (m, 3H), .delta.4.5 (m,
1H), .delta.4.11 (d, J=5.6 Hz, 2H), .delta.2.5 (m, 2H), .delta.2.03
(s, 3H), .delta.2.0 (m, 2H) ppm;
[0269] benzyl 2-benzylthio-1R-cyanomethylcarbamoylethylcarbamate
(Compound 14); MS: m/e 383.8 (theory 383.1); NMR Spectrum
(DMSO-d.sub.6): .delta.8.8 (t, 1H), .delta.7.8 (d, 1H), .delta.7.4
(m, 10H), .delta.5.1 (q, 2H), .delta.4.1 (m, 1H), .delta.4.2 (s,
2H), .delta.3.8 (s, 2H), .delta.2.8 (m, 1H), .delta.2.6 (m, 1H)
ppm;
[0270] methyl
4-benzyloxycarbonylamino4S-cyanomethylcarbamoylbutyrate (Compound
15); MS: m/e 333.6 (theory 333.1); NMR Spectrum (DMSO-d.sub.6 ):
.delta.8.7 (t, 1H), .delta.7.7 (d, 1H), .delta.7.4 (m, 5H),
.delta.5.0 (q, 2H), .delta.4.0 (m, 1H), .delta.3.55 (s, 3H),
.delta.3.3 (d, 2H), .delta.2.3 (t, 2H), .delta.1.8 (m, 2H) ppm;
[0271] tert-butyl 2-benzyloxy-1S-cyanomethylcarbamoylethylcarbamate
(Compound 16); MS: m/e+Na 355.7 (theory 355.1); NMR Spectrum
(DMSO-d.sub.6): .delta.8.7 (t, 1H), .delta.7.0 (d, 1H), .delta.7.3
(m, 5H), .delta.4.45 (s, 2H), .delta.4.2 (m, 1H), .delta.4.1 (d,
2H), .delta.3.55 (m, 2H) .delta.1.4 (s, 9H) ppm;
[0272] benzyl 2-benzyloxy-1S-cyanomethylcarbamoylethylcarbamate
(Compound 17); NMR Spectrum (DMSO-d.sub.6): .delta.8.8 (t, 1H),
.delta.7.7 (d, 1H), .delta.7.4 (m, 10H), .delta.5.0 (q, 2H),
.delta.4.5 (s, 2H), .delta.4.3 (m, 1H), .delta.4.1 (s, 2H),
.delta.3.6 (m, 2H) ppm;
[0273] N-(1-cyanomethylcarbamoylpent-3-ynyl)benzamide (Compound
18); MS: m/e 269.7 (theory 269.1); NMR Spectrum (DMSO-d.sub.6):
.delta.8.8 (t, 1H), .delta.8.65 (d, 1H), .delta.7.9 (d, 2H),
.delta.7.5 (m, 3H), .delta.4.5 (m, 1H), .delta.4.1 (d, 2H),
.delta.2.5 (m, 2H), .delta.1.7 (s, 3H) ppm;
[0274] N-(1S-cyanomethylcarbamoyl-2-naphthalen-1-ylethyl)benzamide
(Compound 19); .sup.1H NMR: .delta.3.45 (dd, 1H, J=14, 9 Hz),
.delta.3.73 (dd, 1H, J=17, 6 Hz), .delta.3.90 (dd, 1H, J=19, 6 Hz),
.delta.4.04 (dd, 1H, J=14, 6 Hz), .delta.4.98 (m, 1H), .delta.6.67
(m, 1H), .delta.6.93 (m, 1H), .delta.7.46 (m, 9H), 7.74 (m, 2H),
.delta.8.23 (d, 1H, J=8 Hz); ES-MS m/z 358 (MH+);
[0275] N-[2-(4-chlorophenyl)-1S-cyanomethylcarbamoylethyl]benzanide
(Compound 20); .sup.1H NMR: .delta.3.19 (m, 2H), .delta.3.96 (dd,
1H, J=19, 4 Hz), .delta.4.10 (dd, 1H, J=20, 6 Hz), .delta.4.98 (m,
1H), .delta.6.79 (d, 1H, J=7 Hz), .delta.7.07 (m, 2H), .delta.7.22
(m, 2H), .delta.7.43 (m, 4H), .delta.7.69 (m, 1H), .delta.8.08 (d,
1H, J=8 Hz); ES-MS m/z 342 (ME+);
[0276] N-(1S-cyanomethylcarbamoyl)-2-naphthalen-2-ylethylbenzamide
(Compound 21); .sup.1H NMR: .delta.3.29 (d, 2H, J=7 Hz),
.delta.3.81 (dd, 2H, J=18, 6 Hz), .delta.3.98 (dd, 1H, J=18, 6 Hz),
.delta.5.09 (dd, 1H, J=15, 7 Hz), .delta.6.74 (br d, 1H, J=7 Hz),
.delta.7.37 (m, 6H), .delta.7.68 (m, 6H); ES-MS m/z 358 (MH+);
[0277] N-[1-cyanomethylcarbamoyl-2-(4-cyanophenyl)ethyl]benzamide
(Compound 22); .sup.1H NMR: .delta.3.18 (dd, 1H, J=14, 7Hz),
.delta.3.30 (dd, 1H, J=15, 7 Hz), .delta.4.03 (dd, 1H, J=17, 6 Hz),
.delta.4.15 (dd, H, J=19, 6 Hz), .delta.4.93 (dd, 1H, J=15, 8 Hz),
.delta.6.81 (d, 1H, J=10 Hz), .delta.7.30 (m, 2H), .delta.7.43 (m,
3H), .delta.7.55 (m, 2H), .delta.7.67 (d, 2H, J=8 Hz); ES-MS m/z
333 (MH+);
[0278]
N-{1S-cyanomethylcarbamoyl-2-[4-(2,6-dichlorobenzyloxy)phenyl]ethyl-
}benzaiide (Compound 23); .sup.1H NMR: .delta.3.15 (m, 2H),
.delta.4.08 (t, 2H, J=6 Hz), .delta.4.84 (dd, 1H, J=16, 7 Hz),
.delta.5.24 (m, 3H), .delta.6.87 (d, 1H, J=8 Hz), .delta.6.98 (m,
4H), .delta.7.18 (d, 2H, J=9 Hz), .delta.7.32 (m, 4H), .delta.7.78
(d, 2H, J=8 Hz); ES-MS m/z 482 (MH+);
[0279] cyclohexyl 4-benzoylamino-4S-cyanomethylcarbamoylbutyrate
(Compound 24); .sup.1H NMR: .delta.1.37 (m, 5H), .delta.1.53 (m,
2H), .delta.1.68 (m, 2H), .delta.1.83 (m, 1H), .delta.2.17 (m, 2H)
.delta.2.42 (m, 1H), .delta.2.66 (m, 1H), .delta.4.15 (m, 2H),
.delta.4.68 (m, 2H), .delta.7.47 (m, 3H), 7.79 (m, 2H); ES-MS m/z
372 (MH+);
[0280]
N-[2-(4-benzoylphenyl)-1S-cyanomethylcarbamoylethyl]benzamide
(Compound 25); .sup.1H NMR: .delta.3.27 (m, 2H), .delta.4.00 (dd,
1H, J=15, 6 Hz), .delta.4.13 (m, 1H, J=17, 6 Hz), .delta.4.23 (d,
1H, J=6 Hz), .delta.4.97 (dd, 1H, J=15, 8 Hz), .delta.6.96 (d, 1H,
J=9 Hz), .delta.7.46 (m, 9H), .delta.7.71 (m, 5H); ES-MS m/z 412
(MH+);
[0281] N-(1S-cyanomethylcarbamoyl-2-phenylethyl)benzamide (Compound
26); .sup.1H NMR: .delta.3.15 (dd, 1H, J=12, 6 Hz), .delta.3.25
(dd, 1H, J=15, 6 Hz), .delta.4.08 (t, 2H, J=6 Hz), .delta.4.84 (dd,
1H, J=15, 6 Hz), .delta.6.68 (br s, 1H), .delta.6.77 (br s, 1H),
.delta.7.29 (m, 5H), .delta.7.41 (m, 2H), .delta.7.53 (m, 1H),
.delta.7.67 (d, 2H, J=9 Hz); ES-MS m/z 308 (MH+);
[0282] N-[1S-cyanomethylcarbamoyl-2-(1H-indol-3-yl)ethyl]benzamide
(Compound 27); .sup.1H NMR: .delta.3.25 (dd, 1H, J=16, 8 Hz),
.delta.3.52 (dd, 1H, J=16, 6 Hz), .delta.3.95 (dd, 1H, J=18, 4 Hz),
.delta.4.07 (dd, 1H, J=18, 6 Hz), .delta.4.93 (m, 1H), .delta.6.44
(br s, 1H), .delta.6.85 (d, 1H, J=5 Hz), .delta.7.22 (m, 3H),
.delta.7.38 (m, 3H), .delta.7.50 (m, 1H), .delta.7.67 (m, 2H, J=8
Hz .delta.7.74 (d, 1H, J=8 Hz), .delta.8.18 (br s, 1H); ES-MS m/z
347 (MH+);
[0283] N-[1S-cyanomethylcarbamoyl-2-(4-fluorophenylethyl)]benzamide
(Compound 28); .sup.1H NMR: .delta.3.15 (m, 2H), .delta.3.97 (dd,
1H, J=18, 6 Hz), .delta.4.11 (dd, 1H, J=18, 6 Hz), .delta.4.90 (dd,
1H, J=15, 8 Hz), .delta.6.95 (m, 3H), .delta.7.20 (m, 2H),
.delta.7.46 (m, 3H), .delta.7.68 d, 1H, J=8 Hz); ES-MS m/z 326
(MH+);
[0284] N-[2-(2-chlorophenyl)-1S-cyanomethylcarbamoylethyl]benzamide
(Compound 29); .sup.1H NMR: .delta.3.34 (m, 2H), .delta.4.04 (dd,
1H, J=16, 6 Hz), .delta.4.17 (dd, 1H, J=16, 6 Hz), .delta.4.93 (dd,
1H, J=16, 6 Hz), .delta.6.85 (m, 1H), .delta.7.24 (m, 4H),
.delta.7.44 (m, 3), .delta.7.72 m, 2H); ES-MS m/z 342 (MH+);
[0285]
N-[1S-cyanomethylcarbamoyl-2-(4-methoxyphenylethyl)]benzamide
(Compound 30); .sup.1H NMR: .delta.3.13 (m, 2H), .delta.3.76 (m,
4H), .delta.4.06 (dd, 1H, J=11, 6 Hz), .delta.4.80 (m, 1H),
.delta.6.83 (m, 4H), .delta.7.16 (d, 1H, J=9 Hz), .delta.7.46 (m,
2H), .delta.7.66 (m, 2H); ES-MS m/z 338 (MH+);
[0286]
N-[2-(4-benzyloxyphenyl)-1-cyanomethylcarbamoylethyl]benzamide
(Compound 31); .sup.1H NMR: .delta.3.07 (m, 2H), .delta.3.90 (m,
1H), .delta.4.02 (m, 1H), .delta.4.94 (s, 2H), .delta.4.95 (m, 1H),
.delta.6.70 (m, 1H), .delta.6.85 (m, 2H), .delta.7.09 (m, 2H),
.delta.7.38 (m, 7H), .delta.7.72 (m, 3H); ES-MS m/z 414 (MH+);
[0287] benzyl
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)isophthalamate
(Compound 32); .sup.1H NMR: .delta.0.86 (m, 2H), .delta.1.09 (m,
2H), .delta.1.39 (m, 5H), .delta.1.67 (m, 4H), .delta.3.04 (m, 1H),
.delta.3.63 (m, 1H), .delta.4.11 (m, 1H), .delta.4.60 (m, 1H),
.delta.4.77 (m, 1H), .delta.5.33 (s, 2H), .delta.7.38 (m, 5H),
.delta.8.01 (d, 1H, J=9 Hz), .delta.8.14 (m, 2H), .delta.8.45 (d,
1H, J=12 Hz); ES-MS m/z 448 (MH+);
[0288] benzyl
N-(1-cyanomethylcarbamoyl-2-cyclohexylethyl)terephthalamate
(Compound 33); .sup.1H NMR: .delta.0.89 (m, 2H), .delta.1.13 (m,
3H), .delta.1.38 (m, 4H), .delta.1.66 (m, 4H), .delta.3.10 (m, 1H),
.delta.3.64 (m, 1H), .delta.4.10 (m, 1H), .delta.4.80 (dd, 1H,
J=15, 8 Hz), .delta.5.324 (d, 2H, J=2 Hz), .delta.7.37 (m, 5H),
.delta.7.84 (d, 2H, J=7 Hz), .delta.8.03 (m, 2H); ES-MS m/z 448
(MH+);
[0289] N-[1-cyanomethylcarbamoyl-2-(2-fluorophenyl)ethyl]benzamide
(Compound 34); .sup.1H NMR: .delta.3.23 (m, 2H), .delta.4.06 (dd,
1H, J=18, 6 Hz), .delta.4.15 (dd, 1H, J=18, 6 Hz), .delta.4.91 (dd,
1H, J=15, 8 Hz), .delta.7.01 (m, 2H), .delta.7.23 (m, 1H),
.delta.7.41 (m, 2H), .delta.7.52 (m, 2H), .delta.7.68 (d, 2H, J=8
Hz); ES-MS m/z 326 (MH+);
[0290]
N-(2-benzylthio-1R-cyanomethylcarbamoylethyl)-2-(3,5-dimethoxypheny-
l)thiazole-4-carboxamide (Compound 35); MS: Calcd. 496; Found
M+1=497;
[0291]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl-2-(3,5-dimethoxyphenyl-
)thiazole-4-carboxamide (Compound 36); MS: Calcd. 456; Found
M+1=457;
[0292] N-(1-cyanomethylcarbamoylpent-3-enyl)benzamide (Compound
37); MS: m/e 271.8 (theory 271.1); NMR Spectrum (DMSO-d.sub.6):
.delta.8.7 (t, 1H), .delta.8.657 (d, 1H), .delta.7.9 (d, 2H),
.delta.7.5 (m, 3H), .delta.5.4 (m, 2H), .delta.4.5 (m, 1H),
.delta.4.1 (d, 2H), .delta.2.5 (m, 2H), .delta.2.6 (d, 3H) ppm;
[0293]
4-tert-butyl-N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)benzamide
(Compound 38); .sup.1H NMR (CDCl.sub.3): .delta.8.02 (br s, 1H),
.delta.7.73 (d, 2H, J=8.7 Hz), .delta.7.43 (d, 2H, J=8.5 Hz),
.delta.7.05 (br d, 1H, J=8.5 Hz), .delta.4.79 (dd, 1H, J=15.1, 8.7
Hz), 4.10 (dd, 2H, J=19.9 Hz, 5.6 Hz), .delta.1.51-1.82 (m, 5H),
.delta.1.30 (s, 9H), .delta.0.83-1.72 (m, 8H); EI MS
(M.sup.+=369.9);
[0294]
N-[1S-cyanomethylcarbamoyl-2-cyclohexylethyl]pyrimidine-5-carboxami-
de (Compound 39); .sup.1H NMR (CDCl.sub.3): .delta.9.33 (s, 1H),
.delta.8.77 (s, 1H), .delta.8.56 (s, 1H), .delta.8.14 (br d, 1H,
J=8.7 Hz), .delta.7.30 (br s, 1H), .delta.4.69 (dd, 1 H, J=14.9,
9.2 Hz), .delta.4.15 (t, 2H, J=3.9 Hz), .delta.0.76-2.30 (m, 13H);
EI MS (M.sup.+=315.9);
[0295]
N-(1-cyanomethylcarbamoyl-2-cyclohexylethyl)naphthalene-1-carboxami-
de (Compound 40); .sup.1H NMR (CDCl.sub.3): .delta.8.19 (br d, 1H,
J=10.0 Hz), .delta.7.81-7.96 (m, 3H), .delta.7.47-7.62 (m, 3H),
.delta.7.35-7.44 (m, 1H), .delta.6.69 (d, 1H, J=8.7 Hz),
.delta.4.90 (dd, 1H, J=15.4, 9.0), .delta.4.03 (d, 2H, J=4.9 Hz),
.delta.0.79-1.89 (m, 13H); EI MS (M+=364.0);
[0296]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-4-fluorobenzamide
(Compound 41); .sup.1H NMR (CDCl.sub.3): .delta.7.70-7.83 (m, 2H),
.delta.7.43 (br s, 1H), .delta.7.11 (t, 2H, J=8.7 Hz), .delta.6.66
(br d, 1H, J=8.5 Hz), .delta.4.69 (dd, 1H, J=15.5, 9.4 Hz),
.delta.4.14 (dd, 2H, J=19.6, 8.4 Hz), .delta.0.67-1.88 (m, 131H);
EI MS (M+=331.6);
[0297]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-4-hydroxybenzamide
(Compound 42); .sup.1H NMR (CDCl.sub.3): .delta.7.64 (d, 2 H, J=9.0
Hz), .delta.7.39 (br s, 1 H), .delta.6.83 (d, 2H, J=9.5 Hz),
.delta.6.43 (br d, 1H, J=11.2 Hz), .delta.4.64 (dd, 1H, J=16.8, 5.6
Hz), .delta.4.14-4.09 (m, 2 H), .delta.0.81-1.89 (m, 13 H); EI MS
(M+=329.8);
[0298]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)naphthalene-2-carboxam-
ide (Compound 43); .sup.1H NMR (CDCl.sub.3): .delta.8.29 (s, 1 H),
.delta.7.76-7.94 (m, 5 H), .delta.7.51-7.61 (m, 2H), .delta.6.57(br
d, 1H, J=19.6Hz), .delta.4.73(dd, 1H, J=19.6, 11.2 Hz),
.delta.4.17(dd, 2 H, J=13.3, 8.4 Hz), .delta.0.80-2.03 (m, 13 H);
EI MS (M+=363.9);
[0299]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-4-trifluoromethylbenz-
amide (Compound 44); .sup.1H NMR (CDCl.sub.3): .delta.7.86-7.91 (m,
2 H), .delta.7.70-7.75 (m, 2 H), .delta.6.85 (br s, 1H),
.delta.6.48 (br d, 1 H, J=8.4 Hz), .delta.4.65 (dd, 1 H, J=19.6,
11.2 Hz), .delta.4.09-4.20 (m, 2 H), .delta.0.86-1.74 (m, 13 H); EI
MS (M+=381.9);
[0300]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-4-methoxybenzaniide
(Compound 45); .sup.1H NMR (CDCl.sub.3): .delta.7.70-7.73 (m, 3H),
.delta.6.94 (d, 2H, J=8.5 Hz), .delta.6.29 (br s, 1H),
.delta.4.57-4.69 (m, 1H), .delta.4.08-4.17 (m, 2H), .delta.3.85 (s,
3H), .delta.0.78-1.73 (m, 13H); EI MS (M+=343.9);
[0301]
N-cyanomethyl-3-cyclohexyl-2S-methylsulfonylaminopropionamide
(Compound 46); .sup.1H NMR (CDCl.sub.3): .delta.7.05 (br s, 1H),
.delta.5.29 (br d, 1H, J=8.7 Hz), .delta.4.12-4.20 (m, 1H),
.delta.3.44 (d, 2H, J=9.7 Hz), .delta.3.01 (s, 3H),
.delta.0.81-1.92 (m, 13H);
[0302] N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)acetamide
(Compound 47); .sup.1H NMR (CDCl.sub.3): .delta.7.51 (br s, 1H),
.delta.6.15 (br d, 1H, J=8.0 Hz), 6, 4.49 (dd, 1H, J=11.4 Hz),
.delta.4.11 (t, 2H, J=18.6 Hz), .delta.2.02 (s, 3H),
.delta.0.72-1.80 (m, 13H); EI MS (M+=251.6);
[0303]
N-(1-cyanomethylcarbamoyl-2-cyclohexylethyl)-3-fluorobenzamide
(Compound 48); .sup.1H NMR (CDCl.sub.3): .delta.7.19-7.55 (m, 5 H),
.delta.6.72 (br s, 1 H, J=8.7 Hz), .delta.4.69 (dd, 1 J=10.8, 3.8
Hz), .delta.4.14 (dd, 2 H, J=2.8, 15.7 Hz), .delta.0.86-1.86 (m, 13
H); EI MS (M+=331.9);
[0304]
4-chloro-N-(1-cyanomethylcarbamoyl-2-cyclohexylethyl)benzamide
(Compound 49); .sup.1H NMR (CDCl.sub.3): .delta.8.78 (br s, 1H),
.delta.8.58 (br d, 1H, J=8.0 Hz), .delta.7.85 (d, 2H, J=9.0 Hz),
.delta.7.48 (d, 2H, J=9.2 Hz), .delta.4.64 (dd, 1H, J=7.4, 14.1
Hz), .delta.4.16 (dd, 2H, J=3.1, 6.1 Hz), .delta.0.87-1.85 (m,
13H); EI MS (M+=347.9);
[0305]
N-(1-cyanomethylcarbamoyl-2-cyclohexylethyl)-2-trifluoromethylbenza-
mide (Compound 50); .sup.1H NMR (CDCl.sub.3): .delta.7.42-7.78 (m,
5 H1), .delta.6.56 (br d, 1 H, J=9.0 Hz .delta.4.81 (dd, 1 H,
J=15.4, 9.2 Hz), .delta.4.10 (t, 2H, J=5.7 Hz), .delta.0.80-1.79
(m, 131H); MS (M+=382.0);
[0306]
N-(1-cyanomethylcarbamoyl-2-cyclohexylethyl)-2-fluorobenzamide
(Compound 51); .sup.1H NMR (CDCl.sub.3): .delta.8.00 (t, 1 H, J=8.4
Hz), .delta.7.64 (br s, 1H), .delta.7.50 (dd, 1H, J=8.1, 2.5 Hz),
.delta.7.24-7.30 (m, 1 H), .delta.7.07-7.18 (m, 2 H), .delta.4.76
(dd, 1H, J=17.2, 8.2 Hz), .delta.4.16 (dd, 2H, J=18.0, 6.2 Hz),
.delta.0.81-1.89(m, 13 H);EI MS (M+=331.9);
[0307]
N-(1-cyanomethylcarbamoyl-2-cyclohexylethyl)-4-trifluoromethoxybenz-
amide (Compound 52); .sup.1H NMR (CDCl.sub.3): .delta.7.01-8.02 (m,
6H), .delta.4.75 (br d, 1H, J=14.6 Hz), .delta.4.14 (dd, 2H, J=6.0,
18.2 Hz), .delta.0.78-1.90 (m, 13 H); EI MS (M+=398.0);
[0308]
N-(1-cyanomethylcarbamoyl-2-cyclohexylethyl)-2,6-difluorobenzaniide
(Compound 53); .sup.1H NMR (CDCl.sub.3): .delta.7.66 (br s, 1H),
.delta.7.39 (t, 1H, J=8.7 Hz), .delta.6.95 (t, 2 H, J=8.7 Hz),
.delta.6.74 (br d, 1 H, J=8.5 Hz), .delta.4.85 (dd, 1H, J=14.9, 9.2
Hz), .delta.0.86-1.87 (m, 13 H); EI MS (M+=349.9);
[0309]
N-(1-cyanomethylcarbamoyl-2-cyclohexylethyl)-2,3-difluorobenzamide
(Compound 54); .sup.1H NMR (CDCl.sub.3): .delta.8.04 (dd, 1H,
J=15.3, 8.7 Hz), .delta.7.55 (br s, 1H), .delta.6.84-7.07 (m, 3H),
.delta.4.74 (dd, 1H, J=16.6, 7.9 Hz), .delta.4.16 (dd, 2H, J=18.0,
5.9 Hz), .delta.0.82-1.89 (m, 13H); EI MS (M+=349.9);
[0310]
N-(1-cyanomethylcarbamoyl-2-cyclohexylethyl)-2,5-difluorobenzamide
(Compound 55); .sup.1H NMR (CDCl.sub.3): .delta.7.69 (m, 1H),
.delta.7.37 (br s, 1H), .delta.7.08-7.27 (m, 3H), .delta.4.71 (dd,
1H, J=15.1, 6.1 Hz), .delta.4.16 (dd, 2H, J=18.0, 6.2 Hz),
.delta.0.84-1.90 (m, 13 H); EI MS (M+=350.1);
[0311]
N-(1-cyanomethylcarbamovy-2-cyclohexylethyl)-2,4-difluorobenzamide
(Compound 56); .sup.1H NMR (CDCl.sub.3): .delta.7.80 (br s, 1H),
.delta.7.65 (t, 1H), .delta.7.14-7.36 (m, 3H), .delta.4.79 (dd, 1H,
J=14.9, 7.2 Hz), .delta.4.15 (dd, 2H, J=18.2, 5.9 Hz),
.delta.0.80-1.81 (m, 13 H); EI MS (M+=349.9);
[0312]
N-(1-cyanomethylcarbamoyl-2-cyclohexylethyl)-3,4-dimethoxybenzamide
(Compound 57); .sup.1H NMR (CDCl.sub.3): .delta.7.66 (br s, 1H),
.delta.7.28-7.41 (m, 2 H), .delta.6.86 (d, 1H, J=8.4 Hz),
.delta.6.73 (br d, 1H, J=7.9 Hz), .delta.4.71 (dd, 1H, J=14.1, 8.4
Hz), .delta.4.14 (dd, 2H, J=17.3, 5.9 Hz), .delta.3.91 (s, 6H),
.delta.0.81-1.88 (m, 13 H); EI MS (M+=374);
[0313]
N-(1-cyanomethylcarbamoyl-2-cyclohexylethyl)-3,5-dimethoxybenzamide
(Compound 58); .sup.1H NMR (CDCl.sub.3): .delta.7.41 (br s, 1H),
.delta.6.88 (d, 2H, J=2.4 Hz), .delta.6.59 (t, 2H, J=2.2 Hz),
.delta.4.67(dd, 1H, J=16.8, 3.0 Hz), .delta.4.12 (dd, 2H, J=17.3,
5.7 Hz), .delta.3.81 (s, 6H), .delta.0.82-1.88 (m, 13H); EI MS
(M+=374);
[0314] N-(1-cyanomethylcarbamoyl-2-thiazol-5-ylethyl)benzamide
(Compound 59); .sup.1H NMR (CDCl.sub.3): .delta.8.30 (d, 2H, J=8.7
Hz), .delta.7.72 (br s, 1H), .delta.7.38-7.67 (m, 4H), .delta.7.13
(t, 2H, J=8.0 Hz), .delta.4.96 (dd, 1H, J=12.3, 5.9 Hz),
.delta.4.02 (t, 2H, J=10.5 Hz), .delta.3.48 (dd, 2H, J=15.7, 5.4
Hz);
[0315] N-(1-cyanomethylcarbamoyl-2-thien-2-ylethyl)benzamide
(Compound .delta.0); .sup.1H NMR (CDCl.sub.3): .delta.7.71 (d, 2H,
1J=8.5 Hz), .delta.7.39-7.55 (m, 4H), .delta.7.14 (d, 1H, J=11.2
Hz), .delta.6.85-6.96 (m, 3H), .delta.4.94 (dd, 1H, J=14.6, 6.9
Hz), .delta.4.09 (m, 2H), .delta.3.41 (t, 2H, J=6.2 Hz); EI MS
(M+=313.8);
[0316] N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)benzamide
(Compound 61); Proton NMR (300 MHz, CDCl3): .delta.7.79 (d, J=7 Hz,
2H), .delta.7.67 (bt, 1H), .delta.7.44 (m, 3H), .delta.6.75 (bd,
1H), .delta.4.74 (m, 1H), .delta.4.10 (m, 2H), .delta.1.50-1.88 (m,
81), .delta.0.83-1.44 (m, 5H). MS (electrospray): mH.sup.+ 313.9
(100%); and
[0317]
N-cyanomethyl-3-cyclohexyl-2S-trifluoromethylsulfonylaminopropionam-
ide (Compound 62).
EXAMPLE 3
tert-Butyl 5-amino-1S-cyanomethylcarbamoylpentylcarbamate (Compound
63)
[0318] 36
[0319] A solution comprised of benzyl
5S-tert-butoxycarbonylamino-5-cyanom- ethylcarbamoylpentylcarbamate
(77 mg, 184 mmol), prepared as in Example 1, in ethanol (2 mL) was
treated with ammoniumformate (116 mg, 1.84 mmol) and 10% wt
palladium on carbon (77 mg). The mixture was stiffed for 15,hours
and then filtered through Celite. The filter cake washed with
ethanol and the combined filtrates were concentrated on a rotary
evaporator to provide tert-butyl
5-amino-1S-cyanomethylcarbamoylpentylcar- bamate (61 mg, 184 mmol)
as a white solid. .sup.1H NMR (DMSO-d.sub.6): .delta.1.42 (m, 17
H), .delta.2.63 (m, 2H), .delta.3.09 (m, 2H); ES-MS rm/z 323
(MK+).
EXAMPLE 4
[0320] N-(1S-Cyanomethylcarbamoyl-2-cyclohexylethyl)isophthal amic
acid (Compound 64) 37
[0321] A solution comprised of benzyl
N-(1S-cyanomethylcarbamoyl-2-cyclohe- xylethyl)isophthalamate (82.4
mg, 184 .mu.mol, 1.0 eq), prepared as in Example 2, in ethanol (2
mL) was treated with ammonium formate (116 mg, 1.84 mmol, 10.0 eq)
and 10% wt palladium on carbon (82.4 mg). The mixture was stirred
for 15 hours and filtered through Celite. The filter cake was
washed with ethanol and the combined filtrates were concentrated on
a rotary evaporator to provide
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl- )terephthalamic acid
(61 mg, 170.7 .mu.mol) as a white solid. .sup.1H NMR
(MeOH-d.sub.4): .delta.0.96 (m, 2H), .delta.1.26 (m, 2H),
.delta.1.38 (m, 4H), .delta.1.76 (m, 5H), .delta.3.23 (d, 1H, J=8
Hz), .delta.3.72 (t, 1H, J=7 Hz), .delta.4.50 (m, 1H), .delta.7.50
(m, 1H), .delta.7.97 (m, 1H), .delta.8.13 (m, 1H), .delta.8.46 (m,
1H); ES-MS mfz 359 (MD+).
[0322] Proceeding as in Example 4 provided the following compounds
of Formula I:
[0323] N-(1-cyanomethylcarbamoyl-2-cyclohexylethyl)terephthalamic
acid (Compound 65); .sup.1H NMR (MeOH-d.sub.4): .delta.0.96 (m,
211), .delta.1.32 (m, 5H), .delta.1.81 (m, 6H), .delta.3.12 (m,
2H), .delta.4.92 (m, 1H), .delta.7.87 (m, 2H), .delta.8.02 (m, 2H);
ES-MS m/z 359 (MD+);
[0324]
N-[1-cyanomethylcarbamoyl-2-(2,6-dichlorophenyl)ethyl]benzamide
(Compound 66); .sup.1H NMR: .delta.3.45 (m, 1H), .delta.3.56 (m,
1H), .delta.84.13 (m, 2H), .delta.5.03 (m, 1H), .delta.7.30 (m,
5H), .delta.7.63 (m, 3H); ES-MS m/z 376 (MH+); and
[0325] N-(1-cyanomethylcarbamoyl-2-cyclohexylethyl)phthalamic acid
(Compound 67); .sup.1H NMR (MeOH-d.sub.4): .delta.0.94 (d, 2H, J=7
Hz), .delta.0.97 (d, 2H, J=7 Hz), .delta.1.28 (d, 2H, J=7 Hz),
.delta.1.47 (m, 1H), .delta.1.73 (m, 6H), .delta.3.09 (t, H; J=6
Hz), .delta.3.29 (m, 1H), .delta.4.45 (dd, 1H, J=11, 5 Hz),
.delta.7.36 (m, 1H ), .delta.7.58 (m, 2H), .delta.7.72 (m, 1H);
ES-MS m/z 359 (MD+).
EXAMPLE 5
N-(1S-Cyanomethylcarbamoyl-2-cyclohexylethyl)morpholine-4-carboxamide
(Compound 68)
[0326] 38
[0327] A mixture of lithium 2S-amino-3-cyclohexylpropionate (260
.mu.mol, 1.0 eq), provided as in Reference 1, EDC (286 .mu.mol, 1.1
eq), HOBt (312 .mu.mo, 1.2 eq) and triethylamine (911 .mu.mol, 3.5
eq) in dry dichloromethane (1 mL) was stirred under a nitrogen
atmosphere for 5 minutes and then treated with aminoacetonitrile
hydrochloride (520 .mu.mol, 2.0 eq). The mixture was stirred 15
hours and then diluted with ethyl acetate (1 mL). The dilution was
washed with 1 M hydrochloric acid (2.times.1 mL),saturated
NaHCO.sub.3 (1 mL) and saturated NaCl (1 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated on a rotary evaporator
to provide N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)morpho-
line-4-carboxamide. 1H NMR (CDCl.sub.3) 0.95 (m, 2H); 1.23 (m, 4H);
1.62 (m, 7H); 3.35 (m, 4H); 3.68 (m, 4H): 4.05 (dd, 2H, J=16, 6
Hz); 4.17 (dd, 2H, J=18, 6 Hz ); 4.27 (m, 1H); 5.01 (d, 1H, J=8
Hz): 7.93 (t, 1H, J=6Hz); ES-MS m/z 323 (MH+).
[0328] Proceeding as in Example 5 provided the following compounds
of Formula I:
[0329]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)piperidine-1-carboxami-
de (Compound 69); 1H NMR 0.95 (CDCl.sub.3) (m, 2H); 1.24 (m, 6H);
1.60 (m, 11H); 3.54 (m, 4H); 4.11 (m, 2H); 4.33 (m, 1H); 4.75 (d,
1H, J=8 Hz); 7.88 (t, 1H, J=6 Hz) ES-MS m/z 321 (MH+);
[0330] tert-butyl
4-(1S-cyanomethylcarbamoyl-2-cyclohexylethylcarbamoyl)
piperazine-1-carboxylate (Compound 70); 1H NMR (CDCl.sub.3) 0.89
(m, 2H); 1.23 (m, 4H); 1.44 (s, 9H); 1.66 (m, 7H); 3.36 (s, 4H );
3.40 (s, 4H); 4.03 (dd, 1H, J=18, 5 Hz); 4.14 (dd, 1H, J=18, 6 Hz);
4.38 (dd, 1H, J=15, 8 Hz); 5.32 (d, 1H, J=8 Hz); 8.21 (t, 1H, J=6
Hz): ES-MS m/z 422 (MH+);
[0331] N-(1S-cyanomethylcarbamoyl
-2-cyclohexylethyl)-4-benzylpiperazine-1- -carboxamiide (Compound
71); 1H NMR (CDCl.sub.3) (0.96 (m, 2H); 1.24 (m, 4H); 1.70 (m, 7H);
2.44 (t, 4H, J=5 Hz); 3.37 (t, 4H, J=5 Hz); 3.52 (s, 2H); 4.06 (dd,
1H, J=18, 6 Hz): 4.15 (dd, 1H, J=18, 6 Hz); 4.32 (m, 1H); 7.30 (m,
5H); 7.72 (t, 1H, J=6 Hz); ES-MS m/z 412 (MH+);
[0332] 3-methoxybenzyl
1S-cyanomethylcarbamoyl-2-cyclohexylethylcarbamic (Compound 72); 1H
NMR 0.96 (m, 2H); 1.24 (m, 4H); 1.70 (m, 7H); 3.78 (s, 3H); 4.12
(m, 2H); 4.21 (m, 1H); 5.11 (m, 2H); 6.89 (m, 3H), 7.32 (m, 1H);
ES-MS m/z 374 (MH+);
[0333] ethyl
4-(1S-cyanomethylcarbamoyl-2-cyclohexylethylcarbamoyl)piperaz-
ine-1-carboxylate (Compound 73); and
[0334]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-4-fur-2-ylcarbonylpip-
erazine-1-carboxamide (Compound 74).
EXAMPLE .delta.
N-Cyanomethyl-3-cyclohexyl-2S-(3-phenethylureido)propionamide
(Compound 75)
[0335] 39
[0336] A solution of tert-butyl
1S-cyanomethylcarbamoyl-2-cyclohexylethylc- arbamate (103 mmol, 1
eq), provided as in Example 1, in diethyl ether (323 mL) was
treated with toluenesulfonic acid monohydrate (206 nmol, 2.0 eq,
azeotroped on a rotary evaporator with 2-propanol 3 times, until a
white solid had formed) for 12 hours. The supernatant was decanted
and the solid was washed extensively with diethyl ether until a
powder had formed. A portion of the resulting acid salt (789
.mu.mol, 1 eq) was suspended in dry acetonitrile (1 mL) and then
treated with phenethylisocyanate (789 .mu.mol, 1.0 eq) and
4-methylmorpholine (789 .mu.mol, 1 eq) for 12 hours. The mixture
was concentrated in vacuo and the residue dissolved in methylene
chloride. The solution was stirred with 100 mg Argonaut
PS-trisamine resin (345 .mu.mol, 0.4 eq) for 2 hours. The mixture
was filtered, diluted with ethyl acetate (1 mL), washed with 1M
hydrochloric acid (1 mL), saturated sodium bicarbonate solution and
saturated NaCl solution, dried over sodium sulfate, filtered and
concentrated to provide
N-cyanomethyl-3-cyclohexyl-2S-(3-phenethylure-
ido)propionamide.
[0337] Proceeding as in Example 6 provided
N-cyanomethyl-3-cyclohexyl-2S-(- 3-isopropylureido)propionamide
(Compound 76).
[0338] Proceeding in a fashion analogous to the procedures
exemplified above provided the following compounds of Formula
I:
[0339] N-[1S-cyanomethylcarbamoyl-3-phenylpropyl]benzamide
(Compound 77);
[0340]
N-[1S-cyanomethylcarbamoyl-2-(4-hydroxyphenylethyl)]benzamide
(Compound 78);
[0341]
N-(1-cyanomethylcarbamoyl-2-cyclohexylethyl)-3-hydroxybenzamide
(Compound 79); NMR 300 mHz (DMSO-d.sub.6), 8.39 (d, J8.5H.sub.3,
1H), 7.26 (m, 3H), 6.96 (m, 1H), 4.64 (m, 1H), 4.14 (dd, J=4.2 and
17.3H.sub.3, 2H), 3.30 (m, 2H), 1.71 (m, 7H), 1.68-0.80 (m, 6H);
MS=329.85 M+=329.40;
[0342]
1-benzyl-5-benzyloxy-N-(1-cyanomethylcarbamoyl-2-phenylethyl)-2-met-
hyl-1H-indole-3-carboxamide (Compound 80); MS: (m/z [mH.sup.+])
557.0;
[0343] N-(1-cyanomethylcarbamoyl-2-phenylethyl)-1-furan-2-ylmethyl
-5-methoxy-2-methyl-1H-indole-3-carboxamide (Compound 81); MS: (m/z
[mH.sup.+]) 470.6;
[0344]
N-(1-cyanomethylcarbamoyl-2-methylpropyl)-5-ethoxy-1-furan-2-ylmeth-
yl-2-methyl-1H-indole-3-carboxamnide (Compound 82); MS: (m/z
[mH.sup.+]) 436.9;
[0345]
1-benzo[1.3]dioxol-4-ylmethyl-N-(2-benzylsulfany-1-cyanomethylcarba-
moylethyl)-5-methoxy-2-methyl-1H-indole-3-carboxamide (Compound
83); MS: (m/z [mH.sup.+]) 570.8;
[0346] benzyl
5-(1-benzo[1,3]dioxol-4-ylmethyl-5-benzyloxy-2-methyl-1H-ind-
ol-3-ylcarbonylamino)-5-cyanomethylcarbamoylpentylcarbamate
(Compound 84); MS: (m/z [mH.sup.+]) 716.0;
[0347] benzyl
5-(1-benzyl-5-benzyloxy-2-methyl-1H-indol-3-ylcarbonylamino)-
-5-cyanomethylcarbamoylpentylcarbamate (Compound 85); MS: (m/z
[mH.sup.+]) 672.4;
[0348] benzyl
5-cyanomethylcarbamoyl-5-(1-furan-2-ylmethyl-5-methoxy-2-met-
hyl-1H-indol-3-ylcarbonylamino)pentylcarbamate (Compound 86); MS:
(m/z [mH.sup.+]) 586.8;
[0349] N-(1-cyanomethylcarbamoylpent-3-enyl)benzamide (Compound
87); NMR 300 mHz (DMSO-d.sub.6), 8.67 (t, J=6H.sub.3, 1H), 8.53 (d,
J=8.5H.sub.3, 1H), 7.86 (m, 2H), 7.50 (m, 3H), 5.3-5.7 (m, 2H),
4.40 (m, 1H), 4.12 (d, J=6H.sub.3, 2H), 2.3-2.6 (m, 2H), 1.57 (d,
J=6.9H.sub.3, 3H); MS=271.8 M+=271.32;
[0350] N-(1-cyanomethylcarbamoylpent-4-enyl)benzamide (Compound
88); NMR 300 mHz (DMSO-d.sub.6), 8.66 (m, 1H), 8.57 (d,
J=8.2H.sub.3, 1H), 7.89 (m, 2H), 7.47 (m, 3H), 5.80 (m, 1H),
4.9-5.05 (m, 2H), 4.4 (m, 1H), 4.11 (d, J=2.5H.sub.3, 2H), 2.1 (m,
2H), 1.83 (m, 2H); MS=271.8 M+=271.32;
[0351] N-(1-cyanomethylcarbamoylbutyl)benzamide (Compound 89); NMR
300 mHz (DMSO-d.sub.6), 8.66 (t, J=5.8H.sub.3, 1h), 8.53 (d,
J=8.8H.sub.3, 1H), 7.90 (m, 2H), 7.46 (m, 3H), 4.41 (m, 1H), 4.12
(m, 2H), 1.70 (m, 2H), 0.87 (t, J=8H.sub.3, 3H); MS=259.8
M+=259.31;
[0352] N-(1-cyanomethylcarbamoylpent-4-ynyl)benzamide (Compound
90); NMR 300 mHz (DMSO-d.sub.6), 8.67 (t, 1H), 8.61 (d,
J=8.5H.sub.3, 1H), 7.91 (m, 2H), 7.50 (m, 3H), 4.5 (m, 1H), 4.12
(m, 2H), 2.83 (t, J=2.5H.sub.3, 1H), 2.25 (m, 2H), 1.97 (m, 2H);
MS=269.8 M+=269.30;
[0353]
2-chloro-N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)benzamide
(Compound 91);
[0354]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-2-iodobenzaniide
(Compound 92); .sup.1H NMR (CDCl.sub.3): 7.68 (t, J=6 Hz, 1H), 7.34
(m, 4H), 6.41 (d, J=8 Hz, 1H), 4.78 (m, 1H), 4.13 (d, J=12 Hz, 2H),
2.0-0.8 (m, 13H); MS m/e 439.9;
[0355]
2-bromo-N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)benzamide
(Compound 93); .sup.1H NMR (CDCl.sub.3): 7.68 (t, J=5.7 Hz, 1H),
7.58 (dd, J=3, 12 Hz, 1H), 7.44 (dd, J=2.1, 12 Hz, 1H), 7.34 (m,
2H), 7.57 (d, J=8 Hz, 1H), 4.79 (m, 1H), 4.13 (d, J=5.7 Hz, 2H),
2.0-0.8 (m, 13H); MS m/c 393.7;
[0356] N-(1S-cyanomethylcarbamoylhexyl)benzamide (Compound 94);
.sup.1H NMR (DMSO): 8.65 (t,J=3 Hz, 1H), 8.54 (d,J=8 Hz, 1H), 7.91
(d,J=7 Hz, 2H), 7.5 (m, 3H), 4.4 (m, 1H), 4.13 (d,J=5 Hz, 2H), 1.74
(m, 2H), 1.3 (m, 6H), 0.85 (t,J=7 Hz, 3H); MS: m/e=287.8;
[0357] N-(1S-cyanomethylcarbamoyl-4-phenylbutyl)benzamide (Compound
95); .sup.1H NMR (DMSO): 8.67 (t,J=7 Hz, 1H), 8.56 (d,J=9 Hz, 1H),
7.88 (d,J=9 Hz, 2H), 7.4 (m, 3H), 7.2 (m, 5H), 4.45 (m, 1H), 4.11
(d,J=5 Hz, 2H), 2.58 (t,J=8 Hz, 2H), 1.7 (m, 4H; MS: m/e=335.9;
[0358]
N-(1S-cyanomethylcarbamoyl-2-cyclobexylethyl)-2-methoxybenzamide
(Compound 96);
[0359]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-3,4,5-trimethoxybenza-
mide (Compound 97);
[0360] benzyl 1S-cyanomethylcarbamoyl-2-cyclohexylethylcarbamate
(Compound 98);
[0361] isobutyl 1S-cyanomethylcarbamoyl-2-cyclohexylethylcarbamate
(Compound 99); cyclohexylmethyl
1S-cyanomethylcarbamoyl-2-cyclohexylethyl- carbamic (Compound
100);
[0362] N-(1S-cyanomethylcarbamoyl-3-cyclohexylpropyl)benzamide
(Compound 101); .sup.1H NMR (DMSO): 8.66 (m, 1H), 8.52 (d,J=8 Hz,
1H), 7.88 (d,J=8 Hz, 2H), 7.45 (m, 3H), 4.37 (m, 1H), 4.12 (m, 2H),
1.9-0,08 (m, 15H); MS: m/e=328.3;
[0363]
N-(1S-cyanomethyjcarbamoyl-2-cyclohexylethyl)-2-trifluoromethoxyben-
zamide (Compound 102); .sup.1H NMR (CDCl.sub.3): 7.90 (dd, J=3, 10
Hz, 1H), 7.79 (m, 1H), 7.535 (m, 1H), 7.395 (m, 1H), 7.31 (m, H),
6.92 (d,J=8 Hz, H), 4.74 (m, 1H), 4.2 (dd,J=6,17 Hz, 1H), 4.1
(dd,J=6,17 Hz, 1H), 0.8-1.8 (m, 13H); MS:m/e=397.9;
[0364]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-3-trifluoromethoxyben-
zamide (Compound 103); .sup.1H NMR (CDCl.sub.3): 7.68 (m, 2H), 7.44
(m, 3H), 7.03 (t, =6.6 Hz, 1H), 4.73 (m, 1H), 4.38 (m, 1H), 4.11
(m, 2H), 0.8-1.8 (m, 1H); MS:m/e=397.9;
[0365]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-3-iodobenzamide
(Compound 104); .sup.1H NMR (CDCl.sub.3): 8.1 (t, J=2.8 Hz, 1H),
7.87 (d,J=6.9 Hz, 1H), 7.70 (d,J=7.7 Hz, 1H), 7.19 (t, J=17.5 Hz,
1H), 6.9 (m, 1H), 6.44 (d,J=12 Hz, 1H), 4.63 (m, 1H), 4.21
(dd,J=9.6, 6.6 Hz, 1H), 4.1 (dd,J=9.6, 6.6 Hz, 1H) 0.8-2.0 (m,
13H); MS:m/e=440.0;
[0366]
3-chloro-N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)benzamide
(Compound 105); .sup.1H NMR (CDCl.sub.3): 7.5 (t, J=5.2 Hz, 1H),
7.65 (d, J=7.63 Hz, 1H), 7.51 (d,J=6 Hz, 1H), 7.39 (t, J=8.8 Hz,
1H), 6.59 (d, J=9.9 Hz, 1H), 2.0-0.8 (m, 13); MS:m/e =348.0;
[0367] 2-methoxyethyl
1S-cyanomethylcarbamoyl-2-cyclohexylethylcarbamate (Compound
106);
[0368]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)cyclohexanecarboxamide
(Compound 107);
[0369]
N-cyanomethyl-3-cyclohexyl-2S-[2-(4-metboxyphenyl)acetylamino]propi-
onamide (Compound 108); .sup.1H NMR (CDCl.sub.3): 7.83 (t, J=6 Hz,
1H), 7.13 (d,J=9 Hz, 2H), 6.86 (d,J=12 Hz, 2H), 6.22 (d, J=8 Hz,
1H), 4.55 (m, 1H), 3.95 (m, 2H), 3.78 (s,J=0 Hz, 3H), 0.8-1.8 (m,
13H); MS:m/e=358.0;
[0370]
N-(1R-cyanomethylcarbamoyl-2-cyclohexylethyl)-2-methylsulfanylbenza-
mide (Compound 109); .sup.1H NMR: (CDCl.sub.3) 8.11 (t, J=5.5 Hz,
1H), 7.50 (d, J=7.5 Hz, 1H), 7.40 (t, J=7.5 Hz, 1H), 7.30 (d, J=1
Hz, J=7.9 Hz, H), 7.17 (t, J=7.7 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H),
4.88 (m, 1H), 4.16 (dd, J=5.7 Hz, J=17.3 Hz, 1H), 4.08 (dd, J=5.7
Hz, J=17.3 Hz, 1H), 2.46 (s, 3H), 1.85-0.80 (m, 13H); MS:
(M.sup.++1) 360;
[0371]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-3,4-difluoro-benzamid-
e (Compound 110); .sup.1H NMR (CDCl.sub.3): 7.5 (t, J=5.1 Hz, 1H),
5.88 (d, J=7.7 Hz, 1H), 4.49 (m, 1H), 4.18 d, J=6 Hz, 1H), 4.11 (d,
J=6 Hz, 1H), 2.12-0.8 (m, 24H); MS:m/e=320.0,
[0372]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-3-methoxybenzarimde
(Compound 111); .sup.1H NMR: (CDCl.sub.3) 7.63 (m, 1H), 7.37-7.28
(m, 3H), 7.06 (m, 1H), 6.76 (d, J=7.7 Hz, 1H), 4.73 (m, 1H), 4.20
(dd, J.5.9 Hz, J=17.3 Hz, 1H), 4.07 (dd, J=5.7 Hz, J=17.3 Hz, 1H),
3.83 (s, 3H), 1.85-0.82 (m, 13H); MS:(M.sup.++1) 344;
[0373]
4-bromo-N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)benzamide
(Compound 112); .sup.1H NMR: (CDCl.sub.3) 7.65-7.57 (m, 4H), 7.10
(m, 1H), 6.48 (d, J=7.7 Hz, 1H), 4.67 (m, 1H), 4.21 (dd, J=5.9 Hz,
J=17.3 Hz, 1H), 4.12 (dd, J=5.7 Hz, J=17.3 Hz, 1H), 1.85-0.82 (m,
13H);. MS: (M.sup.++1) 392/394;
[0374]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)piperazine-1-carboxami-
de (Compound 113);
[0375] benzyl
4-(2-benzoylamino-2S-cyanomethylcarbamoylethyl)piperidine-1--
carboxylate (Compound 114);
[0376]
3-bromo-N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)benzamide
(Compound 115); .sup.1H NMR: (CD.sub.3OD) 8.05 (s, 1H), 7.83.(d,
J=7.7 Hz, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 4.67
(dd, J=6.9 Hz, J=8.7 Hz, 1H), 4.19 (d, J=17.5 Hz, 1H), 4.11 (d,
J=17.3 Hz, 1H), 1.85-0.82 (m, 13H); MS: (M.sup.++1) 392/394;
[0377]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-3-methylbenzamide
(Compound 116); .sup.1H NMR (DMSO): 7.64 (t, 1H), 7.25 (m, 4H),
6.43 (d, J=12 Hz, 1H), 4.67 (m, 1H), 4.13 (m, 2H), 2.4 (s, 3H),
2.0-0.7 (m, 13H); MS m/e 327.8;
[0378] N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)pentanamide
(Compound 117); .sup.1H NMR (CDCl.sub.3): 8.11 (t, 1H), 6.53 (d,
J=8 Hz, 1H), 4.59 (m, 1H), 4.10 (m, 2H), 2.21 (t, J=4.5 Hz, 2H),
1.8-0.8 (m, 20H); MS m/e 293.8;
[0379]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-2-methylbenzamide
(Compound 118); .sup.1H NMR (CDCl.sub.3): 7.91 (d, J=5.7 Hz, 1H),
7.23 (m, 4H), 6.50 (t, J=3Hz, 1H), 4.76 (m, 1H), 4.05 (s, J=18 Hz,
1H), 2.38 (d, 3H), 2.0-0.8 (m, 13H); MS m/e 328;
[0380]
N-(1S-cyanomethylcarbamoyl-2-cyclohcxylethyl)thiophene-3-carboxamid-
e (Compound 119); .sup.1H NMR (CDCl.sub.3): 8.1 (m, 2H), 7.32 (m,
t, 2H), 7.08 (d, J=7.9 Hz, 1H), 4.73 (m, 1H), 4.05 (dd, J=6,17 Hz,
2H), 2.0-0.8 (m, 13H); MS m/e 319.80;
[0381]
2S-[2-(4-benzyloxyphenyl)acetylamino]-N-cyanomethyl-3-cyclohexylpro-
pionamide (Compound 120); .sup.1H NMR (CDCl.sub.3): 7.8 (t, 1H),
7.5-6.9 (m, 9H), 6.10 (d, J=8 Hz, 1H), 5.0 (s, 2H), 4.5 (m, 1H),
3.95 (m, 2H), 3.5 (s, 2H), 1.9-1.0 (m, 13H); MS m/e 434.97;
[0382]
N-cyanomethyl-3-cyclohexyl-2S-[2-(2-methoxyphenyl)acetylamino]propi-
onamide (Compound 121); .sup.1H NMR (CDCl.sub.3): 7.58 (t, J=7.8
Hz, 1H), 7.23 (m, 2H), 6.91 (m, 2H), 6.21 (d, J=7.2 Hz, 1H), 4.44
(m, 1H), 3.94 (d, J=5.7 Hz, 2H), 3.84 (s, 3H), 3.60 (d, J=8 Hz,
1H), 3.49 (d, J=8 Hz, 1H), 1.8-0.5 (m, 13H); MS m/e 357.89;
[0383]
N-cyanomethyl-3-cyclohexyl-2-[2-(4-phenoxyphenyl)acetylamino]propio-
namide (Compound 122); .sup.1H NMR (CDCl.sub.3): 7.55 (t, J=3 Hz,
1H), 7.4-6.9 (m, 9H), 6.04 (d, J=8.8 Hz, 1H), 4.47 (m, 1H), 4.02
(d, J=6 Hz, 2H), 3.54 (s, 2H), 2.0-0.6 (m, 13 H); MS m/e
419.94;
[0384] N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)isonicotinamide
(Compound 123); .sup.1H NMR (DMSO): 8.68 (d, J=4.5 Hz, 2H), 8.2 (t,
J=6.3 Hz, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.66 (d, J=4.7 Hz, 2H), 4.80
(m, 1H), 4.12 (d, J=6 Hz, 2H), 2.0-0.7 (m, 13H); MS m/e 314.8;
[0385]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)thiophene-2-carboxamid-
e (Compound 124); .sup.1H NMR: (CDCl.sub.3) 8.55 (t, J=5.5 Hz, 1H),
7.75 (d, J=7.7 Hz, 1H), 7.64 (dd, J=1 Hz, J=4 Hz, 1H), 7.48 (dd,
J=1 Hz, J=5 Hz, 1H), 7.04 (dd, J=5 Hz, J=4 Hz, 1H), 4.82 (q, J=7.5
Hz, 1H), 4.13 (dd, J=5.9 Hz, J=17 Hz, 1H), 3.93 (dd, J=5.7 Hz, J=17
Hz, 1H), 1.80-0.84 (m, 13H); MS: (M.sup.++1) 319.8;
[0386] N-(1S-cyanomethylcarbamoyl-2-pipclidin-4-ylethyl)benzamide
(Compound 125);
[0387]
N-[1S-cyanomethylcarbamoyl-2-(1-formyl-1H-indol-3-yl)ethyl]benzamid-
e (Compound 126);
[0388]
N-[1S-cyanomethylcarbamoyl-2-(1-formyl-1H-indol-3-yl)ethy]-4-fluoro-
benzamide (Compound 127);
[0389] N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)nicotinanide
(Compound 128); .sup.1H NMR (CDCl.sub.3): 9.01 (d, J=4 Hz, 1H),
8.72 (m, 1H), 8.11 (m, 1H), 7.83 (t, J=3 Hz, 1H), 7.39 (m, 2H),
4.77 (m, 1H), 7.14 (m, 2H), 2.0-0.6 (m, 13H); MS m/e 314.88;
[0390] tert-butyl 3-(1
S-cyanomethylcarbamoyl-2-cyclohexylethylcarbamoyl)p- henylcarbamate
(Compound 129);
[0391] N-[1
S-cyanomethylcarbamoyl-2-(1-formyl-1H-indol-3-yl)ethyl]-4-hydr-
oxybenzamide (Compound 130);
[0392]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-1H-indole-5-carboxami-
de (Compound 131); .sup.1H NMR (CDCl.sub.3): 11.32 (s, 1H), 8.64
(t, J=6 Hz, 1H), 8.35 (d, J=9 Hz, 1H), 8.22 (s, 1H), 7.68 (dd, J=3,
10 Hz, 1H), 7.42 (m, 1H), 6.54 (m, 1H), 4.54 (m, 1H), 4.12 (d,
J=5.7 Hz, 2H), 2.0-0.7 (m, 13H); MS m/e 352.86;
[0393]
N-(1R-cyanomethylcarbamoyl-2-cyclohexylethyl)-4-methylsulfanylbenza-
mide (Compound 132);
[0394]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)-3-fluorobenzamide
(Compound 133); .sup.1H NMR (CDCl.sub.3): 7.18-7.79 (m, 1H), 4.70
(dd,J=13.3, 7.2 Hz, 1H), 4.28 (d,J=7.7 Hz, 1H), 4.22 (d,J=7.4 Hz,
1H), 3.78 (m, 2H), 3.03 (dd,J=14.1, 6.2 Hz, 1H), 2.84 (J=14.1, 7.2
Hz, 1H); MS: m/e=371.88;
[0395]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)-4-fluorobenzamide
(Compound 134); .sup.1H NMR (CDCl.sub.3): 7.74 (m, 2), 7.47
(t,J=5.9 Hz, 1H), 7.29 (m, 4H), 7.09 (m, 4H), 4.72 (dd,J=13.6, 6.9
Hz, 1H), 4.11 (m, 2H), 3.77 (s, 5H), 3.02 (dd, J=13.8, 6.2 Hz, 1H),
2.83 (dd,J=13.8, 7.2 Hz, 1H); MS: m/e=371.79;
[0396]
N-(1S-cyanomethylcarbamoyl-2-(4-methoxybenzylsulfinyl)ethyl]benzami-
de (Compound 135); .sup.1H NMR (DMSO): 8.94 (d,J=8 Hz, 1H), 8.87
(d,J=6 Hz, 1H), 7.87 (d,J=7 Hz, 2H), 7.5 (m, 3H), 7.24 (d,J=10 Hz,
2H), 6.93 (d,J=10 Hz, 2H), 4.80 (dd,J=4, 12 Hz, 1H), 4.14 (d,J=14
Hz, 1H), 4.13 (s, 2H), 3.99 (d,J=14 Hz, 1H), 3.74 (s, 3H), 3.16
(dd,J=12, 14 Hz, 1H), 3.07 (dd,J=14, 4 Hz, 1H); MS: m/e=400.00;
[0397]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-4-methylbenzamide
(Compound 136); .sup.1H NMR (DMSO): 7.7 (t, 1H), 7.65 (d, 2H), 7.25
(d, 2H), 6.65 (d, 1H), 4.75 (m, 1H), 4.2 (dd, 1H), 4.03 (dd, 1H),
2.4 (5, 3H), 2-0.8 (m, 13H); MS: m/e 328.8;
[0398]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-3-phenoxybenzamide
(Compound 137); .sup.1H NMR (CDCl.sub.3): 8.49 (t, J=5.5 Hz, 1H),
7.75 (dd, J=10, 8.5 Hz, 1H), 7.6-6.9 (m, 9H), 4.84 (m, 1H), 3.95
(m, 2H), 2.0-0.8 (m, 13H); MS: m/e=405.93;
[0399] 3-benzoyl-N-(1S-cyanomethylcarbamoyl
-2-cyclohexylethyl)benzamide (Compound 138); .sup.1H NMR
(CDCl.sub.3): 8.19 (t, J=3 Hz, 1H), 8.0 (m, 1H), 7.89 (d,J=8.8 Hz,
1H), 7.76-7.4 (m, 5H), 6.88 (m, 1H), 4.74 (m, 1H), 4.19 (dd,J=6,
6.3 Hz, 1H), 4.08 (dd,J=6, 6.3 Hz, 1H), 2.0-0.8 (m, 13H);
MS:m/e=417.95;
[0400]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)thiophene-3-carbox-
amide (Compound 139);
[0401]
3-acetyl-N-(1R-cyanomethylcarbamoyl-2-cyclohexylethyl)benzamide
(Compound 140); .sup.1H NMR: (CDCl.sub.3) 8.33 (t, J=1.5 Hz, 1H),
8.08 (dt, J=1.7 Hz, J=7.7 Hz, 1H), 7.99 (dt, J=1.7 Hz, J=7.9H, 1H),
7.55 (t, J=7.7 Hz, 1H), 7.45 (t, J=6.7 Hz, 1H), 6.92 (d, J=7.9 Hz,
1H), 4.74 (m, 1H), 4.23-4.05 (m, 2H), 2.63 (s, 3H), 1.90-0.84 (m,
13H); MS: (M.sup.++1) 355.8;
[0402]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)-4-methoxybenzamid-
e (Compound 141); .sup.1H NMR (CDCl.sub.3): 7.81 (t,J=5.7 Hz, 1H),
7.70 (dt,J=8.9, 2.2 Hz, 2H), 7.20-7.32 (m,J=5H), 7.04 (d,J=7.7 Hz,
1H), 6.89 (dt,J=8.9, 2.0 Hz, 2H), 4.82 (dd,J=14.1, 6.7 Hz, 1H),
4.08 (d,J=5.7 Hz, 2H), 3.83 (s, 3H), 3.74 (s, 2H), 3.00 (dd,J=13.9,
6.7 Hz, 1H), 2.86 (dd,J=13.9, 6.7 Hz, 1H); MS: m/e=383.80;
[0403]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)furan-2-carboxamid-
e (Compound 142); .sup.1H NMR (CDCl.sub.3): 7.49 (m, 1), 7.24-7.39
(m, 5H), 7.14 (m, 1H), 7.04 (m,J=2H), 6.53 (dd,J 3.7, 1.7 Hz, 1H),
4.64 (m, 1H), 4.13 (dd,J=5.9, 1.2 Hz, 2H), 3.79 (dd,J=16.1, 13.6
Hz, 2H), 3.03 (ddJ=14.1, 5.9 Hz, 1H), 2.80 (dd,J=14.3 6.9 Hz, 1H);
MS:m/e=343.84;
[0404]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)furan-3-carboxamid-
e (Compound 143); .sup.1H NMR: 8.33 (t,J=5.45 Hz, 1H), 7.16-7.28
(m, 5H), 5.41 (d,J=7.2 Hz, 1H), 4.52 (dd,J=13.9, 6.7 Hz, 1H), 4.06
(d,J=5.7 Hz, 2H), 3.68 (s, 2H), 3.10 (s, 3H), 3.05 (m, 1H), 3.00
(s, 3H), 2.80 (m=1H); MS (320.74);
[0405]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)-2-methoxybenzamid-
e (Compound 144); .sup.1H NMR (CDCl.sub.3): 8.75 (D,J=6.9 Hz, 1H),
8.14 (DDJ=2.0 7.9 Hz, 1H), 7.50 (m, 1H), 7.20-7.35 (m, 6H), 7.12
(m, 1H), 4.78 (dd,J=12.6, 6.2 Hz, 1H), 4.19 (dd, J=12.6 6.2 Hz,
1H), 4.07 (dd,J=13.5, 5.4 Hz, 1H), 3.97 (s, 3H), 3.80 (d,J=3.2 Hz,
2H), 3.08 (dd, J=14.0, 3.7 Hz, 1H0, 2.86 (dd, J=14.1, 6.7 Hz, 1H);
MS:m/e=383.93;
[0406] N-(2-benzyl
sulfanyl-1R-cyanomethylcarbamoylethyl)-3-methoxybenzami- de
(Compound 145); .sup.1H NMR (CDCl.sub.3): 7.96 (t,J=5.7 Hz, 1H),
7.16-7.36 (m, 8H), 7.05 (m, 1H), 4.80 (m, 1H), 4.08 (d,J=5.7 Hz,
1H), 3.80 (s, 3H), 3.77 (s, 2H), 2.98 (dd, J=13.9, 6.4 Hz, 1H),
2.86 (dd, J=6.9, 3.9 Hz, 1H); MS: m/e=383.77;
[0407]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)moipholine-4-carbo-
xamide (Compound 146); .sup.1H NMR (CDCl.sub.3): 7.45 (m, 1H), 7.23
(m, 5H), 5.28 (m, 1H), 4.39 (m, 1H), 4.16 (dd,J=17.6, 5.9 Hz, 1H),
4.06 (dd,J=1.1, 5.5 Hz, 1H), 3.74 (s, 2H), 3.67 (t,J=4.9 Hz, 4H),
3.31 (m, 1H), 3.00 (dd,J=14.1, 6.4 Hz, 1H), 2.77 (dd,J=13.8, 6.7
Hz, 1H); MS: (362.86);
[0408]
6-amino-N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)nicotinami-
de (Compound 147); .sup.1H NMR (CDCl.sub.3): 8.42 (d,J=2.5 Hz, 1H),
7.80 (dd,J=8.7 2.5 Hz, 1H), 7.18-7.30(m, 5H), 6.46 (dd,J=9.4 0.7
Hz, 1H), 4.64 (t,J=6.9 Hz, 1H, 4.08 (s, 2H), 3.70(S, 2H), 2.80 (M,
2H);MS: m/e=369.4474;
[0409]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)-3-pyrid-3-ylacryl-
amide (Compound 148); .sup.1H NMR (CDCl.sub.3): 8.72 (d,J=2.2 Hz,
1H), 8.54(J=4.7 1.5 Hz, 1H), 7.82 (dt,J=7.9, 2.2 Hz, 1H), 7.57
(d,J=15.6 Hz, 1H), 7.18-7.38 (m, 6H), 6.48 (d,J=15.8 Hz, 1H), 4.61
(m, H), 4.10 (s, 2H), 3.73 (s, 2H), 2.80 (m, 2H); MS:
m/e=380.4706;
[0410]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)naphthalene-2-carb-
oxamide (Compound 149); .sup.1H NMR (CDCl.sub.3): 8.28 (m, 1H),
7.90 (m, 3H), 7.78 (dd,J=8.4,1.8 Hz, 1H), 7.57 (m, 2H), 7.17-7.38
(m, 6H), 7.13 (J=7.2 Hz, 1H), 4.77 (m, 1H), 4.14 (d,J=5.9 Hz, 2H),
3.81 (s, 2H), 3.12 (dd,J=14.1, 5.9 Hz, 1H), 2.88 (dd,J=14.1, 7.2
Hz, 1H); MS (403.92);
[0411]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)benzofuran-2-carbo-
xamide (Compound 150); .sup.1H NMR (DMSO): 7.66 (dt,J=7.9, 1.2 Hz,
1H), 7.16-7.54 (m, 9H), 4.74 (m, 1H), 4.15 (d,J=6 Hz, 2H), 3.80
(dd,J=15.3, 13.6 Hz, 2H), 3.07 (dd,J=14.1, 5.9 Hz, 1H), 2.87 (dd,
J=14.1, 7.1 Hz, 1H); MS (393.83);
[0412]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)biphenyl-4-carboxa-
mide (Compound 151); .sup.1H NMR (CDCl.sub.3): 7.81 (dt,J=8.7, 1.5
Hz, 2H), 7.66 (m, 2H), 7.59 (m, 2H), 7.26-7.49 (m, 7H), 7.02
(d,J=7.2 Hz, 1H), 4.73 (m, 1H), 4.14 (dd,J=5.9, 1.2 Hz, 2H), 3.80
(s, 2H), 3.10 (dd,J=14.0, 7.2 Hz, 1H), 2.86 (dd,J=14.1, 7.2 Hz,
1H); MS (429.99);
[0413]
N-(2-benzylsulfanyl-1R-cyanbmethylcarbamoylethyl)benzo[1,3]dioxole--
5-carboxamide (Compound 152); .sup.1H NMR (CDCl.sub.3): 7.21-7.38
(m, 7H), 6.82 (d,J=8.2 Hz, 1H), 6.82 (m, 1H), 4.67 (dd,J=13.3, 6.9
Hz, 1H), 4.11 (dd,J=5.7, 1.6 Hz, 1H), 3.77 (s, 2H), 3.03
(dd,J=14.1, 6.2 Hz, 1H), 2.82 (dd,J=14.1, 6.9 Hz, 1H); MS
(397.82);
[0414]
N-(2-tert-butylsulfanyl-1R-cyanomethylcarbamoylethyl)benzamide
(Compound 153); .sup.1H NMR (DMSO): 8.77 (t,J=6 Hz, 1H), 8.69
(d,J=9 Hz, 1H), 7.89 (d,J=7 Hz, 2H), (m, 3H), 4.58 (m, 1H), 4.13
(t,J=3 Hz, 2H), 3.02 (dd,J=6, 14 Hz, 1H), 2.90 (dd,J=10, 14 Hz,
1H), 1.27 (s, 9H); MS: m/e=319.80;
[0415] N-(1R-cyanomethylcarbamoyl-3-phenylsulfanylpropyl)benzamide
(Compound 154); .sup.1H NMR (DMSO): 8.7 (m, 2H), 7.92 (d,J=7 Hz,
2H), 7.53 (m, 3H), 7.3 (m, 4H), 7.2 (m, 1H), 4.6 (q,J=7 Hz, 1H),
4.13 (d,J=6 Hz, 2H), 3.0 (m, 2H), 2.05 (m, 2H); MS: m/e=353.83;
[0416]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-3-methylthiophene-2-c-
arboxamide (Compound 155); .sup.1H NMR: (CDCl.sub.3) 7.75 (t,J=6
Hz, 1H), 7.32 (d, J=5 Hz, 1H), 6.90 (d, J=5 Hz, 1H), 6.30 (d, J=7.9
Hz, 1H), 4.72 (m, 1H), 4.19 (dd, J=5.7 Hz, J=17.5 Hz, 1H), 4.05
(dd, J=5.7 Hz, J=17.3 Hz, 1H), 2.51 (s, 3H), 1.85-0.85 (m, 13H);
MS: (M.sup.++1) 133.9;
[0417]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-5-methylthiophene-2-c-
arboxamide (Compound 156); .sup.1H NMR: (CDCl.sub.3) 8.14 (t, J=5.7
Hz, 1H), 7.39 (d, J=3.7 Hz, 1H), 6.93 (d, J=7.9 Hz, 1H), 6.72 (dd,
J=1 Hz, J=3.7 Hz, 1H), 4.74 (m, 1H), 4.17 (dd, J=5.9 Hz, J=17 Hz,
1H), 3.97 (dd, J=5.5 Hz, J=17.1 Hz, 1H), 2.50 (s, 3H), 1.80-0.82
(m, 13H); MS: (M.sup.++1) 333.8;
[0418]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-3-chlorothiophene-2-c-
arboxamide (Compound 157); .sup.1H NMR: (CDCl.sub.3) 7.52 (d, J=5.2
Hz, 1H), 7.43 (t, J=5.7 Hz, 1H), 7.32 (d, J=7.4 Hz, 1H), 7.01 (d,
J=5.2 Hz, 1H), 4.68 (m, 1H), 4.23 (dd, J=5.9 Hz, J=17.5 Hz, 1H),
4.08 (dd, J=6 Hz, J=17.3 Hz, 1H), 1.90-0.85 (m, 13H); MS:
(M.sup.++1) 353.8;
[0419]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-3-chlorobenzo[b]thiop-
hene-2-carboxamide (Compound 158); .sup.1H NMR: (CDCl.sub.3)
7.90-7.78 (m, 3H), 7.65 (d, J=7.9 Hz, 1H), 7.51-7.42 (m, 2H), 4.86
(q, J=8 Hz, 1H), 4.28 (dd, J=5.9 Hz, J=17.3 Hz, 1H), 4.12 (dd,
J=5.7 Hz, J=17.3 Hz, 1H), 1.90-0.85 (m, 13H); MS: (M.sup.++1)
403.8;
[0420]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-5-chlorothiophene-2-c-
arboxamide (Compound 159); .sup.1H NMR: (CDCl.sub.3) 8.18 (t, J=5.7
Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.40 (d, J=4 Hz, 1), 6.88 (d, J=4
Hz, 1H), 4.70 (q, J=7.7 Hz, 1H), 4.14 (dd, J=5.7 Hz, J=17 Hz, 1H),
4.05 (dd, J=6 Hz, J=17 Hz, 1H), 1.80-0.84 (m, 13H); MS: (M.sup.++1)
353.8;
[0421]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-3-bromothiophene-2-ca-
rboxamide (Compound 160); .sup.1H NMR (CDCl.sub.3): 7.55-7.39 (m,
3H), 7.07 (d,J=5.5 Hz, 1H), 4.68 (m, 1H), 4.25 (dt, 1H), 4.08 (dt,
1H), 2.0-0.8 (m, 13H); MS:m/e=399.74;
[0422]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-5-bromothiophene-2-ca-
rboxamide (Compound 161); .sup.1H NMR (CDCl.sub.3): 8.18 (t, J=5.4
Hz, 1H), 7.62 (d, J=3.5 Hz, 1H), 7.37 (d, J=4.0 Hz, 1H), 7.04 (d,
J=4.0 Hz, 1H), 4.70 (dd, J=7.2, 18.7 Hz, 1H), 4.15 (dd, J=5.7, 17.8
Hz, 1H), 4.05 (dd, J=5.7, 17.8, 1H), 1.5-1.8 (m, 7H), 0.8-1.50 (m,
6H); MS: m/e (+1) 399.83;
[0423]
N-(1S-cyanomethylearbamoyl-2-cyclohexylethyl)benzo[b]thiophene-2-ca-
rboxamide (Compound 162); NMR (MeOH): 8.06 (s, 1H), 7.91 (m, 2H),
7.43 (m, 2H), 4.64 (dd, J=6.7, 8.7 Hz, 1H), 4.21 (d, J=17.3 Hz,
1H), 4.13 (d, J=17.3 Hz, 1H), 1.61-1.90 (m, 8H), 0.89-1.55 (m, 4H);
MS: m/e=369.78;
[0424]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-3-ethoxybenzamide
(Compound 163); .sup.1H NMR (MeOH): 8.50 (d, J=7.4 Hz, 1H),
7.3-7.43 (m, 3H), 7.07 (d, J=8.2 Hz, 1H), 4.64 (dd, J=7.7, 19.2 Hz,
2H), 4.15 (d, J=4.2 Hz, 2H), 4.09 (d, J=6.9 Hz, 1), 4.04 (d, J=6.9
Hz, 1H), 1.35 (t,J=7.0, 3H), 0.9-1.9 (m, 13H); MS: m/e (+1)
357.94;
[0425] tert-butyl
3-(1S-cyanomethylcarbamoyl-3-methylbutylcarbamoyl)phenyl- carbamate
(Compound 164);
[0426] tert-butyl
3-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethylcarbamoy-
l)phenylcarbamate (Compound 165);
[0427] N-(1-cyanomethylcarbamoyl-3-phenoxypropyl)benzamide
(Compound 166); .sup.1H NMR (DMSO): 8.71 (m,=2H), 7.90 (d,J=14 Hz,
2H), 7.5 (m, 3H), 7.25 (m, 2H), 6.9 (m, 3H), 4.65 (m, 1H), 4.14
(d,J=6 Hz, 2H), 4.04 (m, 2H), 2.25 (m, 2H); MS: m/e=337.84;
[0428] tert-butyl
1S-cyanomethylcarbamoyl-2-(4-nitrophenyl)ethylcarbamate (Compound
167);
[0429] N-(1-cyanomethylcarbamoyl-5-fluoropentyl)benzamide (Compound
168); .sup.1H NMR (DMSO): 8.69 (t,J=6 Hz, 1H), 8.57 (d,J=8 Hz, 1H),
7.90 (d,J=7 Hz, 2H), 7.5 (m, 3H), 4.42 (dt,J=52, 6 Hz, 2H), 4.43
(m, 1H), 4.13 (s, 2H), 1.83-1.3 (m, 6H); MS: m/e=291.84;
[0430] tert-butyl
3-(1S-cyanomethylcarbamoylpentylcarbamoyl)phenylcarbamat- e
(Compound 169);
[0431] tert-butyl
3-cyanomethylcarbamoylmethylcarbamoylphenylcarbamate (Compound
170);
[0432]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)quinoline-3-carbox-
amide (Compound 171); .sup.1H NMR (DMSO): 9.30 (d,J=2.5 Hz, 1H),
8.58 (d,J=2.5 Hz, 1H), 8.16 (d,J=8.7 Hz, 1H), 7.90 (d,J=9.2 Hz,
1H), 7.83 (td,J=8.7, 1.5 Hz, 1H), 7.63 (td,J=6.9, 1.2 Hz, 1H),
7.17-7.42 (m, 5H), 4.77 (dd,J=11.8, 7.2 Hz, 1H), 3.81 (s, 2H), 3.12
(dd,J=13.9, 6.2 Hz, 1H), 2.90 (dd,J=14.0, 7.4 Hz, 1H); MS
(404.77);
[0433] tert-butyl
3-(1S-cyanomethylcarbamoyl-2-cyclohexylethylcarbamoylben-
zyl)carbamate (Compound 172); .sup.1H NMR (CDCl.sub.3): 8.15 (bt,
J=5.45 Hz, 1H), 7.63 (d, J=8.1 Hz, 2H), 7.43 (d, J=7.7 Hz, 1H),
5.18 (s, 1H), 4.81 (dd, J=8.4, 18.8 Hz, 1H), 4.25 (d, J=5.2 Hz,
2H), 4.15 (dd,J=5.9, 17.1 Hz, 1H), 3.98 (dd, J=5.9, 17.1 Hz, 1H),
1.45 (s, 9H), 0.8-1.9 (m, 13H); MS: m/e (+1) 357.94;
[0434]
3-acetylamino-N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)benzamid-
e (Compound 173); .sup.1H NMR (CDCl.sub.3): 8.43 (s, 1H), 8.32 (s,
1H), 7.94 (3, J=7.92 Hz, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.38 (d,
J=7.9 Hz, 1H), 4.83 (dd, J=7.4, 15.3 Hz, 1H), 4.23 (dd, J=5.7, 17.3
Hz, 1H), 4.06 (dd, J=5.7, 17.3 Hz, 1H), 2.14 (s, 3H), 0.95-1.90 (m,
13H); MS: m/e=370.85;
[0435]
2S-[2-(4-butoxyphenyl)acetylamino]-N-cyanomethyl-3-cyclohexylpropio-
namide (Compound 174); NMR (MeOH): 7.19 (d, J=8.9 Hz, 2H), 6.84 (d,
J=8.9 Hz, 2H), 4.38 (dd, J=5.9, 9.4 Hz, 1H), 4.12 (d, J=2.2 Hz,
2H), 3.94(t, J=6.4 Hz, 2H), 3.60 (d, J=14.1 Hz, 1H), 3.46 (d,
J=14.1 Hz, 1H), 1.40-1.78 (m, 1H), 1.05-1.3 (m, 3H), 0.95 (t, J=7.4
Hz, 3H); MS: m/e=399.95;
[0436]
N-[1S-cyanomethylcarbamoyl-2-(4-nitrophenyl)ethyl]morpholine-4-carb-
oxamide (Compound 175);
[0437]
N-cyanomethyl-3-cyclohexyl-2S-(3-naphth-2-ylureido)propionamide
(Compound 176);
[0438] N-cyanomethyl-3-cyclohexyl-2S-(3-hexylureido)propionamide
(Compound 177);
[0439] 2S-(3-allylureido)-N-cyanomethyl-3-cyclohexylpropionannde
(Compound 178);
[0440]
N-cyanomethyl-3-cyclohexyl-2S-[3-(2,2,4-trimethylpentyl)ureido]prop-
ionamide (Compound 179);
[0441]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)quinoline-2-carbox-
amide (Compound 180); .sup.1H NMR (CDCl.sub.3): 8.90 (d,J=7.8 Hz,
1H), 8.35 (m, 1H), 8.22 (m, 3H), 7.89 (m, 1H), 7.81 (td,J=7.2, 1.7
Hz, 1H), 7.66 (td,J=6.9, 1.0 Hz, 1H), 7.37 (m, 2H), 7.14-7.32 (m,
3H), 4.77 (m, 1H), 4.16 (m, 2H), 3.82 (s, 2H), 3.11 (dd,J=14.1, 6.2
Hz, 1H), 3.00 (dd,J=14.1, 6.9 Hz, 1H); MS (404.8);
[0442]
3-benzylsulfanyl-N-cyanomethyl-2R-(3,3-dimethylureido)propionamide
(Compound 181);
[0443]
3-benzoyl-N-(2-benzylsulfanyl-1R-cyanomethylcarbamoyletbyl)benzamid-
e (Compound 182); .sup.1H NMR (CDCl.sub.3): 8.19 (t,J=1.6 Hz, 1H),
7.96 (m, 2H), 7.78 (m, 2H), 7.61 (m, 2H), 7.51 (m, 2H), 7.23-7.37
(m, 5H), 6.99 (d,J=6.2 Hz, 2H), 4.64 (m, 1H), 4.13 (dd,J=5.9, 1.0
Hz, 2H), 3.80 (d,J=2.5 Hz, 2H), 3.09 (dd,J=14.1, 6.9 Hz, 2H), 2.81
(dd,J=14.1, 7.7 Hz, 1H); MS (457.81);
[0444]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-5-pyrid-2-ylthiophene-
-2-carboxamide (Compound 183); .sup.1H NM (CDCl.sub.3): 8.55 (d,
J=4.95 Hz, 1H), 8;05 (5, J=5.4 Hz, 1H), 7.67-7.73 (m, 2H), 7.62 (d,
J=4.0 Hz, 1H), 7.54 (d, J=4.0 Hz, 1H), 7.21 (m, 1H), 7.11 (d, J=7.9
Hz, 1H), 4.77 (dd, J=8.4, 14.3 Hz, 1H), 4.21 (dd, J=5.7, 17.3 Hz,
1H), 4.06 (dd, J=5.7, 17.3 Hz, 1H), 0.8-2.0 (m, 13H); MS:
m/e=396.8;
[0445]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-4-methoxythiophene-3--
carboxamide (Compound 184); .sup.1H NMR (CDCl.sub.3): 8.04 (d,
J=3.7 Hz, 2H), 7.74 d, J=7.4 Hz, 1H), 6.35 (d, J=3.4 Hz, 1H), 4.68
(dd,J=8.4, 13.9Hz, 1H), 4.18 (dd, J=6.2, 17.3 Hz, 1H), 4.12 (dd,
J=6.2, 17.13 Hz, 1H), 3.91 (s, 3H), 0.8-1.9 (m, 13H); MS:
m/e=349.78;
[0446]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-3-(3-methylbenzoyl)
aminobenzamide (Compound 185); .sup.1H NMR (CDCl.sub.3): 8.47 (s,
1H), 8.30 (t, J=5.4 Hz, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.84 (s, 1H),
7.68 (m, 2H), 7.2-7.48 (m, 4H), 4.84 (dd, J=8.2, 14.6 Hz, 1H), 4.26
(dd, J=6.2, 17.3 Hz, 1H), 4.02 (dd, J=6.2, 17.3 Hz, 1H), 2.35 (s,
3H), 0.8-1.9 (m, 14H); MS: m/e=446.90;
[0447]
2S-(3-phenylsulfonylureido)-N-cyanomethyl-3-cyclohexylpropionamide
(Compound 186);
[0448]
4-benzoyl-N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)benzamid-
e (Compound 187); .sup.1H NMR (CDCl.sub.3): 8.348 (1H), 8.11
(d,J=6.6 Hz, 1H), 7.95 (d,J=6.2 Hz, 1H), 7.56 (m, 1H), 7.14-7.54
(m, 7H), 4.73 (m, 1H), 4.16 (d,J=5.9 Hz, 2H), 3.80 (m, 2H), 3.08
(dd,J=13.9, 7.3 Hz, 1H), 2.87 (dd,J=13.9, 6.2 Hz, 1H), 2.64 (s,
3H); MS (459.86);
[0449]
N-[2-(4-aminophenyl)-1S-cyanomethylcarbamoylethyl]morpholine-4-carb-
oxamide (Compound 188);
[0450]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)nicotinamide
(Compound 189);
[0451]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)isonicotinamide
(Compound 190);
[0452]
2S-(3-tert-butylureido)-N-cyanomethyl-3-cyclohexylpropionamide
(Compound 191);
[0453]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-4-methylpentanamide
(Compound 192); .sup.1H NMR (CDCl.sub.3): 8.25 (t, J=5.7 Hz, 1H),
6.60 (d, J=8.2 Hz, 1H), 4.60 (dd, J=8.7, 14.6 Hz, 1H), 4.12 (dd,
J=5.7, 14.8 Hz, 1H), 4.04 (dd, J=5.7, 14.8 Hz, 1H), 2.20 (t, J=8.2
Hz, 2H), 0.85 (d, J=6.5, 6H), 1.1-1.8 (m, 16H); MS: m/e (+1)
307.92;
[0454]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)cyclopent-1-enecarboxa-
mide (Compound 193); .sup.1H NMR (CDCl.sub.3): 7.79 (t, J=5.9 Hz,
1H), 6.49 (m, 1H), 6.08 (d, J=7.9 Hz, 1H), 4.58 (dd, J=8.4, 14.6
Hz, 1H), 4.17 (dd, J=5.9, 17.3 Hz, 1H), 4.04 (dd, J=5.9, 17.3 Hz,
1H), 2.52 (m, 4H), 2.0 (m, 2H), 1.68 (m, 8H), 0.8-1.4 (m, 5H), MS:
m/e (+1) 303.82;
[0455] tert-butyl
2-benzylsulfanyl-1R-cyanomethylcarbamoylethylcarbamate (Compound
194);
[0456]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-1H-imidazole-4-carbox-
amide (Compound 195); .sup.1H NMR (DMSO): 8.10 (s, 1H), 7.60 (m,
4H), 4.62 (m, 1H), 4.10 (d, J=7.2 Hz, 2H), 0.8-1.90 (m, 13H); MS:
m/e (+1) 303.79;
[0457]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-cyclopentanecarboxami-
de (Compound 196); .sup.1H NMR (DMSO): 7.88 (t, J=5.45 Hz, 1H),
6.15 (d, J=8.17 Hz, 1H), 4.55 (dd, J=8.7, 14.6 Hz, 1H), 4.16 (dd,
J=5.7, 17.31 Hz, 1H), 4.06 (dd, J=5.7, 17.3 Hz, 1H), 2.65 (m, 1H),
0.8-1.95 (m, 21H); MS: m/e (+1) 305.91;
[0458]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)cyclohex-1-enecarboxam-
ude (Compound 197); .sup.1H NMR (DMSO): 7.65 (t,J=5.2 Hz, 1H), 6.69
(m, 1H), 6.02 (d, J=7.7 Hz, 1H), 4.56 (dd, J=8.7, 14.1 Hz, 1H),
4.17 (dd, J=5.9, 17.3 Hz, 1H), 4.05 (dd,J=5.9, 17.3 Hz, 1H), 2.19
(m, 4H), 1.48-1.85 (m, 13H), 0.8-1.4 (m, 4H); MS: m/e (+1)
317.86;
[0459]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-5-methylsulfanylthiop-
hene-2-carboxamide (Compound 198); .sup.1H NMR (CDCl.sub.3): 8.12
(t, J=5.4 Hz, 1H), 7.42 (d, J=4.0Hz, 1H), 7.18 (d, J=7.7 Hz, 1H),
6.9 (d, J=4.0 Hz, 1H), 4.73 (dd, J=8.2, 14.6 Hz, 1H), 4.18 (dd,
J=8.2, 14.6 Hz, 1H), 2.55 (s, 3H), 1.75 (m, 8H), 0.8-1.5 (m, 6H);
MS: m/e (+1) 365.77;
[0460] N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)isobutyramide
(Compound 199); .sup.1H NMR (CDCl.sub.3): 7.88 (t, J=5.7 Hz, 1H),
6.14 (d, J=7.9 Hz, 1H), 4.55 (dd, J=8.7, 14.6 Hz, 1H), 4.15 (dd,
J=5.7, 15.6 Hz, 1H), 4.06 (dd, J=5.7, 15.6 Hz, 1H), 2.40 (m, 1H),
1.57-1.80 (m, 8H), 0.8-1.40 (m, 11H); MS: m/e (+1) 279.89;
[0461]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)furan-2-carboxamide
(Compound 200); .sup.1H NMR (CDCl.sub.3): 7.45 (m, 2H1), 7.14 (d,
J=3.5 Hz, 1H), 6.67 (d, J=8.2 Hz, 1H), 6.51 (m, 2H), 4.66 (dd,
J=8.9, 14.1 Hz, 1H), 4.20 (dd, J=5.9, 17.6 Hz, 1H), 4.06 (dd,
J=5.9, 17.6, 1H), 1.5-1.9 (m, 7H), 0.8-1.40 (m, 6H); MS: m/e (+1)
303.83;
[0462]
N-cyanomethyl-3-cyclohexyl-2S-(3-cyclohexylureido)propionamide
(Compound 201);
[0463] N-cyanomethyl-3-cyclohexyl-2S-(3-phenylureido)propionamide
(Compound 202);
[0464] 3-acetylamino-N-(1S-cyanomethylcarbamoylpentyl)benzamide
(Compound 203);
[0465]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)furan-3-carboxamide
(Compound 204); .sup.1H NMR (CDCl.sub.3): 8.5 (t,J=6 Hz, 1H), 7.95
(s, 1H), 7.8 (d,J=6 Hz, 1H), 7.4 (s, 1H), 6.65 (s, 1H), 4.70 (m.
1H), 4.15 (dd,J=6, 6 Hz, 1H), 3.95 (dd,J=6, 6 Hz, 1H), 2.0-0.8 (m,
13H); MS:m/e=303.70;
[0466]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-6-hydroxynicotinamide
(Compound 205); .sup.1H NMR (DMSO): 12.1 (s, 1H), 8.8 (t,J=5.7 Hz,
1H), 8.4 (d,J=7.5 Hz, 1H), 8.1 (d,J=2.1 Hz, 1H), 7.9 (dd,J=3, 10
Hz, 1H), 6.43 (d,J=10 Hz, 1H), 4.5-4.2 (m, 1H), 4.18 (d,J=6 Hz,
1H), 1.8-0.8 (m, 13H); MS:m/e=330.82;
[0467]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)benzofuran-2-carboxami-
de (Compound 206); .sup.1H NMR (CDCl.sub.3): 7.95 (t,J=6 Hz, 1H),
7.8-7.2 (m, 6H), 4.95 (m, 1H), 4.30 (dd,J=6, 6 Hz, 1H), 4.10
(dd,J=6, 6 Hz, 1H), 2.0-0.8 (m, 13H); MS:m/e=303.70;
[0468]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)quinoline-3-carboxamid-
e (Compound 207); .sup.1H NMR (DMSO): 9.2 (s, 1H), 8.8 (s, 1H), 8.0
(d,J=6 Hz, 2H), 7.8 (t,J=6 Hz, 1H), 7.65 (t,J=6 Hz, 1H), 4.2 (m,
2H), 2.0-0.8 (m, 15H); MS:m/e=364.86;
[0469]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-4-hydroxy-3-nitrobenz-
amide (Compound 208); .sup.1H NMR (CDCl.sub.3): 10.7 (s, 1H), 8.3
(s, 2H), 7.9 (d,J=6 Hz, 1H), 7.1 (d,J=6 Hz, 1H), 4.9 (m, 1H), 4.3
(m, 2H), 2.2-0.8 (m, 13H); MS:m/e=374.83;
[0470]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-3-nitrobenzamide
(Compound 209); .sup.1H NMR (DMSO): 8.8-8.2 (m, 4H), 8.1 (d,J=6.8
Hz, 1H), 7.5 (t,J=6.8 Hz, 1H), 4.9 (m, 1H), 4.45 (dd,J=6, 6, 1H),
4.25 (dd,J=6, 6, 1H), 2.0-0.8 (m, 13H); MS:m/e=358.75;
[0471]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-3-methylbutyramide
(Compound 210); .sup.1H NMR (CDCl.sub.3): 7.9 (t, J=3, 6 Hz, 1H),
6.3 (d, J=6 Hz, 1H), 4.6 (m, 1H), 4.1 (m, 2H), 2.3-0.8 (m, 22H);
MS:m/e=293.73;
[0472]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)-1H-indole-5-carbo-
xamide (Compound 2H); .sup.1H NMR (CD.sub.3OD): 8.12 (s, 1H), 7.61
(d,J=7.7 Hz, 1H), 7.39 (d,J=8.4 Hz, 1H), 7.28 (m, 6H), 7.22 (m,
1H), 7.16 (m, 1H), 6.52 (m, 1H), 4.73 (m, 1H), 4.14 (s, 2H), 3.75
(s, 1H), 2.97 (m, 1H), 2.79 (m, 1H); MS (393.2);
[0473]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)-3-phenoxybenzamid-
e (Compound 212); .sup.1H NMR (CDCl.sub.3): 7.55 (m, 1H), 7.45 (m,
1H), 7.39 (m, 1H), 7.26 (m, 6H), 7.12 (m, 3H), 6.97 (m, 2H), 4.67
(m, 1H), 4.11 (d,J=3.7 Hz, 2H), 3.72 (d,J=3.7 Hz, 2H), 2.93 (m,
1H), 2.73 (m, 1H); MS (446.4);
[0474] tert-butyl
3-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethylcarbamoy-
l)benzylcarbamate (Compound 213); .sup.1H NMR (CDCl.sub.3): 7.69
(s, 1H), 7.62 (m, 1H), 7.48 (d,J=7.2 Hz, 1H), 7.41 (d,J=7.8 Hz,
1H), 7.28 (m, 4H), 7.12 (J=7.2 Hz, 1H), 4.74 (dd,J=13.5, 6.9 Hz,
1H), 4.33 (s, 2H), 4.13 (d,J=5.4 Hz, 2H), 3.77 (s, 2H), 3.01
(dd,J=14.4, 6.3 Hz, 1H), 2.85 (dd,J=13.8,7.2 Hz, 1.45 (s, 9H); MS
(483);
[0475]
3-acetyl-N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)benzamide
(Compound 214); .sup.1H NMR (CDCl.sub.3): 8.348 (1H), 8.11 (d,J=6.6
Hz, 1H), 7.95 (d,J=6.2 Hz, 1H), 7.56 (m, 1H), 7.14-7.54 (m, 7H),
4.73 (m, 1H), 4.16 (d,J=5.9 Hz, 2H), 3.80 (m, 2H), 3.08 (dd,J=13.9,
7.3 Hz, 1H), 2.87, (dd,J=13.9, 6.2 Hz, 1H), 2.64 (s, 3H); MS
(396.0);
[0476]
3-(3-methylbenzoylamino-N-(2-benzylsulfanyl-1R-cyanomethylcarbamoyl-
ethyl)benzamide (Compound 215); .sup.1H NMR (CDCl.sub.3): 8.12 (s,
1H), 7.95 (m, 2H), 7.70 (s, 1H), 7.66 (m, 1H), 7.20-7.47 (m, 8H),
7.12 (d,J=6.9 Hz, 1H), 4.74 (m, 1H), 4.16 (d,J=5.7 Hz, 2H), 3.77
(s, 2H), 3.01 (dd,J=13.7, 5.9 Hz, 1H), 2.86 (dd,J=13.8, 6.8 Hz,
1H), 2.42 (s, 3H); MS: (487.4);
[0477] N-[(cyanomethylcarbamoyl)(propoxy)methyl]benzamide (Compound
216); .sup.1H NMR (DMSO): 9.25 (d,J=10 Hz, 1H), 8.65 (t,J=6 Hz,
1H), 7.92 (d,J=7 Hz, 2H), 7.5 (m, 3H), 5.60 (d,J=10 Hz, 1H), 4.18
(m, 2H), 3.51 (m, 2H), 1.56 (h,J,=8 Hz, 2H), 0.88 (t,J=8 Hz,
3H);
[0478] N-(3-benzylsulfanyl-1R-cyanomethylcarbamoylpropyl)benzamide
(Compound 217); .sup.1H NMR (DMSO): 8.69 (t,J=6 Hz, 1H), 8.63
(d,J=8 Hz, 1H), 7.90 (d,J=9 Hz, 2H), 7.5 (m, 3H), 7.2 (m, 5H), 4.54
(m, 1H), 4.13 (d,J=6 Hz, 2H), 3.73 (s, 2H), 2.46 (m, 2H), 2.02 (m,
2H); MS: m/e=367.81;
[0479] N-[(cyanomethylcarbamoyl)(cyclohexyloxy)methyl]benzamide
(Compound 218); .sup.1H NMR (DMSO): 9.26 (d,J=9 Hz, 1H), 8.55
(t,J=6 Hz, 1H), 7.92 (d,J=7 Hz, 2H), 7.51 (m, 3H), 5.72 (d,J=10 Hz,
1H), 4.17 (m, 2H), 3.56 (m, 1H), 1.95 (m, 3H), 1.75 (m, 3H), 1.3
(m, 6H); MS: m/e=315.8;
[0480] N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)succinamic acid
(Compound 219); .sup.1H NMR (CDCl.sub.3): 4.38 (m, 1H), 4.05 (s,
2H), 2.45 (d, J=6.3 Hz, 2H), 2.58 (d, J=6.3 Hz, 2H), 0.8-1.9 (m,
15H); MS: m/e (+1) 309.72;
[0481]
3-[3-(2-chloro-6-methylphenyl)ureidol-N-(1S-cyanomethylcarbamoyl-2--
cyclohexylethyl)benzamide (Compound 220);
[0482] tert-butyl
4-(1S-cyanomethylcarbamoyl-2-cyclohexylethylcarbamoyl)ph-
enylcarbamate (Compound 221);
[0483] N-(1S-cyanomethylcarbamoyl-2-pyrid-4-ylethyl)benzamide
(Compound 222); .sup.1H NMR: (CDCl.sub.3) 8.36 (d, J=6 Hz, 2H),
7.80 (d, J=6.5 Hz, 1H), 7.66 (d, J=7.3 Hz, 2H), 7.47-7.32 (m, 4H),
7.14 (d, J=6 Hz, 2H), 4.79 (m, 1H), 4.06 (d, J=17 Hz, 1H), 3.94 (d,
J=17 Hz, 1H), 3.15 (dd, J=6.6 Hz, J=13.6 Hz, 1H), 3.01 (dd, J=7.5
Hz, J=14 Hz, 1H); MS: (M.sup.++1) 309;
[0484]
N-[1S-cyanomethylcarbamoyl-2-(4-oxocyclohexyl)ethyl]benzamide
(Compound 223); .sup.1H NMR: (CDCl.sub.3) 7.93 (m, 1H), 7.81 (d,
J=7 Hz, 2H), 7.59-7.44 (m, 3H), 7.13 (t, J=8 Hz, 1H), 4.85 (m, 1H),
4.23-4.08 (m, 2H), 2.38-1.25 (m, 11H); MS: (M.sup.++1) 328;
[0485]
N-[1S-cyanomethylcarbamoyl-2-(4,4-difluorocyclohexyl)ethyl]benzamid-
e (Compound 224); .sup.1H NMR: (CDCl.sub.3) 8.04 (m, 1H), 7.80 (d,
J=7.4 Hz, 2H), 7.58-7.42 (m, 3H), 7.20 (d, J=6 Hz, 1H), 4.84 (m,
1H), 4.21-4.03 (m, 2H), 2.20-1.23 (m, 11 H); MS: (M.sup.++1)
350;
[0486]
N-[1S-cyanomethylcarbamoyl-2-cyclohexylethyl]thiomorpholine-4-carbo-
xamide (Compound 225); .sup.1H NMR (DMSO): 7.75 (m, 1H), 4.99 (m,
1H), 4.37 (m, 1H), 4.12 (m, 1H), 3.7 (m, 4H), 2.61 (m, 4H), 2-0.8
(m, 13H); MS: m/e 339.4;
[0487]
4-(1S-cyanomethylcarbamoyl-2-cyclohbexyethylcarbamoyl)butyric acid
(Compound 226);
[0488] N-[(cyanomethylcarbamoyl)(phenethyloxy)methyl]benzamide
(Compound 227); .sup.1H NMR (DMSO): 9.30 (d,J=9 Hz, 1H), 8.69
(t,J=7 Hz, 1H), 7.90 (d,J=8 Hz, 2H), 7.51 (m, 3H), 7.2 (m, 5H),
5.66 (m, 1H), 4.19 (m, 2H), 3.77 (m, 2H), 2.92 (m, 2H); MS:
m/e=337.94;
[0489]
4-amino-N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)benzamide
(Compound 228);
[0490] tert-butyl
4-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethylcarbamoy-
l)piperazine-1-carboxylate (Compound 229); .sup.1H NMR
(CDCl.sub.3): 7.46 (t,J=5.7 Hz, 1H), 7.31 (m, 5H), 5.27 (d,J=6.9
Hz, 1H), 4.38 (dd,J=13.4, 6.7 Hz, 1H), 4.15 (dd,J=17.3, 5.9 Hz,
1H), 4.06 (dd,J=17.3, 9.9 Hz, 1H), 3.73 (s, 2H), 3.42 (t,J=4.9 Hz,
4H), 3.31 (t,J=4.9H), 2.97 (dd,J=14.1, 6.7 Hz, 1H), 2.77
(dd,J=13.9, 6.7 Hz, 1H), 1.46 (s, 9H); MS (462.4);
[0491]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)-4-fur-2-ylcarbony-
lpiperazine-1-carboxamide (Compound 230); .sup.1H NMR (CDCl.sub.3):
7.59 (t,J=5.7 Hz, 1H), 7.50 (dd,J=2.2, 1.0 Hz, 1H), 7.30 (m, 5H),
7.05 (dd,J=2.4, 0.7 Hz, 1H), 6.50 (dd,J=6.9, 1.7 Hz, 1H), 5.42
(d,J=6.9 Hz, 1H), 4.42 (dd,J=13.3, 6.7 Hz, 1H), 4.15 (dd,J=11.6,
5.9 Hz, 1H), 4.06 (dd,J=16.2, 7.2 Hz, 1H), 3.73 (s, 4H), 3.45 (m,
4H), 3.38 (m, 4H), 2.95 (dd,J=13.9, 6.4 Hz, 1H), 2.78 (dd,J=13.9,
6.7 Hz, 1H); MS (456.2);
[0492] ethyl
4-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethylcarbamoyl)pip-
erazine-1-carboxylate (Compound 231); .sup.1H NMR (CDCl.sub.3):
7.58 (t,J=5.7 Hz, 1H), 7.30 (m, 5H), 5.35 (d,J=6.9 Hz, 1H), 4.41
(dd,J=13.3, 6.7 Hz, 1H), 4.15 (q,J=7.1 Hz, 2H), 4.10 (t,J=5.9 Hz,
2H), 3.72 (s, 2H), 3.47 (t,J=4.9 Hz, 4H), 3.34 (t,J=3.7 Hz, 4H),
2.93 (dd,J=13.8, 6.4 Hz, 1H), 2.76 (dd,J=13.8, 6.9 Hz, 1H), 1.26
(t,J=7.1 Hz, 3H); MS (343.4); MS (434.4)
[0493]
N-(2-benzylsulfanyl-1R-cyanomethylcarbanoylethyl)-4-hydroxybenzamid-
e (Compound 232);
[0494]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)-3-hydroxybenzamid-
e (Compound 233);
[0495]
N-[2-(1-acetylpiperidin-4-yl)-1S-cyanomethylcarbamoylethyl]benzamid-
e (Compound 234); MS: (M.sup.++Na) 379;
[0496] N-[(cyanomethylcarbamoyl )(phenylamino)methyl]benzamide
(Compound 235); .sup.1H NMR (DMSO): 9.02 (d,J=9 Hz, 1H), 8.91
(t,J=6 Hz, 1H), 7.86 (d,J=10 Hz, 2H), 7.5 (m, 3H), 7.11 (t,J=9 Hz,
2H), 6.78 (d,J=8 Hz, 2H), 6.65 (t,J=8 Hz, 1H), 6.08 (d,J=9 Hz, 1H),
5.87 (m, 1H), 4.20 (t,J=3 Hz, 2H); MS: m/e=308.99;
[0497]
N-[1S-cyanomethylcarbamoyl-2-(4-methylenecyclohexyl)ethyl]benzamide
(Compound 236); .sup.1H NMR: (CDCl.sub.3) 7.81-7.75 (m, 3H),
7.58-7.43 (m, 3H), 6.88 (d, J=8 Hz, 1H), 4.80 (m, 1H), 4.59 (s,
2H), 4.20 (dd, J=6 Hz, J=17 Hz, 1H), 4.08 (dd, J=5.5 Hz, J=17 Hz,
1H), 2.30-1.48 (m, 9H), 1.15-0.96 (m, 2H); MS: (M.sup.++Na)
348;
[0498]
N-[1S-cyanomethylcarbamoyl-2-(4-ethylidenecyclohexyl)ethyl]benzamid-
e (Compound 237); .sup.1H NMR: (CDCl.sub.3) 7.87 (t, J=6 Hz, 1H),
7.80 (d, J=7 Hz, 2H), 7.58-7.43 (m, 3H), 6.94 (d, J=8 Hz, 1H), 5.12
(q, J=6.5 Hz, 1H), 4.80 (m, 1H), 4.20 (dd, J=6 Hz, 4.20 (dd, J=6
Hz, J=17 Hz, 1H), 4.08 (dd, J=5.5 Hz, J=17 Hz, 1H), 2.55 (m, 1H),
2.17-1.50 (m, 8H), 1.53 (d, J=6.5 Hz, 3H), 1.10-0.91 (m, 2H); MS:
(M.sup.++Na) 362;
[0499]
N-[1S-cyanomethylcarbamoyl-2-(4-propylidenecyclohexyl)ethyl]benzami-
de (Compound 238); .sup.1H NMR: (CDCl.sub.3) 8.15 (m, 1H), 7.81 (d,
J=8 Hz, 2H), 7.56-7.41 (m, 3H), 7.22 (d, J=7 Hz, 1H), 5.05 (t,
J=7.2 Hz, 1H), 4.84 (q, J=7 Hz, 1H), 4.18 (dd, J=6 Hz, J=17 Hz,
1H), 4.05 (dd, J=5.5 Hz, J=17 Hz, 1H), 2.48 (m, 2H), 2.11-1.47 (m,
9H), 1.03-0.90 (m, 2H), 0.90 (t, J=7.7 Hz, 3H); MS: (M.sup.++Na)
376;
[0500]
N-[1S-cyanomethylcarbamoyl-2-(1-ethylpiperidin-4-yl)ethyl]benzamide
(Compound 239); .sup.1H NMR: (DMSO) 8.68 (t, J=6 Hz, 1H), 8.56 (d,
J=7 Hz, 1H), 7.87 (d, J=7 Hz, 2H), 7.54-7.42 (m, 3H), 4.50 (m, 1H),
4.10 (m, 2H), 2.77 (m, 2H), 2.24 (m, 2H), 1.79-1.05 (m, 9H), 0.93
(t, J=7 Hz, 3H); MS: (M.sup.++1) 343;
[0501]
4-[2-benzoylamino-2S-cyanomethylcarbamoylethyl]-1-methylcyclohexyl
trifluoroacetate (Compound 240); .sup.1H NMR: (CDCl.sub.3) 8.25 (t,
J=5 Hz, 1H), 7.80 (d, J=7 Hz, 2H), 7.58-7.39 (m, 4H), 4.86 (q,
J=7.5 Hz, 1H), 4.16 (dd, J=5.5 Hz, J=17 Hz, 1H), 4.04 (dd, J=5.5
Hz, J=17 Hz, 1H), 2.28 (m, 2H), 1.84-1.07 (m, 9H), 1.51 (s, 3H);
MS: (M.sup.++1) 440;
[0502]
N-(2-tert-butyldisulfanyl-1R-cyanomethylcarbamoylethyl)benzamide
(Compound 241); .sup.1H NMR (CDCl.sub.3): 7.83 (m, 1H), 7.65 (m,
1H), 7.55 (m, 1H), 7.43 (m, 2H), 7.16 (m, 1H), 5.00 (m, 1H), 4.19
(m, 2H), 3.33 (m, 1H), 3.27 (m, 1H), 1.34 (s, 9H);
[0503]
N-[1S-cyanomethylcarbamoyl-2-(4-hydroxycyclohexyl)ethyl]benzamide
(Compound 242); .sup.1H NMR: (CDCl.sub.3+10% CD.sub.3OD) 7.75 (d,
J=7 Hz, 2H), 7.54-7.35 (m, 3H), 4.60 (m, 1H), 4.14 (d, J=17.5 Hz,
1H), 4.00 (d, J=17.3 Hz, 1H), 3.44 (m, 1H), 1.91-1.60 (m, 6H),
1.28-0.90 (m, 5H); MS: (M.sup.++Na) 352;
[0504]
cis-4-(2-benzoylamino-2S-cyanomethylcarbamoylethyl)cyclohexyl
acetate (Compound 243); MS: (M.sup.++Na) 394, (M.sup.+-CH.sub.3COO)
312;
[0505] N-[(cyanomethylcarbamoyl)(phenethylsulfanyl)methyl]benzamide
(Compound 244); .sup.1H NMR (DMSO): 9.14 (d,J=10 Hz, 1H), 9.01
(t,J=7 Hz, 1H), 7.94 (d,J 9 Hz, 2H), 7.5 (m, 3H), 7.2 (m, 5H), 5.88
(d,J=10 Hz, 1H), 4.22 (m, 2H), 2.90 (m, 4H); MS: m/e=354.01;
[0506]
N-[1S-cyanomethylcarbamoyl-2-(1-thiazol-2-ylpiperidin-4-yl)ethyl]be-
nzamide (Compound 245); .sup.1H NMR: (CDCl.sub.3+10% CD.sub.3OD)
7.77 (d, J=7 Hz, 2H), 7.51-7.37 (m, 3H), 7.06 (d, J=3.6 Hz, 1H),
6.48 (d, J=3.6 Hz, 1H), 4.68 (t, J=7.3 Hz, 1H), 4.14 (d, J=17.3 Hz,
1H), 4.01 (d, J=17.3 Hz, 1H), 3.91-3.85 (m, 2H), 2.99-2.89 (m, 2),
1.90-1.27 (m, 7H); MS: (M.sup.++Na) 420;
[0507]
N-[(cyanomethylcarbamoyl)(cyclohexylsulfanyl)methyl]benzamide
(Compound 246); .sup.1H NMR (DMSO): 9.10 (d,J=10 Hz, 1H), 8.94
(t,J=6 Hz, 1), 7.92 (d,J=9 Hz, 2H), 7.50 (m, 3H), 5.80 (d,J=10 Hz,
1H), 4.19 (d,J=6 Hz, 2H), 2.96 (m, 1H), 2.00 (m, 1H), 1.88 (m, 1H),
1.67 (m 2H), 1.53 (m, 1H), 1.27 (m 5H); MS: m/e=331.98;
[0508]
N-cyanomethyl-3-cyclohexyl-2R-(2-ethoxyacetylamino)propionamide
(Compound 247);
[0509]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-3-methoxypropionamide
(Compound 248); .sup.1H NMR (CDCl.sub.3): 7.68 (t, J=5.4 Hz, 1H),
6.66 (d, J=7.9 Hz, (dd, J=9.4, 13.4 Hz, 1H), 4.18 (dd, J=5.9, 17.6
Hz, 1H), 4.06 (dd, J=5.9, 17.6 Hz, 1H), 3.65 (m, 2H), 3.38 (s, 3H),
2.50 (t, J=5.7 Hz, 2H), 0.8-1.70 (m, 13H);
[0510]
cis-N-[1S-cyanomethylcarbamoyl-2-(4-methoxycyclohexyl)ethyl]benzami-
de (Compound 249); .sup.1H NMR: (CDCl.sub.3) 8.01 (s, 1H), 7.80 (d,
J=7 Hz, 2H), 7.55-7.42 (m, 3H), 6.84 (d, J=8.3 Hz, 1H), 5.26 (m,
1H), 4.59 (d, J=17.2 Hz, 1H), 4.14 (d, J17.2 Hz, 1H), 3.54 (m, 1H),
3.29 (s, 3H), 2.18-0.94 (m, 11H); MS: (M.sup.++Na) 366;
[0511]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)-3-3-(1-benzylpyrr-
olidin-3R-yl)-3-methylureido]benzamide (Compound 250); ESI-MS m/z
585.3 (M+H.sup.+);
[0512]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)-3-[3-(1-benzylpyr-
rolidin-3S-yl)-3-methylureido]benzamide (Compound 251); ESI-MS m/z
585.4 (M+H.sup.+);
[0513]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)-3-[3-(4-benzylpip-
erazin-1-ylcarbonyl)amino]benzamide (Compound 252); ESI-MS m/z
571.2 (M+H.sup.+);
[0514]
N-(1R-cyanomethylcarbamoyl-2-pentafluorobenzylsulfanylethyl)benzami-
de (Compound 253);
[0515]
N-[1R-cyanomethylcarbamoyl-2-naphth-2-ylmethylsulfanylethyl)benzami-
de (Compound 254); .sup.1H NMR (CDCl.sub.3): 7.80 (m, 4H),
7.12-7.74 (m, 9H), 4.80 (m, 1H), 4.10 (m, 3H), 3.75 (s, 2H), 3.02
(m, 1H), 2.87 (m, 1H), 2.2-2.6 (m);
[0516]
N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)-3-(3-[1,3,4thiadi-
azol-2-ylureido)benzamide (Compound 255); .sup.1H NMR (270 MHz,
DMSO-d.sub.6) .delta.2.78 (m, 1), 2.89 (m, 1), 3.79 (s, 2), 4.18
(d, 2), 4.71 (m, 1), 7.23-7.37 (m, 5), 7.45 (t, 1), 7.61 (d, 1),
7.71 (d, 1), 7.99 (s, 1), 8.75 (d, 1), 8.77 (t, 1), 9.08 (s, 1),
9.22 (s, 1); ESI-MS m/z 496.1 (M+H.sup.+);
[0517]
N-[2-(4-chlorobenzylsulfanyl)-1R-cyanomethylcarbamoylethyl]benzamid-
e (Compound 256); .sup.1H NMR: (DMSO) 8.85 (t, J=5 Hz, 1H), 8.73
(d, J=8.4 Hz, 1H), 7.92 (d, J=7 Hz, 2H), 7.60-7.47 (m, 3H),
7.40-7.33 (m, 4H), 4.69 (dd, J=5.2 Hz, J=9.4 Hz, 1H), 4.16 (s, 2H),
3.78 (s, 2H), 2.90 (dd, J=5.2 Hz, J=13.6 Hz, 1H), 2.77 (dd, J=9.6
Hz, J=13.8 Hz, 1H); MS: (M.sup.++1) 388/390;
[0518]
N-[1R-cyanomethylcarbamoyl-2-(2-methylbenzylsulfanyl)ethyl]benzamid-
e (Compound 257); .sup.1H NMR: (DMSO) 8.87 (t, J=5.4 Hz, 1H), 8.74
(d, J=8.2 Hz, 1H), 7.92 (d, J=7 Hz, 2H), 7.60-7.47 (m, 3H),
7.25-7.08 (m, 4H), 4.75 (m, 1H), 4.17 (d, J=5.7 Hz, 2H), 3.80 (s,
2H), 2.98 (dd, J=5.2 Hz, J=13.6 Hz, H), 2.82 (dd, J=9.6 Hz, J=13.8
Hz, 1H), 2.31 (s, 3H); MS: (M.sup.++1) 368;
[0519]
N-[1R-cyanomethylcarbamoyl-2-(3,5-dimethylbenzylsulfanyl)ethyl]benz-
amide (Compound 258); .sup.1H NMR: (DMSO) 8.86 (t, J=5.4 Hz, 1H),
8.73 (d, J=8.2 Hz, 1H), 7.93 (d, J=7 Hz, 2H), 7.60-7.46 (m, 3H),
6.91 (s, 2H), 6.85 (s, 1H), 4.71 (m, 1H), 4.17 (d, J=5.7 Hz, 2H),
3.70 (s, 2H), 2.92 (dd, J=5.4 Hz, J=13.6 Hz, 1H), 2.76 (dd, J=9.6
Hz, J=13.8 Hz, 1H), 2.22 (s, 6H); MS: (M.sup.++1) 382;
[0520]
N-[1R-cyanomethylcarbamoyl-2-(4-trifluoromethylbenzylsulfanyl)ethyl-
]benzamide (Compound 259); .sup.1H NMR: (DMSO) 8.86 (t, J=5.4 Hz,
1H), 8.74 (d, J=7.9 Hz, 1H), 7.93 (d, J=7 Hz, 2H), 7.68 (d, J=8.2
Hz, 2H), 7.60-7.46 (m, 5H), 4.71 (m, 1H), 4.17 (m, 2H), 3.88 (s,
2H), 2.92 (dd, J=5.4 Hz, J=13.4 Hz, 1H), 2.79 (dd, J=9.6 Hz, J=13.8
Hz, 1H); MS: (M.sup.++1) 422;
[0521]
N-[1R-cyanomethylcarbamoyl-2-(4-trifluoromethoxybenzylsulfanyl)ethy-
l]benzamide (Compound 260); .sup.1H NMR: (DMSO) 8.86 (t, J=5.4 Hz,
1H), 8.74 (d, J=8.2 Hz, 1H), 7.93 (d, J=7 Hz, 2H), 7.60-7.42 (m,
5H), 7.31 (d, J=7.9 Hz, 2H), 4.71 (m, 1H), 4.17 (d, J=5.7 Hz, 2H),
3.83 (s, 2H), 2.92 (dd, J=5.4 Hz, J=13.8 Hz, 1H), 2.79 (dd, J=9.6
Hz, J=13.8 Hz, 1H); MS: (M.sup.++1) 438;
[0522]
N-[1R-cyanomethylcarbamoyl-2-(4-trifluoromethylsulfanylbenzylsulfan-
yl)ethyl]benzamide (Compound 261); .sup.1H NMR: (DMSO) 8.86 (t,
J=5.4 Hz, 1H), 8.75 (d, J=8.2 Hz, 1H), 7.92 (d, J=7 Hz, 2H), 7.66
(d, J=7.9 Hz, 2H), 7.60-7.45 (m, 5H), 4.72 (m, 1H), 4.17 (d, J=5.7
Hz, 2H), 3.86 (s. 2H), 2.92 (dd, J=5.4 Hz, J=13.8 Hz, 1H), 2.80
(dd, J=9.6 Hz, J=13.8 Hz, 1H); MS: (M.sup.++1) 454;
[0523]
N-[1R-cyanomethylcarbamoyl-2-(3-nitrobenzylsulfanyl)ethyl]benzamide
(Compound 262); .sup.1H NMR: (DMSO) 8.83 (t, J=5 Hz, 1H), 8.73 (d,
J=7.7 Hz, 1H), 8.21 (s, 1H), 8.09 (d, J=8 Hz, 1H), 7.99 (m, 2H),
7.79 (d, J=7.7 Hz, 1H), 7.63-7.45 (m, 4H), 466 (m, 1H), 4.14 (d,
J=5 Hz, 2H), 3.94 (s, 2H), 2.90-2.49 (m, 2H); MS: (M.sup.++1)
399.2;
[0524]
N-[[R-cyanomethylcarbamoyl-2-(3-nitrobenzylsulfanyl)ethyl]benzamide
(Compound 263); .sup.1H NMR (DMSO): 8.79 (m, 1H), 8.48 (d, J=5 Hz,
1H), 7.93 (d, J=7 Hz, 2H), 7.75 (dt,J=2,8 Hz, 1H), 7.52 (m, 5H),
7.26 (m, H), 4.71 (m, 1H), 4.15 (m, 2H), 3.88 (s, 2H), 2.89 (m,
2H); MS: m/e=354.97;
[0525]
N-(1R-cyanomethylcarbamoyl-2-pyrid-3-ylmethylsulfanylethyl)benzamid-
e (Compound 264); .sup.1H NMR (DMSO): 8.86 (t,J=6 Hz, 1H), 8.74 (d,
J=9 Hz, 1H), 8.53 (d, J=2 Hz, 1H), 8.44 (dd,J=5, 2 Hz, 1H), 7.91
(m, 2H), 7.74 (m, 1H), 7.54 (m, 3H), 7.34 (m, 1H), 4.72 (m, 1H),
4.17 (m, 2H), 3.82 (s, 2H), 2.84 (m, 2H); MS: m/e=355.04;
[0526]
N-(1R-cyanomethylcarbamoyl-2-pyrid-4-ylmethylsulfanyl)ethyl]benzami-
de (Compound 265); .sup.1H NMR (DMSO): 8.85 (t,J=6 Hz, 1H), 8.75
(d,J=9 Hz, 1H), 8.5 (m, 2H), 7.93 (m, 2H), 7.54 (m, 3H), 7.35 (m,
2H), 4.69 (m, 1H), 4.16 (d,J 6 Hz, 2H), 3.8 (s=2H), 2.91 (dd,J=6,
15 Hz, 1H), 2.79 (dd,J=10, 15 Hz, 1H); MS: m/e=355.02;
[0527]
3-amino-N-(1S-cyanomethylcarbamoyl)-2-cyclohexylethylbenzamide
(Compound 266);
[0528]
3-aminno-N-(2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl)benzamide
(Compound 267);
[0529] 3-amino-N-(1S-cyanomethylcarbamoylpentyl)benzamide (Compound
268);
[0530] methyl
2S-benzoylamino-3-cyclohexylpropionylaminocyanoacetate (Compound
269); MS: (M.sup.++Na) 394;
[0531] 2S-benzoylamino-3-cyclohexylpropionylaminocyanoacetic acid
(Compound 270); MS: (M.sup.++1) 358;
[0532]
N-[1-R-cyanomethylcarbamoyl-2-(3,4-dichlorobenzylsulfanyl)ethyl]ben-
zamide (Compound 271); .sup.1H NMR (DMSO): 8.8 (d,t, 2H), 7.9
(d,J=8 Hz, 2H), 7.8 (m, 3H), 7.1 (m, 4H), 4.7 (m, 1H), 4.2 (S, 2H),
3.7 (s, 2H), 2.9 (m, 1H), 2.7 (m, 1H), 2.3 (s, 3);
MS:m/e=368.0;
[0533]
N-[1R-cyanomethylcarbamoyl-2-(3-methylbenzylsulfanyl)ethyl]benzamid-
e (Compound 272);
[0534]
N-[1R-cyanomethylcarbamoyl-2-(4-nitrobenzylsulfanyl)ethyl]benzamide
(Compound 273); .sup.1H NMR: (DMSO) 8.83 (t, J=5.1 Hz, 1H), 8.72
(d, J=7.7 Hz, 1H), 8.17 (d, J=8 Hz, 2H), 7.89 (d, J=7 Hz, 2H),
7.62-7.45 (m, 5H), 4.67 (m, 1H), 4.15 (d, J=5.4 Hz, 2H), 3.92 (s,
2H), 2.89 (dd, J=5.4 Hz, J=13.8 Hz, 1H), 2.77 (dd, J=9.6 Hz, J=13.8
Hz, 1H); MS: (M.sup.++1) 399.2;
[0535]
N-[1R-cyanomethylcarbamoyl-2-(2-nitrobenzylsulfanyl)ethyl]benzamide
(Compound 274); .sup.1H NMR (CDCl.sub.3): 8.81 (m, 1H), 8.79 (d,
J=8.0 Hz, 1H), 7.95 (d, J=3.9 Hz, 1H), 7.84 (m, 2H), 7.42-7.65 (m,
6H), 4.63 (m, 1H), 4.05 (m, 4H), 3.80 (m, 2H); MS: m/e (+1)
399.2;
[0536]
N-[1R-cyanomethylcarbamoyl-2-(3-trifluoromethylbenzylsulfanyl)ethyl-
]benzamide (Compound 275); .sup.1H NMR (DMSO): 8.86 (m, 1H), 8.74
(d, J=4.9 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 4.72 (m, 1H), 4.15
(d,J=5.1 Hz, 2H), 3.88 (s, 2H), 2.78 (m, 2H), 2.22-2.74 (m, 7H);
MS: m/e (+1) 422.2;
[0537]
N-[1R-cyanomethylcarbamoyl-2-(3-trifluoromethylbenzylsulfanyl)ethyl-
]benzamide (Compound 276); .sup.1H NMR (DMSO): 8.81 (m, 1H), 8.76
(d, J=4.8 Hz, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.10-7.55 (m, 7H), 4.7
(m, 1H), 4.15 (s, 2H), 3.80 (s, 2H); MS: m/e (+1) 438.2;
[0538]
N-[1R-cyanomethylcarbamoyl-2-(2-methylbenzylsulfanyl)ethyl]morpholi-
ne-4-carboxamide (Compound 277); .sup.1H NMR (DMSO): 8.7 (t, J=6
Hz, 1H), 7.2 (m, 4H), 6.67 (d, J=7.8 Hz, 1H), 4.4 (m, 1H), 4.2 (s,
2H), 3.7 (s, 2H), 3.5 (t, 4H), 3.3 (t, 4H), 2.7 (m, 2H), 2.3 (s,
3H); MS m/e 377.2;
[0539]
N-[1R-cyanomethylcarbamoyl-2-(2-nitrobenzylsulfanyl)ethyl]morpholin-
e-4-carboxamide (Compound 278); .sup.1H NMR (DMSO): 8.67 (t, J=6
Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.5 (m, 4H), 4.28 (q, 1H), 4.1 (d,
J=4 Hz, 2H), 4.05 (m, (t, 4H), 2.6 (m, 2H); MS m/e 408.4;
[0540]
N-[1R-cyanomethylcarbamoyl-2-(3-nitrobenzylsulfanyl)ethyl]morpholin-
e-4-carboxamide (Compound 279); .sup.1H NMR (DMSO): 8.7 (t, J=3 Hz,
1H), 8.2 (m, 2H), 7.7 (m, 2H), 6.77 (d, J=3 Hz, 1H), 4.33 (m, 1H),
4.16 (m, 2H), 3.85 (d, J=2.4 Hz, 2H), 3.4 (m, 8H), 2.6 (m, 2H); MS
m/e 408;
[0541]
N-(1S-cyanomethylcarbamoyl-2-cyclohexylethyl)-1,1-dioxo-1.lambda..s-
up.6-thiomorpholine-4-carboxamide (Compound 280); .sup.1H NMR
(DMSO): 8.5 (t, J=3 Hz, 1H), 6.9 (d, J=3 Hz, 1H), 4.11 (m, 3H), 3.8
(t, 4H), 3.1 (t, 4H), 1.8-0.8 (m, 13H); MS m/e 370.8;
[0542] N-(2-allylsulfanyl-1S-cyanomethylcarbamoylethyl)benzamide
(Compound 281); .sup.1H NMR (DMSO): 8.72 (t, 1H), 8.65 (d, J=3 Hz,
1H), 7.9 (d, 2H), 7.5 (m, 3H), 5.7 (m, 1H); 5.1 (m, 2H), 4.1 (d,
J=3 Hz, 2H), 2.8 (m, 2H); MS m/e 304.2;
[0543]
N-(1R-cyanomethylcarbamoyl)-2-(2-fluorobenzylsulfanyl)ethyl]benzami-
de (Compound 282); .sup.1H NMR (DMSO): 8.85 (m, 1H), 8.72 (d,J=4.9
Hz, 1H), 7.90 (d, J=8.3 Hz, 2H), 7.10-7.63 (m, 7H), 4.62 (m, 1H),
4.08 (d,J=5.0 Hz, 2H), 3.89 (s, 2H), 2.88 (m, 2H); MS: m/e (+1)
369.8;
[0544]
N-[2-(2-chlorobenzylsulfanyl)-1R-cyanomethylcarbamoylethyl]benzamid-
e (Compound 283); .sup.1H NMR (DMSO): 8.80 (m, 1H), 8.75 (d,J=4.8,
1H), 7.95 (d, J=8.2 Hz, 2H), 7.12-7.58 (m, 7H), 4.75 (m, 1H), 4.18
(d,J=4.8 Hz, 2H), 3.85 (s, 2H), 2.8 (m, 2H); MS: m/e (+1)
388.2;
[0545]
N-[2-(2-bromobenzylsulfanyl)-1R-cyanomethylcarbamoylethyl]benzamide
(Compound 284); .sup.1H NMR (DMSO): 8.85 (m, 1 H), 8.73 (d,J=4.8
Hz, 1 H), 7.95 (d,J=8.2 Hz, 2H), 7.4-7.65 (m, 5H), 7.37 (t, J=7.2
Hz, 1H), 7.20 (t, J=7.2 Hz, 1H), 4.70 (m, 1H), 4.08 (d,J=5.1 Hz,
2H), 3.90 (s, 2H), 2.90 (m, 2H); MS: m/e (+1) 434.0;
[0546]
N-[1R-cyanomethylcarbamoyl-2-(2-iodobenzylsulfanyl)ethyl]benzamide
(Compound 285); .sup.1H NMR (DMSO): 8.86 (m, 1H), 8.74 (d,J=8.1 Hz,
1H), 7.9 (d,J=8.4 Hz, 2H), 7.83 (d,J=7.6 Hz, 5H), 7.40-7.60 (m,
4H), 7.33 (t, J=7.7 Hz, 1H), 6.99 (t,J=7.4 Hz), 1H ), 4.71 (m, 1H),
4.16 (d,J=5.5 Hz, 2H), 3.83 (s, 2H), 2.88 (m, 2H); MS: m/e (+1)
480.0;
[0547]
N-[2-(4-tert-butyl-benzylsulfanyl)-1R-cyanomethylcarbamoylethyl]ben-
zamide (Compound 286); .sup.1H NMR (CDCl.sub.3): 8.16 (m, 1H), 7.79
(d,J=7.2 Hz, 2H), 7.51 (t,J=7.3 Hz, 2H), 7.40 (t,J=8.0 Hz, 2H),
7.19-7.29 (m, 4H), 4.98 (m, 1H), 4.08 (m, 2H), 3.72 (m, 2H), 2.94
(m, 2H);
[0548]
N-[3-(2-chlorophenylsulfanyl)-1R-cyanomethylcarbamoylpropyl]benzami-
de (Compound 287); .sup.1H NMR (DMSO): 8.73 (m, 2H), 7.92 (m, 2H),
7.38-7.56 (m, 5H), 7.32 (t,J=5.9 Hz, 1H), 7.18 (t,J=5.9 Hz, 1H),
4.64 (m, 1H), 4.14 (d, J=5.8 Hz, 2H), 3.07 (m, 2H), (2.12 (m, 2H);
MS:m/e (+1)=385.9;
[0549] N-(1R-cyanomethylcarbamoyl-3-o-tolylsulfanylpropyl)benzamide
(Compound 288); .sup.1H NMR (DMSO): 8.70 (m, 2H), 7.92 (m, 2H),
7.45-7.60 (m, 3H), 7.30 (d,J=13.3 Hz, 1H), 7.05-7.21 (m, 3H), 4.61
(dd, J=7.7 Hz, 1H), 4.13 (d, J=5.4 Hz, 2H), 3 (m, 2H), 2.28 (s,
3H), 2.10 (m, 2H); MS:m/e (+1)=366.0;
[0550]
N-(1R-cyanomethylcarbamoyl-3-pyrid-2-ylsulfanylpropyl)benzamide
(Compound 289); .sup.1H NMR (DMSO): 8.70 (m, 2H), 8.39 (m, 1H),
7.95 (d, J=13.5, 2H), 7.45-7.68 (m, 4H), 7.29 (d,J=13.5 Hz, 1H),
7.10 (m, 1H), 4.59 (m, 1H), 4.13 (d,J=5.7 Hz), 2H), 3.20 (m, 2H),
2.14 (m, 2H); MS:m/e (+1)=353.0;
[0551] tert-butyl
4-(1R-cyanomethylcarbamoyl-2-pyrid-2-ylmethylsulfanyleth-
ylcarbamoyl)piperidine-1-carboxylate (Compound 290); .sup.1H NMR
(DMSO): 8.72 (t,J=6.5 Hz, 1H), 8.48 (d,J=5.2 Hz, 1H),
8.21.(d,J=11.8 Hz, 1H), (t,J=6.5 Hz, 1H), 7.38 (d,J=7.9 Hz, 1H),
7.25 (m, 1H), 4.80 (m, 1H), 4.14 (d,J=6.6 Hz, 2H), 3.93 (d,J=13.6
Hz, 2H), 3.85 (s, 2H), 3.33 (s, 4H), 2.56-2.83 (m, 4H), 2.35 (m,
1H), 1.35 (s, 9H); MS:m/e (+1)=461.4;
[0552]
N-(1R-cyanomethylcarbamoyl-3-pyrid-4-ylsulfanylpropyl)benzamide
(Compound 291); .sup.1H NMR (DMSO): 8.73 (m, 2H), 8.35 (d,J=6.2 Hz,
2H), 7.95 (m, 2H), 7.51 (m, 3H), 7.28 (d,J=6.2 Hz, 2H), 4.62
(q,J=7.9 Hz, 1H), 4.14 (d,J=5.7 Hz, 2H), 3.13 (m, 2H), 2.14 (m,
2H); MS:m/e (+1)=355.0;
[0553] N-[1-(Cyanomethyl-carbamoyl)-2-cycloheptyl-ethyl]-benzamide
(Compound 292); and
[0554] 2-Benzylamino-N-cyanomethyl-3-cyclohexyl-propionamide
(Compound 293).
EXAMPLE 11
Cathepsin B Assay
[0555] Solutions of test compounds in varying concentrations were
prepared in 10 .mu.L of dimethyl sulfoxide (DMSO) and then diluted
into assay buffer (40 .mu.L, comprising:
N,N-bis(2-hydroxyethyl)-2-aminoethanesulfon- ic acid (BES), 50 mM
(pH 6); polyoxyethylenesorbitan monolaurate, 0.05%; and
dithiothreitol (DIT), 2.5 mM). Human cathepsin B (0.025 pMoles in
25 .mu.L of assay buffer) was added to the dilutions. The assay
solutions were mixed for 5-10 seconds on a shaker plate, covered
and incubated for 30 minutes at room temperature. Z-FR-AMC (20
nMoles in 25 .mu.L of assay buffer) was added to the assay
solutions and hydrolysis was followed spectrophotometrically at
(.lambda.460 nm) for 5 minutes. Apparent inhibition constants
(K.sub.i) were calculated from the enzyme progress curves using
standard mathematical models.
[0556] Compounds of the invention were tested by the
above-described assay and observed to exhibit cathepsin B
inhibitory activity with a K.sub.i of less than or equal to 10
.mu.M.
EXAMPLE 12
Cathepsin K Assay
[0557] Solutions of test compounds in varying concentrations were
prepared in 10 .mu.L of dimethyl sulfoxide (DMSO) and then diluted
into assay buffer (40 .mu.L, comprising: MES, 50 mM (pH 5.5); EDTA,
2.5 mM; and DTT, 2.5 mM). Human cathepsin K (0.0906 pMoles in 25
.mu.L of assay buffer) was added to the dilutions. The assay
solutions were mixed for 5-10 seconds on a shaker plate, covered
and incubated for 30 minutes at room temperature. Z-Phe-Arg-AMC (4
nMoles in 25 .mu.L of assay buffer) was added to the assay
solutions and hydrolysis was followed spectrophotometrically at
(.lambda.460 nm) for 5 minutes. Apparent inhibition constants
(K.sub.i) were calculated from the enzyme progress curves using
standard mathematical models.
[0558] Compounds of the invention were tested by the
above-described assay and observed to exhibit cathepsin K
inhibitory activity with a K.sub.i of less than orequal to 10
.mu.M.
EXAMPLE 13
Cathepsin L Assay
[0559] Solutions of test compounds in varying concentrations were
prepared in 10 .mu.L of dimethyl sulfoxide (DMSO) and then diluted
into assay buffer (40 .mu.L, comprising: MES, 50 mM (pH 5.5); EDTA,
2.5 mM; and DTT, 2.5 mM). Human cathepsin L (0.05 pMoles in 25
.mu.L of assay buffer) was added to the dilutions. The assay
solutions were mixed for 5-10 seconds on a shaker plate, covered
and incubated for 30 minutes at room temperature. Z-Phe-Arg-AMC (1
nMoles in 25 .mu.L of assay buffer) was added to the assay
solutions and hydrolysis was followed spectrophotometrically at
(.lambda.460 nm) for 5 minutes. Apparent inhibition constants
(K.sub.i) were calculated from the enzyme progress curves using
standard mathematical models.
[0560] Compounds of the invention were tested by the
above-described assay and observed to exhibit cathepsin L
inhibitory activity with a K.sub.i of less than or equal to 10
.mu.M.
EXAMPLE 14
Cathepsin S Assay
[0561] Solutions of test compounds in varying concentrations were
prepared in 10 .mu.L of dimethyl sulfoxide (DMSO) and then diluted
into assay buffer (40 .mu.L, comprising: MES, 50 mM (pH 6.5); EDTA,
2.5 mM; and NaCl, 100 mM). Human cathepsin S (0.158 pMoles in 25
.mu.L of assay buffer) was added to the dilutions. The assay
solutions were mixed for 5-10 seconds on a shaker plate, covered
and incubated for 30 minutes at room temperature. Z-Val-Val-Arg-AMC
(9 nMoles in 25 .mu.L of assay buffer) was added to the assay
solutions and hydrolysis was followed spectrophotometrically at
(.lambda.460 nm) for 5 minutes. Apparent inhibition constants
(K.sub.i) were calculated from the enzyme progress curves using
standard mathematical models.
[0562] Compounds of the invention were tested by the
above-described assay and observed to exhibit cathepsin S
inhibitory activity with a K.sub.i of less than or equal to 10
.mu.M.
EXAMPLE 15
Ovalbumin Challenge Mouse
[0563] C57 mice (female) were sensitised with ovalbumin (10 .mu.g,
i.p.) administered together with aluminium hydroxide adjuvant (20
mg, i.p.) on days 0 and 12. Mice are challenged on either day 22,
23 or 24 by exposure for 60 minutes to an aerosol of ovalbumin (10
g/l) twice, 4 hours apart. Mice are dosed p.o. with either vehicle
5 ml/kg (0.5% MC/0.2% Tween 80 in H.sub.2O) or test compound at 0,
8, 23.5 29, 33, 48 and 56 hours.
[0564] Mice were euthanized with pentobarbitone i.p. after 86 hours
(72 hours after the first challenge). The lungs were insufflated
for histological examination as soon as possible after
euthanization. Lungs were insufflated with 10% neutral buffered
formalin (NBF), at 30 cm water pressure. The lungs were removed and
placed in pots of 10% NBF. After fixation in 10% NBF for a minimum
of 24 hours the lungs were processed through graded alcohols to
wax. The lungs were blocked longitudinally and one 2 .mu.m section
for each animal was cut at the level of the main bronchi. Sections
then were stained with haematoxylin and eosin. Pathological
assessment of sections is performed and a grading is assigned.
[0565] Histopathological evaluation of the lung tissue demonstrate
a dose dependant anti-inflammatory effect on vascular and mucosal
beds after treatment with compounds of the invention between 0.03
and 30 mg/kg.
EXAMPLE 16
[0566] Representative Pharmaceutical Formulations Containing a
Compound of Formula I
1 ORAL FORMULATION Compound of Formula I 10-100 mg Citric Acid
Monohydrate 105 mg Sodium Hydroxide 18 mg Flavoring q.s. to 100 mL
Water INTRAVENOUS FORMULATION Compound of Formula I 0.1-10 mg
Dextrose Monohydrate q.s. to make isotonic Citric Acid Monohydrate
1.05 mg Sodium Hydroxide 0.18 mg Water for Injection q.s. to 1.0 mL
TABLET FORMULATION Compound of Formula I 1% Microcrystalline
Cellulose 73% Stearic Acid 25% Colloidal Silica 1%.
* * * * *