U.S. patent application number 11/388182 was filed with the patent office on 2006-09-28 for benzamide inhibitors of the p2x7 receptor.
Invention is credited to Mark A. Dombroski, Allen J. Duplantier, Chakrapani Subramanyam.
Application Number | 20060217430 11/388182 |
Document ID | / |
Family ID | 36613709 |
Filed Date | 2006-09-28 |
United States Patent
Application |
20060217430 |
Kind Code |
A1 |
Dombroski; Mark A. ; et
al. |
September 28, 2006 |
Benzamide inhibitors of the P2X7 receptor
Abstract
The present invention provides benzamide inhibitors of the
P2X.sub.7 receptor of the formula: ##STR1## wherein R.sup.1-R.sup.3
are as defined herein. The compounds of the invention are useful in
the treatment of IL-1 mediated disorders, including, without
limitation, inflammatory diseases such as osteoarthritis and
rheumatoid arthritis; allergies, asthma, COPD, cancer, reperfusion
or ischemia in stroke or heart attack, autoimmune diseases and
other disorders.
Inventors: |
Dombroski; Mark A.;
(Waterford, CT) ; Duplantier; Allen J.; (Ledyard,
CT) ; Subramanyam; Chakrapani; (South Glastonbury,
CT) |
Correspondence
Address: |
WARNER-LAMBERT COMPANY
2800 PLYMOUTH RD
ANN ARBOR
MI
48105
US
|
Family ID: |
36613709 |
Appl. No.: |
11/388182 |
Filed: |
March 23, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10748342 |
Dec 30, 2003 |
7071223 |
|
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11388182 |
Mar 23, 2006 |
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60437228 |
Dec 31, 2002 |
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Current U.S.
Class: |
514/384 ;
514/389 |
Current CPC
Class: |
C07D 249/12
20130101 |
Class at
Publication: |
514/384 ;
514/389 |
International
Class: |
A61K 31/4196 20060101
A61K031/4196; A61K 31/4166 20060101 A61K031/4166 |
Claims
1. A method of treating an IL-1 mediated disease in a mammal in
need thereof, which comprises administering to said mammal a
therapeutically effective amount of a compound of formula I:
##STR94## wherein R.sup.1 is (C.sub.1-C.sub.6)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, or
(C.sub.6-C.sub.10)aryl, wherein each of said
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.10)cycloalkyl, or
(C.sub.6-C.sub.10)aryl, are optionally substituted by one to three
moieties independently selected from the group consisting of
hydroxy, halogen, --CN, (C.sub.1-C.sub.6)alkyl,
HO(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--,
NH.sub.2(C.dbd.O)--, (C.sub.1-C.sub.6)alkoxy, and
(C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one or
more moieties selected from halogen, or (C.sub.1-C.sub.6)alkyl-;
R.sup.2 is hydrogen, halogen, --CN, and (C.sub.1-C.sub.6)alkyl,
wherein said (C.sub.1-C.sub.6)alkyl is optionally substituted by
one to three moieties, independently selected from the group
consisting of halo, hydroxy, amino, --CN, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, --CF.sub.3, CF.sub.3O--,
(C.sub.1-C.sub.6)alkyl-NH--, [(C.sub.1-C.sub.6)alkyl].sub.2-N--,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-(S.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(SO.sub.2)--,
(C.sub.1-C.sub.6)alkyl-O--(C.dbd.O)--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--, and
(C.sub.3-C.sub.6)cycloalkyl; R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of the formula: ##STR95## wherein
R.sup.4 and R.sup.5 are independently selected from the group of
substituents, consisting of hydrogen, halo, hydroxy, --CN,
HO--(C.sub.1-C.sub.6)alkyl, and (C.sub.1-C.sub.6)alkyl, wherein
said (C.sub.1-C.sub.6)alkyl is optionally substituted with one to
three fluoro, (C.sub.1-C.sub.6)alkoxy optionally substituted with
one to three fluoro, HO.sub.2C--,
(C.sub.1-C.sub.6)alkyl-O--(C.dbd.O)--, R.sup.6R.sup.8N(O.sub.2S)--,
(C.sub.1-C.sub.6)alkyl-(O.sub.2S)--NH--,
(C.sub.1-C.sub.6)alkyl-O.sub.2S--[(C.sub.1-C.sub.6)alkyl-N]--,
R.sup.6R.sup.8N(C.dbd.O)--, R.sup.6R.sup.8N(CH.sub.2).sub.m--,
(C.sub.6-C.sub.10)aryl, (C.sub.3-C.sub.8)cycloalkyl,
C.sub.6-C.sub.10)aryl-O--, or (C.sub.3-C.sub.8)cycloalkyl-O--; and
R.sup.7 is independently selected from the group of substituents
consisting of hydrogen and (C.sub.1-C.sub.6)alkyl optionally
substituted with one to three halogens, hydroxy, --CN,
(C.sub.1-C.sub.6)alkoxy-, (C.sub.2-C.sub.6)alkenoxy,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, NH.sub.2--,
((C.sub.1-C.sub.6)alkyl).sub.n-N--,
((C.sub.2-C.sub.6)alkenyl).sub.n-N--,
((C.sub.2-C.sub.6)alkynyl).sub.n-N--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)N--,
((C.sub.1-C.sub.6)alkyl).sub.n-N--(C.dbd.O)--,
(C.sub.2-C.sub.6)alkenyl-(C.dbd.O)N--,
((C.sub.2-C.sub.6)alkenyl).sub.n-N--(C.dbd.O)--,
(C.sub.2-C.sub.6)alkynyl-(C.dbd.O)N--,
((C.sub.2-C.sub.6)alkynyl).sub.n-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.2-C.sub.6)alkenyl-(C.dbd.O)--,
(C.sub.2-C.sub.6)alkynyl-(C.dbd.O)--,
(C.sub.3-C.sub.10)cycloalkyl-(C.dbd.O)--,
(C.sub.6-C.sub.10)aryl-(C.dbd.O),
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)O--,
(C.sub.2-C.sub.6)alkenyl-(C.dbd.O)O--,
(C.sub.2-C.sub.6)alkynyl-(C.dbd.O)O--,
(C.sub.1-C.sub.6)alkyl-O(C.dbd.O)--,
(C.sub.2-C.sub.6)alkenyl-O--(C.dbd.O)--,
(C.sub.2-C.sub.6)alkynyl-O--(C.dbd.O)--, and
(C.sub.3-C.sub.10)cycloalkyl; wherein R.sup.4, R.sup.5 and R.sup.7
may each be optionally substituted on any aliphatic or aromatic
carbon atom by one to three moieties, independently selected from
the group consisting of halo, hydroxy, amino, --CN,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, --CF.sub.3,
CF.sub.3O--, (C.sub.1-C.sub.6)alkyl-NH--,
[(C.sub.1-C.sub.6)alkyl].sub.2-N--, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-(S.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(SO.sub.2)--,
(C.sub.1-C.sub.6)alkyl-O--(C.dbd.O)--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--, and
(C.sub.3-C.sub.6)cycloalkyl; R.sup.6 and R.sup.8 are each
independently selected from the group consisting of hydrogen,
(C.sub.1-C.sub.6)alkyl, HO--(C.sub.2-C.sub.6)alkyl and
(C.sub.3-C.sub.8)cycloalkyl; n is an integer from zero to two; and
m is an integer from one to two; or a pharmaceutically acceptable
salt thereof; wherein said IL-1 mediated disease is selected from
the group consisting of: arthritis, psoriatic arthritis, Reiter's
syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella
arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis,
acute synovitis, inflammatory bowel disease, Crohn's disease,
emphysema, acute respiratory distress syndrome, adult respiratory
distress syndrome, asthma, bronchitis, chronic obstructive
pulmonary disease, chronic pulmonary inflammatory disease,
silicosis, pulmonary sarcoidosis, psoriasis, allergic dermatitis,
hyperresponsiveness of the airway, septic shock,
glomerulonephritis, irritable bowel disease, Crohn's disease,
ulcerative colitis, peripheral neuropathy, and pain.
2. The method of claim 1, wherein R.sup.2 is chloro, methyl or
ethyl.
3. The method of claim 2, wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (IV): ##STR96## R.sup.4
is hydrogen or methyl, and R.sup.7 is selected from the group
consisting of: ##STR97##
4. The method of claim 2, wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (IV), R.sup.4 is hydrogen
or methyl, and R.sup.7 is selected from the group consisting of:
##STR98##
5. The method of claim 2, wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (IV), R.sup.4 is hydrogen
or methyl, and R.sup.7 is ##STR99##
6. The method of claim 2, wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (IV), R.sup.4 is hydrogen
or methyl, and R.sup.7 is selected from: ##STR100##
7. The method of claim 2, wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (IV), R.sup.4 is hydrogen
or methyl, and R.sup.7 is selected from: ##STR101##
8. The method of claim 1, wherein said compound selected from the
group consisting of:
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-methoxy-ethyl)-5-oxo-4,5-
-dihydro-[1,2,4]triazol-1-yl]-benzamide;
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(5-oxo-4,5-dihydro-[1,2,4]tria-
zol-1-yl)-benzamide;
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(3-methyl-5-oxo-4,5-dihydro-[1-
,2,4]triazol-1-yl)-benzamide;
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-ethyl)-5-oxo-4,5-
-dihydro-[1,2,4]triazol-1-yl]-benzamide;
2-Chloro-5-(4-cyanomethyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-N-(1-hyd-
roxy-cycloheptylmethyl)-benzamide;
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-methoxy-ethyl)-3-methyl--
5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide;
2-Chloro-5-(4-cyanomethyl-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-
-N-(1-hydroxy-cycloheptylmethyl)-benzamide;
2-Chloro-N-(1-hydroxy-3,3-dimethyl-cyclohexylmethyl)-5-(3-methyl-5-oxo-4,-
5-dihydro-[1,2,4]triazol-1-yl)-benzamide;
5-(4-Carbamoylmethyl-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-2-ch-
loro-N-(1-hydroxy-cycloheptylmethyl)-benzamide;
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-ethyl)-3-methyl--
5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide;
5-[4-(2-Amino-ethyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-2-ch-
loro-N-(1-hydroxy-cycloheptylmethyl)-benzamide;
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl-
)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide;
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl-
)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide; and
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-2-methyl-propyl)-
-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide; or a
pharmaceutically acceptable salt thereof.
9. The method of claim 1, wherein said IL-1 mediated disease is
selected from the group consisting of: arthritis, psoriatic
arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic
arthritis, rubella arthritis, rheumatoid spondylitis,
osteoarthritis, and gouty arthritis.
10. The method of claim 1, wherein said IL-1 mediated disease is
rheumatoid arthritis.
11. The method of claim 1, wherein said IL-1 mediated disease is
peripheral neuropathy or pain.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a divisional application, and claims
priority from U.S. application Ser. No. 10/748,342, filed Dec. 30,
2003, which claims the benefit of priority to the U.S. Provisional
Application Ser. No. 60/437,228, filed Dec. 31, 2002.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to novel benzamide inhibitors
of the P2X.sub.7 receptor, processes for their preparation,
intermediates useful in their preparation, pharmaceutical
compositions containing them, and their use in therapy. The active
compounds of the present invention are useful in the treatment of
inflammatory diseases such as osteoarthritis and rheumatoid
arthritis; allergies, asthma, COPD, cancer, reperfusion or ischemia
in stroke or heart attack, autoimmune diseases and other disorders.
The active compounds are also antagonists of the P2X.sub.7
receptor.
[0003] The P2X.sub.7 receptor (previously known as P2Z receptor),
which is a ligand-gated ion channel, is present on a variety of
cell types, largely those known to be involved in
inflammatory/immune process, specifically, macrophages, mast cells
and lymphocytes (T and B). Activation of the P2X.sub.7 receptor by
extracellular nucleotides, in particular adenosine triphosphate,
leads to the release of interleukin-1.beta. (IL-1.beta.) and giant
cell formation (macrophages/microglial cells), degranulation (mast
cells) and proliferation (T cells), apoptosis, and L-selectin
shedding (lymphocytes). P2X.sub.7 receptors are also located on
antigen-presenting cells (APC), keratinocytes, salivary acinar
cells (parotid cells), hepatocytes and mesangial cells.
[0004] P2X.sub.7 antagonists are known in the art, such as those
described in International Patent Publications WO 01/46200, WO
01/42194, WO 01/44213, W099/29660, WO 00/61569, WO 99/29661, WO
99/29686, WO 00/71529, and WO 01/44170, as well as in United States
Patent Publication No. 2003-0186981 A1.
[0005] Benzamides, heteroarylamides and reverse amides for uses
other than inhibition of the P2X.sub.7 receptor are described in
various publications, such as International Patent Publications WO
97/22600, EP 138,527, WO 00/71509, WO 98/28269, WO 99/17777 and WO
01/58883.
SUMMARY OF THE INVENTION
[0006] The present invention relates to a compound of the formula
##STR2##
[0007] wherein R.sup.1 is (C.sub.1-C.sub.6)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.6-C.sub.10)aryl, (C.sub.1-C.sub.10)heterocyclyl, or
(C.sub.1-C.sub.10)heteroaryl, wherein each of said
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.6-C.sub.10)aryl, (C.sub.1-C.sub.10)heterocyclyl, or
(C.sub.1-C.sub.10)heteroaryl are optionally substituted by one to
three suitable moieties independently selected from the group
consisting of hydroxy, halogen, CN--, (C.sub.1-C.sub.6)alkyl,
HO(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--,
NH.sub.2(C.dbd.O)--, (C.sub.1-C.sub.6)alkoxy, or
(C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one or
more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-;
[0008] R.sup.2 is hydrogen, halogen, --CN, and
(C.sub.1-C.sub.6)alkyl, wherein said (C.sub.1-C.sub.6)alkyl is
optionally substituted by one to three suitable moieties,
independently selected from the group consisting of halo, hydroxy,
amino, --CN, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
--CF.sub.3, CF.sub.3O--, (C.sub.1-C.sub.6)alkyl-NH--,
[(C.sub.1-C.sub.6)alkyl].sub.2-N--, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-(S.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(SO.sub.2)--,
(C.sub.1-C.sub.6)alkyl-O--(C.dbd.O)--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--, and
(C.sub.3-C.sub.6)cycloalkyl; and
[0009] R.sup.3 is a suitably substituted nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of the formula: ##STR3##
[0010] or the pharmaceutically acceptable salts or solvates or
prodrugs thereof.
[0011] The present invention relates to a compound of the formula
##STR4##
[0012] wherein R.sup.1 is (C.sub.1-C.sub.6)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.6-C.sub.10)aryl, (C.sub.1-C.sub.10)heterocyclyl, or
(C.sub.1-C.sub.10)heteroaryl, wherein each of said
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.6-C.sub.10)aryl, (C.sub.1-C.sub.10)heterocyclyl, or
(C.sub.1-C.sub.10)heteroaryl are optionally substituted by one to
three suitable moieties independently selected from the group
consisting of hydroxy, halogen, CN--, (C.sub.1-C.sub.6)alkyl,
HO(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--,
NH.sub.2(C.dbd.O)--, (C.sub.1-C.sub.6)alkoxy, or
(C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one or
more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-;
[0013] R.sup.2 is hydrogen, halogen, --CN, and
(C.sub.1-C.sub.6)alkyl, wherein said (C.sub.1-C.sub.6)alkyl is
optionally substituted by one to three suitable moieties,
independently selected from the group consisting of halo, hydroxy,
amino, --CN, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
--CF.sub.3, CF.sub.3O--, (C.sub.1-C.sub.6)alkyl-NH--,
[(C.sub.1-C.sub.6)alkyl].sub.2-N--, (C.sub.1-C.sub.6)alkyl-S--,
(C.sub.1-C.sub.6)alkyl-(S.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(SO.sub.2)--,
(C.sub.1-C.sub.6)alkyl-O--(C.dbd.O)--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--, and
(C.sub.3-C.sub.6)cycloalkyl;
[0014] R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl
of the formula: ##STR5##
[0015] wherein R.sup.4 and R.sup.5 are independently selected from
the group of suitable substituents, such as hydrogen, halo,
hydroxy, --CN, HO--(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl,
wherein said (C.sub.1-C.sub.6)alkyl is optionally substituted with
one to three fluoro, (C.sub.1-C.sub.6)alkoxy optionally substituted
with one to three fluoro, HO.sub.2C--,
(C.sub.1-C.sub.6)alkyl-O--(C.dbd.O)--, R.sup.6R.sup.8N(O.sub.2S)--,
(C.sub.1-C.sub.6)alkyl-(O.sub.2S)--NH--,
(C.sub.1-C.sub.6)alkyl-O.sub.2S--[(C.sub.1-C.sub.6)alkyl-N]--,
R.sup.6R.sup.8N(C.dbd.O)--, R.sup.6R.sup.8N(CH.sub.2).sub.m--,
(C.sub.6-C.sub.10)aryl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.10)heteroaryl, (C.sub.1-C.sub.10)heterocyclyl,
(C.sub.6-C.sub.10)aryl-O--, (C.sub.3-C.sub.8)cycloalkyl-O--,
(C.sub.1-C.sub.10)heteroaryl-O-- and
(C.sub.1-C.sub.10)heterocyclyl-O--; and
[0016] R.sup.7 is independently selected from the group of suitable
substituents such as hydrogen and (C.sub.1-C.sub.6)alkyl optionally
substituted with one to three halogens, hydroxy, --CN,
(C.sub.1-C.sub.6)alkoxy-, (C.sub.2-C.sub.6)alkenoxy,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--, NH.sub.2--,
((C.sub.1-C.sub.6)alkyl).sub.n-N--,
((C.sub.2-C.sub.6)alkenyl).sub.n-N--,
((C.sub.2-C.sub.6)alkynyl).sub.n-N--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)N--,
((C.sub.1-C.sub.6)alkyl).sub.n-N--(C.dbd.O)--,
(C.sub.2-C.sub.6)alkenyl-(C.dbd.O)N--,
((C.sub.2-C.sub.6)alkenyl).sub.n-N--(C.dbd.O)--,
(C.sub.2-C.sub.6)alkynyl-(C.dbd.O)N--,
((C.sub.2-C.sub.6)alkynyl).sub.n-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.2-C.sub.6)alkenyl-(C.dbd.O)--,
(C.sub.2-C.sub.6)alkynyl-(C.dbd.O)--,
(C.sub.3-C.sub.10)cycloalkyl-(C.dbd.O)--,
((C.sub.1-C.sub.10)heterocyclyl-(C.dbd.O)--,
(C.sub.6-C.sub.10)aryl-(C.dbd.O),
(C.sub.1-C.sub.10)heteroaryl-(C.dbd.O),
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)O--,
(C.sub.2-C.sub.6)alkenyl-(C.dbd.O)O--,
(C.sub.2-C.sub.6)alkynyl-(C.dbd.O)O--,
(C.sub.1-C.sub.6)alkyl-O(C.dbd.O)--,
(C.sub.2-C.sub.6)alkenyl-O--(C.dbd.O)--,
(C.sub.2-C.sub.6)alkynyl-O--(C.dbd.O)--,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.6-C.sub.10)aryl,
(C.sub.1-C.sub.10)heterocyclyl, and
(C.sub.1-C.sub.10)heteroaryl;
[0017] wherein R.sup.4, R.sup.5 and R.sup.7 may each be optionally
substituted on any aliphatic or aromatic carbon atom by one to
three suitable moieties, independently selected from the group
consisting of halo, hydroxy, amino, --CN, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, --CF.sub.3, CF.sub.3O--,
(C.sub.1-C.sub.6)alkyl-NH--, [(C.sub.1-C.sub.6)alkyl].sub.2-N--,
(C.sub.1-C.sub.6)alkyl-S--, (C.sub.1-C.sub.6)alkyl-(S.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(SO.sub.2)--,
(C.sub.1-C.sub.6)alkyl-O--(C.dbd.O)--, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--, and
(C.sub.3-C.sub.6)cycloalkyl;
[0018] R.sup.6 and R.sup.8 are each independently selected from the
group consisting of hydrogen, (C.sub.1-C.sub.6)alkyl,
HO--(C.sub.2-C.sub.6)alkyl and (C.sub.3-C.sub.8)cycloalkyl, or
R.sup.6 and R.sup.8 may optionally be taken together with the
nitrogen atom to which they are attached to form a 3 to 8 membered
heterocycle;
[0019] n is an integer from zero to two; and
[0020] m is an integer from one to two;
[0021] or the pharmaceutically acceptable salts or solvates or
prodrugs thereof.
[0022] The present invention also relates to the pharmaceutically
acceptable acid addition salts of compounds of the formula I. The
acids which are used to prepare the pharmaceutically acceptable
acid addition salts of the aforementioned base compounds of this
invention are those which form non-toxic acid addition salts, i.e.,
salts containing pharmacologically acceptable anions, such as the
chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate,
acid phosphate, acetate, lactate, citrate, acid citrate, tartrate,
bitartrate, succinate, maleate, fumarate, gluconate, saccharate,
benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate and pamoate [i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
[0023] The invention also relates to base addition salts of formula
I. The chemical bases that may be used as reagents to prepare
pharmaceutically acceptable base salts of those compounds of
formula I that are acidic in nature are those that form non-toxic
base salts with such compounds. Such non-toxic base salts include,
but are not limited to those derived from such pharmacologically
acceptable cations such as alkali metal cations (e.g., potassium
and sodium) and alkaline earth metal cations (e.g., calcium and
magnesium), ammonium or water-soluble amine addition salts such as
N-methylglucamine-(meglumine), and the lower alkanolammonium and
other base salts of pharmaceutically acceptable organic amines.
[0024] This invention also encompasses pharmaceutical compositions
containing prodrugs of compounds of the formula I. Compounds of
formula I having free amino, amido, hydroxy or carboxylic groups
can be converted into prodrugs. Prodrugs include compounds wherein
an amino acid residue, or a polypeptide chain of two or more (e.g.,
two, three or four) amino acid residues which are covalently joined
through peptide bonds to free amino, hydroxy or carboxylic acid
groups of compounds of formula I. The amino acid residues include
the 20 naturally occurring amino acids commonly designated by three
letter symbols and also include, 4-hydroxyproline, hydroxylysine,
demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine,
gamma-aminobutyric acid, citrulline, homocysteine, homoserine,
ornithine and methionine sulfone. Prodrugs also include compounds
wherein carbonates, carbamates, amides and alkyl esters which are
covalently bonded to the above substituents of formula I through
the carbonyl carbon prodrug sidechain.
[0025] This invention also encompasses compounds of formula I
containing protective groups. One skilled in the art will also
appreciate that compounds of the invention can also be prepared
with certain protecting groups that are useful for purification or
storage and can be removed before administration to a patient. The
protection and deprotection of functional groups is described in
"Protective Groups in Organic Chemistry", edited by J. W. F.
McOmie, Plenum Press (1973) and "Protective Groups in Organic
Synthesis", 3rd edition, T. W. Greene and P. G. M. Wuts,
Wiley-Interscience (1999).
[0026] The compounds of this invention include all stereoisomers
(e.g., cis and trans isomers) and all optical isomers of compounds
of the formula I (e.g., R and S enantiomers), as well as racemic,
diastereomeric and other mixtures of such isomers.
[0027] The compounds, salts and prodrugs of the present invention
can exist in several tautomeric forms, including the enol and imine
form, and the keto and enamine form and geometric isomers and
mixtures thereof. All such tautomeric forms are included within the
scope of the present invention. Tautomers exist as mixtures of a
tautomeric set in solution. In solid form, usually one tautomer
predominates. Even though one tautomer may be described, the
present invention includes all tautomers of the present compounds.
One example of a tautomeric structure is when R.sup.3 is a group of
the formula ##STR6##
[0028] One skilled in the art will appreciate that this group can
also be drawn as its tautomer ##STR7##
[0029] The present invention also includes atropisomers of the
present invention. Atropisomers refer to compounds of formula I
that can be separated into rotationally restricted isomers.
[0030] The compounds of this invention may contain olefin-like
double bonds. When such bonds are present, the compounds of the
invention exist as cis and trans configurations and as mixtures
thereof.
[0031] A "suitable substituent" is intended to mean a chemically
and pharmaceutically acceptable functional group i.e., a moiety
that does not negate the biological activity of the inventive
compounds. Such suitable substituents may be routinely selected by
those skilled in the art. Illustrative examples of suitable
substituents include, but are not limited to halo groups,
perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups,
alkenyl groups, alkynyl groups, hydroxy groups, oxo groups,
mercapto groups, alkylthio groups, alkoxy groups, aryl or
heteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl or
heteroaralkyl groups, aralkoxy or heteroaralkoxy groups,
HO--(C.dbd.O)-- groups, amino groups, alkyl- and dialkylamino
groups, carbamoyl groups, alkylcarbonyl groups, alkoxycarbonyl
groups, alkylaminocarbonyl groups dialkylamino carbonyl groups,
arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups,
arylsulfonyl groups and the like. Those skilled in the art will
appreciate that many substituents can be substituted by additional
substituents. Further examples of suitable substituents include
those recited in the definition of compounds of Formula I,
including R.sup.1 through R.sup.7, as defined hereinabove.
[0032] As used herein, the term "spiro" refers to a connection
between two groups, substituents etc., wherein the connection can
be depicted according to the following formula ##STR8##
[0033] As used herein, the term "alkyl," as well as the alkyl
moieties of other groups referred to herein (e.g., alkoxy), may be
linear or branched (such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, iso-butyl, secondary-butyl, tertiary-butyl); optionally
substituted by 1 to 3 suitable substituents as defined above such
as fluoro, chloro, trifluoromethyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryloxy, trifluoromethoxy, difluoromethoxy or
(C.sub.1-C.sub.6)alkyl. The phrase "each of said alkyl" as used
herein refers to any of the preceding alkyl moieties within a group
such alkoxy, alkenyl or alkylamino. Preferred alkyls include
(C.sub.1-C.sub.6)alkyl, more preferred are (C.sub.1-C.sub.4)alkyl,
and most preferred are methyl and ethyl.
[0034] As used herein, the term "cycloalkyl" refers to a mono,
bicyclic or tricyclic carbocyclic ring (e.g., cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]heptanyl,
bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl, etc.); optionally
containing 1 or 2 double bonds and optionally substituted by 1 to 3
suitable substituents as defined above such as fluoro, chloro,
trifluoromethyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryloxy, trifluoromethoxy, difluoromethoxy or
(C.sub.1-C.sub.6)alkyl.
[0035] As used herein, the term "halogen" includes fluoro, chloro,
bromo or iodo or fluoride, chloride, bromide or iodide.
[0036] As used herein, the term "alkenyl" means straight or
branched chain unsaturated radicals of 2 to 6 carbon atoms,
including, but not limited to ethenyl, 1-propenyl, 2-propenyl
(allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl,
and the like; optionally substituted by 1 to 3 suitable
substituents as defined above such as fluoro, chloro,
trifluoromethyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryloxy, trifluoromethoxy, difluoromethoxy or
(C.sub.1-C.sub.6)alkyl.
[0037] As used herein, the term "alkynyl" is used herein to mean
straight or branched hydrocarbon chain radicals having one triple
bond including, but not limited to, ethynyl, propynyl, butynyl, and
the like; optionally substituted by 1 to 3 suitable substituents as
defined above such as fluoro, chloro, trifluoromethyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.6-C.sub.10)aryloxy,
trifluoromethoxy, difluoromethoxy or (C.sub.1-C.sub.6)alkyl.
[0038] As used herein, the term "carbonyl" or "(C.dbd.O)" (as used
in phrases such as alkylcarbonyl, alkyl-(C.dbd.O)-- or
alkoxycarbonyl) refers to the joinder of the >C.dbd.O moiety to
a second moiety such as an alkyl or amino group (i.e. an amido
group). Alkoxycarbonylamino (i.e. alkoxy(C.dbd.O)--NH--) refers to
an alkyl carbamate group. The carbonyl group is also equivalently
defined herein as (C.dbd.O). Alkylcarbonylamino refers to groups
such as acetamide.
[0039] As used herein, the term "oxo" is used herein to mean a
double bonded oxygen (.dbd.O) radical wherein the bond partner is a
carbon atom. Such a radical can also be thought as a carbonyl
group.
[0040] As used herein, the term
"(C.sub.1-C.sub.4)alkyl-O.sub.2S--[(C.sub.1-C.sub.4)alkyl-N]--" is
used herein to mean a radical of the formula ##STR9##
[0041] As used herein, the term "aryl" means aromatic radicals such
as phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like;
optionally substituted by 1 to 3 suitable substituents as defined
above such as fluoro, chloro, trifluoromethyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.6-C.sub.10)aryloxy,
trifluoromethoxy, difluoromethoxy or (C.sub.1-C.sub.6)alkyl.
[0042] As used herein, the term "heteroaryl" refers to an aromatic
heterocyclic group usually with one heteroatom selected from O, S
and N in the ring. In addition to said heteroatom, the aromatic
group may optionally have up to four N atoms in the ring. For
example, heteroaryl group includes pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g.,
1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl,
1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g.,
1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g.,
1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl),
quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, and the
like; optionally substituted by 1 to 3 suitable substituents as
defined above such as fluoro, chloro, trifluoromethyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.6-C.sub.10)aryloxy,
trifluoromethoxy, difluoromethoxy or (C.sub.1-C.sub.6)alkyl.
Particularly preferred heteroaryl groups include oxazolyl,
imidazolyl, pyridyl, thienyl, furyl, thiazolyl and pyrazolyl.
[0043] The term "heterocyclic" as used herein refers to a cyclic
group containing 1-9 carbon atoms and 1 to 4 hetero atoms selected
from N, O, S(O).sub.n or NR. Examples of such rings include
azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl,
piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl,
pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl,
tetrahydrothiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl,
oxazinyl, oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl,
chromanyl, isochromanyl, benzoxazinyl, and the like. Examples of
said monocyclic saturated or partially saturated ring systems are
tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl,
imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl,
pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl,
piperidin-3-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl,
1,3-oxazolidin-3-yl, isothiazolidine, 1,3-thiazolidin-3-yl,
1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, thiomorpholin-yl,
1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl,
tetrahydrothiadiazin-yl, morpholin-yl, 1,2-tetrahydrodiazin-2-yl,
1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl, 1,2,5-oxathiazin-4-yl
and the like; optionally containing 1 or 2 double bonds and
optionally substituted by 1 to 3 suitable substituents as defined
above such as fluoro, chloro, trifluoromethyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.6-C.sub.10)aryloxy,
trifluoromethoxy, difluoromethoxy or (C.sub.1-C.sub.6)alkyl.
Preferred heterocyclics include tetrahydrofuranyl, pyrrolidinyl,
piperidinyl, piperazinyl and morpholinyl.
[0044] Nitrogen heteroatoms as used herein refers to N.dbd., >N
and --NH; wherein --N.dbd. refers to a nitrogen double bond; >N
refers to a nitrogen containing two bond connections and --N refers
to a nitrogen containing one bond.
[0045] "Embodiment" as used herein refers to specific groupings of
compounds or uses into discrete subgenera. Such subgenera may be
cognizable according to one particular substituent such as a
specific R.sup.1 or R.sup.3 group. Other subgenera are cognizable
according to combinations of various substituents, such as all
compounds wherein R.sup.2 is chloro and R.sup.1 is
(C.sub.1-C.sub.4)alkyl, optionally substituted by
(C.sub.3-C.sub.10)cycloalkyl. The phrase "in combination with each
of the aforementioned embodiments" refers to combinations of the
identified embodiment with each embodiment previously identified in
the specification. Thus an embodiment of compounds wherein R.sup.1
is (C.sub.1-C.sub.4)alkyl, optionally substituted by
(C.sub.3-C.sub.10)cycloalkyl "in combination with each of the
aforementioned embodiments" refers to additional embodiments
comprising combinations with each embodiment previously identified
in the specification.
[0046] Thus, the invention also provides compounds in which R.sup.1
is (C.sub.1-C.sub.4)alkyl, optionally substituted by
(C.sub.3-C.sub.10)cycloalkyl, wherein said (C.sub.1-C.sub.4)alkyl
or (C.sub.3-C.sub.10)cycloalkyl are optionally substituted by one
to three suitable moieties independently selected from the group
consisting of hydroxy, halogen, CN--, (C.sub.1-C.sub.6)alkyl,
HO(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--,
NH.sub.2(C.dbd.O)--, (C.sub.1-C.sub.6)alkoxy, or
(C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one or
more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0047] The invention further provides compounds in which R.sup.1 is
(C.sub.1-C.sub.4)alkyl, optionally substituted by
(C.sub.6-C.sub.10)aryl, wherein said (C.sub.1-C.sub.4)alkyl or
(C.sub.6-C.sub.10)aryl are optionally substituted by one to three
suitable moieties independently selected from the group consisting
hydroxy, halogen, CN--, (C.sub.1-C.sub.6)alkyl,
HO(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--,
NH.sub.2(C.dbd.O)--, (C.sub.1-C.sub.6)alkoxy, or
(C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one or
more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0048] Moreover, the invention contemplates compounds in which
R.sup.2 is halogen and (C.sub.1-C.sub.6)alkyl, and preferably
compounds in which R.sup.2 is chloro, methyl or ethyl.
[0049] In one embodiment of the invention, R.sup.3 is a nitrogen
linked (C.sub.1-C.sub.10)heterocyclyl of formula (IV), wherein
R.sup.4 and R.sup.5 are independently hydrogen or
(C.sub.1-C.sub.4)alkyl, preferably hydrogen or methyl, and R.sup.7
is independently selected from the group of suitable substituents
such as hydrogen and (C.sub.1-C.sub.6)alkyl optionally substituted
with one to three substituents independently selected from
halogens, hydroxy, --CN, (C.sub.1-C.sub.6)alkoxy-,
(C.sub.2-C.sub.6)alkenoxy, (C.sub.1-C.sub.6)alkyl-SO.sub.2--,
NH.sub.2--, (C.sub.1-C.sub.6)alkyl).sub.n-N--,
((C.sub.2-C.sub.6)alkenyl).sub.n-N--,
((C.sub.2-C.sub.6)alkynyl).sub.n-N--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)N--,
((C.sub.1-C.sub.6)alkyl).sub.n-N--(C.dbd.O)--,
(C.sub.2-C.sub.6)alkenyl-(C.dbd.O)N--,
((C.sub.2-C.sub.6)alkenyl).sub.n-N--(C.dbd.O)--,
(C.sub.2-C.sub.6)alkynyl-(C.dbd.O)N--,
((C.sub.2-C.sub.6)alkynyl).sub.n-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.2-C.sub.6)alkenyl-(C.dbd.O)--,
(C.sub.2-C.sub.6)alkynyl-(C.dbd.O)--,
(C.sub.3-C.sub.10)cycloalkyl-(C.dbd.O)--,
((C.sub.1-C.sub.10)heterocyclyl-(C.dbd.O)--,
(C.sub.6-C.sub.10)aryl-(C.dbd.O), (C.sub.1
-C.sub.10)heteroaryl-(C.dbd.O),
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)O--,
(C.sub.2-C.sub.6)alkenyl-(C.dbd.O)O--,
(C.sub.2-C.sub.6)alkynyl-(C.dbd.O)O--,
(C.sub.1-C.sub.6)alkyl-O(C.dbd.O)--,
(C.sub.2-C.sub.6)alkenyl-O--(C.dbd.O)--,
(C.sub.2-C.sub.6)alkynyl-O--(C.dbd.O)--,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.6-C.sub.10)aryl,
(C.sub.1-C.sub.10)heterocyclyl, and (C.sub.1-C.sub.10)heteroaryl;
wherein R.sup.7 may optionally be substituted on any ring aliphatic
or aromatic carbon atom by one to three suitable moieties,
independently selected from the group consisting of halo, hydroxy,
amino, --CN, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
--CF.sub.3, CF.sub.3O--, (C.sub.1-C.sub.4)alkyl-NH--,
[(C.sub.1-C.sub.4)alkyl].sub.2-N--, (C.sub.1-C.sub.4)alkyl-S--,
(C.sub.1-C.sub.4)alkyl-(S.dbd.O)--,
(C.sub.1-C.sub.4)alkyl-(SO.sub.2)--,
(C.sub.1-C.sub.4)alkyl-O--(C.dbd.O)--, formyl,
(C.sub.1-C.sub.4)alkyl-(C.dbd.O)--, and
(C.sub.3-C.sub.6)cycloalkyl.
[0050] Another embodiment of the invention are compounds in which
R.sup.3is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of
formula (IV), wherein R.sup.4 and R.sup.5 are independently
hydrogen or (C.sub.1-C.sub.4)alkyl, preferably hydrogen or methyl,
and R.sup.7is hydrogen.
[0051] A further embodiment of the invention are compounds in which
R.sup.3is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of
formula (IV), wherein R.sup.4 and R.sup.5 are independently
hydrogen or (C.sub.1-C.sub.4)alkyl, preferably hydrogen or methyl,
and R.sup.7 is (C.sub.1-C.sub.4)alkyl optionally substituted with
one to three substituents independently selected from halogens,
hydroxy, --CN, (C.sub.1-C.sub.4)alkoxy-, (C.sub.2-C.sub.4)alkenoxy,
and (C.sub.1-C.sub.4)alkyl-SO.sub.2--. Preferably, R.sup.7 is
(C.sub.1-C.sub.4)alkyl optionally substituted with one to three
substituents independently selected from halogens, hydroxy, --CN,
or (C.sub.1-C.sub.4)alkoxy-.
[0052] Still further, the invention provides compounds in which
R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of
formula (IV), wherein R.sup.4 and R.sup.5 are independently
hydrogen or (C.sub.1-C.sub.4)alkyl, preferably hydrogen or methyl,
and R.sup.7 is (C.sub.1-C.sub.4)alkyl optionally substituted with
one to three substituents independently selected from NH.sub.2--,
(C.sub.1-C.sub.4)alkyl).sub.n-N--,
((C.sub.2-C.sub.4)alkenyl).sub.n-N--,
((C.sub.2-C.sub.4)alkynyl).sub.n-N--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.4)alkyl-(C.dbd.O)N--,
((C.sub.1-C.sub.4)alkyl).sub.n-N--(C.dbd.O)--,
(C.sub.2-C.sub.4)alkenyl-(C.dbd.O)N--,
((C.sub.2-C.sub.4)alkenyl).sub.n-N--(C.dbd.O)--,
(C.sub.2-C.sub.4)alkynyl-(C.dbd.O)N--, and
((C.sub.2-C.sub.4)alkynyl).sub.n-N--(C.dbd.O)--. Preferably,
R.sup.7 is (C.sub.1-C.sub.4)alkyl optionally substituted with one
to three substituents independently selected from NH.sub.2--,
(C.sub.1-C.sub.4)alkyl).sub.n-N--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.4)alkyl-(C.dbd.O)N--, and
((C.sub.1-C.sub.4)alkyl).sub.n-N--(C.dbd.O)--.
[0053] The invention also provides compounds in which R.sup.3 is a
nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula (IV),
wherein R.sup.4 and R.sup.5 are independently hydrogen or
(C.sub.1-C.sub.4)alkyl, preferably hydrogen or methyl, and R.sup.7
is (C.sub.1-C.sub.4)alkyl optionally substituted with one to three
substituents independently selected from
(C.sub.1-C.sub.4)alkyl-(C.dbd.O)--,
(C.sub.2-C.sub.4)alkenyl-(C.dbd.O)--,
(C.sub.2-C.sub.4)alkynyl-(C.dbd.O)--,
(C.sub.3-C.sub.10)cycloalkyl-(C.dbd.O)--,
((C.sub.1-C.sub.10)heterocyclyl-(C.dbd.O)--,
(C.sub.6-C.sub.10)aryl-(C.dbd.O), and
(C.sub.1-C.sub.10)heteroaryl-(C.dbd.O), and preferably, R.sup.7 is
(C.sub.1-C.sub.4)alkyl optionally substituted with one to three
substituents independently selected from
(C.sub.1-C.sub.4)alkyl-(C.dbd.O)--,
(C.sub.3-C.sub.10)cycloalkyl-(C.dbd.O)--,
((C.sub.1-C.sub.10)heterocyclyl-(C.dbd.O)--,
(C.sub.6-C.sub.10)aryl-(C.dbd.O), and
(C.sub.1-C.sub.10)heteroaryl-(C.dbd.O).
[0054] Another embodiment of the invention are compounds in which
R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of
formula (IV), wherein R.sup.4 and R.sup.5 are independently
hydrogen or (C.sub.1-C.sub.4)alkyl, preferably hydrogen or methyl,
and R.sup.7 is (C.sub.1-C.sub.4)alkyl optionally substituted with
one to three substituents independently selected from
(C.sub.1-C.sub.4)alkyl-(C.dbd.O)O--,
(C.sub.2-C.sub.4)alkenyl-(C.dbd.O)O--,
(C.sub.2-C.sub.4)alkynyl-(C.dbd.O)O--,
(C.sub.1-C.sub.4)alkyl-O(C.dbd.O)--,
(C.sub.2-C.sub.4)alkenyl-O--(C.dbd.O)--, and
(C.sub.2-C.sub.4)alkynyl-O--(C.dbd.O)--. Preferably, R.sup.7 is
(C.sub.1-C.sub.4)alkyl optionally substituted with one to three
substituents independently selected from
(C.sub.1-C.sub.4)alkyl-(C.dbd.O)O-- and
(C.sub.1-C.sub.4)alkyl-O(C.dbd.O)--.
[0055] Furthermore, the invention provides compounds in which
R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of
formula (IV), wherein R.sup.4 and R.sup.5 are independently
hydrogen or (C.sub.1-C.sub.4)alkyl, preferably hydrogen or methyl,
and R.sup.7 is (C.sub.1-C.sub.4)alkyl optionally substituted with
one to three substituents independently selected from
(C.sub.3-C.sub.10)cycloalkyl-, (C.sub.6-C.sub.10)aryl-,
(C.sub.1-C.sub.10)heterocyclyl-, and
(C.sub.1-C.sub.10)heteroaryl-.
[0056] In one embodiment of the invention, R.sup.3 is a nitrogen
linked (C.sub.1-C.sub.10)heterocyclyl of formula (V), wherein
R.sup.4 and R.sup.5 are independently hydrogen or
(C.sub.1-C.sub.4)alkyl, preferably hydrogen or methyl, and R.sup.7
is independently selected from the group of suitable substituents
such as hydrogen and (C.sub.1-C.sub.6)alkyl optionally substituted
with one to three substituents independently selected from
halogens, hydroxy, --CN, (C.sub.1-C.sub.6)alkoxy-,
(C.sub.2-C.sub.6)alkenoxy, (C.sub.1-C.sub.6)alkyl-SO.sub.2--,
NH.sub.2--, (C.sub.1-C.sub.6)alkyl).sub.n-N--,
((C.sub.2-C.sub.6)alkenyl).sub.n-N--,
((C.sub.2-C.sub.6)alkynyl).sub.n-N--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)N--,
((C.sub.1-C.sub.6)alkyl).sub.n-N--(C.dbd.O)--,
(C.sub.2-C.sub.6)alkenyl-(C.dbd.O)N--,
((C.sub.2-C.sub.6)alkenyl).sub.n-N--(C.dbd.O)--,
(C.sub.2-C.sub.6)alkynyl-(C.dbd.O)N--,
((C.sub.2-C.sub.8)alkynyl).sub.n-N--(C.dbd.O)--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.2-C.sub.6)alkenyl-(C.dbd.O)--,
(C.sub.2-C.sub.6)alkynyl-(C.dbd.O)--,
(C.sub.3-C.sub.10)cycloalkyl-(C.dbd.O)--,
((C.sub.1-C.sub.10)heterocyclyl-(C.dbd.O)--,
(C.sub.6-C.sub.10)aryl-(C.dbd.O),
(C.sub.1-C.sub.10)heteroaryl-(C.dbd.O),
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)O--,
(C.sub.2-C.sub.6)alkenyl-(C.dbd.O)O--,
(C.sub.2-C.sub.6)alkynyl-(C.dbd.O)O--,
(C.sub.1-C.sub.6)alkyl-O(C.dbd.O)--,
(C.sub.2-C.sub.6)alkenyl-O--(C.dbd.O)--,
(C.sub.2-C.sub.6)alkynyl-O--(C.dbd.O)--,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.6-C.sub.10)aryl,
(C.sub.1-C.sub.10)heterocyclyl, and (C.sub.1-C.sub.10)heteroaryl;
wherein R.sup.7 may optionally be substituted on any ring aliphatic
or aromatic carbon atom by one to three suitable moieties,
independently selected from the group consisting of halo, hydroxy,
amino, --CN, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
--CF.sub.3, CF.sub.3O--, (C.sub.1-C.sub.4)alkyl-NH--,
[(C.sub.1-C.sub.4)alkyl].sub.2-N--, (C.sub.1-C.sub.4)alkyl-S--,
(C.sub.1-C.sub.4)alkyl-(S.dbd.O)--,
(C.sub.1-C.sub.4)alkyl-(SO.sub.2)--,
(C.sub.1-C.sub.4)alkyl-O--(C.dbd.O)--, formyl,
(C.sub.1-C.sub.4)alkyl-(C.dbd.O)--, and
(C.sub.3-C.sub.6)cycloalkyl.
[0057] Another embodiment of the invention are compounds in which
R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of
formula (V), wherein R.sup.4 and R.sup.5 are independently hydrogen
or (C.sub.1-C.sub.4)alkyl, preferably hydrogen or methyl, and
R.sup.7 is hydrogen.
[0058] A further embodiment of the invention are compounds in which
R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of
formula (V), wherein R.sup.4 and R.sup.5 are independently hydrogen
or (C.sub.1-C.sub.4)alkyl, preferably hydrogen or methyl, and
R.sup.7 is (C.sub.1-C.sub.4)alkyl optionally substituted with one
to three substituents independently selected from halogens,
hydroxy, --CN, (C.sub.1-C.sub.4)alkoxy-, (C.sub.2-C.sub.4)alkenoxy,
and (C.sub.1-C.sub.4)alkyl-SO.sub.2--. Preferably, R.sup.7 is
(C.sub.1-C.sub.4)alkyl optionally substituted with one to three
substituents independently selected from halogens, hydroxy, --CN,
or (C.sub.1-C.sub.4)alkoxy-.
[0059] Still further, the invention provides compounds in which
R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of
formula (V), wherein R.sup.4 and R.sup.5 are independently hydrogen
or (C.sub.1-C.sub.4)alkyl, preferably hydrogen or methyl, and
R.sup.7 is (C.sub.1-C.sub.4)alkyl optionally substituted with one
to three substituents independently selected from NH.sub.2--,
(C.sub.1-C.sub.4)alkyl).sub.n-N--,
((C.sub.2-C.sub.4)alkenyl).sub.n-N--,
((C.sub.2-C.sub.4)alkynyl).sub.n-N--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.4)alkyl-(C.dbd.O)N--,
((C.sub.1-C.sub.4)alkyl).sub.n-N--(C.dbd.O)--,
(C.sub.2-C.sub.4)alkenyl-(C.dbd.O)N--,
((C.sub.2-C.sub.4)alkenyl).sub.n-N--(C.dbd.O)--,
(C.sub.2-C.sub.4)alkynyl-(C.dbd.O)N--, and
((C.sub.2-C.sub.4)alkynyl).sub.n-N--(C.dbd.O)--. Preferably,
R.sup.7 is (C.sub.1-C.sub.4)alkyl optionally substituted with one
to three substituents independently selected from NH.sub.2--,
(C.sub.1-C.sub.4)alkyl).sub.n-N--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.4)alkyl-(C.dbd.O)N--, and
((C.sub.1-C.sub.4)alkyl).sub.n-N--(C.dbd.O)--.
[0060] The invention also provides compounds in which R.sup.3 is a
nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula (V),
wherein R.sup.4 and R.sup.5 are independently hydrogen or
(C.sub.1-C.sub.4)alkyl, preferably hydrogen or methyl, and R.sup.7
is (C.sub.1-C.sub.4)alkyl optionally substituted with one to three
substituents independently selected from
(C.sub.1-C.sub.4)alkyl-(C.dbd.O)--,
(C.sub.2-C.sub.4)alkenyl-(C.dbd.O)--,
(C.sub.2-C.sub.4)alkynyl-(C.dbd.O)--,
(C.sub.3-C.sub.10)cycloalkyl-(C.dbd.O)--,
((C.sub.1-C.sub.10)heterocyclyl-(C.dbd.O)--,
(C.sub.6-C.sub.10)aryl-(C.dbd.O), and
(C.sub.1-C.sub.10)heteroaryl-(C.dbd.O), and preferably, R.sup.7 is
(C.sub.1-C.sub.4)alkyl optionally substituted with one to three
substituents independently selected from
(C.sub.1-C.sub.4)alkyl-(C.dbd.O)--,
(C.sub.3-C.sub.10)cycloalkyl-(C.dbd.O)--,
((C.sub.1-C.sub.10)heterocyclyl-(C.dbd.O)--,
(C.sub.6-C.sub.10)aryl-(C.dbd.O), and
(C.sub.1-C.sub.10)heteroaryl-(C.dbd.O).
[0061] Another embodiment of the invention are compounds in which
R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of
formula (V), wherein R.sup.4 and R.sup.5 are independently hydrogen
or (C.sub.1-C.sub.4)alkyl, preferably hydrogen or methyl, and
R.sup.7 is (C.sub.1-C.sub.4)alkyl optionally substituted with one
to three substituents independently selected from
(C.sub.1-C.sub.4)alkyl-(C.dbd.O)O--,
(C.sub.2-C.sub.4)alkenyl-(C.dbd.O)O--,
(C.sub.2-C.sub.4)alkynyl-(C.dbd.O)O--,
(C.sub.1-C.sub.4)alkyl-O(C.dbd.O)--,
(C.sub.2-C.sub.4)alkenyl-O--(C.dbd.O)--, and
(C.sub.2-C.sub.4)alkynyl-O-(C.dbd.O)--. Preferably, R.sup.7 is
(C.sub.1-C.sub.4)alkyl optionally substituted with one to three
substituents independently selected from
(C.sub.1-C.sub.4)alkyl-(C.dbd.O)O-- and
(C.sub.1-C.sub.4)alkyl-O(C.dbd.O)--.
[0062] Furthermore, the invention provides compounds in which
R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of
formula (V), wherein R.sup.4 and R.sup.5 are independently hydrogen
or (C.sub.1-C.sub.4)alkyl, preferably hydrogen or methyl, and
R.sup.7 is (C.sub.1-C.sub.4)alkyl optionally substituted with one
to three substituents independently selected from
(C.sub.3-C.sub.10)cycloalkyl-, (C.sub.6-C.sub.10)aryl-,
(C.sub.1-C.sub.10)heterocyclyl-, and
(C.sub.1-C.sub.10)heteroaryl-.
[0063] The present invention also provides compounds of formula (I)
wherein R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl
of formula (IV): ##STR10##
[0064] wherein R.sup.4is hydrogen or methyl,
[0065] and R.sup.7 is selected from the group consisting of:
##STR11##
[0066] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(IV), R.sup.4 is hydrogen or methyl, and R.sup.7 is ##STR12##
[0067] The present invention also contemplates compounds of formula
(I) wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (IV), R.sup.4 is hydrogen
or methyl, and R.sup.7 is selected from the group consisting of:
##STR13##
[0068] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(IV), R.sup.4 is hydrogen or methyl, and R.sup.7 is ##STR14##
[0069] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(IV), R.sup.4 is hydrogen or methyl, and R.sup.7 is selected from:
##STR15##
[0070] Finally, the invention further provides compounds of formula
(I) wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (IV), R.sup.4 is hydrogen
or methyl, and R.sup.7 is selected from: ##STR16##
[0071] The present invention also provides compounds of formula (I)
wherein R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl
of formula (IV),
[0072] R.sup.4 is hydrogen or methyl,
[0073] R.sup.7 is selected from the group consisting of:
##STR17##
[0074] and R.sup.1is (C.sub.1-C.sub.4)alkyl, optionally substituted
by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting hydroxy, halogen,
CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0075] The present invention also provides compounds of formula (I)
wherein R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl
of formula (IV),
[0076] R.sup.4 is hydrogen or methyl,
[0077] R.sup.7 is selected from the group consisting of:
##STR18##
[0078] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0079] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(IV),
[0080] R.sup.4 is hydrogen or methyl,
[0081] R.sup.7 is ##STR19##
[0082] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting hydroxy, halogen,
CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0083] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(IV),
[0084] R.sup.4 is hydrogen or methyl,
[0085] R.sup.7 is ##STR20##
[0086] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0087] The present invention also contemplates compounds of formula
(I) wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (IV),
[0088] R.sup.4 is hydrogen or methyl,
[0089] R.sup.7 is selected from the group consisting of:
##STR21##
[0090] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting hydroxy, halogen,
CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0091] The present invention also contemplates compounds of formula
(I) wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (IV),
[0092] R.sup.4 is hydrogen or methyl,
[0093] R.sup.7 is selected from the group consisting of:
##STR22##
[0094] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0095] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(IV),
[0096] R.sup.4 is hydrogen or methyl,
[0097] R.sup.7 is ##STR23##
[0098] and R.sup.1is (C.sub.1-C.sub.4)alkyl, optionally substituted
by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0099] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(IV),
[0100] R.sup.4 is hydrogen or methyl,
[0101] R.sup.7 is ##STR24##
[0102] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0103] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(IV),
[0104] R.sup.4 is hydrogen or methyl,
[0105] R.sup.7 is selected from: ##STR25##
[0106] and R.sup.1is (C.sub.1-C.sub.4)alkyl, optionally substituted
by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0107] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(IV),
[0108] R.sup.4 is hydrogen or methyl,
[0109] R.sup.7 is selected from: ##STR26##
[0110] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0111] The invention further provides compounds of formula (I)
wherein R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl
of formula (IV),
[0112] R.sup.4 is hydrogen or methyl,
[0113] R.sup.7 is selected from: ##STR27##
[0114] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0115] Finally, the invention further provides compounds of formula
(I) wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (IV),
[0116] R.sup.4 is hydrogen or methyl,
[0117] R.sup.7 is selected from: ##STR28##
[0118] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0119] The present invention also provides compounds of formula (I)
wherein R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl
of formula (IV),
[0120] R.sup.4 is hydrogen or methyl,
[0121] R.sup.7 is selected from the group consisting of:
##STR29##
[0122] R.sup.2 is chloro, methyl or ethyl;
[0123] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0124] The present invention also provides compounds of formula (I)
wherein R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl
of formula (IV),
[0125] R.sup.4 is hydrogen or methyl,
[0126] R.sup.7 is selected from the group consisting of:
##STR30##
[0127] R.sup.2 is chloro, methyl or ethyl;
[0128] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0129] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(IV),
[0130] R.sup.4 is hydrogen or methyl,
[0131] R.sup.7 is ##STR31##
[0132] R.sup.2 is chloro, methyl or ethyl;
[0133] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0134] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(IV),
[0135] R.sup.4 is hydrogen or methyl,
[0136] R.sup.7 is ##STR32##
[0137] R.sup.2 is chloro, methyl or ethyl;
[0138] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0139] The present invention also contemplates compounds of formula
(I) wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (IV),
[0140] R.sup.4 is hydrogen or methyl,
[0141] R.sup.7 is selected from the group consisting of:
##STR33##
[0142] R.sup.2 is chloro, methyl or ethyl;
[0143] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0144] The present invention also contemplates compounds of formula
(I) wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (IV),
[0145] R.sup.4 is hydrogen or methyl,
[0146] R.sup.7 is selected from the group consisting of:
##STR34##
[0147] R.sup.2 is chloro, methyl or ethyl;
[0148] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0149] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(IV),
[0150] R.sup.4 is hydrogen or methyl,
[0151] R.sup.7 is ##STR35##
[0152] R.sup.2 is chloro, methyl or ethyl;
[0153] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0154] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(IV),
[0155] R.sup.4 is hydrogen or methyl,
[0156] R.sup.7 is ##STR36##
[0157] R.sup.2 is chloro, methyl or ethyl;
[0158] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0159] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(IV),
[0160] R.sup.4 is hydrogen or methyl,
[0161] R.sup.7 is selected from: ##STR37##
[0162] R.sup.2 is chloro, methyl or ethyl;
[0163] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0164] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(IV),
[0165] R.sup.4 is hydrogen or methyl,
[0166] R.sup.7 is selected from: ##STR38##
[0167] R.sup.2 is chloro, methyl or ethyl;
[0168] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0169] The invention further provides compounds of formula (I)
wherein R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl
of formula (IV),
[0170] R.sup.4 is hydrogen or methyl,
[0171] R.sup.7 is selected from: ##STR39##
[0172] R.sup.2 is chloro, methyl or ethyl;
[0173] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0174] Finally, the invention further provides compounds of formula
(I) wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (IV),
[0175] R.sup.4 is hydrogen or methyl,
[0176] R.sup.7 is selected from: ##STR40##
[0177] R.sup.2 is chloro, methyl or ethyl;
[0178] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0179] The present invention also provides compounds of formula (I)
wherein R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl
of formula (V): ##STR41##
[0180] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0181] and R.sup.7 is selected from the group consisting of:
##STR42##
[0182] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula (V),
R.sup.4 and R.sup.5 are independently hydrogen or methyl, and
R.sup.7 is ##STR43##
[0183] The present invention also contemplates compounds of formula
(I) wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (V), R.sup.4 and R.sup.5
are independently hydrogen or methyl, and R.sup.7 is selected from
the group consisting of: ##STR44##
[0184] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula (V),
R.sup.4 and R.sup.5 are independently hydrogen or methyl, and
R.sup.7 is ##STR45##
[0185] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula (V),
R.sup.4 and R.sup.5 are independently hydrogen or methyl, and
R.sup.7 is selected from: ##STR46##
[0186] Finally, the invention further provides compounds of formula
(I) wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (V), R.sup.4 and R.sup.5
are independently hydrogen or methyl, and R.sup.7 is selected from:
##STR47##
[0187] The present invention also provides compounds of formula (I)
wherein R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl
of formula (V),
[0188] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0189] R.sup.7 is selected from the group consisting of:
##STR48##
[0190] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting hydroxy, halogen,
CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0191] The present invention also provides compounds of formula (I)
wherein R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl
of formula (V),
[0192] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0193] R.sup.7 is selected from the group consisting of:
##STR49##
[0194] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0195] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(V),
[0196] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0197] R.sup.7 is ##STR50##
[0198] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting hydroxy, halogen,
CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0199] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(V),
[0200] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0201] R.sup.7 is ##STR51##
[0202] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0203] The present invention also contemplates compounds of formula
(I) wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (V),
[0204] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0205] R.sup.7 is selected from the group consisting of:
##STR52##
[0206] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting hydroxy, halogen,
CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0207] The present invention also contemplates compounds of formula
(I) wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (V),
[0208] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0209] R.sup.7 is selected from the group consisting of:
##STR53##
[0210] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0211] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(V),
[0212] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0213] R.sup.7 is ##STR54##
[0214] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0215] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(V),
[0216] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0217] R.sup.7 is ##STR55##
[0218] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0219] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(V),
[0220] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0221] R.sup.7 is selected from: ##STR56##
[0222] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0223] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(V),
[0224] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0225] R.sup.7 is selected from: ##STR57##
[0226] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0227] The invention further provides compounds of formula (I)
wherein R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl
of formula (V),
[0228] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0229] R.sup.7 is selected from: ##STR58##
[0230] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0231] Finally, the invention further provides compounds of formula
(I) wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (V),
[0232] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0233] R.sup.7 is selected from: ##STR59##
[0234] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0235] The present invention also provides compounds of formula (I)
wherein R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl
of formula (V),
[0236] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0237] R.sup.7 is selected from the group consisting of:
##STR60##
[0238] R.sup.2 is chloro, methyl or ethyl;
[0239] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0240] The present invention also provides compounds of formula (I)
wherein R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl
of formula (V),
[0241] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0242] R.sup.7 is selected from the group consisting of:
##STR61##
[0243] R.sup.2 is chloro, methyl or ethyl;
[0244] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0245] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(V),
[0246] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0247] R.sup.7 is ##STR62##
[0248] R.sup.2 is chloro, methyl or ethyl;
[0249] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0250] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(V),
[0251] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0252] R.sup.7 is ##STR63##
[0253] R.sup.2 is chloro, methyl or ethyl;
[0254] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sup.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0255] The present invention also contemplates compounds of formula
(I) wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (V),
[0256] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0257] R.sup.7 is selected from the group consisting of:
##STR64##
[0258] R.sup.2 is chloro, methyl or ethyl;
[0259] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0260] The present invention also contemplates compounds of formula
(I) wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (V),
[0261] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0262] R.sup.7 is selected from the group consisting of:
##STR65##
[0263] R.sup.2 is chloro, methyl or ethyl;
[0264] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0265] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(V),
[0266] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0267] R.sup.7 is ##STR66##
[0268] R.sup.2 is chloro, methyl or ethyl;
[0269] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0270] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(V),
[0271] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0272] R.sup.7 is ##STR67##
[0273] R.sup.2 is chloro, methyl or ethyl;
[0274] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0275] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(V),
[0276] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0277] R.sup.7 is selected from: ##STR68##
[0278] R.sup.2 is chloro, methyl or ethyl;
[0279] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0280] Also provided are compounds of formula (I) wherein R.sup.3
is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl of formula
(V),
[0281] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0282] R.sup.7 is selected from: ##STR69##
[0283] R.sup.2 is chloro, methyl or ethyl;
[0284] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0285] The invention further provides compounds of formula (I)
wherein R.sup.3 is a nitrogen linked (C.sub.1-C.sub.10)heterocyclyl
of formula (V),
[0286] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0287] R.sup.7 is selected from: ##STR70##
[0288] R.sup.2 is chloro, methyl or ethyl;
[0289] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.3-C.sub.10)cycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.3-C.sub.10)cycloalkyl are
optionally substituted by one to three suitable moieties
independently selected from the group consisting of hydroxy,
halogen, CN--, (C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0290] Finally, the invention further provides compounds of formula
(I) wherein R.sup.3 is a nitrogen linked
(C.sub.1-C.sub.10)heterocyclyl of formula (V),
[0291] R.sup.4 and R.sup.5 are independently hydrogen or
methyl,
[0292] R.sup.7 is selected from: ##STR71##
[0293] R.sup.2 is chloro, methyl or ethyl;
[0294] and R.sup.1 is (C.sub.1-C.sub.4)alkyl, optionally
substituted by (C.sub.6-C.sub.10)aryl, wherein said
(C.sub.1-C.sub.4)alkyl or (C.sub.6-C.sub.10)aryl are optionally
substituted by one to three suitable moieties independently
selected from the group consisting of hydroxy, halogen, CN--,
(C.sub.1-C.sub.6)alkyl, HO(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-NH(C.dbd.O)--, NH.sub.2(C.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.3-C.sub.10)cycloalkyl, wherein
said (C.sub.3-C.sub.10)cycloalkyl is optionally substituted by one
or more moieties selected from halogen, or
(C.sub.1-C.sub.6)alkyl-.
[0295] Examples of other compounds of formula I are the
following:
[0296]
2-Chloro-5-(3-ethyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-N-(1-hy-
droxy-cycloheptylmethyl)-benzamide
[0297]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(3-methoxymethyl-5-oxo--
4,5-dihydro-[1,2,4]triazol-1-yl)-benzamide
[0298]
2-Chloro-5-(3-cyclopropyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-N-
-(1-hydroxy-cycloheptylmethyl)-benzamide
[0299]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[3-(2-hydroxy-ethyl)-5--
oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide
[0300]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(5-oxo-3-phenyl-4,5-dih-
ydro-[1,2,4]triazol-1-yl)-benzamide
[0301]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(5-oxo-3-pyridin-4-yl-4-
,5-dihydro-[1,2,4]triazol-1-yl)-benzamide
[0302]
2-Chloro-N-(1-hydroxy-cyclohexylmethyl)-5-(3-methyl-5-oxo-4,5-dihy-
dro-[1,2,4]triazol-1-yl)-benzamide
[0303]
2-Chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-(3-methyl-5-oxo-4,5-dihyd-
ro-[1,2,4]triazol-1-yl)-benzamide
[0304]
2-Chloro-5-(3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-N-(1-p-
-tolyl-cyclohexylmethyl)-benzamide
[0305]
2-Chloro-5-(3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-N-(1-p-
-tolyl-cyclohexylmethyl)-benzamide
[0306]
2-Chloro-5-[4-(2,3-dihydroxy-propyl)-3-methyl-5-oxo-4,5-dihydro-[1-
,2,4]triazol-1-yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0307]
2-Chloro-5-{4-[(cyclopropylmethyl-carbamoyl)-methyl]-3-methyl-5-ox-
o-4,5-dihydro-[1,2,4]triazol-1-yl}-N-(1-hydroxy-cycloheptylmethyl)-benzami-
de
[0308]
2-Chloro-5-(4-dimethylcarbamoylmethyl-3-methyl-5-oxo-4,5-dihydro-[-
1,2,4]triazol-1-yl)-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0309]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(3-methyl-4-methylcarba-
moylmethyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-benzamide
[0310]
2-Chloro-5-(4-ethylcarbamoylmethyl-3-methyl-5-oxo-4,5-dihydro-[1,2-
,4]triazol-1-yl)-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0311]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(3-methyl-4-{[(oxetan-3-
-ylmethyl)-carbamoyl]-methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-benza-
mide
[0312]
5-[4-(Azetidin-3-ylcarbamoylmethyl)-3-methyl-5-oxo-4,5-dihydro-[1,-
2,4]triazol-1-yl]-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0313]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[3-methyl-5-oxo-4-(pyrr-
olidin-3-ylcarbamoylmethyl)-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide
[0314]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[3-methyl-5-oxo-4-(pipe-
ridin-4-ylcarbamoylmethyl)-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide
[0315]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{3-methyl-5-oxo-4-[(tet-
rahydro-pyran-4-ylcarbamoyl)-methyl]-4,5-dihydro-[1,2,4]triazol-1-yl}-benz-
amide
[0316]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{3-methyl-5-oxo-4-[(tet-
rahydro-furan-3-ylcarbamoyl)-methyl]-4,5-dihydro-[1,2,4]triazol-1-yl}-benz-
amide
[0317]
2-Chloro-5-[4-(3-dimethylamino-2-hydroxy-propyl)-3-methyl-5-oxo-4,-
5-dihydro-[1,2,4]triazol-1-yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0318]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-pyrroli-
din-1-yl-propyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide
[0319]
5-[4-(3-Amino-2-hydroxy-propyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]-
triazol-1-yl]-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0320]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{4-[2-hydroxy-3-(oxetan-
-3-yloxy)-propyl]-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}-benzamid-
e
[0321]
5-{4-[3-(Azetidin-3-yloxy)-2-hydroxy-propyl]-3-methyl-5-oxo-4,5-di-
hydro-.lamda.1,2,4]triazol-1-yl}-2-chloro-N-(1-hydroxy-cycloheptylmethyl)--
benzamide
[0322]
5-{4-[3-(Azetidin-3-yloxy)-propyl]-3-methyl-5-oxo-4,5-dihydro-[1,2-
,4]triazol-1-yl}-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0323]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{4-[2-hydroxy-3-(pyrrol-
idin-3-yloxy)-propyl]-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}-benz-
amide
[0324]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{3-methyl-5-oxo-4-[3-(p-
yrrolidin-3-yloxy)-propyl]-4,5-dihydro-[1,2,4]triazol-1-yl}-benzamide
[0325]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{4-[2-hydroxy-3-(piperi-
din-4-yloxy)-propyl]-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}-benza-
mide
[0326]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{3-methyl-5-oxo-4-[3-(p-
iperidin-4-yloxy)-propyl]-4,5-dihydro-[1,2,4]triazol-1-yl}-benzamide
[0327]
2-Chloro-5-[4-(3,4-dihydroxy-butyl)-3-methyl-5-oxo-4,5-dihydro-[1,-
2,4]triazol-1-yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0328]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[3-methyl-5-oxo-4-(2-tr-
ifluoromethoxyethyl)-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide
[0329]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-methoxy-ethyl)-5--
oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide
[0330]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(5-oxo-4,5-dihydro-[1,2-
,4]triazol-1-yl)-benzamide
[0331]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(3-methyl-5-oxo-4,5-dih-
ydro-[1,2,4]triazol-1-yl)-benzamide
[0332]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-ethyl)-5--
oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide
[0333]
2-Chloro-5-(4-cyanomethyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-N-
-(1-hydroxycycloheptylmethyl)-benzamide
[0334]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-methoxy-ethyl)-3--
methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide
[0335]
2-Chloro-5-(4-cyanomethyl-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazo-
l-1-yl)-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0336]
2-Chloro-N-(1-hydroxy-3,3-dimethyl-cyclohexylmethyl)-5-(3-methyl-5-
-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-benzamide
[0337]
5-(4-Carbamoylmethyl-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-y-
l)-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0338]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-ethyl)-3--
methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide
[0339]
5-[4-(2-Amino-ethyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-y-
l]-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0340]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-
-propyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide
[0341]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-
-propyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide
[0342]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-2-methyl--
propyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide
[0343]
2-Chloro-N-(1-hydroxy-cyclohexylmethyl)-5-(4-methyl-2-oxo-2,3-dihy-
dro-imidazol-1-yl)-benzamide
[0344]
2-Chloro-N-(1-hydroxy-cyclohexylmethyl)-5-(2-oxo-2,3-dihydro-imida-
zol-1-yl)-benzamide
[0345]
2-Chloro-5-(4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl)-N-(1-p-tolyl-
-cyclohexylmethyl)-benzamide
[0346]
2-Chloro-5-(2-oxo-2,3-dihydro-imidazol-1-yl)-N-(1-p-tolyl-cyclohex-
ylmethyl)-benzamide
[0347]
2-Chloro-N-(4,4-difluoro-1-p-tolyl-cyclohexylmethyl)-5-(4-methyl-2-
-oxo-2,3-dihydro-imidazol-1-yl)-benzamide
[0348]
2-Chloro-N-(4,4-difluoro-1-p-tolyl-cyclohexylmethyl)-5-(2-oxo-2,3--
dihydro-imidazol-1-yl)-benzamide
[0349]
2-Chloro-5-[3-(2,3-dihydroxy-propyl)-4-methyl-2-oxo-2,3-dihydro-im-
idazol-1-yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0350]
2-Chloro-5-[3-(2,3-dihydroxy-propyl)-2-oxo-2,3-dihydro-imidazol-1--
yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0351]
2-Chloro-5-{3-[(cyclopropylmethyl-carbamoyl)-methyl]-4-methyl-2-ox-
o-2,3-dihydro-imidazol-1-yl}-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0352]
2-Chloro-5-{3-[(cyclopropylmethyl-carbamoyl)-methyl]-2-oxo-2,3-dih-
ydro-imidazol-1-yl}-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0353]
2-Chloro-5-(3-dimethylcarbamoylmethyl-4-methyl-2-oxo-2,3-dihydro-i-
midazol-1-yl)-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0354]
2-Chloro-5-(3-dimethylcarbamoylmethyl-2-oxo-2,3-dihydro-imidazol-1-
-yl)-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0355]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(4-methyl-3-methylcarba-
moylmethyl-2-oxo-2,3-dihydro-imidazol-1-yl)-benzamide
[0356]
2-Chloro-5-(3-dimethylcarbamoylmethyl-2-oxo-2,3-dihydro-imidazol-1-
-yl)-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0357]
2-Chloro-5-(3-ethylcarbamoylmethyl-4-methyl-2-oxo-2,3-dihydro-imid-
azol-1-yl)-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0358]
2-Chloro-5-(3-ethylcarbamoylmethyl-2-oxo-2,3-dihydro-imidazol-1-yl-
)-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0359]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(4-methyl-3-{[(oxetan-3-
-ylmethyl)-carbamol]-methyl}-2-oxo-2,3-dihydro-imidazol-1-yl)-benzamide
[0360]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(3-{[(oxetan-3-ylmethyl-
)-carbamoyl]-methyl}-2-oxo-2,3-dihydro-imidazol-1-yl)-benzamide
[0361]
5-[3-(Azetidin-3-ylcarbamoylmethyl)-4-methyl-2-oxo-2,3-dihydro-imi-
dazol-1-yl]-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0362]
5-[3-(Azetidin-3-ylcarbamoylmethyl)-2-oxo-2,3-dihydro-imidazol-1-y-
l]-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0363]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-methyl-2-oxo-3-(pyrr-
olidin-3-ylcarbamoylmethyl)-2,3-dihydro-imidazol-1-yl]-benzamide
[0364]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[2-oxo-3-(pyrrolidin-3--
ylcarbamoylmethyl)-2,3-dihydro-imidazol-1-yl]-benzamide
[0365]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-methyl-2-oxo-3-(pipe-
ridin-4-ylcarbamoylmethyl)-2,3-dihydro-imidazol-1-yl]-benzamide
[0366]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[2-oxo-3-(piperidin-4-y-
lcarbamoylmethyl)-2,3-dihydro-imidazol-1-yl]-benzamide
[0367]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{4-methyl-2-oxo-3-[(tet-
rahydro-pyran-4-ylcarbamoyl)-methyl]-2,3-dihydro-imidazol-1-yl}-benzamide
[0368]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{2-oxo-3-[(tetrahydro-p-
yran-4-ylcarbamoyl)-methyl]-2,3-dihydro-imidazol-1-yl}-benzamide
[0369]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{4-methyl-2-oxo-3-[(tet-
rahydro-furan-3-ylcarbamoyl)-methyl]-2,3-dihydro-imidazol-1-yl}-benzamide
[0370]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{2-oxo-3-[(tetrahydro-f-
uran-3-ylcarbamoyl)-methyl]-2,3-dihydro-imidazol-1-yl}-benzamide
[0371]
2-Chloro-5-[3-(3-dimethylamino-2-hydroxy-propyl)-4-methyl-2-oxo-2,-
3-dihydro-imidazol-1-yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0372]
2-Chloro-5-[3-(3-dimethylamino-2-hydroxy-propyl)-2-oxo-2,3-dihydro-
-imidazol-1-yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0373]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[3-(2-hydroxy-3-pyrroli-
din-1-yl-propyl)-4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl]-benzamide
[0374]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[3-(2-hydroxy-3-pyrroli-
din-1-yl-propyl)-2-oxo-2,3-dihydro-imidazol-1-yl]-benzamide
[0375]
5-[3-(3-Amino-2-hydroxy-propyl)-4-methyl-2-oxo-2,3-dihydro-imidazo-
l-1-yl]-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0376]
5-[3-(3-Amino-2-hydroxy-propyl)-2-oxo-2,3-dihydro-imidazol-1-yl]-2-
-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0377]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{3-[2-hydroxy-3-(oxetan-
-3-yloxy)-propyl]-4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl}-benzamide
[0378]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{3-[2-hydroxy-3-(oxetan-
-3-yloxy)-propyl]-2-oxo-2,3-dihydro-imidazol-1-yl}-benzamide
[0379]
5-{3-[3-(Azetidin-3-yloxy)-2-hydroxy-propyl]-4-methyl-2-oxo-2,3-di-
hydro-imidazol-1-yl}-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0380]
5-{3-[3-(Azetidin-3-yloxy)-2-hydroxy-propyl]-2-oxo-2,3-dihydro-imi-
dazol-1-yl}-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0381]
5-{3-[3-(Azetidin-3-yloxy)-propyl]-4-methyl-2-oxo-2,3-dihydro-imid-
azol-1-yl}-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0382]
5-{3-[3-(Azetidin-3-yloxy)-propyl]-2-oxo-2,3-dihydro-imidazol-1-yl-
}-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0383]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{3-[2-hydroxy-3-(pyrrol-
idin-3-yloxy)-propyl]-4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl}-benzamide
[0384]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{3-[2-hydroxy-3-(pyrrol-
idin-3-yloxy)-propyl]-2-oxo-2,3-dihydro-imidazol-1-yl}-benzamide
[0385]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{4-methyl-2-oxo-3-[3-(p-
yrrolidin-3-yloxy)-propyl]-2,3-dihydro-imidazol-1-yl}-benzamide
[0386]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{2-oxo-3-[3-(pyrrolidin-
-3-yloxy)-propyl]-2,3-dihydro-imidazol-1-yl}-benzamide
[0387]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{3-[2-hydroxy-3-(piperi-
din-4-yloxy)-propyl]-4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl}-benzamide
[0388]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{3-[2-hydroxy-3-(piperi-
din-4-yloxy)-propyl]-2-oxo-2,3-dihydro-imidazol-1-yl}-benzamide
[0389]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{4-methyl-2-oxo-3-[3-(p-
iperidin-4-yloxy)-propyl]-2,3-dihydro-imidazol-1-yl}-benzamide
[0390]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-{2-oxo-3-[3-(piperidin--
4-yloxy)-propyl]-2,3-dihydro-imidazol-1-yl}-benzamide
[0391]
2-Chloro-5-[3-(3,4-dihydroxy-butyl)-4-methyl-2-oxo-2,3-dihydro-imi-
dazol-1-yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0392]
2-Chloro-5-[3-(3,4-dihydroxy-butyl)-2-oxo-2,3-dihydro-imidazol-1-y-
l]-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0393]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-methyl-2-oxo-3-(2-tr-
ifluoromethoxyethyl)-2,3-dihydro-imidazol-1-yl]-benzamide
[0394]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[2-oxo-3-(2-trifluorome-
thoxy-ethyl)-2,3-dihydro-imidazol-1-yl]-benzamide
[0395]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(4-methyl-2-oxo-2,3-dih-
ydro-imidazol-1-yl)-benzamide
[0396]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(2-oxo-2,3-dihydro-imid-
azol-1-yl)-benzamide
[0397]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[3-(2-hydroxy-ethyl)-4--
methyl-2-oxo-2,3-dihydro-imidazol-1-yl]-benzamide
[0398]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[3-(2-hydroxy-ethyl)-2--
oxo-2,3-dihydro-imidazol-1-yl]-benzamide
[0399]
2-Chloro-5-(3-cyanomethyl-4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl-
)-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0400]
2-Chloro-5-(3-cyanomethyl-2-oxo-2,3-dihydro-imidazol-1-yl)-N-(1-hy-
droxy-cycloheptylmethyl)-benzamide
[0401]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[3-(2-methoxy-ethyl)-4--
methyl-2-oxo-2,3-dihydro-imidazol-1-yl]-benzamide
[0402]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[3-(2-methoxy-ethyl)-2--
oxo-2,3-dihydro-imidazol-1-yl]-benzamide
[0403]
5-(3-Carbamoylmethyl-4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl)-2-c-
hloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0404]
5-(3-Carbamoylmethyl-2-oxo-2,3-dihydro-imidazol-1-yl)-2-chloro-N-(-
1-hydroxy-cycloheptylmethyl)-benzamide
[0405]
5-[3-(2-Amino-ethyl)-4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl]-2-c-
hloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide
[0406]
5-[3-(2-Amino-ethyl)-2-oxo-2,3-dihydro-imidazol-1-yl]-2-chloro-N-(-
1-hydroxy-cycloheptylmethyl)-benzamide
[0407]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[3-(2-hydroxy-3-methoxy-
-propyl)-4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl]-benzamide
[0408]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[3-(2-hydroxy-3-methoxy-
-propyl)-2-oxo-2,3-dihydro-imidazol-1-yl]-benzamide
[0409]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[3-(2-hydroxy-2-methyl--
propyl)-4-methyl-2-oxo-2,3-dihydro-imidazol-1-yl]-benzamide
[0410]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[3-(2-hydroxy-2-methyl--
propyl)-2-oxo-2,3-dihydro-imidazol-1-yl]-benzamide.
[0411] Certain specific compounds of the invention are those
compounds identified in Examples 1-14, which are incorporated
herein by reference.
[0412] The present invention also includes isotopically-labeled
compounds, which are identical to those recited in Formula I, but
for the fact that one or more atoms are replaced by an atom having
an atomic mass or mass number different from the atomic mass or
mass number usually found in nature. Examples of isotopes that can
be incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, and
.sup.36Cl, respectively. Compounds of the present invention,
prodrugs thereof, and pharmaceutically acceptable salts of said
compounds or of said prodrugs which contain the aforementioned
isotopes and/or other isotopes of other atoms are within the scope
of this invention. Certain isotopically-labelled compounds of the
present invention, for example those into which radioactive
isotopes such as .sup.3H and .sup.14C are incorporated, are useful
in drug and/or substrate tissue distribution assays. Tritiated,
i.e., .sup.3H, and carbon-14, i.e., .sup.14C, isotopes are
particularly preferred for their ease of preparation and
detectability. Further, substitution with heavier isotopes such as
deuterium, i.e., .sup.2H, can afford certain therapeutic advantages
resulting from greater metabolic stability, for example increased
in vivo half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances. Isotopically-labelled compounds of
Formula I of this invention and prodrugs thereof can generally be
prepared by carrying out the procedures disclosed in the Schemes
and/or in the Examples and Preparations below, by substituting a
readily available isotopically-labelled reagent for a
non-isotopically-labelled reagent.
[0413] The compounds of Formula I or a pharmaceutically acceptable
salt thereof can be used in the manufacture of a medicament for the
prophylactic or therapeutic treatment of any disease state in a
human, or other mammal, which is exacerbated or caused by excessive
or unregulated cytokine production by such mammal's cells, such as
but not limited to monocytes and/or macrophages.
[0414] The present invention relates to a method for treating an
IL-1 mediated disease in a mammal in need thereof, which comprises
administering to said mammal an effective amount of a compound of
formula I.
[0415] The present invention also relates to a method for treating
an IL-1 mediated condition. As defined herein, an "IL-1 mediated
condition" includes but is not limited to a disease or disorder
selected from the group consisting of arthritis (including
psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout,
traumatic arthritis, rubella arthritis, rheumatoid spondylitis,
osteoarthritis, gouty arthritis and acute synovitis), inflammatory
bowel disease, Crohn's disease, emphysema, acute respiratory
distress syndrome, adult respiratory distress syndrome, asthma,
bronchitis chronic obstructive pulmonary disease, chronic pulmonary
inflammatory disease, silicosis, pulmonary sarcoidosis, allergic
reactions, allergic contact hypersensitivity, eczema, contact
dermatitis, psoriasis, sunburn, cancer, tissue ulceration,
restenosis, periodontal disease, epidermolysis bullosa,
osteoporosis, bone resorption disease, loosening of artificial
joint implants, atherosclerosis, aortic aneurysm, congestive heart
failure, myocardial infarction, stroke, cerebral ischemia, head
trauma, neurotrauma, spinal cord injury, neuro-degenerative
disorders, Alzheimer's disease, Parkinson's disease, migraine,
depression, peripheral neuropathy, pain, cerebral amyloid
angiopathy, nootropic or cognition enhancement, amyotrophic lateral
sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury,
macular degeneration, corneal scarring, scleritis, abnormal wound
healing, burns, autoimmune disorders, Huntington's disease,
diabetes, AIDS, cachexia, sepsis, septic shock, endotoxic shock,
conjunctivitis shock, gram negative sepsis, toxic shock syndrome,
cerebral malaria, cardiac and renal reperfusion injury, thrombosis,
glomerularonephritis, graft vs. host reaction, allograft rejection,
organ transplant toxicity, ulcerative colitis, or muscle
degeneration, in a mammal, including a human, comprising
administering to said mammal an amount of a compound to formula I,
effective in treating such a condition.
[0416] The present invention relates to a pharmaceutical
composition for the treatment of an IL-1 mediated disease in a
mammal which comprises an effective amount of a compound according
of formula I and a pharmaceutically acceptable carrier.
[0417] The present invention relates to a pharmaceutical
composition for the treatment of an IL-1 mediated condition in a
mammal, including a human, comprising an amount of a compound of
formula I, effective in treating such a condition and a
pharmaceutically acceptable carrier.
[0418] Preferably, the compounds of the invention are useful for
the treatment of rheumatoid arthritis, osteoarthritis, psoriasis,
allergic dermatitis, asthma, chronic obstructive pulmonary disease
(COPD), hyperresponsiveness of the airway, septic shock,
glomerulonephritis, irritable bowel disease, Crohn's disease,
ulcerative colitis, atherosclerosis, growth and metastases of
malignant cells, myoblastic leukemia, diabetes, Alzheimer's
disease, meningitis, osteoporosis, burn injury, ischemic heart
disease, stroke and varicose veins.
[0419] The present invention also provides a compound of formula
(I), or a pharmaceutically acceptable salt or solvate thereof, as
hereinbefore defined for use in therapy.
[0420] In another aspect, the invention provides the use of a
compound of formula (I), or a pharmaceutically acceptable salt or
solvate thereof, as hereinbefore defined in the manufacture of a
medicament for use in therapy.
[0421] The invention further provides a method of treating
osteoarthritis which comprises administering a therapeutically
effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt or solvate thereof, as
hereinbefore defined to a patient.
[0422] The invention further provides a method of effecting
immunosuppression (e.g. in the treatment of rheumatoid arthritis,
irritable bowel disease, atherosclerosis or psoriasis) which
comprises administering a therapeutically effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt or
solvate thereof, as hereinbefore defined to a patient.
[0423] The invention also provides a method of treating an
obstructive airways disease (e.g. asthma or COPD) which comprises
administering to a patient a therapeutically effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt or
solvate thereof, as hereinbefore defined to a patient.
[0424] The term "treating", as used herein, refers to reversing,
alleviating, inhibiting the progress of, or preventing the disorder
or condition to which such term applies, or one or more symptoms of
such disorder or condition. The term "treatment", as used herein,
refers to the act of treating, as "treating" is defined immediately
above.
[0425] The present invention also provides a pharmaceutical
composition comprising a compound of formula (I), or a
pharmaceutically acceptable salt or solvate thereof, as
hereinbefore defined in association with a pharmaceutically
acceptable adjuvant, diluent or carrier.
[0426] The invention further provides a process for the preparation
of a pharmaceutical composition of the invention which comprises
mixing a compound of formula (I), or a pharmaceutically acceptable
salt or solvate thereof, as hereinbefore defined with a
pharmaceutically acceptable adjuvant, diluent or carrier.
[0427] For the above-mentioned therapeutic uses the dosage
administered will, of course, vary with the compound employed, the
mode of administration, the treatment desired and the disorder
indicated. The daily dosage of the compound of formula
(I)/salt/solvate (active ingredient) may; be in the range from 1 mg
to 1 gram, preferably 1 mg to 250 mg, more preferably 10 mg to 100
mg.
[0428] The present invention also encompasses sustained release
compositions.
[0429] The present invention also relates to processes of preparing
the compounds of formula I and intermediates used in such
processes.
[0430] One embodiment of the processes of the invention relates to
the preparation of compounds of formula I, which may be carried out
by one or more of the synthetic methods outlined in Schemes I-VIII,
detailed below. The present invention also provides methods and
intermediates useful in the synthesis of compounds of formula (I),
and identified in Schemes I-VIII below.
[0431] One of ordinary skill in the art will appreciate that the
compounds of the invention are useful in treating a diverse array
of diseases. One of ordinary skill in the art will also appreciate
that when using the compounds of the invention in the treatment of
a specific disease that the compounds of the invention may be
combined with various existing therapeutic agents used for that
disease.
[0432] For the treatment of rheumatoid arthritis, the compounds of
the invention may be combined with agents such as TNF-.alpha.
inhibitors such as anti-TNF monoclonal antibodies (such as
Remicade, CDP-870 and D.sub.2E.sub.7) and TNF receptor
immunoglobulin molecules (such as Enbrel.RTM.), COX-2 inhibitors
(such as meloxicam, celecoxib, rofecoxib, valdecoxib, paracoxib,
and etoricoxib) low dose methotrexate, lefunomide; ciclesonide;
hydroxychloroquine, d-penicillamine, auranofin or parenteral or
oral gold.
[0433] The present invention still further relates to the
combination of a compound of the invention together with a
leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor
or 5-lipoxygenase activating protein (FLAP) antagonist selected
from the group consisting of zileuton; ABT-761; fenleuton;
tepoxalin; Abbott-79175; Abbott-85761;
N-(5-substituted)-thiophene-2-alkylsulfonamides;
2,6-di-tert-butylphenol hydrazones; methoxytetrahydropyrans such as
Zeneca ZD-2138; the compound SB-210661; pyridinyl-substituted
2-cyanonaphthalene compounds such as L-739,010; 2-cyanoquinoline
compounds such as L-746,530; indole and quinoline compounds such as
MK-591, MK-886, and BAY x 1005.
[0434] The present invention still further relates to the
combination of a compound of the invention together with a receptor
antagonists for leukotrienes LTB.sub.4, LTC.sub.4, LTD.sub.4, and
LTE.sub.4 selected from the group consisting of the
phenothiazin-3-ones such as L-651,392; amidino compounds such as
CGS-25019c; benzoxalamines such as ontazolast;
benzenecarboximidamides such as BIIL 284/260; and compounds such as
zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679),
RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
[0435] The present invention still further relates to the
combination of a compound of the invention together with a PDE4
inhibitor including inhibitors of the isoform PDE4D.
[0436] The present invention still further relates to the
combination of a compound of the invention together with a
antihistaminic H.sub.1 receptor antagonists including cetirizine,
loratadine, desloratadine, fexofenadine, astemizole, azelastine,
and chlorpheniramine.
[0437] The present invention still further relates to the
combination of a compound of the invention together with a
gastroprotective H.sub.2 receptor antagonist.
[0438] The present invention still further relates to the
combination of a compound of the invention together with an
.alpha..sub.1- and .alpha..sub.2-adrenoceptor agonist
vasoconstrictor sympathomimetic agent, including propylhexedrine,
phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline
hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline
hydrochloride, xylometazoline hydrochloride, and
ethylnorepinephrine hydrochloride.
[0439] The present invention still further relates to the
combination of a compound of the invention together with
anticholinergic agents including ipratropium bromide; tiotropium
bromide; oxitropium bromide; pirenzepine; and telenzepine.
[0440] The present invention still further relates to the
combination of a compound of the invention together with
.beta..sub.1- to .beta..sub.4-adrenoceptor agonists including
metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol,
formoterol, salmeterol, terbutaline, orciprenaline, bitolterol
mesylate, and pirbuterol; or methylxanthanines including
theophylline and aminophylline; sodium cromoglycate; or muscarinic
receptor (M1, M2, and M3) antagonist.
[0441] The present invention still further relates to the
combination of a compound of the invention together with an
insulin-like growth factor type I (IGF-1) mimetic.
[0442] The present invention still further relates to the
combination of a compound of the invention together with an inhaled
glucocorticoid with reduced systemic side effects, including
prednisone, prednisolone, flunisolide, triamcinolone acetonide,
beclomethasone dipropionate, budesonide, fluticasone propionate,
and mometasone furoate.
[0443] The present invention still further relates to the
combination of a compound of the invention together with (a)
tryptase inhibitors; (b) platelet activating factor (PAF)
antagonists; (c) interleukin converting enzyme (ICE) inhibitors;
(d) IMPDH inhibitors; (e) adhesion molecule inhibitors including
VLA-4 antagonists; (f) cathepsins; (g) MAP kinase inhibitors; (h)
glucose-6 phosphate dehydrogenase inhibitors; (i) kinin-B.sub.1-
and B.sub.2-receptor antagonists; () anti-gout agents, e.g.,
colchicine; (k) xanthine oxidase inhibitors, e.g., allopurinol; (I)
uricosuric agents, e.g., probenecid, sulfinpyrazone, and
benzbromarone; (m) growth hormone secretagogues; (n) transforming
growth factor (TGF.beta.); (o) platelet-derived growth factor
(PDGF); (p) fibroblast growth factor, e.g., basic fibroblast growth
factor (bFGF); (q) granulocyte macrophage colony stimulating factor
(GM-CSF); (r) capsaicin cream; (s) Tachykinin NK.sub.1 and NK.sub.3
receptor antagonists selected from the group consisting of
NKP-608C; SB-233412 (talnetant); and D-4418; and (t) elastase
inhibitors selected from the group consisting of UT-77 and
ZD-0892.
[0444] The present invention still further relates to the
combination of a compound of the invention together with an
inhibitor of matrix metalloproteases (MMPs), i.e., the
stromelysins, the collagenases, and the gelatinases, as well as
aggrecanase; especially collagenase-1 (MMP-1), collagenase-2
(MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3),
stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11).
[0445] The compounds of the invention can also be used in
combination with existing therapeutic agents for the treatment of
osteoarthritis. Suitable agents to be used in combination include
standard non-steroidal anti-inflammatory agents (hereinafter
NSAID's) such as piroxicam, diclofenac, propionic acids such as
naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen,
fenamates such as mefenamic acid, indomethacin, sulindac, apazone,
pyrazolones such as phenylbutazone, salicylates such as aspirin,
COX-2 inhibitors such as celecoxib, valdecoxib, rofecoxib and
etoricoxib, analgesics and intraarticular therapies such as
corticosteroids and hyaluronic acids such as hyalgan and
synvisc.
[0446] The compounds of the present invention may also be used in
combination with anticancer agents such as endostatin and
angiostatin or cytotoxic drugs such as adriamycin, daunomycin,
cis-platinum, etoposide, taxol, taxotere and farnesyl transferase
inhibitors, VegF inhibitors, COX-2 inhibitors and antimetabolites
such as methotrexate antineoplastic agents, especially antimitotic
drugs including the vinca alkaloids such as vinblastine and
vincristine;.
[0447] The compounds of the invention may also be used in
combination with antiviral agents such as Viracept, AZT, aciclovir
and famciclovir, and antisepsis compounds such as Valant.
[0448] The compounds of the present invention may also be used in
combination with cardiovascular agents such as calcium channel
blockers, lipid lowering agents such as statins, fibrates,
beta-blockers, Ace inhibitors, Angiotensin-2 receptor antagonists
and platelet aggregation inhibitors.
[0449] The compounds of the present invention may also be used in
combination with CNS agents such as antidepressants (such as
sertraline), anti-Parkinsonian drugs (such as deprenyl, L-dopa,
Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline,
comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake
inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists
and inhibitors of neuronal nitric oxide synthase), and
anti-Alzheimer's drugs such as donepezil, tacrine, COX-2
inhibitors, propentofylline or metryfonate.
[0450] The compounds of the present invention may also be used in
combination with osteoporosis agents such as roloxifene,
droloxifene, lasofoxifene or fosomax and immunosuppressant agents
such as FK-506, rapamycin, cyclosporine, azathioprine, and
methotrexate.
DETAILED DESCRIPTION OF THE INVENTION
[0451] Compounds of the formula I may be prepared according to the
following reaction schemes and discussion. Unless otherwise
indicated R.sup.1 through R.sup.7 in the reaction schemes and
discussion that follows are as defined above. ##STR72## ##STR73##
##STR74## ##STR75## ##STR76## ##STR77## ##STR78## ##STR79##
[0452] Scheme 1 refers to the preparation of compounds of the
formula VI. Compounds of the formula VI can be prepared from
compounds of formula I by reaction with a compound of the formula
VII: L-R.sup.7, in the presence of base, wherein L is a suitable
leaving group, such as chloro, bromo, iodo tosylate or mesylate.
Suitable bases include, but are not limited to, triethylamine,
polymer supported BEMP, cesium carbonate, potassium carbonate, and
sodium hydride, where cesium carbonate is preferred. The aforesaid
reaction can be performed at temperatures ranging from 0.degree. C.
to 100.degree. C. in the presence of a polar solvent including but
not limited to dimethylsulfoxide, dimethylformamide, equal amounts
of dimethylsulfoxide and acetone, or equal amounts of
dimethylformamide and acetone, generally for a period of 2 hours to
72 hours, where the preferred conditions are dimethylsulfoxide at
ambient temperature for 18 hours.
[0453] Compounds of the formula VI may also be prepared from
compounds of the formula I by reaction of an appropriately
substituted epoxide of the formula VIII either neat or in the
presence of a polar solvent including but not limited to
dimethylformamide, dimethylsulfoxide, and tetrahydrofuran. The
aforesaid reaction can be performed at temperatures ranging from
0.degree. C. to 100.degree. C. for a period of 2 to 72 hours, where
the preferred conditions are dimethylforamide at 60.degree. C. for
24 hours.
[0454] Scheme 2 refers to the preparation of compounds of the
formula I. Compounds of the formula I can be prepared from
compounds of formula IX by reacting with a compound of formula XI,
H.sub.2N--R.sup.1, in the presence of a coupling reagent such as
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI),
dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI) and
a base such as dimethylaminopyridine (DMAP) or triethylamine in an
aprotic solvent, such as methylene chloride, dimethylformamide, or
dimethylsulfoxide, preferably
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide and
dimethylaminopyridine in dimethyl formamide. The aforesaid reaction
may be run at a temperature from 22.degree. C. to 60.degree. C.,
for a period of 1 hour to 20 hours, preferably 22.degree. C. for 18
hours.
[0455] Compounds of the formula I may also be prepared from
compounds of the formula X by reaction with a compound of formula
XI in the presence of a base including but not limited to
dimethylaminopyridine (DMAP), triethylamine, aqueous sodium
hydroxide or aqueous potassium hydroxide in an aprotic solvent,
such as methylene chloride, ethyl acetate, dichloroethane,
dimethylformamide, or dimethylsulfoxide, preferably aqueous sodium
hydroxide and dichloroethane. The aforesaid reaction may be run at
a temperature from 22.degree. C. to 60.degree. C., for a period of
1 hour to 24 hours, preferably at ambient temperature for 3 hours.
Compound X can be prepared from compound IX by reaction with a
reagent capable of generating an acid chloride such as thionyl
chloride or oxalyl chloride in the presence of a polar aprotic
solvent such as ethyl acetate, methylene chloride, or
dichloroethane at a temperature of 22.degree. C. to 60.degree. C.,
for a period of 1 hour to 24 hours, preferably oxalyl chloride in
methylene chloride at ambient temperature for 16 hours.
[0456] Scheme 3 refers to the preparation of compounds of the
formula XIV and IX. Compounds of the formula IX can be converted
into compounds of the formula I by the methods described in Scheme
2. A compound of the formula IX can be prepared from a compound of
the formula XIV by reaction with diphenylphosphoryl azide and a
base such as triethylamine, pyridine, or diisopropyl ethylamine,
preferably triethylamine, at a temperature between 80 and
120.degree. C. for a period of 2 to 16 hours, preferably
120.degree. C. for 2 hours.
[0457] Compounds of the formula XIV can be prepared from compounds
of the formula XII by reaction with a compound of the formula XIII,
HO.sub.2C(CO)R.sup.4, in the presence of 10% hydrochloric acid at a
temperature between 20 and 80.degree. C. for a period of 1 to 24
hours, preferably 1.5 hours at ambient temperature.
[0458] Scheme 4 refers to the preparation of compounds of the
formula XVI and XII. Compounds of the formula XII can be converted
into compounds of the formula XIV by the methods described in
Scheme 3. A compound of the formula XII can be prepared from a
compound of the formula XVI by reaction with an acid such as
hydrochloric acid and/or glacial acetic acid, followed by treatment
with sodium nitrite in a solvent such as water at a temperature
from 0.degree. C. to 25.degree. C., and the reaction is generally
run from a period of 30 minutes to about 2 hours, preferably
0.degree. C. for 30 minutes. This intermediate is then treated with
tin(II)chloride dihydrate in a solvent such as acid, preferably
hydrochloric acid at a temperature from 0 to 25.degree. C. for a
period of 2 to 8 hours, preferably 0.degree. C. for 30 minutes.
[0459] A compound of the formula XVI can be prepared from a
compound of the formula XV by reaction with methanol in the
presence of an acid such as sulfuric acid at a temperature between
ambient temperature and reflux for a period of 4 to 24 hours,
preferably at reflux for 4 hours.
[0460] Scheme 5 refers to the preparation of compounds of the
formula XVII. Compounds of the formula XVII can be prepared from
compounds of formula I by reaction with a compound of the formula
VII, in the presence of base, wherein L is a suitable leaving
group, such as chloro, bromo, iodo tosylate or mesylate. Suitable
bases include, but are not limited to, triethylamine, polymer
supported BEMP, cesium carbonate, potassium carbonate, and sodium
hydride, where cesium carbonate is preferred. The aforesaid
reaction can be performed at temperatures ranging from 0.degree. C.
to 100.degree. C. in the presence of a polar solvent including but
not limited to dimethylsulfoxide, dimethylformamide, equal amounts
of dimethylsulfoxide and acetone, or equal amounts of
dimethylformamide and acetone, generally for a period of 2 hours to
72 hours, where the preferred conditions are dimethylsulfoxide at
ambient temperature for 18 hours.
[0461] Compounds of the formula XVII may also be prepared from
compounds of the formula I by reaction of an appropriately
substituted epoxide of the formula VIII either neat or in the
presence of a polar solvent including but not limited to
dimethylformamide, dimethylsulfoxide, and tetrahydrofuran. The
aforesaid reaction can be performed at temperatures ranging from
0.degree. C. to 100.degree. C. for a period of 2 to 72 hours, where
the preferred conditions are dimethylforamide at 60.degree. C. for
24 hours.
[0462] Scheme 6 refers to the preparation of compounds of the
formula XIX. Compounds of the formula XIX can be prepared from
compounds of formula XVIII by reacting with a base such as NaOH,
followed by reaction with a compound of formula XI, in the presence
of a coupling reagent such as
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI),
dicyclohexylcarbodiimide (DCC), 1,1'-carbonyidiimidazole (CDI) and
a base such as dimethylaminopyridine (DMAP) or triethylamine in an
aprotic solvent, such as methylene chloride, dimethylformamide, or
dimethylsulfoxide, preferably
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide and
dimethylaminopyridine in dimethyl formamide. The aforesaid reaction
may be run at a temperature from 22.degree. C. to 60.degree. C.,
for a period of 1 hour to 20 hours, preferably 22.degree. C. for 18
hours.
[0463] Scheme 7 refers to the preparation of compounds of the
formula XXII and XVIII. A compound of the formula XIX can be
prepared from a compound of the formula XXII by reaction with an
acid such as dilute sulfuric acid or concentrated hydrochloric acid
at a temperature from ambient to reflux for 2 to 16 hours.
Compounds of the formula XXII can be prepared from compounds of the
formula XX by reaction with a compound of the formula XXI,
H.sub.2NCH(R.sup.4)CR.sup.5(OCH.sub.3).sub.2, in the presence of an
organic base such as triethylamine, diisopropylethylamine, or
pyridine in a solvent such a dimethyl sulfoxide at a temperature
from ambient temperature to 60.degree. C. for 2 to 24 hours.
[0464] Scheme 8 refers to the preparation of compounds of the
formula XX. Compounds of the formula XX can be converted into
compounds of the formula XXII and XVIII by the methods described in
Scheme 7. A compound of the formula XX can be prepared from a
compound of the formula XVI by reaction with phenyl chloroformate
with an organic base such as pyridine in a solvent such as
tetrahydrofuran at a temperature from 0.degree. C. to ambient
temperature for 2 to 24 hours, preferably ambient for 12 hours.
[0465] The activity of the compounds of the invention for the
various disorders described above can be determined according to
one or more of the following assays. All of the compounds of the
invention that were tested had an IC.sub.50 of less than 10 .mu.M
in the in vitro assay described below.
[0466] Preferably, the compounds of the invention have an IC.sub.50
in the in vitro assays described below of less than 100 nM, more
preferably less than 50 nM, and most preferably less than 10 nM.
Still further, the compounds of the invention preferably have an
IC.sub.50 in the range of 0.01 nM-100 nM, more preferably between
0.05 nM-50 nM, and most preferably between 0.10 nM-10 nM.
Pharmacological Analysis
[0467] Certain compounds such as benzoylbenzoyl adenosine
triphosphate (bbATP) are known to be agonists of the P2X.sub.7
receptor, effecting the formation of pores in the plasma membrane
(Drug Development Research (1996), 37(3), p. 126). Consequently,
when the receptor is activated using bbATP in the presence of
ethidium bromide (a fluorescent DNA probe), an increase in the
fluorescence of intracellular DNA-bound ethidium bromide is
observed. Alternatively, the propidium dye YOPRO-1 can be
substituted for ethidium bromide so as to detect uptake of the dye.
The increase in fluorescence can be used as a measure of P2X.sub.7
receptor activation and therefore to quantify the effect of a
compound on the P2X.sub.7 receptor.
[0468] In this manner, the compounds of the invention can be tested
for antagonist activity at the P2X.sub.7 receptor. 96-Well flat
bottomed microtitre plates are filled with 250 .mu. of test
solution comprising 200 .mu.l of a suspension of THP-1 cells
(2.5.times.10.sup.6 cells/ml, more preferably prestimulated as
described in the literature with a combination of LPS and TNF to
promote receptor expression) containing 10.sup.-4M ethidium
bromide, 25 .mu.l of a high potassium, low sodium buffer solution
(10 mM Hepes, 150 mM KCl, 5 mM D-glucose and 1.0% FBS at pH 7.5)
containing 10.sup.-5M bbATP, and 25 .mu.l of the high potassium
buffer solution containing 3.times.10.sup.-5M test compound (more
preferably 5.times.10.sup.-4M, more preferably 1.times.10.sup.-4M
more preferably 1.times.10.sup.-3M). The plate is covered with a
plastic sheet and incubated at 37.degree. C. for one hour. The
plate is then read in a Perkin-Elmer fluorescent plate reader,
excitation 520 nm, emission 595 nm, slit widths: Ex 15 nm, Em 20
nm. For the purposes of comparison, bbATP (a P2X.sub.7 receptor
agonist) and pyridoxal 5-phosphate (a P2X.sub.7 receptor
antagonist) can be used separately in the test as controls. From
the readings obtained, a pIC.sub.50 figure can be calculated for
each test compound, this figure being the negative logarithm of the
concentration of test compound necessary to reduce the bbATP
agonist activity by 50%.
[0469] In like manner, the compounds of the invention can be tested
for antagonist activity at the P2X.sub.7 receptor using the
cytokine IL-1.beta. as the readout. Blood collected from normal
volunteers in the presence of heparin is fractionated using
lymphocyte separation medium obtained from Organon Technica
(Westchester, Pa.). The region of the resulting gradient containing
banded mononuclear cells is harvested, diluted with 10 ml of
Maintenance Medium (RPMI 1640, 5% FBS, 25 mM Hepes, pH 7.2, 1%
penicillin/streptomycin), and cells are collected by
centrifugation. The resulting cell pellet was suspended in 10 ml of
Maintenance Medium and a cell count was performed. In an average
experiment, 2.times.10.sup.5 mononuclear cells are seeded into each
well of 96-well plates in a total volume of 0.1 ml. Monocytes are
allowed to adhere for 2 hours, after which the supernatants are
discarded and the attached cells are rinsed twice and then
incubated in Maintenance Medium overnight at 37.degree. C. in a 5%
CO.sub.2 environment.
[0470] The cultured monocytes can be activated with 10 ng/ml LPS
(E. coli serotype 055:B5; Sigma Chemicals, St. Louis, Mo.).
Following a 2-hour incubation, the activation medium is removed,
the cells are rinsed twice with 0.1 ml of Chase Medium (RPMI 1640,
1% FBS, 20 mM Hepes, 5 mM NaHCO.sub.3, pH 6.9), and then 0.1 ml of
Chase Medium containing a test agent is added and the plate is
incubated for 30 minutes; each test agent concentration can be
evaluated in triplicate wells. ATP then is introduced (from a 100
mM stock solution, pH 7) to achieve a final concentration of 2 mM
and the plate is incubated at 37.degree. C. for an additional 3
hours. Media were harvested and clarified by centrifugation, and
their IL-1.beta. content was determined by ELISA (R&D Systems;
Minneapolis, Minn.).
[0471] The compositions of the present invention may be formulated
in a conventional manner using one or more pharmaceutically
acceptable carriers. Thus, the active compounds of the invention
may be formulated for oral, buccal, intranasal, parenteral (e.g.,
intravenous, intramuscular or subcutaneous), topical or rectal
administration or in a form suitable for administration by
inhalation or insufflation.
[0472] For oral administration, the pharmaceutical compositions may
take the form of, for example, tablets or capsules prepared by
conventional means with pharmaceutically acceptable excipients such
as binding agents (e.g., pregelatinized maize starch,
polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers
(e.g., lactose, microcrystalline cellulose or calcium phosphate);
lubricants (e.g., magnesium stearate, talc or silica);
disintegrants (e.g., potato starch or sodium starch glycolate); or
wetting agents (e.g., sodium lauryl sulphate). The tablets may be
coated by methods well known in the art. Liquid preparations for
oral administration may take the form of, for example, solutions,
syrups or suspensions, or they may be presented as a dry product
for constitution with water or other suitable vehicle before use.
Such liquid preparations may be prepared by conventional means with
pharmaceutically acceptable additives such as suspending agents
(e.g., sorbitol syrup, methyl cellulose or hydrogenated edible
fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous
vehicles (e.g., almond oil, oily esters or ethyl alcohol); and
preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic
acid).
[0473] For buccal administration, the composition may take the form
of tablets or lozenges formulated in conventional manner.
[0474] The compounds of formula I can also be formulated for
sustained delivery according to methods well known to those of
ordinary skill in the art. Examples of such formulations can be
found in U.S. Pat. Nos. 3,538,214, 4,060,598, 4,173,626, 3,119,742,
and 3,492,397, which are herein incorporated by reference in their
entirety.
[0475] The active compounds of the invention may be formulated for
parenteral administration by injection, including using
conventional catheterization techniques or infusion. Formulations
for injection may be presented in unit dosage form, e.g., in
ampules or in multi-dose containers, with an added preservative.
The compositions may take such forms as suspensions, solutions or
emulsions in oily or aqueous vehicles, and may contain formulating
agents such as suspending, stabilizing and/or dispersing agents.
Alternatively, the active ingredient may be in powder form for
reconstitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use.
[0476] The active compounds of the invention may also be formulated
in rectal compositions such as suppositories or retention enemas,
e.g., containing conventional suppository bases such as cocoa
butter or other glycerides.
[0477] For intranasal administration or administration by
inhalation, the active compounds of the invention are conveniently
delivered in the form of a solution, dry powder formulation or
suspension from a pump spray container that is squeezed or pumped
by the patient or as an aerosol spray presentation from a
pressurized container or a nebulizer, with the use of a suitable
propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or
other suitable gas. In the case of a pressurized aerosol, the
dosage unit may be determined by providing a valve to deliver a
metered amount. The pressurized container or nebulizer may contain
a solution or suspension of the active compound. Capsules and
cartridges (made, for example, from gelatin) for use in an inhaler
or insufflator may be formulated containing a powder mix of a
compound of the invention and a suitable powder base such as
lactose or starch.
[0478] A proposed dose of the active compounds of the invention for
oral, parenteral or buccal administration to the average adult
human for the treatment of the conditions referred to above
(inflammation) is 0.1 to 200 mg of the active ingredient per unit
dose which could be administered, for example, 1 to 4 times per
day.
[0479] The compound of formula (I) and pharmaceutically acceptable
salts and solvates thereof may be used on their own but will
generally be administered in the form of a pharmaceutical
composition in which the formula (I) compound/salt/solvate (active
ingredient) is in association with a pharmaceutically acceptable
adjuvant, diluent or carrier. Depending on the mode of
administration, the pharmaceutical composition will preferably
comprise from 0.05 to 99% w (percent by weight), more preferably
from 0.10 to 70% w, of active ingredient, and, from 1 to 99.95% w,
more preferably from 30 to 99.90% w, of a pharmaceutically
acceptable adjuvant, diluent or carrier, all percentages by weight
being based on total composition.
[0480] Aerosol formulations for treatment of the conditions
referred to above in the average adult human are preferably
arranged so that each metered dose or "puff" of aerosol contains 20
.mu.g to 1000 .mu.g of the compound of the invention. The overall
daily dose with an aerosol will be within the range 100 .mu.g to 10
mg. Administration may be several times daily, for example 2, 3, 4
or 8 times, giving for example, 1, 2 or 3 doses each time.
[0481] Aerosol combination formulations for treatment of the
conditions referred to above (e.g., adult respiratory distress
syndrome) in the average adult human are preferably arranged so
that each metered dose or "puff" of aerosol contains from about 1
.mu.g to 1000 .mu.g of the compound of the invention. The overall
daily dose with an aerosol will be within the range 100 .mu.g to 10
mg. Administration may be several times daily, for example 2, 3, 4
or 8 times, giving for example, 1, 2 or 3 doses each time.
[0482] Aerosol formulations for treatment of the conditions
referred to above (e.g., adult respiratory distress syndrome) in
the average adult human are preferably arranged so that each
metered dose or "puff" of aerosol contains from about 20 .mu.g to
1000 .mu.g of the compound of the invention. The overall daily dose
with an aerosol will be within the range 100.mu.g to 10 mg of the
P2X.sub.7 receptor inhibitor. Administration may be several times
daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or
3 doses each time.
[0483] This invention also encompasses pharmaceutical compositions
containing and methods of treating or preventing comprising
administering prodrugs of compounds of the formula I. Compounds of
formula I having free amino, amido, hydroxy or carboxylic groups
can be converted into prodrugs. Prodrugs include compounds wherein
an amino acid residue, or a polypeptide chain of two or more (e.g.,
two, three or four) amino acid residues which are covalently joined
through peptide bonds to free amino, hydroxy or carboxylic acid
groups of compounds of formula I. The amino acid residues include
the 20 naturally occurring amino acids commonly designated by three
letter symbols and also include, 4-hydroxyproline, hydroxylysine,
demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine,
gamma-aminobutyric acid, citrulline homocysteine, homoserine,
ornithine and methionine sulfone. prodrugs also include compounds
wherein carbonates, carbamates, amides and alkyl esters which are
covalently bonded to the above substituents of formula I through
the carbonyl carbon prodrug sidechain.
[0484] The following Examples illustrate the preparation of the
compounds of the present invention. Melting points are uncorrected.
NMR data are reported in parts per million (d) and are referenced
to the deuterium lock signal from the sample solvent
(deuteriochloroform unless otherwise specified). Mass Spectral data
were obtained using a Micromass ZMD APCI Mass Spectrometer equipped
with a Gilson gradient high performance liquid chromatograph. The
following solvents and gradients were used for the analysis.
Solvent A; 98% water/2% acetonirile/0.01% formic acid and solvent
B; acetonitrile containing 0.005% formic acid. Typically, a
gradient was run over a period of about 4 minutes starting at 95%
solvent A and ending with 100% solvent B. The mass spectrum of the
major eluting component was then obtained in positive or negative
ion mode scanning a molecular weight range from 165 AMU to 1100
AMU. Specific rotations were measured at room temperature using the
sodium D line (589 nm). Commercial reagents were utilized without
further purification. THF refers to tetrahydrofuran. DMF refers to
N,N-dimethylformamide. Chromatography refers to column
chromatography performed using 32-63 mm silica gel and executed
under nitrogen pressure (flash chromatography) conditions. Room or
ambient temperature refers to 20-25.degree. C. All non-aqueous
reactions were run under a nitrogen atmosphere for convenience and
to maximize yields. Concentration at reduced pressure means that a
rotary evaporator was used.
[0485] One of ordinary skill in the art will appreciate that in
some cases protecting groups may be required during preparation.
After the target molecule is made, the protecting group can be
removed by methods well known to those of ordinary skill in the
art, such as described in Greene and Wuts, "Protective Groups in
Organic Synthesis" (3rd Ed, John Wiley & Sons 1999).
EXAMPLE 1
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-methoxy-ethyl)-5-oxo-4,5--
dihydro-[1,2,4]triazol-1-yl]-benzamide
[0486] ##STR80##
(A) 5-Amino-2-chloro-benzoic acid methyl ester
[0487] To a slurry of 5-amino-2-chloro-benzoic acid (20.0 g, 0.12
mol) in methanol (150 mL) was added concentrated sulfuric acid (25
mL). The resulting reaction was heated at reflux for 4 hours,
cooled, and concentrated in vacuo. The residual was taken up in
water and neutralized with Na.sub.2CO.sub.3. The aqueous was
extracted with CH.sub.2Cl.sub.2 (3.times.). The organics were dried
over sodium sulfate and concentrated in vacuo to yield the above
named compound (14.0 g).
(B) 2-Chloro-5-hydrazino-benzoic acid methyl ester hydrochloride
salt
[0488] To 5-amino-2-chloro-benzoic acid methyl ester (14.0 g, 75.0
mmol) in water (100 mL) was added concentrated HCl (100 mL),
followed by glacial acetic acid (100 mL). The solution was stirred
at ambient temperature for 15 minutes. The reaction was then cooled
to 0.degree. C., and a solution of sodium nitrite (5.69, 82.5 mmol)
in water (15 mL) was added dropwise over 30 minutes, maintaining
the temperature at 0.degree. C. The resulting reaction was stirred
for 30 minutes at 0.degree. C., then a solution of
SnCl.sub.2.2H.sub.2O (50.8 g, 225 mmol) in concentrated HCl (100
mL) was added over 30 minutes, maintaining the temperature at
0.degree. C. The slurry was stirred at 0.degree. C. for 30 minutes,
and the resulting precipitate collected by filtration, washed with
water, followed by hexane. The solid was dried in a vacuum oven at
50.degree. C. to give the title compound (16.3 g).
(C) 5-(N'-Carboxymethylene-hydrazino)-2-chloro-benzoic acid methyl
ester
[0489] 2-Chloro-5-hydrazino-benzoic acid methyl ester hydrochloride
salt (2.0 g, 8.5 mmol) and oxoacetic acid (1.0 g, 10 mmol) were
taken up in 10% HCl and stirred at ambient temperature for 1.5
hours. The resulting orange precipitate was collected by
filtration. The filter cake was taken up in EtOAc, washed with
brine, and dried over sodium sulfate. Concentration in vacuo
yielded the above named compound (1.2 g).
(D) 2-Chloro-5-(5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-benzoic acid
methyl ester
[0490] 5-(N-Carboxymethylene-hydrazino)-2-chloro-benzoic acid
methyl ester (514.0 mg, 2.0 mmol), diphenylphosphoryl azide (605.0
mg, 2.2 mmol), and triethylamine (0.3 mL, 2.2 mmol) in toluene (15
mL) were heated at 120.degree. C. for 1 hour under N.sub.2. The
reaction was cooled then 1.0 M NaOH (20 mL) added, and the
resulting solution stirred for 10 minutes. The layers were
separated, and the organic phase acidified to pH 1 using 1.0 N HCl.
The resulting precipitate was collected by filtration, washed with
hexane, and dried at 50.degree. C. in vacuum oven for 12 hours to
give the title compound (0.24 g).
(E)
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(5-oxo-4,5-dihydro-[1,2,4]t-
riazol-1-yl)-benzamide
[0491] To
2-chloro-5-(5-oxo-4,5-dihydro-(1,2,4]triazol-1-yl)-benzoic acid
methyl ester [48.0 mg, 0.2 mmol) in DMF (3 mL) was added
1-aminomethyl-cycloheptanol HCl (54.0 mg, 0.3 mmol),
polymer-supported CDI (660 mg, 0.6 mmol), polymer-supported DMAP
(280 mg, 0.20 mmol), and HOBt (40.0 mg, 0.3 mmol). The resulting
reaction was shaken for 3 hours at ambient temperature. The
reaction was filtered, washed with methanol, and the filtrate
concentrated in vacuo. The residue was purified by reverse phase
HPLC using a (5-100% gradient of 0.1% formic acid in acetonitrile
and 0.1% formic acid in water) to yield 20 mg of the above named
compound.
(F)
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-methoxy-ethyl)-5-oxo--
4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide
[0492] A slurry of
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(5-oxo-4,5-dihydro-[1,2,4]tria-
zol-1-yl)-benzamide (44.4 mg, 0.122 mmol) and Cs.sub.2CO.sub.3
(66.0 mg, 0.202 mmol) were stirred in DMSO (0.813 mL) at ambient
temperature for 20 minutes. 2-Bromoethyl methyl ether (17.0 mg,
0.122 mmol) was added and the reaction stirred at ambient
temperature for 48 hours. The reaction was diluted with water
(15-fold) and the aqueous extracted with CH.sub.2Cl.sub.2
(3.times.). The organics were dried over sodium sulfate, and
concentrated in vacuo. The crude was purified by reverse phase HPLC
reverse phase HPLC using a (25-65% gradient of 0.1% formic acid in
acetonitrile and 0.1% formic acid in water) (to give the title
compound (18 mg). LCMS (m/z) 423.5 M+1.
[0493] The compounds of Examples 2-14, identified in Table 1 below,
can be prepared according to the method of Example 1.
TABLE-US-00001 TABLE 1 DATA EXAMPLE # MOLSTRUCTURE IUPAC NAME LCMS
M/Z 2 ##STR81## 2-Chloro-N-(1- hydroxy-cycloheptylmethyl)-
5-(5-oxo-4,5-dihydro- [1,2,4]triazol-1-yl)- benzamide 365.2 3
##STR82## 2-Chloro-N-(1- hydroxy-cycloheptylmethyl)-
5-(3-methyl-5-oxo-4,5- dihydro-[1,2,4]triazol-1-yl)- benzamide
379.5 4 ##STR83## 2-Chloro-N-(1- hydroxy-cycloheptylmethyl)-
5-[4-(2-hydroxy-ethyl)-5- oxo-4,5-dihydro- [1,2,4]triazol-1-yl]-
benzamide 409.5 5 ##STR84## 2-Chloro-5-(4- cyanomethyl-5-oxo-4,5-
dihydro-[1,2,4]triazol-1-yl)- N-(1-hydroxy- cycloheptylmethyl)-
benzamide 404.5 6 ##STR85## 2-Chloro-N-(1-
hydroxy-cycloheptylmethyl)- 5-[4-(2-methoxy-ethyl)-3-
methyl-5-oxo-4,5-dihydro- [1,2,4]triazol-1-yl]- benzamide 437.6 7
##STR86## 2-Chloro-5-(4- cyanomethyl-3-methyl-5- oxo-4,5-dihydro-
[1,2,4]triazol-1-yl)-N-(1- hydroxy-cycloheptyl- methyl)-benzamide
418.5 8 ##STR87## 2-Chloro-N-(1- hydroxy-3,3-dimethyl-
cyclohexylmethyl)-5-(3- methyl-5-oxo-4,5-dihydro- [1,2,4]triazol-
1-yl)-benzamide 393.5 9 ##STR88## 5-(4- Carbamoylmethyl-3-methyl-
5-oxo-4,5-dihydro- [1,2,4]triazol-1-yl)-2-chloro- N-(1-hydroxy-
cycloheptylmethyl)- benzamide 436.4 10 ##STR89## 2-Chloro-N-(1-
hydroxy-cycloheptylmethyl)- 5-[4-(2-hydroxy-ethyl)-3-
methyl-5-oxo-4,5-dihydro- [1,2,4]triazol-1-yl]- benzamide 423.5 11
##STR90## 5-[4-(2-Amino- ethyl)-3-methyl-5-oxo-4,5-
dihydro-[1,2,4]triazol-1-yl]- 2-chloro-N-(1-hydroxy-
cycloheptylmethyl)- benzamide 422.4
EXAMPLE 12
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-
-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide
[0494] ##STR91##
(A)
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-pro-
pyl)-3-methyl-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl]-benzamide
[0495]
2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(5-oxo-4,5-dihydro-[1,2-
,4]triazol-1-yl)-benzamide (38 mg, 0.1 mmol) and R-(-)-glycidyl
methyl ether (0.3 mL) in DMF (0.1 mL) were heated at 80.degree. C.
for 2 hours. The reaction was concentrated in vacuo, then purified
by reverse phase HPLC using a (25-50% gradient of 0.1% formic acid
in acetonitrile and 0.1% formic acid in water) to give the title
compound (20 mg). LCMS (m/z) 467.6 M+1.
[0496] The compounds of Examples 13-14, identified in Table 2
below, can be prepared according to the method of Example 12.
TABLE-US-00002 TABLE 2 DATA EXAMPLE # MOLSTRUCTURE IUPAC NAME LCMS
M/Z 13 ##STR92## 2-Chloro-N-(1- hydroxy-cycloheptylmethyl)-
5-[4-(2-hydroxy-3-methoxy- propyl)-3-methyl-5-oxo-4,5-
dihydro-[1,2,4]triazol-1-yl]- benzamide 467.6 14 ##STR93##
2-Chloro-N-(1- hydroxy-cycloheptylmethyl)-
5-[4-(2-hydroxy-2-methyl- propyl)-3-methyl-5-oxo-4,5-
dihydro-[1,2,4]triazol-1-yl]- benzamide 451.6
[0497] The present invention is not to be limited in scope by the
specific embodiments described herein. Indeed, various
modifications of the invention in addition to those described
herein will become apparent to those skilled in the art from the
foregoing description and the accompanying figures. Such
modifications are intended to fall within the scope of the appended
claims.
[0498] All patents, applications, publications, test methods,
literature, and other materials cited herein are hereby
incorporated herein by reference in their entireties.
* * * * *