U.S. patent application number 12/719606 was filed with the patent office on 2010-07-01 for amino-5-(5-membered)heteroarylimidazolone compounds and the use thereof for beta-secretase modulation.
This patent application is currently assigned to Wyeth LLC. Invention is credited to Patrick Michael Andrae, James Joseph Erdei, William Floyd Fobare, Iwan Suwandi Gunawan, Michael Sotirios Malamas, Dominick Anthony Quagliato, William Ronald Solvibile, Yinfa Yan, Ping Zhou.
Application Number | 20100168106 12/719606 |
Document ID | / |
Family ID | 37081588 |
Filed Date | 2010-07-01 |
United States Patent
Application |
20100168106 |
Kind Code |
A1 |
Malamas; Michael Sotirios ;
et al. |
July 1, 2010 |
Amino-5-(5-membered)heteroarylimidazolone Compounds And The Use
Thereof For Beta-secretase Modulation
Abstract
The present invention provides a
2-amino-5-heteroaryl-5-phenylimidazolone compound of formula I
##STR00001## The present invention also provides methods for the
use thereof to inhibit .beta.-secretase (BACE) and treat
.beta.-amyloid deposits and neurofibrillary tangles
Inventors: |
Malamas; Michael Sotirios;
(Jamison, PA) ; Zhou; Ping; (Plainsboro, NJ)
; Fobare; William Floyd; (Lawrenceville, NJ) ;
Solvibile; William Ronald; (East Windsor, NJ) ;
Gunawan; Iwan Suwandi; (Somerset, NJ) ; Erdei; James
Joseph; (Philadelphia, PA) ; Yan; Yinfa;
(Bedminster, NJ) ; Andrae; Patrick Michael;
(Jamesburg, NJ) ; Quagliato; Dominick Anthony;
(Bridgewater, NJ) |
Correspondence
Address: |
WYETH LLC;PATENT LAW GROUP
5 GIRALDA FARMS
MADISON
NJ
07940
US
|
Assignee: |
Wyeth LLC
Madison
NJ
|
Family ID: |
37081588 |
Appl. No.: |
12/719606 |
Filed: |
March 8, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12180795 |
Jul 28, 2008 |
7705030 |
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12719606 |
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11478122 |
Jun 29, 2006 |
7417047 |
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12180795 |
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60695353 |
Jun 30, 2005 |
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Current U.S.
Class: |
514/235.8 ;
514/255.05; 514/256; 514/341; 544/131; 544/333; 544/405;
546/274.4 |
Current CPC
Class: |
C07D 417/14 20130101;
C07D 401/14 20130101; C07D 409/04 20130101; C07D 405/14 20130101;
C07D 417/04 20130101; C07D 403/14 20130101; A61P 25/28 20180101;
C07D 409/14 20130101; C07D 403/04 20130101 |
Class at
Publication: |
514/235.8 ;
544/333; 514/256; 546/274.4; 514/341; 544/405; 514/255.05;
544/131 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 403/14 20060101 C07D403/14; A61K 31/506 20060101
A61K031/506; C07D 401/14 20060101 C07D401/14; A61K 31/4439 20060101
A61K031/4439; A61K 31/497 20060101 A61K031/497; C07D 413/14
20060101 C07D413/14; A61P 25/28 20060101 A61P025/28 |
Claims
1. A compound of formula I ##STR00159## wherein W is CO, CS or
CH.sub.2; X is N, NR, NO, S, SO.sub.m, O or CR.sub.9; Y is N, NR,
NO, S, SO.sub.m, O or CR.sub.10; Z is C, N, NR, NO, S, SO.sub.m, O,
CR.sub.11 or CR.sub.11R.sub.12 with the proviso that at least one
of X, Y or Z must be N, NR, NO, S, SO.sub.m or O; m is 1 or 2; R is
H or a C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl or aryl(C.sub.1-C.sub.6)alkyl group each
optionally substituted; R.sub.1 and R.sub.2 are each independently
H, COR.sub.14, CO.sub.2R.sub.15 or an optionally substituted
C.sub.1-C.sub.4alkyl group; R.sub.3 is H, OR.sub.13 or a
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl or aryl(C.sub.1-C.sub.6)alkyl group each
optionally substituted; R.sub.4 R.sub.5, R.sub.9 and R.sub.10 are
each independently H, halogen, NO.sub.2, CN, OR.sub.14,
CO.sub.2R.sub.15, COR.sub.16, NR.sub.17R.sub.18,
SO.sub.pNR.sub.19R.sub.20 or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl or C.sub.3-C.sub.8cycloalkyl group each
optionally substituted; R.sub.6 and R.sub.8 are each independently
H, halogen, NO.sub.2, CN, OR.sub.21, NR.sub.22R.sub.23 or a
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl or
C.sub.3-C.sub.8cycloalkyl group each optionally substituted;
R.sub.7 is H, halogen, NO.sub.2, CN, OR.sub.24, NR.sub.25R.sub.26
or a C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, aryl or heteroaryl group each optionally
substituted; R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.15,
R.sub.16, R.sub.21, R.sub.24, R.sub.27, R.sub.28 and R.sub.29 are
each independently H or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, cycloheteroalkyl
or aryl group each optionally substituted; R.sub.17, R.sub.18,
R.sub.19, R.sub.20, R.sub.22, R.sub.23, R.sub.25, R.sub.26,
R.sub.30, R.sub.31, R.sub.32 and R.sub.33 are each independently H,
COR.sub.34, SO.sub.pR.sub.35 or a C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8
cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each
optionally substituted or R.sub.17, R.sub.18, or R.sub.19, R.sub.20
or R.sub.22, R.sub.23, or R.sub.25, R.sub.26, or R.sub.30,
R.sub.31, or R.sub.32, R.sub.33 may be taken together with the atom
to which they are attached to form an optionally substituted 5- to
7-membered ring optionally containing an additional heteroatom
selected from O, N or S; R.sub.34 is H, or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally
substituted; and R.sub.35 is a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally
substituted; or a tautomer thereof, a stereoisomer thereof or a
pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 wherein W is CO; X is
CR.sub.9; Y is CR.sub.10 and Z is NR or S.
3. The compound according to claim 1 wherein W is CO; X is N; Y is
NR and Z is CR.sub.11R.sub.12.
4. The compound according to claim 1 wherein R.sub.7 is phenyl or
heteroaryl.
5. The compound according to claim 2 wherein R is H or
C.sub.1-C.sub.4alkyl and R.sub.4 is CN or COR.sub.16.
6. The compound according to claim 2 wherein R.sub.7 is phenyl or
heteroaryl.
7. The compound according to claim 3 wherein R.sub.7 is phenyl or
heteroaryl.
8. The compound according to claim 6 wherein R.sub.1 and R.sub.2
are H; and R.sub.3 is methyl.
9. The compound according to claim 1 selected from the group
consisting essentially of:
(5S)-2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluo-
ropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
(5S)-2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-propionyl-1-
-propyl-1H-pyrrol-3-yl)-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluoropyr-
idin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-propionyl-1-prop-
yl-1H-pyrrol-3-yl)-3,5-dihydro-4H-imidazol-4-one;
2-Amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-thien-2-yl-3,5-dihydro-4H-imi-
dazol-4-one;
2-Amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-thien-3-yl-3,5-dihydro-4H-imi-
dazol-4-one;
2-Amino-5-(2',5'-difluoro-1,1'-biphenyl-3-yl)-3-methyl-5-thien-2-yl-3,5-d-
ihydro-4H-imidazol-4-one;
2-Amino-5-(2',5'-difluoro-1,1'-biphenyl-3-yl)-3-methyl-5-thien-3-yl-3,5-d-
ihydro-4H-imidazol-4-one;
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[3-methyl-1-(2,2,2--
trifluoroethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-methyl-1-(2,2,2--
trifluoroethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-5-(1-isobutyl-1H-pyrazol-4-yl)-
-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-butyl-1H-pyrazol-4-yl)-5-[3-(2-fluoropyridin-3-yl)phenyl]-3,-
5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-isobutyl-1H-pyrazol-4-yl)-3-methyl-5-(3-pyrimidin-5-ylphenyl-
)-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-butyl-1H-pyrazol-4-yl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3-
,5-4H-imidazol-4-one;
2-Amino-5-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[1-(2,2,2--
trifluoroethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-5-[1-(2,2,2-trifluor-
oethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-
-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)-5-[4-fluoro-3-(2-fluoropyridin-3-yl)p-
henyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(5-butylthien-2-yl)-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-
-one; Methyl
4-[2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-4,5-dihydro-
-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
Methyl
4-[(4S)-2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-4,5-di-
hydro-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
Methyl
4-[(4R)-2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-4,5-di-
hydro-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
Methyl
4-[2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-4,5-dihydro-
-1H-imidazol-4-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrrole-2-carboxylate;
Methyl
4-{2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5--
oxo-4,5-dihydro-1H-imidazol-4-yl}-1-(2,2,2-trifluoroethyl)-1H-pyrrole-2-ca-
rboxylate; Methyl
4-{2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-
-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
Methyl
4-{2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5--
oxo-4,5-dihydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carboxylate;
Isopropyl
4-{2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-
-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carbox-
ylate;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-flu-
oropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
Methyl
4-{(4S)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl}-1-(2,2,2-trifluoroethyl)-1H-pyrrole-2-carb-
oxylate; Methyl
4-{(4R)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl}-1-(2,2,2-trifluoroethyl)-1H-pyrrole-2-carb-
oxylate;
4-{2-Amino-4-[4-ethoxy-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-
-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-ethyl-N-methyl-1H-pyrrole-2-carboxami-
de; Isopropyl
4-[2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-4,5-dihydro-
-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
N-{3-[2-Amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-oxo-4,5-d-
ihydro-1H-imidazol-4-yl]-phenyl}-butyramide;
N-{3-[2-Amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-oxo-4,5-d-
ihydro-1H-imidazol-4-yl]-phenyl}-propionamide;
N-{3-[2-Amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-4,5-dihyd-
ro-1H-imidazol-4-yl]-phenyl}-2-methoxy-acetamide;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methyl-5-(3-propoxypheny-
l)-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methyl-5-[3-(pentyloxy)p-
henyl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[3-(3,3-dimethylbutoxy)phenyl]-5-(1-ethyl-5-propionyl-1H-pyrrol-
-3-yl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[3-(2-fluoroethoxy)pheny-
l]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(3-butoxyphenyl)-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methy-
l-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[3-(cyclopropylmethoxy)phenyl]-5-(1-ethyl-5-propionyl-1H-pyrrol-
-3-yl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-(3-isobutoxyphenyl
)-3-methyl-3,5-dihydro-4H-imidazol-4-one;
4-{3-[2-Amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-oxo-4,5-d-
ihydro-H-imidazol-4-yl]phenoxy}butanenitrile;
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[1-(3-methylbutyl)--
5-propionyl-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[1-(3-fluoropropyl)-5-propionyl-1H-pyrrol-3-yl]-5-[3-(2-fluorop-
yridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-propionyl-1-prop-
yl-1H-pyrrol-3-yl)-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-propionyl-1H-pyr-
rol-3-yl)-3,5-dihydro-4H-imidazol-4-one;
(5S)-2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluo-
ropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
(5R)-2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluo-
ropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[3-(2-fluoropyridin-3-yl-
)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
5-(5-Acetyl-1-ethyl-1H-pyrrol-3-yl)-2-amino-5-[3-(2-fluoropyridin-3-yl)ph-
enyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; Methyl
4-{(4S)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate-
; Methyl
4-{(4R)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-met-
hyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-car-
boxylate;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-
-dihydro-1H-imidazol-4-yl}-1-ethyl-N-methyl-1H-pyrrole-2-carboxamide;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-N,1-diethyl-1H-pyrrole-2-carboxamide;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-N-propyl-1H-pyrrole-2-carboxamide;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-N-butyl-1-ethyl-1H-pyrrole-2-carboxamide;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-N-isopropyl-1H-pyrrole-2-carboxamide;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-N-cyclopentyl-1-ethyl-1H-pyrrole-2-carboxamide;
2-Amino-5-[1-ethyl-5-(piperidin-1-ylcarbonyl)-1H-pyrrol-3-yl]-5-[3-(2-flu-
oropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[1-ethyl-5-(morpholin-4-ylcarbonyl)-1H-pyrrol-3-yl]-5-[3-(3-yl)-
phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-N,N-dimethyl-1H-pyrrole-2-carboxamide;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-N-(4-fluorobenzyl)-1H-pyrrole-2-carboxamide;
(5S)-2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[3-(2-fluoropyridin-
-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; Methyl
4-{(4S)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carboxylate;
(5S)-5-(5-Acetyl-1-ethyl-1H-pyrrol-3-yl)-2-amino-5-[3-(2-fluoropyridin-3y-
l)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[1-ethyl-5-(methylsulfonyl)-1H-pyrrol-3-yl]-5-[4-fluoro-3-(2-fl-
uoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
Methyl
4-[2-amino-1-methyl-5-oxo-4-(3-pyrimidin-5-ylphenyl)-4,5-dihydro-1H-imida-
zol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; Methyl
4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
Methyl
4-{2-amino-4-[3-(6-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
Methyl
4-[2-amino-4-(2',5'-difluorobiphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H--
imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; Methyl
4-[2-amino-4-(3',5'-difluorobiphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H--
imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; Methyl
4-[2-amino-4-(3'-cyanobiphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H-imidaz-
ol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; Methyl
4-[2-amino-4-(5'-cyano-2'-fluorobiphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-
-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
Methyl
4-[2-amino-4-(3'-methoxybiphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H-imid-
azol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; Methyl
4-{2-amino-1-methyl-5-oxo-4-[3'-(trifluoromethoxy)biphenyl-3-yl]-4,5-dihy-
dro-1H-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; Methyl
4-[2-amino-4-(3',4'-difluorobiphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H--
imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; Methyl
4-{2-amino-4-[3-(1,3-benzodioxol-5-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-methyl-1H-pyrrole-2-carbonitrile;
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-(2-fluoroethyl)-1H-pyrrole-2-carbonitrile;
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-propyl-1H-pyrrole-2-carbonitrile;
4-[2-Amino-1-methyl-5-oxo-4-(3-pyrimidin-5-ylphenyl)-4,5-dihydro-1H-imida-
zol-4-yl]-1-methyl-1H-pyrrole-2-carbonitrile;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-methyl-1H-pyrrole-2-carbonitrile;
4-{2-Amino-4-[3-(2-chloro-5-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-
-dihydro-1H-imidazol-4-yl}-1-methyl-1H-pyrrole-2-carbonitrile;
4-[2-Amino-1-methyl-5-oxo-4-(3-pyrimidin-5-ylphenyl)-4,5-dihydro-1H-imida-
zol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carbonitrile;
4-[2-Amino-1-methyl-5-oxo-4-(3-pyrimidin-5-ylphenyl)-4,5-dihydro-1H-imida-
zol-4-yl]-1-propyl-1H-pyrrole-2-carbonitrile;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-propyl-1H-pyrrole-2-carbonitrile;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carbonitrile;
4-{2-Amino-4-[3-(2-chloro-5-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-
-dihydro-1H-imidazol-4-yl}-1-propyl-1H-pyrrole-2-carbonitrile;
5-(5-Acetyl-1H-pyrrol-3-yl)-2-amino-5-(3-bromophenyl)-3-methyl-3,5-dihydr-
o-imidazol-4-one;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde;
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-H-pyrrole-2-carbaldehyde;
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-ethyl-1H-pyrrole-2-carbaldehyde;
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-(2-fluoroethyl)-1H-pyrrole-2-carbaldehyde;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carbaldehyde;
2-Amino-5-[5-[(diethylamino)methyl]-1-(2-fluoroethyl)-1H-pyrrol-3-yl]-5-[-
3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-{1-(2-fluoroethyl)-5-[(isopropylamino)methyl]-1H-pyrrol-3-yl}-5-
-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[1-(2-fluoroethyl)-5-(pyrrolidin-1-ylmethyl)-1H-pyrrol-3-yl]-5--
[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[5-[(dimethylamino)methyl]-1-(2-fluoroethyl)-1H-pyrrol-3-yl]-5--
[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[5-[(dimethylamino)methyl]-1-(2-fluoroethyl)-1H-pyrrol-3-yl]-5--
[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[1-ethyl-5-(1-hydroxypropyl)-1H-pyrrol-3-yl]-5-[3-(2-fluoropyri-
din-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde O-methyloxime
hydrochloride;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[3-(2-fluoropyridin-3-yl-
)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(3-bromophenyl)-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methyl-
-3,5-dihydro-4H-imidazol-4-one;
(5S)-2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-propionyl-1-
-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
(5R)-2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-propionyl-1-
-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methyl-5-(3-pyrimidin-5--
ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(3'-methoxybiphenyl-3-yl)-3-methyl-5-[5-propionyl-1-(2,2,2-trif-
luoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(3',5'-difluorobiphenyl-3-yl)-3-methyl-5-[5-propionyl-1-(2,2,2--
trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(3'-chlorobiphenyl-3-yl)-3-methyl-5-[5-propionyl-1-(2,2,2-trifl-
uoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(3'-chloro-4'-fluorobiphenyl-3-yl)-3-methyl-5-[5-propionyl-1-(2-
,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
3'-{2-Amino-1-methyl-5-oxo-4-[5-propionyl-1-(2,2,2-trifluoroethyl)-1H-pyr-
rol-3-yl]-4,5-dihydro-1H-imidazol-4-yl}biphenyl-3-carbonitrile;
2-Amino-5-(3-bromo-4-fluorophenyl)-3-methyl-5-[5-propionyl-1-(2,2,2-trifl-
uoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-propion-
yl-1-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-5-[5-propionyl-1-(2,-
2,2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
a tautomer thereof, a stereoisomer thereof; and a pharmaceutically
acceptable salt thereof.
10. A method for the treatment of a disease or disorder associated
with excessive BACE activity in a patient in need thereof which
comprises providing to said patient a therapeutically effective
amount of a compound of formula I ##STR00160## wherein W is CO, CS
or CH.sub.2; X is N, NR, NO, S, SO.sub.m, O or CR.sub.9; Y is N,
NR, NO, S, SO.sub.m, O or CR.sub.10; Z is C, N, NR, NO, S,
SO.sub.m, O, CR.sub.11 or CR.sub.11R.sub.12 with the proviso that
at least one of X, Y or Z must be N, NR, NO, S, SO.sub.m, or O; m
is 1 or 2; R is H or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl or
aryl(C.sub.1-C.sub.6)alkyl group each optionally substituted;
R.sub.1 and R.sub.2 are each independently H, COR.sub.14,
CO.sub.2R.sub.15 or an optionally substituted C.sub.1-C.sub.4alkyl
group; R.sub.3 is H, OR.sub.13 or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl or
aryl(C.sub.1-C.sub.6)alkyl group each optionally substituted;
R.sub.4, R.sub.5, R.sub.9 and R.sub.10 are each independently H,
halogen, NO.sub.2, CN, OR.sub.14, CO.sub.2R.sub.15, COR.sub.16,
NR.sub.17R.sub.18, SO.sub.pNR.sub.19R.sub.20 or a
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl or
C.sub.3-C.sub.8cycloalkyl group each optionally substituted;
R.sub.6 and R.sub.8 are each independently H, halogen, NO.sub.2,
CN, OR.sub.21, NR.sub.22R.sub.23 or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl or C.sub.3-C.sub.8cycloalkyl group each
optionally substituted; R.sub.7 is H, halogen, NO.sub.2, CN,
OR.sub.24, NR.sub.25R.sub.26 or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, aryl or
heteroaryl group each optionally substituted; R.sub.11, R.sub.12,
R.sub.13, R.sub.14, R.sub.15, R.sub.16, R.sub.21, R.sub.24,
R.sub.27, R.sub.28 and R.sub.29 are each independently H or a
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, cycloheteroalkyl or aryl group each
optionally substituted; R.sub.17, R.sub.18, R.sub.19, R.sub.20,
R.sub.22, R.sub.23, R.sub.25, R.sub.26, R.sub.30, R.sub.31,
R.sub.32 and R.sub.33 are each independently H, COR.sub.34,
SO.sub.pR.sub.35 or a C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8 cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally
substituted or R.sub.17, R.sub.15, or R.sub.19, R.sub.20 or
R.sub.22, R.sub.23, or R.sub.25, R.sub.26, or R.sub.30, R.sub.31,
or R.sub.32, R.sub.33 may be taken together with the atom to which
they are attached to form an optionally substituted 5- to
7-membered ring optionally containing an additional heteroatom
selected from O, N or S; R.sub.34 is H, or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally
substituted; and R.sub.35 is a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally
substituted; or a tautomer thereof, a stereoisomer thereof or a
pharmaceutically acceptable salt thereof.
11. The method according to claim 10 wherein said disease or
disorder is selected from the group consisting of: Alzheimer's
disease; cognitive impairment; Down's Syndrome; HCHWA-D; cognitive
decline; senile dementia; cerebral amyloid angiopathy; and a
neurodegenerative disorder.
12. The method according to claim 10 wherein said disease or
disorder is characterized by the production of .beta.-amyloid
deposits or neurofibrillary tangles.
13. A method for modulating the activity of BACE which comprises
contacting a receptor thereof with an effective amount of a
compound of claim 1.
14. A method for the treatment of Alzheimer's disease in a patient
in need thereof which comprises providing to said patient an
effective amount of a compound of claim 1.
15. A pharmaceutical composition which comprises a pharmaceutically
acceptable carrier and an effective amount of a compound of formula
I ##STR00161## wherein W is CO, CS or CH.sub.2; X is N, NR, NO, S,
SO.sub.m, O or CR.sub.9; Y is N, NR, NO, S, SO.sub.m, O or
CR.sub.10; Z is C, N, NR, NO, S, SO.sub.m, O, CR.sub.11 or
CR.sub.11 R.sub.12 with the proviso that at least one of X, Y or Z
must be N, NR, NO, S, SO.sub.m or O; m is 1 or 2; R is H or a
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl or aryl(C.sub.1-C.sub.6)alkyl group each
optionally substituted; R.sub.1 and R.sub.2 are each independently
H, COR.sub.14, CO.sub.2R.sub.15 or an optionally substituted
C.sub.1-C.sub.4alkyl group; R.sub.3 is H, OR.sub.13 or a
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl or aryl(C.sub.1-C.sub.6)alkyl group each
optionally substituted; R.sub.4, R.sub.5, R.sub.9 and R.sub.10 are
each independently H, halogen, NO.sub.2, CN, OR.sub.14,
CO.sub.2R.sub.15, COR.sub.16, NR.sub.17R.sub.18,
SO.sub.pNR.sub.19R.sub.20 or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl or C.sub.3-C.sub.8cycloalkyl group each
optionally substituted; R.sub.6 and R.sub.8 are each independently
H, halogen, NO.sub.2, CN, OR.sub.21, NR.sub.22R.sub.23 or a
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl or
C.sub.3-C.sub.8cycloalkyl group each optionally substituted;
R.sub.7 is H, halogen, NO.sub.2, CN, OR.sub.24, NR.sub.25R.sub.26
or a C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, aryl or heteroaryl group each optionally
substituted; R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.15,
R.sub.16, R.sub.21, R.sub.24, R.sub.27, R.sub.28 and R.sub.29 are
each independently H or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, cycloheteroalkyl
or aryl group each optionally substituted; R.sub.17, R.sub.18,
R.sub.19, R.sub.20, R.sub.22, R.sub.23, R.sub.25, R.sub.26,
R.sub.30, R.sub.31, R.sub.32 and R.sub.33 are each independently H,
COR.sub.34, SO.sub.pR.sub.35 or a C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8
cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each
optionally substituted or R.sub.17, R.sub.18, or R.sub.19, R.sub.20
or R.sub.22, R.sub.23, or R.sub.25, R.sub.26, or R.sub.30,
R.sub.31, or R.sub.32, R.sub.33 may be taken together with the atom
to which they are attached to form an optionally substituted 5- to
7-membered ring optionally containing an additional heteroatom
selected from O, N or S; R.sub.34 is H, or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally
substituted; and R.sub.35 is a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally
substituted; or a tautomer thereof, a stereoisomer thereof or a
pharmaceutically acceptable salt thereof.
16. The composition according to claim 15 having a formula I
compound wherein W is CO; X is CR.sub.9; Y is CR.sub.10 and Z is NR
or S.
17. The composition according to claim 15 having a formula I
compound wherein W is CO; X is N; Y is NR and Z is
CR.sub.11R.sub.12.
18. The composition according to claim 16 having a formula I
compound wherein R.sub.7 is phenyl or heteroaryl.
19. The composition according to claim 18 having a formula I
compound wherein R is H or C.sub.1-C.sub.4alkyl; R.sub.4 is
COR.sub.16, R.sub.1 and R.sub.2 are H; and R.sub.3 is methyl
20. The composition according to claim 15 having a formula I
compound selected from the group consisting essentially of:
(5S)-2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluo-
ropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
(5S)-2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-propionyl-1-
-propyl-1H-pyrrol-3-yl)-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluoropyr-
idin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-propionyl-1-prop-
yl-1H-pyrrol-3-yl)-3,5-dihydro-4H-imidazol-4-one;
2-Amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-thien-2-yl-3,5-dihydro-4H-imi-
dazol-4-one;
2-Amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-thien-3-yl-3,5-dihydro-4H-imi-
dazol-4-one;
2-Amino-5-(2',5'-difluoro-1,1'-biphenyl-3-yl)-3-methyl-5-thien-2-yl-3,5-d-
ihydro-4H-imidazol-4-one;
2-Amino-5-(2',5'-difluoro-1,1'-biphenyl-3-yl)-3-methyl-5-thien-3-yl-3,5-d-
ihydro-4H-imidazol-4-one;
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[3-methyl-1-(2,2,2--
trifluoroethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-methyl-1-(2,2,2--
trifluoroethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-5-(1-isobutyl-1H-pyrazol-4-yl)-
-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-butyl-1H-pyrazol-4-yl)-5-[3-(2-fluoropyridin-3-yl)phenyl]-3--
methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-isobutyl-1H-pyrazol-4-yl)-3-methyl-5-(3-pyrimidin-5-ylphenyl-
)-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-butyl-1H-pyrazol-4-yl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3-
,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[1-(2,2,2--
trifluoroethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-5-[1-(2,2,2-trifluor-
oethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-
-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)-5-[4-fluoro-3-(2-fluoropyridin-3-yl)p-
henyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(5-butylthien-2-yl)-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-
-one; Methyl
4-[2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-4,5-dihydro-
-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
Methyl
4-[(4S)-2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-4,5-di-
hydro-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
Methyl
4-[(4R)-2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-4,5-di-
hydro-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
Methyl
4-[2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-4,5-dihydro-
-1H-imidazol-4-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrrole-2-carboxylate;
Methyl
4-{2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5--
oxo-4,5-dihydro-1H-imidazol-4-yl}-1-(2,2,2-trifluoroethyl)-1H-pyrrole-2-ca-
rboxylate; Methyl
4-{2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-
-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
Methyl
4-{2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5--
oxo-4,5-dihydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carboxylate;
Isopropyl
4-{2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-
-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carbox-
ylate;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-flu-
oropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
Methyl
4-{(4S)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl}-1-(2,2,2-trifluoroethyl)-1H-pyrrole-2-carb-
oxylate; Methyl
4-{(4R)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl}-1-(2,2,2-trifluoroethyl)-1H-pyrrole-2-carb-
oxylate;
4-{2-Amino-4-[4-ethoxy-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-
-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-ethyl-N-methyl-1H-pyrrole-2-carboxami-
de; Isopropyl
4-[2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-4,5-dihydro-
-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
N-{3-[2-Amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-oxo-4,5-d-
ihydro-1H-imidazol-4-yl]-phenyl}-butyramide;
N-{3-[2-Amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-oxo-4,5-d-
ihydro-1H-imidazol-4-yl]-phenyl}-propionamide;
N-{3-[2-Amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-oxo-4,5-d-
ihydro-1H-imidazol-4-yl]-phenyl}-2-methoxy-acetamide;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methyl-5-(3-propoxypheny-
l)-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methyl-5-[3-(pentyloxy)p-
henyl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[3-(3,3-dimethylbutoxy)phenyl]-5-(1-ethyl-5-propionyl-1H-pyrrol-
-3-yl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[3-(2-fluoroethoxy)pheny-
l]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(3-butoxyphenyl)-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methy-
l-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[3-(cyclopropylmethoxy)phenyl]-5-(1-ethyl-5-propionyl-1H-pyrrol-
-3-yl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-(3-isobutoxyphenyl)-3-me-
thyl-3,5-dihydro-4H-imidazol-4-one;
4-{3-[2-Amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-oxo-4,5-d-
ihydro-H-imidazol-4-yl]phenoxy}butanenitrile;
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[1-(3-methylbutyl)--
5-propionyl-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[1-(3-fluoropropyl)-5-propionyl-1H-pyrrol-3-yl]-5-[3-(2-fluropy-
ridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-propionyl-1-prop-
yl-1H-pyrrol-3-yl)-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-propionyl-1H-pyr-
rol-3-yl)-3,5-dihydro-4H-imidazol-4-one;
(5S)-2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluo-
ropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
(5R)-2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluo-
ropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[3-(2-fluoropyridin-3-yl-
)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
5-(5-Acetyl-1-ethyl-1H-pyrrol-3-yl)-2-amino-5-[3-(2-fluoropyridin-3-yl)ph-
enyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; Methyl
4-{(4S)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate-
; Methyl
4-{(4R)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-met-
hyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-car-
boxylate;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-
-dihydro-1H-imidazol-4-yl}-1-ethyl-N-methyl-1H-pyrrole-2-carboxamide;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-N,1-diethyl-1H-pyrrole-2-carboxamide;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-N-propyl-1H-pyrrole-2-carboxamide;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-N-butyl-1-ethyl-1H-pyrrole-2-carboxamide;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-N-isopropyl-1H-pyrrole-2-carboxamide;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-N-cyclopentyl-1-ethyl-1H-pyrrole-2-carboxamide;
2-Amino-5-[1-ethyl-5-(piperidin-1-ylcarbonyl)-1H-pyrrol-3-yl]-5-[3-(2-flu-
ropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[1-ethyl-5-(morpholin-4-ylcarbonyl)-1H-pyrrol-3-yl]-5-[3-(2-flu-
oropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-N,N-dimethyl-1H-pyrrole-2-carboxamide;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-N-(4-fluorobenzyl)-1H-pyrrole-2-carboxamide;
(5S)-2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[3-(2-fluoropyridin-
-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; Methyl
4-{(4S)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carboxylate;
(5S)-5-(5-Acetyl-1-ethyl-1H-pyrrol-3-yl)-2-amino-5-[3-(2-fluoropyridin-3--
yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[1-ethyl-5-(methylsulfonyl)-1H-pyrrol-3-yl]-5-[4-fluoro-3-(2-fl-
uoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
Methyl
4-[2-amino-1-methyl-5-oxo-4-(3-pyrimidin-5-ylphenyl)-4,5-dihydro-1H-imida-
zol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; Methyl
4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
Methyl
4-{2-amino-4-[3-(6-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
Methyl
4-[2-amino-4-(2',5'-difluorobiphenyl-3-yl)-1-methyl-5-oxo-4,5dihydro-1H-i-
midazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; Methyl
4-[2-amino-4-(3',5'-difluorobiphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H--
imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; Methyl
4-[2-amino-4-(3'-cyanobiphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H-imidaz-
ol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; Methyl
4-[2-amino-4-(5'-cyano-2'-fluorobiphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-
-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
Methyl
4-[2-amino-4-(3'-methoxybiphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H-imid-
azol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; Methyl
4-{2-amino-1-methyl-5-oxo-4-[3'-(trifluoromethoxy)biphenyl-3-yl]-4,5-dihy-
dro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
Methyl
4-[2-amino-4-(3',4'-difluorobiphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H--
imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; Methyl
4-{2-amino-4-[3-(1,3-benzodioxol-5-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-methyl-1H-pyrrole-2-carbonitrile;
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-(2-fluoroethyl)-1H-pyrrole-2-carbonitrile;
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-propyl-1H-pyrrole-2-carbonitrile;
4-[2-Amino-1-methyl-5-oxo-4-(3-pyrimidin-5-ylphenyl)-4,5-dihydro-1H-imida-
zol-4-yl]-1-methyl-1H-pyrrole-2-carbonitrile;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-methyl-1H-pyrrole-2-carbonitrile;
4-{2-Amino-4-[3-(2-chloro-5-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-
-dihydro-1H-imidazol-4-yl}-1-methyl-1H-pyrrole-2-carbonitrile;
4-[2-Amino-1-methyl-5-oxo-4-(3-pyrimidin-5-ylphenyl)-4,5-dihydro-1H-imida-
zol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carbonitrile;
4-[2-Amino-1-methyl-5-oxo-4-(3-pyrimidin-5-ylphenyl)-4,5-dihydro-1H-imida-
zol-4-yl]-1-propyl-1H-pyrrole-2-carbonitrile;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-propyl-1H-pyrrole-2-carbonitrile;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carbonitrile;
4-{2-Amino-4-[3-(2-chloro-5-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-
-dihydro-1H-imidazol-4-yl}-1-propyl-1H-pyrrole-2-carbonitrile;
5-(5-Acetyl-1H-pyrrol-3-yl)-2-amino-5-(3-bromophenyl)-3-methyl-3,5-dihydr-
o-imidazol-4-one;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde;
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-pyrrole-2-carbaldehyde;
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-ethyl-1H-pyrrole-2-carbaldehyde;
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-(2-fluoroethyl)-1H-pyrrole-2-carbaldehyde;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carbaldehyde;
2-Amino-5-[5-[(diethylamino)methyl]-1-(2-fluoroethyl)-1H-pyrrol-3-yl]-5-[-
3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-{1-(2-fluoroethyl)-5-[(isopropylamino)methyl]-1H-pyrrol-3-yl}-5-
-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[1-(2-fluoroethyl)-5-(pyrrolidin-1-ylmethyl)-1H-pyrrol-3-yl]-5--
[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[5-[(dimethylamino)methyl]-1-(2-fluoroethyl)-1H-pyrrol-3-yl]-5--
[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[5-[(dimethylamino)methyl]-1-(2-fluoroethyl)-1H-pyrrol-3-yl]-5--
[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[1-ethyl-5-(1-hydroxypropyl)-1H-pyrrol-3-yl]-5-[3-(2-fluoropyri-
din-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde O-methyloxime
hydrochloride;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[3-(2-fluoropyridin-3-yl-
)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(3-bromophenyl)-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methyl-
-3,5-dihydro-4H-imidazol-4-one;
(5S)-2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-propionyl-1-
-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
(5R)-2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-propionyl-1-
-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methyl-5-(3-pyrimidin-5--
ylphenyl)-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(3'-methoxybiphenyl-3-yl)-3-methyl-5-[5-propionyl-1-(2,2,2-trif-
louroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(3',5'-difluorobiphenyl-3-yl)-3-methyl-5-[5-propionyl-1-(2,2,2--
trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(3'-chlorobiphenyl-3-yl)-3-methyl-5-[5-propionyl-1-(2,2,2-trifl-
uoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(3'-chloro-4'-fluorobiphenyl-3-yl)-3-methyl-5-[5-propionyl-1-(2-
,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
3'-{2-Amino-1-methyl-5-oxo-4-[5-propionyl-1-(2,2,2-trifluoroethyl)-1H-pyr-
rol-3-yl]-4,5-dihydro-1H-imidazol-4-yl}biphenyl-3-carbonitrile;
2-Amino-5-(3-bromo-4-fluorophenyl)-3-methyl-5-[5-propionyl-1-(2,2,2-trifl-
uoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-propion-
yl-1-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
2-Amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-5-[5-propionyl-1-(2,-
2,2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
a tautomer thereof, a stereoisomer thereof; and a pharmaceutically
acceptable salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of co-pending U.S.
Divisional application Ser. No. 12/180,795, filed on Jul. 28, 2008
and U.S. application Ser. No. 11/478,122, filed on Jun. 29, 2006,
which claims the benefit of U.S. Provisional Application No.
60/695,353, filed Jun. 30, 2005, each of which is hereby
incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] .beta.-Amyloid deposits and neurofibrillary tangles are two
major pathologic characterizations associated with Alzheimer's
disease (AD). Clinically, AD is characterized by the of loss of
memory, cognition, reasoning, judgment, and orientation. Also
affected, as the disease progresses, are motor, sensory, and
linguistic abilities until global impairment of multiple cognitive
functions occurs. These cognitive losses take place gradually, but
typically lead to severe impairment and eventual death in 4-12
years.
[0003] Amyloidogenic plaques and vascular amyloid angiopathy also
characterize the brains of patients with Trisomy 21 (Down's
Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the
Dutch-type (HCHWA-D), and other neurodegenerative disorders.
Neurofibrillary tangles also occur in other neurodegenerative
disorders including dementia-inducing disorders (Varghese, J., et
al, Journal of Medicinal Chemistry, 2003, 46, 4625-4630).
[0004] .beta.-amyloid deposits are predominately an aggregate of
A.beta. peptide, which in turn is a product of the proteolysis of
amyloid precursor protein (APP). More specifically, A.beta. peptide
results from the cleavage of APP at the C-terminus by one or more
.gamma.-secretases, and at the N-terminus by .beta.-secretase
enzyme (BACE), also known as aspartyl protease, as part of the
.beta.-amyloidogenic pathway.
[0005] BACE activity is correlated directly to the generation of
A.beta. peptide from APP (Sinha, et al, Nature, 1999, 402,
537-540), and studies increasingly indicate that the inhibition of
BACE inhibits the production of A.beta. peptide (Roberds, S. L., et
al, Human Molecular Genetics, 2001, 10, 1317-1324).
[0006] Therefore, it is an object of this invention to provide
compounds which are inhibitors of .beta.-secretase and are useful
as therapeutic agents in the treatment, prevention or amelioration
of a disease or disorder characterized by elevated .beta.-amyloid
deposits or .beta.-amyloid levels in a patient.
[0007] It is another object of this invention to provide
therapeutic methods and pharmaceutical compositions useful for the
treatment, prevention or amelioration of a disease or disorder
characterized by elevated .beta.-amyloid deposits or .beta.-amyloid
levels in a patient.
[0008] It is a feature of this invention that the compounds
provided may also be useful to further study and elucidate the
.beta.-secretase enzyme.
[0009] These and other objects and features of the invention will
become more apparent by the detailed description set forth
hereinbelow.
SUMMARY OF THE INVENTION
[0010] The present invention provides a compound of formula I
##STR00002##
wherein W is CO, CS or CH.sub.2; [0011] X is N, NR, NO, S,
SO.sub.m, O or CR.sub.9; [0012] Y is N, NR, NO, S, SO.sub.m, O or
CR.sub.10; [0013] Z is C, N, NR, NO, S, SO.sub.m, O, CR.sub.11 or
CR.sub.11R.sub.12 with the proviso that at least one of X, Y or Z
must be N, NR, NO, S, SO.sub.m or O; [0014] m is 1 or 2; [0015] R
is H or a C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl or aryl(C.sub.1-C.sub.6)alkyl group each
optionally substituted; [0016] R.sub.1 and R.sub.2 are each
independently H, COR.sub.14, CO.sub.2R.sub.15 or an optionally
substituted C.sub.1-C.sub.4alkyl group; [0017] R.sub.3 is H,
OR.sub.13 or a C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl or aryl(C.sub.1-C.sub.6)alkyl group each
optionally substituted; [0018] R.sub.4, R.sub.5, R.sub.9 and
R.sub.10 are each independently H, halogen, NO.sub.2, CN,
OR.sub.14, CO.sub.2R.sub.15, COR.sub.16, NR.sub.17NR.sub.18,
SO.sub.pNR.sub.19R.sub.20 or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl or C.sub.3-C.sub.8cycloalkyl group each
optionally substituted; [0019] R.sub.6 and R.sub.8 are each
independently H, halogen, NO.sub.2, CN, OR.sub.21,
NR.sub.22R.sub.23 or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl or C.sub.3-C.sub.8cycloalkyl group each
optionally substituted; [0020] R.sub.7 is H, halogen, NO.sub.2, CN,
OR.sub.24, NR.sub.25R.sub.26 or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, aryl or
heteroaryl group each optionally substituted; [0021] R.sub.11,
R.sub.12, R.sub.13, R.sub.14, R.sub.15, R.sub.16, R.sub.21,
R.sub.24, R.sub.27, R.sub.28 and R.sub.29 are each independently H
or a C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, cycloheteroalkyl or aryl group each
optionally substituted;
[0022] R.sub.17, R.sub.18, R.sub.19, R.sub.20, R.sub.22, R.sub.23,
R.sub.25, R.sub.26, R.sub.30, R.sub.31, R.sub.32 and R.sub.33 are
each independently H, COR.sub.34, SO.sub.pR.sub.35 or a
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8 cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally
substituted or R.sub.17, R.sub.18, or R.sub.19, R.sub.20 or
R.sub.22, R.sub.23, or R.sub.25, R.sub.26, or R.sub.30, R.sub.31,
or R.sub.32, R.sub.33 may be taken together with the atom to which
they are attached to form an optionally substituted 5- to
7-membered ring optionally containing an additional heteroatom
selected from O, N or S; [0023] R.sub.34 is H, or a
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, cycloheteroalkyl, aryl or heteroaryl
group each optionally substituted; and [0024] R.sub.35 is a
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, cycloheteroalkyl, aryl or heteroaryl
group each optionally substituted; or a tautomer thereof, a
stereoisomer thereof or a pharmaceutically acceptable salt
thereof.
[0025] The present invention also relates to the use of the formula
I amino-5-heteroaryl-imidazolone compound for the treatment of
.beta.-amyloid deposits and neurofibrillary tangles. The compound
of the invention is particularly useful for treating Alzheimer's
disease, cognitive impairment, Down's Syndrome, HCHWA-D, cognitive
decline, senile dementia, cerebral amyloid angiopathy, degenerative
dementia, or other neurodegenerative disorders.
DETAILED DESCRIPTION OF THE INVENTION
[0026] Alzheimer's disease (AD) is a major degenerative disease of
the brain which presents clinically by progressive loss of memory,
cognition, reasoning, judgement and emotional stability and
gradually leads to profound mental deterioration and death. The
exact cause of AD is unknown, but increasing evidence indicates
that amyloid beta peptide (A-beta) plays a central role in the
pathogenesis of the disease. (D. B. Schenk; R. E. Rydel et al,
Journal of Medicinal Chemistry, 1995, 21,4141 and D. J. Selkoe,
Physiology Review, 2001, 81, 741). Patients with AD exhibit
characteristic neuropathological markers such as neuritic plaques
(and in .beta.-amyloid angiopathy, deposits in cerebral blood
vessels) as well as neurofibrillary tangles detected in the brain
at autopsy. A-beta is a major component of neuritic plaques in AD
brains. In addition, .beta.-amyloid deposits and vascular
.beta.-amyloid angiopathy also characterize individuals with Downs
Syndrome, Hereditary Cerebral Hemmorhage with Amyloidosis of the
Dutch type and other neurodegenerative and dementia-inducing
disorders. Overexpression of the amyloid precursor protein (APP),
altered cleavage of APP to A-beta or a decrease in the clearance of
A-beta from a patient's brain may increase the levels of soluble or
fibrullar forms of A-beta in the brain. The .beta.-site APP
cleaving enzyme, BACE1, also called memapsin-2 or Asp-2, was
identified in 1999 (R. Vassar, B. D. Bennett, et al, Nature, 1999,
402, 537). BACE1 is a membrane-bound aspartic protease with all the
known functional properties and characteristics of
.beta.-secretase. Low molecular weight, non-peptide,
non-substrate-related inhibitors of BACE1 or .beta.-secretase are
earnestly sought both as an aid in the study of the
.beta.-secretase enzyme and as potential therapeutic agents.
[0027] Surprisingly, it has now been found that
amino-5-heteroarylimidazolone compounds of formula I demonstrate
inhibition of .beta.-secretase and the selective inhibition of
BACE1. Advantageously, said heteroarlyimidazolone compounds may be
used as effective therapeutic agents for the treatment, prevention
or amelioration of a disease or disorder characterized by elevated
.beta.-amyloid deposits or .beta.-amyloid levels in a patient.
Accordingly, the present invention provides an amino-pyridine
compound of formula I
##STR00003##
wherein W is CO, CS or CH.sub.2; [0028] X is N, NR, NO, S,
SO.sub.m, O or CR.sub.9; [0029] Y is N, NR, NO, S, SO.sub.m, O or
CR.sub.10; [0030] Z is C, N, NR, NO, S, SO.sub.m, O, CR.sub.11 or
CR.sub.11R.sub.12 with the proviso that at least one of X, Y or Z
must be N, NR, NO, S, SO.sub.m or O; [0031] m is 1 or 2; [0032] R
is H or a C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl or aryl(C.sub.1-C.sub.6)alkyl group each
optionally substituted; [0033] R.sub.1 and R.sub.2 are each
independently H, COR.sub.14, CO.sub.2R.sub.16 or an optionally
substituted C.sub.1-C.sub.4alkyl group; [0034] R.sub.3 is H,
OR.sub.13 or a C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl or aryl(C.sub.1-C.sub.6)alkyl group each
optionally substituted; [0035] R.sub.4, R.sub.5, R.sub.9 and
R.sub.10 are each independently H, halogen, NO.sub.2, CN,
OR.sub.14, CO.sub.2R.sub.15, COR.sub.16, NR.sub.17R.sub.18,
SO.sub.pNR.sub.19R.sub.20 or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl or C.sub.3-C.sub.8cycloalkyl group each
optionally substituted; [0036] R.sub.6 and R.sub.8 are each
independently H, halogen, NO.sub.2, CN, OR.sub.21,
NR.sub.22R.sub.23 or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl or C.sub.3-C.sub.8cycloalkyl group each
optionally substituted; [0037] R.sub.7 is H, halogen, NO.sub.2, CN,
OR.sub.24, NR.sub.25R.sub.26 or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, aryl or
heteroaryl group each optionally substituted; [0038] R.sub.11,
R.sub.12, R.sub.13, R.sub.14, R.sub.15, R.sub.16, R.sub.21,
R.sub.24, R.sub.27, R.sub.28 and R.sub.29 are each independently H
or a C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, cycloheteroalkyl or aryl group each
optionally substituted; [0039] R.sub.17, R.sub.18, R.sub.19,
R.sub.20, R.sub.22, R.sub.23, R.sub.25, R.sub.26, R.sub.30,
R.sub.31, R.sub.32 and R.sub.33 are each independently H,
COR.sub.34, SO.sub.pR.sub.35 or a C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8
cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each
optionally substituted or R.sub.17, R.sub.18, or R.sub.19, R.sub.20
or R.sub.22, R.sub.23, or R.sub.25, R.sub.26, or R.sub.30,
R.sub.31, or R.sub.32, R.sub.33 may be taken together with the atom
to which they are attached to form an optionally substituted 5- to
7-membered ring optionally containing an additional heteroatom
selected from O, N or S;
[0040] R.sub.34 is H, or a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally
substituted; and [0041] R.sub.35 is a C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally
substituted; or a tautomer thereof, a stereoisomer thereof or a
pharmaceutically acceptable salt thereof.
[0042] It is understood that the claims encompass all possible
stereoisomers and prodrugs. Moreover, unless stated otherwise, each
alkyl, alkenyl, alkynyl, cycloalkyl cycloheteroalkyl, aryl or
heteroaryl group is contemplated as being optionally
substituted.
[0043] An optionally substituted moiety may be substituted with one
or more substituents. The substituent groups which are optionally
present may be one or more of those customarily employed in the
development of pharmaceutical compounds or the modification of such
compounds to influence their structure/activity, persistence,
absorption, stability or other beneficial property. Specific
examples of such substituents include halogen atoms, nitro, cyano,
thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy,
haloalkoxy, amino, alkylamino, dialkylamino, formyl,
alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl,
alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl,
benzyloxy, heterocyclyl or cycloalkyl groups, preferably halogen
atoms or lower alkyl or lower alkoxy groups. Unless otherwise
specified, typically, 0-4 substituents may be present. When any of
the foregoing substituents represents or contains an alkyl
substituent group, this may be linear or branched and may contain
up to 12 carbon atoms, preferably up to 6 carbon atoms, more
preferably up to 4 carbon atoms. As used herein, the term "alkyl"
includes both (C.sub.1-C.sub.10) straight chain and
(C.sub.3-C.sub.12) branched-chain (unless defined otherwise)
monovalent saturated hydrocarbon moiety. Examples of saturated
hydrocarbon alkyl moieties include, but are not limited to,
chemical groups such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as
n-pentyl, n-hexyl, and the like. Specifically included within the
definition of "alkyl" are those alkyl groups that are optionally
substituted. Suitable alkyl substitutions include, but are not
limited to, CN, OH, halogen, phenyl, carbamoyl, carbonyl, alkoxy or
aryloxy.
[0044] As used herein the term "haloalkyl" designates a
C.sub.nH.sub.2n+1 group having from one to 2n+1 halogen atoms which
may be the same or different. Examples of haloalkyl groups include
CF.sub.3, CH.sub.2Cl, C.sub.2H.sub.3BrCl, C.sub.3H.sub.5F.sub.2, or
the like.
[0045] The term "alkenyl", as used herein, refers to either a
(C.sub.2-C.sub.5) straight chain or (C.sub.3-C.sub.10)
branched-chain monovalent hydrocarbon moiety containing at least
one double bond. Such hydrocarbon alkenyl moieties may be mono or
polyunsaturated, and may exist in the E or Z configurations. The
compounds of this invention are meant to include all possible E and
Z configurations. Examples of mono or polyunsaturated hydrocarbon
alkenyl moieties include, but are not limited to, chemical groups
such as vinyl, 2-propenyl, isopropenyl, crotyl, 2-isopentenyl,
butadienyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl),
and higher homologs, isomers, or the like.
[0046] The term "cycloalkyl", as used herein, refers to a
monocyclic, bicyclic, tricyclic, fused, bridged, or spiro
monovalent saturated hydrocarbon moiety of 3-10 carbon atoms,
unless otherwise specified, wherein the carbon atoms are located
inside or outside of the ring system. Any suitable ring position of
the cycloalkyl moiety may be covalently linked to the defined
chemical structure. Examples of cycloalkyl moieties include, but
are not limited to, chemical groups such as cyclopropyl,
cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclohexylmethyl, cyclohexylethyl, cycloheptyl, norbornyl,
adamantyl, spiro[4.5]decanyl, and homologs, isomers, or the
like.
[0047] The term "cycloheteroalkyl" as used herein designates a
C.sub.5-C.sub.7cycloalkyl ring system containing 1, 2 or 3
heteroatoms, which may be the same or different, selected from N, O
or S and optionally containing one double bond. Exemplary of the
cycloheteroalkyl ring systems included in the term as designated
herein are the following rings wherein X.sub.1 is NR', O or S and R
is H or an optional substituent as defined hereinbelow.
##STR00004##
[0048] The term "aryl", as used herein, refers to an aromatic
carbocyclic moiety of up to 20 carbon atoms, which may be a single
ring (monocyclic) or multiple rings (bicyclic, up to three rings)
fused together or linked covalently. Any suitable ring position of
the aryl moiety may be covalently linked to the defined chemical
structure. Examples of aryl moieties include, but are not limited
to, chemical groups such as phenyl, 1-naphthyl, 2-naphthyl,
dihydronaphthyl, tetrahydronaphthyl, biphenyl, anthryl,
phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl,
acenaphthylenyl, and the like. The term "aryl" further includes
both unsubstituted carbocylic groups and carbocylic groups
containing 1-5-substitutions.
[0049] The term "heteroaryl" as used herein means an aromatic
heterocyclic ring system, which may be a single ring (monocyclic)
or multiple rings (bicyclic, up to three rings) fused together or
linked covalently. Preferably, heteroaryl is a 5- to 6-membered
ring. The rings may contain from one to four hetero atoms selected
from nitrogen, oxygen, or sulfur, wherein the nitrogen or sulfur
atom(s) are optionally oxidized, or the nitrogen atom(s) are
optionally quarternized. Any suitable ring position of the
heteroaryl moiety may be covalently linked to the defined chemical
structure. Examples of heteroaryl moieties include, but are not
limited to, heterocycles such as furan, thiophene, pyrrole,
N-methylpyrrole, pyrazole, N-methylpyrazole, imidazole,
N-methylimidazole, oxazole, isoxazole, thiazole, isothiazole,
1H-tetrazole, 1-methyltetrazole, 1,3,4-oxadiazole,
1H-1,2,4-triazole, 1-methyl-1,2,4-triazole 1,3,4-triazole,
1-methyl-1,3,4-triazole, pyridine, pyrimidine, pyrazine,
pyridazine, benzoxazole, benzisoxazole, benzothiazole, benzofuran,
benzothiophene, thianthrene, dibenzo[b,d]furan,
dibenzo[b,d]thiophene, benzimidazole, N-methylbenzimidazole,
indole, indazole, quinoline, isoquinoline, quinazoline,
quinoxaline, purine, pteridine, 9H-carbazole, .alpha.-carboline, or
the like.
[0050] The term "halogen", as used herein, designates fluorine,
chlorine, bromine, and iodine.
[0051] The compounds of the present invention may be converted to
salts, in particular pharmaceutically acceptable salts using art
recognized procedures. Suitable salts with bases are, for example,
metal salts, such as alkali metal or alkaline earth metal salts,
for example sodium, potassium or magnesium salts, or salts with
ammonia or an organic amine, such as morpholine, thiomorpholine,
piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for
example ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-,
tributyl- or dimethylpropylamine, or a mono-, di-, or trihydroxy
lower alkylamine, for example mono-, di- or triethanolamine.
Internal salts may furthermore be formed. Salts which are
unsuitable for pharmaceutical uses but which can be employed, for
example, for the isolation or purification of free compounds or
their pharmaceutically acceptable salts, are also included. The
term "pharmaceutically acceptable salt", as used herein, refers to
salts derived form organic and inorganic acids such as, for
example, acetic, propionic, lactic, citric, tartaric, succinic,
fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric,
hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic,
napthalenesulfonic, benzenesulfonic, toluenesulfonic,
camphorsulfonic, and similarly known acceptable acids when a
compound of this invention contains a basic moiety. Salts may also
be formed from organic and inorganic bases, preferably alkali metal
salts, for example, sodium, lithium, or potassium, when a compound
of this invention contains a carboxylate or phenolic moiety, or
similar moiety capable of forming base addition salts.
[0052] Compounds of the invention may exist as one or more
tautomers. One skilled in the art will recognize that compounds of
formula I may also exist as the tautomer It as shown below.
##STR00005##
[0053] Tautomereric formula I compounds also include those
compounds shown below as Ita, Itb and Itc.
##STR00006##
[0054] Tautomers often exist in equilibrium with each other. As
these tautomers interconvert under environmental and physiological
conditions, they provide the same useful biological effects. The
present invention includes mixtures of such tautomers as well as
the individual tautomers, for example the compounds of Formulas I,
It, Ita, Itb and the like.
[0055] The compounds of this invention may contain an asymmetric
carbon atom and some of the compounds of this invention may contain
one or more asymmetric centers and may thus give rise to optical
isomers and diastereomers. While shown without respect to
stereochemistry in Formula I, the present invention includes such
optical isomers and diastereomers; as well as the racemic and
resolved, enantiomerically pure R and S stereoisomers; as well as
other mixtures of the R and S stereoisomers and pharmaceutically
acceptable salts thereof. Where a stereoisomer is preferred, it may
in some embodiments be provided substantially free of the
corresponding enantiomer. Thus, an enantiomer substantially free of
the corresponding enantiomer refers to a compound that is isolated
or separated via separation techniques or prepared free of the
corresponding enantiomer. "Substantially free", as used herein,
means that the compound is made up of a significantly greater
proportion of one steriosomer, preferably less than about 50%, more
preferably less than about 75%, and even more preferably less than
about 90%.
[0056] Examples of X, Y and Z respectively include: CH, CH and NR;
(eg., pyrrol-2-yl or pyrrol-3-yl and such groups N-substituted); S,
CH and CH; (eg., thien-2-yl or -3-yl); N, NR and C (eg., the group
is bonded via Z, such as N-alkylpyrazol-4-yl); CH, S and N (eg,
thiazolyl); which rings are optionally substituted by R.sub.4 and
R.sub.5.
[0057] Preferred compounds of formula I are those compounds wherein
W is CO; X is CR.sub.9; Y is CR.sub.10 and Z is NR or S. Another
group of preferred compounds are those compounds of formula I
wherein W is CO; X is N; Y is NR and Z is CR.sub.11R.sub.12. Also
preferred are those compounds of formula I wherein R.sub.7 is
phenyl or heteroaryl.
[0058] More preferred compounds of the invention are those
compounds of formula I wherein W is CO; X is CR.sub.9; Y is
CR.sub.10; Z is NR or S; R is H or C.sub.1-C.sub.4alkyl and R.sub.4
is CN or COR.sub.16. Another group of more preferred compounds of
the invention are those compounds of formula I wherein W is CO; X
is N; Y is NR and Z is CR.sub.11R.sub.12, and R.sub.7 is phenyl or
heteroaryl. A further group of more preferred compounds of the
invention are those compounds of formula I wherein W is CO; X is
CR.sub.9; Y is CR.sub.10; Z is NR; R is H or C.sub.1-C.sub.4alkyl;
R.sub.4 is COR.sub.16, R.sub.7 is phenyl or heteroaryl; R.sub.1 and
R.sub.2 are H; and R.sub.3 is methyl
[0059] Preferred compounds of the invention include: [0060]
(5S)-2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluo-
ropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
[0061]
(5S)-2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-propionyl-1-
-propyl-1H-pyrrol-3-yl)-3,5-dihydro-4H-imidazol-4-one; [0062]
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluoropyr-
idin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; [0063]
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-propionyl-1-prop-
yl-1H-pyrrol-3-yl)-3,5-dihydro-4H-imidazol-4-one; [0064]
2-Amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-thien-2-yl-3,5-dihydro-4H-imi-
dazol-4-one; [0065]
2-Amino-3-methyl-5-(3-pyridin-3-ylphenyl)-5-thien-3-yl-3,5-dihydro-4H-imi-
dazol-4-one; [0066]
2-Amino-5-(2',5'-difluoro-1,1'-biphenyl-3-yl)-3-methyl-5-thien-2-yl-3,5-d-
ihydro-4H-imidazol-4-one; [0067]
2-Amino-5-(2',5'-difluoro-1,1'-biphenyl-3-yl)-3-methyl-5-thien-3-yl-3,5-d-
ihydro-4H-imidazol-4-one; [0068]
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[3-methyl-1-(2,2,2--
trifluoroethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one;
[0069]
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-methyl-1-(2,2,2--
trifluoroethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one;
[0070]
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-5-(1-isobutyl-1H-pyrazol-4-yl)-
-3-methyl-3,5-dihydro-4H-imidazol-4-one; [0071]
2-Amino-5-(1-butyl-1H-pyrazol-4-yl)-5-[3-(2-fluoropyridin-3-yl)phenyl]-3--
methyl-3,5-dihydro-4H-imidazol-4-one; [0072]
2-Amino-5-(1-isobutyl-1H-pyrazol-4-yl)-3-methyl-5-(3-pyrimidin-5-ylphenyl-
)-3,5-dihydro-4H-imidazol-4-one; [0073]
2-Amino-5-(1-butyl-1H-pyrazol-4-yl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3-
,5-dihydro-4H-imidazol-4-one; [0074]
2-Amino-5-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[1-(2,2,2--
trifluoroethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one;
[0075]
2-Amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-5-[1-(2,2,2-trifluor-
oethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one; [0076]
2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-
-methyl-3,5-dihydro-4H-imidazol-4-one; [0077]
2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)-5-[4-fluoro-3-(2-fluoropyridin-3-yl)p-
henyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; [0078]
2-amino-5-(5-butylthien-2-yl)-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-
-one; [0079] methyl
4-[2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-4,5-dihydro-
-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
[0080] methyl
4-[(4S)-2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-
-4,5-dihydro-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
[0081] methyl
4-[(4R)-2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-4,5-di-
hydro-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
[0082] methyl
4-[2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-4,5--
dihydro-1H-imidazol-4-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrrole-2-carboxylat-
e; [0083] methyl
4-{2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-
-dihydro-1H-imidazol-4-yl}-1-(2,2,2-trifluoroethyl)-1H-pyrrole-2-carboxyla-
te; [0084] methyl
4-{2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-
-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
[0085] methyl
4-{2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-
-dihydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carboxylate; [0086]
isopropyl
4-{2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-
-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carbox-
ylate; [0087]
2-amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluoropyr-
idin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; [0088]
methyl
4-{(4S)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl}-1-(2,2,2-trifluoroethyl)-1H-pyrrole-2-carb-
oxylate; [0089] methyl
4-{(4R)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl}-1-(2,2,2-trifluoroethyl)-1H-pyrrole-2-carb-
oxylate; [0090]
4-{2-amino-4-[4-ethoxy-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-
-dihydro-1H-imidazol-4-yl}-1-ethyl-N-methyl-1H-pyrrole-2-carboxamide;
[0091] isopropyl
4-[2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-4,5-dihydro-
-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
[0092]
N-{3-[2-amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-oxo-4,5-d-
ihydro-1H-imidazol-4-yl]-phenyl}-butyramide; [0093]
N-{3-[2-amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-oxo-4,5-d-
ihydro-1H-imidazol-4-yl]-phenyl}-propionamide; [0094]
N-{3-[2-amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-oxo-4,5-d-
ihydro-1H-imidazol-4-yl]-phenyl}-2-methoxy-acetamide; [0095]
2-amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methyl-5-(3-propoxypheny-
l)-3,5-dihydro-4H-imidazol-4-one; [0096]
2-amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methyl-5-[3-(pentyloxy)p-
henyl]-3,5-dihydro-4H-imidazol-4-one; [0097]
2-amino-5-[3-(3,3-dimethylbutoxy)phenyl]-5-(1-ethyl-5-propionyl-1H-pyrrol-
-3-yl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; [0098]
2-amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[3-(2-fluoroethoxy)pheny-
l]-3-methyl-3,5-dihydro-4H-imidazol-4-one; [0099]
2-amino-5-(3-butoxyphenyl)-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methy-
l-3,5-dihydro-4H-imidazol-4-one; [0100]
2-amino-5-[3-(cyclopropylmethoxy)phenyl]-5-(1-ethyl-5-propionyl-1H-pyrrol-
-3-yl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; [0101]
2-amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-(3-isobutoxyphenyl)-3-me-
thyl-3,5-dihydro-4H-imidazol-4-one; [0102]
4-{3-[2-Amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-oxo-4,5-d-
ihydro-H-imidazol-4-yl]phenoxy}butanenitrile; [0103]
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[1-(3-methylbutyl)--
5-propionyl-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one; [0104]
2-Amino-5-[1-(3-fluoropropyl)-5-propionyl-1H-pyrrol-3-yl]-5-[3-(2-fluorop-
yridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; [0105]
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-propionyl-1-prop-
yl-1H-pyrrol-3-yl)-3,5-dihydro-4H-imidazol-4-one; [0106]
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-propionyl-1H-pyr-
rol-3-yl)-3,5-dihydro-4H-imidazol-4-one; [0107]
(5S)-2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluo-
ropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
[0108]
(5R)-2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluo-
ropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
[0109]
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[3-(2-fluoropyridin-3-yl-
)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; [0110]
5-(5-Acetyl-1-ethyl-1H-pyrrol-3-yl)-2-amino-5-[3-(2-fluoropyridin-3-yl)ph-
enyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; [0111] Methyl
4-{(4S)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate-
; [0112] Methyl
4-{(4R)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate-
; [0113]
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5--
dihydro-1H-imidazol-4-yl}-1-ethyl-N-methyl-1H-pyrrole-2-carboxamide;
[0114]
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-d-
ihydro-1H-imidazol-4-yl}-N,1-diethyl-1H-pyrrole-2-carboxamide;
[0115]
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-N-propyl-1H-pyrrole-2-carboxamide; [0116]
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-N-butyl-1-ethyl-1H-pyrrole-2-carboxamide; [0117]
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-N-isopropyl-1H-pyrrole-2-carboxamide;
[0118]
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-N-cyclopentyl-1-ethyl-1H-pyrrole-2-carboxamide;
[0119]
2-Amino-5-[1-ethyl-5-(piperidin-1-ylcarbonyl)-1H-pyrrol-3-yl]-5-[3-(2-flu-
oropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
[0120]
2-Amino-5-[1-ethyl-5-(morpholin-4-ylcarbonyl)-1H-pyrrol-3-yl]-5-[3-(2-flu-
oropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
[0121]
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-N,N-dimethyl-1H-pyrrole-2-carboxamide;
[0122]
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-N-(4-fluorobenzyl)-1H-pyrrole-2-carboxamide;
[0123]
(5S)-2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[3-(2-fluoro-
pyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; [0124]
Methyl
4-{(4S)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carboxylate;
[0125]
(5S)-5-(5-Acetyl-1-ethyl-1H-pyrrol-3-yl)-2-amino-5-[3-(2-fluoropyridin-3--
yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; [0126]
2-Amino-5-[1-ethyl-5-(methylsulfonyl)-1H-pyrrol-3-yl]-5-[4-fluoro-3-(2-fl-
uoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
[0127] Methyl
4-[2-amino-1-methyl-5-oxo-4-(3-pyrimidin-5-ylphenyl)-4,5-dihydro-1-
H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; [0128]
Methyl
4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
[0129] Methyl
4-{2-amino-4-[3-(6-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-d-
ihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
[0130] Methyl
4-[2-amino-4-(2',5'-difluorobiphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H--
imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; [0131]
Methyl
4-[2-amino-4-(3',5'-difluorobiphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H--
imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; [0132]
Methyl
4-[2-amino-4-(3'-cyanobiphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H-imidaz-
ol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; [0133] Methyl
4-[2-amino-4-(5'-cyano-2'-fluorobiphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-
-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
[0134] Methyl
4-[2-amino-4-(3'-methoxybiphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
[0135] Methyl
4-{2-amino-1-methyl-5-oxo-4-[3'-(trifluoromethoxy)biphenyl-3-yl]-4-
,5-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
[0136] Methyl
4-[2-amino-4-(3',4'-difluorobiphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-1H--
imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate; [0137]
Methyl
4-{2-amino-4-[3-(1,3-benzodioxol-5-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
[0138]
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-methyl-1H-pyrrole-2-carbonitrile; [0139]
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-(2-fluoroethyl)-1H-pyrrole-2-carbonitrile; [0140]
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-propyl-1H-pyrrole-2-carbonitrile; [0141]
4-[2-Amino-1-methyl-5-oxo-4-(3-pyrimidin-5-ylphenyl)-4,5-dihydro-1H-imida-
zol-4-yl]-1-methyl-1H-pyrrole-2-carbonitrile; [0142]
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-methyl-1H-pyrrole-2-carbonitrile; [0143]
4-{2-Amino-4-[3-(2-chloro-5-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-
-dihydro-1H-imidazol-4-yl}-1-methyl-1H-pyrrole-2-carbonitrile;
[0144]
4-[2-Amino-1-methyl-5-oxo-4-(3-pyrimidin-5-ylphenyl)-4,5-dihydro-1H-imida-
zol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carbonitrile; [0145]
4-[2-Amino-1-methyl-5-oxo-4-(3-pyrimidin-5-ylphenyl)-4,5-dihydro-1H-imida-
zol-4-yl]-1-propyl-1H-pyrrole-2-carbonitrile; [0146]
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-propyl-1H-pyrrole-2-carbonitrile; [0147]
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carbonitrile;
[0148]
4-{2-Amino-4-[3-(2-chloro-5-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-
-dihydro-1H-imidazol-4-yl}-1-propyl-1H-pyrrole-2-carbonitrile;
[0149]
5-(5-Acetyl-1H-pyrrol-3-yl)-2-amino-5-(3-bromophenyl)-3-methyl-3,5-dihydr-
o-imidazol-4-one; [0150]
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde; [0151]
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1H-pyrrole-2-carbaldehyde; [0152]
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-ethyl-1H-pyrrole-2-carbaldehyde; [0153]
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-(2-fluoroethyl)-1H-pyrrole-2-carbaldehyde; [0154]
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde; [0155]
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carbaldehyde;
[0156]
2-Amino-5-[5-[(diethylamino)methyl]-1-(2-fluoroethyl)-1H-pyrrol-3-yl]-5-[-
3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
[0157]
2-Amino-5-{1-(2-fluoroethyl)-5-[(isopropylamino)methyl]-1H-pyrrol--
3-yl}-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol--
4-one; [0158]
2-Amino-5-[1-(2-fluoroethyl)-5-(pyrrolidin-1-ylmethyl)-1H-pyrrol-3-yl]-5--
[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
[0159]
2-Amino-5-[5-[(dimethylamino)methyl]-1-(2-fluoroethyl)-1H-pyrrol-3-
-yl]-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-
-one; [0160]
2-Amino-5-[5-[(dimethylamino)methyl]-1-(2-fluoroethyl)-1H-pyrrol-3-yl]-5--
[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
[0161]
2-Amino-5-[1-ethyl-5-(1-hydroxypropyl)-1H-pyrrol-3-yl]-5-[3-(2-flu-
oropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
[0162]
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde O-methyloxime
hydrochloride; [0163]
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[3-(2-fluoropyridin-3-yl-
)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; [0164]
2-Amino-5-(3-bromophenyl)-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methyl-
-3,5-dihydro-4H-imidazol-4-one; [0165]
(5S)-2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-propionyl-1-
-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
[0166]
(5R)-2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-prop-
ionyl-1-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-o-
ne; [0167]
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methyl-5-(3-py-
rimidin-5-ylphenyl)-3,5-dihydro-4H-imidazol-4-one; [0168]
2-Amino-5-(3'-methoxybiphenyl-3-yl)-3-methyl-5-[5-propionyl-1-(2,2,2-trif-
luoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one; [0169]
2-Amino-5-(3',5'-difluorobiphenyl-3-yl)-3-methyl-5-[5-propionyl-1-(2,2,2--
trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
[0170]
2-Amino-5-(3'-chlorobiphenyl-3-yl)-3-methyl-5-[5-propionyl-1-(2,2,-
2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
[0171]
2-Amino-5-(3'-chloro-4'-fluorobiphenyl-3-yl)-3-methyl-5-[5-propionyl-1-(2-
,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
[0172]
3'-{2-Amino-1-methyl-5-oxo-4-[5-propionyl-1-(2,2,2-trifluoroethyl)-1H-pyr-
rol-3-yl]-4,5-dihydro-1H-imidazol-4-yl}biphenyl-3-carbonitrile;
[0173]
2-Amino-5-(3-bromo-4-fluorophenyl)-3-methyl-5-[5-propionyl-1-(2,2,2-trifl-
uoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one; [0174]
2-Amino-5-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-propion-
yl-1-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
[0175]
2-Amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-5-[5-propiony-
l-1-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one;
or a tautomer thereof, a stereoisomer thereof or a pharmaceutically
acceptable salt thereof.
[0176] Compounds of the invention may be prepared employing
conventional methods that utilize readily available reagents and
starting materials. The reagents used in the preparation of the
compounds of this invention can be either commercially obtained or
can be prepared by standard procedures described in the literature.
Representative compounds of the present invention can be prepared
using the following synthetic schemes. The skilled practitioner
will know how to make use of variants of these reaction sequences,
which in themselves are well known in the art. For example,
compounds of formula I wherein W is CO (Ia) may be prepared by
reacting a diketone of formula II with an aminoguanidine derivative
of formula III in the presence of a base such as a metal carbonate
to give the desired formula Ia compound. The reaction is shown in
flow diagram I.
##STR00007##
[0177] Diketone compounds of formula II may be prepared by reacting
an alkyne of formula IV with an oxidizing agent such as
Pd(II)Cl/DMSO, N-bromosuccinimide/DMSO, ozone, sodium periodate
with ruthenium (IV) oxide hydrate, sulfur trioxide, KMnO.sub.4,
I.sub.2/DMSO, or combinations thereof, preferable KMnO.sub.4 and
I.sub.2/DMSO. The reaction is shown in flow diagram II.
##STR00008##
[0178] Alkyne compounds of formula IV may be prepared by reacting
an aryl compound of formula V wherein L is a leaving group such as
Br, I or trifluoromethanesulfonate with a protected acetylene
compound of formula VI wherein P is a protecting group such as
triaryl(alkyl)silyl or hydroydialkyl(aryl)silyl to give the
protected arylalkyne of formula VII; deprotecting the formula VII
compound to give the compound of formula VIII using a deprotecting
reagent such as a metal or ammonium fluoride, a metal carbonate,
for example cesium carbonate or potassium carbonate or a metal
hydroxide; and reacting the formula VIII alkyne with a heteroaryl
compound of formula IX wherein L represents a leaving group as
described hereinabove to give the desired alkyne compound of
formula IV. Similarly, compounds of formula IV may be prepared by
reversing the order of the coupling the aryl and heteroaryl groups.
The reactions are shown in flow diagram III.
##STR00009##
[0179] Alternatively, compounds of formula I wherein R.sub.7 is
aryl or heteroaryl (Ia) may be prepared following the formation of
the hydantoin ring by coupling the appropriate hydantoin compound
of formula X with an aryl or heteroaryl boronic acid of formula XI
to give the desired compounds of formula Ia. The reaction is shown
in flow diagram IV wherein L represents a leaving group as
described hereinabove.
##STR00010##
[0180] Compounds of formula I wherein W is CS (Ic) may be readily
prepared using conventional procedures, such as reacting a compound
of formula Ia with CS.sub.2, in the presence of a solvent to obtain
the desired compound of formula Ic. Similarly, compounds of formula
I wherein W is CH.sub.2 (Id) may be prepared by reacting a compound
of formula Ia with a suitable reducing agent, such as SnCl.sub.2,
to obtain the desired compound of formula Id. The reactions are
shown in flow diagram V.
##STR00011##
[0181] Advantageously, the compounds of formula I act as BACE
inhibitors for the treatment of .beta.-amyloid deposits and
neurofibrillary tangles associated with such diseases as
Alzheimer's disease, Trisomy 21 (Down's Syndrome), Hereditary
Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D),
and other neurodegenerative disorders. Accordingly, the present
invention provides methods for modulating BACE and treating,
preventing, or ameliorating .beta.-amyloid deposits and
neurofibrillary tangles associated with diseases and disorders such
as Alzheimer's disease, Trisomy 21 (Down's Syndrome), Hereditary
Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D),
and other neurodegenerative disorders. Such methods generally
involve administering to a patient suspected of suffering from or
being susceptible to the disease or injury an effective amount of a
compound of formula I. Also according to the present invention
there is provided a method of treating Alzheimer's disease and
related senile dementia's in humans or other mammals which
comprises administering to a human or other mammal an effective
amount of a compound of the present invention.
[0182] The present invention also provides a method for the
treatment of a disorder related to or associated with excessive
BACE activity in a patient in need thereof which comprises
providing said patient a therapeutically effective amount of at
least one compound of formula I. Representative disorders include
Alzheimer's disease, cognitive impairment, Down's Syndrome,
HCHWA-D, cognitive decline, senile dementia, cerebral amyloid
angiopathy, degenerative dementia, or other neurodegenerative
disorders. Certain of these diseases are characterized by
production of .beta.-amyloid deposits or neurofibrillary
tangles.
[0183] The present invention also provides methods for modulating
(and, preferably, inhibiting) the activity of BACE, comprising
administering to a patient and/or contacting a receptor thereof
with an effective amount of at least one compound of formula I.
Certain methods further comprise determining BACE activity, either
before or after said contacting step.
[0184] The present invention also provides methods of ameliorating
.beta.-amyloid deposits in a mammal, comprising administering to
said mammal an effective amount of at least one compound of formula
I. Further methods ameliorate neurofibrillary tangles in a mammal,
and comprise administering to said mammal an effective amount of at
least one compound of formula I.
[0185] Also provided are methods of ameliorating symptoms of
Alzheimer's disease, cognitive impairment, Down's Syndrome,
HCHWA-D, cognitive decline, senile dementia, cerebral amyloid
angiopathy, degenerative dementia, or other neurodegenerative
disorders in a mammal, comprising administering to said mammal an
effective amount of at least one compound of formula I.
[0186] Further methods prevent Alzheimer's disease, cognitive
impairment, Down's Syndrome, HCHWA-D, cognitive decline, senile
dementia, cerebral amyloid angiopathy, degenerative dementia, or
other neurodegenerative disorders in a mammal that is known to
suffer from or suspected to be at risk of suffering from such
diseases. These methods comprise administering to said mammal an
amount of at least one compound of formula I that is effective to
prevent such disease.
[0187] As used in accordance with this invention, the term
"providing," with respect to providing a compound or substance
covered by this invention, means either directly administering such
a compound or substance, or administering a prodrug, derivative, or
analog which will form the effective amount of the compound or
substance within the body. This invention also covers providing the
compounds of this invention to treat the disease states disclosed
herein that the compounds are useful for treating.
[0188] The term "patient", as used herein, refers to a mammal,
preferably a human.
[0189] The terms "administer", "administering", or
"administration", as used herein, refer to either directly
administering a compound or composition to a patient, or
administering a prodrug derivative or analog of the compound to the
patient, which will form an equivalent amount of the active
compound or substance within the patient's body.
[0190] The terms "effective amount", "therapeutically effective
amount" and "effective dosage" as used herein, refer to the amount
of a compound that, when administered to a patient, is effective to
at least partially ameliorate (and, in preferred embodiments, cure)
a condition from which the patient is suspected to suffer.
[0191] It is understood that the effective dosage of the active
compounds of this invention may vary depending upon the particular
compound utilized, the mode of administration, the condition, and
severity thereof, of the condition being treated, as well as the
various physical factors related to the individual being treated.
For treating Alzheimer's disease and other related senile
dementia's, generally, satisfactory results may be obtained when
the compounds of this invention are administered to the individual
in need at a daily dosage of from about 0.1 mg to about 1 mg per
kilogram of body weight, preferably administered in divided doses
two to six times per day, or in a sustained release form. For most
large mammals, the total daily dosage is from about 3.5 mg to about
140 mg preferably from about 3.5 to about 5 mg. In the case of a 70
kg human adult, the total daily dose will generally be from about 7
mg to about 70 mg and may be adjusted to provide the optimal
therapeutic result. This regimen may be adjusted to provide the
optimal therapeutic response.
[0192] In one aspect, the present invention is directed to
compositions comprising one or more compounds of formula I and one
or more pharmaceutically acceptable carriers.
[0193] The present invention also comprises pharmaceutical
compositions comprising compounds of the above-described formula I
and a pharmaceutically acceptable carrier.
[0194] The term "carrier", as used herein, shall encompass
carriers, excipients, and diluents. Examples of carriers are well
known to those skilled in the art and are prepared in accordance
with acceptable pharmaceutical procedures, such as, for example,
those described in Remington's Pharmaceutical Sciences, 17th
edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton,
Pa. (1985), which is incorporated herein by reference in its
entirety. Pharmaceutically acceptable carriers are those that are
compatible with the other ingredients in the formulation and
biologically acceptable.
[0195] The compounds of this invention may be administered orally
or parenterally, neat or in combination with conventional
pharmaceutical carriers. Applicable solid carriers can include one
or more substances which may also act as flavoring agents,
lubricants, solubilizers, suspending agents, fillers, glidants,
compression aids, binders or tablet-disintegrating agents or
encapsulating materials. They are formulated in conventional
manner, for example, in a manner similar to that used for known
antihypertensive agents, diuretics and .beta.-blocking agents. Oral
formulations containing the active compounds of this invention may
comprise any conventionally used oral forms, including tablets,
capsules, buccal forms, troches, lozenges and oral liquids,
suspensions or solutions. In powders, the carrier is a finely
divided solid, which is an admixture with the finely divided active
ingredient. In tablets, the active ingredient is mixed with a
carrier having the necessary compression properties in suitable
proportions and compacted in the shape and size desired. The
powders and tablets preferably contain up to 99% of the active
ingredient.
[0196] Capsules may contain mixtures of the active compound(s) with
inert fillers and/or diluents such as the pharmaceutically
acceptable starches (e.g. corn, potato or tapioca starch), sugars,
artificial sweetening agents, powdered celluloses, such as
crystalline and microcrystalline celluloses, flours, gelatins,
gums, etc.
[0197] Useful tablet formulations may be made by conventional
compression, wet granulation or dry granulation methods and utilize
pharmaceutically acceptable diluents, binding agents, lubricants,
disintegrants, surface modifying agents (including surfactants),
suspending or stabilizing agents, including, but not limited to,
magnesium stearate, stearic acid, sodium lauryl sulfate, talc,
sugars, lactose, dextrin, starch, gelatin, cellulose, methyl
cellulose, microcrystalline cellulose, sodium carboxymethyl
cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine,
alginic acid, acacia gum, xanthan gum, sodium citrate, complex
silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium
phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium
chloride, low melting waxes and ion exchange resins. Preferred
surface modifying agents include nonionic and anionic surface
modifying agents. Representative examples of surface modifying
agents include, but are not limited to, poloxamer 188, benzalkonium
chloride, calcium stearate, cetostearl alcohol, cetomacrogol
emulsifying wax, sorbitan esters, colliodol silicon dioxide,
phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and
triethanolamine. Oral formulations herein may utilize standard
delay or time release formulations to alter the absorption of the
active compound(s). The oral formulation may also consist of
administering the active ingredient in water or fruit juice,
containing appropriate solubilizers or emulisifiers as needed.
[0198] Liquid carriers may be used in preparing solutions,
suspensions, emulsions, syrups and elixirs. The active ingredient
of this invention can be dissolved or suspended in a
pharmaceutically acceptable liquid carrier such as water, an
organic solvent, a mixture of both or pharmaceutically acceptable
oils or fat. The liquid carrier can contain other suitable
pharmaceutical additives such as solubilizers, emulsifiers,
buffers, preservatives, sweeteners, flavoring agents, suspending
agents, thickening agents, colors, viscosity regulators,
stabilizers or osmo-regulators. Suitable examples of liquid
carriers for oral and parenteral administration include water
(particularly containing additives as above, e.g. cellulose
derivatives, preferably sodium carboxymethyl cellulose solution),
alcohols (including monohydric alcohols and polyhydric alcohols,
e.g. glycols) and their derivatives, and oils (e.g. fractionated
coconut oil and arachis oil). For parenteral administration the
carrier can also be an oily ester such as ethyl oleate and
isopropyl myristate. Sterile liquid carriers are used in sterile
liquid form compositions for parenteral administration. The liquid
carrier for pressurized compositions can be halogenated hydrocarbon
or other pharmaceutically acceptable propellant.
[0199] Liquid pharmaceutical compositions, which are sterile
solutions or suspensions, can be utilized by, for example,
intramuscular, intraperitoneal or subcutaneous injection. Sterile
solutions can also be administered intravenously. Compositions for
oral administration may be in either liquid or solid form.
[0200] Preferably the pharmaceutical composition is in unit dosage
form, e.g. as tablets, capsules, powders, solutions, suspensions,
emulsions, granules, or suppositories. In such form, the
composition is sub-divided in unit dose containing appropriate
quantities of the active ingredient; the unit dosage forms can be
packaged compositions, for example, packeted powders, vials,
ampoules, prefilled syringes or sachets containing liquids. The
unit dosage form can be, for example, a capsule or tablet itself,
or it can be the appropriate number of any such compositions in
package form. Such unit dosage form may contain from about 1 mg/kg
to about 250 mg/kg, and may given in a single dose or in two or
more divided doses. Such doses may be administered in any manner
useful in directing the active compounds herein to the recipient's
bloodstream, including orally, via implants, parenterally
(including intravenous, intraperitoneal and subcutaneous
injections), rectally, vaginally, and transdermally. Such
administrations may be carried out using the present compounds, or
pharmaceutically acceptable salts thereof, in lotions, creams,
foams, patches, suspensions, solutions, and suppositories (rectal
and vaginal).
[0201] When administered for the treatment or inhibition of a
particular disease state or disorder, it is understood that the
effective dosage may vary depending upon the particular compound
utilized, the mode of administration, the condition, and severity
thereof, of the condition being treated, as well as the various
physical factors related to the individual being treated. In
therapeutic application, compounds of the present invention are
provided to a patient already suffering from a disease in an amount
sufficient to cure or at least partially ameliorate the symptoms of
the disease and its complications. An amount adequate to accomplish
this is defined as a "therapeutically effective amount". The dosage
to be used in the treatment of a specific case must be subjectively
determined by the attending physician. The variables involved
include the specific condition and the size, age and response
pattern of the patient.
[0202] In some cases it may be desirable to administer the
compounds directly to the airways in the form of an aerosol. For
administration by intranasal or intrabrochial inhalation, the
compounds of this invention may be formulated into an aqueous or
partially aqueous solution.
[0203] The compounds of this invention may be administered
parenterally or intraperitoneally. Solutions or suspensions of
these active compounds as a free base or pharmaceutically
acceptable salt may be prepared in water suitably mixed with a
surfactant such as hydroxyl-propylcellulose. Dispersions may also
be prepared in glycerol, liquid polyethylene glycols and mixtures
thereof in oils. Under ordinary conditions of storage and use,
these preparations contain a preservative to inhibit the growth of
microorganisms.
[0204] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringability exists. It must be
stable under the conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such
as bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (e.g.,
glycerol, propylene glycol and liquid polyethylene glycol),
suitable mixtures thereof, and vegetable oils.
[0205] The compounds of this invention can be administered
transdermally through the use of a transdermal patch. For the
purposes of this disclosure, thransdermal administrations are
understood to include all administrations across the surface of the
body and the inner linings of bodily passages including epithelial
and mucosal tissues. Such administrations may be carried out using
the present compounds, or pharmaceutically acceptable salts
thereof, in lotions, creams, foams, patches, suspensions,
solutions, and suppositories (rectal and vaginal).
[0206] Transdermal administration may be accomplished through the
use of a transdermal patch containing the active compound and a
carrier that is inert to the active compound, is non-toxic to the
skin, and allows delivery of the agent for systemic absorption into
the blood stream via the skin. The carrier may take any number of
forms such as creams and ointments, pastes, gels and occlusive
devices. The creams and ointments may be viscous liquid or
semisolid emulsions of either the oil-in-water or water-in-oil
type. Pastes comprised of absorptive powders dispersed in petroleum
or hydrophilic petroleum containing the active ingredient may also
be suitable. A variety of occlusive devices may be used to release
the active ingredient into the blood stream, such as a
semi-permeable membrane covering a reservoir containing the active
ingredient with or without a carrier, or a matrix containing the
active ingredient. Other occlusive devices are known in the
literature.
[0207] The compounds of this invention may be administered rectally
or vaginally in the form of a conventional suppository. Suppository
formulations may be made from traditional materials, including
cocoa butter, with or without the addition of waxes to alter the
suppository's melting point, and glycerin. Water soluble
suppository bases, such as polyethylene glycols of various
molecular weights, may also be used.
[0208] In certain embodiments, the present invention is directed to
prodrugs. Various forms of prodrugs are known in the art, for
example, as discussed in, for example, Bundgaard, (ed.), Design of
Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in
Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et
al. (ed.), "Design and Application of Prodrugs", Textbook of Drug
Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et
al., Journal of Drug Deliver reviews, 8:1-38 (1992), Bundgaard, J.
of Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and
Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American
Chemical Society (1975), each of which is incorporated by reference
in its entirety.
[0209] It is understood that the dosage, regimen and mode of
administration of these compounds will vary according to the malady
and the individual being treated and will be subject to the
judgment of the medical practitioner involved. It is preferred that
the administration of one or more of the compounds herein begin at
a low dose and be increased until the desired effects are
achieved.
[0210] For a more clear understanding, and in order to illustrate
the invention more clearly, specific examples thereof are set forth
hereinbelow. The following examples are merely illustrative and are
not to be understood as limiting the scope and underlying
principles of the invention in any way.
[0211] Unless otherwise stated, all parts are parts by weight. The
terms TEA, DMSO and DMF designate triethyl amine, dimethyl
sulfoxide and N,N-dimethylformamide, respectively. The terms DME
and THF designate ethylene glycol dimethyl ether and
tetrahydrofuran, respectively. The term TLC designates thin layer
chromatography. The term NMR designates proton nuclear magnetic
resonance and the term MS designates mass spectroscopy with (+)
referring to the positive mode which generally gives a M+1 (or M+H)
absorption where M=the molecular mass. All compounds are analyzed
at least by MS and NMR.
[0212] Proton nuclear magnetic resonance spectra were obtained on a
Bruker AVANCE 300 spectrometer at 300 MHz or VARIAN 400
spectrometer at 400 MHz. Spectra are given in ppm (.delta.) and
coupling constants, J values, are reported in Hertz.
Tetramethylsilane was used as an internal reference standard.
Infrared spectra were obtained on a Nicolet Nexus 470 (ATR)
spectrometer. Mass spectra were obtained on a Perkin Elmer Sciex
100.
Example 1
Preparation of
2-Amino-3-methyl-5-(1-methyl-1H-pyrazol-4-yl)-5-(3-pyrimidin-5-ylphenyl)--
3,5-dihydro-4-imidazol-4-one
##STR00012##
[0213] Step a) Preparation of Compound 2
[0214] A mixture of pyrazole (3.00 g, 44.0 mmol), iodine (6.71 g,
26.4 mmol) and ceric ammonium nitrate (14.5 g, 26.4 mmol) in
acetonitrile (400 mL) was stirred at room temperature for 2.5 h.
The reaction was concentrated and partitioned between ethyl acetate
(250 mL) and 5% aqueous sodium bisulfite (250 mL). Water (150 mL)
was added and the organic layer was separated and washed with brine
(250 mL), dried over magnesium sulfate, filtered and concentrated
to afford 2 (7.80 g, 91%) as a white solid: mp 105-108.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.63 (s, 2H).
Step b) Preparation of Compound 3
[0215] Sodium hydride (0.680 g of a 60% dispersion in oil, 17.0
mmol) was washed with hexanes (2 mL) diluted with THF (12 mL) and
treated with a solution of 2 (3.00 g, 15.5 mmol) in THF (3 mL) over
a period of 10 min. After stirring for 4 h at room temperature, a
solution of methyl iodide (4.39 g, 31.9 mmol) in THF (3 mL) was
added dropwise over a period of 10 min and the mixture stirred at
room temperature for 2.5 h. The mixture was diluted with ether (100
mL) then washed with water (50 mL), brine (50 mL), dried over
magnesium sulfate, filtered and concentrated to afford 3 (2.95 g,
92%) as an off-white solid: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.49 (s, 1H), 7.41 (s, 1H), 3.92 (s, 3H); ESI MS m/z 209
[C.sub.4H.sub.5IN.sub.2+H].sup.+.
Step c) Preparation of Compound 4
[0216] A mixture of 3 (0.400 g, 1.92 mmol), 3-bromophenylacetylene
4 (0.380 g, 2.12 mmol), bis(triphenylphosphine)palladium(II)
chloride (0.040 g, 0.058 mmol), copper (I) iodide (0.007 g, 0.038
mmol) and triethylamine (0.97 g, 9.61 mmol) in dimethylformamide (7
mL) was stirred at room temperature for 4.5 h. The mixture was
diluted with ethyl acetate (50 mL), washed with water (50 mL), 5%
aqueous lithium chloride (2.times.50 mL) and brine (50 mL), dried
over magnesium sulfate, filtered, and concentrated to afford 0.58 g
of an amber syrup. Purification by flash chromatography (silica,
1:4 ethyl acetate/hexanes) afforded 5 (0.27 g, 54%) as an amber
syrup: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.64-7.62 (m, 2H),
7.56 (s, 1H), 7.45-7.37 (m, 2H), 7.19 (t, J=7.9 Hz, 1H), 3.92 (s,
3H); ESI MS m/z 261 [C.sub.12H.sub.9BrN.sub.2+H].sup.+.
Step d) Preparation of Compound 6
[0217] To a stirred solution of 5 (0.100 g, 0.383 mmol) in acetone
(4 mL) was added a solution of sodium bicarbonate (0.019 g, 0.229
mmol) and magnesium sulfate (0.069 g, 0.574 mmol) in water (4 mL),
followed by potassium permanganate (0.133 g, 0.843 mmol) in one
portion. The reaction mixture was stirred for 20 min at room
temperature. After this time the reaction was diluted with 1:1
hexanes/ethyl acetate (4 mL) and water (2 mL) and the solids were
removed by filtration. The aqueous layer was separated then
extracted with ethyl acetate (2.times.10 mL), and the combined
organic layers washed with water (2.times.10 mL) and brine (30 mL),
dried over magnesium sulfate, filtered and concentrated to afford 6
(0.094 g, 85%) as an off-white solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.20 (m, 1H), 8.06 (m, 2H), 7.79 (m, 1H), 7.76
(m, 1H), 7.39 (t, J=7.9 Hz, 1H), 3.92 (s, 3H); ESI MS m/z 293
[C.sub.12H.sub.9BrN.sub.2O.sub.2+H].sup.+.
Step e) Preparation of Compound 7
[0218] A mixture of 6 (0.400 g, 1.36 mmol) and 1-methylguanidine
hydrochloride (0.670 g, 6.14 mmol) in dioxane (18 mL) and ethanol
(12 mL) was stirred at room temperature for 5 min. A solution of
sodium carbonate (0.650 g, 6.14 mmol) in water (5 mL) was then
added and the mixture immersed into an 85.degree. C. oil bath and
stirred for 1 h. The mixture was cooled to room temperature,
concentrated and the residue partitioned between methylene chloride
(100 mL) and water (100 mL). The organic layer was separated,
washed with water (100 mL), brine (100 mL), dried over magnesium
sulfate, filtered and concentrated. Purification by flash
chromatography (silica, 95:5:0.25 methylene
chloride/methanol/concentrated ammonium hydroxide) afforded 7 (0.33
g, 70%) as a white solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.68 (m, 1H), 7.48-7.37 (m, 4H), 7.18 (t, J=7.9 Hz, 1H), 3.85 (s,
3H), 3.09 (s, 3H); m/z 348
[C.sub.14H.sub.14BrN.sub.5O+H].sup.+.
Step f) Preparation of
2-Amino-3-methyl-5-(1-methyl-1H-pyrazol-4-yl)-5-(3-pyrimidin-5-ylphenyl)--
3,5-dihydro-4-imidazol-4-one
[0219] A mixture of 7 (0.100 g, 0.287 mmol), 5-pyrimidine boronic
acid (0.043 g, 0.345 mmol), tetrakistriphenylphosphinopalladium(0)
(0.017 g, 0.0144 mmol) and potassium carbonate (0.099 g, 0.718
mmol) in 5:1 dioxane/water (1.8 mL) was heated at 100.degree. C.
for 4 h. The mixture was cooled to room temperature, concentrated
and the crude product purified by flash chromatography (silica,
95:5:0.25 methylene chloride/methanol/concentrated ammonium
hydroxide) to afford the title compound (0.060 g, 60%) as a white
solid: R.sub.f 0.36 (92:8:0.25 methylene
chloride/methanol/concentrated ammonium hydroxide); .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 9.13 (s, 1H), 9.01 (s, 2H), 7.75-7.42
(m, 6H), 3.85 (s, 3H), 3.10 (s, 3H); IR (ATR) 1663, 1468, 1413,
1400 cm.sup.-1; ESI MS m/z 348
[C.sub.18H.sub.17N.sub.7O+H].sup.+;
Examples 2-11
Preparation of 2-Amino-3-methyl-5-(substituted
pyrazolyl)-3,5-dihydro-4H-imidazol-4-one Compounds
[0220] Using essentially the same procedure described in Example 1
and employing the appropriate iodopyrazole derivative and a
suitable alkyne intermediate, the compounds shown below were
prepared and identified by NMR and mass spectral analyses.
Example 2
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-methyl-1-(2,2,2-t-
rifluoroethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one
##STR00013##
[0222] .sup.1H NMR (DMSOd.sub.6 300 MHz) .delta. 2.0 (s, 3H), 2.95
(s, 3H), 5.0 (q, 2H), 6.6 (b, 2H), 7.3 (s, 1H), 7.4 (m, 4H), 7.6
(s, 1H), 8.0 (m, 1H), 8.2 (m, 1H); MS m/e (M).sup.+ 447; mp
235-238.degree. C.
Example 3
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-5-(1-isobutyl-1H-pyrazol-4-yl)--
3-methyl-3,5-dihydro-4H-imidazol-4-one
##STR00014##
[0224] .sup.1H NMR (DMSOd.sub.6 300 MHz) .delta. 0.8 (d, 6H), 2.0
(m, 1H), 2.95 (s, 3H), 3.8 (d, 2H), 6.6 (b, 2H), 7.3 (s, 1H), 7.4
(m, 3H), 7.5 (m, 1H), 7.6 (s, 1H), 7.7 (s, 1H), 8.0 (m, 1H), 8.2
(m, 1H); MS m/e (M).sup.+ 407; mp=94-98.degree. C.
Example 4
2-Amino-5-(1-butyl-1H-pyrazol-4-yl)-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-m-
ethyl-3,5-dihydro-4H-imidazol-4-one
##STR00015##
[0226] .sup.1H NMR (DMSOd.sub.6 300 MHz) .delta. 0.8 (t, 3H), 1.2
(m, 2H), 1.6 (m, 2H), 2.95 (s, 3H), 4.0 (t, 2H) 6.7 (b, 2H), 7.2
(s, 1H), 7.4 (m, 3H), 7.5 (m, 1H), 7.6 (s, 1H), 7.7 (s, 1H), 8.0
(m, 1H), 8.2 (m, 1H); MS m/e (M).sup.+ 407; mp=88-92.degree. C.
Example 5
2-Amino-5-(1-isobutyl-1H-pyrazol-4-yl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-
-3,5-dihydro-4H-imidazol-4-one
##STR00016##
[0228] .sup.1H NMR (DMSOd.sub.6 300 MHz) .delta. 0.8 (d, 6H), 2.0
(m, 1H), 2.95 (s, 3H), 3.8 (d, 1H), 6.8 (b, 2H), 7.3 (s, 1H), 7.4
(t, 1H), 7.5 (m, 1H), 7.6 (m, 2H), 7.7 (s, 1H), 8.9 (s, 2H), 9.2
(s, 1H); MS m/e (M).sup.+ 390; mp=118-1220.degree. C.
Example 6
2-Amino-5-(1-butyl-1H-pyrazol-4-yl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,-
5-dihydro-4H-imidazol-4-one
##STR00017##
[0230] .sup.1H NMR (DMSOd.sub.6 300 MHz) .delta. 0.8 (t, 3H), 1.2
(m, 2H), 1.6 (m, 2H), 2.95 (s, 3H), 4.0 (t, 2H), 6.6 (b, 2H), 7.3
(s, 1H), 7.4 (t, 1H), 7.5 (m, 1H), 7.6 (m, 2H), 7.7 (s, 1H), 8.9
(s, 2H), 9.2 (s, 1H), MS m/e (M).sup.+ 390; mp=94-98.degree. C.
Example 7
2-Amino-5-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[1-(2,2,2-t-
rifluoroethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one
##STR00018##
[0232] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.: 3.10 (s, 3H),
5.12 (q, 2H, J=8.67 Hz), 7.48 (m, 4H), 7.62 (s, 1H), 7.87 (s, 1H),
7.99 (m, 1H), 8.31 (s, 1H), 9.43 (d, 2H); mp>225.degree. C.; MS
(ES) m/z 451 (M+H).sup.+.
Example 8
2-Amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-5-[1-(2,2,2-trifluoro-
ethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one
##STR00019##
[0234] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.: 2.92 (s, 3H),
5.03 (q, 2H, J=9.15 Hz), 6.67 (s, 2H), 7.32 (m, 1H), 7.47 (s, 1H),
7.63 (m, 2H), 7.75 (s, 1H), 8.89 (s, 2H), 9.19 (s, 1H); mp
115-117.degree. C.; MS (ES) m/z 434.
Example 9
2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3--
methyl-3,5-dihydro-4H-imidazol-4-one
##STR00020##
[0236] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.: 1.26 (t, 3H,
J=7.2 Hz), 2.91 (s, 3H), 4.01 (q, 2H, J=7.2 Hz), 6.59 (s, 2H), 7.30
(m, 2H), 7.65 (m, 3H), 8.90 (s, 2H), 9.18 (s, 1H); mp
120-121.degree. C.; MS (ES) m/z 380.
Example 10
2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)-5-[4-fluoro-3-(2-fluoropyridin-3-yl)ph-
enyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
##STR00021##
[0238] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.: 1.26 (t, 3H,
J=7.32 Hz), 2.90 (s, 3H), 4.01 (q, 2H, J=7.2 Hz), 6.58 (s, 2H),
7.26 (m, 2H), 7.45 (m, 1H), 7.55 (s, 2H), 7.60 (m, 1H), 7.96 (m,
1H), 8.26 (s, 1H); mp 84-85.degree. C.; MS (ES) m/z 397.
Example 11
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[3-methyl-1-(2,2,2-t-
rifluoroethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one
##STR00022##
[0240] MS m/e (M).sup.+ 447; .sup.1H NMR (DMSO d.sub.6 300 MHz)
.delta. 1.8 (s, 3H), 2.95 (s, 3H), 4.95 (q, 2H), 6.6 (b, 2H), 7.4
(m, 5H), 7.6 (s, 1H), 8.0 (m, 1H), 8.2 (m, 1H). mp=128-132.degree.
C.
Examples 12-25
Preparation of
2-Amino-3-methyl-5-thienyl-3,5-dihydro-4H-imidazolone Compounds
##STR00023##
[0242] Using essentially the same procedure described in Example 1,
Steps b-f, and employing the approriate iodothiophene and a
suitable 3-bromophenylalkyne as starting materials, the compounds
shown in Table I were obtained and identified by NMR and mass
spectral analyses.
TABLE-US-00001 TABLE I ##STR00024## Ex. MS No R4 R7 Z Y mp
(.degree. C.) m/z 12 H pyridin-3-yl S CH 219-223 349 13 H
pyridin-3-yl CH S 248 349 14 H 2,5-difluorophenyl CH S 222 384 15 H
Br CH S -- 350 16 H 2,5-difluorophenyl S CH 209-210 384 17 CH.sub.3
Br S CH -- 364 18 CH.sub.3 pyridin-3-yl S CH 218-220 363 19
CH.sub.3 pyrimidin-5-yl S CH 133-135 364 20 H pyrimidin-5-yl CH S
135 350 21 H 3-fluorophenyl CH S 181 366* 22 H 2,3-difluorophenyl
CH S 170 384* 23 H 3,5-difluorophenyl CH S 217 384* 24 H
3-cyanophenyl CH S 220 373* 25 H 2,5-dimethoxyphenyl CH S 143 408*
*(M + H).sup.+
Example 26
Preparation of
2-Amino-5-(5-chloro-2-methylthien-3-yl)-3-methyl-5-(3-pyrimidin-5-ylpheny-
l)-3,5-dihydro-4H-imidazol-4-one
##STR00025##
[0243] Step a) Preparation of Compound 14
[0244] A mixture of 13 (3.17 g, 12.3 mmol), 3-bromophenylacetylene
(2.44 g, 13.5 mmol; see MEC00775; dated Aug. 15, 2003),
bis(triphenylphosphine)palladium(II) chloride (0.258 g, 0.360
mmol), copper(I) iodide (0.046 g, 0.240 mmol) and triethylamine
(3.70 g, 36.8 mmol) in dimethylformamide (60 mL) was stirred at
room temperature for 1.5 h. The mixture was diluted with ethyl
acetate (300 mL), washed with water (2.times.100 mL), brine
(3.times.100 mL), dried over sodium sulfate, filtered, and
concentrated. The crude material was purified by flash
chromatography (silica, hexanes) to afford 14 as a yellow oil,
which was a mixture of product and an unidentified by-product
(which was removed during purification in the following step): APCI
MS m/z 311 [C.sub.13H.sub.8BrClS+H].sup.+.
Step b) Preparation of Compound 15
[0245] To a stirred solution of 14 (2.60 g, 8.30 mmol) in acetone
(200 mL) was added a solution of sodium bicarbonate (0.418 g, 5.00
mmol) and magnesium sulfate (2.00 g, 16.6 mmol) in water (60 mL),
followed by potassium permanganate (3.30 g, 20.9 mmol) in one
portion. The reaction mixture was stirred for 1 h at rt. After this
time the reaction was diluted with 1:1 hexanes/ethyl acetate (100
mL) and water (50 mL) and the solids were removed by filtration.
The aqueous layer was separated then extracted with hexanes
(2.times.75 mL), and the combined organic layers washed with water
(2.times.75 mL), brine (75 mL), dried over sodium sulfate, filtered
and concentrated. The resulting crude material was purified by
flash chromatography (silica, 90:10 hexanes/ethyl acetate) to
afford 15 (1.61 g, 38% over 2 steps) as a yellow oil: .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 8.10 (t, J=1.7 Hz, 1H), 7.87 (dt,
J=7.8, 1.2 Hz, 1H), 7.81-7.74 (m, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.06
(d, J=1.2 Hz, 1H), 2.41 (s, 3H).
Step c) Preparation of Compound 16
[0246] A mixture of 15 (1.58 g, 4.60 mmol) and 1-methylguanidine
hydrochloride (2.27 g, 20.7 mmol) in dioxane (50 mL) and ethanol
(60 mL) was stirred at room temperature for 5 min. A solution of
sodium carbonate (2.19 g, 20.7 mmol) in water (15 mL) was then
added and the mixture immersed into an 85.degree. C. oil bath and
stirred for 45 min. The mixture was cooled to room temperature,
concentrated and the residue partitioned between methylene chloride
(150 mL) and water (150 mL). The organic layer was separated,
washed with water (75 mL), brine (75 mL), dried over sodium
sulfate, filtered and concentrated. The crude material was purified
by flash chromatography (silica, 95:5:0.5 methylene
chloride/methanol/concentrated ammonium hydroxide) to afford a
viscous oil. This oil was dissolved in a minimal amount of
methylene chloride, treated with hexanes and then concentrated to
afford 16 (0.96 g, 52%) as a white solid: .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.70 (br s, 1H), 7.55-7.45 (m, 2H), 7.27 (t,
J=7.9 Hz, 1H), 6.12 (br s, 1H), 3.08 (s, 3H), 2.29 (s, 3H); ESI MS
m/z 398 [C.sub.15H.sub.13BrClN.sub.3OS+H].sup.+.
Step d) Preparation of
2-Amino-5-(5-chloro-2-methylthien-3-yl)-3-methyl-5-(3-pyrimidin-5-ylpheny-
l)-3,5-dihydro-4H-imidazol-4-one
[0247] Ethylene glycol dimethyl ether (12 mL) was added to a
nitrogen purged round bottom flask containing
tris(dibenzylideneacetone)dipalladium(0) (0.034 g, 37.3 .mu.mol)
and triphenylphosphine (0.019 g, 72.5 .mu.mol) and the mixture
stirred for 5 min. 16 (0.30 g, 0.75 mmol), 5-pyrimidine boronic
acid (0.111 g, 0.90 mmol), sodium carbonate (0.238 g, 2.25 mmol)
and water (5 mL) were then added. The mixture was heated at reflux
for 1.5 h, cooled to room temperature and concentrated. The residue
was purified by flash chromatography (silica, 95:5:0.5 methylene
chloride/methanol/concentrated ammonium hydroxide) and then by
semi-preparative chromatography (Method 3) to afford a viscous oil.
The oil was free based by partitioning between methylene chloride
(20 mL) and 1 N sodium hydroxide (20 mL). The layers were separated
and the organic layer dried over sodium sulfate, filtered and
concentrated to afford the title product (0.032 g, 11%) as a white
solid: mp 141-149.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 9.13 (s, 1H), 9.03 (s, 2H), 7.87 (br s, 1H), 7.72-7.67 (m,
2H), 7.55 (t, J=7.8 Hz, 1H), 6.19 (s, 1H), 3.11 (s, 3H), 2.29 (s,
3H); IR (ATR) 3342, 3040, 2953, 2918, 1732, 1663, 1601, 1583, 1553,
1467 cm.sup.-1; ESI MS m/z 398
[C.sub.19H.sub.16ClN.sub.5OS+H].sup.+;
Example 27
Preparation of
2-Amino-5-(2-methylthien-3-yl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-di-
hydro-4H-imidazol-4-one
##STR00026##
[0248] Step a) Preparation of compound 19
[0249] A solution of diisopropylamine (8.28 g, 81.8 mmol) in THF
(190 mL) at -20.degree. C. was treated with n-butyllithium (52 mL
of a 1.6 M solution in hexanes, 83.2 mmol) over a period of 20 min,
then slowly warmed to 0.degree. C. under stirring for 30 min. This
solution was cooled to -78.degree. C. and treated dropwise with a
solution of thiophene-3-carboxylic acid (4.99 g, 38.9 mmol) in THF
(40 mL) over a period of 10 min. The mixture was stirred at
-78.degree. C. for an additional 10 min, then treated with
iodomethane (6.16 g, 43.3 mmol) and stirred for 1 h, allowing the
solution to slowly warm to rt. Water (200 mL) was added, and the
mixture was made acidic by adding 2 N HCl (40 mL). The layers were
separated and the aqueous layer was extracted with ether
(3.times.75 mL), then the combined organic layers were dried over
sodium sulfate, filtered and concentrated. Purification by flash
chromatography (silica, 50:50:1 ethyl acetate/hexanes/acetic acid)
afforded 19 (1.12 g, 20%) as a white solid: .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.45 (d, J=5.4 Hz, 1H), 7.01 (t, J=5.4 Hz, 1H),
2.77 (s, 3H).
Step b) Preparation of Compound 22
[0250] A solution of 19 (0.908 g, 6.39 mmol) and thionyl chloride
(4.59 g, 38.8 mmol) in benzene (7 mL) was heated to reflux for 1 h.
The mixture was concentrated, diluted with toluene (20 mL) and
again concentrated to afford the acid chloride of 20 (1.10 g, 100%)
as a colorless oil. A mixture of 21 (3.27 g, 6.38 mmol) in toluene
(30 mL) was treated with n-butyllithium (5.5 mL of a 1.16 M
solution in hexanes, 6.38 mmol) and stirred at rt for 15 min. A
solution of the acid chloride of 20 (1.10 g, 6.39 mmol) in toluene
(8 mL) was added, and the mixture was stirred at rt for 2 h. The
reaction was concentrated to afford 22 (4.90 g crude, >100%) as
a yellow oil. ESI MS m/z 555 [C.sub.31H.sub.24BrOPS+H].sup.+.
Step c) Preparation of Compound 23
[0251] A mixture of 22 (4.50 g, 6.00 mmol) in acetone (20 mL) was
treated with a solution of sodium bicarbonate (0.323 g, 3.84 mmol)
and magnesium sulfate (1.54 g, 12.8 mmol) in water (10 mL), and the
mixture was stirred at rt for 5 min. Potassium permanganate (2.02
g, 12.8 mmol) was added, and the mixture was heated at 50.degree.
C. for 16 h. The reaction was cooled to room temperature, diluted
with ether (50 mL) and water (75 mL), and the insoluble material
was removed by filtration. The filtrate layers were separated, and
the aqueous layer was extracted with ether (2.times.50 mL). The
combined organic extracts were dried over sodium sulfate, filtered,
and concentrated to afford 2.19 g of a yellow oil, which was a 2:1
mixture of 23 and 22 as determined by .sup.1H NMR analysis. This
material was used in the subsequent step without further
purification.
Step d) Preparation of Compound 24
[0252] The reaction of 23 (0.113 g, .about.67% purity) with
1-methylguanidine hydrochloride was carried out as described in
method E to afford 24 (0.0655 g) as an off-white solid: .sup.1H NMR
(500 MHz, CD.sub.3OD) .delta. 7.56 (t, J=1.8 Hz, 1H), 7.47-7.44 (m,
1H), 7.40-7.37 (m, 1H), 7.25 (t, J=7.9 Hz, 1H), 7.04 (d, J=5.4 Hz,
1H), 6.73 (d, J=5.4 Hz, 1H), 3.10 (s, 3H), 2.09 (s, 3H); ESI MS m/z
364 [C.sub.15H.sub.14BrN.sub.3OS+H].sup.+.
Step e) Preparation of
2-Amino-5-(2-methylthien-3-yl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-di-
hydro-4H-imidazol-4-one
[0253] A mixture of 24 (0.060 g, 0.166 mmol), 5-pyrimidineboronic
acid (0.028 g, 0.224 mmol) and
tetrakis(triphenylphosphino)palladium(0) (0.011 g, 92.6 .mu.mol) in
dioxane (1.5 mL) was treated with a solution of potassium carbonate
(0.074 g, 0.532 mmol) in water (0.3 mL), then heated at reflux for
55 min. The mixture was cooled to room temperature, concentrated,
and the residue partitioned between methylene chloride (50 mL) and
water (50 mL). The layers were separated, and the aqueous layer was
extracted with methylene chloride (2.times.25 mL). The combined
organic extracts were dried over sodium sulfate, filtered, and
concentrated. Purification by flash chromatography (silica,
96:4:0.5 methylene chloride/methanol/concentrated ammonium
hydroxide) afforded the title product (0.046 g, 76%) as a white
solid: mp 154-159.degree. C.: .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 9.12 (s, 1H), 9.01 (s, 2H), 7.73 (d, J=1.8 Hz, 1H),
7.68-7.65 (m, 1H), 7.58-7.51 (m, 2H), 7.05 (s, 1H), 6.77 (d, J=5.3
Hz, 1H), 3.12 (s, 3H), 2.11 (s, 3H); ESI MS m/z 364
[C.sub.19H.sub.17N.sub.5OS+H
Examples 28-37
Preparation of
2-Amino-3-methyl-5-(3-heteroarylphenyl)-5-thien-3ylimidazolone
Compounds
##STR00027##
[0255] Using essentially the same procedure described in Example 27
and employing the appropriate thien-3-yl carboxylic acid as
starting material, the compounds shown in Table II were obtained
and identified by NMR and mass spectral analyses.
TABLE-US-00002 TABLE II ##STR00028## Ex. MS No R4 R5 R7 mp
(.degree. C.) m/z 28 H C.sub.2H.sub.5 Br -- 378 29 H C.sub.2H.sub.5
pyrimidin-5-yl 144-146 378 30 CH.sub.3 C.sub.2H.sub.5 Br -- 392 31
CH.sub.3 C.sub.2H.sub.5 pyrimidin-5-yl 128-134 392 32 H Cl
pyrimidin-5-yl 236-240 384 33 H H 3-pyrazin-2-yl 223 350 34 H H
2-F-pyridin-3-yl 213 365 35 H H 6-F-pyridin-3-yl 228 365 36 H H
6-F-2-CH.sub.3-pyridin-3-yl 140 381 37 H H 5-CH.sub.3O-pyridin-3-yl
197 377
Examples 38-40
Preparation of
2-Amino-3-methyl-5-(4-fluoro-3-pyridin-3-ylphenyl)-5-thien-3-ylimidazolon-
e Compounds
##STR00029##
[0257] Using essentially the same procedure described in Example 27
and employing the thien-3-yl carboxylic acid and
3-bromo-4-fluorophenylalkyne as starting materials, the compounds
shown in Table III were obtained and identified by NMR and mass
spectral analyses.
TABLE-US-00003 TABLE III ##STR00030## Ex. mp MS No R7 (.degree. C.)
m/z 38 2-CH.sub.3O-pyridin-3-yl -- 397 39 2-F-pyridin-3-yl -- 385
40 pyridin-3-yl -- 367
Example 41
Preparation of
2-Amino-3-methyl-5-(3-pyrimidin-5-ylphenyl)-5-(1,3-thiazol-4-yl)-3,5-dihy-
dro-4H-imidazol-4-one
##STR00031##
[0258] Step a) Preparation of Compound 2
[0259] A mixture of 2,4-thiazolidinedione 1 (2.28 g, 19.5 mmol) and
phosphorous oxybromide (25.0 g, 87.0 mmol) was heated at
130.degree. C. for 30 min, then cooled to room temperature. The
reaction was diluted with ice water (300 mL) and carefully
neutralized by the addition of solid sodium carbonate in small
portions. Once neutral, the mixture was extracted with
dichloromethane (3.times.150 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated. Purification
of the residue by flash chromatography (silica, 0:100 to 5:95 ethyl
acetate/hexanes) afforded 2 (3.34 g, 71%) as light yellow crystals:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.21 (s, 1H).
Step b) Preparation of Compound 3
[0260] A solution of 2 (1.10 g, 4.53 mmol) in diethyl ether (8 mL)
was added dropwise to a solution of n-BuLi (2.1 mL of a 2.5 M
solution in hexanes, 5.3 mmol) at -78.degree. C. over 25 min. The
mixture was stirred for 1 h at -78.degree. C., then a solution of
chlorotrimethylsilane (0.585 g, 5.38 mmol) in diethyl ether (3 mL)
was added dropwise over 20 min. The mixture was stirred for an
additional 30 min at -78.degree. C. then quenched by addition of
saturated aqueous sodium bicarbonate (20 mL). After warming to room
temperature, diethyl ether (100 mL) and water (50 ml) were added,
the layers were separated and the aqueous layer was extracted with
diethyl ether (2.times.50 mL). The combined organic extracts were
dried over sodium sulfate, filtered and concentrated to afford 3
(0.95 g, 88%) as a red oil: .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.41 (s, 1H), 0.43 (s, 9H).
Step c) Preparation of Compound 4
[0261] A solution of 3 (0.950 g, 4.02 mmol) in diethyl ether (8 mL)
was added dropwise to a solution of n-BuLi (3.8 mL of a 1.6 M
solution in hexanes, 6.1 mmol) at -78.degree. C. over 20 min. The
mixture was stirred for 40 min at -78.degree. C., then a solution
of iodine (1.58 g, 6.22 mmol) in diethyl ether (15 mL) was added
dropwise over 20 min. The mixture was stirred for an additional 30
min at -78.degree. C. then quenched by addition of saturated
aqueous sodium bicarbonate (20 mL). After warming to room
temperature, diethyl ether (50 mL) and water (100 mL) were added,
the layers were separated and the aqueous layer was extracted with
diethyl ether (2.times.50 mL). The combined organic extracts were
dried over sodium sulfate, filtered and concentrated to afford 5
(1.28 g, >100%) as a red oil: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.73 (d, J=1.9 Hz, 1H), 7.51 (d, J=2.0 Hz, 1H).
Step d) Preparation of Compound 6
[0262] A mixture of crude 4 (1.27 g, 4.02 mmol), 3-bromophenyl
acetylene 5 (1.10 g, 6.07 mmol)
dichlorobis(triphenylphosphino)palladium(II) (0.115 g, 0.164 mmol),
copper(I) iodide (0.0248 g, 0.130 mmol), triethylamine (2.19 g,
21.6 mmol) in DMF (20 mL) was stirred at room temperature
overnight. The reaction was then diluted with ethyl acetate (500
mL) and washed with water (2.times.150 mL), 2% aqueous lithium
chloride (150 mL), dried over sodium sulfate, filtered, and
concentrated. Purification by flash chromatography (silica, 1:19 to
1:9 ethyl acetate/hexanes) afforded 6 (0.376 g, 35%) as a yellow
oil: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.82 (d, J=2.0 Hz,
1H), 7.72 (t, J=1.7 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.48-7.51 (m,
2H), 7.23 (t, J=8.0 Hz, 1H); ESI MS m/z 264
[C.sub.11H.sub.6BrNS+H].sup.+.
Step e) Preparation of Compound 7
[0263] The reaction of 6 (0.236 g, 0.893 mmol) with potassium
permanganate was carried out as described above to afford 7 (0.134
g, 50%) as a yellow solid: .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.90 (d, J=1.9 Hz, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.15 (t,
J=1.7 Hz, 1H), 7.92 (dt, J=7.7, 1.3 Hz, 1H), 7.77-7.80 (m, 1H),
7.40 (t, J=7.9 Hz, 1H); ESI MS m/z 296
[C.sub.11H.sub.6BrNO.sub.2S+H].sup.+.
Step f) Preparation of Compound 8
[0264] The reaction of 7 with methylguanidine hydrochloride was
carried out as described above to afford 8 (0.0965 g, 63%) as an
off-white solid: R.sub.f 0.22 (silica, 90:10:0.5 methylene
chloride/methanol/concentrated ammonium hydroxide); .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.01 (d, J=1.5 Hz, 1H), 7.84 (s,
1H), 7.67 (d, J=7.9 Hz, 1H), 7.50 (dd, J=8.0, 1.0 Hz, 1H), 7.32 (t,
J=7.9 Hz, 1H), 7.16 (s, 1H), 6.73 (br s, 2H), 2.98 (s, 3H); ESI MS
m/z 351, 353 [C.sub.13H.sub.11BrN.sub.4OS+H].sup.+.
Step g) Preparation of
2-Amino-3-methyl-5-(3-pyrimidin-5-ylphenyl)-5-(1,3-thiazol-4-yl)-3,5-dihy-
dro-4H-imidazol-4-one
[0265] The reaction of 8 with 5-pyrimidine boronic acid was carried
out as described above to afford the title product (0.029 g, 27%)
as a white solid: mp 234-237.degree. C.; .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 9.10 (s, 1H), 8.92 (s, 2H), 8.80 (d, J=2.0 Hz,
1H), 7.88-7.92 (m, 1H), 7.76-7.82 (m, 1H), 7.49-7.54 (m, 2H),
7.35-7.42 (m, 1H), 3.16 (s, 3H); ESI MS m/z 351
[C.sub.17H.sub.14N.sub.6OS+H].sup.+;
Example 42
Preparation of
2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-5-(3-pyrimidin-5-yl)-3,5-dih-
ydro-4H-imidazol-4-one
##STR00032##
[0266] Step a) Preparation of Compound 10
[0267] Sodium hydride (0.11 g of a 60% dispersion in oil, 2.84
mmol) was washed with hexanes, diluted with THF (2 mL) and treated
with a solution of 9 (0.50 g, 2.58 mmol) in THF (1 mL) over a
period of 5 min. After stirring for 35 min at room temperature, a
solution of 2-(trimethylsilyl)ethoxymethyl chloride (0.52 g, 3.10
mmol) in THF (1 mL) was added dropwise over a period of 2 min and
the mixture stirred at room temperature for 4.5 h. The mixture was
diluted with ether (20 mL) then washed with water (10 mL), brine 10
mL), dried over magnesium sulfate, filtered and concentrated to
afford 10 (0.85 g, 100%) as an amber oil: .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.65 (s, 1H), 7.55 (s, 1H), 5.41 (s, 2H), 3.58
(m, 2H), 0.91 (m, 2H), 0.50 (s, 9H); ESI MS m/z 325
[C.sub.9H.sub.17IN.sub.2OSi+H].sup.+.
Step b) Preparation of Compound 11
[0268] A mixture of 10 (0.214 g, 0.660 mmol), 3-bromophenyl
acetylene (0.144 g, 0.795 mmol),
bis(triphenylphosphino)palladium(II) chloride (0.023 g, 32.9
.mu.mol), copper(I) iodide (0.004 g, 20.0 .mu.mol) and
triethylamine (0.372 g, 3.68 mmol) in DMF (4 mL) was heated at
90.degree. C. for 30 min. The mixture was cooled to room
temperature, ethyl acetate (200 mL) was added, and the solution
washed with water (100 mL) and 2% aqueous lithium chloride
(2.times.75 mL). The organic layer was then dried over sodium
sulfate, filtered, and concentrated. Purification by flash
chromatography (silica, 5:95 ethyl acetate/hexanes) afforded 11
(0.149 g, 60%) as a red oil: .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.77 (s, 1H), 7.70 (s, 1H), 7.65 (t, J=1.7 Hz, 1H),
7.47-7.44 (m, 1H), 7.43-7.40 (m, 2H), 7.21 (t, J=7.9 Hz, 1H), 5.43
(s, 2H), 3.59 (t, J=8.2 Hz, 2H), 0.93 (t, J=8.3 Hz, 2H), 0.01 (s,
9H); ESI MS m/z 377 [C.sub.17H.sub.21BrN.sub.2OSi+H].sup.+.
Step c) Preparation of Compound 12
[0269] The reaction of 11 (0.393 g, 1.04 mmol) with potassium
permanganate was performed as described in Example 27, Step c, to
afford 12 (0.228 g, 53%) as a yellow solid: .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 8.27 (s, 1H), 8.22 (t, J=1.7 Hz, 1H), 8.13 (s,
1H), 8.01 (dt, J=7.8, 1.2 Hz, 1H), 7.80-7.77 (m, 1H), 7.41 (t,
J=7.9 Hz, 1H), 5.48 (s, 2H), 3.64 (t, J=8.3 Hz, 2H), 0.94 (t, J=8.3
Hz, 2H), 0.01 (s, 9H); ESI MS m/z 409
[C.sub.17H.sub.21BrN.sub.2O.sub.3Si+H].sup.+.
Step d) Preparation of Compound 13
[0270] The reaction of 12 (0.226 g, 0.552 mmol) with
1-methylguanidine hydrochloride was performed as described in
Example 27, Step d, to afford 13 (0.207 g, 80%) as an off-white
solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.71 (s, 1H), 7.64
(s, 1H), 7.58 (s, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.43 (d, J=7.9 Hz,
1H), 7.21 (t, J=7.9 Hz, 1H), 5.40 (s, 2H), 5.18 (br s, 2H), 3.59
(t, J=8.2 Hz, 2H), 0.92 (t, J=8.2 Hz, 2H), -0.01 (s, 9H); APCI MS
m/z 466 [C.sub.19H.sub.26BrN.sub.5O.sub.2Si+H].sup.+.
Step e) Preparation of Compound 14
[0271] The reaction of 13 with 5-pyrimidineboronic acid was
performed as described in Example 27, Step e, to afford 14 (0.039
g, 81%) as a light yellow solid: .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 9.20 (s, 1H), 8.92 (s, 2H), 7.76 (s, 1H), 7.68-7.64 (m,
2H), 7.59 (s, 1H), 7.50-7.46 (m, 2H), 5.37 (s, 2H), 3.56 (t, J=8.1
Hz, 2H), 3.12 (s, 3H), 0.88 (t, J=8.2 Hz, 2H), -0.05 (s, 9H). ESI
MS m/z 464 [C.sub.23H.sub.29N.sub.7O.sub.2Si+H].sup.+.
Step f) Preparation of Compound 15
[0272] A mixture of 14 (0.097 g, 0.209 mmol) in methanol (5 mL) was
treated with hydrochloric acid (5 mL of a 4 N solution, 20 mmol)
and heated to reflux for 24 h. The mixture was concentrated, the
residue was re-dissolved in toluene (5 mL), and again concentrated.
Purification by flash chromatography (90:10:0.5 methylene
chloride/methanol/concentrated ammonium hydroxide) afforded 15
(0.033 g, 47%) as an off-white solid: .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 9.12 (s, 1H), 9.01 (s, 2H), 7.74 (t, J=1.7 Hz,
1H), 7.64 (dd, J=7.6, 1.3 Hz, 1H), 7.61-7.58 (m, 3H), 7.52 (t,
J=7.7 Hz, 1H), 3.12 (s, 3H); ESI MS m/z 334
[C.sub.17H.sub.15N.sub.7O+H].sup.+.
Step g) Preparation of
2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-5-(3-pyrimidin-5-yl)-3,5-dih-
ydro-4H-imidazol-4-one
[0273] A mixture of sodium hydride (0.004 g, 0.098 mmol) in
dimethylformamide (1.2 mL) was treated with a solution of 15 (0.030
g, 0.090 mmol), and the mixture was stirred for 20 min. Iodoethane
(0.016 g, 1.01 mmol) was added, and the mixture was stirred at rt
for 90 min. Ethyl acetate (20 mL) and 2% aqueous lithium chloride
(20 mL) were added, and the layers were separated. The aqueous
layer was extracted with ethyl acetate (2.times.10 mL), and the
combined organic extracts were dried over sodium sulfate, filtered,
and concentrated. Purification by flash chromatography (95:5:0.5
methylene chloride/methanol/concentrated ammonium hydroxide)
afforded the title product (0.009 g, 28%) as an off-white solid: mp
143-147.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.13
(s, 1H), 9.01 (s, 2H), 7.77-7.74 (m, 1H), 7.65 (d, J=7.6 Hz, 1H),
7.62-7.59 (m, 2H), 7.52 (t, J=7.7 Hz, 1H), 7.45 (s, 1H), 4.15 (q,
J=7.3 Hz, 2H), 3.12 (s, 3H), 1.42 (t, J=7.3 Hz, 3H); ESI MS m/z 362
[C.sub.19H.sub.19N.sub.7O+H].sup.+;
Example 43
Preparation of
2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)-5-[3-(2-fluoro-pyridin-3-yl)-phenyl]--
3-methyl-3,5-dihydro-imidazol-4-one
##STR00033##
[0274] Step a) Preparation of Compound 18
[0275] Sodium hydride (0.476 g of a 60% dispersion in oil, 2.84
mmol) was washed with hexanes, diluted with THF (7 mL) and treated
with a solution of 17 (1.99 g, 10.3 mmol) in THF (4 mL) over a
period of 15 min. After stirring for 4 h at room temperature, a
solution of iodoethane (3.12 g, 20.0 mmol) in THF (3 mL) was added
dropwise over a period of 10 min and the mixture stirred at room
temperature for 3 h. The mixture was diluted with ether (75 mL) and
water (75 mL), the layers were separated and the aqueous layer was
extracted with ether (2.times.50 mL). The combined organic extracts
were washed with brine (50 mL), dried over sodium sulfate, filtered
and concentrated. Purification by flash chromatography (silica,
10:90 to 20:80 ethyl acetate/hexanes) afforded 18 (1.36 g, 59%) as
an off-white solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.50
(s, 1H), 7.44 (s, 1H), 4.18 (q, J=7.4 Hz, 2H), 1.48 (t, J=7.3 Hz,
3H); ESI MS m/z 223 [C.sub.5H.sub.7IN.sub.2+H].sup.+.
Step b) Preparation of Compound 19
[0276] A mixture of 18 (1.36 g, 6.13 mmol), 3-bromophenyl acetylene
(1.40 g, 7.73 mmol), bis(triphenylphosphino)palladium(II) chloride
(0.132 g, 0.188 mmol), copper(I) iodide (0.025 g, 0.132 mmol) and
triethylamine (3.21 g, 31.7 mmol) in DMF (24 mL) was stirred at
room temperature for 90 min. Ethyl acetate (500 mL) was added, and
the solution washed with water (150 mL) and 2% aqueous lithium
chloride (2.times.100 mL). The organic layer was then dried over
sodium sulfate, filtered, and concentrated. Purification by flash
chromatography (silica, 10:90 to 20:80 ethyl acetate/hexanes)
afforded 19 (1.09 g, 64%) as a reddish-brown solid: .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 7.65 (s, 1H), 7.62 (t, J=1.7 Hz, 1H),
7.59 (s, 1H), 7.44-7.41 (m, 1H), 7.39 (dt, J=7.8, 1.2 Hz, 1H), 7.19
(t, J=7.9 Hz, 1H), 4.18 (q, J=7.3 Hz, 2H), 1.50 (t, J=7.3 Hz, 3H);
ESI MS m/z 275 [C.sub.13H.sub.11BrN.sub.2+H].sup.+.
Step c) Preparation of Compound 20
[0277] To a stirred solution of 19 (1.08 g, 3.92 mmol) in acetone
(100 mL) was added a solution of sodium bicarbonate (0.210 g, 2.50
mmol) and magnesium sulfate (0.942 g, 7.82 mmol) in water (40 mL),
followed by potassium permanganate (1.25 g, 7.91 mmol) in one
portion. The reaction mixture was stirred for 45 min, diluted with
1:1 hexanes/ethyl acetate (150 mL) and water (75 mL), and the
solids were removed by filtration. The aqueous layer was separated
and extracted with 1:1 hexanes/ethyl acetate (2.times.75 mL). The
combined organic layers were then dried over sodium sulfate,
filtered and concentrated. The crude material was purified by flash
chromatography (silica, 85:15 to 75:25 hexanes/ethyl acetate) to
afford 20 (0.928 g, 77%) as a yellow solid: .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 8.20 (t, J=1.7 Hz, 1H), 8.08 (s, 2H), 7.99 (dt,
J=7.8, 1.2 Hz, 1H), 7.78-7.75 (m, 1H), 7.39 (t, J=7.9 Hz, 1H), 4.23
(q, J=7.3 Hz, 2H), 1.54 (t, J=7.3 Hz, 3H); ESI MS m/z 307
[C.sub.13H.sub.11BrN.sub.2O.sub.2+H].sup.+.
Step d) Preparation of Compound 21
[0278] A mixture of 20 (0.926 g, 3.01 mmol) and 1-methylguanidine
hydrochloride (1.49 g, 13.6 mmol) in dioxane (40 mL) and ethanol
(35 mL) was stirred at room temperature for 5 min. A solution of
sodium carbonate (1.45 g, 13.7 mmol) in water (15 mL) was then
added and the mixture immersed into an 85.degree. C. oil bath and
stirred for 25 min. The mixture was cooled to room temperature,
concentrated and the residue partitioned between methylene chloride
(75 mL) and water (75 mL). The organic layer was separated, washed
with brine (50 mL), dried over sodium sulfate, filtered and
concentrated. The crude material was purified by flash
chromatography (silica, 96:4:0.5 methylene
chloride/methanol/concentrated ammonium hydroxide) to afford a
viscous oil. This oil was dissolved in a minimal amount of
methylene chloride, treated with hexanes and then concentrated to
afford 21 (0.763 g, 70%) as an off-white solid: .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 7.58-7.55 (m, 2H), 7.44-7.41 (m, 3H), 7.24
(t, J=7.9 Hz, 1H), 5.40 (s, 2H), 4.14 (q, J=7.3 Hz, 2H), 3.09 (s,
3H), 1.41 (t, J=7.3 Hz, 3H); APCI MS m/z 362
[C.sub.15H.sub.16BrN.sub.5O+H].sup.+.
Step e) Preparation of Compound 22
[0279] A mixture of 21 (0.152 g, 0.420 mmol),
2-fluoropyridine-3-boronic acid (0.072 g, 0.511 mmol) and
tetrakis(triphenylphosphino)palladium(0) (0.026 g, 22.2 .mu.mol) in
dioxane (4.2 mL) was treated with a solution of potassium carbonate
(0.185 g, 1.34 mmol) in water (0.8 mL), then heated at reflux for
35 min. The mixture was cooled to room temperature, concentrated
and the residue partitioned between methylene chloride (50 mL) and
water (50 mL). The layers were separated and the aqueous layer was
extracted with methylene chloride (2.times.25 mL). The combined
organic extracts were dried over sodium sulfate, filtered and
concentrated. Purification by flash chromatography (silica,
96:4:0.5 to 93:7:0.5 methylene chloride/methanol/concentrated
ammonium hydroxide) afforded (22 (0.109 g, 68%) as a white solid:
R.sub.f 0.40 (90:10:0.5 methylene chloride/methanol/concentrated
ammonium hydroxide); mp 122-127.degree. C.; .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 8.17 (d, J=4.6 Hz, 1H), 8.02-7.98 (m, 1H), 7.65
(d, J=1.4 Hz, 1H), 7.60 (s, 1H), 7.52 (m, 2H), 7.47-7.43 (m, 2H),
7.41-7.38 (m, 1H), 4.15 (q, J=7.3 Hz, 2H), 3.10 (s, 3H), 1.42 (t,
J=7.3 Hz, 3H); IR (ATR) 3344, 3066, 1665, 1466, 1433, 1399, 1330
cm.sup.-1; ESI MS m/z 379 [C.sub.20H.sub.19FN.sub.6O+H].sup.+;
Example 44
Preparation of
(5R)-2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)-5-[3-(2-fluoropyridin-3-yl)pheny-
l]-3-methyl-3,5-dihydro-4H-imidazol-4-one (A) and
(5S)-2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)-5-[3-(2-fluoropyridin-3-yl)pheny-
l]-3-methyl-3,5-dihydro-4H-imidazol-4-one (B)
##STR00034##
[0281] A racemic mixture of
2-amino-5-(1-ethyl-1H-pyrazol-4-yl)-5-[3-(2-fluoro-pyridin-3-yl)-phenyl]--
3-methyl-3,5-dihydro-imidazol-4-one was separated by chiral HPLC to
give the title enantiomeric products: A
(5R)-2-amino-5-(1-ethyl-1H-pyrazol-4-yl)-5-[3-(2-fluoropyridin-3-yl)pheny-
l]-3-methyl-3,5-dihydro-4H-imidazol-4-one, .sup.1H NMR (DMSOd.sub.6
300 MHz) .delta. 1.1 (t, 3H), 2.95 (s, 3H), 4.05 (q, 2H), 6.28 (s,
1H), 6.35-6.45 (m, 3H), 7.55 (m, 2H), 7.7 (m, 1H), 7.95-8.0 (m,
1H), 8.2 (dd, 1H); MS m/e (M+H).sup.+ 379 and B
(5S)-2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)-5-[3-(2-fluoropyridin-3-yl)pheny-
l]-3-methyl-3,5-dihydro-4H-imidazol-4-one, .sup.1H NMR (DMSOd.sub.6
300 MHz) .delta. 1.1 (t, 3H), 2.95 (s, 3H), 4.05 (q, 2H), 6.28 (s,
2H), 6.35-6.45 (m, 3H), 7.55 (m, 2H), 7.7 (m, 1H), 7.95-8.0 (m,
1H), 8.2 (dd, 1H); MS m/e (M+H).sup.+ 379
Example 45
Preparation of
2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)-5-[3-(5-fluoro-pyridin-3-yl)-phenyl]--
3-methyl-3,5-dihydro-imidazol-4-one
##STR00035##
[0283] A mixture of
2-amino-5-(1-ethyl-1H-pyrazol-4-yl)-5-[3-bromophenyl]-3-methyl-3,5-dihydr-
o-imidazol-4-one (0.153 g, 0.422 mmol), 23 (0.256 g, 0.663 mmol)
and bis(triphenylphosphino)palladium(II) chloride (0.019 g, 27.2
.mu.mol) in DMF (6.5 mL) was heated at 150.degree. C. in a sealed
tube for 70 min. The mixture was cooled to room temperature,
diluted with ethyl acetate (150 mL) and washed with water (75 mL)
and 2% lithium chloride (2.times.50 mL). The organic layer was
dried over sodium sulfate, filtered and concentrated. Purification
by flash chromatography (silica, 95:5:0.5 methylene
chloride/methanol/concentrated ammonium hydroxide) afforded the
title product (0.067 g, 42%) as an off-white solid: mp
216-220.degree. C.; .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.63
(s, 1H), 8.44 (d, J=2.6 Hz, 1H), 7.86 (dt, J=9.8, 1.6 Hz, 1H), 7.72
(s, 1H), 7.64-7.55 (m, 3H), 7.51-7.43 (m, 2H), 4.15 (q, J=7.3 Hz,
2H), 3.11 (s, 3H), 1.41 (t, J=7.3 Hz, 3H); IR (ATR) 3120, 1732,
1683, 1474, 1431, 1387, 1320 cm.sup.-1; ESI MS m/z 379
[C.sub.20H.sub.19FN.sub.6O+H].sup.+;
Example 46
Preparation of
2-Amino-5-[3-(5-chloropyridin-3-yl)phenyl]-5-(1-ethyl-1H-pyrazol-4-yl)-3--
methyl-3,5-dihydro-imidazol-4-one
##STR00036##
[0285] A mixture of
2-amino-5-[3-bromophenyl]-5-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-3,5-dihydr-
o-imidazol-4-one (0.143 g, 0.395 mmol), 25 (0.239 g, 0.594 mmol)
and bis(triphenylphosphino)palladium(II) chloride (0.018 g, 25.5
.mu.mol) in DMF (6 mL) was heated at 150.degree. C. in a sealed
tube for 70 min. The mixture was cooled to room temperature,
diluted with ethyl acetate (150 mL) and washed with water (75 mL)
and 2% lithium chloride (2.times.50 mL). The organic layer was
dried over sodium sulfate, filtered and concentrated. Purification
by flash chromatography (silica, 95:5:0.5 methylene
chloride/methanol/concentrated ammonium hydroxide) afforded the
title product (0.064 g, 41%) as an off-white solid: mp
205-210.degree. C.; .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.68
(d, J=1.9 Hz, 1H), 8.53 (d, J=2.2 Hz, 1H), 8.10-8.07 (m, 1H), 7.71
(t, J=1.6 Hz, 1H), 7.63-7.54 (m, 3H), 7.51-7.44 (m, 2H), 4.14 (q,
J=7.3 Hz, 2H), 3.11 (s, 3H), 1.41 (t, J=7.3 Hz, 3H); IR (ATR) 3275,
3048, 1732, 1669, 1470, 1392, 1325 cm.sup.-1; ESI MS m/z 395
[C.sub.20H.sub.19ClN.sub.6O+H].sup.+;
Example 47
Preparation of
1-(3-bromophenyl)-2-(1H-pyrrol-3-yl)ethane-1,2-dione
##STR00037##
[0287] A solution of N-triisopropylsilylpyrrole (3.49 g, 1 mmol),
3-bromo-1-ethynylbenzene (1.81 g, 1 mmol), Pd(PPh.sub.3).sub.4 (800
mg) and CuI (185 mg) in CH.sub.3CN (15 ml) and triethylamine (35
ml) is refluxed for 5 h. The reaction mixture is cooled to room
temperature and the solvent is evaporated on a rotary evaporator.
The crude material is purified by flash chromatographied (silica
gel, 100% hexane) to afford
3-[(3-bromophenyl)ethynyl]-1-(triisopropylsilyl)-1H-pyrrole (2.7 g,
85%) as a clear oil.
[0288] To a solution of
3-[(3-bromophenyl)ethynyl]-1-(triisopropylsilyl)-1H-pyrrole (2.7 g,
8.5 mmol) in acetone (100 mml) is added a solution of MgSO.sub.4
(1.53 g, 12.75 mmol) and NaHCO.sub.3 (316 mg, 3.76 mmol) in water
(50 ml), followed by the addition of KMnO.sub.4 (2.68 g, 17 mmol)
in one portion at room temperature. After refluxing for 5 h, the
reaction mixture is cooled to room temperature and extracted with
ether (2.times.50 mL), the combined organic extracts are dried over
MgSO.sub.4. The crude material is purified flash chromatography
(silica gel, EtOAc/hexane: 30/70 to 50/50) to afford the title
compound as a yellow solid (42%). mp: 111-113.degree. C. MS (-) ES:
276 (M-H).sup.-.
Example 48
Preparation of
1-(3-bromophenyl)-2-(1-ethyl-1H-pyrrol-3-yl)ethane-1,2-dione
##STR00038##
[0290] The title compound is prepared by using essentially the same
procedure as in Example 1, step b, affording an oil (56%). MS (+)
ES: 306 (M+H).sup.+.
Example 49
Preparation of
1-(3-bromophenyl)-2-[1-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]ethane-1,2-d-
ione
##STR00039##
[0292] To a solution of
1-(3-bromophenyl)-2-(1H-pyrrol-3-yl)ethane-1,2-dione (93 mg, 0.33
mmol) in DMF (5.0 mL) was added 2,2,2-trifluoroethyl
4-methylbenzenesulfonate (170 mg, 0.66 mmol), K.sub.2CO.sub.3 (100
mg, 0.73 mmol) and Et.sub.4NCl (5.5 mg, 0.033 mmol) at room
temperature. After heating at 80.degree. C. for 3 days, the
reaction mixture is cooled, diluted with H.sub.2O, EtOAc. The two
layers are separated and the aqueous layer is extracted with EtOAc.
The combined organic extracts are washed with 1N HCl aqueous
H.sub.2O, brine, dried (MgSO.sub.4) and concentrated. The crude
material is purified by chromatography (silica gel, EtOAc/hexane:
20/80) to give the title compound (190 mg, 65%) as a solid. mp:
105-106.degree. C. MS (+) ES: 418 (M+CH.sub.3COO).sup.-.
Example 50
Preparation of
2-Amino-5-(3-bromophenyl)-5-(1-ethyl-1H-pyrrol-3-yl)-3-methyl-3,5-dihydro-
-4H-imidazol-4-one
##STR00040##
[0294] The title compound was prepared using essentially the same
procedure described in Example 21, step c, to give the title
product as a solid (82%), mp 138-140.degree. C., MS (+) ES: 361
(M+H).sup.+.
Example 51
Preparation of
2-Amino-5-(3-bromophenyl)-3-methyl-5-[1-(2,2,2-trifluoroethyl)-1H-pyrrol--
3-yl]-3,5-dihydro-4H-imidazol-4-one
##STR00041##
[0296] The title compound was prepared using essentially the same
procedure described in Example 21, step c, to give the title
product a solid (70%). mp: 74-76.degree. C. MS (+) ES: 415
(M+H).sup.+.
Example 52
Preparation of
2-amino-5-(1-ethyl-1H-pyrrol-3-yl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,-
5-dihydro-4H-imidazol-4-one
##STR00042##
[0298] To a solution of
2-amino-5-(3-bromophenyl)-5-(1-ethyl-1H-pyrrol-3-yl)-3-methyl-3,5-dihydro-
-4H-imidazol-4-one (80 mg, 0.22 mmol) in DME (3 mL) is added
pyrimidin-5-ylboronic acid (57 mg, 0.44 mmol),
tetrakis(triphenylphosphine)palladium (25 mg, 0.022 mmo) and a
solution sodium carbonate (93 mg, 0.88 mmol) in H.sub.2O (0.5 mL)
at room temperature. The reaction mixture is refluxed for 1 h and
cooled. After evaporation of the solvent, the crude material is
purified by chromatography (silica gel, EtOAc/2M ethanolic
NH.sub.3: 92/8) to give the title compound (60 mg, 75%) as a solid.
mp: 100-102.degree. C.; MS(+) ES: 361 (M+H).sup.+.
Examples 53-55
Preparation of
2-amino-5-(1-substituted-1H-pyrrol-3-yl)-5-(3-substituted-phenyl)-3-methy-
l-3,5-dihydro-4H-imidazol-4-one Compounds
##STR00043##
[0300] Using essentially the same procedure described in Example 52
and employing the appropriated 5-(3-bromophenyl)hydantoin and a
suitable boronic acid reagent, the compounds shown in Table IV were
obtained and identified by NMR and mass spectral analyses.
TABLE-US-00004 TABLE IV ##STR00044## Ex. mp No R R7 (.degree. C.) M
+ H 53 C.sub.2H.sub.5 2-fluoropyridin-2-yl 103-105 378 54
CH.sub.2CF.sub.3 pyrimidin-5-yl 103-105 415 55 CH.sub.2CF.sub.3
2-fluoropyridin-2-yl 104-106 432
Example 56
Preparation of 3-benzyloxy-1-ethynylbenzene
##STR00045##
[0302] A mixture of 3-hydroxy-1-ethynylbenzene (4.36 g, 37 mmol),
benzylbromide (6.95 g, 4.1 mmol) and K.sub.2CO.sub.3 (10.2 g, 7.4
mmol) in acetanitrile (50 ml) is stirred at room temperature for 24
hr. The insoluble material is removed by filtration and filtrate is
concentrated. The crude material is purified by flash
chromatography (silica gel, hexane/EtOAc: 95/5) to afford the title
compound as a clear oil 5.2 g (68%). .sup.1HNMR (400 MHz,
CDCl.sub.3): .delta. (ppm) 3.05 (s, 1H), 5.05 (s, 2H), 6.98 (d, 1H)
7.00-7.50 (m, 8H).
Example 57
Preparation of
1-[3-(benzyloxy)phenyl]-2-(1H-pyrrol-3-yl)ethane-1,2-dione
##STR00046##
[0304] The title compound was prepared using essentially the same
procedure described in Example 47 to give the title product as a
solid (29%) mp 124-125.degree. C., MS (+) ES: 306 (M+H).sup.+.
Example 58
Preparation of
2-amino-5-(3-benzyloxyphenyl)-5-(1H-pyrrol-3-yl)-3-methyl-3,5-dihydro-4H--
imidazol-4-one
##STR00047##
[0306] The title compound was prepared using essentially the same
procedure described in Example 21, step c, to give the title
product as a solid (38%) mp 98-100.degree. C. MS (+) ES: 361
(M+H).sup.+.
Example 59
Preparation of
2-amino-5-(3-hydroxyphenyl)-5-(1H-pyrrol-3-yl)-3-methyl-3,5-dihydro-4H-im-
idazol-4-one
##STR00048##
[0308] A mixture of
2-amino-5-(3-benzyloxyphenyl)-5-(1H-pyrrol-3-yl)-3-methyl-3,5-dihydro-4H--
imidazol-4-one (70 mg, 0.2 mmol) and Pd/C (8 mg) in ethanol (10 ml)
is hydrogenated at 45 psi overnight. The catalyst is removed by
filtration and the filtrate is concentrated. The crude material is
purified by flash chromatography (silica gel, EtOAc/2.0M ethanolic
NH.sub.3: 90/10 to 80/20) to afford the title compound as a solid,
49 mg (93%) mp 142-145.degree. C., MS (+) ES: 271 (M+H).sup.+.
Example 60
Preparation of 3-(3-ethynylphenyl)-2-fluoropyridine
##STR00049##
[0310] To a solution of [(3-bromophenyl)ethynyl](trimethyl)silane
(2.28 g, 9.0 mmol) in DME (150 mL) is added
(2-fluoropyridin-3-yl)boronic acid (1.41 g, 10.0 mmol),
tetrakis(triphenylphosphine)palladium (0.52 g, 0.5 mmol) and a
solution of sodium carbonate (3.8 g, 36.0 mmol) in H.sub.2O (15 mL)
at room temperature. After refluxing for 3 h, the reaction mixture
is cooled, quenched with saturated sodium carbonate, diluted with
EtOAc. The two layers are separated and the aqueous layer is
extracted with EtOAc. The combined organic extracts are washed with
brine, dried (MgSO.sub.4) and concentrated. The crude mixture is
purified by chromatography (silica gel, EtOAc/hexane: 5/95) to give
the 2-fluoro-3-{3-[(trimethylsilyl)ethynyl]phenyl}pyridine (2.25 g,
91%) as an oil. MS(+) APPI: 270 (M+H).sup.+.
[0311] To a solution of
2-fluoro-3-{3-[(trimethylsilyl)ethynyl]phenyl}pyridine (2.20 g, 8.1
mmol) in MeOH/CH.sub.2Cl.sub.2 (1/1, 60 mL) is added
Cs.sub.2CO.sub.3 (3.17 g, 9.7 mmol) at room temperature. After
stirring for 1 h, the reaction mixture is diluted with
CH.sub.2Cl.sub.2 and passed through a thin layer of silica gel. The
solution is concentrated and the crude material is purified by
chromatography (silica gel, EtOAc/hexane: 20/80) to give the title
compound (1.23 g, 77%) as a solid. mp: 45-47.degree. C. MS (+) EI:
198 M.sup.+.
Example 61
Preparation of 1-(cyclopropylmethoxy)-3-ethynylbenzene
##STR00050##
[0313] To a solution of 3-ethynylphenol (1.18 g, 10.0 mmol) in
acetone (30 mL) is added (bromomethyl)cyclopropane (1.02 mL, 10.0
mmol), sodium iodide (0.75 g, 5.0 mmol) and Cs.sub.2CO.sub.3 (6.52
g, 20.0 mmol) at room temperature. After refluxing over night, the
reaction mixture is cooled, diluted with Et.sub.2O (300 mL) and
pass through a thin layer of silica gel. The solution is
concentrated. The crude material is purified by chromatography
(silica gel, EtOAc/hexane: 1/99) to give the title compound (1.45
g, 84%) as an oil. MS(+) APPI: 173 (M+H).sup.+.
Example 62
Preparation of 1-(2-fluoroethyl)-4-iodo-1H-pyrazole
##STR00051##
[0315] A solution of 4-iodo-1H-pyrazole (1.10 g, 5.7 mmol) in
anhydrous DMF (25 mL) is treated with NaH (0.23 g, 60% in mineral
oil, 5.7 mmol). After stirring for 20 minutes at room temperature,
the reaction mixture is treated with 1-iodo-2-fluoroethane (1.0 g,
5.7 mmol) and stirred over night at room temperature. The reaction
is quenched with H.sub.2O and diluted with EtOAc. The two layers
are separated and the aqueous is extracted with EtOAc. The combined
organic extracts are washed with H.sub.2O, brine, dried
(Na.sub.2SO.sub.4) and concentrated. The crude material is purified
by chromatography (silica gel, EtOAc/hexane: 15/85) to afford the
title compound (1.08 g, 79%) as an oil. MS (+) ES 240
(M+H).sup.+.
Example 63
Preparation of 4-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazole
##STR00052##
[0317] A mixture of 4-iodo-1H-pyrazole (960 mg, 5 mmol),
2,2,2-trifluoroethyl iodide (3.13 g, 15 mmol) and
Cs.sub.2CO.sub.3(2.4 g, 7.7 mmol) in DMF (5 ml) is heated at
60.degree. C. with stirring overnight. After cooling, the reaction
mixture is partitioned between water (50 ml) and ether (20 ml). The
organic layer is separated, dried (MgSO.sub.4) and concentrated to
afford the title compound as an oil which solidified upon standing
1.0 g (72%). .sup.1HNMR (CDCl.sub.3): .delta. (ppm) 4.70 (m, 2H),
7.56 (s, 1H), 7.59 (s, 1H).
Example 64
Preparation of
2-fluoro-3-(3-{[1-(2-fluoroethyl)-1H-pyrazol-4-yl]ethynyl}phenyl)pyridine
##STR00053##
[0319] To a solution of 1-(2-fluoroethyl)-4-iodo-1H-pyrazole (148
mg, 0.62 mmol) in DMF (5.0 mL) is added
dichlorobis(triphenylphosphine)palladium (16 mg, 0.022 mmol),
copper iodide (3 mg, 0.015 mmol), TEA (0.53 mL, 3.8 mmol) and
3-(3-ethynylphenyl)-2-fluoropyridine (150 mg, 0.76 mmol). The
reaction mixture is heated at 65.degree. C. for 3 h, cooled and
quenched with H.sub.2O. The aqueous layer is extracted with EtOAc.
The combined organic extracts are washed with brine, dried
(MgSO.sub.4) and concentrated. The crude material is purified by
chromatography (silica gel, EtOAc/hexane: 30/70) to afford the
title compound (145 mg, 76%) as an oil. MS (+) ES: 310
(M+H).sup.+.
Example 65
Preparation of
2-fluoro-3-(3-{[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]ethynyl}phenyl)p-
yridine
##STR00054##
[0321] The title compound was prepared using essentially the same
procedure described in Example 64 to give the title compound as an
oil (59%) MS (+) ES: 346 (M+H).sup.+.
Example 66
Preparation of
4-{[3-(cyclopropylmethoxy)phenyl]ethynyl}-1-(2-fluoroethyl)-1H-pyrazole
##STR00055##
[0323] The title compound was prepared using essentially the same
procedure described in Example 64 to give the title compound as an
oil (72%). MS (+) ES: 285 (M+H).sup.+.
Example 67
Preparation of
4-{[3-(cyclopropylmethoxy)phenyl]ethynyl}-1-(2,2,2-trifluoroethyl)-1H-pyr-
azole
##STR00056##
[0325] The title compound was prepared using essentially the same
procedure described in Example 64 to give the title compound as a
solid (81%) mp: 63-65.degree. C., MS (+) ES: 346 (M+H).sup.+.
Example 68
Preparation of
2-amino-5-[1-(2-fluoroethyl)-1H-pyrazol-4-yl-5-[3-(2-fluoropyridin-3-yl)p-
henyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
##STR00057##
[0327] To a solution of
2-fluoro-3-(3-{[1-(2-fluoroethyl)-1H-pyrazol-4-yl]ethynyl}phenyl)pyridine
(140 mg, 0.45 mmol) in acetone (7 mL) is added a warm
(.about.40.degree. C.) solution of NaHCO.sub.3 (23 mg, 0.27 mmol)
and MgSO.sub.4 (82 mg, 0.68 mmol) in H.sub.2O (7 mL) followed by
the addition of solid potassium permanganate (156 mg, 0.99 mmol) in
one portion. After stirring at room temperature for 30 minutes, the
reaction mixture is extracted with Et.sub.2O/hexane (1/1) until no
product left in aqueous layer. The combined organic extracts are
dried (MgSO.sub.4) and concentrated to dryness to afford
1-[1-(2-fluoroethyl)-1H-pyrazol-4-yl]-2-[3-(2-fluoropyridin-3-yl)phenyl]e-
thane-1,2-dione (95 mg, 62%) as an oil. MS (+) ES: 342
(M+H).sup.+.
[0328] To a solution of
1-[1-(2-fluoroethyl)-1H-pyrazol-4-yl]-2-[3-(2-fluoropyridin-3-yl)phenyl]e-
thane-1,2-dione (90 mg, 0.26 mmol) in EtOH (5.0 mL) is added
N-methylguanidine hydrochloride (31 mg, 0.29 mmol) and a solution
of Na.sub.2CO.sub.3 (54 mg, 0.52 mmol) in H.sub.2O (0.5 mL). After
refluxing for 2 h, the solvent is removed on a rotary evaporator.
The crude mixture is purified by chromatography (silica gel,
EtOAc/2.0M methanolic NH.sub.3: 90/10) to give the title compound
(74 mg, 72%) as a solid. mp: 195-197.degree. C. MS (-) ES: 395
(M-H).sup.-.
Example 69
Preparation of
2-amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[1-(2,2,2-trifluoro-
ethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one
##STR00058##
[0330] The title compound was prepared using essentially the same
procedure described in Example 68 to give the title compound as an
oil (77%) mp: 104-106.degree. C., MS (-) ES: 431 (M-H).sup.-.
Example 70
Preparation of
2-amino-5-[3-(cyclopropylmethoxy)phenyl]-5-[1-(2-fluoroethyl)-1H-pyrazol--
4-yl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
##STR00059##
[0332] The title compound was prepared using essentially the same
procedure described in Example 68 to give the title compound as an
oil (78%). mp: 70-72.degree. C. MS (-) ES: 370 (M-H).sup.-.
Example 71
Preparation of
2-amino-5-[3-(cyclopropylmethoxy)phenyl]-3-methyl-5-[1-(2,2,2-trifluoroet-
hyl)-1H-pyrazol-4-yl-3,5-dihydro-4H-imidazol-4-one
##STR00060##
[0334] The title compound was prepared using essentially the same
procedure described in Example 68 to give the title compound as an
oil (73%) mp 78-80.degree. C., MS (+) ES: 408 (M+H).sup.+.
Example 72
Preparation of 1-(Difluoromethoxy)-4-ethynylbenzene
##STR00061##
[0336] A solution of 1-(difluoromethoxy)-4-iodobenzene (12.7 g, 50
mmol) in triethylamine (175 mL) was treated with
tetrakis(triphenylphosphine)palladium (4.0 g, 3.5 mmol), copper
iodide (925 mg, 4.85 mmol), and a solution of
ethynyl(trimethyl)silane (6.9 mL, 50 mmol) in acetonitrile at room
temperature, stirred for 1 h at 60.degree. C. and concentrated in
vacuo. The resultant residue was dissolved in Et.sub.2O, filtered
and the filtrated was concentrated in vacuo. This residue was
purified by chromatography (silica gel, EtOAc/hexane: 5/95) to give
([4-(difluoromethoxy)-phenyl]ethynyl}(trimethyl)silane (11.5 g,
96%) as an oil.
[0337] A solution of
{[4-(difluoromethoxy)phenyl]ethynyl}(trimethyl)silane (10.0 g, 41.7
mmol) in MeOH/CH.sub.2Cl.sub.2 (1/1) was treated with cesium
carbonate (16.3 g, 50 mmol) at room temperature, stirred for 1.5 h,
diluted with CH.sub.2Cl.sub.2 and filtered through a pad of silica
gel. The filtrate was concentrated to dryness to give the title
compound (6.8 g, 97%) as an oil, identified by NMR and mass
spectral analyses. MS (+) EI:168.
Examples 73-78
Preparation of
2-amino-5-[4-(difluoromethoxy)phenyl]-5-heteroaryl-3-methyl-3,5-dihydro-4-
H-imidazol-4-one Compounds
##STR00062##
[0339] Using essentially the same procedure described in Example 68
and employing 1-(difluoromethoxy)-4-ethynylbenzene and the desired
iodoheteroaryl reagent, the compounds shown in Table V were
obtained and identified by NMR and mass spectral analyses.
TABLE-US-00005 TABLE V ##STR00063## Ex. mp No X Y R R5 .degree. C.
M + H 73 NR N 2-fluoroethyl H 140-142 368 74 NR N
2,2,2-trifluoroethyl H 70-72 404 75 NR N benzyl H 74-76 412 76 NR N
pentyl H 138-140 392 77 NR CH H propionyl 108-110 377 78 NR CH
methyl propionyl 171-173 389* *(M - H).sup.-
Example 79
Preparation of
4-[(3-bromophenyl)ethynyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole
##STR00064##
[0341] To a solution of 4-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazole
(4.14 g, 15 mmol) in triethylamine (53 mL) is added
tetrakis(triphenylphosphine)paddadium (1.20 g, 1.04 mmol), copper
iodide (0.28 g, 1.46 mmol) and a solution of
1-bromo-3-ethynylbenzene (2.78 g, 15 mmol) in acetonitrile (15 mL)
at room temperature. After heating for 1 hour at 80.degree. C., the
reaction mixture is cooled and concentrated. The crude material is
purified by chromatography (silica gel, EtOAc/hexane: 5/95) to give
the title compound as a solid (4.91 g, 99%). mp: 107-109.degree. C.
MS (+) EI: 328 M.sup.+.
Example 80
Preparation of
1-(3-bromophenyl)-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]ethane-1,2--
dione
##STR00065##
[0343] To a solution of
4-[(3-bromophenyl)ethynyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole
(4.90 g, 14.9 mmol) in acetone (150 mL) is added a warm
(.about.40.degree. C.) solution of NaHCO.sub.3 (0.75 g, 8.9 mmol)
and MgSO.sub.4 (2.70 g, 22.4 mmol) in H.sub.2O (150 mL) followed by
the addition of solid potassium permanganate (5.2 g, 32.8 mmol) in
one portion. After stirring for 40 minutes at room temperature, the
reaction mixture is extracted with a solution of Et.sub.2O/hexane
(1/1) until no product left in aqueous layer. The combined organic
extracts is dried (MgSO.sub.4) and concentrated to dryness to
afford the title compound (4.4 g, 82%) as a solid. mp:
66-67.degree. C. MS (-) ES: 359 (M-H).sup.-.
Example 81
Preparation of
2-amino-5-(3-bromophenyl)-3-methyl-5-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-
-4-yl]-3,5-dihydro-4H-imidazol-4-one
##STR00066##
[0345] To a solution of
1-(3-bromophenyl)-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]ethane-1,2--
dione (2.4 g, 6.7 mmol) in EtOH (70 mL) is added N-methylguanidine
hydrochloride (0.8 g, 7.3 mmol) and a solution of Na.sub.2CO.sub.3
(1.41 g, 13.3 mmol) in H.sub.2O (7 mL). After refluxing for 1 h,
the reaction mixture is concentrated. The crude material is
purified by chromatography (silica gel, EtOAc/2.0M methanolic
NH.sub.3: 90/10) to give the title compound (2.2 g, 79%) as a
solid. mp: 80-82.degree. C. MS (+) ES: 416 (M+H).sup.+.
Examples 82-89
Preparation of
2-amino-3-methyl-5-(3-arylphenyl)-5-[1-(2,2,2-trifluoroethyl)-1H-pyrazol--
4-yl]-3,5-dihydro-4H-imidazol-4-ones
##STR00067##
[0347] A solution of
2-amino-5-(3-bromophenyl)-3-methyl-5-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-
-4-yl]-3,5-dihydro-4H-imidazol-4-one (104 mg, 0.25 mmol) in
ethylene glycol dimethyl ether was treated with the appropriate
boronic acid (0.5 mmol), tetrakis(triphenylphosphine)palladium (29
mg, 0.03 mmol) and 2.0M aqueous sodium carbonate (0.5 mL, 1.0 mmol)
at room temperature. The reaction mixture was refluxed for 3 hour
and cooled. After evaporation of the solvent, the crude mixture was
purified by chromatography (silica gel, EtOAc/2.0M ethanolic
NH.sub.3: 92/8) to give the compounds shown in Table VI. These
compounds were identified by NMR and mass spectral analyses.
TABLE-US-00006 TABLE VI ##STR00068## Ex. No. R7 mp (.degree. C.) (M
+ H).sup.+ 82 3-methoxyphenyl 95-97 444 83 3-ethoxyphenyl 88-90 458
84 2,5-difluorophenyl 98-100 448* 85 5-fluoro-2-methoxyphenyl
104-106 462 86 5-cyano-2-fluorophenyl 118-120 457 87
2,3-difluorophenyl 103-105 450 88 pyridin-3-yl 202-204 415 89
3-pyrimidin-5-yl 223-225 416 *(M - H).sup.-
Example 90
Preparation of
4-(3-benzyloxyphenylethynyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole
##STR00069##
[0349] The title compound is prepared using essentially the same
procedure described in Example 79 to give the title compound as a
yellow solid (70%), mp: 84-86.degree. C. .sup.1HNMR (CDCl.sub.3):
.delta. (ppm) 4.67 (q, 2H), 5.07 (s, 2H), 6.95 (d, 1H), 7.00-7.50
(m, 8H), 7.70 (d, 2H).
Example 91
Preparation of
1-(3-benzyloxyphenyl)-2-[1-2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]ethane-1-
,2-dione
##STR00070##
[0351] The title compound is prepared using essentially the same
procedure described in Example 80 to give the title compound as a a
solid (92%). .sup.1HNMR (DMSO-d.sub.6): .delta. (ppm) 5.15 (s, 2H),
5.20 (q, 2H), 7.20-7.50 (m, 9H), 8.16 (s, 1H), 8.64 (s, 1H).
Example 92
Preparation of
2-amino-5-[3-(benzyloxy)phenyl]-3-methyl-5-[1-(2,2,2-trifluoroethyl)-1H-p-
yrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one
##STR00071##
[0353] The title compound is prepared using essentially the same
procedure described in Example 81 to give the title compound as a a
solid (68%) mp: 85-87.degree. C., MS (+) ES: 444 (M+H).sup.+.
Example 93
Preparation of
2-amino-5-(3-hydroxyphenyl)-3-methyl-5-[1-(2,2,2-trifluoroethyl)-1H-pyraz-
ol-4-yl]-3,5-dihydro-4H-imidazol-4-one
##STR00072##
[0355] A mixture of
2-amino-5-[3-(benzyloxy)phenyl]-3-methyl-5-[1-(2,2,2-trifluoroethyl)-1H-p-
yrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one (330 mg, 0.74 mmol) and
Pd/C (33 mg) in ethanol (10 ml) is hydrogenated at 45 psi
overnight. After removal of the catalyst by filtration, the
filtrate is concentrated. The crude material is purified by flash
chromatography (silica gel, EtOAc/2.0M ethanolic NH.sub.3: 90/10 to
80/20) to afford the title compound as a solid 250 mg (95%). mp:
118-120.degree. C. MS (+) ES: 354 (M+H).sup.+.
Example 94
Preparation of
4-(3-bromo-4-fluorophenylethynyl)-1-isopropyl-1H-pyrazole
##STR00073##
[0357] The title compound is prepared using essentially the same
procedure described in Example 64 to give the title compound as a
solid (55%). .sup.1HNMR (DMSO-d.sub.6): .delta. (ppm) 1.36 (d, 6H),
4.46 (m, 1H), 7.38 (t, 1H), 7.48 (m, 1H), 7.65 (s, 1H), 7.77 (d,
1H), 8.11 (s, 1H).
Example 95
Preparation of
2-amino-5-(3-bromo-4-fluorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-3-meth-
yl-3,5-dihydro-4H-imidazol-4-one
##STR00074##
[0359] The title compound is prepared using essentially the same
procedure described in Example 68 to give the title compound as a
solid (80%) mp: 80-82.degree. C., MS (+) ES: 395 (M+H).sup.+.
Examples 96-98
Preparation of
2-amino-5-(4-fluoro-3-substituted-phenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-
-3-methyl-3,5-dihydro-imidazol-4-one Compounds
##STR00075##
[0361] Using essentially the same procedure described in Example 82
and employing the appropriated boronic acid reagent, the compounds
shown in Table VII were obtained and identified by NMR and mass
spectral analyses.
TABLE-US-00007 TABLE VII ##STR00076## Ex. No. R7 mp (.degree. C.)
(M + H).sup.+ 96 pyrimidin-5-yl 110-113 394 97 2-fluoropyridin-3-yl
115-117 411 98 3-methoxyphenyl 112-114 422
Examples 99-108
Preparation of
2-amino-5-(3-heteroarylphenyl)-5-(1-substituted-1H-pyrazol-4-yl)-3-methyl-
-3,5-dihydro-imidazol-4-one Compounds
##STR00077##
[0363] Using essentially the same procedures described in Examples
1 and 62-75 and employing the appropriate 5-pyrazol-4-yl hydantoin
substrate and boronic acid reagent, the compounds shown in Table
VIII were obtained and identified by NMR and mass spectral
analyses.
TABLE-US-00008 TABLE VIII ##STR00078## Ex. mp No. R R7 (.degree.
C.) 99 2-ethylbutyl 2-fluoropyridin-3-yl 75-80 100 cyclopentyl
2-fluoropyridin-3-yl 106-109 101 3,3-dimethylbutyl
2-fluoropyridin-3-yl 100-103 102 3-methylbutyl 2-fluoropyridin-3-yl
86-90 103 benzyl 2-fluoropyridin-3-yl 94-97 104 2-cyclohexylethyl
2-fluoropyridin-3-yl 88-90 105 cyclopentyl pyrimidin-5-yl 112-115
106 3,3-dimethylbutyl pyrimidin-5-yl 93-96 107 2-cyclohexylethyl
pyrimidin-5-yl 102-105 108 3-methylbutyl pyrimidin-5-yl 87-90
Example 109
Preparation of
2-Amino-5-(5-butylthien-2-yl)-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-
-one
##STR00079##
[0364] Step a) (5-Butyl-thiophen-2-yl)-oxo-acetic acid ethyl
ester
[0365] To a 0.degree. C. solution containing 2-butyl-thiophene (5
g, 35.6 mmol) dissolved in benzene (90 mL) and diethyloxalate (5.1
g, 35.6 mmol) was added (dropwise) a solution containing TiCl.sub.4
(6.7 g, 35.6 mmol) dissolved in benzene (10 mL). The reaction was
let stir at 5.degree. C. for 1 h then poured into water (300 mL)
and extracted with ether. The organic layer was separated, washed
with brine, then dried over MgSO.sub.4, filtered and stripped. The
residue was purified by flash chromatography on silica gel in
hexane/ethyl acetate 20:1. A yellow oil (4 g, 46% yield) was
recovered. MS m/e 241 (M).sup.+; .sup.1HNMR (400 MHz, DMSO-d.sub.6
300 MHz) .delta. 0.9 (t, 3H), 1.4 (m, 5H), 1.6 (m, 2H), 2.9 (t,
2H), 4.4 (t, 2H), 7.1 (s, 1H), 7.9 (s, 1H).
Step b) (5-Butyl-thiophen-2-yl)-oxo-acetic acid
[0366] To solution containing (5-butyl-thiophen-2-yl)-oxo-acetic
acid ethyl ester (Step a, 1 g, 4.2 mmol) dissolved in ethanol 10
mL) was added K.sub.2CO.sub.3 2N (10 mL). The reaction was stirred
at room temperature 6 h. The ethanol was removed under reduce
pressure and the residue taken in water (50 mL) then washed with
ether. The aqueous was separated and made acidic with concentrated
HCl then extracted with CHCl.sub.3 (2.times.). The organic layers
were separated and combined and dried over MgSO.sub.4, then
filtered and stripped. A white solid (0.6 g, 67% yield) was
recovered. MS m/e 211 (M).sup.-; .sup.1HNMR (DMSO-d.sub.6 300 MHz)
.delta. 0.9 (t, 3H), 1.3 (m, 2H), 1.6 (m, 2H), 2.8 (t, 2H), 4.3 (b,
1H), 7.1 (s, 1H), 7.9 (s, 1H).
Step c) 1-(5-Butyl-thiophen-2-yl)-2-phenyl-ethane-1,2-dione
[0367] Into a flask containing THF (60 mL) was added copper (II)
bromide (5.7 g, 40 mmol) followed by lithium bromide (6.8 g, 80
mmol). The reaction was cooled to 0.degree. C. and a solution of
4-methyl-phenylmagnesium bromide (1N) in ether (48 mmol) was added
dropwise. The reaction was stirred 10 min and a solution containing
(5-butyl-thiophen-2-yl)-oxo-acetyl chloride was added dropwise over
20 min at 0.degree. C. The reaction was poured into HCl 1N
(aqueous) and extracted with ether. The organic layer was separated
and washed with NaOH 2.5N (aqueous), then brine and dried over
MgSO.sub.4, filtered and stripped. MS m/e 273 (M).sup.-; .sup.1HNMR
(DMSO-d.sub.6, 300 MHz) .delta. 0.9 (t, 3H), 1.3 (m, 2H), 1.6 (m,
2H), 2.8 (t, 2H), 7.0 (s, 1H), 7.6 (t, 2H), 7.7 (s, 1H), 7.8 (m,
1H), 7.9 (d, 2H).
Step d)
2-Amino-5-(5-butylthien-2-yl)-3-methyl-5-phenyl-3,5-dihydro-4H-imi-
dazol-4-one
[0368] 1-(5-butyl-thiophen-2-yl)-2-phenyl-ethane-1,2-dione was
dissolved in a solution containing ethanol (15 mL) and water (3
mL). Into this mixture was added 1-methylguanidine hydrochloride
(0.32 g, 3 mmol), and followed by K.sub.2CO.sub.3 (1.2 g, 0.9
mmol). The reaction was set to reflux 3 h, and then cooled to room
temperature and the ethanol removed under reduced pressure. The
crude product was taken in water (50 mL) and extracted with
CHCl.sub.3 (3.times.). The organic layers were separated and
combined, then dried over MgSO.sub.4, filtered and stripped. The
crude product was purified by flash chromatography on silica gel in
10% methanol/ethyl acetate. A white solid was obtained. MS m/e 328
(M).sup.+; .sup.1HNMR (DMSO-d.sub.6, 300 MHz) .delta. 0.9 (m, 3H),
1.2 (m, 2H), 1.5 (m, 1H), 2.6 (t, 2H), 2.95 (s, 3H), 6.5 (s, 1H),
6.6 (b, 2H), 6.8 (s, 1H), 7.2 (m, 3H), 7.5 (m, 2H).
Example 110
Preparation of
2-Amino-5-[5-(4-fluorophenyl)thien-2-yl]-5-(4-methoxy-3-methylphenyl)-3-m-
ethyl-3,5-dihydro-4H-imidazol-4-one
##STR00080##
[0369] Step a)
1-[5-(4-Fluorophenyl)thien-2-yl]-2-(4-methoxy-3-methylphenyl)ethane-1,2-d-
ione
[0370] One equivalent of
4-methoxy-3-methyl-benzyl-triphenyl-phosphonium chloride was
reacted with 5-(4-fluoro-phenyl)-thiophene-2-carboxylic acid
chloride (3 mmol) to give
1-[5-(4-fluorophenyl)thien-2-yl]-2-(4-methoxy-3-methylphenyl)ethane-1,2-d-
ione as a yellow solid (0.26 g, 25% yield, mp 165.degree. C.); MS
m/e (M-H).sup.- 354; .sup.1H NMR (400 MHZ, CDCl.sub.3) .delta. ppm
2.21(s, 3H), 3.90 (s, 3H), 6.82(d, 1H), 7.10 (t, 2H), 7.25 (d, 1H),
7.61 (m, 2H), 7.70 (d, 1H), 7.85 (m, 1H), 7.91(m, 1H).
Step b)
2-Amino-5-[5-(4-fluorophenyl)thien-2-yl]-5-(4-methoxy-3-methylphen-
yl)-3-methyl-3,5-dihydro-4H-imidazol-4-one
[0371] Using substantially the same procedure described in Example
1, step d, and employing
1-[5-(4-fluorophenyl)thien-2-yl]-2-(4-methoxy-3-methylphenyl)ethane-1,2-d-
ione and 1-methylguanidine hydrochloride, the title compound was
obtained as a white solid; mp 110.degree. C.; MS m/e (M-H).sup.-
408; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) .delta. 2.05 (s, 3H), 2.90
(s, 3H), 3.70 (s, 3H), 6.70 (bs, 2H), 6.80 (d, 1H), 6.90 (d, 1H),
7.19 (m, 2H), 7.21 (m, 1H), 7.22 (m, 1H), 7.30 (m, 1H), 7.58 (m,
2H).
Example 111
Preparation of
2-Amino-5-[4-(4-fluorophenyl)thien-2-yl]-5-(4-methoxy-3-methylphenyl)-3-m-
ethyl-3,5-dihydro-4H-imidazol-4-one
##STR00081##
[0372] Step a) 4-(4-Fluorophenyl)thiophene-2-benzoyl chloride
[0373] 4-(4-Fluorophenyl)thiophene-2-carboxcylic acid (1 g, 4.5
mmol) was dissolved in 10 mL of CH.sub.2Cl.sub.2 with 1 drop DMF,
to this was then added oxalyl chloride (1.1 g, 9.0 mmol). The
reaction was stirred at room temperature for 16 h then stripped of
solvent under reduced pressure. The product was carried to the next
step without any further purification.
Step b)
1-[4-(4-Fluorophenyl)thien-2-yl]-2-(4-methoxy-3-methylphenyl)ethan-
e-1,2-dione
[0374] Using substantially the same procedure described in Example
93, step a, and employing 4-(4-fluorophenyl)thiophene-2-benzoyl
chloride and 3-methyl, 4-methoxy-benzyl triphenylphosphonium
chloride,
1-[4-(4-fluorophenyl)thien-2-yl]-2-(4-methoxy-3-methylphenyl)ethane-1,2-d-
ione was obtained as a yellow solid, .sup.1H NMR (DMSOd.sub.6 300
MHz) .delta. 2.2 (s, 3H), 3.9 (s, 3H), 7.15 (dd, 1H), 7.22 (t, 2H),
7.8 (m, 4H), 8.2 (s, 1H), 7.79 (s, 1H).
Step c)
2-Amino-5-[4-(4-fluorophenyl)thien-2-yl]-5-(4-methoxy-3-methylphen-
yl)-3-methyl-3,5-dihydro-4H-imidazol-4-one
[0375] Using essentially the same procedure described in Example
93, step b, and employing
1-[4-(4-fluorophenyl)thien-2-yl]-2-(4-methoxy-3-methylphenyl)ethane-1,2-d-
ione and methylguanidine, the title product was obtained as a tan
solid, MS m/e (M).sup.- 408; .sup.1H NMR (DMSOd.sub.6 300 MHz)
.delta. 2.1 (s, 3H), 2.98 (s, 3H), 3.7 (s, 3H), 6.8 (b, 2H), 6.6
(dd, 1H), 7.2 (t, 2H), 7.3 (m, 3H), 7.6 (m, 3H).
Example 112
Preparation of
2-Amino-5-(3bromophenyl)-5-[5-(2-ethyl-[1,3]dioxolan-2-yl)-thiophen-3-yl]-
-3-methyl-3,5-dihydro-imidazol-4-one
##STR00082##
[0377] Step a) A stirred suspension of aluminum trichloride (6.27
g, 47.1 mmol) in chloroform at room temperature was treated
sequentially with 2-(1-propionyl)thiophene (3.00 g, 21.4 mmol) and
bromine (3.60 g, 22.4 mmol), stirred for 17 h, poured into iced
water and diluted with methylene chloride. The phases were
separated and the aqueous phase was extracted with methylene
chloride. The extracts and the organic phase were combined, washed
with water and brine, dried over sodium sulfate and concentrated to
afford 2 (5.51 g, 117%) as a dark orange oil: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.59 (d, J=1.1 Hz, 1H), 7.51 (d, J=1.1 Hz, 1H),
2.91 (q, J=7.3 Hz, 2H), 1.23 (t, J=7.3 Hz, 3H); ESI MS m/z 219
[C.sub.7H.sub.7BrOS+H].sup.+.
[0378] Step b) A mixture of 2 (5.51 g, ca. 85% purity, 21.4 mmol),
ethylene glycol (2.02 g, 32.6 mmol) and p-toluene sulfonic acid
(0.40 g, 2.14 mmol) in benzene was heated under Dean-Stark
conditions for 22 h. The reaction was then cooled to room
temperature and the solvents evaporated. Purification of the
resultant concentrate by flash chromatography (silica, 90:10
hexanes/ethyl acetate) afforded 3 (4.96 g, 88%) as an orange
liquid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.13 (d, J=1.4
Hz, 1H), 6.92 (d, J=1.4 Hz, 1H), 4.06-3.92 (m, 4H), 1.99 (q, J=7.4
Hz, 2H), 0.94 (t, J=7.4 Hz, 3H).
[0379] Step c) A solution of 3 (2.00 g, 7.60 mmol) in ether at
-78.degree. C. was treated dropwise with n-BuLi (4.20 mL of a 1.98
M solution in hexanes, 8.30 mmol), stirred for 30 min, treated
dropwise with a solution of iodine (2.10 g, 8.3 mmol) in ether,
stirred at -60.degree. C. for a further 30 min, treated with
saturated ammonium chloride solution and diluted with ethyl
acetate. The phases were separated. The organic phase was washed
sequentially with 10% aqueous sodium thiosulfate, water and brine,
dried over sodium sulfate and concentrated. Purification of the
resultant concentrate by flash chromatography (silica, 90:10
hexanes/ethyl acetate) afforded 4 (1.62 g, 68%) as an orange oil
which was a 3:1 mixture of product to starting material: .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 7.29 (d, J=1.4 Hz, 1H), 6.99 (d,
J=1.4 Hz, 1H), 4.04-3.94 (m, 4H), 1.99 (q, J=7.4 Hz, 2H), 0.93 (t,
J=7.4 Hz, 3H).
[0380] Step d) A mixture of 4 (1.62 g, 5.20 mmol),
3-bromophenylethyne (1.04 g, 5.70 mmol),
dichloro(bistriphenylphosphine)palladium(II) (0.11 g, 0.15 mmol),
copper(I) iodide (0.02 g, 0.10 mmol) and triethylamine (2.63 g,
26.0 mmol) in dimethylformamide was stirred at room temperature for
30 min and diluted with water and ethyl acetate. The phases were
separated. The organic phase was washed with brine, dried over
sodium sulfate and concentrated. Purification of the resultant
concentrate by flash chromatography (silica, 95:5 to 90:10
hexanes/ethyl acetate) afforded 6 (1.07 g, 57%) as a colorless
liquid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.64 (t, J=1.7
Hz, 1H), 7.47-7.44 (m, 1H), 7.42 (d, J=1.3 Hz, 1H), 7.42-7.40 (m,
1H), 7.20 (t, J=7.9 Hz, 1H), 7.09 (d, J=1.3 Hz, 1H), 4.04-3.95 (m,
4H), 2.02 (q, J=7.5 Hz, 2H), 0.95 (t, J=7.5 Hz, 3H); ESI MS m/z 363
[C.sub.17H.sub.15BrO.sub.2S+H].sup.+.
[0381] Step e) A stirred solution of 6 (1.05 g, 2.89 mmol) in
acetone was treated with a solution of sodium bicarbonate (0.145 g,
1.73 mmol) and magnesium sulfate (0.690 g, 5.78 mmol) in water,
followed by potassium permanganate (1.14 g, 7.20 mmol) in one
portion. The reaction mixture was stirred for 1 h, treated with a
further portion of potassium permanganate (0.45 g, 2.84 mmol),
stirred for an additional 2.25 h, diluted with 1:1 hexanes/ethyl
acetate and water) and filtered. The filtrate was separated and the
aqueous layer was extracted with ethyl acetate. The extracts were
combined with the filtrate organic layer, washed with brine, dried
over sodium sulfate and concentrated. Purification of the resultant
concentrate by flash chromatography (silica, 90:10 to 80:20
hexanes/ethyl acetate) afforded 7 (0.63 g, 55%) as a yellow oil:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.15 (t, J=1.7 Hz, 1H),
8.12 (d, J=1.4 Hz, 1H), 7.96-7.92 (m, 1H), 7.82-7.76 (m, 1H), 7.55
(d, J=1.4 Hz, 1H), 7.39 (t, J=7.9 Hz, 1H), 4.07-3.96 (m, 4H), 2.03
(q, J=7.5 Hz, 2H), 0.96 (t, J=7.5 Hz, 3H); ESI MS m/z 395
[C.sub.17H.sub.15BrO.sub.4S+H].sup.+.
[0382] Step f) A mixture of 7 (0.63 g, 1.59 mmol) and
1-methylguanidine hydrochloride (0.78 g, 7.15 mmol) in dioxane and
ethanol was stirred at room temperature for 5 min, treated with a
solution of sodium carbonate (0.75 g, 7.15 mmol) in water, stirred
and heated at 80.degree. C. for 1 h, cooled to room temperature and
concentrated in vacuo. The resultant residue was partitioned
between methylene chloride and water. The organic layer was
separated and washed with water and brine, dried over sodium
sulfate and concentrated. Purification of the resultant concentrate
by flash chromatography (silica, 95:5:0.5 methylene
chloride/methanol/concentrated ammonium hydroxide) afforded a
viscous oil, which was coevaporated from methylene chloride and
hexanes to afford the title compound (0.55 g, 77%) as a white
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.70 (br s, 1H),
7.50-7.39 (m, 2H), 7.25-7.14 (m, 2H), 6.95 (br s, 1H), 4.03-3.90
(m, 4H), 3.10 (s, 3H), 1.99 (q, J=7.5 Hz, 2H), 0.90 (t, J=7.5 Hz,
3H); ESI MS m/z 450
[C.sub.19H.sub.20BrN.sub.3O.sub.3S+H].sup.+.
Examples 113 and 114
Preparation of
2-Amino-5-[5-(2-ethyl-[1,3]dioxolan-2-yl)-thiophen-3-yl]-5-(3-heteroarylp-
henyl)-3-methyl-3,5-dihydro-imidazol-4-one Compounds
##STR00083##
[0384] Using essentially the same procedure described in Example 75
and employing the appropriate heteroaryl boronic acid the compounds
shown in Table IX are obtained and identified by NMR and mass
spectral analyses.
TABLE-US-00009 TABLE IX ##STR00084## Ex. mp No. R7 (.degree. C.)
113 2-fluoropyridin-3-yl 93-103 114 pyrimidin-5-yl 105-112
Example 115
Preparation of
2-Amino-5-[3-(2-fluoro-pyridin-3-yl)-phenyl]-3-methyl-5-(5-propionyl-thio-
phen-3-yl)-3,5-dihydro-imidazol-4-one
##STR00085##
[0386] A mixture of
2-amino-5-[5-(2-ethyl-[1,3]dioxolan-2-yl)-thiophen-3-yl]-5-[3-(2-fluoro-p-
yridin-3-yl)-phenyl]-3-methyl-3,5-dihydro-imidazol-4-one (0.11 g,
0.23 mmol) in diethyl ether and 1 N HCl was heated at reflux
temperature for 1 h, cooled to room temperature, diluted with
methylene chloride and basified to pH 9 using 2 N sodium hydroxide.
The phases were separated. The organic phase was washed with brine,
dried over sodium sulfate and concentrated in vacuo. The resultant
concentrate was freeze dried from 1:1 acetonitrile/water (4 mL) to
afford the title compound as a white solid, 0.069 g (71% yield), mp
98-112.degree. C.; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.19
(dt, J=4.7, 1.4 Hz, 1H), 7.85-7.81 (m, 1H), 7.78-7.69 (m, 3H),
7.61-7.55 (m, 1H), 7.52-7.48 (m, 1H), 7.43 (t, J=7.7 Hz, 1H),
7.29-7.23 (m, 1H), 3.12 (s, 3H), 2.88 (q, J=7.3 Hz, 2H), 1.17 (t,
J=7.3 Hz, 3H); ESI MS m/z 423
[C.sub.22H.sub.19FN.sub.4O.sub.2S+H].
Example 116
Preparation of
2-Amino-3-methyl-5-(5-propionyl-thiophen-3-yl)-5-(3-pyrimidin-5-yl-phenyl-
)-3,5-dihydro-imidazol-4-one
##STR00086##
[0388] Using essentially the same procedure described in Example
115 and employing
2-amino-5-[5-(2-ethyl-[1,3]dioxolan-2-yl)-thiophen-3-yl]-3-meth-
yl-5-(3-pyrimidin-5-yl-phenyl)-3,5-dihydro-imidazol-4-one as
starting material, the title product was obtained as a white solid,
mp 167-172.degree. C.; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
9.19 (s, 1H), 8.92 (s, 2H), 7.76-7.72 (m, 3H), 7.66-7.63 (m, 1H),
7.51-7.48 (m, 2H), 3.15 (s, 3H), 2.87 (q, J=7.3 Hz, 2H), 1.17 (t,
J=7.3 Hz, 3H); ESI MS m/z 406
[C.sub.21H.sub.19N.sub.5O.sub.2S+H].sup.+;
Example 117
Preparation of
2-Amino-3-methyl-5-phenyl-5-(5-propionyl-3-thienyl)-3,5-dihydro-4H-imidaz-
ol-4-one
##STR00087##
[0390] Using essentially the same procedure described in Example
115 and employing
2-amino-5-[5-(2-ethyl-[1,3]dioxolan-2-yl)-thiophen-3-yl]-3-meth-
yl-5-phenyl-3,5-dihydro-imidazol-4-one as starting material, the
title product was obtained; .sup.1H NMR (DMSOd.sub.6 300 MHz) 0.98
(s, 3H), 2.76 (q, 2H), 3.9 (s, 3H), 4.5 (s, 2H), 4.6 (m, 2H), 6.65
(brs, 2H), 7.2 (m, 1H), 7.25 (t, 1H), 7.4 (d, 1H), 7.7 (d, 1H); MS
m/e (M+H).sup.+ 328
Example 118
Preparation of Methyl
4-[2-Amino-4-(4-fluoro-3-pyrimidinyl-5-phenyl)-1-methyl-5-oxo-4,5-dihydro-
-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate
##STR00088##
[0391] Step a) 4-Iodo-1H-pyrrole-2-carboxylic acid methyl ester
[0392] To a solution of 300 mL of dry methanol was added 0.52 gm
(0.023 mol) of sodium and the solution was stirred until all sodium
was reacted. The solution was cooled to 0.degree. C. and 19.5 gm
(0.057 mol) of 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)-ethanone
was added as a solid over a 15 min period. After 15 min at
0.degree. C. the solution was warmed to room temperature and
stirred for an additional 2 h. The solvents were removed at reduced
pressure and the residue dissolved in diethyl ether. The ether
layer was washed with H.sub.2O, saturated brine, dried
(Na.sub.2SO.sub.4) and the solvents removed at reduced pressure.
The solid was recystallized from hot hexanes-trace EtOAc to yield
13.7 gm (95% yield) of a light brown solid. This was used without
further purification.
Step b) 1-(2-Fluoro-ethyl)-4-iodo-1H-pyrrole-2-carboxylic acid
methyl ester
[0393] To a solution of 2.87 gm (0.013 mol) of toluene-4-sulfonic
acid 2-fluoro-ethyl ester in 50 mL of DMF was added 1.81 gm (0.013
mol) of potassium carbonate, 0.2 gm (1.2 mmol) of
tetraethylammonium chloride and 3.0 gm (0.012 mol) of
4-iodo-1H-pyrrole-2-carboxylic acid methyl ester. The reaction
mixture was heated to 70.degree. C. for 18 h. The reaction mixture
was cooled and added to 350 mL of EtOAc. The organic layer was
washed 3 times (100 mL) with H.sub.2O, once with saturated brine,
dried (Na.sub.2SO.sub.4) and the solvents removed at reduced
pressure. Chromatography on silica gel using a gradient of hexanes
to 2%-3% EtOAc-hexanes yielded 3.2 gm (90% yield) of a white solid
(m.p. 49-50.5.degree. C.). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 3.80 (s, 3H), 4.58 (m, 2H), 4.63 (m, 1H), 4.76 (m, 1H,),
6.93 (s, 1H), 7.06 (s, 1H).
Step c)
4-(3-Bromo-4-fluoro-phenylethynyl)-1-(2-fluoro-ethyl)-1H-pyrrole-2-
-carboxylic acid methyl ester
[0394] To a solution of 0.88 gm (4.44 mmol) of
2-bromo-4-ethynyl-1-fluoro-benzene, 0.129 gm (0.185 mmol)
bis-triphenylphosphine-palladium dichloride, 0.021 gm (0.11 mmol),
2.8 mL (0.02 mol) of triethylamine in 25 mL of DMF was added 1.10
gm (3.70 mmol) of 1-(2-fluoro-ethyl)-4-iodo-1H-pyrrole-2-carboxylic
acid methyl ester. The mixture was allowed to stir at room
temperature for 2 h. The mixture was added to 300 mL of EtOAc and
washed twice with H.sub.2O (100 mL), once with saturated brine,
dried (Na.sub.2SO.sub.4) and the solvents removed at reduced
pressure. Chromatography on silica gel using a gradient of 2%-4%
EtOAc-hexanes yielded 0.96 gm (71% yield) of a yellow oil. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.: 3.82 (s, 3H), 4.61 (m, 2H), 4.66
(m, 1H), 4.75 (m, 1H,), 7.06 (s, 1H), 7.09 (d, 1H, J=1.74 Hz), 7.14
(s, 1H), 7.37 (m, 1H), 7.67 (dd, 1 H, J=1.97, 6.61 Hz).
Step d)
4-[2-(3-Bromo-4-fluoro-phenyl)-2-oxo-acetyl]-1-(2-fluoro-ethyl)-1H-
-pyrrole-2-carboxylic acid methyl ester
[0395] To a solution of 0.95 gm (2.6 mmol) of
4-(3-bromo-4-fluoro-phenylethynyl)-1-(2-fluoro-ethyl)-1H-pyrrole-2-carbox-
ylic acid methyl ester in 20 mL of acetone was added 0.46 (3.85
mmol) MgSO.sub.4. While stirring at room temperature 0.13 gm (1.54
mmol) of NaHCO.sub.3 in 12 mL of distilled H.sub.2O was added and
then 0.89 gm (5.65 mmol) of KMnO.sub.4 was added as a solid over a
5 minute period. The mixture was allowed to stir at room
temperature for 3 h. 150 mL of 1:1 EtOAc-hexanes was added and the
mixture was filtered through celite. The organic layer was diluted
with 200 mL of EtOAc and washed twice with H.sub.2O (100 mL),
saturated brine then dried (Na.sub.2SO.sub.4) and the solvents were
removed at reduced pressure. This was used without further
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 3.82 (s,
3H), 4.63 (s, 2H), 4.69 (m, 1H), 4.75 (m, 1H,), 7.06 (s, 1H), 7.20
(d, 1H, J=8.4 Hz), 7.22 (d, 1H, J=1.8 Hz), 8.0 (m, 1H), 8.28 (dd,
1H, J=2.1, 6.72 Hz).
Step e)
4-[2-Amino-4-(3-bromo-4-fluoro-phenyl)-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl]-1-(2-fluoro-ethyl)-1H-pyrrole-2-carboxylic acid
methyl ester
[0396] To a solution of 0.742 gm (1.85 mmol) of
4-[2-(3-bromo-4-fluoro-phenyl)-2-oxo-acetyl]-1-(2-fluoro-ethyl)-1H-pyrrol-
e-2-carboxylic acid methyl ester in 18 mL of MeOH and 21 mL of
dioxane in a pressure tube was added 0.40 gm (3.7 mmol) of
N-methylguanidine hydrochloride. After stirring at room temperature
for 15 min, 0.41 gm (3.9 mmol) of Na.sub.2CO.sub.3 in 5.2 mL of
H.sub.2O was added and the reaction mixture was sealed and heated
to 85.degree. C. for 4 h. The mixture was cooled and the solvents
removed at reduced pressure. The residue was taken up in
CH.sub.2Cl.sub.2 (200 mL) and washed with H.sub.2O (100 mL),
saturated brine, dried (Na.sub.2SO.sub.4) and the solvent removed
at reduced pressure. Chromatography on silica gel using a gradient
of EtOAc to 3% MeOH-EtOAc yielded 0.64 gm (76% yield) of a white
foam. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 3.08 (s, 3H), 3.76
(s, 3H), 4.52 (m, 1H), 4.59 (m, 2H,), 4.71 (m, 1H), 6.92 (s, 1H),
6.94 (s, 1H), 7.04 (t, 1H, J=8.47 Hz), 7.50 (m, 1H), 8.28 (dd, 1H,
J=2.2, 4.41 Hz).
Step f)
4-[2-Amino-4-(4-fluoro-3-pyrimidin-5-yl-phenyl)-1-methyl-5-oxo-4,5-
-dihydro-1H-imidazol-4-yl]-1-(2-fluoro-ethyl)-1H-pyrrole-2-carboxylic
acid methyl ester
[0397] In a pressure tube was put 2 mL of MeOH and 2 mL of toluene.
The solution was degassed with argon and 7.5 mg (0.008 mmol) of
Pd.sub.2(dba).sub.3 and 8.6 mg of triphenylphosphine was added
under an argon atmosphere. After 15 min stirring at room
temperature, 47.0 mg (0.38 mmol) of 5-pyrimidyl-boronic acid, 83 mg
(0.78 mmol) of Na.sub.2CO.sub.3, and 125 mg (0.27 mmol) of
4-[2-Amino-4-(3-bromo-4-fluoro-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imid-
azol-4-yl]-1-(2-fluoro-ethyl)-1H-pyrrole-2-carboxylic acid methyl
ester was added and the reaction sealed heated to 110.degree. C.
for 18 h. The reaction mixture was cooled, diluted with 100 mL of
CHCl.sub.3, filtered through celite and the solvent removed at
reduced pressure. Chromatography on silica gel using a gradient of
EtOAc to 2%-8% MeOH-EtOAc yielded 0.08 gm (64% yield) of a white
solid (mp 88-90.degree. C.). .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta.: 3.15 (s, 3H), 3.73 (s, 3H), 4.50 (m, 1H), 4.58 (m, 2H),
4.68 (m, 1H), 6.96 (s, 2H), 7.16 (t, 1H, J=8.66 Hz), 7.65 (m, 2H),
8.88 (m, 2H), 9.15 (s, 1H). MS (ESI) m/z 455.1 ([M+H]).sup.+; MS
(ESI) m/z 453.1 ([M-H]).sup.-.
Example 119
Preparation of Methyl
4-[(4S)2-Amino-4-(4-fluoro-3-pyrimidinyl-5-phenyl)-1-methyl-5-oxo-4,5-dih-
ydro-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate
(A) and of Methyl
4-[(4R)2-Amino-4-(4-fluoro-3-pyrimidinyl-5-phenyl)-1-methyl-5-o-
xo-4,5-dihydro-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylat-
e (B)
##STR00089##
[0399] A racemic mixture of methyl
4-[2-Amino-4-(4-fluoro-3-pyrimidinyl-5-phenyl)-1-methyl-5-oxo-4,5-dihydro-
-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate was
separated by chiral HPLC to give the title enantiomeric
products:
[0400] A: Methyl
4-[(4S)2-Amino-4-(4-fluoro-3-pyrimidinyl-5-phenyl)-1-methyl-5-oxo-4,5-dih-
ydro-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
mp 186-188.degree. C.; [.alpha.].sub.D-83.2 (c 1.0, MeOH); MS (ESI)
m/z (M+H).sup.+455.2; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
3.15 (s, 3H), 3.73 (s, 3H), 4.50 (m, 1H), 4.58 (m, 2H), 4.68 (m,
1H), 6.96 (s, 2H), 7.16 (t, 1H, J=8.66 Hz), 7.65 (m, 2H), 8.88 (m,
2H), 9.15 (s, 1H); and
[0401] B: Methyl
4-[(4R)2-Amino-4-(4-fluoro-3-pyrimidinyl-5-phenyl)-1-methyl-5-oxo-4,5-dih-
ydro-1H-imidazol-4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate;
mp 186-188.degree. C.; [.alpha.].sub.D+72.8 (c 1.0, MeOH); MS (ESI)
m/z (M+H).sup.+455.1; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
3.15 (s, 3H), 3.73 (s, 3H), 4.50 (m, 1H), 4.58 (m, 2H), 4.68 (m,
1H), 6.96 (s, 2H), 7.16 (t, 1H, J=8.66 Hz), 7.65 (m, 2H), 8.88 (m,
2H), 9.15 (s, 1H).
Examples 120-128
Preparation of Alkyl
4-[2-Amino-4-(3-heteroarylphenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol--
4-yl]-1-(substituted)-1H-pyrrole-2-carboxylate Compounds
##STR00090##
[0403] Using essentially the same procedure described in Example
118 and employing the appropriate dione and a suitable heteroaryl
boronic acid, the compounds shown in Table X are obtained and
identified by NMR and mass spectral analyses.
TABLE-US-00010 TABLE X ##STR00091## Ex. mp No R R4 R7 R8 (.degree.
C.) 120 CH.sub.2CF.sub.3 CO.sub.2CH.sub.3 2-F-pyridin-3-yl F
124-128 121 CH.sub.2CF.sub.3 CO.sub.2CH.sub.3 pyrimidin-5-yl F
182-184 122 CH.sub.2CH.sub.2l F CO.sub.2CH.sub.3 2-F-pyridin-3-yl F
127-128 123 CH.sub.2CH.sub.3 CO.sub.2CH.sub.3 2-F-pyridin-3-yl F
113-115 124 CH.sub.2CH.sub.2F CO.sub.2CH(CH.sub.3).sub.2
2-F-pyridin-3-yl F 117-118 125 CH.sub.2CH.sub.3
CO.sub.2C.sub.2H.sub.5 2-F-pyridin-3-yl F 114-115 126*
CH.sub.2CF.sub.3 CO.sub.2CH.sub.3 2-F-pyridin-3-yl F 124-126 127
CH.sub.2CH.sub.2F CO.sub.2CH(CH.sub.3).sub.2 pyrimidin-5-yl F
167-170 128 CH.sub.2CH.sub.3 CONHCH.sub.3 2-F-pyridin-3-yl
OC.sub.2H.sub.5 148-150 *R isomer
Example 129
Preparation of
N-{3-[2-amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-oxo-4,5-d-
ihydro-1H-imidazol-4-yl]-phenyl}-butyramide
##STR00092## ##STR00093##
[0404] Step a) Preparation of Compound 3
[0405] A mixture of 1 (Prepared according to the procedure
described in Gang, L. et al. J. Med. Chem. 2003, 46, 4232-4235;
4.08 g, 18.9 mmol), 2 (5.30 g, 17.2 mmol),
dichlorobis(triphenylphosphine)palladium(II) (0.36 g, 0.51 mmol),
copper(I) iodide (0.064 g, 0.34 mmol) and triethylamine (8.7 g,
86.0 mmol) in dimethylformamide (100 mL) was stirred at room
temperature for 1.5 h and then at 40.degree. C. for a further 1 h.
After this time, the reaction was cooled to room temperature and
diluted with ethyl acetate (300 mL) and water (150 mL). The organic
layer was separated and washed with water (100 mL) and brine (100
mL), dried over sodium sulfate, filtered and concentrated.
Purification by flash chromatography (silica, 80:20 to 50:50
hexanes/ethyl acetate) afforded 2 (4.80 g, 70%) as a dark red oil:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.56 (br s, 1H),
7.25-7.20 (m, 2H), 7.14 (dt, J=7.2, 1.5 Hz, 1H), 7.06 (d, J=1.7 Hz,
1H), 7.02 (d, J=1.7 Hz, 1H), 6.45 (br s, 1H), 4.32 (q, J=7.2 Hz,
2H), 3.70 (s, 3H), 3.34 (s, 3H), 1.52 (s, 9H), 1.40 (t, J=7.2 Hz,
3H).
Step b) Preparation of Compound 4
[0406] A mixture of 3 (4.20 g, 10.6 mmol) in tetrahydrofuran (55
mL) was cooled to 0.degree. C. Ethyl magnesium bromide (7.8 mL of a
3.0 M solution in diethyl ether, 23.3 mmol) was added and the
mixture stirred at 0.degree. C. for 5 min and then at room
temperature for 1.5 h. The reaction mixture was then quenched with
saturated aqueous ammonium chloride (30 mL) and then diluted with
ethyl acetate (200 mL). The organic layer was separated and washed
with water (50 mL) and brine (50 mL), dried over sodium sulfate,
filtered and concentrated. Purification by flash chromatography
(silica, 80:20 hexanes/ethyl acetate) afforded 4 (2.18 g, 56%) as a
pale yellow solid: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.56
(br s, 1H), 7.27-7.21 (m, 2H), 7.14 (dt, J=7.2, 1.5 Hz, 1H),
7.10-7.08 (m, 2H), 6.48 (br s, 1H), 4.37 (q, J=7.1 Hz, 2H), 2.82
(q, J=7.4 Hz, 2H), 1.54 (s, 9H), 1.38 (t, J=7.1 Hz, 3H), 1.19 (t,
J=7.4 Hz, 3H)
Step c) Preparation of Compound 5
[0407] A mixture of 4 (0.500 g, 1.36 mmol), potassium permanganate
(0.537 g, 3.40 mmol), sodium bicarbonate (0.068 g, 0.82 mmol) and
magnesium sulfate (0.327 g, 2.72 mmol) in acetone (60 mL) and water
(30 mL) was stirred at ambient temperature for 1.5 h. The mixture
was heated at 40.degree. C. for an additional 2.5 h. The reaction
was cooled to room temperature, diluted with 1:1 ethyl
acetate/hexanes (200 mL) and filtered. The filtrate was then
separated and the organic layer was washed with brine (3.times.40
mL), dried over sodium sulfate, filtered and concentrated to afford
5 (0.450 g, 83%) as a yellow solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.93 (t, J=1.8 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H),
7.69 (dd, J=7.8, 1.1 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.49 (d,
J=1.7 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 6.62 (s, 1H), 4.39 (dd,
J=14.3, 7.2 Hz, 2H), 2.86 (dd, J=14.7, 7.4 Hz, 2H), 1.52 (s, 9H),
1.40 (t, J=7.1 Hz, 3H), 1.19 (t, J=7.4 Hz, 3H).
Step d) Preparation of Compound 6
[0408] A mixture of 5 (0.450 g, 0.88 mmol) and 4 M HCl/dioxane
(2.25 mL) in dioxane (7 mL) was stirred at room temperature for 3 h
then heated to 50.degree. C. for 1 h. After this time additional 4
M HCl/dioxane (2.25 mL) and dioxane (10 mL) were added and the
mixture was stirred at room temperature for an additional 17 h. The
reaction mixture was then concentrated to half the original volume
then diluted with ether (50 mL). The resulting precipitate was
filtered and washed with ether to afford 6 (0.164 g, 56%) as a
yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.11 (s,
1H), 7.89 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.47 (s, 2H),
4.38-4.36 (m, 2H), 2.83 (dd, J=14.2, 7.0 Hz, 2H), 1.38-1.33 (m,
3H), 1.21-1.15 (m, 3H).
Step e) Preparation of Compound 7
[0409] A mixture of 6 (0.164 g, 0.49 mmol), and
diisopropylethylamine (0.158 g, 1.23 mmol) in methyelene chloride
was cooled to 0.degree. C. then butyryl chloride (0.56 ml, 0.54
mmol) was added and the mixture was stirred at room temperature for
1 h. After this time the mixture was diluted with methylene
chloride (50 mL) and washed with aqueous 1 N HCl solution (50 mL),
saturated aqueous sodium bicarbonate solution (50 mL) and brine (50
mL). The organic layer was dried over sodium sulfate, filtered and
concentrated. Purification by flash chromatography (silica, 1:4
ethyl acetate/hexanes) afforded 7 (0.154 g, 85%) as a yellow solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.05-8.00 (m, 2H), 7.76
(d, J=7.8 Hz, 1H), 7.57 (d, J=1.7 Hz, 1H), 7.54-7.43 (m, 2H), 7.37
(s, 1H), 4.39 (dd, J=14.3, 7.2 Hz, 2H), 2.90-2.82 (m, 2H), 2.35 (t,
J=7.3 Hz, 2H), 1.83-1.70 (m, 2H), 1.50-1.38 (m, 3H), 1.28-1.12 (m,
3H), 1.03-0.96 (m, 3H); ESI MS m/z 369
[C.sub.21H.sub.24N.sub.2O.sub.4+H].sup.+.
Step f) Preparation of
N-{3-[2-amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-oxo-4,5-d-
ihydro-1H-imidazol-4-yl]-phenyl}-butyramide
[0410] A mixture of 7 (0.154 g, 0.42 mmol) and 1-methylguanidine
hydrochloride (0.206 g, 1.88 mmol) in dioxane (4.0 mL) and ethanol
(1.6 mL) was stirred at room temperature for 5 min. A solution of
sodium carbonate (0.199 g, 1.88 mmol) in water (4.0 mL) was then
added, the flask immersed into an oil bath at 85.degree. C. and the
contents stirred for 2 h. After this time the reaction mixture was
cooled to room temperature and concentrated. The residue obtained
was diluted with methylene chloride (50 mL) and water (25 mL). The
organic layer was separated and washed with water (25 mL) and brine
(50 mL), dried over sodium sulfate, filtered and concentrated.
Purification by flash chromatography (silica, 95:5:0.25 methylene
chloride/methanol/concentrated ammonium hydroxide) afforded the
title product as a glass (0.120 g, 67%). A portion of the glass
(0.050 g) was triturated with methelyene chloride and hexanes to
afford the title product (0.027 g) as a white solid: mp
201-205.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.58
(d, J=8.0 Hz, 1H), 7.54 (s, 1H), 7.25 (t, J=7.9 Hz, 1H), 7.10 (d,
J=7.8 Hz, 1H), 7.04 (dd, J=7.4, 1.8 Hz, 2H), 4.31 (dd, J=14.2, 7.1
Hz, 2H), 3.10 (s, 3H), 2.80-2.75 (m, 2H), 2.31 (t, J=7.3 Hz, 2H),
1.71-1.67 (m, 2H), 1.29 (t, J=7.1 Hz, 3H), 1.12 (t, J=7.4 Hz, 3H),
0.98 (t, J=7.4 Hz, 3H), ESI MS m/z 424
[C.sub.23H.sub.29N.sub.5O.sub.3+H].sup.+.
Example 130
Preparation of
N-{3-[2-amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-oxo-4,5-d-
ihydro-1H-imidazol-4-yl]-phenyl}-propionamide
##STR00094##
[0411] Step a) Preparation of Compound 2
[0412] A mixture of 1 (0.250 g, 0.75 mmol), and
diisopropylethylamine (0.243 g, 1.88 mmol) in methyelene chloride
was cooled to 0.degree. C. then propionyl chloride (0.076 g, 0.82
mmol) was added and the mixture stirred at room temperature for 1
h. After this time the mixture was diluted with methylene chloride
(50 mL) and washed with aqueous 1 N HCl (50 mL), saturated aqueous
sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was
dried over sodium sulfate, filtered and concentrated. Purification
by flash chromatography (silica, 1:4 ethyl acetate/hexanes)
afforded 2 (0.238 g, 89%) as a yellow solid: .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 8.03 (d, J=7.6 Hz, 1H), 7.99 (s, 1H), 7.77 (d,
J=7.8 Hz, 1H), 7.57 (d, J=1.7 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.47
(d, J=7.9 Hz, 1H), 7.23 (s, 1H), 4.39 (dd, J=14.3, 7.2 Hz, 2H),
2.87 (dd, J=14.8, 7.4 Hz, 2H), 2.42 (dd, J=15.1, 7.5 Hz, 2H), 1.41
(t, J=7.1 Hz, 3H), 1.26 (t, J=7.5 Hz, 3H), 1.19 (t, J=7.4 Hz, 3H);
ESI MS m/z 355 [C.sub.20H.sub.22N.sub.2O.sub.4+H].sup.+.
Step b) Preparation of
N-{3-[2-amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-oxo-4,5-d-
ihydro-1H-imidazol-4-yl]-phenyl}-propionamide
[0413] A mixture of 2 (0.079 g, 0.22 mmol) and 1-methylguanidine
hydrochloride (0.110 g, 1.01 mmol) in dioxane (2.0 mL) and ethanol
(0.8 mL) was stirred at room temperature for 5 min. A solution of
sodium carbonate (0.107 g, 1.01 mmol) in water (2.0 mL) was then
added, the flask immersed into an oil bath at 85.degree. C. and
stirred at this temperature for 2 h. After this time the reaction
mixture was cooled to room temperature and concentrated. The
residue obtained was diluted with methylene chloride (50 mL) and
water (25 mL). The organic layer was separated and washed with
water (25 mL) and brine (50 mL), dried over sodium sulfate,
filtered and concentrated. Purification by flash chromatography
(silica, 95:5:0.25 methylene chloride/methanol/concentrated
ammonium hydroxide) afforded the title product (0.055 g, 61%) as a
colorless oil, which was solidified from methylene chloride and
hexanes to afford the title product (0.033 g) as a white solid: mp
120-141.degree. C.; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.57
(s, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.19 (s,
1H), 6.92 (dd, J=10.5, 1.7 Hz, 2H), 4.28 (dd, J=14.2, 7.1 Hz, 2H),
3.13 (s, 3H), 2.75 (dd, J=14.8, 7.4 Hz, 2H), 2.36 (dd, J=15.1, 7.6
Hz, 2H), 1.33 (t, J=7.1 Hz, 3H), 1.22 (t, J=7.5 Hz, 3H), 1.12 (t,
J=7.4 Hz, 3H), ESI MS m/z 410
[C.sub.22H.sub.27N.sub.5O.sub.3+H].sup.+.
Example 131
Preparation of
N-{3-[2-amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-oxo-4,5-d-
ihydro-1H-imidazol-4-yl]-phenyl}-2-methoxy-acetamide
##STR00095##
[0414] Step a) Preparation of Compound 2
[0415] A mixture of 1 (0.250 g, 0.75 mmol), and
diisopropylethylamine (0.243 g, 1.88 mmol) in methyelene chloride
was cooled to 0.degree. C. then methoxyacetyl chloride (0.089 g,
0.82 mmol) was added and the mixture stirred at room temperature
for 1 h. After this time the mixture was diluted with methylene
chloride (50 mL) and washed with aqueous 1 N HCl (50 mL), saturated
aqueous sodium bicarbonate (50 mL) and brine (50 mL). The organic
layer was dried over sodium sulfate, filtered and concentrated.
Purification by flash chromatography (silica, 1:4 ethyl
acetate/hexanes) afforded 2 (0.260 g, 94%) as a yellow solid:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.40 (s, 1H), 8.11 (d,
J=8.1 Hz, 1H), 8.04 (t, J=1.8 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.58
(d, J=1.7 Hz, 1H), 7.51-7.48 (m, 2H), 4.40 (dd, J=14.3, 7.1 Hz,
2H), 4.03 (s, 2H), 3.52 (s, 3H), 2.86 (dd, J=14.8, 7.4 Hz, 2H),
1.41 (t, J=7.2 Hz, 3H), 1.19 (t, J=7.4 Hz, 3H); ESI MS m/z 371
[C.sub.20H.sub.22N.sub.2O.sub.5+H].sup.+.
Step b) Preparation of
N-{3-[2-amino-4-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-1-methyl-5-oxo-4,5-d-
ihydro-1H-imidazol-4-yl]-phenyl}-2-methoxy-acetamide
[0416] A mixture of 2 (0.087 g, 0.23 mmol) and 1-methylguanidine
hydrochloride (0.116 g, 1.06 mmol) in dioxane (2.0 mL) and ethanol
(0.8 mL) was stirred at room temperature for 5 min. A solution of
sodium carbonate (0.112 g, 1.06 mmol) in water (2.0 mL) was then
added, the flask immersed into an oil bath at 85.degree. C. and
stirred at this temperature for 2 h. After this time the reaction
mixture was cooled to room temperature and concentrated. The
residue obtained was diluted with methylene chloride (50 mL) and
water (25 mL). The organic layer was separated and washed with
water (25 mL) and brine (50 mL), dried over sodium sulfate,
filtered and concentrated. Purification by flash chromatography
(silica, 95:5:0.25 methylene chloride/methanol/concentrated
ammonium hydroxide) afforded the title product (0.065 g, 66%) as a
colorless oil, which was solidified from methylene chloride and
hexanes to afford the title product (0.042 g) as a white solid: mp
95-115.degree. C.; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.26
(s, 1H), 7.61-7.59 (m, 2H), 7.38 (d, J=7.9 Hz, 1H), 7.31 (t, J=8.3
Hz, 1H), 6.91 (dd, J=10.1, 1.8 Hz, 2H), 4.29 (dd, J=14.3, 7.1 Hz,
2H), 3.98 (d, J=1.6 Hz, 2H), 3.49 (s, 3H), 3.12 (s, 3H), 2.76 (dd,
J=14.8, 7.4 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H), 1.13 (t, J=7.4 Hz,
3H), ESI MS m/z 426 [C.sub.22H.sub.27N.sub.5O.sub.4+H].sup.+.
Example 132
Preparation of
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methyl-5-(3-propoxypheny-
l)-3,5-dihydro-4H-imidazol-4-one
##STR00096## ##STR00097##
[0417] Step a) Preparation of
2,2,2-Trichloro-1(1H-pyrrol-2-yl)ethanone
[0418] Under a nitrogen atmosphere to a solution of trichloroacetyl
chloride (45 g, 246 mmol) in ether was added dropwise a solution of
pyrrole (15.6 g, 233 mmol) in ether over 3 hours. The heat of
reaction caused the mixture to reflux during the addition.
Following the addition the mixture was stirred for 1 hour. Under
cooling (5.degree. C.) a solution of potassium carbonate (20 g, 145
mmol) in water was added slowly. The layers were separated and the
organic phase was washed with brine, dried (MgSO.sub.4), filtered,
treated with charcoal and filtered. The solvent was removed in
vacuo and the residue was dissolved in hexane. The dark colored
solution was cooled in the refrigerator and the product
crystallized (38 g, 77% yield, tan solid), .sup.1H NMR (400 MHZ,
DMSOd.sub.6) .delta. 6.31-6.33 (m, 1H), 7.27-7.31 (m, 2H), MS m/e
(M-H).sup.- 209.9.
Step b) Preparation of
2,2,2-Trichloro-1(4-iodo-1H-pyrrol-2-yl)ethanone
[0419] Under a nitrogen atmosphere to a cold (0.degree. C.)
suspension of 2,2,2-Trichloro-1(1H-pyrrol-2-yl)ethanone (21.1 g,
99.3 mmol) and silver trifluoroacetate (23.2 g, 105 mmol) in
chloroform was added iodine (25.4 g, 100 mmol) portionwise over 10
minutes. The mixture was allowed to warm to room temperature and
stirred for 2 hours. This was filtered through celite and washed
with chloroform. The organic phase was washed sequentially with 5%
Na.sub.2S.sub.2O.sub.5, water, brine, dried (MgSO.sub.4) and
filtered. Evaporation and trituration with 80% hexane/ether (80 mL)
gave the title compound as a white solid (25.5 g, 78% yield), mp
140.degree. C., .sup.1H NMR (400 MHZ, CDCl.sub.3) .delta. 7.2 (m,
2H), 7.4 (m, 1H), (9.5 (bs, 1H), MS m/e (M+H).sup.+339.
Step c) Preparation of Ethyl-4-iodo-1H-pyrrole-2-carboxylic acid
ethyl ester
[0420] Under a nitrogen atmosphere to a solution of
2,2,2-trichloro-1(4-iodo-1H-pyrrol-2-yl)ethanone (9 g, 26.6 mmol)
in DMF (30 mL) was added Cs.sub.2CO.sub.3 (17.4 g, 53.2 mmol) and
stirred for 10 minutes. To this was then added a solution of
iodoethane (8.72 g, 55.86 mmol) in DMF (10 mL). The new mixture was
stirred at room temperature for 20 hours. A worked up TLC sample
indicated the reaction was complete. DMF was removed in vacuo and
the residue was taken back in a mixture of saturated aqueous
NH.sub.4Cl:H.sub.2O (1:1, 200 mL) solution and extracted with
ether. The combined ether extracts were washed with 5%
Na.sub.2S.sub.2O.sub.5, dried (MgSO.sub.4) and filtered.
Evaporation and purification by flash chromatography (hexane/ethyl
acetate 9.7/0.3) gave light yellow oil (7 g, 89% yield), .sup.1H
NMR (400 MHZ, CDCl.sub.3) .delta. 1.3 (t, 3H), 1.35 (t, 3H), 4.22
(q 2H), 4.3 (q, 2H), 6.85 (s, 1H), 7.0 (s, 1H), MS m/e (M).sup.+
293.
Step d) Preparation of
1-Ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid
ethyl ester
[0421] Argon was gently bubbled to a mixture of
ethyl-4-iodo-1H-pyrrole-2-carboxylic acid ethyl ester (4.1 g, 14
mmol), Cul (0.14 g, 0.76 mmol), Et.sub.3N (40 ml, 287 mmol) and
tetrakis(triphenylphosphosphine) palladium (0) (0.64 g, 0.554 mmol)
in ACN (20 mL) over 5 minutes. A prepared solution of
1-ethynyl-3-methoxy-benzene (2.03 g, 15.4 mmol) in ACN (5 mL) was
added into it and the new mixture was reflux under Nitrogen for 3
hours. The resulting brown colored reaction mixture was cooled to
room temperature and concentrated in vacuo. The concentrate was
diluted with water and extracted with ether. The combined ether
extracts were washed with saturated aqueous solution of NH.sub.4Cl,
brine, dried (MgSO.sub.4) and filtered. Evaporation and
purification by flash chromatography on silica gel (Hexane/EtOAc
9.7/0.3) gave the title compound as a yellow brownish oil (3.6 g,
84% yield), .sup.1H NMR (400 MHZ, CDCl.sub.3) .delta. 1.31-1.34 (t,
3H), 1.38-1.40 (t, 3H), 3.78 (s, 3H), 4.25-4.27 (q, 2H), 4.30-4.33
(q, 2H), 6.83 (m, 1H), 6.89 (m, 1H), 7.06 (m, 3H), 7.19 (m, 1H), MS
m/e (M+H).sup.+ 298.1.
Step e) Preparation of
1-Ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid
methyl amide
[0422] To a solution of
1-ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid
ethyl ester (3.5 g, 11.76 mmol) in dioxane (70 mL) was added LiOH
(2M, 35 mL). The reaction mixture was stirred at room temperature
for 3 days, and then concentrated in vacuo. The residue was
dissolved in H.sub.2O (30 ml) and extracted with ether. Under
cooling the aqueous was acidified with HCl (3N) and extracted with
EtOAc. The organic extracts were dried over MgSO.sub.4. Evaporation
and recrystallzation from ether and hexane gave the
1-ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid
intermediate as light yellow solid (2.55 g, 79% yield), mp
129.degree. C., .sup.1H NMR (400 MHZ, CDCl.sub.3) .delta. 1.26 (t,
3H), 3.73 (s, 3H), 4.26-4.28 (q, 2H), 6.96-6.97 (m, 2H), 6.99-7.0
(m, 2H), 7.23-7.24 (m, 1H), 7.46 (s, 1H), 12.46 (bs, 1), MS m/e
(M-H).sup.- 268.1.
[0423] This intermediate (2.5 g, 9.28 mmol) was treated with oxalyl
chloride (4.1 mL, 46.4 mmol), DMF (2 drops) in methylene chloride
(70 mL) and stirred at room temperature for 2 hours to give
1-ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid
chloride (2.7 g, 9.38 mmol) after a usual workup.
1-Ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid
chloride (2.7 g, 9.38 mmol) was diluted with methylene chloride (35
mL) and added to a prepared solution of N,O, dimethyl-hydroxyl
amine hydrochloride (4.6 g, 46.4 mmol) and diisopropyl-ethyl amine
(13 mL, 74.3 mmol) in methylene chloride (35 mL) over 5 minutes.
The reaction was complete after 4 hours. Solvent was removed in
vacuo and the residue was taken back in a mixture of saturated
aqueous NH.sub.4Cl:H.sub.2O (1:1, 150mL) solution and extracted
with ether. Combined ether extracts were washed with brine dried
(MgSO.sub.4) and filtered. Evaporation and purification by flash
chromatography (hexane/ethyl acetate 9/1) gave the title compound
as a light yellow oil (2.48 gg, 82% yield), .sup.1H NMR (400 MHZ,
CDCl.sub.3) 1.35-1.37 (t, 3H), 3.31 (s, 3H), 3.67 (s, 3H), 3.78 (s,
3H), 4.29-4.30 (q, 2H), 6.83 (m, 1H), 6.99 (m, 2H), 7.01 (m, 2H),
7.19 (m, 1H), MS m/e (M+H).sup.+ 313.1.
Step f) Preparation of
1-[1-Ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrol-2-yl]-propan-1-one
[0424] Under a nitrogen atmosphere to a cold (0.degree. C.)
solution of
1-ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid
methyl amide (2.48 g, 7.93 mmol) in THF (40 ml) was added EtMgBr
solution (1 molar in THF, 16 mL) over 10 minutes. The mixture was
allowed to warm to room temperature and stirred for 18 hours, then
poured into ice/1 N HCl solution and extracted with ether. The
combined ether extracts were washed with brine, dried over
MgSO.sub.4 and evaporated to dryness. The resultant residue was
purified by flash chromatography (hexane/ethyl acetate 9.5/0.5) to
give the title compound as an off white solid (1.8 g, 80% yield),
mp 64.degree. C., .sup.1H NMR (400 MHZ, CDCl.sub.3) .delta. 1.16
(t, 3H), 1.35 (t, 3H), 2.8 (q, 2H), 3.79 (s, 3H), 4.35 (q 2H), 6.85
(m, 1H), 6.99-7.03 (m, 2H), 7.05 (m, 2H), 7.08 (m, 1H), MS m/e
(M+H.sup.+ 282.1.
Step g) Preparation of
1-(1-Ethyl-5-propionyl-1H-pyrrol-3yl)-2-(3-methoxy-phenyl)-ethane-1,2-dio-
ne
[0425] To a solution of
1-[1-ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrol-2-yl]-propan-1-one.
(1.8 g, 6.39 mmol) in acetone was added MgSO.sub.4 (1 g, 8.95 mmol)
followed by an aqueous solution of NaHCO.sub.3 (0.32 g, 3.83 mmol)
in H.sub.2O and KMnO.sub.4 (2 g, 12.78 mmol). The suspension was
stirred for 20 hours, then diluted with H.sub.2O and ether and
filtered through a pad of solka floc. The organic phase was
separated, washed with brine, dried over MgSO.sub.4 and evaporated
to dryness to afford the title compound as a light yellow solid
(1.5 g, 75% yield), mp 97.degree. C., .sup.1H NMR (400 MHZ,
CDCl.sub.3) .delta. 1.16 (t, 3H), 1.38 (t, 3H), 2.83 (q, 2H), 3.84
(s, 3H), 4.36 (q, 2H), 7.18 (m, 1H), 7.36 (m, 1H), 7.39 (m, 1H),
7.47-7.55 (m, 3H), MS m/e (M+H).sup.+ 314.1
Step h) Preparation of
2-Amino-5-(1-ethyl-5-propionyl-1-H-pyrrol-3-yl)-5-(3-methoxy-phenyl)-3-me-
thyl-3,5-dihydro-imidazol-4-one
[0426] Using essentially the same procedure described in Example
107, step b, and employing
1-(1-ethyl-5-propionyl-1H-pyrrol-3yl)-2-(3-methoxy-phenyl)-ethane-1,2-dio-
ne (1.5 g, 4.78 mmol), the title product was obtained as a white
solid (1.37 g, 77% yield), mp 79.degree. C., .sup.1H NMR (400 MHZ,
DMSO-d.sub.6) .delta. 1.0 (t, 3H), 1.18 (t, 3H), 2.70 (q, 2H), 2.93
(s, 3H),3.69 (s, 3H), 4.22 (q, 2H), 6.55 (bs, 2H), 6.78 (m, 1H),
6.9 (s, 1H), 7.02 (m, 2H), 7.06 (m, 1H), 7.19 (m, 1H), MS m/e
(M+H).sup.+ 369.2.
Step i) Preparation of
2-Amino-5-(1-ethyl-5-propionyl-1-H-pyrrol-3-yl)-5-(3-hydroxy-phenyl)-3-me-
thyl-3,5-dihydro-imidazol-4-one
[0427] Boron tribromide (1M in dichloromethane, 21 mL, 21.17 mmol)
was added dropwise to a cold (-78.degree. C.) suspension of
2-amino-5-(1-ethyl-5-propionyl-1-H-pyrrol-3-yl)-5-(3-methoxy-phenyl)-3-me-
thyl-3,5-dihydro-imidazol-4-one (1.3 g, 3.52 mmol) in
CH.sub.2Cl.sub.2. The mixture was allowed to warm to room
temperature, stirred for 20 h, and poured slowly into cold
(0.degree. C.) ethyl ether, treated slowly with methanol over a 10
minute period, basified to pH 8 at 0.degree. C. with saturated
aqueous NaHCO.sub.3 and extracted with CHCl.sub.3. The combined
CHCl.sub.3 extracts were washed with brine, dried over MgSO.sub.4
and evaporated to dryness. The resultant residue was purifiied by
flash chromatography (ethyl acetate/methylene chloride/methyl
alcohol/triethyl amine, 5/4.4/0.5/0.1) to give the title compound
as a white solid (0.95 g, 72% yield), mp 101.degree. C., .sup.1H
NMR (400 MHZ, DMSO-d.sub.6) .delta. 0.99 (t, 3H), 1.17 (t, 3H),
2.66-2.68 (q, 2H), 2.90 (s, 3H).4.19-4.21 (q, 2H), 6.5 (bs, 2H),
6.55 (m, 1H), 6.84-6.88 (m, 3H), 7.01 (m, 2H), 9.21 (bs, 1H), MS
m/e (M-H).sup.- 353.1.
Step j) Preparation of
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methyl-5-(3-propoxypheny-
l)-3,5-dihydro-4H-imidazol-4-one
[0428] Under a nitrogen atmosphere, a solution of
2-amino-5-(1-ethyl-5-propionyl-1-H-pyrrol-3-yl)-5-(3-hydroxy-phenyl)-3-me-
thyl-3,5-dihydro-imidazol-4-one (0.08 g, 0.225 mmol) in DMF (5 mL)
was treated with Cs.sub.2CO.sub.3 (0.15 g, 0.45 mmol) and
iodopropane (0.046 g, 0.27 mmol). The reaction mixture was sealed
and stirred at room temperature for 20 hours. The solvent was
removed in vacuo and the residue was dissolved in CHCl.sub.3 and
filtered. The filtrate was evaporated. The resultant residue was
purified by combi flash chromatography (ethyl acetate/methylene
chloride/methyl alcohol/triethyl amine, 5/4.4/0.5/0.1) to give the
title compound as a white solid (0.04 g, 45% yield), mp 95.degree.
C., .sup.1H NMR (400 MHZ, DMSO-d.sub.6) .delta. 0.89-0.99 (dt, 6H),
1.15 (t, 3H), 1.64-1.66 (m, 2H), 2.64-2.68 (m, 2H), 2.9 (s, 3H),
3.81 (m, 2H), 4.20 (m, 2H), 6.50 (bs, 2H), 6.72-6.74 (m, 1H), 6.87
(s, 1H), 7.0-7.02 (m, 3H), 7.14 (m, 1H), MS m/e (M+H).sup.+
397.
Examples 133-140
Preparation of
2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methyl-5-(3-propoxypheny-
l)-3,5-dihydro-4H-imidazol-4-one
##STR00098##
[0430] Using essentially the same procedure described in Example
132, step j, and employing the appropriate alkyl iodide, the
compounds shown on Table XI were obtained and identified by NMR and
mass spectral analyses.
TABLE-US-00011 TABLE XI ##STR00099## Ex. No. R' mp (.degree. C.) (M
- H).sup.- 133 pentyl 70 423.2 134 3,3-dimethylbutyl 93 437.2 135
2-fluoroethyl 76 399.2 136 butyl 76 411.2* 137 cyclopropylmethyl 86
407.2 138 isobutyl 78 411.2* 139
CN--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2 68 421.2* 140
CH.sub.2.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2 69 423.2* *(M +
H)+
Example 141
Preparation of
2-Amino-3-methyl-5-(3-propoxyphenyl)-5-thien-2-yl-3,5-dihydro-4H-imidazol-
-4-one
##STR00100##
[0432] Using essentially the same procedure described in Example
132 and employing 3-methoxyphenyl)-2-thien-2-ylethane-1,2-dione as
starting material, the title product was obtained as a white solid,
mp 79-81.degree. C., identified by NMR and mass spectral analyses.
.sup.1HNMR (DMSOd.sub.6 300 MHz) .delta. 0.9 (t, 3H), 1.75 (m, 2H),
2.95 (s, 3H), 3.9 (q, 2H), 6.8 (b, 3H) 7.0 (m, 1H), 7.1 (m, 3H),
7.2 (m, 1H), 7.35 (m, 1H); MS m/e (M).sup.+ 330
Examples 142-148
Preparation of
2-Amino-3-methyl-5-(3-alkoxyphenyl)-5-thien-3-yl-3,5-dihydro-4H-imidazol--
4-one Compounds
##STR00101##
[0434] Using essentially the same procedure described in Example
109 and employing 1-(3-methoxyphenyl)-2-thien-3-ylethane-1,2-dione
as starting material and the desired alkyl halide, R'X, wherein X
is Cl, Br or I, the compounds shown in Table XII were obtained and
identified by NMR and mass spectral analyses.
TABLE-US-00012 TABLE XII ##STR00102## Ex. M+ No. R' mp (.degree.
C.) m/e 142 methyl 159-162 302.1 143 propyl 161-163 328 144
3-methylbutyl 84-88 358 145 pyridin-3-ylmethyl 210-213 379 146
4,4,4-trifluorobutyl 94-97 398 147 cyclohexylmethyl 88-90 384 148
isobutyl 70-73 344
Example 149
Preparation of
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-propionyl-1-prop-
yl-1H-pyrrol-3-yl)-3,5-dihydro-4H-imidazol-4-one
##STR00103##
[0435] Step a) Preparation of
2-Amino-5-(3-bromophenyl)-3-methyl-5-(5-propionyl-1-propyl-1H-pyrrol-3-yl-
)-3,5-dihydro-imidazol-4-one
[0436] Under a nitrogen atmosphere, to a solution of
2-amino-5-(3-bromo-phenyl)-3-methyl-5-(5-propionyl-1H-pyrrol-3-yl)-3,5-di-
hydro-imidazol-4-one (0.2 g, 0.51 mmol) in DMF (5 mL) was added
Cs.sub.2CO.sub.3 (0.33 g, 1.02 mmol) and iodopropane (0.12 g, 0.70
mmol). The reaction mixture was sealed and stirred at room
temperature for 20 hours. DMF was removed in vacuo, the residue was
taken back CHCl.sub.3 and filtered. Evaporation and purification by
combi flash chromatography (methylene chloride/methyl
alcohol/triethyl amine, 9.5/0.4/0.1) gave the title compound as a
white solid (0.16 g, 72% yield), mp 260.degree. C., .sup.1H NMR
(400 MHZ, CDCl.sub.3) .delta. 0.73 (t, 3H), 1.01 (t, 3H), 1.03 (q,
2H), 2.66 (m, 2H), 2.91 (s, 3H), 4.12 (q, 2H), 6.6 (bs, 2H), 6.87
(s, 1H), 6.98 (s, 1H), 7.23 (m, 1H), 7.37 (m, 1H), 7.45 (m, 1H),
7.57 (m, 1H), MS m/e (M-H).sup.- 429.1.
Step b) Preparation of
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-propionyl-1-prop-
yl-1H-pyrrol-3-yl)-3,5-dihydro-imidazol-4-one
[0437] Using essentially the same procedure described in Example
43, step e, and employing 2-fluoro-pyridin-3-yl boronic acid and
2-amino-5-(3-bromophenyl)-3-methyl-5-(5-propionyl-1-propyl-1H-pyrrol-3-yl-
)-3,5-dihydro-imidazol-4-one as reactants, the title product was
obtained as a white solid, mp 118.degree. C., .sup.1H NMR (400 MHZ,
DMSO-d.sub.6) .delta. 0.73 (t, 3H), 0.96 (t, 3H), 1.54 (m, 2H),
2.67 (m, 2H), 2.92 (s, 3H), 4.13 (m, 2H), 6.60 (bs, 2H), 6.92 (s,
1H), 7.01 (s, 1H), 7.41 (m, 3H), 7.53 (m, 1H), 7.67 (m, 1H), 7.97
(m, 1H), 8.19, (m, 1H), m/e (M-H).sup.- 446.2.
Example 150
Preparation of
2-Amino-5-[3-bromophenyl]-5-[1-(2-fluoroethyl)-5-propionyl-1H-pyrrol-3-yl-
)-3-methyl-3,5-dihydro-4H-imidazol-4-one
##STR00104##
[0439] Using essentially the same procedure described in Example
149, step a, and employing 2-fluoro-1-iodoethane, the title
compound was obtained and identified by NMR and mass spectral
analyses. .sup.1HNMR (DMSOd.sub.6 300 MHz) .delta. 0.98(s,3H),
2.76(q,2H), 3.9(s,3H), 4.5(s,2H), 4.6(m,2H), 6.65(brs,2H),
6.9(s,1H), 7.1(s,1H), 7.2(t,1H), 7.4(m,1H), 7.55(m,1H), 7.6(s,1H);
MS m/e (M+H).sup.+ 435
Example 151
Preparation of
2-Amino-5-[3-(2,5-difluoropyridin-3-yl)phenyl]-5-[1-(2-fluoro-ethyl)-5-pr-
opionyl-1H-pyrrol-3-yl)-3-methyl-3,5-dihydro-4H-imidazol-4-one
##STR00105##
[0441] Using essentially the same procedure described in Example
149, step b, and employing 2,5-difluoropyridin-3-ylboronic acid,
the title compound was obtained and identified by NMR and mass
spectral analyses. .sup.1HNMR (DMSOd.sub.6 300 MHz) .delta.
0.98(s,3H), 2.76(q,2H), 3.9(s,3H), 4.45(s,2H), 4.6(m,2H),
6.6(brs,2H), 6.95 (s,1H), 7.4(m,2H), 7.6(d,1H), 7.78(s,1H),
8.0(m,1H), 8.2(d,1H); MS m/e (M+H).sup.+ 470
Examples 152-182
Preparation of
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-carbonyl-1-susti-
tuted-1H-pyrrol-3-yl)-3,5-dihydro-4H-imidazol-4-one Compounds
##STR00106##
[0443] Using essentially the same procedures described hereinabove
in Examples 132 and 149, the compounds shown in Table XIII were
obtained and identified by NMR and mass spectral analyses.
TABLE-US-00013 TABLE XIII ##STR00107## Ex. mp No R8 R' R'' .degree.
C. 152 H 3-F-propyl ethyl 105 153 H 3-CH.sub.3-butyl ethyl -- 154 H
H ethyl -- 155 H ethyl ethyl 126-128 156 H ethyl methyl 123-124 157
H ethyl NHCH.sub.3 138-140 158 H ethyl NHC.sub.2H.sub.5 132-135 159
H ethyl NH-n-propyl 118-120 160 H ethyl NH-n-butyl 118-120 161 H
ethyl NH-isopropyl 121-123 162 H ethyl NH-cyclopentyl 127-128 163 H
ethyl N-piperidinyl 111-113 164 H ethyl N-morpholinyl 108-109 165 H
ethyl N(CH.sub.3).sub.2 >200 166 H ethyl NH-(4-F-benzyl) 110-112
167 H 2-fluoroethyl ethyl 100 168 H ethyl propyl 82-84 169 H ethyl
pentyl 71-73 170 H ethyl phenyl 104-106 171 H ethyl cyclohexyl
94-100 172 H ethyl cyclopropyl 98-100 173 H ethyl isopropyl 85-88
174 H ethyl sec-butyl 210-211 175 H H ethyl 121-125 176 H
4,4,4-trifluorobutyl ethyl 91-94 177 H cyclopropylmethyl ethyl
111-114 178 H 4-fluorobutyl ethyl 105 179 H isobutyl ethyl 98-102
180 H methyl ethyl 107-111 181 H benzyl ethyl 93-96 182 H
1,3-thiazol-4-ylmethyl ethyl 116-120
Example 183
Preparation of
(5S)-2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluo-
ropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (A)
and
(5R)-2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluo-
ropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
(B)
##STR00108##
[0445] A racemic mixture of
2-amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluoropyr-
idin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one was
separated by chiral HPLC using a Chiralcel AD, 2.times.25 cm column
with 20% EtOH in hexane to give the title products: (A)
(5S)-2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluo-
ropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one, mp
114-116.degree. C.; MS (ES) m/z 452.1 [M+H] and (B)
(5R)-2-amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[4-fluoro-3-(2-fluo-
ropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one, mp
114-117.degree. C.; MS (ES) m/z 452.1 [M+H].
Example 184
Preparation of Methyl
4-{(4S)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate
(A) and Methyl
4-{(4R)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate
(B)
##STR00109##
[0447] A racemic mixture of methyl
4-{2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-
-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate
was separated by chiral HPLC using a Chiralcel AD, 2.times.25 cm
column with 15% EtOH in hexane to give the title products: (A)
Methyl
4-{(4S)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate-
, mp 111-113.degree. C.; [.alpha.].sub.D.sup.25=-65.6.degree. (c=1%
solution, MeOH); MS (APPI) m/z472 [M+H].sup.+ and (B) methyl
4-{(4R)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate-
, mp 110-114.degree. C.; [.alpha.].sub.D.sup.25=+68.2.degree. (c=1%
solution, MeOH); MS (APPI) m/z 472 [M+H].sup.+.
Example 185
Preparation of
(5S)-2-Amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[3-(2-fluoropyridin-
-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
##STR00110##
[0449] A racemic mixture of
2-amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[3-(2-fluoropyridin-3-yl-
)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one was separated by
chiral HPLC using a Chiralcel AD, 2.times.25 cm column with 20%
EtOH in hexane to give the title product, mp 94-97.degree. C.;
[.alpha.].sub.D.sup.25=-68.85.degree. (c=5.47 MG/0.7 ML, MeOH); MS
(ES) m/z 432.1 [M+H].sup.+.
Example 186
Preparation of Methyl
4-{(4S)-2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-ox-
o-4,5-dihydro-1H-imidazol-4-yl]-1-ethyl-1H-pyrrole-2-carboxate
##STR00111##
[0451] A racemic mixture of methyl
4-{2-amino-4-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-
-dihydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carboxylate was
separated by chiral HPLC using a Chiralcel AD, 2.times.25 cm column
with 20% EtOH in hexane to give the title product, mp
114-117.degree. C.; [.alpha.].sub.D.sup.25=-63.2.degree. (c=1%
solution, MeOH); MS (APPI) m/z 454 [M+H].sup.+.
Example 187
Preparation of
(5S)-5-(5-Acetyl-1-ethyl-1H-pyrrol-3-yl)-2-amino-5-[3-(2-fluoropyridin-3--
yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
##STR00112##
[0453] A racemic mixture of
5-(5-acetyl-1-ethyl-1H-pyrrol-3-yl)-2-amino-5-[3-(2-fluoropyridin-3-yl)ph-
enyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one was separated by
chiral HPLC using a Chiralcel AD, 2.times.25 cm column with 20%
EtOH in hexane to give the title product, mp 109-111.degree. C.;
[.alpha.].sub.D.sup.25=-60.6.degree., (c=8.85 MG/0.885 ML, MeOH);
MS (ES) m/z 418.2 [M+H].sup.+.
Example 188
Preparation of
2-Amino-5-[1-ethyl-5-(methylsulfonyl)-1H-pyrrol-3-yl]-5-[4-fluoro-3-(2-fl-
uoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
##STR00113##
[0454] Step 1: 4-Iodo-2-methanesulfonyl-1H-pyrrole
[0455] A solution of 2-(methylsulfonyl)pyrrole (0.3 g, 2.06 mmol)
in DMF at -10.degree. C. was treated with N-iodosuccinimide (0.49
g, 2.17 mmol), stirred at -10.degree. C. for 3.5 h, poured into
CH.sub.2Cl.sub.2, washed sequentially with 20% Na.sub.2CO.sub.3 and
brine. The organic phase was dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. Chromatography of the resultant residue
(silica gel, 5%-40% EtOAc-hexanes as eluent) yielded 0.14 gm (25%
yield) of a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
3.09 (s, 3H), 6.93 (dd, 1H, J=1.5, 2.5 Hz), 7.03 (dd, 1H, J=1.5,
2.8 Hz).
Step 2: 1-Ethyl-4-iodo-2-methanesulfonyl-1H-pyrrole
[0456] A solution of 4-iodo-2-methanesulfonyl-1H-pyrrole (0.14 g,
0.52 mmol) in DMF was treated with Cs.sub.2CO.sub.3 (0.84 g, 2.58
mmol) and ethyl iodide (0.161 g, 1.03 mmol). The reaction mixture
was diluted with EtOAc and washed sequentially with water and
brine. The organic phase was separated, dried (Na.sub.2SO.sub.4)
and concentrated in vacuo. Chromatography of the resultant residue
(silica gel, 10%-30% EtOAc-hexanes as eluent) yielded an oil;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 1.47 (t, 3H, J=7.3 Hz),
3.09 (s, 3H), 4.26 (q, 2H, J=7.3 Hz), 6.90 (m, 1H), 6.95 (s,
1H).
Step 3:
4-(3-Bromo-4-fluoro-phenylethynyl)-1-ethyl-2-methanesulfonyl-1H-py-
rrole
[0457] A solution of 1-ethyl-4-iodo-2-methanesulfonyl-1H-pyrrole
(0.28 g, 0.94 mmol) in DMF was treated with
dichlorobis(triphenylphosphine)-palladium(II) (0.033 g, 0.05 mmol),
triphenylphosphine (0.0054 g, 0.028 mmol) and triethylamine (0.68
mL, 4.9 mmol), treated dropwise with a solution of
2-bromo-4-ethynyl-1-fluorobenzene (0.28 g, 1.4 mmol) in DMF,
stirred at room temperature for 18 h, poured into EtOAc and washed
sequentially with water and brine. The organic phase is separated,
dried (Na.sub.2SO.sub.4) and concentrated in vacuo. Chromatography
of the resultant residue (silica gel, 2%-20% EtOAC-hexanes as
eluent) yielded an oil; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
1.50 (t, 3H, J=7.3 Hz), 3.12 (s, 3H), 4.28 (q, 2H, J=7.3 Hz), 7.01
(d, 1H, J=1.8 Hz), 7.07 (t, 1H, J=8.5 Hz), 7.12 (d, 1H, J=1.8 Hz),
7.37 (m, 1H), 7.66 (dd, 1H, J=2.1, 6.6 Hz).
Step 4:
1-(3-Bromo-4-fluoro-phenyl)-2-(1-ethyl-5-methanesulfonyl-1H-pyrrol-
-3-yl)-ethane-1,2-dione
[0458] A solution of
4-(3-bromo-4-fluoro-phenylethynyl)-1-ethyl-2-methanesulfonyl-1H-pyrrole
(0.35 g, 0.93 mmol) in acetone was treated with NaHCO.sub.3 (0.047
g, 0.56 mmol) and MgSO.sub.4 (0.17 g, 1.4 mmol), treated with
KMnO.sub.4 (0.32 g, 2.05 mmol) and water, stirred at room
temperature for 2 h and fitered. The filtercake was washed with
EtOAC, dried overnight and washed with EtOAc a second time. The
combined filtrates were washed with H.sub.2O and brine, dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to yield 0.32 gm (86%
yield) of an oil. This was used as is in Step 5.
Step 5:
2-Amino-5-(4-bromo-3-fluoro-phenyl)-5-(1-ethyl-5-methanesulfonyl-1-
H-pyrrol-3-yl)-3-methyl-3,5-dihydro-imidazol-4-one
[0459] A solution of
1-(3-bromo-4-fluoro-phenyl)-2-(1-ethyl-5-methanesulfonyl-1H-pyrrol-3-yl)--
ethane-1,2-dione (0.32 g, 0.79 mmol) in dioxane and EtOH was
treated with N-methylguanidine hydrochloride (0.17 g, 1.6 mmol) and
Na.sub.2CO.sub.3(0.18 g, 1.66 mmol), heated to 105.degree. C. for
18 h and concentrated in vacuo. The residue was dissolved in
CHCl.sub.3, washed with H.sub.2O and brine, dried
(Na.sub.2SO.sub.4) and evaporated to dryness at reduced pressure.
Chromatography of this residue (silica gel, EtOAc and 1%-2%
MeOH-EtOAc as eluent) yielded a solid; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 1.44 (t, 3H, J=7.3 Hz), 3.08 (s, 3H), 3.10 (s,
3H), 3.97 (brs, 2H), 4.21 (q, 2H, J=7.3 Hz), 6.85 (d, 1H, J=2.1
Hz), 6.90 (d, 1H, J=2.1 Hz), 7.06 (t, 1H, J=8.5 Hz), 7.51 (m, 1H),
7.77 (dd, 1H, J=2.3, 6.6 Hz).
Step 6:
2-Amino-5-[1-ethyl-5-(methylsulfonyl)-1H-pyrrol-3-yl]-5-[4-fluoro--
3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
[0460] A degassed solution of
dichlorobis(triphenylphosphine)-palladium(II) (0.016 g, 0.023
mmol), triphenylphosphine (0.012 g, 0.046 mmol) in 2.0 mL of 50:50
EtOH-toluene was treated with Na.sub.2CO.sub.3 (0.19 g, 1.8 mmol),
2-fluoropyrinine-3-boronic acid (0.097 g, 0.69 mmol) and a solution
of
2-amino-5-(4-bromo-3-fluoro-phenyl)-5-(1-ethyl-5-methanesulfonyl-1H-pyrro-
l-3-yl)-3-methyl-3,5-dihydro-imidazol-4-one (0.21 g, 0.46 mmol) in
1 mL of degassed 50:50 EtOH-toluene, stirred at 100.degree. C. for
18 h and concentrated in vacuo. The residue was dissolved in
CHCl.sub.3, washed with H.sub.2O and brine, dried
(Na.sub.2SO.sub.4) and evaporated to dryness at reduced pressure.
Chromatography of the resultant residue (silica gel, EtOAc and
1%-4% MeOH-EtOAc as eluent) yielded the title product, 0.16 gm (74%
yield) as a light yellow solid mp 193-195.degree. C. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.: 1.27 (t, 3H, J=7.2 Hz), 2.91 (s,
3H), 3.15 (s, 3H), 4.21 (q, 2H, J=7.2 Hz), 6.63 (d, 1H, J=2.1 Hz),
7.06 (d, 1H, J=2.1 Hz), 7.27 (t, 1H, J=9.3 Hz), 7.45 (m, 1H), 7.63
(m, 1H), 7.97 (m, 1H), 8.27 (m, 1H); MS (ESI) m/z 474.1
([M+H]).sup.+; MS (ESI) m/z 472.1 ([M-H]).sup.-.
Examples 189-199
Preparation of Methyl
4-[2-amino-1-methyl-5-oxo-4-(3-heteroarylphenyl)-4,5-dihydro-1H-imidazol--
4-yl]-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate Compounds
##STR00114##
[0462] Using essentially the same procedure described in Example
188, Step 6, and employing
4-[2-amino-4-(4-bromo-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl-
]-1-(2-fluoro-ethyl)-1H-pyrrole-2-carboxylic acid methyl ester as
substrate and the appropriate heteroarylboronic acid, the compounds
shown on Table XIV were obtained and identified by HNMR and mass
spectral analyses.
TABLE-US-00014 TABLE XIV ##STR00115## Ex. No. R7 mp (.degree. C.)
(M + H).sup.+ 189 pyrimidin-5-yl 181-184 435.1 190
2-fluoropyridin-3-yl 100 452.1 191 6-fluoropyridin-3-yl 206-210
454.1 192 2,5-difluorophenyl 166-170 471.1 193 3,5-difluorophenyl
173-176 471.1 194 3-cyanophenyl 98-101 460.1 195
5-cyano-2-fluorophenyl 147-150 478.1 196 3-methoxyphenyl 121-124
465.5 197 3-(trifluoromethoxy)phenyl 154-157 503.1 198
3,4-difluorophenyl 125-128 471.1 199 1,3-benzodioxol-5-yl 137-140
479.1
Example 200
Preparation of
2-Amino-5-[5-propionyl-1-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-5-[3-(2-f-
luoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
##STR00116##
[0463] Step a) Preparation of
1-[4-Iodo-1-(2,2,2-trifluoro-ethyl)-1H-pyrrole-2-yl)-propan-1-one
[0464] A mixture of 1-(4-Iodo-1H-pyrrole-2-yl)-propan-1-one (3.8 g,
15.3 mmol), 2-Iodo-1,1,1-trifluoroethane (3.83 g, 18.3 mmol) and
Cs.sub.2CO.sub.3 (5.96 g, 183 mmol) in 20 ml DMF is heated with
stirring to 60.degree. C. for until the reaction is finished (TLC).
The mixture then is cooled to room temperature and partitioned
between water (200 ml) and ether (100 ml), the ether phase is
separated and dried with MgSO.sub.4. The product is purified by
flash chromatography with solvent EtOAc/hexane (10/90) to afford
the product as an oil which solidified upon standing 1.8 g (35%).
.sup.iHNMR (DMSO-d.sub.6): .delta. (ppm) 1.00 (t, 3H), 2.79 (q,
2H), 5.29 (q, 2H), 7.36 (s, 1H), 7.39 (s, 1H).
Step b) Preparation of
1-(3-bromo-phenyl)-2-[5-propionyl-1-(2,2,2-trifluoro-ethyl)-1H-pyrrole-3--
yl]-ethane-1,2-dione
[0465] A mixture of
1-[4-Iodo-1-(2,2,2-trifluoro-ethyl)-1H-pyrrole-2-yl)-propan-1-one
(4.8 g, 0.145 mol), 1-bromo-3-ethynyl-benzene (2.62 g, 0.145 mol)
Cul (137 mg, 0.725 mmol) and Pd(PPh.sub.3).sub.4 (670 mg, 0.58
mmol) in a mixture of triethylamine (50 ml) and acetonitrile (20
ml) is heated to reflux for 2 hours before cooled down to room
temperature. The volatile solvent is removed under reduced
pressure, and the residue is partitioned between ethyl acetate (50
ml) and water (200 ml). The organic phase is dried with MgSO.sub.4
and is purified by flash chromatography with EtOAc/hexane
(10/90-20/80) as eluent to afford the alkyne product as a yellow
solid 4.6 g (82%). This solid stirred with KMnO.sub.4 (4.73 g, 2.5
mol), NaHCO.sub.3 (604 mg, 7.2 mmol) and MgSO.sub.4 (2.16 g, 18
mmol) in a mixture of acetone (200 ml) and water (100 ml) at room
temperature for two hours. The mixture is extracted with ether
(2.times.50 ml) to afford the product as a yellow oil 4.5 g (90%).
.sup.1HNMR (DMSO-d.sub.6): .delta. (ppm) 1.03 (t, 3H), 2.92 (q,
2H), 5.38 (q, 2H) 7.56 (t, 1H), 7.74 (s, 1H), 7.92 (d, 1H), 7.95
(d, 2H), 8.06 (s, 1H), 8.12 (s, 1H).
Step c) Preparation of
2-amino-5-(3-bromophenyl)-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methyl-
-3,5-dihydro-4H-imidazol-4-one
[0466] A mixture of
1-(3-bromo-phenyl)-2-[5-propionyl-1-(2,2,2-trifluoro-ethyl)-1H-pyrrole-3--
yl]-ethane-1,2-dione (4.5 g, 0.0108 mol), methylguanidine (2.36 g,
0.0216 mol) and sodium carbonate (2.28 g, 0.0216 mol) in 100 ml
ethanol is heated to reflux for three hours. The solvent is
evaporated to dryness and the residue is flash chromatographed on
silica gel with eluent EtOAc/Ethanol (containing 2 mol ammonia) to
afford the product 3.8 gram (75%) as an off-white solid, mp
100-102.degree. C., MS (+) ES 471 [M+H].sup.+.
Step d) Preparation of
2-amino-5-[5-propionyl-1-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-5-[3-(2-f-
luoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
[0467] A mixture of
2-amino-5-(3-bromophenyl)-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-3-methyl-
-3,5-dihydro-4H-imidazol-4-one (471 mg, 1 mmol),
(2-fluoropyridin-3-yl)boronic acid (280 mg, 2 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (35 mg, 0.05 mmol), PPh.sub.3 (26.1 mg,
0.1 mmol) and sodium carbonate (315 mg, 3 mmol) in a mixture of
toluene/ethanol (50/50) (30 ml) is heated to 110.degree. C. for
three hours. The cooled mixture is partitioned between methelene
chloride (50 ml) and water (150 ml), the organic phase is separated
and dried with MgSO.sub.4. The product is purified by flash
chromatography with solvent EtOAc/Ethanol (containing 2.0M ammonia)
(90/10) to afford the title product as a white solid, 430 mg (89%
yield), mp 108-110.degree. C., MS (+) ES 488 [M+H].sup.+.
Examples 201-208
Preparation of
2-amino-5-[5-propionyl-1-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-5-[3-(het-
eroaryl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
Compounds
##STR00117##
[0469] Using essentially the same procedure described in Example
200 and employing the appropriately substituted bromoethynylbenzene
and a suitable heteroaryl- or arylboronic acid, the compounds shown
in Table XV were obtained and identified by NMR and mass spectral
analyses.
TABLE-US-00015 TABLE XV ##STR00118## Ex. mp No R7 R8 .degree. C. M
+ H 201 pyrimidin-5-yl H 135-137 471.2 202 3-methoxyphenyl H
103-105 499.1 203 3,5-difluorophenyl H 104-106 505.1 204
3-chlorophenyl H 108-110 503.1 205 3-chloro-4-fluorophenyl H
107-108 521.0 206 3-cyanophenyl H 112-114 494.1 207
2-fluoropyridin-3-yl F 122-124 506.1 208 pyrimidin-5-yl F 225-226
489.2
Examples 209-212
Preparation of
2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-carbonyl-1-subst-
ituted-1H-pyrrol-3-yl)-3,5-dihydro-4H-imidazol-4-one Compounds
##STR00119##
[0471] Using essentially the same procedure described in Example
200 and employing the appropriately substituted iodopyrrole, the
compounds shown in Table XVI were obtained and identified by NMR
and mass spectral analyses.
TABLE-US-00016 TABLE XVI ##STR00120## Ex. mp No R R'' .degree. C.
209 3-fluoropropyl H 202-204 210 3-fluoropropyl methyl 218-221 211
H ethyl -- 212 2,2-difluoroethyl ethyl --
Example 213
Preparation of
5-[5-acetyl-1-(3-fluoropropyl)-1H-pyrrol-3-yl]-2-amino-5-(3-hydroxyphenyl-
)-3-methyl-3menthyl-3,5-dihydro-4H-imidazol-4-one
##STR00121##
[0473] Using essentially the same procedure described in Example
200 and employing the appropriately substituted iodopyrrole and
3-hydroxyphenylethyne, the title compound was obtained as a yellow
solid and identified by NMR and mass spectral analyses.
Example 214
Preparation of
3-[(3-{4-[5-Acetyl-1-(3-fluoropropyl)-1H-pyrrol-3-yl]-2-amino-1-methyl-5--
oxo-4,5-dihydro-1H-imidazol-4-yl}phenoxy)methyl]benzamide
##STR00122##
[0475] A mixture of
5-[5-acetyl-1-(3-fluoropropyl)-1H-pyrrol-3-yl]-2-amino-5-(3-hydroxyphenyl-
)-3-methyl-3,5-dihydro-4H-imidazol-4-one,
3-(chloromethyl)benzamide, sodium iodide, and cesium carbonate in
dimethylformamide was heated to 45.degree. C. for 16 hours. The
cooled reaction mixture was poured into ethyl acetate and washed
with water. The organic phase was dried over sodium sulfate and
evaporated. The resultant residue was purified by HPLC using a CN
bonded phase preparative column and by precipitation from hexane to
give the title product as a white solid, identified by NMR and mass
spectral analyses.
Example 215
Preparation of
5-[5-Acetyl-1-(3-fluoropropyl)-1H-pyrrol-3-yl]-2-amino-3-methyl-5-[3-(2-m-
orpholin-4-yl-2-oxoethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one
##STR00123##
[0477] Using essentially the same procedure described in Example T'
and employing 2-chloro-1-morpholinoethanone, the title compound was
obtained as a white solid, identified by NMR and mass spectral
analyses.
Example 216
Preparation of
4-{2-Amino-1-methyl-5-oxo-4-[3-(phenylethynyl)phenyl]-4,5-dihydro-1H-imid-
azol-4-yl}-1-(3-fluoropropyl)-1H-pyrrole-2-carbaldehyde
##STR00124##
[0479] Using essentially the same procedure described in Example
200 and employing
4-{2-amino-1-methyl-5-oxo-4-(3-bromophenyl)-4,5-dihydro-1H-imid-
azol-4-yl}-1-(3-fluoropropyl)-1H-pyrrole-2-carbaldehyde and
phenylethyneboronic acid, the title compound was obtained as a
white solid, mp 85-90.degree. C., identified by NMR and mass
spectral analyses.
Example 217
Preparation of
2-Amino-5-[1-ethyl-5-(methoxymethyl)-1H-pyrrol-3-yl]-5-[3-(2-fluoropyridi-
n-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
##STR00125##
[0481] A solution of
4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde in dry ethanol
was treated with 2 equivalents of sodium borohydride at 0.degree.
C., allowed to come to room temperature, quenched with water and
evaporated to dryness under reduced pressure. The resultant residue
is dispersed in water and extracted with ethyl acetate. The
extracts are combined, dried over MgSO4 and concentrated in vacuo.
The resultant residue was dissolved in 0.5M methanolic HCl, stirred
overnight and evaporated to dryness under reduced pressure. This
residue was dissolved in chloroform, washed with dilute sodium
bicarbonate, dried over sodium sulfate and concentrated in vacuo.
The resultant residue was purified using flash chromatography and
was crystallized from ethylacetate/hexane to give the title
compound as a solid, mp 154-157.degree. C., identified by NMR and
mass spectral analyses.
Examples 218-221
Preparation of
2-Amino-5-[1-ethyl-5-(alkoxymethyl)-1H-pyrrol-3-yl]-5-[3-(2-fluoropyridin-
-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
##STR00126##
[0483] Using essentially the same procedure described in Example
217 and employing the desired alcohol, R''OH, the compounds shown
in Table XVii were obtained and identified by NMR and mass spectral
analyses.
TABLE-US-00017 TABLE XVII ##STR00127## Ex. mp No R'' .degree. C.
218 ethyl 135-141 219 propyl 128-131 220 isopropyl 126-128 221
n-butyl --
Example 222
Preparation of
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(3-fluoropropyl)-1H-pyrrole-2-carbaldehyde
oxime
##STR00128##
[0485] A solution of
4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(3-fluoropropyl)-1H-pyrrole-2-carbaldehyde in
dry tetrahydrofuran was treated with 1.1 equivalent of
hydroxylamine hydrochloride, warmed to 45.degree. C. for 2 hours
and concentrated in vacuo. The resultant residue was dissolved in
chloroform, washed with water, dried over sodium sulfate and
concentrated in vacuo. This residue was purified by HPLC (CN bonded
stationary phase, gradient 30% to 60% of (20% MeOH/methylene
chloride) and hexane to afford the title compound as a white
amorphous solid, mp 119-123.degree. C., identified by NMR and mass
spectral analyses.
Example 223
Preparation of
2-Amino-5-[1-ethyl-5-(4-hydroxybenzyl)-1H-pyrrol-3-yl]-5-[3-(2-fluoropyri-
din-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
##STR00129##
[0487] Using essentially the same procedure described in Example
217 and employing phenolic HCl in step 2, the title compound was
obtained and identified by NMR and mass spectral analyses. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.: 1.04 (t, 3H, J=7.2 Hz), 2.88
(s, 3H), 3.66 (q, 2H, J=7.2 Hz), 3.67 (s, 2H), 5.60 (d, 1H, J=1.9
Hz), 6.52 (d, 2H, J=1.9 Hz), 6.61 (d, 2H, J=8.5 hZ), 6.68 (d, 2H,
J=8.5 hZ), 7.38-7.52 (series of m, 4H), 7.66 (s, 1H), 7.94 (m, 1H),
and 8.20 (m, 1H).
Example 224
Preparation of
(5S)-2-amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-propionyl-1-
-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one
(A) and
(5R)-2-amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-propion-
yl-1-(2,2,2-trifluoroethyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one
(B)
##STR00130##
[0489] A racemic mixture of
2-amino-5-(1-ethyl-5-propionyl-1H-pyrrol-3-yl)-5-[3-(2-fluoropyridin-3-yl-
)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one is chirally
separated on Chiralcel AD, 50.times.5 cm, mobile phase 100%
ethanol, [.alpha.].sub.25=-75 (1% DMSO) the S enantiomer title
product A is obtained as a white solid, mp 108-110.degree. C., MS
(+) ES 488 [M+H].sup.+ and, using mobile phase 100% ethanol,
[.alpha.].sub.25=+71.8 (1% DMSO), the R enantiomer title product B
is obtained as a white solid, mp 108-110.degree. C., MS (+) ES 488
[M+H].sup.+.
Example 225
Preparation of
4-[2-Amino-1-methyl-5-oxo-4-(3-pyrimidin-5-ylphenyl)-4,5-dihydro-1H-imida-
zol-4-yl]-1-methyl-1H-pyrrole-2-carbonitrile
##STR00131##
[0490] Step a-1) Preparation of
4-(3-Bromo-phenylethynyl)-1H-pyrrole-2-carbonitrile
[0491] The dimethylformamide was vigorously deoxygenated with
nitrogen gas before use in this reaction. To a solution of
2-cyano-4-iodopyrrole (2.30 g, 10.52 mmol) in dimethylformamide was
added dichloropalladium(II) bistriphenylphosphine (185 mg),
copper(I) iodide (50 mg) and finally triethylamine (3.85 mL). After
stirring ten minutes, 1-bromo-3-ethynyl-benzene (2.38 g, 13.15
mmol) was added. This mixture was stirred overnight at room
temperature under nitrogen atmosphere. The reaction mixture was
diluted with ethyl acetate and washed with 2% aqueous lithium
chloride and 5% aqueous sodium chloride. The organic phase was
dried (Na.sub.2SO.sub.4), filtered and evaporated. The residue was
purified by flash chromatography (silica gel, 20% ethyl
acetate/hexane) to afford
4-(3-bromo-phenylethynyl)-1H-pyrrole-2-carbonitrile as a yellow
solid, 2.84 g, 99% yield.
Step a-2) Preparation of
4-[2-(3-Bromophenyl)-2-oxo-acetyl]-1H-pyrrole-2-carbonitrile
[0492] A solution of
4-(3-bromo-phenylethynyl)-1H-pyrrole-2-carbonitrile (2.85 g, 10.52
mmol) in acetone was treated with a 45.degree. C. solution of
magnesium sulfate (1.90 g, 15.78 mmol) and sodium bicarbonate (0.53
g, 6.31 mmol) in water, immediately treated with KMnO.sub.4 (3.74
g, 23.67 mmol), stirred for 15 minutes (TLC (silica gel, 25% ethyl
acetate/hexane) indicated complete clean conversion), diluted with
EtOAc and washed with water until the washings were colorless. The
organic phase was dried (MgSO.sub.4), filtered and evaporated. The
resultant residue was crystallized to purity from warm ethyl
acetate/hexane to afford
4-[2-(3-bromophenyl)-2-oxo-acetyl]-1H-pyrrole-2-carbonitrile as a
yellow crystalline solid, 2.68 g, 84% yield.
Step b) Preparation of
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1H-pyrrole-2-carbonitrile
[0493] A mixture of
4-[2-(3-bromophenyl)-2-oxo-acetyl]-1H-pyrrole-2-carbonitrile (2.73
g, 9.0 mmol) and methyl guanidine hydrochloride (1.972 g, 18.0
mmol) in dioxane/ethanol (40 mL/20 mL) was treated with a solution
of sodium carbonate (1.91 g, 18.0 mmol) in water. The reaction
mixture was heated to 80.degree. C. for ten hours (TLC indicated
complete conversion to one more polar material), concentrated in
vacuo and redissolved in 5% methanol/chloroform. This solution was
dried (Na.sub.2SO.sub.4), filtered and evaporated. The resultant
residue was purified by flash chromatography (silica gel, 5%
methanol/chloroform as eluent) to give
4-[2-amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1H-pyrrole-2-carbonitrile as a beige glass, 2.40 g (74.5%
yield).
Step c-1) Preparation of
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-methyl-1H-pyrrole-2-carbonitrile
[0494] To a solution of
4-[2-amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1H-pyrrole-2-carbonitrile (0.50 g, 1.40 mmol) in dimethylformamide
was added cesium carbonate (0.639 g, 1.96 mmol) and methyl iodide
(96 .mu.L, 1.54 mmol). The reaction mixture was stirred overnight
at room temperature while protected from moisture, diluted with
chloroform and washed well with water. The organic phase was dried
(Na.sub.2SO.sub.4), filtered through a short column of silica gel
and evaporated to afford the desired compound as a tan solid, 0.524
g (quantitative yield).
Step c-2) Preparation of
4-[2-Amino-1-methyl-5-oxo-4-(3-pyrimidin-5-ylphenyl)-4,5-dihydro-1H-imida-
zol-4-yl]-1-methyl-1H-pyrrole-2-carbonitrile
[0495] The toluene/ethanol (1/1) solvent mixture was deoxygenated
vigorously with nitrogen gas prior to using in this reaction. A
mixture of
4-[2-amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4--
yl]-1-methyl-1H-pyrrole-2-carbonitrile (173 mg, 0.465 mmol), sodium
carbonate (148 mg, 1.394 mmol), pyrimidine-5-boronic acid (86.4 mg,
0.697 mmol) and tetrakis(triphenylphosphine)palladium(0) (27 mg,
0.023 mmol) in toluene/ethanol (1/1) solvent mixture (10 mL) was
heated in a 100.degree. C. oil bath for eight hours. TLC (5%
methanol/chloroform) shows complete conversion to a new material.
The solvent was removed by evaporation and the residue dissolved in
chloroform and washed with water. The organic phase was dried
(Na.sub.2SO.sub.4), filtered and evaporated. The resultant residue
was purified by HPLC (Luna CN column, normal mobile phase).
Crystallization from warm ethyl acetate/hexane afforded the title
product as a pure crystalline material, mp 214-225.degree. C.; MS
(ES) m/z 370.1.
Examples 226-232
Preparation of
4-[2-Amino-1-methyl-5-oxo-4-(3-heteroarylphenyl)-4,5-dihydro-1H-imidazol--
4-yl]-1-alkyl-1H-pyrrole-2-carbonitrile Compounds
##STR00132##
[0497] Using essentially the same procedure described in Example
225 and employing the appropriate alkyl iodide and a suitable
heteroarylboronic acid, the compounds shown on Table XVIII were
obtained and identified by NMR and mass spectral analyses.
TABLE-US-00018 TABLE XVIII ##STR00133## Ex. mp MS No R R7 .degree.
C. m/z 226 CH.sub.3 2-fluoropyridin-3-yl 213-220 387.1 227 CH.sub.3
2-chloro-5-fluoropyridin-3-yl >225 421.0 228 CH.sub.2CH.sub.2F
pyrimidin-5-yl 193-194 402.1 229 propyl pyrimidin-5-yl 165-166 --
230 propyl 2-fluoropyridin-3-yl 187-188 -- 231 CH.sub.2CH.sub.2F
2-fluoropyridin-3-yl 175-177 -- 232 propyl
2-chloro-5-fluoropyridin-3-yl 132-134 --
Example 233
Preparation of
4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde
##STR00134##
[0498] Step a) Preparation of
4-[(3-Bromophenyl)ethynyl]-1H-pyrrole-2-carbaldehyde
[0499] A solution of 4-iodo-1H-pyrrole-2-carbaldehyde (0.50 g;
2.262 mmol) and bis(triphenylphosphine)palladium-(II)chloride
(0.079 g; 0.113 mmol)) in DMF (15 mL; degassed with nitrogen for 30
minutes) was stirred at ambient temperature for 15 minutes. Then
the following were added: 1-bromo-3-ethynylbenzene (0.61 g; 3.394
mmol), copper iodide (43 mg; 0.226), and triethylamine (1.58 mL,
11.3 mmol). The course of the reaction was followed with TLC (4:1,
hexane:ethyl acetate). After 2 hours the reaction mixture was
diluted with water and the organic material was extracted into
dichloromethane. The organic extracts were washed with water and
brine, dried over MgSO.sub.4, filtered, and evaporated. The residue
was chromatographed on silica gel using 3:1 hexane: ethyl acetate
to yield 0.58 g (93%) of the title compound as a yellow crystalline
solid, mp 152-156.degree. C.; MS (ES) m/z 272.0, [M-H]-.
Step b) Preparation of
4-[(3-Bromophenyl)(oxo)acetyl]-1H-pyrrole-2-carbaldehyde
[0500] To DMSO was added
4-[(3-bromophenyl)ethynyl]-1H-pyrrole-2-carbaldehyde (1.50 g; 5.47
mmol), and palladium(II)chloride (97 mg; 0.547 mmol). The resulting
solution was stirred at 140.degree. C. for one hour. The mixture
was cooled to ambient temperature and diluted with water. The
product was extracted into chloroform and dried over MgSO.sub.4.
The resulting solid was chromatographed on silica gel using 7:3
hexane:ethyl acetate to give 1.21 g of the title compound as a
greenish crystalline solid (72% yield), mp 202-203.degree. C.; MS
(ES) m/z 304.0, [M-H]-.
Step c) Preparation of
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1H-pyrrole-2-carbaldehyde
[0501] To a solution of
4-[(3-bromophenyl)(oxo)acetyl]-1H-pyrrole-2-carbaldehyde (0.10 g;
0.32 mmol), and sodium carbonate (0.038 g; 0.359 mmol) in ethanol
(5 mL), was added 1-methylguanidine hydrochloride (0.039 g; 0.359
mmol). The mixture was stirred at 85.degree. C. for four hours. The
ethanol was evaporated and the residue was taken up in chloroform
and washed twice with water. The solution was dried over
MgSO.sub.4, filtered and evaporated. The product was crystalized by
cooling a hot, saturated ethyl acetate solution to give the title
compound, 0.085 g (72% yield), mp 142-151.degree. C.; MS (ES) m/z
361.0, [M+H]+.
Step d) Preparation of
4-[2-Amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-ethyl-1H-pyrrole-2-carbaldehyde
[0502] In DMF, (7 mL) is dissolved
4-[2-amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1H-pyrrole-2-carbaldehyde (1.50 g; 4.15 mmol). To this solution is
added cesium carbonate (1.35 g; 4.15 mmol) and iodoethane (0.43 mL;
5.4 mmol), and the mixture is stirred for 20 hours at room
temperature. The mixture is diluted to 50 mL with chloroform,
washed twice with water, dried over MgSO.sub.4, filtered, and
evaporated. The residue was crystallized in ethyl acetate to give
the title product as light-brown crystals, 1.18 g (73% yield), mp
194-195.degree. C.; MS (ES) m/z 387.0, [M-H]-.
Step e) Preparation of
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde
[0503] A 1:1 mixture of toluene and ethanol was sparged with
nitrogen for 30 minutes. To the solvent was added
4-[2-amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-
-1-ethyl-1H-pyrrole-2-carbaldehyde (1.10 g; 3.04 mmol),
2-fluoro-3-pyridineboronic acid (0.69 g; 4.9 mmol), sodium
carbonate (1.03 g; 9.75 mmol), and
tetrakis[triphenylphosphine]-palladium(0) (0.53 g; 0.46 mmol). This
mixture was heated at reflux temperature for three hours. The
solvents were evaporated and the residue was crystallized in
CHCl.sub.3 and water to give the title as grey crystals, 0.91 g
(74% yield), mp 198-201.degree. C.; MS (ES) m/z 406.2, [M+H]+.
Example 234
Preparation of
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carbaldehyde
##STR00135##
[0505] Using essentially the same procedure described in Example
233 and employing 2-fluoroethyl iodide as reagent, the title
compound was obtained, mp 218-221.degree. C.; MS (APPI) m/z 424,
[M+H]+.
Example 235
Preparation of
2-Amino-5-[5-[(diethylamino)methyl]-1-(2-fluoroethyl)-1H-pyrrol-3-yl]-5-[-
3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
##STR00136##
[0507] To a glass tube was added methanol (0.5 mL),
4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carbaldehyde (0.05
g; 0.12 mmol), diethylamine (43 .mu.L; 0.41 mmol), and 1.8 mL of a
methanolic solution of ZnCl.sub.2 (0.1 M), and NaBH.sub.3CN (0.2
M). The mixture was stirred 24 hours at room temperature. The
solvent was evaporated and the residue was dissolved in chloroform,
washed with 0.1 N NaOH solution, dried over MgSO.sub.4, and
evaporated to give the title compound as an amorphous white solid,
0.021 g (37% yield), mp 121-140.degree. C.; MS (ES) m/z 479.2,
[M-H]-.
Examples 236-238
Preparation of
2-Amino-5-[5-[(substitutedamino)methyl]-1-(2-fluoroethyl)-1H-pyrrol-3-yl]-
-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
Compounds
##STR00137##
[0509] Using essentially the same procedure described in Example
235 and employing the appropriate amine, the compounds shown on
Table XIX were obtained and identified by NMR and mass spectral
analyses.
TABLE-US-00019 TABLE XIX ##STR00138## Ex. mp MS No R' R'' .degree.
C. m/z 236 H isopropyl 98-99 465.2 237
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2-- 110-120 477.2 238 CH.sub.3
CH.sub.3 118-121 451.1
Example 239
Preparation of
2-Amino-5-[1-ethyl-5-(hydroxymethyl)-1H-pyrrol-3-yl]-5-[3-(2-fluoropyridi-
n-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
##STR00139##
[0511] A solution of
4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde (0.071 g; 0.25
mmol) in THF (20 mL) and methanol (5 mL) was stirred at ambient
temperature as an excess of NaBH.sub.4 (0.071 g; 1.88 mmol) was
added. After one hour the solvents were evaporated and the residue
was taken up into dichloromethane and washed with water. The
dichloromethane phase was dried over MgSO.sub.4, filtered, and
evaporated. The resultant residue was crystallized from ethyl
acetate and hexane to obtain the title product as a white solid, mp
170-172.degree. C.; MS (ES) m/z 406.1; [M-H]-
Example 240
Preparation of
2-Amino-5-[1-ethyl-5-(1-hydroxypropyl)-1H-pyrrol-3-yl]-5-[3-(2-fluoropyri-
din-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
##STR00140##
[0513] A mixture of
4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde (0.10 g; 0.25
mmol) in THF (5 mL; anhydrous) was stirred and cooled to
-15.degree. C. To this was added an excess of EtMgBr (3.1 eq; 0.25
mL of 3.0 M solution in hexane), dropwise. The mixture was stirred
at -15.degree. C. for one hour. The reaction was worked up by
carefully adding 1.0 mL of saturated aqueous ammonium chloride
solution, diluting with dichloromethane (30 mL) and washing with
water. The organic phase was dried over MgSO.sub.4, filtered and
evaporated. Two products were separated from the crude mixture by
chromatography on silica gel. The column was eluted with a
chloroform/methanol mixture on a gradient (9:1 through 7:3). The
more polar product was isolated and crystallized from ethyl
acetate/hexane to give the title product as white crystals, 0.05 g
(46% yield), mp 115-121.degree. C.; MS (ES) m/z 434.2; [M-H]-
Example 241
Preparation of
4-{2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde O-methyloxime
hydrochloride
##STR00141##
[0515] A stirred suspension of
4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde (0.10 g; 0.25
mmol), in THF (5 mL), was added methoxylamine hydrochloride (0.021
g; 0.25 eq). The mixture was stirred at reflux temperature for 2
hours. The mixture was cooled and the solvent was evaporated. The
residue was dissolved in dichloromethane and washed with water. The
dichloromethane solution was dried over MgSO.sub.4, filtered and
evaporated. The resultant residue was crystallized from ethyl
acetate and hexane to yield the title compound, 0.069 g (64%
yield), mp 190-193.degree. C., MS (ES) m/z 433.1; [M-H]-
Example 242
Preparation of
(5S)-2-Amino-5-[3-(2,5-difluoropyridin-3-yl)phenyl]-5-[1-(2-fluoroethyl)--
5-propionyl-1H-pyrrol-3-yl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
(A) and
(5R)-2-Amino-5-[3-(2,5-difluoropyridin-3-yl)phenyl]-5-[1-(2-fluoroethyl)--
5-propionyl-1H-pyrrol-3-yl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
(B)
##STR00142##
[0517] A racemic mixture of
2-amino-5-[3-(2,5-difluoropyridin-3-yl)phenyl]-5-[1-(2-fluoroethyl)-5-pro-
pionyl-1H-pyrrol-3-yl]-3-methyl-3,5-dihydro-4H-imidazol-4-one was
separated by chiral HPLC using a Chiralcel AD, 0.46.times.25 cm
(column) with mobile phase 8:2 hexane:isopropanol (0.1%
diethtylamine) to give the title products: A (5S) isomer, .sup.1H
NMR (DMSOd.sub.6 300 MHz) .delta. 0.98 (s, 3H), 2.76 (q, 2H), 3.9
(s, 3H), 4.45 (s, 2H), 4.6 (m, 2H), 6.6 (brs, 2H), 6.95 (s, 1H),
7.4 (m, 2H), 7.6 (d, 1H), 7.78 (s, 1H), 8.0 (m, 1H), 8.2 (d, 1H);
MS m/e (M+H).sup.+470; [.alpha.]=-72.2 (1% solution in MeOH) and B
(5R) isomer, .sup.1H NMR (DMSOd.sub.6 300 MHz) .delta. 0.98 (s,
3H), 2.76 (q, 2H), 3.9 (s, 3H), 4.45 (s, 2H), 4.6 (m, 2H), 6.6
(brs, 2H), 6.95 (s, 1H), 7.4 (m, 2H), 7.6 (d, 1H), 7.78 (s, 1H),
8.0 (m, 1H), 8.2 (d, 1H); MS m/e (M+H).sup.+470; [.alpha.]=+77.2
(1% solution in MeOH).
Example 243
Preparation of
(5S)-2-Amino-5-[5-(cyclopropylcarbonyl)-1-ethyl-1H-pyrrol-3-yl]-5-[3-(2-f-
luoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
(A) and
(5R)-2-Amino-5-[5-(cyclopropylcarbonyl)-1-ethyl-1H-pyrrol-3-yl]-5-[3-(2-f-
luoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
(B)
##STR00143##
[0519] A racemic mixture of
2-amino-5-[5-(cyclopropylcarbonyl)-1-ethyl-1H-pyrrol-3-yl]-5-[3-(2-fluoro-
pyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one was
separated by chiral HPLC using a Chiralcel AD, 5.times.25 cm
(column) with mobile phase 22% EtOH in hexane to give the title
products: A (5S) isomer, .sup.1H NMR (DMSOd.sub.6 300 MHz) .delta.
0.9 (m, 4H), 1.05 (t, 3H), 1.1 (m. 1H), 3.95 (s, 3H), 4.1 (q, 2H),
6.6 (brs, 2H), 7.05 (s, 1H), 7.1 (s, 1H), 7.4 (m, 3H), 7.6 (m, 1H),
7.7 (s, 1H), 8.0 (m, 1H), 8.2 (m, 1H; MS m/e (M+H).sup.+446;
[.alpha.]=-73 (1% solution in MeOH); and B (5R) isomer, .sup.1H NMR
(DMSOd.sub.6 300 MHz) .delta. 0.9 (m, 4H), 1.05 (t, 3H), 1.1 (m.
1H), 3.95 (s, 3H), 4.1 (q, 2H), 6.6 (brs, 2H), 7.05 (s, 1H), 7.1
(s, 1H), 7.4 (m, 3H), 7.6 (m, 1H), 7.7 (s, 1H), 8.0 (m, 1H), 8.2
(m, 1H); MS m/e (M+H).sup.+446; [.alpha.]=+70.4 (1% solution in
MeOH).
Example 244
Preparation of
(5S)-2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-propionyl-3-
-thienyl)-3,5-dihydro-4H-imidazol-4-one (A) and
(5R)-2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-propionyl-3-
-thienyl)-3,5-dihydro-4H-imidazol-4-one (B)
##STR00144##
[0521] A racemic mixture of
2-amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-(5-propionyl-3-thie-
nyl)-3,5-dihydro-4H-imidazol-4-one was separated by chiral HPLC
using a Chiralcel AD, 0.46.times.10 cm (column) with mobile phase
100% EtOH with 0.1% DEA to give the title products: A (5S) isomer,
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.19 (dt, J=4.7, 1.4 Hz,
1H), 7.85-7.81 (m, 1H), 7.78-7.69 (m, 3H), 7.61-7.55 (m, 1H),
7.52-7.48 (m, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.29-7.23 (m, 1H), 3.12
(s, 3H), 2.88 (q, J=7.3 Hz, 2H), 1.17 (t, J=7.3 Hz, 3H); ESI MS m/z
423; [.alpha.]=-78.6 (1% solution in MeOH); and B (5R) isomer,
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.19 (dt, J=4.7, 1.4 Hz,
1H), 7.85-7.81 (m, 1H), 7.78-7.69 (m, 3H), 7.61-7.55 (m, 1H),
7.52-7.48 (m, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.29-7.23 (m, 1H), 3.12
(s, 3H), 2.88 (q, J=7.3 Hz, 2H), 1.17 (t, J=7.3 Hz, 3H); ESI MS m/z
423; [.alpha.]=+71.8 (1% solution in MeOH).
Example 245
Preparation of
(5R)-2-Amino-3-methyl-5-phenyl-5-(5-propionyl-3-thienyl)-3,5-dihydro-4H-i-
midazol-4-one (A) and
(5S)-2-Amino-3-methyl-5-phenyl-5-(5-propionyl-3-thienyl)-3,5-dihydro-4H-i-
midazol-4-one
##STR00145##
[0523] A racemic mixture of
2-amino-3-methyl-5-phenyl-5-(5-propionyl-3-thienyl)-3,5-dihydro-4H-imidaz-
ol-4-one was separated by chiral HPLC using a Chiralcel AD,
0.46.times.10 cm (column) with mobile phase 12% IPA with DEA in
CO.sub.2 to give the title products: A (5R) isomer, .sup.1H NMR
(DMSOd.sub.6 300 MHz) .delta. 0.98 (s, 3H), 2.76 (q, 2H), 3.9 (s,
3H), 4.45 (s, 2H), 4.6 (m, 2H), 6.6 (brs, 2H), 6.95 (s, 1H), 7.4
(m, 2H), 7.6 (d, 1H), 7.78 (s, 1H), 8.0 (m, 1H), 8.2 (d, 1H); MS
m/e (M+H).sup.+328; [.alpha.]=+74.8 (1% solution in MeOH); and B
(5S) isomer, .sup.1H NMR (DMSOd.sub.6 300 MHz) .delta. 0.98 (s,
3H), 2.76 (q, 2H), 3.9 (s, 3H), 4.45 (s, 2H), 4.6 (m, 2H), 6.6
(brs, 2H), 6.95 (s, 1H), 7.4 (m, 2H), 7.6 (d, 1H), 7.78 (s, 1H),
8.0 (m, 1H), 8.2 (d, 1H); MS m/e (M+H).sup.+328; [.alpha.]=-76 (1%
solution in MeOH).
Example 246
Preparation of
(5S)-5-[5-Acetyl-1-(3-fluoropropyl)-1H-pyrrol-3-yl]-2-amino-5-[3-(2-fluor-
opyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (A)
and
(5R)-5-[5-Acetyl-1-(3-fluoropropyl)-1H-pyrrol-3-yl]-2-amino-5-[3-(2-fluor-
opyridin-3-yl)phenyl]-3-methyl-3-3,5-dihydro-4H-imidazol-4-one
(B)
##STR00146##
[0525] A racemic mixture of
5-[5-acetyl-1-(3-fluoropropyl)-1H-pyrrol-3-yl]-2-amino-5-[3-(2-fluoropyri-
din-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one was
separated by chiral HPLC to give the title products: A (5S) isomer,
[.alpha.]D.sub.25=-64.20.degree. (c=5.3 MG/0.7 ML, MeOH); MS (APPI)
m/z 452; and B (5R) isomer, [.alpha.]D.sub.25=+62.87.degree. (c=5.5
MG/0.7 ML, MeOH); MS (APPI) m/z 452.
Example 247
Preparation of
4-{(4S)-2-Amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dih-
ydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde
##STR00147##
[0527] A racemic mixture of
4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde was separated
by chiral HPLC to give the title product, identified by NMR and
mass spectral analyses. [.alpha.].sup.D.sub.25=-73.0 (1% solution
in DMSO).
Example 248
Preparation of
(5S)-2-Amino-5-[1-(3-fluoropropyl)-5-(2-oxopropyl)-1H-pyrrol-3-yl]-5-[3-(-
2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
##STR00148##
[0529] A racemic mixture of
2-amino-5-[1-(3-fluoropropyl)-5-(2-oxopropyl)-1H-pyrrol-3-yl]-5-[3-(2-flu-
oropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one was
separated by chiral HPLC to give the title product as a yellow
solid, mp 147-150.degree. C., identified by NMR and Mass spectral
analyses. [.alpha.].sup.D.sub.25=-78.0 (1% solution in DMSO).
Example 249
Preparation of
(5S)-5-(5-acetyl-1-methyl-1H-pyrrol-3-yl)-2-amino-3-methyl-5-phenyl-3,5-d-
ihydro-4H-imidazol-4-one (A) and
(5R)-5-(5-acetyl-1-methyl-1H-pyrrol-3-yl)-2-amino-3-methyl-5-phenyl-3,5-d-
ihydro-4H-imidazol-4-one (B)
##STR00149##
[0531] A racemic mixture of
5-(5-acetyl-1-methyl-1H-pyrrol-3-yl)-2-amino-3-methyl-5-phenyl-3,5-dihydr-
o-4H-imidazol-4-one was separated by chiral HPLC using a Chiralcel
AD column to give the title products: A (5S) isomer,
[.alpha.].sup.D.sub.25=-100.0 (1% solution in DMSO); MS (APPI) m/z
311; and B (5R) isomer, [.alpha.].sup.D.sub.25=+90.0 (1% solution
in DMSO); MS (APPI) m/z 311.
Example 250
Preparation of
(5S)-2-Amino-5-[1-(4-fluorobutyl)-5-propionyl-1H-pyrrol-3-yl]-5-[3-(2-flu-
oropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (A)
and
(5R)-2-Amino-5-[1-(4-fluorobutyl)-5-propionyl-1H-pyrrol-3-yl]-5-[3-(2-flu-
oropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
(B)
##STR00150##
[0533] A racemic mixture of
2-amino-5-[1-(4-fluorobutyl)-5-propionyl-1H-pyrrol-3-yl]-5-[3-(2-fluoropy-
ridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one was
separated by chiral HPLC using a Chiralcel AD column to give the
title products: A (5S) isomer, [.alpha.].sup.D.sub.25=-72.2.degree.
(c=1% solution MeOH); and B (5R) isomer,
[.alpha.].sup.D.sub.25=+74.0 (1% solution in DMSO). Both isomers
were identified by NMR and mass spectral analyses.
Example 251
Preparation of
(5S)-2-Amino-5-[1-(cyclopropylmethyl)-5-propionyl-1H-pyrrol-3-yl]-5-[3-(2-
-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
(A) and
(5R)-2-Amino-5-[1-(cyclopropylmethyl)-5-propionyl-1H-pyrrol-3-yl]-5-[3-(2-
-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
(B)
##STR00151##
[0535] A racemic mixture of
2-amino-5-[1-(cyclopropylmethyl)-5-propionyl-1H-pyrrol-3-yl]-5-[3-(2-fluo-
ropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one was
separated by chiral HPLC using a Chiralcel AD column to give the
title products: A (5S) isomer, [.alpha.].sup.D.sub.25=-72.2.degree.
(c=1% solution MeOH); and B (5R) isomer,
[.alpha.].sup.D.sub.25=+79.0 (1% solution in DMSO). Both isomers
were identified by NMR and mass spectral analyses.
Example 252
Preparation of
(5S)-2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-propionyl-1-
-(4,4,4-trifluorobutyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one
(A) and
(5R)-2-Amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-propion-
yl-1-(4,4,4-trifluorobutyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one
(B)
##STR00152##
[0537] A racemic mixture of
2-amino-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-5-[5-propionyl-1-(4,4-
,4-trifluorobutyl)-1H-pyrrol-3-yl]-3,5-dihydro-4H-imidazol-4-one
was separated by chiral HPLC using a Chiralcel AD column to give
the title products: A (5S) isomer,
[.alpha.].sup.D.sub.25=-62.50.degree. (c=1% solution MeOH); and B
(5R) isomer, [.alpha.].sup.D.sub.25=+67.0 (1% solution in DMSO).
Both isomers were identified by NMR and mass spectral analyses.
Example 253
Preparation of
(5S)-2-Amino-5-[1-(2,2-difluoroethyl)-5-propionyl-1H-Pyrrol-3-yl]-5-[3-(2-
-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
(A) and
(5R)-2-Amino-5-[1-(2,2-difluoroethyl)-5-propionyl-1H-pyrrol-3-yl]-5-[3-(2-
-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
(B)
##STR00153##
[0539] A racemic mixture of
2-amino-5-[1-(2,2-difluoroethyl)-5-propionyl-1H-pyrrol-3-yl]-5-[3-(2-fluo-
ropyridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one was
separated by chiral HPLC using a Chiralcel AD column to give the
title products: A (5S) isomer, [.alpha.].sup.D.sub.25=-78.0 (1%
solution in DMSO); and B (5R) isomer, [.alpha.].sup.D.sub.25=+66.0
(1% solution in DMSO). Both isomers were identified by NMR and mass
spectral analyses.
Example 254
Preparation of (A)
(5S)-2-Amino-5-[3-(2-fluoro-pyridin-3-yl)-phenyl]-3-methyl-5-(5-propionyl-
-1-propyl-1H-pyrrol-3-yl)-3,5-dihydro-imidazol-4-one (A) and
(5R)-2-Amino-5-[3-(2-fluoro-pyridin-3-yl)-phenyl]-3-methyl-5-(5-propionyl-
-1-propyl-1H-pyrrol-3-yl)-3,5-dihydro-imidazol-4-one (B)
##STR00154##
[0541] A racemic mixture of
2-amino-5-[3-(2-fluoro-pyridin-3-yl)-phenyl]-3-methyl-5-(5-propionyl-1-pr-
opyl-1H-pyrrol-3-yl)-3,5-dihydro-imidazol-4-one was separated by
chiral HPLC using a Chiralpak AD, 0.46.times.25 cm; mobile phase
hexane/isopropanol 7/3 with 0.1% DEA and a flow rate of 1.0 mL/min
to give the title enantiomeric products: A (5S) isomer, mp
99.degree. C.; [.alpha.].sub.D=-78.4 (c 1.0, MeOH); m/e (M-H).sup.-
446.2; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) .delta. 0.73 (t, 3H),
0.96 (t, 3H), 1.54 (m, 2H), 2.67 (m, 2H), 2.92 (s, 3H), 4.13 (m,
2H), 6.60 (bs, 2H), 6.92 (s, 1H), 7.01 (s, 1H), 7.41 (m, 3H), 7.53
(m, 1H), 7.67 (m, 1H), 7.97 (m, 1H), 8.19, (m, 1H) and B: (5R)
isomer; mp 99.degree. C.; [.alpha.].sub.D=+77.1 (c 1.0, MeOH); m/e
(M-H).sup.- 446.2; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) .delta. 0.73
(t, 3H), 0.96 (t, 3H), 1.54 (m, 2H), 2.67 (m, 2H), 2.92 (s, 3H),
4.13 (m, 2H), 6.60 (bs, 2H), 6.92 (s, 1H), 7.01 (s, 1H), 7.41 (m,
3H), 7.53 (m, 1H), 7.67 (m, 1H), 7.97 (m, 1H), 8.19, (m, 1H).
Example 255
Preparation of (5S)
2-Amino-5-[1-(3-fluoropropyl)-5-propionyl-1H-pyrrol-3-yl]-5-[3-(2-fluorop-
yridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (A) and
(5R)
2-Amino-5-[1-(3-fluoropropyl)-5-propionyl-1H-pyrrol-3-yl]-5-[3-(2-fluorop-
yridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (B)
##STR00155##
[0543] A racemic mixture of
2-amino-5-[1-(3-fluoropropyl)-5-propionyl-1H-pyrrol-3-yl]-5-[3-(2-fluorop-
yridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one was
separated by HPLC using a Chiralpak AD, 0.46.times.25 cm column;
mobile phase hexane/isopropanol 7/3 with 0.1% DEA and a flow rate
of 1.0 mL/min to give the title enantiomeric products: A (5S)
isomer, mp 102.degree. C., [.alpha.].sub.D=-63.0 (c 1.0, MeOH); m/e
(M-H).sup.- 464.2; .sup.1H NMR (400 MHZ, DMSO-d.sub.6) .delta. 0.97
(t, 3H), 1.96-1.98 (m, 2H), 2.68 (q, 2H), 2.92 (s, 3H), 4.26 (m,
3H), 4.38 (m, 1H) 6.57 (bs, 2H), 7.02 (s, 1H), 7.03 (s, 1H),
7.41-7.42 (m, 3H), 7.55 (m, 1H), 7.68 (m, 1H), 7.98 (m, 1H), 8.12,
(m, 1H) and B (5R) isomer, mp 102.degree. C.; [.alpha.].sub.D=+76.0
(c 1.0, MeOH); m/e (M-H).sup.- 464.2; .sup.1H NMR (400 MHZ,
DMSO-d.sub.6) .delta. 0.97 (t, 3H), 1.96-1.98 (m, 2H), 2.68 (q,
2H), 2.92 (s, 3H), 4.26 (m, 3H), 4.38 (m, 1H) 6.57 (bs, 2H), 7.02
(s, 1H), 7.03 (s, 1H), 7.41-7.42 (m, 3H), 7.55 (m, 1H), 7.68 (m,
1H), 7.98 (m, 1H), 8.12, (m, 1H).
Example 256
Preparation of (5S)
2-Amino-5-[1-(2-fluoroethyl)-5-propionyl-1H-pyrrol-3-yl]-5-[3-(2-fluoropy-
ridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (A) and
(5R)
2-Amino-5-[1-(2-fluoroethyl)-5-propionyl-1H-pyrrol-3-yl]-5-[3-(2-fluoropy-
ridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (B)
##STR00156##
[0545] A racemic mixture of
2-amino-5-[1-(2-fluoroethyl)-5-propionyl-1H-pyrrol-3-yl]-5-[3-(2-fluoropy-
ridin-3-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one was
separated by chiral HPLC using a Chiralpak AD, 0.46.times.25 cm
column, mobile phase hexane/isopropanol 7/3 with 0.1% DEA and a
flow rate of 1.0 mL/min to give the title enantiomeric products: A
(5S) isomer, mp 110.degree. C.; [.alpha.].sub.D=-69.6 (c 1.0,
MeOH); m/e (M-H).sup.- 450.2; .sup.1H NMR (400 MHZ, DMSO-d.sub.6)
.delta. 0.81 (m, 1H), 0.95-0.97 (t, 3H), 1.20 (m, 1H), 2.70 (q,
2H), 2.93 (s, 3H), 4.48-4.55 (m, 2H), 6.58 (bs, 2H), 6.99 (s, 1H),
7.05 (s, 1H), 7.41-7.43 (m, 3H), 7.57 (m, 1H), 7.69 (s, 1H), 7.98
(m, 1H), 8.20, (m, 1H) and B (5R) isomer, mp 105.degree. C.,
[.alpha.].sub.D=+82.6 (c 1.0, MeOH); m/e (M-H).sup.- 450.2; .sup.1H
NMR (400 MHZ, DMSO-d.sub.6) .delta. 0.81 (m, 1H), 0.95-0.97 (t,
3H), 1.20 (m, 1H), 2.70 (q, 2H), 2.93 (s, 3H), 4.48-4.55 (m, 2H),
6.58 (bs, 2H), 6.99 (s, 1H), 7.05 (s, 1H), 7.41-7.43 (m, 3H), 7.57
(m, 1H), 7.69 (s, 1H), 7.98 (m, 1H), 8.20, (m, 1H).
Example 257
Preparation of Methyl
4-{(4S)-2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dih-
ydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate
(A) and Methyl
4-{(4R)-2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo--
4,5-dihydro-1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate
(B)
##STR00157##
[0547] A racemic mixture of methyl
4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro--
1H-imidazol-4-yl}-1-(2-fluoroethyl)-1H-pyrrole-2-carboxylate was
separated by chiral HPLC to give the title enantiomeric products: A
(5S) isomer, mp 174-176.degree. C.; [.alpha.].sub.D=-68.00 (c 1.0,
MeOH); and B (5R) isomer, mp 174-176.degree. C.,
[.alpha.].sub.D=+60.2 (c 1.0, MeOH). Both isomers were identified
by NMR and mass spectral analyses.
Example 258
Preparation of Methyl
4-[(4S)-2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-4,5-di-
hydro-1H-imidazol-4-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrrole-2-carboxylate
(A) and Methyl
4-[(4R)-2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-4,5-di-
hydro-1H-imidazol-4-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrrole-2-carboxlate
##STR00158##
[0549] A racemic mixture of methyl
4-[2-amino-4-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-methyl-5-oxo-4,5-dihydro-
-1H-imidazol-4-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrrole-2-carboxylate
was separated by chiral HPLC to give the title enantiomeric
products: A (5S) isomer, mp 128-131.degree. C.;
[.alpha.].sub.D=-65.00 (c 1.0, MeOH); and B (5R) isomer, mp
128-131.degree. C., [.alpha.].sub.D=+73.20 (c 1.0, MeOH). Both
isomers were identified by NMR and mass spectral analyses.
Example 259
Evaluation of BACE-1 Binding Affinity of Test Compounds
Fluorescent Kinetic Assays
[0550] Final Assay Conditions: 10 nM human BACE1 (or 10 nM Murine
BACE1, 1.5 nM human BACE2), 25 .mu.M substrate (WABC-6, MW 1549.6,
from AnaSpec), Buffer: 50 mM Na-Acetate, pH 4.5, 0.05% CHAPS, 25%
PBS, room temperature. Na-Acetate was from Aldrich, Cat. #24,124-5,
CHAPS was from Research Organics, Cat. #1304C 1.times., PBS was
from Mediatech (Cellgro), Cat #21-031-CV, peptide substrate
AbzSEVNLDAEFRDpa was from AnaSpec, Peptide Name: WABC-6
[0551] Determination of stock substrate (AbzSEVNLDAEFRDpa)
concentration: .about.25 mM stock solution is made in DMSO using
the peptide weight and MW, and diluted to .about.25 .mu.M (1:1000)
in 1.times. PBS. Concentration is determined by absorbance at 354
nm using an extinction coefficient c of 18172 M.sup.-1 cm.sup.-1,
the concentration of stock substrate is corrected, and the
substrate stock stored in small aliquots in -80.degree. C.
[Substrate Stock]=ABS.sup.354 nm*10.sup.6/18172 (in mM)
The extinction coefficient .epsilon..sup.354 nm was adapted from
TACE peptide substrate, which had the same quencher-fluorophore
pair.
[0552] Determination of Stock Enzyme Concentration: the stock
concentration of each enzyme is determined by absorbance at 280 nm
using an .epsilon. of 64150 M.sup.-1 cm.sup.-1 for hBACE1 and
MuBACE1, 62870 M.sup.-1 cm.sup.-1 for hBACE2 in 6 M Guanidinium
Hydrochloride (from Research Organics, Cat. #5134G-2), pH .about.6.
The extinction coefficient .epsilon..sup.280 nm for each enzyme was
calculated based on known amino acid composition and published
extinction coefficients for Trp (5.69 M.sup.-1 cm.sup.-1) and Tyr
(1.28 M.sup.-1 cm.sup.-1) residues (Anal. Biochem. 182,
319-326).
[0553] Dilution and mixing steps: total reaction volume: 100
.mu.L
[0554] 2.times. inhibitor dilutions in buffer A (66.7 mM
Na-Acetate, pH 4.5, 0.0667% CHAPS) were prepared,
[0555] 4.times. enzyme dilution in buffer A (66.7 mM Na-Acetate, pH
4.5, 0.0667% CHAPS) were prepared,
[0556] 100 .mu.M substrate dilution in 1.times. PBS was prepared,
and
[0557] 50 .mu.L 2.times. Inhibitor, 25 .mu.L 100 .mu.M substrate
are added to each well of 96-well plate (from DYNEX Technologies,
VWR #: 11311-046), immediately followed by 25 .mu.L 4.times. enzyme
(added to the inhibitor and substrate mix), and the fluorescence
readings are initiated.
[0558] Fluorescence Readings: Readings at .lamda..sub.ex 320 nm and
.lamda..sub.em 420 nm are taken every 40 sec for 30 min at room
temperature and the linear slope for substrate cleavage rate
(v.sub.i) determined.
[0559] Calculation of % Inhibition:
% Inhibition=100*(1.times.v.sub.i/v.sub.0) [0560] v.sub.i:
substrate cleavage rate in the presence of inhibitor [0561]
v.sub.0: substrate cleavage rate in the absence of inhibitor
[0562] IC.sub.50 Determination:
%
Inhibition=((B*IC.sub.50.sup.n)+(100*I.sub.0.sup.n))/(IC.sub.50.sup.n+-
I.sub.0.sup.n)
(Model #39 from LSW Tool Bar in Excel where B is the % inhibition
from the enzyme control, which should be close to 0.) % Inhibition
is plotted vs. Inhibitor Concentration (I.sub.0) and the data fit
to the above equation to obtain IC.sub.50 value and Hill number (n)
for each compound. Testing at least 10 different inhibitor
concentrations is preferred.
[0563] Results are shown in Table XX.
For Table XX
[0564] A=0.01 .mu.M-0.10 .mu.M
[0565] B=0.11 .mu.M-1.00 .mu.M
[0566] C=>1.00 .mu.M
TABLE-US-00020 TABLE XX BACE-1 Example No. IC.sub.50 .mu.M 1 B 2 B
3 A 4 A 5 A 6 A 7 B 8 B 9 A 10 A 11 B 12 A 13 A 14 B 16 B 18 B 19 B
20 A 21 B 22 B 23 B 24 A 25 A 26 B 27 B 29 A 31 B 32 A 33 A 34 A 35
B 36 C 37 A 38 B 39 A 40 A 41 B 42 A 43 A 44 A C 44 B A 45 A 46 A
52 B 53 B 54 B 55 B 58 C 59 C 68 A 69 A 70 B 71 B 73 C 74 C 75 C 76
C 77 C 78 C 82 A 83 A 84 B 85 B 86 B 87 A 88 B 89 B 92 C 93 C 94 A
97 A 98 A 99 A 100 A 101 A 102 A 103 A 104 A 105 A 106 A 107 A 108
A 109 C 110 B 111 B 114 A 116 A 118 A 119 A A 119 B B 120 -- 121 A
122 A 123 A 124 B 125 A 26 B 127 B 128 C 129 B 130 B 131 A 132 A
133 A 134 B 135 B 136 B 137 A 138 A 139 B 140 A 141 B 143 B 144 B
147 C 148 B 149 A 150 B 151 A 152 A 153 A 154 A 155 A 156 A 157 A
158 A 159 B 160 A 161 B 162 B 163 A 164 A 165 B 166 B 167 A 168 A
169 A 170 A 171 A 172 A 173 A 174 A 176 A 177 A 178 A 179 A 180 A
181 A 182 A 183 A A 183 B C 184 A A 184 B B 185 A 186 A 187 A 188 A
189 A 190 A 191 A 192 A 193 A 194 A 195 A 196 A 197 A 198 A 199 B
200 A 201 A 202 A 203 A 204 A 205 A 206 A 207 A 208 A 224 A A 224 B
C 225 B 226 B 227 B 228 B 229 A 230 A 231 A 232 B 233 A 234 A 235 C
236 C 237 C 238 B 239 A 240 B 241 A 242 A A 242 B C 243 A A 243 B C
244 A A 244 B B 247 A 248 A 249 A C 249 B C 250 A A 250 B C 251 A A
251 B C 252 A A 252 B C 253 A A 253 B C 254 A A 254 B C 255 A A 255
B C 256 A A 256 B C 257 A A 257 B B 258 A A 258 B C
* * * * *