U.S. patent application number 12/723511 was filed with the patent office on 2010-07-22 for imidazole compounds for the treatment of neurological disorders.
This patent application is currently assigned to Pfizer Inc. Invention is credited to Michael A. Brodney, Yuhpyng L. Chen, Karen J. Coffman, Edward F. Kleinman, Brian T. O'Neill.
Application Number | 20100184737 12/723511 |
Document ID | / |
Family ID | 37739128 |
Filed Date | 2010-07-22 |
United States Patent
Application |
20100184737 |
Kind Code |
A1 |
Brodney; Michael A. ; et
al. |
July 22, 2010 |
IMIDAZOLE COMPOUNDS FOR THE TREATMENT OF NEUROLOGICAL DISORDERS
Abstract
The present invention relates to compounds of Formula I
##STR00001## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6,
R.sup.7 and A are as defined. Compounds of Formula I have activity
inhibiting production of A.beta.-peptide. The invention also
relates to pharmaceutical compositions and methods for treating
diseases and disorders, for example, neurodegenerative and/or
neurological disorders, e.g., Alzheimer's disease, in a mammal
comprising compounds of Formula I.
Inventors: |
Brodney; Michael A.; (East
Lyme, CT) ; Coffman; Karen J.; (Pawcatuck, CT)
; Kleinman; Edward F.; (Pawcatuck, CT) ; O'Neill;
Brian T.; (Haddam, CT) ; Chen; Yuhpyng L.;
(Waterford, CT) |
Correspondence
Address: |
PFIZER INC
10555 SCIENCE CENTER DRIVE
SAN DIEGO
CA
92121
US
|
Assignee: |
Pfizer Inc
New York
NY
|
Family ID: |
37739128 |
Appl. No.: |
12/723511 |
Filed: |
March 12, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11524425 |
Sep 20, 2006 |
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12723511 |
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60719521 |
Sep 22, 2005 |
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Current U.S.
Class: |
514/210.2 ;
514/218; 514/228.8; 514/235.8; 514/326; 514/343; 514/397; 514/398;
540/575; 544/139; 544/350; 544/96; 546/210; 546/274.7; 548/314.7;
548/326.5 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 17/06 20180101; A61P 29/00 20180101; C07D 233/88 20130101;
C07D 487/08 20130101; C07D 487/04 20130101; C07D 491/04 20130101;
A61P 3/10 20180101; C07D 405/12 20130101; C07D 451/02 20130101;
A61P 11/06 20180101; A61P 9/10 20180101; A61P 37/02 20180101; C07D
403/04 20130101; C07D 413/12 20130101; C07D 401/14 20130101; C07D
405/06 20130101; C07D 409/12 20130101; A61P 1/00 20180101; C07D
403/06 20130101; A61P 25/28 20180101; C07D 403/08 20130101; C07D
405/14 20130101; C07D 401/12 20130101; C07D 403/10 20130101; A61P
19/02 20180101; C07D 233/54 20130101; C07D 403/12 20130101; A61P
25/00 20180101; A61P 35/00 20180101; C07D 401/04 20130101; C07D
401/06 20130101; C07D 413/06 20130101 |
Class at
Publication: |
514/210.2 ;
548/326.5; 546/210; 548/314.7; 546/274.7; 540/575; 544/139; 544/96;
544/350; 514/398; 514/326; 514/397; 514/343; 514/218; 514/235.8;
514/228.8 |
International
Class: |
A61K 31/4178 20060101
A61K031/4178; C07D 233/88 20060101 C07D233/88; C07D 401/06 20060101
C07D401/06; C07D 403/06 20060101 C07D403/06; C07D 401/14 20060101
C07D401/14; C07D 403/10 20060101 C07D403/10; C07D 413/12 20060101
C07D413/12; C07D 487/04 20060101 C07D487/04; A61K 31/454 20060101
A61K031/454; A61K 31/4439 20060101 A61K031/4439; A61K 31/551
20060101 A61K031/551; A61K 31/5377 20060101 A61K031/5377; A61K
31/5355 20060101 A61K031/5355; A61P 25/00 20060101 A61P025/00 |
Claims
1.-19. (canceled)
20. A compound selected from:
N-2-[(2S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]-N-[1-(2-{[(1-hy-
droxycyclohexyl)methyl]amino}-11-dimethylethyl)-1H-imidazol-4-yl]-L-norval-
inamide;
N-2-[(2S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]-N-{1-[1-
-(pyrrolidin-1-ylmethyl)cyclobutyl]-1H-imidazol-4-yl}-L-norvalinamide;
N-2-[(2S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]-N-[1-(1-{[(22-d-
imethylpropyl)amino]methyl}cyclobutyl)-1H-imidazol-4-yl]-L-norvalinamide;
N-2-[(2S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]-N-(1-{1,1-dimet-
hyl-2-[(2-methylbenzyl)amino]-2-oxoethyl}-1H-imidazol-4-yl)-L-norvalinamid-
e;
N-2-[(2S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]-N-(1-{1-methy-
l-2-[(tetrahydro-2H-pyran-4-ylmethyl)amino]ethyl}-1H-imidazol-4-yl)-L-norv-
alinamide; and
N-2-[(2S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]-N-(1-{2-[(3-met-
hoxypropyl)amino]-1,1-dimethyl-2-oxoethyl}-1H-imidazol-4-yl)-L-norvalinami-
de; or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition, comprising a compound according
to claim 20, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
22. A compound selected from:
N-2-[(3,5-difluorophenyl)acetyl]-N-{1-[1-(piperidin-1-ylmethyl)cyclobutyl-
]-1H-imidazol-4-yl}-L-norvalinamide;
N-2-[(3,5-difluorophenyl)acetyl]-N-[1-(1-{[(2,2-dimethylpropyl)amino]meth-
yl}cyclobutyl)-1H-imidazol-4-yl]-L-norvalinamide; and
N-2-[(3,5-difluorophenyl)acetyl]-N-[1-(1-{[(2,2-dimethylpropyl)amino]meth-
yl}cyclobutyl)-1H-imidazol-4-yl]-L-norvalinamide; or a
pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition, comprising a compound according
to claim 22, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims benefit of U.S. Ser. No.
60/719,521 filed on Sep. 22, 2005 which is incorporated by
reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to the treatment of
neurodegenerative and/or neurological disorders, such as
Alzheimer's disease, in mammals, including humans. This invention
also relates to inhibiting, in mammals, including humans, the
production of A.beta.- peptides that can contribute to the
formation of neurological deposits of amyloid protein. More
particularly, this invention relates to imidazole compounds,
pharmaceutical compositions comprising such compounds and methods
of using such compounds, i.e., for the treatment of
neurodegenerative and/or neurological disorders, such as
Alzheimer's disease, related to AR-peptide production.
BACKGROUND OF THE INVENTION
[0003] Dementia results from a wide variety of distinctive
pathological processes. The most common pathological processes
causing dementia are Alzheimer's disease (AD), cerebral amyloid
angiopathy (CAA) and prion-mediated diseases. AD affects nearly
half of all people past the age of 85, the most rapidly growing
portion of the United States population. As such, the number of AD
patients in the United States is expected to increase from about 4
million to about 14 million by the middle of the next century.
[0004] Treatment of AD typically is the support provided by a
family member in attendance. Stimulated memory exercises on a
regular basis have been shown to slow, but not stop, memory loss. A
few drugs, for example Aricept.TM., provide treatment of AD.
[0005] A hallmark of AD is the accumulation in the brain of
extracellular insoluble deposits called amyloid plaques and
abnormal lesions within neuronal cells called neurofibrillary
tangles. Increased plaque formation is associated with an increased
risk of AD. Indeed, the presence of amyloid plaques, together with
neurofibrillary tangles, is the basis for definitive pathological
diagnosis of AD.
[0006] The major components of amyloid plaques are the amyloid
AR-peptides, also called A.beta.-peptides, that consist of several
proteins including 38, 40, 42 or 43 amino acids, designated as the
A.beta..sub.1-38, A.beta..sub.1-40, A.beta..sub.1-42 and
A.beta..sub.1-43 peptides, respectively. The A.beta.-peptides are
thought to cause nerve cell destruction, in part, because they are
toxic to neurons in vitro and in vivo.
[0007] The A.beta. peptides are derived from larger amyloid
precursor proteins (APP proteins), that consist of four proteins
containing 695, 714, 751 or 771 amino acids, designated as the
APP.sub.695, APP.sub.714, ARP.sub.751 and APP.sub.771,
respectively. Proteases are believed to produce the A.beta.
peptides by cleaving specific amino acid sequences within the
various APP proteins. The proteases are named "secretases" because
the A.beta.-peptides they produce are secreted by cells into the
extracellular environment. These secretases are each named
according to the cleavage(s) they make to produce the
A.beta.-peptides. The secretase that forms the amino terminal end
of the A.beta.-peptides is called the beta-secretase. The secretase
that forms the carboxyl terminal end of the A.beta.-peptides is
called the gamma-secretase.
[0008] This invention relates to novel compounds that inhibit
A.beta.-peptide production, to pharmaceutical compositions
comprising such compounds, and to methods of using such compounds
to treat neurodegenerative and/or neurological disorders.
SUMMARY OF THE INVENTION
[0009] The present invention relates to compounds of Formula I
##STR00002##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7 and A
are as defined below. Compounds of Formula I have activity
inhibiting production of A.beta.-peptide. The invention also
relates to pharmaceutical compositions and methods for treating
diseases and disorders, for example, neurodegenerative and/or
neurological disorders, e.g., Alzheimer's disease, in a mammal
comprising compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
[0010] In one embodiment, the present invention relates to
compounds of Formula I wherein A is absent or is selected from
##STR00003##
[0011] Z is selected from --CH.sub.2, --CH(OH),
--CH(C.sub.1-C.sub.6 alkyl), --CH(C.sub.1-C.sub.5 alkoxy),
--CH(NR.sup.3R.sup.10), --CH(CH.sub.2(OH)), --CH(CH(C.sub.1-C.sub.4
alkyl)(OH)) and --CH(C(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4alkyl)(OH));
[0012] R.sup.1 is selected from --C.sub.1-C.sub.20 alkyl,
--C.sub.2-C.sub.20 alkenyl, --C.sub.2-C.sub.20 alkynyl,
--C.sub.1-C.sub.20 alkoxy, --C.sub.2-C.sub.20 alkenoxy,
--C.sub.1-C.sub.20 hydroxyalkyl, --C.sub.3-C.sub.8 cycloalkyl,
benzo(C.sub.3-C.sub.8 cycloalkyl), benzo(C.sub.3-C.sub.8
heterocycloalkyl), --C.sub.4-C.sub.8 cycloalkenyl,
--(C.sub.8-C.sub.11)bi- or tricycloalkyl,
benzo(C.sub.8-C.sub.11)bi- or tricycloalkyl, (C.sub.7-C.sub.11)bi-
or tricycloalkenyl, (3-8 membered) heterocycloalkyl,
--C.sub.6-C.sub.14 aryl and (5-14 membered) heteroaryl, wherein
R.sup.1 is optionally substituted by R.sup.1a;
[0013] wherein R.sup.1a in each instance is independently selected
from --OH, halo, --C.sub.1-C.sub.8 alkoxy, --CN, --NO.sub.2,
--NR.sup.9R.sup.10, --C(.dbd.O)NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.12,
--SO.sub.2--NR.sup.9R.sup.10, --S(O).sub.n--R.sup.11,
--C.sub.3-C.sub.18 cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.8-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy;
[0014] wherein said alkoxy, cycloalkyl, cycloalkenyl, bi- or
tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl,
heteroaryl, aryloxy and heteroaryloxy of R.sup.1a are each
optionally independently substituted with from one to six
substituents independently selected from the group R.sup.1b;
[0015] wherein R.sup.1b in each instance is independently selected
from --OH, --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12 alkenyl,
--C.sub.2-C.sub.12 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.12 alkoxyalkyl --C.sub.1-C.sub.12 hydroxyalkyl,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, halo, --CN,
--NO.sub.2, --NR.sup.9R.sup.10, --C(.dbd.O)NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.12,
--SO.sub.2--NR.sup.9R.sup.10, --C.sub.3-C.sub.15 cycloalkyl,
--C.sub.4-C.sub.15 cycloalkenyl, --(C.sub.5-C.sub.11)bi- or
tricycloalkyl, --(C.sub.7-C.sub.11)bi- or tricycloalkenyl, -(4-20
membered) heterocycloalkyl, --C.sub.6-C.sub.15 aryl, -(5-15
membered) heteroaryl, --C.sub.6-C.sub.15 aryloxy and -(5-15
membered) heteroaryloxy;
[0016] R.sup.2 is selected from H, --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.3-C.sub.8 cycloalkyl and
--C.sub.3-C.sub.8 cycloalkenyl, wherein R.sup.2 is optionally
independently substituted with from one to three substituents
independently selected from --C.sub.1-C.sub.4 alkyl optionally
substituted with from one to three halo atoms, --C.sub.1-C.sub.4
alkoxy optionally substituted with from one to three halo atoms,
halo and --OH;
[0017] or R.sup.1 and R.sup.2 together with the A group when
present and the nitrogen atom to which R.sup.2 is attached, or
R.sup.1 and R.sup.2 together with the nitrogen atom to which
R.sup.1 and R.sup.2 are attached when A is absent, may optionally
form a four to eight membered ring;
[0018] R.sup.3 is selected from H, --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkynyl,
--C.sub.3-C.sub.6 cycloalkyl, --C.sub.5-C.sub.6 cycloalkenyl and
(3-8 membered) heterocycloalkyl, --C.sub.6-C.sub.14 aryl and -(5-14
membered) heteroaryl, wherein said alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl or heteroaryl are
each optionally independently substituted with from one to three
substituents independently selected from --C.sub.1-C.sub.4 alkoxy,
halo, --OH, --S(C.sub.1-C.sub.4)alkyl, --C.sub.1-C.sub.4 alkyl
--C(.dbd.O)OR.sup.9, --SO.sub.2R.sup.9 and -(3-8 membered)
heterocycloalkyl wherein said alkyl, alkoxy, and heterocyloalkyl
may be further substituted by one to six halo;
[0019] R.sup.4 is H, --C.sub.1-C.sub.6 alkyl or halo;
[0020] or R.sup.3 and R.sup.4 may together with the carbon atom to
which they are attached optionally form a moiety selected from
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino,
piperidino, pyrrolidino, tetrahydrofuranyl and perhydro-2H-pyran,
wherein said moiety formed by R.sup.3 and R.sup.4 is optionally
substituted with from one to three substituents independently
selected from --C.sub.1-C.sub.6 alkyl optionally substituted with
from one to three halo atoms, --C.sub.1-C.sub.6 alkoxy optionally
substituted with from one to three halo atoms, halo, --OH, --CN and
allyl;
[0021] R.sup.6 is selected from H, --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkylene, --C.sub.1-C.sub.6 alkoxy, halo, --CN,
--C.sub.3-C.sub.12 cycloalkyl, --C.sub.4-C.sub.12 cycloalkenyl
(5-10 membered) heteroaryl and --C.sub.6-C.sub.10 aryl, wherein
said alkyl, alkylene and alkoxy of R.sup.6 are each optionally
independently substituted with from one to three substituents
independently selected from halo and --CN, and wherein said
cycloalkyl, cycloalkenyl, heteroaryl and aryl of R.sup.6 are each
optionally independently substituted with from one to three
substituents independently selected from --C.sub.1-C.sub.4 alkyl
optionally substituted with from one to three halo atoms,
--C.sub.1-C.sub.4 alkoxy optionally substituted with from one to
three halo atoms, halo and --CN;
[0022] R.sup.7 is --C.sub.1-C.sub.20 alkyl substituted by
--C.sub.3-C.sub.12 cycloalkyl, --C.sub.4-C.sub.12 cycloalkenyl,
--(C.sub.5-C.sub.20) bi- or tricycloalkyl, --(C.sub.7-C.sub.20)bi-
or tricycloalkenyl, -(3-12 membered) heterocycloalkyl, -(7-20
membered) heterobi- or heterotricycloalkyl, --C.sub.6-C.sub.14
aryl, benzo(C.sub.3-C.sub.8 heterocycloalkyl), -(5-15 membered)
heteroaryl, --C.sub.6-C.sub.15 aryloxy and -(5-15 membered)
heteroaryloxy, wherein R.sup.7 is independently substituted with
from one to six substituents independently selected from
R.sup.7a;
[0023] or R.sup.7 is --C.sub.3-C.sub.20 cycloalkyl,
--C.sub.4-C.sub.12 cycloalkenyl, --(C.sub.5-C.sub.20) bi- or
tricycloalkyl, --(C.sub.7-C.sub.20)bi- or tricycloalkenyl, -(3-12
membered) heterocycloalkyl, -(7-20 membered) heterobi- or
heterotricycloalkyl, --C.sub.6-C.sub.14 aryl, benzo(C.sub.3-C.sub.8
cycloalkyl), -(5-15 membered) heteroaryl, --C.sub.6-C.sub.15
aryloxy and -(5-15 membered) heteroaryloxy substituted by at least
one --C.sub.1-C.sub.20 alkyl, wherein said cycloalkyl,
cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl,
heterocycloalkyl, heterobi- or heterotricycloalkyl, aryl,
benzocycloalkyl, heteroaryl, aryloxy and heteroaryloxy is
optionally independently substituted with from one to six
substituents independently selected from R.sup.7a; and wherein said
alkyl is substituted by R.sup.7C;
[0024] wherein R.sup.7a in each instance is independently selected
from --OH, --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12 alkenyl,
--C.sub.2-C.sub.12 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.12 alkoxyalkyl, --C.sub.1-C.sub.12 hydroxyalkyl,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, halo, --CN,
--NO.sub.2, --NR.sup.9R.sup.10, --C(.dbd.O)NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.12,
--SO.sub.2--NR.sup.6R.sup.10, --S(O).sub.n--R.sup.11,
--C.sub.3-C.sub.15 cycloalkyl, cycloalkenyl,
--(C.sub.6-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.16 aryloxy and -(5-15 membered) heteroaryloxy;
wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy,
cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or
tricycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aryloxy and
heteroaryloxy of R.sup.7a are each optionally independently
substituted with from one to six substituents independently
selected from the group R.sup.7b;
[0025] wherein R.sup.7b in each instance is independently selected
from --OH, --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12 alkenyl,
--C.sub.2-C.sub.12 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.12 alkoxyalkyl, --C.sub.1-C.sub.12 hydroxyalkyl,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, halo, --CN,
--NO.sub.2, --NR.sup.9R.sup.10, --C(.dbd.O)NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.12,
--SO.sub.2--NR.sup.9R.sup.10, --S(O).sub.n--R.sup.11,
--C.sub.3-C.sub.15 cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy;
[0026] wherein R.sup.7C in each instance is independently selected
from --C.sub.1-C.sub.6 alkoxy, --CN, --NO.sub.2,
--NR.sup.9R.sup.10, --C(.dbd.O)NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.12,
--SO.sub.2--NR.sup.9R.sup.10, --S(O).sub.n--R.sup.11,
--C.sub.3-C.sub.15 cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy;
wherein said alkenoxy, cycloalkyl, cycloalkenyl, bi- or
tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl,
heteroaryl, aryloxy and heteroaryloxy of R.sup.7c are each
optionally independently substituted with from one to six
substituents independently selected from the group R.sup.7b;
[0027] or R.sup.6 and R.sup.7 may together with the carbon and
nitrogen atoms to which they are respectively attached optionally
form a -(5-8 membered) heterocycloalkyl ring, a -(5-8 membered)
heterocycloalkenyl ring or a -(6-8 membered) heteroaryl ring,
wherein said heterocycloalkyl, heterocycloalkenyl and heteroaryl
rings are each optionally independently substituted with from one
to three substituents independently selected from halo,
--C.sub.1-C.sub.6 alkyl, optionally subsituted with from one to
three halo atoms, --C.sub.1-C.sub.6 alkoxy optionally subsituted
with from one to three halo atoms, --C.sub.1-C.sub.6 hydroxyalkyl,
--OH, --(CH.sub.2).sub.zero-10NR.sup.9R.sup.10,
--(CH.sub.2).sub.zero-10C(.dbd.O)NR.sup.9R.sup.10,
--SO.sub.2NR.sup.9R.sup.10 and --C.sub.3-C.sub.12 cycloalkyl;
[0028] R.sup.9 and R.sup.10 in each instance are each independently
selected from H, --OH, --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12
alkenyl, --C.sub.2-C.sub.12 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.12 alkoxyalkyl --C.sub.1-C.sub.12 hydroxyalkyl,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy,
--C(.dbd.O)NR.sup.11, --C(.dbd.O)OR.sup.12,
--SO.sub.2--NR.sup.11R.sup.12, --S(O).sub.n--R.sup.11,
--C.sub.3-C.sub.15 cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy,
wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy,
cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or
tricycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aryloxy and
heteroaryloxy of R.sup.9 of R.sup.10 are each optionally
independently substituted with from one to six substituents
independently selected from the group R.sup.10a;
[0029] wherein R.sup.10a in each instance is independently selected
from --OH, halo, --C.sub.1-C.sub.12 hydroxyalkyl, --C.sub.1C.sub.6
alkoxy, --CN, --NO.sub.2, --NR.sup.11R.sup.12,
--C(.dbd.)NR.sup.11R.sup.12, --C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.11, --SO.sub.2--NR.sup.11R.sup.12,
--SO.sub.nR.sup.11, --C.sub.3-C.sub.15 cycloalkyl,
--C.sub.4-C.sub.15 cycloalkenyl, --(C.sub.5-C.sub.11)bi- or
tricycloalkyl, --(C.sub.7-C.sub.11)bi- or tricycloalkenyl, -(4-20
membered) heterocycloalkyl, --C.sub.6-C.sub.15 aryl, -(5-15
membered) heteroaryl, --C.sub.6-C.sub.15 aryloxy and -(5-15
membered) heteroaryloxy; wherein said alkoxy, cycloalkyl,
cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl,
heterocycloalkyl, aryl, heteroaryl, aryloxy and heteroaryloxy of
R.sup.10a are each optionally independently substituted with from
one to six substituents independently selected from the group
R.sup.10b);
[0030] wherein R.sup.10b in each instance is independently selected
from --OH, halo; --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12
alkenyl, --C.sub.2-C.sub.12 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.12 alkoxyalkyl --C.sub.1-C.sub.12 hydroxyalkyl,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, halo, --CN,
--NO.sub.2, --NR.sup.11R.sup.12, --C(.dbd.O)NR.sup.11R.sup.12,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.11,
--SO.sub.2--NR.sup.11R.sup.12, --S(O).sub.nR.sup.11,
--C.sub.3-C.sub.15 cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-1 5 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy;
[0031] or NR.sup.9R.sup.10 may form a (4-20 membered)
heterocycloalkyl, (5-18 membered) heterobi- or tricycloalkyl (5-18
membered) heterobi- or tricycloalkenyl, or -(5-15 membered)
heteroaryl, wherein said heterocycloalkyl, heterobi- or
tricycloalkyl, heterobi- or tricycloalkenyl or heteroaryl are
optionally independently substituted with from one to six
substituents independently selected from --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.1-C.sub.6 alkoxy, --C.sub.2-C.sub.6 alkenoxy,
--C.sub.2-C.sub.6 alkynoxy, --C.sub.1-C.sub.6 hydroxyalkyl,
--C.sub.2-C.sub.6 hydroxyalkenyl, --C.sub.2-C.sub.6 hydroxyalkenyl,
halo, --OH, --CN, --NO.sub.2, --NR.sup.11R.sup.12,
--C(.dbd.O)NR.sup.11R.sup.12--C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.11, --S(O).sub.nR.sup.11 and
--S(O).sub.n--NR.sup.11R.sup.12;
[0032] R.sup.11 and R.sup.12 in each instance are each
independently selected from H, --C.sub.1-C.sub.8 alkyl,
--C.sub.3-C.sub.8 cycloalkyl, --C.sub.4-C.sub.8 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, (3-8 membered) heterocycloalkyl,
--C.sub.6-C.sub.10 aryl and -(5-14 membered) heteroaryl, wherein
said alkyl of R.sup.11 is optionally independently substituted with
from one to three substituents independently selected from --OH,
--CN and --C.sub.3-C.sub.8 cycloalkyl, and wherein each hydrogen
atom of said alkyl is optionally independently replaced with a halo
atom, and wherein said cylcoalkyl, cycloalkenyl, heterocycloalkyl,
aryl and hetereoaryl of R.sup.11 are each optionally independently
substituted with from one to three substituents independently
selected from halo, --C.sub.1-C.sub.8 alkyl optionally substituted
with from one to three halo atoms, --OH, --CN and
--C.sub.3-C.sub.8cycloalkyl; and
[0033] n is in each instance an integer independently selected from
zero, 1 and 2;
[0034] or a pharmaceutically acceptable salt thereof.
[0035] In one aspect of the above embodiment, R.sup.7 is a
--C.sub.4-C.sub.8 cycloalkyl, -(4-10 membered) heterocycloalkyl,
--C.sub.6-C.sub.14 aryl or -(5-15 membered) heteroaryl substituted
by a --C.sub.1-C.sub.4 alkyl and wherein said alkyl is further
substituted by R.sup.7C, wherein R.sup.7C is
--NR.sup.9R.sup.10.
[0036] In another aspect of the above embodiment, R.sup.9 is
hydrogen or methyl, R.sup.10 is --C.sub.1-C.sub.8 alkyl or
--C.sub.4-C.sub.6 cycloalkyl, wherein said alkyl or cycloalkyl of
R.sup.10 is optionally substituted with from one to six
substituents selected from R.sup.10a wherein R.sup.10a is selected
from halo, --C.sub.1-C.sub.4 alkyl, --C.sub.4-C.sub.8 cycloalkyl,
-(5-15 membered) heteroaryl or --C.sub.1-C.sub.4 hydroxyalkyl; or
--NR.sup.9R.sup.10 is a -(4-6 membered) heterocycloalkyl optionally
substituted with from one to six substituents selected from halo,
--C.sub.1-C.sub.4 alkyl or --C.sub.1-C.sub.4 hydroxyalkyl.
[0037] In another aspect of the above embodiment, R.sup.7 is a
--C.sub.1-C.sub.8 alkyl substituted by a --C.sub.4-C.sub.8
cycloalkyl; --(C.sub.5-C.sub.20) bi- or tricycloalkyl, -(4-8
membered) heterocycloalkyl, -(7-12 membered) heterobi- or
heterotricycloalkyl, --C.sub.6-C.sub.14 aryl, benzo(C.sub.3-C.sub.8
cycloalkyl), -(5-15 membered) heteroaryl, wherein R.sup.7 is
optionally independently substituted with from one to six
substituents independently selected from R.sup.7a, wherein R.sup.7a
is --NR.sup.9R.sup.10, halo, --C.sub.1-C.sub.4 alkyl or
--C.sub.1-C.sub.4 hydroxyalkyl.
[0038] In another aspect of the above embodiment, R.sup.7 is a
--C.sub.1-C.sub.6 alkyl substituted by a -(4-8 membered)
heterocycloalkyl or --C.sub.6-C.sub.14 aryl, wherein R.sup.7 is
optionally independently substituted with from one to six
substituents independently selected from R.sup.7a, wherein R.sup.7a
is --NR.sup.9R.sup.10, halo, --OH, --C.sub.1-C.sub.4 alkyl or
--C.sub.1-C.sub.4 hydroxyalkyl, wherein said alkyl or hydroxyalkyl
is optional substituted with from one to six halo.
[0039] In another aspect of the above embodiment, A is absent and
R.sup.1 is benzo(C.sub.5-C.sub.6 cycloalkyl) optionally substituted
with from one to three substituents independently selected from
--C.sub.1-C.sub.6 alkyl, halo and --OH; or A is
##STR00004##
Z is --CH.sub.2, --CH(OH) or --CH(C.sub.1-C.sub.6 alkyl) and
R.sup.1 is --C.sub.1-C.sub.10 alkyl, --C.sub.6-C.sub.10 aryl or
(6-10 membered) heteroaryl, wherein said alkyl, aryl and heteroaryl
are optionally independently substituted with from one to three
substituents independently selected from --C.sub.1-C.sub.6 alkyl,
halo and --OH; R.sup.2 is H or --C.sub.1-C.sub.6 alkyl; R.sup.3 is
H, --CH.sub.2CH.sub.2SCH.sub.3 , --CH.sub.2CH.sub.2OCH.sub.3 or
--C.sub.1-C.sub.6 alkyl; R.sup.4 is H and R.sup.6 is H or
--C.sub.1-C.sub.6 alkyl.
[0040] In an another embodiment, the present invention relates to
compounds of Formula I wherein A is absent or is selected from
##STR00005##
[0041] Z is selected from --CH.sub.2, --CH(OH),
--CH(C.sub.1-C.sub.6 alkyl), --CH(C.sub.1-C.sub.6 alkoxy),
--CH(NR.sup.9R.sup.10), --CH(CH.sub.2(OH)), --CH(CH(C.sub.1-C.sub.4
alkyl)(OH)) and --CH(C(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4alkyl)(OH));
[0042] R.sup.1 is selected from --C.sub.1-C.sub.20 alkyl,
--C.sub.2-C.sub.20 alkenyl, --C.sub.2-C.sub.20 alkynyl,
--C.sub.1-C.sub.20 alkoxy, --C.sub.2-C.sub.20 alkenoxy,
--C.sub.1-C.sub.20 hydroxyalkyl, --C.sub.3-C.sub.8 cycloalkyl,
benzo(C.sub.3-C.sub.8 cycloalkyl), benzo(C.sub.3-C.sub.8
heterocycloalkyl), --C.sub.4-C.sub.3 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl,
benzo(C.sub.5-C.sub.11)bi- or tricycloalkyl, (C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(3-8 membered) heterocycloalkyl,
--C.sub.6-C.sub.14 aryl and -(5-14 membered) heteroaryl, wherein
R.sup.1 is optionally substituted by R.sup.1a;
[0043] wherein R.sup.12 in each instance is independently selected
from --OH, halo, --C.sub.1-C.sub.6 alkoxy, --CN, --NO.sub.2,
--NR.sup.9R.sup.10, --C(.dbd.O)NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.12,
--SO.sub.2--NR.sup.9R.sup.10, --S(O).sub.n--R.sup.11,
--C.sub.3-C.sub.15 cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy;
[0044] wherein said alkoxy, cycloalkyl, cycloalkenyl, bi- or
tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl,
heteroaryl, aryloxy and heteroaryloxy of R.sup.1a are each
optionally independently substituted with from one to six
substituents independently selected from the group R.sup.1;
[0045] wherein R.sup.1b in each instance is independently selected
from --OH, --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12 alkenyl,
--C.sub.2-C.sub.12 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.12 alkoxyalkyl --C.sub.1-C.sub.12 hydroxyalkyl,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, halo, --CN,
--NO.sub.2, --NR.sup.9R.sup.10, -C(.dbd.O)NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.12,
--SO.sub.2--NR.sup.6R.sup.10, --S(O).sub.SR.sup.11,
--C.sub.3-C.sub.15 cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy;
[0046] R.sup.2 is selected from H, --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.3-C.sub.8 cycloalkyl and
C.sub.3-C.sub.8 cycloalkenyl, wherein R.sup.2 is optionally
independently substituted with from one to three substituents
independently selected from --C.sub.1-C.sub.4 alkyl optionally
substituted with from one to three halo atoms, --C.sub.1-C.sub.4
alkoxy optionally substituted with from one to three halo atoms,
halo and --OH;
[0047] or R.sup.1 and R.sup.2 together with the A group when
present and the nitrogen atom to which R.sup.2 is attached, or
R.sup.1 and R.sup.2 together with the nitrogen atom to which
R.sup.1 and R.sup.2 are attached when A is absent, may optionally
form a four to eight membered ring;
[0048] R.sup.3 is selected from H, --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkynyl,
--C.sub.3-C.sub.6 cycloalkyl, --C.sub.5-C.sub.6 cycloalkenyl and
(3-8 membered) heterocycloalkyl --C.sub.6-C.sub.14 aryl and (5-14
membered) heteroaryl, wherein said alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, heterocycloalkyl aryl or heteroaryl are
each optionally independently substituted with from one to three
substituents independently selected from --C.sub.1-C.sub.4 alkoxy,
halo, --OH, --S(C.sub.1-C.sub.4)alkyl --C.sub.1-C.sub.4 alkyl
--C(.dbd.O)OR.sup.9, --SO.sub.2R.sup.6 and --(3-8 membered)
heterocycloalkyl wherein said alkyl, alkoxy, and heterocyloalkyl
may be further substituted by one to six halo;
[0049] R.sup.4 is H, --C.sub.1-C.sub.6 alkyl or halo;
[0050] or R.sup.3 and R.sup.4 may together with the carbon atom to
which they are attached optionally form a moiety selected from
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino,
piperidino, pyrrolidino, tetrahydrofuranyl and perhydro-2H-pyran,
wherein said moiety formed by R.sup.3 and R.sup.4 is optionally
substituted with from one to three substituents independently
selected from --C.sub.1-C.sub.6 alkyl optionally substituted with
from one to three halo atoms, --C.sub.1-C.sub.6 alkoxy optionally
substituted with from one to three halo atoms, halo, --OH, --CN and
allyl;
[0051] R.sup.6 is selected from H, --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkylene, --C.sub.1-C.sub.6 alkoxy, halo, --CN,
--C.sub.3-C.sub.12 cycloalkyl, --C.sub.4-C.sub.12 cycloalkenyl
-(5-10 membered) heteroaryl and --C.sub.6-C.sub.10 aryl, wherein
said alkyl, alkylene and alkoxy of R.sup.6 are each optionally
independently substituted with from one to three substituents
independently selected from halo and --CN, and wherein said
cycloalkyl, cycloalkenyl, heteroaryl and aryl of R.sup.6 are each
optionally independently substituted with from one to three
substituents independently selected from --C.sub.1-C.sub.4 alkyl
optionally substituted with from one to three halo atoms,
--C.sub.1-C.sub.4 alkoxy optionally substituted with from one to
three halo atoms, halo and --CN;
[0052] R.sup.7 is selected from --C.sub.1-C.sub.20 alkyl,
--C.sub.1-C.sub.20 alkoxy, --C.sub.1-C.sub.20 hydroxyalkyl,
--C.sub.3-C.sub.12 cycloalkyl, --C.sub.4-C.sub.12 cycloalkenyl,
-(C.sub.5-C.sub.20) bi- or tricycloalkyl, --(C.sub.2-C.sub.20)bi-
or tricycloalkenyl, (3-12 membered) heterocycloalkyl, -(7-20
membered) heterobi- or heterotricycloalkyl, --C.sub.6-C.sub.14
aryl, -(5-15 membered) heteroaryl --C.sub.6-C.sub.15 aryloxy and
-(5-15 membered) heteroaryloxy, wherein said alkyl, alkenyl,
alkynyl, alkoxy, alkenoxy, alkynoxy, cycloalkyl, cycloalkenyl, bi-
or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl,
heteroaryl, aryloxy and heteroaryloxy of R.sup.7 are each
independently substituted with from one to six substituents
independently selected from the group R.sup.7a or are each
independently optionally substituted with from one to six
substituents independently selected from the group R.sup.7d
[0053] wherein R.sup.7a in each instance is independently selected
from --C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.12 alkoxyalkyl,
--NR.sup.9R.sup.10, --C(.dbd.O)NR.sup.9R.sup.10, --C.sub.3-C.sub.15
cycloalkyl, -(4-20 membered) heterocycloalkyl, --C.sub.6-C.sub.15
aryl, -(5-15 membered) heteroaryl, --C.sub.6-C.sub.15 aryloxy and
-(5-15 membered) heteroaryloxy, wherein said alkyl, alkoxy,
alkoxyalkyl, cycloalkyl, heterocycloalkyl, aryl heteroaryl,
aryloxy, and heteroaryloxy of R.sup.7a are each independently
substituted by R.sup.7b;
[0054] wherein R.sup.7d in each instance is independently selected
from: --C.sub.2-C.sub.12 alkenyl, --C.sub.2-C.sub.12 alkynyl,
--C.sub.1-C.sub.12 hydroxyalkyl, --C.sub.2-C.sub.6 alkenoxy,
--C.sub.2-C.sub.6 alkynoxy, --NR.sup.9R.sup.10,
--C(.dbd.O)NR.sup.9R.sup.10, --SO.sub.2--NR.sup.9R.sup.10,
--C.sub.4-C.sub.15 cycloalkenyl, --(C.sub.5-C.sub.11)bi- or
tricycloalkyl, --(C.sub.7-C.sub.11)bi- or tricycloalkenyl, wherein
said alkenyl, alkynyl, hydroxyalkyl, alkenoxy, alkynoxy,
cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl, of
r.sup.d are each optionally independently substituted with from one
to six substituents independently selected from the group
R.sup.7b;
[0055] wherein R.sup.7b in each instance is independently selected
from --C.sub.2-C.sub.12 alkenyl, --C.sub.2-C.sub.12 alkynyl,
--C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.12 alkoxyalkyl
--C.sub.1-C.sub.12 hydroxyalkyl, --C.sub.2-C.sub.6 alkenoxy,
--C.sub.2-C.sub.6 alkynoxy, halo, --CN, --NO.sub.2,
--NR.sup.9R.sup.10, --C(.dbd.O)NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.12,
--SO.sub.2--NR.sup.9R.sup.10, --S(O).sub.n--R.sup.11,
--C.sub.3-C.sub.15 cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy;
[0056] or R.sup.6 and R.sup.7 may together with the carbon and
nitrogen atoms to which they are respectively attached optionally
form a (5-8 membered) heterocycloalkyl ring, a (5-8 membered)
heterocycloalkenyl ring or a (6-8 membered) heteroaryl ring,
wherein said heterocycloalkyl, heterocycloalkenyl and heteroaryl
rings are each optionally independently substituted with from one
to three substituents independently selected from halo,
--C.sub.1-C.sub.6 alkyl, optionally subsituted with from one to
three halo atoms, --C.sub.1-C.sub.6 alkoxy optionally subsituted
with from one to three halo atoms, --C.sub.1-C.sub.6 hydroxyalkyl,
--OH, --(CH.sub.2).sub.zero-10NR.sup.9R.sup.10,
--(CH.sub.2).sub.zero-10C(.dbd.O)NR.sup.9R.sup.10,
--SO.sub.2NR.sup.9R.sup.10 and --C.sub.3-C.sub.12 cycloalkyl;
[0057] R.sup.9 and R.sup.10 in each instance are each independently
selected from --H, --C(.dbd.O)R.sup.13 or --C.sub.1-C.sub.20 alkyl,
wherein at least one of R.sup.9 and R.sup.10 are
--C(.dbd.O)R.sup.13 or --C.sub.1-C.sub.20 alkyl, and wherein each
--C.sub.1-C.sub.20 alkyl is substituted with R.sup.10a
[0058] wherein R.sup.10a in each instance is independently selected
from --C.sub.1-C.sub.6 alkoxy, --CN, --N.sub.2,
--NR.sup.11R.sup.11, --C(.dbd.O)NR.sup.11R.sup.12,
--(.dbd.C)R.sup.11, --C(.dbd.O)OR.sup.11,
--SO.sub.2--NR.sup.11R.sup.12, --S(O).sub.n--R.sup.11,
--C.sub.3-C.sub.15 cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy;
wherein said alkoxy, cycloalkyl, cycloalkenyl, bi- or
tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl,
heteroaryl, aryloxy and heteroaryloxy of R.sup.10a are each
optionally independently substituted with from one to six
substituents independently selected from the group R.sup.10b
[0059] wherein R.sup.10b in each instance is independently selected
from --OH, --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12 alkenyl,
--C.sub.2-C.sub.12 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.12 alkoxyalkyl --C.sub.1-C.sub.12 hydroxyalkyl,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, halo, --CN,
--NO.sub.2, --NR.sup.11R.sup.12, --C(.dbd.O)NR.sup.11R.sup.12,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.11,
--SO.sub.2--NR.sup.11R.sup.12, --S(O).sub.nR.sup.11,
--C.sub.3-C.sub.15 cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-1 5 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy
[0060] or NR.sup.9R.sup.10 may form a (4-20 membered)
heterocycloalkyl, (5-18 membered) heterobi- or tricycloalkyl, (5-18
membered) heterobi- or tricycloalkenyl, or -(5-15 membered)
heteroaryl, wherein said heterocycloalkyl, heterobi- or
tricycloalkyl, heterobi- or tricycloalkenyl or heteroaryl are
optionally independently substituted with from one to six
substituents independently selected from --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.1-C.sub.6 alkoxy, --C.sub.2-C.sub.6 alkenoxy,
--C.sub.2-C.sub.6 alkynoxy, --C.sub.1-C.sub.6 hydroxyalkyl,
--C.sub.2-C.sub.6 hydroxyalkenyl, --C.sub.2-C.sub.6 hydroxyalkenyl,
halo, --OH, --CN, --NO.sub.2, --NR.sup.11R.sup.12,
--C(.dbd.O)NR.sup.11R.sup.12, --C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.11, --S(O).sub.nR.sup.11 and
--S(O).sub.nNR.sup.11R.sup.12;
[0061] R.sup.11 and R.sup.12 in each instance are each
independently selected from H, --C.sub.1-C.sub.8 alkyl,
--C.sub.3-C.sub.8 cycloalkyl, cycloalkenyl, (C.sub.5-C.sub.11)bi-
or tricycloalkyl, --(C.sub.7-C.sub.11)bi- or tricycloalkenyl, (3-8
membered) heterocycloalkyl, --C.sub.6-C.sub.10 aryl and (5-14
membered) heteroaryl, wherein said alkyl of R.sup.11 and R.sup.12is
optionally independently substituted with from one to three
substituents independently selected from --OH, --CN and
--C.sub.3-C.sub.8 cycloalkyl, and wherein each hydrogen atom of
said alkyl is optionally independently replaced with a halo atom,
and wherein said cylcoalkyl, cycloalkenyl, heterocycloalkyl, aryl
and hetereoaryl of R.sup.11 and R.sup.12 are each optionally
independently substituted with from one to three substituents
independently selected from halo, --C.sub.1-C.sub.8 alkyl
optionally substituted with from one to three halo atoms, --OH,
--CN and --C.sub.3-C.sub.8 cycloalkyl;
[0062] R.sup.13 is in each instance is independently selected from
alkyl substituted by --C.sub.1-C.sub.12 alkoxy, --C.sub.3-C.sub.15
cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy;
wherein said alkoxy, cycloalkyl, cycloalkenyl, bi- or
tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl,
heteroaryl, aryloxy and heteroaryloxy of R.sup.13 is optionally
substituted by one to three substituents independently selected
from halo, --C.sub.1-C.sub.8 alkyl optionally substituted with from
one to three halo atoms, --OH, --CN and --C.sub.3-C.sub.8
cycloalkyl;
[0063] n is in each instance an integer independently selected from
zero, 1 and 2;
[0064] or a pharmaceutically acceptable salt thereof.
[0065] In one aspect of the above embodiment, R.sup.7 is a
--C.sub.1-C.sub.8 alkyl substituted by R.sup.7a; R.sup.7a is
--NR.sup.9R.sup.10, R.sup.9 is H or methyl; R.sup.10 is a
--C.sub.1-C.sub.8 alkyl; R.sup.10a is --C.sub.1-C.sub.6 alkoxy,
--C.sub.4-C.sub.8 cycloalkyl, -(4-8 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl or -(5-15 membered) heteroaryl, wherein
said alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl of
R.sup.10a are each optionally independently substituted with from
one to six substituents independently selected from the group
R.sup.10b; wherein R.sup.10b is halo, --OH, --C.sub.1-C.sub.4 alkyl
or --C.sub.1-C.sub.4 hydroxyalkyl, wherein said alkyl or
hydroxyalkyl of R.sup.10b is optionally substituted by one to six
halo.
[0066] In another aspect of the above embodiment, R.sup.7 is a
--C.sub.1-C.sub.8 alkyl substituted by R.sup.7a; R.sup.7a is
--C(.dbd.O)NR.sup.9R.sup.10; R.sup.9 is H or methyl; R.sup.10 is a
--C.sub.1-C.sub.8 alkyl; R.sup.10a is --C.sub.1-C.sub.6 alkoxy,
--C.sub.4-C.sub.8 cycloalkyl, -(4-8 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl or -(5-15 membered) heteroaryl, wherein
said alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
aryloxy and heteroaryloxy of R.sup.10a are each optionally
independently substituted with from one to six substituents
independently selected from the group R.sup.10b; wherein R.sup.10b
is halo, --OH, --C.sub.1-C.sub.4 alkyl or --C.sub.1-C.sub.4
hydroxyalkyl, wherein said alkyl or hydroxyalkyl of R.sup.10b is
optionally substituted by one to six halo.
[0067] In another aspect of the above embodiment A is absent and
R.sup.1 is benzo(C.sub.5-C.sub.6 cycloalkyl) optionally substituted
with from one to three substituents independently selected from
C.sub.1-C.sub.8 alkyl, halo and OH; or A is
##STR00006##
Z is --CH.sub.2, --CH(OH) or --CH(C.sub.1-C.sub.8 alkyl) and
R.sup.1 is C.sub.1-C.sub.10 alkyl, C.sub.6-C.sub.10 aryl or (6-10
membered) heteroaryl, wherein said alkyl, aryl and heteroaryl are
optionally independently substituted with from one to three
substituents independently selected from C.sub.1-C.sub.6 alkyl,
halo and OH; R.sup.2 is H or C.sub.1-C.sub.6 alkyl; R.sup.3 is H,
--CH.sub.2CH.sub.2SCH.sub.3, --CH.sub.2CH.sub.2OCH.sub.3 or
C.sub.1-C.sub.6 alkyl; R.sup.4 is H and R.sup.6 is H or
C.sub.1-C.sub.6 alkyl.
[0068] In an another embodiment, the present invention relates to
compounds of Formula I wherein A is absent or is selected from
##STR00007##
[0069] Z is selected from --CH.sub.2, --CH(OH),
--CH(C.sub.1-C.sub.6 alkyl), --CH(C.sub.1-C.sub.6 alkoxy),
--CH(NR.sup.9R.sup.10), --CH(CH.sub.2(OH)), --CH(CH(C.sub.1-C.sub.4
alkyl)(OH)) and --CH(C(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4alkyl)(OH));
[0070] R.sup.1 is selected from --C.sub.1-C.sub.20 alkyl,
--C.sub.2-C.sub.20 alkenyl, --C.sub.2-C.sub.20 alkynyl,
--C.sub.1-C.sub.20 alkoxy, --C.sub.2-C.sub.20 alkenoxy,
--C.sub.1-C.sub.20 hydroxyalkyl, --C.sub.3-C.sub.8 cycloalkyl,
benzo(C.sub.3-C.sub.8 cycloalkyl), benzo(C.sub.3-C.sub.8
heterocycloalkyl), --C.sub.4-C.sub.8 cycloalkenyl,
--(C.sub.8-C.sub.11)bi- or tricycloalkyl,
benzo(C.sub.8-C.sub.11)bi- or tricycloalkyl,
--(C.sub.7-C.sub.11)bi- or tricycloalkenyl, -(3-8 membered)
heterocycloalkyl, --C.sub.6-C.sub.14 aryl and -(5-14 membered)
heteroaryl, wherein R1 is optionally substituted by R.sup.1a;
[0071] wherein R.sup.1a in each instance is independently selected
from --OH, halo, --C.sub.1-C.sub.6 alkoxy, --CN, --NO.sub.2,
--NR.sup.9R.sup.10, --C(.dbd.O)NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.12,
--SO.sub.2--NR.sup.6R.sup.10, --S(O).sub.n--R.sup.11,
--C.sub.3-C.sub.15 cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy,
[0072] wherein said alkoxy, cycloalkyl, cycloalkenyl, bi- or
tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl,
heteroaryl, aryloxy and heteroaryloxy of R.sup.1a are each
optionally independently substituted with from one to six
substituents independently selected from the group R.sup.1b;
[0073] wherein R.sup.1b in each instance is independently selected
from --OH, --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12 alkenyl,
--C.sub.2-C.sub.12 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.12 alkoxyalkyl --C.sub.1-C.sub.12 hydroxyalkyl,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, halo, --CN,
--NO.sub.2, --NR.sup.9R.sup.10, --C(.dbd.O)NR.sup.9R.sup.10,
--C(.dbd.O).sup.R-C(.dbd.O)OR.sup.12, --SO.sub.2--NR.sup.9R.sup.10,
--S(O).sub.n--R.sup.11, --C.sub.3-C.sub.15cycloalkyl,
--C.sub.4-C.sub.15 cycloalkenyl, --(C.sub.5-C.sub.11)bi- or
tricycloalkyl, --(C.sub.7-C.sub.11)bi- or tricycloalkenyl, -(4-20
membered) heterocycloalkyl, --C.sub.6-C.sub.15 aryl, -(5-15
membered) heteroaryl, --C.sub.6-C.sub.15 aryloxy and -(5-15
membered) heteroaryloxy;
[0074] R.sup.2 is selected from H, --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.3-C.sub.8 cycloalkyl and
--C.sub.3-C.sub.8 cycloalkenyl, wherein R.sup.2 is optionally
independently substituted with from one to three substituents
independently selected from --C.sub.1-C.sub.4 alkyl optionally
substituted with from one to three halo atoms, --C.sub.1-C.sub.4
alkoxy optionally substituted with from one to three halo atoms,
halo and --OH;
[0075] or R.sup.1 and R.sup.2 together with the A group when
present and the nitrogen atom to which R.sup.2 is attached, or
R.sup.1 and R.sup.2 together with the nitrogen atom to which
R.sup.1 and R.sup.2 are attached when A is absent, may optionally
form a four to eight membered ring;
[0076] R.sup.3 is selected from --C.sub.6-C.sub.14 aryl and (5-14
membered) heteroaryl, wherein said aryl or heteroaryl are each
optionally independently substituted with from one to three
substituents independently selected from --C.sub.1-C.sub.4 alkoxy,
halo, --OH, --S(C.sub.1-C.sub.4)alkyl --C.sub.1-C.sub.4 alkyl
--C(.dbd.O)OR.sup.9, --SO.sub.2R.sup.9 and (3-8 membered)
heterocycloalkyl wherein said alkyl, alkoxy, and heterocyloalkyl
may be further substituted by one to six halo;
[0077] R.sup.4 is H, --C.sub.1-C.sub.6 alkyl or halo;
[0078] or R.sup.3 and R.sup.4 may together with the carbon atom to
which they are attached optionally form a moiety selected from
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino,
piperidino, pyrrolidino, tetrahydrofuranyl and perhydro-2H-pyran,
wherein said moiety formed by R.sup.3 and R.sup.4 is optionally
substituted with from one to three substituents independently
selected from --C.sub.1-C.sub.6 alkyl optionally substituted with
from one to three halo atoms, --C.sub.1-C.sub.6 alkoxy optionally
substituted with from one to three halo atoms, halo, --OH, --CN and
allyl;
[0079] R.sup.6 is selected from H, --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkylene, --C.sub.1-C.sub.6 alkoxy, halo, --CN,
--C.sub.3-C.sub.12 cycloalkyl, --C.sub.4-C.sub.12 cycloalkenyl
(5-10 membered) heteroaryl and --C.sub.6-C.sub.10 aryl, wherein
said alkyl, alkylene and alkoxy of R.sup.6 are each optionally
independently substituted with from one to three substituents
independently selected from halo and --CN, and wherein said
cycloalkyl, cycloalkenyl, heteroaryl and aryl of R.sup.6 are each
optionally independently substituted with from one to three
substituents independently selected from --C.sub.1-C.sub.4 alkyl
optionally substituted with from one to three halo atoms,
--C.sub.1-C.sub.4 alkoxy optionally substituted with from one to
three halo atoms, halo and --CN;
[0080] R.sup.7 is selected from H, --C.sub.1-C.sub.20 alkyl,
--C.sub.l-C.sub.20 alkoxy, --C.sub.1-C.sub.20 hydroxyalkyl,
--C.sub.3-C.sub.12 cycloalkyl, --C.sub.4-C.sub.12 cycloalkenyl,
(C.sub.5-C.sub.20) bi- or tricycloalkyl, --(C.sub.7-C.sub.20)bi- or
tricycloalkenyl, (3-12 membered) heterocycloalkyl, -(7-20 membered)
heterobi- or heterotricycloalkyl, --C.sub.6-C.sub.14 aryl and
-(5-15 membered) heteroaryl, wherein said alkyl, alkenyl, alkynyl,
alkoxy, alkenoxy, alkynoxy, cycloalkyl, cycloalkenyl, bi- or
tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl,
heteroaryl, aryloxy and heteroaryloxy of R.sup.7 are each
optionally independently substituted with from one to six
substituents independently selected from the group R.sup.7a;
[0081] wherein R.sup.7a in each instance is independently selected
from --OH, --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12 alkenyl,
--C.sub.2-C.sub.12 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.12 alkoxyalkyl, --C.sub.1-C.sub.12 hydroxyalkyl,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, halo, --CN,
--NO.sub.2, --NR.sup.9R.sup.10, --C(.dbd.O)NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.12,
--SO.sub.2--NR.sup.9R.sup.10, --S(O).sub.n--R.sup.11,
--C.sub.3-C.sub.16 cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.6-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy;
wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy,
cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or
tricycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aryloxy and
heteroaryloxy of R.sup.7a are each optionally independently
substituted with from one to six substituents independently
selected from the group R.sup.7b;
[0082] wherein R.sup.7b in each instance is independently selected
from --OH, --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.C.sub.12
alkenyl, --C.sub.2-C.sub.12 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.12 alkoxyalkyl --C.sub.1-C.sub.12 hydroxyalkyl,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, halo, --CN,
--NO.sub.2, --NR.sup.9R.sup.10, --C(.dbd.O)NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.11,
--SO.sub.2--NR.sup.9R.sup.10, --S(O).sub.n--R.sup.11,
--C.sub.3-C.sub.16 cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.6-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy;
[0083] or R.sup.6 and R.sup.7 may together with the carbon and
nitrogen atoms to which they are respectively attached optionally
form a (5-8 membered) heterocycloalkyl ring, a (5-8 membered)
heterocycloalkenyl ring or a (6-8 membered) heteroaryl ring,
wherein said heterocycloalkyl, heterocycloalkenyl and heteroaryl
rings are each optionally independently substituted with from one
to three substituents independently selected from halo,
--C.sub.1-C.sub.6 alkyl, optionally subsituted with from one to
three halo atoms, --C.sub.1-C.sub.6 alkoxy optionally subsituted
with from one to three halo atoms, --C.sub.1-C.sub.6 hydroxyalkyl,
--OH, .sup.-(CH.sub.2).sub.zero-10NR.sup.9R.sup.10,
--(CH.sub.2).sub.zero-10C(.dbd.O)NR.sup.9R.sup.10,
--SO.sub.2NR.sup.9R.sup.10 and --C.sub.3-C.sub.12 cycloalkyl;
[0084] R.sup.9 and R.sup.10 in each instance are each independently
selected from H, --OH, --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12
alkenyl, --C.sub.2-C.sub.12 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.12 alkoxyalkyl --C.sub.1-C.sub.12 hydroxyalkyl,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy,
--C(.dbd.O)NR.sup.11R.sup.12, --C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.12, --SO.sub.2--NR.sup.10R.sup.11,
--S(O).sub.n--R.sup.11, --C.sub.3-C.sub.15 cycloalkyl,
--C.sub.4-C.sub.15 cycloalkenyl, --(C.sub.5-C.sub.11)bi- or
tricycloalkyl, --(C.sub.7-C.sub.11)bi- or tricycloalkenyl, -(4-20
membered) heterocycloalkyl, --C.sub.6-C.sub.15 aryl, -(5-15
membered) heteroaryl, --C.sub.6-C.sub.15 aryloxy and -(5-15
membered) heteroaryloxy, wherein said alkyl, alkenyl, alkynyl,
alkoxy, alkenoxy, alkynoxy, cycloalkyl, cycloalkenyl, bi- or
tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl,
heteroaryl, aryloxy and heteroaryloxy of R.sup.9 of R.sup.10 are
each optionally independently substituted with from one to six
substituents independently selected from the group R.sup.10a;
[0085] wherein R.sup.10a in each instance is independently selected
from --OH, halo, --C.sub.1-C.sub.6 alkoxy, --CN, --NO.sub.2,
--NR.sup.11R.sup.12, --C(.dbd.O)NR.sup.11R.sup.12,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.12,
--SO.sub.2--NR.sup.11R.sup.12, --S(O).sub.n--R.sup.11,
--C.sub.3-C.sub.15 cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy;
wherein said alkoxy, cycloalkyl, cycloalkenyl, bi- or
tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl,
heteroaryl, aryloxy and heteroaryloxy of R.sup.10a are each
optionally independently substituted with from one to six
substituents independently selected from the group R.sup.10b;
[0086] wherein R.sup.10b in each instance is independently selected
from --OH, halo; --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12
alkenyl, --C.sub.2-C.sub.12 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.12 alkoxyalkyl --C.sub.1-C.sub.12 hydroxyalkyl,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, halo, --CN,
--NO.sub.2, --NR.sup.11R.sup.12, --C(.dbd.O)NR.sup.11R.sup.12,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.12,
--SO.sub.2--NR.sup.11R.sup.12, --S(O).sub.n--R.sup.11,
--C.sub.3-C.sub.15cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy;
[0087] or NR.sup.9R.sup.10 may form may form a -(4-20 membered)
heterocycloalkyl, -(5-18 membered) heterobi- or tricycloalkyl,
-(5-18 membered) heterobi- or tricycloalkenyl, or -(5-15 membered)
heteroaryl, wherein said heterocycloalkyl, heterobi- or
tricycloalkyl, heterobi- or tricycloalkenyl or heteroaryl are
optionally independently substituted with from one to six
substituents independently selected from --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.1-C.sub.6 alkoxy, --C.sub.2-C.sub.6 alkenoxy,
--C.sub.2-C.sub.6 alkynoxy, --C.sub.1-C.sub.6 hydroxyalkyl,
--C.sub.2-C.sub.6 hydroxyalkenyl, --C.sub.2-C.sub.6 hydroxyalkenyl,
halo, --OH, --CN, --NO.sub.2, --NR.sup.11R.sup.12,
--C(.dbd.O)NR.sup.11R.sup.12, --C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.11, --S(O).sub.nR.sup.11 and
--S(O).sub.nNR.sup.11R.sup.12;
[0088] wherein R.sup.11 and R.sup.12 in each instance are each
independently selected from H, --C.sub.1-C.sub.8 alkyl,
--C.sub.3-C.sub.8 cycloalkyl, --C.sub.4-C.sub.8 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(3-8 membered) heterocycloalkyl,
--C.sub.6-C.sub.10 aryl and -(5-14 membered) heteroaryl, wherein
said alkyl of R.sup.11 is optionally independently substituted with
from one to three substituents independently selected from --OH,
--CN and --C.sub.3-C.sub.8 cycloalkyl, and wherein each hydrogen
atom of said alkyl is optionally independently replaced with a halo
atom, and wherein said cylcoalkyl, cycloalkenyl, heterocycloalkyl,
aryl and hetereoaryl of R.sup.11 are each optionally independently
substituted with from one to three substituents independently
selected from halo, --C.sub.1-C.sub.8 alkyl optionally substituted
with from one to three halo atoms, --OH, --CN and
--C.sub.3-C.sub.8cycloalkyl; and
[0089] n is in each instance an integer independently selected from
zero, 1 and 2;
[0090] or a pharmaceutically acceptable salt thereof.
[0091] In an another embodiment, the present invention relates to
compounds of Formula I,
[0092] wherein A is absent;
[0093] R.sup.1 is --C.sub.1-C.sub.20 alkyl; wherein R.sup.1 is
independently substituted with from one to six substituents
independently selected from R.sup.1A;
[0094] wherein R.sup.12 in each instance is independently selected
from --C.sub.1-C.sub.6 alkoxy, --CN, --C.sub.3-C.sub.15 cycloalkyl,
--C.sub.4-C.sub.15 cycloalkenyl, --(C.sub.8-C.sub.11)bi- or
tricycloalkyl, --(C.sub.7-C.sub.11)bi- or tricycloalkenyl, -(4-20
membered) heterocycloalkyl, --C.sub.6-C.sub.15 aryl, -(5-15
membered) heteroaryl, --C.sub.6-C.sub.15 aryloxy and -(5-15
membered) heteroaryloxy;
[0095] wherein said cycloalkyl, cycloalkenyl, bi- or tricycloalkyl,
bi- or tricycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aryloxy
and heteroaryloxy of R.sup.1a are each optionally independently
substituted with from one to six substituents independently
selected from the group R.sup.1b;
[0096] wherein R.sup.1b in each instance is independently selected
from --OH, --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12 alkenyl,
--C.sub.2-C.sub.12 alkynyl, alkoxy, --C.sub.1-C.sub.12 alkoxyalkyl
--C.sub.1-C.sub.12 hydroxyalkyl, --C.sub.2-C.sub.6 alkenoxy,
--C.sub.2-C.sub.8 alkynoxy, halo, --CN, --NO.sub.2,
--NR.sup.9R.sup.10, --C(.dbd.O)NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.12,
--SO.sub.2--NR.sup.9R.sup.10, --S(O).sub.n--R.sup.11,
--C.sub.3-C.sub.18cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.8-C.sub.18 aryl, -(5-15 membered) heteroaryl,
--C.sub.8-C.sub.18 aryloxy and -(5-15 membered) heteroaryloxy;
[0097] R.sup.2 is selected from H, --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.8 alkenyl, --C.sub.3-C.sub.8 cycloalkyl and
--C.sub.3-C.sub.8 cycloalkenyl, wherein R.sup.2 is optionally
independently substituted with from one to three substituents
independently selected from --C.sub.1-C.sub.4 alkyl optionally
substituted with from one to three halo atoms, --C.sub.1-C.sub.4
alkoxy optionally substituted with from one to three halo atoms,
halo and --OH;
[0098] R.sup.3 is selected from H, --C.sub.1-C.sub.8 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkynyl,
--C.sub.3-C.sub.6 cycloalkyl, --C.sub.8-C.sub.8 cycloalkenyl and
(3-8 membered) heterocycloalkyl, --C.sub.6-C.sub.14 aryl and (5-14
membered) heteroaryl, wherein said alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, heterocycloalkyl aryl or heteroaryl are
each optionally independently substituted with from one to three
substituents independently selected from --C.sub.1-C.sub.4 alkoxy,
halo, --OH, --S(C.sub.1-C.sub.4)alkyl --C.sub.1-C.sub.4alkyl
-C(.dbd.O)OR.sup.9, --SO.sub.2R.sup.9 and (3-8 membered)
heterocycloalkyl wherein said alkyl, alkoxy, and heterocyloalkyl
may be further substituted by one to six halo;
[0099] R.sup.4 is H, --C.sub.1-C.sub.8 alkyl or halo;
[0100] or R.sup.3 and R.sup.4 may together with the carbon atom to
which they are attached optionally form a moiety selected from
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino,
piperidino, pyrrolidino, tetrahydrofuranyl and perhydro-2H-pyran,
wherein said moiety formed by R.sup.3 and R.sup.4 is optionally
substituted with from one to three substituents independently
selected from --C.sub.1-C.sub.6 alkyl optionally substituted with
from one to three halo atoms, --C.sub.1-C.sub.6 alkoxy optionally
substituted with from one to three halo atoms, halo, --OH, --CN and
allyl;
[0101] R.sup.6 is selected from H, --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkylene, --C.sub.1-C.sub.6 alkoxy, halo, --CN,
--C.sub.3-C.sub.12 cycloalkyl, --C.sub.4-C.sub.12 cycloalkenyl
(5-10 membered) heteroaryl and --C.sub.6-C.sub.10 aryl, wherein
said alkyl, alkylene and alkoxy of R.sup.6 are each optionally
independently substituted with from one to three substituents
independently selected from halo and --CN, and wherein said
cycloalkyl, cycloalkenyl, heteroaryl and aryl of R.sup.6 are each
optionally independently substituted with from one to three
substituents independently selected from --C.sub.1-C.sub.4 alkyl
optionally substituted with from one to three halo atoms,
--C.sub.1-C.sub.4 alkoxy optionally substituted with from one to
three halo atoms, halo and --CN;
[0102] R.sup.7 is selected from H, --C.sub.1-C.sub.20 alkyl,
--C.sub.1-C.sub.20 alkoxy, --C.sub.1-C.sub.20 hydroxyalkyl,
--C.sub.3-C.sub.12 cycloalkyl, --C.sub.4-C.sub.12 cycloalkenyl,
--(C.sub.5-C.sub.20) bi- or tricycloalkyl, --(C.sub.7-C.sub.20)bi-
or tricycloalkenyl, (3-12 membered) heterocycloalkyl, (-7-20
membered) heterobi- or heterotricycloalkyl, --C.sub.6-C.sub.14 aryl
and (5-15 membered) heteroaryl, wherein said alkyl, alkenyl,
alkynyl, alkoxy, alkenoxy, alkynoxy, cycloalkyl, cycloalkenyl, bi-
or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl,
heteroaryl, aryloxy and heteroaryloxy of R.sup.7 are each
optionally independently substituted with from one to six
substituents independently selected from the group R.sup.7a;
[0103] wherein R.sup.7a in each instance is independently selected
from --OH, --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12 alkenyl,
--C.sub.2-C.sub.12 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.12 alkoxyalkyl, --C.sub.1-C.sub.12 hydroxyalkyl,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, halo, --CN,
--NO.sub.2, --NR.sup.9R.sup.10, --C(.dbd.O)NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.12,
--SO.sub.2--NR.sup.9R.sup.10, --S(O).sub.n--R.sup.11,
--C.sub.3-C.sub.15 cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.6-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy;
wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy,
cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or
tricycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aryloxy and
heteroaryloxy of R.sup.7a are each optionally independently
substituted with from one to six substituents independently
selected from the group R.sup.7b;
[0104] wherein R.sup.7b in each instance is independently selected
from --OH, --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12 alkenyl,
--C.sub.2-C.sub.12 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.12 alkoxyalkyl --C.sub.1-C.sub.12 hydroxyalkyl,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, halo, --CN,
--NO.sub.2, --NR.sup.9R.sup.10, --C(.dbd.O)NR.sup.9R.sup.10,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.11,
--SO.sub.2--NR.sup.9R.sup.10, --S(O).sub.n--R.sup.11,
--C.sub.3-C.sub.15 cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.6-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy;
[0105] or R.sup.6 and R.sup.7 may together with the carbon and
nitrogen atoms to which they are respectively attached optionally
form a -(5-8 membered) heterocycloalkyl ring, a -(5-8 membered)
heterocycloalkenyl ring or a -(6-8 membered) heteroaryl ring,
wherein said heterocycloalkyl, heterocycloalkenyl and heteroaryl
rings are each optionally independently substituted with from one
to three substituents independently selected from halo,
--C.sub.1-C.sub.6 alkyl, optionally subsituted with from one to
three halo atoms, --C.sub.1-C.sub.6 alkoxy optionally subsituted
with from one to three halo atoms, --C.sub.1-C.sub.6 hydroxyalkyl,
--OH, --(CH.sub.2).sub.zero-10NR.sup.9R.sup.10,
--(CH.sub.2).sub.zero-10C(.dbd.O)NR.sup.9R.sup.10,
--SO.sub.2NR.sup.9R.sup.10 and --C.sub.3-C.sub.12 cycloalkyl;
[0106] R.sup.9 and R.sup.10 in each instance are each independently
selected from H, --OH, --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12
alkenyl, --C.sub.2-C.sub.12 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.12 alkoxyalkyl --C.sub.1-C.sub.12 hydroxyalkyl,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy,
--C(.dbd.O)NR.sup.11R.sup.12, --C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.11, SO.sub.2--NR.sup.11R.sup.12,
--S(O).sub.n--R.sup.11, --C.sub.3-C.sub.15 cycloalkyl,
--C.sub.4-C.sub.15 cycloalkenyl, --(C.sub.5-C.sub.11)bi- or
tricycloalkyl, --(C.sub.7-C.sub.11)bi- or tricycloalkenyl, -(4-20
membered) heterocycloalkyl, --C.sub.6-C.sub.15 aryl, -(5-15
membered) heteroaryl, --C.sub.6-C.sub.15 aryloxy and -(5-15
membered) heteroaryloxy, wherein said alkyl, alkenyl, alkynyl,
alkoxy, alkenoxy, alkynoxy, cycloalkyl, cycloalkenyl, bi- or
tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl,
heteroaryl, aryloxy and heteroaryloxy of R.sup.9 of R.sup.10 are
each optionally independently substituted with from one to six
substituents independently selected from the group R.sup.10a;
[0107] wherein R.sup.10a in each instance is independently selected
from --OH, Halo, --C.sub.1-C.sub.6 alkoxy, --CN, --NO.sub.2,
--NR.sup.11R.sup.12, C(.dbd.O)NR.sup.11R.sup.12,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.12,
--SO.sub.2--NR.sup.11R.sup.12, --S(O).sub.n--C.sub.3-C.sub.15
cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy;
wherein said alkoxy, cycloalkyl, cycloalkenyl, bi- or
tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl,
heteroaryl, aryloxy and heteroaryloxy of R.sup.10a are each
optionally independently substituted with from one to six
substituents independently selected from the group R.sup.10b;
[0108] wherein R.sup.10b in each instance is independently selected
from --OH, halo; --C.sub.1-C.sub.12 alkyl, --C.sub.2-C.sub.12
alkenyl, --C.sub.2-C.sub.12 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--C.sub.1-C.sub.12 alkoxyalkyl --C.sub.1-C.sub.12 hydroxyalkyl,
--C.sub.2-C.sub.6 alkenoxy, --C.sub.2-C.sub.6 alkynoxy, halo, --CN,
--NO.sub.2, --NR.sup.11R.sup.12, --C(.dbd.O)NR.sup.11R.sup.12,
--C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.11,
--SO.sub.2--NR.sup.11R.sup.12, --S(O).sub.n--R.sup.11,
--C.sub.3-C.sub.13 cycloalkyl, --C.sub.4-C.sub.15 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,
--C.sub.6-C.sub.15 aryl, -(5-15 membered) heteroaryl,
--C.sub.6-C.sub.15 aryloxy and -(5-15 membered) heteroaryloxy;
[0109] or NR.sup.9R.sup.10 may form a (4-20 membered)
heterocycloalkyl, (5-18 membered) heterobi- or tricycloalkyl (5-18
membered) heterobi- or tricycloalkenyl, or -(5-15 membered)
heteroaryl, wherein said a heterocycloalkyl, heterobi- or
tricycloalkyl, heterobi- or tricycloalkenyl or heteroaryl are
optionally independently substituted with from one to six
substituents independently selected from --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.1-C.sub.6 alkoxy, --C.sub.2-C.sub.6 alkenoxy,
--C.sub.2-C.sub.6 alkynoxy, --C.sub.1-C.sub.6 hydroxyalkyl,
--C.sub.2-C.sub.6 hydroxyalkenyl, --C.sub.2-C.sub.6 hydroxyalkenyl,
halo, --OH, --CN, --NO.sub.2, --NR.sup.11R.sup.12,
--C(.dbd.O)NR.sup.11R.sup.12, --C(.dbd.O)R.sup.11,
--C(.dbd.O)OR.sup.11, --S(O).sub.nR.sup.11 and
--S(O).sub.nNR.sup.11R.sup.12;
[0110] R.sup.11 and R.sup.12 in each instance are each
independently selected from H, --C.sub.1-C.sub.8 alkyl,
--C.sub.3-C.sub.8 cycloalkyl, --C.sub.4-C.sub.8 cycloalkenyl,
--(C.sub.5-C.sub.11)bi- or tricycloalkyl, --(C.sub.7-C.sub.11)bi-
or tricycloalkenyl, -(3-8 membered) heterocycloalkyl,
--C.sub.6-C.sub.10 aryl and -(5-14 membered) heteroaryl, wherein
said alkyl of R.sup.11 is optionally independently substituted with
from one to three substituents independently selected from --OH,
--CN and --C.sub.3-C.sub.8 cycloalkyl, and wherein each hydrogen
atom of said alkyl is optionally independently replaced with a halo
atom, and wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl,
aryl and hetereoaryl of R.sup.11 are each optionally independently
substituted with from one to three substituents independently
selected from halo, --C.sub.1-C.sub.8 alkyl optionally substituted
with from one to three halo atoms, --OH, --CN and --C.sub.3-C.sub.8
cycloalkyl; and
[0111] n is in each instance an integer independently selected from
zero, 1 and 2; or a pharmaceutically acceptable salt thereof.
[0112] Compounds of Formula I may have optical centers and
therefore may occur in different enantiomeric and diastereomeric
configurations. The present invention includes all enantiomers,
diastereomers, and other stereoisomers of such compounds of Formula
I, as well as racemic compounds and racemic mixtures and other
mixtures of stereoisomers thereof.
[0113] Pharmaceutically acceptable salts of the compounds of
Formula I include the acid addition and base salts thereof.
[0114] Suitable acid addition salts are formed from acids which
form non-toxic salts. Examples include, but are not limited to, the
acetate, adipate, aspartate, benzoate, besylate,
bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate,
citrate, cyclamate, edisylate, esylate, formate, fumarate,
gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate,
hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,
isethionate, lactate, malate, maleate, malonate, mandelates
mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate,
nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen
phosphate/dihydrogen phosphate, pyroglutamate, salicylate,
saccharate, stearate, succinate, sulfonate, stannate, tartrate,
tosylate, trifluoroacetate and xinofoate salts.
[0115] Suitable base salts are formed from bases which form
non-toxic salts. Examples include, but are not limited to, the
aluminium, arginine, benzathine, calcium, choline, diethylamine,
diolamine, glycine, lysine, magnesium, meglumine, olamine,
potassium, sodium, tromethamine and zinc salts.
[0116] Hemisalts of acids and bases may also be formed, for
example, hemisuiphate and hemicalcium salts.
[0117] For a review on suitable salts, see Handbook of
Pharmaceutical Salts: Properties, Selection, and Use by Stahl and
Wermuth (Wiley-VCH, 2002).
[0118] Pharmaceutically acceptable salts of compounds of Formula I
may be prepared by one or more of three methods:
[0119] (i) by reacting the compound of Formula I with the desired
acid or base;
[0120] (ii) by removing an acid- or base-labile protecting group
from a suitable precursor of the compound of Formula I or by
ring-opening a suitable cyclic precursor, for example, a lactone or
lactam, using the desired acid or base; or
[0121] (iii) by converting one salt of the compound of Formula I to
another by reaction with an appropriate acid or base or by means of
a suitable ion exchange column.
[0122] All three reactions are typically carried out in solution.
The resulting salt may precipitate out and be collected by
filtration or may be recovered by evaporation of the solvent. The
degree of ionization in the resulting salt may vary from completely
ionised to almost non-ionised.
[0123] The compounds of the invention may exist in a continuum of
solid states ranging from fully amorphous to fully crystalline. The
term `amorphous` refers to a state in which the material lacks long
range order at the molecular level and, depending upon temperature,
may exhibit the physical properties of a solid or a liquid.
Typically such materials do not give distinctive X-ray diffraction
patterns and, while exhibiting the properties of a solid, are more
formally described as a liquid. Upon heating, a change from solid
to liquid properties occurs which is characterised by a change of
state, typically second order (`glass transition`). The term
`crystalline` refers to a solid phase in which the material has a
regular ordered internal structure at the molecular level and gives
a distinctive X-ray diffraction pattern with defined peaks. Such
materials when heated sufficiently will also exhibit the properties
of a liquid, but the change from solid to liquid is characterised
by a phase change, typically first order (`melting point`).
[0124] The compounds of the invention may also exist in unsolvated
and solvated forms. The term `solvate` is used herein to describe a
molecular complex comprising the compound of the invention and one
or more pharmaceutically acceptable solvent molecules, for example,
ethanol. The term `hydrate` is employed when said solvent is
water.
[0125] A currently accepted classification system for organic
hydrates is one that defines isolated site, channel, or metal-ion
coordinated hydrates--see Polymorphism in Pharmaceutical Solids by
K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated
site hydrates are ones in which the water molecules are isolated
from direct contact with each other by intervening organic
molecules. In channel hydrates, the water molecules lie in lattice
channels where they are next to other water molecules. In metal-ion
coordinated hydrates, the water molecules are bonded to the metal
ion.
[0126] When the solvent or water is tightly bound, the complex will
have a well-defined stoichiometry independent of humidity. When,
however, the solvent or water is weakly bound, as in channel
solvates and hygroscopic compounds, the water/solvent content will
be dependent on humidity and drying conditions. In such cases,
non-stoichiometry will be the norm.
[0127] The compounds of the invention may also exist in a
mesomorphic state (mesophase or liquid crystal) when subjected to
suitable conditions. The mesomorphic state is intermediate between
the true crystalline state and the true liquid state (either melt
or solution). Mesomorphism arising as the result of a change in
temperature is described as `thermotropic` and that resulting from
the addition of a second component, such as water or another
solvent, is described as `lyotropic`. Compounds that have the
potential to form lyotropic mesophases are described as
`amphiphilic` and consist of molecules which possess an ionic (such
as --COO.sup.-Na.sup.+, --COO.sup.-K.sup.+, or
--SO.sub.3.sup.-Na.sup.+) or non-ionic (such as
--N.sup.-N.sup.+(CH.sub.3).sub.3) polar head group. For more
information, see Crystals and the Polarizing Microscope by N. H.
Hartshorne and A. Stuart, 4.sup.th Edition (Edward Arnold,
1970).
[0128] Hereinafter all references to compounds of Formula I include
references to salts, solvates, multi-component complexes and liquid
crystals thereof and to solvates, multi-component complexes and
liquid crystals of salts thereof.
[0129] The compounds of the invention include compounds of Formula
I as hereinbefore defined, including all polymorphs and crystal
habits thereof, prodrugs and isomers thereof (including optical,
geometric and tautomeric isomers) as hereinafter defined and
isotopically-labeled compounds of Formula I.
[0130] Unless otherwise indicated, as used herein, the term "A is
absent" means a direct bond between the nitrogen and R.sup.1 (i.e.,
--N--R.sup.1).
[0131] Unless otherwise indicated, as used herein, the terms
"halogen" and "halo" include F, Cl, Br, and I.
[0132] Unless otherwise indicated, as used herein, the term "alkyl"
includes saturated monovalent hydrocarbon radicals having straight
or branched moieties. Examples of alkyl groups include, but are not
limited to, methyl, ethyl, n-propyl, isopropyl, and t-butyl.
[0133] Unless otherwise indicated, as used herein, the term
"alkenyl" includes alkyl moieties having at least one carbon-carbon
double bond wherein alkyl is as defined above. Examples of alkenyl
include, but are not limited to, ethenyl and propenyl.
[0134] Unless otherwise indicated, as used herein, the term
"alkynyl" includes alkyl moieties having at least one carbon-carbon
triple bond wherein alkyl is as defined above. Examples of alkynyl
groups include, but are not limited to, ethynyl and 2-propynyl.
[0135] Unless otherwise indicated, as used herein, the term
"alkoxy', means "alkyl-O--", wherein "alkyl" is as defined above.
Examples of "alkoxy" groups include, but are not limited to,
methoxy, ethoxy, propoxy, butoxy, pentoxy and allyloxy.
[0136] Unless otherwise indicated, as used herein, the term
"alkenoxy", means "alkenyl-O--", wherein "alkenyl" is as defined
above.
[0137] Unless otherwise indicated, as used herein, the term
"cycloalkyl" includes non- aromatic saturated cyclic alkyl moieties
wherein alkyl is as defined above. Examples of cycloalkyl include,
but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl. "Bicycloalkyl" and "tricycloalkyl"
groups are non-aromatic saturated carbocyclic groups consisting of
two or three rings respectively, wherein said rings share at least
one carbon atom. Unless otherwise indicated, for purposes of the
present invention, bicycloalkyl groups include Spiro groups and
fused ring groups. Examples of bicycloalkyl groups include, but are
not limited to, bicyclo-[3.1.0]-hexyl, bicyclo-2.2.1]-hept-1-yl,
norbornyl, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[4.3]octyl, and
spiro[4.2]heptyl. An example of a tricycloalkyl group is
adamantanyl. Other cycloalkyl, bicycloalkyl, and tricycloalkyl
groups are known in the art, and such groups are encompassed by the
definitions "cycloalkyl", "bicycloalkyl" and "tricycloalkyl"
herein.
[0138] "Cycloalkenyl", "bicycloalkenyl", and "tricycloalkenyl"
refer to non-aromatic carbocyclic cycloalkyl, bicycloalkyl, and
tricycloalkyl moieties as defined above, except comprising one or
more carbon-carbon double bonds connecting carbon ring members (an
"endocyclic" double bond) and/or one or more carbon-carbon double
bonds connecting a carbon ring member and an adjacent non-ring
carbon (an "exocyclic" double bond). Examples of cycloalkenyl
groups include, but are not limited to, cyclopentenyl,
cyclobutenyl, and cyclohexenyl, and a non-limiting example of a
bicycloalkenyl group is norbornenyl. Other cycloalkenyl,
bicycloalkenyl, and tricycloalkenyl groups are known in the art,
and such groups are included within the definitions "cycloalkenyl",
"bicycloalkenyl" and "tricycloalkenyl" herein.
[0139] Cycloalkyl, cycloalkenyl, bicycloalkyl, and bicycloalkenyl
groups also include groups that are substituted with one or more
oxo moieties. Examples of such groups with oxo moieties are
oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl, and
norcamphoryl.
[0140] As used herein, the term "benzocycloalkyl" includes, without
limitation, moieties such as tetrahydronaphthyl, indanyl,
1,2-benzocylcoheptanyl and the like.
[0141] Unless otherwise indicated, as used herein, the term "aryl"
includes an organic radical derived from an aromatic hydrocarbon by
removal of one hydrogen, such as phenyl, naphthyl, indenyl,
indanyl, and fluorenyl. "Aryl" encompasses fused ring groups
wherein at least one ring is aromatic.
[0142] Unless otherwise indicated, as used herein, the terms
"heterocyclic" and "heterocycloalkyl" refer to non-aromatic cyclic
groups containing one or more heteroatoms, prefereably from one to
four heteroatoms, each selected from O, S and N.
"Heterobicycloalkyl" groups are non-aromatic two-ringed cyclic
groups, wherein said rings share one or two atoms, and wherein at
least one of the rings contains a heteroatom (O, S, or N).
Heterobicycloalkyl groups for purposes of the present invention,
and unless otherwise indicated, include spiro groups and fused ring
groups. "Heterotricycloalkyl" groups are non-aromatic three-ringed
cyclic groups, wherein said rings are fused to one another or form
a Spiro group (in other words, at least two of said rings share one
or two atoms and the third ring shares one or two atoms with at
least one of said two rings). The heterotricycloalkyl groups of the
compounds of the present invention can include one or more O, S
and/or N heteroatoms. In one embodiment, each ring in the
heterobicycloalkyl or heterotricycloalkyl contains up to four
heteroatoms (i.e. from zero to four heteroatoms, provided that at
least one ring contains at least one heteroatom). The
heterocycloalkyl, heterobicycloalky and heterotricycloalkyl groups
of the present invention can also include ring systems substituted
with one or more oxo moieties. The heterocyclic groups, including
the heterobicyclic and heterotricyclic groups, may comprise double
or triple bonds, e.g. heterocycloalkenyl, heterobicycloalkenyl, and
heterotricycloalkenyl. Examples of non-aromatic heterocyclic groups
are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl,
piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl,
tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,
tetrahydrothiopyranyl, morpholine, thiomorpholino, thioxanyl,
pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,
1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,
quinolizinyl, quinuclidinyl, 1,4-dioxaspiro[4.5]decyl,
1,4-dioxaspiro[4.4]nonyl, 1,4-dioxaspiro[4.3]octyl, and
1,4-dioxaspiro[4.2]heptyl.
[0143] Unless otherwise indicated, as used herein, "heteroaryl"
refers to aromatic groups containing one or more heteroatoms (O, S,
or N), preferably from one to four heteroatoms. A multicyclic group
containing one or more heteroatoms wherein at least one ring of the
group is aromatic is a "heteroaryl" group. The heteroaryl groups of
this invention can also include ring systems substituted with one
or more oxo moieties. Examples of heteroaryl groups are pyridinyl,
pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl,
pyrazinyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydroguinolyl,
tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,
isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl,
cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl,
1,2,4-trizainyl, 1,3,5-triazinyl, isoindolyl, 1-oxoisoindolyl,
purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,
benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl,
tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl,
benzofuryl, furopyridinyl, pyrolopyrimidinyl, and azaindolyl.
[0144] Unless otherwise indicated to the contrary, all the
foregoing groups derived from hydrocarbons may be optionally
substituted by one or more halogen atoms (e.g., --CH.sub.2F,
--CHF.sub.2--CF.sub.3, -PhCl, etc.).
[0145] Unless otherwise indicated, the term "one or more
substituents", as used herein, refers to from one to the maximum
number of substituents possible based on the number of available
bonding sites.
[0146] Unless otherwise indicated, all the foregoing groups derived
from hydrocarbons may have up to about 1 to about 20 carbon atoms
(e.g. C.sub.1-C.sub.20 alkyl, C.sub.2-C.sub.20 alkenyl,
C.sub.3-C.sub.20 cycloalkyl, 3-20 membered heterocycloalkyl;
C.sub.6-C.sub.20 aryl, 5-20 membered heteroaryl, etc.) or 1 to
about 15 carbon atoms (e.g., C.sub.1-C.sub.15 alkyl,
C.sub.2-C.sub.15 alkenyl, C.sub.3-C.sub.15 cycloalkyl, 3-15
membered heterocycloalkyl, C.sub.6-C.sub.15 aryl, 5-15 membered
heteroaryl, etc.), or 1 to about 12 carbon atoms, or 1 to about 8
carbon atoms, or 1 to about 6 carbon atoms.
[0147] As appreciated by the artisan, the use of Formula I is a
convenience, and the invention is understood to envision and
embrace each and every species thereunder as though individually
identified and set forth herein. Thus, the present invention
contemplates each species separately and any and all combinations
and permutations of species falling within Formula I.
[0148] The foregoing groups, as derived from the compounds listed
above, may be C-attached or N-attached where such is possible. For
instance, a group derived from pyrrole may be pyrrol-1-yl
(N-attached) or pyrrol-3-yl (C-attached). The terms referring to
the groups also encompass all possible tautomers.
[0149] As indicated, so-called `prodrugs` of the compounds of
Formula I are also within the scope of the invention. Thus certain
derivatives of compounds of Formula I which may have little or no
pharmacological activity themselves can, when administered into or
onto the body, be converted into compounds of Formula I having the
desired activity, for example, by hydrolytic cleavage. Such
derivatives are referred to as `prodrugs`. Further information on
the use of prodrugs may be found in Pro-drugs as Novel Delivery
Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella)
and Bioreversible Carriers in Drug Design, Pergamon Press, 1987
(Ed. E. B. Roche, American Pharmaceutical Association).
[0150] Prodrugs in accordance with the invention can, for example,
be produced by replacing appropriate functionalities present in the
compounds of Formula I with certain moieties known to those skilled
in the art as `pro-moieties` as described, for example, in Design
of Prodrugs by H. Bundgaard (Elsevier, 1985).
[0151] Some examples of prodrugs in accordance with the invention
include, but are not limited to,
[0152] (i) where the compound of Formula I contains a carboxylic
acid functionality (--COOH), an ester thereof, for example, a
compound wherein the hydrogen of the carboxylic acid functionality
of the compound of Formula (I) is replaced by
(C.sub.1-C.sub.8)alkyl;
[0153] (ii) where the compound of Formula I contains an alcohol
functionality (--OH), an ether thereof, for example, a compound
wherein the hydrogen of the alcohol functionality of the compound
of Formula I is replaced by (C.sub.1-C.sub.6)alkanoyloxymethyl;
and
[0154] (iii) where the compound of Formula I contains a primary or
secondary amino functionality (--NH.sub.2 or --NHR where
R.noteq.H), an amide thereof, for example, a compound wherein, as
the case may be, one or both hydrogens of the amino functionality
of the compound of Formula I is/are replaced by
(C.sub.1-C.sub.10)alkanoyl.
[0155] Further examples of replacement groups in accordance with
the foregoing examples and examples of other prodrug types may be
found in the aforementioned references.
[0156] Moreover, certain compounds of Formula I may themselves act
as prodrugs of other compounds of Formula I.
[0157] Also included within the scope of the invention are
metabolites of compounds of
[0158] Formula I, that is, compounds formed in vivo upon
administration of the drug. Some examples of metabolites in
accordance with the invention include, but are not limited to,
where the compound of Formula I contains a methyl group, an
hydroxymethyl derivative thereof
(--CH.sub.3.fwdarw.--CH.sub.2OH):
[0159] (ii) where the compound of Formula I contains an alkoxy
group, an hydroxy derivative thereof (--OR.fwdarw.--OH);
[0160] (iii) where the compound of Formula I contains a tertiary
amino group, a secondary amino derivative thereof
(--NR.sup.1R.sup.2.fwdarw.--NHR.sup.1 or --NHR.sup.2);
[0161] (iv) where the compound of Formula I contains a secondary
amino group, a primary derivative thereof
(--NHR.sup.1.fwdarw.--NH.sub.2);
[0162] (v) where the compound of Formula I contains a phenyl
moiety, a phenol derivative thereof (-Ph.fwdarw.-PhOH); and
[0163] (vi) where the compound of Formula I contains an amide
group, a carboxylic acid derivative thereof
(--CONH.sub.2.fwdarw.COOH).
[0164] Compounds of Formula I containing one or more asymmetric
carbon atoms can exist as two or more stereoisomers. Where a
compound of Formula I contains an alkenyl or alkenylene group,
geometric cis/trans (or Z/E) isomers are possible. Where structural
isomers are interconvertible via a low energy barrier, tautomeric
isomerism (`tautomerism`) can occur. This can take the form of
proton tautomerism in compounds of Formula I containing, for
example, an imino, keto, or oxime group, or so-called valence
tautomerism in compounds which contain an aromatic moiety. It
follows that a single compound may exhibit more than one type of
isomerism.
[0165] Included within the scope of the present invention are all
stereoisomers, geometric isomers and tautomeric forms of the
compounds of Formula I, including compounds exhibiting more than
one type of isomerism, and mixtures of one or more thereof. Also
included are acid addition or base salts wherein the counterion is
optically active, for example, d-lactate or l-lysine, or racemic,
for example, d/-tartrate or d/-arginine.
[0166] Cis/trans isomers may be separated by conventional
techniques well known to those skilled in the art, for example,
chromatography and fractional crystallisation.
[0167] Conventional techniques for the preparation/isolation of
individual enantiomers include chiral synthesis from a suitable
optically pure precursor or resolution of the racemate (or the
racemate of a salt or derivative) using, for example, chiral high
pressure liquid chromatography (HPLC).
[0168] Alternatively, the racemate (or a racemic precursor) may be
reacted with a suitable optically active compound, for example, an
alcohol, or, in the case where the compound of Formula I contains
an acidic or basic moiety, a base or acid such as
1-phenylethylamine or tartaric acid. The resulting diastereomeric
mixture may be separated by chromatography and/or fractional
crystallization and one or both of the diastereoisomers converted
to the corresponding pure enantiomer(s) by means well known to a
skilled person.
[0169] Chiral compounds of the invention (and chiral precursors
thereof) may be obtained in enantiomerically-enriched form using
chromatography, typically HPLC, on an asymmetric resin with a
mobile phase consisting of a hydrocarbon, typically heptane or
hexane, containing from 0 to 50% by volume of isopropanol,
typically from 2% to 20%, and from 0 to 5% by volume of an
alkylamine, typically 0.1% diethylamine. Concentration of the
eluate affords the enriched mixture.
[0170] When any racemate crystallises, crystals of two different
types are possible. The first type is the racemic compound (true
racemate) referred to above wherein one homogeneous form of crystal
is produced containing both enantiomers in equimolar amounts. The
second type is the racemic mixture or conglomerate wherein two
forms of crystal are produced in equimolar amounts each comprising
a single enantiomer.
[0171] While both of the crystal forms present in a racemic mixture
have identical physical properties, they may have different
physical properties compared to the true racemate.
[0172] Racemic mixtures may be separated by conventional techniques
known to those skilled in the art--see, for example,
Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen
(Wiley, 1994).
[0173] The present invention includes all pharmaceutically
acceptable isotopically-labelled compounds of Formula I wherein one
or more atoms are replaced by atoms having the same atomic number,
but an atomic mass or mass number different from the atomic mass or
mass number which predominates in nature.
[0174] Examples of isotopes suitable for inclusion in the compounds
of the invention include, but are not limited to, isotopes of
hydrogen, such as .sup.2H and .sup.3H, carbon, such as .sup.11C,
.sup.13C and .sup.14C, chlorine, such as .sup.36Cl, fluorine, such
as .sup.18F, iodine, such as .sup.123I and .sup.125I, nitrogen,
such as .sup.13N and .sup.15N, oxygen, such as .sup.15O, .sup.17O
and .sup.15O, phosphorus, such as .sup.32P, and sulphur, such as
.sup.35S.
[0175] Certain isotopically-labelled compounds of Formula I, for
example, those incorporating a radioactive isotope, are useful in
drug and/or substrate tissue distribution studies. The radioactive
isotopes tritium, i.e. .sup.3H, and carbon-14, i.e. .sup.14C, are
particularly useful for this purpose in view of their ease of
incorporation and ready means of detection.
[0176] Substitution with heavier isotopes such as deuterium, i.e.
.sup.2H, may afford certain therapeutic advantages resulting from
greater metabolic stability, for example, increased in vivo
half-life or reduced dosage requirements, and hence may be
preferred in some circumstances.
[0177] Substitution with positron emitting isotopes, such as
.sup.11C, .sup.18F, .sup.15O and .sup.13N, can be useful in
Positron Emission Topography (PET) studies for examining substrate
receptor occupancy.
[0178] Isotopically-labeled compounds of Formula I can generally be
prepared by conventional techniques known to those skilled in the
art or by processes analogous to those described in the
accompanying Examples and Preparations using an appropriate
isotopically-labeled reagent in place of the non-labeled reagent
previously employed.
[0179] Pharmaceutically acceptable solvates in accordance with the
invention include those wherein the solvent of crystallization may
be isotopically substituted, e.g. D.sub.2O, d.sub.6-acetone,
d.sub.5-DMSO.
[0180] Specific embodiments of the present invention include the
compounds exemplified in the Examples below and the
pharmaceutically acceptable salts thereof, complexes thereof, and
derivatives thereof that convert into a pharmaceutically active
compound upon administration:
[0181] Compounds of Formula I of this invention, and their
pharmaceutically acceptable salts, have useful pharmaceutical and
medicinal properties. The compounds of Formula I, and their
pharmaceutically acceptable salts inhibit the production of
A.beta.-peptide (thus, gamma-secretase activity) in mammals,
including humans. Compounds of Formula I, and their
pharmaceutically acceptable salts, are therefore able to function
as therapeutic agents in the treatment of the neurodegenerative
and/or neurological disorders and diseases representatively
enumerated below, for example Alzheimer's disease, in an afflicted
mammal, including a human.
[0182] The present invention also relates to a pharmaceutical
composition for inhibiting A.beta.-peptide production in a mammal,
including a human, comprising an amount of a compound of Formula I,
or a pharmaceutically acceptable salt thereof, that is effective in
inhibiting AR- production, and a pharmaceutically acceptable
carrier.
[0183] The present invention also relates to a pharmaceutical
composition for treating a disease or condition selected from the
group consisting of Alzheimer's disease, hereditary cerebral
hemorrhage with amyloidosis, cerebral amyloid angiopathy, a
prion-mediated disease, inclusion body myositis, stroke, multiple
sclerosis, head trauma, mild cognitive impairment and Down's
Syndrome in a mammal, including a human, comprising an amount of a
compound of Formula I, or a pharmaceutically acceptable salt
thereof, that is effective in inhibiting A.beta.-peptide
production, and a pharmaceutically acceptable carrier.
[0184] The present invention also relates to a pharmaceutical
composition for treating a disease or condition selected from the
group consisting of Alzheimer's disease and Down's Syndrome in a
mammal, including a human, comprising an amount of a compound of
Formula I, or a pharmaceutically acceptable salt thereof, that is
effective in inhibiting A.beta.-peptide production, and a
pharmaceutically acceptable carrier.
[0185] The present invention also relates to a pharmaceutical
composition for treating a disease or a condition selected from the
group consisting of Alzheimer's disease, hereditary cerebral
hemorrhage with amyloidosis, cerebral amyloid angiopathy, a
prion-mediated disease, inclusion body myositis, stroke, multiple
sclerosis, head trauma, mild cognitive impairment and Down's
Syndrome in a mammal, including a human, comprising an amount of a
compound of Formula I, or a pharmaceutically acceptable salt
thereof, that is effective in treating such disease or condition,
and a pharmaceutically acceptable carrier.
[0186] The present invention also relates to a pharmaceutical
composition for treating a disease or a condition selected from the
group consisting of Alzheimer's disease and Down's Syndrome in a
mammal, including a human, comprising an amount of a compound of
Formula I, or a pharmaceutically acceptable salt thereof, that is
effective in treating such disease or condition, and a
pharmaceutically acceptable carrier.
[0187] The present invention also relates to a method of inhibiting
An-peptide production in a mammal, including a human, comprising
administering to said mammal an amount of a compound of Formula I,
or a pharmaceutically acceptable salt thereof, that is effective in
inhibiting A.beta.-production.
[0188] The present invention also relates to a method of treating a
disease or condition selected from Alzheimer's disease, hereditary
cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy,
a prion-mediated disease, inclusion body myositis, stroke, multiple
sclerosis, head trauma, mild cognitive impairment and Down's
Syndrome in a mammal, including a human, comprising administering
to said mammal an amount of a compound of
[0189] Formula I, or a pharmaceutically acceptable salt thereof,
that is effective in inhibiting An- production.
[0190] The present invention also relates to a method of treating a
disease or condition selected from Alzheimer's disease and Down's
Syndrome in a mammal, including a human, comprising administering
to said mammal an amount of a compound of Formula I, or a
pharmaceutically acceptable salt thereof, that is effective in
inhibiting A.beta.-production.
[0191] The present invention also relates to a method of treating a
disease or condition selected from Alzheimer's disease, hereditary
cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy,
a prion-mediated disease, inclusion body myositis, stroke, multiple
sclerosis, head trauma, mild cognitive impairment and Down's
Syndrome in a mammal, including a human, comprising administering
to said mammal an amount of a compound of Formula I, or a
pharmaceutically acceptable salt thereof, that is effective in
treating such condition.
[0192] The present invention also relates to a method of treating a
disease or condition selected from Alzheimer's disease and Down's
Syndrome in a mammal, including a human, comprising administering
to said mammal an amount of a compound of Formula I, or a
pharmaceutically acceptable salt thereof, that is effective in
treating such condition.
[0193] The compounds of Formula I may be used alone or used in
combination with any other drug, including, but not limited to, any
memory enhancement agent, e.g., Aricept.TM. and/or Namenda.TM.,
antidepressant agent, e.g., Zoloft.TM., anxiolytic, antipsychotic
agent, e.g., Geodon.TM., sleep disorder agent, anti-inflammatory
agent, e.g., Celebrex.TM., Bextra.TM., etc., anti-oxidant agent,
cholesterol modulating agent (for example, an agent that lowers LDL
or increases HDL), e.g., Lipitor.TM., Caduet.TM., etc., Histamine
(H2) antagonist, e.g., Cimetadine.TM., and anti-hypertension agent,
e.g., Norvasc.TM., Caduet.TM., etc. Accordingly, the present
invention also relates to the following pharmaceutical compositions
and methods of treatment comprising a compound of Formula I in
combination with other drugs, such as those of the type described
above.
[0194] The present invention also relates to a pharmaceutical
composition for treating a disease or condition associated with
A.beta.-peptide production in a mammal, including a human,
comprising (a) a compound of Formula I, or a pharmaceutically
acceptable salt thereof; (b) a memory enhancement agent, e.g.,
Aricept.TM. and/or Namenda.TM., antidepressant, e.g., Zoloft.TM.,
anxiolytic, antipsychotic agent, e.g., Geodon.TM., sleep disorder
agent, anti-inflammatory agent, e.g., Celebrex.TM., Bextra.TM.,
etc., anti-oxidant agent, cholesterol modulating agent (for
example, an agent that lowers LDL or increases HDL), e.g.,
Lipitor.TM., Caduet.TM., etc., Histamine (H2) antagonist, e.g.,
Cimetadine.TM., and anti-hypertensive agent, e.g., Norvasc.TM.,
Caduet.TM., etc.; and (c) a pharmaceutically acceptable carrier;
wherein the active agents "a" and "b" above are present in amounts
that render the composition effective in treating such disease or
condition.
[0195] The present invention also relates to a pharmaceutical
composition for treating a disease or condition selected from the
group consisting of Alzheimer's disease, hereditary cerebral
hemorrhage with amyloidosis, cerebral amyloid angiopathy, a
prion-mediated disease, inclusion body myositis, stroke, multiple
sclerosis, head trauma, mild cognitive impairment and Down's
Syndrome, in a mammal, including a human, comprising (a) a compound
of Formula I, or a pharmaceutically acceptable salt thereof; (b) a
memory enhancement agent, e.g., Aricept.TM. and/or Namenda.TM.,
antidepressant, e.g., Zoloft.TM., anxiolytic, antipsychotic agent,
e.g., Geodon.TM., sleep disorder agent, anti-inflammatory agent,
e.g., Celebrex.TM., Bextra.TM., etc., anti-oxidant agent,
cholesterol modulating agent (for example, an agent that lowers LDL
or increases HDL), e.g., Lipitor.TM., Caduet.TM., etc., Histamine
(H2) antagonist, e.g., Cimetadine.TM., and anti-hypertensive agent,
e.g., Norvasc.TM., Caduet.TM., etc.; and (c) a pharmaceutically
acceptable carrier; wherein the active agents "a" and "b" above are
present in amounts that render the composition effective in
treating such disease or condition.
[0196] The present invention also relates to a pharmaceutical
composition for treating a disease or condition selected from the
group consisting of Alzheimer's disease and Down's Syndrome, in a
mammal, including a human, comprising (a) a compound of Formula I,
or a pharmaceutically acceptable salt thereof; (b) a memory
enhancement agent, e.g., Aricept.TM. and/or Namenda.TM.,
antidepressant, e.g., Zoloft.TM., anxiolytic, antipsychotic agent,
e.g., Geodon.TM., sleep disorder agent, anti-inflammatory agent,
e.g., Celebrex.TM., Bextra.TM., etc., anti-oxidant agent,
cholesterol modulating agent (for example, an agent that lowers LDL
or increases HDL), e.g., Lipitor.TM., Caduet.TM., etc., Histamine
(H2) antagonist, e.g., Cimetadine.TM., and anti-hypertensive agent,
e.g., Norvasc.TM., Caduet.TM., etc.; and (c) a pharmaceutically
acceptable carrier; wherein the active agents "a" and "b" above are
present in amounts that render the composition effective in
treating such disease or condition.
[0197] The present invention also relates to a method of treating a
disease or condition associated with A.beta.-peptide production in
a mammal, including a human, comprising administering to said
mammal (a) a compound of Formula I, or a pharmaceutically
acceptable salt thereof; and (b) a memory enhancement agent, e.g.,
Aricept.TM. and/or Namenda.TM., antidepressant, e.g., Zoloft.TM.,
anxiolytic, antipsychotic agent, e.g., Geodon.TM., sleep disorder
agent, anti-inflammatory agent, e.g., Celebrex.TM., Bextra.TM.,
etc., anti-oxidant agent, cholesterol modulating agent (for
example, an agent that lowers LDL or increases HDL), e.g.,
Lipitor.TM., Caduet.TM., etc., Histamine (H2) antagonist, e.g.,
Cimetadine.TM., and anti-hypertensive agent, e.g., Norvasc.TM.,
Caduet.TM., etc.; wherein the active agents "a" and "b" above are
present in amounts that render the composition effective in
treating such disease or condition.
[0198] The present invention also relates to a method of treating a
disease or condition selected from the group consisting of
Alzheimer's disease, hereditary cerebral hemorrhage with
amyloidosis, cerebral amyloid angiopathy, a prion-mediated disease,
inclusion body myositis, stroke, multiple sclerosis, head trauma,
mild cognitive impairment and Down's Syndrome, in a mammal,
including a human, comprising administering to said mammal (a) a
compound of Formula I, or a pharmaceutically acceptable salt
thereof; and (b) a memory enhancement agent, e.g., Aricept.TM.
and/or Namenda.TM., antidepressant, e.g., Zoloft.TM., anxiolytic,
antipsychotic agent, e.g., Geodon.TM., sleep disorder agent,
anti-inflammatory agent, e.g., Celebrex.TM., Bextra.TM., etc.,
anti-oxidant agent, cholesterol modulating agent (for example, an
agent that lowers LDL or increases HDL), e.g., Lipitor.TM.,
Caduet.TM., etc., Histamine (H2) antagonist, e.g., Cimetadine.TM.,
and anti-hypertensive agent, e.g., Norvasc.TM., Caduet.TM., etc.;
wherein the active agents "a" and "b" above are present in amounts
that render the composition effective in treating such disease or
condition.
[0199] The present invention also relates to a method of treating a
disease or condition selected from the group consisting of
Alzheimer's disease and Down's Syndrome, in a mammal, including a
human, comprising administering to said mammal (a) a compound of
Formula I, or a pharmaceutically acceptable salt thereof; and (b) a
memory enhancement agent, e.g., Aricept.TM. and/or Namenda.TM.,
antidepressant, e.g., Zoloft.TM., anxiolytic, antipsychotic agent,
e.g., Geodon.TM., sleep disorder agent, anti-inflammatory agent,
e.g., Celebrex.TM., Bextra.TM., etc., anti-oxidant agent,
cholesterol modulating agent (for example, an agent that lowers LDL
or increases HDL), e.g., Lipitor.TM., Caduet.TM., etc., Histamine
(H2) antagonist, e.g., Cimetadine.TM., and anti-hypertensive agent,
e.g., Novasc.TM.; Caduet.TM., etc.; wherein the active agents "a"
and "b" above are present in amounts that render the composition
effective in treating such disease or condition.
[0200] Compounds of Formula I, or any of the combinations described
in the immediately preceding paragraphs, may optionally be used in
conjunction with a known P-glycoprotein inhibitor, such as
verapamil.
[0201] References herein to diseases and conditions "associated
with A.beta.-peptide production" relate to diseases or conditions
that are caused, at least in part, by A.beta.-peptide and/or the
production thereof. Thus, AR-peptide is a contributing factor, but
not necessarily the only contributing factor, to "a disease or
condition associated with A.beta.-peptide production."
[0202] The compounds of Formula I, or their pharmaceutically
acceptable salts may also be used to modulate or inhibit the Notch
signaling pathway in organisms, including humans. The Notch
signaling pathway is an evolutionarily conserved mechanism utilized
by organisms, ranging from worms through humans, to regulate fate
determination of various cell lineages. Notch belongs to the family
of epidermal growth factor-like homeotic genes, which encode
transmembrane proteins with variable numbers of epidermal growth
factor-like repeats in the extracellular domain. There is
increasing evidence for a role of the Notch pathway in human
disease. All of the components of the pathway have yet to be
identified, but among those identified to date, mutations that
affect their interaction with each other can lead to a variety of
syndromes and pathological conditions.
[0203] For example, Notch signaling is typically associated with
cell fate decision. The finding that Notch activation stimulates
capillary outgrowth suggests that Notch receptors must be activated
to allow this process to occur. Therefore, Notch modulation
provides a method for regulating angiogenesis. Specifically,
modulation of Notch signaling can be used to modulate angiogenesis
(e.g., by blocking Notch signaling to block angiogenesis). This
inhibition of angiogenesis in vivo can be used as a therapeutic
means to treat a variety of diseases, including but not limited to
cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis,
inflammatory bowel disease and arteriosclerosis.
[0204] The Notch pathway is also implicated in the development and
maturation of T cells, as described in Radtke, F. et al., Immunity
10:547-558, 1999. The compounds of Formula I, and their
pharmaceutically acceptable salts are therefore useful candidates
for modulating the immune system, including the treatment of
inflamamation, asthma, graft rejection, graft versus host disease,
autoimmune disease and transplant rejection.
[0205] In addition, a number of studies published between 2002 and
2004 have provided convincing evidence that Notch signaling is
frequently elevated in a variety of human tumors (including, but
not limited to breast, prostate, pancreas and T-cell acute
lymphoblastic leukemia). One key study provides a strong genetic
link to Notch's role in important tumor types. Specifically,
Weijzen et al. demonstrated that Notch signaling maintains the
neoplastic phenotype in human Ras-transformed cells. Weijzen et al.
(2002) Nature Med 8: 979. Because 30% of human malignancies may
carry activating mutations in at least one of the three isoforms of
Ras, this finding raises the possibility that Notch inhibitors
would be a powerful addition to anti-cancer therapy. Another
study's findings support a central role for aberrant Notch
signaling in the pathogenesis of human T cell acute lymphoblastic
leukemia/lymphoma. Pear et al., Current Opinion in Hematology
(2004), 11(6), 426-433.
[0206] Accordingly, the compounds of Formula I, or their
pharmaceutically acceptable salts, may be used for treating a
disease or condition selected from the group consisting of cancer,
arteriosclerosis, diabetic retinopathy, rheumatoid arthritis,
psoriasis, inflammatory bowel disease inflammation, asthma, graft
rejection, graft versus host disease, autoimmune disease and
transplant rejection.
[0207] As used herein, the term "treating" refers to reversing,
alleviating or inhibiting the progress of a disease, disorder or
condition, or one or more symptoms of such disease, disorder or
condition, to which such term applies. As used herein, "treating"
may also refer to decreasing the probability or incidence of the
occurrence of a disease, disorder or condition in a mammal as
compared to an untreated control population, or as compared to the
same mammal prior to treatment. For example, as used herein,
"treating" may refer to preventing a disease, disorder or
condition, and may include delaying or preventing the onset of a
disease, disorder or condition, or delaying or preventing the
symptoms associated with a disease, disorder or condition. As used
herein, "treating" may also refer to reducing the severity of a
disease, disorder or condition or symptoms associated with such
disease, disorder or condition prior to a mammal's affliction with
the disease, disorder or condition. Such prevention or reduction of
the severity of a disease, disorder or condition prior to
affliction relates to the administration of the composition of the
present invention, as described herein, to a subject that is not at
the time of administration afflicted with the disease, disorder or
condition. As used herein "treating" may also refer to preventing
the recurrence of a disease, disorder or condition or of one or
more symptoms associated with such disease, disorder or condition.
The terms "treatment" and "therapeutically," as used herein, refer
to the act of treating, as "treating" is defined above.
[0208] Compounds of Formula I, and their pharmaceutically
acceptable salts, may be prepared as described in the following
reaction Schemes and discussion. Unless otherwise indicated, as
referred to in the reaction schemes and discussion that follow,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11, A, Z and n are as defined above.
[0209] The compounds of Formula I may have asymmetric carbon atoms
and may therefore exist as racemic mixtures, diasteroisomers, or as
individual optical isomers.
[0210] Separation of a mixture of isomers of compounds of Formula I
into single isomers may be accomplished according to conventional
methods known in the art.
[0211] The compounds of Formula I may be prepared by the methods
described below, together with synthetic methods known in the art
of organic chemistry, or modifications and derivatisations that are
familiar to those of ordinary skill in the art. Preferred methods
include, but are not limited to, those described below.
[0212] The reactions described below are performed in solvents that
are appropriate to the reagents and materials employed and that are
suitable for use in the reactions described. In the description of
the synthetic methods described below, it is also to be understood
that all reaction conditions, whether actual or proposed, including
choice of solvent, reaction temperature, reaction duration time,
reaction pressure, and other reaction conditions (such as anhydrous
conditions, under argon, under nitrogen, etc.), and work up
procedures, are those conditions that are standard for that
reaction, as would be readily recognized by one of skill in the
art. Alternate methods may also be used.
[0213] Compounds of formula II wherein R.sup.7 contains an alcohol
moiety may be oxidized using standard oxidation method known in
art, such as, e.g., Dess-Martin reagents, Swern oxidation, or use
of SO.sub.3-pyridine, CrO.sub.3, to provide compounds of formula II
wherein R.sup.7 contains a ketone or aldehyde. Compounds of formula
II wherein R.sup.7 is a ketone or aldehyde may convert to the
corresponding compounds of formula II wherein R.sup.7 is an imine
(by reaction with an amine), olefin (by a Wittig reaction), alcohol
(by a Grignard reaction), or other derivative (by standard
reactions).
[0214] The compounds of formula I of the present invention and
their salts can be prepared by a reaction process comprising a
compound of formula II
##STR00008##
with a compound of formula III
##STR00009##
or reacting a compound of formula IV
##STR00010##
with a compound of formula V
##STR00011##
wherein R.sup.1, R.sup.3, R.sup.4, R.sup.6, R.sup.7, and A are as
defined above and L is hydroxy or a suitable leaving group. If
desired, the 4-amino-imidazole derivative of formula I or synthetic
intermediate of formula IV may be converted into a salt by methods
known to those of ordinary skill in the art.
[0215] Examples of specific compounds of formula III and V wherein
L is hydroxy or a suitable leaving group are those wherein L
represents a halogen atom, such as Cl, Br, or I, or A-L is an alkyl
or aryl ester.
[0216] Compounds in formula I can be prepared by reacting a
compound of formula II and a carboxylic acid of formula III, or a
compound of formula IV with a compound of formula V. Compounds of
formula IV can be prepared by reacting a compound of formula II
with a compound of formula VI.
[0217] The reaction between compounds of formula II and compounds
of formula III, between compounds of formula IV and compounds of
formula V, and between compounds of formula II and compounds of
formula VI, can be carried out by standard methods. For example,
wherein L is a hydroxy group, these reactions can be carried out in
the presence of a coupling agent or a polymer supported coupling
agent, such as, for example, carbodiimide, i.e.
1,3-dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC),
N-cyclohexylcarbodiimide, or N'-methylpolystyrene in the presence
or absence of HOBt, in a suitable solvent such as , for instance, a
single solvent or a combination of several solvents selected from
dichloromethane (CH.sub.2Cl.sub.2), chloroform (CHCl.sub.3),
tetrahydrofuran (THF), diethyl ether (Et.sub.2O), 1,4-dioxane,
acetonitrile, (CH.sub.3CN), toluene, N,N-dimethylformamide (DMF),
or dimethylsulfoxide (DMSO), at a suitable temperature such as from
about -10.degree. C. to about reflux, for a suitable time monitored
by chromatography or LC-MS. An alternative method wherein L is OH
is carried out by converting OH to a leaving group by reaction with
oxalyl chloride, thionyl chloride or a mixed anhydride method,
using an alkyl chloroformate, such as C.sub.1-C.sub.4 alkyl
chloroformate, in the presence of a base such as triethylamine,
N,N-diisopropylethylamine, pyridine, or dimethylaminopyridine, in a
suitable solvent such as, for example, methylene chloride,
chloroform, tetrahydrofuran (THF), toluene, diethyl ether,
acetonitrile, 1,4-dioxane, n,N-dimethylformamide, dimethylsulfoxide
(DMSO), N-methyl pyrrolidinone (NMP), or xylene, at a temperature
of from about -30.degree. C. to about room temperature.
[0218] Alternatively, aminoimidazole coupling may be achieved as
follows. A compound of formula I may be prepared by coupling an
amino-imidazole II with III wherein C(.dbd.O)L is an ester, in the
presence of trialkylaluminium preferably trimethylaluminum in an
appropriate solvent such as methylene chloride, THF, dioxane,
toluene, etc., at an appropriate temperature, such as from about
room temperature to about reflux, or in a sealed reactor (such as
sealed tube or inscrewed vials). Similarly, compound IV may be
prepared by reacting an amino-imidazole II, triamethylaluminum and
N-Boc of an alpha-amino acid ester, followed by removal of the Boc
group using standard methods.
[0219] The protected amino compounds of formula VI, where P.sup.1
is a blocking group such as an N-Boc group, can be prepared by
methods well known in the literature, for example the methods
described in Theodora W. Greene's book "Protective Groups in
Organic Synthesis". Compounds of formula IV can be prepared in an
analogous method as above by reacting compound of formula II with a
compound of formula VI, followed by deblocking the P.sup.1 group.
Deprotection can be performed by well-known methods, for example
when P.sup.1 is N-Boc, removal by any methods well-known in the
literature, for example HCl(g) in an appropriate solvent such as
1,4-dioxane, diethylether or trifluoroacetic acid in methylene
chloride. Many other amino protecting groups are known and may also
be used, such as benzyl or p-methoxy-benzyl, trimethylsilyl,
t-butyldimethylsilyl, etc. Methods for deblocking such groups are
also well-known in the literature and may be used.
##STR00012##
[0220] The compounds of formula II, Ill, IV, V and VI, in certain
circumstances, are known compounds or can be obtained according to
methods well known to one of skill in the art.
[0221] Compounds of formula III and V, wherein L is a leaving group
as defined above, can be obtained according to conventional methods
from the corresponding carboxylic acids of formula III where X is
hydroxy.
[0222] Compounds of formula IV can be prepared by reacting a
compound of formula II with a compound of formula V using known
methods.
[0223] An ester group of R.sup.7 in compounds of formula I or II
may be converted to the corresponding amide using a similar method
for amide bond formation, preferably employing trimethylaluminum in
an appropriate solvent or a mixture of solvents, such as
THF/toluene.
[0224] A keto group of R.sup.7 in compounds of formula I or II may
be converted to the corresponding amine using a well-established
reductive amination method by reacting such ketone with an
appropriate amine, with or without acid catalyst/ammonium
acetate/dry agents (such as anhydrous Na.sub.2SO.sub.4 or
MgSO.sub.4), and a reducing agent, such as sodium triacetoxy
borohydride, sodium cyanoborohydride, or sodium borohydride, or the
corresponding polymer bound-NaBH.sub.4, polymer bound-NaBH.sub.3CN,
or polymer bound-NaB(OAc).sub.3H, or any reducing agent (e.g.,
hydrogenation) that is known in the literature for reducing an
imine bond to an amine, in an appropriate solvent, such as
dichloroethane, chloroform, THF, MeOH, ethanol, isopropanol,
t-butanol or toluene, at a temperature from about room temperature
to about reflux, preferably from about room temperature to about
65.degree. C.
[0225] Compounds wherein R.sup.6 is a halo group may be generated
by reacting the starting material wherein R.sup.6 is H with NBS
(N-bromosuccinamide), NCS (N-chlorosuccinamide), or
SO.sub.2Cl.sub.2, I.sub.2 in an appropriate solvent such as
methylene chloride, carbontetrachloride or chloroform. The halo
group may then be replaced with another group using methods known
in the art, such as halogen-metal exchange, followed by quenching
with an electrophile, or using typical Suzuki coupling conditions
employing a catalyst such as a palladium complex, e.g.,
tetrakis(triphenylphosphine)-palladium, with sodium carbonate as a
base, in a suitable solvent such as THF, DME, or ethanol, and a
boronic acid.
[0226] 4-amino-imidazole II may be prepared by the following
methods known in the chemical literature (e. g., Tetrahedron, 1995,
51, 2875-2894; J. Chem. Soc. Perkin 1, 1987, 2819-2828; Bull. Chem.
Soc. Fr. 1994, 131, 200-209; Tetrahedron Lett. 1996, 4423-4426;
Tetrahedron 1996, 37, 4423-4426; Tetrahedron, 1994, 50,
5741-5752;Heterocycles, 1994, 37, 1511-1520; Tetrahedron Lett.
1999, 1623-1626; Organic Lett. 2002, 4, 4133-4134; Organic Lett.
2000, 2, 1233-1236; J. Med. Chem. 1990, 33, 1091-1097; or by the
methods described below.
[0227] Scheme 1 illustrates methods suitable for preparing
amino-imidazole compounds of formula I. Referring to Scheme 1,
treatment of a solution of 1,4-dinitroimidazole (J. Phys. Chem.
(1995) Vol. 99, pp. 5009-5015) in dimethylsulfoxide (DMSO),
pyridine-water, water, an alcohol, or an alcohol-water solvent
system, but preferably in a lower alcohol such as methanol, from
about -20.degree. C. to about 50.degree. C., preferably from about
-5.degree. C. to 35.degree. C., with a primary alkyl or aryl amine
(NR.sup.9R.sup.10) affords 1-N-substituted-4-nitroimidazoles of
formula 2A. 1,4-dinitroimidazole is a highly energetic, semi-stable
substance and should be stored in a freezer at all times it is not
in use. Thermodynamic measurements have shown that it can
potentially generate enough energy at 35.degree. C. under adiabatic
conditions to violently explode. Extreme caution should be
exercised at all time using this material. Reduction of the nitro
compound of formula 2A to the amine of formula 3A may be
accomplished by exposing a mixture of a compound of formula 2A and
a noble metal catalyst, in a solvent such as ethyl acetate,
tetrahydrofuran, dioxane, or a mixture thereof, to an atmosphere of
hydrogen gas at a pressure of about 1 to 100 atmospheres, where a
preferred pressure of hygrogen gas is about one to about ten
atmospheres. Palladium is the preferred noble metal catalyst. The
metal may be conveniently suspended on an inert solid support such
as charcoal and filtered to provide the amine of formula 3A.
Alternatively, the nitro group of formula 2A to the amine of
formula 3A may be accomplished by exposing a mixture of a compound
of formula 2A to zinc/HCl or iron/HCl or with NaBH.sub.4/NiCl.sub.2
or with NaBH.sub.2S.sub.3.
[0228] The resulting amine of formula 3A is reacted immediately
with an acid chloride, acid anhydride, or an activated carboxylic
acid derivative (defined by Formula III), in the presence of a
base, such as triethylamine, diisopropylethylamine, pyridine, or
2,6-lutidine, from about -78.degree. C. to 40.degree. C. The
reaction between compounds of formula 3A and compounds of formula
III can be carried out by standard methods. For example, wherein L
of formula III is a hydroxy group, these reactions can be carried
out in the presence of a coupling agent or a polymer supported
coupling agent, such as, for example, carbodiimide, i.e.
1,3-dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC),
N-cyclohexylcarbodiimide, or N'-methylpolystyrene in the presence
or absence of HOBt, in a suitable solvent such as , for instance, a
single solvent or a combination of several solvents selected from
dichloromethane (CH.sub.2Cl.sub.2), chloroform (CHCl.sub.3),
tetrahydrofuran (THF), diethyl ether (Et.sub.2O), 1,4-dioxane,
acetonitrile, (CH.sub.3CN), toluene, N,N-dimethylformamide (DMF),
or dimethylsulfoxide (DMSO), at a suitable temperature such as from
about -10.degree. C. to about reflux, for a suitable time monitored
by chromatography or LC-MS. An alternative method wherein L is OH
is carried out by converting OH to a leaving group by reaction with
oxalyl chloride, thionyl chloride or a mixed anhydride method,
using an alkyl chloroformate, such as C.sub.1-C.sub.4 alkyl
chloroformate, in the presence of a base such as triethylamine,
N,N-diisopropylethylamine, pyridine, or dimethylaminopyridine, in a
suitable solvent such as, for example, methylene chloride,
chloroform, tetrahydrofuran (THF), toluene, diethyl ether,
acetonitrile, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide
(DMSO), N-methyl pyrrolidinone (NMP), or xylene, at a temperature
of from about -30.degree. C. to about room temperature.
[0229] Alternatively, aminoimidazole coupling may be achieved as
follows. A compound of formula I may be prepared by coupling an
amino-imidazole 3A with a compound of formula III wherein
C(.dbd.O)L is an ester, in the presence of trialkylaluminium
preferably trimethylaluminum in an appropriate solvent such as
methylene chloride, THF, dioxane, toluene, etc., at an appropriate
temperature, such as from about room temperature to about reflux,
or in a sealed reactor (such as sealed tube or inscrewed
vials).
[0230] Alternatively, the resulting amine of formula 3A is reacted
immediately with an acid chloride, acid anhydride, or an activated
carboxylic acid derivative (defined by Formula IV), in the presence
of a base, such as triethylamine, diisopropylethylamine, pyridine,
or 2,6-lutidine, from about -78.degree. C. to 40.degree. C. to form
a compound of formula 4A. The reaction between compounds of formula
3A and compounds of formula IV can be carried out by standard
methods. For example, wherein L of formula IV is a hydroxy group,
these reactions can be carried out in the presence of a coupling
agent or a polymer supported coupling agent, such as, for example,
carbodiimide, i.e. 1,3-dicyclohexylcarbodiimide (DCC),
1,3-diisopropylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC),
N-cyclohexylcarbodiimide, or N'-methylpolystyrene in the presence
or absence of HOBt, in a suitable solvent such as, for instance, a
single solvent or a combination of several solvents selected from
dichloromethane (CH.sub.2Cl.sub.2), chloroform (CHCl.sub.3),
tetrahydrofuran (THF), diethyl ether (Et.sub.2O), 1,4-dioxane,
acetonitrile, (CH.sub.3CN), toluene, N,N-dimethylformamide (DMF),
or dimethylsulfoxide (DMSO), at a suitable temperature such as from
about -10.degree. C. to about reflux, for a suitable time monitored
by chromatography or LC-MS. An alternative method wherein L is OH
is carried out by converting OH to a leaving group by reaction with
oxalyl chloride, thionyl chloride or a mixed anhydride method,
using an alkyl chloroformate, such as C.sub.1-C.sub.4 alkyl
chloroformate, in the presence of a base such as triethylamine,
N,N-diisopropylethylamine, pyridine, or dimethylaminopyridine, in a
suitable solvent such as, for example, methylene chloride,
chloroform, tetrahydrofuran (THF), toluene, diethyl ether,
acetonitrile, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide
(DMSO), N-methyl pyrrolidinone (NMP), or xylene, at a temperature
of from about -30.degree. C. to about room temperature.
[0231] Alternatively, aminoimidazole coupling may be achieved as
follows. A compound of formula 4A may be prepared by coupling an
amino-imidazole 3A with a compound of formula IV wherein C(.dbd.O)L
is an ester, in the presence of trialkylaluminium preferably
trimethylaluminum in an appropriate solvent such as methylene
chloride, THF, dioxane, toluene, etc., at an appropriate
temperature, such as from about room temperature to about reflux,
or in a sealed reactor (such as sealed tube or inscrewed vials).
The protected amino compounds defined as PG, such as a compound
with an Boc group, of formula IV can be prepared by methods well
known in the literature, for example the methods described in
Theodora W. Greene's book "Protective Groups in Organic
Synthesis".
[0232] Compounds defined as by Formula 5A can be prepared from
compounds of formula 4A by deblocking the PG group. Deprotection
can be performed by well-known methods, for example when PG is
N-Boc, removal by any methods well-known in the literature, for
example HCl(g) in an appropriate solvent such as 1,4-dioxane,
diethylether or trifluoroacetic acid in methylene chloride. Many
other amino protecting groups are known and may also be used, such
as benzyl or p-methoxy-benzyl, trimethylsilyl,
t-butyldimethylsilyl, etc. Methods for deblocking such groups are
also well-known in the literature and may be used.
[0233] Compounds of Formula I can be formed by reaction between
compounds of formula 5A and compounds of formula V can be carried
out by standard methods. For example, wherein L is a hydroxy group,
these reactions can be carried out in the presence of a coupling
agent or a polymer supported coupling agent, such as, for example,
carbodiimide, i.e. 1,3-dicyclohexylcarbodiimide (DCC),
1,3-diisopropylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC),
N-cyclohexylcarbodiimide, or N'-methylpolystyrene in the presence
or absence of HOBt, in a suitable solvent such as, for instance, a
single solvent or a combination of several solvents selected from
dichloromethane (CH.sub.2Cl.sub.2), chloroform (CHCl.sub.3),
tetrahydrofuran (THF), diethyl ether (Et.sub.2O), 1,4-dioxane,
acetonitrile, (CH.sub.3CN), toluene, N,N-dimethylformamide (DMF),
or dimethylsulfoxide (DMSO), at a suitable temperature such as from
about -10.degree. C. to about reflux, for a suitable time monitored
by chromatography or LC-MS. An alternative method wherein L is OH
is carried out by converting OH to a leaving group by reaction with
oxalyl chloride, thionyl chloride or a mixed anhydride method,
using an alkyl chloroformate, such as C.sub.1-C.sub.4 alkyl
chloroformate, in the presence of a base such as triethylamine,
N,N-diisopropylethylamine, pyridine, or dimethylaminopyridine, in a
suitable solvent such as, for example, methylene chloride,
chloroform, tetrahydrofuran (THF), toluene, diethyl ether,
acetonitrile, 1,4-dioxane, n,N-dimethylformamide, dimethylsulfoxide
(DMSO), N-methyl pyrrolidinone (NMP), or xylene, at a temperature
of from about -30.degree. C. to about room temperature.
[0234] Alternatively, aminoimidazole coupling may be achieved as
follows. A compound of formula I may be prepared by coupling an
amino-imidazole 5A with V wherein L is an ester, in the presence of
trialkylaluminium preferably trimethylaluminum in an appropriate
solvent such as methylene chloride, THF, dioxane, toluene, etc., at
an appropriate temperature, such as from about room temperature to
about reflux, or in a sealed reactor (such as sealed tube or
inscrewed vials).
[0235] Alternatively, compounds of Formula I can be formed by
reaction between compounds of formula 5A and compounds of formula V
when L is an aldehyde or ketone by using a well-established
reductive amination method by reacting such ketone or aldehyde with
an appropriate amine 5A, with or without acid catalyst/ammonium
acetate/dry agents (such as anhydrous Na.sub.2SO.sub.4 or
MgSO.sub.4), and a reducing agent, such as sodium triacetoxy
borohydride, sodium cyanoborohydride, or sodium borohydride, or the
corresponding polymer bound-NaBH.sub.4, polymer bound-NaBH.sub.3CN,
or polymer bound-NaB(OAc).sub.3H, or any reducing agent (e.g.,
hydrogenation) that is known in the literature for reducing an
imine bond to an amine, in an appropriate solvent, such as
dichloroethane, chloroform, THF, MeOH, ethanol, isopropanol,
t-butanol or toluene, at a temperature from about room temperature
to about reflux, preferably from about room temperature to about
65.degree. C.
##STR00013##
[0236] Scheme 2 illustrates additional methods for the synthesis of
imidazole compounds defined as Formula 2A. Treatment of
nitroimidazole 6A with a base such as sodium hydride, potassium
hydride, alkyl lithium, alkoxides, in a solvent such as
tetrahydrofuran, dimethylformamide, methylene chloride, ether,
preferably dimethylformamide, from about -60.degree. C. to
40.degree. C., where from -10.degree. C. to 20.degree. C. is
preferred, followed by addition of R7-X wherein X is defined as Cl,
Br, I, F, alkylsulfonate, or arylsulfonate followed by warming the
reaction from 23.degree. C. to 150.degree. C. where 30-80.degree.
C. is preferrable, affords imidazoles of formula 2A. Reduction of
the nitro compound and coupling reaction is carried out in a
similar manner described above and is useful for preparing
compounds of Formula I. Alternatively, R7 can be further
functionalized by procedures described within or using methods
known to one skilled in the art.
##STR00014##
[0237] Scheme 3 illustrates additional methods for the synthesis of
nitro-imidazole compounds defined as Formula 2A. A key starting
material for the synthesis is the double-bond compound (a compound
of Formula 16 or 17) substituted with the group ER8 and one to
three groups selected from R.sup.8, where ER8 is defined as an
electron-withdrawing group chosen from C(.dbd.O)R.sup.9,
C(.dbd.O)OR.sup.9, C9=O)NR.sup.9R.sup.10, S(.dbd.O).sub.2R.sup.9,
S(.dbd.O).sub.2NR.sup.9R.sup.10, S(.dbd.O).sub.2OR.sup.9, cyano,
and heteroaryl. Additionally, compounds of formula 16 or 17 may be
defined wherein ER8 is connected to one of the groups R.sup.8 or
directly to the carbon-carbon double bond to form a ring and thus
includes comopunds such as 2-cyclopentene-1-one and
2-cyclohexene-1-one. Alternatively, compounds of formula 17 where L
is defined as Cl, Br, I, OC(.dbd.O)R.sup.9, or
OS(.dbd.O).sub.2R.sup.9 may be used as starting materials; examples
of such compounds are 3-chloro-1-cyclopentanone,
3-acetoxy-1-cyclobutanone. Thus, referring to Scheme 3, treatment
of -=4-nitroimidazole 6A, with a base such as sodium hydride,
potassium hydride, cesium carbonate,
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or tetraalkylammonium
chloride, where DBU is the preferred base, with intermediates 16 or
17 in a solvent such as acetonitrile, methylene chloride,
1,2-dichloroethane, or chloroform, where acetonitrile is the
preferred solvent, at a temperature from about -60.degree. C. to
about 50.degree. C., where -20.degree. C. to 23.degree. C. is the
preferred range, affords addition products of formula 2A. Reduction
of the nitro compound and coupling to give compounds of formula I
is carried out in a similar manner described above.
##STR00015##
[0238] Scheme 4 below illustrates additional methods for the
synthesis of amino-imidazole compounds defined as Formula 2A.
Treatment of ethyl-2-isocyano-3-N,N-dimethylamino acrylate or
benzyl-2-isocyano-3-N-N-dimethylamino acrylate with a primary
amine, R7-NH2, in a solvent such as n-butanol, n-propanol,
l-propanol, or ethanol, or in the absence of solvent, where
n-propanol or no solvent are preferred, from about 23.degree. C. to
about 200.degree. C., where from about 60.degree. C. to 150.degree.
C. is preferred, affords imidazoles of formula 18. Treatment of
ester 18 with a base such as potasium hydroxide, lithium hydroxide,
or sodium hydroxide in a--solvent such as tetrahydrofuran, water,
methanol, ethanol, propanol, wherein methanol is preferred provides
the acid 19. The acid is converted to the acylazide 20 using
methods known to one skilled in the art such as treatment of acid
19 with thionyl chloride or oxalyl chloride from -20 to 50.degree.
C. followed by removal of the residual solvent and quenching with
sodium or potassium azide in a solvent such as toluene,
tetrahydrofuran, methlene chloride, dioxane. The azide 20 undergoes
Curtius rearrangement to the Boc 21 by heating from 5.degree.
C.-200.degree. C. in a solvent such as t-butanol, benzyl alcohol,
and ethanol. If t-butanol is used, deprotection of the N-Boc
protecting group can be accomplished with HCl or triflouroacetic
acid in a solvent such as ether, tetrahydrofuran, where HCl in
methanol is preferred affords the desired aminoimidazole compounds
of formula 2A. If benzyl alcohol is used, deprotection can be
accomplished by the use of a noble metal catalyst, in a solvent
such as ethyl acetate, tetrahydrofuran, dioxane, or a mixture
thereof, to an atmosphere of hydrogen gas at a pressure of about 1
to 100 atmospheres, where a preferred pressure of hygrogen gas is
about one to about ten atmospheres. Palladium is the preferred
noble metal catalyst which affords the desired aminoimidazole
compounds of formula 2A. Alternatively, ester 18 can be treated
with hydrazine in a solvent such as water from a temperature from
50.degree. C. to 200.degree. C. where 80.degree. C. to 120.degree.
C. is preferred provides the hydrazide 22. The hydrazide 22 can be
converted to the acylazide 20 using t-butylnitrite in a solvent or
combination of solvent such as ether, methylene chloride,
dichloroethane, chloroform, where in ether/methylene chloride is
preferred at a temperature from -50.degree. C. to 23.degree. C.
wherein -30.degree. C. to 10.degree. C. is preferred. The acylazide
is then converted onto aminoimidazole compounds of formula 2A as
described above.
##STR00016##
[0239] Scheme 5 below illustrates additional methods for the
synthesis of amino-imidazole compounds defined as Formula I.
Treatment of N-O-dimethyl hydroxyl amine hydrochloride with
trimethylaluminum in 1,2-dichloroethane followed by the addition of
ester 18, prepared as described above and heating at about
30.degree. C. to about 80.degree. C., where a temperature of about
50.degree. C. is preferred, affords imidazole 23. Addition of an
organometallic reagent 24 wherein Z is defined as lithium halide,
magnessium halide, potassium halide, where lithium halide is
preferred, to a solution of amide 23 in a solvent such as
tetrahydrofuran, methylene chloride, or diethyl ether, from a
temperature about -78.degree. C. to about 30.degree. C., where a
range of about -20.degree. C. to about 0.degree. C. is preferred
affords 25. Addition of 25 to a mixture of hydroxyl amine
hydrochloride and potassium acetate in a lower alcoholic solvent,
where in ethanol is preferred, at about 23.degree. C., yields oxime
26 as a mixture of isomers. Treatment of an acetone solution of
oxime 26 at about 0.degree. C. with aqueous hydroxide followed by
paratoluenesulfonyl chloride yields a mixture of O-sulfonyl
compound following extractive workup. Dissolution of the crude
material in a non-polar solvent such as benzene, hexanes, or
toluene, wherein benzene is preferred, and application to a column
of alumina followed by elution with chloroform-methanol (about
10:1) after approximately five minutes provides a compound of
Formula I.
##STR00017##
[0240] Scheme 6 illustrates methods suitable for preparing
amino-imidazole compounds of formula I. Compound of Formula I, 27
can be prepared using methods described above. Converstion of ester
I, 27 to alcohol of compounds I, 28 can be accomplished by
treatment of ester I, 27 with an appropriate reducing agent such as
sodium borohydride or lithium aluminum hydride using conditions
well known to one skilled in the art. Compounds of formula I, 28
may be oxidized using standard oxidation method known in art, such
as, e.g., Dess-Martin reagents, Swern oxidation, or use of
SO.sub.3-pyridine, CrO.sub.3, where Swern oxidation is preferred to
provide compounds containing an aldehyde. The aldehyde can be
converted onto compounds of formula I, 29 using well-established
reductive amination method by reacting the aldehyde with an
appropriate amine 5A, with or without acid catalyst/ammonium
acetate/dry agents (such as anhydrous Na.sub.2SO.sub.4 or
MgSO.sub.4), and a reducing agent, such as sodium triacetoxy
borohydride, sodium cyanoborohydride, or sodium borohydride, or the
corresponding polymer bound--NaBH.sub.4, polymer
bound--NaBH.sub.3CN, or polymer bound- NaB(OAc).sub.3H, or any
reducing agent (e.g., hydrogenation) that is known in the
literature for reducing an imine bond to an amine, in an
appropriate solvent, such as dichloroethane, chloroform, THF, MeOH,
ethanol, isopropanol, t-butanol or toluene, at a temperature from
about room temperature to about reflux, preferably from about room
temperature to about 65.degree. C. Alternatively, the alcohol of I,
28 can be converted to the corresponding alkyl or aryl sulfonate I,
30 by treatment of the alcohol with alkyl or aryl sulfonyl chloride
(where in mesyl chloride is preferred) in a solvent such as
methylene chloride, tetrahydrofuran, toluene wherein methylene
chloride in the presence of an amide such as triethylamine,
diisopropyamine, pyridine, 2,6-lutidine, where in triethylamine is
preferred at a temperature from -50.degree. C. to 23.degree. C.
wherein -0.degree. C. to 30.degree. C. is preferred. The aryl or
alkyl sulfonate is then reacted with an alkali metal azide (wherein
sodium azide is preferred), in a polar solvent such as
dimethylformamide, dimethylsulfoxide, alcohol, wherein ethanol is
preferred produces a compound containing an azide. This
intermediate azide may be reduced by exposing the azide to a noble
metal catalyst, in a solvent such as ethyl acetate,
tetrahydrofuran, dioxane, or a mixture thereof, to an atmosphere of
hydrogen gas at a pressure of about 1 to 100 atmospheres, where a
preferred pressure of hygrogen gas is about one to about ten
atmospheres. Palladium is the preferred noble metal catalyst and
the reaction affords the amine group. The amine group can then be
converted to compounds of Formula 1, 29 using the reductive
amination conditions described above.
##STR00018##
[0241] Referring to Scheme 7, treatment of a solution of
bromoimidazole 30 with a base, such as sodium hydride, potassium
hydride, lithium hydride, cesium carbonate, sodium hydroxide,
potassium hydroxide, cesium hydroxide, lithium diisopropyl amide,
sodium amide, potassium hexamethyldisilazide, sodium
hexamethyldisilazide, sodium tert-butoxide, or potassium
tert-butoxide, in a reaction inert solvent such as tetrahydrofuran,
1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, or toluene,
from about -20.degree. C. to 150.degree. C., where 20.degree. C. to
100.degree. C. is preferred, in the absence or presence of a phase
transfer catalyst, such as tetra-n-butylammonium chloride,
tetra-n-butylammonium bromide, tetra-n-butylammonium iodide,
benzyltrimethyl ammonium chloride, benzyltrimethyl ammonium
bromide, or benzyltrimethyl ammonium fluoride, followed by the
addition of an alkyl, allylic, or benzylic chloride, bromide,
iodide, alkyl sulfonate, aryl sulfonate, or triflate, affords
imidazoles 31.
[0242] Treatment of 1-substituted-4-bromoimidazole (31) with an
intermediate of the formula 32 or PG-NH2 (where PG is defined as
(C.dbd.O)alkyl or benzoyl) and a palladium catalyst such as
palladium (II) acetate, allyl palladium chloride dimer,
tris(dibenzylideneacetone)dipalladium (0),
tris(dibenzylideneacetone)dipalladium (0) chloroform adduct, or
palladium (II) chloride, where palladium (II) acetate,
tris(dibenzylideneacetone)dipalladium (0), and
tris(dibenzylideneacetone)dipalladium (0) chloroform adduct are
preferred, and a phosphine ligand, preferably
9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) is
preferred, and a base, such as cesium carbonate, or potassium
phosphate (K.sub.3PO.sub.4), where potassium phosphate is
preferred, in a reaction inert solvent, such as toluene,
1,4-dioxane, or tetrahydrofuran, from about 0.degree. C. to
150.degree. C., where 20.degree. C. to 110.degree. C. is preferred,
affords the coupled product 1. Alternatively, treatment of
1-substituted-4-bromoimidazole (31) with an intermediate of the
formula 32 or PG--NH2 (where PG is defined as (C.dbd.O)alkyl or
benzoyl) and a diamine, such as 1,2-ethylenediamine,
N,N'-dimethylethylenediamine, or cis-1,2-diaminocyclohexane,
preferably N,N'-dimethylethylenediamine, and cuprous chloride,
bromide or iodide, preferably cuprous iodide, in the presence of a
small amount of water, preferably about 1% to about 4% water, in a
reaction inert solvent such as 1,2-dimethoxyethane, diglyme,
t-butyl methyl ether, tetrahydrofuran, benzene or toluene,
preferably toluene, at a temperature of about 40.degree. C. to
about 150.degree. C., preferably about 80.degree. C. to about
120.degree. C. to yield the compound of formula I or compounds of
formula 33. In the case of compound 33, this can be converted to
compounds of forumla 2A using standard methods described above.
##STR00019##
[0243] The starting materials used in the procedures of the above
Schemes, the syntheses of which are not described above, are either
commercially available, known in the art or readily obtainable from
known compounds using methods that will be apparent to those
skilled in the art.
[0244] The compounds of Formula I, and the intermediates shown in
the above reaction schemes, may be isolated and purified by
conventional procedures, such as recrystallization or
chromatographic separation, such as on silica gel, either with an
ethyl acetate/hexane elution gradient, a methylene
chloride/methanol elution gradient, or a chloroform/methanol
elution gradient. Alternatively, a reverse phase preparative HPLC
or chiral HPLC separation technique may be used.
[0245] In each of the reactions discussed or illustrated above,
pressure is not critical unless otherwise indicated. Pressures from
about 0.5 atmospheres to about 5 atmospheres are generally
acceptable, and ambient pressure, i.e., about 1 atmosphere, is
preferred as a matter of convenience.
[0246] The compounds of Formula I of the present invention are
useful in inhibiting A.beta.-peptide production (thus,
gamma-secretase activity) in mammals, and therefore they are able
to function as therapeutic agents in the treatment of the
aforementioned disorders and diseases in an afflicted mammal.
[0247] A specific compound of Formula I can be determined to
inhibit A.beta.-peptide production using biological assays known to
those of ordinary skill in the art, for example the assays
described below.
[0248] For testing efficacy in vitro, the effect of test compounds
on the secretion of AR from cells in tissue culture was determined.
H4 cells (human brain neuroglioma) were stably transfected with
human APP695 containing the Swedish Familial Alzheimers Disease
mutation. Cells were distributed into 96-well plates at a density
of about 30,000 cells/well and allowed to attach to the plate
surface for approximately 6 hours at 37.degree. C. After this time,
cells were washed to remove secreted A.beta. and fresh media
containing test compound was added. Following incubation with
compound overnight at 37.degree. C., media was harvested and
subjected to immunoassay to determine the amount of A.beta.secreted
from the cells. Various assays for A.beta. peptides known to those
skilled in the art can be applied to these samples for quantitation
of A.beta. secretion. In this application, a two-site sandwich
ELISA utilizing commercially available monoclonal antibodies, 6E10
and 4G8-biotinylated, were employed to provide an estimate of the
amount of most of the physiologically relevant forms of A.beta.,
e.g., A.beta.1-40, A.beta.1-42. Signals from these samples were
compared to standard curves generated with synthetic A.beta.1-40
peptide and used to calculate IC.sub.50 values for each test
compound.
[0249] Using such assay, compounds of the present invention were
determined to have an IC.sub.50 activity for inhibiting
gamma-secretase activity of less than about 800 micromolar.
Preferred compounds of the invention are compounds that were
determined to have an IC.sub.50 activity for inhibiting
gamma-secretase activity of less than about 1 micromolar.
[0250] The following Examples illustrate the present invention. It
is to be understood, however, that the invention, as fully
described herein and as recited in the claims, is not intended to
be limited by the details of the following Examples.
Examples
[0251] General Procedure A:
[0252] Coupling Method for Amide Formation
[0253] a) EDC/HOBt/Trialkylamine Coupling Procedure
[0254] A mixture of a carboxylic acid (1.0 e.q.), amine (1.0 e.q.),
HOBt (1.1-1.5 eq.), EDC (1.2-1.8 eq.) and a trialkylamine
(triethylamine or diisopropylethylamine) (3-6 eq.) in an
appropriate solvent or a mixture of solvents, for example methylene
chloride, dichloroethane, THF, or DMF, was stirred at room
temperature until product formation or disappearance of starting
material. The solvent was removed under reduced pressure, the
residue taken up in ethyl acetate (or similar selected solvent such
as methylene chloride or chloroform) and water. The organic layer
was separated, washed with dilute HCl (if the desired product
contains a basic functional group, washing with dilute HCl may be
omitted), brine, and dried over sodium sulfate. The solvent was
then removed at reduced pressure to provide product.
[0255] b) HATU/Trialkylamine Coupling Procedure
[0256] A mixture of a carboxylic acid (1.0 e.q.), amine (1.0 e.q.),
HATU (1.1-1.5 eq.) and a trialkylamine (triethylamine or
diisopropylethylamine) (3-6 eq.) in an appropriate solvent or a
mixture of solvents, for example methylene chloride,
dichloroethane, THF, or DMF, was stirred at room temperature until
product formation or disappearance of starting material. The
solvent was removed under reduced pressure, the residue taken up in
ethyl acetate (or similar selected solvent such as methylene
chloride or chloroform) and water. The organic layer was separated,
washed with dilute HCl (if the desired product contains a basic
functional group, washing with dilute HCl may be omitted), brine,
and dried over sodium sulfate. The solvent was then removed at
reduced pressure to provide product.
[0257] c) PyBOP/Trialkylamine Coupling Procedure
[0258] A mixture of a carboxylic acid (1.0 e.q.), amine (1.0 e.q.),
PyBOP (1.1-1.5 eq.) and a trialkylamine (triethylamine or
diisopropylethylamine) (3-6 eq.) in an appropriate solvent or a
mixture of solvents, for example methylene chloride,
dichloroethane, THF, or DMF, was stirred at room temperature until
product formation or disappearance of starting material. The
solvent was removed under reduced pressure, the residue taken up in
ethyl acetate (or similar selected solvent such as methylene
chloride or chloroform) and water. The organic layer was separated,
washed with dilute HCl (if the desired product contains a basic
functional group, washing with dilute HCl may be omitted), brine,
and dried over sodium sulfate. The solvent was removed at reduced
pressure to provide product.
[0259] d) HBTU/Trialkylamine Coupling Procedure
[0260] A mixture of a carboxylic acid (1.0 e.q.), amine (1.0 e.q.),
HBTU (1.1-1.5 eq.), and a trialkylamine (triethylamine or
diisopropylethylamine) (3-6 eq.) in an appropriate solvent or a
mixture of solvents, for example methylene chloride,
dichloroethane, THF, or DMF, was stirred at room temperature until
product formation or disappearance of starting material. The
solvent was removed under reduced pressure, the residue taken up in
ethyl acetate (or similar selected solvent such as methylene
chloride or chloroform) and water. The organic layer was separated,
washed with dilute HCl (if the desired product contains a basic
functional group, washing with dilute HCl may be omitted), brine,
and dried over sodium sulfate. The solvent was removed at reduced
pressure to provide product.
[0261] e) Chloro-Alkylformate Coupling Procedure
[0262] A mixture of a carboxylic acid (1 eq.) and triethylamine
(eq.) was dissolved in an appropriate solvent, such as DMF and
cooled to -23.degree. C. Iso-butyl formate (1 eq.) was added
dropwise with stirring. After stirring for a period of time (form
15 min to 2 hr), a 2-amino-thiazole or an amine (1 eq.) was added
and stirring continued for an additional 30 min at -23.degree. C.
The mixture was then warmed to room temperature until amide
formation (typically overnight). The mixture was quenched with
water and brine and extracted with an appropriate solvent such as
ethyl acetate, methylene chloride or chlorform. The organic layer
was washed with dilute NaHSO.sub.4, NaHCO.sub.3 and brine and the
solvent was removed under reduced pressure to provide product.
Purification may be necessary.
[0263] f) TPTU Coupling Procedure
[0264] To the acid (1 equiv) was suspended in dry DMF,
Diisoproplyethyl amine (2-4 equiv) and TPTU (1 equiv) were added
and the resulting mixture was stirred at room temperature for 1 to
2 hour. To an aliquot of this solution was added the appropriate
amine and the mixture was stirred at room temperature over night.
IN NaOH was added and the resulting mixture was extracted with
ethyl acetate. The organic extracts were loaded onto SCX SPE
(Silicycle, 1 g) which was washed with MeOH. The product was then
eluted with 1N triethyl amine in MeOH and the resulting fraction
was concentrated. Purification was on Waters XTerra PrepMS C18 OBD
column (19.times.100 mm) and provided the title compound. Gradient
elution with water/ acetonitrile (18 ml/min) with a 1%
trifluoroacetic acid modifier (2 ml/min).
[0265] General Procedure B:
[0266] Method for Reductive Amination
[0267] a) Sodium Triacetoxyborohydride
[0268] An amine (1-4 eq.) in dichloroethane or THF was added to a
solution of a ketone (1 eq.), NaBH(OAc).sub.3 (1-3 eq.) and acetic
acid (1-3 eq.) in dichloroethane or THF. The mixture was stirred at
room temperature until product formation or disappearance of
starting material. The mixture was quenched with diluted base,
extracted with methylene chloride or other appropriate solvent such
as chloroform or ethyl acetate. The organic layer was separated,
dried and concentrated to give the desired amide. Purification may
be necessary.
[0269] b) Sodium Cyanoborohydride
[0270] A mixture of a ketone or aldehyde (1 eq.), an amine (1-20
eq.), sodium cyanoborohydride (1-5 eq.), acetic acid (1-3 eq.),
sodium acetate (1-3 eq.), anhydrous sodium sulfate in
dichloroethane or THF was stirred at room temperature to 60.degree.
C., preferably heated at 35-50.degree. C. until product formation.
The mixture was quenched with diluted base, extracted with
methylene chloride or other appropriate solvent such as chloroform
or ethyl acetate. The organic layer was separated, dried and
concentrated to give the desired amide. Purification may be
necessary.
[0271] c) Potassium Formate and Palladium Acetate
[0272] A solution of an aldehyde or a ketone (1 eq.) and an amine
(1 eq.) in dry DMF was stirred at room temperature for 4 hr, in the
presence of molecular sieves. To the resulting reaction mixture
were added potassium formate (2 eq.) and palladium acetate
(catalytic amount, 0.02 eq.). The mixture was heated at
40-60.degree. C. to complete reaction (TLC) and after cooling it
was diluted with ice-water. The mixture was extracted with an
appropriate solvent (such as methylene chloride, ethyl acetate, or
chloroform). The organic layer was separated, dried and
concentrated to give the desired amide. Purification may be
necessary.
[0273] General Procedure C:
[0274] Sodium Borohydride Reduction of Ketone or Aldehyde
[0275] A mixture of an aldehyde or a ketone (1 eq.) and sodium
borohydride (1-10 eq.) in an appropriate solvent (methanol or
ethanol) was stirred at 0.degree. C. to room temperature for 10
minutes to complete reaction (TLC). The mixture was concentrated to
a small volume, quenched with water, extracted with an appropriate
solvent (such as methylene chloride, ethyl acetate, or chloroform).
The organic layer was separated, dried and concentrated to give the
desired amide. Purification may be necessary.
[0276] General Procedure D:
[0277] N-tBOC Deprotectinq Procedure
[0278] To a solution of N-tBOC compound in 1,4-dioxane (0.03-0.09
M) was added 4 N HCl in 1,4-dioxane or anhydrous HCl gas under
nitrogen. The reaction mixture was stirred at room temperature for
1-24 hrs until all the starting material consumed (TLC). The
solution was concentrated and pumped in vacuo. The final HCl salt
of the corresponding amine was typically used without further
purification.
[0279] General Procedure E:
[0280] Conjugate Addition to Nitroimidazole
[0281] To a suspension of 4-nitroimidazole (2.0 equiv.) in
acetonitrile is added DBU (1.0 equiv) followed by enone (1.0
equiv.). The reaction is heated for 12-24 hrs and the solvent
removed in vacuo. The resultant solids are removed by filtration
with methylene chloride and the resultant oil concentrated and
purified by silica gel chromatography to provide the desired
nitroimidazole.
[0282] General Proceudre F:
[0283] Alkylation of Nitroimidazole Using Sodium Hydride
[0284] To a suspension of 4-nitroimidazole (1.0 equiv.) in
dimethylformamide at rt under a nitrogen atmosphere is added sodium
hydride (1.2 equiv.) portionwise. The reaction is stirred for 15-30
min. And then the appropriate alkylhalide or alkyl mesylate is
added. The mixture is stirred for 12-24 h at 50.degree. C., cooled
to 0.degree. C., and quenched with water. The aqueous layer is
extrated with methylene chloride, dried, and purified by silica gel
chromatography to provide the desired nitroimidazole.
[0285] Alkylation of Nitroimidazole Using Potassium Carbonate
[0286] To a suspension of 4-nitroimidazole (1.0 equiv.) in
dimethylformamide at it under a nitrogen atmosphere is added
potassium carbonate (1-4 equiv.) portionwise. The reaction is
stirred for 15-30 min. And then the appropriate alkylhalide or
alkyl mesylate is added. The mixture is stirred for 12-24 h at
50.degree. C. to 90.degree. C., cooled to rt, and quenched with
water. The aqueous layer is extrated with methylene chloride,
dried, and purified by silica gel chromatography or recrystalized
to provide the desired nitroimidazole.
[0287] General Procedure G:
[0288] Reduction of Nitroimidazole A
[0289] To a solution of the nitroimidazole (1.0 equiv.) in
ethylacetate is added palladium on carbon (0.25 w/w %). The
reaction is hydrogenated @ 40-60 psi for 2-6 hrs and filtered over
a pad of celite using ethyl acetate. The majority of the
ethylacetate is removed in vacuo and the solution of the amine in
the remaining ethylacetate is used without further
purification.
[0290] Reduction of Nitroimidazole B
[0291] A Parr bottle was charged with nitroimidazole (1 equiv),
dioxane and (1-3 equiv) of Raney nickel which had been washed with
water until the supernatant was at pH=7. The mixture was placed
under 50 psi of hydrogen pressure and shaken for 45 minutes. After
filtration and evaporation, the product, was used directly in the
next step without further purification.
[0292] General Procedure H:
[0293] Reduction of Nitroimidazole-Ester Followed by Reductive
Amination
[0294] To a solution of appropriate ester such as
3-Methyl-3-(4-nitro-imidazol-1-yl)-butyric acid methyl ester (1.0
equiv.) in methylene chloride at -78.degree. C. is added DIBAL (2
equiv.) dropwise. The reaction is stirred for 1 h, quenched with
ethylacetate, removed from cooling bath, and stirred for 10 min. To
the reaction is added water and allowed to warm to rt and stir for
1 h. The reaction is diluted with methylene chloride,
Na.sub.2SO.sub.4 is added and the reaction filtered through celite.
The solvent is removed to afford the aldehyde such as
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde which is used in
the next step without further purification.
[0295] To a solution of the appropriate aldehyde such as
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde (1 equiv.) in
methylene chloride is added an appropriate amine (2 equiv.) and 4A
molecular sieves. The reaction is stirred for 4-6 hours and an
appropriate hydride reducing agent such as sodium
triacetoxyborohydride (2 equiv.) is added. The reaction is stirred
for 6-24 h, quenched with sodium bicarbonate, and the aqueous layer
extracted with methylene chloride. The solvent is removed and
residue purified by silica gel chromatography to provide the
desired nitroimidazole.
[0296] General Procedure I:
[0297] Ester Reduction
[0298] To a solution of ester (1 equiv) in an appropriate solvent
such as diethyl ether or tetrahydrofuran at -78.degree. C. to
0.degree. C. is added lithium aluminum hydride (1 equiv) and the
reaction is stirred at 0.degree. C. for 15 min and warmed to it for
1 h. The reaction is slowly quenched with water and ethyl acetate.
The reaction is filtered and the aqueous is extracted with
ethylacetate, dried, and concentrated. Alternatively, the reaction
is quenched with water, 1N
[0299] NaOH and water, stirred and filtered through celite. The
filtrate was concentrated to dryness. Using either workup, the
resultant residue is purified by silica gel chromatography to
provide the title alcohol.
[0300] General Procedure J
[0301] Swern Oxidation
[0302] To a solution of oxalyl chloride (1.2 equiv) in methylene
chloride at -78.degree. C. is added
[0303] DMSO (3 equiv) dropwiese. The reaction is stirred for 20
min. and the alcohol (1 equiv) is added in methylene chloride. The
reaction is stirred for 1 h, triethylamine (4-5 equiv) is added,
and the reaction warmed to 0.degree. C. for 20 min to 2 hours. The
reaction is quenched with 100 mL of sodium bicarbonate, extracted
with methylene chloride, dried, and concentrated to afford the
title compound.
[0304] Dess Martin Oxidation
[0305] A mixture of 1 eq. of an alcohol and 1 to 1.5 eq. of
Dess-Martin oxidizing agent in methylene chloride (2 mL per mmole
reaction) was stirred at it until reaction done. The mixture was
quenched with water, filtered. The organic layer was separated,
dried and concentrated to give the corresponding aldehyde.
[0306] General Procedure K:
[0307] Epoxide Opening:
[0308] Isopropanol was added to the appropriate amine followed by
the addition of Hunig's base (2 equiv) and the appropriate epoxide
(1 equiv), the reaction mixture was heated at 60-100.degree. C.
overnight. The mixture was quenched with dilute aq bicarb solution
and extracted with dichloromethane. The organic extracts were dried
(Na.sub.2SO.sub.4) and concentrated to afford 200 mg crude material
which was purified on a silica get flash column to afford the
desired compound.
[0309] General Procedure M:
[0310] Substitution of Dinitroimidazole
[0311] A solution of (1 equiv) of 1,4-dinitro-1H-imidazole
(WO99/08699) and appropriate amine (1-2 equiv) in 1:1 MeOH--water
was stirred at room temperature for 48 hrs. The solvent was removed
in vacuo. The residue was taken up in methylene chloride and
chromatographed on silica gel to provide the desired compound.
[0312] General Procedure N:
[0313] Mesylate Formation (A)
[0314] The appropriate alcohol (1 equiv) was dissolved in pyridine
and treated with methansulfonyl chloride (2.2 equiv) at 0.degree.
C. The reaction was warmed to rt and stirred for 4 h, quenched with
sodium bicarbonate, and extracted with methylene chloride. The
extracts were dried and concentrated to provide the appropriate
mesylate which was used without further purification.
[0315] Mesylate Formation (B)
[0316] To the appropriate alcohol (1 equiv), methanesulfonyl
chloride (1 equiv), triethylamine (1 equiv) in methylene chloride
was stirred at rt for 1 to 8 hr. The reaction mixture was quenched
with waster, the organic layer was separated and concentrated to
give the desired mesylate which was used without further
purification.
[0317] General Procedure O:
[0318] Mesylate Displacement:
[0319] A 0.1 M solution of mesylate in acetonitrile was treated
with 3 equiv. of amine and 3 equiv. of K.sub.2CO.sub.3 and heated
at 65-80 C with stirring for 24-75 hrs. Once judged complete by
APCI or TLC, the reaction was quenched with H.sub.2O and extracted
with DCM. Silica gel chromatography or HPLC afforded pure product
in 30-75% yield.
[0320] General Procedure P:
[0321] Benzyl Halide Displacement:
[0322] A 0.1 M solution of imidazole in DMF was treated with
1.1-2.1 equiv of benzyl halide and 2.1 equiv of K.sub.2CO.sub.3 and
heated at 65 C with stirring for 18-30 hrs. In some cases, reaction
was facilitated by the addition of 0.05 equiv of Et.sub.3NBnCl.
Once judged complete by APCI or TLC, the reaction was quenched with
H.sub.2O and extracted with EtOAc. The combined extracts were
washed with H.sub.2O and brine, dried over MgSO.sub.4, filtered and
concentrated.Alternatively, reactions were worked up by extraction
with DCM. Extracts were loaded onto an SCX SPE (1 g, Silicycle)
cartridge. After washing with MeOH, crude product was eluted with 1
N TEA in MeOH. Silica gel chromatography or HPLC afforded pure
product in 30-75% yield.
[0323] General Proceudre R:
[0324] Ester Hydrolysis
[0325] The ester (1 equiv) is dissolved in THF:water (5:1) and LiOH
(1.2 equiv) is added. The reaction is stirred overnight at rt, the
solvent is removed, water added, and the pH is adjusted to 7 using
1N hydrochloric acid. The solid is filtered, washed with water and
diethyl ether, and dried to afford the desired acid.
[0326] The following intermediates were prepared by methods
analogous to those described above for General Method F;
[0327] 1-(3-Methyl-oxetan-3-ylmethyl)-4-nitro-1H-imidazole; H1 NMR,
(400 MHz), CDCl3) .delta. 1.25 (s, 3H), 4.28 (s, 2H), 4.42 (dd,
J=6.6 Hz, 37.3 Hz, 4H), 7.44 (s, 1H), 7.80 (s, 1H).
[0328] 4-Nitro-1-[1-(4-trifluoromethyl-phenyl)-ethyl]-1H-imidazole:
H1 NMR, (400 MHz), CDCl3): .delta. 1.96 (d, 3H), 5.49 (q, 1H), 7.33
(d, 2H), 7.53 (s, 1H), 7.67 (d, 2H), 7.78 (s, 1H).
[0329] 1-Benzyl-4-nitro-1H-imidazole; was prepared according to the
procedure of Searcey, M.; Pye, P. L.; Lee, J. B.; Synth. Commun.;
EN; 19; 7,8; 1989; 1309-1316.
[0330] 1-(4-Nitro-imidazol-1-yl)-cyclobutanecarboxylic acid methyl
ester; MS 240 m/z (M+1).
[0331] 2-(4-Nitro-imidazol-1-yl)-cyclobutanecarboxylic acid methyl
ester; MS 240 m/z (M+1).
[0332] The following intermediates were prepared from
dinitroimidazole by methods analogous to those described above for
General Method M;
[0333] 1-Indan-1-yl-4-nitro-1H-imidazole; MS 230 m/z (M+1).
[0334] (1R,2S)-(1-(4-Nitro-imidazol-1-yl)-indan-2-ol; MS 246 m/z
(M+1).
[0335] (1S,2R)-(1-(4-Nitro-imidazol-1-yl)-indan-2-ol; MS 246 m/z
(M+1).
[0336] 2-(4-fluorophenyl)-2-(4-nitro-1H-imidazol-1)-ethanol; MS 252
m/z (M+1).
[0337] (2-(4-nitro-1H-imidazol-1-yl)phenyl)methanol; MS 220 m/z
(M+1):
[0338] Methyl 2-(4-nitro-1H-imidazol-1-yl)-2-phenylacetate; MS 262
m/z (M+1).
[0339] The following nitroimidazoles were prepared by methods
analogous to those described above for General Method H:
2,2-dimethyl-N-(2-(4-nitro-1H-imidazol-1-yl)-2-phenylethyl)propan-1-amine
[0340] Methyl 2-(4-nitro-1H-imidazol-1-yl)-2-phenylacetate was
converted to the title compound using a method analagous to the
general procedure H to afford the title compound:
[0341] MS 303 m/z (M+1).
[0342] The following prepared as descripted:
4-Nitro-1-(2-pyrrolidin-1-ylmethyl-cyclobutyl)-1H-imidazole
[0343] A mixture of the
2-(4-Nitro-imidazol-1-yl)-cyclobutanecarboxylic acid methyl ester
(2.640 g, 0.01105 mol), borane-dimethyl sulfide complex (1M in
tetrahydrofuran) (33.2 mL, 0.0332 mol) and tetrahydrofuran (10 mL)
was heated at reflux for 17 hours. The reaction was quenched by
water. The volatile solvent was evaporated under reduced pressure.
The residue was diluted with water and extracted with ethyl acetate
three times. The combined extracts were washed with brine and dried
over sodium sulfate. The solvent was then evaporated under reduced
pressure to yield [2-(4-Nitro-imidazol-1-yl)-cyclobutyl]-methanol
(0.825 g, 0.00419 mol) as a white solid. M+1=198.1.
[0344] [2-(4-Nitro-imidazol-1-yl)-cyclobutyl]-methanol was
converted to Methanesulfonic acid
2-(4-nitro-imidazol-1-yl)-cyclobutylmethyl ester following General
Procedure N; MS 276.3 m/z (M+1).
[0345] Methanesulfonic acid
2-(4-nitro-imidazol-1-yl)-cyclobutylmethyl ester was converted to
the title compound following General Procedure O; MS 251.5 m/z
(M+1).
[0346] The following mesylates were prepared by methods analogous
to those described above for General Method N:
Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester
[0347] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(2-hydroxy-ethyl)-1H-imidazol-4-yl]-amide amide (U.S. Ser. No.
11/078,898 filed Mar. 11, 2005) was converted to the title
compound; MS 459.0 m/z (M+1).
Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester
[0348]
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(3-hydroxy-propyl)-1H-imidazol-4-yl]-amide was converted to
the title compound; MS 485 m/z (M+1).
Methanesulfonic acid
2-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester
[0349]
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(2-hydroxy-1-methyl-ethyl)-1H-imidazol-4-yl]-amide was
converted to the title compound; MS 485.5 m/z (M+1).
Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl.delta.-3-methyl-butyl ester
[0350]
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(3-hydroxy-1,1-dimethyl-propyl)-1H-imidazol-4-yl]-amide was
converted to the title compound; MS 513 m/z (M+1).
[0351] The following intermediates were prepared by methods
analogous to those described above for the reduction of the
appropriate nitroimdiazole using General Method G followed by
coupling to the appropriate acid using General Procedure A, method
F.
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1-benzyl-1H-imidazol-4-yl)-amide
[0352] 1-Benzyl-4-nitro-1H-imidazole was reduced and coupled with
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford
the title compound; MS 470 m/z (M+1).
(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-
-acetic acid methyl ester
[0353] (4-Nitro-imidazol-1-yl)-acetic acid methyl ester was reduced
and coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic
acid to afford the title compound; MS 409.1 m/z (M+1).
1-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-y-
l)-cyclobutanecarboxylic acid methyl ester
[0354] 1-(4-Nitro-imidazol-1-yl)-cyclobutanecarboxylic acid methyl
ester was reduced and coupled with
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford
the title compound; MS 463.0 m/z (M+1).
[0355]
2-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-midaz-
ol-1-yl)-cyclobutanecarboxylic acid methyl ester
[0356] 2-(4-Nitro-imidazol-1-yl)-cyclobutanecarboxylic acid methyl
ester was reduced and coupled with
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford
the title compound; MS 463.1 m/z (M+1).
1-{4-[2-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylam-
ino]-imidazol-1-yl}-cyclobutanecarboxylic acid methyl ester
[0357] 1-(4-Nitro-imidazol-1-yl)-cyclobutanecarboxylic acid methyl
ester was reduced and coupled with
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid acid to afford the title compound; MS 475.5 m/z (M+1).
2-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propionylam-
ino]-imidazol-1-yl}-2-methyl-propionic acid methyl ester
[0358] 2-Methyl-2-(4-nitro-imidazol-1-yl)-propionic acid methyl
ester was reduced and coupled with
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propionic
acid to afford the title compound; MS 421.5 m/z (M+1).
2-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylam-
ino]-imidazol-1-yl}-propionic acid methyl ester
[0359] 2-(4-Nitro-imidazol-1-yl)-propionic acid methyl ester was
reduced and coupled with
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid to afford the title compound; MS 435.5 m/z (M+1).
3-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylam-
ino]-imidazol-1-yl}-3-methyl-butyric acid methyl ester
[0360] 3-Methyl-3-(4-nitro-imidazol-1-yl)-butyric acid methyl ester
was reduced and coupled with
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid to afford the title compound; MS 463.5 m/z (M+1).
2-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylam-
ino]-imidazol-1-yl}-2-methyl-propionic acid methyl ester
[0361] 2-Methyl-2-(4-nitro-imidazol-1-yl)-propionic acid methyl
ester was reduced and coupled with
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid to afford the title compound; MS 449.3 m/z (M+1).
{1-[1-(3-oxo-butyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamic acid
tert-butyl ester
[0362] 4-(4-nitro-1H-imidazol-1-yl)butan-2-one was reduced and
coupled with 2-[(tert-butoxycarbonyl)amino]pentanoic acid to afford
the title compound; MS 353 m/z (M+1).
[0363]
3-{4-[2-(6.8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pent-
anoylamino]-imidazol-1-yl}-propionic acid methyl ester; MS 435 m/z
(M+1).
[0364]
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(1-methyl-3-oxo-butyl)-1H-imidazol-4-yl]-amide; MS 433 m/z
(M+1).
[0365] The following Boc groups were removed following general
method D;
[0366] 2-Amino-pentanoic acid
[1-(3-oxo-butyl)-1H-imidazol-4-yl]-amide hydrochloride; MS 253 m/z
(M+1).
[0367] 2-Amino-pentanoic acid
{1-[2-(2,6-dimethyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-
-amide: MS 352.3 m/z (M+1).
[0368] 2-Amino-pentanoic acid
(1-{1,1-dimethyl-3-[(pyridin-2-ylmethyl)-amino]-propyl}-1H-imidazol-4-yl)-
-amide; MS 359 m/z (M+1).
[0369] 2-Amino-pentanoic acid
{1-[1,1-dimethyl-3-(2,2,2-trifluoro-1-phenyl-ethylamino)-propyl]-1H-imida-
zol-4-yl}-amide; MS 426 m/z (M+1).
[0370] 2-Amino-pentanoic acid
{1-[1,1-dimethyl-3-(1-phenyl-ethylamino)-propyl-1H-imidazol-4-yl}-amide;
MS 372 m/z (M+1).
[0371] The following alcohols were prepared by reduction of the
corresponding esters using methods analogous to those described
above using General Method I;
[0372] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(2-hydroxy-ethyl)-1H-imidazol-4-yl]-amide; MS 381.1 m/z
(M+1).
[0373]
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(3-hydroxy-propyl)-1H-imidazol-4-yl]-amide; MS 407 m/z
(M+1).
[0374]
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(2-hydroxy-1-methyl-ethyl)-1H-imidazol-4-yl]amide; MS 407.5
m/z (M+1).
[0375]
{1-[1-(3-Hydroxy-1,1-dimethyl-propyl)-1H-imidazol-4-ylcarbamoyl]-bu-
tyl}-carbamic acid tert-butyl ester; MS 369 m/z (M+1).
[0376] The following aldehydes were prepared by oxidation from
corresponding alcohol using methods analogous to those described
above using General Method J;
[0377] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide; MS 419.1 m/z
(M+1).
[0378]
2-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide; MS 431.5 m/z
(M+1).
[0379]
(2S)-2-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-N-(1-(-
2-formylphenyl)-1H-imidazol-4-yl)pentanamide;
[0380]
{1-[1-(1,1-Dimethyl-3-oxo-propyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-
-carbamic acid tert-butyl ester; MS 367 m/z (M+1).
[0381] The following acids were prepared by hydrolysis from
corresponding esters using methods analogous to those described
above using General Method R;
[0382]
3-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pent-
anoylamino]-imidazol-1-yl}-3-methyl-butyric acid methyl ester; MS
449.6 m/z (M+1).
[0383]
2-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pent-
anoylamino]-imidazol-1-yl}-2-methyl-propionic acid; MS 435.4 m/z
(M+1).
[0384]
2-{4-(2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-prop-
ionylamino]-imidazol-1-yl}-2-methyl-propionic acid; MS 407.5 m/z
(M+1).
Procedure for Synthesis of
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid; General procedure Q
[0385] Combine L-norvaline methyl ester-hydrochloride (1 equiv)
with 6,8-difluoro-3,4-dihydro-1H-naphthalen-2-one (1 equiv) in
methylene chloride and stir 30 min. and add sodium triacetoxy
borohydride (1.1 equiv) and stir at rt overnight. The reaction is
quenched with aqueous sodium bicarbonate, extracted with methylene
chloride, dried, and concentrated. The resultant material is
purified by silica gel chromatography to afford the separated
diastereomers of
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid methyl ester: Diastereomer 1; 13C NMR (100 MHz, CDCl3) 14.0,
19.4, 27.7, 28.2, 29.5, 29.6, 36.3, 51.1, 58.7, 100.7, 100.9,
101.2, 110.5, 110.7, 110.8, 118.5, 118.6, 141.1, 159.7, 159.8,
162.1, 176.7; MS m/z 298.3 (M+1). Diastereomer 2; Diagnostic 13C
NMR (100 MHz, CDCl3) 14.0, 19.3, 28.3, 28.4, 28.5, 30.3, 36.4,
51.1, 52.0, 58.5, 100.7, 100.9, 101.2, 110.5, 110.7, 176.8; MS m/z
298.3 (M+1).
[0386]
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid methyl ester (1 equiv) is dissolved in THF:water (5:1) and
LiOH (1.2 equiv) is added. The reaction is stirred overnight at rt,
the solvent is removed, water added, and the pH is adjusted to 7
using 1N hydrochloric acid. The solid is filtered, washed with
water and diethyl ether, and dried to afford
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid; Acid derived from diasteromer 1: H1 NMR (400 MHz, CD3OD) 0.99
(t, 3H, J=7.5), 1.48 (m, 2H), 1.82 (m, 3H), 2.36 (m, 1H), 2.65 (m,
1H), 2.95 (m, 2H), 3.28 (s, 1H), 3.42 (m, 1H), 3.74 (m, 1H), 6.80
(m, 2H); (MS m/z 284.3 (M+1). Acid derived from diasteromer 2: H1
NMR (400 MHz, CD3OD) 0.94 (t, 3H, J=7.6), 1.42 (m, 2H), 1.56 (m,
3H), 1.96 (m, 1H), 2.25 (m, 1H), 2.85 (m, 3H), 3.15 (m, 1H), 3.25
(m, 1H), 6.64 (m, 2H); MS m/z 284.2 (M+1).
[0387] The following intermdediates were prepared in an analogous
manner to Method Q starting with an appropriate amino acid and
ketone or starting amino-ester and ketone; or the aminoester is
acylated using general procedure A followed by hydrolysis.
[0388] (S)-2-(2-(3,5-difluorophenyl)acetamido)-2-phenylacetic acid;
MS 304 m/z (M-1).
[0389]
(S)-2-(2-(3,5-difluorophenyl)acetamido)-2-(pyridin-3-yl)acetic
acid; MS 305 m/z (M-1).
[0390]
(S)-2-(2-(3,5-difluorophenyl)acetamido)-2-(4-fluorophenyl)acetic
acid; MS 322 m/z (M-1).
[0391]
(S)-2-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-2-pheny-
lacetic acid; MS 316 m/z (M-1).
[0392]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propio-
nic acid; MS 256.5 m/z (M+1).
[0393] (S)-2-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic
acid; MS 246.5 m/z (M-1).
[0394] The following intermediates were prepared in an analogous
manner to Method B starting with an appropriate amine and
ketone/aldehyde.
[0395]
(1-{1-[2-(2,6-Dimethyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imida-
zol-4-ylcarbamoyl}-butyl)-carbamic acid tert-butyl ester; MS 452.1
m/z (M+1).
[0396]
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(3-oxo-butyl)-1H-imidazol-4-yl]-amide; MS 419 m/z
(M+1).
[0397]
[1-(1-{1,1-Dimethyl-3-[(pyridin-2-ylmethyl)-amino]-propyl}-1H-imida-
zol-4-ylcarbamoyl)-butyl]-carbamic acid tert-butyl ester; MS 459
m/z (M+1).
[0398]
(1-{1-[1,1-Dimethyl-3-(2,2,2-trifluoro-1-phenyl-ethylamino)-propyl]-
-1H-imidazol-4-ylcarbamoyl}-butyl)-carbamic acid tert-butyl ester;
MS 526 m/z (M+1).
[0399]
(1-{1-[1,1-Dimethyl-3-(1-phenyl-ethylamino)-propyl]-1H-imidazol-4-y-
lcarbamoyl}-butyl)-carbamic acid tert-butyl ester; MS 472 m/z
(M+1).
[0400] The following Examples were prepared by methods analogous to
those described above for General Procedure O;
Example 1
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3-ethoxy-propylamino)-ethyl]-1H-imidazol-4-yl}-amide
[0401] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with 3-ethoxypropyl amine to provide
the title compound: MS 446.2 m/z (M+1).
Example 2
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(octahydro-pyrazino[1,2-a]azepin-2-yl)-ethyl]-1H-imidazol-4-yl}-ami-
de
[0402] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound: MS 517.2 m/z (M+1).
Example 3
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-([1,4]dioxan-2-ylmethyl-methyl-amino)-ethyl]-1H-imidazol-4-yl}-amid-
e
[0403] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound: MS 494.2 m/z (M+1).
Example 4
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(2-methoxy-1-methyl-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide
[0404] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound: MS 452.2 m/z (M+1).
Example 5
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3-oxo-piperazin-1-yl)-ethyl]-1H-imidazol-4-yl}-amide
[0405] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound: MS 463.2 m/z (M+1).
Example 6
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(2-benzylamino-ethyl)-1H-imidazol-4-yl]-amide
[0406] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
ylyethyl ester was reacted with appropriate amine to provide the
title compound: MS 470.2 m/z (M+1).
Example 7
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3-butoxy-propylamino)-ethyl]-1H-imidazol-4-yl}-amide
[0407] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound: MS 494.2 m/z (M+1).
Example 8
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-(2-((1R,2S)-2-hydroxymethyl-cyclohexylamino)-ethyl]-1H-imidazol-4-yl}--
amide
[0408] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
ylyethyl ester was reacted with appropriate amine to provide the
title compound: MS 492.2 m/z (M+1).
Example 9
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[(4aS,8aS)-2-(octahydro-isoquinolin-2-yl)-ethyl]-1H-imidazol-4-yl}-ami-
de
[0409] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound:
[0410] MS 502.2 m/z (M+1).
Example 10
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3-isopropoxy-propylamino)-ethyl]-1H-imidazol-4-yl}-amide
[0411] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound: MS 480.2 m/z (M+1).
Example 11
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(octahydro-isoquinolin-2-yl)-ethyl]-1H-imidazol-4-yl}-amide
[0412] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound: MS 502.2 m/z (M+1).
Example 12
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3,4,5,6-tetrahydro-2H-[4,4']bipyridinyl-1-yl)-ethyl}-1H-imidazol-4-
-yl}-amide
[0413] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound: MS 525.2 m/z (M+1).
Example 13
S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(2-hydroxy-2-phenyl-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide
[0414] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound: MS 500.2 m/z (M+1).
Example 14
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(indan-1-ylamino)-ethyl]-1H-imidazol-4-yl}-amide
[0415] Methanesulfonic acid
2-(4-(2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound: MS 496.2 m/z (M+1).
Example 15
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(benzyl-methyl-amino)-ethyl]-1H-imidazol-4-yl}-amide
[0416] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound: MS 484.2 m/z (M+1).
Example 16
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(indan-2-ylamino)-ethyl}-1H-imidazol-4-yl}-amide
[0417] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound: MS 496.2 m/z (M+1).
Example 17
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3,4-dihydro-1#H!-isoquinolin-2-yl)-ethyl]-1H-imidazol-4-yl}-amide
[0418] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
ylyethyl ester was reacted with appropriate amine to provide the
title compound: MS 496.2 m/z (M+1).
Example 18
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(2-propoxy-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide
[0419] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
ylyethyl ester was reacted with appropriate amine to provide the
title compound: MS 466.2 m/z (M+1).
Example 19
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3-benzyl-pyrrolidin-1-yl)-ethyl}-1H-imidazol-4-yl}-amide
[0420] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound: MS 524.2 m/z (M+1).
Example 20
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3-pyridin-2-yl-pyrrolidin-1-yl)-ethyl}-1H-imidazol-4-yl}-amide
[0421] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
ylyethyl ester was reacted with appropriate amine to provide the
title compound: MS 511.2 m/z (M+1).
Example 21
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(methyl-pyridin-4-ylmethyl-amino)-ethyl]-1H-imidazol-4-yl}-amide
[0422] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound: MS 485.2 m/z (M+1).
Example 22
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1-{2-[(2-methanesulfonyl-ethyl)-methyl-amino]-ethyl}-1H-imidazol-4-yl)-a-
mide
[0423] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound: MS 500.1 m/z (M+1).
Example 23
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(2-tert-butoxy-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide
[0424] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound: MS 480.2 m/z (M+1).
Example 23A
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3-pyridin-4-yl-pyrrolidin-1-yl)-ethyl]-1H-imidazol-4-yl}-amide
[0425] Methanesulfonic acid
2-(4-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1--
yl)-ethyl ester was reacted with appropriate amine to provide the
title compound: MS 511.2 m/z (M+1).
[0426] The following Examples were prepared by methods analogous to
those described above for General Procedure P;
Example 24
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(2-fluoro-benzyl)-1H-imidazol-4-yl]-amide
[0427] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1H-imidazol-4-yl)-amide was reacted with appropriate benzyl halide
to provide the title compound: MS 445.1 m/z (M+1).
Example 25
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(3-fluoro-benzyl)-1H-imidazol-4-yl]-amide
[0428] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1H-imidazol-4-yl)-amide was reacted with appropriate benzyl halide
to provide the title compound: MS 445.1 m/z (M+1.
Example 26
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(4-methyl-benzyl)-1H-imidazol-4-yl}-amide
[0429] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1H-imidazol-4-yl)-amide was reacted with appropriate benzyl halide
to provide the title compound: MS 441.1 m/z (M+1).
Example 27
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(4-methoxy-benzyl)-1H-imidazol-4-yl]-amide
[0430] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1H-imidazol-4-yl)-amide was reacted with appropriate benzyl halide
to provide the title compound: MS 457.3 m/z (M+1).
Example 28
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(4-tert-butyl-benzyl)-1H-imidazol-4-yl]-amide
[0431] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1H-imidazol-4-yl)-amide was reacted with appropriate benzyl halide
to provide the title compound: MS 483.3 m/z (M+1).
[0432] The following Examples were prepared by methods analogous to
those described above for General Procedure B;
Example 29
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-pyrrolidin-1-ylmethyl-cyclobutyl)-1H-imidazol-4-yl}-amide
[0433] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide was reacted with
appropriate amine to provide the title compound: MS 474.1 m/z
(M+1).
Example 30
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-dimethylaminomethyl-cyclobutyl)-1H-imidazol-4-yl]-amide
[0434] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide was reacted with
appropriate amine to provide the title compound: MS 448.5 m/z
(M+1).
Example 31
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-piperidin-1-ylmethyl-cyclobutyl)-1H-imidazol-4-yl]-amide
[0435] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide was reacted with
appropriate amine to provide the title compound: MS 488.5 m/z
(M+1).
Example 32
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-morpholin-4-ylmethyl-cyclobutyl)-1H-imidazol-4-yl]-amide
[0436] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide was reacted with
appropriate amine to provide the title compound: MS 490.5 m/z
(M+1).
Example 31A
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1-{1-[((2R,6S)-2,6-dimethyl-morpholin-4-yl)methyl]-cyclobutyl}-1H-imidaz-
ol-4-yl)-amide
[0437] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide was reacted with
appropriate amine to provide the title compound: MS 518.5 m/z
(M+1).
Example 32A
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1-{1-[(2,2,2-trifluoro-ethylamino)-methyl]-cyclobutyl}-1H-imidazol-4-yl)-
-amide
[0438] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide was reacted with
appropriate amine to provide the title compound: MS 502.4 m/z
(M+1).
Example 33
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1-{1-[((R)-1-cyclohexyl-ethylamino)-methyl]-cyclobutyl}-1H-imidazol-4-yl-
)-amide
[0439] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide was reacted with
appropriate amine to provide the title compound: MS 530.5 m/z
(M+1).
Example 34
(S)-2-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
[1-(1-pyrrolidin-1-ylmethyl-cyclobutyl)-1H-imidazol-4-yl]-amide
[0440]
2-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide was reacted
with appropriate amine to provide the title compound: MS 486.5 m/z
(M+1).
Example 35
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1-{1-[(2,2-dimethyl-propylamino)-methyl]-cyclobutyl}-1H-imidazol-4-yl)-a-
mide
[0441] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide was reacted with
appropriate amine to provide the title compound: MS 490.5 m/z
(M+1).
Example 36
[0442]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1-[(2,2,2-trifluoro-ethylamino)-methyl]-cyclobutyl}-1H-imidaz-
ol-4-yl)-amide
[0443]
2-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide was reacted
with appropriate amine to provide the title compound: MS 514.5 m/z
(M+1).
Example 37
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1-[(2,2-dimethyl-propylamino)-methyl]-cyclobutyl}-1H-imidazol-4--
yl)-amide
[0444]
2-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide was reacted
with appropriate amine to provide the title compound: MS 502.6 m/z
(M+1).
Example 38
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1-[((R)-1-cyclohexyl-ethylamino)-methyl]-cyclobutyl}-1H-imidazol-
-4-yl)-amide
[0445]
2-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide was reacted
with appropriate amine to provide the title compound: MS 542.6 m/z
(M+1).
Example 39
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
[1-(1-dimethylaminomethyl-cyclobutyl)-1H-imidazol-4-yl]-amide
[0446]
2-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-[1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide was reacted
with appropriate amine to provide the title compound: MS 460.6 m/z
(M+1).
Example 40
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
[1-(1-piperidin-1-ylmethyl-cyclobutyl)-1H-imidazol-4-yl]-amide
[0447]
2-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide was reacted
with appropriate amine to provide the title compound: MS 500.6 m/z
(M+1).
Example 41
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
[1-(1-morpholin-4-ylmethyl-cyclobutyl)-1H-imidazol-4-yl]-amide
[0448]
2-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide was reacted
with appropriate amine to provide the title compound: MS 502.6 m/z
(M+1).
Example 42
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1-[1-[((2R,6S)-2,6-dimethyl-morpholin-4-yl)methyl]-cyclobutyl}-1-
H-imidazol-4-yl)-amide
[0449]
2-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(1-formyl-cyclobutyl)-1H-imidazol-4-yl]-amide was reacted
with appropriate amine to provide the title compound: MS 530.6 m/z
(M+1).
Example 43
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[2-((R)-1-cyclohexyl-ethylamino)-1,1-dimethyl-ethyl]-1H-imidazol--
4-yl}-amide
[0450]
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide (U.S.
Ser. No. 11/078,898 filed Mar. 11, 2005) was treated with the
appropriate amine to afford the title compound MS 530.4 m/z
(M+1).
Example 44
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1,1-dimethyl-2-[(tetrahydro-pyran-4-ylmethyl)-amino]-ethyl}-1H-i-
midazol-4-yl)-amide
[0451]
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide (U.S.
Ser. No. 11/078,898 filed Mar. 11, 2005) was treated with the
appropriate amine to afford the title compound MS 518.4 m/z
(M+1).
Example 45
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{2-[(1-hydroxy-cyclohexylmethyl)-amino]-1,1-dimethyl-ethyl}-1H-im-
idazol-4-yl)-amide
[0452] b
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoi-
c acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide (U.S.
Ser. No. 11/078,898 filed Mar. 11, 2005) was treated with the
appropriate amine to afford the title compound MS 532.6 m/z
(M+1).
Example 46
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{2-[(4-hydroxy-tetrahydro-pyran-4-ylmethyl)-amino]-1,1-dimethyl-e-
thyl}-1H-imidazol-4-yl)-amide
[0453]
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide (U.S.
Ser. No. 11/078,898 filed Mar. 11, 2005) was treated with the
appropriate amine to afford the title compound MS 534.6 m/z
(M+1).
Example 47
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[2-(2-methoxy-2-methyl-propylamino)-1,1-dimethyl-ethyl]-1H-imidaz-
ol-4-yl}-amide
[0454]
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide (U.S.
Ser. No. 11/078,898 filed Mar. 11, 2005) was treated with the
appropriate amine to afford the title compound MS 506.5 m/z
(M+1).
Example 48
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1,1-dimethyl-2-[(3-methyl-oxetan-3-ylmethyl)-amino]-ethyl}-1H-im-
idazol-4-yl)-amide
[0455]
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide (U.S.
Ser. No. 11/078,898 filed Mar. 11, 2005) was treated with the
appropriate amine to afford the title compound MS 504.5 m/z
(M+1).
Example 49
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[2-(cyclohexylmethyl-amino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-
-amide
[0456]
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide (U.S.
Ser. No. 11/078,898 filed Mar. 11, 2005) was treated with the
appropriate amine to afford the title compound MS 516.6 m/z
(M+1).
Example 50
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-((R)-1-cyclohexyl-ethylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-
-amide
[0457] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide (U.S. Ser.
No. 11/078,898 filed Mar. 11, 2005) was treated with the
appropriate amine to afford the title compound MS 518.2 m/z
(M+1).
Example 51
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1-{1,1-dimethyl-2-[(tetrahydro-pyran-4-ylmethyl)-amino]-ethyl}-1H-imidaz-
ol-4-yl)-amide
[0458] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide (U.S. Ser.
No. 11/078,898 filed Mar. 11, 2005) was treated with the
appropriate amine to afford the title compound MS 506.4 m/z
(M+1).
Example 52
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[3-((S)-1-phenyl-ethylamino)-butyl]-1H-imidazol-4-yl}-amide
[0459]
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(3-oxo-butyl)-1H-imidazol-4-yl]-amide was treated with the
appropriate amine to afford the title compound MS 524.1 m/z
(M+1).
Example 53
(S)-2-(Dicyclopropylmethyl-amino)-pentanoic acid
[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide
[0460] 2-Amino-pentanoic acid
[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide
(U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was treated with the
appropriate ketone to afford the title compound MS 402.6 m/z
(M+1).
[0461] The following Examples were prepared by methods analogous to
those described above for General Procedure I;
Example 54
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-hydroxymethyl-cyclobutyl)-1H-imidazol-4-yl]-amide
[0462]
1-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imida-
zol-1-yl)-cyclobutanecarboxylic acid methyl ester was reduced to
afford the title compound: MS 421.1 m/z (M+1).
Example 55
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(2-hydroxymethyl-cyclobutyl)-1H-imidazol-4-yl]-amide
[0463]
2-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imida-
zol-1-yl)-cyclobutanecarboxylic acid methyl ester was reduced to
afford the title compound: MS 421.1 m/z (M+1).
Example 56
(S)-2-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(1-hydroxymethyl-cyclobutyl)-1H-imidazol-4-yl]-amide
[0464]
1-{4-[2-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pent-
anoylamino]-imidazol-1-yl}-cyclobutanecarboxylic acid methyl ester
was reduced to afford the title compound: MS 433.5 m/z (M+1).
[0465] The following Examples were prepared by methods analogous to
those described above for General Procedure K;
Example 57
(S)-2-[2-(2,4-Difluoro-phenyl)-2-hydroxy-ethylamino]-pentanoic acid
[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide
[0466] 2-Amino-pentanoic acid
[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide
(U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was treated with the
appropriate epoxide to afford the title compound: MS 464.3 m/z
(M+1).
Example 58
(S)-2-[2-(3,4-Difluoro-phenyl)-2-hydroxy-ethylamino]-pentanoic acid
[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide
[0467] 2-Amino-pentanoic acid
[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide
(U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was treated with the
appropriate epoxide to afford the title compound: MS 464.3 m/z
(M+1).
Example 59
(S)-2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-ethylamino]-pentanoic acid
[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide
[0468] 2-Amino-pentanoic acid
[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide
(U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was treated with the
appropriate epoxide to afford the title compound: MS 464.5 m/z
(M+1).
Example 60
(S)-2-[2-(2,4-Difluoro-phenyl)-2-hydroxy-ethylamino]-pentanoic acid
{1-[2-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imidaz-
ol-4-yl}-amide
[0469] 2-Amino-pentanoic acid
[1-(1,1-dimethyl-2-(2,6-dimethylmorpholino-1-yl-ethyl)-1H-imidazol-4-yl]--
amide was treated with the appropriate epoxide to afford the title
compound: MS 508.5 m/z (M+1).
Example 61
(S)-2-[(1-Hydroxy-cyclohexylmethyl)-amino]-pentanoic acid
[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide
[0470] 2-Amino-pentanoic acid
[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide
(U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was treated with the
appropriate epoxide to afford the title compound: MS 420.6 m/z
(M+1).
[0471] The following Examples were prepared by methods analogous to
those described above for General Procedure O;
Example 62
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[3-((R)-1-phenyl-ethylamino)-propyl]-1H-imidazol-4-yl}-amide
[0472] Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester was treated with the appropriate
amine to afford the title compound: MS 510.1 m/z (M+1).
Example 63
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[3-(3-methyl-benzylamino)-propyl]-1H-imidazol-4-yl}-amide
[0473] Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester was treated with the appropriate
amine to afford the title compound: MS 510.53 m/z (M+1).
Example 64
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[3-(2-hydroxy-2-phenyl-ethylamino)-propyl]-1H-imidazol-4-yl}-amid-
e
[0474] Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester was treated with the appropriate
amine to afford the title compound: MS 526.54 m/z (M+1).
Example 65
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[3-(2-chloro-benzylamino)-propyl]-1H-imidazol-4-yl}-amide
[0475] Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester was treated with the appropriate
amine to afford the title compound: MS 530.5 m/z (M+1).
Example 66
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-1H-imidazol-4-yl}-am-
ide
[0476] Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester was treated with the appropriate
amine to afford the title compound: MS 522.53 m/z (M+1).
Example 67
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid {1-[3-(indan-2-ylamino)-propyl]-1H-imidazol-4-yl}-amide
[0477] Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester was treated with the appropriate
amine to afford the title compound: MS 522.52 m/z (M+1).
Example 68
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[3-(1-methoxymethyl-propylamino)-propyl]-1H-imidazol-4-yl}-amide
[0478] Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester was treated with the appropriate
amine to afford the title compound: MS 492.53 m/z (M+1).
Example 69
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[3-(4-chloro-benzylamino)-propyl]-1H-imidazol-4-yl}-amide
[0479] Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester was treated with the appropriate
amine to afford the title compound: MS 530.5 m/z (M+1).
Example 70
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[3-(2-methyl-benzylamino)-propyl]-1H-imidazol-4-yl}-amide
[0480] Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester was treated with the appropriate
amine to afford the title compound: MS 510.5 m/z (M+1).
Example 71
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[3-(2-methoxy-ethylamino)-propyl]-1H-imidazol-4-yl}-amide
[0481] Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester was treated with the appropriate
amine to afford the title compound: MS 464.2 m/z (M+1).
Example 72
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{3-[(pyridin-3-ylmethyl)-amino]-propyl}-1H-imidazol-4-yl)-amide
[0482] Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-
pentanoylamino]-imidazol-1-yl)-propyl ester was treated with the
appropriate amine to afford the title compound: MS 497.5 m/z
(M+1).
Example 73
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[3-((S)-1-p-tolyl-ethylamino)-propyl]-1H-imidazol-4-yl}-amide
[0483] Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester was treated with the appropriate
amine to afford the title compound: MS 524.6 m/z (M+1).
Example 74
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[3-(4-methoxy-benzylamino)-propyl]-1H-imidazol-4-yl}-amide
[0484] Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester was treated with the appropriate
amine to afford the title compound: MS 526.5m/z (M+1).
Example 75
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[3-(cyclopropylmethyl-amino)-propyl]-1H-imidazol-4-yl}-amide
[0485] Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester was treated with the appropriate
amine to afford the title compound: MS 460.5 m/z (M+1).
Example 76
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[3-(4-methyl-benzylamino)-propyl]-1H-imidazol-4-yl}-amide
[0486] Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester was treated with the appropriate
amine to afford the title compound: MS 510.5 m/z (M+1).
[0487] The following Examples were prepared by methods analogous to
those described above for General Procedure A, method F using
2-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-2-methyl-propionic acid and an appropriate
amine.
Example 77
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[1-methyl-1-(methyl-phenethyl-carbamoyl)-ethyl]-1H-imidazol-4-yl}-
-amide
[0488] MS 552.58 m/z (M+1).
Example 78
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[1-(1,3-dihydro-isobenzofuran-5-ylcarbamoyl)-1-methyl-ethyl]-1H-i-
midazol-4-yl}-amide
[0489] MS 552.55 m/z (M+1).
Example 79
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[1-(indan-1-ylcarbamoyl)-1-methyl-ethyl]-1H-imidazol-4-yl}-amide
[0490] MS 550.53 m/z (M+1).
Example 80
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[1,1-dimethyl-2-oxo-2-(3-pyridin-4-yl-pyrrolidin-1-yl)-ethyl]-1H--
imidazol-4-yl}-amide
[0491] MS 565.6 m/z (M+1).
Example 81
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1-[2-(3-fluorophenyl)-ethylcarbamoyl]-1-methyl-ethyl}-1H-imidazo-
l-4-yl)-amide
[0492] MS 556.54 m/z (M+1).
Example 82
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[2-(3-cyano-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-1H-imidazol-
-4-yl}-amide
[0493] MS 527.57 m/z (M+1).
Example 83
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1-methyl-1-[methyl-(tetrahydro-pyran-2-ylmethyl)-carbamoyl]-ethy-
l}-1H-imidazol-4-yl)-amide
[0494] MS 546.58 m/z (M+1).
Example 84
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1-[ethyl-(2-pyrazol-1-yl-ethyl)-carbamoyl]-1-methyl-ethyl}-1H-im-
idazol-4-yl)-amide
[0495] MS 556.61 m/z (M+1).
Example 85
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[1,1-dimethyl-2-oxo-2-(2-phenyl-pyrrolidin-1-yl)-ethyl]-1H-imidaz-
ol-4-yl}-amide
[0496] MS 564.59 m/z (M+1).
Example 86
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1-[(furan-2-ylmethyl)-carbamoyl]-1-methyl-ethyl}-1H-imidazol-4-y-
l)-amide
[0497] MS 514.51m/z (M+1).
Example 87
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{2-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-1,1-dimethyl-2-oxo-e-
thyl}-1H-imidazol-4-yl)-amide
[0498] MS 559.57 m/z (M+1).
Example 88
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[1-methyl-1-((3R,4S)-4-methylsulfanyl-tetrahydro-furan-3-ylcarbam-
oyl)-ethyl]-1H-imidazol-4-yl)-amide
[0499] MS 550.53 m/z (M+1).
Example 89
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[2-(4-acetyl-[1,4]diazepan-1-yl)-1,1-dimethyl-2-oxo-ethyl]-1H-imi-
dazol-4-yl}-amide
[0500] MS 559.31 m/z (M+1).
Example 90
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1-methyl-1-[1-(1-methyl-1H-pyrazol-4-yl)-ethylcarbamoyl]-ethyl}--
1H-imidazol-4-yl)-amide
[0501] MS 542.56 m/z (M+1).
Example 91
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[1-(3-methoxy-propylcarbamoyl)-1-methyl-ethyl]-1H-imidazol-4-yl}--
amide
[0502] MS 506.52 m/z (M+1).
Example 92
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1-methyl-1-[(3-methyl[1,2,4]oxadiazol-5-ylmethyl)-carbamoyl]-eth-
yl}-1H-imidazol-4-yl)-amide
[0503] MS 530.54 m/z (M+1).
Example 93
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1-[(2-cyano-ethyl)-methyl-carbamoyl]-1-methyl-ethyl}-1H-imidazol-
-4-yl)-amide
[0504] MS 501.51 m/z (M+1).
Example 94
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[1,1-dimethyl-2-(3-methyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]py-
razin-7-yl)-2-oxo-ethyl]-1H-imidazol-4-yl}-amide
[0505] MS 555.55 m/z (M+1).
Example 95
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1-methyl-1-[methyl-(1-methyl-1H-imidazol-2-ylmethyl)-carbamoyl]--
ethyl}-1H-imidazol-4-yl)-amide
[0506] MS 542.48 m/z (M+1).
Example 96
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1-[(2-diethylamino-ethyl)-methyl-carbamoyl]-1-methyl-ethyl}-1H-i-
midazol-4-yl)-amide
[0507] MS 547.62 m/z (M+1).
[0508] The following Examples were prepared by methods analogous to
those described above for General Procedure A, method F using
2-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propionyla-
mino]-imidazol-1-yl)-2-methyl-propionic acid and an appropriate
amine.
Example 97
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propion-
ylamino]-imidazol-1-yl}-N-indan-1-yl-isobutyramide
[0509] MS 522.56 m/z (M+1).
Example 98
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-N-{1-[1,1-dim-
ethyl-2-oxo-2-(3-pyridin-4-yl-pyrrolidin-1-yl)-ethyl]-1H-imidazol-4-yl}-pr-
opionamide
[0510] MS 537.53 m/z (M+1).
Example 99
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-N-{1-[2-(4-hy-
droxymethyl-4-methyl-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-1H-imidazol-
-4-yl}-propionamide
[0511] MS 528.51 m/z (M+1).
Example 100
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propion-
ylamino]-imidazol-1-yl}-N-methyl-N-phenethyl-isobutyramide
[0512] MS 524.54 m/z (M+1).
Example 101
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propion-
ylamino]-imidazol-1-yl}-N-ethyl-N-(2-pyrazol-1-yl-ethyl)-isobutyramide
[0513] MS 528.49 m/z (M+1).
Example 102
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-N-{1-[2-(4-hy-
droxymethyl-4-methyl-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-1H-imidazol-
-4-yl}-propionamide
[0514] MS 518.53 m/z (M+1).
Example 103
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propion-
ylamino]-imidazol-1-yl}-N-(4-methyl-benzyl)-isobutyramide
[0515] MS 510.49 m/z (M+1).
Example 104
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propion-
ylamino]-imidazol-1-yl}-N-(1,3-dihydro-isobenzofuran-5-yl)-isobutyramide
[0516] MS 524.47 m/z (M+1).
Example 105
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-N-{1-[1,1-dim-
ethyl-2-oxo-2-(2-phenyl-pyrrolidin-1-yl)-ethyl]-1H-imidazol-4-yl}-propiona-
mide
[0517] MS 536.55 m/z (M+1).
Example 106
(S)--N-{1-[2-(3-Cyano-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-1H-imidazo-
l-4-yl}-2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propionam-
ide
[0518] MS 499.46 m/z (M+1).
Example 107
(S)--N-(1-{2-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-1,1-dimethyl-2-oxo--
ethyl}-1H-imidazol-4-yl)-2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-y-
lamino)-propionamide
[0519] MS 531.53 m/z (M+1).
Example 108
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propion-
ylamino]-imidazol-1-yl}-N-((1R,2S)-2-hydroxymethyl-cyclohexyl)-isobutyrami-
de
[0520] MS 518.53 m/z (M+1).
Example 109
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propion-
ylamino]-imidazol-1-yl}-N-(3-methyl-[1,2,4]oxadiazol-5-ylmethyl)-isobutyra-
mide
[0521] MS 502.43 m/z (M+1).
Example 110
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propion-
ylamino]-imidazol-1-yl}-N--((S)-2-methoxy-1-methyl-ethyl)-isobutyramide
[0522] MS 478.51 m/z (M+1).
Example 111
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propion-
ylamino]-imidazol-1-yl}-N-(3-methoxy-propyl)-isobutyramide
[0523] MS 478.58 m/z (M+1).
Example 112
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propion-
ylamino]-imidazol-1-yl}-N-[1-(1-methyl-1H-pyrazol-4-yl)-ethyl]-isobutyrami-
de
[0524] MS 514.51 m/z (M+1).
Example 113
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propion-
ylamino]-imidazol-1-yl}-N-(3-imidazol-1-yl-propyl)-isobutyramide
[0525] MS 514.56 m/z (M+1).
Example 114
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propion-
ylamino]-imidazol-1-yl}-N-(3-morpholin-4-yl-propyl)-isobutyramide
[0526] MS 533.58 m/z (M+1).
[0527] The following Examples were prepared by methods analogous to
those described above for the reduction of the appropriate
nitroimdiazole using General Method G followed by coupling to the
appropriate acid using General Procedure A, method F.
Example 115
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(3-methyl-oxetan-3-ylmethyl)-1H-imidazol-4-yl]-amide
[0528] 1-(3-Methyl-oxetan-3-ylmethyl)-4-nitro-1H-imidazole was
reduced and then coupled with
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the
title compound: MS 433.3 m/z (M+1).
Example 116
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(3-methyl-oxetan-3-ylmethyl)-1H-imidazol-4-yl]-amide
[0529] 1-(3-Methyl-oxetan-3-ylmethyl)-4-nitro-1H-imidazole was
reduced and then coupled with
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S. Ser.
No. 11/078,898 filed Mar. 11, 2005) to afford the title compound:
MS 421.3 m/z (M+1).
Example 117
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[1-(4-trifluoromethyl-phenyl)-ethyl]-1H-imidazol-4-yl}-amide
[0530] 4-Nitro-1-[1-(4-trifluoromethyl-phenyl)-ethyl]-1H-imidazole
was reduced and then coupled with
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the
title compound: MS 521.5 m/z (M+1).
Example 118
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[1-(4-trifluoromethyl-phenyl)-ethyl]-1H-imidazol-4-yl}-amide
[0531] 4-Nitro-1-[1-(4-trifluoromethyl-phenyl)-ethyl]-1H-imidazole
was reduced and then coupled with with
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S. Ser.
No. 11/078,898 filed Mar. 11, 2005) to afford the title compound:
MS 509.5 m/z (M+1).
Example 120
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(2-pyrrolidin-1-ylmethyl-cyclobutyl)-1H-imidazol-4-yl]-amide
[0532] 4-Nitro-1-(2-pyrrolidin-1-ylmethyl-cyclobutyl)-1H-imidazole
was reduced and then coupled with with
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S. Ser.
No. 11/078,898 filed Mar. 11, 2005) to afford the title compound:
MS 474.6 m/z (M+1).
Example 121
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
[1-(2-pyrrolidin-1-ylmethyl-cyclobutyl)-1H-imidazol-4-yl]-amide
[0533] 4-Nitro-1-(2-pyrrolidin-1-ylmethyl-cyclobutyl)-1H-imidazole
was reduced and then coupled with
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the
title compound: MS 486.6 m/z (M+1).
Example 122
(S)-2-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic acid
(1-{1,1-dimethyl-2-[(tetrahydro-pyran-4-ylmethyl)-amino]-ethyl}-1H-imidaz-
ol-4-yl)-amide
[0534]
[2-(4-Nitro-imidazol-1-yl)-propyl-(tetrahydro-pyran-4-ylmethyl)-ami-
ne was reduced and then coupled with
2-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic acid to
afford the title compound: MS 482.6 m/z (M+1).
Example 123
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[2-(2-ethoxy-ethylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-am-
ide
[0535]
(2-Ethoxy-ethyl)-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-amine
was reduced and then coupled with
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the
title compound: MS 492.6 m/z (M+1).
Example 124
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-N-{1-[2-(2-et-
hoxy-ethylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-propionamide
[0536]
(2-Ethoxy-ethyl)-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-amine
was reduced and then coupled with
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propionic
acid to afford the title compound: MS 464.6 m/z (M+1).
[0537] The following Examples were prepared by methods analogous to
those described above for General Procedure A, method F
Example 125
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{2-[(1-hydroxy-cyclohexylmethyl)-carbamoyl]-1,1-dimethyl-ethyl}-1-
H-imidazol-4-yl)-amide
[0538]
3-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pent-
anoylamino]-imidazol-1-yl}-3-methyl-butyric acid was coupled with
the appropriate amine to afford the title compound: MS 560.5 m/z
(M+1).
Example 126
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1-[(1-hydroxy-cyclohexylmethyl)-carbamoyl]-1-methyl-ethyl}-1H-im-
idazol-4-yl)-amide
[0539]
2-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pent-
anoylamino]-imidazol-1-yl}-2-methyl-propionic acid was coupled with
the appropriate amine to afford the title compound: MS 546.6 m/z
(M+1).
Example 127
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1-methyl-1-[(tetrahydro-pyran-4-ylmethyl)-carbamoyl]-ethyl}-1H-i-
midazol-4-yl)-amide
[0540]
2-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pent-
anoylamino]-imidazol-1-yl}-2-methyl-propionic acid was coupled with
the appropriate amine to afford the title compound: MS 532.6 m/z
(M+1).
Example 128
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[1-methyl-1-(2-methyl-benzylcarbamoyl)-ethyl]-1H-imidazol-4-yl}-a-
mide
[0541]
2-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pent-
anoylamino]-imidazol-1-yl}-2-methyl-propionic acid was coupled with
the appropriate amine to afford the title compound: MS 538.52 m/z
(M+1).
Example 129
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[1-(2-methoxy-1-methyl-ethylcarbamoyl)-1-methyl-ethyl]-1H-imidazo-
l-4-yl}-amide
[0542]
2-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pent-
anoylamino]-imidazol-1-yl}-2-methyl-propionic acid was coupled with
the appropriate amine to afford the title compound: MS 505.9 m/z
(M+1).
[0543] The following Examples were prepared by methods analogous to
those described above for General Procedure O;
Example 129a
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-}1-methyl-2-[(tetrahydro-pyran-4-ylmethyl)-amino]-ethyl}-1H-imida-
zol-4-yl)-amide
[0544] Methanesulfonic acid
2-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester was reacted with appropriate
amine to afford the title compound: MS 504.6 m/z (M+1); The
diastereomers were separated using Chiral HPLC conditions (OD-H
column (2.1.times.250 cm); 10 mL/min; 95/5 Heptane/EtOH+0.2%
DEA)
Example 130
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{2-[(1-hydroxy-cyclohexylmethyl)-amino]-ethyl}-1H-imidazol-4-yl)--
amide
[0545] Methanesulfonic acid
2-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-ethyl ester was reacted with the appropriate
amine to afford the title: MS 504.6 m/z (M+1).
Example 131
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{2-[(4-hydroxy-tetrahydro-pyran-4-ylmethyl)-amino]-ethyl}-1H-imid-
azol-4-yl)-amide
[0546] Methanesulfonic acid
2-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-ethyl ester was reacted with the appropriate
amine to afford the title: MS 506.6 m/z (M+1).
Example 132
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{2-[(tetrahydro-pyran-4-ylmethyl)-amino]-ethyl}-1H-imidazol-4-yl)-
-amide
[0547] Methanesulfonic acid
2-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-ethyl ester was reacted with the appropriate
amine to afford the title: 490.5 m/z (M+1).
Example 133
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{2-[(3-methyl-oxetan-3-ylmethyl)-amino]-ethyl}-1H-imidazol-4-yl)--
amide
[0548] Methanesulfonic acid
2-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-ethyl ester was reacted with the appropriate
amine to afford the title: 476.6 m/z (M+1).
Example 133A
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{2-[(1-hydroxy-cyclohexylmethyl)-amino]-1-methyl-ethyl}-1H-imidaz-
ol-4-yl)-amide
[0549] Methanesulfonic acid
2-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester was reacted with the appropriate
amine to afford the title: 518.3 m/z (M+1).
Example 134
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid {1-[2-(2-ethoxy-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide
[0550] Methanesulfonic acid
2-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-ethyl ester was reacted with the appropriate
amine to afford the title: 464.6 m/z (M+1).
Example 135
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid [1-(3-benzylamino-propyl)-1H-imidazol-4-yl]-amide
[0551] Methanesulfonic acid
3-{4-[2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoyla-
mino]-imidazol-1-yl}-propyl ester was reacted with the appropriate
amine to afford the title: 496.3 m/z (M+1);
[0552] The following Examples were prepared by methods analogous to
those described above for General Procedure B;
Example 136
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1,1-dimethyl-3-[(pyridin-2-ylmethyl)-amino]-propyl}-1H-imidazol--
4-yl)-amide
[0553] 2-Amino-pentanoic acid
(1-{1,1-dimethyl-3-[(pyridin-2-ylmethyl)-amino]-propyl}-1H-imidazol-4-yl)-
-amide was reacted with
6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to afford the title:
525.5 m/z (M+1).
Example 137
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[1,1-dimethyl-3-((S)-2,2,2-trifluoro-1-phenyl-ethylamino)-propyl]-
-1H-imidazol-4-yl}-amide
[0554] 2-Amino-pentanoic acid
{1-[1,1-dimethyl-3-(2,2,2-trifluoro-1-phenyl-ethylamino)-propyl]-1H-imida-
zol-4-yl}-amide 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to
afford the title: 592.3 m/z (M+1).
Example 138
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{1-[1,1-dimethyl-3-((R)-1-phenyl-ethylamino)-propyl]-1H-imidazol-4-y-
l}-amide
[0555] 2-Amino-pentanoic acid
{1-[1,1-dimethyl-3-(1-phenyl-ethylamino)-propyl]-1H-imidazol-4-yl}-amide
was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to
afford the title: 538.6 m/z (M+1).
Example 139
(S)-2-(2-Trifluoromethyl-benzylamino)-pentanoic acid
{1-[2-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imidaz-
ol-4-yl}-amide
[0556] 2-Amino-pentanoic acid
{1-[2-(2,6-dimethyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-
-amide was reacted with the appropriate aldehyde to afford the
title compound: 510.5 m/z (M+1).
Example 140
(S)-2-{[(2-Fluoro-3-trifluoromethyl-phenyl)methyl]-amino}-pentanoic
acid
{1-[2-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imidaz-
ol-4-yl}-amide
[0557] 2-Amino-pentanoic acid
{1-[2-(2,6-dimethyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-
-amide was reacted with the appropriate aldehyde to afford the
title compound: 528.6 m/z (M+1).
[0558] The following Examples were prepared by methods analogous to
those described above for the reduction of the appropriate
nitroimdiazole using General Method G followed by coupling to the
appropriate acid using General Procedure A, method F.
Example 140a
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[1-(1,1-dimethyl-2-pyrrolidi-
n-1-yl-ethyl)-1H-imidazol-4-yl]-2-phenyl-acetamide
[0559]
1-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)-4-nitro-1H-imidazole
(U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was reduced and
coupled with (S)-2-(2-(3,5-difluorophenyl)acetamido)-2-phenylacetic
acid to afford the title compound: MS 496 m/z (M+1).
Example 141
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-{1-[2-((2S,6R)-2,6-dimethyl--
morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-2-phenyl-acetamide
[0560]
2,6-Dimethyl-4-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-morpholi-
ne (U.S. Ser. No.
[0561] 11/078,898 filed Mar. 11, 2005) was reduced and coupled with
(S)-2-(2-(3,5-difluorophenyl)acetamido)-2-phenylacetic acid to
afford the title compound: MS 540 m/z (M+1).
Example 142
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-N-{1-[2-(2,2--
dimethyl-propylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-2-phenyl-aceta-
mide
[0562]
2-methyl-N-neopentyl-2-(4-nitro-1H-imidazol-1-yl)propan-1-amine
(U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was reduced and
coupled with
(S)-2-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-2-phenyl-
acetic acid to afford the title compound: MS 524 m/z (M+1).
Example 143
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1-indan-1-yl-1H-imidazol-4-yl)-amide
[0563] 1-(2,3-dihydro-1H-inden-1-yl)-4-nitro-1H-imidazole was
reduced and coupled with
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S.
Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title
compound: MS 453 m/z (M+1).
Example 144
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[(S)-1-((1S,2R)-2-hydroxy-indan-1-yl)-1H-imidazol-4-yl]-amide
[0564]
(1S,2R)-2,3-dihydro-1-(4-nitro-1H-imidazol-1-yl)-1H-inden-2-ol was
reduced and coupled with
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S.
Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title
compound: MS 469 m/z (M+1).
Example 145
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[(R)-1-((1R,2S)-2-hydroxy-indan-1-yl)-1H-imidazol-4-yl]-amide
[0565]
(1R,2S)-2,3-dihydro-1-(4-nitro-1H-imidazol-1-yl)-1H-inden-2-ol was
reduced and coupled with
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S.
Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title
compound: MS 469 m/z (M+1).
Example 146
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[1-(4-fluoro-phenyl)-2-hydroxy-ethyl]-1H-imidazol-4-yl}-amide
[0566] 2-(4-amino-1H-imidazol-1-yl)-2-(4-fluorophenyl)ethanol was
reduced and coupled with
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S.
Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title
compound: MS 475 m/z (M+1).
Example 147
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{(R)-1-[(R)-1-(4-fluoro-phenyl)-2-hydroxy-ethyl]-1H-imidazol-4-yl}-amide
[0567] (R)-2-(4-amino-1H-imidazol-1-yl)-2-(4-fluorophenyl)ethanol
was reduced and coupled with
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S.
Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title
compound: MS 475 m/z (M+1).
Example 148
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(2-hydroxymethyl-phenyl)-1H-imidazol-4-yl]-amide
[0568] (2-(4-nitro-1H-imidazol-1-yl)phenyl)methanol was reduced and
coupled with (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic
acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the
title compound: MS 443 m/z (M+1).
Example 149
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-{1-[2-(2,2-dimethyl-propylam-
ino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-2-phenyl-acetamide
[0569]
2-methyl-N-neopentyl-2-(4-nitro-1H-imidazol-1-yl)propan-1-amine
(U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was reduced and
coupled with (S)-2-(2-(3,5-difluorophenyl)acetamido)-2-phenylacetic
acid to afford the title compound: MS 512 m/z (M+1).
Example 150
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{(S)-1-[2-2,2-dimethyl-propylamino)-1-phenyl-ethyl]-1H-imidazol-4-yl-
}-amide
[0570]
(S)-2,2-dimethyl-N-(2-(4-nitro-1H-imidazol-1-yl)-2-phenylethyl)prop-
an-1-amine was reduced and coupled with
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the
title compound: MS 538 m/z (M+1).
Example 151
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
{(S)-1-[2-(2,2-dimethyl-propylamino)-1-phenyl-ethyl]-1H-imidazol-4-y-
l}-amide
[0571]
(R)-2,2-dimethyl-N-(2-(4-nitro-1H-imidazol-1-yl)-2-phenylethyl)prop-
an-1-amine was reduced and coupled with
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the
title compound: MS 538 m/z (M+1).
Example 152
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-{1-[2-(2,2-dimethyl-propylamino)-
-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-2-(4-fluoro-phenyl)-acetamide
[0572]
2-methyl-N-neopentyl-2-(4-nitro-1H-imidazol-1-yl)propan-1-amine
(U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was reduced and
coupled with
(S)-2-(2-(3,5-difluorophenyl)acetamido)-2-(4-fluorophenyl)acetic
acid to afford the title compound: MS 530 m/z (M+1).
Example 153
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-{1-[2-(2,2-dimethyl-propylamino)-
-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-2-pyridin-3-yl-acetamide
[0573]
2-methyl-N-neopentyl-2-(4-nitro-1H-imidazol-1-yl)propan-1-amine
(U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was reduced and
coupled with
(S)-2-(2-(3,5-difluorophenyl)acetamido)-2-(pyridin-3-yl)acetic acid
to afford the title compound: MS 513 m/z (M+1).
[0574] The following Examples were prepared by methods analogous to
those described using General Method B
Example 154
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{2-[(2,2-dimethyl-propylamino)-methyl]-phenyl}-1H-imidazol-4-yl)--
amide
[0575]
(2S)-2-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-N-(1-(-
2-formylphenyl)-1H-imidazol-4-yl)pentanamide was treated with the
appropriate amine to afford the title compound: MS 524 m/z
(M+1).
Example 155
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{2-[(2-hydroxy-butylamino)-methyl]-phenyl}-1H-imidazol-4-yl)-amid-
e
[0576]
(2S)-2-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-N-(1-(-
2-formylphenyl)-1H-imidazol-4-yl)pentanamide was treated with the
appropriate amine to afford the title compound: MS 526 m/z
(M+1).
[0577] The following Examples were prepared by methods analogous to
those described above.
TABLE-US-00001 MS or NMR Ex Structure data IUPACNAME 156
##STR00020## M + 1 = 532.6 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[(1- hydroxycyclohexyl)methyl]
amino}-11-dimethylethyl)- 1H-imidazol-4-yl]-L- norvalinamide 157
##STR00021## M + 1 = 488.5 N-2-[(3,5- difluorophenyl)acetyl]-N-{1-
[1-(piperidin-1- ylmethyl)cyclobutyl]-1H- imidazol-4-yl}-L-
norvalinamide 158 ##STR00022## M + 1 = 486.5
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[1-(pyrrolidin-1- ylmethyl)cyclobutyl]-1H- imidazol-4-yl}-L-
norvalinamide 159 ##STR00023## M + 1 = 490.1 N-2-[(3,5-
difluorophenyi)acetyl]-N-[1- (1-{[(2,2-dimethyl-
propyl)amino]methyl} cyclobutyl)-1H-imidazol- 4-yl]-L-norvalinamide
160 ##STR00024## M + 1 = 490.1 N-2-[(3,5-
difluorophenyl)acetyl]-N-[1- (1-{[(2,2-dimethylpropyl)
amino]methyl}cyclobutyl)- 1H-imidazol-4-yl]-L- norvalinamide 161
##STR00025## M + 1 = 502.6 N-2-[(2S)-6,8-difluoro-
1,2,3,4-tetrahydronaphthalen- 2-yl]-N-[1-(1-{[(22-
dimethylpropyl)amino] methyl}cyclobutyl)-1H- imidazol-4-yl]-L-
norvalinamide 162 ##STR00026## M + 1 = 538.26
N-2-[(2S)-6,8-difluoro- 1,2,3,4-tetrahydronaphthalen-
2-yl]-N-(1-{1,1-dimethyl-2- [(2-methylbenzyl)amino]-2-
oxoethyl}-1H-imidazol-4-yl)- L-norvalinamide 163 ##STR00027## M + 1
= 504.1 N-2-[(2S)-6,8-difluoro- 1,2,3,4-tetrahydronaphthalen-
2-yl]-N-(1-{1-methyl-2- [(tetrahydro-2H-pyran-4-
ylmethyl)amino]ethyl}-1H- imidazol-4-yl)-L- norvalinamide 164
##STR00028## M + 1 = 506.52 N-2-[(2S)-6,8-difluoro-
1,2,3,4-tetrahydronaphthalen- 2-yl]-N-(1-{2-[(3-
methoxypropyl)amino]-1,1- dimethyl-2-oxoethyl}-1H-
imidazol-4-yl)-L- norvalinamide 165 ##STR00029## M + 1 = 526.64
N-2-[(2S)-6,8-difluoro- 1,2,3,4-tetrahydronaphthalen-
2-yl]-N-[1-(2-{[(2- hydroxybutyl)amino]methyl}
phenyl)-1H-imidazol-4-yl]-L- norvalinamide 166 ##STR00030## M + 1 =
518.5 tert-butyl 3-{[4-({N-[(2S)- 6,8-difluoro-1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalyl}amino)-1H- imidazol-1-
yl]methyl}azetidine-1- carboxylate 167 ##STR00031## M + 1 = 488.5
N-2-[(2S)-6,8-difluoro- 1,2,3,4-tetrahydronaphthalen-
2-yl]-N-(1-{[1-(2,2- dimethylpropyl)azetidin-3-
yl]methyl}-1H-imidazol-4- yl)-L-norvalinamide 168 ##STR00032## M +
1 = 538.65 2-[4-({(2S)-2-[(6,8-difluoro-
1,2,3,4-tetrahydronaphthalen- 2-yl)amino]-2-
phenylacetyl}amino)-1H- imidazol-1-yl]-N-(2,2- dimethylpropyl)-2-
methylpropanamide 169 ##STR00033## M + 1 = 593.09
N-(2-chlorobenzyl)-2-[4- ({(2S)-2-[(6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2- yl)amino]-2- phenylacetyl}amino)-1H-
imidazol-1-yl]-2- methylpropanamide 170 ##STR00034## M + 1 = 584.68
2-[4-({(2S)-2-[(6,8-difluoro- 1,2,3.4- tetrahydronaphthalen-2-
yl)amino]-2- phenylacetyl}amino)-1H- imidazol-1-yl]-N-(2,3-
dihydro-1H-inden-1-yl)-2- methylpropanamide 171 ##STR00035## M + 1
= 578.72 N-[(1R)-1-cyclohexylethyl]- 2-[4-({(2S)-2-[(6,8-difluoro-
1,2,3,4- tetrahydronaphthalen-2- yl)amino]-2-
phenylacetyl}amino)-1H- imidazol-1-yl]-2- methylpropanamide 172
##STR00036## M + 1 = 550.66 (2S)-2-[(6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2- yl)amino]-N-{1-[11- dimethyl-2-(3-
methylpiperidin-1-yl)-2- oxoethyl]-1H-imidazol-4-yl}-
2-phenylacetamide 173 ##STR00037## M + 1 = 564.69
2-[4-({(2S)-2-[(6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-
yl)amino]-2- phenylacetyl}amino)-1H- imidazol-1-yl]-2-methyl-N-
(2-methylcyclohexyl) propanamide 174 ##STR00038## M + 1 = 550.66
(2S)-2-[(6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-
yl)amino]-N-{1-[1,1- dimethyl-2-(2- methylpiperidin-1-yl)-2-
oxoethyl]-1H-imidazol-4-yl}- 2-phenylacetamide 175 ##STR00039## M +
1 = 548.65 (2S)-N-(1-{2-[(1R,4S)-2- azabicyclo[2.2.1]hept-2-yl]-
11-dimethyl-2-oxoethyl}-1H- imidazol-4-yl)-2-[(6,8-
difluoro-1,2,3,4- tetrahydronaphthalen-2- yl)amino]-2-
phenylacetamide 176 ##STR00040## M + 1 = 552.64
2-[4-({(2S)-2-[(6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-
yl)amino]-2- phenylacetyl}amino)-1H- imidazol-1-yl]-2-methyl-N-
(tetrahydro-2H-pyran-4- yl)propanamide 177 ##STR00041## M + 1 =
598.71 (2S)-2-[(6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-
yl)amino]-N-{1-[1,1- dimethyl-2-oxo-2-(3-
phenylpyrrolidin-1-yl)ethyl]- 1H-imidazol-4-yl}-2- phenylacetamide
178 ##STR00042## M + 1 = 594.62 N-(3,4-difluorobenzyl)-2-[4-
({(2S)-2-[(6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-
yl)amino]-2- phenylacetyl}amino)-1H- imidazol-1-yl]-2-
methylpropanamide 179 ##STR00043## M + 1 = 522.61
(2S)-2-[(6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-
yl)amino]-N-[1-(1,1- dimethyl-2-oxo-2-pyrrolidin-
1-ylethyl)-1H-imidazol-4-yl]- 2-phenylacetamide 180 ##STR00044## M
+ 1 = 538.65 2-[4-({(2S)-2-[(6,8-difiuoro- 1,2,3,4-
tetrahydronaphthalen-2- yl)amino]-2- phenylacetyl}amino)-1H-
imidazol-1-yl]-N-(2,2- dimethylpropyl)-2- methylpropanamide 181
##STR00045## M + 1 = 550.66 N-cyclohexyl-2-[4-({(2S)-2-
[(6,8-difluoro-1,2,3,4- tetrahydronaphthalen-2- yl)amino]-2-
phenylacetyl}amino)-1H- imidazol-1-yl]-2- methylpropanamide 182
##STR00046## M + 1 = 572.67 2-[4-({(2S)-2-[(6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2- yl)amino]-2- phenylacetyl}amino)-1H-
imidazol-1-yl]-2-methyl-N- (2-methylbenzyl)propanamide 183
##STR00047## M + 1 = 562.67 (2S)-N-(1-{2-[(1S5R)-6-
azabicyclo[3.2.1]oct-6-yl]- 11-dimethyl-2-oxoethyl}-1H-
imidazol-4-yl)-2-[(6,8- difluoro-1,2,3,4- tetrahydronaphthalen-2-
yl)amino]-2- phenylacetamide 184 ##STR00048## M + 1 = 594.62
N-(2,4-difluorobenzyl)-2-[4- ({(2S)-2-[(6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2- yl)amino]-2- phenylacetyl}amino)-1H-
imidazol-1-yl]-2- methylpropanamide 185 ##STR00049## M + 1 = 599.69
(2S)-2-[(6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-
yl)amino]-N-{1-[1,1- dimethyl-2-oxo-2-(3-pyridin-
4-ylpyrrolidin-1-yl)ethyl]-1H- imidazol-4-yl}-2- phenylacetamide
186 ##STR00050## M + 1 = 564.69 2-[4-({(2S)-2-[(6,8-difluoro-
1,2,3,4- tetrahydronaphthalen-2- yl)amino]-2-
phenylacetyl}amino)-1H- imidazol-1-yl]-2-methyl-N-
(4-methylcyclohexyl) propanamide 187 ##STR00051## M + 1 = 606.77
2-[4-({(2S)-2-[(6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-
yl)amino]-2- phenylacetyl}amino)-1H- imidazol-1-yl]-2-methyl-N-
(3,3,5,5-tetramethyl- cyclohexyl)propanamide 188 ##STR00052## M + 1
= 540.04 N-2-(6,8-difluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-
N-(1-{1,1-dimethyl-2-[(2- methylbenzyl)amino]-2-
oxoethyl}-1H-imidazol-4-yl)- O-methyl-L-serinamide 189 ##STR00053##
M + 1 = 502.5 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{[1-(2,2-
dimethylpropyl)pyrrolidin-2- yl]methyl}-1H-imidazol-4-
yl)-L-norvalinamide 190 ##STR00054## M + 1 = 516.5
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-(1-{[1-(2,2- dimethylpropanoyl)pyrrolidin-
2-yl]methyl}-1H-imidazol-4- yl)-L-norvalinamide 191 ##STR00055## M
+ 1 = 516.4 (2S)-2-{[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2- yl]amino}-N-{1-[1-(2,2- dimethylpropyl)-2-
oxopiperidin-3-yl]-1H- imidazol-4-yl}pentanamide 192 ##STR00056## M
+ 1 = 536.3 (2S)-N-[1-(1-benzyl-2- oxopiperidin-3-yl)-1H-
imidazol-4-yl]-2-{[(2S)-6,8- difluoro-1,2,3,4-
tetrahydronaphthalen-2- yl]amino}pentanamide 193 ##STR00057## M + 1
= 488.4 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{[(2S)-1-(2,2-
dimethylpropyl)azetidin-2- yl]methyl}-1H-imidazol-4-
yl)-L-norvalinamide 194 ##STR00058## M + 1 = 490.3
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-[1-({(2S)-1-[(2S)-2- hydroxybutyl]azetidin-2-
yl}methyl)-1H-imidazol-4- yl]-L-norvalinamide 195 ##STR00059## M +
1 = 534.4 tert-butyl 3-{[4-({N-[(2S)- 6,8-difluoro-1,2,3,4-
tetrahydronaphthalen-2-yl]-L- norvalyl}amino)-1H-imidazol-
1-yl]methyl}-3- hydroxyazetidine-1- carboxylate 196 ##STR00060## M
+ 1 = 504.4 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{[1-(2,2- dimethylpropyl)-3-
hydroxyazetidin-3- yl]methyl}-1H-imidazol-4- yl)-L-norvalinamide
197 ##STR00061## M + 1 = 621.83 N-{1-[(3S,4R)-1-benzyl-4-
{2-[(2,2-dimethylpropyl) amino]ethyl}pyrrolidin-3-
yl]-1H-imidazol-4-yl}-N-2- [(2S)-6,8-difluoro-1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalinamide 198 ##STR00062## M + 1
= 560.65 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[(2,2- dimethylpropyl)amino]
methyl}-45-difluorophenyl)- 1H-imidazol-4-yl]-L- norvalinamide 199
##STR00063## M + 1 = 579.7 N-{1-[2-({3- [acetyl(methyl)amino]
pyrrolidin-1-yl}methyl) phenyl]-1H-imidazol-4-yl}-
N-2-[(2S)-6,8-difluoro- 1,2,3,4-tetrahydronaphthalen-
2-yl]-L-norvalinamide 200 ##STR00064## M + 1 = 628.78
N-{1-[2-({[(1R,2R)-2- (benzyloxy)cyclopentyl]
amino}methyl)phenyl]-1H- imidazol-4-yl}-N-2-[(2S)-
6,8-difluoro-1,2,3,4- tetrahydronaphthalen-2-yl]- L-norvalinamide
201 ##STR00065## M + 1 = 579.7 N-(1-{2-[(4-acetyl-1,4- diazepan-1-
yl)methyl]phenyl}-1H- imidazol-4-yl)-N-2-[(2S)-
6,8-difluoro-1,2,3,4- tetrahydronaphthalen-2-yl]- L-norvalinamide
202 ##STR00066## M + 1 = 581.72 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[2-({[2-(3- hydroxypiperidin-1-
yl)ethyl]amino}methyl) phenyl]-1H-imidazol-4-yl}- L-norvalinamide
203 ##STR00067## M + 1 = 579.75 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[2-({[(1-ethylpiperidin-
3-yl)methyl]amino}methyl) phenyl]-1H-imidazol-4-yl}-
L-norvalinamide 204 ##STR00068## M + 1 = 565.68 N-{1-[2-({[(3R)-1-
acetylpyrrolidin-3- yl]amino}methyl)phenyl]-
1H-imidazol-4-yl}-N-2-[(2S)- 6,8-difluoro-1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalinamide 205 ##STR00069## M + 1
= 551.69 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-[(4-ethylpiperazin-1-
yl)methyl]phenyl}-1H- imidazol-4-yl)-L- norvalinamide 206
##STR00070## M + 1 = 586.7 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[2-({[(1S,2R)-2-
hydroxy-2,3-dihydro-1H- inden-1-yl]amino}methyl)
phenyl]-1H-imidazol-4-yl}- L-norvalinamide 207 ##STR00071## M + 1 =
524.63 N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-(morpholin-4- ylmethyl)phenyl]-1H- imidazol-4-yl}-L-
norvalinamide 208 ##STR00072## M + 1 = 567.69
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-[1-(2-{[(2-morpholin-4- ylethyl)amino]methyl}
phenyl)-1H-imidazol-4-yl]-L- norvalinamide 209 ##STR00073## M + 1 =
581.68 N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[2-(2-oxo-1,3- oxazinan-3- yl)ethyl]amino}methyl)
phenyl]-1H-imidazol-4-yl}- L-norvalinamide 210 ##STR00074## M + 1 =
520.64 N-(1-{2-[(bicyclo[1.1.1]pent- 1-ylamino)methyl]phenyl}-
1H-imidazol-4-yl)-N-2-[(2S)- 6,8-difluoro-1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalinamide 211 ##STR00075## M + 1
= 540.67 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[(2-
propoxyethyl)amino]methyl} phenyl)-1H-imidazol-4-yl]-L-
norvalinamide 212 ##STR00076## M + 1 = 621.78
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[(1- isobutyrylpiperidin-3- yl)methyl]amino}methyl)
phenyl]-1H-imidazol-4-yl}- L-norvalinamide 213 ##STR00077## M + 1 =
642.8 N-{1-[2-({[(1R,2R)-2- (benzyloxy)cyclohexyl]
amino}methyl)phenyl]-1H- imidazol-4-yl}-N-2-[(2S)-
6,8-difluoro-1,2,3,4- tetrahydronaphthalen-2-yl]- L-norvalinamide
214 ##STR00078## M + 1 = 539.64 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[2-({[2- (dimethylamino)-2-
oxoethyl]amino}methyl) phenyl]-1H-imidazol-4-yl}- L-norvalinamide
215 ##STR00079## M + 1 = 556.67 N-2-[(2S)-6,8-difluoro-
1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[2-(2,3-dihydro-1H-
indol-1-ylmethyl)phenyl]- 1H-imidazol-4-yl}-L- norvalinamide 216
##STR00080## M + 1 = 580.64 N-[1-(2-{[(2,4- difluorobenzyl)amino]
methyl}phenyl)-1H-imidazol- 4-yl]-N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalinamide 217 ##STR00081## M + 1
= 592.67 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[2-({[2-(2-
fluorophenoxy)ethyl]amino} methyl)phenyl]-1H- imidazol-4-yl}-L-
norvalinamide 218 ##STR00082## M + 1 = 553.71 N-{1-[2-({[2-
(diethylamino)ethyl]amino} methyl)phenyl]-1H-
imidazol-4-yl}-N-2-[(2S)- 6,8-difluoro-1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalinamide 219 ##STR00083## M + 1
= 567.65 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[2-({[2-(2-oxo-1,3- oxazolidin-3-
yl)ethyl]amino}methyl) phenyl]-1H-imidazol-4-yl}- L-norvalinamide
220 ##STR00084## M + 1 = 566.67 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[2-({[2-(2- oxoimidazolidin-1-
yl)ethyl]amino}methyl) phenyl]-1H-imidazol-4-yl}- L-norvalinamide
221 ##STR00085## M + 1 = 562.68 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[2-({[2-(3-methyl-1H-
pyrazol-1-yl)ethyl]amino} methyl)phenyl]-1H-imidazol-
4-yl}-L-norvalinamide 222 ##STR00086## M + 1 = 554.69
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[1- (hydroxymethyl)pentyl] amino}methyl)phenyl]-1H-
imidazol-4-yl}-L- norvalinamide 223 ##STR00087## M + 1 = 540.67
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-[1-(2-{[(2- isopropoxyethyl)amino] methyl}phenyl)-1H-
imidazol-4-yl]-L- norvalinamide 224 ##STR00088## M + 1 = 526.64
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[(1R)-1- (hydroxymethyl)propyl] amino}methyl)phenyl]-1H-
imidazol-4-yl}-L- norvalinamide 225 ##STR00089## M + 1 = 623.16
N-{1-[2-({[1-(4- chlorobenzyl)-2- hydroxyethyl]amino}methyl)
phenyl]-1H-imidazol-4-yl}- N-2-[(2S)-6,8-dlfluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalinamide 226 ##STR00090## M + 1
= 565.72 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[2-({[(1,3- dimethylpyrrolidin-3-
yl)methyl]amino}methyl) phenyl]-1H-imidazol-4-yl}- L-norvalinamide
227 ##STR00091## M + 1 = 565.72 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[2-({[(1,3- dimethylpyrrolidin-3-
yl)methyl]amino}methyl) phenyl]-1H-imidazol-4-yl}- L-norvalinamide
228 ##STR00092## M + 1 = 565.68 N-(1-{2-[(4-acetylpiperazin-
1-yl)methyl]phenyl}-1H- imidazol-4-yl)-N-2-[(2S)-
6,8-difluoro-1,2,3,4- tetrahydronaphthalen-2-yl]- L-norvalinamide
229 ##STR00093## M + 1 = 607.76 N-{1-[2-({[(1-tert-butyl-5-
oxopyrrolidin-3- yl)methyl]amino}methyl) phenyl]-1H-imidazol-4-yl}-
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
L-norvalinamide 230 ##STR00094## M + 1 = 512.61
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-[1-(2-{[(2- methoxyethyl)amino]methyl} phenyl)-1H-imidazol-4-yl]-
L-norvalinamide 231 ##STR00095## M + 1 = 526.64
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-[1-(2-{[(2- ethoxyethyl)amino]methyl}
phenyl)-1H-imidazol-4-yl]-L- norvalinamide 232 ##STR00096## M + 1 =
581.76 N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[2- (diisopropylamino)ethyl] amino}methyl)phenyl]-1H-
imidazol-4-yl}-L- norvalinamide 233 ##STR00097## M + 1 = 562.68
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[3-(1H-imidazol- 1-yl)propyl]amino}methyl)
phenyl]-1H-imidazol-4-yl}- L-norvalinamide 234 ##STR00098## M + 1 =
554.69 N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[(1S)-1- (hydroxymethyl)-2,2- dimethylpropyl]amino}
methyl)phenyl]-1H-imidazol- 4-yl}-L-norvalinamide 235 ##STR00099##
M + 1 = 539.64 N-2-[(2S)-6,8-difluoro- 1,23,4-
tetrahydronaphthalen-2-yl]- N-{1-[2-({[(1S)-1-methyl-2-
(methylamino)-2- oxoethyl]amino}methyl) phenyl]-1H-imidazol-4-yl}-
L-norvalinamide 236 ##STR00100## M + 1 = 539.68
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[2- (dimethylamino)-1- methylethyl]amino}methyl)
phenyl]-1H-imidazol-4-yl}- L-norvalinamide 237 ##STR00101## M + 1 =
575.68 N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-(1-{2-[(3-methyl-5,6- dihydro[1,2,4]triazolo[4,3-
a]pyrazin-7(8H)- yl)methyl]phenyl}-1H- imidazol-4-yl)-L-
norvalinamide 238 ##STR00102## M + 1 = 550.62
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[(3-methyl-1,2,4- oxadiazol-5- yl)methyl]amino}methyl)
phenyl]-1H-imidazol-4-yl}- L-norvalinamide 239 ##STR00103## M + 1 =
574.68 N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-[-(2-{[(2- phenoxyethyl)amino]methyl} phenyl)-1H-imidazol-4-yl]-
L-norvalinamide 240 ##STR00104## M + 1 = 551.69
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-[1-(2-{[methyl(1- methylpyrrolidin-3- yl)amino]methyl}phenyl)-
1H-imidazol-4-yl]-L- norvalinamide 241 ##STR00105## M + 1 = 536.56
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-[1-(2-{[(2,2,2- trifluoroethyl)amino]methyl}
phenyl)-1H-imidazol-4-yl]-L- norvalinamide 242 ##STR00106## M + 1 =
554.69 N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[(1S,2S)-1- (hydroxymethyl)-2- methylbutyl]amino}methyl)
phenyl]-1H-imidazol-4-yl}- L-norvalinamide 243 ##STR00107## M + 1 =
565.68 N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[2-(2- oxopyrrolidin-1- yl)ethyl]amino}methyl)
phenyl]-1H-imidazol-4-yl}- L-norvalinamide 244 ##STR00108## M + 1 =
570.7 N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-(1-{2-[(2,3-dihydro-1H- inden-2- ylamino)methyl]phenyl]-1H-
imidazol-4-yl)-L- norvalinamide 245 ##STR00109## M + 1 = 539.64
N-{1-[2-({[2- (acetylamino)ethyl]amino} methyl)phenyl]-1H-imidazol-
4-yl}-N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
L-norvalinamide 246 ##STR00110## M + 1 = 525.66
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[2- (dimethylamino)ethyl]amino} methyl)phenyl]-1H-
imidazol-4-yl}-L- norvalinamide 247 ##STR00111## M + 1 = 588.71
N-{1-[2-({[(1R)-1-benzyl-2- hydroxyethyl]amino}methyl)
phenyl]-1H-imidazol-4-yl}- N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalinamide 248 ##STR00112## M + 1
= 550.71 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[(2- methylcyclohexyl)amino]
methyl}phenyl)-1H-imidazol- 4-yl]-L-norvalinamide 249 ##STR00113##
M + 1 = 540.67 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[2-({[(1S)-1- (hydroxymethyl)-2-
methylpropyl]amino}methyl) phenyl]-1H-imidazol-4-yl}-
L-norvalinamide 250 ##STR00114## M + 1 = 508.63
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-(pyrrolidin-1- ylmethyl)phenyl]-1H- imidazol-4-yl}-L-
norvalinamide 251 ##STR00115## M + 1 = 618.74
N-{1-[2-({[3-(benzyloxy)-2- hydroxypropyl]amino}
methyl)phenyl]-1H-imidazol- 4-yl}-N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalinamide 252 ##STR00116## M + 1
= 604.71 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[(2-hydroxy-3-
phenoxypropyl)amino] methyl}phenyl)-1H-imidazol-
4-yl]-L-norvalinamide 253 ##STR00117## M + 1 = 510.64
N-(1-{2-[(tert- butylamino)methyl]phenyl}- 1H-imidazol-4-yl)-N~2~-
[(2S)-6,8-difluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-
L-norvalinamide 254 ##STR00118## M + 1 = 549.64
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[(5- methylisoxazol-3- yl)methyl]amino}methyl)
phenyl-1H-imidazol-4-yl}-L- norvalinamide 255 ##STR00119## M + 1 =
565.72 N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-(1-{2-[({[(2R)-1- ethylpyrrolidin-2- yl]methyl}amino)methyl]
phenyl}-1H-imidazol-4-yl)- L-norvalinamide 256 ##STR00120## M + 1 =
567.74 N-(1-{2-[({2- [butyl(methyl)amino]ethyl}
amino)methyl]phenyl}-1H- imidazol-4-yl)-N-2-[(2S)-
6,8-difluoro-1,2,3,4- tetrahydronaphthalen-2-yl]- L-norvalinamide
257 ##STR00121## M + 1 = 567.74 N-(1-{2-[({2-
[butyl(methyl)amino]ethyl} amino)methyl]phenyl}-1H-
imidazol-4-yl)-N-2-[(2S)- 6,8-difluoro-1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalinamide 258 ##STR00122## M + 1
= 492.58 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-[(prop-2-yn-1-
ylamino)methyl]phenyl}-1H- imidazol-4-yl)-L- norvalinamide 259
##STR00123## M + 1 = 563.66 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[2-({[(3-ethylisoxazol-
5-yl)methyl]amino}methyl) phenyl]-1H-imidazol-4-yl}-
L-norvalinamide 260 ##STR00124## M + 1 = 567.74 N-{1-[2-({[2-
(diethylamino)ethyl](methyl) amino}methyl)phenyl]-1H-
imidazol-4-yl}-N-2-[(2S)- 6,8-difluoro-1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalinamide 261 ##STR00125## M + 1
= 554.69 N-[1-(2-{[(2-tert- butoxyethyl)amino]methyl}
phenyl)-1H-imidazol-4-yl]-N- 2-[(2S)-6,8-difluoro-1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalinamide 262 ##STR00126## M + 1
= 565.72 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-[({[(2S)-1- ethylpyrrolidin-2-
yl]methyl]amino)methyl] phenyl}-1H-imidazol-4-yl)- L-norvalinamide
263 ##STR00127## M + 1 = 607.76 N-2-[(2S)-6,8-difluoro- 1,2,3.4-
tetrahydronaphthalen-2-yl]- N-{1-[2-({[1-(2,2- dimethylpropanoyl)
pyrrolidin-3- yl]amino}methyl)phenyl]- 1H-imidazol-4-yl}-L-
norvalinamide 264 ##STR00128## M + 1 = 540.67
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[1- (hydroxymethyl)butyl] amino}methyl)phenyl]-1H-
imidazol-4-yl}-L- norvalinamide 265 ##STR00129## M + 1 = 572.69
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-[1-(2-{[(1,1- dioxidotetrahydro-3- thienyl)amino]methyl}
phenyl)-1H-imidazol-4-yl]-L- norvalinamide 266 ##STR00130## M + 1 =
544.28 N-[1-(2-{[(1R)-1- cyclohexylethyl]amino}-1,1-
dimethyl-2-oxoethyl)-1H- imidazol-4-yl]-N-2-[(2S)-6,8-
difluoro-1,2,3,4- tetrahydronaphthalen-2-yl]- L-norvalinamide 267
##STR00131## M + 1 = 564.29 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[1,1-dimethyl-2-oxo-2-
(3-phenylpyrrolidin-1- yl)ethyl]-1H-imidazol-4-yl}- L-norvalinamide
268 ##STR00132## M + 1 = 528.25 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(1,1-dimethyl-2-{[(5- methyl-2-
furyl)methyl]amino}-2- oxoethyl)-1H-imidazol-4-yl]- L-norvalinamide
269 ##STR00133## M + 1 = 520.3 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[1- (methoxymethyl)propyl]
amino}-1,1-dimethyl-2- oxoethyl)-1H-imidazol-4-yl]- L-norvalinamide
270 ##STR00134## M + 1 = 520.28 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[1- (methoxymethyl)propyl]
amino}-1,1-dimethyl-2- oxoethyl)-1H-imidazol-4-yl]- L-norvalinamide
271 ##STR00135## M + 1 = 560.22 N-(1-{2-[(3,4-
difluorobenzyl)amino]-1,1- dimethyl-2-oxoethyl}-1H-
imidazol-4-yl)-N-2-[(2S)- 6,8-difluoro-1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalinamide 272 ##STR00136## M + 1
= 542.25 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-[(4- fluorobenzyl)amino]-1,1-
dimethyl-2-axoethyl}-1H- imidazol-4-yl)-L- norvalinamide 273
##STR00137## M + 1 = 528.28 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[2-(2- furyl)ethyl]amino}-1,1-
dimethyl-2-oxoethyl)-1H- imidazol-4-yl]-L- norvalinamide 274
##STR00138## M + 1 = 552.12 N-(1-{2-[benzyl(ethyl) amino]-1,1-
dimethyl-2-oxoethyl}-1H- imidazol-4-yl)-N-2-[(2S)-6,8-
difluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-L- norvalinamide
275 ##STR00139## M + 1 = 548.25 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(1,1-dimethyl-2-
{methyl[2-(1H-pyrazol-1- yl)ethyl]amino}-2-oxoethyl)-
1H-imidazol-4-yl]-L- norvalinamide 276 ##STR00140## M + 1 = 544.31
N-[1-(2-{[(1S)-1- cyclohexylethyl]amino}-1,1-
dimethyl-2-oxoethyl)-1H- imidazol-4-yl]-N-2-[(2S)-6,8-
difluoro-1,2,3,4- tetrahydronaphthalen-2-yl]- L-norvalinamide 277
##STR00141## M + 1 = 560.2 N-(1-{2-[(2,4-
difluorobenzyl)amino]-1,1- dimethyl-2-oxoethyl}-1H-
imidazol-4-yl)-N-2-[(2S)- 6,8-difluoro-1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalinamide 278 ##STR00142## M + 1
= 553.23 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{1,1-dimethyl-2-
[methyl(2-pyridin-2- ylethyl)amino]-2-oxoethyl}-
1H-imidazol-4-yl)-L- norvalinamide 279 ##STR00143## data not
available N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[(4- hydroxytetrahydro-2H-
thiopyran-4- yl)methyl]amino}ethyl)-1H- imidazol-4-yl]-L-
norvalinamide 280 ##STR00144## M + 1 = 464.2
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-(1-{2-[(2-methoxy-1- methylethyl)amino]ethyl}-
1H-imidazol-4-yl)-L- norvalinamide 281 ##STR00145## data not
available N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-[(2-methoxy-1-
methylethyl)amino]ethyl}- 1H-imidazol-4-yl)-L- norvalinamide 282
##STR00146## data not available N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-[(3- ethoxypropyl)amino]ethyl}-
1H-imidazol-4-yl)-L- norvalinamide 283 ##STR00147## M + 1 = 464.3
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-(1-{2-[(3- methoxypropyl)amino] ethyl}-1H-imidazol-4-yl)-L-
norvalinamide 284 ##STR00148## M + 1 = 478.3
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-(1-{2-[(2- isopropoxyethyl)amino] ethyl}-1H-imidazol-4-yl)-L-
norvalinamide 285 ##STR00149## data not available
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-(1-{2-[(2- isopropoxyethyl)amino] ethyl}-1H-imidazol-4-yl)-L-
norvalinamide 286 ##STR00150## M + 1 = 476.3
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-[1-(2-{[(2S)- tetrahydrofuran-2- ylmethyl]amino}ethyl)-1H-
imidazol-4-yl]-L- norvalinamide 287 ##STR00151## data not available
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-[1-(2-{[(2S)- tetrahydrofuran-2- ylmethyl]amino}ethyl)-1H-
imidazol-4-yl]-L- norvalinamide 288 ##STR00152## data not available
N-[1-(2-{[(1R)-1- cyclohexylethyl]amino}
ethyl)-1H-imidazol-4-yl]-N- 2-[(2S)-6,8-difluoro-1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalinamide 289 ##STR00153## data
not available N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-[(3- isopropoxypropyl)amino]
ethyl}-1H-imidazol-4-yl)- L-norvalinamide 290 ##STR00154## data not
available N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[2- (methylthio)ethyl]amino}
ethyl)-1H-imidazol-4-yl]-L- norvalinamide 291 ##STR00155## data not
available N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-[(tetrahydro-2H- pyran-3-
ylmethyl)amino]ethyl}-1H- imidazol-4-yl)-L- norvalinamide 292
##STR00156## data not available N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[(2R)- tetrahydrofuran-2-
ylmethyl]amino}ethyl)-1H- imidazol-4-yl]-L- norvalinamide 293
##STR00157## data not available N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-[(2- methoxyethyl)amino]ethyl}-
1H-imidazol-4-yl)-L- norvalinamide 294 ##STR00158## M + 1 = 504.4
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-[1-({1-[(2S)-2- hydroxybutyl]pyrrolidin-2-
yl}methyl)-1H-imidazol-4- yl]-L-norvalinamide 295 ##STR00159## M +
1 = 532.5 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{[1-(2,2- dimethylpropyl)-3-
hydroxypiperidin-3- yl]methyl}-1H-imidazol-4- yl)-L-norvalinamide
296 ##STR00160## M + 1 = 504.4 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-({1-[(2S)-2-
hydroxybutyl]pyrrolidin-2- yl}methyl)-1H-imidazol-4-
yl]-L-norvalinamide 297 ##STR00161## M + 1 = 601.7
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[(1,3- dimethylpyrrolidin-3- yl)methyl]amino}methyl)-
4,5-difluorophenyl]-1H- imidazol-4-yl}-L- norvalinamide 298*
##STR00162## M + 1 = 603.72 N-(1-{2-[({2-
[butyl(methyl)amino]ethyl} amino)methyl]-45- difluorophenyl}-1H-
imidazol-4-yl)-N-2-[(2S)- 6,8-difluoro-1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalinamide 299 ##STR00163## M + 1
= 502.3 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[1-(2,2- dimethylpropyl)-2-
oxopyrrolidin-3-yl]-1H- imidazol-4-yl}-L- norvalinamide 300
##STR00164## M + 1 = 478.3 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{(1S)-2-[(3-
methoxypropyl)amino]-1- methylethyl}-1H-imidazol-4-
yl)-L-norvalinamide 301 ##STR00165## M + 1 = 558.3
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[(1- hydroxycyclohexyl)methyl]
amino}carbonyl)cyclobutyl]- 1H-imidazol-4-yl}-L- norvalinamide 302
##STR00166## M + 1 = 572.29 N-[1-(2-{[(3,4- difluorobenzyl)amino]
carbonyl}cyclobutyl)-1H- imidazol-4-yl]-N-2-[(2S)-6,8-
difluoro-1,2,3,4- tetrahydronaphthalen-2-yl]- L-norvalinamide 303
##STR00167## M + 1 = 510.23 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-[(2- methylbenzyl)amino]-2-
oxoethyl}-1H-imidazol-4-yl)- L-norvalinamide 304 ##STR00168## M + 1
= 504.26 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-oxo-2-[(tetrahydro- 2H-pyran-2-
ylmethyl)amino]ethyl}-1H- imidazol-4-yl)-L- norvalinamide 305
##STR00169## M + 1 = 532.22 N-(1-{2-[(34- difluorobenzyl)amino]-2-
oxoethyl}-1H-imidazol-4-yl)- N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalinamide 306 ##STR00170## M + 1
= 516.29 N-[1-(2-{[(1S)-1- cyclohexylethyl]amino}-2-
oxoethyl)-1H-imidazol-4-yl]- N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- L-norvalinamide 307 ##STR00171## M + 1
= 514.22 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-[(4- fluorobenzyl)amino]-2-
oxoethyl}-1H-imidazol-4-yl)- L-norvalinamide 308 ##STR00172## M + 1
= 500.22 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[2-(2- furyl)ethyl]amino}-2-
oxoethyl)-1H-imidazol-4-yl]- L-norvalinamide 309 ##STR00173## M + 1
= 525.23 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-[methyl(2-pyridin-2-
ylethyl)amino]-2-oxoethyl}- 1H-imidazol-4-yl)-L- norvalinamide 310
##STR00174## M + 1 = 500.22 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[(5-methyl-2-
furyl)methyl]amino}-2- oxoethyl)-1H-imidazol-4-yl]- L-norvalinamide
311 ##STR00175## M + 1 = 532.21 N-(1-{2-[(24-
difluorobenzyl)amino]-2- oxoethyl}-1H-imidazol-4-yl)-
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
L-norvalinamide 312 ##STR00176## M + 1 = 516.3 N-[1-(2-{[(1R)-1-
cyclohexylethyl]amino}-2- oxoethyl)-1H-imidazol-4-yl]-
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
L-norvalinamide 313 ##STR00177## M + 1 = 490.26
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-[1-(2-oxo-2-{[(2R)- tetrahydrofuran-2- ylmethyl]amino}ethyl)-1H-
imidazol-4-yl]-L- norvalinamide 314 ##STR00178## M + 1 = 524.27
N-(1-{2- [benzyl(ethyl)amino]-2- oxoethyl}-1H-imidazol-4-yl)-
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
L-norvalinamide 315 ##STR00179## M + 1 = 502.2
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[1-(tetrahydro-2H- pyran-4-ylmethyl)azetidin-3-
yl]-1H-imidazol-4-yl}-L- norvalinamide 316 ##STR00180## M + 1 =
476.3 N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-[1-({(2S)-1-[(2S)-2- hydroxypropyl]azetidin-2-
yl}methyl)-1H-imidazol-4- yl]-L-norvalinamide 317 ##STR00181## M +
1 = 619.65 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[2-({[1-
(trifluoroacetyl)pyrrolidin-3- yl]amino}methyl)phenyl]-
1H-imidazol-4-yl}-L- norvalinamide 318 ##STR00182## M + 1 = 605.66
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[1-(2,2,2- trifluoroethyl)pyrrolidin-3-
yl]amino}methyl)phenyl]- 1H-imidazol-4-yl}-L- norvalinamide 319
##STR00183## M + 1 = 492.1 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-[(3- methoxypropyl)amino]-1-
methyl-2-oxoethyl}-1H- imidazol-4-yl)-L- norvalinamide 320
##STR00184## M + 1 = 538.65 N-2-[(2S)-6,8-difluoro-
1,2,3,4-tetrahydronaphthalen- 2-yl]-N-(1-{2-[(tetrahydro-
2H-pyran-4-ylamino)methyl] phenyl}-1H-imidazol-4-yl)-
L-norvalinamide 321 ##STR00185## M + 1 = 605.66
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-[1-(2-{[4-(2,2,2- trifluoroethyl)piperazin-1-
yl]methyl}phenyl)-1H- imidazol-4-yl]-L- norvalinamide 322
##STR00186## M + 1 = 619.65 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[4-
(trifluoroacetyl)piperazin-1- yl]methyl}phenyl)-1H-
imidazol-4-yl]-L- norvalinamide 323 ##STR00187## M + 1 = 465.19
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-(1-{(1S)-2-[(2- methoxyethyl)amino]-1-
methylethyl}-1H-imidazol-4- yl)-L-norvalinamide 324 ##STR00188## M
+ 1 = 514.25 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[(1S)-1-methyl-2-
{methyl[(1-methyl-1H- pyrazol-4- yl)methyl]amino}ethyl]-1H-
imidazol-4-yl}-L- norvalinamide 325 ##STR00189## M + 1 = 503.14
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[(1S)-1-methyl-2-(5- oxo-14-diazepan-1-
yl)ethyl]-1H-imidazol-4-yl}- L-norvalinamide 326 ##STR00190## M + 1
= 514.25 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[(1S)-1-methyl-2-
{methyl[2-(1H-pyrazol-4- yl)ethyl]amino}ethyl]-1H-
imidazol-4-yl}-L- norvalinamide 327 ##STR00191## M + 1 = 508.34
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-(1-{(1S)-2-[(3-ethoxy-2- hydroxypropyl)amino]-1-
methylethyl}-1H-imidazol-4- yl)-L-norvalinamide 328 ##STR00192## M
+ 1 = 478.28 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{(1S)-2-[(2-methoxy-1-
methylethyl)amino]-1- methylethyl]-1H-imidazol-4-
yl)-L-norvalinamide 329 ##STR00193## M + 1 = 478.22
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[(1S)-2-{[(1S)-2- methoxy-1- methylethyl]amino}-1-
methylethyl]-1H-imidazol-4- yl}-L-norvalinamide 330 ##STR00194## M
+ 1 = 514.14 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[(1S)-1-methyl-2-
{methyl[(1-methyl-1H- imidazol-2- yl)methyl]amino}ethyl]-1H-
imidazol-4-yl}-L- norvalinamide 331 ##STR00195## M + 1 = 633.67
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[2-({[1- (trifluoroacetyl)piperidin-4-
yl]amino}methyl)phenyl]- 1H-imidazol-4-yl}-L- norvalinamide 332
##STR00196## M + 1 = 532.4 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[(1-
hydroxycyclopentyl)methyl] amino}-1,1-dimethyl-2-
oxoethyl)-1H-imidazol-4-yl]- L-norvalinamide 333 ##STR00197## M + 1
= 575.95 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-[4-(2-
methoxyethoxy)piperidin-1- yl]-1,1-dimethyl-2-
oxoethyl}-1H-imidazol-4-yl)- L-norvalinamide 334 ##STR00198## M + 1
= 518.23 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[(1- hydroxycyclobutyl)methyl]
amino}-1,1-dimethyl-2- oxoethyl)-1H-imidazol-4-yl]-
L-norvalinamide
335 ##STR00199## M + 1 = 582.29 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-[(2-hydroxy-2-
phenylpropyl)(methyl) amino]-1,1-dimethyl-2-
oxoethyl}-1H-imidazol-4-yl)- L-norvalinamide 336 ##STR00200## M + 1
= 518.22 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[(1-
hydroxycyclopentyl)methyl] amino}-1-methyl-2-
oxoethyl)-1H-imidazol-4-yl]- L-norvalinamide 337 ##STR00201## M + 1
= 504.17 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-[1-(2-{[(1- hydroxycyclobutyl)methyl]
amino}-1-methyl-2- oxoethyl)-1H-imidazol-4-yl]- L-norvalinamide 338
##STR00202## M + 1 = 568.23 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-[(2-hydroxy-2-
phenylpropyl)(methyl) amino]-1-methyl-2- oxoethyl}-1H-imidazol-4-
yl)-L-norvalinamide 339 ##STR00203## M + 1 = 543.21
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-(1-{1-methyl-2-oxo-2- [(tetrahydro-1H-pyrrolizin- 7a(5H)-
ylmethyl)amino]ethyl}-1H- imidazol-4-yl)-L- norvalinamide 340
##STR00204## M + 1 = 532.21 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-(1-{2-[2-(2-
hydroxyethyl)piperidin-1-yl]- 1-methyl-2-oxoethyl}-1H-
imidazol-4-yl)-L- norvalinamide 341 ##STR00205## M + 1 = 520.2
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[1-({[1- (methoxymethyl)propyl] amino}carbonyl)propyl]-1H-
imidazol-4-yl}-L- norvalinamide 342 ##STR00206## M + 1 = 506.1
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[1-({[1- (methoxymethyl)propyl] amino}methyl)propyl]-1H-
imidazol-4-yl}-L- norvalinamide 343 ##STR00207## M + 1 = 559.1
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-{1-[(1S,2S)-2-{[(2- morpholin-4-ylethyl)amino]
carbonyl}cyclobutyl]- 1H-imidazol-4-yl}-L- norvalinamide 344
##STR00208## M + 1 = 532.1 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[(1R,2R)-2-({[1-
(methoxymethyl)propyl] amino}carbonyl)cyclobutyl]-
1H-imidazol-4-yl}-L- norvalinamide 345 ##STR00209## M + 1 = 536.1
N-{1-[(1-benzyl-4- ethylazetidin-2-yl)methyl]-
1H-imidazol-4-yl}-N-2- [(2S)-6,8-difluoro-1,2,3,4-
tetrahydronaphthalen-2-yl]-L- norvalinamide 346 ##STR00210## M + 1
= 518.2 N-2-[(2S)-6,8-difluoro- 1,2,3,4-
tetrahydronaphthalen-2-yl]- N-{1-[1-({[(1-
hydroxycyclobutyl)methyl] amino}carbonyl)propyl]-1H-
imidazol-4-yl}-L- norvalinamide 347 ##STR00211## M + 1 = 432
N-{1-[(4-benzylmorpholin-3- yl)methyl]-1H-imidazol-4-
yl}-N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
L-norvalinamide 348 ##STR00212## M + 1 = 502 N-(1-{[4-(cyclopropyl-
methyl)morpholin-3-yl] methyl}-1H-imidazol-
4-yl)-N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
L-norvalinamide 349 ##STR00213## M + 1 = 446.0
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-(1-{1-[(dimethylamino) methyl]cyclopropyl}-1H- imidazol-4-yl)-L-
norvalinamide 350 ##STR00214## M + 1 = 538
N-{1-[(4-benzylmorpholin-2- yl)methyl]-1H-imidazol-4-
yl}-N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
L-norvalinamide 351 ##STR00215## M + 1 = 460.0
N-2-[(2S)-6,8-difluoro- 1,2,3,4- tetrahydronaphthalen-2-yl]-
N-(1-{1-[(isopropylamino) methyl]cyclopropyl}-1H- imidazol-4-yl)-
L-norvalinamide
Example 352
[0578] The following compounds are prepared utilizing the
procedures described above:
[0579] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3-ethoxy-propylamino)-ethyl]-1H-imidazol-4-yl}-amide;
[0580] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(2-fluoro-benzyl)-1H-imidazol-4-yl]-amide;
[0581] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(3-fluoro-benzyl)-1H-imidazol-4-yl]-amide;
[0582] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(4-methyl-benzyl)-1H-imidazol-4-yl]-amide;
[0583] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(4-methoxy-benzyl)-1H-imidazol-4-yl]-amide;
[0584] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(4-tert-butyl-benzyl)-1H-imidazol-4-yl]-amide;
[0585] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-hydroxymethyl-cyclobutyl)-1H-imidazol-4-yl]-amide;
[0586] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(2-hydroxymethyl-cyclobutyl)-1H-imidazol-4-yl]-amide;
[0587] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-pyrrolidin-1-ylmethyl-cyclobutyl)-1H-imidazol-4-yl]-amide;
[0588]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[2-((R)-1-cyclohexyl-ethylamino)-1,1-dimethyl-ethyl]-1H-imidaz-
ol-4-yl}-amide;
[0589] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-((R)-1-cyclohexyl-ethylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-
-amide;
[0590]
(S)-2-[2-(2,4-Difluoro-phenyl)-2-hydroxy-ethylamino]-pentanoic acid
[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;
[0591]
(S)-2-[2-(3,4-Difluoro-phenyl)-2-hydroxy-ethylamino]-pentanoic acid
[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;
[0592]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1,1-dimethyl-2-[(tetrahydro-pyran-4-ylmethyl)-amino]-ethyl}-1-
H-imidazol-4-yl)-amide;
[0593] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1-{1,1-dimethyl-2-[(tetrahydro-pyran-4-ylmethyl)-amino]ethyl}-1H-imidazo-
l-4-yl)-amide;
[0594]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[3-((S)-1-phenyl-ethylamino)-butyl]-1H-imidazol-4-yl}-amide;
[0595]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
[1-(3-methyl-oxetan-3-ylmethyl)-1H-imidazol-4-yl]-amide;
[0596] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(3-methyl-oxetan-3-ylmethyl)-1H-imidazol-4-yl]-amide;
[0597]
(S)-2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-ethylamino]-pentanoic acid
[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;
[0598]
(S)-2-[2-(2,4-Difluoro-phenyl)-2-hydroxy-ethylamino]-pentanoic acid
{1-[2-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imidaz-
ol-4-yl}-amide;
[0599] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(octahydro-pyrazino[1,2-a]azepin-2-yl)-ethyl]-1H-imidazol-4-yl}-ami-
de;
[0600] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-([1,4]dioxan-2-ylmethyl-methyl-amino)-ethyl]-1H-imidazol-4-yl}-amid-
e;
[0601] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(2-methoxy-1-methyl-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide;
[0602] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3-oxo-piperazin-1-yl)-ethyl]-1H-imidazol-4-yl}-amide;
[0603] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(2-benzylamino-ethyl)-1H-imidazol-4-yl]-amide;
[0604] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3-butoxy-propylamino)-ethyl]-1H-imidazol-4-yl}-amide;
[0605] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-((1R,2S)-2-hydroxymethyl-cyclohexylamino)-ethyl]-1H-imidazol-4-yl}--
amide;
[0606] 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[(4aS,8aS)-2-(octahydro-isoquinolin-2-yl)-ethyl]-1H-imidazol-4-yl}-ami-
de;
[0607] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3-isopropoxy-propylamino)-ethyl]-1H-imidazol-4-yl}-amide;
[0608] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(octahydro-isoquinolin-2-yl)-ethyl]-1H-imidazol-4-yl}-amide;
[0609] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3,4,5,6-tetrahydro-2H-[4,4']bipyridinyl-1-yl)-ethyl]-1H-imidazol-4-
-yl}-amide;
[0610] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(2-hydroxy-2-phenyl-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide;
[0611] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(indan-1-ylamino)-ethyl]-1H-imidazol-4-yl}-amide;
[0612] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(benzyl-methyl-amino)-ethyl]-1H-imidazol-4-yl}-amide;
[0613] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(indan-2-ylamino)-ethyl]-1H-imidazol-4-yl}-amide;
[0614] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3,4-dihydro-1#H!-isoquinolin-2-yl)-ethyl]-1H-imidazol-4-yl}-amide;
[0615] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(2-propoxy-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide;
[0616] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3-benzyl-pyrrolidin-1-yl)-ethyl]-1H-imidazol-4-yl}-amide;
[0617] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3-pyridin-2-yl-pyrrolidin-1-yl)-ethyl]-1H-imidazol-4-yl}-amide;
[0618] (S)-2-]2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(methyl-pyridin-4-ylmethyl-amino)-ethyl]-1H-imidazol-4-yl}-amide;
[0619] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1-{2-[(2-methanesulfonyl-ethyl)-methyl-amino]-ethyl}-1H-imidazol-4-yl)-a-
mide;
[0620] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(2-tert-butoxy-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide;
[0621] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[2-(3-pyridin-4-yl-pyrrolidin-1-yl)-ethyl]-1H-imidazol-4-yl}-amide;
[0622] (S)-2-[(1-Hydroxy-cyclohexylmethyl)-amino]-pentanoic acid
[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide;
[0623]
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-[1-(1,1-dimethyl-2-py-
rrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-2-phenyl-acetamide;
[0624] (S)-2-(Dicyclopropylmethyl-amino)-pentanoic acid
[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]amide;
[0625]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[3-((R)-1-phenyl-ethylamino)-propyl]-1H-imidazol-4-yl}-amide;
[0626]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{2-[(1-hydroxy-cyclohexylmethyl)-amino]-1,1-dimethyl-ethyl}-1H-
-imidazol-4-yl)-amide;
[0627]
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-{1-[2-((2S,6R)-2,6-di-
methyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-2-phenyl-acet-
amide;
[0628]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{2-[(4-hydroxy-tetrahydro-pyran-4-ylmethyl)-amino]-1,1-dimethy-
l-ethyl}-1H-imidazol-4-yl)-amide;
[0629] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-dimethylaminomethyl-cyclobutyl)-1H-imidazol-4-yl]-amide;
[0630] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-piperidin-1-ylmethyl-cyclobutyl)-1H-imidazol-4-yl]-amide;
[0631] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(1-morpholin-4-ylmethyl-cyclobutyl)-1H-imidazol-4-yl]-amide;
[0632] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1-{1-[((2R,6S)-2,6-dimethyl-morpholin-4-yl)methyl]-cyclobutyl}-1H-imidaz-
ol-4-yl)-amide;
[0633] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1-{1-[(2,2,2-trifluoro-ethylamino)-methyl]-cyclobutyl}-1H-imidazol-4-yl)-
-amide;
[0634] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamine]-pentanoic acid
(1-{1-[((R)-1-cyclohexyl-ethylamino)-methyl]-cyclobutyl}-1H-imidazol-4-yl-
)-amide;
[0635]
(S)-2-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
[1-(1-hydroxymethyl-cyclobutyl)-1H-imidazol-4-yl]-amide;
[0636]
(S)-2-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
[1-(1-pyrrolidin-1-ylmethyl-cyclobutyl)-1H-imidazol-4-yl]-amide;
[0637] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1-{1-[(2,2-dimethyl-propylamino)-methyl]-cyclobutyl}-1H-imidazol-4-yl)-a-
mide;
[0638]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-N-{1-[-
2-(2,2-dimethyl-propylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-2-pheny-
l-acetamide;
[0639]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[1-(4-trifluoromethyl-phenyl)-ethyl]-1H-imidazol-4-yl}-amide;
[0640] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[1-(4-trifluoromethyl-phenyl)-ethyl]-1H-imidazol-4-yl}-amide;
[0641]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[2-(2-methoxy-2-methyl-propylamino)-1,1-dimethyl-ethyl]-1H-imi-
dazol-4-yl}-amide;
[0642]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1,1-dimethyl-2-[(3-methyl-oxetan-3-ylmethyl)-amino]-ethyl}-1H-
-imidazol-4-yl)-amide;
[0643]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[2-(cyclohexylmethyl-amino)-1,1-dimethyl-ethyl]-1H-imidazol-4--
yl}-amide;
[0644]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1-methyl-2-[(tetrahydro-pyran-4-ylmethyl)-amino]-ethyl}-1H-im-
idazol-4-yl)-amide;
[0645] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
(1-indan-1-yl-1H-imidazol-4-yl)-amide;
[0646] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[(S)-1-((1S,2R)-2-hydroxy-indan-1-yl)-1H-imidazol-4-yl]-amide;
[0647] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[(R)-1-((1R,2S)-2-hydroxy-indan-1-yl)-1H-imidazol-4-yl]-amide;
[0648] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(2-pyrrolidin-1-ylmethyl-cyclobutyl)-1H-imidazol-4-yl]-amide;
[0649]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
[1-(2-pyrrolidin-1-ylmethyl-cyclobutyl)-1H-imidazol-4-yl]-amide;
[0650] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{1-[1-(4-fluoro-phenyl)-2-hydroxy-ethyl]-1H-imidazol-4-yl}-amide;
[0651]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[3-(3-methyl-benzylamino)-propyl]-1H-imidazol-4-yl}-amide;
[0652]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[3-(2-hydroxy-2-phenyl-ethylamino)-propyl]-1H-imidazol-4-yl]-a-
mide;
[0653]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[3-(2-chloro-benzylamino)-propyl]-1H-imidazol-4-yl}-amide;
[0654]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-propyl-1H-imidazol-4-yl}--
amide;
[0655]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[3-(indan-2-ylamino)-propyl]-1H-imidazol-4-yl}-amide;
[0656]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[3-(1-methoxymethyl-propylamino)-propyl]-1H-imidazol-4-yl}-ami-
de;
[0657]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[3-(4-chloro-benzylamino)-propyl-1H-imidazol-4-yl}-amide;
[0658]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[3-(2-methyl-benzylamino)-propyl]-1H-imidazol-4-yl}-amide;
[0659]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[3-(2-methoxy-ethylamino)-propyl]-1H-imidazol-4-yl}-amide;
[0660]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{3-[(pyridin-3-ylmethyl)-amino]-propyl}-1H-imidazol-4-yl)-amid-
e;
[0661]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[3-((S)-1-p-tolyl-ethylamino)-propyl-1H-imidazol-4-yl}-amide;
[0662]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[3-(4-methoxy-benzylamino)-propyl]-1H-imidazol-4-yl}-amide;
[0663]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[3-(cyclopropylmethyl-amino)-propyl]-1H-imidazol-4-yl}-amide;
[0664]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[3-(4-methyl-benzylamino)-propyl]-1H-imidazol-4-yl}-amide;
[0665]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{2-[(1-hydroxy-cyclohexylmethyl)-carbamoyl]-1,1-dimethyl-ethyl-
}-1H-imidazol-4-yl)-amide;
[0666] (S)-2-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic
acid
(1-{1,1-dimethyl-2-[(tetrahydro-pyran-4-ylmethyl)-amino]-ethyl}-1H-imidaz-
ol-4-yl)-amide;
[0667]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{2-[(1-hydroxy-cyclohexylmethyl)-amino]-ethyl}-1H-imidazol-4-y-
l)-amide;
[0668]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1-[(2,2,2-trifluoro-ethylamino)-methyl]-cyclobutyl}-1H-imidaz-
ol-4-yl)-amide;
[0669]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1-[(2,2-dimethyl-propylamino)-methyl]-cyclobutyl}-1H-imidazol-
-4-yl)-amide;
[0670]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1-[((R)-1-cyclohexyl-ethylamino)-methyl]-cyclobutyl}-1H-imida-
zol-4-yl)-amide;
[0671]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
[1-(1-dimethylaminomethyl-cyclobutyl)-1H-imidazol-4-yl]-amide;
[0672]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
[1-(1-piperidin-1-ylmethyl-cyclobutyl)-1H-imidazol-4-yl]-amide;
[0673]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
[1-(1-morpholin-4-ylmethyl-cyclobutyl)-1H-imidazol-4-yl]-amide;
[0674]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1-[((2R,6S)-2,6-dimethyl-morpholin-4-yl)methyl]-cyclobutyl}-1-
H-imidazol-4-yl)-amide;
[0675]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{2-[(4-hydroxy-tetrahydro-pyran-4-ylmethyl)-amino]-ethyl}-1H-i-
midazol-4-yl)-amide;
[0676]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{2-[(tetrahydro-pyran-4-ylmethyl)-amino]-ethyl}-1H-imidazol-4--
yl)-amide;
[0677]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{2-[(3-methyl-oxetan-3-ylmethyl)-amino]-ethyl}-1H-imidazol-4-y-
l)-amide;
[0678]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{2-[(1-hydroxy-cyclohexylmethyl)-amino]-1-methyl-ethyl}-1H-imi-
dazol-4-yl)-amide;
[0679]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1,1-dimethyl-3-[(pyridin-2-ylmethyl)-amino]-propyl}-1H-imidaz-
ol-4-yl)-amide;
[0680]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1-[(1-hydroxy-cyclohexylmethyl)-carbamoyl]-1-methyl-ethyl}-1H-
-imidazol-4-yl)-amide;
[0681]
(S)-2-{[(2-Fluoro-3-trifluoromethyl-phenyl)methyl]-amino}-pentanoic
acid
{1-[2-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-i-
midazol-4-yl}-amide;
[0682]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[1,1-dimethyl-3-((S)-2,2,2-trifluoro-1-phenyl-ethylamino)-prop-
yl]-1H-imidazol-4-yl}-amide;
[0683]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[1,1-dimethyl-3-((R)-1-phenyl-ethylamino)-propyl]H-imidazol-4--
yl}-amide;
[0684] (S)-2-(2-Trifluoromethyl-benzylamino)-pentanoic acid
{1-[2-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imidaz-
ol-4-yl}-amide;
[0685]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1-methyl-1-[(tetrahydro-pyran-4-ylmethyl)-carbamoyl]-ethyl}-1-
H-imidazol-4-yl)-amide;
[0686]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[2-(2-ethoxy-ethylamino)-ethyl]-1H-imidazol-4-yl}-amide;
[0687] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
{(R)-1-[(R)-1-(4-fluorophenyl)-2-hydroxy-ethyl]-1H-imidazol-4-yl}-amide;
[0688] (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid
[1-(2-hydroxymethyl-phenyl)-1H-imidazol-4-yl]-amide;
[0689]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[2-(2-ethoxy-ethylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-
-amide;
[0690]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-N-{1-[-
2-(2-ethoxy-ethylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-propionamide-
;
[0691]
(S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-{1-[2-(2,2-dimethyl-p-
ropylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-2-phenyl-acetamide;
[0692]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[1-methyl-1-(2-methyl-benzylcarbamoyl)-ethyl]-1H-imidazol-4-yl-
}-amide;
[0693]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[1-(2-methoxy-1-methyl-ethylcarbamoyl)-1-methyl-ethyl]-1H-imid-
azol-4-yl}-amide;
[0694]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{(S)-1-[2-(2,2-dimethyl-propylamino)-1-phenyl-ethyl]-1H-imidazol--
4-yl}-amide;
[0695]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid [1-(3-benzylamino-propyl)-1H-imidazol-4-yl]-amide;
[0696]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{2-[(2,2-dimethyl-propylamino)-methyl]-phenyl}-1H-imidazol-4-y-
l)-amide;
[0697]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{(S)-1-[2-(2,2-dimethyl-propylamino)-1-phenyl-ethyl]-1H-imidazol--
4-yl}-amide;
[0698]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{2-[(2-hydroxy-butylamino)-methyl]-phenyl}-1H-imidazol-4-yl)-a-
mide;
[0699]
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-{1-[2-(2,2-dimethyl-propy-
lamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-2-pyridin-3-yl-acetamide;
[0700]
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-N-{1-[2-(2,2-dimethyl-propy-
lamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-yl}-2-(4-fluoro-phenyl)-acetamid-
e;
[0701]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[1-methyl-1-(methyl-phenethyl-carbamoyl)-ethyl]-1H-imidazol-4--
yl}-amide;
[0702]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[1-(1,3-dihydro-isobenzofuran-5-ylcarbamoyl)-1-methyl-ethyl]-1-
H-imidazol-4-yl}-amide;
[0703]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[1-(indan-1-ylcarbamoyl)-1-methyl-ethyl]-1H-imidazol-4-yl}-ami-
de;
[0704]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[1,1-dimethyl-2-oxo-2-(3-pyridin-4-yl-pyrrolidin-1-yl)-ethyl]--
1H-imidazol-4-yl}-amide;
[0705]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1-[2-(3-fluoro-phenyl)-ethylcarbamoyl]-1-methyl-ethyl}-1H-imi-
dazol-4-yl)-amide;
[0706]
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)--
propionylamino]-imidazol-1-yl}-N-indan-1-yl-isobutyramide;
[0707]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[2-(3-cyano-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-1H-imida-
zol-4-yl}-amide;
[0708]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1-methyl-1-[methyl-(tetrahydro-pyran-2-ylmethyl)-carbamoyl]-e-
thyl}-1H-imidazol-4-yl)-amide;
[0709]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1-[ethyl-(2-pyrazol-1-yl-ethyl)-carbamoyl]-1-methyl-ethyl}-1H-
-imidazol-4-yl)-amide;
[0710]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[1,1-dimethyl-2-oxo-2-(2-phenyl-pyrrolidin-1-yl)-ethyl]-1H-imi-
dazol-4-yl}-amide;
[0711]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-N-{1-[-
1,1-dimethyl-2-oxo-2-(3-pyridin-4-yl-pyrrolidin-1-yl)-ethyl]-1H-imidazol-4-
-yl}-propionamide;
[0712]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1-[(furan-2-ylmethyl)-carbamoyl]-1-methyl-ethyl}-1H-imidazol--
4-yl)-amide;
[0713]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{2-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-1,1-dimethyl-2-ox-
o-ethyl}-1H-imidazol-4-yl)-amide;
[0714]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[1-methyl-1-((3R,4S)-4-methylsulfanyl-tetrahydro-furan-3-ylcar-
bamoyl)-ethyl]-1H-imidazol-4-yl}-amide;
[0715]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[2-(4-acetyl-[1,4]diazepan-1-yl)-1,1-dimethyl-2-oxo-ethyl]-1H--
imidazol-4-yl}-amide;
[0716]
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)--
propionylamino]-imidazol-1-yl}-N-[2-(3-fluoro-phenyl)-ethyl]-isobutyramide-
;
[0717]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1-methyl-1-[1-(1-methyl-1H-pyrazol-4-yl)-ethylcarbamoyl]-ethy-
l}-1H-imidazol-4-yl)-amide;
[0718]
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)--
propionylamino]-imidazol-1-yl}-N-methyl-N-phenethyl-isobutyramide;
[0719]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[1-(3-methoxy-propylcarbamoyl)-1-methyl-ethyl]-1H-imidazol-4-y-
l}-amide;
[0720]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1-methyl-1-[(3-methyl-[1,2,4]oxadiazol-5-ylmethyl)-carbamoyl]-
-ethyl}-1H-imidazol-4-yl)-amide;
[0721]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1-[(2-cyano-ethyl)-methyl-carbamoyl]-1-methyl-ethyl}-1H-imida-
zol-4-yl)-amide;
[0722]
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)--
propionylamino]-imidazol-1-yl}-N-ethyl-N-(2-pyrazol-1-yl-ethyl)-isobutyram-
ide;
[0723]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
{1-[1,1-dimethyl-2-(3-methyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a-
]pyrazin-7-yl)-2-oxo-ethyl]-1H-imidazol-4-yl}-amide;
[0724]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1-methyl-1-[methyl-(1-methyl-1H-imidazol-2-ylmethyl)-carbamoy-
l]-ethyl}-1H-imidazol-4-yl)-amide;
[0725]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-N-{1-[-
2-(4-hydroxymethyl-4-methyl-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-1H-i-
midazol-4-yl}-propionamide;
[0726]
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)--
propionylamino]-imidazol-1-yl}-N-(4-methyl-benzyl)-isobutyramide;
[0727]
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)--
propionylamino]-imidazol-1-yl}-N-(1,3-dihydro-isobenzofuran-5-yl)-isobutyr-
amide;
[0728]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-N-{1-[-
1,1-dimethyl-2-oxo-2-(2-phenyl-pyrrolidin-1-yl)-ethyl]-1H-imidazol-4-yl}-p-
ropionamide;
[0729]
(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentan-
oic acid
(1-{1-[(2-diethylamino-ethyl)-methyl-carbamoyl]-1-methyl-ethyl}-1-
H-imidazol-4-yl)-amide;
[0730]
(S)--N-{1-[2-(3-Cyano-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-1H--
imidazol-4-yl}-2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pr-
opionamide;
[0731]
(S)--N-(1-{2-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-1,1-dimethyl-
-2-oxo-ethyl}-1H-imidazol-4-yl)-2-(6,8-difluoro-1,2,3,4-tetrahydro-naphtha-
len-2-ylamino)-propionamide;
[0732]
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)--
propionylamino]-imidazol-1-yl}-N-((1R,2S)-2-hydroxymethyl-cyclohexyl)-isob-
utyramide;
[0733]
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)--
propionylamino]-imidazol-1-yl}-N-(3-methyl-[1,2,4]oxadiazol-5-ylmethyl)-is-
obutyramide;
[0734]
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)--
propionylamino]-imidazol-1-yl}-N-((S)-2-methoxy-1-methyl-ethyl)-isobutyram-
ide;
[0735]
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)--
propionylamino]-imidazol-1-yl}-N-(3-methoxy-propyl)-isobutyramide;
[0736]
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)--
propionylamino]-imidazol-1-yl}-N-[1-(1-methyl-1H-pyrazol-4-yl)-ethyl]-isob-
utyramide;
[0737]
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)--
propionylamino]-imidazol-1-yl}-N-(3-imidazol-1-yl-propyl)-isobutyramide;
and
[0738]
2-{4-[(S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)--
propionylamino]-imidazol-1-yl}-N-(3-morpholin-4-yl-propyl)-isobutyramide;
[0739] The invention described and claimed herein is not to be
limited in scope by the specific embodiments herein disclosed,
since these embodiments are intended as illustrations of several
aspects of the invention. Any equivalent embodiments are intended
to be within the scope of this invention. Indeed, various
modifications of the invention in addition to those shown and
described herein will become apparent to those skilled in the art
from the foregoing description. Such modifications are also
intended to fall within the scope of the appended claims.
* * * * *