U.S. patent application number 12/055154 was filed with the patent office on 2008-10-02 for inhibitors of cathepsin s.
This patent application is currently assigned to IRM LLC. Invention is credited to Phillip Alper, Badry Bursulaya, Arnab Chatterjee, Robert Epple, Jennifer Leslie Harris, Jun Li, Hong Liu, David Tully, David Woodmansee.
Application Number | 20080242671 12/055154 |
Document ID | / |
Family ID | 33101300 |
Filed Date | 2008-10-02 |
United States Patent
Application |
20080242671 |
Kind Code |
A1 |
Liu; Hong ; et al. |
October 2, 2008 |
INHIBITORS OF CATHEPSIN S
Abstract
The present invention provides compounds, compositions and
methods for the selective inhibition of cathepsin S. In a preferred
aspect, cathepsin S is selectively inhibited in the presence of at
least one other cathepsin isozyme. The present invention also
provides methods for treating a disease state in a subject by
selectively inhibiting cathepsin S.
Inventors: |
Liu; Hong; (San Diego,
CA) ; Alper; Phillip; (San Diego, CA) ;
Chatterjee; Arnab; (Encinitas, CA) ; Tully;
David; (San Diego, CA) ; Bursulaya; Badry;
(San Diego, CA) ; Woodmansee; David; (Basel,
CH) ; Epple; Robert; (San Diego, CA) ; Harris;
Jennifer Leslie; (San Diego, CA) ; Li; Jun;
(San Diego, CA) |
Correspondence
Address: |
GENOMICS INSTITUTE OF THE;NOVARTIS RESEARCH FOUNDATION
10675 JOHN JAY HOPKINS DRIVE, SUITE E225
SAN DIEGO
CA
92121-1127
US
|
Assignee: |
IRM LLC
Hamilton
BM
|
Family ID: |
33101300 |
Appl. No.: |
12/055154 |
Filed: |
March 25, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10807613 |
Mar 23, 2004 |
7384970 |
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12055154 |
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60457848 |
Mar 24, 2003 |
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Current U.S.
Class: |
514/252.03 ;
514/323; 514/415; 514/616; 544/238; 546/201; 548/469; 564/157 |
Current CPC
Class: |
C07D 261/18 20130101;
C07D 209/42 20130101; C07C 311/29 20130101; C07D 307/20 20130101;
C07C 311/19 20130101; C07D 207/12 20130101; C07D 309/08 20130101;
C07D 401/14 20130101; C07D 207/24 20130101; C07D 311/22 20130101;
C07D 213/71 20130101; C07D 333/40 20130101; C07D 231/14 20130101;
C07D 409/14 20130101; C07C 257/18 20130101; C07C 2601/14 20170501;
C07D 307/68 20130101; C07D 335/02 20130101; C07C 237/24 20130101;
C07D 413/06 20130101; C07D 271/10 20130101; C07D 417/12 20130101;
C07C 237/22 20130101; C07D 257/04 20130101; C07D 403/12 20130101;
C07D 417/14 20130101; C07D 405/14 20130101; C07D 401/12 20130101;
C07D 211/60 20130101; C07D 307/24 20130101; C07D 403/06 20130101;
C07D 409/12 20130101; C07D 405/12 20130101; C07D 413/14 20130101;
C07D 413/12 20130101; C07D 209/08 20130101 |
Class at
Publication: |
514/252.03 ;
564/157; 514/616; 514/323; 546/201; 548/469; 514/415; 544/238 |
International
Class: |
A61K 31/501 20060101
A61K031/501; A61K 31/165 20060101 A61K031/165; C07C 233/63 20060101
C07C233/63; A61K 31/454 20060101 A61K031/454; C07D 401/12 20060101
C07D401/12; C07D 209/04 20060101 C07D209/04; A61K 31/404 20060101
A61K031/404; C07D 401/14 20060101 C07D401/14 |
Claims
1. A compound of Formula I: ##STR00021## or a pharmaceutically
acceptable salt or prodrug thereof, wherein: R.sup.1 is a member
selected from the group consisting of H, C.sub.6-C.sub.10 aryl
substituted with 0-3 R.sup.1a, a 5- to 6-membered monocyclic or 8-
to 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms
each independently a member selected from the group consisting of
N, O and S, wherein said heteroaryl is substituted with 0-3
R.sup.1a, a C.sub.3-C.sub.8 cycloalkyl substituted with 0-2
R.sup.1b, wherein said C.sub.3-C.sub.8 cycloalkyl is saturated or
unsaturated; and a C.sub.3-C.sub.8 heterocycle containing 1 to 2
heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heterocycle is substituted
with 0-2 R.sup.1c and is saturated or unsaturated; each R.sup.1a is
independently a member selected from the group consisting of H,
C.sub.1-C.sub.3 perfluoroalkyl, C.sub.3-C.sub.7 cycloalkyl, F, Cl,
Br, CN, NO.sub.2, OR.sup.10, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2R.sup.10, NR.sup.11R.sup.12, acetyl,
C(.dbd.O)OR.sup.13, C(.dbd.O)NR.sup.13R.sup.14,
S(.dbd.O).sub.2NR.sup.13R.sup.14, phenyl substituted with 0-3
R.sup.15, a 5- to 6-membered monocyclic heteroaryl containing 1 to
4 heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R.sup.15, a C.sub.3-C.sub.8 heterocycle containing 1 to 2
heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heterocycle is substituted
with 0-2 R.sup.1c and is saturated or unsaturated, and a
C.sub.1-C.sub.4 alkyl substituted with 0-2 R.sup.16; each R.sup.1b
is independently a member selected from the group consisting of H,
OH, F, Cl, acetyl, .dbd.O, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, CF.sub.3 and OCF.sub.3; each R.sup.1c is independently a
member selected from the group consisting of H, OH, F, Cl, .dbd.O,
C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.16,
C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, C(.dbd.O)R.sup.10,
S(.dbd.O).sub.2R.sup.10, tBoc, Cbz; phenyl substituted with 0-3
R.sup.15; a 5- to 6-membered monocyclic heteroaryl containing 1 to
4 heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R.sup.15; R.sup.2 is a member selected from the group
consisting of a phenyl substituted with 0-3 R.sup.15, a 5- to
6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-2 R.sup.15, a
C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.2a, wherein said
C.sub.1-C.sub.6 alkyl optionally contains a heteroatom selected
from the group consisting of --O--, --S--, and --S(.dbd.O).sub.2--,
a C.sub.2-C.sub.6 alkenyl, a C.sub.2-C.sub.6 alkynyl, a
C.sub.3-C.sub.7 cycloalkyl substituted with 0-2 R.sup.19, wherein
said C.sub.3-C.sub.7 cycloalkyl optionally contains a heteroatom
selected from --O--, --S--, and --S(.dbd.O).sub.2--, and a
C.sub.7-C.sub.11 bicycloalkyl substituted with 0-2 R.sup.19; each
R.sup.2a is independently a member selected from the group
consisting of a C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.15, a 5- to 6-membered monocyclic or 8- to 10-membered
bicyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-3 R.sup.15, a
C.sub.3-C.sub.8 cycloalkyl substituted with 0-2 R.sup.19, and a
C.sub.7-C.sub.11 bicycloalkyl substituted with 0-2 R.sup.19;
R.sup.3 is a member selected from the group consisting of H and
C.sub.1-C.sub.4 alkyl; subscript n is 0 or 1; R.sup.4 is a member
selected from the group consisting of H and C.sub.1-C.sub.6 alkyl;
alternatively, R.sup.2 and R.sup.4 are taken together to form a
C.sub.5-C.sub.7 cycloalkyl substituted with 0-2 R.sup.19; R.sup.5
is a member selected from the group consisting of H,
C.sub.3-C.sub.7 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkyne, phenyl substituted with 0-2 R.sup.15; 5- to
6-membered heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-2 R.sup.15, a
C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.18, wherein said
C.sub.1-C.sub.6 alkyl optionally contains a heteroatom selected
from the group consisting of --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2-- and --NR.sup.17--; Y is a member independently
selected from the group consisting of a bond and
--(CR.sup.20R.sup.21).sub.m--W--(CR.sup.22R.sup.23).sub.p--;
subscript p is 1 or 2; subscript m is 0 or 1; W is a member
independently selected from the group consisting of a bond, --O--,
--S--, --S(.dbd.O)--, --S(.dbd.O).sub.2-- and --NR.sup.12--; X is
selected from the group consisting of --C(.dbd.O)--,
--OC(.dbd.O)--, --NR.sup.24C(.dbd.O)-- and --S(.dbd.O).sub.2--;
each of R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is independently a
member selected from the group consisting of H and C.sub.1-C.sub.4
alkyl; alternatively, R.sup.5 and R.sup.7 are taken together to
form a C.sub.5-C.sub.7 cycloalkyl substituted with 0-2 R.sup.19;
alternatively, R.sup.5 and R.sup.9 are taken together to form a 6-7
membered heterocyclic ring containing 1-2 heteroatoms each
independently a member selected from the group consisting of N, O
and S; Ar is a member selected from the group consisting of phenyl
substituted with 0-3 R.sup.29; and 5- to 6-membered heteroaryl
containing 1 to 4 heteroatoms each independently a member selected
from the group consisting of N, O and S, wherein said heteroaryl is
substituted with 0-3 R.sup.29; each R.sup.10 is independently a
member selected from the group consisting of H, C.sub.3-C.sub.7
cycloalkyl, a C.sub.1-C.sub.3 perfluoroalkyl, a C.sub.1-C.sub.4
alkyl substituted with 0-1 R.sup.25, a phenyl substituted with 0-3
R.sup.15; a 5- to 6-membered heteroaryl containing 1 to 4
heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R , and a C.sub.3-C.sub.8 heterocycle containing 1 to 2
heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heterocycle is substituted
with 0-2 R.sup.1c; each R.sup.11 is independently a member selected
from the group consisting of H, .sup.tBOC, Cbz, C.sub.3-C.sub.8
cycloalkyl, (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--,
(C.sub.1-C.sub.6alkyl)-S(.dbd.O).sub.2-- and a C.sub.1-C.sub.6
alkyl; each of R.sup.12, R.sup.13 and R.sup.14 is independently a
member selected from the group consisting of H and C.sub.1-C.sub.4
alkyl; alternatively, R.sup.13 and R.sup.14 on the same N atom are
taken together to form a C.sub.5-C.sub.7 heterocycle containing 1-2
heteroatoms each independently a member selected from the group
consisting of N, O and S; each R.sup.15 is independently a member
selected from the group consisting of H, OH, F, Cl, Br, I, CN,
NO.sub.2, COOR.sup.13, C(.dbd.O)NR.sup.13R.sup.14,
S(.dbd.O).sub.2NR.sup.13R.sup.14, acetyl, --SCH.sub.3,
--S(.dbd.O)CH.sub.3, --S(.dbd.O).sub.2CH.sub.3, NR.sup.26R.sup.27,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3 perfluoroalkyl,
C.sub.1-C.sub.3 perfluoroalkoxy and a C.sub.1-C.sub.6 alkyl; each
R.sup.16 is independently a member selected from the group
consisting of H, OH, COOR.sup.13, C(.dbd.O)NR.sup.13R.sup.14,
S(.dbd.O).sub.2NR.sup.13R.sup.14, acetyl, --SCH.sub.3,
--S(.dbd.O)CH.sub.3, --S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6
alkoxy, NR.sup.26R.sup.27, a phenyl substituted with 0-3 R.sup.15,
a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-3 R.sup.15,
and a C.sub.3-C.sub.8 heterocycle containing 1 to 2 heteroatoms
each independently a member selected from the group consisting of
N, O and S, wherein said heterocycle is substituted with 0-2
R.sup.15 and is saturated or unsaturated; R.sup.17 is a member
selected from the group consisting of H and C.sub.1-C.sub.4 alkyl;
each R.sup.18 is independently a member selected from the group
consisting of H, OH, F, Cl, CN, NO.sub.2, C(.dbd.O)OR.sup.30,
C(.dbd.O)NR.sup.13R.sup.14, NR.sup.11R.sup.12, a C.sub.1-C.sub.3
perfluoroalkyl, a C.sub.1-C.sub.3 perfluoroalkoxy, a phenyl
substituted with 0-3 R.sup.15, a 5- to 6-membered heteroaryl
containing 1 to 4 heteroatoms each independently a member selected
from the group consisting of N, O and S, wherein said heteroaryl is
substituted with 0-3 R.sup.15, a C.sub.3-C.sub.8 heterocycle
containing 1 to 2 heteroatoms each independently a member selected
from the group consisting of N, O and S, wherein said heterocycle
is substituted with 0-2 R.sup.15 and is saturated or unsaturated;
and C.sub.3-C.sub.8 cycloalkyl; each R.sup.19 is a independently a
member selected from the group consisting of C.sub.1-C.sub.4 alkyl,
F, Cl and C.sub.1-C.sub.4 alkoxy, CF.sub.3 and OCF.sub.3;
alternatively, two R.sup.19 on the same carbon may be combined to
form C.sub.3-C.sub.6 cycloalkyl; each of R.sup.20, R.sup.21,
R.sup.22 and R.sup.23 is independently a member selected from the
group consisting of a bond, H, F, OH, C.sub.1-C.sub.4 alkyl, and
C.sub.1-C.sub.3 alkylhydroxy; alternatively, R.sup.20 and R.sup.21
or R.sup.22 and R.sup.23 are taken together to form a
C.sub.3-C.sub.6 cycloalkyl; R.sup.24 is a member selected from the
group consisting of H and C.sub.1-C.sub.4 alkyl; each R.sup.25 is
independently a member selected from the group consisting of H,
C.sub.3-C.sub.7 cycloalkyl, a phenyl substituted with 0-3 R.sup.15
and a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms
each independently a member selected from the group consisting of
N, O and S, wherein said 5- to 6-membered heteroaryl is substituted
with 0-2 R.sup.15; each R.sup.26 is independently a member selected
from the group consisting of H, C.sub.1-C.sub.4 alkyl,
(C.sub.1-C.sub.4 alkyl)-C(.dbd.O)-- and
(C.sub.1-C.sub.4alkyl)-S(.dbd.O).sub.2--; each R.sup.27 is
independently a member selected from the group consisting of H and
C.sub.1-C.sub.4 alkyl; alternatively, R.sup.26 and R.sup.27 on the
same N atom are taken together to form a C.sub.5-C.sub.7
heterocycle containing 1-2 heteroatoms each independently a member
selected from the group consisting of N, O and S; each R.sup.28 is
independently a member selected from the group consisting of H, a
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, a phenyl
substituted with 0-3 R.sup.15, a benzyl substituted with 0-2
R.sup.15; each R.sup.29 is independently a member selected from the
group consisting of H, F, Cl, Br, I, CN, NO.sub.2, OR.sup.28,
SR.sup.28, S(.dbd.O)R.sup.28, S(.dbd.O).sub.2R.sup.28,
S(.dbd.O).sub.2NR.sup.13R.sup.14, NR.sup.26R.sup.27, acetyl,
C(.dbd.O)NR.sup.13R.sup.14, C(.dbd.O)OR.sup.13,
C.sub.1-C.sub.6alkyl, OCHF.sub.2, SCF.sub.3, OCF.sub.3,
--C(.dbd.NH)NH.sub.2, and 5- to 6-membered heteroaryl containing 1
to 4 heteroatoms each independently a member selected from the
group consisting of N, O and S; alternatively, two R.sup.29
substituted on adjacent atoms may be combined to form a 5 to 6
membered heterocyclic fused radical, wherein said 5 to 6 membered
heterocyclic fused radical comprise 1 or 2 heteroatom(s) selected
from O, S and N; wherein said 5 to 6 membered heterocyclic fused
radical is substituted with 0-1 oxo; alternatively, R.sup.29 and
R.sup.9 are taken together to form a 5- to 7-membered fused
heterocyclic ring containing 1-2 heteroatom(s) each independently a
member selected from the group consisting of N, O and S; wherein
said 5 to 7 membered fused heterocyclic ring is substituted with
0-2 R.sup.19; each R.sup.30 is independently a member selected from
the group consisting of H, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.4 alkyl substituted with 0-1 R.sup.25, a phenyl
substituted with 0-3 R.sup.15, and a 5- to 6-membered heteroaryl
containing 1 to 4 heteroatoms each independently a member selected
from the group consisting of N, O and S, wherein said heteroaryl is
substituted with 0-3 R.sup.15; and with the proviso that R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are not
all hydrogen.
2. The compound of claim 1, according to Formula Ia ##STR00022##
wherein: R.sup.1 is a 5- to 6-membered heteroaryl containing 1 to 4
heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 1 R.sup.1a; R.sup.1a is independently a member selected from
the group consisting of phenyl substituted with 0-2 R.sup.15, and a
5- to 6-membered monocyclic heteroaryl containing 1 to 4
heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R.sup.15; R.sup.2 is a member selected from the group
consisting of a phenyl substituted with 0-3 R.sup.15, a 5- to
6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-2 R.sup.15, a
C.sub.1-C.sub.6 alkyl, a C.sub.1-C.sub.3 alkyl substituted with 1
R.sup.2a, and a C.sub.3-C.sub.7 cycloalkyl substituted with 0-2
R.sup.19; each R.sup.2a is independently a member selected from the
group consisting of a C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.15, a 5- to 6-membered monocyclic or 8- to 10-membered
bicyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-3 R.sup.15, a
C.sub.3-C.sub.8 cycloalkyl substituted with 0-2 R.sup.19 and a
C.sub.7-C.sub.11 bicycloalkyl substituted with 0-2 R.sup.19; and Ar
is phenyl substituted with 0-3 R.sup.29, or alternatively, R.sup.29
and R.sup.9 are taken together to form a 5- to 7-membered fused
heterocyclic ring containing 1-2 heteroatom(s) each independently a
member selected from the group consisting of N, O and S; wherein
said 5- to 7-membered fused heterocyclic ring is substituted with
0-2 R.sup.19.
3. The compound of claim 2, wherein said compound is of the
formula: ##STR00023##
4. The compound of claim 1, wherein: R.sup.1 is a member selected
from the group consisting of phenyl substituted with 0-3 R.sup.1a,
furanyl substituted with 0-3 R.sup.1a, C.sub.3-C.sub.6 cycloalkyl
substituted with 0-3 R.sup.1a, indolyl substituted with 0-3
R.sup.1a, 5- or 6-membered heterocyclyl substituted with 0-3
R.sup.1c, pyidazinyl substituted with 0-3 R.sup.1a, imadazolyl
substituted with 0-3 R.sup.1a, thienyl substituted with 0-3
R.sup.1a, thiazolyl substituted with 0-3 R.sup.1a, oxadiazolyl
substituted with 0-3 R.sup.1a, pyrazolyl substituted with 0-3
R.sup.1a, isoxazolyl substituted with 0-3 R.sup.1a, tetrazolyl
substituted with 0-3 R.sup.1a, oxazolyl substituted with 0-3
R.sup.1a and pyridyl substituted with 0-3 R.sup.1a.
5. The compound of claim 2, according to Formula Ib: ##STR00024##
wherein: each R.sup.15, if present, is independently a member
selected from the group consisting of OH, F, Cl, Br, I, CN,
NO.sub.2, COOR.sup.13, C(.dbd.O)NR.sup.13R.sup.14,
S(.dbd.O).sub.2NR.sup.13R.sup.14, acetyl, --SCH.sub.3,
--S(.dbd.O)CH.sub.3, --S(.dbd.O).sub.2CH.sub.3, NR.sup.26R.sup.27,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3 perfluoroalkyl,
C.sub.1-C.sub.3 perfluoroalkoxy and a C.sub.1-C.sub.6 alkyl; and A
is a 5-membered heteroaryl selected from the group consisting of
furanylene, thienylene, thiazolylene, oxadiazolylene,
isoxazolylene, tetrazolylene, and oxazolylene.
6. The compound of claim 5, wherein: R.sup.2 is a member selected
from the group consisting of a C.sub.1-C.sub.2 alkyl substituted
with 1 R.sup.2a, and C.sub.1-C.sub.6 alkyl; each R.sup.2a is
independently a member selected from the group consisting of a
phenyl substituted with 0-3 R.sup.15, and a C.sub.3-C.sub.8
cycloalkyl substituted with 0-2 R.sup.19; R.sup.5 is a member
selected from the group consisting of H, C.sub.3-C.sub.7
cycloalkyl; a C.sub.1-C.sub.6 alkyl substituted with 0-1 R.sup.18,
wherein said C.sub.1-C.sub.6 alkyl optionally contains a heteroatom
selected from the group consisting of --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2-- and --NR.sup.17--; and each R.sup.18 is
independently a member selected from the group consisting of H, OH,
F, Cl, CN, C(.dbd.O)OR.sup.30, C(.dbd.O)NR.sup.13R.sup.14,
NR.sup.11R.sup.12, a phenyl substituted with 0-3 R.sup.15, a
C.sub.3-C.sub.8 heterocycle containing 1 to 2 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heterocycle is substituted with 0-2 R.sup.15
and is saturated or unsaturated; and C.sub.3-C.sub.8
cycloalkyl.
7. The compound of claim 1, according to Formula Ia ##STR00025##
wherein: R.sup.1 is a member selected from the group consisting of
a C.sub.3-C.sub.8 cycloalkyl substituted with 0-2 R.sup.1b, wherein
said C.sub.3-C.sub.8 cycloalkyl is saturated or unsaturated and a
C.sub.4-C.sub.7 heterocycle containing 1 to 2 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heterocycle is substituted with 0-2 R.sup.1c
and is saturated or unsaturated; R.sup.2 is a member selected from
the group consisting of a phenyl substituted with 0-3 R.sup.15, a
5- to 6-membered monocyclic heteroaryl containing 1 to 4
heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R.sup.15, a C.sub.1-C.sub.6 alkyl substituted with 0-2
R.sup.2a, and a C.sub.3-C.sub.7 cycloalkyl substituted with 0-2
R.sup.19; and Ar is phenyl substituted with 0-3 R.sup.29, or
alternatively, R.sup.29 and R.sup.9 are taken together to form a 5-
to 7-membered fused heterocyclic ring containing 1-2 heteroatom(s)
each independently a member selected from the group consisting of
N, O and S; wherein said 5- to 7-membered fused heterocyclic ring
is substituted with 0-2 R.sup.19.
8. The compound of claim 7, wherein: R.sup.2 is a member selected
from the group consisting of a C.sub.1-C.sub.2 alkyl substituted
with 1 R.sup.2a, and C.sub.1-C.sub.6 alkyl; each R.sup.2a is
independently a member selected from the group consisting of a
phenyl substituted with 0-3 R.sup.15, and a C.sub.3-C.sub.8
cycloalkyl substituted with 0-2 R.sup.19; R.sup.5is a member
selected from the group consisting of H, C.sub.3-C.sub.7
cycloalkyl; a C.sub.1-C.sub.6 alkyl substituted with 0-1 R.sup.18,
wherein said C.sub.1-C.sub.6 alkyl optionally contains a heteroatom
selected from the group consisting of --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2-- and --NR.sup.17--; and each R.sup.18 is
independently a member selected from the group consisting of H, OH,
F, Cl, CN, C(.dbd.O)OR.sup.30, C(.dbd.O)NR.sup.13R.sup.14,
NR.sup.11R.sup.12, a phenyl substituted with 0-3 R.sup.15, a
C.sub.3-C.sub.8 heterocycle containing 1 to 2 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heterocycle is substituted with 0-2 R.sup.15
and is saturated or unsaturated; and C.sub.3-C.sub.8
cycloalkyl.
9. The compound of claim 7, wherein said compound is of the
formula: ##STR00026##
10. The compound of claim 1, according to Formula Ic ##STR00027##
wherein: R.sup.1 is a member selected from the group consisting of
tBu, phenyl substituted with 0-2 R.sup.15, a 5- to 6-membered
heteroaryl containing 1 to 4 heteroatoms each independently a
member selected from the group consisting of N, O and S, wherein
said heteroaryl is substituted with 0-2 R.sup.15, and a
C.sub.4-C.sub.7 heterocycle containing 1 to 2 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heterocycle is substituted with 0-2 R.sup.1c;
each R.sup.1c is independently a member selected from the group
consisting of H, OH, F, Cl, .dbd.O, C.sub.1-C.sub.6 alkyl
substituted with 0-2 R.sup.16, a C.sub.1-C.sub.6 alkoxy, CF.sub.3,
OCF.sub.3, C(.dbd.O)R.sup.10, S(.dbd.O).sub.2R.sup.10, tBoc, Cbz,
phenyl substituted with 0-3 R.sup.5, and a 5- to 6-membered
monocyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-2 R.sup.15; Y
is a member independently selected from the group consisting of a
bond and
--(CR.sup.20R.sup.21).sub.m--W--(CR.sup.22R.sup.23).sub.p--,
wherein m is 0, W is a bond, and R.sup.22R.sup.23 are both H;
R.sup.2 is a member selected from the group consisting of a phenyl
substituted with 0-3 R.sup.15, a 5- to 6-membered monocyclic
heteroaryl containing 1 to 4 heteroatoms each independently a
member selected from the group consisting of N, O and S, wherein
said heteroaryl is substituted with 0-2 R.sup.15, a C.sub.1-C.sub.6
alkyl, a C.sub.1-C.sub.3 alkyl substituted with 1 R.sup.2a, and a
C.sub.3-C.sub.7 cycloalkyl substituted with 0-2 R.sup.19; each
R.sup.2a is independently a member selected from the group
consisting of a C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.15, a 5- to 6-membered monocyclic or 8- to 10-membered
bicyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-3 R.sup.15, a
C.sub.3-C.sub.8 cycloalkyl substituted with 0-2 R.sup.19, and a
C.sub.7-C.sub.11 bicycloalkyl substituted with 0-2 R.sup.19; and Ar
is phenyl substituted with 0-3 R.sup.29, or alternatively, R.sup.29
and R.sup.9 are taken together to form a 5- to 7-membered fused
heterocyclic ring containing 1-2 heteroatom(s) each independently a
member selected from the group consisting of N, O and S; wherein
said 5- to 7-membered fused heterocyclic ring is substituted with
0-2 R.sup.19.
11. The compound of claim 10, wherein: R.sup.2 is a member selected
from the group consisting of a C.sub.1-C.sub.2 alkyl substituted
with 1 R.sup.2a, and C.sub.1-C.sub.6 alkyl; each R.sup.2a is
independently a member selected from the group consisting of a
phenyl substituted with 0-3 R.sup.15, and a C.sub.3-C.sub.8
cycloalkyl substituted with 0-2 R.sup.19; R.sup.5 is a member
selected from the group consisting of H, C.sub.3-C.sub.7
cycloalkyl; a C.sub.1-C.sub.6 alkyl substituted with 0-1 R.sup.18,
wherein said C.sub.1-C.sub.6 alkyl optionally contains a heteroatom
selected from the group consisting of --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2-- and --NR.sup.17--; and each R.sup.18 is
independently a member selected from the group consisting of H, OH,
F, Cl, CN, C(.dbd.O)OR.sup.30, C(.dbd.O)NR.sup.13R.sup.14,
NR.sup.11R.sup.12, a phenyl substituted with 0-3 R.sup.15, a
C.sub.3-C.sub.8 heterocycle containing 1 to 2 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heterocycle is substituted with 0-2 R.sup.15
and is saturated or unsaturated; and C.sub.3-C.sub.8
cycloalkyl.
12. The compound of claim 10, wherein said compound is of the
Formula: ##STR00028##
13. The compound of claim 1, according to Formula Id ##STR00029##
wherein: R.sup.1 is a member selected from the group consisting of
methyl, benzyl, C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.13, and a 5- to 6-membered monocyclic or 8- to 10-membered
bicyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-3 R.sup.1a;
each R.sup.1a is independently a member selected from the group
consisting of H, C.sub.1-C.sub.3 perfluoroalkyl, C.sub.3-C.sub.7
cycloalkyl, F, Cl, Br, CN, NO.sub.2, OR.sup.10, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2R.sup.10, NR.sup.11R.sup.12,
acetyl, C(.dbd.O)OR.sup.13, C(.dbd.O)NR.sup.13R.sup.14,
S(.dbd.O).sub.2NR.sup.13R.sup.14, phenyl substituted with 0-3
R.sup.15, a 5- to 6-membered monocyclic heteroaryl containing 1 to
4 heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R.sup.15; and a C.sub.1-C.sub.4 alkyl; and Ar is phenyl
substituted with 0-3 R.sup.29, or alternatively, R.sup.29 and
R.sup.9 are taken together to form a 5- to 7-membered fused
heterocyclic ring containing 1-2 heteroatom(s) each independently a
member selected from the group consisting of N, O and S; wherein
said 5- to 7-membered fused heterocyclic ring is substituted with
0-2 R.sup.19.
14. The compound of claim 13, wherein: R.sup.2 is a member selected
from the group consisting of a C.sub.1-C.sub.2 alkyl substituted
with 1 R.sup.2a, and C.sub.1-C.sub.6 alkyl; each R.sup.2a is
independently a member selected from the group consisting of a
phenyl substituted with 0-3 R.sup.15, and a C.sub.3-C.sub.8
cycloalkyl substituted with 0-2 R.sup.19; R.sup.5 is a member
selected from the group consisting of H, C.sub.3-C.sub.7
cycloalkyl; a C.sub.1-C.sub.6 alkyl substituted with 0-1 R.sup.18,
wherein said C.sub.1-C.sub.6 alkyl optionally contains a heteroatom
selected from the group consisting of --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2-- and --NR.sup.17--; and each R.sup.18 is
independently a member selected from the group consisting of H, OH,
F, Cl, CN, C(.dbd.O)OR.sup.30, C(.dbd.O)NR.sup.13R.sup.14,
NR.sup.11R.sup.12, a phenyl substituted with 0-3 R.sup.15, a
C.sub.3-C.sub.8 heterocycle containing 1 to 2 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heterocycle is substituted with 0-2 R.sup.15
and is saturated or unsaturated; and C.sub.3-C.sub.8
cycloalkyl.
15. The compound of claim 13, wherein said compound is of the
Formula: ##STR00030##
16. The compound of claim 1, according to Formula Ie ##STR00031##
wherein: R.sup.1 is a member selected from the group consisting of
a C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1a, a 5- to
6-membered monocyclic or 8- to 10-membered bicyclic heteroaryl
containing 1 to 4 heteroatoms each independently a member selected
from the group consisting of N, O and S, wherein said heteroaryl is
substituted with 0-3 R.sup.1a; each R.sup.1a is independently a
member selected from the group consisting of H, C.sub.1-C.sub.3
perfluoroalkyl, C.sub.3-C.sub.7 cycloalkyl, F, Cl, Br, CN,
NO.sub.2, OR.sup.10, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2R.sup.10, NR.sup.11R.sup.12, acetyl,
C(.dbd.O)OR.sup.13, C(.dbd.O)NR.sup.13R.sup.14,
S(.dbd.O).sub.2NR.sup.13R.sup.14, phenyl substituted with 0-3
R.sup.15, a 5- to 6-membered monocyclic heteroaryl containing 1 to
4 heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R.sup.15, a C.sub.3-C.sub.8 heterocycle containing 1 to 2
heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heterocycle is substituted
with 0-2 R.sup.1c and is saturated or unsaturated, and a
C.sub.1-C.sub.4 alkyl substituted with 0-2 R.sup.16; and Ar is
phenyl substituted with 0-3 R.sup.29, or alternatively, R.sup.29
and R.sup.9 are taken together to form a 5- to 7-membered fused
heterocyclic ring containing 1-2 heteroatom(s) each independently a
member selected from the group consisting of N, O and S; wherein
said 5- to 7-membered fused heterocyclic ring is substituted with
0-2 R.sup.19.
17. The compound of claim 16, wherein: R.sup.2 is a member selected
from the group consisting of a C.sub.1-C.sub.2 alkyl substituted
with 1 R.sup.2a, and C.sub.1-C.sub.6 alkyl; each R.sup.2a is
independently a member selected from the group consisting of a
phenyl substituted with 0-3 R.sup.15, and a C.sub.3-C.sub.8
cycloalkyl substituted with 0-2 R.sup.19; and R.sup.5 is a member
selected from the group consisting of H, C.sub.3-C.sub.7
cycloalkyl; a C.sub.1-C.sub.6 alkyl, wherein said C.sub.1-C.sub.6
alkyl optionally contains a heteroatom selected from the group
consisting of --O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2-- and
--NR.sup.17--.
18. The compound of claim 16, wherein said compound is of the
Formula: ##STR00032##
19. The compound of claim 1, according to Formula Ia ##STR00033##
wherein: R.sup.1 is a member selected from the group consisting of
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1a, and a 5- to
6-membered monocyclic or 8- to 10-membered bicyclic heteroaryl
containing 1 to 4 heteroatoms each independently a member selected
from the group consisting of N, O and S, wherein said heteroaryl is
substituted with 0-3 R.sup.1a; each R.sup.1a is independently a
member selected from the group consisting of H, C.sub.1-C.sub.3
perfluoroalkyl, C.sub.3-C.sub.7 cycloalkyl, F, Cl, Br, CN,
NO.sub.2, OR.sup.10, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2R.sup.10, NR.sup.11R.sup.12, acetyl,
C(.dbd.O)OR.sup.13, C(.dbd.O)NR.sup.13R.sup.14,
S(.dbd.O).sub.2NR.sup.13R.sup.14, phenyl substituted with 0-3
R.sup.15; and a C.sub.1-C.sub.4 alkyl substituted with 0-2
R.sup.16; R.sup.2 is a member selected from the group consisting of
a phenyl substituted with 0-3 R.sup.15; a 5- to 6-membered
monocyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-2 R.sup.15, a
C.sub.1-C.sub.6 alkyl, a C.sub.1-C.sub.2 alkyl substituted with
1R.sup.2a, a C.sub.3-C.sub.7 cycloalkyl substituted with 0-2
R.sup.19; each R.sup.2a is independently a member selected from the
group consisting of a C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.15; a 5- to 6-membered monocyclic or 8- to 10-membered
bicyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-3 R.sup.15; a
C.sub.3-C.sub.8 cycloalkyl substituted with 0-2 R.sup.19; and a
C.sub.7-C.sub.11 bicycloalkyl substituted with 0-2 R.sup.19; and Ar
is phenyl substituted with 0-3 R.sup.29, or alternatively, R.sup.29
and R.sup.9 are taken together to form a 5- to 7-membered fused
heterocyclic ring containing 1-2 heteroatom(s) each independently a
member selected from the group consisting of N, O and S; wherein
said 5- to 7-membered fused heterocyclic ring is substituted with
0-2 R.sup.19.
20. The compound of claim 19, wherein said compound is of the
Formula: ##STR00034##
21. The compound of claim 1, wherein R.sup.5 and R.sup.7 are taken
together to form a C.sub.5-C.sub.7 cycloalkyl substituted with 0-2
R.sup.19; and Ar is phenyl substituted with 0-3 R.sup.29, or
alternatively, R.sup.29 and R.sup.9 are taken together to form a 5-
to 7-membered fused heterocyclic ring containing 1-2 heteroatom(s)
each independently a member selected from the group consisting of
N, O and S; wherein said 5- to 7-membered fused heterocyclic ring
is substituted with 0-2 R.sup.19.
22. The compound of claim 1, according to Formula If ##STR00035##
wherein: Y is a member selected from the group consisting of a bond
and --(CR.sup.20R.sup.21).sub.m--W--(CR.sup.22R.sup.23).sub.p--;
subscript p is the integer 1 or 2; subscript m is 0 or 1; W is a
oxygen; and Ar is phenyl substituted with 0-3 R.sup.29, or
alternatively, R.sup.29 and R.sup.9 are taken together to form a 5-
to 7-membered fused heterocyclic ring containing 1-2 heteroatom(s)
each independently a member selected from the group consisting of
N, O and S; wherein said 5- to 7-membered fused heterocyclic ring
is substituted with 0-2 R.sup.19.
23. The compound of claim 1, according to Formula Ig: ##STR00036##
wherein: R.sup.5 is a member selected from the group consisting of
H, C.sub.3-C.sub.7 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkyne, phenyl substituted with 0-2 R.sup.15; 5- to
6-membered heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-2 R.sup.15, a
C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.18, wherein said
C.sub.1-C.sub.6 alkyl optionally contains a heteroatom selected
from the group consisting of --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2-- and --NR.sup.17--.
24. The compound of claim 23, according to Formula Ih:
##STR00037##
25. The compound of claim 1, wherein R.sup.9 is H; and Ar is phenyl
substituted with 0-3 R.sup.29, or alternatively, R.sup.29 and
R.sup.9 are taken together to form a 5- to 7-membered fused
heterocyclic ring containing 1-2 heteroatom(s) each independently a
member selected from the group consisting of N, O and S; wherein
said 5- to 7-membered fused heterocyclic ring is substituted with
0-2 R.sup.19.
26. The compound of claim 1, wherein said compound is a member
selected from the compounds of Table I.
27. A pharmaceutical composition comprising: a compound of Formula
I: ##STR00038## or a pharmaceutically acceptable salt or prodrug
thereof, wherein: R.sup.1 is a member selected from the group
consisting of H, C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.1a, a 5- to 6-membered monocyclic or 8- to 10-membered
bicyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-3 R.sup.1a, a
C.sub.3-C.sub.8 cycloalkyl substituted with 0-2 R.sup.1b, wherein
said C.sub.3-C.sub.8 cycloalkyl is saturated or unsaturated; and a
C.sub.3-C.sub.8 heterocycle containing 1 to 2 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heterocycle is substituted with 0-2 R.sup.1c
and is saturated or unsaturated; each R.sup.1a is independently a
member selected from the group consisting of H, C.sub.1-C.sub.3
perfluoroalkyl, C.sub.3-C.sub.7 cycloalkyl, F, Cl, Br, CN,
NO.sub.2, OR.sup.10, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2R.sup.10, NR.sup.11R.sup.12, acetyl,
C(.dbd.O)OR.sup.13, C(.dbd.O)NR.sup.13R.sup.14,
S(.dbd.O).sub.2NR.sup.13R.sup.14, phenyl substituted with 0-3
R.sup.15, a 5- to 6-membered monocyclic heteroaryl containing 1 to
4 heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R.sup.15, a C.sub.3-C.sub.8 heterocycle containing 1 to 2
heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heterocycle is substituted
with 0-2 R.sup.1c and is saturated or unsaturated, and a
C.sub.1-C.sub.4 alkyl substituted with 0-2 R.sup.16; each R.sup.1b
is independently a member selected from the group consisting of H,
OH, F, Cl, acetyl, .dbd.O, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, CF.sub.3 and OCF.sub.3; each R.sup.1c is independently a
member selected from the group consisting of H, OH, F, Cl, .dbd.O,
C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.16,
C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, C(.dbd.O)R.sup.10,
S(.dbd.O).sub.2R.sup.10, tBoc, Cbz; phenyl substituted with 0-3
R.sup.15; a 5- to 6-membered monocyclic heteroaryl containing 1 to
4 heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R.sup.15; R.sup.2 is a member selected from the group
consisting of a phenyl substituted with 0-3 R.sup.15, a 5- to
6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-2 R.sup.15, a
C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.2a, wherein said
C.sub.1-C.sub.6 alkyl optionally contains a heteroatom selected
from the group consisting of --O--, --S--, and --S(.dbd.O).sub.2--,
a C.sub.2-C.sub.6 alkenyl, a C.sub.2-C.sub.6 alkynyl, a
C.sub.3-C.sub.7 cycloalkyl substituted with 0-2 R.sup.19, wherein
said C.sub.3-C.sub.7 cycloalkyl optionally contains a heteroatom
selected from --O--, --S--, and --S(.dbd.O).sub.2--, and a
C.sub.7-C.sub.11 bicycloalkyl substituted with 0-2 R.sup.19; each
R.sup.2a is independently a member selected from the group
consisting of a C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.15, a 5- to 6-membered monocyclic or 8- to 10-membered
bicyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-3 R.sup.15, a
C.sub.3-C.sub.8 cycloalkyl substituted with 0-2 R.sup.19, and a
C.sub.7-C.sub.11 bicycloalkyl substituted with 0-2 R.sup.19;
R.sup.3 is a member selected from the group consisting of H and
C.sub.1-C.sub.4 alkyl; subscript n is 0 or 1; R.sup.4 is a member
selected from the group consisting of H and C.sub.1-C.sub.6 alkyl;
alternatively, R.sup.2 and R.sup.4 are taken together to form a
C.sub.5-C.sub.7 cycloalkyl substituted with 0-2 R.sup.19; R.sup.5
is a member selected from the group consisting of H,
C.sub.3-C.sub.7 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkyne, phenyl substituted with 0-2 R.sup.15; 5- to
6-membered heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-2 R.sup.15, a
C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.18, wherein said
C.sub.1-C.sub.6 alkyl optionally contains a heteroatom selected
from the group consisting of --O--, --S--, --S(.dbd.O)--,
--(S.dbd.O).sub.2-- and --NR.sup.17--; Y is a member independently
selected from the group consisting of a bond and
--(CR.sup.20R.sup.21).sub.m--W--(CR.sup.22R.sup.23).sub.p--;
subscript p is 1 or 2; subscript m is 0 or 1; W is a member
independently selected from the group consisting of a bond, --O--,
--S--, --S(.dbd.O)--, --S(.dbd.O).sub.2-- and --NR.sup.12--; X is
selected from the group consisting of --C(.dbd.O)--,
--OC(.dbd.O)--, --NR.sup.24C(.dbd.O)-- and --S(.dbd.O).sub.2--;
each of R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is independently a
member selected from the group consisting of H and C.sub.1-C.sub.4
alkyl; alternatively, R.sup.5 and R.sup.7 are taken together to
form a C.sub.5-C.sub.7 cycloalkyl substituted with 0-2 R.sup.19;
alternatively, R.sup.5 and R.sup.9 are taken together to form a 6-7
membered heterocyclic ring containing 1-2 heteroatoms each
independently a member selected from the group consisting of N, O
and S; Ar is a member selected from the group consisting of phenyl
substituted with 0-3 R.sup.29, and 5- to 6-membered heteroaryl
containing 1 to 4 heteroatoms each independently a member selected
from the group consisting of N, O and S, wherein said heteroaryl is
substituted with 0-3 R.sup.29; each R.sup.10 is independently a
member selected from the group consisting of H, C.sub.3-C.sub.7
cycloalkyl, a C.sub.1-C.sub.3 perfluoroalkyl, a C.sub.1-C.sub.4
alkyl substituted with 0-1 R.sup.25, a phenyl substituted with 0-3
R.sup.15; a 5- to 6-membered heteroaryl containing 1 to 4
heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R.sup.15, and a C.sub.3-C.sub.8 heterocycle containing 1
to 2 heteroatoms each independently a member selected from the
group consisting of N, O and S, wherein said heterocycle is
substituted with 0-2 R.sup.1c; each R.sup.11 is independently a
member selected from the group consisting of H, .sup.tBOC, Cbz,
C.sub.3-C.sub.8 cycloalkyl, (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--,
(C.sub.1-C.sub.6alkyl)-S(.dbd.O).sub.2-- and a C.sub.1-C.sub.6
alkyl; each of R.sup.12, R.sup.13 and R.sup.14 is independently a
member selected from the group consisting of H and C.sub.1-C.sub.4
alkyl; alternatively, R.sup.13 and R.sup.14 on the same N atom are
taken together to form a C.sub.5-C.sub.7 heterocycle containing 1-2
heteroatoms each independently a member selected from the group
consisting of N, O and S; each R.sup.15 is independently a member
selected from the group consisting of H, OH, F, Cl, Br, I, CN,
NO.sub.2, COOR.sup.13, C(.dbd.O)NR.sup.13R.sup.14,
S(.dbd.O).sub.2NR.sup.13R.sup.14, acetyl, --SCH.sub.3,
--S(.dbd.O)CH.sub.3, --S(.dbd.O).sub.2CH.sub.3, NR.sup.26R.sup.27,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3 perfluoroalkyl,
C.sub.1-C.sub.3 perfluoroalkoxy and a C.sub.1-C.sub.6 alkyl; each
R.sup.16 is independently a member selected from the group
consisting of H, OH, COOR.sup.13, C(.dbd.O)NR.sup.13R.sup.14,
S(.dbd.O).sub.2NR.sup.13R.sup.14, acetyl, --SCH.sub.3,
--S(.dbd.O)CH.sub.3, --S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6
alkoxy, NR.sup.26R.sup.27, a phenyl substituted with 0-3 R.sup.15,
a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-3 R.sup.15,
and a C.sub.3-C.sub.8 heterocycle containing 1 to 2 heteroatoms
each independently a member selected from the group consisting of
N, O and S, wherein said heterocycle is substituted with 0-2
R.sup.15 and is saturated or unsaturated; R.sup.17 is a member
selected from the group consisting of H and C.sub.1-C.sub.4 alkyl;
each R.sup.18 is independently a member selected from the group
consisting of H, OH, F, Cl, CN, NO.sub.2, C(.dbd.O)OR.sup.30,
C(.dbd.O)NR.sup.13R.sup.14, NR.sup.11R.sup.12, a C.sub.1-C.sub.3
perfluoroalkyl, a C.sub.1-C.sub.3 perfluoroalkoxy, a phenyl
substituted with 0-3 R.sup.15, a 5- to 6-membered heteroaryl
containing 1 to 4 heteroatoms each independently a member selected
from the group consisting of N, O and S, wherein said heteroaryl is
substituted with 0-3 R.sup.15, a C.sub.3-C.sub.8 heterocycle
containing 1 to 2 heteroatoms each independently a member selected
from the group consisting of N, O and S, wherein said heterocycle
is substituted with 0-2 R.sup.15 and is saturated or unsaturated;
and C.sub.3-C.sub.8 cycloalkyl; each R.sup.19 is a independently a
member selected from the group consisting of C.sub.1-C.sub.4 alkyl,
F, Cl and C.sub.1-C.sub.4 alkoxy, CF.sub.3 and OCF.sub.3;
alternatively, two R.sup.19 on the same carbon may be combined to
form C.sub.3-C.sub.6 cycloalkyl; each of R.sup.20, R.sup.21,
R.sup.22 and R.sup.23 is independently a member selected from the
group consisting of a bond, H, F, OH, C.sub.1-C.sub.4 alkyl, and
C.sub.1-C.sub.3 alkylhydroxy; alternatively, R.sup.20 and R.sup.21
or R.sup.22 and R.sup.23 are taken together to form a
C.sub.3-C.sub.6 cycloalkyl; R.sup.24 is a member selected from the
group consisting of H and C.sub.1-C.sub.4 alkyl; each R.sup.25 is
independently a member selected from the group consisting of H,
C.sub.3-C.sub.7 cycloalkyl, a phenyl substituted with 0-3 R.sup.15
and a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms
each independently a member selected from the group consisting of
N, O and S, wherein said 5- to 6-membered heteroaryl is substituted
with 0-2 R.sup.15; each R.sup.26 is independently a member selected
from the group consisting of H, C.sub.1-C.sub.4 alkyl,
(C.sub.1-C.sub.4 alkyl)-C(.dbd.O)-- and
(C.sub.1-C.sub.4alkyl)-S(.dbd.O).sub.2--; each R.sup.27 is
independently a member selected from the group consisting of H and
C.sub.1-C.sub.4 alkyl; alternatively, R.sup.26 and R.sup.27 on the
same N atom are taken together to form a C.sub.5-C.sub.7
heterocycle containing 1-2 heteroatoms each independently a member
selected from the group consisting of N, O and S; each R.sup.28 is
independently a member selected from the group consisting of H, a
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, a phenyl
substituted with 0-3 R.sup.15, a benzyl substituted with 0-2
R.sup.15; each R.sup.29 is independently a member selected from the
group consisting of H, F, Cl, Br, I, CN, NO.sub.2, OR.sup.28,
SR.sup.28, S(.dbd.O)R.sup.28, S(.dbd.O).sub.2R.sup.28,
S(.dbd.O).sub.2NR.sup.13R.sup.14, NR.sup.26R.sup.27, acetyl,
C(.dbd.O)NR.sup.13R.sup.14, C(.dbd.O)OR.sup.13,
C.sub.1-C.sub.6alkyl, OCHF.sub.2, SCF.sub.3, OCF.sub.3,
--C(.dbd.NH)NH.sub.2, and 5- to 6-membered heteroaryl containing 1
to 4 heteroatoms each independently a member selected from the
group consisting of N, O and S; alternatively, two R.sup.29
substituted on adjacent atoms may be combined to form a 5 to 6
membered heterocyclic fused radical, wherein said 5 to 6 membered
heterocyclic fused radical comprise 1 or 2 heteroatom(s) selected
from O, S and N; wherein said 5 to 6 membered heterocyclic fused
radical is substituted with 0-1 oxo; alternatively, R.sup.29 and
R.sup.9 are taken together to form a 5- to 7-membered fused
heterocyclic ring containing 1-2 heteroatom(s) each independently a
member selected from the group consisting of N, O and S; wherein
said 5 to 7 membered fused heterocyclic ring is substituted with
0-2 R.sup.19; each R.sup.30 is independently a member selected from
the group consisting of H, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.4 alkyl substituted with 0-1 R.sup.25, a phenyl
substituted with 0-3 R.sup.15, and a 5- to 6-membered heteroaryl
containing 1 to 4 heteroatoms each independently a member selected
from the group consisting of N, O and S, wherein said heteroaryl is
substituted with 0-3 R.sup.15; with the proviso that R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are not
all hydrogen; and an excepient.
28. The composition of claim 27, wherein said compound is a member
selected from the compounds of Table I.
29. A method of selectively inhibiting cathepsin S activity in a
mammal in need thereof, comprising administering to said mammal a
therapeutically effective amount of a compound of Formula I:
##STR00039## or a pharmaceutically acceptable salt or prodrug
thereof, wherein: R.sup.1 is a member selected from the group
consisting of H, C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.1a, a 5- to 6-membered monocyclic or 8- to 10-membered
bicyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-3 R.sup.1a, a
C.sub.3-C.sub.8 cycloalkyl substituted with 0-2 R.sup.1b, wherein
said C.sub.3 -C.sub.8 cycloalkyl is saturated or unsaturated; and a
C.sub.3-C.sub.8 heterocycle containing 1 to 2 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heterocycle is substituted with 0-2 R.sup.1c
and is saturated or unsaturated; each R.sup.1a is independently a
member selected from the group consisting of H, C.sub.1-C.sub.3
perfluoroalkyl, C.sub.3-C.sub.7 cycloalkyl, F, Cl, Br, CN,
NO.sub.2, OR.sup.10, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2R.sup.10, NR.sup.11R.sup.12, acetyl,
C(.dbd.O)OR.sup.13, C(.dbd.O)NR.sup.13R.sup.14,
S(.dbd.O).sub.2NR.sup.13R.sup.14, phenyl substituted with 0-3
R.sup.15, a 5- to 6-membered monocyclic heteroaryl containing 1 to
4 heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R.sup.15, a C.sub.3-C.sub.8 heterocycle containing 1 to 2
heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heterocycle is substituted
with 0-2 R.sup.1c and is saturated or unsaturated, and a
C.sub.1-C.sub.4 alkyl substituted with 0-2 R.sup.16; each R.sup.1b
is independently a member selected from the group consisting of H,
OH, F, Cl, acetyl, .dbd.O, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, CF.sub.3 and OCF.sub.3; each R.sup.1c is independently a
member selected from the group consisting of H, OH, F, Cl, .dbd.O,
C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.16,
C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, C(.dbd.O)R.sup.10,
S(.dbd.O).sub.2R.sup.10, tBoc, Cbz; phenyl substituted with 0-3
R.sup.15; a 5- to 6-membered monocyclic heteroaryl containing 1 to
4 heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R.sup.15; R.sup.2 is a member selected from the group
consisting of a phenyl substituted with 0-3 R.sup.15, a 5- to
6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-2 R.sup.15, a
C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.2a, wherein said
C.sub.1-C.sub.6 alkyl optionally contains a heteroatom selected
from the group consisting of --O--, --S--, and --S(.dbd.O).sub.2--,
a C.sub.2-C.sub.6 alkenyl, a C.sub.2-C.sub.6 alkynyl, a
C.sub.3-C.sub.7 cycloalkyl substituted with 0-2 R.sup.19, wherein
said C.sub.3-C.sub.7 cycloalkyl optionally contains a heteroatom
selected from --O--, --S--, and --S(.dbd.O).sub.2--, and a
C.sub.7-C.sub.11 bicycloalkyl substituted with 0-2 R.sup.19; each
R.sup.2a is independently a member selected from the group
consisting of a C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.15, a 5- to 6-membered monocyclic or 8- to 10-membered
bicyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-3 R.sup.15, a
C.sub.3-C.sub.8 cycloalkyl substituted with 0-2 R.sup.19, and a
C.sub.7-C.sub.11 bicycloalkyl substituted with 0-2 R.sup.19;
R.sup.3 is a member selected from the group consisting of H and
C.sub.1-C.sub.4 alkyl; subscript n is 0 or 1; R.sup.4 is a member
selected from the group consisting of H and C.sub.1-C.sub.6 alkyl;
alternatively, R.sup.2 and R.sup.4 are taken together to form a
C.sub.5-C.sub.7 cycloalkyl substituted with 0-2 R.sup.19; R.sup.5
is a member selected from the group consisting of H,
C.sub.3-C.sub.7 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkyne, phenyl substituted with 0-2 R.sup.15; 5- to
6-membered heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-2 R.sup.15, a
C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.18, wherein said
C.sub.1-C.sub.6 alkyl optionally contains a heteroatom selected
from the group consisting of --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2-- and --NR.sup.17--; Y is a member independently
selected from the group consisting of a bond and
--(CR.sup.20R.sup.21).sub.m--W--(CR.sup.22R.sup.23).sub.p--;
subscript p is 1 or 2; subscript m is 0 or 1; W is a member
independently selected from the group consisting of a bond, --O--,
--S--, --S(.dbd.O)--, --S(.dbd.O).sub.2-- and --NR.sup.12--; X is
selected from the group consisting of --C(.dbd.O)--,
--OC(.dbd.O)--, --NR.sup.24C(.dbd.O)-- and --S(.dbd.O).sub.2--;
each of R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is independently a
member selected from the group consisting of H and C.sub.1-C.sub.4
alkyl; alternatively, R.sup.5 and R.sup.7 are taken together to
form a C.sub.5-C.sub.7 cycloalkyl substituted with 0-2 R.sup.19;
alternatively, R.sup.5 and R.sup.9 are taken together to form a 6-7
membered heterocyclic ring containing 1-2 heteroatoms each
independently a member selected from the group consisting of N, O
and S; Ar is a member selected from the group consisting of phenyl
substituted with 0-3 R.sup.29, and 5- to 6-membered heteroaryl
containing 1 to 4 heteroatoms each independently a member selected
from the group consisting of N, O and S, wherein said heteroaryl is
substituted with 0-3 R.sup.29; each R.sup.10 is independently a
member selected from the group consisting of H, C.sub.3-C.sub.7
cycloalkyl, a C.sub.1-C.sub.3 perfluoroalkyl, a C.sub.1-C.sub.4
alkyl substituted with 0-1 R.sup.25, a phenyl substituted with 0-3
R.sup.15; a 5- to 6-membered heteroaryl containing 1 to 4
heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R.sup.15, and a C.sub.3-C.sub.8 heterocycle containing 1
to 2 heteroatoms each independently a member selected from the
group consisting of N, O and S, wherein said heterocycle is
substituted with 0-2 R.sup.1c; each R.sup.11 is independently a
member selected from the group consisting of H, .sup.tBOC, Cbz,
C.sub.3-C.sub.8 cycloalkyl, (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--,
(C.sub.1-C.sub.6alkyl)-S(.dbd.O).sub.2-- and a C.sub.1-C.sub.6
alkyl; each of R.sup.12, R.sup.13 and R.sup.14 is independently a
member selected from the group consisting of H and C.sub.1-C.sub.4
alkyl; alternatively, R.sup.13 and R.sup.14 on the same N atom are
taken together to form a C.sub.5-C.sub.7 heterocycle containing 1-2
heteroatoms each independently a member selected from the group
consisting of N, O and S; each R.sup.15 is independently a member
selected from the group consisting of H, OH, F, Cl, Br, I, CN,
NO.sub.2, COOR.sup.13, C(.dbd.O)NR.sup.13R.sup.14,
S(.dbd.O).sub.2NR.sup.13R.sup.14, acetyl, --SCH.sub.3,
--S(.dbd.O)CH.sub.3, --S(.dbd.O).sub.2CH.sub.3, NR.sup.26R.sup.27,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3 perfluoroalkyl,
C.sub.1-C.sub.3 perfluoroalkoxy and a C.sub.1-C.sub.6 alkyl; each
R.sup.16 is independently a member selected from the group
consisting of H, OH, COOR.sup.13, C(.dbd.O)NR.sup.13R.sup.14,
S(.dbd.O).sub.2NR.sup.13R.sup.14, acetyl, --SCH.sub.3,
--S(.dbd.O)CH.sub.3, --S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6
alkoxy, NR.sup.26R.sup.27, a phenyl substituted with 0-3 R.sup.15,
a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-3 R.sup.15,
and a C.sub.3-C.sub.8 heterocycle containing 1 to 2 heteroatoms
each independently a member selected from the group consisting of
N, O and S, wherein said heterocycle is substituted with 0-2
R.sup.15 and is saturated or unsaturated; R.sup.17 is a member
selected from the group consisting of H and C.sub.1-C.sub.4 alkyl;
each R.sup.18 is independently a member selected from the group
consisting of H, OH, F, Cl, CN, NO.sub.2, C(.dbd.O)OR.sup.30,
C(.dbd.O)NR.sup.13R.sup.14, NR.sup.11R.sup.12, a C.sub.1-C.sub.3
perfluoroalkyl, a C.sub.1-C.sub.3 perfluoroalkoxy, a phenyl
substituted with 0-3 R.sup.15, a 5- to 6-membered heteroaryl
containing 1 to 4 heteroatoms each independently a member selected
from the group consisting of N, O and S, wherein said heteroaryl is
substituted with 0-3 R.sup.15, a C.sub.3-C.sub.8 heterocycle
containing 1 to 2 heteroatoms each independently a member selected
from the group consisting of N, O and S, wherein said heterocycle
is substituted with 0-2 R.sup.15 and is saturated or unsaturated;
and C.sub.3-C.sub.8 cycloalkyl; each R.sup.19 is a independently a
member selected from the group consisting of C.sub.1-C.sub.4 alkyl,
F, Cl and C.sub.1-C.sub.4 alkoxy, CF.sub.3 and OCF.sub.3;
alternatively, two R.sup.19 on the same carbon may be combined to
form C.sub.3-C.sub.6 cycloalkyl; each of R.sup.20, R.sup.21,
R.sup.22 and R.sup.23 is independently a member selected from the
group consisting of a bond, H, F, OH, C.sub.1-C.sub.4 alkyl, and
C.sub.1-C.sub.3 alkylhydroxy; alternatively, R.sup.20 and R.sup.21
or R.sup.22 and R.sup.23 are taken together to form a
C.sub.3-C.sub.6 cycloalkyl; R.sup.24 is a member selected from the
group consisting of H and C.sub.1-C.sub.4 alkyl; each R.sup.25 is
independently a member selected from the group consisting of H,
C.sub.3-C.sub.7 cycloalkyl, a phenyl substituted with 0-3 R.sup.15
and a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms
each independently a member selected from the group consisting of
N, O and S, wherein said 5- to 6-membered heteroaryl is substituted
with 0-2 R.sup.15; each R.sup.26 is independently a member selected
from the group consisting of H, C.sub.1-C.sub.4 alkyl,
(C.sub.1-C.sub.4 alkyl)-C(.dbd.O)-- and
(C.sub.1-C.sub.4alkyl)-S(.dbd.O).sub.2--; each R.sup.27 is
independently a member selected from the group consisting of H and
C.sub.1-C.sub.4 alkyl; alternatively, R.sup.26 and R.sup.27 on the
same N atom are taken together to form a C.sub.5-C.sub.7
heterocycle containing 1-2 heteroatoms each independently a member
selected from the group consisting of N, O and S; each R.sup.28 is
independently a member selected from the group consisting of H, a
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, a phenyl
substituted with 0-3 R.sup.15, a benzyl substituted with 0-2
R.sup.15; each R.sup.29 is independently a member selected from the
group consisting of H, F, Cl, Br, I, CN, NO.sub.2, OR.sup.28,
SR.sup.28, S(.dbd.O)R.sup.28, S(.dbd.O).sub.2R.sup.28,
S(.dbd.O).sub.2NR.sup.13R.sup.14, NR.sup.26R.sup.27, acetyl,
C(.dbd.O)NR.sup.13R.sup.14, C(.dbd.O)OR.sup.13,
C.sub.1-C.sub.6alkyl, OCHF.sub.2, SCF.sub.3, OCF.sub.3,
--C(.dbd.NH)NH.sub.2, and 5- to 6-membered heteroaryl containing 1
to 4 heteroatoms each independently a member selected from the
group consisting of N, O and S; alternatively, two R.sup.29
substituted on adjacent atoms may be combined to form a 5 to 6
membered heterocyclic fused radical, wherein said 5 to 6 membered
heterocyclic fused radical comprise 1 or 2 heteroatom(s) selected
from O, S and N; wherein said 5 to 6 membered heterocyclic fused
radical is substituted with 0-1 oxo; alternatively, R.sup.29 and
R.sup.9 are taken together to form a 5- to 7-membered fused
heterocyclic ring containing 1-2 heteroatom(s) each independently a
member selected from the group consisting of N, O and S; wherein
said 5 to 7 membered fused heterocyclic ring is substituted with
0-2 R.sup.19; each R.sup.30 is independently a member selected from
the group consisting of H, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.4 alkyl substituted with 0-1 R.sup.25, a phenyl
substituted with 0-3 R.sup.15, and a 5- to 6-membered heteroaryl
containing 1 to 4 heteroatoms each independently a member selected
from the group consisting of N, O and S, wherein said heteroaryl is
substituted with 0-3 R.sup.15; and with the proviso that R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are not
all hydrogen.
30. The method of claim 29, wherein the cathepsin S inhibition
constant for a compound of Formula I is less than 10 .mu.M.
31. The method of claim 30, wherein the cathepsin S inhibition
constant for a compound of Formula I is less than 1.0 .mu.M.
32. The method of claim 31, wherein the cathepsin S inhibition
constant for a compound of Formula I is less than 0.1 .mu.M.
33. The method of claim 29, wherein cathepsin S is selectively
inhibited in the presence of at least one other cathepsin.
34. The method of claim 33, wherein the inhibition constant of a
compound of Formula I for said at least one other cathepsin is at
least 10 times greater than a cathepsin S inhibition constant of a
compound of Formula I.
35. The method of claim 34, wherein the inhibition constant of a
compound of Formula I for said at least one other cathepsin is at
least 100 times greater than said cathepsin S inhibition constant
of a compound of Formula I.
36. The method of claim 35, wherein the inhibition constant of a
compound of Formula I for said at least one other cathepsin is at
least 1000 times greater than said cathepsin S inhibition constant
of a compound of Formula I.
37. The method of claim 29, wherein said compound is a member
selected from the compounds of Table I.
38. The compound of claim 1, selected from the group consisting of:
N-{cis-2-[2-(4-Methoxy-phenylamino)-ethylcarbamoyl]-cyclohexyl}-3-methyl--
benzamide; 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide; 1-Benzoyl-piperidine-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide; Furan-2-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide; Furan-3-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide; 1-(4-Chloro-benzenesulfonyl)-piperidine-4-carboxylic
acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;
N-{1-(S)-[2-(4-Methoxy-phenylamino)-propylcarbamoyl]-3-methyl-butyl}-3-me-
thyl-benzamide;
N-{1-(S)-[2-(4-Methoxy-phenylamino)-1-methyl-ethylcarbamoyl]-3-methyl-but-
yl}-3-methyl-benzamide;
N-{1-(S)-[2-(4-Methoxy-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-3-methyl-
-butyl}-3-methyl-benzamide;
N-{1-(S)-[2-(4-Methoxy-phenylamino)-1-(R)-methyl-ethylcarbamoyl]-3-methyl-
-butyl}-3-methyl-benzamide; 1H-Indole-2-carboxylic acid
{3-cyclohexyl-(1S)-[2-(4-methoxy-phenylamino)-(1S)-methyl-ethylcarbamoyl]-
-propyl}-amide; 1H-Indole-2-carboxylic acid
{3-cyclohexyl-(1S)-[2-(4-methoxy-phenylamino)-(1R)-methyl-ethylcarbamoyl]-
-propyl}-amide;
N-{2-Cyclohexyl-(1S)-[2-(4-methoxy-phenylamino)-(1R)-methyl-ethylcarbamoy-
l]-ethyl}-3-methoxy-benzamide;
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid
{3-cyclohexyl-(1S)-[2-(4-methoxy-phenylamino)-(1S)-methyl-ethylcarbamoyl]-
-propyl}-amide; Tetrahydrofuran-2-(S)-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide; Tetrahydrofuran-2-(R)-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide;
N-{1-(S)-[1-(4-Methoxy-phenyl)-piperidin-3-(S)-ylcarbamoyl]-3-methyl-buty-
l}-3-methyl-benzamide;
N-{1-(S)-[1-(4-Methoxy-phenyl)-piperidin-3-(R)-ylcarbamoyl]-3-methyl-buty-
l}-3-methyl-benzamide;
N-{1-(S)-[cis-2-(4-Methoxy-phenylamino)-cyclohexylcarbamoyl]-3-methyl-but-
yl}-3-methyl-benzamide;
N-{1-(S)-[trans-2-(4-Methoxy-phenylamino)-cyclohexylcarbamoyl]-3-methyl-b-
utyl}-3-methyl-benzamide;
N-{1-(S)-[1-(R)-Benzyloxymethyl-2-(4-methoxy-phenylamino)-ethylcarbamoyl]-
-3-methyl-butyl}-3-methyl-benzamide;
N--(S)-{[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylc-
arbamoyl]-phenyl-methyl}-3-methoxy-benzamide;
N-[1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl-
carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-3-methoxy-benzamide;
N-{1-(S)-[(2-Benzyloxy-1-(R)-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-ethy-
lcarbamoyl]-3-cyclohexyl-propyl}-3-methoxy-benzamide;
1H-Indole-2-carboxylic acid
{(1S)-[2-benzyloxy-(1R)-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-ethylcarb-
amoyl]-3-cyclohexyl-propyl}-amide;
(S,S)--N-{1-[1-(5-Fluoro-2,3-dihydro-indol-1-ylmethyl)-3-ureido-propylcar-
bamoyl]-3-methyl-butyl}-3-methyl-benzamide;
(S,S)--N-{3-Cyclohexyl-1-[1-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-3-mor-
pholin-4-yl-propylcarbamoyl]-propyl}-3-methoxy-benzamide;
N-{1-(S)-[2-(R)-Benzyloxy-1-(R)-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-p-
ropylcarbamoyl]-3-cyclohexyl-propyl}-3-methoxy-benzamide;
N-{1-(R)-[1-(R)-Benzylsulfanylmethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)--
ethylcarbamoyl]-3-cyclohexyl-propyl}-3-methoxy-benzamide;
(S,S)-[5-[4-Cyclohexyl-2-(3-methoxy-benzoylamino)-butyrylamino]-6-(5-fluo-
ro-2,3-dihydro-indol-1-yl)-hexyl]-carbamic acid benzyl ester;
1-(6-Chloro-pyridazin-3-yl)-piperidine-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide; 1-(4-Methoxy-benzenesulfonyl)-piperidine-4-carboxylic
acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide; 1-Benzenesulfonyl-piperidine-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide; 1-Methyl-1H-imidazole-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide; 1-Benzyl-5-oxo-pyrrolidine-3-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide; 1-(4-Fluoro-benzenesulfonyl)-piperidine-4-carboxylic
acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;
N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoy-
l]-ethyl}-4-(piperidin-4-yloxy)-benzamide;
N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoy-
l]-ethyl}-4-(1-methanesulfonyl-piperidin-4-yloxy)-benzamide;
4-(1-Acetyl-piperidin-4-yloxy)-N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-di-
hydro-indol-1-yl)-ethylcarbamoyl]-ethyl}-benzamide;
5-Methanesulfonyl-thiophene-2-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide; 5-Oxo-1-thiophen-2-ylmethyl-pyrrolidine-3-carboxylic
acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide; 1-Furan-2-ylmethyl-5-oxo-pyrrolidine-3-carboxylic
acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide; 5-Phenyl-furan-2-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide; 2-Phenyl-thiazole-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide; 1-Methanesulfonyl-piperidine-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]e-
thyl}-amide; 5-Methyl-2-trifluoromethyl-furan-3-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide; 5-Phenyl-thiophene-2-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]e-
thyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic
acid
{2-cyclohexyl-1-(S)-[2-(4-difluoromethoxy-phenylamino)-1-(S)-methyl-ethyl-
carbamoyl]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(benzo[1,3]dioxol-5-ylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cyc-
lohexyl-ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-methoxy-phenylamino)-1-(S)-methyl-ethylcarbamoy-
l]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(3,5-difluoro-phenylamino)-1-(S)-methyl-ethylcarba-
moyl]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(3-methanesulfonyl-phenylamino)-1-(S)-methyl-ethyl-
carbamoyl]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-methanesulfonyl-phenylamino)-1-(S)-methyl-ethyl-
carbamoyl]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(2,3-difluoro-phenylamino)-1-(S)-methyl-ethylcarba-
moyl]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(2,5-difluoro-phenylamino)-1-(S)-methyl-ethylcarba-
moyl]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(2,6-difluoro-phenylamino)-1-(S)-methyl-ethylcarba-
moyl]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(4-cyano-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cyclohexyl-
-ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-chloro-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cyclohexy-
l-ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(2-fluoro-phenylamino)-1-(S)-methyl-ethylcarbamoyl-
]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-chloro-2-fluoro-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2--
cyclohexyl-ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic
acid
{1-(S)-[2-(5-chloro-2-fluoro-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2--
cyclohexyl-ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic
acid
{1-(S)-[2-(3-carbamoyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cycloh-
exyl-ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(3-fluoro-phenylamino)-1-(S)-methyl-ethylcarbamoyl-
]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-cyano-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cyclohexyl-
-ethyl}-amide; 5-(4-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]ethyl}-amide; 5-(4-Fluoro-phenyl)-furan-2-carboxylic
acid
{2-cyclohexyl-1-(S)-[2-(4-difluoromethoxy-phenylamino)-1-(S)-methyl-ethyl-
carbamoyl]ethyl}-amide; 5-(4-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-methoxy-phenylamino)-1-(S)-methyl-ethylcarbamoy-
l]ethyl}-amide; 5-(4-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(3-methanesulfonyl-phenylamino)-1-(S)-methyl-ethyl-
carbamoyl]ethyl}-amide; 5-(4-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-methanesulfonyl-phenylamino)-1-(S)-methyl-ethyl-
carbamoyl]ethyl}-amide;
3-(3-Fluoro-phenyl)-[1,2,4]oxadiazole-5-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-
-ethylcarbamoyl]-ethyl}-amide;
3-(4-Fluoro-phenyl)-[1,2,4]oxadiazole-5-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide; 3-[2-(S)-(3-Cyclohexyl-2-(S)-
{[5-(3-fluoro-phenyl)-furan-2-carbonyl]-amino}-propionylamino)-propylamin-
o]-benzoic acid methyl ester;
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(3-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic
acid
{1-(S)-[2-(2-chloro-5-fluoro-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2--
cyclohexyl-ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic
acid
{1-(S)-[2-(2-chloro-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cyclohexy-
l-ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-methoxy-2,6-dimethyl-phenylamino)-1-(S)-methyl--
ethylcarbamoyl]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic
acid
{2-cyclohexyl-1-(S)-[2-(4-methoxy-3,5-dimethyl-phenylamino)-1-(S)-methyl--
ethylcarbamoyl]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic
acid
{2-cyclohexyl-1-(S)-[2-(2-methanesulfonyl-phenylamino)-1-(S)-methyl-ethyl-
carbamoyl]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-methylsulfanyl-phenylamino)-ethylc-
arbamoyl]-ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-methylsulfamoyl-phenylamino)-ethyl-
carbamoyl]-ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic
acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethylsulfanyl-phenylamin-
o)-ethylcarbamoyl]-ethyl}-amide;
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(3-dimethylcarbamoyl-phenylamino)-1-(S)-methy-
l-ethylcarbamoyl]ethyl}-amide;
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(2-carbamoyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cycloh-
exyl-ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-dimethylcarbamoyl-phenylamino)-1-(S)-methyl-eth-
ylcarbamoyl]ethyl}-amide;
3-Cyclohexyl-2-(S)-(3-methoxy-propionylamino)-N-[1-(S)-methyl-2-(4-triflu-
oromethoxy-phenylamino)-ethyl]-propionamide;
3-Cyclohexyl-2-(S)-(2-methoxy-acetylamino)-N-[1-(S)-methyl-2-(4-trifluoro-
methoxy-phenylamino)-ethyl]-propionamide;
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-hydroxy-phenylamino)-1-(S)-methyl-ethylcarbamoy-
l]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-fluoro-phenylamino)-1-(S)-methyl-ethylcarbamoyl-
]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{3,3-dimethyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-butyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic
acid
{1-(S)-[2-(4-difluoromethoxy-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-3,-
3-dimethyl-butyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic
acid
{1-(S)-[2-(4-methanesulfonyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-3,-
3-dimethyl-butyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic
acid
{1-(S)-[2-(3-methanesulfonyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-3,-
3-dimethyl-butyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic
acid
{1-(S)-[2-(3-carbamoyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-3,3-dime-
thyl-butyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(4-methoxy-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-3,3-dimeth-
yl-butyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(5-methyl-isoxazol-3-ylamino)-ethylca-
rbamoyl]ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-acetylamino-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cycl-
ohexyl-ethyl}-amide; Tetrahydropyran-4-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic
acid
(2-cyclohexyl-1-(S)-{1-(S)-methyl-2-[4-(morpholine-4-sulfonyl)-phenylamin-
o]-ethylcarbamoyl}-ethyl)-amide;
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(3-oxo-1,3-dihydro-isobenzofuran-
-5-ylamino)-ethylcarbamoyl]ethyl}-amide;
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-sulfamoyl-phenylamino)-ethylcarbam-
oyl]-ethyl}-amide; Tetrahydropyran-4-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,2-dimethyl-2,3-dihydro-indol-1-yl)-1-(-
S)-methyl-ethylcarbamoyl]-ethyl}-amide;
Tetrahydrofuran-3-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,2-dimethyl-2,3-dihydro-indol-1-yl)-1-(-
S)-methyl-ethylcarbamoyl]-ethyl}-amide;
1-(3-Fluoro-phenyl)-1H-pyrazole-4-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]ethyl}-amide;
1-(4-Fluoro-phenyl)-1H-pyrazole-4-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]ethyl}-amide; 5-Pyridin-3-yl-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide; 5-(1-Oxy-pyridin-3-yl)-furan-2-carboxylic
acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide;
3-(3-Fluoro-phenyl)-isoxazole-5-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide;
3-(4-Fluoro-phenyl)-isoxazole-5-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide;
5-(3-Fluoro-phenyl)-[1,3,4]oxadiazole-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide;
N-{1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl-
carbamoyl]-2-cyclohexyl-ethyl}-3-methoxy-benzamide;
N-{2-Cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(S)-morpholi-
n-4-ylmethyl-ethylcarbamoyl]-ethyl}-3-methoxy-benzamide;
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid
{1-(S)-[1-(R)-benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylca-
rbamoyl]-2-cyclohexyl-ethyl}-amide;
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(R)-hydroxymet-
hyl-ethylcarbamoyl]ethyl}-amide;
{1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylca-
rbamoyl]-3,3-dimethyl-butyl}-carbamic acid tert-butyl ester;
N-{1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl-
carbamoyl]-3,3-dimethyl-butyl}-3-methoxy-benzamide
{1-(S)-[1-(S)-(5-Fluoro-2,3-dihydro-indol-1-ylmethyl)-3-methanesulfonyl-p-
ropylcarbamoyl]-3,3-dimethyl-butyl}-carbamic acid tert-butyl ester;
3-(S)-(2-(S)-Benzyloxycarbonylamino-4,4-dimethyl-pentanoylamino)-4-(5-flu-
oro-2,3-dihydro-indol-1-yl)-butyric acid tert-butyl ester;
3-(S)-(2-(S)-Benzyloxycarbonylamino-4,4-dimethyl-pentanoylamino)-4-(5-flu-
oro-2,3-dihydro-indol-1-yl)-butyric acid;
{1-(S)-[2-Cyano-1-(S)-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-ethylcarbam-
oyl]-3,3-dimethyl-butyl}-carbamic acid tert-butyl ester;
N-{1-(S)-[2-(5-Fluoro-2,3-dihydro-indol-1-yl)-1-(S)-(1H-tetrazol-5-ylmeth-
yl)-ethylcarbamoyl]-3,3-dimethyl-butyl}-3-methoxy-benzamide;
3-(S)-(2-(S)-Benzyloxycarbonylamino-3-cyclohexyl-propionylamino)-4-(5-flu-
oro-2,3-dihydro-indol-1-yl)-butyric acid benzyl ester;
1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcar-
bamoyl]-2-cyclohexyl-ethyl}-carbamic acid benzyl ester;
N-{3-Cyclohexyl-1-(S)-[2-(3,5-dimethoxy-benzyloxy)-1-(R)-(5-fluoro-2,3-di-
hydro-indol-1-ylmethyl)-ethylcarbamoyl]-propyl}-3-methoxy-benzamide;
4-{2-(R)-[4-Cyclohexyl-2-(S)-(3-methoxy-benzoylamino)-butyrylamino]-3-(5--
fluoro-2,3-dihydro-indol-1-yl)-propoxymethyl}-benzoic acid methyl
ester; Tetrahydropyran-4-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1-(-
S)-methyl-ethylcarbamoyl]-ethyl}-amide;
{2-Cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(S)-methyl-eth-
ylcarbamoyl]-ethyl}-carbamic acid benzyl ester;
4-Benzyloxy-N--(R,S)-{[2-(4-amidinophenylamino)-1-(S)-methyl-ethylcarbamo-
yl]-(2,4-dichloro-phenyl)-methyl}-benzamide;
{1-(S)-[2-(5-Fluoro-2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethylcarbamoyl]--
3,3-dimethyl-butyl}-carbamic acid benzyl ester;
Pyridazine-4-carboxylic acid
{1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethylcarbam-
oyl]-3,3-dimethyl-butyl}-amide;
4,4-Dimethyl-2-(S)-(2-1H-tetrazol-5-yl-acetylamino)-pentanoic acid
[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethyl]-amide;
(2-Cyclohexyl-1-(S)-{1-(S)-methyl-2-[3-(1H-tetrazol-5-yl)-phenylamino]-et-
hylcarbamoyl}-ethyl)-carbamic acid benzyl ester;
(S,S)-2-(3-Chloro-benzenesulfonylamino)-3-cyclohexyl-N-[1-methyl-2-(4-tri-
fluoromethoxy-phenylamino)-ethyl]-propionamide;
(S,S)-3-Cyclohexyl-N-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-ethyl]--
2-(3-trifluoromethoxy-benzenesulfonylamino)-propionamide;
(S,S)-3-Cyclohexyl-N-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-ethyl]--
2-(pyridine-3-sulfonylamino)-propionamide;
(S,S)-{2-Cyclohexyl-1-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-ethylc-
arbamoyl]-ethyl}-carbamic acid tetrahydro-pyran-4-yl ester;
3-(R)-{2-Cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino-
)-ethylcarbamoyl]-ethylcarbamoyloxy}-pyrrolidine-1-carboxylic acid
tert-butyl ester;
(S,S)-{2-Cyclohexyl-1-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-ethylc-
arbamoyl]-ethyl}-carbamic acid
1,1-dioxo-hexahydro-1.lamda..sup.6-thiopyran-4-yl ester;
{2-Cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-carbamic acid pyrrolidin-3-(R)-yl ester;
{2-Cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-carbamic acid tetrahydrofuran-3-(R)-yl ester;
{2-Cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-carbamic acid tetrahydrofuran-3-(S)-yl ester;
(S,S)-{2-Cyclopentyl-1-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-ethyl-
carbamoyl]-ethyl}-carbamic acid tetrahydropyran-4-yl ester;
(S,S)-{2-Cyclopentyl-1-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-ethyl-
carbamoyl]-ethyl}-carbamic acid tetrahydrofuran-3-(R)-yl ester;
(S,S)-{2-Cyclopentyl-1-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-ethyl-
carbamoyl]-ethyl}-carbamic acid tetrahydrofuran-3-(S)-yl ester;
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-cyclopropylethyl)-5--
(3-(trifluoromethyl)phenyl)furan-2-carboxamide;
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-(3-chlorophenyl)ethy-
l)-5-(3-(trifluoromethyl)phenyl)furan-2-carboxamide;
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-(4-chlorophenyl)ethy-
l)-5-(3-(trifluoromethyl)phenyl)furan-2-carboxamide;
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-cyclopentylethyl)-5--
(3-(trifluoromethyl)phenyl)furan-2-carboxamide;
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-3,3-dimethylbutyl)-5-(-
3-(trifluoromethyl)phenyl)furan-2-carboxamide;
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-phenylethyl)-5-(3-(t-
rifluoromethyl)phenyl)furan-2-carboxamide;
N--(R,S)-((3-(benzyloxy)-1-(5-fluoroindolin-1-yl)propan-2-(R)-ylcarbamoyl-
)(2,4-dichlorophenyl)methyl)furan-2-carboxamide;
N--(S)-((3-(5-fluoroindolin-1-yl)-1-hydroxypropan-2-(R)-ylcarbamoyl)(2,4--
dichlorophenyl)methyl)furan-2-carboxamide;
(S,S)-3-Cyclohexyl-2-(2,4-dimethyl-thiazole-5-sulfonylamino)-N-[2-(5-fluo-
ro-2,3-dihydro-indol-1-yl)-1-methyl-ethyl]-propionamide;
N--(S)-((3-(benzyloxy)-1-(5-fluoroindolin-1-yl)propan-2-(R)-ylcarbamoyl)(-
2,4-dichlorophenyl)methyl)-3,4-difluorobenzamide;
N---(S)-((3-(5-fluoroindolin-1-yl)-1-hydroxypropan-2-(R)-ylcarbamoyl)(2,4-
-dichlorophenyl)methyl)furan-2-carboxamide;
(S,S)-{2-Cyclohexyl-1-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1-
-methyl-ethylcarbamoyl]-ethyl}-carbamic acid tetrahydro-pyran-4-yl
ester;
{2-Cyclohexyl-1-(S)-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1-(-
S)-methyl-ethylcarbamoyl]-ethyl}-carbamic acid
(R)-tetrahydrofuran-3-yl ester;
(S,S)-{2-Cyclohexyl-1-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol--
1-yl)-1-methyl-ethylcarbamoyl]-ethyl}-carbamic acid
(S)-tetrahydro-furan-3-yl ester;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[3-(5-ph-
enyl-thiophen-2-yl)-ureido]-propionamide;
(S)-3-Cyclohexyl-2-[3-(3,5-dimethyl-isoxazol-4-yl)-ureido]-N-[2-(5-fluoro-
-2,3-dihydro-indol-1-yl)-ethyl]-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(5-methy-
l-1-phenyl-1H-pyrazole-4-sulfonylamino)-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(5-isoxa-
zol-3-yl-thiophene-2-sulfonylamino)-propionamide;
(S)-{2-Cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-carbamic acid benzyl ester;
(S)-2-(4-Bromo-3-chloro-thiophene-2-sulfonylamino)-3-cyclohexyl-N-[2-(5-f-
luoro-2,3-dihydro-indol-1-yl)-ethyl]-propionamide;
(S)-2-(3-Biphenyl-4-yl-ureido)-3-cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-in-
dol-1-yl)-ethyl]-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4-pheno-
xy-benzenesulfonylamino)-propionamide;
(S)-2-(5-Chloro-thiophene-2-sulfonylamino)-3-cyclohexyl-N-[2-(5-fluoro-2,-
3-dihydro-indol-1-yl)-ethyl]-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(naphtha-
lene-1-sulfonylamino)-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4-trifl-
uoromethyl-benzenesulfonylamino)-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4-trifl-
uoromethoxy-benzenesulfonylamino)-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[5-(2-me-
thyl-5-trifluoromethyl-2H-pyrazol-3-yl)-thiophene-2-sulfonylamino]-propion-
amide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(3-
-methyl-3H-imidazole-4-sulfonylamino)-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[3-(5-me-
thyl-[1,3,4]oxadiazol-2-yl)-benzenesulfonylamino]-propionamide;
(S)-2-(Benzo[b]thiophene-2-sulfonylamino)-3-cyclohexyl-N-[2-(5-fluoro-2,3-
-dihydro-indol-1-yl)-ethyl]-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(thiophe-
ne-2-sulfonylamino)-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[4-(4-fl-
uoro-phenoxy)-benzenesulfonylamino]-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[5-(2-me-
thyl-thiazol-4-yl)-thiophene-2-sulfonylamino]-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4'-meth-
oxy-biphenyl-4-sulfonylamino)-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4-metho-
xy-benzenesulfonylamino)-propionamide;
(S)-3-Cyclohexyl-2-(4-difluoromethoxy-benzenesulfonylamino)-N-[2-(5-fluor-
o-2,3-dihydro-indol-1-yl)-ethyl]-propionamide;
(S)-2-(5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-3-cyclohexyl-N--
[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-phenylme-
thanesulfonylamino-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(toluene-
-3-sulfonylamino)-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[4-(4-me-
thoxy-phenoxy)-benzenesulfonylamino]-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(3-metho-
xy-benzenesulfonylamino)-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4-oxazo-
l-5-yl-benzenesulfonylamino)-propionamide;
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(3-methyl-isoxazol-5-ylamino)-ethylca-
rbamoyl]ethyl}-amide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(thiophe-
ne-3-sulfonylamino)-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-methanes-
ulfonylamino-propionamide;
(S,S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-methyl-ethyl]-
-2-(5-oxazol-5-yl-thiophene-3-sulfonylamino)-propionamide;
(S,S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-methyl-ethyl]-
-2-(toluene-3-sulfonylamino)-propionamide;
(S,S)-3-[4,4-Dimethyl-2-(toluene-3-sulfonylamino)-pentanoylamino]-4-(5-fl-
uoro-2,3-dihydro-indol-1-yl)-butyric acid tert-butyl ester;
(S,S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-methyl-ethyl]-
-2-(2-methyl-4-trifluoromethyl-furan-3-sulfonylamino)-propionamide;
(S,S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-methyl-ethyl]-
-2-(3-trifluoromethoxy-benzenesulfonylamino)-propionamide;
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(1-methy-
l-1H-imidazole-4-sulfonylamino)-propionamide;
(S)-2-(5-Benzenesulfonyl-thiophene-2-sulfonylamino)-3-cyclohexyl-N-[2-(5--
fluoro-2,3-dihydro-indol-1-yl)-ethyl]-propionamide;
(S)-2-(2-Acetylamino-4-methyl-thiazole-5-sulfonylamino)-3-cyclohexyl-N-[2-
-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-propionamide;
(S)-3-Cyclohexyl-2-(4,5-dichloro-thiophene-2-sulfonylamino)-N-[2-(5-fluor-
o-2,3-dihydro-indol-1-yl)-ethyl]-propionamide;
(S,S)-2-(3-Chloro-benzenesulfonylamino)-3-cyclohexyl-N-[2-(5-fluoro-2,3-d-
ihydro-indol-1-yl)-1-methyl-ethyl]-propionamide;
(S,S)-3-(2-tert-Butoxycarbonylamino-3-cyclohexyl-propionylamino)-4-(5-flu-
oro-2,3-dihydro-indol-1-yl)-butyric acid benzyl ester;
(S,S)-3-[4,4-Dimethyl-2-(toluene-3-sulfonylamino)-pentanoylamino]-4-(5-fl-
uoro-2,3-dihydro-indol-1-yl)-butyric acid;
(S,S)-3-Cyclohexyl-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-[2-(5-flu-
oro-2,3-dihydro-indol-1-yl)-1-methyl-ethyl]-propionamide;
(S,S)-2-Benzenesulfonylamino-3-cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indo-
l-1-yl)-1-methyl-ethyl]-propionamide;
(S,S)-4,4-Dimethyl-2-(toluene-3-sulfonylamino)-pentanoic acid
[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-methyl-ethyl]-amide;
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(4-benzyloxy-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cycloh-
exyl-ethyl}-amide; 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(3-methyl-isothiazol-5-ylamino)-ethyl-
carbamoyl]ethyl}-amide; Tetrahydrofuran-2-(R)-carboxylic acid
{3,3-dimethyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-butyl}-amide; Tetrahydropyran-4-carboxylic acid
{3,3-dimethyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-butyl}-amide; Tetrahydro-pyran-4-carboxylic acid
{1-(S)-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1-(S)-methyl-eth-
ylcarbamoyl]-3,3-dimethyl-butyl}-amide;
Tetrahydro-furan-2-(R)-carboxylic acid
{1-(S)-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1-(S)-methy-
l-ethylcarbamoyl]-3,3-dimethyl-butyl}-amide;
Tetrahydrofuran-3-(R,S)-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide; Tetrahydrofuran-2-(R)-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1-(-
S)-methyl-ethylcarbamoyl]ethyl}-amide, and
Tetrahydrofuran-2-(R)-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,2-dimethyl-2,3-dihydro-indol-1-yl)-1-(-
S)-methyl-ethylcarbamoyl]ethyl}-amide.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a Divisional Application of U.S. patent
application Ser. No. 10/807,613 filed Mar. 23, 2004 which claims
the benefit of U.S. Provisional Patent Application No. 60/457,848,
filed Mar. 24, 2003, the disclosures of which are hereby
incorporated by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] Cysteine proteases represent an enzymatic class of proteins
that catalyze the hydrolysis of peptide bonds by a nucleophilic
sulfhydryl group of a cysteine residue in the active site of the
enzyme. Several normal and disease processes in mammals have been
associated with cysteine protease activity and include, but are not
limited to: osteoporosis, osteoarthritis (Inui, T., O. Ishibashi, J
Biol Chem 1997, 272(13), 8109-12; Saftig, P., E. Hunziker, et al.,
Adv Exp Med Biol 2000+ADs 2000, 477, 293-303; Saftig, P., E.
Hunziker, et al., Proc Natl Acad Sci USA 1998, 95(23), 13453-8),
periodontal diseases, Paget's disease, atherosclerosis (Jormsjo,
S., D. M. Wuttge, et al., Am J Pathol 2002 161(3), 939-45),
multiple sclerosis (Beck, H., G. Schwarz, et al., Eur J Immunol
2001, 31(12), 3726-36), rheumatoid arthritis (Nakagawa, T. Y., W.
H. Brissette, et al., Immunity 1999, 10(2), 207-17; Hou, W. S., Z.
Li, et al., Am J Pathol 2001, 159(6), 2167-77), juvenile onset
diabetes, lupus, asthma (Cimerman, N., P. M. Brguljan, et al.,
Pflugers Arch 2001, 442(6 Suppl 1), R204-6), tissue rejection,
Alzheimer's disease (Lemere, C. A., J. S. Munger, et al., Am J
Pathol 1995, 146(4), 848-60), Parkinson's disease (Liu, Y., L.
Fallon, et al., Cell 2002, 111(2), 209-18), neuronal degeneration,
shock (Jaeschke, H., M. A. Fisher, et al., J Immunol 1998, 160(7),
3480-6), cancer (Fernandez, P. L., X. Farre, et al., Int J Cancer
2001, 95(1), 51-5), malaria (Malhotra, P., P. V. Dasaradhi, et al.,
Mol Microbiol 2002, 45(5), 1245-54), Chagas (Eakin, A. E., A. A.
Mills, et al., J Biol Chem 1992, 267(11), 7411-20), leishmaniasis,
shistosomiasis, and African trypanosomiasis (Caffrey, C. R., S.
Scory, et al., Curr Drug Targets 2000, 1(2), 155-62; Lalmanach, G.,
A. Boulange, et al., Biol Chem 2002, 383(5), 739-49).
[0003] Cathepsins are a subclass of cysteine protease that belong
to the enzyme classification EC 3.4.22 (Barrett, A. J., N. D.
Rawlings, et al., Handbook of proteolytic enzymes. London, Academic
Press). Cathepsins play a major role in lysosomal, endosomal, and
extracellular protein degradation and have thus been implicated in
many disease processes. For example, Cathepsin B [EC 3.4.22.1] has
been postulated to play a role in tumor metastasis (Berquin, I. M.
and B. F. Sloane Adv Exp Med Biol 1996, 389, 281-94).
[0004] Cathepsin S [EC 3.4.22.27] is largely expressed in
professional antigen presenting cells such as macrophages and
dendritic cells. Cathepsin S has been shown to be required for
proper MHC class II antigen presentation (Shi, G. P., J. A.
Villadangos, et al., Immunity 1999, 10(2) 197-206). As a result of
its non-redundant role in MHC class II antigen presentation,
cathepsin S has been associated with inflammation, arthritis, and
atherosclerosis. The selective expression of cathepsin K [EC
3.4.22.38] in osteoclasts coupled with the ability of cathepsin K
to degrade type I collagen suggests that it plays a role in normal
and pathogenic bone remodeling (Bromme, D., K. Okamoto, et al., J
Biol Chem 1996, 27](4), 2126-32). There is a need in the art for
compounds and methods that selectively inhibit specific cysteine
proteases for treating several pathogenic disorders in mammals. The
present invention satisfies these and other needs.
BRIEF SUMMARY OF THE INVENTION
[0005] The present invention provides compounds, compositions and
methods for the selective inhibition of cathepsin S. The compounds
of the present invention are selective for cathepsin S in the
presence of other cathepsin isozymes (e.g. cathepsin K). The
present invention also provides methods for treating a disease
state in a subject by selectively inhibiting cathepsin S in the
presence of other cathepsin isozymes.
[0006] As such, in one embodiment, the present invention provides a
compound of Formula I:
##STR00001## [0007] or a pharmaceutically acceptable salt or
prodrug thereof, [0008] wherein: [0009] R.sup.1 is a member
selected from the group of H, C.sub.6-C.sub.10 aryl substituted
with 0-3 R.sup.1a, a 5- to 6-membered monocyclic or 8- to
10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-3 R.sup.1a, a
C.sub.3-C.sub.8 cycloalkyl substituted with 0-2 R.sup.1b, wherein
said C.sub.3-C.sub.8 cycloalkyl is saturated or unsaturated; and a
C.sub.3-C.sub.8 heterocycle containing 1 to 2 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heterocycle is substituted with 0-2 R.sup.1c
and is saturated or unsaturated; [0010] each R.sup.1a is
independently a member selected from the group of H,
C.sub.1-C.sub.3 perfluoroalkyl, C.sub.3-C.sub.7 cycloalkyl, F, Cl,
Br, CN, NO.sub.2, OR.sup.10, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2R.sup.10, NR.sup.11R.sup.12, acetyl,
C(.dbd.O)OR.sup.13, C(.dbd.O)NR.sup.13R.sup.14,
S(.dbd.O).sub.2NR.sup.13R.sup.14, phenyl substituted with 0-3
R.sup.15, a 5- to 6-membered monocyclic heteroaryl containing 1 to
4 heteroatoms each independently a member selected from the group
of N, O and S, wherein said heteroaryl is substituted with 0-2
R.sup.15, a C.sub.3-C.sub.8 heterocycle containing 1 to 2
heteroatoms each independently a member selected from the group of
N, O and S, wherein said heterocycle is substituted with 0-2
R.sup.1c and is saturated or unsaturated, and a C.sub.1-C.sub.4
alkyl substituted with 0-2 R.sup.16; [0011] each R.sup.1b is
independently a member selected from the group of H, OH, F, Cl,
acetyl, .dbd.O, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
CF.sub.3 and OCF.sub.3; [0012] each R.sup.1c is independently a
member selected from the group of H, OH, F, Cl, .dbd.O,
C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.16,
C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, C(.dbd.O)R.sup.10,
S(.dbd.O).sub.2R.sup.10, tBoc, Cbz; phenyl substituted with 0-3
R.sup.15; a 5- to 6-membered monocyclic heteroaryl containing 1 to
4 heteroatoms each independently a member selected from the group
of N, O and S, wherein said heteroaryl is substituted with 0-2
R.sup.15; [0013] R.sup.2 is a member selected from the group of a
phenyl substituted with 0-3 R.sup.15, a 5- to 6-membered monocyclic
heteroaryl containing 1 to 4 heteroatoms each independently a
member selected from the group of N, O and S, wherein said
heteroaryl is substituted with 0-2 R.sup.15, a C.sub.1-C.sub.6
alkyl substituted with 0-2 R.sup.2a, wherein said C.sub.1-C.sub.6
alkyl optionally contains a heteroatom selected from the group of
--O--, --S--, and --S(.dbd.O).sub.2--, a C.sub.2-C.sub.6 alkenyl, a
C.sub.2-C.sub.6 alkynyl, a C.sub.3-C.sub.7 cycloalkyl substituted
with 0-2 R.sup.19, wherein said C.sub.3-C.sub.7 cycloalkyl
optionally contains a heteroatom selected from --O--, --S--, and
--S(.dbd.O).sub.2--, and a C.sub.7-C.sub.11 bicycloalkyl
substituted with 0-2 R.sup.19; [0014] each R.sup.2a is
independently a member selected from the group of a
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.15, a 5- to
6-membered monocyclic or 8- to 10-membered bicyclic heteroaryl
containing 1 to 4 heteroatoms each independently a member selected
from the group of N, O and S, wherein said heteroaryl is
substituted with 0-3 R.sup.15, a C.sub.3-C.sub.8 cycloalkyl
substituted with 0-2 R.sup.19, and a C.sub.7-C.sub.11 bicycloalkyl
substituted with 0-2 R.sup.19; [0015] R.sup.3 is a member selected
from the group of H and C.sub.1-C.sub.4 alkyl; [0016] subscript n
is 0 or 1; [0017] R.sup.4is a member selected from the group of H
and C.sub.1-C.sub.6 alkyl; [0018] alternatively, R.sup.2 and
R.sup.4 are taken together to form a C.sub.5-C.sub.7 cycloalkyl
substituted with 0-2 R.sup.19; [0019] R.sup.5 is a member selected
from the group of H, C.sub.3-C.sub.7 cycloalkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkyne, phenyl substituted with 0-2
R.sup.15; 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms
each independently a member selected from the group of N, O and S,
wherein said heteroaryl is substituted with 0-2 R.sup.15, a
C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.18, wherein said
C.sub.1-C.sub.6 alkyl optionally contains a heteroatom selected
from the group of --O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--
and --NR.sup.17--; [0020] Y is a member independently selected from
the group of a bond and
--(CR.sup.20R.sup.21).sub.m--W--(CR.sup.22R.sup.23).sub.p--; [0021]
subscript p is 1 or 2; [0022] subscript m is 0 or 1; [0023] W is a
member independently selected from the group of a bond, --O--,
--S--, --S(.dbd.O)--, --S(.dbd.O).sub.2-- and --NR.sup.12--; [0024]
X is selected from the group of --C(.dbd.O)--, --OC(.dbd.O)--,
--NR.sup.24C(.dbd.O)-- and --S(.dbd.O).sub.2--; [0025] each of
R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is independently a member
selected from the group of H and C.sub.1-C.sub.4 alkyl; [0026]
alternatively, R.sup.5 and R.sup.7 are taken together to form a
C.sub.5-C.sub.7 cycloalkyl substituted with 0-2 R.sup.19; [0027]
alternatively, R.sup.5 and R.sup.9 are taken together to form a 6-7
membered heterocyclic ring containing 1-2 heteroatoms each
independently a member selected from the group of N, O and S;
[0028] Ar is a member selected from the group of phenyl substituted
with 0-3 R.sup.29, and 5- to 6-membered heteroaryl containing 1 to
4 heteroatoms each independently a member selected from the group
of N, O and S, wherein said heteroaryl is substituted with 0-3
R.sup.29; each R.sup.10 is independently a member selected from the
group of H, C.sub.3-C.sub.7 cycloalkyl, a C.sub.1-C.sub.3
perfluoroalkyl, a C.sub.1-C.sub.4 alkyl substituted with 0-1
R.sup.25, a phenyl substituted with 0-3 R.sup.15; a 5- to
6-membered heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group of N, O and S,
wherein said heteroaryl is substituted with 0-2 R.sup.15, and a
C.sub.3-C.sub.8 heterocycle containing 1 to 2 heteroatoms each
independently a member selected from the group of N, O and S,
wherein said heterocycle is substituted with 0-2 R.sup.1c; [0029]
each R.sup.11 is independently a member selected from the group of
H, .sup.tBOC, Cbz, C.sub.3-C.sub.8 cycloalkyl, (C.sub.1-C.sub.6
alkyl)-C(.dbd.O)--, (C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2-- and a
C.sub.1-C.sub.6 alkyl; [0030] each of R.sup.12, R.sup.13 and
R.sup.14 is independently a member selected from the group of H and
C.sub.1-C.sub.4 alkyl; [0031] alternatively, R.sup.13 and R.sup.14
on the same N atom are taken together to form a C.sub.5-C.sub.7
heterocycle containing 1-2 heteroatoms each independently a member
selected from the group of N, O and S; [0032] each R.sup.15 is
independently a member selected from the group of H, OH, F, Cl, Br,
I, CN, NO.sub.2, COOR.sup.13, C(.dbd.O)NR.sup.13R.sup.14,
S(.dbd.O).sub.2NR.sup.13R.sup.14, acetyl, --SCH.sub.3,
--S(.dbd.O)CH.sub.3, --S(.dbd.O).sub.2CH.sub.3, NR.sup.26R.sup.27,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3 perfluoroalkyl,
C.sub.1-C.sub.3 perfluoroalkoxy and a C.sub.1-C.sub.6 alkyl; [0033]
each R.sup.16 is independently a member selected from the group of
H, OH, COOR.sup.13, C(.dbd.O)NR.sup.13R.sup.14,
S(.dbd.O).sub.2NR.sup.13R.sup.14, acetyl, --SCH.sub.3,
--S(.dbd.O)CH.sub.3, --S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6
alkoxy, NR.sup.26R.sup.27, a phenyl substituted with 0-3 R.sup.15,
a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group of N, O and S,
wherein said heteroaryl is substituted with 0-3 R.sup.15, and a
C.sub.3-C.sub.8 heterocycle containing 1 to 2 heteroatoms each
independently a member selected from the group of N, O and S,
wherein said heterocycle is substituted with 0-2 R.sup.15 and is
saturated or unsaturated; [0034] R.sup.17 is a member selected from
the group of H and C.sub.1-C.sub.4 alkyl; [0035] each R.sup.18 is
independently a member selected from the group of H, OH, F, Cl, CN,
NO.sub.2, C(.dbd.O)OR.sup.30, C(.dbd.O)NR.sup.13R.sup.14,
NR.sup.11R.sup.12, a C.sub.1-C.sub.3 perfluoroalkyl, a
C.sub.1-C.sub.3 perfluoroalkoxy, a phenyl substituted with 0-3
R.sup.15, a 5- to 6-membered heteroaryl containing 1 to 4
heteroatoms each independently a member selected from the group of
N, O and S, wherein said heteroaryl is substituted with 0-3
R.sup.15, a C.sub.3-C.sub.8 heterocycle containing 1 to 2
heteroatoms each independently a member selected from the group of
N, O and S, wherein said heterocycle is substituted with 0-2
R.sup.15 and is saturated or unsaturated; and C.sub.3-C.sub.8
cycloalkyl; [0036] each R.sup.19 is a independently a member
selected from the group of C.sub.1-C.sub.4 alkyl, F, Cl and
C.sub.1-C.sub.4 alkoxy, CF.sub.3 and OCF.sub.3; [0037]
alternatively, two R.sup.19 on the same carbon may be combined to
form C.sub.3-C.sub.6 cycloalkyl; [0038] each of R.sup.20, R.sup.21,
R.sup.22 and R.sup.23 is independently a member selected from the
group of a bond, H, F, OH, C.sub.1-C.sub.4 alkyl, and
C.sub.1-C.sub.3 alkylhydroxy; [0039] alternatively, R.sup.20 and
R.sup.21 or R.sup.22 and R.sup.23 are taken together to form a
C.sub.3-C.sub.6 cycloalkyl; [0040] R.sup.24 is a member selected
from the group of H and C.sub.1-C.sub.4 alkyl; [0041] each R.sup.25
is independently a member selected from the group of H,
C.sub.3-C.sub.7 cycloalkyl, a phenyl substituted with 0-3 R.sup.15
and a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms
each independently a member selected from the group of N, O and S,
wherein said 5- to 6-membered heteroaryl is substituted with 0-2
R.sup.15; [0042] each R.sup.26 is independently a member selected
from the group of H, C.sub.1-C.sub.4 alkyl, (C.sub.1-C.sub.4
alkyl)-C(.dbd.O)-- and (C.sub.1-C.sub.4 alkyl)-S(.dbd.O).sub.2--;
[0043] each R.sup.27 is independently a member selected from the
group of H and C.sub.1-C.sub.4 alkyl; [0044] alternatively,
R.sup.26 and R.sup.27 on the same N atom are taken together to form
a C.sub.5-C.sub.7 heterocycle containing 1-2 heteroatoms each
independently a member selected from the group of N, O and S;
[0045] each R.sup.28 is independently a member selected from the
group of H, a C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, a
phenyl substituted with 0-3 R.sup.15, a benzyl substituted with 0-2
R.sup.15; [0046] each R.sup.29 is independently a member selected
from the group of H, F, Cl, Br, I, CN, NO.sub.2, OR.sup.28,
SR.sup.28, S(.dbd.O)R.sup.28, S(.dbd.O).sub.2R.sup.28,
S(.dbd.O).sub.2NR.sup.13R.sup.14, NR.sup.26R.sup.27, acetyl,
C(.dbd.O)NR.sup.13R.sup.14, C(.dbd.O)OR.sup.13, C.sub.1-C.sub.6
alkyl, OCHF.sub.2, SCF.sub.3, OCF.sub.3, --C(.dbd.NH)NH.sub.2, and
5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group of N, O and S;
[0047] alternatively, two R.sup.29 substituted on adjacent atoms
may be combined to form a 5 to 6 membered heterocyclic fused
radical, wherein said 5 to 6 membered heterocyclic fused radical
comprise 1 or 2 heteroatom(s) selected from O, S and N; wherein
said 5 to 6 membered heterocyclic fused radical is substituted with
0-1 oxo; [0048] alternatively, R.sup.29 and R.sup.9 are taken
together to form a 5- to 7-membered fused heterocyclic ring
containing 1-2 heteroatom(s) each independently a member selected
from the group of N, O and S; wherein said 5 to 7 membered fused
heterocyclic ring is substituted with 0-2 R.sup.19; [0049] each
R.sup.30 is independently a member selected from the group of H,
C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.4 alkyl substituted with
0-1 R.sup.25, a phenyl substituted with 0-3 R.sup.15, and a 5- to
6-membered heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group of N, O and S,
wherein said heteroaryl is substituted with 0-3 R.sup.15; and with
the proviso that R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, and R.sup.9 are not all hydrogen.
[0050] In a second aspect, the present invention provides a
pharmaceutical composition comprising a compound of Formula I, as
described above, and a pharmaceutically acceptable excipient.
[0051] In a third aspect, the present invention provides a method
of selectively inhibiting the cathepsin S activity in a mammal in
need thereof, comprising administering to the mammal a
therapeutically effective amount of a compound of Formula I, as
described above, or a pharmaceutically acceptable salt or prodrug
thereof.
[0052] These and other aspects, objects and embodiments will become
more apparent when read with the accompanying figure and detailed
description which follows.
BRIEF DESCRIPTION OF THE DRAWINGS
[0053] FIG. 1 depicts MHC II antigen presentation.
DETAILED DESCRIPTION OF THE INVENTION
I. DEFINITIONS
[0054] Unless defined otherwise, all technical and scientific terms
used herein generally have the same meaning as commonly understood
by one of ordinary skill in the art to which this invention
belongs. Generally, the nomenclature used herein and the laboratory
procedures for organic and analytical chemistry are those well
known and commonly employed in the art.
[0055] As used in this disclosure, the following abbreviations and
terms have the defined meaning, unless expressly modified in the
context in which the term is used: [0056] Ac acetyl [0057] Bn
benzyl [0058] Boc t-butoxycarbonyl [0059] Cbz or Z
benzyloxycarbonyl [0060] DCC N,N'-dicyclohexylcarbodiimide [0061]
DCM dichoromethane [0062] DIBAL diisobutylaluminum hydride [0063]
DIC N,N'-diisopropylcarbodiimide [0064] DIEA or DIPEA
diisopropylethylamine [0065] DMAP 4-(dimethylamino)pyridine [0066]
DMF dimethylformamide [0067] DMSO dimethyl sulfoxide [0068] EDC or
EDCI 1-ethyl-3-(dimethylaminopropyl)-carbodiimide [0069] Fmoc
9-fluorenylmethoxycarbonyl [0070] HATU
O-(7-azabenzoatriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0071] HOBt 1-hydroxybenzotriazole [0072] KHMDS
potassium hexamethyldisilazide [0073] LAH lithium aluminum hydride
[0074] LDA lithium diisopropylamide [0075] LHMDS lithium
hexamethyldisilazide [0076] m-CPBA m-chloroperbenzoic acid [0077]
MW microwave [0078] NaHMDS sodium hexamethyldisilazide [0079] PCC
pyridinium chlorochromate [0080] PDC pyridinium dichromate [0081]
PG protecting group [0082] PTSA p-toluenesulfonic acid [0083] Py
pyridine [0084] RT or rt room temperature [0085] TEA triethylamine
[0086] Tf trifluoromethanesulfonyl [0087] TFA trifluoroacetic acid
[0088] THF tetrahydrofuran [0089] Tol p-tolyl [0090] TPAP
tetrapropylammonium perruthenate
[0091] The term "lower" referred to above and hereinafter in
connection with organic radicals or compounds respectively defines
a compound or radical which can be branched or unbranched with up
to and including 7, preferably up to and including 4 and (as
unbranched) one or two carbon atoms.
[0092] The term "perfluoro" referred to above and hereinafter in
connection with organic radicals or compounds respectively, defines
a compound or radical which has at least two available hydrogens
substituted with fluorine. For example, perfluorophenyl refers to
1,2,3,4,5-pentafluorophenyl, perfluoromethyl refers to
1,1,1-trifluoromethyl, and perfluoromethoxy refers to
1,1,1-trifluoromethoxy.
[0093] An alkyl group is branched or unbranched and contains 1 to 7
carbon atoms, preferably 1-4 carbon atoms. Alkyl represents, for
example, methyl, ethyl, propyl, butyl, isopropyl or isobutyl.
[0094] Alkenyl represents either straight chain or branched alkenyl
of 2 to 7 carbon atoms, preferably 2-4 carbon atoms, e.g. as vinyl,
propenyl, isopropenyl, butenyl, isobutenyl or butadienyl.
[0095] Alkynyl represents either straight chain or branched alkynyl
of 2 to 7 carbon atoms, preferably 2-4 carbon atoms, e.g. as
acetylenyl, propynyl, isoprpropynyl, butynyl or isobutynyl.
[0096] Alkyl, alkenyl or alkynyl can be substituted by up to 3
substituents selected from alkoxy, aryl, heterocyclyl, hydroxy,
halogen, cyano, optionally substituted amino, or optionally
substituted amino-oxy or trifluoromethyl.
[0097] Alkylene represents either straight chain or branched
alkylene of 1 to 7 carbon atoms, i.e. a divalent hydrocarbon
radical of 1 to 7 carbon atoms; for instance, straight chain
alkylene being the bivalent radical of Formula --(CH.sub.2).sub.n,
where n is 1, 2, 3, 4, 5, 6 or 7. Preferably alkylene represents
straight chain alkylene of 1 to 4 carbon atoms, e.g. a methylene,
ethylene, propylene or butylene chain, or the methylene, ethylene,
propylene or butylene chain mono-substituted by
C.sub.1-C.sub.3-alkyl (preferably methyl) or disubstituted on the
same or different carbon atoms by C.sub.1-C.sub.3-alkyl (preferably
methyl), the total number of carbon atoms being up to and including
7.
[0098] An alkoxy (or alkyloxy) group preferably contains 1-7 carbon
atoms, more preferably 1-6 carbon atoms, and represents for example
ethoxy, propoxy, isopropoxy, isobutoxy, preferably methoxy. Alkoxy
includes cycloalkyloxy and cycloalkyl-alkyloxy.
[0099] Halogen (halo) preferably represents chloro or fluoro, but
may also be bromo or iodo.
[0100] Aryl represents monocyclic, bicyclic or tricyclic aryl, for
example, phenyl or phenyl mono-, di- or tri-substituted by one, two
or three radicals selected from alkyl, alkoxy, aryl, hydroxy,
halogen, cyano, amino, amino-alkyl, trifluoromethyl, alkylenedioxy
and oxy-C.sub.2-C.sub.3-alkylene; all of which are optionally
further substituted, for instance as hereinbefore defined; or 1- or
2-naphthyl; or 1- or 2-phenanthrenyl. Alkylenedioxy is a divalent
substitute attached to two adjacent carbon atoms of phenyl, e.g.
methylenedioxy or ethylenedioxy. Oxy-C.sub.2-C.sub.3-alkylene is
also a divalent substituent attached to two adjacent carbon atoms
of phenyl, e.g. oxyethylene or oxypropylene. An example for
oxy-C.sub.2-C.sub.3-alkylene-phenyl is
2,3-dihydrobenzofuran-5-yl.
[0101] Preferred as aryl is naphthyl, phenyl or phenyl mono- or
disubstituted by alkoxy, phenyl, halogen, alkyl or trifluoromethyl,
especially phenyl or phenyl-mono- or disubstituted by alkoxy,
halogen or trifluoromethyl, and in particular phenyl.
[0102] Examples of substituted phenyl groups as R are, e.g.
4-chlorophen-1-yl, 3,4-dichlorophen-1-yl, 4-methoxyphen-1-yl,
4-methylphen-1-yl, 4-aminomethylphen-1-yl,
4-methoxyethylaminomethylphen-1-yl,
4-hydroxyethylaminomethylphen-1-yl,
4-hydroxyethyl-(methyl)-aminomethylphen-1-yl,
3-aminomethylphen-1-yl, 4-N-acetylaminomethylphen-1-yl,
4-aminophen-1-yl, 3-aminophen-1-yl, 2-aminophen-1-yl,
4-phenyl-phen-1-yl, 4-(imidazol-1-yl)-phen-yl,
4-(imidazol-1-ylmethyl)-phen-1-yl, 4-(morpholin-1-yl)-phen-1-yl,
4-(morpholin-1-ylmethyl)-phen-1-yl,
4-(2-methoxyethylaminomethyl)-phen-1-yl and
4-(pyrrolidin-1-ylmethyl)-phen-1-yl, 4-(thiophenyl)-phen-1-yl,
4-(3-thiophenyl)-phen-1-yl, 4-(4-methylpiperazin-1-yl)-phen-1-yl,
and 4-(piperidinyl)-phenyl and 4-(pyridinyl)-phenyl optionally
substituted in the heterocyclic ring.
[0103] Benzyl represents a phenyl-CH.sub.2-- group. Substituted
benzyl means a benzyl group in which the phenyl ring is substituted
with one or more ring system substituents. Representative benzyl
groups include 4-bromobenzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl,
and the like.
[0104] Heteroaryl represents monocyclic or bicyclic heteroaryl, for
example pyridyl, pyridyl N-oxide, indolyl, indazolyl, quinoxalinyl,
quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl,
benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl,
benzothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl,
pyrazolyl, imidazolyl, thienyl, or any other radicals substituted,
especially mono- or di-substituted, by e.g. alkyl, nitro or
halogen. Pyridyl represents 2-, 3- or 4-pyridyl, advantageously 2-
or 3-pyridyl. Thienyl represents 2- or 3-thienyl. Quinolinyl
represents preferably 2-, 3- or 4-quinolinyl. Isoquinolinyl
represents preferably 1-, 3- or 4-isoquinolinyl. Benzopyranyl,
benzothiopyranyl represents preferably 3-benzopyranyl or
3-benzothiopyranyl, respectively. Thiazolyl represents preferably
2- or 4-thiazolyl, and most preferred, 4-thiazolyl. Triazolyl is
preferably 1-, 2- or 5-(1,2,4-triazolyl). Tetrazolyl is preferably
5-tetrazolyl.
[0105] Preferably, heteroaryl is pyridyl, pyridyl N-oxide, indolyl,
quinolinyl, pyrrolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl,
pyrazolyl, imidazolyl, thienyl, furanyl, benzothiazolyl,
benzofuranyl, isoquinolinyl, benzothienyl, oxazolyl, indazolyl, or
any of the radicals substituted, especially mono- or
di-substituted.
[0106] Biaryl may preferably be, e.g., biphenyl, namely 2, 3 or
4-biphenyl, preferably, 4-biphenyl, each optionally substituted by,
e.g., alkyl, alkoxy, halogen, trifluoromethyl or cyano, or
heterocyclic-carbocyclic biaryl, preferably, e.g., thienylphenyl,
pyrrolylphenyl and pyrazolylphenyl.
[0107] Cycloalkyl represents a saturated cyclic hydrocarbon
optionally substituted by alkyl which contains 3 to 10 ring carbons
and is advantageously cyclopentyl, cyclohexyl, cycloheptyl or
cyclooctyl optionally substituted by alkyl.
[0108] Bicycloalkyl represents a saturated bicyclic ring group of
7-15 carbon atoms. Exemplary bicycloalkyl rings include
[3.3.0]bicyclooctanyl, [2.2.2]bicyclooctanyl, [4.3.0]bicyclononane,
[4.4.0]bicyclodecane (decalin), spiro [3.4]octanyl,
spiro[2.5]octanyl, and so forth, optionally substituted by
alkyl.
[0109] Amino can be optionally substituted by, e.g., alkyl.
[0110] Carbocyclic represents a saturated or partially unsaturated
cyclic hydrocarbon with 5 to 7 ring members, wherein 1 to 2 ring
members can optionally be replaced with one of the following
groups: --O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2-- and
--NR--, wherein R is a radical of the present invention.
[0111] Heterocyclyl represents a saturated cyclic hydrocarbon
containing one or more, preferably 1 or 2 heteroatoms selected from
O, N or S, and from 3 to 10, preferably 5 to 8, ring atoms; for
example, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl,
piperidinyl, piperazinyl or morpholino; all of which can be
optionally substituted, for instance as hereinbefore defined for
aryl.
[0112] Pharmaceutically acceptable salts of the acidic compounds of
the present invention are salts formed with bases, namely cationic
salts such as alkali and alkaline earth metal salts, such as
sodium, lithium, potassium, calcium, magnesium, as well as ammonium
salts, such as ammonium, trimethyl-ammonium, diethylammonium, and
tris-(hydroxymethyl)-methyl-ammonium salts.
[0113] Similarly acid addition salts, such as of mineral acids,
organic carboxylic and organic sulfonic acids, e.g., hydrochloric
acid, methanesulfonic acid, maleic acid, are also possible provided
a basic group, such as pyridyl, constitutes part of the
structure.
[0114] "Treat", "treating" and "treatment" refer to a method of
alleviating or abating a disease and/or its attendant symptoms.
[0115] "Inhibition", "inhibits" and "inhibitor" refer to a compound
that prohibits, or a method of prohibiting, a specific action or
function.
[0116] "Inhibition constant", K.sub.i, is the dissociation constant
of the enzyme-inhibitor complex, or the reciprocal of the binding
affinity of the inhibitor to the enzyme. For classical inhibition
the value of K.sub.i is much greater than the enzyme concentration
and the K.sub.i can be measured by monitoring the rate of reaction
for a competitive substrate at multiple inhibitor concentrations.
The inhibited rates are then fit by nonlinear regression to the
following equation:
v i / v o = K m + [ S ] K m ( 1 + [ I ] / K i ) + [ S ]
##EQU00001##
where v.sub.o is the initial rate of substrate processing in the
absence of inhibitor, v.sub.i is the initial rate of substrate
processing at a concentration [I] of inhibitor, K.sub.m is the
steady state Michaelis constant (Fersht, A. Structure and Mechanism
in Protein Science. New York, W.H. Freeman and Company, 1999), and
[S] is the concentration of competitive substrate.
[0117] The assumption being made for the classical inhibition
described above is that the free inhibitor concentration is equal
to the total inhibitor concentration. For inhibitors that have
K.sub.i's that are approximately equal to the enzyme concentration
[E], the assumption that the free inhibitor concentration is equal
to the total inhibitor concentration is no longer valid and an
alternative equation has to be fit for determination of the
apparent inhibition constant, K.sub.i.sup.app using described
methods (Kuzmic, P., K. C. Elrod, et al., Anal Biochem 2000,
286(1), 45-50):
v i / v o = [ E ] - [ I ] - K i app + SQRT ( ( [ E ] - [ I ] - K i
app ) 2 + 4 [ E ] K i app ) 2 [ E ] . ##EQU00002##
The inhibition constant, K.sub.i, can be determined from the
apparent inhibition constant, K.sub.i.sup.app, for competitive
inhibitors by using the following relationship:
K i = K i app 1 + [ S ] / K m . ##EQU00003##
[0118] "Therapeutically effective amount" refers to that amount of
the compound being administered sufficient to prevent development
of or alleviate to some extent one or more of the symptoms of the
condition or disorder being treated.
[0119] "Composition" as used herein is intended to encompass a
product comprising the specified ingredients in the specified
amounts, as well as any product which results, directly or
indirectly, from combination of the specified ingredients in the
specified amounts. By "pharmaceutically acceptable" it is meant the
carrier, diluent or excipient must be compatible with the other
ingredients of the Formulation and deleterious to the recipient
thereof.
[0120] "Subject" refers to animals such as mammals, including, but
not limited to, primates (e.g., humans), cows, sheep, goats,
horses, dogs, cats, rabbits, rats, mice and the like. In certain
aspects, the subject is a human.
[0121] "Prodrug" refers to the compounds of this invention which
may be modified by appending appropriate functionalities to enhance
selective biological properties. Such modifications are known in
the art and include those which increase penetration into a given
biological compartment (e.g. central nervous system), increase oral
bioavailability, increase solubility to allow administration by
injection, alter metabolism and alter rate and/or route of
excretion. In addition, the compounds may be altered to prodrug
form such that the desired compound is created in the body of the
patient as the result of the action of metabolic or other
biochemical processes on the prodrug.
[0122] It will be apparent to one skilled in the art that certain
compounds of this invention may exist in tautomeric forms or
hydrated forms, all such forms of the compounds being within the
scope of the invention.
[0123] Structures depicted herein are also meant to include
compounds that differ only in the presence of isotopically enriched
atoms. For example, compounds having the present structures except
for the replacement of a hydrogen by a deuterium are expressly
included in the present invention.
II. GENERAL
[0124] Cathepsin S is a cysteine protease that has been associated
with several normal and disease processes in mammals. Specifically,
cathepsin S has been directly associated with inflammation,
arthritis, and atherosclerosis, as a result of its role in MHC
class II antigen presentation. In a preferred aspect, the present
invention provides compounds that inhibit the activity of cathepsin
S. The present invention also provides methods for treating several
disease states in mammals by inhibiting the activity of cathepsin
S. In a more preferred aspect, the compounds of the present
invention selectively inhibit cathepsin S in the presence of at
least one cathepsin isozyme (e.g. cathepsin K).
III. COMPOUNDS
[0125] A. Preparation of Compounds
[0126] In the following schemes, several methods of preparing the
compounds of the present invention are illustrative. One of skill
in the art will appreciate that these methods are representative,
and in no way inclusive of all methods for preparing the compounds
of the present invention. The radicals in the schemes are as
described in Formula I.
[0127] Compounds of the present invention can be made via the route
shown in Scheme 1.
##STR00002##
[0128] Polystyrene aldehyde (PAL) resin was reductively aminated
with a monoaryl diamine (NH.sub.2CH.sub.2CH.sub.2NR.sup.9Ar) which
was made as per literature protocol [Altman, E.; Renaud, J.; Green,
J.; Farley, D.; Cutting, B; Jahnke W. J. Med Chem. 2002, 45,
2352-54 and references cited therein] to obtain the resin 1-A
(Scheme 1). This material was acylated with an N-protected amino
acid using standard conditions [as described in A. R. Chamberlin,
Chem. Rev. 1997, 97, 2243-66; M. Bodanszky et al. The Practice of
Peptide Synthesis 2.sup.nd, Springer-Verlag, 1984] and the product
was then deprotected with piperidine to furnish 1-B. After
acylation with R.sup.1CO.sub.2H under standard amide coupling
condition, cleavage from resin using TFA furnished 1-C. In scheme
1, Q is defined as --CR.sup.2R.sup.3--.
[0129] Compounds of the present invention can be made via the route
shown in Scheme 2.
##STR00003##
[0130] A conjugate 2-A (Scheme 2) was synthesized by
Schotten-Bauman reaction of an acyl chloride with the appropriate
amino acid in 1 M NaOH. The intermediate 2-B was synthesized by
acylating NH.sub.2CR.sup.5R.sup.6CH.sub.2OH with 2-A using standard
conditions. The alcohol 2-B was then oxidized. The resulting
aldehyde was reacted with an aromatic amine in methanol in the
presence of acetic acid and NaCNBH.sub.3 to give product 2-C.
[0131] The arylaminoethylamines 3-A (Scheme 3) used in the present
invention can be prepared by a decarboxylative ring opening of
oxazolidin-2-one with an aromatic amine as described in E. Altman
et al J. Med Chem. 2002, 45, 2352-54 and references cited
therein.
##STR00004##
[0132] Mono-arylated diamine intermediates used in the present
invention can be made via the route described in Scheme 4.
##STR00005##
[0133] An aryl bromide (or iodide) was reacted with a diamine using
a Pd-BINAP catalyst and tBuOK as base (Frost, C. G.; Mendonca, P.
Tetrahedron:Asymmetry 1999, 10, 1831-4 and references cited
therein). Intermediate 4-A (scheme 4) can be coupled to an amino
acid conjugate under standard condition to yield 4-B.
[0134] Another synthetic route to compounds of the present
invention of general formula (I), in which R.sup.5 and/or
R.sup.6.noteq.H, is described in Scheme 5.
##STR00006##
[0135] A N-protected amino acid can be reduced using either the
BH.sub.3 method or NaBH.sub.4 reduction of the corresponding mixed
anhydride [see R. C. Larock A guide to functional group
preparations pp. 548-552, Wiley-VCH, 1989] to obtain 5-A (Scheme
5). One can then oxidize the alcohol to the aldehyde and
reductively aminate the resulting aldehyde with an amine to afford
5-B. This intermediate can then be deprotected using the
appropriate reagents for the PG, such as TFA for Boc, and the
resulting amine can be acylated to give access to 5-C.
[0136] To access compounds of the present invention with cyclic
diamines incorporated, the protocol illustrated in Scheme 6 can be
used.
##STR00007##
[0137] An amide derivative of a cyclic amino acid can be N-arylated
under Pd catalysis to afford 6-A (Scheme 6). This intermediate can
then be hydrolyzed using strong acid such as 6 M HCl at elevated
temperature for an extended period of time to furnish 6-B. This
acid can then be degraded via Curtius rearrangement using DPPA in
an t-BuOH solvent to obtain the carbamate 6-C. After the removal of
the Boc protecting group, the intermediate can be coupled with an
amino acid conjugate under standard condition to afford 6-D.
[0138] Synthetic approaches to indolines used in this invention are
widely describe in the literature and well know to one skilled in
the art. The typical methods are illustrated , but are not limited
to, in the following references. See: (a) G. W. Gribble et al
Synthesis 1977, 859; (b) A. Smith et al Chem. Commun. 1965, 427;
(c) G. W. Gribble et al J. Am. Chem. Soc. 1974, 96, 7812; (d) J. G.
Berger Synthesis 1974, 508; (e) L. J. Dolby et al J. Heterocycl.
Chem. 1966, 3, 124; (f) W. A. Remers at al J. Org. Chem. 1971, 36,
279; (g) S. O'Brien et al J. Chem. Soc. 1960, 4609; (h) Y. Kikugawa
et al Synthesis 1978, 477.
[0139] Synthetic approaches to non-commercially available .alpha.-
and .beta.-amino acids used in the present invention are widely
described in the literature. The typical methods are illustrated in
the following references. See: (a) D. J. Ager et al. Current
opinion in drug discovery & development 2001, 4, 800-807; (b)
R. O. Duthaler Tetrahedron 1994, 50, 1539-1650; (c) M. J. O'Donnell
Aldrichimica Acta 2001, 34, 3-15; (d) K. B. Sharpless et al J. Am.
Chem. Soc. 1998, 120, 1207-17; (e) E. Juaristi et al. Aldrichimica
Acta 1994, 27, 3-11; (f) D. C. Cole Tetrahedron 1994, 50,
9517-9582, and references cited therein.
[0140] Compounds of the present invention in which, for example,
R.sup.1 is furanyl or thienyl; and R.sup.1a is phenyl or 5- to
6-membered heteroaryl substituted with 0-2 R.sup.15, are prepared
(a) by Suzuki coupling (N. Miyaura et al. Synth. Commun. 1981,
11(7), 513-19; A. Suzuki et al. Chem Rev. 1995, 95, 2457-2483) of
appropriate phenyl- or heteroaryl-boronic acid with
bromofurancarboxylic acid or bromothiophenecarboxylic acid; (b)
according to Bartoli, J. et. al. J. Med. Chem. 1998, 41, 1855-1868;
Holzer, W. et al. J. Hetcycl. Chem. 1993, 30(4), 865-872; Molteni,
G. et al. New J. Chem. 2002, 26(10), 1340-1345; Seigo I. et al.
Bioorg. Med. Chem. 2001, 11(7), 879-882, when R.sup.1 is pyrazolyl;
and R.sup.1a is phenyl or 5- to 6-membered heteroaryl substituted
with 0-2 R.sup.15 (c) according to Evans, D. L. et. al. J. Org.
Chem. 1979, 44, 497; Takeuchi, K. et. al. J. Med. Chem. 1998, 41,
5362-5374; Dondoni, A. et al. J. Org. Chem. 1987, 52(15),
3413-3420; Millan, D. S. et al. Tetrahedron 2000, 56(5), 811-816;
Duarte, M. P. et al. Tetrahedron Lett. 2000, 41(39), 7433-7435,
when R.sup.1 is oxazolyl; and R.sup.1a is phenyl or 5- to
6-membered heteroaryl substituted with 0-2 R.sup.15; (d) according
to Bartroli, J. et al. J. Med. Chem. 1998, 41(11), 1855-1868;
Wright, S. W. et al J. Med. Chem. 2002, 45(18), 3865-3877; Janusz,
J. M. et al. J. Med. Chem. 1998, 41(18), 3515-3529; Tanaka, C. et
al. Chem. Pharm. Bulletin 1982, 30(11), 4195-8, when R.sup.1 is
thiazolyl; and R.sup.1a is phenyl or 5- to 6- membered heteroaryl
substituted with 0-2 R.sup.15; (e) Liu, G. et al. J. Med. Chem.
2003, 46(20), 4232-5; Hamper, B. C. et al. J. Heterocycl. Chem.
2003, 40(4), 575-583, when R.sup.1 is isoxazolyl; and R.sup.1a is
phenyl or 5- to 6-membered heteroaryl substituted with 0-2
R.sup.15; (f) Bartroli, J. et al. J. Med. Chem. 1998, 41(11),
1855-1868, when R.sup.1 is 1,3,4-oxadiazolyl; and R.sup.1a is
phenyl or 5- to 6-membered heteroaryl substituted with 0-2
R.sup.15.
[0141] B. Preferred Compounds
[0142] In one aspect, preferred compounds of the present invention
have formula Ia:
##STR00008##
wherein: [0143] R.sup.1 is a 5- to 6-membered heteroaryl containing
1 to 4 heteroatoms each independently a member selected from the
group consisting of N, O and S, wherein said heteroaryl is
substituted with 1 R.sup.1a; [0144] R.sup.1a is independently a
member selected from the group consisting of phenyl substituted
with 0-2 R.sup.15, and a 5- to 6-membered monocyclic heteroaryl
containing 1 to 4 heteroatoms each independently a member selected
from the group consisting of N, O and S, wherein said heteroaryl is
substituted with 0-2 R.sup.15; [0145] R.sup.2 is a member selected
from the group consisting of a phenyl substituted with 0-3
R.sup.15, a 5- to 6-membered monocyclic heteroaryl containing 1 to
4 heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R.sup.15, a C.sub.1-C.sub.6 alkyl, a C.sub.1-C.sub.3 alkyl
substituted with 1R.sup.2a, and a C.sub.3-C.sub.7 cycloalkyl
substituted with 0-2 R.sup.19; [0146] each R.sup.2a is
independently a member selected from the group consisting of a
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.15, a 5- to
6-membered monocyclic or 8- to 10-membered bicyclic heteroaryl
containing 1 to 4 heteroatoms each independently a member selected
from the group consisting of N, O and S, wherein said heteroaryl is
substituted with 0-3 R.sup.15, a C.sub.3-C.sub.8 cycloalkyl
substituted with 0-2 R.sup.19 and a C.sub.7-C.sub.11 bicycloalkyl
substituted with 0-2 R.sup.19; and [0147] Ar is phenyl substituted
with 0-3 R.sup.29, or alternatively, R.sup.29 and R.sup.9 are taken
together to form a 5- to 7-membered fused heterocyclic ring
containing 1-2 heteroatom(s) each independently a member selected
from the group consisting of N, O and S; wherein said 5- to
7-membered fused heterocyclic ring is substituted with 0-2
R.sup.19.
[0148] Alternatively, in another aspect, preferred compounds of the
present invention have formula Ia wherein: [0149] R.sup.1 is a
member selected from the group consisting of a C.sub.3-C.sub.8
cycloalkyl substituted with 0-2 R.sup.1b, wherein said
C.sub.3-C.sub.8 cycloalkyl is saturated or unsaturated and a
C.sub.4-C.sub.7 heterocycle containing 1 to 2 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heterocycle is substituted with 0-2 R.sup.1c
and is saturated or unsaturated; [0150] R.sup.2 is a member
selected from the group consisting of a phenyl substituted with 0-3
R.sup.15, a 5- to 6-membered monocyclic heteroaryl containing 1 to
4 heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R.sup.15, a C.sub.1-C.sub.6 alkyl substituted with 0-2
R.sup.2a, and a C.sub.3-C.sub.7 cycloalkyl substituted with 0-2
R.sup.19; and [0151] Ar is phenyl substituted with 0-3 R.sup.29, or
alternatively, R.sup.29 and R.sup.9 are taken together to form a 5-
to 7-membered fused heterocyclic ring containing 1-2 heteroatom(s)
each independently a member selected from the group consisting of
N, O and S; wherein said 5- to 7-membered fused heterocyclic ring
is substituted with 0-2 R.sup.9.
[0152] In still another aspect, preferred compounds of the present
invention have formula Ia wherein: [0153] R.sup.1 is a member
selected from the group consisting of C.sub.6-C.sub.10 aryl
substituted with 0-3 R.sup.1a, and a 5- to 6-membered monocyclic or
8- to 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms
each independently a member selected from the group consisting of
N, O and S, wherein said heteroaryl is substituted with 0-3
R.sup.1a; [0154] each R.sup.1a is independently a member selected
from the group consisting of H, C.sub.1-C.sub.3 perfluoroalkyl,
C.sub.3-C.sub.7 cycloalkyl, F, Cl, Br, CN, NO.sub.2, OR.sup.10,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2R.sup.10,
NR.sup.11R.sup.12, acetyl, C(.dbd.O)OR.sup.13,
C(.dbd.O)NR.sup.13R.sup.14, S(.dbd.O).sub.2NR.sup.13R.sup.14,
phenyl substituted with 0-3 R.sup.15; and a C.sub.1-C.sub.4 alkyl
substituted with 0-2 R.sup.16; [0155] R.sup.2 is a member selected
from the group consisting of a phenyl substituted with 0-3
R.sup.15; a 5- to 6-membered monocyclic heteroaryl containing 1 to
4 heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R.sup.15, a C.sub.1-C.sub.6 alkyl, a C.sub.1-C.sub.2 alkyl
substituted with 1R.sup.2a; a C.sub.3-C.sub.7 cycloalkyl
substituted with 0-2 R.sup.19; [0156] each R.sup.2a is
independently a member selected from the group consisting of a
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.15; a 5- to
6-membered monocyclic or 8- to 10-membered bicyclic heteroaryl
containing 1 to 4 heteroatoms each independently a member selected
from the group consisting of N, O and S, wherein said heteroaryl is
substituted with 0-3 R.sup.15; a C.sub.3-C.sub.8 cycloalkyl
substituted with 0-2 R.sup.19; and a C.sub.7-C.sub.11 bicycloalkyl
substituted with 0-2 R.sup.19; and [0157] Ar is phenyl substituted
with 0-3 R.sup.29, or alternatively, R.sup.29 and R.sup.9 are taken
together to form a 5- to 7-membered fused heterocyclic ring
containing 1-2 heteroatom(s) each independently a member selected
from the group consisting of N, O and S; wherein said 5- to
7-membered fused heterocyclic ring is substituted with 0-2
R.sup.19.
[0158] In another aspect, preferred compounds of the present
invention have formula Ib:
##STR00009## [0159] wherein: [0160] each R.sup.15, if present, is
independently a member selected from the group consisting of OH, F,
Cl, Br, I, CN, NO.sub.2, COOR.sup.13, C(.dbd.O)NR.sup.13R.sup.14,
S(.dbd.O).sub.2NR.sup.13R.sup.14, acetyl, --SCH.sub.3,
--S(.dbd.O)CH.sub.3, --S(.dbd.O).sub.2CH.sub.3, NR.sup.26R.sup.27,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3 perfluoroalkyl,
C.sub.1-C.sub.3 perfluoroalkoxy and a C.sub.1-C.sub.6 alkyl; and
[0161] A is a 5-membered heteroaryl selected from the group
consisting of furanylene, thienylene, thiazolylene, oxadiazolylene,
isoxazolylene, tetrazolylene, and oxazolylene.
[0162] In another aspect, preferred compounds of the present
invention have formula Ic:
##STR00010## [0163] wherein: [0164] R.sup.1 is a member selected
from the group consisting of tBu, phenyl substituted with 0-2
R.sup.15, a 5- to 6-membered heteroaryl containing 1 to 4
heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R.sup.15, and a C.sub.4-C.sub.7 heterocycle containing 1
to 2 heteroatoms each independently a member selected from the
group consisting of N, O and S, wherein said heterocycle is
substituted with 0-2 R.sup.1c; [0165] each R.sup.1c is
independently a member selected from the group consisting of H, OH,
F, Cl, .dbd.O, C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.16,
a C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, C(.dbd.O)R.sup.10,
S(.dbd.O).sub.2R.sup.10, tBoc, Cbz, phenyl substituted with 0-3
R.sup.15, and a 5- to 6-membered monocyclic heteroaryl containing 1
to 4 heteroatoms each independently a member selected from the
group consisting of N, O and S, wherein said heteroaryl is
substituted with 0-2 R.sup.15; [0166] Y is a member independently
selected from the group consisting of a bond and
--(CR.sup.20R.sup.21).sub.m--W--(CR.sup.22R.sup.23).sub.p--,
wherein m is 0, W is a bond, and R.sup.22R.sup.23 are both H;
[0167] R.sup.2 is a member selected from the group consisting of a
phenyl substituted with 0-3 R.sup.15, a 5- to 6-membered monocyclic
heteroaryl containing 1 to 4 heteroatoms each independently a
member selected from the group consisting of N, O and S, wherein
said heteroaryl is substituted with 0-2 R.sup.15, a C.sub.1-C.sub.6
alkyl, a C.sub.1-C.sub.3 alkyl substituted with 1R.sup.2, and a
C.sub.3-C.sub.7 cycloalkyl substituted with 0-2 R.sup.19; [0168]
each R.sup.2a, is independently a member selected from the group
consisting of a C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.15, a 5- to 6-membered monocyclic or 8- to 10-membered
bicyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-3 R.sup.15, a
C.sub.3-C.sub.8 cycloalkyl substituted with 0-2 R.sup.19, and a
C.sub.7-C.sub.11 bicycloalkyl substituted with 0-2 R.sup.19; and
[0169] Ar is phenyl substituted with 0-3 R.sup.29, or
alternatively, R.sup.29 and R.sup.9 are taken together to form a 5-
to 7-membered fused heterocyclic ring containing 1-2 heteroatom(s)
each independently a member selected from the group consisting of
N, O and S; wherein said 5- to 7-membered fused heterocyclic ring
is substituted with 0-2 R.sup.9.
[0170] In yet another aspect, preferred compounds of the present
invention have formula Id:
##STR00011## [0171] wherein: [0172] R.sup.1 is a member selected
from the group consisting of methyl, benzyl, C.sub.6-C.sub.10 aryl
substituted with 0-3 R.sup.1a, and a 5- to 6-membered monocyclic or
8- to 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms
each independently a member selected from the group consisting of
N, O and S, wherein said heteroaryl is substituted with 0-3
R.sup.1a; [0173] each R.sup.1a is independently a member selected
from the group consisting of H, C.sub.1-C.sub.3 perfluoroalkyl,
C.sub.3-C.sub.7 cycloalkyl, F, Cl, Br, CN, NO.sub.2, OR.sup.10,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2R.sup.10,
NR.sup.11R.sup.12, acetyl, C(.dbd.O)OR.sup.13,
C(.dbd.O)NR.sup.13R.sup.14, S(.dbd.O).sub.2NR.sup.13R.sup.14,
phenyl substituted with 0-3 R.sup.15, a 5- to 6-membered monocyclic
heteroaryl containing 1 to 4 heteroatoms each independently a
member selected from the group consisting of N, O and S, wherein
said heteroaryl is substituted with 0-2 R.sup.15; and a
C.sub.1-C.sub.4 alkyl; and [0174] Ar is phenyl substituted with 0-3
R.sup.29, or alternatively, R.sup.29 and R.sup.9 are taken together
to form a 5- to 7-membered fused heterocyclic ring containing 1-2
heteroatom(s) each independently a member selected from the group
consisting of N, O and S; wherein said 5- to 7-membered fused
heterocyclic ring is substituted with 0-2 R.sup.19.
[0175] In still yet another aspect, preferred compounds of the
present invention have formula Ie:
##STR00012## [0176] wherein: [0177] R.sup.1 is a member selected
from the group consisting of a C.sub.6-C.sub.10 aryl substituted
with 0-3 R.sup.1a, a 5- to 6-membered monocyclic or 8- to
10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heteroaryl is substituted with 0-3 R.sup.1a;
[0178] each R.sup.1a is independently a member selected from the
group consisting of H, C.sub.1-C.sub.3 perfluoroalkyl,
C.sub.3-C.sub.7 cycloalkyl, F, Cl, Br, CN, NO.sub.2, OR.sup.10,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2R.sup.10,
NR.sup.11R.sup.12, cetyl, C(.dbd.O)OR.sup.13,
C(.dbd.)NR.sup.13R.sup.14, S(.dbd.O).sub.2NR.sup.13R.sup.14, phenyl
substituted with 0-3 R.sup.15, a 5- to 6-membered monocyclic
heteroaryl containing 1 to 4 heteroatoms each independently a
member selected from the group consisting of N, O and S, wherein
said heteroaryl is substituted with 0-2 R.sup.15, a C.sub.3-C.sub.8
heterocycle containing 1 to 2 heteroatoms each independently a
member selected from the group consisting of N, O and S, wherein
said heterocycle is substituted with 0-2 R.sup.1c and is saturated
or unsaturated, and a C.sub.1-C.sub.4 alkyl substituted with 0-2
R.sup.16; and [0179] Ar is phenyl substituted with 0-3 R.sup.29, or
alternatively, R.sup.29 and R.sup.9 are taken together to form a 5-
to 7-membered fused heterocyclic ring containing 1-2 heteroatom(s)
each independently a member selected from the group consisting of
N, O and S; wherein said 5- to 7-membered fused heterocyclic ring
is substituted with 0-2 R.sup.19.
[0180] In yet another aspect, preferred compounds of the present
invention have formula If:
##STR00013## [0181] wherein: [0182] Y is a member selected from the
group consisting of a bond and
--(CR.sup.20R.sup.21).sub.m--W--(CR.sup.22R.sup.23).sub.p--; [0183]
subscript p is the integer 1 or 2; [0184] subscript m is 0 or 1;
[0185] W is a oxygen; and [0186] Ar is phenyl substituted with 0-3
R.sup.29, or alternatively, R.sup.29 and R.sup.9 are taken together
to form a 5- to 7-membered fused heterocyclic ring containing 1-2
heteroatom(s) each independently a member selected from the group
consisting of N, O and S; wherein said 5- to 7-membered fused
heterocyclic ring is substituted with 0-2 R.sup.19.
[0187] In another aspect, preferred compounds of the present
invention have formula Ig:
##STR00014## [0188] wherein: [0189] R.sup.5 is a member selected
from the group consisting of H, C.sub.3-C.sub.7 cycloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkyne, phenyl substituted
with 0-2 R.sup.15; 5- to 6-membered heteroaryl containing 1 to 4
heteroatoms each independently a member selected from the group
consisting of N, O and S, wherein said heteroaryl is substituted
with 0-2 R.sup.15, a C.sub.1-C.sub.6 alkyl substituted with 0-2
R.sup.18, wherein said C.sub.1-C.sub.6 alkyl optionally contains a
heteroatom selected from the group consisting of --O--, --S--,
--S(.dbd.O)--, --S(.dbd.O).sub.2-- and --NR.sup.17--.
[0190] In another aspect, preferred compounds of the present
invention have formula Ih:
##STR00015##
[0191] In another aspect, the present invention provides compounds
wherein R.sup.9 is H; and Ar is phenyl substituted with 0-3
R.sup.29, or alternatively, R.sup.29 and R.sup.9 are taken together
to form a 5- to 7-membered fused heterocyclic ring containing 1-2
heteroatom(s) each independently a member selected from the group
consisting of N, O and S; wherein said 5- to 7-membered fused
heterocyclic ring is substituted with 0-2 R.sup.19.
[0192] In another aspect, compounds of formula I wherein R.sup.5
and R.sup.7 are taken together to form a C.sub.5-C.sub.7 cycloalkyl
substituted with 0-2 R.sup.19; and Ar is phenyl substituted with
0-3 R.sup.29, or alternatively, R.sup.29 and R.sup.9 are taken
together to form a 5- to 7-membered fused heterocyclic ring
containing 1-2 heteroatom(s) each independently a member selected
from the group consisting of N, O and S; wherein said 5- to
7-membered fused heterocyclic ring is substituted with 0-2 R.sup.19
are preferred.
[0193] In one aspect, with respect to formulae Ia, Ib Ic, Id, and
Ie, compounds wherein: [0194] R.sup.2 is a member selected from the
group consisting of a C.sub.1-C.sub.2 alkyl substituted with 1
R.sup.2a, and C.sub.1-C.sub.6 alkyl; [0195] each R.sup.2a is
independently a member selected from the group consisting of a
phenyl substituted with 0-3 R.sup.15, and a C.sub.3-C.sub.8
cycloalkyl substituted with 0-2 R.sup.19; [0196] R.sup.5 is a
member selected from the group consisting of H, C.sub.3-C.sub.7
cycloalkyl; a C.sub.1-C.sub.6 alkyl substituted with 0-1 R.sup.18,
wherein said C.sub.1-C.sub.6 alkyl optionally contains a heteroatom
selected from the group consisting of --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2-- and --NR.sup.17--; and [0197] each R.sup.18 is
independently a member selected from the group consisting of H, OH,
F, Cl, CN, C(.dbd.O)OR.sup.30, C(.dbd.O)NR.sup.13R.sup.14,
NR.sup.11R.sup.12, a phenyl substituted with 0-3 R.sup.15, a
C.sub.3-C.sub.8 heterocycle containing 1 to 2 heteroatoms each
independently a member selected from the group consisting of N, O
and S, wherein said heterocycle is substituted with 0-2 R.sup.15
and is saturated or unsaturated; and C.sub.3-C.sub.8 cycloalkyl are
preferred.
[0198] In formulae Ia, Ib, Ic, Id, and Ie, in one aspect, R.sup.29
and R.sup.9 are taken together to form a 5- to 7-membered fused
heterocyclic ring containing 1-2 heteroatom(s) each independently a
member selected from the group consisting of N, O and S; wherein
the 5- to 7-membered fused heterocyclic ring is substituted with
0-2 R.sup.19. The heterocyclic ring is fused with the Ar portion,
such that the total number of ring atoms within these fused systems
is between 8-11 (e.g. 8, 9, 10 and 11 ring atoms). Within this
embodiment, in one preferred aspect, compounds have the following
indoline structure:
##STR00016##
[0199] The compounds set forth below in Table I are especially
preferred compounds of the invention.
TABLE-US-00001 TABLE I 1.
N-{cis-2-[2-(4-Methoxy-phenylamino)-ethylcarbamoyl]-cyclohexyl}-3-methy-
l- benzamide; 2. 5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic
acid (S)-{2-cyclohexyl-1-[2-(5-
fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-ethyl}-amide; 3.
(S)--N-{1-[2-(5-Fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-3-methyl-
-butyl}-3- methyl-benzamide; 4.
N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbam-
oyl]-ethyl}- 4-phenoxy-benzamide; 5.
1-Benzoyl-piperidine-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-
dihydro-indol-1-yl)-ethylcarbamoyl]-ethyl}-amide; 6.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[2-(4--
methoxy- phenyl)-acetylamino]-propionamide; 7.
(S)--N-{1-[2-(5-Chloro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-3-methyl-
-butyl}-3- methyl-benzamide; 8.
(S)--N-{3-Cyclohexyl-1-[2-(7-methoxy-2,3-dihydro-indol-1-yl)-ethylcarba-
moyl]- propyl}-3-methoxy-benzamide; 9. Furan-2-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-
ethylcarbamoyl]-ethyl}-amide; 10.
(S)--N-{3-Cyclohexyl-1-[2-(6-fluoro-2,3-dihydro-indol-1-yl)-ethylcarba-
moyl]- propyl}-3-methoxy-benzamide; 11.
(S)--N-{3-Cyclohexyl-1-[2-(7-fluoro-2,3-dihydro-indol-1-yl)-ethylcarba-
moyl]- propyl}-3-methoxy-benzamide; 12.
(S)--N-{3-Cyclohexyl-1-[2-(5-cyano-2,3-dihydro-indol-1-yl)-ethylcarbam-
oyl]- propyl}-3-methoxy-benzamide; 13. Furan-3-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-
ethylcarbamoyl]-ethyl}-amide; 14. Cyclopropanecarboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-
yl)-ethylcarbamoyl]-ethyl}-amide; 15.
(S)--N-{3-Cyclohexyl-1-[2-(4-methoxy-2,3-dihydro-indol-1-yl)-ethylcarb-
amoyl]- propyl}-3-methoxy-benzamide; 16.
(S)--N-{3-Cyclohexyl-1-[2-(5-methoxy-2,3-dihydro-indol-1-yl)-ethylcarb-
amoyl]- propyl}-3-methoxy-benzamide; 17.
1-(4-Chloro-benzenesulfonyl)-piperidine-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-
(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-ethyl}-amide; 18.
(S)--N-{3-Cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarba-
moyl]- propyl}-3-methoxy-benzamide; 19.
(S)--N-{3-Cyclohexyl-1-[2-(5-benzyloxy-2,3-dihydro-indol-1-yl)-ethylca-
rbamoyl]- propyl}-3-methoxy-benzamide; 20.
N-{1-(S)-[2-(4-Methoxy-phenylamino)-propylcarbamoyl]-3-methyl-butyl}-3-
-methyl- benzamide; 21.
N-{1-(S)-[2-(4-Methoxy-phenylamino)-1-methyl-ethylcarbamoyl]-3-methyl--
butyl}- 3-methyl-benzamide; 22.
N-{1-(S)-[2-(4-Methoxy-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-3-met-
hyl- butyl}-3-methyl-benzamide; 23.
N-{1-(S)-[2-(4-Methoxy-phenylamino)-1-(R)-methyl-ethylcarbamoyl]-3-met-
hyl- butyl}-3-methyl-benzamide; 24. 1H-Indole-2-carboxylic acid
{3-cyclohexyl-(1S)-[2-(4-methoxy-phenylamino)-(1S)-
methyl-ethylcarbamoyl]-propyl}-amide; 25. 1H-Indole-2-carboxylic
acid {3-cyclohexyl-(1S)-[2-(4-methoxy-phenylamino)-(1R)-
methyl-ethylcarbamoyl]-propyl}-amide; 26.
N-{2-Cyclohexyl-(1S)-[2-(4-methoxy-phenylamino)-(1R)-methyl-ethylcarba-
moyl]- ethyl}-3-methoxy-benzamide; 27.
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid
{3-cyclohexyl-(1S)-[2-(4-
methoxy-phenylamino)-(1S)-methyl-ethylcarbamoyl]-propyl}-amide; 28.
N-{(1S)-[2-(5-Fluoro-2,3-dihydro-indol-1-yl)-1,1-dimethyl-ethylcarbamo-
yl]-2- phenyl-ethyl}-3-methyl-benzamide; 29.
Tetrahydrofuran-2-(S)-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-
trifluoromethoxy-phenylamino)-ethylcarbamoyl]-ethyl}-amide; 30.
Tetrahydrofuran-2-(R)-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-
trifluoromethoxy-phenylamino)-ethylcarbamoyl]-ethyl}-amide; 31.
N-{1-(S)-[1-(4-Methoxy-phenyl)-piperidin-3-(S)-ylcarbamoyl]-3-methyl-b-
utyl}-3- methyl-benzamide; 32.
N-{1-(S)-[1-(4-Methoxy-phenyl)-piperidin-3-(R)-ylcarbamoyl]-3-methyl-b-
utyl}-3- methyl-benzamide; 33.
N-{1-(S)-[cis-2-(4-Methoxy-phenylamino)-cyclohexylcarbamoyl]-3-methyl--
butyl}-3- methyl-benzamide; 34.
N-{1-(S)-[trans-2-(4-Methoxy-phenylamino)-cyclohexylcarbamoyl]-3-methy-
l-butyl}- 3-methyl-benzamide; 35.
N-{1-(S)-[1-(R)-Benzyloxymethyl-2-(4-methoxy-phenylamino)-ethylcarbamo-
yl]-3- methyl-butyl}-3-methyl-benzamide; 36.
N--(S)-{[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-
ethylcarbamoyl]-phenyl-methyl}-3-methoxy-benzamide; 37.
N-[1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-
ethylcarbamoyl]-2-(4-fluoro-phenyl)-ethyl]-3-methoxy-benzamide; 38.
N-{1-(S)-[(2-Benzyloxy-1-(R)-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-
ethylcarbamoyl]-3-cyclohexyl-propyl}-3-methoxy-benzamide; 39.
N-{3-Cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(R)-hydro-
xymethyl- ethylcarbamoyl]-propyl}-3-methoxy-benzamide; 40.
N-{3-Cyclohexyl-1-(R)-[(S)-2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(R)-
hydroxymethyl-ethylcarbamoyl]-propyl}-3-methoxy-benzamide; 41.
1H-Indole-2-carboxylic acid
{(1S)-[2-benzyloxy-(1R)-(5-fluoro-2,3-dihydro-indol-1-
ylmethyl)-ethylcarbamoyl]-3-cyclohexyl-propyl}-amide; 42.
(S,S)-5-(5-Fluoro-2,3-dihydro-indol-1-yl)-4-[4-methyl-2-(3-methyl-benz-
oylamino)- pentanoylamino]-pentanoic acid benzyl ester; 43.
(S,S)-5-(5-Fluoro-2,3-dihydro-indol-1-yl)-4-[4-methyl-2-(3-methyl-benz-
oylamino)- pentanoylamino]-pentanoic acid; 44.
(S,S)--N-{1-[3-Carbamoyl-1-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-
propylcarbamoyl]-3-methyl-butyl}-3-methyl-benzamide; 45.
(S,S)--N-{1-[1-(5-Fluoro-2,3-dihydro-indol-1-ylmethyl)-3-ureido-propyl-
carbamoyl]-3- methyl-butyl}-3-methyl-benzamide; 46.
(S,S)-3-[4-Cyclohexyl-2-(3-methoxy-benzoylamino)-butyrylamino]-4-(5-fl-
uoro-2,3- dihydro-indol-1-yl)-butyric acid benzyl ester; 47.
(S,S)-3-[4-Cyclohexyl-2-(3-methoxy-benzoylamino)-butyrylamino]-4-(5-fl-
uoro-2,3- dihydro-indol-1-yl)-butyric acid; 48.
(S,S)--N-{1-[1-Benzyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamo-
yl]-3- cyclohexyl-propyl}-3-methoxy-benzamide; 49.
(S,S)--N-{3-Cyclohexyl-1-[1-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-3--
methyl- butylcarbamoyl]-propyl}-3-methoxy-benzamide; 50.
(S,S)--N-{3-Cyclohexyl-1-[1-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-2--
methyl- propylcarbamoyl]-propyl}-3-methoxy-benzamide; 51.
(S,S)--N-{3-Cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-phenyl-
- ethylcarbamoyl]-propyl}-3-methoxy-benzamide; 52.
(S,S)--N-{3-Cyclohexyl-1-[1-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-3--
morpholin-4- yl-propylcarbamoyl]-propyl}-3-methoxy-benzamide; 53.
N-{1-(S)-[2-(R)-Benzyloxy-1-(R)-(5-fluoro-2,3-dihydro-indol-1-ylmethyl-
)- propylcarbamoyl]-3-cyclohexyl-propyl}-3-methoxy-benzamide; 54.
N-{1-(R)-[1-(R)-Benzylsulfanylmethyl-2-(5-fluoro-2,3-dihydro-indol-1-y-
l)- ethylcarbamoyl]-3-cyclohexyl-propyl}-3-methoxy-benzamide; 55.
(S,S)-[5-[4-Cyclohexyl-2-(3-methoxy-benzoylamino)-butyrylamino]-6-(5-f-
luoro-2,3- dihydro-indol-1-yl)-hexyl]-carbamic acid benzyl ester;
56. 1-(6-Chloro-pyridazin-3-yl)-piperidine-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-
fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-ethyl}-amide; 57.
1-(4-Methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-
(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-ethyl}-amide; 58.
1-Benzenesulfonyl-piperidine-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-
dihydro-indol-1-yl)-ethylcarbamoyl]-ethyl}-amide; 59.
N-{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbam-
oyl]-ethyl}- 2-(2-fluoro-biphenyl-4-yl)-propionamide; 60.
N-{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbam-
oyl]-ethyl}- 2-p-tolyl-propionamide; 61.
N-{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbam-
oyl]-ethyl}- 2-o-tolyl-propionamide; 62.
N-{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbam-
oyl]-ethyl}- 2-(4-fluoro-phenyl)-propionamide; 63.
1-Methyl-1H-imidazole-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-
dihydro-indol-1-yl)-ethylcarbamoyl]-ethyl}-amide; 64.
2-(4-Chloro-phenyl)-N-{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-ind-
ol-1-yl)- ethylcarbamoyl]-ethyl}-propionamide; 65.
1-Benzyl-5-oxo-pyrrolidine-3-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-
dihydro-indol-1-yl)-ethylcarbamoyl]-ethyl}-amide; 66.
1-(4-Fluoro-benzenesulfonyl)-piperidine-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-
fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-ethyl}-amide; 67.
N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarba-
moyl]-ethyl}- 4-(piperidin-4-yloxy)-benzamide; 68.
N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarba-
moyl]-ethyl}- 4-(1-methanesulfonyl-piperidin-4-yloxy)-benzamide;
69.
4-(1-Acetyl-piperidin-4-yloxy)-N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-
-dihydro- indol-1-yl)-ethylcarbamoyl]-ethyl}-benzamide; 70.
N-{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbam-
oyl]-ethyl}- 2-(R)-phenyl-propionamide; 71.
N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarba-
moyl]-ethyl}- 3-methyl-benzamide; 72.
5-Methanesulfonyl-thiophene-2-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-
dihydro-indol-1-yl)-ethylcarbamoyl]-ethyl}-amide; 73.
5-Oxo-1-thiophen-2-ylmethyl-pyrrolidine-3-carboxylic acid
(S)-{2-cyclohexyl-1-[2-
(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-ethyl}-amide; 74.
1-Furan-2-ylmethyl-5-oxo-pyrrolidine-3-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-
fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-ethyl}-amide; 75.
5-Phenyl-furan-2-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-
1-yl)-ethylcarbamoyl]-ethyl}-amide; 76.
2-Phenyl-thiazole-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-
indol-1-yl)-ethylcarbamoyl]-ethyl}-amide; 77.
1-Methanesulfonyl-piperidine-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-
2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-ethyl}-amide; 78.
5-Methyl-2-trifluoromethyl-furan-3-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-
2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-ethyl}-amide; 79.
N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarba-
moyl]-ethyl}- 4-(methanesulfonylamino-methyl)-benzamide; 80.
N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarba-
moyl]-ethyl}- 3-methanesulfonyl-benzamide; 81.
N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarba-
moyl]-ethyl}- 4-methanesulfonylamino-benzamide; 82.
5-Phenyl-thiophene-2-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-
indol-1-yl)-ethylcarbamoyl]-ethyl}-amide; 83.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-
trifluoromethoxy-phenylamino)-ethylcarbamoyl]-ethyl}-amide; 84.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-
difluoromethoxy-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide;
85. 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(benzo[1,3]dioxol-5-ylamino)-
1-(S)-methyl-ethylcarbamoyl]-2-cyclohexyl-ethyl}-amide; 86.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-methoxy-
phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide; 87.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(3,5-difluoro-
phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide; 88.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(3-
methanesulfonyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide;
89. 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-
methanesulfonyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide;
90. 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(2,3-difluoro-
phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide; 91.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(2,5-difluoro-
phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide; 92.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(2,6-difluoro-
phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide; 93.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(4-cyano-phenylamino)-1-(S)-
methyl-ethylcarbamoyl]-2-cyclohexyl-ethyl}-amide; 94.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-chloro-phenylamino)-1-(S)-
methyl-ethylcarbamoyl]-2-cyclohexyl-ethyl}-amide; 95.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(2-fluoro-
phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide; 96.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-chloro-2-fluoro-
phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cyclohexyl-ethyl}-amide;
97. 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(5-chloro-2-fluoro-
phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cyclohexyl-ethyl}-amide;
98. 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-carbamoyl-phenylamino)-1-
(S)-methyl-ethylcarbamoyl]-2-cyclohexyl-ethyl}-amide; 99.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(3-fluoro-
phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide; 100.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-cyano-phenylamino)-1-
(S)-methyl-ethylcarbamoyl]-2-cyclohexyl-ethyl}-amide; 101.
N-{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarba-
moyl]- ethyl}-2-(4-hydroxy-phenyl)-propionamide; 102.
4-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(S)-(2-(-
R)-phenyl- propionylamino)-butyramide; 103.
5-(4-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-
(4-trifluoromethoxy-phenylamino)-ethylcarbamoyl]-ethyl}-amide; 104.
5-(4-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-
difluoromethoxy-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide;
105. 5-(4-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-methoxy-
phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide; 106.
5-(4-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(3-
methanesulfonyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide;
107. 5-(4-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-
methanesulfonyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide;
108. 3-(3-Fluoro-phenyl)-[1,2,4]oxadiazole-5-carboxylic acid
{2-cyclohexyl-1-(S)-[1-
(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethylcarbamoyl]-ethyl}-amid-
e; 109. 3-(4-Fluoro-phenyl)-[1,2,4]oxadiazole-5-carboxylic acid
{2-cyclohexyl-1-(S)-[1-
(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethylcarbamoyl]-ethyl}-amid-
e; 110.
3-[2-(S)-(3-Cyclohexyl-2-(S)-{[5-(3-fluoro-phenyl)-furan-2-carbonyl]--
amino}- propionylamino)-propylamino]-benzoic acid methyl ester;
111. 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-
(3-trifluoromethoxy-phenylamino)-ethylcarbamoyl]-ethyl}-amide; 112.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(2-chloro-5-fluoro-
phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cyclohexyl-ethyl}-amide;
113. 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(2-chloro-phenylamino)-1-
(S)-methyl-ethylcarbamoyl]-2-cyclohexyl-ethyl}-amide; 114.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-methoxy-
2,6-dimethyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide;
115. 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-methoxy-
3,5-dimethyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide;
116. 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(2-
methanesulfonyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide;
117. 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-
(4-methylsulfanyl-phenylamino)-ethylcarbamoyl]-ethyl}-amide; 118.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-
(4-methylsulfamoyl-phenylamino)-ethylcarbamoyl]-ethyl}-amide; 119.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-
(4-trifluoromethylsulfanyl-phenylamino)-ethylcarbamoyl]-ethyl}-amide;
120. 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(3-
dimethylcarbamoyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide;
121. 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(2-carbamoyl-phenylamino)-
1-(S)-methyl-ethylcarbamoyl]-2-cyclohexyl-ethyl}-amide; 122.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-
dimethylcarbamoyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide;
123.
3-Cyclohexyl-2-(S)-(3-methoxy-propionylamino)-N-[1-(S)-methyl-2-(4-
trifluoromethoxy-phenylamino)-ethyl]-propionamide; 124.
3-Cyclohexyl-2-(S)-(2-methoxy-acetylamino)-N-[1-(S)-methyl-2-(4-
trifluoromethoxy-phenylamino)-ethyl]-propionamide; 125.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-hydroxy-
phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide; 126.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-fluoro-
phenylamino)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide; 127.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{3,3-dimethyl-1-(S)-[1-(S)-methyl-2-
(4-trifluoromethoxy-phenylamino)-ethylcarbamoyl]-butyl}-amide; 128.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(4-difluoromethoxy-
phenylamino)-1-(S)-methyl-ethylcarbamoyl]-3,3-dimethyl-butyl}-amide;
129. 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(4-methanesulfonyl-
phenylamino)-1-(S)-methyl-ethylcarbamoyl]-3,3-dimethyl-butyl}-amide;
130. 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-methanesulfonyl-
phenylamino)-1-(S)-methyl-ethylcarbamoyl]-3,3-dimethyl-butyl}-amide;
131. 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-carbamoyl-phenylamino)-
1-(S)-methyl-ethylcarbamoyl]-3,3-dimethyl-butyl}-amide; 132.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(4-methoxy-phenylamino)-1-
(S)-methyl-ethylcarbamoyl]-3,3-dimethyl-butyl}-amide; 133.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-
(5-methyl-isoxazol-3-ylamino)-ethylcarbamoyl]-ethyl}-amide; 134.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-acetylamino-
phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cyclohexyl-ethyl}-amide;
135. Tetrahydropyran-4-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-
trifluoromethoxy-phenylamino)-ethylcarbamoyl]-ethyl}-amide; 136.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
(2-cyclohexyl-1-(S)-{1-(S)-methyl-2-
[4-(morpholine-4-sulfonyl)-phenylamino]-ethylcarbamoyl}-ethyl)-amide;
137. 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-
(3-oxo-1,3-dihydro-isobenzofuran-5-ylamino)-ethylcarbamoyl]-ethyl}-amide;
138. 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-
(4-sulfamoyl-phenylamino)-ethylcarbamoyl]-ethyl}-amide; 139.
Tetrahydropyran-4-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,2-dimethyl-
2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide;
140. Tetrahydrofuran-3-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,2-dimethyl-
2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide;
141. 1-(3-Fluoro-phenyl)-1H-pyrazole-4-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-
methyl-2-(4-trifluoromethoxy-phenylamino)-ethylcarbamoyl]-ethyl}-amide;
142. 1-(4-Fluoro-phenyl)-1H-pyrazole-4-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-
methyl-2-(4-trifluoromethoxy-phenylamino)-ethylcarbamoyl]-ethyl}-amide;
143. 5-Pyridin-3-yl-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-
trifluoromethoxy-phenylamino)-ethylcarbamoyl]-ethyl}-amide; 144.
5-(1-Oxy-pyridin-3-yl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-
2-(4-trifluoromethoxy-phenylamino)-ethylcarbamoyl]-ethyl}-amide;
145. 3-(3-Fluoro-phenyl)-isoxazole-5-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-
methyl-2-(4-trifluoromethoxy-phenylamino)-ethylcarbamoyl]-ethyl}-amide;
146. 3-(4-Fluoro-phenyl)-isoxazole-5-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-
methyl-2-(4-trifluoromethoxy-phenylamino)-ethylcarbamoyl]-ethyl}-amide;
147. 5-(3-Fluoro-phenyl)-[1,3,4]oxadiazole-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-
(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethylcarbamoyl]-ethyl}-amid-
e; 148.
N-{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarba-
moyl]- ethyl}-2-(R)-phenyl-butyramide; 149.
N-{1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-
ethylcarbamoyl]-2-cyclohexyl-ethyl}-3-methoxy-benzamide; 150.
N-{2-Cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(R)-hydr-
oxymethyl- ethylcarbamoyl]-ethyl}-3-methoxy-benzamide; 151.
N-{2-Cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(S)-morp-
holin-4- ylmethyl-ethylcarbamoyl]-ethyl}-3-methoxy-benzamide; 152.
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {1-(S)-[1-(R)-
benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-2-cyc-
lohexyl- ethyl}-amide; 153.
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-
fluoro-2,3-dihydro-indol-1-yl)-1-(R)-hydroxymethyl-ethylcarbamoyl]-ethyl}-
-amide; 154.
{1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-
ethylcarbamoyl]-3,3-dimethyl-butyl}-carbamic acid tert-butyl ester;
155.
N-{1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-
ethylcarbamoyl]-3,3-dimethyl-butyl}-3-methoxy-benzamide; 156.
N-{1-(S)-[2-(5-Fluoro-2,3-dihydro-indol-1-yl)-1-(R)-hydroxymethyl-
ethylcarbamoyl]-3,3-dimethyl-butyl}-3-methoxy-benzamide; 157.
{1-(S)-[1-(S)-(5-Fluoro-2,3-dihydro-indol-1-ylmethyl)-3-methanesulfon-
yl- propylcarbamoyl]-3,3-dimethyl-butyl}-carbamic acid tert-butyl
ester; 158.
3-(S)-(2-(S)-Benzyloxycarbonylamino-4,4-dimethyl-pentanoylamino)-4-(5-
-fluoro- 2,3-dihydro-indol-1-yl)-butyric acid tert-butyl ester;
159.
3-(S)-(2-(S)-Benzyloxycarbonylamino-4,4-dimethyl-pentanoylamino)-4-(5-
-fluoro- 2,3-dihydro-indol-1-yl)-butyric acid; 160.
4-(5-Fluoro-2,3-dihydro-indol-1-yl)-3-(S)-[2-(S)-(3-methoxy-benzoylam-
ino)-4,4- dimethyl-pentanoylamino]-butyric acid tert-butyl ester;
161.
3-(S)-[3-Cyclohexyl-2-(S)-(3-methoxy-benzoylamino)-propionylamino]-4--
(5- fluoro-2,3-dihydro-indol-1-yl)-butyric acid benzyl ester; 162.
3-(S)-[3-Cyclohexyl-2-(S)-(3-methoxy-benzoylamino)-propionylamino]-4--
(5- fluoro-2,3-dihydro-indol-1-yl)-butyric acid; 163.
4-(5-Fluoro-2,3-dihydro-indol-1-yl)-3-(S)-[2-(S)-(3-methoxy-benzoylam-
ino)-4,4- dimethyl-pentanoylamino]-butyric acid ethyl ester; 164.
{1-(S)-[2-Cyano-1-(S)-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-ethylca-
rbamoyl]- 3,3-dimethyl-butyl}-carbamic acid tert-butyl ester; 165.
N-{1-(S)-[2-Cyano-1-(S)-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-ethyl-
carbamoyl]- 3,3-dimethyl-butyl}-3-methoxy-benzamide; 166.
N-{1-(S)-[2-(5-Fluoro-2,3-dihydro-indol-1-yl)-1-(S)-(1H-tetrazol-5-yl-
methyl)- ethylcarbamoyl]-3,3-dimethyl-butyl}-3-methoxy-benzamide;
167.
N-{1-(S)-[5-Amino-1-(S)-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-
pentylcarbamoyl]-3-cyclohexyl-propyl}-3-methoxy-benzamide; 168.
3-(S)-(2-(S)-Benzyloxycarbonylamino-3-cyclohexyl-propionylamino)-4-(5-
-fluoro-
2,3-dihydro-indol-1-yl)-butyric acid benzyl ester; 169.
1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-
ethylcarbamoyl]-2-cyclohexyl-ethyl}-carbamic acid benzyl ester;
170.
N-{3-Cyclohexyl-1-(S)-[2-(3,5-dimethoxy-benzyloxy)-1-(R)-(5-fluoro-2,-
3-dihydro-
indol-1-ylmethyl)-ethylcarbamoyl]-propyl}-3-methoxy-benzamide; 171.
4-{2-(R)-[4-Cyclohexyl-2-(S)-(3-methoxy-benzoylamino)-butyrylamino]-3-
-(5- fluoro-2,3-dihydro-indol-1-yl)-propoxymethyl}-benzoic acid
methyl ester; 172.
(S,S)--N-{3-Cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(4-hy-
droxy- benzyl)-ethylcarbamoyl]-propyl}-3-methoxy-benzamide; 173.
Tetrahydropyran-4-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-fluoro-3,3-dimethyl-
2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amide;
174.
{2-Cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(S)-methyl-
- ethylcarbamoyl]-ethyl}-carbamic acid benzyl ester; 175.
4-Benzyloxy-N--(R,S)-{[2-(4-amidinophenylamino)-1-(S)-methyl-ethylcar-
bamoyl]- (2,4-dichloro-phenyl)-methyl}-benzamide; 176.
{1-(S)-[2-(5-Fluoro-2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethylcarbamo-
yl]-3,3- dimethyl-butyl}-carbamic acid benzyl ester; 177.
Cyclopropanecarboxylic acid
{1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(S)-
methyl-ethylcarbamoyl]-3,3-dimethyl-butyl}-amide; 178.
Pyridazine-4-carboxylic acid
{1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(S)-
methyl-ethylcarbamoyl]-3,3-dimethyl-butyl}-amide; 179.
4,4-Dimethyl-2-(S)-(2-1H-tetrazol-5-yl-acetylamino)-pentanoic acid
[2-(5-fluoro- 2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethyl]-amide;
180.
(2-Cyclohexyl-1-(S)-{1-(S)-methyl-2-[3-(1H-tetrazol-5-yl)-phenylamino-
]- ethylcarbamoyl}-ethyl)-carbamic acid benzyl ester; 181.
(S,S)-2-(3-Chloro-benzenesulfonylamino)-3-cyclohexyl-N-[1-methyl-2-(4-
- trifluoromethoxy-phenylamino)-ethyl]-propionamide; 182.
(S,S)-3-Cyclohexyl-N-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-eth-
yl]-2-(3- trifluoromethoxy-benzenesulfonylamino)-propionamide; 183.
(S,S)-3-Cyclohexyl-N-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-eth-
yl]-2- (pyridine-3-sulfonylamino)-propionamide; 184.
(S,S)-{2-Cyclohexyl-1-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-
ethylcarbamoyl]-ethyl}-carbamic acid tetrahydro-pyran-4-yl ester;
185.
3-(R)-{2-Cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyla-
mino)- ethylcarbamoyl]-ethylcarbamoyloxy}-pyrrolidine-1-carboxylic
acid tert-butyl ester; 186.
(S,S)-{2-Cyclohexyl-1-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-
ethylcarbamoyl]-ethyl}-carbamic acid
1,1-dioxo-hexahydro-1.lamda..sup.6-thiopyran-4-yl ester; 187.
{2-Cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-
ethylcarbamoyl]-ethyl}-carbamic acid pyrrolidin-3-(R)-yl ester;
188.
{2-Cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-
ethylcarbamoyl]-ethyl}-carbamic acid tetrahydrofuran-3-(R)-yl
ester; 189.
{2-Cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-
ethylcarbamoyl]-ethyl}-carbamic acid tetrahydrofuran-3-(S)-yl
ester; 190.
(S,S)-{2-Cyclopentyl-1-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-
ethylcarbamoyl]-ethyl}-carbamic acid tetrahydropyran-4-yl ester;
191.
(S,S)-{2-Cyclopentyl-1-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-
ethylcarbamoyl]-ethyl}-carbamic acid tetrahydrofuran-3-(R)-yl
ester; 192.
(S,S)-{2-Cyclopentyl-1-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-
ethylcarbamoyl]-ethyl}-carbamic acid tetrahydrofuran-3-(S)-yl
ester; 193.
N-((S)-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)(cyclohexyl)methyl)-3-
methylbenzamide; 194.
N-((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-cyclopropylethyl)-
-5-(3- (trifluoromethyl)phenyl)furan-2-carboxamide; 195.
N-((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-(2-chlorophenyl)e-
thyl)-3- methylbenzamide; 196.
N-((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-(3-chlorophenyl)e-
thyl)-5-(3- (trifluoromethyl)phenyl)furan-2-carboxamide; 197.
N-((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-(3-chlorophenyl)e-
thyl)-3- methylbenzamide; 198.
N-((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-(4-chlorophenyl)e-
thyl)-5-(3- (trifluoromethyl)phenyl)furan-2-carboxamide; 199.
N-((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-(4-chlorophenyl)e-
thyl)-3- methylbenzamide; 200.
N-((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-cyclopentylethyl)-
-5-(3- (trifluoromethyl)phenyl)furan-2-carboxamide; 201.
(S)--N-{2-Cyclopentyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcar-
bamoyl]- ethyl}-3-methyl-benzamide; 202.
N-((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-3,3-dimethylbutyl)--
5-(3- (trifluoromethyl)phenyl)furan-2-carboxamide; 203.
N-((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-3,3-dimethylbutyl)--
3- methylbenzamide; 204.
N-((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-3-cyclohexylpropyl)-
-3- methylbenzamide; 205.
N-((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-phenylethyl)-3-
methylbenzamide; 206.
N-((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-phenylethyl)-5-(3-
- (trifluoromethyl)phenyl)furan-2-carboxamide; 207.
N--(R,S)-((3-(benzyloxy)-1-(5-fluoroindolin-1-yl)propan-2-(R)-ylcarba-
moyl)(2,4- dichlorophenyl)methyl)furan-2-carboxamide; 208.
N--(R,S)-((3-(5-fluoroindolin-1-yl)-1-hydroxypropan-2-(R)-ylcarbamoyl-
)(2,4- dichlorophenyl)methyl)-3,4-difluorobenzamide; 209.
N--(S)-((3-(5-fluoroindolin-1-yl)-1-hydroxypropan-2-(R)-ylcarbamoyl)(-
2,4- dichlorophenyl)methyl)furan-2-carboxamide; 210.
(S,S)-3-Cyclohexyl-2-(2,4-dimethyl-thiazole-5-sulfonylamino)-N-[2-(5--
fluoro-2,3- dihydro-indol-1-yl)-1-methyl-ethyl]-propionamide; 211.
N--(S)-((3-(benzyloxy)-1-(5-fluoroindolin-1-yl)propan-2-(R)-ylcarbamo-
yl)(2,4- dichlorophenyl)methyl)-3,4-difluorobenzamide; 212.
N--(S)-((3-(5-fluoroindolin-1-yl)-1-hydroxypropan-2-(R)-ylcarbamoyl)(-
2,4- dichlorophenyl)methyl) furan-2-carboxamide; 213.
(R,S)--N-((2-(5-fluoroindolin-1-yl)ethylcarbamoyl)(2,4-dichlorophenyl-
)methyl)-3- methylbenzamide; 214.
(S,S)--N-((3-(5-fluoroindolin-1-yl)-1-hydroxypropan-2-ylcarbamoyl)(2,-
4- dichlorophenyl)methyl)-3,4-difluorobenzamide; 215.
(S,S)-{2-Cyclohexyl-1-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-y-
l)-1-methyl- ethylcarbamoyl]-ethyl}-carbamic acid
tetrahydro-pyran-4-yl ester; 216.
{2-Cyclohexyl-1-(S)-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-
-1-(S)- methyl-ethylcarbamoyl]-ethyl}-carbamic acid
(R)-tetrahydrofuran-3-yl ester; 217.
(S,S)-{2-Cyclohexyl-1-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-y-
l)-1-methyl- ethylcarbamoyl]-ethyl}-carbamic acid
(S)-tetrahydro-furan-3-yl ester; 218.
(S,S)-4-(5-Fluoro-2,3-dihydro-indol-1-yl)-3-[2-(3-methoxy-benzoylamin-
o)-4,4- dimethyl-pentanoylamino]-butyric acid; 219.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[3-(-
5-phenyl- thiophen-2-yl)-ureido]-propionamide; 220.
(S)-{2-Cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamo-
yl]-ethyl}- carbamic acid benzyl ester 221.
(S)-3-Cyclohexyl-2-[3-(3,5-dimethyl-isoxazol-4-yl)-ureido]-N-[2-(5-fl-
uoro-2,3- dihydro-indol-1-yl)-ethyl]-propionamide; 222.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(5-m-
ethyl-1- phenyl-1H-pyrazole-4-sulfonylamino)-propionamide; 223.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(5-i-
soxazol-3-yl- thiophene-2-sulfonylamino)-propionamide; 224.
(S)-2-(4-Bromo-3-chloro-thiophene-2-sulfonylamino)-3-cyclohexyl-N-[2--
(5-fluoro- 2,3-dihydro-indol-1-yl)-ethyl]-propionamide; 225.
(S)-2-(3-Biphenyl-4-yl-ureido)-3-cyclohexyl-N-[2-(5-fluoro-2,3-dihydr-
o-indol-1- yl)-ethyl]-propionamide; 226.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4-p-
henoxy- benzenesulfonylamino)-propionamide; 227.
(S)-2-(5-Chloro-thiophene-2-sulfonylamino)-3-cyclohexyl-N-[2-(5-fluor-
o-2,3- dihydro-indol-1-yl)-ethyl]-propionamide; 228.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(nap-
hthalene-1- sulfonylamino)-propionamide; 229.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4-
trifluoromethyl-benzenesulfonylamino)-propionamide; 230.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4-
trifluoromethoxy-benzenesulfonylamino)-propionamide; 231.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[5-(-
2-methyl-5-
trifluoromethyl-2H-pyrazol-3-yl)-thiophene-2-sulfonylamino]-propionamide;
232.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(3-m-
ethyl-3H- imidazole-4-sulfonylamino)-propionamide; 233.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[3-(-
5-methyl-
[1,3,4]oxadiazol-2-yl)-benzenesulfonylamino]-propionamide; 234.
(S)-2-(Benzo[b]thiophene-2-sulfonylamino)-3-cyclohexyl-N-[2-(5-fluoro-
-2,3- dihydro-indol-1-yl)-ethyl]-propionamide; 235.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(thi-
ophene-2- sulfonylamino)-propionamide; 236.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[4-(-
4-fluoro- phenoxy)-benzenesulfonylamino]-propionamide; 237.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[5-(-
2-methyl- thiazol-4-yl)-thiophene-2-sulfonylamino]-propionamide;
238.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4'--
methoxy- biphenyl-4-sulfonylamino)-propionamide; 239.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4-m-
ethoxy- benzenesulfonylamino)-propionamide; 240.
(S)-3-Cyclohexyl-2-(4-difluoromethoxy-benzenesulfonylamino)-N-[2-(5-f-
luoro-2,3- dihydro-indol-1-yl)-ethyl]-propionamide; 241.
(S)-2-(5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-3-cyclohexy-
l-N-[2-(5- fluoro-2,3-dihydro-indol-1-yl)-ethyl]-propionamide; 242.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-
phenylmethanesulfonylamino-propionamide; 243.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(tol-
uene-3- sulfonylamino)-propionamide; 244.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[4-(-
4-methoxy- phenoxy)-benzenesulfonylamino]-propionamide; 245.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(3-m-
ethoxy- benzenesulfonylamino)-propionamide; 246.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4-o-
xazol-5-yl- benzenesulfonylamino)-propionamide; 247.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-
(3-methyl-isoxazol-5-ylamino)-ethylcarbamoyl]-ethyl}-amide; 248.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(thi-
ophene-3- sulfonylamino)-propionamide; 249.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-
methanesulfonylamino-propionamide; 250.
(S,S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-methyl-et-
hyl]-2-(5- oxazol-5-yl-thiophene-3-sulfonylamino)-propionamide;
251.
(S,S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-methyl-et-
hyl]-2- (toluene-3-sulfonylamino)-propionamide; 252.
(S,S)-3-[4,4-Dimethyl-2-(toluene-3-sulfonylamino)-pentanoylamino]-4-(-
5-fluoro- 2,3-dihydro-indol-1-yl)-butyric acid tert-butyl ester;
253.
(S,S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-methyl-et-
hyl]-2-(2-
methyl-4-trifluoromethyl-furan-3-sulfonylamino)-propionamide; 254.
(S,S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-methyl-et-
hyl]-2-(3-
trifluoromethoxy-benzenesulfonylamino)-propionamide; 255.
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(1-m-
ethyl-1H- imidazole-4-sulfonylamino)-propionamide; 256.
(S)-2-(5-Benzenesulfonyl-thiophene-2-sulfonylamino)-3-cyclohexyl-N-[2-
-(5- fluoro-2,3-dihydro-indol-1-yl)-ethyl]-propionamide; 257.
(S)-2-(2-Acetylamino-4-methyl-thiazole-5-sulfonylamino)-3-cyclohexyl--
N-[2-(5- fluoro-2,3-dihydro-indol-1-yl)-ethyl]-propionamide; 258.
(S)-3-Cyclohexyl-2-(4,5-dichloro-thiophene-2-sulfonylamino)-N-[2-(5-f-
luoro-2,3- dihydro-indol-1-yl)-ethyl]-propionamide; 259.
(S,S)-2-(3-Chloro-benzenesulfonylamino)-3-cyclohexyl-N-[2-(5-fluoro-2-
,3- dihydro-indol-1-yl)-1-methyl-ethyl]-propionamide; 260.
(S,S)--N-{3-Cyclohexyl-1-[1-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-3-
-hydroxy- propylcarbamoyl]-propyl}-3-methoxy-benzamide; 261.
(S,S)-3-(2-tert-Butoxycarbonylamino-3-cyclohexyl-propionylamino)-4-(5-
-fluoro- 2,3-dihydro-indol-1-yl)-butyric acid benzyl ester; 262.
(S,S)-3-[4,4-Dimethyl-2-(toluene-3-sulfonylamino)-pentanoylamino]-4-(-
5-fluoro- 2,3-dihydro-indol-1-yl)-butyric acid; 263.
(S,S)-3-Cyclohexyl-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-[2-(5-
-fluoro- 2,3-dihydro-indol-1-yl)-1-methyl-ethyl]-propionamide; 264.
(S,S)-2-Benzenesulfonylamino-3-cyclohexyl-N-[2-(5-fluoro-2,3-dihydro--
indol-1- yl)-1-methyl-ethyl]-propionamide; 265.
(S,S)-4,4-Dimethyl-2-(toluene-3-sulfonylamino)-pentanoic acid
[2-(5-fluoro-2,3- dihydro-indol-1-yl)-1-methyl-ethyl]-amide; 266.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(4-benzyloxy-phenylamino)-
1-(S)-methyl-ethylcarbamoyl]-2-cyclohexyl-ethyl}-amide; 267.
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-
(3-methyl-isothiazol-5-ylamino)-ethylcarbamoyl]-ethyl}-amide; 268.
Tetrahydrofuran-2-(R)-carboxylic acid
{3,3-dimethyl-1-(S)-[1-(S)-methyl-2-(4-
trifluoromethoxy-phenylamino)-ethylcarbamoyl]-butyl}-amide; 269.
Tetrahydropyran-4-carboxylic acid
{3,3-dimethyl-1-(S)-[1-(S)-methyl-2-(4-
trifluoromethoxy-phenylamino)-ethylcarbamoyl]-butyl}-amide; 270.
Tetrahydro-pyran-4-carboxylic acid
{1-(S)-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-
indol-1-yl)-1-(S)-methyl-ethylcarbamoyl]-3,3-dimethyl-butyl}-amide;
271. Tetrahydro-furan-2-(R)-carboxylic acid
{1-(S)-[2-(5-fluoro-3,3-dimethyl-2,3-
dihydro-indol-1-yl)-1-(S)-methyl-ethylcarbamoyl]-3,3-dimethyl-butyl}-amid-
e; 272. Tetrahydrofuran-3-(R,S)-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-
trifluoromethoxy-phenylamino)-ethylcarbamoyl]-ethyl}-amide; 273.
Tetrahydrofuran-2-(R)-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-fluoro-3,3-
dimethyl-2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amid-
e; 274. Tetrahydrofuran-2-(R)-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,2-
dimethyl-2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethylcarbamoyl]-ethyl}-amid-
e.
[0200] Compounds of the present invention are either obtained in
the free form, or as a salt thereof if salt forming groups are
present, or as esters if ester forming groups are present.
[0201] Compounds of the present invention that have acidic groups
can be converted into salts with pharmaceutically acceptable bases,
e.g., an aqueous alkali metal hydroxide, advantageously in the
presence of an ethereal or alcoholic solvent, such as a lower
alkanol. Resulting salts can be converted into the free compounds,
e.g., by treatment with acids. These, or other salts can also be
used for purification of the compounds obtained. Ammonium salts are
obtained by reaction with the appropriate amine, e.g.,
diethylamine, and the like.
[0202] In certain aspects, compounds of the present invention
having basic groups can be converted into acid addition salts,
especially pharmaceutically acceptable salts. These are formed, for
example, with inorganic acids, such as mineral acids, for example,
sulfuric acid, a phosphoric or hydrohalic acid, or with organic
carboxylic acids, such as (C.sub.1-C.sub.4) alkane carboxylic acids
which, for example, are unsubstituted or substituted by halogen,
for example, acetic acid, such as saturated or unsaturated
dicarboxylic acids, for example, oxalic, succinic, maleic or
fumaric acid, such as hydroxycarboxylic acids, for example,
glycolic, lactic, malic, tartaric or citric acid, such as amino
acids, for example, aspartic or glutamic acid, or with organic
sulfonic acids, such as (C.sub.1-C.sub.4)-alkylsuflonic acids (for
example, methanesulfonic acid) or arylsulfonic acids which are
unsubstituted or substituted (for example, by halogen). Preferred
are salts formed with hydrochloric acid, methanesulfonic acid and
maleic acid.
[0203] In view of the close relationship between the free compounds
and the compounds in the form of their salts or esters, whenever a
compound is referred to in this context, a corresponding salt or
ester is also intended, provided such is possible or appropriate
under the circumstances.
[0204] The compounds, including their salts, can also be obtained
in the form of their hydrates, or include other solvents used for
their crystallization.
[0205] The compounds of the present invention that comprise free
hydroxyl groups may also exist in the form of pharmaceutically
acceptable, physiologically cleavable esters, and as such are
included within the scope of the invention. Such pharmaceutically
acceptable esters are preferably prodrug ester derivatives, such
being convertible by solvolysis or cleavage under physiological
conditions to the corresponding compounds of the present invention
which comprise free hydroxyl groups. Suitable pharmaceutically
acceptable prodrug esters are those derived from a carboxylic acid,
a carbonic acid monoester or a carbamic acid, preferably esters
derived from an optionally substituted lower alkanoic acid or an
arylcarboxylic acid.
[0206] As will be apparent to one of skill in the art, certain
compounds of the present invention possess asymmetric carbon atoms
(optical centers) or double bonds; the racemates, diastereomers,
enantiomers, geometric isomers and individual isomers are all
intended to be encompassed within the scope of the present
invention.
[0207] The present invention provides compounds which inhibit
cathepsin S selectively. In certain preferred aspects, the present
invention provides compounds which selectively inhibit cathepsin S
in the presence of cathepsin isozymes, such as cathepsin A, B, C,
D, E, F, G, H, K, L, M, O, P, Q, R, V, W, X and combinations
thereof.
[0208] Compounds of the present invention useful for treating
cathepsin S dependent conditions, preferably have cathepsin S
inhibition constants less than 10 .mu.M. More preferably, compounds
of the present invention useful for treating cathepsin S dependent
conditions have cathepsin S inhibition constants of less than 1.0
.mu.M. Most preferably, compounds of the present invention useful
for treating cathepsin S dependent conditions have cathepsin S
inhibition constants of less than 0.1 .mu.M.
[0209] In a preferred aspect, compounds of the present invention
that selectively inhibit cathepsin S in the presence of a cathepsin
isozyme (e.g. cathepsin K), have a cathepsin isozyme inhibition
constant at least 10 times greater than their cathepsin S
inhibition constant. In a more preferred aspect, compounds of the
present invention that selectively inhibit cathepsin S in the
presence of cathepsin isozyme, have a cathepsin isozyme inhibition
constant at least 100 times greater than their cathepsin S
inhibition constant. In a most preferred aspect, compounds of the
present invention that selectively inhibit cathepsin S in the
presence of cathepsin isozyme, have a cathepsin isozyme inhibition
constant at least 1000 times greater than their cathepsin S
inhibition constant.
IV. COMPOSITIONS
[0210] The pharmaceutical compositions according to the invention
are those suitable for enteral, such as oral or rectal,
transdermal, topical, and parenteral administration to mammals,
including humans, to inhibit cathepsin S activity, and for the
treatment of cathepsin S dependent disorders, in particular chronic
neuropathic pain (see, WO 03/020287), Alzheimer's disease and
certain autoimmune disorders, including, but not limited to,
juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris,
Graves' disease, myasthenia gravis, systemic lupus erythemotasus,
rheumatoid arthritis and Hashimoto's thyroiditis; allergic
disorders, including, but not limited to, asthma; and allogeneic
immune responses, including, but not limited to, rejection of organ
transplants or tissue grafts.
[0211] More particularly, the pharmaceutical compositions comprise
an effective cathepsin S inhibiting amount of a compound of the
present invention.
[0212] The pharmacologically active compounds of the present
invention are useful in the manufacture of pharmaceutical
compositions comprising an effective amount thereof in conjunction
or mixture with excipients or carriers suitable for either enteral
or parenteral application.
[0213] Preferred are tablets and gelatin capsules comprising the
active ingredient together with a) diluents, e.g., lactose,
dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b)
lubricants, e.g., silica, talcum, stearic acid, its magnesium or
calcium salt and/or polyethyleneglycol; for tablets also c)
binders, e.g., magnesium aluminum silicate, starch paste, gelatin,
tragacanth, methylcellulose, sodium carboxymethylcellulose and or
polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches,
agar, alginic acid or its sodium salt, or effervescent mixtures;
and/or e) absorbents, colorants, flavors and sweeteners. Injectable
compositions are preferably aqueous isotonic solutions or
suspensions, and suppositories are preferably prepared from fatty
emulsions or suspensions. The compositions may be sterilized and/or
contain adjuvants, such as preserving, stabilizing, wetting or
emulsifying agents, solution promoters, salts for regulating the
osmotic pressure and/or buffers. In addition, they may also contain
other therapeutically valuable substances. The compositions are
prepared according to conventional mixing, granulating or coating
methods, respectively, and contain about 0.1 to 75%, preferably
about 1 to 50%, of the active ingredient.
[0214] Tablets may be either film coated or enteric coated
according to methods known in the art.
[0215] Suitable formulations for transdermal application include an
effective amount of a compound of the present invention with
carrier. Preferred carriers include absorbable pharmacologically
acceptable solvents to assist passage through the skin of the host.
For example, transdermal devices are in the form of a bandage
comprising a backing member, a reservoir containing the compound
optionally with carriers, optionally a rate controlling barrier to
deliver the compound to the skin of the host at a controlled and
predetermined rate over a prolonged period of time, and means to
secure the device to the skin. Matrix transdermal formulations may
also be used.
[0216] Suitable formulations for topical application, e.g., to the
skin and eyes, are preferably aqueous solutions, ointments, creams
or gels well-known in the art. Such may contain solubilizers,
stabilizers, tonicity enhancing agents, buffers and
preservatives.
[0217] The pharmaceutical formulations contain an effective
cathepsin S inhibiting amount of a compound of the present
invention as defined above, either alone or in combination with
another therapeutic agent.
[0218] In conjunction with another active ingredient, a compound of
the present invention may be administered either simultaneously,
before or after the other active ingredient, either separately by
the same or different route of administration or together in the
same pharmaceutical formulation.
[0219] The dosage of active compound administered is dependent on
the species of warm-blooded animal (mammal), the body weight, age
and individual condition, and on the form of administration. A unit
dosage for oral administration to a mammal of about 50 to 70 kg may
contain between about 5 and 500 mg of the active ingredient.
[0220] In a preferred aspect, the pharmaceutical composition of the
present invention provides a compound according to Formula I.
[0221] In one aspect of the present invention, compositions of the
present invention that comprise compounds of the present invention
and pharmaceutically acceptable excipients, selectively inhibit
cathepsin S in the presence of other cathepsin isozymes (e.g.
cathepsin K).
[0222] In another aspect of the present invention, compositions of
the present invention useful for treating cathepsin S dependent
conditions, preferably have cathepsin S inhibition constants less
than 10 .mu.M. More preferably, compositions of the present
invention useful for treating cathepsin S dependent conditions have
cathepsin S inhibition constants of less than 1.0 .mu.M. Most
preferably, compositions of the present invention useful for
treating cathepsin S dependent conditions have cathepsin S
inhibition constants of less than 0.1 .mu.M.
[0223] In a preferred aspect, compositions of the present invention
utilize compounds that selectively inhibit cathepsin S in the
presence of a cathepsin isozyme (e.g. cathepsin K), have a
cathepsin isozyme inhibition constant at least 10 times greater
than their cathepsin S inhibition constant. In a more preferred
aspect, compounds of the present invention that selectively inhibit
cathepsin S in the presence of cathepsin isozyme, have a cathepsin
isozyme inhibition constant at least 100 times greater than their
cathepsin S inhibition constant. In a most preferred aspect,
compounds of the present invention that selectively inhibit
cathepsin S in the presence of cathepsin isozyme, have a cathepsin
isozyme inhibition constant at least 1000 times greater than their
cathepsin S inhibition constant.
V. METHODS
[0224] In view of their activity as inhibitors of cathepsin S,
compounds of the present invention are particularly useful in
mammals as agents for treatment and prophylaxis of diseases and
medical conditions involving elevated levels of cathepsin S. For
example, the compounds of the present invention are useful in
treating Alzheimer's disease and certain autoimmune disorders,
including, but not limited to juvenile onset diabetes, multiple
sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis,
systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto's
thyroiditis; allergic disorders, including, but not limited to
asthma; and allogeneic immune responses, including, but not limited
to, rejection of organ transplants or tissue grafts.
[0225] Beneficial effects are evaluated in vitro and in vivo
pharmacological tests generally known in the art, and as
illustrated herein.
[0226] The above cited properties are demonstrable in vitro and in
vivo tests, using advantageously mammals, e.g., rats, mice, dogs,
rabbits, monkeys or isolated organs and tissues, as well as
mammalian enzyme preparations, either natural or prepared by, e.g.,
recombinant technology. Compounds of the present invention can be
applied in vitro in the form of solutions, e.g., preferably aqueous
solutions or suspensions, and in vivo either enterally or
parenterally, preferably orally, e.g., as a suspension or in
aqueous solution, or as a solid capsule formulation. The dosage in
vitro may range between about 10.sup.-5 molar and 10.sup.-9 molar
concentrations. The dosage in vivo may range, depending on the
route of administration, between about 0.1 and 100 mg/kg.
[0227] The antiarthritic efficacy of the compounds of the present
invention for the treatment of rheumatoid arthritis can be
determined using models such as, or similar to, the rat model of
adjuvant arthritis, as described previously (R. E. Esser, et al.,
J. Rheumatology 1993, 20, 1176). The efficacy of the compounds of
the present invention for the treatment of osteoarthritis can be
determined using models such as, or similar to, the rabbit partial
lateral meniscectomy model, as described previously (Colombo et
al., Arth. Rheum. 1993, 26, 875-886). The efficacy of the compounds
in the model can be quantified using histological scoring methods,
as described previously (O'Byrne et al., Inflamm. Res. 1995, 44, S
177-S118).
[0228] The present invention also relates to methods of using
compounds of the present invention and their pharmaceutically
acceptable salts, or pharmaceutical compositions thereof, in
mammals for inhibiting cathepsin S, and for the treatment of
cathepsin S dependent conditions, such as the cathepsin S dependent
conditions described herein, e.g., inflammation, rheumatoid
arthritis and osteoarthritis.
[0229] In a preferred aspect, the present invention relates to a
method of treating rheumatoid arthritis, osteoarthritis, and
inflammation (and other diseases as identified above) in mammals
comprising administering to a mammal in need thereof, a
correspondingly effective amount of a compound of the present
invention.
[0230] In a preferred aspect, the method of the present invention
provides a compound according to Formula I.
[0231] Methods of the present invention useful for treating
cathepsin S dependent conditions, preferably use compounds that
have cathepsin S inhibition constants less than 10 .mu.M. More
preferably, methods of the present invention useful for treating
cathepsin S dependent conditions use compounds that have cathepsin
S inhibition constants of less than 1.0 .mu.M. Most preferably,
methods of the present invention useful for treating cathepsin S
dependent conditions use compounds that have cathepsin S inhibition
constants of less than 0.1 .mu.M.
[0232] Moreover, the present invention relates to a method of
selectively inhibiting cathepsin S activity in a mammal which
comprises administering to a mammal in need thereof, an effective
cathepsin S inhibiting amount of a compound of the present
invention. In a preferred aspect, the methods of the present
invention use compounds that selectively inhibit cathepsin S in the
presence of a cathepsin isozyme, such as cathepsin A, B, C, D, E,
F, G, H, K, L, M, O, P, Q, R, V, W, X and combinations thereof.
[0233] In a preferred aspect, methods of the present invention use
compounds that selectively inhibit cathepsin S in the presence of a
cathepsin isozyme (e.g. cathepsin K), have a cathepsin isozyme
inhibition constant at least 10 times greater than their cathepsin
S inhibition constant. In a more preferred aspect, compounds of the
present invention that selectively inhibit cathepsin S in the
presence of cathepsin isozyme, have a cathepsin isozyme inhibition
constant at least 100 times greater than their cathepsin S
inhibition constant. In a most preferred aspect, compounds of the
present invention that selectively inhibit cathepsin S in the
presence of cathepsin isozyme, have a cathepsin isozyme inhibition
constant at least 1000 times greater than their cathepsin S
inhibition constant.
VI. EXAMPLES
[0234] A. Compounds
[0235] General Procedure. All solvents stated as anhydrous were
purchased that way from the manufacturer and used as received. All
other purchased reagents were used as received. Unless otherwise
stated, all reactions were carried out under a positive pressure of
nitrogen. Silica gel chromatography was performed using pre-packed
cartridges and an instrument for making a linear solvent gradient
along with automated fraction collection. .sup.1H NMR spectral data
were reported as follows: chemical shift on the .delta. scale
(using residual protio solvent as the internal standard),
multiplicity (s=singlet, d=doublet, t=triplet, q=quartet,
m=multiplet), integration and coupling constant in hertz. .sup.13C
spectra were recorded as APT experiments and were reported in ppm
with residual solvent for internal standard.
Preparation 1. Synthesis of 2,2-dimethyl-5-fluoroindoline
[0236] Step A: A solution of N-Boc-4-fluoroaniline (9.02 g, 42.7
mmol) in THF (112 mL) was cooled to -60.degree. C. using a cryocool
instrument. The solution was treated with 1.7 M t-BuLi in pentane
(63 mL, 106.7 mmol) dropwise. After the first equivalent of base
was consumed, a yellow solution formed. The reaction was allowed to
warm to -20.degree. C. and was stirred at that temperature for 2.5
hours. The reaction was then treated with a solution of methallyl
bromide (5.67 g, 42.7 mmol) in THF (35 mL) dropwise and stirred for
an additional 1.5 hours at -20.degree. C. The reaction was then
quenched by addition of water. After coming to room temperature,
the reaction was treated with ethyl acetate and extracted with
water and brine, dried over MgSO.sub.4 and filtered. The solvent
was then removed and the residue was purified on silica gel using a
gradient of 0-25% ethyl acetate in hexane to afford 11.3 g (80%
yield) of [4-Fluoro-2-(2-methyl-allyl)-phenyl]-carbamic acid
tert-butyl ester as a white solid; .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 1.50 (s, 9H), 1.72 (s, 3H), 3.28 (s, 2H), 4.71 (s,
1H), 4.92 (s, 1H), 6.32-6.50 (m, 1H), 6.86 (dd, 1H, J.sub.1=3.0,
J.sub.2=9.1), 6.93 (ddd, 1H, J.sub.1=3.0, J.sub.2=8.5,
J.sub.3=11.5), 7.65-7.82 (m, 1H); HPLC-MS calcd. for
C.sub.15H.sub.20FNO.sub.2 (M+H.sup.+-tBu) 210.1, found 210.3.
[0237] Step B: A sample of
[4-Fluoro-2-(2-methyl-allyl)-phenyl]-carbamic acid tert-butyl ester
(1.10 g, 4.14 mmol) was treated with anisole (5 mL),
dichloromethane (5 mL) and trifluoroacetic acid (5 mL) and stirred
for 4 hours. The solvent was removed and the reaction was
transferred to a microwave reaction vial using methanesulfonic acid
(3 mL). The reaction was heated to 170.degree. C. for 10 minutes.
The reaction was cooled to room temperature and quenched into
excess stirring 1 M NaOH. The aqueous phase was extracted twice
with ethyl acetate and the combined organics were dried over
MgSO.sub.4 and filtered. The resulting oil was purified on silica
gel using a gradient of 0-70% t-butyl ethyl ether and hexane to
afford 450 mg (66% yield) of 2,2-dimethyl-5-fluoroindoline; .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 1.08 (s, 6H), 2.58 (s, 2H), 6.24
(dd, 1H, J.sub.1=4.4, J.sub.2=8.4), 6.43-6.48 (m, 1H), 6.53-6.56
(m, 1H); HPLC-MS calcd. for C.sub.10H.sub.12FN (M+H.sup.+) 166.1,
found 166.4.
Preparation 2. Synthesis of 3,3-dimethyl-5-fluoroindoline
[0238] According to the procedure described in S. Coulton et al.
WO9925709 with the following modifications.
N-(4-Fluoro-phenyl)-N-(2-methyl-allyl)-acetamide (5 grams, 24.12
mmol) was added to a microwave tube with aluminum trichloride (7
grams, 52.4 mmol). The tube was capped and heated to 150.degree. C.
for 20 minutes under microwave. The slurry was worked up with water
and ethyl acetate, the organic layer was extracted with 3 washes of
saturated sodium bicarbonate solution and the organic layer was
dried over magnesium sulfate. The solution was then filtered and
rotary evaporated to yield pure
1-(5-Fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone in
quantitative yield. This was converted to the free indoline by
suspending the entire 5 grams of product in 20 mL of 6 M HCl and
heating in a microwave to 200.degree. C. for 10 minutes. The
resulting 5-Fluoro-3,3-dimethyl-2,3-dihydro-1H-indole crystallized
on cooling as the hydrochloride salt in quantitative yield. This
material was identical to the previously reported compound.
Preparation 3. Synthesis of
(S)-[1-Cyclopropyl-2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethyl-
]-carbamic acid benzyl ester
[0239] Step A: (S)-cyclopropyl glycine was prepared according to a
modified procedure from that reported in D. J. Bayston et al. U.S.
Pat. No. 6,191,306. A sample of (R)-phenethyl-(S)-cyclopropyl
glycine (16.8 g, 76.7 mmol) was treated with THF (200 mL), water
(100 mL) and 10% Pd/C (4.76 g). To the stirring mixture was added
formic acid (17 mL) and the reaction was stirred overnight. The
catalyst was then removed by filtration through a pad of celite and
the solvent was removed by rotary evaporation. The material was
co-evaporated with methanol several times and dried under vacuum to
afford 4.75 g (54% yield) of the desired material as a solid which
was used without further purification.
[0240] The material from the previous step (4.75 g, 41 mmol) was
dissolved in 130 mL of 1 N NaOH and treated with benzyl
chloroformate (5.92 g, 49.5 mmol) with vigorous stirring. The
reaction was stirred overnight and then extracted with
dichloromethane twice. The organics were discarded and the aqueous
phase was acidified with conc. HCl and extracted with
dichloromethane three times. The combined organics were dried over
MgSO.sub.4 and the solvent was removed to afford 7.38 g (72% yield)
of the (S)-benzyloxycarbonylamino-cyclopropyl-acetic acid as a
white solid.
[0241] Step B: A solution of
(S)-benzyloxycarbonylamino-cyclopropyl-acetic acid (3.2 g, 12.8
mmol) in THF (20 mL) was cooled in an ice/water bath and treated
with a 1 M solution of BH.sub.3 in THF (16.7 mL, 16.7 mmol). The
reaction was stirred for 4 hours and then treated with 1 M HCl
until the bubbling ceased. The reaction was stirred overnight and
the organic solvent was removed by rotary evaporation. The residue
was treated with ethyl acetate and transferred to a separatory
funnel. The aqueous phase was discarded and the organics were
washed twice with 1 M NaOH, dried over MgSO.sub.4 and the solvent
was removed. The residue was purified on silica gel using a
gradient of 0-100% ethyl acetate in hexane to afford 1.5 g (50%
yield) of (S)-(1-Cyclopropyl-2-hydroxy-ethyl)-carbamic acid benzyl
ester as a white solid; .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
0.26-0.37 (m, 1H), 0.34-0.44 (m, 1H), 0.47-0.61 (m, 2H), 0.83-0.94
(m, 1H), 2.95-3.04 (m, 1H), 3.70 (dd, 1H, J.sub.1=5.8,
J.sub.2=11.1), 3.79-3.88 (m, 1H), 5.00-5.12 (m, 1H), 5.10 (s, 2H),
7.29-7.31 (m, 5H); HPLC-MS calcd. for C.sub.13H.sub.17NO.sub.3
(M+H.sup.+) 236.1, found 236.3.
[0242] Step C:
(S)-[1-Cyclopropyl-2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethyl-
]-carbamic acid benzyl ester was prepared in 67% yield an analogous
manner to example 22, step A except that the alcohol from the
previous step and 1 equivalent of 3,3-dimethyl-5-fluoroindoline (WO
9925709) were used as coupling partners; HPLC-MS calcd. for
C.sub.23H.sub.27FN.sub.2O.sub.2 (M+H.sup.+) 383.2, found 383.4.
Preparation 4. Synthesis of
(S)-[1-Cyclopropyl-2-(5-fluoro-3,3-spirocycloprpyl-indol-1-yl)-ethyl]-car-
bamic acid benzyl ester
[0243] Step A: A solution of 5-fluoroisatin (5 g, 30.2 mmol) in DMF
(60 mL) was cooled in an ice/water bath and treated with sodium
hydride (1.44 g, 60.6 mmol) portionwise. The reaction was stirred
for 15 minutes after the addition of the last portion and then
treated with p-methoxybenzyl chloride (5.32 g, 45.3 mmol) and
allowed to stir for 1 hour. The reaction was then quenched by slow
addition of excess methanol. After bubbling had stopped, the
reaction was poured into water (100 mL) and extracted twice with
ethyl acetate. The organics were combined, dried over MgSO.sub.4
and the solvent was removed. The residue was purified by silica gel
chromatography using a gradient of 0-100% ethyl acetate in hexane
to afford 7.1 g (82%) of
5-Fluoro-1-(4-methoxy-benzyl)-1H-indole-2,3-dione; .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 3.79 (s, 3H), 4.86 (s, 2H), 6.75 (dd,
1H, J.sub.1=3.6, J.sub.2=8.6), 6.84-6.90 (m, 2H), 7.19 (ddd, 1H,
J.sub.1=J.sub.2=8.6, J.sub.3=3.6), 7.22-7.27 (m, 1H), 7.26-7.31 (m,
2H); HPLC-MS calcd. for C.sub.16H.sub.12FNO.sub.3 (M+H.sup.+)
286.1, found 286.3.
[0244] Step B: A solution of
5-fluoro-1-(4-methoxy-benzyl)-1H-indole-2,3-dione (7.1 g, 24.9
mmol) in hydrazine hydrate (35 mL) and ethanol (15 mL) was refluxed
overnight, diluted with water and extracted twice with ethyl
acetate. The combined organics were dried over Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified by silica gel
chromatography using a gradient of 0-100% ethyl acetate in hexane
to afford 6.1 g (90%) of
5-fluoro-1-(4-methoxy-benzyl)-1,3-dihydro-indol-2-one; .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 3.59 (s, 2H), 3.77 (s, 3H), 4.83 (s,
2H), 6.63 (dd, 1H, J.sub.1=4.2, J.sub.2=8.6), 6.82-6.91 (m, 3H),
6.96-7.01 (m, 1H), 7.19-7.23 (m, 1H), 7.27-7.31 (m, 1H); HPLC-MS
calcd. for C.sub.16H.sub.14FNO.sub.2 (M+H.sup.+) 272.1, found
272.3.
[0245] Step C: A solution of
5-fluoro-1-(4-methoxy-benzyl)-1,3-dihydro-indol-2-one (6.12 g, 22.6
mmol) in DMF (65 mL) was cooled in an ice/water bath and treated
with dibromoethane (6.35 g, 33.8 mmol) followed by sodium hydride
(1.09 g, 45 mmol) portionwise. After stirring at 0.degree. C. for 1
hour, the reaction was cooled to -78.degree. C. and treated with
excess methanol. After bubbling had stopped, the reaction was
poured into water (100 mL) and extracted twice with ethyl acetate.
The organics were combined, dried over Na.sub.2SO.sub.4 and the
solvent was removed. The residue was purified by silica gel
chromatography using a gradient of 0-100% ethyl acetate in hexane
to afford 4.1 g (61%) of
5-fluoro-1-(4-methoxy-benzyl)-siprocyclopropyloxindole; .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.54 (dd, 2H, J.sub.1=4.0,
J.sub.2=7.8), 1.83 (dd, 2H, J.sub.1=4.3, J.sub.2=8.1), 3.77 (s,
3H), 4.91 (s, 2H), 6.57 (dd, 1H, J.sub.1=2.5, J.sub.2=8.0), 6.69
(dd, 1H, J.sub.1=4.2, J.sub.2=8.5), 6.81 (dd, 1H, J.sub.1=2.5,
J.sub.2=9.3), 6.83-6.87 (m, 2H), 7.22-7.25 (m, 2H); HPLC-MS calcd.
for C.sub.18H.sub.16FNO.sub.2 (M+H.sup.+) 298.1, found 298.3.
[0246] Step D: A solution of
5-fluoro-1-(4-methoxy-benzyl)-siprocyclopropyloxindole (3.38 g,
11.4 mmol) in TFA (20 mL) was stirred at 60.degree. C. overnight.
The solvent was then removed and the reaction was diluted with
ethyl acetate and washed with saturated aqueous NaHCO.sub.3 until
the washings were neutral. The organic phase was then washe with
brine, dried over Na.sub.2SO.sub.4 and the solvent was removed. The
residue was purified by silica gel chromatography using a gradient
of 0-100% ethyl acetate in hexane to afford 1.94 g (96%) of
5-fluoro-siprocyclopropyloxindole; .sup.1H NMR (MeOD, 400 MHz)
.delta. 1.76-1.86 (m, 4H), 6.91-6.94 (m, 1H), 7.07-7.11 (m, 2H);
HPLC-MS calcd. for C.sub.10H.sub.8FNO (M+H.sup.+) 178.2, found
178.3.
[0247] Step E: A sample of 5-fluoro-siprocyclopropyloxindole (172
mg, 97 .mu.mol) was cooled in an ice/water bath and treated with a
1.0 M solution of LAH (1.94 ml, 1.9 mmol). The reaction was stirred
at room temperature for 15 minutes and then at 50.degree. C. for 3
hours and finally was cooled back down with an ice/water bath. The
reaction was treated with 1 M NaOH (1.9 mL) followed by water (1.9
mL). The reaction was filtered over celite and dried over
MgSO.sub.4. After filtration, the solvent was removed and the crude
material of 5-fluoro-siprocyclopropylindoline was used as the
indoline partner to prepare
[1-Cyclopropyl-2-(5-fluoro-3,3-spirocycloprpyl-indol-1-yl)-ethyl]-
-carbamic acid benzyl ester in 62% yield in an analogous manner to
example 22, step A; HPLC-MS calcd. for
C.sub.23H.sub.25FN.sub.2O.sub.2 (M+H.sup.+) 381.2, found 381.4.
[0248] In addition, synthesis of other
3,3-spiro-cycloalkylindolines are also described in (1) Jackson, A.
H. et al. Tetrahedron (1968), 24(1), 403-13; (2) Jansen, A. B. A.
et al. Tetrahedron (1965), 21(6), 1327-31; (3) Bermudez, J. et al.
J. Med. Chem. (1990), 33(7), 1929-32; (4) Nishio, T. et al. Helv.
Chim. Acta (1990), 73(6), 1719-23; (5) Nishio, T. et al. J. Chem.
Soc., Perkin Trans 1 (1991), (1), 141-3; (6) Kucerovy, A. et al.
Synth. Commun. (1992), 22(5), 729-33; (7) Kato, M. et al. Chem.
Pharm. Bull. (1995), 43(8), 1351-7.
Preparation 5. Synthesis of 4-nitrophenyl tetrahydropyran-4-yl
carbonate
[0249] To a solution of tetrahydro-4H-pyran-4-ol (408 mg, 102 mmol)
and pyridine (632 mg, 19.1 mmol) in 15 mL of CH.sub.2Cl.sub.2 was
added p-nitrophenyl chloroformate (968 mg, 102 mmol). The mixture
was stirred at rt for 30 h. Water was added and the organic layer
was separated, and washed with 5% aq. citric acid. The organic
layer was treated with an aq. solution of ammonia
(NH.sub.4OH/H.sub.2O: 1/4 v/v) for 15 min. The organic layer was
separated, washed with aq. sodium bicarbonate and brine. After the
solvent was removed, the desire product was isolated as a solid.
.sup.1H NMR (CD.sub.3Cl, 400 MHz) .delta. 1.80 (m, 2H), 2.00 (m,
2H), 3.52 (m, 2H), 3.92 (m, 2H), 4.88 (m, 1H), 7.32 (d, J=7 Hz,
2H), 8.21 (d, J=7 Hz, 2H).
Preparation 6. Synthesis of (S)-2-(4-Methoxy-phenylamino)-1-methyl
ethyl amine
[0250] Step A: Preparation of
(S)-2-(tert-Butoxycarbonylamino)-propionaldehyde.
[0251] (S)-(-)-2-(tert-Butoxycarbonylamino)-1-propanol (523 mg,
2.98 mmol, 1.0 equiv.) was dissolved in 45 mL methylene chloride in
a 100 mL r.b. flask with a magnetic stir bar. To this clear
homogeneous solution, Dess-Martin periodinane (1.523 g, 3.591 mmol,
1.2 equiv.) was added in one part and the cloudy white reaction
mixture was allowed to stir at room temperature for 2 h. Thin-layer
chromotography monitored the reaction to completion. The reaction
mixture was diluted with 100 mL ethyl acetate. Sodium bisulfite
solution (2 M, 20 mL) was added to the reaction mixture and the
organic layer was separated. The aqueous layer was washed with
3.times.30 mL EtOAc. The combined organic layers were washed with
50 mL 1 M NaOH, followed by saturated NaCl (30 mL) and dried over
MgSO.sub.4. Filtration and rotary evaporation produced the desired
product as a yellow oil (475 mg, 92% yield, R.sub.f=0.63, 1:1
hexanes/ethyl acetate).
[0252] Step B: Preparation of
[2-(4-methoxy-phenylamino)-(1S)-methyl-ethyl]-carbamic acid
tert-butyl ester.
[0253] (S)-2-(tert-Butoxycarbonylamino)-propionaldehyde (473 mg,
2.74 mmol) and p-anisidine (1.031 g, 8.371 mmol, 3.0 equiv.) was
dissolved in 45 mL of MeOH at 0.degree. C. in a 100 mL r.b. flask
with a magnetic stir bar. Optionally, acetic acid (469 .mu.L, 8.21
mmol, 3.0 equiv.) can be added via syringe to assist in the
reaction. To the stirring dark colored solution was added sodium
cyanoborohydride (326 mg, 5.82 mmol, 1.89 equiv.). Gas evolution
and disappearance of color were observed. The reaction was allowed
to slowly warm to room temperature with stirring over 30 minutes
and the reaction was monitored by LC/MS. At the completion of the
reaction, the mixture was quenched with 1 M NaOH, and extracted
3.times.50 mL ethyl acetate. The resulting organics were washed
with 50 mL saturated NaHCO.sub.3, 40 mL saturated NaCl, and dried
over MgSO.sub.4. Evaporation of ethyl acetate provided 728 mg of a
brown oil. Purification by automated ISCO chromatography provided a
clear oil of [2-(4-methoxy-phenylamino)-(1S)-methyl-ethyl]-carbamic
acid tert-butyl ester (583 mg, 2.079 mmol, 76% yield). HPLC-MS
calcd. for C.sub.15H.sub.24N.sub.2O.sub.3 (M+H.sup.+) 281.2, found
281.5. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.21 (d, 6H, J=6.6
Hz), 1.47 (s, 9H), 3.05 (dd, 1H, J=12.2, 7.3 Hz), 3.13 (dd, 1H,
J=12.2, 4.6 Hz), 3.76 (s, 3H), 3.93 (broad s, 1H), 4.62 (broad s,
1H), 6.60 (d, 2H, J=6.8 Hz), 6.80 (2H, d, J=6.8 Hz).
[0254] Step C:
[2-(4-Methoxy-phenylamino)-(1S)-methyl-ethyl]-carbamic acid
tert-butyl ester (383 mg, 1.37 mmol) was added to 10 mL of a
trifluroacetic acid solution (10 v/v % in methylene chloride) at
room temperature in a 25 mL r.b. flask with a magnetic stirbar. The
reaction turns dark purple/black in color after 5 minutes. The
reaction is allowed to stir at room temperature until the reaction
is judged complete by HPLC/MS. The solvent is removed by
evaporation and to provide
2-(4-Methoxy-phenylamino)-(1S)-methyl-ethyl-ammonium
trifluoroacetate salt as a brown oil (394 mg, 1.34 mmol, 98% yield)
and used directly in the next reaction. HPLC-MS calcd. for
C.sub.10H.sub.16N.sub.2O (M+H.sup.+) 181.1, found 181.5.
Preparation 7.
(R)-3-Benzyloxy-N.sup.1-(4-methoxy-phenyl)-propane-1,2-diamine
[0255] Step A: N-Boc-OBn-Serine (750 mg, 2.54 mmol), p-anisidine
(344 mg, 2.79 mmol) and HOBt (377 mg, 2.79 mmol) were charged to a
50 mL roundbottom flask and treated with CH.sub.2C.sub.2 (6 mL).
The reaction was then treated with EDCI (535 mg, 2.79 mmol) and
allowed to stir for 2 hours. The reaction was then diluted with
ethyl acetate and extracted twice with water, twice with 1 M HCl
and twice with 1 M NaOH. The organics were then dried over
MgSO.sub.4 and the solvent was removed to afford 450 mg (44%) of a
white solid: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.49 (s,
9H), 3.63-3.72 (m, 1H), 3.81 (s, 3H), 4.00-4.08 (m, 1H), 4.47-4.50
(m, 1H), 4.55-4.70 (m, 2H), 5.45-5.60 (m, 1H), 6.87 (d, 2H, J=8.8),
7.30-7.41 (m, 7H), 8.20-8.33 (m, 1H); HPLC-MS calcd. for
C.sub.22H.sub.28N.sub.2O.sub.5 (M+H.sup.+) 401.2, found 401.4.
[0256] Step B: The product from Step A (400 mg, 1.00 mmol) was
added to an ice cold solution of borane (1 M) in THF. The cooling
bath was removed and the reaction was allowed to stir for 24 h at
which point the excess reagent was quenched using 5% NaHSO.sub.4.
The reaction was diluted with ethyl acetate and extracted twice
with 1 M NaOH. The organics were dried over MgSO.sub.4 and the
solvent was removed. The resulting residue contained material that
was missing the Boc group and some material that still had it (by
HPLC-MS). The oil was treated with MeOH (2 mL) and 4 M HCl (2 mL)
and stirred for 3 hours. The solvent was then removed and the
reaction was partitioned between ethyl acetate and 1 M NaOH. The
aqueous phase was extracted twice more with ethyl acetate and the
combined organics were dried over MgSO.sub.4 and the solvent was
removed.
Preparation 8. Synthesis of
(S)--N1-(4-trifluoromethoxy-phenyl)-propane-1,2-diamine
[0257] Step A: (S)-2-(benzylcarbonylamino)-propionaldehyde.
[0258] (S)-2-(benzylcarbonylamino)-propanol (5 g, 23.9 mmol) was
dissolved in CH.sub.2Cl.sub.2 (200 mL) and treated with Dess-Martin
periodinane (12.26 g, 1.1 eq). The mixture was stirred for 2 hours,
then quenched with sodium thiosulphate, and the solvent removed in
vacuo. The residue was then separated between sodium hydroxide (1M,
500 mL) and ethyl acetate (500 mL). The organics were washed with
brine, dried (MgSO.sub.4) and evaporated in vacuo to yield a clear
oil which was used immediately in the next step without further
purification.
[0259] Step B:
[1-(S)-Methyl-2-(4-trifluoromethoxy-phenylamino)-ethyl]-carbamic
acid benzyl ester.
[0260] (S)-2-(benzylcarbonylamino)-propionaldehyde was dissolved in
methanol (300 mL). Acetic acid (4 mL, 2.9 eq) was added and the
mixture treated with 4-trifluoromethoxy aniline (9.6 mL, 3 eq) and
stirred for 15 minutes then sodium cyanoborohydride (4.36 g, 2.9
eq) was added with some effervescence. The mixture was stirred for
3 hours, and then the solvent reduced in vacuo. This was then
separated between hydrochloric acid (1M, 500 mL.times.2) and ethyl
acetate (500 mL). The organics were washed with sodium bicarbonate
(500 mL), brine(500 mL), dried (MgSO.sub.4) and evaporated in vacuo
to give a clear oil which was purified by silica gel chromatography
eluted with a gradient of 0-100% ethyl acetate/hexane.
[0261] Step C:
(S)--N1-(4-Trifluoromethoxy-phenyl)-propane-1,2-diamine.
[0262]
[1-(S)-Methyl-2-(4-trifluoromethoxy-phenylamino)-ethyl]-carbamic
acid benzyl ester (23.9 mmol) was dissolved in ethanol (200 mL)
then placed under nitrogen. 10% Palladium on carbon was added (0.5
g) and the mixture was stirred under hydrogen (atmospheric
pressure) overnight. When reaction was complete, the mixture was
filtered through celite. The celite was washed with ethanol
(5.times.50 ml) then evaporated in vacuo to give a brown oil (4.03
g, 17.21 mmol, 72% yield over 3 steps).
Preparation 9. Synthesis of 2,2,-5-trifluoroindoline
[0263] Step A: 5-Fluoro-1H-indole-2,3-dione (956 mg, 5.79 mmol, 1
eq) was added as a solution in dry DMF to a stirred slurry of
sodium hydride (278 mg, 11.6 mmol, 2 eq) in dry DMF drop wise over
15 minutes under an inert atmosphere with adequate pressure release
to accommodate H.sub.2 evolution. The resulting mixture was stirred
for 1 hour and p-methoxybenzyl chloride was added via syringe to
the reaction. The solution was then stirred ca 2 hours and worked
up by addition of water followed by extraction into ethyl acetate.
The organic layer was washed twice with water and then dried over
MgSO.sub.4. Column chromatography with ethyl acetate/hexane
afforded 5-Fluoro-1-(4-methoxy-benzyl)-1H-indole-2,3-dione as a red
solid (1.3 g, 80% yield). .sup.1H NMR (CDCl.sub.3) .delta. (ppm):
7.3-7.24 (m, 3H), 7.20 (td, J=8.7, 2.7 Hz, 1H), 6.9-6.86 (m, 2H),
6.76 (dd, J=8.6, 3.6 Hz, 1H), 3.81 (s, 2H), 3.78 (s, 3H).
LC/MS=286.1 (M+1).
[0264] Step B: The product from step A (200 mg, 0.701 mmol, 1 eq)
was dissolved in 10 mL of dry DCM and placed under and inert
atmosphere. DAST (339 mg, 2.103 mmol, 3 eq) was added via syringe
and the reaction was stirred overnight. The reaction was worked up
by addition of saturated aqueous sodium bicarbonate and the organic
layer was dried over MgSO.sub.4, filtered, and rotary evaporated to
dryness. The resulting crude material was purified by flash
chromatography using ethyl acetate/ hexane as a solvent system.
.sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.3-7.28 (m, 1H), 7.22 (d,
J=8.7 Hz, 2H), 7.09 (td, J=8.7, 1.3 Hz, 1H), 6.87 (d, J=8.7 Hz,
2H), 6.73 (m, 1H), 4.83 (s, 2H), 3.79 (s, 3H).
LC/MS=308.1(M+1).
[0265] Step C: The product from step B (1.178 g, 3.83 mmol, 1 eq)
was dissolved in 75 mL of dry THF and placed under an inert
atmosphere. LiAlH.sub.4 (291 mg, 7.66 mmol, 2 eq) was added as a
solid under a positive pressure of N.sub.2 at -78.degree. C. The
reaction was allowed to stir at this temperature for 30 min and
then allowed to warm to room temp over a period of 6 hours. The
reaction was worked up by addition of water dropwise followed by 4
equivalents of aqueous KOH. The slurry was diluted with 500 mL of
water and extracted with 2.times.200 mL portions of ethyl acetate.
The organic layers were combined, dried over MgSO.sub.4, filtered,
and rotary evaporated to dryness. The resulting crude material was
purified by flash chromatography using ethyl acetate/hexane as a
solvent system yielding 320 mg of pure material (28%). .sup.1H NMR
(CD.sub.30D) .delta. (ppm): 7.21 (d, J=8.8 Hz, 2H), 7.06 (dd,
J=8.2, 1.3 Hz, 1H), 6.89 (m, 1H), 6.84 (d, J=8.7 Hz, 2H), 6.77 (dd,
J=8.6, 4.3 Hz, 1H), 4.83 (s, 2H), 3.73 (s, 3H), 3.12 (s, 2H).
LC/MS=294.1(M+1).
[0266] Step D: The product from step C (50 mg, 0.1704 mmol, 1 eq)
was taken up in 1 mL of TFA. The solution was placed in a microwave
tube, sealed, and heated to 175.degree. C. for 5 minutes. The
resulting black solution was neutralized with saturated sodium
bicarbonate and extracted with 2.times.50 mL portions of ethyl
acetate. The organic layers were dried over MgSO.sub.4, filtered,
and rotary evaporated to dryness. The resulting solid was dissolved
in a 50:50 mix of DMSO/MeOH and purified by prep HPLC. Yield 23.8
mg of white solid (81%). .sup.1H NMR (DMSO D.sub.6) .delta. (ppm):
10.41 (s, 1H), 7.13 (dd, J=8.6, 2.4 Hz, 1H), 7.01 (td, J=8.6, 2.7
Hz, 1H), 6.8 (dd, J=8.5, 4.5 Hz, 1H), 3.5 (s, 2H). [0267] *
Compounds synthesized according to the procedure described in
Example 1. [0268] .sup.# Compounds synthesized according to the
procedure described in Example 83. [0269] .sup.$ Compounds
synthesized according to the procedure described in Example 141.
[0270] .sup.& Compounds synthesized according to the procedure
described in Example 22. [0271] *** Compounds synthesized according
to the procedure described in Example 181. [0272] .sup.$$$
Compounds synthesized according to the procedure described in
Example 184.
Example 1
N-{cis-2-[2-(4-Methoxy-phenylamino)-ethylcarbamoyl]-cyclohexyl}-3-methyl-b-
enzamide
##STR00017##
[0274] Step A: An aldehyde-functionalized polystyrene resin 1
("Pal-Resin", 10.30 g @ 1.05 mmol/g, 10.8 mmol) was swelled in DMF
(50 mL) for 10 min. N1-(4-Methoxy-phenyl)-ethane-1,2-diamine (3.59
g, 21.6 mmol, prepared according to the procedures in E. Altmann et
al J. Med. Chem. 2002, 45, 2352 and references cited therein) in
DMF (150 mL) was added followed by acetic acid (5.0 ml, 86.4 mmol)
and the mixture was agitated for 90 min at room temperature. Sodium
triacetoxyborohydride (6.87 g, 32.4 mmol) was added and the mixture
was shaken for 14 hours at room temperature. The reductively
aminated resin 2 was then filtered and washed (DMF.times.3,
alternate MeOH/DCM.times.4, MeCN.times.3).
[0275] Step B: Resin 2 (60 mg, 0.05 mmol) was swelled in DMF (1.5
mL) and a solution of Fmoc-cis-2-amino-1-cyclohexane carboxylic
acid (55 mg, 0.15 mmol), HOBt (21 mg, 0.15 mg) and DIC (24 .mu.L,
0.15 mmol) was added. The mixture was shaken for 3 hours at room
temperature, then filtered and washed (DMF.times.5) to yield resin
3.
[0276] Step C: Resin 3 (0.05 mmol) was swelled in DMF (1.5 mL) and
a solution of 20 v/v % piperidine in DMF (1.5 mL) was added. The
mixture was shaken for 30 min at room temperature, then filtered
and washed (DMF.times.5) to yield resin 4.
[0277] Step D: Resin 4 (0.05 mmol) was swelled in DMF (1.5 mL) and
a solution of m-toluic acid (21 mg, 0.15 mmol), HOBt (21 mg, 0.15
mg) and DIC (24 .mu.L, 0.15 mmol) was added. The mixture was shaken
for 3 h at room temperature, then filtered and washed (DMF.times.3,
alternate MeOH/DCM.times.4, MeCN.times.3) to yield resin 5.
[0278] Step E: To resin 5 (0.05 mmol) was added a solution of
trifluoroacetic acid/DCM/H.sub.2O in the v/v ratio 45:45:10. The
mixture was shaken for 1 h at room temperature and filtered. Step E
was repeated once, the filtrates combined and dried in vacuo.
Reverse phase HPLC chromatography yielded the title compound 6 (10
mg, 0.025 mmol, 50%) as a white solid. MS calcd. for
C.sub.24H.sub.32N.sub.3O.sub.3 (M+H.sup.+) 410.24, found 410.2.
Example 2
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0279] C.sub.31H.sub.33F.sub.4N.sub.3O.sub.3; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 8.07(m, 1H), 7.85(m, 2H), 7.48(m, 3H),
7.10(m, 2H), 7.00(m, 2H), 6.73(m, 1H), 4.52(m, 1H), 3.76(m, 2H),
3.65(m, 2H), 3.42(m, 2H), 3.14(m, 2H), 1.63(m, 7H), 1.34(m, 1H),
1.14(m, 3H), 0.87(m, 2H); LCMS: 572.5 (M+H).sup.+.
Example 3
(S)--N-{1-[2-(5-Fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-3-methyl-bu-
tyl}-3-methyl-benzamide
[0280] Step A: Preparation of
(S)-4-Methyl-2-(3-methyl-benzoylamino)-pentanoic acid. (L)-Leucine
(2.54 g, 19.4 mmol) was dissolved in 1 M aqueous NaOH solution.
This solution was cooled to 0.degree. C. using an ice/water bath.
After initiation of vigorous stirring, m-toluloyl chloride was
added dropwise via syringe. The reaction was allowed to come to
room temperature overnight. The reaction was then treated with
concentrated HCl until the pH was highly acidic. The resulting
solid was collected and dissolved in EtOH (30 mL). Water (.about.20
mL) was added to this mixture and the solution was rotary
evaporated at a pressure of 30 mBar until the product solidified.
The resulting solid was collected and dried to afford 3.5 g (72%)
of product.
[0281] Step B: Preparation of
(S)--N-[1-(2-Hydroxy-ethylcarbamoyl)-3-methyl-butyl]-3-methyl-benzamide.
(S)-4-Methyl-2-(3-methyl-benzoylamino)-pentanoic acid (1 g. 4.0
mmol), ethanolamine (270 mg, 4.4 mmol) and HOBt (596 mg, 4.4 mmol)
were treated with DCM (20 mL) followed by EDCI (845 mg, 4.4 mmol).
The reaction was allowed to stir for 2 h and then purified directly
by silica gel column chromatography using ethyl acetate and hexane
to afford the product (350 mg, 30%) as a solid: .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 0.89-0.99 (m, 6H), 1.67-1.79 (m, 3H),
2.37 (s, 3H), 3.31-3.41 (m, 1H), 3.42-3.52 (m, 1H), 3.61 (dd, 1H,
J.sub.1=2.7, J.sub.2=8.1), 7.24-7.34 (m, 2H), 7.43 (dd, 1H,
J.sub.1=J.sub.2=5.3), 7.57-7.63 (m, 2H); HPLC-MS calcd. for
C.sub.16H.sub.24N.sub.2O.sub.3 (M+H.sup.+) 292.18, found 292.2.
[0282] Step C:
(S)--N-[1-(2-Hydroxy-ethylcarbamoyl)-3-methyl-butyl]-3-methyl-benzamide
(803 mg, 2.75 mmol) was dissolved in DCM (10 mL) and treated with
the Dess-Martin periodinane (1.3 g, 5.4 mmol). The reaction was
allowed to stir for 2 hours and then diluted with DCM and extracted
with 1 M Na.sub.2S.sub.2O.sub.3 solution (1.times.) and saturated
aqueous NaHCO.sub.3 solution (1.times.). The organics were dried
and the solvent was removed. The resulting solid was partitioned
into lots and used for several reductive aminations as described
below:
[0283] A 100 mg (0.34 mmol) portion of the material prepared as
above along with NaCNBH.sub.3 (65 mg, 1.0 mmol) and
5-fluoroindoline (95 mg, 0.69 mmol) were dissolved in DMF (1 mL)
and treated with acetic acid (112 mg, 1.9 mmol). Optionally, MeOH
may be used as solvent in this reaction. The resulting solution was
allowed to stand overnight at room temperature and diluted with
ethyl acetate. The organic portion was extracted with aqueous
NaHCO.sub.3 solution (1.times.), dried over MgSO.sub.4 and
evaporated. The resulting oil was purified over silica gel using
ethyl acetate and hexane as the solvents to afford the title
compound (60.7 mg, 43%)as an oil: .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 0.92-1.00 (m, 6H), 1.62-1.83 (m, 3H), 2.40 (s, 3H),
2.85-3.00 (m, 2H), 3.10-3.22 (m, 2H), 3.30-3.41 (m, 2H), 3.45-3.58
(m, 2H), 4.62-4.70 (m, 1H), 6.38 (dd, 1H, J.sub.1=4.1,
J.sub.2=8.4), 6.53-6.61 (m, 1H), 6.63-6.75 (m, 2H), 6.77-6.83(m,
1H), 7.27-7.35(m, 2H), 7.50-7.57 (m, 2H); HPLC-MS calcd. for
C.sub.24H.sub.30FN.sub.3O.sub.2 (M+H.sup.+) 412.2, found 412.2.
Example 4
N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl-
]-ethyl}-4-phenoxy-benzamide;*
[0284] C.sub.32H.sub.36FN.sub.3O.sub.3; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 8.04(m, 1H), 7.66(m, 2H), 7.30(m, 2H), 7.11(m, 3H),
6.95(m, 6H), 4.50(m, 1H), 3.75(m, 2H), 3.63(m, 2H), 3.39(m, 2H),
3.12(m, 2H), 1.61(m, 7H), 1.31(m, 1H), 1.09(m, 3H), 0.87(m, 2H);
LCMS: 530.5 (M+H).sup.+.
Example 5
1-Benzoyl-piperidine-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0285] C.sub.32H.sub.41FN.sub.4O.sub.3; LCMS: 549.6
(M+H).sup.+.
Example 6
[0286]
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[2-
-(4-methoxy-phenyl)-acetylamino]-propionamide;*
[0287] C.sub.28H.sub.36FN.sub.3O.sub.3; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.91(m, 1H), 7.00(m, 5H), 6.85(m, 2H), 6.46(m, 1H),
4.29(m, 1H), 3.75(m, 3H), 3.66(m, 4H), 3.40(m, 2H), 3.16(m, 2H),
1.59(m, 7H), 1.12(m, 4H), 0.86(m, 2H); LCMS: 482.5(M+H).sup.+.
Example 7
[0288]
(S)--N-{1-[2-(5-Chloro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-3-me-
thyl-butyl}-3-methyl-benzamide
[0289] The title compound (12 mg, 8%) was prepared in the same
manner as Example 3 except that the reductive amination partner in
Step C was 5-chloroindoline instead of 5-fluoroindoline: .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 0.95 (dd, 6H,
J.sub.1=J.sub.2=4.9), 1.60-1.80 (m, 3H), 2.40 (s, 3H), 2.84-2.99
(m, 2H), 3.12-3.24 (m, 2H), 3.38 (dd, 1H, J.sub.1=J.sub.2=8.4),
3.43-3.55 (m, 2H), 4.62-4.70 (m, 1H), 6.35 (d, 1H, J=8.3), 3.62
(dd, 1H, J.sub.1=4.6, J.sub.2=8.0), 6.77-6.84 (m, 1H), 3.94 (dd,
1H, J.sub.1=2.0, J.sub.2=8.3), 6.97-7.00 (m, 1H), 7.27-7.35(m, 2H),
7.50-7.57 (m, 2H); HPLC-MS calcd. for
C.sub.24H.sub.30FN.sub.3O.sub.2 (M+H.sup.+) 428.2, found 428.2.
Example 8
(S)--N-{3-Cyclohexyl-1-[2-(7-methoxy-2,3-dihydro-indol-1-yl)-ethylcarbamoy-
l]-propyl}-3-methoxy-benzamide
[0290] Following the procedures of Example 3, except using
m-anisoyl chloride, (S)-2-amino-4-cyclohexyl-butyric acid,
ethanolamine and 7-methoxyindoline as starting materials, the title
compound was prepared in 30% yield. The final material was purified
by reverse phase preparative HPLC Using TFA as a modifier. The
final compound is therefore a partial TFA salt and the properties
are reported for the material as it appeared after solvent removal:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.78-0.92 (m, 2H),
1.05-1.32 (m, 6H), 1.59-1.81 (m, 6H), 1.94-2.05 (m, 1H),
3.10-3.20(m, 2H), 3.45-3.72 (m, 5H), 3.80 (s, 3H), 3.86 (s, 3H),
4.62 (dd, 1H, J.sub.1=7.8, J.sub.2=13.7), 6.78 (d, 1H,
J.sub.1=8.2), 6.86 (d, 1H, J.sub.1=7.2), 7.00-7.08 (m, 2H),
7.18-7.23 (m, 1H), 7.30-7.47 (m, 3H), 7.53-7.62 (m, 1H); HPLC-MS
calcd. for C.sub.29H.sub.39N.sub.3O.sub.4 (M+H.sup.+) 494.3, found
494.5.
Example 9
Furan-2-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0291] C.sub.24H.sub.30FN.sub.3O.sub.3; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 8.21(m, 1H), 7.48(m, 1H), 7.31(m, 1H), 7.16(m, 1H),
7.06(m, 2H), 6.50(m, 1H), 6.43(m, 1H), 4.52(m, 1H), 3.92(m, 2H),
3.75(m, 2H), 3.53(m, 2H), 3.26(m, 2H), 1.69(m, 7H), 1.41(m, 1H),
1.16(m, 3H), 0.89(m, 2H); LCMS: 428.5 (M+H).sup.+.
Example 10
(S)--N-{3-Cyclohexyl-1-[2-(6-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl-
]-propyl}-3-methoxy-benzamide
[0292] Following the procedures of Example 3, except using
m-anisoyl chloride, (S)-2-amino-4-cyclohexyl-butyric acid,
ethanolamine and 6-fluoroindoline as starting materials, the title
compound was prepared in 40% yield. The final material was purified
by reverse phase preparative HPLC using TFA as a modifier. The
final compound is therefore a partial TFA salt and the properties
are reported for the material as it appeared after solvent removal:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.72-0.86 (m, 2H),
1.03-1.28 (m, 6H), 1.58-1.69 (m, 6H), 1.85-1.96 (m, 1H), 2.89 (dd,
2H, J.sub.1=J.sub.2=8.1), 3.19 (dd, 2H, J.sub.1=J.sub.2=6.0), 3.43
(dd, 2H, J.sub.1=J.sub.2=8.4), 3.37-3.47 (m, 1H), 3.53-3.62 (m,
1H), 3.84 (s, 3H), 4.64 (dd, 1H, J.sub.1=7.0, J.sub.2=14.1), 6.16
(d, 1H, J=10.2), 6.26-6.33 (m, 1H), 6.92 (dd, 1H,
J.sub.1=J.sub.2=6.7), 7.02-7.07 (m, 2H), 7.12-7.19 (m, 2H),
7.26-7.39 (m, 3H); HPLC-MS calcd. for
C.sub.28H.sub.36FN.sub.3O.sub.3 (M+H.sup.+) 482.3, found 482.5.
Example 11
(S)--N-{3-Cyclohexyl-1-[2-(7-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl-
]-propyl}-3-methoxy-benzamide
[0293] Following the procedures of Example 3, except using
m-anisoyl chloride, (S)-2-amino-4-cyclohexyl-butyric acid,
ethanolamine and 7-fluoroindoline as starting materials, the title
compound was prepared in 40% yield. The final material was purified
by reverse phase preparative HPLC using TFA as a modifier. The
final compound is therefore a partial TFA salt and the properties
are reported for the material as it appeared after solvent removal:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.73-0.87 (m, 2H),
1.03-1.28 (m, 6H), 1.58-1.78 (m, 6H), 1.83-1.95 (m, 1H), 3.01 (dd,
2H, J.sub.1=J.sub.2=8.4), 3.41-3.50 (m, 4H), 3.55-3.72 (m, 1H),
3.84 (s, 3H), 4.63 (dd, 1H, J.sub.1=7.1, J.sub.2=14.3), 6.53-6.68
(m, 2H), 6.78 (dd, 1H, J.sub.1=8.5, J.sub.2=12.3), 6.86 (d, 1H,
J.sub.1=7.0), 7.01-7.08 (m, 2H), 7.20 (d, 1H, J.sub.1=7.8),
7.26-7.39 (m, 3H); HPLC-MS calcd. for
C.sub.28H.sub.36FN.sub.3O.sub.3 (M+H.sup.+) 482.3, found 482.5.
Example 12
(S)--N-{3-Cyclohexyl-1-[2-(5-cyano-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-
-propyl}-3-methoxy-benzamide
[0294] Following the procedures of Example 3, except using
m-anisoyl chloride, (S)-2-amino-4-cyclohexyl-butyric acid,
ethanolamine and 5-cyanoindoline as starting materials, the title
compound was prepared in 20% yield. The final material was purified
by reverse phase preparative HPLC using TFA as a modifier. The
final compound is therefore a partial TFA salt and the properties
are reported for the material as it appeared after solvent removal:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.64-0.77 (m, 2H),
0.97-1.15 (m, 6H), 1.49-1.64 (m, 6H), 1.72-1.84 (m, 1H), 2.84-2.92
(m, 2H), 3.16-3.30 (m, 2H), 3.32-3.51 (m, 4H), 3.77 (s, 3H), 4.49
(dd, 1H, J.sub.1=7.4, J.sub.2=14.4), 6.24 (d, 1H, J.sub.1=8.3),
6.97-7.02 (m, 1H), 7.04-7.07 (m, 1H), 7.09-7.15 (m, 2H), 7.18-7.28
(m, 2H); HPLC-MS calcd. for C.sub.29H.sub.36N.sub.4O.sub.3
(M+H.sup.+) 482.3, found 482.5.
Example 13
Furan-3-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0295] C.sub.24H.sub.30FN.sub.3O.sub.3; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 8.14(m, 1H), 7.88(m, 1H), 7.35(m, 1H), 7.19(m, 2H),
6.97(m, 2H), 6.60(m, 1H), 4.46(m, 1H), 3.80(m, 2H), 3.64(m, 2H),
3.40(m, 2H), 3.16(m, 2H), 1.57(m, 7H), 1.29(m, 1H), 1.13(m, 3H),
0.84(m, 2H); LCMS: 428.5 (M+H).sup.+.
Example 14
Cyclopropanecarboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0296] C.sub.23H.sub.32FN.sub.3O.sub.2; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.90(m, 1H), 7.10(m, 1H), 6.97(m, 2H), 6.76(m, 1H),
4.34(m, 1H), 3.70(m, 4H), 3.41(m, 2H), 3.16(m, 2H), 1.61(m, 7H),
1.30(m, 3H), 1.13(m, 1H), 0.75(m, 7H); LCMS:402.5 (M+H).sup.+.
Example 15
[0297]
(S)--N-{3-Cyclohexyl-1-[2-(4-methoxy-2,3-dihydro-indol-1-yl)-ethylc-
arbamoyl]-propyl}-3-methoxy-benzamide
[0298] Following the procedures of Example 3, except using
m-anisoyl chloride, (S)-2-amino-4-cyclohexyl-butyric acid,
ethanolamine and 4-methoxyindoline as starting materials, the title
compound was prepared in 30% yield. The final material was purified
by reverse phase preparative HPLC using TFA as a modifier. The
final compound is therefore a partial TFA salt and the properties
are reported for the material as it appeared after solvent removal:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.67-0.80 (m, 2H),
0.92-1.21 (m, 6H), 1.46-1.67 (m, 6H), 1.79-1.92 (m, 1H), 2.88 (dd,
1H, J.sub.1=J.sub.2=8.1), 3.16-3.21 (m, 2H), 3.41 (dd, 1H,
J.sub.1=J.sub.2=8.1), 3.51-3.43 (m, 2H), 3.71 (s, 3H), 3.73 (s,
3H), 4.44 (dd, 1H, J.sub.1=7.1, J.sub.2=13.9), 6.27 (d, 1H, J=7.9),
6.33 (d, 1H, J=8.2), 6.84-6.78 (m, 1H), 6.91-6.97 (m, 1H), 6.99
(dd, 1H, J.sub.1=J.sub.2=8.0), 7.14-7.17 (m, 2H), 7.17-7.27 (m,
3H); HPLC-MS calcd. for C.sub.29H.sub.39N.sub.3O.sub.4 (M+H.sup.+)
494.3, found 494.5.
Example 16
(S)--N-{3-Cyclohexyl-1-[2-(5-methoxy-2,3-dihydro-indol-1-yl)-ethylcarbamoy-
l]-propyl}-3-methoxy-benzamide
[0299] Following the procedures of Example 3, except using
m-anisoyl chloride, (S)-2-amino-4-cyclohexyl-butyric acid,
ethanolamine and 5-methoxyindoline as starting materials, the title
compound was prepared in 20% yield. The final material was purified
by reverse phase preparative HPLC using TFA as a modifier. The
final compound is therefore a partial TFA salt and the properties
are reported for the material as it appeared after solvent removal:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.58-0.72 (m, 2H),
0.85-1.10 (m, 6H), 1.37-1.59 (m, 6H), 1.62-1.73 (m, 1H), 2.54-2.67
(m, 2H), 2.85-2.98 (m, 2H), 3.20-3.33 (m, 2H), 3.41 (s, 3H),
3.55-3.70 (m, 2H), 3.64 (s, 3H), 4.34 (dd, 1H, J.sub.1=7.1,
J.sub.2=13.9), 6.72-6.78 (m, 2H), 6.84-6.90 (m, 2H), 7.06-7.19 (m,
5H); HPLC-MS calcd. for C.sub.29H.sub.39N.sub.3O.sub.4 (M+H.sup.+)
494.3, found 494.5.
Example 17
1-(4-Chloro-benzenesulfonyl)-piperidine-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0300] C.sub.31H.sub.40ClFN.sub.4O.sub.4S; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 8.16(m, 1H), 7.61(m, 2H), 7.45(m, 2H), 7.25(m, 1H),
7.02(m, 2H), 6.72(m, 1H), 4.25(m, 2H), 3.83(m, 2H), 3.69(m, 3H),
3.45(m, 2H), 3.21(m, 2H), 2.25(m, 2H), 2.09(m, 1H), 1.76(m, 2H),
1.59(m, 7H), 1.47(m, 2H), 1.18(m, 1H), 1.05(m, 3H), 0.80(m, 2H);
LCMS: 619.5 (M+H).sup.+.
Example 18
(S)--N-{3-Cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl-
]-propyl}-3-methoxy-benzamide
[0301] Following the procedures of Example 3, except using
m-anisoyl chloride, (S)-2-amino-4-cyclohexyl-butyric acid,
ethanolamine and 5-fluoroindoline as starting materials, the title
compound was prepared in 40% yield. The final material was purified
by reverse phase preparative HPLC using TFA as a modifier. The
final compound is therefore a partial TFA salt and the properties
are reported for the material as it appeared after solvent removal:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.50-0.65 (m, 2H),
0.79-1.05 (m, 6H), 1.33-1.53 (m, 6H), 1.60-1.74 (m, 1H), 2.70 (dd,
2H, J.sub.1=J.sub.2=8.1), 2.94 (dd, 2H, J.sub.1=J.sub.2=6.0), 3.15
(dd, 2H, J.sub.1=J.sub.2=8.1), 3.20-3.43 (m, 2H), 3.60 (s, 3H),
4.30-4.38 (m, 1H), 6.17-6.23 (m, 1H), 6.45-6.55 (m, 1H), 6.56-6.60
(m, 1H), 6.62-6.74 (m, 2H), 6.78-6.88 (m, 1H), 6.94-7.15 (m, 3H);
HPLC-MS calcd. for C.sub.28H.sub.36FN.sub.3O.sub.3 (M+H.sup.+)
482.3, found 482.5.
Example 19
(S)--N-{3-Cyclohexyl-1-[2-(5-benzyloxy-2,3-dihydro-indol-1-yl)-ethylcarbam-
oyl]-propyl}-3-methoxy-benzamide
[0302] Following the procedures of Example 3, except using
m-anisoyl chloride, (S)-2-amino-4-cyclohexyl-butyric acid,
ethanolamine and 5-benzyloxyindoline as starting materials, the
title compound was prepared in 10% yield. The final material was
purified by reverse phase preparative HPLC using TFA as a modifier.
The final compound is therefore a partial TFA salt: HPLC-MS calcd.
for C.sub.35H.sub.43N.sub.3O.sub.4 (M+H.sup.+) 570.3, found
570.6.
Example 20 and Example 21
N-{1-(S)-[2-(4-Methoxy-phenylamino)-propylcarbamoyl]-3-methyl-butyl}-3-met-
hyl-benzamide and
N-{1-(S)-[2-(4-Methoxy-phenylamino)-1-methyl-ethylcarbamoyl]-3-methyl-but-
yl}-3-methyl-benzamide
[0303] Step A: In a flame-dried flask, sodium t-butoxide (1.38 g,
14.4 mmol), BINAP (0.897 g, 1.44 mmol) and Pd.sub.2dba.sub.3 (0.443
g, 0.484 mmol) were treated with anhydrous dioxane (10 mL) followed
by 4-bromoanisole (1.49 g, 7.99 mmol) and 1,2-diaminopropane (0.671
g, 9.06 mmol). The flask was sealed with a 3-way stopper and
immersed into a 90.degree. C. pre-heated oil bath and allowed to
stir overnight. The reaction flask was cooled to rt. Dioxane was
removed prior to extraction. The concentrated mixture was diluted
with ethyl acetate and extracted with water (2.times.). The
organics were extracted with 1 M NaOH (2.times.) followed by 1 M
HCl (2.times.). The aqueous layer was collected and treated with
NaOH pellets until the pH was highly basic. The aqueous portion was
once again extracted with ethyl acetate. The organics were
collected, dried over MgSO.sub.4 and concentrated. The resulting
material was used for the next acylation step in the synthesis
without purification.
[0304] Step B: The material from the Step A (117 mg, 0.650 mmol)
was dissolved with DMF followed by the addition of
(S)-4-Methyl-2-(3-methyl-benzoylamino)-pentanoic acid (128 mg,
0.510 mmol, prepared according to Example 3, Step A), HATU (277 mg,
0.73 mmol) and DIPEA (210 mg, 1.62 mmol). The reaction was allowed
to stir at rt overnight. The mixture was diluted with ethyl acetate
and extracted with water followed by 1 M HCl. The organics were
collected, dried over MgSO.sub.4 and concentrated. The final
material was purified by reverse phase preparative HPLC using TFA
as a modifier. The final compound is therefore a partial TFA salt
and the properties are reported for the material as it appeared
after solvent removal. The data are reported for the diastereomeric
mixtures.
[0305] The first material to come off was Example 20,
N-{1-(S)-[2-(4-Methoxy-phenylamino)-propylcarbamoyl]-3-methyl-butyl}-3-me-
thyl-benzamide (10%): .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
0.85-1.02 (m, 6H), 1.02-1.35 (m, 3H), 1.65-1.82 (m, 3H), 2.37 and
2.38 (s's, 3, H),3.40-3.58 (m, 2H), 3.63-3.80 (m, 1H), 3.79 (s,
3H), 4.42-4.54 (m, 1H), 4.60-5.30 (m, 2H), 6.79-6.88 (m, 2H),
6.93-7.07 (m, 2H), 7.23-7.38 (m, 3H), 7.41-7.59 (m, 2H); HPLC-MS
calcd. for C.sub.24H.sub.33N.sub.3O.sub.3 (M+H.sup.+) 412.3, found
412.2.
[0306] The second material to come off (in 2 peaks that were
combined) was Example 21,
N-{1-(S)-[2-(4-Methoxy-phenylamino)-1-methyl-ethylcarbamoyl]-3-methyl-but-
yl}-3-methyl-benzamide (10%): .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 0.85-1.00 (m, 6H), 1.27-1.30 (m, 3H), 1.62-1.80 (m, 3H),
2.36 and 2.37 (s's, 3H), 3.09-3.18 (m, 2H), 3.71 and 3.74 (s's,
3H), 3.71-3.92 (m, 1H), 4.13-4.28 (m, 1H), 4.53-4.64 (m, 1H),
6.57-6.92 (m, 6H), 7.27-7.33 (m, 2H), 7.49-7.62 (m, 2H); HPLC-MS
calcd. for C.sub.24H.sub.33N.sub.3O.sub.3 (M+H.sup.+) 412.3, found
412.2.
[0307] The identity of Example 21 was further confirmed by
comparing its NMR spectrum with those of Examples 22 and 23.
Example 22
N-{1-(S)-[2-(4-Methoxy-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-3-methyl--
butyl}-3-methyl-benzamide
[0308] Step A: Preparation of
(S)-2-(tert-Butoxycarbonyl-1-amino)-1-propionaldehyde.
[0309] (S)-(-)-2-(tert-Butoxycarbonyl-1-amino)-1-propanol (523 mg,
2.98 mmol, 1.0 equiv.) was dissolved in 45 mL methylene chloride in
a 100 mL r.b. flask with a magnetic stir bar. To this clear
homogeneous solution, Dess-Martin periodinane (1.523 g, 3.591, 1.2
equiv.) was added in one part and the cloudy white solution
reaction was allowed to stir at room temperature for 2 h.
Thin-layer chromatography monitored the reaction to completion. The
reaction mixture was diluted with 100 mL ethyl acetate. Sodium
bisulfate solution (2 M, 20 mL) was added to the reaction mixture
and the organic layer was separated. The aqueous layer was washed
with 3.times.30 mL EtOAc. The combined organic layers were washed
with 50 mL 1 M NaOH, followed by saturated NaCl (30 mL) and dried
over MgSO.sub.4. Filtration and rotary evaporation produced the
desired product as a yellow oil (475 mg, 92% yield, R.sub.f=0.63,
1:1 hexanes/ethyl acetate).
[0310] Step B: Preparation of
[2-(4-Methoxy-phenylamino)-(1S)-methyl-ethyl]-carbamic acid
tert-butyl ester.
(S)-2-(tert-Butoxycarbonyl-1-amino)-1-propionaldehyde (473 mg, 2.74
mmol) and p-anisidine (1.031 g, 8.371 mmol, 3.0 equiv.) was
dissolved in 45 mL of MeOH at 0.degree. C. in a 100 mL r.b. flask
with a magnetic stir bar. Optionally, acetic acid (469 .mu.L, 8.21
mmol, 3.0 equiv.) can be added via syringe to assist in the
reaction. To the stirring dark colored solution was added sodium
cyanoborohydride (326 mg, 5.82 mmol, 1.89 equiv.). Gas evolution
and disappearance of color were observed. The reaction was allowed
to slowly warm to room temperature with stirring over 30 minutes
and the reaction was monitored by LC/MS. At the completion of the
reaction, the mixture was quenched with 1 M NaOH, and extracted
3.times.50 mL ethyl acetate. The resulting organics were washed
with 50 mL saturated NaHCO.sub.3, 40 mL saturated NaCl, and dried
over MgSO.sub.4. Evaporation of ethyl acetate provided 728 mg of a
brown oil. Purification by automated ISCO chromatography provided a
clear oil of [2-(4-Methoxy-phenylamino)-(1S)-methyl-ethyl]-carbamic
acid tert-butyl ester (583 mg, 2.079 mmol, 76% yield). HPLC-MS
calcd. for C.sub.15H.sub.24N.sub.2O.sub.3 (M+H.sup.+) 281.2, found
281.5. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.21 (d, 6H, J=6.6
Hz), 1.47 (s, 9H), 3.05 (dd, 1H, J=12.2, 7.3 Hz), 3.13 (dd, 1H,
J=12.2, 4.6 Hz), 3.76 (s, 3H), 3.93 (broad s, 1H), 4.62 (broad s,
1H), 6.60 (d, 2H, J=6.8 Hz), 6.80 (2H, d, J=6.8 Hz).
[0311] Step C:
[2-(4-Methoxy-phenylamino)-(1S)-methyl-ethyl]-carbamic acid
tert-butyl ester (383 mg, 1.37 mmol) was added to 10 mL of a
trifluoroacetic acid solution (10 v/v % in methylene chloride) at
room temperature in a 25 mL r.b. flask with a magnetic stirbar. The
reaction turns dark purple/black in color after 5 minutes. The
reaction is allowed to stir at room temperature until the reaction
is judged complete by HPLC/MS. The solvent is removed by
evaporation and to provide
2-(4-Methoxy-phenylamino)-(1S)-methyl-ethyl-ammonium;
trifluoro-acetate salt as a brown oil (394 mg, 1.34 mmol, 98%
yield) and used directly in the next reaction. HPLC-MS calcd. for
C.sub.10H.sub.16N.sub.2O (M+H.sup.+) 181.1, found 181.5.
[0312] Step D: 2-(4-Methoxy-phenylamino)-(1S)-methyl-ethyl-ammonium
trifluoro-acetate salt (253 mg, 0.860, 1.0 equiv.),
4-Methyl-(2S)-(3-methyl-benzoylamino)-pentanoic acid (Example 3,
step A, 212 mg, 0.850 mmol, 1.0 equiv.), HATU (327 mg, 0.866 mmol,
1.0 equiv.), and CH.sub.2Cl.sub.2 (15 mL) were combined in a 50 mL
r.b. flask with a magnetic stir-bar. The resulting cloudy white
solution reaction was allowed to stir at room temperature for 20
minutes, upon which DIPEA (450 .mu.L, 2.583 mmol, 3.0 equiv.) was
added via syringe. The reaction mixture turned dark yellow in
color. The resulting solution was allowed to stir at room
temperature for 3 h. When the reaction was complete by LC/MS, it
was extracted with 35 mL water, washed the organic layer with 10 mL
saturated NaCl and dried over MgSO.sub.4. After evaporation of
solvent, the crude mixture was purified by ISCO normal phase
separation to provide (37 mg, 0.090 mmol, 10% yield) of a white
solid. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.95 (m, 6H), 1.16
(d, 3H, J=6.8 Hz), 1.72 (m, 3H), 2.36 (s, 3H), 3.14 (d, 2H, J=6.2
Hz), 3.75 (s, 3H), 4.19 (m, 1H), 4.75 (m, 1H), 6.60 (d, 1H, J=8.8
Hz), 6.77 (d, 1H, J=8.8 Hz), 6.77-6.84 (m, 1H), 7.01 (m, 1H), 7.30
(m, 1H), 7.59 (m, 1H); HPLC-MS calcd. for
C.sub.24H.sub.33N.sub.3O.sub.3 (M+H.sup.+) 412.3, found 412.5.
Example 23
N-{1-(S)-[2-(4-Methoxy-phenylamino)-1-(R)-methyl-ethylcarbamoyl]-3-methyl--
butyl}-3-methyl-benzamide
[0313] Following the procedures of Example 22, except it uses
(R)-(+)-2-(tert-Butoxycarbonyl-1-amino)-1-propanol as the starting
material in step A, the title compound was prepared: HPLC-MS calcd.
for C.sub.24H.sub.33N.sub.3O.sub.3 (M+H.sup.+) 412.3, found
412.5.
Example 24
1H-Indole-2-carboxylic acid
{3-cyclohexyl-(1S)-[2-(4-methoxy-phenylamino)-(1S)-methyl-ethylcarbamoyl]-
-propyl}-amide
[0314] The title compound was prepared following the procedures of
Example 22, except that in step D it uses
4-cyclohexyl-(2S)-[(1H-indole-2-carbonyl)-amino]-butyric acid
instead of Methyl-(2S)-(3-methyl-benzoylamino)-pentanoic acid. The
final compound is isolated as a mixture of diastereomers in a 1.5:1
ratio. HPLC-MS calcd. for C.sub.29H.sub.38N.sub.4O.sub.3
(M+H.sup.+) 491.3, found 491.5. .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 0.55-1.38 (m, 16H), 1.53-1.71 (m, 2H), 2.89 (m, 2H), 3.49
(s, 3H), 4.03 (m, 1H), 4.41 (m, 1H), 6.35-7.17 (m, 9H), 7.40 (1H,
m), 9.48 (s,
1H).4-Cyclohexyl-(2S)-[(1H-indole-2-carbonyl)-amino]-butyric acid
is made by the following procedure:
(+)-Ethyl-(S)-2-amino-4-cyclohexylbutyrate hydrochloride (1.643 g,
6.577 mmol, 1.0 equiv.), 2-indolecarboxylic acid(1.166 g, 7.235
mmol, 1.1 equiv.), HATU (2.750 g, 7.232 mmol, 1.1 equiv.), and
CH.sub.2Cl.sub.2 (80 mL) were combined in a 100 mL r.b. flask with
a magnetic stir-bar. The resulting cloudy white solution reaction
was allowed to stir at room temperature for 20 minutes, upon which
DIPEA (5.8 mL, 33.29 mmol, 4.6 equiv.) was added via syringe. The
reaction mixture turned dark yellow in color. The resulting
solution was allowed to stir at rt for 3 h. When the reaction was
complete by LC/MS, it was extracted with 100 mL water, washed the
organic layer with 50 mL saturated NaCl and dried over MgSO.sub.4.
After evaporation of solvent, the crude mixture was purified by
ISCO normal phase separation to provide (2.161 g, 6.062 mmol, 92%
yield) of 4-cyclohexyl-(2S)-[(1H-indole-2-carbonyl)-amino]-butyric
acid ethyl ester as a clear liquid. HPLC-MS calcd. for
C.sub.21H.sub.28N.sub.2O.sub.3(M+H.sup.+) 357.5, found 357.5.
[0315] 4-Cyclohexyl-(2S)-[(1H-indole-2-carbonyl)-amino]-butyric
acid ethyl ester (2.27 g, 6.37 mmol, 1.0 equiv.) was dissolved in
40 mL MeOH and 20 mL H.sub.2O in a 100 mL r.b. flask containing a
magnetic stir-bar at 0.degree. C. Lithium hydroxide (188 mg, 7.849
mmol, 1.2 equiv.) is added in one-part. The reaction is allowed to
slowly warm and the reaction is monitored to completion by LC/MS.
Extraction of the clear reaction solution with 4.times.75 mL ethyl
acetate, dried over MgSO.sub.4 and evaporation provides (2.07 g,
6.30 mmol, 99% yield) of a off-white solid of
4-Ccyclohexyl-2-[(1H-indole-2-carbonyl)-amino]-butyric acid.
HPLC-MS calcd. for C.sub.19H.sub.24N.sub.2O.sub.3 (M+H.sup.+)
328.3, found 329.5.
Example 25
1H-Indole-2-carboxylic acid
{3-cyclohexyl-(1S)-[2-(4-methoxy-phenylamino)-(1R)-methyl-ethylcarbamoyl]-
-propyl}-amide
[0316] Following the procedures of Example 22, except using
4-cyclohexyl-(2S)-[(1H-indole-2-carbonyl)-amino]-butyric acid (see
Example 24) and (R)-(+)-2-(tert-butoxycarbonyl-1-amino)-1-propanol
as starting materials, the title compound was prepared. HPLC-MS
calcd. for C.sub.29H.sub.38N.sub.4O.sub.3 (M+H.sup.+) 491.3, found
491.5.
Example 26
N-{2-Cyclohexyl-(1S)-[2-(4-methoxy-phenylamino)-(1R)-methyl-ethylcarbamoyl-
]-ethyl}-3-methoxy-benzamide
[0317] Following the procedures of Example 22, except using
m-anisoyl chloride, 3-cyclohexyl-L-alanine and
(R)-(+)-2-(tert-butoxycarbonyl-1-amino)-1-propanol as starting
materials, the title compound was prepared. The final product was
isolated as a 1.2:1 mixture of diastereomers. HPLC-MS calcd. for
C.sub.27H.sub.37N.sub.3O.sub.4 (M+H.sup.+) 468.3, found 468.5.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.88-1.71 (m, 14H),
3.19-3.23 (m, 2H), 3.70 (s, 6H), 4.11-4.25 (m, 2H), 4.35-4.42 (m,
1H), 4.41 (m, 1H), 6.79-7.33 (m, 7H), 7.91-8.02 (1H, m).
Example 27
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid
{3-cyclohexyl-(1S)-[2-(4-methoxy-phenylamino)-(1S)-methyl-ethylcarbamoyl]-
-propyl}-amide
[0318] Following the procedures of Example 24, except using
5-(3-trifluoromethyl-phenyl)-furan-2-carboxylic acid and
(S)-2-amino-4-cyclohexyl-butyric acid as starting materials, the
title compound was prepared. HPLC-MS calcd. for
C.sub.32H.sub.38F.sub.3N.sub.3O.sub.4 (M+H.sup.+) 586.3, found
586.5. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.78-1.64 (m,
16H), 1.72-1.88 (m, 2H), 3.19-3.23 (m, 2H), 3.63-3.74 (m, 4H), 4.14
(m, 1H), 6.67-7.81 (m, 10H), 8.24 (m, 2H).
Example 28
N-{(1S)-[2-(5-Fluoro-2,3-dihydro-indol-1-yl)-1,1-dimethyl-ethylcarbamoyl]--
2-phenyl-ethyl}-3-methyl-benzamide
[0319] Step A: 2-(3-Methyl-benzoylamino)-3-phenyl-propionic acid
was prepared according to the procedure of Example 3, Step A,
except using (L)-phenylalanine instead of (L)-leucine.
[0320] Step B: Synthesis of
N-[1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-(2S)-phenyl-ethyl]-3-methyl--
benzamide. 2-(3-Methyl-benzoylamino)-3-phenyl-propionic acid (1.087
g, 3.866 mmol, 1.05 equiv.) and Bis(2-oxo-3-oxazolidinyl)phosphonic
chloride (BOP-Cl, 930 mg, 3.65 mmol, 1.0 equiv.) was dissolved in
CH.sub.2Cl.sub.2 at 0.degree. C. To the resulting white suspension
was added was added a 2 mL CH.sub.2Cl.sub.2 of
2-amino-2-methyl-propan-1-ol (364 mg, 4.08 mmol, 1.11 equiv.) and
triethylamine (500 .mu.L, 3.59 mmol, 1.0 equiv) were added via
syringe. To the resulting solution, slow addition of triethylamine
(500 .mu.L, 3.59 mmol, 1.0 equiv) in 2 mL CH.sub.2Cl.sub.2 was
added by addition funnel over a 2 h period. The resulting solution
was allowed to warm overnight and the reaction was monitored by
LC/MS. The reaction was worked up by quenching with water (20 mL)
and addition of 4M HCl until reaction reaches pH 1. The organic
layer was separated and the aqueous layer was washed 3.times.35 mL
ethyl acetate. The combined organic extracts were washed with
saturated NaHCO.sub.3 (20 mL), saturated NaCl (30 mL) and dried
over MgSO.sub.4. After rotary evaporation 325 mg of crude material
was obtained. Automated ISCO chromatography was performed and 171
mg (0.4827 mmol, 13.2% isolated yield) of a clear oil was obtained
(R.sub.f=0.43 in 1:1 hexane:ethyl acetate). HPLC-MS calcd. for
C.sub.21H.sub.26N.sub.2O.sub.3 (M+H.sup.+) 355.2, found 355.5.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.22 (s, 6H), 2.03 (s,
1H), 2.40 (s, 3H), 3.32-3.06 (m, 2H), 3.62 (d, 1H, J=11.1 Hz), 3.46
(d, 1H, J=11.1 Hz), 4.75 (m, 1H), 7.23-7.58 (m, 9H), 8.23 (m,
1H).
[0321] Step C: Following the procedures of Example 3, Step C,
N-[1-(2-Hydroxy-1,1-dimethyl-ethylcarbamoyl)-(2S)-phenyl-ethyl]-3-methyl--
benzamide was converted to the title compound. HPLC-MS calcd. for
C.sub.29H.sub.32FN.sub.3O.sub.2 (M+H.sup.+) 474.2, found 474.6.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.21 (s, 3H), 1.29 (s,
3H), 2.31 (s, 3H), 2.83-3.00 (m, 4H), 3.16-3.31 (m, 4H), 4.66
(broad s, 1H), 6.60-7.47 (m, 11H).
Example 29
Tetrahydrofuran-2-(S)-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide*
[0322] C.sub.24H.sub.34F.sub.3N.sub.3O.sub.4; LCMS: 486.4
(M+H).sup.+.
Example 30
Tetrahydrofuran-2-(R)-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide*
[0323] C.sub.24H.sub.34F.sub.3N.sub.3O.sub.4; LCMS: 486.4
(M+H).sup.+.
Example 31 and Example 32
N-{1-(S)-[1-(4-Methoxy-phenyl)-piperidin-3-(S)-ylcarbamoyl]-3-methyl-butyl-
}-3-methyl-benzamide and
N-{1-(S)-[1-(4-Methoxy-phenyl)-piperidin-3-(R)-ylcarbamoyl]-3-methyl-buty-
l}-3-methyl-benzamide
[0324] Step A: N,N-Diethylnipecotamide (2.00 g, 10.8 mmol),
4-bromoanisole (2.44 g, 13.0 mmol), Pd.sub.2dba.sub.3 (149 mg, 0.16
mmol), 2-(di-t-butylphosphino)biphenyl (194 mg, 0.65 mmol) and THF
(11 mL) were charged to a 100 mL roundbottom flask with a threaded
top capable of being sealed. Then, t-BuOK (1.70 g, 15.9 mmol) was
added in one portion and the flask was sealed. The flask got hot
and after 15 min a gel formed. After overnight stirring, the
reaction was partitioned between ethyl acetate and water and the
aqueous layer was discarded. The organic layer was then extracted
twice with 5% KHSO.sub.4 and discarded. The acidic aqueous layer
was made basic with solid KOH pellets, extracted twice with ethyl
acetate and discarded. The final organics were then dried over
MgSO.sub.4 and the solvent was removed to yield 1.8 g (57%) of
solid. HPLC-MS calcd. for C.sub.17H.sub.26N.sub.2O.sub.2
(M+H.sup.+) 291.2, found 291.2.
[0325] Step B: The product from Step A (1.3 g, 4.5 mmol) was
treated with 6 M HCl (20 mL) in a sealed reaction vessel and heated
to 90.degree. C. for 3 days. The reaction was cooled to room
temperature and the solvent was removed. Analysis of the mixture by
HPLC-MS indicated that the reaction was roughly half done. The
reaction was diluted with water and filtered. The aqueous solution
was then made basic with solid KOH and extracted twice with ethyl
acetate and organics were discarded. The aqueous solution was then
brought to pH 5 with 1 M HCl and extracted with ethyl acetate. The
organics from the last extraction were dried over MgSO.sub.4 and
the solvent was removed to yield 500 mg (47%) of solid: .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.72-1.87 (m, 2H), 1.84-2.03 (m, 2H),
2.13 (s, 1H), 2.76-2.89 (m, 1H), 2.87-3.00 (m, 1H), 3.05-3.26 (m,
2H), 3.30-3.45 (m, 2H), 6.80-6.90 (m, 1H), 7.00-7.10 (m, 2H),
10.75-10.95 (m, 2H).
[0326] Step C: The product from Step B (440 mg, 1.87 mmol) was
suspended in tBuOH and treated with diphenylphosphoryl azide (618
mg, 2.24 mmol) followed by triethylamine (454 mg, 4.49 mmol). The
reaction was then refluxed overnight and the solvent was removed.
The reaction was partitioned between ethyl acetate and water and
the water was discarded. The organics were extracted with 1 M NaOH
twice and water twice. The solvent was removed and the reaction was
treated with MeOH. After being allowed to crystallize overnight,
the solid was filtered off and the mother liquor was rotary
evaporated and purified by silica gel column chromatography using a
linear gradient of ethyl acetate and hexane to afford the product
the Boc protected piperidine amine as a solid (120 mg, 21%):
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.48 (s, 9H), 1.50-1.70
(m, 1H), 1.65-1.91 (m, 3H), 2.80-3.10 (m, 3H), 3.21 (d, 1H,
J=10.8), 3.78 (s, 1H), 3.83-3.93 (m, 1H), 4.94-5.10 (m, 1H), 6.84
(d, 1H, J=9.0), 6.92 (d, 1H, J=9.0); HPLC-MS calcd. for
C.sub.17H.sub.26N.sub.2O.sub.3 (M+H.sup.+) 307.2, found 307.2.
[0327] Step D: The material from Step C (60 mg, 200 .mu.mol) was
charged to a 25 mL round bottom flask and treated with MeOH (1 mL)
and 4 M HCl in dioxane (1 mL). After 4 h, the solvent was removed
and the reaction was dried on the high vacuum overnight. The
resulting material was treated with
(S)-4-Methyl-2-(3-methyl-benzoylamino)-pentanoic acid (59 mg, 240
.mu.mol, prepared according to Example 3, Step A) and HATU (96 mg,
250 .mu.mol) and dissolved in DMF (2 mL). The resulting solution
was treated with DIPEA (126 mg, 980 .mu.mol) and allowed to stir
for 6 hours. The reaction was diluted with ethyl acetate and
extracted with water twice and 1 M NaOH twice, dried over
MgSO.sub.4 and rotary evaporated. The resulting oil was
chromatographed over silica gel using ethyl acetate and hexane as
solvents. The two diastereomers of the product were separated and
were arbitrarily assigned the chirality about the piperidine
carbon.
[0328] The faster eluting compound (16.6 mg, 19%) was assigned as
Example 31: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.95-1.05 (m,
6H), 1.64-1.90 (m, 8H), 2.39 (s, 3H), 2.89-2.98 (m, 2H), 3.03-3.11
(m, 1H), 3.14 (dd, 1H, J.sub.1=2.8, J.sub.2=11.8), 3.77 (s, 3H),
4.13-4.22 (m, 1H), 4.67-4.76 (m, 1H), 6.70 (d, 1H, J=8.1), 6.76 (d,
1H, J=7.6), 6.78-6.83 (m, 2H), 6.85-6.91 (m, 2H), 7.29-7.34 (m,
2H), 7.54-7.62 (m, 2H).
[0329] The slower eluting compound (18.3 mg, 21.5%) was assigned as
Example 32: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.95-1.04 (m,
6H), 1.56-1.90 (m, 8H), 2.40 (s, 3H), 2.90-2.98 (m, 2H), 3.02-3.12
(m, 1H), 3.20 (dd, 1H, J.sub.1=2.8, J.sub.2=11.6), 3.79 (s, 3H),
4.13-4.21 (m, 1H), 4.63-4.72 (m, 1H), 6.71 (d, 1H, J=8.1), 6.74 (d,
1H, J=7.6), 6.82-6.86 (m, 2H), 6.88-6.94 (m, 2H), 7.29-7.34 (m,
2H), 7.57-7.63 (m, 2H).
Example 33
N-{1-(S)-[cis-2-(4-Methoxy-phenylamino)-cyclohexylcarbamoyl]-3-methyl-buty-
l}-3-methyl-benzamide
[0330] The title compound was prepared according to the procedures
of Examples 20 and 21, except that cis-diaminocyclohexane was used
in the Step A. The final material was purified by reverse phase
preparative HPLC using TFA as a modifier. The final compound is
therefore a partial TFA salt and the properties are reported for
the material as it appeared after solvent removal (20%): .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 0.91 (d, 3H, J=6.1), 0.95 (d, 3H,
J=6.2), 1.21-1.35 (m, 1H), 1.35-1.48 (m, 1H), 1.51-1.97 (m, 9H),
2.29 (s, 3H), 3.71-3.80 (m, 1H), 3.80 (s, 3H), 4.36-4.61 (m, 2H),
6.83-6.91 (m, 2H), 7.18-7.31 (m, 2H), 7.38-7.53 (m, 4H), 7.63-7.78
(m, 1H), 8.33-8.41 (m, 1H), 8.80-9.50 (m, 2H).
Example 34
N-{1-(S)-[trans-2-(4-Methoxy-phenylamino)-cyclohexylcarbamoyl]-3-methyl-bu-
tyl}-3-methyl-benzamide
[0331] The title compound was prepared according to the procedures
of Examples 20 and 21, except that trans-diaminocyclohexane was
used in the Step A. The final material was purified by reverse
phase preparative HPLC using TFA as a modifier. The final compound
is therefore a partial TFA salt and the properties are reported for
the material as it appeared after solvent removal (20%): .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 0.85-1.05 (m, 6H), 1.05-1.41 (m,
3H), 1.43-1.51 (m, 1H), 1.60-1.96 (m, 7H), 2.32 (s, 3H), 3.81 (s,
3H), 3.70-3.95 (m, 2H), 4.24-4.33 (m, 1H), 6.88 (d, 1H, J=8.6),
7.22-7.39 (m, 4H), 7.51-7.59 (m, 2H), 7.74-7.85 (m, 1H), 8.68-8.80
(m, 1H), 9.30-9.90 (m, 2H).
Example 35
N-{1-(S)-[1-(R)-Benzyloxymethyl-2-(4-methoxy-phenylamino)-ethylcarbamoyl]--
3-methyl-butyl}-3-methyl-benzamide
[0332] Step A: N-Boc-OBn-Serine (750 mg, 2.54 mmol), p-anisidine
(344 mg, 2.79 mmol) and HOBt (377 mg, 2.79 mmol) were charged to a
50 mL roundbottom flask and treated with DCM (6 mL). The reaction
was then treated with EDCI (535 mg, 2.79 mmol) and allowed to stir
for 2 hours. The reaction was then diluted with ethyl acetate and
extracted twice with water, twice with 1 M HCl and twice with 1 M
NaOH. The organics were then dried over MgSO4 and the solvent was
removed to afford 450 mg (44%) of a white solid: .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.49 (s, 9H), 3.63-3.72 (m, 1H), 3.81
(s, 3H), 4.00-4.08 (m, 1H), 4.47-4.50 (m, 1H), 4.55-4.70 (m, 2H),
5.45-5.60 (m, 1H), 6.87 (d, 2H, J=8.8), 7.30-7.41 (m, 7H),
8.20-8.33 (m, 1H); HPLC-MS calcd. for
C.sub.22H.sub.28N.sub.2O.sub.5 (M+H.sup.+) 401.2, found 401.4.
[0333] Step B: The product from Step A (400 mg, 1.00 mmol) was
added to an ice cold solution of borane (1 M) in THF. The cooling
bath was removed and the reaction was allowed to stir for 24 h at
which point the excess reagent was quenched using 5% NaHSO.sub.4.
The reaction was diluted with ethyl acetate and extracted twice
with 1 M NaOH. The organics were dried over MgSO.sub.4 and the
solvent was removed. The resulting residue contained material that
was missing the Boc group and some material that still had it (by
HPLC-MS). The oil was treated with MeOH (2 mL) and 4 M HCl (2 mL)
and stirred for 3 hours. The solvent was then removed and the
reaction was partitioned between ethyl acetate and 1 M NaOH. The
aqueous phase was extracted twice more with ethyl acetate and the
combined organics were dried over MgSO.sub.4 and the solvent was
removed. The residue was treated with
(S)-4-Methyl-2-(3-methyl-benzoylamino)-pentanoic acid (249 mg, 1
mmol, obtained from Example 3, Step A), HOBt (148 mg, 1.1 mmol) and
DCM (5 mL). The reaction was then treated with EDCI (211 mg, 1.1
mmol) and allowed to stir for 3 hours. The reaction was then
diluted with ethyl acetate and extracted with 1 M NaOH twice. The
combined organics were dried over MgSO.sub.4 and the solvent was
removed. The residue was purified by silica gel column
chromatography using ethyl acetate and hexane as solvents to afford
a white solid (100 mg, 19%). The material is most likely partially
racemized at the leucine so the data are reported for the major
species: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.90-1.02 (m,
6H), 1.62-1.79 (m, 3H), 2.38 (s, 3H), 3.24-3.38 (m, 2H), 3.51 (dd,
1H, J.sub.1=J.sub.2=5.3), 3.61-3.65 (m, 1H), 3.75 (s, 3H),
3.70-3.87 (m, 1H), 4.24-4.37 (m, 1H), 4.68-4.78 (m, 2H), 6.59 (d,
2H, J.sub.1=8.5), 6.77 (d, 2H, J.sub.1=8.4), 6.89 (d, 2H,
J.sub.1=8.0), 7.26-7.40 (m, 6H), 7.58-7.66 (m, 2H); HPLC-MS calcd.
for C.sub.31H.sub.39N.sub.3O.sub.4 (M+H.sup.+) 518.3, found
518.3.
Example 36
N--(S)-{[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylca-
rbamoyl]-phenyl-methyl}-3-methoxy-benzamide
[0334] Following the procedures of Example 22, except using
N-Boc-OBn-serinol, 5-fluoroindoline, (L)-phenylglycine and anisoyl
chloride as starting materials, the title compound was prepared.
The chiral center on the phenylglycine completely racemized during
the reaction so the data are reported for the 50-50 diastereomeric
mixture (60% yield): .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
2.75-2.82 (m, 1H), 2.86-2.93 (m, 1H), 2.96 (dd, 0.5H, J.sub.1=7.3,
J.sub.2=13.7), 3.07 (dd, 0.5H, J.sub.1=6.0, J.sub.2=13.8),
3.12-3.18 (m, 2H), 3.32-3.42 (m, 1.5H), 3.55 (dd, 0.5H,
J.sub.1=4.5, J.sub.2=9.3), 3.69-3.56 (m, 1H), 3.82 (s, 3H),
4.23-4.34 (m, 1H), 4.36 (dd, 1H, J.sub.1=11.9, J.sub.2=21.2), 4.52
(dd, 1H, J.sub.1=11.9, J.sub.2=18.7), 5.58 (d, 1H, J=6.3), 6.13 (d,
0.5H, J=8.3), 6.12-6.28 (m, 2H), 6.41 (dd, 0.5H, J.sub.1=4.0,
J.sub.2=8.5), 6.11-6.82 (m, 2H), 7.04 (d, 1H, J.sub.1=7.9),
7.12-7.17 (m, 1H), 7.25-7.47 (m, 11H), 7.54 (dd, 1H, J.sub.1=6.5,
J.sub.2=11.2); HPLC-MS calcd. for C.sub.34H.sub.34FN.sub.3O.sub.4
(M+H.sup.+) 568.3, found 568.3.
Example 37
N-[1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylc-
arbamoyl]-2-(4-fluoro-phenyl)-ethyl]-3-methoxy-benzamide
[0335] Following the procedures of Example 22, except using
N-Boc-OBn-serinol, 5-fluoroindoline, (L)-4-fluoropheylalanine and
anisoyl chloride as starting materials, the title compound was
prepared. The chiral center on the 4-fluorophnylalanine partially
racemized during the reaction and the data are reported for the
major diastereomer (30% yield): .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 2.85-3.24 (m, 6H), 3.24-3.47 (m, 3H), 3.53-3.64 (m, 1H),
3.81 (s, 3H), 4.14-4.22 (m, 1H), 4.37-4.49 (m, 2H), 4.75 (dd, 1H,
J.sub.1=7.2, J.sub.2=14.0), 6.08-6.17 (m, 1H), 6.38-6.43 (m, 1H),
6.67-6.86 (m, 2H), 6.85-6.95 (m, 2H), 7.00-7.06 (m, 1H), 7.14-7.33
(m, 11H); HPLC-MS calcd. for C.sub.35H.sub.35F.sub.2N.sub.3O.sub.4
(M+H.sup.+) 600.3, found 600.5.
Example 38
N-{1-(S)-[(2-Benzyloxy-1-(R)-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-ethyl-
carbamoyl]-3-cyclohexyl-propyl}-3-methoxy-benzamide
[0336] Following the procedures of Example 22, except using
5-fluoroindoline, m-anisoyl chloride,
(R)-(+)-3-benzyloxy-2-(tert-butoxycarbonylamino)-1-propanol and
(S)-2-amino-4-cyclohexyl-butyric acid as starting materials, the
title compound was prepared as a mixture of two diastereomers.
HPLC-MS calcd. for C.sub.36H.sub.44FN.sub.3O.sub.4 (M+H.sup.+)
602.3, found 602.5.
Example 39 and Example 40
[0337]
N-{3-Cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(R)-hy-
droxymethyl-ethylcarbamoyl]-propyl}-3-methoxy-benzamide and
N-{3-Cyclohexyl-1-(R)-[(S)-2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(R)-hydr-
oxymethyl-ethylcarbamoyl]-propyl}-3-methoxy-benzamide
[0338] The title compound of Example 38 (492 mg, 818 .mu.mol) and
10% Pd/C (20 mg) were treated with MeOH (3.5 mL) and 4 M HCl in
dioxane (0.5 mL). The atmosphere in the reaction was then exchanged
for hydrogen and the reaction was stirred under hydrogen for 1 h.
The atmosphere in the reaction was then exchanged back to nitrogen
and the reaction was filtered through a plug of celite and the
solvent was removed. The reaction was diluted with DCM and
extracted with saturated aqueous NaHCO.sub.3 solution. The organics
were dried over MgSO.sub.4 and the solvent was removed. The residue
was purified by silica gel column chromatography using ethyl
acetate and hexane as solvents to afford 2 products. The faster
running material (Example 39) was present in much less abundance
than the slower material (Example 40) and was assigned as being the
diastereomer that was racemized during the coupling step. The
yields and data are as follows:
Example 39
[0339] (80 mg, 18% yield); .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 0.71-0.84 (m, 2H), 0.98-1.22 (m, 6H), 1.51-1.65 (m, 5H),
1.62-1.75 (m, 1H), 1.85-1.96 (m, 1H), 2.80-2.89 (m, 2H), 3.01-3.09
(m, 1H), 3.12-3.22 (m, 1H), 3.20-3.32 (m, 1H), 3.36-3.44 (m, 1H),
3.58-3.76 (m, 2H), 3.76 (s, 3H), 4.06-4.14 (m, 1H), 4.52 (dd, 1H,
J.sub.1=7.5, J.sub.2=13.7), 6.39-6.47 (m, 1H), 6.61-6.68 (m, 1H),
6.68-6.81 (m, 2H), 6.89-7.02 (m, 2H), 7.18-7.28 (m, 3H); HPLC-MS
calcd. for C.sub.29H.sub.38FN.sub.3O.sub.4 (M+H.sup.+) 512.3, found
512.5.
Example 40
[0340] (270 mg, 65% yield); .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 0.61-0.77 (m, 2H), 0.93-1.20 (m, 6H), 1.47-1.60 (m, 5H),
1.61-1.73 (m, 1H), 1.77-1.89 (m, 1H), 2.78-2.81 (m, 2H), 3.02 (dd,
1H, J.sub.1=6.5, J.sub.2=13.5), 3.15-3.29 (m, 2H), 3.40-3.50 (m,
1H), 3.62-3.75 (m, 2H), 3.75 (s, 3H), 4.09-4.18 (m, 1H), 4.53 (dd,
1H, J.sub.1=7.0, J.sub.2=13.8), 6.36-6.42 (m, 1H), 6.61-6.68 (m,
1H), 6.69-6.74 (m, 1H), 6.93-6.99 (m, 2H), 7.02-7.12 (m, 1H),
7.20-7.27 (m, 3H); HPLC-MS calcd. for
C.sub.29H.sub.38FN.sub.3O.sub.4 (M+H.sup.+) 512.3, found 512.5.
Example 41
1H-Indole-2-carboxylic acid
{(1S)-[2-benzyloxy-(1R)-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-ethylcarb-
amoyl]-3-cyclohexyl-propyl}-amide
[0341] Following the procedures of Example 22, except using
5-fluoroindoline, 2-indolecarboxylic acid,
(R)-(+)-3-benzyloxy-2-(tert-butoxycarbonylamino)-1-propanol and
(S)-2-amino-4-cyclohexyl-butyric acid as starting materials, the
title compound was prepared. The final compound was isolated as a
5:1 mixture of diastereomers. HPLC-MS calcd. for
C.sub.37H.sub.43FN.sub.4O.sub.3 (M+H.sup.+) 611.3, found 611.6.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.47-1.36 (m, 13H),
1.47-1.67 (m, 2H), 2.89 (broad s, 2H), 3.34-3.59 (m, 6H), 4.01 (m,
2H), 4.41 (m, 2H), 6.35-7.41 (m, 10H), 9.61 (broad s, 1H).
Example 42
(S,S)-5-(5-Fluoro-2,3-dihydro-indol-1-yl)-4-[4-methyl-2-(3-methyl-benzoyla-
mino)-pentanoylamino]-pentanoic acid benzyl ester
[0342] N-Boc-(L)-glutamic acid-.delta.-benzyl ester (2.00 g, 5.93
mmol) was dissolved in THF (5 mL) and cooled to ice bath
temperature and treated with a 1 M solution of borane in THF (12
mL, 12 mmol). After 1.5 hours of stirring while cold, the reaction
was cautiously quenched with MeOH followed by a solution of 5%
KHSO.sub.4 in water. The reaction was then diluted with ethyl
acetate and extracted 4 times with 1 M NaOH solution. The organics
were dried over MgSO.sub.4 and the solvent was removed. The residue
was purified by silica gel column chromatography using ethyl
acetate and hexane as solvents to afford a white solid (900 mg,
47%); HPLC-MS calcd. for C.sub.17H.sub.25NO.sub.5 (M+H.sup.+)
324.2, found 324.2. Following the procedures of Example 22, this
material was converted to the title compound (80% overall yield):
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.84-0.94 (m, 6H),
1.57-1.72 (m, 3H), 1.72-1.88 (m, 1H), 2.02-2.13 (m, 1H), 2.36 (s,
3H), 2.41-2.50 (m, 2H), 2.86-3.04 (m, 2H), 3.16 (dd, 1H,
J.sub.1=6.6, J.sub.2=12.8), 3.26-3.38 (m, 1H), 3.47 (dd, 1H,
J.sub.1=7.8, J.sub.2=15.9), 4.13-4.27 (m, 1H), 4.63-4.72 (m, 1H),
5.06 (s, 2H), 6.31-6.37 (m, 2H), 6.69 (dd, 1H,
J.sub.1=J.sub.2=8.9), 6.79 (d, 1H, J=8.0), 6.86 (d, 1H, J=7.9),
6.98 (d, 1H, J=8.3), 7.24-7.39 (m, 6H), 7.52-7.60 (m, 2H); HPLC-MS
calcd. for C.sub.34H.sub.40FN.sub.3O.sub.4 (M+H.sup.+) 574.3, found
574.5.
Example 43
(S,S)-5-(5-Fluoro-2,3-dihydro-indol-1-yl)-4-[4-methyl-2-(3-methyl-benzoyla-
mino)-pentanoylamino]-pentanoic acid
[0343] The title compound of Example 42 (200 mg, 0.348 mmol) and
10% Pd/C were treated with MeOH (2 mL) and the atmosphere in the
reaction was switched to hydrogen. After stirring overnight, the
atmosphere in the reaction was switched back to nitrogen and the
reaction was filtered through celite. Removal of solvent and drying
afforded a white solid (168 mg, 94); HPLC-MS calcd. for
C.sub.27H.sub.34FN.sub.3O.sub.4 (M+H.sup.+) 484.3, found 484.4.
Example 44
(S,S)--N-{1-[3-Carbamoyl-1-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-propylc-
arbamoyl]-3-methyl-butyl}-3-methyl-benzamide
[0344] The title compound of Example 43 (30 mg, 61 .mu.mol) was
treated with dioxane (2 mL) and concentrated ammonia (0.2 mL). HATU
(35 mg, 92 .mu.mol) was added and the reaction was stirred
overnight. Another portion of HATU (80 mg, 210 .mu.mol) was added
and the reaction was stirred for an additional 3 hours. The
reaction was then diluted with ethyl acetate and extracted once
with 1 M NaOH solution. The organics were dried over MgSO.sub.4 and
the solvent was removed. The residue was purified by silica gel
column chromatography using DCM and methanol as solvents to afford
the title compound (25 mg, 84%); .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 0.90 (s, 3H), 0.91 (s, 3H), 0.88-0.99 (m, 1H), 1.58-1.80
(m, 4H), 1.97-2.12 (m, 2H), 2.23-2.30 (m, 2H), 2.37 (s, 3H), 2.82
(s, 2H), 2.85-3.04 (m, 3H), 3.15 (dd, 1H, J.sub.1=6.5,
J.sub.2=13.6), 3.34 (dd, 1H, J.sub.1=8.4, J.sub.2=16.9), 3.48 (dd,
1H, J.sub.1=8.1, J.sub.2=16.0), 4.12-4.21 (m, 1H), 4.40-4.72 (m,
1H), 5.86 (s, 1H), 6.32-6.47 (m, 2H), 6.72 (dd, 1H,
J.sub.1=J.sub.2=8.4), 6.79 (d, 1H, J=7.4), 6.94 (d, 1H, J=7.6),
7.06 (d, 1H, J=8.4), 7.23-7.36 (m, 2H), 7.52-7.61 (m, 2H); HPLC-MS
calcd. for C.sub.27H.sub.35FN.sub.4O.sub.3 (M+H.sup.+) 483.3, found
483.5.
Example 45
(S,S)--N-{1-[1-(5-Fluoro-2,3-dihydro-indol-1-ylmethyl)-3-ureido-propylcarb-
amoyl]-3-methyl-butyl}-3-methyl-benzamide
[0345] The title compound of Example 43 (58.8 mg, 121 .mu.mol) was
treated with tBuOH (2 mL), diphenylphosphoryl azide (70 mg, 254
.mu.mol)and triethylamine (60 mg, 592 .mu.mol). The reaction was
heated at 90.degree. C. for 3 hours and cooled to rt. HPLC-MS
analysis indicated that the Curtius rearrangement had occurred, but
that the intermediate isocyanate had been hydrolyzed to the
carbamic acid and activated as the azide rather than being
intercepted by the alcohol. The solvent was removed and the
reaction was extractively worked up with ethyl acetate and water,
dried over MgSO.sub.4 and rotary evaporated. The residue was
treated with concentrated ammonia and allowed to stir overnight.
The reaction was again extractively worked up and then
chromatographed on silica gel using DCM an MeOH as eluent to afford
the title material (12 mg, 20%); .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 0.88 (d, 3H, J=6.3), 0.91 (d, 3H, J=6.3), 1.55-1.80 (m,
4H), 1.85-1.95 (m, 1H), 2.37 (s, 3H), 2.90-3.03 (m, 3H), 3.06-3.26
(m, 2H), 3.37 (dd, 1H, J.sub.1=8.7, J.sub.2=17.1), 3.48-3.61 (m,
2H), 4.01-4.26 (m, 1H), 4.26-4.38 (m, 1H), 4.50 (dd, 1H, J=7.7,
J.sub.2=15.0), 6.00-6.20 (m, 1H), 6.49 (dd, 1H, J.sub.1=4.0,
J.sub.2=8.4), 6.74 (ddd, 1H, J.sub.1=2.5, J.sub.2=J.sub.3=8.9),
6.78-6.83 (m, 1H), 7.16-7.20 (m, 1H), 7.23-7.37 (m, 3H), 7.50-7.57
(m, 2H).
Example 46
(S,S)-3-[4-Cyclohexyl-2-(3-methoxy-benzoylamino)-butyrylamino]-4-(5-fluoro-
-2,3-dihydro-indol-1-yl)-butyric acid benzyl ester
[0346] Following the procedures of Example 42, the title compound
was prepared (82% overall yield); HPLC-MS calcd. for
C.sub.37H.sub.44FN.sub.3O.sub.5 (M+H.sup.+) 630.3, found 630.5.
Example 47
(S,S)-3-[4-Cyclohexyl-2-(3-methoxy-benzoylamino)-butyrylamino]-4-(5-fluoro-
-2,3-dihydro-indol-1-yl)-butyric acid
[0347] The title compound of Example 46 (300 mg, 0.476 mmol) was
treated with 10% Pd/C (40 mg), MeOH (5 mL) and THF (5 mL). The
atmosphere in the reaction was exchanged for hydrogen and the
reaction was allowed to stir for 1 h under a balloon of hydrogen.
The atmosphere was then exchanged back to nitrogen, the reaction
was filtered through a pad of celite and the solvent was removed to
afford 244 mg (95%) of a crystalline solid; .sup.1H NMR (DMSO, 400
MHz) .delta. 0.55-0.88 (m, 2H), 1.00-1.22 (m, 7H), 2.93 (dd, 1H,
J.sub.1=5.8, J.sub.2=13.6), 3.11 (dd, 1H, J.sub.1=7.6,
J.sub.2=13.7), 3.25 (dd, 1H, J.sub.1=8.7, J.sub.2=17.5), 3.34 (s,
3H), 3.41-3.50 (m, 1H), 3.81 (s, 3H), 4.30-4.41 (m, 1H), 6.71-6.79
(m, 1H), 6.85-6.89 (m, 1H), 7.07-7.12 (m, 1H), 7.37 (dd, 1H,
J.sub.1=J.sub.2=7.8), 7.40-7.48 (m, 2H), 7.98 (d, 1H, J=8.6), 8.32
(d, 1H, J=8.1); HPLC-MS calcd. for C.sub.30H.sub.38FN.sub.3O.sub.5
(M+H.sup.+) 483.3, found 483.5.
Example 48
(S,S)--N-{1-[1-Benzyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
3-cyclohexyl-propyl}-3-methoxy-benzamide
[0348] Following the procedures of Example 22, except using
N-Boc-(L)-phenylalaninol, the title compound was prepared. The
final material was purified by preparative HPLC using TFA as a
modifier. The final compound is therefore a partial TFA salt and
the properties are reported for the material as it appeared after
solvent removal. (40% overall yield); .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 0.60-0.78 (m, 2H), 0.82-1.15 (m, 6H), 1.33-1.94 (m,
9H), 2.63-3.52 (m, 5H), 3.75-3.81 (m, 3H), 4.01-4.54 (m, 3H),
6.26-6.36 (m, 1H), 6.41-6.46 (m, 0.5H), 6.56-6.88 (m, 2H),
6.96-7.33 (m, 11H); HPLC-MS calcd. for
C.sub.35H.sub.42FN.sub.3O.sub.3 (M+H.sup.+) 572.3, found 572.5.
Example 49
(S,S)--N-{3-Cyclohexyl-1-[1-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-3-meth-
yl-butylcarbamoyl]-propyl}-3-methoxy-benzamide
[0349] Following the procedures of Example 22, except using
N-Boc-(L)-leucinol, the title compound was prepared. The final
material was purified by preparative HPLC using TFA as a modifier.
The final compound is therefore a partial TFA salt and the
properties are reported for the material as it appeared after
solvent removal (40% overall yield); .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 0.64-0.88 (m, 8H), 0.95-1.24 (m, 6H), 1.25-1.45 (m,
2H), 1.45-1.88 (m, 10H), 2.86-3.57 (m, 3H), 3.76-3.81 (m, 3H),
3.94-4.48 (m, 3H), 6.20-6.37 (m, 1H), 6.49-6.90 (m, 2H), 6.96-7.18
(m, 2H) 7.21-7.33 (m, 3H); HPLC-MS calcd. for
C.sub.32H.sub.44FN.sub.3O.sub.3 (M+H.sup.+) 538.3, found 538.5.
Example 50
(S,S)--N-{3-Cyclohexyl-1-[1-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-2-meth-
yl-propylcarbamoyl]-propyl}-3-methoxy-benzamide
[0350] Following the procedures of Example 22, except using
N-Boc-(L)-valinol, the title compound was prepared. The final
material was purified by reverse phase preparative HPLC using TFA
as a modifier. The final compound is therefore a partial TFA salt
and the properties are reported for the material as it appeared
after solvent removal (40% overall yield); .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta. 0.53-0.82 (m, 2H), 0.84-1.22 (m, 11H), 1.39-1.63
(m, 6H), 1.70-1.97 (m, 2H), 2.87-2.97 (m, 2H), 3.04-3.20 (m, 1H),
3.35-3.54 (m, 1H), 3.75-3.81 (m, 3H), 3.98-4.20 (m, 2H), 4.40-4.60
(m, 1H) 6.17-6.38 (m, 1H), 6.48-6.74 (m, 2H), 6.75-6.88 (m, 1H),
6.94-7.18 (m, 3H), 7.20-7.30 (m, 3H); HPLC-MS calcd. for
C.sub.31H.sub.42FN.sub.3O.sub.3 (M+H.sup.+) 524.3, found 524.5.
Example 51
(S,S)--N-{3-Cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-phenyl-eth-
ylcarbamoyl]-propyl}-3-methoxy-benzamide
[0351] Following the procedures of Example 22, except using
N-Boc-(L)-phenylglycinol, the title compound was prepared. The
final material was purified by reverse phase preparative HPLC using
TFA as a modifier. The final compound is therefore a partial TFA
salt and the properties are reported for the material as it
appeared after solvent removal (40% overall yield); .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 0.62-0.77 (m, 2H), 0.94-1.20 (m, 6H),
1.42-1.77 (m, 8H), 1.81-1.93 (m, 1H), 2.79-2.81 (m, 1H), 3.09-3.20
(m, 1H), 3.32-3.47 (m, 1H), 3.69-3.81 (m, 3H), 4.36-4.65 (m, 1H),
5.13-5.35 (m, 1H) 6.26-6.36 (m, 1H), 6.57-6.87 (m, 4H), 6.73-6.99
(m, 1H), 7.06-7.35 (m, 8H); HPLC-MS calcd. for
C.sub.34H.sub.40FN.sub.3O.sub.3 (M+H.sup.+) 558.3, found 558.5.
Example 52
(S,S)--N-{3-Cyclohexyl-1-[1-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-3-morp-
holin-4-yl-propylcarbamoyl]-propyl}-3-methoxy-benzamide
[0352] The title compound was prepared following the procedure
described in Example 151. .sup.1H NMR (MeOD, 400 MHz) .delta.
0.65-0.81 (m, 2H), 0.85-0.99 (m, 1H), 1.03-1.34 (m, 11H), 1.52-1.81
(m, 9H), 1.81-1.98 (m, 2H), 2.15-2.25 (m, 1H), 2.85-2.98 (m, 2H),
2.99 (dd, 1H, J.sub.1=4.9, J.sub.2=13.7), 3.10-3.47 (m, 11H),
3.53-3.63 (m, 2H), 3.86 (s, 3H), 3.62-3.90 (m, 5H), 3.93-4.03 (m,
1H), 4.05-4.14 (m, 1H), 4.22-4.35 (m, 2H), 4.45-4.55 (m, 1H), 6.51
(dd, 1H, J.sub.1=4.1, J.sub.2=8.6), 6.75 (ddd, 1H, J.sub.1=2.5,
J.sub.2=J.sub.3=8.9), 6.83 (dd, 1H, J.sub.1=2.5, J.sub.2=8.4),
7.09-7.14 (m, 2H), 7.36-7.45 (m, 4H); HPLC-MS calcd. for
C.sub.34H.sub.47FN.sub.4O.sub.4 (M+H.sup.+) 595.4, found 595.5.
Example 53
N-{1-(S)-[2-(R)-Benzyloxy-1-(R)-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-pr-
opylcarbamoyl]-3-cyclohexyl-propyl}-3-methoxy-benzamide
[0353] Following the procedures of Example 22, except using
N-Boc-O-Bn-ether-(L)-threoninol, the title compound was prepared.
The final material was purified by preparative HPLC using TFA as a
modifier. The final compound is therefore a partial TFA salt and
the properties are reported for the material as it appeared after
solvent removal (40% overall yield); .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 0.60-0.85 (m, 3H), 0.85-1.25 (m, 9H), 1.44-1.85 (m,
8H), 2.80-3.29 (m, 2H), 2.94-3.08 (m, 2H), 3.17-3.25 (m, 1H),
3.28-3.38 (m, 2H), 3.75-3.80 (m, 3H), 4.04-4.13 (m, 1H), 4.20-4.32
(m, 2H) 4.47-4.65 (m, 3H), 6.18-6.48 (m, 2H), 6.58-6.91 (m, 3H),
6.95-7.03 (m, 1H), 7.09-7.41 (m, 8H); HPLC-MS calcd. for
C.sub.37H.sub.46FN.sub.3O.sub.4 (M+H.sup.+) 616.3, found 616.5.
Example 54
N-{1-(R)-[1-(R)-Benzylsulfanylmethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-e-
thylcarbamoyl]-3-cyclohexyl-propyl}-3-methoxy-benzamide
[0354] Following the procedures of Example 22, except using
N-Boc-S-Bn-(L)-cystinol, the title compound was prepared. The final
material was purified by preparative HPLC using TFA as a modifier.
(20% overall yield); HPLC-MS calcd. for
C.sub.36H.sub.44FN.sub.3O.sub.3S (M+H.sup.+) 618.3, found
618.5.
Example 55
(S,S)-[5-[4-Cyclohexyl-2-(3-methoxy-benzoylamino)-butyrylamino]-6-(5-fluor-
o-2,3-dihydro-indol-1-yl)-hexyl]-carbamic acid benzyl ester
[0355] Following the procedures of Example 22, except using
N-Boc-N-Cbz-(L)-lysinol, the title compound was prepared. The final
material was purified by reverse phase preparative HPLC using TFA
as a modifier. The final compound is therefore a partial TFA salt
and the properties are reported for the material as it appeared
after solvent removal (40% overall yield); .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta. 0.58-0.83 (m, 2H), 0.93-1.22 (m, 7H), 1.22-1.95
(m, 16H), 2.76-3.48 (m, 8H), 3.72-3.79 (m, 3H), 4.00-4.23 (m, 2H),
4.42-4.55 (m, 1H), 4.80-5.08 (m, 3H), 6.23-6.45 (m, 2H), 6.30-7.12
(m, 5H) 7.17-7.30 (m, 8H); HPLC-MS calcd. for
C.sub.40H.sub.51FN.sub.4O.sub.5 (M+H.sup.+) 687.4, found 687.5.
Example 56
1-(6-Chloro-pyridazin-3-yl)-piperidine-4-carboxylic acid
(S)-12-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0356] C.sub.29H.sub.38ClFN.sub.6O.sub.2; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.97(m, 1H), 7.27(m, 1H), 7.18(m, 1H), 7.09(m, 1H),
6.95(m, 3H), 4.22(m, 3H), 3.77(m, 2H), 3.61(m, 2H), 3.41(m, 2H),
3.10(m, 4H), 2.66(m, 1H), 1.89(m, 2H), 1.72(m, 2H), 1.60(m, 7H),
1.09(m, 4H), 0.81(m, 2H); LCMS: 557.5 (M+H).sup.+.
Example 57
1-(4-Methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0357] .sup.1H NMR (CDCl.sub.3) .delta.(ppm) 7.99(m, 1H), 7.60(m,
2H), 7.17(m, 1H), 6.97(m, 4H), 6.62(d, J=6.4 Hz, 1H), 4.24(m, 1H),
3.80(s, 3H), 3.77(m, 1H), 3.64(m, 4H), 3.40(m, 2H), 3.17(m, 2H),
2.18(m, 2H), 2.04(m, 1H), 1.74(m, 2H), 1.60(m, 9H), 1.44(m, 1H),
1.17(m, 1H), 1.05(m, 3H), 0.80(m, 2H); LCMS: 615.5 (M+H).sup.+.
Example 58
1-Benzenesulfonyl-piperidine-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0358] C.sub.31H.sub.41FN.sub.4O.sub.4S; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.95(m, 1H), 7.66(m, 3H), 7.51(m, 3H), 7.13(m, 1H),
6.97(m, 1H), 6.58(m, 1H), 4.24(m, 1H), 3.72(m, 4H), 3.61(m, 2H),
3.39(m, 2H), 3.16(m, 2H), 2.20(m, 2H), 2.11(m, 1H), 1.68(m, 2H),
1.58(m, 9H), 1.17(m, 1H), 1.04(m, 3H), 0.80(m, 2H); LCMS:
585.5(M+H).sup.+.
Example 59
N-{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-
-ethyl}-2-(2-fluoro-biphenyl-4-yl)-propionamide;*
[0359] C.sub.34H.sub.39F.sub.2N.sub.3O.sub.2; LCMS:
560.6(M+H).sup.+.
Example 60
N-{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-
-ethyl}-2-p-tolyl-propionamide;*
[0360] C.sub.29H.sub.38FN.sub.3O.sub.2; LCMS: 480.5
(M+H).sup.+.
Example 61
N-{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-
-ethyl}-2-o-tolyl-propionamide
[0361] C.sub.29H.sub.38FN.sub.3O.sub.2; LCMS: 480.5 (M+H).sup.+
Example 62
N-{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-
-ethyl}-2-(4-fluoro-phenyl)-propionamide;*
[0362] C.sub.28H.sub.35F.sub.2N.sub.3O.sub.2; LCMS:
484.5(M+H).sup.+.
Example 63
1-Methyl-1H-imidazole-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0363] C.sub.24H.sub.32FN.sub.5O.sub.2; .sup.1H NMR (CD.sub.3OD)
.delta.(ppm) 8.63(s, 1H), 7.86(s, 1H), 6.70(m, 1H), 6.60(m, 1H),
6.36(m, 1H), 4.46(m, 1H), 3.83(s, 3H), 3.31(m, 4H), 3.08(m, 2H),
2.83(m, 2H), 1.56(m, 7H), 1.25(m, 1H), 1.07(m, 3H), 0.81(m, 2H);
LCMS: 442.5 (M+H).sup.+.
Example 64
2-(4-Chloro-phenyl)-N-{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-
-yl)-ethylcarbamoyl]-ethyl}-propionamide;*
[0364] C.sub.28H.sub.35ClFN.sub.3O.sub.2; LCMS:(M+H)
500.4(.sup.35ClM+H).sup.+, 502.5 (.sup.37ClM+H).sup.+.
Example 65
1-Benzyl-5-oxo-pyrrolidine-3-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0365] C.sub.31H.sub.39FN.sub.4O.sub.3; LCMS: 535.5(M+H).sup.+.
Example 66
1-(4-Fluoro-benzenesulfonyl)-piperidine-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0366] C.sub.31H.sub.40F.sub.2N.sub.4O.sub.4S; .sup.1H NMR
(CD.sub.3OD) .delta.(ppm) 7.84(m, 2H), 7.35(m, 2H), 6.91(m, 1H),
6.85(m, 1H), 6.74(m, 1H), 4.31(m, 1H), 3.72(m, 2H), 3.55(m, 2H),
3.47(m, 2H), 3.31(m, 2H), 3.26(m, 2H), 3.03(m, 2H), 2.35(m, 2H),
2.19(m, 1H), 1.79(m, 3H), 1.67(m, 6H), 1.51(m, 2H), 1.28(m, 2H),
1.15(m, 3H), 0.89(m, 2H); LCMS: 603.5 (M+H).sup.+.
Example 67
N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl-
]-ethyl}-4-(piperidin-4-yloxy)-benzamide;*
[0367] C.sub.31H.sub.41FN.sub.4O.sub.3; LCMS: 537.5(M+H).sup.+.
Example 68
N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl-
]-ethyl}-4-(1-methanesulfonyl-piperidin-4-yloxy)-benzamide;*
[0368] C.sub.32H.sub.43FN.sub.4O.sub.5S; .sup.1H NMR (CD.sub.3OD)
.delta.(ppm) 7.81(m, 2H), 6.98(m, 2H), 6.92(m, 1H), 6.82(m, 2H),
4.57(m, 1H), 3.52(m, 6H), 3.29(m, 5H), 3.03(m, 2H), 2.87(s, 3H),
2.07(m, 2H), 1.91(m, 2H), 1.79(m, 2H), 1.69(m, 5H), 1.40(m, 1H),
1.20(m, 3H), 0.97(m, 2H); LCMS: 615.5(M+H).sup.+.
Example 69
4-(1-Acetyl-piperidin-4-yloxy)-N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dih-
ydro-indol-1-yl)-ethylcarbamoyl]-ethyl}-benzamide;*
[0369] C.sub.33H.sub.43FN.sub.4O.sub.4; .sup.1H NMR (CD.sub.3OD)
67(ppm) 7.81(m, 2H), 7.01(m, 2H), 6.93(m, 1H), 6.82(m, 1H), 6.75(m,
1H), 4.74(m, 1H), 4.58(m, 1H), 3.79(m, 2H), 3.54(m, 6H), 3.30(m,
2H), 3.01(m, 2H), 2.13(s, 3H), 2.00(m, 2H), 1.69(m, 9H), 1.40(m,
1H), 1.19(m, 3H), 0.95(m, 2H); LCMS: 579.5 (M+H).sup.+.
Example 70
N-{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-
-ethyl}-2-(R)-phenyl-propionamide;*
[0370] C.sub.28H.sub.36FN.sub.3O.sub.2; .sup.1H NMR (CD.sub.3OD)
.delta.(ppm) 7.27(m, 5H), 6.94(m, 1H), 6.82(m, 1H), 6.82(m, 1H),
6.67(m, 1H), 4.33(m, 1H), 3.72(m, 1H), 3.36(m, 4H), 2.94(m, 2H),
1.69(m, 5H), 1.55(m, 2H), 1.44(d, J=7.2 Hz, 3H), 1.17(m, 4H),
0.93(m, 2H); LCMS: 466.5(M+H).sup.+.
Example 71
N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl-
]-ethyl}-3-methyl-benzamide;*
[0371] C.sub.27H.sub.34FN.sub.3O.sub.2; .sup.1H NMR (CD.sub.3OD)
.delta.(ppm) 7.61(m, 2H), 7.34(m, 2H), 6.87(m, 1H), 6.78(m, 1H),
6.67(m, 1H), 4.58(m, 1H), 3.49(m, 4H), 3.26(m, 2H), 2.97(m, 2H),
2.38(s, 3H), 1.68(m, 7H), 1.39(m, 1H), 1.17(m, 3H), 0.95(m, 2H);
LCMS: 452.5 (M+H).sup.+.
Example 72
5-Methanesulfonyl-thiophene-2-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0372] C.sub.25H.sub.32FN.sub.3O.sub.4S.sub.2; .sup.1H NMR
(CD.sub.3OD) .delta.(ppm) 7.70(m, 1H), 7.62(m, 1H), 6.76(m, 1H),
6.66(m, 1H), 6.52(m, 1H), 4.45(m, 1H), 3.38(m, 4H), 3.19(m, 5H),
2.88(m, 2H), 1.63(m, 7H), 1.28(m, 1H), 1.08(m, 3H), 0.85(m, 2H);
LCMS: 522.5(M+H).sup.+.
Example 73
5-Oxo-1-thiophen-2-ylmethyl-pyrrolidine-3-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0373] .sup.1H NMR (CD.sub.3OD) .delta.(ppm) 7.34(m, 1H), 7.01(m,
2H), 6.97(m, 1H), 6.91(m, 1H), 6.80(m, 1H), 6.67(m, 1H), 4.59(m,
2H), 4.31(m, 1H), 3.47(m, 7H), 3.23(m, 3H), 2.99(m, 2H), 2.62(m,
2H), 1.68(m, 3H), 1.52(m, 2H), 1.17(m, 5H), 0.92(m, 2H); LCMS:
541.5 (M+H).sup.+.
Example 74
1-Furan-2-ylmethyl-5-oxo-pyrrolidine-3-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0374] C.sub.29H.sub.37FN.sub.4O.sub.4; .sup.1H NMR (CD.sub.3OD)
.delta.(ppm) 7.34(s, 1H), 6.79(m, 1H), 6.68(m, 1H), 6.50(m, 1H),
6.23(m, 2H), 4.33(m, 1H), 4.27(m, 2H), 3.37(m, 7H), 3.21(m, 3H),
2.87(m, 2H), 2.50(m, 2H), 1.57(m, 3H), 1.43(m, 2H), 1.06(m, 5H),
0.81(m, 2H); LCMS: 525.5(M+H).sup.+.
Example 75
5-Phenyl-furan-2-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0375] C.sub.30H.sub.34FN.sub.3O.sub.3; LCMS: 504.5(M+H).sup.+.
Example 76
2-Phenyl-thiazole-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0376] C.sub.29H.sub.33FN.sub.4O.sub.2S; LCMS:
521.5(M+H).sup.+.
Example 77
1-Methanesulfonyl-piperidine-4-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0377] C.sub.26H.sub.39FN.sub.4O.sub.4S; LCMS:
523.5(M+H).sup.+.
Example 78
[0378] 5-Methyl-2-trifluoromethyl-furan-3-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0379] C.sub.26H.sub.31F.sub.4N.sub.3O.sub.3; .sup.1H NMR
(CD.sub.3OD) .delta.(ppm) 6.86(m, 1H), 6.77(m, 1H), 6.62(m, 1H),
6.41(m, 1H), 4.50(m, 1H), 3.48(m, 4H), 3.24(m, 2H), 2.99(m, 2H),
2.34(s, 3H), 1.64(m, 7H), 1.35(m, 1H), 1.17(m, 3H), 0.92(m, 2H);
LCMS: 510.5(M+H).sup.+.
Example 79
N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl-
]-ethyl}-4-(methanesulfonylamino-methyl)-benzamide;*
[0380] C.sub.28H.sub.37FN.sub.4O.sub.4S; .sup.1H NMR (CD.sub.3OD)
.delta.(ppm) 7.82(m, 2H), 7.47(m, 2H), 6.85(m, 1H), 6.76(m, 1H),
6.62(m, 1H), 4.59(m, 1H), 4.31(s, 2H), 3.48(m, 4H), 3.22(m, 2H),
2.95(m, 2H), 2.89(s, 3H), 1.68(m, 7H), 1.39(m, 1H), 1.18(m, 3H),
0.94(m, 2H); LCMS: 545.5(M+H).sup.+.
Example 80
N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl-
]-ethyl}-3-methanesulfonyl-benzamide;*
[0381] C.sub.27H.sub.34FN.sub.3O.sub.4S; .sup.1H NMR (CD.sub.3OD)
.delta.(ppm) 8.41(m, 1H), 8.12(m, 2H), 7.72(m, 1H), 6.87(m, 1H),
6.77(m, 1H), 6.65(m, 1H), 4.60(m, 1H), 3.50(m, 4H), 3.27(m, 2H),
3.16(s, 3H), 2.98(m, 2H), 1.70(m, 7H), 1.39(m, 1H), 1.18(m, 3H),
0.95(m, 2H); LCMS: 516.5(M+H).sup.+.
Example 81
N--(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl-
]-ethyl}-4-methanesulfonylamino-benzamide;*
[0382] C.sub.27H.sub.35FN.sub.4O.sub.4S; .sup.1H NMR (CD.sub.3OD)
.delta.(ppm) 7.81(d, J=8.0 Hz, 2H), 7.28(d, J=8.0 Hz, 2H), 6.90(m,
1H), 6.79(m, 1H), 6.71(m, 1H), 4.58(m, 1H), 3.52(m, 4H), 3.28(m,
2H), 3.02(s, 3H), 2.98(m, 2H), 1.68(m, 7H), 1.38(m, 1H), 1.18(m,
3H), 0.95(m, 2H); LCMS: 531.5(M+H).sup.+.
Example 82
5-Phenyl-thiophene-2-carboxylic acid
(S)-{2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]--
ethyl}-amide;*
[0383] C.sub.30H.sub.34FN.sub.3O.sub.2S; .sup.1H NMR (CD.sub.3OD)
.delta.(ppm) 7.75(m, 1H), 7.67(m, 2H), 7.40(m, 4H), 6.88(m, 1H),
6.80(m, 1H), 6.70(m, 1H), 4.56(m, 1H), 3.52(m, 4H), 3.28(m, 2H),
2.98(m, 2H), 1.71(m, 7H), 1.41(m, 1H), 1.19(m, 3H), 0.94(m, 2H);
LCMS: 521.5 (M+H).sup.+.
Example 83
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide
[0384] The title compound was prepared according to the following
scheme.
##STR00018##
[0385] C.sub.30H.sub.33F.sub.4N.sub.3O.sub.4; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.51(m, 1H), 7.41(m, 1H), 7.32(m, 2H),
7.08(m, 7H), 6.67(m, 1H), 4.44(m, 1H), 4.17(m, 1H), 3.45(m, 1H),
3.23(m, 1H), 1.65(m, 7H), 1.26(m, 4H), 1.08(m, 3H), 0.98(m, 2H);
LCMS: 576.4(M+H).sup.+.
Example 84
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-difluoromethoxy-phenylamino)-1-(S)-methyl-ethyl-
carbamoyl]-ethyl}-amide;.sup.#
[0386] C.sub.30H.sub.34F.sub.3N.sub.3O.sub.4; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 8.28(m, 1H), 7.40(m, 1H), 7.32(m, 1H),
7.22(m, 1H), 7.06(m, 7H), 6.67(m, 1H), 6.41(t, J=72 Hz, 1H),
4.38(m, 1H), 4.15(m, 1H), 3.54(m, 1H), 3.26(m, 1H), 1.63(m, 7H),
1.31(m, 1H), 1.28(d, J=8.0 Hz, 3H), 1.10(m, 3H), 0.89(m, 2H); LCMS:
558.2(M+H).sup.+.
Example 85
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(benzo[1,3]dioxol-5-ylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cyc-
lohexyl-ethyl}-amide;.sup.#
[0387] C.sub.30H.sub.34FN.sub.3O.sub.5; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 8.12(m, 1H), 7.40(m, 1H), 7.31(m, 2H), 7.03(m, 3H),
6.89(m, 2H), 6.74(m, 2H), 5.94(s, 2H), 4.30(m, 1H), 4.11(m, 1H),
3.60(m, 1H), 3.26(m, 1H), 1.68(m, 7H), 1.32(m, 4H), 1.16(m, 3H),
0.93(m, 2H); LCMS: 536.4(M+H).sup.+.
Example 86
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-methoxy-phenylamino)-1-(S)-methyl-ethylcarbamoy-
l]-ethyl}-amide;.sup.#
[0388] C.sub.30H.sub.36FN.sub.3O.sub.4; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 8.12(m, 1H), 7.40(m, 1H), 7.30(m, 4H), 7.01(m, 3H),
6.84(m, 2H), 6.63(d, J=4.0 Hz, 1H), 4.32(m, 1H), 4.15(m, 1H),
3.73(s, 3H), 3.63(m, 1H), 3.26(m, 1H), 1.63(m, 7H), 1.32(m, 4H),
1.14(m, 3H), 0.88(m, 2H); LCMS: 522.4(M+H).sup.+.
Example 87
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(3,5-difluoro-phenylamino)-1-(S)-methyl-ethylcarba-
moyl]-ethyl}-amide;.sup.#
[0389] C.sub.29H.sub.32F.sub.3N.sub.3O.sub.3; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.49(m, 1H), 7.40(m, 3H), 7.15(m, 1H),
6.98(m, 1H), 6.85(m, 1H), 6.70(m, 1H), 6.09(m, 3H), 4.59(m, 1H),
4.15(m, 1H), 3.13(m, 2H), 1.60(m, 7H), 1.24(m, 4H), 1.05(m, 3H),
0.86(m, 2H); LCMS: 528.4 (M+H).sup.+.
Example 88
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(3-methanesulfonyl-phenylamino)-1-(S)-methyl-ethyl-
carbamoyl]-ethyl}-amide;.sup.#
[0390] C.sub.30H.sub.36FN.sub.3O.sub.5S; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.50(m, 1H), 7.28(m, 4H), 7.19(m, 1H), 7.20(m, 1H),
7.12(m, 1H), 6.91(m, 3H), 6.71(m, 1H), 4.58(m, 1H), 4.18(m, 1H),
3.22(m, 2H), 2.98(s, 3H), 1.57(m, 7H), 1.22(m, 4H), 1.05(m, 3H),
0.86(m, 2H); LCMS: 570.4(M+H).sup.+.
Example 89
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-methanesulfonyl-phenylamino)-1-(S)-methyl-ethyl-
carbamoyl]-ethyl}-amide;.sup.#
[0391] C.sub.30H.sub.36FN.sub.3O.sub.5S; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.62(m, 2H), 7.47(m, 1H), 7.34(m, 3H), 7.18(m, 1H),
7.00(m, 1H), 6.88(m, 1H), 6.71(m, 1H), 6.58(m, 2H), 4.59(m, 1H),
4.20(m, 1H), 3.19(m, 2H), 2.93(s, 3H), 1.59(m, 7H), 1.22(m, 4H),
1.03(m, 3H), 0.86(m, 2H); LCMS: 570.4(M+H).sup.+.
Example 90
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(2,3-difluoro-phenylamino)-1-(S)-methyl-ethylcarba-
moyl]-ethyl}-amide;.sup.#
[0392] C.sub.29H.sub.32F.sub.3N.sub.3O.sub.3; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.46(m, 1H), 7.34(m, 2H), 7.19(m, 1H),
7.10(m, 1H), 6.98(m, 1H), 6.81(m, 1H), 6.70(m, 1H), 6.45(m, 3H),
4.58(m, 1H), 4.19(m, 1H), 3.18(d, J=4.0 Hz, 2H), 1.60(m, 7H),
1.22(m, 4H), 1.05(m, 3H), 0.86(m, 2H); LCMS: 528.4(M+H).sup.+.
Example 91
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(2,5-difluoro-phenylamino)-1-(S)-methyl-ethylcarba-
moyl]-ethyl}-amide;#
[0393] C.sub.29H.sub.32F.sub.3N.sub.3O.sub.3; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.48(m, 1H), 7.35(m, 3H), 7.19(m, 1H),
6.99(m, 1H), 6.70(m, 3H), 6.38(m, 1H), 6.20(m, 1H), 4.63(m, 1H),
4.19(m, 1H), 3.14(m, 2H), 1.59(m, 7H), 1.20(m, 4H), 1.04(m, 3H),
0.83(m, 2H); LCMS: 528.4(M+H).sup.+.
Example 92
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(2,6-difluoro-phenylamino)-1-(S)-methyl-ethylcarba-
moyl]-ethyl}-amide;.sup.#
[0394] C.sub.29H.sub.32F.sub.3N.sub.3O.sub.3; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.51(m, 1H), 7.40(m, 2H), 7.32(m, 1H),
7.17(m, 1H), 6.95(m, 1H), 6.72(m, 5H), 4.64(m, 1H), 4.11(m, 1H),
3.40(m, 1H), 3.25(m, 1H), 1.60(m, 7H), 1.31(m, 1H), 1.14(m, 6H),
0.86(m, 2H); LCMS: 528.4(M+H).sup.+.
Example 93
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(4-cyano-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cyclohexyl-
-ethyl}-amide;.sup.#
[0395] C.sub.30H.sub.33FN.sub.4O.sub.3; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.44(m, 1H), 7.33(m, 4H), 7.13(d, J=3.6 Hz, 1H),
6.98(m, 2H), 6.70(d, J=3.6 Hz, 1H), 6.64(m, 1H), 6.51(d, J=8.8 Hz,
2H), 4.55(m, 1H), 4.17(m, 1H), 3.15(m, 2H), 1.58(m, 7H), 1.21(m,
1H), 1.18(d, J=6.8 Hz, 3H), 1.02(m, 3H), 0.84(m, 2H); LCMS:
517.4(M+H).sup.+.
Example 94
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-chloro-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cyclohexy-
l-ethyl}-amide;.sup.#
[0396] C.sub.29H.sub.33FClN.sub.3O.sub.3; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.42(m, 1H), 7.33(m, 2H), 7.10(m, 4H), 6.96(m, 1H),
6.72(m, 2H), 6.67(m, 2H), 4.48(m, 1H), 4.14(m, 1H), 3.17(m, 2H),
1.61(m, 7H), 1.40(m, 1H), 1.20(d, J=6.8 Hz, 3H), 1.08(m, 3H),
0.88(m, 2H); LCMS: 526.3 (M+H).sup.+.
Example 95
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(2-fluoro-phenylamino)-1-(S)-methyl-ethylcarbamoyl-
]-ethyl}-amide;.sup.#
[0397] C.sub.29H.sub.33F.sub.2N.sub.3O.sub.3; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.44(m, 1H), 7.33(m, 2H), 7.11(d, J=3.6
Hz, 1H), 6.93(m, 4H), 6.74(m, 1H), 6.67(d, J=3.6 Hz, 1H), 6.53(m,
2H), 4.58(m, 1H), 4.18(m, 1H), 3.19(m, 2H), 1.60(m, 7H), 1.31(m,
1H), 1.18(d, J=6.8 Hz, 3H), 1.06(m, 3H), 0.86(m, 2H); LCMS: 510.4
(M+H).sup.+.
Example 96
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-chloro-2-fluoro-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2--
cyclohexyl-ethyl}-amide;.sup.#
[0398] C.sub.29H.sub.32ClF.sub.2N.sub.3O.sub.3; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.45(m, 1H), 7.31(m, 3H), 7.13(d, J=3.6
Hz, 1H), 6.98(m, 1H), 6.83(m, 1H), 6.69(d, J=3.6 Hz, 1H), 6.58(m,
3H), 4.60(m, 1H), 4.17(m, 1H), 3.17(m, 2H), 1.58(m, 7H), 1.31(m,
1H), 1.17(d, J=6.8 Hz, 3H), 1.05(m, 3H), 0.85(m, 2H); LCMS:
544.4(M+H).sup.+.
Example 97
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(5-chloro-2-fluoro-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2--
cyclohexyl-ethyl}-amide;.sup.#
[0399] C.sub.29H.sub.32ClF.sub.2N.sub.3O.sub.3; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.43(m, 1H), 7.34(m, 2H), 7.11(d, J=3.6
Hz, 1H), 7.0(m, 2H), 6.75(m, 1H), 6.68(d, J=3.6 Hz, 1H), 6.59(m,
2H), 6.48(m, 1H), 4.60(m, 1H), 4.19(m, 1H), 3.11(m, 2H), 1.56(m,
7H), 1.29(m, 1H), 1.17(d, J=3.6 Hz, 3H), 1.02(m, 3H), 0.84(m, 2H);
LCMS: 544.3(M+H).sup.+.
Example 98
5-(.sup.3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-carbamoyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cycloh-
exyl-ethyl}-amide;.sup.#
[0400] C.sub.30H.sub.35FN.sub.4O.sub.4; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.46(m, 1H), 7.25(m, 5H), 7.11(m, 2H), 6.94(m, 4H),
6.67(d, J=4.0 Hz, 1H), 4.52(m, 1H), 4.52(m, 1H), 4.18 (m, 1H),
3.35(m, 1H), 3.12(m, 1H), 1.58(m, 7H), 1.33(m, 1H), 1.17(d, J=6.8
Hz, 3H), 1.06(m, 3H), 0.85(m, 2H); LCMS: 535.4 (M+H).sup.+.
Example 99
5-(.sup.3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(3-fluoro-phenylamino)-1-(S)-methyl-ethylcarbamoyl-
]-ethyl}-amide;.sup.#
[0401] C.sub.29H.sub.33F.sub.2N.sub.3O.sub.3; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.42(m, 1H), 7.33(m, 2H), 7.09(m, 2H),
6.99(m, 2H), 6.89(m, 1H), 6.67(d,J=3.6 Hz, 1H), 6.45(m, 3H),
4.51(m, 1H), 4.14(m, 1H), 3.17(m, 2H), 1.61(m, 7H), 1.31(m, 1H),
1.19(d, J=6.8 Hz, 3H), 1.04(m, 3H), 0.87(m, 2H); LCMS:
510.4(M+H).sup.+.
Example 100
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-cyano-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cyclohexyl-
-ethyl}-amide;.sup.#
[0402] C.sub.30H.sub.33FN.sub.4O.sub.3; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.44(m, 1H), 7.34(m, 2H), 7.13(m, 2H), 6.99(m, 2H),
6.91(m, 1H), 6.77(m, 2H), 6.70(d, J=3.6 Hz, 1H), 6.63(m, 1H),
4.54(m, 1H), 4.17(m, 1H), 3.13(m, 2H), 1.59(m, 7H), 1.28(m, 1H),
1.19(d, J=6.8 Hz, 3H), 1.03(m, 3H), 0.86(m, 2H); LCMS:
517.4(M+H).sup.+.
Example 101
N-{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-
-ethyl}-2-(4-hydroxy-phenyl)-propionamide;*
[0403] C.sub.28H.sub.36FN.sub.3O.sub.3; .sup.1H NMR (CD.sub.3OD)
.delta.(ppm) 7.02(m, 2H), 6.83(m, 2H), 6.61(m, 3H), 4.19(m, 1H),
3.43(m, 4H), 3.21(m, 1H), 3.16(m, 1H), 2.89(m, 3H), 1.60(m, 2H),
1.45(m, 5H), 1.26(m, 3H), 0.70(m, 6H); LCMS: 482.5(M+H).sup.+.
Example 102
4-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(S)-(2-(R)-ph-
enyl-propionylamino)-butyramide;*
[0404] C.sub.29H.sub.38FN.sub.3O.sub.2; .sup.1H NMR (CH.sub.3CD)
.delta.(ppm) 7.17(m, 5H), 6.62(m, 2H), 6.26(m, 1H), 4.11(m, 1H),
3.62(m, 1H), 3.25(m, 1H), 3.20(m, 3H), 3.16(m, 2H), 2.92(m, 2H),
2.76(m, 2H), 1.82(m, 1H), 1.52(m, 5H), 1.34(d, J=8.0 Hz, 4H),
1.06(m, 6H), 0.67(m, 2H); LCMS: 480.4 (M+H).sup.+.
Example 103
5-(4-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide;.sup.#
[0405] C.sub.30H.sub.33F.sub.4N.sub.3O.sub.4; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.62(m, 2H), 7.07(m, 3H), 6.97(d, J=8.4
Hz, 2H), 6.83(m, 1H), 6.69(m, 1H), 6.60(m, 3H), 4.55(m, 1H),
4.16(m, 1H), 3.13(m, 2H), 1.61(m, 7H), 1.33(m, 1H), 1.18(d,
J=6.8Hz, 3H), 1.04(m, 3H), 0.86(m, 2H); LCMS: 576.5
(M+H).sup.+.
Example 104
5-(4-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-difluoromethoxy-phenylamino)-1-(S)-methyl-ethyl-
carbamoyl]-ethyl}-amide;.sup.#
[0406] C.sub.30H.sub.34F.sub.3N.sub.3O.sub.4; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.60(m, 2H), 7.06(m, 3H), 6.90(m, 3H),
6.61(m, 3H), 6.30(t, J=74 Hz, 1H), 4.84(m, 1H), 4.57(m, 1H),
4.15(m, 1H), 3.15(m, 2H), 1.62(m, 7H), 1.33(m, 1H), 1.16(d, J=6.8
Hz, 3H), 1.05(m, 3H),0.88(m, 2H); LCMS: 558.2 (M+H).sup.+.
Example 105
5-(4-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-methoxy-phenylamino)-1-(S)-methyl-ethylcarbamoy-
l]-ethyl}-amide;.sup.#
[0407] .sup.1NMR (CDCl.sub.3) .delta.(ppm) 8.27(m, 1H), 7.56(m,
2H), 7.30(m, 3H), 6.99(m, 3H), 6.78(m, 2H), 6.51(d, J=3.2, 1H),
4.26(m, 1H), 3.68(m, 1H), 3.63(s, 3H), 3.60(m, 1H), 3.21(m, 1H),
1.59(m, 7H), 1.24(m, 4H), 1.05(m, 3H), 0.82(m, 2H); LCMS: 522.2
(M+H).sup.+.
Example 106
5-(4-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(3-methanesulfonyl-phenylamino)-1-(S)-methyl-ethyl-
carbamoyl]-ethyl}-amide;.sup.#
[0408] C.sub.30H.sub.36FN.sub.3O.sub.5S; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.61(m, 2H), 7.20(m, 1H), 7.06(m, 5H), 6.79(M, 3H),
6.60(d, J=3.2 Hz, 1H), 4.58(m, 1H), 4.17(m, 1H), 3.15(m, 2H),
2.95(s, 3H), 1.60(m, 7H), 1.27(m, 1H), 1.15(d, J=6.8 Hz, 3H),
1.00(m, 3H), 0.82(m, 2H); LCMS: 570.5 (M+H).sup.+.
Example 107
5-(4-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-methanesulfonyl-phenylamino)-1-(S)-methyl-ethyl-
carbamoyl]-ethyl}-amide;.sup.#
[0409] C.sub.30H.sub.36FN.sub.3O.sub.5S; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.62(m, 4H), 7.08(m, 3H), 6.61(m, 2H), 6.55(m, 3H),
4.57(m, 1H), 4.19(m, 1H), 3.15(m, 2H), 2.91(s, 3H), 1.63(m, 7H),
1.28(m, 1H), 1.76(d, J=6.8 Hz, 3H), 1.04(m, 3H), 0.85(m, 2H); LCMS:
570.5 (M+H).sup.+.
Example 108
3-(3-Fluoro-phenyl)-[1,2,4]oxadiazole-5-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide;*
[0410] C.sub.28H.sub.31F.sub.4N.sub.5O.sub.4; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.82(d, J=8.0 Hz, 1H), 7.72(m, 2H),
7.39(m, 1H), 7.15(m, 4H), 6.99(m, 2H), 4.52(m, 1H), 4.21(m, 1H),
3.40(m, 1H), 3.22(m, 1H), 1.64(m, 7H), 1.29(m, 4H), 1.08(m, 3H),
0.89(m, 2H); LCMS: 578.5 (M+H).sup.+.
Example 109
3-(4-Fluoro-phenyl)-[1,2,4]oxadiazole-5-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide;*
[0411] .sup.1H NMR (CDCl.sub.3) .delta.(ppm) 8.04(m, 2H), 7.65(d,
J=8.0 Hz, 1H), 7.08(m, 4H), 6.75(d, J=8.0 Hz, 2H), 6.62(m, 1H),
4.55(m, 1H), 4.20(m, 1H), 3.21(m, 2H), 1.63(m, 7H),1.23(m, 4H),
1.05(m, 3H), 0.85(m, 2H); LCMS: 578.5 (M+H).sup.+.
Example 110
3-[2-(S)-(3-Cyclohexyl-2-(S)-{[5-(3-fluoro-phenyl)-furan-2-carbonyl]-amino-
}-propionylamino)-propylamino]-benzoic acid methyl ester;.sup.#
[0412] C.sub.31H.sub.36FN.sub.3O.sub.5; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.80(m, 2H), 7.44(m, 1H), 7.33(m, 2H), 7.13(m, 1H),
6.99(m, 2H), 6.69(m, 1H), 6.55(m, 3H), 4.55(m, 1H), 4.20(m, 1H),
3.78(s, 3H), 3.21(m, 2H), 1.56(m, 7H), 1.27(m, 1H), 1.20(d, J=6.8
Hz, 3H), 1.04(m, 3H), 0.84(m, 2H); LCMS: 550.4(M+H).sup.+.
Example 111
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(3-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide;.sup.#
[0413] C.sub.30H.sub.33F.sub.4N.sub.3O.sub.4; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.44(m, 1H), 7.34(m, 2H), 7.12(m, 2H),
6.98(m, 2H), 6.69(m, 2H), 6.57(m, 2H), 6.48(s, 1H), 4.53(m, 1H),
4.19(m, 1H), 1.61(m, 7H), 1.24(m, 1H), 1.21 (d, J=6.8 Hz, 3H),
1.04(m, 3H), 0.88(m, 2H); LCMS: 576.4(M+H).sup.+.
Example 112
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(2-chloro-5-fluoro-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2--
cyclohexyl-ethyl}-amide;.sup.#
[0414] C.sub.29H.sub.32ClF.sub.2N.sub.3O.sub.3; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.45(m, 1H), 7.35(m, 2H), 7.09(m, 3H),
6.99(m, 1H), 6.69(m, 1H), 6.56(m, 1H), 6.34(m, 1H), 6.26(m, 1H),
4.62(m, 1H), 4.25(m, 1H), 3.12(m, 2H), 1.63(m, 7H), 1.25(m, 1H),
1.20(d, J=6.8 Hz, 3H), 1.03(m, 3H), 0.85(m, 2H); LCMS:
544.3(M+H).sup.+.
Example 113
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(2-chloro-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cyclohexy-
l-ethyl}-amide;.sup.#
[0415] C.sub.29H.sub.33ClFN.sub.3O.sub.3; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.47(m, 1H), 7.32(m, 3H), 7.17(m, 1H), 7.16(m, 1H),
7.14(m, 1H), 6.96(m, 1H), 6.68(m, 3H), 6.59(m, 1H), 4.63(m, 1H),
4.25(m, 1H), 3.20(d, J=6.4 Hz, 2H), 1.60(m, 7H), 1.26(m, 1H),
1.20(d, J=6.8 Hz, 3H), 1.03(m, 3H), 0.86(m, 2H); LCMS:
526.3(M+H).sup.+.
Example 114
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-methoxy-2,6-dimethyl-phenylamino)-1-(S)-methyl--
ethylcarbamoyl]-ethyl}-amide;.sup.#
[0416] C.sub.32H.sub.40FN.sub.3O.sub.4; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 9.09(s, 1H), 7.41(m, 1H), 7.32(m, 2H), 7.01(m, 3H),
6.64(m, 1H), 6.55(s, 2H), 4.27(m, 2H), 3.71(s, 3H), 3.37(m, 2H),
2.40(s, 6H), 1.76(m, 7H), 1.38(m, 4H), 1.20(m, 3H), 0.81(m, 2H);
LCMS: 550.4(M+H).sup.+.
Example 115
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-methoxy-3,5-dimethyl-phenylamino)-1-(S)-methyl--
ethylcarbamoyl]-ethyl}-amide;.sup.#
[0417] C.sub.32H.sub.40FN.sub.3O.sub.4; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.41(m, 1H), 7.32(m, 3H), 7.11(m, 1H), 7.06(s, 2H),
6.99(m, 2H), 6.65(m, 1H), 4.30(m, 1H), 4.16(m, 1H), 3.68(m, 1H),
3.64(s, 3H), 3.30(m, 1H), 2.20(s, 6H), 1.67(m, 7H), 1.33(m, 4H),
1.17(m, 3H), 0.91(m, 2H); LCMS: 550.4(M+H).sup.+.
Example 116
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(2-methanesulfonyl-phenylamino)-1-(S)-methyl-ethyl-
carbamoyl]-ethyl}-amide;.sup.#
[0418] C.sub.30H.sub.36FN.sub.3O.sub.5S; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.68(m, 1H), 7.49(M, 1H), 7.38(m, 4H), 7.15(d,
J=3.6Hz, 1H), 6.99(m, 1H), 6.84(d, J=8.4 Hz, 1H), 6.71(m, 3H),
4.65(m, 1H), 4.20(m, 1H), 3.31(m, 1H): 3.17(m, 1H), 2.97(s, 3H),
1.63(7H), 1.31(m, 1H), 1.20(d, J=6.8 Hz, 3H), 1.08(m, 3H), 0.91(m,
2H); LCMS: 570.3(M+H).sup.+.
Example 117
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-methylsulfanyl-phenylamino)-ethylc-
arbamoyl]-ethyl}-amide;.sup.#
[0419] C.sub.30H.sub.36FN.sub.3O.sub.3S; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.52(m, 1H), 7.41(d, J=8.0 Hz, 1H), 7.33(m, 2H),
7.17(s, 2H), 7.05(m, 5H), 6.66(d, J=3.6 Hz, 1H), 4.39(m, 1H),
4.16(m, 1H), 3.45(m, 1H), 3.22(m, 1H), 2.38(s, 3H), 1.66(m, 7H),
1.32(m, 1H), 1.27(d, J=7.2 Hz, 3H), 1.09(m, 3H), 0.89(m, 2H); LCMS:
538.4(M+H).sup.+.
Example 118
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-methylsulfamoyl-phenylamino)-ethyl-
carbamoyl]-ethyl}-amide;.sup.#
[0420] C.sub.30H.sub.37FN.sub.4O.sub.5S; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.54(m, 2H), 7.44(m, 2H), 7.34(m, 2H), 7.13(m, 1H),
6.96(m, 2H), 6.69(m, 2H), 6.53(m, 2H), 4.59(m, 1H), 4.19(m, 1H),
3.16(m, 2H), 2.53(s, 3H), 1.60(m, 7H), 1.28(m, 1H), 1.19(d, J=7.2
Hz, 3H), 1.02(m, 3H), 0.86(m, 2H); LCMS: 585.3 (M+H).sup.+.
Example 119
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethylsulfanyl-phenylamin-
o)-ethylcarbamoyl]-ethyl}-amide;.sup.#
[0421] C.sub.30H.sub.33F.sub.4N.sub.3O.sub.3S; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.46(m, 1H), 7.37(m, 4H), 7.12(d, J=3.6
Hz, 1H), 7.03(m, 2H), 6.69(d, J=3.6 Hz, 1H), 6.63(m, 3H), 4.58(m,
1H), 4.19(m, 1H), 3.19(m, 2H), 1.55(m, 7H), 1.27(m, 1H), 1.20(d,
J=6.8 Hz, 3H), 1.02(m, 3H), 0.84(m, 2H); LCMS: 592.3
(M+H).sup.+.
Example 120
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(3-dimethylcarbamoyl-phenylamino)-1-(S)-methyl-eth-
ylcarbamoyl]-ethyl}-amide;.sup.#
[0422] C.sub.32H.sub.39FN.sub.4O.sub.4; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.43(m, 1H), 7.32(m, 2H), 7.16(m, 1H), 7.10(m, 3H),
6.98(m, 1H), 6.79(m, 2H), 6.80(d, J=7.2 Hz, 1H), 6.68(d, J=3.6 Hz,
1H), 4.46(m, 1H), 4.13(m, 1H), 3.26(m, 1H), 3.19(m, 1H), 3.04(s,
3H), 2.92(s, 3H), 1.61(m, 7H), 1.31(m, 1H), 1.21(d, J=6.8 Hz, 3H),
1.08(m, 3H), 0.88(m, 2H); LCMS: 563.4 (M+H).sup.+.
Example 121
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(2-carbamoyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cycloh-
exyl-ethyl}-amide;.sup.#
[0423] C.sub.30H.sub.35FN.sub.4O.sub.4; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.46(m, 1H), 7.31(m, 4H), 7.13(m, 2H), 6.96(m, 1H),
6.83(m, 1H), 6.69(m, 2H), 6.59(m, 2H), 6.12(s, 1H), 4.62(m, 1H),
4.19(m, 1H), 3.30(m, 1H), 3.17(m, 1H), 1.59(m, 7H), 1.31(m, 1H),
1.19(d, J=7.8 Hz, 3H), 1.06(m, 3H), 0.84(m, 2H); LCMS: 535.4
(M+H).sup.+.
Example 122
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-dimethylcarbamoyl-phenylamino)-1-(S)-methyl-eth-
ylcarbamoyl]-ethyl}-amide;.sup.#
[0424] C.sub.32H.sub.39FN.sub.4O.sub.4; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.44(d, J=8.0 Hz, 1H), 7.34(m, 2H), 7.25(d, J=8.8 Hz,
2H), 7.12(d, J=3.6 Hz, 1H), 6.96(m, 2H), 6.79(m, 1H), 6.67(m, 3H),
4.53(m, 1H), 4.16(m, 1H), 3.18(m, 2H), 3.01(s, 6H), 1.63(m, 7H),
1.30(m, 1H), 1.20(d, J=6.8 Hz, 3H), 1.06(m, 3H), 0.88(m, 2H); LCMS:
563.4 (M+H).sup.+.
Example 123
3-Cyclohexyl-2-(S)-(3-methoxy-propionylamino)-N-[1-(S)-methyl-2-(4-trifluo-
romethoxy-phenylamino)-ethyl]-propionamide*
[0425] C.sub.23H.sub.34F.sub.3N.sub.3O.sub.4; LCMS: 474.5
(M+H).sup.+.
Example 124
3-Cyclohexyl-2-(S)-(2-methoxy-acetylamino)-N-[1-(S)-methyl-2-(4-trifluorom-
ethoxy-phenylamino)-ethyl]-propionamide*
[0426] C.sub.22H.sub.32F.sub.3N.sub.3O.sub.4; LCMS: 460.5
(M+H).sup.+.
Example 125
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-hydroxy-phenylamino)-1-(S)-methyl-ethylcarbamoy-
l]-ethyl}-amide..sup.#
[0427] C.sub.29H.sub.34FN.sub.3O.sub.4; LCMS: 508.4
(M+H).sup.+.
Example 126
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(4-fluoro-phenylamino)-1-(S)-methyl-ethylcarbamoyl-
]-ethyl}-amide;.sup.#
[0428] C.sub.29H.sub.33F.sub.2N.sub.3O.sub.3; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 8.14(d, J=7.2, 1H), 7.41(m, 3H), 7.32(m,
2H), 7.08(m, 3H), 6.99(m, 2H), 6.65(d, J=3.6 Hz, 1H), 4.30(m, 1H),
4.13(m, 1H), 3.71(m, 1H), 3.31(m, 1H), 1.67(m, 7H), 1.40(m, 1H),
1.32(d, J=6.8 Hz, 3H), 1.14(m, 3H), 0.91(m, 2H); LCMS: 510.4
(M+H).sup.+.
Example 127
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{3,3-dimethyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-butyl}-amide;.sup.#
[0429] C.sub.28H.sub.31F.sub.4N.sub.3O.sub.4; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.40(m, 1H), 7.32(m, 2H), 7.07(m, 5H),
6.86(m, 3H), 6.68(d, J=3.6 Hz, 1H), 4.44(m, 1H), 4.14(m, 1H),
3.31(m, 1H), 3.18(m, 1H), 1.91(m, 1H), 1.63(m, 1H), 1.22(d, J=6.8
Hz, 3H), 0.94(s, 9H); LCMS: 550.4 (M+H).sup.+.
Example 128
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(4-difluoromethoxy-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-3,-
3-dimethyl-butyl}-amide;.sup.#
[0430] C.sub.28H.sub.32F.sub.3N.sub.3O.sub.4; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.38(m, 1H), 7.31(m, 3H), 7.05(m, 1H),
6.99(m, 5H), 6.89(m, 1H), 6.68(m, 1H), 6.37(t, J=74 Hz, 1H),
4.41(m, 1H), 4.12(m, 1H), 3.39(m, 1H), 3.20(m, 1H), 1.92(m, 1H),
1.65(m, 1H), 1.25(d, J=6.8 Hz, 3H), 0.95(s, 9H); LCMS:
532.4(M+H).sup.+.
Example 129
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(4-methanesulfonyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-3,-
3-dimethyl-butyl}-amide;.sup.#
[0431] C.sub.28H.sub.34FN.sub.3O.sub.5S; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.61(m, 2H), 7.46(m, 1H), 7.34(m, 2H), 7.17(m, 2H),
6.99(m, 1H), 6.76(m, 1H), 6.72(d, J=3.6 Hz, 1H), 6.56(d, 8.0 Hz,
2H), 4.56(m, 1H), 4.16(m, 1H), 3.19(d, 8.0 Hz, 2H), 2.93(s, 3H),
1.89(m, 1H), 1.60(m, 1H), 1.20(d, J=6.8 Hz, 3H), 0.90(s, 9H); LCMS:
544.3 (M+H).sup.+.
Example 130
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-methanesulfonyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-3,-
3-dimethyl-butyl}-amide;.sup.#
[0432] C.sub.28H.sub.34FN.sub.3O.sub.5S; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.50(m, H), 7.29(m, 4H), 7.17(m, 2H), 7.12(m, 1H),
6.99(m, 2H), 6.87(m, 1H), 6.71(m, 1H), 4.55(m, 1H), 4.15(m, 1H),
3.22(m, 2H), 2.98(s, 3H), 1.84(m, 1H), 1.62(m, 1H), 1.21(d, J=6.8
Hz, 3H), 0.90(s, 9H); LCMS: 544.3(M+H).sup.+.
Example 131
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-carbamoyl-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-3,3-dime-
thyl-butyl}-amide;.sup.#
[0433] C.sub.28H.sub.33FN.sub.4O.sub.4; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.67(s, 1H), 7.61(m, 1H), 7.48(m, 1H), 7.40(m, 1H),
7.33(m, 3H), 7.14(m, 4H), 6.99(m, 1H), 6.68(d, J=3.6 Hz, 1H),
4.44(m, 1H), 4.21(m, 1H), 3.51(m, 1H), 3.18(m, 1H), 1.87(m, 1H),
1.67(m, 1H), 1.22(d, J=8.0 Hz, 3H), 0.99(s, 9H); LCMS:
509.4(M+H).sup.+.
Example 132
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(4-methoxy-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-3,3-dimeth-
yl-butyl}-amide;.sup.#
[0434] C.sub.28H.sub.34FN.sub.3O.sub.4; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 8.33(m, 1H), 7.37(m, 5H), 7.04(m, 1H), 6.99(m, 2H),
6.87(m, 2H), 6.63(d, J=3.6 Hz, 1H), 4.28(m, 1H), 4.17(m, 1H),
3.75(s, 3H), 3.63(m, 1H), 3.29(m, 1H), 1.88(m, 1H), 1.72(m, 1H),
1.31(d, J=8.0 Hz, 3H), 0.99(s, 9H); LCMS: 496.4(M+H).sup.+.
Example 133
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(5-methyl-isoxazol-3-ylamino)-ethylca-
rbamoyl]-ethyl}-amide;.sup.#
[0435] C.sub.27H.sub.33FN.sub.4O.sub.4; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.47(m, 1H), 7.44(m, 2H), 7.14(m, 1H), 6.93(m, 2H),
6.80(m, 1H), 6.69(m, 1H), 5.51(s, 1H), 4.57(m, 1H), 4.09(m, 1H),
3.23(m, 2H), 2.20(s, 3H), 1.73(m, 1H), 1.58(m, 6H), 1.30(m, 1H),
1.16(m, 6H), 0.86(m, 2H); LCMS: 497.5(M+H).sup.+.
Example 134
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(3-acetylamino-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cycl-
ohexyl-ethyl}-amide;.sup.#
[0436] C.sub.31H.sub.37FN.sub.4O.sub.4; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.92(s, 1H), 7.61(m, 1H), 7.31(m, 5H), 7.10(m, 3H),
6.98(m, 1H), 6.82(m, 1H), 6.66(d, J=3.6 Hz, 1H), 4.43(m, 1H),
4.12(m, 1H), 3.48(m, 1H), 3.25(m, 1H), 2.08(s, 3H), 1.58(m, 7H),
1.36(m, 1H), 1.14(m, 6H), 0.89(m, 2H); LCMS: 549.5 (M+H).sup.+.
Example 135
Tetrahydropyran-4-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide*
[0437] C.sub.25H.sub.36F.sub.3N.sub.3O.sub.4; LCMS: 500.4
(M+H).sup.+.
Example 136
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
(2-cyclohexyl-1-(S)-{1-(S)-methyl-2-[4-(morpholine-4-sulfonyl)-phenylamin-
o]-ethylcarbamoyl}-ethyl)-amide;.sup.#
[0438] C.sub.33H.sub.41FN.sub.4O.sub.6S; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.48(m, 3H), 7.35(m, 3H), 7.16(d, J=3.6 Hz, 1H),
7.00(m, 1H), 6.78(m, 1H), 6.72(d, J=3.6Hz, 1H), 6.58(m, 2H),
4.60(m, 1H), 4.21(m, 1H), 3.67(m, 4H), 3.19(d, J=6.4 Hz, 2H),
2.89(m, 4H), 1.63(m, 7H), 1.28(m, 1H), 1.22(d, J=6.8 Hz, 3H),
1.03(m, 3H), 0.87(m, 2H); LCMS: 641.5 (M+H).sup.+.
Example 137
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(3-oxo-1,3-dihydro-isobenzofuran-5-yl-
amino)-ethylcarbamoyl]-ethyl}-amide;.sup.#
[0439] C.sub.31H.sub.34FN.sub.3O.sub.5; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.45(m, 1H), 7.35(m, 2H), 7.22(m, 2H), 7.15(d, J=4.0
Hz, 1H), 7.10(m, 1H), 7.02(m, 2H), 6.93(m, 1H), 6.71(d, J=4.0 Hz,
1H), 5.15(s, 2H), 4.56(m, 1H), 4.20(m, 1H), 3.24(m, 2H), 1.59(m,
7H), 1.29(m, 1H), 1.22(d, J=6.8Hz, 3H), 1.04(m, 3H), 0.85(m, 2H);
LCMS: 548.5(M+H).sup.+.
Example 138
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-sulfamoyl-phenylamino)-ethylcarbam-
oyl]-ethyl}-amide;.sup.#
[0440] C.sub.29H.sub.35FN.sub.4O.sub.5S; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 7.60(m, 3H), 7.50(m, 1H), 7.39(m, 1H), 7.32(m, 1H),
7.16(m, 2H), 6.98(m, 1H), 6.70(d, J=3.6 Hz, 1H), 6.54(d, J=8.8 Hz,
2H), 4.64(m, 1H), 4.17(m, 1H), 3.20(m, 2H), 1.24(m, 7H), 1.22(m,
4H), 1.02(m, 3H), 0.84(m, 2H); 571.5(M+H).sup.+.
Example 139
Tetrahydropyran-4-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,2-dimethyl-2,3-dihydro-indol-1-yl)-1-(-
S)-methyl-ethylcarbamoyl]-ethyl}-amide..sup.$
[0441] C.sub.28H.sub.42FN.sub.3O.sub.3; LCMS: 488.5
(M+H).sup.+.
Example 140
Tetrahydrofuran-3-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,2-dimethyl-2,3-dihydro-indol-1-yl)-1-(-
S)-methyl-ethylcarbamoyl]-ethyl}-amide..sup.$
[0442] C.sub.27H.sub.40FN.sub.3O.sub.3; LCMS: 474.5
(M+H).sup.+.
Example 141
1-(3-Fluoro-phenyl)-1H-pyrazole-4-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide
[0443] The title compound was prepared following the procedures
described in example 181, except in step E, HATU mediated amide
coupling with 1-(3-Fluoro-phenyl)-1H-pyrazole-4-carboxylic acid was
conducted. C.sub.29H.sub.33F.sub.4N.sub.5O.sub.3; .sup.1H NMR
(CD.sub.3OD) .delta.(ppm) 8.67(s, 1H), 8.05(s, 1H), 7.52(m, 2H),
7.43(m, 1H), 7.03(m, 1H), 6.87(d, J=8.8 Hz, 2H), 7.52(m, 2H),
7.43(m, 1H), 4.05(m, 1H), 3.05(m, 2H), 1.58(m, 7H), 1.32(m, 1H),
1.10(m, 6H), 0.84(m, 2H); LCMS: 576.5 (M+H).sup.+.
Example 142
1-(4-Fluoro-phenyl)-1H-pyrazole-4-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide;.sup.$
[0444] C.sub.29H.sub.33F.sub.4N.sub.5O.sub.3; .sup.1H NMR
(CD.sub.3OD) .delta.(ppm) 8.56(s, 1H), 8.04(s, 1H), 7.68(m, 2H),
7.17(m, 2H), 6.88(d, J=8.8 Hz, 2H), 6.57(m, 2H), 4.47(m, 1H),
4.04(m, 1H), 3.05(m, 2H), 1.57(m, 7H), 1.30(m, 1H), 1.08(m, 6H),
0.85(m, 2H); LCMS: 576.5 (M+H).sup.+.
Example 143
5-Pyridin-3-yl-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide;.sup.$
[0445] C.sub.29H.sub.33F.sub.3N.sub.4O.sub.4; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 9.18(s, 1H), 8.58(d, J=4.8Hz, 1H),
8.42(d, J=4.0 Hz, 1H), 7.71(m, 1H), 7.61(d, J=7.2 Hz, 1H), 7.32(d,
J=7.6 Hz, 1H), 7.13(d, J=3.6 Hz, 1H), 7.04(m, 2H), 6.92(m, 3H),
4.52(m, 1H), 4.20(m, 1H), 3.33(m, 1H), 3.19(m, 1H), 1.66(m, 7H),
1.30(m, 1H), 1.22(d, J=6.8 Hz, 3H), 1.07(m, 3H), 0.87(m, 2H); LCMS:
559.5(M+H).sup.+.
Example 144
5-(1-Oxy-pyridin-3-yl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide;.sup.$
[0446] C.sub.29H.sub.33F.sub.3N.sub.4O.sub.5; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 9.27(s, 1H), 8.26(d, J=6.4 Hz, 1H),
7.81(d, J=8.0 Hz, 1H), 7.48(m, 1H), 7.34(m, 1H), 7.13(d, J=3.6 Hz,
1H), 6.98(m, 2H), 6.89(d, J=4.0 Hz, 1H), 6.71(m, 3H), 4.50(m, 1H),
4.17(m, 1H), 3.18(m, 2H), 1.65(m, 7H), 1.30(m, 1H), 1.21(d, J=6.8
Hz, 3H), 1.06(m, 3H), 0.86(m, 2H); LCMS: 575.5(M+H).sup.+.
Example 145
3-(3-Fluoro-phenyl)-isoxazole-5-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide;.sup.$
[0447] C.sub.29H.sub.32F.sub.4N.sub.4O.sub.4; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.48(m, 3H), 7.14(m, 2H), 7.10(s, 1H),
7.06(m, 2H), 6.83(m, 2H), 6.76(m, 1H), 4.46(m, 1H), 4.19(m, 1H),
3.30(m, 1H), 3.19(m, 1H), 1.65(m, 7H), 1.33(m, 1H), 1.24(d, J=6.8
Hz, 3H), 1.09(m, 3H), 0.89(m, 2H); LCMS: 577.5 (M+H).sup.+.
Example 146
3-(4-Fluoro-phenyl)-isoxazole-5-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide;.sup.$
[0448] C.sub.29H.sub.32F.sub.4N.sub.4O.sub.4; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.72(m, 2H), 7.08(m, 6H), 6.95(m, 3H),
4.44(m, 1H), 4.19(m, 1H), 3.36(m, 1H), 3.21(m, 1H), 1.65(m, 7H),
1.33(m, 1H), 1.25(d, J=6.8 Hz, 3H), 1.11(m, 3H), 0.89(m, 2H); LCMS:
577.5 (M+H).sup.+.
Example 147
5-(3-Fluoro-phenyl)-[1,3,4]oxadiazole-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide;.sup.$
[0449] C.sub.28H.sub.31F.sub.4N.sub.5O.sub.4; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.83(d, J=8.0 Hz, 1H), 7.76(m, 2H),
7.44(m, 2H), 7.07(m, 2H), 6.90(m, 3H), 4.51(m, 1H), 4.19(m, 1H),
3.33(m, 1H), 3.20(m, 1H), 1.66(m, 7H), 1.33(m, 1H), 1.23(d, J=6.8
Hz, 3H), 1.07(m, 3H), 0.90(m, 2H); LCMS: 578.5 (M+H).sup.+.
Example 148
N-{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-
-ethyl}-2-(R)-phenyl-butyramide;*
[0450] C.sub.28H.sub.31F.sub.4N.sub.5O.sub.4; .sup.1H NMR
(CH.sub.3CD) .delta.(ppm) 7.24(m, 2H), 7.16(m, 2H), 7.10(m, 1H),
6.68(m, 1H), 6.59(m, 1H), 6.24(m, 1H), 4.31(m, 1H), 3.34(m, 1H),
3.14(m, 4H), 2.88(m, 2H), 2.74(m, 2H), 1.91(m, 1H), 1.62(m, 7H),
1.42(m, 2H), 1.22(m, 1H), 1.07(m, 3H), 0.81(m, 5H); LCMS: 480.6
(M+H).sup.+.
Example 149
N-{1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylc-
arbamoyl]-2-cyclohexyl-ethyl}-3-methoxy-benzamide
[0451] Step A: Following the procedures of Example 22, except using
N-Boc-OBn-serinol, 5-fluoroindoline (1 eq) and
Boc-cyclohexylalanine as starting materials,
{1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)
-ethylcarbamoyl]-2-cyclohexyl-ethyl}-carbamic acid tert-butyl ester
was prepared in 40% overall yield.
[0452] Step B: A sample of
{1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylca-
rbamoyl]-2-cyclohexyl-ethyl}-carbamic acid tert-butyl ester (210
mg, 0.34 mmol) was treated with a mixture of trifluoroacetic acid,
dichloromethane and water (45:45:10) and allowed to age for 2
hours. The solvent was then removed by rotary evaporation. The
resulting oil was treated with m-anisic acid (75 mg, 0.49 mmol),
HATU (187 mg, 0.49 mmol) and dichloromethane (2 mL). The reaction
was then treated with diisopropylethylamine (245 mg, 1.9 mmol) and
stirred for 2 hours. The reaction was diluted with ethyl acetate,
extracted with saturated aqueous NaHCO.sub.3 twice, dried over
MgSO.sub.4 and the solvent was removed. The resulting oil was
purified over silica gel using a gradient of 0 to 100% ethyl
acetate in hexane to afford 195 mg (87%) of the title material;
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.84-1.03 (m, 2H),
1.06-1.22 (m, 3H), 1.32-1.45 (m, 1H), 1.58-1.87 (m, 7H), 2.92 (dd,
1H, J.sub.1=J.sub.2=8.2), 3.13-3.25 (m, 2H), 3.31-3.46 (m, 2H),
3.54 (dd, 1H, J.sub.1=54.2, J.sub.2=9.4), 3.68 (dd, 1H,
J.sub.1=2.4, J.sub.2=9.3), 3.84 (s, 3H), 4.26-4.36 (m, 1H), 4.53
(dd, 2H, J.sub.1=11.8, J.sub.2=26.0), 4.65-4.74 (m, 1H), 6.46 (dd,
1H, J.sub.1=4.1, J.sub.2=8.4), 6.46 (d, 1H, J=8.3), 6.69-6.83 (m,
2H), 7.02-7.09 (m, 1H), 7.27-7.39 (m, 7H); HPLC-MS calcd. for
C.sub.35H.sub.42FN.sub.3O.sub.4 (M+H.sup.+) 587.3, found 587.5.
Example 150
N-{2-Cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(R)-hydroxyme-
thyl-ethylcarbamoyl]-ethyl}-3-methoxy-benzamide
[0453] This material was prepared in 71% yield using an identical
procedure to example 40; .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
0.70-0.85 (m, 2H), 0.93-1.07 (m, 3H), 1.22-1.35 (m, 1H), 1.44-1.68
(m, 7H), 2.72-2.88 (m, 2H), 2.96 (dd, 1H, J.sub.1=6.9,
J.sub.2=13.5), 3.10 (dd, 1H, J.sub.1=7.5, J.sub.2=13.5), 3.20 (q,
1H, J=8.6), 3.32-3.41 (m, 1H), 3.58 (dd, 2H, J.sub.1=4.9,
J.sub.2=11.4), 3.65-3.74 (m, 1H), 3.71 (s, 3H), 4.09-4.19 (m, 1H),
4.52-4.60 (m, 1H), 6.23 (dd, 1H, J.sub.1=4.2, J.sub.2=8.6), 6.56
(ddd, 1H, J.sub.1=2.6, J.sub.2=J.sub.3=9.0), 6.66-6.71 (m, 1H),
6.92-6.97 (m, 1H), 7.08 (d, 1H, J=7.8), 7.16-7.25 (m, 3H), 7.31 (d,
1H, J=8.2); HPLC-MS calcd. for C.sub.28H.sub.36FN.sub.3O.sub.4
(M+H.sup.+) 498.3, found 498.5.
Example 151
N-{2-Cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(S)-morpholin-
-4-ylmethyl-ethylcarbamoyl]-ethyl}-3-methoxy-benzamide
[0454] A solution of the title compound of example 150 (21 mg, 43
.mu.mol) in dichloromethane (1 mL) was treated with triethylamine
(43 mg, 0.43 mmol) and cooled in an ice/water bath. The reaction
mixture was then treated with methanesulfonyl chloride (9.8 mg, 85
.mu.mol) and stirred for 1 hour. The reaction was then treated with
saturated aqueous NaHCO.sub.3 (2 mL) and stirred for 1 hour. The
aqueous phase was extracted a total of 3 times with dichloromethane
and the combined organic layers were dried over MgSO.sub.4 and the
solvent was removed. The resulting oil was dissolved in morpholine
(2 mL) and heated 55.degree. C. for 1 hour. The solvent was removed
and the reaction was dissolved in ethyl acetate and extracted twice
with 1 M aqueous NaOH. The organics were dried over MgSO.sub.4 and
the solvent was removed. The resulting oil was purified over silica
gel using a gradient of 0-100% ethyl acetate in hexane with a 10
minute elution using pure ethyl acetate afterward to afford 4.2 mg
(17%) of the title material as an oil; .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 0.82-1.06 (m, 2H), 1.12-1.31 (m, 4H), 1.31-1.43 (m,
1H), 1.59-1.86 (m, 8H), 2.31-2.60 (m, 8H), 2.90-2.99 (m, 2H), 3.14
(dd, 1H, J.sub.1=5.8, J.sub.2=13.9), 3.27 (dd, 1H, J.sub.1=5.0,
J.sub.2=14.0), 3.37 (dd, 1H, J.sub.1=8.5, J.sub.2=17.1), 3.48 (dd,
1H, J.sub.1=8.1, J.sub.2=16.3), 3.58-3.78 (m, 2H), 3.71 (dd, 1H,
J.sub.1=J.sub.2=4.6), 4.21-4.30 (m, 1H), 4.61-4.71 (m, 1H), 6.15
(dd, 1H, J.sub.1=4.2, J.sub.2=8.4), 6.46-6.60 (m, 1H), 6.72-6.78
(m, 1H), 6.78-6.82 (m, 1H), 7.05-7.10 (m, 1H), 7.27-7.38 (m, 3H);
HPLC-MS calcd. for C.sub.32H.sub.43FN.sub.4O.sub.4 (M+H.sup.+)
567.3, found 567.5.
Example 152
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid
{1-(S)-[1-(R)-benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylca-
rbamoyl]-2-cyclohexyl-ethyl}-amide
[0455] This material was prepared in 92% yield from
{1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylca-
rbamoyl]-2-cyclohexyl-ethyl}-carbamic acid tert-butyl ester
(example 149, step A) using a protocol analogous to example 149,
step B; HPLC-MS calcd. for C.sub.39H.sub.41F.sub.4N.sub.3O.sub.4
(M+H.sup.+) 692.3, found 692.4.
Example 153
5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(R)-hydroxymet-
hyl-ethylcarbamoyl]-ethyl}-amide
[0456] This material was prepared in 71% yield using an identical
procedure to example 40; HPLC-MS calcd. for
C.sub.32H.sub.35F.sub.4N.sub.3O.sub.4 (M+H.sup.+) 602.3, found
602.4.
Example 154
{1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcar-
bamoyl]-3,3-dimethyl-butyl}-carbamic acid tert-butyl ester
[0457] Following the procedures of example 22, except using
N-Boc-OBn-serinol, 5-fluoroindoline and Boc-cyclohexylalanine as
starting materials, the title compound was prepared in 40% overall
yield; .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.93 (s, 9H),
1.29-1.38 (m, 1H), 1.41 (s, 9H), 1.86 (dd, 1H, J.sub.1=3.7,
J.sub.2=14.5), 2.90 (dd, 2H, J.sub.1=J.sub.2=8.3), 3.14 (d, 2H,
J=7.1), 3.35 (dd, 2H, J.sub.1=J.sub.2=8.4), 3.50 (dd, .sup.1H,
J.sub.1=4.3, J.sub.2=9.3), 3.68 (dd, 1H, J.sub.1=2.8, J.sub.2=9.3),
4.05-4.13 (m, 1H), 4.18-4.27 (m, 1H), 4.53 (dd, 2H, J.sub.1=11.9,
J.sub.2=24.4), 4.73-4.79 (m, 1H), 6.45 (dd, 1H, J.sub.1=4.2,
J.sub.2=8.5), 6.53 (d, 1H, J=8.4), 6.68-6.74 (m, 1H), 6.75-6.79 (m,
1H), 7.28-7.39 (m, 5H); HPLC-MS calcd. for
C.sub.30H.sub.42FN.sub.3O.sub.4 (M+H.sup.+) 528.3, found 528.6.
Example 155
N-{1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylc-
arbamoyl]-3,3-dimethyl-butyl}-3-methoxy-benzamide
[0458] This material was prepared in an analogous fashion to
example 149, step B in 95% yield; .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 0.96 (s, 9H), 1.62 (dd, 1H, J.sub.1=8.5, J.sub.2=14.5),
1.90 (dd, 1H, J.sub.1=4.1, J.sub.2=14.5), 2.88 (dd, 1H,
J.sub.1=J.sub.2=8.3), 3.15-3.18 (m, 1H), 3.28-3.41 (m, 2H), 3.48
(dd, 1H, J.sub.1=4.4, J.sub.2=9.4), 3.64 (dd, 1H, J.sub.1=3.1,
J.sub.2=9.4), 3.79 (s, 3H), 4.19-4.30 (m, 1H), 4.49 (dd, 1H,
J.sub.1=11.8, J.sub.2=28.9), 4.68 (ddd, 1H, J.sub.1=4.1,
J.sub.2=8.5, J.sub.3=12.5), 6.43 (dd, 1H, J.sub.1=4.2, 4.2,
J.sub.2=8.5), 6.67-6.78 (m, 4H), 6.98-7.05 (m, 1H), 7.25-7.32 (m,
7H), 7.33-7.35 (m, 1H); HPLC-MS calcd. for
C.sub.33H.sub.40FN.sub.3O.sub.4 (M+H.sup.+) 562.3, found 562.5.
Example 156
N-{1-(S)-[2-(5-Fluoro-2,3-dihydro-indol-1-yl)-1-(R)-hydroxymethyl-ethylcar-
bamoyl]-3,3-dimethyl-butyl}-3-methoxy-benzamide
[0459] This material was prepared in 71% yield using an identical
procedure to example 40; .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
0.74 (s, 9H), 1.41 (dd, 1H, J.sub.1=8.3, J.sub.2=14.5), 1.70 (dd,
1H, J.sub.1=4.4, J.sub.2=14.5), 2.57-2.72 (m, 2H), 2.85 (dd, 1H,
J.sub.1=6.8, J.sub.2=13.6), 3.02 (dd, 1H, J.sub.1=7.7,
J.sub.2=13.6), 3.07 (dd, 1H, J.sub.1=8.7, J.sub.2=17.4), 3.17-3.26
(m, 1H), 3.48 (dd, 1H, J.sub.1=4.5, J.sub.2=11.4), 3.55 (dd, 1H,
J.sub.1=3.4, J.sub.2=11.4), 3.60 (s, 3H), 3.88-3.98 (m, 1H), 4.43
(ddd, 1H, J.sub.1=4.3, J.sub.2=8.1, J.sub.3=12.3), 6.16 (dd, 1H,
J.sub.1=4.1, J.sub.2=8.5), 6.41 (d, 1H, J=7.7), 6.48 (ddd, 1H,
J.sub.1=2.6, J.sub.2=J.sub.3=9.0), 6.52-6.56 (m, 1H), 6.75-6.79 (m,
1H), 6.78-6.84 (m, 1H), 6.98-7.10 (m, 3H); HPLC-MS calcd. for
C.sub.26H.sub.34FN.sub.3O.sub.4 (M+H.sup.+) 472.3, found 472.5.
Example 157
{1-(S)-[1-(S)-(5-Fluoro-2,3-dihydro-indol-1-ylmethyl)-3-methanesulfonyl-pr-
opylcarbamoyl]-3,3-dimethyl-butyl}-carbamic acid tert-butyl
ester
[0460] Step A: A solution of (L)-N-Boc-methioninol (700 mg, 3.0
mmol) in dichloromethane (20 mL) was cooled in an ice/water bath
and treated with solid 77% mCPBA (1.40 g, 6.25 mmol). After 1 hour
of stirring, an additional 300 mg of mCPBA was added and the
reaction was stirred an additional hour and was then judged to be
complete by HPLC-MS analysis. The reaction was filtered and the
solvent was removed by rotary evaporation. The residue was treated
with water (30 mL) and 5 g of Na.sub.2S.sub.2O.sub.3. The aqueous
phase was made basic with NaHCO.sub.3 and water was removed by
rotary evaporation until some salts started precipitating. The
aqueous phase was then exracted with dichloromethane 4 times and
discarded. The combined organic extracts were dried over MgSO.sub.4
and the solvent was removed to afford 795 mg (86%) of the
corresponding sulfone as a white solid; .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta. 1.38 (s, 9H), 1.89-2.11 (m, 2H), 2.52-2.67 (m,
1H), 2.88 (s, 3H), 3.08 (dd, 2H, J.sub.1=J.sub.2=8.0), 3.54-3.72
(m, 3H), 4.98 (d, 1H, J=8.4); HPLC-MS calcd. for
C.sub.10H.sub.21NO.sub.5S (M+Na.sup.+) 562.3, found 562.5.
[0461] Step B:
[1-(S)-(5-Fluoro-2,3-dihydro-indol-1-ylmethyl)-3-methanesulfonyl-propyl]--
carbamic acid tert-butyl ester was prepared in 72% yield an
analogous manner to example 22, step A, except that the sulfone
from the previous step and 1 equivalent of 5-fluoroindoline were
used as coupling partners; .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 1.56 (s, 9H), 2.01-2.16 (m, 1H), 2.32-2.43 (m, 1H), 3.06
(s, 3H), 3.07 (dd, 1H, J.sub.1=J.sub.2=4.0), 3.13-3.23 (m, 2H),
3.23-3.34 (m, 2H), 3.95-4.06 (m, 1H), 4.70-4.79 (m, 1H), 6.48 (dd,
1H, J.sub.1=4.1, J.sub.2=8.5), 6.84-6.92 (m, 1H), 6.93-6.97 (m,
1H); HPLC-MS calcd. for C.sub.18H.sub.27FN.sub.2O.sub.4S
(M+H.sup.+) 387.2, found 387.4.
[0462] Steps C and D: These transformations were performed in 76%
yield in an analogous fashion to Example 22 steps C and D; .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 0.81 (s, 9H), 0.75-0.86 (m, 1H),
1.25 (dd, 1H, J.sub.1=8.6, J.sub.2=14.4), 1.29 (s, 9H), 1.69 (dd,
1H, J.sub.1=3.5, J.sub.2=14.4), 1.84-1.96 (m, 1H), 2.09-2.22 (m,
1H), 2.82 (s, 3H), 2.78-2.87 (m, 2H), 2.94 (dd, 1H, J.sub.1=6.4,
J.sub.2=13.9), 2.97-3.08 (m, 3H), 3.20-3.33 (m, 2H), 3.86 (ddd, 1H,
J.sub.1=3.8, J.sub.2=8.1, J.sub.3=12.0), 4.06-4.15 (m, 1H),
4.59-4.67 (m, 1H), 6.17-6.25 (m, 1H), 6.25 (dd, 1H, J.sub.1=4.1,
J.sub.2=8.5), 8.58-8.66 (m, 1H), 8.67-8.71 (m, 1H); HPLC-MS calcd.
for C.sub.25H.sub.40FN.sub.3O.sub.5S (M+H.sup.+) 514.3, found
514.5.
Example 158
3-(S)-(2-(S)-Benzyloxycarbonylamino-4,4-dimethyl-pentanoylamino)-4-(5-fluo-
ro-2,3-dihydro-indol-1-yl)-butyric acid tert-butyl ester
[0463] Step A:
3-(S)-Benzyloxycarbonylamino-4-(5-fluoro-2,3-dihydro-indol-1-yl)-butyric
acid tert-butyl ester was prepared in 71% yield an analogous manner
to example 22, step A except that N-Cbz-.gamma.-O-tBu-aspartinol
and 1 equivalent of 5-Fluoroindoline were used as coupling
partners; HPLC-MS calcd. for C.sub.124H.sub.29FN.sub.2O.sub.4
(M+H.sup.+) 429.2, found 429.4.
[0464] Step B: A sample of the product of step A (1.3 g, 3.0 mmol)
was treated with 20% Pd(OH).sub.2 on carbon (260 mg) and methanol
(2 mL). The atmosphere in the reaction was exchanged for hydrogen
by sparging the solution with a long needle for 3 minutes and the
reaction was stirred under 1 atmosphere of hydrogen for 2 hours.
The atmosphere was exchanged back to nitrogen by again sparging the
solution with a long needle for 3 minutes. The reaction mixture was
filtered through celite and the solvent was removed. The resulting
oil was treated with Cbz-tBu-ala DCHA salt (1.8 g, 3.7 mmol), HATU
(1.4 g, 3.8 mmol) and DMF (2 mL). The reaction was then treated
with diisopropylethylamine (1.2 g, 9.2 mmol) and stirred overnight.
The reaction was diluted with ethyl acetate and extracted with
water twice and 1 M NaOH once. The organics were then dried over
MgSO.sub.4 and the solvent was removed. The residue was purified
over silica gel using a gradient of 0 to 100% ethyl acetate in
hexane to afford 1.3 g (77%) of the title material as a solid;
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.92 (s, 9H), 1.39 (dd,
1H, J.sub.1=5.8, J.sub.2=14.4), 1.44 (s, 9H), 1.82 (dd, 1H,
J.sub.1=3.7, J.sub.2=14.5), 2.51 (dd, 1H, J.sub.1=5.5,
J.sub.2=16.2), 2.61 (dd, 1H, J.sub.1=4.7, J.sub.2=16.3), 2.92 (dd,
1H, J.sub.1=J.sub.2=3.07 (dd, 1H, J.sub.1=7.4, J.sub.2=13.6), 3.17
(dd, 1H, J.sub.1=6.0, J.sub.2=13.8), 3.28-3.47 (m, 2H), 4.09-4.17
(m, 1H), 4.33-4.43 (m, 1H), 4.98-5.13 (m, 3H), 6.40 (dd, 1H,
J.sub.1=4.0, J.sub.2=8.4), 6.69-6.84 (m, 3H), 7.26-7.37 (m, 5H);
HPLC-MS calcd. for C.sub.31H.sub.42FN.sub.3O.sub.5 (M+H.sup.+)
556.3, found 556.5.
Example 159
3-(S)-(2-(S)-Benzyloxycarbonylamino-4,4-dimethyl-pentanoylamino)-4-(5-fluo-
ro-2,3-dihydro-indol-1-yl)-butyric acid
[0465] The title compound of example 158 (46 mg, 83 .mu.mol) was
dissolved in a mixture of TFA, dichloromethane and water in a ratio
of 45:45:10 (1 mL) and stirred overnight. The solvent was removed
and the reaction was lyophilized to afford 58.1 mg (114% of theory)
of material that likely had some water or multiple TFA salts
included; .sup.1H NMR (MeOD, 400 MHz) .delta. 0.91 (s, 9H), 1.49
(dd, 1H, J.sub.1=9.3, J.sub.2=14.4), 1.67 (dd, 1H, J.sub.1=3.1,
J.sub.2=14.5), 2.63 (d, 1H, J=6.5), 2.98 (dd, 1H,
J.sub.1=J.sub.2=8.1), 3.17 (dd, 1H, J.sub.1=5.5, J.sub.2=13.6),
3.26-3.34 (m, 1H), 3.47 (dd, 1H, J.sub.1=8.6, J.sub.2=17.3), 3.58
(dd, 1H, J.sub.1=8.4, J.sub.2=16.6), 4.13 (dd, 1H, J.sub.1=3.0,
J.sub.2=9.3), 4.46-4.55 (m, 1H), 4.98-5.11 (m, 2H), 6.68 (dd, 1H,
J.sub.1=4.1, J.sub.2=8.6), 6.77-6.84 (m, 1H), 6.86-6.91 (m, 1H),
7.24-7.33 (m, 5H); HPLC-MS calcd. for
C.sub.27H.sub.34FN.sub.3O.sub.5 (M+H.sup.+) 500.2, found 500.5.
Example 160
4-(5-Fluoro-2,3-dihydro-indol-1-yl)-3-(S)-[2-(S)-(3-methoxy-benzoylamino)--
4,4-dimethyl-pentanoylamino]-butyric acid tert-butyl ester
[0466] This material was prepared in 92% yield in an analogous
fashion to example 158 except that
3-(S)-(2-(S)-Benzyloxycarbonylamino-4,4-dimethyl-pentanoylamino)-4-(5-flu-
oro-2,3-dihydro-indol-1-yl)-butyric acid tert-butyl ester was
deprotected and m-anisic acid was used as the acid; .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 0.95 (s, 9H), 1.40 (s, 9H), 1.57 (dd,
1H, J.sub.1=8.5, J.sub.2=14.5), 1.88 (dd, 1H, J.sub.1=4.0,
J.sub.2=14.5), 2.51 (dd, 1H, J.sub.1=5.9, J.sub.2=16.3), 2.61 (dd,
1H, J.sub.1=5.1, J.sub.2=16.3), 2.81-2.96 (m, 2H), 3.07 (dd, 1H,
J.sub.1=7.4, J.sub.2=13.8), 3.22 (dd, 1H, J.sub.1=6.5,
J.sub.2=13.8), 3.34 (dd, 1H, J.sub.1=8.5, J.sub.2=17.1), 3.44 (dd,
1H, J.sub.1=8.6, J.sub.2=16.3), 3.82 (s, 3H), 4.34-4.43 (m, 1H),
4.64 (ddd, 1H, J.sub.1=4.0, J.sub.2=J.sub.3=8.5), 6.39 (dd, 1H,
J.sub.1=4.1, J.sub.2=8.5), 6.57 (d, 1H, J=8.4), 6.66-6.75 (m, 1H),
6.73-6.78 (m, 1H), 6.97 (d, 1H, J=8.5), 6.98-7.04 (m, 1H),
7.23-7.33 (m, 3H); HPLC-MS calcd. for
C.sub.31H.sub.42FN.sub.3O.sub.5 (M+H.sup.+) 556.3, found 556.5.
Example 161
3-(S)-[3-Cyclohexyl-2-(S)-(3-methoxy-benzoylamino)-propionylamino]-4-(5-fl-
uoro-2,3-dihydro-indol-1-yl)-butyric acid benzyl ester
[0467] This material was prepared in 47% yield using an identical
procedure to example 149; .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
0.66-0.87 (m, 2H), 0.94-1.07 (m, 3H), 1.13-1.27 (m, 1H), 1.37-1.69
(m, 8H), 2.55 (dd, 1H, J.sub.1=5.6, J.sub.2=16.4), 2.62 (dd, 1H,
J.sub.1=5.0, J.sub.2=16.4), 2.76 (dd, 1H, J.sub.1=J.sub.2=8.3),
2.94 (dd, 1H, J.sub.1=7.4, J.sub.2=13.7), 3.08 (dd, 1H,
J.sub.1=6.7, J.sub.2=13.7), 3.26 (dd, 1H, J.sub.1=8.4,
J.sub.2=16.5), 3.70 (s, 3H), 4.32-4.40 (m, 1H), 4.44-4.52 (m, 1H),
4.93 (s, 2H), 6.18 (dd, 1H, J=4.1, J.sub.2=8.6), 6.34 (d, 1H,
J=8.1), 6.55 (ddd, 1H, J.sub.1=2.5, J.sub.2=8.8,
J.sub.3=11.3),6.61-6.66 (m, 1H), 6.67 (d, 1H, J=8.6), 6.39 (dddd,
1H, J.sub.1=1.0, J.sub.2=2.6, J.sub.2=8.1, J.sub.2=9.1), 7.12-7.23
(m, 3H); HPLC-MS calcd. for C.sub.36H.sub.42FN.sub.3O.sub.5
(M+H.sup.+) 616.3, found 616.5.
Example 162
3-(S)-[3-Cyclohexyl-2-(S)-(3-methoxy-benzoylamino)-propionylamino]-4-(5-fl-
uoro-2,3-dihydro-indol-1-yl)-butyric acid
[0468] The title compound of example 161 (242 mg, 0.40 mmol) was
treated with 20% Pd(OH).sub.2 on carbon (50 mg) and methanol (5
mL). The atmosphere in the reaction was exchanged for hydrogen by
sparging the solution with a long needle for 3 minutes and the
reaction was stirred under 1 atmosphere of hydrogen for 2.5 hours.
The atmosphere was exchanged back to nitrogen by again sparging the
solution with a long needle for 3 minutes. The reaction was
filtered through celite and the solvent was removed to afford 150
mg (72%) of the title compound as a solid. The material was made
into the mesylate salt in quantitative yield by treating an ether
solution with stoichiometric methanesulfonic acid and the data are
given for the salt; .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.
0.90-1.04 (m, 2H), 1.16-1.32 (m, 4H), 1.35-1.46 (m, 1H), 1.62-1.84
(m, 7H), 2.64-2.71 (m, 1H), 2.69 (s, 3H), 2.81 (dd, 1H,
J.sub.1=7.4, J.sub.2=16.8), 3.44-3.51 (m, 1H), 3.80 (s, 3H),
3.82-3.94 (m, 2H), 4.09-4.18 (m, 1H), 4.47 (dd, 1H, J.sub.1=6.7,
J.sub.2=8.8), 4.51-4.60 (m, 1H), 7.05-7.13 (m, 2H), 7.18-7.23 (m,
1H), 7.28-7.34 (m, 2H), 7.34-7.37 (m, 2H); HPLC-MS calcd. for
C.sub.29H.sub.36FN.sub.3O.sub.5 (M+H.sup.+) 526.3, found 526.5.
Example 163
4-(5-Fluoro-2,3-dihydro-indol-1-yl)-3-(S)-[2-(S)-(3-methoxy-benzoylamino)--
4,4-dimethyl-pentanoylamino]-butyric acid ethyl ester
[0469] The title compound of example 218 (75 mg, 0.15 mmol) was
treated with triethylorthoformate (270 mg, 1.8 mmol), ethanol (2
mL) and camphorsulfonic acid (53 mg, 0.23 mmol) and stirred
overnight. The reaction was then diluted with ethyl acetate and
extracted with saturated aqueous NaHCO.sub.3. The organic layer was
then dried over MgSO.sub.4 and the solvent was removed. The
resulting oil was purified over silica gel using a gradient of
0-100% ethyl acetate in hexane to afford 35 mg (44%) of the title
compound as a solid; HPLC-MS calcd. for
C.sub.29H.sub.38FN.sub.3O.sub.5 (M+H.sup.+) 528.3, found 528.5.
Example 164
{1-(S)-[2-Cyano-1-(S)-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-ethylcarbamo-
yl]-3,3-dimethyl-butyl}-carbamic acid tert-butyl ester
[0470] Step A: A solution of N-Boc cyanoalanine (2 g, 9.3 mmol) in
THF (30 mL) was cooled in an ice/NaCl bath to -10.degree. C. and
treated with triethylamine (0.94 g, 9.3 mmol) followed by dropwise
addition of isobutyl chloroformate (1.35 g, 9.9 mmol). The reaction
mixture was stirred for 4 minutes at -10.degree. C. and filtered
through a coarse scintered glass funnel. Meanwhile, in another
flask, a solution of NaBH.sub.4 (0.71 g, 19 mmol) in water (10 mL)
was prepared and cooled in an ice/water bath. The filtered solution
of the mixed anhydride was added dropwise to the cold NaBH.sub.4
solution and the resulting mixture was stirred for 2 hours. The THF
was removed on the rotary evaporator and the reaction was acidified
with 5% NaHSO.sub.4 solution to pH 3 and diluted with ethyl acetate
and water. The organics were extracted twice with aqueous
NaHCO.sub.3 and dried over MgSO.sub.4. The solvent was removed to
afford 1.2 g (64%) of (S)-(2-Cyano-1-hydroxymethyl-ethyl)-carbamic
acid tert-butyl ester; .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
1.45 (s, 9H), 2.09-2.17 (m, 1H), 2.73 (d, 1H, J=6.0), 3.76 (dd, 1H,
J.sub.1=4.7, J.sub.2=10.8), 3.80-3.86 (m, 1H), 3.91-3.99 (m, 1H),
4.98-5.07 (m, 1H).
[0471] Step B:
(S)-[2-Cyano-1-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-ethyl]-carbamic
acid tert-butyl ester was prepared in 27% yield an analogous manner
to example 22 step A, except that the nitrile from the previous
step and 1 equivalent of 5-Fluoroindoline were used as coupling
partners; HPLC-MS calcd. for C.sub.17H.sub.22FN.sub.3O.sub.2
(M+H.sup.+) 320.2, found 320.4.
[0472] Steps C and D: These transformations were performed in 48%
yield in an analogous fashion to Example 22 steps C and D; HPLC-MS
calcd. for C.sub.24H.sub.35FN.sub.4O.sub.3 (M+H.sup.+) 447.3, found
447.5.
Example 165
N-{1-(S)-[2-Cyano-1-(S)-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-ethylcarba-
moyl]-3,3-dimethyl-butyl}-3-methoxy-benzamide
[0473] This material was prepared in 25% yield using an identical
procedure to example 149 step B; HPLC-MS calcd. for
C.sub.27H.sub.33FN.sub.4O.sub.3 (M+H.sup.+) 481.3, found 481.5.
Example 166
N-{1-(S)-[2-(5-Fluoro-2,3-dihydro-indol-1-yl)-1-(S)-(1H-tetrazol-5-ylmethy-
l)-ethylcarbamoyl]-3,3-dimethyl-butyl}-3-methoxy-benzamide
[0474] The title compound of example 165 (50 mg, 0.10 mmol) in THF
(1 mL) was treated with tributyltin azide (55 mg, 0.17 mmol) and
sealed in a gastight vial. The reaction was stirred for 3 days and
the solvent was removed. The residue was purified by preperative
HPLC to afford 10 mg (20%) of the title material; HPLC-MS calcd.
for C.sub.27H.sub.34FN.sub.7O.sub.3 (M+H.sup.+) 524.3, found
524.5.
Example 167
N-{1-(S)-[5-Amino-1-(S)-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-pentylcarb-
amoyl]-3-cyclohexyl-propyl}-3-methoxy-benzamide..sup.&
[0475] HPLC-MS calcd. for C.sub.32H.sub.45FN.sub.4O.sub.3
(M+H.sup.+) 553.4, found 553.6.
Example 168
3-(S)-(2-(S)-Benzyloxycarbonylamino-3-cyclohexyl-propionylamino)-4-(5-fluo-
ro-2,3-dihydro-indol-1-yl)-butyric acid benzyl ester..sup.&
[0476] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.0.80-0.95 (m, 2H),
1.11-1.18 (m, 3H), 1.26-1.32 (m, 1H), 1.37-1.44 (m, 1H), 1.55-1.75
(m, 6H), 2.59-2.76 (m, 2H), 2.89 (t, 2H, J.sub.1=8.0 Hz), 3.03-3.09
(m, 1H), 3.15-3.20 (m, 1H), 3.27-3.42 (m, 2H), 4.13-4.19 (m, 1H),
4.48-4.50 (m, 1H), 5.04-5.19 (m, 4H), 6.30-6.33 (m, 1H), 6.67-6.72
(m, 1H), 6.76-6.79 (m, 2H), 7.30-7.38 (m, 9H); HPLC-MS calcd. for
C.sub.36H.sub.42FN.sub.3O.sub.5 (M+H.sup.+) 616.3, found 616.5.
Example 169
1-(S)-[1-(R)-Benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarb-
amoyl]-2-cyclohexyl-ethyl}-carbamic acid benzyl
ester..sup.&
[0477] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.83-0.98 (m, 2H),
1.09-1.24 (m, 3H), 1.26-1.35 (m, 1H), 1.40-1.51 (m, 1H), 1.55-1.75
(m, 6H), 2.93 (t, 2H, J=7.6 Hz), 3.13-3.26 (m, 1H), 3.34-3.43(m,
1H), 3.51-3.53 (m, 1H), 3.67 (d, 1H, J=7.6 Hz), 4.15-4.20 (m, 1H),
4.27-4.30 (m, 1H), 4.43-4.56 (m, 2H), 5.03-5.18 (m, 4H), 6.51-6.57
(m, 1H), 6.73-6.81 (m, 1H), 6.94-6.98 (m, 1H), 7.27-7.39 (m, 10H);
HPLC-MS calcd. for C.sub.35H.sub.42FN.sub.3O.sub.4 (M+H.sup.+)
588.3, found 588.5.
Example 170
N-{3-Cyclohexyl-1-(S)-[2-(3,5-dimethoxy-benzyloxy)-1-(R)-(5-fluoro-2,3-dih-
ydro-indol-1-ylmethyl)-ethylcarbamoyl]-propyl}-3-methoxy-benzamide..sup.&
[0478] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.74-0.93 (m, 2H),
1.11-1.81 (m, 10H), 1.84-2.01 (m, 3H), 2.41-2.50 (m, 1H), 2.62-2.73
(m, 3H), 3.04-3.16 (m, 2H), 3.55 (s, 3H), 3.66 (broad s, 5H), 3.79
(s, 3H), 4.42-4.55 (m, 4H), 6.01 (s, 2H), 6.45 (s, 1H), 6.88-7.28
(m, 7H) HPLC-MS calcd. for C.sub.38H.sub.48FN.sub.3O.sub.6
(M+H.sup.+) 662.4, found 662.6.
Example 171
4-{2-(R)-[4-Cyclohexyl-2-(S)-(3-methoxy-benzoylamino)-butyrylamino]-3-(5-f-
luoro-2,3-dihydro-indol-1-yl)-propoxymethyl}-benzoic acid methyl
ester..sup.&
[0479] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.82-0.88 (m, 2H),
1.17-1.25 (m, 3H), 1.62-1.75 (m, 10H), 3.27-3.81 (m, 4H), 3.84 (s,
3H), 3.93 (s, 3H), 4.23-4.36 (m, 2H), 4.51-4.56 (m, 4H), 6.42 (d,
1H, J=2.8 Hz), 6.57-6.61 (m, 1H), 6.92-6.96 (m, 1H), 7.03-7.09 (m,
1H), 7.22-7.45 (m, 5H), 8.00 (d, 2H, J=8.4 Hz), HPLC-MS calcd. for
C.sub.38H.sub.46FN.sub.3O.sub.6 (M+H.sup.+) 660.3, found 660.6.
Example 172
(S,S)--N-{3-Cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(4-hydroxy-
-benzyl)-ethylcarbamoyl]-propyl}-3-methoxy-benzamide..sup.&
[0480] HPLC-MS calcd. for C.sub.35H.sub.42FN.sub.3O.sub.4
(M+H.sup.+) 588.3, found 588.5.
Example 173
Tetrahydropyran-4-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1-(-
S)-methyl-ethylcarbamoyl]-ethyl}-amide..sup.$
[0481] C.sub.28H.sub.42FN.sub.3O.sub.3; LCMS: 486.6
(M+H).sup.+.
Example 174
{2-Cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethy-
lcarbamoyl]-ethyl}-carbamic acid benzyl ester..sup.&
[0482] .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 0.69-0.80 (m, 2H),
1.00-1.10 (m, 5H), 1.10 (d, 3H, J=6.8 Hz), 2.75-2.81 (m, 3H),
3.00-3.05 (m, 1H), 3.13 (q, 1H, J=8.8 Hz), 3.39 (dd, 1H, J=15.2,
8.4 Hz), 3.90-4.12 (m, 2H), 4.89-4.91 (m, 2H), 6.28-6.35 (m, 1H),
6.58-6.32 (m, 1H), 6.68 (d, 1H, J=8.0 Hz), 7.18-7.24 (m, 5H).
HPLC-MS calcd. for C.sub.28H.sub.36FN.sub.3O.sub.3 (M+H.sup.+)
482.3, found 482.5.
Example 175
4-Benzyloxy-N--(R,S)-{[2-(4-amidinophenylamino)-1-(S)-methyl-ethylcarbamoy-
l]-(2,4-dichloro-phenyl)-methyl}-benzamide..sup.&
[0483] HPLC-MS calcd. for C.sub.32H.sub.31Cl.sub.2N.sub.5O.sub.3
(M+H.sup.+) 604.2, found 604.4.
Example 176
{1-(S)-[2-(5-Fluoro-2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethylcarbamoyl]-3-
,3-dimethyl-butyl}-carbamic acid benzyl ester..sup.$
[0484] HPLC-MS calcd. for C.sub.26H.sub.34FN.sub.3O.sub.3
(M+H.sup.+) 456.3, found 456.5.
Example 177
Cyclopropanecarboxylic acid
{1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethylcarbamoyl]--
3,3-dimethyl-butyl}-amide..sup.$
[0485] HPLC-MS calcd. for C.sub.22H.sub.32FN.sub.3O.sub.2
(M+H.sup.+) 390.2, found 390.5.
Example 178
Pyridazine-4-carboxylic acid
{1-(S)-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethylcarbamoyl]--
3,3-dimethyl-butyl}-amide..sup.$
[0486] HPLC-MS calcd. for C.sub.23H.sub.30FN.sub.5O.sub.2
(M+H.sup.+) 428.2, found 428.5.
Example 179
4,4-Dimethyl-2-(S)-(2-1H-tetrazol-5-yl-acetylamino)-pentanoic acid
[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethyl]-amide..sup.$
[0487] HPLC-MS calcd. for C.sub.21H.sub.30FN.sub.7O.sub.2
(M+H.sup.+) 432.2, found 432.5.
Example 180
(2-Cyclohexyl-1-(S)-{1-(S)-methyl-2-[3-(1H-tetrazol-5-yl)-phenylamino]-eth-
ylcarbamoyl}-ethyl)-carbamic acid benzyl ester..sup.$
[0488] HPLC-MS calcd. for C.sub.27H.sub.35N.sub.7O.sub.3
(M+H.sup.+) 506.3, found 506.5.
Example 181
(S,S)-2-(3-Chloro-benzenesulfonylamino)-3-cyclohexyl-N-[1-methyl-2-(4-trif-
luoromethoxy-phenylamino)-ethyl]-propionamide
##STR00019##
[0490] Step A:
(S)-[1-Methyl-2-(4-trifluoromethoxy-phenylamino)-ethyl]-carbamic
acid tert-butyl ester was produced as follows: S--N-Boc-Alinol (259
mg, 1.47 mmol) and Dess-Martin periodane (748 mg, 1.76 mmol) were
dissolved in 25 mL of dry DCM and stirred for 1 hour. The resulting
slurry was partitioned with Na.sub.2S.sub.2O.sub.3 and sodium
bicarbonate, washed with brine, dried over magnesium sulfate and
dried down to a white solid. The resulting aldehyde was treated
with a methanol solution of 4-trifluoromethoxyaniline (260 mg, 1.47
mmol), NaCNBH.sub.3 (179 mg, 2.94 mmol), and acetic acid (353 mg,
5.88 mmol) sequentially. The resulting solution was stirred for 1
hour, stripped to dryness, taken up in ethyl acetate and washed
with sodium bicarbonate. The organic layer was then dried over
magnesium sulfate, stripped down and purified by column
chromatography, yield 418 mg (85%).
[0491] Step B: S--N-(4-Trifluoromethoxy-phenyl)-propane-1,2-diamine
was prepared as follows:
[1-Methyl-2-(4-trifluoromethoxy-phenylamino)-ethyl]-carbamic acid
tert-butyl ester was dissolved in 50% TFA/DCM for 3 hours. The
reaction was worked up by stripping off the volatiles and ethyl
acetate was added. The organic layer was then washed with sodium
bicarbonate, dried over magnesium sulfate and stripped to dryness.
The resulting compound was then purified by flash
chromatography.
[0492] Step C:
(S,S)-{2-Cyclohexyl-1-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-ethylc-
arbamoyl]-ethyl}-carbamic acid benzyl ester:
(S)--N-(4-trifluoromethoxy-phenyl)-propane-1,2-diamine (76.7 mg,
0.328 mmol), (S)-2-benzyloxycarbonylamino-3-cyclohexyl-propionic
acid (100 mg, 0.328 mmol) and HATU (125 mg, 0.328 mmol) were added
to a round bottom flask with 20 mL of dry DCM. DIPEA (127 mg, 0.982
mmol) was added dropwise over three minutes with vigorous stirring.
The resulting slurry was stirred for 1.5 hours. The solution was
then washed with sodium bicarbonate, the organic layer was
separated and partially concentrated and the concentrate was
purified by flash chromatography. Yield 138 mg, 81%.
[0493] Step D:
(S,S)-2-Amino-3-cyclohexyl-N-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-
-ethyl]-propionamide: The product from step C (138 mg, 0.265 mmol)
and 5 mol % of 10% palladium on carbon (14 mg) was dissolved in 20
mL of methanol and purged with nitrogen. Balloon pressure of
hydrogen was added and the resulting slurry was stirred for 5
hours. The septum was removed and the slurry was filtered through
celite and concentrated. Yield 98 mg, quantitative.
[0494] Step E: The product from step D (15.4 mg, 39.7 .mu.mol) was
added to a flask with DMAP (14.5 mg, 0.119 mmol) and dry DMF (0.5
mL). 3-Chloro-benzenesulfonyl chloride (8.37 mg, 39.7 .mu.mol) was
added as a solution in 0.5 mL of dry DMF dropwise over 3 minutes.
The resulting solution was stirred for 12 hours and the volatiles
were stripped off. The solids were taken up in methanol and
purified by prep HPLC. Yield 15 mg, 67%. .sup.1H NMR (CDCl.sub.3)
.delta. (ppm): 7.9 (s, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.6 (d, J=8 Hz,
1H), 7.5(t, J=7.9 Hz, 1H), 7.05 (d, J=8.3 Hz, 2H), 6.6 (d, J=8.9
Hz, 2H), 6.15 (s, 1H), 5.1 (s, 1H), 4.1 (m, 1H), 3.65 (m, 1H), 3.25
(dd J=4.7, 12.9 Hz, 1H), 3.1 (dd J=7.5, 12.7 Hz, 1H), 1.6 (m, 7H),
1.4 (m, 1H), 1.3 (m, 1H), 1.2 (d, J=8.4 Hz, 3H), 1.07 (m, 3H), 0.65
(m, 1H). C.sub.25H.sub.31ClF.sub.3N.sub.3O.sub.4S: LC/MS=562.2
(M+1).
Example 182
(S,S)-3-Cyclohexyl-N-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-ethyl]-2-
-(3-trifluoromethoxy-benzenesulfonylamino)-propionamide
[0495] C.sub.26H.sub.31F.sub.6N.sub.3O.sub.5S: LC/MS: 612.19
(M+1).sup.+.***
Example 183
(S,S)-3-Cyclohexyl-N-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-ethyl]-2-
-(pyridine-3-sulfonylamino)-propionamide
[0496] C.sub.24H.sub.31F.sub.3N.sub.4O.sub.4S: LC/MS: 529.20
(M+1).sup.+.***
Example 184
(S,S)-{2-Cyclohexyl-1-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-ethylca-
rbamoyl]-ethyl}-carbamic acid tetrahydro-pyran-4-yl ester
##STR00020##
[0498] The conjugate from step D,
(S,S)-2-amino-3-cyclohexyl-N-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-
-ethyl]-propionamide was prepared according to Example 181, steps
A-D.
[0499] Step E: The conjugate from step D (25.4 mg, 65.5 .mu.mol)
and 4-nitrophenyl tetrahydropyran-4-yl carbonate (19.3 mg, 72.1
.mu.mol) were placed in a vial and 1.0 mL of dry DMF was added
through a septum by syringe. DIPEA (25.4 mg, 196.5 .mu.mol) was
added by syringe and the reaction was stirred overnight. The
solution was diluted with methanol and purified by prep HPLC, yield
21 mg (62%). .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.04 (d, J=8.0
Hz, 2H); 6.66 (d, J=8.0 Hz, 2H); 6.1 (s, 1H); 5.15 (s, 1H); 4.80
(m, 1H); 4.27 (q, J=6.5 Hz, 1H); 4.1 (q, J=9.0 Hz, 1H); 3.88 (m,
2H); 3.48 (m, 2H); 3.18 (m, 2H); 1.85 (m, 2H); 1.66 (m, 9H); 1.48
(m, 1H); 1.27 (d, J=6.8 Hz, 3H); 1.13 (m, 3H).
C.sub.25H.sub.36F.sub.3N.sub.3O.sub.5: LC/MS=516.26
(M+1).sup.+.
Example 185
3-(R)-{2-Cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-
-ethylcarbamoyl]-ethylcarbamoyloxy}-pyrrolidine-1-carboxylic acid
tert-butyl ester
[0500] C.sub.29H.sub.43F.sub.3N.sub.4O.sub.6; LC/MS: 601.31
(M+1).sup.+..sup.$$$
Example 186
(S,S)-{2-Cyclohexyl-1-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-ethylca-
rbamoyl]-ethyl}-carbamic acid
1,1-dioxo-hexahydro-1.lamda..sup.6-thiopyran-4-yl ester
[0501] C.sub.25H.sub.36F.sub.3N.sub.3O.sub.6S; LC/MS: 564.23
(M+1).sup.+..sup.$$$
Example 187
{2-Cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethyl-
carbamoyl]-ethyl}-carbamic acid pyrrolidin-3-(R)-yl ester
[0502] C.sub.24H.sub.35F.sub.3N.sub.4O.sub.4; LC/MS: 501.26
(M+1).sup.+..sup.$$$
Example 188
{2-Cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethyl-
carbamoyl]-ethyl}-carbamic acid tetrahydrofuran-3-(R)-yl ester
[0503] C.sub.24H.sub.34F.sub.3N.sub.3O.sub.5; LC/MS: 502.25
(M+1).sup.+..sup.$$$
Example 189
{2-Cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethyl-
carbamoyl]-ethyl}-carbamic acid tetrahydrofuran-3-(S)-yl ester
[0504] C.sub.24H.sub.34F.sub.3N.sub.3O.sub.5; LC/MS: 502.25
(M+1).sup.+..sup.$$$
Example 190
(S,S)-{2-Cyclopentyl-1-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-ethylc-
arbamoyl]-ethyl}-carbamic acid tetrahydropyran-4-yl ester
[0505] C.sub.24H.sub.34F.sub.3N.sub.3O.sub.5; LC/MS: 502.25
(M+1).sup.+..sup.$$$
Example 191
(S,S)-{2-Cyclopentyl-1-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-ethylc-
arbamoyl]-ethyl}-carbamic acid tetrahydrofuran-3-(R)-yl ester
[0506] C.sub.23H.sub.32F.sub.3N.sub.3O.sub.5; LC/MS: 488.23
(M+1).sup.+..sup.$$$
Example 192
(S,S)-{2-Cyclopentyl-1-[1-methyl-2-(4-trifluoromethoxy-phenylamino)-ethylc-
arbamoyl]-ethyl}-carbamic acid tetrahydrofuran-3-(S)-yl ester
[0507] C.sub.23H.sub.32F.sub.3N.sub.3O.sub.5; LC/MS: 488.23
(M+1).sup.+..sup.$$$
Example 193
N--((S)-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)(cyclohexyl)methyl)-3-meth-
ylbenzamide*
[0508] LC/MS for C.sub.26H.sub.32FN.sub.3O.sub.2 438.5
(M+H.sup.+).
Example 194
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-cyclopropylethyl)-5-(-
3-(trifluoromethyl)phenyl)furan-2-carboxamide*
[0509] LC/MS for C.sub.28H.sub.27F.sub.4N.sub.3O.sub.3 530.4
(M+H.sup.+).
Example 195
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-(2-chlorophenyl)ethyl-
)-3-methylbenzamide*
[0510] LC/MS for C.sub.27H.sub.27ClFN.sub.3O.sub.2 480.4
(M+H.sup.+).
Example 196
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-(3-chlorophenyl)ethyl-
)-5-(3-(trifluoromethyl)phenyl)furan-2-carboxamide*
[0511] LC/MS for C.sub.31H.sub.26ClF.sub.4N.sub.3O.sub.3 600.4
(M+H.sup.+).
Example 197
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-(3-chlorophenyl)ethyl-
)-3-methylbenzamide*
[0512] LC/MS for C.sub.27H.sub.27ClFN.sub.3O.sub.2 480.4
(M+H.sup.+).
Example 198
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-(4-chlorophenyl)ethyl-
)-5-(3-(trifluoromethyl)phenyl)furan-2-carboxamide*
[0513] LC/MS for C.sub.31H.sub.26ClF.sub.4N.sub.3O.sub.3 600.4
(M+H.sup.+).
Example 199
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-(4-chlorophenyl)ethyl-
)-3-methylbenzamide*
[0514] LC/MS for C.sub.27H.sub.27ClFN.sub.3O.sub.2 480.4
(M+H.sup.+).
Example 200
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-cyclopentylethyl)-5-(-
3-(trifluoromethyl)phenyl)furan-2-carboxamide*
[0515] LC/MS for C.sub.30H.sub.31F.sub.4N.sub.3O.sub.3 558.5
(M+H.sup.+).
Example 201
(S)--N-{2-Cyclopentyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoy-
l]-ethyl}-3-methyl-benzamide*
[0516] LC/MS for C.sub.26H.sub.32FN.sub.3O.sub.2 438.5
(M+H.sup.+).
Example 202
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-3,3-dimethylbutyl)-5-(3-
-(trifluoromethyl)phenyl)furan-2-carboxamide*
[0517] LC/MS for C.sub.29H.sub.31F.sub.4N.sub.3O.sub.3 546.4
(M+H.sup.+).
Example 203
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-3,3-dimethylbutyl)-3-me-
thylbenzamide*
[0518] LC/MS for C.sub.25H.sub.32FN.sub.3O.sub.2 426.5
(M+H.sup.+).
Example 204
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-3-cyclohexylpropyl)-3-m-
ethylbenzamide*
[0519] LC/MS for C.sub.28H.sub.36FN.sub.3O.sub.2 466.5
(M+H.sup.+).
Example 205
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-phenylethyl)-3-methyl-
benzamide*
[0520] LC/MS for C.sub.27H.sub.28FN.sub.3O.sub.2 446.5
(M+H.sup.+).
Example 206
N--((S)-1-(2-(5-fluoroindolin-1-yl)ethylcarbamoyl)-2-phenylethyl)-5-(3-(tr-
ifluoromethyl)phenyl)furan-2-carboxamide*
[0521] LC/MS for C.sub.31H.sub.27F.sub.4N.sub.3O.sub.3 566.4
(M+H.sup.+).
Example 207
N--(R,S)-((3-(benzyloxy)-1-(5-fluoroindolin-1-yl)propan-2-(R)-ylcarbamoyl)-
(2,4-dichlorophenyl)methyl)furan-2-carboxamide.sup.&
[0522] LC/MS for C.sub.31H.sub.28Cl.sub.2FN.sub.3O.sub.4 596.4
(M+H.sup.+).
Example 208
N--(R,S)-((3-(5-fluoroindolin-1-yl)-1-hydroxypropan-2-(R)-ylcarbamoyl)(2,4-
-dichlorophenyl)methyl)-3,4-difluorobenzamide.sup.&
[0523] LC/MS for C.sub.26H.sub.22Cl.sub.2F.sub.3N.sub.3O.sub.3
552.3 (M+H.sup.+).
Example 209
N--(S)-((3-(5-fluoroindolin-1-yl)-1-hydroxypropan-2-(R)-ylcarbamoyl)(2,4-d-
ichlorophenyl)methyl)furan-2-carboxamide.sup.&
[0524] LC/MS for C.sub.24H.sub.22Cl.sub.2FN.sub.3O.sub.4 506.3
(M+H.sup.+).
Example 210
(S,S)-3-Cyclohexyl-2-(2,4-dimethyl-thiazole-5-sulfonylamino)-N-[2-(5-fluor-
o-2,3-dihydro-indol-1-yl)-1-methyl-ethyl]-propionamide***
[0525] LC/MS for C.sub.25H.sub.35FN.sub.4O.sub.3S.sub.2 523.5
(M+H.sup.+).
Example 211
N--(S)-((3-(benzyloxy)-1-(5-fluoroindolin-1-yl)propan-2-(R)-ylcarbamoyl)(2-
,4-dichlorophenyl)methyl)-3,4-difluorobenzamide.sup.&
[0526] LC/MS for C.sub.33H.sub.28Cl.sub.2F.sub.3N.sub.3O.sub.3
642.4 (M+H.sup.+).
Example 212
N--(S)-((3-(5-fluoroindolin-1-yl)-1-hydroxypropan-2-(R)-ylcarbamoyl)(2,4-d-
ichlorophenyl)methyl)furan-2-carboxamide.sup.&
[0527] LC/MS for C.sub.24H.sub.22Cl.sub.2FN.sub.3O.sub.4 506.4
(M+H.sup.+).
Example 213
(R,S)--N-((2-(5-fluoroindolin-1-yl)ethylcarbamoyl)(2,4-dichlorophenyl)meth-
yl)-3-methylbenzamide*
[0528] LC/MS for C.sub.26H.sub.24Cl.sub.2FN.sub.3O.sub.2 500.3
(M+H.sup.+).
Example 214
(S,S)--N-((3-(5-fluoroindolin-1-yl)-1-hydroxypropan-2-ylcarbamoyl)(2,4-dic-
hlorophenyl)methyl)-3,4-difluorobenzamide.sup.&
[0529] LC/MS for C.sub.26H.sub.22Cl.sub.2F.sub.3N.sub.3O.sub.3
552.3 (M+H.sup.+).
Example 215
(S,S)-{2-Cyclohexyl-1-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1--
methyl-ethylcarbamoyl]-ethyl}-carbamic acid tetrahydro-pyran-4-yl
ester
[0530] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 6.7 (m, 2H), 6.4 (s,
1H), 6.05 (s, 1H), 5.07(d, J=8.3 Hz, 1H), 4.78 (s, 1H), 4.2 (s,
1H), 4.1 (s, 1H), 3.88 (m, 2H), 3.51 (m, 2H), 3.24 (m, 1H), 3.13
(m, 2H), 2.95 (m, 1H), 1.89 (m, 7H), 1.76 (m, 1H), 1.7 (m, 7H), 1.3
(m, 10H), 1.13 (m, 3H), 0.89 (m, 2H).
C.sub.28H.sub.42FN.sub.3O.sub.4: LC/MS=504.2
(M+1).sup.+..sup.$$$
Example 216
{2-Cyclohexyl-1-(S)-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1-(S-
)-methyl-ethylcarbamoyl]-ethyl}-carbamic acid
(R)-tetrahydrofuran-3-yl ester
[0531] C.sub.27H.sub.40FN.sub.3O.sub.4: LC/MS: 490.3
(M+1).sup.+..sup.$$$
Example 217
(S,S)-{2-Cyclohexyl-1-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1--
methyl-ethylcarbamoyl]-ethyl}-carbamic acid
(S)-tetrahydro-furan-3-yl ester
[0532] C.sub.27H.sub.40FN.sub.3O.sub.4: LC/MS: 490.3
(M+1).sup.+..sup.$$$
Example 218
(S,S)-4-(5-Fluoro-2,3-dihydro-indol-1-yl)-3-[2-(3-methoxy-benzoylamino)-4,-
4-dimethyl-pentanoylamino]-butyric acid
[0533] The title compound of example 160 (80 mg, 0.14 mmol) was
dissolved in a mixture of TFA, dichloromethane and water in a ratio
of 45:45:10 (1 mL) and stirred overnight. The solvent was removed
and the reaction was partitioned between water and dichloromethane.
The aqueous layer was extracted with dichloromethane 3 times and
the combined organics were dried over MgSO.sub.4 and the solvent
was removed to afford 72 mg (100%) of the title compound as a
solid; .sup.1H NMR (MeOD, 400 MHz) .delta. 0.94 (s, 9H), 1.70 (d,
1H, J=1.1), 2.62 (d, 1H, J=6.5), 2.79-2.93 (m, 2H), 3.06 (dd, 1H,
J.sub.1=6.0, J.sub.2=13.7), 3.19 (dd, 1H, J.sub.1=7.7,
J.sub.2=13.7), 3.45 (dd, 1H, J.sub.1=8.6, J.sub.2=15.9), 4.42-4.52
(m, 1H), 4.59-4.67 (m, 1H), 6.43 (dd, 1H, J.sub.1=4.2,
J.sub.2=8.5), 6.62-6.68 (m, 1H), 6.72-6.78 (m, 1H), 7.05-7.08 (m,
1H), 7.29-7.38 (m, 3H), 7.96 (d, 1H, J=8.6), 8.37 (d, 1H, J=8.2);
HPLC-MS calcd. for C.sub.27H.sub.34FN.sub.3O.sub.5 (M+H.sup.+)
500.2, found 500.5.
Example 219
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[3-(5-phe-
nyl-thiophen-2-yl)-ureido]-propionamide
[0534] LC/MS for C.sub.30H.sub.35FN.sub.4O.sub.2S 535.5
(M+H.sup.+).
Example 220
(S)-3-Cyclohexyl-2-[3-(3,5-dimethyl-isoxazol-4-yl)-ureido]-N-[2-(5-fluoro--
2,3-dihydro-indol-1-yl)-ethyl]-propionamide
[0535] LC/MS for C.sub.25H.sub.34FN.sub.5O.sub.3 472.5
(M+H.sup.+).
Example 221
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(5-methyl-
-1-phenyl-1H-pyrazole-4-sulfonylamino)-propionamide***
[0536] LC/MS for C.sub.29H.sub.36FN.sub.5O.sub.3S 554.5
(M+H.sup.+).
Example 222
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(5-isoxaz-
ol-3-yl-thiophene-2-sulfonylamino)-propionamide***
[0537] LC/MS for C.sub.26H.sub.31FN.sub.4O.sub.4S.sub.2 547.4
(M+H.sup.+).
Example 223
(S)-{2-Cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylcarbamoyl]-e-
thyl}-carbamic acid benzyl ester
[0538] LC/MS for C.sub.27H.sub.34FN.sub.3O.sub.3 468.4
(M+H.sup.+).
Example 224
(S)-2-(4-Bromo-3-chloro-thiophene-2-sulfonylamino)-3-cyclohexyl-N-[2-(5-fl-
uoro-2,3-dihydro-indol-1-yl)-ethyl]-propionamide***
[0539] LC/MS for C.sub.23H.sub.28BrClFN.sub.3O.sub.3S.sub.2 594.3
(M+H.sup.+).
Example 225
(S)-2-(3-Biphenyl-4-yl-ureido)-3-cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-ind-
ol-1-yl)-ethyl]-propionamide
[0540] LC/MS for C.sub.32H.sub.37FN.sub.4O.sub.2 529.5
(M+H.sup.+).
Example 226
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4-phenox-
y-benzenesulfonylamino)-propionamide***
[0541] LC/MS for C.sub.31H.sub.36FN.sub.3O.sub.4S 566.5
(M+H.sup.+).
Example 227
(S)-2-(5-Chloro-thiophene-2-sulfonylamino)-3-cyclohexyl-N-[2-(5-fluoro-2,3-
-dihydro-indol-1-yl)-ethyl]-propionamide***
[0542] LC/MS for C.sub.23H.sub.29ClFN.sub.3O.sub.3S.sub.2 514.4
(M+H.sup.+).
Example 228
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(naphthal-
ene-1-sulfonylamino)-propionamide***
[0543] LC/MS for C.sub.29H.sub.34FN.sub.3O.sub.3S 524.5
(M+H.sup.+).
Example 229
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4-triflu-
oromethyl-benzenesulfonylamino)-propionamide***
[0544] LC/MS for C.sub.26H.sub.31F.sub.4N.sub.3O.sub.3S 542.4
(M+H.sup.+).
Example 230
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4-triflu-
oromethoxy-benzenesulfonylamino)-propionamide***
[0545] LC/MS for C.sub.26H.sub.31F.sub.4N.sub.3O.sub.4S 558.4
(M+H.sup.+).
Example 231
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[5-(2-met-
hyl-5-trifluoromethyl-2H-pyrazol-3-yl)-thiophene-2-sulfonylamino]-propiona-
mide***
[0546] LC/MS for C.sub.28H.sub.33F.sub.4N.sub.5O.sub.3S.sub.2 628.4
(M+H.sup.+).
Example 232
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(3-methyl-
-3H-imidazole-4-sulfonylamino)-propionamide***
[0547] LC/MS for C.sub.23H.sub.32FN.sub.5O.sub.3S 478.5
(M+H.sup.+).
Example 233
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[3-(5-met-
hyl-[1,3,4]oxadiazol-2-yl)-benzenesulfonylamino]-propionamide***
[0548] LC/MS for C.sub.28H.sub.34FN.sub.5O.sub.4S 556.5
(M+H.sup.+).
Example 234
(S)-2-(Benzo[b]thiophene-2-sulfonylamino)-3-cyclohexyl-N-[2-(5-fluoro-2,3--
dihydro-indol-1-yl)-ethyl]-propionamide***
[0549] LC/MS for C.sub.27H.sub.32FN.sub.3O.sub.3S.sub.2 530.4
(M+H.sup.+).
Example 235
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(thiophen-
e-2-sulfonylamino)-propionamide***
[0550] LC/MS for C.sub.23H.sub.30FN.sub.3O.sub.3S.sub.2 480.4
(M+H.sup.+).
Example 236
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[4-(4-flu-
oro-phenoxy)-benzenesulfonylamino]-propionamide***
[0551] LC/MS for C.sub.31H.sub.35F.sub.2N.sub.3O.sub.4S 584.5
(M+H.sup.+).
Example 237
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[5-(2-met-
hyl-thiazol-4-yl)-thiophene-2-sulfonylamino]-propionamide***
[0552] LC/MS for C.sub.27H.sub.33FN.sub.4O.sub.3S.sub.3 577.4
(M+H.sup.+).
Example 238
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4'-metho-
xy-biphenyl-4-sulfonylamino)-propionamide***
[0553] LC/MS for C.sub.32H.sub.38FN.sub.3O.sub.4S 580.5
(M+H.sup.+).
Example 239
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4-methox-
y-benzenesulfonylamino)-propionamide***
[0554] LC/MS for C.sub.26H.sub.34FN.sub.3O.sub.4S 504.5
(M+H.sup.+).
Example 240
(S)-3-Cyclohexyl-2-(4-difluoromethoxy-benzenesulfonylamino)-N-[2-(5-fluoro-
-2,3-dihydro-indol-1-yl)-ethyl]-propionamide***
[0555] LC/MS for C.sub.26H.sub.32F.sub.3N.sub.3O.sub.4S 540.5
(M+H.sup.+).
Example 241
(S)-2-(5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-3-cyclohexyl-N-[-
2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-propionamide***
[0556] LC/MS for C.sub.24H.sub.33ClFN.sub.5O.sub.3S 526.5
(M+H.sup.+).
Example 242
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-phenylmet-
hanesulfonylamino-propionamide***
[0557] LC/MS for C.sub.26H.sub.34FN.sub.3O.sub.3S 488.5
(M+H.sup.+).
Example 243
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(toluene--
3-sulfonylamino)-propionamide***
[0558] LC/MS for C.sub.26H.sub.34FN.sub.3O.sub.3S 488.5
(M+H.sup.+).
Example 244
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-[4-(4-met-
hoxy-phenoxy)-benzenesulfonylamino]-propionamide***
[0559] LC/MS for C.sub.32H.sub.38FN.sub.3O.sub.5S 596.4
(M+H.sup.+).
Example 245
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(3-methox-
y-benzenesulfonylamino)-propionamide***
[0560] LC/MS for C.sub.26H.sub.34FN.sub.3O.sub.4S 504.5
(M+H.sup.+).
Example 246
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(4-oxazol-
-5-yl-benzenesulfonylamino)-propionamide***
[0561] LC/MS for C.sub.28H.sub.33FN.sub.4O.sub.4S 541.5
(M+H.sup.+).
Example 247
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(3-methyl-isoxazol-5-ylamino)-ethylca-
rbamoyl]-ethyl}-amide.sup.#
[0562] C.sub.27H.sub.33FN4O4; LCMS: 497.5 (M+H).sup.+.
Example 248
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(thiophen-
e-3-sulfonylamino)-propionamide***
[0563] LC/MS for C.sub.23H.sub.30FN.sub.3O.sub.3S.sub.2 480.5
(M+H.sup.+).
Example 249
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-methanesu-
lfonylamino-propionamide***
[0564] LC/MS for C.sub.20H.sub.30FN.sub.3O.sub.3S 412.5
(M+H.sup.+).
Example 250
(S,S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-methyl-ethyl]--
2-(5-oxazol-5-yl-thiophene-3-sulfonylamino)-propionamide***
[0565] LC/MS for C.sub.27H.sub.33FN.sub.4O.sub.4S.sub.2 561.5
(M+H.sup.+).
Example 251
(S,S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-methyl-ethyl]--
2-(toluene-3-sulfonylamino)-propionamide***
[0566] LC/MS for C.sub.27H.sub.36FN.sub.3O.sub.3S 502.5
(M+H.sup.+).
Example 252
(S,S)-3-[4,4-Dimethyl-2-(toluene-3-sulfonylamino)-pentanoylamino]-4-(5-flu-
oro-2,3-dihydro-indol-1-yl)-butyric acid tert-butyl ester***
[0567] LC/MS for C.sub.30H.sub.42FN.sub.3O.sub.5S 576.5
(M+H.sup.+).
Example 253
(S,S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-methyl-ethyl]--
2-(2-methyl-4-trifluoromethyl-furan-3-sulfonylamino)-propionamide***
[0568] LC/MS for C.sub.26H.sub.33F.sub.4N.sub.3O.sub.4S 560.5
(M+H.sup.+).
Example 254
(S,S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-methyl-ethyl]--
2-(3-trifluoromethoxy-benzenesulfonylamino)-propionamide***
[0569] LC/MS for C.sub.27H.sub.33F.sub.4N.sub.3O.sub.4S 572.4
(M+H.sup.+).
Example 255
(S)-3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(1-methyl-
-1H-imidazole-4-sulfonylamino)-propionamide***
[0570] LC/MS for C.sub.23H.sub.32FN.sub.5O.sub.3S 478.5
(M+H.sup.+).
Example 256
(S)-2-(5-Benzenesulfonyl-thiophene-2-sulfonylamino)-3-cyclohexyl-N-[2-(5-f-
luoro-2,3-dihydro-indol-1-yl)-ethyl]-propionamide***
[0571] LC/MS for C.sub.29H.sub.34FN.sub.3O.sub.5S.sub.3 620.4
(M+H.sup.+).
Example 257
(S)-2-(2-Acetylamino-4-methyl-thiazole-5-sulfonylamino)-3-cyclohexyl-N-[2--
(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-propionamide***
[0572] LC/MS for C.sub.25H.sub.34FN.sub.5O.sub.4S.sub.2 552.5
(M+H.sup.+).
Example 258
(S)-3-Cyclohexyl-2-(4,5-dichloro-thiophene-2-sulfonylamino)-N-[2-(5-fluoro-
-2,3-dihydro-indol-1-yl)-ethyl]-propionamide***
[0573] LC/MS for C.sub.23H.sub.28Cl.sub.2FN.sub.3O.sub.3S.sub.2
548.4 (M+H.sup.+).
Example 259
(S,S)-2-(3-Chloro-benzenesulfonylamino)-3-cyclohexyl-N-[2-(5-fluoro-2,3-di-
hydro-indol-1-yl)-1-methyl-ethyl]-propionamide***
[0574] LC/MS for C.sub.26H.sub.33ClFN.sub.3O.sub.3S 522.4
(M+H.sup.+).
Example 260
(S,S)--N-{3-Cyclohexyl-1-[1-(5-fluoro-2,3-dihydro-indol-1-ylmethyl)-3-hydr-
oxy-propylcarbamoyl]-propyl}-3-methoxy-benzamide
[0575] A sample of the title compound of example 47 (114 mg, 0.21
mmol) in THF (5 mL) was cooled in an ice/water bath and treated
with triethylamine (21 mg, 0.21 mmol) followed by isobutyl
chloroformate. After stirring for 25 minutes, the solution was
transferred to a precooled (ice/water bath) stirring solution of
excess NaBH.sub.4 in water (5 mL). After stirring for 1 hour, the
solution was quenched by addition of excess 1 M HCl at 0.degree. C.
The reaction was diluted with ethyl acetate and extracted with 1 M
NaOH solution. The organics were dried over MgSO.sub.4 and the
solvent was removed. The residue was purified on silica gel using a
gradient of 0 to 100% ethyl acetate in hexane to afford 57 mg (51%)
of the title material as a solid; .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 0.65-0.82 (m, 2H), 1.00-1.25 (m, 6H), 1.47-1.66 (m, 6H),
1.66-1.78 (m, 2H), 1.82-1.97 (m, 2H), 2.88-2.95 (m, 2H), 3.01 (dd,
1H, J.sub.1=5.6, J.sub.2=13.7), 3.21 (dd, 1H, J.sub.1=7.7,
J.sub.2=13.7), 3.29 (dd, 1H, J.sub.1=8.7, J.sub.2=17.3), 3.44-3.52
(m, 1H), 3.55-3.68 (m, 2H), 3.83 (s, 3H), 4.31-4.41 (m, 1H), 4.64
(dd, 1H, J.sub.1=6.9, J.sub.2=14.1), 6.34 (dd, 1H, J.sub.1=4.1,
J.sub.2=8.6), 6.568 (ddd, 1H, J.sub.1=2.5, J.sub.2=J.sub.3=8.9),
6.79 (dd, 1H, J.sub.1=8.3), 7.03-7.08 (m, 1H), 7.15 (d, 1H, J=7.7),
7.22 (d, 1H, J=8.8), 7.29-7.35 (m, 3H); HPLC-MS calcd. for
C.sub.30H.sub.40FN.sub.3O.sub.4 (M+H.sup.+) 526.3, found 526.5.
Example 261
(S,S)-3-(2-tert-Butoxycarbonylamino-3-cyclohexyl-propionylamino)-4-(5-fluo-
ro-2,3-dihydro-indol-1-yl)-butyric acid benzyl ester
[0576] Following the procedures of Example 22, except using
N-Boc-.gamma.-OBn-aspartinol, 5-fluoroindoline (1 eq) and
Boc-cyclohexylalanine as starting materials, the title compound was
prepared in 15% overall yield; HPLC-MS calcd. for
C.sub.33H.sub.44FN.sub.3O.sub.5 (M+H.sup.+) 582.3, found 582.5.
Example 262
(S,S)-3-[4,4-Dimethyl-2-(toluene-3-sulfonylamino)-pentanoylamino]-4-(5-flu-
oro-2,3-dihydro-indol-1-yl)-butyric acid***
[0577] LC/MS for C.sub.26H.sub.34FN.sub.3O.sub.5S 520.4
(M+H.sup.+).
Example 263
(S,S)-3-Cyclohexyl-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-[2-(5-fluo-
ro-2,3-dihydro-indol-1-yl)-1-methyl-ethyl]-propionamide***
[0578] LC/MS for C.sub.25H.sub.35FN.sub.4O.sub.4S 507.4
(M+H.sup.+).
Example 264
(S,S)-2-Benzenesulfonylamino-3-cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-
-1-yl)-1-methyl-ethyl]-propionamide***
[0579] LC/MS for C.sub.26H.sub.34FN.sub.3O.sub.3S 488.5
(M+H.sup.+).
Example 265
(S,S)-4,4-Dimethyl-2-(toluene-3-sulfonylamino)-pentanoic acid
[2-(5-fluoro-2,3-dihydro-indol-1-yl)-1-methyl-ethyl]-amide***
[0580] LC/MS for C.sub.25H.sub.34FN.sub.3O.sub.3S 476.5
(M+H.sup.+).
Example 266
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{1-(S)-[2-(4-benzyloxy-phenylamino)-1-(S)-methyl-ethylcarbamoyl]-2-cycloh-
exyl-ethyl}-amide.sup.#
[0581] C.sub.36H.sub.40FN.sub.3O.sub.4; LCMS:598.6 (M+H).sup.+.
Example 267
5-(3-Fluoro-phenyl)-furan-2-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(3-methyl-isothiazol-5-ylamino)-ethyl-
carbamoyl]-ethyl}-amide.sup.#
[0582] C.sub.27H.sub.33FN.sub.4O.sub.3S; LCMS:
513.5(M+H).sup.+.
Example 268
Tetrahydrofuran-2-(R)-carboxylic acid
{3,3-dimethyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-butyl}-amide.sup.$
[0583] C.sub.22H.sub.32F.sub.3N.sub.3O.sub.4; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.02(m, 2H); 6.70(m, 2H); 4.42(m, 1H);
4.24(m, 1H); 4.00(m, 2H); 3.84(m, 1H); 3.30(m, 2H); 2.18(m, 1H);
1.87(m, 3H); 1.61(m, 3H); 1.20(d, J=6.8 Hz, 2H); 0.93(s, 9H). LCMS:
460.4 (M+H).sup.+.
Example 269
Tetrahydropyran-4-carboxylic acid
{3,3-dimethyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-butyl}-amide.sup.$
[0584] C.sub.23H.sub.34F.sub.3N.sub.3O.sub.4; .sup.1H NMR
(CDCl.sub.3) .delta.(ppm) 7.03(m, 2H); 6.72(m, 2H); 4.38(m, 1H);
4.18(m, 1H); 3.93(m, 2H); 3.40(m, 2H); 3.30(m, 2H); 2.48(m, 1H);
1.66(m, 6H); 1.20(d, J=6.8 Hz, 3H); 0.93(s, 9H). LCMS: 474.5
(M+H).sup.+.
Example 270
Tetrahydro-pyran-4-carboxylic acid
{1-(S)-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1-(S)-methyl-eth-
ylcarbamoyl]-3,3-dimethyl-butyl}-amide.sup.$
[0585] C.sub.26H.sub.40FN.sub.3O.sub.3; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 6.67(m, 2H); 6.50(m, 1H); 6.33(m, 1H); 6.22(m, 1H);
4.35(m, 1H); 4.09(m, 1H); 3.90(m, 2H); 3.31(m, 2H); 3.15(m, 1H);
3.01(m, 2H); 2.83(dd, 1H); 2.26(m, 1H); 1.68(m, 5H); 1.45(m, 1H);
1.20(m, 6H); 1.10(d, J=6.8 Hz, 3H); 0.81(s, 9H) LCMS: 462.5
(M+H).sup.+.
Example 271
Tetrahydro-furan-2-(R)-carboxylic acid
{1-(S)-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1-(S)-methyl-eth-
ylcarbamoyl]-3,3-dimethyl-butyl}-amide.sup.$
[0586] C.sub.26H.sub.40FN.sub.3O.sub.3; .sup.1H NMR (CDCl.sub.3)
.delta.(ppm) 6.88(m, 1H); 6.68(m, 2H); 6.33(m, 1H); 6.22(m, 1H);
4.25(m, 2H); 4.15(m, 1H); 3.89(m, 1H); 3.77(m, 1H); 3.15(m, 1H);
3.04(m, 2H); 2.85(dd, 1H); 2.17(m, 1H); 1.82(m, 4H); 1.38(dd, 1H);
1.20(m, 6H); 1.11(d, J=6.8 Hz, 3H); 0.82(s, 9H) LCMS: 448.6
(M+H).sup.+.
Example 272
Tetrahydrofuran-3-(R,S)-carboxylic acid
{2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenylamino)-ethy-
lcarbamoyl]-ethyl}-amide.sup.$
[0587] C.sub.24H.sub.34F.sub.3N.sub.3O.sub.4; LCMS: 486.5
(M+H).sup.+.
Example 273
Tetrahydrofuran-2-(R)-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1-(-
S)-methyl-ethylcarbamoyl]-ethyl}-amide.sup.$
[0588] C.sub.27H.sub.40FN.sub.3O.sub.3; LCMS: 474.5
(M+H).sup.+.
Example 274
Tetrahydrofuran-2-(R)-carboxylic acid
{2-cyclohexyl-1-(S)-[2-(5-fluoro-2,2-dimethyl-2,3-dihydro-indol-1-yl)-1-(-
S)-methyl-ethylcarbamoyl]-ethyl}-amide.sup.$
[0589] C.sub.27H.sub.40FN.sub.3O.sub.3; LCMS: 474.5
(M+H).sup.+.
[0590] B. Assays for Cathepsin Inhibitory Activity
Cathepsin S
[0591] The optimal substrate for cathepsin S,
acetyl-histidine-proline-valine-lysine-amino carbamoyl coumarin,
was identified from screening a combinatorial library of
fluorogenic peptide substrates (Harris, J. L., B. J. Backes, et
al., Proc Natl Acad Sci USA 2000, 97(14), 7754-9). Kinetic
measurements are performed in a total reaction volume of 30 .mu.l
in 384-well microtiter plates. Cathepsin S, at a final
concentration of 0.3-3 nM (active site), is incubated with the
compounds at twelve varying concentrations in a buffer containing
100 mM NaAc (pH5.5), 1 mM EDTA, 100 mM NaCl, 0.01% Brij-35 for 20
minutes at room temperature. Control reactions in the absence of
inhibitor are performed in replicates of 24. The reactions are
initiated by adding the substrate,
acetyl-histidine-proline-valine-lysine-amino carbamoyl coumarin, to
a final concentration of 50 .mu.M. The rate of substrate hydrolysis
is measured by monitoring the increase in fluorescence at an
excitation wavelength of 380 nm and an emission wavelength of 450
nm that results from cleavage of the aniline bond in the substrate
by the enzyme. The apparent inhibition constants for the compounds
are determined from the enzyme progress curves (Kuzmic, P., K. C.
Elrod, et al., Anal Biochem 2000, 286(1), 45-50) and are then used
to calculate the inhibition constants for competitive
inhibitors.
Cathepsin K
[0592] The optimal substrate for cathepsin K,
acetyl-lysine-histidine-proline-lysine-amino carbamoyl coumarin,
was identified from screening a combinatorial library of
fluorogenic peptide substrates (Harris, J. L., B. J. Backes, et
al., Proc Natl Acad Sci USA 2000, 97(14), 7754-9). Kinetic
measurements are performed in a total reaction volume of 30 .mu.l
in 384-well microtiter plates. Cathepsin K, at a final
concentration of 3.5 nM (active site), is incubated with the
compounds at twelve varying concentrations in a buffer containing
100 mM NaAc (pH5.5), 1 mM EDTA, 100 mM NaCl, 0.01% Brij-35 for 20
minutes at room temperature. Control reactions in the absence of
inhibitor are performed in replicates of 24. The reactions are
initiated by adding the substrate,
acetyl-lysine-histidine-proline-lysine-amino carbamoyl coumarin, to
a final concentration of 40 .mu.M. The rate of substrate hydrolysis
is measured by monitoring the increase in fluorescence at an
excitation wavelength of 380 nm and an emission wavelength of 450
nm that results from cleavage of the aniline bond in the substrate
by the enzyme. The apparent inhibition constants for the compounds
are determined from the enzyme progress curves (Kuzmic, P., K. C.
Elrod, et al., Anal Biochem 2000, 286(1), 45-50) and are then used
to calculate the inhibition constants for competitive
inhibitors.
Cathepsin L
[0593] The optimal substrate for cathepsin L,
acetyl-histidine-lysine-phenylalanine-lysine-amino carbamoyl
coumarin, was identified from screening a combinatorial library of
fluorogenic peptide substrates (Harris, J. L., B. J. Backes, et
al., Proc Natl Acad Sci USA 2000, 97(14), 7754-9). Kinetic
measurements are performed in a total reaction volume of 30 .mu.l
in 384-well microtiter plates. Cathepsin L, at a final
concentration of 0.1 nM (active site), is incubated with the
compounds at twelve varying concentrations in a buffer containing
100 mM NaAc (pH5.5), 1 mM EDTA, 100 mM NaCl, 0.01% Brij-35 for 20
minutes at room temperature. Control reactions in the absence of
inhibitor are performed in replicates of 24. The reactions are
initiated by adding the substrate,
acetyl-histidine-lysine-phenylalanine-lysine-amino carbamoyl
coumarin, to a final concentration of 20 .mu.M. The rate of
substrate hydrolysis is measured by monitoring the increase in
fluorescence at an excitation wavelength of 380 nm and an emission
wavelength of 450 nm that results from cleavage of the aniline bond
in the substrate by the enzyme. The apparent inhibition constants
for the compounds are determined from the enzyme progress curves
(Kuzmic, P., K. C. Elrod, et al., Anal Biochem 2000, 286(1), 45-50)
and are then used to calculate the inhibition constants for
competitive inhibitors.
Cathepsin B
[0594] The optimal substrate for cathepsin B,
acetyl-histidine-proline-valine-lysine-amino carbamoyl coumarin,
was identified from screening a combinatorial library of
fluorogenic peptide substrates (Harris, J. L., B. J. Backes, et
al., Proc Natl Acad Sci USA 2000, 97(14), 7754-9). Kinetic
measurements are performed in a total reaction volume of 30 .mu.l
in 384-well microtiter plates. Cathepsin B, at a final
concentration of 1.5 nM (active site), is incubated with the
compounds at twelve varying concentrations in a buffer containing
100 mM NaAc (pH5.5), 1 mM EDTA, 100 mM NaCl, 0.01% Brij-35 for 20
minutes at room temperature. Control reactions in the absence of
inhibitor are performed in replicates of 24. The reactions are
initiated by adding the substrate,
acetyl-histidine-proline-valine-lysine-amino carbamoyl coumarin, to
a final concentration of 10 .mu.M. The rate of substrate hydrolysis
is measured by monitoring the increase in fluorescence at an
excitation wavelength of 380 nm and an emission wavelength of 450
nm that results from cleavage of the aniline bond in the substrate
by the enzyme. The apparent inhibition constants for the compounds
are determined from the enzyme progress curves (Kuzmic, P., K. C.
Elrod, et al., Anal Biochem 2000, 286(1), 45-50) and are then used
to calculate the inhibition constants for competitive
inhibitors.
[0595] Preferred cathepsin S inhibition constants for compounds of
the present invention are less than 10 .mu.M. More preferred
inhibition constants for compounds of the present invention are
less than 1.0 .mu.M. Most preferred inhibition constants for
compounds of the present invention are less than 0.1 .mu.M.
[0596] Selectivity for cathepsin S in the presence of cathepsin
isozymes was determined by the ratio of the cathepsin isozyme
inhibition constant of a compound of the present invention to the
cathepsin S inhibition constant of the same compound. Preferred
compounds of the present invention selective for cathepsin S have
ratios of greater than 10. More preferred compounds of the present
invention selective for cathepsin S have ratios of greater than
100. Most preferred compounds of the present invention selective
for cathepsin S have ratios of greater than 1000.
TABLE-US-00002 TABLE II Assay Data for Inhibitors of Cathepsin
K.sub.i Compound Cat. S.sup.a 1 + 2 +++ 3 ++ 4 +++ 5 ++ 6 ++ 7 ++ 8
+ 9 +++ 10 + 11 + 12 + 13 +++ 14 +++ 15 + 16 + 17 ++ 18 + 19 + 20 +
21 +++ 22 +++ 23 ++ 24 ++ 25 + 26 +++ 27 +++ 28 + 29 +++ 30 +++ 31
+ 32 + 33 ++ 34 ++ 35 +++ 36 +++ 37 +++ 38 +++ 39 +++ 40 + 41 +++
42 +++ 43 +++ 44 +++ 45 ++ 46 ++ 47 +++ 48 ++ 49 +++ 50 +++ 51 + 52
++ 53 +++ 54 ++ 55 ++ 56 ++ 57 ++ 58 ++ 59 +++ 60 +++ 61 +++ 62 ++
63 ++ 64 +++ 65 ++ 66 ++ 67 ++ 68 ++ 69 ++ 70 +++ 71 +++ 72 +++ 73
+++ 74 ++ 75 +++ 76 +++ 77 ++ 78 +++ 79 +++ 80 +++ 81 +++ 82 +++ 83
+++ 84 +++ 85 +++ 86 +++ 87 +++ 88 +++ 89 +++ 90 +++ 91 +++ 92 +++
93 ++ 94 +++ 95 +++ 96 ++ 97 ++ 98 +++ 99 +++ 100 +++ 101 +++ 102
+++ 103 +++ 104 +++ 105 +++ 106 +++ 107 +++ 108 +++ 109 +++ 110 ++
111 +++ 112 ++ 113 +++ 114 +++ 115 +++ 116 +++ 117 +++ 118 +++ 119
+++ 120 +++ 121 ++ 122 +++ 123 +++ 124 +++ 125 +++ 126 +++ 127 +++
128 +++ 129 +++ 130 +++ 131 +++ 132 +++ 133 ++ 134 +++ 135 +++ 136
++ 137 +++ 138 ++ 139 +++ 140 +++ 141 +++ 142 +++ 143 +++ 144 +++
145 ++ 146 +++ 147 +++ 148 +++ 149 +++ 150 +++ 151 +++ 152 +++ 153
+++ 154 +++ 155 +++ 156 +++ 157 +++ 158 ++ 159 ++ 160 +++ 161 +++
162 +++ 163 +++ 164 ++ 165 +++ 166 +++ 167 +++ 168 +++ 169 +++ 170
+++ 171 +++ 172 +++ 173 +++ 174 +++ 175 ++ 176 +++ 177 +++ 178 +++
179 ++ 180 ++ 181 +++ 182 +++ 183 +++ 184 +++ 185 ++ 186 +++ 187 +
188 +++ 189 +++ 190 +++ 191 +++ 192 +++ 193 ++ 194 ++ 195 ++ 196 ++
197 ++ 198 ++ 199 +++ 200 +++ 201 +++ 202 +++ 203 +++ 204 ++ 205 ++
206 ++ 207 +++ 208 +++ 209 +++ 210 +++ 211 +++ 212 ++ 213 ++ 214 ++
215 +++ 216 +++ 217 +++ 218 +++ 219 + 220 ++ 221 ++ 222 ++ 223 ++
224 ++ 225 ++ 226 +++ 227 +++ 228 ++ 229 ++ 230 ++ 231 +++ 232 +
233 +++ 234 ++ 235 ++ 236 ++ 237 +++ 238 +++ 239 ++ 240 ++ 241 ++
242 + 243 +++ 244 +++
245 ++ 246 +++ 247 ++ 248 ++ 249 + 250 +++ 251 +++ 252 ++ 253 +++
254 +++ 255 ++ 256 ++ 257 +++ 258 ++ 259 +++ 260 ++ 261 - 262 +++
263 +++ 264 +++ 265 +++ 266 +++ 267 ++ 268 + 269 ++ 270 ++ 271 +
272 +++ 273 +++ 274 ++ .sup.aCathepsin S inhibition constant for
compounds of Formula I: +, <10 .mu.M; ++, <1.0 .mu.M; +++,
<0.1 .mu.M.
TABLE-US-00003 TABLE III Assay Data for Inhibitors of Cathepsin S
showing selectivity over other Cathepsin isoenzymes K.sub.i Ki Ki
Ki Compound Cat. S.sup.a Cat. K.sup.b Cat. L.sup.c Cat. B.sup.d 21
+++ +++ +++ - 31 + + ++ - 41 +++ - ++ ++ 51 + - - - 61 +++ - +++ -
71 +++ + +++ - 81 +++ + + - 91 +++ + ++ + 101 +++ - + - 110 ++ + +
- 121 ++ + + + 131 +++ ++ - - 141 +++ - + - 151 +++ + +++ - 171 +++
- + - 181 +++ - + - 191 +++ + - - 201 +++ + ++ - 211 +++ - + - 221
++ - - - 231 +++ - - - 241 ++ - + - 251 +++ - + - .sup.aCathepsin
Sinhibition constant for compounds of Formula I: +, <10 .mu.M;
++, <1.0 .mu.M; +++, <0.1 .mu.M. .sup.bCathepsin K inhibition
constant for compounds of Formula I: +, <10 .mu.M; ++, <1.0
.mu.M; +++, <0.1 .mu.M; -, >10 .mu.M. .sup.cCathepsin L
inhibition constant for compounds of Formula I: +, <10 .mu.M;
++, <1.0 .mu.M; +++, <0.1 .mu.M; -, >10 .mu.M.
.sup.dCathepsin B inhibition constant for compounds of Formula I:
+, <10 .mu.M; ++, <1.0 .mu.M; +++, <0.1 .mu.M; -, >10
.mu.M.
[0597] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, it will be obvious that certain changes and
modifications may be practiced within the scope of the appended
claims. In addition, each reference provided herein is incorporated
by reference in its entirety to the same extent as if each
reference was individually incorporated by reference.
* * * * *