U.S. patent application number 10/370872 was filed with the patent office on 2004-07-01 for substituted heterocycle fused gamma-carbolines.
Invention is credited to Calvello, Emilie J.B., Chen, Wenting, Deng, Wei, Lee, Taekyu, Mc Clung, Christopher D., Mitchell, Ian S., Robichaud, Albert J., Zawrotny, David M..
Application Number | 20040127482 10/370872 |
Document ID | / |
Family ID | 22486095 |
Filed Date | 2004-07-01 |
United States Patent
Application |
20040127482 |
Kind Code |
A1 |
Robichaud, Albert J. ; et
al. |
July 1, 2004 |
Substituted heterocycle fused gamma-carbolines
Abstract
The present invention is directed to methods of treating
addictive behavior and sleep disorders by administering compounds
represented by structural Formula (I) 1 or pharmaceutically
acceptable salt forms thereof, wherein R.sup.1, R.sup.5, R.sup.6a,
R.sup.6b, R.sup.7, R.sup.8, R.sup.9, X, b, k, m, and n, and the
dashed lines are described herein. The compounds used in the method
of treatment of this invention are serotonin agonists and
antagonists and are useful in the control or prevention of central
nervous system disorders including addictive behavior and sleep
disorders.
Inventors: |
Robichaud, Albert J.;
(Landenberg, PA) ; Lee, Taekyu; (Wilmington,
DE) ; Deng, Wei; (Wilmington, DE) ; Mitchell,
Ian S.; (Philadelphia, PA) ; Chen, Wenting;
(Exton, PA) ; Mc Clung, Christopher D.;
(Wilmington, DE) ; Calvello, Emilie J.B.; (Bryn
Mawr, PA) ; Zawrotny, David M.; (Moorestown,
NJ) |
Correspondence
Address: |
STEPHEN B. DAVIS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
22486095 |
Appl. No.: |
10/370872 |
Filed: |
February 20, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10370872 |
Feb 20, 2003 |
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09594008 |
Jun 15, 2000 |
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6548493 |
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60139321 |
Jun 15, 1999 |
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Current U.S.
Class: |
514/214.02 ;
514/248 |
Current CPC
Class: |
A61P 25/00 20180101;
C07D 221/18 20130101; C07D 495/06 20130101; A61P 1/00 20180101;
A61P 25/18 20180101; A61P 15/00 20180101; A61P 43/00 20180101; A61P
25/20 20180101; A61P 25/22 20180101; A61P 25/06 20180101; A61P
25/24 20180101; C07D 471/06 20130101; C07D 223/32 20130101; C07D
491/06 20130101; A61P 3/04 20180101 |
Class at
Publication: |
514/214.02 ;
514/248 |
International
Class: |
A61K 031/55; A61K
031/498 |
Claims
What is claimed is:
1. A method for treating a human suffering from addictive behavior
associated with 5HT2C receptor modulation, comprising administering
to a patient in need thereof a therapeutically. effective amount of
a compound of formula (I): 58or stereoisomers or pharmaceutically
acceptable salt forms thereof, wherein: b is a single bond; X is
--CHR.sup.10-- or --C(=O)--; R.sup.1 is selected from H,
C(=O)R.sup.2, C(=O) OR.sup.2, C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-6 alkyl
substituted with Z, C.sub.2-6 alkenyl substituted with Z, C.sub.2-6
alkynyl substituted with Z, C.sub.3-6 cycloalkyl substituted with
Z, aryl substituted with Z, 5-6 membered heterocyclic ring system
containing at least one heteroatom selected from the group
consisting of N, O, and S, said heterocyclic ring system
substituted with Z; C.sub.1-3 alkyl substituted with Y, C.sub.2-3
alkenyl substituted with Y, C.sub.2-3 alkynyl substituted with Y,
C.sub.1-6 alkyl substituted with 0-2 R.sup.2, C.sub.2-6 alkenyl
substituted with 0-2 R.sup.2, C.sub.2-6 alkynyl substituted with
0-2 R.sup.2, aryl substituted with 0-2 R.sup.2, and 5-6 membered
heterocyclic ring system containing at least one heteroatom
selected from the group consisting of N, O, and S, said
heterocyclic ring system substituted with 0-2 R.sup.2; Y is
selected from C.sub.3-6 cycloalkyl substituted with Z, aryl
substituted with Z, 5-6 membered heterocyclic ring system
containing at least one heteroatom selected from the group
consisting of N, O, and S, said heterocyclic ring system
substituted with Z; C.sub.3-6 cycloalkyl substituted with
--(C.sub.1-3 alkyl)--Z, aryl substituted with --(C.sub.1-3
alkyl)--Z, and 5-6 membered heterocyclic ring system containing at
least one heteroatom selected from the group consisting of N, O,
and S, said heterocyclic ring system substituted with --(C.sub.1-3
alkyl)--Z; Z is selected from H, --CH(OH)R.sup.2,
--C(ethylenedioxy)R.sup.2, --SR.sup.2, --NR.sup.2R.sup.3,
--C(O)R.sup.2, --C(O)NR.sup.2R.sup.3, --NR.sup.3C(O)R.sup.2,
--C(O)OR.sup.2, --OC(O)R.sup.2, --CH(=NR.sup.4)NR.sup.2R.sup.3,
--NHC(=NR.sup.4)NR.sup.2R.sup.3, --S(O)R.sup.2,
--S(O).sup.2R.sup.2, --S(O).sup.2NR.sup.2R.sup.3, and
--NR.sup.3S(O).sub.2R.sup.2; R.sup.2, at each occurrence, is
independently selected from halo, C.sub.1-3 haloalkyl, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl,
aryl substituted with 0-5 R.sup.42; C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.41, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.41; R.sup.3,
at each occurrence, is independently selected from H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and C.sub.1-4 alkoxy;
alternatively, R.sup.2 and R.sup.3 join to form a 5- or 6-membered
ring optionally substituted with --O-- or --N(R.sup.4)--; R.sup.4,
at each occurrence, is independently selected from H and C.sub.1-4
alkyl; R.sup.5 is H or C.sub.1-4 alkyl; R.sup.6a and R.sub.6b, at
each occurrence, are independently selected from H, --OH,
--NR.sup.46R.sup.47, --CF.sub.3, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.3-6 cycloalkyl, and aryl substituted with 0-3 R.sup.44;
R.sup.7 and R.sup.9, at each occurrence, are independently selected
from H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN, --NO.sub.2,
--NR.sup.46R.sup.47, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, (C.sub.1-4
haloalkyl)oxy, C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
C.sub.1-4 alkyl substituted with 0-2 R.sup.11, C.sub.3-10
carbocyclic group substituted with 0-3 R.sup.33, aryl substituted
with 0-5 R.sup.33, 5-10 membered heterocyclic ring system
containing from 1-4 heteroatoms selected from the group consisting
of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12, SR.sup.12,
NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12, NR.sup.14S(O).sub.2R.sup.12,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15; R.sup.8
is selected from H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, (C.sub.1-4 haloalkyl)oxy,
C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33, C.sub.1-4
alkyl substituted with 0-2 R.sup.11, C.sub.2-4 alkenyl substituted
with 0-2 R.sup.11, C.sub.2-4 alkynyl substituted with 0-1 R.sup.11,
C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33, aryl
substituted with 0-5 R.sup.33, 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12,
SR.sup.12, NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12,
C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12, C(O)OR.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12, NR.sup.14S(O).sub.2R.sup.12,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15; R.sup.10
is selected from H, --OH, C.sub.1-6 alkyl substituted with 0-1
R.sup.10B, C.sub.2-6 alkenyl substituted with 0-1 R.sup.10B,
C.sub.2-6 alkynyl substituted with 0-1 R.sup.10B, and C.sub.1-6
alkoxy; R.sup.10B is selected from C.sub.1-4 alkoxy, C.sub.3-6
cycloalkyl, C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, phenyl substituted with 0-3 R.sup.33, and 5-6 membered
heterocyclic ring system containing 1, 2, or 3 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-2
R.sup.44; R.sup.11 is selected from H, halo, --CF.sub.3, --CN,
--NO.sub.2, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, C.sub.3-10 cycloalkyl,
C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33, aryl
substituted with 0-5 R.sup.33, 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12,
SR.sup.12, NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12,
C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12, C(O)OR.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12, NR.sup.14S(O).sub.2R.sup.12,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.1- 5, and NR.sup.12C(O)NHR.sup.15,
R.sup.12, at each occurrence, is independently selected from
C.sub.1-4 alkyl substituted with 0-1 R.sup.12a, C.sub.2-4 alkenyl
substituted with 0-1 R.sup.12a, C.sub.2-4 alkynyl substituted with
0-1 R.sup.12a, C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.33,
phenyl substituted with 0-5 R.sup.33; C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.33, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; R.sup.12a,
at each occurrence, is independently selected from phenyl
substituted with 0-5 R.sup.33; C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.33, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; R.sup.13,
at each occurrence, is independently selected from H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl; alternatively,
R.sup.12 and R.sup.13 join to form a 5- or 6-membered ring
optionally substituted with --O-- or --N(R.sup.14)--;
alternatively, R.sup.12 and R.sup.13 when attached to N may be
combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S, wherein said bicyclic heterocyclic ring
system is unsaturated or partially saturated, wherein said bicyclic
heterocyclic ring system is substituted with 0-3 R.sup.16;
R.sup.14, at each occurrence, is independently selected from H and
C.sub.1-4 alkyl; R.sup.15, at each occurrence, is independently
selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl; R.sup.16 at each occurrence, is independently selected
from H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, C.sub.1-3 haloalkyl-oxy-,
and C.sub.1-3 alkyloxy-; R.sup.31, at each occurrence, is
independently selected from H, OH, halo, CF.sub.3,
SO.sub.2R.sup.45, NR.sup.46R.sup.47, and C.sub.1-4 alkyl; R.sup.33,
at each occurrence, is independently selected from H, OH, halo, CN,
NO.sub.2, CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47, --C(=O)H,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6
cycloalkyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkyl-oxy-,
C.sub.1-4 alkyloxy-, C.sub.1-4 alkylthio-, C.sub.1-4
alkyl--C(=O)--, C.sub.1-4 alkyl-C(=O)NH--, C.sub.1-4
alkyl--OC(=O)--, C.sub.1-4 alkyl--C(=O)O--, C.sub.3-6
cycloalkyl-oxy-, C.sub.3-6 cycloalkylmethyl-oxy-; C.sub.1-6 alkyl
substituted with OH, methoxy, ethoxy, propoxy, or butoxy; and
C.sub.2-6 alkenyl substituted with OH, methoxy, ethoxy, propoxy, or
butoxy; R.sup.41, at each occurrence, is independently selected
from H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, =O; C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl C.sub.1-4 alkyl
substituted with 0-1 R.sup.43, aryl substituted with 0-3 R.sup.42,
and 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44; R.sup.42, at each occurrence, is
independently selected from H, CF.sub.3, halo, OH, CO.sub.2H,
SO.sub.2R.sup.45, SOR.sup.45, SR.sup.45, NR.sup.46SO.sub.2R.sup.45,
NR.sup.46COR.sup.45, NR.sup.46R.sup.47, NO.sub.2, CN,
CH(=NH)NH.sub.2, NHC(=NH)NH.sub.2, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.3-6
cycloalkyl, C.sub.1-4 alkyl substituted with 0-1 R.sup.43, aryl
substituted with 0-3 R.sup.44, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.44; R.sup.43
is C.sub.3-6 cycloalkyl or aryl substituted with 0-3 R.sup.44;
R.sup.44, at each occurrence, is independently selected from H,
halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, and
C.sub.1-4 alkoxy; R.sup.45 is C.sub.1-4 alkyl; R.sup.46, at each
occurrence, is independently selected from H and C.sub.1-4 alkyl;
R.sup.47, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl, --C(=O)NH(C.sub.1-4 alkyl), --SO.sub.2(C.sub.1-4
alkyl), --C(=O)O(C.sub.1-4 alkyl), --C(=O)(C.sub.1-4 alkyl), and
--C(=O)H; k is 1 or 2; m is 0, 1, or 2; n is 0, 1, 2, or 3;
provided when m is 0 or 1 then k is 1 or 2; provided when m is 2
then k is 1; provided that when R.sup.6 or R.sup.6ais NH.sub.2,
then X is not --CH(R.sup.10); and provided that when n=O, then
R.sup.6 or R.sup.6ais not NH.sub.2 or --OH.
2. The method as defined in claim 1 where in the compound
administered: X is --CHR.sup.10-- or --C(=O)--; R.sup.1 is selected
from H, C(=O)R.sup.2, C(=O)OR.sup.2, C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-6 alkyl
substituted with 0-2 R.sup.2, C.sub.2-6 alkenyl substituted with
0-2 R.sup.2, C.sub.2-6 alkynyl substituted with 0-2 R.sup.2, aryl
substituted with 0-2 R.sup.2, and 5-6 membered heterocyclic ring
system containing at least one heteroatom selected from the group
consisting of N, O, and S, said heterocyclic ring system
substituted with 0-2 R.sup.2; R.sup.2, at each occurrence, is
independently selected from F, Cl, CH.sub.2F, CHF.sub.2, CF.sub.3,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-6
cycloalkyl, phenyl substituted with 0-5 R.sup.42; C.sub.3-10
carbocyclic group substituted with 0-3 R.sup.41, and 5-10 membered
heterocyclic ring system containing from 1-4 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-3
R.sup.41; R.sup.5 is H, methyl, ethyl, propyl, or butyl; R.sup.6ais
selected from H, --OH, --NR.sup.46R.sup.47, --CF.sub.3, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, and aryl substituted
with 0-3 R.sup.44; R.sup.6b is H; R.sup.7 and R.sup.9, at each
occurrence, are independently selected from H, halo, --CF.sub.3,
--OCF.sub.3, --OH, --CN, --NO.sub.2, --NR.sup.46R.sup.47, C.sub.1-8
alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 haloalkyl,
C.sub.1-8 alkoxy, (C.sub.1-4 haloalkyl)oxy, C.sub.3-10 cycloalkyl
substituted with 0-2 R.sup.33, C.sub.1-4 alkyl substituted with 0-2
R.sup.11, C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, aryl substituted with 0-5 R.sup.33, 5-10 membered
heterocyclic ring system containing from 1-4 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-3
R.sup.31; OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12,
C(O)OR.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12,
CH(=NR.sup.14)NR.sup.12R.sup.13, NHC(=NR.sup.14)NR.sup.12R.sup.13,
S(O,R.sup.12, S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup.13, NR.sup.14S(O)R.sup.12,
NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.1- 5, and
NR.sup.12C(O)NHR.sup.15; R8 is selected from H, halo, --CF.sub.3,
--OCF.sub.3, --OH, --CN, --NO.sub.2, C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy,
(C.sub.1-4 haloalkyl)oxy, C.sub.3-10 cycloalkyl substituted with
0-2 R.sup.33, C.sup.1-4 alkyl substituted with 0-2 R.sup.11,
C.sub.2-4 alkenyl substituted with 0-2 R.sup.11, C.sub.2-4 alkynyl
substituted with 0-1 R.sup.11, C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.33, aryl substituted with 0-5 R.sup.33,
5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31; OR.sup.12, SR.sup.12,
NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12, NR.sup.14S(O).sub.2R.sup.12,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15; R.sup.10
is selected from H, --OH, C.sub.1-6 alkyl substituted with 0-1
R.sup.10B, C.sub.2-6 alkenyl substituted with 0-1 R.sup.10B,
C.sub.2-6 alkynyl substituted with 0-1 R.sup.10B, and C.sub.1-6
alkoxy; R.sup.10B is selected from C.sub.1-4 alkoxy, C.sub.3-6
cycloalkyl, C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, phenyl substituted with 0-3 R.sup.33, and 5-6 membered
heterocyclic ring system containing 1, 2, or 3 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-2
R.sup.44; R.sup.11 is selected from H, halo, --CF.sub.3, --CN,
--NO.sub.2, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, C.sub.3-10 cycloalkyl,
C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33, aryl
substituted with 0-5 R.sup.33, 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12,
SR.sup.12, NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12,
C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12, C(O)OR.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12, NR.sup.14S(O).sub.2R.sup.12,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.1- 5, and NR.sup.12C(O)NHR.sup.15;
R.sup.12, at each occurrence, is independently selected from
C.sub.1-.sub.4 alkyl substituted with 0-1 R.sup.12a, C.sub.2-4
alkenyl substituted with 0-1 R.sup.12a, C.sub.2-4 alkynyl
substituted with 0-1 R.sup.12a, C.sub.3-6 cycloalkyl substituted
with 0-3 R.sup.33, phenyl substituted with 0-5 R.sup.33; C.sub.3-10
carbocyclic group substituted with 0-3 R.sup.33, and 5-10 membered
heterocyclic ring system containing from 1-4 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-3
R.sup.31; R.sup.12a, at each occurrence, is independently selected
from phenyl substituted with 0-5 R.sup.33; C.sub.3-10 carbocyclic
group substituted with 0-3 R.sup.33, and 5-10 membered heterocyclic
ring system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; R.sup.13,
at each occurrence, is independently selected from H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl; alternatively,
R.sup.12 and R.sup.13 join to form a 5- or 6-membered ring
optionally substituted with --O-- or --N(R.sup.14)--;
alternatively, R.sup.12 and R.sup.13 when attached to N may be
combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S, wherein said bicyclic heterocyclic ring
system is unsaturated or partially saturated, wherein said bicyclic
heterocyclic ring system is substituted with 0-3 R.sup.16;
R.sup.14, at each occurrence, is independently selected from H and
C.sub.1-4 alkyl; R.sup.15, at each occurrence, is independently
selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl; R.sup.16, at each occurrence, is independently selected
from H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, C.sub.1-3 haloalkyl-oxy-,
and C.sub.1-3 alkyloxy-; R.sup.31, at each occurrence, is
independently selected from H, OH, halo, CF.sub.3,
SO.sub.2R.sup.45, NR.sup.46R.sup.47, and C.sub.1-4 alkyl; R.sup.33,
at each occurrence, is independently selected from H, OH, halo, CN,
NO.sub.2, CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47, --C(=O)H,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6
cycloalkyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkyl-oxy-,
C.sub.1-4 alkyloxy-, C.sub.1-4 alkylthio-, C.sub.1-4 alkyl-C(=O)--,
C.sub.1-4 alkyl-C(=O)NH--, C.sub.1-4 alkyl--OC(=O)--, C.sub.1-4
alkyl--C(=O)O--, C.sub.3-6 cycloalkyl-oxy-, C.sub.3-6
cycloalkylmethyl-oxy-; C.sub.1-6 alkyl substituted with OH,
methoxy, ethoxy, propoxy, or butoxy; and C.sub.2-6 alkenyl
substituted with OH, methoxy, ethoxy, propoxy, or butoxy; R.sup.41,
at each occurrence, is independently selected from H, CF.sub.3,
halo, OH, CO.sub.2H, SO.sub.2R.sup.45, NR.sup.46R.sup.47, NO.sub.2,
CN; C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
aryl substituted with 0-3 R.sup.42, and 5-10 membered heterocyclic
ring system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.44; R.sup.42,
at each occurrence, is independently selected from H, CF.sub.3,
halo, OH, CO.sub.2H, SO.sub.2R.sup.45, NR.sup.46R.sup.47, NO.sub.2,
CN, CH(=NH)NH.sub.2, NHC(=NH)NH.sub.2, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.3-6
cycloalkyl, C.sub.1-4 alkyl substituted with 0-1 R.sup.43, aryl
substituted with 0-3 R.sup.44, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.44; R.sup.43
is C.sub.3-6 cycloalkyl or aryl substituted with 0-3 R.sup.44;
R.sup.44, at each occurrence, is independently selected from H,
halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, and
C.sub.1-4 alkoxy; R.sup.45 is C.sub.1-4 alkyl; R.sup.46, at each
occurrence, is independently selected from H and C.sub.1-4 alkyl;
R.sup.47, at each occurrence, is independently selected from H and
C.sub.1-4 alkyl; k is 1 or 2; m is 0, 1, or 2; and n is 0, 1, 2, or
3.
3. The method as defined in claim 2 where in the compound
administered: X is --CHR.sup.10--; R.sup.1 is selected from H,
C(=O)R.sup.2, C(=O) OR.sup.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.1-4 alkyl
substituted with 0-2 R.sup.2, C.sub.2-4 alkenyl substituted with
0-2 R.sup.2, and C.sub.2-4 alkynyl substituted with 0-2 R.sup.2;
R.sup.2, at each occurrence, is independently selected from
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-6
cycloalkyl, phenyl substituted with 0-5 R.sup.42; C.sub.3-10
carbocyclic group substituted with 0-3 R.sup.41, and 5-10 membered
heterocyclic ring system containing from 1-4 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-3
R.sup.41; R.sup.5 is H, methyl, ethyl, propyl, or butyl; R.sup.6ais
selected independently from H, --OH, --NR.sup.46R.sup.47,
--CF.sub.3, C.sub.1-3 alkyl, and C.sub.1-3 alkoxy; R.sup.6b is H;
R.sup.7 and R.sup.9, at each occurrence, are independently selected
from H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN, --NO.sub.2,
--NR.sup.46R.sup.47, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, (C.sub.1-4
haloalkyl)oxy, C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
C.sub.1-4 alkyl substituted with 0-2 R.sup.11, C.sub.3-10
carbocyclic group substituted with 0-3 R.sup.33, aryl substituted
with 0-5 R.sup.33, 5-10 membered heterocyclic ring system
containing from 1-4 heteroatoms selected from the group consisting
of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12, SR.sup.12,
NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12, and NR.sup.14S(O).sub.2R.sup.12; R.sup.8 is
selected from H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, (C.sub.1-4 haloalkyl)oxy,
C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33, C.sub.1-4
alkyl substituted with 0-2 R.sup.11, C.sub.2-4 alkenyl substituted
with 0-2 R.sup.11, C.sub.2-4 alkynyl substituted with 0-1 R.sup.11,
C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33, aryl
substituted with 0-5 R.sup.33, 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12,
SR.sup.12, NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12,
C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12, C(O)OR.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12, NR.sup.14S(O).sub.2R.sup.12,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15; R.sup.10
is selected from H, --OH, C.sub.1-6 alkyl substituted with 0-1
R.sup.10B, C.sub.2-6 alkenyl substituted with 0-1 R.sup.10B,
C.sub.2-6 alkynyl substituted with 0-1 R.sup.10B, and C.sub.1-6
alkoxy; R.sup.10B is selected from C.sub.1-4 alkoxy, C.sub.3-6
cycloalkyl, C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, phenyl substituted with 0-3 R.sup.33, and 5-6 membered
heterocyclic ring system containing 1, 2, or 3 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-2
R.sup.44; R.sup.11 is selected from H, halo, --CF.sub.3, --CN,
--NO.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl,
C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33, aryl
substituted with 0-5 R.sup.33, 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12,
SR.sup.12, NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12,
C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12, C(O)OR.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12, and NR.sup.14S(O).sub.2R.sup.12; R.sup.12,
at each occurrence, is independently selected from C.sub.1-4 alkyl
substituted with 0-1 R.sup.12a, C.sub.2-4 alkenyl substituted with
0-1 R.sup.12a, C.sub.2-4 alkynyl substituted with 0-1 R.sup.12a,
C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.33, phenyl
substituted with 0-5 R.sup.33; C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.33, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; R.sup.12a,
at each occurrence, is independently selected from phenyl
substituted with 0-5 R.sup.33; C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.33, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; R.sup.13,
at each occurrence, is independently selected from H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl; alternatively,
R.sup.12 and R.sup.13 join to form a 5- or 6-membered ring
optionally substituted with --O-- or --N(R.sup.14)--;
alternatively, R.sup.12 and R.sup.13 when attached to N may be
combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S, wherein said bicyclic heterocyclic ring
system is unsaturated or partially saturated, wherein said bicyclic
heterocyclic ring system is substituted with 0-3 R.sup.16;
R.sup.14, at each occurrence, is independently selected from H,
methyl, ethyl, propyl, and butyl; R.sup.15, at each occurrence, is
independently selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
and C.sub.2-4 alkynyl; R.sup.16, at each occurrence, is
independently selected from H, OH, F, Cl, CN, NO.sub.2, CF.sub.3,
SO.sub.2R.sup.45, NR.sup.46R.sup.47, --C(=O)H, methyl, ethyl,
methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; R.sup.31,
at each occurrence, is independently selected from H, OH, halo,
CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47, and C.sub.1-4 alkyl;
R.sup.33, at each occurrence, is independently selected from H, OH,
halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47,
--C(=O)H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-6 cycloalkyl, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkyl-oxy-, C.sub.1-4 alkyloxy-, C.sub.1-4 alkylthio-,
C.sub.1-4 alkyl--C(=O)--, C.sub.1-4 alkyl-C(=O)NH--, C.sub.1-4
alkyl--OC(=O)--, C.sub.1-4 alkyl--C(=O)O--, C.sub.3-6
cycloalkyl-oxy-, C.sub.3-6 cycloalkylmethyl-oxy-; C.sub.1-6 alkyl
substituted with OH, methoxy, ethoxy, propoxy, or butoxy; and
C.sub.2-6 alkenyl substituted with OH, methoxy, ethoxy, propoxy, or
butoxy; R.sup.41, at each occurrence, is independently selected
from H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl C.sub.1-4 alkyl
substituted with 0-1 R.sup.43, aryl substituted with 0-3 R.sup.42,
and 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44; R.sup.42, at each occurrence, is
independently selected from H, CF.sub.3, halo, OH, CO.sub.2H,
SO.sub.2R.sup.45, NR.sup.46R.sup.47, NO.sub.2, CN, CH(=NH)NH.sub.2,
NHC(=NH)NH.sub.2, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl, C.sub.1-4 alkyl
substituted with 0-1 R.sup.43, aryl substituted with 0-3 R.sup.44,
and 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44; R.sup.43 is C.sub.3-6 cycloalkyl or
aryl substituted with 0-3 R.sup.44; R.sup.44, at each occurrence,
is independently selected from H, halo, --OH, NR.sup.46R.sup.47,
CO.sub.2H, SO.sub.2R.sup.45, --CF.sub.3, --OCF.sub.3, --CN,
--NO.sub.2, C.sub.1-4 alkyl, and C.sub.1-4 alkoxy; R.sup.45 is
C.sub.1-4 alkyl; R.sup.46, at each occurrence, is independently
selected from H and C.sub.1-4 alkyl; R.sup.47, at each occurrence,
is independently selected from H and C.sub.1-4 alkyl; k is 1 or 2;
m is 0 or 1; and n is 0, 1 or 2.
4. The method as defined in claim 2 where in the compound
administered: X is --CH.sub.2--; R.sup.1 is selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-4
cycloalkyl, C.sub.1-3 alkyl substituted with 0-1 R.sup.2, C.sub.2-3
alkenyl substituted with 0-1 R.sup.2, and C.sub.2-3 alkynyl
substituted with 0-1 R.sup.2; R.sup.2, at each occurrence, is
independently selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, phenyl substituted with
0-5 R.sup.42; C.sub.3-6 carbocyclic group substituted with 0-3
R.sup.41, and 5-6 membered heterocyclic ring system containing 1,
2, or 3 heteroatoms selected from the group consisting of N, O, and
S substituted with 0-3 R.sup.41; R.sup.5 is H, methyl, ethyl,
propyl, or butyl; R.sup.6ais H, methyl, ethyl, methoxy, --OH, or
--CF.sub.3; R.sup.6b is H; R.sup.7 and R.sup.9, at each occurrence,
are independently selected from H, halo, --CF.sub.3, --OCF.sub.3,
--OH, --CN, --NO.sub.2, --NR.sup.46R.sup.47, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy, (C.sub.1-4 haloalkyl)oxy, C.sub.3-10 cycloalkyl
substituted with 0-2 R.sup.33, C.sub.1-4 alkyl substituted with 0-2
R.sup.11, C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, aryl substituted with 0-5 R.sup.33, and 5-6 membered
heterocyclic ring system containing 1, 2, or 3 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-3
R.sup.31; R.sup.8 is selected from H, halo, --CF.sub.3,
--OCF.sub.3, --OH, --CN, --NO.sub.2, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy,
(C.sub.1-4 haloalkyl)oxy, C.sub.3-10 cycloalkyl substituted with
0-2 R.sup.33, C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
C.sub.2-4 alkenyl substituted with 0-2 R.sup.11, C.sub.2-4 alkynyl
substituted with 0-1 R.sup.11, C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.33, aryl substituted with 0-5 R.sup.33,
5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31; OR.sup.12, SR.sup.12,
NR.sup.12R.sup.13, NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.1- 5, and NR.sup.12C(O)NHR.sup.15;
R.sup.11 is selected from H, halo, --CF.sub.3, --CN, --NO.sub.2,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, C.sub.1-4 alkoxy, (C.sub.1-4 haloalkyl)oxy, C.sub.3-10
cycloalkyl substituted with 0-2 R.sup.33, C.sub.3-10 carbocyclic
group substituted with 0-3 R.sup.33, aryl substituted with 0-5
R.sup.33, and 5-6 membered heterocyclic ring system containing 1,
2, or 3 heteroatoms selected from the group consisting of N, O, and
S substituted with 0-3 R.sup.31; R.sup.12, at each occurrence, is
independently selected from C.sub.1-4 alkyl substituted with 0-1
R.sup.12a, C.sub.2-4 alkenyl substituted with 0-1 R.sup.12a,
C.sub.2-4 alkynyl substituted with 0-1 R.sup.12a, C.sub.3-6
cycloalkyl substituted with 0-3 R.sup.33, phenyl substituted with
0-5 R.sup.33; C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, and 5-10 membered heterocyclic ring system containing
from 1-4 heteroatoms selected from the group consisting of N, O,
and S substituted with 0-3 R.sup.31; R.sup.12a, at each occurrence,
is independently selected from phenyl substituted with 0-5
R.sup.33; C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, and 5-10 membered heterocyclic ring system containing
from 1-4 heteroatoms selected from the group consisting of N, O,
and S substituted with 0-3 R.sup.31; R.sup.13, at each occurrence,
is independently selected from H, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, and C.sub.2-4 alkynyl; alternatively, R.sup.12 and
R.sup.13 join to form a 5- or 6-membered ring optionally
substituted with --O-- or --N(R.sup.14)--; alternatively, R.sup.12
and R.sup.13 when attached to N may be combined to form a 9- or
10-membered bicyclic heterocyclic ring system containing from 1-3
heteroatoms selected from the group consisting of one N, two N,
three N, one N one O, and one N one S; wherein said bicyclic
heterocyclic ring system is unsaturated or partially saturated,
wherein said bicyclic heterocyclic ring system is substituted with
0-2 R.sup.16; R.sup.14, at each occurrence, is independently
selected from H, methyl, ethyl, propyl, and butyl; R.sup.15, at
each occurrence, is independently selected from H, methyl, ethyl,
propyl, and butyl; R.sup.16 at each occurrence, is independently
selected from H, OH, F, Cl, CN, NO.sub.2, methyl, ethyl, methoxy,
ethoxy, trifluoromethyl, and trifluoromethoxy; R.sup.31, at each
occurrence, is independently selected from H, OH, halo, CF.sub.3,
methyl, ethyl, and propyl; R.sup.33, at each occurrence, is
independently selected from H, OH, halo, CN, NO.sub.2, CF.sub.3,
SO.sub.2R.sup.45, NR.sup.46R.sup.47, --C(=O)H, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkyl-oxy-, C.sub.1-4 alkyloxy-,
C.sub.1-4 alkylthio-, C.sub.1-4 alkyl--C(=O)--, C.sub.1-4
alkyl-C(=O)NH--, C.sub.1-4 alkyl--OC(=O)--, C.sub.1-4
alkyl--C(=O)O--, C.sub.3-6 cycloalkyl-oxy-, C.sub.3-6
cycloalkylmethyl-oxy-; C.sub.1-6 alkyl substituted with OH,
methoxy, ethoxy, propoxy, or butoxy; and C.sub.2-6 alkenyl
substituted with OH, methoxy, ethoxy, propoxy, or butoxy; R.sup.41,
at each occurrence, is independently selected from H, CF.sub.3,
halo, OH, CO.sub.2H, SO.sub.2R.sup.45, NR.sup.46R.sup.47, NO.sub.2,
CN, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy,
C.sub.1-3 haloalkyl, and C.sub.1-3 alkyl; R.sup.42, at each
occurrence, is independently selected from H, CF.sub.3, halo, OH,
CO.sub.2H, SO.sub.2R.sup.45, NR.sup.46R.sup.47, NO.sub.2, CN,
CH(=NH)NH.sub.2, NHC(=NH)NH.sub.2, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkyl, C.sub.3-6
cycloalkyl, and C.sub.1-3 alkyl; R.sup.43 is cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl, each
substituted with 0-3 R.sup.44; R.sup.44, at each occurrence, is
independently selected from H, halo, --OH, NR.sup.46R.sup.47,
CO.sub.2H, SO.sub.2R.sup.45, --CF.sub.3, --OCF.sub.3, --CN,
--NO.sub.2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,
and butoxy; R.sup.45 is methyl, ethyl, propyl, or butyl; R.sup.46,
at each occurrence, is independently selected from H, methyl,
ethyl, propyl, and butyl; R.sup.47, at each occurrence, is
independently selected from from H, methyl, ethyl, propyl, and
butyl; k is 1; m is 1; and n is 0, 1 or 2.
5. The method as defined in claim 2 where in the compound
administered: X is --CH.sub.2--; R.sup.1 is selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C-3-4
cycloalkyl, C.sub.1-3 alkyl substituted with 0-1 R.sup.2, C.sub.2-3
alkenyl substituted with 0-1 R.sup.2, and C.sub.2-3 alkynyl
substituted with 0-1 R.sup.2; R.sup.2, at each occurrence, is
independently selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, phenyl substituted with
0-5 R.sup.42; C.sub.3-6 carbocyclic group substituted with 0-3
R.sup.41, and 5-6 membered heterocyclic ring system containing 1,
2, or 3 heteroatoms selected from the group consisting of N, O, and
S substituted with 0-3 R.sup.41; R.sup.5 is H, methyl, ethyl,
propyl, or butyl; R.sup.6ais H, methyl, ethyl, methoxy, --OH, or
--CF.sub.3; R.sup.6b is H; R.sup.7 and R.sup.9, at each occurrence,
are independently selected from H, F, Cl, --CH.sub.3, --OCH.sub.3,
--CF.sub.3, --OCF.sub.3, --CN, and --NO.sub.2, R.sup.8 is selected
from H, F, Cl, Br, --CF.sub.3, --OCF.sub.3, --OH, --CN, --NO.sub.2,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, C.sub.1-4 alkoxy, (C.sub.1-4 haloalkyl)oxy, C.sub.3-10
cycloalkyl substituted with 0-2 R.sup.33, C.sub.1-4 alkyl
substituted with 0-2 R.sup.11, C.sub.2-4 alkenyl substituted with
0-2 R.sup.11, C.sub.2-4 alkynyl substituted with 0-1 R.sup.11,
C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33 aryl
substituted with 0-5 R.sup.33, 5-6 membered heterocyclic ring
system containing 1, 2, or 3 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12,
SR.sup.12, NR.sup.12R.sup.13, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15, and
NR.sup.12C(O)NHR.sup.15; R.sup.11 is selected from H, halo,
--CF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy,
(C.sub.1-4 haloalkyl)oxy, C.sub.3-10 cycloalkyl substituted with
0-2 R.sup.33, C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, aryl substituted with 0-5 R.sup.33, and 5-6 membered
heterocyclic ring system containing 1, 2, or 3 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-3
R.sup.31; R.sup.12, at each occurrence, is independently selected
from C.sub.1-4 alkyl substituted with 0-1 R.sup.12a, C.sub.2-4
alkenyl substituted with O-1 R.sup.12a, C.sub.2-4 alkynyl
substituted with 0-1 R.sup.12a, C.sub.3-6 cycloalkyl substituted
with 0-3 R.sup.33, phenyl substituted with 0-5 R.sup.33; C.sub.3-10
carbocyclic group substituted with 0-3 R.sup.33, and 5-10 membered
heterocyclic ring system containing from 1-4 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-3
R.sup.31; R.sup.12a, at each occurrence, is independently selected
from phenyl substituted with 0-5 R.sup.33; C.sub.3-10 carbocyclic
group substituted with 0-3 R.sup.33, and 5-10 membered heterocyclic
ring system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; R.sup.13,
at each occurrence, is independently selected from H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl; alternatively,
R.sup.12 and R.sup.13 join to form a 5- or 6-membered ring
optionally substituted with --O-- or --N(R.sup.14)--;
alternatively, R.sup.12 and R.sup.13 when attached to N may be
combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S; wherein said bicyclic heterocyclic ring
system is selected from indolyl, indolinyl, indazolyl,
benzimidazolyl, benzimidazolinyl, benztriazolyl, benzoxazolyl,
benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl; wherein said
bicyclic heterocyclic ring system is substituted with 0-1 R.sup.16;
R.sup.14, at each occurrence, is independently selected from H,
methyl, ethyl, propyl, and butyl; R.sup.15, at each occurrence, is
independently selected from H, methyl, ethyl, propyl, and butyl;
R.sup.16 at each occurrence, is independently selected from H, OH,
F, Cl, CN, NO.sub.2, methyl, ethyl, methoxy, ethoxy,
trifluoromethyl, and trifluoromethoxy; R.sup.31, at each
occurrence, is independently selected from H, OH, halo, CF.sub.3,
methyl, ethyl, and propyl; R.sup.33, at each occurrence, is
independently selected from H, OH, halo, CN, NO.sub.2, CF.sub.3,
SO.sub.2R.sup.45, NR.sup.46R.sup.47, --C(=O)H, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkyl-oxy-, C.sub.1-4 alkyloxy-,
C.sub.1-4 alkylthio-, C.sub.1-4 alkyl--C(=O)--, C.sub.1-4
alkyl-C(=O)NH--, C.sub.1-4 alkyl--OC(=O)--, C.sub.1-4
alkyl--C(=O)O--, C.sub.3-6 cycloalkyl-oxy-, C.sub.3-6
cycloalkylmethyl-oxy-; C.sub.1-6 alkyl substituted with OH,
methoxy, ethoxy, propoxy, or butoxy; and C.sub.2-6 alkenyl
substituted with OH, methoxy, ethoxy, propoxy, or butoxy; R.sup.41,
at each occurrence, is independently selected from H, CF.sub.3,
halo, OH, CO.sub.2H, SO.sub.2R.sup.45, NR.sup.46R.sup.47, NO.sub.2,
CN, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy,
C.sub.1-3 haloalkyl, and C.sub.1-3 alkyl; R.sup.42, at each
occurrence, is independently selected from H, CF.sub.3, halo, OH,
CO.sub.2H, SO.sub.2R.sup.45, NR.sup.46R.sup.47, NO.sub.2, CN,
CH(=NH)NH.sub.2, NHC(=NH)NH.sub.2, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkyl, C.sub.3-6
cycloalkyl, and C.sub.1-.sub.3 alkyl; R.sup.43 is cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl, each
substituted with 0-3 R.sup.44; R.sup.44, at each occurrence, is
independently selected from H, halo, --OH, NR.sup.46R.sup.47,
CO.sub.2H, SO.sub.2R.sup.45, --CF.sub.3, --OCF.sub.3, --CN,
--NO.sub.2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,
and butoxy; R.sup.45 is methyl, ethyl, propyl, or butyl; R.sup.46,
at each occurrence, is independently selected from H, methyl,
ethyl, propyl, and butyl; R.sup.47, at each occurrence, is
independently selected from from H, methyl, ethyl, propyl, and
butyl; k is 1; m is 1; and n is 0, 1 or 2.
6. The method as defined in claim 2 where in the compound
administered: X is --CH.sub.2--; R.sup.1 is selected from H,
C.sub.15 alkyl substituted with 0-1 R.sup.2, C.sub.2-5 alkenyl
substituted with 0-1 R.sup.2, and C.sub.2-3 alkynyl substituted
with 0-1 R.sup.2; R.sup.2 is C.sub.3-6 cycloalkyl; R.sup.5 is H,
methyl, ethyl, or propyl; R.sup.6ais H, methyl, or ethyl; R.sup.6b
is H; R.sup.7 and R.sup.9, at each occurrence, are independently
selected from H, F, Cl, --CH.sub.3, --OCH.sub.3, --CF.sub.3,
--OCF.sub.3, --CN, and --NO.sub.2, R.sup.8 is selected from methyl
substituted with R.sup.11; ethenyl substituted with R.sup.11;
OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15, and
NR.sup.12C(O)NHR.sup.15; R.sup.11 is selected from phenyl-
substituted with 0-5 fluoro;
2-(H.sub.3CCH.sub.2C(=O))-phenyl-substituted with R.sup.33;
2-(H.sub.3CC(=O))-phenyl-substituted with R.sup.33;
2-(HC(=O))-phenyl-substituted with R.sup.33;
2-(H.sub.3CCH(OH))-phenyl-su- bstituted with R.sup.33;
2-(H.sub.3CCH.sub.2CH(OH))-phenyl-substituted with R.sup.33;
2-(HOCH.sub.2)-phenyl-substituted with R.sup.33;
2-(HOCH.sub.2CH.sub.2)-phenyl-substituted with R.sup.33;
2-(H.sub.3COCH.sub.2)-phenyl-substituted with R.sup.33;
2-(H.sub.3COCH.sub.2CH.sub.2)-phenyl-substituted with R.sup.33;
2-(H.sub.3CCH(OMe))-phenyl-substituted with R.sup.33;
2-(H.sub.3COC(=O))-phenyl-substituted with R.sup.33;
2-(HOCH.sub.2CH=CH)-phenyl-substituted with R.sup.33;
2-((MeOC=O)CH=CH)-phenyl-substituted with R.sup.33;
2-(methyl)-phenyl-substituted with R.sup.33;
2-(ethyl)-phenyl-substituted with R.sup.33;
2-(i-propyl)-phenyl-substituted with R.sup.33;
2-(F.sub.3C)-phenyl-substituted with R.sup.33;
2-(NC)-phenyl-substituted with R.sup.33;
2-(H.sub.3CO)-phenyl-substituted with R.sup.33;
2-(fluoro)-phenyl-substituted with R.sup.33;
2-(chloro)-phenyl-substitute- d with R.sup.33;
3-(NC)-phenyl-substituted with R.sup.33;
3-(H.sub.3CO)-phenyl-substituted with R.sup.33;
3-(fluoro)-phenyl-substit- uted with R.sup.33;
3-(chloro)-phenyl-substituted with R.sup.33;
4-(NC)-phenyl-substituted with R.sup.33;
4-(fluoro)-phenyl-substituted with R.sup.33;
4-(chloro)-phenyl-substituted with R.sup.33;
4-(H.sub.3CS)-phenyl-substituted with R.sup.33;
4-(H.sub.3CO)-phenyl-subs- tituted with R.sup.33;
4-(ethoxy)-phenyl-substituted with R.sup.33;
4-(i-propoxy)-phenyl-substituted with R.sup.33;
4-(i-butoxy)-phenyl-subst- ituted with R.sup.33;
4-(H.sub.3CCH.sub.2CH.sub.2C(=O))-phenyl-substituted with R.sup.33;
4-((H.sub.3C)2CHC(=O))-phenyl-substituted with R.sup.33;
4-(H.sub.3CCH.sub.2C(=O))-phenyl-substituted with R.sup.33;
4-(H.sub.3CC(=O))-phenyl-substituted with R.sup.33;
4-(H.sub.3CCH.sub.2CH.sub.2CH(OH))-phenyl-substituted with
R.sup.33; 4-((H.sub.3C)2CHCH(OH))-phenyl-substituted with R.sup.33;
4-(H.sub.3CCH.sub.2CH(OH))-phenyl-substituted with R.sup.33;
4-(H.sub.3CCH(OH))-phenyl-substituted with R.sup.33;
4-(cyclopropyloxy)-phenyl-substituted with R.sup.33;
4-(cyclobutyloxy)-phenyl-substituted with R.sup.33; and
4-(cyclopentyloxy)-phenyl-substituted with R.sup.33; R.sup.12 is
selected from phenyl-substituted with 0-5 fluoro;
2-(H.sub.3CCH.sub.2C(=O))-phenyl- -substituted with R.sup.33;
2-(H.sub.3CC(=O))-phenyl-substituted with R.sup.33;
2-(HC(=O))-phenyl-substituted with R.sup.33;
2-(H.sub.3CCH(OH))-phenyl-substituted with R.sup.33;
2-(H.sub.3CCH.sub.2CH(OH))-phenyl-substituted with R.sup.33;
2-(HOCH.sub.2)-phenyl-substituted with R.sup.33;
2-(HOCH.sub.2CH.sub.2)-p- henyl-substituted with R.sup.33;
2-(H.sub.3COCH.sub.2)-phenyl-substituted with R.sup.33;
2-(H.sub.3COCH.sub.2CH.sub.2)-phenyl-substituted with R.sup.33;
2-(H.sub.3CCH(OMe))-phenyl-substituted with R.sup.33;
2-(H.sub.3COC(=O))-phenyl-substituted with R.sup.33;
2-(HOCH.sub.2CH=CH)-phenyl-substituted with R.sup.33;
2-((MeOC=O)CH=CH)-phenyl-substituted with R.sup.33;
2-(methyl)-phenyl-substituted with R.sup.33;
2-(ethyl)-phenyl-substituted with R.sup.33;
2-(i-propyl)-phenyl-substituted with R.sup.33;
2-(F.sub.3C)-phenyl-substituted with R.sup.33;
2-(NC)-phenyl-substituted with R.sup.33;
2-(H.sub.3CO)-phenyl-substituted with R.sup.33;
2-(fluoro)-phenyl-substituted with R.sup.33;
2-(chloro)-phenyl-substitute- d with R.sup.33;
3-(NC)-phenyl-substituted with R.sup.33;
3-(H.sub.3CO)-phenyl-substituted with R.sup.33;
3-(fluoro)-phenyl-substit- uted with R.sup.33;
3-(chloro)-phenyl-substituted with R.sup.33;
4-(NC)-phenyl-substituted with R.sup.33;
4-(fluoro)-phenyl-substituted with R.sup.33;
4-(chloro)-phenyl-substituted with R.sup.33;
4-(H.sub.3CS)-phenyl-substituted with R.sup.33;
4-(H.sub.3CO)-phenyl-subs- tituted with R.sup.33;
4-(ethoxy)-phenyl-substituted with R.sup.33;
4-(i-propoxy)-phenyl-substituted with R.sup.33;
4-(i-butoxy)-phenyl-subst- ituted with R.sup.33;
4-(H.sub.3CCH.sub.2CH.sub.2C(=O))-phenyl-substituted with R.sup.33;
4-((H.sub.3C)2CHC(=O))-phenyl-substituted with R.sup.33;
4-(H.sub.3CCH.sub.2C(=O))-phenyl-substituted with R.sup.33;
4-(H.sub.3CC(=O))-phenyl-substituted with R.sup.33;
4-(H.sub.3CCH.sub.2CH.sub.2CH(OH))-phenyl-substituted with
R.sup.33; 4-((H.sub.3C).sub.2CHCH(OH))-phenyl-substituted with
R.sup.33; 4-(H.sub.3CCH.sub.2CH(OH))-phenyl-substituted with
R.sup.33; 4-(H.sub.3CCH(OH))-phenyl-substituted with R.sup.33;
4-(cyclopropyloxy)-phenyl-substituted with R.sup.33;
4-(cyclobutyloxy)-phenyl-substituted with R.sup.33; and
4-(cyclopentyloxy)-phenyl-substituted with R.sup.33; R.sup.13 is H,
methyl, or ethyl; alternatively, R.sup.12 and R.sup.13 join to form
a 5- or 6-membered ring selected from pyrrolyl, pyrrolidinyl,
imidazolyl, piperidinyl, piperizinyl, methylpiperizinyl,and
morpholinyl; alternatively, R.sup.12 and R.sup.13 when attached to
N may be combined to form a 9- or 10-membered bicyclic heterocyclic
ring system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S; wherein said bicyclic heterocyclic ring
system is selected from indolyl, indolinyl, indazolyl,
benzimidazolyl, benzimidazolinyl, benztriazolyl, benzoxazolyl,
benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl; wherein said
bicyclic heterocyclic ring system is substituted with 0-1 R.sup.16;
R.sup.15 is H, methyl, ethyl, propyl, or butyl; R.sup.16, at each
occurrence, is independently selected from H, OH, F, Cl, CN,
NO.sub.2, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and
trifluoromethoxy; R.sup.33, at each occurrence, is independently
selected from H, F, Cl, --CH.sub.3, --OCH.sub.3, --CF.sub.3,
--OCF.sub.3, --CN, and --NO.sub.2; k is 1; m is 1; and n is 1 or
2.
7. The method as defined in claim 2 where the compound administered
is a compound of Formula (I-a): 59wherein: b is a single bond; X is
--CH.sub.2--, --CH(OH)--, or --C(=O)--; R.sup.1 is selected from
hydrogen, methyl, ethyl, n-propyl, n-butyl, s-butyl, t-butyl,
n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl, 2-hexyl,
2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl,
3-methylpentyl, 3-methylbutyl, 4-methylpentyl, 2-fluoroethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-propenyl,
2-methyl-2-propenyl, trans-2-butenyl, 3-methyl-butenyl, 3-butenyl,
trans-2-pentenyl, cis-2-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,
3,3-dichloro-2-propenyl, trans-3-phenyl-2-propenyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl,
2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2,5-dimethylbenzyl,
2,4-dimethylbenzyl, 3,5-dimethylbenzyl, 2,4,6-trimethyl-benzyl,
3-methoxy-benzyl, 3,5-dimethoxy-benzyl, pentafluorobenzyl,
2-phenylethyl, 1-phenyl-2-propyl, 4-phenylbutyl, 4-phenylbenzyl,
2-phenylbenzyl, (2,3-dimethoxy-phenyl)C(=O)--,
(2,5-dimethoxy-phenyl)C(=O)--, (3,4-dimethoxy-phenyl)C(=O)--,
(3,5-dimethoxy-phenyl)C(=O)--, cyclopropyl--C(=O)--,
isopropyl--C(=O)--, ethyl--CO.sub.2-, propyl--CO.sub.2-,
t-butyl--CO.sub.2-, 2,6-dimethoxy-benzyl, 2,4-dimethoxy-benzyl,
2,4,6-trimethoxy-benzyl, 2,3-dimethoxy-benzyl,
2,4,5-trimethoxy-benzyl, 2,3,4-trimethoxy-benzyl,
3,4-dimethoxy-benzyl, 3,4,5-trimethoxy-benzyl,
(4-fluoro-phenyl)ethyl, --CH=CH.sub.2, --CH.sub.2--CH=CH.sub.2,
--CH=CH--CH.sub.3, --C.ident.CH, --C.ident.C--CH.sub.3, and
--CH.sub.2--C.ident.CH; R.sup.7, R.sup.8, and R.sup.9, at each
occurrence, are independently selected from hydrogen, fluoro,
chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl,
t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy,
trifluoromethoxy, phenyl, methylC(=O)--, ethylC(=O)--,
propylC(=O)--, isopropylC(=O)--, butylC(=O)--, phenylC(=O)--,
methylCO.sub.2-, ethylCO.sub.2-, propylCO.sub.2-,
isopropylCO.sub.2-, butylCO.sub.2-, phenylCO.sub.2-,
dimethylamino-S(=O)--, diethylamino-S(=O)--, dipropylamino-S(=O)--,
di-isopropylamino-S(=O)--, dibutylamino-S(=O)--,
diphenylamino-S(=O)--, dimethylamino--SO.sub.2--,
diethylamino--SO.sub.2-- -, dipropylamino--SO.sub.2--,
di-isopropylamino--SO.sub.2--, dibutylamino--SO.sub.2--,
diphenylamino-SO.sub.2--, dimethylamino--C(=O)--,
diethylamino--C(=O)--, dipropylamino--C(=O)--,
di-isopropylamino--C(=O)--, dibutylamino--C(=O)--,
diphenylamino--C(=O)--, 2-chlorophenyl, 2-fluorophenyl,
2-bromophenyl, 2-cyanophenyl, 2-methylphenyl,
2-trifluoromethylphenyl, 2-methoxyphenyl, 2-trifluoromethoxyphenyl,
3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-cyanophenyl,
3-methylphenyl, 3-ethylphenyl, 3-propylphenyl, 3-isopropylphenyl,
3-butylphenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl,
3-isopropoxyphenyl, 3-trifluoromethoxyphenyl, 3-thiomethoxyphenyl,
4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-cyanophenyl,
4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl,
4-butylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl,
4-isopropoxyphenyl, 4-trifluoromethoxyphenyl, 4-thiomethoxyphenyl,
2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethylphenyl,
2,3-ditrifluoromethylphenyl, 2,3-dimethoxyphenyl,
2,3-ditrifluoromethoxyphenyl, 2,4-dichlorophenyl,
2,4-difluorophenyl, 2,4-dimethylphenyl,
2,4-ditrifluoromethylphenyl, 2,4-dimethoxyphenyl,
2,4-ditrifluoromethoxyphenyl, 2,5-dichlorophenyl,
2,5-difluorophenyl, 2,5-dimethylphenyl,
2,5-ditrifluoromethylphenyl, 2,5-dimethoxyphenyl,
2,5-ditrifluoromethoxyphenyl, 2,6-dichlorophenyl,
2,6-difluorophenyl, 2,6-dimethylphenyl,
2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl,
2,6-ditrifluoromethoxyphenyl, 3,4-dichlorophenyl,
3,4-difluorophenyl, 3,4-dimethylphenyl,
3,4-ditrifluoromethylphenyl, 3,4-dimethoxyphenyl,
3,4-ditrifluoromethoxyphenyl, 2,4,6-trichlorophenyl,
2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl,
2,4,6-tritrifluoromethylphe- nyl, 2,4,6-trimethoxyphenyl,
2,4,6-tritrifluoromethoxyphenyl, 2-chloro-4-CF.sub.3-phenyl,
2-fluoro-3-chloro-phenyl, 2-chloro-4-CF.sub.3-phenyl,
2-chloro-4-methoxy-phenyl, 2-methoxy-4-isopropyl-phenyl,
2-CF.sub.3-4-methoxy-phenyl, 2-methyl-4-methoxy-5-fluoro-phenyl,
2-methyl-4-methoxy-phenyl, 2-chloro-4-CF.sub.3O-phenyl,
2,4,5-trimethyl-phenyl, 2-methyl-4-chloro-phenyl, methyl-C(=O)NH--,
ethyl-C(=O)NH--, propyl-C(=O)NH--, isopropyl-C(=O)NH--,
butyl-C(=O)NH--, phenyl-C(=O)NH--, 4-acetylphenyl,
3-acetamidophenyl, 4-pyridyl, 2-furanyl, 2-thiophenyl, 2-naphthyl;
2-Me-5-F-phenyl, 2-F-5-Me-phenyl, 2-MeO-5-F-phenyl,
2-Me-3-Cl-phenyl, 3-NO.sub.2-phenyl, 2-NO.sub.2-phenyl,
2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl,
2-Cl-6-F-phenyl, 2-Cl-4-(CHF.sub.2)O-phenyl, 2,4-diMeO-6-F-phenyl,
2-CF.sub.3-6-F-phenyl, 2-MeS-phenyl, 2,6-diCl-4-MeO-phenyl,
2,3,4-triF-phenyl, 2,6-diF-4--Cl-phenyl, 2,3,4,6-tetraF-phenyl,
2,3,4,5,6-pentaF-phenyl, 2-CF.sub.3-4-EtO-phenyl,
2-CF.sub.3-4-iPrO-phenyl, 2-CF.sub.3-4-Cl-phenyl,
2-CF.sub.3-4-F-phenyl, 2-Cl-4-EtO-phenyl, 2-Cl-4-iPrO-phenyl,
2-Et-4-MeO-phenyl, 2-CHO-4-MeO-phenyl, 2-CH(OH)Me-4-MeO-phenyl,
2-CH(OMe)Me-4-MeO-phenyl, 2-C(=O)Me-4-MeO-phenyl,
2-CH.sub.2(OH)-4-MeO-phenyl, 2-CH.sub.2(OMe)-4-MeO-phenyl,
2-CH(OH)Et-4-MeO-phenyl, 2-C(=O)Et-4-MeO-phenyl,
(Z)-2-CH=CHCO.sub.2Me-4-MeO-phenyl,
2-CH.sub.2CH.sub.2CO.sub.2Me-4-MeO-phenyl,
(Z)-2-CH=CHCH.sub.2(OH)-4-MeO-- phenyl,
(E)-2-CH=CHCO.sub.2Me-4-MeO-phenyl, (E)-2-CH=CHCH.sub.2(OH)-4-MeO--
phenyl, 2-CH.sub.2CH.sub.2Me-4-MeO-phenyl, 2-F-4-MeO-phenyl,
2-Cl-4-F-phenyl, (2-Cl-phenyl)-CH=CH--, (3-Cl-phenyl)-CH=CH--,
(2,6-diF-phenyl)-CH=CH--, --CH.sub.2CH=CH.sub.2, phenyl-CH=CH--,
(2-Me-4-MeO-phenyl)-CH=CH--, cyclohexyl, cyclopentyl,
cyclohexylmethyl, --CH.sub.2CH.sub.2CO.sub.2Et,
--(CH.sub.2).sub.3CO.sub.2Et, --(CH.sub.2).sub.4CO.sub.2Et, benzyl,
2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 3-MeO-benzyl, 3-OH-benzyl,
2-MeO-benzyl, 2-OH-benzyl, 2-CO.sub.2Me-3-MeO-phenyl,
2-Me-4-CN-phenyl, 2-Me-3-CN-phenyl, 2-CF.sub.3-4-CN-phenyl,
3-CHO-phenyl, 3-CH.sub.2(OH)-phenyl, 3-CH.sub.2(OMe)-phenyl,
3-CH.sub.2(NMe2)-phenyl, 3-CN-4-F-phenyl, 3-CONH.sub.2-4-F-phenyl,
2-CH.sub.2(NH.sub.2)-4-MeO-phenyl-, phenyl-NH--, (4-F-phenyl)-NH--,
(2,4-diCl-phenyl)-NH--, phenyl-C(=O)NH--, benzyl-NH--,
(2-Me-4-MeO-phenyl)-NH--, (2-F-4-MeO-phenyl)-NH--,
(2-Me-4-F-phenyl)-NH--, phenyl-S--, --NMe.sub.2, 1-pyrrolidinyl,
and --N(tosylate).sub.2, provided that two of R.sup.7, R.sup.8, and
R.sup.9, are independently selected from hydrogen, fluoro, chloro,
bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl,
nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, and
trifluoromethoxy; m is 1; and n is 0, 1 or 2.
8. The method as defined in claim 7 where the compound administered
is a compound of Formula (V): 60wherein: b is a single bond,
wherein the bridge hydrogens are in a cis position; R.sup.1 is
selected from hydrogen, methyl, ethyl, n-propyl, n-butyl, s-butyl,
t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl, 2-hexyl,
2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl,
3-methylpentyl, 3-methylbutyl, 4-methylpentyl, 2-fluoroethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-propenyl,
2-methyl-2-propenyl, trans-2-butenyl, 3-methyl-butenyl, 3-butenyl,
trans-2-pentenyl, cis-2-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,
3,3-dichloro-2-propenyl, trans-3-phenyl-2-propenyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,
--CH=CH.sub.2, --CH.sub.2-CH=CH.sub.2, --CH=CH--CH.sub.3,
--C.ident.CH, --C.ident.C--CH.sub.3, and --CH.sub.2--C.ident.CH;
R.sup.7 and R.sup.9, at each occurrence, are independently selected
from hydrogen, fluoro, methyl, trifluoromethyl, and methoxy;
R.sup.8 is selected from hydrogen, fluoro, chloro, bromo, cyano,
methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro,
trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy,
phenyl, methylC(=O)--, ethylC(=O)--, propylC(=O)--,
isopropylC(=O)--, butylC(=O)--, phenylC(=O)--, methylCO.sub.2--,
ethylCO.sub.2--, propylCO.sub.2--, isopropylCO.sub.2--,
butylCO.sub.2--, phenylCO.sub.2--, dimethylamino-S(=O)--,
diethylamino-S(=O)--, dipropylamino-S(=O)--,
di-isopropylamino-S(=O)--, dibutylamino-S(=O)--,
diphenylamino-S(=O)--, dimethylamino-SO.sub.2--,
diethylamino--SO.sub.2--, dipropylamino--SO.sub.2--,
di-isopropylamino--SO.sub.2--, dibutylamino--SO.sub.2--,
diphenylamino--SO.sub.2--, dimethylamino-C(=O)--,
diethylamino-C(=O)--, dipropylamino-C(=O)--,
di-isopropylamino-C(=O)--, dibutylamino-C(=O)--,
diphenylamino-C(=O)--, 2-chlorophenyl, 2-fluorophenyl,
2-bromophenyl, 2-cyanophenyl, 2-methylphenyl,
2-trifluoromethylphenyl, 2-methoxyphenyl, 2-trifluoromethoxyphenyl,
3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-cyanophenyl,
3-methylphenyl, 3-ethylphenyl, 3-propylphenyl, 3-isopropylphenyl,
3-butylphenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl,
3-isopropoxyphenyl, 3-trifluoromethoxyphenyl, 3-thiomethoxyphenyl,
4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-cyanophenyl,
4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl,
4-butylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl,
4-isopropoxyphenyl, 4-trifluoromethoxyphenyl, 4-thiomethoxyphenyl,
2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethylphenyl,
2,3-ditrifluoromethylphenyl, 2,3-dimethoxyphenyl,
2,3-ditrifluoromethoxyphenyl, 2,4-dichlorophenyl,
2,4-difluorophenyl, 2,4-dimethylphenyl,
2,4-ditrifluoromethylphenyl, 2,4-dimethoxyphenyl,
2,4-ditrifluoromethoxyphenyl, 2,5-dichlorophenyl,
2,5-difluorophenyl, 2,5-dimethylphenyl,
2,5-ditrifluoromethylphenyl, 2,5-dimethoxyphenyl,
2,5-ditrifluoromethoxyphenyl, 2,6-dichlorophenyl,
2,6-difluorophenyl, 2,6-dimethylphenyl,
2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl,
2,6-ditrifluoromethoxyphenyl, 3,4-dichlorophenyl,
3,4-difluorophenyl, 3,4-dimethylphenyl,
3,4-ditrifluoromethylphenyl, 3,4-dimethoxyphenyl,
3,4-ditrifluoromethoxyphenyl, 2,4,6-trichlorophenyl,
2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl,
2,4,6-tritrifluoromethylphe- nyl, 2,4,6-trimethoxyphenyl,
2,4,6-tritrifluoromethoxyphenyl, 2-chloro-4-CF.sub.3-phenyl,
2-fluoro-3-chloro-phenyl, 2-chloro-4-CF.sub.3-phenyl,
2-chloro-4-methoxy-phenyl, 2-methoxy-4-isopropyl-phenyl,
2-CF.sub.3-4-methoxy-phenyl, 2-methyl-4-methoxy-5-fluoro-phenyl,
2-methyl-4-methoxy-phenyl, 2-chloro-4-CF.sub.30-phenyl,
2,4,5-trimethyl-phenyl, 2-methyl-4-chloro-phenyl, methyl-C(=O)NH--,
ethyl-C(=O)NH--, propyl-C(=O)NH--, isopropyl-C(=O)NH--,
butyl-C(=O)NH--, phenyl-C(=O)NH--, 4-acetylphenyl,
3-acetamidophenyl, 4-pyridyl, 2-furanyl, 2-thiophenyl, 2-naphthyl;
2-Me-5-F-phenyl, 2-F-5-Me-phenyl, 2-MeO-5-F-phenyl,
2-Me-3-Cl-phenyl, 3-NO.sub.2-phenyl, 2-NO.sub.2-phenyl,
2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl,
2-Cl-6-F-phenyl, 2-Cl-4-(CHF.sub.2)O-phenyl, 2,4-diMeO-6-F-phenyl,
2-CF.sub.3-6-F-phenyl, 2-MeS-phenyl, 2,6-diCl-4-MeO-phenyl,
2,3,4-triF-phenyl, 2,6-diF-4-Cl-phenyl, 2,3,4,6-tetraF-phenyl,
2,3,4,5,6-pentaF-phenyl, 2-CF.sub.3-4-EtO-phenyl,
2-CF.sub.3-4-iPrO-phenyl, 2-CF.sub.3-4-Cl-phenyl,
2-CF.sub.3-4-F-phenyl, 2-Cl-4-EtO-phenyl, 2-Cl-4-iPrO-phenyl,
2-Et-4-MeO-phenyl, 2-CHO-4-MeO-phenyl, 2-CH(OH)Me-4-MeO-phenyl,
2-CH(OMe)Me-4-MeO-phenyl, 2-C(=O)Me-4-MeO-phenyl,
2-CH.sub.2(OH)-4-MeO-phenyl, 2-CH.sub.2(OMe)-4-MeO-phenyl,
2-CH(OH)Et-4-MeO-phenyl, 2-C(=O)Et-4-MeO-phenyl,
(Z)-2-CH=CHCO.sub.2Me-4-MeO-phenyl,
2-CH.sub.2CH.sub.2CO.sub.2Me-4-MeO-phenyl,
(Z)-2-CH=CHCH.sub.2(OH)-4-MeO-- phenyl,
(E)-2-CH=CHCO.sub.2Me-4-MeO-phenyl, (E)-2-CH=CHCH.sub.2(OH)-4-MeO--
phenyl, 2-CH.sub.2CH.sub.2OMe-4-MeO-phenyl, 2-F-4-MeO-phenyl,
2-Cl-4-F-phenyl, (2-Cl-phenyl)-CH=CH--, (3-Cl-phenyl)-CH=CH--,
(2,6-diF-phenyl)-CH=CH--, --CH.sub.2CH=CH.sub.2, phenyl-CH=CH--,
(2-Me-4-MeO-phenyl)-CH=CH--, cyclohexyl, cyclopentyl,
cyclohexylmethyl, --CH.sub.2CH.sub.2CO.sub.2Et,
--(CH.sub.2).sub.3CO.sub.2Et, --(CH.sub.2).sub.4CO.sub.2Et, benzyl,
2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 3-MeO-benzyl, 3-OH-benzyl,
2-MeO-benzyl, 2-OH-benzyl, 2-CO.sub.2Me-3-MeO-phenyl,
2-Me-4-CN-phenyl, 2-Me-3-CN-phenyl, 2-CF.sub.3-4-CN-phenyl,
3-CHO-phenyl, 3-CH.sub.2(OH)-phenyl, 3-CH.sub.2(OMe)-phenyl,
3-CH.sub.2(NMe2)-phenyl, 3-CN-4-F-phenyl, 3-CONH.sub.2-4-F-phenyl,
2-CH.sub.2(NH.sub.2)-4-MeO-phenyl-, phenyl-NH--, (4-F-phenyl)-NH--,
(2,4-diCl-phenyl)-NH--, phenyl-C(=O)NH--, benzyl-NH--,
(2-Me-4-MeO-phenyl)-NH--, (2-F-4-MeO-phenyl)-NH--,
(2-Me-4-F-phenyl)-NH--, phenyl-S--, --NMe.sub.2, 1-pyrrolidinyl,
and --N(tosylate).sub.2; and n is 0, 1 or 2.
9. The method as defined in claim 1 where in the compound
administered: X is --CHR.sup.10-- or --C(=O)--; R.sup.1 is selected
from C.sub.1-6 alkyl substituted with Z, C.sub.2-6 alkenyl
substituted with Z, C.sub.2-6 alkynyl substituted with Z, C.sub.3-6
cycloalkyl substituted with Z, aryl substituted with Z, 5-6
membered heterocyclic ring system containing at least one
heteroatom selected from the group consisting of N, O, and S, said
heterocyclic ring system substituted with Z; C.sub.1-6 alkyl
substituted with 0-2 R.sup.2, C.sub.2-6 alkenyl substituted with
0-2 R.sup.2, C.sub.2-6 alkynyl substituted with 0-2 R.sup.2, aryl
substituted with 0-2 R.sup.2, and 5-6 membered heterocyclic ring
system containing at least one heteroatom selected from the group
consisting of N, O, and S, said heterocyclic ring system
substituted with 0-2 R.sup.2; Z is selected from H,
--CH(OH)R.sup.2, --C(ethylenedioxy)R.sup.2, --OR.sup.2, --SR.sup.2,
--NR.sup.2R.sup.3, --C(O)R.sup.2, C(O)NR.sup.2R.sup.3,
--NR.sup.3C(O)R.sup.2, --C(O)OR.sup.2, --OC(O)R.sup.2,
--CH(=NR.sup.4)NR.sup.2R.sup.3, --NHC(=NR.sup.4)NR.sup.2R.sup.3,
--S(O)R.sup.2, --S(O).sub.2R.sup.2, --S(O).sub.2NR.sup.2R.sup.3,
and --NR.sup.3S(O).sub.2R.sup.2; R.sup.2, at each occurrence, is
independently selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, aryl substituted with 0-5
R.sup.42; C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.41, and 5-10 membered heterocyclic ring system containing
from 1-4 heteroatoms selected from the group consisting of N, O,
and S substituted with 0-3 R.sup.41; R.sup.3, at each occurrence,
is independently selected from H, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, and C.sub.1-4 alkoxy; alternatively,
R.sup.2 and R.sup.3 join to form a 5- or 6-membered ring optionally
substituted with --O-- or --N(R.sup.4)--; R.sup.4, at each
occurrence, is independently selected from H, methyl, ethyl,
propyl, and butyl; R.sup.5 is H, methyl, ethyl, propyl, or butyl;
R.sup.6ais selected from H, --OH, --NR.sup.46R.sup.47, --CF.sub.3,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl, and aryl
substituted with 0-3 R.sup.44; R.sup.6b is H; R.sup.7, R.sup.8, and
R.sup.9, at each occurrence, are independently selected from H,
halo, --CF.sub.3, --OCF.sub.3, --OH, --CN, --NO.sub.2,
--NR.sup.46R.sup.47, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, (C.sub.1-4
haloalkyl)oxy, C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33, aryl
substituted with 0-5 R.sup.33, 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12,
SR.sup.12, NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12,
C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12, C(O)OR.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12, S(O).sub.2R12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12, NR.sup.14S (O).sub.2R.sup.12,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15; R.sup.10
is selected from H, --OH, C.sub.1-6 alkyl substituted with 0-1
R.sup.10B, C.sub.2-6 alkenyl substituted with 0-1 R.sup.10B,
C.sub.2-6 alkynyl substituted with 0-1 R.sup.10B, and C.sub.1-6
alkoxy; R.sup.10B is selected from C.sub.1-4 alkoxy, C.sub.3-6
cycloalkyl, C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, phenyl substituted with 0-3 R.sup.33, and 5-6 membered
heterocyclic ring system containing 1, 2, or 3 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-2
R.sup.44; R.sup.11 is selected from H, halo, --CF.sub.3, --CN,
--NO.sub.2, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, C.sub.3-10 cycloalkyl,
C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33, aryl
substituted with 0-5 R.sup.33, 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12,
SR.sup.12, NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12,
C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12, C(O)OR.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O),2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12, and NR.sup.14S(O).sub.2R.sup.12; R.sup.12,
at each occurrence, is independently selected from C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, phenyl
substituted with 0-5 R.sup.33; C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.33, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; R.sup.13,
at each occurrence, is independently selected from H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl; alternatively,
R.sup.12 and R.sup.13 join to form a 5- or 6-membered ring
optionally substituted with --O-- or --N(R.sup.14)--; R.sup.14, at
each occurrence, is independently selected from H and C.sub.1-4
alkyl; R.sup.31, at each occurrence, is independently selected from
H, OH, halo, CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47, methyl,
ethyl, and propyl; R.sup.33, at each occurrence, is independently
selected from H, OH, halo, CN, NO.sub.2, CF.sub.3,
SO.sub.2R.sup.45, NR.sup.46R.sup.47, C.sub.1-3 alkyl, C.sub.2-3
alkenyl, C.sub.2-3 alkynyl, C.sub.3-5 cycloalkyl, C.sub.1-3
haloalkyl, C.sub.1-3 haloalkyl-oxy-, C.sub.1-3 alkyloxy-, C.sub.1-3
alkylthio-, C.sub.1-3 alkyl- C(=O)--, and C.sub.1-3
alkyl-C(=O)NH--; R.sup.41, at each occurrence, is independently
selected from H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, =O, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl C.sub.1-4 alkyl
substituted with 0-1 R.sup.43, aryl substituted with 0-3 R.sup.42,
and 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44; R.sup.42, at each occurrence, is
independently selected from H, CF.sub.3, halo, OH, CO.sub.2H,
SO.sub.2R.sup.45, SR.sup.45, NR.sup.46R.sup.47, OR.sup.48,
NO.sub.2, CN, CH(=NH)NH.sub.2, NHC(=NH)NH.sub.2, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.3-6
cycloalkyl, C.sub.1-4 alkyl substituted with 0-1 R.sup.43, aryl
substituted with 0-3 R.sup.44, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group 10
consisting of N, O, and S substituted with 0-3 R.sup.44; R.sup.43
is C.sub.3-6 cycloalkyl or aryl substituted with 0-3 R.sup.44;
R.sup.44, at each occurrence, is independently selected from H,
halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, and
C.sub.1-4 alkoxy; R.sup.45 is C.sub.1-4 alkyl; R.sup.46, at each
occurrence, is independently selected from H and C.sub.1-4 alkyl;
R.sup.47, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl, --C(=O)NH(C.sub.1-4 alkyl), --SO.sub.2(C.sub.1-4
alkyl), --SO.sub.2(phenyl), --C(=O)O(C.sub.1-4 alkyl),
--C(=O)(C.sub.1-4 alkyl), and --C(=O) H; R.sup.48, at each
occurrence, is independently selected from H, C.sub.1-4 alkyl,
--C(=O)NH(C.sub.1-4 alkyl), --C(=O)O(C.sub.1-4 alkyl), --C(=O)(
C.sub.1-4 alkyl), and --C(=O)H; k is 1 or 2; m is 0, 1, or 2; and n
is 0, 1 or 2.
10. The method as defined in claim 9 where in the compound
administered: X is --CHR.sup.10-- or --C(=O)--; R.sup.1 is selected
from C.sub.2-5 alkyl substituted with Z, C.sub.2-5 alkenyl
substituted with Z, C.sub.2-5 alkynyl substituted with Z, C.sub.3-6
cycloalkyl substituted with Z, aryl substituted with Z, 5-6
membered heterocyclic ring system containing at least one
heteroatom selected from the group consisting of N, O, and S, said
heterocyclic ring system substituted with Z; C.sub.1-5 alkyl
substituted with 0-2 R.sup.2, C.sub.2-5 alkenyl substituted with
0-2 R.sup.2, and C.sub.2-5 alkynyl substituted with 0-2 R.sup.2; Z
is selected from H, --CH(OH)R.sup.2, --C(ethylenedioxy)R.sup.2,
--OR.sup.2, --SR.sup.2, --NR.sup.2R.sup.3, --C(O)R.sup.2, --C(O)
NR.sup.2R.sup.3, --NR.sup.3C(O)R.sup.2, --C(O)OR.sup.2,
--OC(O)R.sup.2, --CH(=NR.sup.4)NR.sup.2R.sup.3,
--NHC(=NR.sup.4)NR.sup.2R.sup.3, --S(O)R.sup.2,
--S(O).sub.2R.sup.2, --S(O).sub.2NR.sup.2R.sup.3, and
--NR.sup.3S(O).sub.2R.sup.2; R.sup.2, at each occurrence, is
independently selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, aryl substituted with 0-5
R.sup.42; C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.41, and 5-10 membered heterocyclic ring system containing
from 1-4 heteroatoms selected from the group consisting of N, O,
and S substituted with 0-3 R.sup.41; R.sup.3, at each occurrence,
is independently selected from H, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, and C.sub.1-4 alkoxy; alternatively,
R.sup.2 and R.sup.3 join to form a 5- or 6-membered ring optionally
substituted with --O-- or --N(R.sup.4)--; R.sup.4, at each
occurrence, is independently selected from H, methyl, ethyl,
propyl, and butyl; R.sup.5 is H, methyl, or ethyl; R.sup.6ais
selected from H, --OH, --NR.sup.46R.sup.47, --CF.sub.3, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, and C.sub.3-6 cycloalkyl; R.sup.6b is H;
R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are
independently selected from H, halo, --CF.sub.3, --OCF.sub.3, --OH,
--OCH.sub.3, --CN, --NO.sub.2, --NR.sup.46R.sup.47, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl,
C.sub.1-6 alkoxy, (C.sub.1-4 haloalkyl)oxy, C.sub.1-4 alkyl
substituted with 0-2 R.sup.11, C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.33, aryl substituted with 0-5 R.sup.33,
5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31; OR.sup.12 SR.sup.12,
NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
CH(=NR.sup.14)NR.sup.12R.sup.13, NHC(=NR.sup.14)NR.sup.12R-
.sup.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O).sub.2NR.sup.12R.sup.13, NR.sup.14S (O).sub.2R.sup.12,
NR.sup.14S(O)R.sup.12, NR.sup.14S (O).sub.2R.sup.12,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15; R.sup.10
is selected from H, --OH, C.sub.1-6 alkyl, C.sub.1-4 alkoxy, and
C.sub.1-2 alkyl substituted with 0-1 R.sup.10B; R.sup.10B is
C.sub.3-6 cycloalkyl or phenyl substituted with 0-3 R.sup.33;
R.sup.11 is selected from H, halo, --CF.sub.3, --OCF.sub.3, --OH,
--OCH.sub.3, --CN, --NO.sub.2, --NR.sup.46R.sup.47, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl,
C.sub.1-6 alkoxy, (C.sub.1-4 haloalkyl)oxy, C.sub.3-10 carbocyclic
group substituted with 0-3 R.sup.33, aryl substituted with 0-5
R.sup.33, 5-10 membered heterocyclic ring system containing from
1-4 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31; OR.sup.12, SR.sup.12,
NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
CH(=NR.sup.14)NR.sup.12R.sup.13, NHC(=NR.sup.14)NR.sup.12R.sup.13,
S(O)R.sup.12, S(O).sub.2R.sup.12, S(O).sub.2NR.sup.12R.sup.13, and
NR.sup.14S(O).sub.2R.sup.12; R.sup.12, at each occurrence, is
independently selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, phenyl substituted with
0-5 R.sup.33; C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, and 5-10 membered heterocyclic ring system containing
from 1-4 heteroatoms selected from the group consisting of N, O,
and S substituted with 0-3 R.sup.31; R.sup.13, at each occurrence,
is independently selected from H, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, and C.sub.2-4 alkynyl; alternatively, R.sup.12 and
R.sup.13 join to form a 5- or 6-membered ring optionally
substituted with --O-- or --N(R.sup.14)--; R.sup.14, at each
occurrence, is independently selected from H and C.sub.1-4 alkyl;
R.sup.31, at each occurrence, is independently selected from H, OH,
halo, CF.sub.3, methyl, and ethyl; R.sup.33, at each occurrence, is
independently selected from H, OH, halo, CN, NO.sub.2, CF.sub.3,
methyl, and ethyl; R.sup.41, at each occurrence, is independently
selected from H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, =O, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 alkyl
substituted with 0-1 R.sup.43, aryl substituted with 0-3 R.sup.42,
and 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44; R.sup.42, at each occurrence, is
independently selected from H, CF.sub.3, halo, OH, CO.sub.2H,
SO.sub.2R.sup.45, SR.sup.45, NR.sup.46R.sup.47, OR.sup.48,
NO.sub.2, CN, CH(=NH)NH.sub.2, NHC(=NH)NH.sub.2, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.3-6
cycloalkyl, C.sub.1-4 alkyl substituted with 0-1 R.sup.43, aryl
substituted with 0-3 R.sup.44, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.44; R.sup.43
is C.sub.3-6 cycloalkyl or aryl substituted with 0-3 R.sup.44;
R.sup.44, at each occurrence, is independently selected from H,
halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, and
C.sub.1-4 alkoxy; R.sup.45 is C.sub.1-4 alkyl; R.sup.46, at each
occurrence, is independently selected from H and C.sub.1-3 alkyl;
R.sup.47, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl, --C(=O)NH(C.sub.1-4 alkyl), --SO.sub.2(C.sub.1-4
alkyl), --SO.sub.2(phenyl), --C(=O)O(C.sub.1-4 alkyl), --C(=O)(
C.sub.1-4 alkyl), and --C(=O)H; R.sup.48, at each occurrence, is
independently selected from H. C.sub.1-4 alkyl, --C(=O)NH(C.sub.1-4
alkyl), --C(=O)O(C.sub.1-4 alkyl), --C(=O)( C.sub.1-4 alkyl), and
--C(=O)H; k is 1 or 2; m is 0, 1, 2; and n is 0, 1 or 2.
11. The method as defined in claim 9 where in the compound
administered: X is --CH.sub.2--; R.sup.1 is selected from C.sub.2-4
alkyl substituted with Z, C.sub.2-4 alkenyl substituted with Z,
C.sub.2-4 alkynyl substituted with Z, C.sub.3-6 cycloalkyl
substituted with Z, aryl substituted with Z, 5-6 membered
heterocyclic ring system containing at least one heteroatom
selected from the group consisting of N, O, and S, said
heterocyclic ring system substituted with z; C.sub.2-4 alkyl
substituted with 0-2 R.sup.2, and C.sub.2-4 alkenyl substituted
with 0-2 R.sup.2; z is selected from H, --CH (OH)R.sup.2,
--C(ethylenedioxy)R.sup.- 2, --OR.sup.2, ---SR.sup.2,
--NR.sup.2R.sup.3, --C(O)R.sup.2, --C(O) NR.sup.2R.sup.3,
--NR.sup.3C(O)R.sup.2, --C(O)OR.sup.2, --S(O)R.sup.2, --S(O)
2R.sup.2, --S(O).sub.2NR.sup.2R.sup.3, and --NR.sup.3S(O).sub.2R.s-
up.2; R.sup.2, at each occurrence, is independently selected from
phenyl substituted with 0-5 R.sup.42; C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.41, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.41; R.sup.3,
at each occurrence, is independently selected from H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and C.sub.1-4 alkoxy;
alternatively, R.sup.2 and R.sup.3 join to form a 5- or 6-membered
ring optionally substituted with --O-- or --N(R.sup.4)--; R.sup.4,
at each occurrence, is independently selected from H, methyl,
ethyl, propyl, and butyl; R.sup.5 is H; R.sup.6ais selected from H,
--OH, --CF.sub.3, methyl, ethyl, propyl, butyl, methoxy, and,
ethoxy; R.sup.6b is H; R.sup.7, R.sup.8, and R.sup.9, at each
occurrence, are independently selected from H, halo, --CF.sub.3,
--OCF.sub.3, --OH, --OCH.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, (C.sub.1-3 haloalkyl)oxy,
and C.sub.1-4 alkyl substituted with 0-2 R.sup.11; R.sup.11 is
selected from H, halo, --CF.sub.3, --OCF.sub.3, --OH, --OCH.sub.3,
--CN, --NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
alkoxy, and (C.sub.1-3 haloalkyl)oxy; R.sup.33, at each occurrence,
is independently selected from H, OH, halo, CF.sub.3, and methyl;
R.sup.41, at each occurrence, is independently selected from H,
CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45, NR.sup.46R.sup.47,
NO.sub.2, CN, =O, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 alkyl substituted with 0-1
R.sup.43, aryl substituted with 0-3 R.sup.42, and 5-10 membered
heterocyclic ring system containing from 1-4 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-3
R.sup.44; R.sup.42, at each occurrence, is independently selected
from H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45, SR.sup.45,
NR.sup.46R.sup.47, OR.sup.48, NO.sub.2, CN, CH(=NH)NH.sub.2,
NHC(=NH)NH.sub.2, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl, C.sub.1-4 alkyl
substituted with 0-1 R.sup.43, aryl substituted with 0-3 R.sup.44,
and 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44; R.sup.43 is cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, phenyl, or pyridyl, each substituted with
0-3 R.sup.44; R.sup.44, at each occurrence, is independently
selected from H, halo, --OH, NR.sup.46R.sup.47, CO.sub.2H,
SO.sub.2R.sup.45, --CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2,
methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and butoxy;
R.sup.45 is methyl, ethyl, propyl, or butyl; R.sup.46, at each
occurrence, is independently selected from H, methyl, ethyl,
propyl, and butyl; R.sup.47, at each occurrence, is independently
selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl,
i-butyl, --C(=O)NH(methyl), --C(=O)NH(ethyl), --SO.sub.2(methyl),
--SO.sub.2(ethyl), --SO.sub.2(phenyl),
--C(=O)O(methyl),--C(=O)O(ethyl), --C(=O)(methyl), --C(=O)(ethyl),
and --C(=O)H; R.sup.48, at each occurrence, is independently
selected from H, methyl, ethyl, n-propyl, i-propyl,
C(=O)NH(methyl), --C(=O)NH(ethyl), --C(=O)O(methyl),
--C(=O)O(ethyl), --C(=O) (methyl), --C(=O) (ethyl), and --C(=O)H; k
is 1; m is 0, 1, or 2; and n is 0, 1 or 2.
12. The method as defined in claim 9 where in the compound
administered: X is --CH.sub.2--; R.sup.1 is selected from ethyl
substituted with Z, propyl substituted with Z, butyl substituted
with Z, propenyl substituted with Z, butenyl substituted with Z,
ethyl substituted with R.sup.2, propyl substituted with R.sup.2,
butyl substituted with R.sup.2, propenyl substituted with R.sup.2,
and butenyl substituted with R.sup.2; Z is selected from H, --CH
(OH) R.sup.2, --OR.sup.2, --SR.sup.2, --NR.sup.2R.sup.3,
--C(O)R.sup.2, --C(O)NR.sup.2R.sup.3, --NR.sup.3C(O)R.sup.2, --C(O)
OR.sup.2, --S(O)R.sup.2 , --S(O).sub.2R.sup.2,
--S(O).sub.2NR.sup.2R.sup.3, and --NR.sup.3S(O).sub.2R.sup.2;
R.sup.2, at each occurrence, is independently selected from phenyl
substituted with 0-3 R.sup.42; naphthyl substituted with 0-3
R.sup.42; cyclopropyl substituted with 0-3 R.sup.41; cyclobutyl
substituted with 0-3 R.sup.41; cyclopentyl substituted with 0-3
R.sup.41; cyclohexyl substituted with 0-3 R.sup.41; pyridyl
substituted with 0-3 R.sup.41; indolyl substituted with 0-3
R.sup.41; indolinyl substituted with 0-3 R.sup.41; benzimidazolyl
substituted with 0-3 R.sup.41; benzotriazolyl substituted with 0-3
R.sup.41; benzothienyl substituted with 0-3 R.sup.41; benzofuranyl
substituted with 0-3 R.sup.41; phthalimid-1-yl substituted with 0-3
R.sup.41; inden-2-yl substituted with 0-3 R.sup.41;
2,3-dihydro-1H-inden-2-yl substituted with 0-3 R.sup.41; indazolyl
substituted with 0-3 R.sup.41; tetrahydroquinolinyl substituted
with 0-3 R.sup.41; and tetrahydro-isoquinolinyl substituted with
0-3 R.sup.41; R.sup.3, at each occurrence, is independently
selected from H, methyl, and ethyl; R.sup.5 is H; R.sup.6ais
selected from H, --OH, methyl, and methoxy; R.sup.6b is H; R.sup.7,
R.sup.8, and R.sup.9, at each occurrence, are independently
selected from H, F, Cl, methyl, ethyl, methoxy, --CF.sub.3, and
--OCF.sub.3; R.sup.41, at each occurrence, is independently
selected from H, F, Cl, Br, OH, CF.sub.3, NO.sub.2, CN, =O, methyl,
ethyl, propyl, butyl, methoxy, and ethoxy; R.sup.42, at each
occurrence, is independently selected from H, F, Cl, Br, OH,
CF.sub.3, SO.sub.2R.sup.45, SR.sup.45, NR.sup.46R.sup.47,
OR.sup.48, NO.sub.2, CN, =O, methyl, ethyl, propyl, butyl, methoxy,
and ethoxy; R.sup.45 is methyl, ethyl, propyl, or butyl; R.sup.46,
at each occurrence, is independently selected from H, methyl,
ethyl, propyl, and butyl; R.sup.47, at each occurrence, is
independently selected from H, methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, --C(=O)NH(methyl), --C(=O)NH(ethyl),
--SO.sub.2(methyl), --SO.sub.2(ethyl), --SO.sub.2(phenyl),
--C(=O)O(methyl),--C(=O)O(ethyl), --C(=O)(methyl), --C((=O)(ethyl),
and --C(=O)H; R.sup.48, at each occurrence, is independently
selected from H, methyl, ethyl, n-propyl, i-propyl,
--C(=O)NH(methyl), --C(=O)NH(ethyl), --C(=O)O(methyl),
--C(=O)O(ethyl), --C(=O)(methyl), --C(=O)(ethyl), and --C(=O)H; k
is 1; m is 0, 1, or 2; and n is 0, 1 or 2.
13. The method as defined in claim 9 where the compound
administered is a compound of Formula (I-a): 61wherein: b is a
single bond; X is --CH.sub.2--, CH(OH)--, or --C(=O)--R.sup.1 is
selected from --(CH.sub.2).sub.3C(=O)(4-fluoro-phenyl),
--(CH.sub.2).sub.3C(=O)(4-bromo- -phenyl),
--(CH.sub.2).sub.3C(=O)(4-methyl-phenyl),
--(CH.sub.2).sub.3C(=O)(4-methoxy-phenyl),
--(CH.sub.2).sub.3C(=O)(4-(3,4- -dichloro-phenyl)phenyl),
--(CH.sub.2).sub.3C(=O)(3-methyl-4-fluoro-phenyl- ),
--(CH.sub.2).sub.3C(=O)(2,3-dimethoxy-phenyl),
--(CH.sub.2).sub.3C(=O)(- phenyl),
--(CH.sub.2).sub.3C(=O)(4-chloro-phenyl), --(CH.sub.2).sub.3C(=O)-
(3-methyl-phenyl), --(CH.sub.2).sub.3C(=O)(4-t-butyl-phenyl),
--(CH.sub.2).sub.3C(=O)(3,4-difluoro-phenyl),
--(CH.sub.2).sub.3C(=O)(2-m- ethoxy-5-fluoro-phenyl),
--(CH.sub.2).sub.3C(=O)(4-fluoro-1-naphthyl),
--(CH.sub.2).sub.3C(=O)(benzyl),
--(CH.sub.2).sub.3C(=O)(4-pyridyl),
--(CH.sub.2).sub.3C(=O)(3-pyridyl),
--(CH.sub.2).sub.3CH(OH)(4-fluoro-phe- nyl),
--(CH.sub.2).sub.3CH(OH)(4-pyridyl),
--(CH.sub.2).sub.3CH(OH)(2,3-di- methoxy-phenyl),
--(CH.sub.2).sub.3S(3-fluoro-phenyl),
--(CH.sub.2).sub.3S(4-fluoro-phenyl),
--(CH.sub.2).sub.3S(=O)(4-fluoro-ph- enyl),
--(CH.sub.2).sub.3SO.sub.2(3-fluoro-phenyl),
--(CH.sub.2).sub.3SO.sub.2(4-fluoro-phenyl),
--(CH.sub.2).sub.3O(4-fluoro- -phenyl),
--(CH.sub.2).sub.3O(phenyl), --(CH.sub.2).sub.3O(3-pyridyl),
--(CH.sub.2).sub.3O(4-pyridyl),
--(CH.sub.2).sub.3O(2-NH.sub.2-phenyl),
--(CH.sub.2).sub.3O(2-NH.sub.2-5-F-phenyl),
--(CH.sub.2).sub.3O(2-NH.sub.- 2-4-F-phenyl),
--(CH.sub.2).sub.3O(2-NH.sub.2-3-F-phenyl),
--(CH.sub.2).sub.3O(2-NH.sub.2-4-Cl-phenyl),
--(CH.sub.2).sub.3O(2-NH.sub- .2-4-OH-phenyl),
--(CH.sub.2).sub.3O(2-NH.sub.2-4-Br-phenyl),
--(CH.sub.2).sub.3O(2-NHC(=O)Me-4-F-phenyl),
--(CH.sub.2).sub.3O(2-NHC(=O- )Me-phenyl),
--(CH.sub.2).sub.3NH(4-fluoro-phenyl),
--(CH.sub.2).sub.3N(methyl)(4-fluoro-phenyl),
--(CH.sub.2).sub.3CO.sub.2(- ethyl),
--(CH.sub.2).sub.3C(=O)N(methyl)(methoxy), --(CH.sub.2).sub.3C(=O)-
NH(4-fluoro-phenyl), --(CH.sub.2).sub.2NHC(=O)(phenyl),
--(CH.sub.2).sub.2NMeC(=O)(phenyl),
--(CH.sub.2).sub.2NHC(=O)(2-fluoro-ph- enyl),
--(CH.sub.2).sub.2NMeC(=O)(2-fluoro-phenyl),
--(CH.sub.2).sub.2NHC(=O)(4-fluoro-phenyl),
--(CH.sub.2).sub.2NMeC(=O)(4-- fluoro-phenyl),
--(CH.sub.2).sub.2NHC(=O)(2,4-difluoro-phenyl),
--(CH.sub.2).sub.2NMeC(=O)(2,4-difluoro-phenyl),
--(CH.sub.2).sub.3(3-ind- olyl),
--(CH.sub.2).sub.3(1-methyl-3-indolyl),
--(CH.sub.2).sub.3(1-indoly- l), --(CH.sub.2).sub.3(1-indolinyl),
--(CH.sub.2).sub.3(1-benzimidazolyl),
--(CH.sub.2).sub.3(1H-1,2,3-benzotriazol-1-yl),
--(CH.sub.2).sub.3(1H-1,2- ,3-benzotriazol-2-yl),
--(CH.sub.2).sub.2(1H-1,2,3-benzotriazol-1-yl),
--(CH.sub.2).sub.2(1H-1,2,3-benzotriazol-2-yl),
--(CH.sub.2).sub.3(3,4dih- ydro-1(2H)-quinolinyl),
--(CH.sub.2).sub.2C(=O)(4-fluoro-phenyl),
--(CH.sub.2).sub.2C(=O)NH(4-fluoro-phenyl),
--CH.sub.2CH.sub.2(3-indolyl)- ,
--CH.sub.2CH.sub.2(1-phthalimidyl),
--(CH.sub.2).sub.4C(=O)N(methyl)(met- hoxy),
--(CH.sub.2).sub.4CO.sub.2(ethyl), --(CH.sub.2).sub.4C(=O)(phenyl),
--(CH.sub.2).sub.4(cyclohexyl), --(CH.sub.2).sub.3CH(phenyl).sub.2,
--CH.sub.2CH.sub.2CH=C(phenyl).sub.2,
--CH.sub.2CH.sub.2CH=CMe(4-F-phenyl- ),
--(CH.sub.2).sub.3CH(4-fluoro-phenyl)2,
--CH.sub.2CH.sub.2CH=C(4-fluoro- -phenyl)2,
--(CH.sub.2).sub.2(2,3-dihydro-1H-inden-2-yl),
--(CH.sub.2).sub.3C(=O)(2-NH.sub.2-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NH.- sub.2-5-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NH.sub.2-3-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2- -NH.sub.2-4-Cl-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-OH-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-Br-phenyl),
--(CH.sub.2).sub.3(1H-in- dazol-3-yl),
--(CH.sub.2).sub.3(5-F-1H-indazol-3-yl),
--(CH.sub.2).sub.3(7-F-1H-indazol-3-yl),
--(CH.sub.2).sub.3(6-Cl-1H-indaz- ol-3-yl),
--(CH.sub.2).sub.3(6-Br-1H-indazol-3-yl),
--(CH.sub.2).sub.3C(=O)(2-NHMe-phenyl),
--(CH.sub.2).sub.3(1-benzothien-3- -yl),
--(CH.sub.2).sub.3(6-F-1H-indol-1-yl),
--(CH.sub.2).sub.3(5-F-1H-ind- ol-1-yl),
--(CH.sub.2).sub.3(6-F-2,3-dihydro-1H-indol-1-yl),
--(CH.sub.2).sub.3(5-F-2,3-dihydro-1H-indol-1-yl),
--(CH.sub.2).sub.3(6-F-1H-indol-3-yl),
--(CH.sub.2).sub.3(5-F-1H-indol-3-- yl),
--(CH.sub.2).sub.3(5-F-1H-indol-3-yl),
--(CH.sub.2).sub.3(9H-purin-9-- yl),
--(CH.sub.2).sub.3(7H-purin-7-yl),
--(CH.sub.2).sub.3(6-F-1H-indazol-- 3-yl),
--(CH.sub.2).sub.3C(=O)(2-NHSO.sub.2Me-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NHC(=O)Me-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(- 2-NHC(=O)Me-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NHCO.sub.2Et-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NHC(=O)NHEt-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NHCH0-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-OH- -4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-MeS-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NHSO.sub.2Me-4-F-phenyl),
--(CH.sub.2).sub.2C(Me)CO.sub.2Me,
--(CH.sub.2).sub.2C(Me)CH(OH)(4-F-phen- yl)2
--(CH.sub.2).sub.2C(Me)CH(OH)(4-Cl-phenyl)2,
--(CH.sub.2).sub.2C(Me)C- (=O)(4-F-phenyl),
--(CH.sub.2).sub.2C(Me)C(=O)(2-MeO-4-F-phenyl),
--(CH.sub.2).sub.2C(Me)C(=O)(3-Me-4-F-phenyl),
--(CH.sub.2).sub.2C(Me)C(=- O)(2-Me-phenyl),
--(CH.sub.2).sub.2C(Me)C(=O)phenyl, 62R.sup.7, R.sup.8, and
R.sup.9, at each occurrence, are independently selected from
hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl,
isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy,
isopropoxy, trifluoromethoxy, phenyl, benzyl, HC(=O)--,
methylC(=O)--, ethylC(=O)--, propylC(=O)--, isopropylC(=O)--,
n-butylC(=O)--, isobutylC(=O)--, secbutylC(=O)--, tertbutylC(=O)--,
phenylC(=O)--, methylC(=O)NH--, ethylC(=O)NH --, propylC(=O)NH--,
isopropylC(=O)NH--, n-butylC(=O)NH--, isobutylC(=O)NH--,
secbutylC(=O)NH--, tertbutylC(=O)NH--, phenylC(=O)NH--,
methylamino-, ethylamino-, propylamino-, isopropylamino-,
n-butylamino-, isobutylamino-, secbutylamino-, tertbutylamino-,
phenylamino-, provided that two of substituents R.sup.7, R.sup.8,
and R.sup.9, are independently selected from hydrogen, fluoro,
chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl,
t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, and
trifluoromethoxy; k is 1 or 2; m is 1 or 2; and n is 0, 1 or 2.
14. The method as defined in claim 13 where the compound
administered is a compound of Formula (V-a): 63wherein: b is a
single bond, wherein the bridge hydrogens are in a cis position;
R.sup.1 is selected from --(CH.sub.2).sub.3C(=O)(4-fluoro-phenyl),
--(CH.sub.2).sub.3C(=O)(4-bromo- -phenyl),
--(CH.sub.2).sub.3C(=O)(4-methyl-phenyl),
--(CH.sub.2).sub.3C(=O)(4-methoxy-phenyl),
--(CH.sub.2).sub.3C(=O)(4-(3,4- -dichloro-phenyl)phenyl),
--(CH.sub.2).sub.3C(=O)(3-methyl-4-fluoro-phenyl- ),
--(CH.sub.2).sub.3C(=O)(2,3-dimethoxy-phenyl),
--(CH.sub.2).sub.3C(=O)(- phenyl),
--(CH.sub.2).sub.3C(=O)(4-chloro-phenyl), --(CH.sub.2).sub.3C(=O)-
(3-methyl-phenyl), --(CH.sub.2).sub.3C(=O)(4-t-butyl-phenyl),
--(CH.sub.2).sub.3C(=O)(3,4-difluoro-phenyl),
--(CH.sub.2).sub.3C(=O)(2-m- ethoxy-5-fluoro-phenyl),
--(CH.sub.2).sub.3C(=O)(4-fluoro-1-naphthyl),
--(CH.sub.2).sub.3C(=O)(benzyl),
--(CH.sub.2).sub.3C(=O)(4-pyridyl),
--(CH.sub.2).sub.3C(=O)(3-pyridyl),
--(CH.sub.2).sub.3CH(OH)(4-fluoro-phe- nyl),
--(CH.sub.2).sub.3CH(OH)(4-pyridyl),
--(CH.sub.2).sub.3CH(OH)(2,3-di- methoxy-phenyl),
--(CH.sub.2).sub.3S(3-fluoro-phenyl),
--(CH.sub.2).sub.3S(4-fluoro-phenyl),
--(CH.sub.2).sub.3S(=O)(4-fluoro-ph- enyl),
--(CH.sub.2).sub.3SO.sub.2(3-fluoro-phenyl),
--(CH.sub.2).sub.3SO.sub.2(4-fluoro-phenyl),
--(CH.sub.2).sub.3O(4-fluoro- -phenyl),
--(CH.sub.2).sub.3O(phenyl), --(CH.sub.2).sub.3NH(4-fluoro-pheny-
l), --(CH.sub.2).sub.3N(methyl)(4-fluoro-phenyl),
--(CH.sub.2).sub.3CO.sub- .2(ethyl),
--(CH.sub.2).sub.3C(=O)N(methyl)(methoxy),
--(CH.sub.2).sub.3C(=O)NH(4-fluoro-phenyl),
--(CH.sub.2).sub.2NHC(=O)(phe- nyl),
--(CH.sub.2).sub.2NMeC(=O)(phenyl)
--(CH.sub.2).sub.2NHC(=O)(2-fluor- o-phenyl),
--(CH.sub.2).sub.2NMeC(=O)(2-fluoro-phenyl),
--(CH.sub.2).sub.2NHC(=O)(4-fluoro-phenyl),
--(CH.sub.2).sub.2NMeC(=O)(4-- fluoro-phenyl),
--(CH.sub.2).sub.2NHC(=O)(2,4-difluoro-phenyl),
--(CH.sub.2).sub.2NMeC(=O)(2,4-difluoro-phenyl),
--(CH.sub.2).sub.3(3-ind- olyl),
--(CH.sub.2).sub.3(1-methyl-3-indolyl),
--(CH.sub.2).sub.3(1-indoly- l), --(CH.sub.2).sub.3(1-indolinyl),
--(CH.sub.2).sub.3(1-benzimidazolyl),
--(CH.sub.2).sub.3(1H-1,2,3-benzotriazol-1-yl),
--(CH.sub.2).sub.3(1H-1,2- ,3-benzotriazol-2-yl),
--(CH.sub.2).sub.2(1H-1,2,3-benzotriazol-1-yl),
--(CH.sub.2).sub.2(1H-1,2,3-benzotriazol-2-yl),
--(CH.sub.2).sub.3(3,4 dihydro-1(2H)-quinolinyl),
--(CH.sub.2).sub.2C(=O)(4-fluoro-phenyl),
--(CH.sub.2).sub.2C(=O)NH(4-fluoro-phenyl),
--CH.sub.2CH.sub.2(3-indolyl)- ,
--CH.sub.2CH.sub.2(1-phthalimidyl),
--(CH.sub.2).sub.4C(=O)N(methyl)(met- hoxy),
--(CH.sub.2).sub.4CO.sub.2(ethyl), --(CH.sub.2).sub.4C(=O)(phenyl),
--(CH.sub.2).sub.4(cyclohexyl), --(CH.sub.2).sub.3CH(phenyl).sub.2,
--CH.sub.2CH.sub.2CH=C(phenyl).sub.2,
--CH.sub.2CH.sub.2CH=CMe(4-F-phenyl- ),
--(CH.sub.2).sub.3CH(4-fluoro-phenyl).sub.2,
--CH.sub.2CH.sub.2CH=C(4-f- luoro-phenyl)2,
--(CH.sub.2).sub.2(2,3-dihydro-1H-inden-2-yl),
--(CH.sub.2).sub.3C(=O)(2-NH.sub.2-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NH.- sub.2-5-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NH.sub.2-3-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2- -NH.sub.2-4-Cl-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-OH-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-Br-phenyl),
--(CH.sub.2).sub.3(1H-in- dazol-3-yl),
--(CH.sub.2).sub.3(5-F-1H-indazol-3-yl),
--(CH.sub.2).sub.3(7-F-1H-indazol-3-yl),
--(CH.sub.2).sub.3(6-Cl-1H-indaz- ol-3-yl),
--(CH.sub.2).sub.3(6-Br-1H-indazol-3-yl),
--(CH.sub.2).sub.3C(=O)(2-NHMe-phenyl),
--(CH.sub.2).sub.3(1-benzothien-3- -yl),
--(CH.sub.2).sub.3(6-F-1H-indol-1-yl),
--(CH.sub.2).sub.3(5-F-1H-ind- ol-1-yl),
--(CH.sub.2).sub.3(6-F-2,3-dihydro-1H-indol-1-yl),
--(CH.sub.2).sub.3(5-F-2,3-dihydro-1H-indol-1-yl),
--(CH.sub.2).sub.3(6-F-1H-indol-3-yl),
--(CH.sub.2).sub.3(5-F-1H-indol-3-- yl),
--(CH.sub.2).sub.3(5-F-1H-indol-3-yl),
--(CH.sub.2).sub.3(9H-purin-9-- yl),
--(CH.sub.2).sub.3(7H-purin-7-yl),
--(CH.sub.2).sub.3(6-F-1H-indazol-- 3-yl),
--(CH.sub.2).sub.3C(=O)(2-NHSO.sub.2Me-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NHC(=O)Me-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(- 2-NHC(=O)Me-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NHCO.sub.2Et-4-F-phenyl- ),
--(CH.sub.2).sub.3C(=O)(2-NHC(=O)NHEt-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NHCHO-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-OH- -4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-MeS-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NHSO.sub.2Me-4-F-phenyl),
--(CH.sub.2).sub.2C(Me)CO.sub.2Me,
--(CH.sub.2).sub.2C(Me)CH(OH)(4-F-phen- yl).sub.2,
--(CH.sub.2).sub.2C(Me)CH(OH)(4-Cl-phenyl).sub.2,
--(CH.sub.2).sub.2C(Me)C(=O)(4-F-phenyl),
--(CH.sub.2).sub.2C(Me)C(=O)(2-- MeO-4-F-phenyl),
--(CH.sub.2).sub.2C(Me)C(=O)(3-Me-4-F-phenyl),
--(CH.sub.2).sub.2C(Me)C(=O)(2-Me-phenyl),
--(CH.sub.2).sub.2C(Me)C(=O)ph- enyl, 64R.sup.7, R.sup.8, and
R.sup.9, at each occurrence, are independently selected from
hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl,
isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy,
isopropoxy, trifluoromethoxy, methylC(=O)--, ethylC(=O)--,
propylC(=O)--, isopropylC(=O)--, methylC(=O)NH--, ethylC(=O)NH--,
propylC(=O)NH--, isopropylC(=O)NH, methylamino-, ethylamino-,
propylamino-, and isopropylamino-, provided that two of
substituents R.sup.7, R.sup.8, and R.sup.9, are independently
selected from hydrogen, fluoro, chloro, methyl, trifluoromethyl,
methoxy, and trifluoromethoxy; m is 1 or 2; and n is 0, 1 or 2.
15. The method as defined in claim 1 where the compound
administered is selected from the group:
(.+-.)-cis-9-(cyclopropylcarbonyl)-4,5,6a,7,8,9,-
10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
(.+-.)-cis-9-isobutyryl-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo-
[3,2,1-hi]indole; tert-butyl
(.+-.)-cis-2-(2-chlorophenyl)-4,5,7,8,10,10a--
hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
tert-butyl
(.+-.)-cis-2-(2,4-dichlorophenyl)-4,5,7,8,10,10a-hexahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate; tert-butyl
(.+-.)-cis-2-(3,4-dichlorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]py-
rrolo[3,2,1-hi]indole-9(6aH)-carboxylate; tert-butyl
(.+-.)-cis-2-(2,3-dichlorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]py-
rrolo[3,2,1-hi]indole-9(6aH)-carboxylate; tert-butyl
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-4,5,7,8,10,10a-hexahydr-
opyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
tert-butyl
(.+-.)-cis-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,-
3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate; tert-butyl
(.+-.)-cis-2-(5-isopropyl-2-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido-
[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate; tert-butyl
(.+-.)-cis-2-(3-fluorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrol-
o[3,2,1-hi]indole-9(6aH)-carboxylate; tert-butyl
(.+-.)-cis-2-(2,4-dimetho-
xyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6-
aH)-carboxylate;
(.+-.)-cis-2-(2-chlorophenyl)-4,5,6a,7,8,9,10,10a-octahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
(.+-.)-cis-2-(2,4-dichlorophenyl)--
4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
(.+-.)-cis-2-(3,4-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-
-b]pyrrolo[3,2,1-hi]indole;
(.+-.)-cis-2-(2,3-dichlorophenyl)-4,5,6a,7,8,9-
,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,10a-oct-
ahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
(.+-.)-cis-2-(2-chloro-4-metho-
xyphenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indol-
e;
(.+-.)-cis-2-(4-isopropyl-2-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octahydr-
opyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
(.+-.)-cis-2-(3-fluorophenyl)-4,5,6-
a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
(.+-.)-cis-2-(2,4-dimethoxyphenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,-
3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(.+-.)-cis-5,6,8,9,11,11a-hexahydr-
o-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate;
tert-butyl
(.+-.)-cis-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,-
5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate; tert-butyl
(.+-.)-cis-2-(2,3-dichlorophenyl)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4-
':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate; tert-butyl
(.+-.)-cis-2-(3,4-dichlorophenyl)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4-
':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate; tert-butyl
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-5,6,8,9,11,11a-hexahydr-
o-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate;
(.+-.)-cis-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrid-
o[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(.+-.)-cis-2-(3,4-dichlorophenyl)--
5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinol-
ine;
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11-
a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
4-((.+-.)-cis-2-(2-chlorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyr-
rolo[3,2,1-hi]indol-9(6aH)-yl)-1-(4-fluorophenyl)-1-butanone;
4-((.+-.)-cis-2-(2,4-dichlorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b-
]pyrrolo[3,2,1-hi]indol-9(6aH)-yl)-1-(4-fluorophenyl)-1-butanone;
4-((.+-.)-cis-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1--
ij]qionolin-10(7aH)-yl)-1-(4-fluorophenyl)-1-butanone;
4-((.+-.)-cis-4,5,7,8,10,10a-hexahydropyrido[4.3-b]pyrrolo[3,2,1-hi]indol-
-9(6aH)-yl)-1-(4-fluorophenyl)-1-butanone;
(6aS,10aR)-2-(2-fluoro-4-methox-
yphenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-
; tert-butyl
(6aS,10aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-4,5,7,8,10,-
10a-hexahydropyrido
[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
(6aS,10aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,10a-oct-
ahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-(4-chloro-2-fluorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-
-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
(6aS,10aR)-2-(4-chloro-2-fl-
uorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]ind-
ole; tert-butyl
(6aS,10aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-4,5,-
7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylat-
e;
(6aS,10aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,1-
0a-octahydropyrido [4,3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
(6aS,10aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,10a-oc-
tahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-phenyl-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi-
]indole-9(6aH)-carboxylate;
(6aS,10aR)-2-phenyl-4,5,6a,7,8,9,10,10a-octahy- dropyrido
[4,3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-(2-methylphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrol-
o[3,2,1-hi]indole-9(6aH)-carboxylate;
(6aS,10aR)-2-(2-methylphenyl)-4,5,6a-
,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
tert-butyl
(6aS,10aR)-2-[2-(trifluoromethyl)phenyl]-4,5,7,8,10,10a-hexahydropyrido[4-
,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
(6aS,10aR)-2-[2-(trifluor- omethyl)phenyl]-4,5,6a,
7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-h- i]indole;
tert-butyl (6aS,10aR)-2-(3,4-dimethoxyphenyl)-4,5,7,8,10,10a-hex-
ahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
(6aS,10aR)-2-(3,4-dimethoxyphenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,-
3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-(2,5-dichlorophenyl)--
4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carbox-
ylate;
(6aS,10aR)-2-(2,5-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-(3,5-dichlorophe-
nyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-c-
arboxylate;
(6aS,10aR)-2-(3,5-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydr-
opyrido[4,3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-(2-isopropy-
l-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]i-
ndole-9(6aH)-carboxylate;
(6aS,10aR)-2-(2-isopropyl-4-methoxyphenyl)-4,5,6-
a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
tert-butyl
(6aS,10aR)-2-(5-fluoro-4-methoxy-2-methylphenyl)-4,5,7,8,10,10a-hexahydro-
pyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
(6aS,10aR)-2-(5-fluoro-4-methoxy-2-methylphenyl)-4,5,6a,7,8,9,10,10a-octa-
hydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-(4-methoxy-2-methylphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,-
3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
(6aS,10aR)-2-(4-methoxy-2--
methylphenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]i-
ndole; tert-butyl
(6aS,10aR)-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a-h-
exahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
(6aS,10aR)-2-(2-chloro-4-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-(3-chloro-2-meth-
ylphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6-
aH)-carboxylate;
(6aS,10aR)-2-(3-chloro-2-methylphenyl)-4,5,6a,7,8,9,10,10-
a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
2-[(6aS,10aR)-4,5,6a,7,8,-
9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]-2-yl]-5-methoxybenzaldehy-
de;
(6aS,10aR)-2-(2,6-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[-
4,3-b]pyrrolo[3,2,1-hi]indole;
N-[4-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahy-
dropyrido[4,3-b]pyrrolo[3,2,1-hi]indol-2-yl]-3-(trifluoromethyl)phenyl]-N--
methylamine;
4-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrro-
lo[3,2,1-hi]indol-2-yl]-3-(trifluoromethyl)phenylamine;
1-(2-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1--
hi]indol-2-yl]-5-methoxyphenyl)ethanol; tert-butyl
(.+-.)-cis-4,5,6,7,8a,9-
,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carbox-
ylate; tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate;
(8aS,12aR)-2-(2,4-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazep-
ino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(2,3-dichlorophenyl)-4,5,6,-
7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(3,4-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazep-
ino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(3,5-dichlorophenyl)-4,5,6,-
7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(2,5-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazep-
ino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(2,6-dichlorophenyl)-4,5,6,-
7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(2-chlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[-
3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(3-chlorophenyl)-4,5,6,7,8a,9,1-
0,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(4-chlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[-
3,2,1-hi]pyrido[4,3-b]indole;
(.+-.)-cis-2-(2,6-difluorophenyl)-4,5,6,7,8a-
,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(2,6-difluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazep-
ino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(2,3-difluorophenyl)-4,5,6,-
7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(3,4-difluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazep-
ino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(3-fluorophenyl)-4,5,6,7,8a-
,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-[2-chloro-4-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12,1-
2a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(2-chloro-4-
-methoxyphenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido-
[4,3-b]indole;
(8aS,12aR)-2-(2-fluoro-4-methoxyphenyl)-4,5,6,7,8a,9,10,11,-
12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(4-methoxy-2-methylphenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-[4-methoxy-2-(trifluo-
romethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrid-
o[4,3-b]indole;
(8aS,12aR)-2-[2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,1-
1,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,-
12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-[2,4-bis(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a-d-
ecahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-[4-fluoro-2-(tr-
ifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]-
pyrido[4,3-b]indole;
4-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazep-
ino[3,2,1-hi]pyrido[4,3-b]indol-2-yl]-3-(trifluoromethyl)aniline;
4-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[-
4,3-b]indol-2-yl]-N-methyl-3-(trifluoromethyl)aniline;
2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[-
4,3-b]indol-2-yl]benzaldehyde;
{2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-de-
cahydroazepino[3,2,.sub.1-hi]pyrido[4,3-b]indol-2-yl]phenyl}methanol;
2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[-
4,3-b]indol-2-yl]-5-methoxybenzaldehyde;
{2-[(8aS,12aR)-4,5,6,7,8a,9,10,11-
,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indol-2-yl]-5-methoxyphenyl-
}methanol;
4-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1--
hi]pyrido[4,3-b]indol-2-yl]-3-methylbenzonitrile;
1-{2-[(8aS,12aR)-4,5,6,7-
,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indol-2-yl]-5-me-
thoxyphenyl}ethanol; tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-oc-
tahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate-
;
(7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyri-
do[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(3,4-dichlorophenyl)-
-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quino-
line;
(7aS,11aR)-2-(3,5-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H--
pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(2,5-dichlorophe-
nyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]q-
uinoline;
(7aS,11aR)-2-(2,6-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-
-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(2-chlorophe-
nyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]q-
uinoline;
(7aS,11aR)-2-(3-chlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H--
pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(4-chlorophenyl)-
-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quino-
line;
(7aS,11aR)-2-(2,6-difluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H--
pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(2,6-difluorophe-
nyl)-10-methyl-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinoline;
(7aS,11aR)-2-(2,3-difluorophenyl)-5,6,7a,8,9,10,11,11a-
-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(3,4-difluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrid-
o[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(3-fluorophenyl)-5,6,-
7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-[2-chloro-4-methoxyphenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-[2-fluoro-4-met-
hoxyphenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2-
,1-ij]quinoline;
(7aS,11aR)-2-(4-methoxy-2-methylphenyl)-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-o-
ctahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-2-yl]-3-(trifluoromethyl)phenol;
(7aS,11aR)-2-[2-(triflu-
oromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrro-
lo[3,2,1-ij]quinoline;
(7aS,11aR)-2-[4-isopropoxy-2-(trifluoromethyl)pheny-
l]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]qui-
noline;
(7aS,11aR)-2-[2,4-bis(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-
-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-[4-fluoro-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-oc-
tahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-2-yl]-3-(trifluoromethyl)aniline;
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-2-yl]-N-methyl-3-(trifluoromethyl)aniline;
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-2-yl]-3-methylbenzonitrile;
2-[(7aS,11aR)-5,6,7a,8,9,10,-
11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-2-yl]benzal-
dehyde;
{2-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]-
pyrrolo[3,2,1-ij]quinolin-2-yl]phenyl}methanol;
2-[(7aS,11aR)-5,6,7a,8,9,1-
0,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-2-yl]-5-m-
ethoxybenzaldehyde;
{2-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrid-
o[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-2-yl]-5-methoxyphenyl}methanol;
(8aS,12aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12,1-
2a-decahydroazepino[3,2,1-hi]pyrido[4,3b]indole;
(7aS,11aR)-2-[4-ethoxy-2--
(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,-
5]pyrrolo[3,2,1-ij]quinoline;
(8aS,12aR)-2-[3-chloro-2-methylphenyl]-4,5,6-
,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3b]indole;
(7aS,11aR)-2-[3-chloro-2-methylphenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H--
pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-[5-fluoro-2-meth-
ylphenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-
-ij]quinoline;
(.+-.)-cis-2-(2,3-dichlorophenyl)-10-propyl-5,6,7a,8,9,10,1-
1,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(2,3-dichlorophenyl)-10-propyl-5,6,7a,8,9,10,11,11a-octahydr-
o-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(.+-.)-cis-10-butyl-2-(2-
,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrr-
olo[3,2,1-ij]quinoline;
(7aS,11aR)-10-butyl-2-(2,3-dichlorophenyl)-5,6,7a,-
8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
(7aS,11aR)-2-(2,3-dichlorophenyl)-10-(4-pentenyl)-5,6,7a,8,9,10,11,11a-oc-
tahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(2,3-dichlorophenyl)-10-(3-methyl-2-butenyl)-5,6,7a,8,9,10,1-
1,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(2,4-dichlorophenyl)-10-propyl-5,6,7a,8,9,10,11,11a-octahydr-
o-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-10-butyl-2-(2-
,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrr-
olo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(2,4-dichlorophenyl)-10-(4-pentenyl)--
5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinol-
ine;
(7aS,11aR)-2-(2,4-dichlorophenyl)-10-(3-methyl-2-butenyl)-5,6,7a,8,9,-
10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-10-(cyclobutylmethyl)-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-methyl-5,6,7a,8,9,1-
0,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-10-ethyl-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10-
,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-propyl-5,6,7a,8,9,1-
0,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-10-butyl-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-methyl-5,6-
,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-
;
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-(4-pentenyl)-5,6,7-
a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-(3-methyl-2-butenyl-
)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quin-
oline;
(7aS,11aR)-10-(2-fluoroethyl)-2-[4-methoxy-2-(trifluoromethyl)pheny-
l]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]qui-
noline;
(7aS,11aR)-10-(2,2-difluoroethyl)-2-[4-methoxy-2-(trifluoromethyl)-
phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-i-
j]quinoline;
(7aS,11aR)-10-(cyclobutylmethyl)-2-[4-methoxy-2-(trifluoromet-
hyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2-
,1-ij]quinoline;
4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,-
5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)-1-(4-fluorophenyl)-1-butanone;
4-((7aR,11aS)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1--
ij]quinolin-10(7aH)-yl)-1-(4-fluorophenyl)-1-butanone;
4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1--
ij]quinolin-10(7aH)-yl)-1-(2-aminophenyl)-1-butanone;
4-((7aR,11aS)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1--
ij]quinolin-10(7aH)-yl)-1-(2-aminophenyl)-1-butanone;
(.+-.)-cis-3-(5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1--
ij]quinolin-10(7aH)-yl)propyl4-fluorophenyl ether;
4-((.+-.)-cis-5,6,8,9,1-
1,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)--
1-(4-pyridinyl)-1-butanone;
(.+-.)-cis-10-[3-(6-fluoro-1,2-benzisoxazol-3--
yl)propyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,-
1-ij]quinoline;
(7aS,11aR)-10-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-5-
,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoli-
ne;
(.+-.)-cis-4-(4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-
-b]indol-11(8aH)-yl)-1-(4-fluorophenyl)-1-butanone;
4-((8aS,12aR)-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]-
indol-11(8aH)-yl)-1-(4-fluorophenyl)-1-butanone;
4-((8aR,12aS)-4,5,6,7,9,1-
0,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indol-11(8aH)-yl)-1-(4-flu-
orophenyl)-1-butanone;
4-((.+-.)-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,-
1-hi]pyrido[4,3-b]indol-11(8aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone;
4-((.+-.)-cis-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1--
ij]quinolin-10(7aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone ;
4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1--
ij]quinolin-10(7aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone; and
4-((7aR,11aS)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1--
ij]quinolin-10(7aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone.
16. The method as defined in claim 1 where the compound
administered is selected from the group:
4-[(.+-.)-5,6,8,9,10,11,12,12a-octahydro-4H,7aH--
azepino[4',5':4,5]pyrrolo
[3,2,1-ij]quinolin-10-yl]-1-(4-fluorophenyl)-1-b- utanone;
4-[(.+-.)-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':4,5-
]pyrrolo
[3,2,1-ij]quinolin-10-yl]-1-(2-amino-4-fluorophenyl)-1-butanone;
4-[(.+-.)-4,5,6,7,9,10,11,12,13,13a-decahydro-11H-diazepino[4,5-b:3,2,1-h-
i]indol-11-yl]-1-(4-fluorophenyl)-1-butanone;
4-[(.+-.)-4,5,6,7,9,10,11,12-
,13,13a-decahydro-11H-diazepino[4,5-b:3,2,1-hi]indol-11-yl]-1-(2-amino-4-f-
luorophenyl)-1-butanone; tert-butyl (.+-.)-cis-5,
6,8,9,10,11,12,12a-octah-
ydro-4H,7aH-azepino[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-11-carboxylate;
tert-butyl
(.+-.)-cis-2-bromo-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepi-
no[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-11-carboxylate; and
(.+-.)-cis-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,8,9,10,11,12,12a-o-
ctahydro-4H,7aH-azepino[3',4':4,5]pyrrolo[3,2,1-ij]quinoline.
17. The method as defined in claim 1 where the compound
administered is selected from the group: tert-butyl
(.+-.)-cis-2-bromo-4-oxo-4,5,6,7,9,10-
,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate;
tert-butyl
(.+-.)-cis-2-(2,4-dichlorophenyl)-4-oxo-4,5,6,7,9,10,12,12a-oc-
tahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate;
(.+-.)-cis-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydroazepino[-
3,2,1-hi]pyrido[4,3-b]indol-4(5H)-one;
(8aS,12aR)-2-(2,4-dichlorophenyl)-6-
,7,8a,9,10,11,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indol-4(5H)-on-
e;
(8aR,12aS)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydroazepin-
o[3,2,1-hi]pyrido[4,3-b]indol-4(5H)-one;
(8aS,12aR)-2-(2,4-dichlorophenyl)-
-6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indol-4-ol;
and
(8aR,12aS)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-decahydroazep-
ino[3,2,1-hi]pyrido[4,3-b]indol-4-ol.
18. A method for treating a human suffering from sleep disorders
associated with 5HT2A receptor modulation, comprising administering
to a patient in need thereof a therapeutically effective amount of
a compound of formula (I): 65or stereoisomers or pharmaceutically
acceptable salt forms thereof, wherein: b is a single bond; X is
--CHR.sup.10-- or --C(=O)--; R.sup.1 is selected from H,
C(=O)R.sup.2, C(=O)OR.sup.2, C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-6 alkyl
substituted with Z, C.sub.2-6 alkenyl substituted with Z, C.sub.2-6
alkynyl substituted with Z, C.sub.3-6 cycloalkyl substituted with
Z, aryl substituted with Z, 5-6 membered heterocyclic ring system
containing at least one heteroatom selected from the group
consisting of N, O, and S, said heterocyclic ring system
substituted with Z; C.sub.1-3 alkyl substituted with Y, C.sub.2-3
alkenyl substituted with Y, C.sub.2-3 alkynyl substituted with Y,
C.sub.1-6 alkyl substituted with 0-2 R.sup.2, C.sub.2-6 alkenyl
substituted with 0-2 R.sup.2, C.sub.2-6 alkynyl substituted with
0-2 R.sup.2, aryl substituted with 0-2 R.sup.2, and 5-6 membered
heterocyclic ring system containing at least one heteroatom
selected from the group consisting of N, O, and S, said
heterocyclic ring system substituted with 0-2 R.sup.2; Y is
selected from C.sub.3-6 cycloalkyl substituted with Z, aryl
substituted with Z, 5-6 membered heterocyclic ring system
containing at least one heteroatom selected from the group
consisting of N, O, and S, said heterocyclic ring system
substituted with Z; C.sub.3-6 cycloalkyl substituted with
--(C.sub.1-3 alkyl)-Z, aryl substituted with --(C.sub.1-3 alkyl)-Z,
and 5-6 membered heterocyclic ring system containing at least one
heteroatom selected from the group consisting of N, O, and S, said
heterocyclic ring system substituted with --(C.sub.1-3 alkyl)-Z; Z
is selected from H, --CH(OH)R.sup.2, --C(ethylenedioxy)R.sup.2,
--OR.sup.2, --SR.sup.2, --NR.sup.2R.sup.3, --C(O)R.sup.2,
--C(O)NR.sup.2R.sup.3, --NR.sup.3C(O)R.sup.2, --C(O)OR.sup.2,
--OC(O)R.sup.2, --CH(=NR.sup.4)NR.sup.2R.sup.3,
--NHC(=NR.sup.4)NR.sup.2R.sup.3, --S(O)R.sup.2,
--S(O).sub.2R.sup.2, --S(O)2NR.sup.2R.sup.3, and
--NR.sup.3S(O).sub.2R.sup.2; R.sup.2, at each occurrence, is
independently selected from halo, C.sub.1-3 haloalkyl, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl,
aryl substituted with 0-5 R.sup.42; C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.41, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.41; R.sup.3,
at each occurrence, is independently selected from H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, and C.sub.1-4 alkoxy;
alternatively, R.sup.2 and R.sup.3 join to form a 5- or 6-membered
ring optionally substituted with --O-- or --N(R.sup.4)--; R.sup.4,
at each occurrence, is independently selected from H and C.sub.1-4
alkyl; R.sup.5 is H or C.sub.1-4 alkyl; R.sup.6a and R.sup.6b, at
each occurrence, are independently selected from H, --OH,
--NR.sup.46R.sup.47, --CF.sub.3, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.3-6 cycloalkyl, and aryl substituted with 0-3 R.sup.44;
R.sup.7 and R.sup.9, at each occurrence, are independently selected
from H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN, --NO.sub.2,
--NR.sup.46R.sup.47, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, (C.sub.1-4
haloalkyl)oxy, C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
C.sub.1-4 alkyl substituted with 0-2 R.sup.11, C.sub.3-10
carbocyclic group substituted with 0-3 R.sup.33, aryl substituted
with 0-5 R.sup.33, 5-10 membered heterocyclic ring system
containing from 1-4 heteroatoms selected from the group consisting
of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12, SR.sup.12,
NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12 NR.sup.14S(O).sub.2R.sup.12,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15; R.sup.8
is selected from H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, (C.sub.1-4 haloalkyl)oxy,
C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33, C.sub.1-4
alkyl substituted with 0-2 R.sup.11, C.sub.2-4 alkenyl substituted
with 0-2 R.sup.11, C.sub.2-4 alkynyl substituted with 0-1 R.sup.11,
C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33, aryl
substituted with 0-5 R.sup.33, 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12,
SR.sup.12, NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12,
C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12, C(O)OR.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12 NR.sup.14S(O).sub.2R.sup.12,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15; R.sup.10
is selected from H, --OH, C.sub.1-6 alkyl substituted with 0-1
R.sup.10B, C.sub.2-6 alkenyl substituted with 0-1 R.sup.10B,
C.sub.2-6 alkynyl substituted with 0-1 R.sup.10B, and C.sub.1-6
alkoxy; R.sup.10B is selected from C.sub.1-4 alkoxy, C.sub.3-6
cycloalkyl, C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, phenyl substituted with 0-3 R.sup.33, and 5-6 membered
heterocyclic ring system containing 1,2, or 3 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-2
R.sup.44; R.sup.11 is selected from H, halo, --CF.sub.3, --CN,
--NO.sub.2, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, C.sub.3-10 cycloalkyl,
C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33, aryl
substituted with 0-5 R.sup.33, 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12,
SR.sup.12, NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12,
C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12, C(O)OR.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12 NR.sup.14S(O).sub.2R.sup.12,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15; R.sup.12,
at each occurrence, is independently selected from C.sub.1-4 alkyl
substituted with 0-1 R.sup.12a, C.sub.2-4 alkenyl substituted with
0-1 R.sup.12a, C.sub.2-4 alkynyl substituted with 0-1 R.sup.12a,
C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.33, phenyl
substituted with 0-5 R.sup.33; C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.33, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; R.sup.12a,
at each occurrence, is independently selected from phenyl
substituted with 0-5 R.sup.33; C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.33, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; R.sup.13,
at each occurrence, is independently selected from H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl; alternatively,
R.sup.12 and R.sup.13 join to form a 5- or 6-membered ring
optionally substituted with --O-- or --N(R.sup.14)--;
alternatively, R.sup.12 and R.sup.13 when attached to N may be
combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S, wherein said bicyclic heterocyclic ring
system is unsaturated or partially saturated, wherein said bicyclic
heterocyclic ring system is substituted with 0-3 R.sup.16;
R.sup.14, at each occurrence, is independently selected from H and
C.sub.1-4 alkyl; R.sup.15, at each occurrence, is independently
selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl; R.sup.16; at each occurrence, is independently selected
from H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, C.sub.1-3 haloalkyl-oxy-,
and C.sub.1-3 alkyloxy-; R.sup.31, at each occurrence, is
independently selected from H, OH, halo, CF.sub.3,
SO.sub.2R.sup.45, NR.sup.46R.sup.47, and C.sub.1-4 alkyl; R.sup.33,
at each occurrence, is independently selected from H, OH, halo, CN,
NO.sub.2, CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47, --C(=O)H,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6
cycloalkyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkyl-oxy-,
C.sub.1-4 alkyloxy-, C.sub.1-4 alkylthio-, C.sub.1-4 alkyl-C(=O)--,
C.sub.1-4 alkyl-C(=O)NH--, C.sub.1-4 alkyl-OC(=O)--, C.sub.1-4
alkyl-C(=O)O--, C.sub.3-6 cycloalkyl-oxy-, C.sub.3-6
cycloalkylmethyl-oxy-; C.sub.1-6 alkyl substituted with OH,
methoxy, ethoxy, propoxy, or butoxy; and C.sub.2-6 alkenyl
substituted with OH, methoxy, ethoxy, propoxy, or butoxy; R.sup.41,
at each occurrence, is independently selected from H, CF.sub.3,
halo, OH, CO.sub.2H, SO.sub.2R.sup.45, NR.sup.46R.sup.47, NO.sub.2,
CN, =O; C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
aryl substituted with 0-3 R.sup.42, and 5-10 membered heterocyclic
ring system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.44; R.sup.42,
at each occurrence, is independently selected from H, CF.sub.3,
halo, OH, CO.sub.2H, SO.sub.2R.sup.45, SOR.sup.45, SR.sup.45,
NR.sup.46SO.sub.2R.sup.45, NR.sup.46COR.sup.45, NR.sup.46R.sup.47,
NO.sub.2, CN, CH(=NH)NH.sub.2, NHC(=NH)NH.sub.2, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.3-6
cycloalkyl, C.sub.1-4 alkyl substituted with 0-1 R.sup.43, aryl
substituted with 0-3 R.sup.44, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.44; R.sup.43
is C.sub.3-6 cycloalkyl or aryl substituted with 0-3 R.sup.44;
R.sup.44, at each occurrence, is independently selected from H,
halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, and
C.sub.1-4 alkoxy; R.sup.45 is C.sub.1-4 alkyl; R.sup.46, at each
occurrence, is independently selected from H and C.sub.1-4 alkyl;
R.sup.47, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl, --C(=O)NH(C.sub.1-4 alkyl), --SO.sub.2(C.sub.1-4
alkyl), --C(=O)O(C.sub.1-4 alkyl), --C(=O)(C.sub.1-4 alkyl), and
--C(=O)H; k is 1 or 2; m is 0, 1, or 2; n is 0, 1, 2, or 3;
provided when m is 0 or 1 then k is 1 or 2; provided when m is 2
then k is 1; provided that when R.sup.6 or R.sup.6a is NH.sub.2,
then X is not --CH(R.sup.10); and provided that when n=0, then
R.sup.6 or R.sup.6a is not NH.sub.2 or --OH.
19. The method as defined in claim 18 where in the compound
administered: X is --CHR.sup.10-- or --C(=O)--; R.sup.1 is selected
from H, C(=O)R.sup.2, C(=O)OR.sup.2, C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-6 alkyl
substituted with 0-2 R.sup.2, C.sub.2-6 alkenyl substituted with
0-2 R.sup.2, C.sub.2-6 alkynyl substituted with 0-2 R.sup.2, aryl
substituted with 0-2 R.sub.2, and 5-6 membered heterocyclic ring
system containing at least one heteroatom selected from the group
consisting of N, O, and S, said heterocyclic ring system
substituted with 0-2 R.sup.2; R.sup.2, at each occurrence, is
independently selected from F, Cl, CH.sub.2F, CHF.sub.2, CF.sub.3,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-6
cycloalkyl, phenyl substituted with 0-5 R.sup.42; C.sub.3-10
carbocyclic group substituted with 0-3 R.sup.41, and 5-10 membered
heterocyclic ring system containing from 1-4 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-3
R.sup.41; R.sup.5 is H, methyl, ethyl, propyl, or butyl; R.sup.6a
is selected from H, --OH, --NR.sup.46R.sup.47, --CF.sub.3,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, and aryl
substituted with 0-3 R.sup.44; R.sup.6b is H; R.sup.7 and R.sup.9,
at each occurrence, are independently selected from H, halo,
--CF.sub.3, --OCF.sub.3, --OH, --CN, --NO.sub.2,
--NR.sup.46R.sup.47, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, (C.sub.1-4
haloalkyl)oxy, C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
C.sub.1-4 alkyl substituted with 0-2 R.sup.11, C.sub.3-10
carbocyclic group substituted with 0-3 R.sup.33, aryl substituted
with 0-5 R.sup.33, 5-10 membered heterocyclic ring system
containing from 1-4 heteroatoms selected from the group consisting
of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12, SR.sup.12,
NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sub.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sub.13,
NR.sup.14S(O)R.sup.12 NR.sup.14S(O).sub.2R.sup.12,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15; R.sup.8
is selected from H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, (C.sub.1-4 haloalkyl)oxy,
C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33, C.sub.1-4
alkyl substituted with 0-2 R.sup.11, C.sub.2-4 alkenyl substituted
with 0-2 R.sup.11, C.sub.2-4 alkynyl substituted with 0-1 R.sup.11,
C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33, aryl
substituted with 0-5 R.sup.33, 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12,
SR.sup.12, NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12,
C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12, C(O)OR.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12 NR.sup.14S(O).sub.2R.sup.12
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15; R.sup.10
is selected from H, --OH, C.sub.1-6 alkyl substituted with 0-1
R.sup.10B, C.sub.2-6 alkenyl substituted with 0-1 R.sup.10B,
C.sub.2-6 alkynyl substituted with 0-1 R.sup.10B, and C.sub.1-6
alkoxy; R.sup.10B is selected from C.sub.1-4 alkoxy, C.sub.3-6
cycloalkyl, C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, phenyl substituted with 0-3 R.sup.33, and 5-6 membered
heterocyclic ring system containing 1, 2, or 3 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-2
R.sup.44; R.sup.11is selected from H, halo, --CF.sub.3, --CN,
--NO.sub.2, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, C.sub.3-10 cycloalkyl,
C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33, aryl
substituted with 0-5 R.sup.33, 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12,
SR.sup.12, NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12,
C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12, C(O)OR.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12, NR.sup.14S(O).sub.2R.sup.12,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.1- 5, and NR.sup.12C(O)NHR.sup.15;
R.sup.12, at each occurrence, is independently selected from
C.sub.1-4 alkyl substituted with 0-1 R.sup.12a, C.sub.2-4 alkenyl
substituted with 0-1 R.sup.12a, C.sub.2-4 alkynyl substituted with
0-1 R.sup.12a, C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.33,
phenyl substituted with 0-5 R.sup.33; C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.33, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; R.sup.12a,
at each occurrence, is independently selected from phenyl
substituted with 0-5 R.sup.33; C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.33, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; R.sup.13,
at each occurrence, is independently selected from H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl; alternatively,
R.sup.12 and R.sup.13 join to form a 5- or 6-membered ring
optionally substituted with --O-- or --N(R.sup.14)--;
alternatively, R.sup.12 and R.sup.13 when attached to N may be
combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S, wherein said bicyclic heterocyclic ring
system is unsaturated or partially saturated, wherein said bicyclic
heterocyclic ring system is substituted with 0-3 R.sup.16;
R.sup.14, at each occurrence, is independently selected from H and
C.sub.1-4 alkyl; R.sup.15, at each occurrence, is independently
selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl; R.sup.16, at each occurrence, is independently selected
from H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, C.sub.1-3 haloalkyl-oxy-,
and C.sub.1-3 alkyloxy-; R.sup.31, at each occurrence, is
independently selected from H, OH, halo, CF.sub.3,
SO.sub.2R.sup.45, NR.sup.46R.sup.47, and C.sub.1-4 alkyl; R.sup.33,
at each occurrence, is independently selected from H, OH, halo, CN,
NO.sub.2, CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47, --C(=O)H,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6
cycloalkyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkyl-oxy-,
C.sub.1-4 alkyloxy-, C.sub.1-4 alkylthio-, C.sub.1-4 alkyl-C(=O)--,
C.sub.1-4 alkyl-C(=O)NH--, C.sub.1-4 alkyl-OC(=O)--, C.sub.1-4
alkyl-C(=O)O--, C.sub.3-6 cycloalkyl-oxy-, C.sub.3-6
cycloalkylmethyl-oxy-; C.sub.1-6 alkyl substituted with OH,
methoxy, ethoxy, propoxy, or butoxy; and C.sub.2-6 alkenyl
substituted with OH, methoxy, ethoxy, propoxy, or butoxy; R.sup.41,
at each occurrence, is independently selected from H, CF.sub.3,
halo, OH, CO.sub.2H, SO.sub.2R.sup.45, NR.sup.46R.sup.47, NO.sub.2,
CN; C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
aryl substituted with 0-3 R.sup.42, and 5-10 membered heterocyclic
ring system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.44; R.sup.42,
at each occurrence, is independently selected from H, CF.sub.3,
halo, OH, CO.sub.2H, SO.sub.2R.sup.45, NR.sup.46R.sup.47, NO.sub.2,
CN, CH(=NH)NH.sub.2, NHC(=NH)NH.sub.2, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.3-6
cycloalkyl, C.sub.1-4 alkyl substituted with 0-1 R.sup.43, aryl
substituted with 0-3 R.sup.44, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.44; R.sup.43
is C.sub.3-6 cycloalkyl or aryl substituted with 0-3 R.sup.44;
R.sup.44, at each occurrence, is independently selected from H,
halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, and
C.sub.1-4 alkoxy; R.sup.45 is C.sub.1-4 alkyl; R.sup.46, at each
occurrence, is independently selected from H and C.sub.1-4 alkyl;
R.sup.47, at each occurrence, is independently selected from H and
C.sub.1-4 alkyl; k is 1 or 2; m is 0, 1, or 2; and n is 0, 1, 2, or
3.
20. The method as defined in claim 19 where in the compound
administered: X is --CHR.sup.10--; R.sup.1 is selected from H,
C(=O)R.sup.2, C(=O)OR.sup.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.1-4 alkyl
substituted with 0-2 R.sup.2, C.sub.2-4 alkenyl substituted with
0-2 R.sup.2, and C.sub.2-4 alkynyl substituted with 0-2 R.sup.2;
R.sup.2, at each occurrence, is independently selected from
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-6
cycloalkyl, phenyl substituted with 0-5 R.sup.42; C.sub.3-10
carbocyclic group substituted with 0-3 R.sup.41, and 5-10 membered
heterocyclic ring system containing from 1-4 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-3
R.sup.41; R.sup.5 is H, methyl, ethyl, propyl, or butyl; R.sup.6a
is selected independently from H, --OH, --NR.sup.46R.sup.47,
--CF.sub.3, C.sub.1-3 alkyl, and C.sub.1-3 alkoxy; R.sup.6b is H;
R.sup.7 and R.sup.9, at each occurrence, are independently selected
from H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN, --NO.sub.2,
--NR.sup.46R.sup.47, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, (C.sub.1-4
haloalkyl)oxy, C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
C.sub.1-4 alkyl substituted with 0-2 R.sup.11, C.sub.3-10
carbocyclic group substituted with 0-3 R.sup.33, aryl substituted
with 0-5 R.sup.33, 5-10 membered heterocyclic ring system
containing from 1-4 heteroatoms selected from the group consisting
of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12, SR.sup.12,
NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12, C(O)NR.sup.12R.sup.13
NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12 S(O)hd 2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12, and NR.sup.14S(O).sub.2R.sup.12; R.sup.8 is
selected from H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, (C.sub.1-4 haloalkyl)oxy,
C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33, C.sub.1-4
alkyl substituted with 0-2 R.sup.11, C.sub.2-4 alkenyl substituted
with 0-2 R.sup.11, C.sub.2-4 alkynyl substituted with 0-1 R.sup.11,
C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33, aryl
substituted with 0-5 R.sup.33, 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12,
SR.sup.12NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12,
C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12, C(O)OR.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.3, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12, NR.sup.14S(O).sub.2R.sup.12,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15; R.sup.10
is selected from H, --OH, C.sub.1-6 alkyl substituted with 0-1
R.sup.10B, C.sub.2-6 alkenyl substituted with 0-1 R.sub.10B,
C.sub.2-6 alkynyl substituted with 0-1 R.sub.10B, and C.sub.1-6
alkoxy; R.sup.10B is selected from C.sub.1-4 alkoxy, C.sub.3-6
cycloalkyl, C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, phenyl substituted with 0-3 R.sup.33, and 5-6 membered
heterocyclic ring system containing 1, 2, or 3 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-2
R.sup.44; R.sup.11 is selected from H, halo, --CF.sub.3, --CN,
--NO.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl,
C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33, aryl
substituted with 0-5 R.sup.33, 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12,
SR.sup.12, NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12,
C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12, C(O)OR.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12 S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12, and NR.sup.14S(O).sub.2R.sup.12; R.sup.12,
at each occurrence, is independently selected from C.sub.1-4 alkyl
substituted with 0-1 R.sup.12a, C.sub.2-4 alkenyl substituted with
0-1 R.sup.12a, C.sub.2-4 alkynyl substituted with 0-1 R.sup.12a,
C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.33, phenyl
substituted with 0-5 R.sup.33; C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.33, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; R.sup.12a,
at each occurrence, is independently selected from phenyl
substituted with 0-5 R.sup.33; C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.33, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; R.sup.13,
at each occurrence, is independently selected from H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl; alternatively,
R.sup.12 and R.sup.13 join to form a 5- or 6-membered ring
optionally substituted with --O-- or --N(R.sup.14)--;
alternatively, R.sup.12 and R.sup.13 when attached to N may be
combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S, wherein said bicyclic heterocyclic ring
system is unsaturated or partially saturated, wherein said bicyclic
heterocyclic ring system is substituted with 0-3 R.sup.16;
R.sup.14, at each occurrence, is independently selected from H,
methyl, ethyl, propyl, and butyl; R.sup.15, at each occurrence, is
independently selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
and C.sub.2-4 alkynyl; R.sup.16 at each occurrence, is
independently selected from H, OH, F, Cl, CN, NO.sub.2, CF.sub.3,
SO.sub.2R.sup.45, NR.sup.46R.sup.47, --C(=O)H, methyl, ethyl,
methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; R.sup.31,
at each occurrence, is independently selected from H, OH, halo,
CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47, and C.sub.1-4 alkyl;
R.sup.33, at each occurrence, is independently selected from H, OH,
halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47,
--C(=O)H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-6 cycloalkyl, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkyl-oxy-, C.sub.1-4 alkyloxy-, C.sub.1-4 alkylthio-,
C.sub.1-4 alkyl-C(=O)--, C.sub.1-4 alkyl-C(=O)NH--, C.sub.1-4
alkyl-OC(=O)--, C.sub.1-4 alkyl-C(=O)O--, C.sub.3-6
cycloalkyl-oxy-, C.sub.3-6 cycloalkylmethyl-oxy-; C.sub.1-6 alkyl
substituted with OH, methoxy, ethoxy, propoxy, or butoxy; and
C.sub.2-6 alkenyl substituted with OH, methoxy, ethoxy, propoxy, or
butoxy; R.sup.41, at each occurrence, is independently selected
from H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl C.sub.1-4 alkyl
substituted with 0-1 R.sup.43, aryl substituted with 0-3 R.sup.42,
and 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44; R.sup.42, at each occurrence, is
independently selected from H, CF.sub.3, halo, OH, CO.sub.2H,
SO.sub.2R.sup.45, NR.sup.46R.sup.47, NO.sub.2, CN, CH(=NH)NH.sub.2,
NHC(=NH)NH.sub.2, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl, C.sub.1-4 alkyl
substituted with 0-1 R.sup.43, aryl substituted with 0-3 R.sup.44,
and 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44; R.sup.43 is C.sub.3-6 cycloalkyl or
aryl substituted with 0-3 R.sup.44; R.sup.44, at each occurrence,
is independently selected from H, halo, --OH, NR.sup.46R.sup.47,
CO.sub.2H, SO.sub.2R.sup.45, --CF.sub.3, --OCF.sub.3, --CN,
--NO.sub.2, C.sub.1-4 alkyl, and C.sub.1-4 alkoxy; R.sup.45 is
C.sub.1-4 alkyl; R.sup.46, at each occurrence, is independently
selected from H and C.sub.1-4 alkyl; R.sup.47, at each occurrence,
is independently selected from H and C.sub.1-4 alkyl; k is 1 or 2;
m is 0 or 1; and n is 0, 1 or 2.
21. The method as defined in claim 19 where in the compound
administered: X is --CH.sub.2--; R.sup.1 is selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-4
cycloalkyl, C.sub.1-3 alkyl substituted with 0-1 R.sup.2, C.sub.2-3
alkenyl substituted with 0-1 R.sup.2, and C.sub.2-3 alkynyl
substituted with 0-1 R.sup.2; R.sup.2, at each occurrence, is
independently selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, phenyl substituted with
0-5 R.sup.42; C.sub.3-6 carbocyclic group substituted with 0-3
R.sup.41, and 5-6 membered heterocyclic ring system containing 1,
2, or 3 heteroatoms selected from the group consisting of N, O, and
S substituted with 0-3 R.sup.41; R.sup.5 is H, methyl, ethyl,
propyl, or butyl; R.sup.6a is H, methyl, ethyl, methoxy, --OH, or
--CF.sub.3; R.sup.6b is H; R.sup.7 and R.sup.9, at each occurrence,
are independently selected from H, halo, --CF.sub.3, --OCF.sub.3,
--OH, --CN, --NO.sub.2, --NR.sup.46R.sup.47, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy, (C.sub.1-4 haloalkyl)oxy, C.sub.3-10 cycloalkyl
substituted with 0-2 R.sup.33, C.sub.1-4 alkyl substituted with 0-2
R.sup.11, C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, aryl substituted with 0-5 R.sup.33, and 5-6 membered
heterocyclic ring system containing 1, 2, or 3 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-3
R.sup.31; R.sup.8 is selected from H, halo, --CF.sub.3,
--OCF.sub.3, --OH, --CN, --NO.sub.2, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy,
(C.sub.1-4 haloalkyl)oxy, C.sub.3-10 cycloalkyl substituted with
0-2 R.sup.33, C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
C.sub.2-4 alkenyl substituted with 0-2 R.sup.11, C.sub.2-4 alkynyl
substituted with 0-1 R.sup.11, C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.33, aryl substituted with 0-5 R.sup.33,
5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31; OR.sup.12, SR.sup.12,
NR.sup.12R.sup.13, NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.1- 5, and NR.sup.12C(O)NHR.sup.15;
R.sup.11 is selected from H, halo, --CF.sub.3, --CN, --NO.sub.2,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, C.sub.1-4 alkoxy, (C.sub.1-4 haloalkyl)oxy, C.sub.3-10
cycloalkyl substituted with 0-2 R.sup.33, C.sub.3-10 carbocyclic
group substituted with 0-3 R.sup.33, aryl substituted with 0-5
R.sup.33, and 5-6 membered heterocyclic ring system containing 1,
2, or 3 heteroatoms selected from the group consisting of N, O, and
S substituted with 0-3 R.sup.31; R.sup.12, at each occurrence, is
independently selected from C.sub.1-4 alkyl substituted with 0-1
R.sup.12a, C.sub.2-4 alkenyl substituted with 0-1 R.sup.12a,
C.sub.2-4 alkynyl substituted with 0-1 R.sup.12a, C.sub.3-6
cycloalkyl substituted with 0-3 R.sup.33, phenyl substituted with
0-5 R.sup.33; C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, and 5-10 membered heterocyclic ring system containing
from 1-4 heteroatoms selected from the group consisting of N, O,
and S substituted with 0-3 R.sup.31; R.sup.12a, at each occurrence,
is independently selected from phenyl substituted with 0-5
R.sup.33; C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, and 5-10 membered heterocyclic ring system containing
from 1-4 heteroatoms selected from the group consisting of N, O,
and S substituted with 0-3 R.sup.31; R.sup.13, at each occurrence,
is independently selected from H, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, and C.sub.2-4 alkynyl; alternatively, R.sup.12 and
R.sup.13 join to form a 5- or 6-membered ring optionally
substituted with --O-- or --N(R.sup.14)--; alternatively, R.sup.12
and R.sup.13 when attached to N may be combined to form a 9- or
10-membered bicyclic heterocyclic ring system containing from 1-3
heteroatoms selected from the group consisting of one N, two N,
three N, one N one O, and one N one S; wherein said bicyclic
heterocyclic ring system is unsaturated or partially saturated,
wherein said bicyclic heterocyclic ring system is substituted with
0-2 R.sup.16; R.sup.14, at each occurrence, is independently
selected from H, methyl, ethyl, propyl, and butyl; R.sup.15, at
each occurrence, is independently selected from H, methyl, ethyl,
propyl, and butyl; R.sup.16, at each occurrence, is independently
selected from H, OH, F, Cl, CN, NO.sub.2, methyl, ethyl, methoxy,
ethoxy, trifluoromethyl, and trifluoromethoxy; R.sup.31, at each
occurrence, is independently selected from H, OH, halo, CF.sub.3,
methyl, ethyl, and propyl; R.sup.33, at each occurrence, is
independently selected from H, OH, halo, CN, NO.sub.2, CF.sub.3,
SO.sub.2R.sup.45, NR.sup.46R.sup.47, --C(=O)H, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkyl-oxy-, C.sub.1-4 alkyloxy-,
C.sub.1-4 alkylthio-, C.sub.1-4, alkyl-C(=O)--, C.sub.1-4
alkyl-C(=O)NH--, C.sub.1-4 alkyl-OC(=O)--, C.sub.1-4
alkyl-C(=O)O--, C.sub.3-6 cycloalkyl-oxy-, C.sub.3-6
cycloalkylmethyl-oxy-; C.sub.1-6 alkyl substituted with OH,
methoxy, ethoxy, propoxy, or butoxy; and C.sub.2-6 alkenyl
substituted with OH, methoxy, ethoxy, propoxy, or butoxy; R.sup.41,
at each occurrence, is independently selected from H, CF.sub.3,
halo, OH, CO.sub.2H, SO.sub.2R.sup.45, NR.sup.46R.sup.47, NO.sub.2,
CN, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy,
C.sub.1-3 haloalkyl, and C.sub.1-3 alkyl; R.sup.42, at each
occurrence, is independently selected from H, CF.sub.3, halo, OH,
CO.sub.2H, SO.sub.2R.sup.45, NR.sup.46R.sup.47, NO.sub.2, CN,
CH(=NH)NH.sub.2, NHC(=NH)NH.sub.2, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkyl, C.sub.3-6
cycloalkyl, and C.sub.1-3 alkyl; R.sup.43 is cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl, each
substituted with 0-3 R.sup.44; R.sup.44, at each occurrence, is
independently selected from H, halo, --OH, NR.sup.46R.sup.47,
CO.sub.2H, SO.sub.2R.sup.45, --CF.sub.3, --OCF.sub.3, --CN,
--NO.sub.2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,
and butoxy; R.sup.45 is methyl, ethyl, propyl, or butyl; R.sup.46,
at each occurrence, is independently selected from H, methyl,
ethyl, propyl, and butyl; R.sup.47, at each occurrence, is
independently selected from from H, methyl, ethyl, propyl, and
butyl; k is 1; m is 1; and n is 0, 1 or 2.
22. The method as defined in claim 19 where in the compound
administered: X is --CH.sub.2--; R.sup.1 is selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-4
cycloalkyl, C.sub.1-3 alkyl substituted with 0-1 R.sup.2, C.sub.2-3
alkenyl substituted with 0-1 R.sup.2, and C.sub.2-3 alkynyl
substituted with 0-1 R.sup.2; R.sup.2, at each occurrence, is
independently selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, phenyl substituted with
0-5 R.sup.42; C.sub.3-6 carbocyclic group substituted with 0-3
R.sup.41, and 5-6 membered heterocyclic ring system containing 1,
2, or 3 heteroatoms selected from the group consisting of N, O, and
S substituted with 0-3 R.sup.41; R.sup.5 is H, methyl, ethyl,
propyl, or butyl; R.sup.6a is H, methyl, ethyl, methoxy, --OH, or
--CF.sub.3; R.sup.6b is H; R.sup.7 and R.sup.9, at each occurrence,
are independently selected from H, F, Cl, --CH.sub.3, --OCH.sub.3,
--CF.sub.3, --OCF.sub.3, --CN, and --NO.sub.2, R.sup.8 is selected
from H, F, Cl, Br, --CF.sub.3, --OCF.sub.3, --OH, --CN, --NO.sub.2,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
haloalkyl, C.sub.1-4 alkoxy, (C.sub.1-4 haloalkyl)oxy, C.sub.3-10
cycloalkyl substituted with 0-2 R.sup.33, C.sub.1-4 alkyl
substituted with 0-2 R.sup.11, C.sub.2-4 alkenyl substituted with
0-2 R.sup.11, C.sub.2-4 alkynyl substituted with 0-1 R.sup.11,
C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33, aryl
substituted with 0-5 R.sup.33, 5-6 membered heterocyclic ring
system containing 1, 2, or 3 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12,
SR.sup.12, NR.sup.12R.sup.13, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15, and
NR.sup.12C(O)NHR.sup.15; R.sup.11 is selected from H, halo,
--CF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy,
(C.sub.1-4 haloalkyl)oxy, C.sub.3-10 cycloalkyl substituted with
0-2 R.sup.33, C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, aryl substituted with 0-5 R.sup.33, and 5-6 membered
heterocyclic ring system containing 1, 2, or 3 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-3
R.sup.31; R.sup.12 at each occurrence, is independently selected
from C.sub.1-4 alkyl substituted with 0-1 R.sup.12a, C.sub.2-4
alkenyl substituted with 0-1 R.sup.12a, C.sub.2-4 alkynyl
substituted with 0-1 R.sup.12a, C.sub.3-6 cycloalkyl substituted
with 0-3 R.sup.33, phenyl substituted with 0-5 R.sup.33; C.sub.3-10
carbocyclic group substituted with 0-3 R.sup.33, and 5-10 membered
heterocyclic ring system containing from 1-4 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-3
R.sup.31; R.sup.12a, at each occurrence, is independently selected
from phenyl substituted with 0-5 R.sup.33; C.sub.3-10 carbocyclic
group substituted with 0-3 R.sup.33, and 5-10 membered heterocyclic
ring system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; R.sup.13,
at each occurrence, is independently selected from H, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl; alternatively,
R.sup.12 and R.sup.13 join to form a 5- or 6-membered ring
optionally substituted with --O-- or --N(R.sup.14)--;
alternatively, R.sup.12 and R.sup.13 when attached to N may be
combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S; wherein said bicyclic heterocyclic ring
system is selected from indolyl, indolinyl, indazolyl,
benzimidazolyl, benzimidazolinyl, benztriazolyl, benzoxazolyl,
benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl; wherein said
bicyclic heterocyclic ring system is substituted with 0-1 R.sup.16;
R.sup.14, at each occurrence, is independently selected from H,
methyl, ethyl, propyl, and butyl; R.sup.15, at each occurrence, is
independently selected from H, methyl, ethyl, propyl, and butyl;
R.sup.16, at each occurrence, is independently selected from H, OH,
F, Cl, CN, NO.sub.2, methyl, ethyl, methoxy, ethoxy,
trifluoromethyl, and trifluoromethoxy; R.sup.31, at each
occurrence, is independently selected from H, OH, halo, CF.sub.3,
methyl, ethyl, and propyl; R.sup.33, at each occurrence, is
independently selected from H, OH, halo, CN, NO.sub.2, CF.sub.3,
SO.sub.2R.sup.45, NR.sup.46R.sup.47, --C(=O)H, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkyl-oxy-, C.sub.1-4 alkyloxy-,
C.sub.1-4 alkylthio-, C.sub.1-4 alkyl-C(=O)--, C.sub.1-4
alkyl-C(=O)NH--, C.sub.1-4 alkyl-OC(=O)--, C.sub.1-4
alkyl-C(=O)O--, C.sub.3-6 cycloalkyl-oxy-, C.sub.3-6
cycloalkylmethyl-oxy-; C.sub.1-6 alkyl substituted with OH,
methoxy, ethoxy, propoxy, or butoxy; and C.sub.2-6 alkenyl
substituted with OH, methoxy, ethoxy, propoxy, or butoxy; R.sup.41,
at each occurrence, is independently selected from H, CF.sub.3,
halo, OH, CO.sub.2H, SO.sub.2R.sup.45, NR.sup.46R.sup.47, NO.sub.2,
CN, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy,
C.sub.1-3 haloalkyl, and C.sub.1-3 alkyl; R.sup.42, at each
occurrence, is independently selected from H, CF.sub.3, halo, OH,
CO.sub.2H, SO.sub.2R.sup.45, NR.sup.46R.sup.47, NO.sub.2, CN,
CH(=NH)NH.sub.2, NHC(=NH)NH.sub.2, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkyl, C.sub.3-6
cycloalkyl, and C.sub.1-3 alkyl; R.sup.43 is cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or pyridyl, each
substituted with 0-3 R.sup.44; R.sup.44, at each occurrence, is
independently selected from H, halo, --OH, NR.sup.46R.sup.47,
CO.sub.2H, SO.sub.2R.sup.45, --CF.sub.3, --OCF.sub.3, --CN,
--NO.sub.2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,
and butoxy; R.sup.45 is methyl, ethyl, propyl, or butyl; R.sup.46,
at each occurrence, is independently selected from H, methyl,
ethyl, propyl, and butyl; R.sup.47, at each occurrence, is
independently selected from from H, methyl, ethyl, propyl, and
butyl; k is 1; m is 1; and n is 0, 1 or 2.
23. The method as defined in claim 19 where in the compound
administered: X is --CH.sub.2--; R.sup.1 is selected from H,
C.sub.1-5 alkyl substituted with 0-1 R.sup.2, C.sub.2-5 alkenyl
substituted with 0-1 R.sup.2, and C.sub.2-3 alkynyl substituted
with 0-1 R.sup.2; R.sup.2 is C.sub.3-6 cycloalkyl; R.sup.5 is H,
methyl, ethyl, or propyl; R.sup.6a is H, methyl, or ethyl; R.sup.6b
is H; R.sup.7 and R.sup.9, at each occurrence, are independently
selected from H, F, Cl, --CH.sub.3, --OCH.sub.3, --CF.sub.3,
--OCF.sub.3, --CN, and --NO.sub.2, R.sup.8 is selected from methyl
substituted with R.sup.11; ethenyl substituted with R.sup.11;
OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15, and
NR.sup.12C(O)NHR.sup.15; R.sup.11 is selected from phenyl-
substituted with 0-5 fluoro; 2-(H.sub.3CCH.sub.2C(=O))-phenyl-
substituted with R.sup.33; 2-(H.sub.3CC(=O))-phenyl- substituted
with R.sup.33; 2-(HC(=O))-phenyl- substituted with R.sup.33;
2-(H.sub.3CCH(OH))-phenyl- substituted with R.sup.33;
2-(H.sub.3CCH.sub.2CH(OH))-phenyl- substituted with R.sup.33;
2-(HOCH.sub.2)-phenyl- substituted with R.sup.33;
2-(HOCH.sub.2CH.sub.2)-phenyl- substituted with R.sup.33;
2-(H.sub.3COCH.sub.2)-phenyl- substituted with R.sup.33;
2-(H.sub.3COCH.sub.2CH.sub.2)-phenyl- substituted with R.sup.33;
2-(H.sub.3CCH(OMe))-phenyl- substituted with R.sup.33;
2-(H.sub.3COC(=O))-phenyl- substituted with R.sup.33;
2-(HOCH.sub.2CH=CH)-phenyl- substituted with R.sup.33;
2-((MeOC=O)CH=CH)-phenyl- substituted with R.sup.33;
2-(methyl)-phenyl- substituted with R.sup.33; 2-(ethyl)-phenyl-
substituted with R.sup.33; 2-(i-propyl)-phenyl- substituted with
R.sup.33; 2-(F.sub.3C)-phenyl- substituted with R.sup.33;
2-(NC)-phenyl- substituted with R.sup.33; 2-(H.sub.3CO)-phenyl-
substituted with R.sup.33; 2-(fluoro)-phenyl- substituted with
R.sup.33; 2-(chloro)-phenyl- substituted with R.sup.33;
3-(NC)-phenyl- substituted with R.sup.33; 3-(H.sub.3CO)-phenyl-
substituted with R.sup.33; 3-(fluoro)-phenyl- substituted with
R.sup.33; 3-(chloro)-phenyl- substituted with R.sup.33;
4-(NC)-phenyl- substituted with R.sup.33; 4-(fluoro)-phenyl-
substituted with R.sup.33; 4-(chloro)-phenyl- substituted with
R.sup.33; 4-(H.sub.3CS)-phenyl- substituted with R.sup.33;
4-(H.sub.3CO)-phenyl- substituted with R.sup.33; 4-(ethoxy)-phenyl-
substituted with R.sup.33; 4-(i-propoxy)-phenyl- substituted with
R.sup.33; 4-(i-butoxy)-phenyl- substituted with R.sup.33;
4-(H.sub.3CCH.sub.2CH.sub.2C(=O))-phenyl- substituted with
R.sup.33; 4-((H.sub.3C).sub.2CHC(=O))-phenyl- substituted with
R.sup.33; 4-(H.sub.3CCH.sub.2C(=O))-phenyl- substituted with
R.sup.33; 4-(H.sub.3CC(=O))-phenyl- substituted with R.sup.33;
4-(H.sub.3CCH.sub.2CH.sub.2CH(OH))-phenyl- substituted with
R.sup.33; 4-((H.sub.3C).sub.2CHCH(OH))-phenyl- substituted with
R.sup.33; 4-(H.sub.3CCH.sub.2CH(OH))-phenyl- substituted with
R.sup.33; 4-(H.sub.3CCH(OH))-phenyl- substituted with R.sup.33;
4-(cyclopropyloxy)-phenyl- substituted with R.sup.33;
4-(cyclobutyloxy)-phenyl- substituted with R.sup.33; and
4-(cyclopentyloxy)-phenyl- substituted with R.sup.33; R.sup.12 is
selected from phenyl- substituted with 0-5 fluoro;
2-(H.sub.3CCH.sub.2C(=O))-phenyl- substituted with R.sup.33;
2-(H.sub.3CC(=O))-phenyl- substituted with R.sup.33;
2-(HC(=O))-phenyl- substituted with R.sup.33;
2-(H.sub.3CCH(OH))-phenyl- substituted with R.sup.33;
2-(H.sub.3CCH.sub.2CH(OH))-phenyl- substituted with R.sup.33;
2-(HOCH.sub.2)-phenyl- substituted with R.sup.33;
2-(HOCH.sub.2CH.sub.2)-- phenyl- substituted with R.sup.33;
2-(H.sub.3COCH.sub.2)-phenyl- substituted with R.sup.33;
2-(H.sub.3COCH.sub.2CH.sub.2)-phenyl- substituted with R.sup.33;
2-(H.sub.3CCH(OMe))-phenyl- substituted with R.sup.33;
2-(H.sub.3COC(=O))-phenyl- substituted with R.sup.33;
2-(HOCH.sub.2CH=CH)-phenyl- substituted with R.sup.33;
2-((MeOC=O)CH=CH)-phenyl- substituted with R.sup.33;
2-(methyl)C-phenyl- substituted with R.sup.33; 2-(ethyl)-phenyl-
substituted with R.sup.33; 2-(i-propyl)-phenyl- substituted with
R.sup.33; 2-(F.sub.3C)-phenyl- substituted with R.sup.33;
2-(NC)-phenyl- substituted with R.sup.33; 2-(H.sub.3CO)-phenyl-
substituted with R.sup.33; 2-(fluoro)-phenyl- substituted with
R.sup.33; 2-(chloro)-phenyl- substituted with R.sup.33;
3-(NC)-phenyl- substituted with R.sup.33; 3-(H.sub.3CO)-phenyl-
substituted with R.sup.33; 3-(fluoro)-phenyl- substituted with
R.sup.33; 3-(chloro)-phenyl- substituted with R.sup.33;
4-(NC)-phenyl- substituted with R.sup.33; 4-(fluoro)-phenyl-
substituted with R.sup.33; 4-(chloro)-phenyl- substituted with
R.sup.33; 4-(H.sub.3CS)-phenyl- substituted with R.sup.33;
4-(H.sub.3CO)-phenyl- substituted with R.sup.33; 4-(ethoxy)-phenyl-
substituted with R.sup.33; 4-(i-propoxy)-phenyl- substituted with
R.sup.33; 4-(i-butoxy)-phenyl- substituted with R.sup.33;
4-(H.sub.3CCH.sub.2CH.sub.2C(=O))-phenyl- substituted with
R.sup.33; 4-((H.sub.3C).sub.2CHC(=O))-phenyl- substituted with
R.sup.33; 4-(H.sub.3CCH.sub.2C(=O))-phenyl- substituted with
R.sup.33; 4-(H.sub.3CC(=O))-phenyl- substituted with R.sup.33;
4-(H.sub.3CCH.sub.2CH.sub.2CH(OH))-phenyl- substituted with
R.sup.33; 4-((H.sub.3C).sub.2CHCH(OH))-phenyl- substituted with
R.sup.33; 4-(H.sub.3CCH.sub.2CH(OH))-phenyl- substituted with
R.sup.33; 4-(H.sub.3CCH(OH))-phenyl- substituted with R.sup.33;
4-(cyclopropyloxy)-phenyl- substituted with R.sup.33;
4-(cyclobutyloxy)-phenyl- substituted with R.sup.33; and
4-(cyclopentyloxy)-phenyl- substituted with R.sup.33; R.sup.13 is
H, methyl, or ethyl; alternatively, R.sup.12 and R.sup.13 join to
form a 5- or 6-membered ring selected from pyrrolyl, pyrrolidinyl,
imidazolyl, piperidinyl, piperizinyl, methylpiperizinyl,and
morpholinyl; alternatively, R.sup.12 and R.sup.13 when attached to
N may be combined to form a 9- or 10-membered bicyclic heterocyclic
ring system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S; wherein said bicyclic heterocyclic ring
system is selected from indolyl, indolinyl, indazolyl,
benzimidazolyl, benzimidazolinyl, benztriazolyl, benzoxazolyl,
benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl; wherein said
bicyclic heterocyclic ring system is substituted with 0-1 R.sup.16;
R.sup.15 is H, methyl, ethyl, propyl, or butyl; R.sup.16, at each
occurrence, is independently selected from H, OH, F, Cl, CN,
NO.sub.2, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and
trifluoromethoxy; R.sup.33, at each occurrence, is independently
selected from H, F, Cl, --CH.sub.3, --OCH.sub.3, --CF.sub.3,
--OCF.sub.3, --CN, and --NO.sub.2; k is 1; m is 1; and n is 1 or
2.
24. The method as defined in claim 19 where the compound
administered is a compound of Formula (I-a): 66wherein: b is a
single bond; X is --CH.sub.2--, --CH(OH)--, or --C(=O)--; R.sup.1
is selected from hydrogen, methyl, ethyl, n-propyl, n-butyl,
s-butyl, t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl,
2-hexyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl,
2-ethylbutyl, 3-methylpentyl, 3-methylbutyl, 4-methylpentyl,
2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-propenyl,
2-methyl-2-propenyl, trans-2-butenyl, 3-methyl-butenyl, 3-butenyl,
trans-2-pentenyl, cis-2-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,
3,3-dichloro-2-propenyl, trans-3-phenyl-2-propenyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl,
2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2,5-dimethylbenzyl,
2,4-dimethylbenzyl, 3,5-dimethylbenzyl, 2,4,6-trimethyl-benzyl,
3-methoxy-benzyl, 3,5-dimethoxy-benzyl, pentafluorobenzyl,
2-phenylethyl, 1-phenyl-2-propyl, 4-phenylbutyl, 4-phenylbenzyl,
2-phenylbenzyl, (2,3-dimethoxy-phenyl)C(=O)--,
(2,5-dimethoxy-phenyl)C(=O)--, (3,4-dimethoxy-phenyl)c(=O)--,
(3,5-dimethoxy-phenyl)C(=O)--, cyclopropyl-C(=O)--,
isopropyl-C(=O)--, ethyl-CO.sub.2--, propyl-CO.sub.2--,
t-butyl-CO.sub.2--, 2,6-dimethoxy-benzyl, 2,4-dimethoxy-benzyl,
2,4,6-trimethoxy-benzyl, 2,3-dimethoxy-benzyl,
2,4,5-trimethoxy-benzyl, 2,3,4-trimethoxy-benzyl, 3,
4-dimethoxy-benzyl, 3,4,5-trimethoxy-benzyl,
(4-fluoro-phenyl)ethyl, --CH=CH.sub.2, --CH.sub.2--CH=CH.sub.2,
--CH=CH--CH.sub.3, --C.ident.CH, --C.ident.C--CH.sub.3, and
--CH.sub.2--C.ident.CH; R.sup.7, R.sup.8, and R.sup.9, at each
occurrence, are independently selected from hydrogen, fluoro,
chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl,
t-butyl, nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy,
trifluoromethoxy, phenyl, methylC(=O)--, ethylC(=O)--,
propylC(=O)--, isopropylC(=O)--, butylC(=O) --, phenylC(=O)--,
methylCO.sub.2--, ethylCO.sub.2--, propylCO.sub.2--,
isopropylCO.sub.2--, butylCO.sub.2--, phenylCO.sub.2--,
dimethylamino-S(=O)--, diethylamino-S(=O)--, dipropylamino-S(=O)--,
di-isopropylamino-S(=O)--, dibutylamino-S(=O)--,
diphenylamino-S(=O)--, dimethylamino-SO.sub.2--,
diethylamino-SO.sub.2--, dipropylamino-SO.sub.2--,
di-isopropylamino-SO.sub.2--, dibutylamino-SO.sub.2--,
diphenylamino-SO.sub.2--, dimethylamino-C(=O)--,
diethylamino-C(=O)--, dipropylamino-C(=O)--,
di-isopropylamino-C(=O)--, dibutylamino-C(=O)--,
diphenylamino-C(=O)--, 2-chlorophenyl, 2-fluorophenyl,
2-bromophenyl, 2-cyanophenyl, 2-methylphenyl,
2-trifluoromethylphenyl, 2-methoxyphenyl, 2-trifluoromethoxyphenyl,
3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-cyanophenyl,
3-methylphenyl, 3-ethylphenyl, 3-propylphenyl, 3-isopropylphenyl,
3-butylphenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl,
3-isopropoxyphenyl, 3-trifluoromethoxyphenyl, 3-thiomethoxyphenyl,
4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-cyanophenyl,
4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl,
4-butylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl,
4-isopropoxyphenyl, 4-trifluoromethoxyphenyl, 4-thiomethoxyphenyl,
2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethylphenyl,
2,3-ditrifluoromethylphenyl, 2,3-dimethoxyphenyl,
2,3-ditrifluoromethoxyp- henyl, 2,4-dichlorophenyl,
2,4-difluorophenyl, 2,4-dimethylphenyl,
2,4-ditrifluoromethylphenyl, 2,4-dimethoxyphenyl,
2,4-ditrifluoromethoxyp- henyl, 2,5-dichlorophenyl,
2,5-difluorophenyl, 2,5-dimethylphenyl,
2,5-ditrifluoromethylphenyl, 2,5-dimethoxyphenyl,
2,5-ditrifluoromethoxyp- henyl, 2,6-dichlorophenyl,
2,6-difluorophenyl, 2,6-dimethylphenyl,
2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl,
2,6-ditrifluoromethoxyp- henyl, 3,4-dichlorophenyl,
3,4-difluorophenyl, 3,4-dimethylphenyl,
3,4-ditrifluoromethylphenyl, 3,4-dimethoxyphenyl,
3,4-ditrifluoromethoxyp- henyl, 2,4,6-trichlorophenyl,
2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl,
2,4,6-tritrifluoromethylphenyl, 2,4,6-trimethoxyphenyl,
2,4,6-tritrifluoromethoxyphenyl, 2-chloro-4-CF.sub.3-phenyl,
2-fluoro-3-chloro-phenyl, 2-chloro-4-CF.sub.3-phenyl,
2-chloro-4-methoxy-phenyl, 2-methoxy-4-isopropyl-phenyl,
2-CF.sub.3-4-methoxy-phenyl, 2-methyl-4-methoxy-5-fluoro-phenyl,
2-methyl-4-methoxy-phenyl, 2-chloro-4-CF.sub.3O-phenyl,
2,4,5-trimethyl-phenyl, 2-methyl-4-chloro-phenyl, methyl-C(=O)NH--,
ethyl-C(=O)NH--, propyl-C(=O)NH--, isopropyl-C(=O)NH--,
butyl-C(=O)NH--, phenyl-C(=O)NH--, 4-acetylphenyl,
3-acetamidophenyl, 4-pyridyl, 2-furanyl, 2-thiophenyl, 2-naphthyl;
2-Me-5-F-phenyl, 2-F-5-Me-phenyl, 2-MeO-5-F-phenyl,
2-Me-3-Cl-phenyl, 3-NO.sub.2-phenyl, 2-NO.sub.2-phenyl,
2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl,
2-Cl-6-F-phenyl, 2-Cl-4-(CHF.sub.2)O-phenyl, 2,4-diMeO-6-F-phenyl,
2-CF.sub.3-6-F-phenyl, 2-MeS-phenyl, 2,6-diCl-4-MeO-phenyl,
2,3,4-triF-phenyl, 2,6-diF-4-Cl-phenyl, 2,3,4,6-tetraF-phenyl,
2,3,4,5,6-pentaF-phenyl, 2-CF.sub.3-4-EtO-phenyl,
2-CF.sub.3-4-iPrO-phenyl, 2-CF.sub.3-4-Cl-phenyl,
2-CF.sub.3-4-F-phenyl, 2-Cl-4-EtO-phenyl, 2-Cl-4-iPrO-phenyl,
2-Et-4-MeO-phenyl, 2-CHO-4-MeO-phenyl, 2-CH(OH)Me-4-MeO-phenyl,
2-CH(OMe)Me-4-MeO-phenyl, 2-C(=O)Me-4-MeO-phenyl,
2-CH.sub.2(OH)-4-MeO-phenyl, 2-CH.sub.2(OMe)-4-MeO-phenyl,
2-CH(OH)Et-4-MeO-phenyl, 2-C(=O)Et-4-MeO-phenyl,
(Z)-2-CH=CHCO.sub.2Me-4-MeO-phenyl,
2-CH.sub.2CH.sub.2CO.sub.2Me-4-MeO-phenyl,
(Z)-2-CH=CHCH.sub.2(OH)-4-MeO-- phenyl,
(E)-2-CH=CHCO.sub.2Me-4-MeO-phenyl, (E)-2-CH=CHCH.sub.2(OH)-4-MeO--
phenyl, 2-CH.sub.2CH.sub.2OMe-4-MeO-phenyl, 2-F-4-MeO-phenyl,
2-Cl-4-F-phenyl, (2-Cl-phenyl)-CH=CH--, (3-Cl-phenyl)-CH=CH--,
(2,6-diF-phenyl)-CH=CH--, --CH.sub.2CH=CH.sub.2, phenyl-CH=CH--,
(2-Me-4-MeO-phenyl)-CH=CH--, cyclohexyl, cyclopentyl,
cyclohexylmethyl, --CH.sub.2CH.sub.2CO.sub.2Et,
--(CH.sub.2).sub.3CO.sub.2Et, --(CH.sub.2).sub.4CO.sub.2Et, benzyl,
2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 3-MeO-benzyl, 3-OH-benzyl,
2-MeO-benzyl, 2-OH-benzyl, 2-CO.sub.2Me-3-MeO-phenyl,
2-Me-4-CN-phenyl, 2-Me-3-CN-phenyl, 2-CF.sub.3-4-CN-phenyl,
3-CHO-phenyl, 3-CH.sub.2(OH)-phenyl, 3-CH.sub.2(OMe)-phenyl,
3-CH.sub.2(NMe.sub.2)-phenyl, 3-CN-4-F-phenyl,
3-CONH.sub.2-4-F-phenyl, 2-CH.sub.2(NH.sub.2)-4-MeO-phenyl--,
phenyl-NH--, (4-F-phenyl) --NH--, (2,4-diCl-phenyl) --NH--,
phenyl-C(=O)NH--, benzyl-NH--, (2-Me-4-MeO-phenyl)--NH--,
(2-F-4-MeO-phenyl)--NH--, (2-Me-4-F-phenyl)--NH--, phenyl-S-,
--NMe.sub.2, 1-pyrrolidinyl, and ---N(tosylate).sub.2, provided
that two of R.sup.7, R.sup.8, and R.sup.9, are independently
selected from hydrogen, fluoro, chloro, bromo, cyano, methyl,
ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl,
methoxy, ethoxy, isopropoxy, and trifluoromethoxy; m is 1; and n is
0, 1 or 2.
25. The method as defined in claim 24 where the compound
administered is a compound of Formula (V): 67wherein: b is a single
bond, wherein the bridge hydrogens are in a cis position; R.sup.1
is selected from hydrogen, methyl, ethyl, n-propyl, n-butyl,
s-butyl, t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl,
2-hexyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl,
2-ethylbutyl, 3-methylpentyl, 3-methylbutyl, 4-methylpentyl,
2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-propenyl,
2-methyl-2-propenyl, trans-2-butenyl, 3-methyl-butenyl, 3-butenyl,
trans-2-pentenyl, cis-2-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,
3,3-dichloro-2-propenyl, trans-3-phenyl-2-propenyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,
--CH=CH.sub.2, --CH.sub.2--CH=CH.sub.2, --CH=CH--CH.sub.3,
--C.ident.CH, --C.ident.C--CH.sub.3, and --CH.sub.2--C.ident.CH;
R.sup.7 and R.sup.9, at each occurrence, are independently selected
from hydrogen, fluoro, methyl, trifluoromethyl, and methoxy;
R.sup.8 is selected from hydrogen, fluoro, chloro, bromo, cyano,
methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro,
trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy,
phenyl, methylC(=O)--, ethylC(=O)--, propylC(=O)--,
isopropylC(=O)--, butylC(=O)--, phenylC(=O)--, methylCO.sub.2--,
ethylCO.sub.2--, propylCO.sub.2--, isopropylCO.sub.2--,
butylCO.sub.2--, phenylCO.sub.2--, dimethylamino-S(=O)--,
diethylamino-S(=O)--, dipropylamino-S(=O)--,
di-isopropylamino-S(=O)--, dibutylamino-S(=O)--,
diphenylamino-S(=O)--, dimethylamino-SO.sub.2--,
diethylamino-SO.sub.2--, dipropylamino-SO.sub.2--,
di-isopropylamino-SO.sub.2--, dibutylamino-SO.sub.2--,
diphenylamino-SO.sub.2--, dimethylamino-C(=O)--,
diethylamino-C(=O)--, dipropylamino-C(=O)--,
di-isopropylamino-C(=O)--, dibutylamino-C(=O)--,
diphenylamino-C(=O)--, 2-chlorophenyl, 2-fluorophenyl,
2-bromophenyl, 2-cyanophenyl, 2-methylphenyl,
2-trifluoromethylphenyl, 2-methoxyphenyl, 2-trifluoromethoxyphenyl,
3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-cyanophenyl,
3-methylphenyl, 3-ethylphenyl, 3-propylphenyl, 3-isopropylphenyl,
3-butylphenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl,
3-isopropoxyphenyl, 3-trifluoromethoxyphenyl, 3-thiomethoxyphenyl,
4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-cyanophenyl,
4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl,
4-butylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl,
4-isopropoxyphenyl, 4-trifluoromethoxyphenyl, 4-thiomethoxyphenyl,
2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethylphenyl,
2,3-ditrifluoromethylphenyl, 2,3-dimethoxyphenyl,
2,3-ditrifluoromethoxyp- henyl, 2,4-dichlorophenyl,
2,4-difluorophenyl, 2,4-dimethylphenyl,
2,4-ditrifluoromethylphenyl, 2,4-dimethoxyphenyl,
2,4-ditrifluoromethoxyp- henyl, 2,5-dichlorophenyl,
2,5-difluorophenyl, 2,5-dimethylphenyl,
2,5-ditrifluoromethylphenyl, 2,5-dimethoxyphenyl,
2,5-ditrifluoromethoxyp- henyl, 2,6-dichlorophenyl,
2,6-difluorophenyl, 2,6-dimethylphenyl,
2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl,
2,6-ditrifluoromethoxyp- henyl, 3,4-dichlorophenyl,
3,4-difluorophenyl, 3,4-dimethylphenyl,
3,4-ditrifluoromethylphenyl, 3,4-dimethoxyphenyl,
3,4-ditrifluoromethoxyp- henyl, 2,4,6-trichlorophenyl,
2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl,
2,4,6-tritrifluoromethylphenyl, 2,4,6-trimethoxyphenyl,
2,4,6-tritrifluoromethoxyphenyl, 2-chloro-4-CF.sub.3-phenyl,
2-fluoro-3-chloro-phenyl, 2-chloro-4-CF.sub.3-phenyl,
2-chloro-4-methoxy-phenyl, 2-methoxy-4-isopropyl-phenyl,
2-CF.sub.3-4-methoxy-phenyl, 2-methyl-4-methoxy-5-fluoro-phenyl,
2-methyl-4-methoxy-phenyl, 2-chloro-4-CF.sub.3O-phenyl,
2,4,5-trimethyl-phenyl, 2-methyl-4-chloro-phenyl, methyl-C
(=O)NH--, ethyl-C (=O)NH--, propyl-C (=O)NH--, isopropyl-C(=O)NH--,
butyl-C(=O)NH--, phenyl-C(=O)NH--, 4-acetylphenyl,
3-acetamidophenyl, 4-pyridyl, 2-furanyl, 2-thiophenyl, 2-naphthyl;
2-Me-5-F-phenyl, 2-F-5-Me-phenyl, 2-MeO-5-F-phenyl,
2-Me-3-Cl-phenyl, 3-NO.sub.2-phenyl, 2-NO.sub.2-phenyl,
2-C1-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl,
2-Cl-6-F-phenyl, 2-Cl-4-(CHF.sub.2)O-phenyl, 2,4-diMeO-6-F-phenyl,
2-CF.sub.3-6-F-phenyl, 2-MeS-phenyl, 2,6-diCl-4-MeO-phenyl,
2,3,4-triF-phenyl, 2,6-diF-4-Cl-phenyl, 2,3,4,6-tetraF-phenyl,
2,3,4,5,6-pentaF-phenyl, 2-CF.sub.3-4-EtO-phenyl,
2-CF.sub.3-4-iPrO-phenyl, 2-CF.sub.3-4-Cl-phenyl,
2-CF.sub.3-4-F-phenyl, 2-Cl-4-EtO-phenyl, 2-Cl-4-iPrO-phenyl,
2-Et-4-MeO-phenyl, 2-CHO-4-MeO-phenyl, 2-CH(OH)Me-4-MeO-phenyl,
2-CH(OMe)Me-4-MeO-phenyl, 2-C(=O)Me-4-MeO-phenyl,
2-CH.sub.2(OH)-4-MeO-phenyl, 2-CH.sub.2(OMe)-4-MeO-phenyl,
2-CH(OH)Et-4-MeO-phenyl, 2-C(=O)Et-4-MeO-phenyl,
(Z)-2-CH=CHCO.sub.2Me-4-MeO-phenyl,
2-CH.sub.2CH.sub.2CO.sub.2Me-4-MeO-phenyl,
(Z)-2-CH=CHCH.sub.2(OH)-4-MeO-- phenyl,
(E)-2-CH=CHCO.sub.2Me-4-MeO-phenyl, (E)-2-CH=CHCH.sub.2(OH)-4-MeO--
phenyl, 2-CH.sub.2CH.sub.2OMe-4-MeO-phenyl, 2-F-4-MeO-phenyl,
2-Cl-4-F-phenyl, (2-Cl-phenyl)--CH=CH--, (3-Cl-phenyl)--CH=CH--,
(2,6-diF-phenyl)--CH=CH--, --CH.sub.2CH=CH.sub.2, phenyl-CH=CH--,
(2-Me-4-MeO-phenyl)--CH=CH--, cyclohexyl, cyclopentyl,
cyclohexylmethyl, --CH.sub.2CH.sub.2CO.sub.2Et,
--(CH.sub.2).sub.3CO.sub.2Et, --(CH.sub.2).sub.4CO.sub.2Et, benzyl,
2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 3-MeO-benzyl, 3-OH-benzyl,
2-MeO-benzyl, 2-OH-benzyl, 2-CO2Me-3-MeO-phenyl, 2-Me-4-CN-phenyl,
2-Me-3-CN-phenyl, 2-CF.sub.3-4-CN-phenyl, 3-CHO-phenyl,
3-CH.sub.2(OH)-phenyl, 3-CH.sub.2(OMe)-phenyl,
3-CH.sub.2(NMe.sub.2)-phenyl, 3-CN-4-F-phenyl,
3-CONH.sub.2-4-F-phenyl, 2-CH.sub.2(NH.sub.2)-4-MeO-phenyl-,
phenyl-NH--, (4-F-phenyl) --NH--, (2,4-diCl-phenyl) --NH--,
phenyl-C(=O)NH--, benzyl-NH--, (2-Me-4-MeO-phenyl)-NH--,
(2-F-4-MeO-phenyl) --NH--, (2-Me-4-F-phenyl) --NH--, phenyl-S-,
--NMe.sub.2, 1-pyrrolidinyl, and --N(tosylate).sub.2; and n is 0, 1
or 2.
26. The method as defined in claim 18 where in the compound
administered: X is --CHR.sup.10-- or --C(=O)--; R.sup.1 is selected
from C.sub.1-6 alkyl substituted with Z, C.sub.2-6 alkenyl
substituted with Z, C.sub.2-6 alkynyl substituted with Z, C.sub.3-6
cycloalkyl, substituted with Z, aryl substituted with Z, 5-6
membered heterocyclic ring system containing at least one
heteroatom selected from the group consisting of N, O, and S, said
heterocyclic ring system substituted with Z; C.sub.1-6 alkyl
substituted with 0-2 R.sup.2, C.sub.2-6 alkenyl substituted with
0-2 R.sup.2, C.sub.2-6 alkynyl substituted with 0-2 R.sup.2, aryl
substituted with 0-2 R.sup.2, and 5-6 membered heterocyclic ring
system containing at least one heteroatom selected from the group
consisting of N, O, and S, said heterocyclic ring system
substituted with 0-2 R.sup.2; Z is selected from H,
--CH(OH)R.sup.2, --C(ethylenedioxy)R.sup.2, --OR.sup.2, --SR.sup.2,
--NR.sup.2R.sup.3, --C(O)R.sup.2, --C(O)NR.sup.2R.sup.3,
--NR.sup.3C(O) R.sup.2, --C(O)OR.sup.2, --OC(O)R.sup.2,
--CH(=NR.sup.4)NR.sup.2R.sup.3, --NHC(=NR.sup.4)NR.sup.2R.sup.3,
--S(O)R.sup.2, --S(O).sub.2R.sup.2, --S(O).sub.2NR.sup.2R.sup.3,
and --NR.sup.3S(O).sub.2R.sup.2; R.sup.2, at each occurrence, is
independently selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, aryl substituted with 0-5
R.sup.42; C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.41, and 5-10 membered heterocyclic ring system containing
from 1-4 heteroatoms selected from the group consisting of N, O,
and S substituted with 0-3 R.sup.41; R.sup.3, at each occurrence,
is independently selected from H, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, and C.sub.1-4 alkoxy; alternatively,
R.sup.2 and R.sup.3 join to form a 5- or 6-membered ring optionally
substituted with --O-- or --N(R.sup.4)--; R.sup.4, at each
occurrence, is independently selected from H, methyl, ethyl,
propyl, and butyl; R.sup.5 is H, methyl, ethyl, propyl, or butyl;
R.sup.6a is selected from H, --OH, --NR.sup.46R.sup.47, --CF.sub.3,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl, and aryl
substituted with 0-3 R.sup.44; R.sup.6b is H; R.sup.7, R.sup.8, and
R.sup.9, at each occurrence, are independently selected from H,
halo, --CF.sub.3, --OCF.sub.3, --OH, --CN, --NO.sub.2,
--NR.sup.46R.sup.47, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, (C.sub.1-4
haloalkyl)oxy, C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33, aryl
substituted with 0-5 R.sup.33, 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.31; OR.sup.12,
SR.sup.12, NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12,
C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12, C(O)OR.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(--NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12,
S(O).sub.2R.sub.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup.13, NR.sup.14S(O)R.sup.12
NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15, and
NR.sup.12C(O)NHR.sup.15; R.sup.10 is selected from H, --OH,
C.sub.1-6 alkyl substituted with 0-1 R.sup.10B, C.sub.2-6 alkenyl
substituted with 0-1 R.sup.10B, C.sub.2-6 alkynyl substituted with
0-1 R.sup.10B, and C.sub.1-6 alkoxy; R.sup.10B is selected from
C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.3-10 carbocyclic
group substituted with 0-3 R.sup.33, phenyl substituted with 0-3
R.sup.33, and 5-6 membered heterocyclic ring system containing 1,
2, or 3 heteroatoms selected from the group consisting of N, O, and
S substituted with 0-2 R.sup.44; R.sup.11 is selected from H, halo,
--CF.sub.3, --CN, --NO.sub.2, C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy,
C.sub.3-10 cycloalkyl, C.sub.3-10 carbocyclic group substituted
with 0-3 R.sup.33, aryl substituted with 0-5 R.sup.33, 5-10
membered heterocyclic ring system containing from 1-4 heteroatoms
selected from the group consisting of N, O, and S substituted with
0-3 R.sup.31; OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12,
C(O)OR.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12,
CH(=NR.sup.14)NR.sup.12R.sup.13, NHC(=NR.sup.14)NR.sup.12R.sup.13,
S(O)R.sup.12 S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup.13, NR.sup.14S(O)R.sup.12, and
NR.sup.14S(O).sub.2R.sup.12; R.sup.12, at each occurrence, is
independently selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, phenyl substituted with
0-5 R.sup.33; C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33, and 5-10 membered heterocyclic ring system containing
from 1-4 heteroatoms selected from the group consisting of N, O,
and S substituted with 0-3 R.sup.31; R.sup.13, at each occurrence,
is independently selected from H, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, and C.sub.2-4 alkynyl; alternatively, R.sup.12 and
R.sup.13 join to form a 5- or 6-membered ring optionally
substituted with --O-- or --N(R.sup.14)--; R.sup.14, at each
occurrence, is independently selected from H and C.sub.1-4 alkyl;
R.sup.31, at each occurrence, is independently selected from H, OH,
halo, CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47, methyl, ethyl,
and propyl; R.sup.33, at each occurrence, is independently selected
from H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3
alkynyl, C.sub.3-5 cycloalkyl, C.sub.1-3 haloalkyl, C.sub.1-3
haloalkyl-oxy-, C.sub.1-3 alkyloxy-, C.sub.1-3 alkylthio-,
C.sub.1-3 alkyl-C(=O)--, and C.sub.1-3 alkyl-C(=O)NH--; R.sup.41,
at each occurrence, is independently selected from H, CF.sub.3,
halo, OH, CO.sub.2H, SO.sub.2R.sup.45, NR.sup.46R.sup.47, NO.sub.2,
CN, =O, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
aryl substituted with 0-3 R.sup.42, and 5-10 membered heterocyclic
ring system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.44; R.sup.42,
at each occurrence, is independently selected from H, CF.sub.3,
halo, OH, CO.sub.2H, SO.sub.2R.sup.45, SR.sup.45,
NR.sup.46R.sup.47, OR.sup.48, NO.sub.2, CN, CH(=NH)NH.sub.2,
NHC(=NH)NH.sub.2, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl, C.sub.1-4 alkyl
substituted with 0-1 R.sup.43, aryl substituted with 0-3 R.sup.44,
and 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44; R.sup.43 is C3-6 cycloalkyl or aryl
substituted with 0-3 R.sup.44; R.sup.44, at each occurrence, is
independently selected from H, halo, --OH, NR.sup.46R.sup.47,
CO.sub.2H, SO.sub.2R.sup.45, --CF.sub.3, --OCF.sub.3, --CN,
--NO.sub.2, C.sub.1-4 alkyl, and C.sub.1-4 alkoxy; R.sup.45 is
C.sub.1-4 alkyl; R.sup.46, at each occurrence, is independently
selected from H and C.sub.1-4 alkyl; R.sup.47, at each occurrence,
is independently selected from H, C.sub.1-4 alkyl,
--C(=O)NH(C.sub.1-4 alkyl), --SO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2(phenyl), --C(=O)O(C.sub.1-4 alkyl), --C(=O)(C.sub.1-4
alkyl), and --C(=O)H; R.sup.48, at each occurrence, is
independently selected from H, C.sub.1-4 alkyl, --C(=O)NH(C.sub.1-4
alkyl), --C(=O)O(C.sub.1-4 alkyl), --C(=O)(C.sub.1-4 alkyl), and
--C(=O)H; k is 1 or 2; m is 0, 1, or 2; and n is 0, 1 or 2.
27. The method as defined in claim 26 where in the compound
administered: X is --CHR.sup.10-- or --C(=O)--; R.sup.1 is selected
from C.sub.2-5 alkyl substituted with Z, C.sub.2-5 alkenyl
substituted with Z, C.sub.2-5 alkynyl substituted with Z, C.sub.3-6
cycloalkyl substituted with Z, aryl substituted with Z, 5-6
membered heterocyclic ring system containing at least one
heteroatom selected from the group consisting of N, O, and S, said
heterocyclic ring system substituted with Z; C.sub.1-5 alkyl
substituted with 0-2 R.sup.2, C.sub.2-5 alkenyl substituted with
0-2 R.sup.2, and C.sub.2-5 alkynyl substituted with 0-2 R.sup.2; Z
is selected from H, --CH(OH)R.sup.2, --C(ethylenedioxy)R.sup.2,
--OR.sup.2.sub.1, --SR.sup.2, --NR.sup.2R.sup.3, --C(O)R.sup.2,
--C(O)NR.sup.2R.sup.3, --NR.sup.3C(O)R.sup.2, --C(O)OR.sup.2,
--OC(O)R.sup.2, --CH(=NR.sup.4)NR.sup.2R.sup.3,
--NHC(=NR.sup.4)NR.sup.2R- .sup.3, --S(O)R.sup.2,
--S(O).sub.2R.sup.2, --S(O).sub.2NR.sup.2R.sup.3, and
--NR.sup.3S(O).sub.2R.sup.2; R.sup.2, at each occurrence, is
independently selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, aryl substituted with 0-5
R.sup.42; C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.41, and 5-10 membered heterocyclic ring system containing
from 1-4 heteroatoms selected from the group consisting of N, O,
and S substituted with 0-3 R.sup.41; R.sup.3, at each occurrence,
is independently selected from H, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, and C.sub.1-4 alkoxy; alternatively,
R.sup.2 and R.sup.3 join to form a 5- or 6-membered ring optionally
substituted with --O-- or --N(R.sub.4)--; R.sup.4, at each
occurrence, is independently selected from H, methyl, ethyl,
propyl, and butyl; R.sup.5 is H, methyl, or ethyl; R.sup.6a is
selected from H, --OH, --NR.sup.46R.sup.47, --CF.sub.3, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, and C.sub.3-6 cycloalkyl; R.sup.6b is H;
R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are
independently selected from H, halo, --CF.sub.3, --OCF.sub.3, --OH,
--OCH.sub.3, --CN, --NO.sub.2, --NR.sup.46R.sup.47, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl,
C.sub.1-6 alkoxy, (C.sub.1-4 haloalkyl)oxy, C.sub.1-4 alkyl
substituted with 0-2 R.sup.11, C.sub.3-10 carbocyclic group
substituted with 0-3 R.sup.33, aryl substituted with 0-5 R.sup.33,
5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31; OR.sup.12, SR.sup.12,
NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12, C(O)NR.sup.12R.sup.13 ,
NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
CH(=NR.sup.14)NR.sup.12R.sup.13, NHC(=NR.sup.14)NR.sup.12R-
.sup.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O).sub.2NR.sup.12R.sup.13, NR.sup.14S(O).sub.2R.sup.12,
NR.sup.14S(O)R.sup.12, NR.sup.14S(O).sub.2R.sup.12,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15; R.sup.10
is selected from H, --OH, C.sub.1-6 alkyl, C.sub.1-4 alkoxy, and
C.sub.1-2 alkyl substituted with 0-1 R.sup.10B; R.sup.10B is
C.sub.3-6 cycloalkyl or phenyl substituted with 0-3 R.sup.33;
R.sup.11 is selected from H, halo, --CF.sub.3, --OCF.sub.3, --OH,
--OCH.sub.3, --CN, --NO.sub.2, --NR.sup.46R.sup.47, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl,
C.sub.1-6 alkoxy, (C.sub.1-4 haloalkyl)oxy, C.sub.3-10 carbocyclic
group substituted with 0-3 R.sup.33, aryl substituted with 0-5
R.sup.33, 5-10 membered heterocyclic ring system containing from
1-4 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31; OR.sup.12, SR.sup.12,
NR.sup.12R.sup.13, C(O)H, C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
CH(=NR.sup.14)NR.sup.12R.sup.13, NHC(=NR.sup.14)NR.sup.12R-
.sup.13, S(O)R.sup.12, S(O).sub.2R.sup.12,
S(O).sub.2NR.sup.12R.sup.13, and NR.sup.14S(O).sub.2R.sup.12;
R.sup.12 at each occurrence, is independently selected from
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-6
cycloalkyl, phenyl substituted with 0-5 R.sup.33; C.sub.3-10
carbocyclic group substituted with 0-3 R.sup.33, and 5-10 membered
heterocyclic ring system containing from 1-4 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-3
R.sup.31; R.sup.13, at each occurrence, is independently selected
from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl;
alternatively, R.sup.12 and R.sup.13 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.14)--; R.sup.14, at each occurrence, is independently
selected from H and C.sub.1-4 alkyl; R.sup.31, at each occurrence,
is independently selected from H, OH, halo, CF.sub.3, methyl, and
ethyl; R.sup.33, at each occurrence, is independently selected from
H, OH, halo, CN, N.sub.2, CF.sub.3, methyl, and ethyl; R.sup.41, at
each occurrence, is independently selected from H, CF.sub.3, halo,
OH, CO.sub.2H, SO.sub.2R.sup.45, NR.sup.46R.sup.47, NO.sub.2, CN,
=O, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
aryl substituted with 0-3 R.sup.42, and 5-10 membered heterocyclic
ring system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.44; R.sup.42,
at each occurrence, is independently selected from H, CF.sub.3,
halo, OH, CO.sub.2H, SO.sub.2R.sup.45, SR.sup.45,
NR.sup.46R.sup.47, OR.sup.48, NO.sub.2, CN, CH(=NH)NH.sub.2,
NHC(=NH)NH.sub.2, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl, C.sub.1-4 alkyl
substituted with 0-1 R.sup.43, aryl substituted with 0-3 R.sup.44,
and 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44; R.sup.43 is C.sub.3-6 cycloalkyl or
aryl substituted with 0-3 R.sup.44; R.sup.44, at each occurrence,
is independently selected from H, halo, --OH, NR.sup.46R.sup.47,
CO.sub.2H, SO.sub.2R.sup.45, --CF.sub.3, --OCF.sub.3, --CN,
--NO.sub.2, C.sub.1-4 alkyl, and C.sub.1-4 alkoxy; R.sup.45 is
C.sub.1-4 alkyl; R.sup.46, at each occurrence, is independently
selected from H and C.sub.1-3 alkyl; R.sup.47, at each occurrence,
is independently selected from H, C.sub.1-4 alkyl,
--C(=O)NH(C.sub.1-4 alkyl), --SO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2(phenyl), --C(=O)O(C.sub.1-4 alkyl), --C(=O)(C.sub.1-4
alkyl), and --C(=O)H; R.sup.48, at each occurrence, is
independently selected from H, C.sub.1-4 alkyl, --C(=O)NH(C.sub.1-4
alkyl), --C(=O)O(C.sub.1-4 alkyl), --C(=O)(C.sub.1-4 alkyl), and
--C(=O)H; k is 1 or 2; m is 0, 1, 2; and n is 0, 1 or 2.
28. The method as defined in claim 26 where in the compound
administered: X is --CH2--; R.sup.1 is selected from C.sub.2-4
alkyl substituted with Z, C.sub.2-4 alkenyl substituted with Z,
C.sub.2-4 alkynyl substituted with Z, C.sub.3-6 cycloalkyl
substituted with Z, aryl substituted with Z, 5-6 membered
heterocyclic ring system containing at least one heteroatom
selected from the group consisting of N, O, and S, said
heterocyclic ring system substituted with z; C.sub.2-4 alkyl
substituted with 0-2 R.sup.2, and C.sub.2-4 alkenyl substituted
with 0-2 R.sup.2; Z is selected from H, --CH(OH)R.sup.2,
--C(ethylenedioxy)R.sup.2, --OR.sup.2, --SR.sup.2,
--NR.sup.2R.sup.3, --C(O)R.sup.2, --C(O)NR.sup.2R.sup.3,
--NR.sup.3C(O)R.sup.2, --C(O)OR.sup.2, --S(O) R.sup.2,
--S(O).sub.2R.sup.2, --S(O).sub.2NR.sup.2R.sup.3, and
--NR.sup.3S(O).sub.2R.sup.2; R.sup.2, at each occurrence, is
independently selected from phenyl substituted with 0-5 R.sup.42;
C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.41, and
5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.41; R.sup.3, at each occurrence, is
independently selected from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, and C.sub.1-4 alkoxy; alternatively, R.sup.2 and
R.sup.3 join to form a 5- or 6-membered ring optionally substituted
with --O-- or --N(R.sup.4)--; R.sup.4, at each occurrence, is
independently selected from H, methyl, ethyl, propyl, and butyl;
R.sup.5 is H; R.sup.6a is selected from H, --OH, --CF.sub.3,
methyl, ethyl, propyl, butyl, methoxy, and, ethoxy; R.sup.6b is H;
R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are
independently selected from H, halo, --CF.sub.3, --OCF.sub.3, --OH,
--OCH3, --CN, --NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy, (C.sub.1-3 haloalkyl)oxy, and C.sub.1-4 alkyl
substituted with 0-2 R.sup.11; R.sup.11is selected from H, halo,
--CF.sub.3, --OCF.sub.3, --OH, --OCH.sub.3, --CN, --NO.sub.2,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, and
(C.sub.1-3 haloalkyl)oxy; R.sup.33, at each occurrence, is
independently selected from H, OH, halo, CF.sub.3, and methyl;
R.sup.41, at each occurrence, is independently selected from H,
CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45, NR.sup.46R.sup.47,
NO.sub.2, CN, =O, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 alkyl substituted with 0-1
R.sup.43, aryl substituted with 0-3 R.sup.42, and 5-10 membered
heterocyclic ring system containing from 1-4 heteroatoms selected
from the group consisting of N, O, and S substituted with 0-3
R.sup.44; R.sup.42, at each occurrence, is independently selected
from H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45, SR.sup.45,
NR.sup.46R.sup.47, OR.sup.48, NO.sub.2, CN,
CH(=NH)NH.sub.2,NHC(=NH)NH.sub.2, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.3-6
cycloalkyl, C.sub.1-4 alkyl substituted with 0-1 R.sup.43, aryl
substituted with 0-3 R.sup.44, and 5-10 membered heterocyclic ring
system containing from 1-4 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-3 R.sup.44; R.sup.43
is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or
pyridyl, each substituted with 0-3 R.sup.44; R.sup.44, at each
occurrence, is independently selected from H, halo, --O,
NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45, --CF.sub.3,
--OCF.sub.3, --CN, --NO.sub.2, methyl, ethyl, propyl, butyl,
methoxy, ethoxy, propoxy, and butoxy; R.sup.45 is methyl, ethyl,
propyl, or butyl; R.sup.46, at each occurrence, is independently
selected from H, methyl, ethyl, propyl, and butyl; R.sup.47, at
each occurrence, is independently selected from H, methyl, ethyl,
n-propyl, i-propyl, n-butyl, i-butyl, --C(=O)NH(methyl),
--C(=O)NH(ethyl), --SO.sub.2(methyl), --SO.sub.2(ethyl),
--SO.sub.2(phenyl), --C(=O)O(methyl),--C(=O)O(ethyl),
--C(=O)(methyl), --C(=O)(ethyl), and --C(=O)H; R.sup.48, at each
occurrence, is independently selected from H, methyl, ethyl,
n-propyl, i-propyl, --C(=O)NH(methyl), --C(=O)NH(ethyl),
--C(=O)O(methyl),--C(=O)O(- ethyl), --C(=O)(methyl),
--C(=O)(ethyl), and --C(=O)H; k is 1; m is 0, 1, or 2; and n is 0,
1 or 2.
29. The method as defined in claim 26 where in the compound
administered: X is --CH.sub.2--; R.sup.1 is selected from ethyl
substituted with Z, propyl substituted with Z, butyl substituted
with Z, propenyl substituted with Z, butenyl substituted with Z,
ethyl substituted with R.sup.2, propyl substituted with R.sup.2,
butyl substituted with R.sup.2, propenyl substituted with R.sup.2,
and butenyl substituted with R.sup.2; Z is selected from H,
--CH(OH)R.sup.2, --OR.sup.2, --SR.sup.2, --NR.sup.2R.sup.3,
--C(O)R.sup.2, --C(O)NR.sup.2R.sup.3, --NR.sup.3C (O) R.sup.2,
--C(O)OR.sup.2, --S(O)R.sup.2, --S(O).sub.2R.sup.2,
--S(O).sub.2NR.sup.2R.sup.3, and --NR.sup.3S(O).sub.2R.sup.2;
R.sup.2, at each occurrence, is independently selected from phenyl
substituted with 0-3 R.sup.42; naphthyl substituted with 0-3
R.sup.42; cyclopropyl substituted with 0-3 R.sup.41; cyclobutyl
substituted with 0-3 R.sup.41; cyclopentyl substituted with 0-3
R.sup.41; cyclohexyl substituted with 0-3 R.sup.41; pyridyl
substituted with 0-3 R.sup.41; indolyl substituted with 0-3
R.sup.41; indolinyl substituted with 0-3 R.sup.41; benzimidazolyl
substituted with 0-3 R.sup.41; benzotriazolyl substituted with 0-3
R.sup.41; benzothienyl substituted with 0-3 R.sup.41; benzofuranyl
substituted with 0-3 R.sup.41; phthalimid-1-yl substituted with 0-3
R.sup.41; inden-2-yl substituted with 0-3 R.sup.41;
2,3-dihydro-1H-inden-2-yl substituted with 0-3 R.sup.41; indazolyl
substituted with 0-3 R.sup.41; tetrahydroquinolinyl substituted
with 0-3 R.sup.41; and tetrahydro-isoquinolinyl substituted with
0-3 R41; R.sup.3, at each occurrence, is independently selected
from H, methyl, and ethyl; R.sup.5 is H; R.sup.6ais selected from
H, --OH, methyl, and methoxy; R.sup.6bis H; R.sup.7, R.sup.8, and
R.sup.9, at each occurrence, are independently selected from H, F,
Cl, methyl, ethyl, methoxy, --CF.sub.3, and --OCF.sub.3; R.sup.41,
at each occurrence, is independently selected from H, F, Cl, Br,
OH, CF.sub.3, NO.sub.2, CN, =O, methyl, ethyl, propyl, butyl,
methoxy, and ethoxy; R.sup.42, at each occurrence, is independently
selected from H, F, Cl, Br, OH, CF.sub.3, SO.sub.2R.sup.45,
SR.sup.45, NR.sup.46R.sup.47, OR.sup.48; NO.sub.2, CN, =O, methyl,
ethyl, propyl, butyl, methoxy, and ethoxy; R.sup.45 is methyl,
ethyl, propyl, or butyl; R.sup.46, at each occurrence, is
independently selected from H, methyl, ethyl, propyl, and butyl;
R.sup.47, at each occurrence, is independently selected from H,
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
--C(=O)NH(methyl), --C(=O)NH(ethyl), --SO.sub.2(methyl),
--SO.sub.2(ethyl), --SO.sub.2(phenyl),
--C(=O)O(methyl),--C(=O)O(ethyl), --C(=O)(methyl), --C(=O)(ethyl),
and --C(=O)H; R.sup.48, at each occurrence, is independently
selected from H, methyl, ethyl, n--propyl, i--propyl,
--C(=O)NH(methyl), --C(=O)NH(ethyl),
--C(=O)O(methyl),--C(=O)O(ethyl), --C(=O)(methyl), --C(=O)(ethyl),
and --C(=O)H; k is 1; m is 0, 1, or 2; and n is 0, 1 or 2.
30. The method as defined in claim 26 where the compound
administered is a compound of Formula (I-a): 68wherein: b is a
single bond; X is --CH.sub.2--, CH(OH)--, or --C(=O)--R.sup.1 is
selected from --(CH.sub.2).sub.3C(=O)(4-fluoro-phenyl),
--(CH.sub.2).sub.3C(=O)(4-bromo- -phenyl),
--(CH.sub.2).sub.3C(=O)(4-methyl-phenyl),
--(CH.sub.2).sub.3C(=O)(4-methoxy-phenyl),
--(CH.sub.2).sub.3C(=O)(4-(3,4- -dichloro-phenyl)phenyl),
--(CH.sub.2).sub.3C(=O)(3-methyl-4-fluoro-phenyl- ),
--(CH.sub.2).sub.3C(=O)(2,3-dimethoxy-phenyl),
--(CH.sub.2).sub.3C(=O)(- phenyl),
--(CH.sub.2).sub.3C(=O)(4-chloro-phenyl), --(CH.sub.2).sub.3C(=O)-
(3-methyl-phenyl), --(CH.sub.2).sub.3C(=O)(4-t-butyl-phenyl),
--(CH.sub.2).sub.3C(=O)(3,4-difluoro-phenyl),
--(CH.sub.2).sub.3C(=O)(.su- b.2-methoxy-5-fluoro-phenyl),
--(CH.sub.2).sub.3C(=O)(4-fluoro-1-naphthyl)- ,
--(CH.sub.2).sub.3C(=O)(benzyl),
--(CH.sub.2).sub.3C(=O)(4-pyridyl),
--(CH.sub.2).sub.3C(=O)(3-pyridyl), --(CH.sub.2).sub.3CH(OH)
(4-fluoro-phenyl), --(CH.sub.2).sub.3CH(OH) (4-pyridyl),
--(CH.sub.2).sub.3CH(OH) (2,3-dimethoxy-phenyl),
--(CH.sub.2).sub.3S(3-fl- uoro-phenyl),
--(CH.sub.2).sub.3S(4-fluoro-phenyl),
--(CH.sub.2).sub.3S(=O)(4-fluoro-phenyl),
--(CH.sub.2).sub.3SO.sub.2(3-fl- uoro-phenyl),
--(CH.sub.2).sub.3SO.sub.2(4-fluoro-phenyl),
--(CH.sub.2).sub.3O(4-fluoro-phenyl), --(CH.sub.2).sub.3O(phenyl),
--(CH.sub.2).sub.3O(3-pyridyl), --(CH.sub.2).sub.3O(4-pyridyl),
--(CH.sub.2).sub.3O(2.sub.2-NH.sub.2-phenyl),
--(CH.sub.2).sub.3O(2-NH.su- b.2-5-F-phenyl),
--(CH.sub.2).sub.3O(2-NH.sub.2-4-F-phenyl),
--(CH.sub.2).sub.3O(2-NH.sub.2-3-F-phenyl),
--(CH.sub.2).sub.3O(2-NH.sub.- 2-4-Cl-phenyl),
--(CH.sub.2).sub.3O(2-NH.sub.2-4-OH-phenyl),
--(CH.sub.2).sub.3O(2-NH.sub.2-4-Br-phenyl),
--(CH.sub.2).sub.3O(2-NHC(=O- )Me-4-F-phenyl),
--(CH.sub.2).sub.3O(2-NHC(=O)Me-phenyl),
--(CH.sub.2).sub.3NH(4-fluoro-phenyl),
--(CH.sub.2).sub.3N(methyl)(4-fluo- ro-phenyl),
--(CH.sub.2).sub.3CO.sub.2(ethyl), --(CH.sub.2).sub.3C(=O)N(me-
thyl)(methoxy), --(CH.sub.2).sub.3C(=O)NH(4-fluoro-phenyl),
--(CH.sub.2).sub.2NHC(=O)(phenyl),
--(CH.sub.2).sub.2NMeC(=O)(phenyl),
--(CH.sub.2).sub.2NHC(=O)(2-fluoro-phenyl),
--(CH.sub.2).sub.2NMeC(=O)(2-- fluoro-phenyl),
--(CH.sub.2).sub.2NHC(=O)(4-fluoro-phenyl),
--(CH.sub.2).sub.2NMeC(=O)(4-fluoro-phenyl),
--(CH.sub.2).sub.2NHC(=O)(2,- 4-difluoro-phenyl),
--(CH.sub.2).sub.2NMeC(=O)(2,4-difluoro-phenyl),
--(CH.sub.2).sub.3(3-indolyl),
--(CH.sub.2).sub.3(1-methyl-3-indolyl),
--(CH.sub.2).sub.3(1-indolyl), --(CH.sub.2).sub.3(1-indolinyl),
--(CH.sub.2).sub.3(1-benzimidazolyl),
--(CH.sub.2).sub.3(1H-1,2,3-benzotr- iazol-1-yl),
--(CH.sub.2).sub.3(1H-1,2,3-benzotriazol-2-yl),
--(CH.sub.2).sub.2(1H-1,2,3-benzotriazol-1-yl),
--(CH.sub.2).sub.2(1H-1,2- ,3-benzotriazol-2-yl),
--(CH.sub.2).sub.3(3,4 dihydro-1(2H)-quinolinyl),
--(CH.sub.2).sub.2C(=O)(4-fluoro-phenyl),
--(CH.sub.2).sub.2C(=O)NH(4-flu- oro-phenyl),
--CH.sub.2CH.sub.2(3-indolyl), --CH.sub.2CH.sub.2(1-phthalimi-
dyl), --(CH.sub.2).sub.4C(=O)N(methyl)(methoxy),
--(CH.sub.2).sub.4CO.sub.- 2(ethyl),
--(CH.sub.2).sub.4C(=O)(phenyl), --(CH.sub.2).sub.4(cyclohexyl),
--(CH.sub.2).sub.3CH(phenyl).sub.2,
--CH.sub.2CH.sub.2CH=C(phenyl).sub.2,
--CH.sub.2CH.sub.2CH=CMe(4-F-phenyl),
--(CH.sub.2).sub.3CH(4-fluoro-pheny- l).sub.2,
--CH.sub.2CH.sub.2CH=C(4-fluoro-phenyl).sub.2,
--(CH.sub.2).sub.2(2,3-dihydro-1H-inden-.sub.2-yl),
--(CH.sub.2).sub.3C(=O)(2-NH.sub.2-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NH.- sub.2-5-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NH.sub.2-3-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2- -NH.sub.2-4-Cl-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-OH-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-Br-phenyl),
--(CH.sub.2).sub.3(1H-in- dazol-3-yl),
--(CH.sub.2).sub.3(5-F-1H-indazol-3-yl),
--(CH.sub.2).sub.3(7-F-1H-indazol-3-yl),
--(CH.sub.2).sub.3(6-Cl-1H-indaz- ol-3-yl),
--(CH.sub.2).sub.3(6-Br-1H-indazol-3-yl),
--(CH.sub.2).sub.3C(=O)(.sub.2-NHMe-phenyl),
--(CH.sub.2).sub.3(1-benzoth- ien-3-yl),
--(CH.sub.2).sub.3(6-F-1H-indol-1-yl), --(CH.sub.2).sub.3(5-F-1-
H-indol-1-yl), --(CH.sub.2).sub.3(6-F-2,3-dihydro-1H-indol-1-yl),
--(CH.sub.2).sub.3(5-F-2,3-dihydro-1H-indol-1-yl),
--(CH.sub.2).sub.3(6-F-1H-indol-3-yl),
--(CH.sub.2).sub.3(5-F-1H-indol-3-- yl),
--(CH.sub.2).sub.3(5-F-1H-indol-3-yl),
--(CH.sub.2).sub.3(9H-purin-9-- yl),
--(CH.sub.2).sub.3(7H-purin-7-yl),
--(CH.sub.2).sub.3(6-F-1H-indazol-- 3-yl),
--(CH.sub.2).sub.3C(=O)(2-NHSO.sub.2Me-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NHC(=O)Me-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(- 2-NHC(=O)Me-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NHCO.sub.2Et-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NHC(=O)NHEt-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NHCHO-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-OH- -4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-MeS-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-NHSO.sub.2Me-4-F-phenyl),
--(CH.sub.2).sub.2C(Me)CO.sub.2Me,
--(CH.sub.2).sub.2C(Me)CH(OH)(4-F-phen- yl).sub.2,
--(CH.sub.2).sub.2C(Me)CH(OH)(4-Cl-phenyl).sub.2,
--(CH.sub.2).sub.2C(Me)C(=O)(4-F-phenyl),
--(CH.sub.2).sub.2C(Me)C(=O)(2-- MeO-4-F-phenyl),
--(CH.sub.2).sub.2C(Me)C(=O)(3-Me-4-F-phenyl),
--(CH.sub.2).sub.2C(Me)C(=O)(2-Me-phenyl),
--(CH.sub.2).sub.2C(Me)C(=O)ph- enyl, 69R.sup.7, R.sup.8, and
R.sup.9, at each occurrence, are independently selected from
hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl,
isopropyl,-butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy,
isopropoxy, trifluoromethoxy, phenyl, benzyl, HC(=O)--,
methylC(=O)--, ethylC(=O)--, propylC(=O)--, isopropylC(=O)--,
n--butylC(=O)--, isobutylC(=O)--, secbutylC(=O)--,
tertbutylC(=O)--, phenylC(=O)--, methylC(=O)NH--, ethylC(=O)NH --,
propylC(=O)NH--, isopropylC--(=O)NH--, n--butylC(=O)NH--,
isobutylC(=O)NH--, secbutylC(=O)NH--, tertbutylC(=O)NH--,
phenylC(=O)NH--, methylamino-, ethylamino-, propylamino-,
isoplopylamino-, n-butylamino-, isobutylamino-, secbutylamino-,
tertbutylamino-, phenylamino-, provided that two of substituents
R.sup.7, R.sup.8, and R.sup.9, are independently selected from
hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl,
isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy,
isopropoxy, and trifluoromethoxy; k is 1 or 2; m is 1 or 2; and n
is 0, 1 or 2.
31. The method as defined in claim 30 where the compound
administered is a compound of Formula (V-a): 70wherein: b is a
single bond, wherein the bridge hydrogens are in a cis position;
R.sup.1 is selected from --(CH.sub.2).sub.3C(=O)(4-fluoro-phenyl),
--(CH.sub.2).sub.3C(=O)(4-bromo- -phenyl),
--(CH.sub.2).sub.3C(=O)(4-methyl-phenyl),
--(CH.sub.2).sub.3C(=O)(4-methoxy-phenyl),
--(CH.sub.2).sub.3C(=O)(4-(3,4- -dichloro-phenyl)phenyl),
--(CH.sub.2).sub.3C(=O)(3-methyl-4-fluoro-phenyl- ),
--(CH.sub.2).sub.3C(=O)(2,3-dimethoxy-phenyl),
--(CH.sub.2).sub.3C(=O)(- phenyl),
--(CH.sub.2).sub.3C(=O)(4-chloro-phenyl), --(CH.sub.2).sub.3C(=O)-
(3-methyl-phenyl), --(CH.sub.2).sub.3C(=O)(4-t-butyl-phenyl),
--(CH.sub.2).sub.3C(=O)(3,4-difluoro-phenyl),
--(CH.sub.2).sub.3C(=O)(2-m- ethoxy-5-fluoro-phenyl),
--(CH.sub.2).sub.3C(=O)(4-fluoro-1-naphthyl),
--(CH.sub.2).sub.3C(=O)(benzyl),
--(CH.sub.2).sub.3C(=O)(4-pyridyl),
--(CH.sub.2).sub.3C(=O)(3-pyridyl),
--(CH.sub.2).sub.3CH(OH)(4-fluoro-phe- nyl),
--(CH.sub.2).sub.3CH(OH)(4-pyridyl),
--(CH.sub.2).sub.3CH(OH)(2,3-di- methoxy-phenyl),
--(CH.sub.2).sub.3S(3-fluoro-phenyl),
--(CH.sub.2).sub.3S(4-fluoro-phenyl),
--(CH.sub.2).sub.3S(=O)(4-fluoro-ph- enyl),
--(CH.sub.2).sub.3SO.sub.2(3-fluoro-phenyl),
--(CH.sub.2).sub.3SO.sub.2(4-fluoro-phenyl),
--(CH.sub.2).sub.3O(4-fluoro- -phenyl),
--(CH.sub.2).sub.3O(phenyl), --(CH.sub.2).sub.3NH(4-fluoro-pheny-
l), --(CH.sub.2).sub.3N(methyl)(4-fluoro-phenyl),
--(CH.sub.2).sub.3CO.sub- .2(ethyl),
--(CH.sub.2).sub.3C(=O)N(methyl)(methoxy),
--(CH.sub.2).sub.3C(=O)NH(4-fluoro-phenyl),
--(CH.sub.2).sub.2NHC(=O)(phe- nyl),
--(CH.sub.2).sub.2NMeC(=O)(phenyl),
--(CH.sub.2).sub.2NHC(=O)(2-fluo- ro-phenyl),
--(CH.sub.2).sub.2NMeC(=O)(2-fluoro-phenyl),
--(CH.sub.2).sub.2NHC(=O)(4-fluoro-phenyl),
--(CH.sub.2).sub.2NMeC(=O)(4-- fluoro-phenyl),
--(CH.sub.2).sub.2NHC(=O)(2,4-difluoro-phenyl),
--(CH.sub.2).sub.2NMeC(=O)(2,4-difluoro-phenyl),
--(CH.sub.2).sub.3(3-ind- olyl),
--(CH.sub.2).sub.3(1-methyl-3-indolyl),
--(CH.sub.2).sub.3(1-indoly- l), --(CH.sub.2).sub.3(1-indolinyl),
--(CH.sub.2).sub.3(1-benzimidazolyl),
--(CH.sub.2).sub.3(1H-1,2,3-benzotriazol-1-yl),
--(CH.sub.2).sub.3(1H-1,2- ,3-benzotriazol-2-yl),
--(CH.sub.2).sub.2(1H-1,2,3-benzotriazol-1-yl),
--(CH.sub.2).sub.2(1H-1,2,3-benzotriazol-.sub.2-yl),
--(CH.sub.2).sub.3(3,4 dihydro-1(2H)-quinolinyl),
--(CH.sub.2).sub.2C(=O)- (4-fluoro-phenyl),
--(CH.sub.2).sub.2C(=O)NH(4-fluoro-phenyl),
--CH.sub.2CH.sub.2(3-indolyl), --CH.sub.2CH.sub.2(1-phthalimidyl),
--(CH.sub.2).sub.4C(=O)N(methyl)(methoxy),
--(CH.sub.2).sub.4CO.sub.2(eth- yl),
--(CH.sub.2).sub.4C(=O)(phenyl), --(CH.sub.2).sub.4(cyclohexyl),
--(CH.sub.2).sub.3CH(phenyl).sub.2,
--CH.sub.2CH.sub.2CH=C(phenyl).sub.2,
--CH.sub.2CH.sub.2CH=CMe(4-F-phenyl),
--(CH.sub.2).sub.3CH(4-fluoro-pheny- l).sub.2,
--CH.sub.2CH.sub.2CH=C(4-fluoro-phenyl).sub.2,
--(CH.sub.2).sub.2(2,3-dihydro-1H-inden-.sub.2-yl),
--(CH.sub.2).sub.3C(=O)(2--NH.sub.2-phenyl),
--(CH.sub.2).sub.3C(=O)(2--N- H.sub.2-5-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2--NH.sub.2-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2--NH.sub.2-3-F-phenyl),
--(CH.sub.2).sub.3C(=O)(- 2--NH.sub.2-4--Cl-phenyl),
--(CH.sub.2).sub.3C(=O)(2--NH.sub.2-4--OH-pheny- l),
--(CH.sub.2).sub.3C(=O)(2--NH.sub.2-4-Br-phenyl),
--(CH.sub.2).sub.3(1H-indazol-3-yl),
--(CH.sub.2).sub.3(5-F-1H-indazol-3-- yl),
--(CH.sub.2).sub.3(7-F-1H-indazol-3-yl),
--(CH.sub.2).sub.3(6--Cl-1H-- indazol-3-yl),
--(CH.sub.2).sub.3(6-Br-1H-indazol-3-yl),
--(CH.sub.2).sub.3C(=O)(2--NHMe-phenyl),
--(CH.sub.2).sub.3(1-benzothien-- 3-yl),
--(CH.sub.2).sub.3(6-F-1H-indol-1-yl),
--(CH.sub.2).sub.3(5-F-1H-in- dol-1-yl),
--(CH.sub.2).sub.3(6-F-2,3-dihydro-1H-indol-1-yl),
--(CH.sub.2).sub.3(5-F-2,3-dihydro-1H-indol-1-yl),
--(CH.sub.2).sub.3(6-F-1H-indol-3-yl)
--(CH.sub.2).sub.3(5-F-1H-indol-3-y- l),
--(CH.sub.2).sub.3(5-F-1H-indol-3-yl),
--(CH.sub.2).sub.3(9H-purin-9-y- l),
--(CH.sub.2).sub.3(7H-purin-7-yl),
--(CH.sub.2).sub.3(6-F-1H-indazol-3- -yl),
--(CH.sub.2).sub.3C(=O)(2--NHSO.sub.2Me-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2--NHC(=O)Me-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)- (2--NHC(=O)Me-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2--NHCO.sub.2Et-4-F-phe- nyl),
--(CH.sub.2).sub.3C(=O)(2--NHC(=O)NHEt-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2--NHCHO-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2--- OH-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2-MeS-4-F-phenyl),
--(CH.sub.2).sub.3C(=O)(2--NHSO.sub.2Me-4-F-phenyl),
--(CH.sub.2).sub.2C(Me)CO.sub.2Me,
--(CH.sub.2).sub.2C(Me)CH(OH)(4-F-phen- yl).sub.2,
--(CH.sub.2).sub.2C(Me)CH(OH)(4--Cl-phenyl).sub.2,
--(CH.sub.2).sub.2C(Me)C(=O)(4-F-phenyl),
--(CH.sub.2).sub.2C(Me)C(=O)(2-- MeO-4-F-phenyl),
--(CH.sub.2).sub.2C(Me)C(=O)(3-Me-4-F-phenyl),
--(CH.sub.2).sub.2C(Me)C(=O)(2-Me-phenyl),
--(CH.sub.2).sub.2C(Me)C(=O)ph- enyl, 71R.sup.7, R.sup.8, and
R.sup.9, at each occurrence, are independently selected from
hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl,
isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy,
isopropoxy, trifluoromethoxy, methylC(=O)--, ethylC(=O)--,
propylC(=O)--, isopropylC(=O)--, methylC(=O)NH--, ethylC(=O)NH --,
propylC(=O)NH--, isopropylC(=O)NH, methylamino-, ethylamino-,
propylamino-, and isopropylamino-, provided that two of
substituents R.sup.7, R.sup.8, and R.sup.9, are independently
selected from hydrogen, fluoro, chloro, methyl, trifluoromethyl,
methoxy, and trifluoromethoxy; m is 1 or 2; and n is 0, 1 or 2.
32. The method as defined in claim 18 where the compound
administered is selected from the group:
(.+-.)-cis-9-(cyclopropylcarbonyl)-4,5,6a,7,8,9,-
10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
(.+-.)-cis-9-isobutyryl-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo-
[3,2,1-hi]indole; tert-butyl
(.+-.)-cis-2-(2-chlorophenyl)-4,5,7,8,10,10a--
hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
tert-butyl
(.+-.)-cis-2-(2,4-dichlorophenyl)-4,5,7,8,10,10a-hexahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate; tert-butyl
(.+-.)-cis-2-(3,4-dichlorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]py-
rrolo[3,2,1-hi]indole-9(6aH)-carboxylate; tert-butyl
(.+-.)-cis-2-(2,3-dichlorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]py-
rrolo[3,2,1-hi]indole-9(6aH)-carboxylate; tert-butyl
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-4,5,7,8,10,10a-hexahydr-
opyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
tert-butyl
(.+-.)-cis-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,-
3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate; tert-butyl
(.+-.)-cis-2-(5-isopropyl-2-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido-
[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate; tert-butyl
(.+-.)-cis-2-(3-fluorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3b]pyrrolo-
[3,2,1-hi]indole-9(6aH)-carboxylate; tert-butyl
(.+-.)-cis-2-(2,4-dimethox-
yphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6a-
H)-carboxylate;
(.+-.)-cis-2-(2-chlorophenyl)-4,5,6a,7,8,9,10,10a-octahydr-
opyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
(.+-.)-cis-2-(2,4-dichlorophenyl)-4-
,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
(.+-.)-cis-2-(3,4-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-
-b]pyrrolo[3,2,1-hi]indole;
(.+-.)-cis-2-(2,3-dichlorophenyl)-4,5,6a,7,8,9-
,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,10a-oct-
ahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
(.+-.)-cis-2-(2-chloro-4-metho-
xyphenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-]pyrrolo[3,2,1-hi]indole-
;
(.+-.)-cis-2-(4-isopropyl-2-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octahydro-
pyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
(.+-.)-cis-2-(3-fluorophenyl)-4,5,6a-
,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
(.+-.)-cis-2-(2,4-dimethoxyphenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,-
3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(.+-.)-cis-5,6,8,9,11,11a-hexahydr-
o-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate;
tert-butyl
(.+-.)-cis-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,-
5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate; tert-butyl
(.+-.)-cis-2-(2,3dichlorophenyl)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4'-
:4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate; tert-butyl
(.+-.)-cis-2-(3,4-dichlorophenyl)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4-
':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate; tert-butyl
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-5,6,8,9,11,11a-hexahydr-
o-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate;
(.+-.)-cis-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrid-
o[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(.+-.)-cis-2-(3,4-dichlorophenyl)--
5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinol-
ine;
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11-
a-octahydro-4H--pyrido[3',40 :4,5]pyrrolo[3,2,1-ij]quinoline;
4-((.+-.)-cis-2-(2-chlorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyr-
rolo[3 ,2 ,1-hi]indol-9(6aH)-yl)-1-4-fluorophenyl)-1-butanone;
4-((.+-.)-cis-2-(2,4-dichlorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b-
]pyrrolo[3,2,1-hi[indol-9(6aH)-1-(4-fluorophenyl)-1-butanone; 4
-((.+-.)-cis-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-i-
j]qionolin-10(7aH)-yl)-1-(4-fluorophenyl)-1-butanone;
4-((.+-.)-cis-4,5,7,8,10,10a-hexahydropyrido[4.3-b]pyrrolo[3,2,1-hi]indol-
-9(6aH)-yl)-1-(4-fluorophenyl)-1-butanone;
(6aS,10aR)-2-(2-fluoro-4-methox-
yphenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-
; tert-butyl
(6aS,10aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-4,5,7,8,10,-
10a-hexahydropyrido
[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
(6aS,10aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,10a-oct-
ahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-(4-chloro-2-fluorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-
-b]pyrrolo[3,2,1-hi]indole-9 (6aH)-carboxylate;
(6aS,10aR)-2-(4-chloro-2-f-
luorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]in-
dole; tert-butyl
(6aS,10aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-4,5-
,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxyla-
te;
(6aS,10aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,-
10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
(6aS,10aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,10a-oc-
tahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-phenyl-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3
,2,1-hi]indole-9(6aH)-carboxylate;
(6aS,10aR)-2-phenyl-4,5,6a,7,8,9,10,10-
a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-(2-methylphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrol-
o[3,2,1-hi]indole-](6aH)-carboxylate;
(6aS,10aR)-2-(2-methylphenyl)-4,5,6a-
,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
tert-butyl
(6aS,10aR)-2-[2-(trifluoromethyl)phenyl]-4,5,7,8,10,10a-hexahydropyrido[4-
,3-b]pyrrolo[3 ,2,1-hi]indole-9 (6aH)-carboxylate;
(6aS,10aR)-2-[2-(triflu-
oromethyl)phenyl]-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1--
hi]indole; tert-butyl
(6aS,10aR)-2-(3,4-dimethoxyphenyl)-4,5,7,8,10,10a-he-
xahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9 (6aH)-carboxylate;
(6aS,10aR)-2-(3,4-dimethoxyphenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,-
3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-(2,5-dichlorophenyl)--
4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carbox-
ylate;
(6aS,10aR)-2-(2,5-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do [4,3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-(3,5-dichloroph-
enyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)--
carboxylate;
(6aS,10aR)-2-(3,5-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahyd-
ropyrido [4,3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-(2-isopropyl-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido-
[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
(6aS,10aR)-2-(2-isoprop-
yl-4-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,-
1-hi]indole; tert-butyl
(6aS,10aR)-2-(5-fluoro-4-methoxy-2-methylphenyl)-4-
,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxy-
late;
(6aS,10aR)-2-(5-fluoro-4-methoxy-2-methylphenyl)-4,5,6a,7,8,9,10,10a-
-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-(4-methoxy-2-methylphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,-
3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
(6aS,10aR)-2-(4-methoxy-2--
methylphenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]i-
ndole; tert-butyl
(6aS,10aR)-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a-h-
exahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
(6aS,10aR)-2-(2-chloro-4-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole; tert-butyl
(6aS,10aR)-2-(3-chloro-2-meth-
ylphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6-
aH)-carboxylate;
(6aS,10aR)-2-(3-chloro-2-methylphenyl)-4,5,6a,7,8,9,10,10-
a-octahydropyrido [4,3-b]pyrrolo[3,2,1-hi]indole;
2-[(6aS,10aR)-4,5,6a,7,8-
,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]-2-yl]-5-methoxybenzaldeh-
yde;
(6aS,10aR)-2-(2,6-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido-
[4,3-b]pyrrolo[3,2,1-hi]indole;
N-[4-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octah-
ydropyrido[4,3-b]pyrrolo[3,2,1-hi]indol-2-yl]-3-(trifluoromethyl)phenyl]-N-
-methylamine;
4-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrr-
olo[3,2,1-hi]indol-2-yl]-3-(trifluoromethyl)phenylamine;
1-(2-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-bjpyrrolo[3,2,1--
hi]indol-2-yl]-5-methoxyphenyl)ethanol; tert-butyl
(.+-.)-cis-4,5,6,7,8a,9-
,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b
]indole-11(8aH)-carboxylate; tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,8a,9,1-
0,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxyl-
ate;
(8aS,12aR)-2-(2,4-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydro-
azepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(2,3-dichlorophenyl)-4,-
5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(3,4-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazep-
ino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(3,5-dichlorophenyl)-4,5,6,-
7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(2,5-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazep-
ino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(2,6-dichlorophenyl)-4,5,6,-
7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(2-chlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[-
3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-3-(2-chlorophenyl)-4,5,6,7,8a,9,1-
0,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-4-(2-chlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[-
decahydroazepino[3,2 1-hi]pyrido[4,3-b]indole;
(.+-.)-cis-2-(2,6-difluorop-
henyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]in-
dole;
(8aS,12aR)-2-(2,6-difluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydr-
oazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(2,3-difluorophenyl)-4-
,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(3,4-difluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazep-
ino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(3-fluorophenyl)-4,5,6,7,8a-
,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-[2-chloro-4-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12,1-
2a-decahydroazepino[3,2,1- hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(2-chloro--
4-methoxyphenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrid-
o[4,3-b]indole;
(8aS,12aR)-2-(2-fluoro-4-methoxyphenyl)-4,5,6,7,8a,9,10,11-
,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-(4-methoxy-2-methylphenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-[4-methoxy-2-(trifluo-
romethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrid-
o[4,3-b]indole;
(8aS,12aR)-2-[2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,1-
1,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,-
12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-[2,4-bis(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a-d-
ecahydroazepino[3,2,1-hi]hi]pyrido[4,3-b]indole;
(8aS,12aR)-2-[4-fluoro-2--
(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1--
hi]pyrido[4,3-b]indole;
(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazep-
ino[3,2,1-hi]pyrido[4,3-b]indol-2-yl]-3-(trifluoromethyl)aniline;
4-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[-
4,3-b]indol-2-yl]--N-methyl-3-(trifluoromethyl)aniline;
2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[-
4,3-b]indol-2-yl]benzaldehyde;
{2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,1.2,12a-d-
ecahydroazepino[3,2,1-hi]pyrido[4,3-b]indol-2-yl]phenyl}methanol;
2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[-
4,3-b]indol-2-yl]-5-methoxybenzaldehyde;
{2-[(8aS,12aR)-4,5,6,7,8a,9,10,11-
,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indol-2-yl]-5-methoxyphenyl-
}methanol;
4-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1--
hi]pyrido[4,3-b]indol-2-yl]-3-methylbenzonitrile;
1-{2-[(8aS,12aR)-4,5,6,7-
,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indol-2-yl]-5-me-
thoxyphenyl}ethanol; tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-oc-
tahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate-
;
(7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyri-
do[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(3,4-dichlorophenyl)-
-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quino-
line;
(7aS,11aR)-2-(3,5-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H--
pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(2,5-dichlorophe-
nyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]q-
uinoline;
(7aS,11aR)-2-(2,6-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-
-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(2-chlorophe-
nyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]q-
uinoline;
(7aS,11aR)-2-(3-chlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H--
pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline; (7aS,11aR)
2-(4-chlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyr-
rolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(2,6-difluorophenyl)-5,6,7a,8,9,10,1-
1,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,l-ij]quinoline;
(7aS,11aR)-2-(2,6-difluorophenyl)-10-methyl-5,6,7a,8,9,10,11,11a-octahydr-
o-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(2,3-difluo-
rophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-
-ij]quinoline;
(7aS,11aR)-2-(3,4-difluorophenyl)-5,6,7a,8,9,10,11,11a-octa-
hydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(3-fluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3'-
,4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-[2-chloro-4-methoxyphenyl-
)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quin-
oline;
(7aS,11aR)-2-[2-fluoro-4-methoxyphenyl)-5,6,7a,8,9,10,11,11a-octahy-
dro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(4-methoxy-2-methylphenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5 5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-[4-methoxy-2--
(trifluoromethyl)phenyl]5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5-
]pyrrolo[3,2,1-ij]quinoline;
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro--
4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-2-yl]-3-(trifluoromethyl)phe-
nol;
(7aS,11aR)-2-[2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahyd-
ro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-[4-isoprop-
oxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3'-
,4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-[2,4-bis(trifluoromethyl)-
phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-i-
j]quinoline;
(7aS,11aR)-2-[4-fluoro-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,-
10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,l-ij]quinolin-2-yl]-3-(trifluoromethyl)aniline;
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-2-yl]--N-methyl-3-(trifluoromethyl)aniline;
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-2-yl]-3-methylbenzonitrile;
2-[(7aS,11aR)-5,6,7a,8,9,10,-
11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-2-yl]benzal-
dehyde;
{2-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]-
pyrrolo[3,2,1-ij]quinolin-2-yl]phenyl}methanol;
2-[(7aS,11aR)-5,6,7a,8,9,1-
0,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-2-yl]-5-m-
ethoxybenzaldehyde;
{2-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrid-
o[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-2-yl]-5-methoxyphenyl}methanol;
(8aS,12aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12,1-
2a-decahydroazepino[3,2,1-hi]pyrido[4,3b]indole;
(7aS,11aR)-2-[4-ethoxy-2--
(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,-
5]pyrrolo[3,2,1-ij]quinoline;
(8aS,12aR)-2-[3-chloro-2-methylphenyl]-4,5,6-
,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3b]indole;
(7aS,11aR)-2-[3-chloro-2-methylphenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H--
pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-[5-fluoro-2-meth-
ylphenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-
-ij]quinoline;
(.+-.)-cis-2-(2,3-dichlorophenyl)-10-propyl-5,6,7a,8,9,10,1-
1,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(2,3-dichlorophenyl)-10-propyl-5,6,7a,8,9,10,11,11a-octahydr-
o-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(.+-.)-cis-10-butyl-2-(2-
,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrr-
olo[3,2,1-ij]quinoline;
(7aS,11aR)-10-butyl-2-(2,3-dichlorophenyl)-5,6,7a,-
8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(2,3-dichlorophenyl)-10-(4-pentenyl)-5,6,7a,8,9,10,11,11a-oc-
tahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(2,3-dichlorophenyl)-10-(3-methyl-2-butenyl)-5,6,7a,8,9,10,1-
1,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(2,4-dichlorophenyl)-10-propyl-5,6,7a,8,9,10,11,11a-octahydr-
o-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-10-butyl-2-(2-
,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrr-
olo[3,2,1-ij]quinoline;
(7aS,11aR)-2-(2,4-dichlorophenyl)-10-(4-pentenyl)--
5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinol-
ine;
(7aS,11aR)-2-(2,4-dichlorophenyl)-10-(3-methyl-2-butenyl)-5,6,7a,8,9,-
10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-10-(cyclobutylmethyl)-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-methyl-5,6,7a,8,9,1-
0,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-10-ethyl-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10-
,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-propyl-5,6,7a,8,9,1-
0,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-10-butyl-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-methyl-5,6-
,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-
;
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-(4-pentenyl)-5,6,7-
a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-(3-methyl-2-butenyl-
)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quin-
oline;
(7aS,11aR)-10-(2-fluoroethyl)-2-[4-methoxy-2-(trifluoromethyl)pheny-
l]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]qui-
noline;
(7aS,11aR)-10-(2,2-difluoroethyl)-2-[4-methoxy-2-(trifluoromethyl)-
phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-i-
j]quinoline;
(7aS,11aR)-10-(cyclobutylmethyl)-2-[4-methoxy-2-(trifluoromet-
hyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2-
,1-ij]quinoline;
4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,-
5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)-1-(4-fluorophenyl)-1-butanone;
4-((7aR,11aS)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1--
ij]quinolin-10(7aH)-yl)-1-(4-fluorophenyl)-1-butanone;
4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1--
ij]quinolin-10(7aH)-yl)-1-(2-aminophenyl)-1-butanone;
4-((7aR,11aS)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1--
ij]quinolin-10(7aH)-yl)-1-(2-aminophenyl)-1-butanone;
(.+-.)-cis-3-(5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1--
ij]quinolin-10(7aH)-yl)propyl 4-fluorophenyl ether;
4-((.+-.)-cis-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1--
ij]quinolin-10(7aH)-yl)-1-(4-pyridinyl)-1-butanone;
(.+-.)-cis-10-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-5,6,7a,8,9,10,11-
,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(7aS,11aR)-10-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-5,6,7a,8,9,10,11-
,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
(.+-.)-cis-4-(4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]-
indol-l1(8aH)-yl)-1-(4-fluorophenyl)-1-butanone;
4-((8aS,12aR)-4,5,6,7,9,1-
0,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indol-11(8aH)-yl)-1-(4-flu-
orophenyl)-1-butanone;
4-((8aR,12aS)-4,5,6,7,9,10,12,12a-octahydroazepino[-
3,2,1-hi]pyrido[4,3-b]indol-11(8aH)-yl)-1-(4-fluorophenyl)-1-butanone;
4-((.+-.)-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indo-
l-11(8aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone;
4-((.+-.)-cis-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1--
ij]quinolin-10(7aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone;
4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1--
ij]quinolin-10(7aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone; and
4-((7aR,11aS)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1--
ij]quinolin-10(7aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone.
33. The method as defined in claim 18 where the compound
administered is selected from the group:
4-[(.+-.)-5,6,8,9,10,11,12,12a-octahydro-4H,7aH--
azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinolin-10-yl]-1-(4-fluorophenyl)-1-bu-
tanone;
4-[(.+-.)-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':4,5]-
pyrrolo[3,2,1-ij]quinolin-10-yl]-1-(2-amino-4-fluorophenyl)-1-butanone;
4-[(.+-.)-4,5,6,7,9,10,11,12,13,13a-decahydro-11H-diazepino[4,5-b:3,2,1-h-
i]indol-11-yl]-1-(4-fluorophenyl)-1-butanone;
4-[(.+-.)-4,5,6,7,9,10,11,12-
,13,13a-decahydro-11H-diazepino[4,5-b:3,2,1-hi]indol-11-yl]-1-(2-amino-4-f-
luorophenyl)-1-butanone; tert-butyl
(.+-.)-cis-5,6,8,9,10,11,12,12a-octahy-
dro-4H,7aH-azepino[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-11-carboxylate;
tert-butyl
(.+-.)-cis-2-bromo-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepi-
no[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-11-carboxylate; and
(.+-.)-cis-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,8,9,10,11,12,12a-o-
ctahydro-4H,7aH-azepino[3',4':4,5]pyrrolo[3,2,1-ij]quinoline.
34. The method as defined in claim 18 where the compound
administered is selected from the group: tert-butyl
(.+-.)-cis-2-bromo-4-oxo-4,5,6,7,9,10-
,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate;
tert-butyl
(.+-.)-cis-2-(2,4-dichlorophenyl)-4-oxo-4,5,6,7,9,10,12,12a-oc-
tahydroazepino[3,2,-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate;
(.+-.)-cis-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydroazepino[-
3,2,1-hi]pyrido[4,3-b]indol-4(5H)-one;
(8aS,12aR)-2-(2,4-dichlorophenyl)-6-
,7,8a,9,10,11,12,12a-octahydroazepino[3,2,-hi]pyrido[4,3-b]indol-4(5H)-one-
;
(8aR,12aS)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydroazepino-
[3,2,1-hi]pyrido[4,3-b]indol-4(5H)-one;
(8aS,12aR)-2-(2,4-dichlorophenyl)--
6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indol-4-ol;
and
(8aR,12aS)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-decahydroazep-
ino[3,2,1-hi]pyrido[4,3-b]indol-4-ol.
Description
[0001] This application is a divisional of U.S. Pat. application
Ser. No. 09/594,008 filed on Jun. 15, 2000 which application claims
priority from U.S. Provisional Application No. 60/139,321 filed
Jun. 15, 1999.
FIELD OF THE INVENTION
[0002] The present invention is directed to certain novel compounds
represented by structural Formula (I) 2
[0003] or pharmaceutically acceptable salt forms thereof, wherein
R.sup.1, R.sup.5, R.sup.6a, R.sup.6b, R.sup.7, R.sup.8, R.sup.9, X,
b, k, m, and n, and the dashed lines are described herein. The
invention is also, concerned with pharmaceutical formulations
comprising these novel compounds as active ingredients and the use
of the novel compounds and their formulations in the treatment of
certain disorders. The compounds of this invention are serotonin
agonists and antagonists and are useful in the control or
prevention of central nervous system disorders including obesity,
anxiety, depression, psychosis, schizophrenia, sleep disorders,
sexual disorders, migraine, conditions associated with cephalic
pain, social phobias, and gastrointestinal disorders such as
dysfunction of the gastrointestinal tract motility.
BACKGROUND OF THE INVENTION
[0004] There exists a substantial correlation for the relationship
between 5-HT2 receptor modulation and a variety of diseases and
therapies. To date, three subtypes of the 5-HT2 receptor class have
been identified, 5-HT2A, 5-HT2B, and 5-HT2C. Prior to the early
1990's the 5-HT2C and 5-HT2A receptors were referred to as 5-HT1C
and 5-HT2, respectively.
[0005] The agonism or antagonism of 5-HT2 receptors, either
selectively or nonselectively, has been associated with the
treatment of various central nervous system (CNS) disorders.
Ligands possessing affinity for the 5-HT2 receptors have been shown
to have numerous physiological and behavioral effects (Trends in
Pharmacological Sciences, 11, 181, 1990). In the recent past the
contribution of serotonergic activity to the mode of action of
antidepressant drugs has been well documented. Compounds that
increase the overall basal tone of serotonin in the CNS have been
successfully developed as antidepressants. The serotonin selective
reuptake inhibitors (SSRI) function by increasing the amount of
serotonin present in the nerve synapse. These breakthrough
treatments, however, are not without side effects and suffer from
delayed onset of action (Leonard, J. Clin. Psychiatry, 54(suppl),
3, 1993). Due to the mechanism of action of the SSRIs, they effect
the activity of a number of serotonin receptor subtypes. This
non-specific modulation of the serotonin family of receptors most
likely plays a significant role in the side effect profile. In
addition, these compounds often have a high affinity for a number
of the serotonin receptors as well as a multitude of other
monoamine neurotransmitters and nuisance receptors. Removing some
of the receptor cross reactivity would allow for the examination
and possible development of potent therapeutic ligands with an
improved side effect profile.
[0006] There is ample evidence to support the role of selective
5-HT2 receptor ligands in a number of disease therapies. Modulation
of 5-HT2 receptors has been associated with the treatment of
schizophrenia and psychoses (Ugedo, L., et.al., Psychopharmacology,
98, 45, 1989). Mood, behavior and hallucinogenesis can be affected
by 5-HT2 receptors in the limbic system and cerebral cortex. 5-HT2
receptor modulation in the hypothalamus can influence appetite,
thermoregulation, sleep, sexual behavior, motor activity, and
neuroendocrine function (Hartig, P., et.al., Annals New York
Academy of Science, 149, 159). There is also evidence indicating
that 5-HT2 receptors mediate hypoactivity, effect feeding in rats,
and mediate penile erections (Pyschopharmacology, 101, 57,
1990).
[0007] Compounds exhibiting selectivity for the 5-HT2B receptor are
useful in treating conditions such as tachygastria, hypermotility
associated with irritable bowel disorder, constipation, dyspepsia,
and other peripherally mediated conditions.
[0008] 5-HT2A antagonists have been shown to be effective in the
treatment of schizophrenia, anxiety, depression, and migraines
(Koek, W., Neuroscience and Behavioral reviews, 16, 95, 1996).
Aside from the beneficial antipsychotic effects, classical
neuroleptic are frequently responsible for eliciting acute
extrapyramidal side effects and neuroendocrine disturbances. These
compounds generally possess signifcant dopamine D2 receptor
affinity (as well as other nuisance receptor affinity) which
frequently is associated with extra pyramidal symptoms and tardive
dyskinesia, thus detracting from their efficacy as front line
treatments in schizophrenia and related disorders. Compounds
possessing a more favorable selectivity profile would represent a
possible improvement for the treatment of CNS disorders.
[0009] Serotonin (5HT) may have a critical role in the regulation
of some drug-induced addictive behaviors. Serotonin is involved in
neuronal processes related to inhibitory control and impulsivity.
(Roy et al., Acta Psychiotr. Scand. 78 (1988) 529-535; Soubrie et
al., Behav. Brain. Sci. 9 (1986) 319-364) Some studies have
implicated serotonergic mechanisms in the development or expression
of drug-induced sensitization (King et al., Psychopharmacology 130
(1997) 159-165; Olausson et al., Psychopharmacology 142 (1999)
111-119) The relationship between 5HT and impulsive behavior as
well as drug intake has been described, and manipulations that
attenuate 5HT neurotransmission both increase impulsive behavior
(Roy et al., Acta Psychiotr. Scand. 78 (1988) 529-535; Soubrie et
al., Behav. Brain. Sci. 9 (1986) 319-364) and elevate the intake of
various drugs of abuse (Engel et al., in Naranjo, C. A., Sellers,
E. M. (Eds.). Novel Pharmacological Interventions for Alcoholism,
Springer, New York, pp. 68-82 (1999); Roberts et al., Pharmacol.
Biochem. Behav. 49 (1994) 177-182)
[0010] A series of animal investigations have reported that central
5HT2 receptors are related to the many symptoms associated with
drug-dependent withdrawal. Withdrawal from chronic exposure to low
doses of cocaine causes reversible supersensitivity of 5HT2
receptors in mice. (Baumann et al., Neuropharmacology 35 (1996)
295-301; Darmani et al., Neurotoxicol. Tertol. 22 (2000) 61-69)
Moreover, the 5HT2 receptor antagonists, ketanserin and mianserin,
block or attenuate morphine withdrawal syndrome in rats. (Neal et
al., J. Pharmacol. Exp. Ther. 236 (1986) 157-165; Neal et al., Eur.
J. Pharmacol. 132 (1986) 299-304)
[0011] The effects of 5HT receptor agonists on the behavioral and
neurochemical consequences of repeated nicotine treatment have also
been studied. (Olausson et al., Eur. J. Pharmacol. 420 (2001)
45-54) The results of that study provided evidence that repeated
daily nicotine treatment is associated with both locomotor
sensitization and behavioral disinhibition, and that the expression
of those behaviors can be modulated by specific agonists at 5HT
receptor subtypes.
[0012] Studies with experimental animals have shown that nicotine
withdrawal leads to increased sensitivity of serotonergic neurons
in the dorsal raphe to 5HT1A agonists in rats. (Rasmussen et al.,
Psychopharmacology (Berl) 133 (1997) 343-346) Other findings
suggest that cessation of chronic nicotine increases the
sensitivity to 5HT2 receptor systems, and that the 5HT2 receptor
systems may be related to some aspect of the nicotine withdrawal
syndrome. (Suemaru et al., Psychopharmacology (Berl) 159 (2001)
31-38) Other studies have also examined the effect of nicotine
cessation on the central serotonergic systems in mice and the
involvement of 5HT2 receptors. (Yasuda et al.,
Naunyn-Schmiedeberg's Arch. Pharmacol. 366 (2002) 276-281) The
studies by Yasuda et al. suggested that cessation of repeated
nicotine administration resulted in increased sensitivity to 5HT2
receptor systems and decreased 5HT2 turnover, and that these
phenomena may be related to the manifestation of nicotine
withdrawal symptoms.
[0013] Modulation of the 5-HT2 receptors has been observed to play
a role in sleep disorders. Ritanserin, a selective 5HT2 receptor
antagonist, massively enhances slow save sleep (stage 3 and 4) in
humans (Declerck et al., Curr. Ther. Res. 41 (1987)427-432;
Idzikowsky et al., Psychopharmacology 93 (1987) 416-420; Ikzikowsky
et al., Brain Res. 378 (1986) 164-168) and increases deep slow wave
sleep in rats. (Detari et al., Psychopharmacology 142 (1999)
318-326; Dugovic et al., Eur. J. Pharmaol. 137 (1987) 145-146;
Kantor et al., J. Physiol. 526 (2000) 66-67) Ritanserin and other
5HT2 receptor antagonists increase low frequency EEG activity
administered at the beginning of the passive phase of sleep, that
is in the light period in rats (Borbely et al., Eur. J. Pharmacol.
156 (1988) 275-278) and in the dark period in humans (Dijk et al.,
Eur. J. Pharmacol. 171 (1989) 207-218).
[0014] The effects of the 5HT2 receptor antagonist ritanserin on
electroencephalogram (EEG) power spectra, sleep and motor activity
have also been studied. (Kantor et al., Brain Research 943 (2002)
105-111) The studies by Kantor et al. showed that the 5HT2 receptor
antagonist ritanserin has longterm effects on EEG power spectra,
sleep and motility. Kantor et al. concluded that because ritanserin
is a 5HT2 receptor antagonist, under physiological conditions,
serotonin increases electroencephalogram (EEG) synchronization and
produces an increase in vigilance level and motor activity by tonic
activation of 5HT2 receptors. The proposed regulatory mechanism
plays an important role in the waking process and the appearances
of its effects in the light and dark phases were markedly
different.
[0015] U.S. Pat. Nos. 3,914,421; 4,013,652; 4,115,577; 4,183,936;
and 4,238,607 disclose pyridopyrrolobenz-heterocycles of formula:
3
[0016] where X is O, S, S(=O), or SO.sub.2; n is 0 or 1; R.sup.1 is
various carbon substituents, and Z is a monosubstituent of H,
methyl, or chloro.
[0017] U.S. Pat. No 4,219,550 discloses
pyridopyrrolo-benzheterocycles of formula: 4
[0018] where X is O or S; R.sup.1 is C.sub.1-4 alkyl or
cyclopropyl; R.sup.2 is H, CH.sub.3, OCH.sub.3, Cl, Br, F, or
CF.sub.3; and (A) is --CH.sub.2--, --CH(CH.sub.3)--, or
--CH.sub.2CH.sub.2--.
SUMMARY OF THE INVENTION
[0019] One object of the present invention is to provide methods
for treating central nervous system disorders including addictive
behavior and sleep disorders, comprising administering to a host in
need of such treatment a therapeutically effective amount of
compounds which are useful as agonists or antagonists of 5-HT2
receptors, more specifically 5-HT2A and 5-HT2C receptors, or
pharmaceutically acceptable salts or prodrugs thereof.
[0020] This and other objects, which will become apparent during
the following detailed description, have been achieved by the
inventors' discovery that compounds of Formula (I): 5
[0021] or pharmaceutically acceptable salt or prodrug forms
thereof, wherein R.sup.1, R.sup.5, R.sup.6a, R.sup.6b, R.sup.7,
R.sup.8, R.sup.9, X, b, k, m, and n are defined below, are
effective agonists or antagonists of 5-HT2 receptors and can be
used in the treatment of central nervous system disorders including
addictive behavior and sleep disorders.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0022] [1] Thus, in a first embodiment, the present invention
provides a method for treating a human suffering from addictive
behavior associated with 5HT2C receptor modulation, comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of formula (I): 6
[0023] or stereoisomers or pharmaceutically acceptable salt forms
thereof, wherein:
[0024] b is a single bond;
[0025] X is --CHR.sup.10-- or --C(=O)--;
[0026] R.sup.1 is selected from
[0027] H,
[0028] C(=O)R.sup.2,
[0029] C(=O)OR.sup.2,
[0030] C.sub.1-8 alkyl,
[0031] C.sub.2-8 alkenyl,
[0032] C.sub.2-8 alkynyl,
[0033] C.sub.3-7 cycloalkyl,
[0034] C.sub.1-6 alkyl substituted with Z,
[0035] C.sub.2-6 alkenyl substituted with Z,
[0036] C.sub.2-6 alkynyl substituted with Z,
[0037] C.sub.3-6 cycloalkyl substituted with Z, aryl substituted
with Z,
[0038] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with Z;
[0039] C.sub.1-3 alkyl substituted with Y,
[0040] C.sub.2-3 alkenyl substituted with Y,
[0041] C.sub.2-3 alkynyl substituted with Y,
[0042] C.sub.1-6 alkyl substituted with 0-2 R.sup.2,
[0043] C.sub.2-6 alkenyl substituted with 0-2 R.sup.2,
[0044] C.sub.2-6 alkynyl substituted with 0-2 R.sup.2, aryl
substituted with 0-2 R.sup.2, and
[0045] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with 0-2 R.sup.2;
[0046] Y is selected from
[0047] C.sub.3-6 cycloalkyl substituted with Z,
[0048] aryl substituted with Z,
[0049] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with Z;
[0050] C.sub.3-6 cycloalkyl substituted with --(C.sub.1-3
alkyl)--Z,
[0051] aryl substituted with --(C.sub.1-3 alkyl)--Z, and
[0052] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with --(C.sub.1-3
alkyl)--Z;
[0053] Z is selected from H,
[0054] --CH(OH)R.sup.2,
[0055] --C(ethylenedioxy)R.sup.2,
[0056] --OR.sup.2,
[0057] --SR.sup.2,
[0058] --NR.sup.2R.sup.3,
[0059] --C(O)R.sup.2,
[0060] --C(O)NR.sup.2R.sup.3,
[0061] --NR.sup.3C(O)R.sup.2,
[0062] --C(O)OR.sup.2,
[0063] --OC(O)R.sup.2,
[0064] --CH(=NR.sup.4)NR.sup.2R.sup.3,
[0065] --NHC(=NR.sup.4)NR.sup.2R.sup.3,
[0066] --S(O)R.sup.2,
[0067] --S(O).sub.2R.sup.2,
[0068] --S(O).sub.2NR.sup.2R.sup.3, and
--NR.sup.3S(O).sub.2R.sup.2;
[0069] R.sup.2, at each occurrence, is independently selected from
halo,
[0070] C.sub.1-3 haloalkyl,
[0071] C.sub.1-4 alkyl,
[0072] C.sub.2-4 alkenyl,
[0073] C.sub.2-4 alkynyl,
[0074] C.sub.3-6 cycloalkyl,
[0075] aryl substituted with 0-5 R.sup.42;
[0076] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.41,
and
[0077] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.41;
[0078] R.sup.3, at each occurrence, is independently selected
from
[0079] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
and C.sub.1-4 alkoxy;
[0080] alternatively, R.sup.2 and R.sup.3 join to form a 5- or
6-membered ring optionally substituted with --O--or
--N(R.sup.4)--;
[0081] R.sup.4, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[0082] R.sup.5 is H or C.sub.1-4 alkyl;
[0083] R.sup.6a and R.sup.6b, at each occurrence, are independently
selected from
[0084] H, --OH, --NR.sup.46R.sup.47, --CF.sub.3, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.3-6 cycloalkyl, and
[0085] aryl substituted with 0-3 R.sup.44;
[0086] R.sup.7 and R.sup.9, at each occurrence, are independently
selected from
[0087] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN, --NO.sub.2,
--NR.sup.46R.sup.47,
[0088] C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C1-8 alkoxy, (C.sub.1-4 haloalkyl)oxy,
[0089] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[0090] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[0091] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0092] aryl substituted with 0-5 R.sup.33,
[0093] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0094] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
[0095] NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12,
[0096] CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12,
[0097] S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup- .13, NR.sup.14S(O)R.sup.12,
[0098] NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15,
[0099] and NR.sup.12C(O)NHR.sup.15;
[0100] R.sup.8 is selected from
[0101] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2,
[0102] C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[0103] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[0104] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[0105] C.sub.2-4 alkenyl substituted with 0-2 R.sup.11,
[0106] C.sub.2-4 alkynyl substituted with 0-1 R.sup.11,
[0107] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0108] aryl substituted with 0-5 R.sup.33,
[0109] 5-10 membered heterocyclic ring system containing from
[0110] 1-4 heteroatoms selected from the group consisting of N, O,
and S substituted with 0-3 R.sup.31;
[0111] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
[0112] NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12,
[0113] CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12,
[0114] S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup- .13, NR.sup.14S(O)R.sup.12
[0115] NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15, and
NR.sup.12C(O)NHR.sup.15;
[0116] R.sup.10 is selected from H, --OH,
[0117] C.sub.1-6 alkyl substituted with 0-1 R.sup.10B,
[0118] C.sub.2-6 alkenyl substituted with 0-1 R.sup.10B,
[0119] C.sub.2-6 alkynyl substituted with 0-1 R.sup.10B, and
[0120] C.sub.1-6 alkoxy;
[0121] R.sup.10Bis selected from
[0122] C.sub.1-4 alkoxy,
[0123] C.sub.3-6 cycloalkyl,
[0124] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0125] phenyl substituted with 0-3 R.sup.33, and
[0126] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R.sup.44;
[0127] R.sup.11is selected from
[0128] H, halo, --CF.sub.3, --CN, --NO.sub.2,
[0129] C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, C.sub.3-10 cycloalkyl,
[0130] C.sub.3-10 carbocyclic group substituted with -0-3
R.sup.33,
[0131] aryl substituted with 0-5 R.sup.33,
[0132] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0133] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
[0134] NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12,
[0135] CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12,
[0136] S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup- .13, NR.sup.14S(O)R.sup.12,
[0137] NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15,
[0138] and NR.sup.12C(O)NHR.sup.15;
[0139] R.sup.12, at each occurrence, is independently selected
from
[0140] C.sub.1-4 alkyl substituted with 0-1 R.sup.12a,
[0141] C.sub.2-4 alkenyl substituted with 0-1 R.sup.12a,
[0142] C.sub.2-4 alkynyl substituted with 0-1 R.sup.12a,
[0143] C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.33,
[0144] phenyl substituted with 0-5 R.sup.33;
[0145] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[0146] 5-10 membered heterocyclic ring system containing from
[0147] 1-4 heteroatoms selected from the group consisting of N, O,
and S substituted with 0-3 R.sup.31;
[0148] R.sup.12a, at each occurrence, is independently selected
from phenyl substituted with 0-5 R.sup.33;
[0149] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[0150] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0151] R.sup.13, at each occurrence, is independently selected
from
[0152] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[0153] alternatively, R.sup.12 and R.sup.13 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.14)--;
[0154] alternatively, R.sup.12 and R.sup.13 when attached to N may
be combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S, wherein said bicyclic heterocyclic ring
system is unsaturated or partially saturated, wherein said bicyclic
heterocyclic ring system is substituted with 0-3 R.sup.16;
[0155] R.sup.14, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[0156] R.sup.15, at each occurrence, is independently selected
from
[0157] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[0158] R.sup.16, at each occurrence, is independently selected
from
[0159] H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H,
[0160] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl,
[0161] C.sub.1-3 haloalkyl-oxy-, and C.sub.1-3 alkyloxy-;
[0162] R.sup.31, at each occurrence, is independently selected
from
[0163] H, OH, halo, CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47,
and C.sub.1-4 alkyl;
[0164] R.sup.33, at each occurrence, is independently selected
from
[0165] H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H,
[0166] C.sub.1-6 alkyl, C.sub.1-6 alkenyl, C.sub.1-6 alkynyl,
[0167] C.sub.3-6 cycloalkyl, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkyl-oxy-,
[0168] C.sub.1-4 alkyloxy-,
[0169] C.sub.1-4 alkylthio-, C.sub.1-4 alkyl-C(=O)--, C.sub.1-4
alkyl-C(=
[0170] O)NH--, C.sub.1-4 alkyl-OC(=O)--,
[0171] C.sub.1-4 alkyl-C(=O)O--, C.sub.3-6 cycloalkyl-oxy-,
C.sub.3-6 cycloalkylmethyl-oxy-;
[0172] C.sub.1-6 alkyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy; and
[0173] C.sub.1-6 alkenyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy;
[0174] R.sup.41, at each occurrence, is independently selected
from
[0175] H, CF.sub.3, halo, OH, C.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, =O;
[0176] C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl
[0177] C.sub.1-4 alkyl substituted with 0-1 R.sup.43, aryl
substituted with 0-3 R.sup.42, and
[0178] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[0179] R.sup.42, at each occurrence, is independently selected
from
[0180] H, CF.sub.3, halo, OH, C.sub.2H, SO.sub.2R.sup.45,
SOR.sup.45, SR.sup.45, NR.sup.46SO.sub.2R.sup.45,
NR.sup.46COR.sup.45, NR.sup.46R.sup.47, NO.sub.2, CN,
CH(=NH)NH.sub.2, NHC(=NH)NH.sub.2,
[0181] C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl,
[0182] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[0183] aryl substituted with 0-3 R.sup.44, and
[0184] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[0185] R.sup.43 is C.sub.3-6 cycloalkyl or aryl substituted with
0-3 R.sup.44;
[0186] R.sup.44, at each occurrence, is independently selected from
H, halo, --OH, NR.sup.46R.sup.47, C.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, and
C.sub.1-4 alkoxy;
[0187] R.sup.45 is C.sub.1-4 alkyl;
[0188] R.sup.46, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[0189] R.sup.47, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --C(=O)NH(C.sub.1-4 alkyl),
--SO.sub.2(C.sub.1-4 alkyl), --C(=O)O(C.sub.1-4 alkyl),
--C(=O)(C.sub.1-4 alkyl), and --C(=O)H;
[0190] k is 1 or 2;
[0191] m is 0, 1, or 2;
[0192] n is 0, 1, 2, or 3;
[0193] provided when m is 0 or 1 then k is 1 or 2;
[0194] provided when m is 2 then k is 1;
[0195] provided that when R.sup.6 or R.sup.6a is NH2, then X is not
--CH(R.sup.10); and
[0196] provided that when n=0, then R.sup.6 or R.sup.6a is not NH2
or --OH.
[0197] [2] In a preferred embodiment, the present invention
provides the method as defined in Claim 1 where in the compound
administered:
[0198] X is --CHR.sup.10-- or --C(=O)--;
[0199] R.sup.1 is selected from
[0200] H,
[0201] C(=O)R.sup.2,
[0202] C(=O)OR.sup.2,
[0203] C.sub.1-8 alkyl,
[0204] C.sub.2-8 alkenyl,
[0205] C.sub.2-8 alkynyl,
[0206] C.sub.3-7 cycloalkyl,
[0207] C.sub.1-6 alkyl substituted with 0-2 R.sup.2,
[0208] C.sub.1-6 alkenyl substituted with 0-2 R.sup.2,
[0209] C.sub.1-6 alkynyl substituted with 0-2 R.sup.2,
[0210] aryl substituted with 0-2 R.sup.2, and
[0211] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with 0-2 R.sup.2;
[0212] R.sup.2, at each occurrence, is independently selected
from
[0213] F, Cl, CH.sub.2F, CHF.sub.2, CF.sub.3,
[0214] C.sub.1-4 alkyl,
[0215] C.sub.2-4 alkenyl,
[0216] C.sub.2-4 alkynyl,
[0217] C.sub.3-6 cycloalkyl,
[0218] phenyl substituted with 0-5 R.sup.42;
[0219] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.41,
and
[0220] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.41;
[0221] R.sup.5 is H, methyl, ethyl, propyl, or butyl;
[0222] R.sup.6a is selected from
[0223] H, --OH, ---NR.sup.46R.sup.47, --CF.sub.3,
[0224] C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
and
[0225] aryl substituted with 0-3 R.sup.44;
[0226] R.sup.6b is H;
[0227] R.sup.7 and R.sup.9, at each occurrence, are independently
selected from
[0228] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN, --NO.sub.2,
--NR.sup.46R.sup.47,
[0229] C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[0230] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[0231] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[0232] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0233] aryl substituted with 0-5 R.sup.33,
[0234] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0235] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
[0236] NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12,
[0237] CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12,
[0238] S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup- .13, NR.sup.14S(O)R.sup.12
[0239] NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15,
[0240] and NR.sup.12C(O)NHR.sup.15;
[0241] R.sup.8 is selected from
[0242] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2,
[0243] C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[0244] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[0245] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[0246] C.sub.2-4 alkenyl substituted with 0-2 R.sup.11,
[0247] C.sub.2-4 alkynyl substituted with 0-1 R.sup.11,
[0248] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0249] aryl substituted with 0-5 R.sup.33,
[0250] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0251] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
[0252] NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12,
[0253] CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12,
[0254] S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup- .13, NR.sup.14S(O)R.sup.12
[0255] NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15,
[0256] and NR.sup.12C(O)NHR.sup.15,
[0257] R.sup.10 is selected from H, --OH,
[0258] C.sub.1-6 alkyl substituted with 0-1 R.sup.10B,
[0259] C.sub.2-6 alkenyl substituted with 0-1 R.sup.10B,
[0260] C.sub.2-6 alkynyl substituted with 0-1 R.sup.10B, and
[0261] C.sub.1-6 alkoxy;
[0262] R.sup.10Bis selected from
[0263] C.sub.1-4 alkoxy,
[0264] C.sub.3-6 cycloalkyl,
[0265] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0266] phenyl substituted with 0-3 R.sup.33, and
[0267] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R.sup.44;
[0268] R.sup.11 is selected from
[0269] H, halo, --CF.sub.3, --CN, --NO.sub.2,
[0270] C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, C.sub.3-10 cycloalkyl,
[0271] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0272] aryl substituted with 0-5 R.sup.33,
[0273] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0274] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
[0275] NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12,
[0276] CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12,
[0277] S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup- .13, NR.sup.14S(O))R.sup.12,
[0278] NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15,
[0279] and NR.sup.12C(O)NHR.sup.15;
[0280] R.sup.12, at each occurrence, is independently selected
from
[0281] C.sub.1-4 alkyl substituted with 0-1 R.sup.12a,
[0282] C.sub.2-4 alkenyl substituted with 0-1 R.sup.12a,
[0283] C.sub.2-4 alkynyl substituted with 0-1 R.sup.12a,
[0284] C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.33,
[0285] phenyl substituted with 0-5 R.sup.33;
[0286] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[0287] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0288] R.sup.12a, at each occurrence, is independently selected
from phenyl substituted with 0-5 R.sup.33;
[0289] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[0290] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0291] R.sup.13, at each occurrence, is independently selected
from
[0292] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[0293] alternatively, R.sup.12 and R.sup.13 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.14)--;
[0294] alternatively, R.sup.12 and R.sup.13 when attached to N may
be combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S, wherein said bicyclic heterocyclic ring
system is unsaturated or partially saturated, wherein said bicyclic
heterocyclic ring system is substituted with 0-3 R.sup.16;
[0295] R.sup.14.sub.1 at each occurrence, is independently selected
from H and C.sub.1-4 alkyl;
[0296] R.sup.15, at each occurrence, is independently selected
from
[0297] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[0298] R.sup.16, at each occurrence, is independently selected
from
[0299] H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H,
[0300] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl,
[0301] C.sub.1-3 haloalkyl-oxy-, and C.sub.1-3 alkyloxy-;
[0302] R.sup.31, at each occurrence, is independently selected
from
[0303] H, OH, halo, CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47,
and C.sub.1-4 alkyl;
[0304] R.sup.33, at each occurrence, is independently selected
from
[0305] H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H,
[0306] C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
[0307] C.sub.3-6 cycloalkyl, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkyl-oxy-,
[0308] C.sub.1-4 alkyloxy-,
[0309] C.sub.1-4 alkylthio-, C.sub.1-4 alkyl-C(=O)--, C.sub.1-4
alkyl-C(=O)NH--, C.sub.1-4 alkyl-OC(=O)--,
[0310] C.sub.1-4 alkyl-C(=O)O--, C.sub.3-6 cycloalkyl-oxy-,
C.sub.3-6 cycloalkylmethyl-oxy-;
[0311] C.sub.1-6 alkyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy; and
[0312] C.sub.2-6 alkenyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy;
[0313] R.sup.41, at each occurrence, is independently selected
from
[0314] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN;
[0315] C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl
[0316] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[0317] aryl substituted with 0-3 R.sup.42, and
[0318] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[0319] R.sup.42, at each occurrence, is independently selected
from
[0320] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, CH(=NH)NH.sub.2,
NHC(=NH)NH.sub.2,
[0321] C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl,
[0322] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[0323] aryl substituted with 0-3 R.sup.44, and
[0324] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[0325] R.sup.43 is C.sub.3-6 cycloalkyl or aryl substituted with
0-3 R.sup.44;
[0326] R.sup.44, at each occurrence, is independently selected from
H,
[0327] halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, and
C.sub.1-4 alkoxy;
[0328] R.sup.45 is C.sub.1-4 alkyl;
[0329] R.sup.46, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[0330] R.sup.47, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[0331] k is 1 or 2;
[0332] m is 0, 1, or 2; and
[0333] n is 0, 1, 2, or 3.
[0334] [3] In a more preferred embodiment, the present invention
provides the method as defined in Claim 2 where in the compound
administered:
[0335] X is --CHR.sup.10--;
[0336] R.sup.1 is selected from
[0337] H,
[0338] C(=O)R.sup.2,
[0339] C(=O)OR.sup.2,
[0340] C.sub.1-6 alkyl,
[0341] C.sub.2-6 alkenyl,
[0342] C.sub.2-6 alkynyl,
[0343] C.sub.3-6 cycloalkyl,
[0344] C.sub.1-4 alkyl substituted with 0-2 R.sup.2,
[0345] C.sub.2-4 alkenyl substituted with 0-2 R.sup.2, and
[0346] C.sub.2-4 alkynyl substituted with 0-2 R.sup.2;
[0347] R.sup.2, at each occurrence, is independently selected
from
[0348] C.sub.1-4 alkyl,
[0349] C.sub.2-4 alkenyl,
[0350] C.sub.2-4 alkynyl,
[0351] C.sub.3-6 cycloalkyl,
[0352] phenyl substituted with 0-5 R.sup.42;
[0353] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.41,
and
[0354] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.41;
[0355] R.sup.5 is H, methyl, ethyl, propyl, or butyl;
[0356] R.sup.6a is selected independently from
[0357] H, --OH, --NR.sup.46R.sup.47, --CF.sub.3, C.sub.1-3 alkyl,
and C.sub.1-3 alkoxy;
[0358] R.sup.6b is H;
[0359] R.sup.7 and R.sup.9, at each occurrence, are independently
selected from
[0360] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN, --NO.sub.2,
--NR.sup.46R.sup.47,
[0361] C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[0362] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[0363] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[0364] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0365] aryl substituted with 0-5 R.sup.33,
[0366] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0367] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13 , NR.sup.14C(O)R.sup.12,
C(O)OR.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12,
CH(=NR.sup.14)NR.sup.12R.sup.13, NHC(=NR.sup.14)NR.sup.12R.sup.13,
S(O)R.sup.12 S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup.13, NR.sup.14S(O)R.sup.12, and
NR.sup.14S(O).sub.2R.sup.12;
[0368] R.sup.8 is selected from
[0369] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2,
[0370] C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[0371] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[0372] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[0373] C.sub.2-4 alkenyl substituted with 0-2 R.sup.11,
[0374] C.sub.2-4 alkynyl substituted with 0-1 R.sup.11,
[0375] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0376] aryl substituted with 0-5 R.sup.33,
[0377] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0378] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
[0379] NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12,
[0380] CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12,
[0381] S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup- .13, NR.sup.14S(O)R.sup.12 ,
[0382] NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15, and
NR.sup.12C(O)NHR.sup.15;
[0383] R.sup.10 is selected from H --OH,
[0384] C.sub.2-6 alkyl substituted with 0-1 R.sup.10B,
[0385] C.sub.2-6 alkenyl substituted with 0-1 R.sup.10B,
[0386] C.sub.1-6 alkynyl substituted with 0-1 R.sup.10B, and
[0387] C.sub.1-6 alkoxy;
[0388] R.sup.10Bis selected from
[0389] C.sub.1-4 alkoxy,
[0390] C.sub.3-6 cycloalkyl,
[0391] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0392] phenyl substituted with 0-3 R.sup.33, and
[0393] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R.sup.44;
[0394] R.sup.11is selected from
[0395] H, halo, --CF.sub.3, --CN, --NO.sub.2, C.sub.1-6 alkyl,
[0396] C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl,
C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl,
[0397] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0398] aryl substituted with 0-5 R.sup.33,
[0399] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0400] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13 NR.sup.14C(O)R.sup.12,
C(O)OR.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12,
CH(=NR.sup.14)NR.sup.12R.sup.13, NHC(=NR.sup.14)NR.sup.12R.sup.13,
S(O)R.sup.12, S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup.13, NR.sup.14S(O)R.sup.12, and NR.sup.14S
(0).sub.2R.sup.12;
[0401] R.sup.12, at each occurrence, is independently selected
from
[0402] C.sub.1-4 alkyl substituted with 0-1 R.sup.12a,
[0403] C.sub.2-4 alkenyl substituted with 0-1 R.sup.12a,
[0404] C.sub.2-4 alkynyl substituted with 0-1 R.sup.12a,
[0405] C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.33,
[0406] phenyl substituted with 0-5 R.sup.33;
[0407] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[0408] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0409] R.sup.12a, at each occurrence, is independently selected
from phenyl substituted with 0-5 R.sup.33;
[0410] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[0411] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0412] R.sup.13, at each occurrence, is independently selected
from
[0413] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[0414] alternatively, R.sup.12 and R.sup.13 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.14)--;
[0415] alternatively, R.sup.12 and R.sup.13 when attached to N may
be combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S, wherein said bicyclic heterocyclic ring
system is unsaturated or partially saturated, wherein said bicyclic
heterocyclic ring system is substituted with 0-3 R.sup.16;
[0416] R.sup.14, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[0417] R.sup.15, at each occurrence, is independently selected
from
[0418] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[0419] R.sup.16, at each occurrence, is independently selected
from
[0420] H, OH, F, Cl, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H, methyl, ethyl, methoxy, ethoxy,
trifluoromethyl, and trifluoromethoxy;
[0421] R.sup.31, at each occurrence, is independently selected
from
[0422] H, OH, halo, CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47,
and C.sub.1-4 alkyl;
[0423] R.sup.33, at each occurrence, is independently selected
from
[0424] H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H,
[0425] C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
[0426] C.sub.3-6 cycloalkyl, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkyl-oxy-,
[0427] C.sub.1-4 alkyloxy-,
[0428] C.sub.1-4 alkylthio-, C.sub.1-4 alkyl-C(=O)--, C.sub.1-4
alkyl-C(=O)NH--, C.sub.1-4 alkyl-OC(=O)--, --C.sub.1-4
alkyl-C(=O)O--, C.sub.3-6 cycloalkyl-oxy-, C.sub.3-6
cycloalkylmethyl-oxy-;
[0429] C.sub.1-6 alkyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy; and
[0430] C.sub.1-6 alkenyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy;
[0431] R.sup.41, at each occurrence, is independently selected
from
[0432] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN,
[0433] C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl
[0434] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[0435] aryl substituted with 0-3 R.sup.42, and
[0436] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[0437] R.sup.42, at each occurrence, is independently selected
from
[0438] H, CF.sub.3, halo, OH, C.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, CH(=NH)NH.sub.2,
NHC(=NH)NH.sub.2,
[0439] C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl,
[0440] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[0441] aryl substituted with 0-3 R.sup.44, and
[0442] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[0443] R.sup.43 is C.sub.3-6 cycloalkyl or aryl substituted with
0-3 R.sup.44;
[0444] R.sup.44, at each occurrence, is independently selected from
H, halo, --OH, NR.sup.46R.sup.47, C.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, and
C.sub.1-4 alkoxy;
[0445] R.sup.45 is C.sub.1-4 alkyl;
[0446] R.sup.46, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[0447] R.sup.47, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[0448] k is 1 or 2;
[0449] m is 0 or 1; and
[0450] n is 0, 1 or 2.
[0451] [4] In a more preferred embodiment, the present invention
provides the method as defined in Claim 2 where in the compound
administered:
[0452] X is --CH.sub.2--;
[0453] R.sup.1 is selected from
[0454] H,
[0455] C.sub.1-4 alkyl,
[0456] C.sub.2-4 alkenyl,
[0457] C.sub.2-4 alkynyl,
[0458] C.sub.3-4 cycloalkyl,
[0459] C.sub.1-3 alkyl substituted with 0-1 R.sup.2,
[0460] C.sub.2-3 alkenyl substituted with 0-1 R.sup.2, and
[0461] C.sub.2-3 alkynyl substituted with 0-1 R.sup.2;
[0462] R.sup.2, at each occurrence, is independently selected
from
[0463] C.sub.1-4 alkyl,
[0464] C.sub.2-4 alkenyl,
[0465] C.sub.2-4 alkynyl,
[0466] C.sub.3-6 cycloalkyl,
[0467] phenyl substituted with 0-5 R.sup.42;
[0468] C.sub.3-6 carbocyclic group substituted with 0-3 R.sup.41,
and
[0469] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.41;
[0470] R.sup.5 is H, methyl, ethyl, propyl, or butyl;
[0471] R.sup.6a is H, methyl, ethyl, methoxy, --OH, or
--CF.sub.3;
[0472] R.sup.6b is H;
[0473] R.sup.7 and R.sup.9, at each occurrence, are independently
selected from
[0474] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN, --NO.sub.2,
--NR.sup.46R.sup.47,
[0475] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[0476] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[0477] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[0478] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0479] aryl substituted with 0-5 R.sup.33, and
[0480] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0481] R.sup.8 is selected from
[0482] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2,
[0483] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[0484] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[0485] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[0486] C.sub.2-4 alkenyl substituted with 0-2 R.sup.11,
[0487] C.sub.2-4 alkynyl substituted with 0-1 R.sup.11,
[0488] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0489] aryl substituted with 0-5 R.sup.33,
[0490] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0491] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15;
[0492] R.sup.11is selected from
[0493] H, halo, --CF.sub.3, --CN, --NO.sub.2,
[0494] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, (C.sub.1-.sub.4
haloalkyl)oxy,
[0495] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[0496] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0497] aryl substituted with 0-5 R.sup.33, and
[0498] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0499] R.sup.12, at each occurrence, is independently selected
from
[0500] C.sub.1-4 alkyl substituted with 0-1 R.sup.12a,
[0501] C.sub.2-4 alkenyl substituted with 0-1 R.sup.12a,
[0502] C.sub.2-4 alkynyl substituted with 0-1 R.sup.12a,
[0503] C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.33,
[0504] phenyl substituted with 0-5 R.sup.33;
[0505] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[0506] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0507] R.sup.12a, at each occurrence, is independently selected
from
[0508] phenyl substituted with 0-5 R.sup.33;
[0509] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[0510] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0511] R.sup.13, at each occurrence, is independently selected
from
[0512] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[0513] alternatively, R.sup.12 and R.sup.13 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.14)--;
[0514] alternatively, R.sup.12 and R.sup.13 when attached to N may
be combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of one N, two N, three N, one N one O, and one N one S;
wherein said bicyclic heterocyclic ring system is unsaturated or
partially saturated, wherein said bicyclic heterocyclic ring system
is substituted with 0-2 R.sup.16;
[0515] R.sup.14, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[0516] R.sup.15, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[0517] R.sup.16, at each occurrence, is independently selected
from
[0518] H, OH, F, Cl, CN, NO.sub.2, methyl, ethyl, methoxy, ethoxy,
trifluoromethyl, and trifluoromethoxy;
[0519] R.sup.31, at each occurrence, is independently selected
from
[0520] H, OH, halo, CF.sub.3, methyl, ethyl, and propyl;
[0521] R.sup.33, at each occurrence, is independently selected
from
[0522] H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H,
[0523] C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
[0524] C.sub.3-6 cycloalkyl, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkyl-oxy-,
[0525] C.sub.1-4 alkyloxy-,
[0526] C.sub.1-4 alkylthio-, C.sub.1-4 alkyl-C(=O)--, C.sub.1-4
alkyl-C(=O)NH--, C.sub.1-4 alkyl-OC(=O)--,
[0527] C.sub.1-4 alkyl-C(=O)O--, C.sub.3-6 cycloalkyl-oxy-,
C.sub.3-6 cycloalkylmethyl-oxy-;
[0528] C.sub.1-6 alkyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy; and
[0529] C.sub.2-6 alkenyl substituted with OH, methoxy, ethoxy,
[0530] propoxy, or butoxy;
[0531] R.sup.41, at each occurrence, is independently selected
from
[0532] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN,
[0533] C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy,
C.sub.1-3 haloalkyl, and C.sub.1-3 alkyl;
[0534] R.sup.42, at each occurrence, is independently selected
from
[0535] H, CF.sub.3, halo, OH, C.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, CH(=NH)NH.sub.2,
NHC(=NH)NH.sub.2,
[0536] C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-.sub.3 alkoxy,
C.sub.1-3 haloalkyl, C.sub.3-6 cycloalkyl, and C.sub.1-3 alkyl;
[0537] R.sup.43 is cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, phenyl, or pyridyl, each substituted with 0-3
R.sup.44;
[0538] R.sup.44, at each occurrence, is independently selected-from
H, halo, --OH, NR.sup.46R.sup.47, C.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, NO.sub.2, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy, and butoxy;
[0539] R.sup.45 is methyl, ethyl, propyl, or butyl;
[0540] R.sup.46, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[0541] R.sup.47, at each occurrence, is independently selected from
from H, methyl, ethyl, propyl, and butyl;
[0542] k is 1;
[0543] m is 1; and
[0544] n is 0, 1 or 2.
[0545] [5] In a more preferred embodiment, the present invention
provides the method as defined in Claim 2 where in the compound
administered:
[0546] X is --CH.sub.2--;
[0547] R.sup.1 is selected from
[0548] H,
[0549] C.sub.1-4 alkyl,
[0550] C.sub.2-4 alkenyl,
[0551] C.sub.2-4 alkynyl,
[0552] C.sub.3-4 cycloalkyl,
[0553] C.sub.1-3 alkyl substituted with 0-1 R.sup.2,
[0554] C.sub.2-3 alkenyl substituted with 0-1 R.sup.2, and
[0555] C.sub.2-3 alkynyl substituted with 0-1 R.sup.2;
[0556] R.sup.2, at each occurrence, is independently selected
from
[0557] C.sub.1-4 alkyl,
[0558] C.sub.2-4 alkenyl,
[0559] C.sub.2-4 alkynyl,
[0560] C.sub.3-6 cycloalkyl,
[0561] phenyl substituted with 0-5 R.sup.42;
[0562] C.sub.3-6 carbocyclic group substituted with 0-3 R.sup.41,
and
[0563] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.41;
[0564] R.sup.5 is H, methyl, ethyl, propyl, or butyl;
[0565] R.sup.6a is H, methyl, ethyl, methoxy, --OH, or
--CF.sub.3;
[0566] R.sup.6b is H;
[0567] R.sup.7 and R.sup.9, at each occurrence, are independently
selected from
[0568] H, F, Cl, --CH.sub.3, --OCH.sub.3, --CF.sub.3, --OCF.sub.3,
--CN, and --NO.sub.2,
[0569] R.sup.8 is selected from
[0570] H, F, Cl, Br, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2,
[0571] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[0572] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[0573] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[0574] C.sub.2-4 alkenyl substituted with 0-2 R.sup.11,
[0575] C.sub.2-4 alkynyl substituted with 0-1 R.sup.11,
[0576] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0577] aryl substituted with 0-5 R.sup.33,
[0578] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0579] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15;
[0580] R.sup.11is selected from
[0581] H, halo, --CF.sub.3, --CN, --NO.sub.2,
[0582] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[0583] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[0584] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0585] aryl substituted with 0-5 R.sup.33, and
[0586] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0587] R.sup.12, at each occurrence, is independently selected
from
[0588] C.sub.1-4 alkyl substituted with 0-1 R.sup.12a,
[0589] C.sub.2-4 alkenyl substituted with 0-1 R.sup.12a,
[0590] C.sub.2-4 alkynyl substituted with 0-1 R.sup.12a,
[0591] C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.33,
[0592] phenyl substituted with 0-5 R.sup.33;
[0593] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[0594] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0595] R.sup.12a, at each occurrence, is independently selected
from
[0596] phenyl substituted with 0-5 R.sup.33;
[0597] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[0598] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0599] R.sup.13, at each occurrence, is independently selected
from
[0600] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[0601] alternatively, R.sup.12 and R.sup.13 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.14)--;
[0602] alternatively, R.sup.12 and R.sup.13 when attached to N may
be combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S; wherein said bicyclic heterocyclic ring
system is selected from indolyl, indolinyl, indazolyl,
benzimidazolyl, benzimidazolinyl, benztriazolyl, benzoxazolyl,
benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl; wherein said
bicyclic heterocyclic ring system is substituted with 0-1
R.sup.16;
[0603] R.sup.14, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[0604] R.sup.15, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[0605] R.sup.16, at each occurrence, is independently selected
from
[0606] H, OH, F, Cl, CN, NO.sub.2, methyl, ethyl, methoxy, ethoxy,
trifluoromethyl, and trifluoromethoxy;
[0607] R.sup.31, at each occurrence, is independently selected
from
[0608] H, OH, halo, CF.sub.3, methyl, ethyl, and propyl;
[0609] R.sup.33, at each occurrence, is independently selected
from
[0610] H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H,
[0611] C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
[0612] C.sub.3-6 cycloalkyl, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkyl-oxy-,
[0613] C.sub.1-4 alkyloxy-,
[0614] C.sub.1-4 alkylthio-, C.sub.1-4 alkyl-C(=O)--, C.sub.1-4
alkyl-C(=O)NH--, C.sub.1-4 alkyl-OC(=O)--,
[0615] C.sub.1-4 alkyl-C(=O)O--, C.sub.3-6 cycloalkyl-oxy-,
C.sub.3-6 cycloalkylmethyl-oxy-;
[0616] C.sub.1-6 alkyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy; and
[0617] C.sub.2-6 alkenyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy;
[0618] R.sup.41, at each occurrence, is independently selected
from
[0619] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN,
[0620] C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy,
C.sub.1-3 haloalkyl, and C.sub.1-3 alkyl;
[0621] R.sup.42, at each occurrence, is independently selected
from
[0622] H, CF.sub.3, halo, OH, C.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, CH(=NH)NH.sub.2,
NHC(=NH)NH.sub.2,
[0623] C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy,
C.sub.1-3 haloalkyl, C.sub.3-6 cycloalkyl, and C.sub.1-3 alkyl;
[0624] R.sup.43 is cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, phenyl, or pyridyl, each substituted with 0-3
R.sup.44;
[0625] R.sup.44, at each occurrence, is independently selected from
H, halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy, and butoxy;
[0626] R.sup.45 is methyl, ethyl, propyl, or butyl;
[0627] R.sup.46, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[0628] R.sup.47, at each occurrence, is independently selected from
from H, methyl, ethyl, propyl, and butyl;
[0629] k is 1;
[0630] m is 1; and
[0631] n is 0, 1 or 2.
[0632] [6] In a more preferred embodiment, the present invention
provides the method as defined in Claim 2 where in the compound
administered:
[0633] X is --CH.sub.2--;
[0634] R.sup.1 is selected from H,
[0635] C.sub.1-5 alkyl substituted with 0-1 R.sup.2,
[0636] C.sub.2-5 alkenyl substituted with 0-1 R.sup.2, and
[0637] C.sub.2-3 alkynyl substituted with 0-1 R.sup.2;
[0638] R.sup.2 is C.sub.3-6 cycloalkyl;
[0639] R.sup.5 is H, methyl, ethyl, or propyl;
[0640] R.sup.6a is H, methyl, or ethyl;
[0641] R.sup.6b is H;
[0642] R.sup.7 and R.sup.9, at each occurrence, are independently
selected from
[0643] H, F, Cl, --CH.sub.3, --OCH.sub.3, --CF.sub.3, --OCF.sub.3,
--CN, and --NO.sub.2,
[0644] R.sup.8 is selected from
[0645] methyl substituted with R.sup.11;
[0646] ethenyl substituted with R.sup.11; OR.sup.12, SR.sup.12,
NR.sup.12R.sup.13, NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15;
[0647] R.sup.11is selected from
[0648] phenyl-substituted with 0-5 fluoro;
[0649] 2-(H.sub.3CCH.sub.2C(=O))-phenyl-substituted with
R.sup.33;
[0650] 2-(H.sub.3CC(=O))-phenyl-substituted with R.sup.33;
[0651] 2-(HC(=O))-phenyl-substituted with R.sup.33;
[0652] 2-(H.sub.3CCH(OH))-phenyl-substituted with R.sup.33;
[0653] 2-(H.sub.3CCH.sub.2CH(OH))-phenyl-substituted with
R.sup.33;
[0654] 2-(HOCH.sub.2)-phenyl-substituted with R.sup.33;
[0655] 2-(HOCH.sub.2CH.sub.2)-phenyl-substituted with R.sup.33;
[0656] 2-(H.sub.3COCH.sub.2)-phenyl-substituted with R.sup.33;
[0657] 2-(H.sub.3COCH.sub.2CH.sub.2)-phenyl-substituted with
R.sup.33;
[0658] 2-(H.sub.3CCH(OMe))-phenyl-substituted with R.sup.33;
[0659] 2-(H.sub.3COC(=O))-phenyl-substituted with R.sup.33;
[0660] 2-(HOCH.sub.2CH=CH)-phenyl-substituted with R.sup.33;
[0661] 2-((MeOC=O)CH=CH)-phenyl-substituted with R.sup.33;
[0662] 2-(methyl)-phenyl-substituted with R.sup.33;
[0663] 2-(ethyl)-phenyl-substituted with R.sup.33;
[0664] 2-(i-propyl)-phenyl-substituted with R.sup.33;
[0665] 2-(F3C)-phenyl-substituted with R.sup.33;
[0666] 2-(NC)-phenyl-substituted with R.sup.33;
[0667] 2-(H.sub.3CO)-phenyl-substituted with R.sup.33;
[0668] 2-(fluoro)-phenyl-substituted with R.sup.33;
[0669] 2-(chloro)-phenyl-substituted with R.sup.33;
[0670] 3-(NC)-phenyl-substituted with R.sup.33;
[0671] 3-(H.sub.3CO)-phenyl-substituted with R.sup.33;
[0672] 3-(fluoro)-phenyl-substituted with R.sup.33;
[0673] 3-(chloro)-phenyl-substituted with R.sup.33;
[0674] 4-(NC)-phenyl-substituted with R.sup.33;
[0675] 4-(fluoro)-phenyl-substituted with R.sup.33;
[0676] 4-(chloro)-phenyl-substituted with R.sup.33;
[0677] 4-(H.sub.3CS)-phenyl-substituted with R.sup.33;
[0678] 4-(H.sub.3CO)-phenyl-substituted with R.sup.33;
[0679] 4-(ethoxy)-phenyl-substituted with R.sup.33;
[0680] 4-(i-propoxy)-phenyl-substituted with R.sup.33;
[0681] 4-(i-butoxy)-phenyl-substituted with R.sup.33;
[0682] 4-(H.sub.3CCH.sub.2CH.sub.2C(=O))-phenyl-substituted with
R.sup.33;
[0683] 4-((H.sub.3C).sub.2CHC(=O))-phenyl-substituted with
R.sup.33;
[0684] 4-(H.sub.3CCH.sub.2C(=O))-phenyl-substituted with
R.sup.33;
[0685] 4-(H.sub.3CC(=O))-phenyl-substituted with R.sup.33;
[0686] 4-(H.sub.3CCH.sub.2CH.sub.2CH(OH))-phenyl-substituted with
R.sup.33;
[0687] 4-((H.sub.3C).sub.2CHCH(OH))-phenyl-substituted with
R.sup.33;
[0688] 4-(H.sub.3CCH.sub.2CH(OH))-phenyl-substituted with
R.sup.33;
[0689] 4-(H.sub.3CCH(OH))-phenyl-substituted with R.sup.33;
[0690] 4-(cyclopropyloxy)-phenyl-substituted with R.sup.33;
[0691] 4-(cyclobutyloxy)-phenyl-substituted with R.sup.33; and
[0692] 4-(cyclopentyloxy)-phenyl-substituted with R.sup.33;
[0693] R.sup.12 is selected from
[0694] phenyl-substituted with 0-5 fluoro;
[0695] 2-(H.sub.3CCH.sub.2C(=O))-phenyl-substituted with
R.sup.33;
[0696] 2-(H.sub.3CC(=O))-phenyl-substituted with R.sup.33;
[0697] 2-(HC(=O))-phenyl-substituted with R.sup.33;
[0698] 2-(H.sub.3CCH(OH))-phenyl-substituted with R.sup.33;
[0699] 2-(H.sub.3CCH.sub.2CH(OH))-phenyl-substituted with
R.sup.33;
[0700] 2-(HOCH.sub.2)-phenyl-substituted with R.sup.33;
[0701] 2-(HOCH.sub.2CH.sub.2)-phenyl-substituted with R.sup.33;
[0702] 2-(H.sub.3COCH.sub.2)-phenyl-substituted with R.sup.33;
[0703] 2-(H.sub.3COCH.sub.2CH.sub.2)-phenyl-substituted with
R.sup.33;
[0704] 2-(H.sub.3CCH(OMe))-phenyl-substituted with R.sup.33;
[0705] 2-(H.sub.3COC(=O))-phenyl-substituted with R.sup.33;
[0706] 2-(HOCH.sub.2CH=CH)-phenyl-substituted with R.sup.33;
[0707] 2-((MeOC=O)CH=CH)-phenyl-substituted with R.sup.33;
[0708] 2-(methyl)-phenyl-substituted with R.sup.33;
[0709] 2-(ethyl)-phenyl-substituted with R.sup.33;
[0710] 2-(i-propyl)-phenyl-substituted with R.sup.33;
[0711] 2-(F3C)-phenyl-substituted with R.sup.33;
[0712] 2-(NC)-phenyl-substituted with R.sup.33;
[0713] 2-(H.sub.3CO)-phenyl-substituted with R.sup.33;
[0714] 2-(fluoro)-phenyl-substituted with R.sup.33;
[0715] 2-(chloro)-phenyl-substituted with R.sup.33;
[0716] 3-(NC)-phenyl-substituted with R.sup.33;
[0717] 3-(H.sub.3CO)-phenyl-substituted with R.sup.33;
[0718] 3-(fluoro)-phenyl-substituted with R.sup.33;
[0719] 3-(chloro)-phenyl-substituted with R.sup.33;
[0720] 4-(NC)-phenyl-substituted with R.sup.33;
[0721] 4-(fluoro)-phenyl-substituted with R.sup.33;
[0722] 4-(chloro)-phenyl-substituted with R.sup.33;
[0723] 4-(H.sub.3CS)-phenyl-substituted with R.sup.33;
[0724] 4-(H.sub.3CO)-phenyl-substituted with R.sup.33;
[0725] 4-(ethoxy)-phenyl-substituted with R.sup.33;
[0726] 4-(i-propoxy)-phenyl-substituted with R.sup.33;
[0727] 4-(i-butoxy)-phenyl-substituted with R.sup.33;
[0728] 4-(H.sub.3CCH.sub.2CH.sub.2C(=O))-phenyl-substituted with
R.sup.33;
[0729] 4-((H.sub.3C).sub.2CHC(=O))-phenyl-substituted with
R.sup.33;
[0730] 4-(H.sub.3CCH.sub.2C(=O))-phenyl-substituted with
R.sup.33;
[0731] 4-(H.sub.3CC(=O))-phenyl-substituted with R.sup.33;
[0732] 4-(H.sub.3CCH.sub.2CH.sub.2CH(OH))-phenyl-substituted with
R.sup.33;
[0733] 4-((H.sub.3C).sub.2CHCH(OH))-phenyl-substituted with
R.sup.33;
[0734] 4-(H.sub.3CCH.sub.2CH(OH))-phenyl-substituted with
R.sup.33;
[0735] 4-(H.sub.3CCH(OH))-phenyl-substituted with R.sup.33;
[0736] 4-(cyclopropyloxy)-phenyl-substituted with R.sup.33;
[0737] 4-(cyclobutyloxy)-phenyl-substituted with R.sup.33; and
[0738] 4-(cyclopentyloxy)-phenyl-substituted with R.sup.33;
[0739] R.sup.13 is H, methyl, or ethyl;
[0740] alternatively, R.sup.12 and R.sup.13 join to form a 5- or
6-membered ring selected from pyrrolyl, pyrrolidinyl, imidazolyl,
piperidinyl, piperizinyl, methylpiperizinyl,and morpholinyl;
[0741] alternatively, R.sup.12 and R.sup.13 when attached to N may
be combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S; wherein said bicyclic heterocyclic ring
system is selected from indolyl, indolinyl, indazolyl,
benzimidazolyl, benzimidazolinyl, benztriazolyl, benzoxazolyl,
benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl; wherein said
bicyclic heterocyclic ring system is substituted with 0-1
R.sup.16;
[0742] R.sup.15 is H, methyl, ethyl, propyl, or butyl;
[0743] R.sup.16, at each occurrence, is independently selected
from
[0744] H, OH, F, Cl, CN, NO.sub.2, methyl, ethyl, methoxy, ethoxy,
trifluoromethyl, and trifluoromethoxy;
[0745] R.sup.33, at each occurrence, is independently selected
from
[0746] H, F, Cl, --CH.sub.3, --OCH.sub.3, --CF.sub.3, --OCF.sub.3,
--CN, and --NO.sub.2;
[0747] k is 1;
[0748] m is 1; and
[0749] n is 1 or 2.
[0750] [7] In a more preferred embodiment, the present invention
provides the method as defined in Claim 2 where the compound
administered is a compound of Formula (I-a): 7
[0751] wherein:
[0752] b is a single bond;
[0753] X is --CH.sub.2--, --CH(OH)--, or --C(=O)--;
[0754] R.sup.1 is selected from
[0755] hydrogen, methyl, ethyl, n-propyl, n-butyl, s-butyl,
t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl, 2-hexyl,
2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl,
3-methylpentyl, 3-methylbutyl, 4-methylpentyl, 2-fluoroethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl,
[0756] 2-propenyl, 2-methyl-2-propenyl, trans-2-butenyl,
3-methyl-butenyl, 3-butenyl, trans-2-pentenyl, cis-2-pentenyl,
4-pentenyl, 4-methyl-3-pentenyl, 3,3-dichloro-2-propenyl,
trans-3-phenyl-2-propenyl,
[0757] cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl,
[0758] benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl,
2,5-dimethylbenzyl, 2,4-dimethylbenzyl, 3,5-dimethylbenzyl,
2,4,6-trimethyl-benzyl, 3-methoxy-benzyl, 3,5-dimethoxy-benzyl,
pentafluorobenzyl, 2-phenylethyl, 1-phenyl-2-propyl, 4-phenylbutyl,
4-phenylbenzyl, 2-phenylbenzyl,
[0759] (2,3-dimethoxy-phenyl)C(=O)--,
(2,5-dimethoxy-phenyl)C(=O)--, (3,4-dimethoxy-phenyl)C(=O)--,
(3,5-dimethoxy-phenyl)C(=O)--, cyclopropyl-C(=O)--,
isopropyl-C(=O)--, ethyl-CO.sub.2--, propyl-CO.sub.2--,
t-butyl-CO.sub.2--, 2,6-dimethoxy-benzyl, 2,4-dimethoxy-benzyl,
2,4,6-trimethoxy-benzyl, 2,3-dimethoxy-benzyl,
2,4,5-trimethoxy-benzyl, 2,3,4-trimethoxy-benzyl,
3,4-dimethoxy-benzyl, 3,4,5-trimethoxy-benzyl,
(4-fluoro-phenyl)ethyl,
[0760] --CH=CH.sub.2, --CH.sub.2-CH=CH.sub.2, --CH=CH-CH.sub.3,
--C.ident.CH, --C.ident.C-CH.sub.3, and --CH.sub.2-C.ident.CH;
[0761] R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are
independently selected from
[0762] hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl,
propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy,
ethoxy, isopropoxy, trifluoromethoxy, phenyl,
[0763] methylC(=O)--, ethylC(=O)--, propylC(=O)--,
isopropylC(=O)--, butylC(=O)--, phenylC(=O)--, methylC.sub.2--,
ethylC.sub.2--, propylC.sub.2--, isopropylC.sub.2--,
butylCO.sub.2--, phenylCO.sub.2--,
[0764] dimethylamino-S(=O)--, diethylamino-S(=O)--,
dipropylamino-S(=O)--, di-isopropylamino-S(=O)--,
dibutylamino-S(=O)--, diphenylamino-S(=O)--,
[0765] dimethylamino-SO.sub.2--, diethylamino-SO.sub.2--,
dipropylamino-SO.sub.2--, di-isopropylamino-SO.sub.2--,
dibutylamino-SO.sub.2--, diphenylamino-SO.sub.2--,
dimethylamino-C(=O)--, diethylamino-C(=O)--, dipropylamino-C(=O)--,
di-isopropylamino-C(=O)--, dibutylamino-C(=O)--,
diphenylamino-C(=O)--,
[0766] 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl,
2-cyanophenyl, 2-methylphenyl, 2-trifluoromethylphenyl,
2-methoxyphenyl, 2-trifluoromethoxyphenyl,
[0767] 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl,
3-cyanophenyl, 3-methylphenyl, 3-ethylphenyl, 3-propylphenyl,
3-isopropylphenyl, 3-butylphenyl, 3-trifluoromethylphenyl,
3-methoxyphenyl, 3-isopropoxyphenyl, 3-trifluoromethoxyphenyl,
3-thiomethoxyphenyl,
[0768] 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl,
4-cyanophenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl,
4-isopropylphenyl, 4-butylphenyl, 4-trifluoromethylphenyl,
4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethoxyphenyl,
4-thiomethoxyphenyl,
[0769] 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethylphenyl,
2,3-ditrifluoromethylphenyl, 2,3-dimethoxyphenyl,
2,3-ditrifluoromethoxyp- henyl,
[0770] 2,4-dichlorophenyl, 2,4-difluorophenyl,
2,4-dimethylphenyl,
[0771] 2,4-ditrifluoromethylphenyl, 2,4-dimethoxyphenyl,
2,4-ditrifluoromethoxyphenyl,
[0772] 2,5-dichlorophenyl, 2,5-difluorophenyl, 2,5-dimethylphenyl,
2,5-ditrifluoromethylphenyl, 2,5-dimethoxyphenyl,
2,5-ditrifluoromethoxyp- henyl,
[0773] 2,6-dichlorophenyl, 2,6-difluorophenyl, 2,6-dimethylphenyl,
2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl,
2,6-ditrifluoromethoxyp- henyl,
[0774] 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl,
3,4-ditrifluoromethylphenyl, 3,4-dimethoxyphenyl,
3,4-ditrifluoromethoxyp- henyl,
[0775] 2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl,
2,4,6-trimethylphenyl, 2,4,6-tritrifluoromethylphenyl,
2,4,6-trimethoxyphenyl, 2,4,6-tritrifluoromethoxyphenyl,
[0776] 2-chloro-4-CF.sub.3-phenyl, 2-fluoro-3-chloro-phenyl,
2-chloro-4-CF.sub.3-phenyl, 2-chloro-4-methoxy-phenyl,
2-methoxy-4-isopropyl-phenyl, 2-CF.sub.3-4-methoxy-phenyl,
2-methyl-4-methoxy-5-fluoro-phenyl, 2-methyl-4-methoxy-phenyl,
2-chloro-4-CF.sub.3O-phenyl, 2,4,5-trimethyl-phenyl,
2-methyl-4-chloro-phenyl,
[0777] methyl-C(=O)NH--, ethyl-C(=O)NH--, propyl-C(=O)NH--,
isopropyl-C(=O)NH--, butyl-C(=O)NH--, phenyl-C(=O)NH--,
[0778] 4-acetylphenyl, 3-acetamidophenyl, 4-pyridyl, 2-furanyl,
2-thiophenyl, 2-naphthyl;
[0779] 2-Me-5-F-phenyl, 2-F-5-Me-phenyl, 2-MeO-5-F-phenyl,
2-Me-3-Cl-phenyl, 3-NO.sub.2-phenyl, 2-NO.sub.2-phenyl,
2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl,
2-Cl-6-F-phenyl, 2-Cl-4-(CHF.sub.2)O-phenyl, 2,4-diMeO-6-F-phenyl,
2-CF.sub.3-6-F-phenyl, 2-MeS-phenyl, 2,6-diCl-4-MeO-phenyl,
2,3,4-triF-phenyl, 2,6-diF-4-Cl-phenyl, 2,3,4,6-tetraF-phenyl,
2,3,4,5,6-pentaF-phenyl, 2-CF.sub.3-4-EtO-phenyl,
2-CF.sub.3-4-iPrO-phenyl, 2-CF.sub.3-4-Cl-phenyl,
2-CF.sub.3-4-F-phenyl, 2-Cl-4-EtO-phenyl, 2-Cl-4-iPrO-phenyl,
2-Et-4-MeO-phenyl, 2-CHO-4-MeO-phenyl, 2-CH(OH)Me-4-MeO-phenyl,
2-CH(OMe)Me-4-MeO-phenyl, 2--C(=O)Me-4-MeO-phenyl,
2-CH.sub.2(OH)-4-MeO-phenyl, 2-CH.sub.2(OMe)-4-MeO-phenyl,
2-CH(OH)Et-4-MeO-phenyl, 2--C(=O)Et-4-MeO-phenyl,
2-CH=CHC.sub.2Me-4-MeO-phenyl,
2-CH.sub.2CH.sub.2CO.sub.2Me-4-MeO-phenyl,
(Z)-2-CH=CHCH.sub.2(OH)-4-MeO-- phenyl,
(E)-2-CH=CHC.sub.2Me-4-MeO-phenyl, (E)-2-CH=CHCH.sub.2(OH)-4-MeO-p-
henyl, 2-CH.sub.2CH.sub.2OMe-4-MeO-phenyl, 2-F-4-MeO-phenyl,
2-Cl-4-F-phenyl, (2-Cl-phenyl)--CH=CH--, (3-Cl-phenyl)--CH=CH--,
(2,6-diF-phenyl)--CH=CH--, --CH.sub.2CH=CH.sub.2, phenyl-CH=CH--,
(2-Me-4-MeO-phenyl)--CH=CH--, cyclohexyl, cyclopentyl,
cyclohexylmethyl, --CH.sub.2CH.sub.2CO.sub.2Et,
--(CH.sub.2).sub.3CO.sub.2Et, --(CH.sub.2).sub.4CO.sub.2Et, benzyl,
2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 3-MeO-benzyl, 3-OH-benzyl,
2-MeO-benzyl, 2-OH-benzyl, 2-CO.sub.2Me-3-MeO-phenyl,
2-Me-4-CN-phenyl, 2-Me-3-CN-phenyl, 2-CF.sub.3-4-CN-phenyl,
3-CHO-phenyl, 3-CH.sub.2(OH)-phenyl, 3-CH.sub.2(OMe)-phenyl,
3-CH.sub.2(NMe2)-phenyl, 3-CN-4-F-phenyl, 3-CONH.sub.2-4-F-phenyl,
2-CH.sub.2(NH.sub.2)-4-MeO-phenyl-, phenyl-NH--,
(4-F-phenyl)--NH--, (2,4-diCl-phenyl)--NH--, phenyl-C(=O)NH--,
benzyl-NH--, (2-Me-4-MeO-phenyl)--NH--, (2-F-4-MeO-phenyl)--NH--,
(2-Me-4-F-phenyl)--NH--, phenyl-S--, --NMe.sub.2, 1-pyrrolidinyl,
and --N(tosylate).sub.2,
[0780] provided that two of R.sup.7, R.sup.8, and R.sup.9, are
independently selected from hydrogen, fluoro, chloro, bromo, cyano,
methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro,
trifluoromethyl, methoxy, ethoxy, isopropoxy, and
trifluoromethoxy;
[0781] m is 1; and
[0782] n is 0, 1 or 2.
[0783] [8] In a more preferred embodiment, the present invention
provides the method as defined in Claim 7 where the compound
administered is a compound of Formula (V): 8
[0784] wherein:
[0785] b is a single bond, wherein the bridge hydrogens are in a
cis position;
[0786] R.sup.1 is selected from hydrogen, methyl, ethyl, n-propyl,
n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl,
2-pentyl, 2-hexyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl,
2-ethylbutyl, 3-methylpentyl, 3-methylbutyl, 4-methylpentyl,
2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-propenyl,
2-methyl-2-propenyl, trans-2-butenyl, 3-methyl-butenyl, 3-butenyl,
trans-2-pentenyl, cis-2-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,
3,3-dichloro-2-propenyl, trans-3-phenyl-2-propenyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,
--CH=CH.sub.2, --CH.sub.2--CH=CH.sub.2, --CH=CH--CH.sub.3,
--C.ident.CH, --C=C.ident.CH.sub.3, and --CH.sub.2--C.ident.CH;
[0787] R.sup.7 and R.sup.9, at each occurrence, are independently
selected from hydrogen, fluoro, methyl, trifluoromethyl, and
methoxy;
[0788] R.sup.8 is selected from
[0789] hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl,
propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy,
ethoxy, isopropoxy, trifluoromethoxy, phenyl,
[0790] methylC(=O)--, ethylC(=O)--, propylC(=O)--,
isopropylC(=O)--, butylC(=O)--, phenylC(=O)--,
[0791] methylCO.sub.2--, ethylCO.sub.2--, propylCO.sub.2--,
isopropylCO.sub.2--, butylCO.sub.2--, phenylCO.sub.2--,
[0792] dimethylamino-S(=O)--, diethylamino-S(=O)--,
dipropylamino-S(=O)--, di-isopropylamino-S(=O)--,
dibutylamino-S(=O)--, diphenylamino-S(=O)--,
[0793] dimethylamino-SO.sub.2--, diethylamino-SO.sub.2--,
dipropylamino-SO.sub.2--, di-isopropylamino-SO.sub.2--,
dibutylamino-SO.sub.2--, diphenylamino-SO.sub.2--,
[0794] dimethylamino--C(=O)--, diethylamino--C(=O)--,
dipropylamino--C(=O)--, di-isopropylamino--C(=O)--,
dibutylamino--C(=O)--, diphenylamino--C(=O)--,
[0795] 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl,
2-cyanophenyl, 2-methylphenyl, 2-trifluoromethylphenyl,
2-methoxyphenyl, 2-trifluoromethoxyphenyl,
[0796] 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl,
3-cyanophenyl, 3-methylphenyl, 3-ethylphenyl, 3-propylphenyl,
3-isopropylphenyl, 3-butylphenyl, 3-trifluoromethylphenyl,
3-methoxyphenyl, 3-isopropoxyphenyl, 3-trifluoromethoxyphenyl,
3-thiomethoxyphenyl,
[0797] 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl,
4-cyanophenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl,
4-isopropylphenyl, 4-butylphenyl, 4-trifluoromethylphenyl,
4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethoxyphenyl,
4-thiomethoxyphenyl,
[0798] 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethylphenyl,
2,3-ditrifluoromethylphenyl, 2,3-dimethoxyphenyl,
2,3-ditrifluoromethoxyp- henyl,
[0799] 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dimethylphenyl,
2,4-ditrifluoromethylphenyl, 2,4-dimethoxyphenyl,
2,4-ditrifluoromethoxyp- henyl,
[0800] 2,5-dichlorophenyl, 2,5-difluorophenyl, 2,5-dimethylphenyl,
2,5-ditrifluoromethylphenyl, 2,5-dimethoxyphenyl,
2,5-ditrifluoromethoxyp- henyl,
[0801] 2,6-dichlorophenyl, 2,6-difluorophenyl, 2,6-dimethylphenyl,
2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl,
2,6-ditrifluoromethoxyp- henyl,
[0802] 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl,
3,4-ditrifluoromethylphenyl, 3,4-dimethoxyphenyl,
3,4-ditrifluoromethoxyp- henyl,
[0803] 2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl,
2,4,6-trimethylphenyl, 2,4,6-tritrifluoromethylphenyl,
2,4,6-trimethoxyphenyl, 2,4,6-tritrifluoromethoxyphenyl,
[0804] 2-chloro-4-CF.sub.3-phenyl, 2-fluoro-3-chloro-phenyl,
2-chloro-4-CF.sub.3-phenyl, 2-chloro-4-methoxy-phenyl,
2-methoxy-4-isopropyl-phenyl, 2-CF.sub.3-4-methoxy-phenyl,
2-methyl-4-methoxy-5-fluoro-phenyl, 2-methyl-4-methoxy-phenyl,
2-chloro-4-CF.sub.3O-phenyl, 2,4,5-trimethyl-phenyl,
2-methyl-4-chloro-phenyl,
[0805] methyl-C-(=O)NH--, ethyl-C(=O)NH--, propyl-C-(=O)NH--,
isopropyl-C(=O)NH--, butyl-C(=O)NH--, phenyl-C(=O)NH--,
[0806] 4-acetylphenyl, 3-acetamidophenyl, 4-pyridyl, 2-furanyl,
2-thiophenyl, 2-naphthyl;
[0807] 2-Me-5-F-phenyl, 2-F-5-Me-phenyl, 2-MeO-5-F-phenyl,
2-Me-3-Cl-phenyl, 3-NO.sub.2-phenyl, 2-NO.sub.2-phenyl,
2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl,
2-Cl-6-F-phenyl, 2-Cl-4-(CHF.sub.2)O-phenyl, 2,4-diMeO-6-F-phenyl,
2-CF.sub.3-6-F-phenyl, 2-MeS-phenyl, 2,6-diCl-4-MeO-phenyl,
2,3,4-triF-phenyl, 2,6-diF-4-Cl-phenyl, 2,3,4,6-tetraF-phenyl,
2,3,4,5,6-pentaF-phenyl, 2-CF.sub.3-4-EtO-phenyl,
2-CF.sub.3-4-iPrO-phenyl, 2-CF.sub.3-4-Cl-phenyl,
2-CF.sub.3-4-F-phenyl, 2-Cl-4-EtO-phenyl, 2-Cl-4-iPrO-phenyl,
2-Et-4-MeO-phenyl, 2-CHO-4-MeO-phenyl, 2-CH(OH)Me-4-MeO-phenyl,
2-CH(OMe)Me-4-MeO-phenyl, 2--C(=O)Me-4-MeO-phenyl,
2-CH.sub.2(OH)-4-MeO-phenyl, 2-CH.sub.2(OMe)-4-MeO-phenyl,
2-CH(OH)Et-4-MeO-phenyl, 2--C(=O)Et-4-MeO-phenyl,
(Z)-2-CH=CHC.sub.2Me-4-MeO-phenyl,
2-CH.sub.2CH.sub.2CO.sub.2Me-4-MeO-phenyl,
(Z)-2-CH=CHCH.sub.2(OH)-4-MeO-- phenyl,
(E)-2-CH=CHC.sub.2Me-4-MeO-phenyl, (E)-2-CH=CHCH.sub.2(OH)-4-MeO-p-
henyl, 2-CH.sub.2CH.sub.2OMe-4-MeO-phenyl, 2-F-4-MeO-phenyl,
2-Cl-4-F-phenyl, (2-Cl-phenyl)--CH=CH--, (3-Cl-phenyl)--CH=CH--,
(2,6-diF-phenyl)--CH=CH--, --CH.sub.2CH=CH.sub.2, phenyl-CH=CH--,
(2-Me-4-MeO-phenyl)--CH=CH--, cyclohexyl, cyclopentyl,
cyclohexylmethyl, --CH.sub.2CH.sub.2CO.sub.2Et,
--(CH.sub.2).sub.3CO.sub.2Et, --(CH.sub.2).sub.4 CO.sub.2Et,
benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 3-MeO-benzyl,
3-OH-benzyl, 2-MeO-benzyl, 2-OH-benzyl, 2-CO.sub.2Me-3-MeO-phenyl,
2-Me-4-CN-phenyl, 2-Me-3-CN-phenyl, 2-CF.sub.3-4-CN-phenyl,
3-CHO-phenyl, 3-CH.sub.2(OH)-phenyl, 3-CH.sub.2(OMe)-phenyl,
3-CH.sub.2(NMe.sub.2)-phenyl, 3-CN-4-F-phenyl,
3-CONH.sub.2-4-F-phenyl, 2-CH.sub.2(NH.sub.2)-4-MeO-phenyl--,
phenyl-NH--, (4-F-phenyl)--NH--, (2,4-diCl-phenyl)--NH--,
phenyl-C(=O)NH--, benzyl-NH--, (2-Me-4-MeO-phenyl)--NH--,
(2-F-4-MeO-phenyl)--NH--, (2-Me-4-F-phenyl)--NH--, phenyl-S--,
--NMe.sub.2, 1-pyrrolidinyl, and --N(tosylate).sub.2; and
[0808] n is 0, 1 or 2.
[0809] [9] In a more preferred embodiment, the present invention
provides the method as defined in Claim 1 where in the compound
administered:
[0810] X is --CHR.sup.10-- or --C(=O)--;
[0811] R.sup.1 is selected from
[0812] C.sub.1-6 alkyl substituted with Z,
[0813] C.sub.2-6 alkenyl substituted with Z,
[0814] C.sub.2-6 alkynyl substituted with Z,
[0815] C.sub.3-6 cycloalkyl substituted with Z,
[0816] aryl substituted with Z,
[0817] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with Z;
[0818] C.sub.1-6 alkyl substituted with 0-2 R.sup.2,
[0819] C.sub.2-6 alkenyl substituted with 0-2 R.sup.2,
[0820] C.sub.2-6 alkynyl substituted with 0-2 R.sup.2,
[0821] aryl substituted with 0-2 R.sup.2, and
[0822] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with 0-2 R.sup.2; Z is
selected from H,
[0823]
[0824] --CH(OH)R.sup.2,
[0825] --C(ethylenedioxy)R.sup.2,
[0826] --OR.sup.2,
[0827] --SR.sup.2.sub.1
[0828] --NR.sup.2R.sup.3,
[0829] --C(O)R.sup.2,
[0830] --C(O)NR.sup.2R.sup.3,
[0831] --NR.sup.3C(O)R.sup.2,
[0832] --C(O)OR.sup.2,
[0833] --OC(O)R.sup.2,
[0834] --CH(=NR.sup.4 )NR.sup.2R.sup.3,
[0835] --NHC(=NR.sup.4)NR.sup.2R.sup.3,
[0836] --S(O)R.sup.2,
[0837] --S(O).sup.2R.sup.2, --S(O).sub.2NR.sup.2R.sup.3, and
--NR.sup.3S(O).sub.2R.sup.2;
[0838] R.sup.2, at each occurrence, is independently selected
from
[0839] C.sub.1-4 alkyl,
[0840] C.sub.2-4 alkenyl,
[0841] C.sub.2-4 alkynyl,
[0842] C.sub.3-6 cycloalkyl,
[0843] aryl substituted with 0-5 R.sup.42;
[0844] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.41,
and
[0845] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.41;
[0846] R.sup.3, at each occurrence, is independently selected
from
[0847] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
and C.sub.1-4 alkoxy;
[0848] alternatively, R.sup.2 and R.sup.3 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.4)--;
[0849] R.sup.4, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[0850] R.sup.5 is H, methyl, ethyl, propyl, or butyl;
[0851] R.sup.6a is selected from
[0852] H, --OH, --NR.sup.46R.sup.47, --CF.sub.3,
[0853] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 alkoxy,
[0854] C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl, and
[0855] aryl substituted with 0-3 R.sup.44;
[0856] R.sup.6b is H;
[0857] R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are
independently selected from
[0858] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN, --NO.sub.2,
--NR.sup.46R.sup.47,
[0859] C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[0860] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[0861] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0862] aryl substituted with 0-5 R.sup.33,
[0863] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0864] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12,
C(O)OR.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12,
CH(=NR.sup.14)NR.sup.12R.sup.13, NHC(=NR.sup.14)NR.sup.12R.sup.13,
S(O)R.sup.12, S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup.13, NR.sup.14S(O)R.sup.12,
NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.1- 5, and
NR.sup.12C(O)NHR.sup.15;
[0865] R.sup.10 is selected from H, --OH,
[0866] C.sub.1-6 alkyl substituted with 0-1 R.sup.10B,
[0867] C.sub.2-6 alkenyl substituted with 0-1 R.sup.10B,
[0868] C.sub.2-6 alkynyl substituted with 0-1 R.sup.10B, and
[0869] C.sub.1-6 alkoxy;
[0870] R.sup.10B is selected from
[0871] C.sub.1-4 alkoxy,
[0872] C.sub.3-6 cycloalkyl,
[0873] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0874] phenyl substituted with 0-3 R.sup.33, and
[0875] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R.sup.44;
[0876] R.sup.11is selected from
[0877] H, halo, --CF.sub.3, --CN, --NO.sub.2,
[0878] C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, C.sub.3-10 cycloalkyl,
[0879] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0880] aryl substituted with 0-5 R.sup.33,
[0881] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0882] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12,
C(O)OR.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12,
[0883] CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12 S(O).sub.2R.sup.12,
S(O)NR.sup.12R.sup.13, S(O).sub.2NR.sup.12R.sup.13,
NR.sup.14S(O)R.sup.12, and NR.sup.14S(O).sub.2R.sup.12;
[0884] R.sup.12, at each occurrence, is independently selected
from
[0885] C.sub.1-4 alkyl,
[0886] C.sub.2-4 alkenyl,
[0887] C.sub.2-4 alkynyl,
[0888] C.sub.3-6 cycloalkyl,
[0889] phenyl substituted with 0-5 R.sup.33;
[0890] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[0891] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0892] R.sup.13, at each occurrence, is independently selected
from
[0893] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[0894] alternatively, R.sup.12 and R.sup.13 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.14)--;
[0895] R.sup.14, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[0896] R.sup.31, at each occurrence, is independently selected
from
[0897] H, OH, halo, CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47,
methyl, ethyl, and propyl;
[0898] R.sup.33, at each occurrence, is independently selected
from
[0899] H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3
alkynyl, C.sub.3-5 cycloalkyl, C.sub.1-3 haloalkyl, C.sub.1-3
haloalkyl-oxy-, C.sub.1-3 alkyloxy-, C.sub.1-3 alkylthio-,
C.sub.1-3 alkyl-C(=O)--, and C.sub.1-3 alkyl-C(=O)NH--;
[0900] R.sup.41, at each occurrence, is independently selected
from
[0901] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, =O,
[0902] C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl
[0903] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[0904] aryl substituted with 0-3 R.sup.42, and
[0905] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[0906] R.sup.42, at each occurrence, is independently selected
from
[0907] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45.sub.1
SR.sup.45, NR.sup.46R.sup.47, OR.sup.48, NO.sub.2, CN,
CH(=NH)NH.sub.2, NHC(=NH)NH.sub.2,
[0908] C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl,
[0909] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[0910] aryl substituted with 0-3 R.sup.44, and
[0911] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[0912] R.sup.43 is C3-6 cycloalkyl or aryl substituted with 0-3
R.sup.44;
[0913] R.sup.44, at each occurrence, is independently selected from
H, halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, and
C.sub.1-4 alkoxy;
[0914] R.sup.45 is C.sub.1-4 alkyl;
[0915] R.sup.46, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[0916] R.sup.47, at each occurrence, is independently selected from
H,
[0917] C.sub.1-4 alkyl, --C(=O)NH(C.sub.1-4 alkyl),
--SO.sub.2(C.sub.1-4 alkyl), --SO.sub.2(phenyl), --C(=O)O(C.sub.1-4
alkyl), --C(=O)(C.sub.1-4 alkyl), and --C(=O)H;
[0918] R.sup.48, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --C(=O)NH(C.sub.1-4 alkyl), --C(=O)O(C.sub.1-4
alkyl), --C(=O)(C.sub.1-4 alkyl), and --C(=O)H;
[0919] k is 1 or 2;
[0920] m is 0, 1, or 2; and
[0921] n is 0, 1 or 2.
[0922] [10] In a more preferred embodiment, the present invention
provides the method as defined in Claim 9 where in the compound
administered:
[0923] X is --CHR.sup.10-- or --C(=O)--;
[0924] R.sup.1 is selected from
[0925] C.sub.2-5 alkyl substituted with Z,
[0926] C.sub.2-5 alkenyl substituted with Z,
[0927] C.sub.2-5 alkynyl substituted with Z,
[0928] C.sub.3-6 cycloalkyl substituted with Z,
[0929] aryl substituted with Z,
[0930] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with Z;
[0931] C.sub.1-5 alkyl substituted with 0-2 R.sup.2,
[0932] C.sub.2-5 alkenyl substituted with 0-2 R.sup.2.sub.1 and
[0933] C.sub.2-5 alkynyl substituted with 0-2 R.sup.2;
[0934] Z is selected from H,
[0935] --CH(OH)R.sup.2,
[0936] --C(ethylenedioxy)R.sup.2,
[0937] --OR.sup.2,
[0938] --SR.sup.2,
[0939] --NR.sup.2R.sup.3,
[0940] --C(O)R.sup.2,
[0941] --C(O)NR.sup.2R.sup.3,
[0942] --NR.sup.3C(O)R.sup.2,
[0943] --C(O)OR.sup.2,
[0944] --OC(O)R.sup.2,
[0945] --CH(=NR.sup.4)NR.sup.2R.sup.3,
[0946] --NHC(=NR.sup.4)NR.sup.2R.sup.3,
[0947] --S(O).sub.2R.sup.2,
[0948] --S(O).sub.2NR.sup.2R.sup.3, and
--NR.sup.3S(O).sub.2R.sup.2;
[0949] R.sup.2, at each occurrence, is independently selected
from
[0950] C.sub.1-4 alkyl,
[0951] C.sub.2-4 alkenyl,
[0952] C.sub.2-4 alkynyl,
[0953] C.sub.3-6 cycloalkyl,
[0954] aryl substituted with 0-5 R.sup.42;
[0955] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.41,
and
[0956] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.41;
[0957] R.sup.3, at each occurrence, is independently selected
from
[0958] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
and C.sub.1-4 alkoxy;
[0959] alternatively, R.sup.2 and R.sup.3 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.4)--;
[0960] R.sup.4, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[0961] R.sup.5 is H, methyl, or ethyl;
[0962] R.sup.6a is selected from
[0963] H, --OH, --NR.sup.46R.sup.47, --CF.sub.3,
[0964] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 alkoxy,
[0965] C.sub.1-4 haloalkyl, and C.sub.3-6 cycloalkyl;
[0966] R.sup.6b is H;
[0967] R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are
independently selected from
[0968] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --OCH.sub.3, --CN,
--NO.sub.2, --NR.sup.46R.sup.47,
[0969] C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-6 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[0970] C.sub.1-4 alkyl substituted with 0-2 R.sup.11
[0971] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0972] aryl substituted with 0-5 R.sup.33,
[0973] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0974] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13
[0975] NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
CH(=NR.sup.14)NR.sup.12R.sup.13,
[0976] NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12,
S(O).sub.2R.sup.12, S(O).sub.2NR.sup.12R.sup.13,
[0977] NR.sup.14S(O).sub.2R.sup.12, NR.sup.14S(O)R.sup.12,
NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
[0978] NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15, and
NR.sup.12C(O)NHR.sup.15;
[0979] R.sup.10 is selected from H, --OH, C.sub.1-6 alkyl,
C.sub.1-4 alkoxy, and C.sub.1-2 alkyl substituted with 0-1
R.sup.10B;
[0980] R.sup.10Bis C.sub.3-6 cycloalkyl or phenyl substituted with
0-3 R.sup.33;
[0981] R.sup.11 is selected from
[0982] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --OCH.sub.3, --CN,
--NO.sub.2, --NR.sup.46R.sup.47,
[0983] C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-6 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[0984] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[0985] aryl substituted with 0-5 R.sup.33,
[0986] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0987] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12,
C(O)OR.sup.12, OC(O)R.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R- .sup.13, S(O)R.sup.12,
S(O).sub.2R.sup.12, S(O).sub.2NR.sup.12R.sup.13, and
NR.sup.14S(O).sub.2R.sup.12;
[0988] R.sup.12, at each occurrence, is independently selected
from
[0989] C.sub.1-4 alkyl,
[0990] C.sub.2-4 alkenyl,
[0991] C.sub.2-4 alkynyl,
[0992] C.sub.3-6 cycloalkyl,
[0993] phenyl substituted with 0-5 R.sup.33;
[0994] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[0995] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[0996] R.sup.13, at each occurrence, is independently selected
from
[0997] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[0998] alternatively, R.sup.12 and R.sup.13 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.14)--;
[0999] R.sup.14, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[1000] R.sup.31, at each occurrence, is independently selected
from
[1001] H, OH, halo, CF.sub.3, methyl, and ethyl;
[1002] R.sup.33, at each occurrence, is independently selected
from
[1003] H, OH, halo, CN, NO.sub.2, CF.sub.3, methyl, and ethyl;
[1004] R.sup.41, at each occurrence, is independently selected
from
[1005] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, =O,
[1006] C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl,
[1007] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[1008] aryl substituted with 0-3 R.sup.42, and
[1009] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[1010] R.sup.42, at each occurrence, is independently selected
from
[1011] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
SR.sup.45, NR.sup.46R.sup.47, OR.sup.48, NO.sub.2, CN,
CH(=NH)NH.sub.2, NHC(=NH)NH.sub.2,
[1012] C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl,
[1013] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[1014] aryl substituted with 0-3 R.sup.44, and
[1015] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[1016] R.sup.43 is C.sub.3-6 cycloalkyl or aryl substituted with
0-3 R.sup.44;
[1017] R.sup.44, at each occurrence, is independently selected from
H, halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, and
C.sub.1-4 alkoxy;
[1018] R.sup.45 is C.sub.1-4 alkyl;
[1019] R.sup.46, at each occurrence, is independently selected from
H and C.sub.1-3 alkyl;
[1020] R.sup.47, at each occurrence, is independently selected from
H,
[1021] C.sub.1-4 alkyl, --C(=O)NH(C.sub.1-4 alkyl),
--SO.sub.2(C.sub.1-4 alkyl), --SO.sub.2(phenyl), --C(=O)O(C.sub.1-4
alkyl), --C(=O)(C.sub.1-4 alkyl), and --C(=O)H;
[1022] R.sup.48, at each occurrence, is independently selected from
H,
[1023] C.sub.1-4 alkyl, --C(=O)NH(C.sub.1-4 alkyl),
--C(=O)O(C.sub.1-4 alkyl), --C(=O)(C.sub.1-4 alkyl), and
--C(=O)H;
[1024] k is 1 or 2;
[1025] m is 0, 1, 2; and
[1026] n is 0, 1 or 2.
[1027] [11] In a more preferred embodiment, the present invention
provides the method as defined in Claim 9 where in the compound
administered:
[1028] X is --CH.sub.2--;
[1029] R.sup.1 is selected from
[1030] C.sub.2-4 alkyl substituted with Z,
[1031] C.sub.2-4 alkenyl substituted with Z,
[1032] C.sub.2-4 alkynyl substituted with Z,
[1033] C.sub.3-6 cycloalkyl substituted with Z,
[1034] aryl substituted with Z,
[1035] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with Z;
[1036] C.sub.2-4 alkyl substituted with 0-2 R.sup.2, and
[1037] C.sub.2-4 alkenyl substituted with 0-2 R.sup.2;
[1038] Z is selected from H,
[1039] --CH(OH)R.sup.2,
[1040] --C(ethylenedioxy)R.sup.2,
[1041] --OR.sup.2,
[1042] --SR.sup.2,
[1043] --NR.sup.2R.sup.3,
[1044] --C(O)R.sup.2,
[1045] --C(O)NR.sup.2R.sup.3,
[1046] --NR.sup.3C(O)R.sup.2,
[1047] --C(O)OR.sup.2,
[1048] --S(O)R.sup.2,
[1049] --S(O).sub.2R.sup.2,
[1050] --S(O).sub.2NR.sup.2R.sup.3, and
--NR.sup.3S(O).sub.2R.sup.2;
[1051] R.sup.2, at each occurrence, is independently selected
from
[1052] phenyl substituted with 0-5 R.sup.42;
[1053] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.41,
and
[1054] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.41;
[1055] R.sup.3, at each occurrence, is independently selected
from
[1056] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
and C.sub.1-4 alkoxy;
[1057] alternatively, R.sup.2 and R.sup.3 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.4)--;
[1058] R.sup.4, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[1059] R.sup.5 is H;
[1060] R.sup.6a is selected from H, --OH, --CF.sub.3, methyl,
ethyl, propyl, butyl, methoxy, and, ethoxy;
[1061] R.sup.6b is H;
[1062] R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are
independently selected from
[1063] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --OCH.sub.3, --CN,
--NO.sub.2,
[1064] C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy,
(C.sub.1-3 haloalkyl)oxy, and
[1065] C.sub.1-4 alkyl substituted with 0-2 R.sup.11;
[1066] R.sup.11is selected from
[1067] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --OCH.sub.3, --CN,
--NO.sub.2,
[1068] C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, and
(C.sub.1-3 haloalkyl)oxy;
[1069] R.sup.33, at each occurrence, is independently selected
from
[1070] H, OH, halo, CF.sub.3, and methyl;
[1071] R.sup.41, at each occurrence, is independently selected
from
[1072] H, CF.sub.3, halo, OH, C.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, =O,
[1073] C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl,
[1074] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[1075] aryl substituted with 0-3 R.sup.42, and
[1076] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[1077] R.sup.42, at each occurrence, is independently selected
from
[1078] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
SR.sup.45, NR.sup.46R.sup.47, OR.sup.48, NO.sub.2, CN,
CH(=NH)NH.sub.2, NHC(=NH)NH.sub.2,
[1079] C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl,
[1080] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[1081] aryl substituted with 0-3 R.sup.44, and
[1082] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[1083] R.sup.43 is cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl,
[1084] phenyl, or pyridyl, each substituted with 0-3 R.sup.44;
[1085] R.sup.44, at each occurrence, is independently selected from
H, halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy, and butoxy;
[1086] R.sup.45 is methyl, ethyl, propyl, or butyl;
[1087] R.sup.46, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[1088] R.sup.47, at each occurrence, is independently selected
from
[1089] H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
--C(=O)NH(methyl), --C(=O)NH(ethyl), --SO.sub.2(methyl),
--SO.sub.2(ethyl), --SO.sub.2(phenyl),
--C(=O)O(methyl),--C(=O)O(ethyl), --C(=O)(methyl), --C(=O)(ethyl),
and --C(=O)H;
[1090] R.sup.48, at each occurrence, is independently selected
from
[1091] H, methyl, ethyl, n-propyl, i-propyl, --C(=O)NH(methyl),
--C(=O)NH(ethyl), --C(=O)O(methyl),--C(=O)O(ethyl),
--C(=O)(methyl), --C(=O)(ethyl), and --C(=O)H;
[1092] k is 1;
[1093] m is 0, 1, or 2; and
[1094] n is 0, 1 or 2.
[1095] [12] In a more preferred embodiment, the present invention
provides the method as defined in Claim 9 where in the compound
administered:
[1096] X is --CH.sub.2--;
[1097] R.sup.1 is selected from
[1098] ethyl substituted with Z,
[1099] propyl substituted with Z,
[1100] butyl substituted with Z,
[1101] propenyl substituted with Z,
[1102] butenyl substituted with Z,
[1103] ethyl substituted with R.sup.2,
[1104] propyl substituted with R.sup.2,
[1105] butyl substituted with R.sup.2,
[1106] propenyl substituted with R.sup.2, and
[1107] butenyl substituted with R.sup.2;
[1108] Z is selected from H,
[1109] --CH(OH)R.sup.2,
[1110] --OR.sup.2,
[1111] --SR.sup.2,
[1112] --NR.sup.2R.sup.3,
[1113] --C(O)R.sup.2,
[1114] --C(O)NR.sup.2R.sup.3,
[1115] --NR.sup.3C(O)R.sup.2,
[1116] --C(O)OR.sup.2,
[1117] --S(O)R.sup.2,
[1118] --S(O).sub.2R.sup.2,
[1119] --S(O).sub.2NR.sup.2R.sup.3, and
--NR.sup.3S(O).sub.2R.sup.2;
[1120] R.sup.2, at each occurrence, is independently selected
from
[1121] phenyl substituted with 0-3 R.sup.42;
[1122] naphthyl substituted with 0-3 R.sup.42;
[1123] cyclopropyl substituted with 0-3 R.sup.41;
[1124] cyclobutyl substituted with 0-3 R.sup.41;
[1125] cyclopentyl substituted with 0-3 R.sup.41;
[1126] cyclohexyl substituted with 0-3 R.sup.41;
[1127] pyridyl substituted with 0-3 R.sup.41;
[1128] indolyl substituted with 0-3 R.sup.41;
[1129] indolinyl substituted with 0-3 R41;
[1130] benzimidazolyl substituted with 0-3 R.sup.41;
[1131] benzotriazolyl substituted with 0-3 R.sup.41;
[1132] benzothienyl substituted with 0-3 R.sup.41;
[1133] benzofuranyl substituted with 0-3 R.sup.41;
[1134] phthalimid-1-yl substituted with 0-3 R.sup.41;
[1135] inden-2-yl substituted with 0-3 R.sup.41;
[1136] 2,3-dihydro-1H-inden-2-yl substituted with 0-3 R.sup.41;
[1137] indazolyl substituted with 0-3 R.sup.41;
[1138] tetrahydroquinolinyl substituted with 0-3 R.sup.41; and
[1139] tetrahydro-isoquinolinyl substituted with 0-3 R.sup.41;
[1140] R.sup.3, at each occurrence, is independently selected
from
[1141] H, methyl, and ethyl;
[1142] R.sup.5 is H;
[1143] R.sup.6a is selected from H, --OH, methyl, and methoxy;
[1144] R.sup.6b is H;
[1145] R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are
independently selected from H, F, Cl, methyl, ethyl, methoxy,
--CF.sub.3, and --OCF.sub.3;
[1146] R.sup.41, at each occurrence, is independently selected
from
[1147] H, F, Cl, Br, OH, CF.sub.3, NO.sub.2, CN, =O, methyl, ethyl,
propyl, butyl, methoxy, and ethoxy;
[1148] R.sup.42, at each occurrence, is independently selected
from
[1149] H, F, Cl, Br, OH, CF.sub.3, SO.sub.2R.sup.45, SR.sup.45,
NR.sup.46R.sup.47, OR.sup.48, NO.sub.2, CN, =O, methyl, ethyl,
propyl, butyl, methoxy, and ethoxy;
[1150] R.sup.45 is methyl, ethyl, propyl, or butyl;
[1151] R.sup.46, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[1152] R.sup.47, at each occurrence, is independently selected
from
[1153] H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
--C(=O)NH(methyl), --C(=O)NH(ethyl), --SO.sub.2(methyl),
--SO.sub.2(ethyl), --SO.sub.2(phenyl),
--C(=O)O(methyl),--C(=O)O(ethyl), --C(=O)(methyl), --C(=O)(ethyl),
and --C(=O)H;
[1154] R.sup.48, at each occurrence, is independently selected
from
[1155] H, methyl, ethyl, n-propyl, i-propyl, --C(=O)NH(methyl),
--C(=O)NH(ethyl), --C(=O)O(methyl),--C(=O)O(ethyl),
--C(=O)(methyl), --C(=O)(ethyl), and --C(=O)H;
[1156] k is 1;
[1157] m is 0, 1, or 2; and
[1158] n is 0, 1 or 2.
[1159] [13 ] In a more preferred embodiment, the present invention
provides the method as defined in Claim 9 where the compound
administered is a compound of Formula (I-a): 9
[1160] wherein:
[1161] b is a single bond;
[1162] X is --CH.sub.2--, CH(OH)--, or --C(=O)--
[1163] R.sup.1 is selected from
[1164] --(CH.sub.2).sub.3C(=O)(4-fluoro-phenyl),
[1165] --(CH.sub.2).sub.3C(=O)(4-bromo-phenyl),
[1166] --(CH.sub.2).sub.3C(=O)(4-methyl-phenyl),
[1167] --(CH.sub.2).sub.3C(=O)(4-methoxy-phenyl),
[1168] --(CH.sub.2).sub.3C(=O)(4-(3,4-dichloro-phenyl)phenyl),
[1169] --(CH.sub.2).sub.3C(=O)(3-methyl-4-fluoro-phenyl),
[1170] --(CH.sub.2).sub.3C(=O)(2,3-dimethoxy-phenyl),
[1171] --(CH.sub.2).sub.3C(=O)(phenyl),
[1172] --(CH.sub.2).sub.3C(=O)(4-chloro-phenyl),
[1173] --(CH.sub.2).sub.3C(=O)(3-methyl-phenyl),
[1174] --(CH.sub.2).sub.3C(=O)(4-t-butyl-phenyl),
[1175] --(CH.sub.2).sub.3C(=O)(3,4-difluoro-phenyl),
[1176] --(CH.sub.2).sub.3C(=O)(2-methoxy-5-fluoro-phenyl),
[1177] --(CH.sub.2).sub.3C(=O)(4-fluoro-l-naphthyl),
[1178] --(CH.sub.2).sub.3C(=O)(benzyl),
[1179] --(CH.sub.2).sub.3C(=O)(4-pyridyl),
[1180] --(CH.sub.2).sub.3C(=O)(3-pyridyl),
[1181] --(CH.sub.2).sub.3CH(OH)(4-fluoro-phenyl),
[1182] --(CH.sub.2).sub.3CH(OH)(4-pyridyl),
[1183] --(CH.sub.2).sub.3CH(OH)(2,3-dimethoxy-phenyl),
[1184] --(CH.sub.2).sub.3S(3-fluoro-phenyl),
[1185] --(CH.sub.2).sub.3S(4-fluoro-phenyl),
[1186] --(CH.sub.2).sub.3S(=O)(4-fluoro-phenyl),
[1187] --(CH.sub.2).sub.3SO.sub.2(3-fluoro-phenyl),
[1188] --(CH.sub.2).sub.3SO.sub.2(4-fluoro-phenyl),
[1189] --(CH.sub.2).sub.3O(4-fluoro-phenyl),
[1190] --(CH.sub.2).sub.3O(phenyl),
[1191] --(CH.sub.2).sub.3O(3-pyridyl),
[1192] --(CH.sub.2).sub.3O(4-pyridyl),
[1193] --(CH.sub.2).sub.3O(2-NH.sub.2-phenyl),
[1194] --(CH.sub.2).sub.3O(2-NH.sub.2-5-F-phenyl),
[1195] --(CH.sub.2).sub.3O(2-NH.sub.2-4-F-phenyl),
[1196] --(CH.sub.2).sub.3O(2-NH.sub.2-3-F-phenyl),
[1197] --(CH.sub.2).sub.3O(2-NH.sub.2-4-Cl-phenyl),
[1198] --(CH.sub.2).sub.3O(2-NH.sub.2-4-OH-phenyl),
[1199] --(CH.sub.2).sub.3O(2-NH.sub.2-4-Br-phenyl),
[1200] --(CH.sub.2).sub.3O(2-NHC(=O)Me-4-F-phenyl),
[1201] --(CH.sub.2).sub.3O(2-NHC(=O)Me-phenyl),
[1202] --(CH.sub.2).sub.3NH(4-fluoro-phenyl),
[1203] --(CH.sub.2).sub.3N(methyl)(4-fluoro-phenyl),
[1204] --(CH.sub.2).sub.3CO.sub.2(ethyl),
[1205] --(CH.sub.2).sub.3C(=O)N(methyl)(methoxy),
[1206] --(CH.sub.2).sub.3C(=O)NH(4-fluoro-phenyl),
[1207] --(CH.sub.2).sub.2NHC(=O)(phenyl),
[1208] --(CH.sub.2).sub.2NMeC(=O)(phenyl),
[1209] --(CH.sub.2).sub.2NHC(=O)(2-fluoro-phenyl),
[1210] --(CH.sub.2).sub.2NMeC(=O)(2-fluoro-phenyl),
[1211] --(CH.sub.2).sub.2NHC(=O)(4-fluoro-phenyl),
[1212] --(CH.sub.2).sub.2NMeC(=O)(4-fluoro-phenyl),
[1213] --(CH.sub.2).sub.2NHC(=O)(2,4-difluoro-phenyl),
[1214] --(CH.sub.2).sub.2NMeC(=O)(2,4-difluoro-phenyl),
[1215] --(CH.sub.2).sub.3(3-indolyl),
[1216] --(CH.sub.2).sub.3(1-methyl-3-indolyl),
[1217] --(CH.sub.2).sub.3(1-indolyl),
[1218] --(CH.sub.2).sub.3(1-indolinyl),
[1219] --(CH.sub.2).sub.3(1-benzimidazolyl),
[1220] --(CH.sub.2).sub.3(1H-1,2,3-benzotriazol-1-yl),
[1221] --(CH.sub.2).sub.3(1H-1,2,3-benzotriazol-2-yl),
[1222] --(CH.sub.2).sub.2(1H-1,2,3-benzotriazol-1-yl),
[1223] --(CH.sub.2).sub.2(1H-1,2,3-benzotriazol-2-yl),
[1224] --(CH.sub.2).sub.3(3,4 dihydro-1(2H)-quinolinyl),
[1225] --(CH.sub.2).sub.2C(=O)(4-fluoro-phenyl),
[1226] --(CH.sub.2).sub.2C(=O)NH(4-fluoro-phenyl),
[1227] --CH.sub.2CH.sub.2(3-indolyl),
[1228] --CH.sub.2CH.sub.2(1-phthalimidyl),
[1229] --(CH.sub.2).sub.4 C(=O)N(methyl)(methoxy),
[1230] --(CH.sub.2).sub.4 CO.sub.2(ethyl),
[1231] --(CH.sub.2).sub.4 C(=O)(phenyl),
[1232] --(CH.sub.2).sub.4 (cyclohexyl),
[1233] --(CH.sub.2).sub.3CH(phenyl).sub.2,
[1234] --CH.sub.2CH.sub.2CH=C(phenyl).sub.2,
[1235] --CH.sub.2CH.sub.2CH=CMe(4-F-phenyl),
[1236] --(CH.sub.2).sub.3CH(4-fluoro-phenyl).sub.2,
[1237] --CH.sub.2CH.sub.2CH=C(4-fluoro-phenyl).sub.2,
[1238] --(CH.sub.2).sub.2(2,3-dihydro-1H-inden-2-yl),
[1239] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-phenyl),
[1240] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-5-F-phenyl),
[1241] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-F-phenyl),
[1242] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-3-F-phenyl),
[1243] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-Cl-phenyl),
[1244] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-OH-phenyl),
[1245] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-Br-phenyl),
[1246] --(CH.sub.2).sub.3(1H-indazol-3-yl),
[1247] --(CH.sub.2).sub.3(5-F-1H-indazol-3-yl),
[1248] --(CH.sub.2).sub.3(7-F-1H-indazol-3-yl),
[1249] --(CH.sub.2).sub.3(6-Cl-1H-indazol-3-yl),
[1250] --(CH.sub.2).sub.3(6-Br-1H-indazol-3-yl),
[1251] --(CH.sub.2).sub.3C(=O)(2-NHMe-phenyl),
[1252] --(CH.sub.2).sub.3(1-benzothien-3-yl),
[1253] --(CH.sub.2).sub.3(6-F-1H-indol-1-yl),
[1254] --(CH.sub.2).sub.3(5-F-1H-indol-1-yl),
[1255] --(CH.sub.2).sub.3(6-F-2,3-dihydro-1H-indol-1-yl),
[1256] --(CH.sub.2).sub.3(5-F-2,3-dihydro-1H-indol-1-yl),
[1257] --(CH.sub.2).sub.3(6-F-1H-indol-3-yl),
[1258] --(CH.sub.2).sub.3(5-F-1H-indol-3-yl),
[1259] --(CH.sub.2).sub.3(5-F-1H-indol-3-yl),
[1260] --(CH.sub.2).sub.3(9H-purin-9-yl),
[1261] --(CH.sub.2).sub.3(7H-purin-7-yl),
[1262] --(CH.sub.2).sub.3(6-F-1H-indazol-3-yl),
[1263] --(CH.sub.2).sub.3C(=O)(2-NHSO.sub.2Me-4-F-phenyl),
[1264] --(CH.sub.2).sub.3C(=O)(2-NHC(=O)Me-4-F-phenyl),
[1265] --(CH.sub.2).sub.3C(=O)(2-NHC(=O)Me-phenyl),
[1266] --(CH.sub.2).sub.3C(=O)(2-NHCO.sub.2Et-4-F-phenyl),
[1267] --(CH.sub.2).sub.3C(-O)(2-NHC(=O)NHEt-4-F-phenyl),
[1268] --(CH.sub.2).sub.3C(=O)(2-NHCHO-4-F-phenyl),
[1269] --(CH.sub.2).sub.3C(=O)(2-OH-4-F-phenyl),
[1270] --(CH.sub.2).sub.3C(=O)(2-MeS-4-F-phenyl),
[1271] --(CH.sub.2).sub.3C(=O)(2-NHSO.sub.2Me-4-F-phenyl),
[1272] --(CH.sub.2).sub.2C(Me)CO.sub.2Me,
[1273] --(CH.sub.2).sub.2C(Me)CH(OH)(4-F-phenyl).sub.2,
[1274] --(CH.sub.2).sub.2C(Me)CH(OH)(4-Cl-phenyl).sub.2,
[1275] --(CH.sub.2).sub.2C(Me)C(=O)(4-F-phenyl),
[1276] --(CH.sub.2).sub.2C(Me)C(=O)(2-MeO-4-F-phenyl),
[1277] --(CH.sub.2).sub.2C(Me)C(=O)(3-Me-4-F-phenyl),
[1278] --(CH.sub.2).sub.2C(Me)C(=O)(2-Me-phenyl),
[1279] --(CH.sub.2).sub.2C(Me)C(=O)phenyl, 10
[1280] R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are
independently selected from
[1281] hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl,
propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy,
ethoxy, isopropoxy, trifluoromethoxy, phenyl, benzyl,
[1282] HC(=O)--, methylC(=O)--, ethylC(=O)--, propylC(=O)--,
isopropylC(=O)--, n-butylC(=O)--, isobutylC(=O)--, secbutylC(=O)--,
tertbutylC(=O)--, phenylC(=O)--, methylC(=O)NH--, ethylC(=O)NH --,
propylC(=O)NH--, isopropylC(=O)NH--, n-butylC(=O)NH--,
isobutylC(=O)NH--, secbutylC(=O)NH--, tertbutylC(=O)NH--,
phenylC(=O)NH--,
[1283] methylamino-, ethylamino-, propylamino-, isopropylamino-,
n-butylamino-, isobutylamino-, secbutylamino-, tertbutylamino-,
phenylamino-,
[1284] provided that two of substituents R.sup.7, R.sup.8, and
R.sup.9, are independently selected from hydrogen, fluoro, chloro,
bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl,
nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, and
trifluoromethoxy;
[1285] k is 1 or 2;
[1286] m is 1 or 2; and
[1287] n is 0, 1 or 2.
[1288] [14] In a more preferred embodiment, the present invention
provides the method as defined in Claim 13 where the compound
administered is a compound of Formula (V-a): 11
[1289] wherein:
[1290] b is a single bond, wherein the bridge hydrogens are in a
cis position;
[1291] R.sup.1 is selected from
[1292] --(CH.sub.2).sub.3C(=O)(4-fluoro-phenyl),
[1293] --(CH.sub.2).sub.3C(=O)(4-bromo-phenyl),
[1294] --(CH.sub.2).sub.3C(=O)(4-methyl-phenyl),
[1295] --(CH.sub.2).sub.3C(=O)(4-methoxy-phenyl),
[1296] --(CH.sub.2).sub.3C(=O)(4-(3,4-dichloro-phenyl)phenyl),
[1297] --(CH.sub.2).sub.3C(=O)(3-methyl-4-fluoro-phenyl),
[1298] --(CH.sub.2).sub.3C(=O)(2,3-dimethoxy-phenyl),
[1299] --(CH.sub.2).sub.3C(=O)(phenyl),
[1300] --(CH.sub.2).sub.3C(=O)(4-chloro-phenyl),
[1301] --(CH.sub.2).sub.3C(=O)(3-methyl-phenyl),
[1302] --(CH.sub.2).sub.3C(=O)(4-t-butyl-phenyl),
[1303] --(CH.sub.2).sub.3C(=O)(3,4-difluoro-phenyl),
[1304] --(CH.sub.2).sub.3C(=O)(2-methoxy-5-fluoro-phenyl),
[1305] --(CH.sub.2).sub.3C(=O)(4-fluoro-l-naphthyl),
[1306] --(CH.sub.2).sub.3C(=O)(benzyl),
[1307] --(CH.sub.2).sub.3C(=O)(4-pyridyl),
[1308] --(CH.sub.2).sub.3C(=O)(3-pyridyl),
[1309] --(CH.sub.2).sub.3CH(OH)(4-fluoro-phenyl),
[1310] --(CH.sub.2).sub.3CH(OH)(4-pyridyl),
[1311] --(CH.sub.2).sub.3CH(OH)(2,3-dimethoxy-phenyl),
[1312] --(CH.sub.2).sub.3S(3-fluoro-phenyl),
[1313] --(CH.sub.2).sub.3S(4-fluoro-phenyl),
[1314] --(CH.sub.2).sub.3S(=O)(4-fluoro-phenyl),
[1315] --(CH.sub.2).sub.3SO.sub.2(3-fluoro-phenyl),
[1316] --(CH.sub.2).sub.3SO.sub.2(4-fluoro-phenyl),
[1317] --(CH.sub.2).sub.3O(4-fluoro-phenyl),
[1318] --(CH.sub.2).sub.3O(phenyl),
[1319] --(CH.sub.2).sub.3NH(4-fluoro-phenyl),
[1320] --(CH.sub.2).sub.3N(methyl)(4-fluoro-phenyl),
[1321] --(CH.sub.2).sub.3C.sub.2(ethyl),
[1322] --(CH.sub.2).sub.3C(=O)N(methyl)(methoxy),
[1323] --(CH.sub.2).sub.3C(=O)NH(4-fluoro-phenyl),
[1324] --(CH.sub.2).sub.2NHC((=O)(phenyl),
[1325] --(CH.sub.2).sub.2NMeC(=O)(phenyl),
[1326] --(CH.sub.2).sub.2NHC(=O)(2-fluoro-phenyl),
[1327] --(CH.sub.2).sub.2NMeC(=O)(2-fluoro-phenyl),
[1328] --(CH.sub.2).sub.2NHC(=O)(4-fluoro-phenyl),
[1329] --(CH.sub.2).sub.2NMeC(=O)(4-fluoro-phenyl),
[1330] --(CH.sub.2).sub.2NHC(=O)(2,4-difluoro-phenyl),
[1331] --(CH.sub.2).sub.2NMeC(=O)(2,4-difluoro-phenyl),
[1332] --(CH.sub.2).sub.3(3-indolyl),
[1333] --(CH.sub.2).sub.3(1-methyl-3-indolyl),
[1334] --(CH.sub.2).sub.3(1-indolyl),
[1335] --(CH.sub.2).sub.3(1-indolinyl),
[1336] --(CH.sub.2).sub.3(1-benzimidazolyl),
[1337] --(CH.sub.2).sub.3(1H-1,2,3-benzotriazol-1-yl),
[1338] --(CH.sub.2).sub.3(1H-1,2,3-benzotriazol-2-yl),
[1339] --(CH.sub.2).sub.2(1H-1,2,3-benzotriazol-1-yl),
[1340] --(CH.sub.2).sub.2(1H-1,2,3-benzotriazbl-2-yl),
[1341] --(CH.sub.2).sub.3(3,4 dihydro-1(2H)-quinolinyl),
[1342] --(CH.sub.2).sub.2C(=O)(4-fluoro-phenyl),
[1343] --(CH.sub.2).sub.2C(=O)NH(4-fluoro-phenyl),
[1344] --CH.sub.2CH.sub.2(3-indolyl),
[1345] --CH.sub.2CH.sub.2(1-phthalimidyl),
[1346] --(CH.sub.2).sub.4 C(=O)N(methyl)(methoxy),
[1347] --(CH.sub.2).sub.4 CO.sub.2(ethyl),
[1348] --(CH.sub.2).sub.4 C(=O)(phenyl),
[1349] --(CH.sub.2).sub.4 (cyclohexyl),
[1350] --(CH.sub.2).sub.3CH(phenyl).sub.2,
[1351] --CH.sub.2CH.sub.2CH=C(phenyl).sub.2,
[1352] --CH.sub.2CH.sub.2CH=CMe(4-F-phenyl),
[1353] --(CH.sub.2).sub.3CH(4-fluoro-phenyl).sub.2,
[1354] --CH.sub.2CH.sub.2CH=C(4-fluoro-phenyl).sub.2,
[1355] --(CH.sub.2).sub.2(2,3-dihydro-1H-inden-2-yl),
[1356] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-phenyl),
[1357] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-5-F-phenyl),
[1358] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-F-phenyl),
[1359] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-3-F-phenyl),
[1360] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-Cl-phenyl),
[1361] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-OH-phenyl),
[1362] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-Br-phenyl),
[1363] --(CH.sub.2).sub.3(1H-indazol-3-yl),
[1364] --(CH.sub.2).sub.3(5-F-1H-indazol-3-yl),
[1365] --(CH.sub.2).sub.3(7-F-1H-indazol-3-yl),
[1366] --(CH.sub.2).sub.3(6-Cl-1H-indazol-3-yl),
[1367] --(CH.sub.2).sub.3(6-Br-1H-indazol-3-yl),
[1368] --(CH.sub.2).sub.3C(=O)(2-NHMe-phenyl),
[1369] --(CH.sub.2).sub.3(1-benzothien-3-yl),
[1370] --(CH.sub.2).sub.3(6-F-1H-indol-1-yl),
[1371] --(CH.sub.2).sub.3(5-F-1H-indol-1-yl),
[1372] --(CH.sub.2).sub.3(6-F-2,3-dihydro-1H-indol-1-yl),
[1373] --(CH.sub.2).sub.3(5-F-2,3-dihydro-1H-indol-1-yl),
[1374] --(CH.sub.2).sub.3(6-F-1H-indol-3-yl),
[1375] --(CH.sub.2).sub.3(5-F-1H-indol-3-yl),
[1376] --(CH.sub.2).sub.3(5-F-1H-indol-3-yl),
[1377] --(CH.sub.2).sub.3(9H-purin-9-yl),
[1378] --(CH.sub.2).sub.3(7H-purin-7-yl),
[1379] --(CH.sub.2).sub.3(6-F-1H-indazol-3-yl),
[1380] --(CH.sub.2).sub.3C(=O)(2-NHSO.sub.2Me-4-F-phenyl),
[1381] --(CH.sub.2).sub.3C(=O)(2-NHC(=O)Me-4-F-phenyl),
[1382] --(CH.sub.2).sub.3C(=O)(2-NHC(=O)Me-4-F-phenyl),
[1383] --(CH.sub.2).sub.3C(=O)(2-NHC.sub.2Et-4-F-phenyl),
[1384] --(CH.sub.2).sub.3C(=O)(2-NHC(=O)NHEt-4-F-phenyl),
[1385] --(CH.sub.2).sub.3C(=O)(2-NHCHO-4-F-phenyl),
[1386] --(CH.sub.2).sub.3C(=O)(2-OH-4-F-phenyl),
[1387] --(CH.sub.2).sub.3C(=O)(2-MeS-4-F-phenyl),
[1388] --(CH.sub.2).sub.3C(=O)(2-NHSO.sub.2Me-4-F-phenyl),
[1389] --(CH.sub.2).sub.2C(Me)CO.sub.2Me,
[1390] --(CH.sub.2).sub.2C(Me)CH(OH)(4-F-phenyl).sub.2,
[1391] --(CH.sub.2).sub.2C(Me)CH(OH)(4-Cl-phenyl).sub.2,
[1392] --(CH.sub.2).sub.2C(Me)C(=O)(4-F-phenyl),
[1393] --(CH.sub.2).sub.2C(Me)C(=O)(2-MeO-4-F-phenyl),
[1394] --(CH.sub.2).sub.2C(Me)C(=O)(3-Me-4-F-phenyl),
[1395] --(CH.sub.2).sub.2C(Me)C(=O)(2-Me-phenyl),
[1396] --(CH.sub.2).sub.2C(Me)C(=O)phenyl, 12
[1397] R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are
independently selected from hydrogen, fluoro, chloro, bromo, cyano,
methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro,
trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy,
methylC(=O)--, ethylC(=O)--, propylC(=O)--, isopropylC(=O)--,
methylC(=O)NH--, ethylC(=O)NH --, propylC(=O)NH--,
isopropylC(=O)NH, methylamino-, ethylamino-, propylamino-, and
isopropylamino-,
[1398] provided that two of substituents R.sup.7, R.sup.8, and
R.sup.9, are independently selected from hydrogen, fluoro, chloro,
methyl, trifluoromethyl, methoxy, and trifluoromethoxy;
[1399] m is 1 or 2; and
[1400] n is 0, 1 or 2.
[1401] [15] In a more preferred embodiment, the present invention
provides the method as defined in claim 1 where the compound
administered is selected from the group:
[1402]
(.+-.)-cis-9-(cyclopropylcarbonyl)-4,5,6a,7,8,9,10,10a-octahydropyr-
ido[4,3-b]pyrrolo[3,2,1-hi]indole;
[1403] (.+-.)-cis-9-isobutyryl-4, 5,
6a,7,8,9,10,10a-octahydropyrido[4,3-b-
]pyrrolo[3,2,1-hi]indole;
[1404] tert-butyl
(.+-.)-cis-2-(2-chlorophenyl)-4,5,7,8,10,10a-hexahydropy-
rido[4,3-b]pyrrolo[3, 2,1-hi]indole-9(6aH)-carboxylate;
[1405] tert-butyl
(.+-.)-cis-2-(2,4-dichlorophenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1406] tert-butyl
(.+-.)-cis-2-(3,4-dichlorophenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1407] tert-butyl
(.+-.)-cis-2-(2,3-dichlorophenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1408] tert-butyl
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-4,5,7,-
8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1409] tert-butyl (.+-.)
-cis-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a--
hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1410] tert-butyl
(.+-.)-cis-2-(5-isopropyl-2-methoxyphenyl)-4,5,7,8,10,10-
a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1411] tert-butyl
(.+-.)-cis-2-(3-fluorophenyl)-4,5,7,8,10,10a-hexahydropy-
rido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1412] tert-butyl
(.+-.)-cis-2-(2,4-dimethoxyphenyl)-4,5,7,8,10,10a-hexahy-
dropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1413]
(.+-.)-cis-2-(2-chlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4-
,3-b]pyrrolo[3,2,1-hi]indole;
[1414]
(.+-.)-cis-2-(2,4-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole;
[1415]
(.+-.)-cis-2-(3,4-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole;
[1416]
(.+-.)-cis-2-(2,3-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole;
[1417]
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,1-
0a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
[1418]
(.+-.)-cis-2-(2-chloro-4-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
[1419]
(.+-.)-cis-2-(4-isopropyl-2-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octa-
hydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
[1420]
(.+-.)-cis-2-(3-fluorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4-
,3-b]pyrrolo[3,2,1-hi]indole;
[1421]
(.+-.)-cis-2-(2,4-dimethoxyphenyl)-4,5,6a,7,8,9,10,10a-octahydropyr-
ido[4,3-b]pyrrolo[3,2,1-hi]indole;
[1422] tert-butyl
(.+-.)-cis-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]-
pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate;
[1423] tert-butyl
(.+-.)-cis-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyrido[3'-
,4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate;
[1424] tert-butyl
(.+-.)-cis-2-(2,3-dichlorophenyl)-5,6,8,9,11,11a-hexahyd-
ro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)
-carboxylate;
[1425] tert-butyl
(.+-.)-cis-2-(3,4-dichlorophenyl)-5,6,8,9,11,11a-hexahyd-
ro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate;
[1426] tert-butyl
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-5,6,8,-
9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)--
carboxylate;
[1427]
(.+-.)-cis-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1428]
(.+-.)-cis-2-(3,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1429]
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1430]
4-((.+-.)-cis-2-(2-chlorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-
-b]pyrrolo[3,2,1-hi]indol-9(6aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[1431]
4-((.+-.)-cis-2-(2,4-dichlorophenyl)-4,5,7,8,10,10a-hexahydropyrido-
[4,3-b]pyrrolo[3,2,1-hi]indol-9(6aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[1432]
4-((.+-.)-cis-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]qionolin-10(7aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[1433]
4-((.+-.)-cis-4,5,7,8,10,10a-hexahydropyrido[4.3-b]pyrrolo[3,2,1-hi-
]indol-9(6aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[1434]
(6aS,10aR)-2-(2-fluoro-4-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
[1435] tert-butyl
(6aS,10aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-4,5,7,-
8,10,10a-hexahydropyrido
[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate- ;
[1436]
(6aS,10aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,1-
0a-octahydropyrido [4,3-b]pyrrolo[3,2,1-hi]indole;
[1437] tert-butyl
(6aS,10aR)-2-(4-chloro-2-fluorophenyl)-4,5,7,8,10,10a-he-
xahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1438]
(6aS,10aR)-2-(4-chloro-2-fluorophenyl)-4,5,6a,7,8,9,10,10a-octahydr-
opyrido [4,3-b]pyrrolo[3,2,1-hi]indole;
[1439] tert-butyl
(6aS,10aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-4,-
5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxyl-
ate;
[1440]
(6aS,10aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,-
10,10a-octahydropyrido [4,3-b]pyrrolo[3,2,1-hi]indole;
[1441] tert-butyl
(6aS,10aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-4,5,7-
,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate-
;
[1442]
(6aS,10aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,-
10a-octahydropyrido [4,3-b]pyrrolo[3,2,1-hi]indole;
[1443] tert-butyl
(6aS,10aR)-2-phenyl-4,5,7,8,10,10a-hexahydropyrido[4,3-b-
]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1444] (6aS,10aR)-2-phenyl-4,5,6a,7,8,9,10,10a-octahydropyrido
[4,3-b]pyrrolo[3,2,1-hi]indole;
[1445] tert-butyl
(6aS,10aR)-2-(2-methylphenyl)-4,5,7,8,10,10a-hexahydropy-
rido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1446]
(6aS,10aR)-2-(2-methylphenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido
[4,3-b]pyrrolo[3,2,1-hi]indole;
[1447] tert-butyl
(6aS,10aR)-2-[2-(trifluoromethyl)phenyl]-4,5,7,8,10,10a--
hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1448]
(6aS,10aR)-2-[2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,10a-octahy-
dropyrido [4,3-b]pyrrolo[3,2,1-hi]indole;
[1449] tert-butyl
(6aS,10aR)-2-(3,4-dimethoxyphenyl)-4,5,7,8,10,10a-hexahy-
dropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1450]
(6aS,10aR)-2-(3,4-dimethoxyphenyl)-4,5,6a,7,8,9,10,10a-octahydropyr-
ido [4,3-b]pyrrolo[3,2,1-hi]indole;
[1451] tert-butyl
(6aS,10aR)-2-(2,5-dichlorophenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1452]
(6aS,10aR)-2-(2,5-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do [4,3-b]pyrrolo[3,2,1-hi]indole;
[1453] tert-butyl
(6aS,10aR)-2-(3,5-dichlorophenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1454]
(6aS,10aR)-2-(3,5-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do [4,3-b]pyrrolo[3,2,1-hi]indole;
[1455] tert-butyl
(6aS,10aR)-2-(2-isopropyl-4-methoxyphenyl)-4,5,7,8,10,10-
a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1456]
(6aS,10aR)-2-(2-isopropyl-4-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octa-
hydropyrido [4,3-b]pyrrolo[3,2,1-hi]indole;
[1457] tert-butyl
(6aS,10aR)-2-(5-fluoro-4-methoxy-2-methylphenyl)-4,5,7,8-
,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1458]
(6aS,10aR)-2-(5-fluoro-4-methoxy-2-methylphenyl)-4,5,6a,7,8,9,10,10-
a-octahydropyrido [4,3-b]pyrrolo[3,2,1-hi]indole;
[1459] tert-butyl
(6aS,10aR)-2-(4-methoxy-2-methylphenyl)-4,5,7,8,10,10a-h-
exahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1460]
(6aS,10aR)-2-(4-methoxy-2-methylphenyl)-4,5,6a,7,8,9,10,10a-octahyd-
ropyrido [4,3-b]pyrrolo[3,2,1-hi]indole;
[1461] tert-butyl
(6aS,10aR)-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a-h-
exahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1462]
(6aS,10aR)-2-(2-chloro-4-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octahyd-
ropyrido [4,3-b]pyrrolo[3,2,1-hi]indole;
[1463] tert-butyl
(6aS,10aR)-2-(3-chloro-2-methylphenyl)-4,5,7,8,10,10a-he-
xahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[1464]
(6aS,10aR)-2-(3-chloro-2-methylphenyl)-4,5,6a,7,8,9,10,10a-octahydr-
opyrido [4,3-b]pyrrolo[3,2,1-hi]indole;
[1465]
2-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2-
,1-hi]-2-yl]-5-methoxybenzaldehyde;
[1466]
(6aS,10aR)-2-(2,6-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole;
[1467]
N-[4-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[-
3,2,1-hi]indol-2-yl]-3-(trifluoromethyl)phenyl]-N-methylamine;
[1468]
4-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2-
,1-hi]indol-2-yl]-3-(trifluoromethyl)phenylamine;
[1469]
1-(2-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[-
3,2,1-hi]indol-2-yl]-5-methoxyphenyl)ethanol;
[1470] tert-butyl
(.+-.)-cis-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,-
2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate;
[1471] tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,8a,9,10,11,12,12a-deca-hydroa-
zepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate;
[1472]
(8aS,12aR)-2-(2,4-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1473]
(8aS,12aR)-2-(2,3-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1474]
(8aS,12aR)-2-(3,4-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1475]
(8aS,12aR)-2-(3,5-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1476]
(8aS,12aR)-2-(2,5-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1477]
(8aS,12aR)-2-(2,6-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1478]
(8aS,12aR)-2-(2-chlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indole;
[1479]
(8aS,12aR)-2-(3-chlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indole;
[1480]
(8aS,12aR)-2-(4-chlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indole;
[1481]
(.+-.)-cis-2-(2,6-difluorophenyl)-4,5,6,7,8a,9,;10,11,12,12a-decahy-
droazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1482]
(8aS,12aR)-2-(2,6-difluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1483]
(8aS,12aR)-2-(2,3-difluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1484]
(8aS,12aR)-2-(3,4-difluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1485]
(8aS,12aR)-2-(3-fluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indole;
[1486]
(8aS,12aR)-2-[2-chloro-4-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,1-
1,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1487]
(8aS,12aR)-2-(2-chloro-4-methoxyphenyl)-4,5,6,7,8a,9,10,11,12,12a-d-
ecahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1488]
(8aS,12aR)-2-(2-fluoro-4-methoxyphenyl)-4,5,6,7,8a,9,10,11,12,12a-d-
ecahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1489]
(8aS,12aR)-2-(4-methoxy-2-methylphenyl)-4,5,6,7,8a,9,10,11,12,12a-d-
ecahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1490]
(8aS,12aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,-
11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1491]
(8aS,12aR)-2-[2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a--
decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1492]
(8aS,12aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,-
10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1493]
(8aS,12aR)-2-[2,4-bis(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12-
,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1494]
(8aS,12aR)-2-[4-fluoro-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,1-
1,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[1495]
4-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]p-
yrido[4,3-b]indol-2-yl]-3-(trifluoromethyl)aniline;
[1496]
4-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]p-
yrido[4,3-b]indol-2-yl]-N-methyl-3-(trifluoromethyl)aniline;
[1497]
2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]p-
yrido[4,3-b]indol-2-yl]benzaldehyde;
[1498]
{2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]-
pyrido[4,3-b]indol-2-yl]phenyl}methanol;
[1499] 2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino
[3,2,1-hi]pyrido[4,3-b]indol-2-yl]-5-methoxybenzaldehyde;
[1500]
{2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]-
pyrido[4,3-b]indol-2-yl]-5-methoxyphenyl}methanol;
[1501]
4-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]p-
yrido[4,3-b]indol-2-yl]-3-methylbenzonitrile;
[1502]
1-{2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-h-
i]pyrido[4,3-b]indol-2-yl]-5-methoxyphenyl}ethanol;
[1503] tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro-4H-pyr-
ido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate;
[1504]
(7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1505]
(7aS,11aR)-2-(3,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1506]
(7aS,11aR)-2-(3,5-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1507]
(7aS,11aR)-2-(2,5-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1508]
(7aS,11aR)-2-(2,6-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1509]
(7aS,11aR)-2-(2-chlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyr-
ido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1510]
(7aS,11aR)-2-(3-chlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyr-
ido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1511]
(7aS,11aR)-2-(4-chlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyr-
ido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1512]
(7aS,11aR)-2-(2,6-difluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1513]
(7aS,11aR)-2-(2,6-difluorophenyl)-10-methyl-5,6,7a,8,9,10,11,11a-oc-
tahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1514]
(7aS,11aR)-2-(2,3-difluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1515]
(7aS,11aR)-2-(3,4-difluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1516]
(7aS,11aR),-2-(3-fluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-py-
rido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1517]
(7aS,11aR)-2-[2-chloro-4-methoxyphenyl)-5,6,7a,8,9,10,11,11a-octahy-
dro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1518]
(7aS,11aR)-2-[2-fluoro-4-methoxyphenyl)-5,6,7a,8,9,10,11,11a-octahy-
dro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1519]
(7aS,11aR)-2-(4-methoxy-2-methylphenyl)-5,6,7a,8,9,10,11,11a-octahy-
dro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1520]
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11-
,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1521]
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]py-
rrolo[3,2,1-ij]quinolin-2-yl]-3-(trifluoromethyl)phenol;
[1522]
(7aS,11aR)-2-[2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octah-
ydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1523]
(7aS,11aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10-
,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1524]
(7aS,11aR)-2-[2,4-bis(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a--
octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1525]
(7aS,11aR)-2-[4-fluoro-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1526]
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]py-
rrolo[3,2,1-ij]quinolin-2-yl]-3-(trifluoromethyl)aniline;
[1527]
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]py-
rrolo[3,2,1-ij]quinolin-2-yl]-N-methyl-3-(trifluoromethyl)aniline;
[1528]
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]py-
rrolo[3,2,1-ij]quinolin-2-yl]-3-methylbenzonitrile;
[1529]
2-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]py-
rrolo[3,2,1-ij]quinolin-2-yl]benzaldehyde;
[1530]
{2-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]p-
yrrolo[3,2,1-ij]quinolin-2-yl]phenyl}methanol;
[1531]
2-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]py-
rrolo[3,2,1-ij]quinolin-2-yl]-5-methoxybenzaldehyde;
[1532]
{2-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]p-
yrrolo[3,2,1-ij]quinolin-2-yl]-5-methoxyphenyl}methanol;
[1533]
(8aS,12aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,1-
1,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3b]indole;
[1534]
(7aS,11aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1535]
(8aS,12aR)-2-[3-chloro-2-methylphenyl]-4,5,6,7,8a,9,10,11,12,12a-de-
cahydroazepino[3,2,1-hi]pyrido[4,3b]indole;
[1536]
(7aS,11aR)-2-[3-chloro-2-methylphenyl]-5,6,7a,8,9,10,11,11a-octahyd-
ro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1537]
(7aS,11aR)-2-[5-fluoro-2-methylphenyl]-5,6,7a,8,9,10,11,11a-octahyd-
ro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1538] (.+-.)-cis-2-(2,
3-dichlorophenyl)-10-propyl-5,6,7a,8,9,10,11,11a-o-
ctahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline ;
[1539] (7aS,11aR)-2-(2,
3-dichlorophenyl)-10-propyl-5,6,7a,8,9,10,11,11a-o-
ctahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline ;
[1540]
(.+-.)-cis-10-butyl-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-oct-
ahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline ;
[1541]
(7aS,11aR)-10-butyl-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-oct-
ahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline ;
[1542]
(7aS,11aR)-2-(2,3-dichlorophenyl)-10-(4-pentenyl)-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[1543]
(7aS,11aR)-2-(2,3-dichlorophenyl)-10-(3-methyl-2-butenyl)-5,6,7a,8,-
9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[1544]
(7aS,11aR)-2-(2,4-dichlorophenyl)-10-propyl-5,6,7a,8,9,10,11,11a-oc-
tahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[1545]
(7aS,11aR)-10-butyl-2-(2,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-oct-
ahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[1546]
(7aS,11aR)-2-(2,4-dichlorophenyl)-10-(4-pentenyl)-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[1547]
(7aS,11aR)-2-(2,4-dichlorophenyl)-10-(3-methyl-2-butenyl)-5,6,7a,8,-
9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[1548]
(7aS,11aR)-10-(cyclobutylmethyl)-2-(2,3-dichlorophenyl)-5,6,7a,8,9,-
10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[1549]
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-methyl-5,6,7a-
,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1550]
(7aS,11aR)-10-ethyl-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,-
8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1551]
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-propyl-5,6,7a-
,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1552]
(7aS,11aR)-10-butyl-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-meth-
yl-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]qui-
noline;
[1553]
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-(4-pentenyl)--
5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinol-
ine;
[1554]
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-(3-methyl-2-b-
utenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-i-
j]quinoline;
[1555]
(7aS,11aR)-10-(2-fluoroethyl)-2-[4-methoxy-2-(trifluoromethyl)pheny-
l]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]qui-
noline ;
[1556]
(7aS,11aR)-10-(2,2-difluoroethyl)-2-[4-methoxy-2-(trifluoromethyl)p-
henyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij-
]quinoline;
[1557]
(7aS,11aR)-10-(cyclobutylmethyl)-2-[4-methoxy-2-(trifluoromethyl)ph-
enyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]-
quinoline;
[1558]
4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[1559]
4-((7aR,11aS)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[1560]
4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(2-aminophenyl)-1-butanone;
[1561]
4-((7aR,11aS)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(2-aminophenyl)-1-butanone;
[1562]
(.+-.)-cis-3-(5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)propyl 4-fluorophenyl ether;
[1563]
4-((.+-.)-cis-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(4-pyridinyl)-1-butanone;
[1564]
(.+-.)-cis-10-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-5,6,7a,8,9-
,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1565]
(7aS,11aR)-10-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-5,6,7a,8,9-
,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[1566]
(.+-.)-cis-4-(4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[-
4,3-b]indol-11(8aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[1567]
4-((8aS,12aR)-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[-
4,3-b]indol-11(8aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[1568]
4-((8aR,12aS)-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[-
4,3-b]indol-11(8aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[1569]
4-((.+-.)-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3--
b]indol-11(8aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone;
[1570]
4-((.+-.)-cis-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone;
[1571]
4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone;
and
[1572]
4-((7aR,11aS)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone.
[16]In a more preferred embodiment, the present invention provides
the method as defined in claim 1 where the compound administered is
selected from the group:
[1573]
4-[(.+-.)-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':4,5]p-
yrrolo [3,2,1-ij]quinolin-10-yl]-1-(4-fluorophenyl)-1-butanone;
[1574]
4-[(.+-.)-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':4,5]p-
yrrolo
[3,2,1-ij]quinolin-10-yl]-1-(2-amino-4-fluorophenyl)-1-butanone;
[1575]
4-[(.+-.)-4,5,6,7,9,10,11,12,13,13a-decahydro-11H-diazepino[4,5-b:3-
,2,1-hi]indol-11-yl]-1-(4-fluorophenyl)-1-butanone;
[1576]
4-[(.+-.)-4,5,6,7,9,10,11,12,13,13a-decahydro-11H-diazepino[4,5-b:3-
,2,1-hi]indol-11-yl]-1-(2-amino-4-fluorophenyl)-1-butanone;
[1577] tert-butyl (.+-.)-cis-5,
6,8,9,10,11,12,12a-octahydro-4H,7aH-azepin-
o[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-11-carboxylate;
[1578] tert-butyl
(.+-.)-cis-2-bromo-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-
-azepino[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-l1-carboxylate;
and
[1579]
(.+-.)-cis-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,8,9,10,11,12-
,12a-octahydro-4H,7aH-azepino[3',4':4,5]pyrrolo[3,2,1-ij]quinoline.
[1580] [17]In a more preferred embodiment, the present invention
provides the method as defined in claim 1 where the compound
administered is selected from the group:
[1581] tert-butyl
(.+-.)-cis-2-bromo-4-oxo-4,5,6,7,9,10,12,12a-octahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate;
[1582] tert-butyl
(.+-.)-cis-2-(2,4-dichlorophenyl)-4-oxo-4,5,6,7,9,10,12,-
12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate;
[1583] (.+-.)-cis-2-(2,
4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydroa- zepino
[3,2,1-hi]pyrido[4,3-b]indol-4(5H)-one;
[1584]
(8aS,12aR)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indol-4(5H)-one;
[1585]
(8aR,12aS)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indol-4(5H)-one;
[1586]
(8aS,12aR)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indol-4-ol; and
[1587]
(8aR,12aS)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indol-4-ol.
[1588] [18]Thus, in a second embodiment, the present invention
provides a method for treating a human suffering from sleep
disorders associated with 5HT2A receptor modulation, comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of formula (I): 13
[1589] or stereoisomers or pharmaceutically acceptable salt forms
thereof, wherein:
[1590] b is a single bond;
[1591] X is --CHR.sup.10-- or --C(=O)--;
[1592] R.sup.1 is selected from
[1593] H,
[1594] C (=O)R.sup.2,
[1595] C (=O)OR.sup.2,
[1596] C.sub.1-8 alkyl,
[1597] C.sub.2-8 alkenyl,
[1598] C.sub.2-8 alkynyl,
[1599] C.sub.3-7 cycloalkyl,
[1600] C.sub.1-6 alkyl substituted with Z,
[1601] C.sub.2-6 alkenyl substituted with Z,
[1602] C.sub.2-6 alkynyl substituted with Z.
[1603] C.sub.3-6 cycloalkyl substituted with Z, aryl substituted
with Z,
[1604] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with Z;
[1605] C.sub.1-3 alkyl substituted with Y,
[1606] C.sub.2-3 alkenyl substituted with Y,
[1607] C.sub.2-3 alkynyl substituted with Y,
[1608] C.sub.1-6 alkyl substituted with 0-2 R.sup.2,
[1609] C.sub.2-6 alkenyl substituted with 0-2 R.sup.2,
[1610] C.sub.2-6 alkynyl substituted with 0-2 R.sup.2,
[1611] aryl substituted with 0-2 R.sup.2, and
[1612] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with 0-2 R.sup.2;
[1613] Y is selected from
[1614] C.sub.3-6 cycloalkyl substituted with Z,
[1615] aryl substituted with Z,
[1616] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with z;
[1617] C.sub.3-6 cycloalkyl substituted with --(C.sub.1-3
alkyl)--Z,
[1618] aryl substituted with --(C.sub.1-3 alkyl)--Z, and
[1619] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with --(C.sub.1-3
alkyl)--Z;
[1620] Z is selected from H,
[1621] --CH (OH) R.sup.2,
[1622] --C(ethylenedioxy)R.sup.2,
[1623] --OR.sup.2,
[1624] --SR.sup.2,
[1625] --NR.sup.2R.sup.3,
[1626] --C(O)R.sup.2,
[1627] --C (O)NR.sup.2R.sup.3,
[1628] --NR.sup.3C (O) R.sup.2,
[1629] --C(O)OR.sup.2,
[1630] --OC (O) R.sup.2,
[1631] --CH (=NR.sup.4)NR.sup.2R.sup.3,
[1632] --NHC (=NR.sup.4)NR.sup.2R.sup.3,
[1633] --S(O) R.sup.2,
[1634] --S(O).sub.2R.sup.2,
[1635] --S(O).sub.2NR.sup.2R.sup.3, and
--NR.sup.3S(O).sub.2R.sup.2;
[1636] R.sup.2, at each occurrence, is independently selected
from
[1637] halo,
[1638] C.sub.1-3 haloalkyl,
[1639] C.sub.1-4 alkyl,
[1640] C.sub.2-4 alkenyl,
[1641] C.sub.2-4 alkynyl,
[1642] C.sub.3-6 cycloalkyl,
[1643] aryl substituted with 0-5 R.sup.42;
[1644] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.41,
and
[1645] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.41;
[1646] R.sup.3, at each occurrence, is independently selected
from
[1647] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
and
[1648] C.sub.1-4 alkoxy;
[1649] alternatively, R.sup.2 and R.sup.3 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.4)--;
[1650] R.sup.4, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[1651] R.sup.5 is H or C.sub.1-4 alkyl;
[1652] R.sup.6a and R.sup.6b, at each occurrence, are independently
selected from
[1653] H, --OH, --NR.sup.46R.sup.47, --CF.sub.3, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4
[1654] alkynyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.3-6
cycloalkyl, and
[1655] aryl substituted with 0-3 R.sup.44;
[1656] R.sup.7 and R.sup.9, at each occurrence, are independently
selected from
[1657] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN, --NO.sub.2,
--NR.sup.46R.sup.47,
[1658] C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[1659] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[1660] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[1661] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[1662] aryl substituted with 0-5 R.sup.33,
[1663] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[1664] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
[1665] NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12,
[1666] CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12,
[1667] S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup- .13, NR.sup.14S(O)R.sup.12
[1668] NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)R.sup.15, NR.sup.12S(O).sub.2R.sup.15,
[1669] and NR.sup.12C(O)NHR.sup.15;
[1670] R.sup.8 is selected from
[1671] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2,
[1672] C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[1673] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[1674] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[1675] C.sub.2-4 alkenyl substituted with 0-2 R.sup.11,
[1676] C.sub.2-4 alkynyl substituted with 0-1 R.sup.11,
[1677] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[1678] aryl substituted with 0-5 R.sup.33,
[1679] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[1680] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
[1681] NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12,
[1682] CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12,
[1683] S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup- .13, NR.sup.14S(O)R.sup.12
[1684] NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15,
[1685] and NR.sup.12C(O)NHR.sup.15;
[1686] R.sup.10 is selected from H, --OH,
[1687] C.sub.1-6 alkyl substituted with 0-1 R.sup.10B,
[1688] C.sub.2-6 alkenyl substituted with 0-1 R.sup.10B,
[1689] C.sub.2-6 alkynyl substituted with 0-1 R.sup.10B, and
[1690] C.sub.1-6 alkoxy;
[1691] R.sup.10B is selected from
[1692] C.sub.1-4 alkoxy,
[1693] C.sub.3-6 cycloalkyl,
[1694] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[1695] phenyl substituted with 0-3 R.sup.33, and
[1696] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R.sup.44;
[1697] R.sup.11 is selected from
[1698] H, halo, --CF.sub.3, --CN, --NO.sub.2,
[1699] C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, C.sub.3-10 cycloalkyl,
[1700] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[1701] aryl substituted with 0-5 R.sup.33,
[1702] 5-10- membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[1703] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
[1704] NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12,
[1705] CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12,
[1706] S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup- .13, NR.sup.14S(O)R.sup.12,
[1707] NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(Q).sub.2R.sup.15,
[1708] and NR.sup.12C(O)NHR.sup.15;
[1709] R.sup.12, at each occurrence, is independently selected
from
[1710] C.sub.1-4 alkyl substituted with 0-1 R.sup.12a,
[1711] C.sub.2-4 alkenyl substituted with 0-1 R.sup.12a,
[1712] C.sub.2-4 alkynyl substituted with 0-1 R.sup.12a,
[1713] C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.33,
[1714] phenyl substituted with 0-5 R.sup.33;
[1715] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[1716] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[1717] R.sup.12a, at each occurrence, is independently selected
from phenyl substituted with 0-5 R.sup.33;
[1718] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[1719] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[1720] R.sup.13, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl;
[1721] alternatively, R.sup.12 and R.sup.13 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.14)--;
[1722] alternatively, R.sup.12 and R.sup.13 when attached to N may
be combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S, wherein said bicyclic heterocyclic ring
system is unsaturated or partially saturated, wherein said bicyclic
heterocyclic ring system is substituted with 0-3 R.sup.16;
[1723] R.sup.14, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[1724] R.sup.15, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl;
[1725] R.sup.16, at each occurrence, is independently selected
from
[1726] H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H,
[1727] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl,
[1728] C.sub.1-3 haloalkyl-oxy-, and C.sub.1-3 alkyloxy-;
[1729] R.sup.31, at each occurrence, is independently selected
from
[1730] H, OH, halo, CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47,
and C.sub.1-4 alkyl;
[1731] R.sup.33, at each occurrence, is independently selected
from
[1732] H, OH, halo, CN, NO2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H,
[1733] C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
[1734] C.sub.3-6 cycloalkyl, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkyl-oxy-,
[1735] C.sub.1-4 alkyloxy-,
[1736] C.sub.1-4 alkylthio-, C.sub.1-4 alkyl-C(=O)--, C.sub.1-4
alkyl-C(=O)NH--, C.sub.1-4 alkyl-OC(=O)--,
[1737] C.sub.1-4 alkyl-C(=O)O--, C.sub.3-6 cycloalkyl-oxy-,
C.sub.3-6 cycloalkylmethyl-oxy-;
[1738] C.sub.1-6 alkyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy; and
[1739] C.sub.2-6 alkenyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy;
[1740] R.sup.41, at each occurrence, is independently selected
from
[1741] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, =O;
[1742] C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl
[1743] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[1744] aryl substituted with 0-3 R.sup.42, and
[1745] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[1746] R.sup.42, at each occurrence, is independently selected
from
[1747] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
SOR.sup.45, SR.sup.45, NR.sup.46SO.sub.2R.sup.45,
NR.sup.46COR.sup.45, NR.sup.46R.sup.47 NO.sub.2 CN CH(=NH)NH.sub.2,
NHC(=NH)NH.sub.2,
[1748] C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl,
[1749] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[1750] aryl substituted with 0-3 R.sup.44, and
[1751] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[1752] R.sup.43 is C.sub.3-6 cycloalkyl or aryl substituted with
0-3 R.sup.44;
[1753] R.sup.44, at each occurrence, is independently selected from
H, halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, and
C.sub.1-4 alkoxy;
[1754] R.sup.45 is C.sub.1-4 alkyl;
[1755] R.sup.46, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[1756] R.sup.47, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --C(=O)NH(C.sub.1-4 alkyl),
--SO.sub.2(C.sub.1-4 alkyl), --C(=O)O(C.sub.1-4 alkyl), --C(=O)(
C.sub.1-4 alkyl), and --C(=O)H;
[1757] k is 1 or 2;
[1758] m is 0, 1, or 2;
[1759] n is 0, 1, 2, or 3;
[1760] provided when m is 0 or 1 then k is 1 or 2;
[1761] provided when m is 2 then k is 1;
[1762] provided that when R.sup.6 or R.sup.6a is NH.sub.2, then X
is not --CH(R.sup.10); and
[1763] provided that when n=0, then R.sup.6 or R.sup.6a is not
NH.sub.2 or --OH.
[1764] [19] In a preferred embodiment, the present invention
provides the method as defined in claim 18 where in the compound
administered:
[1765] X is --CHR.sup.10-- or --C(=O)--;
[1766] R.sup.1 is selected from
[1767] H,
[1768] C(=O)R.sup.2,
[1769] C(=O)OR.sup.2,
[1770] C.sub.1-8 alkyl,
[1771] C.sub.2-8 alkenyl,
[1772] C.sub.2-8 alkynyl,
[1773] C.sub.3-7 cycloalkyl,
[1774] C.sub.1-6 alkyl substituted with 0-2 R.sup.2,
[1775] C.sub.2-6 alkenyl substituted with 0-2 R.sup.2,
[1776] C.sub.2-6 alkynyl substituted with 0-2 R.sup.2,
[1777] aryl substituted with 0-2 R.sup.2, and
[1778] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with 0-2 R.sup.2;
[1779] R.sup.2, at each occurrence, is independently selected
from
[1780] F, Cl, CH.sub.2F, CHF.sub.2, CF.sub.3,
[1781] C.sub.1-4 alkyl,
[1782] C.sub.2-4 alkenyl,
[1783] C.sub.2-4 alkynyl,
[1784] C.sub.3-6 cycloalkyl,
[1785] phenyl substituted with 0-5 R.sup.42;
[1786] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.41,
and
[1787] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.41;
[1788] R.sup.5 is H, methyl, ethyl, propyl, or butyl;
[1789] R.sup.6a is selected from
[1790] H, --OH, --NR.sup.46R.sup.47, --CF.sub.3,
[1791] C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
and
[1792] aryl substituted with 0-3 R.sup.44;
[1793] R.sup.6b is H;
[1794] R.sup.7 and R.sup.9, at each occurrence, are independently
selected from
[1795] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2,--NR.sup.46R.sup.47,
[1796] C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[1797] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[1798] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[1799] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[1800] aryl substituted with 0-5 R.sup.33,
[1801] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[1802] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
[1803] NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12,
[1804] CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12,
[1805] S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup- .13, NR.sup.14S(O)R.sup.12,
[1806] NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)R.sup.15, NR.sup.12S(O).sub.2R.sup.15,
[1807] and NR.sup.12C(O)NHR.sup.15,
[1808] R.sup.8 is selected from
[1809] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2,
[1810] C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[1811] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[1812] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[1813] C.sub.2-4 alkenyl substituted with 0-2 R.sup.11,
[1814] C.sub.2-4 alkynyl substituted with 0-1 R.sup.11,
[1815] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[1816] aryl substituted with 0-5 R.sup.33,
[1817] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[1818] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
[1819] NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)0OR.sup.12,
[1820] CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12,
[1821] S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup- .13, NR.sup.14S(O)R.sup.12,
[1822] NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15, and
NR.sup.12C(O)NHR.sup.15;
[1823] R.sup.10 is selected from H, --OH,
[1824] C.sub.1-6 alkyl substituted with 0-1 R.sup.10B,
[1825] C.sub.2-6 alkenyl substituted with 0-1 R.sup.10B,
[1826] C.sub.2-6 alkynyl substituted with 0-1 R.sup.10B, and
[1827] C.sub.1-6 alkoxy;
[1828] R.sup.10B is selected from
[1829] C.sub.1-4 alkoxy,
[1830] C.sub.3-6 cycloalkyl,
[1831] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[1832] phenyl substituted with 0-3 R.sup.33, and
[1833] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R.sup.44;
[1834] R.sup.11 is selected from
[1835] H, halo, --CF.sub.3, --CN, --NO.sub.2,
[1836] C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, C.sub.3-10 cycloalkyl,
[1837] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[1838] aryl substituted with 0-5 R.sup.33,
[1839] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[1840] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
[1841] NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12,
[1842] CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12,
[1843] S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup- .13, NR.sup.14S(O)R.sup.12
[1844] NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15,
[1845] and NR.sup.12C(O)NHR.sup.15;
[1846] R.sup.12, at each occurrence, is independently selected
from
[1847] C.sub.1-4 alkyl substituted with 0-1 R.sup.12a,
[1848] C.sub.2-4 alkenyl substituted with 0-1 R.sup.12a,
[1849] C.sub.2-4 alkynyl substituted with 0-1 R.sup.12a,
[1850] C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.33,
[1851] phenyl substituted with 0-5 R.sup.33;
[1852] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[1853] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[1854] R.sup.12a, at each occurrence, is independently selected
from
[1855] phenyl substituted with 0-5 R.sup.33;
[1856] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[1857] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[1858] R.sup.13, at each occurrence, is independently selected
from
[1859] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[1860] alternatively, R.sup.12 and R.sup.13 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.14)--;
[1861] alternatively, R.sup.12 and R.sup.13 when attached to N may
be combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S, wherein said bicyclic heterocyclic ring
system is unsaturated or partially saturated, wherein said bicyclic
heterocyclic ring system is substituted with 0-3 R.sup.16;
[1862] R.sup.14, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[1863] R.sup.15, at each occurrence, is independently selected
from
[1864] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[1865] R.sup.16, at each occurrence, is independently selected
from
[1866] H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H,
[1867] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl,
[1868] C.sub.1-3 haloalkyl-oxy-, and C.sub.1-3 alkyloxy-;
[1869] R.sup.31, at each occurrence, is independently selected
from
[1870] H, OH, halo, CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47,
and C.sub.1-4 alkyl;
[1871] R.sup.33, at each occurrence, is independently selected
from
[1872] H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H,
[1873] C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
[1874] C.sub.3-6 cycloalkyl, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkyl-oxy-,
[1875] C.sub.1-4 alkyloxy-,
[1876] C.sub.1-4 alkylthio-, C.sub.1-4 alkyl-C(=O)--, C.sub.1-4
alkyl-C(=O)NH--,
[1877] C.sub.1-4 alkyl-OC(=O)--,
[1878] C.sub.1-4 alkyl-C(=O)O--, C.sub.3-6 cycloalkyl-oxy-,
C.sub.3-6 cycloalkylmethyl-oxy-;
[1879] C.sub.1-6 alkyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy; and
[1880] C.sub.2-6 alkenyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy;
[1881] R.sup.41, at each occurrence, is independently selected
from
[1882] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN;
[1883] C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl
[1884] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[1885] aryl substituted with 0-3 R.sup.42, and
[1886] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[1887] R.sup.42, at each occurrence, is independently selected
from
[1888] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, CH(=NH)NH.sub.2,
NHC(=NH)NH.sub.2,
[1889] C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl,
[1890] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[1891] aryl substituted with 0-3 R.sup.44, and
[1892] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[1893] R.sup.43 is C.sub.3-6 cycloalkyl or aryl substituted with
0-3 R.sup.44;
[1894] R.sup.44, at each occurrence, is independently selected from
H, halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, and
C.sub.1-4 alkoxy;
[1895] R.sup.45 is C.sub.1-4 alkyl;
[1896] R.sup.46, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[1897] R.sup.47, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[1898] k is 1 or 2;
[1899] m is 0, 1, or 2; and
[1900] n is 0, 1, 2, or 3.
[1901] [20]In a more preferred embodiment, the present invention
provides the method as defined in claim 19 where in the compound
administered:
[1902] X is --CHR.sup.10--;
[1903] R.sup.1 is selected from
[1904] H,
[1905] C(=O)R.sup.2,
[1906] C(=O)OR.sup.2,
[1907] C.sub.1-6 alkyl,
[1908] C.sub.2-6 alkenyl,
[1909] C.sub.2-6 alkynyl,
[1910] C.sub.3-6 cycloalkyl,
[1911] C.sub.1-4 alkyl substituted with 0-2 R.sup.2,
[1912] C.sub.2-4 alkenyl substituted with 0-2 R.sup.2, and
[1913] C.sub.2-4 alkynyl substituted with 0-2 R.sup.2;
[1914] R.sup.2, at each occurrence, is independently selected
from
[1915] C.sub.1-4 alkyl,
[1916] C.sub.2-4 alkenyl,
[1917] C.sub.2-4 alkynyl,
[1918] C.sub.3-6 cycloalkyl,
[1919] phenyl substituted with 0-5 R.sup.42;
[1920] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.41,
and
[1921] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.41;
[1922] R.sup.5 is H, methyl, ethyl, propyl, or butyl;
[1923] R.sup.6a is selected independently from
[1924] H, --OH, --NR.sup.46R.sup.47, --CF.sub.3, C.sub.1-3 alkyl,
and C.sub.1-3 alkoxy;
[1925] R.sup.6b is H;
[1926] R.sup.7 and R.sup.9, at each occurrence, are independently
selected from
[1927] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2,--NR.sup.46R.sup.47,
[1928] C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[1929] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[1930] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[1931] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[1932] aryl substituted with 0-5 R.sup.33,
[1933] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[1934] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12,
C(O)OR.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12,
CH(=NR.sup.14)NR.sup.12R.sup.13, NHC(=NR.sup.14)NR.sup.12R.sup.13,
S(O)R.sup.12, S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup.13, NR.sup.14S(O)R.sup.12, and
NR.sup.14S(O).sub.2R.sup.12;
[1935] R.sup.8 is selected from
[1936] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2,
[1937] C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[1938] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[1939] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[1940] C.sub.2-4 alkenyl substituted with 0-2 R.sup.11,
[1941] C.sub.2-4 alkynyl substituted with 0-1 R.sup.11,
[1942] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[1943] aryl substituted with 0-5 R.sup.33,
[1944] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[1945] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
[1946] NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12,
[1947] CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12,
[1948] S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup- .13, NR.sup.14S(O)R.sup.12,
[1949] NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)R.sup.15, NR.sup.12S(O).sub.2R.sup.15,
[1950] and NR.sup.12C(O)NHR.sup.15;
[1951] R.sup.10 is selected from H, --OH,
[1952] C.sub.1-6 alkyl substituted with 0-1 R.sup.10B,
[1953] C.sub.2-6 alkenyl substituted with 0-1 R.sup.10B,
[1954] C.sub.2-6 alkynyl substituted with 0-1 R.sup.10B, and
[1955] C.sub.1-6 alkoxy;
[1956] R.sup.10B is selected from
[1957] C.sub.1-4 alkoxy,
[1958] C.sub.3-6 cycloalkyl,
[1959] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[1960] phenyl substituted with 0-3 R.sup.33, and
[1961] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R.sup.44;
[1962] R.sup.11 is selected from
[1963] H, halo, --CF.sub.3, --CN, --NO.sub.2, C.sub.1-6 alkyl,
[1964] C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl,
C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl,
[1965] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[1966] aryl substituted with 0-5 R.sup.33,
[1967] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[1968] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12,
C(O)OR.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12,
CH(=NR.sup.14)NR.sup.12R.sup.13, NHC(=NR.sup.14)NR.sup.12R.sup.13,
S(O)R.sup.12 S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup.13, NR.sup.14S(O)R.sup.12, and
NR.sup.14S(O).sub.2R.sup.12;
[1969] R.sup.12, at each occurrence, is independently selected
from
[1970] C.sub.1-4 alkyl substituted with 0-1 R.sup.12a,
[1971] C.sub.2-4 alkenyl substituted with 0-1 R.sup.12a,
[1972] C.sub.2-4 alkynyl substituted with 0-1 R.sup.12a,
[1973] C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.33, phenyl
substituted with 0-5 R.sup.33;
[1974] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[1975] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[1976] R.sup.12a, at each occurrence, is independently selected
from
[1977] phenyl substituted with 0-5 R.sup.33;
[1978] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[1979] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[1980] R.sup.13.sub.4 at each occurrence, is independently selected
from
[1981] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[1982] alternatively, R.sup.12 and R.sup.13 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.14)--;
[1983] alternatively, R.sup.12 and R.sup.13 when attached to N may
be combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S, wherein said bicyclic heterocyclic ring
system is unsaturated or partially saturated, wherein said bicyclic
heterocyclic ring system is substituted with 0-3 R.sup.16;
[1984] R.sup.14, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[1985] R.sup.15, at each occurrence, is independently selected
from
[1986] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[1987] R.sup.16, at each occurrence, is independently selected
from
[1988] H, OH, F, Cl, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H, methyl, ethyl, methoxy, ethoxy,
trifluoromethyl, and trifluoromethoxy;
[1989] R.sup.31, at each occurrence, is independently selected
from
[1990] H, OH, halo, CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47,
and C.sub.1-4 alkyl;
[1991] R.sup.33, at each occurrence, is independently selected
from
[1992] H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H,
[1993] C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
[1994] C.sub.3-6 cycloalkyl, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkyl-oxy-,
[1995] C.sub.1-4 alkyloxy-,
[1996] C.sub.1-4 alkylthio-, C.sub.1-4 alkyl-C(=O)--, C.sub.1-4
alkyl-C(=O)NH--, C.sub.1-4 alkyl-OC(=O)--,
[1997] C.sub.1-4 alkyl-C(=O)O--, C.sub.3-6 cycloalkyl-oxy-,
C.sub.3-6 cycloalkylmethyl-oxy-;
[1998] C.sub.1-6 alkyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy; and
[1999] C.sub.2-6 alkenyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy;
[2000] R.sup.41, at each occurrence, is independently selected
from
[2001] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN,
[2002] C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl
[2003] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[2004] aryl substituted with 0-3 R.sup.42, and
[2005] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[2006] R.sup.42, at each occurrence, is independently selected
from
[2007] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, CH(=NH)NH.sub.2,
NHC(=NH)NH.sub.2,
[2008] C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl,
[2009] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[2010] aryl substituted with 0-3 R.sup.44, and
[2011] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[2012] R.sup.43 is C.sub.3-6 cycloalkyl or aryl substituted with
0-3 R.sup.44;
[2013] R.sup.44, at each occurrence, is independently selected from
H, halo, --OH, NR.sup.46R.sup.47, CO2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, and
C.sub.1-4 alkoxy;
[2014] R.sup.45 is C.sub.1-4 alkyl;
[2015] R.sup.46, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[2016] R.sup.47, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[2017] k is 1 or 2;
[2018] m is 0 or 1; and
[2019] n is 0, 1 or 2.
[2020] [21] In a more preferred embodiment, the present invention
provides the method as defined in claim 19 where in the compound
administered:
[2021] X is --CH.sub.2--;
[2022] R.sup.1 is selected from
[2023] H,
[2024] C.sub.1-4 alkyl,
[2025] C.sub.2-4 alkenyl,
[2026] C.sub.2-4 alkynyl,
[2027] C.sub.3-4 cycloalkyl,
[2028] C.sub.1-3 alkyl substituted with 0-1 R.sup.2,
[2029] C.sub.2-3 alkenyl substituted with 0-1 R.sup.2, and
[2030] C.sub.2-3 alkynyl substituted with 0-1 R.sup.2;
[2031] R.sup.2, at each occurrence, is independently selected
from
[2032] C.sub.1-4 alkyl,
[2033] C.sub.2-4 alkenyl,
[2034] C.sub.2-4 alkynyl,
[2035] C.sub.3-6 cycloalkyl,
[2036] phenyl substituted with 0-5 R.sup.42;
[2037] C.sub.3-6 carbocyclic group substituted with 0-3 R.sup.41,
and
[2038] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.41;
[2039] R.sup.5 is H, methyl, ethyl, propyl, or butyl;
[2040] R.sup.6a is H, methyl, ethyl, methoxy, --OH, or
--CF.sub.3;
[2041] R.sup.6b is H;
[2042] R.sup.7 and R.sup.9, at each occurrence, are independently
selected from
[2043] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2,--NR.sup.46R.sup.47,
[2044] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[2045] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[2046] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[2047] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[2048] aryl substituted with 0-5 R.sup.33, and
[2049] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[2050] R.sup.8 is selected from
[2051] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2,
[2052] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[2053] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[2054] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[2055] C.sub.2-4 alkenyl substituted with 0-2 R.sup.11,
[2056] C.sub.2-4 alkynyl substituted with 0-1 R.sup.11,
[2057] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[2058] aryl substituted with 0-5 R.sup.33,
[2059] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[2060] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15;
[2061] R.sup.11 is selected from
[2062] H, halo, --CF.sub.3, --CN, --NO.sub.2,
[2063] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[2064] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[2065] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[2066] aryl substituted with 0-5 R.sup.33, and
[2067] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[2068] R.sup.12, at each occurrence, is independently selected
from
[2069] C.sub.1-4 alkyl substituted with 0-1 R.sup.12a,
[2070] C.sub.2-4 alkenyl substituted with 0-1 R.sup.12a,
[2071] C.sub.2-4 alkynyl substituted with 0-1 R.sup.12a,
[2072] C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.33,
[2073] phenyl substituted with 0-5 R.sup.33;
[2074] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[2075] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[2076] R.sup.12a, at each occurrence, is independently selected
from phenyl substituted with 0-5 R.sup.33;
[2077] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[2078] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[2079] R.sup.13, at each occurrence, is independently selected
from
[2080] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[2081] alternatively, R.sup.12 and R.sup.13 join to form a 5- or
6-membered ring optionally substituted with --O-- or
-N(R.sup.14)-;
[2082] alternatively, R.sup.12 and R.sup.13 when attached to N may
be combined to form a 9- or 10-membered bidyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of one N, two N, three N, one N one O, and one N one S;
wherein said bicyclic heterocyclic ring system is unsaturated or
partially saturated, wherein said bicyclic heterocyclic ring system
is substituted with 0-2 R.sup.16;
[2083] R.sup.14, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[2084] R.sup.15, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[2085] R.sup.16, at each occurrence, is independently selected from
H, OH, F, Cl, CN, NO.sub.2, methyl, ethyl, methoxy, ethoxy,
trifluoromethyl, and trifluoromethoxy;
[2086] R.sup.31, at each occurrence, is independently selected from
H, OH, halo, CF.sub.3, methyl, ethyl, and propyl;
[2087] R.sup.33, at each occurrence, is independently selected
from
[2088] H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H,
[2089] C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
[2090] C.sub.3-6 cycloalkyl, C.sub.1-4 haloalkyl, Cl-.sub.4
haloalkyl-oxy-,
[2091] C.sub.1-4 alkyloxy-,
[2092] C.sub.1-4 alkylthio-, C.sub.1-4 alkyl-C(=O)--, C.sub.14
alkyl-C(=O)NH--, C.sub.1-4 alkyl-OC(=O)--,
[2093] C.sub.1-4 alkyl-C(=O)O--, C.sub.3-6 cycloalkyl-oxy-,
C.sub.3-6 cycloalkylmethyl-oxy-;
[2094] C.sub.1-6 alkyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy; and
[2095] C.sub.2-6 alkenyl substituted with OH, methoxy, ethoxy,
propoxy, or butoxy;
[2096] R.sup.41, at each occurrence, is independently selected
from
[2097] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN,
[2098] C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy,
C.sub.1-3 haloalkyl, and C.sub.1-3 alkyl;
[2099] R.sup.42, at each occurrence, is independently selected
from
[2100] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, CH(=NH)NH.sub.2,
NHC(=NH)NH.sub.2,
[2101] C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy,
C.sub.1-3 haloalkyl, C.sub.3-6 cycloalkyl, and C.sub.1-3 alkyl;
[2102] R.sup.43 is cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, phenyl, or pyridyl, each substituted with 0-3
R.sup.44;
[2103] R.sup.44, at each occurrence, is independently selected from
H, halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy, and butoxy;
[2104] R.sup.45 is methyl, ethyl, propyl, or butyl;
[2105] R.sup.46, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[2106] R.sup.47, at each occurrence, is independently selected from
from H, methyl, ethyl, propyl, and butyl;
[2107] k is 1;
[2108] m is 1; and
[2109] n is 0, 1 or 2.
[2110] [22] In a more preferred embodiment, the present invention
provides the method as defined in claim 19 where in the compound
administered:
[2111] X is --CH.sub.2--;
[2112] R.sup.1 is selected from
[2113] H,
[2114] C.sub.1-4 alkyl,
[2115] C.sub.2-4 alkenyl,
[2116] C.sub.2-4 alkynyl,
[2117] C.sub.3-4 cycloalkyl,
[2118] C.sub.1-3 alkyl substituted with 0-1 R.sup.2,
[2119] C.sub.2 3 alkenyl substituted with 0-1 R.sup.2, and
[2120] C.sub.2-3 alkynyl substituted with 0-1 R.sup.2;
[2121] R.sup.2, at each occurrence, is independently selected
from
[2122] C.sub.1-4 alkyl,
[2123] C.sub.2-4 alkenyl,
[2124] C.sub.2-4 alkynyl,
[2125] C.sub.3-6 cycloalkyl,
[2126] phenyl substituted with 0-5 R.sup.42;
[2127] C.sub.3-6 carbocyclic group substituted with 0-3 R.sup.41,
and
[2128] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.41;
[2129] R.sup.5 is H, methyl, ethyl, propyl, or butyl;
[2130] R.sup.6a is H, methyl, ethyl, methoxy, --OH, or
--CF.sub.3;
[2131] R.sup.6b is H;
[2132] R.sup.7 and R.sup.9, at each occurrence, are independently
selected from H, F, Cl , --CH.sub.3, --OCH.sub.3, --CF.sub.3,
--OCF.sub.3, --CN, and --NO.sub.2,
[2133] R.sup.8 is selected from
[2134] H, F, Cl, Br, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2,
[2135] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[2136] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[2137] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[2138] C.sub.2-4 alkenyl substituted with 0-2 R.sup.11,
[2139] C.sub.2-4 alkynyl substituted with 0-1 R.sup.11,
[2140] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[2141] aryl substituted with 0-5 R.sup.33,
[2142] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[2143] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
NR.sup.12S(O).sub.2R.sup.15, and NR.sup.12C(O)NHR.sup.15;
[2144] R.sup.11 is selected from
[2145] H, halo, --CF.sub.3, --CN, --NO.sub.2,
[2146] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[2147] C.sub.3-10 cycloalkyl substituted with 0-2 R.sup.33,
[2148] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[2149] aryl substituted with 0-5 R.sup.33, and
[2150] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[2151] R.sup.12, at each occurrence, is independently selected
from
[2152] C.sub.1-4 alkyl substituted with 0-1 R.sup.12a,
[2153] C.sub.2-4 alkenyl substituted with 0-1 R.sup.12a,
[2154] C.sub.2-4 alkynyl substituted with 0-1 R.sup.12a,
[2155] C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.33,
[2156] phenyl substituted with 0-5 R.sup.33;
[2157] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[2158] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[2159] R.sup.12a, at each occurrence, is independently selected
from phenyl substituted with 0-5 R.sup.33;
[2160] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[2161] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[2162] R.sup.13, at each occurrence, is independently selected
from
[2163] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[2164] alternatively, R.sup.12 and R.sup.13 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.14)--;
[2165] alternatively, R.sup.12 and R.sup.13 when attached to N may
be combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S; wherein said bicyclic heterocyclic ring
system is selected from indolyl, indolinyl, indazolyl,
benzimidazolyl, benzimidazolinyl, benztriazolyl, benzoxazolyl,
benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl; wherein said
bicyclic heterocyclic ring system is substituted with 0-1
R.sup.16;
[2166] R.sup.14, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[2167] R.sup.15, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[2168] R.sup.16, at each occurrence, is independently selected
from
[2169] H, OH, F, Cl, CN, NO.sub.2, methyl, ethyl, methoxy, ethoxy,
trifluoromethyl, and trifluoromethoxy;
[2170] R.sup.31, at each occurrence, is independently selected
from
[2171] H, OH, halo, CF.sub.3, methyl, ethyl, and propyl;
[2172] R.sup.33, at each occurrence, is independently selected
from
[2173] H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, --C(=O)H,
[2174] C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
[2175] C.sub.3-6 cycloalkyl, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkyl-oxy-,
[2176] C.sub.1-4 alkyloxy-,
[2177] C.sub.1-4 alkylthio-, C.sub.1-4 alkyl-C(=O)--, C.sub.1-4
alkyl-C(=O)NH--,
[2178] C.sub.1-4 alkyl-OC(=O)--,
[2179] C.sub.1-4 alkyl-C(=O)O--, C.sub.3-6 cycloalkyl-oxy-,
C.sub.3-6 cycloalkylmethyl-oxy-;
[2180] C.sub.1-6 alkyl substituted with OH, methoxy, ethoxy,
[2181] propoxy, or butoxy; and
[2182] C.sub.2-6 alkenyl substituted with OH, methoxy, ethoxy,
[2183] propoxy, or butoxy;
[2184] R.sup.41, at each occurrence, is independently selected
from
[2185] H, CF.sub.3, halo, OH, CO.sub.2H, SO2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN,
[2186] C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy,
C.sub.1-3 haloalkyl, and C.sub.1-3 alkyl;
[2187] R.sup.42, at each occurrence, is independently selected
from
[2188] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, CH(=NH)NH.sub.2,
NHC(=NH)NH.sub.2,
[2189] C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy,
C.sub.1-3 haloalkyl, C.sub.3-6 cycloalkyl, and C.sub.1-3 alkyl;
[2190] R.sup.43 is cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, phenyl, or pyridyl, each substituted with 0-3
R.sup.44;
[2191] R.sup.44, at each occurrence, is independently selected from
H, halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy, and butoxy;
[2192] R.sup.45 is methyl, ethyl, propyl, or butyl;
[2193] R.sup.46, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[2194] R.sup.47, at each occurrence, is independently selected from
from H, methyl, ethyl, propyl, and butyl;
[2195] k is 1;
[2196] m is 1; and
[2197] n is 0, 1 or 2.
[2198] [23] In a more preferred embodiment, the present invention
provides the method as defined in claim 19 where in the compound
administered:
[2199] X is --CH.sub.2--;
[2200] R.sup.1 is selected from H,
[2201] C.sub.1-5 alkyl substituted with 0-1 R.sup.2,
[2202] C.sub.2-5 alkenyl substituted with 0-1 R.sup.2, and
[2203] C.sub.2-3 alkynyl substituted with 0-1 R.sup.2;
[2204] R.sup.2 is C.sub.3-6 cycloalkyl;
[2205] R.sup.5 is H, methyl, ethyl, or propyl;
[2206] R.sup.6a is H, methyl, or ethyl;
[2207] R.sup.6b is H;
[2208] R.sup.7 and R.sup.9, at each occurrence, are independently
selected from
[2209] H, F, Cl, --CH.sub.3, --OCH.sub.3, --CF.sub.3, --OCF.sub.3,
--CN, and --NO.sub.2,
[2210] R.sup.8 is selected from
[2211] methyl substituted with R.sup.11;
[2212] ethenyl substituted with R.sup.11;
[2213] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13,
NR.sup.12C(O)R.sup.15, NR.sup.12C(O)OR.sup.15,
[2214] NR.sup.12S(O).sub.2R.sup.15, and
NR.sup.12C(O)NHR.sup.15;
[2215] R.sup.11 is selected from
[2216] phenyl-substituted with 0-5 fluoro;
[2217] 2-(H.sub.3CCH.sub.2C(=O))-phenyl-substituted with
R.sup.33;
[2218] 2-(H.sub.3CC(=O))-phenyl-substituted with R.sup.33;
[2219] 2-(HC(=O))-phenyl-substituted with R.sup.33;
[2220] 2-(H.sub.3CCH(OH))-phenyl-substituted with R.sup.33;
[2221] 2-(H.sub.3CCH.sub.2CH(OH))-phenyl-substituted with
R.sup.33;
[2222] 2-(HOCH.sub.2)-phenyl-substituted with R.sup.33;
[2223] 2-(HOCH.sub.2CH.sub.2)-phenyl-substituted with R.sup.33;
[2224] 2-(H.sub.3COCH.sub.2)-phenyl-substituted with R.sup.33;
[2225] 2-(H.sub.3COCH.sub.2CH.sub.2)-phenyl-substituted with
R.sup.33;
[2226] 2-(H.sub.3CCH(OMe))-phenyl-substituted with R.sup.33;
[2227] 2-(H.sub.3COC(=O))-phenyl-substituted with R.sup.33;
[2228] 2-(HOCH.sub.2CH=CH)-phenyl-substituted with R.sup.33;
[2229] 2-((MeOC=O)CH=CH)-phenyl-substituted with R.sup.33;
[2230] 2-(methyl)-phenyl-substituted with R.sup.33;
[2231] 2-(ethyl)-phenyl-substituted with R.sup.33;
[2232] 2-(i-propyl)-phenyl-substituted with R.sup.33;
[2233] 2-(F.sub.3C)-phenyl-substituted with R.sup.33;
[2234] 2-(NC)-phenyl-substituted with R.sup.33;
[2235] 2-(H.sub.3CO)-phenyl-substituted with R.sup.33;
[2236] 2-(fluoro)-phenyl-substituted with R.sup.33;
[2237] 2-(chloro)-phenyl-substituted with R.sup.33;
[2238] 3-(NC)-phenyl-substituted with R.sup.33;
[2239] 3-(H.sub.3CO)-phenyl-substituted with R.sup.33;
[2240] 3-(fluoro)-phenyl-substituted with R.sup.33;
[2241] 3-(chloro)-phenyl-substituted with R.sup.33;
[2242] 4-(NC)-phenyl-substituted with R.sup.33;
[2243] 4-(fluoro)-phenyl-substituted with R.sup.33;
[2244] 4-(chloro)-phenyl-substituted with R.sup.33;
[2245] 4-(H.sub.3CS)-phenyl-substituted with R.sup.33;
[2246] 4-(H.sub.3CO)-phenyl-substituted with R.sup.33;
[2247] 4-(ethoxy)-phenyl-substituted with R.sup.33;
[2248] 4-(i-propoxy)-phenyl-substituted with R.sup.33;
[2249] 4-(i-butoxy)-phenyl-substituted with R.sup.33;
[2250] 4-(H.sub.3CCH.sub.2CH.sub.2C(=O))-phenyl-substituted with
R.sup.33;
[2251] 4-((H.sub.3C).sub.2CHC(=O))-phenyl-substituted with
R.sup.33;
[2252] 4-(H.sub.3CCH.sub.2C(=O))-phenyl-substituted with
R.sup.33;
[2253] 4-(H.sub.3CC(=O))-phenyl-substituted with R.sup.33;
[2254] 4-(H.sub.3CCH.sub.2CH.sub.2CH(OH))-phenyl-substituted with
R.sup.33;
[2255] 4-((H.sub.3C).sub.2CHCH(OH))-phenyl-substituted with
R.sup.33;
[2256] 4-(H.sub.3CCH.sub.2CH(OH))-phenyl-substituted with
R.sup.33;
[2257] 4-(H.sub.3CCH(OH))-phenyl-substituted with R.sup.33;
[2258] 4-(cyclopropyloxy)-phenyl-substituted with R.sup.33;
[2259] 4-(cyclobutyloxy)-phenyl-substituted with R.sup.33; and
[2260] 4-(cyclopentyloxy)-phenyl-substituted with R.sup.33;
[2261] R.sup.12 is selected from
[2262] phenyl-substituted with 0-5 fluoro;
[2263] 2-(H.sub.3CCH.sub.2C(=O))-phenyl-substituted with
R.sup.33;
[2264] 2-(H.sub.3CC(=O))-phenyl-substituted with R.sup.33;
[2265] 2-(HC(=O))-phenyl-substituted with R.sup.33;
[2266] 2-(H.sub.3CCH(OH))-phenyl-substituted with R.sup.33;
[2267] 2-(H.sub.3CCH.sub.2CH(OH))-phenyl-substituted with
R.sup.33;
[2268] 2-(HOCH.sub.2)-phenyl-substituted with R.sup.33;
[2269] 2-(HOCH.sub.2CH.sub.2)-phenyl-substituted with R.sup.33;
[2270] 2-(H.sub.3COCH.sub.2)-phenyl-substituted with R.sup.33;
[2271] 2-(H.sub.3COCH.sub.2CH.sub.2)-phenyl-substituted with
R.sup.33;
[2272] 2-(H.sub.3CCH(OMe))-phenyl-substituted with R.sup.33;
[2273] 2-(H.sub.3COC(=O))-phenyl-substituted with R.sup.33;
[2274] 2-(HOCH.sub.2CH=CH)-phenyl-substituted with R.sup.33;
[2275] 2-((MeOC=O)CH=CH)-phenyl-substituted with R.sup.33;
[2276] 2-(methyl)-phenyl-substituted with R.sup.33;
[2277] 2-(ethyl)-phenyl-substituted with R.sup.33;
[2278] 2-(i-propyl)-phenyl-substituted with R.sup.33;
[2279] 2-(F.sub.3C)-phenyl-substituted with R.sup.33;
[2280] 2-(NC)-phenyl-substituted with R.sup.33;
[2281] 2-(H.sub.3CO)-phenyl-substituted with R.sup.33;
[2282] 2-(fluoro)-phenyl-substituted with R.sup.33;
[2283] 2-(chloro)-phenyl-substituted with R.sup.33;
[2284] 3-(NC)-phenyl-substituted with R.sup.33;
[2285] 3-(H.sub.3CO)-phenyl-substituted with R.sup.33;
[2286] 3-(fluoro)-phenyl-substituted with R.sup.33;
[2287] 3-(chloro)-phenyl-substituted with R.sup.33;
[2288] 4-(NC)-phenyl-substituted with R.sup.33;
[2289] 4-(fluoro)-phenyl-substituted with R.sup.33;
[2290] 4-(chloro)-phenyl-substituted with R.sup.33;
[2291] 4-(H.sub.3CS)-phenyl-substituted with R.sup.33;
[2292] 4-(H.sub.3CO)-phenyl-substituted with R.sup.33;
[2293] 4-(ethoxy)-phenyl-substituted with R.sup.33;
[2294] 4-(i-propoxy)-phenyl-substituted with R.sup.33;
[2295] 4-(i-butoxy)-phenyl-substituted with R.sup.33;
[2296] 4-(H.sub.3CCH.sub.2CH.sub.2C(=O))-phenyl-substituted with
R.sup.33;
[2297] 4-((H.sub.3C).sub.2CHC(=O))-phenyl-substituted with
R.sup.33;
[2298] 4-(H.sub.3CCH.sub.2C(=O))-phenyl-substituted with
R.sup.33;
[2299] 4-(H.sub.3CC(=O))-phenyl-substituted with R.sup.33;
[2300] 4-(H.sub.3CCH.sub.2CH.sub.2CH(OH))-phenyl-substituted with
R.sup.33;
[2301] 4-((H.sub.3C).sub.2CHCH(OH))-phenyl-substituted with
R.sup.33;
[2302] 4-(H.sub.3CCH.sub.2CH(OH))-phenyl-substituted with
R.sup.33;
[2303] 4-(H.sub.3CCH(OH))-phenyl-substituted with R.sup.33;
[2304] 4-(cyclopropyloxy)-phenyl-substituted with R.sup.33;
[2305] 4-(cyclobutyloxy)-phenyl-substituted with R.sup.33; and
[2306] 4-(cyclopentyloxy)-phenyl-substituted with R.sup.33;
[2307] R.sup.13 is H, methyl, or ethyl;
[2308] alternatively, R.sup.12 and R.sup.13 join to form a 5- or
6-membered ring selected from pyrrolyl, pyrrolidinyl, imidazolyl,
piperidinyl, piperizinyl, methylpiperizinyl,and morpholinyl;
[2309] alternatively, R.sup.12 and R.sup.13 when attached to N may
be combined to form a 9- or 10-membered bicyclic heterocyclic ring
system containing from 1-3 heteroatoms selected from the group
consisting of N, O, and S; wherein said bicyclic heterocyclic ring
system is selected from indolyl, indolinyl, indazolyl,
benzimidazolyl, benzimidazolinyl, benztriazolyl, benzoxazolyl,
benzoxazolinyl, benzthiazolyl, and dioxobenzthiazolyl; wherein said
bicyclic heterocyclic ring system is substituted with 0-1
R.sup.16;
[2310] R.sup.15 is H, methyl, ethyl, propyl, or butyl;
[2311] R.sup.16, at each occurrence, is independently selected from
H, OH, F, Cl, CN, NO.sub.2, methyl, ethyl, methoxy, ethoxy,
trifluoromethyl, and trifluoromethoxy;
[2312] R.sup.33, at each occurrence, is independently selected from
H, F, Cl, --CH.sub.3, --OCH.sub.3, --CF.sub.3, --OCF.sub.3, --CN,
and --NO.sub.2;
[2313] k is 1;
[2314] m is 1; and
[2315] n is 1 or 2.
[2316] [24] In a more preferred embodiment, the present invention
provides the method as defined in claim 19 where the compound
administered is a compound of Formula (I-a): 14
[2317] wherein:
[2318] b is a single bond;
[2319] X is --CH.sub.2--, --CH(OH)--, or --C(=O)--;
[2320] R.sup.1 is selected from
[2321] hydrogen, methyl, ethyl, n-propyl, n-butyl, s-butyl,
t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl, 2-hexyl,
2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl,
3-methylpentyl, 3-methylbutyl, 4-methylpentyl, 2--fluoroethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl,
[2322] 2-propenyl, 2-methyl-2-propenyl, trans-2-butenyl,
3-methyl-butenyl, 3-butenyl, trans-2-pentenyl, cis-2-pentenyl,
4-pentenyl, 4-methyl-3-pentenyl, 3,3-dichloro-2-propenyl,
trans-3-phenyl-2-propenyl,
[2323] cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl,
[2324] benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl,
2,5-dimethylbenzyl, 2,4-dimethylbenzyl, 3,5-dimethylbenzyl,
2,4,6-trimethyl-benzyl, 3-methoxy-benzyl, 3,5-dimethoxy-benzyl,
pentafluorobenzyl, 2-phenylethyl; 1-phenyl-2-propyl, 4-phenylbutyl,
4-phenylbenzyl, 2-phenylbenzyl,
[2325] (2,3-dimethoxy-phenyl)C(=O)--,
(2,5-dimethoxy-phenyl)C(=O)--, (3,4-dimethoxy-phenyl)C(=O)--,
(3,5-dimethoxy-phenyl)C(=O)--, cyclopropyl-C(=O)--,
isopropyl-C(=O)--, ethyl-CO.sub.2--, propyl-CO.sub.2--,
t-butyl-CO.sub.2--, 2,6-dimethoxy-benzyl, 2,4-dimethoxy-benzyl,
2,4,6-trimethoxy-benzyl, 2,3-dimethoxy-benzyl,
2,4,5-trimethoxy-benzyl, 2,3,4-trimethoxy-benzyl,
3,4-dimethoxy-benzyl, 3,4,5-trimethoxy-benzyl,
(4-fluoro-phenyl)ethyl, --CH=CH.sub.2, --CH.sub.2--CH=CH.sub.2,
--CH=CH--CH.sub.3, --C.ident.--CH, --C.ident.--C--CH.sub.3, and
--CH.sub.2--C.ident.CH;
[2326] R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are
independently selected from
[2327] hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl,
propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy,
ethoxy, isopropoxy, trifluoromethoxy, phenyl,
[2328] methylC(=O)--, ethylC(=O)--, propylC(=O)--,
isopropylC(=O)--, butylC(=O)--, phenylC(=O)--,
[2329] methylCO.sub.2--, ethylCO.sub.2--, propylCO.sub.2--,
isopropylCO.sub.2--, butylCO.sub.2--, phenylCO.sub.2--,
[2330] dimethylamino-S(=O)--, diethylamino-S(=O)--,
dipropylamino-S(=O)--, di-isopropylamino-S(=O)--,
dibutylamino-S(=O)--, diphenylamino-S(=O)--,
[2331] dimethylamino-SO.sub.2--, diethylamino-SO.sub.2--,
dipropylamino-SO.sub.2--, di-isopropylamino-SO.sub.2--,
dibutylamino-SO.sub.2--, diphenylamino-SO.sub.2--,
[2332] dimethylamino-C(=O)--, diethylamino-C(=O)--,
dipropylamino-C(=O)--, di-isopropylamino-C(=O)--,
dibutylamino-C(=O)--, diphenylamino-C(=O)--, 2-chlorophenyl,
2-fluorophenyl, 2-bromophenyl, 2-cyanophenyl, 2-methylphenyl,
2-trifluoromethylphenyl, 2-methoxyphenyl, 2-trifluoromethoxyphenyl,
3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-cyanophenyl,
3-methylphenyl, 3-ethylphenyl, 3-propylphenyl, 3-isopropylphenyl,
3-butylphenyl, 3-trifluoromethylphenyl; 3-methoxyphenyl,
3-isopropoxyphenyl, 3-trifluoromethoxyphenyl,
3-thiomethoxyphenyl,
[2333] 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl,
4-cyanophenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl,
4-isopropylphenyl, 4-butylphenyl, 4-trifluoromethylphenyl,
4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethoxyphenyl,
4-thiomethoxyphenyl,
[2334] 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethylphenyl,
2,3-ditrifluoromethylphenyl, 2,3-dimethoxyphenyl,
2,3-ditrifluoromethoxyp- henyl,
[2335] 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dimethylphenyl,
2,4-ditrifluoromethylphenyl, 2,4-dimethoxyphenyl,
2,4-ditrifluoromethoxyp- henyl,
[2336] 2,5-dichlorophenyl, 2,5-difluorophenyl, 2,5-dimethylphenyl,
2,5-ditrifluoromethylphenyl, 2,5-dimethoxyphenyl,
2,5-ditrifluoromethoxyp- henyl,
[2337] 2,6-dichlorophenyl, 2,6-difluorophenyl, 2,6-dimethylphenyl,
2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl,
2,6-ditrifluoromethoxyp- henyl,
[2338] 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl,
3,4-ditrifluoromethylphenyl, 3,4-dimethoxyphenyl,
3,4-ditrifluoromethoxyp- henyl,
[2339] 2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl,
2,4,6-trimethylphenyl, 2,4,6-tritrifluoromethylphenyl,
2,4,6-trimethoxyphenyl, 2,4,6-tritrifluoromethoxyphenyl,
2-chloro-4-CF.sub.3-phenyl, 2-fluoro-3-chloro-phenyl,
2-chloro-4-CF.sub.3-phenyl, 2-chloro-4-methoxy-phenyl,
2-methoxy-4-isopropyl-phenyl, 2-CF.sub.3-4-methoxy-phenyl,
2-methyl-4-methoxy-5-fluoro-phenyl, 2-methyl-4-methoxy-phenyl,
2-chloro-4-CF.sub.3O-phenyl, 2,4,5-trimethyl-phenyl,
2-methyl-4-chloro-phenyl,
[2340] methyl-C(=O)NH--, ethyl-C(=O)NH--, propyl-C(=O)NH--,
isopropyl-C(=O)NH--, butyl-C(=O)NH--, phenyl-C(=O)NH--,
[2341] 4-acetylphenyl, 3-acetamidophenyl, 4-pyridyl, 2-furanyl,
2-thiophenyl, 2-naphthyl;
[2342] 2-Me-5-F-phenyl, 2-F-5-Me-phenyl, 2-MeO-5-F-phenyl,
2-Me-3-Cl-phenyl, 3-NO.sub.2-phenyl, 2-NO.sub.2-phenyl,
2-C.sub.1-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl,
2-C.sub.1-6-F-phenyl, 2-C.sub.1-4-(CHF.sub.2)O-phenyl,
2,4-diMeO-6-F-phenyl, 2-CF.sub.3-6-F-phenyl, 2-MeS-phenyl,
2,6-diC.sub.1-4-MeO-phenyl, 2,3,4-triF-phenyl, 2,6-diF-4-Cl-phenyl,
2,3,4,6-tetraF-phenyl, 2,3,4,5,6-pentaF-phenyl,
2-CF.sub.3-4-EtO-phenyl, 2-CF.sub.3-4-iPrO-phenyl,
2-CF.sub.3-4-Cl-phenyl, 2-CF.sub.3-4-F-phenyl,
2-C.sub.1-4-EtO-phenyl, 2-C.sub.1-4-iPrO-phenyl, 2-Et-4-MeO-phenyl,
2-CHO-4-MeO-phenyl, 2-CH(OH)Me-4-MeO-phenyl,
2-CH(OMe)Me-4-MeO-phenyl, 2-C(=O)Me-4-MeO-phenyl,
2-CH.sub.2(OH)-4-MeO-phenyl, 2-CH.sub.2(OMe)-4-MeO-phenyl,
2-CH(OH)Et-4-MeO-phenyl, 2-C(=O)Et-4-MeO-phenyl,
(Z)-2-CH=CHCO.sub.2Me-4-MeO-phenyl,
2-CH.sub.2CH.sub.2CO.sub.2Me-4-MeO-phenyl,
(Z)-2-CH=CHCH.sub.2(OH)-4-MeO-- phenyl,
(E)-2-CH=CHCO.sub.2Me-4-MeO-phenyl, (E)-2-CH=CHCH.sub.2(OH)-4-MeO--
phenyl, 2-CH.sub.2CH.sub.2OMe-4-MeO-phenyl, 2-F-4-MeO-phenyl,
2-C.sub.1-4-F-phenyl, (2-Cl-phenyl)--CH=CH--,
(3-Cl-phenyl)--CH=CH--, (2,6-diF-phenyl)--CH=CH--,
--CH.sub.2CH=CH.sub.2, phenyl-CH=CH--,
(2-Me-4-MeO-phenyl)--CH=CH--, cyclohexyl, cyclopentyl,
cyclohexylmethyl, --CH.sub.2CH.sub.2CO.sub.2Et,
--(CH.sub.2)3CO.sub.2Et, --(CH.sub.2).sub.4CO.sub.2Et, benzyl,
2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 3-MeO-benzyl, 3-OH-benzyl,
2-MeO-benzyl, 2-OH-benzyl, 2-CO.sub.2Me-3-MeO-phenyl,
2-Me-4-CN-phenyl, 2-Me-3-CN-phenyl, 2-CF.sub.3-4-CN-phenyl,
3-CHO-phenyl, 3-CH.sub.2(OH)-phenyl, 3-CH.sub.2(OMe)-phenyl,
3-CH.sub.2(NMe2)-phenyl, 3-CN-4-F-phenyl, 3-CONH.sub.2-4-F-phenyl,
2-CH.sub.2(NH.sub.2)-4-MeO-phenyl-, phenyl-NH--, (4-F-phenyl)-NH--,
(2,4-diCl-phenyl)-NH--, phenyl-C(=O)NH--, benzyl-NH--,
(2-Me-4-MeO-phenyl)-NH--, (2-F-4-MeO-phenyl)-NH--,
(2-Me-4-F-phenyl)-NH--, phenyl-S--, --NMe.sub.2, 1-pyrrolidinyl,
and -N(tosylate).sub.2,
[2343] provided that two of R.sup.7, R.sup.8, and R.sup.9, are
independently selected from hydrogen, fluoro, chloro, bromo, cyano,
methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro,
trifluoromethyl, methoxy, ethoxy, isopropoxy, and
trifluoromethoxy;
[2344] m is 1; and
[2345] n is 0, 1 or 2.
[2346] [25] In a more preferred embodiment, the present invention
provides the method as defined in claim 24 where the compound
administered is a compound of Formula (V): 15
[2347] wherein:
[2348] b is a single bond, wherein the bridge hydrogens are in a
cis position;
[2349] R.sup.1 is selected from
[2350] hydrogen, methyl, ethyl, n-propyl, n-butyl, s-butyl,
t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl, 2-hexyl,
2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl,
3-methylpentyl, 3-methylbutyl, 4-methylpentyl, 2-fluoroethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-propenyl,
2-methyl-2-propenyl, trans-2-butenyl, 3-methyl-butenyl, 3-butenyl,
trans-2-pentenyl, cis-2-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,
3,3-dichloro-2-propenyl, trans-3-phenyl-2-propenyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,
--CH=CH.sub.2, --CH.sub.2--CH=CH.sub.2, --CH=CH--CH.sub.3,
--C.ident.CH, --C.ident.C--CH.sub.3, and
--CH.sub.2--C.ident.CH;
[2351] R.sup.7 and R.sup.9, at each occurrence, are independently
selected from hydrogen, fluoro, methyl, trifluoromethyl, and
methoxy;
[2352] R.sup.8 is selected from
[2353] hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl,
propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy,
ethoxy, isopropoxy, trifluoromethoxy, phenyl,
[2354] methylC(=O)--, ethylC(=O)--, propylC(=O)--,
isopropylC(=O)--, butylC(=O)--, phenylC(=O)--,
[2355] methylCO.sub.2--, ethylCO.sub.2--, propylCO.sub.2--,
isopropylCO.sub.2--, butylCO.sub.2--, phenylCO.sub.2--,
[2356] dimethylamino-S(=O)--, diethylamino-S(=O)--,
dipropylamino-S(=O)--, di-isopropylamino-S(=O)--,
dibutylamino-S(=O)--, diphenylamino-S(=O)--,
dimethylamino-SO.sub.2--, diethylamino-SO.sub.2--,
dipropylamino-SO.sub.2--, di-isopropylamino-SO.sub.2--,
dibutylamino-SO.sub.2--, diphenylamino-SO.sub.2--,
[2357] dimethylamino-C(=O)--, diethylamino-C(=O)--,
dipropylamino-C(=O)--, di-isopropylamino-C(=O)--,
dibutylamino-C(=O)--, diphenylamino-C(=O)--,
[2358] 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl,
2-cyanophenyl, 2-methylphenyl, 2-trifluoromethylphenyl,
2-methoxyphenyl, 2-trifluoromethoxyphenyl,
[2359] 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl,
3-cyanophenyl, 3-methylphenyl, 3-ethylphenyl, 3-propylphenyl,
3-isopropylphenyl, 3-butylphenyl, 3-trifluoromethylphenyl,
3-methoxyphenyl, 3-isopropoxyphenyl, 3-trifluoromethoxyphenyl,
3-thiomethoxyphenyl,
[2360] 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl,
4-cyanophenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl,
4-isopropylphenyl, 4-butylphenyl, 4-trifluoromethylphenyl,
4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethoxyphenyl,
4-thiomethoxyphenyl,
[2361] 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethylphenyl,
2,3-ditrifluoromethylphenyl, 2,3-dimethoxyphenyl,
2,3-ditrifluoromethoxyp- henyl,
[2362] 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dimethylphenyl,
2,4-ditrifluoromethylphenyl, 2,4-dimethoxyphenyl,
2,4-ditrifluoromethoxyp- henyl,
[2363] 2,5-dichlorophenyl, 2,5-difluorophenyl, 2,5-dimethylphenyl,
2,5-ditrifluoromethylphenyl, 2,5-dimethoxyphenyl,
2,5-ditrifluoromethoxyp- henyl,
[2364] 2,6-dichlorophenyl, 2,6-difluorophenyl, 2,6-dimethylphenyl,
2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl,
2,6-ditrifluoromethoxyp- henyl,
[2365] 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl,
3,4-ditrifluoromethylphenyl, 3,4-dimethoxyphenyl,
3,4-ditrifluoromethoxyp- henyl,
[2366] 2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl,
2,4,6-trimethylphenyl, 2,4,6-tritrifluoromethylphenyl,
2,4,6-trimethoxyphenyl, 2,4,6-tritrifluoromethoxyphenyl,
[2367] 2-chloro-4-CF.sub.3-phenyl, 2-fluoro-3-chloro-phenyl,
2-chloro-4-CF.sub.3-phenyl, 2-chloro-4-methoxy-phenyl,
2-methoxy-4-isopropyl-phenyl, 2-CF.sub.3-4-methoxy-phenyl,
2-methyl-4-methoxy-5-fluoro-phenyl, 2-methyl-4-methoxy-phenyl,
2-chloro-4-CF.sub.3O-phenyl, 2,4,5-trimethyl-phenyl,
2-methyl-4-chloro-phenyl,
[2368] methyl-C(=O)NH--, ethyl-C(=O)NH--, propyl-C(=O)NH--,
isopropyl-C(=O)NH--, butyl-C(=O)NH--, phenyl-C(=O)NH--,
[2369] 4-acetylphenyl, 3-acetamidophenyT, 4-pyridyl, 2-furanyl,
2-thiophenyl, 2-naphthyl;
[2370] 2-Me-5-F-phenyl, 2-F-5-Me-phenyl, 2-MeO-5-F-phenyl,
2-Me-3-Cl-phenyl, 3-NO.sub.2-phenyl, 2-NO.sub.2-phenyl,
2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl,
2-Cl-6-F-phenyl, 2-C.sub.1-4-(CHF.sub.2)0-phenyl,
2,4-diMeO-6-F-phenyl, 2-CF.sub.3-6-F-phenyl, 2-MeS-phenyl,
2,6-diCl-4-MeO-phenyl, 2,3,4-triF-phenyl, 2,6-diF-4-Cl-phenyl,
2,3,4,6-tetraF-phenyl, 2,3,4,5,6-pentaF-phenyl,
2-CF.sub.3-4-EtO-phenyl, 2-CF.sub.3-4-iPrO-pheny- l,
2-CF.sub.3-4-Cl-phenyl, 2-CF.sub.3-4-F-phenyl, 2-Cl-4-EtO-phenyl,
2-Cl-4-iPrO-phenyl, 2-Et-4-MeO-phenyl, 2-CHO-4-MeO-phenyl,
2-CH(OH)Me-4-MeO-phenyl, 2-CH(OMe)Me-4-MeO-phenyl,
2-C(=O)Me-4-MeO-phenyl, 2-CH.sub.2(OH)-4-MeO-phenyl,
2-CH.sub.2(OMe)-4-MeO-phenyl, 2-CH(OH)Et-4-MeO-phenyl,
2-C(=O)Et-4-MeO-phenyl, (Z)-2-CH=CHCO.sub.2Me-4-MeO-phenyl,
2-CH.sub.2CH.sub.2CO.sub.2Me-4-MeO-phenyl,
(Z)-2-CH=CHCH.sub.2(OH)-4-MeO-- phenyl,
(E)-2-CH=CHCO.sub.2Me-4-MeO-phenyl, (E)-2-CH=CHCH.sub.2(OH)-4-MeO--
phenyl, 2-CH.sub.2CH.sub.2OMe-4-MeO-phenyl, 2-F-4-MeO-phenyl,
2-Cl-4-F-phenyl, (2-Cl-phenyl)--CH=CH-, (3-Cl-phenyl)--CH=CH--,
(2,6-diF-phenyl)--CH=CH--, --CH.sub.2CH=CH.sub.2, phenyl-CH=CH--,
(2-Me-4-MeO-phenyl)--CH=CH--, cyclohexyl, cyclopentyl,
cyclohexylmethyl, --CH.sub.2CH.sub.2CO.sub.2Et,
--(CH.sub.2).sub.3CO.sub.2Et, --(CH.sub.2)4CO.sub.2Et, benzyl,
2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 3-MeO-benzyl, 3-OH-benzyl,
2-MeO-benzyl, 2-OH-benzyl, 2-CO.sub.2Me-3-MeO-phenyl,
2-Me-4-CN-phenyl, 2-Me-3-CN-phenyl, 2-CF.sub.3-4-CN-phenyl,
3-CHO-phenyl, 3-CH.sub.2(OH)-phenyl, 3-CH.sub.2(OMe)-phenyl,
3-CH.sub.2(NMe2)-phenyl, 3-CN-4-F-phenyl, 3-CONH.sub.2-4-F-phenyl,
2-CH.sub.2(NH.sub.2)-4-MeO-phenyl-, phenyl-NH--, (4-F-phenyl)-NH--,
(2,4-diCl-phenyl)-NH--, phenyl-C(=O)NH--, benzyl-NH--,
(2-Me-4-MeO-phenyl)-NH--, (2-F-4-MeO-phenyl)-NH--,
(2-Me-4-F-phenyl)-NH--, phenyl-S--, --NMe.sub.2, 1-pyrrolidinyl,
and --N(tosylate).sub.2; and
[2371] n is 0, 1 or 2.
[2372] [26] In a more preferred embodiment, the present invention
provides the method as defined in claim 18 where in the compound
administered:
[2373] X is --CHR.sup.10-- or --C(=O)--;
[2374] R.sup.1 is selected from
[2375] C.sub.1-6 alkyl substituted with Z,
[2376] C.sub.2-6 alkenyl substituted with Z,
[2377] C.sub.2-6 alkynyl substituted with Z,
[2378] C.sub.3-6 cycloalkyl substituted with Z,
[2379] aryl substituted with Z,
[2380] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with Z;
[2381] C.sub.1-6 alkyl substituted with 0-2 R.sup.2,
[2382] C.sub.2-6 alkenyl substituted with 0-2 R.sup.2,
[2383] C.sub.2-6 alkynyl substituted with 0-2 R.sup.2,
[2384] aryl substituted with 0-2 R.sup.2, and
[2385] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with 0-2 R.sup.2;
[2386] Z is selected from H,
[2387] --CH(OH)R.sup.2,
[2388] --C(ethylenedioxy)R.sup.2,
[2389] --OR.sup.2,
[2390] --SR.sup.2,
[2391] --NR.sup.2R.sup.3,
[2392] --C (O) R.sup.2,
[2393] --C (O) NR.sup.2R.sup.3,
[2394] --NR.sup.3C (O) R.sup.2,
[2395] --C(O)OR.sup.2,
[2396] --OC (O) R.sup.2,
[2397] --CH(=NR.sup.4)NR.sup.2R.sup.3,
[2398] --NHC (=NR.sup.4)NR.sup.2R.sup.3.
[2399] --S (O) R.sup.2,
[2400] --S (O).sub.2R.sup.2,
[2401] --S(O).sub.2NR.sup.2R.sup.3, and
--NR.sup.3S(O).sub.2R.sup.2;
[2402] R.sup.2, at each occurrence, is independently selected
from
[2403] C.sub.1-4 alkyl,
[2404] C.sub.2-4 alkenyl,
[2405] C.sub.2-4 alkynyl,
[2406] C.sub.3-6 cycloalkyl,
[2407] aryl substituted with 0-5 R.sup.42;
[2408] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.41,
and
[2409] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.41;
[2410] R.sup.3, at each occurrence, is independently selected
from
[2411] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
and C.sub.1-4 alkoxy;
[2412] alternatively, R.sup.2 and R.sup.3 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.4)--;
[2413] R.sup.4, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[2414] R.sup.5 is H, methyl, ethyl, propyl, or butyl;
[2415] R.sup.6a is selected from
[2416] H, --OH, --NR.sup.46R.sup.47, --CF.sub.3,
[2417] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 alkoxy,
[2418] C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl, and
[2419] aryl substituted with 0-3 R.sup.44;
[2420] R.sup.6b is H;
[2421] R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are
independently selected from
[2422] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --CN,
--NO.sub.2,--NR.sup.46R.sup.47,
[2423] C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[2424] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[2425] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[2426] aryl substituted with 0-5 R.sup.33,
[2427] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[2428] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13,
[2429] NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
OC(O)OR.sup.12,
[2430] CH (=NR.sup.14)NR.sup.12R.sup.13, NHC
(=NR.sup.14)NR.sup.12R.sup.13- , S(O)R.sup.12,
[2431] S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup- .13, NR.sup.1.sup.4S(O)R.sup.12,
[2432] NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15,
[2433] and NR.sup.12C(O)NHR.sup.15;
[2434] R.sup.10 is selected from H, --OH,
[2435] C.sub.1-6 alkyl substituted with 0-1 R.sup.10B,
[2436] C.sub.2-6 alkenyl substituted with 0-1 R.sup.10B,
[2437] C.sub.2-6 alkynyl substituted with 0-1 R.sup.10B, and
[2438] C.sub.1-6 alkoxy;
[2439] R.sup.10B is selected from
[2440] C.sub.1-4 alkoxy,
[2441] C.sub.3-6 cycloalkyl,
[2442] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[2443] phenyl substituted with 0-3 R.sup.33, and
[2444] 5-6 membered heterocyclic ring system containing 1, 2, or 3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R.sup.44;
[2445] R.sup.11 is selected from
[2446] H, halo, --CF.sub.3, --CN, --NO.sub.2,
[2447] C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-8 alkoxy, C.sub.3-10 cycloalkyl,
[2448] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[2449] aryl substituted with 0-5 R.sup.33,
[2450] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[2451] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12,
C(O)R.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12,
CH(=NR.sup.14)NR.sup.12R.sup.13, NHC(=NR.sup.14)NR.sup.12R.sup.13,
S(O)R.sup.12, S(O).sub.2R.sup.12, S(O)NR.sup.12R.sup.13,
S(O).sub.2NR.sup.12R.sup.13, NR.sup.14S(O)R.sup.12, and
NR.sup.14S(O).sub.2R.sup.12;
[2452] R.sup.12 at each occurrence, is independently selected
from
[2453] C.sub.1-4 alkyl,
[2454] C.sub.2-4 alkenyl,
[2455] C.sub.2-4 alkynyl,
[2456] C.sub.3-6 cycloalkyl,
[2457] phenyl substituted with 0-5 R.sup.33;
[2458] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[2459] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[2460] R.sup.13, at each occurrence, is independently selected
from
[2461] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[2462] alternatively, R.sup.12 and R.sup.13 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.14)--;
[2463] R.sup.14, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[2464] R.sup.31, at each occurrence, is independently selected
from
[2465] H, OH, halo, CF.sub.3, SO.sub.2R.sup.45, NR.sup.46R.sup.47,
methyl, ethyl, and propyl;
[2466] R.sup.33, at each occurrence, is independently selected
from
[2467] H, OH, halo, CN, NO.sub.2, CF.sub.3, SO.sub.2R.sup.45,
NR.sup.46R.sup.47,
[2468] C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl,
C.sub.3-5 cycloalkyl, C.sub.1-3 haloalkyl, C.sub.1-3
haloalkyl-oxy-, C.sub.1-3 alkyloxy-, C.sub.1-3 alkylthio-,
C.sub.1-3 alkyl-C(=O)--, and C.sub.1-3 alkyl-C(=O)NH--;
[2469] R.sup.41, at each occurrence, is independently selected
from
[2470] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, =O,
[2471] C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl
[2472] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[2473] aryl substituted with 0-3 R.sup.42, and
[2474] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[2475] R.sup.42, at each occurrence, is independently selected
from
[2476] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
SR.sup.45, NR.sup.46R.sup.47, OR.sup.48, NO.sub.2, CN,
CH(=NH)NH.sub.2, NHC(=NH)NH.sub.2,
[2477] C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl,
[2478] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[2479] aryl substituted with 0-3 R.sup.44, and
[2480] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[2481] R.sup.43 is C.sub.3-6 cycloalkyl or aryl substituted with
0-3 R.sup.44;
[2482] R.sup.44, at each occurrence, is independently selected from
H, halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, and
C.sub.1-4 alkoxy;
[2483] R.sup.45 is C.sub.1-4 alkyl;
[2484] R.sup.46, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[2485] R.sup.47, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --C(=O)NH(C.sub.1-4 alkyl),
--SO.sub.2(C.sub.1-4 alkyl), --SO.sub.2(phenyl), --C(=O)O(C.sub.1-4
alkyl), --C(=O)( C.sub.1-4 alkyl), and --C(=O)H;
[2486] R.sup.48, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --C(=O)NH(C.sub.1-4 alkyl), --C(=O)O(C.sub.1-4
alkyl), --C(=O)( C.sub.1-4 alkyl), and --C(=O)H;
[2487] k is 1 or 2;
[2488] m is 0, 1, or 2; and
[2489] n is 0, 1 or 2.
[2490] [27] In a more preferred embodiment, the present invention
provides the method as defined in claim 26 where in the compound
administered:
[2491] X is --CHR.sup.10-- or --C(=O)--;
[2492] R.sup.1 is selected from
[2493] C.sub.2-5 alkyl substituted with Z,
[2494] C.sub.2-5 alkenyl substituted with Z,
[2495] C.sub.2-5 alkynyl substituted with Z,
[2496] C.sub.3-6 cycloalkyl substituted with Z,
[2497] aryl substituted with Z,
[2498] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with Z;
[2499] C.sub.1-5 alkyl substituted with 0-2 R.sup.2,
[2500] C.sub.2-5 alkenyl substituted with 0-2 R.sup.2, and
[2501] C.sub.2-5 alkynyl substituted with 0-2 R.sup.2;
[2502] Z is selected from H,
[2503] --CH(OH)R.sup.2,
[2504] --C(ethylenedioxy)R.sup.2,
[2505] --OR.sup.2,
[2506] --SR.sup.2,
[2507] --NR.sup.2R.sup.3,
[2508] --C(O)R.sup.2,
[2509] --C(O)NR.sup.2R.sup.3,
[2510] --NR.sup.3C (O) R.sup.2,
[2511] --C (O) OR.sup.2,
[2512] --OC (O) R.sup.2,
[2513] --CH(=NR.sup.4)NR.sup.2R.sup.3,
[2514] --NHC(=NR.sup.4)NR.sup.2R.sup.3,
[2515] --S (O) R.sup.2,
[2516] --S (O).sub.2R.sup.2,
[2517] --S(O).sub.2NR.sup.2R.sup.3, and
--NR.sup.3S(O).sub.2R.sup.2;
[2518] R.sup.2, at each occurrence, is independently selected
from
[2519] C.sub.1-4 alkyl,
[2520] C.sub.2-4 alkenyl,
[2521] C.sub.2-4 alkynyl,
[2522] C.sub.3-6 cycloalkyl,
[2523] aryl substituted with 0-5 R.sup.42;
[2524] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.41,
and
[2525] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.41;
[2526] R.sup.3, at each occurrence, is independently selected
from
[2527] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
and
[2528] C.sub.1-4 alkoxy;
[2529] alternatively, R.sup.2 and R.sup.3 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.4)--;
[2530] R.sup.4, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[2531] R.sup.5 is H, methyl, or ethyl;
[2532] R.sup.6a is selected from
[2533] H, --OH, --NR.sup.46R.sup.47, --CF.sub.3,
[2534] C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, and C.sub.3-6
cycloalkyl;
[2535] R.sup.6b is H;
[2536] R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are
independently selected from
[2537] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --OCH.sub.3, --CN,
--NO.sub.2,--NR.sup.46R.sup.47,
[2538] C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-4 haloalkyl, C.sub.1-6 alkoxy, (C.sub.1-4
haloalkyl)oxy,
[2539] C.sub.1-4 alkyl substituted with 0-2 R.sup.11,
[2540] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[2541] aryl substituted with 0-5 R.sup.33,
[2542] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[2543] 0R.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)NR.sup.12R.sup.13,
[2544] NR.sup.14C(O)R.sup.12, C(O)OR.sup.12, OC(O)R.sup.12,
CH(=NR.sup.14)NR.sup.12R.sup.13,
[2545] NHC(=NR.sup.14)NR.sup.12R.sup.13, S(O)R.sup.12,
S(O).sub.2R.sup.12, S(O).sub.2NR.sup.12R.sup.13,
[2546] NR.sup.14S(O).sub.2R.sup.12, NR.sup.14S(O)R.sup.12,
NR.sup.14S(O).sub.2R.sup.12, NR.sup.12C(O)R.sup.15,
[2547] NR.sup.12C(O)OR.sup.15, NR.sup.12S(O).sub.2R.sup.15, and
NR.sup.12C(O)NHR.sup.15;
[2548] R.sup.10 is selected from H, --OH, C.sub.1-6 alkyl,
C.sub.1-4 alkoxy, and
[2549] C.sub.1-2 alkyl substituted with 0-1 R.sup.10B;
[2550] R.sup.10B is C.sub.3-6 cycloalkyl or phenyl substituted with
0-3 R.sup.33;
[2551] R.sup.11 is selected from
[2552] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --OCH.sub.3, --CN,
--NO.sub.2,--NR.sup.46R.sup.47, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-4 haloalkyl, C.sub.1-6 alkoxy,
(C.sub.1-4 haloalkyl)oxy,
[2553] C.sub.3-10 carbocyclic group substituted with 0-3
R.sup.33,
[2554] aryl substituted with 0-5 R.sup.33,
[2555] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[2556] OR.sup.12, SR.sup.12, NR.sup.12R.sup.13, C(O)H,
C(O)R.sup.12, C(O)NR.sup.12R.sup.13, NR.sup.14C(O)R.sup.12,
C(O)OR.sup.12, OC(O)R.sup.12, CH(=NR.sup.14)NR.sup.12R.sup.13,
NHC(=NR.sup.14)NR.sup.12R- .sup.13, S(O)R.sup.12,
S(O).sub.2R.sup.12, S(O).sub.2NR.sup.12R.sup.13, and
NR.sup.14S(O).sub.2R.sup.12;
[2557] R.sup.12, at each occurrence, is independently selected
from
[2558] C.sub.1-4 alkyl,
[2559] C.sub.2-4 alkenyl,
[2560] C.sub.2-4 alkynyl,
[2561] C.sub.3-6 cycloalkyl,
[2562] phenyl substituted with 0-5 R.sup.33;
[2563] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.33,
and
[2564] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.31;
[2565] R.sup.13, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl;
[2566] alternatively, R.sup.12 and R.sup.13 join to form a 5- or
6-membered ring optionally substituted with --O-- or
-N(R.sup.14)-;
[2567] R.sup.14, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[2568] R.sup.31, at each occurrence, is independently selected from
H, OH, halo, CF.sub.3, methyl, and ethyl;
[2569] R.sup.33, at each occurrence, is independently selected from
H, OH, halo, CN, NO.sub.2, CF.sub.3, methyl, and ethyl;
[2570] R.sup.41, at each occurrence, is independently selected
from
[2571] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, =O,
[2572] C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl,
[2573] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[2574] aryl substituted with 0-3 R.sup.42, and
[2575] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[2576] R.sup.42, at each occurrence, is independently selected
from
[2577] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
SR.sup.45, NR.sup.46R.sup.47, OR.sup.48, NO.sub.2, CN,
CH(=NH)NH.sub.2, NHC(=NH)NH.sub.2,
[2578] C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl,
[2579] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[2580] aryl substituted with 0-3 R.sup.44, and
[2581] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[2582] R.sup.43 is C.sub.3-6 cycloalkyl or aryl substituted with
0-3 R.sup.44;
[2583] R.sup.44, at each occurrence, is independently selected from
H, halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, C.sub.1-4 alkyl, and
C.sub.1-4 alkoxy;
[2584] R.sup.45 is C.sub.1-4 alkyl;
[2585] R.sup.46, at each occurrence, is independently selected from
H and C.sub.1-3 alkyl;
[2586] R.sup.47, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --C(=O)NH(C.sub.1-4 alkyl),
--SO.sub.2(C.sub.1-4 alkyl), --SO.sub.2(phenyl), --C(=O)O(C.sub.1-4
alkyl), --C(=O)( C.sub.1-4 alkyl), and --C(=O)H;
[2587] R.sup.48, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --C(=O)NH(C.sub.1-4 alkyl), --C(=O)O(C.sub.1-4
alkyl), --C(=O)( C.sub.1-4 alkyl), and --C(=O)H;
[2588] k is 1 or 2;
[2589] m is 0, 1, 2; and
[2590] n is 0, 1 or 2.
[2591] [28] In a more preferred embodiment, the present invention
provides the method as defined in claim 26 where in the compound
administered:
[2592] X is --CH.sub.2--;
[2593] R.sup.1 is selected from
[2594] C.sub.2-4 alkyl substituted with Z,
[2595] C.sub.2-4 alkenyl substituted with Z,
[2596] C.sub.2-4 alkynyl substituted with Z,
[2597] C.sub.3-6 cycloalkyl substituted with Z,
[2598] aryl substituted with Z,
[2599] 5-6 membered heterocyclic ring system containing at least
one heteroatom selected from the group consisting of N, O, and S,
said heterocyclic ring system substituted with Z;
[2600] C.sub.2-4 alkyl substituted with 0-2 R.sup.2, and
[2601] C.sub.2-4 alkenyl substituted with 0-2 R.sup.2;
[2602] Z is selected from H.
[2603] --CH(OH)R.sup.2,
[2604] --C(ethylenedioxy)R.sup.2,
[2605] --OR.sup.2,
[2606] --SR.sup.2,
[2607] --NR.sup.2R.sup.3,
[2608] --C(O)R.sup.2,
[2609] --C(O)NR.sup.2R.sup.3,
[2610] --NR.sup.3C(O)R.sup.2,
[2611] --C(O)OR.sup.2,
[2612] --S(O)R.sup.2,
[2613] --S(O).sub.2R.sup.2,
[2614] --S(O).sub.2NR.sup.2R.sup.3, and
--NR.sup.3S(O).sub.2R.sup.2;
[2615] R.sup.2, at each occurrence, is independently selected from
phenyl substituted with 0-5 R.sup.42;
[2616] C.sub.3-10 carbocyclic group substituted with 0-3 R.sup.41,
and
[2617] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.41;
[2618] R.sup.3, at each occurrence, is independently selected
from
[2619] H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
and C.sub.1-4 alkoxy;
[2620] alternatively, R.sup.2 and R.sup.3 join to form a 5- or
6-membered ring optionally substituted with --O-- or
--N(R.sup.4)--;
[2621] R.sup.4, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[2622] R.sup.5 is H;
[2623] R.sup.6a is selected from H, --OH, --CF.sub.3, methyl,
ethyl, propyl, butyl, methoxy, and, ethoxy;
[2624] R.sup.6b is H;
[2625] R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are
independently selected from
[2626] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --OCH.sub.3, --CN,
--NO.sub.2,
[2627] C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy,
(C.sub.1-3 haloalkyl)oxy, and
[2628] C.sub.1-4 alkyl substituted with 0-2 R.sup.11;
[2629] R.sup.11 is selected from
[2630] H, halo, --CF.sub.3, --OCF.sub.3, --OH, --OCH.sub.3, --CN,
--NO.sub.2,
[2631] C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, and
(C.sub.1-3 haloalkyl)oxy;
[2632] R.sup.33, at each occurrence, is independently selected from
H, OH, halo, CF.sub.3, and methyl;
[2633] R.sup.41, at each occurrence, is independently selected
from
[2634] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
NR.sup.46R.sup.47, NO.sub.2, CN, =O,
[2635] C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl,
[2636] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[2637] aryl substituted with 0-3 R.sup.42, and
[2638] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[2639] R.sup.42, at each occurrence, is independently selected
from
[2640] H, CF.sub.3, halo, OH, CO.sub.2H, SO.sub.2R.sup.45,
SR.sup.45, NR.sup.46R.sup.47, OR.sup.48, NO.sub.2, CN,
CH(=NH)NH.sub.2, NHC(=NH)NH.sub.2,
[2641] C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.3-6 cycloalkyl,
[2642] C.sub.1-4 alkyl substituted with 0-1 R.sup.43,
[2643] aryl substituted with 0-3 R.sup.44, and
[2644] 5-10 membered heterocyclic ring system containing from 1-4
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-3 R.sup.44;
[2645] R.sup.43 is cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, phenyl, or pyridyl, each substituted with 0-3
R.sup.44;
[2646] R.sup.44, at each occurrence, is independently selected from
H, halo, --OH, NR.sup.46R.sup.47, CO.sub.2H, SO.sub.2R.sup.45,
--CF.sub.3, --OCF.sub.3, --CN, --NO.sub.2, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy, and butoxy;
[2647] R.sup.45 is methyl, ethyl, propyl, or butyl;
[2648] R.sup.46, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[2649] R.sup.47, at each occurrence, is independently selected from
H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, 13
C(=O)NH(methyl), 13 C(=O)NH(ethyl), --SO.sub.2(methyl),
--SO.sub.2(ethyl), --SO.sub.2(phenyl), --C(=O)O(methyl),
--C(=O)O(ethyl), --C(=O)(methyl), --C(=O)(ethyl), and --C(=O)H;
[2650] R.sup.48, at each occurrence, is independently selected from
H, methyl, ethyl, n-propyl, i-propyl, --C(=O)NH(methyl),
--C(=O)NH(ethyl), --C(=O)O(methyl), --C(=O)O(ethyl), --C(=O)
(methyl), --C(=O) (ethyl), and --C(=O)H;
[2651] k is 1;
[2652] m is 0, 1, or 2; and
[2653] n is 0, 1 or 2.
[2654] [29] In a more preferred embodiment, the present invention
provides the method as defined in claim 26 where in the compound
administered:
[2655] X is --CH.sub.2--;
[2656] R.sup.1 is selected from
[2657] ethyl substituted with Z,
[2658] propyl substituted with Z,
[2659] butyl substituted with Z,
[2660] propenyl substituted with Z,
[2661] butenyl substituted with Z,
[2662] ethyl substituted with R.sup.2,
[2663] propyl substituted with R.sup.2,
[2664] butyl substituted with R.sup.2,
[2665] propenyl substituted with R.sup.2, and
[2666] butenyl substituted with R.sup.2;
[2667] Z is selected from H,
[2668] --CH(OH)R.sup.2,
[2669] --OR.sup.2,
[2670] --SR.sup.2,
[2671] --NR.sup.2R.sup.3,
[2672] --C(O)R.sup.2,
[2673] --C(O)NR.sup.2R.sup.3,
[2674] --NR.sup.3C(O)R.sup.2,
[2675] --C(O)OR.sup.2,
[2676] --S(O)R.sup.2,
[2677] --S(O).sub.2R.sup.2,
[2678] --S(O).sub.2NR.sup.2R.sup.3, and
--NR.sup.3S(O).sub.2R.sup.2;
[2679] R.sup.2, at each occurrence, is independently selected
from
[2680] phenyl substituted with 0-3 R.sup.42;
[2681] naphthyl substituted with 0-3 R.sup.42;
[2682] cyclopropyl substituted with 0-3 R.sup.41;
[2683] cyclobutyl substituted with 0-3 R.sup.41;
[2684] cyclopentyl substituted with 0-3 R.sup.41;
[2685] cyclohexyl substituted with 0-3 R.sup.41;
[2686] pyridyl substituted with 0-3 R.sup.41;
[2687] indolyl substituted with 0-3 R.sup.41;
[2688] indolinyl substituted with 0-3 R.sup.41;
[2689] benzimidazolyl substituted with 0-3 R.sup.41;
[2690] benzotriazolyl substituted with 0-3 R.sup.41;
[2691] benzothienyl substituted with 0-3 R.sup.41;
[2692] benzofuranyl substituted with 0-3 R.sup.41;
[2693] phthalimid-1-yl substituted with 0-3 R.sup.41;
[2694] inden-2-yl substituted with 0-3 R.sup.41;
[2695] 2,3-dihydro-1H-inden-2-yl substituted with 0-3 R.sup.41;
[2696] indazolyl substituted with 0-3 R.sup.41;
[2697] tetrahydroquinolinyl substituted with 0-3 R.sup.41; and
[2698] tetrahydro-isoquinolinyl substituted with 0-3 R.sup.41;
[2699] R.sup.3, at each occurrence, is independently selected from
H, methyl, and ethyl;
[2700] R.sup.5 is H;
[2701] R.sup.6a is selected from H, --OH, methyl, and methoxy;
[2702] R.sup.6b is H;
[2703] R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are
independently
[2704] selected from H, F, Cl, methyl, ethyl, methoxy, --CF3, and
--OCF.sub.3;
[2705] R.sup.41, at each occurrence, is independently selected
from
[2706] H, F, Cl, Br, OH, CF.sub.3, NO.sub.2, CN, =O, methyl, ethyl,
propyl, butyl, methoxy, and ethoxy;
[2707] R.sup.42, at each occurrence, is independently selected
from
[2708] H, F, Cl, Br, OH, CF.sub.3, SO.sub.2R.sup.45, SR.sup.45,
NR.sup.46R.sup.47, OR.sup.48, NO.sub.2, CN, =O, methyl, ethyl,
propyl, butyl, methoxy, and ethoxy;
[2709] R.sup.45 is methyl, ethyl, propyl, or butyl;
[2710] R.sup.46, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
[2711] R.sup.47, at each occurrence, is independently selected from
H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
--C(=O)NH(methyl), --C(=O)NH(ethyl), --SO.sub.2(methyl),
--SO.sub.2(ethyl), --SO.sub.2(phenyl),
--C(=O)O(methyl),--C(=O)O(ethyl), --C(=O)(methyl), --C(=O)(ethyl),
and --C(=O)H;
[2712] R.sup.48, at each occurrence, is independently selected from
H, methyl, ethyl, n-propyl, i-propyl, --C(=O)NH(methyl),
--C(=O)NH(ethyl), --C(=O)O(methyl),--C(=O)O(ethyl), --C(=O)
(methyl), --C(=O) (ethyl), and --C(=O)H;
[2713] k is 1;
[2714] m is 0, 1, or 2; and
[2715] n is 0, 1 or .sub.2.
[2716] [30] In a more preferred embodiment, the present invention
provides the method as defined in claim 26 where the compound
administered is a compound of Formula (I-a): 16
[2717] wherein:
[2718] b is a single bond;
[2719] X is --CH.sub.2--, CH(OH)--, or --C(=O)--
[2720] R.sup.1 is selected from
[2721] --(CH.sub.2).sub.3C(=O)(4-fluoro-phenyl),
[2722] --(CH.sub.2).sub.3C(=O)(4-bromo-phenyl),
[2723] --(CH.sub.2).sub.3C(=O)(4-methyl-phenyl),
[2724] --(CH.sub.2).sub.3C(=O)(4-methoxy-phenyl),
[2725] --(CH.sub.2).sub.3C(=O)(4-(3,4-dichloro-phenyl)phenyl),
[2726] --(CH.sub.2).sub.3C(=O)(3-methyl-4-fluoro-phenyl),
[2727] --(CH.sub.2).sub.3C(=O)(2,3-dimethoxy-phenyl),
[2728] --(CH.sub.2).sub.3C(=O)(phenyl),
[2729] --(CH.sub.2).sub.3C(=O)(4-chloro-phenyl),
[2730] --(CH.sub.2).sub.3C(=O)(3-methyl-phenyl),
[2731] --(CH.sub.2).sub.3C(=O)(4-t-butyl-phenyl),
[2732] --(CH.sub.2).sub.3C(=O)(3,4-difluoro-phenyl),
[2733] --(CH.sub.2).sub.3C(=O)(2-methoxy-5-fluoro-phenyl),
[2734] --(CH.sub.2).sub.3C(=O)(4-fluoro-1-naphthyl),
[2735] --(CH.sub.2).sub.3C(=O)(benzyl),
[2736] --(CH.sub.2).sub.3C(=O)(4-pyridyl),
[2737] --(CH.sub.2).sub.3C(=O)(3-pyridyl),
[2738] --(CH.sub.2).sub.3CH(OH)(4-fluoro-phenyl),
[2739] --(CH.sub.2).sub.3CH(OH)(4-pyridyl),
[2740] --(CH.sub.2).sub.3CH(OH)(2,3-dimethoxy-phenyl),
[2741] --(CH.sub.2).sub.3S(3-fluoro-phenyl),
[2742] --(CH.sub.2).sub.3S(4-fluoro-phenyl),
[2743] --(CH.sub.2).sub.3S(=O)(4-fluoro-phenyl),
[2744] --(CH.sub.2).sub.3SO.sub.2(3-fluoro-phenyl),
[2745] --(CH.sub.2).sub.3SO.sub.2(4-fluoro-phenyl),
[2746] --(CH.sub.2).sub.3O(4-fluoro-phenyl),
[2747] --(CH.sub.2).sub.3O(phenyl),
[2748] --(CH.sub.2).sub.3O(3-pyridyl),
[2749] --(CH.sub.2).sub.3O(4-pyridyl),
[2750] --(CH.sub.2).sub.3O(2-NH.sub.2-phenyl),
[2751] --(CH.sub.2).sub.3O(2-NH.sub.2-5-F-phenyl),
[2752] --(CH.sub.2).sub.3O(2-NH.sub.2-4-F-phenyl),
[2753] --(CH.sub.2).sub.3O(2-NH.sub.2-3-F-phenyl),
[2754] --(CH.sub.2).sub.3O(2-NH.sub.2-4-Cl-phenyl),
[2755] --(CH.sub.2).sub.3O(2-NH.sub.2-4-OH-phenyl),
[2756] --(CH.sub.2).sub.3O(2-NH.sub.2-4-Br-phenyl),
[2757] --(CH.sub.2).sub.3O(2-NHC(=O)Me-4-F-phenyl),
[2758] --(CH.sub.2).sub.3O(2-NHC(=O)Me-phenyl),
[2759] --(CH.sub.2).sub.3NH(4-fluoro-phenyl),
[2760] --(CH.sub.2).sub.3N(methyl)(4-fluoro-phenyl),
[2761] --(CH.sub.2).sub.3CO.sub.2(ethyl),
[2762] --(CH.sub.2).sub.3C(=O)N(methyl)(methoxy),
[2763] --(CH.sub.2).sub.3C(=O)NH(4-fluoro-phenyl),
[2764] --(CH.sub.2).sub.2NHC(=O)(phenyl),
[2765] --(CH.sub.2).sub.2NMeC(=O)(phenyl),
[2766] --(CH.sub.2).sub.2NHC(=O)(2-fluoro-phenyl),
[2767] --(CH.sub.2).sub.2NMeC(=O)(2-fluoro-phenyl),
[2768] --(CH.sub.2).sub.2NHC(=O)(4-fluoro-phenyl),
[2769] --(CH.sub.2).sub.2NMeC(=O)(4-fluoro-phenyl),
[2770] --(CH.sub.2).sub.2NHC(=O)(2,4-difluoro-phenyl),
[2771] --(CH.sub.2).sub.2NMeC(=O)(2,4-difluoro-phenyl),
[2772] --(CH.sub.2).sub.3(3-indolyl),
[2773] --(CH.sub.2).sub.3(1-methyl-3-indolyl),
[2774] --(CH.sub.2).sub.3(1-indolyl),
[2775] --(CH.sub.2).sub.3(1-indolinyl),
[2776] --(CH.sub.2).sub.3(1-benzimidazolyl),
[2777] --(CH.sub.2).sub.3(1H-1,2,3-benzotriazol-1-yl),
[2778] --(CH.sub.2).sub.3(1H-1,2,3-benzotriazol-2-yl),
[2779] --(CH.sub.2).sub.2(1H-1,2,3-benzotriazol-1-yl),
[2780] --(CH.sub.2).sub.2(1H-1,2,3-benzotriazol-2-yl),
[2781] --(CH.sub.2).sub.3(3,4 dihydro-1(2H)-quinolinyl),
[2782] --(CH.sub.2).sub.2C(=O)(4-fluoro-phenyl),
[2783] --(CH.sub.2).sub.2C(=O)NH(4-fluoro-phenyl),
[2784] --CH.sub.2CH.sub.2(3-indolyl),
[2785] --CH.sub.2CH.sub.2(1-phthalimidyl),
[2786] --(CH.sub.2).sub.4C(=O)N(methyl)(methoxy),
[2787] --(CH.sub.2).sub.4CO.sub.2(ethyl),
[2788] --(CH.sub.2).sub.4C(=O)(phenyl),
[2789] --(CH.sub.2).sub.4(cyclohexyl),
[2790] --(CH.sub.2).sub.3CH(phenyl).sub.2,
[2791] --CH.sub.2CH.sub.2CH=C(phenyl).sub.2,
[2792] --CH.sub.2CH.sub.2CH=CMe(4-F-phenyl),
[2793] --(CH.sub.2).sub.3CH(4-fluoro-phenyl).sub.2,
[2794] --CH.sub.2CH.sub.2CH=C(4-fluoro-phenyl).sub.2,
[2795] --(CH.sub.2).sub.2(.sub.2,3-dihydro-1H-inden-.sub.2-yl),
[2796] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-phenyl),
[2797] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-5-F-phenyl),
[2798] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-F-phenyl),
[2799] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-3-F-phenyl),
[2800] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-Cl-phenyl),
[2801] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-OH-phenyl),
[2802] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-Br-phenyl),
[2803] --(CH.sub.2).sub.3(1H-indazol-3-yl),
[2804] --(CH.sub.2).sub.3(5-F-1H-indazol-3-yl),
[2805] --(CH.sub.2).sub.3(7-F-1H-indazol-3-yl),
[2806] --(CH.sub.2).sub.3(6-Cl-1H-indazol-3-yl),
[2807] --(CH.sub.2).sub.3(6-Br-1H-indazol-3-yl),
[2808] --(CH.sub.2).sub.3C(=O)(.sub.2-NHMe-phenyl),
[2809] --(CH.sub.2).sub.3(1-benzothien-3-yl),
[2810] --(CH.sub.2).sub.3(6-F-1H-indol-1-yl),
[2811] --(CH.sub.2).sub.3(5-F-1H-indol-1-yl),
[2812] --(CH.sub.2).sub.3(6-F-2,3-dihydro-1H-indol-1-yl),
[2813] --(CH.sub.2).sub.3(5-F-2,3-dihydro-1H-indol-1-yl),
[2814] --(CH.sub.2).sub.3(6-F-1H-indol-3-yl),
[2815] --(CH.sub.2).sub.3(5-F-1H-indol-3-yl),
[2816] --(CH.sub.2).sub.3(5-F-1H-indol-3-yl),
[2817] --(CH.sub.2).sub.3(9H-purin-9-yl),
[2818] --(CH.sub.2).sub.3(7H-purin-7-yl),
[2819] --(CH.sub.2).sub.3(6-F-1H-indazol-3-yl),
[2820] --(CH.sub.2).sub.3C(=O)(2-NHSO.sub.2Me-4-F-phenyl),
[2821] --(CH.sub.2).sub.3C(=O)(2-NHC(=O)Me-4-F-phenyl),
[2822] --(CH.sub.2).sub.3C(=O)(2-NHC(=O)Me-phenyl),
[2823] --(CH.sub.2).sub.3C(=O)(2-NHCO.sub.2Et-4-F-phenyl),
[2824] --(CH.sub.2).sub.3C(=O)(2-NHC(=O)NHEt-4-F-phenyl),
[2825] --(CH.sub.2).sub.3C(=O)(2-NHCHO-4-F-phenyl),
[2826] --(CH.sub.2).sub.3C(=O)(2-OH-4-F-phenyl),
[2827] --(CH.sub.2).sub.3C(=O)(2-MeS-4-F-phenyl),
[2828] --(CH.sub.2).sub.3C(=O)(2-NHSO.sub.2Me-4-F-phenyl),
[2829] --(CH.sub.2).sub.2C(Me)CO.sub.2Me,
[2830] --(CH.sub.2).sub.2C(Me)CH(OH)(4-F-phenyl).sub.2,
[2831] --(CH.sub.2).sub.2C(Me)CH(OH)(4-Cl-phenyl).sub.2,
[2832] --(CH.sub.2).sub.2C(Me)C(=O)(4-F-phenyl),
[2833] --(CH.sub.2).sub.2C(Me)C(=O)(2-MeO-4-F-phenyl),
[2834] --(CH.sub.2).sub.2C(Me)C(=O)(3-Me-4-F-phenyl),
[2835] --(CH.sub.2).sub.2C(Me)C(=O)(2-Me-phenyl),
[2836] --(CH.sub.2).sub.2C(Me)C(=O)phenyl, 17
[2837] R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are
independently selected from
[2838] hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl,
propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy,
ethoxy, isopropoxy, trifluoromethoxy, phenyl, benzyl,
[2839] HC(=O)--, methylC(=O)--, ethylC(=O)--, propylC(=O)--,
isopropylC(=O)--, n-butylC(=O)--, isobutylC(=O)--, secbutylC(=O)--,
tertbutylC(=O)--, phenylC(=O)--,
[2840] methylC(=O)NH--, ethylC(=O)NH--, propylC(=O)NH--,
isopropylC(=O)NH--, n-butylC(=O)NH--, isobutylC(=O)NH--,
secbutylC(=O)NH--, tertbutylC(=O)NH--, phenylC(=O)NH--,
[2841] methylamino-, ethylamino-, propylamino-, isopropylamino-,
n-butylamino-, isobutylamino-, secbutylamino-, tertbutylamino-,
phenylamino-,
[2842] provided that two of substituents R.sup.7, R.sup.8, and
R.sup.9, are independently selected from hydrogen, fluoro, chloro,
bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl,
nitro, trifluoromethyl, methoxy, ethoxy, isopropoxy, and
trifluoromethoxy;
[2843] k is 1 or 2;
[2844] m is 1 or 2; and
[2845] n is 0, 1 or 2.
[2846] [31] In a more preferred embodiment, the present invention
provides the method as defined in claim 30 where the compound
administered is a compound of Formula (V-a): 18
[2847] wherein:
[2848] b is a single bond, wherein the bridge hydrogens are in a
cis position;
[2849] R.sup.1 is selected from
[2850] --(CH.sub.2).sub.3C(=O)(4-fluoro-phenyl),
[2851] --(CH.sub.2).sub.3C(=O)(4-bromo-phenyl),
[2852] --(CH.sub.2).sub.3C(=O)(4-methyl-phenyl),
[2853] --(CH.sub.2).sub.3C(=O)(4-methoxy-phenyl),
[2854] --(CH.sub.2).sub.3C(=O)(4-(3,4-dichloro-phenyl)phenyl),
[2855] --(CH.sub.2).sub.3C(=O)(3-methyl-4-fluoro-phenyl),
[2856] --(CH.sub.2).sub.3C(=O)(2,3-dimethoxy-phenyl),
[2857] --(CH.sub.2).sub.3C(=O)(phenyl),
[2858] --(CH.sub.2).sub.3C(=O)(4-chloro-phenyl),
[2859] --(CH.sub.2).sub.3C(=O)(3-methyl-phenyl),
[2860] --(CH.sub.2).sub.3C(=O)(4-t-butyl-phenyl),
[2861] --(CH.sub.2).sub.3C(=O)(3,4-difluoro-phenyl),
[2862] --(CH.sub.2).sub.3C(=O)(2-methoxy-5-fluoro-phenyl),
[2863] --(CH.sub.2).sub.3C(=O)(4-fluoro-1-naphthyl),
[2864] --(CH.sub.2).sub.3C(=O)(benzyl),
[2865] --(CH.sub.2).sub.3C(=O)(4-pyridyl),
[2866] --(CH.sub.2).sub.3C(=O)(3-pyridyl),
[2867] --(CH.sub.2).sub.3CH(OH)(4-fluoro-phenyl),
[2868] --(CH.sub.2).sub.3CH(OH) (4-pyridyl),
[2869] --(CH.sub.2).sub.3CH(OH) (2,3-dimethoxy-phenyl),
[2870] --(CH.sub.2).sub.3S(3-fluoro-phenyl),
[2871] --(CH.sub.2).sub.3S(4-fluoro-phenyl),
[2872] --(CH.sub.2).sub.3S(=O)(4-fluoro-phenyl),
[2873] --(CH.sub.2).sub.3SO.sub.2(3-fluoro-phenyl),
[2874] --(CH.sub.2).sub.3SO.sub.2(4-fluoro-phenyl),
[2875] --(CH.sub.2).sub.3O(4-fluoro-phenyl),
[2876] --(CH.sub.2).sub.3O(phenyl),
[2877] --(CH.sub.2).sub.3NH(4-fluoro-phenyl),
[2878] --(CH.sub.2).sub.3N(methyl)(4-fluoro-phenyl),
[2879] --(CH.sub.2).sub.3CO.sub.2(ethyl),
[2880] --(CH.sub.2).sub.3C(=O)N(methyl)(methoxy),
[2881] --(CH.sub.2).sub.3C(=O)NH(4-fluoro-phenyl),
[2882] --(CH.sub.2).sub.2NHC(=O)(phenyl),
[2883] --(CH.sub.2).sub.2NMeC(=O)(phenyl),
[2884] --(CH.sub.2).sub.2NHC(=O)(2-fluoro-phenyl),
[2885] --(CH.sub.2).sub.2NMeC(=O)(2-fluoro-phenyl),
[2886] --(CH.sub.2).sub.2NHC(=O)(4-fluoro-phenyl),
[2887] --(CH.sub.2).sub.2NMeC(=O)(4-fluoro-phenyl),
[2888] --(CH.sub.2).sub.2NHC(=O) (2,4-difluoro-phenyl),
[2889] --(CH.sub.2).sub.2NMeC(=O)(2,4-difluoro-phenyl),
[2890] --(CH.sub.2).sub.3(3-indolyl),
[2891] --(CH.sub.2).sub.3(1-methyl-3-indolyl),
[2892] --(CH.sub.2).sub.3(1-indolyl),
[2893] --(CH.sub.2).sub.3(1-indolinyl),
[2894] --(CH.sub.2).sub.3(1-benzimidazolyl),
[2895] --(CH.sub.2).sub.3(1H-1,2,3-benzotriazol-1-yl),
[2896] --(CH.sub.2).sub.3(1H-1,2,3-benzotriazol-2-yl),
[2897] --(CH.sub.2).sub.2(1H-1,2,3-benzotriazol-1-yl),
[2898] --(CH.sub.2).sub.2(1H-1,2,3-benzotriazol-2-yl),
[2899] --(CH.sub.2).sub.3(3,4 dihydro-1(2H)-quinolinyl),
[2900] --(CH.sub.2).sub.2C(=O)(4-fluoro-phenyl),
[2901] --(CH.sub.2).sub.2C(=O)NH(4-fluoro-phenyl),
[2902] --CH.sub.2CH.sub.2(3-indolyl),
[2903] --CH.sub.2CH.sub.2(1-phthalimidyl),
[2904] --(CH.sub.2)4C(=O)N(methyl)(methoxy),
[2905] --(CH.sub.2)4CO.sub.2(ethyl),
[2906] --(CH.sub.2)4C(=O)(phenyl),
[2907] --(CH.sub.2)4(cyclohexyl),
[2908] --(CH.sub.2).sub.3CH(phenyl).sub.2,
[2909] --CH.sub.2CH.sub.2CH=C(phenyl).sub.2,
[2910] --CH.sub.2CH.sub.2CH=CMe(4-F-phenyl),
[2911] --(CH.sub.2).sub.3CH(4-fluoro-phenyl).sub.2,
[2912] --CH.sub.2CH.sub.2CH=C(4-fluoro-phenyl).sub.2,
[2913] --(CH.sub.2).sub.2(2,3-dihydro-1H-inden-.sub.2-yl),
[2914] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-phenyl),
[2915] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-5-F-phenyl),
[2916] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-F-phenyl),
[2917] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-3-F-phenyl),
[2918] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-Cl-phenyl),
[2919] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-OH-phenyl),
[2920] --(CH.sub.2).sub.3C(=O)(2-NH.sub.2-4-Br-phenyl),
[2921] --(CH.sub.2).sub.3(1H-indazol-3-yl),
[2922] --(CH.sub.2).sub.3(5-F-1H-indazol-3-yl),
[2923] --(CH.sub.2).sub.3(7-F-1H-indazol-3-yl),
[2924] --(CH.sub.2).sub.3(6-Cl-1H-indazol-3-yl),
[2925] --(CH.sub.2).sub.3(6-Br-1H-indazol-3-yl),
[2926] --(CH.sub.2).sub.3C(=O)(2-NHMe-phenyl),
[2927] --(CH.sub.2).sub.3(1-benzothien-3-yl),
[2928] --(CH.sub.2).sub.3(6-F-1H-indol-1-yl),
[2929] --(CH.sub.2).sub.3(5-F-1H-indol-1-yl),
[2930] --(CH.sub.2).sub.3(6-F-2,3-dihydro-1H-indol-1-yl),
[2931] --(CH.sub.2).sub.3(5-F-2,3-dihydro-1H-indol-1-yl),
[2932] --(CH.sub.2).sub.3(6-F-1H-indol-3-yl),
[2933] --(CH.sub.2).sub.3(5-F-1H-indol-3-yl),
[2934] --(CH.sub.2).sub.3(5-F-1H-indol-3-yl),
[2935] --(CH.sub.2).sub.3(9H-purin-9-yl),
[2936] --(CH.sub.2).sub.3(7H-purin-7-yl),
[2937] --(CH.sub.2).sub.3(6-F-1H-indazol-3-yl),
[2938] --(CH.sub.2).sub.3C(=O)(2-NHSO.sub.2Me-4-F-phenyl),
[2939] --(CH.sub.2).sub.3C(=O)(2-NHC(=O)Me-4-F-phenyl),
[2940] --(CH.sub.2).sub.3C(=O)(2-NHC(=O)Me-4-F-phenyl),
[2941] --(CH.sub.2).sub.3C(=O)(2-NHCO.sub.2Et-4-F-phenyl),
[2942] --(CH.sub.2).sub.3C(=O)(2-NHC(=O)NHEt-4-F-phenyl),
[2943] --(CH.sub.2).sub.3C(=O)(2-NHCHO-4-F-phenyl),
[2944] --(CH.sub.2).sub.3C(=O)(2-OH-4-F-phenyl),
[2945] --(CH.sub.2).sub.3C(=O)(2-MeS-4-F-phenyl),
[2946] --(CH.sub.2).sub.3C(=O)(2-NHSO.sub.2Me-4-F-phenyl),
[2947] --(CH.sub.2).sub.2C(Me)CO.sub.2Me,
[2948] --(CH.sub.2).sub.2C(Me)CH(OH)(4-F-phenyl)2,
[2949] --(CH.sub.2).sub.2C(Me)CH(OH)(4-Cl-phenyl)2,
[2950] --(CH.sub.2).sub.2C(Me)C(=O)(4-F-phenyl),
[2951] --(CH.sub.2).sub.2C(Me)C(=O)(2-MeO-4-F-phenyl),
[2952] --(CH.sub.2).sub.2C(Me)C(=O)(3-Me-4-F-phenyl),
[2953] --(CH.sub.2).sub.2C(Me)C(=O)(2-Me-phenyl),
[2954] --(CH.sub.2).sub.2C(Me)C(=O)phenyl, 19
[2955] R.sup.7, R.sup.8, and R.sup.9, at each occurrence, are
independently
[2956] selected from hydrogen, fluoro, chloro, bromo, cyano,
methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro,
trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy,
methylC(=O)--, ethylC(=O)--, propylC(=O)--, isopropylC(=O)--,
methylC(=O)NH--, ethylC(=O)NH --, propylC(=O)NH--,
isopropylC(=O)NH, methylamino-, ethylamino-, propylamino-, and
isopropylamino-,
[2957] provided that two of substituents R.sup.7, R.sup.8, and
R.sup.9, are independently selected from hydrogen, fluoro, chloro,
methyl, trifluoromethyl, methoxy, and trifluoromethoxy;
[2958] m is 1 or 2; and
[2959] n is 0, 1 or 2.
[2960] [32] In a more preferred embodiment, the present invention
provides the method as defined in claim 18 where the compound
administered-is selected from the group:
[2961]
(.+-.)-cis-9-(cyclopropylcarbonyl)-4,5,6a,7,8,9,10,10a-octahydropyr-
ido[4,3-b]pyrrolo[3,2,1-hi]indole;
[2962]
(.+-.)-cis-9-isobutyryl-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]p-
yrrolo[3,2,1-hi]indole; tert-butyl
(.+-.)-cis-2-(2-chlorophenyl)-4,5,7,8,1-
0,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[2963] tert-butyl
(.+-.)-cis-2-(2,4-dichlorophenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[2964] tert-butyl
(.+-.)-cis-2-(3,4-dichlorophenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[2965] tert-butyl
(.+-.)-cis-2-(2,3-dichlorophenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[2966] tert-butyl
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-4,5,7,-
8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[2967] tert-butyl
(.+-.)-cis-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a-h-
exahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[2968] tert-butyl
(.+-.)-cis-2-(5-isopropyl-2-methoxyphenyl)-4,5,7,8,10,10-
a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[2969] tert-butyl
(.+-.)-cis-2-(3-fluorophenyl)-4,5,7,8,10,10a-hexahydropy-
rido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[2970] tert-butyl
(.+-.)-cis-2-(2,4-dimethoxyphenyl)-4,5,7,8,10,10a-hexahy-
dropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[2971]
(.+-.)-cis-2-(2-chlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4-
,3-b]pyrrolo[3,2,1-hi]indole;
[2972]
(.+-.)-cis-2-(2,4-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole;
[2973]
(.+-.)-cis-2-(3,4-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do[4,3-b]pyrrolo[3, 2,1-hi]indole;
[2974]
(.+-.)-cis-2-(2,3-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole;
[2975]
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,1-
0a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
[2976]
(.+-.)-cis-2-(2-chloro-4-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octahyd-
ropyrido[4,3-b]pyrrolo[3, 2,1-hi]indole;
[2977]
(.+-.)-cis-2-(4-isopropyl-2-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octa-
hydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
[2978]
(.+-.)-cis-2-(3-fluorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4-
,3-b]pyrrolo[3, 2,1-hi]indole;
[2979] (.+-.)-cis-2-(2,
4-dimethoxyphenyl)-4,5,6a,7,8,9,10,10a-octahydropy-
rido[4,3-b]pyrrolo[3,2,1-hi]indole;
[2980] tert-butyl (.+-.)-cis-5,
6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5-
]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate;
[2981] tert-butyl
(.+-.)-cis-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyrido[3'-
,4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate;
[2982] tert-butyl
(.+-.)-cis-2-(2,3-dichlorophenyl)-5,6,8,9,11,11a-hexahyd-
ro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate;
[2983] tert-butyl
(.+-.)-cis-2-(3,4-dichlorophenyl)-5,6,8,9,11,11a-hexahyd-
ro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate;
[2984] tert-butyl
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-5,6,8,-
9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)--
carboxylate;
[2985] (.+-.)-cis-2-(2,
3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4-
H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[2986]
(.+-.)-cis-2-(3,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[2987]
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[2988]
4-((.+-.)-cis-2-(2-chlorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-
-b]pyrrolo
[3,2,1-hi]indol-9(6aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[2989]
4-((.+-.)-cis-2-(2,4-dichlorophenyl)-4,5,7,8,10,10a-hexahydropyrido-
[4,3-b]pyrrolo[3,2,1-hi]indol-9(6aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[2990]
4-((.+-.)-cis-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]qionolin-10(7aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[2991]
4-((.+-.)-cis-4,5,7,8,10,10a-hexahydropyrido[4.3-b]pyrrolo[3,
2,1-hi]indol-9(6aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[2992]
(6aS,10aR)-2-(2-fluoro-4-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
[2993] tert-butyl
(6aS,10aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-4,5,7,-
8,10,10a-hexahydropyrido
[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate- ;
[2994]
(6aS,10aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,1-
0a-octahydropyrido [4,3-b]pyrrolo[3,2,1-hi]indole;
[2995] tert-butyl
(6aS,10aR)-2-(4-chloro-2-fluorophenyl)-4,5,7,8,10,10a-he-
xahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[2996]
(6aS,10aR)-2-(4-chloro-2-fluorophenyl)-4,5,6a,7,8,9,10,10a-octahydr-
opyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
[2997] tert-butyl
(6aS,10aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-4,-
5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxyl-
ate;
[2998]
(6aS,10aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,-
10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
[2999] tert-butyl
(6aS,10aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-4,5,7-
,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate-
;
[3000]
(6aS,10aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,-
10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
[3001] tert-butyl
(6aS,10aR)-2-phenyl-4,5,7,8,10,10a-hexahydropyrido[4,3-b-
]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[3002] (6aS,10aR)-2-phenyl-4,5,6a,7,8,9,10,10a-octahydropyrido
[4,3-b]pyrrolo[3,2,1-hi]indole;
[3003] tert-butyl
(6aS,10aR)-2-(2-methylphenyl)-4,5,7,8,10,10a-hexahydropy-
rido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[3004]
(6aS,10aR)-2-(2-methylphenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4-
,3-b]pyrrolo[3,2,1-hi]indole;
[3005] tert-butyl
(6aS,10aR)-2-[2-(trifluoromethyl)phenyl]-4,5,7,8,10,10a--
hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[3006]
(6aS,10aR)-2-[2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,10a-octahy-
dropyrido [4,3-b]pyrrolo[3,2,1-hi]indole;
[3007] tert-butyl
(6aS,10aR)-2-(3,4-dimethoxyphenyl)-4,5,7,8,10,10a-hexahy-
dropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[3008]
(6aS,10aR)-2-(3,4-dimethoxyphenyl)-4,5,6a,7,8,9,10,10a-octahydropyr-
ido[4,3-b]pyrrolo[3,2,1-hi]indole;
[3009] tert-butyl
(6aS,10aR)-2-(2,5-dichlorophenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[3010]
(6aS,10aR)-2-(2,5-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole;
[3011] tert-butyl
(6aS,10aR)-2-(3,5-dichlorophenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[3012]
(6aS,10aR)-2-(3,5-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole;
[3013] tert-butyl
(6aS,10aR)-2-(2-isopropyl-4-methoxyphenyl)-4,5,7,8,10,10-
a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[3014]
(6aS,10aR)-2-(2-isopropyl-4-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octa-
hydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
[3015] tert-butyl
(6aS,10aR)-2-(5-fluoro-4-methoxy-2-methylphenyl)-4,5,7,8-
,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[3016]
(6aS,10aR)-2-(5-fluoro-4-methoxy-2-methylphenyl)-4,5,6a,7,8,9,10,10-
a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
[3017] tert-butyl
(6aS,10aR)-2-(4-methoxy-2-methylphenyl)-4,5,7,8,10,10a-h-
exahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[3018]
(6aS,10aR)-2-(4-methoxy-2-methylphenyl)-4,5,6a,7,8,9,10,10a-octahyd-
ropyrido [4,3-b]pyrrolo[3,2,1-hi]indole;
[3019] tert-butyl
(6aS,10aR)-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a-h-
exahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[3020]
(6aS,10aR)-2-(2-chloro-4-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
[3021] tert-butyl
(6aS,10aR)-2-(3-chloro-2-methylphenyl)-4,5,7,8,10,10a-he-
xahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate;
[3022]
(6aS,10aR)-2-(3-chloro-2-methylphenyl)-4,5,6a,7,8,9,10,10a-octahydr-
opyrido[4,3-b]pyrrolo[3,2,1-hi]indole;
[3023]
2-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2-
,1-hi]-2-yl]-5-methoxybenzaldehyde;
[3024]
(6aS,10aR)-2-(2,6-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole;
[3025]
N-[4-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[-
3,2,1-hi]indol-2-yl]-3-(trifluoromethyl)phenyl]-N-methylamine;
[3026]
4-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2-
,1-hi]indol-2-yl]-3-(trifluoromethyl)phenylamine;
[3027]
1-(2-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[-
3,2,1-hi]indol-2-yl]-5-methoxyphenyl)ethanol;
[3028] tert-butyl
(.+-.)-cis-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,-
2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate;
[3029] tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate;
[3030]
(8aS,12aR)-2-(2,4-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3031]
(8aS,12aR)-2-(2,3-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3032]
(8aS,12aR)-2-(3,4-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3033]
(8aS,12aR)-2-(3,5-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3034]
(8aS,12aR)-2-(2,5-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3035]
(8aS,12aR)-2-(2,6-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3036]
(8aS,12aR)-2-(2-chlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indole;
[3037]
(8aS,12aR)-2-(3-chlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indole;
[3038]
(8aS,12aR)-2-(4-chlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indole;
[3039]
(.+-.)-cis-2-(2,6-difluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3040]
(8aS,12aR)-2-(2,6-difluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3041]
(8aS,12aR)-2-(2,3-difluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3042]
(8aS,12aR)-2-(3,4-difluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3043]
(8aS,12aR)-2-(3-fluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indole;
[3044]
(8aS,12aR)-2-[2-chloro-4-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,1-
1,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3045]
(8aS,12aR)-2-(2-chloro-4-methoxyphenyl)-4,5,6,7,8a,9,10,11,12,12a-d-
ecahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3046]
(8aS,12aR)-2-(2-fluoro-4-methoxyphenyl)-4,5,6,7,8a,9,10,11,12,12a-d-
ecahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3047]
(8aS,12aR)-2-(4-methoxy-2-methylphenyl)-4,5,6,7,8a,9,10,11,12,12a-d-
ecahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3048]
(8aS,12aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,-
11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3049]
(8aS,12aR)-2-[2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a--
decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3050]
(8aS,12aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,-
10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3051]
(8aS,12aR)-2-[2,4-bis(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12-
,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3052]
(8aS,12aR)-2-[4-fluoro-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,1-
1,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole;
[3053]
4-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]p-
yrido[4,3-b]indol-2-yl]-3-(trifluoromethyl)aniline;
[3054]
4-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]p-
yrido[4,3-b]indol-2-yl]-N-methyl-3-(trifluoromethyl)aniline;
[3055]
2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]p-
yrido[4,3-b]indol-2-yl]benzaldehyde;
[3056]
{2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]-
pyrido[4,3-b]indol-2-yl]phenyl}methanol;
[3057]
2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]p-
yrido[4,3-b]indol-2-yl]-5-methoxybenzaldehyde;
[3058]
{2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]-
pyrido[4,3-b]indol-2-yl]-5-methoxyphenyl}methanol;
[3059]
4-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]p-
yrido[4,3-b]indol-2-yl]-3-methylbenzonitrile;
[3060]
1-{2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-h-
i]pyrido[4,3-b]indol-2-yl]-5-methoxyphenyl}ethanol;
[3061] tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro-4H-pyr-
ido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate;
[3062]
(7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3063]
(7aS,11aR)-2-(3,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3064]
(7aS,11aR)-2-(3,5-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3065]
(7aS,11aR)-2-(2,5-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3066]
(7aS,11aR)-2-(2,6-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3067]
(7aS,11aR)-2-(2-chlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyr-
ido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3068]
(7aS,11aR)-2-(3-chlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyr-
ido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3069]
(7aS,11aR)-2-(4-chlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyr-
ido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3070]
(7aS,11aR)-2-(2,6-difluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3071]
(7aS,11aR)-2-(2,6-difluorophenyl)-10-methyl-5,6,7a,8,9,10,11,11a-oc-
tahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3072]
(7aS,11aR)-2-(2,3-difluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3073]
(7aS,11aR)-2-(3,4-difluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3074]
(7aS,11aR)-2-(3-fluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyr-
ido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3075]
(7aS,11aR)-2-[2-chloro-4-methoxyphenyl)-5,6,7a,8,9,10,11,11a-octahy-
dro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3076]
(7aS,11aR)-2-[2-fluoro-4-methoxyphenyl)-5,6,7a,8,9,10,11,11a-octahy-
dro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3077]
(7aS,11aR)-2-(4-methoxy-2-methylphenyl)-5,6,7a,8,9,10,11,11a-octahy-
dro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3078]
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11-
,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3079]
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]py-
rrolo[3,2,1-ij]quinolin-2-yl]-3-(trifluoromethyl)phenol;
[3080]
(7aS,11aR)-2-[2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octah-
ydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3081]
(7aS,11aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10-
,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3082]
(7aS,11aR)-2-[2,4-bis(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a--
octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3083]
(7aS,11aR)-2-[4-fluoro-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3084]
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]py-
rrolo[3,2,1-ij]quinolin-2-yl]-3-(trifluoromethyl)aniline;
[3085]
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]py-
rrolo[3,2,1-ij]quinolin-2-yl]-N-methyl-3-(trifluoromethyl)aniline;
[3086]
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]py-
rrolo[3,2,1-ij]quinolin-2-yl]-3-methylbenzonitrile;
[3087]
2-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]py-
rrolo[3,2,1-ij]quinolin-2-yl]benzaldehyde;
[3088]
{2-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]p-
yrrolo[3,2,1-ij]quinolin-2-yl]phenyl}methanol;
[3089]
2-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]py-
rrolo[3,2,1-ij]quinolin-2-yl]-5-methoxybenzaldehyde;
[3090]
{2-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]p-
yrrolo[3,2,1-ij]quinolin-2-yl]-5-methoxyphenyl}methanol;
[3091]
(8aS,12aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,1-
1,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3b]indole;
[3092]
(7aS,11aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3093]
(8aS,12aR)-2-[3-chloro-2-methylphenyl]-4,5,6,7,8a,9,10,11,12,12a-de-
cahydroazepino[3,2,1-hi]pyrido[4,3b]indole;
[3094]
(7aS,11aR)-2-[3-chloro-2-methylphenyl]-5,6,7a,8,9,10,11,11a-octahyd-
ro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3095]
(7aS,11aR)-2-[5-fluoro-2-methylphenyl]-5,6,7a,8,9,10,11,11a-octahyd-
ro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3096]
(.+-.)-cis-2-(2,3-dichlorophenyl)-10-propyl-5,6,7a,8,9,10,11,11a-oc-
tahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline ;
[3097]
(7aS,11aR)-2-(2,3-dichlorophenyl)-10-propyl-5,6,7a,8,9,10,11,11a-oc-
tahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline ;
[3098]
(.+-.)-cis-10-butyl-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-oct-
ahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline ;
[3099]
(7aS,11aR)-10-butyl-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-oct-
ahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3100]
(7aS,11aR)-2-(2,3-dichlorophenyl)-10-(4-pentenyl)-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3101]
(7aS,11aR)-2-(2,3-dichlorophenyl)-10-(3-methyl-2-butenyl)-5,6,7a,8,-
9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
;
[3102]
(7aS,11aR)-2-(2,4-dichlorophenyl)-10-propyl-5,6,7a,8,9,10,11,11a-oc-
tahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline ;
[3103]
(7aS,11aR)-10-butyl-2-(2,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-oct-
ahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3104]
(7aS,11aR)-2-(2,4-dichlorophenyl)-10-(4-pentenyl)-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3105]
(7aS,11aR)-2-(2,4-dichlorophenyl)-10-(3-methyl-2-butenyl)-5,6,7a,8,-
9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3106]
(7aS,11aR)-10-(cyclobutylmethyl)-2-(2,3-dichlorophenyl)-5,6,7a,8,9,-
10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3107]
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-methyl-5,6,7a-
,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3108]
(7aS,11aR)-10-ethyl-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,-
8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3109]
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-propyl-5,6,7a-
,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3110]
(7aS,11aR)-10-butyl-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-meth-
yl-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]qui-
noline;
[3111]
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-(4-pentenyl)--
5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinol-
ine;
[3112]
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-(3-methyl-2-b-
utenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-i-
j]quinoline;
[3113]
(7aS,11aR)-10-(2-fluoroethyl)-2-[4-methoxy-2-(trifluoromethyl)pheny-
l]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]qui-
noline;
[3114]
(7aS,11aR)-10-(2,2-difluoroethyl)-2-[4-methoxy-2-(trifluoromethyl)p-
henyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij-
]quinoline;
[3115]
(7aS,11aR)-10-(cyclobutylmethyl)-2-[4-methoxy-2-(trifluoromethyl)ph-
enyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]-
quinoline;
[3116]
4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[3117]
4-((7aR,11aS)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[3118]
4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(2-aminophenyl)-1-butanone;
[3119]
4-((7aR,11aS)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(2-aminophenyl)-1-butanone;
[3120]
(.+-.)-cis-3-(5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)propyl 4-fluorophenyl ether;
[3121]
4-((.+-.)-cis-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(4-pyridinyl)-1-butanone;
[3122]
(.+-.)-cis-10-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-5,6,7a,8,9-
,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3123]
(7aS,11aR)-10-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-5,6,7a,8,9-
,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline;
[3124]
(.+-.)-cis-4-(4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[-
4,3-b]indol-11(8aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[3125]
4-((8aS,12aR)-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[-
4,3-b]indol-11(8aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[3126]
4-((8aR,12aS)-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[-
4,3-b]indol-11(8aH)-yl)-1-(4-fluorophenyl)-1-butanone;
[3127]
4-((.+-.)-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3--
b]indol-11(8aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone;
[3128]
4-((.+-.)-cis-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone
;
[3129]
4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone;
and
[3130]
4-((7aR,11aS)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone.
[3131] [33] In a more preferred embodiment, the present invention
provides the method as defined in claim 18 where the compound
administered is selected from the group:
[3132]
4-[(.+-.)-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':4,5]p-
yrrolo [3,2,1-ij]quinolin-10-yl]-1-(4-fluorophenyl)-1-butanone;
[3133]
4-[(.+-.)-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':4,5]p-
yrrolo
[3,2,1-ij]quinolin-10-yl]-1-(2-amino-4-fluorophenyl)-1-butanone;
[3134]
4-[(.+-.)-4,5,6,7,9,10,11,12,13,13a-decahydro-11H-diazepino[4,5-b:3-
,2,1-hi]indol-11-yl]-1-(4-fluorophenyl)-1-butanone;
[3135]
4-[(.+-.)-4,5,6,7,9,10,11,12,13,13a-decahydro-11H-diazepino[4,5-b:3-
,2,1-hi]indol-11-yl]-1-(2-amino-4-fluorophenyl)-1-butanone;
[3136] tert-butyl
(.+-.)-cis-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino-
[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-11-carboxylate;
[3137] tert-butyl
(.+-.)-cis-2-bromo-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-
-azepino[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-11-carboxylate;
and
[3138]
(.+-.)-cis-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,8,9,10,11,12-
,12a-octahydro-4H,7aH-azepino[3',4':4,5]pyrrolo[3,2,1-ij]quinoline.
[3139] [34] In a more preferred embodiment, the present invention
provides the method as defined in claim 18 where the compound
administered is selected from the group:
[3140] tert-butyl
(.+-.)-cis-2-bromo-4-oxo-4,5,6,7,9,10,12,12a-octahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate;
[3141] tert-butyl
(.+-.)-cis-2-(2,4-dichlorophenyl)-4-oxo-4,5,6,7,9,10,12,-
12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate;
[3142]
(.+-.)-cis-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indol-4(5H)-one;
[3143]
(8aS,12aR)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indol-4(5H)-one;
[3144]
(8aR,12aS)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indol-4 (5H)-one;
[3145]
(8aS,12aR)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indol-4-ol; and
[3146]
(8aR,12aS)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indol-4-ol.
DEFINITIONS
[3147] As used herein, the term "addictive behavior" includes
behaviors associated with and/or caused by physical and/or
psychological dependence on narcotics, opiates, analgesics,
painkillers, amphetamines, cocaine, heroin, opium, marijuana,
alcohol, smoking, nicotine, gambling and eating.
[3148] The term "sleep disorders," as used herein, includes
insomnia, narcolepsy and sleep apnea.
[3149] The compounds herein described may have asymmetric centers.
Compounds of the present invention containing an asymmetrically
substituted atom may be isolated in optically active or racemic
forms. It is well known in the art how to prepare optically active
forms, such as by resolution of racemic forms or by synthesis from
optically active starting materials. Many geometric isomers of
olefins, C=N double bonds, and the like can also be present in the
compounds described herein, and all such stable isomers are
contemplated in the present invention. Cis and trans geometric
isomers of the compounds of the present invention are described and
may be isolated as a mixture of isomers or as separated isomeric
forms. All chiral, diastereomeric, racemic forms and all geometric
isomeric forms of a structure are intended, unless the specific
stereochemistry or isomeric form is specifically indicated.
[3150] The numbering of the tetracyclic ring-system present in the
compounds of Formula (I), as defined by nomenclature known to one
skilled in the art, is shown for two examples in Formula (I'), when
k is 1, m is 1, and n is 1; and in Formula (I"), when k is 1, m is
1, and n is 2: 20
[3151] The tetracyclic ring-system present in compounds of Formula
(I) occur as "cis" or "trans" isomers when the carbon-carbon bond b
in Formula (I) is a single bond. As such, the terms "cis" and
"trans", in conjunction with the tetracyclic ring structure, refer
to the configuration of hydrogen atoms on carbon atoms 7a and 11a
in Formula (I') or, for example, on carbon atoms 8a and 12a in
Formula (I"), above. When both hydrogens are on the same side of
the mean plane determined by the octahydro tetracyclic moiety then
the configuration is designated "cis", if not, the configuration is
designated "trans". It is understood that the above example is for
demonstrative puproses only and not intended to limit the scope of
the tetracyclic ring-system present in compounds of Formula (I). As
such, it is understood that one skilled in the art of organic
chemistry can apply the above numbering system to other values of
k, m, and n in the scope of compounds of Formula (I) to deterine
the appropriate numbering. Additional Examples of the numbering of
the tetracyclic ring-system are further provided below in the
synthetic Examples. Lastly, it is understood that the use of "cis"
or "trans" in the identification of the tetracyclic ring-system is
not meant to construe the configuration of any other cis or trans
geometric isomer in the molecule, for example, cis or trans
butene.
[3152] The term "substituted," as used herein, means that any one
or more hydrogens on the designated atom is replaced with a
selection from the indicated group, provided that the designated
atom's normal valency is not exceeded, and that the substitution
results in a stable compound. When a substituent is keto (i.e.,
=O), then 2 hydrogens on the atom are replaced.
[3153] When any variable (e.g., R.sup.2) occurs more than one time
in any constituent or formula for a compound, its definition at
each occurrence is independent of its definition at every other
occurrence. Thus, for example, if a group is shown to be
substituted with 0-2 R.sup.2, then said group may optionally be
substituted with up to two R.sup.2 groups and R.sup.2 at each
occurrence is selected independently from the definition of
R.sup.2. Also, combinations of substituents and/or variables are
permissible only if such combinations result in stable
compounds.
[3154] When a bond to a substituent is shown to cross a bond
connecting two atoms in a ring, then such substituent may be bonded
to any atom on the ring. When a substituent is listed without
indicating the atom via which such substituent is bonded to the
rest of the compound of a given formula, then such substituent may
be bonded via any atom in such substituent. Combinations of
substituents and/or variables are permissible only if such
combinations result in stable compounds.
[3155] As used herein, "alkyl" or "alkylene" is intended to include
both branched and straight-chain saturated aliphatic hydrocarbon
groups having the specified number of carbon atoms; for example,
"C.sub.1-C.sub.6 alkyl" denotes alkyl having 1 to 6 carbon atoms.
Examples of alkyl include, but are not limited to, methyl, ethyl,
n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl,
n-hexyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl,
3-methylpentyl, and 4-methylpentyl.
[3156] "Alkenyl" or "alkenylene" is intended to include hydrocarbon
chains of either a straight or branched configuration having the
specified number of carbon atoms and one or more unsaturated
carbon-carbon bonds which may occur in any stable point along the
chain. Examples of alkenyl include, but are not limited to,
ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl,
3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,
5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the
like.
[3157] "Alkynyl" or "alkynylene" is intended to include hydrocarbon
chains of either a straight or branched configuration and one or
more carbon-carbon triple bonds which may occur in any stable point
along the chain, such as ethynyl, propynyl, butynyl, pentynyl,
hexynyl and the like.
[3158] "Cycloalkyl" is intended to include saturated ring groups,
having the specified number of carbon atoms. For example,
"C.sub.3-C.sub.6 cycloalkyl" denotes such as cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl.
[3159] "Alkoxy" or "alkyloxy" represents an alkyl group as defined
above with the indicated number of carbon atoms attached through an
oxygen bridge. Examples of alkoxy include, but are not limited to,
methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy,
t-butoxy, n-pentoxy, and s-pentoxy. Similarly, "alkylthio" is
represents an alkyl group as defined above with the indicated
number of carbon atoms attached through a sulpher bridge.
[3160] "Halo" or "halogen" as used herein refers to fluoro, chloro,
bromo, and iodo; and "counterion" is used to represent a small,
negatively charged species such as chloride, bromide, hydroxide,
acetate, sulfate, and the like.
[3161] "Haloalkyl" is intended to include both branched and
straight-chain saturated aliphatic hydrocarbon groups having the
specified number of carbon atoms, substituted with 1 or more
halogen (for example --C.sub.vF.sub.w where v=1 to 3 and w=1 to
(2v+1)). Examples of haloalkyl include, but are not limited to,
trifluoromethyl, trichloromethyl, pentafluoroethyl,
pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and
heptachloropropyl.
[3162] As used herein, "carbocycle" is intended to mean any stable
3- to 7-membered monocyclic or bicyclic or 7- to 13-membered
bicyclic or tricyclic, any of which may be saturated, partially
unsaturated, or aromatic. Examples of such carbocycles include, but
are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,
[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane
(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl,
indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
[3163] As used herein, the term "heterocycle" or "heterocyclic
ring" is intended to mean a stable 5- to 7-membered monocyclic or
bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is
saturated partially unsaturated or unsaturated (aromatic), and
which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms
independently selected from the group consisting of N, O and S and
including any bicyclic group in which any of the above-defined
heterocyclic rings is fused to a benzene ring. The nitrogen and
sulfur heteroatoms may optionally be oxidized. The heterocyclic
ring may be attached to its pendant group at any heteroatom or
carbon atom which results in a stable structure. The heterocyclic
rings described herein may be substituted on carbon or on a
nitrogen atom if the resulting compound is stable. If specifically
noted, a nitrogen in the heterocycle may optionally be quaternized.
It is preferred that when the total number of S and O atoms in the
heterocycle exceeds 1, then these heteroatoms are not adjacent to
one another. It is preferred that the total number of S and O atoms
in the heterocycle is not more than 1.
[3164] Examples of heterocycles include, but are not limited to,
1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl,
3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,
6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl,
4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl,
decahydroquinolinyl, 2H, 6H-1, 5,2-dithiazinyl,
dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, imidazolopyridinyl,
1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,
isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl,
isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,
isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl,
oxazolidinylperimidinyl, oxindolyl, phenanthridinyl,
phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl,
phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,
piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,
purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,
pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazole,
pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,
tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thiazolopyridinyl, thienyl, thienothiazolyl, thienooxazolyl,
thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
Preferred heterocycles include, but are not limited to, pyridinyl,
furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl,
imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl,
benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl,
benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl,
isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl,
oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.
Preferred 5 to 6 membered heterocycles include, but are not limited
to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,
piperazinyl, imidazolyl, and oxazolidinyl. Also included are fused
ring and spiro compounds containing, for example, the above
heterocycles.
[3165] As used herein, the term "bicyclic heterocyclic ring system"
is intended to mean a stable 9- to 10-membered bicyclic
heterocyclic ring formed from the substituent NR.sup.12R.sup.13,
which is partially unsaturated or unsaturated (aromatic), and which
consists of carbon atoms, a nitrogen atom, and 1 or 2 additional
heteroatoms independently selected from the group consisting of N,
O and S. The additional nitrogen or sulfur heteroatoms may
optionally be oxidized. The heterocyclic ring is attached to its
pendant group by the nitrogen atom of the group NR.sup.12R.sup.13
and for which results in a stable structure. The heterocyclic rings
described herein may be substituted on carbon or on a nitrogen atom
if the resulting compound is stable. If specifically noted, a
nitrogen in the heterocycle may optionally be quaternized. It is
preferred that when the total number of S and O atoms in the
heterocycle exceeds 1, then these heteroatoms are not adjacent to
one another. It is preferred that the total number of S and O atoms
in the heterocycle is not more than 1. The term "bicyclic
heterocyclic ring system" is intended to be a subset of the term
"heterocyclic ring system". Preferred examples of a 9- to
10-membered bicyclic heterocyclic ring system are benzimidazolyl,
benzimidazolinyl, benzoxazolinyl, dihydrobenzthiazolyl,
dihydrodioxobenzthiazolyl, benzisoxazolinyl, 1H-indazolyl, indolyl,
indolinyl, isoindolinyl, tetrahydro-isoquinolinyl,
tetrahydro-quinolinyl, and benzotriazolyl.
[3166] Additionally, a subclass of preferred heterocycles are
heterocycles which function as an isostere of a cyclic but
non-heterocyclic substitutent such as --CH.sub.2--C(=O)-phenyl.
Preferred examples of such heterocycles include, but are not
limited to, benzimidazolyl, benzofuranyl, benzothiophenyl,
benzoxazolyl, benzthiazolyl, benzisoxazolyl, furanyl, imidazolinyl,
1H-indazolyl, indolinyl, isoindolinyl, isoquinolinyl, oxazolyl,
piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, quinolinyl,
thiazolyl, thiophenyl, and 1,2,3-triazolyl.
[3167] As used herein, the term "aryl", or aromatic residue, is
intended to mean an aromatic moiety containing the specified number
of carbon atoms, such as phenyl, pyridinyl and naphthyl.
[3168] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[3169] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines;
alkali or organic salts of acidic residues such as carboxylic
acids; and the like. The pharmaceutically acceptable salts include
the conventional non-toxic salts or the quaternary ammonium salts
of the parent compound formed, for example, from non-toxic
inorganic or organic acids. For example, such conventional
non-toxic salts include those derived from inorganic acids such as
hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric
and the like; and the salts prepared from organic acids such as
acetic, propionic, succinic, glycolic, stearic, lactic, malic,
tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicylic, sulfanilic,
2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane
disulfonic, oxalic, isethionic, and the like.
[3170] The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound which
contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two; generally, nonaqueous media like ether, ethyl
acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists
of suitable salts are found in Remington's Pharmaceutical Sciences,
17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the
disclosure of which is hereby incorporated by reference.
[3171] "Prodrugs" are intended to include any covalently bonded
carriers which release the active parent drug according to formula
(I) in vivo when such prodrug is administered to a mammalian
subject. Prodrugs of a compound of formula (I) are prepared by
modifying functional groups present in the compound in such a way
that the modifications are cleaved, either in routine manipulation
or in vivo, to the parent compound. Prodrugs include compounds of
formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded
to any group that, when the prodrug or compound of formula (I) is
administered to a mammalian subject, cleaves to form a free
hydroxyl, free amino, or free sulfhydryl group, respectively.
Examples of prodrugs include, but are not limited to, acetate,
formate and benzoate derivatives of alcohol and amine functional
groups in the compounds of Formula (I), and the like.
[3172] "Stable compound" and "stable structure" are meant to
indicate a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[3173] Synthesis
[3174] Throughout the details of the invention, the following
abbreviations are used with the following meanings:
1 Reagents: MCPBA m-chloroperoxybenzoic acid DIBAL diisobutyl
aluminum hydride Et.sub.3N triethylamine TFA trifluoroacetic acid
LAH lithium aluminum hydride NBS N-bromo succinimide Red-A1 Sodium
bis(2-methoxyethoxy)aluminu- m hydride Pd.sub.2dba.sub.3
Tris(dibenzylideneacetone)dipalladium(- 0) ACE-Cl
2-chloroethylchloroformate Solvents: THF tetrahydrofuran MeGH
methanol EtOH ethanol EtOAc ethyl acetate HOAc acetic acid DMF
dimethyl formamide DMSO dimethyl sulfoxide DME dimethoxyethane
Et.sub.2O diethylether iPrOH isopropanol MEK methyl ethyl ketone
Others: Ar aryl Ph phenyl Me methyl Et ethyl NMR nuclear magnetic
resonance MHz megahertz BOC tert-butoxycarbonyl CBZ
benzyloxycarbonyl Bn benzyl Bu butyl Pr propyl cat. catalytic mL
milliliter nM nanometer ppm part per million mmol millimole mg
milligram g gram kg kilogram TLC thin layer chromatography HPLC
high pressure liquid chromatography RPM revolutions per minute rt
room temperature aq. aqueous sat. saturated
[3175] The compounds of the present invention can be prepared in a
number of ways well known to one skilled in the art of organic
synthesis. The compounds of the present invention can be
synthesized using the methods described below, together with
synthetic methods known in the art of synthetic organic chemistry,
or variations thereon as appreciated by those skilled in the art.
Preferred methods include, but are not limited to, those described
below. All references cited herein are hereby incorporated in their
entirety herein by reference.
[3176] The novel compounds of this invention may be prepared using
the reactions and techniques described in this section. The
reactions are performed in solvents appropriate to the reagents and
materials employed and are suitable for the transformations being
effected. Also, in the description of the synthetic methods
described below, it is to be understood that all proposed reaction
conditions, including choice of solvent, reaction atmosphere,
reaction temperature, duration of the experiment and workup
procedures, are chosen to be the conditions standard for that
reaction, which should be readily recognized by one skilled in the
art. It is understood by one skilled in the art of organic
synthesis that the functionality present on various portions of the
molecule must be compatible with the reagents and reactions
proposed. Such restrictions to the substituents which are
compatible with the reaction conditions will be readily apparent to
one skilled in the art and alternate methods must then be used.
[3177] The preparation of compounds of Formula (I) of the present
invention may be carried out in a convergent or sequential
synthetic manner. Detailed synthetic preparations of the compounds
of Formula (I) are shown in the following reaction schemes. The
skills required in preparation and purification of the compounds of
Formula (I) and the intermediates leading to these compounds are
known to those in the art. Purification procedures include, but are
not limited to, normal or reverse phase chromatography,
crystallization, and distillation.
[3178] Several methods for the preparation of the compounds of the
present invention are illustrated in the schemes and examples shown
below. The substitutions are as described and defined above.
[3179] Compounds of Formula (I) of this invention may be prepared
as shown in Scheme 1. Thus, preparation of an aryl hydrazine (III)
is accomplished, for example, by treatment of a corresponding
substituted aniline (II) with NaNO.sub.2 followed by reduction of
the N-nitroso intermediate with a reducing agent such as LAH or
zinc and an organic acid, such as acetic acid or trifluoroacetic
acid at low temperature. Assembly of the core tetracyclic
intermediate indole (V) is accomplished by Fischer indole
cyclization of the aryl hydrazine and a suitably substituted ketone
(i.e. (IV)) by methods described by, but not limited to, R. J.
Sundberg, "Indoles, Best Synthetic Methods" 1996, Academic Press,
San Diego, Calif. For example, treatment of the aryl hydrazine
(III) as the free base or the corresponding mineral acid salt with
the ketone (IV) (R.sup.1=H, Bn, CBZ, CO.sub.2Et, etc) in an
alcoholic solvent in the presence of mineral acid affords the
indoles (V) as the free bases (after treatment with aq. NaOH).
Reduction of the indoles to the corresponding cis or trans
substituted dihydroindoles is accomplished by, for example,
treatment with hydrogen in the presence of a catalyst such as
platinum oxide or palladium on carbon, or with a metal such as zinc
and a mineral acid such as hydrochloric acid, or with sodium and
liquid ammonia, or with borane-amine complex such as
borane-triethylamine in tetrahydofuran, or preferably by treatment
with NaCNBH.sub.3 in an acid such as acetic or trifluoroacetic
acid.
[3180] The corresponding enantiomers can be isolated by separation
of the racemic mixture of (I) on a chiral stationary phase column
utilizing normal or reverse phase HPLC techniques, the details of
which are described in the examples. Alternatively, a
diastereomeric mixture of (I) can be prepared by treatment of (I,
R.sup.1=H) with an appropriate chiral acid (or suitably activated
derivative), for example dibenzoyl tartrate or the like (see, for
example, Kinbara, K., et. al., J. Chem. Soc., Perkin Trans. 2,1996,
2615; and Tomori, H., et. al., Bull. Chem. Soc. Jpn., 1996, 3581).
The diastereomers would then be separated by traditional techniques
(i.e. silica chromatography, crystallization, HPLC, etc) followed
by removal of the chiral auxiliary to afford enantiomerically pure
(I).
[3181] In the cases where the carboline nitrogen has been protected
(VI) (i.e. R.sup.1=Boc, Bn, CBZ, CO.sub.2R), it may be removed
under a variety of conditions as described in Greene, T. W., Wuts,
P. G. W., "Protective Groups in Organic Synthesis, 2nd Edition",
John Wiley and Sons, Inc., New York, pages 309-405, 1991. The free
secondary amine could then be alkylated, for example, by treatment
with a suitably substituted alkyl halide (R.sup.1Cl, or R.sup.1I)
and a base to afford additional compounds of type (I), as
described, for example, by Glennon, R. A., et. al., Med. Chem.
Res., 1996, 197. 21
[3182] Alternatively, compounds of Formula (I) can be prepared as
described in Scheme 2. Treatment of an ortho halonitrobenzene
compound (VII) with a nucleophilic alkyl halide (X=OH, SH, NHR,
(VIII)) (as described by Kharasch, N., Langford, R. B., J. Org.
Chem., 1963, 1903) and a suitable base followed by subsequent
reduction of the corresponding nitroaryl derivative to the aniline
(IX). The reduction may be accomplished with a variety of reducing
agents, for example, LAH, SnCl.sub.2, NaBH.sub.4, N.sub.2H.sub.4,
etc. or with hydrogen in the presence of a suitable catalyst, such
as palladium on carbon, or platinum oxide, etc., (see Hudlicky, M.,
"Reductions in Organic Chemistry", Ellis Horwood, Ltd., Chichester,
UK, 1984). Formation of the aryl hydrazine (X) may be accomplished
as described previously in Scheme 1 or more directly by treatment
of the aniline (IX) with aq. hydrochloric acid, stannous chloride
and NaNO.sub.2 at room temperature (see, Buck, J. S., Ide, W. S.,
Org. Syn., Coll. Vol., 2,1943, 130). This primary aryl hydrazine
(X) can then be cyclized under Fischer indole cyclization
conditions as detailed above for compound (V), to afford the indole
(XI) as the corresponding salt. Upon treatment of the indole (XI)
with a base such potassium hydroxide or potassium t-butoxide in a
solvent such as DME or THF affords the tetracyclic indole
intermediates (V). These indoles can also be reduced to the
corresponding cis or trans indolines (I) as described previously in
Scheme 1. 22
[3183] Still another related route to compounds of Formula (I) is
shown in Scheme 3. Initiating the synthesis with a nitrobenzene
derivative such as (XII), this approach allows for a variety of
derivatization. More highly substituted nitrobenzenes can be
obtained by traditional synthetic manipulation (i.e. aromatic
substitution) and are known by those in the art (see Larock, R. C.,
Comprehensive Organic Transformations, VCH Publishers, New York,
1989). Treatment of nitrobenzene derivative with a reducing agent
such as LAH, etc., as described previously (see Hudlicky, et. al.),
affords the corresponding aniline intermediate. Subsequent
formation of the hydrazine followed by Fischer indole cyclization
with a suitably functionalized ketone as described above (i.e.
Scheme 1, (III) to (V)) affords the g-carboline indole (XIII). At
this point the fused ring may be appended by condensation of a
haloalkyl carboxylic acid or a related activated carboxylic acid
(i.e. acid chloride, mixed anhydride, etc.) such as (XIV).
Reduction of the resultant heterocyclic carbonyl may be effected
with various reducing agents, for example, sodium borohydride,
diisobutyl aluminum hydride and the like (see Larock, R. C.,
Comprehensive Organic Transformations, VCH Publishers, New York,
1989 and/or Hudlicky, M., "Reductions in Organic Chemistry", Ellis
Horwood, Ltd., Chichester, UK, 1984) to afford the tetracyclic
indoles (V). Further reduction of the indole (V) to the indolines
(I) is as described previously in Scheme 1. 23
[3184] Preparation of the aniline precursors (II) to the Fischer
indole cyclizations is shown in Scheme 4. Treatment of a suitably
ortho-functionalized aniline (XVI) with a chloroalkyl carboxylic
acid or ester (or equivalent substrate, i.e. acrylic acid, acryloyl
chloride, etc.) and concomitant condensation, followed by reduction
of the resultant heterocyclic carbonyl with a reducing agent such
as LAH, DIBAL, or Red-Al affords the fused heterocyclic benzene
derivatives (II). More diverse intermediates of (II) may be
obtained by formation of the ortho substitiuted aniline from the
corresponding ortho substituted nitobenzenes and concomitant
reduction of the nitro moiety as described above. Furthermore,
aromatic substitution of the fluoro (or other halo derived
nitrobenzene) functionality of (XV) for an oxygen, or sulphur
moiety is accomplished, for example, by treatment of (XV) with a
nucleophile, such as sodium sulfide or an alcohol, followed by
formation of the requisite thiophenol or phenol, respectively,
using standard techniques known by those in the art (see Larock, R.
C., Comprehensive Organic Transformations, VCH Publishers, New
York, 1989, page 481). Reduction of the nitro as before affords the
substituted anilines (XVI). 24
[3185] An alternate approach to the substituted fused anilines (II)
is shown in Scheme 5. Treatment of the phenol (X=OH), thiophenol
(X=SH), or other nucleophilically aromatic substituted derivative
(XVII) with, for example, a haloalkyl carboxylic acid (or
equivalent activated haloalkylcarboxylic acid, (i.e. acid halide,
mixed anhydride, acrylic acid, acryloyl chloride, etc.), affords
the derivative (XVIII) which when treated under Friedel-Crafts
acylation conditions (see Ed. G. A. Olah, "Friedel-Crafts and
Related Reactions", J. Wiley and Sons, New York, 1964, Vol 3, Pts 1
and 2 or Chem. Rev., 1955, 229, or Olah, G. A., "Friedel-Crafts
Chemistry", Wiley Interscience, New York, 1973, for varying
conditions and protocols), i.e. strong Lewis acids (AlCl.sub.3,
FeCl.sub.3, etc.), affords the cyclic alkylphenones (XIX).
Incorporation of the nitrogen functionality can be accomplished in
several ways. For example, Schmidt rearrangement (as described by
Smith, P. A. S., J. Am. Chem. Soc., 1948, 320) is effected by
treatment of the carbonyl derivative (XIX) with NaN.sub.3 and
methanesulfonic acid to afford the bicyclic lactam (XX).
Alternatively, this transformation may be carried out under
Hoffmann rearrangement protocol (see, for example, Dike, S. Y., et.
al., Bioorg. Med . Chem. Lett., 1991, 383), by initial formation of
the oxime derivative of (XXI) by treatment with hydroxylamine
hydrochloride. Subsequent rearrangement to the lactam is
efficiently accomplished by heating in polyphosphoric acid to
afford the lactam (XX). Reduction of the lactam (XX) can be
accomplished with a variety of reducing agents, for example, DIBAL,
Red-Al and the like to afford the aniline (II). 25
[3186] The preparation of compounds of Formula (I) with additional
diversity of functionalization of the aromatic A ring of the
tetracycle is shown in Scheme 6 and Scheme 7 and described here.
Due to the nature of the synthetic route of Scheme 1 to derivatives
of Formula (I), compounds with halogen substituents on the A-ring
are difficult to prepare. However, bromination of the indolines (I,
R.sup.8=H) when the amine is protected, for example, with the Boc
or CBZ protecting groups, with, for example, NBS in DMF affords the
R.sup.8 brominated derivatives (XXII). These activated aryl
derivatives (XXII) act as excellent counterparts for a number of
important synthetic transformations.
[3187] For example, biaryl coupling is accomplished under Suzuki
coupling protocol. For a review and leading references of palladium
catalyzed cross coupling reactions, see Miyaura, N., Suzuki, A.,
Chem. Rev., 1995, 2457. One such procedure entails treatment of the
aryl bromide (XXII) with a functionalized aryl boronic acid (XXIII)
in the presence of a catalytic Pd(0) species, such as
Pd(PPh.sub.3).sub.4, Pd(PPh.sub.3).sub.2Cl.sub.2, Pd(OAc).sub.2,
Pd.sub.2(dba).sub.3 and a suitable ligand such as PPh.sub.3,
AsPh.sub.3, etc., or other such Pd(0) catalyst, and a base such as
Na.sub.2CO.sub.3 or Et.sub.3N in a suitable solvent such as DMF,
toluene, THF, DME or the like, to afford the indolines (XXIV).
Alternatively formation of the indole boronic acid from the bromine
derivative (XXII) (i.e. (I, R.sup.8=B(OH).sub.2)) would allow for
greater diversity in the subsequent coupling of this indole boronic
acid with commercially available haloaromatic derivatives in a
similar Suzuki coupling strategy as described above to afford the
indolines (XXIV). 26
[3188] Similarly biaryl coupling of the bromine derivatives (XXV),
readily obtained by the synthetic sequence exemplified in Scheme 2,
(starting with the suitably functionalized bromo nitrobenzenes
(II)), is shown in Scheme 7. This approach allows for the
preparation of biaryl indoles as well as the corresponding indoline
derivatives. Protection of the amine functionality must be carried
out if R.sup.1=H (see Greene et.al for protections of amines). This
is readily accomplished, for example, by treatment of bromo
derivatives (XXV) with (Boc).sub.2O in aqueous sodium hydroxide and
dioxane. Subsequent Suzuki coupling with a variety of aryl boronic
acids is carried out as described above in Scheme 6, to afford the
biaryl adducts (XXVI). This protocol is amenable to R.sup.7,
R.sup.8, and R.sup.9 bromide, iodide, triflates, and/or diazo
derivatives (see Miyaura, N., Suzuki, A., Chem. Rev., 1995, 2457,
for a review of aryl couplings). 27
[3189] Furthermore and as an extension of this approach to a rapid
preparation of a large array of biaryl indole and indoline
derivatives, these bromide derivatives (XXV) can be bound to a
solid support and the Suzuki couplings can be carried out on solid
support (see XXVIII) as illustrated in Scheme 8. Towards that end
treatment of indoline (XXV) with TFA in CH.sub.2Cl.sub.2, to remove
the Boc protecting group, followed extraction from aqueous base
provides the free amine (XXXVII). The free amine can be loaded onto
a suitable solid support such as (XXVIII) using conditions well
known to those skilled in the art. Thus, p-nitrophenylchloroformate
Wang resin (XXVIII) which can be obtained commercially from sources
such as Novabiochem, Inc. is swollen in a suitable solvent such as
N-methyl pyrrolidinone and treated with 1.5 equiv. of amine to
afford the functionalized resin (XXIX). Suzuki couplings are then
carried out in array format by treatment of resins (XXIX) with a
suitable palladium source such as Pd(PPh.sub.3).sub.4 or
Pd(dppf)Cl.sub.2 and a suitable base such as 2M aqueous
K.sub.2CO.sub.3 or Na.sub.2CO.sub.3 or triethylamine with an excess
(typically 5 equivalents) of an aryl boronic acid (procedures for
solid-phase Suzuki and other palladium couplings are well-known by
those in the art, see for instance L. A. Thompson and J. A. Ellman,
Chem. Rev. 1996, 96, (1), 555-600). The coupling may be repeated to
ensure complete conversion to the desired coupled product. Cleavage
from the solid support by treatment with TFA affords the
corresponding indoles and indolines (XXX) as their TFA salts.
28
[3190] In addition, there exists a wide range of procedures and
protocols for functionalizing haloaromatics, aryldiazonium and
aryltriflate compounds. These procedures are well known by those in
the art and described, for example, by Stanforth, S. P.,
Tetrahedron, 1998, 263; Buchwald, S. L., et. al., J. Am. Chem.
Soc., 1998, 9722; Stille, J. K., et. al., J. Am. Chem. Soc., 1984,
7500. Among these procedures are biaryl couplings, alkylations,
acylations, aminations, and amidations. The power of palladium
catalyzed functionalization of aromatic cores has been explored in
depth in the last decade. An excellent review of this field can be
found in J. Tsuji, "Palladium Reagents and Catalysts, Innovations
in Organic Synthesis", J. Wiley and Sons, New York, 1995.
[3191] One such method to prepare compounds of Formula (I) with
substituted R.sup.1 sidechains in a more direct manner is shown in
Scheme 9. Alkylation of the indole or indoline derivatives (I,
R.sup.1=H) with a haloalkyl ester, such as
ClCH.sub.2(CH.sub.2).sub.pCO.sub.2Me, in the presence of NaI or KI
and a base such as K.sub.2CO.sub.3, Na.sub.2CO.sub.3 or the like,
in dioxane or THF or other such solvent while heating (see Glennon,
R. A., et. al., Med. Chem. Res., 1996, 197) affords the R.sup.1
alkylated esters. Subsequent formation of the activated amides
(XXXI) is accomplished by treatment of the ester with
N,O-dimethylhydroxylamine hydrochloride and a Lewis acid such as
trimethylaluminum or triethylaluminum in toluene (see, for example,
Golec, J. M. C., et. al., Tetrahedron, 1994, 809) at 0.degree. C.
Treatment of the amide (XXXI) with a variety of organometallic
agents, such as Grignard reagents R.sup.1aMgBr, alkyl and aryl
lithium reagents etc. (see Sibi, M. P., et. al., Tetrahedron Lett.,
1992,1941; and more generally House, H. O., Modern Synthetic
Reactions, W. A. Benjamin, Inc., Menlo Park, Calif., 1972), in a
suitable solvent such as THF, ether, etc. at low temperatures
affords the substituted ketones (XXXII). 29
[3192] Preparation of compounds of Formula (I) where m=0, k=1 is
outlined in Scheme 10 and described here. Fischer indole
cyclization of the previously described hydrazine (III) with a
known protected 2,3-dioxopyrolidine (Carlson, E. H., et. al., J.
Org. Chem., 1956, 1087) under a variety of typical cyclization
conditions affords the tetracyclic indole (XXXIII). The reduction
may be accomplished with a variety of reducing agents, for example,
LAH, DIBAL, etc., to yield the pyrole fused indole (XXXIV). This
derivative can then be deprotected and subsequently alkylated as
described previously (see Greene, T. W., Wuts, P. G. W.,
"Protective Groups in Organic Synthesis, 2nd Edition", John Wiley
and Sons, Inc., New York, 1991, and Scheme 1), to give the R.sup.1
alkylated indole analogs (XXXV).
[3193] Alternatively, reduction of the indole to the indoline, as
described previously (see Scheme 1), followed by deprotection of
the benzyl group to give (XXXVI) and alkylation gives access to the
corresponding R.sup.1 alkylated indoline derivatives (XXXVII). All
the previously described methods to functionalize the aromatic
ring, and to afford derivatives of varying R.sup.1 sidecahins are
applicable to these cores. 30
EXAMPLES
[3194] Chemical abbreviations used in the Examples are defined
above. The detailed processes for preparing the compounds of
Formula (I) are illustrated by the following Examples. It is,
however, understood that this invention is not limited to the
specific details of these examples. The Examples as set forth below
are intended to demonstrate the scope of the invention but are not
intended to limit the scope of the invention. Proton nuclear
magnetic resonance spectra (.sup.1H NMR) were measured in
chloroform-d (CDCl3) unless otherwise specified and the peaks are
reported in parts per million (ppm) downfield from
tetramethylsilane (TMS). The coupling patterns are reported as
follows: s, singlet; d, doublet; dd, doublet of doublets; t,
triplet; q, quartet; m, multiplet; bs, broad singlet; bm, broad
multiplet.
Example 1
[3195] 4,5,7,8,9,10-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole
hydrochloride
[3196] A mixture of 1-amino-2,3-dihydroindole (1.0 g, 5.9 mmol),
piperidone hydrochloride monohydrate (0.91 g, 5.9 mmol) and
isopropanol (29 mL) was brought to reflux for 4 hours. The
resulting brown solid was filtered and washed with cold
diethylether (20 mL) and dried under vacuum, affording the title
compound (1.01 g, 74%). .sup.1H NMR (CD.sub.3OD, 300 MHz)
.delta.7.15 (d, 1H, J=7.7 Hz), 6.85-6.96 (m, 2H), 4.39-4.50 (m,
4H), 3.75 (t, 2H, J =7.3 Hz), 3.57 (t, 2H, J=6.2 Hz), 3.15 (t, 2H,
J=6.2 Hz) ppm.
Example 2
[3197]
9-cyclopropyl-4,5,7,8,9,10-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]i-
ndole hydrochloride
[3198] The title compound was prepared by substituting
cyclopropylpiperidone for the monohydrate piperidone hydrochloride
by the procedure of Example 1 in 64%. .sup.1H NMR (DMSO, 300 MHz)
.delta.7.16 (d, 1H, J=7.3), 7.85-7.93 (m, 2H), 4.6 (d, 1H, J=6.6),
4.38-4.48 (m, 3H), 3.72-3.85 (m, 1H), 3.7 (t, 2H, J=7 Hz),
3.58-3.62 (m, 1H), 3.0-3.18 (m, 3H), 1.07-1.12 (m, 2H), 0.83-0.9
(m, 2H) ppm.
Example 3
[3199]
(.+-.)-cis-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1--
hi]indole
[3200] 4,5,7,8,9,10-Hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole
from Example 1 (0.50 g, 2.14 mmol) was stirred under N.sub.2 in TFA
(15.5 mL) at 0.cndot. C. for 10 minutes. NaBH.sub.4 (0.44 g, 6.4
mmol) was added slowly keeping the temperature below 2.cndot. C.
The reaction was allowed to warm to room temperature and stirred
overnight. Ice chips were then added and the reaction basified to
pH 12 with 50% aqueous NaOH. The aqueous layer was then extracted
with CHCl.sub.3 (3.times.20 mL). The combined extracts were washed
with brine, H.sub.2O and dried (Na.sub.2SO.sub.4) and evaporated
affording the title compound (0.42 g, 100%). .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.6.94 (d, 1H, J=7.7 Hz), 6.88 (d, 1H,
J=6.9 Hz), 6.63 (t, 7.3, 1H, J=7.3 Hz), 3.64 (dt, 1H, J=8.0, 1.5
Hz), 3.29-3.5 (m, 2H), 3.05-3.29 (m, 3H), 3.03 (dd, 1H, J=11.7, 3.6
Hz), 2.72-3.02 (m, 2H), 1.66-1.90 (m, 2H) ppm.
Example 16
[3201]
5,6,8,9,10,11-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinol-
ine
[3202] Step A:
[3203] 1,2,3,4-Tetrahydroquinoline (2.12 g, 15.9 mmol) was
dissolved in AcOH (3 OmL) and water (10 mL). The solution was
cooled to 0.degree. C. An aqueous solution of NaNO.sub.2 (1.20 g,
17.5 mmol in 3 mL water) was added dropwise. The reaction was
warmed to RT and stirred 2 hrs. Water (2 OmL) and EtOAc (20 mL)
were added. The layers were separated and the aqueous phase was
extracted (2.times.20 mL) with EtOAc. The combined organic layers
were washed with brine, dried, and concentrated to afford a crude
orange oil (2.62 g). The product was purified by column
chromatography (20-40% EtOAc/hexane) to afford
1-nitroso-1,2,3,4-tetrahyd- roquinoline (2.48 g, 96%) as a yellow
oil. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.07 (d, 1H, J=8.1
Hz), 7.21-7.34 (m, 3H), 3.91 (t, 2H, J=6.2 Hz), 3.81 (t, 2H, J=6.2
Hz), 1.97-2.05 (m, 2H) ppm.
[3204] Step B:
[3205] 1-Nitroso-1,2,3,4-tetrahydroquinoline (1.51 g, 9.0 mmol) was
dissolved in THF. The solution was cooled to 0.degree. C. 1M LAH in
THF (9 mL, 9.0 mmol) was added dropwise. The reaction was allowed
to warm to RT and was stirred over night. The reaction was cooled
to 0.degree. C. and was quenched with 20 mL a saturated aqueous
Rochelle salt solution (20 mL). The suspension was stirred for 2 h
and the layers were separated. The aqueous phase was extracted with
EtOAc (3.times.20 mL). The combined organic layers were washed with
brine, dried, and concentrated to afford an orange solid (1.26 g).
The crude product was purified by column chromatography (20-0%
hexane/CH.sub.2Cl.sub.2) to afford 1,2,3,4-tetrahydroquinoylamine
(1.02 g, 76%) as a yellow solid. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.09-7.18 (m, 2H), 6.97 (dd, 1H, J=0.7 Hz, 7.3 Hz),
6.68-6.74 (m, 1H), 3.64 (m, 2H), 3.31 (t, 2H, J=6.0 Hz), 2.77 (t,
2H, J=6.6 Hz), 2.02-2.11 (m, 2H) ppm.
[3206] Step C:
[3207] 1,2,3,4-Tetrahydroquinoylamine (0.925 g, 6.25 mmol) and
4-piperidone monohydrate hydrochloride (0.960g, 6.25 mmol) were
dissolved in EtOH (15 mL). Conc. HCl (0.52 mL, 6.25 mmol) was
added. The reaction was refluxed for 3 hrs and then cooled to RT.
The precipitate was collected by vacuum filtration. The residue was
washed with 5 mL of EtOH, to afford the title compound (1.32 g,
85%) as a pure, white powder. .sup.1H NMR (CD.sub.3OD, 300MHz)
.delta.7.22 (d, 1H, J=8.1 Hz), 6.92-6.97 (m, 1H), 6.86 (d, 1H,
J=7.2 Hz), 4.87 (s, 2H), 4.05 (t, 2H, J=6.0Hz), 3.61 (t, 2H,
J=6.0Hz), 3.14 (t, 2H, J=6.0Hz), 2.94 (t, 2H, J=6.3 Hz), 2.16-2.24
(m, 2H) ppm.
Example 17
[3208] (.+-.)-cis-5,6,7a,8,9,10,11,
11a-octahydro-4H-pyrido[3',4':4,5]pyrr- olo[3,2,1-ij]quinoline
[3209]
5,6,8,9,10,11-Hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinol-
ine (2.84 g, 11.4 mmol) was dissolved in TFA (35 mL). The reaction
was cooled to 0.degree. C. NaCNBH.sub.3 (2.15 g, 34.27 mmol) was
added in small portions over 30 min, keeping the temperature less
than 5.degree. C. The reaction was stirred at, 0.degree. C. for 2
h. Ice was added to the reaction flask, and the reaction was
basified with 50% NaOH until pH=14. Water (20 mL) was added to
dissolve the precipitate. The reaction was extracted with
CHCl.sub.3 (3.times.20 mL). The combined organic layers were washed
with brine, dried, and concentrated to afford the title compound
(1.67 g, 68%) as a pale-brown, amorphous solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.6.80-7.00 (m, 2H), 6.55-6.6.70 (m,
1H), 3.20-3.40 (m, 2H), 2.95-3.20 (m, 2H), 2.75-2.95 (m, 2H),
2.50-2.75 (m, 4H), 2.00-2.20 (m, 2H), 1.85-2.00 (m, 1H), 1.70-1.85
(m, 1H) ppm.
Example 37
[3210]
(.+-.)-cis-9-(cyclopropylcarbonyl)-4,5,6a,7,8,9,10,10a-octahydropyr-
ido[4,3-b]pyrrolo[3,2,1-hi]indole
[3211]
(.+-.)-cis-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1--
hi]indole from Example 3 (0.050 g, 0.25 mmol) was dissolved in
CH.sub.2Cl.sub.2 (5 mL) with Et.sub.3N (0.75 mL) and cooled to
0.degree. C. The cyclopropanecarbonyl chloride (0.026 g, 0.26 mmol)
was then added dropwise. The solution was stirred at 0.degree. C.
for 1 h and then warmed to room temperature and stirred for 1 h.
The reaction mixture was partitioned between water and CHCl.sub.3
(3.times.15 mL) and the layers separated. The aqueous layer was
extracted with CHCl.sub.3. The combined organics were washed with
brine, H.sub.2O and dried (Na.sub.2SO.sub.4) and evaporated
affording a light yellow liquid which was further purified by
preparatory silica gel TLC (5% MeOH/CH.sub.2Cl.sub.2). The title
compound was isolated as a clear colorless liquid (0.042 g, 65%).
.sup.1H NMR (CD.sub.3OD, 300 MHz) .delta.7.22-7.58 (m, 3H),
4.62-4.75 (m, 1H), 3.85-4.30 (m, 5H), 3.55-3.62 (m, 2H), 1.9-2.18
(m, 3H), 0.75-0.9 (m, 4H) ppm.
Example 38
[3212]
(.+-.)-cis-9-isobutyryl-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]p-
yrrolo[3,2,1-hi]indole
[3213] The title compound was prepared by substituting
isobutyrlchloride for cyclopropanecarbonyl chloride by the
procedure of Example 37 in 53% yield. .sup.1H NMR (CD.sub.3OD, 300
MHz) .delta.6.85-6.95 (m, 2H), 6.6 (t, 1H, J=7.3), 4.48 (dd, 0.5 H,
J=8.4, 4.0 Hz), 4.21 (br d, 0.5 H, J=13.2 Hz), 4.05 (dd, 0.5 H,
J=11.7, 4 Hz), 3.85 (br d, 0.5 H, J=13.9 Hz), 3.47-3.7 (m, 2H),
3.18-3.45 (m, 4H), 2.85-3.18 (m, 3H), 2.72-2.85 (m, 1H), 1.75-2.05
(m, 2H), 1.15 (t, 3H, J=6.5 Hz), 1.05 (t, 3H, J=6.9 Hz) ppm.
Example 89
[3214] tert-butyl
(.+-.)-cis-2-(2-chlorophenyl)-4,5,7,8,10,10a-hexahydropy-
rido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3215] Step A:
[3216]
(.+-.)-cis-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1--
hi]indole (387 mg, 1.93 mmol) was dissolved in CHCl.sub.3 (8 mL).
BOC.sub.2O (464 mg, 2.13 mmol) was added. The reaction was stirred
at RT 18 h. 1M aqueous NaOH (10 mL) was added. The biphasic mixture
was stirred 10 min, and the layers were separated. The aqueous
phase was extracted with CH.sub.2Cl.sub.2 (3.times.10 mL). The
combined organic layers were washed with brine, dried, and
concentrated to afford an amorphous white solid (820 mg). The crude
product was purified by column chromatography (0-10%
MeOH/CH.sub.2Cl.sub.2) to afford tert-butyl
(.+-.)-cis-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9-
(6aH)-carboxylate (596 mg, 100%) as an amorphous white solid.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.6.97 (d, 1H, J=7.3 Hz),
6.93 (d, 1H, J=7.3 Hz), 6.60-6.75 (m, 1H), 3.75-3.90 (m, 1H),
3.50-3.72 (m, 1H), 3.05-3.48 (m, 5H), 2.70-2.90 (m, 1H), 1.70-1.90
(m, 2H) ppm. MS (CI, NH.sub.3): 301 (base, M+H)
[3217] Step B:
[3218] To a solution of tert-butyl
(.+-.)-cis-4,5,7,8,10,10a-hexahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (0.576 g, 1.92
mmol) in DMF (4 mL) at 0.degree. C., freshly recrystalized NBS
(0.375 g, 2.1 mmol) was added as a solution in DMF (4 mL). The
reaction was stirred at 0.degree. C. for 20 min, after which it was
warmed to RT. The reaction was stirred at RT for 0.5 h. Water (10
mL) and EtOAc (10 mL) were added. The layers were separated, and
the aqueous phase was extracted with EtOAc (2.times.20 mL). The
combined organic layers were washed with brine (2.times.20 mL) and
dried. Concentration afforded a crude brown oil. The crude product
was purified by column chromatography (MeOH/CH.sub.2Cl.sub.2).
Tert-butyl (.+-.)-cis-2-bromo-4,5,7,8,10,10a-hex-
ahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (550
mg, 75%) was isolated as a brown amorphous solid. 21H NMR
(CDCl.sub.3, 300 MHz) .delta.7.06 (s, 1H), 7.02 (s, 1H), 3.70-3.90
(m, 1H), 3.50-3.70 (m, 1H), 3.00-3.45 (m, 6H), 2.70-2.90 (m, 2H),
1.70-1.90 (m, 2H), 1.48 (s, 9H) ppm.
[3219] Step C:
[3220] Tert-butyl
(.+-.)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]-
pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (87.5 mg, 0.23 mmol) was
dissolved benzene (4 mL). 2M sodium carbonate (0.4 mL) added.
2-Chlorophenylboronic acid (71.9 mg, 0.46 mmol) was added, followed
by Pd(PPh.sub.3).sub.2Cl.sub.2 (8.1 mg, 0.0115 mmol). The reaction
was evacuated and kept under a nitrogen atmosphere. The suspension
was refluxed for 18 h and then cooled to RT. The reaction was
concentrated in vacuo, after which water (10 mL) and EtOAc (10 mL)
were added. The layers were separated and the aqueous phase was
extracted with EtOAc (2.times.10 mL). The organic layers were
washed with brine (2.times.10 mL), dried, and concentrated to
afford a crude brown amorphous solid (110.9 mg). The residue was
purified by column chromatography (20-40% EtOAc/Hexane) to afford
the title compound (62 mg, 66%) as a white amorphous solid. MS (CI,
NH3): 411 (base, M+H).
Example 90
[3221] tert-butyl
(.+-.)-cis-2-(2,4-dichlorophenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3222] The title compound (55.9 mg, 50%) was prepared by the method
of Example 89 Step C from tert-butyl
(.+-.)-cis-2-bromo-4,5,7,8,10,10a-hexah-
ydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (94 mg,
0.25 mmol) and 2,4-dichlorophenylboronic acid (95 mg, 0.5 mmol) as
a white amorphous solid. MS (CI, NH3): 445 (base, M+H).
Example 91
[3223] tert-butyl
(.+-.)-cis-2-(3,4-dichlorophenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3224] Tert-butyl
(.+-.)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]-
pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (135 mg, 0.30 mmol) was
dissolved in DME (4 mL). 2M sodium carbonate (0.75 mL)was added.
3,4-Dichlorophenylboronic acid (114 mg, 0.60 mmol) was added,
followed by Pd.sub.2(dba).sub.3 (15 mg, .015 mmol). PPh.sub.3 (16
mg, 0.06 mmol) was added. The reaction flask was degassed and kept
under a nitrogen atmosphere. The suspension was refluxed for 18 h
cooled to RT. The reaction was concentrated in vacuo, after which
water (10 mL) and EtOAc (10 mL) were added. The layers were
separated and the aqueous phase was extracted with EtOAc
(2.times.10 mL). The combined organic layers were washed with brine
(2.times.10 mL), dried, and concentrated to afford a crude brown
amorphous solid (214 mg). The residue was purified by column
chromatography (20-40% EtOAc/Hexane) to afford the title compound
(120 mg, 90%) as a white amorphous solid. .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta.7.55 (d, 1H, J=1.5 Hz), 7.41 (d, 1H, J=8.4 Hz),
7.30 (dd, 1H, J=1.8 Hz, 8.4 Hz), 7.26 (s, 1H), 7.13 (s, 1H),
3.75-3.90 (m, 1H), 3.60-3.70 (m, 1H), 3.10-3.50 (m, 7H), 2.80-3.00
(m, 1H), 1.70-1.90 (m, 2H), 1.48 (s, 9H) ppm. MS (CI, NH3): 445
(base, M+H).
Example 92
[3225] tert-butyl
(.+-.)-cis-2-(2,3-dichlorophenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3226] The title compound was prepared by the method of Example 90
from tert-butyl
(.+-.)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrol-
o[3,2,1-hi]indole-9(6aH)-carboxylate (124 mg, 0.27 mmol) and
corresponding 2,3-dichlorophenylboronic acid (104 mg, 0.54 mmol),
to afford after chromatographic purification the title compound
(157 mg, 99%) as a white amorphous solid. .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta.7.30-7.40 (m, 1H), 7.20 (s, 1H), 7.18 (d, 1H, J=3.6
Hz), 6.99 (s, 1H), 6.94 (s, 1H), 3.80-3.90 (m, 1H), 3.60-3.80 (m,
1H), 3.10-3.50 (m, 7H), 2.80-3.00 (m, 1H), 1.70-1.90 (m, 2H), 1.47
(s, 9H) ppm. MS (CI, NH3): 445 (base, M+H).
Example 93
[3227] tert-butyl
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-4,5,7,-
8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3228] The title compound was prepared by the method of Example 90
from tert-butyl
(.+-.)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrol-
o[3,2,1-hi]indole-9(6aH)-carboxylate (136 mg, 0.30 mmol) and
corresponding 2-chloro-4-trifluoromethylphenylboronic acid (128 mg,
0.60 mmol), to afford after chromatographic purification the title
compound (160 mg, 99%) as a white amorphous solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.7.70 (br, 1H), 7.51 (dd, 1H, J=1.1 Hz,
8.0 Hz), 7.42 (d, 1H, J=8.0 Hz), 7.03 (s, 1H), 6.99 (s, 1H),
3.80-3.90 (m, 1H), 3.60-3.80 (m, 1H), 3.10-3.50 (m, 7H), 2.80-3.00
(m, 1H), 1.70-1.90 (m, 2H), 1.48 (s, 9H) ppm. MS (CI, NH3): 479
(base, M+H).
Example 94
[3229] tert-butyl
(.+-.)-cis-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a-h-
exahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3230] The title compound was prepared by the method of Example 90
from tert-butyl
(.+-.)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrol-
o[3,2,1-hi]indole-9(6aH)-carboxylate (121 mg, 0.27 mmol) and
corresponding 2-chloro-4-methoxyphenylboronic acid (100 mg, 0.54
mmol), to afford after chromatographic purification the title
compound (141 mg, 68%) as a white amorphous solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.7.21 (d, 1H, J=8.4 Hz), 6.94-6.99 (m,
3H), 6.82 (dd, 1H, J=2.9 Hz, 8.8 Hz), 3.75-4.00 (m, 7H), 3.60-3.70
(m, 1H), 3.10-3.50 (m, 7H), 2.80-3.00 (m, 1H), 1.70-1.90 (m, 2H),
1.48 (s, 9H) ppm. MS (CI, NH3): 441 (base, M+H).
Example 95
[3231] tert-butyl
(.+-.)-cis-2-(5-isopropyl-2-methoxyphenyl)-4,5,7,8,10,10-
a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3232] The title compound was prepared by the method of Example 90
from tert-butyl
(.+-.)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrol-
o[3,2,1-hi]indole-9(6aH)-carboxylate (127 mg, 0.28 mmol) and
corresponding 4-isopropyl-2-methoxyphenylboronic acid (109 mg, 0.56
mmol), to afford after chromatographic purification the title
compound (58.4 mg, 46%) as a white amorphous solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.7.00-7.20 (m, 4H), 6.87 (d, 1H, J=8.4
Hz), 3.85-4.0 (m, 1H), 3.79 (s, 3H), 3.60-3.75 (m, 1H), 3.10-3.50
(m, 6H), 2.70-3.00 (m, 2H), 1.70-1.90 (m, 2H), 1.48 (s, 9H), 1.25
(d, 6 H, J=7.0 Hz) ppm. MS (CI, NH3): 449 (base, M+H).
Example 96
[3233] tert-butyl
(.+-.)-cis-2-(3-fluorophenyl)-4,5,7,8,10,10a-hexahydropy-
rido[4,3-b]pyrrolo [3,2,1-hi]indole-9(6aH)-carboxylate
[3234] The title compound was prepared by the method of Example 90
tert-butyl
(.+-.)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrol-
o[3,2,1-hi]indole-9(6aH)-carboxylate (125 mg, 0.28 mmol) and
corresponding 3-fluorophenylboronic acid (77 mg, 0.56 mmol), to
afford after chromatographic purification the title compound (48
mg, 44%) as a white amorphous solid. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta.7.20-7.40 (m, 2H), 7.10-7.20 (m, 3H), 6.80-7.00 (m,
1H), 3.80-3.90 (m, 1H), 3.60-3.80 (m, 1H), 3.10-3.50 (m, 7H),
2.80-3.00 (m, 1H), 1.70-1.90 (m, 2H), 1.48 (s, 9H) ppm. MS (CI,
NH3): 395 (base, M+H).
Example 97
[3235] tert-butyl
(.+-.)-cis-2-(2,4-dimethoxyphenyl)-4,5,7,8,10,10a-hexahy-
dropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3236] The title compound was prepared by the method of Example 90
from tert-butyl
(.+-.)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrol-
o[3,2,1-hi]indole-9(6aH)-carboxylate (143 mg, 0.32 mmol) and
corresponding 2,4-dimethoxyphenylboronic acid (115 mg, 0.63 mmol),
to afford after chromatographic purification the title compound (92
mg, 66%) as a white amorphous solid. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta.7.15-7.18 (m, 1H), 7.08 (s, 1H), 7.04 (s, 1H),
6.40-6.60 (m, 2H), 3.75-4.00 (m, 7H), 3.60-3.70 (m, 1H), 3.00-3.50
(m, 7H), 2.70-2.90 (m, 1H), 1.70-1.90 (m, 2H), 1.48 (s, 9H) ppm. MS
(CI, NH3): 437 (base, M+H).
Example 98
[3237]
(.+-.)-cis-2-(2-chlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4-
,3-b]pyrrolo[3,2,1-hi]indole
[3238] Tert-butyl
(.+-.)-cis-2-(2-chlorophenyl)-4,5,7,8,10,10a-hexahydropy-
rido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (45.1 mg,
0.11 mmol) was dissolved in 20% TFA in methylene chloride (4 mL)
and was stirred at RT for 2 h. The reaction was solution was cooled
to 0.degree. C. and basified with 1M NaOH until pH>14. The
layers were separated. The aqueous phase was extracted the
methylene chloride (2.times.10 ml). The organic layers were washed
with brine and dried. Concentration afforded the title compound
(29.3 mg, 86%) as a pale yellow amorphous solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.7.42 (dd, 1H, J=1.4, 7.3 Hz),
7.16-7.33 (m, 3H), 7.02 (s, 1H), 6.96 (s, 1H), 3.69 (dt, 1H, J=1.4,
8.1 Hz), 3.15-3.50 (m, 5H), 3.06 (dt, 1H, J=3.2,12.3 Hz), 2.82-2.97
(m, 3H), 1.78-1.93 (m, 2H) ppm. MS (CI, NH3): 311 (base, M+H).
Example 99
[3239]
(.+-.)-cis-2-(2,4-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole
[3240] The title compound was prepared by the method of Example 98
from tert-butyl (.+-.)-cis-2-(2,
4-dichlorophenyl)-4,5,7,8,10,10a-hexahydropyr-
ido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (44.3 mg,
0.99mmol) to afford the title compound (35 mg, 100%) as a pale
yellow amorphous solid. The enatiomers of
(.+-.)-cis-2-(2,4-dichlorophenyl)-4,5,6a,7,8,9,1-
0,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole were separated
by preparative HPLC on a chiracel OD column using isocratic 6%
IPA/hexane as the eluent. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.44 (s, 1H), 7.23-7.26 (m, 2H), 6.97 (s, 1H), 6.92 (s, 1H),
3.70 (dt, 1H, J=1.4, 8.0 Hz), 3.15-3.50 (m, 5H), 3.06 (dt, 1H,
J=3.3, 11.3 Hz), 2.77-2.96 (m, 3H), 1.76-1.93 (m, 2H) ppm. MS (CI,
NH3): 345 (base, M+H).
Example 100
[3241]
(.+-.)-cis-2-(3,4-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole
[3242] The title compound was prepared by the method of Example 98
from tert-butyl
(.+-.)-cis-2-(3,4-dichlorophenyl)-4,5,7,8,10,10a-hexahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (110 mg, 0.25
mmol) to afford the title compound (71 mg, 82%) as a pale yellow
amorphous solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.57 (d,
1H, J=2.2 Hz), 7.41 (d, 1H, J=8.4 Hz), 7.30 (dd, 1H, J=1.8, 8.1
Hz), 7.13 (s, 1H), 7.07 (s, 1H), 3.70 (dt, 1H, J=1.8,7.6 Hz),
3.15-3.50 (m, 5H), 3.04 (dt, 1H, J=3.6, 12.4 Hz), 2.83-2.95 (m,
3H), 1.76-1.92 (m, 2H) ppm. MS (CI, NH3): 345 (base, M+H).
Example 101
[3243]
(.+-.)-cis-2-(2,3-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole
[3244] The title compound was prepared by the method of Example 98
from tert-butyl
(.+-.)-cis-2-(2,3-dichlorophenyl)-4,5,7,8,10,10a-hexahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (128 mg, 0.29
mmol) to afford the title compound (99 mg, 100%) as a pale yellow
amorphous solid. The enatiomers were separated by preparative HPLC
on a chiracel OD column using isocratic 6% IPA/hexane as the
eluent. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.38 (dd, 1H,
J=2.6, 7.3 Hz), 7.14-7.23 (m, 2H), 7.02 (s, 1H), 6.98 (s, 1H), 6.92
(s, 1H), 3.70 (dt, 1H, J=1.8, 8.1 Hz), 3.15-3.50 (m, 5H), 3.05 (dt,
1H, J=3.3, 12.2 Hz), 2.85-2.95 (m, 3H), 1.73-1.93 (m, 2H) ppm. MS
(CI, NH3): 345 (base, M+H).
Example 102
[3245]
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,1-
0a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole
[3246] The title compound was prepared by the method of Example 98
tert-butyl
(.+-.)-cis-2-[2,-chloro-4-(trifluoromethyl)phenyl]-4,5,7,8,10,-
10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
(80 mg, 0.17 mmol) to afford the title compound (65.3 mg, 100%) as
a pale yellow amorphous solid. The enantiomers were separated by
preparative HPLC on a chiracel OD column using isocratic 3%
IPA/hexane as the eluent. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.69 (s, 1H), 7.51 (d, 1H, J=8.1 Hz), 7.42 (d, 1H, J=8.0
Hz), 7.02 (s, 1H), 6.96 (s, 1H), 3.68-3.73 (m, 1H), 3.16-3.50 (m,
5H), 2.85-3.09 (m, 4H), 1.75-1.93 (m, 2H) ppm. MS (CI, NH3): 379
(base, M+H).
Example 103
[3247]
(.+-.)-cis-2-(2-chloro-4-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole
[3248] The title compound was prepared by the method of Example 98
from tert-butyl
(.+-.)-cis-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (60 mg,
0.14 mmol) to afford the title compound (50.4 mg, 100%) as a pale
yellow amorphous solid. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.22 (d, 1H, J=8.8 Hz), 6.95-7.00 (m, 2H), 7.02 (s, 1H),
6.92 (s, 1H), 6.81 (dd, 1H, J=2.7, 8.5 Hz), 3.82 (s, 3H), 3.69 (dt,
1H, J=1.4, 7.7 Hz), 3.13-3.50 (m, 5H), 3.00-3.10 (dt, 1H, J=3.3,
11.7 Hz), 2.84-2.94 (m, 3H), 1.74-1.92 (m, 2H) ppm. MS (CI, NH3):
341 (base, M+H).
Example 104
[3249]
(.+-.)-cis-2-(4-isopropyl-2-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octa-
hydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole
[3250] The title compound was prepared by the method of Example 98
from tert-butyl
(.+-.)-cis-2-(4-isopropyl-2-methoxyphenyl)-4,5,7,8,10,10a-hexa-
hydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (52
mg, 0.12 mmol) to afford the title compound (42 mg, 100%) as a pale
yellow amorphous solid. .sup.1H NMR (CDCl.sub.1, 300 MHz)
.delta.7.07-7.14 (m, 4H), 6.88 (d, 1H, J=8.4 Hz), 3.79 (s, 3H),
3.68 (dt, 1H, J=1.4, 8.0 Hz), 3.14-3.50 (m, 5H), 3.05 (dt, 1H,
J=3.3, 12.1 Hz), 2.79-2.94 (m, 3H), 1.60-1.93 (m, 3H), 1.25 (d, 6H,
J=6.9 Hz) ppm. MS (CI, NH3): 349 (base, M+H).
Example 105
[3251]
(.+-.)-cis-2-(3-fluorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4-
,3-b]pyrrolo[3,2,1,-hi]indole
[3252] The title compound was prepared by the method of Example 98
from tert-butyl
(.+-.)-cis-2-(3-fluorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4-
,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (39.5 mg, 0.10
mmol) to afford the title compound (35.4 mg, 90%) as a pale yellow
amorphous solid. The enatiomers were separated by preparative HPLC
on a chiracel OD column using isocratic 5% IPA/hexane as the
eluent. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.19-7.35 (m, 3H),
7.16 (s, 1H), 7.11 (s, 1H), 6.89-6.96 (m, 1H), 3.69 (dt, 1H, J=1.8,
8.0 Hz), 3.15-3.50 (m, 5H), 3.04 (dt, 1H, J=3.3, 12.1 Hz),
2.83-2.95 (m, 3H), 1.76-1.92 (m, 2H) ppm. MS (CI, NH3): 295 (base,
M+H).
Example 106
[3253]
(.+-.)-cis-2-(2,4-dimethoxyphenyl)-4,5,6a,7,8,9,10,10a-octahydropyr-
ido[4,3-b]pyrrolo[3,2,1-hi] indole
[3254] The title compound was prepared by the method of Example 98
from tert-butyl (.+-.)-cis-2-(2,
4-dimethoxyphenyl)-4,5,7,8,10,10a-hexahydropy-
rido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (85.0 mg,
0.19 mmol) to afford the title compound (55.0 mg, 86%) as a pale
yellow amorphous solid. The enatiomers were separated by
preparative HPLC on a chiracel OD column using isocratic 8%
IPA/hexane as the eluent. .sup.1H NMR (CDCl.sub.1, 300 MHz)
.delta.7.17 (dd, 1H, J=1.4, 6.9 Hz), 7.06 (s, 1H), 7.01 (s, 1H),
6.50-6.60 (m, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 3.67 (dt, 1H, J=1.5,
7.7 Hz), 3.12-3.49 (m, 5H), 3.05 (dt, 1H, J=3.3, 12.1 Hz),
2.78-2.98 (m, 3H), 1.73-1.91 (m, 2H) ppm. MS (CI, NH3): 337 (base,
M+H).
Example 107
[3255] Lert-butyl (.+-.)-cis-5,
6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5-
]pyrrolo[3,2,1-ij]quinoline-10 (7aH)-carboxylate
[3256]
(.+-.)-Cis-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrro-
lo[3,2,1-ij]quinoline, from Example 17 (1.67 g, 7.79 mmol) was
dissolved in dioxane (16 mL) and 1M NaOH (8 mL). The reaction was
cooled to 0.degree.C. BOC.sub.2O (1.87 g, 8.57 mmol) was added. The
reaction was stirred at RT 18 hrs. EtOAc (10 mL) was added and the
biphasic mixture was stirred for 10 min. the layers were separated.
The aqueous phase was extracted with EtOAc (3.times.10 mL). The
combined organic layers were washed with brine, dried, and
concentrated to afford an amorphous white solid (2.30 g). The crude
product was purified by column chromatography (20-40% EtOAc/hexane)
to afford the title compound (2.17 g, 69%) as an amorphous white
solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.6.93 (d, 1H, J=7.3
Hz), 6.86 (d, 1H, J=7.3 Hz), 6.61-6.66 (m, 1H), 3.65-3.80 (m, 1H),
3.30-3.50 (m, 1H), 3.10-3.31 (m, 3H), 2.70 (t, 2H, J=6.6 Hz),
2.50-2.65 (m, 1H), 2.00-2.20 (m, 2H), 1.75-1.90 (m, 2H) ppm. MS
(CI, NH3): 315 (base, M+H)
Example 108
[3257] tert-butyl
(.+-.)-cis-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyrido[3'-
,4':4,5]pyrrolo[3,2,1-ij]quinoline-10 (7aH)-carboxylate
[3258] The title compound (0.81 g, 35%) was prepared by the method
of Example 89 Step B using tert-butyl
(.+-.)-cis-5,6,8,9,11,11a-hexahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10 (7aH)-carboxylate
(1.85 g) as an amorphous white solid. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta.7.01 (s, 1H), 6.98 (s, 1H), 3.50-3.70 (m, 1H),
3.30-3.50 (m, 1H), 3.00-3.30 (m, 5H), 2.50-2.70 (m, 3H), 2.00-2.30
(m, 2H), 1.70-1.90 (m, 2H), 1.48 (s, 9H) ppm.
Example 109
[3259] tert-butyl
(.+-.)-cis-2-(2,3-dichlorophenyl)-5,6,8,9,11,11a-hexahyd-
ro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate
[3260] Tert-butyl
(.+-.)-cis-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyrido[3'-
,4':4,5]pyrrolo[3,2,1-ij]quinoline-10 (7aH)-carboxylate (110 mg,
0.28 mmol) was dissolved in DME (4 mL). 2M aqueous sodium carbonate
(0.75 ml) was added. 2,3-Dichlorophenylboronic acid (107 mg, 0.56
mmol) was added, followed by Pd.sub.2 (dba).sub.3 (14.5 mg, 0.014
mmol) . P(Ph).sub.3 (14.7 mg, 0.056 mmol) was added. The reaction
flask was degassed and kept under a nitrogen atmosphere. The
suspension was refluxed for 18 h cooled to rt. The reaction was
concentrated in vacuo, after which water (10 mL) and EtOAc (10 mL)
were added. The layers were separated and the aqueous phase was
extracted with EtOAc (2.times.10 mL). The combined organic layers
were washed with brine (2.times.10 mL), dried, and concentrated to
afford a crude brown amorphous solid (162 mg). The residue was
purified by column chromatography (20-0% hexane/CH.sub.2Cl.sub.2)
to afford the title compound (96.8 mg, 75%) as a white amorphous
solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.61-7.94 (m, 1H),
7.20 (s, 1 H), 7.18 (d, 1H, 3.3 Hz), 7.00 (s, 1H), 6.93 (s, 1H),
3.70-3.74 (m, 1H), 3.45-60 (m, 1H), 3.15-3.35 (m, 4H), 2.65-2.80
(m, 4H), 2.10-2.20 (m, 2H), 1.80-2.00 (m, 2H), 1.46 (s, 9H)
ppm.
Example 110
[3261] tert-butyl
(.+-.)-cis-2-(3,4-dichlorophenyl)-5,6,8,9,11,11a-hexahyd-
ro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate
[3262] The title compound was prepared by the method of Example 109
from tert-butyl
(.+-.)-cis-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,-
5]pyrrolo[3,2,1,-ij]quinoline-10(7aH)-carboxylate (101.7 mg, 0.26
mmol) and 3,4-dichlorophenylboronic acid (97 mg, 0.52 mmol), after
chromatographic purification (91.6 mg, 77%) as a white amorphous
solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.57 (d, 1H, J=1.8
Hz), 7.42 (d, 1 H, J=8.4 Hz), 7.31 (dd, 1H, J=2.2, 8.4 Hz), 7.12
(bs, 1H), 7.07 (bs, 1H), 3.62-3.75 (m, 1H), 3.48-60 (m, 1H),
3.15-3.35 (m, 4H), 2.65-2.80 (m, 4H), 2.10-2.20 (m, 2H), 1.85-2.00
(m, 2H), 1.46 (s, 9H) ppm.
Example 111
[3263] tert-butyl
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-5,6,8,-
9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate
[3264] The title compound was prepared by the method of Example 109
from tert-butyl
(.+-.)cis-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5-
]pyrrolo[3,2,1,-ij]quinoline-10(7aH)-carboxylate (63 mg, 0.16 mmol)
and 2-chloro-4-(trifluoromethyl)phenylboronic acid (69 mg, 0.32
mmol), after chromatographic purification (35.9 mg, 46%) as a white
amorphous solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.69 (s,
1H), 7.51 (bd, 1 H, J=8.0 Hz), 7.42 (d, 1H, J=8.1 Hz), 7.04 (s,
1H), 6.97 (s, 1H), 3.60-3.75 (m, 1H), 3.48-60 (m, 1H), 3.15-3.35
(m, 4H), 2.65-2.80 (m, 4H), 2.10-2.20 (m, 2H), 1.85-2.00 (m, 2H),
1.46 (s, 9H) ppm. MS (CI, NH3): 493 (base, M+H).
Example 112
[3265]
(.+-.)-cis-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3266] Tert-butyl
(.+-.)-cis-2-(2,3-dichlorophenyl)-5,6,8,9,11,11a-hexahyd-
ro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (55 mg, 0.12 mmol) was dissolved in 20% TFA in
methylene chloride (4 mL) and was stirred at RT for 2 h. The
reaction was solution was cooled to 0.degree. C. and basified with
1M NaOH until pH >14. The layers were separated. The aqueous
phase was extracted the methylene chloride (2.times.10 ml). The
organic layers were washed with brine and dried. Concentration
afforded the title compound (43 mg, 100%) as a pale yellow
amorphous solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.37 (dd,
1H, J=2.6, 7.3 Hz), 7.15-7.23 (m, 2 H), 6.97 (s, 1H), 6.92 (s, 1H),
3.43-3.46 (m, 1H), 3.31 (dt, 1H, J=4.4, 10.2), 3.03-3.11 (m, 2H),
2.81-2.94 (m, 2H), 2.60-2.80 (m, 4H), 2.11-2.20 (m, 2H), 1.89-1.98
(m, 1H), 1.74-1.85 (m, 1H) ppm. MS (CI, NH.sub.3): 359 (base,
M+H).
Example 113
[3267]
(.+-.)-cis-2-(3,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3268] The title compound (72.6 mg, 100%) was prepared by the
method of Example 112 from tert-butyl
(.+-.)-cis-2-(3,4-dichlorophenyl)-5,6,8,9,11,-
11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1,-ij]quinoline-10
(7aH)-carboxylate (90 mg, 0.20 mmol) as pale yellow amorphous
solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.58 (d, 1H, J=2.2
Hz), 7.41 (d, 1 H, J=8.4 Hz), 7.32 (dd, 1H, J=2.2, 8.4 Hz), 7.09
(s, 1H), 7.07 (s, 1H), 3.34-3.46 (m, 1H), 3.31 (dt, 1H, J=4.4, 10.7
Hz), 3.03-3.13 (m, 2H), 2.83-2.92 (m, 2H), 2.61-2.78 (m, 4H),
2.10-2.19 (m, 2H), 1.74-1.91 (m, 2H) ppm. MS (CI, NH.sub.3): 359
(base, M+H).
Example 114
[3269]
(.+-.)-cis-2-[2-chloro-4-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3270] The title compound (21 mg, 90%) was prepared by the method
of Example 112 from tert-butyl
(.+-.)-cis-2-(3,4-dichlorophenyl)-5,6,8,9,11,-
11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (28.5 mg, 0.06 mmol) as a pale yellow amorphous
solid. The enantiomers of the title compound were separated by
preparative HPLC on a Chiracel OD column using isocratic 6%
IPA/hexane as the eluent. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.46 (s, 1H), 7.69 (s, 1H), 7.49 (d, 1H, J=8.0 Hz), 7.43 (d,
1H, J=8.08 Hz), 7.02 (s, 1H), 6.96 (s, 1H), 3.45-3.50 (m, 1H), 3.32
(dt, 1H, J=4.4, 10.3 Hz), 3.01-3.12 (m, 2H), 2.84-2.89 (m, 2H),
2.64-2.81 (m, 4H), 2.11-2.23 (m, 2H), 1.90-1.98 (m, 1H), 175-1.86
(m, 1H) ppm. MS (CI, NH3): 393 (base, M+H).
Example 189
[3271]
4-((.+-.)-cis-2-(2-chlorophenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-
-b]pyrrolo[3,2,1,-hi]indol-9(6aH)-yl)-1-(4-fluorophenyl)-1-butanone
[3272]
(.+-.)-Cis-2-(2-chlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4-
,3-b]pyrrolo[3,2,1-hi]indole (26.4mg, 0.085 mmol) 0.7 ml of MEK. KI
(14 mg, 0.085 mmol) and K.sub.2CO.sub.3 (22 mg, 0.26 mmol), and
4-chloro-4'-fluorobutyrophenone (22.2 mg, 0.11 mmol) were added.
The suspension was refluxed for 48 h and then cooled to rt. The
suspension was filtered and the residue was washed with
CH.sub.2Cl.sub.2 (5ml). The solution was concentrated in vacuo. The
residue was purified by column chromatography (10%
MeOH-CH.sub.2Cl.sub.2) to afford the title compound (18.8 mg, 47%)
as a white amorphous solid. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.8.00-8.04 (m, 2 H), 7.41 (dd, 1H, J=1.5, 7.3 Hz), 7.30 (dd,
1H, J=1.8, 7.3 Hz), 7.10-7.20 (m, 4H), 7.01 (s, 1H), 6.96 (s, 1H),
3.68 (bt, 1H, J=6.6 Hz), 3.30-3.50 (m, 2H), 3.10-3.30 (m, 2H),
2.92-3.08 (m, 3H), 2.60-2.92 (m, 2H), 2.38-2.58 (m, 3H), 2.27 (t,
1H, J=11.3 Hz), 1.70-2.05 (m, 4H) ppm. MS (CI, NH.sub.3): 475
(base, M+H).
Example 190
[3273]
4-((.+-.)-cis-2-(2,4-dichlorophenyl)-4,5,7,8,10,10a-hexahydropyrido-
[4,3-b]pyrrolo[3,2,1-hi]indol-9(6aH)-yl)-1-(4-fluorophenyl)-1-butanone
[3274] The title compound (36 mg, 37%) was prepared by the method
of Example 189 from
(.+-.)-cis-2-(2,4-dichlorophenyl)-4,5,6a,7,8,9,10,10a-oc-
tahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole (65.8 mg, 0.19 mmol),
4-chloro-4'-fluorobutyrophenone (50.0 mg, 0.25 mmol), KI (31.5 mg,
0.19 mmol), and K.sub.2CO.sub.3 (50.0 mg, 0.57 mmol) after
chromatographic purification as a white amorphous solid. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta.7.90-7.95 (m, 2 H), 7.37 (s, 1H),
7.16 (s, 2H), 7.03 (t, 2H, J=8.8 Hz), 6.91 (s, 1H), 6.85 (s, 1H),
3.49 (bt, 1H, J=8.0 Hz), 3.25-3.45 (m, 2H), 3.02-3.22 (m, 2H),
2.90-3.02 (m, 3H), 2.50-2.88 (m, 2H), 2.10-2.45 (m, 4H), 1.70-2.00
(m, 4H) ppm. MS (CI, NH.sub.3): 509 (base, M+H).
Example 191
[3275]
4-((.+-.)-cis-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]qionolin-10 (7aH)-yl)-1-(4-fluorophenyl)-1-butanone
[3276] The title compound (19.1 mg, 56%) was prepared by the method
of Example 189 from
(.+-.)-cis-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4-
':4,5]pyrrolo[3,2,1-ij]qionoline (30.0 mg, 0.0.09 mmol),
4-chloro-4'-fluorobutyrophenone (23.0 mg, 0.12 mmol), KI (15.0 mg,
0.09 mmol), and K.sub.2CO.sub.3 (37.0 mg, 0.27 mmol) after
chromatographic purification as a white amorphous solid. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta.7.91-7.96 (m, 2 H), 7.01-7.19 (m,
2H), 6.82 (d, 1H, J=12.1 Hz), 6.80 (d, 1H, J=11.7 Hz), 2.98-3.25
(m, 3H), 2.94 (t, 2H, J=6.9 Hz), 2.80-2.85 (m, 1H), 2.55-2.75 (m,
3H), 2.20-2.55 (m, 4H), 1.80-2.18 (m, 7H) ppm. MS (ESI): 379 (base,
M+H).
Example 265
[3277]
4-((.+-.)-cis-4,5,7,8,10,10a-hexahydropyrido[4.3-b]pyrrolo[3,2,1-hi-
]indol-9(6aH)-yl)-1-(4-fluorophenyl)-1-butanone
[3278] A mixture of
(.+-.)-cis-4,5,6a,7,8,9,10,10a-octahydropyrido[4.3-b]p-
yrrolo[3,2,1-hi] indole (2.8 g, 14 mmol),
4-chloro-4'-fluorobutyrophenone (4.21 g, 21 mmol), triethylamine (3
mL), KI (3.48 g, 21 mmol), dioxane (25 mL), and toluene (25 mL) was
stirred and refluxed for 15 h under an atmosphere of nitrogen and
then,evaporated under reduced pressure to remove the volatiles. The
residue was triturated with a small volume of dichloromethane and
decanted from the insoluble material. The process was repeated two
more times and the combined dichloromethane solution was added to
0.5N solution of hydrogen chloride in ether(200 mL). The salt that
separated was filtered off, washed with ether, dissolved
immediately in a minimum quantity of water and the solution
extracted with ether. The ether extract was discarded and aqueous
layer basified with 10% aqueous sodium hydroxide. The resulting
mixture was extracted with dichloro- methane (2.times.) and the
extract dried over magnesium sulfate and stripped of the solvent
under reduced pressure to yield the title compound (3.3 g, 65%) as
a highly viscous light brown liquid. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta.1.70-1.80 (m, 2H), 1.80-2.02 (m, 2H), 2.19 (t, J=10.9
Hz, 1H), 2.30-2.52 (m, 3H), 2.62-2.72 (m, 1H), 2.72-2.85 (m, 1H),
2.99 (t, J=7.0 Hz, 2H), 3.02-3.20 (m, 2H), 3.25-3.42 (m, 2H),
3.59-3.65 (m, 1H), 6.85 (s, 1H), 6.90 (s, 1H0, 7.01 (t, J=7.0 Hz,
2H), 7.98-8.03 (m, 2H) ppm. MS (CI): 365 (M+H+).
Example 274
[3279]
(6aS,10aR)-2-(2-fluoro-4-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole
[3280] Step A:
[3281] Tert-butyl
(6aS,10aR)-2-(2-fluoro-4-methoxyphenyl)-4,5,7,8,10,10a-h-
exahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
(116 mg, 55%) was prepared by the method of Example 89 step C from
tert-butyl
(6aS,10R)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]i-
ndole-9(6aH)-carboxylate (189 mg, 0.5 mmol) and 2-
fluoro-4-methoxyphenylb- oronic acid (158 mg, 1.0 mmol).
[3282] Step B:
[3283] The title compound was prepared by the method of Example 98
from tert-butyl
(6aS,10aR)-2-(2-fluoro-4-methoxyphenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate to afford
the title compound (82 mg, 93%). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.24-7.30 (m, 1H), 7.08 (s, 1H), 7.02 (s, 1H), 6.65-6.73 (m,
2H), 3.81 (s, 3H), 3.66-3.71 (m, 1H), 3.32-3.49 (m, 3H), 3.01-3.30
(m, 4H), 2.82-2.97 (m, 2H), 2.25 (bs, 1H), 1.79-1.93 (m, 2H) ppm.
MS-ESI: 325 [MH].sup.+.
Example 275
[3284] tert-butyl
(6aS,10aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-4,5,7,-
8,10,10a-hexahydropyrido
[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3285] Tert-butyl
(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]-
pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) was
dissolved in DME (7.8 mL). Ba(OH).sub.2 8H.sub.2O (236.6 mg, 0.75
mmol) in H.sub.2O (2.6 mL) was added.
4-ethoxy-2-trifluoromethylphenyl boronic acid (140 mg, 0.6 mmol)
was added followed by Pd(PPh.sub.3).sub.4 (12 mg, 0.01 mmol). The
reaction flask was degassed and refluxed under a nitrogen
atmosphere for 18 hrs. After cooling to RT, the reaction was
concentrated in vacuo. Water (10 mL) and EtOAc (10 mL) were added.
The layers were separated and the aqueous phase was extracted with
EtOAc (2.times.10 mL). The combined organic layer was washed with
brine (2.times.10 mL), dried over MgSO.sub.4 and concentrated in
vacuo and after chromatographic purification (30% EtOAc/Hexane) to
afford the title compound (140 mg, 57%). .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta.7.20 (d, 2H, J=5.9 Hz), 7.19 (s, 1H), 7.01 (dd, 1H,
J=6.2, 2.2 Hz), 6.85 (s, 1H), 6.81 (s, 1H), 4.05-4.10 (m, 3H),
3.82-3.94 (m, 1H), 3.64-3.68 (m, 1H), 3.22-3.44 (m, 4H), 2.84-3.10
(m, 3H), 1.80-1.90 (m, 2H), 1.42-1.47 (m, 12H) ppm. MS-APCI: 489
[M+H.sup.+].
Example 276
[3286]
(6aS,10aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,1-
0a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole
[3287] The title compound was prepared by the method of Example 98
from tert-butyl
(6aS,10aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-4,5,7,8,10,1-
0a-hexahydropyrido
[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate to afford the
title compound (97 mg, 87%). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.17 (d, 1H, J=8.1 Hz), 7.12 (d, 1H, J=2.9 Hz), 6.93 (dd,
1H, J=8.4, 2.6 Hz), 6.77 (s, 1H), 6.71 (s, 1H), 4.00 (q, 2H, J=6.9
Hz), 3.61 (t, 1H, J=8.0 Hz), 2.93-3.41 (m, 6H), 2.75-2.86 (m, 3H),
1.62-1.97 (m, 3H), 1.37 (t, 3H, J=6.9 Hz) ppm. MS-ApCI: 389
[M+H.sup.+].
Example 277
[3288] tert-butyl
(6aS,10aR)-2-(4-chloro-2-fluorophenyl)-4,5,7,8,10,10a-he-
xahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3289] The title compound was prepared by the method of Example 89
step C from tert-butyl
(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]p-
yrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and
corresponding 4-chloro-2-fluorophenyl boronic acid (175 mg, 1.0
mmol) to afford after chromatographic purification the title
compound (128 mg, 60%). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.28-7.29 (m,1H), 7.05-7.15 (m, 4H), 3.6-4.2 (m, 3H),
2.80-3.50 (m, 7H), 1.80-1.90 (m, 2H), 1.48 (s, 9H) ppm. MS-ApCI:
429 [M+H.sup.+].
Example 278
[3290]
(6aS,10aR)-2-(4-chloro-2-fluorophenyl)-4,5,6a,7,8,9,10,10a-octahydr-
opyrido[4,3-b]pyrrolo[3,2,1-hi]indole
[3291] The title compound was prepared by the method of Example 98
from tert-butyl
(6aS,10aR)-2-(4-chloro-2-fluorophenyl)-4,5,7,8,10,10a-hexahydr-
opyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate to afford
the title compound (66 mg, 67%). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.29-7.35 (m, 1H), 6.99-7.15 (m, 4H), 3.60-3.80 (m, 1H),
2.80-3.50 (m, 9H), 1.70-1.95 (m, 2H), 1.62 (bs, 1H) ppm. MS-ApCI:
329 [M+H.sup.+].
Example 279
[3292] tert-butyl
(6aS,10aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-4,-
5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxyl-
ate
[3293] The title compound was prepared by the method of Example 89
step C from tert-butyl
(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]p-
yrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and
4-isopropoxy-2-(trifluoromethyl)phenylboronic acid (248 mg, 1.0
mmol) to afford after chromatographic purification the title
compound (186 mg, 74%). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.11-7.18 (m,2H), 6.90-6.94 (m, 1H), 6.78 (s, 1H), 6.74 (s,
1H), 4.50-4.54 (m, 1H), 3.75-3.85 (m, 1H), 3.59-3.70 (m, 1H),
2.79-3.40 (m, 8H), 1.74-1.84 (m, 2H), 1.40 (s, 9H), 1.21 (d, 6H,
J=5.9 Hz) ppm. MS-ApCI: 503 [M+H.sup.+].
Example 280
[3294]
(6aS,10aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,-
10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole
[3295] The title compound was prepared by the method of Example 98
from tert-butyl (6aS,10aR)-2-[4-isopropoxy-2-
(trifluoromethyl)phenyl]-4,5,7,8-
,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
to afford the title compound (96 mg, 65%). .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta.7.14 (d, 1H, J=8.4 Hz), 7.10 (d, 1H, J=2.5 Hz),
6.90 (dd, 1H, J=2.6, 8.4 Hz), 6.75 (s, 1H), 6.69 (s, 1H), 4.46-4.54
(m, 1H), 3.56-3.62 (m, 1H), 2.91-3.39 (m, 6H), 2.73-2.83 (m, 3H),
1.64-1.82 (m, 3H), 1.46 (d, 6H, J=5.8 Hz) ppm. MS-ApCI: 403
[M+H.sup.+].
Example 281
[3296] tert-butyl
(6aS,10aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-4,5,7-
,8,10,10a-hexahydropyrido[4,3-b] pyrrolo[3,2,
l-hi]indole-9(6aH)-carboxyla- te
[3297] The title compound was prepared by the method of Example 89
step C from tert-butyl
(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]
pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and
4-methoxy-2-(trifluoromethyl)phenylboronic acid (248 mg, 1.0 mmol)
to afford after chromatographic purification the title compound
(196 mg, 83%). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.21-7.26
(m,2H), 7.01-7.05 (m, 1H), 6.86 (s, 1H), 6.82 (s, 1H), 3.90-4.30
(m, 3H), 3.86 (s, 3H), 3.3.64-3.75 (m, 1H), 3.25-3.50 (m, 4H),
3.05-3.12 (m, 1H), 2.85-2.95 (m, 1H), 1.80-1.90 (m, 2H), 1.47 (s,
9H) ppm. MS-ApCI: 475 [M+H.sup.+].
Example 282
[3298]
(6aS,10aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,-
10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole
[3299] The title compound was prepared by the method of Example 98
from tert-butyl
(6aS,10aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-4,5,7,8,10,-
10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
to afford the title compound (94 mg, 61%). .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta.7.20-7.25 (m, 2H), 7.02 (dd, 1H, J=8.6, 2.5 Hz),
6.85 (s, 1H), 6.77 (m, 1H), 3.86 (s, 1H), 3.64-3.74 (m, 1H),
3.26-3.48 (m, 3H), 3.02-3.24 (m, 3H), 2.82-2.98 (m, 3H), 1.74-1.96
(m, 3H) ppm. MS-ApCI: 375 [M+H.sup.+].
Example 283
[3300] tert-butyl
(6aS,10aR)-2-phenyl-4,5,7,8,10,10a-hexahydropyrido[4,3-b-
]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3301] The title compound was prepared by the method of Example 89
step C from tert-butyl
(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]p-
yrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and
phenylboronic acid (122 mg, 1.0 mmol) to afford after
chromatographic purification the title compound (74 mg, 20%).
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.49 (d, 2H, J=7.7 Hz),
7.34-7.40 (m, 2H), 7.25-7.30 (m, 1H), 7.20 (s, 1H), 7.15 (s, 1H),
3.85-3.95 (m, 1H), 3.68-3.70 (m, 1H), 3.24-3.52 (m, 4H), 2.84-3.22
(m, 4H), 1.82-1.94 (m, 2H), 1.49 (s, 9H) ppm. MS-ApCI: 377
[M+H.sup.+].
Example 284
[3302] (6aS,10aR)-2-phenyl-4,5,6a,7,8,9,10,10a-octahydropyrido
[4,3-b]pyrrolo[3,2,1,-hi]indole
[3303] The title compound was prepared by the method of Example 98
from tert-butyl
(6aS,10aR)-2-phenyl-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrro-
lo[3,2,1-hi]indole-9(6aH)-carboxylate to afford the title compound
(35 mg, 64%). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.49 (d, 2H,
J=7.7 Hz), 7.34-7.40 (m, 2H), 7.22-7.27 (m, 1H), 7.19 (s, 1H), 7.13
(s, 1H), 3.68-3.73 (m, 1H), 2.98-3.56 (m, 6H), 2.82-2.96 (m, 3H),
1.70-1.96 (m, 2H), 1.63 (bs, 1H) ppm. MS-ApCI: 277 [M+H.sup.+].
Example 285
[3304] tert-butyl
(6aS,10aR)-2-(2-methylphenyl)-4,5,7,8,10,10a-hexahydropy-
rido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3305] The title compound was prepared by the method of Example 89
step C from tert-butyl
(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]p-
yrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and
2-methylphenylboronic acid (136 mg, 1.0 mmol) to afford after
chromatographic purification the title compound (90 mg, 46%).
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.11-7.18 (m,4H), 6.82 (s,
1H), 6.77 (s, 1H), 3.86-4.30 (m, 2H), 3.58-3.64 (m, 1H), 2.76-3.42
(m, 7H), 2.20 (s, 3H), 1.70-1.85 (m, 2H), 1.40 (s, 9H) ppm.
MS-ApCI: 391 [M+H.sup.+].
Example 286
[3306]
(6aS,10aR)-2-(2-methylphenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido
[4,3-b]pyrrolo[3,2,1-hi]indole
[3307] The title compound was prepared by the method of Example 98
from tert-butyl
(6aS,10aR)-2-(2-methylphenyl)-4,5,7,8,10,10a-hexahydropyrido[4-
,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate to afford the title
compound (52 mg, 78%). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.09-7.18 (m, 4H), 6.80 (s, 1H), 6.74 (s, 1H), 3.59-3.65 (m,
1H), 2.93-3.42 (m, 6H), 2.74-2.87 (m, 3H), 2.20 (s, 3H), 1.66-1.85
(m, 2H), 1.51 (bs, 1H) ppm. MS-ApCI: 291 [M+H.sup.+].
Example 287
[3308] tert-butyl
(6aS,10aR)-2-[2-(trifluoromethyl)phenyl]-4,5,7,8,10,10a--
hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3309] The title compound was prepared by the method of Example 89
step C from tert-butyl
(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]p-
yrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and
2-(trifluoromethyl)phenylboronic acid (190 mg, 1.0 mmol) to afford
after chromatographic purification the title compound (175 mg,
79%). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.69 (d, 1H, J=7.7
Hz), 7.50 (dd, 1H, J=7.3, 7.7 Hz), 7.40 (dd, 1H, J=7.7, 7.3 Hz),
7.31 (d, 1H, J=7.3 Hz), 6.89 (s, 1H), 6.85 (s, 1H), 3.82-4.30 (m,
2H), 3.66-3.71 (m, 1H), 2.88-3.50 (m, 7H), 1.80-1.90 (m, 2H), 1.47
(s, 9H) ppm. MS-ApCI: 445 [M+H.sup.+].
Example 288
[3310]
(6aS,10aR)-2-[2-(trifluoromethyl)phenyl]-4,5,6a,7,8,9,10,10a-octahy-
dropyrido[4,3-b]pyrrolo[3,2,1-hi]indole
[3311] The title compound was prepared by the method of Example 98
from tert-butyl
(6aS,10aR)-2-[2-(trifluoromethyl)phenyl]-4,5,7,8,10,10a-hexahy-
dropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate to
afford the title compound (92 mg, 68%). .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta.7.71 (d, 1H, J=7.6 Hz), 7.51 (dd, 1H, J=6.9, 7.4
Hz), 7.33-7.42 (m, 2H), 6.89 (s, 1H), 6.83 (s, 1H), 3.68-3.73 (m,
1H), 3.03-3.48 (m, 7H), 2.83-2.99 (m, 3H), 1.74-1.94 (m, 2H), 1.59
(bs, 1H) ppm. MS-ApCI: 345 [M+H.sup.+].
Example 289
[3312] tert-butyl
(6aS,10aR)-2-(3,4-dimethoxyphenyl)-4,5,7,8,10,10a-hexahy-
dropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3313] The title compound was prepared by the method of Example 89
step C from tert-butyl
(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]p-
yrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and
corresponding 3,4-dimethoxyphenyl boronic acid (182 mg, 1.0 mmol)
to afford after chromatographic purification the title compound (92
mg, 42%). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.15 (s, 1H),
7.11 (s, 1H), 7.01-7.04 (m, 2H), 6.89 (d, 1H, J=8.0 Hz), 4.02-4.10
(m, 1H), 3.92 (d, 6H, J=8.1 Hz), 3.64-3.78 (m, 1H), 2.82-3.52 (m,
8H), 1.82-1.90 (m, 2H), 1.49 (s, 9H) ppm. MS-ApCI: 437
[M+H.sup.+].
Example 290
[3314]
(6aS,10aR)-2-(3,4-dimethoxyphenyl)-4,5,6a,7,8,9,10,10a-octahydropyr-
ido [4,3-b]pyrrolo[3,2,1-hi]indole
[3315] The title compound was prepared by the method of Example 98
from tert-butyl
(6aS,10aR)-2-(3,4-dimethoxyphenyl)-4,5,7,8,10,10a-hexahydropyr-
ido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate to afford the
title compound (52 mg, 73%). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.16 (s, 1H), 7.10 (s, 1H), 7.03-7.06 (m, 2H), 6.91(d, 1H,
J=8.8 Hz), 3.93 (d, 6H, J=8.1 Hz), 3.69-3.75 (m, 1H), 2.83-3.52 (m,
9H), 1.74-1.94 (m, 3H) ppm. MS-ApCI: 337 [M+H.sup.+].
Example 291
[3316] tert-butyl
(6aS,10aR)-2-(2,5-dichlorophenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3317] The title compound was prepared by the method of Example 89
step C from tert-butyl
(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]p-
yrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and
2,5-dichlorophenylboronic acid (191 mg, 1.0 mmol) to afford after
chromatographic purification the title compound (105 mg, 47%).
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.30-7.36 (m, 2H),
7.15-7.19 (m, 1H), 7.01 (s, 1H), 3.82-4.22 (m, 2H), 3.82-3.96 (m,
1H), 2.82-3.52 (m, 7H), 1.82-1.90 (m, 2H), 1.48 (s, 9H) ppm.
MS-ApCI: 445 [M+H.sup.+].
Example 292
[3318]
(6aS,10aR)-2-(2,5-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do [4,3-b]pyrrolo[3,2,1 -hi]indole
[3319] The title compound was prepared by the method of Example 98
from tert-butyl
(6aS,10aR)-2-(2,5-dichlorophenyl)-4,5,7,8,10,10a-hexahydropyri-
do[4,3-b]pyrrolo[3,2,1 -hi]indole-9(6aH)-carboxylate to afford the
title compound (60 mg, 74%). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.18-7.28 (m, 2H), 7.08 (dd, 1H, J=2.6, 8.4 Hz), 6.92 (s,
1H) , 6.86 (s, 1H), 3.59-3.64 (m, 1H) , 3.06-3.41 (m, 6H),
2.74-3.01 (m, 3H), 1.64-1.83 (m, 2H), 1.48 (bs, 1H) ppm. MS-ApCI:
345 [M+H.sup.+].
Example 293
[3320] tert-butyl
(6aS,10aR)-2-(3,5-dichlorophenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3321] The title compound was prepared by the method of Example 89
step C from tert-butyl
(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]p-
yrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and
3,5-dichlorophenylboronic acid (191mg, 1.0 mmol) to afford after
chromatographic purification the title compound (85 mg, 38%).
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.35 (s, 2H), 7.21-7.23
(m, 1H), 7.13 (s, 1H), 7.10 (s, 1H), 3.82-4.22 (m, 2H), 3.65-3.75
(m, 1H), 2.84-3.52 (m, 7H), 1.80-1.90 (m, 2H), 1.49 (s, 9H) ppm.
MS-ApCI: 445 [M+H.sup.+].
Example 294
[3322]
(6aS,10aR)-2-(3,5-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do [4,3-b]pyrrolo[3,2,1-hi]indole
[3323] The title compound was prepared by the method of Example 98
from tert-butyl
(6aS,10aR)-2-(3,5-dichlorophenyl)-4,5,7,8,10,10a-hexahydropyri-
do[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate to afford the
title compound (60 mg, 74%). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.27 (d, 2H, J=1.9 Hz), 7.12-7.14 (m, 1H), 7.05 (s, 1H),
6.99 (s, 1H), 3.59-3.65 (m, 1H), 3.00-3.41 (m, 5H), 2.91-2.99 (m,
1H), 2.74-2.89 (m, 3H), 1.65-1.83 (m, 2H), 1.49 (bs, 1H) ppm.
MS-ApCI: 345 [M+H.sup.+].
Example 295
[3324] tert-butyl
(6aS,10aR)-2-(2-isopropyl-4-methoxyphenyl)-4,5,7,8,10,10-
a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3325] The title compound was prepared by the method of Example 89
step C from tert-butyl
(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]p-
yrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and
corresponding 2-isopropyl-4-methoxyphenyl boronic acid (178 mg, 1.0
mmol) to afford after chromatographic purification the title
compound (152 mg, 68%). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.09 (d, 1H, J=8.4 Hz), 6.88 (d, 1H, J=2.5 Hz), 6.83 (s,
1H), 6.78 (s, 1H), 6.72 (dd, 1H, J=8.4, 2.9 Hz), 3.80-4.20 (m, 2H),
3.84 (s, 3H), 3.74-3.78 (m, 1H), 3.05-3.50 (m, 7H), 2.84-2.98 (m,
1H), 1.82-1.94 (m, 2H), 1.48 (s, 9H), 1.12-1.17 (m, 6H) ppm.
MS-ApCI: 449 [M+H.sup.+].
Example 296
[3326]
(6aS,10aR)-2-(2-isopropyl-4-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octa-
hydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole
[3327] The title compound was prepared by the method of Example 98
from tert-butyl
(6aS,10aR)-2-(2-isopropyl-4-methoxyphenyl)-4,5,7,8,10,10a-hexa-
hydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate to
afford the title compound (88 mg, 75%). .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta.7.10 (d, 1H, J=8.0 Hz), 6.87 (d, 1H, J=3.0 Hz),
6.81 (s, 1H), 6.70-6.75 (m, 2H), 3.84 (s, 3H), 3.67-3.73 (m, 1H),
3.01-3.50 (m, 7H), 2.82-2.94 (m, 3H), 1.73-1.93 (m, 2H), 1.67 (bs,
1H), 1.14 (m, 6H) ppm. MS-ApCI: 349 [M+H.sup.+].
Example 297
[3328] tert-butyl
(6aS,10aR)-2-(5-fluoro-4-methoxy-2-methylphenyl)-4,5,7,8-
,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3329] The title compound was prepared by the method of Example 89
step C from tert-butyl
(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]p-
yrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and
corresponding 5-fluoro-4-methoxy-2-methylphenyl boronic acid (184
mg, 1.0 mmol) to afford after chromatographic purification the
title compound (130 mg, 60%). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.6.94 (d, 1H, J=12.5 Hz), 6.84 (s, 1H), 6.79-6.82 (m, 2H),
4.02-4.22 (m, 1H), 3.90 (s, 3H), 3.82-3.92 (m, 1H), 3.64-3.74 (m,
1H), 3.24-3.54 (m, 4H), 2.86-3.22 (m, 3H), 2.22 (s, 3H), 1.82-1.94
(m, 2H), 1.48 (s, 9H) ppm. MS-ApCI: 439 [M+H.sup.+].
Example 298
[3330]
(6aS,10aR)-2-(5-fluoro-4-methoxy-2-methylphenyl)-4,5,6a,7,8,9,10,10-
a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole
[3331] The title compound was prepared by the method of Example 98
from tert-butyl
(6aS,10aR)-2-(5-fluoro-4-methoxy-2-methylphenyl)-4,5,7,8,10,10-
a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
to afford the title compound (85 mg, 85%). .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta.6.93 (d, 1H, J=13.1 Hz), 6.77-6.82 (m, 3H), 3.90
(s, 3H), 3.66-3.72 (m, 1H), 3.01-3.49 (m, 6H), 2.81-2.94 (m, 3H),
2.23 (s, 3H), 1.69-1.93 (m, 3H) ppm. MS-ApCI: 339 [M+H.sup.+].
Example 299
[3332] tert-butyl
(6aS,10aR)-2-(4-methoxy-2-methylphenyl)-4,5,7,8,10,10a-h-
exahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3333] The title compound was prepared by the method of Example 89
step C from tert-butyl
(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]p-
yrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and
4-methoxy-2-methylphenylboronic acid (166 mg, 1.0 mmol) to afford
after chromatographic purification the title compound (105 mg,
50%). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.04 (d, 1H, J=8.5
Hz), 6.65-6.79 (m, 4H), 3.75-4.22 (m, 2H), 3.74 (s, 3H), 3.58-3.68
(m, 1H), 3.18-3.42 (m, 4H), 2.76-3.16 (m, 3H), 2.17 (s, 3H),
1.70-1.84 (m, 2H), 1.40 (s, 9H) ppm. MS-ApCI: 421 [M+H.sup.+].
Example 300
[3334]
(6aS,10aR)-2-(4-methoxy-2-methylphenyl)-4,5,6a,7,8,9,10,10a-octahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole
[3335] The title compound was prepared by the method of Example 98
from tert-butyl
(6aS,10aR)-2-(4-methoxy-2-methylphenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate to afford
the title compound (50 mg, 63%). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.14 (d, 1H, J=8.5 Hz), 6.85 (s, 1H), 6.73-6.79 (m, 3H),
3.82 (s, 3H), 3.67-3.69 (m, 1H), 3.02-3.50 (m, 6H), 2.82-2.94 (m,
3H), 2.26 (s, 3H), 1.73-1.93 (m, 2H), 1.63 (bs, 1H) ppm. MS-ApCI:
321 [M+H.sup.+].
Example 301
[3336] tert-butyl
(6aS,10aR)-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a-h-
exahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3337] The title compound was prepared by the method of Example 89
step C from tert-butyl
(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]p-
yrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and
2-chloro-4-methoxyphenylboronic acid (187 mg, 1.0 mmol) to afford
after chromatographic purification the title compound (133 mg,
60%). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.23 (d, 1H, J=8.8
Hz), 7.01 (s, 2H), 6.97 (s, 1H), 6.84 (dd, 1H, J=8.5, 2.6 Hz),
3.84-4.24 (m, 2H), 3.84 (s, 3H), 3.68-3.74 (m, 1H), 3.24-3.54 (m,
4H), 2.86-3.26 (m, 3H), 1.84-1.8 (m, 2H), 1.49 (s, 9H) ppm.
MS-ApCI: 441 [M+H.sup.+].
Example 302
[3338]
(6aS,10aR)-2-(2-chloro-4-methoxyphenyl)-4,5,6a,7,8,9,10,10a-octahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole
[3339] The title compound was prepared by the method of Example 98
from tert-butyl
(6aS,10aR)-2-(2-chloro-4-methoxyphenyl)-4,5,7,8,10,10a-hexahyd-
ropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate to afford
the title compound (66 mg, 64%) .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.24 (d, 1H, J=8.4 Hz), 7.00-7.01 (m, 2H), 6.94 (s, 1H),
6.83 (dd, 1H, J=8.7, 2.6 Hz), 3.84 (s, 3H), 3.68-3.74 (m, 1H),
3.02-3.51 (m, 6H), 2.85-2.95 (m, 3H), 1.76-1.93 (m, 2H), 1.63 (bs,
1H) ppm. MS-ApCI: 341 [M+H.sup.+].
Example 303
[3340] tert-butyl
(6aS,10aR)-2-(3-chloro-2-methylphenyl)-4,5,7,8,10,10a-he-
xahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate
[3341] The title compound was prepared by the method of Example 89
step C from tert-butyl
(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]
pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and
3-chloro-2-methylphenylboronic acid (140 mg, 1.0 mmol) to afford
after chromatographic purification the title compound (99 mg, 47%).
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.28-7.31 (m, 1H), 7.10
(d, 2H, J=4.4 Hz), 6.85 (s, 1H), 6.81 (s, 1H), 3.82-4.24 (m, 2H),
3.64-3.74 (m, 1H), 3.24-3.54 (m, 4H), 2.86-3.26 (m, 3H), 1.86 (s,
3H),1.84-1.89 (m, 2H), 1.48 (s, 9H) ppm. MS-ApCI: 425
[M+H.sup.+].
Example 304
[3342]
(6aS,10aR)-2-(3-chloro-2-methylphenyl)-4,5,6a,7,8,9,10,-10a-octahyd-
ropyrido [4,3-b]pyrrolo[3,2,1-hi]indole
[3343] The title compound was prepared by the method of Example 98
from tert-butyl
(6aS,10aR)-2-(3-chloro-2-methylphenyl)-4,5,7,8,10,10a-hexahydr-
opyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate to afford
the title compound (48 mg, 63%). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.7.27-7.30 (m, 1H), 7.07-7.13 (m, 2H), 6.83 (s, 1H), 6.78
(s,1H), 3.67-3.73 (m, 1H), 3.01-3.50 (m, 6H), 2.83-2.94 (m, 3H),
2.29 (s, 3H), 1.75-1.93 (m, 2H), 1.62 (bs, 1H) ppm. MS-ApCI: 325
[M+H.sup.+].
Example 305
[3344]
2-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2-
,1-hi]-2-yl]-5-methoxybenzaldehyde
[3345] Step A:
[3346] To a solution of tert-butyl(6aS,
l0aR)-2-bromo-4,5,7,8,10,10a-hexah-
ydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (0.600
g, 1.59 mmol) in DME (35 mL) was added
2-formyl-4-methoxybenzeneboronic acid (0.344 g, 1.91 mmol),
tetrakis(triphenylphosphine)palladium(0) (0.110 g), barium
hydroxide octahydrate (0.753 g, 2.39 mmol), and H.sub.2O (10 mL).
The combined mixture was refluxed for 20 h. Once at room
temperature, the mixture was taken up in H.sub.2O (300 mL) and
extracted with EtOAc (3.times.100 mL). The combined extracts were
dried over MgSO.sub.4 and stripped of solvent under reduced
pressure. Purification by normal phase HPLC using 25% EtOAc in
hexanes afforded 0.280 g (41%) of tert-butyl
(6aS,10aR)-2-(2-formyl-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,-
3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate.
[3347] Step B:
[3348] A solution of tert-butyl
(6aS,10aR)-2-(2-formyl-4-methoxyphenyl)-4,-
5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxyl-
ate (0.066 g, 0.15 mmol) in CH.sub.2Cl.sub.2 (5 mL) was treated
with TFA (2 mL) and stirred at room temperature for 18 h in a
closed vial. The solution was basified with 1N NaOH (50 mL) and
extracted with CH.sub.2Cl.sub.2 (3.times.25 mL). The combined
extracts were dried over Na.sub.2SO.sub.4, and stripped of the
solvent under reduced pressure to yield 0.042 g (82%) of
2-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[-
4,3-b]pyrrolo[3,2,1-hi]-2-yl]-5-methoxybenzaldehyde as a foam.
.sup.1H NMR (CDCl.sub.13, 300 MHz) .delta.7.45 (d, 1H), 7.35 (d,
1H), 7.16 (dd, 1H), 6.92 (d, 1H), 6.86 (d, 1H), 3.88 (s, 1H), 3.74
(td, 1H), 3.51-3.24 (m, 3H), 3.23-3.00 (m, 2H), 2.98-2.83 (m, 1H),
2.00-1.92 (m, 2H). MS (CI): 337 (M+H.sup.+).
Example 306
[3349]
(6aS,10aR)-2-(2,6-dichlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyri-
do[4,3-b] pyrrolo[3,2,1-hi]indole
[3350] The title compound was prepared by Example 305, Step A, from
tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo-
[3,2,1-hi]indole-9(6aH)-carboxylate and the corresponding
2,6-dichlorobenzeneboronic acid followed by hydrolysis of the
resultant BOC protected amine adduct by the procedure of Example
305, Step B. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.38 (dd,
2H), 7.15 (t, 1H), 6.80 (d, 1H), 6.73 (d, 1H), 3.69 (td, 1H),
3.57-3.30(m, 3H), 3.28-3.00 (m, 3H), 3.00-2.83 (m, 3H), 2.20 (bs,
2H), 2.00-1.81 (m, 2H). MS (CI): 346 (M+H.sup.+).
Example 307
[3351]
N-[4-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[-
3,2,1-hi]indol-2-yl]-3-(trifluoromethyl)phenyl]-N-methylamine
[3352] The title compound was prepared by Example 305, Step A, from
tert-butyl(6aS,10)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3-
,2,1-hi]indole-9(6aH)-carboxylate and the corresponding
2-(trifluoromethyl)benzeneboronic acid followed by hydrolysis of
the resultant BOC protected amine adduct by the procedure of
Example 305, Step B. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.09
(d, 1H), 6.76 (dd, 2H), 6.70 (dd, 1H), 6.63 (dd, 2H), 3.80 (bs,
1H), 3.60 (t, 1H), 3.41-2.96 (m, 5H), 2.95-2.73 (m, 4H), 2.10 (bs,
2H), 1.98-1.75 (m, 2H). MS (CI): 374 (M+H.sup.+).
Example 308
[3353]
4-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[
3,2,1-hi]indol-2-yl]-3-(trifluoromethyl)phenylamine
[3354] The title compound was prepared by Example 305, Step A, from
tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo-
[3,2,1,-hi]indole-9(6aH)-carboxylate and the corresponding
2-(trifluoromethyl)benzeneboronic acid followed by hydrolysis of
the resultant BOC protected amine adduct by the procedure of
Example 305, Step B. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.03
(d, 1H), 6.90 (d, 1H), 6.79-6.70 (m, 3H), 3.78 (bs, 1H), 3.60 (t,
1H), 3.41-3.18 (m, 2H), 3.17-2.79 (m, 5H), 2.27 (bs, 2H), 1.90-1.80
(m, 2H). MS (CI): 360 (M+H.sup.+).
Example 309
[3355]
1-(2-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[-
3,2,1-hi]indol-2-yl]-5-methoxyphenyl)ethanol
[3356] To a solution of
2-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[-
4,3-b]pyrrolo[3,2,1-hi]-2-yl]-5-methoxybenzaldehyde (0.156 g, 0.47
mmol) from Example 305 in freshly distilled THF (8 mL) at
-78.degree. C. was added 3.0 M methylmagnesiumbromide in
diethylether (0.88 mL, 2.65 mmol). The reaction was stirred at room
temperature for 18 h under a nitrogen atmosphere. The reaction
mixture was quenched with aqueous ammonium chloride (20 mL) and
extracted with EtOAc (3.times.10 mL). The combined extracts were
dried over.Na.sub.2SO.sub.4 and evaporated to dryness under reduced
pressure to yield a 60% mixture of product and 40% starting
material. Purification by reverse phase HPLC using a gradient of
0-100% water, acetonitrile with 0.1% TFA afforded 0.024 g (15%) of
1-(2-[(6aS,10aR)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1--
hi]indol-2-yl]-5-methoxyphenyl)ethanol after generation of the free
base. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.18 (d, 1H), 7.13
(dd, 1H), 6.80 (dd, 2H), 6.77 (d, 1H), 5.03-4.96 (m, 1H), 3.85 (s,
3H), 3.68 (dt, 1H), 3.51-3.39 (m, 1H), 3.36-3.28 (m, 2H), 3.21-3.00
(m, 3H), 2.98-280 (m, 3H), 2.00-1.78 (m, 2H), 1.19 (q, 3H). MS
(CI): 351 (M+H.sup.+).
Example 310
[3357]
(.+-.)-cis-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyri-
do[4,3-b]indole
[3358] Step A:
[3359] Sodium azide (1.95 g, 30 mmol) was added in small portions
to a solution of 3,4-dihydro-1(2H)-naphthalenone (2.92 g, 20 mmol)
in CH.sub.3SO.sub.3H (50 mL) at 0.degree. C. The mixture was
stirred at 0.degree. C. for 15 min, 1 hr at room temperature,
poured into ice (400 mL), basified until pH >8 with 1N NaOH at
0.degree. C. and extracted with ether (3.times.100 mL). The
combined organic layer was dried (MgSO.sub.4), concentrated in
vacuo and flash column chromatography (EtOAc:hexane/1:1) gave
1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (2.71 g, 85%) as a white
solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.2.18-2.32 (m, 2H),
2.36 (t, J=7.1 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 6.99 (d, J=8.1 Hz,
1H), 7.13 (td, J=7.6, 1.5 Hz, 1H), 7.22 (d, J=7.0 Hz, 2H), 8.10
(br, 1H) ppm.
[3360] Step B:
[3361] A solution of 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (2.71
g, 16.7 mmol) in THF (40 mL) was added dropwise to a suspension of
LAH (1.27 g, 33.4 mmol) in ether (150 mL) at room temperature. The
mixture was refluxed for 16 h. Saturated Rochelle's salt solution
(15 mL) was added to the mixture cooled with an ice-water bath. The
mixture was stirred for 2 hrs and the two layers were separated.
The aqueous layer was extracted with ether (2.times.25 mL). The
combined organic layer was dried (Na.sub.2SO.sub.4), concentrated
in vacuo and flash column chromatography (EtOAc:hexane/3:7) gave
2,3,4,5-tetrahydro-1H-1-benzazepine (2.40 g, 98%) as a yellow
liquid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.58-1.70 (m, 2H),
1.72-1.86 (m, 2H), 2.72-2.82 (m, 2H), 3.00-3.10 (m, 2H), 3.78 (br,
1H), 6.74 (dd, J=1.1, 7.7 Hz, 1H), 6.82 (td, J=7.3, 1.1 Hz, 1H),
7.04 (td, J=7.5, 1.5 Hz, 1H), 7.11(d, J=7.4 Hz, 1H) ppm.
[3362] Step C:
[3363] A solution of sodium nitrite (1.35 g, 19.6 mmol) in water
(4.0 mL) was added dropwise to a solution of
2,3,4,5-tetrahydro-1H-1-benzazepine (2.40 g, 16.3 mmol) in AcOH (10
mL) at 0-10.degree. C. The mixture was stirred at 5.degree. C. for
10 min, room temperature for 1 h and extracted with
CH.sub.2Cl.sub.2 (3.times.20 mL). The organic layer was dried
(MgSO.sub.4), concentrated in vacuo and flash column chromatography
(EtOAc:hexane/1:9) gave
1-nitroso-2,3,4,5-tetrahydro-1H-1-benzazepine (2.60 g, 91%) as a
brown liquid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.70-1.85
(m, 4H), 2.70-2.82 (m, 2H), 3.92 (br, 2H), 7.25-7.32 (m, 1H),
7.32-7.40 (m, 2H), 7.40-7.48 (m, 1H) ppm.
[3364] Step D:
[3365] A solution of 1-nitroso-2,3,4,5-tetrahydro-1H-1-benzazepine
(2.60 g, 14.7 mmol) in THF (40 mL) was added dropwise under N.sub.2
to a suspension of LAH (0.56 g, 14.7 mmol) in THF (10 mL) cooled
with an ice-bath such that the temperature did not rise above
15.degree. C. The mixture was stirred at room temperature for 1 h,
quenched with saturated Rochelle's salt solution (15 mL) and
extracted with ether (3.times.20 mL). The organic layer was dried
(Na.sub.2SO.sub.4), concentrated in vacuo and flash column
chromatography (EtOAc:hexane/1:4) gave
2,3,4,5-tetrahydro-1H-1-benzazepin-amine (1.63 g, 68%) as a light
yellow solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.72
(m, 2H), 1.78-1.92 (m, 2H), 2.70-2.82 (m, 2H), 3.180-3.22 (m, 2H),
3.78 (br, 2H), 6.91 (td, J=7.3, 1.5 Hz, 1H), 7.10 (dd, J=1.1, 7.4
Hz, 1H), 7.21 (td, J=8.0, 1.4 Hz, 1H), 7.28 (dd, J=1.4, 8.0 Hz, 1H)
ppm.
[3366] Step E:
[3367] A mixture of 4-piperidone monohydrate HCl (1.54 g, 10 mmol)
and 2,3,4,5-tetrahydro-1H-1-benzazepin-amine (1.62 g, 10 mmol) in
IPA (50 mL) was refluxed for 2 h and cooled to room temperature.
Concentrated HCl (0.82 mL, 10 mmol) was added and the resultant
mixture was refluxed for 3 hrs before being cooled to room
temperature. The solid was filtered, rinsed with cold IPA
(2.times.20 mL) and concentrated in vacuo.
4,5,6,7,9,10,11,12-Octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole
hydrochloride (1.88 g, 71%) was obtained as a pink solid.
4,5,6,7,9,10,11,12-Octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole
hydrochloride (20 mg, 0.076 mmol) in water (1.0 mL) was basified
with 1N NaOH until pH>14 and extracted with CHCl.sub.3
(3.times.10 mL). The combined organic layer was washed with brine
(10 mL), dried (MgSO.sub.4) and concentrated in vacuo.
4,5,6,7,9,10,11,12-Octahydroazepino[3,2,1-hi]p- yrido[4,3-b]indole
(16 mg, 95%) was obtained as a white foam. .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta.1.83 (br, 1H), 2.00-2.20 (m, 4H), 2.72 (t, J=5.7
Hz, 2H), 3.05-3.20 (m, 2H), 3.25 (t, J=5.6 Hz, 2H), 3.92-4.02 (m,
2H), 4.05 (t, J=1.6 Hz, 2H), 6.92 (d, J=6.3 Hz, 1H), 6.98 (t, J=7.4
Hz, 1H), 7.25 (dd, J=1.0, 7.4 Hz, 1H) ppm.
[3368] Step F:
[3369] NaCNBH.sub.3 (0.94 g, 15 mmol) was added in small portions
to a solution of
4,5,6,7,9,10,11,12-octahydroazepino[3,2,1-hi]pyrido[4,3-b]ind- ole
hydrochloride (1.32 g, 5.0 mmol) in TFA (15 mL) at 0.degree. C.
After stirring at room temperature for 2 h, the mixture was
carefully treated with 6 N HCl (10 mL) and refluxed for 1 h. The
mixture was basified with 50% NaOH and extacted with
CH.sub.2Cl.sub.2 (3.times.20 mL). The organic layer was dried
(MgSO.sub.4) and concentrated in vacuo. The title compound (1.0 g,
89%) was obtained as a yellow oil. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta.1.48-1.68 (m, 1H), 1.68-2.10 (m, 7H), 2.42-2.72 (m,
3H), 2.80-3.00 (m, 3H), 3.05 (dd, J=6.3, 12.4 Hz, 1H), 3.12-3.55
(m, 2H), 6.69 (t, J=7.4 Hz, 1H), 6.92 (dd, J=2.5, 7.4 Hz, 2H)
ppm.
Example 311
[3370] tert-butyl
(.+-.Y)-cis-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3-
,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
[3371] 1 N NaOH (10 mL) was added to a solution of
(.+-.)-cis-4,5,6,7,8a,9-
,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole (1.00
g, 4.37 mmol) and di-tert-butyl dicarbonate (1.05 g, 4.8 mmol) in
1,4-dioxane (20 mL) and the mixture was stirred for 2 h at room
temperature. The solvent was concentrated in vacuo and EtOAc (30
mL) was added. The solution was washed with brine (30 mL), dried
(MgSO.sub.4), concentrated in vacuo and flash column chromatography
(EtOAc:hexane/1:4) gave the title compound (1.2 g, 83%) as a white
solid.
Example 312
[3372]
(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyri-
do[4,3-b]indole
[3373] Step A:
[3374] Tert-Butyl
(8aS,12aR)-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi-
]pyrido[4,3-b]indole-11(8aH)-carboxylate was obtained from
(.+-.)-tert-butyl
cis-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrid-
o[4,3-b]indole-11(8aH)-carboxylate by using preparative HPLC on a
Chiracel.RTM. OD column (2% IPA in hexane).
[3375] Step B:
[3376] Tert-Butyl
(8aS,12aR)-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi-
]pyridd[4,3-b]indole-11(8aH)-carboxylate (0.24 g, 0.73 mmol) was
stirred in 20% TFA in CH.sub.2Cl.sub.2 (10 mL) at room temperature
for 2 h before the solution was basified with saturated NH.sub.40H
until pH>10. The layers were separated and the aqueous layer was
extracted with CH.sub.2Cl.sub.2 (3.times.20 mL). The combined
organic layer was washed with brine (20 mL), dried (MgSO.sub.4) and
concentrated in vacuo. The title compound (0.16 g, 94%) was
obtained as a white foam. .sup.1H NMR was identical to
(.+-.)-cis-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,-
2,1-hi]pyrido[4,3-b]indole of Example 310.
Example 313
[3377]
(8aR,12aS)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyri-
do[4,3-b] indole
[3378] Step A:
[3379] Tert-butyl
(8aR,12aS)-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi-
]pyrido[4,3-b] indole-11(8aH)-carboxylate was obtained from
(.+-.)-tert-butyl
cis-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrid-
o[4,3-b]indole-11(8aH)-carboxylate by using preparative HPLC on a
Chiracel.RTM. OD column (2% IPA in hexane).
[3380] Step B:
[3381] The title compound (0.063 g, 98%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aR,12aS)-4,5,6,7,9,10,12,-
12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.092 g, 0.28 mmol) as a white foam. .sup.1H NMR was identical to
(.+-.)-cis-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-
-b]indole of Example 310.
Example 314
[3382] tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b] indole-11(8aH)-carboxylate
[3383] A solution of NBS (0.29 g, 1.6 mmol) in DMF (2.0 mL) was
added dropwise to a solution of tert-butyl
(8aS,12aR)-4,5,6,7,9,10,12,12a-octah-
ydroazepino[3,2,1-hi]pyrido[4,3-b]-indole-11(8aH)-carboxylate (0.53
g, 1.6 mmol) in DMF (3.0 mL) at 0.degree.C. The mixture was stirred
at 0.degree.C. for 15 min and room temperature for 0.5 h before
poured into water (10 mL). The milky mixture was extracted with
EtOAc (3.times.10 mL) and the extract was dried (MgSO.sub.4),
concentrated in vacuo and flash column chromatography
(EtOAc:hexane/1:4) gave the title compound (0.58 g, 89%) as a white
solid.
Example 315
[3384]
(8aS,12aR)-2-(2,4-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole
[3385] Step A:
[3386] A mixture of tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octa-
hydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20
g, 0.50 mmol), 2,4-dichlorophenylboronic acid (0.19 g, 1.0 mmol),
Ba(OH).sub.2. 8H.sub.2O (0.32 g, 1.0 mmol), Pd.sub.2(dba).sub.3
(7.5 mg, 0.0075 mmol) and PPh.sub.3 (5.24 mg, 0.02 mmol) in DME (10
mL) and water (2.5 mL) was degassed and refluxed for 18 h and
cooled to room temperature. The mixture was concentrated in vacuo
and EtOAc (20 mL) was added. The solution was washed with saturated
Na.sub.2CO.sub.3 (2.times.10 mL), dried (Na.sub.2SO.sub.4),
concentrated in vacuo and flash column chromatography
(EtOAc:hexane/1:9) gave tert-butyl
(8aS,12aR)-2-(2,4-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazep-
ino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.16 g, 66%)
as a white foam.
[3387] Step B:
[3388] The title compound (0.087 g, 77%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(2,4-dichlorop-
henyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]in-
dole-11(8aH)-carboxylate (0.14 g, 0.30 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H),
1.70-1.90 (m, 2H), 1.90-2.10 (m, 4H), 2.48-2.80 (m, 3H), 2.80-3.00
(m, 3H), 3.04 (dd, J=6.3, 12.4 Hz, 1H), 3.10-3.25 (m, 1H),
3.25-3.42 (m, 2H), 6.96 (s,1H), 7.00 (s, 1H), 7.20-7.30 (m, 2H),
7.44 (d, J=1.1 Hz, 1H) ppm.
Example 316
[3389] (8aS,12aR)
-2-(2,3-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahy-
droazepino[3,2,1-hi]pyrido[4,3-b] indole
[3390] Step A:
[3391] Tert-butyl (8aS,12aR) -2-(2,3-dichlorophenyl)
-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole--
11(8aH)-carboxylate (0.14 g, 59%) was prepared by the general
method of Example 89, step C from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-
-octahydroazepino[3,2,1-hi]pyrido[4,3-b] indole-1 (8aH)
-carboxylate (0.20 g, 0.50 mmol), 2,3-dichlorophenyl boronic acid
(0.19 g, 1.0 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025
mmol), Na.sub.2CO.sub.3 (2.0 M, 1.0 mL, 2.0 mmol) as a white
foam.
[3392] Step B:
[3393] The title compound (0.10 g, 92%) was prepared by the general
method of Example 312, step B from tert-butyl (8aS,12aR)
-2-(2,3-dichlorophenyl) -4,5,6,7,8a,9,10,11,12,12a-decahydroazepino
[3,2,1-hi]pyrido[4,3-b]indole- -11(8aH)-carboxylate (0.14 g, 0.30
mmol) as a white foam. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.1.50-1.70 (m, 1H), 1.70-1.92 (m, 2H), 1.92-2.08 (m, 3H),
2.15-2.80 (m, 4H), 2.80-3.00 (m, 3H), 3.05 (dd, J=6.3, 12.4 Hz,
1H), 3.10-3.34 (m, 2H), 3.34-3.42 (m, 1H), 6.96 (d, J=1.6 Hz, 1H),
7.00 (d, J=1.6 Hz, 1H), 7.12-7.25 (m, 2H), 7.38 (dd, J=2.4, 7.2 Hz,
1H) ppm. MS (ESI): 373 (base, M+H).
Example 317
[3394]
(8aS,12aR)-2-(3,4-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b] indole
[3395] Step A:
[3396] Tert-butyl
(8aS,12aR)-2-(3,4-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,-
12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.070 g, 30%) was prepared by the general method of Example 89,
step C from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3-
,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50
mmol), 3,4-dichlorophenyl boronic acid (0.19 g, 1.0 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025 mmol), Na.sub.2CO.sub.3
(2.0 M, 1.0 mL, 2.0 mmol) as a white foam.
[3397] Step B:
[3398] The title compound (0.040 g, 72%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(3,4-dichlorop-
henyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]in-
dole-11(8aH)-carboxylate (0.070 g, 0.15 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H),
1.70-1.92 (m, 2H), 1.92-2.10 (m, 3H), 2.23 (br, 1H), 2.48-2.80 (m,
3H), 2.80-3.00 (m, 3H), 3.06 (dd, J=6.3, 12.4 Hz, 1H), 3.14-3.25
(m, 1H), 3.25-3.40 (m, 2H), 7.11 (s, 2H), 7.35 (dd, J=2.2, 8.4 Hz,
1H), 7.42 (d, J=8.4 Hz, 1H), 7.61 (d, J=2.2 Hz, 1H) ppm.
Example 318
[3399]
(8aS,12aR)-2-(3,5-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b] indole
[3400] Step A:
[3401] Tert-butyl
(8aS,12aR)-2-(3,5-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,-
12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.13 g, 55%) was prepared by the general method of Example 89,
step C from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3-
,2,1-hi]pyrido[4,3-b] indole-11(8aH)-carboxylate (0.20 g, 0.50
mmol), 3,5-dichlorophenyl boronic acid (0.19 g, 1.0 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025 mmol), Na.sub.2CO.sub.3
(2.0 M, 1. 0 mL, 2.0 mmol) as a white foam. MS (ESI): 473 (base,
M+H).
[3402] Step B:
[3403] The title compound (0.10 g, 92%) was prepared by the general
method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(3,5-dichlorophenyl)--
4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11-
(8aH)-carboxylate (0.14 g, 0.30 mmol) as a white foam. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H), 1.70-1.90 (m, 2H),
1.90-2.15 (m, 5H), 2.48-65 (m, 2H), 2.65-2.80 (m, 1H), 2.82-2.90
(m, 2H), 3.07 (dd, J=6.3, 12.4 Hz, 1H), 3.12-3.26 (m, 1H),
3.26-3.40 (m, 2H), 7.10 (s, 2H), 7.22 (t, J=1.8 Hz, 2H), 7.39 (d,
J=1.8 Hz, 2H) ppm. MS (ESI): 373 (base, M+H).
Example 319
[3404]
(8aS,12aR)-2-(2,5-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b] indole
[3405] Step A:
[3406] A mixture of tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octa-
hydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.10
g, 0.25 mmol), 2,5-dichlorophenyl boronic acid (0.10 g, 0.50 mmol)
and Ba(OH).sub.2 (0.17 M, 3.0 mL, 0.51 mmol) in DME (15 mL) was
degassed at 40-50.degree. C. before Pd(PPh.sub.3).sub.4 (12 mg,
0.010 mmol) was added. The mixture was degassed again as described
before and refluxed for 16 h. The mixture was concentrated in vacuo
and EtOAc (20 mL) was added. The solution was washed with saturated
Na.sub.2CO.sub.3 (2.times.10 mL), dried (Na.sub.2SO.sub.4),
concentrated in vacuo and flash column chromatography
(EtOAc:hexane/1:9) gave tert-butyl
(8aS,12aR)-2-(2,5-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazep-
ino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.098 g, 83%)
as a white foam. MS (ESI): 473 (base, M+H).
[3407] Step B:
[3408] The title compound (0.077 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(2,5-dichlorop-
henyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]in-
dole-11(8aH)-carboxylate (0.098 g, 0.21 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 2H),
1.70-1.90 (m, 2H), 1.90-2.10 (m, 3H), 2.48-2.80 (m, 3H), 2.85-3.00
(m, 3H), 3.08 (dd, J=6.3, 12.4 Hz, 1H), 3.15-3.35 (m, 2H),
3.35-3.44 (m, 1H), 6.98 (s, 1H), 7.02 (s, 1H), 7.18 (dd, J=2.6, 8.6
Hz, 1H), 7.32 (d, J=2.6 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H) ppm. MS
(ESI): 373 (base, M+H).
Example 320
[3409]
(8aS,12aR)-2-(2,6-dichlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole Step A:
[3410] A mixture of tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octa-
hydroazepino[3,2,1,-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.10 g, 0.25 mmol), 2,6-dichlorophenylboronic acid (0.10 g, 0.50
mmol), Pd(dppf).sub.2Cl.sub.2 (10 mg, 0.012 mmol) and TEA (1.0 mL,
7.2 mmol) in DME (15 mL) was degassed at 40-50.degree. C. and
refluxed for 32 h. The mixture was concentrated in vacuo and EtOAc
(20 mL) was added. The solution was washed with saturated
Na.sub.2CO.sub.3 (2.times.10 mL), dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. Normal phase HPLC (5% EtOAc in hexane) gave
tert-butyl (8aS,12aR)-2-(2,6-dichlorophenyl)-4,5,6,-
7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)--
carboxylate (0.030 g, 26%) as a white foam. MS (ESI): 473 (base,
M+H).
[3411] Step B:
[3412] The title compound (0.025 g, 100%) was prepared by the
general method of Example 312, step. B from tert-butyl
(8aS,12aR)-2-(2,6-dichloro-
phenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]i-
ndole-11(8aH)-carboxylate (0.030 g, 0.060 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H),
1.70-1.88 (m, 2H), 1.88-2.10 (m, 3H), 2.48-2.80 (m, 4H), 2.82-3.00
(m, 3H), 3.06 (dd, J=6.3, 12.4 Hz, 1H), 3.15-3.38 (m, 2H),
3.38-3.44 (m, 1H), 6.79 (s, 2H), 7.14 (t, J=8.0 Hz, 1H), 7.35 (d,
J=8.0 Hz, 2H) ppm. MS (ESI): 373 (base, M+H).
Example 321
[3413]
(8aS,12aR)-2-(2-chlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1,-hi]pyrido[4,3-b]indole
[3414] Step A:
[3415] Tert-butyl
(8aS,12aR)-2-(2-chlorophenyl)-4,5,6,7,8a,9,10,11,12,12a--
decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.15 g, 67%) was prepared by the general method of Example 89,
step C from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1--
hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50 mmol),
2-chlorophenylboronic acid (0.16 g, 1.0 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.- 2 (17 mg, 0.025 mmol), Na.sub.2CO.sub.3
(2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 439 (base,
M+H).
[3416] Step B:
[3417] The title compound (0.087 g, 77%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(2-chloropheny-
l)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-
-11(8aH)-carboxylate (0.15 g, 0.33 mmol) as a white foam. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H), 1.70-2.10 (m,
5H), 2.48-2.78 (m, 3H), 2.88-3.02 (m, 3H), 3.10 (dd, J=6.3, 12.4
Hz, 1H), 3.20-3.35 (m, 2H), 3.35-3.42 (m, 1H), 3.63 (br, 1H), 7.01
(s, 1H), 7.05 (s, 1H), 7.15-7.35 (m, 3H), 7.43 (dd, J=1.7, 7.5 Hz,
1H) ppm. MS (ESI): 339 (base, M+H).
Example 322
[3418]
(8aS,12aR)-2-(3-chlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indole
[3419] Step A:
[3420] Tert-butyl
(8aS,12aR)-2-(3-chlorophenyl)-4,5,6,7,8a,9,10,11,12,12a--
decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.12 g, 55%) was prepared by the general method of Example 89,
step C from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1--
hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50 mmol),
3-chlorophenylboronic acid (0.16 g, 1.0 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.- 2 (17 mg, 0.025 mmol), Na.sub.2CO.sub.3
(2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 439 (base,
M+H).
[3421] Step B:
[3422] The title compound (0.045 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(3-chloropheny-
l)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-
-11(8aH)-carboxylate (0.058 g, 0.13 mmol) as a white foam. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta.1.43 (br, 1H), 1.50-1.70 (m, 1H),
1.70-2.10 (m, 5H), 2.40-2.80 (m, 3H), 2.80-3.00 (m, 3H), 3.08 (dd,
J=6.3, 12.4 Hz, 1H), 3.10-3.42 (m, 3H), 7.14 (s, 2H), 7.21 (d,
J=7.5 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.52
(s, 1H) ppm. MS (ESI): 339 (base, M+H).
Example 323
[3423]
(8aS,12aR)-2-(4-chlorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indole
[3424] Step A:
[3425] Tert-butyl
(8aS,12aR)-2-(4-chlorophenyl)-4,5,6,7,8a,9,10,11,12,12a--
decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.11 g, 50%) was prepared by the general method of Example 89,
step C from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1--
hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50 mmol),
4-chlorophenylboronic acid (0.16 g, 1.0 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.- 2 (17 mg, 0.025 mmol), Na.sub.2CO.sub.3
(2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 439 (base,
M+H).
[3426] Step B:
[3427] The title compound (0.084 g, 99%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(4-chloropheny-
l)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-
-11(8aH)-carboxylate (0.11 g, 0.25 mmol) as a white foam. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H), 1.70-2.10 (m,
5H), 2.48-2.80 (m, 3H), 2.80-3.05 (m, 4H), 3.12 (dd, J=6.3, 12.4
Hz, 1H), 3.20-3.42 (m, 3H), 7.14 (s, 2H), 7.36 (d, J=8.4 Hz, 2H),
7.46 (d, J=8.4 Hz, 2H) ppm. MS (ESI): 339 (base, M+H).
Example 324
[3428]
(.+-.)-cis-2-(2,6-difluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole
[3429] Step A:
[3430] Tert-butyl
(.+-.)-2-(2,6-difluorophenyl)-4,5,6,7,8a,9,10,11,12,12a--
decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.045 g, 21%) was prepared by the general method of Example 320,
step A from tert-butyl
(.+-.)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]p-
yrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50 mmol),
2,6-difluorophenylboronic acid (0.32 g, 2.0 mmol),
Pd(dppf).sub.2Cl.sub.2 (24 mg, 0.030 mmol), TEA (1.6 mL, 11 mmol)
as a white foam.
[3431] Step B:
[3432] The title compound (0.017 g, 49%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(2,6-difluorop-
henyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]in-
dole-11(8aH)-carboxylate (0.045 g, 0.10 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H),
1.70-2.10 (m, 5H), 2.50-2.80 (m, 3H), 2.80-3.05 (m, 3H), 3.05-3.20
(m, 2H), 3.20-3.35 (m, 2H), 3.35-3.42 (m, 1H), 6.94 (t, J=8.1 Hz,
2H), 7.04 (s, 2H), 7.15-7.22 (m, 1H) ppm.
Example 325
[3433]
(8aS,12aR)-2-(2,6-difluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole
[3434] Step A:
[3435] Tert-butyl
(8aS,12aR)-2-(2,6-difluorophenyl)-4,5,6,7,8a,9,10,11,12,-
12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.040 g, 18%) was prepared by the general method of Example 320,
step A from tert-butyl
(8aS,11aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3-
,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50
mmol), 2,6-difluorophenylboronic acid (0.32 g, 2.0 mmol),
Pd(dppf).sub.2Cl.sub.2 (24 mg, 0.030 mmol), TEA (1.6 mL, 11 mmol)
as a white foam.
[3436] Step B:
[3437] The title compound (9.0 mg, 29%) was prepared by the general
method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(2,6-difluorophenyl)--
4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11-
(8aH)-carboxylate (0.040 g, 0.091 mmol) as a white foam. .sup.1H
NMR was identical to that of
(.+-.)-cis-2-(2,6-difluorophenyl)-4,5,6,7,8a,9,10,11-
,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole
Example 326
[3438]
(8aS,12aR)-2-(2,3-difluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole
[3439] Step A:
[3440] Tert-butyl
(8aS,12aR)-2-(2,3-difluorophenyl)-4,5,6,7,8a,9,10,11,12,-
12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.069 g, 63%) was prepared by the general method of Example 319,
step A from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3-
,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.10 g, 0.25
mmol), 2,3-difluorophenylboronic acid (0.080 g, 0.5 mmol),
Pd(PPh.sub.3).sub.4 (12 mg, 0.010 mmol), and Ba(OH).sub.2 (0.17 M,
3.0 mL, 0.51 mmol) as a white foam. MS (ESI): 441 (base, M+H).
[3441] Step B:
[3442] The title compound (0.053 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(2,3-difluorop-
henyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]in-
dole-11(8aH)-carboxylate (0.069 g, 0.16 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H),
1.70-2.10 (m, 5H), 2.48-2.80 (m, 3H), 2.85-3.02 (m, 3H), 3.12 (dd,
J=6.3, 12.4 Hz, 1H), 3.20-3.60 (m, 4H), 7.00-7.22 (m, 5H) ppm. MS
(ESI): 341 (base, M+H).
Example 327
[3443]
(8aS,12aR)-2-(3,4-difluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole
[3444] Step A:
[3445] Tert-butyl
(8aS,12aR)-2-(3,4-difluorophenyl)-4,5,6,7,8a,9,10,11,12,-
12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.078 g, 71%) was prepared by the general method of Example 319,
step A from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3-
,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.10 g, 0.25
mmol), 3,4-difluorophenyqboronic acid (0.080 g, 0.50 mmol),
Pd(PPh.sub.3).sub.4 (12 mg, 0.010 mmol), and Ba(OH).sub.2 (0.17 M,
3.0 mL, 0.51 mmol) as a white foam. MS (ESI): 441 (base, M+H).
[3446] Step B:
[3447] The title compound (0.055 g, 92%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(3,4-difluorop-
henyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]in-
dole-11(8aH)-carboxylate (0.078 g, 0.18 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H),
1.70-2.12 (m, 5H), 2.50-2.80 (m, 3H), 2.92-3.05 (m, 3H), 3.14 (dd,
J=6.3, 12.4 Hz, 1H), 3.22-3.42 (m, 3H), 3.49 (s, 1H), 7.05-7.40 (m,
5H) ppm. MS (ESI): 341 (base, M+H).
Example 328
[3448]
(8aS,12aR)-2-(3-fluorophenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indole
[3449] Step A:
[3450] Tert-butyl
(8aS,12aR)-2-(3-fluorophenyl)-4,5,6,7,8a,9,10,11,12,12a--
decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.13 g, 62%) was prepared by the general method of Example 89,
step C from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1--
hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50 mmol),
3-fluorophenylboronic acid (0.14 g, 1.0 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.- 2 (17 mg, 0.025 mmol), Na.sub.2CO.sub.3
(2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 423 (base,
M+H).
[3451] Step B:
[3452] The title compound (0.025 g, 93%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(3-fluoropheny-
l)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1,-hi]pyrido[4,3-b]indol-
e-11(8aH)-carboxylate (0.035 g, 0.083 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H),
1.70-2.17 (m, 6H), 2.48-2.82 (m, 3H), 2.82-3.05 (m, 3H), 3.08 (dd,
J=6.3, 12.4 Hz, 1H), 3.15-3.40 (m, 3H), 6-88-6.96 (m, 1H), 7.15 (s,
2H), 7.18-7.26 (m, 1H), 7.28-7.35 (m, 2H) ppm. MS (ESI): 323 (base,
M+H).
Example 329
[3453]
(8aS,12aR)-2-[2-chloro-4-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,1-
1,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole
[3454] Step A:
[3455] Tert-butyl
(8aS,12aR)-2-[2-chloro-4-(trifluoromethyl)phenyl]-4,5,6,-
7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)--
carboxylate (0.21 g, 82%) was prepared by the general method of
Example 89, step C from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahyd-
roazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g,
0.50 mmol), 2-chloro-4-(trifluoromethyl)phenylboronic acid (0.22 g,
1.0 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025 mmol),
Na.sub.2CO.sub.3 (2.0 M, 1.0 mL, 2.0 mmol) as a white foam.
[3456] Step B:
[3457] The title compound (0.15 g, 87%) was prepared by the general
method of Example 312, step B from tert-butyl
(8aS,12aR)-2-[2-chloro-4-(trifluor-
omethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido-
[4,3-b]indole-11(8aH)-carboxylate (0.21 g, 0.41 mmol) as a white
foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H),
1.70-1.90 (m, 2H), 1.90-2.20 (m, 4H), 2.48-2.80 (m, 3H), 2.80-3.00
(m, 3H), 3.05 (dd, J=6.3, 12.4 Hz, 1H), 3.10-3.25 (m, 1H),
3.25-3.36 (m, 1H), 3.36-3.45 (m, 1H), 7.00 (d, J=1.5 Hz, 1H), 7.05
(d, J=1.5 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.51 (dd, J=1.1, 8.1 Hz,
1H), 7.70 (s, 1H) ppm.
Example 330
[3458]
(8aS,12aR)-2-(2-chloro-4-methoxyphenyl)-4,5,6,7,8a,9,10,11,12,12a-d-
ecahydroazepino[3,2,1-hi]pyrido[4,3-b]indole
[3459] Step A:
[3460] Tert-butyl
(8aS,12aR)-2-(2-chloro-4-methoxyphenyl)-4,5,6,7,8a,9,10,-
11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylat-
e (0.15 g, 64%) was prepared by the general method of Example 89,
step C from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3-
,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50
mmol), 2-chloro-4-methoxyphenylboronic acid (0.19 g, 1.0 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025 mmol), Na.sub.2CO.sub.3
(2.0 M, 1.0 mL, 2.0 mmol) as a white foam.
[3461] Step B:
[3462] The title compound (0.12 g, 97%) was prepared by the general
method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(2-chloro-4-methoxyph-
enyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]ind-
ole-11(8aH)-carboxylate (0.15 g, 0.32 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H),
1.70-1.85 (m, 2H), 1.90-2.10 (m, 3H), 2.10-2.30 (m, 2H), 2.48-2.72
(m, 3H), 2.88-3.00 (m, 1H), 3.08-3.40 (m, 4H), 3.48-3.58 (m, 1H),
3.81 (s, 3H), 6.82 (dd, J=2.4, 8.4 Hz, 1H), 6.92-7.05 (m, 3H), 7.19
(d, J=8.4 Hz, 1H) ppm.
Example 331
[3463]
(8aS,12aR)-2-(2-fluoro-4-methoxyphenyl)-4,5,6,7,8a,9,10,11,12,12a-d-
ecahydroazepino[3,2,1-hi]pyrido[4,3-b]indole
[3464] Step A:
[3465] Tert-butyl
(8aS,12aR)-2-(2-fluoro-4-methoxyphenyl)-4,5,6,7,8a,9,10,-
11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylat-
e (0.16 g, 69%) was prepared by the general method of Example 89,
step C from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3-
,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50
mmol), 2-fluoro-4-methoxyphenylboronic acid (0.17 g, 1.0 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025 mmol), Na.sub.2CO.sub.3
(2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 453 (base,
M+H).
[3466] Step B:
[3467] The title compound (0.11 g, 94%) was prepared by the general
method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(2-fluoro-4-methoxyph-
enyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]ind-
ole-11(8aH)-carboxylate (0.15 g, 0.34 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H),
1.70-1.90 (m, 2H), 1.90-2.10 (m, 3H), 2.50-2.80 (m, 3H), 2.80-3.00
(m, 3H), 3.05 (dd, J=6.3, 12.4 Hz, 1H), 3.10-3.25 (m, 1H),
3.25-3.40 (m, 2H), 3.82 (s, 3H), 6.64-6.76 (m, 2H), 7.07 (s, 1H),
7.08 (s, 1H), 7.31 (t, J=8.8 Hz, 1H) ppm. MS (ESI): 353 (base,
M+H).
Example 332
[3468]
(8aS,12aR)-2-(4-methoxy-2-methylphenyl)-4,5,6,7,8a,9,10,11,12,12a-d-
ecahydroazepino[3,2,1-hi]pyrido[4,3-b]indole
[3469] Step A:
[3470] Tert-butyl
(8aS,12aR)-2-(4-methoxy-2-methylphenyl)-4,5,6,7,8a,9,10,-
11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylat-
e (0.095 g, 42%) was prepared by the general method of Example 89,
step C from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3-
,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50
mmol), 4-methoxy-2-methylphenyl boronic acid (0.17 g, 1.0 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025 mmol), Na.sub.2CO.sub.3
(2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 449 (base,
M+H).
[3471] Step B:
[3472] The title compound (0.071 g, 96%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(4-methoxy-2-m-
ethylphenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,-
3-b]indole-11(8aH)-carboxylate (0.095 g, 0.21 mmol) as a white
foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H),
1.70-1.92 (m, 2H), 1.92-2.10 (m, 3H), 2.28 (s, 3H), 2.45-2.60 (m,
3H), 2.62-2.78 (m, 1H), 2.85-2.98 (m, 3H), 3.08 (dd, J=6.3, 12.4
Hz, 1H), 3.12-3.40 (m, 3H), 3.82 (s, 3H), 6.70-6.80 (m, 3H), 6.84
(s, 1H), 6.85 (s, 1H), 7.14 (d, J=8.4 Hz, 1H) ppm. MS (ESI): 349
(base, M+H).
Example 333
[3473]
(8aS,12aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,-
11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b] indole
[3474] Step A:
[3475] Tert-butyl
(8aS,12aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-4,5,6-
,7,8a,9,10,11,12,12a-decahydroazepino[3, 2,1-hi]pyrido[4,3-b]
indole-11(8aH)-carboxylate (0.20 g, 78%) was prepared by the
general method of Example 89, step C from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9-
,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxyla-
te (0.20 g, 0.50 mmol), 4-methoxy-2-(trifluoromethyl)phenylboronic
acid (0.22 g, 1.0 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025
mmol), Na.sub.2CO.sub.3 (2.0 M, 1.0 mL, 2.0 mmol) as a white foam.
MS (ESI): 503 (base, M+H).
[3476] Step B:
[3477] The title compound (0.13 g, 84%) was prepared by the general
method of Example 312, step B from tert-butyl
(8aS,12aR)-2-[4-methoxy-2-(trifluo-
romethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrid-
o[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.39 mmol) as a white
foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H),
1.70-1.90 (m, 2H), 1.90-2.10 (m, 4H), 2.45-2.62 (m, 2H), 2.62-2.75
(m, 1H), 2.80-2.95 (m, 3H), 3.08 (dd, J=6.3, 12.4 Hz, 1H),
3.08-3.20 (m, 1H), 3.25-3.40 (m, 2H), 3.86 (s, 3H), 6.83 (s, 1H),
6.85 (s, 1H), 7.03 (dd, J=2.2, 8.4 Hz, 1H), 7.18-7.25 (m, 2H) ppm.
MS (ESI): 403 (base, M+H).
Example 334
[3478]
(8aS,12aR)-2-[2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a--
decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole
[3479] Step A:
[3480] Tert-butyl
(8aS,12aR)-2-[2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10-
,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxyla-
te (0.15 g, 61%) was prepared by the general method of Example 89,
step C from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3-
,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50
mmol), 2-(trifluoromethyl)phenylboronic acid (0.19 g, 1.0 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025 mmol), Na.sub.2CO.sub.3
(2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 473 (base,
M+H).
[3481] Step B:
[3482] The title compound (0.11 g, 96%) was prepared by the general
method of Example 312, step B from tert-butyl
(8aS,12aR)-2-[2-(trifluoromethyl)p-
henyl]-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]in-
dole-11(8aH)-carboxylate (0.15 g, 0.31 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H),
1.70-1.92 (m, 2H), 1.92-2.25 (m, 3H), 2.45-2.65 (m, 2H), 2.65-2.80
(m, 1H), 2.80-3.00 (m, 4H), 3.08 (dd, J=6.3, 12.4 Hz, 1H),
3.12-3.25 (m, 1H), 3.25-3.42 (m, 2H), 6.88 (s, 1H), 6.90 (s, 1H),
7.30-7.45 (m, 2H), 7.52 (t, J=7.3 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H)
ppm. MS (ESI): 373 (base, M+H).
Example 335
[3483]
(8aS,12aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,-
10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole
[3484] Step A:
[3485] Tert-butyl
(8aS,12aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-4,-
5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8-
aH)-carboxylate (0.17 g, 63%) was prepared by the general method of
Example 89, step C from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-
-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.20 g, 0.50 mmol), 4-isopropoxy-2-(trifluoromethyl)phenylboronic
acid (0.18 g, 1.0 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025
mmol), Na.sub.2CO.sub.3 (2.0 M, 1.0 mL, 2.0 mmol) as a white foam.
MS (ESI): 531 (base, M+H).
[3486] Step B:
[3487] The title compound (0.14 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-[4-isopropoxy--
2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,-
1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.17 g, 0.32 mmol) as
a white foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70
(m, 1H), 1.39,(d, J=6.0 Hz, 6H), 1.70-2.10 (m, 5H), 2.45-2.78 (m,
3H), 2.85-3.00 (m, 3H), 3.00-3.10 (m, 1H), 3.12-3.32 (m, 4H), 4.62
(p, J=6.0 Hz, 1H), 6.86 (s, 1H), 6.87 (s, 1H), 6.98-7.08 (m, 1H),
7.18-7.26 (m, 2H) ppm. MS (ESI): 431 (base, M+H).
Example 336
[3488] (8aS,12aR)
-2-[2,4-bis(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,1-
2,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole
[3489] Step A:
[3490] Tert-butyl
(8aS,12aR)-2-[2,4-bis(trifluoromethyl)phenyl]-4,5,6,7,8a-
,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carb-
oxylate (0.047 g, 17%) was prepared by the general method of
Example 319, step A from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g,
0.50 mmol), 2,4-bis(trifluoromethyl)phenylboronic acid (0.26 g, 1.0
mmol), Pd(PPh.sub.3).sub.4 (12 mg, 0.010 mmol), and Ba(OH).sub.2 (2
M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 541 (base,
M+H).
[3491] Step B:
[3492] The title compound (0.038 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-[2,4-bis(trifl-
uoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyr-
ido[4,3-b]indole-11(8aH)-carboxylate (0.047 g, 0.087 mmol) as a
white foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.40-1.80 (m,
3H), 1.80-2.30 (m, 5H), 2.30-2.72 (m, 3H), 2.72-3.00 (m, 1H),
3.00-3.50 (m, 5H), 6.83 (s, 1H), 6.84 (s, 1H), 7.36 (d, J=8.3 Hz,
1H), 7.69 (d, J=8.3 Hz, 1H), 7.87 (s, 1H) ppm. MS (ESI): 441 (base,
M+H).
Example 337
[3493]
(8aS,12aR)-2-[4-fluoro-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,1-
1,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole
[3494] Step A:
[3495] Tert-butyl
(8aS,12aR)-2-[4-fluoro-2-(trifluoromethyl)phenyl]-4,5,6,-
7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)--
carboxylate (0.10 g, 84%) was prepared by the general method of
Example 319, step A from tert-butyl (8aS,12aR)-2-
bromo-4,5,6,7,9,10,12,12a-octah-
ydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.10
g, 0.25 mmol), 4-fluoro-2-(trifluoromethyl)phenylboronic acid (0.10
g, 0.50 mmol), Pd(PPh.sub.3).sub.4 (12 mg, 0.010 mmol), and Ba(OH)
.sub.2 (0.17 M, 3.0 mL, 0.51 mmol) as a white foam. MS (ESI): 491
(base, M+H).
[3496] Step B:
[3497] The title compound (0.042 g, 52%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-[4-fluoro-2-(t-
rifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi-
]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.10 g, 0.21 mmol) as a
white foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m,
1H), 1.70-2.10 (m, 5H), 2.48-2.65 (m, 2H), 2.65-2.80 (m, 1H),
2.85-3.20 (m, 4H), 3.20-3.42 (m, 4H), 7.10 (s, 2H), 7.20 (t, J=9.3
Hz, 1H), 6.60-7.70 (m, 1H), 7.70-7.72 (m, 1H) ppm. MS (ESI): 391
(base, M+H).
Example 338
[3498]
4-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]p-
yrido[4,3-b]indol-2-yl]-3-(trifluoromethyl)aniline
[3499] Step A:
[3500] Tert-butyl (8aS,12aR)-2-[4-[
(tert-butoxycarbonyl)amino]-2-(trifluo-
romethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrid-
o[4,3-b]indole-11(8aH)-carboxylate (0.12 g, 84%) was prepared by
the general method of Example 319, step A from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4-
,3-b]indole-11(8aH)-carboxylate (0.10 g, 0.25 mmol),
4-[(tert-butoxycarbonyl)amino]-2-(trifluoromethyl)phenylboronic
acid (0.15 g, 0.50 mmol), Pd(PPh.sub.3).sub.4 (12 mg, 0.010 mmol),
and Ba(OH).sub.2 (0.17 M, 3.0 mL, 0.51 mmol) as a white foam. MS
(ESI): 588 (base, M+H).
[3501] Step B:
[3502] The title compound (0.079 g, 98%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-[4-[(tert-buto-
xycarbonyl)amino]-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a-dec-
ahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.12 g, 0.21 mmol) as a white foam. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta.1.50-1.70 (m, 2H), 1.70-1.95 (m, 2H), 1.95-2.10 (m,
3H), 2.28-2.76 (m, 3H), 2.80-3.00 (m, 3H), 3.08 (dd, J=6.3, 12.4
Hz, 1H), 3.10-3.40 (m, 3H), 3.84 (br, 2H), 6.77-6.90 (m, 3H), 7.01
(d, J=2.6 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H) ppm. MS (ESI): 388 (lost
two BOC groups) (base, M+H).
Example 339
[3503]
4-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]p-
yrido[4,3-b]indol-2-yl]-N-methyl-3-(trifluoromethyl)aniline
[3504] Step A:
[3505] Tert-butyl (8aS,12aR)-2-[4-[(tert-butoxycarbonyl)
(methyl)amino]-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a-decah-
ydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.12
g, 81%) was prepared by the general method of Example 319, step A
from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4-
,3-b]indole-11(8aH)-carboxylate (0.10 g, 0.25 mmol),
4-[(tert-butoxycarbonyl)
(methyl)amino)-2-(trifluoromethyl)phenylboronic acid (0.16 g, 0.50
mmol), Pd(PPh.sub.3).sub.4 (12 mg, 0.010 mmol), and Ba(OH).sub.2
(0.17 M, 3.0 mL, 0.51 mmol) as a white foam. MS (ESI): 602 (base,
M+H).
[3506] Step B:
[3507] The title compound (0.081 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-[4-[(tert-buto-
xycarbonyl)(methyl)amino]-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12-
1,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.12 g, 0.20 mmol) as a white foam. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta.1.50-1.70 (m, 1H), 1.70-2.10 (m, 5H), 2.48-2.78 (m,
3H), 2.80-3.00 (m, 4H), 3.08 (dd, J=6.3, 12.4 Hz, 1H), 3.10-3.40
(m, 3H), 3.91 (br, 1H), 6.74 (dd, J=2,6, 8.2 Hz, 1H) , 6.86 (s, 1H)
, 6.87 (s, 1H) , 6.91 (d, J=2.6 Hz, 1H), 7.15 (d, J=8.2 Hz, 1H)
ppm. MS (ESI): 402 (lost two BOC groups) (base, M+H).
Example 340
[3508]
2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]p-
yrido[4,3-b]indol-2-yl]benzaldehyde
[3509] Step A:
[3510] Tert-butyl
(8aS,12aR)-2-(2-formylphenyl)-4,5,6,7,8a,9,10,11,12,12a--
decahydroazepino[3,2,1,-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.081 g, 38%) was prepared by the general method of Example 89,
step C from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1--
hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50 mmol),
2-formylphenylboronic acid (0.15 g, 1.0 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.- 2 (17 mg, 0.025 mmol), Na.sub.2CO.sub.3
(2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 433 (base,
M+H).
[3511] Step B:
[3512] The title compound (0.021 g, 91%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(2-formylpheny-
l)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]
indole-11(8aH)-carboxylate (0.030 g, 0.070 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.88 (m, 3H),
1.90-2.12 (m, 4H), 2.52-2.80 (m, 3H), 2.87-3.04 (m, 3H), 3.08-3.20
(m, 1H), 3.24-3.38 (m, 2H), 3.38-3.44 (m, 1H), 6.93 (s, 1H), 6.97
(s, 1H), 7.38-7.46 (m, 2H), 7.66 (td, J=7.5, 1.4 Hz, 1H), 7.99 (dd,
J=1.4, 8.0 Hz, 1H), 10.02 (s, 1H) ppm. MS (ESI): 333 (base,
M+H).
Example 341
[3513]
{2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]-
pyrido[4,3-b]indol-2-yl]phenyl}methanol
[3514] Step A:
[3515] NaBH.sub.4 (0.050 g, 1.3 mmol) was added in one portion to a
solution of tert-butyl
(8aS,12aR)-2-(2-formylphenyl)-4,5,6,7,8a,9,10,11,1-
2,12a-decahydroazepino[3,2,1,-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.051 g, 0.12 mmol) in MeOH (12 mL) at room temperature. The
mixture was stirred at room temperature for 1 h, quenched with
acetone (5.0 mL) and concentrated in vacuo. Water (10 mL) was added
to the residue and extracted with EtOAc (3.times.10 mL). The
combined organic layer was dried, concentrated in vacuo and flash
column chromatography (EtOAc:hexane/1:4) gave tert-butyl
(8aS,12aR)-2-[2-(hydroxymethyl)phenyl]-
-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-1-
1(8aH)-carboxylate (0.043, 84%) as a white solid. MS (ESI): 435
(base, M+H).
[3516] Step B:
[3517] The title compound (0.033 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-[2-(hydroxymet-
hyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-
-b]indole-11(8aH)-carboxylate (0.043 g, 0.10 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.95 (m, 3H),
1.95-2.10 (m, 3H), 2.44-2.80 (m, 3H), 2.80-3.00 (m, 3H), 3.00-3.10
(m, 1H), 3.10-3.40 (m, 3H), 4.65 (br, 2H), 6.92 (s, 1H), 6.95 (s,
1H), 7.22-7.38 (m, 3H), 7.50-7.57 (m, 1H) ppm. MS (ESI): 335 (base,
M+H).
Example 342
[3518]
2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]p-
yrido[4,3-b]indol-2-yl]-5-methoxybenzaldehyde
[3519] Step A:
[3520] Tert-butyl
(8aS,12aR)-2-(2-formyl-4-methoxyphenyl)-4,5,6,7,8a,9,10,-
11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylat-
e (0.094 g, 41%) was prepared by the general method of Example 89,
step C from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3-
,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50
mmol), 2-formyl-4-methoxyphenylboronic acid (0.18 g, 1.0 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025 mmol), Na.sub.2CO.sub.3
(2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 463 (base,
M+H).
[3521] Step B:
[3522] The title compound (0.060 g, 81%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(2-formyl-4-me-
thoxyphenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,-
3-b]indole-11(8aH)-carboxylate (0.094 g, 0.20 mmol) as a white
foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H),
1.70-1.90 (m, 2H), 1.90-2.10 (m, 4H), 2.50-2.76 (m, 3H), 2.85-3.08
(m, 3H), 3.08-3.20 (m, 1H), 3.25-3.42 (m, 3H), 3.47 (s, 1H), 3.88
(s, 3H), 6.88 (s, 1H), 6.91 (s, 1H), 7.16 (dd, J=2.6, 8.4 Hz, 1H),
7.35 (d, J=8.4 Hz, 1H),7.46 (d, J=2.6 Hz, 1H), 9.95 (s, 1H) ppm. MS
(ESI): 363 (base, M+H).
Example 343
[3523]
{2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]-
pyrido[4,3-b]indol-2-yl]-5-methoxyphenyl}methanol
[3524] Step A:
[3525] Tert-butyl
(8aS,12aR)-2-[2-(hydroxymethyl)-4-methoxyphenyl]-4,5,6,7-
,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-c-
arboxylate (0.54 g) was obtained as a byproduct of Example 342 as a
white foam. MS (ESI): 465 (base, M+H).
[3526] Step B:
[3527] The title compound (0.42 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-[2-(hydroxymet-
hyl)-4-methoxyphenyl]-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]-
pyrido[4,3-b]indole-11(8aH)-carboxylate (0.054 g, 0.12 mmol) as a
white foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.68 (m,
1H), 1.68-2.10 (m, 5H), 2.40-2.80 (m, 3H), 2.80-3.00 (m, 3H),
3.00-3.10 (m, 1H), 3.10-3.40 (m, 3H), 3.86 (s, 3H), 4.62 (br, 2H),
6.78-6.92 (m, 3H), 7.10 (d, J=3.0 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H),
ppm. MS (ESI): 365 (base, M+H).
Example 344
[3528]
4-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]p-
yrido[4,3-b]indol-2-yl]-3-methylbenzonitrile
[3529] Step A:
[3530] Tert-butyl
(8aS,12aR)-2-(4-cyano-2-methylphenyl)-4,5,6,7,8a,9,10,11-
,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.095 g, 86%) was prepared by the general method of Example 319,
step A from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3-
,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.10 g, 0.25
mmol), 4-cyano-2-methylphenylboronic acid (0.080 g, 0.50 mmol),
Pd(PPh.sub.3).sub.4 (12 mg, 0.010 mmol), and Ba(OH).sub.2 (0.17 M,
3.0 mL, 0.51 mmol) as a white foam. MS (ESI): 444 (base, M+H).
[3531] Step B:
[3532] The title compound (0.074 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(8aS,12aR)-2-(4-cyano-2-met-
hylphenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3--
b]indole-11(8aH)-carboxylate (0.095 g, 0.21 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.50-1.70 (m, 1H),
1.70-2.10 (m, 5H), 2.32 (s, 3H), 2.85-3.00 (m, 3H), 3.08 (dd,
J=6.3, 12.4 Hz, 1H), 3.20-3.50 (m, 4H), 6.85 (s, 2H), 7.29 (d,
J=7.9 Hz, 1H),7.47 (d, J=7.9 Hz, 1H), 7.51 (s, 1H) ppm. MS (ESI):
344 (base, M+H).
Example 345
[3533]
1-{2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-h-
i]pyrido[4,3-b]indol-2-yl]-5-methoxyphenyl}ethanol
[3534] CH.sub.3MgBr (1 M, 2.3 mL, 2.3 mmol) was added to a solution
of
2-[(8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[-
4,3-b]indol-2-yl]-5-methoxybenzaldehyde (0.080 g, 0.23 mmol) in THF
(5 mL) at 0.degree. C. The mixture was stirred at room temperature
for 18 h and quenched with water (5.0 mL). The mixture was
extracted with CH.sub.2Cl.sub.2 (3.times.10 mL) and the organic
layer was dried (Na.sub.2SO.sub.4) and concentrated in vacuo.
Reverse phase HPLC (H.sub.2O--CH.sub.3CN-TFA (0.05%)) gave the
title compound (2.0 mg, 4%). MS (ESI): 379 (base, M+H)
Example 346
[3535] tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro-4H-pyr-
ido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate
[3536] The title compound (7.73 g, 97%) was prepared by the method
of Example 314 from tert-butyl
(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H--
pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10 (7aH)-carboxylate
(6.40 g, 20 mmol) and NBS (3.63 g, 20 mmol) as a white solid.
Example 347
[3537]
(7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3538] Step A:
[3539] Tert-butyl
(7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-o-
ctahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.15 g, 63%) was prepared by the method of
Example 315 from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro-4H-pyri-
do[3',4':4,5]pyrrolo[3,2,1,-ij]quinoline-10 (7aH)-carboxylate (0.20
g, 0.50 mmol), 2,4-dichlorophenylboronic acid (0.19 g, 1.0 mmol),
Ba(OH).sub.2-8H.sub.2O (0.32 g, 1.0 mmol), Pd.sub.2(dba).sub.3 (7.5
mg, 0.0075 mmol) and PPh.sub.3 (5.24 mg, 0.02 mmol) as a white
foam.
[3540] Step B:
[3541] The title compound (0.087 g, 77%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-(2,4-dichlorop-
henyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij-
]quinoline-10(7aH)-carboxylate (0.15 g, 0.32 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.75-2.00 (m, 2H),
2.08-2.30 (m, 3H), 2.60-2.80 (m, 4H), 2.80-2.92 (m, 2H), 3.07-3.15
(m, 2H), 3.28-3.35 (m, 1H), 3.38-3.48 (m, 1H), (s, 1H), 6.98 (s,
1H), 7.23 (d, J=1.9 Hz, 2H), 7.44 (t, J=1.3 Hz, 1H) ppm.
Example 348
[3542]
(7aS,11aR)-2-(3,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3543] Step A:
[3544] Tert-butyl
(7aS,11aR)-2-(3,4-dichlorophenyl)-5,6,7a,8,9,10,11,11-oc-
tahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1,-ij]quinoline-10
(7aH)-carboxylate (0.085 g, 37%) was prepared by the general method
of Example 89, step C from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11-
a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.20 g, 0.50 mmol), 3,4-dichlorophenylboronic
acid (0.19 g, 1.0 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025
mmol), Na.sub.2CO.sub.3 (2.0 M, 1.0 mL, 2.0 mmol) as a white foam.
MS (ESI) 459 (base, M+H).
[3545] Step B:
[3546] The title compound (0.066 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-(3,4-dichlorop-
henyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij-
]quinoline-10(7aH)-carboxylate (0.085 g, 0.19 mmol) as a white
foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.80-2.05 (m, 2H),
2.05-2.20 (m, 2H), 2.55-2.80 (m, 4H), 2.82-2.98 (m, 2H), 3.07-3.20
(m, 2H), 3.20-3.38 (m, 1H), 3.38-3.48 (m, 1H), 3.64 (br, 1H), 7.01
(s, 1H), 7.11 (s, 1H), 7.34 (dd, J=1.8, 8.4 Hz, 1H), 7.43 (d, J=8.4
Hz, 2H), 7.59 (d, J=1.8 Hz, 1H) ppm. MS (ESI): 359 (base, M+H).
Example 349
[3547]
(7aS,11aR)-2-(3,5-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3548] Step A:
[3549] Tert-butyl
(7aS,11aR)-2-(3,5-dichlorophenyl)-5,6,7a,8,9,10,11,11a-o-
ctahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1,-ij]quinoline-10
(7aH)-carboxylate (0.045 g, 40%) was prepared by the general method
of Example 89, step C from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11-
a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1,-ij]quinoline-10
(7aH)-carboxylate (0.098 g, 0.25 mmol), 3,5-dichlorophenylboronic
acid (0.10 g, 0.5 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (8.8 mg, 0.013
mmol), Na.sub.2CO.sub.3 (2.0 M, 0.5 mL, 1.0 mmol) as a white foam.
MS (ESI): 459 (base, M+H).
[3550] Step B:
[3551] The title compound (0.035 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-(3,5-dichlorop-
henyl)-5,6,7a,8,9,10,11,l1a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij-
]quinoline-10(7aH)-carboxylate (0.045 g, 0.10 mmol) as a white
foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) * 1.80-2.05 (m, 2H),
2.05-2.20 (m, 2H), 2.55-2.80 (m, 4H), 2.88-2.96 (m, 3H), 3.07-3.20
(m, 2H), 3.23-3.36 (m, 1H), 3.38-3.48 (m, 1H), 7.08 (s, 1H), 7.10
(s, 1H), 7.21 (t, J=1.9 Hz, 1H), 7.37 (d, J=1.9 Hz, 2H) ppm. MS
(ESI): 359 (base, M+H).
Example 350
[3552]
(7aS,11aR)-2-(2,5-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3553] Step A:
[3554] Tert-butyl
(7aS,11aR)-2-(2,5-dichlorophenyl)-5,6,7a,8,9,10,11,11a-o-
ctahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.080 g, 55%) was prepared by the general method
of Example 319, step A from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,1-
1a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.13 g, 0.32 mmol), 2,5-dichlorophenylboronic
acid (0.12 g, 0.64 mmol), Pd(PPh.sub.3).sub.4 (14 mg, 0.012 mmol),
and Ba(OH).sub.2 (0.17 M, 3.0 mL, 0.51 mmol) as a white foam. MS
(ESI): 459 (base, M+H).
[3555] Step B:
[3556] The title compound (0.063 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-(2,5-dichlorop-
henyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1,-i-
j]quinoline-10(7aH)-carboxylate (0.080 g, 0.17 mmol) as a white
foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.80-2.05 (m, 2H),
2.05-2.20 (m, 2H), 2.55-2.80 (m, 4H), 2.88-2.96 (m, 3H), 3.07-3.20
(m, 2H), 3.23-3.36 (m, 1H), 3.38-3.48 (m, 1H), 6.95 (s, 1H), 6.99
(s, 1H), 7.16 (dd, J=2.7, 8.4 Hz, 1H), 7.30 (d, J=2.7 Hz,, 1H),
7.34 (d, J=8.4 Hz) ppm. MS (ESI): 359 (base, M+H).
Example 351
[3557]
(7aS,11aR)-2-(2,6-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3558] Step A:
[3559] Tert-butyl
(7aS,11aR)-2-(2,6-dichlorophenyl)-5,6,7a,8,9,10,11,11a-o-
ctahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.023 g, 19%) was prepared by the general method
of Example 320, step A from tert-butyl
(8aS,11aR)-2-bromo-4,5,6,7,9,10,12,12-
a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.10 g, 0.26 mmol), 2,6-dichlorophenyl boronic acid (0.10 g, 0.52
mmol), Pd(dppf).sub.2Cl.sub.2 (10 mg, 0.012 mmol), TEA (1.0 mL, 7.2
mmol) as a white foam.
[3560] Step B:
[3561] The title compound (0.018 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-(2,6-dichlorop-
henyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij-
]quinoline-10(7aH)-carboxylate (0.023 g, 0.050 mmol) as a white
foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.80-2.05 (m, 2H),
2.05-2.20 (m, 2H), 2.55-2.80 (m, 4H), 2.88-2.96 (m, 3H), 3.07-3.20
(m, 2H), 3.23-3.36 (m, 1H), 3.38-3.48 (m, 1H), 6.73 (s, 1H), 6.79
(s, 1H), 7.16 (t, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz) ppm. MS (ESI):
359 (base, M+H).
Example 352
[3562]
(7aS,11aR)-2-(2-chlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyr-
ido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3563] Step A:
[3564] Tert-butyl
(7aS,11aR)-2-(2-chlorophenyl)-5,6,7a,8,9,10,11,11a-octah- ydro-4H-
pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10 (7aH)-carboxylate
(0.054 g, 51%) was prepared by the general method of Example 89,
step C from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro-4H-pyri-
do[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10 (7aH)-carboxylate (0.098
g, 0.25 mmol), 2-chlorophenylboronic acid (0.078 g, 0.5 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (8.8 mg, 0.013 mmol), Na.sub.2CO.sub.3
(2.0 M, 0.5 mL, 1.0 mmol) as a white foam. MS (ESI): 425 (base,
M+H)
[3565] Step B:
[3566] The title compound (0.040 g, 99%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-(2-chloropheny-
l)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]qui-
noline-10(7aH)-carboxylate (0.054 g, 0.13 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.80-2.05 (m, 2H),
2.05-2.20 (m, 2H), 2.55-2.80 (m, 4H), 2.88-2.96 (m, 3H), 3.07-3.20
(m, 2H), 3.23-3.36 (m, 1H), 3.38-3.48 (m, 1H), 6.97 (s, 1H), 7.02
(s, 1H), 7.12-7.35 (m, 3H), 7.35-7.46 (m, 2H) ppm. MS (ESI): 325
(base, M+H).
Example 353
[3567]
(7aS,11aR)-2-(3-chlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyr-
ido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3568] Step A:
[3569] Tert-butyl
(7aS,11aR)-2-(3-chlorophenyl)-5,6,7a,8,9,10,11,11a-octah-
ydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.060 g, 57%) was prepared by the general method
of Example 89, step C from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro-4H-pyri-
do[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10 (7aH)-carboxylate (0.098
g, 0.25 mmol), 3-chlorophenylboronic acid (0.078 g, 0.5 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (8.8 mg, 0.013 mmol), Na.sub.2CO.sub.3
(2.0 M, 0.5 mL, 1.0 mmol) as a white foam. MS (ESI): 425 (base,
M+H)
[3570] Step B:
[3571] The title compound (0.046 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-(3-chloropheny-
l)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]qui-
noline-10(7aH)-carboxylate (0.060 g, 0.14 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.80-2.05 (m, 2H),
2.05-2.20 (m, 2H), 2.55-2.80 (m, 4H), 2.88-2.96 (m, 3H), 3.07-3.20
(m, 2H), 3.23-3.36 (m, 1H), 3.38-3.48 (m, 1H), 7.11 (s, 1H), 7.12
(s, 1H), 7.20-7.40 (m, 3H), 7.48 (t, J=1.7 Hz, 1H) ppm. MS (ESI):
325 (base, M+H).
Example 354
[3572]
(7aS,11aR)-2-(4-chlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyr-
ido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3573] Step A:
[3574] Tert-butyl
(7aS,11aR)-2-(4-chlorophenyl)-5,6,7a,8,9,10,11,11a-octah-
ydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.045 g, 21%) was prepared by the general method
of Example 89, step C from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro-4H-pyri-
do[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10 (7aH)-carboxylate (0.20
g, 0.50 mmol), 4-chlorophenylboronic acid (0.16 g, 1.0 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025 mmol), Na.sub.2CO.sub.3
(2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 425 (base,
M+H).
[3575] Step B:
[3576] The title compound (0.033 g, 99%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-(4-chloropheny-
l)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]qui-
noline-10(7aH)-carboxylate (0.045 g, 0.11 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.80-2.05 (m, 2H),
2.05-2.20 (m, 2H), 2.58-2.82 (m, 4H), 2.82-3.06 (m, 3H), 3.07-3.20
(m, 2H), 3.23-3.40 (m, 1H), 3.40-3.48 (m, 1H), 7.11 (s, 1H), 7.13
(s, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz) ppm. MS (ESI):
325 (base, M+H).
Example 355
[3577]
(7aS,11aR)-2-(2,6-difluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3578] Step A:
[3579] Tert-butyl
(7aS,11aR)-2-(2,6-difluorophenyl)-5,6,7a,8,9,10,11,11a-o-
ctahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.064 g, 15%) was prepared by the general method
of Example 320, step A from tert-butyl
(8aS,11aR)-2-bromo-4,5,6,7,9,10,12,12-
a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(0.39 g, 1.0 mmol), 2,6-difluorophenylboronic acid (0.63 g, 4.0
mmol), Pd(dppf).sub.2Cl.sub.2 (48 mg, 0.06 mmol), TEA (3.0 mL, 22
mmol) as a white foam.
[3580] Step B:
[3581] The title compound (0.029 g, 59%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-(2,6-difluorop-
henyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij-
]quinoline-10(7aH)-carboxylate (0.064 g, 0.15 mmol) as a white
foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.80-2.05 (m, 2H),
2.05-2.25 (m, 2H), 2.58-2.83 (m, 4H), 2.83-3.08 (m, 2H), 3.08-3.60
(m, 5H), 6.85-7.08 (m, 4H), 7.08-7.22 (m, 1H) ppm.
Example 356
[3582]
(7aS,11aR)-2-(2,6-difluorophenyl)-10-methyl-5,6,7a,8,9,10,11,11a-oc-
tahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline A mixture of
(7aS,11aR)-2-(2,6-difluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrid-
o[3',4':4,5]pyrrolo[3,2,1,-ij]quinoline (0.050, 0.15 mmol), HCHO
(0.20 mL, 2.9 mmol) and formic acid (1.0 mL, 2.9 mmol) was heated
at 80.degree. C. for 4 h and cooled to room temperature. Water (5.0
mL) was added and the solution was basified with saturated
Na.sub.2CO.sub.3 until pH>8.The mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.10 mL), dried (Na.sub.2SO.sub.4) and
flash column chromatography (1-5% MeOH in CHCl.sub.3) gave the
title compound (0.032 g, 62%) as a white foam. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.2.00-2.20 (m, 5H), 2.20-2.50 (m, 4H),
2.55-2.68 (m, 1H), 2.68-2.82 (m, 3H), 2.86-2.98 (m, 1H), 3.28-3.42
(m, 3H), 6.90-7.08 (m, 4H), 7.14-7.25 (m, 1H) ppm. MS (ESI): 341
(base, M+H).
Example 357
[3583]
(7aS,11aR)-2-(2,3-difluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3584] Step A:
[3585] Tert-butyl
(7aS,11aR)-2-(2,3-difluorophenyl)-5,6,7a,8,9,10,11,11a-o-
ctahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1,-ij]quinoline-10
(7aH)-carboxylate (0.15 g, 70%) was prepared by the general method
of Example 89, step C from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11-
a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1,-ij]quinoline-10
(7aH)-carboxylate (0.20 g, 0.50 mmol), 2,3-difluorophenyl boronic
acid (0.16 g, 1.0 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025
mmol), Na.sub.2CO.sub.3 (2.0 M, 1.0 mL, 2.0 mmol) as a white foam.
MS (ESI): 427 (base, M+H).
[3586] Step B:
[3587] The title compound (0.10 g, 88%) was prepared by the general
method of Example 312, step B from tert-butyl
(7aS,11aR)-2-(2,3-difluorophenyl)--
5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinol-
ine-10(7aH)-carboxylate (0.15 g, 0.35 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.75-2.00 (m, 2H),
2.05-2.30 (m, 3H), 2.60-2.80 (m, 4H), 2.80-2.90 (m, 2H), 3.02-3.16
(m, 2H), 3.24-3.38 (m, 1H), 3.38-3.48 (m, 1H), 6.94-7.20 (m, 5H)
ppm. MS (ESI): 327 (base, M+H).
Example 358
[3588]
(7aS,11aR)-2-(3,4-difluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3589] Step A:
[3590] Tert-butyl
(7aS,11aR)-2-(3,4-difluorophenyl)-5,6,7a,8,9,10,11,11-oc-
tahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1,-ij]quinoline-10
(7aH)-carboxylate (0.077 g, 72%) was prepared by the general method
of Example 319, step A from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,1-
1a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.10 g, 0.25 mmol), 3,4-difluorophenyl boronic
acid (0.080 g, 0.50 mmol), Pd(PPh.sub.3).sub.4 (12 mg, 0.010 mmol),
and Ba(OH).sub.2 (0.17 M, 3.0 mL, 0.51 mmol) as a white foam. MS
(ESI): 427 (base, M+H).
[3591] Step B:
[3592] The title compound (0.054 g, 90%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-(3,4-difluorop-
henyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij-
]quinoline-10(7aH)-carboxylate (0.077 g, 0.18 mmol) as a white
foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.70-2.00 (m, 4H),
2.10-2.50 (m, 3H), 2.50-2.70 (m, 1H), 2.79-2.85 (m, 2H), 3.10-3.60
(m, 5H), 7.06-7.35(m, 5H) ppm. MS (ESI): 327 (base, M+H).
Example 359
[3593]
(7aS,11aR)-2-(3-fluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyr-
ido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3594] Step A:
[3595] Tert-butyl
(7aS,11aR)-2-(3-fluorophenyl)-5,6,7a,8,9,10,11,11a-octah-
ydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.055 g, 52%) was prepared by the general method
of Example 319, step A from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro-4H-pyri-
do[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10 (7aH)-carboxylate (0.10
g, 0.25 mmol), 3-fluorophenyl boronic acid (0.070 g, 0.50 mmol),
Pd(PPh.sub.3).sub.4 (12 mg, 0.010 mmol), and Ba(OH).sub.2 (0.17 M,
3.0 mL, 0.51 mmol) as a white foam. MS (ESI): 409 (base, M+H).
[3596] Step B:
[3597] The title compound (0.042 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-(3-fluoropheny-
l)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1,-ij]qu-
inoline-10(7aH)-carboxylate (0.055 g, 0.13 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.2.05-2.22 (m, 4H),
2.55-2.68 (m, 1H), 2.68-2.80 (m, 3H), 3.00-3.20 (m, 2H), 3.2-3.48
(m, 4H), 5.00-5.50 (br, 1H), 6.85-7.00 (m, 1H), 7.08-7).40 (m, 5H)
ppm. MS (ESI): 309 (base, M+H).
Example 360
[3598]
(7aS,11aR)-2-[2-chloro-4-methoxyphenyl)-5,6,7a,8,9,10,11,11a-octahy-
dro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3599] Step A:
[3600] Tert-butyl
(7aS,11aR)-2-[2-chloro-4-methoxyphenyl)-5,6,7a,8,9,10,11-
,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.053 g, 23%) was prepared by the general method
of Example 89, step C from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11-
a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1,-ij]quinoline-10
(7aH)-carboxylate (0.20 g, 0.50 mmol), 2-chloro-4-methoxyphenyl
boronic acid (0.19 g, 1.0 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (17
mg, 0.025 mmol), Na.sub.2CO.sub.3 (2.0 M, 1.0 mL, 2.0 mmol) as a
white foam.
[3601] Step B:
[3602] The title compound (0.035 g, 85%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-[2-chloro-4-me-
thoxyphenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,-
2,1,-ij]quinoline-10 (7aH)-carboxylate (0.053 g, 0.12 mmol) as a
white foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.80-2.05 (m,
2H), 2.05-2.20 (m, 3H), 2.58-2.68 (m, 1H), 2.68-2.80 (m, 2H),
2.85-3.05 (m, 3H), 3.07-3.20 (m, 2H), 3.23-3.36 (m, 1H), 3.38-3.48
(m, 1H), 6.95 (s, 1H), 6.99 (s, 1H), 7.16 (dd, J=2.7, 8.4 Hz, 1H),
7.30 (d, J=2.7 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H) ppm.
Example 361
[3603]
(7aS,11aR)-2-[2-fluoro-4-methoxyphenyl)-5,6,7a,8,9,10,11,11a-octahy-
dro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3604] Step A:
[3605] Tert-butyl
(7aS,11aR)-2-[2-fluoro-4-methoxyphenyl)-5,6,7a,8,9,10,11-
,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.15 g, 68%) was prepared by the general method
of Example 89, step C from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11-
a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.20 g, 0.50 mmol),
2-fluoro-4-methoxyphenylboronic acid (0.17 g, 1.0 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025 mmol), Na.sub.2CO.sub.3
(2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 339 (base,
M+H).
[3606] Step B:
[3607] The title compound (0.11 g, 94%) was prepared by the general
method of Example 312, step B from tert-butyl
(7aS,11aR)-2-[2-fluoro-4-methoxyph-
enhyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij-
]quinoline-10 (7aH)-carboxylate (0.15 g, 0.34 mmol) as a white
foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.70-1.88 (m, 1H),
1.88-2.00 (m, 1H), 2.00-2.20 (m, 3H), 2.55-2.80 (m, 4H), 2.80-2.96
(m, 2H), 3.02-3.12 (m, 2H), 3.28-3.37 (m, 1H), 3.38-3.48 (m, 1H),
3.81 (s, 3H), 6.64-6.75 (m, 2H), 7.03 (s, 1H), 7.07 (s, 1H), 7.29
(t, J=8.8 Hz, 1H) ppm. MS (ESI): 339 (base, M+H).
Example 362
[3608]
(7aS,11aR)-2-(4-methoxy-2-methylphenyl)-5,6,7a,8,9,10,11,11a-octahy-
dro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1,-ij]quinoline
[3609] Step A:
[3610] Tert-butyl
(7aS,11aR)-2-(4-methoxy-2-methylphenyl)-5,6,7a,8,9,10,11-
,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.15 g, 68%) was prepared by the general method
of Example 89, step C from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11-
a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.20 g, 0.50 mmol),
4-methoxy-2-methylphenylboronic acid (0.17 g, 1.0 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025 mmol), Na.sub.2CO.sub.3
(2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 449 (base,
M+H).
[3611] Step B:
[3612] The title compound (0.095 g, 97%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-(4-methoxy-2-m-
ethylphenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,-
2,1-ij]quinoline-10 (7aH)-carboxylate (0.13 g, 0.29 mmol) as a
white foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.74-1.88 (m,
1H), 1.88-2.00 (m, 1H), 2.05-2.28 (m, 3H), 2.28 (s, 3H), 2.55-2.80
(m, 4H), 2.80-2.92 (m, 2H), 3.00-3.12 (m, 2H), 3.28-3.36 (m, 1H),
3.36-3.45 (m, 1H), 3.82 (s, 3H), 6.70-6.82 (m, 3H), 6.84 (s, 1H),
7.14 (d, J=8.4 Hz, 1H) ppm. MS (ESI): 349 (base, M+H).
Example 363
[3613]
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11-
,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3614] Step A:
[3615] Tert-butyl
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7-
a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-1-
0 (7aH)-carboxylate (3.02 g, 61%) was prepared by the general
method of Example 89, step C from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11-
a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (3.93 g, 10 mmol),
4-methoxy-2-(trifluoromethyl)phenylb- oronic acid (4.40 g, 20
mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (0.35 g, 0.50 mmol),
Na.sub.2CO.sub.3 (2.0 M, 20 mL, 40 mmol) as a white solid. MS
(ESI): 489 (base, M+H).
[3616] Step B:
[3617] The title compound (2.38 g, 99%) was prepared by the general
method of Example 312, step B from tert-butyl
(7aS,11aR)-2-[4-methoxy-2-(trifluo-
romethyl)phenyl]-5,6,7a,8,9,10,11,l1a-octahydro-4H-pyrido[3',4':4,5]pyrrol-
o[3,2,1,-ij]quinoline-10 (7aH)-carboxylate (3.02 g, 6.1 mmol) as a
white foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.80-2.05 (m,
2H), 2.08-2.10 (m, 3H), 2.60-2.80 (m, 4H), 2.80-2.96 (m, 2H),
3.04-3.15 (m, 2H), 3.32 (td, J=4.0, 10.0 Hz, 1H), 3.40-3.48 (m,
1H), 3.88 (s, 3H), 6.81 (s, 1H), 6.85 (s, 1H), 7.04 (dd, J=2.7, 8.4
Hz, 1H), 7.20-7.28 (m, 2H) ppm. MS (ESI): 389 (base, M+H).
Example 364
[3618]
2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,8,9,10,11-hexahydro-4H--
pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3619] Step A:
[3620] Tert-butyl
2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,8,9,10,11-he-
xahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.78 g) was obtained as a byproduct of Example
363 as a white solid.
[3621] Step B:
[3622] The title compound (0.60 g, 98%) was prepared by the general
method of Example 312, step B from tert-butyl
2-[4-methoxy-2-(trifluoromethyl)ph-
enyl]-5,6,8,9,10,11-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoli-
ne-10 (7aH)-carboxylate (0.78 g, 1.6 mmol) as a white foam. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta.2.20-2.30 (m, 2H), 2.79 (t, J=5.4
Hz, 2H), 2.90-3.20 (m, 3H), 3.30 (t, J=5.8 Hz, 2H), 3.91 (s, 3H),
3.98 (t, J=5.8 Hz, 2H), 4,12 (s, 2H), 6.84 (s, 1H), 7.07 (dd,
J=2.,5, 8.4 Hz, 1H), 7.18 (s, 1H), 7.25-7.35 (m, 2H) ppm. MS (ESI):
428 (base, M+CH.sub.3CN).
Example 365
[3623]
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]py-
rrolo[3,2,1-ij]quinolin-2-yl]-3-(trifluoromethyl)phenol
[3624] BBr.sub.3 in CH.sub.2Cl.sub.2 (0.91 M, 0.66 mL, 0.60 mmol)
was added dropwise to a solution of tert-butyl
(7aS,11aR)-2-[4-methoxy-2-(tri-
fluoromethyl)phenyl]-5,6,7a,8,9,10,11,11-octahydro-4H-pyrido[3',4':4,5]pyr-
rolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.049 g, 0.10 mmol) in
CH.sub.2Cl.sub.2 (5.0 mL) at room temperature under N.sub.2. The
mixture was stirred for 18 h before quenched with water (5.0 mL).
The mixture was basified with saturated NaHCO.sub.3 until
pH.about.8 and-extracted with CH.sub.2Cl.sub.2 (3.times.10 mL). The
combined organic layer was dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. Reverse phase HPLC (H.sub.2O
--CH.sub.3CN--TFA (0.05%)) gave the title compound (0.012 g, 32%)
as a white solid. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.2.00-2.22 (m, 2H), 2.05-2.20 (m, 2H), 2.55-2.80 (m, 4H),
2.88-2.96 (m, 2H), 3.07-3.20 (m, 2H), 3.23-3.36 (m, 1H), 3.38-3.48
(m, 1H), 6.95 (s, 1H), 6.99 (s, 1H), 7.16 (dd, J=2.7, 8.4 Hz, 1H),
7.30 (d, J=2.7 Hz, 1H), 7.34 (d, J=8.4 Hz) ppm. MS (ESI): 375
(base, M+H).
Example 366
[3625]
(7aS,11aR)-2-[2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octah-
ydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1,-ij]quinoline
[3626] Step A:
[3627] Tert-butyl
(7aS,11aR)-2-[2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,1-
1,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1,-ij]quinoline-10
(7aH)-carboxylate (0.041 g, 18%) was prepared by the general method
of Example 89, step C from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11-
-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1,-ij]quinoline-10
(7aH)-carboxylate (0.20 g, 0.50 mmol), 2-(trifluoromethyl)phenyl
boronic acid (0.19 g, 1.0 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (17
mg, 0.025 mmol), Na.sub.2CO.sub.3 (2.0 M, 1.0 mL, 2.0 mmol) as a
white foam. MS (ESI): 459 (base, M+H).
[3628] Step B:
[3629] The title compound (0.030 g, 94%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-[2-(trifluorom-
ethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3-
,2,1-ij]quinoline-10 (7aH)-carboxylate (0.041 g, 0.090 mmol) as a
white foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.80-2.08 (m,
2H), 2.08-2.28 (m, 2H), 2.43 (br, 1H), 2.60-2.80 (m, 4H), 2.85-2.98
(m, 2H), 3.07-3.20 (m, 2H), 3.25-3.40 (m, 1H), 3.40-3.48 (m, 1H),
6.84 (s, 1H), 6.88 (s, 1H), 7.34 (d, J=7.7 Hz, 1H), 7. 40 (t, J=7.6
Hz, 1H), 7.51 (t, J=7.4 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H) ppm. MS
(ESI): 359 (base, M+H).
Example 367
[3630]
(7aS,11aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10-
,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3631] Step A:
[3632] Tert-butyl
(7aS,11aR)-2-[4-isopropoxy-2-(trifluoromethyl)phenyl]-5,-
6,7a,8,9,10,11,11-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-
-10 (7aH)-carboxylate (0.16 g, 61%) was prepared by the general
method of Example 89, step C from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11- a-octahydro-4H-
pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10 (7aH)-carboxylate
(0.20 g, 0.50 mmol), 4-isopropoxy-2-(trifluoromethyl)ph-
enylboronic acid (0.18 g, 0.73 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2
(17 mg, 0.025 mmol), Na.sub.2CO.sub.3 (2.0 M, 1.0 mL, 2.0 mmol) as
a white foam. MS (ESI): 517 (base, M+H).
[3633] Step B:
[3634] The title compound (0.13 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-[4-isopropoxy--
2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':-
4,5]pyrrolo[3,2,1-ij]quinoline-10 (7aH)-carboxylate (0.16 g, 0.31
mmol) as a white foam. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.1.38 (d, J=6.0 Hz, 6H), 1.70-1.88 (m, 1H), 1.88-2.00 (m,
1H), 2.02-2.18 (m, 3H), 2.55-2.80 (m, 4H), 2.80-2.98 (m, 2H),
3.00-3.13 (m, 2H), 3.25-3.37 (m, 1H), 3.38-3.55 (m, 1H), 4.61, (p,
J=6.0 Hz, 1H), 6.81 (s, 1H), 6.85 (s, 1H), 7.01 (dd, J=1.2, 8.6 Hz,
1H), 7.18-7.26 (m, 2H) ppm. MS (ESI)-: 417 (base, M+H).
Example 368
[3635]
(7aS,11aR)-2-[2,4-bis(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a--
octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3636] Step A:
[3637] Tert-butyl
(7aS,11aR)-2-[2,4-bis(trifluoromethyl)phenyl]-5,6,7a,8,9-
,10,i1,11-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.029 g, 11%) was prepared by the general method
of Example 89, step C from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11-
a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.20 g, 0.50 mmol),
2,4-bis(trifluoromethyl)phenylboro- nic acid (0.26 g, 1.0 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025 mmol), Na.sub.2CO.sub.3
(2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 527 (base,
M+H).
[3638] Step B:
[3639] The title compound (0.023 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-[2,4-bis(trifl-
uoromethyl)phenyl]-5,6,7a,8,9,10,11,11-octahydro-4H-pyrido[3',4':4,5]pyrro-
lo[3,2,1-ij]quinoline-10 (7aH)-carboxylate (0.029 g, 0.055 mmol) as
a white foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.2.10-2.30
(m, 4H), 2.50-2.70 (m, 3H), 2.70-2.86 (m, 3H), 3.10-3.55 (m, 5H),
6.90 -(s, 2H), 7.45 (d, J=7.8 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.97
(s, 1H) ppm. MS (ESI): 427 (base, M+H).
Example 369
[3640]
(7aS,11aR)-2-[4-fluoro-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3641] Step A:
[3642] Tert-butyl
(7aS,11aR)-2-[4-fluoro-2-(trifluoromethyl)phenyl]-5,6,7a-
,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.093 g, 75%) was prepared by the general method
of Example 319, step A from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,1-
1a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10
(7aH)-carboxylate (0.10 g, 0.26 mmol),
4-fluoro-2-(trifluoromethyl)phenyl- boronic acid (0.11 g, 0.51
mmol), Pd(PPh.sub.3).sub.4 (12 mg, 0.010 mmol), and Ba(OH).sub.2
(0.17 M, 3.0 mL, 0.51 mmol) as a white foam. MS (ESI): 477 (base,
M+H).
[3643] Step B:
[3644] The title compound (0.071 g, 97%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-[4-fluoro-2-(t-
rifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]-
pyrrolo[3,2,1-ij]quinoline-10 (7aH)-carboxylate (0.093 g, 0.19
mmol) as a white foam. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.2.08-2.12 (m, 4H), 2.58-2.85 (m, 4H), 3.02-3.24 (m, 2H),
3.28-3.50 (m, 5H), 7.11 (s, 1H), 7.12 (s, 1H), 7.21 (t, J=9.4 Hz,
1H), 7.58-7.68 (m, 1H), 7.68-7.75 (m, 1H) ppm. MS (ESI): 377 (base,
M+H).
Example 370
[3645] 4-[ (7aS,11aR) -5,6,7a, 8,9,10,11,
11a-octahydro-4H-pyrido[3',4':4,-
5]pyrrolo[3,2,1-ij]quinolin-2-yl]-3-(trifluoromethyl)aniline
[3646] Step A:
[3647] Tert-butyl
(7aS,11aR)-2-[4-[(tert-butoxycarbonyl)amino]-2-(trifluor-
omethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo-
[3,2,1-ij]quinoline-10 (7aH)-carboxylate (0.13 g, 93%) was prepared
by the general method of Example 319, step A from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',
4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.10 g, 0.25
mmol),
4-[(tert-butoxycarbonyl)amino]-2-(trifluoromethyl)phenylboronic
acid (0.15 g, 0.50 mmol), Pd(PPh.sub.3).sub.4 (12 mg, 0.010 mmol),
and Ba(OH).sub.2 (0.17 M, 3.0 mL, 0.51 mmol) as a white foam. MS
(ESI): 574 (base, M+H).
[3648] Step B:
[3649] The title compound (0.079 g, 72%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-[4-[(tert-buto-
xycarbonyl)amino]-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydr-
o-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate
(0.13 g, 0.23 mmol) as a white foam. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta.1.78-2.00 (m, 2H), 2.05-2.22 (m, 2H), 2.58-2.80 (m,
4H), 2.80-2.98 (m, 2H), 3.04-3.16 (m, 2H), 3.28-3.38 (m, 1H),
3.38-3.48 (m, 1H), 3.82 (br, 3H), 6.72-6.88 (m, 3H), 7.00 (d, J=2.6
Hz, 1H), 7.11 (d, J=8.1 Hz, 1H) ppm. MS (ESI): 374 (base, M+H).
Example 371
[3650]
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]py-
rrolo[3,2,1-ij]quinolin-2-yl]-N-methyl-3-(trifluoromethyl)aniline
[3651] Step A:
[3652] Tert-butyl
(7aS,11aR)-2-[4-[(tert-butoxycarbonyl)(methyl)amino]-2-(-
trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5-
]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.12 g, 82%) was
prepared by the general method of Example 319, step A from
tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyr-
rolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.10 g, 0.25 mmol),
4-[(tert-butoxycarbonyl)(methyl)amino]-2-(trifluoromethyl)phenylboronic
acid (0.16 g, 0.50 mmol), Pd(PPh.sub.3).sub.4 (12 mg, 0.010 mmol),
and Ba(OH).sub.2 (0.17 M, 3.0 mL, 0.51 mmol) as a white foam. MS
(ESI): 588 (base, M+H).
[3653] Step B:
[3654] The title compound (0.071 g, 71%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-[4-[(tert-buto-
xycarbonyl)(methyl)amino]-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a--
octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,l-ij]quinoline-10(7aH)-carboxyla-
te (0.12 g, 0.20 mmol) as a white foam. .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta.1.78-2.00 (m, 2H), 2.05-2.25 (m, 2H), 2.60-2.80 (m,
4H), 2.80-3.00 (m, 5H), 3.00-3.20 (m, 2H), 3.28-3.40 (m, 1H),
3.40-3.50 (m, 1H), 3.91 (br, 2H), 6.73 (dd, J=2.6, 8.3 Hz, 1H),
6.81 (s, 1H), 6.85 (s, 1H), 6.91 (d, J=2.6 Hz, 1H), 7.15 (d, J=8.3
Hz, 1H) ppm. MS (ESI): 388 (base, M+H).
Example 372
[3655]
4-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]py-
rrolo[3,2,l-ij]quinolin-2-yl]-3-methylbenzonitrile
[3656] Step A:
[3657] Tert-butyl
(7aS,11aR)-2-(4-cyano-2-methylphenyl)-5,6,7a,8,9,10,11,1-
1a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carbox-
ylate (0.073 g, 65%) was prepared by the general method of Example
319, step A from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro--
4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate
(0.10 g, 0.26 mmol), 4-cyano-2-methylphenylboronic acid (0.088 g,
0.52 mmol), Pd(PPh.sub.3).sub.4 (12 mg, 0.010 mmol), and
Ba(OH).sub.2 (0.17 M, 3.0 mL, 0.51 mmol) as a white foam. MS (ESI):
430 (base, M+H).
[3658] Step B:
[3659] The title compound (0.050 g, 89%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-(4-cyano-2-met-
hylphenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,-
1-ij]quinoline-10(7aH)-carboxylate (0.073 g, 0.17 mmol) as a white
foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.2.10-2.20 (m, 4H),
2.30 (s, 3H), 2.55-2.70 (m, 1H), 2.70-2.80 (m, 3H), 3.07-3.26 (m,
2H), 3.26-3.48 (m, 5H), 6.84 (s, 2H), 7.25 (d, J=7.7 Hz, 1H), 7.47
(d, J=7.7 Hz, 1H), 7.51 (s, 1H) ppm. MS (ESI): 330 (base, M+H).
Example 373
[3660]
2-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]py-
rrolo[3,2,1-ij]quinolin-2-yl]benzaldehyle
[3661] Step A:
[3662] Tert-butyl
(7aS,11aR)-2-(2-formylphenyl)-5,6,7a,8,9,10,11,11a-octah-
ydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate
(0.091 g, 44%) was prepared by the general method of Example 89,
step C from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro-4H-pyri-
do[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.20
g, 0.50 mmol), 2-formylphenylboronic acid (0.15 g, 1.0 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025 mmol), Na.sub.2CO.sub.3
(2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 419 (base,
M+H).
[3663] Step B:
[3664] The title compound (0.021 g, 91%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-(2-formylpheny-
l)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]qui-
noline-10(7aH)-carboxylate (0.030 g, 0.070 mmol) as a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.94-2.24 (m, 4H),
2.59-2.82 (m, 5H), 3.00-3.24 (m, 2H), 3.28-3.42 (m, 3H), 3.44-3.52
(m, 1H), 6.90 (s, 1H), 6.97 (s, 1H), 7.38-7.46 (m, 2H), 7.66 (td,
J=7.5, 1.4 Hz, 1H), 7.99 (dd, J=1.4, 8.0 Hz, 1H), 10.01 (s, 1H)
ppm. MS (ESI): 319 (base, M+H).
Example 374
[3665]
{2-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]p-
yrrolo[3,2,1-ij]quinolin-2-yl]phenyl}methanol
[3666] Step A:
[3667] Tert-butyl
(7aS,11aR)-2-[2-(hydroxymethyl)phenyl]-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carbo-
xylate (0.42 g, 69%) was prepared by the method of Example 341 from
tert-butyl
(7aS,11aR)-2-(2-formylphenyl)-5,6,7a,8,9,10,11,11a-octahydro-4-
H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate
(0.061 g, 0.15 mmol) and NaBH.sub.4 (0.060 g, 1.6 mmol) as a white
solid. MS (ESI): 421 (base, M+H).
[3668] Step B:
[3669] The title compound (0.032 g, 100%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-[2-(hydroxymet-
hyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2-
,1-ij]quinoline-10(7aH)-carboxylate (0.042 g, 0.10 mmol) as a white
foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.80-2.04 (m, 2H),
2.08-2.20 (m, 2H), 2.50-2.80 (m, 4H), 2.82-2.97 (m, 2H), 3.04-3.20
(m, 2H), 3.20-3.38 (m, 1H), 3.38-3.42 (m, 1H), 4.65 (s, 2H), 6.89
(s, 1H), 6.93 (s, 1H), 7.22-7.38 (m, 3H), 7.50-7.57 (m, 1H) ppm. MS
(ESI): 321 (base, M+H).
Example 375
[3670]
2-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]py-
rrolo[3,2,1-ij]quinolin-2-yl]-5-methoxybenzaldehyde
[3671] Step A:
[3672] Tert-butyl
(7aS,11aR)-2-(2-formyl-4-methoxyphenyl)-5,6,7a,8,9,10,11-
,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carb-
oxylate (0.084 g, 38%) was prepared by the general method of
Example 89, step C from tert-butyl
(7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro--
4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate
(0.20 g, 0.50 mmol), 2-formyl-4-methoxyphenylboronic acid (0.18 g,
1.0 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (17 mg, 0.025 mmol),
Na.sub.2CO.sub.3 (2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS
(ESI): 449 (base, M+H).
[3673] Step B:
[3674] The title compound (0.056 g, 86%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-(2-formyl-4-me-
thoxyphenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,-
2,1-ij]quinoline-10(7aH)-carboxylate (0.084 g, 0.19 mmol) as a
white foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.2.00-2.10 (m,
2H), 2.10-2.25 (m, 2H), 2.59-2.82 (m, 4H), 2.98-3.20 (m, 2H),
3.20-3.40 (m, 3H), 3.42-3.52 (m, 2H), 3.92 (s, 3H), 6.86 (s, 1H),
6.92 (s, 1H), 7.18 (dd, J=8.4, 2.6 Hz, 1H), 7.35 (d, J-8.4 Hz, 1H),
7.47 (d, J=2.6 Hz, 1H), 9.97 (s, 1H) ppm. MS (ESI): 349 (base,
M+H).
Example 376
[3675]
{2-[(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]p-
yrrolo[3,2,1-ij]quinolin-2-yl]-5-methoxyphenyl}methanol
[3676] Step A:
[3677] Tert-butyl
(7aS,11aR)-2-[2-(hydroxymethyl)-4-methoxyphenyl]-5,6,7a,-
8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(-
7aH)-carboxylate (0.016 g) was obtained as a byproduct of Example
375. MS (ESI): 451 (base, M+H).
[3678] Step B:
[3679] The title compound (0.010 g, 83%) was prepared by the
general method of Example 312, step B from tert-butyl
(7aS,11aR)-2-[2-(hydroxymet-
hyl)-4-methoxyphenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]p-
yrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.016 g, 0.036 mmol)
as a white foam. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.70-2.02
(m, 2H), 2.08-2.20 (m, 2H), 2.50-2.80 (m, 4H), 2.80-2.95 (m, 2H),
3.00-3.14 (m, 2H), 3.28-3.38 (m, 1H), 3.38-3.46 (m, 1H), 3.87 (s,
3H), 4.65 (s, 2H), 6.80-6.90 (m, 3H), 7.10 (d, J=3.0 Hz, 1H), 7.19
(d, J=8.4 Hz, 1H) ppm. MS (ESI): 351 (base, M+H).
Example 377
[3680]
(8aS,12aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,1-
1,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3b]indole
[3681] The title compound was afforded as a yellow oil (81 mg, 79%)
according to the method of Example 319, step A followed by Example
312, step B from tert-butyl
(8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroaz-
epino[3,2,1-hi]pyrido[4,3b]indole-11(8H)-carboxylate (100 mg, 0.25
mmol) and 4-ethoxy-2-(trifluoromethyl)phenylboronic acid (83 mg,
0.5 mmol). 1H NMR (CDCl.sub.3) .delta.1.37 (t, 3H, J=7.0 Hz),
1.44-1.58 (m, 1H), 1.66-1.84 (m, 2H), 1.89-2.00 (m, 3H), 2.42-2.73
(m, 3H), 2.80-3.04 (m, 5H), 3.10-3.36 (m, 3H), 4.01 (q, 2H, J=7.00
Hz), 6.77 (d, 2H, J=5.2 Hz), 6.94 (dd, 1H, J=2.5, 8.5 Hz),
7.13-7.19 (m, 2H) ppm. MS (ESI): 417 (base, M+H).
Example 378
[3682]
(7aS,11aR)-2-[4-ethoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3683] The title compound was afforded as a yellow oil (56 mg, 56%)
according to the method of Example 319, step A followed by Example
312, step B from tert-butyl
(7aS,11aR)-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyr-
ido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (100
mg, 0.25 mmol) and 4-methoxy-2-(trifluoromethyl)phenylboronic acid
(76 mg, 0.5 mmol). .sup.1H NMR (CDCl.sub.3) .delta.1.46 (t, 3H,
J=7.0 Hz), 1.86-2.03 (m, 2H), 2.10-2.21 (m, 2H), 2.62-2.80 (m, 5H),
2.84-2.96 (m, 2H), 3.09-3.19 (m, 2H), 3.33-3.39 (m, 1H), 3.42-3.47
(m, 1H), 4.10 (q, 2H, J=7.0 Hz), 6.83 (d, 2H, J=11.0 Hz), 7.02 (dd,
1H, J=2.7, 8.3 Hz), 7.16-7.28 (m, 2H) ppm. MS (ESI): 403 (base,
M+H).
Example 379
[3684]
(8aS,12aR)-2-[3-chloro-2-methylphenyl]-4,5,6,7,8a,9,10,11,12,12a-de-
cahydroazepino[3,2,1-hi] pyrido[4,3b]indole
[3685] The title compound was afforded as a yellow oil (49 mg, 53%)
according to the method of Example 319, step A followed by Example
312, step B from tert-butyl
(8aS,12aR)2-bromo-4,5,6,7,9,10,12,12a-octahydroaze-
pino[3,2,1-hi]pyrido[4,3b]indole-11(8H)-carboxylate (100 mg, 0.24
mmol) and 3-chloro-2-methylphenylboronic acid (84 mg, 0.48 mmol).
MS (ESI): 353 (base, M+H).
Example 380
[3686]
(7aS,11aR)-2-[3-chloro-2-methylphenyl]-5,6,7a,8,9,10,11,11a-octahyd-
ro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3687] The title compound was afforded as a yellow oil (55 mg, 65%)
according to the method of Example 319, step A followed by Example
312, step B from tert-butyl
(7aS,11aR)-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyr-
ido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (100
mg, 0.24 mmol) and 3-chloro-2-methylphenylboronic acid (80 mg, 0.48
mmol). MS (ESI): 339 (base, M+H).
Example 381
[3688]
(7aS,11aR)-2-[5-fluoro-2-methylphenyl]-5,6,7a,8,9,10,11,11a-octahyd-
ro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3689] The title compound was afforded as a yellow oil (29 mg, 91%)
according to the method of Example 319, step A followed by Example
312, step B from tert-butyl
(7aS,11aR)-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyr-
ido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (50
mg, 0.13 mmol) and 5-fluoro-2-methylphenylboronic acid (39 mg, 0.25
mmol). MS (ESI): 323 (base, M+H).
Example 382
[3690]
(.+-.)-cis-2-(2,3-dichlorophenyl)-10-propyl-5,6,7a,8,9,10,11,11a-oc-
tahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3691] To a solution of
(.+-.)-cis-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11-
,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline (30
mg, 0.083 mmol) in 1,4-dioxane (0.5 mL) and
N,N-diisopropylethylamine)-(108 mg, 0.83 mmol) were added
1-bromopropane (21 mg, 0.17 mmol) and KI (catalytic amount). The
reaction mixture was heated at 100.degree. C. for 15 h. The
reaction mixture was cooled to 20.degree. C. then concentrated in
vacuo and chromatographed on a silica gel column by elution with
CHCl.sub.3/MeOH (99/1) to give the title compound (27 mg, 82%) as a
yellow oil. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.0.92(t, J=7.3
Hz, 3H), 1.58-1.75 (br, 2H), 2.03-2.23 (m, 5H), 2.42-2.55 (br, 2H),
2.58-2.67 (m, 1H), 2.75 (t, J=7.4 Hz, 2H), 2.85-2.95 (br, 1H),
2.98-3.12 (br, 1H), 3.31 (dt, J=10.3, 3.6 Hz, 1H), 3.37-3.45 (br,
2H), 6.94 (s, 1H), 6.97 (s, 1H), 7.15-7.20 (m, 2H), 7.36-7.42 (m,
1H) ppm.
Example 383
[3692]
(7aS,11aR)-2-(2,3-dichlorophenyl)-10-propyl-5,6,7a,8,9,10,11,11a-oc-
tahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3693] The title compound was prepared by the method of Example 382
as a yellow oil (22 mg, 66%) from
(7aS,11aR)-2-(2,3-dichlorophenyl)-5,6,7a,8,9-
,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
(30 mg, 0.083 mmol). The title compound was spectroscopically
identical to Example 382. MS (CI, NH.sub.3): 401.1 (base, M+H).
Example 384
[3694]
(.+-.)-cis-10-butyl-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-oct-
ahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3695] The title compound was prepared by the method of Example 382
as a yellow oil (28 mg, 82%) from
(.+-.)-cis-2-(2,3-dichlorophenyl)-5,6,7a,8,9-
,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
(30 mg, 0.083 mmol) and 1-bromobutane (23 mg, 0.17 mmol). .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta.0.92(t, J=7.3 Hz, 3H), 1.32 (se,
J=7.3 Hz, 2H), 1.53-1.65 (br, 2H), 2.02-2.25 (m, 5H), 2.38-2.53
(br, 2H), 2.58-2.68 (m, 1H), 2.75 (t, J=6.4 Hz, 2H), 2.80-2.92 (br,
1H), 2.95-3.07 (br, 1H), 3.31 (dt, J=10.3, 3.6 Hz, 1H), 3.37-3.45
(br, 2H), 6.94 (s, 1H), 6.99 (s, 1H), 7.15-7.21 (m, 2H), 7.35-7.40
(m, 1H) ppm.
Example 385
[3696]
(7aS,11aR)-10-butyl-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-oct-
ahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3697] The title compound was prepared by the method of Example
382as a yellow oil (23 mg, 62%) from
(7aS,11aR)-2-(2,3-dichlorophenyl)-5,6,7a,8,9-
,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
(30 mg, 0.083 mmol). The title compound was spectroscopically
identical to Example 384. MS (CI, NH.sub.3): 415.1 (base, M+H).
Example 386
[3698]
(7aS,11aR)-2-(2,3-dichlorophenyl)-10-(4-pentenyl)-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3699] The title compound was prepared by the method of Example 382
as a yellow oil (22 mg, 62%) from
(7aS,11aR)-2-(2,3-dichlorophenyl)-5,6,7a,8,9-
,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
(30 mg, 0.083 mmol) and 5-bromo-1-pentene (25 mg, 0.17 mmol).
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.62-1.75 (br, 2H),
2.01-2.22 (m, 7H), 2.35-2.53 (br, 3H), 2.58-2.65 (m, 1H), 2.74 (t,
J=6.6 Hz, 2H), 2.75-2.85 (br, 1H), 2.88-3.05 (br, 1H), 3.28-3.41
(m, 3H), 4.97 (d, J=13.5 Hz, 1H), 5.02 (dd, J=17.6, 1.5 Hz, 1H),
5.73-5.83 (m, 1H), 6.93 (s, 1H), 6.98 (s, 1H), 7.15-7.21 (m, 2H),
7.36-7.40 (m, 1H) ppm. MS (CI, NH.sub.3): 427.1 (base, M+H).
Example 387
[3700]
(7aS,11aR)-2-(2,3-dichlorophenyl)-10-(3-methyl-2-butenyl)-5,6,7a;8,-
9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3701] The title compound was prepared by the method of Example 382
as a yellow oil (27 mg, 76%) from
(7aS,11aR)-2-(2,3-dichlorophenyl)-5,6,7a,8,9-
,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
(30 mg, 0.083 mmol) and 4-bromo-2-methyl-2-butene (25 mg, 0.17
mmol). MS (CI, NH.sub.3): 427.1 (base, M+H).
Example 388
[3702]
(7aS,11aR)-2-(2,4-dichlorophenyl)-10-propyl-5,6,7a,8,9,10,11,11a-oc-
tahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3703] The title compound was prepared by the method of Example 382
as a yellow oil (21 mg, 65%) from
(7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9-
,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
(30 mg, 0.083 mmol) and 1-bromopropane (30 mg, 0.24 mmol). .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta.0.92 (t, J=7.3 Hz, 3H), 1.61-1.75
(m, 2H), 2.02-2.35 (m, 6H), 2.45-2.63 (m, 3H), 2.75 (t, J=6.5 Hz,
2H), 2.87-2.98 (br, 1H), 3.00-3.08 (br, 1H), 3.30 (dt, J=10.6, 4.0
Hz, 1H), 3.35-3.48 (m, 2H), 6.94 (s, 1H), 6.99 (s, 1H), 7.21-7.25
(m, 1H), 7.44 (d, J=1.5 Hz, 1H) ppm. MS (CI, NH.sub.3): 401.1
(base, M+H).
Example 389
[3704]
(7aS,11aR)-10-butyl-2-(2,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-oct-
ahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3705] The title compound was prepared by the method of Example 382
as a yellow oil (21 mg, 61%) from
(7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9-
,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
(30 mg, 0.083 mmol) and 1-bromobutane (23 mg, 0.17 mmol). MS (CI,
NH.sub.3): 415.1 (base, M+H).
Example 390
[3706]
(7aS,11aR)-2-(2,4-dichlorophenyl)-10-(4-pentenyl)-5,6,7a,8,9,10,11,-
11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3707] The title compound was prepared by the method of Example 382
as a yellow oil (23 mg, 67%) from
(7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9-
,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
(30 mg, 0.083 mmol) and 5-bromo-1-pentene (25 mg, 0.16 mmol). MS
(CI, NH.sub.3): 427.1 (base, M+H).
Example 391
[3708]
(7aS,11aR)-2-(2,4-dichlorophenyl)-10-(3-methyl-2-butenyl)-5,6,7a,8,-
9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3709] The title compound was prepared by the method of Example 382
as a yellow oil (26 mg, 76%) from
(7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9-
,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
(30 mg, 0.083 mmol) and 4-bromo-2-methyl-2-butene (25 mg, 0.16
mmol). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.68 (s, 3H), 1.81
(s, 3H), 2.12-2.23 (m, 3H), 2.26-2.42 (m, 1H), 2.55-2.70 (m, 2H),
2.78 (t, J=6.6 Hz, 2H), 3.10-3.45 (m, 6H), 3.63-3.77 (m, 2H),
5.42-5.55 (br, 1H), 6.99 (s, 1H), 7.03 (s, 1H), 7.24-7.217.29 (m,
2H), 7.47 (d, J=1.8 Hz, 1H) ppm. MS (CI, NH.sub.3): 427.1 (base,
M+H).
Example 392
[3710]
(7aS,11aR)-10-(cyclobutylmethyl)-2-(2,3-dichlorophenyl)-5,6,7a,8,9,-
10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3711] The title compound was prepared by the method of Example 382
as a yellow oil (22 mg, 58%) from
(7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9-
,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
(32 mg, 0.089 mmol) and (bromomethyl)cyclobutane (27 mg, 0.18
mmol). MS (CI, NH.sub.3): 427.1 (base, M+H).
Example 393
[3712]
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-methyl-5,6,7a-
,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
The solution of
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a-
,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
(30 mg, 0.077 mmol) in formaldehyde (37 wt % aqueous solution, 97
mg, 1.16 mmol) and formic acid (54 mg, 1.16 mmol) was heated at
80.degree. C. for 2 h. The reaction mixture was diluted with
H.sub.2O then basified with 1N NaOH to pH 12 and extract with
CHCl.sub.3. The combined organic solution was dried over
MgSO.sub.4, concentrated in vacuo, and the residue was
chromatographed (silica gel; CHCl.sub.3: MeOH 99:1-95:5) to give
the title compound as a pale yellow oil (19 mg, 61%). MS (CI,
NH.sub.3): 403.1 (base, M+H).
Example 394
[3713]
(7aS,11aR)-10-ethyl-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,-
8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
To a solution of
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8-
,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
(30 mg, 0.077 mmol) in acetic acid (0.28 mL) was added NaBH.sub.4
(30 mg, 0.80 mmol) in 2 portion in 10 min interval at 55.degree. C.
The reaction mixture was stirred for 15 h at 55.degree. C. then
quenched by addition of H.sub.2O. The aqueous solution was basified
with 50% NaOH then extracted with CHCl.sub.3. The combined organic
solution was dried over MgSO.sub.4, concentrated in vacuo. The
residue was chromatographed (silica gel; CHCl.sub.3: MeOH
99:1-98:2) to give the title compound as a yellow oil (26 mg, 81%).
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.21-1.35 (m, 3H),
2.05-2.30 (m, 5H), 2.53-2.78 (m, 6H), 2.98-3.07 (br, 1H), 3.08-3.18
(br, 1H), 3.27-3.42 (m, 2H), 3.43-3.57 (br, 1H), 3.88 (s, 3H), 6.83
(s, 1H), 6.86 (s, 1H), 7.04 (dd, J=8.8, 2.9 Hz, 1H), 7.20-7.26 (m,
2H) ppm. MS (CI, NH.sub.3): 417.1 (base, M+H).
Example 395
[3714]
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-propyl-5,6,7a-
,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3715] The title compound was prepared by the method of Example
382as a yellow oil (23 mg, 69%) from
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)p-
henyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij-
]quinoline (30 mg, 0.077 mmol) and 1-bromopropane (20 mg, 0.15
mmol). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.0.98 (t, J=7.3 Hz,
3H), 1.78-1.92 (br, 2H), 2.11-2.25 (m, 5H), 2.28-2.42 (m, 1H),
2.53-2.80 (m, 5H), 3.05-3.25 (br, 2H), 3.31 (dt, J=10.2, 3.6 Hz,
1H), 3.37-3.45 (br, 1H), 3.60-3.72 (br, 1H), 3.89 (s, 3H), 6.85 (s,
1H), 6.87 (s, 1H), 7.05 (dd, J=8.7, 2.6 Hz, 1H), 7.21-7.27 (m, 2H)
ppm. MS (CI, NH.sub.3): 431.2 (base, M+H).
Example 396
[3716]
(7aS,11aR)-10-butyl-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-meth-
yl-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]qui-
noline
[3717] The title compound was prepared by the method of Example 382
as a yellow oil (23 mg, 67%) from
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)p-
henyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij-
]quinoline (30 mg, 0.077 mmol) and 1-bromobutane (21 mg, 0.15
mmol). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.0.93 (t, J=7.3 Hz,
3H), 1.34 (se, J=7.3 Hz, 2H), 1.65-1.77 (br, 2H), 2.05-2.23 (m,
5H), 2.25-2.38 (br, 1H), 2.55-2.77 (m, 3H), 2.95-3.15 (br, 2H),
3.30 (dt, J=10.2, 3.7 Hz, 1H), 3.32-3.40 (br, 1H), 3.42-3.55 (br,
1H), 3.86 (s, 3H), 6.82 (s, 1H), 6.85 (s, 1H), 7.03 (dd, J=8.8, 2.6
Hz, 1H), 7.20-7.25 (m, 2H) ppm. MS (CI, NH.sub.3): 445.2 (base,
M+H).
Example 397
[3718]
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-(4-pentenyl)--
5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinol-
ine
[3719] The title compound was prepared by the method of Example 382
as a yellow oil (22 mg, 63%) from
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)p-
henyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij-
]quinoline (30 mg, 0.077 mmol) and 5-bromo-1-pentene (23 mg, 0.15
mmol). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.68-1.79 (m, 2H) ,
2.01-2.26 (m, 7H), 2.43-2.62 (m, 4H), 2.71 (t, J=6.3 Hz, 2H),
2.83-2.92 (br, 1H), 2.95-3.07 (br, 1H), 3.27-3.44 (m, 3H), 3.86 (s,
3H), 4.93-5.05 (m, 2H), 5.70-5.85 (m, 1H), 6.80 (s, 1H), 6.84 (s,
1H), 7.02 (dd, J=8.1, 2.6 Hz, 1H), 7.18-7.24 (m, 2H) ppm. MS (CI,
NH.sub.3): 457.2 (base, M+H).
Example 398
[3720]
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-10-(3-methyl-2-b-
utenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-i-
j]quinoline
[3721] The title compound was prepared by the method of Example 382
as a yellow oil (25 mg, 71%) from
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)p-
henyl]-5,6,7a,8,9,10,11,a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]q-
uinoline (30 mg, 0.077 mmol) and 4-bromo-2-methyl-2-butene (23 mg,
0.15 mmol). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.65 (s, 3H),
1.79 (s, 3H), 2.12-2.22 (m, 3H), 2.24-2.40 (m, 1H), 2.57 (se, J=7.7
Hz, 2H), 2.72 (t, J=6.6 Hz, 2H), 2.74-2.84 (br, 1H), 3.05-3.45 (m,
6H), 3.59-3.77 (m, 1H), 3.86 (s, 3H), 5.42-5.55 (br, 1H), 6.83 (s,
1H), 6.85 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 7.17-7.25 (m, 2H) ppm.
MS (CI, NH.sub.3): 457.2 (base, M+H).
Example 399
[3722]
(7aS,11aR)-10-(2-fluoroethyl)-2-[4-methoxy-2-(trifluoromethyl)pheny-
l]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]qui-
noline
[3723] The title compound was prepared by the method of Example 382
as a yellow oil (32 mg, 96%) from
(7aS,11aR)-2[-4-methoxy-2-(trifluoromethyl)p-
henyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij-
]quinoline (30 mg, 0.077 mmol) and 1-bromo-2-fluoroethane (30 mg,
0.23 mmol). MS (CI, NH.sub.3): 435.1 (base, M+H).
Example 400
[3724]
(7aS,11aR)-10-(2,2-difluoroethyl)-2-[4-methoxy-2-(trifluoromethyl)p-
henyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij-
]quinoline
[3725] The title compound was prepared by the method of Example 382
as a yellow oil (27 mg, 77%) from
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)p-
henyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij-
]quinoline (30 mg, 0.077 mmol) and 2-bromo-1,1-difluoroethane (35
mg, 0.23 mmol). MS (CI, NH.sub.3): 453.1 (base, M+H).
Example 401
[3726]
(7aS,11aR)-10-(cyclobutylmethyl)-2-[4-methoxy-2-(trifluoromethyl)ph-
enyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]-
quinoline
[3727] The title compound was prepared by the method of Example 382
as a yellow oil (32 mg, 96%) from
(7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)p- henyl]
-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-i-
j]quinoline (30 mg, 0.077 mmol) and 1-bromo-2-fluoroethane (30 mg,
0.23 mmol). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.70-1.82 (m,
4H), 1.85-1.98 (m, 1H), 2.02-2.30 (m, 7H), 2.53-2.63 (m, 1H),
2.68-2.88 (m, 5H), 2.92-3.15 (br, 2H), 3.25-3.38 (m, 2H), 3.52-3.62
(br, 1H), 3.87 (s, 3H), 6.82 (s, 1H), 6.84 (s, 1H), 7.03 (dd,
J=8.5, 2.5 Hz, 1H), 7.20-7.25 (m, 2H) ppm. MS (CI, NH.sub.3): 457.2
(base, M+H) .MS (CI, NH.sub.3): 457.2 (base, M+H).
Example 402
[3728]
4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(4-fluorophenyl)-1-butanone To a
solution of
(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinoline (0.21 g, 1.0 mmol)) in 1,4-dioxane (7.0 mL) were
added 4-chloro-4'-fluorobutyrophenone (0.40 g, 2.0 mmol), KI
(catalytic amount) and K.sub.2CO.sub.3 (0.28 g, 2.0 mmol). The
reaction mixture was heated at 100.degree. C. for 48 h. The
reaction mixture was cooled to 20.degree. C. then diluted with
CHCl.sub.3. The solution was filtered to remove excess
K.sub.2CO.sub.3 and the filtrate was concentrated in vacuo and
chromatographed (silica gel, CHCl.sub.3: MeOH 98:2) to give the
title compound (0.22 g, 58%) as a white amorphous solid. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta.1.75-2.20 (m, 7H), 2.20-2.35 (m,
1H), 2.35-2.48 (m, 2H), 2.48-2.60 (m, 1H), 2.60-2.78 (m, 3H),
2.78-2.90 (m, 1H), 2.99 (t, J=7.2 Hz, 2H), 3.05-3.15 (m, 1H),
3.18-3.32 (m, 2H), 6.62 (t, J=7.3 Hz, 1H), 6.86 (d, J=7.3 Hz, 1H),
7.12 (t, J=8.6 Hz, 2H), 7.90-8.08 (m, 2H) ppm.
Example 403
[3729]
4-((7aR,11aS)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(4-fluorophenyl)-1-butanone The
title compound (0.16 g, 42%) was prepared by the general method of
Example 402 from
(7aR,11aS)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrol-
o[3,2,1-ij]quinoline (0.21 g, 1.0 mmol),
4-chloro-4'-fluorobutyrophenone (0.40 g, 2.0 mmol), KI (catalytic)
and K.sub.2CO.sub.3 (0.28 g, 2.0 nmol) after chromatographic
purification as a white amorphous solid. The .sup.1H NMR was
identical to that of Example 402, 4-((7aS,11aR)-5,6,8,9,1-
1,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)--
1-(4-fluorophenyl)-1-butanone
Example 404
[3730]
4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(2-aminophenyl)-1-butanone
[3731] The title compound (0.031 g, 16%) was prepared by the
general method of Example 402 from
(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-p-
yrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline (0.11 g, 0.50 mmol),
4-chloro-2'-aminobutyrophenone (0.20 g, 1.0 mmol), KI (catalytic)
and K.sub.2CO.sub.3 (0.14 g, 1.0 mmol) after chromatographic
purification as a white amorphous solid. .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta.1.80-2.20 (m, 7H), 2.20-2.60 (m, 3H), 2.82-2.95 (m,
1H), 2.98 (t, J=7.4 Hz, 2H), 3.05-3.20 (m, 2H), 3.20-3.38 (m, 2H),
3.64 (t, J=6.6 Hz, 1H), 3.68-3.80 (m, 1H), 3.81 (t, J=6.0 Hz, 1H),
6.26 (br, 2H), 6.58-6.68 (m, 2H), 6.80-6.92 (m, 2H), 7.10-7.30 (m,
2H), 7.52-7.72 (m, 1H), 7.77 (dd, J=1.3, 8.4 Hz, 1H), 8.09 (td,
J=1.6, 8.4 Hz, 1H) ppm.
Example 405
[3732]
4-((7aR,11aS)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(2-aminophenyl)-1-butanone
[3733] The title compound (0.080 g, 42%) was prepared by the
general method of Example 402 from
(7aR,11aS)-5,6,7a,8,9,10,11,11a-octahydro-4H-p-
yrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline (0.11 g, 0.50 mmol),
4-chloro-2'-aminobutyrophenone (0.20 g, 1.0 mmol), KI (catalytic)
and K.sub.2CO.sub.3 (0.14 g, 1.0 mmol) after chromatographic
purification as a white amorphous solid. The .sup.1H NMR was
identical to that of Example 404,
4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3-
,2,1-ij]quinolin-10(7aH)-yl)-1-(2-aminophenyl)-1-butanone
Example 406
[3734]
(.+-.)-cis-3-(5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)propyl 4-fluorophenyl ether
[3735] The title compound (0.14 g, 32%) was prepared by the general
method of Example 402 from
(.+-.)-cis-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3-
',4':4,5]pyrrolo[3,2,1-ij]quinoline (0.25 g, 1.2 mmol),
1-(3-chloropropoxy)-4-fluorobezene (0.37 g, 2.0 mmol), KI
(catalytic) and K.sub.2CO.sub.3 (0.28 g, 2.0 mmol) after
chromatographic purification as a white amorphous solid. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta.1.78-2.08 (m, 7H), 2.10-2.30 (m,
1H), 2.32-2.50 (m, 3H), 2.51-2.72 (m, 3H), 2.75-2.82 (m, 1H),
3.00-3.12 (m, 1H), 3.12-3.25 (m, 2H), 3.89 (t, J=6.3 Hz, 2H), 6.55
(t, J=7.5 Hz, 1H), 6.70-6.92 (m, 6H) ppm.
Example 407
[3736]
4-((.+-.)-cis-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(4-pyridinyl)-1-butanone
[3737] The title compound (0.080 g, 18%) was prepared by the
general method of Example 402 from
(.+-.)-cis-5,6,7a,8,9,10,11,11a-octahydro-4H-p-
yrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline (0.25 g, 1.2 mmol),
4-chloro-1-(4-pyridinyl)-1-butanone (0.36 g, 2.0 mmol), KI
(catalytic) and K.sub.2CO.sub.3 (0.28 g, 2.0 mmol) after
chromatographic purification as a white amorphous solid. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta.1.68-2.18 (m, 7H), 2.20-2.65 (m,
5H), 2.69 (t, J=6.4 Hz, 2H), 2.72-2.82 (m, 1H), 2.92-3.08, (m, 3H),
3.15-3.28 (m, 2H), 6.62 (t, J-7.5 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H),
6.89 (d, J=7.4 Hz, 1H), 7.70-7.80 (m, 2H), 8.75-8.82 (m, 2H)
ppm.
Example 408
[3738]
(.+-.)-cis-10-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-5,6,7a,8,9-
,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3739] The title compound (0.15 g, 32%) was prepared by the general
method of Example 402 from
(.+-.)-cis-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3-
',4':4,5]pyrrolo[3,2,1-ij]quinoline (0.25 g, 1.2 mmol),
3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole (0.43 g, 2.0 mmol),
KI (catalytic) and K.sub.2CO.sub.3 (0.28 g, 2.0 mmol) after
chromatographic purification as a white amorphous solid. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta.1.80-2.18 (m, 7H), 2.25 (td,
J=11.5, 3.0 Hz, 1H), 2.35-2.68 (m, 4H), 2.70 (t, J=6.6 Hz, 2H),
2.75-2.88 (m, 1H), 3.01 (t, J=7.6 Hz, 2H), 3.05-3.15 (m, 1H),
3.20-3.30 (m, 2H), 6.62 (t, J=7.5 Hz, 1H), 6.86 (d, J=7.5 Hz, 1H),
6.92 (d, J=7.5 Hz, 1H), 7.06 (td, J=9.0, 2.1 Hz, 1H), 7.20-7.26 (m,
1H), 7.61 (dd, J=4.8, 8.7 Hz, 1H) ppm.
Example 409
[3740]
(7aS,11aR)-10-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-5,6,7a,8,9-
,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3741] The title compound (0.31 g, 75%) was prepared by the general
method of Example 402 from
(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3-
',4':4,5]pyrrolo[3,2,1-ij]quinoline (0.21 g, 1.0 mmol),
3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole (0.43 g, 2.0 mmol),
KI (catalytic) and K.sub.2CO.sub.3 (0.28 g, 2.0 mmol) after
chromatographic purification as a white amorphous solid. The
.sup.1H NMR was identical to that of Example 408,
(.+-.)-cis-10-[3-(6-fluoro-1,2-benzisoxazol-3-yl)pro-
pyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]q-
uinoline
Example 410
[3742]
1-(4-fluorophenyl)-4-(5,6,8,11-tetrahydro-4H-pyrido[3',4':4,5]pyrro-
lo[3,2,1-ij]quinolin-10(9H)-yl)-1-butanone
[3743] The title compound (0.060 g, 28%) was prepared by the
general method of Example 402 from
5,6,8,11-tetrahydro-4H-pyrido[3',4':4,5]pyrrol-
o[3,2,1-ij]quinoline (0.12 g, 0.57 mmol),
4-chloro-4'-fluorobutyrophenone (0.40 g, 2.0 mmol), KI (catalytic)
and K.sub.2CO.sub.3 (0.28 g, 2.0 mmol) after chromatographic
purification as a white amorphous solid. .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta.1.80-2.15 (m, 2H), 2.15-2.30 (m, 2H), 2.71 (t,
J=7.0 Hz, 2H), 2.82 (d, J=5.1 Hz, 2H), 2.90 (t, J=5.8 Hz, 2H), 2.97
(t, J=6.1 Hz, 2H), 3.02-3.20 (m, 2H), 3.73 (s, 2H), 3.98 (t, J=5.7
Hz, 2H), 6.84 (d, J=6.9 Hz, 1H), 6.97 (t, J=7.5 Hz, 1H), 7.02-7.20
(m, 2H), 7.25 (d, J=7.7 Hz, 1H), 7.20-7.25 (m, 1H), 7.95-8.20 (m,
2H) ppm.
Example 411
[3744]
(.+-.)-cis-4-(4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[-
4,3-b]indol-l1(8aH)-yl)-1-(4-fluorophenyl)-1-butanone
[3745] The title compound (0.17 g, 74%) was prepared by the general
method of Example 402 from
(.+-.)-cis-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino-
[3,2,1-hi]pyrido[4,3-b]indole (0.14 g, 0.59 mmol),
4-chloro-4'-fluorobutyr- ophenone (0.20 g, 1.0 mmol), KI
(catalytic) and K.sub.2CO.sub.3 (0.14 g, 1.0 mmol) after
chromatographic purification as a white amorphous solid. .sup.1H
NMR (CDCl.sub.3, 300 MHz) -1.42-1.62 (m, 1H), 1.62-1.80 (m, 1H),
1.88-2.22 (m, 7H), 2.40-2.70 (m, 5H), 2.80-3.12 (m, 5H), 3.12-3.30
(m, 2H), 3.32-3.50 (m, 1H), 6.69 (t, J=7.5 Hz, 1H), 6.80-7.00 (m,
2H), 7.05-7.20 (m, 2H), 7.90-8.03 (m, 2H) ppm.
Example 412
[3746]
4-((8aS,12aR)-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[-
4,3-b]indol-11(8aH)-yl)-1-(4-fluorophenyl)-1-butanone
[3747] The title compound was prepared by preparative HPLC
separation of
(.+-.)-cis-4-(4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]-
indol-11(8aH)-yl)-1-(4-fluorophenyl)-1-butanone on a CHIRALPAK.RTM.
AD column (CH.sub.3CN/Ethanol/DEA=85/15/0.05).
Example 413
[3748]
4-((8aR,12aS)-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[-
4,3-b]indol-11(8aH)-yl)-1-(4-fluorophenyl)-1-butanone
[3749] The title compound was prepared by preparative HPLC
separation of
(.+-.)-cis-4-(4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]-
indol-11(8aH)-yl)-1-(4-fluorophenyl)-1-butanone on a CHIRALPAK.RTM.
AD column (CH.sub.3CN/Ethanol/DEA=85/15/0.05).
Example 414
[3750]
4-((.+-.)-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3--
b]indol-11(8aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone
[3751] The title compound (0.16 g, 67%) was prepared by the general
method of Example 402 from
(.+-.)-cis-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino-
[3,2,1-hi]pyrido[4,3-b]indole (0.14 g, 0.59 mmol),
4-chloro-2'-amino-4'-fl- uorobutyrophenone (0.22 g, 1.0 mmol), KI
(catalytic) and K.sub.2CO.sub.3 (0.14 g, 1.0 mmol) after
chromatographic purification as a white amorphous solid. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta.1.45-1.62 (m, 2H), 1.62-2.10 (m,
8H), 2.20-2.52 (m, 4H), 2.52-2.72 (m, 2H), 2.72-2.84 (m, 1H),
2.84-3.00 (m, 2H), 3.12-3.30 (m, 3H), 6.20-6.60 (m, 4H), 6.67 (t,
J=7.3 Hz, 1H), 6.91 (t, J=7.7 Hz, 2H), 7.77 (dd, J=6.4, 9.0 Hz, 1H)
ppm.
Example 415
[3752]
4-((.+-.)-cis-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone
[3753] The title compound was prepared by the method of Example 402
as a red oil (99 mg, 54%) from
(.+-.)-cis-5,6,7a,8,9,10,11,11a-octahydro-4H-py-
rido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline (100 mg, 0.47 mmol) and
1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone (152 mg, 0.70 mmol).
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.95-2.15 (m, 7H),
2.37-2.57 (m, 5H), 2.67-2.85 (m, 3H), 2.90-3.05 (m, 3H), 3.24-3.33
(m, 2H), 6.27-6.39 (m, 2H), 6.41-6.50 (br, 2H), 6.64 (t, J=7.3 Hz,
1H), 6.85-6.94 (m, 2H), 7.77 (dd, J=9.2, 6.6 Hz, 1H) ppm.
Example 416
[3754]
4-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone
[3755] The title compound was prepared by the method of Example 402
as a yellow oil (35 mg, 20%) from
(7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline (100 mg, 0.47 mmol)
and 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone (202 mg, 0.93
mmol). The title compound was spectroscopically identical to
Example 415.
Example 417
[3756]
4-((7aR,11aS)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[-
3,2,1-ij]quinolin-10(7aH)-yl)-1-(2-amino-4-fluorophenyl)-1-butanone
[3757] The title compound was prepared by the method of Example 402
as a yellow oil (95 mg, 34%) from
(7aR,11aS)-5,6,7a,8,9,10,11,11a-octahydro-4H-
-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline (150 mg, 0.70 mmol)
and 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone (303 mg, 1.40
mmol). The title compound was spectroscopically identical to
Example 415.
Example 418
[3758]
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]pyrrolo[3,2,1-ij]q-
uinoline To a solution of 3,4-dihydro-1(2H)-quinolinamine (1.0 g,
14 mmol) and hexahydro-4H-azepin-4-one hydrochloride (1.0 g, 14
mmol) in EtOH (13 mL) was added concentrated HCl (1.2 mL). The
reaction was stirred at reflux for 14 h, then cooled to 20.degree.
C. A brown precipitate was filtered from the reaction mixture,
affording the title compound (800 mg, 45%) as a brown solid.
.sup.1H NMR (CD.sub.3OD, 300 MHz) .delta.2.14-2.23 (m, 2H), 2.91
(t, 2H, J=6.0 Hz), 3.16-3.21 (m, 2H), 3.27-3.33 (m, 2H), 3.39-3.50
(m, 4H), 4.04 (t, 2H, J=5.7 Hz), 6.70 (d, 1H, J=6.9 Hz), 6.87-6.93
(m, 1H), 7.22 (d, 1H, J=8.0 Hz) ppm. MS (ESI): 227.2 (base,
M+H).
Example 419
[3759]
(.+-.)-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':4,5]pyrr-
olo[3,2,1-ij]quinoline
[3760] Step A:
[3761] To a solution of
5,6,9,10,11,12-hexahydro-4H,8H-azepino[4',5':4,5]p-
yrrolo[3,2,1-ij]quinoline (150 mg, 0.65 mmol) in TFA (7.5 mL) was
added NaCNBH.sub.3 (123 mg, 1.95 mmol) in small portions at
0.degree. C. The reaction mixture was stirred for 1 h. To the
reaction mixture was added concentrated HCl (5 mL) and the reaction
was heated at reflux for 10 m. The reaction mixture was
concentrated in vacuo and basified to pH 14 with 50% NaOH. To this
was added 1,4-dioxane (14 mL), and to this solution was added
di-tert-butyl dicarbonate (700 mg, 3.2 mmol). The solution was
stirred at 20.degree. C. for 16 h. Purification by column
chromatography (hexanes:EtOAc 19:1) afforded tert-butyl
(.+-.)-5,6,8,9,10,11,12,12a-octa-
hydro-4H,7aH-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate
as a colorless oil.
[3762] Step B:
[3763] To a solution of tert-butyl
(.+-.)-5,6,8,9,10,11,12,12a-octahydro-4-
H,7aH-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate
in CH.sub.2Cl.sub.2 (2.4 mL) was added TFA (0.6 mL). This was
stirred at 20.degree. C., for 3 h. The reaction mixture was diluted
with CH.sub.2Cl.sub.2 (50 mL) and washed with saturated NaHCO.sub.3
(50 mL) and brine (50 mL), dried over MgSO.sub.4 and concentrated
in vacuo to afford the title compound as a yellow oil (87 mg, 59%).
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.77-2.13 (m, 7H),
2.56-2.79 (m, 5H), 2.83-2.93 (m, 1H), 3.00-3.16 (m, 2H), 3.33-3.41
(td, 1H, J=3.7, 9.2 Hz), 3.60 (td, 1H, J=4.4, 9.1 Hz), 6.50 (t, 1H,
J=7.3 Hz), 6.76 (t, 2H, 8.0 Hz) ppm.
Example 420
[3764]
4-[(.+-.)-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':4,5]p-
yrrolo [3,2,1-ij]quinolin-10-yl]-1-(4-fluorophenyl)-1-butanone
[3765] The title compound was isolated as a yellow oil (55 mg, 37%)
according to the method of Example 402 from
(.+-.)-5,6,8,9,10,11,12,12a-o-
ctahydro-4H,7aH-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (87
mg, 0.38 mmol) and 4-chloro-1-(4-fluorophenyl)-1-butanone (153 mg,
0.76 mmol). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.2.04-2.36 (m,
6H), 2.65-2.89 (m, 6H), 2.93-3.39 (m, 8H), 3.50-3.59 (m, 1H),
3.71-3.80 (m, 1H), 6.65 (t, 1H, J=7.3 Hz), 6.87 (t, 2H, J=6.9 Hz),
7.09-7.17 (m, 2H), 7.94-8.01 (m, 2H) ppm.
Example 421
[3766]
4-[(.+-.)-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4',5':4,5]p-
yrrolo
[3,2,1-ij]quinolin-10-yl]-1-(2-amino-4-fluorophenyl)-1-butanone
[3767] The title compound was isolated as a yellow oil (23 mg, 12%)
according to the method of Example 402 from
(.+-.)-5,6,8,9,10,11,12,12a-o-
ctahydro-4H,7aH-azepino[4',5':4,5]pyrrolo[3,2,1-ij]quinoline (111
mg, 0.49 mmol) and 4-chloro-1-(2-amino-4-fluorophenyl)-1-butanone
(210 mg, 0.97 mmol). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.1.98-2.11 (m, 5H), 2.38-2.57 (m, 2H), 2.60-2.69 (m, 3H),
2.71-3.13 (m, 10H), 3.39-3.47 (m, 1H), 3.63-3.70 (m, 1H), 6.20-6.41
(m, 4H), 6.56 (t, 1H, J=7.3 Hz), 6.79 (d, 2H, 7.7 Hz), 7.63-7.69
(m, 1H) ppm.
Example 422
[3768] 4,5,6,9,10,11,12,13-octahydro-9H-diazepino[4,5-b:3,2,1-hi]
indole
[3769] The title compound was prepared as a brown solid (287 mg,
65%) according to the method of Example 418 from
2,3,4,5-tetrahydro-1H-1-benza- zepin-1-amine (300 mg, 1.85 mmol)
and hexahydro-4H-azepin-4-one hydrochloride (277 mg, 1.85 mmol).
.sup.1H NMR (CD.sub.3OD, 300 MHz) .delta.1.99-2.16 (m, 4H),
3.04-3.12 (m, 5H), 3.16-3.21 (m, 2), 3.32-3.41 (m, 3H), 4.09-4.15
(m, 2H), 6.80-6.91 (m, 2H), 7.22 (d, 1H, J=6.9 Hz) ppm.
Example 423
[3770]
(.+-.)-4,5,6,7,9,10,11,12,13,13a-decahydro-8aH-diazepino[4,5-b:3,2,-
1-hi] indole
[3771] The title compound was isolated as a yellow oil (38 mg, 25%)
according to the procedure of Example 419, Steps A and B from
4,5,6,9,10,11,12,13-octahydro-9H-diazepino[4,5-b:3,2,1-hi]indole
(152 mg, 0.63 mmol). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.1.37-1.55 (m, 1H), 1.64-1.80 (m, 1H), 1.85-2.09 (m, 4H),
2.11-2.23 (m, 2H), 2.56-2.97 (m, 6H), 3.12-3.23 (m, 2H), 3.57-3.71
(m, 2H), 6.68 (t, 1H, J=7.4 Hz), 6.87-6.91 (m, 2H) ppm.
Example 424
[3772]
4-[(.+-.)-4,5,6,7,9,10,11,12,13,13a-decahydro-11H-diazepino[4,5-b:3-
,2,1-hi] indol-11-yl]-1-(4-fluorophenyl)-1-butanone
[3773] The title compound was isolated as a yellow oil (20 mg, 60%)
according to the method of Example 402 from
(.+-.)-4,5,6,7,9,10,11,12,13,-
13a-decahydro-8aH-diazepino[4,5-b:3,2,1-hi]indole (20 mg, 0.08
mmol) and 4-chloro-1-(4-fluorophenyl)-1-butanone (32 mg, 0.16
mmol). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.37-1.45 (m, 1H),
1.59-1.77 (m, 1H), 1.91-2.04 (m, 6H), 2.13-2.22 (m, 2H), 2.55-2.71
(m, 6H), 2.85-3.19 (m, 6H), 3.53-3.67 (m, 2H), 6.68 (t, 1H, J=7.3
Hz), 6.88 (d, 2H, J=7.3 Hz), 7.08-7.16 (m, 2H), 7.97-8.03 (m, 2H)
ppm.
Example 425
[3774]
4-[(.+-.)-4,5,6,7,9,10,11,12,13,13a-decahydro-11H-diazepino[4,5-b:3-
,2,1-hi] indol-11-yl]-1-(2-amino-4-fluorophenyl)-1-butanone
[3775] The title compound was isolated as a yellow oil (23 mg, 66%)
according to the method of Example 402 from
(.+-.)-4,5,6,7,9,10,11,12,13,-
13a-decahydro-8aH-diazepino[4,5-b:3,2,1-hi]indole (20 mg, 0.08
mmol) and 4-chloro-1-(2-amino-4-fluorophenyl)-1-butanone (53 mg,
0..25 mmol). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.1.30-1.43 (m,
1H), 1.53-1.64 (m, 1H), 1.88-2.01 (m, 6H), 2.10-2.22 (m, 2H),
2.50-2.70 (m, 6H), 2.70-3.09 (m, 6H), 3.26-3.44 (m, 2H), 6.20-6.30
(m, 2H), 6.36 (br, 2H), 6.62 (t, 1H, J=7.4 Hz), 6.79-6.85 (m, 2H),
7.65-7.70 (m, 1H) ppm.
Example 426
[3776]
(.+-.)-cis-6,7,8a,9,10,11,12,12a-octahydroazepino[3,2,1-hi]pyrido[4-
,3-b]indol-4(5H)-one
[3777] Step A:
[3778] To a stirred solution of 1M BCl.sub.3 in toluene (8.8 mL,
8.8 mmol) was added ethyl
(.+-.)-cis-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-
-2-carboxylate (984 mg, 4.0 mmol) in benzene (32 mL) at 0C. To the
above solution was added 4-chlorobutanenitrile(0.39 mL, 4.4mmol),
and AlCl.sub.3 (587 mg, 4.4 mmol), the reaction mixture was stirred
at r.t.. for 10 min., then was heated in a sealed tube for 18 h.
After cooled down to r.t., was added 5N HCl (32mL) and heated at
80.degree. C. for 30 min. The reaction mixture was neutralized by
50% NaOH at 0C., adjusted pH=14, extracted with CH.sub.2Cl.sub.2
(200mL), the organic layer was dried over MgSO.sub.4, and
concentrated in vacuo to afford after chromatographic purification
ethyl (.+-.)-cis-6-(4-chlorobutanoyl)-1,3,4,4a,5,9b-hexahydr-
o-2H-pyrido[4,3-b]indole-2-carboxylate (413 mg, 30%).
[3779] Step B:
[3780] To ethyl
(.+-.)-cis-6-(4-chlorobutanoyl)-1,3,4,4a,5,9b-hexahydro-2H-
-pyrido[4,3-b]indole-2-carboxylate (100 mg, 0.29 mmol) in butanol
(3 mL) was added KOH(50 mg) and heated at 109.degree. C. for 5 hr..
After cooled down to r.t., KOH(50 mg) and KI(20 mg) were added. The
reaction mixture was heated at 109.degree. C. in a sealed tube for
18 h. The reaction mixture was cooled down to r.t., extracted with
CH.sub.2Cl.sub.2, dried over MgSO.sub.4 to afford
(.+-.)-cis-6,7,8a,9,10,11,12,12a-octahydroazepi-
no[3,2,1-hi]pyrido[4,3-b]indol-4(5H)-one (69 mg, 99%).
[3781] Step C:
[3782] To
(.+-.)-cis-6,7,8a,9,10,11,12,12a-octahydroazepino[3,2,1-hi]pyrid-
o[4,3-b] indol-4(5H)-one (61 mg, 0.25 mmol) in dioxane(1 mL) and 1N
NaOH (1 mL) was added Boc.sub.2O (60 mg, 0.27mmol), stirred at r.t.
for 18 h. After extracted with CH.sub.2Cl.sub.2, dried over
MgSO.sub.4, concentrated in vacuo to afford tert-butyl
(.+-.)-cis-4-oxo-4,5,6,7,9,10,-
12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
(40 mg, 47%).
[3783] Step D:
[3784] The title compound was prepared by the method of Example 98
from tert-butyl
(.+-.)-cis-4-oxo-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi-
]pyrido[4,3-b]indole-11(8aH)-carboxylate to afford the title
compound (25 mg, 88%). .sup.1H NMR (CD.sub.3OD, 300 MHz)
.delta.7.86-7.89(m, 1H), 7.34(d, 1H, 6.9Hz), 6.73-6.78(m, 1H),
4.02-4.04(m, 1H), 3.37-3.39(m, 2H), 3.20-3.27(m, 2H), 2.82-2.92(m,
1H), 2.74-2.80(m, 1H), 2.10-2.14(m, 2H), 0.94-1.07(m, 5H) ppm.
MS-ESI: 243 [MH]+.
Example 427
[3785] tert-butyl
(.+-.)-cis-2-bromo-4-oxo-4,5,6,7,9,10,12,12a-octahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
[3786] The title compound was prepared by the method of Example 89
step B from tert-butyl
(.+-.)-cis-4-oxo-4,5,6,7,9,10,12,12a-octahydroazepino[3,2-
,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (88 mg, 0.26 mmol) to
afford the title compound (110 mg, 100%).
Example 428
[3787] tert-butyl (.+-.)
-cis-2-(2,4-dichlorophenyl)-4-oxo-4,5,6,7,9,10,12-
,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate
[3788] The title compound was prepared by the method of Example 89
step C from tert-butyl
(.+-.)-cis-2-bromo-4-oxo-4,5,6,7,9,10,12,12a-octahydroaze-
pino[3,2,1,-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (110 mg,
0.26 mmol) and corresponding 2,4-dichlorophenylboronic acid (60 mg,
0.31 mmol) to afford after chromatographic purification the title
compound (70 mg, 55%).
Example 429
[3789] (.+-.)
-cis-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydroa-
zepino[3,2,1-hi]pyrido[4,3-b]indol-4(5H)-one
[3790] The title compound was prepared by the method of Example 98
from tert-butyl
(.+-.)-cis-2-(2,4-dichlorophenyl)-4-oxo-4,5,6,7,9,10,12,12a-oc-
tahydroazepino[3,2,1-hi]pyrido[4,3-b] indole-11(8aH)-carboxylate to
afford the title compound (50 mg, 90%). .sup.1H NMR (CD.sub.3OD,
300 MHz) .delta.7.78(d, 1H, 1.4Hz), 7.48(d, 1H, 1.9Hz),
7.28-7.32(m, 2H),7.01(s, 1H), 4.06-4.12(m, 1H), 2.59-3.22(m, 6H),
1.71-2.04(m, 3H), 0.95-1.28(m, 4H) ppm. MS-ApCI: 387 [M+H+].
Example 430
[3791]
(8aS,12aR)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydroaz-
epino[3,2,1-hi] pyrido[4,3-b] indol-4(5H)-one The resolution of
2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydroazepino[3,2,1-hi]py-
rido[4,3-b]indol-4(5H)-one was carried out by High Performance
Liquid Chromatography using a chiral column to afford the title
compound.
Example 431
[3792]
(8aR,12aS)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydroaz-
epino[3,2,1,-hi]pyrido[4,3-b]indol-4(5H)-one The resolution of
2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydroazepino[3,2,1-hi]py-
rido[4,3-b]indol-4(5H)-one was carried out by High Performance
Liquid Chromatography using a chiral column to afford the title
compound.
Example 432
[3793]
(8aS,12aR)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indol-4-ol
[3794] To
(8aS,12aR)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydr-
oazepino[3,2,1-hi]pyrido[4,3-b]indol-4(5H)-one (12 mg, 0.03 mmol)
in CH.sub.30H(l mL) at RT was added NaBH.sub.4 (5.4 mg, 0.15 mmol)
in three portions. The reaction mixture was stirred at RT for 2 h 2
drops of 1NHCl were added to the reaction mixture, concentrated in
vacuo. NH.sub.4OH (1 mL) and water (2 mL) were added, extracted
with CH.sub.2Cl.sub.2 (3.times.3 mL). The combined organic layer
was dried over MgSO.sub.4, concentrated to afford the title
compound (8 mg, 69%). MS-ESI: 389 [MH]+.
Example 433
[3795]
(8aR,12aS)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-decahydroaz-
epino[3,2,1-hi]pyrido[4,3-b]indol-4-ol
[3796] The title compound was prepared by the method of Example 432
from
(8aR,12aS)-2-(2,4-dichlorophenyl)-6,7,8a,9,10,11,12,12a-octahydroazepino[-
3,2,1-hi]pyrido[4,3-b]indol-4(5H)-one (14 mg, 0.04 mmol) to afford
the title compound (12 mg, 86%). MS-ESI: 389 [MH]+.
Example 434
[3797]
(.+-.)-cis-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[3',4':4,5]-
pyrrolo[3,2,1-ij]quinoline
[3798] Step A:
[3799] 3,4-Dihydro-1 (2H)-quinolinamine hydrochloride (5.0 g, 27
mmol) and 1,3-cyclohexanedione (3.1 g, 27 mmol) was mixed in AcOH
(4.3 mL) and H.sub.2O (4.3 mL). The mixture was heated at
40.degree. C. for 10 min until dissolved completely. The mixture
was then concentrated to dryness. The residue was washed with
acetonitrile then filtered to yield
3-(3,4-dihydro-1(2H)-quinolinylimino)-1-cyclohexen-1-ol
hydrochloride (5.2 g, 69%) as a yellow solid.
[3800] Step B:
[3801] 3-(3,4-Dihydro-1(2H)-quinolinylimino)-1-cyclohexen-1-ol
hydrochloride (4.78 g, 17 mmol) was mixed with AcOH (37 mL) and
conc. HCl (6.1 mL). The reaction mixture was refluxed for 1 h and
cooled to RT. The reaction mixture was concentrated in vacuo then
the residue was dissolved in CH.sub.2Cl.sub.2. The organic solution
was washed with H.sub.2O and brine, dried over MgSO.sub.4, filtered
and concentrated in vacuo. The residue was chromatographed in
silica gel (hex:EtOAc 1:1) to give
5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one (1.25 g,
33%) as a light yellow solid.
[3802] Step C:
[3803] To a solution of
5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11- (8H)-one (820
mg, 3.6 mmol) in ethanol (7.5 mL) and H20 (3.6 mL) was added
hydroxylamine hydrochloride (380 mg, 5.5 mmol) and sodium acetate
(452 mg, 5.5 mmol). The reaction mixture was refluxed for 15 h then
cooled to RT.
[3804] The precipitated solid was filtered and washed with
H.sub.2O. The solid was dried under vacuum to give
5,6,9,10-tetrahydro-4H-pyrido[3,2,1-- jk]carbazol-11(8H)-one oxime
(824 mg, 95%) as a gray powder.
[3805] Step D:
[3806] To a preheated polyphosphoric acid (25 g) was added
5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one oxime
(810 mg, 3.3 mmol) in one portion at 110.degree. C. The reaction
mixture was stirred for 30 min at the same temperature then pour
into ice water (100 mL) and triturated to complete the dissolution
of the polyphosphoric acid. After 1 h stirring at 20.degree. C.,
gummy solid was formed, and it was washed with H.sub.2O and
NH.sub.4OH. The solid was crystallized in EtOAc to give
5,6,8,9,10,11-hexahydro-4H,12H-azepino[3',4':4,5]pyrrolo[3,-
2,1-ij]quinolin-12-one (320 mg, 40%) as a yellow solid.
[3807] Step E:
[3808] To a suspension of LiAlH.sub.4 in 1,4-dioxane (26 mL) was
added
5,6,8,9,10,11-hexahydro-4H,12H-azepino[3',4':4,5]pyrrolo[3,2,1-ij]quinoli-
n-12-one (300 mg, 1.25 mmol) under N.sub.2 at 20.degree. C. The
reaction mixture was refluxed for 15 h. The reaction mixture was
cooled in an ice bath and added successively with H.sub.2O (0.3
mL), 15% NaOH (0.3 mL) and H.sub.2O (0,8 mL). The mixture was
stirred for 1 h at 20.degree. C. then filtered. The filtrate was
concentrated in vacuo. The residue was dissolved in dilute AcOH and
washed with Et.sub.2O. The aqueous solution was basified with 1N
NaOH. A white solid was precipitated and filtered to yield
5,6,9,10,11,12-hexahydro-4H,8H-azepino[3',4':4,5]pyrrolo[3,2,1-ij]q-
uinoline (270 mg, 95%).
[3809] Step F:
[3810] To a solution of
5,6,9,10,11,12.-hexahydro-4H,8H-azepino[3',4':4,5]-
pyrrolo[3,2,1-ij]quinoline (240 mg, 1.06 mmol) in TFA (4.0 mL) was
added Et.sub.3SiH (2.0 mL). The mixture was stirred for 3 days then
concentrated in vacuo. The residue was dissolved in dilute AcOH and
washed with Et.sub.2O. The aqueous solution was basified with 1N
NaOH. A white solid was precipitated and filtered to yield the
title compound as a pale yellow viscous oil (200 mg, 83%). MS (CI,
NH.sub.3): 229.4 (base, M+H).
Example 435
[3811] tert-butyl
(.+-.)-cis-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino-
[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-11-carboxylate
[3812] The title compound (114 mg, 99%) was prepared by the method
of Example 311 from
(.+-.)-cis-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino-
[3',4':4,5]pyrrolo[3,2,1-ij]quinoline (80 mg, 0.35 mmol) as a
viscous colorless oil. MS (ESI): 329.4 (base, M+H).
Example 436
[3813] tert-butyl
(.+-.)-cis-2-bromo-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-
-azepino[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-11-carboxylate
[3814] The title compound (120 mg, 81%) was prepared by the method
of Example 314 from tert-butyl
(.+-.)-cis-5,6,8,9,10,11,12,12a-octahydro-4H,-
7aH-azepino[3',4':4,5]pyrrolo[3,2,1-ij]quinoline (114 mg, 0.35
mmol) as a viscous colorless oil.
Example 437
[3815]
(.+-.)-cis-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,8,9,10,11,12-
,12a-octahydro-4H,7aH-azepino[3',4':4,5]pyrrolo[3,2,1-ij]quinoline
[3816] Step A:
[3817] Tert-butyl
(.+-.)-cis-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,8-
,9,10,11,12,12a-octahydro-4H,7aH-azepino[3',4':4,5]pyrrolo[3,2,1-ij]quinol-
ine-11-carboxylate (56 mg, 91%) was prepared by the general method
of Example 319, step A from tert-butyl
(.+-.)-cis-2-bromo-5,6,8,9,10,11,12,1-
2a-octahydro-4H,7aH-azepino[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-11-carbox-
ylate (50 mg, 0.12 mmol) and
4-methoxy-2-2-(trifluoromethyl)phenylboronic acid (54 mg, 0.25
mmol) as a white foam. MS (ESI): 503.6 (base, M+H).
[3818] Step B:
[3819] The title compound (44 mg, 99%) was prepared by the general
method of Example 312, step B from tert-Butyl
(.+-.)-cis-2-[4-methoxy-2-(trifluo-
romethyl)phenyl]-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[3',4':4,5]p-
yrrolo[3,2,1-ij]quinoline-11-carboxylate (54 mg, 0.11 mmol) as a
white foam. MS (CI): 403.4 (base, M+H).
UTILITY
[3820] The compounds of the present invention have therapeutic
utility for illnesses or disorders involving the neurotransmitter
serotonin (5-hydroxy tryptamine or 5-HT) and either agonism or
antagonism of 5-HT2 receptors, as demonstrated by the assays
described below. Therapeutic utility for these illnesses or
disorders could involve numerous biological processes affected by
serotonin including, but not limited to, appetite, mood, sleep,
sexual activity, and arterial constriction. These biological
processes may also be important to numerous central nervous system
(CNS) disorders including those related to the affective disorders
of depression, anxiety, psychosis, and schizophrenia, as well as,
disorders of food intake such as anorexia, bulemia, and obesity.
The compounds of the present invention potentially have therapeutic
utility in other conditions in which serotonin has been implicated,
such as migraine, attention deficit disorder or attention deficit
hyperactivity disorder, addictive behavior, and
obsessive-compulsive disorder, as well as, conditions associated
with cephalic pain, social phobias, and gastrointestinal disorders
such as dysfunction of the gastrointestinal tract motility. Lastly,
compounds of the present invention potentially have therapeutic
utility in neurodegenerative diseases and traumatic conditions
represented by the examples of Alzheimer's disease and brain/spinal
cord trauma.
[3821] The pharmacological analysis of each compound fro either
antagonism or agonism of at 5-HT2A and 5-HT2C receptors consisted
of in vitro and in vivo studies. In vitro analyses included Ki
determinations at 5-HT2A and 5-HT2C receptors and an assessment of
functional (i.e., agonism or antagonism) activity at each receptor
class by IP3 hydrolysis assays. Additional receptor assays were
conducted to evaluate receptor specificity of 5-HT2A and 5-HT2C
receptors over monoamine and nuisance receptors (e.g. histamine,
dopamine, and muscarinic). A compound is considered active as a
5-HT2A antagonist or a 5-HT2C agonist if it has an IC.sub.50 value
or a K.sub.i value of less than about 1 micromolar; preferably less
than about 0.1 micromolar; more preferably less than about 0.01
micromolar. Compounds of the invention have been shown to have an
IC.sub.50 value of less than about 1 micromolar for 5-HT2A
antagonism or a 5-HT2C agonism.
[3822] In vivo assays assessed compound activity in a variety of
behavioral paradigms including quipazine head twitch, acute and
chronic feeding models, anxiety and depression models
(learned-helplessness, elevated plus maze, Geller-Siefter,
conditioned taste aversion, taste reactivity, satiety sequence). In
aggregate, these models reflect activity as a 5-HT2A antagonist
(quipazine head twitch, depression models) or 5-HT2C agonist
(feeding models, anxiety models, depression models) and provide
some indication as to bioavailability, metabolism and
pharmacokinetics.
[3823] Radioligand binding experiments were conducted on
recombinant human 5-HT2A and 5-HT2C receptors expressed in HEK293E
cells. The affinities of compounds of the present invention to bind
at these receptors is determined by their capacity to compete for
[.sup.125I]-1-(2,5-dimethoxy-- 4-iodophenyl)-2-amino-propane (DOI)
binding at the 5-HT2A or 5-HT2C. General references for binding
assays include 1) Lucaites V L, Nelson D L, Wainscott D B, Baez M
(1996) Receptor subtype and density determine the coupling
repertoire of the 5-HT2 receptor subfamily. Life Sci.,
59(13):1081-95. J Med Chem 1988 Jan;31(1-:5-7; 2) Glennon R A,
Seggel M R, Soine W H, Herrick-Davis K, Lyon R A, Titeler M (1988)
[125I]-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane: an iodinated
radioligand that specifically labels the agonist high-affinity
state of 5-HT2 serotonin receptors. J Med. Chem. 31(1-:5-7 and 3)
Leonhardt S, Gorospe E, Hoffman B J, Teitler M (1992) Molecular
pharmacological differences in the interaction of serotonin with
5-hydroxytryptaminelC and 5-hydroxytryptamine2 receptors. Mol
Pharmacol., 42(2):328-35.
[3824] The functional properties of compounds (efficacy and
potency) were determined in whole cells expressing 5-HT2A or 5-HT2C
receptors by assessing their ability to stimulate or inhibit
receptor-mediated phosphoinositol hydrolysis. The procedures used
are described below.
[3825] In Vitro Binding Assays
[3826] Stable Expression of 5-HT2A and 5-HT2C Receptors in HEK293E
Cells.
[3827] Stable cell lines were generated by transfecting 293EBNA
cells with plasmids containing human 5-HT2A , 5-HT2B, or 5-HT2C
(VNV edited isoform) cDNA using calcium phosphate. These plasmids
also contained the cytomegalovirus (CMV) immediate early promoter
to drive receptor expression and EBV oriP for their maintenance as
an extrachromosomal element, and the hph gene from E. Coli to yield
hygromycin B resistance (Horlick et al., 1997). Transfected cells
were maintained in Dulbecco's Modified Eagle medium (DMEM)
containing dialyzed 10% fetal bovine serum at 37.degree. C. in a
humid environment (5% CO.sub.2) for 10 days. The 5-HT2A cells were
adapted to spinner culture for bulk processing whereas it was
necessary to maintain the other lines as adherent cultures. On the
day of harvest, cells were washed in phosphate-buffered saline
(PBS), counted, and stored at -80.degree. C.
[3828] Membrane Preparation
[3829] On the day of assay, pellets of whole cells (containing
approximately 1.times.108 cells) expressing the 5-HT2A or 5-HT2C
receptor were thawed on ice and homogenized in 50 mM Tris HCl (pH
7.7) containing 1.0 mM EDTA using a Brinkman Polytron (PT-10,
setting 6 for 10 sec). The homogenate was centrifuged at
48,000.times.g for 10 min and the resulting pellet washed twice by
repeated homogenization and centrifugation steps. The final pellet
was resuspended in tissue buffer and protein determinations were
made by the bichichoninic acid (BCA) assay (Pierce Co., Ill.) using
bovine serum albumin as the standard.
[3830] Radioligand Binding Assays for the 5-HT2A and 5-HT2C
Receptors.
[3831] Radioligand binding studies were conducted to determine the
binding affinities (KI values) of compounds for the human
recombinant 5-HT2A, 5-HT2B, and 5-HT2C receptors (Fitzgerald et
al., 1999). Assays were conducted in disposable polypropylene
96-well plates (Costar Corp., Cambridge, Mass.) and were initiated
by the addition of 5-HT2A , 5-HT2B, or 5-HT2C membrane homogenate
in tissue buffer (10-30 (g/well) to assay buffer (50 mM Tris HCl,
0.5 mM EDTA, 10 mM pargyline, 10 mM MgSO.sub.4, 0.05% ascorbic
acid, pH 7.5) containing [.sup.125I]DOI for the 5-HT2A and 5-HT2C
receptors (0.3-0.5 nM, final) or [.sup.3H]LSD (2-2.5 nM, final) for
the 5-HT2B receptor, with or without competing drug (i.e, newly
synthesized chemical entity). For a typical competition experiment,
a fixed concentration of radioligand was competed with duplicate
concentrations of ligand (12 concentrations ranging from 10
picomolar to 10 micromolar). The reaction mixtures were incubated
to equilibrium for 45 min at 37.degree. C. and terminated by rapid
filtration (cell harvestor; Inotech Biosystems Inc., Lansing,
Mich.) over GFF glass-fiber filters that had been pre-soaked in
0.3% polyethyleneimine. Filters were washed in ice-cold 50 mM Tris
HCl buffer (pH 7.5) and then counted in a gamma counter for the
5-HT2A and 5-HT2C assays, or by liquid scintillation spectroscopy
for the 5-HT2B assay.
[3832] Phosphoinositide Hydrolysis Studies.
[3833] The ability of newly synthesized compounds to stimulate
phosphoinositide (PI) hydrolysis was monitored in whole cells using
a variant (Egan et al., 1998) of a protocol described previously
(Berridge et al., 1982). HEK293E cells expressing the human 5-HT2A,
5-HT2B, or 5-HT2C receptor were lifted with 0.5 mM EDTA and plated
at a density of 100,000/well onto poly-D-lysine-coated 24-well
plates (Biocoat; Becton Dickinson, Bedford, Mass.) in Dulbecco's
modified Eagle's serum (DMEM; Gibco BRL) containing high glucose, 2
mM glutamine, 10% dialyzed fetal calf serum, 250 (g/ml hygromycin
B, and 250(g/ml G418. Following a 24-48 hr period, the growth media
was removed and replaced with DMEM without fetal calf serum and
inositol (Gibco BRL). The cells were then incubated with DMEM
(without serum and inositol) containing a final concentration of
0.5 uCi/well myo-[.sup.3H]inositol for 16-18 hr. Following this
incubation, the cells were washed with DMEM (without serum or
inositol) containing 10 mM LiCl and 10 (M pargyline and then
incubated for 30 min with the same media but now containing one of
several test compounds. Reactions were terminated by aspirating the
media and lysing the cells by freeze-thaw.
[.sup.3H]phosphoinositides were extracted with chloroform/methanol
(1:2 v/v), separated by anion exchange chromatography (Bio-Rad
AGI-X8 resin), and counted by liquid scintillation spectroscopy as
described previously (Egan et al., 1998).
[3834] Data Analyses
[3835] The equilibrium apparent dissociation constants (Ki's) from
the competition experiments were calculated using an iterative
nonlinear regression curve-fitting program (GraphPad Prism; San
Diego, Calif.). For the PI hydrolysis experiments, EC50's were
calculated using a one-site `pseudo` Hill model:
y=((Rmax-Rmin)/(l+R/EC50)nH))+Rmax where R= response (DeltaGraph,
Monterey, Calif.). Emax (maximal response) was derived from the
fitted curve maxima (net IP stimulation) for each compound.
Intrinsic activity (IA) was determined by expressing the Emax of a
compound as a percentage of the Emax of 5-HT (IA=1.0).
[3836] In Vivo Experiments for Serotonergic Ligands.
[3837] Preclinical Efficacy, Potency, and Side Effect
Liability.
[3838] a) Anti-Serotonin Efficacy.
[3839] Antagonism of Quipazine-Induced Head Twitch in Rat.
Quipazine, an agonist at 5-HT receptors, produces a characteristic
head twitch response in rats. 5-HT receptor antagonists effectively
antagonize this 5-HT agonist-induced behavioral effect (Lucki et
al., 1984). Accordingly, the quipazine-induced head twitch model in
rat can function as an in vivo behavioral correlate to 5-HT
receptor binding. Compounds are administered 30 minutes before
behavioral testing (and 25 minutes before quipazine), and a
dose-related antagonism of the quipazine response is
determined.
[3840] b) Antipsychotic Efficacy.
[3841] Inhibition of the Conditioned Avoidance Response (CAR) in
Rat. Rats are trained to consistently avoid (by climbing onto a
pole suspended from the ceiling of the test chamber) an electric
foot shock (0.75 mA) delivered to the grid floor of the testing
chamber. All antipsychotic drugs effectively inhibit this
conditioned avoidance response (Arnt, 1982). The ability of a
compound to inhibit this response is used to determine the
antipsychotic efficacy of potential drug candidates.
[3842] c) Extrapyramidal Side Effect Liability.
[3843] Induction of Catalepsy in Rat. Typical antipsychotic drugs
produce extrapyramidal side effects (EPS) at clinically effective
doses. The most widely accepted preclinical indicator of EPS
liability in humans is a drug-induced catalepsy syndrome in rat
(Costall and Naylor, 1975), a condition whereby the animal will
remain immobile in an externally imposed posture (analogous to a
catatonic stupor in humans). Rats are tested for induction of
catalepsy in a dose-response test after oral administration of
compounds.
[3844] d) CNS penetration; In vivo brain receptor occupancy.
[3845] In Vivo Binding. To determine the level of in vivo receptor
occupancy, an in vivo receptor binding protocol is used. This
procedure uses an appropriate radioligand to label the receptor of
interest. For example, to measure both Dopamine D2 and 5-HT2A
receptors in vivo, one can use .sup.3H-N-methyl spiperone (.sup.3H
-NMSP), (Frost, et. al. 1987) The procedure uses rats (or mice)
fasted overnight. To measure the effects of compounds on the
receptors of interest, compounds are dosed, usually p.o. for
example in 2 microliters/gram body weight in 0.25% Methocel
suspension. The radiolabeled compound (in this example,
.sup.3H-NMSP) is administered by i.v. tail vein injection (10
microcuries label/200 gram rat). Time course experiments are used
to determine the optimal time of binding for both the radiolabeled
and unlabeled compound. These optimal time frames are used for all
subsequent dose-response experiments. After the appropriate time
frame of compound/radioligand exposure, the animals are sacrificed
and the relevant brain regions dissected (frontal cortex for 5-HT2A
and striatum for D2 receptors) and examined for their content of
radioactivity. The level of non-specific binding is determined by
examining a brain region known not to contain the receptor of
interest (in this case the cerebellum) or by administering an
excess of compound known pharmacologically to interact with the
receptor.
[3846] References
[3847] Arnt, J. Acta Pharmacol. et Toxicol. 1982: 51, 321-329.
[3848] Berridge M. J., Downes P. C. , Hanley M. R. (1982) Lithium
amplifies agonist-dependent phosphotidyinositol response in brain
and salivary glands. Biochem. J., 206, 587-595.
[3849] Costall, B and Naylor, R J. Psychopharmacology. 1975: 43,
69-74.
[3850] Egan C. T., Herrick-Davis K., Miller K., Glennon R. A., and
Teitler M. (1998) Agonist activity of LSD and lisuride at cloned
5-HT2A and 5-HT2C receptors. Psychopharmacology, 136, 409-414.
[3851] Fitzgerald L W, Conklin D S, Krause C M, Marshall A P,
Patterson J P, Tran D P, Iyer G, Kostich W A, Largent B L, Hartig P
R (1999) High-affinity agonist binding correlates with efficacy
(intrinsic activity) at the human serotonin 5-HT2A and 5-HT2C
receptors: evidence favoring the ternary complex and two-state
models of agonist action. J. Neurochem., 72, 2127-2134.
[3852] Frost, J. J., Smith, A. C., Kuhar, M. J., Dannals, R. F.,
Wagner, H. N., 1987, In Vivo Binding of 3H-N-Methylspiperone to
Dopamine and Serotonin Receptors. Life Sciences, 40:987-995.
[3853] Horlick, R. A., Sperle, K., Breth, L. A., Reid, C. C., Shen,
E. S., Robbinds, A. K., Cooke, G. M., Largent, B. L. (1997) Rapid
Generation of stable cell lines expressing corticotrophin-releasing
hormone receptor for drug discovery. Protein Expr. Purif. 9,
301-308.
[3854] Lucki, I, Nobler, M. S., Frazer, A., 1984, Differential
actions of serotonin antagonists on two behavioral models of
serotonin receptor activation in the rat. J. Pharmacol. Exp. Ther.
228(l):133-139.
Dosage and Formulation
[3855] The serotonin agonist and serotonin antagonist compounds of
this invention can be administered as treatment for the control or
prevention of central nervous system disorders including obesity,
anxiety, depression, psychosis, schizophrenia, sleep and sexual
disorders, migraine and other conditions associated with cephalic
pain, social phobias, and gastrointestinal disorders such as
dysfunction of the gastrointestinal tract motility by any means
that produces contact of the active agent with the agent's site of
action, i.e., 5-HT2 receptors, in the body of a mammal. It can be
administered by any conventional means available for use in
conjunction with pharmaceuticals, either as an individual
therapeutic agent or in a combination of therapeutic agents. It can
be administered alone, but preferably is administered with a
pharmaceutical carrier selected on the basis of the chosen route of
administration and standard pharmaceutical practice.
[3856] The compounds of the present invention can be administered
in such oral dosage forms as tablets, capsules (each of which
includes sustained release or timed release formulations), pills,
powders, granules, elixirs, tinctures, suspensions, syrups, and
emulsions. Likewise, they may also be administered in intravenous
(bolus or infusion), intraperitoneal, subcutaneous, or
intramuscular form, all using dosage forms well known to those of
ordinary skill in the pharmaceutical arts.
[3857] The dosage administered will, of course, vary depending upon
known factors, such as the pharmacodynamic characteristics of the
particular agent and its mode and route of administration; the age,
health and weight of the recipient; the nature and extent of the
symptoms; the kind of concurrent treatment; the frequency of
treatment; and the effect desired. By way of general guidance, a
daily dosage of active ingredient can be expected to be about 0.001
to about 1000 milligrams per kilogram of body weight, with the
preferred dose being about 0.01 to about 100 mg/kg; with the more
preferred dose being about 0.1 to about 30 mg/kg. Advantageously,
compounds of the present invention may be administered in a single
daily dose, or the total daily dosage may be administered in
divided doses of two, three, or four times daily.
[3858] Dosage forms of compositions suitable for administration
contain from about 1 mg to about 100 mg of active ingredient per
unit. In these pharmaceutical compositions the active ingredient
will ordinarily be present in an amount of about 0.5-95% by weight
based on the total weight of the composition. The active ingredient
can be administered orally in solid dosage forms, such as capsules,
tablets and powders, or in liquid dosage forms, such as elixirs,
syrups and suspensions. It can also be administered parenterally,
in sterile liquid dosage forms.
[3859] Gelatin capsules contain the active ingredient and powdered
carriers, such as lactose, starch, cellulose derivatives, magnesium
stearate, stearic acid, and the like. Similar diluents can be used
to make compressed tablets. Both tablets and capsules can be
manufactured as sustained release products to provide for
continuous release of medication over a period of hours. Compressed
tablets can be sugar coated or film coated to mask any unpleasant
taste and protect the tablet from the atmosphere, or enteric coated
for selective disintegration in the gastrointestinal tract.
Liquid,dosage forms for oral administration can contain coloring
and flavoring to increase patient acceptance.
[3860] In general, water, a suitable oil, saline, aqueous dextrose
(glucose), and related sugar solutions and glycols such as
propylene glycol or polyethylene glycols are suitable carriers for
parenteral solutions. Solutions for parenteral administration
preferably contain a water soluble salt of the active ingredient,
suitable stabilizing agents, and if necessary, buffer substances.
Antioxidizing agents such as sodium bisulfite, sodium sulfite, or
ascorbic acid, either alone or combined, are suitable stabilizing
agents. Also used are citric acid and its salts, and sodium EDTA.
In addition, parenteral solutions can contain preservatives, such
as benzalkonium chloride, methyl- or propyl-paraben and
chlorobutanol. Suitable pharmaceutical carriers are described in
Remington's Pharmaceutical Sciences, supra, a standard reference
text in this field.
[3861] Useful pharmaceutical dosage-forms for administration of the
compounds of this invention can be illustrated as follows:
[3862] Capsules
[3863] A large number of unit capsules can be prepared by filling
standard two-piece hard gelatin capsules each with 100 mg of
powdered active ingredient, 150 mg oflactose, 50 mg of cellulose,
and 6 mg magnesium stearic.
[3864] Soft Gelatin CaDsules
[3865] A mixture of active ingredient in a digestible oil such as
soybean oil, cottonseed oil or olive oil can be prepared and
injected by means of a positive displacement pump into gelatin to
form soft gelatin capsules containing 100 mg of the active
ingredient. The capsules should then be washed and dried.
[3866] Tablets
[3867] A large number of tablets can be prepared by conventional
procedures so that the dosage unit is 100 mg of active ingredient,
0.2 mg of colloidal silicon dioxide, 5 milligrams of magnesium
stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and
98.8 mg of lactose. Appropriate coatings may be applied to increase
palatability or delay absorption.
[3868] Suspension
[3869] An aqueous suspension can be prepared for oral
administration so that each 5 ml contain 25 mg of finely divided
active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg
of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025
mg of vanillin.
[3870] Injectable
[3871] A parenteral composition suitable for administration by
injection can be prepared by stirring 1.5% by weight of active
ingredient in 10% by volume propylene glycol and water. The
solution is sterilized by commonly used techniques.
[3872] The Tables below provide representative Examples, the
synthesis of which are described above, of the compounds of Formula
(I) of the present invention.
2TABLE 1 31 Ex # n R7 R8 R9 b R1 1 1 H H H dbl H 2 1 H H H dbl
cycPropyl 3 1 H H H sgl H 16 2 H H H dbl H 17 2 H H H sgl H 37 1 H
H H sgl --C(.dbd.O)cycPropyl 38 1 H H H sgi --C(.dbd.O)iPropyl 89 1
H 2-Cl-phenyl H sgl --CO.sub.2-tButyl 90 1 H 2,4-diCl-phenyl H sgl
--CO.sub.2-tButyl 91 1 H 3,4-diCl-pheny1 H sgl --CO.sub.2-tButyl 92
1 H 2,3-diCl-phenyl H sgl --CO.sub.2-tButyl 93 1 H
2-Cl-4-CF.sub.3-phenyl H sgl --CO.sub.2-tButyl 94 1 H
2-Cl-4-MeO-phenyl H sgl --CO.sub.2-tButyl 95 1 H
2-MeO-4-iPr-phenyl. H sgl --CO.sub.2-tButyl 96 1 H 3-F-phenyl H sgl
--CO.sub.2-tButyl 97 1 H 2,4-diMeO-phenyl H sgl --CO.sub.2-tButyl
98 1 H 2-Cl-phenyl H sgl H 99 1 H 2,4-diCl-phenyl H sgl H 100 1 H
3,4-diCl-phenyl H sgl H 101 1 H 2,3-diCl-phenyl H sgl H 102 1 H
2-Cl-4-CF.sub.3-phenyl H sgl H 103 1 H 2-Cl-4-MeO-phenyl H sgl H
104 1 H 2-MeO-4-iPr-phenyl H sgl H 105 1 H 3-F-phenyl H sgl H 106 1
H 2,4-diMeO-phenyl H sgl H 107 2 H H H sgl --CO.sub.2-tButyl 108 2
H Br H sgl --CO.sub.2-tButyl 109 2 H 2,3-diCl-phenyl H sgl
--CO.sub.2-tButyl 110 2 H 3,4-diCl-phenyl H sgl --CO.sub.2-tButyl
111 2 H 2-Cl-4-CF.sub.3-phenyl H sgl --CO.sub.2-tButyl 112 2 H
2,3-diCl-phenyl H sgl H 113 2 H 3,4-diCl-phenyl H sgl H 114 2 H
2-Cl-4-CF.sub.3-phenyl H sgl H 189 1 H 2-Cl-phenyl H sgl
--(CH.sub.2).sub.3C(.dbd.O) (4-F- phenyl) 190 1 H 2,4-diCl-phenyl H
sgl --(CH.sub.2).sub.3C(.dbd.O) (4-F- phenyl) 191 2 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O) (4-F- phenyl) 265 1 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O) (4-F- phenyl) 274 1 H 2-F-4-MeO-phenyl
H sgl H 275 1 H 2-CF.sub.3-4-EtO-phenyl H sgl --CO.sub.2-tButyl 276
1 H 2-CF.sub.3-4-EtO-phenyl H sgl H 277 1 H 2-F-4-Cl-phenyl H sgl
--CO.sub.2-tButyl 278 1 H 2-F-4-Cl-phenyl H sgl H 279 1 H
2-CF.sub.3-4-iPrO-phenyl H sgl --CO.sub.2-tButyl 280 1 H
2-CF.sub.3-4-iPrO-phenyl H sgl H 281 1 H 2-CF.sub.3-4-MeO-phenyl H
sgl --CO.sub.2-tButyl 282 1 H 2-CF.sub.3-4-MeO-phenyl H sgl H 283 1
H phenyl H sgl --CO.sub.2-tButyl 284 1 H phenyl H sgl H 285 1 H
2-Me-phenyl H sgl --CO.sub.2-tButyl 286 1 H 2-Me-phenyl H sgl H 287
1 H 2-CF.sub.3-phenyl H sgl CO.sub.2-tButyl 288 1 H
2-CF.sub.3-phenyl H sgl H 289 1 H 3,4-diMeO-phenyl H sgl
--CO.sub.2-tButyl 290 1 H 3,4-diMeO-phenyl H sgl H 291 1 H
2,4-diCl-phenyl H sgl --CO.sub.2-tButyl 292 1 H 2,4-diCl-phenyl H
sgl H 293 1 H 3,5-diCl-phenyl H sgl --CO.sub.2-tButyl 294 1 H
3,5-diCl-phenyl H sgl H 295 1 H 4-MeO-2-iPr-phenyl H sgl
CO.sub.2-tButyl 296 1 H 4-MeO-2-iPr-phenyl H sgl H 297 1 H
5-F-4-MeO-2-Me- H sgl CO.sub.2-tButyl phenyl 298 1 H
5-F-4-MeO-2-Me- H sgl H phenyl 299 1 H 4-MeO-2-Me-phenyl H sgl
--CO.sub.2-tButyl 300 1 H 4-MeO-2-Me-phenyl H sgl H 301 1 H
2-Cl-4-MeO-phenyl H sgl --CO.sub.2-tButyl 302 1 H 2-Cl-4-MeO-phenyl
H sgl H 303 1 H 4-Cl-2-Me-phenyl H sgl --CO.sub.2-tButyl 304 1 H
4-Cl-2-Me-phenyl H sgl H 305 1 H 2-CHO-4-MeO-phenyl H sgl H 306 1 H
2,6-diCl-phenyl H sgl H 307 1 H 2-CF.sub.3-4-MeNH-phenyl H sgl H
308 1 H 2-CF.sub.3-4-NH.sub.2-phenyl H sgl H 309 1 H
4-MeO-2-CH.sub.3CH(OH)- H sgl H phenyl 310 3 H H H sgl H 311 3 H H
H sgl --CO.sub.2-tButyl 312 3 H H H sgl H 313 3 H H H sgl H 314 3 H
H H sgl --CO.sub.2-tButyl 315 3 H 2,4-diCl-phenyl H sgl H 316 3 H
2,3-diCl-phenyl H sgl H 317 3 H 3,4-diCl-phenyl H sgl H 318 3 H
3,5-diCl-phenyl H sgl H 319 3 H 2,5-diCl-phenyl H sgl H 320 3 H
2,6-diCl-phenyl H sgl H 321 3 H 2-Cl-phenyl H sgl H 322 3 H
3-Cl-phenyl H sgl H 323 3 H 4-Cl-phenyl H sgl H 324 3 H
2,6-diF-phenyl H sgl H 325 3 H 2,6-diF-phenyl H sgl H 326 3 H
2,3-diF-phenyl H sgl H 327 3 H 3,4-diF-phenyl H sgl H 328 3 H
3-F-phenyl H sgl H 329 3 H 2-Cl-4-CF.sub.3-phenyl H sgl H 330 3 H
2-Cl-4-MeO-phenyl H sgl H 331 3 H 2-F-4-MeO-phenyl H sgl H 332 3 H
4-MeO-2-Me-phenyl H sgl H 333 3 H 2-CF.sub.3-4-MeO-phenyl H sgl H
334 3 H 2-CF.sub.3-phenyl H sgl H 335 3 H 2-CF.sub.3-4-iPrO-phenyl
H sgl H 336 3 H 2,4-diCF.sub.3-phenyl H sgl H 337 3 H
2-F-2-CF.sub.3-phenyl H sgl H 338 3 H 2-CF.sub.3-4-NH.sub.2-phenyl
H sgl H 339 3 H 2-CF.sub.3-4-MeNH-phenyl H sgl H 340 3 H
2-CHO-phenyl H sgl H 341 3 H 2-CH.sub.2(OH)-phenyl H sgl H 342 3 H
4-MeO-2-CHO-phenyl H sgl H 343 3 H 4-MeO-2-CH.sub.2(OH)-- H sgl H
phenyl 344 3 H 4-CN-2-Me-phenyl H sgl H 345 3 H
4-MeO-2-CH.sub.3CH(OH)-- H sgl H phenyl 346 2 H Br H sgl
--CO.sub.2-tButyl 347 2 H 2,4-diCl-phenyl H sgl H 348 2 H
3,4-diCl-phenyl H sgl H 349 2 H 3,5-diCl-phenyl H sgl H 350 2 H
2,5-diCl-phenyl H sgl H 351 2 H 2,6-diCl-phenyl H sgl H 352 2 H
2-Cl-phenyl H sgl H 353 2 H 3-Cl-phenyl H sgl H 354 2 H 4-Cl-phenyl
H sgl H 355 2 H 2,6-diF-phenyl H sgl H 356 2 H 2,6-diF-phenyl H sgl
Me 357 2 H 2,3-diF-phenyl H sgl H 358 2 H 3,4-diF-phenyl H sgl H
359 2 H 3-F-phenyl H sgl H 360 2 H 2-Cl-4-MeO-phenyl H sgl H 361 2
H 2-F-4,MeO-phenyl H sgl H 362 2 H 4-MeO-2-Me-phenyl H sgl H 363 2
H 2-CF.sub.3-4-MeO-phenyl H sgl H 364 2 H 2-CF.sub.3-4-MeO-phenyl H
dbl H 365 2 H 2-CF.sub.3-4-OH-phenyl H sgl H 366 2 H
2-CF.sub.3-phenyl H sgl H 367 2 H 2-CF.sub.3-4-iPrO-phenyl H sgl H
368 2 H 2,4-diCF.sub.3-phenyl H sgl H 369 2 H 2-CF.sub.3-4-F-phenyl
H sgl H 370 2 H 2-CF.sub.3-4-NH.sub.2-phenyl H sgl H 371 2 H
2-CF.sub.3-4-MeNH-phenyl H sgl H 372 2 H 4-CN-2-Me-phenyl H sgl H
373 2 H 2-CHO-phenyl H sgl H 374 2 H 2-CH.sub.2(OH)-phenyl H sgl H
375 2 H 4-MeO-2-CHO-phenyl H sgl H 376 2 H 4-MeO-2-CH.sub.3CH(OH)--
H sgl H phenyl 377 3 H 2-CF.sub.3-4 EtO-phenyl H sgl H 378 2 H
2-CF.sub.3-4-EtO-phenyl H sgl H 379 3 H 3-Cl-2-Me-phenyl H sgl H
380 2 H 3-Cl-2-Me-phenyl H sgl H 381 2 H 5-F-2-Me-phenyl H sgl H
382 2 H 2,3-diCl-phenyl H sgl Pr 383 2 H 2,3-diCl-phenyl H sgl Pr
384 2 H 2,3-diCl-phenyl H sgl Bu 385 2 H 2,3-diCl-phenyl H sgl Bu
386 2 H 2,3-diCl-phenyl H sgl 4-pentenyl 387 2 H 2,3-diCl-phenyl H
sgl 3-Me-2-butenyl 388 2 H 2,4-diCl-phenyl H sgl Pr 389 2 H
2,4-diCl-phenyl H sgl Bu 390 2 H 2,4-diCl-phenyl H sgl 4-pentenyl
391 2 H 2,4-diCl-phenyl H sgl 3-Me-2-butenyl 392 2 H
2,4-diCl-phenyl H sgl cyclobutylmethyl 393 2 H
2-CF.sub.3-4-Meo-phenyl H sgl Me 394 2 H 2-CF.sub.3-4-MeO-phenyl H
sgl Et 395 2 H 2-CF.sub.3-4-MeO-phenyl H sgl Pr 396 2 H
2-CF.sub.3-4-MeO-phenyl H sgl Bu 397 2 H 2-CF.sub.3-4-MeO-phenyl H
sgl 4-pentenyl 398 2 H 2-CF.sub.3-4-MeO-phenyl H sgl 3-Me-2-butenyl
399 2 H 2-CF.sub.3-4-MeO-phenyl H sgl 2-F-ethyl 400 2 H
2-CF.sub.3-4-MeO-phenyl H sgl 2,2-diF-ethyl 401 2 H
2-CF.sub.3-4-MeO-phenyl H sgl cyclobutylmethyl 402 2 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O) (4-F- phenyl) 403 2 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O) (4-F- phenyl) 403 2 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O) (4-F- phenyl) 404 2 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O) (2- NH.sub.2-phenyl) 405 2 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O) (2- NH.sub.2-phenyl) 406 2 H H H sgl
--(CH.sub.2).sub.3O(4-F- phenyl) 407 2 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O) (4- pyridyl) 408 2 H H H sgl 32 409 2 H
H H sgl 33 410 2 H H H dbl --(CH.sub.2).sub.3C(.dbd.O) (4-F-
phenyl) 411 3 H H H sgl (CH.sub.2).sub.3C(.dbd.- O) (4-F- phenyl)
412 3 H H H sgl (CH.sub.2).sub.3C(.dbd.O) (4-F- phenyl) 413 3 H H H
sgl --(CH.sub.2).sub.3C(.dbd.O) (4-F- phenyl) 414 3 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O) (4-F- 2-NH.sub.2-phenyl) 415 2 H H H
sgl --(CH.sub.2).sub.3C(.dbd.O) (4-F- 2-NH.sub.2-phenyl) 416 2 H H
H sgl --(CH.sub.2).sub.3C(.dbd.O) (4-F- 2-NH.sub.2-phenyl) 417 2 H
H H sgl --(CH.sub.2).sub.3C(.dbd.O) (4-F- 2-NH.sub.2-phenyl)
[3873]
3TABLE 2 34 Ex # n k R7 R8 R9 b R1 418 2 2 H H H dbl H 419 2 2 H H
H sgl H 420 2 2 H H H sgl --(CH.sub.2).sub.3C(.dbd.O)(4-F- phenyl)
421 2 2 H H H sgl --(CH.sub.2).sub.3C(.dbd.O) (4-F-
2-NH.sub.2-phenyl) 422 3 2 H H H dbl H 423 3 2 H H H sgl H 424 3 2
H H H sgl --(CH.sub.2).sub.3C(.dbd.O)(4-F- phenyl) 425 3 2 H H H
sgl --(CH.sub.2).sub.3C(.dbd.O) (4-F- 2-NH.sub.2-phenyl) 434 2 1 H
H H sgl H 435 2 1 H H H sgl --CO.sub.2-tButyl 436 2 1 H Br H sgl
--CO.sub.2-tButyl 437 2 1 H 2-CF.sub.3-4-MeO- H sgl H phenyl
[3874]
4TABLE 3 35 Ex # X R7 R8 R9 b R1 426 C.dbd.O H H H sgl H 427
C.dbd.O H H H sgl --CO.sub.2-tButy1 428 C.dbd.O H 2,4-diCl-phenyl H
sgl --CO.sub.2-tButyl 429 C.dbd.O H 2,4-diCl-phenyl H sgl H 430
C.dbd.O H 2,4-diCl-phenyl H sgl H 431 C.dbd.O H 2,4-diCl-phenyl H
sgl H 450 CH(OH) H 2,4-diCl-phenyl H sgl H 433 CH(OH) H
2,4-diCl-phenyl H sgl H
[3875]
5TABLE 4 36 Ex # X n k R7 R8 R9 b R1 196 NHCO 1 1 H H H dbl
--(CH.sub.2(.sub.3C(.dbd- .O)(4-F-phenyl) 210 NMe 2 1 H H H sgl
--(CH.sub.2(.sub.3C(.dbd.O)(4- -pyridyl) 211 NH 2 1 H H H sgl H 212
NH 2 1 H H H sgl --(CH.sub.2(.sub.3C(.dbd.O)(4-F-phenyl) 217 NMe 2
1 H H H sgl 37 218 NMe 2 1 H H H sgl 38 255 NMe 2 1 H H H sgl H 256
NEC 2 1 H H H sgl H 257 NPr 2 1 H H H sgl H 258 N(i-Pr) 2 1 H H H
sgl H 259 N(n-Bu) 2 1 H H H sgl H 260 N(CH.sub.2Ph) 2 1 H H H sgl H
261 NMe 2 1 H H H sgl --(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl) 262
NEC 2 1 H H H sgl --(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl) 263
N(i-Pr) 2 1 H H H sgl --(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl) 264
N(CH.sub.2Ph) 2 1 H H H sgl --(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl)
269 NEe 2 1 H H H sgl --(CH.sub.2).sub.3O(4-F-phenyl) N274 NMe 2 1
H 2,4-diCl-phenyl H sgl H N275 NH 2 1 H 2,4-diCl-phenyl H sgl H
N276 NEe 2 1 H Br H sgl --(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl)
N277 NMe 2 1 H MeO H sgl --(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl)
N278 NMe 2 1 H 2,4-diCl-phenyl H sgl H N279 NH 3 1 H 4-MeO-2-Me- H
sgl H phenyl N280 NHCO 2 1 H 2,4 diCl-pehnyl H sgl H N281 NMe 2 2 H
H H sgl H N282 NMe 2 2 H H H sgl --(CH.sub.2(.sub.3C(.dbd.O)-
(4-F-pheny1) N283 NHCH(Me) 1 1 H 2,4-diCl-phenyl H sgl H
[3876]
6TABLE 5 39 Ex # R7 R8 R9 b R1 4 H H F dbl --CO.sub.2Et 5 H H F dbl
H 6 H H Me dbl H 7 H H Me dbl --CO.sub.2-tBu 8 H H Me sgl H 9 H H H
sgl H 10 H H NO.sub.2 dbl H 11 H H NO.sub.2 sgl H 12 Cl H H dbl H
13 Cl H H sgl H 14 Me H H dbl H 15 Me H H sgl H 18 H H Br dbl H 19
H H Br sgl H 25 H H H sgl --C(.dbd.O)(3,4-diMeO-phenyl) 26 H H H
sgl --C(.dbd.O)(2,5-diMeO-phenyl) 27 H H H sgl
--C(.dbd.O)(3,5-diMeO-p- henyl) 28 H H H sgl 2,6-diMeO-benzyl 29 H
H H sgl 2,4-diMeO-benzyl 30 H H H sgl 2,4,6-triMeO-benzyl 31 H H H
sgl 2,3-diMeO-benzyl 32 H H H sgl 2,4,5-triMeO-benzyl 33 H H H sgl
cyclohexylmethyl 34 H H H sgl 2,3,4-triMeO-benzyl 35 H H H sgl
3,4-diMeO-benzyl 36 H H H sgl 3,4,5-triMeO-benzyl 39 H H H sgl
--CO.sub.2Et 40 H --C(.dbd.O)CH.sub.3 H sgl --CO.sub.2Et 41 H
--NHC(.dbd.O)CH.sub.3 H sgl --CO.sub.2Et 42 H H H sgl
--CH.sub.2CH.sub.2(4-F-phenyl) 43 H H H sgl Et 44 H H H sgl Pr 45 H
H H sgl butyl 46 H H H sgl pentyl 47 H H H sgl hexyl 48 H H H sgl
2-propyl 49 H H H sgl 2-butyl 50 H H H sgl 2-pentyl 51 H H H sgl
2-hexyl 52 H H H sgl 2-Me-propyl 53 H H H sgl 2-Me-butyl 54 H H H
sgl 2-Me-pentyl 55 H H H sgl 2-Et-butyl 56 H H H sgl 3-Me-pentyl 57
H H H sgl 3-Me-butyl 58 H H H sgl 4-Me-pentyl 59 H H H sgl
cyclopropylmethyl 60 H H H sgl cyclobutylmethyl 61 H H H sgl
cyclohexylmethyl 62 H H H sgl 2-propenyl 63 H H H sgl
2-Me-2-propenyl 64 H H H sgl trans-2-butenyl 65 H H H sgl
3-Me-butenyl 66 H H H sgl 3-butenyl 67 H H H sgl trans-2-pentenyl
68 H H H sgl cis-2-pentenyl 69 H H H sgl 4-pentenyl 70 H H H sgl
4-Me-3-pentenyl 71 H H H sgl 3,3-diCl-2-propenyl 72 H H H sgl
benzyl 73 H H H sgl 2-Me-benzyl 74 H H H sgl 3-Me-benzyl 75 H H H
sgl 4-Me-benzyl 76 H H H sgl 2,5-diMe-benzyl 77 H H H sgl
2,4-diMe-benzyl 78 H H H sgl 3,5-diMe-benzyl 79 H H H sgl
2,4,6-triMe-benzyl 80 H H H sgl 3-MeO-benzyl 81 H H H sgl
3,5-diMeO-benzyl 82 H H H sgl pentafluorobenzyl 83 H H H sgl
2-phenylethyl 84 H H H sgl 1-phenyl-2-propyl 85 H H H sgl
trnas-3-phenyl-2- propenyl 86 H H H sgl 4-phenylbutyl 87 H H H sgl
4-phenylbenzyl 88 H H H sgl 2-phenylbenzyl 169 H Me H sgl H 170 H
CN H sgl H 171 H Et H sgl H 175 H H H dbl Me 176 H H H sgl Me 177 H
H H sgl H 178 Cl H H sgl --(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl)
179 Me H H sgl --(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl) 180 H H H
sgl --(CH.sub.2).sub.3S(3-F-phenyl) 181 H H H sgl
--(CH.sub.2).sub.3CH(OH)(4-F-phenyl) 186 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl) 187 H MeO H sgl
--(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl) 192 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(4-Br-phenyl) 193 H H H sgl
--(CH.sub.2).sub.3SO.sub.2(3-F-phenyl) 194 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(4-(3,4-diCl- phenyl)phenyl) 197 H H H
sgl --(CH.sub.2).sub.3C(.dbd.O)(4-Me-phenyl) 198 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl) 199 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(4-MeO-phenyl) 200 H H H sgl
--(CH.sub.2).sub.2C(.dbd.O)(4-F-phenyl) 201 H H H sgl
--(CH.sub.2).sub.3SO.sub.2(4-F-phenyl) 202 H H H sgl
--(CH.sub.2).sub.3S(.dbd.O)(4-F-phenyl) 203 H H H sgl
--(CH.sub.2).sub.3O(4-F-phenyl) 204 H H H sgl
--(CH.sub.2).sub.3O(phenyl) 205 H H H sgl --(CH.sub.2).sub.3S(4-F--
phenyl) 206 H H H sgl --(CH.sub.2).sub.3NH(4-F-phenyl) 207 H H H
sgl --(CH.sub.2).sub.3N(CH.sub.3)(4-F-phenyl) 208 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(4-pyridyl) 209 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(3-pyridyl) 214 H H H sgl 40 215 H H H
sgl 41 219 H H H sgl --(CH.sub.2).sub.3CO.sub.2Et 220 H H H sgl
--(CH.sub.2).sub.4CO.su- b.2Et 221 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)N(CH.sub.3)(OCH.sub.- 3) 222 H H H sgl
--(CH.sub.2).sub.4C(.dbd.O)N(CH.sub.3)(OCH.sub.3) 223 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(3-Me-4-F-phenyl) 224 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(phenyl) 225 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(4-Cl-phenyl) 226 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(3-Me-phenyl) 227 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(4-tBu-phenyl) 228 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(3,4-diF-phenyl) 229 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(2-MeO-5-F-phenyl) 230 H H H sgl
--(CH.sub.2).sub.4C(.dbd.O)(phenyl) 231 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(4-F-1-naphthyl) 232 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(benzyl) 233 H H H sgl
--(CH.sub.2).sub.2C(.dbd.O)NH(4-F-phenyl) 234 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)NH(4-F-phenyl) 235 H H H sgl
--(CH.sub.2).sub.3CH(OH)(4-F-phenyl) 236 H H H sgl
--(CH.sub.2).sub.3CH(OH)(4-pyridyl) 237 H H H sgl
--(CH.sub.2).sub.3CH(OH)(2,3-diMeO- phenyl) 238 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(2,3-diMeO-phenyl) 239 H H H sgl
--(CH.sub.2).sub.4(cyclohexyl) 240 H H H sgl
--(CH.sub.2).sub.3CH(phenyl).sub.2 241 H H H sgl
--CH.sub.2CH.sub.2CH.dbd.C(phenyi).sub.2 242 H H H sgl
--(CH.sub.2).sub.3CH(4-F-phenyl).sub.2 243 H H H sgl
--CH.sub.2CH.sub.2CH.dbd.C(4-F-phenyl).sub.2 244 H H H sgl
--(CH.sub.2).sub.2NHC(.dbd.O)(phenyl) 245 H H H sgl
--(CH.sub.2).sub.2NHC(.dbd.O)(2-F-phenyl) 246 H H H sgl
--(CH.sub.2).sub.2NHC(.dbd.O)(4-F-phenyl) 247 H H H sgl
--(CH.sub.2).sub.3(3-indolyl) 248 H H H sgl
--(CH.sub.2).sub.3(1-Me-3-indolyl) 249 H H H sgl
--CH.sub.2CH.sub.2(3-indolyl) 250 H H H sgl
--(CH.sub.2).sub.3(1-indolyl) 251 H H H sgl
--(CH.sub.2).sub.3(1-indolinyl) 252 H H H sgl
--(CH.sub.2).sub.3(1-benzimidazolyl) 253 H H H sgl 42 254 H H H sgl
43 268 H F H sgl --(CH.sub.2).sub.3C(.dbd.O)(4-F- phenyl) 271 H H H
sgl H 273 H F H sgl H S274 Br H H sgl H S275 2,6-diF-phenyl H H sgl
H S276 2-Me-4-MeO-phenyl H H sgl H S277 4-CF.sub.3-phenyl H H sgl H
S278 2,3-diCl-phenyl H H sgl H S279 2,4-diCl-phenyl H H sgl H S280
2-Cl-4-CF.sub.3-phenyl H H sgl H S281 CN H H sgl H S282 CN Br H sgl
H S283 benzyl H H sgl H S284 CHO H H sgl H S285 CO.sub.2H H H sgl H
S286 H H H sgl --(CH.sub.2).sub.2NHC(.dbd.O)(2,4-diF- phenyl) S287
H H H sgl --(CH.sub.2).sub.2NMeC(.dbd.O)-phenyl S288 H H H sgl
--(CH.sub.2).sub.2NNeC(.dbd.O)(2-F- phenyl) S289 H H H sgl
--(CH.sub.2).sub.2NMeC(.dbd.O)(2,4- diF-phenyl) S290 H H H sgl
--(CH.sub.2).sub.2NMeC(.dbd.O)(4-F- phenyl) S291 H H H sgl
--(CH.sub.2).sub.3(1H-1,2,3- benzotriazol-1-yl) S292 H H H sgl
--(CH.sub.2).sub.3(1H-1,2,3- - benzotriazol-2-yl) S293 H H H sgl 44
S294 H H H sgl 45 S295 H H H sgl 46 S296 H H H sgl
--(CH.sub.2).sub.2(1H-1,2,3- benzotriazol-1-yl) S297 H H H sgl 47
S298 H H H sgl --(CH.sub.2).sub.2(1H-1,2,3- benzotriazol-2-yl) S299
H H H sgl --(CH.sub.2).sub.3(3,4-dihydro- 1(2H)-quinolinyl) S300 H
H H sgl --CH.sub.2CH.sub.2CH.dbd.CMe(4-F- phenyl) S301 H H H sgl
--(CH.sub.2).sub.2(2,3-dihydro- 1H-inden-2-yl) S302 H H H sgl
--(CH.sub.2).sub.3C(.dbd- .O)(2-NH.sub.2- phenyl) S303 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(2-NH.sub.2- phenyl) S304 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(2-NH.sub.2-5- F-phenyl) S305 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(2-NH.sub.2-3- F-phenyl) S306 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(2-NH.sub.2-4- Cl-phenyl) S307 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(- 2-NH.sub.2-4- OH-phenyl) S308 H H H
sgl --(CH.sub.2).sub.3C(.dbd.O)(2-NH.sub.2-4- Br-phenyl) S309 H H H
sgl --(CH.sub.2).sub.3(1H-indazol-3- yl) S310 H H H sgl
--(CH.sub.2).sub.3(5-F-1H- indazol-3 -yl) S311 H H H sgl
--(CH.sub.2).sub.3(7-F-1H- indazol-3-yl) S312 H H H sgl
--(CH.sub.2).sub.3(6-Cl-1H- indazol-3-yl) S313 H H H sgl
--(CH.sub.2).sub.3(6-Br-1H- indazal-3-yl) S314 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(2-NHMe- phenyl) S315 H H H sgl
--(CH.sub.2).sub.3(1-benzothien- 3-yl) S355 H H H sgl 48 S356 H H H
sgl --(CH.sub.2).sub.3(6-F-1H-indol- 1-yl) S357 H H H sgl
--(CH.sub.2).sub.3(5-F-1H-indol- 1-yl) S358 H H H sgl
--(CH.sub.2).sub.3(6-F-2,3- dihydro-1H-indol-1- yl) S359 H H H sgl
--(CH.sub.2).sub.3(5-F-2,3- dihydro-1H-indol-1- yl) S360 H H H sgl
--(CH.sub.2).sub.3(6-F-1H- indol-3-yl) S361 H H H sgl
--(CH.sub.2).sub.3(6-F-1H- indol-3-yl) S362 H H H sgl
--(CH.sub.2).sub.3(5-F-1H- indol-3 -yl) S363 H H H sgl
--(CH.sub.2).sub.3(5-F-1H- indol-3-yl) S364 H H H sgl
--(CH.sub.2).sub.3(9H-purin-9- yl) S365 H H H sgl
--(CH.sub.2).sub.3(7H-purin-7- yl) S366 H H H sgl 49 S367 H H H sgl
--(CH.sub.2).sub.3(6-F-1H- indazol-3 -yl) S368 H H H sgl
--(CH.sub.2).sub.3(6-F-1H- indazol-3-yl) S369 H H H sgl
--(CH.sub.2).sub.3(6-F-1H- indazol-3 -yl) S370 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(2-- NH.sub.2-4- F-phenyl) S371 H H H
sgl (CH.sub.2).sub.3C(.dbd.O)(2-NH.sub.2-4-F- phenyl) S372 H H H
sgl --(CH.sub.2).sub.3C(.dbd.O)(2-NHSO.sub.2Me- 4-F-phenyl) S373 H
H H sgl --(CH.sub.2).sub.3C(.dbd.O)(2- NHC(.dbd.O)Me-4-F-phenyl)
S374 H H H sgl --(CH.sub.2).sub.3C(.dbd.O)(2- NHC(.dbd.O)
Me-4-F-phenyl) S375 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(2-NHCO.sub.2Et- 4-F-phenyl) S376 H H H
sgl --(CH.sub.2).sub.3C(.dbd.O)(2- NHC(.dbd.O) NHEt-4-F-phenyl)
S377 H H H sgl --(CH.sub.2).sub.3C(.dbd.O)(2-NHCHO-4- F-phenyl)
S378 H H H sgl --(CH.sub.2).sub.3C(.dbd.O)(2-OH-4-F- phenyl) S379 H
H H sgl --(CH.sub.2).sub.3C(.dbd.O)(2-MeS-4-F- phenyl) 442 H H H
sgl --(CH.sub.2).sub.3C(.dbd.O)(2-NHSO.sub.2Me- 4-F-phenyl) 485 H H
H sgl --(CH.sub.2).sub.2C(Me)CO.su- b.2Me 486 H H H sgl
--(CH.sub.2).sub.2C(Me)C(OH)(4-F- phenyl).sub.2 487 H H H sgl
--(CH.sub.2).sub.2C(Me)C(OH)(4-Cl- phenyl).sub.2 489 H H H sgl
--(CH.sub.2).sub.2C(Me)C(.dbd.- O)(4-F- phenyl) 490 H H H sgl
--(CH.sub.2).sub.2C(Me)C(- .dbd.O)(2- MeO-4-F-phenyl) 491 H H H sgl
--(CH.sub.2).sub.2C(Me)C(.dbd.O)(3-Me- 4-F-phenyl) 492 H H H sgl
--(CH.sub.2).sub.2C(Me)C(.dbd.O)(2-Me- phenyl) 493 H H H sgl
--(CH.sub.2).sub.2C(Me)C(.dbd.O)phenyl 591 Cl H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(2-NH.sub.2-4-F- -phenyl
[3877]
7TABLE 5A 50 Ex # R7 R8 R9 b R1 115 H H Br dbl --CO.sub.2-tBu 116 H
H 2,3-diCl-phenyl dbl --CO.sub.2-tBu 117 H H 3,4-diCl-phenyl dbl
--CO.sub.2-tBu 118 H H 2-Cl-4-CF.sub.3-phenyl dbl --CO.sub.2-tBu
119 H H 2,3-diCl-phenyl dbl H 120 H H 3,4-diCl-phenyl dbl H 121 H H
2-Cl-4-CF.sub.3-phenyl dbl H 122 H H 2,3-diCl-phenyl sgl H 123 H H
3,4-diCl-phenyl sgl H 124 H H 2-Cl-4-CF.sub.3-phenyl sgl H 125 H H
Br sgl --CO.sub.2-tBu 126 H H 2,6-diF-phenyl sgl --CO.sub.2-tBu 127
H H 2,6-diF-phenyl sgl H 128 H 2,4-diCl-phenyl H sgl H 129 H phenyl
H sgl H 130 H 4-F-phenyl H sgl H 131 H 4-Cl-phenyl H sgl H 132 H
2-Cl-phenyl H sgl H 133 H 2-MeO-phenyl H sgl H 134 H
2-Cl-4-CF.sub.3-phenyl H sgl H 135 H 2,4-diMe-phenyl H sgl H 136 H
2-Cl-4-MeO-phenyl H sgl H 137 H 4-iPr-phenyl H sgl H 138 H
4-Bu-phenyl H sgl H 139 H 2-Me-4-MeO-5-F-- H sgl H phenyl 140 H
2-Me-4-MeO-phenyl H sgl H 141 H 2-Cl-4-CF.sub.3O-phenyl H sgl H 142
H 2,4,5-triMe-phenyl H sgl H 143 H 3-Cl-phenyl H sgl H 144 H
4-Me-phenyl H sgl H 145 H 2-Me-4-Cl-phenyl H sgl H 146 H
2,5-diCl-phenyl H sgl H 147 H 2-MeO-4-iPr-phenyl H sgl H 148 H
2,6-diCl-phenyl H sgl H 149 H 2,6-diF-phenyl H sgl H 150 H
2-CF.sub.3-4-MeO-phenyl H sgl H 151 H 2-CF.sub.3-phenyl H sgl H 152
H 4-pyridyl H sgl H 153 H 2-furanyl H sgl H 154 H 2-thiophenyl H
sgl H 155 H 4-F-phenyl H sgl H 156 H 2,3-diCl-phenyl H sgl H 157 H
4-Et-phenyl H sgl H 158 H 2,4-diMeO-phenyl H sgl H 159 H
2-F-3-Cl-phenyl H sgl H 160 H 4-MeO-phenyl H sgl H 161 H
4-Mes-phenyl H sgl H 162 H 4-CN-phenyl H sgl H 163 H
3-CF.sub.3-phenyl H sgl H 164 H 2-MeO-phenyl H sgl H 165 H
2-naphthyl H sgl H 166 H 4-acetylphenyl H sgl H 167 H
3-acetamidophenyl H sgl H 168 H 2,4-diCl-phenyl H sgl Me S316 H
2,3-diMe-phenyl H sgl H S317 H 2-Me-5-F-phenyl H sgl H S318 H
2-F-5-Me-phenyl H sgl H S319 H 2-MeO-5-F-phenyl H sgl H S320 H
2-Me-3-Cl-phenyl H sgl H S321 H 3-NO.sub.2-phenyl H sgl H S322 H
2-NO.sub.2-phenyl H sgl H S323 H 2-Cl-3-Me-phenyl H sgl H S324 H
2-MeO-phenyl H sgl H S325 H 2,3-diCl-phenyl H sgl H S326 H
2-Cl-4-CF.sub.3-phenyl H sgl H S327 H 2-Me-4-ELO-phenyl H sgl H
S328 H 2-Me-4-F-phenyl H sgl H S329 H 4-Bu-phenyl H sgl H S330 H
2-CF.sub.3-phenyl H sgl H S331 H 2-Cl-6-F-phenyl H sgl H S332 H
2-Cl-4-(CHF.sub.2)O- H sgl H phenyl S333 H 4-CF.sub.3-phenyl H sgl
H S334 H 4-Me-phenyl H sgl H S335 H 4-CF.sub.3O-phenyl H sgl H S336
H 2,4-diMeo-6-F- H sgl H phenyl S337 H 2-Me-phenyl H sgl H S338 H
2-CF.sub.3-6-F-phenyl H sgl H S339 H 2-MeS-phenyl H sgl H S340 H
2,4,6-triF-phenyl H sgl H S341 H 2,4,6-triCl-phenyl H sgl H S342 H
2,6-diCl-4-MeO- H sgl H phenyl S343 H 2,3,4-triF-phenyl H sgl H
S344 H 2,6-diF-4-Cl- H sgl H phenyl S345 H 2,3,4,6-tetraF- H sgl H
phenyl S346 H 2,3,4,5,6-pentaF- H sgl H phenyl S347 H
2,6-diCF.sub.3-phenyl H sgl H S348 H 2-CF.sub.3O-phenyl H sgl H
S349 H 2-CF.sub.3-4-EtO-phenyl H sgl H S350 H 2-CF.sub.3-4-iPrO- H
sgl H phenyl S351 H 2-naphtyl H sgl H S352 H 2-CF.sub.3-4-Cl-phenyl
H sgl H S353 H 2-CF.sub.3-4-F-phenyl H sgl H S354 H 2,4-diF-phenyl
H sgl Me S380 H 2-Cl-4-EtO-phenyl H sgl H S381 H 2-Cl-4-iPrO-phenyl
H sgl H S382 H 2-Et-4-MeO-phenyl H sgl H S383 H 2-CHO-4-MeO-phenyl
H sgl H S384 H 2-CH(OH)Me-4-MeO-- H sgl H phenyl S385 H
2-CH(OMe)Me-4-MeO-- H sgl H phenyl S386 H 2-C(.dbd.O)Me-4-MeO-- H
sgl H phenyl S387 H 2-CH.sub.2(OH)-4-MeO-- H sgl H phenyl S388 H
2-CH.sub.2(OMe)-4-MeO-- H sgl H phenyl S389 H 2-CH(OH)Et-4-MeO-- H
sgl H phenyl S390 H 2-C(.dbd.O)Et-4-MeO-- H sgl H phenyl S391 H
(Z)-2-CH.dbd.CHCO.sub.2Me-4- H sgl H MeO-phenyl S392 H
2-CH.sub.2CH.sub.2CO.sub.2Me-4- H sgl H MeO-phenyl S393 H
(Z)-2-CH.dbd.CHCH.sub.2(OH)-- H sgl H 4-MeO-phenyl S394 H
(E)-2-CH.dbd.CHCO.sub.2Me-4- H sgl H MeO-phenyl S395 H
(E)-2-CH.dbd.CHCH.sub.2(OH)-- H sgl H 4-MeO-phenyl S396 H
2-CH.sub.2CH.sub.2OMe-4-MeO-- H sgl H phenyl S397 H
2-F-4-MeO-phenyl H sgl H S403 H 2-Cl-4-F-phenyl H sgl H S405 H
(2-Cl-phenyl)- H sgl H CH.dbd.CH S406 H (3-Cl-phenyl)- H sgl H
CH.dbd.CH S407 H (2,6-diF-phenyl)- H sgl H CH.dbd.CH S410 H
cyclohexyl H sgl H S411 H cyclopentyl H sgl H S412 H
cyclohexylmethyl H sgl H S413 H --CH.sub.2CH.sub.2CO.sub.2Et H sgl
H S414 H --(CH.sub.2).sub.3CO.sub.2Et H sgl H S415 H
--(CH.sub.2).sub.4CO.sub.2Et H sgl H S416 H
--CH.sub.2CH.dbd.CH.sub.2 H sgl H S417 H Pr H sgl H S418 H benzyl H
sgl H S419 H 2-F-benzyl H sgl H S420 H 3-F-benzyl H sgl H S421 H
4-F-benzyl H sgl H S422 H 3-MeO-benzyl H sgl H S423 H 3-OH-benzyl H
sgl H S424 H 2-MeO-benzyl H sgl H S425 H 2-OH-benzyl H sgl H S426 H
2--CO.sub.2Me-3-MeO-- H sgl H phenyl S427 H 2,6-diF-phenyl H sgl H
S428 H phenyl-CH.dbd.CH-- H sgl H S429 H (2-Me-4-MeO-- H sgl H
phenyl)-CH.dbd.CH S430 H --NMe.sub.2 H sgl H S431 H 1-pyrrolidinyl
H sgl H S432 H --NTs.sub.2 H sgl H S433 H MeO H sgl H 445 H
2-Me-4-MeO-phenyl Me sgl H 446 H 2-CF.sub.3-4-MeO-phenyl Me sgl H
458 Me 2-CF.sub.3-4-MeO-phenyl H sgl H 459 Me 2,4-diCl-phenyl H sgl
H 460 H 3-CN-phenyl H sgl H 461 H 2-Me-4-CN-phenyl H sgl H 462 H
2-Me-3-CN-phenyl H sgl H 463 H 2-CN-phenyl H sgl H 464 H
2-CF.sub.3-4-CN-phenyl Me sgl H 465 H 3-CHO-phenyl Me sgl H 466 H
3-CH.sub.2(OH)-phenyl Me sgl H 467 H 3-CH.sub.2(OMe)-phenyl Me sgl
H 468 H 3-CH.sub.2(NMe2)-phenyl Me sgl H 469 H 3-CN-4-F-phenyl Me
sgl H 470 H 3--CONH.sub.2-4-F-phenyl Me sgl H 580 NH.sub.2 H H sgl
H 581 H phenyl-NH-- H sgl H 582 phenyl-NH-- H H sgl H 583 H
(4-F-phenyl)-NH-- H sgl H 584 H (2,4-diCl-phenyl)-NH-- H sgl H 585
H phenyl-C(.dbd.O)NH-- H sgl H 586 H benzyl-NH-- H sgl H 587 H
phenyl-S-- H sgl H 588 MeO H H sgl H 589 H
2-CH.sub.2(NH.sub.2)-4-MeO-- H sgl H phenyl- 590 H
2-Me-4-MeO-phenyl- H sgl H 592 H (2-Me-4-MeO-phenyl)- H sgl H NH--
593 H (2-F-4-MeO-phenyl)- H sgl H NH-- 595 H (2-Me-4-F-phenyl)-NH--
H sgl H
[3878]
8TABLE 6 51 Ex # n k m R7 R8 R9 b R1 471 2 2 1 H H H sgl H 472 2 2
1 H H H sgl --(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl) 473 2 2 1 H H H
sgl --(CH.sub.2).sub.3O(4-F-phenyl) 474 2 2 1 H H H sgl
--(CH.sub.2).sub.3(6-F-benzisoxazol- 3-yl) 475 2 2 1 H H H sgl
--(CH.sub.2).sub.3C(O)(4-pyridyl) 476 2 3 0 H H H sgl H 477 2 3 0 H
H H sgl --(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl) 478 2 3 0 H H H sgl
--(CH.sub.2)2(6-F-benzisoxazol- 3-yl) 483 2 2 1 H Br H sgl
--(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl) 484 2 2 1 H Br H sgl
--(CH.sub.2).sub.3O(4-F-phenyl) 488 1 2 1 H Br H sgl
--CO.sub.2-tBu
[3879]
9TABLE 6A 52 Ex # n k m R7 R8 R9 b R1 479 2 2 1 H 2,4-diCl-phenyl H
sgl H 480 2 2 1 H 2-Cl-4-MeO-phenyl H sgl H 481 2 2 1 H
2-Me-4-MeO-phenyl H sgl H 482 2 2 1 H Br H sgl H 497 1 1 1 H
2-Cl-phenyl H sgl H 498 1 1 1 H 3-Cl-phenyl H sgl H 499 1 1 1 H
3-F-phenyl H sgl H 500 1 1 1 H 4-Cl-phenyl H sgl H 501 1 1 1 H
4-F-phenyl H sgl H 502 1 1 1 H 2,3-diCl-phenyl H sgl H 503 1 1 1 H
2,3-diF-phenyl H sgl H 504 1 1 1 H 3,5-diCl-phenyl H sgl H 505 1 1
1 H 3,5-diF-phenyl H sgl H 506 1 1 1 H 3,4-diCl-phenyl H sgl H 507
1 1 1 H 3,4-diF-phenyl H sgl H 508 1 1 1 H 3-Cl-4-F-phenyl H sgl H
509 1 1 1 H 2-F-4-Cl-phenyl H sgl H
[3880]
10TABLE 7 53 Ex # n k m R7 R8 R9 b R1 172 2 1 1 H H H sgl H 173 1 1
1 H 2,4-diCl-phenyl H sgl H 174 1 1 1 H 2-Cl-4-MeO-phenyl H sgl H
436 1 1 1 H 2-Cl-phenyl H sgl H 497 1 1 1 H 2-Cl-phenyl H sgl H 498
1 1 1 H 3-Cl--phenyl H sgl H 499 1 1 1 H 3-F-phenyl H sgl H 500 1 1
1 H 4-Cl-phenyl H sgl H 501 1 1 1 H 4-F-phenyl H sgl H 502 1 1 1 H
2,3-diCl-phenyl H sgl H 503 1 1 1 H 2,3-diF-phenyl H sgl H 504 1 1
1 H 3,5-diCl-phenyl H sgl H 505 1 1 1 H 3,5-diF-phenyl H sgl H 506
1 1 1 H 3,4-diCl-phenyl H sgl H 507 1 1 1 H 3,4-diF-phenyl H sgl H
508 1 1 1 H 3-Cl-4-F-phenyl H sgl H 509 1 1 1 H 2-F-4-Cl-phenyl H
sgl H 510 1 1 1 H 2-Cl-4-F-phenyl H sgl H 511 1 1 1 H
2,5-diCl-phenyl H sgl H 512 1 1 1 H 2,6-diCl-phenyl H sgl H 513 1 1
1 H 2-CF.sub.3-phenyl H sgl H 514 1 1 1 H 4-CF.sub.3-phenyl H sgl H
515 1 1 1 H 2,4-diCF.sub.3-phenyl H sgl H 516 1 1 1 H
2-Cl-4-CF.sub.3-phenyl H sgl H 517 1 1 1 H 2-MeO-phenyl H sgl H 518
1 1 1 H 2,4-diMeO-phenyl H sgl H 519 1 1 1 H 2-MeO-5-iPr-phenyl H
sgl H 520 1 1 1 H 3-NO.sub.2-phenyl H sgl H 521 1 1 1 H
2-CHO-phenyl H sgl H 522 1 1 1 H 2-CH(Me)(OH)- H sgl H phenyl 523 1
1 1 H 2-CH.sub.2(OH)-phenyl H sgl H 524 1 1 1 H 2-CHO-4-MeO-phenyl
H sgl H 525 1 1 1 H 2-OH-phenyl H sgl H 526 1 1 1 H
2-CF.sub.3-4-ELO-phenyl H sgl H 527 1 1 1 H 2-CF.sub.3-4-iPrO- H
sgl H phenyl 532 1 1 1 H 2-Me-4-MeO-phenyl H sgl H 533 1 1 1 H
2-CF.sub.3-4-MeO-phenyl H sgl H 534 1 2 1 H 3,4,5-triMeO- H sgl H
phenyl 535 1 2 1 H 1-naphthyl H sgl H 536 1 2 1 H 3-MeO-phenyl H
sgl H 537 1 2 1 H 2,4-diCl-phenyl H sgl H 538 1 1 2 H H H sgl H 541
2 1 1 H H H dbl H 542 2 1 1 H H H sgl H 543 2 1 1 H 2,6-diF-phenyl
H sgl H 545 1 2 1 H H H sgl H 547 2 1 1 H 2-CF.sub.3-4-MeO-phenyl H
sgl H 548 2 1 1 H 2-Me-4-MeO-phenyl H sgl H 549 2 1 1 H
2-Cl-4-CF.sub.3-phenyl H sgl H 550 2 1 1 H 2,3-diCl-phenyl H sgl H
551 2 1 1 H 2,4-diMeo-phenyl H sgl H 552 2 1 1 H 3,4-diMeO-phenyl H
sgl H 553 2 1 1 H 2,4-diCl-phenyl H sgl H 554 2 1 1 H
3,4-diCl-phenyl H sgl H 555 2 1 1 H 2,5-diCl-phenyl H sgl H 556 2 1
1 H 2-CF.sub.3-phenyl H sgl H 557 2 1 1 H 2-Me-phenyl H sgl H 558 2
1 1 H 2-Cl-phenyl H sgl H 559 2 1 1 H 3-F-phenyl H sgl H 560 2 1 1
H phenyl H sgl H 561 2 1 1 H 2-CF.sub.3-4-EtO-phenyl H sgl H 562 2
1 1 H 2-CF.sub.3-4-iPrO- H sgl H phenyl 563 2 1 1 H
2-MeO-4-iPr-phenyl H sgl H 564 2 1 1 H 2-F-4-Cl-phenyl H sgl H 565
2 1 1 H 2-Cl-4-MeO-phenyl H sgl H 566 2 1 1 H 2-CHO-phenyl H sgl H
567 2 1 1 H 2-CHO-4-MeO-phenyl H sgl H 568 2 1 1 H
2-CH.sub.2(OH)-4-MeO- H sgl H phenyl 569 2 1 1 H
2-CH.sub.2(OH)-phenyl H sgl H 570 2 1 1 H 2-CF.sub.3-4-NHMe- H sgl
H phenyl 571 2 1 1 H 2-CF.sub.3-4-NH.sub.2-pheny- l H sgl H 572 2 1
1 H 2-C(=O)Me phenyl H sgl H 573 2 1 1 H 2-C(=O)Me-4-MeO H sgl H
phenyl 574 2 1 1 H 2-CH(Me)(OH)-- H sgl H phenyl 575 2 1 1 H
2-CH(Me)(OH)-4- H sgl H MeO-phenyl 576 2 1 1 H
2-CF.sub.3-4-OH-phenyl H sgl H 577 2 1 1 H 2-CF.sub.3-4-O(C=O)Me- H
sgl H phenyl
[3881]
11TABLE 7A 54 Ex # n k m R7 R8 R9 b R1 182 1 1 1 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)- (4-F- phenyl) 266 1 1 1 H H Me sgl
--(CH.sub.2).sub.3C(.dbd.O)(4-F- phenyl) 270 1 1 1 H H H sgl
--(CH.sub.2).sub.3O(4-F- phenyl) 272 1 1 1 H H H sgl H 494 1 1 1 H
H H sgl --(CH.sub.2).sub.3C(.dbd.O)(2-NH- .sub.2- phenyl) 495 1 1 1
H H H sgl --(CH.sub.2).sub.3C(.dbd.O)(2-NH.sub.2- phenyl) 496 1 1 1
H H H sgl --(CH.sub.2).sub.3(1H-indazol- 3-yl) 528 1 1 1 H H H sgl
--(CH.sub.2).sub.3(6-F-1H- indazol-3-yl) 529 1 1 1 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(2-NH- .sub.2- 4-F-phenyl) 530 1 1 1 H H
H sgl --(CH.sub.2).sub.3C(.dbd.O)(2-NH.sub.2- 4-F-phenyl) 531 1 1 1
H H H sgl --(CH.sub.2).sub.3C(.dbd.O)(2-OH- 4-F-phenyl) 539 1 2 1 H
H H sgl --(CH.sub.2).sub.3O(4-F- phenyl) 540 1 2 1 H H H sgl
--(CH.sub.2).sub.3(6-F-1,2- benzisoxazol-3-yl) 544 2 1 1 H H H sgl
--(CH.sub.2).sub.3C(=O)(4-F- phenyl) 546 1 2 1 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(4-F- phenyl)
[3882]
12TABLE 8 55 Ex # R7 R8 R9 b R1 183 H H CF.sub.3 dbl
--(CH.sub.2).sub.3CH(OH)(4-F-phe- nyl) 184 H H CF.sub.3 dbl
--(CH.sub.2).sub.3C(OCH.sub.2CH.sub.2O)(4- -F-phenyl) 185 H H
CF.sub.3 sgl --(CH.sub.2).sub.4(4-F-phenyl) 188 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl) 195 H H CF.sub.3 dbl
--(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl) 213 H CH.sub.3 H sgl
--(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl) 438 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(2-NH.sub.2-phenyl) 439 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(2-NH.sub.2-phenyl) 440 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(2-NH.sub.2-4-F-phenyl) 441 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(2-NH.sub.2-4-F-phenyl) 456 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl) 457 H H H sgl
--(CH.sub.2).sub.3C(.dbd.O)(4-F-phenyl)
[3883]
13TABLE 8A 56 Ex # R7 R8 R9 b R1 443 2,3-diCl-phenyl H H sgl H 444
2,3-diF-phenyl H H sgl H 447 2,6-diCl-phenyl H H sgl H 452
2-Me-4-MeO-phenyl H H sgl H 453 2-Cl-6-F-phenyl H H sgl H 454
2,6-diF-phenyl H H sgl H 455 2,4-diCl-phenyl H H sgl H
[3884]
14TABLE 9 57 Ex # X n R7 R8 R9 b R1 S398 SO.sub.2 2 H
2,4-diCl-phenyl H sgl H S399 SO.sub.2 2 H 2,6-diF-phenyl H sgl H
S400 SO.sub.2 2 H 2-Cl-phenyl H sgl H S401 SO.sub.2 2 H
2-F-4-MeO-phenyl H sgl H S402 SO.sub.2 2 H 2-Me-4-MeO-phenyl H sgl
H 5404 SO 2 H 2-Cl-4-F-phenyl H sgl H S434 SO 2 H 2,4-diCl-phenyl H
sgl H S435 SO 2 H 2-Me-4-MeO-phenyl H sgl H 448 SO.sub.2 1 H H H
sgl H 449 SO 1 H H H sgl H 450 SO.sub.2 1 H 2-CF.sub.3-4-MeO-phenyl
H sgl H 451 SO.sub.2 1 H 2,4-diCl-phenyl H sgl H
* * * * *