U.S. patent application number 11/996751 was filed with the patent office on 2008-10-30 for 6-arylalkylamino-2,3,4,5-tetrahydro-1h-benzo[d]azepines as 5-ht2c receptor agonists.
Invention is credited to Maria Adeva Bartolome, Karin Briner, Manuel Javier Cases-Thomas, Christopher Stanley Galka, Alicia Marcos Llorente, Maria Angeles Martinez-Grau, Michael Philip Mazanetz, John Cunningham O' Toole, Richard Edmund Rathmell, Matthew Robert Reinhard, Selma Sapmaz, Andrew Caerwyn Williams.
Application Number | 20080269196 11/996751 |
Document ID | / |
Family ID | 39892208 |
Filed Date | 2008-10-30 |
United States Patent
Application |
20080269196 |
Kind Code |
A1 |
Briner; Karin ; et
al. |
October 30, 2008 |
6-Arylalkylamino-2,3,4,5-Tetrahydro-1H-Benzo[D]Azepines as 5-Ht2c
Receptor Agonists
Abstract
The present invention provides 6-substituted
2,3,4,5-tetrahydro-1H-benzo[d]azepines of Formula (I) as selective
5-HT2c receptor agonists for the treatment of 5-HT2c associated
disorders including obesity, obsessive/compulsive disorder,
depression, and anxiety, where, R6 is --NR10R11, where R10 is
substituted phenylalkyl or substituted pyridylalkyl and other
substituents are as defined in the specification. ##STR00001##
Inventors: |
Briner; Karin;
(Indianapolis, IN) ; Bartolome; Maria Adeva;
(Madrid, ES) ; Cases-Thomas; Manuel Javier;
(Hampshire, GB) ; Galka; Christopher Stanley;
(Carmel, IN) ; Llorente; Alicia Marcos; (Madrid,
ES) ; Martinez-Grau; Maria Angeles; (Madrid, ES)
; Mazanetz; Michael Philip; (Hampshire, GB) ; O'
Toole; John Cunningham; (Indianapolis, IN) ;
Rathmell; Richard Edmund; (Hampshire, GB) ; Reinhard;
Matthew Robert; (Indianapolis, IN) ; Sapmaz;
Selma; (Hampshire, GB) ; Williams; Andrew
Caerwyn; (Hampshire, GB) |
Correspondence
Address: |
ELI LILLY & COMPANY
PATENT DIVISION, P.O. BOX 6288
INDIANAPOLIS
IN
46206-6288
US
|
Family ID: |
39892208 |
Appl. No.: |
11/996751 |
Filed: |
September 1, 2006 |
PCT Filed: |
September 1, 2006 |
PCT NO: |
PCT/US06/34335 |
371 Date: |
January 25, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60731081 |
Oct 28, 2005 |
|
|
|
Current U.S.
Class: |
514/217.01 ;
540/594 |
Current CPC
Class: |
C07D 417/14 20130101;
A61P 25/20 20180101; A61P 25/28 20180101; A61P 25/22 20180101; A61P
25/14 20180101; C07D 413/12 20130101; C07D 403/12 20130101; A61P
15/08 20180101; A61P 25/16 20180101; A61P 43/00 20180101; C07D
223/16 20130101; A61P 25/04 20180101; A61P 15/10 20180101; A61P
25/30 20180101; A61P 25/18 20180101; C07D 409/12 20130101; A61P
25/00 20180101; A61P 25/02 20180101; C07D 401/12 20130101; A61P
3/04 20180101; A61P 3/00 20180101; A61P 25/24 20180101; C07D 417/12
20130101 |
Class at
Publication: |
514/217.01 ;
540/594 |
International
Class: |
A61K 31/55 20060101
A61K031/55; C07D 223/16 20060101 C07D223/16 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 1, 2005 |
EP |
05380191.6 |
Claims
1. A compound of Formula I: ##STR00219## where: R.sup.1 is
hydrogen; R.sup.2, R.sup.3, and R.sup.4 are each hydrogen; R.sup.5
is hydrogen; R.sup.6 is
--(C.sub.1-C.sub.3)alkyl-S--(C.sub.0-C.sub.3)alkyl-R.sup.10,
--(C.sub.1-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl-R.sup.11,
or --(C.sub.1-C.sub.3)alkyl-O--(C.sub.0-C.sub.3)alkyl-R.sup.13;
R.sup.7 is chloro; R.sup.8 is hydrogen; R.sup.9 is hydrogen;
R.sup.10 is a) an aromatic heterocycle substituent selected from
the group consisting of tetrazolyl, 1,2,3-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-oxadiazolyl,
1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl, any one of which may
optionally be substituted with a substituent selected from the
group consisting of (C.sub.1-C.sub.4)alkyl optionally substituted
with 1 to 5 fluoro substituents, Ph.sup.1-(C.sub.0-C.sub.3)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl, (C.sub.1-C.sub.4)alkyl-C(O)--,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--,
(C.sub.1-C.sub.4)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl-
optionally substituted on the on the and (C.sub.1-C.sub.4)alkyl
moiety with 1 to 5 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.-
sub.3)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl;
b) an aromatic heterocycle substituent selected from the group
consisting of imidazolyl, thiazolyl, isothiazolyl, thiophenyl,
pyrazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
or a heterocycle selected from thiazolinyl, any one of which may be
optionally substituted with one to two substituents selected from
the group consisting of (C.sub.1-C.sub.6)alkyl optionally
substituted with 1 to 6 fluoro substituents,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl optionally substituted on the alkyl
moiety with 1 to 6 fluoro substituents,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl optionally substituted on the
alkyl moiety with 1 to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkyl-C(O)--,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--,
(C.sub.1-C.sub.6)alkyl-NH--C(O)-- optionally substituted with 1 to
6 fluoro substituents, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--C(O)--
optionally substituted on the alkyl moiety with 1 to 6 fluoro
substituents, and Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--C(O)--
optionally substituted on the alkyl moiety with 1 to 6 fluoro
substituents, or optionally substituted on ring carbon atoms with
one or two substituents selected from the group consisting of halo,
cyano, (C.sub.1-C.sub.6)alkyl-CH.dbd.CH-- optionally substituted
with 1 to 6 fluoro substituents, (C.sub.1-C.sub.6)alkoxy optionally
substituted with 1 to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkylthio optionally substituted with 1 to 6
fluoro substituents, Ph.sup.1-(C.sub.0-C.sub.3)alkylthio,
(C.sub.1-C.sub.6)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl-
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.-
sub.3)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl-,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl-,
Het.sup.1-(C.sub.0-C.sub.3)alkyl-,
(C.sub.1-C.sub.6)alkyl-C(O)--NH--,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--NH--,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--NH--,
(C.sub.1-C.sub.6)alkyl-O--C(O)--NH-- optionally substituted with 1
to 6 fluoro substituents,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--C(O)--NH-- optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents,
and Ar.sup.1--(C.sub.0-C.sub.3)alkyl-O--C(O)--NH-- optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents, or
optionally substituted on two adjacent ring atoms with a bivalent 3
to 4 carbon hydrocarbon substituent which, together with the ring
atoms to which it is attached, form a benzene ring or a partially
saturated five- or six-membered ring; c) phenyl optionally
substituted with: i) 1 to 5 independently selected halo
substituents; or ii) 1 to 3 substituents independently selected
from the group consisting of halo, cyano, --SCF.sub.3, nitro,
hydroxy, (C.sub.1-C.sub.6)alkyl optionally further substituted with
1 to 6 fluoro substituents, and (C.sub.1-C.sub.6)alkoxy optionally
further substituted with 1 to 6 fluoro substituents; or iii) 0, 1,
or 2 substituents independently selected from the group consisting
of halo, cyano, --SCF.sub.3, methyl, --CF.sub.3, methoxy,
--OCF.sub.3, nitro, and hydroxy, together with one substituent
selected from the group consisting of
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.5)alkyl optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents and
optionally substituted independently on the cycloalkyl moiety with
1 to 6 substituents selected from fluoro and methyl provided that
no more than 2 substituents are methyl,
Ph.sup.1-(C.sub.0-C.sub.5)alkyl, Ar.sup.1--(C.sub.0-C.sub.5)alkyl,
thiazolyl-(C.sub.0-C.sub.1)alkyl optionally substituted with a
substituent independently selected from the group consisting of
halo, (C.sub.1-C.sub.6)alkyl optionally further substituted with 1
to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl-
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents, and
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.-
sub.3)alkyl, (C.sub.1-C.sub.6)alkyl-CH.dbd.CH-- optionally
substituted with 1 to 6 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-CH.dbd.CH--
optionally substituted with 1 to 6 fluoro substituents on alkyl and
optionally substituted independently on the cycloalkyl moiety with
1 to 6 substituents selected from fluoro and methyl provided that
no more than 2 substituents are methyl,
(C.sub.1-C.sub.6)alkyl-S--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-O--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5-
)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl- C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)a-
lkyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
Het.sup.1-(C.sub.0-C.sub.3)alkyl-,
(C.sub.1-C.sub.6)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)-
alkyl,
(C.sub.3-C.sub.7)cycloalkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--SO.sub.2--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--SO.sub.2--(C.sub.0-
-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--NH--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--NH--(C.sub.0-
-C.sub.5)alkyl; d) an aromatic heterocycle substituent selected
from the group consisting of pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, any of which may be optionally substituted with 1 or 2
substituents independently selected from the group consisting of
halo, cyano, --SCF.sub.3, methyl, --CF.sub.3, methoxy, --OCF.sub.3,
nitro, hydroxy, and optionally further substituted with a
substituent selected from the group consisting of
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.5)alkyl optionally
further substituted on the alkyl moiety with 1 to 6 fluoro
substituents and optionally substituted independently on the
cycloalkyl moiety with 1 to 6 substituents selected from fluoro and
methyl provided that no more than 2 substituents are methyl,
Ph.sup.1-(C.sub.0-C.sub.5)alkyl, Ar.sup.1--(C.sub.0-C.sub.5)alkyl,
thiazolyl-(C.sub.0-C.sub.1)alkyl optionally substituted with a
substituent independently selected from the group consisting of
halo, (C.sub.1-C.sub.6)alkyl optionally further substituted with 1
to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl-
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents, and
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.-
sub.3)alkyl, (C.sub.1-C.sub.6)alkyl-CH.dbd.CH-- optionally
substituted with 1 to 6 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-CH.dbd.CH--
optionally substituted with 1 to 6 fluoro substituents on alkyl and
optionally substituted independently on the cycloalkyl moiety with
1 to 6 substituents selected from fluoro and methyl provided that
no more than 2 substituents are methyl,
(C.sub.1-C.sub.6)alkyl-S--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-O--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5-
)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)a-
lkyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
Het.sup.1-(C.sub.0-C.sub.5)alkyl-,
(C.sub.1-C.sub.6)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl;
or e) alpha-naphthalyl, quinolin-2-yl, quinolin-3-yl, or
quinolin-4-yl; R.sup.11 is a) phenyl optionally substituted with:
i) 1 to 5 independently selected halo substituents; or ii) 1 to 3
substituents independently selected from the group consisting of
halo, cyano, methyl, --CF.sub.3, --SCF.sub.3, methoxy, nitro, and
hydroxy; or iii) 0, 1 or 2 substituents independently selected from
the group consisting of halo, cyano, methyl, --CF.sub.3,
--SCF.sub.3, methoxy, nitro, and hydroxy and further substituted
with a substituent selected from the group consisting of:
(C.sub.1-C.sub.6)alkyl optionally further substituted with 1 to 6
fluoro substituents,
(C.sub.1-C.sub.6)alkyl-O--(C.sub.0-C.sub.5)alkyl optionally further
substituted with 1 to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkyl-CH.dbd.CH-- optionally substituted with 1 to
6 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-CH.dbd.CH--
optionally substituted with 1 to 6 fluoro substituents on alkyl and
optionally substituted independently on the cycloalkyl moiety with
1 to 6 substituents selected from fluoro and methyl provided that
no more than 2 substituents are methyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-S--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5-
)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)a-
lkyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
Het.sup.1-(C.sub.0-C.sub.5)alkyl-,
(C.sub.1-C.sub.6)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
and
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl;
b) pyridyl optionally substituted with i) 1 to 3 substituents
independently selected from the group consisting of halo, cyano,
methyl, --CF.sub.3, --SCF.sub.3, methoxy, nitro, and hydroxy; or
ii) 0, 1 or 2 substituents independently selected from the group
consisting of halo, cyano, methyl, --CF.sub.3, --SCF.sub.3,
methoxy, nitro, and hydroxy, and further substituted with a
substituent selected from the group consisting of:
(C.sub.1-C.sub.6)alkyl optionally further substituted with 1 to 6
fluoro substituents,
(C.sub.1-C.sub.6)alkyl-O--(C.sub.0-C.sub.5)alkyl optionally further
substituted with 1 to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkyl-CH.dbd.CH-- optionally substituted with 1 to
6 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-CH.dbd.CH--
optionally substituted with 1 to 6 fluoro substituents on alkyl and
optionally substituted independently on the cycloalkyl moiety with
1 to 6 substituents selected from fluoro and methyl provided that
no more than 2 substituents are methyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-S--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5-
)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)a-
lkyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.s-
ub.5)alkyl, and
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl;
c) pyridazinyl optionally substituted with 1 or 2 substituents
independently selected from the group consisting of halo, cyano,
hydroxy, (C.sub.1-C.sub.6)alkyl optionally further substituted with
1 to 6 fluoro substituents, (C.sub.1-C.sub.6)alkoxy optionally
further substituted with 1 to 6 fluoro substituents; and
(C.sub.1-C.sub.6)alkylthio optionally further substituted with 1 to
6 fluoro substituents; or d) a five-membered aromatic heterocycle
selected from the group of thiophenyl, thiazole, isothiazole
optionally substituted with 1 or 2 substituents independently
selected from the group consisting of halo, cyano, hydroxy,
(C.sub.1-C.sub.6)alkyl optionally further substituted with 1 to 6
fluoro substituents, (C.sub.1-C.sub.6)alkoxy optionally further
substituted with 1 to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkylthio optionally further substituted with 1 to
6 fluoro substituents, (C.sub.1-C.sub.6)alkylamino optionally
further substituted with 1 to 6 fluoro substituents, and
(C.sub.1-C.sub.6)alkyl-C(O)--; R.sup.12 is hydrogen or methyl
R.sup.13 is a) phenyl optionally substituted with: i) 1 to 5
independently selected halo substituents; or ii) 1 to 3
substituents independently selected from the group consisting of
halo, cyano, --SCF.sub.3, nitro, hydroxy, (C.sub.1-C.sub.6)alkyl
optionally further substituted with 1 to 6 fluoro substituents, and
(C.sub.1-C.sub.6)alkoxy optionally further substituted with 1 to 6
fluoro substituents; or iii) 0, 1, or 2 substituents independently
selected from the group consisting of halo, cyano, --SCF.sub.3,
methyl, --CF.sub.3, methoxy, --OCF.sub.3, nitro, and hydroxy,
together with one substituent selected from the group consisting of
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.5)alkyl optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents and
optionally substituted independently on the cycloalkyl moiety with
1 to 6 substituents selected from fluoro and methyl provided that
no more than 2 substituents are methyl,
Ph.sup.1-(C.sub.0-C.sub.5)alkyl, Ar.sup.1--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-CH.dbd.CH-- optionally substituted with 1 to
6 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-CH.dbd.CH--
optionally substituted with 1 to 6 fluoro substituents on alkyl and
optionally substituted independently on the cycloalkyl moiety with
1 to 6 substituents selected from fluoro and methyl provided that
no more than 2 substituents are methyl,
(C.sub.1-C.sub.6)alkyl-S--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-O--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5-
)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl- C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)a-
lkyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
Het.sup.1-(C.sub.0-C.sub.3)alkyl-,
(C.sub.1-C.sub.6)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)-
alkyl,
(C.sub.3-C.sub.7)cycloalkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--SO.sub.2--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--SO.sub.2--(C.sub.0-
-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--NH--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--NH--(C.sub.0-
-C.sub.5)alkyl; or b) thiophenyl optionally substituted with one to
two substituents selected from the group consisting of halo, cyano,
(C.sub.1-C.sub.6)alkyl optionally substituted with 1 to 6 fluoro
substituents, Ph.sup.1-(C.sub.0-C.sub.3)alkyl optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl optionally substituted on the
alkyl moiety with 1 to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkyl-C(O)--,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--,
(C.sub.1-C.sub.6)alkyl-NH--C(O)-- optionally substituted with 1 to
6 fluoro substituents, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--C(O)--
optionally substituted on the alkyl moiety with 1 to 6 fluoro
substituents, Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--C(O)--
optionally substituted on the alkyl moiety with 1 to 6 fluoro
substituents, (C.sub.1-C.sub.6)alkyl-CH.dbd.CH-- optionally
substituted with 1 to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkoxy optionally substituted with 1 to 6 fluoro
substituents, (C.sub.1-C.sub.6)alkylthio optionally substituted
with 1 to 6 fluoro substituents,
Ph.sup.1-(C.sub.0-C.sub.3)alkylthio,
(C.sub.1-C.sub.6)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl-
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.-
sub.3)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl-,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl-,
Het.sup.1-(C.sub.0-C.sub.3)alkyl-,
(C.sub.1-C.sub.6)alkyl-C(O)--NH--,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--NH--,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--NH--,
(C.sub.1-C.sub.6)alkyl-O--C(O)--NH-- optionally substituted with 1
to 6 fluoro substituents,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--C(O)--NH-- optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents,
and Ar.sup.1--(C.sub.0-C.sub.3)alkyl-O--C(O)--NH-- optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents;
Ar.sup.1 is pyridyl, optionally substituted with 1 to 4
independently selected halo substituents, or with 1 to 3
substituents independently selected from the group consisting of
halo, cyano, hydroxy, acetyl, methyl, --CF.sub.3, methoxy,
--OCF.sub.3, methylthio, --SCF.sub.3; Ph.sup.1 is phenyl optionally
substituted with 1 to 5 independently selected halo substituents,
or with 1 to 3 substituents independently selected from the group
consisting of halo, cyano, hydroxy, acetyl, methylthio,
--SCF.sub.3, (C.sub.1-C.sub.6)alkyl optionally further substituted
with 1 to 6 fluoro substituents, and (C.sub.1-C.sub.6)alkoxy
optionally further substituted with 1 to 6 fluoro substituents;
Het.sup.1 is a saturated, nitrogen-containing heterocycle
substituent selected from the group consisting of pyrrolidinyl,
piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl,
homomorpholinyl, and homothiomorpholinyl, any of which may
optionally be substituted with (C.sub.1-C.sub.6)alkyl or with 2
methyl substituents; or a pharmaceutically acceptable salt
thereof.
2. A compound of Formula (Ia): ##STR00220## wherein R.sup.7a is
chloro; and R.sup.10 is a) an aromatic heterocycle substituent
selected from the group consisting of tetrazolyl
1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl any one
of which may optionally be substituted with a substituent selected
from the group consisting of (C.sub.1-C.sub.4)alkyl optionally
substituted with 1 to 5 fluoro substituents,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl Ar.sup.1(C.sub.0-C.sub.3)alkyl
(C.sub.1-C.sub.4)alkyl-C(O)--,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.4)alkyl-NR.sup.12---
(C.sub.0-C.sub.3)alkyl-optionally substituted on the on the and
(C.sub.1-C.sub.4)alkyl moiety with 1 to 5 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.-
sub.3)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl;
b) an aromatic heterocycle substituent selected from the group
consisting of imidazolyl thiazolyl isothiazolyl thiophenyl
pyrazolyl oxazolyl isoxazolyl 1,2,3-triazolyl, 1,2,4-triazolyl or a
heterocycle selected from thiazolinyl any one of which may be
optionally substituted with one to two substituents selected from
the group consisting of (C.sub.1-C.sub.6)alkyl optionally
substituted with 1 to 6 fluoro substituents,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl optionally substituted on the alkyl
moiety with 1 to 6 fluoro substituents,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl optionally substituted on the
alkyl moiety with 1 to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkyl-C(O)--,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--,
(C.sub.1-C.sub.6)alkyl-NH--C(O)-- optionally substituted with 1 to
6 fluoro substituents, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--C(O)--
optionally substituted on the alkyl moiety with 1 to 6 fluoro
substituents, and Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--C(O)--
optionally substituted on the alkyl moiety with 1 to 6 fluoro
substituents, or optionally substituted on ring carbon atoms with
one or two substituents selected from the group consisting of halo,
cyano, (C.sub.1-C.sub.6)alkyl-CH.dbd.CH-- optionally substituted
with 1 to 6 fluoro substituents, (C.sub.1-C.sub.6)alkoxy optionally
substituted with 1 to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkylthio optionally substituted with 1 to 6
fluoro substituents, Ph.sup.1-(C.sub.0-C.sub.3)alkylthio,
(C.sub.1-C.sub.6)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl-
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.-
sub.3)alkyl-,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl-,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl-,
Het.sup.1-(C.sub.0-C.sub.3)alkyl-,
(C.sub.1-C.sub.6)alkyl-C(O)--NH--,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--NH--,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--NH--,
(C.sub.1-C.sub.6)alkyl-O--C(O)--NH-- optionally substituted with 1
to 6 fluoro substituents,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--C(O)--NH-- optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents,
and Ar.sup.1--(C.sub.0-C.sub.3)alkyl-O--C(O)--NH-- optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents, or
optionally substituted on two adjacent ring atoms with a bivalent 3
to 4 carbon hydrocarbon substituent which together with the ring
atoms to which it is attached form a benzene ring or a partially
saturated five- or six-membered ring: c) phenyl optionally
substituted with: i) 1 to 5 independently selected halo
substituents; or ii) 1 to 3 substituents independently selected
from the group consisting of halo, cyano, --SCF.sub.3, nitro,
hydroxy (C.sub.1-C.sub.6)alkyl optionally further substituted with
1 to 6 fluoro substituents, and (C.sub.1-C.sub.6)alkoxy optionally
further substituted with 1 to 6 fluoro substituents; or iii) 0, 1
or 2 substituents independently selected from the group consisting
of halo, cyano, --SCF.sub.3 methyl, --CF.sub.3, methoxy --OCF.sub.3
nitro, and hydroxy, together with one substituent selected from the
group consisting of
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.5)alkyl optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents and
optionally substituted independently on the cycloalkyl moiety with
1 to 6 substituents selected from fluoro and methyl provided that
no more than 2 substituents are methyl
Ph.sup.1-(C.sub.0-C.sub.5)alkyl, Ar.sup.1--(C.sub.0-C.sub.5)alkyl,
thiazolyl-(C.sub.0-C.sub.1)alkyl optionally substituted with a
substituent independently selected from the group consisting of
halo, (C.sub.1-C.sub.6)alkyl optionally further substituted with 1
to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl-
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents, and
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.-
sub.3)alkyl, (C.sub.1-C.sub.6)alkyl-CH.dbd.CH-- optionally
substituted with 1 to 6 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-CH.dbd.CH--
optionally substituted with 1 to 6 fluoro substituents on alkyl and
optionally substituted independently on the cycloalkyl moiety with
1 to 6 substituents selected from fluoro and methyl provided that
no more than 2 substituents are methyl
(C.sub.1-C.sub.6)alkyl-S--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5
alkyl Ph.sup.1-(C.sub.1-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-O--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl
(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5-
)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6 alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)a-
lkyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
Het.sup.1-(C.sub.0-C.sub.3 alkyl-,
(C.sub.1-C.sub.6)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)-
alkyl,
(C.sub.3-C.sub.7)cycloalkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--SO.sub.2--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--SO.sub.2--(C.sub.0-
-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--NH--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--NH--(C.sub.0-
-C.sub.5)alkyl; d) an aromatic heterocycle substituent selected
from the group consisting of pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, any of which may be optionally substituted with 1 or 2
substituents independently selected from the group consisting of
halo, cyano, --SCF.sub.3, methyl --CF.sub.3 methoxy, --OCF.sub.3,
nitro, hydroxy and optionally further substituted with a
substituent selected from the group consisting of
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.5)alkyl optionally
further substituted on the alkyl moiety with 1 to 6 fluoro
substituents and optionally substituted independently on the
cycloalkyl moiety with 1 to 6 substituents selected from fluoro and
methyl provided that no more than 2 substituents are methyl,
Ph.sup.1-(C.sub.0-C.sub.5)alkyl, Ar.sup.1--(C.sub.0-C.sub.5)alkyl,
thiazolyl-(C.sub.0-C.sub.1)alkyl optionally substituted with a
substituent independently selected from the group consisting of
halo, (C.sub.1-C.sub.6)alkyl optionally further substituted with 1
to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl-
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents, and
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.-
sub.3)alkyl, (C.sub.1-C.sub.6)alkyl-CH.dbd.CH-- optionally
substituted with 1 to 6 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-CH.dbd.CH--
optionally substituted with 1 to 6 fluoro substituents on alkyl and
optionally substituted independently on the cycloalkyl moiety with
1 to 6 substituents selected from fluoro and methyl provided that
no more than 2 substituents are methyl,
(C.sub.1-C.sub.6)alkyl-S--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-O--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-SO--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.1)alkyl-SO.sub.2--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.1-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5-
)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)a-
lkyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
Het.sup.1-(C.sub.0-C.sub.5)alkyl-,
(C.sub.1-C.sub.6)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl;
or e) alpha-naphthalyl, quinolin-2-yl, quinolin-3-yl, or
quinolin-4-yl; Ar.sup.1 is pyridyl optionally substituted with 1 to
4 independently selected halo substituents, or with 1 to 3
substituents independently selected from the group consisting of
halo, cyano, hydroxy, acetyl methyl --CF.sub.3, methoxy,
--OCF.sub.3 methylthio, --SCF.sub.3; Ph.sup.1 is phenyl optionally
substituted with 1 to 5 independently selected halo substituents,
or with 1 to 3 substituents independently selected from the group
consisting of halo, cyano, hydroxy, acetyl, methylthio,
--SCF.sub.3, (C.sub.1-C.sub.6)alkyl optionally further substituted
with 1 to 6 fluoro substituents, and (C.sub.1-C.sub.6)alkoxy
optionally further substituted with 1 to 6 fluoro substituents;
Het.sup.1 is a saturated, nitrogen-containing heterocycle
substituent selected from the group consisting of pyrrolidinyl,
piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl,
homomorpholinyl, and homothiomorpholinyl, any of which may
optionally be substituted with (C.sub.1-C.sub.6)alkyl or with 2
methyl substituents; or a pharmaceutically acceptable salt
thereof.
3. A compound of Formula (Ib): ##STR00221## wherein R.sup.7a is
chloro; R.sup.11 is; a) phenyl optionally substituted with: i) 1 to
5 independently selected halo substituents; or ii) 1 to 3
substituents independently selected from the group consisting of
halo, cyano, methyl --CF.sub.3, --SCF.sub.3 methoxy, nitro, and
hydroxy; or iii) 0, 1 or 2 substituents independently selected from
the group consisting of halo, cyano, methyl --CF.sub.3, --SCF.sub.3
methoxy, nitro, and hydroxy and further substituted with a
substituent selected from the group consisting of:
(C.sub.1-C.sub.6)alkyl optionally further substituted with 1 to 6
fluoro substituents,
(C.sub.1-C.sub.6)alkyl-O--(C.sub.0-C.sub.5)alkyl optionally further
substituted with 1 to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkyl-CH.dbd.CH-- optionally substituted with 1 to
6 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-CH.dbd.CH--
optionally substituted with 1 to 6 fluoro substituents on alkyl and
optionally substituted independently on the cycloalkyl moiety with
1 to 6 substituents selected from fluoro and methyl provided that
no more than 2 substituents are methyl
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-S--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5-
)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)-(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)a-
lkyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
Het.sup.1-(C.sub.0-C.sub.5)alkyl-,
(C.sub.1-C.sub.6)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
and
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl;
b) pyridyl optionally substituted with i) 1 to 3 substituents
independently selected from the group consisting of halo, cyano,
methyl, --CF.sub.3, --SCF.sub.3, methoxy, nitro, and hydroxy; or
ii) 0, 1 or 2 substituents independently selected from the group
consisting of halo, cyano, methyl, --CF.sub.3, --SCF.sub.3,
methoxy, nitro, and hydroxy and further substituted with a
substituent selected from the group consisting of:
(C.sub.1-C.sub.6)alkyl optionally further substituted with 1 to 6
fluoro substituents,
(C.sub.1-C.sub.6)alkyl-O--(C.sub.0-C.sub.5)alkyl optionally further
substituted with 1 to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkyl-CH.dbd.CH-optionally substituted with 1 to 6
fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-CH.dbd.CH--
optionally substituted with 1 to 6 fluoro substituents on alkyl and
optionally substituted independently on the cycloalkyl moiety with
1 to 6 substituents selected from fluoro and methyl provided that
no more than 2 substituents are methyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)
alkyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-S--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-SO--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.5)alkyl-SO.sub.2--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5-
)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)a-
lkyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.s-
ub.5)alkyl and
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl;
c) pyridazinyl optionally substituted with 1 or 2 substituents
independently selected from the group consisting of halo, cyano,
hydroxy (C.sub.1-C.sub.6)alkyl optionally further substituted with
1 to 6 fluoro substituents, (C.sub.1-C.sub.6)alkoxy optionally
further substituted with 1 to 6 fluoro substituents; and
(C.sub.1-C.sub.6)alkylthio optionally further substituted with 1 to
6 fluoro substituents; or d) a five-membered aromatic heterocycle
selected from the group of thiophenyl, thiazole, isothiazole
optionally substituted with 1 or 2 substituents independently
selected from the group consisting of halo, cyano, hydroxy,
(C.sub.1-C.sub.6)alkyl optionally further substituted with 1 to 6
fluoro substituents, (C.sub.1-C.sub.6)alkoxy optionally further
substituted with 1 to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkylthio optionally further substituted with 1 to
6 fluoro substituents, (C.sub.1-C.sub.6)alkylamino optionally
further substituted with 1 to 6 fluoro substituents, and
(C.sub.1-C.sub.6)alkyl-C(O)--; R.sup.12 is hydrogen or methyl
Ar.sup.1 is pyridyl, optionally substituted with 1 to 4
independently selected halo substituents, or with 1 to 3
substituents independently selected from the group consisting of
halo, cyano, hydroxy, acetyl, methyl --CF.sub.3, methoxy,
--OCF.sub.3, methylthio, --SCF.sub.3; Ph.sup.1 is phenyl optionally
substituted with 1 to 5 independently selected halo substituents,
or with 1 to 3 substituents independently selected from the group
consisting of halo, cyano, hydroxy, acetyl, methylthio,
--SCF.sub.3, (C.sub.1-C.sub.6)alkyl optionally further substituted
with 1 to 6 fluoro substituents, and (C.sub.1-C.sub.6)alkoxy
optionally further substituted with 1 to 6 fluoro substituents;
Het.sup.1 is a saturated, nitrogen-containing heterocycle
substituent selected from the group consisting of pyrrolidinyl,
piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl,
homomorpholinyl, and homothiomorpholinyl, any of which may
optionally be substituted with (C.sub.1-C.sub.6)alkyl or with 2
methyl substituents; or a pharmaceutically acceptable salt
thereof.
4. A compound of Formula (Ic): ##STR00222## wherein R.sup.7a is
chloro; R.sup.13 is a) phenyl optionally substituted with: i) 1 to
5 independently selected halo substituents; or ii) 1 to 3
substituents independently selected from the group consisting of
halo, cyano, --SCF.sub.3, nitro, hydroxy, (C.sub.1-C.sub.6)alkyl
optionally further substituted with 1 to 6 fluoro substituents, and
(C.sub.1-C.sub.6)alkoxy optionally further substituted with 1 to 6
fluoro substituents; or iii) 0, 1 or 2 substituents independently
selected from the group consisting of halo, cyano, --SCF.sub.3,
methyl --CF.sub.3, methoxy --OCF.sub.3, nitro, and hydroxy,
together with one substituent selected from the group consisting of
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.5)alkyl optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents and
optionally substituted independently on the cycloalkyl moiety with
1 to 6 substituents selected from fluoro and methyl provided that
no more than 2 substituents are methyl,
Ph.sup.1-(C.sub.0-C.sub.5)alkyl, Ar.sup.1--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-CH.dbd.CH-- optionally substituted with 1 to
6 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-CH.dbd.CH--
optionally substituted with 1 to 6 fluoro substituents on alkyl and
optionally substituted independently on the cycloalkyl moiety with
1 to 6 substituents selected from fluoro and methyl provided that
no more than 2 substituents are methyl,
(C.sub.1-C.sub.6)alkyl-S--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-O--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)al-
kyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-SO--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5-
)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)a-
lkyl, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--(C.sub.0-C.sub.5)alkyl,
Het.sup.1-(C.sub.0-C.sub.3)alkyl-,
(C.sub.1-C.sub.6)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.s-
ub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--C(O)--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--NH--(C.sub.0-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-NH--SO.sub.2--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NH--SO.sub.2--(C.sub.0-
-C.sub.5)alkyl,
(C.sub.1-C.sub.6)alkyl-SO.sub.2--NH--(C.sub.0-C.sub.5)alkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--NH--(C.sub.1-
-C.sub.5)alkyl; or b) thiophenyl optionally substituted with one to
two substituents selected from the group consisting of halo, cyano,
(C.sub.1-C.sub.6)alkyl optionally substituted with 1 to 6 fluoro
substituents, Ph.sup.1-(C.sub.0-C.sub.3)alkyl optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl optionally substituted on the
alkyl moiety with 1 to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkyl-C(O)--,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--,
(C.sub.1-C.sub.6)alkyl-NH--C(O)-- optionally substituted with 1 to
6 fluoro substituents, Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NH--C(O)--
optionally substituted on the alkyl moiety with 1 to 6 fluoro
substituents, Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NH--C(O)--
optionally substituted on the alkyl moiety with 1 to 6 fluoro
substituents, (C.sub.1-C.sub.6)alkyl-CH.dbd.CH-- optionally
substituted with 1 to 6 fluoro substituents,
(C.sub.1-C.sub.6)alkoxy optionally substituted with 1 to 6 fluoro
substituents, (C.sub.1-C.sub.6)alkylthio optionally substituted
with 1 to 6 fluoro substituents,
Ph.sup.1-(C.sub.0-C.sub.3)alkylthio,
(C.sub.1-C.sub.6)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl-optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.-
sub.3)alkyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.sub.5)alkyl-,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-NR.sup.12--(C.sub.0-C.sub.3)alkyl-,
Het.sup.1-(C.sub.0-C.sub.3)alkyl-,
(C.sub.1-C.sub.6)alkyl-C(O)--NH--,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--NH--,
Ar.sup.1--(C.sub.0-C.sub.3)alkyl-C(O)--NH--,
(C.sub.1-C.sub.6)alkyl-O--C(O)--NH-- optionally substituted with 1
to 6 fluoro substituents,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--C(O)--NH-- optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents,
and Ar.sup.1--(C.sub.0-C.sub.3)alkyl-O--C(O)--NH-- optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents;
Ar.sup.1 is pyridyl, optionally substituted with 1 to 4
independently selected halo substituents, or with 1 to 3
substituents independently selected from the group consisting of
halo, cyano, hydroxy, acetyl, methyl --CF.sub.3, methoxy,
--OCF.sub.3, methylthio, --SCF.sub.3, Ph.sup.1 is phenyl optionally
substituted with 1 to 5 independently selected halo substituents,
or with 1 to 3 substituents independently selected from the group
consisting of halo, cyano, hydroxy, acetyl methylthio, --SCF.sub.3,
(C.sub.1-C.sub.6)alkyl optionally further substituted with 1 to 6
fluoro substituents, and (C.sub.1-C.sub.6)alkoxy optionally further
substituted with 1 to 6 fluoro substituents; Het.sup.1 is a
saturated, nitrogen-containing heterocycle substituent selected
from the group consisting of pyrrolidinyl, piperidinyl,
homopiperidinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, and
homothiomorpholinyl, any of which may optionally be substituted
with (C.sub.1-C.sub.6)alkyl or with 2 methyl substituents; or a
pharmaceutically acceptable salt thereof.
5. (canceled)
6. A pharmaceutical composition comprising a compound according to
claim 1, or a pharmaceutically acceptable salt thereof, as an
active ingredient in association with a pharmaceutically acceptable
carrier, diluent or excipient.
7. (canceled)
8. A method for the treatment of obesity in mammals, comprising
administering to a mammal in need of such treatment an effective
amount of a compound according to claim 1.
9. The method of claim 8, where the mammal is human.
10. A method for the treatment of obsessive compulsive disorder in
mammals, comprising administering to a mammal in need of such
treatment an effective amount of a compound according to claim
1.
11. The method of claim 10, where the mammal is human.
12. A method for the treatment of depression in mammals, comprising
administering to a mammal in need of such treatment an effective
amount of a compound according to claim 1.
13. The method of claim 12, where the mammal is human.
14. A method for the treatment of anxiety in mammals, comprising
administering to a mammal in need of such treatment an effective
amount of a compound according to claim 1.
15. The method of claim 14, where the mammal is human.
16-27. (canceled)
Description
[0001] The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT)
has a rich pharmacology arising from a heterogeneous population of
at least seven receptor classes. The serotonin 5-HT.sub.2 class is
further subdivided into at least three subtypes, designated
5-HT.sub.2A, 5-HT.sub.2B, and 5-HT.sub.2C. The 5-HT.sub.2C receptor
has been isolated and characterized (Julius, et al., U.S. Pat. No.
4,985,352), and transgenic mice lacking the 5-HT.sub.2C receptor
have been reported to exhibit seizures and an eating disorder
resulting in increased consumption of food (Julius et al., U.S.
Pat. No. 5,698,766). The 5-HT.sub.2C receptor has also been linked
to various other neurological disorders including obesity (Vickers
et al., Psychopharmacology, 167: 274-280 (2003)), hyperphagia
(Tecott et al., Nature, 374: 542-546 (1995)), obsessive compulsive
disorder (Martin et al., Pharmacol. Biochem. Behav., 71: 615
(2002); Chou-Green et al., Physiology & Behavior, 78: 641-649
(2003)), depression (Leysen, Kelder, Trends in Drug Research II,
29: 49-61 (1998)), anxiety (Curr. Opin. Invest. Drugs 2(4), p. 317
(1993)), substance abuse, sleep disorder (Frank et al.,
Neuropsychopharmacology 27: 869-873 (2002)), hot flashes (EP
1213017 A2), epilepsy (Upton et al., Eur. J. Pharmacol., 359: 33
(1998); Fitzgerald, Ennis, Annual Reports in Medicinal Chemistry,
37: 21-30 (2002)), and hypogonadism (Curr. Opin. Invest. Drugs
2(4), p. 317 (1993)).
[0002] Certain substituted 2,3,4,5-tetrahydro-1H-benzo[d]azepine
compounds have been disclosed as useful therapeutics as for
example:
[0003] U.S. Pat. No. 4,265,890 describes certain substituted
2,3,4,5-tetrahydro-1H-benzo[d]azepine compounds as dopaminergic
receptor antagonists for use as antipsychotics and antiemetics,
inter alia.
[0004] EP 0 285 287 describes certain substituted
2,3,4,5-tetrahydro-1H-benzo[d]azepine compounds for use as agents
to treat gastrointestinal motility disorders, inter alia.
[0005] WO 93/03015 and WO 93/04686 describe certain substituted
2,3,4,5-tetrahydro-1H-benzo[d]azepine compounds as alpha-adrenergic
receptor antagonists for use as agents to treat hypertension and
cardiovascular diseases in which changes in vascular resistance are
desirable, inter alia.
[0006] WO 02/074746 A1 describes certain substituted
2,3,4,5-tetrahydro-1H-benzo[d]azepine compounds as 5-HT.sub.2C
agonists for the treatment of hypogonadism, obesity, hyperphagia,
anxiety, depression, sleep disorder, inter alia.
[0007] WO 03/006466 A1 describes certain substituted tricyclic
hexahydroazepinoindole and indoline compounds as 5-HT ligands and
consequently their usefulness for treating diseases wherein
modulation of 5-HT activity is desired.
[0008] WO 05/019180 describes
6-(2,2,2-trifluoroethylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azep-
ine as a potent and selective 5-HT.sub.2C agonist for the treatment
of obesity, anxiety, depression, and obsessive-compulsive
disorder.
[0009] High affinity 5-HT.sub.2C receptor agonists would provide
useful therapeutics for the treatment of the above mentioned
5-HT.sub.2C receptor-associated disorders including obesity,
hyperphagia, obsessive/compulsive disorder, depression, anxiety,
substance abuse, sleep disorder, hot flashes, and hypogonadism.
High affinity 5-HT.sub.2C receptor agonists that are also selective
for the 5-HT.sub.2C receptor, would provide such therapeutic
benefit without the undesirable adverse events associated with
current therapies. Achieving selectivity for the 5-HT.sub.2C
receptor, particularly as against the 5-HT.sub.2A and 5-HT.sub.2B
receptors, has proven difficult in designing 5-HT.sub.2C agonists.
5-HT.sub.2A receptor agonists have been associated with problematic
hallucinogenic adverse events. (Nelson et al.,
Naunyn-Schmiedeberg's Arch. Pharm., 359: 1-6 (1999)). 5-HT.sub.2B
receptor agonists have been associated with cardiovascular related
adverse events, such as valvulopathy. (V. Setola et al., Mol.
Pharmacology, 63: 1223-1229 (2003), and ref. cited therein).
[0010] Previous references to substituted
2,3,4,5-tetrahydro-1H-benzo[d]azepine compounds as potential
therapeutics have predominantly recited their uses as alpha
adrenergic and/or dopaminergic modulators. Adrenergic modulators
are often associated with the treatment of cardiovascular diseases
(Frishman, Kotob, Journal of Clinical Pharmacology, 39: 7-16
(1999)). Dopaminergic receptors are primary targets in the
treatment of schizophrenia and Parkinson's disease (Seeman, Van
Tol, Trends in Pharmacological Sciences, 15: 264-270 (1994)). It
will be appreciated by those skilled in the art that selectivity as
against these and other physiologically important receptors will
generally also be preferred characteristics for therapeutics for
the specific treatment of 5-HT.sub.2C associated disorders as
described above.
[0011] The present invention provides selective 5-HT.sub.2C agonist
compounds of Formula I:
##STR00002##
where: [0012] R.sup.1 is hydrogen, fluoro, or
(C.sub.1-C.sub.3)alkyl; [0013] R.sup.2, R.sup.3, and R.sup.4 are
each independently hydrogen, methyl, or ethyl; [0014] R.sup.5 is
hydrogen, fluoro, methyl, or ethyl; [0015] R.sup.6 is
--NR.sup.10R.sup.11; [0016] R.sup.7 is hydrogen, halo, cyano,
(C.sub.1-C.sub.6)alkyl optionally substituted with 1 to 6 fluoro
substituents, (C.sub.2-C.sub.6)alkenyl optionally substituted with
1 to 6 fluoro substituents, (C.sub.3-C.sub.7)cycloalkyl optionally
substituted with 1 to 4 fluoro substituents,
(C.sub.1-C.sub.6)alkoxy optionally substituted with 1 to 6 fluoro
substituents, (C.sub.1-C.sub.6)alkylthio optionally substituted
with 1 to 6 fluoro substituents, Ph.sup.1-(C.sub.0-C.sub.3)alkyl
optionally substituted with 1 to 6 fluoro substituents,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O-- optionally substituted with 1
to 6 fluoro substituents, or Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--
optionally substituted with 1 to 6 fluoro substituents; [0017]
R.sup.8 is hydrogen, halo, cyano, --SCF.sub.3, or hydroxy; [0018]
R.sup.9 is hydrogen, halo, cyano, --CF.sub.3, --SCF.sub.3, hydroxy,
or (C.sub.1-C.sub.3)alkoxy optionally substituted with 1 to 6
fluoro substituents; [0019] R.sup.10 is
Ph.sup.2-(C.sub.1-C.sub.3)-n-alkyl or
Ar.sup.1--(C.sub.1-C.sub.3)-n-alkyl, wherein the n-alkyl moiety is
optionally substituted with (C.sub.1-C.sub.3)alkyl, dimethyl,
gem-ethano or 1 to 2 fluoro substituents; [0020] R.sup.11 is
hydrogen, (C.sub.1-C.sub.3)alkyl optionally substituted with 1 to 6
fluoro substituents, or allyl; [0021] Ph.sup.1 is phenyl optionally
substituted with 1 to 5 independently selected halo substituents,
or with 1 to 3 substituents independently selected from the group
consisting of halo, cyano, --SCF.sub.3, (C.sub.1-C.sub.6)alkyl
optionally further substituted with 1 to 6 fluoro substituents, and
(C.sub.1-C.sub.6)alkoxy optionally further substituted with 1 to 6
fluoro substituents; [0022] Ph.sup.2 is phenyl substituted with
R.sup.12 and optionally further substituted with 1 or 2
substituents independently selected from the group consisting of
halo, cyano, --SCF.sub.3, methyl, --CF.sub.3, methoxy, --OCF.sub.3,
nitro, and hydroxy; [0023] Ar.sup.1 is 5--R.sup.13-pyridin-2-yl or
6--R.sup.13-pyridin-3-yl optionally further substituted with one or
two substituents independently selected from the group consisting
of halo, cyano, methyl, --CF.sub.3, hydroxy, and methoxy; [0024]
R.sup.12 is a substituent selected from the group consisting of:
[0025] a) Het.sup.1-(C.sub.0-C.sub.3)alkyl optionally substituted
on the alkyl moiety with 1 to 6 fluoro substituents; [0026] b)
Het.sup.2-(C.sub.0-C.sub.3)alkyl optionally substituted on the
alkyl moiety with 1 to 6 fluoro substituents; [0027] c)
Het.sup.3-(C.sub.0-C.sub.3)alkyl optionally substituted on the
alkyl moiety with 1 to 6 fluoro substituents; [0028] d)
Ar.sup.2--(C.sub.0-C.sub.3)alkyl optionally substituted on the
alkyl moiety with 1 to 6 fluoro substituents; [0029] e)
(C.sub.1-C.sub.6)alkyl-C(R.sup.14)=C(R.sup.14)-- optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents;
[0030] f) (R.sup.14).sub.2C.dbd.C[(C.sub.1-C.sub.6)alkyl]-
optionally substituted on the alkyl moiety with 1 to 6 fluoro
substituents; [0031] g)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(R.sup.14).dbd.C(R.su-
p.15)-- optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on the alkyl
moiety with 1 to 4 fluoro substituents; [0032] h)
(R.sup.15)CH.dbd.C[(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl]-
optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on the alkyl
moiety with 1 to 4 fluoro substituents; [0033] i)
(C.sub.1-C.sub.6)alkyl-C.ident.C-- optionally substituted on the
alkyl moiety with 1 to 6 fluoro substituents; [0034] j)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C.ident.C--
optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on the alkyl
moiety with 1 to 4 fluoro substituents; [0035] k)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.5-
)alkyl optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on either or both
alkyl moieties independently with 1 to 4 fluoro substituents;
[0036] l)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.5)alkyl
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0037] m)
pyridyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.5)alkyl,
optionally substituted on the pyridyl moiety with 1 to 3
substituents independently selected from the group consisting of
halo, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, --CF.sub.3,
--O--CF.sub.3, nitro, cyano, and trifluoromethylthio, and
independently optionally substituted on either or both alkyl
moieties independently with 1 to 4 fluoro substituents; [0038] n)
(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.3)alkyl-C(O)-- optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents and independently optionally substituted on the
(C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents;
[0039] o)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-O--(C.sub.1-C.sub.3)al-
kyl-C(O)-- optionally substituted on the cycloalkyl moiety with 1
to 4 substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on either or both
alkyl moieties independently with 1 to 4 fluoro substituents;
[0040] p)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.1-C.sub.3)alkyl-C(O)--
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0041] q)
(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.3)alkyl-C(O)-- optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents and independently optionally substituted on the
(C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents;
[0042] r)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.3)al-
kyl-C(O)-- optionally substituted on the cycloalkyl moiety with 1
to 4 substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on either or both
alkyl moieties independently with 1 to 4 fluoro substituents;
[0043] s)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.3)alkyl-C(O)--
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0044] t)
(C.sub.1-C.sub.6)alkyl-NR.sup.16--(C.sub.1-C.sub.3)alkyl-C(O)--
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents and independently optionally substituted
on the (C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro
substituents; [0045] u)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NR.sup.16--(C.sub.1-C.-
sub.3)alkyl-C(O)-- optionally substituted on the cycloalkyl moiety
with 1 to 4 substituents selected from the group consisting of
methyl and fluoro, and independently optionally substituted on
either or both alkyl moieties independently with 1 to 4 fluoro
substituents; [0046] v)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NR.sup.16--(C.sub.1-C.sub.3)alkyl-C(O)--
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0047] w)
(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.3)alkyl-SO.sub.2--
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents and independently optionally substituted
on the (C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro
substituents; [0048] x)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-O--(C.sub.1-C.sub.3)al-
kyl-SO.sub.2-- optionally substituted on the cycloalkyl moiety with
1 to 4 substituents selected from the group consisting of methyl
and fluoro, and independently optionally substituted on either or
both alkyl moieties independently with 1 to 4 fluoro substituents;
[0049] y)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.1-C.sub.3)alkyl-SO.sub.2--
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0050] z)
(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.3)alkyl-SO.sub.2--
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents and independently optionally substituted
on the (C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro
substituents; [0051] aa)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.3)al-
kyl-SO.sub.2-- optionally substituted on the cycloalkyl moiety with
1 to 4 substituents selected from the group consisting of methyl
and fluoro, and independently optionally substituted on either or
both alkyl moieties independently with 1 to 4 fluoro substituents;
[0052] ab)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.3)alkyl-SO.sub.2--
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0053] ac)
(C.sub.1-C.sub.6)alkyl-NR.sup.16--(C.sub.1-C.sub.3)alkyl-SO.sub.2--
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents and independently optionally substituted
on the (C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro
substituents; [0054] ad)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NR.sup.16--(C.sub.1-C.-
sub.3)alkyl-SO.sub.2-- optionally substituted on the cycloalkyl
moiety with 1 to 4 substituents selected from the group consisting
of methyl and fluoro, and independently optionally substituted on
either or both alkyl moieties independently with 1 to 4 fluoro
substituents; [0055] ae)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NR.sup.16--(C.sub.1-C.sub.3)alkyl-SO.sub.-
2-- optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0056] af)
R.sup.17R.sup.18--N--C(O)--(C.sub.1-C.sub.5)alkyl optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents;
[0057] ag) R.sup.17R.sup.18--N--C(S)--(C.sub.1-C.sub.5)alkyl
optionally substituted on the alkyl moiety with 1 to 6 fluoro
substituents; [0058] ah)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S-- optionally
substituted on the cycloalkyl moiety with 1 to 4 substituents
selected from the group consisting of methyl and fluoro, and
independently optionally substituted on the alkyl moiety with 1 to
4 fluoro substituents; [0059] ai)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.5)al-
kyl optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on either or both
alkyl moieties independently with 1 to 4 fluoro substituents;
[0060] aj)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.5)alkyl
optionally substituted on the (C.sub.1-C.sub.5)alkyl moiety with 1
to 6 fluoro substituents and independently optionally substituted
on the --(C.sub.0-C.sub.3)alkyl moiety with 1 to 4 fluoro
substituents; [0061] ak)
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.5)alkyl
optionally substituted on the (C.sub.1-C.sub.5)alkyl moiety with 1
to 6 fluoro substituents and independently optionally substituted
on the --(C.sub.0-C.sub.3)alkyl moiety with 1 to 4 fluoro
substituents; [0062] al)
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-O--(C.sub.1-C.sub.5)alkyl
optionally substituted on the (C.sub.1-C.sub.5)alkyl moiety with 1
to 6 fluoro substituents and independently optionally substituted
on the -(C.sub.0-C.sub.3)alkyl moiety with 1 to 4 fluoro
substituents; [0063] am)
Het.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl wherein
Het.sup.1 is linked through any carbon atom of Het.sup.1 and
wherein the (C.sub.0-C.sub.5)alkyl moiety is optionally substituted
with 1 to 6 fluoro substituents and independently optionally
substituted on the -(C.sub.0-C.sub.3)alkyl moiety with 1 to 4
fluoro substituents; [0064] an)
Het.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)allyl wherein
Het.sup.1 is linked through any carbon atom of Het.sup.1 and
wherein the (C.sub.0-C.sub.5)alkyl moiety is optionally substituted
with 1 to 6 fluoro substituents and independently optionally
substituted on the -(C.sub.0-C.sub.3)alkyl moiety with 1 to 4
fluoro substituents; [0065] ao)
Het.sup.2-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.5)alkyl moiety with 1
to 6 fluoro substituents and independently optionally substituted
on the --(C.sub.0-C.sub.3)alkyl moiety with 1 to 4 fluoro
substituents; [0066] ap)
R.sup.16R.sup.19--N--C(O)--S--(C.sub.0-C.sub.5)alkyl optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents;
[0067] aq) R.sup.16R.sup.19--N--C(O)--O--(C.sub.0-C.sub.5)alkyl
optionally substituted on the alkyl moiety with 1 to 6 fluoro
substituents; [0068] ar)
R.sup.16R.sup.19--N--C(O)--NR.sup.16--(C.sub.0-C.sub.5)alkyl
optionally substituted on the alkyl moiety with 1 to 6 fluoro
substituents; [0069] as)
(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.3)alkyl-S-- optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents and independently optionally substituted on the
(C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents;
[0070] at)
(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.3)alkyl-S--
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents and independently optionally substituted
on the (C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro
substituents; [0071] au)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3-
)alkyl-O-- optionally substituted on the cycloalkyl moiety with 1
to 4 substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on either or both
alkyl moieties independently with 1 to 4 fluoro substituents;
[0072] av)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.1-C.s-
ub.3)alkyl-O-- optionally substituted on the cycloalkyl moiety with
1 to 4 substituents selected from the group consisting of methyl
and fluoro, and independently optionally substituted on either or
both alkyl moieties independently with 1 to 4 fluoro substituents;
[0073] aw)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3-
)alkyl-S-- optionally substituted on the cycloalkyl moiety with 1
to 4 substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on either or both
alkyl moieties independently with 1 to 4 fluoro substituents;
[0074] ax)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.1-C.s-
ub.3)alkyl-S-- optionally substituted on the cycloalkyl moiety with
1 to 4 substituents selected from the group consisting of methyl
and fluoro, and independently optionally substituted on either or
both alkyl moieties independently with 1 to 4 fluoro
substituents;
[0075] ay)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.1-C.sub.3)alkyl-O--
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0076] az)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3)alkyl-S--
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0077] ba)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.1-C.sub.3)alkyl-S--
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0078] bb)
R.sup.17R.sup.18N--C(O)--(C.sub.1-C.sub.3)alkyl-S-- optionally
substituted on the alkyl moiety with 1 to 4 fluoro substituents;
[0079] bc) R.sup.17R.sup.18N--C(S)--(C.sub.1-C.sub.3)alkyl-S--
optionally substituted on the alkyl moiety with 1 to 4 fluoro
substituents; [0080] bd)
R.sup.17R.sup.18--C(S)--(C.sub.1-C.sub.3)alkyl-O-- optionally
substituted on the alkyl moiety with 1 to 4 fluoro substituents;
[0081] be)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.1-
-C.sub.5)alkyl optionally substituted on the cycloalkyl moiety with
1 to 4 substituents selected from the group consisting of methyl
and fluoro, and independently optionally substituted on the
(C.sub.0-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents and
further optionally substituted on the (C.sub.1-C.sub.5)alkyl moiety
with 1 to 6 fluoro substituents; [0082] bf)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.1-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and independently optionally substituted
on the (C.sub.1-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0083] bg)
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.1-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and independently optionally substituted
on the (C.sub.1-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0084] bh)
Het.sup.2-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and independently optionally substituted
on the (C.sub.1-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0085] bi) R.sup.17R.sup.18N--(C.sub.1-C.sub.3)alkyl
optionally substituted on the alkyl moiety with 1 to 4 fluoro
substituents; [0086] bj)
(C.sub.1-C.sub.6)alkyl-C(O)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on either or both alkyl moieties
independently with 1 to 6 fluoro substituents; [0087] bk)
(C.sub.3-C.sub.7)cycloalkyl-C(O)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on the alkyl
moiety with 1 to 6 fluoro substituents; [0088] bl)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and independently optionally substituted
on the (C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0089] bm)
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-C(O)--N(R.sup.16)--(C.sub.0-C.sub.5)alky-
l optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with
1 to 4 fluoro substituents and independently optionally substituted
on the (C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0090] bn)
(C.sub.1-C.sub.6)alkyl-C(S)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on either or both alkyl moieties
independently with 1 to 6 fluoro substituents; [0091] bo)
(C.sub.3-C.sub.7)cycloalkyl-C(S)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on the alkyl
moiety with 1 to 6 fluoro substituents; [0092] bp)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(S)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and independently optionally substituted
on the (C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0093] bq)
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-C(S)--N(R.sup.16)--(C.sub.0-C.sub.5)alky-
l optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with
1 to 4 fluoro substituents and independently optionally substituted
on the (C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0094] br)
(C.sub.1-C.sub.6)alkyl-O--N.dbd.C(CH.sub.3)-- optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents; [0095] bs)
(C.sub.0-C.sub.3)alkyl-O--N.dbd.C[(C.sub.1-C.sub.6)alkyl]-
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and independently optionally substituted
on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents; [0096] bt)
HO--N.dbd.C[(C.sub.0-C.sub.1)alkyl-(C.sub.3-C.sub.7)cycloalkyl]-
optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on either or both
alkyl moieties independently with 1 to 2 fluoro substituents;
[0097] bu)
CH.sub.3--O--N.dbd.C[(C.sub.0-C.sub.1)alkyl-(C.sub.3-C.sub.7)cycloalkyl]-
optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on either or both
alkyl moieties independently with 1 to 2 fluoro substituents;
[0098] R.sup.13 is a substituent selected from the group consisting
of: [0099] a) Het.sup.2-(C.sub.0-C.sub.3)alkyl optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents;
[0100] b) Het.sup.3-(C.sub.0-C.sub.3)alkyl optionally substituted
on the alkyl moiety with 1 to 6 fluoro substituents; [0101] c)
Ar.sup.2--(C.sub.0-C.sub.3)alkyl optionally substituted on the
alkyl moiety with 1 to 6 fluoro substituents; [0102] d)
(C.sub.1-C.sub.6)alkyl-C(R.sup.14)=C(R.sup.14)-- optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents;
[0103] e) (R.sup.14).sub.2C.dbd.C[(C.sub.1-C.sub.6)alkyl]-
optionally substituted on the alkyl moiety with 1 to 6 fluoro
substituents; [0104] f)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(R.sup.14).dbd.C(R.su-
p.15)-- optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on the alkyl
moiety with 1 to 4 fluoro substituents; [0105] g)
(R.sup.15)CH.dbd.C[(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl]-
optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on the alkyl
moiety with 1 to 4 fluoro substituents; [0106] h)
(C.sub.1-C.sub.6)alkyl-C.ident.C-- optionally substituted on the
alkyl moiety with 1 to 6 fluoro substituents; [0107] i)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.1)alkyl-C.ident.C--
optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on the alkyl
moiety with 1 to 2 fluoro substituents; [0108] j)
(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.5)alkyl optionally
optionally substituted on either or both alkyl moieties
independently with 1 to 6 fluoro substituents; [0109] k)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)al-
kyl optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on the
(C.sub.0-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents and
further optionally substituted on the (C.sub.0-C.sub.5)alkyl moiety
with 1 to 6 fluoro substituents; [0110] l)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and independently optionally substituted
on the (C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0111] m)
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and independently optionally substituted
on the (C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0112] n)
Het.sup.2-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and independently optionally substituted
on the (C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0113] o)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.5-
)alkyl optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on the
(C.sub.0-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents and
further optionally substituted on the (C.sub.1-C.sub.5)alkyl moiety
with 1 to 6 fluoro substituents; [0114] p)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and independently optionally substituted
on the (C.sub.1-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0115] q)
pyridyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.5)alkyl
optionally be substituted on the pyridyl moiety with 1 to 3
substituents independently selected from the group consisting of
halo, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, --CF.sub.3,
--O--CF.sub.3, nitro, cyano, and trifluoromethylthio, and
independently optionally substituted on the (C.sub.0-C.sub.3)alkyl
moiety with 1 to 4 fluoro substituents, and independently
optionally substituted on the (C.sub.1-C.sub.5)alkyl moiety with 1
to 6 fluoro substituents; [0116] r)
(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.3)alkyl-O-- optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents and independently optionally substituted on the
(C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents;
[0117] s)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3-
)alkyl-O-- optionally substituted on the cycloalkyl moiety with 1
to 4 substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on either or both
of the alkyl moieties independently with 1 to 4 fluoro
substituents; [0118] t)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3)alkyl-O--
optionally substituted on either or both of the alkyl moieties
independently with 1 to 4 fluoro substituents; [0119] u)
pyridyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3)alkyl-O--
optionally be substituted on the pyridyl moiety with 1 to 3
substituents independently selected from the group consisting of
halo, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, --CF.sub.3,
--O--CF.sub.3, nitro, cyano, and trifluoromethylthio, and
independently optionally substituted on either or both of the alkyl
moieties independently with 1 to 4 fluoro substituents; [0120] v)
R.sup.17R.sup.15N--C(O)--(C.sub.1-C.sub.3)alkyl-O-- optionally
substituted on the alkyl moiety with 1 to 4 fluoro substituents;
[0121] w) R.sup.17R.sup.18N--C(S)--(C.sub.1-C.sub.3)alkyl-O--
optionally substituted on the alkyl moiety with 1 to 4 fluoro
substituents; [0122] x)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S-- substituted
on the cycloalkyl moiety with 1 to 4 substituents selected from the
group consisting of methyl and fluoro, and independently optionally
substituted on either or both of the alkyl moieties independently
with 1 to 4 fluoro substituents; [0123] y)
(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.5)alkyl optionally
substituted on either or both alkyl moieties independently with 1
to 6 fluoro substituents; [0124] z)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.5)al-
kyl optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on the
(C.sub.0-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents, and
independently optionally substituted on the (C.sub.1-C.sub.5)alkyl
moiety with 1 to 6 fluoro substituents; [0125] aa)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and independently optionally substituted
on the (C.sub.1-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0126] ab)
Ar.sup.3--(C.sub.0-C.sub.3)allyl-S--(C.sub.1-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and independently optionally substituted
on the (C.sub.1-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0127] ac)
(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.3)alkyl-S-- optionally
substituted on the (C.sub.1-C.sub.6)allyl moiety with 1 to 6 fluoro
substituents and independently optionally substituted on the
(C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents;
[0128] ad)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3-
)alkyl-S-- optionally substituted on the cycloalkyl moiety with 1
to 4 substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on either or both
of the alkyl moieties independently with 1 to 4 fluoro
substituents; [0129] ae)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3)alkyl-S--
optionally substituted on either or both of the alkyl moieties
independently with 1 to 4 fluoro substituents; [0130] af)
pyridyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3)alkyl-S--
optionally be substituted on the pyridyl moiety with 1 to 3
substituents independently selected from the group consisting of
halo, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, --CF.sub.3,
--O--CF.sub.3, nitro, cyano, and trifluoromethylthio, and
independently optionally substituted on either or both of the alkyl
moieties independently with 1 to 4 fluoro substituents; [0131] ag)
R.sup.17R.sup.18N--C(O)--(C.sub.1-C.sub.3)alkyl-S-- optionally
substituted on the alkyl moiety with 1 to 4 fluoro substituents;
[0132] ah) R.sup.17R.sup.18N--C(S)--(C.sub.1-C.sub.3)alkyl-S--
optionally substituted on the alkyl moiety with 1 to 4 fluoro
substituents; [0133] ai)
(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl optionally
substituted on either or both of the alkyl moieties independently
with 1 to 6 fluoro substituents; [0134] aj)
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.s-
ub.5)alkyl optionally substituted on the cycloalkyl moiety with 1
to 4 substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on the
(C.sub.0-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents, and
independently optionally substituted on the (C
.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents; [0135]
ak)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and independently optionally substituted
on the (C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0136] al)
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and independently optionally substituted
on the (C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0137] am)
Het.sup.2-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and independently optionally substituted
on the (C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0138] an)
R.sup.17R.sup.15--N--C(O)--(C.sub.1-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0139] ao)
R.sup.17R.sup.18--N--C(S)--(C.sub.1-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0140] ap) R.sup.17R.sup.18N--(C.sub.1-C.sub.3)alkyl
optionally substituted on the (C.sub.1-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents; [0141] aq)
(C.sub.1-C.sub.6)alkyl-C(O)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on either or both of the alkyl moieties
independently with 1 to 6 fluoro substituents; [0142] ar)
(C.sub.3-C.sub.7)cycloalkyl-C(O)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on the
(C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0143] as)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and independently optionally substituted
on the (C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0144] at)
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-C(O)--N(R.sup.16)--(C.sub.0-C.sub.5)alky-
l optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with
1 to 4 fluoro substituents and independently optionally substituted
on the (C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0145] au)
(C.sub.1-C.sub.6)alkyl-C(S)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on either or both of the alkyl moieties
independently with 1 to 6 fluoro substituents; [0146] av)
(C.sub.3-C.sub.7)cycloalkyl-C(S)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and independently optionally substituted on the
(C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0147] aw)
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(S)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and independently optionally substituted
on the (C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0148] ax)
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-C(S)--N(R.sup.16)--(C.sub.0-C.sub.5)alky-
l optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with
1 to 4 fluoro substituents and independently optionally substituted
on the (C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0149] R.sup.14 is hydrogen or (C.sub.1-C.sub.2)alkyl
optionally substituted with 1 to 5 fluoro substituents; [0150]
R.sup.15 is hydrogen or methyl optionally substituted with 1 to 3
fluoro substituents; [0151] R.sup.16 is hydrogen or
(C.sub.1-C.sub.3)alkyl optionally substituted with 1 to 5 fluoro
substituents; [0152] R.sup.17 is (C.sub.1-C.sub.6)alkyl optionally
substituted with 1 to 6 fluoro substituents,
Ph.sup.1-(C.sub.1-C.sub.3)alkyl optionally substituted on the alkyl
moiety with 1 to 4 fluoro substituents, or
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl optionally
substituted on the cycloalkyl moiety with 1 to 4 substituents
independently selected from methyl and fluoro and independently
optionally substituted on the alkyl moiety with 1 to 4 fluoro
substituents; [0153] R.sup.18 is hydrogen or
(C.sub.1-C.sub.3)alkyl, or R.sup.17 and R.sup.18 taken together
with the nitrogen atom to which they are attached, form Het.sup.1,
imidazolidin-2-onyl, imidazolidin-2,4-dionyl, or
tetrahydropyrimidin-2-onyl optionally substituted with 1 or 2
methyl substituents; [0154] R.sup.19 is (C.sub.1-C.sub.3)alkyl
optionally substituted with 1 to 5 fluoro substituents; [0155] Ar
is an aromatic heterocycle substituent selected from the group
consisting of pyrrolyl, pyrazolyl, imidazolyl, pyrimidinyl,
oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, thiophenyl, thiazolyl,
isothiazolyl, and 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, wherein the heterocycle is substituted with a
substituent selected from the group consisting of H.sub.2N--,
R.sup.15R.sup.17N--, R.sup.17NH--C(O)--, R.sup.17C(O)NH--,
R.sup.17O--C(O)NH--, (C.sub.1-C.sub.6)alkyl-C(O)--,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl, N-linked
Het.sup.1, and N-linked Het.sup.1-C(O)--, and which is optionally
further substituted with a substituent selected from the group
consisting of methyl, cyano, halo, and trifluoromethyl; [0156]
Ar.sup.3 is an aromatic heterocycle substituent selected from the
group consisting of pyrrolyl, furanyl, thiophenyl, thiazolyl,
isothiazolyl, oxazolyl, isoxazolyl, and pyridyl, any of which may
optionally be substituted with 1 to 3 substituents independently
selected from the group consisting of halo, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)alkoxy, --CF.sub.3, --O--CF.sub.3, nitro, cyano,
and trifluoromethylthio; [0157] Het.sup.1 is a saturated,
nitrogen-containing heterocycle substituent selected from the group
consisting of pyrrolidinyl, piperidinyl, homopiperidinyl,
morpholinyl, thiomorpholinyl, homomorpholinyl, and
homothiomorpholinyl, any of which may optionally be substituted
with (C.sub.1-C.sub.6)alkyl or with 2 methyl substituents; [0158]
Het.sup.2 is a saturated, oxygen-containing heterocycle substituent
selected from the group consisting of tetrahydrofuranyl and
tetrahydropyranyl, any of which may optionally be substituted with
(C.sub.1-C.sub.6)alkyl or with 2 methyl substituents; [0159]
Het.sup.3 is a nitrogen containing heterocycle selected from the
group consisting of pyrrolidin-2-onyl, piperidin-2-onyl,
oxazolidin-2-onyl, pyrrolin-2-onyl, and dihydropyridin-2-onyl; or a
pharmaceutically acceptable salt or solvate thereof.
[0160] This invention also provides pharmaceutical compositions
which comprise a compound of Formula I, or a pharmaceutically
acceptable salt or solvate thereof, in association with a
pharmaceutically acceptable carrier, diluent, or excipient.
[0161] In another aspect of the present invention, there is
provided a method for increasing activation of the 5-HT.sub.2C
receptor in mammals comprising administering to a mammal in need of
such activation an effective amount of a compound of Formula I, or
a pharmaceutically acceptable salt or solvate thereof.
[0162] The present invention also provides a method for treating
obesity in mammals comprising administering to a mammal in need of
such treatment an effective amount of a compound of Formula I, or a
pharmaceutically acceptable salt or solvate thereof.
[0163] The present invention also provides a method for treating
obsessive/compulsive disorder in mammals comprising administering
to a mammal in need of such treatment an effective amount of a
compound of Formula I, or a pharmaceutically acceptable salt or
solvate thereof.
[0164] Furthermore, the present invention provides a method for
treating depression in mammals comprising administering to a mammal
in need of such treatment an effective amount of a compound of
Formula I, or a pharmaceutically acceptable salt or solvate
thereof.
[0165] Furthermore, the present invention provides a method for
treating anxiety in mammals comprising administering to a mammal in
need of such treatment an effective amount of a compound of Formula
I, or a pharmaceutically acceptable salt or solvate thereof.
[0166] In preferred embodiments of the above methods of treatment
utilizing a compound of Formula I, or a pharmaceutically acceptable
salt or solvate thereof, the mammal is a human.
[0167] In another aspect of the present invention, there is
provided a compound of Formula I, or a pharmaceutically acceptable
salt or solvate thereof, for use in selectively increasing
activation of the 5-HT.sub.2C receptor and/or for use in treating a
variety of disorders associated with decreased activation of
5-HT.sub.2C receptors. Preferred embodiments of this aspect of the
invention include a compound of Formula I, or a pharmaceutically
acceptable salt or solvate thereof, for use in the treatment of
obesity, hyperphagia, obsessive/compulsive disorder, depression,
anxiety, substance abuse, sleep disorder, hot flashes, and/or
hypogonadism. Particularly preferred embodiments of this aspect of
the invention include the treatment of obesity,
obsessive/compulsive disorder, depression, and/or anxiety.
[0168] In another aspect of the present invention, there is
provided the use of one or more compounds of Formula I, or a
pharmaceutically acceptable salt or solvate thereof, in the
manufacture of a medicament for the activation of 5-HT.sub.2C
receptors in a mammal. In preferred embodiments of this aspect of
the invention, there is provided the use of one or more compounds
of Formula I, or a pharmaceutically acceptable salt or solvate
thereof, in the manufacture of a medicament for the treatment of
obesity, hyperphagia, obsessive/compulsive disorder, depression,
anxiety, substance abuse, sleep disorder, hot flashes, and/or
hypogonadism. Particularly preferred embodiments of this aspect of
the invention include the use of one or more compounds of Formula
I, or a pharmaceutically acceptable salt or solvate thereof, in the
manufacture of medicaments for the treatment of obesity,
obsessive/compulsive disorder, depression, and/or anxiety.
[0169] Additionally, the present invention provides a
pharmaceutical formulation adapted for the treatment of obesity, or
for the treatment of obsessive/compulsive disorder, or for the
treatment of depression, or for the treatment of anxiety, each of
which comprise a compound of Formula I, or a pharmaceutically
acceptable salt or solvate thereof, in association with a
pharmaceutically acceptable carrier, diluent or excipient.
[0170] In those instances where the disorders which can be treated
by 5-HT.sub.2C agonists are known by established and accepted
classifications, their classifications can be found in various
sources. For example, at present, the fourth edition of the
Diagnostic and Statistical Manual of Mental Disorders (DSMIV.TM.)
(1994, American Psychiatric Association, Washington, D.C.),
provides a diagnostic tool for identifying many of the disorders
described herein. Also, the International Classification of
Diseases, Tenth Revision (ICD-10), provides classifications for
many of the disorders described herein. The skilled artisan will
recognize that there are alternative nomenclatures, nosologies, and
classification systems for disorders described herein, including
those as described in the DSM-IV and ICD-10, and that terminology
and classification systems evolve with medical scientific
progress.
[0171] The general chemical terms used throughout have their usual
meanings. For example, the term "alkyl" refers to a branched or
unbranched saturated hydrocarbon group. The term "n-alkyl" refers
to an unbranched alkyl group. By way of illustration, but without
limitation, the term "(C.sub.1-C.sub.2)alkyl" refers to methyl and
ethyl. The term "(C.sub.1-C.sub.3)n-alkyl" refers to methyl, ethyl,
and propyl. The term "(C.sub.1-C.sub.3)alkyl" refers to methyl,
ethyl, propyl, and isopropyl. The term "(C.sub.1-C.sub.5)alkyl"
refers to all branched and unbranched alkyl groups having from one
to five carbon atoms. The term "(C.sub.1-C.sub.6)alkyl" refers to
all branched and unbranched alkyl groups having from one to six
carbon atoms. The term "(C.sub.3-C.sub.6)alkyl" refers to all
branched and unbranched alkyl groups having from three to six
carbon atoms. The term "(C.sub.2-C.sub.6)alkyl" refers to all
branched and unbranched alkyl groups having from two to six carbon
atoms.
[0172] (C.sub.x--C.sub.y)alkyl may also be used in conjunction with
other substituents to indicate a branched or unbranched saturated
hydrocarbon linker for the substituent, where x and y indicate the
range of carbon atoms permitted in the linker moiety. By way of
illustration, but without limitation, --(C.sub.0-C.sub.1)alkyl
refers to a single bond or a methylene linker moiety;
--(C.sub.0-C.sub.2)alkyl refers to a single bond, methylene,
methyl-methylene, or ethylene linker moiety;
-(C.sub.0-C.sub.3)alkyl further includes trimethylene, alpha- or
beta-methyl ethylene, or ethyl methylene; --(C.sub.0-C.sub.5)alkyl
refers to a bond or a saturated, branched or unbranched hydrocarbon
linker having from 1 to 5 carbon atoms. --(C.sub.1-C.sub.2)alkyl,
--(C.sub.1-C.sub.3)alkyl, --(C.sub.1-C.sub.5)alkyl, and
--(C.sub.1-C.sub.6)alkyl refer to branched or unbranched allylene
linkers having from 1 to 2, 3, 5, or 6 carbon atoms,
respectively.
[0173] The term "alkenyl" refers to a branched or unbranched
hydrocarbon group having one or more carbon-carbon double bonds. By
way of illustration, but without limitation, the term
"(C.sub.2-C.sub.6)alkenyl" refers to a branched or unbranched
hydrocarbon group having from 2 to 6 carbon atoms and 1 or more
carbon-carbon double bonds. Allyl means a propyl-2-en-1-yl moiety
(CH.sub.2.dbd.CH--CH.sub.2--).
[0174] The term "(C.sub.3-C.sub.7)cycloalkyl" refers to
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Cycloalkylalkyl refers to a cycloalkyl moiety linked through a
branched or unbranched alkylene linker, as for example, but without
limitation, --CH.sub.2--, --CH.sub.2CH.sub.2--, --CH(CH.sub.3)--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH(CH.sub.3)--,
--CH(CH.sub.3)CH.sub.2--, --CH(CH.sub.2CH.sub.3)--, and the like.
(C.sub.3-C.sub.7)cycloalkyl(C.sub.0-C.sub.1, 2 or 3)alkyl, refers
to a cycloalkyl moiety linked through a single bond (i.e.
C.sub.0-alkyl) or an alkylene linker having 1, 2, or 3 carbon
atoms, respectively. Each alkyl, cycloalkyl, and cycloalkylalkyl
group may be optionally substituted as provided for herein.
[0175] The terms "alkoxy", "phenyloxy", "sulfonyloxy", and
"carbonyloxy" refer to an alkyl group, phenyl group, sulfonyl
group, or carbonyl group, respectively, that is bonded through an
oxygen atom.
[0176] The terms "alkylthio", "trifluoromethylthio",
"cycloalkylthio" ("cyclohexylthio"), "phenylthio", and
"furanylthio" refer to an alkyl group, trifluoromethyl group,
cycloalkyl (cyclohexyl) group, phenyl group, or furanyl group,
respectively, that is bonded through a sulfur atom.
[0177] The terms "alkylcarbonyl", "alkoxycarbonyl",
"phenylcarbonyl", and "phenyloxycarbonyl", refer to an alkyl,
alkoxy, phenyl, or phenyloxy group bonded through a carbonyl
moiety.
[0178] The terms "alkylsulfonyl" (t-butylsulfonyl),
"(C.sub.3-C.sub.7)cycloalkylsulfonyl", "phenylsulfonyl",
"Ph.sup.1-(C.sub.0-C.sub.3)alkylsulfonyl", and
"Ar.sup.2--(C.sub.0-C.sub.3)alkylsulfonyl", refer to an alkyl
(t-butyl), (C.sub.3-C.sub.7)cycloalkyl, phenyl,
Ph.sup.1-(C.sub.0-C.sub.3)alkyl, or
Ar.sup.2--(C.sub.0-C.sub.3)alkyl group bonded through a sulfonyl
moiety (--SO.sub.2--).
[0179] The term "N-linked" means that the referenced moiety is
linked through its nitrogen atom, by way of illustration, but
without limitation, N-linked Het.sup.1 means the Het.sup.1 moiety
is linked through a nitrogen atom in the ring of the Het.sup.1
moiety.
[0180] The term "halo" refers to fluoro, chloro, bromo, or iodo.
Preferred halo groups are fluoro, chloro, and bromo. More preferred
halo groups are fluoro and chloro.
[0181] The terms "gem-", "geminal", or "geminate" refer to two
identical substituents bonded to a common carbon atom, as for
example, but without limitation, gem-methyl, 5 meaning two methyl
groups bound to a common carbon atom, as for instance in a
3,3-dimethyltetrahydrobenzofuranyl group. For the purposes of this
application, gem-ethano means an ethylene substituent wherein both
carbons are bound to the same carbon atom of the substituted group
to form a cyclopropyl moiety, as for example, but without
limitation, the ethano substituent on the
2-phenyl-(1,1-ethano)ethylamino group below:
##STR00003##
[0182] The term "amino protecting group" as used in this
specification refers to a substituent commonly employed to block or
protect the amino functionality while reacting other functional
groups on the compound. Examples of such amino protecting groups
include the formyl group, the trityl group, the acetyl group, the
trichloroacetyl group, the trifluoroacetyl group, the chloroacetyl,
bromoacetyl, and iodoacetyl groups, carbamoyl-type blocking groups
such as benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl ("FMOC"),
t-butoxycarbonyl (t-BOC), and like amino protecting groups. The
species of amino protecting group employed is not critical so long
as the derivatized amino group is stable to the conditions of
subsequent reactions on other positions of the molecule and can be
removed at the appropriate point without disrupting the remainder
of the molecule. The selection and use (addition and subsequent
removal) of amino protecting groups is well known within the
ordinary skill of the art. Further examples of groups referred to
by the above terms are described by T. W. Greene and P. G. M. Wuts,
"Protective Groups in Organic Synthesis", 3.sup.rd edition, John
Wiley and Sons, New York, N.Y., 1999, chapter 7, hereafter referred
to as "Greene".
[0183] The term "pharmaceutical" or "pharmaceutically acceptable"
when used herein as an adjective, means substantially non-toxic and
substantially non-deleterious to the recipient.
[0184] By "pharmaceutical composition" it is further meant that the
carrier, solvent, excipients and/or salt must be compatible with
the active ingredient of the composition (e.g. a compound of
Formula I). It is understood by those of ordinary skill in this art
that the terms "pharmaceutical formulation" and "pharmaceutical
composition" are generally interchangeable, and they are so used
for the purposes of this application.
[0185] The term "effective amount" means an amount of a compound of
Formula I which is capable of activating 5-HT.sub.2C receptors
and/or eliciting a given pharmacological effect.
[0186] The term "suitable solvent" refers to any solvent, or
mixture of solvents, inert to the ongoing reaction that
sufficiently solubilizes the reactants to afford a medium within
which to effect the desired reaction.
[0187] It is understood that compounds of the present invention may
exist as stereoisomers. As such, all enantiomers, diastereomers,
and mixtures thereof, are included within the scope of the present
invention. Where specific stereochemistries are identified in this
application, the Cahn-Prelog-Ingold designations of (R)-- and (S)--
and the cis and trans designation of relative stereochemistry are
used to refer to specific isomers and relative stereochemistry.
Known optical rotations are designated by (+) and (-) for
dextrorotatary and levorotatary, respectively. Where a chiral
compound is resolved into its isomers, but absolute configurations
or optical rotations are not determined, the isomers are
arbitrarily designated as isomer 1, isomer 2, etc. While all
enantiomers, diastereomers, and mixtures thereof, are contemplated
within the present invention, preferred embodiments are single
enantiomers and single diastereomers.
[0188] It is generally understood by those skilled in this art,
that compounds intended for use in pharmaceutical compositions are
routinely, though not necessarily, converted to a salt form in
efforts to optimize such characteristics as the handling
properties, stability, pharmacokinetic, and/or bioavailability,
etc. Methods for converting a compound to a given salt form are
well known in the art (see for example, Berge, S. M, Bighley, L.D.,
and Monkhouse, D. C., J. Pharm. Sci., 66:1, (1977)). In that the
compounds of the present invention are amines and therefore basic
in nature, they readily react with a wide variety of
pharmaceutically acceptable organic and inorganic acids to form
pharmaceutically acceptable acid addition salts therewith. Such
salts are also embodiments of this invention.
[0189] Typical inorganic acids used to form such salts include
hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric,
phosphoric, hypophosphoric, metaphosphoric, pyrophosphoric acid,
and the like. Salts derived from organic acids, such as aliphatic
mono and dicarboxylic acids, phenyl substituted alkanoic acids,
hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids,
aliphatic and aromatic sulfonic acids, may also be used. Such
pharmaceutically acceptable salts thus include chloride, bromide,
iodide, nitrate, acetate, phenylacetate, trifluoroacetate,
acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate,
hydroxybenzoate, methoxybenzoate, methylbenzoate,
o-acetoxybenzoate, isobutyrate, phenylbutyrate,
.alpha.-hydroxybutyrate, butyne-1,4-dicarboxylate,
hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, citrate,
formate, fumarate, glycolate, heptanoate, hippurate, lactate,
malate, maleate, hydroxymaleate, malonate, mandelate, nicotinate,
isonicotinate, oxalate, phthalate, terephthalate, propiolate,
propionate, phenylpropionate, salicylate, sebacate, succinate,
suberate, benzenesulfonate, p-bromobenzenesulfonate,
chlorobenzenesulfonate, ethylsulfonate, 2-hydroxyethylsulfonate,
methylsulfonate (mesylate), naphthalene-1-sulfonate,
naphthalene-2-sulfonate, naphthalene-1,5-sulfonate,
p-toluenesulfonate, xylenesulfonate, tartrate, and the like.
[0190] It is well known that such compounds can form salts in
various molar ratios with the acid to provide, for example, the
hemi-acid, mono-acid, di-acid salt, etc. Where in the salt
formation procedure, the acid is added in a specific stoichiometric
ratio, unless otherwise analyzed to confirm, the salt is presumed,
but not known, to form in that molar ratio. Terms such as
"(acid).sub.x" are understood to mean that the molar ratio of the
salt formed is not known and can not be presumed, as for example,
but without limitation, (HCl).sub.x and (methanesulfonic
acid).sub.x.
[0191] Abbreviations used herein are defined as follows: [0192]
"ADPP" means 1,1'-(azodicarbonyl)dipiperidine. [0193] "AIBN" means
2,2'-azobisisobutyronitrile. [0194] "BINAP" means
(.+-.)-2,2'-bis(diphenylphosphino)-1,1'-binaplithalene. [0195]
"Boc" or "t-Boc" means tert-butoxycarbonyl. [0196] "Brine" means a
saturated aqueous sodium chloride solution. [0197] "t-Bu" means
tert-butyl. [0198] "CV" means calorific value of oxygen. [0199]
"DCE" means 1,2-dichloroethane. [0200] "DCM" means dichloromethane
(i.e. methylene chloride, CH.sub.2Cl.sub.2). [0201] "DIBAL-H" means
diisobutylaluminum hydride. [0202] "DMAP" means
4-dimethylaminopyridine. [0203] "DMF" means N,N-dimethylformamide.
[0204] "DMSO" means dimethylsulfoxide. [0205] "DOI" means
(.+-.)-1-(2,5-dimethoxy-4-[.sup.125,]-iodophenyl)-2-aminopropane.
[0206] "DPPF" means 1,1'-bis(diphenylphosphino)ferrocene. [0207]
"EDC" means 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride. [0208] "EDTA" means ethylenediaminetetraacetic acid.
[0209] "ee" means enantiomeric excess. [0210] "EE" means energy
expenditure. [0211] "EtOAc" means ethyl acetate. [0212] "EtOH"
means ethanol. [0213] "GC-MS" means gas chromatography-mass
spectrometry. [0214] "GDP" means guanosine diphosphate. [0215]
"GTP" means guanosine triphosphate. [0216] "GTP.gamma.[.sup.35S]"
means guanosine triphosphate having the terminal phosphate
substituted with .sup.35S in place of an oxygen. [0217] "HOBt"
means 1-hydroxybenzotriazole hydrate. [0218] "HPLC" means
high-pressure liquid chromatography. [0219] "ISPA" means
immunoadsorption scintillation proximity assay. [0220] "MeOH" means
methanol. [0221] "MS (APCI+)" means mass spectroscopy using
atmospheric pressure chemical ionization. [0222] "MS (ES+)" means
mass spectroscopy using electrospray ionization. [0223] "NBS" means
N-bromosuccinimide. [0224] "NMP" means 1-methyl-2-pyrrolidinone.
[0225] "Pd/C" means palladium on activated carbon. [0226] "psi"
means pounds per square inch. [0227] "RQ" means respiratory
quotient.
[0228] "SCX chromatography" means chromatography on a SCX column or
cartridge. [0229] "SCX column" or "SCX cartridge", as used herein,
refers to a Varian Bond Elute.RTM. silica based strong cation
exchange resin column or disposable cartridge or equivalent. [0230]
"SFC" means supercritical fluid chromatography. [0231] "Tf" in a
chemical structure means the trifluoromethaiiesulfonyl moiety
(--SO.sub.2CF.sub.3). [0232] "Ts" in a chemical structure means the
4-methylbenzenesulfonyl moiety. [0233] "TFA" means trifluoroacetic
acid. [0234] "THF" means tetrahydrofuran.
[0235] While all of the compounds of the present invention are
useful as 5-HT.sub.2C agonists, certain classes are preferred, as
for example, compounds having any of the following enumerated
selections of substituents: Compounds wherein [0236] 1) R.sup.7 is
halo; [0237] 2) R.sup.7 is chloro; [0238] 3) R.sup.7 is fluoro;
[0239] 4) R.sup.7 is (C.sub.1-C.sub.6)alkyl optionally substituted
with 1 to 6 fluoro substituents; [0240] 5) R.sup.7 is
(C.sub.1-C.sub.3)alkyl optionally substituted with 1 to 6 fluoro
substituents; [0241] 6) R.sup.7 is --CF.sub.3; [0242] 7) R.sup.7 is
(C.sub.3-C.sub.6)alkenyl optionally substituted with 1 to 6 fluoro
substituents; [0243] 8) R.sup.7 is (C.sub.3-C.sub.6)alkenyl; [0244]
9) R.sup.7 is cyano; [0245] 10) R.sup.1-5 are each hydrogen; [0246]
11) R.sup.5 is methyl or ethyl; [0247] 12) R.sup.5 is methyl;
[0248] 13) R.sup.3 is methyl; [0249] 14) R.sup.8 is hydrogen;
[0250] 15) R.sup.9 is hydrogen; [0251] 16) R.sup.9 is
(C.sub.1-C.sub.3)alkoxy; [0252] 17) R.sup.9 is methoxy; [0253] 18)
R.sup.9 is halo; [0254] 19) R.sup.9 is chloro; [0255] 20) R.sup.9
is cyano; [0256] 21) R.sup.9 is --CF.sub.3; [0257] 22) R.sup.11 is
hydrogen; [0258] 23) R.sup.11 is methyl; [0259] 24) R.sup.10 is
Ph.sup.2-methyl-; [0260] 25) R.sup.10 is
Ph.sup.2-CH(CH.sub.3)--(i.e. C.sub.1-n-alkyl substituted with
methyl); [0261] 26) R.sup.10 is
Ph.sup.2-CH(CH.sub.2CH.sub.3)--(i.e. C.sub.1-n-alkyl substituted
with ethyl); [0262] 27) R.sup.10 is
##STR00004##
[0262] (i.e. C.sub.1-n-alkyl substituted with gem-ethano); [0263]
28) R.sup.10 is Ar.sup.1-methyl-; [0264] 29) R.sup.10 is
Ar.sup.1-CH(CH.sub.3)--(i.e. C.sub.1-n-alkyl substituted with
methyl); [0265] 30) R.sup.10 is Ar.sup.2--CH(CH.sub.2CH.sub.3)--
(i.e. C.sub.1-n-alkyl substituted with ethyl); [0266] 31) R.sup.10
is
##STR00005##
[0266] (i.e. C.sub.1-n-alkyl substituted with gem-ethano); [0267]
32) Ph.sup.2 is substituted in the para position; [0268] 33)
Ph.sup.2 is substituted in the para position and further
substituted in the meta-position with halo, hydroxy, or cyano;
[0269] 34) Ph.sup.2 is substituted in the para position and further
substituted in the meta-position with fluoro or chloro; [0270] 35)
Ph.sup.2 is monosubstituted; [0271] 36) Ph.sup.2 is monosubstituted
in the para position; [0272] 37) Ph.sup.2 is substituted with
Het.sup.1-(C.sub.0-C.sub.3)alkyl optionally substituted on the
alkyl moiety with 1 to 6 fluoro substituents; [0273] 38) Ph.sup.2
is substituted with Het.sup.2-(C.sub.0-C.sub.3)alkyl optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents;
[0274] 39) Ph.sup.2 is substituted with
Het.sup.3-(C.sub.0-C.sub.3)alkyl optionally substituted on the
alkyl moiety with 1 to 6 fluoro substituents; [0275] 40) Ph.sup.2
is substituted with Ar.sup.1(C.sub.0-C.sub.3)alkyl optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents;
[0276] 41) Ph.sup.2 is substituted with
(C.sub.1-C.sub.6)alkyl-C(R.sup.14).dbd.C(R.sup.14)-- optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents;
[0277] 42) Ph.sup.2 is substituted with
(R.sup.14).sub.2C.dbd.C[(C.sub.1-C.sub.6)alkyl]- optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents;
[0278] 43) Ph.sup.2 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(R.sup.14).dbd.C(R.su-
p.15)-- optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on the alkyl moiety with
1 to 4 fluoro substituents; [0279] 44) Ph.sup.2 is substituted with
(R.sup.15)CH.dbd.C[(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl]
-optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on the alkyl moiety with
1 to 4 fluoro substituents; [0280] 45) Ph.sup.2 is substituted with
(C.sub.1-C.sub.6)alkyl-C.ident.C-- optionally substituted on the
alkyl moiety with 1 to 6 fluoro substituents; [0281] 46) Ph.sup.2
is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C.ident.C--
optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on the alkyl moiety with
1 to 4 fluoro substituents; [0282] 47) Ph.sup.2 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.5-
)alkyl optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on either or both alkyl
moieties independently with 1 to 4 fluoro substituents; [0283] 48)
Ph.sup.2 is substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.5)alkyl
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0284] 49) Ph.sup.2
is substituted with
pyridyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.5)alkyl,
optionally substituted on the pyridyl moiety with 1 to 3
substituents independently selected from the group consisting of
halo, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, --CF.sub.3,
--O--CF.sub.3, nitro, cyano, and trifluoromethylthio, and
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0285] 50) Ph.sup.2
is substituted with
(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.3)alkyl-C(O)-- optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents and further optionally substituted on the
(C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents;
[0286] 51) Ph.sup.2 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-O--(C.sub.1-C.sub.3)al-
kyl-C(O)-- optionally substituted on the cycloalkyl moiety with 1
to 4 substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on either or both alkyl
moieties independently with 1 to 4 fluoro substituents; [0287] 52)
Ph.sup.2 is substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.1-C.sub.3)alkyl-C(O)--
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0288] 53) Ph.sup.2
is substituted with
(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.3)alkyl-C(O)-- optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents and further optionally substituted on the
(C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents;
[0289] 54) Ph.sup.2 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.3)al-
kyl-C(O)-- optionally substituted on the cycloalkyl moiety with 1
to 4 substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on either or both alkyl
moieties independently with 1 to 4 fluoro substituents; [0290] 55)
Ph.sup.2 is substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.3)alkyl-C(O)--
optionally substituted on either or both alkyl moieties with 1 to 4
fluoro substituents; [0291] 56) Ph.sup.2 is substituted with
(C.sub.1-C.sub.6)alkyl-NR.sup.16--(C.sub.1-C.sub.3)alkyl-C(O)--
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents and further optionally substituted on the
(C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents;
[0292] 57) Ph.sup.2 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NR.sup.16--(C.sub.1-C.-
sub.3)alkyl-C(O)-- optionally substituted on the cycloalkyl moiety
with 1 to 4 substituents selected from the group consisting of
methyl and fluoro, and further optionally substituted on either or
both alkyl moieties independently with 1 to 4 fluoro substituents;
[0293] 58) Ph.sup.2 is substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NR.sup.16--(C.sub.1-C.sub.3)alkyl-C(O)--
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0294] 59) Ph.sup.2
is substituted with
(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.3)alkyl-SO.sub.2--
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents and further optionally substituted on the
(C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents;
[0295] 60) Ph.sup.2 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-O--(C.sub.1-C.sub.3)al-
kyl-SO.sub.2-- optionally substituted on the cycloalkyl moiety with
1 to 4 substituents selected from the group consisting of methyl
and fluoro, and further optionally substituted on either or both
alkyl moieties independently with 1 to 4 fluoro substituents;
[0296] 61) Ph.sup.2 is substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.1-C.sub.3)alkyl-SO.sub.2--
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0297] 62) Ph.sup.2
is substituted with
(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.3)alkyl-SO.sub.2--
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents and further optionally substituted on the
(C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents;
[0298] 63) Ph.sup.2 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.3)al-
kyl-SO.sub.2-optionally substituted on the cycloalkyl moiety with 1
to 4 substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on either or both alkyl
moieties independently with 1 to 4 fluoro substituents; [0299] 64)
Ph.sup.2 is substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.3)alkyl-SO.sub.2--
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0300] 65) Ph.sup.2
is substituted with
(C.sub.1-C.sub.6)alkyl-NR.sup.16--(C.sub.1-C.sub.3)alkyl-SO.sub.2--
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents and further optionally substituted on the
(C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents;
[0301] 66) Ph.sup.2 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-NR.sup.16--(C.sub.1-C.-
sub.3)alkyl-SO.sub.2-- optionally substituted on the cycloalkyl
moiety with 1 to 4 substituents selected from the group consisting
of methyl and fluoro, and further optionally substituted on either
or both alkyl moieties independently with 1 to 4 fluoro
substituents; [0302] 67) Ph.sup.2 is substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-NR.sup.16--(C.sub.1-C.sub.3)alkyl-SO.sub.-
2-- optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0303] 68) Ph.sup.2
is substituted with
R.sup.17R.sup.18R--N--C(O)--(C.sub.1-C.sub.5)alkyl optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents;
[0304] 69) Ph.sup.2 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S-- optionally
substituted on the cycloalkyl moiety with 1 to 4 substituents
selected from the group consisting of methyl and fluoro, and
further optionally substituted on the alkyl moiety with 1 to 4
fluoro substituents; [0305] 70) Ph.sup.2 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.5)al-
kyl optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on either or both alkyl
moieties independently with 1 to 4 fluoro substituents; [0306] 71)
Ph.sup.2 is substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.5)alkyl
optionally substituted on the (C.sub.1-C.sub.5)alkyl moiety with 1
to 6 fluoro substituents; [0307] 72) Ph.sup.2 is substituted with
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.5)alkyl
optionally substituted on the (C.sub.1-C.sub.5)alkyl moiety with 1
to 6 fluoro substituents; [0308] 73) Ph.sup.2 is substituted with
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-O--(C.sub.1-C.sub.5)alkyl
optionally substituted on the (C.sub.1-C.sub.5)alkyl moiety with 1
to 6 fluoro substituents; [0309] 74) Ph.sup.2 is substituted with
Het.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl wherein
Het.sup.1 is linked through any carbon atom of Het.sup.1 and
wherein the (C.sub.0-C.sub.5)alkyl moiety is optionally substituted
with 1 to 6 fluoro substituents; [0310] 75) Ph.sup.2 is substituted
with Het.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl
wherein Het.sup.1 is linked through any carbon atom of Het.sup.1
and wherein the (C.sub.0-C.sub.5)alkyl moiety is optionally
substituted with 1 to 6 fluoro substituents; [0311] 76) Ph.sup.2 is
substituted with
Het.sup.2-(C.sub.0-C.sub.3)alkyl-S--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.5)alkyl moiety with 1
to 6 fluoro substituents; [0312] 77) Ph.sup.2 is substituted with
R.sup.16R.sup.19--N--C(O)--S--(C.sub.0-C.sub.5)alkyl optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents;
[0313] 78) Ph.sup.2 is substituted with
R.sup.16R.sup.19--N--C(O)--O--(C.sub.0-C.sub.5)alkyl optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents;
[0314] 79) Ph.sup.2 is substituted with
R.sup.16R.sup.19--N--C(O)--NR.sup.16--(C.sub.0-C.sub.5)alkyl
optionally substituted on the alkyl moiety with 1 to 6 fluoro
substituents; [0315] 80) Ph.sup.2 is substituted with
(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.3)alkyl-S-- optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents and further optionally substituted on the
(C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents;
[0316] 81) Ph.sup.2 is substituted with
(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.3)alkyl-S--
optionally substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1
to 6 fluoro substituents and further optionally substituted on the
(C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents;
[0317] 82) Ph.sup.2 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3-
)alkyl-O-- optionally substituted on the cycloalkyl moiety with 1
to 4 substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on either or both alkyl
moieties independently with 1 to 4 fluoro substituents; [0318] 83)
Ph.sup.2 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.1-C.s-
ub.3)alkyl-O-- optionally substituted on the cycloalkyl moiety with
1 to 4 substituents selected from the group consisting of methyl
and fluoro, and further optionally substituted on either or both
alkyl moieties independently with 1 to 4 fluoro substituents;
[0319] 84) Ph.sup.2 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3-
)alkyl-S-- optionally substituted on the cycloalkyl moiety with 1
to 4 substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on either or both alkyl
moieties independently with 1 to 4 fluoro substituents; [0320] 85)
Ph.sup.2 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.1-C.s-
ub.3)alkyl-S-optionally substituted on the cycloalkyl moiety with 1
to 4 substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on either or both alkyl
moieties independently with 1 to 4 fluoro substituents; [0321] 86)
Ph.sup.2 is substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.1-C.sub.3)alkyl-O--
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0322] 87) Ph.sup.2
is substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3)alkyl-S--
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0323] 88) Ph.sup.2
is substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.1-C.sub.3)alkyl-S--
optionally substituted on either or both alkyl moieties
independently with 1 to 4 fluoro substituents; [0324] 89) Ph.sup.2
is substituted with
R.sup.17R.sup.18N--C(O)--(C.sub.1-C.sub.3)alkyl-S-- optionally
substituted on the alkyl moiety with 1 to 4 fluoro substituents;
[0325] 90) Ph.sup.2 is substituted
with(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.1-
-C.sub.5)alkyl optionally substituted on the cycloalkyl moiety with
1 to 4 substituents selected from the group consisting of methyl
and fluoro, and further optionally substituted on the
(C.sub.0-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents and
further optionally substituted on the (C.sub.1-C.sub.5)alkyl moiety
with 1 to 6 fluoro substituents; [0326] 91) Ph.sup.2 is substituted
with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.1-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3
)alkyl moiety with 1 to 4 fluoro substituents and further
optionally substituted on the (C.sub.1-C.sub.5)alkyl moiety with 1
to 6 fluoro substituents; [0327] 92) Ph.sup.2 is substituted with
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.1-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and further optionally substituted on the
(C.sub.1-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0328] 93) Ph.sup.2 is substituted with
Het.sup.2-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and further optionally substituted on the
(C.sub.1-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0329] 94) Ph.sup.2 is substituted with
R.sup.17R.sup.18N--(C.sub.1-C.sub.3)alkyl optionally substituted on
the alkyl moiety with 1 to 4 fluoro substituents; [0330] 95)
Ph.sup.2 is substituted
with(C.sub.1-C.sub.6)alkyl-C(O)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on either or both alkyl moieties
independently with 1 to 6 fluoro substituents; [0331] 96) Ph.sup.2
is substituted
with(C.sub.3-C.sub.7)cycloalkyl-C(O)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on the alkyl moiety with
1 to 6 fluoro substituents; [0332] 97) Ph.sup.2 is substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and further optionally substituted on the
(C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0333] 98) Ph.sup.2 is substituted with
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-C(O)--N(R.sup.6)--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and further optionally substituted on the
(C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0334] 99) Ph.sup.2 is substituted
with(C.sub.1-C.sub.6)alkyl-O--N.dbd.C(CH.sub.3)-- optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents; [0335] 100) Ph.sup.2 is substituted
with(C.sub.0-C.sub.3)alkyl-O--N.dbd.C[(C.sub.1-C.sub.6)alkyl]-
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and further optionally substituted on the
(C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro substituents;
[0336] 101) Ph.sup.2 is substituted with
HO--N.dbd.C[(C.sub.0-C.sub.1)alkyl-(C.sub.3-C.sub.7)cycloalkyl]
-optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on either or both alkyl
moieties independently with 1 to 2 fluoro substituents; [0337] 102)
Ph.sup.2 is substituted with
CH.sub.3--O--N.dbd.C[(C.sub.0-C.sub.1)alkyl-(C.sub.3-C.sub.7)cycloalkyl]
-optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on either or both alkyl
moieties independently with 1 to 2 fluoro substituents; [0338] 103)
Ar.sup.1 is 5--R.sup.13-pyridin-2-yl; [0339] 104) Ar.sup.1 is
5--R.sup.13-pyridin-2-yl and R.sup.13 is
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and further optionally substituted on the
(C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0340] 105) Ar.sup.1 is 5--R.sup.13-pyridin-2-yl and R.sup.13 is
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl;
[0341] 106) Ar.sup.1 is 6-R.sup.13-pyridin-3-yl; [0342] 107)
Ar.sup.1 is substituted with Het.sup.2-(C.sub.0-C.sub.3)alkyl
optionally substituted on the alkyl moiety with 1 to 4 fluoro
substituents; [0343] 108) Ar.sup.1 is substituted with
Het.sup.3-(C.sub.0-C.sub.3)alkyl optionally substituted on the
alkyl moiety with 1 to 4 fluoro substituents; [0344] 109) Ar.sup.1
is substituted with Ar.sup.2--(C.sub.0-C.sub.3)alkyl optionally
substituted on the alkyl moiety with 1 to 4 fluoro substituents;
[0345] 110) Ar.sup.1 is substituted with
(C.sub.1-C.sub.6)alkyl-C(R.sup.14).dbd.C(R.sup.14)-- optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents;
[0346] 111) Ar.sup.1 is substituted with
(R.sup.14).sub.2C.dbd.C[(C.sub.1-C.sub.6)alkyl]- optionally
substituted on the alkyl moiety with 1 to 6 fluoro substituents;
[0347] 112) Ar.sup.1 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(R.sup.14).dbd.C(R.su-
p.14)-- optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on the alkyl moiety with
1 to 4 fluoro substituents; [0348] 113) Ar.sup.1 is substituted
with
(R.sup.15)CH.dbd.C[(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl]
-optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on the alkyl moiety with
1 to 4 fluoro substituents; [0349] 114) Ar.sup.1 is substituted
with (C.sub.1-C.sub.6)alkyl-C.ident.C-- optionally substituted on
the alkyl moiety with 1 to 6 fluoro substituents; [0350] 115)
Ar.sup.1 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.1)alkyl-C.ident.C--
optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on the alkyl moiety with
1 to 2 fluoro substituents; [0351] 116) Ar.sup.1 is substituted
with (C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.5)alkyl optionally
optionally substituted on either or both alkyl moieties
independently with 1 to 6 fluoro substituents; [0352] 117) Ar.sup.1
is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)al-
kyl optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on the
(C.sub.0-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents and
further optionally substituted on the (C.sub.0-C.sub.5)alkyl moiety
with 1 to 6 fluoro substituents; [0353] 118) Ar.sup.1 is
substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and further optionally substituted on the
(C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0354] 119) Ar.sup.1 is substituted with
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and further optionally substituted on the
(C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0355] 120) Ar.sup.1 is substituted with
Het.sup.2-(C.sub.0-C.sub.3)alkyl-O--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and further optionally substituted on the
(C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0356] 121) Ar.sup.1 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.5-
)alkyl optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on the
(C.sub.0-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents and
further optionally substituted on the (C.sub.1-C.sub.5)alkyl moiety
with 1 to 6 fluoro substituents; [0357] 122) Ar.sup.1 is
substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and further optionally substituted on the
(C.sub.1-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0358] 123) Ar.sup.1 is substituted with
pyridyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.5)alkyl
optionally be substituted on the pyridyl moiety with 1 to 3
substituents independently selected from the group consisting of
halo, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, --CF.sub.3,
--O--CF.sub.3, nitro, cyano, and trifluoromethylthio, and
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and further optionally substituted on the
(C.sub.1-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0359] 124) Ar.sup.1 is substituted with
(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.3)alkyl-O-- optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents and further optionally substituted on the
(C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents;
[0360] 125) Ar.sup.1 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3-
)alkyl-O-- optionally substituted on the cycloalkyl moiety with 1
to 4 substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on either or both of the
alkyl moieties independently with 1 to 4 fluoro substituents;
[0361] 126) Ar.sup.1 is substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3)alkyl-O--
optionally substituted on either or both of the alkyl moieties
independently with 1 to 4 fluoro substituents; [0362] 127) Ar.sup.1
is substituted with
pyridyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3)alkyl-O--
optionally be substituted on the pyridyl moiety with 1 to 3
substituents independently selected from the group consisting of
halo, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, --CF.sub.3,
--O--CF.sub.3, nitro, cyano, and trifluoromethylthio, and
optionally substituted on either or both of the alkyl moieties
independently with 1 to 4 fluoro substituents; [0363] 128) Ar.sup.1
is substituted with
R.sup.17R.sup.18N--C(O)--(C.sub.1-C.sub.3)alkyl-O-- optionally
substituted on the alkyl moiety with 1 to 4 fluoro substituents;
[0364] 129) Ar.sup.1 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S-- substituted
on cycloalkyl moiety with 2 to 4 methyl substituents and further
optionally substituted on the alkyl moiety with 1 to 4 fluoro
substituents; [0365] 130) Art is substituted with
(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.5)alkyl optionally
substituted on either or both alkyl moieties independently with 1
to 6 fluoro substituents; [0366] 131) Ar.sup.1 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.5)al-
kyl optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on the
(C.sub.0-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents, and
further optionally substituted on the (C.sub.1-C.sub.5)alkyl moiety
with 1 to 6 fluoro substituents; [0367] 132) Ar.sup.1 is
substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and further optionally substituted on the
(C.sub.1-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0368] 133) Ar.sup.1 is substituted with
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-S--(C.sub.1-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and further optionally substituted on the
(C.sub.1-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0369] 134) Ar.sup.1 is substituted with
(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.3)alkyl-S-- optionally
substituted on the (C.sub.1-C.sub.6)alkyl moiety with 1 to 6 fluoro
substituents and further optionally substituted on the
(C.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents;
[0370] 135) Ar.sup.1 is substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3-
)alkyl-S-- optionally substituted on the cycloalkyl moiety with 1
to 4 substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on either or both of the
alkyl moieties independently with 1 to 4 fluoro substituents;
[0371] 136) Ar.sup.1 is substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3)alkyl-S--
optionally substituted on either or both of the alkyl moieties
independently with 1 to 4 fluoro substituents; [0372] 137) Ar.sup.1
is substituted with
pyridyl-(C.sub.0-C.sub.3)alkyl-C(O)--(C.sub.1-C.sub.3)alkyl-S--
optionally be substituted on the pyridyl moiety with 1 to 3
substituents independently selected from the group consisting of
halo, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, --CF.sub.3,
--O--CF.sub.3, nitro, cyano, and trifluoromethylthio, and
optionally substituted on either or both of the alkyl moieties
independently with 1 to 4 fluoro substituents; [0373] 138) Ar.sup.1
is substituted with
R.sup.17R.sup.18N--C(O)--(C.sub.1-C.sub.3)alkyl-S-- optionally
substituted on the alkyl moiety with 1 to 4 fluoro substituents;
[0374] 139) Ar.sup.1 is substituted with
(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl optionally
substituted on either or both of the alkyl moieties independently
with 1 to 6 fluoro substituents; [0375] 140) Ar.sup.1 is
substituted with
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.s-
ub.5)alkyl optionally substituted on the cycloalkyl moiety with 1
to 4 substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on the
(C.sub.0-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents and
further optionally substituted on the (C.sub.0-C.sub.5)alkyl moiety
with 1 to 6 fluoro substituents; [0376] 141) Ar.sup.1 is
substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and further optionally substituted on the
(C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0377] 142) Ar.sup.1 is substituted with
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and further optionally substituted on the
(C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0378] 143) Ar.sup.1 is substituted with
Het.sup.2-(C.sub.0-C.sub.3)alkyl-SO.sub.2--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and further optionally substituted on the
(C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0379] 144) Ar.sup.1 is substituted with
R.sup.17R.sup.18--N--C(O)--(C.sub.1-C.sub.5)alkyl optionally
substituted on the (C.sub.1-C.sub.5)alkyl moiety with 1 to 6 fluoro
substituents; [0380] 145) Ar.sup.1 is substituted with
R.sup.17R.sup.18N--(C.sub.1-C.sub.3)alkyl optionally substituted on
the (C
.sub.1-C.sub.3)alkyl moiety with 1 to 4 fluoro substituents; [0381]
146) Ar.sup.1 is substituted with
(C.sub.1-C.sub.6)alkyl-C(O)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on either or both of the alkyl moieties
independently with 1 to 6 fluoro substituents; [0382] 147) Ar.sup.1
is substituted with
(C.sub.3-C.sub.7)cycloalkyl-C(O)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on the cycloalkyl moiety with 1 to 4
substituents selected from the group consisting of methyl and
fluoro, and further optionally substituted on the
(C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0383] 148) Ar.sup.1 is substituted with
Ph.sup.1-(C.sub.0-C.sub.3)alkyl-C(O)--N(R.sup.16)--(C.sub.0-C.sub.5)alkyl
optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with 1
to 4 fluoro substituents and further optionally substituted on the
(C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0384] 149) Ar.sup.1 is substituted with
Ar.sup.3--(C.sub.0-C.sub.3)alkyl-C(O)--N(R.sup.16)--(C.sub.0-C.sub.5)alky-
l optionally substituted on the (C.sub.0-C.sub.3)alkyl moiety with
1 to 4 fluoro substituents and further optionally substituted on
the (C.sub.0-C.sub.5)alkyl moiety with 1 to 6 fluoro substituents;
[0385] 150) Ar.sup.2 is substituted with R.sup.15R.sup.17N--,
wherein R.sup.15 is hydrogen and R.sup.17 is (C.sub.1-C.sub.6)alkyl
or (C.sub.3-C.sub.7)cycloalkyl-(C.sub.0-C.sub.3)alkyl; [0386] 151)
Ar.sup.2 is thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, or
pyrazolyl; [0387] 152) Het.sup.1 is pyrrolidinyl, piperidinyl,
homopiperidinyl, or morpholinyl optionally be substituted with
(C.sub.1-C.sub.6)alkyl or with 2 methyl substituents; [0388] 153)
Het.sup.1 is pyrrolidinyl, piperidinyl, homopiperidinyl, or
morpholinyl; [0389] 154) Het.sup.1 is pyrrolidinyl, piperidinyl,
homopiperidinyl optionally be substituted with
(C.sub.1-C.sub.6)alkyl or with 2 methyl substituents; [0390] 155)
Het.sup.1 is pyrrolidinyl, piperidinyl, homopiperidinyl;
[0391] It will be understood that the above classes are preferred
selections for each substitutent and may be combined with preferred
selections for other substitutents to form additional preferred
classes. Exemplary combinations include, but are not limited to:
[0392] 156) Any one of preferred embodiments 1) through 9) (the
preferred selections for R.sup.7), combined with any one of
preferred embodiments 24) through 155) (the preferred selections
for R.sup.10 and substituents thereon); [0393] 157) Any one of
preferred embodiments 24) through 155) (the preferred selections
for R.sup.10 and substituents thereon), wherein R.sup.7 is halogen;
[0394] 158) Any one of preferred embodiments 24) through 155) (the
preferred selections for R.sup.10 and substituents thereon),
wherein R.sup.7 is chloro; [0395] 159) Any one of preferred
embodiments 32) through 36) (the preferred positions for
substituents on Ph.sup.2), combined with any one of preferred
embodiments 37) through 102) (the preferred selections for
substituents on Ph.sup.2); [0396] 160) Any one of preferred
embodiments 103) through 149) (the preferred selections for
mono-substitutions on Ar.sup.1), wherein Ar.sup.1 is further
substituted with a substituent selected from the group consisting
of halo, cyano, methyl, --CF.sub.3, and methoxy; [0397] 161) A
preferred combination according to any one of 156) through 160),
wherein R.sup.1-5, R.sup.8, and R.sup.9 are each hydrogen; [0398]
162) A preferred combination according to any one of 156) through
161), wherein R.sup.11 is hydrogen;
[0399] Generally, a methylene linker from the 6-position nitrogen
atom to the phenyl or pyridyl moiety is preferred over longer or
larger linkers, as in compounds wherein R.sup.10 is
Ph.sup.2-methyl- or R.sup.10 is Ar.sup.1-methyl-.
[0400] Also generally, for 6-benzylamino compounds, (i.e. compounds
wherein R.sup.10 is Ph.sup.2) substitution at the para-position of
the phenyl moiety is particularly preferred. One favored group of
compounds of the present invention is that represented by formula
(Ia), and pharmaceutically acceptable salts thereof:
##STR00006##
wherein
[0401] R.sup.7a is halogen, and especially chloro;
[0402] R.sup.12 is as defined in relation to formula (I); and
[0403] R.sup.20 is halo, hydroxy, or cyano;
or a pharmaceutically acceptable salt or solvate thereof.
[0404] Preferred compounds according to formula (Ia) are those
wherein R.sup.20 is fluoro or chloro.
[0405] Another favored group of compounds of the present invention
is that represented by formula (Ib), and pharmaceutically
acceptable salts thereof:
##STR00007##
wherein
[0406] R.sup.7a is halogen, and especially chloro;
[0407] R.sup.13 is as defined in relation to formula (I); and
[0408] R.sup.20 is halo, hydroxy, or cyano;
or a pharmaceutically acceptable salt or solvate thereof.
[0409] Preferred compounds according to formula (Ib) are those
wherein R.sup.20 is fluoro or chloro.
[0410] Yet another favored group of compounds of the present
invention is that represented by formula (Ic), and pharmaceutically
acceptable salts thereof:
##STR00008##
wherein
[0411] R.sup.7a is halogen, and especially chloro;
[0412] R.sup.13 is as defined in relation to formula (I); and
[0413] R.sup.20 is halo, hydroxy, or cyano;
or a pharmaceutically acceptable salt or solvate thereof.
[0414] Preferred compounds according to formula (Ic) are those
wherein R.sup.20 is fluoro or chloro.
[0415] Generally, compounds according to formula (Ib) are preferred
over compounds of formula (Ic).
[0416] Specific preferred compounds of the present invention are
those described in the Examples herein, including the free bases
and the pharmaceutically acceptable salts and solvates thereof.
[0417] It will be appreciated that the preferred definitions of the
various substituents recited herein may be taken alone or in
combination and, unless otherwise stated, apply to the generic
formula (I) for compounds of the present invention, as well as to
the preferred classes of compounds represented by formulae (Ia),
(Ib), and/or (Ic).
[0418] The compounds of the invention can be prepared according to
the following synthetic schemes by methods well known and
appreciated in the art. Suitable reaction conditions for the steps
of these schemes are well known in the art and appropriate
substitutions of solvents and co-reagents are within the skill of
the art. Likewise, it will be appreciated by those skilled in the
art that synthetic intermediates may by isolated and/or purified by
various well known techniques as needed or desired, and that
frequently, it will be possible to use various intermediates
directly in subsequent synthetic steps with little or no
purification. Furthermore, the skilled artisan will appreciate that
in some circumstances, the order in which moieties are introduced
is not critical. The particular order of steps required to produce
the compounds of Formula I is dependent upon the particular
compound being synthesized, the starting compound, and the relative
liability of the substituted moieties as is well appreciated by
those of ordinary skill in the art. All substituents, unless
otherwise indicated, are as previously defined, and all reagents
are well known and appreciated in the art.
[0419] The compounds of Formula I may be prepared by a variety of
procedures, some of which are described below. All substituents,
unless otherwise indicated, are as previously defined, and all
reagents are well known and appreciated in the art. The products of
each step can be recovered by conventional methods including
extraction, evaporation, precipitation, chromatography, filtration,
trituration, crystallization, and the like.
[0420] In Scheme I, appropriately substituted
6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepines
(a) can be converted to the compounds (c), under Buchwald's
coupling conditions, by treatment with an appropriate amine (b) in
the presence of an effective palladium catalyst/ligand system, and
a base in a suitable solvent, typically toluene or 1,4-dioxane
under an inert atmosphere. While a variety of catalysts and ligands
can be used, typical catalysts include
tris(dibenzylideneacetone)-dipalladium(0), palladium(II) acetate or
a mixture of both, and typical ligands include
(.+-.)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP).
Introduction of a second substituent R.sup.11, if needed, may be
performed to provide compounds (d). Pg is a suitable protecting
group for a secondary amine such as, but not limited to,
trifluoroacetyl, tert-butoxycarbonyl, or benzyl. Compounds of
Formula (Ia) where R.sup.3 is H, may be obtained from compounds (d)
by removing the protecting group Pg under conditions well known to
the skilled artisan. Compounds of Formula (Ia) where R.sup.3 is
methyl or ethyl, may be either obtained from intermediates (c)
where Pg is methyl or ethyl, respectively; or, alternately,
compounds of Formula (Ia) where R.sup.3 is H, may be converted to
the N-methyl or N-ethyl derivatives (Ia) where R.sup.3 is methyl or
ethyl via alkylation conditions well known in the art. An
appropriate compound of Formula (Ia) is one in which variables
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.8,
R.sup.9, R.sup.10 and R.sup.11 are as previously defined for
Formula I.
##STR00009##
[0421] Amines (b) are either commercially available or may be
prepared by a variety of methods. For example, as illustrated in
Scheme II, amines of formula (f) and (h) can be prepared from
nitrites (e) and (g) in the presence of hydrogen, at atmospheric
pressure or 60 psi, using Degussa-type Pd/C as catalyst in a
suitable solvent, such as methanol/hydrochloric acid,
ethanol/hydrochloric acid, methanol/water/acetic acid,
ethanol/water/acetic acid, THF/iso-propanol and the like.
Alternately, hydrogenation can be performed at atmospheric pressure
or 60 psi using Raney Nickel.RTM. as catalyst in a suitable
solvent, typically methanol or ethanol in the presence of ammonia.
Alternately, nitrites (e) and (g) can be reduced using lithium
aluminum hydride or borane (THF or dimethylsulfide complex) in a
suitable solvent, typically THF. Nitriles (e) and (g) can be also
reduced using cobalt(II) chloride hexahydrate or nickel(II)
chloride hexahydrate and sodium borohydride in a suitable solvent,
typically methanol or ethanol. Nitriles (e) and (g) are either
commercially available or may be prepared by methods well known to
the skilled artisan.
##STR00010##
[0422] As illustrated in Scheme III, nitrites (e) and (g) can be
also reduced in the presence of a suitable protecting group for an
amine such as, but not limited to, di-tert-butyl-dicarbonate.
Reduction of nitrites (e) and (g) can be performed by hydrogen, at
atmospheric pressure or 60 psi, using Degussa-type Pd/C as catalyst
in a suitable solvent, such as methanol, ethanol, THF/iso-propanol,
ethyl acetate and the like in the presence of
di-tert-butyl-dicarbonate. Alternately, other suitable reducing
agents could be cobalt(II) chloride hexahydrate or nickel(II)
chloride hexahydrate and sodium borohydride in a suitable solvent,
typically methanol or ethanol in the presence of
di-tert-butyl-dicarbonate. Deprotection of the nitrogen gives the
desired amines (f) and (h). Nitriles (e) and (g) are either
commercially available or may be prepared by methods well known to
the skilled artisan.
##STR00011##
[0423] Amines (fa) and (ha) can also be prepared as illustrated in
Scheme IV. Bromination of compounds (k) and (n) using NBS and AIBN
in a suitable solvent, typically carbon tetrachloride, chloroform
or dichloromethane provides bromides (l) and (.+-.), respectively.
Reaction of compounds (l) and (.+-.) with
di-tert-butyl-iminodicarboxylate in the presence of a base such as
sodium hydride, potassium carbonate, cesium carbonate or potassium
tert-butoxide, in a suitable solvent, typically DMF or THF, afford
compounds (m) and (p). Deprotection gives the desired amines (f)
and (h). Compounds (k) and (n) are either commercially available or
may be prepared by methods well known to the skilled artisan.
##STR00012##
[0424] Amines (fb) and (hb) may be prepared from the corresponding
alcohols (q) and (s), respectively, via reaction sequences well
known to the skilled in the art, as illustrated in Scheme V. The
alcohols are converted to intermediates (r) and (s) with a suitable
leaving group, such as but not limited to chloride, bromide, or
mesylate, which may be displaced by a nucleophile such as azide
(N.sub.3.sup.-), using a reagent such as sodium azide,
di-tert-butyl-iminodicarboxylate in the presence of a suitable base
or ammonia. The intermediates obtained from displacement with azide
(N.sub.3.sup.-) or di-tert-butyl-iminodicarboxylate may be
converted to the amines (fb) and (hb) via well known standard
procedures.
##STR00013##
[0425] Amines (fc) and (hc) may also be prepared as illustrated in
Scheme VI via reductive amination procedures. The corresponding
aldehydes (u), R.dbd.H, or ketones (u), R=allyl, are converted to
the amines by reaction with a amine reagent, such as but not
limited to a ammonium salt, in the presence of a reducing agent,
such as sodium 5 triacetoxy borohydride, or sodium cyano
borohydride.
##STR00014##
[0426] Amines (fd), (fe), (hd), (he) may also be prepared as
illustrated in Scheme VII. The corresponding nitriles (va) or
esters (wa) may be dialkylated in the alpha-positions according to
methods well known in the art. For example, reaction of compounds
(va) with ethylene dibromide or ethylene dichloride in the presence
of an appropriate base and in a suitable solvent, such as but not
limited to K[NSi(CH.sub.3).sub.2] in THF, can afford the gem-ethano
compounds (vb). Reduction of the nitrile under conditions some of
which have been described above may yield amines (fe) and (he).
Alternately, hydrolysis of the nitrile to the primary amide under
conditions well described in the literature and rearrangement of
the primary amide in the presence of NaOCl or NaOBr (Hofman
rearrangement of primary amides) may lead to the amines (fd) and
(hd). Alternately, esters (wb) can be hydrolyzed to the
corresponding carboxylic acids, which then can be converted to the
amines (fd) and (hd), via a Curtius-type rearrangement in the
presence of sodium azide and sulfuric acid. Gem-ethano esters (wb)
may also be obtained from the corresponding unsaturated esters
(wc), for example by reaction with CHBr.sub.3 in the presence of
base, such as for example NaOH under phase transfer catalysis
conditions, followed by debromination for example with Mg in
methanol, or by reaction with diazomethane under suitable
conditions.
##STR00015##
[0427] Amines (ff) and (hf) can be prepared, as illustrated in
Scheme VIII, by transformation of appropriately substituted
intermediates (xa), (xc), (xd), (xe) into the appropriately
substituted heteroaromatic compounds (xb) according to procedures
known in the art. Transformations of the nitrile by following the
procedures previously described give the desired amines (ff) and
(hf). Compounds (xa), (xc), (xd), and (xe) are either commercially
available or may be prepared by methods well known to the skilled
artisan.
##STR00016##
[0428] Amines (fg) and (hg) can be also prepared, as illustrated in
Scheme IX, by the couling of boronic acids (ya) with an
appropriately substituted heteroaromatic bromide, chloride, iodide
or triflate in the presence of a suitable palladium catalyst/ligand
system, and a base in a suitable solvent, typically toluene, DMF or
1,4-dioxane under an inert atmosphere. Transformations of the
nitriles (yb) by following the procedures previously described
gives the desired amines (fg) and (hg). Boronic acids (ya) are
either commercially available or may be prepared by methods well
known to the skilled artisan. Alternately, intermediates (yb) can
be obtained by reaction of compounds (yc) with an appropriately
activated heteroaryl derivative, under appropriate transition metal
catalysis, especially in the presence of a suitable palladium
reagent, as described in the literature and well known to the
skilled artisan [see for example, Li and Gribble, Palladium in
Heterocyclic Chemistry, Pergamon, Amsterdam (2000)].
##STR00017##
[0429] As illustrated in Scheme X, compounds of Formula (Ia) can be
prepared alternately from
6-amino-2,3,4,5-tetrahydro-1H-benzo[d]azepines (za) by reaction
with an appropriate bromide (zb), and an appropriate base, such as
sodium hydride, potassium carbonate or cesium carbonate, in a
suitable solvent, typically DMF, toluene, acetonitrile and the
like. Introduction of a second substituent R.sup.11, if needed, may
be performed to provide compounds (d). Pg is a suitable protecting
group for a secondary amine such as, but not limited to,
trifluoroacetyl or tert-butoxycarbonyl. Compounds of formula (d)
are deprotected to give compounds of Formula (Ia). An appropriate
compound of Formula (Ia) is one in which variables R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.8, R.sup.9,
R.sup.10 and R.sup.11 are as previously defined for Formula I.
Bromides (zb) are either commercially available or may be prepared
by methods well known to the skilled artisan.
##STR00018##
[0430] The appropriately substituted
6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepines
(a) may be prepared as described in Scheme XI starting from
1-naphthol. 1-Naphthol can be converted to
5-hydroxy-1,4-dihydronaphthalene (aa) by Birch reduction using
ammonia and lithium metal at low temperature. Methylation of the
6-hydroxy group affords the compound (ab). Ozonolysis of compound
(ab) and subsequent reduction with sodium borohydride provide the
diol (ac). After converting the two hydroxyl groups into two good
leaving groups, for example methanesulfonates, cyclize the compound
(ad) to the 6-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepines (ae)
with aqueous ammonia under pressure. Protect the ring nitrogen by
treatment with a variety of alkyl halides, acid chlorides or
anhydrides such as trifluoroacetic anhydride to give compounds
(af). Subsequently convert the methyl ether (af) to the phenol (ag)
with BBr.sub.3 in dichloromethane or other methods well known in
the literature [see for example, Greene and Wuts, Protective Groups
in Organic Synthesis, 3.sup.rd Ed., John Wiley and sons, Chapter
III, New York (1999)]. Functionalization of the aromatic ring to
introduce substituents R.sup.7, R.sup.8 and R.sup.9 are well known
in the art and very depending on the substitution desired.
Subsequent trifluoromethanesulfonylation of the appropriately
substituted 6-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azepines (ah)
affords the desired
6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepines
(a).
##STR00019##
[0431] The skilled artisan will also appreciate that not all of the
substituents in the compounds of Formula I will tolerate certain
reaction conditions employed to synthesize the compounds. These
moieties may be introduced at a convenient point in the synthesis,
or may be protected and then deprotected as necessary or desired,
as is well known in the art. The skilled artisan will appreciate
that the protecting groups may be removed at any convenient point
in the synthesis of the compounds of the present invention. Methods
for introducing and removing protecting groups used in this
invention are well known in the art; see, for example, Greene and
Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John
Wiley and sons, New York (1999).
[0432] The following Preparations and Examples are illustrative of
methods useful for the synthesis of the compounds of the present
invention. Exemplified compounds are also particularly preferred
compounds of the present invention.
General Procedure 1-1
[0433] Dissolve
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (1 equiv.), palladium(II) acetate
(0.1-0.2 equiv.), BINAP (0.2-0.4 equiv.; BINAP/catalyst ratio 2:1)
and cesium carbonate (1.4-3.0 equiv.) in toluene or dioxane
(0.05-0.5 M solution). Add the amine (1.2-3.0 equiv.), degas the
mixture with vacuum/nitrogen purge and heat at 90-100.degree. C.
for 16 h. Cool the mixture to room temperature, dilute with EtOAc,
filter through Celite.RTM. washing with EtOAc and evaporate the
solvent to obtain the crude mixture. Alternatively partition the
reaction mixture between brine or saturated aqueous NaHCO.sub.3 and
EtOAc, ether or DCM, dry the organic phase over Na.sub.2SO.sub.4,
and concentrate to obtain the crude mixture. Purify the crude
mixture by chromatography on silica gel eluting with hexane/EtOAc
mixtures and further SCX chromatography if needed.
General Procedure 1-2
[0434] Dissolve
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (1 equiv.),
tris(dibenzylideneacetone)-dipalladium(0) (0.1-0.3 equiv.), BINAP
(0.2-0.6 equiv.; BINAP/catalyst ratio 2:1) and cesium carbonate
(1.4-3.0 equiv.) in toluene or dioxane (0.05-0.5 M solution). Degas
under vacuum and fill three times with nitrogen. Add the
appropriately substituted amine (1.2-3.0 equiv.) and heat the
mixture to 90-100.degree. C. for 16 h under a nitrogen atmosphere.
Cool the reaction flask to room temperature, dilute the mixture
with EtOAc, filter through Celite.RTM. and concentrate in vacuo.
Purify by chromatography on silica gel eluting with hexane/EtOAc
mixtures and further SCX chromatography if needed.
General Procedure 1-3
[0435] Add
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonylox-
y-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1 equiv.), the appropriate
amine (1.2-3.0 equiv.), palladium(II) acetate (0.1 equiv.),
tris(dibenzylideneacetone)dipalladium(0) (0.2 equiv.), BINAP (0.6
equiv.; BINAP/catalysts ratio 2:1), cesium carbonate (1.4-3.0
equiv.) and toluene or dioxane (0.05-0.5 M solution) to a flask,
degas and fill three times with nitrogen. Heat the mixture at
90-100.degree. C. for 16 h. Dilute the mixture with EtOAc, wash
with saturated aqueous NaHCO.sub.3 and brine, dry over
Na.sub.2SO.sub.4, filter and concentrate in vacuo to give the crude
mixture. Alternatively remove the volatiles from the reaction
mixture to give directly the crude mixture, or filter the reaction
mixture through Celite.RTM. and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc mixtures and
further SCX chromatography if needed.
General Procedure 2-1
[0436] Dissolve the appropriately substituted
7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(1.0 equiv.) in methanol. Add a 0.5 M aqueous solution of potassium
carbonate (4.0 equiv.) and stir at room temperature for 6 h.
Concentrate in vacuo and partition the residue between water and
DCM. Extract the aqueous phase twice with DCM. Dry the combined
organic extracts over Na.sub.2SO.sub.4, filter and concentrate in
vacuo. Purify, if necessary, by chromatography on silica gel
eluting with 1-20% 2M ammonia/methanol in DCM, or by SCX
chromatography eluting with methanol followed by 1.0-7.0 M ammonia
in methanol.
General Procedure 2-2
[0437] Dissolve the appropriately substituted
7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
in ammonia/methanol solution (1.0-7.0 M). Stir for 1-16 h at room
temperature unless otherwise specified. Remove the volatiles in
vacuo. Purify, if necessary, by chromatography on silica gel
eluting with 1-20% 2M ammonia/methanol in DCM, or by SCX
chromatography eluting with methanol followed by 1.0-7.0 M ammonia
in methanol.
General Procedure 2-3
[0438] Dissolve the appropriately substituted
7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(1.0 equiv.) in methanol or ethanol (0.1-2M solution) and add from
10-50% by volume of 1.0-5.0 N aqueous sodium hydroxide or lithium
hydroxide. Stir the reaction mixture at room temperature for
0.25-16 h and concentrate in vacuo. Partition the residue between
EtOAc or DCM and water. Separate and dry the organic phase over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo. Purify, if
necessary, by chromatography on silica gel eluting with 1-20% 2M
ammonia/methanol in DCM, or by SCX chromatography eluting with
methanol followed by 1.0-7.0 M ammonia in methanol, or by reverse
phase HPLC.
General Procedure 3-1
[0439] Dissolve the purified free base (1 equiv.) in acetone or
methanol and add a solution of succinic acid (1 equiv.) in acetone
or methanol. Stir for 1 h at room temperature. Concentrate to an
oil, add a minimal volume of DCM and diethyl ether,
tert-butylmethyl ether, hexane or pentane to precipitate out the
salt. Alternatively, to precipitate out the salt, allow the
reaction mixture to stand 1-16 h at room temperature, 4.degree. C.
or -10.degree. C. and add ether or hexane. Filter and wash the
solid with ether or hexane to obtain the succinate salt.
Alternatively, evaporate the solvent in vacuo, wash the solid with
ether and filter or decant the solvent to obtain the succinate as a
solid. Dry the solid in vacuo or under a stream of nitrogen.
General Procedure 3-2
[0440] Dissolve the purified free base (1 equiv.) in methanol and
add a solution of (L)-tartaric acid in methanol. If a solid
precipitate out, filter and wash the solid with diethyl ether,
tert-butylmethyl ether, hexane or pentane. If no solid formation is
observed, remove all the volatiles in vacuo to form a foam. Dry in
vacuo or under a stream of nitrogen to obtain the (L)-tartaric acid
salt.
Preparation 1
7-Chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-t-
etrahydro-1H-benzo[d]azepine
##STR00020##
[0442] 5-Methoxy-1,4-dihydronaphthalene: Add powdered potassium
carbonate (193.1 g, 1.397 mol) to a solution of
5-hydroxy-1,4-dihydronaphthalene [68.08 g, 90% potency based on
.sup.1H-NMR, 0.4657 mol, from Societa Italiana Medicinala
Scandicci, s.r.l., Reggello (Firenze), Italy] in ethanol (700 mL).
Cool the solution to 0.degree. C. with ice/water and add dimethyl
sulfate (88.1 g, 66.1 mL, 0.699 mol) dropwise, maintaining the
temperature between 5.degree. C. and 10.degree. C. Then heat the
reaction mixture to 40.degree. C. until the TLC (10:1 hexane/EtOAc)
shows the absence of starting material (about 2 h). Filter off the
solids by vacuum filtration and remove the solvent in vacuo. Dilute
the residual brown oil with diethyl ether (500 mL), wash with 10%
aqueous NH.sub.4OH (500 mL), water (500 mL), brine (500 mL), dry
the organic layer over Na.sub.2SO.sub.4, filter and concentrate in
vacuo to give the crude product as a brown oil (73 g). Purify the
crude mixture by short path distillation under vacuum (bp
120-130.degree. C./5 Torr) to give the desired intermediate as a
clear oil (69.0 g, 92.5% potency corrected) (contains some
1,2,3,4-tetrahydro-5-methoxynaphthalene as an impurity). .sup.1H
NMR (300 MHz, CDCl.sub.3), 7.15 (t, 1H, J=7.9), 6.72 (dd, 2H,
J=15.7, 7.9), 5.93-5.88 (m, 2H), 3.83 (s, 3H), 3.42-3.39 (m, 2H),
3.30-3.28 (m, 2H); R.sub.f=0.58 eluting with 10:1 hexane/EtOAc.
[0443] 2,3-Bis-(2-hydroxyethyl)-1-methoxybenzene: Charge a
four-neck 5 L flask equipped with an over-head mechanical stirrer,
reflux condenser, thermocouple, and gas dispersion apparatus with
5-methoxy-1,4-dihydronaphthalene (264.54 g, 89.5% potency based on
.sup.1H-NMR, 1.478 mol) in DCM (1.3 L) and 2B-3 ethanol (1 L). Add
sudan III (10 mg) to give a faint red color. Cool the solution to
-65.degree. C. or lower, then pass O.sub.3 through the solution
until the solution turns a light yellow color and the TLC (10:1
hexane/EtOAc, KMnO.sub.4 stain) shows the absence of the starting
material (about 30 h). Transfer the solution via cannula into a
slurry of NaBH.sub.4 (97.8 g, 2.59 mol) in 2B-3 ethanol (500 mL)
cooled in ice/water. It is important that the temperature be
maintained at or above 0.degree. C., as for example between
0.degree. C. and 10.degree. C., throughout the transfer to ensure
the ozonide is completely reduced to the diol. After the transfer
is complete, warm the solution to ambient temperature and stir for
about 30 min. Cool the slurry to 0.degree. C. with ice/water then
slowly add acetone (540 mL, 7.4 mol) to remove excess NaBH.sub.4.
After all the solids dissolve, remove the solvent in vacuo.
Dissolve the yellow solid in DCM (1 L) and water (1 L), separate
the layers and extract the aqueous layer with DCM (750 mL). Wash
the combined organic layers with brine (1.5 L), add toluene (750
mL) and remove the solvent in vacuo. Dissolve the solid in DCM (500
mL) with heating, then add toluene (750 mL) and concentrate the
solution in vacuo to give the desired intermediate as a light
yellow solid (283.7 g, 89% potency corrected, mp 82-83.degree. C.)
(contains 1,2,3,4-tetrahydro-5-methoxynaphthalene as an impurity
(8.6%)). Further purify the product by vacuum drying overnight at
75.degree. C., S Torr, to remove all but trace amount of the
1,2,3,4-tetrahydro-5-methoxynaphthalene impurity. .sup.1H NMR (300
MHz, CDCl.sub.3), .delta. 7.16 (dd, 1H, J=8.2, 7.6), 6.83 (s, 1H,
J=7.0), 6.76 (s, 1H, J=8.2), 3.85-3.77 (m, 7H), 3.01-2.91 (m, 4H),
2.35 (s, 2H); .sup.13 C NMR (300 MHz, DMSO-d.sub.6), .delta. 157.5,
138.9, 126.5, 125.2, 122.0, 108.4, 62.1, 60.5, 55.3, 36.1, 29.6; IR
(KBr): 3006, 2960, 2886, 2829, 1583, 1461, 1440, 1264, 1091, 1041
cm .sup.-1; MS (ES+) m/z 178 (M+H).sup.+; Anal. Calc'd for
C.sub.11H.sub.16O.sub.3: C, 67.32; H, 8.22; N, 0. Found: C, 67.26,
H, 8.10; N, 0.21; R.sub.f=0.23 eluting with 95:5 DCM/methanol.
[0444] 2,3-Bis-(2-methanesulfonyloxethyl)-1-methoxybenzene: To a
slurry of 2,3-bis-(2-hydroxyethyl)-1-methoxybenzene (50.6 g, 0.258
mol, 1 equiv.) and triethylamine (78.3 g, 0.774 mol, 3 equiv.) in
DCM (500 mL) at 0.degree. C., add dropwise a solution of
methanesulfonyl chloride (65.0 g, 0.567 mol, 2.2 equiv.) in DCM
(100 mL) over 45 min. The addition is exothermic and the
methanesulfonyl chloride is added at a rate to keep the temperature
below 10.degree. C. After the addition is complete, warm the
reaction to ambient temperature. Wash the solution with water
(2.times.500 mL), and then brine (750 mL). Dry the organic layer
over Na.sub.2SO.sub.4, filter and concentrate in vacuo to obtain
the desired intermediate as a dark yellow oil (87.4 g, 96.2%),
which is used in the next reaction without further purification. An
analytical sample is obtained by flash column chromatography
eluting with 100% diethyl ether. .sup.1H NMR (300 MHz, CDCl.sub.3),
.delta. 7.20 (t, 1H, J=7.9), 6.82 (s, 1H, J=7.2), 6.80 (s, 1H,
J=8.2), 4.41-4.34 (m, 4H), 3.83 (s, 3H), 3.16-3.09 (m, 4H), 2.91
(s, 3H), 2.87 (s, 3H); .sup.13C NMR (300 MHz, CDCl.sub.3), .delta.
158.07, 136.55, 128.26, 123.34, 122.39, 109.24, 69.88, 69.08,
55.55, 37.35, 37.14, 32.57, 26.47; .sup.13C NMR (300 MHz,
DMSO-d.sub.6), 157.58, 136.79, 127.81, 122.91, 122.00, 109.33,
70.19, 68.88, 55.55, 36.49, 36.47, 31.56, 25.72; IR (KBr): 1586.8,
1469.4, 1358.51, 1267.3, 1173.9, 1105.4, 972.4, 954.6, 914.3
cm.sup.-1; MS (ES+) m/z 257 (M+H).sup.+; Anal. Calc'd. for
C.sub.13H.sub.20O.sub.7S.sub.2: C, 44.31; H, 5.72; N, 0. Found: C,
44.22, H, 5.68; N, 0.13; R.sub.f=0.72 eluting with 95:5
DCM/methanol.
[0445] 6-Methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine: Dissolve
2,3-bis-(2-methanesulfonyloxyethyl)-1-methoxybenzene (474.4 g,
1.346 mol) in acetonitrile (7 L) and split the mixture into two
equal lots. In two separate runs, add concentrated aqueous
NH.sub.4OH (3.5 L) and charge the solution to a pressure vessel
(Parr apparatus). Heat the solution in a closed reactor to
100.degree. C. over 20 min (internal pressure reaches about 100
psi), and maintain at 100.degree. C. until the reaction is complete
(about 1 h, HPLC monitored). Cool the reaction mixture to ambient
temperature. Combine the two lots and remove the solvent in vacuo.
Dissolve the residue in MTBE (3.5 L) and water (3.5 L). Adjust the
pH to 6.5 using 2M aqueous NaOH or 1M aqueous HCl as appropriate
(typically the pH is about pH=5.1 and the adjustment requires about
50 mL 2M aqueous NaOH). Discard the organic layer, adjust the
aqueous layer to pH=13 using 50% NaOH (about 150 mL). Extract with
MTBE (2.times.3.5 L), wash the combined organic layers with brine
(3.5 L), dry over Na.sub.2SO.sub.4, filter and concentrate in vacuo
to give the title compound as a crude yellow oil that solidifies
upon standing (179.3 g). Use the material for the next step without
further purification. Prepare an analytical sample by purification
by two Kugelrohr distillations to give a clear oil that solidifies
upon standing, mp 44.3-45.0.degree. C. .sup.13C NMR (300 MHz,
DMSO-d.sub.6), .delta. 156.1, 144.4, 130.3, 126.2, 121.5, 108.9,
55.5, 48.2, 47.9, 39.9, 29.1; MS (ES+) m/z 163 (M+H).sup.+; Anal.
Calc'd for C.sub.11H.sub.15NO: C, 74.54; H, 8.53; N, 7.90. Found:
C, 74.28, H, 8.62; N, 7.86.
[0446] 6-Methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine
Hydrochloride: Dissolve crude
6-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (35.1 g, 0.198 mol)
in 2B-3 ethanol (250 .mu.L), heat the solution to reflux and add 2M
HCl in ethanol (108.9 mL, 0.218 mol, 1.1 equiv.). Slowly add
heptane (700 mL) over 10 min, then remove the heating mantle and
cool the solution to ambient temperature, and finally continue the
cooling with an ice/water mixture. Collect the resulting solid by
vacuum filtration and wash with cold ethanol:heptane (1:2)
(3.times.100 mL), air-dry for 15 min under vacuum, then further dry
the product in a vacuum oven at 60.degree. C. for 1 h to give the
desired intermediate as a white granular solid (35.53 g, 63%): mp
246.6-246.9.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6),
.delta. 9.82 (broad s, 1H), 7.12 (dd, 1H, J=7.6, 7.9), 6.88 (d, 1H
J=8.2), 6.78 (d, 1H, J=7.3), 3.75 (s, 3H), 3.20-3.00 (m, 8H);
.sup.13C NMR (300 MHz, DMSO-d.sub.6), .delta. 156.2, 141.3, 127.4,
127.2, 121.6, 109.7, 55.7, 44.9, 44.7, 31.6, 21.7; MS (ES+) m/z 178
(M+H).sup.+; Anal. Calc'd for C.sub.11H.sub.15ClNO: C, 62.12; H,
7.11; N, 6.59. Found: C, 61.95, H, 7.64; N, 6.58.
[0447]
6-Methoxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]a-
zepine: To a slurry of
6-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (35.3
g, 0.165 mol, 1 equiv.) and triethylamine (69.1 mL, 0.496 mol, 3
equiv.) in DCM (300 mL) cooled at 0.degree. C. with ice/water, add
dropwise a solution of trifluoroacetic anhydride (25.7 mL, 0.182
mol, 1.1 equiv.) in DCM (40 mL) over 30 min, but at a rate that
maintains the temperature below 10.degree. C. After the addition is
complete, warm the reaction mixture to ambient temperature and stir
until the reaction is complete (verify by TLC using 9:1
CH.sub.2Cl.sub.2:methanol, about 2 h.). Wash the solution with
water (2.times.350 mL), and then brine (350 mL), dry the organic
layer over Na.sub.2SO.sub.4, filter and concentrate in vacuo to
give desired intermediate as a yellow oil that solidifies upon
standing (44.9 g, 96%). Use the material without further
purification in the next step. Prepare an analytical sample by
chromatography on silica gel eluting with 40% diethyl ether in
hexane, mp 74-76.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3),
.delta. 7.16-7.11 (m, 1H), 6.81-6.74 (m, 2H), 3.81 (s, 3H),
3.79-3.64 (m, 4H), 3.11-3.07 (m, 2H), 2.99-2.95 (m, 2H); .sup.1H
NMR (300 MHz, DMSO-d.sub.6), 87.13 (dd, 1H, J=1.5, 7.0), 7.08 (d,
1H, J=1.5), 6.88-6.74 (m, 1H), 3.75 (s, 3H), 3.67-3.61 (m, 4H),
3.04-2.92 (m, 4H); .sup.13C NMR (300 MHz, DMSO-d.sub.6), .delta.
156.43, 156.38, 155.06, 155.00, 154.60, 154.54, 154.14, 154.08,
141.31, 141.04, 127.44, 127.18, 127.05, 127.01, 122.27, 121.94,
121.90, 118.46, 114.64, 110.80, 109.52, 109.41, 55.63, 55.61,
47.11, 47.07, 46.67, 46.63, 45.61, 45.16, 35.90, 34.65, 26.18,
24.91; Anal. Calc'd for C.sub.13H.sub.14F.sub.3NO.sub.2: C, 57.14;
H, 5.16; N, 5.13. Found: C, 57.17, H, 5.27; N, 5.08.
[0448]
6-Hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]a-
zepine: To a 1M solution of BBr.sub.3 (1.1 L, 1.6 equiv.), cooled
at 0.degree. C. with an ice-water bath, add
6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(187 g, 0.684 mol) in DCM (200 mL) over 1 h., while maintaining the
temperature between 0.degree. C. and 10.degree. C. Warm the
reaction mixture to ambient temperature and stir until HPLC
indicates completion of the reaction (about 2 h.). Cool the
solution to 0.degree. C. and transfer it via cannula into an
ice/water solution (1.2 L), thereby precipitating the product as a
white solid. Add EtOAc (2 L) to dissolve most of the precipitate,
separate the layers and concentrate the organic layer in vacuo.
Extract the aqueous layer three times with EtOAc (2.times.2 L,
1.times.1 L). Wash the combined organic layers with water (2 L),
and then brine (2 L), dry over Na.sub.2SO.sub.4, filter and
concentrate in vacuo to give the desired intermediate as a light
yellow solid (166.3 g, 94%). Use the product for the next step
without further purification. Prepare an analytical sample by
chromatography on silica gel eluting with 40% diethyl ether in
hexane: mp 183.0-185.2.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6), .delta. 9.39 (s, 1H), 6.94-6.88 (m, 1H), 6.72-6.68
(m, 1H), 6.61-6.57 (m, 1H), 3.67-3.32 (m, 4H), 2.99-2.86 (m, 4H);
.sup.13C NMR (300 MHz, DMSO-d.sub.6), 154.50, 141.47, 141.18,
126.77, 126.64, 125.77, 125.33, 120.38, 120.32, 118.49, 114.67,
113.64, 113.47, 47.31, 47.27, 47.00, 46.96, 45.83, 45.49, 36.17,
34.93, 26.46, 25.18, 20.66, 14.00; MS (ES+) m/z 260 (M+H).sup.+;
Anal. Calc'd. for C.sub.12H.sub.12F.sub.3NO.sub.2: C, 55.60; H,
4.67; N, 5.40. Found: C, 55.51, H, 4.71; N, 5.29.
[0449]
7-Chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H--
benzo[d]azepine: Heat a mixture of
6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(120 g, 0.4629 mol) and toluene (14.4 L) to 70.degree. C. for 45
min until most of the starting material is dissolved. Add
diisobutylamine (1.197 g, 1.62 mL, 9.26 mmol) followed by addition
of sulfuryl chloride (62.48 g, 37.19 mL, 0.463 mol) in toluene (360
mL) over 20 min. Stir the reaction mixture for 50 min and then add
additional sulfuryl chloride (4.536 g, 2.70 mL, 0.0336 mol) neat
and stir the reaction mixture for 15 min at 70.degree. C. Cool the
reaction mixture to 24.degree. C. over 30 min and then add 1N
hydrochloric acid (2 L). Separate, wash the organic layer with
saturated aqueous NaHCO.sub.3 (2 L), brine (2 L) and then dry over
Na2SO4. Filter and remove the solvent with a rotary evaporator at
70.degree. C. until about 672.5 g remains using the minimum
effective vacuum in order to maintain a vapor phase sufficient to
prevent drying above the solvent line and self-seeding, thus
preventing crystallization under these conditions. Using toluene
heated to 70.degree. C., transfer the light-yellow solution to a
preheated (70.degree. C.) 3-neck flask equipped with a mechanical
stirrer. Lower the temperature to 58.degree. C. over 1 h. If
available, seed the solution with crystals of
7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[-
d]azepine from a prior synthesis to enhance crystallization. After
30 min, reduce the temperature further to 55.degree. C. and observe
the initiation of the crystallization process. Hold the temperature
at 55.degree. C. for 2 h followed by 4 h at 45.degree. C., then
turn off the heat allowing the mixture to slowly reach 24.degree.
C. (ambient temperature). After stirring for 8 h with the heat off,
cool the mixture to 0.degree. C. for 2 h followed by 2 h at
-10.degree. C. Collect the resulting dense, white, granular
crystals by vacuum filtration at -10.degree. C. Rinse the crystals
twice with cold (-10.degree. C.) toluene and vacuum dry at
50.degree. C., 5 Torr, for 12 h., to obtain the desired
intermediate as a white solid (120.7 g, 99.5% purity, 88.8%): mp
133-134.degree. C. MS (ES+) m/z 294 (M+H).sup.+. Anal. Calc'd for
C.sub.12H.sub.11ClF.sub.3NO.sub.2: C, 49.08; H, 3.78; N, 4.77; Cl,
12.07. Found: C, 49.01; H, 3.63; N, 4.72; Cl, 12.32.
[0450]
7-Chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,-
3,4,5-tetrahydro-1H-benzo[d]azepine: Cool a solution of
7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[-
d]azepine (60 g, 0.204 mol), triethylamine (62.6 mL, 0.448 mol, 2.2
equiv.), and DCM (590 mL) in an ice bath and add dropwise
trifluoromethanesulfonic anhydride (43.5 mL, 0.258 mol, 1.26
equiv.) over 70 min. Remove the ice bath and stir the reaction
mixture for 2 h. Wash the reaction mixture sequentially with water
(500 mL), 1N aqueous HCl (500 mL), water (500 mL), and brine (500
mL). Dry the organic layer over Na.sub.2SO.sub.4 and concentrate in
vacuo to give the crude product as a brown solid (90 g). Dissolve
the solid in warm toluene (200 mL). Further purify by plug
filtration chromatography over silica gel (500 g) eluting
sequentially with hexane (1 L), hexane/EtOAc (9:1, 1 L),
hexane/EtOAc (4:1, 1 L), and hexane/EtOAc (7:3, 9 L). Pool the
eluents and evaporate the solvent to obtain the product as a yellow
tan solid (86.3 g). Dissolve the solid in warm EtOAc (86 mL) and
then add hexane (700 mL). If available, seed the solution with
crystals of
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanelsulfonyloxy-2,3,4,5-
-tetrahydro-1H-benzo[d]azepine from a prior synthesis to enhance
crystallization. Allow the mixture to stand at ambient temperature
for 30 min. Cool the mixture at about -10.degree. C. for 2 h.,
filter, rinse the crystals with cold (-10.degree. C.) hexane/EtOAc,
and air-dry on the filter under vacuum to obtain the title compound
as a first crop of crystals (73.54 g). Concentrate the mother
liquor to obtain a solid (12.7 g). Recrystallize the solid in a
mixture of EtOAc/hexane (15 mL: 121 mL) to obtain additional title
compound (7.65 g, total yield: 81.19 g, 93%).
Preparation 2
6-(4-Acetyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrah-
ydro-1H-benzo[d]azepine
##STR00021##
[0452]
7-Chloro-6-[4-(2-methyl-[1,3]-dioxolan-2-yl)-benzylamino]-3-(2,2,2--
trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine: Use a
method similar to the General Procedure 1-3 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (200 mg, 0.47 mmol) with
4-(2-methyl-[1,3]dioxolan-2-yl)-benzylamine (prepared by following
the procedure described in J. Med. Chem. 1978, 21, 507) (182 mg,
0.94 mmol). Purify by chromatography on silica gel eluting with
hexane/EtOAc (1:0, 19:1 and 9:1) to obtain the desired intermediate
as an oil (150 mg, 68%). GC-MS m/z: 468 (M.sup.+).
[0453]
6-(4-Acetyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-
-tetrahydro-1H-benzo[d]azepine: Dissolve
7-chloro-6-[4-(2-methyl-[1,3]dioxolan-2-yl)-benzylamino]-3-(2,2,2-trifluo-
roacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (150 mg, 0.32 mmol)
in methanol (5 mL) and add 1N aqueous HCl (1 mL). Stir the solution
at room temperature for 2 h. Remove the solvent, dissolve the
residue in DCM and wash with saturated aqueous NaHCO.sub.3. Dry the
organic phase over Na.sub.2SO.sub.4, filter and concentrate in
vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (1:0, 9:1, 17:3 and 4:1) to obtain the title compound
as an oil (107 mg, 79%). GC-MS m/z: 424 (M.sup.+).
Preparation 3
7-Chloro-6-[4-(3-methyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,-
3,4,5-tetrahydro-1H-benzo[d]azepine
##STR00022##
[0455] 3-Methyl-1-p-tolyl-butan-1-one: Portionwise add aluminum
trichloride (3.35 g, 25 mmol) to a solution of isovaleryl chloride
(2 mL, 16.4 mmol) in anhydrous toluene (50 mL) at 0.degree. C. Warm
to room temperature and stir 12 h. Cool to 0.degree. C. and slowly
add cold water (500 mL). Extract with EtOAc, wash the organic phase
with brine, dry over Na.sub.2SO.sub.4 and concentrate in vacuo to
obtain the desired intermediate (2.8 g, 97%) as an orange oil
suitable for use without additional purification. MS (APCI+) m/z:
176 (M.sup.+).
[0456] 1-(4-Bromomethyl-phenyl)-3-methyl-butan-1-one: Add NBS (1.6
g, 9.2 mmol) to a solution of 3-methyl-1-p-tolyl-butan-1-one (1.5
g, 8.4 mmol) and AIBN (1.4 g, 8.4 mmol) in carbon tetrachloride (30
mL) and heat to reflux for 18 h. Cool the reaction mixture to room
temperature and pour into water (500 mL). Extract with EtOAc
(3.times.100 mL), wash the combined organic extracts with brine
(300 mL), dry over Na.sub.2SO.sub.4 and concentrate in vacuo to
obtain 2.9 g of a brown oil, consisting of the desired intermediate
with a small amount of unreacted 3-methyl-1-p-tolyl-butan-1-one and
1-(4,4-dibromomethyl-phenyl)-3-methyl-butan-1-one. Use this mixture
in the next step without additional purification. MS (APCI+) m/z:
255 (M.sup.+).
[0457] N-Di-(tert-butoxycarbonyl)-4-(3-methyl-butyryl)-benzylamine:
Add di-tert-butyl-iminodicarboxylate (5.2 g, 24 mmol) to a slurry
of sodium hydride (60% dispersion in mineral oil, 0.7 g, 17.6 mmol)
in anhydrous DMF (75 mL) and stir at room temperature under
nitrogen for 5 min. Add a solution of
1-(4-bromomethyl-phenyl)-3-methyl-butan-1-one in DMF (20 mL) and
stir under nitrogen for 2 h. Quench with slow addition of water (50
mL) and partition between EtOAc/water (1: 1, 500 mL). Separate and
dry the organic phase over Na.sub.2SO.sub.4 and concentrate in
vacuo to obtain the desired intermediate (5.4 g, 85%) as a brown
oily solid suitable for use without additional purification.
[0458] 4-(3-Methyl-butyryl)-benzylamine: Dissolve
N-di-(tert-butoxycarbonyl)-4-(3-methyl-butyryl)-benzylamine (0.5 g,
1.28 mmol) in EtOAc (10 mL). Add 4N hydrogen chloride in dioxane
(15 mL) and stir at room temperature for 20 h. Concentrate in
vacuo, suspend the resulting tan solid in diethyl ether (30 mL),
add hexane (150 mL) and filter the resulting tan precipitate. Wash
with hexane (20 mL), suspend in DCM (50 mL), add saturated aqueous
NaHCO.sub.3 (100 mL) and stir until both layers are clear (15
min).
[0459] Separate layers and extract the aqueous phase with DCM
(2.times.30 mL). Wash the combined organic extracts with brine, dry
over Na.sub.2SO.sub.4, and concentrate in vacuo to obtain the
desired intermediate as a light yellow syrup (160 mg, 65%). MS
(ES+) m/z: 192 (M+H).sup.+.
[0460]
7-Chloro-6-[4-(3-methyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroace-
tyl)-2, tetrahydro-1H-benzo[d]azepine: Use a method similar to the
General Procedure 1-3, using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (175 mg, 0.42 mmol) and
4-(3-methyl-butyryl)-benzylamine (160 mg, 0.8 mmol) to obtain the
title compound as a yellow syrup (85 mg, 45%). MS (ES+) m/z: 467
(M+H).sup.+.
Preparation 4
4-(2-Methylamino-thiazol-4-yl)-benzylamine
##STR00023##
[0462] 4-(2-Methylamino-thiazol-4-yl)-benzonitrile: Slurry
4-cyanophenacyl bromide (1.12 g, 5 mmol) in absolute ethanol (25
mL). Heat to 40.degree. C. to dissolve, then add N-methyl-thiourea
(0.45 g, 5 mmol) and sodium bicarbonate (0.42 g, 5 mmol), and heat
to reflux for 5 h. Cool to room temperature, filter the resulting
off-white solid and wash with hexane (10 mL). Partition
aqueous/ethanolic filtrate between water/EtOAc (4:1) and extract
aqueous phase with EtOAc (2.times.25 mL). Dry the combined organic
extracts over Na.sub.2SO.sub.4, concentrate in vacuo and combine
with filtered solid from crude reaction mixture to obtain the
desired intermediate (1.1 g, 99%) as an off-white solid suitable
for use without additional purification. MS (ES+) m/z: 216
(M+H).sup.+.
[0463] 4-(2-Methylamino-thiazol-4-yl)-benzylamine: Add 1M lithium
aluminum hydride in THF (5.6 mL, 5.6 mmol) under nitrogen to a
solution of 4-(2-methylamino-thiazol-4-yl)-benzonitrile (0.4 g,
1.86 mmol) in anhydrous THF (5 mL). After gas evolution stops, heat
the reaction mixture to reflux for 30 min. Cool to room
temperature, quench by slow addition of water (0.5 mL), 5N aqueous
NaOH (5 mL) and additional water (1.5 mL). Add EtOAc (50 mL), stir
vigorously for 20 min and filter through Celite.RTM.. Separate and
dry the organic phase over Na.sub.2SO.sub.4. Concentrate in vacuo
to obtain the title compound (0.4 g, 98%) as a white solid suitable
for use without additional purification. MS (ES+) m/z: 220
(M+H).sup.+.
Preparations 5-10
[0464] The compounds of Preparations 5-10 may be prepared
essentially as described in Preparation 4 by using 4-cyanophenacyl
bromide and the appropriately substituted thiourea.
iso-Butylthiourea was prepared by following the procedure described
in Tetrahedron Letters, 1988, 29, 1755-1758. Overall yields and MS
(ES+) data are shown in the Table below.
TABLE-US-00001 ##STR00024## Yield MS (ES+) Prep. R R' Compound (%)
m/z 5 Ethyl H 4-(2-Ethylamino- 85 234 thiazol-4-yl)-benzylamine (M
+ H).sup.+ 6 iso- H 4-(2-iso-Propylamino- 65 248 Propyl
thiazol-4-yl)-benzylamine (M + H).sup.+ 7 n-Propyl H
4-(2-n-Propylamino- 61 248 thiazol-4-yl)-benzylamine (M + H).sup.+
8 --(CH.sub.2).sub.5-- 4-(2-Piperidin-1-yl- 43 274
thiazol-4-yl)-benzylamine (M + H).sup.+ 9 Cyclo- H
4-(2-Cyclopropyl- 53 260 propylmethyl methylamino- (M + H).sup.+
thiazol-4-yl)-benzylamine 10 iso- H 4-(2-iso-Butylamino- 64 262
Butyl thiazol-4-yl)-benzylamine (M + H).sup.+
Preparation 11
4-(2-Methylamino-oxazol-4-yl)-benzylamine Hydrochloride
##STR00025##
[0466] 4-(2-Methylamino-oxazol-4-yl)-benzonitrile: Dissolve
4-cyanophenacyl bromide (10 g, 44.6 mmol) and methylurea (6.5 g,
89.3 mmol) in DMF (125 mL). Stir the reaction at 90.degree. C. for
16 h under a nitrogen atmosphere. Cool to room temperature, dilute
with hexane/EtOAc (1:1, 250 mL) and wash with 10% aqueous NaCl
(4.times.75 mL). Collect the organic phase, concentrate in vacuo
and purify the crude mixture by chromatography on silica gel (330
g) eluting with DCM/methanol (1:0 to 24:1 gradient) to obtain the
desired intermediate (2.3 g, 26%). MS (ES+) m/z: 200.2
(M+H).sup.+.
[0467]
N-(tert-Butoxycarbonyl)-4-(2-methylamino-oxazol-4-yl)-benzylamine:
Dissolve 4-(2-methylamino-oxazol-4-yl)-benzonitrile (1.6 g, 7.9
mmol) in methanol (200 mL). Add di-tert-butyl-dicarbonate (2.2 g,
10.3 mmol) and nickel(II) chloride hexahydrate (188 mg, 0.8 mmol).
Cool the solution to 0.degree. C. under a nitrogen atmosphere. Add
sodium borohydride (1.5 g, 39.7 mmol) portionwise over 5 min at
0.degree. C. under a nitrogen atmosphere. Stir the resulting black
mixture for 1 h at room temperature. Concentrate the mixture in
vacuo, dilute the residue with EtOAc (150 mL) and wash with
saturated aqueous NaHCO.sub.3 (30 mL). Collect the organic phase,
concentrate in vacuo and purify by chromatography on silica gel (40
g) eluting with hexane/EtOAc (20:1 to 3:2 gradient) to obtain the
desired intermediate (1.6 g, 67%). MS (ES+) m/z: 204.1
(M-Boc+H).sup.+.
[0468] 4-(2-Methylamino-oxazol-4-yl)-benzylamine Hydrochloride: Add
4N hydrogen chloride in dioxane (10.5 mL) to a solution of
N-(tert-butoxycarbonyl)-4-(2-methylamino-oxazol-4-yl)-benzylamine
(624 mg, 1.6 mmol) in DCM (250 mL). Stir the solution at room
temperature for 16 h in a sealed flask. Concentrate the mixture in
vacuo to a solid. Slurry the solid in excess of diethyl ether and
filter. Collect the white solid to obtain the title compound (1.48
g, 95%). MS (ES+) m/z: 204.1 (M+H).sup.+.
Preparation 12
4-(Cyclopentylthiomethyl)-benzylamine
##STR00026##
[0470] 4-(Cyclopentylthiomethyl)-benzonitrile: Add sodium
bis(trimethylsilyl)amide (20 mL, 40 mmol, 2M solution in THF) to a
solution of cyclopentanethiol (4.3 mL, 40 mmol) in anhydrous THF
(100 mL) and stir at room temperature under nitrogen for 1 h. Add
4-bromomethyl-benzonitrile (7.85 g, 40 mmol) and stir the mixture
for 24 h at room temperature. Reduce solvent in vacuo and wash with
saturated aqueous NaHCO.sub.3. Extract with DCM (50 mL), wash
organic phase with brine (50 mL) and dry over MgSO.sub.4 to obtain
a light yellow oil suitable for use without additional
purification. GC-MS m/z: 217 (M.sup.+).
[0471] 4-(Cyclopentylthiomethyl)-benzylamine: Add borane-THF
complex (13.6 mL, 13.6 mmol, 1M solution in THF) dropwise to a
solution of 4-(cyclopentylthiomethyl)-benzonitrile (1.5 g, 6.8
mmol) in anhydrous THF (8 mL) at room temperature and heat the
mixture at reflux overnight. Cool to room temperature, add methanol
cautiously and stir vigorously until gas evolution stops.
Concentrate in vacuo and purify the crude mixture by SCX
chromatography to obtain the title compound (0.86 g, 59%). MS (ES+)
m/z: 205 (M-NH.sub.3+H).sup.+.
Preparation 13
[0472] The compound of Preparation 13 may be prepared essentially
as described in Preparation 12 using 4-bromomethyl-benzonitrile and
the appropriate thiol. Overall yield and MS (ES+) data are shown in
the Table below.
TABLE-US-00002 Yield MS (ES+) Prep. Structure Compound (%) m/z 13
##STR00027## 4-(Cyclohexyl-thiomethyl)-benzylamine 56 219(M -
NH.sub.3+H).sup.+
Preparation 14
2-Aminomethyl-5-cyclopentylthiomethyl-pyridine
##STR00028##
[0474] 2-Chloro-5-cyclopentylthiomethyl-pyridine: Slurry
2-chloro-5-chloromethyl-pyridine (8.1 g, 45 mmol) and potassium
hydroxide (10.3 g, 225 mmol) in methanol at 0.degree. C. under
nitrogen atmosphere. Add cyclopentyl mercaptan (4.8 mL, 45 mmol),
warm the mixture 5 to room temperature and stir for 16 h.
Concentrate in vacuo and partition the residue between water (50
.mu.L) and DCM (200 mL). Collect the organic phase, concentrate in
vacuo and purify the crude mixture by chromatography on silica gel
(330 g) eluting with hexane/EtOAc (49:1 to 4:1 gradient) to obtain
the desired intermediate as an oil (8.4 g, 82%). MS (APCI+) m/z:
227 (M).sup.+.
[0475] 5-Cyclopentylthiomethyl-pyridine-2-carbonitrile: Set up
reaction in 3 separate flasks. To flask number 1 slurry
2-chloro-5-cyclopentylthiomethyl-pyridine (1 g, 4.4 mmol) and
copper(I) cyanide (0.78 g, 8.7 mmol) in DMF (5 mL). To flask number
2 slurry 2-chloro-5-cyclopentylthiolmethyl-pyridine (1 g, 4.4 mmol)
and copper(I) cyanide (0.78 g, 8.7 mmol) in DMF (5 mL). To flask
number 3 slurry 2-chloro-5-cyclopentyl-thiomethyl-pyridine (2 g,
8.8 mmol) and copper(I) cyanide (1.6 g, 17.6 mmol) in DMF (10 mL).
Stir each reaction in a sealed flask at 170.degree. C. for 16 h.
Follow the reactions by GC/MS. Cool all reaction flasks to room
temperature. Combine the flask contents and pour into a solution of
NH.sub.4OH (120 mL) and hexane/EtOAc (1:1, 100 mL). Collect the
organic phase and extract the aqueous phase twice with hexane/EtOAc
(1:1, 100 mL). Concentrate in vacuo the combined organic extracts.
Purify by chromatography on silica gel (90 g) eluting with
hexane/EtOAc (49:1 to 4:1 gradient) to obtain the desired
intermediate (2 g, 40%) that contains approximately 10% starting
material. Use the material in the next step without additional
purification. MS (APCI+) m/z: 218 (M).sup.+.
[0476] 2-Aminomethyl-5-cyclopentylthiomethyl-pyridine: Add
borane-dimethylsulfide complex (6.9 mL, 13.7 mmol, 2M solution in
THF) to a solution of
5-cyclopentylthiomethyl-pyridine-2-carbonitrile (1 g, 4 mmol) in
THF (12 mL) at room temperature under a nitrogen atmosphere. Stir
the solution at room temperature for 16 h. Concentrate the solution
in vacuo, dissolve the residue in chloroform (50 mL), add
ethylenediamine (0.72 g, 12 mmol) and stir at 50.degree. C. for 1
h. Wash the mixture with water (10 mL), dry the organic phase over
Na.sub.2SO.sub.4 and concentrate in vacuo. Purify the residue by
SCX chromatography followed by chromatography on silica gel (10 g)
elating with DCM/2M ammonia in methanol (1:0 to 9:1 gradient) to
obtain the title compound (0.24 g, 27%). MS (ES+) m/z: 223.1
(M+H).sup.+.
Preparation 15
[0477] The compound of Preparation 15 may be prepared essentially
as described in Preparation 14 using
2-chloro-5-chloromethyl-pyridine and cyclohexyl mercaptan. Overall
yield and MS (ES+) data are shown in the Table below.
TABLE-US-00003 Yield MS (ES+) Prep. Structure Compound (%) m/z 15
##STR00029## 2-Amino-methyl-5-cyclohexyl-thiomethyl-pyridine 8
237.1(M + H).sup.+
Preparation 16
2-Aminomethyl-5-iso-propylthiomethyl-pyridine
##STR00030##
[0479] 5-Bromomethyl-pyridine-2-carbonitrile: Add AIBN (0.25 g, 1.5
mmol) to a slurry of 5-methyl-pyridine-2-carbonitrile (2.5 g, 21.1
mmol) and NBS (3.7 g, 21.1 mmol) in carbon tetrachloride (150 mL)
at reflux under a nitrogen atmosphere. Add AIBN (3.times.0.25 g,
3.times.1.5 mmol) to the reaction in 0.25 g portions every hour for
3 h. Stir the resulting mixture for one additional hour at reflux.
Cool the mixture to room temperature and wash with saturated
aqueous NaHCO.sub.3 (30 mL). Collect the organic phase, concentrate
in vacuo and purify the residue by chromatography on silica gel
(330 g) eluting with DCM to obtain the desired intermediate (1.8 g,
44%). MS (ES+) m/z: 199 (M+2).sup.+.
[0480] 5-iso-Propylthiomethyl-pyridine-2-carbonitrile: Add
2-propanethiol (0.53 mL, 5.6 mmol) to a slurry of
5-bromomethyl-pyridine-2-carbonitrile (1.1 g, 5.6 mmol) and cesium
carbonate (1.8 g, 5.6 mmol) in DMF (10 mL) at room temperature
under a nitrogen atmosphere. Stir the mixture for 16 h at room
temperature. Dilute the mixture with hexane/EtOAc (1:1, 100 mL) and
wash with 5% aqueous NaCl (3.times.30 mL). Collect the organic
phase, concentrate in vacuo and purify the residue by
chromatography on silica gel (40 g) eluting with hexane/EtOAc (20:1
to 7:3 gradient) to obtain the desired intermediate (0.83 g, 77%).
MS (ES+) m/z: 193.2 (M+H).sup.+.
[0481] 2-Aminomethyl-5-iso-propylthiomethyl-pyridine: Add
borane-dimethylsulfide complex (6.5 mL, 12.9 mmol, 2M solution in
THF) to a solution of
5-iso-propylthiomethyl-pyridine-2-carbonitrile (0.83 g, 4.3 mmol)
in THF (12 mL) at room temperature under a nitrogen atmosphere.
Stir the solution at room temperature for 16 h. Add 5N aqueous HCl
(2 mL) and stir for 2 h. Concentrate in vacuo to obtain the
hydrochloride salt. Elute the compound through a SCX column to
obtain the free base. Dissolve the resulting residue in DCM (30 mL)
and wash with saturated aqueous NaHCO.sub.3 (5 mL). Collect the
organic phase, dry over Na.sub.2SO.sub.4 and concentrate in vacuo
to obtain the title compound (0.3 g, 36%). MS (ES+) m/z: 197.3
(M+H).sup.+.
Preparation 17
[0482] The compound of Preparation 17 may be prepared essentially
as described in Preparation 16 using
5-bromomethyl-pyridine-2-carbonitrile and 2-methyl-propanethiol.
Overall yield and MS (ES+) data are shown in the Table below.
TABLE-US-00004 Yield MS (ES+) Prep. Structure Compound (%) m/z 17
##STR00031## 2-Aminomethyl-5-(2-methyl-propyl)thio-methyl-pyridine
4 211.12(M + H).sup.+
Preparation 18
3-Aminomethyl-6-[(2,2-dimethylpropyl)thiomethyl]-pyridine
##STR00032##
[0484] 6-[(2,2-Dimethylpropyl)thiomethyl]-pyridine-3-carbonitrile:
To a solution of 2,2-dimethylpropylthiol (0.782 g, 7.32 mmol) in
DMF (10 mL) add potassium tert-butoxide (0.82 g, 7.32 mmol) and
stir at room temperature for 10 min. Add
6-bromomethyl-pyridine-3-carbonitrile (1.2 g, 6.1 mmol) and stir
the solution at room temperature for 18h. Cool the mixture, dilute
with water (100 mL) and extract with EtOAc (50 mL). Dry the organic
phase over MgSO.sub.4, filter and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (9:1) to
obtain the desired intermediate as a clear oil (0.5 g, 37%).
[0485] 3-Aminomethyl-6-[(2,2-dimethylpropyl)thiomethyl]-pyridine:
To a slurry of Raney Nickel (0.5 g, 50% in water) in ethanol (100
mL) add a solution of
6-[(2,2-dimethylpropyl)thiomethyl]-pyridine-3-carbonitrile (1 g) in
ethanol (10 mL) followed by aqueous ammonia (0.88 M, 5 mL) and
hydrogenate the mixture in a Parr shaker at 60 psi for 3 h. Filter
the mixture through Celite.RTM. washing the filter cake with
ethanol (50 mL). Remove the solvent in vacuo to obtain the title
compound as a colourless oil (1.07 g, 100%).
Preparation 19
3-Aminomethyl-6-[(3,3-dimethylcyclohexyl)thio]-pyridine
##STR00033##
[0487] S-(3,3-dimethylcyclohexyl)-O-ethyl dithiocarbonate: To a
solution of 3,3-dimethylcyclohexyl 4-methylbenzenesulfonate (10 g,
35.4 mmol) [prepared by following the procedure described in J.
Org. Chem. 1996, 61, 4716] in DMF (100 mL) add potassium ethyl
xanthate (11.3 g, 70.8 mmol) and heat at 50.degree. C. for 48 h.
Cool the mixture and dilute with diethyl ether (500 mL), wash with
water (3.times.500 mL) and brine (2.times.500 mL). Dry the organic
phase over MgSO.sub.4, filter and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/diethyl ether
(20:1) to obtain the desired intermediate as a clear oil (4 g,
49%).
[0488] 3,3-Dimethylcyclohexanethiol: To a solution of
S-(3,3-dimethylcyclohexyl)-O-ethyl dithiocarbonate (4 g, 17.2 mmol)
in DCM (100 mL) add ethylenediamine (6 mL) and stir at room
temperature for 18 h. Treat the solution with 2N aqueous HCl
(3.times.100 mL). Dry the organic phase over MgSO.sub.4, filter and
concentrate in vacuo, while keeping the water-bath temperature
below 25.degree. C., to obtain the desired intermediate as a
colourless oil (2 g, 80%).
[0489] 6-[(3,3-Dimethylcyclohexyl)thio]-pyridine-3-carbonitrile:
Add potassium tert-butoxide (777 mg, 6.94 mmol) to a solution of
3,3-dimethylcyclohexanethiol (1 g, 6.94 mmol) in DMF (10 mL) and
stir at room temperature for 10 min. Add 6-chloro-nicotinonitrile
(547 mg, 3.96 mmol) and warm the solution to 60.degree. C. for 18
h. Cool the mixture, dilute with water (100 mL) and extract with
EtOAc (50 mL). Dry the organic phase over MgSO.sub.4, filter and
concentrate in vacuo. Purify by chromatography on silica gel
eluting with hexane/EtOAc (9:1) to obtain the desired intermediate
as a clear oil that solidifies on standing to a white solid (0.37
g, 38%).
[0490] 3-Aminomethyl-6-[(3,3-dimethylcyclohexyl)thio]-pyridine: To
a slurry of Raney Nickel (0.2 g, 50% in water) in ethanol (35 mL)
add a solution of
6-[(3,3-dimethylcyclohexyl)thio]-pyridine-3-carbonitrile (0.37 g,
1.5 mmol) in ethanol (5 mL) followed by aqueous ammonia (0.88 M, 2
mL) and hydrogenate the mixture in a Parr 5 shaker at 60 psi for 3
h. Filter the mixture through Celite.RTM. washing the filter cake
with ethanol. Remove the solvent in vacuo to obtain the title
compound as an oil (0.2 g, 53%).
Preparation 20
4-[(3,3-Dimethylcyclohexyl)thio]-benzylamine
##STR00034##
[0492] 4-[(3,3-Dimethylcyclohexyl)thio]-benzonitrile: To a solution
of 4-cyanothiophenol (1 g, 7.4 mmol) in DMF (15 mL) add
3,3-dimethylcyclohexyl tosylate (2.06 g, 7.4 mmol) and potassium
carbonate (3.06 g, 22.2 mmol), and warm to 60.degree. C. for 18 h.
Dilute the mixture with EtOAc (50 mL) and wash sequentially with
water (3.times.50 mL), saturated aqueous NaHCO.sub.3 (50 mL) and
brine (50 mL). Dry the organic phase over MgSO.sub.4, filter and
concentrate in vacuo. Purify by chromatography on silica gel
eluting with hexane/EtOAc (9:1) to obtain the desired intermediate
as a clear oil that solidifies on standing (0.35 g, 20%).
[0493] 4-[(3,3-Dimethylcyclohexyl)thio]-benzylamine: To a slurry of
Raney Nickel (0.2 g, 50% in water) in ethanol (35 mL) add a
solution of 4-[(3,3-dimethylcyclohexyl)-thio]-benzonitrile (0.35 g,
1.43 mmol) in ethanol (5 mL) followed by aqueous ammonia (0.88 M, 2
mL) and hydrogenate the mixture in a Parr shaker at 60 psi for 3 h.
Filter the mixture through Celite.RTM. washing the filter cake with
ethanol. Remove the solvent in vacuo to obtain the title compound
as a pale yellow oil (0.24 g, 67%).
Preparation 21
4-[(3,3-Dimethylcyclohexyl)thiomethyl]-benzylamine
##STR00035##
[0495] 4-[(3,3-Dimethylcyclohexyl)thiomethyl]-benzonitrile: To a
solution of 3,3-dimethylcyclohexanethiol (0.6 g, 4.16 mmol) in
acetonitrile (50 mL) add potassium carbonate (1.72 g, 12.48 mmol)
and stir at room temperature for 10 min. Add 4-cyanobenzyl bromide
(816 mg, 4.16 mmol) and stir the suspension for 18 h. Dilute with
water (50 mL) and extract with EtOAc (50 mL). Dry the organic phase
over MgSO.sub.4, filter and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (10:1) to
obtain the desired intermediate as a clear oil (0.4 g, 37%).
[0496] 4-[(3,3-Dimethylcyclohexyl)thiomethyl]-benzylamine: To a
slurry of Raney Nickel (0.25 g, 50% in water) in ethanol (40 mL)
add a solution of
4-[(3,3-dimethylcyclohexyl)thiomethyl]-benzonitrile (0.4 g, 1.54
mmol) in ethanol (5 mL) 15 followed by aqueous ammonia (0.88 M, 2.5
mL) and hydrogenate the mixture in a Parr shaker at 60 psi for 3 h.
Filter the mixture through Celite.RTM. washing the filter cake with
ethanol. Remove the solvent in vacuo to obtain the title compound
as an oil (0.4 g, 100%).
Preparation 22
3-Aminomethyl-6-(tert-butylthio)methyl-pyridine
##STR00036##
[0498] 6-Bromomethyl-pyridine-3-carbonitrile: Dissolve
6-methyl-nicotinonitrile (2 g, 17 mmol) and NBS (3.01 g, 17 mmol)
in anhydrous DCE (56 mL) under nitrogen. Add AIBN (277 mg, 1.7
mmol) and heat the mixture at 80.degree. C. for 1.5-2 h. Add
another batch of AIBN (277 mg, 1.7 mmol) and heat the mixture at
80.degree. C. for a further 1-2 h. Then add a third batch of AIBN
(277 mg, 1.7 mmol) and heat the mixture at 80.degree. C. for a
further 1-2 h. Cool the reaction to room temperature and
concentrate in vacuo. Dissolve the residue in DCM, add silica gel
and concentrate in vacuo. Purify by chromatography on silica gel
(120 g, pre-packed cartridge) eluting with cyclohexane/EtOAc (98:2
to 7:3 gradient over 55 min, 40 mL/min) to isolate the desired
intermediate (2 g, 60%) as a white solid that turns red on standing
at room temperature. MS (ES+) m/z: 199 (M+2).sup.+.
[0499] 6-(tert-Butylthio)methyl-pyridine-3-carbonitrile: Dissolve
6-bromomethyl-pyridine-3-carbonitrile (6.2 g, 31.4 mmol) in
anhydrous DMF (60 mL) under nitrogen. Add tert-butylthiol (5.32 mL,
47.2 mmol) followed by cesium carbonate (15.3 g, 47.2 mmol) and
stir the resulting suspension overnight. Dissolve the reaction
mixture in DCM (200 mL) and add water (200 mL). Extract the aqueous
phase with DCM (2.times.200 mL) and dry the combined organic
extracts over MgSO.sub.4. Filter, add silica gel and concentrate
the mixture in vacuo. Purify the residue by chromatography on
silica gel (40 g) eluting with cyclohexane/EtOAc (98:2 to 65:35
gradient) to obtain the desired material as a yellow solid (4.92 g,
76%). MS (ES+) m/z: 207 (M+H).sup.+.
[0500] 3-Aminomethyl-6-(tert-butylthio)methyl-pyridine: Dissolve
6-(tert-butylthio)methyl-pyridine-3-carbonitrile (4.9 g, 23.8 mmol)
in anhydrous THF (20 mL) under nitrogen and cool the mixture at
0.degree. C. Add borane-THF complex (71.3 mL, 71.3 mmol, 1M
solution in THF). Stir the reaction mixture at room temperature
overnight. Pour slowly the reaction mixture into ice-cold 2N
aqueous HCl (200 mL) and stir the resulting solution for 4 h.
Concentrate in vacuo, take up the resulting solid with a minimum
amount of methanol and filter through SCX-2 column eluting with
methanol followed by 3N ammonia in methanol to obtain the title
compound as a yellow oil (3.8 g, 77%). MS (ES+) m/z: 211
(M+H).sup.+.
[0501] The compounds of Preparations 23-24 may be prepared
essentially as described in Preparation 22 using
6-bromomethyl-pyridine-3-carbonitrile and the appropriate thiol.
Overall yields and MS (ES+) data are shown in the Table below.
TABLE-US-00005 Yield MS (ES+) Prep. Structure Compound (%) m/z 23
##STR00037## 3-Aminomethyl-6-(cyclopentyl-thio)methyl-pyridine 46
223(M + H).sup.+ 24 ##STR00038##
3-Aminomethyl-6-(cyclohexyl-thio)methyl-pyridine 52 237(M +
H).sup.+
Preparation 25
3-Aminomethyl-6-cyclohexyloxy-pyridine
##STR00039##
[0503] 6-Cyclohexyloxy-pyridine-3-carbonitrile: Add sodium
bis(trimethylsilyl)amide (3.9 mL, 7.93 mmol, 2M solution in THF) to
a solution of cyclohexanol (824 .mu.L, 7.93 mmol) in THF (10 mL).
Stir for 30 min at room temperature and then add a solution of
6-chloro-nicotinonitrile (1 g, 7.2 mmol) in anhydrous THF (5 mL).
Stir at room temperature overnight and then quench the reaction by
addition of saturated aqueous NaHCO.sub.3 (100 mL) and extract the
aqueous phase with DCM (3.times.100 mL). Wash the combined organic
extracts with brine (100 mL), dry over MgSO.sub.4 and concentrate
in vacuo to obtain the desired intermediate as a yellow solid (1.04
g, 71%).
[0504] 3-Aminomethyl-6-cyclohexyloxy-pyridine: Dissolve
6-cyclohexyloxy-pyridine-3-carbonitrile (1 g, 5 mmol) in anhydrous
THF (7 mL) under nitrogen and cool the mixture at 0.degree. C. Add
borane-THE complex (15 mL, 15 mmol, 1M solution in THF) and stir
the reaction mixture at room temperature overnight. Pour slowly the
reaction mixture into an ice-cold 5N aqueous HCl (50 mL) and stir
the resulting solution for 4 h. Concentrate in vacuo, take up the
resulting solid with a minimum amount of methanol and filter
through a SCX-2 column eluting with methanol followed by 3N ammonia
in methanol to obtain the title compound as a yellow oil (621 mg,
62%). MS (ES+) m/z: 207 (M+H).sup.+.
Preparation 26
[0505] The compound of Preparation 26 may be prepared essentially
as described in Preparation 25 using 6-chloro-nicotinonitrile and
4,4-dimethyl-cyclohexanol. Overall yield and MS (ES+) data are
shown in the Table below.
TABLE-US-00006 MS Yield (ES+) e.e. Prep. Structure Compound (%) m/z
(%) 26 ##STR00040##
3-Aminomethyl-6-(4,4,-dimethyl-cyclohexyloxy)-pyridine 40 235(M
+H).sup.+ --
Preparations 27 and 28
3-Aminomethyl-6-(3,3-dimethyl-cyclohexyloxy)-pyridine Isomer 1 and
3-Aminomethyl-6-(3,3-dimethyl-cyclohexyloxy)-pyridine Isomer 2
##STR00041##
[0507] 6-(3,3-Dimethyl-cyclohexyloxy)-pyridine-3-carbonitrile:
Dissolve 3,3-dimethylcyclohexanol (6 g, 47 mmoles) in anhydrous THF
(70 mL) under nitrogen atmosphere and cool at -78.degree. C. Add
sodium bis(trimethylsilyl)amide (23.4 mL, 47 mmol, 2M solution in
THF) to this solution and stir at -78.degree. C. for 30 min before
raising to room temperature. Cool down again to -78.degree. C. and
add a solution of 2-chloro-5-cyanopyridine (7.1 g, 51.7 mmoles) in
anhydrous THF (20 mL) and stir overnight while warming to room
temperature. Add saturated aqueous NaHCO.sub.3 (100 mL) and extract
the aqueous layer with DCM (3.times.100 mL). Wash the combined
organic extracts with brine (200 mL). Dry over MgSO.sub.4, filter
and concentrate in vacuo. Purify the crude mixture by
chromatography on silica gel eluting with cyclohexane/EtOAc (1:0 to
9:1 gradient) to afford the desired intermediate as a solid (9.14
g, 84%). MS (ES+) m/z: 231.1 (M+H).sup.+.
[0508]
(.+-.)-3-Aminomethyl-6-(3,3-dimethyl-cyclohexyloxy)-pyridine:
Dissolve 6-(3,3-dimethyl-cyclohexyloxy)-pyridine-3-carbonitrile
(9.14 g, 39.7 mmoles) in THF (20 mL) at 0.degree. C. under nitrogen
and add borane-THF complex (119 mL, 119 mmol, 1M solution in THF).
Stir the resulting solution overnight while warming to room
temperature. Slowly add the reaction mixture to a mixture of 5N
aqueous HCl (100 mL) and THF (50 mL) at 0.degree. C. and stir for 2
h. Concentrate in vacuo and take-up the residue in a minimum amount
of methanol for filtration through a SCX-2 column (10 g) eluting
with methanol followed by 3N ammonia in methanol to obtain the
desired intermediate as an oil (5.85 g, 63%). MS (ES+) m/z: 207
(M+H).sup.+.
[0509] 3-Aminomethyl-6-(3,3-dimethyl-cyclohexyloxy)-pyridine Isomer
1 and 3-Aminomethyl-6-(3,3-dimethyl-cyclohexyloxy)-pyridine Isomer
2: Separate enantiomers of
(.+-.)-3-aminomethyl-6-(3,3-dimethyl-cyclohexyloxy)-pyridine by
chiral Supercritical Fluid Chromatography (Instrument: Berger SFC
Multigram; Column: 2.times.AD-H columns in series, 21.2.times.250
mm each; flow rate: 40 mL/min; mobile phase: 12% methanol with 0.2%
dimethylethylamine/88% CO.sub.2).
3-Aminomethyl-6-(3,3-dimethyl-cyclohexyloxy)-pyridine Isomer 1 [MS
(ES+) m/z: 235 (M+H).sup.+, ee =99%;
3-Aminomethyl-6-(3,3-dimethyl-cyclohexyloxy)-pyridine Isomer 2 [MS
(ES+) m/z: 235 (M+H).sup.+, ee =96%.
Preparation 29
3-Aminomethyl-6-(iso-propoxy)methyl-pyridine
##STR00042##
[0511] 6-(iso-Propoxy)methyl-pyridine-3-carbonitrile: Add
iso-propanol (2.2 g, 25 mmol) and tetrabutylammonium sulfate (28
mg, 0.08 mmol) to a solution of potassium hydroxide (7.1 g, 127
mmol) in water (7 mL) and stir at room temperature for 15 min. Add
6-bromomethyl-pyridine-3-carbonitrile (1 g, 5.08 mmol) and stir the
mixture for 24 h at room temperature. Add water (15 mL) and extract
with DCM (15 mL). Filter through an IST.RTM. phase separator frit
to separate the organic phase and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (1:0 to 1:1
gradient) to obtain the desired intermediate as a crystalline solid
(0.4 g, 45%). MS (ES+) m/z: 177 (M+H).sup.+.
[0512] 3-Aminomethyl-6-(iso-propoxy)methyl-pyridine: Add a solution
of borane-THF complex (4.5 mL, 4.54 mmol, 1M solution in THF) to
neat 6-(iso-propoxy)methyl-pyridine-3-carbonitrile (0.4 g, 2.27
mmol) and stir the mixture for 16 h at reflux. Cool to room
temperature and stir for 48 h. Add 2N aqueous HCl (10 mL) until gas
evolution stops and 10 then concentrate in vacuo. Dissolve the
crude mixture in methanol and filter through a SCX-2 column eluting
with methanol followed by 3N ammonia in methanol to obtain the
title compound (190 mg, 46%).
Preparations 30-32
[0513] The compounds of Preparations 30-32 may be prepared
essentially as described in Preparation 29 using and
6-bromomethyl-pyridine-3-carbonitrile and the appropriate alcohol.
Overall yields and MS (ES+) data are shown in the Table below.
TABLE-US-00007 Yield MS (ES+) Prep. Structure Compound (%) m/z 30
##STR00043##
3-Aminomethyl-6-[(2,2-dimethyl-propoxy)-methyl]-pyridine 20 209(M +
H).sup.+ 31 ##STR00044##
3-Aminomethyl-6-(cyclopentyl-oxy)methyl-pyridine 14 207(M +
H).sup.+ 32 ##STR00045##
3-Aminomethyl-6-(cyclohexyl-oxy)methyl-pyridine 12 221(M +
H).sup.+
Preparation 33
2-Aminomethyl-5-cyclohexyloxy-pyridine
##STR00046##
[0515] 6-Chloro-3-cyclohexyloxy-pyridine: Under a nitrogen
atmosphere add 6-chloro-pyridin-3-ol (2.5 g, 19.3 mmol),
cyclohexanol (1.93 g, 19.3 mmol), tri-n-butylphosphine (5.07 g,
25.1 mmol), and ADDP (6.32 g, 25.1 mmol) to benzene (100 mL) and
THF (10 mL) at 0.degree. C. Stir the mixture at 0.degree. C. for 1
h and at room temperature for 12 h. Dilute with EtOAc and water.
Separate the layers and extract the aqueous layer with EtOAc. Wash
the organic phase with water (30 mL) and brine (20 mL). Dry the
organic phase over Na.sub.2SO.sub.4, filter, and concentrate in
vacuo. Purify the crude mixture by chromatography on silica gel
(400 g) eluting with hexane/EtOAc (1:0 to 98:2 gradient) to obtain
the desired intermediate as clear oil (1.8 g, 58%). MS (APCI+) m/z:
212 (M+H).sup.+.
[0516] 5-Cyclohexyloxy-pyridine-2-carbonitrile: Under a nitrogen
atmosphere, add 6-chloro-3-cyclohexyloxy-pyridine (1.5 g, 7.1 mmol)
and copper(I) cyanide (1.89 g, 21 mmol) to NMP (15 mL). Heat the
mixture at 180.degree. C. overnight. Cool the mixture to room
temperature and add copper(I) cyanide (0.63 g, 7.1 mmol). Heat the
mixture at 180.degree. C. for 6 h. Cool the mixture to room
temperature, dilute with 5N aqueous NH.sub.4OH and extract with
DCM. Separate the layers and extract the aqueous phase with
additional DCM. Wash the combined organic extracts with water and
brine. Dry the organic phase over Na.sub.2SO.sub.4, filter, and
concentrate in I vacuo. Purify the residue by chromatography on
silica gel (500 g) eluting with hexane/EtOAc (20:1) to obtain the
desired intermediate (820 mg, 57%). MS (ES+) m/z: 203
(M+H).sup.+.
[0517] 2-Aminomethyl-5-cyclohexyloxy-pyridine: Under a nitrogen
atmosphere, add borane-dimethylsulfide complex (20.3 mL, 40.6 mmol,
2M solution in THF) to a solution of
5-cyclohexyloxy-pyridine-2-carbonitrile (0.82 g, 4.06 mmol) in THF
(800 mL) at 0.degree. C. Warm the mixture to room temperature and
stir overnight. Cool the mixture in an ice-bath, add methanol (15
mL) and concentrated HCl (2 mL). Stir for 2 h, and concentrate in
vacuo. Dissolve the residue in saturated aqueous K.sub.2CO.sub.3.
Extract with DCM and wash the organic phase with water and brine.
Dry the organic phase over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to obtain the title compound (0.3 g, 36%). MS
(ES+) m/z: 207 (M+H).sup.+.
Preparation 34
2-Aminomethyl-5-cycloheptyloxy-pyridine
##STR00047##
[0519] 6-Chloro-3-cycloheptyloxy-pyridine: Add
6-chloro-pyridin-3-ol (2 g, 15.4 mmol), cycloheptanol (1.93 g, 17
mmol), tri-n-butylphosphine (4.67 mL, 19.3 mmol), and ADDP (4.87 g,
19.3 mmol) to THF (60 mL) at 0.degree. C. under a nitrogen
atmosphere. Stir the mixture at 0.degree. C. for 1 h and at room
temperature for 12 h. Dilute with EtOAc (50 mL), add water (50 mL)
and separate the layers. Extract the aqueous layer with EtOAc
(4.times.30 mL). Wash the combined organic extracts with water (30
mL) and brine (20 mL). Dry the organic phase over Na.sub.2SO.sub.4,
filter, and concentrate in vacuo. Purify the crude mixture by
chromatography on silica gel (120 g, pre-packed cartridge) eluting
with hexane/EtOAc (1:0 to 1:1 gradient over 1.25 h, 80 mL/min) to
obtain the desired intermediate as a colorless oil (2.36 g, 68%).
MS (APCI+) m/z: 226 (M+H).sup.+.
[0520] 5-Cycloheptyloxy-pyridine-2-carbonitrile: Add
6-chloro-3-cycloheptyloxy-pyridine (2.35 g, 10.4 mmol) and
copper(I) cyanide (1.16 g, 13.1 mmol) to NMP (25 mL). Heat the
mixture to 190.degree. C. and stir overnight. Cool the mixture to
room temperature, add water (50 mL) and diethyl ether (30 mL).
Extract the aqueous phase with diethyl ether (3.times.25 mL). Wash
the combined organic extracts with brine (20 mL), dry over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo. Purify the
crude mixture by chromatography on silica gel (45 g, pre-packed
cartridge) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 60
min, 80 mL/min) to obtain the desired intermediate as a colorless
oil (1.21 g, 54%). MS (APCI+) m/z: 217 (M+H).sup.+.
[0521]
2-(tert-Butoxycarbonylamino-methyl)-5-cycloheptyloxy-pyridine: Add
5-cycloheptyloxy-pyridine-2-carbonitrile (1.6 g, 7.33 mmol),
di-tert-butyl-dicarbonate (3.17 g, 14.7 mmol) and 10% Pd/C (100 mg)
to ethanol (25 mL). Bubble hydrogen (via balloon) through the
vigorously stirred solution for 8 h and under static pressure
overnight. Filter the mixture through cellulose powder (20
.quadrature.m) and rinse with ethanol. Concentrate in vacuo and
purify by chromatography on silica gel (45 g, pre-packaged
cartridge) eluting with hexane/EtOAc (1:0 to 4:1 over 30 min, 80
mL/min) to obtain the desired intermediate as a colorless oil (1.91
g, 81%). MS (APCI+) m/z: 321 (M+H).sup.+.
[0522] 2-Aminomethyl-5-cycloheptyloxy-pyridine: Dissolve
2-(tert-butoxycarbonylamino-methyl)-5-cycloheptyloxy-pyridine (1.9
g, 5.95 mmol) in methanol (25 mL) and cool to 0.degree. C. Bubble
hydrogen chloride through the vigorously stirred solution for 30
min. Evaporate in vacuo and partition the residue between 3N
aqueous NaOH (10 mL) and DCM (20 mL). Separate the two layers and
extract the aqueous layer with DCM (2.times.20 mL). Wash the
combined organic extracts with brine (20 mL), dry over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo to obtain the
title compound as a colorless oil (941 mg, 72%). MS (APCI+) m/z:
221 (M+H).sup.+.
Preparation 35
2-Aminomethyl-5-(3,3-dimethylcyclohexyloxy)-pyridine
##STR00048##
[0524] 3,3-Dimethylcyclohexyl 4-methylbenzenesulfonate: Under a
nitrogen atmosphere, add 3,3-dimethylcyclohexanol (1 g, 9.75 mmol),
DMAP (238 mg, 1.95 mmol), triethylamine (2.70 mL, 19.5 mmol), and
p-toluenesulfonyl chloride (2.045 g, 10.72 mmol) to DCM (25 mL) at
0.degree. C. Stir the mixture for 1 h at 0.degree. C. and warm to
room temperature overnight. Add saturated aqueous NaHCO.sub.3 (20
mL) and separate the layers. Extract the aqueous layer with DCM
(3.times.20 mL). Wash the combined organic extracts with water and
brine. Dry the organic phase over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo. Purify the crude mixture by chromatography on
silica gel (45 g, pre-packed cartridge) eluting with hexane/EtOAc
(1:0 to 1:1 gradient over 60 min, 80 mL/min) to obtain the desired
5 intermediate as a clear oil (1.93 g, 70%). MS (APCI+) m/z: 283
(M+H).sup.+.
[0525] 6-Chloro-3-(3,3-dimethylcyclohexyloxy)-pyridine: Under a
nitrogen atmosphere, add 3,3-dimethylcyclohexyl
4-methylbenzenesulfonate (1.2 g, 4.25 mmol), 6-chloro-pyridin-3-ol
(0.5 g, 3.86 mmol) and potassium hydroxide (238 mg, 4.25 mmol) to
DMF (10 mL). Heat the mixture to 60.degree. C. and stir overnight.
Add water (20 mL) and diethyl ether (20 mL) and separate the
layers. Extract the aqueous layer with diethyl ether (3.times.20
mL). Wash the combined organic extracts with brine (20 mL), dry
over Na.sub.2SO.sub.4, filter, and concentrate in vacuo. Purify by
chromatography on silica gel (80 g, pre-packed cartridge) eluting
with hexane/EtOAc (1:0 to 1:1 over 60 min, 80 mL/min) to obtain the
desired intermediate as a white solid (728 mg, 79%). MS (APCI+)
m/z: 240 (M+H).sup.+.
[0526] 5-(3,3-Dimethylcyclohexyloxy)-pyridine-2-carbonitrile: Add
6-chloro-3-(3,3-dimethylcyclohexyloxy)-pyridine (1.1 g, 4.59 mmol)
and copper(I) cyanide (1.23 g, 13.8 mmol) to NMP (20 mL). Heat the
mixture to 190.degree. C. and stir overnight. Cool the mixture to
room temperature, add water (30 mL) and diethyl ether (30 mL).
Extract the aqueous phase with diethyl ether (3.times.20 mL). Wash
the combined organic extracts with brine (20 mL), dry over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo. Purify the
crude mixture by chromatography on silica gel (80 g, pre-packed
cartridge) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 60
min, 80 mL/min) to obtain the desired intermediate as a colorless
oil (412 mg, 39%). MS (APCI+) m/z: 231 (M+H).sup.+.
[0527] 2-Aminomethyl-5-(3,3-dimethylcyclohexyloxy)-pyridine: Under
a nitrogen atmosphere, add lithium aluminum hydride (264 mg, 6.95
mmol) to THF (15 mL) at 0.degree. C. Add a solution of
5-(3,3-dimethylcyclohexyloxy)-pyridine-2-carbonitrile (0.4 g, 1.74
mmol) in THF (5 mL), stir at 0.degree. C. for 1 h and warm to room
temperature overnight. Cool the mixture at 0.degree. C. and
carefully add water (0.3 mL). Add diethyl ether (25 mL), 3N aqueous
NaOH (0.3 mL) and water (0.9 mL), and stir for 1 h at room
temperature. Filter the solid residue and concentrate the filtrate
in vacuo to obtain the title compound as a colorless oil (360 mg,
88%). MS (APCI+) m/z: 235 (M+H).sup.+.
Preparation 36
(Z)-4-(2-Cyclohexylvinyl)-benzylamine
##STR00049##
[0529] N-(tert-Butoxycarbonyl)-4-bromo-benzylamine: Slurry
4-bromo-benzylamine hydrochloride (25 g, 112.6 mmol)-in DCM (400
mL). Add triethylamine (31.4 mL, 225.2 mmol) and
di-tert-butyl-dicarbonate (24.55 g, 112.6 mmol) and stir the
solution at room temperature for 16 h under a nitrogen atmosphere.
Wash the mixture with water, dry the organic-phase over
Na.sub.2SO.sub.4 and concentrate in vacuo to obtain a solid. Wash
the solid with hexane, filter and dry to obtain the desired
intermediate as a white solid (31.735 g, 99%) suitable for use
without further purification. MS (ES+) m/z: 230
[M-(t-Bu)+H].sup.+.
[0530] N-(tert-Butoxycarbonyl)-4-cyclohexylethynyl-benzylamine: Add
cyclohexylacetylene (1.1 mL, 8.4 mmol) to a slurry of
N-(tert-butoxycarbonyl)-4-bromo-benzylamine (2 g, 6.9 mmol),
dichlorobis(triphenylphosphine)palladium (147 mg, 0.2 mmol),
copper(I) iodide (67 mg, 0.4 mmol) and triethylamine (1.4 mL, 9.7
mmol) in DMF (7 mL). Stir the reaction in a sealed flask at
110.degree. C. for 16 h. Cool to room temperature, dilute with
water (10 mL) and hexane/EtOAc (1:1, 100 mL). Filter the bi-phasic
mixture through Celite.RTM., collect the organic phase and wash
with 5% aqueous NaCl (3.times.30 mL). Concentrate the organic phase
in vacuo and purify by chromatography on silica gel (120 g) eluting
with hexane/EtOAc (20:1 to 3:2 gradient) to obtain the desired
intermediate (0.75 g, 34%). MS (ES+) m/z: 258
[M-(t-Bu)+H].sup.+.
[0531]
(Z)-N-(tert-Butoxycarbonyl)-4-(2-cyclohexylvinyl)-benzylamine:
Dissolve N-(tert-butoxycarbonyl)-4-cyclohexylethynyl-benzylamine
(0.5 g, 1.6 mmol) in EtOAc (20 mL). Transfer the solution to a
pressure vessel and hydrogenate at 30 psi for 3 h in the presence
of 5% palladium on calcium carbonate (poisoned with 3.5% lead, 0.25
g). Filter the catalyst through Celite.RTM., wash the filter cake
with excess of EtOAc followed by excess of DCM and concentrate the
filtrate in vacuo to an oil (HPLC shows starting material still
present). Dissolve the oil in EtOAc (20 mL) again. Transfer the
solution to a pressure vessel and hydrogenate contents at 30 psi
for 2 h in the presence of 5% palladium on calcium carbonate
(poisoned with 3.5% lead, 0.25 g). Filter the catalyst through
Celite.RTM., wash the filter cake with excess of EtOAc followed by
excess of DCM and concentrate the filtrate in vacuo to an oil (HPLC
shows all starting material consumed). Use this material in the
next step without additional purification (0.49 g). MS (ES+) m/z:
260.2 [M-(t-Bu)+H].sup.+.
[0532] (Z)-4-(2-Cyclohexylvinyl)-benzylamine: Add trifluoroacetic
acid (1 mL) to a solution of
(Z)-N-(tert-butoxycarbonyl)-4-(2-cyclohexylvinyl)-benzylamine (0.49
g, 1.5 mmol) in DCM (10 mL). Stir the mixture at room temperature
for 2 h, concentrate in vacuo and purify the residue by SCX
chromatography to obtain the title compound (0.3 g, 87%, estimate
10% of alkane present). Use this material in the next step without
additional purification. MS (ES+) m/z: 199.3
(M-NH.sub.3+H).sup.+.
Preparation 37
(E)-3-Aminomethyl-6-(2-cyclohexylvinyl)-pyridine
##STR00050##
[0534] 25 3-(tert-Butoxycarbonylamino-methyl)-6-chloropyridine:
Dissolve 3-aminomethyl-6-chloropyridine (1.65 g, 11.57 mmol) in DCM
(58 mL) and add triethylamine (2.42 mL, 17.26 mmol) followed by
di-tert-butyl-dicarbonate (3.03 g, 13.88 mmol). Stir the resulting
solution at room temperature overnight. Add DCM and saturated
aqueous NaHCO.sub.3. Separate the aqueous phase and extract twice
with DCM. Dry the combined organic extracts over MgSO.sub.4, filter
and concentrate in vacuo. Purify by chromatography on silica gel
(120 g, pre-packed cartridge) eluting stepwise with hexane/EtOAc
(1:0 over 5 min, 19:1 over 5 min, 9:1 over 5 min and 85:15 over 5
min; 50 mL/min) to obtain the desired intermediate (2.41 g, 86%).
MS (APCI+) m/z: 187 [M-(t-Bu)+H].sup.+.
[0535]
(E)-3-(tert-Butoxycarbonylamino-methyl)-6-(2-cyclohexylvinyl)-pyrid-
ine: Combine 3-(tert-butoxycarbonylamino-methyl)-6-chloropyridine
(1.42 g, 5.85 mmol), 2-cyclohexylvinyl boronic acid (1.35 g, 8.78
mmol), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)
complex with DCM (239 mg, 0.293 mmol), and 2M aqueous
Na.sub.2CO.sub.3 (9.65 mL, 19.2 mmol) in 1,4-dioxane (60 mL). Purge
the resulting solution with nitrogen for 5 min and heat at
90.degree. C. overnight. Cool the reaction mixture to room
temperature and partition the mixture between EtOAc and water.
Separate the aqueous phase and extract twice with EtOAc. Dry the
combined organic extracts over MgSO.sub.4, filter and concentrate
in vacuo. Purify by chromatography on silica gel (120 g, pre-packed
cartridge) eluting stepwise with hexane/EtOAc (1:0 over 5 min, 49:1
over 5 min, 19:1 over 5 min, 9:1 over 5 min and 85:15 over 5 min;
50 mL/min) to obtain the desired intermediate (1.3 g, 70%). MS
(APCI+) m/z: 317 (M+H).sup.+.
[0536] (E)-3-Aminomethyl-6-(2-cyclohexylvinyl)-pyridine: Dissolve
(E)-3-(tert-butoxycarbonylamino-methyl)-6-(2-cyclohexylvinyl)-pyridine
(1.3 g, 4.11 mmol) in EtOAc (60 mL) and bubble hydrogen chloride
through the solution for 20 min. Stir the mixture overnight at room
temperature. Concentrate the mixture in vacuo and dissolve the
resulting solid in water. Adjust the pH to 9-11 with 20% aqueous
K.sub.2CO.sub.3 and extract with DCM. Dry the combined organic
extracts over MgSO.sub.4, filter and concentrate in vacuo to obtain
the title compound (0.78 g, 88%). MS (APCI+) m/z: 217
(M+H).sup.+.
Preparation 38
(E)-2-Aminomethyl-5-(2-cyclohexylvinyl)-pyridine
##STR00051##
[0538] (E)-5-(2-Cyclohexylvinyl)-pyridine-2-carbonitrile: Combine a
mixture of 5-bromo-2-cyano-pyridine (2 g, 10.93 mmol),
2-cyclohexylvinyl boronic acid (2.52 g, 16.39 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
with DCM (446 mg, 0.546 mmol) and 2M aqueous Na.sub.2CO.sub.3 (18.2
mL, 36.07 mmol) in 1,4-dioxane (110 mL). Purge with nitrogen and
heat at 90.degree. C. overnight. Cool the reaction to room
temperature and partition between EtOAc and water. Separate the
aqueous phase and extract with EtOAc. Dry the combined organic
extracts over MgSO.sub.4, filter and concentrate in vacuo. Purify
by chromatography on silica gel (120 g, pre-packed cartridge)
eluting stepwise with hexane/EtOAc (1:0 over 5 min, 49:1 over 5 min
and 19:1 over 5 min; 50 mL/min) to obtain the desired intermediate
(1.76 g, 76%). MS (APCI+) m/z: 213 (M+H).sup.+.
[0539] (E)-2-Aminomethyl-5-(2-cyclohexylvinyl)-pyridine: Cool a
stirred solution of
(E)-5-(2-cyclohexylvinyl)-pyridine-2-carbonitrile (1.76 g, 8.3
mmol) in THF (55 mL) to 0.degree. C. under nitrogen. Carefully add
lithium aluminum-hydride (1.26 g, 33.2 mmol) and warm to room
temperature overnight. Quench the reaction mixture with sequential
addition of water (1.26 mL), 15% aqueous NaOH (1.26 mL) and water
(3.times.1.26 mL), and stir for 3 h. Filter the mixture through
Celite.RTM., wash with EtOAc, and concentrate in vacuo. Purify the
crude mixture by chromatography on silica gel (120 g, pre-packed
cartridge) eluting stepwise with
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) (1:0 over
5 min, 49:1 over 5 min, 19:1 over 5 min, 93:7 over 5 min and 9:1
over 5 min; 50 mL/min) to obtain the title compound (608 mg, 34%).
MS (APCI+) m/z: 217 (M+H).sup.+.
Preparation 39
(Z)-3-Aminomethyl-6-(2-cyclohexylvinyl)-pyridine
##STR00052##
[0541]
3-(tert-Butoxycarbonylamino-methyl)-6-cyclohexylethynyl-pyridine:
Under a nitrogen atmosphere, add
3-(tert-butoxycarbonylamino-methyl)-6-chloropyridine (1 g, 4.12
mmol), cyclohexylacetylene (0.446 g, 4.12 mmol),
dichlorobis(triphenylphosphine)-palladium (578 mg, 0.824 mmol),
copper(I) iodide (157 mg, 0.824 mmol) and triethylamine (8.6 mL,
6.18 mmol) to THF (20 mL). Heat the mixture to reflux overnight.
Cool the mixture to room temperature, and dilute with saturated
aqueous NaHCO.sub.3 (50 mL) and EtOAc (50 mL). Separate the layers
and extract the aqueous layer with EtOAc (4.times.30 mL). Wash the
combined organic extracts with brine (20 mL), dry over
Na.sub.2SO.sub.4, filter and concentrate in vacuo. Purify the crude
mixture by chromatography on silica gel (120 g, pre-packed
cartridge) eluting with hexane/EtOAc (1:0 to 6:1 gradient over 1.25
h, 80 mL/min) to obtain the desired intermediate as a colorless oil
(0.71 g, 55%). MS (APCI+) m/z: 215 (M-Boc+H).sup.+.
[0542]
(Z)-3-(tert-Butoxycarbonylamino-methyl)-6-(2-cyclohexylvinyl)-pyrid-
ine: Add
3-(tert-butoxycarbonylamino-methyl)-6-cyclohexylethynyl-pyridine
(0.7 g, 2.21 mmol) and Lindlar's Catalyst (0.1 g) to EtOAc (20 mL).
Bubble hydrogen (via balloon) through the mixture for 2 h and stir
under static atmosphere of hydrogen overnight. Filter the catalyst
through Celite.RTM. and concentrate the filtrate in vacuo. Purify
the crude mixture by chromatography on silica gel (80 g, pre-packed
cartridge) eluting with hexane/EtOAc (1:0 to 9:1 gradient over 1.25
h, 80 mL/min) to obtain the desired intermediate as a colorless oil
(0.21 g, 30%) and starting material (0.42 g, 60%). Repeat the
reaction on the recovered starting material to obtain the desired
intermediate (242 mg, 57%; 452 mg total, 64% overall). MS (APCI+)
m/z: 217 (M-Boc+H).sup.+.
[0543] (Z)-3-Aminomethyl-6-(2-cyclohexylvinyl)-pyridine: Add
(Z)-3-(tert-butoxycarbonylamino-methyl)-6-(2-cyclohexylvinyl)-pyridine
(0.42 g, 1.33 mmol) to methanol (20 mL) and cool to 0.degree. C.
Bubble hydrogen chloride into the solution until saturated, and
allow the mixture to warm to room temperature. Concentrate the
mixture in vacuo and partition the residue between 3N aqueous NaOH
(30 mL) and DCM (30 mL). Separate the layers and extract the
aqueous phase with DCM (3.times.30 mL). Wash the combined organic
extracts with brine (30 mL), dry over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo to obtain the title compound as a colorless
oil (0.89 gi 80%). MS (APCI+) m/z: 217 (M+H).sup.+.
Preparation 40
(Z)-2-Aminomethyl-5-(2-cyclohexylvinyl)-pyridine
##STR00053##
[0545] 5-Cyclohexylethynyl-pyridine-2-carbonitrile: Under a
nitrogen atmosphere, add 5-bromo-2-cyano-pyridine (1.5 g, 8.2
mmol), cyclohexylacetylene (0.887 g, 8.2 mmol),
dichlorobis(triphenylphosphine)palladium (575 mg, 0.82 mmol),
copper(I) iodide (234 mg, 1.23 mmol) and triethylamine (11.4 mL, 82
mmol) to THF (50 mL). Heat the mixture to reflux and stir for 4 h.
Cool the mixture to room temperature and dilute with saturated
aqueous NaHCO.sub.3 (50 mL) and EtOAc (50 mL). Separate the layers
and extract the aqueous layer with EtOAc (4.times.30 mL). Wash the
combined organic extracts with brine (20 mL), dry over
Na.sub.2SO.sub.4, filter and concentrate in vacuo. Purify the crude
mixture by chromatography on silica gel (120 g, pre-packed
cartridge) eluting with hexane/EtOAc (1:0 to 9:1 gradient over 1.25
h, 80 mL/min) to obtain the desired intermediate as a colorless oil
(1.28 g, 74%). MS (APCI+) m/z: 211 (M+H).sup.+.
[0546] (Z)-5-(2-Cyclohexylvinyl)-pyridine-2-carbonitrile: Add
5-cyclohexylethynyl-pyridine-2-carbonitrile (1.4 g, 4.16 mmol) and
Lindlar's Catalyst (0.5 g) to EtOAc (20 mL). Bubble hydrogen (via
balloon) through the mixture for 2 h and stir under static
atmosphere of hydrogen overnight. Filter the catalyst through
Celite.RTM. and concentrate the filtrate in vacuo. Purify by
chromatography on silica gel (80 g, pre-packed cartridge) eluting
with hexane/EtOAc (1:0 to 9:1 gradient over 1.25 h, 80 mL/min) to
obtain the desired intermediate as a colorless oil (0.89 g, 80%).
MS (APCI+) m/z: 213 (M+H).sup.+.
[0547] (Z)-2-Aminomethyl-5-(2-cyclohexylvinyl)-pyridine: Under a
nitrogen atmosphere, add lithium aluminum hydride (965 mg, 25.4
mmol) to THF (20 mL) at 0.degree. C. Add a solution of
(Z)-5-(2-cyclohexylvinyl)-pyridine-2-carbonitrile (1.8 g, 1.74
mmol) in THF (5 mL) and stir at 0.degree. C. for 1 h and to room
temperature overnight. Cool the mixture to 0.degree. C. and
carefully add water (0.95 mL). Add diethyl ether (125 mL), 3N
aqueous NaOH (0.95 mL), and water (2.85 mL) and stir for 1 h at
room temperature. Filter the solid residue and concentrate in vacuo
to obtain the title compound as a colorless oil (0.49 g, 30%). MS
(APCI+) m/z: 217 (M+H).sup.+.
Preparation 41
4-(2-Cyclohexyl-2-oxo-ethyl)-benzylamine
##STR00054##
[0549] 4-(2-Cyclohexyl-2-oxo-ethyl)-benzonitrile: Add
4-iodobenzonitrile (1.0 g, 4.37 mmol) and 1-cyclohexyl-ethanone
(717 mg, 5.68 mmol) to a suspension of
tris(dibenzylideneacetone)dipalladium(0) (60 mg, 0.065 mmol), BINAP
(98 mg, 0.157 mmol) and sodium tert-butoxide (546 mg, 5.68 mmol) in
anhydrous THF (26 mL). Heat the mixture at 70.degree. C. under
nitrogen atmosphere. After 6 h, add
tris(dibenzylideneacetone)dipalladium(0) (60 mg, 0.065 mmol), BINAP
(98 mg, 0.157 mmol), sodium tert-butoxide (294 mg, 3.06 mmol) and
1-cyclohexyl-ethanone (386 mg, 3.06 mmol) and allow to stir the
mixture at 70.degree. C. under nitrogen overnight. Add water and
extract twice with EtOAc. Dry the combined organic extracts over
MgSO.sub.4, filter and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (92:8) to
obtain the desired intermediate as a yellow oil (902 mg, 91%).
[0550] 4-(2-Cyclohexyl-2-oxo-ethyl)-benzylamine: Bubble nitrogen
for 10 min into a solution of
4-(2-cyclohexyl-2-oxo-ethyl)-benzonitrile (478 mg, 2.10 mmol) in
methanol (80 mL) with concentrated HCl (5 drops). Add 10% Pd/C
(Degussa type E101, 96 mg) and submit the mixture to hydrogenation
at atmospheric pressure overnight. Filter the catalyst through
Celite.RTM. and concentrate in vacuo to obtain the hydrochloride
salt of the title compound. Wash with diethyl ether/hexane (1:1)
and filter the white solid. Add saturated aqueous NaHCO.sub.3 and
extract twice with EtOAc. Dry the combined organic extracts over
MgSO.sub.4, filter and concentrate in vacuo to obtain the title
compound as a yellow oil (145 mg, 30%). MS (ES+) m/z: 232
(M+H).sup.+.
Preparation 42
4-(Morpholin-4-ylmethyl)-benzylamine
##STR00055##
[0552] 4-(Morpholin-4-ylmethyl)-benzonitrile: Dissolve
4-cyanobenzaldehyde (5 g, 38.1 mmol), morpholine (4.15 g, 47.7
mmol) and acetic acid (2.2 mL, 38.1 mmol) in DCE (100 mL). Add
sodium cyanoborohydride (3.59 g, 57.2 mmol), and stir the mixture
overnight. Add water (100 mL), separate the layers and extract the
aqueous layer with DCM (3.times.50 mL). Wash the combined organic
extracts with brine, dry over Na.sub.2SO.sub.4, filter and
concentrate in vacuo. Purify by chromatography on silica gel (80 g,
pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:2 over
1.25 h, 80 mL/min) to obtain the desired intermediate as a
colorless oil (6.1 g, 79%). MS (APCI+) m/z: 203 (M+H).sup.+.
[0553] 4-(Morpholin-4-ylmethyl)-benzylamine: Under a nitrogen
atmosphere, add lithium aluminum hydride (1.13 g, 29.7 mmol) to THF
(50 mL) at 0.degree. C. followed by a solution of
4-(morpholin-4-ylmethyl)-benzonitrile (2 g, 9.89 mmol) in THF (10
mL). Stir at 0.degree. C. for 1 h and at room temperature
overnight. Cool the mixture to 0.degree. C., and carefully add
water (1.15 mL). Add diethyl ether (125 mL), 3N aqueous NaOH (1.15
mL), water (3.45 mL), and stir for 1 h at room temperature. Filter
the solid residue and concentrate the filtrate in 5 vacuo to obtain
the title compound as a colorless oil (1.87 g, 94%). MS (APCI+)
m/z: 207 (M+H).sup.+.
Preparation 43
4-(Pyrrolidin-1-ylmethyl)-benzylamine
##STR00056##
[0555] 4-(Pyrrolidin-1-ylmethyl)-benzonitrile: Add pyrrolidine
(0.89 mL, 10.74 mmol) to a stirred solution of
4-bromomethyl-benzonitrile (1 g, 5.1 mmol) and triethylamine (1.5
mL, 10.74 mmol) in anhydrous THF (26 mL). Stir reaction overnight
at room temperature. Partition the reaction mixture between EtOAc
and water. Extract the aqueous phase twice 15 with EtOAc. Dry the
combined organic extracts over MgSO.sub.4, filter, and concentrate
in vacuo to obtain the desired intermediate (918 mg, 97%) suitable
for use without further purification. MS (APCI+) m/z: 187
(M+H).sup.+.
[0556] 4-(Pyrrolidin-1-ylmethyl)-benzylamine: Dissolve
4-(pyrrolidin-1-ylmethyl)-benzonitrile (918 mg, 4.93 mmol) in
methanol (32 mL). Add cobalt(II) chloride hexahydrate (2.7 g, 9.87
mmol) and stir for 20 min. Cool the mixture to 0.degree. C., and
carefully add sodium borohydride (1.86 g, 49.3 mmol) in small
batches. Stir the mixture for 1.5 h at room temperature. Quench the
mixture with water and partition between water and chloroform.
Extract the aqueous phase three times with chloroform/iso-propanol
(3:1). Dry the combined organic extracts over MgSO.sub.4, filter,
and concentrate in vacuo. Purify by chromatography on silica gel
(80 g) eluting with a gradient of
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) (1:0 over
5 min, 19:1 over 5 min, 9:1 over 5 min, 85:15; 50 mL/min) to give
the title compound (421 mg, 45%). MS (ES+) m/z: 191
(M+H).sup.+.
Preparation 44
4-(Piperidin-1-ylmethyl)-benzylamine
##STR00057##
[0558] 4-(Piperidin-1-ylmethyl)-benzonitrile: Under a nitrogen
atmosphere, add sodium cyanoborohydride (5.77 g, 91.6 mmol) to a
solution of 4-cyanobenzaldehyde (3 g, 22.9 mmol), piperidine (5.84
g, 68.7 mmol) and acetic acid (2.75 g, 45.8 mmol) in methanol (30
mL) at 0.degree. C. with stirring. Warm the mixture to room
temperature and stir overnight. Add water (100 mL), saturated
aqueous K.sub.2CO.sub.3 (50 mL), and extract with DCM. Wash the
combined organic extracts with water and brine. Dry the organic
phase over Na.sub.2SO.sub.4, filter, and concentrate in vacuo.
Purify by chromatography on silica gel (400 g) eluting with
hexane/EtOAc (1:0 to 4:1 gradient) to obtain the desired
intermediate as a clear oil (2.48 g, 54%). MS (APCI+) m/z: 201
(M+H).sup.+.
[0559] 4-(Piperidin-1-ylmethyl)-benzylamine: Add
4-(piperidin-1-ylmethyl)-benzonitrile (890 mg, 4.45 mmol), 2M
hydrogen chloride in ether (8.9 mL, 17.8 mmol) and 10% Pd/C (90 mg)
to methanol (100 mL) in a pressure vessel. Flush the vessel three
times with hydrogen and charge to 50 psi with hydrogen. Stir at
room temperature for 2 h. Filter the catalyst through Celite.RTM.
and concentrate the filtrate in vacuo. Purify by chromatography on
silica gel (100 g) eluting with a gradient of DCM to 4:1
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) to obtain
the title compound as a colorless oil (0.82 g, 90%). MS (ES+) m/z:
205 (M+H).sup.+.
Preparation 45
[0560] The compound of Preparation 45 may be prepared essentially
as described in Preparation 44 by using 4-cyanobenzaldehyde and
(.+-.)-1-methyl-2,2,2-trifluoro-ethylamine. MS (ES+) data is shown
in the Table below.
TABLE-US-00008 Prep. Structure Compound MS (ES+) m/z 45
##STR00058##
(.+-.)-4-[(1-Methyl-2,2,2-trifluoro-ethylamino)-methyl]-benzylamine
233 (M + H).sup.+
Preparation 46
(R)-1-Methyl-2,2,2-trifluoro-ethylamine Hydrochloride
##STR00059##
[0562]
(S)-(1-Phenylethyl)-(2',2',2'-trifluoro-1-methylethylidene)-amine:
Use a 22 liter 3-neck round-bottom flask equipped with a dry ice
condenser and inlet tube in one side neck, mechanical stirrer in
center neck and a Dean-Stark trap with dry ice condenser at top in
other side neck. Chill a solution of cold 1,1,1-trifluoroacetone
(2100 g, 18.74 mol) and cold toluene (1000 mL) in a wet ice-acetone
bath at all times. To a cold mixture of
(S)-(-)-.alpha.-methylbenzylamine (550 g, 4.54 mol) and
p-toluenesulfonic acid monohydrate (8.63 g, 0.0454 mol) in toluene
(1000 mL) at 0.degree. C. add a cooled solution of
1,1,1-trifluoroacetone (753 g, 6.72 mol) in cold toluene via teflon
tubing under positive pressure of nitrogen (with the Teflon tubing
below the surface of the reaction mixture and stopcock to prevent
back-up). Remove the dry ice condenser in side neck and replace it
with inlet with tubing. However, keep the Dean-Stark trap and dry
ice condenser on the other side neck. Heat the reaction mixture
slowly to 111.degree. C. Remove water distillate and turn off heat.
Slowly add the organic distillate to the reaction mixture at a rate
to keep trifluoroacetone distillation under control. Heat the
reaction slowly to 111.degree. C. Turn off heat and remove water
and organic distillate. Add a cooled solution of
1,1,1-trifluoroacetone (789 g, 7.04 mol) in toluene to the hot
reaction mixture at a rate to keep trifluoroacetone distillation
under control. Heat the reaction mixture slowly to 111.degree. C.
Turn off heat and remove the distillate. Cool the reaction mixture
and concentrate in vacuo at 60.degree. C. Add hexane (4 L) in
portions to aid in removal of toluene to obtain the desired
intermediate as a pale yellow oil of the crude product (1410
g).
[0563]
(R)-(1'-Phenylethylidene)-(2,2,2-trifluoro-1-methylethyl)-amine: To
crude
(S)-(1-phenylethyl)-(2',2',2'-trifluoro-1-methylethylidene)-amine
(1410 g, 4.54 mol theory) and washings with 20 g of toluene at room
temperature, add DBU (1050 g, 6.897 mol) in portions to keep
temperature below 60.degree. C. Heat the reaction at 60.degree. C.
overnight (14 h) under nitrogen until the starting material
rearranges to the desired intermediate (2460 g of solution). MS
(ES+) m/z: 216.2 (M+H).sup.+.
[0564] (R)-1-Methyl-2,2,2-trifluoro-ethylamine Hydrochloride:
Dilute the first half (1230 g) of the above reaction mixture with
heptane (1500 mL) and DCM (1500 mL). Add 5N aqueous HCl (1250 mL)
to the solution mixture and stir for 30 min until only acetophenone
is present in the organic phase. Wash the bottom aqueous phase with
1:1 heptane/DCM (2.times.500 mL) and then cool the aqueous phase in
an ice bath. Add ice-cold DCM (1500 mL) and then cold 5N aqueous
NaOH (1250 mL) dropwise to the biphasic mixture and stir for 15
min. Separate the bottom organic phase. Extract the aqueous phase
with DCM (2.times.500 mL) and distill the combined organic phase
carefully (40-60.degree. C. pot temperature) while cooling the
receiving flask in a dry ice/acetone bath. Collect the distillate.
Add cold 5N aqueous HCl (500 mL) dropwise and stir for 30 min.
Concentrate the mixture in vacuo, using toluene for azeotropic
removal of water, to afford the title compound as a white solid.
Repeat the procedure with the second half of the previous reaction
mixture to obtain the title compound as a white solid (451 g total,
66%). MS (ES+) m/z: 114.1 (M+H).sup.+. [.alpha.].sub.D=-1.40
(c=0.5, MeOH).
Preparation 47
(R)-4-[(1-Methyl-2,2,2-trifluoro-ethylamino)-methyl]-benzylamine
##STR00060##
[0566]
(R)-4-[(1-Methyl-2,2,2-trifluoro-ethylamino)-methyl]-benzonitrile:
Add sodium cyanoborohydride (3.36 g, 53.5 mmol) to a solution of
4-cyanobenzaldehyde (1.75 g, 13.35 mmol) and
(R)-1-methyl-2,2,2-trifluoro-ethylamine hydrochloride (2 g, 13.37
mmol) in methanol (17 mL) containing acetic acid (1.53 mL, 26.75
mmol). Stir the mixture at room temperature overnight. Partition
the mixture between 1N aqueous NaOH/DCM (1: 1, 500 mL) and extract
the aqueous layer twice with DCM. Dry the combined organic extracts
over MgSO.sub.4, concentrate in vacuo and purify by chromatography
on silica gel (120 g) eluting with hexane/EtOAc (19:1, 9:1, 85:15
and 4:1) to obtain the desired intermediate (0.83 g, 27%). MS (ES+)
m/z: 229 (M+H).sup.+.
[0567]
(R)-4-[(1-Methyl-2,2,2-trifluoro-ethylamino)-methyl]-benzylamine:
Add cobalt(II) chloride hexahydrate (1.45 g, 6.09 mmol) to a
solution of
(R)-4-[(1-methyl-2,2,2-trifluoro-ethylamino)-methyl]-benzonitrile
(695 mg, 3.045 mmol) in methanol (20 mL). Add sodium borohydride
(1.15 g, 30.45 mmol) in small batches and stir at room temperature
for 3 h. Quench with water, add chloroform and filter the mixture
through Celite.RTM.. Separate layers and extract the aqueous phase
twice with chloroform. Dry the combined organic extracts over
MgSO.sub.4, filter and concentrate in vacuo. Purify by
chromatography on silica gel (40 g) eluting with a gradient of DCM
to 19:1 and 9:1 DCM/(chloroform:methanol:concentrated NH.sub.4OH
80:18:2) to obtain the title compound as an oil (0.4 g, 57%). MS
(ES+) m/z: 233 (M+H).sup.+.
Preparation 48
[0568] The compound of Preparation 48 may be prepared essentially
as described in Preparation 47 by using 4-cyanobenzaldehyde and
homopiperidine. Overall yield and MS (ES+) data are shown in the
Table below.
TABLE-US-00009 Yield MS (ES+) Prep. Structure Compound (%) m/z 48
##STR00061## 4-(Azepan-1-ylmethyl)-benzylamine 18 219 (M +
H).sup.+
Preparation 49
4-[(2,2,2-Trifluoroethylamino)-methyl]-benzylamine
##STR00062##
[0570] 4-[(2,2,2-Trifluoroethylamino)-methyl]-benzonitrile: Add
sodium cyanoborohydride (957 mg, 15.24 mmol) to a stirred solution
of 4-cyanobenzaldehyde (500 mg, 3.81 mmol),
2,2,2-trifluoroethylamine (0.3 mL, 3.81 mmol) and acetic acid (0.44
mL, 7.62 mmol) in methanol (5 mL). Stir the mixture overnight at
room temperature. Partition the mixture between 1N aqueous NaOH and
DCM. Extract the aqueous phase twice with DCM. Dry the combined
organic extracts over MgSO.sub.4, filter and concentrate in vacuo
to obtain the desired intermediate (749 mg, 92%) suitable for use
without further purification. MS (ES+) m/z: 215 (M+H).sup.+.
[0571] 4-[(2,2,2-Trifluoroethylamino)-methyl]-benzylamine: Dissolve
4-[(2,2,2-trifluoroethylamino)-methyl]-benzonitrile (633 mg, 2.955
mmol) in methanol (22 mL). Add cobalt(II) chloride hexahydrate
(1.41 g, 5.91 mmol) and stir for 20 min. Carefully add sodium
borohydride (1.12 g, 29.55 mmol) in small batches and stir the
mixture overnight. Quench the mixture with water and filter through
celite, washing filtercake with chloroform:methanol:concentrated
NH.sub.4OH (80:18:2). Concentrate the filtrate in vacuo, and
partition the residue between water and chloroform. Extract the
aqueous phase three times with chloroform/iso-propanol (3:1). Dry
the combined organic extracts over MgSO.sub.4, filter and
concentrate in vacuo. Purify by chromatography on silica gel (40 g,
pre-packed cartridge) eluting with
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) (1:0 over
5 min, 19:1 over 5 min, 9:1 over 5 min, 85:15 over 5 min, 4:1; 50
mL/min) to obtain the title compound (316 mg, 49%). MS (ES+) m/z:
219 (M+H).sup.+.
Preparation 50
4-[N-(tert-Butoxycarbonyl)-N-(cyclohexyl)-aminomethyl]-benzylamine
##STR00063##
[0573] 4-(Cyclohexylamino-methyl)-benzonitrile: Under a nitrogen
atmosphere, add sodium cyanoborohydride (9.6 g, 152 mmol) to a
solution of 4-cyanobenzaldehyde (5 g, 38 mmol), cyclohexylamine
(3.8 g, 38 mmol) and acetic acid (0.46 g, 7.6 mmol) in methanol
(100 mL) at 0.degree. C. Warm the mixture to room temperature and
stir overnight. Add water (100 mL) and adjust the pH to 10 with 3N
aqueous NaOH. Extract with DCM and wash the organic phase with
water and brine. Dry the organic phase over Na.sub.2SO.sub.4,
filter and concentrate in vacuo. Purify by chromatography on silica
gel (500 g) eluting with hexane/EtOAc (1:0 to 1:1 gradient) to
obtain the desired intermediate (6.9 g, 86%). MS (APCI+) m/z: 215
(M+H).sup.+.
[0574]
4-[N-(tert-Butoxycarbonyl)-N-(cyclohexyl)-aminomethyl]-benzonitrile-
: Add 4-(cyclohexylamino-methyl)-benzonitrile (3.5 g, 16.3 mmol),
triethylamine (2.26 mL, 16.3 mmol), and di-tert-butyl-dicarbonate
(3.55 g, 16.3 mmol) to DCM (20 mL). Stir the mixture at room
temperature overnight and concentrate in vacuo. Purify by
chromatography on silica gel (150 g) eluting with hexane/EtOAc (1:0
to 9:1 gradient) to obtain the desired intermediate (3.7 g, 72%).
MS (APCI+) m/z: 215 (M-Boc+H).sup.+.
[0575]
4-[N-(tert-Butoxycarbonyl)-N-(cyclohexyl)-aminomethyl]-benzylamine:
Under a nitrogen atmosphere, add borane-dimethylsulfide complex
(29.3 mL, 58.7 mmol, 2M solution in THF) to
4-[N-(tert-butoxycarbonyl)-N-(cyclohexyl)-aminomethyl]-benzonitrile
(3.7 g, 11.7 mmol) in THF (100 mL) at 0.degree. C. Warm to room
temperature and stir overnight. Heat the mixture under reflux for
30 min. Cool the mixture in an ice-bath, and add methanol (20 mL).
Warm to room temperature, and add KHSO.sub.4 (20 g in 100 mL of
water). Stir the mixture for 2 h and adjust the pH to 10 with 3N
aqueous NaOH. Extract the mixture with DCM. Dry the organic phase
over Na.sub.2SO.sub.4, filter, and concentrate in vacuo. Purify by
chromatography on silica gel (150 g) eluting with a gradient of DCM
to 1:1 DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) to
obtain the title compound as an oil (2.43 g, 65%). MS (ES+) m/z:
319 (M+H).sup.+.
Preparation 51
4-[N-(tert-Butoxycarbonyl)-N-(iso-butyl)-aminomethyl]-benzylamine
##STR00064##
[0577] 4-(iso-Butylamino-methyl)-benzonitrile: Under a nitrogen
atmosphere add sodium cyanoborohydride (5.77 g, 91.6 mmol) to
4-cyanobenzaldehyde (3 g, 22.9 mmol), iso-butylamine (3.34 g, 45.8
mmol) and acetic acid (1.37 g, 22.9 mmol) in methanol (30 mL) at
0.degree. C. Warm the mixture to room temperature and stir
overnight. Add water (40 mL), 15 saturated aqueous K.sub.2CO.sub.3
(30 mL) and extract with DCM. Wash the combined organic extracts
with water and brine. Dry the organic phase over Na.sub.2SO.sub.4,
filter and concentrate in vacuo. Purify the residue by
chromatography on silica gel (500 g) eluting with 9:1
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) to obtain
the desired intermediate (3.63 g, 84%). MS (APCI+) m/z: 189
(M+H).sup.+.
[0578]
4-[N-(tert-Butoxycarbonyl)-N-(iso-butyl)-aminomethyl]-benzonitrile:
Add 4-(iso-butylamino-methyl)-benzonitrile (2 g, 10.6 mmol),
triethylamine (3 mL, 21.2 mmol), and di-tert-butyl-dicarbonate
(2.44 g, 11.2 mmol) to DCM (30 mL). Stir the mixture at room
temperature for 1 h and concentrate in vacuo. Purify by
chromatography on silica gel (80 g) eluting with hexane/EtOAc (1:0
to 9:1 gradient) to obtain the desired intermediate as a clear oil
(3.01 g, 98%). MS (ES+) m/z: 189 (M-Boc+H).sup.+.
[0579]
4-[N-(tert-Butoxycarbonyl)-N-(iso-butyl)-aminomethyl]-benzylamine:
Under a nitrogen atmosphere, add borane-dimethylsulfide complex (13
mL, 26 mmol, 2M solution in THF) to
4-[N-(tert-butoxycarbonyl)-N-(iso-butyl)-aminomethyl]-benzonitrile
(1.5 g, 5.2 mmol) in THF (20 mL) at 0.degree. C. Heat the mixture
under reflux overnight. Cool the mixture in an ice-bath and add
methanol (20 mL). Warm to room temperature and add KHSO.sub.4 (7 g
in 50 mL of water). Stir for 2 h at room temperature and basify
with 3N aqueous NaOH. Extract with DCM, dry the organic phase over
Na.sub.2SO.sub.4, and concentrate in vacuo. Purify by
chromatography on silica gel (150 g) eluting with a gradient of DCM
to 4:1 DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) to
obtain the title compound as an oil (0.72 g, 47%). MS (APCI+) m/z:
293 (M+H).sup.+.
Preparation 52
4-[N-(tert-Butoxycarbonyl)-N-(iso-propyl)-aminomethyl]-benzylamine
##STR00065##
[0581] 4-(iso-Propylamino-methyl)-benzonitrile: Under a nitrogen
atmosphere, add sodium cyanoborohydride (5.77 g, 91.6 mmol) to a
solution of 4-cyanobenzaldehyde (3 g, 22.9 mmol), iso-propylamine
(2.03 g, 34.4 mmol) and acetic acid (1.37 g, 22.9 mmol) in methanol
(30 mL) at 0.degree. C. with stirring. Warm the mixture to room
temperature and stir overnight. Add water (100 mL), saturated
aqueous K.sub.2CO.sub.3 (50 mL), and extract with DCM. Wash the
combined organic extracts with water and brine. Dry the organic
phase over Na.sub.2SO.sub.4, filter and concentrate in vacuo.
Purify by chromatography on silica gel (300 g) eluting with 9:1
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) to obtain
the desired intermediate (1.53 g, 38%). MS (APCI+) m/z: 175
(M+H).sup.+.
[0582]
4-[N-(tert-Butoxycarbonyl)-N-(iso-propyl)-aminomethyl]-benzonitrile-
: Add 4-(iso-propylamino-methyl)-benzonitrile (1.53 g, 8.9 mmol),
triethylamine (2.48 mL, 17.8 mmol) and di-tert-butyl-dicarbonate
(2.01 g, 9.23 mmol) to DCM (30 mL). Stir the mixture at room
temperature for 2 h and concentrate in vacuo. Purify by
chromatography on silica gel (100 g) eluting with hexane/EtOAc (1:0
to 9:1 gradient) to obtain the desired intermediate as a clear oil
(2.3 g, 95%). MS (ES+) m/z: 175 (M-Boc+H).sup.+.
[0583]
4-[N-(tert-Butoxycarbonyl)-N-(iso-propyl)-aminomethyl]-benzylamine:
Under a nitrogen atmosphere add borane-dimethylsulfide complex
(13.7 mL, 27.4 mmol, 2M solution in THF) to
4-[N-(tert-butoxycarbonyl)-N-(iso-propyl)-aminomethyl]-benzonitrile
(1.5 g, 5.5 mmol) in THF (20 mL) at 0.degree. C. Warm to room
temperature and stir overnight. Heat the mixture under reflux for 2
h. Cool the mixture in an ice-bath and add methanol (20 mL). Warm
to room temperature and add KHSO.sub.4 (7 g in 50 mL of water).
Stir for 2 h at room temperature and basify with 3N aqueous NaOH.
Extract with DCM, dry the organic phase over Na.sub.2SO.sub.4 and
concentrate in vacuo. Purify by chromatography on silica gel (150
g) eluting with a gradient of DCM to 4:1
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) to obtain
the title compound as an oil (1.3 g, 85%). MS (APCI+) m/z: 279
(M+H).sup.+.
Preparation 53
4-[(N-methyl-iso-propylamino)-methyl]-benzylamine
##STR00066##
[0585] 4-[(N-methyl-iso-propylamino)-methyl]-benzonitrile: Add
4-bromomethyl-benzonitrile (784 mg, 4 mmol) to a stirring mixture
of N-isopropyl-methylamine (730 mg, 10 mmol), triethylamine (1.4
mL, 10 mmol) and THF (20 mL) at room temperature, and stir for 12
h. Dilute the mixture with water and EtOAc. Extract the aqueous
layer with EtOAc and wash the organic phase with water and brine.
Dry the organic solution over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo. Purify by chromatography on silica gel (12 g)
eluting with a gradient of DCM to 9:1
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) to obtain
the desired compound (660 mg, 88%). MS (APCI+) m/z: 189
(M+H).sup.+.
[0586] 4-[(N-methyl-iso-propylamino)-methyl]-benzylamine: Under a
nitrogen atmosphere, add borane-dimethyl sulfide complex (8.7 mL,
17.4 mmol, 2M solution in THF) to a solution of
4-[(N-methyl-iso-propylamino)-methyl]-benzonitrile (660 mg, 3.51
mmol) in THF (20 mL) at room temperature then heat to reflux for 30
min. Cool the mixture in an ice-bath and carefully add methanol (10
mL). Warm the mixture to room temperature and add concentrated HCl
(10 mL). Stir the mixture for 12 h, and concentrate in vacuo.
Purify by chromatography on silica gel (25 g) eluting with a
gradient of DCM to 1:1 DCM/(chloroform:methanol:concentrated
NH.sub.4OH 80:18:2) to obtain the title compound (550 mg, 82%). MS
(ES+) m/z: 193 (M+H).sup.+.
Preparation 54
6-Aminomethyl-3-[N-(cyclohexyl)-N-(2,2,2-trifluoroacetyl)-aminomethyl]-pyr-
idine
##STR00067##
[0588] 6-Chloro-3-(cyclohexylamino-methyl)-pyridine: Under a
nitrogen atmosphere, add sodium cyanoborohydride (3.53 g, 56 mmol)
to a solution of 3-aminomethyl-6-chloro-pyridine (2 g, 14 mmol),
cyclohexanone (1.38 g, 14 mmol) and acetic acid (168 mg, 0.2 mmol)
in methanol (20 mL) at 0.degree. C. Warm the mixture to room
temperature and stir overnight. Add water (100 mL) and saturated
aqueous K.sub.2CO.sub.3. Extract three times with DCM and wash the
combined organic extracts with water and brine. Dry over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo. Purify by
chromatography on silica gel (150 g) eluting with 9:1
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) to obtain
the desired intermediate (2.86 g, 91%). MS (APCI+) m/z: 225
(M+H).sup.+.
[0589]
6-Chloro-3-[N-(cyclohexyl)-N-(2,2,2-trifluoroacetyl)-aminomethyl]-p-
yridine: Add trifluoroacetic anhydride (4 g, 19.1 mmol) to
6-chloro-3-(cyclohexylamino-methyl)-pyridine (2.86 g, 12.7 mmol)
and triethylamine (2.66 mL, 19.1 mmol) in DCM (20 mL) at 0.degree.
C. Warm to room temperature and stir for 12 h. Concentrate in vacuo
and dilute with water and EtOAc. Separate the layers and extract
the aqueous layer with EtOAc. Wash the combined organic extracts
with water and brine. Dry over Na.sub.2SO.sub.4, filter and
concentrate in vacuo. Purify by chromatography on silica gel (400
g) eluting with hexane/EtOAc (1:0 to 4:1 gradient) to obtain the
desired intermediate as a white solid (3.7 g, 91%). MS (APCI+) m/z:
321 (M+H).sup.+.
[0590]
6-Cyano-3-[N-(cyclohexyl)-N-(2,2,2-trifluoroacetyl)-aminomethyl]-py-
ridine: Under a nitrogen atmosphere add
6-chloro-3-[N-(cyclohexyl)-N-(2,2,2-trifluoroacetyl)-aminomethyl]-pyridin-
e (3.7 g, 11.5 mmol), zinc cyanide (2.02 g, 17.3 mmol),
tris(dibenzylideneacetone)dipalladium(0) (0.48 g, 0.57 mmol) and
DPPF (0.63 g, 1.15 mmol) to DMF (40 mL). Heat the mixture at
95.degree. C. for 2 h. Cool the mixture to room temperature and
dilute with water and EtOAc. Separate the layers and extract the
aqueous layer with EtOAc. Wash the combined organic extracts with
water and brine. Dry the organic phase over Na.sub.2SO.sub.4,
filter and concentrate in vacuo. Purify by chromatography on silica
gel (400 g) eluting with hexane/EtOAc (1:0 to 3:2 gradient) to
obtain the desired intermediate (3.33 g, 93%). MS (APCI+) m/z: 312
(M+H).sup.+.
[0591]
6-Aminomethyl-3-[N-(cyclohexyl)-N-(2,2,2-trifluoroacetyl)-aminometh-
yl]-pyridine: Add
6-cyano-3-[N-(cyclohexyl)-N-(2,2,2-trifluoroacetyl)-aminomethyl]-pyridine
(1.5 g, 4.8 mmol), 2M hydrogen chloride in ether (7.2 mL, 14.4
mmol) and 10% Pd/C (0.3 g) to methanol (30 mL) in a pressure
vessel. Flush the vessel three times with hydrogen and charge to 50
psi with hydrogen. Stir at room temperature for 4 h. Filter the
mixture through Whatman.RTM. GF/B glass microfiber filter paper,
and concentrate in vacuo. Purify the residue by chromatography on
silica gel (100 g) eluting with a gradient of DCM to 4:1
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) to obtain
the title compound as a clear oil (1.6 g, 99%). MS (ES+) m/z: 316
(M+H).sup.+.
Preparation 55
5-Aminomethyl-2-(piperidin-1-ylmethyl)-pyridine
##STR00068##
[0593] 3-(tert-Butoxycarbonylamino-methyl)-6-cyano-pyridine: Under
a nitrogen atmosphere, add
3-(tert-butoxycarbonylamino-methyl)-6-chloropyridine (13.1 g, 54
mmol), zinc cyanide (9.5 g, 81 mmol),
tris(dibenzylideneacetone)dipalladium(0) (494 mg, 0.54 mmol), and
dppf (550 mg, 0.81 mmol) to DMF (130 mL). Heat the mixture at
70.degree. C. overnight.
[0594] Cool the mixture to room temperature and dilute with water
and EtOAc. Separate the layers, and extract the aqueous layer with
EtOAc. Wash the combined organic extracts with water and brine. Dry
the organic solution over Na.sub.2SO.sub.4, filter, and concentrate
in vacuo. Purify by chromatography on silica gel (500 g) eluting
with hexane/EtOAc (1:0 to 7:3 gradient) to provide the desired
intermediate as a white solid (11.3 g, 90%). MS (ES+) m/z: 234
(M+H).sup.+.
[0595] 3-(tert-Butoxycarbonylamino-methyl)-6-hydrox
methyl-pyridine: Add
3-(tert-butoxycarbonylamino-methyl)-6-cyano-pyridine (10.81 g, 46.4
mmol), KHSO.sub.4 (18.9 g, 16.2 mmol), 5% Pd/C (Degussa type E101,
4 g) to a mixture of methanol (250 mL) and water (20 mL) in a
pressure vessel. Flush the vessel three times with hydrogen and
charge with hydrogen to 50 psi. Stir at room temperature,
recharging to 50 psi hydrogen as necessary, until no change in
pressure is observed. Add an aqueous NaOH solution (6.11 g of NaOH
in 20 mL of water) to the mixture and stir for 15 min. Filter the
mixture through glass microfiber filter paper. Dilute the filtrate
with water and DCM. Separate the layers, and extract the aqueous
layer with DCM. Wash the combined organic extracts with water and
brine. Dry the organic solution over Na.sub.2SO.sub.4, filter and
concentrate in vacuo. Purify by chromatography on silica gel (600
g) eluting with DCM/(chloroform:methanol:concentrated NH.sub.4OH
80:18:2) (1:0 to 7:3 gradient) to obtain
6-aminomethyl-3-(tert-butoxycarbonylamino-methyl)-pyridine as a
clear oil [3.4 g, 31%, MS (ES+) m/z/z: 238 (M+H).sup.+] and the
desired intermediate
3-(tert-butoxycarbonylamino-methyl)-6-hydroxymethyl-pyridine as
colorless oil (5.6 g, 52%). MS (ES+) m/z: 239 (M+H).sup.+.
[0596] 3-(tert-Butoxycarbonylamino-methyl)-6-chloromethyl-pyridine:
Add 3-(tert-butoxycarbonylamino-methyl)-6-hydroxymethyl-pyridine
(2.3 g, 9.65 mmol) and triethylamine (2.05 mL, 14.5 mmol) to DCM
(30 mL). Cool the mixture to 0.degree. C. and add methanesulfonyl
chloride (0.83 mL, 10.6 mmol) to the mixture. Allow the mixture to
warm to room temperature and stir overnight. Dilute the mixture
with water (10 mL) and saturated aqueous NaHCO.sub.3 (10 mL).
Separate the layers, and extract the aqueous layer with DCM
(3.times.20 mL). Dry the combined organic extracts over
Na.sub.2SO.sub.4, filter and concentrate in vacuo. Purify by
chromatography on silica gel (80 g) eluting with hexane/EtOAc (1:0
to 1:1 gradient over 60 min, 80 mL/min) to obtain the desired
intermediate as a colorless oil (1.14 g, 46%). MS (APCI+) m/z: 257
(M+H).sup.+.
[0597]
3-(tert-Butoxycarbonylamino-methyl)-6-(piperidin-1-ylmethyl)-pyridi-
ne: Add 3-(tert-butoxycarbonylamino-methyl)-6-chloromethyl-pyridine
(500 mg, 1.95 mmol) to a solution of piperidine (0.58 mL, 5.84
mmol) and saturated aqueous NaHCO.sub.3 (2.5 mL) in acetonitrile
(15 mL). Stir the mixture at room temperature overnight. Dilute the
mixture with water (20 mL) and DCM (25 mL), separate the layers and
extract the aqueous layer with DCM (3.times.20 mL). Dry the
combined organic extracts over Na.sub.2SO.sub.4, filter and
concentrate in vacuo. Purify by chromatography on silica gel (80 g
pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:1
gradient over 60 min, 80 mL/min) to obtain the desired intermediate
as a colorless oil (547 mg, 92%). MS (APCI+) m/z: 306
(M+H).sup.+.
[0598] 5-Aminomethyl-2-(piperidin-1-ylmethyl)-pyridine: Dissolve
3-(tert-butoxycarbonylamino-methyl)-6-(piperidin-1-ylmethyl)-pyridine
(540 mg, 1.76 mmol) in methanol (10 mL) and cool to 0.degree. C.
Bubble hydrogen chloride through the vigorously stirred solution
for 30 min. Concentrate in vacuo. Partition the residue between 3N
aqueous NaOH (10 mL) and DCM (20 mL). Separate the two layers and
extract the aqueous layer with DCM (2.times.20 mL). Wash the
combined organic extracts with brine (20 mL). Dry over
Na.sub.2SO.sub.4, filter and concentrate in vacuo to obtain the
desired intermediate as a colorless oil (351 mg, 95%). MS (APCI+)
m/z: 206 (M+H).sup.+.
Preparation 56
4-(2,2-Dimethyl-propionylamino)-benzylamine
##STR00069##
[0600] 4-(2,2-Dimethyl-propionylamino)-benzonitrile: Add dropwise
trimethylacetyl chloride (3.3 mL, 27 mmol) to a mixture of
4-aminobenzonitrile (2.92 g, 24.7 mmol) and triethylamine (3.8 mL,
27 mmol) in anhydrous DCM (25 mL) at 0.degree. C. Stir the mixture
to room temperature overnight. Partition the reaction mixture
between DCM (500 mL) and water (250 mL) and extract the aqueous
phase with DCM (250 mL). Wash the combined organic extracts with
water (3.times.250 mL), dry over Na.sub.2SO.sub.4, filter and
concentrate in vacuo to obtain the desired intermediate (5 g,
100%). MS (ES+) m/z: 203.2 (M+H).sup.+.
[0601]
N-(tert-Butoxycarbonyl)-4-(2,2-dimethyl-propionylamino)-benzylamine
Add a solution of 4-(2,2-dimethyl-propionylamino)-benzonitrile (5
g, 24.7 mmol) in THF/iso-propanol (1:2, 60 mL) to 10% Pd/C (Degussa
type E101, 3 g, 1.41 mmol) via cannula under nitrogen. Add a
solution of di-tert-butyl-dicarbonate (6.74 g, 30.9 mmol) in THF
(19 mL) to the reaction mixture via cannula under nitrogen. Purge
the reaction mixture with nitrogen and then submit to hydrogenation
at 50 psi overnight. Filter the catalyst through Celite.RTM. and
wash thoroughly with iso-propanol (500 mL) and THF (500 mL).
Concentrate in vacuo to obtain a solid. Recrystallize from EtOAc,
cool to 0.degree. C., filter and wash with cold EtOAc to obtain the
desired intermediate as a white solid (5.748 g, 76%). MS (ES+) m/z:
307.3 (M+H).sup.+.
[0602] 4-(2,2-Dimethyl-propionylamino)-benzylamine: Add 4M hydrogen
chloride in dioxane (20 mL) to a solution of
N-(tert-butoxycarbonyl)-4-(2,2-dimethyl-propionylamino)-benzylamine
(2 g, 6.53 mmol) in anhydrous 1,4-dioxane (50 mL) at room
temperature. Stir overnight and partition the reaction mixture
between saturated aqueous NaHCO.sub.3 (200 mL) and DCM (500 mL).
Extract the aqueous phase with DCM/iso-propanol (85:15, 2.times.100
mL) and then with DCM/iso-propanol (3:1, 2.times.100 mL). Dry the
combined organic extracts over Na.sub.2SO.sub.4, filter and
concentrate in vacuo. Purify by SCX chromatography eluting with DCM
and DCM/2M ammonia in methanol (1:1) to obtain the title compound
as a waxy colorless oil (1.13 g, 84%). MS (ES-) m/z: 205.1
(M-H).sup.-.
Preparations 57-58
[0603] The compounds of Preparations 57-58 may be prepared
essentially as described in Preparation 56 using
4-aminobenzonitrile and the appropriate acid chloride. Overall
yields and MS (ES+) data are shown in the Table below. Step 1 of
Preparation 58 was purified by chromatography on silica gel eluting
with hexane/EtOAc (1:0 to 67:33 gradient over 71 min and 67:33 to
0:1 gradient over 71 min; 50 mL/min).
TABLE-US-00010 Yield MS (ES+) Prep. Structure Compound (%) m/z 57
##STR00070## 4-(Cyclopropane-carbonyl-amino)-benzylamine 39 191(M +
H).sup.+ 58 ##STR00071##
4-[(1-Methyl-cyclopropane-carbonyl)-amino]-benzylamine 34 205(M +
H).sup.+
Preparation 59
4-[(2,2,3,3-Tetramethyl-cyclopropanecarbonyl)-amino]-benzylamine
##STR00072##
[0605]
4-[(2,2,3,3-Tetramethyl-cyclopropanecarbonyl)-amino]-benzonitrile:
Add a solution of 2,2,3,3-tetramethyl-cyclopropane-carbonyl
chloride (5 g, 31.1 mmol) in anhydrous DCM to a mixture of
4-aminobenzonitrile (3.34 g, 28.3 mmol) and triethylamine (4.3 mL,
31 mmol) in anhydrous DCM (20 mL) at 0.degree. C. After stirring at
0.degree. C. for 20 min, warm the mixture to room temperature and
stir overnight. Partition the reaction mixture between DCM (500 mL)
and water (250 mL) and extract the aqueous phase with DCM (250 mL).
Wash combined organic extracts with water (3.times.250 mL), dry
over Na.sub.2SO.sub.4, filter and concentrate in vacuo. Purify the
crude mixture by chromatography on silica gel eluting with
hexane/EtOAc (1:0 over 36 min; 1:0 to 3:1 gradient over 36 min; 3:1
to 1:1 gradient over 71 min; 50 mL/min) to obtain the desired
intermediate as a solid (2.31 g, 34%). MS (ES+) m/z: 243.2
(M+H).sup.+.
[0606]
N-(tert-Butoxycarbonyl)-4-[(2,2,3,3-tetramethyl-cyclopropanecarbony-
l)-amino]-benzylamine: Add a solution of di-tert-butyl-dicarbonate
(1.8 g, 82.6 mmol) in methanol (7 mL) and nickel(II) chloride
hexahydrate (0.098 g, 0.41 mmol) to a cooled solution of
4-[(2,2,3,3-tetramethyl-cyclopropanecarbonyl)-amino]-benzonitrile
(1 g, 41.3 mmol) in methanol (30 mL) at 0.degree. C. Add sodium
borohydride (0.89 g, 23.5 mmol) in portions over 25 min under a
nitrogen atmosphere at a rate to keep gas evolution under control.
Stir the reaction mixture at 0.degree. C. for 6 h and then slowly
warm the reaction mixture in cooling bath until the reaction is
complete. Concentrate in vacuo and partition the residue between
EtOAc (250 mL) and saturated aqueous NaHCO.sub.3 (100 mL). Extract
the aqueous phase with EtOAc (3.times.50 mL). Dry the combined
organic extracts over Na.sub.2SO.sub.4, filter and concentrate in
vacuo. Slurry the residue in enough DCM and filter undissolved
solid product (0.58 g). Concentrate in vacuo and purify by
chromatography on silica gel eluting with hexane/EtOAc (1:0 to 3:1
gradient over 30 min; 3:1 over 3 min; 3:1 to 1:1 gradient over 30
min and 1:1 over 3 min; 35 mL/min) to obtain crude product.
Dissolve the undissolved solid filtered above (0.58 g) in EtOAc
(5.8 mL). Add hexane (11.6 mL) to precipitate out solid. Heat the
slurry to reflux until homogeneous and then cool to room
temperature and 0.degree. C. Filter and wash solid with cold hexane
(10 mL) and dry to obtain 0.173 g (12%) of the desired intermediate
as a white solid. Combine the filtrate with the crude product
isolated from the chromatography and concentrate in vacuo to obtain
1.766 g. Dissolve this material in EtOAc (12.6 mL) and add hexane
(25.2 mL) to precipitate out solid. Heat the slurry to reflux until
homogeneous and then cool to room temperature and store in freezer
overnight. Filter and wash solid with cold hexane (10 mL) and dry
to obtain the desired intermediate as a white solid (0.548 g, 50%
overall). MS (ES+) m/z: 347.3 (M+H).sup.+.
[0607]
4-[(2,2,3,3-Tetramethyl-cyclopropanecarbonyl)-amino]-benzylamine
Add 4M hydrogen chloride in dioxane (6.1 mL) to a solution of
N-(tert-butoxycarbonyl)-4-[(2,2,3,3-tetramethyl-cyclopropanecarbonyl)-ami-
no]-benzylamine (0.678 g, 1.958 mmol) in anhydrous 1,4-dioxane
(12.2 mL) at room temperature. After stirring at room temperature
for 3 h, the reaction is a solid mass. Add more 1,4-dioxane (12.2
mL), DCM (24.4 mL) and more 4M hydrogen chloride in dioxane (6.1
mL), and stir overnight. Concentrate in vacuo and partition the
residue between saturated aqueous NaHCO.sub.3 (200 mL) and DCM (500
mL). Dry the organic phase over Na.sub.2SO.sub.4, filter and
concentrate in vacuo. The aqueous phase was extracted with
DCM/iso-propanol (3:1, 4.times.200 mL). Dry the combined organic
extracts over Na.sub.2SO.sub.4, filter, combine with the organic
fraction isolated above and concentrate in vacuo. Purify by SCX
chromatography eluting with DCM and DCM/2M ammonia in methanol
(1:1) to obtain the title compound (0.519 g, 100%). MS (ES+) m/z:
247.2 (M+H).sup.+.
Preparation 60
(.+-.)-trans-4-[(2-Methyl-cyclopropanecarbonyl)-amino]-benzylamine
##STR00073##
[0609] (.+-.)-cis- and (.+-.)-trans-2-Methyl-cyclopropanecarbonyl
chloride: Add thionyl chloride (39.3 mL, 539 mmol) at room
temperature to a mixture of (.+-.)-cis- and
(.+-.)-trans-2-methyl-cyclopropanecarboxylic acid (5 g, 49.9 mmol).
Heat the reaction mixture at reflux overnight. Cool reaction
mixture to room temperature and remove thionyl chloride by
short-path distillation to afford a mixture of (.+-.)-cis- and
(.+-.)-trans-2-methyl-cyclopropanecarbonyl chloride (5.53 g, 93%)
as an amber oil. Trans/cis ratio is 16.7/1.0 by .sup.1H NMR.
[0610]
(.+-.)-trans-4-[(2-Methyl-cyclopropanecarbonyl)-amino]-benzonitrile-
: To a mixture of 4-aminobenzonitrile (4.53 g, 38.4 mmol) and
triethylamine (5.9 mL, 42 mmol) in anhydrous DCM (38.4 mL), add
dropwise at 0.degree. C. a solution of (.+-.)-cis- and
(.+-.)-trans-2-methyl-cyclopropanecarbonyl chloride (5 g, 42.2
mmol) in anhydrous DCM (9 mL). Stir at 0.degree. C. for 20 min,
warm the mixture to room temperature and stir overnight. Partition
the reaction mixture between DCM (500 mL) and water (250 mL) and
extract the aqueous layer with DCM (250 mL). Wash the combined
organic extracts with water (3.times.250 mL), dry over
Na.sub.2SO.sub.4, filter and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (1:0 to 3:1
over 71 min; 3:1 to 1:1 over 71 min; 50 mL/min) to afford
(.+-.)-trans-4-[(2-methyl-cyclopropanecarbonyl)-amino]-benzonitrile
as a solid (2.31 g, 30%) and a fraction containing a mixture of
both isomers.
[0611]
(.+-.)-trans-N-(tert-Butoxycarbonyl)-4-[(2-methyl-cyclopropanecarbo-
nyl)-amino]-benzylamine: Add a solution of
(.+-.)-trans-4-[(2-methyl-cyclopropanecarbonyl)-amino]-benzonitrile
(2.316 g, 11.6 mmol) in THF/iso-propanol (1.0:1.8, 28 mL) to 10%
Pd/C (Degussa type E101, 1.41 g, 0.66 mmol) via cannula under
nitrogen. Add a solution of di-tert-butyl dicarbonate (3.16 g, 14.5
mmol) in THF (8 mL) via cannula under N.sub.2. Purge the reaction
mixture with nitrogen and then with hydrogen. Stir under 50 psi of
hydrogen overnight. Filter the mixture over Celite.RTM., wash with
iso-propanol (100 mL) and THF (100 mL), and concentrate in vacuo to
give a solid. Recrystallize the crude mixture in EtOAc (89 mL) and
cool to 0.degree. C. Filter and wash the solid with cold hexane
(2.times.10 mL) to afford the desired intermediate as a white solid
(1.893 g, 54%). More material can be obtained by recrystallizing
again the compound remaining in filtrate.
[0612]
(.+-.)-trans-4-[(2-Methyl-cyclopropanecarbonyl)-amino]-benzylamine:
Add 4M hydrogen chloride in dioxane (17.7 mL) to a solution of
(.+-.)-trans-N-(tert-butoxycarbonyl)-4-[(2-methyl-cyclopropanecarbonyl)-a-
mino]-benzylamine (1.72 g, 5.65 mmol) in dioxane (35.4 mL). Stir at
room temperature overnight, add diethyl ether and concentrate in
vacuo several times. Partition the residue between saturated
aqueous NaHCO.sub.3 (200 mL) and DCM (500 mL). Extract the aqueous
phase with DCM/iso-propanol (3:1, 4.times.200 mL). Dry the combined
organic extracts over Na.sub.2SO.sub.4, filter and concentrate in
vacuo. Load the compound into a SCX column (10 g), wash the column
with DCM (100 mL), and then elute with 2M ammonia in methanol/DCM
(1:1, 100 mL) to afford the title compound (0.935 g, 81%) as a waxy
colorless oil.
Preparation 61
4-(N-Methyl-2,2-dimethyl-propionylamino)-benzylamine
##STR00074##
[0614] 4-(N-Methyl-2,2-dimethyl-propionylamino)-benzonitrile: Add
sodium hydride (0.21 g, 8.6 mmol, 95%) to a solution of
4-(2,2-dimethyl-propionylamino)-benzonitrile (1.589 g, 7.857 mmol)
in anhydrous DMF (16 mL) at 0.degree. C. under nitrogen. Add methyl
iodide (0.54 mL, 8.6 mmol) after bubbling ceased (.about.20 min).
Stir the mixture to room temperature overnight. Partition the
reaction mixture between DCM (250 mL) and water (100 mL). Wash the
organic phase with water (2.times.100 mL). Dry over
Na.sub.2SO.sub.4, filter and concentrate in vacuo. Purify the crude
mixture by chromatography on silica gel eluting with hexane/EtOAc
(1:0 to 1:1 gradient over 71 min; 50 mL/min) to obtain the desired
intermediate as a white solid (1.201 g, 71%).
[0615] 4-(N-Methyl-2,2-dimethyl-propionylamino)-benzylamine: Add a
solution of 4-(N-methyl-2,2-dimethyl-propionylamino)-benzonitrile
(55 mg, 0.25 mmol) in THF/iso-propanol (1:1, 8 mL) to 10% Pd/C
(Degussa type E101, 31 mg, 0.15 mmol) under nitrogen. Purge the
reaction mixture with nitrogen and then submit to hydrogenation at
50 psi for 1 h. Filter the catalyst through Celite.RTM. and wash
thoroughly with THF (100 mL) and iso-propanol (100 mL). Concentrate
in vacuo and purify the crude mixture by chromatography on silica
gel eluting with DCM/2M ammonia in methanol (1:0 to 9:1 gradient
over 30 min and 9:1 over 3 min; 35 mL/min) to obtain the title
compound as a colorless oil (41 mg, 73%). MS (ES+) m/z: 221.2
(M+H).sup.+.
Preparation 62
6-(4-Amino-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahy-
dro-1H-benzo[d]-azepine Hydrochloride
##STR00075##
[0617] 4-(tert-Butoxycarbonylamino)-benzonitrile: Add a solution of
di-tert-butyl-dicarbonate (9.23, 42.3 mmol) in anhydrous toluene
(2.3 mL) to 4-aminobenzonitrile (5 g, 42.3 mmol) in anhydrous
toluene (20 mL) and heat the mixture at 100.degree. C. for 3 days.
Concentrate in vacuo and purify the crude mixture by chromatography
on silica gel eluting with hexane/EtOAc (1:0 to 4:1 gradient over
71 min and 4:1 to 1:1 gradient over 71 min; 50 mL/min) to obtain
the desired intermediate as a white solid (5.43 g, 59%). MS (ES+)
m/z: 219.2 (M+H).sup.+.
[0618] 4-(tert-Butoxycarbonylamino)-benzylamine: Add a solution of
4-(tert-butoxycarbonylamino)-benzonitrile (1 g, 4.58 mmol) in
THF/iso-propanol (1:1, 142 mL) to 10% Pd/C (Degussa type E101, 0.56
g, 0.26 mmol) via syringe under N.sub.2. Purge the reaction mixture
with nitrogen and submit the mixture to hydrogenation at 50 psi
overnight. Filter the catalyst through Celite.RTM. and wash
thoroughly with iso-propanol (100 mL) and THF (100 mL). Concentrate
in vacuo and purify the crude mixture by chromatography on silica
gel eluting with DCM/2M ammonia in methanol (1:0 to 95:5 gradient
over 30 min; 95:5 over 3 min; 95:5 to 9:1 gradient over 30 min and
9:1 over 30 min) to obtain the desired intermediate (0.364 g, 36%).
MS (ES-) m/z: 220.1 (M-2H).sup.-.
[0619]
6-(4-tert-Butoxycarbonylamino-benzylamino)-7-chloro-3-(2,2,2-triflu-
oroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine: Use a method
similar to the General Procedure 1-3 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (0.32 g, 0.76 mmol) with a solution
of 4-(tert-butoxycarbonylamino)-benzylamine (0.338 g, 1.524 mmol)
in anhydrous toluene/dioxane (4:1, 10 mL). Purify the crude mixture
by chromatography on silica gel eluting with hexane/EtOAc (1:0 to
3:1 gradient over 30 min; 3:1 over 3 min; 3:1 to 1:1 gradient over
30 min and 1:1 over 3 min; 35 mL/min) to obtain the desired
intermediate as a yellow oil 5 (0.338 g, 89%). MS (ES+) m/z: 498.2
(M+H).sup.+.
[0620]
6-(4-Amino-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5--
tetrahydro-1H-benzo[d]-azepine Hydrochloride: Add 4M hydrogen
chloride in dioxane (20 mL, 20 mmol) to a solution of
6-(4-tert-butoxycarbonylamino-benzylamino)-7-chloro-3-(2,2,2-trifluoroace-
tyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine (0.219, 0.44 mmol) in
1,4-dioxane/DCM (1:1, 40 mL). Stir overnight at room temperature,
add diethyl ether and concentrate in vacuo to obtain the title
compound (0.219 g, 100%) that was dried in vacuo.
Preparation 63
4-[(2,2-Dimethyl-propionylamino)-methyl]-benzylamine
##STR00076##
[0622] 4-[(2,2-Dimethyl-propionylamino)-methyl]-benzonitrile: Add
triethylamine (0.3 mL, 2.12 mmol) to a solution of
4-cyano-benzylamine (1.0 g, 7.58 mmol) in DCM (11 mL) and cool the
mixture at 0.degree. C. Add 2,2-dimethyl-propionyl chloride (0.93
mL, 7.58 mmol) dropwise and allow to stir the mixture at 0.degree.
C. for 15 min and at room temperature for 2 h. Add water, separate
the organic phase and extract the aqueous phase twice with DCM. Dry
the combined organic extracts over Na.sub.2SO.sub.4, filter and
concentrate in vacuo to obtain the desired intermediate (1.23 g,
75%).
[0623] 4-[(2,2-Dimethyl-propionylamino)-methyl]-benzylamine: Bubble
nitrogen for 15 min into a solution of
4-[(2,2-dimethyl-propionylamino)-methyl]-benzonitrile (0.4 g, 1.85
mmol) in methanol (50 mL) with concentrated HCl (8 drops). Add 10%
Pd/C (Degussa type E101, 40 mg) and submit the mixture to
hydrogenation at atmospheric pressure overnight. Filter the
catalyst through Celite.RTM. and concentrate in vacuo to obtain the
hydrochloride salt of the title compound. Add saturated aqueous
NaHCO.sub.3 and extract twice with EtOAc. Dry the combined organic
extracts over MgSO.sub.4, filter and concentrate in vacuo to obtain
the title compound as a yellow oil (315 mg, 77%). MS (ES+) m/z: 221
(M+H).sup.+.
Preparation 64
4-[(Cyclopropanecarbonyl-amino)-methyl]-benzylamine
##STR00077##
[0625]
N-(tert-Butoxycarbonyl)-4-[(cyclopropanecarbonyl-amino)-methyl]-ben-
zylamine: Add cyclopropane carbonyl chloride (0.3 mL, 3.3 mmol) to
a stirred solution of ethyldiisopropylamine (1.35 mL, 7.73 mmol)
and 4-(tert-butoxycarbonyl-aminomethyl)-benzylamine (0.6 g, 2.54
mmol) in DCM (12 mL). Stir the mixture for 1 h at room temperature.
Partition the mixture between DCM and water. Extract the aqueous
phase twice with DCM. Dry the combined organic extracts over
MgSO.sub.4, filter and concentrate in vacuo. Purify by
chromatography on silica gel (120 g) eluting with
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) (1:0 over
5 min, 19:1 over 5 min, 9:1 over 5 min, 85:15; 50 mL/min) to obtain
the desired intermediate (529 mg, 68%). MS (APCI+) m/z: 249
[M-(t-Bu)+H].sup.+.
[0626] 4-[(Cyclopronanecarbonyl-amino)-methyl]-benzylamine:
Dissolve
N-(tert-butoxycarbonyl)-4-[(cyclopropanecarbonyl-amino)-methyl]-benzylami-
ne (529 mg, 1.74 mmol) in EtOAc (20 mL) and MeOH (15 mL). Bubble
hydrogen chloride through the solution for 15 min, and stir the
mixture overnight at room temperature. Concentrate the mixture in
vacuo and dissolve the resulting solid in water. Adjust the pH to
9-11 with 20% aqueous K.sub.2CO.sub.3 (w/w %) and extract three
times with chloroform/iso-propanol (3:1). Dry the combined organic
extracts over MgSO.sub.4, filter and concentrate in vacuo. Purify
the crude mixture by chromatography on silica gel (40 g, pre-packed
cartridge) eluting with DCM/(chloroform:methanol:concentrated
NH.sub.4OH 80:18:2) (1:0 over 5 min, 19:1 over 5 min, 9:1 over 5
min, 4:1 over 5 min, 1:1 over 10 min, 1:3; 50 mL/min) to obtain the
desired intermediate (275 mg, 77%). MS (APCI+) m/z: 188
(M-NH.sub.3+H).sup.+.
Preparation 65
4-[2-(2,2-Dimethyl-propionylamino)-ethyl]-benzylamine
##STR00078##
[0628] 4-[2-(2,2-Dimethyl-propionylamino)-ethyl]-benzonitrile:
Dissolve 4-(2-amino-ethyl)-benzonitrile hydrochloride (300 mg, 1.65
mmol) into saturated aqueous NaHCO.sub.3 and extract twice with
EtOAc. Dry the combined organic extracts over Na.sub.2SO.sub.4 and
concentrate in vacuo to obtain 4-(2-amino-ethyl)-benzonitrile (205
mg, 85%). Dissolve 4-(2-amino-ethyl)-benzonitrile (200 mg, 1.37
mmol) in DCM (2 mL), add triethylamine (54 .mu.L, 0.38 mmol) and
cool the mixture at 0.degree. C. Add 2,2-dimethyl-propionyl
chloride (169 .mu.L, 1.37 mmol) dropwise and allow to stir the
mixture at 0.degree. C. for 15 min and at room temperature for 2 h.
Add water, separate the organic phase and extract the aqueous phase
twice with DCM. Dry the combined organic extracts over
Na.sub.2SO.sub.4, filter and concentrate in vacuo to obtain the
desired intermediate (182 mg, 58%).
[0629] 4-[2-(2,2-Dimethyl-propionylamino)-ethyl]-benzylamine:
Bubble nitrogen for 15 min into a solution of
4-[2-(2,2-dimethyl-propionylamino)-ethyl]-benzonitrile (175 mg,
0.76 mmol) in methanol (31 mL) with concentrated HCl (3 drops). Add
10% Pd/C (Degussa type E101, 18 mg) and submit the mixture to
hydrogenation at atmospheric pressure for 64h. Filter the catalyst
through Celite(and concentrate in vacuo to obtain the hydrochloride
salt of the title compound. Add saturated aqueous NaHCO.sub.3 and
extract twice with EtOAc. Dry the combined organic extracts over
MgSO.sub.4, filter and concentrate in vacuo to obtain the title
compound as a yellow oil (110 mg, 62%). MS (ES+) m/z: 235
(M+H).sup.+.
Preparation 66
4-(iso-Propylcarbamoyl-methyl)-benzylamine
##STR00079##
[0631] [4-(tert-Butoxycarbonylaminomethyl)-phenyl]-acetic acid: Add
NaOH (0.992 g, 24.8 mmol) and di-tert-butyl-dicarbonate (5.4 g,
24.8 mmol) to a solution of (4-aminomethyl-phenyl)-acetic acid
hydrochloride (5.0 g, 24.8 mmol) in dioxane/water (1:1, 40 mL) and
stir for 24 h. Remove dioxane in vacuo and acidify the aqueous
phase with 10% aqueous citric acid. Extract twice with EtOAc, dry
the combined organic extracts over Na.sub.2SO.sub.4, filter and
concentrate in vacuo to obtain a solid. Wash the solid with hexane,
filter and dry to obtain the desired intermediate (3.3 g, 50%).
[0632]
N-(tert-Butoxycarbonyl)-4-(iso-propylcarbamoyl-methyl)-benzylamine:
Combine [4-(tert-butoxycarbonylaminomethyl)-phenyl]-acetic acid
(400 mg, 1.5 mmol), isopropylamine (0.14 mL, 1.65 mmol), EDC (345
mg, 1.8 mmol), HOBt (243 mg, 1.8 mmol), triethylamine (0.63 mL, 4.5
mmol) and DMAP (18.3 mg, 0.15 mmol) in anhydrous DCM (15 mL). Stir
at room temperature for 1 day under nitrogen. Concentrate in vacuo
and purify the crude mixture by chromatography on silica gel
eluting with hexane/EtOAc (1:1) to obtain the desired intermediate
as a white solid (426 mg, 92%). MS (ES+) m/z: 324
(M+NH.sub.4.sup.+).sup.+.
[0633] 4-(iso-Propylcarbamoyl-methyl)-benzylamine: Dissolve
N-(tert-butoxycarbonyl)-4-(iso-propylcarbamoyl-methyl)-benzylamine
(426 mg, 1.4 mmol) in DCM (5 mL). Add 4M hydrogen chloride in
dioxane (3.5 mL, 14 mmol) and stir at room temperature for 1 h.
Concentrate in vacuo and elute the compound through a SCX column to
obtain the title compound as a white solid (281 mg, 98%). MS (ES+)
m/z: 207 (M+H).sup.+.
Preparation 67
[0634] The compound of Preparation 67 may be prepared essentially
as described in Preparation 66 by using
[4-(tert-butoxycarbonylaminomethyl)-phenyl]-acetic acid and
2,2-dimethyl-propylamine. Overall yield and MS (ES) data are shown
in the Table below.
TABLE-US-00011 Yield MS (ES) Prep. Structure Compound (%) m/z 67
##STR00080## 4-[(2,2-Dimethyl-propylcarbamoyl)-methyl]-benzylamine
83 235(M + H).sup.+
Preparation 68
4-(2-Oxo-2-pyrrolidin-1-yl-ethyl)-benzylamine
##STR00081##
[0636]
N-(tert-Butoxycarbonyl)-4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-benzylami-
ne: Combine 4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-benzonitrile (200 mg,
0.93 mmol), di-tert-butyl-dicarbonate (244 mg, 1.1 mmol) and 10%
Pd/C (Degussa type E101, 100 mg) in methanol (18 mL). Submit the
mixture to hydrogenation at atmospheric pressure for 40 h. Filter
the catalyst through Celite.RTM. and concentrate the filtrate in
vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (1:1) to obtain the desired intermediate as a white
solid (267 mg, 90%).
[0637] 4-(2-Oxo-2-pyrrolidin-1-yl-ethyl)-benzylamine: Dissolve
N-(tert-butoxycarbonyl)-4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-benzylamine
(267 mg, 0.8 mmol) in DCM (4 mL). Add 4M hydrogen chloride in
dioxane (2 mL, 8 mmol) and stir at room temperature for 1 h.
Concentrate in vacuo and elute the compound through a SCX column to
obtain the title compound (179 mg, 98%). MS (ES+) m/z: 219
(M+H).sup.+.
Preparation 69
(R)-4-[(1-Methyl-2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzylamine
##STR00082##
[0639]
(R)--N-(tert-Butoxycarbonyl)-4-[(1-methyl-2,2,2-trifluoro-ethylcarb-
amoyl)-methyl]-benzylamine: Dissolve
[4-(tert-butoxycarbonylamino-methyl)-phenyl]-acetic acid (190 mg,
0.63 mmol) in DCM (12.4 mL) and add triethylamine (354 .mu.L, 2.5
mmol), DMAP (8 mg, 0.063 mmol), EDC (145 mg, 0.756 mmol), HOBt (102
mg, 0.756 mmol) and (R)-1-methyl-2,2,2-trifluoro-ethylamine
hydrochloride (71 mg, 0.63 mmol) under nitrogen atmosphere. Stir
the reaction overnight at room temperature. Concentrate in vacuo
and purify by chromatography on silica gel eluting with
hexane/EtOAc (1:1 and 0:1) to obtain the desired intermediate (155
mg, 68%).
[0640]
(R)-4-[(1-Methyl-2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzylamin-
e: Dissolve
(R)--N-(tert-butoxycarbonyl)-4-[(1-methyl-2,2,2-trifluoro-ethylcarbamoyl)-
-methyl]-benzylamine (155 mg, 0.43 mmol) in DCM (8 mL). Add 4M
hydrogen chloride in dioxane (0.85 mL) and stir at room temperature
overnight. Concentrate in vacuo and partition the hydrochloride
salt between saturated aqueous NaHCO.sub.3 and EtOAc. Extract the
aqueous phase twice with EtOAc. Dry the combined organic extracts
over Na.sub.2SO.sub.4, filter and concentrate in vacuo to obtain
the title compound (105 mg, 91%). MS (ES+) m/z: 261
(M+H).sup.+.
Preparation 70
(.+-.)-4-[1-(2,2-Dimethylpropyl-carbamoyl)-ethyl]-benzylamine
##STR00083##
[0642]
(.+-.)-4-[1-(2,2-Dimethylpropyl-carbamoyl)-ethyl]-benzonitrile Add
AlMe.sub.3 (1.72 mL, 3.44 mmol, 2M solution in hexane) to a
solution of 2,2-dimethyl-propylamine (402 .mu.L, 3.44 mmol) in DCM
(0.5 mL) under nitrogen atmosphere. Stir the mixture for 15 min at
room temperature and add ethyl 2-(4-cyanophenyl)propanoate. Heat
the mixture at 40.degree. C. overnight. Quench the reaction with
10N aqueous HCl and extract twice with DCM. Dry the combined
organics extracts over Na.sub.2SO.sub.4, filter and concentrate in
vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (7:3) to obtain the desired intermediate (170 mg,
41%).
[0643]
(.+-.)-4-[1-(2,2-Dimethylpropyl-carbamoyl)-ethyl]-benzylamine:
Bubble nitrogen into a solution of
(.+-.)-4-[1-(2,2-dimethylpropyl-carbamoyl)-ethyl]-benzonitrile (80
mg, 0.33 mmol) in methanol (9 mL) with 2 drops of concentrated HCl
for 10 min. Add 10% Pd/C (Degussa type E101, 8 mg) and submit the
mixture to hydrogenation at atmospheric pressure overnight. Filter
the catalyst over Celite.RTM. and concentrate the filtrate in
vacuo. Partition the solid between saturated aqueous NaHCO.sub.3
and EtOAc, and extract again with EtOAc. Dry the combined organics
extracts over MgSO.sub.4, filter and concentrate in vacuo to afford
the title compound as a yellow oil (69 mg, 85%). MS (ES+) m/z: 249
(M+H).sup.+.
Preparation 71
[0644] The compound of Preparation 71 may be prepared essentially
as described in Preparation 70 using methyl (4-cyanophenyl)acetate
and cyclohexylmethyl amine. Overall yield and MS (ES+) data are
shown in the Table below.
TABLE-US-00012 Yield MS (ES) Prep. Structure Compound (%) m/z 71
##STR00084## 4-[(Cyclohexylmethyl-carbamoyl)-methyl]-benzylamine 48
261(M + H).sup.+
Preparation 72
4-[(3,3-Dimethylbutyl-carbamoyl)-methyl]-benzylamine
##STR00085##
[0646] 4-[(3,3-Dimethylbutyl-carbamoyl)-methyl]-benzonitrile:
Dissolve 3,3-dimethylbutylamine (0.8 mL, 6.4 mmol) in anhydrous THF
(2 mL) under nitrogen. Cool the solution at 0.degree. C. and add
DIBAL-H (6.2 mL, 6.2 mmol, 1M solution in toluene). Allow the
mixture to warm up to room temperature and stir for 2 h. Add this
complex to a solution of methyl (4-cyanophenyl)acetate (192 mg, 1.1
mmol) in THF (4 mL) and stir at room temperature overnight. Dilute
with EtOAc and quench with 5% KHSO.sub.4. Dry the organic phase
over MgSO.sub.4, filter and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (7:3) to
obtain the desired intermediate (160 mg, 60%). MS (ES+) m/z: 245
(M+H).sup.+.
[0647] 4-[(3,3-Dimethylbutyl-carbamoyl)-methyl]-benzylamine: Bubble
nitrogen into a solution of
4-[(3,3-dimethylbutyl-carbamoyl)-methyl]-benzonitrile (240 mg, 0.9
mmol) in methanol (20 mL) with 3 drops of concentrated HCl for 10
min. Add 10% Pd/C (Degussa type E101, 48 mg) and submit the mixture
to hydrogenation at atmospheric pressure overnight. Filter the
catalyst over Celite.RTM. and concentrate the filtrate in vacuo.
Elute the compound through a SCX column to obtain the title
compound (240 mg, 98%). MS (ES+) m/z: 249 (M+H).sup.+.
Preparation 73
4-[2-(tert-Butylcarbamoyl)-ethyl]-benzylamine
##STR00086##
[0649] 4-[2-(tert-Butylcarbamoyl)-ethyl]-benzonitrile: Dissolve
3-(4-cyanophenyl)-propionic acid (0.4 g, 2.48 mmol) and thionyl
chloride (1.1 mL, 14.9 mmol) in toluene (2 mL) and reflux the
mixture for 2 h. Concentrate in vacuo, dissolve the residue in DCM
(1.5 mL) and add the solution to a cold solution (0.degree. C.) of
tert-butylamine (300 .mu.L, 2.85 mmol) in DCM (1.5 mL) and
triethylamine (97 .mu.L, 0.69 mmol). Allow the mixture to stir at
0.degree. C. for 15 min and at room temperature for 16 h. Add
water, separate the organic phase and extract the aqueous phase
twice with DCM. Dry the combined organic extracts over
Na.sub.2SO.sub.4, filter and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (65:35) to
obtain the desired intermediate (306 mg, 54%).
[0650] 4-[2-(tert-Butylcarbamoyl)-ethyl]-benzylamine: Add 10% Pd/C
(Degussa type E101, 62 mg) to a solution of ethanol/water/acetic
acid (10:5.6:0.6 mL). Add a solution of
4-[2-(tert-butylcarbamoyl)-ethyl]-benzonitrile (306 mg, 1.33 mmol)
in ethanol (3.5 mL) and submit the mixture to hydrogenation at 60
psi overnight. Filter the catalyst through Celite.RTM. and
concentrate in vacuo to obtain the acetate salt of the title
compound. Wash with diethyl ether and filter the solid in vacuo.
Add saturated aqueous NaHCO.sub.3 and extract twice with EtOAc. Dry
the combined organic extracts over MgSO.sub.4, filter and
concentrate in vacuo to obtain the title compound as a yellow oil
(70 mg, 26%). MS (ES+) m/z: 235 (M+H).sup.+.
Preparation 74
4-[2-(2,2-Dimethylpropyl-carbamoyl)-ethyl]-benzylamine
##STR00087##
[0652] 4-[2-(2,2-Dimethylpropyl-carbamoyl)-ethyl]-benzonitrile:
Combine 3-(4-cyanophenyl)-propionic acid (870 mg, 4.9 mmol),
2,2-dimethylpropylamine (0.6 mL, 5.4 mmol), EDCI (1.0 g, 5.4 mmol),
HOBT (804 mg, 5.9 mmol), triethylamine (2 mL, 14.8 mmol) and DMAP
(60.5 mg, 0.5 mmol) in anhydrous DCM (50 mL). Stir at room
temperature for 1 day under nitrogen. Concentrate the mixture in
vacuo and purify by chromatography on silica gel eluting with
hexane/EtOAc (1:1) to obtain the desired intermediate as a white
solid (740 mg, 61%). MS (ES+) m/z: 245 (M+H).sup.+.
[0653] 4-[2-(2,2-Dimethylpropyl-carbamoyl)-ethyl]-benzylamine:
Bubble nitrogen into a solution of
4-[2-(2,2-dimethylpropyl-carbamoyl)-ethyl]-benzonitrile (740 mg,
3.0 mmol) in methanol (60 mL) with 3 drops of concentrated HCl for
10 min. Add 10% Pd/C (Degussa type E101, 148 mg) and submit the
mixture to hydrogenation at atmospheric pressure overnight. Filter
the catalyst over Celite.RTM. and concentrate the filtrate in
vacuo. Elute the compound through a SCX column to obtain the title
compound (717 mg, 95%). MS (ES+) m/z: 249 (M+H).sup.+.
Preparation 75
4-Cyclohexanesulfonyl-benzylamine
##STR00088##
[0655] 4-Cyclohexylthio-benzonitrile: Dissolve sodium metal (343
mg, 14.9 mmoles) in anhydrous ethanol (20 mL) at room temperature
under nitrogen atmosphere. Then add cyclohexyl mercaptan (2 mL,
16.37 mmoles) and stir at room temperature for 30 min. Add then
neat 4-fluoro-benzonitrile (1.8 g, 14.9 mmol) and heat the
resulting solution at 80.degree. C. overnight. Cool the reaction to
room temperature and quench the reaction by adding 1N aqueous HCl
(100 mL). Concentrate the mixture in vacuo and take up the residue
with EtOAc (100 mL). Wash the organic layer with saturated aqueous
NaHCO.sub.3 (100 mL) and brine (100 mL). Dry the organic phase over
MgSO.sub.4 and concentrate in vacuo. Purify the crude mixture by
chromatography on silica gel (120 g, pre-packed cartridge) eluting
with cyclohexane/EtOAc (98:2 to 80:20 gradient) to afford the
desired intermediate (2.2 g, 68%). GC-MS 7m/z: 217 (M.sup.+).
[0656] 4-Cyclohexanesulfonyl-benzonitrile: Dissolve
4-cyclohexylthio-benzonitrile (1.17 g, 5.4 mmol) in acetone (10 mL)
and add water until the sulfide starts to come out of solution.
Then add a drop of acetone to rehomogenize the solution. Cool the
mixture to 0.degree. C. and then add oxone (4.2 g, 6.73 mmol) in
one portion while stirring vigourously at 0.degree. C. for 5 h.
Concentrate in vacuo, take Up the residue in DCM and filter the
suspension through a frit. Concentrate in vacuo to obtain the
desired intermediate (1.27 g, 94%) as a white solid.
[0657] 4-Cyclohexanesulfonyl-benzylamine: Dissolve
4-cyclohexanesulfonyl-benzonitrile (1.27 g, 5.1 mmol) in anhydrous
THF (15 mL) at 0.degree. C. under nitrogen and then add a solution
of borane-THF complex (15.3 mL, 15.3 mL, 1M solution in THF). Stir
overnight while warming to room temperature. Add the reaction to a
mixture of 5N aqueous HCl (50 mL), THF (50 mL) and ice and stir for
1 hour. Concentrate the mixture in vacuo and take up the resulting
white residue through a SCX-2 column eluting with methanol followed
by 3N ammonia in methanol to obtain the title compound as a white
solid (625 mg, 50%). MS (ES+) m/z: 254.1 (M+H).sup.+
Preparation 76
3-Aminomethyl-6-[(2-methyl-2-propane)sulfonylmethyl]-pyridine
##STR00089##
[0659]
1-Hydroxy-6-[(2-methyl-2-propane)sulfonylmethyl]-pyridine-3-carboni-
trile: To a solution of
6-(tert-butylthio)methyl-pyridine-3-carbonitrile (2.5 g, 12.13
mmol) in TFA (17 mL) at 0.degree. C. add dropwise a solution of
hydrogen peroxide in water (16.8 mL, 30% sol.) and warm the
reaction to room temperature overnight. Concentrate in vacuo and
take-up the resulting crude into saturated aqueous NaHCO.sub.3 (50
mL). Extract the aqueous layer several times with EtOAc (100 mL
each). Dry the combined organic extracts over MgSO.sub.4, filter
and concentrate in vacuo to obtain the desired intermediate as a
white solid (2.8 g, 100%). MS (ES+) m/z: 255 (M+H).sup.+, 277
(M+Na).sup.+.
[0660]
3-Aminomethyl-6-[(2-methyl-2-propane)sulfonylmethyl]-pyridine: Add
a solution of
1-hydroxy-6-[(2-methyl-2-propane)sulfonylmethyl]-pyridine-3-carbonitrile
(150 mg, 0.59 mmol) in ethanol (12 mL) to an aqueous slurry of
Raney Ni (50%, 1 g). Submit the suspension to hydrogenation at 60
psi for 10 h and then filtrate the mixture through Celite.RTM. to
provide an inseparable mixture of the title compound and the
corresponding N-oxide. Take this mixture up in DCM (5 mL), add
di-tert-butyl-dicarbonate (196 mg, 0.9 mmol) and stir overnight at
room temperature. Concentrate in vacuo and purify by chromatography
on silica gel eluting with DCM/EtOAc (7:3 to 0:1 gradient) to
obtain
3-(tert-butoxycarbonylamino-methyl)-6-[(2-methyl-2-propane)sulfonylmethyl-
]-pyridine as a white solid (93 mg). Dilute this material in DCM (5
mL), add trifluoroacetic acid at room temperature and stir for 30
min. Concentrate in vacuo, take the residue up in methanol and
filter through a SCX-2 column eluting with methanol followed by 3N
ammonia in methanol to obtain the title compound as a colourless
oil (66 mg, 46%). MS (ES+) m/z: 243 (M+H).sup.+.
Preparation 77
3-Aminomethyl-6-[(2,2-dimethylpropane)sulfonylmethyl]-pyridine
##STR00090##
[0662] 2,2-Dimethyl-propane-1-thiol: Add sulfur (3.05 g, 95 mmol)
and ether (60 mL) to 2,2-dimethylpropylmagnesium chloride (95 mL,
95 mmol, 1M solution in diethyl ether) under nitrogen at 0.degree.
C. Warm the mixture to room temperature and stir for 2 h. Cool to
0.degree. C. and add 1N aqueous HCl (120 mL). Extract into diethyl
ether (.about.100 mL) by continuous extraction. Distill diethyl
ether through a 22 cm long Vigreux column by heating with an oil
bath (50-120.degree. C.) under nitrogen. Cool and remove the
Vigreux column and install a short path distillation head. Distill
the product (60-100.degree. C.) with the oil bath at -140.degree.
C. to obtain the desired intermediate (8.5 g, 86%).
[0663]
3-(tert-Butoxycarbonylamino-methyl)-6-[(2,2-dimethylpropyl)thiometh-
yl]-pyridine: Under a nitrogen atmosphere, add sodium methoxide
(630 mg, 3.51 mmol, 30% w/w in methanol) to a stirring mixture of
2,2-dimethyl-propane-1-thiol (365 mg, 3.51 mmol) and methanol (10
mL) at room temperature and stir for 30 min. Add
3-(tert-butoxycarbonylamino-methyl)-6-chloromethyl-pyridine (450
mg, 1.76 mmol) in methanol (5 mL) and stir the mixture for 2 h.
Dilute the mixture with water and ethyl acetate. Separate the
layers and extract the aqueous layer with ethyl acetate. Wash the
combined organic extracts with water and brine. Dry the organic
phase over Na.sub.2SO.sub.4, filter, and concentrate in vacuo to
obtain the desired intermediate suitable for use without additional
purification. MS (APCI+) m/z: 325 (M+H).sup.+.
[0664]
3-(tert-Butoxycarbonylamino-methyl)-6-[(2,2-dimethyl-propane)-sulfo-
nylmethyl]-pyridine: Add m-CPBA (977 mg, 4.36 mmol, 70-77% pure) to
a solution of
3-(tert-butoxycarbonylamino-methyl)-6-[(2,2-dimethylpropyl)thiomethyl]-py-
ridine (700 mg, 2.16 mmol) in DCM (20 mL) at 0.degree. C. Warm the
mixture to room temperature and stir overnight. Dilute the mixture
with 10% aqueous K.sub.2CO.sub.3 (30 mL) and DCM. Separate the
layers and extract the aqueous phase with DCM. Wash the combined
organic extracts with water and brine. Dry the organic phase over
Na.sub.2SO.sub.4, filter and concentrate in vacuo. Purify the
residue by chromatography on silica gel (45 g, pre-packed
cartridge) eluting with hexane/EtOAc (1:0 to 1:1 gradient) to
obtain the desired intermediate (480 mg, 62%). MS (APCI+) m/z: 357
(M+H).sup.+.
[0665]
3-Aminomethyl-6-[(2,2-dimethyl-propane)sulfonylmethyl]-pyridine:
Bubble hydrogen chloride into a mixture of
3-(tert-butoxycarbonylamino-methyl)-6-[(2,2-dimethyl-propane)sulfonylmeth-
yl]-pyridine (480 mg, 1.35 mmol), methanol (10 mL) and EtOAc (10
mL) at room temperature until saturated. After stirring for 1 h,
concentrate the mixture in vacuo. Purify by chromatography on
silica gel (25 g, pre-packed cartridge) eluting with
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) (1:0 to
1:1 gradient) to obtain the title compound (325 mg, 94%). MS
(APCI+) mm/z: 257 (M+H).sup.+.
Preparation 78
[0666] The compound of Preparation 78 may be prepared essentially
as described in Preparation 77 by using
3-(tert-butoxycarbonylamino-methyl)-6-chloromethyl-pyridine and
cyclohexanethiol. Overall yield and MS (ES) data are shown in the
Table below.
TABLE-US-00013 Yield MS (ES) Prep. Structure Compound (%) m/z 78
##STR00091## 3-Aminomethyl-6-(cyclohexanesulfonyl)methyl-pyridine
43 269(M + H).sup.+
Preparation 79
4-(2,2-Dimethylpropane-sulfonylmethyl)-benzylamine
##STR00092##
[0668] 4-(2,2-Dimethylpropane-thiomethyl)-benzonitrile: Add sodium
hydride (317 mg, 7.92 mmol, 60% dispersion in mineral oil) to a
solution of 2,2-dimethyl-propane-1-thiol (635 mg, 6.09 mmol) in
anhydrous DMF (50 mL) under nitrogen at 0.degree. C. Stir the
mixture for 15 min, add 4-(bromomethyl)-benzonitrile (597 mg, 3.04
mmol) and stir the resulting mixture overnight at room temperature.
Add water and extract the aqueous phase twice with EtOAc. Wash the
combined organic extracts twice with water, dry over
Mg.sub.2SO.sub.4, filter, and concentrate in vacuo to obtain the
desired compound (867 mg, 100%) suitable for use without further
purification. MS (ES+) m/z: 220 (M+H).sup.+.
[0669] 4-(2,2-Dimethylpropane-sulfonylmethyl)-benzonitrile:
Dissolve 4-(2,2-dimethylpropane-thiomethyl)-benzonitrile (867 mg,
3.95 mmol) in DCM (20 mL). Cool the mixture to 0.degree. C., and
add m-CPBA (1.95 g, 8.69 mmol, 70-77% pure) slowly. Allow the
mixture to warm to room temperature and stir overnight. Dilute the
mixture with DCM and wash with saturated aqueous Na.sub.2SO.sub.3
followed by saturated aqueous NaHCO.sub.3 (2.times.). Dry over
MgSO.sub.4, filter, and concentrate in vacuo to obtain the desired
compound (966 mg, 97%) suitable for use without further
purification. MS (APCI+) m/z: 252 (M+H).sup.+.
[0670] 4-(2,2-Dimethylpropane-sulfonylmethyl)-benzylamine: Add
cobalt(II) chloride hexahydrate (1.83 mg, 7.7 mmol) to a solution
of 4-(2,2-dimethylpropane-sulfonylmethyl)-benzonitrile (966 mg,
3.85 mmol) in methanol (25 mL). Cool the mixture to 0.degree. C.
and stir for 15 min. Carefully add sodium borohydride (1.46 g,
38.49 mmol) in small batches, allow the mixture to warm to room
temperature and stir for 2 h. Dilute the mixture with water and
partition between water and chloroform. Extract the aqueous phase
three times with chloroform/iso-propanol (3:1). Dry the combined
organic extracts over MgSO.sub.4, filter and concentrate in vacuo.
Purify by chromatography on silica gel (80 g) eluting with
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) (1:0 over
5 min, 19:1 over 5 min, 9:1 over 35 min, 85:15; 50 mL/min) to give
the title compound (181 mg, 49%). MS (APCI+) m/z: 256
(M+H).sup.+.
Preparation 80
3-(tert-Butoxycarbonyl)-7-chloro-6-(4-dimethylcarbamoylthio-benzylamino)-2-
,3,4,5-tetrahydro-1H-benzo[d]azepine
##STR00093##
[0672] 4-Dimethylthiocarbamoyloxy-benzonitrile: Add sodium hydride
(1.21 g, 95%) to a solution of 4-cyanophenol (5.71 g, 47.98 mmol)
in anhydrous THF (70 mL) and stir the mixture for 5 min. Add
dimethylthiocarbamoyl chloride (5.93 g, 47.98 mmol) and heat the
mixture at reflux for 3 h. Cool the mixture to room temperature and
add water. Extract the aqueous phase with EtOAc, dry the organic
phase over MgSO.sub.4, filter and concentrate in vacuo to obtain a
solid. Wash the solid with diethyl ether, filter and dry in vacuo
to obtain the desired intermediate as a solid (4.41 g, 75%).
[0673] 4-Dimethylcarbamoylthio-benzonitrile: Place
4-dimethylthiocarbamoyloxy-benzonitrile (8.3 g, 40.29 mmol) into a
sealed tube equipped with a magnetic stirrer. Immerse the tube in a
preheated oil bath at 210.degree. C. and stir at this temperature
for 2 h. Cool to room temperature, dissolve the content in DCM and
transfer the solution to a round bottom flask. Concentrate in vacuo
to obtain a solid. Wash the solid with hexane and then with cold
diethyl ether. Filter and dry in vacuo to obtain the desired
intermediate as a beige solid (7.5 g, 90%).
[0674] 4-Dimethylcarbamoylthio-benzylamine: Dissolve
4-dimethylcarbamoylthio-benzonitrile (3.07 g, 14.9 mmol) in
anhydrous THF (30 mL). Add borane-dimethylsulfide complex (4.24 mL,
44.7 mmol, 1M solution in diethyl ether) and stir the mixture at
room temperature for 3 h. Add methanol dropwise until hydrogen
evolution ceases. Concentrate the mixture in vacuo and purify the
crude mixture by SCX chromatography eluting with methanol and 2M
ammonia in methanol to obtain the title compound as a slightly
impure oil (2.9 g). Dissolve the oil (2.9 g) in DCM and add 2M
hydrogen chloride in ether. Stir the mixture for 1 h and
concentrate in vacuo to obtain a solid. Suspend the solid in DCM
and add diethyl ether to precipitate the salt. Filter and dry the
solid in vacuo to obtain the hydrochloride salt of the title
compound as a white solid (2.33 g, 64%). Elute the compound through
a SCX column to obtain the desired intermediate as an oil. MS (ES+)
m/z: 211 (M+H).sup.+.
[0675]
7-Chloro-6-(4-dimethylcarbamoylthio-benzylamino)-3-(2,22-trifluoroa-
cetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine: Use a method similar
to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (348 mg, 0.8 mmol) with
4-dimethylcarbamoylthio-benzylamine (345 mg, 1.6 mmol). Purify by
chromatography on silica gel eluting with hexane/EtOAc (4:1) to
obtain the desired intermediate (170 mg, 43%).
[0676]
7-Chloro-6-(4-dimethylcarbamoylthio-benzylamino)-2,3,4,5-tetrahydro-
-1H-benzo[d]azepine: Use a method similar to the General Procedure
2-1, using
7-chloro-6-(4-dimethylcarbamoylthio-benzylamino)-3-(2,2,2-trifluoro-
acetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (151 mg, 0.3 mmol),
to obtain the desired intermediate as an oil (114 mg, 94%) suitable
for use without additional purification.
[0677]
3-(tert-Butoxycarbonyl)-7-chloro-6-(4-dimethylcarbamoylthio-benzyla-
mino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine: Dissolve
7-chloro-6-(4-dimethylcarbamoylthio-benzylamino)-2,3,4,5-tetrahydro-1H-be-
nzo[d]azepine (114 mg, 0.29 mmol) in anhydrous DCM (3 mL). Cool the
solution at 0.degree. C. and add di-tert-butyl-dicarbonate (64 mg,
0.29 mmol) and triethylamine (0.12 mL, 0.88 mmol). Stir at room
temperature overnight. Concentrate in vacuo and purify the crude
mixture by chromatography on silica gel eluting with hexane/EtOAc
(4:1) to obtain the title compound (130 mg, 91%).
Preparation 81
3-Aminomethyl-6-(3,3-dimethyl-2-oxo-butoxy)-pyridine
##STR00094##
[0679] 6-(3,3-Dimethyl-2-oxo-butoxy)-pyridine-3-carbonitrile:
Dissolve sodium hydride (380 mg, 9.5 mmol) in anhydrous DMF (7 mL).
Cool at 0.degree. C., add dropwise
1-hydroxy-3,3-dimethylbutan-2-one (1.1 g, 9.5 mmol) and stir at
this temperature for 30 min. Add a solution of
6-bromo-nicotinonitrile in DMF (7 mL) and heat at 70.degree. C.
overnight. Cool the reaction mixture with ice/water and work-up
sequentially with EtOAc and water. Dry the organic fraction over
MgSO.sub.4, filter and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (4:1) to
obtain the desired intermediate (424 mg, 50%). MS (ES+) 7/z: 219
(M+H).sup.+.
[0680] 3-Aminomethyl-6-(3,3-dimethyl-2-oxo-butoxy)-pyridine: Bubble
nitrogen into a solution of
6-(3,3-dimethyl-2-oxo-butoxy)-pyridine-3-carbonitrile (400 mg, 1.8
mmol) in methanol (36 mL) with 3 drops of concentrated HCl for 10
min. Add 10% Pd/C (Degussa type E101, 80 mg) and submit the mixture
to hydrogenation at atmospheric pressure overnight. Filter the
reaction mixture over Celite.RTM.. Concentrate the filtrate in
vacuo and purify by SCX chromatography to obtain the title compound
(223 mg, 55%). MS (ES+) m/z: 223 (M+H).sup.+.
Preparation 82
3-Aminomethyl-6-[(2,2-dimethyl-propylcarbamoyl)-methoxy]-pyridine
##STR00095##
[0682] 6-Methoxycarbonylmethoxy-pyridine-3-carbonitrile: Dissolve
sodium hydride (380 mg, 9.5 mmol) in anhydrous DMF (7 mL). Cool at
0.degree. C., add dropwise methyl 2-hydroxyacetate (0.7 mL, 9.5
mmol) and stir at this temperature for 30 min. Add a solution of
6-bromo-nicotinonitrile in DMF (7 mL) and heat at 70.degree. C.
overnight. Cool the reaction mixture with ice/water and work-up
sequentially with EtOAc and water. Dry the organic phase over
MgSO.sub.4, filter and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (4:1) to
obtain the desired intermediate (461 mg, 63%). MS (ES+) m/z: 193
(M+H).sup.+.
[0683]
6-[(2,2-Dimethyl-propylcarbamoyl)-methoxy]-pyridine-3-carbonitrile:
Dissolve under nitrogen 2,2-dimethylpropylamine (1.7 mL, 14.1 mmol)
in anhydrous THF (10 mL). Cool the solution at 0.degree. C. and add
DIBAL-H (13.6 mL, 13.6 mmol, 1M solution in toluene). 2.5 Allow the
mixture to warm up to room temperature and stir for 1 h. Add this
complex to a solution of
6-methoxycarbonylmethoxy-pyridine-3-carbonitrile (461 mg, 2.4 mmol)
in THF (10 mL) and stir at room temperature overnight. Dilute with
EtOAc, and quench with 5% KHSO.sub.4. Dry the organic phase over
MgSO.sub.4, filter and concentrate in vacuo. Purify by
chromatography on silica gel eluting with hexane/EtOAc (1:1) to
obtain the desired intermediate (320 mg, 54%). MS (ES+) m/z: 248
(M+H).sup.+.
[0684]
3-Aminomethyl-6-[(2,2-dimethyl-propylcarbamoyl)-methoxy]-pyridine:
Bubble nitrogen into a solution of
6-[(2,2-dimethyl-propylcarbamoyl)-methoxy]-pyridine-3-carbonitrile
(320 mg, 1.3 mmol) in methanol (26 mL) with 3 drops of concentrated
HCl for 10 min. Add 10% Pd/C (Degussa type E101, 64 mg) and submit
the mixture to hydrogenation at atmospheric pressure overnight.
Filter the reaction mixture over Celite.RTM., concentrate the
filtrate in vacuo and purify by SCX chromatography to obtain the
title compound (314 mg, 96%). MS (ES+) m/z: 252 (M+H).sup.+.
Preparation 83
4-[5-(Cyclopropylmethyl-amino)-isothiazol-3-yl]-benzylamine
##STR00096##
[0686]
3-[(4-Bromo-phenyl)-isothiazol-5-yl]-cyclopropylmethyl-amine: Add
acetic acid (1.4 mL, 23.5 mmol) to a slurry
3-(4-bromo-phenyl)-isothiazol-5-ylamine (1.0 g, 3.9 mmol), sodium
triacetoxyborohydride (2.5 g, 11.8 mmol) and cyclopropane
carboxaldehyde (275 mg, 3.9 mmol) at room temperature under a
nitrogen atmosphere. Stir the resulting solution for 3 h at ambient
temperature. Dilute the solution with DCM (40 mL) and wash with
saturated aqueous NaHCO.sub.3 (50 mL). Collect the organic layer,
dry over Na.sub.2SO.sub.4, filter and concentrate in vacuo. Purify
the residue by chromatography on silica gel (40 g) eluting with
hexane/EtOAc (9:1 to 3:2 gradient) to obtain the desired
intermediate (800 mg, 66%). MS (ES+) m/z: 309.1 (M.sup.+).
[0687]
4-[5-(Cyclopropylmethyl-amino)-isothiazol-3-yl]-benzonitrile:
Slurry 3-[(4-bromo-phenyl)-isothiazol-5-yl]-cyclopropylmethyl-amine
(800 mg, 2.6 mmol), tris(dibenzylideneacetone)-dipalladium(0) (119
mg, 0.13 mmol), DPPF (172 mg, 0.31 mmol) and zinc cyanide (182 mg,
1.6 mmol) in DMF at room temperature. Stir the mixture for 16 h at
120.degree. C. under a nitrogen atmosphere. Cool the mixture to
room temperature, add EtOAc (50 mL) and wash with 5% aqueous NaCl
(20 mL). Collect the organic layer and back extract the aqueous
layer with EtOAc (20 mL). Dry the combined organic extracts over
Na.sub.2SO.sub.4, and concentrate in vacuo. Purify the residue by
chromatography on silica gel (25 g) eluting with hexane/EtOAc (9:1
to 3:2 gradient) to obtain the desired intermediate (450 mg, 68%).
MS (ES+) m/z: 256.1 (M+H).sup.+.
[0688]
4-[1-Amino-2-(cyclopropylmethyl-thiocarbamoyl)-vinyl]-benzylamine:
Add 1 M lithium aluminum hydride in THF (3.0 mL, 3.0 mmol) to a
solution of
4-[5-(cyclopropylmethyl-amino)-isothiazol-3-yl]-benzonitrile (210
mg, 0.82 mmol) in THF (8 mL) at room temperature under a nitrogen
atmosphere. Stir the mixture at ambient temperature for 45 min,
then quench the reaction sequentially with water (0.3 mL) and 5N
aqueous NaOH (0.3 mL). Filter the slurry through Celite.RTM., dry
the filtrate over Na.sub.2SO.sub.4, filter and concentrate in
vacuo. Purify the residue by chromatography on silica gel (8 g)
eluting with DCM/2M ammonia in methanol (20:1) to obtain the
desired intermediate (110 mg, 51%). MS (ES+) m/z: 245.1
(M-NH.sub.3+H).sup.+.
[0689] 4-[5-(Cyclopropylmethyl-amino)-isothiazol-3-yl]-benzylamine:
Add 30% hydrogen peroxide solution (0.13 mL, 1.1 mmol) to a
solution of
4-[1-amino-2-(cyclopropylmethyl-thiocarbamoyl)-vinyl]-benzylamine
(150 mg, 0.57 mmol) in methanol (5 mL). Stir the solution for 16 h
at room temperature. Quench the reaction with aqueous saturated
sodium hydrogensulfite (1 mL). Extract the mixture with EtOAc
(2.times.30 mL), collect the organic layer and concentrate in
vacuo. Purify the residue by chromatography on silica gel (4 g)
eluting with DCM/ammonia in methanol (97:3) to obtain the title
compound as a yellow solid (68 mg, 46%). MS (ES+) nm/: 243.1
(M-NH.sub.3+H).sup.+.
Preparation 84
4-[2-(3-Methyl-butylamino)-thiazol-4-yl]-benzylamine
##STR00097##
[0691] 4-(2-Amino-thiazol-4-yl)-benzonitrile: Slurry
4-cyanophenacyl bromide (40 g, 179 mmol), thiourea (13.6 g, 181
mmol) and sodium bicarbonate (15.3 g, 181 mmol) in absolute ethanol
(560 mL). Stir the mixture at reflux for 20 h under a nitrogen
atmosphere. Cool the slurry to room temperature, filter, wash the
solids with ethanol (100 mL), water (3.times.75 mL) and hexane
(3.times.75 mL). Collect the yellow solid, add water (200 mL) and
stir the slurry for 30 min at room temperature. Filter and wash the
solid with hexane (excess). Slurry the solid in EtOAc (50 mL) and
concentrate in vacuo twice to remove residual water. Collect the
desired intermediate as a light yellow solid (36 g, 99%). MS (ES+)
m/z: 202.1 (M+H).sup.+.
[0692] 4-[2-(3-Methyl-butylamino)-thiazol-4-yl]-benzonitrile:
Slurry 4-(2-amino-thiazol-4-yl)-benzonitrile (2.0 g, 9.9 mmol),
sodium triacetoxyborohydride (6.3 g, 29.7 mmol), isovaleraldehyde
(1.7 g, 19.8 mmol) and acetic acid (3.6 mL) in 1,2-dichloroethane
(100 mL) at room temperature under a nitrogen atmosphere. Stir the
mixture for 16 h at room temperature. Quench the reaction with
saturated aqueous NaHCO.sub.3 (75 mL, pH to 7.0-7.5). Extract the
mixture twice with DCM (100 mL) and concentrate in vacuo. Purify
the crude mixture by chromatography on silica gel (40 g) eluting
with hexane/EtOAc (20:1 to 3:2 gradient) to obtain the desired
intermediate (1.8 g, 67%). MS (ES+) m/z: 272 (M+H).sup.+.
[0693] 4-[2-(3-Methyl-butylamino)-thiazol-4-yl]-benzylamine: Add
lithium aluminum hydride (210 mg, 5.5 mmol) portionwise over 3 min
to a solution of
4-[2-(3-methyl-butylamino)-thiazol-4-yl]-benzonitrile (500 mg, 1.8
mmol) in THF (20 mL) at room temperature under a nitrogen
atmosphere. Stir the mixture for 1 h at 60.degree. C. Cool the
mixture, quench slowly with water (0.2 mL) and 1N NaOH (0.2 mL).
Add sodium sulfate to absorb residual water, filter the mixture
through Celite.RTM., wash with DCM (50 mL) and concentrate in
vacuo. Purify the residue by SCX chromatography to obtain the
desired intermediate (493 mg, 97%). MS (ES+) m/z: 276
(M+H).sup.+.
Preparations 85-88
[0694] The compounds of Preparations 85-88 may be prepared
essentially as described in Preparation 84 using
4-(2-amino-thiazol-4-yl)-benzonitrile and the appropriate aldehyde.
Overall yields and MS (ES+) data are shown in the Table below.
TABLE-US-00014 Yield MS (ES+) Prep. Structure Compound (%) m/z 85
##STR00098##
4-[2-(2,2-Dimethyl-propylamino)-thiazol-4-yl]-benzylamine 26 276 86
##STR00099## 4-(2-Cyclopentylmethylamino-thiazol-4-yl)-benzylamine
18 288 87 ##STR00100##
4-(2-Cyclohexylmethylamino-thiazol-4-yl)-benzylamine 38 302.3 88
##STR00101##
4-[2-(3,3,3-Trifluoropropylamino)-thiazol-4-yl]-benzylamine 14
302
Preparation 89
[0695] The compound of Preparation 89 may be prepared essentially
as described in Preparation 4 by using 4-cyanophenacyl bromide and
benzylthiourea. Overall yield and MS (ES+) data are shown in the
Table below.
TABLE-US-00015 Yield MS (ES+) Prep. Structure Compound (%) m/z 89
##STR00102## 4-(2-Benzylamino-thiazol-4-yl)-benzylamine 25 296(M +
H).sup.+
Preparation 90
4-(2-Cyclopropylmethylamino-5-methyl-thiazol-4-yl)-benzylamine
##STR00103##
[0697]
1-Bromo-4-(2-cyclopropylmethylamino-5-methyl-thiazol-4-yl)-benzene:
Slurry 2,4'-dibromopropiophenone (2.92 g, 10 mmol),
cyclopropopylmethyl-thiourea (1.3 g, 10 mmol) and sodium
bicarbonate (840 mg, 10 mmol) in absolute ethanol (50 mL). Stir the
mixture at reflux overnight under a nitrogen atmosphere. Cool to
room temperature and pour into water (400 mL) and filter the
resulting off-white solid. Wash the solid with hexane (10 mL) and
dry in vacuo to obtain the desired intermediate as a white solid
(2.4 g, 74%). MS (ES-) m/z: 321 (M-H).sup.-.
[0698]
4-(2-Cyclopropylmethylamino-5-methyl-thiazol-4-yl)-benzonitrile:
Slurry
1-bromo-4-(2-cyclopropylmethylamino-5-methyl-thiazol-4-yl)-benzene
(1.0 g, 3.09 mmol), 1,1'-bis-(diphenylphosphino)ferrocene (275 mg,
0.494 mmol), zinc cyanide (325 mg, 2.75 mmol) and
tris(dibenzylideneacetone)dipalladium(0) (254 mg, 0.28 mmol) in DMF
(6 mL) and heat in a sealed tube at 110.degree. C. overnight. Cool
the mixture to room temperature, dilute with dichloromethane (100
mL) and filter over Celite.RTM.. Concentrate in vacuo and purify
the crude mixture by chromatography on silica gel (40 g) eluting
with hexane/EtOAc (19:1 to 7:3 gradient over 30 min; 40 mL/min) to
obtain the desired intermediate (416 mg, 52%) as a yellow solid. MS
(ES+) m/z: 270 (M+H).sup.+.
[0699]
4-(2-Cyclopropylmethylamino-5-methyl-thiazol-4-yl)-benzylamine: Add
a solution of 1M lithium aluminum hydride in THF (4.6 mL, 4.6 mmol)
over 5 min to a solution of
4-(2-cyclopropylmethylamino-5-methyl-thiazol-4-yl)-benzonitrile
(410 mg, 1.52 mmol) in anhydrous THF (10 mL). Heat to reflux for 30
min, cool to room temperature and quench by dropwise addition of
water (5 mL), ether (50 mL), 3N NaOH (5 mL) and additional water
(15 mL). Stir vigorously for 30 min and filter over a bed of
Celite.RTM.. Wash the filtrate with water (2.times.100 mL) and
brine (100 mL). Dry the organic phase over MgSO.sub.4, filter and
concentrate in vacuo to obtain the title compound as a yellow oil
(340 mg, 82%) that was used without further purification. MS (ES+)
m/z: 274 (M+H).sup.+.
Preparation 91
4-[2-(2,2,2-Trifluoroethylamino)-thiazol-4-yl]-benzylamine
##STR00104##
[0701] 1-Benzoyl-3-(2,2,2-trifluoroethyl)-thiourea: Dissolve
trifluoroethylamine (2.2 g, 22 mmol) in chloroform (20 mL) and add
the solution to a mixture of benzoyl isothiocyanate (3.5 g, 22
mmol) in chloroform (20 mL) at room temperature. Stir the mixture
in a sealed flask for 16 h at room temperature. Concentrate the
mixture in vacuo to obtain the desired intermediate as a solid (5.5
g, 95%). MS (ES+) m/z: 263 (M+H).sup.+.
[0702] 2,2,2-Trifluoroethyl-thiourea: Slurry
1-benzoyl-3-(2,2,2-trifluoroethyl)-thiourea (5.5 g, 21.2 mmol) and
potassium carbonate (11.7 g, 84.7 mmol) in methanol (180 mL) and
water (40 mL). Stir the mixture at room temperature for 16 h.
Concentrate the solution in vacuo to a paste. Triturate with hot
water (20 mL, 60.degree. C.), filter off the solids, wash with
water (20 mL, 25.degree. C.) and hexane (excess). Collect the
solids, slurry in EtOAc and concentrate in vacuo twice to remove
residual water. Dry the material in a vacuum oven at 45.degree. C.
for 16 h to obtain the desired intermediate as an off-white solid
(2.2 g, 66%). MS (ES+) m/z: 159.1 (M+H).sup.+.
[0703] 4-[2-(2,2,2-Trifluoroethylamino)-thiazol-4-yl]-benzonitrile:
Slurry 4-cyanophenacyl bromide (1.4 g, 6.3 mmol),
2,2,2-trifluoroethyl-thiourea (1.0 g, 6.3 mmol) and sodium
bicarbonate (529 mg, 6.3 mmol) in absolute ethanol (30 mL). Stir
the mixture at reflux for 1 h under a nitrogen atmosphere. Cool to
room temperature and concentrate in vacuo. Partition the residue
between DCM (100 mL) and water (20 mL). Dry the organic layer over
Na.sub.2SO.sub.4 and concentrate in vacuo to obtain the desired
intermediate (1.7 g, 95%). MS (ES+) m/z: 284 (M+H).sup.+.
[0704] 4-[2-(2,2,2-Trifluoroethylamino)-thiazol-4-yl]-benzylamine:
Add lithium aluminum hydride (402 mg, 10.6 mmol) portionwise over 3
min to a solution of
4-[2-(2,2,2-trifluoroethylamino)-thiazol-4-yl]-benzonitrile (1.0 g,
3.5 mmol) in THF (40 mL) at room temperature under a nitrogen
atmosphere. Stir the mixture for 1 h at 55.degree. C. Cool the
mixture to room temperature, quench slowly with water (0.4 mL) and
1N NaOH (0.4 mL). Add sodium sulfate to absorb residual water,
filter through Celite.RTM., wash with DCM (50 mL) and concentrate
in vacuo. Purify the residue by SCX chromatography to obtain the
desired intermediate (902 mg, 90%). MS (ES+) m/z: 288
(M+H).sup.+.
Preparation 92
(R)-4-[2-(1-Methyl-2,2,2-trifluoroethylamino)-thiazol-4-yl]-benzylamine
##STR00105##
[0706] (R)-1-Benzoyl-3-(1-methyl-2,2,2-trifluoroethyl)-thiourea:
Dissolve (R)-1-methyl-2,2,2-trifluoroethylamine hydrochloride (3.73
g, 25 mmol) in chloroform (50 mL) containing triethylamine (3.5 mL,
25 mmol). Cool to 0.degree. C. in an ice bath and dropwise add
benzoyl isothiocyanate (3.35 mL, 25 mmol) over 10 min. Warm the
mixture to room temperature and stir overnight. Concentrate in
vacuo and purify by chromatography on silica gel (200 g) eluting
with hexane/EtOAc (19:1 to 4:1 over 40 min; 50 mL/min) to afford
the desired intermediate as a light yellow oil (6.2 g, 90%).
[0707] (R)-(1-Methyl-2,2,2-trifluoroethyl)-thiourea: Dissolve
(R)-1-benzoyl-3-(1-methyl-2,2,2-trifluoroethyl)-thiourea (6.2 g,
22.5 mmol) in methanol and add a solution of potassium carbonate
(13.8 g, 100 mmol) in water (30 mL). Stir vigorously at room
temperature overnight. Evaporate to dryness, dissolve residue in
hot water (ca. 100 mL) and filter the resulting white crystals.
Cool filtrate to 0.degree. C., seed with crystals from hot water
filtration, filter and collect resulting white crystals to obtain
the desired intermediate (2.9 g, 74%). MS (ES+) m/z: 173
(M+H).sup.+.
[0708]
(R)-4-[2-(1-Methyl-2,2,2-trifluoroethylamino)-thiazol-4-yl]-benzoni-
trile: Dissolve 4-cyanophenacyl bromide (1.82 g, 8.14 mmol),
(R)-(1-methyl-2,2,2-trifluoroethyl)-thiourea (1.4 g, 8.14 mmol) and
sodium bicarbonate (0.68 g, 8.14 mmol) in absolute ethanol. Heat at
reflux 2 h, cool to room temperature and let stand over 2 days.
Filter and collect the resulting crude product as a tan solid.
Purify by chromatography on silica gel (34 g) eluting with
hexane/EtOAc (19:1 to 4:1 over 30 min, 4:1 over 10 min; 40 mL/min)
to obtain the desired intermediate as a white solid (1.23 g, 52%).
MS (ES+) m/z: 298 (M+H).sup.+.
[0709]
(R)-4-[2-(1-Methyl-2,2,2-trifluoroethylamino)-thiazol-4-yl]-benzyla-
mine: Add a solution of 1 M lithium aluminum hydride in THF (12 mL,
12 mmol) dropwise to an ice-cooled solution of
(R)-4-[2-(1-methyl-2,2,2-trifluoroethylamino)-thiazol-4-yl]-benzonitrile
in anhydrous THF (10 mL). Heat to reflux for 1 h, cool to room
temperature, quench by slow addition of water (12 mL), ether (50
mL), 1N NaOH (12 mL) and additional water (36 mL). Add EtOAc (50
mL), stir vigorously for 20 min and filter over a bed of
Celite.RTM.. Dry the organic phase over MgSO.sub.4, filter and
concentrate in vacuo to obtain the title compound (765 mg, 64%). MS
(ES+) tm/z: 302 (M+H).sup.+.
Preparation 93
[0710] The compound of Preparation 93 may be prepared essentially
as described in Preparation 92 by using
(S)-1-methyl-2,2,2-trifluoroethylamine hydrochloride. Overall yield
and MS (ES+) data are shown in the Table below.
TABLE-US-00016 MS (ES+) Structure Compound Yield m/z 93
##STR00106##
(S)-4-[2-(1-Methyl-2,2,2-trifluoroethylamino)-thiazol-4-yl]-benzylamine
51 302(M + H).sup.+
Preparation 94
Cyclopropylmethyl-thiourea
##STR00107##
[0712] 1-Benzoyl-3-cyclopropylmethyl-thiourea: Add benzoyl
isothiocyanate (500 g, 3.06 mol) to chloroform (5 L) and cool to
<5.degree. C. Add a solution of cyclopropylmethylamine (230 g,
3.22 mol) in chloroform (500 mL) with vigorous stirring maintaining
a temperature below 20.degree. C. Remove the ice-water bath, and
stir the mixture at room temperature overnight. Concentrate the
mixture in vacuo to obtain the desired intermediate as a white
solid (720 g, 100%). MS (APCI) m/z: 235 (M+H).sup.+.
[0713] Cyclopropylmethyl-thiourea: Add
1-benzoyl-3-cyclopropylmethyl-thiourea (718 g, 3.06 mol) to
methanol (6 L) and heat gently to dissolve. Add a solution of
potassium carbonate (1.70 kg, 12.3 mol) in water (2 L) and stir
overnight at room temperature. Filter any solids that form and
concentrate the filtrate in vacuo until 10% of the volume. Dilute
the residue with water (2 L) and EtOAc (-3.5 L) and extract the
aqueous phase with EtOAc (4.times.2.5 L). Wash the combined organic
extracts with aqueous 1N NaOH (2.times.1 L) and brine (2 L). Dry
the organic layer over Na.sub.2SO.sub.4, filter, and concentrate in
vacuo. Redissolve the residue in warm EtOAc (4 L), concentrate in
vacuo until .about.20% of the volume and filter the precipitate,
rinsing with cold (.about.5.degree. C.) EtOAc (.about.500 mL). Dry
the solid under high vacuum to obtain the title compound as an
off-white solid (220 g, 55%). Concentrate the filtrate in vacuo
until .about.10% of the volume and filter the precipitate, rinsing
with cold EtOAc. Dry the solid under high vacuum to provide a
second crop of cyclopropylmethyl-thiourea as an off-white solid
(103 g, 26%). Total yield (323 g, 81%). MS (APCI) i/z: 131
(M+H).sup.+.
Preparation 95
2-Aminomethyl-5-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine
##STR00108##
[0715] 2-Bromo-5-(2-bromo-acetyl)-pyridine: Add pyridinium
tribromide (7.0 g, 22 mmol) to a solution of
5-acetyl-2-bromo-pyridine (4.0 g, 20 mmol) in THF (100 mL) at room
temperature. Stir the mixture for 16 h at room temperature under a
nitrogen atmosphere. Quench the mixture with saturated aqueous
NaHCO.sub.3 (50 mL, pH to 7.8). Extract the mixture with EtOAc (150
mL). Wash the organic layer with brine (50 mL) and concentrate in
vacuo to obtain the desired intermediate as a dark brown oil (11.5
g) that was used without further purification. MS (ES+) m/z: 280
(M+H).sup.+.
[0716] 6-Bromo-3-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine:
Slurry crude 2-bromo-5-(2-bromo-acetyl)-pyridine (11.5 g, ca. 48%),
cyclopropylmethyl-thiourea (2.2 g, 16.9 mmol) and sodium
bicarbonate (1.7 g, 20 mmol) in ethanol (100 mL) at room
temperature. Stir the mixture at reflux for 1 h under a nitrogen
atmosphere. Turn off heat and stir the mixture for 16 h at room
temperature. Filter the slurry, then wash the solids with ethanol
(50 mL), water (2.times.50 mL) and hexane (excess). Dry the solid
in a vacuum oven for 20 h at 50.degree. C. to obtain the desired
intermediate as a tan solid (3.2 g, 61% over 2 steps). MS (ES+)
m/z: 312 (M+2).sup.+.
[0717]
5-(2-Cyclopropylmethylamino-thiazol-4-yl)-pyridine-2-carbonitrile:
Slurry 6-bromo-3-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine
(1.1 g, 3.6 mmol), 1,1'-bis-(diphenylphosphino)ferrocene (320 mg,
0.6 mmol), zinc cyanide (337 mg, 2.9 mmol) and
tris(dibenzylideneacetone)dipalladium(0) (231 mg, 0.25 mmol) in wet
DMF (6 mL). Stir the mixture in a sealed tube at 115.degree. C. for
6 h. Cool the mixture to room temperature, dilute with EtOAc (50
mL) and wash with 5% aqueous sodium chloride (3.times.30 mL).
Collect the organic layer and concentrate in vacuo. Purify the
residue by chromatography on silica gel (40 g) eluting with
hexane/(THF with 1% methanol) (4:1) to obtain the desired
intermediate (350 mg, 38%). MS (ES+) m/z: 257.3 (M+H).sup.+.
[0718]
2-Aminomethyl-5-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine:
Add lithium aluminum hydride (75 mg, 2.0 mmol) portionwise over 1
minute to a solution of
5-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine-2-carbonitrile
(340 mg, 1.3 mmol) in THF (20 mL) at room temperature under a
nitrogen atmosphere. Stir the mixture for 10 min at room
temperature. Quench the mixture successively with water (0.1 mL)
and 1N NaOH (0.1 mL). Add sodium sulfate to absorb residual water,
filter through Celite.RTM., wash with DCM (30 mL) and concentrate
in vacuo. Purify the residue by chromatography on silica gel (12 g)
eluting with DCM/2M ammonia in methanol (97:3) to obtain the title
compound (180 mg, 52%). MS (ES+) m/z: 261.3 (M+H).sup.+.
Preparation 96
3-Aminomethyl-6-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine
##STR00109##
[0720] 6-(1-Ethoxy-vinyl)-nicotinonitrile: Slurry
6-bromo-nicotinonitrile (8.0 g, 43.7 mmol),
1-ethoxyvinyl-tributylstannane (17.4 g, 48 mmol), and
dichlorobis(triphenylphosphine)-palladium (1.5 g, 2.2 mmol) in
acetonitrile (680 mL) at room temperature. Stir the mixture at
reflux for 16 h under a nitrogen atmosphere. Cool the mixture to
room 5 temperature, add aqueous saturated potassium fluoride (100
mL), stir 30 min then filter and wash with EtOAc (200 mL). Wash the
organic phase with water (250 mL). Dry the organic layer over
Na.sub.2SO.sub.4, filter and concentrate in vacuo to obtain the
desired intermediate (14.5 g) that was used without further
purification. MS (ES+) m/z: 175 (M+H).sup.+.
[0721] 6-Acetyl-nicotinonitrile: Dissolve crude
6-(1-ethoxy-vinyl)-nicotinonitrile (14.5 g, ca. 80%) in THF (120
mL) and 2.5 N hydrochloric acid (40 mL). Stir the solution for 16 h
at room temperature. Quench the reaction with saturated aqueous
NaHCO.sub.3 (pH to 7.5). Extract the mixture with EtOAc (200 mL).
Dry the organic layer over Na.sub.2SO.sub.4, filter and concentrate
in vacuo. Purify the crude mixture by chromatography on silica gel
(120 g) eluting with hexane/EtOAc (9:1 to 3:1 gradient) to obtain
the desired intermediate (4.2 g, 65%).
[0722] 6-(2-Bromo-acetyl)-nicotinonitrile: Add pyridinium
tribromide (9.2 g, 28.7 mmol) to a solution of
6-acetyl-nicotinonitrile (4.2 g, 28.7 mmol) in THF (200 mL) at room
temperature. Filter off the solids and wash with minimal THF.
Recrystallize the solid from EtOAc/hexane to obtain the desired
intermediate as a light orange solid (5.2 g, 80%) that was used
without further purification. MS (ES-) m/z: 223 (M-H).sup.-.
[0723] 6-[2-(Cyclopropylmethylamino)-thiazol-4-yl]-nicotinonitrile:
Slurry crude 6-(2-bromo-acetyl)-nicotinonitrile (5.2 g),
cyclopropylmethyl-thiourea (2.7 g, 20.8 mmol) and sodium
bicarbonate (1.95 g, 23.1 mmol) in ethanol (135 mL) at room
temperature. Stir the mixture at reflux for 1 h under a nitrogen
atmosphere. Cool the mixture to room temperature and concentrate in
vacuo to a solid. Recrystallize from ethanol (20 mL) and water (100
mL) at 5.degree. C. to obtain the desired intermediate as a tan
solid (4.8 g, 81%). MS (ES+) m/z: 257 (M+H).sup.+.
[0724]
3-Aminomethyl-6-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine:
Add 6-[2-(cyclopropylmethylamino)-thiazol-4-yl]-nicotinonitrile
(2.0 g, 7.8 mmol), Raney Nickel (2.0 mL), and 2M ammonia in
methanol (200 mL) to a pressure vessel under a nitrogen atmosphere.
Pressurize the vessel to 60 psi with hydrogen, and stir the mixture
for 6 h at 40.degree. C. Filter the mixture through Celite.RTM. and
concentrate in vacuo to an oil. Dissolve the oil in EtOAc (300 mL)
and saturated ammonium hydroxide (50 mL). Stir the solution for 20
h in a sealed flask at room temperature. Collect the organic layer
and concentrate in vacuo. Purify the crude mixture by SCX
chromatography followed by chromatography on silica gel (150 g)
eluting with DCM/2M ammonia in methanol (99:1 to 85:15 gradient) to
obtain the title compound (1.05 g, 51%). MS (ES+) m/z: 261
(M+H).sup.+.
Preparation 97
4-[(2-Cyclopropanecarbonyl-amino)-thiazol-4-yl]-benzylamine
##STR00110##
[0726] 4-(2-Aminothiazol-4-yl)-N-(tert-butoxycarbonyl)-benzylamine:
To a mechanically-stirred slurry of lithium aluminum hydride (2.64
g, 69.7 mmol) in anhydrous dioxane (150 mL) at room temperature,
add a warmed slurry of 4-(2-amino-thiazol-4-yl)-benzonitrile (4 g,
19.9 mmol) in dioxane (200 mL) in portions. Heat the reaction
mixture at 75.degree. C. for 4 h and then cool the mixture to
0.degree. C. Quench the reaction with water (2.6 mL) dropwise. Add
15% aqueous NaOH (2.6 mL) and water (8 mL). Stir the mixture for 2
h at room temperature and filter the slurry over Celite.RTM.. Wash
the Celite.RTM. filter pad with dioxane (500 mL) and concentrate
the filtrate. Dissolve the residue in dioxane (300 mL) and then add
a solution of di-tert-butyl dicarbonate (5.2 g, 23.8 mmol) in
dioxane (100 mL). Stir at room temperature for 24 h and concentrate
the reaction mixture in vacuo. Dissolve the residue in EtOAc (500
mL) and wash the solution with saturated aqueous NaHCO.sub.3 (250
mL). Dry the organic phase over Na.sub.2SO.sub.4, filter and
concentrate in vacuo. Dissolve the residue in dichloromethane, add
silica gel (12 g) and concentrate the mixture to a powder. Load the
powder on to a dry column attached to an Analogix.RTM. column (330
g) and elute by preparative liquid chromatography (0:1 to 2:3
EtOAc/hexane over 33 min, 2:3 EtOAc/hexane over 33 min, 2:3 to 1:0
EtOAc/hexane over 33 min, 1:1 EtOAc/DCM over 99 min; 35 mL/min) to
afford the desired intermediate (2.98 g, 49%) as a yellow solid. MS
(ES+) m/z: 306.2 (M+H).sup.+.
[0727]
4-[(2-Cyclopropanecarbonyl-amino)-thiazol-4-yl]-N-(tert-butoxycarbo-
nyl)-benzylamine: To a mixture of
4-(2-aminothiazol-4-yl)-N-(tert-butoxycarbonyl)-benzylamine (2.98
g, 9.76 mmol) in DCM/dioxane (2:1, 150 mL) at room temperature, add
triethylamine (2.0 mL, 15 mmol) and cyclopropanecarbonyl chloride
(1.1 mL, 12 mmol). Stir at room temperature overnight and partition
the reaction mixture between EtOAc (500 mL) and saturated aqueous
NaHCO.sub.3 (250 mL). Dry the organic extract over
Na.sub.2SO.sub.4, filter and concentrate in vacuo. Combine the
residue with DCM and silica gel (12 g) and concentrate to a powder.
Load powder on to a dry column attached to an Analogix.RTM. column
(330 g) and purify by preparative liquid chromatography (0:1 to 1:4
EtOAc/hexane over 33 min, 1:4 EtOAc/hexane over 33 min, 1:4 to 1:1
EtOAc/hexane over 33 min, 1:1 EtOAc/hexane over 66 min; 35 mL/min)
to afford the desired intermediate (2.381 g, 65%) as a yellow
solid. MS (ES+) m/z: 374.2 (M+H).sup.+.
[0728] 4-[(2-Cyclopropanecarbonyl-amino)-thiazol-4-yl]-benzylamine:
To a solution of
4-[(2-cyclopropanecarbonyl-amino)-thiazol-4-yl]-N-(tert-butoxycarbonyl)-b-
enzylamine (2.381 g, 6.376 mmol) in anhydrous DCM (53 mL), add
trifluoroacetic acid (45 mL) at room temperature and stir
overnight. Concentrate the reaction mixture in vacuo and elute the
residue through a SCX column (20 g). Dissolve the residue in DCM,
add silica gel (14 g) and concentrate to a powder. Load the powder
on to a dry column attached to an Analogix.RTM. column (150 g) and
purify by preparative liquid chromatography (0:1 to 1:4 2M ammonia
in methanol/DCM over 33 min, 1:4 2M ammonia in methanol/DCM over 33
min; 35 mL/min) to afford the title compound (1.668 g, 96%) as an
off-white solid. MS (ES+) m/z: 274.1 (M+H).sup.+.
Preparation 98
4-[3-(Cyclopropylmethyl-amino)-pyrazol-1-yl]-benzylamine
##STR00111##
[0730] 4-(3-Amino-pyrazol-1-yl)-benzonitrile: Suspend 4-cyanophenyl
hydrazine hydrochloride (5 g, 29.58 mmol) in tert-butanol (60 mL).
Add methoxyacrylonitrile (2.458 g, 29.58 mmol) and potassium
tert-butoxide (3.975 g, 35.49 mmol) and heat the mixture at
90.degree. C. overnight. Concentrate in vacuo and partition the
residue between EtOAc/water. Extract the organic phase with 10%
hydrochloric acid. Neutralize the aqueous phase with saturated
aqueous NaHCO.sub.3 and extract twice with EtOAc. Dry the combined
organic extracts over MgSO.sub.4, filter and concentrate in vacuo
to obtain a solid that was washed with ether/hexane. Filter and dry
the solid in vacuo to obtain the desired intermediate.
[0731] 4-[3-(Cyclopropylmethyl-amino)-pyrazol-1-yl]-benzonitrile:
Dissolve 4-(3-amino-pyrazol-1-yl)-benzonitrile (200 mg) in
1,2-dichloroethane (12 mL). Add acetic acid (0.36 mL) and
cyclopropanecarboxaldehyde (0.08 mL, 1.06 mmol) and stir the
mixture at room temperature under a nitrogen atmosphere for 40 min.
Add sodium triacetoxyborohydride (674 mg, 3.18 mmol) and stir for 3
h at room temperature. Quench the reaction with water. Extract the
mixture three timed with EtOAc. Dry the combined organic extracts
over Na.sub.2SO.sub.4, filter and concentrate in vacuo to obtain
the desired intermediate (136 mg, 54%) that was used without
further purification.
[0732] 4-[3-(Cyclopropylmethyl-amino)-pyrazol-1-yl]-benzylamine:
Add a solution of 1M lithium aluminum hydride in THF (1.4 mL, 1.4
mmol) to a solution of
4-[3-(cyclopropylmethyl-amino)-pyrazol-1-yl]-benzonitrile (136 mg,
0.57 mmol) in THF (10 mL) at room temperature under a nitrogen
atmosphere. Stir the mixture for 1 h at 60.degree. C. Cool the
mixture to room temperature and quench slowly with water, 1N NaOH
and additional water. Dilute with EtOAc, stir vigorously for 20 min
and filter through Celite.RTM.. Dry the organic phase over
Na.sub.2SO.sub.4, filter and concentrate in vacuo. Purify the
residue by SCX chromatography to obtain the desired intermediate
that was used without further purification (130 mg, 94%). MS (ES+)
m/z: 243 (M+H).sup.+.
Preparation 99
4-(1-Cyclopropylmethyl-1H-pyrazol-3-yl)-benzylamine
##STR00112##
[0734] 4-(1-Cyclopropylmethyl-1H-pyrazol-3-yl)-benzonitrile: Add
sodium hydride (64 mg, 2.65 mmol) to a solution of
4-(1H-pyrazol-3-yl)-benzonitrile (300 mg, 1.77 mmol) in DMF (5 mL)
under nitrogen atmosphere. Stir the mixture for 15 min at 0.degree.
C. and add (bromomethyl)cyclopropane (206 .quadrature.1, 2.12
mmol). Stir the mixture for 5 min at 0.degree. C. and then at room
temperature overnight. Quenck the reaction mixture with water and
extract twice with EtOAc. Dry the combined organics extracts over
Na.sub.2SO.sub.4, filter and concentrate in vacuo. Purify the crude
mixture by chromatography on silica gel eluting with hexane/EtOAc
(75:25) to obtain the desired intermediate (256 mg, 65%).
[0735] 4-(1-Cyclopropylmethyl-1H-pyrazol-3-yl)-benzylamine: Bubble
nitrogen into a solution of
4-(1-cyclopropylmethyl-1H-pyrazol-3-yl)-benzonitrile (256 mg, 1.15
mmol) in methanol (48 mL) with 5 drops of concentrated hydrochloric
acid for 10 min. Add 10% Pd/C (Degussa type, 48 mg) and submit the
mixture to hydrogenation at atmospheric pressure overnight. Filter
the mixture over Celite.RTM. and concentrate in vacuo. Add
saturated aqueous NaHCO.sub.3 and extract twice with AcOEt. Dry the
combined organic extracts over MgSO.sub.4, filter and concentrate
in vacuo to give the title compound as a yellow oil (207 mg, 80%).
MS (ES+) m/z: 228 (M+H).sup.+.
Preparation 100
4-[6-(Cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzylamine
##STR00113##
[0737] 6-Chloro-4-(cyclopropylmethyl-amino)-pyrimidine: In a
microwave reaction vessel, slurry 4,6-dichloropyrimidine (540 mg,
3.6 mmol), cyclopropylmethylamine (280 .quadrature.L, 3.24 mmol),
and diisopropylethylamine (1.25 mL, 7.2 mmol) in iso-propanol (3
mL). Irradiate in microwave (300 watts) at 140.degree. C. for 40
min. Cool to room temperature and concentrate in vacuo. Purify by
chromatography on silica gel (40 g) eluting with hexane/EtOAc (9:1
to 3:1 over 30 min; 40 mL/min) to obtain the desired intermediate
(567 mg, 86%) as an off-white solid. MS (ES+) m/z: 184
(M+H).sup.+.
[0738]
4-[6-(Cyclopropylmethyl-amino)-pyrimidin-4-yl]-N-(tert-butoxycarbon-
yl)-benzylamine: In a microwave reaction vessel, slurry
6-chloro-4-(cyclopropylmethyl-amino)-pyrimidine (560 mg, 3 mmol),
[4-(N-tert-butoxycarbonyl-aminomethyl)phenyl]boronic acid (1.1 g, 4
mmol), and tetrakis(triphenylphosphine)palladium(0) (190 mg, 0.15
mmol) in toluene (4 mL). Add ethanol (1 mL) followed by potassium
carbonate (0.9 g, 6 mmol) dissolved in water (300 .quadrature.L).
Irradiate in microwave (300 watts) at 120.degree. C. for 60 min.
Cool to room temperature, pour reaction mixture into 1N NaOH (250
mL) and extract with DCM (3.times.100 mL). Wash the combined
organic extracts with brine, dry over MgSO.sub.4, filter and
concentrate in vacuo. Purify by chromatography on silica gel (40 g)
eluting with hexane/EtOAc (4:1 to 2:3 over 45 min; 40 mL/min) to
obtain the desired intermediate (450 mg, 38%) as a yellow solid. MS
(ES+) m/z: 355 (M+H).sup.+.
[0739] 4-[6-(Cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzylamine:
Dissolve
4-[6-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-N-(tert-butoxycar-
bonyl)-benzylamine (450 mg, 1.2 mmol) in DCM (5 mL). Add
trifluoroacetic acid (3 mL) and stir under nitrogen for 3 h.
Concentrate in vacuo and purify the crude mixture by SCX
chromatography (5 g) to obtain the title compound (305 mg, 93%)
suitable for use without additional purification. MS (ES+) m/z: 255
(M+H).sup.+.
Preparation 101
4-[4-(Cyclopropylmethyl-amino)-pyrimidin-2-yl]-benzylamine
##STR00114##
[0741] 2-Chloro-4-(cyclopropylmethyl-amino)-pyrimidine: In a
microwave reaction vessel, slurry 2,4-dichloropyrimidine (0.5 g,
3.36 mmol), cyclopropylmethylamine (275 .mu.L, 3.18 mmol), and
diisopropylethylamine (1.17 mL, 6.72 mmol) in iso-propanol (2 mL).
Irradiate in microwave (300 watts) at 130.degree. C. for 15 min.
Cool to room temperature and concentrate in vacuo. Purify by
chromatography on silica gel (40 g) eluting with hexane/EtOAc (4:1
to 1:3 over 45 min; 40 mL/min) to obtain the desired intermediate
(374 mg, 65%) as a colorless oil.
[0742]
4-[4-(Cyclopropylmethyl-amino)-pyrimidin-2-yl]-N-(tert-butoxycarbon-
yl)-benzylamine: Slurry
2-chloro-4-(cyclopropylmethyl-amino)-pyrimidine (370 mg, 2 mmol),
[4-(N-tert-butoxycarbonyl-aminomethyl)phenyl]boronic acid (710 mg,
2.83 mmol), and tetrakis(triphenylphosphine)palladium(0) (116 mg,
0.10 mmol) in toluene (3 mL). Add ethanol (0.5 mL) followed by
potassium carbonate (550 mg, 4 mmol) dissolved in water (300
.mu.L). Irradiate in microwave (300 watts) at 120.degree. C. for 90
min. Cool to room temperature, pour reaction mixture into water
(100 mL) containing 1N NaOH (25 mL) and extract with DCM
(3.times.50 mL). Wash the combined organic extracts with brine, dry
over MgSO.sub.4, filter and concentrate in vacuo. Purify by
chromatography on silica gel (40 g) eluting with hexane/EtOAc (4:1
to 1:4 over 45 min; 40 mL/min) to obtain the desired intermediate
(105 mg, 20%) as a yellow solid. MS (ES+) m/z: 355 (M+H).sup.+.
Additionally recovered unreacted
2-chloro-4-(cyclopropylmethyl-amino)-pyrimidine (100 mg).
[0743] 4-[4-(Cyclopropylmethyl-amino)-pyrimidin-2-yl]-benzylamine:
Dissolve
4-[4-(cyclopropylmethyl-amino)-pyrimidin-2-yl]-N-(tert-butoxycar-
bonyl)-benzylamine (100 mg, 0.28 mmol) in DCM (3 mL) containing
trifluoroacetic acid (2 mL). Stir under nitrogen for 3 h.
Concentrate in vacuo and purify the crude mixture by SCX
chromatography (5 g) to obtain the title compound (68.5 mg, 90%)
suitable for use without additional purification. MS (ES+) m/z: 255
(M+H).sup.+.
Preparation 102
4-[2-(Cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzylamine
##STR00115##
[0745] 4-Chloro-2-(Cyclopropylmethyl-amino)-pyrimidine: In a
microwave reaction vessel, slurry 2,4-dichloropyrimidine (1.0 g,
6.7 mmol), cyclopropylmethylamine (550 .mu.L, 6.0 mmol), and
diisopropylethylamine (2.35 mL, 13.4 mmol) in toluene (3 mL).
Irradiate in microwave (300 watts) at 120.degree. C. for 30 min.
Cool to room temperature and concentrate in vacuo. Purify by
chromatography on silica gel (40 g) eluting with hexane/EtOAc (4:1
to 3:7 over 30 min; 40 mL/min) to obtain the desired intermediate
(157.5 mg, 15%) as a colorless oil.
[0746]
4-[2-(Cyclopropylmethyl-amino)-pyrimidin-4-yl]-N-(tert-butoxycarbon-
yl)-benzylamine: Slurry
4-chloro-2-(cyclopropylmethyl-amino)-pyrimidine (155 mg, 0.62
mmol), [4-(N-tert-butoxycarbonyl-aminomethyl)phenyl]boronic acid
(160 mg, 0.86 mmol), and tetrakis(triphenylphosphine)palladium(0)
(36 mg, 0.031 mmol) in toluene (3 mL). Add ethanol (0.5 mL)
followed by potassium carbonate (175 mg, 1.24 mmol) dissolved in
water (300 .mu.L). Irradiate in microwave (300 watts) at
120.degree. C. for 60 min. Cool to room temperature, pour reaction
mixture into water (100 mL) containing 1N NaOH (25 mL) and extract
with DCM (3.times.50 mL). Wash the combined organic extracts with
brine, dry over MgSO.sub.4, filter and concentrate in vacuo. Purify
by chromatography on silica gel (12 g) eluting with hexane/EtOAc
(4:1 to 3:7 over 30 min; 30 mL/min) to obtain the desired
intermediate (200 mg, 90%) as a light yellow solid. MS (ES+) m/z:
355 (M+H).sup.+.
[0747] 4-[2-(Cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzylamine:
Dissolve
4-[2-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-N-(tert-butoxycar-
bonyl)-benzylamine (195 mg, 0.55 mmol) in DCM (3 mL) and add
trifluoroacetic acid (1.5 mL). Stir at room temperature for 3 h.
Concentrate in vacuo and purify the crude mixture by SCX
chromatography (5 g) to obtain the title compound (140 mg, 93%)
suitable for use without additional purification. MS (ES+) m/z: 255
(M+H).sup.+.
Preparation 103
4-[5-(3,3-Dimethylbutyryl)tiophen-2-yl]-benzylamine
##STR00116##
[0749] 2-Bromo-5-(3,3-dimethylbutyryl)-thiophene: Stir overnight at
room temperature a mixture of 5-bromothiophene (1 g, 6.1 mmol),
3,3-dimethylbutyryl chloride (1.3 mL, 9.1 mmol) and ytterbium(III)
trifluoromethanesulfonate (378 mg, 0.6 mmol) in nitromethane (15
mL). Wash the mixture sequentially with water, saturated aqueous
NaHCO.sub.3 and water. Extract with chloroform, dry over
MgSO.sub.4, filter and concentrate in vacuo. Purify the crude
mixture by chromatography on silica gel eluting with hexane to
obtain the desired intermediate (1.3 g, 80%).
[0750]
N-(tert-Butoxycarbonyl)-4-[5-(3,3-dimethylbutyryl)tiophen-2-yl]-ben-
zylamine: To a solution of
2-bromo-5-(3,3-dimethylbutyryl)-thiophene (187 mg, 0.7 mmol) in
dioxane (7 mL) add a solution of aqueous 2M Na.sub.2CO.sub.3 (0.9
mL), [4-(N-tert-butoxycarbonyl-aminomethyl)phenyl]boronic acid (216
mg, 0.8 mmol) and tetrakis(triphenylphosphine)-palladium(0) (41 mg,
0.03 mmol). Heat the mixture at 90.degree. C. overnight. Cool at
room temperature, add water and extract with EtOAc. Dry the organic
phase over MgSO.sub.4, filter and concentrate in vacuo. Purify the
crude mixture by chromatography on silica gel eluting with
hexane/EtOAc (4:1) to obtain the desired intermediate (174 mg,
63%).
[0751] 4-[5-(3,3-Dimethylbutyryl)tiophen-2-yl]-benzylamine: To a
solution of
N-(tert-butoxycarbonyl)-4-[5-(3,3-dimethylbutyryl)tiophen-2-yl]-benzyl-
amine (174 mg, 0.4 mmol) in anhydrous dichloromethane (0.3 mL) add
a solution of 4M hydrogen chloride in dioxane (1.7 mL, 6.7 mmol)
and stir for 2 h at room temperature. Concentrate in vacuo and
purify the crude mixture by SCX chromatography to obtain the title
compound (128 mg, 99%). MS (ES+) m/z: 288 (M+H).sup.+.
Preparation 104
3-Aminomethyl-6-[(2,2-dimethylpropane)sulfonyl]-pyridine
##STR00117##
[0753]
N-(tert-Butoxycarbonyl)-3-aminomethyl-6-[(2,2-dimethylpropane)thio]-
-pyridine: Add sodium hydride (590 mg, 15.5 mmol, 60% in mineral
oil) to DMF (50 mL) and cool to 0.degree. C. Add
2,2-dimethyl-propane-1-thiol (966 mg, 9.27 mmol) and stir the
mixture for 1 h at 0.degree. C. Add
3-(tert-butoxycarbonylamino-methyl)-6-chloropyridine (1.5 g, 6.18
mmol) to the mixture and heat to 70.degree. C. overnight. Cool the
mixture to room temperature and carefully dilute with water (50
mL). Extract the mixture with EtOAc (5.times.25 mL). Wash the
combined organic extracts with water (3.times.20 mL) and brine (50
mL). Dry the organic layer over Na.sub.2SO.sub.4, filter, and
concentrate in vacuo. Purify the residue by chromatography on
silica gel (120 g) eluting with hexane:EtOAc (1:0 to 1:1 over 1 h,
80 mL/min) to provide the desired intermediate as a light yellow
oil (915 mg, 48%). MS (APCI) m/z: 211
(M-C.sub.5H.sub.8O.sub.2+H).sup.+.
[0754]
N-(tert-Butoxycarbonyl)-3-aminomethyl-6-[(212-dimethylpropane)sulfo-
nyl]-pyridine: Add 3-chloroperbenzoic acid (1.83 g, .about.70%,
7.44 mmol) to DCM (25 mL) and cool to 0.degree. C. Slowly add a
solution of
N-(tert-butoxycarbonyl)-3-aminomethyl-6-[(2,2-dimethylpropane)thio]-pyrid-
ine (924 mg, 2.98 mmol) in DCM (10 mL) maintaining the temperature
below 10.degree. C. Allow the mixture to warm to room temperature
and stir for 3 h. Wash the mixture with aqueous 3N NaOH (3.times.25
mL), water (25 mL), and brine (25 mL). Dry the organic layer over
Na.sub.2SO.sub.4, filter, and concentrate in vacuo. Purify the
crude mixture by chromatography on silica gel (120 g), eluting with
DCM/(chloroform:methanol:concentrated NH.sub.4OH) (1:1 over 1.5 h,
80 mL/min) to provide the desired intermediate as a light yellow
oil (961 mg, 94%). MS (APCI) m/z: 243
(M-C.sub.5H.sub.8O.sub.2+H).sup.+.
[0755] 3-Aminomethyl-6-[(2,2-dimethylpropane)sulfonyl]-pyridine:
Add
N-(tert-butoxycarbonyl)-3-aminomethyl-6-[(2,2-dimethylpropane)sulfonyl]-p-
yridine (1.13 g, 3.21 mmol) to methanol (25 mL) and cool to
0.degree. C. Bubble anhydrous hydrogen chloride gas into the
mixture until saturated and stir for 1 h. Concentrate the mixture
in vacuo. Purify the residue by chromatography on silica gel (45
g), eluting with DCM/(chloroform:methanol:concentrated NH.sub.4OH)
(1:3 over 30 min; 80 mL/min) to provide the desired intermediate as
a light yellow oil (344 mg, 42%). MS (APCI) m/z: 243
(M+H).sup.+.
Preparation 105
4-[2-(2,2,2-Trifluoroethylthio)-1,1-(ethylenedioxy)ethyl]-benzylamine
##STR00118##
[0757] 4-(2,2,2-Trifluoroethylthiomethylcarbonyl)-benzonitrile: To
a solution of 2,2,2-trifluoroethanethiol (1.5 mL, 17.2 mmol) in
anhydrous THF (28 mL) at 0.degree. C. under nitrogen, add sodium
hydride (629 mg, 15.7 mmol) and stir for 15 min. Then, add
4-cyanophenacyl bromide (3.2 g, 14.3 mmol) and stir at ambient
temperature overnight. Quench with water and extract with EtOAc.
Dry the combined organics extracts over MgSO.sub.4, filter and
concentrate in vacuo. Purify the crude mixture by chromatography on
silica gel eluting with hexane/EtOAc (7:3) to obtain the desired
intermediate (3.1 mg, 84%).
[0758]
4-[2-(2,2,2-Trifluoroethylthio)-1,1-(ethylenedioxy)ethyl]-benzonitr-
ile: To a solution of
4-(2,2,2-trifluoroethylthiomethylcarbonyl)-benzonitrile (770 mg,
2.9 mmol) in anhydrous toluene (15 mL), add ethyleneglycol (0.33
mL, 5.9 mmol) and p-toluenesulfonic acid (564 mg, 2.9 mmol) and
reflux with a Dean-Stark apparatus overnight. Cool to room
temperature, wash with saturated aqueous NaHCO.sub.3 and brine. Dry
the combined organic extracts over MgSO.sub.4, filter and
concentrate in vacuo. Purify the crude mixture by chromatography on
silica gel eluting with hexane/EtOAc (4:1), to obtain the desired
intermediate (459 mg, 51%).
[0759]
4-[2-(2,2,2-Trifluoroethylthio)-1,1-(ethylenedioxy)ethyl]-benzylami-
ne: To a solution of
4-[2-(2,2,2-trifluoroethylthio)-1,1-(ethylenedioxy)ethyl]-benzonitrile
(248 mg, 0.8 mmol) in anhydrous THF (8 mL) under nitrogen, add
borane-tetrahydrofurane complex (9.8 mL, 9.8 mmol) and heat at
60.degree. C. for 3 h. Cool to room temperature and quench with
methanol dropwise. Concentrate in vacuo and purify by SCX
chromatography to obtain the title compound (250 mg, 99%). MS (ES+)
tm/z: 308 (M+H).sup.+.
EXAMPLE 1
7-Chloro-6-[4-(1-methoxyimino-ethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-be-
nzo[d]azepine Succinate
##STR00119##
[0761] Add O-methylhydroxylamine hydrochloride (10 mg, 0.12 mmol)
and pyridine (0.02 mL, 0.24 mmol) to a solution of
6-(4-acetyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetra-
hydro-1H-benzo[d]azepine (50 mg, 0.12 mmol) in ethanol (10 mL).
Heat the mixture to reflux for 1.5 h. Remove the solvent in vacuo
and partition the residue between DCM and 0.1N aqueous HCl. Dry the
organic phase over Na.sub.2SO.sub.4, filter and concentrate in
vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (95:5 to 1:1 gradient over 30 min). Concentrate in
vacuo to obtain
7-chloro-6-[4-(1-methoxyimino-ethyl)-benzylamino]-3-(2,2,2-trifluoroacety-
l)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (45 mg,
83%). MS (ES+) m/z: 454 (M+H).sup.+.
[0762] Use a method similar to the General Procedure 2-1, using
7-chloro-6-[4-(1-methoxyimino-ethyl)-benzylamino]-3-(2,2,2-trifluoroacety-
l)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (45 mg, 0.099 mmol), to
obtain
7-chloro-6-[4-(1-methoxyiminoethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-be-
nzo[d]azepine as a colorless oil (30 mg, 85%) suitable for use
without additional purification.
[0763] Use a method similar to the General Procedure 3-1, using
7-chloro-6-[4-(1-methoxyiminoethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-be-
nzo[d]azepine (30 mg, 0.084 mmol) to obtain the title compound, a
mixture of E- and Z-isomers, as a white solid (35.7 mg, 89%). MS
(ES+) m/z: 358 (M+H).sup.+.
EXAMPLES 2-3
[0764] Examples 2-3 may be prepared essentially as described in
Example 1 by using
6-(4-acetyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,-
4,5-tetrahydro-1H-benzo[d]azepine and the appropriate
O-alkylhydroxylamine hydrochloride. Overall yields and MS (ES+)
data are shown in the Table below.
TABLE-US-00017 ##STR00120## Yield MS (ES+) Ex. R Compound (%) m/z 2
Ethyl 7-Chloro-6-[4-(1-ethoxyimino- 55 372
ethyl)-benzylamino]-2,3,4,5- (M + H).sup.+
tetrahydro-1H-benzo[d]azepine Succinate 3 iso-Butyl
7-Chloro-6-[4-(1-iso-butoxyimino- 45 400
ethyl)-benzylamino]-2,3,4,5- (M + H).sup.+
tetrahydro-1H-benzo[d]azepine Succinate
EXAMPLE 4
7-Chloro-6-[4-(1-hydroxyimino-3-methyl-butyl)-benzylamino]-2,3,4,5-tetrahy-
dro-1H-benzo[d]azepine Succinate
##STR00121##
[0766] Add hydroxylamine hydrochloride (6.3 mg, 0.091 mmol) and
pyridine (15 uL, 0.182 mmol) to a solution of
7-chloro-6-[4-(3-methyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2-
,3,4,5-tetrahydro-1H-benzo[d]azepine (42 mg, 0.091 mmol) in ethanol
(1 mL). Heat the mixture to reflux for 18 h. Remove the solvent in
vacuo and partition the residue between DCM and 0.1N aqueous HCl.
Dry the organic phase over Na.sub.2SO.sub.4, filter and concentrate
in vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (95:5 to 1:1 gradient over 30 min). Concentrate in
vacuo to obtain
7-chloro-6-[4-(1-hydroxyimino-3-methyl-butyl)-benzylamino]-3-(2,2,2-trifl-
uoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an off-white
solid (19.1 mg, 44%). MS (ES+) m/z: 482 (M+H).sup.+.
[0767] Use a method similar to the General Procedure 2-1, using
7-chloro-6-[4-(1-hydroxyimino-3-methyl-butyl)-benzylamino]-3-(2,2,2-trifl-
uoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (45 mg, 0.099
mmol), to obtain
7-chloro-6-[4-(1-hydroxyimino-3-methyl-butyl)-benzylamino]-2,3,4,5-
-tetrahydro-1H-benzo[d]azepine as a colorless oil (14.5 mg,
42%).
[0768] Use a method similar to the General Procedure 3-1, using
7-chloro-6-[4-(1-hydroxyimino-3-methyl-butyl)-benzylamino]-2,3,4,5-tetrah-
ydro-1H-benzo[d]azepine (14.5 mg, 0.084 mmol) to obtain the title
compound, a mixture of E- and Z-isomers, as an off-white solid (15
mg, 90%). MS (ES+) m/z: 386 (M+H).sup.+.
EXAMPLE 5
[0769] Example 5 may be prepared essentially as described in
Example 4 using
7-chloro-6-[4-(3-methyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroace-
tyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine and
O-methylhydroxylamine hydrochloride. Example 5 was obtained as a
mixture of E- and Z-isomers.
TABLE-US-00018 Yield MS (ES+) Ex. Structure Compound (%) m/z 5
##STR00122##
7-Chloro-6-[4-(1-methoxyimino-3-methyl-butyl)-benzylamino]-2,3,4,5-tetrah-
ydro-1H-benzo[d]azepine Succinate 44 400(M + H).sup.+
EXAMPLE 6
7-Chloro-6-[4-(2-methylamino-thiazol-4-yl)-benzylamino]-2,3,4,5-tetrahydro-
-1H-benzo[d]azepine Succinate
##STR00123##
[0771] Use a method similar to the General Procedure 1-3, using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (0.48 g, 1.14 mmol) and
4-(2-methylamino-thiazol-4-yl)-benzylamine (0.4 g, 1.8 mmol), to
obtain
7-chloro-6-[4-(2-methylamino-thiazol-4-yl)-benzylamino]-3-(2,2,2-trifluor-
oacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an off-white
solid (0.12 g, 21%). MS (ES+) m/z: 495 (M+H).sup.+.
[0772] Use a method similar to the General Procedure 2-1 to
deprotect
7-chloro-6-[4-(2-methylamino-thiazol-4-yl)-benzylamino]-3-(2,2,2-trifluor-
oacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (112 mg, 0.227 mmol)
to obtain
7-chloro-6-[4-(2-methylamino-thiazol-4-yl)-benzylamino]-2,3,4,5-te-
trahydro-1H-benzo[d]azepine as an off-white foam (70 mg, 78%).
[0773] Use a method similar to the General Procedure 3-1, using
7-chloro-6-[4-(2-methylamino-thiazol-4-yl)-benzylamino]-2,3,4,5-tetrahydr-
o-1H-benzo[d]azepine (69 mg, 0.17 mmol) to obtain the title
compound as an off-white foam (76.6 mg, 85%). MS (ES+) m/z: 399
(M+H).sup.+.
EXAMPLES 7-12
[0774] Examples 7-12 may be prepared essentially as described in
Example 6 using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,-
3,4,5-tetrahydro-1H-benzo[d]azepine and the appropriately
substituted benzylamine. For Examples 11-12, deprotection to obtain
the free base was performed using a method similar to the General
Procedure 2-2. Overall yields and MS (ES+) data are shown in the
Table below.
TABLE-US-00019 ##STR00124## Yield MS (ES+) Ex. R, R' Compound (%)
m/z 7 Ethyl, H 7-Chloro-6-[4-(2- 16 413 ethylamino-thiazol-4-yl)-
(M + H).sup.+ benzylamino]-2,3,4,5- tetrahydro-1H- benzo[d]azepine
Succinate 8 iso-Propyl, H 7-Chloro-6-[4-(2-iso- 48 427
propylamino-thiazol-4-yl)- (M + H).sup.+ benzylamino]-2,3,4,5-
tetrahydro-1H- benzo[d]azepine Succinate 9 n-Propyl, H
7-Chloro-6-[4-(2-n- 64 427 propylamino-thiazol-4-yl)- (M + H).sup.+
benzylamino]-2,3,4,5- tetrahydro-1H- benzo[d]azepine Succinate 10
--(CH.sub.2).sub.5-- 7-Chloro-6-[4-(2-piperidin- 77 453
1-yl-thiazol-4-yl)- (M + H).sup.+ benzylamino]-2,3,4,5-
tetrahydro-1H- benzo[d]azepine Succinate 11 Cyclopropylmethyl,
7-Chloro-6-[4-(2- 82 439 H cyclopropylmethylamino- (M + H).sup.+
thiazol-4-yl)- benzylamino]-2,3,4,5- tetrahydro-1H- benzo[d]azepine
Succinate 12 iso-Butyl, H 7-Chloro-6-[4-(2-iso- 36 441
butylamino-thiazol-4-yl)- (M + H).sup.+ benzylamino]-2,3,4,5-
tetrahydro-1H- benzo[d]azepine Succinate
EXAMPLE 13
7-Chloro-6-[4-(2-methylamino-oxazol-4-yl)-benzylamino]-2,3,4,5-tetrahydro--
1H-benzo[d]azepine (L)-Tartrate
##STR00125##
[0776] Slurry 4-(2-methylamino-oxazol-4-yl)-benzylamine
hydrochloride (485 mg, 1.8 mmol) in toluene (10 mL) and DMF (1 mL)
at 90.degree. C. under a nitrogen atmosphere. Degass and place
under vacuum then purge with nitrogen three times. Add
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (0:5 g, 1.17 mmol),
tris(dibenzylideneacetone)dipalladium(0) (161 mg, 0.18 mmol), BINAP
(219 mg, 0.35 mmol) and cesium carbonate (1.6 g, 4.9 mmol) to the
slurry at 90.degree. C. Stir the mixture at 95.degree. C. for 16 h
in a sealed flask. Cool the reaction to room temperature, dilute
with EtOAc (100 mL), filter through Celite.RTM., and concentrate in
vacuo to an oil. Purify by chromatography on silica gel (10 g,
pre-packed cartridge) eluting with hexane/THF (40:1 to 4:1
gradient) followed by SCX chromatography (10 g) eluting with DCM
and DCM/2M ammonia in methanol (1: 1, 50 mL) to obtain
7-chloro-6-[4-(2-methylamino-oxazol-4-yl)-benzylamino]-35-(2,2,2-trifluor-
oacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (110 mg, 20%). MS
(ES+) m/z: 479.2 (M+H).sup.+.
[0777] Use a method similar to the General Procedure 2-2 to
deprotect
7-chloro-6-[4-(2-methylamino-oxazol-4-yl)-benzylamino]-3-(2,2,2-trifluoro-
acetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine. Purify by
chromatography on silica gel eluting with DCM/2M ammonia in
methanol (1:0 to 30:1 gradient) to obtain
7-chloro-6-[4-(2-methylamino-oxazol-4-yl)-benzylamino]-2,3,4,5--
tetrahydro-1H-benzo[d]azepine. Dissolve
7-chloro-6-[4-(2-methylamino-oxazol-4-yl)-benzylamino]-2,3,4,5-tetrahydro-
-1H-benzo[d]azepine (27 mg, 0.07 mmol) and (L)-tartaric acid (11
mg) in methanol. Concentrate in vacuo to an oil. Triturate oil with
diethyl ether and remove solvent in vacuo to obtain the title
compound as a solid (30 mg, 24%). MS (ES+) m/z: 383.1
(M+H).sup.+.
EXAMPLE 14
7-Chloro-6-[4-(cyclopentylthiomethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-b-
enzo[d]azepine (L)-Tartrate
##STR00126##
[0779] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (0.4 g, 0.94 mmol) with
4-(cyclopentylthiomethyl)-benzylamine (229 mg, 1.03 mmol) in
toluene (10 mL). Purify the crude mixture by chromatography on
silica gel eluting with isohexane/EtOAc (1:0 to 4:1 gradient) to
obtain
7-chloro-6-[4-(cyclopentylthiomethyl)-benzylamino]-3-(2,2,2-trifluoroacet-
yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (190 mg, 41%). MS (ES+)
m/z: 498 (M+H).sup.+.
[0780] Use a method similar to the General Procedure 2-1 to
deprotect
7-chloro-6-[4-(cyclopentylthiomethyl)-benzylamino]-3-(2,2,2-trifluoroacet-
yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (190 mg, 0.38 mmol).
Purify by SCX chromatography eluting with methanol and 3N ammonia
in methanol to obtain
7-chloro-6-[4-(cyclopentylthio-methyl)-benzylamino]-2,3,4,5-tetrah-
ydro-1H-benzo[d]azepine (142 mg). Use a method similar to the
General Procedure 3-2 to obtain the title compound (195.4 mg, 93%
over two steps). MS (ES+) m/z: 402 (M+H).sup.+.
EXAMPLE 15
[0781] Example 15 may be prepared essentially as described in
Example 14 using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,-
3,4,5-tetrahydro-1H-benzo[d]azepine and
4-(cyclohexylthiomethyl)-benzylamine. Overall yield and MS (ES+)
data are shown in the Table below.
TABLE-US-00020 Yield MS (ES+) Ex. Structure Compound (%) m/z 15
##STR00127##
7-Chloro-6-[4-(cyclohexylthiomethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-b-
enzo[d]azepine (L)-Tartrate 53 416(M + H).sup.+
EXAMPLE 16
7-Chloro-6-[(5-cyclopentylthiomethyl-pyridin-2-ylmethyl)-amino]-2,3,4,5-te-
trahydro-1H-benzo[d]azepine (L)-Tartrate
##STR00128##
[0783] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (245 mg, 0.58 mmol) with
2-aminomethyl-5-cyclopentylthiomethyl-pyridine (230 mg, 1 mmol) in
toluene (5 mL). Purify the crude mixture by chromatography on
silica gel eluting with hexane/THF (49:1 to 7:3 gradient) to obtain
7-chloro-6-[(5-cyclopentylthiomethyl-pyridin-2-ylmethyl)-amino]-3-(2,2,2--
trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (170 mg,
59%). MS (ES+) m/z: 498.1 (M+H).sup.+.
[0784] Use a method similar to the General Procedure 2-3 to
deprotect
7-chloro-6-[(5-cyclopentylthiomethyl-pyridin-2-ylmethyl)-amino]-3-(2,2,2--
trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine. Purify by
chromatography on silica gel eluting with DCM/2M ammonia in
methanol (99:1 to 9:1 gradient) to obtain
7-chloro-6-[(5-cyclopentylthiomethyl-pyridin-2-ylmethyl)-amino]-2,3,4,5-t-
etrahydro-1H-benzo[d]azepine. Dissolve
7-chloro-6-[(5-cyclopentylthiomethyl-pyridin-2-ylmethyl)-amino]-2,3,4,5-t-
etrahydro-1H-benzo[d]azepine (68 mg, 0.14 mmol) and (L)-tartaric
acid (21 mg, 0.14 mmol) in methanol. Concentrate in vacuo to an
oil. Triturate oil with diethyl ether and remove solvent in vacuo
to obtain the title compound as a solid (85 mg, 48%). MS (ES+) m/z:
402.1 (M+H).sup.+.
EXAMPLES 17-19
[0785] Examples 17-19 may be prepared essentially as described in
Example 16 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine and the appropriately substituted
2-aminomethyl-pyridine. Overall yields and MS (ES+) data are shown
in the Table below.
TABLE-US-00021 Yield MS (ES+) Ex. Structure Compound (%) m/z 17
##STR00129##
7-Chloro-6-[(5-cyclohexylthio-methyl-pyridin-2-ylmethyl)-amino]-2,3,4,5-t-
etrahydro-1H-benzo[d]azepine (L)-Tartrate 10 416.1(M + H).sup.+ 18
##STR00130##
7-Chloro-6-[(5-iso-propylthio-methyl-pyridin-2-ylmethyl)-amino]-2,3,4,5-t-
etrahydro-1H-benzo[d]azepine (L)-Tartrate 12 376.1(M + H).sup.+ 19
##STR00131##
7-Chloro-6-[(5-iso-butylthio-methyl-pyridin-2-ylmethyl)-amino]-2,3,4,5-te-
trahydro-1H-benzo[d]azepine (L)-Tartrate 10 390.1(M + H).sup.+
EXAMPLE 20
7-Chloro-6-{6-[(2,2-dimethyl-propylthiomethyl)-pyridin-3-ylmethyl]-amino}--
2,3,4,5-tetrahydro-1H-benzo[d]azepine (L)-Tartrate
##STR00132##
[0787] Use a method similar to the General Procedure 1-3 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (586 mg, 1.37 mmol) with
3-aminomethyl-6-[(2,2-dimethylpropyl)thiomethyl]-pyridine (340 mg,
1.51 mmol) in 1,4-dioxane (15 mL). Purify by chromatography on
silica gel eluting with hexane/EtOAc (10:1, 5:1 and 3:1) followed
by SCX chromatography eluting with DCM and DCM/2M ammonia in
methanol (1:1). Concentrate in vacuo to obtain
7-chloro-6-{6-[(2,2-dimethyl-propylthiomethyl)-pyridin-3-ylmethyl]-amino}-
-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as
a yellow oil (0.2 g, 29%).
[0788] Use a method similar to the General Procedure 2-1 to
deprotect
7-chloro-6-{6-[(2,2-dimethyl-propylthiomethyl)-pyridin-3-ylmethyl]-amino}-
-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(0.2 g, 0.4 mmol). Purify by chromatography on silica gel eluting
with DCM/2M ammonia in methanol (99:1 to 90:10) to obtain
7-chloro-6-{6-[(2,2-dimethyl-propylthiomethyl)-pyridin-3-ylmethyl]-amino}-
-2,3,4,5-tetrahydro-1H-benzo[d]azepine. Use a method similar to the
General Procedure 3-2 to obtain the title compound (103 mg, 62%).
MS (ES+) m/z: 405 (M+H).sup.+.
EXAMPLES 21-23
[0789] Examples 21-23 may be prepared essentially as described in
Example 20 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine and the appropriately substituted
amine. Overall yields and MS (ES+) data are shown in the Table
below.
TABLE-US-00022 Yield MS (ES+) Ex. Structure Compound (%) m/z 21
##STR00133##
7-Chloro-6-[4-(3,3-dimethyl-cyclohexylthiomethyl)-benzylamino]-2,3,4,5-te-
trahydro-1H-benzo[d]azepine (L)-Tartrate 59 443(M + H).sup.+ 22
##STR00134##
7-Chloro-6-[4-(3,3-dimethyl-cyclohexylthio)-benzylamino]-2,3,4,5-tetrahyd-
ro-1H-benzo[d]azepine (L)-Tartrate 67 429(M + H).sup.+ 23
##STR00135##
7-Chloro-6-{6-[(3,3-dimethyl-cyclohexylthio)-pyridin-3-ylmethyl]-amino}-2-
,3,4,5-tetrahydro-1H-benzo[d]azepine (L)-Tartrate 71 430(M +
H).sup.+
EXAMPLE 24
6-[(6-tert-Butylthiomethyl-pyridin-3-ylmethyl)-amino]-7-chloro-2,3,4,5-tet-
rahydro-1H-benzo[d]azepine (L)-Tartrate
##STR00136##
[0791] Use a method similar to the General Procedure 1-3. Add
3-aminomethyl-6-(tert-butylthio)methyl-pyridine (2.99 g, 14.2
mmol),
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (5.05 g, 11.9 mmol),
tris(dibenzylideneacetone)dipalladium(0) (275 mg, 0.3 mmol),
palladium(II) acetate (133 mg, 0.6 mmol), BINAP (560 mg, 0.9 mmol)
and cesium carbonate (5.82 g, 17.9 mmol) to toluene (100 mL) under
a nitrogen atmosphere. Heat the mixture at 90.degree. C. for 12 h.
Cool the mixture to room temperature. Purify by chromatography on
silica gel eluting with hexane/EtOAc (100:0 to 85:15 gradient) to
obtain
6-[(6-tert-butylthiomethyl-pyridin-3-ylmethyl)-amino]-7-chloro-3-(2,2,2-t-
rifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (4.1 g, 71%).
MS (APCI+) m/z: 486 (M+H).sup.+.
[0792] Dissolve
6-[(6-tert-butylthiomethyl-pyridin-3-ylmethyl)-amino]-7-chloro-3-(2,2,2-t-
rifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (4.46 g, 9.24
mmol) in methanol (20 mL). Add a solution of potassium carbonate
(5.1 g, 37 mmol) in water (10 mL) and stir at room temperature for
12 h. Remove methanol in vacuo, dilute the residue with water, and
extract the aqueous phase with DCM. Purify the crude mixture by SCX
chromatography (20 g) eluting with methanol and a solution of
NH.sub.4OH (40 mL) in methanol (140 mL). Concentrate in vacuo to
obtain pure
6-[(6-tert-butylthiomethyl-pyridin-3-ylmethyl)-amino]-7-chloro-2,3,4,5-te-
trahydro-1H-benzo[d]azepine (3.6 g, 100%). MS (APCI+) m/z: 390
(M+H).sup.+.
[0793] Dissolve
6-[(6-tert-butylthiomethyl-pyridin-3-ylmethyl)-amino]-7-chloro-2,3,4,5-te-
trahydro-1H-benzo[d]azepine (3.6 g, 9.24 mmol) in methanol and add
(L)-tartaric acid (1.25 g, 8.32 mmol). Stir the mixture until
homogeneous. Concentrate the mixture in vacuo, dissolve in water,
and freeze dry to provide the title compound as a solid (4.4 g,
88%). MS (APCI+) m/z: 390 (M+H).sup.+.
EXAMPLE 25
7-Chloro-6-{6-[(3,3-dimethyl-cyclohexyloxy)-pyridin-3-ylmethyl]-amino}-2,3-
,4,5-tetrahydro-1H-benzo[d]azepine (L)-Tartrate Isomer 1
##STR00137##
[0795] Use a method similar to the General Procedure 1-3 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (1 g, 2.54 mmoles) with
3-aminomethyl-6-(3,3-dimethyl-cyclohexyloxy)-pyridine isomer 1 (596
mg, 2.54 mmoles). Purify by chromatography on silica gel (40 g,
pre-packed cartridge) eluting with cyclohexane/EtOAc (1:0 to 7:3
gradient) to afford
7-chloro-6-{6-[(3,3-dimethyl-cyclohexyloxy)-pyridin-3-ylmethyl]-amino}-3--
(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
isomer 1 as an oil (870 mg, 62%).
[0796] Use a method similar to the General Procedure 2-2, using 7N
ammonia in methanol/water/THF (10:1:1 ratio) as solvent, to
deprotect
7-chloro-6-{6-[(3,3-dimethyl-cyclohexyloxy)-pyridin-3-ylmethyl]-amino}-3--
(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
isomer 1. Purify by SCX-2 chromatography eluting with methanol
followed by 3N ammonia in methanol to obtain
7-chloro-6-{6-[(3,3-dimethyl-cyclohexyloxy)-pyridin-3-ylmethyl]-amino}-2,-
3,4,5-tetrahydro-1H-benzo[d]azepine isomer 1 (673 mg).
[.alpha.].sub.D=-15.5.degree.(c=0.23, EtOH).
[0797] Use a method similar to the General Procedure 3-2 to obtain
the title compound as a solid (916 mg, 69% three steps). MS (ES+)
m/z: 414.2 (M+H).sup.+.
EXAMPLES 26-32
[0798] Examples 26-32 may be prepared essentially as described in
Example 25 using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-
-2,3,4,5-tetrahydro-1H-benzo[d]azepine and the appropriately
substituted amine. Overall yields and MS (ES+) data are shown in
the Table below. Optical rotation for Example 26 is also shown in
the Table below.
TABLE-US-00023 Yield MS (ES+) Ex. Structure Compound (%) m/z 26
##STR00138##
7-Chloro-6-{6-[(3,3-dimethyl-cyclohexyloxy)-pyridin-3-ylmethyl]-amino}-2,-
3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate Isomer 2 35 414(M +
H).sup.+Free base:[.alpha.].sub.D = +19.degree.(c = 0.25,EtOH) 27
##STR00139##
7-Chloro-6-[(6-cyclopentylthiomethyl-pyridin-3-ylmethyl)-amino]-2,3,4,5-t-
etrahydro-1H-benzo[d]azepine(L)-Tartrate 30 402(M + H).sup.+ 28
##STR00140##
7-Chloro-6-[(6-cyclohexylthiomethyl-pyridin-3-ylmethyl)-amino]-2,3,4,5-te-
trahydro-1H-benzo[d]azepine(L)-Tartrate 21 416(M + H).sup.+ 29
##STR00141##
7-Chloro-6-[(6-cyclohexyloxy-pyridin-3-ylmethyl)-amino]-2,3,4,5-tetrahydr-
o-1H-benzo[d]azepine(L)-Tartrate 45 386(M + H).sup.+ 30
##STR00142##
7-Chloro-6-{6-[(4,4-dimethyl-cyclohexyloxy)-pyridin-3-ylmethyl]-amino}-2,-
3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 60 414(M + H).sup.+
32 ##STR00143##
7-Chloro-6-[6-(2-methyl-2-propane-sulfonylmethyl)-pyridin-3-ylmethyl]-ami-
no}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (L)-Tartrate 55 422(M +
H).sup.+
EXAMPLE 33
7-Chloro-6-[(6-iso-propoxymethyl-pyridin-3-ylmethyl)-amino]-2,3,4,5-tetrah-
ydro-1H-benzo[d]azepine (L)-Tartrate
##STR00144##
[0800] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (408 mg, 0.96 mmol) with
3-aminomethyl-6-(iso-propoxy)methyl-pyridine (190 mg, 1.05 mmol) in
toluene (8 mL). Purify the crude mixture by chromatography on
silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient) to
obtain
7-chloro-6-[(6-iso-propoxymethyl-pyridin-3-ylmethyl)-amino]-3-(2,2,2-trif-
luoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine. MS (ES+) m/z:
456 (M+H).sup.+.
[0801] Use a method similar to the General Procedure 2-1 to
deprotect
7-chloro-6-[(6-iso-propoxymethyl-pyridin-3-ylmethyl)-amino]-3-(2,2,2-trif-
luoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine. Purify by SCX
chromatography eluting with methanol and 3N ammonia in methanol and
then by reverse phase HPLC (Princeton SPHER-C.sub.18 100 .ANG.
column 5 .quadrature.m, 100.times.20 mm; 20-95% of solvent B in 11
min then 95% of solvent B in 4 min; solvent A: water, 0.1% acetic
acid; solvent B: acetonitrile, 0.1% acetic acid; 20 mL/min). Use a
method similar to the General Procedure 3-2 to obtain the title
compound (76 mg, 22%). MS (ES+) m/z: 361 (M+H).sup.+.
EXAMPLES 34-36
[0802] Examples 34-36 may be prepared essentially as described in
Example 33 using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-
-2,3,4,5-tetrahydro-1H-benzo[d]azepine and the appropriately
substituted-3-aminomethyl-pyridine. Overall yields and MS (ES+)
data are shown in the Table below.
TABLE-US-00024 ##STR00145## Yield MS (ES+) Ex. R Compound (%) m/z
34 2,2-Dimethyl- 7-Chloro-6-[(2,2- 9 388 propyl
dimethylpropoxymethyl- (M + H).sup.+ pyridin-3-ylmethyl)-amino]-
2,3,4,5-tetrahydro-1H- benzo[d]azepine (L)-Tartrate 35 Cyclopentyl
7-Chloro-6- 50 387 [(cyclopentyloxymethyl- (M + H).sup.+
pyridin-3-ylmethyl)-amino]- 2,3,4,5-tetrahydro-1H- benzo[d]azepine
(L)-Tartrate 36 Cyclohexyl 7-Chloro-6- 11 401
[(cyclohexyloxymethyl- (M + H).sup.+ pyridin-3-ylmethyl)-amino]-
2,3,4,5-tetrahydro-1H- benzo[d]azepine (L)-Tartrate
EXAMPLE 37
7-Chloro-6-[(5-cyclohexyloxy-pyridin-2-ylmethyl)-amino]-2,3,4,5-tetrahydro-
-1H-benzo[d]azepine Succinate
##STR00146##
[0804] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (705 mg, 1.66 mmol) and
2-aminomethyl-5-cyclohexyloxy-pyridine (410 mg, 1.99 mmol). Purify
the crude mixture by chromatography on silica gel (150 g,
pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 9:1
gradient) to obtain
7-chloro-6-[(5-cyclohexyloxy-pyridin-2-ylmethyl)-amino]-3-(2,2,2-trifluor-
oacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (520 mg, 65%). MS
(APCI+) m/z: 482 (M+H).sup.+.
[0805] Use a method similar to the General Procedure 2-1 to
deprotect
7-chloro-6-[(5-cyclohexyloxy-pyridin-2-ylmethyl)-amino]-3-(2,2,2-trifluor-
oacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (520 mg). Purify the
crude mixture by SCX chromatography to obtain
7-chloro-6-[(5-cyclohexyloxy-pyridin-2-ylmethyl)-amino]-2,3,4,5-tetrahydr-
o-1H-benzo[d]azepine (510 mg, 92%).
[0806] Use a method similar to the General Procedure 3-1, using
7-chloro-6-[(5-cyclohexyloxy-pyridin-2-ylmethyl)-amino]-2,3,4,5-tetrahydr-
o-1H-benzo[d]azepine (510 mg) to obtain the title compound as a
white solid (590 mg, 82%). MS (APCI+) m/z: 386 (M+H).sup.+.
EXAMPLE 38
[0807] Example 38 may be prepared essentially as described in
Example 37 using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,-
3,4,5-tetrahydro-1H-benzo[d]azepine and
2-aminomethyl-5-cycloheptyloxy-pyridine. Deprotection to obtain the
free base was performed using a method similar to the General
Procedure 2-3. Overall yields and MS (ES+) data are shown in the
Table below.
TABLE-US-00025 Yield MS (ES+) Ex. Structure Compound (%) m/z 38
##STR00147##
7-Chloro-6-[(5-cycloheptyloxy-pyridin-2-ylmethyl)-amino]-2,3,4,5-tetrahyd-
ro-1H-benzo[d]azepine Succinate 32 400(M + H).sup.+
EXAMPLE 39
7-Chloro-6-{5-[(3,3-dimethylcyclohexyloxy)-pyridin-2-ylmethyl]-amino}-2,3,-
4,5-tetrahydro-1H-benzo[d]azepine Succinate
##STR00148##
[0809] Use a method similar to the General Procedure 1-1 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (378 mg, 0.888 mmol) and
2-aminomethyl-5-(3,3-dimethylcyclohexyloxy)-pyridine (260 mg, 1.11
mmol). Purify by chromatography on silica gel eluting with
hexane/EtOAc (1:0 to 2:1 gradient) to obtain
7-chloro-6-{5-[(3,3-dimethylcyclohexyloxy)-pyridin-2-ylmethyl]-amino}-3-(-
2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a
light yellow oil (107 mg, 24%). MS (APCI+) m/z: 510
(M+H).sup.+.
[0810] Use a method similar to the General Procedure 2-1, using
7-chloro-6-{5-[(3,3-dimethylcyclohexyloxy)-pyridin-2-ylmethyl]-amino}-3-(-
2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (106
mg, 0.208 mmol) to obtain
7-chloro-6-{5-[(3,3-dimethylcyclohexyloxy)-pyridin-2-ylmethyl]-amino}-2,3-
,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (68 mg, 79%).
MS (APCI+) m/z: 482 (M+H).sup.+.
[0811] Use a method similar to the General Procedure 3-1, using
7-chloro-6-{5-[(3,3-dimethylcyclohexyloxy)-pyridin-2-ylmethyl]-amino}-2,3-
,4,5-tetrahydro-1H-benzo[d]azepine (65 mg, 0.157 mmol) to obtain
the title compound as an off-white solid (71 mg, 85%). MS (APCI+)
m/z: 414 (M+H).sup.+.
EXAMPLE 40
[0812]
(E)-7-Chloro-6-{6-[(2-cyclohexyl-vinyl)-pyridin-3-ylmethyl]-amino}--
2,3,4,5-tetrahydro-1H-benzo[d]azepine Succinate
##STR00149##
[0813] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (579 mg, 1.361 mmol) and
(E)-3-aminomethyl-6-(2-cyclohexylvinyl)-pyridine (368 mg, 1.701
mmol). Purify by chromatography on silica gel (80 g, pre-packed
cartridge) eluting sequentially with hexane/EtOAc (1:0, 49:1, 19:1,
93:7, 9:1 and 85:15) to obtain
(E)-7-chloro-6-{6-[(2-cyclohexyl-vinyl)-pyridin-3-ylmethyl]-amino}-3-(2,2-
,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (445 mg,
66%). MS (APCI+) m/z: 492 (M+H).sup.+.
[0814] Use a method similar to the General Procedure 2-3 to
deprotect
(E)-7-chloro-6-{6-[(2-cyclohexyl-vinyl)-pyridin-3-ylmethyl]-amino}-3-(2,2-
,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (607 mg,
1.234 mmol) using lithium hydroxide monohydrate (525 mg, 12.52
mmol) in methanol (15 mL) for 2 h. Purify by chromatography on
silica gel (120 g, pre-packed cartridge) eluting sequentially with
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) (49:1,
19:1, 9:1 and 17:3) to obtain
(E)-7-chloro-6-{6-[(2-cyclohexyl-vinyl)-pyridin-3-ylmethyl]-amino}-2,3,4,-
5-tetrahydro-1H-benzo[d]azepine (481 mg, 98%). MS (APCI+) m/z: 396
(M+H).sup.+.
[0815] Use a method similar to the General Procedure 3-1, using
(E)-7-chloro-6-{6-[(2-cyclohexyl-vinyl)-pyridin-3-ylmethyl]-amino}-2,3,4,-
5-tetrahydro-1H-benzo[d]azepine (481 mg, 1.215 mmol) to obtain the
title compound (605 mg, 97%). MS (APCI+) m/z: 396 (M+H).sup.+.
EXAMPLES 41-44
[0816] Examples 41-44 may be prepared essentially as described in
Example 40 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine and the appropriately substituted
amine. For Example 44, (L)-Tartrate salt was prepared essentially
as described in General Procedure 3-2. Overall yields and MS (ES+)
data are shown in the Table below.
TABLE-US-00026 Yield MS (ES+) Ex. Structure Compound (%) m/z 41
##STR00150##
(E)-7-Chloro-6-{5-[(2-cyclohexyl-vinyl)-pyridin-2-ylmethyl]-amino}-2,3,4,-
5-tetrahydro-1H-benzo[d]azepine Succinate 3 396 (M + H).sup.+ 42
##STR00151##
(Z)-7-Chloro-6-{6-[(2-cyclohexyl-vinyl)-pyridin-3-ylmethyl]-amino}-2,3,4,-
5-tetrahydro-1H-benzo[d]azepine Succinate 50 396 (M + H).sup.+ 43
##STR00152##
(Z)-7-Chloro-6-{5-[(2-cyclohexyl-vinyl)-pyridin-2-ylmethyl]-amino}-2,3,4,-
5-tetrahydro-1H-benzo[d]azepine Succinate 4 396 (M + H).sup.+ 44
##STR00153##
(Z)-7-Chloro-6-[4-(2-cyclohexyl-vinyl)-benzylamino]-2,3,4,5-tetrahydro-1H-
-benzo[d]azepine (L)-Tartrate 12 395.2(M + H).sup.+
EXAMPLE 45
7-Chloro-6-[4-(2-cyclohexyl-2-oxo-ethyl)-benzylamino]-2,3,4,5-tetrahydro-1-
H-benzo[d]azepine (L)-Tartrate
##STR00154##
[0818] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (137 mg, 0.325 mmol) and
4-(2-cyclohexyl-2-oxo-ethyl)-benzylamine (150 mg, 0.65 mmol).
Purify by chromatography on silica gel eluting with hexane/EtOAc
(95:5) to obtain
7-chloro-6-[4-(2-cyclohexyl-2-oxo-ethyl)-benzylamino]-3-(2,2,2-trifluoroa-
cetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (76
mg, 46%). MS (ES+) m/z: 507 (M+H).sup.+.
[0819] Use a method similar to the General Procedure 2-1, using
7-chloro-6-[4-(2-cyclohexyl-2-oxo-ethyl)-benzylamino]-3-(2,2,2-trifluoroa-
cetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (76 mg, 0.150 mmol) to
obtain
7-chloro-6-[4-(2-cyclohexyl-2-oxo-ethyl)-benzylamino]-2,3,4,5-tetrahydro--
1H-benzo[d]azepine (59 mg, 93%) as a yellow oil suitable for use
without additional purification.
[0820] Use a method similar to the General Procedure 3-2, using
7-chloro-6-[4-(2-cyclohexyl-2-oxo-ethyl)-benzylamino]-2,3,4,5-tetrahydro--
1H-benzo[d]azepine (59 mg, 0.142 mmol) to obtain the title compound
as a white solid (79 mg, 99%). MS (ES+) m/z: 411 (M+H).sup.+.
EXAMPLE 46
7-Chloro-6-[4-(morpholin-4-ylmethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-be-
nzo[d]azepine Succinate
##STR00155##
[0822] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (400 mg, 0.94 mmol) with
4-(morpholin-4-ylmethyl)-benzylamine (291 mg, 1.41 mmol). Purify by
chromatography on silica gel (80 g, pre-packed cartridge) eluting
with hexane/EtOAc (1:0 to 2:1 gradient) to obtain
7-chloro-6-[4-(morpholin-4-ylmethyl)-benzylamino]-3-(2,2,2-trifluoroacety-
l)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (304 mg, 67%). MS (APCI+)
m/z: 482 (M+H).sup.+.
[0823] Use a method similar to the General Procedure 2-2, using
7-chloro-6-[4-(morpholin-4-ylmethyl)-benzylamino]-3-(2,2,2-trifluoroacety-
l)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (294 mg, 0.61 mmol) to
obtain
7-chloro-6-[4-(morpholin-4-ylmethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-b-
enzo[d]azepine as a colorless oil (230 mg, 98%). MS (APCI+) m/z:
386 (M+H).sup.+.
[0824] Use a method similar to the General Procedure 3-1, using
7-chloro-6-[4-(morpholin-4-ylmethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-b-
enzo[d]azepine (230 mg, 0.596 mmol) to obtain the title compound as
an off-white solid (295 mg, 98%). MS (APCI+) m/z: 386
(M+H).sup.+.
EXAMPLES 47-48
[0825] Examples 47-48 may be prepared essentially as described in
Example 46 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine and the appropriately substituted
benzylamine. Enantiomeric excess of Example 47 was 92.7%
[Analytical chiral conditions: Chiralpak.RTM. AD column;
250.times.4.6 mm, eluting with hexane/iso-propanol (95:5 with 0.1%
diethylamine)]. Overall yields and MS (ES+) data are shown in the
Table below.
TABLE-US-00027 Yield MS (ES+) m/z; Ex. Structure Compound (%)
[.alpha.].sub.D (c, solvent) 47 ##STR00156##
(R)-7-Chloro-6-{4-[(1-methyl-2,2,2-trifluoro-ethylamino)-methyl]-benzylam-
ino}-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine Succinate 38
412 (M + H).sup.+;[.quadrature.].sub.D = -8.2.degree.(c = 0.5,
MeOH) 48 ##STR00157##
7-Chloro-6-{4-[(2,2,2-trifluoroethylamino)-methyl]-benzylamino}-7-chloro--
2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 43 398 (M +
H).sup.+
EXAMPLE 49
7-Chloro-6-[4-(piperidin-1-ylmethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-be-
nzo[d]azepine Succinate
##STR00158##
[0827] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethansulfonyloxy-2,3,4,5-t-
etrahydro-1H-benzo[d]azepine (300 mg, 0.69 mmol) and
4-(piperidin-1-ylmethyl)-benzylamine (174 mg, 0.84 mmol). Purify by
chromatography on silica gel (150 g) eluting with a gradient of DCM
to 4:1 DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) to
obtain
7-chloro-6-[4-(piperidin-1-ylmethyl)-benzylamino]-3-(2,2,2-trifluoroacety-
l)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (240 mg, 71%).
MS (ES+) m/z: 480 (M+H).sup.+.
[0828] Use a method similar to the General Procedure 2-2, using
7-chloro-6-[4-(piperidin-1-ylmethyl)-benzylamino]-3-(2,2,2-trifluoroacety-
l)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (370 mg, 0.77 mmol).
Purify by chromatography on silica gel (12 g, pre-packed cartridge)
eluting with a gradient of DCM to 4:1
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) to obtain
7-chloro-6-[4-(piperidin-1-ylmethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-b-
enzo[d]azepine as a clear oil (270 mg, 95%). MS (APCI+) m/z: 384
(M+H).sup.+.
[0829] Use a method similar to the General Procedure 3-1, using
7-chloro-6-[4-(piperidin-1-ylmethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-b-
enzo[d]azepine (270 mg, 0.7 mmol) to obtain the title compound as
an off-white solid (335 mg, 96%). MS (APCI+) m/z: 384
(M+H).sup.+.
EXAMPLES 50-52
[0830] Examples 50-52 may be prepared essentially as described in
Example 49 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine and the appropriately substituted
benzylamine. Overall yields and MS (ES+) data are shown in the
Table below.
TABLE-US-00028 Yield MS (APCI+) Ex. Structure Compound (%) m/z 50
##STR00159##
7-Chloro-6-[4-(pyrrolidin-1-ylmethyl)-benzylamino]-2,3,4,5-tetrahydro-1H--
benzo[d]azepineSuccinate 51 370(M + H).sup.+ 51 ##STR00160##
7-Chloro-6-[4-(azepan-1-ylmethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benz-
o[d]azepineSuccinate 12 398(M + H).sup.+ 52 ##STR00161##
7-Chloro-6-{4-[(1-methyl-2,2,2-trifluoro-ethylamino)-methyl]-benzylamino}-
-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine Succinate 40 412(M
+ H).sup.+
EXAMPLE 53
7-Chloro-6-{4-[N-(cyclohexyl)-aminomethyl]-benzylamino}-2,3,4,5-tetrahydro-
-1H-benzo[d]azepine Succinate
##STR00162##
[0832] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (300 mg, 0.71 mmol) and
4-[N-(tert-butoxycarbonyl)-N-(cyclohexyl)-aminomethyl]-benzylamine
(335 mg, 1.05 mmol). Purify by chromatography on silica gel (150 g)
eluting with hexane/EtOAc (1:0 to 9:1 gradient) to obtain
6-{4-[N-(tert-butoxycarbonyl)-N-(cyclohexyl)-aminomethyl]-benzylamino}-7--
chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(320 mg, 76%). MS (ES+) m/z: 494 (M-Boc+H).sup.+.
[0833] Bubble hydrogen chloride into a solution of
6-{4-[N-(tert-butoxycarbonyl)-N-(cyclohexyl)-aminomethyl]-benzylamino}-7--
chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(355 mg, 0.6 mmol) in EtOAc (5 mL) at room temperature. Stir the
mixture for 1 h, and concentrate in vacuo. Dissolve the residue in
methanol (5 mL) and add water (2 mL) and K.sub.2CO.sub.3 (1 g, 7.2
mmol). Stir the mixture at room temperature overnight. Concentrate
the mixture in vacuo and partition the residue between water (20
mL) and DCM (20 mL). Extract the aqueous phase with DCM (2.times.20
mL). Dry the combined organic extracts over Na.sub.2SO.sub.4,
filter, and concentrate in vacuo. Purify by reverse phase
chromatography [Phenomonex C18(2) column (5.times.25 cm) eluting
with a gradient of water:acetonitrile (0.1% TFA in each) 9:1
through 2:3 over 50 min, 118 mL/min]. Concentrate pure fractions
and apply to a SCX column (3.5 g) eluting with methanol and 3N
ammonia in methanol to obtain
7-chloro-6-{4-[N-(cyclohexyl)-aminomethyl]-benzylamino}-2,3,4,5-tetrahydr-
o-1H-benzo[d]azepine (204 mg, 86%).
[0834] Use a method similar to the General Procedure 3-1, using
7-chloro-6-{4-[N-(cyclohexyl)-aminomethyl]-benzylamino}-2,3,4,5-tetrahydr-
o-1H-benzo[d]azepine (204 mg, 0.51 mmol) to obtain the title
compound as an off-white solid (245 mg, 93%). MS (APCI+) m/z: 398
(M+H).sup.+.
EXAMPLES 54-55
[0835] Examples 54-55 may be prepared essentially as described in
Example 53 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine and the appropriately substituted
benzylamine. Overall yields and MS (ES+) data are shown in the
Table below.
TABLE-US-00029 Yield Ex. Structure Compound (%) 54 ##STR00163##
6-{4-[N-(iso-Butyl)-aminomethyl]-benzylamino}-7-chloro-2,3,4,5-tetrahydro-
-1H-benzo[d]azepine Succinate 42 55 ##STR00164##
7-Chloro-6-{4-[N-(iso-propyl)-aminomethyl]-benzylamino}-2,3,4,5-tetrahydr-
o-1H-benzo[d]azepine Succinate 52
EXAMPLE 56
7-Chloro-6-{4-[(N-methyl-iso-propylamino)-methyl]-benzylamino}-2,3,4,5-tet-
rahydro-1H-benzo[d]azepine Succinate
##STR00165##
[0837] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (500 mg, 1.18 mmol) with
4-[(N-methyl-iso-propylamino)-methyl]-benzylamine (270 mg, 1.41
mmol) in toluene (10 mL). Purify by chromatography on silica gel
(75 g) eluting with a gradient of 100% DCM to 9:1
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) to obtain
7-chloro-6-{4-[(N-methyl-iso-propylamino)-methyl]-benzylamino}-3-(2,2,2-t-
rifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (350 mg,
64%). MS (APCI) m/z: 468 (M+H).sup.+.
[0838] Dissolve
7-chloro-6-{4-[(N-methyl-iso-propylamino)-methyl]-benzylamino}-3-(2,2,2-t-
rifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (350 mg, 0.75
mmol) in concentrated NH.sub.4OH (10 mL) and MeOH (10 mL). Stir the
reaction mixture overnight. Concentrate the mixture in vacuo.
Purify by chromatography on silica gel (45 g) eluting with a
gradient of 100% DCM to 1:1 DCM/(chloroform:methanol:concentrated
NH.sub.4OH 80:18:2) to obtain
7-chloro-6-{4-[(N-methyl-iso-propylamino)-methyl]-benzylamino}-2,3-
,4,5-tetrahydro-1H-benzo[d]azepine (260 mg, 93%). MS (APCI+) 7m/z:
372 (M+H).sup.+.
[0839] Dissolve
7-chloro-6-{4-[(N-methyl-iso-propylamino)-methyl]-benzylamino}-2,3,4,5-te-
trahydro-1H-benzo[d]azepine (250 mg, 0.67 mmol) in methanol and add
succinic acid (75 mg, 0.63 mmol). Stir the mixture until
homogeneous. Concentrate the mixture in vacuo, dissolve in water,
and freeze dry the solution to obtain the title compound (325 mg,
95%). MS (APCI+) 7f/z: 372 (M+H).sup.+.
EXAMPLE 57
7-Chloro-6-{5-[(N-cyclohexyl-aminomethyl)-pyridin-2-yl-methyl]-amino}-2,3,-
4,5-tetrahydro-1H-benzo[d]azepine Succinate
##STR00166##
[0841] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (400 mg, 0.94 mmol) and
6-aminomethyl-3-[N-(cyclohexyl)-N-(2,2,2-trifluoroacetyl)-aminomethyl]-py-
ridine (440 mg, 1.41 mmol). Purify the crude mixture by
chromatography on silica gel (150 g) eluting with hexane/EtOAc (1:0
to 7:3 gradient) to obtain
7-chloro-6-{5-[(N-cyclohexyl-N-(2,2,2-trifluoroacetyl)-aminomethyl-
)-pyridin-2-yl-methyl]-amino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-
-1H-benzo[d]azepine as an oil (350 mg, 63%). MS (APCI+) m/z: 591
(M+H).sup.+.
[0842] Dissolve
7-chloro-6-{5-[(N-cyclohexyl-N-(2,2,2-trifluoroacetyl)-aminomethyl)-pyrid-
in-2-yl-methyl]-amino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-ben-
zo[d]azepine (350 mg, 0.59 mmol) in K.sub.2CO.sub.3 (400 mg, 2.9
mmol), methanol (10 mL), and water (10 mL), and stir for 12 h at
60.degree. C. Extract with DCM and purify the crude mixture by SCX
chromatography (4 g) eluting with methanol and 3N ammonia in
methanol to obtain
7-chloro-6-{5-[(N-cyclohexyl-aminomethyl)-pyridin-2-yl-methyl]-amino}-2,3-
,4,5-tetrahydro-1H-benzo[d]azepine as an oil (210 mg, 89%). MS
(APCI+) m/z: 399 (M+H).sup.+.
[0843] Use a method similar to the General Procedure 3-1, using
7-chloro-6-{5-[(N-cyclohexyl-aminomethyl)-pyridin-2-yl-methyl]-amino}-2,3-
,4,5-tetrahydro-1H-benzo[d]azepine (210 mg, 0.53 mmol) to obtain
the title compound as a yellow solid (260 mg, 96%). MS (APCI+) m/z:
399 (M+H).sup.+.
EXAMPLE 58
7-Chloro-6-{6-[(piperidin-1-ylmethyl)-pyridin-3-yl-methyl]-amino}-2,3,4,5--
tetrahydro-1H-benzo[d]azepine Succinate
##STR00167##
[0845] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (340 mg, 0.799 mmol) and
5-aminomethyl-2-(piperidin-1-ylmethyl)-pyridine (246 mg, 1.19
mmol). Purify by chromatography on silica gel (80 g) eluting with
hexane/EtOAc (1:0 to 1:2 gradient over 1.25 h, 80 mL/min) to obtain
7-chloro-6-{6-[(piperidin-1-ylmethyl)-pyridin-3-yl-methyl]-amino}-3-(2,2,-
2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a light
yellow oil (305 mg, 79%). MS (APCI+) m/z: 481 (M+H).sup.+.
[0846] Add
7-chloro-6-{6-[(piperidin-1-ylmethyl)-pyridin-3-yl-methyl]-amin-
o}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(300 mg, 0.623 mmol) in methanol (10 mL). Add lithium hydroxide
hydrate (456 mg, 19.0 mmol) and stir at room temperature overnight.
Concentrate its vacuo and dissolve the residue in water (10 mL).
Extract the aqueous layer with DCM (3.times.15n mL). Dry the
combined organic extracts over Na.sub.2SO.sub.4, filter and
concentrate in vacuo to provide
7-chloro-6-{6-[(piperidin-1-ylmethyl)-pyridin-3-yl-methyl]-amino}-2,3,4,5-
-tetrahydro-1H-benzo[d]azepine as an off-white foam (234 mg, 96%).
MS (APCI+) m/z: 385 (M+H).sup.+.
[0847] Use a method similar to the General Procedure 3-1, using
7-chloro-6-{6-[(piperidin-1-ylmethyl)-pyridin-3-yl-methyl]-amino}-2,3,4,5-
-tetrahydro-1H-benzo[d]azepine (230 mg, 0.597 mmol) to obtain the
title compound as an off-white solid (303 mg, 100%). MS (APCI+)
m/z: 385 (M+H).sup.+.
EXAMPLE 59
7-Chloro-6-[4-(2,2-dimethyl-propionylamino)-benzylamino]-2,3,4,5-tetrahydr-
o-1H-benzo[d]-azepine Succinate
##STR00168##
[0849] Use a method similar to the General Procedure 1-3 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (0.33 g, 0.78 mmol) with a solution
of 4-(2,2-dimethyl-propionylamino)-benzylamine (0.32 g, 1.6 mmol)
in anhydrous toluene/dioxane (4: 1, 10 mL). Purify the crude
mixture by chromatography on silica gel eluting with hexane/EtOAc
(1:0 to 7:3 gradient over 30 min; 35 mL/min) and then by SCX
chromatography to obtain
7-chloro-6-[4-(2,2-dimethyl-propionylamino)-benzylamino]-3-(2,2,2-trifluo-
roacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine as a yellow oil
(0.266 g, 70%). MS (ES+) m/z: 482 (M+H).sup.+.
[0850] Use a method similar to the General Procedure 2-1 to
deprotect
7-chloro-6-[4-(2,2-dimethyl-propionylamino)-benzylamino]-3-(2,2,2-trifluo-
roacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine (0.259 g, 0.538
mmol). Purify the crude mixture by chromatography on silica gel
eluting with DCM/2M ammonia in methanol (1:0 to 9:1 gradient over
30 min; 9:1 over 3 min; 9:1 to 4:1 gradient over 30 min and 4:1
over 3 min; 35 mL/min) to obtain
7-chloro-6-[4-(2,2-dimethyl-propionylamino)-benzylamino]-2,3,4,5-t-
etrahydro-1H-benzo[d]-azepine as a white foam (0.173 g, 84%).
[0851] Use a method similar to the General Procedure 3-1, using
7-chloro-6-[4-(2,2-dimethyl-propionylamino)-benzylamino]-2,3,4,5-tetrahyd-
ro-1H-benzo[d]-azepine (0.171 g, 0.443 mmol) to obtain the title
compound as a white solid (215.5 mg, 96%). MS (ES+) m/z: 386.2
(M+H).sup.+.
EXAMPLES 60-61
[0852] Examples 60-61 may be prepared essentially as described in
Example 59 using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-
-2,3,4,5-tetrahydro-1H-benzo[d]azepine and the appropriately
substituted benzylamine. Overall yields and MS (ES+) data are shown
in the Table below.
TABLE-US-00030 ##STR00169## Yield MS (ES+) Ex. R Compound (%) m/z
60 Cyclopropyl 7-Chloro-6-[4- 47 370 (cyclopropanecarbonyl- (M +
H).sup.+ amino)-benzylamino]- 2,3,4,5-tetrahydro-1H-
benzo[d]-azepine Succinate 61 1-Methyl- 7-Chloro-6-{4-[(1-methyl-
35 384 cyclopropyl cyclopropanecarbonyl)- (M + H).sup.+
amino]-benzylamino}- 2,3,4,5-tetrahydro-1H- benzo[d]-azepine
Succinate 62 2,2,3,3- 7-Chloro-6-{4-[(2,2,3,3- 49 426 Tetramethyl-
tetramethyl- (M + H).sup.+ cyclopropyl cyclopropanecarbonyl)-
amino]-benzylamino}- 2,3,4,5-tetrahydro-1H- benzo[d]-azepine
Succinate
EXAMPLES 63 AND 64
(.+-.)-7-Chloro-6-{4-[(2-methyl-cyclopropanecarbonyl)-amino]-benzylamino}--
2,3,4,5-tetrahydro-1H-benzo[d]-azepine Succinate and
(-)-7-Chloro-6-{4-[(2-methyl-cyclopropanecarbonyl)-amino]-benzylamino}-2,-
3,4,5-tetrahydro-1H-benzo[d]-azepine Succinate
##STR00170##
[0854] Use a method similar to the General Procedure 1-3 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (0.94 g, 2.2 mmol) with a solution of
(.+-.)-trans-4-[(2-methyl-cyclopropanecarbonyl)-amino]-benzylamine
(0.899 g, 4.403 mmol) in anhydrous toluene (22 mL) and anhydrous
dioxane (5.8 mL). Purify by chromatography on silica gel to afford
(.+-.)-trans-7-chloro-6-{4-[(2-methyl-cyclopropanecarbonyl)-amino]-benzyl-
amino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine
(0.834 g, 79%) as an orange oil.
[0855] Separate both enantiomers from the racemic mixture (0.747 g)
by chiral chromatography (Chiralpak AD-H, 4.6.times.150 mm column;
elute with 2B-3 ethanol (100%); 0.6 mL/min) to afford Isomer 1 (330
mg, 62%) and Isomer 2 (265 mg, 50%).
[0856] Use a method similar to the General Procedure 2-1 to
deprotect each isomer independently and a method similar to the
General Procedure 3-1 to prepare independently the title compounds.
MS (ES+) data and optical rotation for each enantiomer are shown in
the Table below.
TABLE-US-00031 MS (ES+) m/z Ex. Structure Compound [.alpha.].sub.D
(c, solvent) 63 ##STR00171##
(+)-7-Chloro-6-{4-[(2-methyl-cyclopropanecarbonyl)-amino]-benzylamino}-2,-
3,4,5-tetrahydro-1H-benzo[d]-azepine Succinate 384.2 (M +
H).sup.++36.degree. (c = 0.5, MeOH) 64 ##STR00172##
(-)-7-Chloro-6-{4-[(2-methyl-cyclopropanecarbonyl)-amino]-benzylamino}-2,-
3,4,5-tetrahydro-1H-benzo[d]-azepine Succinate 384.2 (M +
H).sup.+-40.degree. (c = 0.5, MeOH)
EXAMPLE 65
7-Chloro-6-[4-(N-methyl-2,2-dimethyl-propionylamino)-benzylamino]-2,3,4,5--
tetrahydro-1H-benzo[d]-azepine Succinate
##STR00173##
[0858] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (0.23 g, 0.53 mmol) with a solution
of 4-(N-methyl-2,2-dimethyl-propionylamino)-benzylamine (0.23 g,
1.06 mmol) in anhydrous toluene/dioxane (4:1, 7 mL). Purify by
chromatography on silica gel eluting with hexane/EtOAc (1:0 to 17:3
gradient over 30 min, 17:3 over 30 min, 17:3 to 7:3 gradient over
30 min and 7:3 over 30 min; 35 mL/min) to obtain
7-chloro-6-[4-(N-methyl-2,2-dimethyl-propionylamino)-benzylamino]-3-(2,2,-
2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine as a
yellow oil (0.235 g, 90%).
[0859] Use a method similar to the General Procedure 2-1 to
deprotect
7-chloro-6-[4-(N-methyl-2,2-dimethyl-propionylamino)-benzylamino]-3-(2,2,-
2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine (0.217 g,
0.437 mmol). Purify by chromatography on silica gel eluting with
DCM/2M ammonia in methanol (1:0 to 9:1 over 30 min, 9:1 over 3 min;
35 mL/min) to obtain
7-chloro-6-[4-(N-methyl-2,2-dimethyl-propionylamino)-benzylamino]-2,3,4,5-
-tetrahydro-1H-benzo[d]-azepine as a colorless oil (0.127 g,
73%).
[0860] Use a method similar to the General Procedure 3-1, using
7-chloro-6-[4-(N-methyl-2,2-dimethyl-propionylamino)-benzylamino]-2,3,4,5-
-tetrahydro-1H-benzo[d]-azepine (0.124 g, 0.309 mmol) to obtain the
title compound as a white solid (154 mg, 96%). MS (ES+) m/z: 400.2
(M+H).sup.+.
EXAMPLE 66
7-Chloro-6-[4-(cyclohexanecarbonyl-amino)-benzylamino]-2,3,4,5-tetrahydro--
1H-benzo[d]-azepine Succinate
##STR00174##
[0862] Add a solution of triethylamine (24 mg, 0.117 mmol) in DCM
(3.6 mL) to a hetereogeneous mixture of
6-(4-amino-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrah-
ydro-1H-benzo[d]-azepine hydrochloride (181 mg, 0.385 mmol) in
anhydrous DCM (18.2 mL) at 0.degree. C. Add a solution of
cyclohexanecarbonyl chloride (56 mg, 0.39 mmol) in anhydrous DCM
(3.6 mL). Stir at 0.degree. C. for 15 min and then at room
temperature overnight. Partition the reaction mixture between DCM
(100 mL) and water (50 mL). Extract the aqueous phase with DCM (50
mL). Wash the combined organic extracts with water (3.times.25 mL),
dry over Na.sub.2SO.sub.4, filter and concentrate in vacuo. Purify
by chromatography on silica gel eluting with hexane/EtOAc (1:0 to
3:1 over 30 min; 3:1 over 3 min; 3:1 to 1:1 over 30 min and 1:1
over 3 min; 35 mL/min) to obtain
7-chloro-6-[4-(cyclohexanecarbonyl-amino)-benzylamino]-3-(2,2,2-triluoroa-
cetyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine (0.161 g, 83%). MS
(ES+) m/z: 508.3 (M+H).sup.+.
[0863] Use a method similar to the General Procedure 2-3, using
7-chloro-6-[4-(cyclohexanecarbonyl-amino)-benzylamino]-3-(2,2,2-triluoroa-
cetyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine (0.120 g, 0.236 mmol)
to obtain
7-chloro-6-[4-(cyclohexanecarbonyl-amino)-benzylamino]-2,3,4,5-tet-
rahydro-1H-benzo[d]-azepine (74 mg, 76%). MS (ES+) m/z: 412.3
(M+H).sup.+. Use a method similar to the General Procedure 3-1 to
obtain the title compound as a white solid (95 mg, 100%). MS (ES+)
m/z: 412.3 (M+H).sup.+.
EXAMPLES 67-68
[0864] Examples 67-68 may be prepared essentially as described in
Example 66 using
6-(4-amino-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4-
,5-tetrahydro-1H-benzo[d]-azepine hydrochloride and the appropriate
carbonyl chloride. Overall yields and MS (ES+) data are shown in
the Table below.
TABLE-US-00032 ##STR00175## Yield MS (ES+) Ex. R Compound (%) m/z
67 Cyclopentyl 7-Chloro-6-[4- 59 398.3
(cyclopentanecarbonyl-amino)- (M + H).sup.+ benzylamino]-2,3,4,5-
tetrahydro-1H-benzo[d]-azepine Succinate 68 Cycloheptyl
7-Chloro-6-[4- 57 426.2 (cycloheptanecarbonyl-amino)- (M + H).sup.+
benzylamino]-2,3,4,5- tetrahydro-1H-benzo[d]-azepine Succinate
EXAMPLE 69
7-Chloro-6-{4-[(2,2-dimethyl-propionylamino)-methyl]-benzylamino}-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (L)-Tartrate
##STR00176##
[0866] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (299 mg, 0.704 mmol) and
4-[(2,2-dimethyl-propionylamino)-methyl]-benzylamine (310 mg, 1.41
mmol). Purify the crude mixture by chromatography on silica gel
eluting with hexane/EtOAc (3:2) to obtain
7-chloro-6-{4-[(2,2-dimethyl-propionylamino)-methyl]-benzylamino}-3-(2,2,-
2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a
yellow oil (265 mg, 76%). MS (ES+) m/z: 496 (M+H).sup.+.
[0867] Use a method similar to the General Procedure 2-1 to
deprotect
7-chloro-6-{4-[(2,2-dimethyl-propionylamino)-methyl]-benzylamino}-3-(2,2,-
2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (265 mg,
0.53 mmol). Purify by reverse phase HPLC [Xterra MS C18 column,
100.times.19 mm, 5 .quadrature.M; flow rate: 25 mL/min, eluting
with 3:7 to 6:4 acetonitrile/ammonium bicarbonate (20 mM at pH=8)]
to obtain
7-chloro-6-{4-[(2,2-dimethyl-propionylamino)-methyl]-benzylamino}-2,3,4,5-
-tetrahydro-1H-benzo[d]azepine as a yellow oil (155 mg, 73%). MS
(ES+) m/z: 400 (M+H).sup.+.
[0868] Use a method similar to the General Procedure 3-2, using
7-chloro-6-{4-[(2,2-dimethyl-propionylamino)-methyl]-benzylamino}-2,3,4,5-
-tetrahydro-1H-benzo[d]azepine (150 mg, 0.375 mmol) to obtain the
title compound as a white solid (206 mg, 99%). MS (ES+) m/z: 400
(M+H).sup.+.
EXAMPLE 70
7-Chloro-6-{4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamino}-2,3,4,5-t-
etrahydro-1H-benzo[d]azepine Succinate
##STR00177##
[0870] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (458 mg, 1.076 mmol) with
4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamine (275 mg, 1.346
mmol) using tris(dibenzylideneacetone)dipalladium(0) (99 mg, 0.108
mmol), BINAP (134 mg, 0.215 mmol) and cesium carbonate (710 mg,
2.17 mmol) in toluene (17 mL). Purify by chromatography on silica
gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0
over 5 min, 49:1 over 5 min, 19:1 over 5 min, 9:1 over 5 min, 85:15
over 5 min, 3:1 over 30 min, 1:1; 50 mL/min) to obtain
7-chloro-6-{4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamino}-3-(2,2,2-
-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (335 mg,
65%) as a white solid. MS (ES+) m/z: 480 (M+H).sup.+.
[0871] Dissolve
7-chloro-6-{4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamino}-3-(2,2,2-
-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (335 mg,
0.698 mmol) in MeOH (10 mL). Add LiOH.H.sub.2O (293 mg, 6.98 mmol)
and stir overnight. Partition the reaction mixture between
chloroform and water. Separate the aqueous phase and extract three
times with chloroform and once with chloroform/iso-propanol (3:1).
Dry the combined organic extracts over MgSO.sub.4, filter and
concentrate in vacuo. Purify the crude mixture by chromatography on
silica gel (40 g, pre-packed cartridge) eluting with
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) (1:0 over
5 min, 19:1 over 5 min, 9:1 over 5 min, 85:15; 50 mL/min) to obtain
7-chloro-6-{4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamino}-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (244 mg, 91%). MS (APCI+) m/z: 384
(M+H).sup.+.
[0872] Use a method similar to the General Procedure 3-1, using
7-chloro-6-{4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamino}-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (240 mg, 0.625 mmol) to obtain the
title compound (323 mg, 100%).
[0873] MS (APCI+) m/z: 384 (M+H).sup.+.
EXAMPLE 71
7-Chloro-6-{4-[2-(2,2-dimethyl-propionylamino)-ethyl]-benzylamino}-2,3,4,5-
-tetrahydro-1H-benzo[d]azepine (L)-Tartrate
##STR00178##
[0875] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (106 mg, 0.251 mmol) and
4-[2-(2,2-dimethyl-propionylamino)-ethyl]-benzylamine (110 mg,
0.427 mmol). Purify the crude mixture by chromatography on silica
gel eluting with hexane/EtOAc (6:4) to obtain
7-chloro-6-{4-[2-(2,2-dimethyl-propionylamino)-ethyl]-benzylamino}-3-(2,2-
,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a
yellow oil (90 mg, 70%). MS (ES+) m/z: 510 (M+H).sup.+.
[0876] Use a method similar to the General Procedure 2-1, using
7-chloro-6-{4-[2-(2,2-dimethyl-propionylamino)-ethyl]-benzylamino}-3-(2,2-
,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (90 mg,
0.176 mmol) to obtain
7-chloro-6-{4-[2-(2,2-dimethyl-propionylamino)-ethyl]-benzylamino}-2,3,4,-
5-tetrahydro-1H-benzo[d]azepine (70 mg, 96%) as a yellow oil
suitable for use without additional purification.
[0877] Use a method similar to the General Procedure 3-2, using
7-chloro-6-{4-[2-(2,2-dimethyl-propionylamino)-ethyl]-benzylamino}-2,3,4,-
5-tetrahydro-1H-benzo[d]azepine (70 mg, 0.169 mmol) to obtain the
title compound as a white solid (95 mg, 99%). MS (ES+) m/z: 414
(M+H).sup.+.
EXAMPLE 72
7-Chloro-6-[4-(iso-propylcarbamoyl-methyl)-benzylamino]-2,3,4,5-tetrahydro-
-1H-benzo[d]azepine (L)-Tartrate
##STR00179##
[0879] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (162 mg, 0.38 mmol) and
4-(iso-propylcarbamoyl-methyl)-benzylamine (157 mg, 0.76 mmol).
Purify by chromatography on silica gel eluting with hexane/EtOAc
(9:1, 4:1, 2:1 and 1:1) to obtain
7-chloro-6-[4-(iso-propylcarbamoyl-methyl)-benzylamino]-3-(2,2,2-trifluor-
oacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (117 mg,
64%).
[0880] Use a method similar to the General Procedure 2-1, using
7-chloro-6-[4-(iso-propylcarbamoyl-methyl)-benzylamino]-3-(2,2,2-trifluor-
oacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (117 mg, 0.24 mmol)
to obtain
7-chloro-6-[4-(iso-propylcarbamoyl-methyl)-benzylamino]-2,3,4,5-te-
trahydro-1H-benzo[d]azepine as an oil (83 mg, 89%) suitable for use
without additional purification.
[0881] Use a method similar to the General Procedure 3-2, using
7-chloro-6-[4-(iso-propylcarbamoyl-methyl)-benzylamino]-2,3,4,5-tetrahydr-
o-1H-benzo[d]azepine (45 mg, 0.11 mmol) to obtain the title
compound as a white solid (106 mg, 92%). MS (ES+) m/z: 386
(M+H).sup.+.
EXAMPLES 73-77
[0882] Examples 73-77 may be prepared essentially as described in
Example 72 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine and the appropriately substituted
benzylamine. Overall yields and MS (ES+) data are shown in the
Table below.
TABLE-US-00033 Yield MS (ES+) Ex. Structure Compound (%) m/z 73
##STR00180##
7-Chloro-6-{4-[(2,2-dimethylpropyl-carbamoyl)-methyl]-benzylamino}-2,3,4,-
5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 41 414(M + H).sup.+ 74
##STR00181##
7-Chloro-6-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-benzylamino]-2,3,4,5-tetrah-
ydro-1H-benzo[d]azepine (L)-Tartrate 64 398(M + H).sup.+ 75
##STR00182##
(.+-.)-7-Chloro-6-{4-[1-(2,2-dimethylpropyl-carbamoyl)-ethyl]-benzylamino-
}-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 50 428(M +
H).sup.+ 76 ##STR00183##
7-Chloro-6-{4-[(cyclohexylmethyl-carbamoyl)-methyl]-benzylamino}-2,3,4,5--
tetrahydro-1H-benzo[d]azepine(L)-Tartrate 21 440(M + H).sup.+ 77
##STR00184##
7-Chloro-6-{4-[(3,3-dimethylbutyl-carbamoyl)-methyl]-benzylamino}-2,3,4,5-
-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 44 428(M + H).sup.+
EXAMPLE 78
(R)-7-Chloro-6-{4-[(1-methyl-2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzy-
lamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (L)-Tartrate
##STR00185##
[0884] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (84 mg, 0.196 mmol) and
(R)-4-[(1-methyl-2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzylamine
(102 mg, 0.39 mmol). Purify by chromatography on silica gel eluting
with hexane/EtOAc (4:1) to obtain
(R)-7-chloro-6-{4-[(1-methyl-2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benz-
ylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
as a yellow oil (47 mg, 45%). MS (ES+) m/z: 536 (M+H).sup.+.
[0885] Use a method similar to the General Procedure 2-1 to
deprotect
(R)-7-chloro-6-{4-[(1-methyl-2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benz-
ylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(45 mg, 0.08 mmol). Purify by reverse phase HPLC [Xterra MS C18
column, 100.times.19 mm, 5 .mu.M; flow rate: 25 mL/min, eluting
with 3:7 to 9:11 acetonitrile/ammonium bicarbonate (10 mM at pH=8)]
to obtain
(R)-7-chloro-6-{4-[(1-methyl-2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benz-
ylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (15
mg, 42%).
[0886] Use a method similar to the General Procedure 3-2, using
(R)-7-chloro-6-{4-[(1-methyl-2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benz-
ylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (15 mg, 0.03 mmol)
to obtain the title compound as a white solid (20 mg, 99%). MS
(ES+) m/z: 440 (M+H).sup.+. [.alpha.].sub.D=-4.degree. (c=0.225,
MeOH).
EXAMPLE 79
6-{4-[2-(tert-Butylcarbamoyl)-ethyl]-benzylamino}-7-chloro-2,3,4,5-tetrahy-
dro-1H-benzo[d]azepine (L)-Tartrate
##STR00186##
[0888] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (85 mg, 0.2 mmol) and
4-[2-(tert-butylcarbamoyl)-ethyl]-benzylamine (80 mg, 0.34 mmol).
Purify the crude mixture by chromatography on silica gel eluting
with hexane/EtOAc (95:5 to 1:1 gradient) to obtain
6-{4-[2-(tert-butylcarbamoyl)-ethyl]-benzylamino}-7-chloro-3-(2,2,2-trifl-
uoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil
(75 mg, 74%). MS (ES+) m/z: 510 (M+H).sup.+.
[0889] Use a method similar to the General Procedure 2-1, using
6-{4-[2-(tert-butylcarbamoyl)-ethyl]-benzylamino}-7-chloro-3-(2,2,2-trifl-
uoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (71 mg, 0.14
mmol) to obtain
6-{4-[2-(tert-butylcarbamoyl)-ethyl]-benzylamino}-7-chloro-2,3,4,5-
-tetrahydro-1H-benzo[d]azepine (57 mg, 99%) as a yellow oil
suitable for use without additional purification.
[0890] Use a method similar to the General Procedure 3-2, using
6-{4-[2-(tert-butylcarbamoyl)-ethyl]-benzylamino}-7-chloro-2,3,4,5-tetrah-
ydro-1H-benzo[d]azepine (57 mg, 0.14 mmol) to obtain the title
compound as a white solid (76 mg, 99%). MS (ES+) m/z: 414
(M+H).sup.+.
EXAMPLE 80
[0891] Example 80 may be prepared essentially as described in
Example 79 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-
-2,3,4,5-tetrahydro-1H-benzo[d]azepine and
4-[2-(2,2-dimethylpropyl-carbamoyl)-ethyl]-benzylamine. Overall
yield and MS (ES+) data are shown in the Table below.
TABLE-US-00034 Yield MS (ES+) Ex. Structure Compound (%) m/z 80
##STR00187##
7-Chloro-6-{4-[2-(2,2-dimethylpropyl-carbamoyl)-ethyl]-benzylamino}-2,3,4-
,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 63 428(M +
H).sup.+
EXAMPLE 81
7-Chloro-6-{6-[(2,2-dimethyl-propanesulfonylmethyl)-pyridin-3-ylmethyl]-am-
ino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine Succinate
##STR00188##
[0893] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (450 mg, 1.06 mmol) with
3-aminomethyl-6-[(2,2-dimethylpropane)sulfonylmethyl]-pyridine (325
mg, 1.27 mmol) using tris(dibenzylideneacetone)dipalladium(0) (95
mg, 0.1 mmol), BINAP (95 mg, 0.15 mmol) and cesium carbonate (520
mg, 1.5 mmol) in toluene (10 mL). Heat the mixture at 90.degree. C.
for 12 h. Cool the mixture to room temperature and purify by
chromatography on silica gel (75 g) eluting with hexane/EtOAc (1:0
to 1:1 gradient) to obtain
7-chloro-6-{6-[(2,2-dimethyl-propanesulfonylmethyl)-pyridin-3-ylmethyl]-a-
mino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(470 mg, 83%). MS (APCI+) m/z: 532 (M+H).sup.+.
[0894] Dissolve
7-chloro-6-{6-[(2,2-dimethyl-propanesulfonylmethyl)-pyridin-3-ylmethyl]-a-
mino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(470 mg, 0.88 mmol) in concentrated NH.sub.4OH/methanol (1: 1, 20
mL) and stir the mixture overnight at room temperature. Concentrate
the mixture in vacuo. Purify by chromatography on silica gel (45 g,
pre-packed cartridge) eluting with a gradient of DCM to 4:1
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) to obtain
7-chloro-6-{6-[(2,2-dimethyl-propanesulfonylmethyl)-pyridin-3-ylmethyl]-a-
mino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (380 mg, 99%). MS
(APCI+) m/z: 436 (M+H).sup.+.
[0895] Dissolve
7-chloro-6-{6-[(2,2-dimethyl-propanesulfonylmethyl)-pyridin-3-ylmethyl]-a-
mino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (380 mg, 0.87 mmol) in
methanol and add succinic acid (98 mg, 0.83 mmol). Stir the mixture
until homogeneous. Concentrate the mixture in vacuo, dissolve in
water, and freeze dry the solution to obtain the title compound
(470 mg, 98%) as a light yellow solid. MS (APCI+) m/z: 436
(M+H).sup.+.
EXAMPLE 82
[0896] Example 82 may be prepared essentially as described in
Example 81 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-
-2,3,4,5-tetrahydro-1H-benzo[d]azepine and
3-aminomethyl-6-(cyclohexanesulfonyl)methyl-pyridine. Overall yield
and MS (ES+) data are shown in the Table below.
TABLE-US-00035 Yield MS (ES+) Ex. Structure Compound (%) m/z 82
##STR00189##
7-Chloro-6-[(6-cyclohexanesulfonylmethyl-pyridin-3-ylmethyl)-amino]-2,3,4-
,5-tetrahydro-1H-benzo[d]azepine Succinate 81 448(M + H).sup.+
EXAMPLE 83
7-Chloro-6-[4-(2,2-dimethyl-propanesulfonylmethyl)-benzylamino]-2,3,4,5-te-
trahydro-1H-benzo[d]azepine Succinate
##STR00190##
[0898] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (639 mg, 1.50 mmol) with
4-(2,2-dimethyl-propanesulfonylmethyl)-benzylamine (479 mg, 1.88
mmol), using tris(dibenzylideneacetone)dipalladium(0) (137 mg, 0.15
mmol), BINAP (187 mg, 0.3 mmol) and cesium carbonate (977 mg, 3
mmol) in toluene (20 mL).
[0899] Heat the mixture at 90.degree. C. overnight. Cool the
mixture to room temperature and purify by chromatography on silica
gel (80 g) eluting with hexane/EtOAc (1:0 to 4:1 gradient over 15
min; 50 mL/min) to give
7-chloro-6-[4-(2,2-dimethyl-propanesulfonyl-methyl)-benzylamino]-3-(-
2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (615
mg, 77%). MS (APCI+) m/z: 531 (M+H).sup.+.
[0900] Dissolve
7-chloro-6-[4-(2,2-dimethyl-propanesulfonylmethyl)-benzylamino]-3-(2,2,2--
trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (605 mg,
1.14 mmol) in methanol (8 mL) and add LiOH H.sub.2O (478 mg, 11.4
mmol). Stir the reaction mixture overnight. Partition the mixture
between water and chloroform. Extract the aqueous phase three times
with chloroform and chloroform/iso-propanol (3:1). Dry the combined
organic extracts over MgSO.sub.4, filter and concentrate in vacuo.
Purify by chromatography on silica gel (40 g) eluting with
DCM/(chloroform:methanol:concentrated NH.sub.4OH 80:18:2) (1:0 over
5 min, 19:1 over 5 min, 9:1; 50 mL/min) to obtain
7-chloro-6-[4-(2,2-dimethyl-propanesulfonylmethyl)-benzylamino]-2,-
3,4,5-tetrahydro-1H-benzo[d]azepine (467 mg, 94%). MS (APCI+) m/z:
435 (M+H).sup.+.
[0901] Dissolve
7-chloro-6-[4-(2,2-dimethyl-propanesulfonylmethyl)-benzylamino]-2,3,4,5-t-
etrahydro-1H-benzo[d]azepine (316 mg, 0.726 mmol) in methanol (10
mL) and add succinic acid (86 mg, 0.726 mmol). Stir the mixture for
2 h. Concentrate the mixture in vacuo and dry under high vacuum at
50.degree. C. to obtain the title compound (380 mg, 94%). MS
(APCI+) m/z: 435 (M+H).sup.+.
EXAMPLE 84
7-Chloro-6-(4-dimethylcarbamoylthio-benzylamino)-2,3,4,5-tetrahydro-1H-ben-
zo[d]azepine Succinate
##STR00191##
[0903] Use a method similar to the General Procedure 3-1, using
7-chloro-6-(4-dimethylcarbamoylthio-benzylamino)-2,3,4,5-tetrahydro-1H-be-
nzo[d]azepine (56 mg, 0.14 mmol) to obtain the title compound as a
solid (67 mg, 92%). MS (ES+) m/z: 390 (M+H).sup.+.
EXAMPLE 85
7-Chloro-6-[4-(3,3-dimethyl-2-oxobutylthio)-benzylamino]-2,3,4,5-tetrahydr-
o-1H-benzo[d]azepine (L)-Tartrate
##STR00192##
[0905]
3-(tert-Butoxycarbonyl)-7-chloro-6-[4-(3,3-dimethyl-2-oxobutylthio)-
-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine: Dissolve
3-(tert-butoxycarbonyl)-7-chloro-6-(4-dimethylcarbamoylthio-benzylamino)--
2,3,4,5-tetrahydro-1H-benzo[d]azepine (57 mg, 0.1 mmol) in methanol
(5 mL). Add potassium hydroxide (65 mg, 1.1 mmol) and heat the
mixture for 3 h at 65.degree. C. Then add
1-bromo-3,3-dimethyl-2-butanone and heat at 65.degree. C. for 2 h.
Cool the mixture and dilute with EtOAc. Wash the organic phase with
water, dry over MgSO.sub.4, filter and concentrate in vacuo. Purify
by chromatography on silica gel eluting with hexane/diethyl ether
(7:3) to obtain the desired intermediate as an oil (18 mg,
30%).
[0906]
7-Chloro-6-[4-(3,3-dimethyl-2-oxobutylthio)-benzylamino]-2,3,4,5-te-
trahydro-1H-benzo[d]azepine: Dissolve
3-(tert-butoxycarbonyl)-7-chloro-6-[4-(3,3-dimethyl-2-15
oxobutylthio)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(35 mg, 0.06 mmol) in DCM (0.2 mL). Add 4M hydrogen chloride in
dioxane (0.3 mL, 1.3 mmol) and stir at room temperature for 1 h.
Concentrate in vacuo and purify by SCX chromatography to obtain the
desired intermediate (26 mg, 93%).
[0907]
7-Chloro-6-[4-(3,3-dimethyl-2-oxobutylthio)-benzylamino]-2,3,4,5-te-
trahydro-1H-benzo[d]azepine (L)-Tartrate: Use a method similar to
the General Procedure 3-2, using
7-chloro-6-[4-(3,3-dimethyl-2-oxobutylthio)-benzylamino]-2,3,4,5-tetrahyd-
ro-1H-benzo[d]azepine (26 mg, 0.06 mmol) to obtain the title
compound as a white solid (35 mg, 99%). MS (ES+) m/z: 418
(M+H).sup.+.
EXAMPLE 86
7-Chloro-6-{4-[(2,2-dimethyl-propylcarbamoyl)-methylthio]-benzylamino}-2,3-
,4,5-tetrahydro-1H-benzo[d]azepine (L)-Tartrate
##STR00193## ##STR00194##
[0909]
3-(tert-Butoxycarbonyl)-7-chloro-6-(4-methoxycarbonylmethylthio-ben-
zylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine: Dissolve
3-(tert-butoxycarbonyl)-7-chloro-6-(4-dimethylcarbamoylthio-benzylamino)--
2,3,4,5-tetrahydro-1H-benzo[d]azepine (270 mg, 0.5 mmol) in
methanol (20 mL). Add potassium hydroxide (308 mg, 5.5 mmol) and
heat the mixture for 3 h at 65.degree. C. Add methyl bromoacetate
(0.52 mL, 5.5 mmol) and heat at 65.degree. C. for 3 h. Cool the
mixture to room temperature and dilute with EtOAc. Wash the organic
phase with water, dry over MgSO.sub.4, filter and concentrate in
vacuo. Purify by chromatography on silica gel eluting with
hexane/EtOAc (4:1) to obtain the desired intermediate as an oil
(203 mg, 75%).
[0910]
3-(tert-Butoxycarbonyl)-7-chloro-6-{4-[(2,2-dimethyl-propylcarbamoy-
l)-methylthio]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine:
Dissolve 2,2-dimethyl-propylamine (0.1 mL, 0.84 mmol) in anhydrous
THF (0.6 mL) under nitrogen. Cool the solution at 0.degree. C. and
add DIBAL-H (0.79 mL, 0.79 mmol, 1M solution in toluene). Allow the
mixture warm up to room temperature and stir for 2 h. Add this
complex to a solution of
3-(tert-butoxycarbonyl)-7-chloro-6-(4-methoxycarbonylmethylthio-benzylami-
no)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (70 mg, 0.14 mmol) in THF
(0.3 mL) and stir at room temperature overnight. Dilute with EtOAc
and quench with 5% aqueous KHSO.sub.4. Dry the organic phase over
MgSO.sub.4, filter and concentrate in vacuo. Purify the crude
mixture by chromatography on silica gel eluting with hexane/EtOAc
(4:1) to obtain the desired intermediate as an oil (51 mg,
65%).
[0911]
7-Chloro-6-{4-[(2,2-dimethyl-propylcarbamoyl)-methylthio]-benzylami-
no}-2,3,4,5-tetrahydro-1H-benzo[d]azepine: Dissolve
3-(tert-butoxycarbonyl)-7-chloro-6-{4-[(2,2-dimethyl-propylcarbamoyl)-met-
hylthio]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (51 mg,
0.09 mmol) in DCM (0.2 ml). Add 4M hydrogen chloride in dioxane
(0.5 mL, 1.8 mmol) and stir at room temperature for 1 h.
Concentrate in vacuo and purify by SCX chromatography to obtain the
desired intermediate (39 mg, 93%).
[0912]
7-Chloro-6-{4-[(2,2-dimethyl-propylcarbamoyl)-methylthio]-benzylami-
no}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (L)-Tartrate: Use a
method similar to the General Procedure 3-2, using
7-chloro-6-{4-[(2,2-dimethyl-propylcarbamoyl)-methylthio]-benzylamino}-2,-
3,4,5-tetrahydro-1H-benzo[d]azepine (39 mg, 0.08 mmol) to obtain
the title compound as a white solid (51 mg, 98%). MS (ES+) tm/z:
446 (M+H).sup.+.
EXAMPLE 87
7-Chloro-6-{[6-(3,3-dimethyl-2-oxo-butoxy)-pyridin-3-ylmethyl]-amino}-2,3,-
4,5-tetrahydro-1H-benzo[d]azepine (L)-Tartrate
##STR00195##
[0914] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (210 mg, 0.5 mmol) with
3-aminomethyl-6-(3,3-dimethyl-2-oxo-butoxy)-pyridine (220 mg, 1
mmol). Purify by chromatography on silica gel eluting with
hexane/EtOAc (4:1) to give
7-chloro-6-{[6-(3,3-dimethyl-2-oxo-butoxy)-pyridin-3-ylmethyl]-amino-
}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(122 mg, 50%). MS (ES+) m/z: 498 (M+H).sup.+.
[0915] Use a method similar to the General Procedure 2-1, using
7-chloro-6-{[6-(3,3-dimethyl-2-oxo-butoxy)-pyridin-3-ylmethyl]-amino}-3-(-
2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (122
mg, 0.2 mmol) to give
7-chloro-6-{[6-(3,3-dimethyl-2-oxo-butoxy)-pyridin-3-ylmethyl]-amino}-2,3-
,4,5-tetrahydro-1H-benzo[d]azepine (80 mg, 81%) suitable for use
without further purification.
[0916] Use a method similar to the General Procedure 3-2, using
7-chloro-6-{[6-(3,3-dimethyl-2-oxo-butoxy)-pyridin-3-ylmethyl]-amino}-2,3-
,4,5-tetrahydro-1H-benzo[d]azepine to afford the title compound as
a white solid (108 mg, 99%). MS (ES+) m/z: 402 (M+H).sup.+.
EXAMPLE 88
7-Chloro-6-({6-[(2,2-dimethyl-propylcarbamoyl)-methoxy]-pyridin-3-ylmethyl-
}-amino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (L)-Tartrate
##STR00196##
[0918] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (265 mg, 0.6 mmol) with
3-aminomethyl-6-[(2,2-dimethyl-propylcarbamoyl)-methoxy]-pyridine
(314 mg, 1.2 mmol). Purify by chromatography on silica gel eluting
with hexane/EtOAc (1:1) to give
7-chloro-6-({6-[(2,2-dimethyl-propylcarbamoyl)-methoxy]-pyridin-3-ylmethy-
l}-amino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(145 mg, 44%). MS (ES+) iii/z: 527 (M+H).sup.+.
[0919] Use a method similar to the General Procedure 2-1, using
7-chloro-6-({6-[(2,2-dimethyl-propylcarbamoyl)-methoxy]-pyridin-3-ylmethy-
l}-amino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(145 mg, 0.2 mmol) to give
7-chloro-6-({6-[(2,2-dimethyl-propylcarbamoyl)-methoxy]-pyridin-3-ylmethy-
l}-amino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (100 mg, 84%)
suitable for use without further purification.
[0920] Use a method similar to the General Procedure 3-2, using
7-chloro-6-({6-[(2,2-dimethyl-propylcarbamoyl)-methoxy]-pyridin-3-ylmethy-
l}-amino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (100 mg, 0.2 mmol)
to give the title compound as a white solid (125 mg, 92%). MS (ES+)
m/z: 431 (M+H).sup.+.
EXAMPLE 89
7-Chloro-6-{4-[5-(cyclopropylmethyl-amino)-isothiazol-3-yl]-benzylamino}-2-
,3,4,5-tetrahydro-1H-benzo[d]azepine Succinate
##STR00197##
[0922] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (75 mg, 0.18 mmol) with
4-[5-(cyclopropylmethyl-amino)-isothiazol-3-yl]-benzylamine (68 mg,
0.26 mmol) in toluene (3 mL). Purify the crude mixture by
chromatography on silica gel (4 g) eluting with hexane/EtOAc with
2% methanol (9:1 to 4:1 gradient) to obtain
7-chloro-6-{4-[5-(cyclopropylmethyl-amino)-isothiazol-3-yl]-benzylamino}--
3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (38
mg, 40%). MS (ES+) m/z: 535.3 (M+H).sup.+.
[0923] Use a method similar to the General Procedure 2-2 to
deprotect
7-chloro-6-{4-[5-(cyclopropylmethyl-amino)-isothiazol-3-yl]-benzylamino}--
3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (38
mg). Purify by chromatography on silica gel (1 g) eluting with
DCM/2M ammonia in methanol (1:0 to 9:1 gradient) to give
7-chloro-6-{4-[5-(cyclopropylmethyl-amino)-isothiazol-3-yl]-benzylamino}--
2,3,4,5-tetrahydro-1H-benzo[d]azepine. Use a method similar to the
General Procedure 3-1 to obtain the title compound (28 mg, 70%). MS
(ES+) m/z: 439.2 (M+H).sup.+.
EXAMPLE 90
7-Chloro-6-{4-[2-(2,2,2-trifluoroethylamino-thiazol-4-yl)]-benzylamino}-2,-
3,4,5-tetrahydro-1H-benzo[d]azepine Succinate
##STR00198##
[0925] Dissolve
4-[2-(2,2,2-trifluoroethylamino)-thiazol-4-yl]-benzylamine (899 mg,
3.1 mmol) in toluene (16 mL) and DMF (2 mL) under nitrogen at
95.degree. C. Add
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (665 mg, 1.56 mmol),
tris(dibenzylideneacetone)dipalladium(0) (286 mg, 0.31 mmol), BINAP
(389 mg, 0.62 mmol) and cesium carbonate (711 mg, 2.2 mmol). Stir
the mixture for 12 h at 95.degree. C. under a nitrogen atmosphere
and check by GC to determine if the triflate is consumed. Add
additional
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (500 mg, 1.17 mmol),
tris(dibenzylideneacetone)dipalladium(0) (286 mg, 0.31 mmol), BINAP
(389 mg, 0.62 mmol) and cesium carbonate (711 mg, 2.2 mmol) to the
mixture and stir for 16 h at 95.degree. C. (check by LC/MS to
determine if the starting amine is consumed). Cool the mixture to
room temperature, filter through Celite.RTM. and wash with DCM (50
mL). Concentrate in vacuo and purify the residue by chromatography
on silica gel (25 g) eluting with hexane/(EtOAc with 1% methanol)
(20:1 to 1:1 gradient) to obtain
7-chloro-3-(2,2,2-trifluoroacetyl)-6-{4-[2-(2,2,2-trifluoroethylamino-thi-
azol-4-yl)]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (250
mg, 16%). MS (ES+) m/z: 563.1 (M+H).sup.+.
[0926] Use a method similar to the General Procedure 2-2 to
deprotect
7-chloro-3-(2,2,2-trifluoroacetyl)-6-{4-[2-(2,2,2-trifluoroethylamino-thi-
azol-4-yl)]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Purify by chromatography on silica gel (40 g) eluting with DCM/2M
ammonia in methanol (33:1) to give
7-chloro-6-{4-[2-(2,2,2-trifluoroethylamino-thiazol-4-yl)]-benzylamino}-2-
,3,4,5-tetrahydro-1H-benzo[d]azepine. Use a method similar to the
General Procedure 4-1 to obtain the title compound (89 mg). MS
(ES+) m/z: 467.3 (M+H).sup.+.
EXAMPLE 91
7-Chloro-6-{4-[2-(3-methyl-butylamino)-thiazol-4-yl]-benzylamino}-2,3,4,5--
tetrahydro-1H-benzo[d]azepine Succinate
##STR00199##
[0928] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (380 mg, 0.89 mmol) with
4-[2-(3-methyl-butylamino)-thiazol-4-yl]-benzylamine (443 mg, 1.6
mmol) in toluene (12 mL). Purify the crude mixture by
chromatography on silica gel (25 g) eluting with hexane/(EtOAc with
1% methanol) (20:1 to 7:3 gradient) to obtain
7-chloro-6-{4-[2-(3-methyl-butylamino)-thiazol-4-yl]-benzylamino}-3-(2,2,-
2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (368 mg,
75%). MS (ES+) m/z: 551.4 (M+H).sup.+.
[0929] Use a method similar to the General Procedure 2-2 to
deprotect
7-chloro-6-{4-[2-(3-methyl-butylamino)-thiazol-4-yl]-benzylamino}-3-(2,2,-
2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine. Purify by
chromatography on silica gel (25 g) eluting with DCM/2M ammonia in
methanol (20:1) to give
7-chloro-6-{4-[2-(3-methyl-butylamino)-thiazol-4-yl]-benzylamino}-2,3,4,5-
-tetrahydro-1H-benzo[d]azepine. Use a method similar to the General
Procedure 3-1 to obtain the title compound (240 mg, 63%). MS (ES+)
m/z: 455 (M+H).sup.+.
EXAMPLES 92-95
[0930] Examples 92-95 may be-prepared essentially as described in
Example 91 by using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine and the appropriate benzylamine.
Overall yields and MS (ES+) data are as in the Table below.
TABLE-US-00036 Yield MS (ES+) Ex. Structure Compound (%) m/z 92
##STR00200##
7-Chloro-6-{4-[2-(2,2-dimethyl-propylamino)-thiazol-4-yl]-benzylamino}-2,-
3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 45 455(M + H).sup.+ 93
##STR00201##
7-Chloro-6-[4-(2-cyclopentylmethylamino-thiazol-4-yl)-benzylamino]-2,3,4,-
5-tetrahydro-1H-benzo[d]azepineSuccinate 50 467(M + H).sup.+ 94
##STR00202##
7-Chloro-6-[4-(2-cyclohexylmethylamino-thiazol-4-yl)-benzylamino]-2,3,4,5-
-tetrahydro-1H-benzo[d]azepineSuccinate 65 481(M + H).sup.+ 95
##STR00203##
7-Chloro-6-[4-(2-cyclopropylmethylamino-5-methyl-thiazol-4-yl)-benzylamin-
o]-2,3,4,5-tetrahydro-1H-benzo[d]azepine Succinate 54 453(M +
H).sup.+
EXAMPLES 96-99
[0931] Examples 96-99 may be prepared essentially as described in
Example 6 using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy--
2,3,4,5-tetrahydro-1H-benzo[d]azepine and the appropriate
benzylamine. Examples 98-99 were prepared by using the General
Procedure 2-2 for deprotection. Overall yields and MS (ES+) data
are shown in the Table below.
TABLE-US-00037 Yield MS (ES+) m/z; Ex. Structure Compound (%)
[.alpha.].sub.D (c, solvent) 96 ##STR00204##
(R)-7-Chloro-6-{4-[2-(1-methyl-2,2,2-trifluoroethyl-amino)-thiazol-4-yl]--
benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine Succinate 25 481
(M + H).sup.+[.alpha.].sub.D = -20.degree.(c = 0.5, MeOH) 97
##STR00205##
(S)-7-Chloro-6-{4-[2-(1-methyl-2,2,2-trifluoroethyl-amino)-thiazol-4-yl]--
benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine Succinate 40 481
(M + H).sup.+[.alpha.].sub.D = +18.6.degree.(c = 0.5, MeOH) 98
##STR00206##
6-[4-(2-Benzylamino-thiazol-4-yl)-benzylamino]-7-chloro-2,3,4,5-tetrahydr-
o-1H-benzo[d]azepineSuccinate 12 475 (M + H).sup.+ 99 ##STR00207##
7-Chloro-6-{4-[2-(3,3,3-trifluoropropylamino)-thiazol-4-yl]-benzylamino}--
2,3,4,5-tetrahydro-1H-benzo[d]azepine Succinate 67 427 (M +
H).sup.+
EXAMPLE 100
7-Chloro-6-{[5-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridin-2-ylmethyl]-
-amino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine Succinate
##STR00208##
[0933] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (316 mg, 0.74 mmol) with
2-aminomethyl-5-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine
(296 mg, 1.11 mmol) in toluene (8 mL). Filter the crude mixture
over Celite.RTM., followed by activated charcoal and wash with
dichloromethane. Concentrate the filtrate in vacuo and purify the
crude mixture by chromatography on silica gel (12 g) eluting with
hexane/(EtOAc with 1% methanol) (20:1 to 3:2 gradient) to obtain
7-chloro-6-{[5-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridin-2-ylmethyl-
]-amino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(120 mg, 30%). MS (ES+) m/z: 536.3 (M+H).sup.+.
[0934] Use a method similar to the General Procedure 2-2 to
deprotect
7-chloro-6-{[5-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridin-2-ylmethyl-
]-amino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Purify by chromatography on silica gel (4 g) eluting with DCM/2M
ammonia in methanol (49:1 to 24:1) to give
7-chloro-6-{[5-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridin-2-ylmethyl-
]-amino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine. Use a method
similar to the General Procedure 3-1 to obtain the title compound
(63 mg, 50%). MS (ES+) m/z: 440 (M+H).sup.+.
EXAMPLE 101
[0935] Example 101 may be prepared essentially as described in
Example 100 using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,-
3,4,5-tetrahydro-1H-benzo[d]azepine and
3-aminomethyl-6-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine.
Overall yield and MS (ES+) data are shown in the Table below.
TABLE-US-00038 Yield MS (ES+) Ex. Structure Compound (%) m/z 101
##STR00209##
7-Chloro-6-{[6-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridin-3-ylmethyl-
]-amino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 29 440.3(M
+ H).sup.+
EXAMPLE 102
7-Chloro-6-{4-[2-(cyclopropanecarbonyl-amino)-thiazol-4-yl]-benzylamino}-2-
,3,4,5-tetrahydro-1H-benzo[d]azepine Succinate
##STR00210##
[0937] To a slurry of
4-[2-(cyclopropanecarbonyl-amino)-thiazol-4-yl]-benzylamine (1.654
g, 6.052 mmol) in toluene (30.2 mL)/dioxane (7.8 mL), at
100.degree. C., add a solid mixture of
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (1.29 g, 3.03 mmol),
tris(dibenzylideneacetone)-dipalladium(0) (0.55 g, 0.61 mmol),
BINAP (0.75 g, 0.12 mmol) and cesium carbonate (3.45 g, 10.6 mmol)
all at once. Purge the reaction mixture with nitrogen and heat at
100.degree. C. overnight. After cooling to room temperature, filter
the reaction mixture over Celite.RTM. and wash with DCM (500 mL).
Concentrate in vacuo, dissolve the residue in DCM and load on to an
Analogix.RTM. column (150 g). Purify by preparative liquid
chromatography (0:1 to 1:9 2M ammonia in methanol/DCM over 33 min,
1:9 to 1:3 2M ammonia in methanol/DCM over 33 min, 1:3 to 1:1 2M
ammonia in methanol/DCM over 33 min; 35 mL/min) to afford
7-chloro-6-{4-[2-(cyclopropanecarbonyl-amino)-thiazol-4-yl]-benzyl-
amino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(0.318 g, 19%) as a yellow foam. MS (ES+) m/z: 549.1
(M+H).sup.+.
[0938] To
7-chloro-6-{4-[2-(cyclopropanecarbonyl-amino)-thiazol-4-yl]-benz-
ylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(0.310 g, 5.648 mmol) at room temperature, add 2M ammonia in
methanol (18 mL). After stirring for 30 min, add 7M ammonia in
methanol (124 mL) to the reaction mixture. After stirring at room
temperature overnight, concentrate the reaction mixture in vacuo
and elute the residue through a SCX column (20 g). Dissolve the
residue in DCM and load the solution on to a RediSep.RTM. column
(40 g). Purify by preparative liquid chromatography (0:1 to 1:9 2M
ammonia in methanol/DCM over 33 min, 1:9 to 1:4 2M ammonia in
methanol/DCM over 33 min; 35 mL/min) to afford
7-chloro-6-{4-[2-(cyclopropanecarbonyl-amino)-thiazol-4-yl]-benzylamino}--
2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.140 g, 55%) as a white
foam. MS (ES+) m/z: 453.1 (M+H).sup.+.
[0939] To a slurry of
7-chloro-6-{4-[2-(cyclopropanecarbonyl-amino)-thiazol-4-yl]-benzylamino}--
2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.136 g, 0.3 mmol) in
absolute ethanol (5 mL) at room temperature, add dichloromethane (5
mL). Add succinic acid (0.035 g, 0.301 mmol) to the mixture and
stir for 1 h. Concentrate in vacuo. Combine the residue with MTBE
(5 mL) and concentrate three times to afford a white solid. Dry the
white solid in a vacuum oven at 40.degree. C. overnight to afford
the title compound (160 mg, 93%) as a white solid. MS (ES+) m/z:
453 (M+H).sup.+.
EXAMPLE 103
7-Chloro-6-[4-(1-cyclopropylmethyl-1H-pyrazol-3-yl)-benzylamino]-2,3,4,5-t-
etrahydro-1H-benzo[d]azepine (L)-Tartrate
##STR00211##
[0941] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (193 mg, 0.45 mmol) with
4-(1-cyclopropylmethyl-1H-pyrazol-3-yl)-benzylamine (207 mg, 0.91
mmol) using tris(dibenzylideneacetone)dipalladium(0) (83 mg, 0.091
mmol), BINAP (113 mg, 0.182 mmol) and cesium carbonate (207 mg,
0.627 mmol) in toluene (21 mL). Purify by chromatography on silica
gel eluting with hexane:EtOAc (9:1) to give
7-chloro-6-[4-(1-cyclopropylmethyl-1H-pyrazol-3-yl)-benzylamino]-3-(2,2,2-
-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow
oil (135 mg, 59%). MS (ES+) m/z: 503 (M+H).sup.+.
[0942] Use a method similar to General Procedure 2-1, using
7-chloro-6-[4-(1-cyclopropylmethyl-1H-pyrazol-3-yl)-benzylamino]-3-(2,2,2-
-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (135 mg,
0.27 mmol) to give
7-chloro-6-[4-(1-cyclopropylmethyl-1H-pyrazol-3-yl)-benzylamino]-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (97 mg, 89%) as a yellow oil.
[0943] Use a method similar to the General Procedure 4-2, using
7-chloro-6-[4-(1-cyclopropylmethyl-1H-pyrazol-3-yl)-benzylamino]-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (97 mg, 0.088 mmol) to give the title
compound as a white solid (122 mg, 98%). MS (ES+) m/z: 407
(M+H).sup.+.
EXAMPLE 104
[0944] Example 104 may be prepared essentially as described in
Example 103 using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,-
3,4,5-tetrahydro-1H-benzo[d]azepine and
4-[3-(cyclopropylmethyl-amino)-pyrazol-1-yl]-benzylamine. Overall
yield and MS (ES+) data are shown in the Table below.
TABLE-US-00039 Yield MS (ES+) Ex. Structure Compound (%) m/z 104
##STR00212##
7-Chloro-6-{[4-(3-cyclopropylmethylamino)-pyrazol-1-yl]-benzylamino}-2,3,-
4,5-tetrahydro-1H-benzo[d]azepine (L)-Tartrate 55 422(M +
H).sup.+
EXAMPLE 105
7-Chloro-6-{4-[6-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzylamino}-2,-
3,4,5-tetrahydro-1H-benzo[d]azepine Succinate
##STR00213##
[0946] Use a method similar to the General Procedure 1-3, using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (260 mg, 0.6 mmol) and
4-[6-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzylamine (300 mg,
1.18 mmol), to give
7-chloro-6-{4-[6-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzylamino}-3-
-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as
an off-white foam (250 mg, 78%). MS (ES+) m/z: 530 (M+H).sup.+.
[0947] Use a method similar to the General Procedure 2-1 to
deprotect
7-chloro-6-{4-[6-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzylamino}-3-
-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (250
mg, 0.47 mmol) to give
7-chloro-6-{4-[6-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzylamino}-2-
,3,4,5-tetrahydro-1H-benzo[d]azepine (145 mg, 71%) as an off-white
foam. MS (ES+) m/z: 434 (M+H).sup.+.
[0948] Use a method similar to the General Procedure 4-1, using
7-chloro-6-{4-[6-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzylamino}-2-
,3,4,5-tetrahydro-1H-benzo[d]azepine (175 mg, 0.4 mmol) to give the
title compound (175 mg, 98%) as an off-white solid. MS (ES+) m/z:
434 (M+H).sup.+.
EXAMPLES 106-107
[0949] Examples 106-107 may be prepared essentially as described in
Example 105 using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine and the appropriate benzylamine.
Overall yields and MS (ES+) data are shown in the Table below.
TABLE-US-00040 Yield MS (ES+) Ex. Structure Compound (%) m/z 106
##STR00214##
7-Chloro-6-{4-[4-(cyclopropylmethyl-amino)-pyrimidin-2-yl]-benzylamino}-2-
,3,4,5-tetrahydro-1H-benzo[d]azepine Succinate 75 434(M + H).sup.+
107 ##STR00215##
7-Chloro-6-{4-[2-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzylamino}-2-
,3,4,5-tetrahydro-1H-benzo[d]azepine Succinate 22 434(M +
H).sup.+
EXAMPLE 108
7-Chloro-6-{4-[5-(3,3-dimethylbutyryl)-tiophen-2-yl]-benzylamino}-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (L)-Tartrate
##STR00216##
[0951] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (93.5 mg, 0.2 mmol) with
4-[5-(3,3-dimethylbutyryl)tiophen-2-yl]-benzylamine (129 mg, 0.4
mmol) using tris(dibenzylideneacetone)dipalladium(0) (40.3 mg, 0.04
mmol), BINAP (58.3 mg, 0.08 mmol) and cesium carbonate (100 mg, 0.3
mmol) in toluene/DMF (11:1, 12 mL). Purify by chromatography on
silica gel eluting with hexane/EtOAc (4:1) to give
7-chloro-6-{4-[5-(3,3-dimethylbutyryl)-tiophen-2-yl]-benzylamino}-3-(2,2,-
2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a
yellow oil (77 mg, 62%). MS (ES+) m/z: 563 (M+H).sup.+.
[0952] Use a method similar to the General Procedure 2-1, using
7-chloro-6-{4-[5-(3,3-dimethylbutyryl)-tiophen-2-yl]-benzylamino}-3-(2,2,-
2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (77 mg,
0.1 mmol) to give
7-chloro-6-{4-[5-(3,3-dimethylbutyryl)-tiophen-2-yl]-benzylamino}-
-2,3,4,5-tetrahydro-1H-benzo[d]azepine (55 mg, 87%) as a yellow
oil.
[0953] Use a method similar to the General Procedure 3-2, using
7-chloro-6-{4-[5-(3,3-dimethylbutyryl)-tiophen-2-yl]-benzylamino}-2,3,4,5-
-tetrahydro-1H-benzo[d]azepine (55 mg, 0.1 mmol) to give the title
compound as a white solid (70 mg, 96%). MS (ES+) m/z: 467
(M+H).sup.+.
EXAMPLE 109
7-Chloro-6-{[6-(2,2-dimethylpropane-sulfonyl)-pyridin-3-yl-methyl]-amino}--
2,3,4,5-tetrahydro-1H-benzo[d]azepine Succinate
##STR00217##
[0955] Under a nitrogen atmosphere, add
3-aminomethyl-6-[(2,2-dimethylpropane)-sulfonyl]-pyridine (300 mg,
1.23 mmol),
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethansulfonyloxy-2,-
3,4,5-tetrahydro-1H-benzo[d]azepine (350 mg, 822 .mu.mol),
tris(dibenzylideneacetone)dipalladium(0) (75 mg, 82 .mu.mol), BINAP
(77 mg, 123 .mu.mol), and cesium carbonate (402 mg, 1.23 mmol) to
toluene (100 mL). Heat the mixture at 95.degree. C. overnight. Cool
the mixture to room temperature, and concentrate the mixture in
vacuo. Purify the crude mixture by chromatography on silica gel
eluting with DCM/(chloroform:methanol:concentrated NH.sub.4OH) (1:0
to 1:1 over 1.5 h, 80 mL/min) to provide
7-chloro-6-{[6-(2,2-dimethylpropane-sulfonyl)-pyridin-3-yl-methyl]-amino}-
-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(142 mg, 33%) and additional impure product (150 mg, 33%). MS (ES+)
m/z: 518 (M+H).sup.+.
[0956] Dissolve
7-chloro-6-{[6-(2,2-dimethylpropane-sulfonyl)-pyridin-3-yl-methyl]-amino}-
-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(142 mg, 0.27 mmol) in methanol (5 mL). Add lithium hydroxide
hydrate (23 mg, 0.54 mmol) and stir for 1 h. Mix with silica gel (1
g), concentrate in vacuo, and purify by chromatography on silica
gel (12 g) eluting with DCM/(chloroform:methanol:concentrated
NH.sub.4OH) (1:0 to 9:1 gradient) to give
7-chloro-6-{[6-(2,2-dimethylpropane-sulfonyl)-pyridin-3-yl-methyl-
]-amino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (91 mg, 78%). MS
(APCI) m/z: 422 (M+H).sup.+.
[0957] Dissolve
7-chloro-6-{[6-(2,2-dimethylpropane-sulfonyl)-pyridin-3-yl-methyl]-amino}-
-2,3,4,5-tetrahydro-1H-benzo[d]azepine (171 mg, 0.4 mmol) in
methanol and add succinic acid (45 mg, 0.38 mmol). Stir the mixture
until homogeneous. Concentrate the mixture in vacuo, dissolve in
water, and freeze dry the solution to provide the title compound
(215 mg, 99%). MS (APCI) m/z: 422 (M+H).sup.+.
EXAMPLE 110
7-Chloro-6-[4-(2,2,2-trifluoroethylthio-methylcarbonyl)-benzylamino]-2,3,4-
,5-tetrahydro-1H-benzo[d]azepine (L)-Tartrate
##STR00218##
[0959] Use a method similar to the General Procedure 1-2 to couple
7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5--
tetrahydro-1H-benzo[d]azepine (173 mg, 0.4 mmol) with
4-[2-(2,2,2-trifluoroethylthio)-1,1-(ethylenedioxy)ethyl]-benzylamine
(250 mg, 0.8 mmol) using tris(dibenzylideneacetone)dipalladium(0)
(73.2 mg, 0.08 mmol), BINAP (106 mg, 0.16 mmol) and cesium
carbonate (182 mg, 0.6 mmol) in toluene (20 mL). Purify by
chromatography on silica gel eluting with hexane/EtOAc (75:25) to
give
7-chloro-3-(2,2,2-trifluoroacetyl)-6-{4-[2-(2,2,2-trifluoroethylthio)-1,1-
-(ethylenedioxy)ethyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(97 mg, 41%).
[0960] To a solution of
7-chloro-3-(2,2,2-trifluoroacetyl)-6-{4-[2-(2,2,2-trifluoroethylthio)-1,1-
-(ethylenedioxy)ethyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(97 mg, 0.16 mmol) in anhydrous dichloromethane (0.5 mL), add a
solution of 4M hydrogen chloride in dioxane (1.2 mL) and reflux
overnight. Dilute with dichloromethane and wash with saturated
aqueous NaHCO.sub.3. Dry the organics extracts over MgSO.sub.4,
filter and concentrate in vacuo. Purify the crude mixture by
chromatography on silica gel eluting with hexane/EtOAc (4:1) to
obtain
7-chloro-3-(2,2,2-trifluoroacetyl)-6-[4-(2,2,2-trifluoroethylthio-methylc-
arbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (37 mg,
41%). MS (ES+) m/z: 539 (M+H).sup.+.
[0961] Use a method similar to the General Procedure 2-1, using
7-chloro-3-(2,2,2-trifluoroacetyl)-6-[4-(2,2,2-trifluoroethylthio-methylc-
arbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (37 mg,
0.07 mmol) to give
7-chloro-6-[4-(2,2,2-trifluoroethylthio-methylcarbonyl)-benzylamino]-2,3,-
4,5-tetrahydro-1H-benzo[d]azepine (16 mg, 53%).
[0962] Use a method similar to the General Procedure 3-2, using
7-chloro-6-[4-(2,2,2-trifluoroethylthio-methylcarbonyl)-benzylamino]-2,3,-
4,5-tetrahydro-1H-benzo[d]azepine (16 mg, 0.04 mmol) to give the
title compound as a white solid (21 mg, 98%). MS (ES+) m/z: 443
(M+H).sup.+.
[0963] The compounds of the present invention are relatively
selective for the 5-HT.sub.2C receptor. The compounds of the
present invention are particularly relatively selective for the
5-HT.sub.2C receptor in comparison to other 5-HT receptor subtypes
and specifically the 5-HT.sub.2A and 5-HT.sub.2B receptors. This
selectivity is demonstrated in the following agonist activity
assays and receptor binding assays.
[0964] Agonist Activity Assays (G Alpha q-GTP.gamma.[.sup.35S]
Binding Assays)
[0965] The 5-HT.sub.2 receptors are functionally coupled to
specific G-proteins. Agonist activation of 5-HT.sub.2
G-protein-coupled receptors results in the release of GDP from the
.alpha.-subunit (G alpha q or G alpha i) of the G-protein and the
subsequent binding of GTP. The binding of the stable analog
GTP.gamma.[.sup.35S] is an indicator of receptor activation (i.e.
agonist activity).
[0966] The G alpha q-GTP.gamma.[.sup.35S] binding assay is used to
determine the in vitro potency (EC.sub.50) and maximal efficacy
(E.sub.max, normalized to the 5-HT response) of a test compound at
the 5-HT.sub.2A, 5-HT.sub.2B, and 5-HT.sub.2C receptors. The area
under the dose response curve (AUC) is also determined for each
receptor subtype and used to measure the test compound's
selectivity for the 5-HT.sub.2C receptor over the 5-HT.sub.2A and
5-HT.sub.2B receptors, expressed as Selectivity Ratios (AUC 2C/2A
and AUC 2C/2B, respectively). The Selectivity Ratios allow the
assessment of selectivity based on both potency and efficacy. A
selectivity measure that incorporates both potency and efficacy at
the 5-HT.sub.2C receptor, as compared to the 5-HT.sub.2A and
5-HT.sub.2B, receptors, is considered important due to the adverse
events associated with 5-HT.sub.2A and 5-HT.sub.2B agonist activity
(see introduction).
[0967] Membrane Preparation: Grow AV12 cells stably transfected
with the human 5-HT.sub.2A, 5-HT.sub.2B, or 5-HT.sub.2C receptors
in suspension, harvest by centrifugation, wash the cell pellet with
phosphate buffered saline, pH 7.4, pellet the cells again, remove
the supernatant, freeze the cell pellet on dry ice and store at
-70.degree. C. Thaw stock cell pellet and resuspend in 50 mM Tris,
pH 7.4, aliquot into 1-2 mL volumes and refreeze at -70.degree. C.
for subsequent assays. (As is appreciated in the art, optimal cell
quantities used per aliquot will vary with the individual
transfected cell line used. In one embodiment, 5-HT.sub.2A and
5-HT.sub.2C transfected cells are typically used at about
6.times.10.sup.8 cells per aliquot, while 5-HT.sub.2B cells are
typically used at about 7.5.times.10.sup.8 cells per aliquot).
[0968] On the day of assay, thaw membranes, wash the membranes with
assay buffer (50 mM Tris-HCl (pH 7.4), 10 mM MgCl.sub.2, 100 mM
NaCl, and 0.2 mM EDTA), resuspend in assay buffer and incubate for
10 min. at 37.degree. C. to hydrolyze any residual endogenous 5-HT.
Wash the membranes again with assay buffer, and resuspend in assay
buffer at a concentration to provide aliquots of about
1-4.times.10.sup.6 cell equivalents per well (typically about
1-2.times.10.sup.6 cell equivalents for assays with 5-HT.sub.2A or
5-HT.sub.2C receptor assays, and about 3-4.times.10.sup.6 cell
equivalents for assays with 5-HT.sub.2B receptor assays).
Homogenize the cells with a tissue grinder and use the homogenate
directly in the assay as described below.
[0969] G alpha q-GTP.gamma.[.sup.35S] Binding Assays: The
immunoadsorption scintillation proximity assay (ISPA) of
[.sup.35S]-GTP.gamma.S binding to G alpha q is modified from
published conditions (DeLapp et al, JPET 289 (1999) 946-955).
Dissolve test compounds in DMSO and dilute in assay buffer to
provide a range of concentrations to generate a concentration
response curve. In wells of a 96 well microtiter plate, mix diluted
test compound, GDP (0.1 .mu.M final concentration), and
[.sup.35S]-GTP.gamma.S (between 0.5 and 1.0 nM final
concentration). Add an aliquot of membranes to the incubation
mixture and mix the plates to initiate agonist stimulation of the
nucleotide exchange (200 .mu.l final volume). Incubate the
microtiter plates for 30 min. at room temperature. Quench the
incubation with IGEPAL.RTM. CA-630 detergent (0.27% final
concentration). Add affinity purified polyclonal rabbit anti-G
alpha q antibody (about 1-2 .mu.g per well), and anti-rabbit Ig
scintillation proximity assay beads (Amersham; about 1.25 mg per
well; 300 .mu.l final volume). Seal the plates and incubate the
mixture for 3 h at room temperature. Centrifuge the microtiter
plates briefly to pellet beads. Quantitate the GTP.gamma.[.sup.35S]
binding by microtiter plate scintillation spectrometry (Wallac
Trilux MicroBeta.TM. scintillation counter).
[0970] Data Analysis: For each concentration response curve for a
test compound at a given receptor, analyze the data with GraphPad
Prism.TM. software (v3.02; GraphPad Software, San Diego, Calif.)
running on a personal computer with MicroSoft Windows OS.RTM.,
using nonlinear regression analysis curve fitting to determine the
EC.sub.50 and E.sub.max (normalized to 5-HT control curves).
Determine the Area Under the agonist concentration-response Curve
(AUC) with GraphPad Prism by the trapezoidal method.
[0971] To calculate the Selectivity Ratios, first, determine the
AUC for the test compound for each receptor subtype as described
above. Second, normalize the AUC's at each receptor subtype
relative to the AUC determined for 5-HT at that receptor. The
normalized AUC for a test compound at a given receptor is therefore
expressed as a percentage of the AUC determined for 5-HT at that
receptor. For example:
5 HT 2 A Normalized AUC = a = ( AUC test compound at 5 HT 2 A
receptor ) ( AUC 5 - HT at 5 HT 2 A receptor ) .times. 100 %
##EQU00001## 5 HT 2 B Normalized AUC = b = ( AUC test compound at 5
HT 2 B receptor ) ( AUC 5 - HT at 5 HT 2 B recpetor ) .times. 100 %
##EQU00001.2## 5 HT 2 C Normalized AUC = c = ( AUC test compound at
5 HT 2 C receptor ) ( AUC 5 - HT at 5 HT 2 C receptor ) .times. 100
% ##EQU00001.3##
[0972] Third, calculate the Selectivity Ratios for the test
compound as follows:
[0973] Selectivity Ratio for 5-HT.sub.2C receptor/5-HT.sub.2A
receptor (AUC 2C/2A)=c/a
[0974] Selectivity Ratio for 5-HT.sub.2C receptor/5-HT.sub.2B
receptor (AUC 2C/2B)=c/b
[0975] For reference purposes, the AUC 2C/2A and AUC 2C/2B for 5-HT
are each 1.0. Likewise, the ratios for mCPP
(meta-chlorophenylpiperazine) are tested and are found to be 2.1
and 2.1 respectively.
[0976] Representative compounds of the present invention are tested
in the G alpha q-GTP.gamma.[.sup.35S] assays for the 5-HT.sub.2A,
5-HT.sub.2B, and 5-HT.sub.2C receptors essentially as described
above and are found to be a highly potent and selective agonists of
the 5-HT.sub.2C receptor, with EC.sub.50's typically less than or
equal to 250 nM, and AUC 2C/2A and AUC 2C/2B 5 ratios greater than
1.5. Preferred compounds are those with EC50's less than or equal
to 100 nM, and AUC 2C/2A and AUC 2C/2B ratios greater than or equal
to 2.0. More preferred are those with EC50's less than or equal to
50 nM, and AUC 2C/2A and AUC 2C/2B ratios greater than or equal to
3.0.
Ligand Binding Assays
[0977] The ligand binding affinity of the compounds of the present
invention to the 5-HT.sub.2C receptor subtype is measured
essentially as described by Wainscott (Wainscott, et al., Journal
of Pharmacology and Experimental Therapeutics, 276:720-727 (1996)).
Data is analyzed by nonlinear regression analysis on the
concentration response curves using the four parameter logistic
equation described by DeLean (DeLean, et al., Molecular
Pharmacology, 21, 5-16 (1982)). IC.sub.50 values are converted to
K.sub.i values using the Cheng-Prusoff equation (Cheng, et al.,
Biochem. Pharmacol., 22, 3099-3108 (1973)).
[0978] Representative compounds of the present invention are tested
essentially as described above and are found to have excellent
affinity for the 5-HT.sub.2C receptor, with K.sub.i's typically
less than or equal to about 250 nM. Preferred compounds are those
with K.sub.i's of less than or equal to about 100 nM. More
preferred are those with K.sub.i's less than or equal to 50 nM.
[0979] Affinities for other receptor subtypes can readily be
determined by slight modification of the above described
radioligand receptor binding assay using cells transfected with the
desired receptor in place of cells transfected with the 5-HT.sub.2C
receptor subtype and using an appropriate radioligand. The binding
affinities for representative compounds of the present invention
for a variety of receptors are determined in such assays and the
compounds are found to have surprisingly higher affinity for the
5-HT.sub.2C receptor. Affinity for the 5-HT.sub.2C receptor is
found to be significantly higher than for other 5-HT receptor
subtypes, and notably higher than the 5-HT.sub.2A and 5-HT.sub.2B B
receptor subtypes. Preferred compounds are those with IC.sub.50 's
equal to or greater than 300 nM for the alpha 1 and alpha 2
adrenergic receptors and equal to or greater than 500 nM for
D.sub.1 and D.sub.2 dopaminergic receptors. More preferred
compounds are those with IC.sub.50's equal to or greater than 1000
nM for the alpha 1 and alpha 2 adrenergic receptors and the D.sub.1
and D.sub.2 dopaminergic receptors. Still more preferred are those
compounds with IC.sub.50's equal to or greater than 3000 nM for the
alpha 1 and alpha 2 adrenergic receptors and the D.sub.1 and
D.sub.2 dopaminergic receptors.
[0980] For the above in vitro assays, exemplified compounds are
assayed and found to have either an EC.sub.50 or a K; value of
equal to or less than 50 nM, and to have AUC 2C/2A and AUC 2C/2B
ratios of greater than or equal to 2.0. Exemplified compounds are
assayed and found to typically have alpha 1 and alpha 2 adrenergic
receptor IC.sub.50's equal to or greater than 300 nM, and D.sub.1
and D.sub.2 dopaminergic receptor IC.sub.50's equal to or greater
than 500 nM.
Rat Feeding Assays
[0981] The ability of the compounds of the present invention to
treat obesity is 15 demonstrated by testing in acute and chronic
rat feeding assays.
Animals: Obtain male Long-Evans rats (Harlan Sprague-Dawley,
Indianapolis, Ind.) that are approximately one hundred-days old and
have been maintained on a calorie rich diet since weaning (TD
95217, 40% calories from fat; Teklad, Madison, Wis.). House the
rats individually with a 12 h:12 h light:dark cycle (lights on from
about 22:00 h to about 10:00 h) and maintain rats on the same diet
(TD 95217) with free access to water, for about 1-2 weeks to
acclimate the rats to the environment. Dose rats orally with
vehicle (10% acacia with 0.15% saccharin in water) once daily for
at least 1 day (typically 1-2 days) to acclimate the rats to the
procedures. Randomize the rats into groups so each group has
similar mean body weights. Calorimetric Acute Feeding Assay: At
approximately 8:00 h on the day of assay, weigh each rat and
transfer to individual chambers of an open circuit calorimetry
system (Oxymax, Columbus Instruments International Corporation;
Columbus, Ohio), with free access to food (pre-weighed) and water,
and begin measuring VO.sub.2 and VCO.sub.2. At approximately 10:00
h, dose rats orally with vehicle or test compound, return them to
their calorimetry chambers, and continue measuring VO.sub.2 and
VCO.sub.2 at regular time intervals (approximately hourly). At
approximately 8:00 h the following day, measure rat body weight and
the remaining food, assuming the difference in weight of food is
equal to the mass of food consumed. Calculate the 24 h energy
expenditure (EE) and respiratory quotient (RQ) essentially as
described in Chen, Y. and Heiman, M. L., Regulatory 5 Peptide,
92:113-119 (2000). EE during light photoperiod is indicative of the
resting metabolic rate and RQ is indicative of the fuel source the
animal utilizes (pure carbohydrate metabolism gives an RQ of about
1.0, pure fat metabolism gives an RQ of about 0.7, mixed
carbohydrate and fat metabolism gives intermediate values for
RQ).
[0982] Calculate EE as the product of calorific value (CV) and
VO.sub.2 per body weight (kg); where CV=3.815+1.232*RQ, and RQ is
the ratio of CO.sub.2 produced (VCO.sub.2) to O.sub.2 consumed
(VO.sub.2). Caloric intake is calculated as (mass of 24 h food
intake in grams).times.(physiological fuel value of the diet in
kilocalorie/g) per kg of body weight.
Acute Feeding Assay with a selective 5-HT.sub.2C receptor
antagonist: The above calorimetric acute feeding assay is conducted
with the following modifications. Open circuit calorimetry systems
are not used and only the 24 h periodic food intake and body weight
are measured. Three groups of rats are used with the first group
receiving a subcutaneous dose of saline (0.5 mL) about 15 minutes
prior to the oral dose of vehicle, the second group receiving a
subcutaneous dose of saline (0.5 mL) about 15 minutes prior to the
oral dose of test compound in vehicle, and the third group
receiving a subcutaneous injection of a selective 5-HT.sub.2C
receptor antagonist,
6-chloro-5-methyl-N-{2-[(2-methylpyridin-3-yl-oxy)pyridin-5-yl]aminocarbo-
nyl}-2,3-dihydroindole (3 mg/Kg, in 35% cyclodextrin, 0.5 mL),
about 15 min. prior to the oral dose of test compound in
vehicle.
[0983] Chronic Feeding Assay: At between approximately 8:00 h and
10:00 h on day one of the assay, weigh and orally dose each rat
with vehicle or test compound and return the animal to its home
cage, with free access to food (pre-weighed) and water. For each of
days 2-15, at between approximately 8:00 h and 10:00 h, measure rat
body weight and the weight of food consumed in the last 24 h
period, and administer daily oral dose of test compound or vehicle.
On days -2 and 15 measure total fat mass and lean mass by nuclear
magnetic resonance (NMR) using an EchoMRI.TM. system (Echo Medical
Systems, Houston Tex.). (See Frank C. Tinsley, Gersh Z. Taicher,
and Mark L. Heiman, "Evaluation of a New Quantitative Magnetic
Resonance (QMR) Method for Mouse Whole Body Composition Analysis",
Obesity Research, submitted May 1, 2003.)
[0984] Representative compounds of the present invention are tested
in acute and chronic feeding assays essentially as described above.
In the acute assays, the compounds are found to significantly
reduce 24 h food intake, which effect is blocked by
pre-administration of the 5-HT.sub.2C receptor antagonist. The
compounds also are found to dose-dependently reduce RQ without
significantly changing the energy expenditure during the light
photo-period. Thus the compounds are found to reduce caloric intake
and increase the proportion of fuel deriving from fat utilization,
without significantly changing the resting metabolic rate. In the
chronic assay, the compounds are found to significantly decrease
cumulative food intake and cumulative body weight change in a
dose-dependent manner compared to control animals. The decrease in
body weight is found to be due to loss of adipose tissue while lean
body mass is not changed.
[0985] The ability of the 5-HT.sub.2C receptor agonists of the
present invention to treat obsessive/compulsive disorder is
demonstrated by testing in a variety of in vivo assays as
follows:
Marble Burying Assay
[0986] Marble burying in mice has been used to model anxiety
disorders including obsessive-compulsive disorders (OCD) due to
ethological study of the behavior (e.g. Gyertyan I. "Analysis of
the marble burying response: Marbles serve to measure digging
rather than evoke burying", Behavioural Pharmacology 6: 24-31,
(1995)) and due to the pharmacological effects of clinical
standards (c.f., Njung'E K. Handley S L. "Evaluation of
marble-burying behavior as a model of anxiety", Pharmacology,
Biochemistry & Behavior. 38: 63-67, (1991)); Borsini F.,
Podhoma J., and Marazziti, D. "Do animal models of anxiety predict
anxiolytic effects of antidepressants?", Psychopharmacology 163:
121-141, (2002)). Thus, drugs used in the treatment of generalized
anxiety in humans (e.g. benzodiazepines) as well as compounds used
to treat OCD (e.g. SSRIs like fluoxetine) decrease burying.
[0987] House experimentally-naive male, NIH Swiss mice (Harlan
Sprague-Dawley, Indianapolis, Ind.) weighing between 28-35 g in
groups of 12 for at least three days prior to testing in a vivarium
with 12 h light and dark cycles. Conduct experiments during the
light cycle in a dimly lit experimental testing room. Dose mice
with vehicle or test compound and, after a specified pretreatment
interval (generally 30 min.), place each mouse individually on a
rotorod (Ugo Basile 7650) operating at a speed of 6
revolutions/min. and observe for falling. After 2 min. on the
rotorod, place the mice individually in a 17.times.28.times.12 cm
high plastic tub with 5 mm sawdust shavings on the floor that are
covered with 20 blue marbles (1.5 cm diameter) placed in the
center. After 30 min., count the number of marbles buried (2/3
covered with sawdust). Assess the test compound's effect on marble
burying with Dunnett's test and the effect on rotorod performance
by Fisher's exact test.
[0988] Clinically effective standard compounds suppress marble
burying at doses that are devoid of motor-impairing effects as
measured on the rotorod. The in vivo efficacy of 5HT.sub.2C
compounds at the 5HT.sub.2C receptor is confirmed by the prevention
of effects of the 5HT.sub.2C agonists on marble burying by
co-administration of the 5HT.sub.2C receptor antagonist,
6-chloro-5-methyl-N-{2-[(2-methylpyridin-3-yl-oxy)pyridin-5-yl]aminocarbo-
nyl}-2,3-dihydroindole.
[0989] Representative compounds of the present invention are
assayed in the marble burying assay essentially as described and
are surprisingly found to reduce burying behavior in the test mice.
The reduction of burying behavior is found to be blocked by
co-administration of the 5-HT.sub.2C antagonist. In contrast to the
compounds of the present invention, the anxiolytic compound
chlordiazepoxide and the antipsychotic compound chlorpromazine
decrease marble burying only at doses that also disrupt rotorod
performance.
Nestlet Shredding
[0990] Mice naturally will construct nests of material available in
their living environment. Since this behavior is obsessive in
nature, it has been used to model OCD (Xia Li, Denise Morrow and
Jeffrey M. Witkin, "Decreases in nestlet shredding of mice by
serotonin uptake inhibitors: comparison with marble burying",
Psychopharmacology, submitted Jul. 14, 2003). House
experimentally-naive male, NIH Swiss mice (Harlan Sprague-Dawley,
Indianapolis, Ind.) weighing between 28-35 g in groups of 12 for at
least three days prior to testing in a vivarium with a 12 h
light/dark cycle. Conduct experiments during the light cycle in an
experimental room with normal overhead fluorescent lighting. Dose
mice with vehicle or test compound and after a specified
pretreatment interval (generally 30 min.), place the mice
individually in a 17.times.28.times.12 cm high plastic tub with
about 5 mm sawdust shavings on the floor along with a pre-weighed
multi-ply gauze pad (51 mm square). After 30 min., weigh the
remainder of the gauze pad not removed by the mouse. Determine the
weight of the gauze used for nestlet construction by subtraction.
Compare the results for test compound treated mice to the results
for vehicle control treated mice with Dunnett's test.
[0991] Clinically effective OCD treatment standard compounds
suppress nestlet shredding at doses that are devoid of
motor-impairing effects as measured by the rotorod test. The ill
vivo efficacy of 5HT.sub.2C compounds at the 5HT.sub.2C receptor is
confirmed by the prevention of effects of the 5HT.sub.2C agonists
on nestlet shredding by co-administration of the 5HT.sub.2C
receptor antagonist,
6-chloro-5-methyl-N-{2-[(2-methylpyridin-3-yl-oxy)pyridin-5-yl]aminocarbo-
nyl}-2,3-dihydroindole. Representative compounds of the present
invention are assayed essentially as described above and are
surprisingly found to suppress nestlet shredding at doses that are
devoid of motor-impairing effects as measured by the rotorod
test.
[0992] In contrast to the compounds of the present invention, the
anxiolytic chlordiazepoxide and the psychomotor stimulant
d-amphetamine decreases nestlet shredding only at doses that
produce motoric side effects (depression or stimulation,
respectively).
Schedule-Induced Polydipsia
[0993] Food-deprived rats exposed to intermittent presentations of
food will drink amounts of water that are far in excess of their
normal daily intake and in excess of their intake when given all of
their food at one time (Falk J L. "Production of polydipsia in
normal rats by an intermittent food schedule", Science 133:
195-196, (1961)). This excessive behavior is persistent and has
been used to model OCD.
[0994] Maintain Wistar rats on a food restricted diet (to maintain
85% free feeding weight), but with free access to water. Train the
rats in a behavioral testing chamber to press a lever to receive a
food pellet under a fixed interval schedule, such that the rats are
rewarded with a 45 mg food pellet the first time they press a lever
after a 120 second interval has elapsed. The fixed interval is then
reset to 120 seconds and the process repeated. Thus, during a 90
min. test session, the rats can earn a maximum of 45 pellets. The
behavioral chamber is also equipped with a water bottle that is
weighed before and after the session to determine the amount of
water consumed.
[0995] Administer test compounds on Tuesdays and Fridays. Determine
control day performances on Thursdays. Administer compounds either
orally at 60 min. before the beginning of a test session, or
subcutaneously at 20 min. before the beginning of a test session.
Compare the rates of lever pressing and water consumption for each
animal's performance during sessions after test compound treatment
with that animal's performance during control sessions, expressed
as a percent of the control rate. Average the individual percent of
control rates for each dose and calculate the standard error of the
mean.
[0996] Clinically effective OCD treatment standard compounds (e.g.
chlomipramine, fluoxetine) suppress schedule-induced polydipsia
without producing notable changes in motor patterns, food intake,
or behavior the following day. The in vivo efficacy of 5HT.sub.2C
compounds at the 5HT.sub.2C receptor is confirmed by the prevention
of effects of the 5HT.sub.2C agonists on excessive drinking by
co-administration of the 5HT.sub.2C receptor antagonist,
6-chloro-5-methyl-N-{2-[(2-methylpyridin-3-yl-oxy)pyridin-5-yl]aminocarbo-
nyl}-2,3-dihydroindole.
[0997] Representative compounds of the present invention are
assayed in the schedule-induced polydipsia assay essentially as
described above and are surprisingly found to suppress
schedule-induced polydipsia without producing notable changes in
motor patterns, food intake, or behavior the following day. The
behavior suppression is blocked by co-administration of the
5-HT.sub.2C antagonist.
[0998] In contrast to the compounds of the present invention, the
psychomotor stimulant d-amphetamine decreases excessive drinking
only at behaviorally stimulating doses and these effects are not
prevented by the 5HT.sub.2C receptor antagonist.
[0999] While it is possible to administer compounds employed in the
methods of this invention directly without any formulation, the
compounds are usually administered in the form of pharmaceutical
compositions comprising a pharmaceutically acceptable excipient and
at least one compound of Formula I or a pharmaceutically acceptable
salt thereof.
[1000] These compositions can be administered by a variety of
routes including oral, rectal, transdermal, subcutaneous,
intravenous, intramuscular, and intranasal. The compounds employed
in the methods of this invention are effective as both injectable
and oral compositions. Such compositions are prepared in a manner
well known in the pharmaceutical art. See, e.g. REMINGTON'S
PHARMACEUTICAL SCIENCES, (16th ed. 1980).
[1001] In making the compositions employed in the present invention
the active ingredient is usually mixed with at least one excipient,
diluted by at least one excipient, or enclosed within such a
carrier which can be in the form of a capsule, sachet, paper or
other container. When the excipient serves as a diluent, it can be
a solid, semi-solid, or liquid material, which acts as a vehicle,
carrier or medium for the active ingredient. Thus, the compositions
can be in the form of tablets, pills, powders, lozenges, sachets,
cachets, elixirs, suspensions, emulsions, solutions, syrups,
aerosols (as a solid or in a liquid medium), ointments containing
for example up to 10% by weight of the active compound, soft and
hard gelatin capsules, suppositories, sterile injectable solutions,
and sterile packaged powders.
[1002] In preparing a formulation, it may be necessary to mill the
compound to provide the appropriate particle size prior to
combining with the other ingredients. If the active compound is
substantially insoluble, it ordinarily is milled to a particle size
of less than 200 mesh. If the active compound is substantially
water soluble, the particle size is normally adjusted by milling to
provide a substantially uniform distribution in the formulation,
e.g. about 40 mesh.
[1003] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, water, syrup, and methyl cellulose. The formulations can
additionally include: lubricating agents such as talc, magnesium
stearate, and mineral oil; wetting agents; emulsifying and
suspending agents; preserving agents such as methyl- and
propylhydroxybenzoates; sweetening agents; and flavoring agents.
The compositions of the invention can be formulated so as to
provide quick, sustained or delayed release of the active
ingredient after administration to the patient by employing
procedures known in the art.
[1004] The compositions are preferably formulated in a unit dosage
form, each dosage containing from about 0.05 to about 100 mg, more
usually about 1.0 to about 30 mg, of the active ingredient. The
term "unit dosage form" refers to physically discrete units
suitable as unitary dosages for human subjects and other mammals,
each unit containing a predetermined quantity of active material
calculated to produce the desired therapeutic effect, in
association with a suitable pharmaceutical excipient.
[1005] The compounds are generally effective over a wide dosage
range. For examples, dosages per day normally fall within the range
of about 0.01 to about 30 mg/kg. In the treatment of adult humans,
the range of about 0.1 to about 15 mg/kg/day, in single or divided
dose, is especially preferred. However, it will be understood that
the amount of the compound actually administered will be determined
by a physician, in the light of the relevant circumstances,
including the condition to be treated, the chosen route of
administration, the actual compound or compounds administered, the
age, weight, and response of the individual patient, and the
severity of the patient's symptoms, and therefore the above dosage
ranges are not intended to limit the scope of the invention in any
way. In some instances dosage levels below the lower limit of the
aforesaid range may be more than adequate, while in other cases
still larger doses may be employed.
[1006] Another preferred formulation employed in the methods of the
present invention employs transdermal delivery devices ("patches").
Such transdermal patches may be used to provide continuous or
discontinuous infusion of the compounds of the present invention in
controlled amounts. The construction and use of transdermal patches
for the delivery of pharmaceutical agents is well known in the art.
See, e.g., U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein
incorporated by reference. Such patches may be constructed for
continuous, pulsatile, or on demand delivery of pharmaceutical
agents.
[1007] Under some circumstances, it will be desirable or necessary
to introduce the pharmaceutical composition to the brain, either
directly or indirectly. Direct techniques usually involve placement
of a drug delivery catheter into the host's ventricular system to
bypass the blood-brain barrier. One such implantable delivery
system, used for the transport of biological factors to specific
anatomical regions of the body, is described in U.S. Pat. No.
5,011,472, issued Apr. 30, 1991, which is herein incorporated by
reference.
[1008] Indirect techniques, which are generally preferred, usually
involve formulating the compositions to provide for drug
latentiation by the conversion of hydrophilic drugs into
lipid-soluble drugs or prodrugs. Latentiation is generally achieved
through blocking of the hydroxy, carbonyl, sulfate, and primary
amine groups present on the drug to render the drug more lipid
soluble and amenable to transportation across the blood-brain
barrier. Alternatively, the delivery of hydrophilic drugs may be
enhanced by intra-arterial infusion of hypertonic solutions which
can transiently open the blood-brain barrier.
[1009] The type of formulation employed for the administration of
the compounds employed in the methods of the present invention may
be dictated by the particular compound employed, the type of
pharmacokinetic profile desired from the route of administration,
and the state of the patient.
* * * * *