U.S. patent application number 12/548844 was filed with the patent office on 2010-02-04 for aryl sulfamide derivatives and methods of their use.
This patent application is currently assigned to Wyeth. Invention is credited to Stephen Todd Cohn, Andrew Fensome, Joel Adam Goldberg, Charles William Mann, Michael Anthony Marella, Casey Cameron McComas, David John O'Neill, Joseph Peter Sabatucci, Eugene Anthony Terefenko, Eugene John Trybulski, An Thien Vu, Richard Page Woodworth, JR., Puwen Zhang.
Application Number | 20100029641 12/548844 |
Document ID | / |
Family ID | 39273293 |
Filed Date | 2010-02-04 |
United States Patent
Application |
20100029641 |
Kind Code |
A1 |
McComas; Casey Cameron ; et
al. |
February 4, 2010 |
ARYL SULFAMIDE DERIVATIVES AND METHODS OF THEIR USE
Abstract
The present invention is directed to aryl sulfamide derivatives
of formula I: ##STR00001## or a pharmaceutically acceptable salt,
stereoisomer or tautomer thereof, which are monoamine reuptake
inhibitors, compositions containing these derivatives, and methods
of their use for the prevention and treatment of conditions,
including, inter alia, vasomotor symptoms, sexual dysfunction,
gastrointestinal disorders and genitourinary disorder, depression
disorders, endogenous behavioral disorders, cognitive disorders,
diabetic neuropathy, pain, and other diseases or disorders.
Inventors: |
McComas; Casey Cameron;
(Phoenixville, PA) ; Cohn; Stephen Todd; (Spring,
TX) ; Fensome; Andrew; (Wayne, PA) ; Goldberg;
Joel Adam; (Philadelphia, PA) ; Mann; Charles
William; (Plymouth Meeting, PA) ; Marella; Michael
Anthony; (Limerick, PA) ; O'Neill; David John;
(Collegeville, PA) ; Sabatucci; Joseph Peter;
(Collegeville, PA) ; Terefenko; Eugene Anthony;
(Center Valley, PA) ; Trybulski; Eugene John;
(Huntingdon Valley, PA) ; Vu; An Thien;
(Pottstown, PA) ; Woodworth, JR.; Richard Page;
(North Wales, PA) ; Zhang; Puwen; (Audubon,
PA) |
Correspondence
Address: |
WYETH;PATENT LAW GROUP
5 GIRALDA FARMS
MADISON
NJ
07940
US
|
Assignee: |
Wyeth
Madison
NJ
|
Family ID: |
39273293 |
Appl. No.: |
12/548844 |
Filed: |
August 27, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11955018 |
Dec 12, 2007 |
7601722 |
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12548844 |
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11955195 |
Dec 12, 2007 |
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11955018 |
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11955204 |
Dec 12, 2007 |
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11955195 |
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60869644 |
Dec 12, 2006 |
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60869644 |
Dec 12, 2006 |
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60869644 |
Dec 12, 2006 |
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Current U.S.
Class: |
514/234.2 ;
514/322; 514/362; 544/134; 546/199; 548/126 |
Current CPC
Class: |
A61P 25/02 20180101;
A61P 7/12 20180101; C07D 417/06 20130101; A61P 13/00 20180101; A61P
9/00 20180101; A61P 25/24 20180101; A61P 25/22 20180101; A61P 25/04
20180101; C07D 417/04 20130101; A61P 1/00 20180101; A61P 25/00
20180101; A61P 25/20 20180101; A61P 29/00 20180101; A61P 21/00
20180101; A61P 25/28 20180101; C07D 285/14 20130101; A61P 7/00
20180101; A61P 3/00 20180101; A61P 15/00 20180101 |
Class at
Publication: |
514/234.2 ;
548/126; 546/199; 544/134; 514/362; 514/322 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 285/14 20060101 C07D285/14; C07D 417/06 20060101
C07D417/06; A61K 31/41 20060101 A61K031/41; A61K 31/454 20060101
A61K031/454; A61P 15/00 20060101 A61P015/00; A61P 1/00 20060101
A61P001/00; A61P 25/00 20060101 A61P025/00; A61P 7/12 20060101
A61P007/12 |
Claims
1. A compound of formula I: ##STR00244## or a pharmaceutically
acceptable salt, stereoisomer or tautomer thereof; wherein: n is an
integer from 0 to 4; m is an integer from 0 to 6; X is,
independently at each occurrence, C(R.sup.7).sub.2, N(R.sup.3), O,
S, S(.dbd.O), or S(.dbd.O).sub.2; Y is C; or Y and an adjacent X
together form --CR.sup.7.dbd.CR.sup.7--, --C.ident.C--, or arylenyl
substituted with 0-3 R.sup.10; R.sup.1 is, independently at each
occurrence, H, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl substituted
with 0-3 R.sup.11, heteroaryl substituted with 0-3 R.sup.11,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide
substituted with 0-3 R.sup.5, alkylamido, or arylamido substituted
with 0-3 R.sup.5; R.sup.2 is aryl substituted with 0-3 R.sup.9 or
heteroaryl substituted with 0-3 R.sup.9; R.sup.3 is, independently
at each occurrence, H, halo, hydroxy, alkyl substituted with 0-3
R.sup.13, a heterocyclic ring, aryl substituted with 0-3 R.sup.12,
or heteroaryl substituted with 0-3 R.sup.12; R.sup.4 is,
independently at each occurrence, H, alkyl substituted with 0-3
R.sup.13, arylalkyl substituted with 0-3 R.sup.13 or
heteroarylmethyl substituted with 0-3 R.sup.13; R.sup.5 is,
independently at each occurrence, alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido;
R.sup.6 is, independently at each occurrence, H, hydroxy,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkoxy, halo, aryl
substituted with 0-3 R.sup.1, heteroaryl substituted with 0-3
R.sup.1, --N(R.sup.3).sub.2, --S(R.sup.3), or
--R.sup.8--O--R.sup.3; or both R.sup.6 groups form a cycloalkyl, a
heterocyclic ring, .dbd.O or .dbd.N--OH; provided that if each
R.sup.3 is H, each X is CH.sub.2, and either each R.sup.6 is H or
one R.sup.6 is hydroxy; then, both of said R.sup.4, together with
the nitrogen through which they are attached, form a monocyclic or
bicyclic heterocyclic ring of 3 to 12 ring atoms, where one carbon
may be optionally replaced with N, O, S, or SO.sub.2, and where any
carbon ring atom may be optionally substituted with one or two
alkyl, hydroxyalkyl, aminoalkyl, or a heterocyclic ring, F, or
CF.sub.3; and where any additional N atom may be optionally
substituted with C.sub.1-C.sub.4 alkyl; R.sup.7 is, independently
at each occurrence, H, hydroxy, alkoxy, or C.sub.1-C.sub.4 alkyl;
R.sup.8 is, independently at each occurrence, straight or branched
alkylenyl; or one of said R.sup.3 and one of said R.sup.4, together
with the nitrogen and carbon atoms through which they are attached,
form a monocyclic or bicyclic heterocyclic ring of 3 to 12 ring
atoms, where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, F, or CF.sub.3; and where any
additional N atom may be optionally substituted with alkyl; or both
of said R.sup.4, together with the nitrogen through which they are
attached, form a monocyclic or bicyclic heterocyclic ring of 3 to
12 ring atoms, where one carbon may be optionally replaced with N,
O, S, or SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, hydroxyalkyl, aminoalkyl, a
heterocyclic ring, F, or CF.sub.3; and where any additional N atom
may be optionally substituted with alkyl; or one of said R.sup.6 or
one of said R.sup.7 and one of said R.sup.4, together with the
nitrogen and carbon atoms through which they are attached, form a
monocyclic or bicyclic heterocyclic ring of 3 to 12 ring atoms,
where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two C.sub.1-C.sub.4 alkyl, F, or CF.sub.3;
and where any additional N atom may be optionally substituted with
C.sub.1-C.sub.4 alkyl; provided that R.sup.4 and R.sup.7, taken
together, do not form a piperidinyl ring; R.sup.9 is, independently
at each occurrence, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl
substituted with 0-3 R.sup.11, heteroaryl substituted with 0-3
R.sup.11, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
arylsulfonamide, alkylamido, or arylamido; R.sup.10 is,
independently at each occurrence, alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl; R.sup.11 is, independently at each occurrence, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl; R.sup.12 and R.sup.13 are each,
independently at each occurrence, alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, hydroxyalkyl, aminoalkyl, a heterocyclic ring,
alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl; and wherein 1-3
carbon atoms in ring A may optionally be replaced with N.
2. The compound of claim 1, wherein: R.sup.4 and R.sup.6, taken
together, form a morpholinyl group optionally substituted with
C.sub.1-C.sub.4 alkyl, F, or CF.sub.3.
3. The compound of claim 2, wherein: R.sup.4 and R.sup.6, taken
together, form morpholin-2-yl.
4. The compound of claim 3, wherein: R.sup.4 and R.sup.6, taken
together, form (R)-morpholin-2-yl.
5. The compound of claim 3, wherein: R.sup.4 and R.sup.6, taken
together, form (S)-morpholin-2-yl.
6. The compound of claim 1, wherein: n is an integer from 0 to
2.
7. The compound of claim 1, wherein: m is an integer from 1 to
6.
8. The compound of claim 1, wherein: X is, independently at each
occurrence, C(R.sup.7).sub.2, N(R.sup.3), or O.
9. The compound of claim 1, wherein: X is, independently at each
occurrence, C(R.sup.7).sub.2.
10. The compound of claim 1, wherein: R.sup.1 is, independently at
each occurrence, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3 or
nitrile.
11. The compound of claim 1, wherein: R.sup.2 is aryl substituted
with 0-3 R.sup.9.
12. The compound of claim 1, wherein: R.sup.2 is phenyl,
fluoro-phenyl, difluoro-phenyl, trifluoro-phenyl, chloro-phenyl,
fluoro-chloro-phenyl, bromo-phenyl, trifluoromethyl-phenyl
trifluoromethoxy-phenyl, methyl-fluoro-phenyl,
methoxy-fluoro-phenyl, or naphthyl.
13. The compound of claim 1, wherein: R.sup.2 is heteroaryl
substituted with 0-3 R.sup.9.
14. The compound of claim 1, wherein: R.sup.2 is pyridinyl,
methyl-pyridinyl, ethyl-pyridinyl, methoxy-pyridinyl, or
quinolinyl.
15. The compound of claim 1, wherein: R.sup.3 is, independently at
each occurrence, H, methyl, or phenyl.
16. The compound of claim 1, wherein: R.sup.4 is, independently at
each occurrence, hydrogen, methyl, ethyl, cyclopropyl, or
n-butyl.
17. The compound of claim 1, wherein: both of said R.sup.4,
together with the nitrogen through which they are attached, form a
heterocyclic ring of 4 to 7 atoms, where one carbon may be
optionally replaced with N or O; where any carbon ring atom may be
optionally substituted with one or two C.sub.1-C.sub.4 alkyl, F, or
CF.sub.3; and where any additional N atom may be optionally
substituted with C.sub.1-C.sub.4 alkyl.
18. The compound of claim 1, wherein: R.sup.5 is, independently at
each occurrence, alkyl, alkoxy, halo, or OCF.sub.3.
19. The compound of claim 1, wherein: R.sup.6 is, independently at
each occurrence, H methyl, or fluoro.
20. The compound of claim 1, wherein: R.sup.7 is, independently at
each occurrence, H, methyl, or phenyl.
21. The compound of claim 1, wherein: Y and an adjacent X together
form --CH.dbd.CH--, --C.ident.C--, or phenylenyl.
22. The compound of claim 1, wherein: m is an integer from 1 to 3;
X is, independently at each occurrence, C(R.sup.7).sub.2,
N(R.sup.3), or O; Y is C; R.sup.1 is, independently at each
occurrence, alkyl, alkoxy, halo, CF.sub.3, or OCF.sub.3; R.sup.2 is
aryl substituted with 0-3 R.sup.9 or heteroaryl substituted with
0-3 R.sup.9; R.sup.3 is, independently at each occurrence, H or
C.sub.1-C.sub.4 alkyl; R.sup.4 is, independently at each
occurrence, H or C.sub.1-C.sub.6 alkyl; R.sup.6 is, independently
at each occurrence, H, C.sub.1-C.sub.4 alkyl, or halo; and R.sup.7
is, independently at each occurrence, H or C.sub.1-C.sub.4
alkyl.
23. The compound of claim 1, wherein: m is an integer from 0 to 1;
X is, independently at each occurrence, C(R.sup.7).sub.2; Y is C;
R.sup.1 is, independently at each occurrence, alkyl, alkoxy, halo,
CF.sub.3, or OCF.sub.3; R.sup.2 is aryl substituted with 0-3
R.sup.9 or heteroaryl substituted with 0-3 R.sup.9; R.sup.3 is,
independently at each occurrence, H or C.sub.1-C.sub.4 alkyl;
R.sup.6 is, independently at each occurrence, H, C.sub.1-C.sub.4
alkyl, or halo; and R.sup.7 is, independently at each occurrence, H
or C.sub.1-C.sub.4 alkyl; or both of said R.sup.4, together with
the nitrogen through which they are attached, form a heterocyclic
ring of 4 to 7 atoms, where one carbon may be optionally replaced
with N or O, where any carbon ring atom may be optionally
substituted with one or two C.sub.1-C.sub.4 alkyl, F, or CF.sub.3;
and where any additional N atom may be optionally substituted with
C.sub.1-C.sub.4 alkyl.
24. The compound of claim 1, wherein: m is an integer from 0-1; X
is, independently at each occurrence, C(R.sup.7).sub.2 Y is C
R.sup.1 is, independently at each occurrence, alkyl, alkoxy, halo,
CF.sub.3, or OCF.sub.3; R.sup.2 is aryl substituted with 0-3
R.sup.9 or heteroaryl substituted with 0-3 R.sup.9; R.sup.3 is,
independently at each occurrence, H or C.sub.1-C.sub.4 alkyl;
R.sup.6 is, independently at each occurrence, H, C.sub.1-C.sub.4
alkyl, or halo; and R.sup.7 is, independently at each occurrence, H
or C.sub.1-C.sub.4 alkyl, or one of said R.sup.6 or one of said
R.sup.7 and one of said R.sup.4, together with the nitrogen and
carbon atoms through which they are attached, form a monocyclic or
bicyclic heterocyclic ring of 3 to 12 atoms, where one carbon may
be optionally replaced with N, O, S, or SO.sub.2, and where any
carbon ring atom may be optionally substituted with one or two
C.sub.1-C.sub.4 alkyl, F, or CF.sub.3; and where any additional N
atom may be optionally substituted with C.sub.1-C.sub.4 alkyl.
25. The compound of claim 1, wherein the pharmaceutically
acceptable salt is a hydrochloride (HCl) salt.
26. A compound of formula II: ##STR00245## or a pharmaceutically
acceptable salt, stereoisomer or tautomer thereof; wherein: n is an
integer from 0 to 4; m is an integer from 1 to 6; X is,
independently at each occurrence, C(R.sup.7).sub.2, N(R.sup.3), O,
S, S(.dbd.O), or S(.dbd.O).sub.2; Z is O, N(R.sup.3), S, or
C(R.sup.7).sub.2; R.sup.1 is, independently at each occurrence, H,
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, aryl substituted with 0-3
R.sup.11, heteroaryl substituted with 0-3 R.sup.11, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, arylsulfonamide substituted with
0-3 R.sup.5, alkylamido, or arylamido substituted with 0-3 R.sup.5;
R.sup.2 is aryl substituted with 0-3 R.sup.9 or heteroaryl
substituted with 0-3 R.sup.9; R.sup.3 is, independently at each
occurrence, H, C.sub.1-C.sub.4 alkyl, aryl substituted with 0-3
R.sup.12, or heteroaryl substituted with 0-3 R.sup.12; R.sup.4 is
H, C.sub.1-C.sub.6 alkyl, arylalkyl substituted with 0-3 R.sup.13
or heteroarylmethyl substituted with 0-3 R.sup.13; R.sup.5 is,
independently at each occurrence, alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido;
R.sup.6a is H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkoxy, halo,
aryl substituted with 0-3 R.sup.1, heteroaryl substituted with 0-3
R.sup.1, --N(R.sup.3).sub.2, --S(R.sup.3), or
--R.sup.8--O--R.sup.3; R.sup.7 is, independently at each
occurrence, H, hydroxy, C.sub.1-C.sub.6 alkoxy, or C.sub.1-C.sub.4
alkyl; R.sup.8 is, independently at each occurrence, straight or
branched C.sub.1-C.sub.6 alkylenyl; or one of said R.sup.3 and one
of said R.sup.4, together with the nitrogen and carbon atoms
through which they are attached, form a monocyclic or bicyclic
heterocyclic ring of 3 to 12 ring atoms, where one carbon may be
optionally replaced with N, O, S, or SO.sub.2, and where any carbon
ring atom may be optionally substituted with one or two
C.sub.1-C.sub.4 alkyl, F, or CF.sub.3; and where any additional N
atom may be optionally substituted with C.sub.1-C.sub.4 alkyl;
R.sup.9 is, independently at each occurrence, alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,
alkynyl, aryl substituted with 0-3 R.sup.11, heteroaryl substituted
with 0-3 R.sup.11, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
arylsulfonamide, alkylamido, or arylamido; R.sup.10 is,
independently at each occurrence, alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl; R.sup.11 is, independently at each occurrence, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl; R.sup.12 and R.sup.13 are each,
independently at each occurrence, alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, hydroxyalkyl, aminoalkyl, a heterocyclic ring,
alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl; and wherein 1-3
carbon atoms in ring A may optionally be replaced with N.
27. The compound of claim 26, wherein Z is O.
28. The compound of claim 26, wherein Z is N(R.sup.3).
29. The compound of claim 26, wherein X is CH.sub.2 and m is 2 to
4.
30. The compound of claim 26, wherein: ring A is composed of all
carbon atoms; R.sup.1 is H; R.sup.2 is phenyl substituted with one
to three fluoro (F) atoms; each R.sup.3 is H; R.sup.4 is H; and
R.sup.6a is H.
31. The compound of claim 26, wherein the compound is: ##STR00246##
##STR00247## ##STR00248##
32. The compound of claim 1, selected from the group consisting of:
1-(morpholin-2-ylmethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide;
1-[(2R)-morpholin-2-ylmethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide;
1-[(2S)-morpholin-2-ylmethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide;
1-[(4-methylmorpholin-2-yl)methyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide;
1-(2-chloro-4-fluorophenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethy-
l}-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide;
1-(2-chloro-4-fluorophenyl)-3-{2-piperazin-1-ylethyl}-1,3-dihydro-2,1,3-b-
enzothiadiazole-2,2-dioxide;
1-(4-fluoro-2-methylphenyl)-3-{2-piperazin-1-ylethyl}-1,3-dihydro-2,1,3-b-
enzothiadiazole-2,2-dioxide;
1-(4-fluoro-2-methylphenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethy-
l}-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide;
1-(4-fluoro-2-methoxyphenyl)-3-{2-piperazin-1-ylethyl}-1,3-dihydro-2,1,3--
benzothiadiazole-2,2-dioxide;
1-[2-(2,5-diazabicyclo[2.2.1]hept-2-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3--
benzothiadiazole 2,2-dioxide;
2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethox-
y}ethanamine;
2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethox-
y}-N-methylethanamine;
2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethox-
y}-N,N-dimethylethanamine;
1-{2-[2-(3,5-dimethylpiperazin-1-yl)ethoxy]ethyl}-3-(2-fluorophenyl)-1,3--
dihydro-2,1,3-benzothiadiazole 2,2-dioxide;
1-[5-(3,5-dimethylpiperazin-1-yl)pentyl]-3-(2-fluorophenyl)-1,3-dihydro-2-
,1,3-benzothiadiazole 2,2-dioxide;
(2R)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2--
methylpropan-1-amine;
(2S)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2--
methylpropan-1-amine;
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2--
amine;
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-
-methylbutan-1-amine;
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbutan-2-amine;
(2R)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,-
2-dimethylpropan-1-amine;
(2S)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,-
2-dimethylpropan-1-amine;
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1--
amine;
1-Phenyl-3-(piperidin-4-ylmethyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide;
1-(2,6-Difluorophenyl)-3-(morpholin-2-ylmethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide;
1-(2,6-Difluorophenyl)-3-[(2R)-morpholin-2-ylmethyl]-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide;
1-(2,6-Difluorophenyl)-3-[(2S)-morpholin-2-ylmethyl]-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide;
1-(2,3-Difluorophenyl)-3-(morpholin-2-ylmethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide;
1-(Morpholin-2-ylmethyl)-3-[2-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-
-benzothiadiazole 2,2-dioxide;
1-Phenyl-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide
1-Phenyl-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-
-dioxide;
4-Fluoro-3-phenyl-1-(piperidin-4-ylmethyl)-1,3-dihydro-2,1,3-ben-
zothiadiazole-2,2-dioxide;
4-Fluoro-3-phenyl-1-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide;
4-Fluoro-3-phenyl-1-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadi-
azole-2,2-dioxide;
4-Fluoro-3-(morpholin-2-ylmethyl)-1-phenyl-1,3-dihydro-2,1,3-benzothiadia-
zole-2,2-dioxide;
1-Phenyl-3-(3-piperidin-4-ylpropyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,-
2-dioxide;
1-Phenyl-3-(2-piperidin-2-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole-2,2-dioxide
1-(2,6-Difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide;
1-(2,6-Difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide;
1-Phenyl-3-(piperidin-3-ylmethyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2--
dioxide;
1-Phenyl-3-[(3R)-piperidin-3-ylmethyl]-1,3-dihydro-2,1,3-benzothi-
adiazole-2,2-dioxide;
1-Phenyl-3-[(3S)-piperidin-3-ylmethyl]-1,3-dihydro-2,1,3-benzothiadiazole-
-2,2-dioxide;
1-Phenyl-3-(2-piperidin-3-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-
-dioxide;
1-Phenyl-3-{2-[(3S)-piperidin-3-yl]ethyl}-1,3-dihydro-2,1,3-benz-
othiadiazole-2,2-dioxide;
1-Phenyl-3-{2-[(3R)-piperidin-3-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiaz-
ole-2,2-dioxide;
1-(2,3-Difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide;
1-(2,5-Difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide;
1-(2,3-Difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide;
1-(2,5-Difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide;
1-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-be-
nzothiadiazole-2,2-dioxide;
1-(2-Fluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole-2,2-dioxide;
1-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-(2-fluorophenyl)-1,3-dihydr-
o-2,1,3-benzothiadiazole-2,2-dioxide;
1-[3-(cis-3,5-Dimethylpiperazin-1-yl)propyl]-3-phenyl-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide;
1-(2,6-Difluorophenyl)-3-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-1,3-di-
hydro-2,1,3-benzothiadiazole-2,2-dioxide;
1-(2-piperazin-1-ylethyl)-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-ben-
zothiadiazole-2,2-dioxide;
1-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-(2,4,6-trifluorophenyl)-1,3-
-dihydro-2,1,3-benzothiadiazole-2,2-dioxide;
1-Phenyl-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,-
2-dioxide;
1-(4-Fluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3--
benzothiadiazole-2,2-dioxide;
1-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-(4-fluorophenyl)-1,3-dihydr-
o-2,1,3-benzothiadiazole-2,2-dioxide;
1-(2,4-difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide;
1-(2,4-difluorophenyl)-3-[2-(3,5-dimethylpiperazin-1-yl)ethyl]-1,3-dihydr-
o-2,1,3-benzothiadiazole-2,2-dioxide;
1-[2-(3,5-dimethylpiperazin-1-yl)ethyl]-4-fluoro-3-(2-fluorophenyl)-1,3-d-
ihydro-2,1,3-benzothiadiazole 2,2-dioxide;
1-(2-{[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
methyl}phenyl)-N-methylmethanamine;
3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethyl-1-phenylpropan-1-amine;
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
l-1-phenylpropan-1-amine;
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbut-2-yn-1-amine;
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dim-
ethylbut-2-yn-1-amine;
(2E)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N--
methylbut-2-en-1-amine;
(2E)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,-
N-dimethylbut-2-en-1-amine;
3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethyl}-4-fluoro-1-(2-fluoropheny-
l)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide;
2,2-difluoro-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]-N-methylpropan-1-amine;
1-(2-Fluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide;
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazol-
e-2,2-dioxide;
1-(2,4-Difluorophenyl)-4-fluoro-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1-
,3-benzothiadiazole-2,2-dioxide;
3-(2,4-Difluorophenyl)-4-fluoro-1-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1-
,3-benzothiadiazole-2,2-dioxide
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,-
3-benzothiadiazole-2,2-dioxide
1-{2-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]ethyl}-3-(2,4,6-trifluorop-
henyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide;
3-[2-(1,4-Diazepan-1-yl)ethyl]-1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydr-
o-2,1,3-benzothiadiazole 2,2-dioxide;
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide;
1-{2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl}-3-(2-fluorophenyl)--
1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide;
1-Phenyl-3-(2-piperidin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-
-dioxide;
1-(2,4-Difluorophenyl)-3-[2-(cis-3,5-dimethylpiperazin-1-yl)ethy-
l]-4-fluoro-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide;
1-[3-(1,4-Diazepan-1-yl)propyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazo-
le-2,2-dioxide;
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-b-
enzothiadiazole-2,2-dioxide;
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-b-
enzothiadiazole-2,2-dioxide;
1-{2-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]ethyl}-3-(2,4-difluorophen-
yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide;
1-(2,4-Difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide;
1-(2,4-Difluorophenyl)-3-[2-(4-methylpiperazin-1-yl)ethyl]-1,3-dihydro-2,-
1,3-benzothiadiazole 2,2-dioxide;
1-(2,4-Difluorophenyl)-4-fluoro-3-[2-(4-methylpiperazin-1-yl)ethyl]-1,3-d-
ihydro-2,1,3-benzothiadiazole 2,2-dioxide;
1-(2,4-Difluorophenyl)-3-[2-(4-methyl-1,4-diazepan-1-yl)ethyl]-1,3-dihydr-
o-2,1,3-benzothiadiazole 2,2-dioxide;
1-[2-(4-Methyl-1,4-diazepan-1-yl)ethyl]-3-(2,4,6-trifluorophenyl)-1,3-dih-
ydro-2,1,3-benzothiadiazole 2,2-dioxide;
N-{2-[3-(2-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}-N,N'-dimethylethane-1,2-diamine;
N-{2-[3-(2,4-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thyl}-N,N'-dimethylethane-1,2-diamine;
N-{2-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-y-
l]ethyl}-N,N'-dimethylethane-1,2-diamine;
1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propy-
l}piperidin-4-amine;
1-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]piperidi-
n-4-amine;
1-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]ethyl}piperidin-4-amine;
1-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}-N-methylpiperidin-4-amine;
1-{2-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperidin-
-4-amine;
1-{2-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}-
-N-methylpiperidin-4-amine;
1-{1-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]pyrrol-
idin-3-yl}methanamine;
1-phenyl-3-[2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethyl]-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide;
2-{2-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]ethoxy}-N-methylethanamine;
2-{2-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]ethoxy}-N,N-dimethylethanamine;
1-(4-chloro-2-fluorophenyl)-3-(2-piperazin-1-yl-ethyl)-1,3-dihydro-2,1,3--
benzothiadiazole 2,2-dioxide;
1-(4-chloro-2-fluorophenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethy-
l}-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide;
1-(4-chloro-2-fluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide;
1-(4-chloro-2-methylphenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethy-
l}-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide;
1-(4-chloro-2-methylphenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide;
1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)butan-2-one;
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino-
)butan-2-one;
1-(cyclopropylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)--
yl)butan-2-one;
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)bu-
tan-2-one;
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]-1-(methylamino)butan-2-one;
(2Z)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylami-
no)butan-2-one oxime;
(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2--
methoxy-N-methylbutan-1-amine;
(2S)-2-methoxy-N-methyl-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothia-
diazol-1(3H)-yl]butan-1-amine;
(2S)-2-methoxy-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1-
(3H)-yl]-N-methylbutan-1-amine;
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-methoxy-N-methy-
lbutan-1-amine;
(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-methoxy-N--
methylbutan-1-amine;
(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-methoxy-N--
methylbutan-1-amine;
N-{(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-2-methoxybutyl}cyclopropanamine;
N-{(2S)-2-methoxy-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
-1(3H)-yl]butyl}cyclopropanamine;
N-{(2S)-2-methoxy-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazo-
l-1(3H)-yl]butyl}cyclopropanamine;
N-{(2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]-2-methoxybutyl}cyclopropanamine;
N-{(2S)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]-2-methoxybutyl}cyclopropanamine;
N-{(2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]-2-methoxybutyl}cyclopropanamine;
2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-2-methoxy-N-methylbutan-1-amine;
(2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-2-methoxy-N-methylbutan-1-amine;
1-(2-morpholin-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide;
1-{2-[(2S)-morpholin-2-yl]ethyl}-3-phenyl-1,3-dihydro-2,1,3-benzothiadiaz-
ole 2,2-dioxide;
1-{2-[(2R)-morpholin-2-yl]ethyl}-3-phenyl-1,3-dihydro-2,1,3-benzothiadiaz-
ole 2,2-dioxide;
1-(4-fluorophenyl)-3-(2-morpholin-2-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide;
1-(4-fluorophenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide;
1-(4-fluorophenyl)-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide;
1-(2,4-difluorophenyl)-3-(2-morpholin-2-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide;
1-(2,4-difluorophenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-
-benzothiadiazole 2,2-dioxide;
1-(2,4-difluorophenyl)-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-
-benzothiadiazole 2,2-dioxide;
1-(2-morpholin-2-ylethyl)-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide;
1-{2-[(2S)-morpholin-2-yl]ethyl}-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,-
1,3-benzothiadiazole 2,2-dioxide;
1-{2-[(2R)-morpholin-2-yl]ethyl}-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,-
1,3-benzothiadiazole 2,2-dioxide;
1-(3-methoxyphenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide;
1-(3-methoxyphenyl)-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide;
1-(2-fluorophenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide;
1-(2-fluorophenyl)-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide;
1-(2,6-difluorophenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-
-benzothiadiazole 2,2-dioxide;
1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3
benzothiadiazol-1(3H)-yl]methyl}phenyl)-N-methylmethanamine;
1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)methanamine;
1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)-N,N-dimethylmethanamine;
1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)-N,N-dimethylmethanamine;
1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)methanamine;
1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)-N-methylmethanamine;
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]-N-methylbut-2-en-1-amine;
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]but-2-en-1-amine;
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]-N,N-dimethylbut-2-en-1-amine;
(2Z)-N-ethyl-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadi-
azol-1(3H)-yl]but-2-en-1-amine;
1-(3,4-difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide;
1-(3,4-difluorophenyl)-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide;
1-(3,4-difluorophenyl)-3-[3-(3,5-dimethylpiperazin-1-yl)propyl]-1,3-dihyd-
ro-2,1,3-benzothiadiazole 2,2-dioxide;
2-{2-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N-methylethanamine;
1-(2-piperazin-1-ylethyl)-3-(2,3,4-trifluorophenyl)-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide;
1-(2-methylphenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide;
1-(2-chlorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide;
2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N-methylethanamine;
2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}ethanamine;
2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N,N-dimethylethanamine;
(2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylbut-2-en-1-amine;
(2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N,N-dimethylbut-2-en-1-amine;
(2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]but-2-en-1-amine;
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]ethoxy}ethyl)cyclopropanamine;
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]ethoxy}ethyl)cyclobutanamine;
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]ethoxy}ethyl)cyclopentanamine;
2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N-methylethanamine;
2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N-ethylethanamine;
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]ethoxy}ethyl)propan-2-amine;
1-(4-chlorophenyl)-3-(4-morpholin-4-ylbutyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide;
1-(2-Fluorophenyl)-4-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide;
1-(2-Fluorophenyl)-4-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide;
1-(2-Fluorophenyl)-5-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide;
1-(2-Fluorophenyl)-5-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide;
1-(2-Fluorophenyl)-6-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide;
1-(2-Fluorophenyl)-6-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide;
1-(2-Fluorophenyl)-7-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide;
1-(2-Fluorophenyl)-7-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide;
1-(2,6-Difluorophenyl)-4-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide;
1-(2,6-Difluorophenyl)-4-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide;
1-(2,6-Difluorophenyl)-5-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide;
1-(2,6-Difluorophenyl)-5-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide;
1-(2,6-Difluorophenyl)-6-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide;
1-(2,6-Difluorophenyl)-6-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide;
1-(2,6-Difluorophenyl)-7-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide;
1-(2,6-Difluorophenyl)-7-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide; and pharmaceutically
acceptable salts thereof.
33. A composition, comprising: a. at least one compound of formula
I: ##STR00249## or a pharmaceutically acceptable salt, stereoisomer
or tautomer thereof; wherein: n is an integer from 0 to 4; m is an
integer from 0 to 6; X is, independently at each occurrence,
C(R.sup.7).sub.2, N(R.sup.3), O, S, S(.dbd.O), or S(.dbd.O).sub.2;
Y is C; or Y and an adjacent X together form
--CR.sup.7.dbd.CR.sup.7--, --C.ident.C--, or arylenyl substituted
with 0-3 R.sup.10; R.sup.1 is, independently at each occurrence, H,
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, aryl substituted with 0-3
R.sup.11, heteroaryl substituted with 0-3 R.sup.11, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, arylsulfonamide substituted with
0-3 R.sup.5, alkylamido, or arylamido substituted with 0-3 R.sup.5;
R.sup.2 is aryl substituted with 0-3 R.sup.9 or heteroaryl
substituted with 0-3 R.sup.9; R.sup.3 is, independently at each
occurrence, H, halo, hydroxy, alkyl substituted with 0-3 R.sup.13,
a heterocyclic ring, aryl substituted with 0-3 R.sup.12, or
heteroaryl substituted with 0-3 R.sup.12; R.sup.4 is, independently
at each occurrence, H, alkyl substituted with 0-3 R.sup.13,
arylalkyl substituted with 0-3 R.sup.13 or heteroarylmethyl
substituted with 0-3 R.sup.13; R.sup.5 is, independently at each
occurrence, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, or alkylamido; R.sup.6 is,
independently at each occurrence, H, hydroxy, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.6 alkoxy, halo, aryl substituted with 0-3
R.sup.1, heteroaryl substituted with 0-3 R.sup.1,
--N(R.sup.3).sub.2, --S(R.sup.3), or --R.sup.8--O--R.sup.3; or both
R.sup.6 groups form a cycloalkyl, a heterocyclic ring, .dbd.O or
.dbd.N--OH; provided that if each R.sup.3 is H, each X is CH.sub.2,
and either each R.sup.6 is H or one R.sup.6 is hydroxy; then, both
of said R.sup.4, together with the nitrogen through which they are
attached, form a monocyclic or bicyclic heterocyclic ring of 3 to
12 ring atoms, where one carbon may be optionally replaced with N,
O, S, or SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, hydroxyalkyl, aminoalkyl, or a
heterocyclic ring, F, or CF.sub.3; and where any additional N atom
may be optionally substituted with C.sub.1-C.sub.4 alkyl; R.sup.7
is, independently at each occurrence, H, hydroxy, alkoxy, or
C.sub.1-C.sub.4 alkyl; R.sup.8 is, independently at each
occurrence, straight or branched alkylenyl; or one of said R.sup.3
and one of said R.sup.4, together with the nitrogen and carbon
atoms through which they are attached, form a monocyclic or
bicyclic heterocyclic ring of 3 to 12 ring atoms, where one carbon
may be optionally replaced with N, O, S, or SO.sub.2, and where any
carbon ring atom may be optionally substituted with one or two
alkyl, F, or CF.sub.3; and where any additional N atom may be
optionally substituted with alkyl; or both of said R.sup.4,
together with the nitrogen through which they are attached, form a
monocyclic or bicyclic heterocyclic ring of 3 to 12 ring atoms,
where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, hydroxyalkyl, aminoalkyl, a
heterocyclic ring, F, or CF.sub.3; and where any additional N atom
may be optionally substituted with alkyl; or one of said R.sup.6 or
one of said R.sup.7 and one of said R.sup.4, together with the
nitrogen and carbon atoms through which they are attached, form a
monocyclic or bicyclic heterocyclic ring of 3 to 12 ring atoms,
where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two C.sub.1-C.sub.4 alkyl, F, or CF.sub.3;
and where any additional N atom may be optionally substituted with
C.sub.1-C.sub.4 alkyl; provided that R.sup.4 and R.sup.7, taken
together, do not form a piperidinyl ring; R.sup.9 is, independently
at each occurrence, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl
substituted with 0-3 R.sup.11, heteroaryl substituted with 0-3
R.sup.11, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
arylsulfonamide, alkylamido, or arylamido; R.sup.10 is,
independently at each occurrence, alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl; R.sup.11 is, independently at each occurrence, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl; R.sup.12 and R.sup.13 are each,
independently at each occurrence, alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, hydroxyalkyl, aminoalkyl, a heterocyclic ring,
alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl; and wherein 1-3
carbon atoms in ring A may optionally be replaced with N; and b. at
least one pharmaceutically acceptable carrier.
34. A method for treating or preventing a condition selected from
the group consisting of a vasomotor symptom, sexual dysfunction,
gastrointestinal disorder, genitourinary disorder, chronic fatigue
syndrome, fibromyalgia syndrome, depression disorder, diabetic
neuropathy, endogenous behavioral disorder, cognitive disorder,
pain, and combinations thereof in a subject in need thereof,
comprising the step of: administering to said subject an effective
amount of a compound of formula I: ##STR00250## or a
pharmaceutically acceptable salt, stereoisomer or tautomer thereof;
wherein: n is an integer from 0 to 4; m is an integer from 0 to 6;
X is, independently at each occurrence, C(R.sup.7).sub.2,
N(R.sup.3), O, S, S(.dbd.O), or S(.dbd.O).sub.2; Y is C; or Y and
an adjacent X together form --CR.sup.7.dbd.CR.sup.7--,
--C.ident.C--, or arylenyl substituted with 0-3 R.sup.10; R.sup.1
is, independently at each occurrence, H, alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,
alkynyl, aryl substituted with 0-3 R.sup.11, heteroaryl substituted
with 0-3 R.sup.11, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
arylsulfonamide substituted with 0-3 R.sup.5, alkylamido, or
arylamido substituted with 0-3 R.sup.5; R.sup.2 is aryl substituted
with 0-3 R.sup.9 or heteroaryl substituted with 0-3 R.sup.9;
R.sup.3 is, independently at each occurrence, H, halo, hydroxy,
alkyl substituted with 0-3 R.sup.13, a heterocyclic ring, aryl
substituted with 0-3 R.sup.12, or heteroaryl substituted with 0-3
R.sup.12; R.sup.4 is, independently at each occurrence, H, alkyl
substituted with 0-3 R.sup.13, arylalkyl substituted with 0-3
R.sup.13 or heteroarylmethyl substituted with 0-3 R.sup.13; R.sup.5
is, independently at each occurrence, alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl,
alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or
alkylamido; R.sup.6 is, independently at each occurrence, H,
hydroxy, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkoxy, halo, aryl
substituted with 0-3 R.sup.1, heteroaryl substituted with 0-3
R.sup.1, --N(R.sup.3).sub.2, --S(R.sup.3), or
--R.sup.3--O--R.sup.3; or both R.sup.6 groups form a cycloalkyl, a
heterocyclic ring, .dbd.O or .dbd.N--OH; provided that if each
R.sup.3 is H, each X is CH.sub.2, and either each R.sup.6 is H or
one R.sup.6 is hydroxy; then, both of said R.sup.4, together with
the nitrogen through which they are attached, form a monocyclic or
bicyclic heterocyclic ring of 3 to 12 ring atoms, where one carbon
may be optionally replaced with N, O, S, or SO.sub.2, and where any
carbon ring atom may be optionally substituted with one or two
alkyl, hydroxyalkyl, aminoalkyl, or a heterocyclic ring, F, or
CF.sub.3; and where any additional N atom may be optionally
substituted with C.sub.1-C.sub.4 alkyl; R.sup.7 is, independently
at each occurrence, H, hydroxy, alkoxy, or C.sub.1-C.sub.4 alkyl;
R.sup.8 is, independently at each occurrence, straight or branched
alkylenyl; or one of said R.sup.3 and one of said R.sup.4, together
with the nitrogen and carbon atoms through which they are attached,
form a monocyclic or bicyclic heterocyclic ring of 3 to 12 ring
atoms, where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, F, or CF.sub.3; and where any
additional N atom may be optionally substituted with alkyl; or both
of said R.sup.4, together with the nitrogen through which they are
attached, form a monocyclic or bicyclic heterocyclic ring of 3 to
12 ring atoms, where one carbon may be optionally replaced with N,
O, S, or SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, hydroxyalkyl, aminoalkyl, a
heterocyclic ring, F, or CF.sub.3; and where any additional N atom
may be optionally substituted with alkyl; or one of said R.sup.6 or
one of said R.sup.7 and one of said R.sup.4, together with the
nitrogen and carbon atoms through which they are attached, form a
monocyclic or bicyclic heterocyclic ring of 3 to 12 ring atoms,
where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two C.sub.1-C.sub.4 alkyl, F, or CF.sub.3;
and where any additional N atom may be optionally substituted with
C.sub.1-C.sub.4 alkyl; provided that R.sup.4 and R.sup.7, taken
together, do not form a piperidinyl ring; R.sup.9 is, independently
at each occurrence, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl
substituted with 0-3 R.sup.11, heteroaryl substituted with 0-3
R.sup.11, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
arylsulfonamide, alkylamido, or arylamido; R.sup.10 is,
independently at each occurrence, alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl; R.sup.11 is, independently at each occurrence, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl; R.sup.12 and R.sup.13 are each,
independently at each occurrence, alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, hydroxyalkyl, aminoalkyl, a heterocyclic ring,
alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl; and wherein 1-3
carbon atoms in ring A may optionally be replaced with N.
35. The method of claim 34, wherein said vasomotor symptom is hot
flush.
36. The method of claim 34, wherein said sexual dysfunction is
desire-related or arousal-related.
37. The method of claim 34, wherein said gastrointestinal disorder
or said genitourinary disorder is stress incontinence or urge
incontinence.
38. The method of claim 34, wherein said condition is chronic
fatigue syndrome or fibromyalgia syndrome.
39. The method of claim 34, wherein said condition is a depression
disorder selected from the group consisting of major depressive
disorder, generalized anxiety disorder, panic disorder, attention
deficit disorder with or without hyperactivity, sleep disturbance,
social phobia, and combinations thereof.
40. The method of claim 34, wherein said condition is diabetic
neuropathy.
41. The method of claim 34, wherein said condition is pain.
42. The method of claim 41, wherein said pain is acute centralized
pain, acute peripheral pain, or a combination thereof.
43. The method of claim 41, wherein said pain is chronic
centralized pain, chronic peripheral pain, or a combination
thereof.
44. The method of claim 41, wherein said pain is neuropathic pain,
visceral pain, musculoskeletal pain, bony pain, cancer pain,
inflammatory pain, or a combination thereof.
45. The method of claim 44, wherein said neuropathic pain is
associated with diabetes, post traumatic pain of amputation, lower
back pain, cancer, chemical injury, toxins, major surgery,
peripheral nerve damage due to traumatic injury compression,
post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical
radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex
sympathetic dystrophy, casualgia, thalamic syndrome, nerve root
avulsion, reflex sympathetic dystrophy or post thoracotomy pain,
nutritional deficiencies, viral infection, bacterial infection,
metastatic infiltration, adiposis dolorosa, burns, central pain
conditions related to thalamic conditions, or a combination
thereof.
46. The method of claim 44, wherein said neuropathic pain is
post-herpetic neuralgia.
47. The method of claim 44, wherein said visceral pain is
associated with ulcerative colitis, irritable bowel syndrome,
irritable bladder, Crohn's disease, rheumatologic (arthralgias),
tumors, gastritis, pancreatitis, infections of the organs, biliary
tract disorders, or a combination thereof.
48. The method of claim 41, wherein said subject is female.
49. The method of claim 48, wherein said pain is female-specific
pain.
50. A process for the preparation of a compound of formula I:
##STR00251## or a pharmaceutically acceptable salt, stereoisomer or
tautomer thereof; wherein: n is an integer from 0 to 4; m is an
integer from 0 to 6; X is, independently at each occurrence,
C(R.sup.7).sub.2, N(R.sup.3), O, S, S(.dbd.O), or S(.dbd.O).sub.2;
Y is C; or Y and an adjacent X together form
--CR.sup.7.dbd.CR.sup.7--, --C.ident.C--, or arylenyl substituted
with 0-3 R.sup.10; R.sup.1 is, independently at each occurrence, H,
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, aryl substituted with 0-3
R.sup.11, heteroaryl substituted with 0-3 R.sup.11, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, arylsulfonamide substituted with
0-3 R.sup.5, alkylamido, or arylamido substituted with 0-3 R.sup.5;
R.sup.2 is aryl substituted with 0-3 R.sup.9 or heteroaryl
substituted with 0-3 R.sup.9; R.sup.3 is, independently at each
occurrence, H, halo, hydroxy, alkyl substituted with 0-3 R.sup.13,
a heterocyclic ring, aryl substituted with 0-3 R.sup.12, or
heteroaryl substituted with 0-3 R.sup.12; R.sup.4 is, independently
at each occurrence, H, alkyl substituted with 0-3 R.sup.13,
arylalkyl substituted with 0-3 R.sup.13 or heteroarylmethyl
substituted with 0-3 R.sup.13; R.sup.5 is, independently at each
occurrence, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, or alkylamido; R.sup.6 is,
independently at each occurrence, H, hydroxy, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.6 alkoxy, halo, aryl substituted with 0-3
R.sup.1, heteroaryl substituted with 0-3 R.sup.1,
--N(R.sup.3).sub.2, --S(R.sup.3), or --R.sup.8--O--R.sup.3; or both
R.sup.6 groups form a cycloalkyl, a heterocyclic ring, .dbd.O or
.dbd.N--OH; provided that if each R.sup.3 is H, each X is CH.sub.2,
and either each R.sup.6 is H or one R.sup.6 is hydroxy; then, both
of said R.sup.4, together with the nitrogen through which they are
attached, form a monocyclic or bicyclic heterocyclic ring of 3 to
12 ring atoms, where one carbon may be optionally replaced with N,
O, S, or SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, hydroxyalkyl, aminoalkyl, or a
heterocyclic ring, F, or CF.sub.3; and where any additional N atom
may be optionally substituted with C.sub.1-C.sub.4 alkyl; R.sup.7
is, independently at each occurrence, H, hydroxy, alkoxy, or
C.sub.1-C.sub.4 alkyl; R.sup.8 is, independently at each
occurrence, straight or branched alkylenyl; or one of said R.sup.3
and one of said R.sup.4, together with the nitrogen and carbon
atoms through which they are attached, form a monocyclic or
bicyclic heterocyclic ring of 3 to 12 ring atoms, where one carbon
may be optionally replaced with N, O, S, or SO.sub.2, and where any
carbon ring atom may be optionally substituted with one or two
alkyl, F, or CF.sub.3; and where any additional N atom may be
optionally substituted with alkyl; or both of said R.sup.4,
together with the nitrogen through which they are attached, form a
monocyclic or bicyclic heterocyclic ring of 3 to 12 ring atoms,
where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, hydroxyalkyl, aminoalkyl, a
heterocyclic ring, F, or CF.sub.3; and where any additional N atom
may be optionally substituted with alkyl; or one of said R.sup.6 or
one of said R.sup.7 and one of said R.sup.4, together with the
nitrogen and carbon atoms through which they are attached, form a
monocyclic or bicyclic heterocyclic ring of 3 to 12 ring atoms,
where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two C.sub.1-C.sub.4 alkyl, F, or CF.sub.3;
and where any additional N atom may be optionally substituted with
C.sub.1-C.sub.4 alkyl; provided that R.sup.4 and R.sup.7, taken
together, do not form a piperidinyl ring; R.sup.9 is, independently
at each occurrence, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl
substituted with 0-3 R.sup.11, heteroaryl substituted with 0-3
R.sup.11, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
arylsulfonamide, alkylamido, or arylamido; R.sup.10 is,
independently at each occurrence, alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl; R.sup.11 is, independently at each occurrence, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl; R.sup.12 and R.sup.13 are each,
independently at each occurrence, alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, hydroxyalkyl, aminoalkyl, a heterocyclic ring,
alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl; and wherein 1-3
carbon atoms in ring A may optionally be replaced with N; the
process comprising: (d) reacting a compound of formula IA:
##STR00252## with a compound of formula IB: ##STR00253## wherein, T
is an --N(R.sup.4).sub.2 or an activating group; wherein, if T is
--N(R.sup.4).sub.2, then the compound of formula I is formed; or if
T is an activating group, then a compound of formula IC is formed:
##STR00254## and the process further comprises: (e) reacting the
compound formula IC with --N(R.sup.4)R.sup.P to form a compound of
formula ID: ##STR00255## wherein, R.sup.P is R.sup.4 or a
protecting group; wherein, if R.sup.P is R.sup.4, the compound of
formula I is formed; or if R.sup.P is a protecting group, the
process further comprises: (f) deprotecting the compound of formula
ID to form a deprotected compound; and (g) reacting the deprotected
compound with an activated-R.sup.4 group, provided that R.sup.4 in
the activated-R.sup.4 group is not H; wherein the compound of
formula I is formed.
51. The process of claim 50, wherein step (d) further comprises
contacting the compound of formula IA and IB with dialkyl
azodicarboxylate and triphenylphosphine.
52. The process of claim 51, wherein the dialkyl azodicarboxylate
is diisopropyl azodicarboxylate.
53. The process of claim 50, wherein the activating group is
selected from the group consisting of halo, tosylate, mesylate,
triflate, and oxo.
54. The process of claim 53, wherein the activating group is
Br.
55. The process of claim 50, wherein the protecting group is
selected from the group consisting of BOC, benzyl, acetyl, PMB,
alkyl, Fmoc, Cbz, trifluoroacetyl, tosyl and triphenylmethyl.
56. The process of claim 55, wherein the protecting group is
BOC.
57. The process of claim 50, wherein the deprotecting step is
performed in the presence of at least one agent selected from
hydrochloric acid (HCl), tin(II)chloride, ammonium chloride, zinc,
trifluoroacetic acid (TFA), tosic acid, a halotrimethylsilane, or
aluminum chloride.
58. The process of claim 50, wherein any one of steps (d)-(g) is
performed at or above 30.degree. C. or any one of steps (d)-(g)
includes a purification step comprising at least one of:
filtration, extraction, chromatography, trituration, or
recrystallization.
59. The process of claim 50, wherein the activated-R.sup.4 group is
halo-R.sup.4 or O.dbd.R.sup.4.
60. The process of claim 50, wherein the compound of formula IA is
prepared by: (a) reacting a compound of formula IE: ##STR00256##
wherein R.sup.B is F or Cl; with R.sup.2--NH.sub.2 to form a
compound of formula IF: ##STR00257## (b) hydrogenating the compound
of formula IF to form a compound of formula IG: ##STR00258## and
(c) reacting the compound of formula IG with sulfamide in diglyme
to form the compound of formula IA.
61. The process of claim 60, wherein the hydrogenating step is
performed in the presence of hydrogen (H.sub.2) and Pd/C.
62. The process of claim 60, wherein any one of steps (a)-(c) is
performed at or above 30.degree. C.
63. The process of claim 60, wherein any one of steps (a)-(c)
includes a purification step comprising at least one of:
filtration, extraction, chromatography, trituration, or
recrystallization.
64. A process for the preparation of a compound of formula I:
##STR00259## or a pharmaceutically acceptable salt, stereoisomer or
tautomer thereof; wherein: n is an integer from 0 to 4; m is an
integer from 0 to 6; X is, independently at each occurrence,
C(R.sup.7).sub.2, N(R.sup.3), O, S, S(.dbd.O), or S(.dbd.O).sub.2;
Y is C; or Y and an adjacent X together form
--CR.sup.7.dbd.CR.sup.7--, --C.ident.C--, or arylenyl substituted
with 0-3 R.sup.10; R.sup.1 is, independently at each occurrence, H,
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, alkynyl, aryl substituted with 0-3
R.sup.11, heteroaryl substituted with 0-3 R.sup.11, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, arylsulfonamide substituted with
0-3 R.sup.5, alkylamido, or arylamido substituted with 0-3 R.sup.5;
R.sup.2 is aryl substituted with 0-3 R.sup.9 or heteroaryl
substituted with 0-3 R.sup.9; R.sup.3 is, independently at each
occurrence, H, halo, hydroxy, alkyl substituted with 0-3 R.sup.13,
a heterocyclic ring, aryl substituted with 0-3 R.sup.12, or
heteroaryl substituted with 0-3 R.sup.12; R.sup.4 is, independently
at each occurrence, H, alkyl substituted with 0-3 R.sup.13,
arylalkyl substituted with 0-3 R.sup.13 or heteroarylmethyl
substituted with 0-3 R.sup.13; R.sup.5 is, independently at each
occurrence, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, or alkylamido; R.sup.6 is,
independently at each occurrence, H, hydroxy, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.6 alkoxy, halo, aryl substituted with 0-3
R.sup.1, heteroaryl substituted with 0-3 R.sup.1,
--N(R.sup.3).sub.2, --S(R.sup.3), or --R.sup.8--O--R.sup.3; or both
R.sup.6 groups form a cycloalkyl, a heterocyclic ring, .dbd.O or
.dbd.N--OH; provided that if each R.sup.3 is H, each X is CH.sub.2,
and either each R.sup.6 is H or one R.sup.6 is hydroxy; then, both
of said R.sup.4, together with the nitrogen through which they are
attached, form a monocyclic or bicyclic heterocyclic ring of 3 to
12 ring atoms, where one carbon may be optionally replaced with N,
O, S, or SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, hydroxyalkyl, aminoalkyl, or a
heterocyclic ring, F, or CF.sub.3; and where any additional N atom
may be optionally substituted with C.sub.1-C.sub.4 alkyl; R.sup.7
is, independently at each occurrence, H, hydroxy, alkoxy, or
C.sub.1-C.sub.4 alkyl; R.sup.8 is, independently at each
occurrence, straight or branched alkylenyl; or one of said R.sup.3
and one of said R.sup.4, together with the nitrogen and carbon
atoms through which they are attached, form a monocyclic or
bicyclic heterocyclic ring of 3 to 12 ring atoms, where one carbon
may be optionally replaced with N, O, S, or SO.sub.2, and where any
carbon ring atom may be optionally substituted with one or two
alkyl, F, or CF.sub.3; and where any additional N atom may be
optionally substituted with alkyl; or both of said R.sup.4,
together with the nitrogen through which they are attached, form a
monocyclic or bicyclic heterocyclic ring of 3 to 12 ring atoms,
where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, hydroxyalkyl, aminoalkyl, a
heterocyclic ring, F, or CF.sub.3; and where any additional N atom
may be optionally substituted with alkyl; or one of said R.sup.6 or
one of said R.sup.7 and one of said R.sup.4, together with the
nitrogen and carbon atoms through which they are attached, form a
monocyclic or bicyclic heterocyclic ring of 3 to 12 ring atoms,
where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two C.sub.1-C.sub.4 alkyl, F, or CF.sub.3;
and where any additional N atom may be optionally substituted with
C.sub.1-C.sub.4 alkyl; provided that R.sup.4 and R.sup.7, taken
together, do not form a piperidinyl ring; R.sup.9 is, independently
at each occurrence, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3,
hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl
substituted with 0-3 R.sup.11, heteroaryl substituted with 0-3
R.sup.11, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
arylsulfonamide, alkylamido, or arylamido; R.sup.10 is,
independently at each occurrence, alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl; R.sup.11 is, independently at each occurrence, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl; R.sup.12 and R.sup.13 are each,
independently at each occurrence, alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, hydroxyalkyl, aminoalkyl, a heterocyclic ring,
alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl; and wherein 1-3
carbon atoms in ring A may optionally be replaced with N; the
process comprising: (d) reacting R.sup.2(BOH).sub.2 and a
transitional metal salt with a compound of formula IH: ##STR00260##
wherein, R.sup.P is R.sup.4 or a protecting group; and if R.sup.P
is R.sup.4, the compound of formula I is formed; or if R.sup.P is a
protecting group, the process further comprises: (e) deprotecting
the compound of formula IH to form a deprotected compound; and (g)
reacting the deprotected compound with an activated-R.sup.4 group,
provided that R.sup.4 group in the activated-R.sup.4 group is not
H; wherein the compound of formula I is formed.
65. The process of claim 64, wherein the transitional metal salt is
copper(II)acetate.
66. The process of claim 64, wherein the activated-R.sup.4 group is
halo-R.sup.4 or O.dbd.R.sup.4.
67. The process of claim 64, wherein the protecting group is
selected from the group consisting of BOC, benzyl, acetyl, PMB,
alkyl, Fmoc, Cbz, trifluoroacetyl, tosyl and triphenylmethyl.
68. The process of claim 67, wherein the protecting group is
BOC.
69. The process of claim 64, wherein the deprotecting step is
performed in the presence of at least one agent selected from
hydrochloric acid (HCl), tin(II)chloride, ammonium chloride, zinc,
trifluoroacetic acid (TFA), tosic acid, a halotrimethylsilane, or
aluminum chloride.
70. The process of claim 64, wherein any one of steps (d)-(g) is
performed at or above 30.degree. C. or any one of steps (d)-(g)
includes a purification step comprising at least one of:
filtration, extraction, chromatography, trituration, or
recrystallization.
71. The process of claim 64, wherein the compound of formula IH is
prepared by: (a) reacting a compound of formula IJ: ##STR00261##
wherein R.sup.B is F or Cl; with a compound of formula IK:
##STR00262## to form a compound of formula IL: ##STR00263## (b)
hydrogenating the compound of formula IL to form a compound of
formula IM: ##STR00264## and (c) reacting the compound of formula
IM with sulfamide and diglyme to form the compound of formula
IH.
72. The process of claim 71, wherein the hydrogenating step is
performed in the presence of hydrogen (H.sub.2) and Pd/C.
73. The process of claim 71, wherein any one of steps (a)-(c) is
performed at or above 30.degree. C.
74. The process of claim 71, wherein any one of steps (a)-(c)
includes a purification step comprising at least one of:
filtration, extraction, chromatography, trituration, or
recrystallization.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e) to co-pending U.S. Provisional Application Ser. No.
60/869,644, filed Dec. 12, 2006, which is hereby incorporated by
reference in its entirety.
FIELD
[0002] The present invention relates to aryl sulfamide derivatives,
which are monoamine reuptake inhibitors, compositions containing
these derivatives, and methods of their use for the prevention and
treatment of diseases or disorders including vasomotor symptoms,
depression disorders, endogenous behavioral disorders, cognitive
disorders, sexual dysfunction, or pain conditions, in particular
vasomotor symptoms.
BACKGROUND
[0003] Vasomotor symptoms (VMS), referred to as hot flushes and
night sweats, are the most common symptoms associated with
menopause, occurring in 60% to 80% of all women following natural
or surgically-induced menopause. VMS are likely an adaptive
response of the central nervous system (CNS) to declining sex
steroids. To date, the most effective therapies for VMS are
hormone-based treatments, including estrogens and/or some
progestins. Hormonal treatments are very effective at alleviating
VMS, but they are not appropriate for all women.
[0004] VMS are caused by fluctuations of sex steroid levels and can
be disruptive and disabling in both males and females. A hot flush
can last up to thirty minutes and vary in their frequency from
several times a week to multiple occurrences per day. The patient
experiences a hot flush as a sudden feeling of heat that spreads
quickly from the face to the chest and back and then over the rest
of the body. It is usually accompanied by outbreaks of profuse
sweating, and may sometimes occur several times an hour, and it
often occurs at night. Hot flushes and outbreaks of sweats
occurring during the night can cause sleep deprivation.
Psychological and emotional symptoms are also observed, such as
nervousness, fatigue, irritability, insomnia, depression, memory
loss, headache, anxiety, nervousness or inability to concentrate,
and are caused by the sleep deprivation following hot flush and
night sweats (Kramer et al., In: Murphy et al., 3.sup.rd Int'l
Symposium on Recent Advances in Urological Cancer Diagnosis and
Treatment-Proceedings, Paris, France: SCI: 3-7 (1992)).
[0005] Hot flushes may be even more severe in women treated for
breast cancer for several reasons. Many survivors of breast cancer
are given tamoxifen, the most prevalent side effect of which is hot
flush, and many women treated for breast cancer undergo premature
menopause from chemotherapy Women with a history of breast cancer
are also generally been denied estrogen therapy because of concerns
about potential recurrence of breast cancer (Loprinzi, et al.,
Lancet, 2000, 356 (9247): 2059-2063).
[0006] Men also experience hot flushes following steroid hormone
(androgen) withdrawal. This is true in cases of age-associated
androgen decline (Katovich, et al., Proceedings of the Society for
Experimental Biology & Medicine, 1990, 193 (2): 129-35) as well
as in extreme cases of hormone deprivation associated with
treatments for prostate cancer (Berendsen, et al., European Journal
of Pharmacology, 2001, 419 (1): 47-54. As many as one-third of
these patients will experience persistent and frequent symptoms
severe enough to cause significant discomfort and
inconvenience.
[0007] The precise mechanism of these vasomotor symptoms is unknown
but generally is thought to represent disturbances to normal
homeostatic mechanisms controlling thermoregulation and vasomotor
activity (Kronenberg et al., "Thermoregulatory Physiology of
Menopausal Hot Flashes: A Review," Can. J. Physiol. Pharmacol.,
1987, 65:1312-1324).
[0008] The fact that estrogen treatment (e.g. estrogen replacement
therapy) relieves the symptoms establishes the link between these
symptoms and an estrogen deficiency. For example, the menopausal
stage of life is associated with a wide range of other acute
symptoms as described above and these symptoms are generally
estrogen responsive.
[0009] It has been suggested that estrogens may stimulate the
activity of both the norepinephrine (NE) and/or serotonin (5-HT)
systems (J. Pharmacology & Experimental Therapeutics, 1986, 236
(3) 646-652). It is hypothesized that estrogens modulate NE and
5-HT levels providing homeostasis in the thermoregulatory center of
the hypothalamus. The descending pathways from the hypothalamus via
brainstem/spinal cord and the adrenals to the skin are involved in
maintaining normal skin temperature. The action of NE and 5-HT
reuptake inhibitors is known to impinge on both the CNS and
peripheral nervous system (PNS). The pathophysiology of VMS is
mediated by both central and peripheral mechanisms and, therefore,
the interplay between the CNS and PNS may account for the efficacy
of dual acting SRI/NRIs in the treatment of thermoregulatory
dysfunction. In fact, the physiological aspects and the CNS/PNS
involvement in VMS may account for the lower doses proposed to
treat VMS (Loprinzi, et al., Lancet, 2000, 356:2059-2063; Stearns
et al., JAMA, 2003, 289:2827-2834) compared to doses used to treat
the behavioral aspects of depression. The interplay of the CNS/PNS
in the pathophysiology of VMS supports the claims that the
norepinephrine system could be targeted to treat VMS.
[0010] Although VMS are most commonly treated by hormone therapy,
some patients cannot tolerate estrogen treatment (Berendsen,
Maturitas, 2000, 36 (3): 164, Fink et al., Nature, 1996, 383
(6598): 306). In addition, hormone replacement therapy is usually
not recommended for women or men with or at risk for hormonally
sensitive cancers (e.g. breast or prostate cancer). Thus,
non-hormonal therapies (e.g. fluoxetine, paroxetine [SRIs] and
clonidine) are being evaluated clinically. WO9944601 discloses a
method for decreasing hot flushes in a human female by
administering fluoxetine. Other options have been studied for the
treatment of hot flushes, including steroids, alpha-adrenergic
agonists, and beta-blockers, with varying degree of success
(Waldinger et al., Maturitas, 2000, 36 (3): 165-168).
[0011] .alpha..sub.2-Adrenergic receptors play a role in
thermoregulatory dysfunctions (Freedman et al., Fertility &
Sterility, 2000, 74 (1): 20-3). These receptors are located both
pre- and post-synaptically and mediate an inhibitory role in the
central and peripheral nervous system. There are four distinct
subtypes of the adrenergic.sub..alpha.2 receptors, i.e., are
.alpha..sub.2A, .alpha..sub.2B, .alpha..sub.2C and .alpha..sub.2D
(Mackinnon et al., TIPS, 1994, 15: 119; French, Pharmacol. Ther.,
1995, 68: 175). A non-select .alpha..sub.2-adrenoceptor antagonist,
yohimbine, induces a flush and an .alpha..sub.2-adrenergic receptor
agonist, clonidine, alleviates the yohimbine effect (Katovich, et
al., Proceedings of the Society for Experimental Biology &
Medicine, 1990, 193 (2): 129-35, Freedman et al., Fertility &
Sterility, 2000, 74 (1): 20-3). Clonidine has been used to treat
hot flush. However, using such treatment is associated with a
number of undesired side effects caused by high doses necessary to
abate hot flush described herein and known in the related arts.
[0012] Chronic pain comes in many forms, including visceral,
inflammatory or neuropathic and crosses all therapeutic areas. It
is a debilitating condition that exerts a high social cost in terms
of productivity, economic impact and quality of life and current
therapies have limited efficacy. Currently, first-line
pharmacological treatments for neuropathic pain (i.e., diabetic
neuropathy and post-herpetic neuralgia) and fibromyalgia include
off-label use of the tricyclic (TCA) antidepressants (e.g.,
amytriptyline) and anticonvulsants (e.g., gabapentin) (Collins et
al., J. Pain Symptom Manage. 2000, 20 (6):449-58; and Marcus Expert
Opin Pharmacother. 2003, 4 (10): 1687-95). However, these therapies
are only effective in 30-50% of patients and produce only a partial
reduction in pain (.about.50%). In addition, the clinical benefits
of these therapies are often outweighed by the side effects,
including dry mouth and sedation. Therefore, newer classes of
compounds including non-TCA antidepressants are being evaluated
preclinically and clinically for chronic pain indications, and
recently duloxetine was approved for the treatment of diabetic
neuropathy. Although more tolerable than the older tricyclic
antidepressants, these newer compounds are not devoid of side
effects that include sexual dysfunction, weight gain and
nausea.
[0013] While the precise pathophysiological mechanisms involved in
the development and maintenance of chronic pain states are not
fully understood, the pathways involved in pain perception and
modulation have been well described and characterized (Gebhart, In:
Yaksh T L, editor. Spinal afferent processing, New York: Plenum,
1986. pp 391-416; Fields, et al., Annual Review of Neuroscience
1991, 14: 219-245; Fields, et al. In: Wall P D, Melzack R, editors.
Textbook of pain, London: Churchill Livingstone, 1999, pp 309-329;
Millan, et al. Progress in Neurobiology; 2002, 66:355-474). A major
component of this descending pain inhibitory system involves the
noradrenergic pathway (Zhuo, et al., Brain Research 1991;
550:35-48; Holden, et al. Neuroscience 1999; 91: 979-990). It is
assumed that norepinephrine (NE), and to a lesser extent serotonin
(5-HT) reuptake inhibitor NRIs and SRIs, attenuate pain by
preventing presynaptic reuptake of NE/5-HT leading to increased
postsynaptic NE/5-HT levels and sustained activation of this
descending pain inhibitory pathway. A meta-analysis of
antidepressants and neuropathic pain comparing the efficacy of
known NRIs, mixed NRI/SRIs and SRIs determined that compounds with
NRI activity were more effective in reducing pain, and that select
SRIs did not significantly differ from placebo (Collins et al., J.
Pain Symptom Manage. 2000, 20 (6): 449-58). This analysis suggests
that compounds with greater NRI versus SRI activity will be more
effective for the treatment of pain.
[0014] Given the complex multifaceted nature of pain and of
thermoregulation and the interplay between the CNS and PNS in
maintaining thermoregulatory the homeostasis, multiple therapies
and approaches can be developed to target the treatment of pain and
vasomotor symptoms. The present invention provides novel compounds
and compositions containing these compounds directed to these and
other important uses.
SUMMARY
[0015] The present invention is directed to aryl sulfamide
derivatives, which are monoamine reuptake inhibitors, compositions
containing these derivatives, and methods of their use for the
prevention and treatment of conditions, including, inter alia,
vasomotor symptoms (such as hot flush), sexual dysfunction (such as
desire-related or arousal-related dysfunction), gastrointestinal
disorders and genitourinary disorder (such as stress incontinence
or urge incontinence), chronic fatigue syndrome, fibromyalgia
syndrome, depression disorders (such as major depressive disorder,
generalized anxiety disorder, panic disorder, attention deficit
disorder with or without hyperactivity, sleep disturbance, and
social phobia), diabetic neuropathy, pain, and combinations
thereof.
[0016] One aspect of the invention provides a compound of formula
I:
##STR00002##
[0017] or a pharmaceutically acceptable salt, stereoisomer or
tautomer thereof;
[0018] wherein:
[0019] n is an integer from 0 to 4;
[0020] m is an integer from 0 to 6;
[0021] X is, independently at each occurrence, C(R.sup.7).sub.2,
N(R.sup.3), O, S, S(.dbd.O), or S(.dbd.O).sub.2;
[0022] Y is C; or
[0023] Y and an adjacent X together form --CR.sup.7.dbd.CR.sup.7--,
--C.ident.C--, or arylenyl substituted with 0-3 R.sup.10;
[0024] R.sup.1 is, independently at each occurrence, H, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, alkynyl, aryl substituted with 0-3 R.sup.11,
heteroaryl substituted with 0-3 R.sup.11, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, arylsulfonamide substituted with
0-3 R.sup.5, alkylamido, or arylamido substituted with 0-3
R.sup.5;
[0025] R.sup.2 is aryl substituted with 0-3 R.sup.9 or heteroaryl
substituted with 0-3 R.sup.9;
[0026] R.sup.3 is, independently at each occurrence, H, halo,
hydroxy, alkyl substituted with 0-3 R.sup.13, a heterocyclic ring,
aryl substituted with 0-3 R.sup.12, or heteroaryl substituted with
0-3 R.sup.12;
[0027] R.sup.4 is, independently at each occurrence, H, alkyl
substituted with 0-3 R.sup.13, arylalkyl substituted with 0-3
R.sup.13 or heteroarylmethyl substituted with 0-3 R.sup.13;
[0028] R.sup.5 is, independently at each occurrence, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
or alkylamido;
[0029] R.sup.6 is, independently at each occurrence, H, hydroxy,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkoxy, halo, aryl
substituted with 0-3 R.sup.1, heteroaryl substituted with 0-3
R.sup.1, --N(R.sup.3).sub.2, --S(R.sup.3), or
--R.sup.8--O--R.sup.3; or both R.sup.6 groups form a cycloalkyl, a
heterocyclic ring, .dbd.O or .dbd.N--OH;
[0030] provided that if each R.sup.3 is H, each X is CH.sub.2, and
either each R.sup.6 is H or one R.sup.6 is hydroxy; then, both of
said R.sup.4, together with the nitrogen through which they are
attached, form a monocyclic or bicyclic heterocyclic ring of 3 to
12 ring atoms, where one carbon may be optionally replaced with N,
O, S, or SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, hydroxyalkyl, aminoalkyl, or a
heterocyclic ring, F, or CF.sub.3; and where any additional N atom
may be optionally substituted with C.sub.1-C.sub.4 alkyl;
[0031] R.sup.7 is, independently at each occurrence, H, hydroxy,
alkoxy, or C.sub.1-C.sub.4 alkyl;
[0032] R.sup.8 is, independently at each occurrence, straight or
branched alkylenyl;
[0033] or
[0034] one of said R.sup.3 and one of said R.sup.4, together with
the nitrogen and carbon atoms through which they are attached, form
a monocyclic or bicyclic heterocyclic ring of 3 to 12 ring atoms,
where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, F, or CF.sub.3; and where any
additional N atom may be optionally substituted with alkyl;
[0035] or
[0036] both of said R.sup.4, together with the nitrogen through
which they are attached, form a monocyclic or bicyclic heterocyclic
ring of 3 to 12 ring atoms, where one carbon may be optionally
replaced with N, O, S, or SO.sub.2, and where any carbon ring atom
may be optionally substituted with one or two alkyl, hydroxyalkyl,
aminoalkyl, a heterocyclic ring, F, or CF.sub.3; and where any
additional N atom may be optionally substituted with alkyl;
[0037] or
[0038] one of said R.sup.6 or one of said R.sup.7 and one of said
R.sup.4, together with the nitrogen and carbon atoms through which
they are attached, form a monocyclic or bicyclic heterocyclic ring
of 3 to 12 ring atoms, where one carbon may be optionally replaced
with N, O, S, or SO.sub.2, and where any carbon ring atom may be
optionally substituted with one or two C.sub.1-C.sub.4 alkyl, F, or
CF.sub.3; and where any additional N atom may be optionally
substituted with C.sub.1-C.sub.4 alkyl;
[0039] R.sup.9 is, independently at each occurrence, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, alkynyl, aryl substituted with 0-3 R.sup.11, heteroaryl
substituted with 0-3 R.sup.11, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, arylsulfonamide, alkylamido, or arylamido;
[0040] R.sup.10 is, independently at each occurrence, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl;
[0041] R.sup.11 is, independently at each occurrence, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl;
[0042] R.sup.12 and R.sup.13 are each, independently at each
occurrence, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
hydroxyalkyl, aminoalkyl, a heterocyclic ring, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl; and
[0043] wherein 1-3 carbon atoms in ring A may optionally be
replaced with N.
[0044] In a more particular embodiment, R.sup.4 and R.sup.7, taken
together, do not form a piperidinyl ring.
[0045] Another aspect of the invention provides a compound of
formula II:
##STR00003##
[0046] or a pharmaceutically acceptable salt, stereoisomer or
tautomer thereof;
[0047] wherein:
[0048] n is an integer from 0 to 4;
[0049] m is an integer from 1 to 6;
[0050] X is, independently at each occurrence, C(R.sup.7).sub.2,
N(R.sup.3), O, S, S(.dbd.O), or S(.dbd.O).sub.2;
[0051] Z is O, N(R.sup.3), S, or C(R.sup.7).sub.2;
[0052] R.sup.1 is, independently at each occurrence, H, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, alkynyl, aryl substituted with 0-3 R.sup.11,
heteroaryl substituted with 0-3 R.sup.11, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, arylsulfonamide substituted with
0-3 R.sup.5, alkylamido, or arylamido substituted with 0-3
R.sup.5;
[0053] R.sup.2 is aryl substituted with 0-3 R.sup.9 or heteroaryl
substituted with 0-3 R.sup.9;
[0054] R.sup.3 is, independently at each occurrence, H,
C.sub.1-C.sub.4 alkyl, aryl substituted with 0-3 R.sup.12, or
heteroaryl substituted with 0-3 R.sup.12;
[0055] R.sup.4 is H, C.sub.1-C.sub.6 alkyl, arylalkyl substituted
with 0-3 R.sup.13 or heteroarylmethyl substituted with 0-3
R.sup.13;
[0056] R.sup.5 is, independently at each occurrence, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
or alkylamido;
[0057] R.sup.6a is H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6
alkoxy, halo, aryl substituted with 0-3 R.sup.1, heteroaryl
substituted with 0-3 R.sup.1, --N(R.sup.3).sub.2, --S(R.sup.3), or
--R.sup.8--O--R.sup.3;
[0058] R.sup.7 is, independently at each occurrence, H, hydroxy,
C.sub.1-C.sub.6 alkoxy, or C.sub.1-C.sub.4 alkyl;
[0059] R.sup.8 is, independently at each occurrence, straight or
branched C.sub.1-C.sub.6 alkylenyl;
[0060] or
[0061] one of said R.sup.3 and one of said R.sup.4, together with
the nitrogen and carbon atoms through which they are attached, form
a monocyclic or bicyclic heterocyclic ring of 3 to 12 ring atoms,
where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two C.sub.1-C.sub.4 alkyl, F, or CF.sub.3;
and where any additional N atom may be optionally substituted with
C.sub.1-C.sub.4 alkyl;
[0062] R.sup.9 is, independently at each occurrence, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, alkynyl, aryl substituted with 0-3 R.sup.11, heteroaryl
substituted with 0-3 R.sup.11, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, arylsulfonamide, alkylamido, or arylamido;
[0063] R.sup.10 is, independently at each occurrence, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl;
[0064] R.sup.11 is, independently at each occurrence, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl;
[0065] R.sup.12 and R.sup.13 are each, independently at each
occurrence, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
hydroxyalkyl, aminoalkyl, a heterocyclic ring, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl; and
[0066] wherein 1-3 carbon atoms in ring A may optionally be
replaced with N.
[0067] Another aspect of the invention provides a composition,
comprising:
[0068] a. at least one compound of formula I or formula II; and
[0069] b. at least one pharmaceutically acceptable carrier.
[0070] Another aspect of the invention provides a method for
treating or preventing a condition selected from the group
consisting of a vasomotor symptom, sexual dysfunction,
gastrointestinal disorder, genitourinary disorder, chronic fatigue
syndrome, fibromyalgia syndrome, depression disorder, diabetic
neuropathy, endogenous behavioral disorder, cognitive disorder,
pain, and combinations thereof in a subject in need thereof,
comprising the step of: [0071] administering to said subject an
effective amount of a compound of formula I or formula II.
[0072] Another aspect of the invention provides a process for the
preparation of a compound of formula I:
[0073] the process comprising:
[0074] (d) reacting a compound of formula IA:
##STR00004##
[0075] with a compound of formula IB:
##STR00005##
[0076] wherein,
[0077] T is an --N(R.sup.4).sub.2 or an activating group;
[0078] wherein,
[0079] if T is --N(R.sup.4).sub.2, then the compound of formula I
is formed; or
[0080] if T is an activating group, then a compound of formula IC
is formed:
##STR00006##
[0081] and the process further comprises:
[0082] (e) reacting the compound formula IC with
--N(R.sup.4)R.sup.P to form a compound of formula ID:
##STR00007##
[0083] wherein,
[0084] R.sup.P is R.sup.4 or a protecting group;
[0085] wherein,
[0086] if R.sup.P is R.sup.4, the compound of formula I is formed;
or
[0087] if R.sup.P is a protecting group, the process further
comprises:
[0088] (f) deprotecting the compound of formula ID to form a
deprotected compound; and
[0089] (g) reacting the deprotected compound with an
activated-R.sup.4 group, provided that R.sup.4 in the
activated-R.sup.4 group is not H;
[0090] wherein the compound of formula I is formed.
[0091] In another aspect of the invention, the compound of formula
IA is prepared by: [0092] (a) reacting a compound of formula
IE:
##STR00008##
[0093] wherein R.sup.B is F or Cl;
[0094] with R.sup.2--NH.sub.2 to form a compound of formula IF:
##STR00009## [0095] (b) hydrogenating the compound of formula IF to
form a compound of formula IG:
[0095] ##STR00010## [0096] and (c) reacting the compound of formula
IG with sulfamide in diglyme to form the compound of formula
IA.
[0097] Another aspect of the invention provides a process for the
preparation of a compound of formula I:
##STR00011##
[0098] or a pharmaceutically acceptable salt, stereoisomer or
tautomer thereof;
[0099] wherein:
[0100] n is an integer from 0 to 4;
[0101] m is an integer from 0 to 6;
[0102] X is, independently at each occurrence, C(R.sup.7).sub.2,
N(R.sup.3), O, S, S(.dbd.O), or S(.dbd.O).sub.2;
[0103] Y is C; or
[0104] Y and an adjacent X together form --CR.sup.7.dbd.CR.sup.7--,
--C.ident.C--, or arylenyl substituted with 0-3 R.sup.10;
[0105] R.sup.1 is, independently at each occurrence, H, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, alkynyl, aryl substituted with 0-3 R.sup.11,
heteroaryl substituted with 0-3 R.sup.11, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, arylsulfonamide substituted with
0-3 R.sup.5, alkylamido, or arylamido substituted with 0-3
R.sup.5;
[0106] R.sup.2 is aryl substituted with 0-3 R.sup.9 or heteroaryl
substituted with 0-3 R.sup.9;
[0107] R.sup.3 is, independently at each occurrence, H, halo,
hydroxy, alkyl substituted with 0-3 R.sup.13, a heterocyclic ring,
aryl substituted with 0-3 R.sup.12, or heteroaryl substituted with
0-3 R.sup.12;
[0108] R.sup.4 is, independently at each occurrence, H, alkyl
substituted with 0-3 R.sup.13, arylalkyl substituted with 0-3
R.sup.13 or heteroarylmethyl substituted with 0-3 R.sup.13;
[0109] R.sup.5 is, independently at each occurrence, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
or alkylamido;
[0110] R.sup.6 is, independently at each occurrence, H, hydroxy,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkoxy, halo, aryl
substituted with 0-3 R.sup.1, heteroaryl substituted with 0-3
R.sup.1, --N(R.sup.3).sub.2, --S(R.sup.3), or
--R.sup.3--O--R.sup.3; or both R.sup.6 groups form a cycloalkyl, a
heterocyclic ring, .dbd.O or .dbd.N--OH;
[0111] provided that if each R.sup.3 is H, each X is CH.sub.2, and
either each R.sup.6 is H or one R.sup.6 is hydroxy; then, both of
said R.sup.4, together with the nitrogen through which they are
attached, form a monocyclic or bicyclic heterocyclic ring of 3 to
12 ring atoms, where one carbon may be optionally replaced with N,
O, S, or SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, hydroxyalkyl, aminoalkyl, or a
heterocyclic ring, F, or CF.sub.3; and where any additional N atom
may be optionally substituted with C.sub.1-C.sub.4 alkyl;
[0112] R.sup.7 is, independently at each occurrence, H, hydroxy,
alkoxy, or C.sub.1-C.sub.4 alkyl;
[0113] R.sup.8 is, independently at each occurrence, straight or
branched alkylenyl;
[0114] or
[0115] one of said R.sup.3 and one of said R.sup.4, together with
the nitrogen and carbon atoms through which they are attached, form
a monocyclic or bicyclic heterocyclic ring of 3 to 12 ring atoms,
where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, F, or CF.sub.3; and where any
additional N atom may be optionally substituted with alkyl;
[0116] or
[0117] both of said R.sup.4, together with the nitrogen through
which they are attached, form a monocyclic or bicyclic heterocyclic
ring of 3 to 12 ring atoms, where one carbon may be optionally
replaced with N, O, S, or SO.sub.2, and where any carbon ring atom
may be optionally substituted with one or two alkyl, hydroxyalkyl,
aminoalkyl, a heterocyclic ring, F, or CF.sub.3; and where any
additional N atom may be optionally substituted with alkyl;
[0118] or
[0119] one of said R.sup.6 or one of said R.sup.7 and one of said
R.sup.4, together with the nitrogen and carbon atoms through which
they are attached, form a monocyclic or bicyclic heterocyclic ring
of 3 to 12 ring atoms, where one carbon may be optionally replaced
with N, O, S, or SO.sub.2, and where any carbon ring atom may be
optionally substituted with one or two C.sub.1-C.sub.4 alkyl, F, or
CF.sub.3; and where any additional N atom may be optionally
substituted with C.sub.1-C.sub.4 alkyl; provided that R.sup.4 and
R.sup.7, taken together, do not form a piperidinyl ring;
[0120] R.sup.9 is, independently at each occurrence, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, alkynyl, aryl substituted with 0-3 R.sup.11, heteroaryl
substituted with 0-3 R.sup.11, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, arylsulfonamide, alkylamido, or arylamido;
[0121] R.sup.10 is, independently at each occurrence, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl;
[0122] R.sup.11 is, independently at each occurrence, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl;
[0123] R.sup.12 and R.sup.13 are each, independently at each
occurrence, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
hydroxyalkyl, aminoalkyl, a heterocyclic ring, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl; and wherein 1-3 carbon atoms in ring
A may optionally be replaced with N;
[0124] the process comprising: [0125] (d) reacting
R.sup.2(BOH).sub.2 and a transitional metal salt with a compound of
formula IH:
##STR00012##
[0126] wherein,
[0127] R.sup.P is R.sup.4 or a protecting group; and
[0128] if R.sup.P is R.sup.4, the compound of formula I is formed;
or
[0129] if R.sup.P is a protecting group, the process further
comprises: [0130] (e) deprotecting the compound of formula IH to
form a deprotected compound; and [0131] (g) reacting the
deprotected compound with an activated-R.sup.4 group, provided that
R.sup.4 group in the activated-R.sup.4 group is not H;
[0132] wherein the compound of formula I is formed.
[0133] In another aspect of the invention, the compound of formula
IH is prepared by: [0134] (a) reacting a compound of formula
IJ:
##STR00013##
[0135] wherein R.sup.B is F or Cl;
[0136] with a compound of formula IK:
##STR00014##
[0137] to form a compound of formula IL:
##STR00015## [0138] (b) hydrogenating the compound of formula IL to
form a compound of formula IM:
[0138] ##STR00016## [0139] and (c) reacting the compound of formula
IM with sulfamide and diglyme to form the compound of formula
IH.
[0140] Other objects, features and advantages of the present
invention will become apparent from the following detailed
description. It should be understood, however, that the detailed
description and the specific examples, while indicating embodiments
of the invention, are given by way of illustration only, since
various changes and modifications within the spirit and scope of
the invention will become apparent to those skilled in the art from
this detailed description.
DETAILED DESCRIPTION
[0141] The following definitions are provided for the full
understanding of terms and abbreviations used in this
specification.
[0142] As used herein and in the appended claims, the singular
forms "a," "an," and "the" include the plural reference unless the
context clearly indicates otherwise. Thus, for example, a reference
to "an antagonist" includes a plurality of such antagonists, and a
reference to "a compound" is a reference to one or more compounds
and equivalents thereof known to those skilled in the art, and so
forth.
[0143] The abbreviations in the specification correspond to units
of measure, techniques, properties, or compounds as follows: "min"
means minutes, "h" means hour(s), ".mu.L" means microliter(s), "mL"
means milliliter(s), "mM" means millimolar, "M" means molar,
"mmole" means millimole(s), "cm" means centimeters, "SEM" means
standard error of the mean and "IU" means International Units.
".DELTA..degree. C." and .DELTA. "ED.sub.50 value" means dose which
results in 50% alleviation of the observed condition or effect (50%
mean maximum endpoint).
[0144] "Norepinephrine transporter" is abbreviated NET.
[0145] "Human norepinephrine transporter" is abbreviated hNET.
[0146] "Serotonin transporter" is abbreviated SERT.
[0147] "Human serotonin transporter" is abbreviated hSERT.
[0148] "Norepinephrine reuptake inhibitor" is abbreviated NRI.
[0149] "Selective norepinephrine reuptake inhibitor" is abbreviated
SNRI.
[0150] "Serotonin reuptake inhibitor" is abbreviated SRI.
[0151] "Selective serotonin reuptake inhibitor" is abbreviated
SSRI.
[0152] "Norepinephrine" is abbreviated NE.
[0153] "Serotonin is abbreviated 5-HT.
[0154] "Subcutaneous" is abbreviated sc.
[0155] "Intraperitoneal" is abbreviated ip.
[0156] "Oral" is abbreviated po.
[0157] In the context of this disclosure, a number of terms are
utilized. The term "treat," "treatment" or "treating" as used
herein includes preventative (e.g., prophylactic), curative or
palliative treatment.
[0158] The term "effective amount," as used herein, refers to an
amount effective, at dosages, and for periods of time necessary, to
achieve the desired result with respect to treatment of a given
disease or disorder. An effective amount is also one in which any
toxic or detrimental effects of the components are outweighed by
the therapeutically beneficial effects. In particular, with respect
to vasomotor symptoms, "effective amount" refers to the amount of
compound or composition of compounds that would increase
norepinephrine levels to compensate in part or total for the lack
of steroid availability in subjects subject afflicted with a
vasomotor symptom. Varying hormone levels will influence the amount
of compound required in the present invention. For example, the
pre-menopausal state may require a lower level of compound due to
higher hormone levels than the peri-menopausal state.
[0159] The effective amount of components of the present invention
will vary from patient to patient not only with the particular
compound, component or composition selected, the route of
administration, and the ability of the components (alone or in
combination with one or more additional active agents) to elicit a
desired response in the individual, but also with factors such as
the disease state or severity of the condition to be alleviated,
hormone levels, age, sex, weight of the individual, the state of
being of the patient, and the severity of the pathological
condition being treated, concurrent medication or special diets
then being followed by the particular patient, and other factors
which those skilled in the art will recognize, with the appropriate
dosage ultimately being at the discretion of the attendant
physician. Dosage regimens may be adjusted to provide the improved
therapeutic response.
[0160] Preferably, the compounds of the present invention are
administered at a dosage and for a time such that the number of hot
flushes is reduced as compared to the number of hot flushes prior
to the start of treatment. Such treatment can also be beneficial to
reduce the overall severity or intensity distribution of any hot
flushes still experienced, as compared to the severity of hot
flushes prior to the start of the treatment. With respect to sexual
dysfunction, gastrointestinal disorder, genitourinary disorder,
chronic fatigue syndrome, fibromyalgia syndrome, depression
disorder, diabetic neuropathy, or pain, the compounds of the
present invention are administered at a dosage and for a time
sufficient to treat the symptom or condition.
[0161] For example, for a patient, compounds of formula I, or a
pharmaceutically acceptable salt thereof, may be administered,
preferably, at a dosage of from about 0.1 mg/day to about 1500
mg/day, dosed one or two times daily, more preferably from about 1
mg/day to about 200 mg/day and most preferably from about 1 mg/day
to 100 mg/day for a time sufficient to reduce and/or substantially
eliminate the number and/or severity of hot flushes or symptom or
condition of the sexual dysfunction, gastrointestinal disorder,
genitourinary disorder, chronic fatigue syndrome, fibromyalgia
syndrome, depression disorder, diabetic neuropathy, or pain.
[0162] The terms "component," "composition," "composition of
compounds," "compound," "drug," or "pharmacologically active agent"
or "active agent" or "medicament" are used interchangeably herein
to refer to a compound or compounds or composition of matter which,
when administered to a subject (human or animal) induces a desired
pharmacological and/or physiologic effect by local and/or systemic
action.
[0163] The term "modulation" refers to the capacity to either
enhance or inhibit a functional property of a biological activity
or process; for example, receptor binding or signaling activity.
Such enhancement or inhibition may be contingent on the occurrence
of a specific event, such as activation of a signal transduction
pathway and/or may be manifest only in particular cell types. The
modulator is intended to comprise any compound; e.g., antibody,
small molecule, peptide, oligopeptide, polypeptide, or protein, and
is preferably small molecule, or peptide.
[0164] As used herein, the term "inhibitor" refers to any agent
that inhibits, suppresses, represses, or decreases a specific
activity, such as norepinephrine reuptake activity. The term
"inhibitor" is intended to comprise any compound; e.g., antibody,
small molecule, peptide, oligopeptide, polypeptide, or protein
(preferably small molecule or peptide) that exhibits a partial,
complete, competitive and/or inhibitory effect on mammalian
(preferably the human norepinephrine reuptake or both serotonin
reuptake and norepinephrine reuptake) thus diminishing or blocking
(preferably diminishing) some or all of the biological effects of
endogenous norepinephrine reuptake or of both serotonin reuptake
and the norepinephrine reuptake.
[0165] Within the present invention, the compounds of formula I,
may be prepared in the form of pharmaceutically acceptable salts.
As used herein, the term "pharmaceutically acceptable salts" refers
to salts prepared from pharmaceutically acceptable non-toxic acids,
including inorganic salts and organic salts. Suitable non-organic
salts include inorganic and organic acids such as acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, malic, maleic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid,
p-toluenesulfonic and the like. Particularly preferred are
hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most
preferred is the hydrochloride salt.
[0166] "Administering," as used herein, means either directly
administering a compound or composition of the present invention,
or administering a prodrug, derivative or analog which will form an
equivalent amount of the active compound or substance within the
body.
[0167] The term "subject" or "patient" refers to an animal
including the human species that is treatable with the compounds,
compositions, and/or methods of the present invention. The term
"subject" or "subjects" is intended to refer to both the male and
female gender unless one gender is specifically indicated.
Accordingly, the term "patient" comprises any mammal which may
benefit from treatment or prevention of a disease or disorder, such
as a human, especially if the mammal is female, either in the
pre-menopausal, peri-menopausal, or post-menopausal period.
Furthermore, the term patient includes female animals including
humans and, among humans, not only women of advanced age who have
passed through menopause but also women who have undergone
hysterectomy or for some other reason have suppressed estrogen
production, such as those who have undergone long-term
administration of corticosteroids, suffer from Cushing's syndrome
or have gonadal dysgenesis. However, the term "patient" is not
intended to be limited to a woman.
[0168] "Side effect" refers to a consequence other than the one(s)
for which an agent or measure is used, as one or more adverse
effects produced by a drug, especially on a tissue or organ system
other then the one sought to be benefited by its administration. In
the case, for example, of high doses of NRIs or NRI/SRI compounds
alone, the term "side effect" may refer to such conditions as, for
example, vomiting, nausea, sweating, and hot flushes (Janowsky, et
al., Journal of Clinical Psychiatry, 1984, 45 (10 Pt 2): 3-9), the
entire disclosure of which is hereby incorporated by reference.
[0169] "Vasomotor symptoms," (also called "vasomotor instability
symptoms" and "vasomotor disturbances") include, but are not
limited to, hot flushes (flushes), insomnia, sleep disturbances,
mood disorders, irritability, excessive perspiration, night sweats,
fatigue, and the like, caused by, inter alia, thermoregulatory
dysfunction.
[0170] The term "hot flush" (sometimes called "hot flash") is an
art-recognized term that refers to an episodic disturbance in body
temperature typically consisting of a sudden skin flushing, usually
accompanied by perspiration in a subject.
[0171] The terms "premature menopause" or "artificial menopause"
refer to ovarian failure of unknown cause that may occur before age
40. It may be associated with smoking, living at high altitude, or
poor nutritional status. Artificial menopause may result from
oophorectomy, chemotherapy, radiation of the pelvis, or any process
that impairs ovarian blood supply.
[0172] The term "pre-menopausal" means before the menopause, the
term "peri-menopausal" means during the menopause and the term
"post-menopausal" means after the menopause. "Ovariectomy" means
removal of an ovary or ovaries and can be effected according to
Merchenthaler et al., Maturitas, 1998, 30 (3): 307-316, the entire
disclosure of which is hereby incorporated by reference.
[0173] The term "sexual dysfunction" includes, but is not limited
to, conditions relating to disorders of sexual desire and/or
arousal.
[0174] As used herein, "gastrointestinal and genitourinary
disorders" includes irritable bowel syndrome, symptomatic GERD,
hypersensitive esophagus, nonulcer dyspepsia, noncardiac chest
pain, biliary dyskinesia, sphincter of Oddi dysfunction,
incontinence (i.e., urge incontinence, stress incontinence, genuine
stress incontinence, and mixed incontinence, including the
involuntary voiding of feces or urine, and dribbling or leakage or
feces or urine which may be due to one or more causes including but
not limited to pathology altering sphincter control, loss of
cognitive function, overdistention of the bladder, hyperreflexia
and/or involuntary urethral relaxation, weakness of the muscles
associated with the bladder or neurologic abnormalities),
interstitial cystitis (irritable bladder), and chronic pelvic pain
(including, but not limited to vulvodynia, prostatodynia, and
proctalgia).
[0175] As used herein, "chronic fatigue syndrome" (CFS) is a
condition characterized by physiological symptoms selected from
weakness, muscle aches and pains, excessive sleep, malaise, fever,
sore throat, tender lymph nodes, impaired memory and/or mental
concentration, insomnia, disordered sleep, localized tenderness,
diffuse pain and fatigue, and combinations thereof, whether or not
correlated with Epstein-Barr virus infection.
[0176] As used herein, "fibromyalgia syndrome" (FMS) includes FMS
and other somatoform disorders, including FMS associated with
depression, somatization disorder, conversion disorder, pain
disorder, hypochondriasis, body dysmorphic disorder,
undifferentiated somatoform disorder, and somatoform NOS. FMS and
other somatoform disorders are accompanied by physiological
symptoms selected from a generalized heightened perception of
sensory stimuli, abnormalities in pain perception in the form of
allodynia (pain with innocuous stimulation), abnormalities in pain
perception in the form of hyperalgesia (increased sensitivity to
painful stimuli), and combinations thereof.
[0177] As used herein, the term "depression disorder" includes
major depressive disorder, generalized anxiety disorder, panic
disorder, attention deficit disorder with or without hyperactivity,
sleep disturbance, social phobia, and combinations thereof.
[0178] The compounds of the present invention can also be used to
treat a cognitive disorder or an endogenous behavioral disorder. As
used herein, a "cognitive disorder" includes changes or defects in
alertness; mild cognitive impairment (MCI), characterized by
problems with memory, language, or other mental functions which is
severe enough to be noticeable or be detected by tests, but not
serious enough to significantly interfere with daily life;
cognitive disorder NOS (not otherwise specified), characterized by
a syndrome of cognitive impairment that does not meet the criteria
for delirium, dementia or amnesic disorders; age-related cognitive
decline (ARCD); and cognitive arousal (such as increased arousal
states). A cognition disorder can be ideopathic, or can be caused
by a variety of other factors such as a congenital defect, alcohol
or drug addiction, transient or permanent pharmacologic effects of
drugs, organic or infectious disease (e.g., Alzheimer's disease,
Parkinson's disease, AIDS), trauma (e.g., brain injury, stroke) or
advanced age. As used herein, an "endogenous behavioral disorder"
includes attention deficit disorder/attention deficit hyperactivity
disorder (ADD/ADHD, including adult and pediatric forms of
predominantly inattentive, predominantly hyperactive, or combined
types), obsessive-compulsive disorder (OCD), oppositional or
oppositional explosive defiant disorder (ODD/OEDD), anxiety and
panic disorders (APD) and temper, rage and outburst behavior
disorder (TROBD).
[0179] As used herein, "pain" includes both acute and chronic
nociceptic or neuropathic pain, which includes centralized pain,
peripheral pain, or combination thereof. The term includes many
different types of pain, including, but not limited to, visceral
pain, musculoskeletal pain, bony pain, cancer pain, inflammatory
pain, and combinations thereof, such as lower back pain, atypical
chest pain, headache such as cluster headache, migraine, herpes
neuralgia, phantom limb pain, pelvic pain, myofascial face pain,
abdominal pain, neck pain, central pain, dental pain, opioid
resistant pain, visceral pain, surgical pain, bone injury pain,
pain during labor and delivery, pain resulting from burns, post
partum pain, angina pain, peripheral neuropathy and diabetic
neuropathy, post-operative pain, and pain which is co-morbid with
nervous system disorders described herein.
[0180] As used herein, the term "acute pain" refers to centralized
or peripheral pain that is intense, localized, sharp, or stinging,
and/or dull, aching, diffuse, or burning in nature and that occurs
for short periods of time.
[0181] As used herein, the term "chronic pain" refers to
centralized or peripheral pain that is intense, localized, sharp,
or stinging, and/or dull, aching, diffuse, or burning in nature and
that occurs for extended periods of time (i.e., persistent and/or
regularly reoccurring), including, for the purposes of the present
invention, neuropathic pain and cancer pain. Chronic pain includes
neuropathic pain, hyperalgesia, and/or allodynia.
[0182] As used herein, the term "neuropathic pain" refers to
chronic pain caused by damage to or pathological changes in the
peripheral or central nervous systems. Examples of pathological
changes related to neuropathic pain include prolonged peripheral or
central neuronal sensitization, central sensitization related
damage to nervous system inhibitory and/or exhibitory functions and
abnormal interactions between the parasympathetic and sympathetic
nervous systems. A wide range of clinical conditions may be
associated with or form the basis for neuropathic pain including,
for example, diabetes, post traumatic pain of amputation (nerve
damage cause by injury resulting in peripheral and/or central
sensitization such as phantom limb pain), lower back pain, cancer,
chemical injury, toxins, other major surgeries, peripheral nerve
damage due to traumatic injury compression, post-herpetic
neuralgia, trigeminal neuralgia, lumbar or cervical
radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex
sympathetic dystrophy, casualgia, thalamic syndrome, nerve root
avulsion, reflex sympathetic dystrophy or post thoracotomy pain,
nutritional deficiencies, or viral or bacterial infections such as
shingles or human immunodeficiency virus (HIV), and combinations
thereof. Also included in the definition of neuropathic pain is a
condition secondary to metastatic infiltration, adiposis dolorosa,
burns, central pain conditions related to thalamic conditions, and
combinations thereof.
[0183] As used herein, the term "hyperalgesia" refers to pain where
there is an increase in sensitivity to a typically noxious
stimulus.
[0184] As used herein, the term "allodynia" refers to an increase
in sensitivity to a typically non-noxious stimulus.
[0185] As used herein, the term "visceral pain" refers to pain
associated with or resulting from maladies of the internal organs,
such as, for example, ulcerative colitis, irritable bowel syndrome,
irritable bladder, Crohn's disease, rheumatologic (arthralgias),
tumors, gastritis, pancreatitis, infections of the organs, biliary
tract disorders, and combinations thereof.
[0186] As used herein, the term "female-specific pain" refers to
pain that may be acute and/or chronic pain associated with female
conditions. Such groups of pain include those that are encountered
solely or predominately by females, including pain associated with
menstruation, ovulation, pregnancy or childbirth, miscarriage,
ectopic pregnancy, retrograde menstruation, rupture of a follicular
or corpus luteum cyst, irritation of the pelvic viscera, uterine
fibroids, adenomyosis, endometriosis, infection and inflammation,
pelvic organ ischemia, obstruction, intra-abdominal adhesions,
anatomic distortion of the pelvic viscera, ovarian abscess, loss of
pelvic support, tumors, pelvic congestion or referred pain from
non-gynecological causes, and combinations thereof.
[0187] "Alkyl," as used herein, refers to an optionally
substituted, saturated straight, branched, or cyclic hydrocarbon
having from about 1 to about 20 carbon atoms (and all combinations
and subcombinations of ranges and specific numbers of carbon atoms
therein), with from about 1 to about 8 carbon atoms or 1 to 6
carbon atoms (C.sub.1-C.sub.6) being preferred, and with from about
1 to about 4 carbon atoms, herein referred to as "lower alkyl",
being more preferred. Alkyl groups include, but are not limited to,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,
n-pentyl, cyclopentyl, cyclopropyl, isopentyl, neopentyl, n-hexyl,
isohexyl, cyclohexyl, cyclooctyl, adamantyl, 3-methylpentyl,
2,2-dimethylbutyl, and 2,3-dimethylbutyl. A branched alkyl group
has at least 3 carbon atoms (e.g., an isopropyl group), and in
various embodiments, has up to 6 carbon atoms, i.e., a branched
lower alkyl group. A branched alkyl group has at least 3 carbon
atoms (e.g., an isopropyl group), and in various embodiments, has
up to 6 carbon atoms, i.e., a branched lower alkyl group. Examples
of branched lower alkyl groups include, but are not limited to:
##STR00017##
[0188] "Alkenyl," as used herein, refers to an alkyl group of at
least two carbon atoms having one or more double bonds, wherein
alkyl is as defined herein. Preferred alkenyl groups have from 2 to
6 carbon atoms (C.sub.2-C.sub.6). Alkenyl groups can be optionally
substituted.
[0189] "Alkynyl," as used herein, refers to an alkyl group of at
least two carbon atoms having one or more triple bonds, wherein
alkyl is as defined herein. Preferred alkynyl groups have from 2 to
6 carbon atoms (C.sub.2-C.sub.6). Alkynyl groups can be optionally
substituted.
[0190] "Alkylenyl", "alkenylenyl", "alkynylenyl", and "arylenyl"
refer to the subsets of alkyl, alkenyl, alkynyl and aryl groups,
respectively, as defined herein, including the same residues as
alkyl, alkenyl, alkynyl, and aryl but having two points of
attachment within a chemical structure. Examples of
C.sub.1-C.sub.6alkylenyl include methylenyl (--CH.sub.2--),
ethylenyl (--CH.sub.2CH.sub.2--), propylenyl
(--CH.sub.2CH.sub.2CH.sub.2--), and dimethylpropylenyl
(--CH.sub.2C(CH.sub.3).sub.2CH.sub.2--). Likewise, examples of
C.sub.2-C.sub.6alkenylenyl include ethenylenyl (--CH.dbd.CH-- and
propenylenyl (--CH.dbd.CH--CH.sub.2--). Examples of
C.sub.2-C.sub.6alkynylenyl include ethynylenyl (--C.ident.C--) and
propynylenyl (--C.ident.C--CH.sub.2--).
[0191] Examples of arylenyl groups include phenylenyl;
##STR00018##
Preferably, arylenyl groups contain 6 carbon atoms (C.sub.6).
[0192] "Halo," as used herein, refers to chloro, bromo, fluoro, and
iodo.
[0193] "Aryl" as used herein, refers to an optionally substituted,
mono-, di-, tri-, or other multicyclic aromatic ring system having
from about 5 to about 50 carbon atoms (and all combinations and
subcombinations of ranges and specific numbers of carbon atoms
therein), with from about 6 to about 10 carbons (C.sub.6-C.sub.10)
being preferred. Non-limiting examples include, for example,
phenyl, naphthyl, anthracenyl, and phenanthrenyl.
[0194] "Heteroaryl," as used herein, refers to an optionally
substituted, mono-, di-, tri-, or other multicyclic aromatic ring
system that includes at least one, and preferably from 1 to about 4
heteroatom ring members selected from sulfur, oxygen and nitrogen.
Heteroaryl groups can have, for example, from about 3 to about 50
carbon atoms (and all combinations and subcombinations of ranges
and specific numbers of carbon atoms therein), with from about 4 to
about 10 carbons being preferred. Non-limiting examples of
heteroaryl groups include, for example, pyrryl, furyl, pyridyl,
1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl,
tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,
thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl,
purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.
[0195] "Heterocyclic ring," as used herein, refers to a stable 4-
to 12-membered monocyclic or bicyclic or 7- to 10-membered bicyclic
heterocyclic ring that is saturated, partially unsaturated or
unsaturated (aromatic), and which contains carbon atoms and from 1
to 4 heteroatoms independently selected from the group consisting
of N, O and S and including any bicyclic group in which any of the
above defined heterocyclic rings is fused to a benzene ring. The
nitrogen and sulfur heteroatoms may optionally be oxidized. The
heterocyclic ring may be attached to its pendant group at any
heteroatom or carbon atom that results in a stable structure. The
heterocyclic rings described herein may be substituted on carbon or
on a nitrogen atom if the resulting compound is stable. If
specifically noted, a nitrogen atom in the heterocycle may
optionally be quaternized. It is preferred that when the total
number of S and O atoms in the heterocycle exceeds one, then these
heteroatoms are not adjacent to one another. It is preferred that
the total number of S and O atoms in the heterocycle is not more
than two. Examples of heterocycles include, but are not limited to,
1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl,
3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,
6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalonyl, carbazolyl, 4H-carbazolyl,
.alpha.-, .beta.-, or .gamma.-carbolinyl, chromanyl, chromenyl,
cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,
indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,
isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl, oxazolyl, oxazolidinylpyrimidinyl, phenanthridinyl,
phenanthrolinyl, phenoxazinyl, phenazinyl, phenothiazinyl,
phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,
piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,
purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,
pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,
pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,
quinuclidinyl, carbolinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles
include, but are not limited to, pyridinyl, furanyl, thienyl,
pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl,
1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl,
oxindolyl, benzoxazolinyl, or isatinyl. Also included are fused
ring and spiro compounds containing, for example, the above
heterocycles.
[0196] "Alkoxy," as used herein, refers to the group R--O-- where R
is an alkyl group, as defined herein. Preferred alkoxy groups have
from 1 to 6 carbon atoms (C.sub.1-C.sub.6).
[0197] "Arylalkyl," as used herein, refers to the group R'--R--
where R' is an aryl group, as defined herein, and R is an alkyl
group, as defined herein. Preferred arylalkyl groups have from 7 to
16 carbon atoms (C.sub.7-C.sub.16).
[0198] "Heteroarylalkyl," as used herein, refers to the group
R''--R-- where R'' is a heteroaryl group, as defined herein, and R
is an alkyl group, as defined herein.
[0199] "Heteroarylmethyl," as used herein, refers to the group
R''--CH.sub.2-- where R'' is a heteroaryl group, as defined
herein.
[0200] "Alkanoyloxy," as used herein, refers to the group
R--C(.dbd.O)--O-- where R is an alkyl group, as defined herein, of
1 to 5 carbon atoms (C.sub.1-C.sub.5).
[0201] "Alkylsulfoxide," as used herein, refers to as used herein,
refers to --S(.dbd.O)--R', where R is alkyl, as defined herein.
Preferred alkysulfoxide groups have from 1 to 6 carbon atoms
(C.sub.1-C.sub.6).
[0202] "Arylsulfoxide," as used herein, refers to as used herein,
refers to --S(.dbd.O)--R', where R' is aryl, as defined herein.
Preferred arylsulfoxide groups have from 6 to 10 carbon atoms
(C.sub.6-C.sub.10).
[0203] "Alkylsulfone," as used herein, refers to
--S(.dbd.O).sub.2--R, where R is alkyl, as defined herein.
Preferred alkylsulfone groups have from 1 to 6 carbon atoms
(C.sub.1-C.sub.6).
[0204] "Arylsulfone," as used herein, refers to
--S(.dbd.O).sub.2--R', where R' is aryl, as defined herein.
Preferred arylsulfone groups have from 6 to 10 carbon atoms
(C.sub.6-C.sub.10).
[0205] "Alkylsulfonamide," as used herein, refers to
--NR--S(.dbd.O).sub.2--R, where each R is independently, alkyl, as
defined above, or the NR part may also be NH. Preferred
alkylsulfonamide groups have from 1 to 6 carbon atoms
(C.sub.1-C.sub.6).
[0206] "Arylsulfonamide," as used herein, refers to
--NR--S(.dbd.O).sub.2--R', where R is H or alkyl, as defined
herein, and R' is aryl, as defined herein. Preferred
arylsulfonamide groups have from 6 to 10 carbon atoms
(C.sub.6-C.sub.10).
[0207] "Heteroarylsulfonamide," as used herein, refers to
--NR--S(.dbd.O).sub.2--R'', where R is H or alkyl, as defined
herein, and R'' is aryl, as defined herein.
[0208] "Alkylamido," as used herein, refers to --NR--C(.dbd.O)--R,
where each R is independently, alkyl, as defined above, or the NR
part may also be NH. Preferred alkylamido groups have from 1 to 6
carbon atoms (C.sub.1-C.sub.6).
[0209] "Arylamido," as used herein, refers to --NR--C(.dbd.O)--R'',
where R is H or alkyl, as defined herein, and R'' is aryl, as
defined herein. Preferred arylamido groups have from 6 to 10 carbon
atoms (C.sub.6-C.sub.10).
[0210] "Phenylamido," as used herein, refers to
--NR--C(.dbd.O)-phenyl, where R is H or alkyl, as defined
above.
[0211] As used herein, the terms "optionally substituted" or
"substituted or unsubstituted" are intended to refer to the
optional replacement of up to four hydrogen atoms with up to four
independently selected substituent groups as defined herein. Unless
otherwise specified, suitable substituent groups independently
include hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl,
aminocarbonyl, carbonylamino, carbonyl, oxo, guanidine, carboxyl,
formyl, alkyl, perfluoroalkyl, alkylamino, dialkylamino, alkoxy,
alkoxyalkyl, alkylcarbonyl, arylcarbonyl, alkylthio, aryl,
heteroaryl, a heterocyclic ring, cycloalkyl, hydroxyalkyl,
carboxyalkyl, haloalkyl, alkenyl, alkynyl, arylalkyl, aryloxy,
heteroaryloxy, heteroarylalkyl, and the like. Substituent groups
that have one or more available hydrogen atoms can in turn
optionally bear further independently selected substituents, to a
maximum of three levels of substitutions. For example, the term
"optionally substituted alkyl" is intended to mean an alkyl group
that can optionally have up to four of its hydrogen atoms replaced
with substituent groups as defined above (i.e., a first level of
substitution), wherein each of the substituent groups attached to
the alkyl group can optionally have up to four of its hydrogen
atoms replaced by substituent groups as defined above (i.e., a
second level of substitution), and each of the substituent groups
of the second level of substitution can optionally have up to four
of its hydrogen atoms replaced by substituent groups as defined
above (i.e., a third level of substitution).
[0212] Unless indicated otherwise, the nomenclature of substituents
that are not explicitly defined herein are arrived at by naming the
terminal portion of the functionality followed by the adjacent
functionality toward the point of attachment. For example, the
substituent "arylalkoxycabonyl" refers to the group
(aryl)-(alkyl)-O--C(O)--.
[0213] It is understood that the above definitions are not intended
to include impermissible substitution patterns (e.g., methyl
substituted with 5 fluoro groups, multiple consecutive oxygen
atoms, or other noncompatible consecutive or proximal heteroatoms).
Such impermissible substitution patterns are well known to the
skilled artisan.
[0214] At various places in the present specification, substituents
of compounds are disclosed in groups or in ranges. It is
specifically intended that the description include each and every
individual subcombination of the members of such groups and ranges.
For example, the term "C.sub.1-6 alkyl" is specifically intended to
individually disclose C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5,
C.sub.6, C.sub.1-C.sub.6, C.sub.1-C.sub.5, C.sub.1-C.sub.4,
C.sub.1-C.sub.3, C.sub.1-C.sub.2, C.sub.2-C.sub.6, C.sub.2-C.sub.5,
C.sub.2-C.sub.4, C.sub.2-C.sub.3, C.sub.3-C.sub.6, C.sub.3-C.sub.5,
C.sub.3-C.sub.4, C.sub.4-C.sub.6, C.sub.4-C.sub.5, and
C.sub.5-C.sub.6 alkyl. By way of another example, the term "5-9
membered heteroaryl group" is specifically intended to individually
disclose a heteroaryl group having 5, 6, 7, 8, 9, 5-9, 5-8, 5-7,
5-6, 6-9, 6-8, 6-7, 7-9, 7-8, and 8-9 ring atoms.
[0215] The term "protecting group" or "G.sub.p" with respect to
amine groups, hydroxyl groups and sulfhydryl groups refers to forms
of these functionalities which are protected from undesirable
reaction with a protecting group known to those skilled in the art,
such as those set forth in Protective Groups in Organic Synthesis,
Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York,
N.Y., (3rd Edition, 1999) which can be added or removed using the
procedures set forth therein. Examples of protected hydroxyl groups
include, but are not limited to, silyl ethers such as those
obtained by reaction of a hydroxyl group with a reagent such as,
but not limited to, t-butyldimethyl-chlorosilane,
trimethylchlorosilane, triisopropylchlorosilane,
triethylchlorosilane; substituted methyl and ethyl ethers such as,
but not limited to methoxymethyl ether, methythiomethyl ether,
benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl
ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether,
benzyl ether; esters such as, but not limited to, benzoylformate,
formate, acetate, trichloroacetate, and trifluoracetate. Examples
of protected amine groups include, but are not limited to, amides
such as, formamide, acetamide, trifluoroacetamide, and benzamide;
carbamates; e.g. BOC; imides, such as phthalimide, Fmoc, Cbz, PMB,
benzyl, and dithiosuccinimide; and others. Examples of protected or
capped sulfhydryl groups include, but are not limited to,
thioethers such as S-benzyl thioether, and S-4-picolyl thioether;
substituted S-methyl derivatives such as hemithio, dithio and
aminothio acetals; and others.
[0216] Reference to "activated" or "an activating group" or
"G.sub.a" as used herein indicates having an electrophilic moiety
bound to a substituent, capable of being displaced by a
nucleophile. Examples of preferred activating groups are halogens,
such as Cl, Br or I, and F; triflate; mesylate, or tosylate;
esters; aldehydes; ketones; epoxides; and the like. An example of
an activated group is acetylchloride, which is readily attacked by
a nucleophile, such as piperidine group to form a
N-acetylpiperidine functionality.
[0217] The term "deprotecting" refers to removal of a protecting
group, such as removal of a benzyl or BOC group bound to an amine.
Deprotecting may be preformed by heating and/or addition of
reagents capable of removing protecting groups. In preferred
embodiments, the deprotecting step involves addition of an acid,
base, reducing agent, oxidizing agent, heat, or any combination
thereof. One preferred method of removing BOC groups from amino
groups is to add HCl in ethyl acetate. Many deprotecting reactions
are well known in the art and are described in Protective Groups in
Organic Synthesis, Greene, T. W., John Wiley & Sons, New York,
N.Y., (1st Edition, 1981), the entire disclosure of which is herein
incorporated by reference.
[0218] One aspect of the invention provides a compound of formula
I:
##STR00019##
[0219] or a pharmaceutically acceptable salt, stereoisomer or
tautomer thereof;
[0220] wherein:
[0221] n is an integer from 0 to 4;
[0222] m is an integer from 0 to 6;
[0223] X is, independently at each occurrence, C(R.sup.7).sub.2,
N(R.sup.3), O, S, S(.dbd.O), or S(.dbd.O).sub.2;
[0224] Y is C; or
[0225] Y and an adjacent X together form --CR.sup.7.dbd.CR.sup.7--,
--C.ident.C--, or arylenyl substituted with 0-3 R.sup.10;
[0226] R.sup.1 is, independently at each occurrence, H, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, alkynyl, aryl substituted with 0-3 R.sup.11,
heteroaryl substituted with 0-3 R.sup.11, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, arylsulfonamide substituted with
0-3 R.sup.5, alkylamido, or arylamido substituted with 0-3
R.sup.5;
[0227] R.sup.2 is aryl substituted with 0-3 R.sup.9 or heteroaryl
substituted with 0-3 R.sup.9,
[0228] R.sup.3 is, independently at each occurrence, H, halo,
hydroxy, alkyl substituted with 0-3 R.sup.13, a heterocyclic ring,
aryl substituted with 0-3 R.sup.12, or heteroaryl substituted with
0-3 R.sup.12;
[0229] R.sup.4 is, independently at each occurrence, H, alkyl
substituted with 0-3 R.sup.13, arylalkyl substituted with 0-3
R.sup.13 or heteroarylmethyl substituted with 0-3 R.sup.13;
[0230] R.sup.5 is, independently at each occurrence, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
or alkylamido;
[0231] R.sup.6 is, independently at each occurrence, H, hydroxy,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkoxy, halo, aryl
substituted with 0-3 R.sup.1, heteroaryl substituted with 0-3
R.sup.1, --N(R.sup.3).sub.2, --S(R.sup.3), or
--R.sup.3--O--R.sup.3; or both R.sup.6 groups form a cycloalkyl, a
heterocyclic ring, .dbd.O or .dbd.N--OH;
[0232] provided that if each R.sup.3 is H, each X is CH.sub.2, and
either each R.sup.6 is H or one R.sup.6 is hydroxy; then, both of
said R.sup.4, together with the nitrogen through which they are
attached, form a monocyclic or bicyclic heterocyclic ring of 3 to
12 ring atoms, where one carbon may be optionally replaced with N,
O, S, or SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, hydroxyalkyl, aminoalkyl, or a
heterocyclic ring, F, or CF.sub.3; and where any additional N atom
may be optionally substituted with C.sub.1-C.sub.4 alkyl;
[0233] R.sup.7 is, independently at each occurrence, H, hydroxy,
alkoxy, or C.sub.1-C.sub.4 alkyl;
[0234] R.sup.8 is, independently at each occurrence, straight or
branched alkylenyl;
[0235] or
[0236] one of said R.sup.3 and one of said R.sup.4, together with
the nitrogen and carbon atoms through which they are attached, form
a monocyclic or bicyclic heterocyclic ring of 3 to 12 ring atoms,
where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, F, or CF.sub.3; and where any
additional N atom may be optionally substituted with alkyl;
[0237] or
[0238] both of said R.sup.4, together with the nitrogen through
which they are attached, form a monocyclic or bicyclic heterocyclic
ring of 3 to 12 ring atoms, where one carbon may be optionally
replaced with N, O, S, or SO.sub.2, and where any carbon ring atom
may be optionally substituted with one or two alkyl, hydroxyalkyl,
aminoalkyl, a heterocyclic ring, F, or CF.sub.3; and where any
additional N atom may be optionally substituted with alkyl;
[0239] or
[0240] one of said R.sup.6 or one of said R.sup.7 and one of said
R.sup.4, together with the nitrogen and carbon atoms through which
they are attached, form a monocyclic or bicyclic heterocyclic ring
of 3 to 12 ring atoms, where one carbon may be optionally replaced
with N, O, S, or SO.sub.2, and where any carbon ring atom may be
optionally substituted with one or two C.sub.1-C.sub.4 alkyl, F, or
CF.sub.3; and where any additional N atom may be optionally
substituted with C.sub.1-C.sub.4 alkyl; provided that R.sup.4 and
R.sup.7, taken together, do not form a piperidinyl ring;
[0241] R.sup.9 is, independently at each occurrence, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, alkynyl, aryl substituted with 0-3 R.sup.11, heteroaryl
substituted with 0-3 R.sup.11, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, arylsulfonamide, alkylamido, or arylamido;
[0242] R.sup.10 is, independently at each occurrence, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl;
[0243] R.sup.11 is, independently at each occurrence, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl;
[0244] R.sup.12 and R.sup.13 are each, independently at each
occurrence, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy,
hydroxyalkyl, aminoalkyl, a heterocyclic ring, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl; and
[0245] wherein 1-3 carbon atoms in ring A may optionally be
replaced with N.
[0246] In another embodiment, [0247] R.sup.4 and R.sup.6, taken
together, form a morpholinyl group optionally substituted with
C.sub.1-C.sub.4 alkyl, F, or CF.sub.3.
[0248] In another embodiment, [0249] R.sup.4 and R.sup.6, taken
together, form morpholin-2-yl.
[0250] In another embodiment, [0251] R.sup.4 and R.sup.6, taken
together, form (R)-morpholin-2-yl.
[0252] In another embodiment, [0253] R.sup.4 and R.sup.6, taken
together, form (S)-morpholin-2-yl.
[0254] In another embodiment, [0255] n is an integer from 0 to
2.
[0256] In another embodiment, [0257] m is an integer from 1 to
6.
[0258] In another embodiment, m is an integer from 2 to 6. More
particularly, m is 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4,
2 to 3, 3 to 6, 3 to 5, 3 to 4, 4 to 6, or 4 to 5. In another
embodiment, m is 1, m is 2, m is 3, m is 4, m is 5 or m is 6.
[0259] In another embodiment, [0260] X is, independently at each
occurrence, C(R.sup.7).sub.2, N(R.sup.3), or O.
[0261] In another embodiment, [0262] X is, independently at each
occurrence, C(R.sup.7).sub.2.
[0263] In another embodiment, [0264] R.sup.1 is, independently at
each occurrence, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3 or
nitrile.
[0265] In another embodiment, [0266] R.sup.2 is aryl substituted
with 0-3 R.sup.9.
[0267] In another embodiment, [0268] R.sup.2 is phenyl,
fluoro-phenyl, difluoro-phenyl, trifluoro-phenyl, chloro-phenyl,
fluoro-chloro-phenyl, bromo-phenyl, trifluoromethyl-phenyl
trifluoromethoxy-phenyl, methyl-fluoro-phenyl,
methoxy-fluoro-phenyl, or naphthyl.
[0269] In another embodiment, [0270] R.sup.2 is heteroaryl
substituted with 0-3 R.sup.9.
[0271] In another embodiment, [0272] R.sup.2 is pyridinyl,
methyl-pyridinyl, ethyl-pyridinyl, methoxy-pyridinyl, or
quinolinyl.
[0273] In another embodiment, R.sup.2 is:
##STR00020##
[0274] wherein,
[0275] each R.sup.5a, R.sup.6a, R.sup.7a, R.sup.8a and R.sup.9a are
independently selected from the group consisting of H, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, alkynyl, aryl substituted, heteroaryl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide,
alkylamido, or arylamido.
[0276] In another embodiment, R.sup.9a is F. In another embodiment,
R.sup.5a, R.sup.6a, R.sup.7a and R.sup.8a are H. In another
embodiment, R.sup.5a, R.sup.6a, R.sup.7a, R.sup.8a and R.sup.9a are
independently H, halo, alkyl or alkoxy. In another embodiment,
R.sup.5a, R.sup.6a, R.sup.7a and R.sup.8a are H. In another
embodiment R.sup.5a is H or F, R.sup.6a is H or F, R.sup.7a is H or
F, R.sup.8a is H or F and R.sup.9a is H or F. In another
embodiment, R.sup.5a, R.sup.6a, R.sup.7a, R.sup.8a and R.sup.9a are
H, halo, alkyl or alkoxy.
[0277] In another embodiment, [0278] R.sup.3 is, independently at
each occurrence, H, methyl, or phenyl.
[0279] In another embodiment, [0280] R.sup.4 is, independently at
each occurrence, hydrogen, methyl, ethyl, cyclopropyl, or
n-butyl.
[0281] In another embodiment, [0282] both of said R.sup.4, together
with the nitrogen through which they are attached, form a
heterocyclic ring of 4 to 7 atoms, where one carbon may be
optionally replaced with N or O; where any carbon ring atom may be
optionally substituted with one or two C.sub.1-C.sub.4 alkyl, F, or
CF.sub.3; and where any additional N atom may be optionally
substituted with C.sub.1-C.sub.4 alkyl.
[0283] In another embodiment, [0284] R.sup.5 is, independently at
each occurrence, alkyl, alkoxy, halo, or OCF.sub.3.
[0285] In another embodiment, [0286] R.sup.6 is, independently at
each occurrence, H methyl, or fluoro.
[0287] In another embodiment, [0288] R.sup.7 is, independently at
each occurrence, H, methyl, or phenyl.
[0289] In another embodiment, [0290] Y and an adjacent X together
form --CH.dbd.CH--, --C.ident.C--, or phenylenyl.
[0291] In another embodiment, [0292] m is an integer from 1 to 3;
[0293] X is, independently at each occurrence, C(R.sup.7).sub.2,
N(R.sup.3), or O; [0294] Y is C; [0295] R.sup.1 is, independently
at each occurrence, alkyl, alkoxy, halo, CF.sub.3, or OCF.sub.3;
[0296] R.sup.2 is aryl substituted with 0-3 R.sup.9 or heteroaryl
substituted with 0-3 R.sup.9; [0297] R.sup.3 is, independently at
each occurrence, H or C.sub.1-C.sub.4 alkyl; [0298] R.sup.4 is,
independently at each occurrence, H or C.sub.1-C.sub.6 alkyl;
[0299] R.sup.6 is, independently at each occurrence, H,
C.sub.1-C.sub.4 alkyl, or halo; and [0300] R.sup.7 is,
independently at each occurrence, H or C.sub.1-C.sub.4 alkyl.
[0301] In another embodiment, [0302] m is an integer from 0 to 1;
[0303] X is, independently at each occurrence, C(R.sup.7).sub.2;
[0304] Y is C; [0305] R.sup.1 is, independently at each occurrence,
alkyl, alkoxy, halo, CF.sub.3, or OCF.sub.3; [0306] R.sup.2 is aryl
substituted with 0-3 R.sup.9 or heteroaryl substituted with 0-3
R.sup.9; [0307] R.sup.3 is, independently at each occurrence, H or
C.sub.1-C.sub.4 alkyl; [0308] R.sup.6 is, independently at each
occurrence, H, C.sub.1-C.sub.4 alkyl, or halo; and [0309] R.sup.7
is, independently at each occurrence, H or C.sub.1-C.sub.4 alkyl;
or [0310] both of said R.sup.4, together with the nitrogen through
which they are attached, form a heterocyclic ring of 4 to 7 atoms,
where one carbon may be optionally replaced with N or O, where any
carbon ring atom may be optionally substituted with one or two
C.sub.1-C.sub.4 alkyl, F, or CF.sub.3; and where any additional N
atom may be optionally substituted with C.sub.1-C.sub.4 alkyl.
[0311] In another embodiment, [0312] m is an integer from 0-1;
[0313] X is, independently at each occurrence, C(R.sup.7).sub.2
[0314] Y is C [0315] R.sup.1 is, independently at each occurrence,
alkyl, alkoxy, halo, CF.sub.3, or OCF.sub.3; [0316] R.sup.2 is aryl
substituted with 0-3 R.sup.9 or heteroaryl substituted with 0-3
R.sup.9; [0317] R.sup.3 is, independently at each occurrence, H or
C.sub.1-C.sub.4 alkyl; [0318] R.sup.6 is, independently at each
occurrence, H, C.sub.1-C.sub.4 alkyl, or halo; and [0319] R.sup.7
is, independently at each occurrence, H or C.sub.1-C.sub.4 alkyl,
or [0320] one of said R.sup.6 or one of said R.sup.7 and one of
said R.sup.4, together with the nitrogen and carbon atoms through
which they are attached, form a monocyclic or bicyclic heterocyclic
ring of 3 to 12 atoms, where one carbon may be optionally replaced
with N, O, S, or SO.sub.2, and where any carbon ring atom may be
optionally substituted with one or two C.sub.1-C.sub.4 alkyl, F, or
CF.sub.3; and where any additional N atom may be optionally
substituted with C.sub.1-C.sub.4 alkyl.
[0321] In another embodiment, the compound is selected from the
group consisting of: [0322]
1-(morpholin-2-ylmethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide; [0323]
1-[(2R)-morpholin-2-ylmethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide; [0324]
1-[(2S)-morpholin-2-ylmethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide; [0325]
1-[(4-methylmorpholin-2-yl)methyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide; [0326]
1-(2-chloro-4-fluorophenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethy-
l}-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide; [0327]
1-(2-chloro-4-fluorophenyl)-3-{2-piperazin-1-ylethyl}-1,3-dihydro-2,1,3-b-
enzothiadiazole-2,2-dioxide; [0328]
1-(4-fluoro-2-methylphenyl)-3-{2-piperazin-1-ylethyl}-1,3-dihydro-2,1,3-b-
enzothiadiazole-2,2-dioxide; [0329]
1-(4-fluoro-2-methylphenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethy-
l}-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide; [0330]
1-(4-fluoro-2-methoxyphenyl)-3-{2-piperazin-1-ylethyl}-1,3-dihydro-2,1,3--
benzothiadiazole-2,2-dioxide; [0331]
1-[2-(2,5-diazabicyclo[2.2.1]hept-2-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3--
benzothiadiazole 2,2-dioxide; [0332]
2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethox-
y}ethanamine; [0333]
2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethox-
y}-N-methylethanamine; [0334]
2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethox-
y}-N,N-dimethylethanamine; [0335]
1-{2-[2-(3,5-dimethylpiperazin-1-yl)ethoxy]ethyl}-3-(2-fluorophenyl)-1,3--
dihydro-2,1,3-benzothiadiazole 2,2-dioxide; [0336]
1-[5-(3,5-dimethylpiperazin-1-yl)pentyl]-3-(2-fluorophenyl)-1,3-dihydro-2-
,1,3-benzothiadiazole 2,2-dioxide; [0337]
(2R)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2--
methylpropan-1-amine; [0338]
(2S)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2--
methylpropan-1-amine; [0339]
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2--
amine; [0340]
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbutan-1-amine; [0341]
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbutan-2-amine; [0342]
(2R)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,-
2-dimethylpropan-1-amine; [0343]
(2S)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,-
2-dimethylpropan-1-amine; [0344]
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1--
amine; [0345]
1-Phenyl-3-(piperidin-4-ylmethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide; [0346]
1-(2,6-Difluorophenyl)-3-(morpholin-2-ylmethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide; [0347]
1-(2,6-Difluorophenyl)-3-[(2R)-morpholin-2-ylmethyl]-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide; [0348]
1-(2,6-Difluorophenyl)-3-[(2S)-morpholin-2-ylmethyl]-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide; [0349]
1-(2,3-Difluorophenyl)-3-(morpholin-2-ylmethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide; [0350]
1-(Morpholin-2-ylmethyl)-3-[2-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-
-benzothiadiazole 2,2-dioxide; [0351]
1-Phenyl-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide [0352]
1-Phenyl-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-
-dioxide; [0353]
4-Fluoro-3-phenyl-1-(piperidin-4-ylmethyl)-1,3-dihydro-2,1,3-benzothiadia-
zole-2,2-dioxide; [0354]
4-Fluoro-3-phenyl-1-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide; [0355]
4-Fluoro-3-phenyl-1-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadi-
azole-2,2-dioxide; [0356]
4-Fluoro-3-(morpholin-2-ylmethyl)-1-phenyl-1,3-dihydro-2,1,3-benzothiadia-
zole-2,2-dioxide; [0357]
1-Phenyl-3-(3-piperidin-4-ylpropyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,-
2-dioxide; [0358]
1-Phenyl-3-(2-piperidin-2-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-
-dioxide [0359]
1-(2,6-Difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide; [0360]
1-(2,6-Difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide; [0361]
1-Phenyl-3-(piperidin-3-ylmethyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2--
dioxide; [0362]
1-Phenyl-3-[(3R)-piperidin-3-ylmethyl]-1,3-dihydro-2,1,3-benzothiadiazole-
-2,2-dioxide; [0363]
1-Phenyl-3-[(3S)-piperidin-3-ylmethyl]-1,3-dihydro-2,1,3-benzothiadiazole-
-2,2-dioxide; [0364]
1-Phenyl-3-(2-piperidin-3-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-
-dioxide; [0365]
1-Phenyl-3-{2-[(3S)-piperidin-3-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiaz-
ole-2,2-dioxide; [0366]
1-Phenyl-3-{2-[(3R)-piperidin-3-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiaz-
ole-2,2-dioxide; [0367]
1-(2,3-Difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide; [0368]
1-(2,5-Difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide; [0369]
1-(2,3-Difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide; [0370]
1-(2,5-Difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide; [0371]
1-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-be-
nzothiadiazole-2,2-dioxide; [0372]
1-(2-Fluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole-2,2-dioxide; [0373]
1-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-(2-fluorophenyl)-1,3-dihydr-
o-2,1,3-benzothiadiazole-2,2-dioxide; [0374]
1-[3-(cis-3,5-Dimethylpiperazin-1-yl)propyl]-3-phenyl-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide; [0375]
1-(2,6-Difluorophenyl)-3-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-1,3-di-
hydro-2,1,3-benzothiadiazole-2,2-dioxide; [0376]
1-(2-piperazin-1-ylethyl)-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-ben-
zothiadiazole-2,2-dioxide; [0377]
1-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-(2,4,6-trifluorophenyl)-1,3-
-dihydro-2,1,3-benzothiadiazole-2,2-dioxide; [0378]
1-Phenyl-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,-
2-dioxide; [0379]
1-(4-Fluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole-2,2-dioxide; [0380]
1-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-(4-fluorophenyl)-1,3-dihydr-
o-2,1,3-benzothiadiazole-2,2-dioxide; [0381]
1-(2,4-difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide; [0382]
1-(2,4-difluorophenyl)-3-[2-(3,5-dimethylpiperazin-1-yl)ethyl]-1,3-dihydr-
o-2,1,3-benzothiadiazole-2,2-dioxide; [0383]
1-[2-(3,5-dimethylpiperazin-1-yl)ethyl]-4-fluoro-3-(2-fluorophenyl)-1,3-d-
ihydro-2,1,3-benzothiadiazole 2,2-dioxide; [0384]
1-(2-{[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
methyl}phenyl)-N-methylmethanamine; [0385]
3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethyl-1-phenylpropan-1-amine; [0386]
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
l-1-phenylpropan-1-amine; [0387]
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbut-2-yn-1-amine; [0388]
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dim-
ethylbut-2-yn-1-amine; [0389]
(2E)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N--
methylbut-2-en-1-amine; [0390]
(2E)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,-
N-dimethylbut-2-en-1-amine; [0391]
3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethyl}-4-fluoro-1-(2-fluoropheny-
l)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide; [0392]
2,2-difluoro-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]-N-methylpropan-1-amine; [0393]
1-(2-Fluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide; [0394]
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazol-
e-2,2-dioxide; [0395]
1-(2,4-Difluorophenyl)-4-fluoro-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1-
,3-benzothiadiazole-2,2-dioxide; [0396]
3-(2,4-Difluorophenyl)-4-fluoro-1-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1-
,3-benzothiadiazole-2,2-dioxide [0397]
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,-
3-benzothiadiazole-2,2-dioxide [0398]
1-{2-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]ethyl}-3-(2,4,6-trifluorop-
henyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide; [0399]
3-[2-(1,4-Diazepan-1-yl)ethyl]-1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydr-
o-2,1,3-benzothiadiazole 2,2-dioxide; [0400]
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide; [0401]
1-{2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl}-3-(2-fluorophenyl)--
1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide; [0402]
1-Phenyl-3-(2-piperidin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-
-dioxide; [0403]
1-(2,4-Difluorophenyl)-3-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-4-fluo-
ro-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide; [0404]
1-[3-(1,4-Diazepan-1-yl)propyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazo-
le-2,2-dioxide; [0405]
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-b-
enzothiadiazole-2,2-dioxide; [0406]
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-b-
enzothiadiazole-2,2-dioxide; [0407]
1-{2-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]ethyl}-3-(2,4-difluorophen-
yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide; [0408]
1-(2,4-Difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide; [0409]
1-(2,4-Difluorophenyl)-3-[2-(4-methylpiperazin-1-yl)ethyl]-1,3-dihydro-2,-
1,3-benzothiadiazole 2,2-dioxide; [0410]
1-(2,4-Difluorophenyl)-4-fluoro-3-[2-(4-methylpiperazin-1-yl)ethyl]-1,3-d-
ihydro-2,1,3-benzothiadiazole 2,2-dioxide; [0411]
1-(2,4-Difluorophenyl)-3-[2-(4-methyl-1,4-diazepan-1-yl)ethyl]-1,3-dihydr-
o-2,1,3-benzothiadiazole 2,2-dioxide; [0412]
1-[2-(4-Methyl-1,4-diazepan-1-yl)ethyl]-3-(2,4,6-trifluorophenyl)-1,3-dih-
ydro-2,1,3-benzothiadiazole 2,2-dioxide; [0413]
N-{2-[3-(2-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}-N,N'-dimethylethane-1,2-diamine; [0414]
N-{2-[3-(2,4-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thyl}-N,N'-dimethylethane-1,2-diamine; [0415]
N-{2-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-y-
l]ethyl}-N,N'-dimethylethane-1,2-diamine; [0416]
1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propy-
l}piperidin-4-amine; [0417]
1-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]piperidi-
n-4-amine; [0418]
1-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}piperidin-4-amine; [0419]
1-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}-N-methylpiperidin-4-amine; [0420]
1-{2-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperidin-
-4-amine; [0421]
1-{2-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}-N-methyl-
piperidin-4-amine; [0422]
1-{1-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]pyrrol-
idin-3-yl}methanamine; [0423]
1-phenyl-3-[2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethyl]-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide; [0424]
2-{2-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]ethoxy}-N-methylethanamine; [0425]
2-{2-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]ethoxy}-N,N-dimethylethanamine; [0426]
1-(4-chloro-2-fluorophenyl)-3-(2-piperazin-1-yl-ethyl)-1,3-dihydro-2,1,3--
benzothiadiazole 2,2-dioxide; [0427]
1-(4-chloro-2-fluorophenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethy-
l}-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide; [0428]
1-(4-chloro-2-fluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide; [0429]
1-(4-chloro-2-methylphenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethy-
l}-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide; [0430]
1-(4-chloro-2-methylphenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide; [0431]
1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)butan-2-one; [0432]
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino-
)butan-2-one; [0433]
1-(cyclopropylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)--
yl)butan-2-one; [0434]
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)bu-
tan-2-one; [0435]
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(meth-
ylamino)butan-2-one; [0436]
(2Z)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylami-
no)butan-2-one oxime; [0437]
(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2--
methoxy-N-methylbutan-1-amine; [0438]
(2S)-2-methoxy-N-methyl-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothia-
diazol-1(3H)-yl]butan-1-amine; [0439]
(2S)-2-methoxy-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1-
(3H)-yl]-N-methylbutan-1-amine; [0440]
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-methoxy-N-methy-
lbutan-1-amine; [0441]
(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-methoxy-N--
methylbutan-1-amine; [0442]
(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-methoxy-N--
methylbutan-1-amine; [0443]
N-{(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-2-methoxybutyl}cyclopropanamine; [0444]
N-{(2S)-2-methoxy-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
-1(3H)-yl]butyl}cyclopropanamine; [0445]
N-{(2S)-2-methoxy-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazo-
l-1(3H)-yl]butyl}cyclopropanamine; [0446]
N-{(2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]-2-methoxybutyl}cyclopropanamine; [0447]
N-{(2S)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]-2-methoxybutyl}cyclopropanamine; [0448]
N-{(2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]-2-methoxybutyl}cyclopropanamine; [0449]
2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-2-methoxy-N-methylbutan-1-amine; [0450]
(2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-2-methoxy-N-methylbutan-1-amine; [0451]
1-(2-morpholin-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide; [0452]
1-{2-[(2S)-morpholin-2-yl]ethyl}-3-phenyl-1,3-dihydro-2,1,3-benzothiadiaz-
ole 2,2-dioxide; [0453]
1-{2-[(2R)-morpholin-2-yl]ethyl}-3-phenyl-1,3-dihydro-2,1,3-benzothiadiaz-
ole 2,2-dioxide; [0454]
1-(4-fluorophenyl)-3-(2-morpholin-2-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide; [0455]
1-(4-fluorophenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide; [0456]
1-(4-fluorophenyl)-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide; [0457]
1-(2,4-difluorophenyl)-3-(2-morpholin-2-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide; [0458]
1-(2,4-difluorophenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-
-benzothiadiazole 2,2-dioxide; [0459]
1-(2,4-difluorophenyl)-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-
-benzothiadiazole 2,2-dioxide; [0460]
1-(2-morpholin-2-ylethyl)-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide; [0461]
1-{2-[(2S)-morpholin-2-yl]ethyl}-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,-
1,3-benzothiadiazole 2,2-dioxide; [0462]
1-{2-[(2R)-morpholin-2-yl]ethyl}-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,-
1,3-benzothiadiazole 2,2-dioxide;
[0463]
1-(3-methoxyphenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2-
,1,3-benzothiadiazole 2,2-dioxide; [0464]
1-(3-methoxyphenyl)-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide; [0465]
1-(2-fluorophenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide; [0466]
1-(2-fluorophenyl)-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide; [0467]
1-(2,6-difluorophenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-
-benzothiadiazole 2,2-dioxide; [0468]
1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3
benzothiadiazol-1(3H)-yl]methyl}phenyl)-N-methylmethanamine; [0469]
1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)methanamine; [0470]
1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)-N,N-dimethylmethanamine; [0471]
1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)-N,N-dimethylmethanamine; [0472]
1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)methanamine; [0473]
1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)-N-methylmethanamine; [0474]
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]-N-methylbut-2-en-1-amine; [0475]
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]but-2-en-1-amine; [0476]
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]-N,N-dimethylbut-2-en-1-amine; [0477]
(2Z)-N-ethyl-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadi-
azol-1(3H)-yl]but-2-en-1-amine; [0478]
1-(3,4-difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide; [0479]
1-(3,4-difluorophenyl)-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide; [0480]
1-(3,4-difluorophenyl)-3-[3-(3,5-dimethylpiperazin-1-yl)propyl]-1,3-dihyd-
ro-2,1,3-benzothiadiazole 2,2-dioxide; [0481]
2-{2-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N-methylethanamine; [0482]
1-(2-piperazin-1-ylethyl)-3-(2,3,4-trifluorophenyl)-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide; [0483]
1-(2-methylphenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide; [0484]
1-(2-chlorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide; [0485]
2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N-methylethanamine; [0486]
2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}ethanamine; [0487]
2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N,N-dimethylethanamine; [0488]
(2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylbut-2-en-1-amine; [0489]
(2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N,N-dimethylbut-2-en-1-amine; [0490]
(2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]but-2-en-1-amine; [0491]
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]ethoxy}ethyl)cyclopropanamine; [0492]
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]ethoxy}ethyl)cyclobutanamine; [0493]
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]ethoxy}ethyl)cyclopentanamine; [0494]
2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N-methylethanamine; [0495]
2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N-ethylethanamine; [0496]
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]ethoxy}ethyl)propan-2-amine; [0497]
1-(4-chlorophenyl)-3-(4-morpholin-4-ylbutyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide; [0498]
1-(2-Fluorophenyl)-4-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide; [0499]
1-(2-Fluorophenyl)-4-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide; [0500]
1-(2-Fluorophenyl)-5-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide; [0501]
1-(2-Fluorophenyl)-5-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide; [0502]
1-(2-Fluorophenyl)-6-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide; [0503]
1-(2-Fluorophenyl)-6-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide; [0504]
1-(2-Fluorophenyl)-7-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide; [0505]
1-(2-Fluorophenyl)-7-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide; [0506]
1-(2,6-Difluorophenyl)-4-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide; [0507]
1-(2,6-Difluorophenyl)-4-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide; [0508]
1-(2,6-Difluorophenyl)-5-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide; [0509]
1-(2,6-Difluorophenyl)-5-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide; [0510]
1-(2,6-Difluorophenyl)-6-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide; [0511]
1-(2,6-Difluorophenyl)-6-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide; [0512]
1-(2,6-Difluorophenyl)-7-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide; [0513]
1-(2,6-Difluorophenyl)-7-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide; and
[0514] pharmaceutically acceptable salts thereof.
[0515] Another aspect of the invention provides a compound of
formula II:
##STR00021## [0516] or a pharmaceutically acceptable salt,
stereoisomer or tautomer thereof;
[0517] wherein:
[0518] n is an integer from 0 to 4;
[0519] m is an integer from 1 to 6;
[0520] X is, independently at each occurrence, C(R.sup.7).sub.2,
N(R.sup.3), O, S, S(.dbd.O), or S(.dbd.O).sub.2;
[0521] Z is O, N(R.sup.3), S, or C(R.sup.7).sub.2;
[0522] R.sup.1 is, independently at each occurrence, H, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, alkynyl, aryl substituted with 0-3 R.sup.11,
heteroaryl substituted with 0-3 R.sup.11, alkylsulfoxide,
alkylsulfone, alkylsulfonamide, arylsulfonamide substituted with
0-3 R.sup.5, alkylamido, or arylamido substituted with 0-3
R.sup.5;
[0523] R.sup.2 is aryl substituted with 0-3 R.sup.9 or heteroaryl
substituted with 0-3 R.sup.9;
[0524] R.sup.3 is, independently at each occurrence, H,
C.sub.1-C.sub.4 alkyl, aryl substituted with 0-3 R.sup.12, or
heteroaryl substituted with 0-3 R.sup.12;
[0525] R.sup.4 is H, C.sub.1-C.sub.6 alkyl, arylalkyl substituted
with 0-3 R.sup.13 or heteroarylmethyl substituted with 0-3
R.sup.13;
[0526] R.sup.5 is, independently at each occurrence, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
or alkylamido;
[0527] R.sup.6a is H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6
alkoxy, halo, aryl substituted with 0-3 R.sup.1, heteroaryl
substituted with 0-3 R.sup.1, --N(R.sup.3).sub.2, --S(R.sup.3), or
--R.sup.8--O--R.sup.3;
[0528] R.sup.7 is, independently at each occurrence, H, hydroxy,
C.sub.1-C.sub.6 alkoxy, or C.sub.1-C.sub.4 alkyl;
[0529] R.sup.8 is, independently at each occurrence, straight or
branched C.sub.1-C.sub.6 alkylenyl;
[0530] or
[0531] one of said R.sup.3 and one of said R.sup.4, together with
the nitrogen and carbon atoms through which they are attached, form
a monocyclic or bicyclic heterocyclic ring of 3 to 12 ring atoms,
where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two C.sub.1-C.sub.4 alkyl, F, or CF.sub.3;
and where any additional N atom may be optionally substituted with
C.sub.1-C.sub.4 alkyl;
[0532] R.sup.9 is, independently at each occurrence, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, alkynyl, aryl substituted with 0-3 R.sup.11, heteroaryl
substituted with 0-3 R.sup.11, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, arylsulfonamide, alkylamido, or arylamido;
[0533] R.sup.10 is, independently at each occurrence, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl;
[0534] R.sup.11 is, independently at each occurrence, alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro,
nitrile, alkenyl, or alkynyl;
[0535] R.sup.12 and R.sup.13 are each, independently at each
occurrence, alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxyalkyl,
aminoalkyl, a heterocyclic ring, alkanoyloxy, nitro, nitrile,
alkenyl, or alkynyl; and
[0536] wherein 1-3 carbon atoms in ring A may optionally be
replaced with N.
[0537] In another embodiment, Z is O.
[0538] In another embodiment, Z is N(R.sup.3).
[0539] In another embodiment, X is CH.sub.2 and m is 2 to 4.
[0540] In another embodiment:
[0541] ring A is composed of all carbon atoms;
[0542] R.sup.1 is H;
[0543] R.sup.2 is phenyl substituted with one to three fluoro (F)
atoms;
[0544] each R.sup.3 is H;
[0545] R.sup.4 is H; and
[0546] R.sup.6a is H.
[0547] In another embodiment, the compound is:
##STR00022## ##STR00023## ##STR00024##
[0548] Another aspect of the invention provides a compound selected
from the group consisting of: [0549]
1-(morpholin-2-ylmethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide; [0550]
1-[(2R)-morpholin-2-ylmethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide; [0551]
1-[(2S)-morpholin-2-ylmethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide; [0552]
1-[(4-methylmorpholin-2-yl)methyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide; [0553]
1-(2-chloro-4-fluorophenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethy-
l}-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide; [0554]
1-(2-chloro-4-fluorophenyl)-3-{2-piperazin-1-ylethyl}-1,3-dihydro-2,1,3-b-
enzothiadiazole-2,2-dioxide; [0555]
1-(4-fluoro-2-methylphenyl)-3-{2-piperazin-1-ylethyl}-1,3-dihydro-2,1,3-b-
enzothiadiazole-2,2-dioxide; [0556]
1-(4-fluoro-2-methylphenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethy-
l}-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide; [0557]
1-(4-fluoro-2-methoxyphenyl)-3-{2-piperazin-1-ylethyl}-1,3-dihydro-2,1,3--
benzothiadiazole-2,2-dioxide; [0558]
1-[2-(2,5-diazabicyclo[2.2.1]hept-2-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3--
benzothiadiazole 2,2-dioxide; [0559]
2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethox-
y}ethanamine; [0560]
2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethox-
y}-N-methylethanamine; [0561]
2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethox-
y}-N,N-dimethylethanamine; [0562]
1-{2-[2-(3,5-dimethylpiperazin-1-yl)ethoxy]ethyl}-3-(2-fluorophenyl)-1,3--
dihydro-2,1,3-benzothiadiazole 2,2-dioxide; [0563]
1-[5-(3,5-dimethylpiperazin-1-yl)pentyl]-3-(2-fluorophenyl)-1,3-dihydro-2-
,1,3-benzothiadiazole 2,2-dioxide; [0564]
(2R)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2--
methylpropan-1-amine; [0565]
(2S)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2--
methylpropan-1-amine; [0566]
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2--
amine; [0567]
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbutan-1-amine; [0568]
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbutan-2-amine; [0569]
(2R)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,-
2-dimethylpropan-1-amine; [0570]
(2S)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,-
2-dimethylpropan-1-amine; [0571]
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1--
amine; [0572]
1-Phenyl-3-(piperidin-4-ylmethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide; [0573]
1-(2,6-Difluorophenyl)-3-(morpholin-2-ylmethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide; [0574]
1-(2,6-Difluorophenyl)-3-[(2R)-morpholin-2-ylmethyl]-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide; [0575]
1-(2,6-Difluorophenyl)-3-[(2S)-morpholin-2-ylmethyl]-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide; [0576]
1-(2,3-Difluorophenyl)-3-(morpholin-2-ylmethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide; [0577]
1-(Morpholin-2-ylmethyl)-3-[2-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-
-benzothiadiazole 2,2-dioxide; [0578]
1-Phenyl-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide [0579]
1-Phenyl-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-
-dioxide; [0580]
4-Fluoro-3-phenyl-1-(piperidin-4-ylmethyl)-1,3-dihydro-2,1,3-benzothiadia-
zole-2,2-dioxide; [0581]
4-Fluoro-3-phenyl-1-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide; [0582]
4-Fluoro-3-phenyl-1-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadi-
azole-2,2-dioxide; [0583]
4-Fluoro-3-(morpholin-2-ylmethyl)-1-phenyl-1,3-dihydro-2,1,3-benzothiadia-
zole-2,2-dioxide; [0584]
1-Phenyl-3-(3-piperidin-4-ylpropyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,-
2-dioxide; [0585]
1-Phenyl-3-(2-piperidin-2-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-
-dioxide [0586]
1-(2,6-Difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide; [0587]
1-(2,6-Difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide; [0588]
1-Phenyl-3-(piperidin-3-ylmethyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2--
dioxide; [0589]
1-Phenyl-3-[(3R)-piperidin-3-ylmethyl]-1,3-dihydro-2,1,3-benzothiadiazole-
-2,2-dioxide; [0590]
1-Phenyl-3-[(3S)-piperidin-3-ylmethyl]-1,3-dihydro-2,1,3-benzothiadiazole-
-2,2-dioxide; [0591]
1-Phenyl-3-(2-piperidin-3-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-
-dioxide; [0592]
1-Phenyl-3-{2-[(3S)-piperidin-3-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiaz-
ole-2,2-dioxide; [0593]
1-Phenyl-3-{2-[(3R)-piperidin-3-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiaz-
ole-2,2-dioxide; [0594]
1-(2,3-Difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide; [0595]
1-(2,5-Difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide; [0596]
1-(2,3-Difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide; [0597]
1-(2,5-Difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide; [0598]
1-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-be-
nzothiadiazole-2,2-dioxide; [0599]
1-(2-Fluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole-2,2-dioxide; [0600]
1-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-(2-fluorophenyl)-1,3-dihydr-
o-2,1,3-benzothiadiazole-2,2-dioxide; [0601]
1-[3-(cis-3,5-Dimethylpiperazin-1-yl)propyl]-3-phenyl-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide; [0602]
1-(2,6-Difluorophenyl)-3-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-1,3-di-
hydro-2,1,3-benzothiadiazole-2,2-dioxide; [0603]
1-(2-piperazin-1-ylethyl)-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-ben-
zothiadiazole-2,2-dioxide; [0604]
1-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-(2,4,6-trifluorophenyl)-1,3-
-dihydro-2,1,3-benzothiadiazole-2,2-dioxide; [0605]
1-Phenyl-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,-
2-dioxide; [0606]
1-(4-Fluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole-2,2-dioxide; [0607]
1-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-(4-fluorophenyl)-1,3-dihydr-
o-2,1,3-benzothiadiazole-2,2-dioxide; [0608]
1-(2,4-difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide; [0609]
1-(2,4-difluorophenyl)-3-[2-(3,5-dimethylpiperazin-1-yl)ethyl]-1,3-dihydr-
o-2,1,3-benzothiadiazole-2,2-dioxide; [0610]
1-[2-(3,5-dimethylpiperazin-1-yl)ethyl]-4-fluoro-3-(2-fluorophenyl)-1,3-d-
ihydro-2,1,3-benzothiadiazole 2,2-dioxide; [0611]
1-(2-{[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
methyl}phenyl)-N-methylmethanamine; [0612]
3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethyl-1-phenylpropan-1-amine; [0613]
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
l-1-phenylpropan-1-amine; [0614]
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbut-2-yn-1-amine; [0615]
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dim-
ethylbut-2-yn-1-amine; [0616]
(2E)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N--
methylbut-2-en-1-amine; [0617]
(2E)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,-
N-dimethylbut-2-en-1-amine; [0618]
3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethyl}-4-fluoro-1-(2-fluoropheny-
l)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide; [0619]
2,2-difluoro-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]-N-methylpropan-1-amine; [0620]
1-(2-Fluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide; [0621]
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazol-
e-2,2-dioxide; [0622]
1-(2,4-Difluorophenyl)-4-fluoro-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1-
,3-benzothiadiazole-2,2-dioxide; [0623]
3-(2,4-Difluorophenyl)-4-fluoro-1-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1-
,3-benzothiadiazole-2,2-dioxide [0624]
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,-
3-benzothiadiazole-2,2-dioxide [0625]
1-{2-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]ethyl}-3-(2,4,6-trifluorop-
henyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide; [0626]
3-[2-(1,4-Diazepan-1-yl)ethyl]-1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydr-
o-2,1,3-benzothiadiazole 2,2-dioxide; [0627]
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide; [0628]
1-{2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl}-3-(2-fluorophenyl)--
1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide; [0629]
1-Phenyl-3-(2-piperidin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-
-dioxide; [0630]
1-(2,4-Difluorophenyl)-3-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-4-fluo-
ro-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide; [0631]
1-[3-(1,4-Diazepan-1-yl)propyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazo-
le-2,2-dioxide; [0632]
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-b-
enzothiadiazole-2,2-dioxide; [0633]
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-b-
enzothiadiazole-2,2-dioxide; [0634]
1-{2-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]ethyl}-3-(2,4-difluorophen-
yl)-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide; [0635]
1-(2,4-Difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole-2,2-dioxide; [0636]
1-(2,4-Difluorophenyl)-3-[2-(4-methylpiperazin-1-yl)ethyl]-1,3-dihydro-2,-
1,3-benzothiadiazole 2,2-dioxide; [0637]
1-(2,4-Difluorophenyl)-4-fluoro-3-[2-(4-methylpiperazin-1-yl)ethyl]-1,3-d-
ihydro-2,1,3-benzothiadiazole 2,2-dioxide; [0638]
1-(2,4-Difluorophenyl)-3-[2-(4-methyl-1,4-diazepan-1-yl)ethyl]-1,3-dihydr-
o-2,1,3-benzothiadiazole 2,2-dioxide; [0639]
1-[2-(4-Methyl-1,4-diazepan-1-yl)ethyl]-3-(2,4,6-trifluorophenyl)-1,3-dih-
ydro-2,1,3-benzothiadiazole 2,2-dioxide; [0640]
N-{2-[3-(2-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}-N,N'-dimethylethane-1,2-diamine; [0641]
N-{2-[3-(2,4-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thyl}-N,N'-dimethylethane-1,2-diamine; [0642]
N-{2-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-y-
l]ethyl}-N,N'-dimethylethane-1,2-diamine; [0643]
1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propy-
l}piperidin-4-amine; [0644]
1-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]piperidi-
n-4-amine; [0645]
1-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}piperidin-4-amine; [0646]
1-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}-N-methylpiperidin-4-amine; [0647]
1-{2-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperidin-
-4-amine; [0648]
1-{2-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}-N-methyl-
piperidin-4-amine; [0649]
1-{1-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]pyrrol-
idin-3-yl}methanamine; [0650]
1-phenyl-3-[2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethyl]-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide; [0651]
2-{2-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]ethoxy}-N-methylethanamine; [0652]
2-{2-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]ethoxy}-N,N-dimethylethanamine; [0653]
1-(4-chloro-2-fluorophenyl)-3-(2-piperazin-1-yl-ethyl)-1,3-dihydro-2,1,3--
benzothiadiazole 2,2-dioxide; [0654]
1-(4-chloro-2-fluorophenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethy-
l}-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide; [0655]
1-(4-chloro-2-fluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide; [0656]
1-(4-chloro-2-methylphenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethy-
l}-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide; [0657]
1-(4-chloro-2-methylphenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide; [0658]
1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)butan-2-one; [0659]
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino-
)butan-2-one; [0660]
1-(cyclopropylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)--
yl)butan-2-one; [0661]
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)bu-
tan-2-one; [0662]
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(meth-
ylamino)butan-2-one; [0663]
(2Z)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylami-
no)butan-2-one oxime; [0664]
(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2--
methoxy-N-methylbutan-1-amine; [0665]
(2S)-2-methoxy-N-methyl-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothia-
diazol-1(3H)-yl]butan-1-amine; [0666]
(2S)-2-methoxy-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1-
(3H)-yl]-N-methylbutan-1-amine; [0667]
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-methoxy-N-methy-
lbutan-1-amine; [0668]
(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-methoxy-N--
methylbutan-1-amine; [0669]
(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-methoxy-N--
methylbutan-1-amine; [0670]
N-{(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-2-methoxybutyl}cyclopropanamine; [0671]
N-{(2S)-2-methoxy-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
-1(3H)-yl]butyl}cyclopropanamine; [0672]
N-{(2S)-2-methoxy-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazo-
l-1(3H)-yl]butyl}cyclopropanamine; [0673]
N-{(2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]-2-methoxybutyl}cyclopropanamine; [0674]
N-{(2S)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]-2-methoxybutyl}cyclopropanamine; [0675]
N-{(2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]-2-methoxybutyl}cyclopropanamine; [0676]
2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-2-methoxy-N-methylbutan-1-amine; [0677]
(2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-2-methoxy-N-methylbutan-1-amine; [0678]
1-(2-morpholin-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide; [0679]
1-{2-[(2S)-morpholin-2-yl]ethyl}-3-phenyl-1,3-dihydro-2,1,3-benzothiadiaz-
ole 2,2-dioxide; [0680]
1-{2-[(2R)-morpholin-2-yl]ethyl}-3-phenyl-1,3-dihydro-2,1,3-benzothiadiaz-
ole 2,2-dioxide; [0681]
1-(4-fluorophenyl)-3-(2-morpholin-2-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide; [0682]
1-(4-fluorophenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide; [0683]
1-(4-fluorophenyl)-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide; [0684]
1-(2,4-difluorophenyl)-3-(2-morpholin-2-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide; [0685]
1-(2,4-difluorophenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-
-benzothiadiazole 2,2-dioxide; [0686]
1-(2,4-difluorophenyl)-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-
-benzothiadiazole 2,2-dioxide; [0687]
1-(2-morpholin-2-ylethyl)-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide; [0688]
1-{2-[(2S)-morpholin-2-yl]ethyl}-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,-
1,3-benzothiadiazole 2,2-dioxide;
[0689]
1-{2-[(2R)-morpholin-2-yl]ethyl}-3-(2,4,6-trifluorophenyl)-1,3-dih-
ydro-2,1,3-benzothiadiazole 2,2-dioxide; [0690]
1-(3-methoxyphenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide; [0691]
1-(3-methoxyphenyl)-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide; [0692]
1-(2-fluorophenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide; [0693]
1-(2-fluorophenyl)-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide; [0694]
1-(2,6-difluorophenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-
-benzothiadiazole 2,2-dioxide; [0695]
1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3
benzothiadiazol-1(3H)-yl]methyl}phenyl)-N-methylmethanamine; [0696]
1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)methanamine; [0697]
1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)-N,N-dimethylmethanamine; [0698]
1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)-N,N-dimethylmethanamine; [0699]
1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)methanamine; [0700]
1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)-N-methylmethanamine; [0701]
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]-N-methylbut-2-en-1-amine; [0702]
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]but-2-en-1-amine; [0703]
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]-N,N-dimethylbut-2-en-1-amine; [0704]
(2Z)-N-ethyl-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadi-
azol-1(3H)-yl]but-2-en-1-amine; [0705]
1-(3,4-difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide; [0706]
1-(3,4-difluorophenyl)-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide; [0707]
1-(3,4-difluorophenyl)-3-[3-(3,5-dimethylpiperazin-1-yl)propyl]-1,3-dihyd-
ro-2,1,3-benzothiadiazole 2,2-dioxide; [0708]
2-{2-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N-methylethanamine; [0709]
1-(2-piperazin-1-ylethyl)-3-(2,3,4-trifluorophenyl)-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide; [0710]
1-(2-methylphenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide; [0711]
1-(2-chlorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide; [0712]
2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N-methylethanamine; [0713]
2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}ethanamine; [0714]
2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N,N-dimethylethanamine; [0715]
(2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylbut-2-en-1-amine; [0716]
(2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N,N-dimethylbut-2-en-1-amine; [0717]
(2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]but-2-en-1-amine; [0718]
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]ethoxy}ethyl)cyclopropanamine; [0719]
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]ethoxy}ethyl)cyclobutanamine; [0720]
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]ethoxy}ethyl)cyclopentanamine; [0721]
2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N-methylethanamine; [0722]
2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N-ethylethanamine; [0723]
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]ethoxy}ethyl)propan-2-amine; [0724]
1-(4-chlorophenyl)-3-(4-morpholin-4-ylbutyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide; [0725]
1-(2-Fluorophenyl)-4-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide; [0726]
1-(2-Fluorophenyl)-4-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide; [0727]
1-(2-Fluorophenyl)-5-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide; [0728]
1-(2-Fluorophenyl)-5-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide; [0729]
1-(2-Fluorophenyl)-6-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide; [0730]
1-(2-Fluorophenyl)-6-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide; [0731]
1-(2-Fluorophenyl)-7-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide; [0732]
1-(2-Fluorophenyl)-7-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide; [0733]
1-(2,6-Difluorophenyl)-4-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide; [0734]
1-(2,6-Difluorophenyl)-4-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide; [0735]
1-(2,6-Difluorophenyl)-5-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide; [0736]
1-(2,6-Difluorophenyl)-5-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide; [0737]
1-(2,6-Difluorophenyl)-6-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide; [0738]
1-(2,6-Difluorophenyl)-6-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide; [0739]
1-(2,6-Difluorophenyl)-7-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide; [0740]
1-(2,6-Difluorophenyl)-7-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide; and
[0741] pharmaceutically acceptable salts thereof.
[0742] Another aspect of the invention provides a composition,
comprising:
[0743] a. at least one compound of formula I or formula II; and
[0744] b. at least one pharmaceutically acceptable carrier.
[0745] Another aspect of the invention provides a method for
treating or preventing a condition selected from the group
consisting of a vasomotor symptom, sexual dysfunction,
gastrointestinal disorder, genitourinary disorder, chronic fatigue
syndrome, fibromyalgia syndrome, depression disorder, diabetic
neuropathy, endogenous behavioral disorder, cognitive disorder,
pain, and combinations thereof in a subject in need thereof,
comprising the step of: [0746] administering to said subject an
effective amount of a compound of formula I or formula II.
[0747] In certain embodiments, the vasomotor symptom is hot
flush.
[0748] In certain embodiments, the sexual dysfunction is
desire-related or arousal-related.
[0749] In certain embodiments, the gastrointestinal disorder or the
genitourinary disorder is stress incontinence or urge
incontinence.
[0750] In certain embodiments, the condition is chronic fatigue
syndrome.
[0751] In certain embodiments, the condition is fibromyalgia
syndrome.
[0752] In certain embodiments, the condition is a depression
disorder selected from the group consisting of major depressive
disorder, generalized anxiety disorder, panic disorder, attention
deficit disorder with or without hyperactivity, sleep disturbance,
social phobia, and combinations thereof.
[0753] In certain embodiments, the disorder is an endogenous
behavioral disorder or a cognitive disorder.
[0754] In certain embodiments, the condition is diabetic
neuropathy.
[0755] In certain embodiments, the condition is pain.
[0756] In certain embodiments, the pain is acute centralized pain,
acute peripheral pain, or a combination thereof.
[0757] In certain embodiments, the pain is chronic centralized
pain, chronic peripheral pain, or a combination thereof.
[0758] In certain embodiments, the pain is neuropathic pain,
visceral pain, musculoskeletal pain, bony pain, cancer pain,
inflammatory pain, or a combination thereof.
[0759] In certain embodiments, the neuropathic pain is associated
with diabetes, post traumatic pain of amputation, lower back pain,
cancer, chemical injury, toxins, major surgery, peripheral nerve
damage due to traumatic injury compression, post-herpetic
neuralgia, trigeminal neuralgia, lumbar or cervical
radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex
sympathetic dystrophy, casualgia, thalamic syndrome, nerve root
avulsion, reflex sympathetic dystrophy or post thoracotomy pain,
nutritional deficiencies, viral infection, bacterial infection,
metastatic infiltration, adiposis dolorosa, burns, central pain
conditions related to thalamic conditions, or a combination
thereof.
[0760] In certain embodiments, the neuropathic pain is
post-herpetic neuralgia.
[0761] In certain embodiments, the visceral pain is associated with
ulcerative colitis, irritable bowel syndrome, irritable bladder,
Crohn's disease, rheumatologic (arthralgias), tumors, gastritis,
pancreatitis, infections of the organs, biliary tract disorders, or
a combination thereof.
[0762] In certain embodiments, the pain is female-specific
pain.
[0763] The present invention provides a treatment for vasomotor
symptoms by methods of recovering the reduced activity of
norepinephrine. Without wishing to be bound by any theory,
norepinephrine activity in the hypothalamus or in the brainstem can
be elevated by (i) blocking the activity of the NE transporter,
(ii) blocking the activity of the presynaptic adrenergic
.sub..alpha.2 receptor with an antagonist, or (iii) blocking the
activity of 5-HT on NE neurons with a 5-HT.sub.2a antagonist.
[0764] The compounds of the invention are also useful to prevent
and treat pain. The pain may be, for example, acute pain or chronic
pain. The pain may also be centralized or peripheral.
[0765] Examples of pain that can be acute or chronic and that can
be treated in accordance with the methods of the present invention
include inflammatory pain, musculoskeletal pain, bony pain,
lumbosacral pain, neck or upper back pain, visceral pain, somatic
pain, neuropathic pain, cancer pain, pain caused by injury or
surgery such as burn pain or dental pain, or headaches such as
migraines or tension headaches, or combinations of these pains. One
skilled in the art will recognize that these pains may overlap one
another. For example, a pain caused by inflammation may also be
visceral or musculoskeletal in nature.
[0766] In a preferred embodiment of the present invention the
compounds useful in the present invention are administered in
mammals to treat chronic pain such as neuropathic pain associated
for example with damage to or pathological changes in the
peripheral or central nervous systems; cancer pain; visceral pain
associated with for example the abdominal, pelvic, and/or perineal
regions or pancreatitis; musculoskeletal pain associated with for
example the lower or upper back, spine, fibromyalgia,
temporomandibular joint, or myofascial pain syndrome; bony pain
associated with for example bone or joint degenerating disorders
such as osteoarthritis, rheumatoid arthritis, or spinal stenosis;
headaches such migraine or tension headaches; or pain associated
with infections such as HIV, sickle cell anemia, autoimmune
disorders, multiple sclerosis, or inflammation such as
osteoarthritis or rheumatoid arthritis.
[0767] In a more preferred embodiment, the compounds useful in this
invention are used to treat chronic pain that is neuropathic pain,
visceral pain, musculoskeletal pain, bony pain, cancer pain or
inflammatory pain or combinations thereof, in accordance with the
methods described herein. Inflammatory pain can be associated with
a variety of medical conditions such as osteoarthritis, rheumatoid
arthritis, surgery, or injury. Neuropathic pain may be associated
with for example diabetic neuropathy, peripheral neuropathy,
post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical
radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex
sympathetic dystrophy, casualgia, thalamic syndrome, nerve root
avulsion, or nerve damage cause by injury resulting in peripheral
and/or central sensitization such as phantom limb pain, reflex
sympathetic dystrophy or postthoracotomy pain, cancer, chemical
injury, toxins, nutritional deficiencies, or viral or bacterial
infections such as shingles or HIV, or combinations thereof. The
methods of use for compounds of this invention further include
treatments in which the neuropathic pain is a condition secondary
to metastatic infiltration, adiposis dolorosa, burns, or central
pain conditions related to thalamic conditions.
[0768] As mentioned previously, the methods of the present
invention may be used to treat pain that is somatic and/or visceral
in nature. For example, somatic pain that can be treated in
accordance with the methods of the present invention include pains
associated with structural or soft tissue injury experienced during
surgery, dental procedures, burns, or traumatic body injuries.
Examples of visceral pain that can be treated in accordance with
the methods of the present invention include those types of pain
associated with or resulting from maladies of the internal organs
such as ulcerative colitis, irritable bowel syndrome, irritable
bladder, Crohn's disease, rheumatologic (arthralgias), tumors,
gastritis, pancreatitis, infections of the organs, or biliary tract
disorders, or combinations thereof. One skilled in the art will
also recognize that the pain treated according to the methods of
the present invention may also be related to conditions of
hyperalgesia, allodynia, or both. Additionally, the chronic pain
may be with or without peripheral or central sensitization.
[0769] The compounds useful in this invention may also be used to
treat acute and/or chronic pain associated with female conditions,
which may also be referred to as female-specific pain. Such groups
of pain include those that are encountered solely or predominately
by females, including pain associated with menstruation, ovulation,
pregnancy or childbirth, miscarriage, ectopic pregnancy, retrograde
menstruation, rupture of a follicular or corpus luteum cyst,
irritation of the pelvic viscera, uterine fibroids, adenomyosis,
endometriosis, infection and inflammation, pelvic organ ischemia,
obstruction, intra-abdominal adhesions, anatomic distortion of the
pelvic viscera, ovarian abscess, loss of pelvic support, tumors,
pelvic congestion or referred pain from non-gynecological
causes.
[0770] Another aspect of the invention provides a process for the
preparation of a compound of formula I:
[0771] the process comprising:
[0772] (d) reacting a compound of formula IA:
##STR00025##
[0773] with a compound of formula IB:
##STR00026##
[0774] wherein,
[0775] T is an --N(R.sup.4).sub.2 or an activating group;
[0776] wherein,
[0777] if T is --N(R.sup.4).sub.2, then the compound of formula I
is formed; or
[0778] if T is an activating group, then a compound of formula IC
is formed:
##STR00027##
[0779] and the process further comprises:
[0780] (e) reacting the compound formula IC with
--N(R.sup.4)R.sup.P to form a compound of formula ID:
##STR00028##
[0781] wherein,
[0782] R.sup.P is R.sup.4 or a protecting group;
[0783] wherein,
[0784] if R.sup.P is R.sup.4, the compound of formula I is formed;
or
[0785] if R.sup.P is a protecting group, the process further
comprises:
[0786] (f) deprotecting the compound of formula ID to form a
deprotected compound; and
[0787] (g) reacting the deprotected compound with an
activated-R.sup.4 group,
[0788] provided that R.sup.4 in the activated-R.sup.4 group is not
H;
[0789] wherein the compound of formula I is formed.
[0790] In another embodiment, step (d) further comprises contacting
the compound of formula IA and IB with dialkyl azodicarboxylate and
triphenylphosphine.
[0791] In another embodiment, the dialkyl azodicarboxylate is
diisopropyl azodicarboxylate.
[0792] In another embodiment, the activating group is selected from
the group consisting of halo, tosylate, mesylate, triflate, and
oxo.
[0793] In another embodiment, the activating group is Br.
[0794] In another embodiment, the protecting group is selected from
the group consisting of BOC, benzyl, acetyl, PMB, alkyl, Fmoc, Cbz,
trifluoroacetyl, tosyl and triphenylmethyl.
[0795] In another embodiment, the protecting group is BOC.
[0796] In another embodiment, the deprotecting step is performed in
the presence of at least one agent selected from hydrochloric acid
(HCl), tin(II)chloride, ammonium chloride, zinc, trifluoroacetic
acid (TFA), tosic acid, a halotrimethylsilane, or aluminum
chloride.
[0797] In another embodiment, any one of steps (d)-(g) is performed
at or above 30.degree. C. or any one of steps (d)-(g) includes a
purification step comprising at least one of: filtration,
extraction, chromatography, trituration, or recrystallization.
[0798] In another embodiment, the activated-R.sup.4 group is
halo-R.sup.4 or O.dbd.R.sup.4.
[0799] In another aspect of the invention, the compound of formula
IA is prepared by: [0800] (a) reacting a compound of formula
IE:
##STR00029##
[0801] wherein R.sup.B is F or Cl;
[0802] with R.sup.2--NH.sub.2 to form a compound of formula IF:
##STR00030## [0803] (b) hydrogenating the compound of formula IF to
form a compound of formula IG:
[0803] ##STR00031## [0804] and (c) reacting the compound of formula
IG with sulfamide in diglyme to form the compound of formula
IA.
[0805] In another embodiment, the hydrogenating step is performed
in the presence of hydrogen (H.sub.2) and Pd/C.
[0806] In another embodiment, any one of steps (a)-(c) is performed
at or above 30.degree. C.
[0807] In another embodiment, any one of steps (a)-(c) includes a
purification step comprising at least one of: filtration,
extraction, chromatography, trituration, or recrystallization.
[0808] Another aspect of the invention provides a process for the
preparation of a compound of formula I:
##STR00032## [0809] or a pharmaceutically acceptable salt,
stereoisomer or tautomer thereof; [0810] wherein: [0811] n is an
integer from 0 to 4; [0812] m is an integer from 0 to 6; [0813] X
is, independently at each occurrence, C(R.sup.7).sub.2, N(R.sup.3),
O, S, S(.dbd.O), or S(.dbd.O).sub.2; [0814] Y is C; or [0815] Y and
an adjacent X together form --CR.sup.7.dbd.CR.sup.7--,
--C.ident.C--, or arylenyl substituted with 0-3 R.sup.10; [0816]
R.sup.1 is, independently at each occurrence, H, alkyl, alkoxy,
halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile,
alkenyl, alkynyl, aryl substituted with 0-3 R.sup.11, heteroaryl
substituted with 0-3 R.sup.11, alkylsulfoxide, alkylsulfone,
alkylsulfonamide, arylsulfonamide substituted with 0-3 R.sup.5,
alkylamido, or arylamido substituted with 0-3 R.sup.5; [0817]
R.sup.2 is aryl substituted with 0-3 R.sup.9 or heteroaryl
substituted with 0-3 R.sup.9; [0818] R.sup.3 is, independently at
each occurrence, H, halo, hydroxy, alkyl substituted with 0-3
R.sup.13, a heterocyclic ring, aryl substituted with 0-3 R.sup.12,
or heteroaryl substituted with 0-3 R.sup.12; [0819] R.sup.4 is,
independently at each occurrence, H, alkyl substituted with 0-3
R.sup.13, arylalkyl substituted with 0-3 R.sup.13 or
heteroarylmethyl substituted with 0-3 R.sup.13; [0820] R.sup.5 is,
independently at each occurrence, alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido;
[0821] R.sup.6 is, independently at each occurrence, H, hydroxy,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkoxy, halo, aryl
substituted with 0-3 R.sup.1, heteroaryl substituted with 0-3
R.sup.1, --N(R.sup.3).sub.2, --S(R.sup.3), or
--R.sup.8--O--R.sup.3; or both R.sup.6 groups form a cycloalkyl, a
heterocyclic ring, .dbd.O or .dbd.N--OH; [0822] provided that if
each R.sup.3 is H, each X is CH.sub.2, and either each R.sup.6 is H
or one R.sup.6 is hydroxy; then, both of said R.sup.4, together
with the nitrogen through which they are attached, form a
monocyclic or bicyclic heterocyclic ring of 3 to 12 ring atoms,
where one carbon may be optionally replaced with N, O, S, or
SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, hydroxyalkyl, aminoalkyl, or a
heterocyclic ring, F, or CF.sub.3; and where any additional N atom
may be optionally substituted with C.sub.1-C.sub.4 alkyl; [0823]
R.sup.7 is, independently at each occurrence, H, hydroxy, alkoxy,
or C.sub.1-C.sub.4 alkyl; [0824] R.sup.8 is, independently at each
occurrence, straight or branched alkylenyl; [0825] or [0826] one of
said R.sup.3 and one of said R.sup.4, together with the nitrogen
and carbon atoms through which they are attached, form a monocyclic
or bicyclic heterocyclic ring of 3 to 12 ring atoms, where one
carbon may be optionally replaced with N, O, S, or SO.sub.2, and
where any carbon ring atom may be optionally substituted with one
or two alkyl, F, or CF.sub.3; and where any additional N atom may
be optionally substituted with alkyl; [0827] or [0828] both of said
R.sup.4, together with the nitrogen through which they are
attached, form a monocyclic or bicyclic heterocyclic ring of 3 to
12 ring atoms, where one carbon may be optionally replaced with N,
O, S, or SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two alkyl, hydroxyalkyl, aminoalkyl, a
heterocyclic ring, F, or CF.sub.3; and where any additional N atom
may be optionally substituted with alkyl; [0829] or [0830] one of
said R.sup.6 or one of said R.sup.7 and one of said R.sup.4,
together with the nitrogen and carbon atoms through which they are
attached, form a monocyclic or bicyclic heterocyclic ring of 3 to
12 ring atoms, where one carbon may be optionally replaced with N,
O, S, or SO.sub.2, and where any carbon ring atom may be optionally
substituted with one or two C.sub.1-C.sub.4 alkyl, F, or CF.sub.3;
and where any additional N atom may be optionally substituted with
C.sub.1-C.sub.4 alkyl; provided that R.sup.4 and R.sup.7, taken
together, do not form a piperidinyl ring; [0831] R.sup.9 is,
independently at each occurrence, alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl,
aryl substituted with 0-3 R.sup.11, heteroaryl substituted with 0-3
R.sup.11, alkylsulfoxide, alkylsulfone, alkylsulfonamide,
arylsulfonamide, alkylamido, or arylamido; [0832] R.sup.10 is,
independently at each occurrence, alkyl, alkoxy, halo, CF.sub.3,
OCF.sub.3, hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl; [0833] R.sup.11 is, independently at each occurrence,
alkyl, alkoxy, halo, CF.sub.3, OCF.sub.3, hydroxy, alkanoyloxy,
nitro, nitrile, alkenyl, or alkynyl; [0834] R.sup.12 and R.sup.13
are each, independently at each occurrence, alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, hydroxy, hydroxyalkyl, aminoalkyl, a
heterocyclic ring, alkanoyloxy, nitro, nitrile, alkenyl, or
alkynyl; and
[0835] wherein 1-3 carbon atoms in ring A may optionally be
replaced with N;
[0836] the process comprising: [0837] (d) reacting
R.sup.2(BOH).sub.2 and a transitional metal salt with a compound of
formula IH:
##STR00033##
[0838] wherein,
[0839] R.sup.P is R.sup.4 or a protecting group; and
[0840] if R.sup.P is R.sup.4, the compound of formula I is formed;
or
[0841] if R.sup.P is a protecting group, the process further
comprises: [0842] (e) deprotecting the compound of formula IH to
form a deprotected compound; and [0843] (g) reacting the
deprotected compound with an activated-R.sup.4 group, provided that
R.sup.4 group in the activated-R.sup.4 group is not H;
[0844] wherein the compound of formula I is formed.
[0845] In another embodiment, the transitional metal salt is
copper(II)acetate.
[0846] In another embodiment, the activated-R.sup.4 group is
halo-R.sup.4 or O.dbd.R.sup.4.
[0847] In another embodiment, the protecting group is selected from
the group consisting of BOC, benzyl, acetyl, PMB, alkyl, Fmoc, Cbz,
trifluoroacetyl, tosyl and triphenylmethyl.
[0848] In another embodiment, the protecting group is BOC.
[0849] In another embodiment, the deprotecting step is performed in
the presence of at least one agent selected from hydrochloric acid
(HCl), tin(II)chloride, ammonium chloride, zinc, trifluoroacetic
acid (TFA), tosic acid, a halotrimethylsilane, or aluminum
chloride.
[0850] In another embodiment, any one of steps (d)-(g) is performed
at or above 30.degree. C. or any one of steps (d)-(g) includes a
purification step comprising at least one of: filtration,
extraction, chromatography, trituration, or recrystallization.
[0851] In another embodiment, the compound of formula IH is
prepared by: [0852] (a) reacting a compound of formula IJ:
##STR00034##
[0853] wherein R.sup.B is F or Cl;
[0854] with a compound of formula IK:
##STR00035##
[0855] to form a compound of formula IL:
##STR00036## [0856] (b) hydrogenating the compound of formula IL to
form a compound of formula IM:
[0856] ##STR00037## [0857] and (c) reacting the compound of formula
IM with sulfamide and diglyme to form the compound of formula
IH.
[0858] In another embodiment, the hydrogenating step is performed
in the presence of hydrogen (H.sub.2) and Pd/C.
[0859] In another embodiment, any one of steps (a)-(c) is performed
at or above 30.degree. C.
[0860] In another embodiment, any one of steps (a)-(c) includes a
purification step comprising at least one of: filtration,
extraction, chromatography, trituration, or recrystallization.
[0861] Some of the compounds of the present invention may contain
chiral centers and such compounds may exist in the form of
stereoisomers (i.e. enantiomers or diastereomers). The present
invention includes all such stereoisomers and any mixtures thereof
including racemic mixtures. Racemic mixtures of the stereoisomers
as well as the substantially pure stereoisomers are within the
scope of the invention. The term "substantially pure," as used
herein, refers to at least about 90 mole %, more preferably at
least about 95 mole %, and most preferably at least about 98 mole %
of the desired stereoisomer is present relative to other possible
stereoisomers. Preferred enantiomers may be isolated from racemic
mixtures by any method known to those skilled in the art, including
high performance liquid chromatography (HPLC) and the formation and
crystallization of chiral salts or prepared by methods described
herein. See, for example, Jacques, et al., Enantiomers, Racemates
and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H.,
et al., Tetrahedron, 33:2725 (1977); Eliel, E. L. Stereochemistry
of Carbon Compounds, (McGraw-Hill, NY, 1962); Wilen, S. H. Tables
of Resolving Agents and Optical Resolutions, p. 268 (E. L. Eliel,
Ed., University of Notre Dame Press, Notre Dame, Ind. 1972), the
entire disclosures of which are herein incorporated by
reference.
[0862] The present invention includes prodrugs of the compounds of
formula I. "Prodrug," as used herein, means a compound which is
convertible in vivo by chemical or metabolic means (e.g. by
hydrolysis) to a compound of formula I. Various forms of prodrugs
are known in the art, for example, as discussed in Bundgaard,
(ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.),
Methods in Enzymology, vol. 4, Academic Press (1985);
Krogsgaard-Larsen, et al., (ed). "Design and Application of
Prodrugs," Textbook of Drug Design and Development, Chapter 5,
113-191 (1991), Bundgaard, et al., Journal of Drug Deliver Reviews,
1992, 8:1-38, Bundgaard, J. of Pharmaceutical Sciences, 1988,
77:285 et seq.; and Higuchi and Stella (eds.) Prodrugs as Novel
Drug Delivery Systems, American Chemical Society (1975), the entire
disclosures of which are herein incorporated by reference.
[0863] Further, the compounds of formula I may exist in unsolvated
as well as in solvated forms with pharmaceutically acceptable
solvents such as water, ethanol, and the like. In general, the
solvated forms are considered equivalent to the unsolvated forms
for the purpose of the present invention.
[0864] The compounds of the present invention may be prepared in a
number of ways well known to those skilled in the art. The
compounds can be synthesized, for example, by the methods described
below, or variations thereon as appreciated by the skilled artisan.
All processes disclosed in association with the present invention
are contemplated to be practiced on any scale, including milligram,
gram, multigram, kilogram, multikilogram or commercial industrial
scale.
[0865] As will be readily understood, functional groups present may
contain protecting groups during the course of synthesis.
Protecting groups are known per se as chemical functional groups
that can be selectively appended to and removed from
functionalities, such as hydroxyl groups and carboxyl groups. These
groups are present in a chemical compound to render such
functionality inert to chemical reaction conditions to which the
compound is exposed. Any of a variety of protecting groups may be
employed with the present invention. Protecting groups that may be
employed in accordance with the present invention may be described
in Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic
Synthesis 2d. Ed., Wiley & Sons, 1991, the entire disclosure of
which is herein incorporated by reference.
[0866] Compounds of the present invention are suitably prepared in
accordance with the following general description and specific
examples. Variables used are as defined for formula I, unless
otherwise noted. The reagents used in the preparation of the
compounds of this invention can be either commercially obtained or
can be prepared by standard procedures described in the literature.
In accordance with this invention, compounds of formula I may be
produced by the following reaction schemes (Schemes 1 and 2).
[0867] The compounds of this invention contain chiral centers,
providing for various stereoisomeric forms such as diastereomeric
mixtures, enantiomeric mixtures as well as optical isomers. The
individual optical isomers can be prepared directly through
asymmetric and/or stereospecific synthesis or by conventional
chiral separation of optical isomers from the enantiomeric
mixture.
##STR00038## ##STR00039##
[0868] Following Scheme 1, an appropriate fluoronitroarene 1 may be
substituted with an aryl amine using a base under standard
conditions to provide an aminonitroarene 2. Typically conditions
for this reaction a base such as sodium hydride in DMF or an
organometallic base such as butyllithium in THF. Reduction of the
nitro group in structure 2 is accomplished under standard
conditions using hydrogen and a suitable catalyst such as palladium
or Raney nickel to provide a dianiline 3. Nitro reduction is a
common transformation and one could employ a number of alternative
procedures including reduction conditions using metal salts such as
aqueous HCl with tin(II)chloride or aqueous ammonium chloride with
zinc metal. The dianiline 3 is then treated a suitable sulfate
containing reagent to form arylsulfamide of structure 4. In a
typical example, 3 was heated with sulfamide in diglyme to provide
the cyclized product 4. The acidic nitrogen is then combined with a
suitably substituted side chain providing products 5 or 6 defending
on the structure of the desired side chain. An effective method for
attaching the side chain to sulfamide 4 is the Mitsunobu reaction
in which an alcohol is activated and displaced by treating with a
phosphine and an activating reagent. In accordance with the
embodiment of the invention, typical conditions for effecting the
attachment of the sulfamide to the alcohol containing side chain
were treatment with diisopropyl azodicarboxylate and
triphenylphosphine in THF. Another suitable method for
accomplishing side chain attachment is direct nucleophilic
substitution of a leaving group containing side chain with the
sulfamide and can be facilitated by addition of a base in a
suitable solvent. Typically compounds of structure 5 with a bromine
containing side chain were treated with an excess of the desired
amine to provide the desired compounds of formula I. An alternative
method for the synthesis of compounds of formula I is possible from
6 where the side chain is attached with the amine present in
protected form (the protecting group is represented by the letter
P). Any suitable amine protecting group, t-butoxycarbonyl in a
typical example, may be used. The protecting group is then removed,
in the case of t-butoxycarbonyl using an acid such as hydrochloric
acid, to give compounds of formula I.
##STR00040## ##STR00041##
[0869] An additional method for the synthesis of compounds of
formula I is described in Scheme 2. An appropriate fluoronitroarene
is substituted with an amine bearing the desired side chain to give
compounds of structure 7. Reduction of the nitro group under
conditions described in Scheme 1 provides 8. Compounds of structure
8 can be converted to arylsulfamide of structure 9 by treatment
with a suitable sulfate containing reagent. In a typical example, 8
was heated with sulfamide in diglyme to provide the cyclized
product 9. An aryl group may then be attached to the sulfamide 9
using conventional methods for formation of an aryl-nitrogen bond.
In a typical example an aryl boronic acid forms an aryl-nitrogen
bond in the presence of a transition metal salt such as
copper(II)acetate to provide 6. Subsequent deprotection of the
protecting group P in 6 affords compounds of formula I. As
described in Scheme 1, the protecting group t-butoxycarbonyl was
useful for this purpose and is readily removed using an acid such
as hydrochloric acid to give compounds of formula I.
[0870] In other embodiments, the invention is directed to
pharmaceutical compositions, comprising: [0871] a. at least one
compound of formula I, or pharmaceutically acceptable salt thereof;
and [0872] b. at least one pharmaceutically acceptable carrier.
[0873] Generally, the compound of formula I, or a pharmaceutically
acceptable salt thereof, will be present at a level of from about
0.1%, by weight, to about 90% by weight, based on the total weight
of the pharmaceutical composition, based on the total weight of the
pharmaceutical composition. Preferably, the compound of formula I,
or a pharmaceutically acceptable salt thereof, will be present at a
level of at least about 1%, by weight, based on the total weight of
the pharmaceutical composition. More preferably, the compound of
formula I, or a pharmaceutically acceptable salt thereof, will be
present at a level of at least about 5%, by weight, based on the
total weight of the pharmaceutical composition. Even more
preferably, the compound of formula I, or a pharmaceutically
acceptable salt thereof will be present at a level of at least
about 10%, by weight, based on the total weight of the
pharmaceutical composition. Yet even more preferably, the compound
of formula I, or a pharmaceutically acceptable salt thereof, will
be present at a level of at least about 25%, by weight, based on
the total weight of the pharmaceutical composition.
[0874] Such compositions are prepared in accordance with acceptable
pharmaceutical procedures, such as described in Remington's
Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro,
Mack Publishing Company, Easton, Pa. (1985), the entire disclosure
of which is herein incorporated by reference. Pharmaceutically
acceptable carriers are those that are compatible with the other
ingredients in the formulation and biologically acceptable.
[0875] The compounds of this invention may be administered orally
or parenterally, neat or in combination with conventional
pharmaceutical carriers. Applicable solid carriers can include one
or more substances that may also act as flavoring agents,
lubricants, solubilizers, suspending agents, fillers, glidants,
compression aids, binders or tablet-disintegrating agents or an
encapsulating material. In powders, the carrier is a finely divided
solid that is in admixture with the finely divided active
ingredient. In tablets, the active ingredient is mixed with a
carrier having the necessary compression properties in suitable
proportions and compacted in the shape and size desired. The
powders and tablets preferably contain up to about 99% of the
active ingredient. Suitable solid carriers include, for example,
calcium phosphate, magnesium stearate, talc, sugars, lactose,
dextrin, starch, gelatin, cellulose, methyl cellulose, sodium
carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes
and ion exchange resins.
[0876] Liquid carriers may be used in preparing solutions,
suspensions, emulsions, syrups, and elixirs. The active ingredient
of this invention can be dissolved or suspended in a
pharmaceutically acceptable liquid carrier such as water, an
organic solvent, a mixture of both or pharmaceutically acceptable
oils or fat. The liquid carrier can contain other suitable
pharmaceutical additives such as solubilizers, emulsifiers,
buffers, preservatives, sweeteners, flavoring agents, suspending
agents, thickening agents, colors, viscosity regulators,
stabilizers, or osmo-regulators. Suitable examples of liquid
carriers for oral and parenteral administration include water
(particularly containing additives as above, e.g. cellulose
derivatives, preferably sodium carboxymethyl cellulose solution),
alcohols (including monohydric alcohols and polyhydric alcohols,
e.g. glycols) and their derivatives, and oils (e.g. fractionated
coconut oil and arachis oil). For parenteral administration, the
carrier can also be an oily ester such as ethyl oleate and
isopropyl myristate. Sterile liquid carriers are used in sterile
liquid form compositions for parenteral administration.
[0877] Liquid pharmaceutical compositions for parenteral
administration, which are sterile solutions or suspensions, can be
administered by, for example, intramuscular, intraperitoneal or
subcutaneous injection. Sterile solutions can also be administered
intravenously. Oral administration may be either liquid or solid
composition form.
[0878] Preferably the pharmaceutical composition is in unit dosage
form, e.g. as tablets, capsules, powders, solutions, suspensions,
emulsions, granules, or suppositories. In such form, the
composition is sub-divided in unit dose containing appropriate
quantities of the active ingredient; the unit dosage forms can be
packaged compositions, for example packeted powders, vials,
ampoules, prefilled syringes or sachets containing liquids. The
unit dosage form can be, for example, a capsule or tablet itself,
or it can be the appropriate number of any such compositions in
package form.
[0879] In another embodiment of the present invention, the
compounds useful in the present invention may be administered to a
mammal with one or more other pharmaceutical active agents such as
those agents being used to treat any other medical condition
present in the mammal. Examples of such pharmaceutical active
agents include pain relieving agents, anti-angiogenic agents,
anti-neoplastic agents, anti-diabetic agents, anti-infective
agents, or gastrointestinal agents, or combinations thereof.
[0880] The one or more other pharmaceutical active agents may be
administered in a therapeutically effective amount simultaneously
(such as individually at the same time, or together in a
pharmaceutical composition), and/or successively with one or more
compounds of the present invention.
[0881] The term "combination therapy" refers to the administration
of two or more therapeutic agents or compounds to treat a
therapeutic condition or disorder described in the present
disclosure, for example hot flush, sweating,
thermoregulatory-related condition or disorder, or other condition
or disorder. Such administration includes use of each type of
therapeutic agent in a concurrent manner. In either case, the
treatment regimen will provide beneficial effects of the drug
combination in treating the conditions or disorders described
herein.
[0882] The route of administration may be any enteral or parenteral
route which effectively transports the active compound of formula
I, or a pharmaceutically acceptable salt thereof, to the
appropriate or desired site of action; such as oral, nasal,
pulmonary, transdermal, such as passive or iontophoretic delivery,
or parenteral, e.g. rectal, depot, subcutaneous, intravenous,
intraurethral, intramuscular, intrathecal, intra-articular,
intranasal, ophthalmic solution or an ointment. Furthermore, the
administration of compound of formula I, or pharmaceutically
acceptable salt thereof, with other active ingredients may be
separate, consecutive or simultaneous.
[0883] The present invention is further defined in the following
Examples, in which all parts and percentages are by weight and
degrees are Celsius, unless otherwise stated. It should be
understood that these examples, while indicating preferred
embodiments of the invention, are given by way of illustration
only. From the above discussion and these examples, one skilled in
the art can ascertain the essential characteristics of this
invention, and without departing from the spirit and scope thereof,
can make various changes and modifications of the invention to
adapt it to various usages and conditions.
EXAMPLES
General Procedures
General Procedure I
Synthesis of 1-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
core
##STR00042##
[0885] Step 1: 2-Fluoroaniline (1.45 mL, 15 mmol) was dissolved in
DMF (10 mL) and sodium hydride (0.58 g, 15 mmol) was added and the
mixture was stirred for 30 minutes. 2-Fluoronitrobenzene (1.05 mL,
10 mmol) was added and the mixture was stirred for 16 hours. The
mixture was quenched with saturated NH.sub.4Cl and diluted with
ether. The mixture was washed with water, brine, dried over
anhydrous magnesium sulfate, and concentrated. The crude product
was purified via Isco chromatography (Redisep, silica, gradient
5-30% ethyl acetate in hexane) to afford 1.4 g
2-fluoro-N-(2-nitrophenyl)aniline that was carried on directly to
the next step. MS (ES) m/z 232.9.
[0886] Step 2: 2-fluoro-N-(2-nitrophenyl)aniline (1.4 g, 6.0 mmol)
was dissolved in ethyl acetate (20 mL) and 10% palladium on
activated carbon (150 mg) was added. The mixture was shaken under a
hydrogen atmosphere (40 psi) for 2 hours. The mixture was filtered
through a pad of Celite and concentrated to give
N-(2-fluorophenyl)benzene-1,2-diamine (1.2 g) that was carried on
directly to the next step.
[0887] MS (ES) m/z 203.0.
[0888] Step 3: Dry diglyme (10 mL) was added to a flask equipped
with a dropping funnel under a nitrogen atmosphere and brought to a
vigorous reflux N-(2-fluorophenyl)benzene-1,2-diamine (1.2 g, 6.0
mmol) and sulfamide (0.69 g, 7.2 mmol) were dissolved in 5 mL of
diglyme and placed in the dropping funnel. The mixture was added
dropwise to the flask over 15 minutes and then refluxing was
continued for an additional 15 minutes. The mixture was cooled to
ambient temperature and diluted with ether, washed with water, 2N
HCl, water, brine, dried over anhydrous magnesium sulfate, and
concentrated. The crude product was purified via Isco
chromatography (Redisep, silica, gradient 5-50% (ethyl acetate
containing 2% formic acid) in hexane) to afford
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.37 g).
[0889] MS (ES) m/z 263.0; HPLC purity 100.0% at 210-370 nm, 8.9
minutes; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for
10 minutes, hold 4 minutes.
General Procedure II
Installation of Boc-Protected Side-Chain and Deprotection
1-(2-morpholin-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide
##STR00043##
[0891] Step 1: To a solution of
1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (made
analogously as in general procedure I, 0.2 g, 0.8 mmol) in THF (10
mL) was added triphenylphosphine (0.26 g, 1 mmol), tert-butyl
2-(2-hydroxyethyl)morpholine-4-carboxylate (0.2 g, 0.9 mmol) and
DIAD (0.2 g, 1 mmol) at 0.degree. C. The mixture was allowed to
warm to ambient temperature overnight then concentrated and
chromatographed on silica gel (0 to 40% EtOAc in hexane).
[0892] Step 2: The resulting mostly pure carbamate was dissolved in
dichloromethane (10 mL) and treated with HCl (4 mL, 4M in dioxane).
The resulting salt was chromatographed on silica (0 to 100% of (7N
NH.sub.3/MeOH) in dichloromethane) giving the desired product as a
clear oil (0.23 g, 80%). HRMS: calcd for C18H21N3O3S+H+, 360.1376;
found (ESI, [M+H]+), 360.1377. HPLC purity 100% at 210-370 nm, 6.9
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4
min.
General Procedure III
Resolution of Racemic Agents
1-{2-[(2S)-morpholin-2-yl]ethyl}-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide
##STR00044##
[0894]
1-(2-morpholin-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazo-
le-2,2-dioxide was dissolved in methanol. 200 uL of the resulting
solution was repetitively injected onto the Supercritical Fluid
Chromatography instrument, and the baseline resolved enantiomers
were separately collected using the conditions described below. The
chiral purity of each enantiomer was determined under the same
Supercritical Fluid Chromatography conditions using a Chiralpak
AS-H 5 m, 250 mm.times.4.6 mm ID column at 2.0 mL/min flow rate
using Analytical Supercritical Fluid Chromatography (Berger
Instruments, Inc. Newark, Del.). Both enantiomers were found to be
>99.9% enantiomerically pure.
SFC Instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc.
Newark, Del.)
Column: Chiralpak AS-H; 5 m; 250 mm L.times.20 mm ID (Chiral
Technologies, Inc, Exton, Pa.)
[0895] Column temperature: 35.degree. C.
SFC Modifier: 18% MeOH w 0.2% DMEA
[0896] Flow rate: 50 mL/min
Outlet Pressure: 100 bar
Detector: UV at 220 nm.
[0897] HRMS: calcd for C18H21N3O3S+H+, 360.1376; found (ESI,
[M+H]+), 360.1378
[0898] HPLC purity 100% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min
General Procedure IV
Installation of Bromo-Substituted Side-Chain By Alkylation
##STR00045##
[0900] Cesium carbonate (0.29 g, 0.9 mmol) was added to a solution
of 1-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (Made analogously as in general procedure I, 0.25 g,
0.9 mmol), and 1,4-dibromobutane (0.42 mL, 3.6 mmol) in dry DMF
(5.0 mL) under nitrogen. After 3 h, the reaction mixture was
diluted with diethyl ether and washed with water and brine. The
ether layer was dried over magnesium sulfate, filtered and
concentrated in vacuo to give 0.41 g of crude product. The crude
product was pre-adsorbed onto Celite and purified via Isco
chromatography (Redisep, silica, gradient 5-30% ethyl acetate in
hexane) to afford 0.22 g (59%) of
1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide.
General Procedure V
Substitution of Bromo-Substituted Side-Chain with an Amine
1-(4-chlorophenyl)-3-(4-morpholin-4-ylbutyl)-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide
##STR00046##
[0902] Morpholine (2 mL, 23 mmol) was added to a round bottom flask
containing (50 mg, 0.12 mmol) of
1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (made in general procedure IV). The reaction flask was
covered with a septum and stirred overnight at room temperature.
The reaction solution was concentrated in vacuo and the crude
product was pre-adsorbed onto Celite and purified via Isco
chromatography (Redisep, silica, gradient 1-8% methanol in
dichloromethane with ammonia) to afford 29 mg (78%) of
1-(4-chlorophenyl)-3-(4-morpholin-4-ylbutyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 22-dioxide. HPLC purity 100.0% at 210-370 nm, 8.2 minutes;
Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes,
hold 4 minutes.
[0903] HRMS: calculated for
C.sub.20H.sub.24ClN.sub.3O.sub.3S+H.sup.+, 422.12996; found (ESI,
[M+H].sup.+), 422.1296.
General Procedure VI
Installation of Bromo-Substituted Side-Chain By Mitsunobu
##STR00047##
[0905]
1-(4-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared analogously as described in general procedure
I, 0.35 g, 1.3 mmol) was treated with triphenylphosphine (0.46 g,
1.5 mmol), 2-bromoethanol (0.21 g, 1.4 mmol) and
diisopropylazodicarboxylate (0.35 g, 1.7 mmol) to provide 0.32 g of
1-(2-bromoethyl)-3-(4-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 22-dioxide. HRMS: calculated for C15H14BrFN.sub.2O.sub.2S,
383.99434; found (EI, M+.), 383.9958
Examples
Example 1
1-(morpholin-2-ylmethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride
##STR00048##
[0907] Step 1: A mixture of
1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared
analogously as in general procedure I, 246 mg, 1.00 mmol),
tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (228 mg, 1.05
mmol, 1.05 equiv.) and triphenylphosphine (289 mg, 1.10 mmol, 1.1
equiv.) in tetrahydrofuran (5 mL) was cooled to 0.degree. C. in an
ice bath. Diispropyl azodicarboxylate (0.22 mL, 1.1 mmol, 1.1
equiv.) was added dropwise via a syringe. The reaction mixture was
stirred overnight while warming to room temperature. Solvent was
removed under reduced pressure and the residue was purified by Isco
flash column chromatography (silica gel, 3-30% ethyl
acetate/hexane) to give 398 mg (89%) of tert-butyl
2-[(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)methyl]morpholine-
-4-carboxylate as a white foam. MS (ESI) m/z 445.9
([M+H].sup.+).
[0908] Step 2: To a solution of tert-butyl
2-[(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)methyl]morpholine-
-4-carboxylate (385 mg, 0.864 mmol) in methanol (5 mL) was added
slowly an ethereal solution of hydrochloric acid (1M, 10 mL). The
mixture was swirled for 20 minutes. All volatiles were removed
under reduced pressure. The white precipitate was redissolved in
minutesimal amount of methanol (.about.1 mL). Isopropyl ether was
added until the solution became slightly cloudy. The mixture was
cooled to -30.degree. C. in a freezer. The white solid formed was
collected by decantation, washed with hexane and dried in vacuo to
give 327 mg (99%) of
1-(morpholin-2-ylmethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride as a white powder. MS (ESI) m/z 345.9
([M+H].sup.+).
Example 2
1-[(2R)-morpholin-2-ylmethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride
##STR00049##
[0910] Step 1: Racemic
1-(morpholin-2-ylmethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride (Example 1, 164 mg, 0.429 mmol) was
dissolved in methanol (4 mL). 500 .mu.L of the resulting solution
was repetitively injected onto the Supercritical Fluid
Chromatography instrument, and the baseline resolved enantiomers
were separately collected using the conditions described below. The
chiral purity of each enantiomer was determined under the same
Supercritical Fluid Chromatography conditions using a Chiralcel
OJ-H 5 u, 250 mm.times.4.6 mm ID column at 2.0 mL/min flow rate
using Analytical Supercritical Fluid Chromatography (Berger
Instruments, Inc. Newark, Del.). Both enantiomers were found to be
>99.9% enantiomerically pure.
SFC Instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc.
Newark, Del. [0911] Column: Chiralcel OJ-H; 5 u; 250 mm L.times.20
mm ID (Chiral Technologies, Inc, Exton, Pa., USA) Column
temperature: 35.degree. C. SFC Modifier: 15% MeOH/85% CO.sub.2 with
0.2% DEA Flow rate: 50 mL/min
Outlet Pressure: 100 bar
Detector: UV at 220 nm
[0912] Step 2: A solution of
1-[(2R)-morpholin-2-ylmethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide, isolated as Peak 1 of the above chiral HPLC
separation, in dichloromethane (3 mL) was treated with an ethereal
solution of hydrochloric acid (1 M, 0.2 mL, 0.2 mmol). To the
resulting solution was added hexane until white powder formed,
which was collected, washed with hexane, and dried in vacuo to
yield 44 mg (27%) of
1-[(2R)-morpholin-2-ylmethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride. Absolute stereochemistry was arbitrarily
assigned. MS (ESI) m/z 346.2 ([M+H].sup.+).
Example 3
1-[(2S)-morpholin-2-ylmethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride
##STR00050##
[0914] In an analogous manner to Example 2,
1-[(2S)-morpholin-2-ylmethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride was prepared as a white powder from
racemic
1-(morpholin-2-ylmethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride (Example 1), which was isolated as peak 2
of the chiral HPLC separation (Example 2, Step 1). Absolute
stereochemistry was arbitrarily assigned. MS (ESI) m/z 346.2
([M+H].sup.+).
Example 4
1-[(4-methylmorpholin-2-yl)methyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadia-
zole 2,2-dioxide hydrochloride
##STR00051##
[0916] To a solution of
1-(morpholin-2-ylmethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride (Example 1, 76 mg, 0.20 mmol) in methanol
(2 mL) was added a solution of formaldehyde (37% in water, 0.15 mL)
and the mixture was stirred for 30 minutes. Sodium cyanoborohydride
(38 mg, 0.60 mmol, 3 equiv.) was added portionwise and the mixture
was stirred for an additional 3 hours. Saturated aqueous sodium
bicarbonate (5 mL) was added slowly followed by the addition of
water (5 mL). The reaction mixture was extracted with ethyl acetate
(2.times.15 mL). The combined organic extracts were washed with
brine, dried (anhydrous sodium sulfate), and concentrated. The
crude liquid residue was purified by Isco flash column
chromatography (silica gel, 0-10% methanol/dichloromethane) to give
70 mg (98%) of
1-[(4-methylmorpholin-2-yl)methyl]-3-phenyl-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide as viscous colorless liquid. This free
base was dissolved in dichloromethane (3 mL) and was treated with
an ethereal solution of hydrochloric acid (1 M, 0.3 mL, 0.3 mmol).
To the resulting solution was added hexane until white powder
formed, which was collected, washed with hexane, and dried in vacuo
to yield 76 mg (96%) of
1-[(4-methylmorpholin-2-yl)methyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide hydrochloride. MS (ESI) m/z 360.2
([M+H].sup.+).
Example 5
1-(2-chloro-4-fluorophenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethyl-
}-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
##STR00052##
[0918] Step 1:
1-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (made analogously as in general procedure I, 0.33 g,
1.1 mmol) was treated with triphenylphosphine (0.36 g, 1.4 mmol),
2-bromo ethanol (0.16 g, 1.4 mmol), and diisopropylazodicarboxylate
(0.28 g, 1.4 mmol) to provide 0.30 g of
1-(2-bromoethyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide. HRMS: calculated for C14H11BrClFN2O2S,
403.93971; found (EI, M+), 403.9386
[0919] Step 2 0.20 g (0.5 mmol) of
1-(2-bromoethyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide, 0.09 g (0.75 mmol) of cis-2,6-dimethyl
piperazine and 0.35 g (1 mmol) of cesium carbonate were dissolved
in ethanol and heated to 90.degree. C. for 30 hr. At the end of
this time the solution was concentrated and the residue placed on a
pad of silica gel eluting first with 20% ethyl acetate:hexane then
90% chloroform:methanol. The chloroform eluent was concentrated and
the residue dissolved in ethanol, whereupon 2 mL of 2N HCl in ether
added. The solution was concentrated to a smaller volume and
triturated with ether and the solid removed by filtration to
provide 0.11 g of
1-(2-chloro-4-fluorophenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethy-
l}-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
dihydrochloride.
[0920] HPLC purity 95.9% at 210-370 nm, 9.6 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammon.
Bicarb Buff. pH=9.5/ACN+MeOH) for 10 minutes hold 4 minutes
[0921] HRMS: calculated for C.sub.20H.sub.24ClFN.sub.4O.sub.2S+H+,
439.13653; found (ESI, [M+H].sup.+), 439.1368.
Example 6
1-(2-chloro-4-fluorophenyl)-3-{2-piperazin-1-ylethyl}-1,3-dihydro-2,1,3-be-
nzothiadiazole-2,2-dioxide
##STR00053##
[0923] Step 1:
1-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (made analogously as in general procedure I, 0.35 g,
1.2 mmol) was treated with triphenylphosphine (0.46 g, 1.5 mmol),
t-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.33 g, 1.4
mmol), and diisopropylazodicarboxylate (0.32 g, 1.5 mmol) to
provide 0.30 g of an oil, which was used as is in the next
step.
[0924] Step 2: The residue isolated from Step 1 (0.3 g) was
dissolved in ether:methanol (10:1) and 2 mL of 2N HCl in ether
added. The solution was allowed to stand for 16 hours whereupon the
solid was collected by filtration to 0.29 g of
1-(2-chloro-4-fluorophenyl)-3-{2-piperazin-1-ylethyl}-1,3-dihydro-2,1,3-b-
enzothiadiazole-2,2-dioxide dihydrochloride.
[0925] MS (ES) m/z 410.9; HPLC purity 98.8% at 210-370 nm, 9.0
minutes; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2
mL/minutes 85/15-5/95 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10
minutes hold 4 minutes; HRMS: calculated for
C.sub.18H.sub.20ClFN.sub.4O.sub.2S+H+, 411.10523; found (ESI,
[M+H].sup.+), 411.1066.
Example 7
1-(4-fluoro-2-methylphenyl)-3-{2-piperazin-1-ylethyl}-1,3-dihydro-2,1,3-be-
nzothiadiazole-2,2-dioxide
##STR00054##
[0927] Step 1: In an analogous manner to general procedure II,
1-(4-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.35 g, 1.3 mmol) was treated with triphenylphosphine
(0.46 g, 1.5 mmol), t-butyl
4-(2-hydroxyethyl)piperazine-1-carboxylate (0.33 g, 1.4 mmol), and
diisopropylazodicarboxylate (0.32 g, 1.5 mmol) to provide 0.31 g of
an oil, which was treated with HCl to provide 0.29 g of
1-(4-fluoro-2-methylphenyl)-3-{2-piperazin-1-ylethyl}-1,3-dihydro-2,1,3-b-
enzothiadiazole-2,2-dioxide dihydrochloride.
[0928] MS (ES) m/z 391.0;
[0929] HPLC purity 98.6% at 210-370 nm, 9.2 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammon.
Bicarb Buff. pH=9.5/ACN+MeOH) for 10 minutes hold 4 minutes
[0930] HRMS: calculated for C.sub.19H.sub.23FN.sub.4O.sub.2S+H+,
391.15985; found (ESI, [M+H].sup.+), 391.1604.
Example 8
1-(4-fluoro-2-methylphenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethyl-
}-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
##STR00055##
[0932] 0.19 g (0.5 mmol) of
1-(2-bromoethyl)-3-(4-fluoro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide (prepared as described in general procedure I),
0.09 g (0.75 mmol) of cis-2,6-dimethyl piperazine and 0.35 g (1
mmol) of cesium carbonate were dissolved in ethanol and heated to
90.degree. C. for 30 hr. At the end of this time the solution was
concentrated and the residue placed on a pad of silica gel eluting
first with 20% ethyl acetate:hexane then 90% chloroform:methanol.
The chloroform eluent was concentrated and the residue dissolved in
ethanol, whereupon 2 mL of 2N HCl in ether added. The solution was
concentrated to a smaller volume and triturated with ether and the
solid removed by filtration to provide 0.11 g of
1-(4-fluoro-2-methylphenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethy-
l}-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide
dihydrochloride.
[0933] MS (ES) m/z 419.2;
[0934] HPLC purity 93.4% at 210-370 nm, 9.8 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammon.
Bicarb Buff. pH=9.5/ACN+MeOH) for 10 minutes hold 4 minutes
[0935] HRMS: calculated for C.sub.21H.sub.27FN.sub.4O.sub.2S+H+,
419.19115; found (ESI, [M+H].sup.+), 419.1921.
Example 9
1-(4-fluoro-2-methoxyphenyl)-3-{2-piperazin-1-ylethyl}-1,3-dihydro-2,1,3-b-
enzothiadiazole-2,2-dioxide
##STR00056##
[0937] Step 1: In an analogous manner as in general procedure II,
1-(4-fluoro-2-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared analogously as described in general procedure
I, 0.41 g, 1.4 mmol) was treated with triphenylphosphine (0.46 g,
1.5 mmol), t-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.33
g, 1.4 mmol), and diisopropylazodicarboxylate (0.32 g, 1.5 mmol) to
provide 0.32 g of an oil, which was used as is in the next
step.
[0938] Step 2: 0.3 g of the product from Step 1 was converted to
0.30 g of
1-(4-fluoro-2-methoxyphenyl)-3-{2-piperazin-1-ylethyl}-1,3-dihydro-2,1,3--
benzothiadiazole-2,2-dioxide dihydrochloride:
[0939] HPLC purity 100.0% at 210-370 nm, 7.2 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
HRMS: calculated for C.sub.19H.sub.23FN.sub.4O.sub.3S+H+,
407.15476; found (ESI, [M+H].sup.+), 407.1552.
Example 10
1-[2-(2,5-diazabicyclo[2.2.1]hept-2-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide
##STR00057##
[0941] Step 1 In an analogous manner as described in general
procedure V, 0.051 g of
tert-butyl-1-[2-(2,5-diazabicyclo[2.2.1]hept-2-yl)ethyl]-3-phenyl-1,3-dih-
ydro-2,1,3-benzothiadiazole 2,2-dioxide-4-carboxylate was prepared
from 0.15 g (0.42 mmol) of
1-(2-bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (see Example 50, Step 1) and 0.125 g (0.63 mmol) of
tert-butyl (1-S,4S-(-)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
as an oil an used in the next step.
[0942] Step 2 In an analogous manner as described in general
procedure II, step 2,
1-[2-(2,5-diazabicyclo[2.2.1]hept-2-yl)ethyl]-3-phenyl-1,3-dihydr-
o-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride was prepared
from
tert-butyl-1-[2-(2,5-diazabicyclo[2.2.1]hept-2-yl)ethyl]-3-phenyl-1,3-dih-
ydro-2,1,3-benzothiadiazole 2,2-dioxide-4-carboxylate. MS (ES) m/z
371.2; HPLC purity 100.0% at 210-370 nm, 7.0 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Example 11
Preparation of
2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethox-
y}ethanamine
##STR00058##
[0944] Step 1: In an analogous manner to general procedure I, step
3, N-(2-fluorophenyl)benzene-1,2-diamine (1.0 g, 5.0 mmol) was
treated with sulfamide (0.58 g, 6.0 mmol) to provide 0.52 g (40%)
of 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide. HRMS: calculated for
C.sub.12H.sub.9FN.sub.2O.sub.2S+Na.sup.+, 287.02609; found (ESI,
[M+Na].sup.+), 287.0263; HPLC purity 100.0% at 210-370 nm, 8.4
minutes; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2
mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for
10 minutes hold 4 minutes.
[0945] Step 2: In an analogous manner as described in general
procedure IV, 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.22 g, 0.83 mmol) was treated with cesium carbonate
(0.27 g, 0.83 mmol) and 1-Bromo-2-(2-bromo-ethoxy)-ethane (0.03 mL,
3.3 mmol) to provide 0.23 g (67%) of
1-[2-(2-bromoethoxy)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide. HRMS: calculated for
C.sub.16H.sub.16BrFN.sub.2O.sub.3S+H.sup.+, 415.01218; found (ESI,
[M+H].sup.+), 415.0127; HPLC purity 100.0% at 210-370 nm, 10.1
minutes; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2
mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for
10 minutes hold 4 minutes.
[0946] Step 3: In an analogous manner as described in general
procedure V,
1-[2-(2-bromoethoxy)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide (0.07 g, 0.16 mmol) was treated with ammonia
(10 mL) to prepare 0.04 g (71%) of
2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethox-
y}ethanamine.
[0947] MS (ES) m/z 351.9; HRMS: calculated for
C.sub.16H.sub.18FN.sub.3O.sub.3S+H.sup.+, 352.11257; found (ESI,
[M+H].sup.+), 352.1128; HPLC purity 100.0% at 210-370 nm, 8.1
minutes; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2
mL/minutes 85/15-5/95 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10
minutes hold 4 minutes.
Example 12
Preparation of
2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethox-
y}-N-methylethanamine
##STR00059##
[0949] In an analogous manner as described in general procedure V,
1-[2-(2-bromoethoxy)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide (0.07 g, 0.16 mmol) was treated with
methylamine (10 mL) to provide 0.05 g (95%) of
2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethox-
y}-N-methylethanamine. MS (ES) m/z 366.0; HRMS: calculated for
C.sub.17H.sub.20FN.sub.3O.sub.3S+H.sup.+, 366.12822; found (ESI,
[M+H].sup.+), 366.1285; HPLC purity 100.0% at 210-370 nm, 8.4
minutes; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2
mL/minutes 85/15-5/95 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10
minutes hold 4 minutes.
Example 13
Preparation of
2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethox-
y}-N,N-dimethylethanamine
##STR00060##
[0951] In an analogous manner as described in general procedure V,
1-[2-(2-bromoethoxy)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide (0.07 g, 0.16 mmol) was treated with
dimethylamine (10 mL) to provide 0.05 g (95%) of
2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethox-
y}-N,N-dimethylethanamine. MS (ES) m/z 380.0; HRMS: calculated for
C.sub.18H.sub.22FN.sub.3O.sub.3S+H.sup.+, 380.14387; found (ESI,
[M+H].sup.+), 380.1443; HPLC purity 98.1% at 210-370 nm, 9.1
minutes; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2
mL/minutes 85/15-5/95 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10
minutes hold 4 minutes.
Example 14
Preparation of
1-{2-[2-(3,5-dimethylpiperazin-1-yl)ethoxy]ethyl}-3-(2-fluorophenyl)-1,3--
dihydro-2,1,3-benzothiadiazole 2,2-dioxide
##STR00061##
[0953] In an analogous manner as described in general procedure V,
1-[2-(2-bromoethoxy)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide (0.07 g, 0.18 mmol) was treated with
2,6-Dimethyl-piperazine (0.06 g, 0.54 mmol) to provide 0.07 g (92%)
of
1-{2-[2-(3,5-dimethylpiperazin-1-yl)ethoxy]ethyl}-3-(2-fluorophenyl)-1,3--
dihydro-2,1,3-benzothiadiazole 2,2-dioxide. MS (ES) m/z 449.0;
HRMS: calculated for C.sub.22H.sub.29FN.sub.4O.sub.3S+H.sup.+,
449.20171; found (ESI, [M+H].sup.+), 449.202; HPLC purity 98.4% at
210-370 nm, 7.1 minutes; Xterra RP18, 3.5 u, 150.times.4.6 mm
column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer
pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Example 15
Preparation of
1-[5-(3,5-dimethylpiperazin-1-yl)pentyl]-3-(2-fluorophenyl)-1,3-dihydro-2-
,1,3-benzothiadiazole 2,2-dioxide
##STR00062##
[0955] In an analogous manner as described in general procedure V,
1-(5-bromopentyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.07 g, 0.18 mmol) was treated with
2,6-Dimethyl-piperazine (0.06 g, 0.54 mmol) to provide 0.08 g (88%)
of
1-[5-(3,5-dimethylpiperazin-1-yl)pentyl]-3-(2-fluorophenyl)-1,3-dihydro-2-
,1,3-benzothiadiazole 2,2-dioxide. MS (ES) m/z 447.0; HRMS:
calculated for C.sub.23H.sub.31FN.sub.4O.sub.2S+H.sup.+, 447.22245;
found (ESI, [M+H].sup.+), 447.2234 and HPLC purity 100.0% at
210-370 nm, 7.9 minutes; Xterra RP18, 3.5 u, 150.times.4.6 mm
column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer
pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Example 16
(2R)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2-m-
ethylpropan-1-amine
##STR00063##
[0957] In an analogous manner to Example 23,
(2R)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2--
methylpropan-1-amine was prepared from
1-[(2S)-3-bromo-2-methylpropyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benz-
othiadiazole 2,2-dioxide, potassium phthalimide and methyl
hydrazine giving the desired product.
[0958] HRMS: calculated for C17H15FN2O+H.sup.+, 336.1182; found
(ESI, [M+H]+),
[0959] HPLC purity 99.1% at 210-370 nm, 7.0 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Example 17
(2S)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2-m-
ethylpropan-1-amine
##STR00064##
[0961] In an analogous manner to Example 23,
(2S)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2--
methylpropan-1-amine was prepared from
1-[(2R)-3-bromo-2-methylpropyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benz-
othiadiazole 2,2-dioxide, potassium pthalimide and methyl hydrazine
giving the desired product. HRMS: calculated for C17H15FN2O+H+,
336.1182; found (ESI, [M+H]+), 336.1177. HPLC purity 100% at
210-370 nm, 7.0 minutes; Xterra RP18, 3.5 u, 150.times.4.6 mm
column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer
pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Example 18
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-a-
mine
##STR00065##
[0963] In an analogous manner to Example 23,
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2--
amine was prepared from
1-(3-bromobutyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide, potassium pthalimide and methyl hydrazine giving the
desired product. HRMS: calculated for C17H15FN2O+H+, 336.1182;
found (ESI, [M+H]+), 336.118 HPLC purity 91.2% at 210-370 nm, 7.0
minutes; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2
mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for
10 minutes hold 4 minutes.
Example 19
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
butan-1-amine
##STR00066##
[0965] Step 1:
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(general procedure I 0.2 g, 0.8 mmol) was dissolved in
tetrahydrofuran (10 mL) and triphenylphosphine (0.54 g, 0.9 mmol)
was added followed by 4-bromobutan-2-ol (0.14 g, 0.9 mmol) and
diisopropyl azodicarboxylate (0.18 g, 0.9 mmol). The mixture was
stirred for 18 hours at 23.degree. C. The mixture was concentrated
and purified via Isco chromatography (Redisep, silica, gradient
0-50% ethyl acetate in hexane) to afford 0.22 g of
1-(3-bromo-1-methylpropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide.
[0966] HRMS: calculated for C17H15FN2O, Exact Mass: 398.0100; found
(ESI, [M+], 398.0102
[0967] HPLC purity 96.4% at 210-370 nm, 10.6 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
[0968] Step 2:
1-(3-bromo-1-methylpropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide (0.04 g, 0.09 mmol) was dissolved in 2 mL of
MeNH.sub.2 solution (8M in EtOH). The solution was irradiated in a
microwave cuvette at 100.degree. C. for 3 minutes. The reaction
mixture was concentrated then loaded directly onto silica gel and
purified via Isco chromatography (Redisep, silica, gradient 0-10%
7M ammonia/MeOH solution in dichloromethane) to afford 44 mg of
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbutan-1-amine.
[0969] HRMS: calculated for C17H15FN2O+H+, 350.1339; found (ESI,
[M+H]+), 350.1335
[0970] HPLC purity 97% at 210-370 nm, 7.2 minutes; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Example 20
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
butan-2-amine
##STR00067##
[0972] Step 1: In an analogous manner to Example 19, step 1,
1-(3-bromobutyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
and 3-bromobutan-1-ol giving 0.27 g of the desired product.
[0973] HRMS: calculated for C17H.sub.15FN2O, Exact Mass: 398.0100;
found (ESI, [M+], 398.0106
[0974] HPLC purity 93.6% at 210-370 nm, 10.7 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
[0975] Step 2: In an analogous manner to Example 19, step 2,
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbutan-2-amine was prepared from
1-(3-bromobutyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and MeNH.sub.2 solution (8M in EtOH) giving 51 mg of
the desired product.
[0976] HRMS: calculated for C17H15FN2O+H+, 350.1339; found (ESI,
[M+H]+), 350.1338
[0977] HPLC purity 100% at 210-370 nm, 7.1 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Example 21
(2R)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,2-
-dimethylpropan-1-amine
##STR00068##
[0979] Step 1: In an analogous manner to Example 19, step 1,
1-[(2S)-3-bromo-2-methylpropyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benz-
othiadiazole 2,2-dioxide was prepared from
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
and (S)-3-bromo-2-methylpropan-1-ol giving 0.26 g of the desired
product.
[0980] HRMS: calculated for C17H15FN2O, Exact Mass: 398.0100; found
(ESI, [M+], 398.0111
[0981] HPLC purity 100% at 210-370 nm, 10.7 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
[0982] Step 2: In an analogous manner to Example 19, step 2,
(2R)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,-
2-dimethylpropan-1-amine was prepared from
1-[(2S)-3-bromo-2-methylpropyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benz-
othiadiazole 2,2-dioxide and MeNH.sub.2 solution (8M in EtOH)
giving 65 mg of the desired product.
[0983] HRMS: calculated for C17H15FN2O+H+, 350.1339; found (ESI,
[M+H]+), 350.1335
[0984] HPLC purity 97.6% at 210-370 nm, 7.1 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Example 22
(2S)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,2-
-dimethylpropan-1-amine
##STR00069##
[0986] Step 1: In an analogous manner to Example 19, step 1,
1-[(2R)-3-bromo-2-methylpropyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benz-
othiadiazole 2,2-dioxide was prepared from
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
and (R)-3-bromo-2-methylpropan-1-ol giving 0.27 g of the desired
product.
[0987] HRMS: calculated for C17H15FN2O, Exact Mass: 398.0100; found
(ESI, [M+], 398.0103
[0988] HPLC purity 100% at 210-370 nm, 10.7 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
[0989] Step 2: In an analogous manner to Example 19, step 2,
(2S)-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,-
2-dimethylpropan-1-amine was prepared from
1-[(2R)-3-bromo-2-methylpropyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benz-
othiadiazole 2,2-dioxide and MeNH.sub.2 solution (8M in EtOH)
giving 65 mg of the desired product.
[0990] HRMS: calculated for C17H15FN2O+H+, 350.1339; found (ESI,
[M+H]+), 350.1337
[0991] HPLC purity 98.1% at 210-370 nm, 7.1 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Example 23
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-1-a-
mine
##STR00070##
[0993]
1-(3-bromo-1-methylpropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide (0.1 g, 0.25 mmol) was dissolved in
dimethylformamide (2 mL) in a microwave cuvette and potassium
phthalimide (0.06 g, 0.3 mmol) was added. The mixture was
irradiated at 100.degree. C. for 3 minutes. Upon cooling the
mixture was diluted with EtOAc and washed with water and brine then
dried with Na.sub.2SO.sub.4. Upon concentration, the residue was
dissolved in MeOH (5 mL), methyl hydrazine (0.06 g, 1.25 mmol) was
added and the mixture heated to reflux for 5 hours. Upon cooling
the reaction was concentrated and water (10 ml) added followed by
acetic acid (to pH 4). After 1 hour the mixture was filtered and
basified to pH 14 with NaOH then extracted with dichloromethane.
The organic extracts were washed with water, dried with
Na.sub.2SO.sub.4 and purified via Isco chromatography (Redisep,
silica, gradient 0-10% 7M ammonia/MeOH solution in dichloromethane)
to afford 32 mg of
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methy-
lbutan-1-amine.
[0994] HRMS: calculated for C17H15FN2O+H+, 336.1182; found (ESI,
[M+H]+), 336.1182
[0995] HPLC purity 100% at 210-370 nm, 7.1 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Example 24
1-Phenyl-3-(piperidin-4-ylmethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride
##STR00071##
[0997] In an analogous manner as described in general procedure II,
1-phenyl-3-(piperidin-4-ylmethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride was prepared from
1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared
in an analogous manner as described in general procedure I) and
N-Boc-4-piperidinemethanol as a light yellow powder. MS (ESI) m/z
343.8 ([M+H].sup.+).
Example 25
1-(2,6-Difluorophenyl)-3-(morpholin-2-ylmethyl)-1,3-dihydro-2,1,3-benzothi-
adiazole 2,2-dioxide hydrochloride
##STR00072##
[0999] In an analogous manner as described in general procedure II,
1-(2,6-difluorophenyl)-3-(morpholin-2-ylmethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide hydrochloride was prepared from
1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure I) and tert-butyl
2-(hydroxymethyl)morpholine-4-carboxylate as a light yellow powder.
MS (ESI) m/z 382.1 ([M+H].sup.+).
Example 26
1-(2,6-Difluorophenyl)-3-[(2R)-morpholin-2-ylmethyl]-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide hydrochloride
##STR00073##
[1001] Step 1: Racemic tert-butyl
2-{[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]met-
hyl}morpholine-4-carboxylate (Example 25, step 1, 119 mg, 0.247
mmol) was dissolved in methanol (3 mL). 300 .mu.L of the resulting
solution was repetitively injected onto the Supercritical Fluid
Chromatography instrument, and the baseline resolved enantiomers
were separately collected using the conditions described below. The
chiral purity of each enantiomer was determined under the same
Supercritical Fluid Chromatography conditions using a Chiralpak
AD-H, 5 u, 250 mm.times.4.6 mm ID column at 2.0 mL/min flow rate
using Analytical Supercritical Fluid Chromatography (Berger
Instruments, Inc. Newark, Del.). Both enantiomers were found to be
>99.9% enantiomerically pure. Absolute stereochemistry of the
two enantiomers was arbitrarily assigned. [1002] SFC Instrument:
Berger MultiGram Prep SFC (Berger Instruments, Inc. Newark, Del.
[1003] Column: Chiralpak AD-H; 5 u; 250 mm L.times.20 mm ID (Chiral
Technologies, Inc, Exton, Pa., USA) Column temperature: 35.degree.
C.
SFC Modifier: 10% MeOH/90% CO.sub.2
[1004] Flow rate: 50 mL/min
Outlet Pressure: 100 bar
Detector: UV at 220 nm
[1005] Step 2 In an analogous manner as described in general
procedure II, step 2,
1-(2,6-difluorophenyl)-3-[(2R)-morpholin-2-ylmethyl]-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide hydrochloride was prepared as a
light yellow powder from tert-butyl
(2R)-2-{[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]methyl}morpholine-4-carboxylate (absolute stereochemistry was
arbitrarily assigned) which was isolated as Peak 1 of the above
chiral HPLC separation (step 1). MS (ESI) m/z 382.1
([M+H].sup.+).
Example 27
1-(2,6-Difluorophenyl)-3-[(2S)-morpholin-2-ylmethyl]-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide hydrochloride
##STR00074##
[1007] In an analogous manner as described in general procedure II,
step 2,
1-(2,6-difluorophenyl)-3-[(2S)-morpholin-2-ylmethyl]-1,3-dihydro-2,1,3-
-benzothiadiazole 2,2-dioxide hydrochloride was prepared as a light
yellow powder from tert-butyl
(2S)-2-{[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]methyl}morpholine-4-carboxylate (absolute stereochemistry was
arbitrarily assigned) which was isolated as Peak 2 the chiral HPLC
separation of Example 26, step 1. MS (ESI) m/z 382.1
([M+H].sup.+).
Example 28
1-(2,3-Difluorophenyl)-3-(morpholin-2-ylmethyl)-1,3-dihydro-2,1,3-benzothi-
adiazole 2,2-dioxide hydrochloride
##STR00075##
[1009] In an analogous manner as described in general procedure II,
1-(2,3-difluorophenyl)-3-(morpholin-2-ylmethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide hydrochloride was prepared from
1-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (Prepared in an analogous manner as described in
general procedure V) and tert-butyl
2-(hydroxymethyl)morpholine-4-carboxylate as a white powder. MS
(ESI) m/z 382.1 ([M+H].sup.+).
Example 29
1-(Morpholin-2-ylmethyl)-3-[2-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3--
benzothiadiazole 2,2-dioxide hydrochloride
##STR00076##
[1011] In an analogous manner as described in general procedure II,
1-(morpholin-2-ylmethyl)-3-[2-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-
-benzothiadiazole 2,2-dioxide hydrochloride was prepared from
1-[2-(trifluoromethoxy)phenyl]-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (Prepared in an analogous manner as described in
general procedure V) and tert-butyl
2-(hydroxymethyl)morpholine-4-carboxylate as a tan powder. MS (ESI)
m/z 430.1 ([M+H].sup.+).
Example 30
1-Phenyl-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride
##STR00077##
[1013] In an analogous manner as described in general procedure II,
1-phenyl-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride was prepared from
1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (Prepared
in an analogous manner as described in general procedure I) and
N-Boc-4-piperidineethanol as a white powder. MS (ESI) m/z 358.0
([M+H].sup.+).
Example 31
1-Phenyl-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide dihydrochloride
##STR00078##
[1015] In an analogous manner as described in general procedure II,
1-phenyl-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide dihydrochloride was prepared from
1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (Prepared
in an analogous manner as described in general procedure I) and
tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate as a
off-white solid. MS (ESI) m/z 359.2 ([M+H].sup.+).
Example 32
4-Fluoro-3-phenyl-1-(piperidin-4-ylmethyl)-1,3-dihydro-2,1,3-benzothiadiaz-
ole 2,2-dioxide hydrochloride
##STR00079##
[1017] In an analogous manner as described in general procedure II,
4-fluoro-3-phenyl-1-(piperidin-4-ylmethyl)-1,3-dihydro-2,1,3-benzothiadia-
zole 2,2-dioxide hydrochloride was prepared from
7-fluoro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(Prepared in an analogous manner as described in general procedure
I) and N-Boc-4-piperidinemethanol as white crystals. MS (ESI) m/z
361.9 ([M+H].sup.+). MS (ESI) m/z 361.9 ([M+H-Boc].sup.+).
Example 33
4-Fluoro-3-phenyl-1-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzothiadia-
zole 2,2-dioxide hydrochloride
##STR00080##
[1019] In an analogous manner as described in general procedure II,
4-fluoro-3-phenyl-1-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide hydrochloride was prepared from
7-fluoro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(prepared in an analogous manner as described in general procedure
I) and N-Boc-4-piperidineethanol as gray crystals. MS (ESI) m/z
375.8 ([M+H].sup.+).
Example 34
4-Fluoro-3-phenyl-1-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadia-
zole 2,2-dioxide dihydrochloride
##STR00081##
[1021] In an analogous manner as described in general procedure II,
4-fluoro-3-phenyl-1-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide dihydrochloride was prepared from
7-fluoro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(prepared in an analogous manner as described in general procedure
I) and tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate as an
off-white solid. MS (ESI) m/z 377.2 ([M+H].sup.+).
Example 35
4-Fluoro-3-(morpholin-2-ylmethyl)-1-phenyl-1,3-dihydro-2,1,3-benzothiadiaz-
ole 2,2-dioxide hydrochloride
##STR00082##
[1023] In an analogous manner as described in general procedure II,
4-fluoro-3-(morpholin-2-ylmethyl)-1-phenyl-1,3-dihydro-2,1,3-benzothiadia-
zole 2,2-dioxide hydrochloride was prepared from
4-fluoro-1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(prepared in an analogous manner as described in general procedure
I) and tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate as a
white powder. MS (ESI) m/z 364.1 ([M+H].sup.+).
Example 36
1-Phenyl-3-(3-piperidin-4-ylpropyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride
##STR00083##
[1025] In an analogous manner as described in general procedure II,
1-phenyl-3-(3-piperidin-4-ylpropyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride was prepared from
1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared
in an analogous manner as described in general procedure I) and
tert-butyl 4-(3-hydroxypropyl)tetrahydro-1(2H)-pyridinecarboxylate
as a tan powder. MS (ESI) m/z 371.9 ([M+H].sup.+).
Example 37
1-Phenyl-3-(2-piperidin-2-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride
##STR00084##
[1027] In an analogous manner as described in general procedure II,
1-phenyl-3-(2-piperidin-2-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride was prepared from
1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared
in an analogous manner as described in general procedure I) and
Boc-2-(2-piperidyl)ethanol as an ivory solid. HRMS: calculated for
C.sub.19H.sub.23N.sub.3O.sub.2S+H.sup.+, 358.1584; found (ESI,
[M+H].sup.+), 358.1588.
Example 38
1-(2,6-Difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide hydrochloride
##STR00085##
[1029] In an analogous manner as described in general procedure II,
1-(2,6-difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide hydrochloride was prepared from
1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure I) and N-Boc-4-piperidineethanol as white
crystals. MS (ESI) m/z 394.3 ([M+H].sup.+). HRMS: calculated for
C.sub.19H.sub.21F.sub.2N.sub.3O.sub.2S+H.sup.+, 394.1395; found
(ESI, [M+H].sup.+), 394.1382.
Example 39
1-(2,6-Difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide dihydrochloride
##STR00086##
[1031] In an analogous manner as described in general procedure II,
1-(2,6-Difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide dihydrochloride was prepared from
1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure I) and tert-butyl
4-(2-hydroxyethyl)piperazine-1-carboxylate as a tan solid. MS (ESI)
m/z 394.6 ([M+H].sup.+). HRMS: calculated for
C.sub.18H.sub.20F.sub.2N.sub.4O.sub.2S+H.sup.+, 395.1348; found
(ESI, [M+H].sup.+), 395.1362.
Example 40
1-Phenyl-3-(piperidin-3-ylmethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride
##STR00087##
[1033] In an analogous manner as described in general procedure II,
1-phenyl-3-(piperidin-3-ylmethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride was prepared from
1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared
in an analogous manner as described in general procedure I) and
3-hydroxymethyl-1-N-Boc-piperidine as white crystals. MS (ESI) m/z
344.0 ([M+H].sup.+). HRMS: calculated for
C.sub.18H.sub.21N.sub.3O.sub.2S+H.sup.+, 344.1427; found (ESI,
[M+H].sup.+), 344.1425.
Example 41
1-Phenyl-3-[(3R)-piperidin-3-ylmethyl]-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride
##STR00088##
[1035] Step 1: Racemic tert-butyl
3-[(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)methyl]piperidine-
-1-carboxylate (Example 40, step 1, 163 mg, 0.367 mmol) was
dissolved in methanol (4 mL). 300 .mu.L of the resulting solution
was repetitively injected onto the Supercritical Fluid
Chromatography instrument, and the baseline resolved enantiomers
were separately collected using the conditions described below. The
chiral purity of each enantiomer was determined under the same
Supercritical Fluid Chromatography conditions using a Chiralpak
AD-H, 5 u, 250 mm.times.4.6 mm ID column at 2.0 mL/min flow rate
using Analytical Supercritical Fluid Chromatography (Berger
Instruments, Inc. Newark, Del.). Both enantiomers were found to be
>99.7% enantiomerically pure. Absolute stereochemistry of the
two enantiomers was arbitrarily assigned. [1036] SFC Instrument:
Berger MultiGram Prep SFC (Berger Instruments, Inc. Newark, Del.
[1037] Column: Chiralpak AD-H; 5 u; 250 mm L.times.20 mm ID (Chiral
Technologies, Inc, Exton, Pa., USA) Column temperature: 35.degree.
C.
SFC Modifier: 10% MeOH/90% CO.sub.2
[1038] Flow rate: 50 mL/min
Outlet Pressure: 100 bar
Detector: UV at 220 nm
[1039] Step 2: In an analogous manner as described in general
procedure II, step 2,
1-phenyl-3-[(3R)-piperidin-3-ylmethyl]-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride was prepared as a tan solid from
tert-butyl
(3R)-3-[(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)methyl]piper-
idine-1-carboxylate (absolute stereochemistry was arbitrarily
assigned) which was isolated as Peak 1 of the above chiral HPLC
separation (step 1). HRMS: calculated for
C.sub.18H.sub.21N.sub.3O.sub.2S+H.sup.+, 344.1427; found (ESI,
[M+H].sup.+), 344.1437.
Example 42
1-Phenyl-3-[(3S)-piperidin-3-ylmethyl]-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride
##STR00089##
[1041] In an analogous manner as described in general procedure II,
step 2,
1-phenyl-3-[(3S)-piperidin-3-ylmethyl]-1,3-dihydro-2,1,3-benzothiadiaz-
ole 2,2-dioxide hydrochloride was prepared as a tan solid from
tert-butyl
(3S)-3-[(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)methyl]piper-
idine-1-carboxylate (absolute stereochemistry was arbitrarily
assigned) which was isolated as Peak 2 the chiral HPLC separation
of Example 41, step 1. HRMS: calculated for
C.sub.18H.sub.21N.sub.3O.sub.2S+H.sup.+, 344.1427; found (ESI,
[M+H].sup.+), 344.1442.
Example 43
1-Phenyl-3-(2-piperidin-3-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride
##STR00090##
[1043] Step 1: In an analogous manner as described in general
procedure II,
1-phenyl-3-(2-piperidin-3-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride was prepared from
1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared
in an analogous manner as described in general procedure I) and
1-N-Boc-piperidine-3-ethanol as white crystals. MS (ESI) m/z 358.1
([M+H].sup.+). HRMS: calculated for
C.sub.19H.sub.23N.sub.3O.sub.2S+H.sup.+, 358.1584; found (ESI,
[M+H].sup.+), 358.1587.
Example 44
1-Phenyl-3-{2-[(3S)-piperidin-3-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide hydrochloride
##STR00091##
[1045] Step 1: Racemic tert-butyl
3-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]piperidin-
e-1-carboxylate (Example 43, step 1, 164 mg, 0.358 mmol) was
dissolved in methanol (4 mL). 300 .mu.L of the resulting solution
was repetitively injected onto the Supercritical Fluid
Chromatography instrument, and the baseline resolved enantiomers
were separately collected using the conditions described below. The
chiral purity of each enantiomer was determined under the same
Supercritical Fluid Chromatography conditions using a Chiralpak
AD-H, 5 u, 250 mm.times.4.6 mm ID column at 2.0 mL/min flow rate
using Analytical Supercritical Fluid Chromatography (Berger
Instruments, Inc. Newark, Del.). One enantiomer (Peak 1) was found
to be 99.5% enantiomerically pure, and the other enantiomer (Peak
2) was found to be 98.1% enantiomerically pure. Absolute
stereochemistry of the two enantiomers was arbitrarily assigned.
[1046] SFC Instrument: Berger MultiGram Prep SFC (Berger
Instruments, Inc. Newark, Del. [1047] Column: Chiralpak AD-H; 5 u;
250 mm L.times.20 mm ID (Chiral Technologies, Inc, Exton, Pa., USA)
Column temperature: 35.degree. C.
SFC Modifier: 10% MeOH/90% CO.sub.2
[1048] Flow rate: 50 mL/min
Outlet Pressure: 100 bar
Detector: UV at 220 nm
[1049] Step 2: In an analogous manner as described in general
procedure II, step 2,
1-phenyl-3-{2-[(3S)-piperidin-3-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiaz-
ole 2,2-dioxide hydrochloride was prepared as a white powder from
tert-butyl
(3S)-3-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]pipe-
ridine-1-carboxylate (absolute stereochemistry was arbitrarily
assigned) which was isolated as Peak 1 of the above chiral HPLC
separation (step 1). HRMS: calculated for
C.sub.19H.sub.23N.sub.3O.sub.2S+H.sup.+, 358.1584; found (ESI,
[M+H].sup.+), 358.1595.
Example 45
1-Phenyl-3-{2-[(3R)-piperidin-3-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide hydrochloride
##STR00092##
[1051] In an analogous manner as described in general procedure II,
step 2,
1-phenyl-3-{2-[(3R)-piperidin-3-yl]ethyl}-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide hydrochloride was prepared as a light pink
powder from tert-butyl
(3R)-3-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]pipe-
ridine-1-carboxylate (absolute stereochemistry was arbitrarily
assigned) which was isolated as Peak 2 the chiral HPLC separation
of Example 44, step 1. HRMS: calculated for
C.sub.19H.sub.23N.sub.3O.sub.2S+H.sup.+, 358.1584; found (ESI,
[M+H].sup.+), 358.1594.
Example 46
1-(2,3-Difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide hydrochloride
##STR00093##
[1053] In an analogous manner as described in general procedure II,
1-(2,3-difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide hydrochloride was prepared from
1-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure I) and N-Boc-4-piperidineethanol as white
crystals. MS (ESI) m/z 394.1 ([M+H].sup.+). HRMS: calculated for
C.sub.19H.sub.21F.sub.2N.sub.3O.sub.2S+H.sup.+, 394.1395; found
(ESI, [M+H].sup.+), 394.1403.
Example 47
1-(2,5-Difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide hydrochloride
##STR00094##
[1055] In an analogous manner as described in general procedure II,
1-(2,5-difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide hydrochloride was prepared from
1-(2,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure I) and N-Boc-4-piperidineethanol as a gray
solid.
[1056] HRMS: calculated for
C.sub.19H.sub.21F.sub.2N.sub.3O.sub.2S+H.sup.+, 394.1395; found
(ESI, [M+H].sup.+), 394.1396.
Example 48
1-(2,3-Difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide dihydrochloride
##STR00095##
[1058] In an analogous manner as described in general procedure II,
1-(2,3-difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide dihydrochloride was prepared from
1-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure I) and tert-butyl
4-(2-hydroxyethyl)piperazine-1-carboxylate as a gray solid. HRMS:
calculated for C.sub.18H.sub.20F.sub.2N.sub.4O.sub.2S+H.sup.+,
395.1348; found (ESI, [M+H].sup.+), 395.1353.
Example 49
1-(2,5-Difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide dihydrochloride
##STR00096##
[1060] In an analogous manner as described in general procedure II,
1-(2,5-difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide dihydrochloride was prepared from
1-(2,5-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure I) and tert-butyl
4-(2-hydroxyethyl)piperazine-1-carboxylate as a brown solid. HRMS:
calculated for C.sub.18H.sub.20F.sub.2N.sub.4O.sub.2S+H.sup.+,
395.1348; found (ESI, [M+H].sup.+), 395.1347.
Example 50
1-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide dihydrochloride
##STR00097##
[1062] Step 1: Diisopropyl azodicarboxylate (0.47 mL, 2.4 mmol, 1.2
equiv.) was added dropwise to a solution of
1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared
in an analogous manner as described in general procedure I, 493 mg,
2.00 mmol), 2-bromoethanol (275 mg, 2.20 mmol, 1.1 equiv.) and
triphenylphosphine (630 mg, 2.40 mmol, 1.2 equiv.) in dry THF (10
mL) at 0.degree. C. under nitrogen. The solution was stirred
overnight while warming to room temperature. Solvent was removed
and the oil residue was pre-adsorbed onto Florisil and purified via
Isco flash column chromatography (40-g redisep silica gel column,
0-30% ethyl acetate/hexane) to give 706 mg (86%) of
1-(2-bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide as a viscous, colorless liquid. HRMS: calculated for
C.sub.14H.sub.13BrN.sub.2O.sub.2S+Na.sup.+, 374.9773; found (ESI,
[M+H].sup.+), 374.9780.
[1063] Step 2: A mixture of
1-(2-bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (212 mg, 0.600 mmol), cis-2,6-dimethylpiperazine (411
mg, 3.60 mmol, 6 equiv.) and ethanol (5 mL) in a sealed reaction
vessel was heated at 90.degree. C. for 8 h. After cooling, solvent
was removed, and the residue was dissolved in ethyl acetate (15
mL). The resulting solution was washed with an aqueous potassium
carbonate solution, water, dried (anhydrous sodium sulfate), and
concentrated. The crude oil was pre-adsorbed onto Florisil and
purified via Isco flash column chromatography (4-g redisep silica
gel column, 1-18% methanol/dichloromethane, with 1% triethylamine
as eluent additive) to give 162 mg (70%) of
1-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide as a viscous, colorless liquid. This
free base was dissolved in ethanol (2 mL), and was treated with an
ethereal solution of hydrochloric acid (1 M, 3.0 mL, 3.0 mmol in
ethyl ether). To the resulting solution was added ethyl ether until
it became cloudy, then cooled to -25.degree. C. in a freezer
overnight. The white crystals formed was collected, washed with
hexane, and dried in vacuo to yield 176 mg of
1-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,-
1,3-benzothiadiazole 2,2-dioxide dihydrochloride. HRMS: calculated
for C.sub.20H.sub.26N.sub.4O.sub.2S+H.sup.+, 387.1849; found (ESI,
[M+H].sup.+), 387.1861.
Example 51
1-(2-Fluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide dihydrochloride
##STR00098##
[1065] In an analogous manner as described in general procedure II,
1-(2-fluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide dihydrochloride was prepared from
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(prepared in an analogous manner as described in general procedure
I) and tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate as
white crystals. MS (ESI) m/z 377.1 ([M+H].sup.+).
Example 52
1-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-
-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride
##STR00099##
[1067] In an analogous manner as described in general procedure VI,
1-(2-bromoethyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(prepared in an analogous manner as described in general procedure
I) and 2-bromoethanol as a viscous, colorless liquid. MS (ESI) m/z
370.8 ([M+H].sup.+). HRMS: calculated for
C.sub.14H.sub.12BrFN.sub.2O.sub.2S+H.sup.+, 370.9860; found (ESI,
[M+H].sup.+), 370.9863.
[1068] In an analogous manner as described in general procedure V,
1-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-3-(2-fluorophenyl)-1,3-dihydr-
o-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride was prepared
from
1-(2-bromoethyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide as a white powder. MS (ESI) m/z 405.2
([M+H].sup.+).
Example 53
1-[3-(cis-3,5-Dimethylpiperazin-1-yl)propyl]-3-phenyl-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide dihydrochloride
##STR00100##
[1070] In an analogous manner as described in general procedure V,
1-[3-(cis-3,5-dimethylpiperazin-1-yl)propyl]-3-phenyl-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide dihydrochloride was prepared from
1-(3-bromopropyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure VI) as a white powder. MS (ESI) m/z 401.2
([M+H].sup.+).
Example 54
1-(2,6-Difluorophenyl)-3-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-1,3-dih-
ydro-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride
##STR00101##
[1072] In an analogous manner as described in general procedure VI,
1-(2-bromoethyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide was prepared from
1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure I) and 2-bromoethanol as a white solid. HRMS:
calculated for C.sub.14H.sub.11BrF.sub.2N.sub.2O.sub.2S+H.sup.+,
388.9765; found (ESI, [M+H].sup.+), 388.9772.
[1073] In an analogous manner as described in general procedure V,
1-(2,6-difluorophenyl)-3-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-1,3-di-
hydro-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride was
prepared from
1-(2-bromoethyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide as a white powder. MS (ESI) m/z 423.0 ([M+H].sup.+).
HRMS: calculated for
C.sub.20H.sub.24F.sub.2N.sub.4O.sub.2S+H.sup.+, 423.1661; found
(ESI, [M+H].sup.+), 423.1662.
Example 55
1-(2-piperazin-1-ylethyl)-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-benz-
othiadiazole 2,2-dioxide dihydrochloride
##STR00102##
[1075] Step 1: In an analogous manner to general procedure I, step
1, 2,4,6-trifluoro-N-(2-nitrophenyl)aniline was prepared from
2,4,6-trifluoroaniline and 1-fluoro-2-nitrobenzene as a bright
yellow solid. MS (ESI) m/z 269.0 ([M+H].sup.+).
[1076] Step 2: In an analogous manner to general procedure I, step
2, N-(2,4,6-trifluorophenyl)benzene-1,2-diamine was prepared from
2,4,6-trifluoro-N-(2-nitrophenyl)aniline as a gray solid. MS (ESI)
m/z 239.1 ([M+H].sup.+).
[1077] Step 3: In an analogous manner to general procedure I, step
3, 1-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from
N-(2,4,6-trifluorophenyl)benzene-1,2-diamine as a white solid. MS
(ESI) m/z 298.8 ([M-H].sup.-). HRMS: calculated for
C.sub.12H.sub.7F.sub.3N.sub.2O.sub.2S, 300.0180; found (EI,
M.sup.+.), 300.0186.
[1078] Step 4: In an analogous manner as described in general
procedure II,
1-(2-piperazin-1-ylethyl)-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-
-benzothiadiazole 2,2-dioxide dihydrochloride was prepared from
1-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and tert-butyl
4-(2-hydroxyethyl)piperazine-1-carboxylate as a white solid. MS
(ESI) m/z 413.0 ([M+H].sup.+). HRMS: calculated for
C.sub.18H.sub.19F.sub.3N.sub.4O.sub.2S+H.sup.+, 413.1254; found
(ESI, [M+H].sup.+), 413.1266.
Example 56
1-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-(2,4,6-trifluorophenyl)-1,3--
dihydro-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride
##STR00103##
[1080] In an analogous manner as described in general procedure VI,
1-(2-bromoethyl)-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadia-
zole 2,2-dioxide was prepared from
1-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure I) and 2-bromoethanol as white needles. HRMS:
calculated for C.sub.14H.sub.10BrF.sub.3N.sub.2O.sub.2S, 405.9598;
found (EI, M.sup.+.), 405.9602.
[1081] In an analogous manner as described in general procedure V,
1-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-3-(2,4,6-trifluorophenyl)-1,3-
-dihydro-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride was
prepared from
1-(2-bromoethyl)-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide as a white powder. MS (ESI) m/z 441.0
([M+H].sup.+). HRMS: calculated for
C.sub.20H.sub.23F.sub.3N.sub.4O.sub.2S+H.sup.+, 441.1567; found
(ESI, [M+H].sup.+), 441.1582.
Example 57
1-Phenyl-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide dihydrochloride
##STR00104##
[1083] Step 1: A mixture of
1-(3-bromopropyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure V), 1-Boc-piperazine (624 mg, 3.35 mmol, 6
equiv.), sodium carbonate (granular, 355 mg, 3.35 mmol, 6 equiv.),
and ethanol (5 mL) in a sealed reaction vessel was heated at
90.degree. C. for 8 h. After cooling, solid sodium carbonate was
removed by decantation, and the supernatant was concentrated and
re-dissolved in ethyl acetate (15 mL). The resulting solution was
washed with water, dried (anhydrous sodium sulfate), and
concentrated. The crude oil was pre-adsorbed onto Florisil and
purified via Isco flash column chromatography (4-g redisep silica
gel column, 5-60% ethyl acetate/hexane) to give 252 mg (96%) of
tert-butyl
4-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]piperazi-
ne-1-carboxylate as a viscous, brown liquid. MS (ESI) m/z 473.1
([M+H].sup.+).
[1084] Step 2: In an analogous manner as described in general
procedure II, step 2,
1-phenyl-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide dihydrochloride was prepared from tert-butyl
4-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]piperazi-
ne-1-carboxylate as a light pink solid. MS (ESI) m/z 372.9
([M+H].sup.+). HRMS: calculated for
C.sub.19H.sub.24N.sub.4O.sub.2S+H.sup.+, 373.1693; found (ESI,
[M+H].sup.+), 373.1694.
Example 58
1-(4-Fluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide dihydrochloride
##STR00105##
[1086] In an analogous manner as described in general procedure II,
1-(4-fluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide dihydrochloride was prepared from
1-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(prepared in an analogous manner as described in general procedure
I) and tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate as a
white powder. HRMS: calculated for
C.sub.18H.sub.21FN.sub.4O.sub.2S+H.sup.+, 377.1442; found (ESI,
[M+H].sup.+), 377.1443.
Example 59
1-[2-(cis-3,5-Dimethylpiperazin-1-yl)ethyl]-3-(4-fluorophenyl)-1,3-dihydro-
-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride
##STR00106##
[1088] In an analogous manner as described in general procedure VI,
1-(2-bromoethyl)-3-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from
1-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(prepared in an analogous manner as described in general procedure
I) and 2-bromoethanol as a white solid. HRMS: calculated for
C.sub.14H.sub.12BrFN.sub.2O.sub.2S+Na.sup.+, 392.9679; found (ESI,
[M+Na].sup.+), 392.9680.
[1089] In an analogous manner as described in general procedure V,
1-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-3-(4-fluorophenyl)-1,3-dihydr-
o-2,1,3-benzothiadiazole 2,2-dioxide was prepared from
1-(2-bromoethyl)-3-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide as a white powder. MS (ESI) m/z 404.9 ([M+H].sup.+).
HRMS: calculated for C.sub.20H.sub.25FN.sub.4O.sub.2S+H.sup.+,
405.1755; found (ESI, [M+H].sup.+), 405.1756.
Example 60
1-(2,4-difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide hydrochloride
##STR00107##
[1091] In an analogous manner to General procedure II, step 3,
1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from
N-(2,4-difluorophenyl)benzene-1,2-diamine and sulfamide as a white
solid. MS (ES) m/z 280.8.
[1092] In an analogous manner as described in general procedure II,
1-(2,4-difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide hydrochloride was prepared from
1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and tert-butyl
4-(2-hydroxyethyl)piperazine-1-carboxylate as an off-white solid.
MS (ES) m/z 394.9; HRMS: calculated for
C.sub.18H.sub.20F.sub.2N.sub.4O.sub.2S+H.sup.+, 395.13478; found
(ESI, [M+H].sup.+), 395.1356.
Example 61
1-(2,4-difluorophenyl)-3-[2-(3,5-dimethylpiperazin-1-yl)ethyl]-1,3-dihydro-
-2,1,3-benzothiadiazole 2,2-dioxide hydrochloride
##STR00108##
[1094] In an analogous manner to General procedure VI,
1-(2-bromoethyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide was prepared from
1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure I) and 2-bromo-ethanol as a oil. MS (ES) m/z
[M+H].sup.+ 388.9.
[1095] In an analogous manner to general procedure V,
1-(2,4-difluorophenyl)-3-[2-(3,5-dimethylpiperazin-1-yl)ethyl]-1,3-dihydr-
o-2,1,3-benzothiadiazole 2,2-dioxide hydrochloride was prepared
from
1-(2-bromoethyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide and 2,6-dimethylpiperazine as grey solid. MS (ES) m/z
423.1; HRMS: calculated for
C.sub.20H.sub.24F.sub.2N.sub.4O.sub.2S+H+, 423.16608; found (ESI,
[M+H].sup.+), 423.1665.
Example 62
1-[2-(3,5-dimethylpiperazin-1-yl)ethyl]-4-fluoro-3-(2-fluorophenyl)-1,3-di-
hydro-2,1,3-benzothiadiazole 2,2-dioxide hydrochloride
##STR00109##
[1097] In an analogous manner to General procedure VI,
1-(2-bromoethyl)-4-fluoro-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide was prepared from
7-fluoro-1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure I) and 2-bromo-1-ethanol as a brown oil. MS (ES)
m/z 388.8.
[1098] In an analogous manner to General procedure VI,
1-[2-(3,5-dimethylpiperazin-1-yl)ethyl]-4-fluoro-3-(2-fluorophenyl)-1,3-d-
ihydro-2,1,3-benzothiadiazole 2,2-dioxide hydrochloride was
prepared from
1-(2-bromoethyl)-4-fluoro-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide as a white solid. HRMS: calculated for
C.sub.20H.sub.24F.sub.2N.sub.4O.sub.2S+H+, 423.16608; found (ESI,
[M+H]+), 434.1786.
Example 63
1-(2-{[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]m-
ethyl}phenyl)-N-methylmethanamine
##STR00110##
[1100] Step 1: In an analogous manner to general procedure IV,
1-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure I, 75 mg, 0.27 mmol) was treated with cesium
carbonate (132 mg, 0.4 mmol) and
.alpha.,.alpha.-dibromo-ortho-xylene (346 mg, 1.32 mmol) to give 68
mg of
1-[2-(bromomethyl)benzyl]-3-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide.
[1101] HPLC purity 88.5% at 210-370 nm, 11.1 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH)
for 10 minutes hold 4 minutes.
[1102] HRMS: calculated for
C.sub.20H.sub.15BrF.sub.2N.sub.2O.sub.2S, 464.00056; found (EI,
M.sup.+.--SO.sub.2), 400.0129;
[1103] Step 2: In an analogous manner to general procedure V,
1-[2-(bromomethyl)benzyl]-3-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide (38 mg, 0.082 mmol) was treated with methyl
amine to give
1-(2-{[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1-
(3H)-yl]methyl}phenyl)-N-methylmethanamine hydrochloride (18 mg,
48%) after treatment with HCl.
[1104] HPLC purity 97.5% at 210-370 nm, 8.1 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH)
for 10 minutes hold 4 minutes.
[1105] HRMS: calculated for
C.sub.21H.sub.19F.sub.2N.sub.3O.sub.2S+H.sup.+, 416.12388; found
(ESI, [M+H].sup.+), 416.1225
Example 64
3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-me-
thyl-1-phenylpropan-1-amine
[1106] Step 1: A solution of 3-(methylamino)-3-phenylpropan-1-ol
(800 mg, 4.85 mmol) in THF was treated with Boc-anhydride (1M in
THF, 6 mL, 6 mmol) and stirred for 16 h. The mixture was
concentrated and the crude product was purified via Isco
chromatography (Redisep, silica, gradient 5-75% ethyl acetate in
hexane) to afford 0.74 g of tert-butyl
(3-hydroxy-1-phenylpropyl)methylcarbamate.
[1107] HPLC purity 100.0% at 210-370 nm, 8.7 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH)
for 10 minutes hold 4 minutes.
[1108] HRMS: calculated for C.sub.15H.sub.23NO.sub.3+Na.sup.+,
288.15701; found (ESI, [M+Na].sup.+), 288.1575
[1109] Step 2: In an analogous manner to general procedure II,
1-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure I, 115 mg, 0.41 mmol) was treated with
triphenylphosphine (0.13 g, 0.49 mmol), tert-butyl
(3-hydroxy-1-phenylpropyl)methylcarbamate (0.12 g, 0.45 mmol), and
diisopropylazodicarboxylate (0.095 mL, 0.49 mmol) to provide 0.12 g
tert-butyl
{3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
phenylpropyl}methylcarbamate.
[1110] HPLC purity 97.8% at 210-370 nm, 11.4 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH)
for 10 minutes hold 4 minutes.
[1111] HRMS: calculated for
C.sub.27H.sub.29F.sub.2N.sub.3O.sub.4S+Na.sup.+, 552.17390; found
(ESI, [M+Na].sup.+), 552.1733
[1112] Step 3: tert-butyl
{3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
phenylpropyl}methylcarbamate (0.10 g, 0.19 mmol) was treated with
an excess of 2N HCl in ether. The precipitated amine salt was
collected to give 65 mg of
3-[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethyl-1-phenylpropan-1-amine.
[1113] HPLC purity 98.8% at 210-370 nm, 8.5 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH)
for 10 minutes hold 4 minutes.
[1114] HRMS: calculated for
C.sub.22H.sub.21F.sub.2N.sub.3O.sub.2S+H.sup.+, 430.13953; found
(ESI, [M+H].sup.+), 430.1394
Example 65
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
-1-phenylpropan-1-amine
[1115] Step 1: In an analogous manner to general procedure II,
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(prepared in an analogous manner as described in general procedure
I, 108 mg, 0.41 mmol) was treated with triphenylphosphine (0.13 g,
0.49 mmol), tert-butyl (3-hydroxy-1-phenylpropyl)methylcarbamate
(0.12 g, 0.45 mmol), and diisopropylazodicarboxylate (0.095 mL,
0.49 mmol) to provide 0.13 g tert-butyl
{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-phen-
ylpropyl}methylcarbamate.
[1116] HPLC purity 100.0% at 210-370 nm, 11.3 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH)
for 10 minutes hold 4 minutes.
[1117] HRMS: calculated for
C.sub.27H.sub.30FN.sub.3O.sub.4S+Na.sup.+, 534.18332; found (ESI,
[M+Na].sup.+), 534.1827
[1118] Step 2: tert-butyl
{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-phen-
ylpropyl}methylcarbamate (0.11 g, 0.22 mmol) was treated with an
excess of 2N HCl in ether. The precipitated amine salt was
collected to give 55 mg of
3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-me-
thyl-1-phenylpropan-1-amine.
[1119] HPLC purity 100.0% at 210-370 nm, 8.3 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH)
for 10 minutes hold 4 minutes.
[1120] HRMS: calculated for
C.sub.22H.sub.22FN.sub.3O.sub.2S+H.sup.+, 412.14895; found (ESI,
[M+H].sup.+), 412.1493;
Example 66
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-
but-2-yn-1-amine
[1121] Step 1: In an analogous manner to general procedure IV,
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(prepared in an analogous manner as described in general procedure
I, 0.79 g, 3.0 mmol) was treated with cesium carbonate (1.46 g, 4.5
mmol) and but-2-yne-1,4-diyl dimethane-sulfonate (3.63 g, 15.0
mmol) to give 0.55 g of
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]but-2-yn-1-yl methanesulfonate.
[1122] MS (ES) m/z 410.8;
[1123] HPLC purity 95.2% at 210-370 nm, 9.1 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH)
for 10 minutes hold 4 minutes.
[1124] Step 2: In an analogous manner to general procedure V,
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]but-2-yn-
-1-yl methanesulfonate (0.25 g, 0.60 mmol) was treated with methyl
amine to give
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N-methylbut-2-yn-1-amine hydrochloride (78 mg) after treatment
with HCl.
[1125] HPLC purity 100.0% at 210-370 nm, 8.7 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammon.
Bicarb Buff. pH=9.5/ACN+MeOH)
for 10 minutes hold 4 minutes.
[1126] HRMS: calculated for
C.sub.17H.sub.16FN.sub.3O.sub.2S+H.sup.+, 346.10200; found (ESI,
[M+H].sup.+), 346.1027;
Example 67
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dime-
thylbut-2-yn-1-amine
[1127] In an analogous manner to General Procedure V,
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]but-2-yn-
-1-yl methanesulfonate (0.25 g, 0.60 mmol) was treated with
dimethyl amine to
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N--
dimethylbut-2-yn-1-amine hydrochloride (48 mg) after treatment with
HCl.
[1128] HPLC purity 100.0% at 210-370 nm, 9.2 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammon.
Bicarb Buff. pH=9.5/ACN+MeOH)
for 10 minutes hold 4 minutes.
[1129] HRMS: calculated for
C.sub.18H.sub.18FN.sub.3O.sub.2S+H.sup.+, 360.11765; found (ESI,
[M+H].sup.+), 360.118;
Example 68
(2E)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-m-
ethylbut-2-en-1-amine
[1130] Step 1: In an analogous manner to general procedure IV,
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(prepared in an analogous manner as described in general procedure
I, 0.264 g, 1.0 mmol) was treated with cesium carbonate (0.49 g,
1.5 mmol) and (E)-1,4-dibromobut-2-ene (1.07 g, 5.0 mmol) to give
0.26 g of
1-[(2E)-4-bromobut-2-en-1-yl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide.
[1131] HPLC purity 100.0% at 210-370 nm, 10.3 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH)
for 10 minutes hold 4 minutes.
[1132] HRMS: calculated for
C.sub.16H.sub.14BrFN.sub.2O.sub.2S+H.sup.+, 397.00161; found (ESI,
[M+H].sup.+), 397.0025;
[1133] Step 2: In an analogous manner to general procedure V,
1-[(2E)-4-bromobut-2-en-1-yl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide (0.13 g, 0.33 mmol) was treated with methyl
amine to give
(2E)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]-N-methylbut-2-en-1-amine (105 mg) after treatment with
HCl.
[1134] HPLC purity 100.0% at 210-370 nm, 8.7 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammon.
Bicarb Buff. pH=9.5/ACN+MeOH)
for 10 minutes hold 4 minutes.
[1135] HRMS: calculated for
C.sub.17H.sub.18FN.sub.3O.sub.2S+H.sup.+, 348.11765; found (ESI,
[M+H].sup.+), 348.1181;
Example 69
(2E)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-
-dimethylbut-2-en-1-amine
[1136] Step 1: In an analogous manner to general procedure V,
1-[(2E)-4-bromobut-2-en-1-yl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide (0.13 g, 0.33 mmol) was treated with
dimethyl amine to give
(2E)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]-N,N-dimethylbut-2-en-1-amine (90 mg) after treatment with
HCl.
[1137] HPLC purity 100.0% at 210-370 nm, 9.4 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammon.
Bicarb Buff. pH=9.5/ACN+MeOH)
for 10 minutes hold 4 minutes.
[1138] HRMS: calculated for
C.sub.18H.sub.20FN.sub.3O.sub.2S+H.sup.+, 362.13330; found (ESI,
[M+H].sup.+), 362.135;
Example 70
3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethyl}-4-fluoro-1-(2-fluorophenyl-
)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
[1139] Step 1: In an analogous manner to general procedure VI,
4-fluoro-1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure I, 0.5 g, 1.77 mmol), was treated with
triphenylphosphine (0.56 g, 2.13 mmol), 3-bromoethanol (0.125 mL,
1.77 mmol), and diisopropylazodicarboxylate (0.41 mL, 2.13 mmol) to
provide 0.51 g
3-(2-bromoethyl)-4-fluoro-1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide.
[1140] HPLC purity 95.2% at 210-370 nm, 10.4 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH)
for 10 minutes hold 4 minutes.
[1141] Step 2: In an analogous manner to general procedure V, Step
3,
3-(2-bromoethyl)-4-fluoro-1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide (0.50 g, 1.29 mmol) was treated with
2,6-dimethylpiperazine (0.44 g, 3.85 mL) in DMF (5 mL) to provide
3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethyl}-4-fluoro-1-(2-fluoropheny-
l)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride
(0.23 g) after treatment with HCl.
[1142] HPLC purity 100.0% at 210-370 nm, 7.8 minutes; Xterra RP18,
3.5 u, 150.times.4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium
formate buffer pH=3.5/ACN+MeOH)
for 10 minutes hold 4 minutes.
[1143] HRMS: calculated for
C.sub.20H.sub.24F.sub.2N.sub.4O.sub.2S+H.sup.+, 423.16608; found
(ESI, [M+H].sup.+), 423.1662;
Example 71
2,2-difluoro-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]-N-methylpropan-1-amine hydrochloride
##STR00111##
[1145] To a solution of methylamine in methanol (33% wt, 10 mL) was
added methyl 2,2-difluoro-3-hydroxypropanoate (1.0 g, 7.1 mmol) and
the mixture stirred at room temperature overnight. After
evaporation the residue was recrystallized from diethyl
ether/hexanes to afford
2,2-difluoro-3-hydroxy-N-methylpropanamide.
[1146] In an analogous manner as described in general procedure VI,
2,2-difluoro-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]-N-methylpropanamide was prepared from
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
and 2,2-difluoro-3-hydroxy-N-methylpropanamide to afford the
product as an impure solid.
[1147] To a stirred solution of
2,2-difluoro-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]-N-methylpropanamide (ca. 1 mmol) at 0.degree. C., was added
borane-tetrahydrofuran complex (1 M in THF, 3 mL, 3 mmol). After
stirring for 2 h, the mixture was quenched with dilute hydrochloric
acid, basified (2 N NaOH) and extracted with ethylacetate. The
organic layer was washed with water, dried (MgSO.sub.4) and
evaporated. The residue was purified by silica gel column
chromatography (hexanes: ethylacetate, gradient elution) to afford
the crude product which was further purified by reverse phase hplc
(Xterra RP18 19.times.150 mm, 5 u, 55% MeOH 45% H.sub.2O w/0.05%
NH.sub.4OH, 20 mL/min). The residue obtained was dissolved in
diethyl ether, treated with excess ethereal HCl and lyophilized to
afford
2,2-difluoro-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]-N-methylpropan-1-amine hydrochloride as a white solid.
[1148] MS (ESI) m/z 372; HPLC purity 100.0% at 210-370 nm, 6.9
minutes; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2
mL/minutes 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for
10 minutes hold 4 minutes.
[1149] HRMS: calculated for
C.sub.16H.sub.16F.sub.3N.sub.3O.sub.2S+H.sup.+, 372.09881; found
(ESI, [M+H].sup.+), 372.0982
Example 72
1-(2-Fluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide hydrochloride
##STR00112##
[1151] In an analogous manner as described in general procedure II,
tert-butyl
4-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}piperidine-1-carboxylate was prepared from
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(general procedure I) and N-boc-4-piperidineethanol as a viscous,
colorless liquid. MS (ESI) m/z 475.9 ([M+H].sup.+).
[1152] HRMS: calcd for C.sub.24H.sub.30FN.sub.3O.sub.4S+H.sup.+,
476.2014; found (ESI, [M+H].sup.+), 476.2016.
[1153] HPLC purity 93.9% at 210-370 nm, 11.1 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1154] In an analogous manner as described in general procedure II,
step 2,
1-(2-fluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide hydrochloride was prepared from tert-butyl
4-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}piperidine-1-carboxylate as a white powder. MS (ESI) m/z 376.2
([M+H].sup.+). HPLC purity 95.2% at 210-370 nm, 7.4 min.; Xterra
RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 73
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide dihydrochloride
##STR00113##
[1156] Step 1: A mixture of
1-(2-bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure VI, 112 mg, 0.317 mmol), tert-butyl
1-homopiperazinecarboxylate (381 mg, 1.90 mmol, 6 equiv.), sodium
carbonate (202 mg, 1.90 mmol, 6 equiv.) and ethanol (4 mL) in a
sealed reaction vessel was heated at 90.degree. C. for 8 h. After
cooling, solvent was removed, and the residue was dissolved in
ethyl acetate (15 mL). The resulting solution was washed with an
aqueous potassium carbonate solution, water, dried (anhydrous
sodium sulfate), and concentrated. The crude liquid was
pre-adsorbed onto Florisil and purified via Isco flash column
chromatography (4-g redisep silica gel column, 10-60% ethyl
acetate/hexane) to give tert-butyl
4-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]-1,4-diaz-
epane-1-carboxylate as a viscous, colorless liquid. Yield: 121 mg
(81%). MS (ESI) m/z 473.0 ([M+H].sup.+). HPLC purity 100.0% at
210-370 nm, 9.7 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column,
1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10
min, hold 4 min.
[1157] Step 2: In an analogous manner as described in general
procedure II, step 2,
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide dihydrochloride was prepared from tert-butyl
4-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]-1,4-diaz-
epane-1-carboxylate as a white powder. MS (ESI) m/z 372.9
([M+H].sup.+). HPLC purity 100.0% at 210-370 nm, 7.4 min.; Xterra
RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 74
1-(2,4-Difluorophenyl)-4-fluoro-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,-
3-benzothiadiazole 2,2-dioxide dihydrochloride
##STR00114##
[1159] Step 1: In an analogous manner to general procedure I, step
1, N-(2,4-difluorophenyl)-3-fluoro-2-nitroaniline was prepared from
2,4-difluoroaniline and 2,6-difluoronitrobenzene as a white powder.
MS (ESI) m/z 268.8 ([M+H].sup.+). HPLC purity 97.9% at 210-370 nm,
10.1 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
[1160] Step 2: In an analogous manner to general procedure I, step
2, N1-(2,4-difluorophenyl)-3-fluorobenzene-1,2-diamine was prepared
from N-(2,4-difluorophenyl)-3-fluoro-2-nitroaniline as a dark
solid. MS (ESI) m/z 238.9 ([M+H].sup.+). HPLC purity 96.7% at
210-370 nm, 9.6 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column,
1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10
min, hold 4 min.
[1161] Step 3: In an analogous manner to general procedure I, step
3,
1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from
N1-(2,4-difluorophenyl)-3-fluorobenzene-1,2-diamine as a white
solid. MS (ESI) m/z 298.7 ([M-H].sup.-).
[1162] Step 4: In an analogous manner as described in general
procedure II, tert-butyl
4-{2-[3-(2,4-difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1-
(3H)-yl]ethyl}piperazine-1-carboxylate was t prepared from
1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and tert-butyl
4-(2-hydroxyethyl)piperazine-1-carboxylate as a viscous, colorless
liquid. MS (ESI) m/z 512.9 ([M+H].sup.+). HPLC purity 100.0% at
210-370 nm, 10.8 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column,
1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10
min, hold 4 min.
[1163] Step 5: In an analogous manner as described in general
procedure II, step 2,
1-(2,4-difluorophenyl)-4-fluoro-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1-
,3-benzothiadiazole 2,2-dioxide dihydrochloride was prepared from
tert-butyl
4-{2-[3-(2,4-difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1-
(3H)-yl]ethyl}piperazine-1-carboxylate as a white powder. MS (ESI)
m/z 412.8 ([M+H].sup.+). HRMS: calcd for
C.sub.18H.sub.19F.sub.3N.sub.4O.sub.2S+H.sup.+, 413.1254; found
(ESI, [M+H].sup.+), 413.1261. HPLC purity 99.2% at 210-370 nm, 8.6
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
Example 75
3-(2,4-Difluorophenyl)-4-fluoro-1-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,-
3-benzothiadiazole 2,2-dioxide dihydrochloride
##STR00115##
[1165] Step 1: In an analogous manner to general procedure I, step
1, 2,4-difluoro-N-(2-fluoro-6-nitrophenyl)aniline was prepared from
2,4-difluoroaniline and 2,3-difluoronitrobenzene as orange needles.
MS (ESI) m/z 268.8 ([M+H].sup.+). HPLC purity 97.1% at 210-370 nm,
10.1 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
[1166] Step 2: In an analogous manner to General procedure I, step
2, N2-(2,4-difluorophenyl)-3-fluorobenzene-1,2-diamine was prepared
from 2,4-difluoro-N-(2-fluoro-6-nitrophenyl)aniline as a white
solid. MS (ESI) m/z 238.9 ([M+H].sup.+). HPLC purity 99.7% at
210-370 nm, 9.3 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column,
1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10
min, hold 4 min.
[1167] Step 3: In an analogous manner to general procedure I, step
3,
1-(2,4-difluorophenyl)-7-fluoro-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from
N2-(2,4-difluorophenyl)-3-fluorobenzene-1,2-diamine as a white
solid. MS (ESI) m/z 298.7 ([M-H].sup.-).
[1168] Step 4: In an analogous manner as described in general
procedure II, tert-butyl
4-{2-[3-(2,4-difluorophenyl)-4-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1-
(3H)-yl]ethyl}piperazine-1-carboxylate was prepared from
1-(2,4-difluorophenyl)-7-fluoro-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and tert-butyl
4-(2-hydroxyethyl)piperazine-1-carboxylate as a viscous, colorless
liquid. MS (ESI) m/z 512.8 ([M+H].sup.+). HRMS: calcd for
C.sub.23H.sub.27F.sub.3N.sub.4O.sub.4S+H.sup.+, 513.1778; found
(ESI, [M+H].sup.+), 513.1776. HPLC purity 96.4% at 210-370 nm, 10.7
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
[1169] Step 5: In an analogous manner as described in general
procedure II, step 2,
3-(2,4-difluorophenyl)-4-fluoro-1-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1-
,3-benzothiadiazole 2,2-dioxide dihydrochloride was prepared from
tert-butyl
4-{2-[3-(2,4-difluorophenyl)-4-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1-
(3H)-yl]ethyl}piperazine-1-carboxylate as a white powder. MS (ESI)
m/z 412.8 ([M+H].sup.+). HRMS: calcd for
C.sub.18H.sub.19F.sub.3N.sub.4O.sub.2S+H.sup.+, 413.1254; found
(ESI, [M+H].sup.+), 413.1259. HPLC purity 98.2% at 210-370 nm, 7.7
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
Example 76
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-
-benzothiadiazole 2,2-dioxide dihydrochloride
##STR00116##
[1171] Step 1: In an analogous manner as described in general
procedure V, step tert-butyl
4-{2-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-y-
l]ethyl}-1,4-diazepane-1-carboxylate 1, was prepared from
1-(2-bromoethyl)-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadia-
zole 2,2-dioxide a viscous, colorless liquid. MS (ESI) m/z 527.0
([M+H].sup.+). HRMS: calcd for
C.sub.24H.sub.29F.sub.3N.sub.4O.sub.4S+H.sup.+, 527.1934; found
(ESI, [M+H].sup.+), 527.1935. HPLC purity 95.5% at 210-370 nm, 9.1
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
[1172] Step 2: In an analogous manner as described in general
procedure II, step 2,
1-[2-(1,4-diazepan-1-yl)ethyl]-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,-
3-benzothiadiazole 2,2-dioxide dihydrochloride was prepared from
tert-butyl
4-{2-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-y-
l]ethyl}-1,4-diazepane-1-carboxylate as a white powder. MS (ESI)
m/z 426.9 ([M+H].sup.+).
[1173] HRMS: calcd for
C.sub.19H.sub.21F.sub.3N.sub.4O.sub.2S+H.sup.+, 427.1410; found
(ESI, [M+H].sup.+), 427.1421.
[1174] HPLC purity 96.5% at 210-370 nm, 7.2 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 77
1-{2-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]ethyl}-3-(2,4,6-trifluoroph-
enyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
dihydrochloride
##STR00117##
[1176] Step 1: In an analogous manner as described in general
procedure V, tert-butyl
(1S,4S)-5-{2-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-
-1(3H)-yl]ethyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was
prepared as a white foam from
1-(2-bromoethyl)-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadia-
zole 2,2-dioxide and 2 equiv. of tert-butyl
(1-S,4S-(-)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate using 3
equiv. of sodium carbonate. MS (ESI) m/z 524.9 ([M+H].sup.+). HRMS:
calcd for C.sub.24H.sub.27F.sub.3N.sub.4O.sub.4S+H.sup.+, 525.1778;
found (ESI, [M+H].sup.+), 525.1785. HPLC purity 100.0% at 210-370
nm, 8.5 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2
mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min,
hold 4 min.
[1177] Step 2: In an analogous manner as described in general
procedure II, step 2,
1-{2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl}-3-(2,4,6-trifluorop-
henyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
dihydrochloride was prepared from tert-butyl
(1S,4S)-5-{2-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-
-1(3H)-yl]ethyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate MS
(ESI) m/z 424.8 ([M+H].sup.+). HRMS: calcd for
C.sub.19H.sub.19F.sub.3N.sub.4O.sub.2S+H.sup.+, 425.1254; found
(ESI, [M+H].sup.+), 425.1260.
Example 78
3-[2-(1,4-Diazepan-1-yl)ethyl]-1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydro-
-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride
##STR00118##
[1179] Step 1: In an analogous manner as described in general
procedure VI,
3-(2-bromoethyl)-1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide was prepared from
1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and 2-bromoethanol as a viscous, colorless liquid. HPLC
purity 97.5% at 210-370 nm, 10.4 min.; Xterra RP18, 3.5 u,
150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff
pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1180] Step 2: In an analogous manner as described in general
procedure V, tert-butyl
4-{2-[3-(2,4-difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1-
(3H)-yl]ethyl}-1,4-diazepane-1-carboxylate was prepared from
3-(2-bromoethyl)-1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide a viscous, colorless liquid. HPLC purity
96.2% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm
column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH)
for 10 min, hold 4 min.
[1181] Step 3: In an analogous manner as described in general
procedure II, step 2,
3-[2-(1,4-diazepan-1-yl)ethyl]-1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydr-
o-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride was prepared
from tert-butyl
4-{2-[3-(2,4-difluorophenyl)-7-fluoro-2,2-dioxido-2,1,3-benzothiadiazol-1-
(3H)-yl]ethyl}-1,4-diazepane-1-carboxylate as a white powder. HRMS:
calcd for C.sub.19H.sub.21F.sub.3N.sub.4O.sub.2S+H.sup.+, 427.1410;
found (ESI, [M+H].sup.+), 427.1420. HPLC purity 100.0% at 210-370
nm, 7.6 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2
mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min,
hold 4 min.
Example 79
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide dihydrochloride
##STR00119##
[1183] In an analogous manner as described in general procedure V,
tert-butyl
4-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}-1,4-diazepane-1-carboxylate was prepared from
1-(2-bromoethyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure VI) a viscous, colorless liquid. MS (ESI) m/z
490.9 ([M+H].sup.+). HRMS: calcd for
C.sub.24H.sub.31FN.sub.4O.sub.4S+H.sup.+, 491.2123; found (ESI,
[M+H].sup.+), 491.2119. HPLC purity 95.9% at 210-370 nm, 8.9 min.;
Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1184] In an analogous manner as described in general procedure II,
step 2,
1-[2-(1,4-diazepan-1-yl)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide dihydrochloride was prepared from
tert-butyl
4-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}-1,4-diazepane-1-carboxylate as a white powder. MS (ESI) m/z 390.9
([M+H].sup.+). HRMS: calcd for
C.sub.19H.sub.23FN.sub.4O.sub.2S+H.sup.+, 391.1599; found (ESI,
[M+H].sup.+), 391.1599. HPLC purity 98.4% at 210-370 nm, 7.0 min.;
Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 80
1-{2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl}-3-(2-fluorophenyl)-1-
,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride
##STR00120##
[1186] In an analogous manner as described in general procedure V,
tert-butyl
(1S,4S)-5-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)--
yl]ethyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was prepared
as a viscous, colorless liquid from
1-(2-bromoethyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure VI) and 2 equiv. of tert-butyl
(1-S,4S-(-)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate using 3
equiv. of sodium carbonate. MS (ESI) m/z 488.9 ([M+H].sup.+). HRMS:
calcd for C.sub.24H.sub.29FN.sub.4O.sub.4S+H.sup.+, 489.1966; found
(ESI, [M+H].sup.+), 489.1969.
[1187] In an analogous manner as described in general procedure II,
step 2,
1-{2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl}-3-(2-fluoropheny-
l)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride
was prepared from tert-butyl
(1S,4S)-5-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)--
yl]ethyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as a white
powder. MS (ESI) m/z 388.8 ([M+H].sup.+). HRMS: calcd for
C.sub.19H.sub.21FN.sub.4O.sub.2S+H.sup.+, 389.1442; found (ESI,
[M+H].sup.+), 389.1450.
Example 81
1-Phenyl-3-(2-piperidin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride
##STR00121##
[1189] In an analogous manner as described in general procedure V,
1-phenyl-3-(2-piperidin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide hydrochloride was prepared from
1-(2-bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure VI) and piperidine as a white powder. MS (ESI)
m/z 358.2 ([M+H].sup.+). HPLC purity 100.0% at 210-370 nm, 7.2
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
Example 82
1-(2,4-Difluorophenyl)-3-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-4-fluor-
o-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
dihydrochloride
##STR00122##
[1191] In an analogous manner as described in general procedure V,
1-(2,4-difluorophenyl)-3-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-4-fluo-
ro-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride
was prepared from
3-(2-bromoethyl)-1-(2,4-difluorophenyl)-4-fluoro-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide (prepared in an analogous manner as
described in general procedure VI) and cis-2,6-dimethylpiperazine
as a white powder. MS (ESI) m/z 440.9 ([M+H].sup.+). HRMS: calcd
for C.sub.20H.sub.23F.sub.3N.sub.4O.sub.2S+H.sup.+, 441.1567; found
(ESI, [M+H].sup.+), 441.1566. HPLC purity 100.0% at 210-370 nm, 8.0
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
Example 83
1-[3-(1,4-Diazepan-1-yl)propyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide dihydrochloride
##STR00123##
[1193] In an analogous manner as described in general procedure V,
tert-butyl
4-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]-1,4-dia-
zepane-1-carboxylate was prepared from
1-(3-bromopropyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner as described in
general procedure VI) as a viscous, colorless liquid. MS (ESI) m/z
486.9 ([M+H].sup.+). HRMS: calcd for
C.sub.25H.sub.34N.sub.4O.sub.4S+H.sup.+, 487.2373; found (ESI,
[M+H].sup.+), 487.2375. HPLC purity 99.3% at 210-370 nm, 8.5 min.;
Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1194] In an analogous manner as described in general procedure II,
step 2,
1-[3-(1,4-diazepan-1-yl)propyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide dihydrochloride was prepared from tert-butyl
4-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]-1,4-dia-
zepane-1-carboxylate as a white powder. MS (ESI) m/z 386.8
([M+H].sup.+). HRMS: calcd for
C.sub.20H.sub.26N.sub.4O.sub.2S+H.sup.+, 387.1849; found (ESI,
[M+H].sup.+), 387.1852. HPLC purity 100.0% at 210-370 nm, 6.0 min.;
Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 84
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide dihydrochloride
##STR00124##
[1196] In an analogous manner as described in general procedure V,
tert-butyl
4-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thyl}-1,4-diazepane-1-carboxylate was prepared from
1-(2-bromoethyl)-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide (prepared in an analogous manner as described in
general procedure VI) as a viscous, colorless liquid. MS (ESI) m/z
508.9 ([M+H].sup.+). HRMS: calcd for
C.sub.24H.sub.30F.sub.2N.sub.4O.sub.4S+H.sup.+, 509.2029; found
(ESI, [M+H].sup.+), 509.2033. HPLC purity 100.0% at 210-370 nm, 8.5
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
[1197] In an analogous manner as described in general procedure II,
step 2,
1-[2-(1,4-diazepan-1-yl)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,-
3-benzothiadiazole 2,2-dioxide dihydrochloride was prepared from
tert-butyl
4-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thyl}-1,4-diazepane-1-carboxylate as a white powder. MS (ESI) m/z
408.9 ([M+H].sup.+).
[1198] HRMS: calcd for
C.sub.19H.sub.22F.sub.2N.sub.4O.sub.2S+H.sup.+, 409.1504; found
(ESI, [M+H].sup.+), 409.1510.
[1199] HPLC purity 98.7% at 210-370 nm, 6.8 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 85
1-[2-(1,4-Diazepan-1-yl)ethyl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide dihydrochloride
##STR00125##
[1201] Step 1: In an analogous manner as described in general
procedure V, tert-butyl
4-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thyl}-1,4-diazepane-1-carboxylate was prepared from
1-(2-bromoethyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide (prepared in an analogous manner as described in
general procedure VI) as a viscous, colorless liquid. MS (ESI) m/z
508.9 ([M+H].sup.+). HRMS: calcd for
C.sub.24H.sub.30F.sub.2N.sub.4O.sub.4S+H.sup.+, 509.2029; found
(ESI, [M+H].sup.+), 509.2031. HPLC purity 98.3% at 210-370 nm, 9.0
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
[1202] Step 2: In an analogous manner as described in general
procedure II, step 2,
1-[2-(1,4-diazepan-1-yl)ethyl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide dihydrochloride was prepared from
tert-butyl
4-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thyl}-1,4-diazepane-1-carboxylate as a white powder. MS (ESI) m/z
408.9 ([M+H].sup.+).
[1203] HRMS: calcd for
C.sub.19H.sub.22F.sub.2N.sub.4O.sub.2S+H.sup.+, 409.1504; found
(ESI, [M+H].sup.+), 409.1509.
[1204] HPLC purity 100.0% at 210-370 nm, 7.3 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 86
1-{2-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]ethyl}-3-(2,4-difluoropheny-
l)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
dihydrochloride
##STR00126##
[1206] In an analogous manner as described in general procedure V,
tert-butyl
(1S,4S)-5-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)--
yl]ethyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was prepared
as a white solid from
1-(2-bromoethyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide (prepared in an analogous manner as described in
general procedure VI) and 2 equiv. of tert-butyl
(1-S,4S-(-)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate using 3
equiv. of sodium carbonate. MS (ESI) m/z 507.0 ([M+H].sup.+). HRMS:
calcd for C.sub.24H.sub.28F.sub.2N.sub.4O.sub.4S+H.sup.+, 507.1872;
found (ESI, [M+H].sup.+), 507.1878. HPLC purity 97.6% at 210-370
nm, 9.2 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2
mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min,
hold 4 min.
[1207] In an analogous manner as described in general procedure II,
step 2,
1-{2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl}-3-(2,4-difluorop-
henyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
dihydrochloride was prepared from tert-butyl
(1S,4S)-5-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)--
yl]ethyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as a white
powder.
[1208] HRMS: calcd for
C.sub.19H.sub.20F.sub.2N.sub.4O.sub.2S+H.sup.+, 407.1348; found
(ESI, [M+H].sup.+), 407.1349.
[1209] HPLC purity 98.9% at 210-370 nm, 7.2 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 87
1-(2,4-Difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide hydrochloride
##STR00127##
[1211] In an analogous manner as described in general procedure II,
tert-butyl
4-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thyl}piperidine-1-carboxylate was prepared from
1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and N-boc-4-piperidineethanol as a white foam. MS (ESI)
m/z 493.8 ([M+H].sup.+). HRMS: calcd for
C.sub.24H.sub.29F.sub.2N.sub.3O.sub.4S+H.sup.+, 494.1920; found
(ESI, [M+H].sup.+), 494.1925. HPLC purity 100.0% at 210-370 nm,
11.1 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
[1212] In an analogous manner as described in general procedure II,
step 2,
1-(2,4-difluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide hydrochloride was prepared from
tert-butyl
4-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thyl}piperidine-1-carboxylate as a white powder. HRMS: calcd for
C.sub.19H.sub.21F.sub.2N.sub.3O.sub.2S+H.sup.+, 394.1395; found
(ESI, [M+H].sup.+), 394.1397. HPLC purity 96.1% at 210-370 nm, 7.6
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
Example 88
1-(2,4-Difluorophenyl)-3-[2-(4-methylpiperazin-1-yl)ethyl]-1,3-dihydro-2,1-
,3-benzothiadiazole 2,2-dioxide dihydrochloride
##STR00128##
[1214] In an analogous manner to Example
4,1-(2,4-difluorophenyl)-3-[2-(4-methylpiperazin-1-yl)ethyl]-1,3-dihydro--
2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride was prepared
from
1-(2,4-difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide dihydrochloride as a white powder. MS (ESI)
m/z 409.0 ([M+H].sup.+). HRMS: calcd for
C.sub.19H.sub.22F.sub.2N.sub.4O.sub.2S+H.sup.+, 409.1504; found
(ESI, [M+H].sup.+), 409.1504. HPLC purity 99.5% at 210-370 nm, 7.2
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
Example 89
1-(2,4-Difluorophenyl)-4-fluoro-3-[2-(4-methylpiperazin-1-yl)ethyl]-1,3-di-
hydro-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride
##STR00129##
[1216] In an analogous manner to Example
4,1-(2,4-difluorophenyl)-4-fluoro-3-[2-(4-methylpiperazin-1-yl)ethyl]-1,3-
-dihydro-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride was
prepared from
1-(2,4-difluorophenyl)-4-fluoro-3-(2-piperazin-1-ylethyl)-1,3-dihydr-
o-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride as a white
powder. MS (ESI) m/z 427.0 ([M+H].sup.+). HRMS: calcd for
C.sub.19H.sub.21F.sub.3N.sub.4O.sub.2S+H.sup.+, 427.1410; found
(ESI, [M+H].sup.+), 427.1408. HPLC purity 98.2% at 210-370 nm, 7.4
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
Example 90
1-(2,4-Difluorophenyl)-3-[2-(4-methyl-1,4-diazepan-1-yl)ethyl]-1,3-dihydro-
-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride
##STR00130##
[1218] In an analogous manner to Example
4,1-(2,4-difluorophenyl)-3-[2-(4-methyl-1,4-diazepan-1-yl)ethyl]-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride was prepared
from
1-[2-(1,4-diazepan-1-yl)ethyl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide dihydrochloride as a white powder. MS
(ESI) m/z 422.8 ([M+H].sup.+). HRMS: calcd for
C.sub.20H.sub.24F.sub.2N.sub.4O.sub.2S+H.sup.+, 423.1661; found
(ESI, [M+H].sup.+), 423.1659. HPLC purity 99.1% at 210-370 nm, 7.5
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
Example 91
1-[2-(4-Methyl-1,4-diazepan-1-yl)ethyl]-3-(2,4,6-trifluorophenyl)-1,3-dihy-
dro-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride
##STR00131##
[1220] In an analogous manner to Example 4,
1-[2-(4-methyl-1,4-diazepan-1-yl)ethyl]-3-(2,4,6-trifluorophenyl)-1,3-dih-
ydro-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride was
prepared from
1-[2-(1,4-diazepan-1-yl)ethyl]-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,-
3-benzothiadiazole 2,2-dioxide dihydrochloride as a white powder.
MS (ESI) m/z 440.8 ([M+H].sup.+). HRMS: calcd for
C.sub.20H.sub.23F.sub.3N.sub.4O.sub.2S+H.sup.+, 441.1567; found
(ESI, [M+H].sup.+), 441.1566. HPLC purity 98.6% at 210-370 nm, 7.4
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
Example 92
N-{2-[3-(2-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}-
-N,N'-dimethylethane-1,2-diamine dihydrochloride
##STR00132##
[1222] Step 1: To a solution of N,N'-dimethylethylenediamine (10.58
g, 120 mmol, 4 equiv.) in tetrahydrofuran (200 mL) at 0.degree. C.
was added dropwise over 35 min a solution of di-tert-butyl
dicarbonate (6.55 g, 30.0 mmol, 1 equiv.) in tetrahydrofuran (60
mL) via an addition funnel. The reaction mixture was stirred at
0.degree. C. for 1 h, and at room temperature overnight. All
volatiles were removed under reduced pressure, and the residue was
partitioned between ethyl acetate and water. The organic layer was
washed with brine, dried (anhydrous sodium sulfate), filtered, and
concentrated to give tert-butyl
methyl[2-(methylamino)ethyl]carbamate as a colorless liquid. Yield:
4.75 g (84%).
[1223] Step 2: A mixture of
1-(2-bromoethyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (171 mg, 0.461 mmol), tert-butyl
methyl[2-(methylamino)ethyl]carbamate (695 mg, 3.69 mmol, 8
equiv.), sodium carbonate (489 mg, 4.61 mmol, 10 equiv.) and
N,N-dimethylformamide (5 mL) was sealed and heated at 125.degree.
C. for 5 h. After cooling, the reaction mixture was partitioned
between ethyl acetate (40 mL) and water (40 mL). The organic layer
was washed with brine, dried (anhydrous sodium sulfate), and
concentrated. The crude liquid was pre-adsorbed onto Florisil and
purified via Isco flash column chromatography (12-g redisep silica
gel column, 15-70% ethyl acetate/hexane) to give tert-butyl
{2-[{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]eth-
yl}(methyl)amino]ethyl}methylcarbamate as a viscous, colorless
liquid.
[1224] Yield: 142 mg (64%). MS (ESI) m/z 479.0 ([M+H].sup.+). HRMS:
calcd for C.sub.23H.sub.31FN.sub.4O.sub.4S+H.sup.+, 479.2123; found
(ESI, [M+H].sup.+), 479.2129. HPLC purity 96.6% at 210-370 nm, 9.0
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
[1225] Step 3: In an analogous manner as described in general
procedure II, step 2,
N-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}-N,N'-dimethylethane-1,2-diamine dihydrochloride was prepared from
tert-butyl
{2-[{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]eth-
yl}(methyl)amino]ethyl}methylcarbamate as a white powder. MS (ESI)
m/z 379.0 ([M+H].sup.+). HRMS: calcd for
C.sub.18H.sub.23FN.sub.4O.sub.2S+H.sup.+, 379.1599; found (ESI,
[M+H].sup.+), 379.1604. HPLC purity 95.1% at 210-370 nm, 7.1 min.;
Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 93
N-{2-[3-(2,4-Difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]et-
hyl}-N,N'-dimethylethane-1,2-diamine dihydrochloride
##STR00133##
[1227] In an analogous manner to Example 92, step 2, tert-butyl
{2-[{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]ethyl}(methyl)amino]ethyl}methylcarbamate was prepared from
1-(2-bromoethyl)-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide as a viscous, colorless liquid. HRMS: calcd for
C.sub.23H.sub.30F.sub.2N.sub.4O.sub.4S+H.sup.+, 497.2029; found
(ESI, [M+H].sup.+), 497.2032. HPLC purity 98.0% at 210-370 nm, 9.5
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
[1228] In an analogous manner as described in general procedure II,
step 2,
N-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]ethyl}-N,N'-dimethylethane-1,2-diamine dihydrochloride was
prepared from tert-butyl
{2-[{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]ethyl}(methyl)amino]ethyl}methylcarbamate as a white powder. HRMS:
calcd for C.sub.18H.sub.22F.sub.2N.sub.4O.sub.2S+H.sup.+, 397.1504;
found (ESI, [M+H].sup.+), 397.1512. HPLC purity 100.0% at 210-370
nm, 7.4 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2
mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min,
hold 4 min.
Example 94
N-{2-[2,2-Dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-yl-
]ethyl}-N,N'-dimethylethane-1,2-diamine dihydrochloride
##STR00134##
[1230] In an analogous manner to Example 92, step 2, tert-butyl
{2-[{2-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-
-yl]ethyl}(methyl)amino]ethyl}methylcarbamate was prepared from
1-(2-bromoethyl)-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadia-
zole 2,2-dioxide a viscous, colorless liquid. HRMS: calcd for
C.sub.23H.sub.29F.sub.3N.sub.4O.sub.4S+H.sup.+, 515.1934; found
(ESI, [M+H].sup.+), 515.1938. HPLC purity 100.0% at 210-370 nm, 9.3
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
[1231] In an analogous manner as described in general procedure II,
step 2,
N-{2-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H-
)-yl]ethyl}-N,N'-dimethylethane-1,2-diamine dihydrochloride was
prepared from tert-butyl
{2-[{2-[2,2-dioxido-3-(2,4,6-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-
-yl]ethyl}(methyl)amino]ethyl}methylcarbamate as a white powder. MS
(ESI) m/z 415.0 ([M+H].sup.+). HRMS: calcd for
C.sub.18H.sub.21F.sub.3N.sub.4O.sub.2S+H.sup.+, 415.1410; found
(ESI, [M+H].sup.+), 415.1417. HPLC purity 99.2% at 210-370 nm, 7.2
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4
min.
Example 95
1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl-
}piperidin-4-amine dihydrochloride
##STR00135##
[1233] Step 1:
1-(3-bromopropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.61 g, 1.56 mmol) was dissolved in 5 mL of DMF along
with 430 mg (3.1 mmol) of potassium carbonate and 0.32 g (1.56 mol)
of tert-butyl piperidin-4-ylcarbamate. The solution was heated to
70.degree. C. for 16 hours then poured in water. The solution was
extracted 2.times. with ethyl acetate and the water layer
discarded. The combined organic phase was washed 3 times with
brine, then dried (MgSO.sub.4) and concentrated. The residue was
subjected to Biotage chromatography (10-50% ethyl acetate-hexane)
to afford 0.45 g (55%) of tert-butyl
(1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]prop-
yl}piperidin-4-yl)carbamate. MS (ES) m/z 505.1; HPLC purity 97.9%
at 210-370 nm, 10.5 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm
column, 1.2 mL/min, 85/15-5/95 (Ammon. Bicarb Buff.
Ph=9.5/ACN+MeOH) for 10 min, hold 4 min.
[1234] HRMS: calcd for C.sub.25H.sub.33FN.sub.4O.sub.4S+H+,
505.22793; found (ESI, [M+H]+ Obs'd), 505.2283.
[1235] Step 2: tert-butyl
(1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]prop-
yl}piperidin-4-yl)carbamate (0.40 g, 0.80 mmol) was dissolved in
ether:methanol (9:1) and 2 mL of 2N HCl in ether added. The
solution was allowed to stand for 16 hr whereupon a colorless solid
had formed. The solid was removed by filtration and washed with
ether to afford 0.33 g (87%)
1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]propyl}piperidin-4-amine dihydrochloride. HPLC purity 98.7% at
210-370 nm, 5.5 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column,
1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10
min, hold 4 min. HRMS: calcd for C20H25FN4O2S+H+, 405.17550; found
(ESI, [M+H]+ Obs'd), 405.1768.
Example 97
1-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]piperidin-
-4-amine dihydrochloride
##STR00136##
[1237] Step 1: In an analogous manner to Example 95, step 1,
1-(3-bromopropyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.34 g, 0.92 mmol) was treated with 255 mg (1.85 mmol)
of potassium carbonate and 0.32 g (1.56 mol) of tert-butyl
piperidin-4-yl carbamate to afford tert-butyl
(1-{3-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperid-
in-4-yl)carbamate (0.26 g).
[1238] Step 2: In an analogous manner to Example 95, step 2,
1-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]piperidi-
n-4-amine dihydrochloride was prepared from tert butyl
N-{3-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperidi-
n-4-amine carbonate. MS (ES) m/z 386.9; HPLC purity 99.3% at
210-370 nm, 5.6 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column,
1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10
min, hold 4 min. HRMS: calcd for C20H26N4O2S+H+, 387.18492; found
(ESI, [M+H]+ Obs'd), 387.1858.
Example 99
1-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}-
piperidin-4-amine dihydrochloride
##STR00137##
[1240] Step 1: In an analogous manner to Example 95, step 1,
1-(3-bromoethyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.61 g, 1.6 mmol) was treated with 255 mg (1.85 mmol)
of potassium carbonate and 0.49 g (1.6 mol) of tert-butyl
piperidin-4-yl carbamate to afford tert-butyl
(1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethy-
l}piperidin-4-yl)carbamate (0.45 g).
[1241] Step 2: In an analogous manner to Example 95, step 2,
1-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}piperidin-4-amine dihydrochloride (0.32 g) was prepared from 0.40
g of tert-butyl
(1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethy-
l}piperidin-4-yl)carbamate. MS (ES) m/z 390.8; HPLC purity 98.8% at
210-370 nm, 5.9 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column,
1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10
min, hold 4 min. HRMS: calcd for C19H23FN4O2S+H+, 391.15985; found
(ESI, [M+H]+ Obs'd), 391.1601.
Example 100
1-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}-
-N-methylpiperidin-4-amine dihydrochloride
##STR00138##
[1243] Step 1: A solution of 0.28 g (0.57 mmol) of tert-butyl
(1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethy-
l}piperidin-4-yl)carbamate (see Example 99, step 1) in 5 mL of DMF
was added dropwise to a solution of sodium hydride (0.052 g, 1.3
mmol, 60% dispersion) in 3 mL of DMF. After stirring 1/2 hr, 0.12 g
(0.85 mmol) of methyl iodide was added. The solution was heated to
70.degree. C. for 4 hr then poured in water. The solution was
extracted 2.times. with ethyl acetate and the water layer
discarded. The combined organic phase was washed 3 times with
brine, then dried (MgSO.sub.4) and concentrated. The residue was
subjected to Biotage chromatography (10-50% ethyl acetate-hexane)
to afford 0.23 g of tert-butyl
(1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethy-
l}-N-methylpiperidin-4-yl)carbamate used as such in the next
step.
[1244] Step 2: In an analogous manner to Example 95, step 2,
1-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}-N-methylpiperidin-4-amine dihydrochloride (0.15 g) was prepared
from 0.20 g of tert-butyl
(1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethy-
l}-N-methylpiperidin-4-yl)carbamate. MS (ES) m/z 404.8; HPLC purity
97.7% at 210-370 nm, 6.2 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm
column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)
for 10 min, hold 4 min.
[1245] HRMS: calcd for C20H25FN4O2S+H+, 405.17550; found (ESI,
[M+H]+ Obs'd), 405.1762.
Example 102
1-{2-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperidin--
4-amine dihydrochloride
##STR00139##
[1247] Step 1: In an analogous manner to Example 95, step 1,
tert-butyl
(1-{3-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperidi-
n-4-yl)carbamate was prepared from
1-(3-bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole and
tert-butyl piperidin-4-yl carbamate.
[1248] Step 2: In an analogous manner to Example 95, step 2,
1-{2-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperidin-
-4-amine dihydrochloride was prepared from
tert-butyl(1-{3-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)yl]ethyl-
}piperidin-4-yl)carbamate. MS (ES) m/z 372.9; HPLC purity 99.4% at
210-370 nm, 5.5 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column,
1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10
min, hold 4 min.
Example 103
1-{2-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}-N-methylp-
iperidin-4-amine dihydrochloride
##STR00140##
[1250] Step 1: In an analogous manner to Example 100, step 1,
tert-butyl
(1-{3-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}-N-methy-
lpiperidin-4-yl)carbamate was prepared from tert-butyl
(1-{3-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperidi-
n-4-yl)carbamate and used in the next step.
[1251] Step 2: In an analogous manner to Example 95, step 2,
1-{2-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}-N-methyl-
piperidin-4-amine dihydrochloride was prepared from tert-butyl
(1-{3-[3-phenyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}-N-methy-
lpiperidin-4-yl)carbamate. MS (ES) m/z 386.8; HPLC purity 93.8% at
210-370 nm, 6.4 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column,
1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10
min, hold 4 min. HRMS: calcd for C20H26N4O2S+H+, 387.18492; found
(ESI, [M+H]+ Obs'd), 387.1853.
Example 105
1-{1-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]pyrroli-
din-3-yl}methanamine dihydrochloride
##STR00141##
[1253] Step 1: In an analogous manner to general procedure V, tert
butyl
1-{1-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]pyrrol-
idin-3-yl}methanamine carbonate was prepared from
1-(3-bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and tert-butyl pyrrolidin-3-ylmethylcarbamate.
[1254] Step 2: In an analogous manner to general procedure II, step
2,
1-{1-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]pyrrol-
idin-3-yl}methanamine dihydrochloride was prepared from tert butyl
1-{1-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]pyrrol-
idin-3-yl}methanamine carbonate. MS (ES) m/z 372.9; HPLC purity
93.1% at 210-370 nm, 7.0 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm
column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)
for 10 min, hold 4 min.
Example 106
1-phenyl-3-[2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethyl]-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide dihydrochloride
##STR00142##
[1256] In an analogous manner to general procedure V,
1-phenyl-3-[2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethyl]-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide dihydrochloride was prepared from
1-(3-bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and 4-(pyrrolidin-1-yl)piperidine. The resulting
product was converted to the dihydrochloride with 2N HCl in ether.
MS (ES) m/z 426.9; HPLC purity 100.0% at 210-370 nm, 6.8 min.;
Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 107
2-{2-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)--
yl]ethoxy}-N-methylethanamine hydrochloride
##STR00143##
[1258] Step 1: In an analogous manner to general procedure IV,
1-[2-(2-bromoethoxy)ethyl]-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3--
benzothiadiazole 2,2-dioxide was prepared from
1-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (prepared in an analogous manner to general procedure
I) and 1-bromo-2-(2-bromoethoxy)ethane. MS (ES) m/z 448.6; HPLC
purity 85.1% at 210-370 nm, 10.5 min.; Xterra RP18, 3.5 u,
150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1259] Step 2: In an analogous manner to general procedure V,
2-{2-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]ethoxy}-N-methylethanamine hydrochloride was prepared from
1-[2-(2-bromoethoxy)ethyl]-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3--
benzothiadiazole 2,2-dioxide and methylamine (33% in ethanol). MS
(ES) m/z 399.8; HPLC purity 84.9% at 210-370 nm, 7.5 min.; Xterra
RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS:
calcd for C17H19ClFN3O3S+H.sup.+, 400.08924; found (ESI, [M+H]+
Obs'd), 400.0896
Example 108
2-{2-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)--
yl]ethoxy}-N,N-dimethylethanamine hydrochloride
##STR00144##
[1261] In an analogous manner to general procedure IV,
2-{2-[3-(2-chloro-4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-
-yl]ethoxy}-N,N-dimethylethanamine hydrochloride was prepared from
1-[2-(2-bromoethoxy)ethyl]-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3--
benzothiadiazole 2,2-dioxide and dimethyl amine (.about.5.6 M in
ethanol). MS (ES) m/z 413.8; HPLC purity 85.5% at 210-370 nm, 8.3
min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min,
85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4
min.
Example 109
1-(4-chloro-2-fluorophenyl)-3-(2-piperazin-1-yl-ethyl)-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide
##STR00145##
[1263] Step 1: To a stirring solution of
1-(3-bromopropyl)-3-(4-chloro-2-fluorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide (150 mg, 0.502 mmol), 2-bromoethanol (71 uL,
1.00 mmol), and triphenylphosphine (263 mg, 1.00 mmol) in anhydrous
tetrahydrofuran was added diisopropylazodicarboxylate (195 uL, 1.00
mmol) and the solution stirred, capped, at room temperature for 18
hr. The reaction mixture was concentrated then loaded directly onto
silica gel and purified via Isco chromatography (Redisep, silica,
gradient 0-25% ethyl acetate in hexane to afford 0.07 g of
1-(2-bromoethyl)-3-(4-chloro-2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide as a white solid.
[1264] HRMS: calcd for C14H11 BrClFN2O2S+Na+, 403.94; found (ESI,
[M+Na]+, 426.9293
[1265] HPLC purity 99.3% at 210-370 nm, 10.6 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1266] Step 2:
1-(4-chloro-2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (50 mg, 0.123 mmol) and piperazine-1-carboxylic acid
tert-butyl ester (115 mg, 0.616 mmol) were stirred in anhydrous
dimethylformamide (2 mL) in a sealed vial at room temperature for
18 hr. This reaction was transferred to a separatory funnel with
ethyl acetate and washed with water. The organic layer was dried
(MgSO.sub.4), filtered and the solvent removed. This material was
dissolved in diethyl ether and 2N HCl in Et.sub.2O to give a grey
solid as the mono-HCl salt (24 mg, 44% Yield).
[1267] HRMS: calcd for
[1268] HPLC purity 100% at 210-370 nm, 8.0 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 110
1-(4-chloro-2-fluorophenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethyl-
}-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
##STR00146##
[1270]
1-(2-bromoethyl)-3-(4-chloro-2-fluorophenyl)-1,3-dihydro-2,1,3-benz-
othiadiazole 2,2-dioxide (220 mg, 0.542 mmol) and cis-2,6-dimethyl
piperazine (372 mg, 3.25 mmol) were heated in absolute ethyl
alcohol (5 mL) in a sealed vial at 90.degree. C. for 18 hr. The
solvent was removed, in vacuo, and the material purified by Gilson
RP-HPLC (YMC CombiPrep ProC18 50.times.20 mm I.D. column, S-5 m, 12
nm. Flow rate 20 mL/min. Gradient: 10/90 Acetonitrile/Water to 100%
acetonitrile over 10 minutes then hold for three minutes at 100%
acetonitrile and ramp back to 10/90 acetonitrile/water over two
minutes) to give a white solid. This material was dissolved in
diethyl ether and methanol and 4N HCl in dioxane was added to give
a white solid (119 mg, 46% Yield) as the mono-HCl salt.
[1271] HRMS: calcd for C20H24ClFN4O2S+Na+, 438.13; found (ESI,
[M+Na]+, 439.1377
[1272] HPLC purity 99.3% at 210-370 nm, 8.4 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 111
1-(4-chloro-2-fluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide
##STR00147##
[1274] Step 1: To a stirring solution of
1-(4-chloro-2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (100 mg, 0.335 mmol), tert-butyl
4-(2-hydroxyethyl)piperidine-1-carboxylate (147 uL, 0.67 mmol), and
triphenylphosphine (176 mg, 0.67 mmol) in anhydrous tetrahydrofuran
was added diisopropylazodicarboxylate (130 uL, 0.67 mmol) and the
solution stirred, capped, at room temperature for 18 hr. The
reaction mixture was concentrated then loaded directly onto silica
gel and purified via Isco chromatography (Redisep, silica, gradient
0-35% ethyl acetate in hexane to afford
1-(4-chloro-2-fluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihyd-
ro-2,1,3-benzothiadiazole 2,2-dioxide carbamic acid tert-butyl
ester as an orange colored wax. This material was dissolved in
diethyl ether and methanol and 2N HCl in diethyl ether was added a
precipitate formed. The mixture was filtered to afford impure
product. This material was dissolved in DMSO and purified by Gilson
RP-HPLC (YMC CombiPrep ProC18 50.times.20 mm I.D. column, S-5 m, 12
nm. Flow rate 20 mL/min. Gradient: 10/90 Acetonitrile/Water to 100%
acetonitrile over 10 minutes then hold for three minutes at 100%
acetonitrile and ramp back to 10/90 acetonitrile/water over two
minutes) to give 0.089 g of
1-(4-chloro-2-fluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-b-
enzothiadiazole 2,2-dioxide as an orange solid.
[1275] HRMS: calcd for C19H21ClFN.sub.3O.sub.2S+H+, 409.10; found
(ESI, [M+H]+, 410.1102
[1276] HPLC purity 100% at 210-370 nm, 11.5 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 112
1-(4-chloro-2-methylphenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethyl-
}-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
##STR00148##
[1278]
1-(4-chloro-2-methylphenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-y-
l]ethyl}-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was
prepared using
1-(2-bromoethyl)-3-(4-chloro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide and cis-2,6-dimethyl piperazine analogous to the
conditions used general procedure V.
[1279] HRMS: calcd for C21H27ClN4O2S+H+, 435.1616; found (ESI,
[M+H]+, 435.1625
[1280] HPLC purity 97.7% at 210-370 nm, 8.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 113
1-(4-chloro-2-methylphenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide
##STR00149##
[1282]
1-(4-Chloro-2-methylphenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2-
,1,3-benzothiadiazole 2,2-dioxide was prepared using
1-(4-chloro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide and tert-butyl
4-(2-hydroxyethyl)piperidine-1-carboxylate analogous to the
conditions used in general procedure VI followed by removal of Boc
group. HRMS: calcd for C19H23ClN4O2S+H+, 407.1303; found (ESI,
[M+H]+, 407.1307; calcd for C19H22ClN4O2S+Na+, 429.1123; found
(ESI, [M+H]+, 429.1123; HPLC purity 100% at 210-370 nm, 11.5 min.;
Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 114
1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl-
)butan-2-one hydrochloride
##STR00150##
[1284] Step 1:
1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)butan-2-ol (115 mg, 0.295 mmol) and di-tert-butyl dicarbonate (71
mg, 0.325 mmol) were stirred in dichloromethane (5 mL) in a sealed
vial at room temperature for 18 hr. The reaction mixture was
concentrated then loaded directly onto silica gel and purified via
Isco chromatography (Redisep, silica, gradient 0-50% ethyl acetate
in hexane to afford 0.02 g of
1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H-
)-yl)butan-2-ol-carbamic acid tert-butyl ester as a clear oil.
[1285] HRMS: calcd for C25H35N3O5S+H+, 490.2370; found (ESI,
[M+H]+), 490.2373
[1286] HPLC purity 97.0% at 210-370 nm, 10.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1287] Step 2:
1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)butan-2-ol-carbamic acid tert-butyl ester (15 mg, 0.031 mmol) and
Dess Martin periodinane (20 mg, 0.046 mmol) were stirred in
dichloromethane (5 mL) in a sealed vial at room temperature for 18
hr. The reaction mixture was concentrated then loaded directly onto
silica gel and purified via Isco chromatography (Redisep, silica,
gradient 0-50% ethyl acetate in hexane to afford 0.023 g of
1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)butan-2-one-carbamic acid tert-butyl ester as a clear oil.
[1288] HRMS: calcd for C25H33N3O5S+H+, 510.2033; found (ESI,
[M+H]+), 510.2035
[1289] HPLC purity 100% at 210-370 nm, 11.1 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1290] Step 3: The clear oil,
1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)butan-2-one-carbamic acid tert-butyl ester, was dissolved in
diethyl ether and methanol and 4N HCl in dioxane was added a
precipitate formed. The reaction was filtered to afford 12 mg of
1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)butan-2-one hydrochloride as a white solid.
[1291] HRMS: calcd for C20H25N3O3S+H+, 388.1689; found (ESI,
[M+H]+), 388.1690
[1292] HPLC purity 97.6% at 210-370 nm, 7.6 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 115
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino)-
butan-2-one hydrochloride
##STR00151##
[1294]
4-(2,2-Dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropy-
lamino)butan-2-one hydrochloride was prepared using
1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-
butan-2-ol analogous to the conditions used in steps 2 and 3 of
example 114.
[1295] HRMS: calcd for C19H23N3O3S+H+, 374.1533; found (ESI,
[M+H]+), 374.1537
[1296] HPLC purity 94.5% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 116
1-(cyclopropylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-y-
l)butan-2-one hydrochloride
##STR00152##
[1298]
1-(Cyclopropylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol--
1(3H)-yl)butan-2-one hydrochloride was prepared using
1-(cyclopropylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)--
yl)butan-2-ol analogous to the conditions used in steps 2 and 3 of
example 114.
[1299] HRMS: calcd for C19H21N3O3S+H+, 372.1376; found (ESI,
[M+H]+), 372.1379
[1300] HPLC purity 88.5% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 117
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)but-
an-2-one hydrochloride
##STR00153##
[1302]
4-(2,2-Dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylam-
ino)butan-2-one hydrochloride was prepared using
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)bu-
tan-2-ol analogous to the conditions used in steps 2 and 3 of
example 114.
[1303] HRMS: calcd for C17H19N3O3S+H+, 346.1220; found (ESI,
[M+H]+), 346.1223
[1304] HPLC purity 95.6% at 210-370 nm, 7.0 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 118
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methy-
lamino)butan-2-one hydrochloride
##STR00154##
[1306] Step 1:
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(prepared using general procedure I, 0.5 g, 1.9 mmol) was dissolved
in acetone (5 mL) and potassium carbonate (0.52 g, 3.8 mmol) was
added followed by S(-)-4-bromo-1,2-epoxybutane (0.57 g, 3.8 mmol).
The mixture was stirred for 18 hours at 50.degree. C. in a sealed
vial then diluted with EtOAc (100 mL) and washed with water
(2.times.), brine then dried (Na.sub.2SO.sub.4). After
concentration the residue was dissolved in 10 mL of MeNH.sub.2
solution (8M in EtOH). The solution was irradiated in a microwave
cuvette at 100.degree. C. for 3 minutes. The reaction mixture was
concentrated then loaded directly onto silica gel and purified via
Isco chromatography (Redisep, silica, gradient 0-100% of 10% 7M
ammonia in MeOH/dichloromethane) to afford 387 mg of
(S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(-
methylamino)butan-2-ol.
[1307] HRMS: calcd for C17H20FN3O3S+H+, 366.1288; found (ESI,
[M+H]+), 366.1279
[1308] HPLC purity 100% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1309] Step 2:
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(meth-
ylamino)butan-2-one hydrochloride was prepared using
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(meth-
ylamino)butan-2-ol analogous to the conditions used in steps 2 and
3 of example 114.
[1310] HRMS: calcd for C17H19N3O3S+H+, 346.1220; found (ESI,
[M+H]+), poor signal
[1311] HPLC purity 92.6% at 210-370 nm, 7.0 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 119
(2Z)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamin-
o)butan-2-one oxime
##STR00155##
[1313] tert-butyl
[4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-oxobutyl]methy-
lcarbamate (50 mg, 0.112 mmol), hydroxylamine hydrochloride (50 mg,
0.720 mmol), and pyridine (1.5 mL) were stirred in ethyl alcohol (3
mL) in a sealed vial at 70.degree. C., for 3 hr. The reaction was
allowed to cool to room temperature and transferred to a separatory
funnel with dichloromethane and washed with a saturation aqueous
solution of sodium bicarbonate, brine, dried (MgSO.sub.4), filtered
and the solvent removed, in vacuo, to give a clear oil. This
material was adsorbed onto silica gel and purified via Isco
chromatography (Redisep, silica, gradient 0-50% ethyl acetate in
hexane to afford a white solid. This material was dissolved in
diethyl ether and methanol and 4N HCl in dioxane was added a
precipitate formed. The mixture was filtered to afford 0.028 g (62%
Yield) of
(2Z)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1--
(methylamino)butan-2-one oxime as an off white solid.
[1314] HRMS: calcd for C17H20N4O3S+H+, 361.1329; found (ESI,
[M+H]+), 361.1337
[1315] HPLC purity 96.8% at 210-370 nm, 7.3 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 120
(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2-m-
ethoxy-N-methylbutan-1-amine
##STR00156##
[1317] Step 1:
4-[3-(2-Fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(meth-
ylamino)butan-2-ol-carbamic acid tert-butyl ester was prepared
using
(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1--
(methylamino)butan-2-ol analogous to the conditions used in step 1
of example 114.
[1318] HPLC purity 93.1% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1319] Step 2:
4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(meth-
ylamino)butan-2-ol-carbamic acid tert-butyl ester (75 mg, 0.161
mmol), trimethyloxonium tetrafluoroborate (71 mg, 0.483 mmol),
proton sponge (121 mg, 0.564 mmol) and 4 A molecular sieves were
stirred in dichloromethane (5 mL) in a sealed vial at room
temperature for 18 hr. The reaction mixture was concentrated then
loaded directly onto silica gel and purified via Isco
chromatography (Redisep, silica, gradient 0-50% ethyl acetate in
hexane to afford 0.065 g of
(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2--
methoxy-N-methylbutan-1-amine-carbamic acid tert-butyl ester as a
clear oil. This material was dissolved in diethyl ether and
methanol and 4N HCl in dioxane was added a precipitate formed. The
mixture was filtered to afford 0.050 g of
(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-2--
methoxy-N-methylbutan-1-amine as a brown solid.
[1320] HRMS: calcd for C18H22FN3O3S+H+, 380.1439; found (ESI,
[M+H]+, 380.1438
[1321] HPLC purity 86.0% at 210-370 nm, 7.2 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 121
(2S)-2-methoxy-N-methyl-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiad-
iazol-1(3H)-yl]butan-1-amine
##STR00157##
[1323]
(2S)-2-methoxy-N-methyl-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-ben-
zothiadiazol-1(3H)-yl]butan-1-amine was prepared using
(2S)-1-(methylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadia-
zol-1(3H)-yl]butan-2-ol analogous to the conditions used in step 2
of example 120.
[1324] HRMS: calcd for C19H25N3O3S+H+, 362.1533; found (ESI,
[M+H]+), 362.1533
[1325] HPLC purity 100% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 122
(2S)-2-methoxy-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]-N-methylbutan-1-amine
##STR00158##
[1327]
(2S)-2-Methoxy-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadi-
azol-1(3H)-yl]-N-methylbutan-1-amine was prepared using
(2S)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-
-(methylamino)butan-2-ol analogous to the conditions used in step 2
of example 120.
[1328] HRMS: calcd for C19H25N3O4S+H+, 392.1639; found (ESI,
[M+H]+, 392.1638
[1329] calcd for C19H25N3O4S+Na+, 414.1458; found (ESI, [M+Na]+,
414.1455
[1330] HPLC purity 99.3% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 123
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-methoxy-N-methyl-
butan-1-amine
##STR00159##
[1332]
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-methoxy-N-
-methylbutan-1-amine was prepared using
4-[3-(3-phenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamin-
o)butan-2-ol analogous to the conditions used in step 2 of example
120.
[1333] HRMS: calcd for C18H23N3O3S+H+, 362.1533; found (ESI,
[M+H]+, 362.1537
[1334] calcd for C19H25N3O4S+Na+, 414.1458; found (ESI, [M+Na]+,
414.1455
[1335] HPLC purity 97.9% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 124
(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-methoxy-N-m-
ethylbutan-1-amine
##STR00160##
[1337]
(2R)-4-(2,2-Dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-meth-
oxy-N-methylbutan-1-amine was prepared by separating
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-methoxy-N-methy-
lbutan-1-amine via chiral HPLC. The compound was dissolved in
methanol. 200 uL of the resulting solution was repetitively
injected onto the Supercritical Fluid Chromatography instrument,
and the baseline resolved enantiomers were separately collected
using the conditions described below. The chiral purity of each
enantiomer was determined under the same Supercritical Fluid
Chromatography conditions using a Chiralpak AS-H 5 m, 250
mm.times.4.6 mm ID column at 2.0 mL/min flow rate using Analytical
Supercritical Fluid Chromatography (Berger Instruments, Inc.
Newark, Del.). Both enantiomers were found to be >99.9%
enantiomerically pure.
SFC Instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc.
Newark, Del.)
Column: Chiralpak AS-H; 5 m; 250 mm L.times.20 mm ID (Chiral
Technologies, Inc, Exton, Pa.)
[1338] Column temperature: 35.degree. C.
SFC Modifier: 18% MeOHw 0.2% DMEA
[1339] Flow rate: 50 mL/min
Outlet Pressure: 100 bar
Detector: UV at 220 nm.
[1340] HRMS: calcd for C18H23N3O3S+H+, 362.1533; found (ESI,
[M+H]+, 362.1542
[1341] calcd for C19H25N3O4S+Na+, 414.1458; found (ESI, [M+Na]+,
414.1455
[1342] HPLC purity 98% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5 u,
150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 125
(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-methoxy-N-m-
ethylbutan-1-amine
##STR00161##
[1344]
(2S)-4-(2,2-Dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-meth-
oxy-N-methylbutan-1-amine was prepared by separating
4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-2-methoxy-N-methy-
lbutan-1-amine via chiral HPLC. The compound was dissolved in
methanol. 200 uL of the resulting solution was repetitively
injected onto the Supercritical Fluid Chromatography instrument,
and the baseline resolved enantiomers were separately collected
using the conditions described below. The chiral purity of each
enantiomer was determined under the same Supercritical Fluid
Chromatography conditions using a Chiralpak AS-H 5 m, 250
mm.times.4.6 mm ID column at 2.0 mL/min flow rate using Analytical
Supercritical Fluid Chromatography (Berger Instruments, Inc.
Newark, Del.). Both enantiomers were found to be >99.9%
enantiomerically pure.
SFC Instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc.
Newark, Del.)
Column: Chiralpak AS-H; 5 m; 250 mm L.times.20 mm ID (Chiral
Technologies, Inc, Exton, Pa.)
[1345] Column temperature: 35.degree. C.
SFC Modifier: 18% MeOHw 0.2% DMEA
[1346] Flow rate: 50 mL/min
Outlet Pressure: 100 bar
Detector: UV at 220 nm.
[1347] HRMS: calcd for C18H23N3O3S+H+, 362.1533; found (ESI,
[M+H]+, 362.1539
[1348] calcd for C19H25N3O4S+Na+, 414.1458; found (ESI, [M+Na]+,
414.1455
[1349] HPLC purity 100% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 126
N-{(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]--
2-methoxybutyl}cyclopropanamine
##STR00162##
[1351]
N-{(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]-2-methoxybutyl}cyclopropanamine was prepared using
(2S)-1-(cyclopropylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzoth-
iadiazol-1(3H)-yl]butan-2-ol analogous to the conditions used in
step 2 of example 120.
[1352] HRMS: calcd for C20H24FN3O3S+H+, 406.1595; found (ESI,
[M+H]+, 406.1594
[1353] calcd for C20H24FN3O3S+Na+, 428.1415; found (ESI, [M+Na]+,
428.1413
[1354] HPLC purity 95.6% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 127
N-{(2S)-2-methoxy-4-[3-(2-methylphenyl)-2,2-dioxido-3-benzothiadiazol-1(3H-
)-yl]butyl}cyclopropanamine
##STR00163##
[1356]
N-{(2S)-2-Methoxy-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothia-
diazol-1(3H)-yl]butyl}cyclopropanamine was prepared using
(2S)-1-(cyclopropylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzoth-
iadiazol-1(3H)-yl]butan-2-ol analogous to the conditions used in
step 2 of example 120.
[1357] HRMS: calcd for C21H27N3O3S+H+, 402.1846; found (ESI,
[M+H]+, 402.1847
[1358] calcd for C21H27N3O3S+Na+, 424.1665; found (ESI, [M+Na]+,
424.1661
[1359] HPLC purity 100% at 210-370 nm, 8.3 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 128
N-{(2S)-2-methoxy-4-[3-(3-methoxyphenyl)-2,2-dioxido-3-benzothiadiazol-1(3-
H)-yl]butyl}cyclopropanamine
##STR00164##
[1361]
N-{(2S)-2-methoxy-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothi-
adiazol-1(3H)-yl]butyl}cyclopropanamine was prepared using
(2S)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-
-(methylamino)butan-2-ol analogous to the conditions used in step 2
of example 120.
[1362] HRMS: calcd for C21H27N3O4S+H+, 418.1795; found (ESI,
[M+H]+, 418.1796
[1363] calcd for C21H27N3O4S+Na+, 440.1615; found (ESI, [M+Na]+,
440.1615
[1364] HPLC purity 99.2% at 210-370 nm, 8.1 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 129
N-{(2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)--
yl]-2-methoxybutyl}cyclopropanamine
##STR00165##
[1366]
N-{(2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
-1(3H)-yl]-2-methoxybutyl}cyclopropanamine was prepared using
(2S)-1-(cyclopropylamino)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-ben-
zothiadiazol-1(3H)-yl]butan-2-ol analogous to the conditions used
in step 2 of example 120.
[1367] HRMS: calcd for C20H23F2N3O3S+H+, 424.1501; found (ESI,
[M+H]+, 424.1500
[1368] calcd for C20H23F2N3O3S+Na+, 446.1320; found (ESI, [M+Na]+,
446.1320
[1369] HPLC purity 83.5% at 210-370 nm, 8.0 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 130
N-{(2S)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)--
yl]-2-methoxybutyl}cyclopropanamine
##STR00166##
[1371]
N-{(2S)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
-1(3H)-yl]-2-methoxybutyl}cyclopropanamine was prepared using
(2S)-1-(cyclopropylamino)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-ben-
zothiadiazol-1(3H)-yl]butan-2-ol analogous to the conditions used
in step 2 of example 120.
[1372] HRMS: calcd for C20H23F2N3O3S+H+, 424.1501; found (ESI,
[M+H]+, 424.1503
[1373] calcd for C20H23F2N3O3S+Na+, 446.1320; found (ESI, [M+Na]+,
446.1318
[1374] HPLC purity 94.6% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 131
N-{(2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)--
yl]-2-methoxybutyl}cyclopropanamine
##STR00167##
[1376]
N-{(2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-
-1(3H)-yl]-2-methoxybutyl}cyclopropanamine was prepared using
(2S)-1-(cyclopropylamino)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-ben-
zothiadiazol-1(3H)-yl]butan-2-ol analogous to the conditions used
in step 2 of example 120.
[1377] HRMS: calcd for C20H23F2N3O3S+H+, 424.1501; found (ESI,
[M+H]+, 424.1498
[1378] calcd for C20H23F2N3O3S+Na+, 446.1320; found (ESI, [M+Na]+,
446.1317
[1379] HPLC purity 100% at 210-370 nm, 7.6 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 132
2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]--
2-methoxy-N-methylbutan-1-amine
##STR00168##
[1381]
2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]-2-methoxy-N-methylbutan-1-amine was prepared using
(2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol analogous to the conditions used in
step 2 of example 120.
[1382] HRMS: calcd for C18H21F2N3O3S+H+, 398.1345; found (ESI,
[M+H]+, 398.1346
[1383] calcd for C18H21F2N3O3S+Na+, 420.1164; found (ESI, [M+Na]+,
420.1165
[1384] HPLC purity 95.6% at 210-370 nm, 7.1 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 133
(2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-2-methoxy-N-methylbutan-1-amine
##STR00169##
[1386]
(2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(-
3H)-yl]-2-methoxy-N-methylbutan-1-amine was prepared using
(2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-1-(methylamino)butan-2-ol analogous to the conditions used in
step 2 of example 120.
[1387] HRMS: calcd for C18H21F2N3O3S+H+, 398.1345; found (ESI,
[M+H]+, 398.1333
[1388] calcd for C18H21F2N3O3S+Na+, 420.1164; found (ESI, [M+Na]+,
420.1151
[1389] HPLC purity 100% at 210-370 nm, 7.5 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 134 (General Procedure II)
1-(2-morpholin-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide
##STR00170##
[1391] Step 1: To a solution of
1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.2 g, 0.8
mmol) in THF (10 mL) was added triphenylphosphine (0.26 g, 1 mmol),
tert-butyl 2-(2-hydroxyethyl)morpholine-4-carboxylate (0.2 g, 0.9
mmol) and DIAD (0.2 g, 1 mmol) at 0.degree. C. The mixture was
allowed to warm to ambient temperature overnight then concentrated
and chromatographed on silica gel (0 to 40% EtOAC in hexane). The
resulting mostly pure carbamate was dissolved in dichloromethane
(10 mL) and treated with HCL (4 mL, 4M in dioxane). The resulting
salt was chromatographed on silica (0 to 100% of (7N NH.sub.3/MeOH)
in dichloromethane) giving the desired product as a clear oil (0.23
g, 80%).
[1392] HRMS: calcd for C18H21N3O3S+H+, 360.1376; found (ESI,
[M+H]+), 360.1377
[1393] HPLC purity 100% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 135 (General Procedure III)
1-{2-[(2S)-morpholin-2-yl]ethyl}-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide
##STR00171##
[1395]
1-(2-morpholin-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazo-
le2,2-dioxide was dissolved in methanol. 200 uL of the resulting
solution was repetitively injected onto the Supercritical Fluid
Chromatography instrument, and the baseline resolved enantiomers
were separately collected using the conditions described below. The
chiral purity of each enantiomer was determined under the same
Supercritical Fluid Chromatography conditions using a Chiralpak
AS-H 5 um, 250 mm.times.4.6 mm ID column at 2.0 mL/min flow rate
using Analytical Supercritical Fluid Chromatography (Berger
Instruments, Inc. Newark, Del.). Both enantiomers were found to be
>99.9% enantiomerically pure.
SFC Instrument: Berger MultiGram Prep SFC (Berger Instruments, Inc.
Newark, Del.)
Column: Chiralpak AS-H; 5 m; 250 mm L.times.20 mm ID (Chiral
Technologies, Inc, Exton, Pa.)
[1396] Column temperature: 35.degree. C.
SFC Modifier: 18% MeOH w 0.2% DMEA
[1397] Flow rate: 50 mL/min
Outlet Pressure: 100 bar
Detector: UV at 220 nm.
[1398] HRMS: calcd for C18H21N3O3S+H+, 360.1376; found (ESI,
[M+H]+), 360.1378
[1399] HPLC purity 100% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min
Example 136
1-{2-[(2R)-morpholin-2-yl]ethyl}-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide
##STR00172##
[1401] This compound was prepared from
1-(2-morpholin-2-ylethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2--
dioxide as described in example 135.
[1402] HRMS: calcd for C18H21N3O3S+H+, 360.1376; found (ESI,
[M+H]+), 360.1379
[1403] HPLC purity 100% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min
Example 137
1-(4-fluorophenyl)-3-(2-morpholin-2-ylethyl)-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide
##STR00173##
[1405] This compound was prepared using
1-(4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
analogous to the conditions used in general procedure II.
[1406] HRMS: calcd for C18H20FN3O3S+H+, 378.1282; found (ESI,
[M+H]+), 378.1283
[1407] HPLC purity 99.4% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 138
1-(4-fluorophenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-benz-
othiadiazole 2,2-dioxide
##STR00174##
[1409] This compound was prepared using
1-(4-fluorophenyl)-3-(2-morpholin-2-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide analogous to the conditions used in general
procedure III.
[1410] HRMS: calcd for C18H20FN3O3S+H+, 378.1282; found (ESI,
[M+H]+), 378.1271
[1411] HPLC purity 100% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 139
1-(4-fluorophenyl)-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-benz-
othiadiazole 2,2-dioxide
##STR00175##
[1413] This compound was prepared using
1-(4-fluorophenyl)-3-(2-morpholin-2-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide analogous to the conditions used in general
procedure II.
[1414] HRMS: calcd for C18H20FN3O3S+H+, 378.1282; found (ESI,
[M+H]+), 378.1272
[1415] HPLC purity 100% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 140
1-(2,4-difluorophenyl)-3-(2-morpholin-2-ylethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide
##STR00176##
[1417] This compound was prepared using
1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide analogous to the conditions used in general procedure
II.
[1418] HRMS: calcd for C18H19F2N3O3S+H+, 396.1189; found (ESI,
[M+H]+), 396.1189
[1419] HPLC purity 98.8% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 141
1-(2,4-difluorophenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3--
benzothiadiazole 2,2-dioxide
##STR00177##
[1421] This compound was prepared using
1-(2,4-difluorophenyl)-3-(2-morpholin-2-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide analogous to the conditions used in general
procedure III.
[1422] HRMS: calcd for C18H19F2N3O3S+H+, 396.1189; found (ESI,
[M+H]+), 396.1178
[1423] HPLC purity 100% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 142
1-(2,4-difluorophenyl)-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3--
benzothiadiazole 2,2-dioxide
##STR00178##
[1425] This compound was prepared using
1-(2,4-difluorophenyl)-3-(2-morpholin-2-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide analogous to the conditions used in general
procedure III.
[1426] HRMS: calcd for C18H19F2N3O3S+H+, 396.1189; found (ESI,
[M+H]+), 396.1178
[1427] HPLC purity 98.6% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 143
1-(2-morpholin-2-ylethyl)-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-benz-
othiadiazole 2,2-dioxide
##STR00179##
[1429] This compound was prepared using
1-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide analogous to the conditions used in general procedure
II.
[1430] HRMS: calcd for C18H18F3N3O3S+H+, 414.1094; found (ESI,
[M+H]+), 414.1096
[1431] HPLC purity 98.8% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 144
1-{2-[(2S)-morpholin-2-yl]ethyl}-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1-
,3-benzothiadiazole 2,2-dioxide
##STR00180##
[1433] This compound was prepared using
1-(4-fluorophenyl)-3-(2-morpholin-2-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide analogous to the conditions used in general
procedure III.
[1434] HRMS: calcd for C18H18F3N3O3S+H+, 414.1094; found (ESI,
[M+H]+), 414.1081
[1435] HPLC purity 100% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 145
1-{2-[(2R)-morpholin-2-yl]ethyl}-3-(2,4,6-trifluorophenyl)-1,3-dihydro-2,1-
,3-benzothiadiazole 2,2-dioxide
##STR00181##
[1437] This compound was prepared using
1-(4-fluorophenyl)-3-(2-morpholin-2-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide analogous to the conditions used in general
procedure III.
[1438] HRMS: calcd for C18H18F3N3O3S+H+, 414.1094; found (ESI,
[M+H]+), 414.1080
[1439] HPLC purity 95.3% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 146
1-(3-methoxyphenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide
##STR00182##
[1441] This compound was prepared using
1-(3-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
analogous to the conditions used in general procedures II and
III.
[1442] HRMS: calcd for C19H23N3O4S+H+, 390.1482; found (ESI,
[M+H]+), 390.1472
[1443] HPLC purity 100% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 147
1-(3-methoxyphenyl)-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-ben-
zothiadiazole 2,2-dioxide
##STR00183##
[1445] This compound was prepared using
1-(3-methoxyphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
analogous to the conditions used in general procedures II and
III.
[1446] HRMS: calcd for C19H23N3O4S+H+, 390.1482; found (ESI,
[M+H]+), 390.1472
[1447] HPLC purity 100% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 148
1-(2-fluorophenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-benz-
othiadiazole 2,2-dioxide
##STR00184##
[1449] This compound was prepared using
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
analogous to the conditions used in general procedure II and
III.
[1450] HRMS: calcd for C18H20FN3O3S+H+, 378.1282; found (ESI,
[M+H]+), 378.1272
[1451] HPLC purity 97% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5 u,
150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 149
1-(2-fluorophenyl)-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3-benz-
othiadiazole 2,2-dioxide
##STR00185##
[1453] This compound was prepared using
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
analogous to the conditions used in general procedure II and
III.
[1454] HRMS: calcd for C18H20FN3O3S+H+, 378.1282; found (ESI,
[M+H]+), 378.1273
[1455] HPLC purity 92.9% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 150
1-(2,6-difluorophenyl)-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2,1,3--
benzothiadiazole 2,2-dioxide
##STR00186##
[1457] This compound was prepared using
1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide analogous to the conditions used in general procedures
II and III.
[1458] HRMS: calcd for C18H19F2N3O3S+H+, 396.1188; found (ESI,
[M+H]+), 396.1178
[1459] HPLC purity 100% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 151
1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3
benzothiadiazol-1(3H)-yl]methyl}phenyl)-N-methylmethanamine
##STR00187##
[1461] Step 1: In an analogous manner to general procedure IV,
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.20 g, 0.75 mmol) was treated with cesium carbonate (0.24 g, 0.75
mmol) and 1,3-bis(bromomethyl)benzene) (0.80 g, 3.00 mmol) to
provide 0.23 g (70%) of
1-[3-(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide. MS (ES) m/z 446.7; HPLC purity 98.5% at
210-370 nm, 10.8 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column,
1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10
min, hold 4 min
[1462] Step 2: In an analogous manner to general procedure V, 1-[3
(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol-
e 2,2-dioxide (0.08 g, 0.18 mmol) was treated with methylamine (10
mL) to provide 0.05 g (71%) of
1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)-N-methylmethanamine. HRMS: calcd for
C.sub.21H.sub.20FN.sub.3O.sub.2S+H+, 398.13330; found (ESI,
[M+H]+), 398.1337; HPLC purity 95.4% at 210-370 nm, 7.7 min.;
Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 152
1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]methy-
l}phenyl)methanamine
##STR00188##
[1464] In an analogous manner to general procedure V,
1-[3-(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide (0.08 g, 0.18 mmol) was treated with ammonia (10
mL) to prepare 0.05 g (78%) of
1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)
yl]methyl}phenyl)methanamine. HRMS: calcd for
C.sub.20H.sub.18FN.sub.3O.sub.2S+H+, 384.11765; found (ESI,
[M+H]+), 384.1181; HPLC purity 100.0% at 210-370 nm, 7.7 min.;
Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 153
1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]methy-
l}phenyl)-N,N-dimethylmethanamine
##STR00189##
[1466] In an analogous manner to general procedure V,
1-[3-(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide (0.07 g, 0.18 mmol) was treated with
dimethylamine (10 mL) to provide 0.03 g (39%) of
1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)-N,N-dimethylmethanamine. HRMS: calcd for
C.sub.22H.sub.22FN.sub.3O.sub.2S+H+, 412.14895; found (ESI,
[M+H]+), 412.1493; HPLC purity 96.3% at 210-370 nm, 7.7 min.;
Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 154
1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]methy-
l}phenyl)-N,N-dimethylmethanamine
##STR00190##
[1468] Step 1: Diisopropyl azodicarboxylate (0.34 mL, 1.77 mmol)
was added to a solution of
1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.39 g, 1.47 mmol), 4-(bromomethyl)phenyl)methanol (0.3 g, 1.47
mmol) and triphenylphosphine (0.46 g, 1.77 mmol) in dry THF (2 mL)
under nitrogen. The solution was stirred overnight at room
temperature. The reaction was concentrated in vacuo to provide the
crude product. The crude product was pre-adsorbed onto Celite and
purified via Isco chromatography (Redisep, silica gel, gradient
5-50% ethyl acetate in hexane) to afford 0.34 g (52%) of
1-[4-(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide. HRMS: calcd for
C.sub.20H.sub.16BrFN.sub.2O.sub.2S+H+, 447.01726; found (ESI,
[M+H]+), 447.0172; HPLC purity 95.2% at 210-370 nm, 10.8 min.;
Xterra RP18, 3.5 u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1469] Step 2: In an analogous manner to general procedure V,
1-[4-(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide (0.11 g, 0.24 mmol) was treated with
dimethylamine (10 mL) to provide 0.09 g, (92%) of
1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)-N,N-dimethylmethanamine. MS (ES) m/z 411.0. HPLC purity
97.3% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm
column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH)
for 10 min, hold 4 min.
Example 155
1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]methy-
l}phenyl)methanamine
##STR00191##
[1471] In an analogous manner to general procedure V,
1-[4-(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide (0.11 g, 0.24 mmol) was treated with ammonia (10
mL) to provide 0.09 g, (100%) of
1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)methanamine. MS (ES) m/z 383.0. HPLC purity 100.0% at
210-370 nm, 7.6 min.; Xterra RP18, 3.5 u, 150.times.4.6 mm column,
1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10
min, hold 4 min.
Example 156
1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]methy-
l}phenyl)-N-methylmethanamine
##STR00192##
[1473] In an analogous manner to general procedure V,
1-[4-(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide (0.11 g, 0.24 mmol) was treated with methylamine
(10 mL) to provide 0.09 g, (100%) of
1-(4-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]meth-
yl}phenyl)-N-methylmethanamine. MS (ES) m/z 397.0. HPLC purity
100.0% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5 u, 150.times.4.6
mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 157
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]-N-methylbut-2-en-1-amine
##STR00193##
[1475] Step 1: A solution of 2-fluoro-4-methylaniline (6.8 mL, 60
mmol) in tetrahydrofuran (200 mL) was cooled to -78.degree. C. and
treated with n-butyllithium (26 mL of a 2.5 M solution in hexanes,
66 mmol) and stirred for 1 h. A solution of 2-fluoronitrobenzene
(6.3 mL, 60 mmol) in tetrahydrofuran (20 mL) was added dropwise
over 5 min, and the reaction mixture was stirred at -78.degree. C.
for 0.5 h, then warmed to 22.degree. C. After 16 h, the reaction
mixture was concentrated, diluted with ethyl ether (200 mL), washed
with 2 M hydrochloric acid (200 mL), dried (Na.sub.2SO.sub.4), and
concentrated to a black oil. A solution of this black oil in a
mixture of methanol (100 mL) and ethyl acetate (100 mL) was treated
with 10% palladium on carbon (1 g) and stirred under a hydrogen
atmosphere at 65 psi for 2 h, and then the reaction mixture was
filtered, and concentrated. Flash chromatography (SiO.sub.2,
10.fwdarw.100% dichloromethane/hexanes) provided
N-(2-fluoro-4-methylphenyl)benzene-1,2-diamine (7.0 g) as an orange
solid:
[1476] HPLC purity 92.2% at 210-370 nm, 9.6 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1477] HRMS: calcd for C13H13FN2+H+, 217.11355; found (ESI,
[M+H]+), 217.113
[1478] Step 2: A solution of
N-(2-fluoro-4-methylphenyl)benzene-1,2-diamine (3.9 g, 18 mmol) in
diglyme (36 mL) was treated with sulfamide (2.1 g, 22 mmol) and
added dropwise over 10 min to a refluxing solution of sulfamic acid
(0.9 g, 9 mmol) in diglyme (36 mL), and the reaction mixture was
kept at reflux for an additional 15 minutes, then cooled to room
temperature and concentrated. The residue was dissolved in ethyl
ether (300 mL), washed with 2 N hydrochloric acid (100 mL),
evaporated, and flash chromatographed (SiO.sub.2, 0.fwdarw.50%
ethyl acetate/hexanes) provided
1-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (2.6 g) as a red solid:
[1479] HPLC purity 98.0% at 210-370 nm, 9.1 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1480] HRMS: calcd for C13H11FN2O2S+H+, 279.05980; found (ESI,
[M+H]+), 301.0421.
[1481] Step 3: A solution of
-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.5 g, 1.8 mmol) in dimethylformamide (15 mL) was
treated with cesium carbonate (1.2 g, 3 mmol) and
cis-1,4-dichloro-2-butene (3.2 mL, 20 mmol) and stirred at
22.degree. C. for 14 h. The reaction mixture was diluted with ethyl
ether (100 mL), washed with 2 M hydrochloric acid (100 mL) and
concentrated. Flash chromatography (SiO.sub.2, 10.fwdarw.50% ethyl
acetate/hexanes) provided
1-[(2Z)-4-chlorobut-2-en-1-yl]-3-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,-
1,3-benzothiadiazole 2,2-dioxide (0.5 g) as a yellow oil:
[1482] MS (ES) m/z 366.9;
[1483] HPLC purity 98.2% at 210-370 nm, 10.6 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1484] Step 4: A solution of
1-[(2Z)-4-chlorobut-2-en-1-yl]-3-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,-
1,3-benzothiadiazole 2,2-dioxide (0.1 g) was stirred in an 8 M
methylamine-ethanol solution at 22.degree. C. for 16 h. The
reaction mixture was concentrated under reduced pressure to provide
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]-N-methylbut-2-en-1-amine hydrochloride (0.12 g) as a white
solid:
[1485] HPLC purity 97.7% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1486] HRMS: calcd for C18H20FN3O2S+H+, 362.13330; found (ESI,
[M+H]+ Obs'd), 362.1337
Example 158
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]but-2-en-1-amine
##STR00194##
[1488] In an analogous manner to general procedure V,
1-[(2Z)-4-chlorobut-2-en-1-yl]-3-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,-
1,3-benzothiadiazole 2,2-dioxide was reacted with ammonia to
provide
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]but-2-en-1-amine hydrochloride:
[1489] HPLC purity 92.1% at 210-370 nm, 7.6 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1490] HRMS: calcd for C17H18FN3O2S+H+, 348.11765; found (ESI,
[M+H]+ Obs'd), 348.1182
Example 159
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H-
)-yl]-N,N-dimethylbut-2-en-1-amine
##STR00195##
[1492] In an analogous manner to general procedure V,
1-[(2Z)-4-chlorobut-2-en-1-yl]-3-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,-
1,3-benzothiadiazole 2,2-dioxide was reacted with dimethylamine to
provide
(2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3-
H)-yl]-N,N-dimethylbut-2-en-1-amine hydrochloride:
[1493] HPLC purity 100.0% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 160
(2Z)-N-ethyl-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadia-
zol-1(3H)-yl]but-2-en-1-amine
##STR00196##
[1495] In an analogous manner to general procedure V,
1-[(2Z)-4-chlorobut-2-en-1-yl]-3-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,-
1,3-benzothiadiazole 2,2-dioxide was reacted with ethylamine to
provide
(2Z)-N-ethyl-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadi-
azol-1(3H)-yl]but-2-en-1-amine hydrochloride:
[1496] HPLC purity 98.6% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1497] HRMS: calcd for C19H22FN3O2S+H+, 376.14895; found (ESI,
[M+H]+ Obs'd), 376.1495.
Example 161
1-(3,4-difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzoth-
iadiazole 2,2-dioxide
##STR00197##
[1499] Step 1: A solution of 3,4-difluoroaniline (10.0 mL, 1.0 mol)
in tetrahydrofuran (200 mL) was cooled to -78.degree. C., treated
with n-butyllithium solution (44 mL of a 2.5 M hexanes solution,
1.1 mol), stirred at -78.degree. C. for 1 h and then warmed to
0.degree. C. for 30 min. The reaction mixture was cooled to
-78.degree. C. and 1-fluoro-2-nitrobenzene (9.5 mL, 0.9 mol) in
tetrahydrofuran (10 mL) was slowly added and the reaction, after
which the reaction was warmed to room temperature. The reaction
mixture was evaporated to provide
3,4-difluoro-N-(2-nitrophenyl)aniline (22.76 g, 91%) as a brown
solid. The crude product was taken on to the next step.
[1500] Step 2: A solution of 3,4-difluoro-N-(2-nitrophenyl)aniline
(22.76 g, 91 mmol) in 50% ethyl acetate/methanol (500 mL) was treat
with palladium on carbon 10 w. % loading, matrix activated carbon
support (3.07 g). The reaction mixture was placed on the Parr
shaker for 3 h at 60 psi. The reaction mixture was filtered through
celite and evaporated. The crude reaction product was purified by
flash chromatography (SiO.sub.2, 3-50% ethyl acetate/heptane) to
provided N-(3,4-difluorophenyl)benzene-1,2-diamine (10.17 g, 51%)
as a brown solid:
[1501] HPLC purity 99.9% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1502] HRMS: calcd for C12H10F2N2+H+, 221.08848; found (ESI,
[M+H]+), 221.0887;
[1503] Step 3: Dry diglyme (10 mL) was added to a flask equipped
with a dropping funnel under a nitrogen atmosphere and brought to a
vigorous reflux. N-(3,4-difluorophenyl)benzene-1,2-diamine (1.03 g,
4.7 mmol) and sulfamide (0.54 g, 5.6 mmol) were dissolved in 5 mL
of diglyme and placed in the dropping funnel. The mixture was added
dropwise to the flask over 15 minutes and then refluxing was
continued for an additional 15 minutes. The mixture was cooled to
ambient temperature and the reaction mixture was evaporated using
high temperature. The crude reaction product was purified by flash
chromatography (SiO.sub.2, 3-50% ethyl acetate/hexane) to provide
1-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.62 g, 47%) as a pink solid:
[1504] MS (ES) m/z 280.8;
[1505] HPLC purity 95.7% at 210-370 nm, 9.0 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1506] Step 4: A solution of
1-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.29 g, 1.0 mmol) in tetrahydrofuran (10 mL) was
cooled to 0.degree. C., treated with triphenylphosphine (0.41 g,
1.5 mmol), tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate
(0.47 g, 2.1 mmol) were added followed by
diisopropylazodicarboxylate (0.3 mL, 1.5 mmol). The reaction
mixture stirred for 2 hours at ambient temperature and then was
evaporated. The crude reaction product was purified by flash
chromatography (SiO.sub.2, 3-70% ethyl acetate/hexane) to provide
tert-butyl
4-{2-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thyl}piperazine-1-carboxylate (0.39 g, 76%) as a pink solid:
[1507] MS (ES) m/z 494.9;
[1508] HPLC purity 96.9% at 210-370 nm, 10.8 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1509] Step 5: A solution of tert-butyl
4-{2-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thyl}piperazine-1-carboxylate (0.34 g, 0.69 mmol) in
dichloromethane (5 mL) was treated with hydrogen chloride (2.0 mL
of a 4 M solution in dioxane), resulting in a white precipitate
that was evaporated and dried under vacuum to provided
1-(3,4-difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide (0.2 g, 74%) as a white solid:
[1510] MS (ES) m/z 394.9;
[1511] HPLC purity 99.1% at 210-370 nm, 7.6 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Example 162
1-(3,4-difluorophenyl)-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2,1,3-benzot-
hiadiazole 2,2-dioxide
##STR00198##
[1513] Step 1: A solution of
1-(3-bromopropyl)-3-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (0.2, 0.5 mmol) in anhydrous dimethylformamide (3
mL) was treated with tert-butyl piperazine-1-carboxylate (0.19 g, 1
mmol) and N,N-diisopropylethylamine (0.17 mL, 1 mmol). The reaction
mixture stirred at ambient for 48 h. The reaction mixture was
diluted with ethyl ether (10 mL) and washed with H.sub.2O
(2.times.10 mL), the organic layer was isolated, dried with
MgSO.sub.4 and evaporated. The crude reaction product was purified
by flash chromatography (SiO.sub.2, 3-50% ethyl acetate/hexane) to
provided tert-butyl
4-{3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]p-
ropyl}piperazine-1-carboxylate (0.17 g, 67%) as a white solid:
[1514] MS (ES) m/z 508.9;
[1515] HPLC purity 98.4% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1516] Step 2: A solution of tert-butyl
4-{3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]p-
ropyl}piperazine-1-carboxylate (0.16 g, 0.3 mmol) in
dichloromethane (10 mL) was treated with hydrogen chloride (6.0 mL
of a 4 M solution in dioxane), resulting in a white precipitate
that was evaporated and dried under vacuum to provided
1-(3,4-difluorophenyl)-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide (0.11 g, 81%) as a white solid:
[1517] HPLC purity 96.8% at 210-370 nm, 7.8 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1518] HRMS: calcd for C19H22F2N4O2S+H+, 409.15043; found (ESI,
[M+H]+ Obs'd), 409.1506;
[1519] HRMS: calcd for C19H22F2N4O2S+H+, 409.15043; found (ESI,
[M+H]+ Calc'd), 409.1504;
Example 163
1-(3,4-difluorophenyl)-3-[3-(3,5-dimethylpiperazin-1-yl)propyl]-1,3-dihydr-
o-2,1,3-benzothiadiazole 2,2-dioxide
##STR00199##
[1521] In an analogous manner as general procedure V,
1-(3-bromopropyl)-3-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazo-
le 2,2-dioxide (0.2, 0.51 mmol) was treated with
2,6-dimethylpiperazine (0.21 g, 1.8 mmol) to provide
1-(3,4-difluorophenyl)-3-[3-(3,5-dimethylpiperazin-1-yl)propyl]-1,3-dihyd-
ro-2,1,3-benzothiadiazole 2,2-dioxide (0.19 g, 85%) as a white
solid:
[1522] HPLC purity 100.0% at 210-370 nm, 8.2 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1523] HRMS: calcd for C21H26F2N4O2S+H+, 437.18173; found (ESI,
[M+H]+ Obs'd), 437.1829;
Example 164
2-{2-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]et-
hoxy}-N-methylethanamine
##STR00200##
[1525] Step 1: In an analogous manner as general procedure V,
2-{2-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N-methylethanamine was prepared from
1-[2-(2-bromoethoxy)ethyl]-3-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide as a white solid.
[1526] HPLC purity 98.0% at 210-370 nm, 7.6 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1527] HRMS: calcd for C17H19F2N3O3S+H+, 384.11879; found (ESI,
[M+H]+ Obs'd), 384.1186;
Example 165
1-(2-piperazin-1-ylethyl)-3-(2,3,4-trifluorophenyl)-1,3-dihydro-2,1,3-benz-
othiadiazole 2,2-dioxide
##STR00201##
[1529] Step 1: In an analogous manner as general procedure I,
1-(2,3,4-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide was prepared from 2,3,4-trifluoroaniline as a solid. MS
(ES) m/z 298.7;
[1530] HPLC purity 83.7% at 210-370 nm, 9.0 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1531] Step 2: In an analogous manner as general VI, a solution of
1-(2,3,4-trifluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (0.21 g, 0.7 mmol) in tetrahydrofuran (10 mL) was
cooled to 0.degree. C., treated with triphenylphosphine (0.27 g,
1.0 mmol), tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate
(0.38 g, 1.4 mmol) were added followed by
diisopropylazodicarboxylate (0.2 mL, 1.0 mmol to provide tert-butyl
4-{2-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-y-
l]ethyl}piperazine-1-carboxylate (0.22 g, 62 5) as white solid:
[1532] HPLC purity 95.5% at 210-370 nm, 10.5 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1533] HRMS: calcd for C23H27F3N4O4S+H+, 513.17779; found (ESI,
[M+H]+ Obs'd), 513.1799;
[1534] Step 3: In an analogous manner as general procedure II, step
2, a solution of tert-butyl
4-{2-[2,2-dioxido-3-(2,3,4-trifluorophenyl)-2,1,3-benzothiadiazol-1(3H)-y-
l]ethyl}piperazine-1-carboxylate (0.2 g, 0.39 mmol) in
dichloromethane (5 mL) was treated with hydrogen chloride (2.0 mL
of a 4 M solution in dioxane), resulting in a white precipitate
that was evaporated and dried under vacuum to provided
3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-(-
2,2,2-trifluoroethyl)propan-1-amine (0.12 g, 77%) as a white solid.
HPLC purity 99.5% at 210-370 nm, 7.6 min.; Xterra RP18, 3.5 u,
150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for
C18H19F3N.sub.4O.sub.2S+H+, 413.12536; found (ESI, [M+H]+ Obs'd),
413.1259.
Example 166
1-(2-methylphenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide
##STR00202##
[1536] Step 1: In an analogous manner as general procedure II, step
1, a solution of
1-(2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.2 g, 0.77 mmol) in tetrahydrofuran (10 mL) was cooled to
0.degree. C., treated with triphenylphosphine (0.3 g, 1.2 mmol),
tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.36 g, 1.54
mmol) were added followed by diisopropylazodicarboxylate (0.23 mL,
1.2 mmol to provide tert-butyl
4-{2-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}piperazine-1-carboxylate (0.25 g, 69%) as a white foam. HPLC
purity 100.0% at 210-370 nm, 10.7 min.; Xterra RP18, 3.5 u,
150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for
C24H32N4O4S+H+, 473.22170; found (ESI, [M+H]+ Obs'd), 473.2229;
[1537] Step 2: In an analogous manner as general procedure II, step
2, a solution of tert-butyl
4-{2-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}piperazine-1-carboxylate (0.22 g, 0.47 mmol) in dichloromethane
(10 mL) was treated with hydrogen chloride (3.0 mL of a 4 M
solution in dioxane), resulting in a white precipitate that was
evaporated and dried under vacuum to provided
1-(2-methylphenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide (0.16 g, 92%) as a white solid:
[1538] HPLC purity 99.0% at 210-370 nm, 7.5 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1539] HRMS: calcd for C19H24N4O2S+H+, 373.16927; found (ESI,
[M+H]+ Obs'd), 373.1692;
Example 167
1-(2-chlorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide
##STR00203##
[1541] Step 1: In an analogous manner as general procedure II, step
1, a solution of
1-(2-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
(0.23 g, 0.8 mmol) in tetrahydrofuran (10 mL) was cooled to
0.degree. C., treated with triphenylphosphine (0.32 g, 1.2 mmol),
tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.37 g, 1.6
mmol) were added followed by diisopropylazodicarboxylate (0.23 mL,
1.2 mmol) to provide tert-butyl
4-{2-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}piperazine-1-carboxylate (0.24 g, 61%) as a white foam:
[1542] HPLC purity 98.1% at 210-370 nm, 10.5 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1543] HRMS: calcd for C23H29ClN4O.sub.4S+H+, 493.16708; found
(ESI, [M+H]+ Obs'd), 493.1675;
[1544] Step 2: In an analogous manner as general procedure II, step
2, a solution of tert-butyl
4-{2-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl-
}piperazine-1-carboxylate (0.22 g, 0.45 mmol) in dichloromethane
(10 mL) was treated with hydrogen chloride (3.0 mL of a 4 M
solution in dioxane), resulting in a white precipitate that was
evaporated and dried under vacuum to provided
1-(2-chlorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide (0.14 g, 81%) as a white solid:
[1545] HPLC purity 98.7% at 210-370 nm, 7.3 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form.
Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
[1546] HRMS: calcd for C18H21ClN4O2S+H+, 393.11465; found (ESI,
[M+H]+ Obs'd), 393.1149.
Example 168
2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]et-
hoxy}-N-methylethanamine hydrochloride
##STR00204##
[1548] Step 1: In an analogous manner to general procedure IV,
1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (2.07 g, 7.3 mmol) was treated with
1-bromo-2-(2-bromoethoxy)ethane (3.2 mL, 25.7 mmol) and cesium
carbonate (2.4 g, 7.3 mmol) to give
1-[2-(2-bromoethoxy)ethyl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide (1.72 g, 53%) as a white amorphous solid.
MS (ES) m/z 368.7 [M+H--SO.sub.2].sup.+.
[1549] Step 2: In an analogous manner to general procedure V,
1-[2-(2-bromoethoxy)ethyl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide (0.66 g, 1.5 mmol) was treated with 8N
methylamine in methanol to give
2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N-methylethanamine which was treated with 1N hydrochloric
acid in ether to afford its hydrochloride salt as a white solid
(0.10 g, 16%). MS (ES) m/z 384.3 ([M+H].sup.+).
Example 169
2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]et-
hoxy}ethanamine hydrochloride
##STR00205##
[1551] Step 1: In an analogous manner to general procedure V,
1-[2-(2-bromoethoxy)ethyl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide (0.53 g, 1.2 mmol) was treated with 7N
ammonia in methanol to give
2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}ethanamine which was treated with 1N hydrochloric acid in
ether to afford its hydrochloride salt as a white solid (0.042 g,
8.6%). MS (ES) m/z 369.9 ([M+H].sup.+).
Example 170
2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]et-
hoxy}-N,N-dimethylethanamine hydrochloride
##STR00206##
[1553] In an analogous manner to general procedure V,
1-[2-(2-bromoethoxy)ethyl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide (0.53 g, 1.2 mmol) was treated with 33%
dimethylamine in ethanol to give
2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N,N-dimethylethanamine which was treated with 1N
hydrochloric acid in ether to give its hydrochloride salt as a
white solid (0.157 g, 30%). MS (ES) m/z 397.9 ([M+H].sup.+). HPLC
retention time: 7.1 min.
Example 171
(2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N-methylbut-2-en-1-amine hydrochloride
##STR00207##
[1555] Step 1: In an analogous manner to general procedure IV,
1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (3.37 g, 11.9 mmol) was treated with
(E)-1,4-dibromobut-2-ene (8.9 g, 41.7 mmol) and cesium carbonate
(3.9 g, 11.9 mmol) to give
1-[(2E)-4-bromobut-2-en-1-yl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide (3.3 g, 67%) as a clear oil.
[1556] Step 2: In an analogous manner to general procedure V,
1-[(2E)-4-bromobut-2-en-1-yl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide (0.52 g, 1.2 mmol) was treated with 8N
methylamine in methanol to give
(2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N-methylbut-2-en-1-amine which was treated with 1N hydrochloric
acid in ether to give its hydrochloride salt as a white solid (0.27
g, 54%). MS (ES) m/z 365.9 ([M+H].sup.+).
Example 172
(2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
-N,N-dimethylbut-2-en-1-amine hydrochloride
##STR00208##
[1558] Step 1: In an analogous manner to general procedure V,
1-[(2E)-4-bromobut-2-en-1-yl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide (0.18 g, 0.43 mmol) was treated with 33%
dimethylamine in ethanol to give
(2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]-N,N-dimethylbut-2-en-1-amine which was treated with 1N
hydrochloric acid in ether to give its hydrochloride salt as a
white solid (0.018 g, 10%). MS (ES) m/z 379.8 ([M+H].sup.+).
Example 173
(2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-
but-2-en-1-amine hydrochloride
##STR00209##
[1560] Step 1: In an analogous manner to general procedure V,
1-[(2E)-4-bromobut-2-en-1-yl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-be-
nzothiadiazole 2,2-dioxide (0.14 g, 0.33 mmol) was treated with 7N
ammonia in methanol to give
(2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]but-2-en-1-amine which was treated with 1N hydrochloric acid in
ether to give hydrochloride salt as a white solid (0.052 g, 40%).
MS (ES) m/z 351.9 ([M+H].sup.+).
[1561] HPLC retention time: 7.0 min.
Example 174
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]ethoxy}ethyl)cyclopropanamine hydrochloride
##STR00210##
[1563] Step 1: In an analogous manner to general procedure IV,
1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxide (2.69 g, 9.5 mmol) was treated with
1-bromo-2-(2-bromoethoxy)ethane (3.6 mL, 28.6 mmol) and cesium
carbonate (3.1 g, 9.5 mmol) to give
1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide as a clear oil (3.1 g, 76%). MS (ES) m/z
432.7.
[1564] Step 2: In an analogous manner to general procedure V,
1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide (0.1 g, 0.23 mmol) was treated with
cyclopropylamine (0.64 mL, 9.2 mmol) in methanol to give
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]ethoxy}ethyl)cyclopropanamine which was treated with 1N
hydrochloric acid in ether to give its hydrochloride salt as a
white solid (0.63 g, 57%). HRMS: calcd for
C.sub.19H.sub.21F.sub.2N.sub.3O.sub.3S+H.sub.+, 410.13444; found
(ESI, [M+H].sub.+ Obs'd), 410.1341.
Example 175
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]ethoxy}ethyl)cyclobutanamine hydrochloride
##STR00211##
[1566] Step 1: In an analogous manner to general procedure V,
1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide (0.1 g, 0.23 mmol) was treated with
cyclobutylamine (0.8 mL, 9.2 mmol) in methanol to give
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]ethoxy}ethyl)cyclobutanamine which was treated with 1N
hydrochloric acid in ether to give its hydrochloride salt as a
white solid (0.59 g, 56%). HRMS: calcd for
C.sub.20H.sub.23F.sub.2N.sub.3O.sub.3S+H.sup.+, 424.15009; found
(ESI, [M+H].sup.+ Obs'd), 424.1497.
Example 176
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]ethoxy}ethyl)cyclopentanamine hydrochloride
##STR00212##
[1568] Step 1: In an analogous manner to general procedure V,
1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide (0.1 g, 0.23 mmol) was treated with
cyclopentylamine (2.4 mL, 9.2 mmol) in methanol to give
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]ethoxy}ethyl)cyclopentanamine which was treated with 1N
hydrochloric acid in ether to give its hydrochloride salt as a
white sold (0.94 g, 87%). HRMS: calcd for
C.sub.21H.sub.25F.sub.2N.sub.3O.sub.3S+H.sup.+, 438.16574; found
(ESI, [M+H].sup.+ Obs'd), 438.1652.
Example 177
2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]et-
hoxy}-N-methylethanamine hydrochloride
##STR00213##
[1570] Step 1: In an analogous manner to general procedure V,
1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide (0.1 g, 0.23 mmol) was treated with 8N
methyllamine in methanol to give
2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N-methylethanamine which was treated with 1N hydrochloric
acid in ether to give its hydrochloride salt as a white solid (0.24
g, 25%). HRMS: calcd for
C.sub.17H.sub.19F.sub.2N.sub.3O.sub.3S+H.sup.+, 384.11879; found
(ESI, [M+H].sup.+ Obs'd), 384.1184.
Example 178
2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]et-
hoxy}-N-ethylethanamine hydrochloride
##STR00214##
[1572] Step 1: In an analogous manner to general procedure V,
1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide (0.1 g, 0.23 mmol) was treated with 30-40%
ethylamine in methanol to give
2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]e-
thoxy}-N-ethylethanamine which was treated with 1N hydrochloric
acid in ether to give its hydrochloride salt as a white solid (0.67
g, 67%). HRMS: calcd for
C.sub.18H.sub.21F.sub.2N.sub.3O.sub.3S+H.sup.+, 398.13444; found
(ESI, [M+H].sup.+ Obs'd), 398.1341.
Example 179
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl-
]ethoxy}ethyl)propan-2-amine hydrochloride
##STR00215##
[1574] Step 1: In an analogous manner to general procedure V,
1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzo-
thiadiazole 2,2-dioxide (0.1 g, 0.23 mmol) was treated with
isopropylamine (0.8 mL, 9.2 mmol) in methanol to give
N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-y-
l]ethoxy}ethyl)propan-2-amine which was treated with 1N
hydrochloric acid in ether to give its hydrochloride salt as a
white solid (0.32 g, 31%). HRMS: calcd for
C.sub.19H.sub.23F.sub.2N.sub.3O.sub.3S+H.sup.+, 412.15009; found
(ESI, [M+H].sup.+ Obs'd), 412.1497.
Example 180
1-(4-chlorophenyl)-3-(4-morpholin-4-ylbutyl)-1,3-dihydro-2,1,3-benzothiadi-
azole 2,2-dioxide
##STR00216##
[1576] In an analogous manner to General Procedure V, morpholine (2
mL, 23 mmol) and
1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothia-
diazole 2,2-dioxide (50 mg, 0.12 mmol) were stirred overnight to
prepare 29 mg (45%) of
1-(4-chlorophenyl)-3-(4-morpholin-4-ylbutyl)-1,3-dihydro-2,1,3-benzothiad-
iazole 2,2-dioxide as the TFA salt.
[1577] HPLC purity 100.0% at 210-370 nm, 8.2 min.; Xterra RP18, 3.5
u, 150.times.4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium
formate buffer pH=3.5, acetonitrile/MeOH) for 10 min, hold 4
min.
[1578] HRMS: calculated for
C.sub.20H.sub.24ClN.sub.3O.sub.3S+H.sup.+, 422.12996; found (ESI,
[M.sup.+H]+), 422.1296
[1579] Examples 181-196 are prepared as described in Examples 134
and 135.
Example 181
1-(2-Fluorophenyl)-4-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2-
,1,3-benzothiadiazole 2,2-dioxide
##STR00217##
[1580] Example 182
1-(2-Fluorophenyl)-4-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2-
,1,3-benzothiadiazole 2,2-dioxide
##STR00218##
[1581] Example 183
1-(2-Fluorophenyl)-5-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2-
,1,3-benzothiadiazole 2,2-dioxide
##STR00219##
[1582] Example 184
1-(2-Fluorophenyl)-5-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2-
,1,3-benzothiadiazole 2,2-dioxide
##STR00220##
[1583] Example 185
1-(2-Fluorophenyl)-6-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2-
,1,3-benzothiadiazole 2,2-dioxide
##STR00221##
[1584] Example 186
1-(2-Fluorophenyl)-6-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2-
,1,3-benzothiadiazole 2,2-dioxide
##STR00222##
[1585] Example 187
1-(2-Fluorophenyl)-7-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihydro-2-
,1,3-benzothiadiazole 2,2-dioxide
##STR00223##
[1586] Example 188
1-(2-Fluorophenyl)-7-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihydro-2-
,1,3-benzothiadiazole 2,2-dioxide
##STR00224##
[1587] Example 189
1-(2,6-Difluorophenyl)-4-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihyd-
ro-2,1,3-benzothiadiazole 2,2-dioxide
##STR00225##
[1588] Example 190
1-(2,6-Difluorophenyl)-4-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihyd-
ro-2,1,3-benzothiadiazole 2,2-dioxide
##STR00226##
[1589] Example 191
1-(2,6-Difluorophenyl)-5-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihyd-
ro-2,1,3-benzothiadiazole 2,2-dioxide
##STR00227##
[1590] Example 192
1-(2,6-Difluorophenyl)-5-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihyd-
ro-2,1,3-benzothiadiazole 2,2-dioxide
##STR00228##
[1591] Example 193
1-(2,6-Difluorophenyl)-6-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihyd-
ro-2,1,3-benzothiadiazole 2,2-dioxide
##STR00229##
[1592] Example 194
1-(2,6-Difluorophenyl)-6-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihyd-
ro-2,1,3-benzothiadiazole 2,2-dioxide
##STR00230##
[1593] Example 195
1-(2,6-Difluorophenyl)-7-fluoro-3-{2-[(2R)-morpholin-2-yl]ethyl}-1,3-dihyd-
ro-2,1,3-benzothiadiazole 2,2-dioxide
##STR00231##
[1594] Example 196
1-(2,6-Difluorophenyl)-7-fluoro-3-{2-[(2S)-morpholin-2-yl]ethyl}-1,3-dihyd-
ro-2,1,3-benzothiadiazole 2,2-dioxide
##STR00232##
[1596] hNET Assay Procedure Protocol A: Inhibition of [.sup.3H] NE
Uptake into Cloned Human NE Transporters (MDCK Cells) ("hNET
Uptake")
[1597] The hNET uptake assay procedure was used to screen for
compounds that inhibit the reuptake of norepinephrine and to
determine IC.sub.50 values for compounds identified as hNET
reuptake inhibitors.
[1598] Materials and Methods:
[1599] Cell Line and Culture Reagents:
[1600] [.sup.3H] NE uptake studies were performed using MDCK cells
stably expressing human norepinephrine transporter (hNET) (See
Pacholczyk T, Blakely R D and Amara S G (1991) Expression cloning
of a cocaine- and antidepressant-sensitive human noradrenaline
transporter. Nature. 350:350-354) cultured in growth medium
containing high glucose DMEM (Gibco, Cat. No. 11995), 10% FBS
(dialyzed, heat-inactivated, US Bio-Technologies, Lot FBD1129HI)
and 500 .mu.g/ml G418 (Gibco, Cat. No. 10131). Cells were seeded at
300,000/T75 flask, and split twice weekly.
[1601] Norepinephrine Uptake Assays:
[1602] All uptake experiments were performed in 96-well plates
(Falcon Optilux, cat #353947) in a total volume of 250 .mu.l/well.
MDCK cells were plated at 50,000 cells/well. At the time of the
assay, the media was removed, and 200 .mu.l assay buffer (25 mM
Hepes, 120 mM NaCl, 5 mM KCl, 2.5 mM CaCl.sub.2, 1.2 mM
MgSO.sub.4.7H.sub.2O, 2 mg/ml glucose, 0.2 mg/ml ascorbic acid, 1
.mu.M pargyline, pH 7.4) was added to each well. 25 .mu.l of each
test compound was subsequently added to plates in triplicate and
incubated at 37.degree. C. for 5 minutes. All test compounds were
dissolved in 100% DMSO and diluted in 4% DMSO/H.sub.2O, and assayed
using a 7-point dose response curve (1 nM-10 .mu.M). Next, 25 .mu.l
of [.sup.3H] NE (74.9 Ci/mmol, Perkin Elmer, Boston, Mass.) was
added to all wells and incubated at 37.degree. C. for an additional
5 minutes. Non-specific uptake was defined by 20 .mu.M desipramine.
The final concentrations of [.sup.3H] NE was 16 nM, respectively.
The reaction was terminated by aspiration and washed with ice cold
50 mM Tris (pH 7.4). The plates were left to air dry for roughly 30
min, and MDCK cells were lysed by the addition of 25 .mu.l of 0.25
M NaOH. 100 .mu.l of Microscint-20 were added to each well
(Packard, Perkin Elmer, Boston, Mass.), and the plates were counted
using a TopCount (Perkin Elmer, Downer's Grove, Ill.) liquid
scintillation counter.
[1603] Analysis of Results:
% Inhibition of uptake=((mean cpm control wells-each cpm drug
well)/(mean cpm control wells-non-specific wells).times.100.
[1604] IC.sub.50 values were calculated using a Prism.RTM.
nonlinear regression program where % inhibition is plotted versus
concentration of inhibitor.
[1605] See: Pacholczyk T, Blakely R D and Amara S G (1991)
Expression cloning of a cocaine- and antidepressant-sensitive human
noradrenaline transporter. Nature. 350:350-354.
[1606] See also: Ramamoorthy J D, Ramamoorthy S, Papapetropoulos A,
Catravas J D, Leibach F H and Ganaphthy V (1995) Cyclic
AMP-independent up-regulation of the human serotonin transporter by
staurosporine in choriocarcinoma cells. Journal of Biological
Chemistry. 270:17189-17195, the contents of which is hereby
incorporated by reference.
[1607] hNET Assay Procedure Protocol B: Cell Based Norepinephrine
(NE) Reuptake Assay Using the Recombinant Human Norepinephrine
Transporter (hNET) ("hNET Uptake")
[1608] The hNET uptake assay procedure was used to screen for
compounds that inhibit the reuptake of norepinephrine and to
determine IC.sub.50 values for compounds identified as hNET
reuptake inhibitors.
[1609] Materials and Methods:
[1610] Compounds:
[1611] For screening, hydrochloride salts of compounds were
dissolved in solution and 25 .mu.l aliquots of compound solution at
a 1 .mu.M or 10 .mu.M final concentration delivered directly to
cells. For IC.sub.50 determinations, stock compounds were prepared
at 10 mM from powder. The stock solution was diluted according to
compound testing range. Typically, the compound testing range was
from 6 nM to 6 .mu.M by half log dilutions. On the day of assay, 25
.mu.l of compound solution at the specified concentrations was
added to the plates containing cells. A DMSO stock of desipramine
was prepared at 10 mM in DMSO and diluted for a final concentration
of 20 .mu.M to determine the non-specific reuptake. The radioligand
in this assay is .sup.3H-norepinephrine (NE) (PerkinElmer; NET678;
40-80 Ci/mmol) was delivered at approximately 16 nM final
concentration for both single point testing and compound IC.sub.50
determinations.
[1612] Tissue Culture Conditions:
[1613] MDCK-Net6 cells, stably transfected with human hNET (See
Pacholczyk T, Blakely R D and Amara S G (1991) Expression cloning
of a cocaine- and antidepressant-sensitive human noradrenaline
transporter. Nature. 350:350-354) was maintained in growth media
[high glucose DMEM (Gibco Cat. 11995), 10% FBS (dialyzed,
heat-inactivated, Sigma, dialysed, heat inactivated, Lot# K0922 or
equivalent) 1.times. Pen/Strep, and 500 .mu.g/ml G418 (Gibco Cat.
10131)]. Cells were plated at 300,000/T75 flask and cells were
split twice weekly.
[1614] Functional Reuptake Assay:
[1615] Cells were plated at 3,000 cells/well on day 1 in BD Falcon
Microtest 96-well sterile cell culture plates, Optilux White/Clear
Bottom TC plate (VWR; #62406-466 or equivalent) in growth media and
maintained in a cell incubator (37.degree. C., 5% CO.sub.2). On Day
2, cells were removed from the cell incubator and the growth media
is replaced by 200 .mu.l of assay buffer (25 mm HEPES 120 mM NaCL;
5 mM KCl; 2.5 mM CaCl.sub.2; 1.2 mM MgSO.sub.4; 2 mg/ml glucose (pH
7.4, 37.degree. C.)) containing 0.2 mg/ml ascorbic acid and 1 .mu.M
pargyline. For screening, 25 .mu.l of compound in 4% DMSO is added
directly to each well and the plate is incubated for 5 min
(37.degree. C.). To initiate the norepinephrine reuptake, 16 nM
(final concentration) of .sup.3H norepinephrine (specific activity;
40-80 Ci/mmol) in assay buffer was delivered in 25 .mu.l aliquots
to each well, and the plates were incubated for 5 min at 37.degree.
C. The reaction was aspirated from the plate and the cells washed
with 250 .mu.l of 50 mM Tris Buffer (4.degree. C.). The plates were
left to dry for 1 hour. The cells were lysed using 0.25 M NaOH
solution then placed on a shake table and vigorously shaken for 10
min. After cell lysis, 100 .mu.l of Microscint 20 (PerkinElmer;
#87-051101) was added to the plates and the plates were sealed with
film tape and replaced on the shake table for a minimum of 10 min.
The plates were counted in a TopCount counter (PerkinElmer).
[1616] Analysis of Results:
[1617] For screening single point determinations, each compound
plate contained at least 3 control wells (maximum NE reuptake
determinant) and 3 non-specific wells determined by adding 20 .mu.M
of desipramine (minimum NE reuptake determinant). Determination of
active compounds were calculated using a Microsoft Excel spread
sheet applying the following formula:
% inhibition=[1-((mean cpm test compound wells-mean cpm
non-specific wells)/(mean cpm control wells-mean cpm non-specific
wells))].times.100
[1618] For IC.sub.50 determination, raw cpm values were generated
in a data file from the TopCount counter. The data was organized
Microsoft Excel and transferred into PRIZM graphing and statistical
program, which calculated the estimated IC.sub.50 value.
Calculation of IC.sub.50 values was made using non-linear
regression analysis with a sigmoidal dose response with variable
slope. The statistical program used wells containing .sup.3H
norepinephrine only as the maximal NE reuptake determinant and
wells containing .sup.3H norepinephrine plus 20 .mu.M desipramine
as the minimal NE reuptake determinant (non-specific determinant).
Estimation of the IC.sub.50 value is completed on a log scale and
the line is fit between the maximal and minimal NE reuptake values.
In the event that the highest test concentration does not exceed
50% reuptake inhibition, data will be reported as percent maximal
NE reuptake at the highest concentration tested.
[1619] See: Pacholczyk, T., Blakely, R. D., and Amara, S. G. (1991)
Expression cloning of a cocaine- and antidepressant-sensitive human
noradrenaline transporter. Nature, 350, 350-354, the contents of
which is hereby incorporated by reference.
[1620] Results are shown in the following tables:
TABLE-US-00001 Example IC.sub.50 (nM) NE uptake (Protocol B) 1 145
2 207 3 199 4 4310 5 347 6 157 7 135 8 229 9 341 10 17.5 11 2.61 12
0.389 13 27.7 14 453 15 5473 16 205 17 207 18 18 19 6.91 20 71.5 21
305 22 602 23 6.13 24 548 25 12.9 26 45.3 27 147 28 8.92 29 6000 30
3.64 31 7.39 32 1133 33 187 34 900 35 41.1 36 105 37 736 38 36.6 39
6.72 40 51.9 41 9.4 42 415 43 32.8 44 61.2 45 43.4 46 16.3 47 40.6
48 4.65 49 3.11 50 29.4 51 5.06 52 5.11 53 1284 54 31.8 55 13.4 56
58.6 57 62.4 58 21.4 59 59.7 60 6.25 61 19 62 87.9 63 532 64 702 65
210 66 8.5 67 2.04 68 0.764 69 0.206 70 33.9 71 238 72 15 73 15 74
29 75 473 76 19 77 59 78 70 79 8 80 9 81 2114 82 59 83 348 84 7 85
27 86 99 87 430 88 439 89 430 90 1260 91 1647 92 154 93 2555 94
3569 95 522 97 1846 99 3628 100 3103 102 34 103 52% inhibition @ 6
uM 105 binding IC50 289 nM* 106 1464 107 381 108 6499 109 559 110
102 111 7% inhibition @ 6 uM 112 2315 113 422 114 1136 115 2948 116
352 117 4 118 5 119 78 120 21 121 360 122 175 123 45 124 27 125 151
126 103 127 2745 128 1594 129 3680 130 119 131 82 132 20 133 372
134 18 135 13 136 11 137 516 138 704 139 611 140 164 141 173 142
199 143 101 144 133 145 91 146 163 147 89 148 16 149 20 150 17 151
656 152 273 153 1158 154 2489 155 1003 156 1607 157 19 158 137 159
19 160 95 161 28 162 597 163 4190 164 84 165 39 166 35 167 23 168
18 169 17 170 binding IC50 206.6 nM* 171 7 172 1 173 71 174 213 175
157 176 1265 177 13 178 43.9 179 343 NE uptake (Protocol A) 180
1761 *For hNET binding performed according to: P. E. Mahaney et al.
Bioorg. Med. Chem. 14 (2006) 8455-8466, the contents of which is
hereby incorporated by reference in its entirety.
Rat Liver Microsomal Stability Assay:
[1621] DMSO stock solutions of test compounds were prepared at 0.5
mM concentration. Diluted solutions of test compounds were prepared
by adding 50 uL of each DMSO stock solution to 200 uL of
acetonitrile to make 0.1 mM solutions in 20% DMSO/80% acetonitrile.
Rat liver microsomal solution was prepared by adding 1.582 mL of
concentrated rat liver microsomes (20 mg/mL protein concentration)
to 48.291 mL of pre-warmed (to 37.degree. C.) 0.1M potassium
phosphate buffer (pH 7.4) containing 127 uL of 0.5 M EDTA to make a
0.6329 mg/mL (protein) microsomal solution. 11.2 uL of each test
compound diluted solution was each added directly to 885 uL of rat
liver microsomal solution (allowing direct binding of drugs to
microsomal proteins and lipids to minimize precipitation and
non-specific binding to the plasticware). This solution was mixed
and 180 uL was transferred to "Time 0" and "Time 15 min" plates
(each in duplicate wells). For the Time 15 min plate, NADPH
regenerating agent (45 uL) was added to each well to initiate the
reaction, the plate was incubated at 37.degree. C. for 15 min,
followed by quenching of the reaction by adding 450 uL of cold
acetonitrile to each well. For the Time 0 plate, 450 uL of cold
acetonitrile was added to each well, followed by addition of NADPH
regenerating agent (45 uL) and no incubation. All of the plates
were centrifuged at 3000 rpm for 15 min and the supernatants were
transferred to other well plates for analysis by LC-MS.
Dopamine Transporter (hDAT) Membrane Binding Assay
[1622] The method for this radioligand binding assay was modified
from the methods supplied with hDAT membranes (catalog number
RBHDATM; Perkin Elmer Life Analytical Sciences), and those
modifications are listed within this method section. Frozen
membrane samples from a cell line that expresses hDAT were diluted
to 7.5 ml in binding buffer (50 mM Tris-HCl; pH 7.4, 100 mM NaCl),
homogenized with a tissue-tearer (Polytron PT 1200C, Kinematica AG)
and delivered at a volume of 75 .mu.l to each well of a
polypropylene 96-well plate. The binding reaction was run in
polypropylene 96-well plates (Costar General Assay Plate, Cat. No.
3359; Lid, Cat. No. 3930). A stock solution of mazindol was
prepared in DMSO (10 mM) and delivered to triplicate wells
containing membrane for a final test concentration of 10 uM.
Mazindol is a DA transporter inhibitor with a 50% inhibitory
concentration (IC.sub.50) value of 18.0.+-.6.0 nM in the present
assays. Data from wells containing mazindol (10 uM) were used to
define non-specific (NSB) hDAT binding (minimum hDAT binding).
Total binding is defined by addition of 5 .mu.l of binding buffer
alone in the presence of [.sup.3H] WIN-35,428. Stock solutions of
compounds to be tested were prepared in DMSO at concentrations of
10 mM to 10 uM. On the day of assay, test compounds were diluted in
assay buffer according to test range (100,000 to 10 nM) ensuring a
maximal DMSO concentration of less than 0.5% in the assay reaction
wells. Homogenized membranes were pre-incubated with test compounds
for 20 min at 4.degree. C. before the initiation of the binding
reaction. The binding reaction is initiated by addition of 25 .mu.l
of .sup.3[H]-WIN 35,428 diluted in binding buffer. The final
concentration of .sup.3[H]-WIN 35,428 delivered was 10 nM. The
K.sub.D value estimated for .sup.3[H]-WIN-35,428 in hDAT membranes
(Lot#296-083-A) was 6.9 nM. The radioligand concentration, [L],
used in the competition binding assays is a factor difference of
1.4 compared to the K.sub.D value and was used to calculate the
K.sub.i value. The plate containing the radioligand binding
reactions were incubated for 2 h at 4.degree. C. on a shaking table
(Bellco, Vineland, N.J.) at 3 revolutions per minute. The
MultiScreen-FB opaque 96-well filtration plates contained Millipore
glass fiber filters (Millipore glass fiber B, Cat. No. MAFBN0B)
were used to terminate the binding reactions and to separate bound
from free radioligand. The plates were presoaked with 0.5%
polyethylenimine (PEI; Sigma Cat. No. P-3143) in water for a
minimum of two hours at room temperature to reduce nonspecific
binding of .sup.3[H]-WIN 35,428 during the harvest procedure.
Before harvesting the reaction plates, the PEI solution is
aspirated from the filter plates using a vacuum manifold. Aliquots
of each reaction (90 .mu.l of each 100 .mu.l reaction well) were
transferred from the reaction plates to the filter plates using a
Zymark Rapid Plate-96 automated pipette station. The binding
reaction is terminated by vacuum filtration through the glass fiber
filters. The filter plates were aspirated at 5-10 inches of Hg, and
the wells are washed 9 times with 200 .mu.l wash buffer (50 mM
Tris-HCl, 0.9% NaCl, pH 7.4; 4.degree. C.) using a 12 channel
aspiration/wash system. Plastic bottom supports are removed from
the filter plates and the plates are placed in plastic liners. A
100 .mu.l aliquot of scintillation fluid was added to each well and
the top of each plate is sealed with adhesive film. The plates are
vigorously shaken at 5 rpm for 10-15 minutes to ensure adequate
equilibration of aqueous to solvent partitioning. The collection of
raw counts per minute (cpm) data was done using a Wallac Microbeta
counter (Perkin Elmer).
Evaluation of Results
[1623] For each experiment, a data stream of cpm values collected
from the Wallac Microbeta counter was downloaded to a Microsoft
Excel statistical application program. Calculations of IC.sub.50
values were made using the transformed-both-sides logistic dose
response program that uses mean cpm values from wells representing
maximum binding (total) (assay buffer) and mean cpm values from
wells representing minimum binding (NSB, 10 .mu.M mazindol).
Estimation of the IC.sub.50 values was completed on a log scale and
the line was fit between the maximum and minimum binding values.
The K.sub.i value is a function of the concentration of the
compound required to inhibit 50% of the radioligand (IC.sub.50
value) divided by the free radioligand concentration [L] divided by
the K.sub.D value plus one (K.sub.i=IC.sub.50/(1+[L]/K.sub.D)). The
K.sub.i value for these studies was determined by dividing the
IC.sub.50 value by a factor of 2.4 to account for the concentration
of .sup.3[H]-WIN 35,428 used in the assay.
[1624] Results are shown in the following table:
TABLE-US-00002 TABLE A Structure hNET Function hDAT Binding RLM
stability CHEMISTRY IC50 (nM) IC50 (nM) tl/2 (min) ##STR00233##
13.1 479.3 5 ##STR00234## 10.8 598.5 3 ##STR00235## 16.2 1402.3 4
##STR00236## 20.0 2190.4 5 ##STR00237## 17.3 3 ##STR00238## 173.0 2
##STR00239## 199.0 N/A ##STR00240## 611.0 10 ##STR00241## 516.0 9
##STR00242## 163.0 5 ##STR00243## 89.0 N/A
[1625] When ranges are used herein for physical properties, such as
molecular weight, or chemical properties, such as chemical
formulae, all combinations and subcombinations of ranges specific
embodiments therein are intended to be included.
[1626] The disclosures of each patent, patent application and
publication cited or described in this document are hereby
incorporated herein by reference, in its entirety.
[1627] Those skilled in the art will appreciate that numerous
changes and modifications can be made to the preferred embodiments
of the invention and that such changes and modifications can be
made without departing from the spirit of the invention. It is,
therefore, intended that the appended claims cover all such
equivalent variations as fall within the true spirit and scope of
the invention.
* * * * *