U.S. patent application number 12/710234 was filed with the patent office on 2010-06-17 for compounds having 5-ht6 receptor affinity.
This patent application is currently assigned to MEMORY PHARMACEUTICALS CORPORATION. Invention is credited to Robert Dunn, Truc Minh Nguyen, Ashok Tehim, Wenge Xie.
Application Number | 20100152177 12/710234 |
Document ID | / |
Family ID | 38109618 |
Filed Date | 2010-06-17 |
United States Patent
Application |
20100152177 |
Kind Code |
A1 |
Dunn; Robert ; et
al. |
June 17, 2010 |
COMPOUNDS HAVING 5-HT6 RECEPTOR AFFINITY
Abstract
The present disclosure provides compounds having affinity for
the 5HT6 receptor which are of the formula (I): ##STR00001##
wherein R.sup.1-R.sup.3 A, B, D, E, G, Q, and x are as defined
herein. The disclosure also relates to methods of preparing such
compounds, compositions containing such compounds, and methods of
use thereof.
Inventors: |
Dunn; Robert; (Towaco,
NJ) ; Nguyen; Truc Minh; (New York, NY) ; Xie;
Wenge; (Mahwah, NJ) ; Tehim; Ashok;
(Ridgewood, NJ) |
Correspondence
Address: |
DARBY & DARBY P.C.
P.O. BOX 770, Church Street Station
New York
NY
10008-0770
US
|
Assignee: |
MEMORY PHARMACEUTICALS
CORPORATION
Montvale
NJ
|
Family ID: |
38109618 |
Appl. No.: |
12/710234 |
Filed: |
February 22, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11676203 |
Feb 16, 2007 |
7696229 |
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12710234 |
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60774399 |
Feb 17, 2006 |
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Current U.S.
Class: |
514/230.5 ;
514/256; 514/300; 544/105; 544/333; 546/113 |
Current CPC
Class: |
A61P 25/06 20180101;
A61P 9/10 20180101; A61P 25/24 20180101; A61P 37/04 20180101; C07D
471/04 20130101; A61P 25/14 20180101; A61P 25/08 20180101; A61P
25/18 20180101; A61P 1/04 20180101; A61P 7/04 20180101; A61P 25/20
20180101; C07D 405/14 20130101; A61P 3/04 20180101; A61P 25/00
20180101; A61P 3/00 20180101; A61P 9/00 20180101; A61P 25/32
20180101; A61P 25/28 20180101; A61P 43/00 20180101; C07D 403/14
20130101; A61P 25/22 20180101; A61P 25/34 20180101; A61P 39/02
20180101; A61P 25/36 20180101; A61P 25/16 20180101; A61P 31/12
20180101; A61P 37/08 20180101; A61P 1/10 20180101; C07D 417/14
20130101; A61P 1/14 20180101; C07D 401/04 20130101 |
Class at
Publication: |
514/230.5 ;
546/113; 544/333; 544/105; 514/300; 514/256 |
International
Class: |
A61K 31/437 20060101
A61K031/437; C07D 471/00 20060101 C07D471/00; A61K 31/538 20060101
A61K031/538; A61K 31/506 20060101 A61K031/506; A61P 25/00 20060101
A61P025/00; A61P 25/28 20060101 A61P025/28; A61P 25/16 20060101
A61P025/16; A61P 25/22 20060101 A61P025/22; A61P 25/24 20060101
A61P025/24; A61P 25/06 20060101 A61P025/06; A61P 25/18 20060101
A61P025/18 |
Claims
1. A compound of formula I: ##STR00148## wherein A, B, D, E and G,
are each CH, CR.sup.4 or N wherein at least one of A, B, D, E, or G
is N; - - - - - represents a single bond or a double bond; Q is C
when - - - - is a double bond, and Q is CH or N when - - - - - is a
single bond; x is 0, 1, 2, 3, or 4; R.sup.1 is SO.sub.2Ar, wherein
Ar is selected from formulas (a)-(r): ##STR00149## ##STR00150##
Wherein J is CR.sup.7 or N; in formula (o), one K is N and the
other is CH; J is CR.sup.7 or N; K is, in each instance
independently, CH or N; W is O, S, or is absent; X is, in each
instance independently, O or NR.sup.7; Y is O, NR.sup.7 or S; Z is
S or NR.sup.7; a is 1, 2, 3, 4 or 5; b, l, m and v are
independently 0, 1, 2, 3 or 4; c, f, h, n, o, q, s, and u are
independently 0, 1, 2 or 3; d, and e are independently 1, 2 or 3;
g, i, j, and p are independently 0, 1 or 2; k and t are 0 or 1;
R.sup.2 is H or alkyl having 1 to 8 carbon atoms, cycloalkyl having
3 to 12 carbon atoms, or cycloalkylalkyl having 4 to 12 carbon
atoms, each of which is branched or unbranched and each of which is
unsubstituted or substituted one or more times with halogen,
C.sub.1-4-alkyl, C.sub.1-4-alkoxy, oxo, or any combination thereof;
R.sup.3 is H or alkyl having 1 to 8 carbon atoms, which is
unsubstituted or substituted one or more times by halogen,
C.sub.1-4-alkyl, C.sub.1-4-alkoxy, oxo, or any combination thereof;
R.sup.4 is halogen, nitro, alkyl having 1 to 8 carbon atoms,
cycloalkyl having 3 to 12 carbon atoms, or cycloalkylalkyl having 4
to 12 carbon atoms, each of which is branched or unbranched and
wherein the alkyl, cycloalkyl or cycloalkylalkyl is unsubstituted
or substituted one or more times with halogen, C.sub.1-4-alkyl,
C.sub.1-4-alkoxy, oxo, or any combination thereof, an alkoxy having
1 to 8 carbon atoms, or a heterocyclic group, which is saturated,
partially saturated or unsaturated, having 5 to 10 ring atoms in
which at least 1 ring atom is an N, O or S atom, which is
unsubstituted or substituted one or more times by halogen, hydroxy,
C.sub.5-7-aryl, C.sub.1-4-alkoxy, cyano, halogenated alkyl, nitro,
or any combination thereof, R.sup.5 is amino, C.sub.1-4-alkylamino,
C.sub.1-4-dialkylamino, NR.sup.6C(O)R.sup.8, a heterocyclic group,
which is saturated, partially saturated or unsaturated, having 5 to
10 ring atoms in which at least 1 ring atom is an N, O or S atom,
which is unsubstituted or substituted one or more times by halogen,
hydroxy, C.sub.5-7-aryl, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, cyano,
halogenated C.sub.1-4-alkyl, or --O--Ar', wherein Ar' is an
C.sub.5-7-aryl; R.sup.6 is H or alkyl having 1 to 8 carbon atoms,
which is branched or unbranched and which is unsubstituted or
substituted one or more times with halogen, C.sub.1-4-alkyl,
C.sub.1-4-alkoxy, oxo, or any combination thereof; R.sup.7 is, in
each instance, independently H, halogen C(O)R.sup.8,
CO.sub.2R.sup.8, NR.sup.6COR.sup.8, an alkyl having 1 to 12 carbon
atoms, which is branched or unbranched and which is unsubstituted
or substituted one or more times by halogen, hydroxy, cyano,
C.sub.1-4-alkoxy, oxo or any combination thereof, and wherein
optionally one or more --CH.sub.2CH.sub.2-- groups is replaced in
each instance by --CH.dbd.CH-- or --C--.dbd.C--, alkoxy having 1 to
8 carbon atoms, which is branched or unbranched and which is
unsubstituted or substituted one or more times by halogen,
cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or
substituted one or more times by halogen, hydroxy, oxo, cyano,
C.sub.1-4-alkyl, C.sub.1-4-alkoxy, or any combination thereof,
cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted
or substituted in the cycloalkyl portion and/or the alkyl portion
one or more times by halogen, oxo, cyano, hydroxy, C.sub.1-4-alkyl,
C.sub.1-4-alkoxy or any combination thereof, aryl having 6 to 14
carbon atoms, which is unsubstituted or substituted one or more
times by halogen, CF.sub.3, OCF.sub.3, C.sub.1-4-alkyl, hydroxy,
C.sub.1-4-alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or
any combination thereof, arylalkyl in which the aryl portion has 6
to 14 carbon atoms and the alkyl portion, which is branched or
unbranched, has 1 to 5 carbon atoms, wherein the arylalkyl radical
is unsubstituted, substituted in the aryl portion one or more times
by halogen, CF.sub.3, OCF.sub.3, C.sub.1-4-alkyl, hydroxy,
C.sub.1-4-alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or
any combination thereof, and/or substituted in the alkyl portion
one or more times by halogen, oxo, hydroxy, cyano, or any
combination thereof, and wherein in the alkyl portion one or more
--CH.sub.2CH.sub.2-- groups are each optionally replaced by
--CH.dbd.CH-- or --C/C-- and one or more --CH.sub.2-groups are each
optionally replaced by --O-- or --NH--, a heterocyclic group, which
is saturated, partially saturated or unsaturated, having 5 to 10
ring atoms in which at least 1 ring atom is an N, O or S atom,
which is unsubstituted or substituted one or more times by halogen,
hydroxy, C.sub.5-7-aryl, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, cyano,
trifluoromethyl, nitro, oxo, or any combination thereof, or a
heterocycle-alkyl group, wherein the heterocyclic portion is
saturated, partially saturated or unsaturated, and has 5 to 10 ring
atoms in which at least 1 ring atom is an N, O or S atom, and the
alkyl portion is branched or unbranched and has 1 to 5 carbon
atoms, the heterocycle-alkyl group is unsubstituted, substituted
one or more times in the heterocyclic portion by halogen,
OCF.sub.3, hydroxy, C.sub.5-7-aryl, C.sub.1-4-alkyl,
C.sub.1-4-alkoxy, cyano, trifluoromethyl, nitro, oxo, or any
combination thereof, and/or substituted in the alkyl portion one or
more times by halogen, oxo, hydroxy, cyano, or any combination
thereof, and wherein in the alkyl portion one or more
--CH.sub.2CH.sub.2-- groups are each optionally replaced by
--CH.dbd.CH-- or --C/C--, and one or more --CH.sub.2-- groups are
each optionally replaced by --O-- or --NH--; R.sup.8 is in each
instance, independently, H or alkyl having 1 to 8, carbon atoms
carbon atoms, which is branched or unbranched and which is
unsubstituted or substituted one or more times by halogen; or a
pharmaceutically acceptable salt thereof; with the following
provisos: (i) when Ar is represented by formula (j) and G is CH or
CR.sup.4, then at least one of A, B, D, or E represents CR.sup.4 in
which R.sup.4 is other than H, halogen, alkyl, halogenated alkyl,
or alkoxy; or when Ar is represented by formula (j) and G is N,
then at least one of A, B, D, or E represents CR.sup.4 in which
R.sup.4 is other than H, halogen, alkyl, halogenated alkyl, alkoxy,
--OH, --NH.sub.2, or NO.sub.2; (ii) when one of A, B, D, or E
represents N and the rest are CH, G is CH, and Ar is represented by
one of formulas (d)-(i), then at least one R.sup.7 substituent on
said formula (d)-(i) is other than H, halogen, hydroxyl, alkyl,
alkoxy, halogenated alkyl, halogenated alkoxy; and (iii) when G is
N and A, B, and D are CH or CR.sup.4, then: (1) R.sub.2 is alkyl
having 1 to 8 carbon atoms, (2) Q is N, (3) Ar is selected from
formulas (d)-(g), or (4) a combination of at least two of
(1)-(3).
2. The compound of claim 1, wherein R.sub.2 is H.
3. The compound of claim 1, wherein - - - - - represents a single
bond and Q is CH or N.
4. The compound of claim 1, wherein Ar is (a).
5. The compound of claim 1, wherein Ar is (c).
6. (canceled)
7. The compound of claim 1, wherein Ar is (k).
8. The compound of claim 1, wherein Ar is (n).
9. The compound of claim 8, wherein Ar is ##STR00151## wherein W is
O or is absent and X is, in each instance independently, O, NH, or
N--CH.sub.3.
10. (canceled)
11. The compound of claim 1, wherein Q is N, A, B, and D are CH, E
is CH or NH, R.sub.2 is H or CH.sub.3, R.sub.3 is H, and R.sup.1 is
SO.sub.2Ar wherein Ar is a heterocycle selected from formulas (a),
(c) and (n).
12-35. (canceled)
36. The compound of claim 1, wherein A, D, and G are CH, E is N, B
is CR.sup.4 wherein R.sup.4 is H, halogen or halogenated alkyl, and
R.sup.1 is SO.sub.2Ar wherein Ar is phenyl substituted at least
once by amino, dialkylamino, NR.sup.6COR.sup.8,
N(CH.sub.3)COCH.sub.3), or substituted or unsubstituted
heterocyclic group, pyridinyl substituted at least once by
substituted or unsubstituted heterocyclic group, unsubstituted or
substituted moiety selected from the group consisting of
dihydrobenzofuranyl, dihydrobenzodioxepinyl, dihydroindoly, and
tetrahydroisoquinolinyl, or thiazolyl substituted at least once by
aryl.
37. The compound of claim 1, wherein A, D, and G are CH, E is N, B
is CR.sup.4 wherein R.sup.4 is H, halogen or halogenated alkyl, and
R.sup.1 is SO.sub.2Ar wherein Ar is phenyl substituted at least
once by amino, dialkylamino, NR.sup.6COR.sup.8,
N(CH.sub.3)COCH.sub.3), or substituted or unsubstituted
heterocyclic group, pyridinyl substituted at least once by
substituted or unsubstituted heterocyclic group, unsubstituted or
substituted dihydrobenzofuranyl, unsubstituted or substituted
dihydrobenzodioxepinyl, thiazolyl substituted at least once by
aryl, unsubstituted dihydroindolyl or dihydroindolyl substituted by
one or more acetyl and/or alkyl groups, or unsubstituted
tetrahydroisoquinolinyl or tetrahydroisoquinolinyl substituted by
one or more alkyl groups.
38. The compound of claim 1, wherein A, B, D, and G are CH, E is N,
and R.sup.1 is SO.sub.2Ar wherein Ar is 4-aminophenyl,
4-dimethylaminophenyl, 3-dimethylaminophenyl,
p-C.sub.6H.sub.4(NHCOCH.sub.3),
p-C.sub.6H.sub.4(N(CH.sub.3)COCH.sub.3).sub.,
3-(2-methylpyrimidin-4-yl)phenyl, 4-morpholin-4-ylphenyl,
4-pyrrolidin-1-ylphenyl, 3-pyrrolidin-1-ylphenyl,
4-morpholin-4-yl-pyridin-3-yl, 2,3-dihydrobenzofuran-5-yl,
3,4-dihydro-2H-1,5-benzodioxepin-7-yl,
4-methyl-2-phenyl-1,3-thiazol-5yl, 2,3,dihydro-1-H-indol-5-yl,
1-acetyl-2,3,dihydro-1-H-indol-5-yl,
1-methyl-2,3,dihydro-1-H-indol-5-yl,
1-ethyl-2,3,dihydro-1-H-indol-5-yl),
1,2,3,4-tetrahydroisoquinolin-7-yl,
1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl, or
1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl.
39-40. (canceled)
41. The compound of claim 1, wherein A, D and G are CH, B is
CR.sup.4 wherein R.sup.4 is H, halogen, halogenated alkyl, nitro,
pyridine, dimethylpyrrole, tetrahydropyrrole, tetrahydropyridine,
or tetrahydrooxazine, E is N, R.sub.2 is CH.sub.3, R.sub.3 is H, -
- - is a double bond and Q is C.
42-44. (canceled)
45. The compound of claim 1, wherein the compound is selected from
the group consisting of:
N-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyrid-
in-1-yl]sulfonyl}phenyl)acetamide, 1
(2,3-dihydro-1-benzofuran-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyr-
idin-4-yl)-1H-pyrrolo[2,3-b]pyridine, 1
(3,4-dihydro-2H-1,5-benzodioxepin-7-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetra-
hydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine,
1-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine,
1-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetra-
hydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, Methyl
5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin--
1-yl]sulfonyl}-2-furoate,
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, 1
(1,3-benzodioxol-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl-
)-1H-pyrrolo[2,3-b]pyridine,
1-{[3-(2-methylpyrimidin-4-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3,6-tetrah-
ydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, and
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, or a
pharmaceutically acceptable salt thereof.
46. (canceled)
47. The compound of claim 1, wherein the salt is the hydrochloride
salt.
48. (canceled)
49. The compound of claim 1, wherein the salt is the hydroformate
salt
50. The compound of claim 73 wherein the compound is
7-{[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl]sulf-
onyl}-2H-1,4-benzoxazin-3(4H)-one or a pharmaceutically acceptable
salt thereof.
51-52. (canceled)
53. The method of claim 58, further comprising treating a central
nervous system disorder (CNS), a memory/cognitive impairment, a
gastrointestinal (GI) disorder, or a polyglutamine-repeat disease
by administering a pharmacologically effective amount of a compound
according to claim 1 to a patient in need thereof.
54. The method of claim 53, wherein the CNS disorder is Alzheimer's
disease, Parkinson's disease, Huntington's disease, anxiety,
depression, manic depression, epilepsy, obsessive compulsive
disorders, migraine, sleep disorders, feeding disorders such as
anorexia and bulimia, panic attacks, attention deficit
hyperactivity disorder (ADHD), attention deficit disorder (ADD),
withdrawal from drug abuse, psychoses, or disorders associated with
spinal trauma and/or head injury.
55. The method of claim 53, wherein the memory/cognitive impairment
is associated with Alzheimer's disease, schizophrenia, Parkinson's
disease, Huntington's disease Pick's disease, Creutzfeld Jakob
disease, HIV, cardiovascular disease, head trauma or age-related
cognitive decline.
56. (canceled)
57. The method of claim 53, wherein the compound of claim 1 is
administered in a pharmaceutically acceptable carrier.
58. A method of modulating 5-HT6 receptor activity comprising
administering a pharmacologically effective amount of a compound
according to claim 1 to a patient in need thereof.
59. (canceled)
60. A pharmaceutical composition comprising a therapeutically
effective amount of the compound of claim 1 and a pharmaceutically
acceptable carrier.
61-62. (canceled)
63. A compound of formula I: ##STR00152## wherein A, B, D, E and G,
are each CH, CR.sup.4, or N, wherein at least one of A, B, D, E and
G is N, at least one of A, B, D, or E is CR.sup.4, where R.sup.4 is
a substituted or unsubstituted heterocyclic group; - - - - -
represents a single bond or a double bond; Q is C when - - - - is a
double bond, and Q is CH or N when - - - - - is a single bond; x is
0, 1, 2, 3, or 4; R.sup.1 is SO.sub.2Ar, wherein Ar is
unsubstituted phenyl or unsubstituted pyridinyl; R.sup.2 is H or
alkyl having 1 to 8 carbon atoms, cycloalkyl having 3 to 12 carbon
atoms, or cycloalkylalkyl having 4 to 12 carbon atoms, each of
which is branched or unbranched and each of which is unsubstituted
or substituted one or more times with halogen, C.sub.1-4-alkyl,
C.sub.1-4-alkoxy, oxo, or any combination thereof; R.sup.3 is H or
alkyl having 1 to 8 carbon atoms, which is unsubstituted or
substituted one or more times by halogen, C.sub.1-4-alkyl,
C.sub.1-4-alkoxy, oxo, or any combination thereof; and R.sup.4 is
halogen, nitro, alkyl having 1 to 8 carbon atoms, cycloalkyl having
3 to 12 carbon atoms, or cycloalkylalkyl having 4 to 12 carbon
atoms, each of which is branched or unbranched and which is
unsubstituted or substituted one or more times with halogen,
C.sub.1-4-alkyl, C.sub.1-4-alkoxy, oxo, or any combination thereof,
an alkoxy having 1 to 8 carbon atoms, or a heterocyclic group,
which is saturated, partially saturated or unsaturated, having 5 to
10 ring atoms in which at least 1 ring atom is an N, O or S atom,
which is unsubstituted or substituted one or more times by halogen,
hydroxy, C.sub.5-7-aryl, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, cyano,
halogenated alkyl, nitro, or any combination thereof, or a
pharmaceutically acceptable salt thereof.
64. The compound of claim 1, wherein the compound is selected from
the group consisting of:
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(6-morpholin-4-ylpyridin-3-
-yl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine,
1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-
in-4-yl)-1H-pyrrolo[2,3-b]pyridine,
4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin--
1-yl]sulfonyl}aniline,
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-morpholin-4-ylphenyl)su-
lfonyl]-1H-pyrrolo[2,3-b]pyridine,
N,N-dimethyl-4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2-
,3-b]pyridin-1-yl]sulfonyl}aniline,
N,N-dimethyl-3-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2-
,3-b]pyridin-1-yl]sulfonyl}aniline,
1-[(1-methyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine,
1-[(1-ethyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetra-
hydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine,
N-methyl-N-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,-
3-b]pyridin-1-yl]sulfonyl}phenyl)acetamide, and
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin--
1-yl]sulfonyl}-1,2,3,4-tetrahydroquinoline, or a pharmaceutically
acceptable salt thereof.
65. The compound of claim 1, wherein the compound is selected from
the group consisting of
methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]p-
yridin-1-yl]sulfonyl}-1,2,3,4-tetrahydroquinoline,
methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]p-
yridin-1-yl]sulfonyl}-1,2,3,4-tetrahydroquinoline,
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-pyrrolidin-1-ylphenyl)s-
ulfonyl]-1H-pyrrolo[2,3-b]pyridine,
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(3-pyrrolidin-1-ylphenyl)s-
ulfonyl]-1H-pyrrolo[2,3-b]pyridine,
1-[(1-methyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine,
1-(2,2-dimethylpropanoyl)-5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-pyrrolo[2,3 b]pyridin-1-yl]sulfonyl}-1H-indazole
6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin--
1-yl]sulfonyl}dihydroquinolin-2(1H)-one,
methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]p-
yridin-1-yl]sulfonyl}-3,4-dihydroquinolin-2(1H)-one, and
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methylpiperidin-4-yl)-1-
H-pyrrolo[2,3-b]pyridine, or a pharmaceutically acceptable salt
thereof.
66. The compound of claim 1, wherein the compound is selected from
the group consisting of:
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1,2,3,6-tetrahydropyridin-
-4-yl)-1H-pyrrolo[2,3-b]pyridine,
1-{[6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]sulfonyl}-3-(1-methyl-1,2,3,-
6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine,
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin--
1-yl]sulfonyl}-2H-1,4-benzoxazin-3(4H)-one,
1-[(1-acetyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine,
4-methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b-
]pyridin-1-yl]sulfonyl}-3,4->dihydro-2H-1,4-benzoxazine,
1-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyrid-
in-1-yl]sulfonyl}phenyl)pyrrolidin-2-one,
methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]p-
yridin-1-yl]sulfonyl}-1,3-benzoxazol-2(3H)-one,
1-[(1-methyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, and
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, or a
pharmaceutically acceptable salt thereof.
67. The compound of claim 1, wherein the compound is selected from
the group consisting of:
6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin--
1-yl]sulfonyl}-2H-1,4-benzoxazin-3(4H)-one,
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1,2,3,6-tetrahydropyr-
idin-4-yl)-1H-pyrrolo[2,3-b]pyridine,
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methylpiperidin-4-y-
l)-1H-pyrrolo[2,3-b]pyridine,
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-piperidin-4-yl-1H-pyrrolo[-
2,3-b]pyridine,
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine,
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-piperidin-4-yl-1H-pyrr-
olo[2,3-b]pyridine,
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine,
1-(3-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyrid-
in-1-yl]sulfonyl}phenyl)pyrrolidin-2-one,
1-[(5-bromo-2,3-dihydro-1-benzofuran-7-yl)sulfonyl]-3-(1-methyl-1,2,3,6-t-
etrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, and
6-ethyl-1-[(1-methyl-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, or a pharmaceutically
acceptable salt thereof.
68. The compound of claim 1, wherein the compound is selected from
the group consisting of:
6-ethyl-1-[(1-methyl-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine,
6-ethyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(3-pyrrolidin-1-yl-
phenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine,
6-ethyl-1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,-
3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine,
1-(3-{[6-ethyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-
-b]pyridin-1-yl]sulfonyl}phenyl)pyrrolidin-2-one,
1-[(5-bromo-2,3-dihydro-1-benzofuran-7-yl)sulfonyl]-6-ethyl-3-(1-methyl-1-
,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine,
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-6-ethyl-3-(1-methyl-1,2,-
3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine,
1-[(1-acetyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine,
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-piperazin-1-yl-1H-pyrr-
olo[2,3-b]pyridine, and
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-piperazin-1-yl-1H-pyrr-
olo[2,3-b]pyridine, or a pharmaceutically acceptable salt
thereof.
69. The compound of claim 1, wherein the compound is selected from
the group consisting of:
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-1H-pyrrolo[3-2-b]pyridine,
4-methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3-2-b-
]pyridin-1-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine,
1-[(1-methyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[3-2-b]pyridine,
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[3-2-b]pyridine,
1-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3-2-b]pyrid-
in-1-yl]sulfonyl}phenyl)pyrrolidin-2-one,
3-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3-2-b-
]pyridin-1-yl]sulfonyl}-1,3-benzoxazol-2(3H)-one,
5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3-2-b]pyri
din-1-yl]sulfonyl}-1,3-dihydro-2H-benzimidazol-2-one,
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3-2-b]pyridin--
1-yl]sulfonyl}-2H-1,4-benzoxazin-3(4H)-one,
6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3-2-b]pyridin--
1-yl]sulfonyl}-2H-1,4-benzoxazin-3(4H)-one, and
1-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylsulfonyl)-3-(1-methyl-1,2,3,6-tet-
rahydropyridin-4-yl)-1H-pyrrolo[3-2-b]pyridine, or a
pharmaceutically acceptable salt thereof.
70. The compound of claim 1, wherein the compound is selected from
the group consisting of:
4-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3-2-b-
]pyridin-1-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine,
4-methyl-7-{[3-(1-methylpiperidin-4-yl)-1H-pyrrolo[3-2-b]pyridin-1-yl]sul-
fonyl}-3,4-dihydro-2H-1,4-benzoxazine,
4-methyl-7-{[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3-2-b]pyridin--
1-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine,
4-methyl-7-[(3-piperidin-4-yl-1H-pyrrolo[3-2-b]pyridin-1-yl)sulfonyl]-3,4-
-dihydro-2H-1,4-benzoxazine,
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[3-2-b]pyridine,
1-(3-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3-2-b]pyri
din-1-yl]sulfonyl}phenyl)pyrrolidin-2-one,
1-[(5-bromo-2,3-dihydro-1-benzofuran-7-yl)sulfonyl]-3-(1-methyl-1,2,3,6-t-
etrahydropyridin-4-yl)-1H-pyrrolo[3-2-b]pyridine,
4-Methyl-7-(3-piperidin-4-yl-pyrrolo[3-2-b]pyridine-1-sulfonyl)-3,4-dihyd-
ro-2H-benzo[1,4]oxazine,
1-(3-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3-2-b]pyrid-
in-1-yl]sulfonyl}phenyl)pyrrolidin-3-ol, and
1-[(6-morpholin-4-ylpyridin-3-yl)sulfonyl]-3-(1,2,3,6-tetrahydropyridin-4-
-yl)-1H-pyrrolo[3-2-b]pyridine, or a pharmaceutically acceptable
salt thereof.
71. The compound of claim 1, wherein the compound is selected from
the group consisting of:
1-{[6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]sulfonyl}-3-(1,2,3,6-tetrahy-
dropyridin-4-yl)-1,1-pyrrolo[3-2-b]pyridine,
1-[(5-methoxypyridin-3-yl)sulfonyl]-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-
-pyrrolo[3-2-b]pyridine,
1-{[5-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]sulfonyl}-3-(1,2,3,6-tetrahy-
dropyridin-4-yl)-1H-pyrrolo[3-2-b]pyridine,
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1,2,3,6-tetrahydropyr-
idin-4-yl)-1H-pyrrolo[3-2-13]pyridine,
7-{[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3-2-b]pyridin-1-yl]sulf-
onyl}-2H-1,4-benzoxazin-3(4H)-one,
7-{[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3-2-b]pyridin-1-yl]sulf-
onyl}-3,4-dihydroquinolin-2(1H)-one,
4-methyl-6-{[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3-2-b]pyridin--
1-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine,
6-{[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3-2-b]pyridin-1-yl]sulf-
onyl}-2H-1,4-benzoxazin-3(4H)-one,
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(6-phenoxypyridin-3-yl)sul-
fonyl]-1H-pyrrolo[3-2-b]pyridine, and
2-methyl-8-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3-2-b-
]pyridin-1-yl]sulfonyl}-1,2,3,4-tetrahydroisoquinoline, or a
pharmaceutically acceptable salt thereof.
72. The compound of claim 1, wherein the compound is selected from
the group consisting of:
1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydr-
opyridin-4-yl)-1H-indazole,
1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2,3,6--
tetrahydropyridin-4-yl)-1H-indazole,
1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydr-
opyridin-4-yl)-5-(trifluoromethyl)-1H-indazole,
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl]sulfonyl}-
-2H-1,4-benzoxazin-3(4H)-one,
1-[(1-methyl-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyridi-
n-4-yl)-1H-indazole,
4-methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl]-
sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine,
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-indazole,
4-acetyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl]-
sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine,
5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl]sulfonyl}-
-1,2-benzisoxazole,
1-(1-benzothien-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-indazole,
1-(1-benzofuran-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-indazole,
6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl]sulfonyl}-
-2H-1,4-benzoxazin-3(4H)-one, and
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-indazole, or a pharmaceutically
acceptable salt thereof.
73. The compound of claim 1, wherein the compound is selected from
the group consisting of:
5-fluoro-1-[(1-methyl-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahy-
dropyridin-4-yl)-1H-indazole,
5-fluoro-1-[(1-methyl-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahy-
dropyridin-4-yl)-1H-indazole,
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(4-methylpiperazin-1-y-
l)-1H-indazole,
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-piperazin-1-yl-1H-inda-
zole,
7-[(3-piperazin-1-yl-1H-indazol-1-yl)sulfonyl]-2H-1,4-benzoxazin-3(4-
H)-one,
7-{[3-(4-methylpiperazin-1-yl)-1H-indazol-1-yl]sulfonyl}-2H-1,4-be-
nzoxazin-3(4H)-one,
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(4-methylpiperazin-1-y-
l)-1H-indazole,
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-piperazin-1-yl-1H-inda-
zole, 3-piperazin-1-yl-1-(pyridin-3-ylsulfonyl)-1H-indazole,
4-methyl-7-{[3-(4-methylpiperazin-1-yl)-1H-indazol-1-yl]sulfonyl}-3,4-dih-
ydro-2H-1,4-benzoxazine,
4-methyl-7-[(3-piperazin-1-yl-1H-indazol-1-yl)sulfonyl]-3,4-dihydro-2H-1,-
4-benzoxazine, and
7-[(3-piperazin-1-yl-1H-indazol-1-yl)sulfonyl]-2H-1,4-benzoxazin-3(4H)-on-
e, or a pharmaceutically acceptable salt thereof.
74. The compound of claim 1, wherein the compound is selected from
the group consisting of:
1-(1-benzofuran-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-pyrazolo[4,3-b]pyridine,
1-(1-benzothien-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-pyrazolo[4,3-b]pyridine,
1-(1-benzofuran-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-pyrazolo[3,4-b]pyridine,
1-(1-benzothien-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-pyrazolo[3,4-b]pyridine,
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrazolo[4,3-b]pyridine,
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine,
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-
-1-yl]sulfonyl}-2H-1,4-benzoxazin-3(4H)-one,
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-
-1-yl]sulfonyl}-2H-1,4-benzoxazin-3(4H)-one,
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine,
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrazolo[4,3-b]pyridine,
1-(1,2-benzisoxazol-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-
-yl)-1H-pyrazolo[4,3-b]pyridine, and
1-(1,2-benzisoxazol-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-
-yl)-1H-pyrazolo[3,4-b]pyridine, or a pharmaceutically acceptable
salt thereof.
Description
[0001] This application claims priority to U.S. Provisional
Application 60/774,399 which was filed Feb. 17, 2006, and is hereby
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates generally to the field of
serotonin 5-HT6 affinity. More specifically, this invention relates
to novel compounds having affinity for the 5-HT6 receptor, in
particular to compounds having selective 5-HT6 affinity, methods of
preparing such compounds, compositions containing such compounds,
and methods of use thereof.
BACKGROUND OF THE INVENTION
[0003] The human 5-hydroxytryptamine-6 (5HT6) receptor, one of the
most recently cloned serotonergic receptors, is a 440-amino acid
polypeptide with seven transmembrane spanning domains typical of
the G-protein-coupled receptors. It is one of the 14 receptors that
mediate the effects of the neurotransmitter 5-hydroxytryptamine
(5-HT, serotonin) (foyer et al., Neuropharmacology, 1997, 36:419).
Within the transmembrane region, the human 5HT6 receptor shows
about 30-40% homology to other human 5-HT receptors and is found to
be positively coupled to adenylyl cyclase.
[0004] The prominent localization of 5HT6 receptor mRNA in the
nucleus accumbens, striatum, olfactory tubercle, substantia nigra,
and hippocampus of the brain (Ward et al., Neuroscience, 1995,
64:1105) together with its high affinity for several
therapeutically important antipsychotics and antidepressants,
suggest a possible role for this receptor in the treatment of
schizophrenia and depression. In fact, the prototypic atypical
antipsychotic agent clozapine exhibits greater affinity for the
5HT6 receptor than for any other receptor subtype (Monsma et al.,
J. Pharmacol. Exp. Ther., 1994, 268:1403).
[0005] Although the 5HT6 receptor has a distinct pharmacological
profile, in vivo investigation of receptor function has been
hindered by the lack of selective agonists and antagonists. Recent
experiments demonstrated that chronic intracerebroventricular
treatment with an antisense oligonucleotide, directed at 5HT6
receptor mRNA, elicited a behavioral syndrome in rats consisting of
yawning, stretching, and chewing. This syndrome in the
antisense-treated rats was dose-dependently antagonized by atropine
(a muscarinic antagonist), implicating 5HT6 receptor in the control
of cholinergic neurotransmission. Therefore, 5HT6 receptor
antagonists may be useful for the treatment of memory dysfunction
(Bourson et al., J. Pharmacol. Exp. Ther., 1995, 274:173), and to
treat other central nervous system (CNS) disorders.
[0006] The high affinity of a number of antipsychotic agents for
the 5-HT6 receptor, in addition to its mRNA localization in
striatum, olfactory tubercle and nucleus accumbens suggests that
some of the clinical actions of these compounds may be mediated
through this receptor. Compounds which interact with, stimulate, or
inhibit the 5-HT6 receptor are commonly referred to as 5-HT6
ligands. In particular, 5-HT6 selective ligands have been
identified as potentially useful in the treatment of certain CNS
disorders such as Parkinson's disease, Huntington's disease,
anxiety, depression, manic depression, psychoses, epilepsy,
obsessive compulsive disorders, migraine, Alzheimer's disease
(enhancement of cognitive memory), sleep disorders, feeding
disorders such as anorexia and bulimia, panic attacks, attention
deficit hyperactivity disorder (ADHD), attention deficit disorder
(ADD), withdrawal from drug abuse such as cocaine, ethanol,
nicotine and benzodiazepines, schizophrenia, bipolar disorder, and
also disorders associated with spinal trauma and/or head injury
such as hydrocephalus. Such compounds are also expected to be of
use in the treatment of certain gastrointestinal (GI) disorders
such as functional bowel disorder and irritable bowel syndrome (See
for ex. B. L. Roth et al., J. Pharmacol. Exp. Ther., 1994, 268,
pages 1403-14120, D. R. Sibley et al., Mol. Pharmacol., 1993, 43,
320-327, A. J. Sleight et al., Neurotransmission, 1995, 11, 1-5,
and A. J. Sleight et al. Serotonin ID Research Alert, 1997, 2 (3),
115-8). Furthermore, the effect of 5-HT6 antagonist and 5-HT6
antisense oligonucleotides to reduce food intake in rats has been
reported (Br. J. Pharmac., 1999 Suppl. 126, page 66 and J.
Psychopharmacol Suppl. A64, 1997, page 255).
[0007] Therefore, it is an object of this invention to provide
compounds which are useful as therapeutic agents in the treatment
of a variety of central nervous system disorders related to or
affected by the 5-HT6 receptor.
[0008] It is another object of this invention to provide
therapeutic methods and pharmaceutical compositions useful for the
treatment of central nervous system disorders related to or
affected by the 5-HT6 receptor.
[0009] The following patents and publications also provide relevant
background to the present invention. All references cited below are
incorporated herein by reference in their entirety and to the same
extent as if each reference was individually incorporated by
reference. U.S. Pat. Nos. 6,100,291, 6,133,287, 6,191,141,
6,251,893, 6,686,374, 6,767,912, 6,897,215, 6,903,112, and
6,916,818; Published U.S. Application Nos. 2005/0124603, and
2005/0171118.
SUMMARY OF THE INVENTION
[0010] The present invention relates to novel compounds that have
affinity, preferably selectively, for the serotonin 5-HT6 receptor,
methods of use thereof, and the synthesis thereof.
[0011] Still further, the present invention provides methods for
synthesizing compounds with such activity and selectivity, as well
as methods of and corresponding pharmaceutical compositions for
treating a disorder (e.g. a mood disorder and/or a cognitive
disorder) in a patient, wherein the disorder is related to or
affected by the 5HT6 receptor.
DETAILED DESCRIPTION OF THE INVENTION
[0012] The present invention includes compounds of formula I:
##STR00002##
wherein [0013] A, B, D, E and G, are each independently CH,
CR.sup.4 or N; [0014] - - - - - represents a single bond or a
double bond; [0015] Q is C when - - - - is a double bond, and Q is
CH or N when - - - - - is a single bond; [0016] x is 0, 1, 2, 3, or
4; [0017] R.sup.1 is SO.sub.2Ar, wherein [0018] Ar is selected from
formulas (a)-(r):
##STR00003## ##STR00004##
[0018] wherein [0019] J is CR.sup.7 (e.g., CH) or N; [0020] K is,
in each instance independently, CH or N; [0021] W is O, S, or is
absent; [0022] X is, in each instance independently, O or NR.sup.7;
[0023] Y is O, NR.sup.7 or S; [0024] Z is S or NR.sup.2; [0025] a
is 1, 2, 3, 4 or 5; [0026] b, l, m and v are independently 0, 1, 2,
3 or 4; [0027] c, f, h, n, o, q, s, and u are independently 0, 1, 2
or 3; [0028] d and e are independently 1, 2 or 3; [0029] g, i, j,
and p are independently 0, 1 or 2; [0030] k and t are 0 or 1;
[0031] R.sup.2 is H or alkyl having 1 to 8, preferably 1 to 4
carbon atoms (e.g., CH.sub.3), cycloalkyl having 3 to 12,
preferably 3 to 8 carbon atoms, or cycloalkylalkyl having 4 to 12,
preferably 4 to 8 carbon atoms, each of which is branched or
unbranched and each of which is unsubstituted or substituted one or
more times with halogen, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, oxo, or
any combination thereof; [0032] R.sup.3 is H or alkyl having 1 to
8, preferably 1 to 4 carbon atoms, which is unsubstituted or
substituted one or more times by halogen, C.sub.1-4-alkyl,
C.sub.1-4-alkoxy, oxo, or any combination thereof; [0033] R.sup.4
is halogen (e.g., F), nitro, [0034] alkyl having 1 to 8, preferably
1 to 4 carbon atoms, cycloalkyl having 3 to 12, preferably 3 to 8
carbon atoms, or cycloalkylalkyl having 4 to 12, preferably 4 to 8
carbon atoms, each of which is branched or unbranched and which is
unsubstituted or substituted one or more times with halogen,
C.sub.1-4-alkyl, C.sub.1-4-alkoxy, oxo, or any combination thereof
(e.g., CHF.sub.2, or CF.sub.3), [0035] an alkoxy having 1 to 8,
preferably 1 to 4 carbon atoms, or [0036] a heterocyclic group,
which is saturated, partially saturated or unsaturated, having 5 to
10 ring atoms in which at least 1 ring atom is an N, O or S atom,
which is unsubstituted or substituted one or more times by halogen,
hydroxy, C.sub.5-7-aryl, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, cyano,
halogenated C.sub.1-4-alkyl (e.g., trifluoromethyl), nitro, or any
combination thereof (e.g., substituted or unsubstituted
morpholinyl, substituted or unsubstituted pyrrolyl, substituted or
unsubstituted pyrrolidinyl, substituted or unsubstituted
piperidinyl, substituted or unsubstituted pyridyl), [0037] R.sup.5
is amino(NH.sub.2), C.sub.1-4-alkylamino, C.sub.1-4-dialkylamino
(e.g., NMe.sub.2), or NR.sup.6C(O)R.sup.8 (e.g., --NHC(O)CH.sub.3,
or --N(CH.sub.3)C(O)CH.sub.3)), [0038] a heterocyclic group, which
is saturated, partially saturated or unsaturated, having 5 to 10
ring atoms in which at least 1 ring atom is an N, O or S atom,
which is unsubstituted or substituted one or more times by halogen,
hydroxy, C.sub.5-7-aryl, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, cyano,
halogenated C.sub.1-4-alkyl (e.g., trifluoromethyl), nitro, or any
combination thereof (e.g., substituted or unsubstituted
morpholinyl, substituted or unsubstituted pyrimidinyl, substituted
or unsubstituted pyrrolidinyl), or [0039] --O--Ar', wherein Ar' is
an aryl, [0040] R.sup.6 is H or alkyl having 1 to 8, preferably 1
to 4 carbon atoms, which is branched or unbranched and which is
unsubstituted or substituted one or more times with halogen,
C.sub.1-4-alkyl, C.sub.1-4-alkoxy, oxo, or any combination thereof;
[0041] R.sup.7 is, in each case, independently [0042] H, halogen
(e.g., F, Cl, Br), C(O)R.sup.8 (e.g., COCH.sub.3), CO.sub.2R.sup.8
(e.g., CO.sub.2CH.sub.3), NR.sup.6COR.sup.8 (e.g., NHCOCH.sub.3),
[0043] alkyl having 1 to 12, preferably 1 to 8 carbon atoms, which
is branched or unbranched and which is unsubstituted or substituted
one or more times by halogen, hydroxy, cyano, C.sub.1-4-alkoxy, oxo
or any combination thereof (e.g., CH.sub.3, CH.sub.2CH.sub.3,
CHF.sub.2, CF.sub.3, etc.), and wherein optionally one or more
--CH.sub.2CH.sub.2-- groups is replaced in each case by
--CH.dbd.CH-- or --C.ident.C--, [0044] alkoxy having 1 to 8,
preferably 1 to 4 carbon atoms, which is branched or unbranched and
which is unsubstituted or substituted one or more times by halogen
(e.g., OCHF.sub.2, or OCF.sub.3), [0045] cycloalkyl having 3 to 10,
preferably 3 to 8 carbon atoms, which is unsubstituted or
substituted one or more times by halogen, hydroxy, oxo, cyano,
C.sub.1-4-alkyl, C.sub.1-4-alkoxy, or any combination thereof
(e.g., cyclopentyl), [0046] cycloalkylalkyl having 4 to 16,
preferably 4 to 12 carbon atoms, which is unsubstituted or
substituted in the cycloalkyl portion and/or the alkyl portion one
or more times by halogen, oxo, cyano, hydroxy, C.sub.1-4-alkyl,
C.sub.1-4-alkoxy or any combination thereof (e.g.,
cyclopentylmethyl or cyclopropylmethyl), [0047] aryl having 6 to 14
carbon atoms, which is unsubstituted or substituted one or more
times by halogen, CF.sub.3, OCF.sub.3, C.sub.1-4-alkyl, hydroxy,
C.sub.1-4-alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or
any combination thereof (e.g., substituted or unsubstituted phenyl,
or substituted or unsubstituted pyridinyl.), [0048] arylalkyl in
which the aryl portion has 6 to 14 carbon atoms and the alkyl
portion, which is branched or unbranched, has 1 to 5 carbon atoms,
wherein the arylalkyl radical is unsubstituted, substituted in the
aryl portion one or more times by halogen, CF.sub.3, OCF.sub.3,
C.sub.1-4-alkyl, hydroxy, C.sub.1-4-alkoxy, nitro, cyano, [0049]
methylenedioxy, ethylenedioxy, or any combination thereof, and/or
substituted in the alkyl portion one or more times by halogen, oxo,
hydroxy, cyano, or any combination thereof, and wherein in the
alkyl portion one or more --CH.sub.2CH.sub.2-- groups are each
optionally replaced by --CH.dbd.CH-- or --C.ident.C--, and one or
more --CH.sub.2-- groups are each optionally replaced by --O-- or
--NH-- (e.g., phenylethyl, phenylpropyl, phenylbutyl,
methoxyphenylethyl, methoxyphenylpropyl, chlorophenylethyl,
chlorophenylpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl,
chlorophenoxyethyl, or chlorophenylaminoethyl.), [0050] a
heterocyclic group, which is saturated, partially saturated or
unsaturated, having 5 to 10 ring atoms in which at least 1 ring
atom is an N, O or S atom, which is unsubstituted or substituted
one or more times by halogen, hydroxy, C.sub.5-7-aryl,
C.sub.1-4-alkyl, C.sub.1-4-alkoxy, cyano, trifluoromethyl, nitro,
oxo, or any combination thereof (e.g., substituted or unsubstituted
morpholinyl), or [0051] a heterocycle-alkyl group, wherein the
heterocyclic portion is saturated, partially saturated or
unsaturated, and has 5 to 10 ring atoms in which at least 1 ring
atom is an N, O or S atom, and the alkyl portion is branched or
unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group
is unsubstituted, substituted one or more times in the heterocyclic
portion by halogen, OCF.sub.3, hydroxy, C.sub.5-7-aryl,
C.sub.1-4-alkyl, C.sub.1-4-alkoxy, cyano, trifluoromethyl, nitro,
oxo, or any combination thereof, and/or substituted in the alkyl
portion one or more times by halogen, oxo, hydroxy, cyano, or any
combination thereof, and wherein in the alkyl portion one or more
--CH.sub.2CH.sub.2-- groups are each optionally replaced by
--CH.dbd.CH-- or --C.ident.C--, and one or more --CH.sub.2-- groups
are each optionally replaced by --O-- or --NH--; [0052] R.sup.8 is
in each instance, independently, H or alkyl having 1 to 8, carbon
atoms, preferably 1 to 4 carbon atoms, which is branched or
unbranched and which is unsubstituted or substituted one or more
times by halogen (e.g., CH.sub.3, CH.sub.2CH.sub.3, CHF.sub.2, or
CF.sub.3);
[0053] and pharmaceutically acceptable salts or solvates (e.g.,
hydrates) thereof, or solvates of pharmaceutically acceptable salts
thereof;
with the following provisos: [0054] (i) when Ar is represented by
formula (j) and G is CH or CR.sup.4, then at least one of A, B, D,
or E represents CR.sup.4 in which R.sup.4 is other than H, halogen,
alkyl, halogenated alkyl, or alkoxy; [0055] when Ar is represented
by formula (j) and G is N, then at least one of A, B, D, or E
represents CR.sup.4 in which R.sup.4 is other than H, halogen,
alkyl, halogenated alkyl, alkoxy, --OH, --NH.sub.2, or NO.sub.2;
[0056] (ii) when A, B, D, E and G are CH, and Ar is represented by
formula (b), and each X is O, then d is 3; [0057] (iii) when one of
A, B, D, or E represents N and the rest are CH, G is CH, and Ar is
represented by one of formulas (d)-(i), then at least one R.sup.7
substituent on said formula (d)-(i) is other than H, halogen,
hydroxyl, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy;
[0058] (iv) when G is N and A, B, and D are CH or CR.sup.4, then:
[0059] (1) R.sub.2 is alkyl having 1 to 8 carbon atoms, [0060] (2)
Q is N, [0061] (3) Ar is selected from formulas (d)-(g) (preferably
formula (d)), or [0062] (4) a combination of at least two of
(1)-(3) (preferably a combination of (1) and (3); [0063] (v) when
Ar is represented by the formula (o), one K is N and the other K is
CH; [0064] (vi) said compound is not: [0065]
1-[(4-aminophenyl)sulfonyl]-5-nitro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H
indole, [0066]
1-[(4-aminophenyl)sulfonyl]-5-bromo-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H
indole, [0067]
1-[(4-aminophenyl)sulfonyl]-5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1-
11 indole, [0068]
1-[(4-aminophenyl)sulfonyl]-6-chloro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1-
H indole, [0069]
1-[(4-aminophenyl)sulfonyl]-6-nitro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H
indole, [0070]
1-[(4-aminophenyl)sulfonyl]-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H
indole, [0071]
5-(4-methyl-2-thiazolyl)-1-(phenylsulfonyl)-3-(1,2,3,6-tetrahydro--
4-pyridinyl)-1H indole, [0072]
1-[(4-aminophenyl)sulfonyl]-5-fluoro-3-(4-piperidinyl)-1H indole,
[0073]
3,6-dihydro-4-[5(4-methyl-2-thiazolyl)-1-(phenylsulfonyl)-1H-indol-3-yl)--
1,1-dimethylethylester;
[0074] or a pharmaceutically acceptable salt thereof, or a solvate
thereof, or a solvate of a pharmaceutically acceptable salt
thereof.
[0075] In one embodiment of the present invention, the invention
includes compounds of formula I:
##STR00005##
wherein [0076] A, B, D, E and G, are each independently CH,
CR.sup.4 or N; [0077] - - - - - represents a single bond or a
double bond; [0078] Q is C when - - - - is a double bond, and Q is
CH when - - - - - is a single bond; [0079] x is 0, 1, 2, 3, or 4;
[0080] R.sup.1 is SO.sub.2Ar, wherein [0081] Ar is selected from
formulas (a)-(n):
##STR00006## ##STR00007##
[0081] wherein [0082] J is CR.sup.7 (e.g., CH) or N; [0083] K is CH
or N; [0084] W is O, S, or is absent; [0085] X is O or NR.sup.7;
[0086] Y is O, NR.sup.7 or S; [0087] Z is S or NR.sup.7; [0088] a
is 1, 2, 3, 4 or 5; [0089] b, l and m are independently 0, 1, 2, 3
or 4; [0090] c, f, h, n, o, q and s are independently 0, 1, 2 or 3;
[0091] d and e are independently 1, 2 or 3; [0092] g, i, j, and p
are independently 0, 1 or 2; [0093] k and t are 0 or 1; [0094]
R.sup.2 is H or alkyl having 1 to 8, preferably 1 to 4 carbon atoms
(e.g., CH.sub.3), cycloalkyl having 3 to 12, preferably 3 to 8
carbon atoms, or cycloalkylalkyl having 4 to 12, preferably 4 to 8
carbon atoms, each of which is branched or unbranched and each of
which is unsubstituted or substituted one or more times with
halogen, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, oxo, or combinations
thereof; [0095] R.sup.3 is H or alkyl having 1 to 8, preferably 1
to 4 carbon atoms, which is unsubstituted or substituted one or
more times by halogen, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, oxo, or
combinations thereof; [0096] R.sup.4 is halogen (e.g., F), nitro,
[0097] alkyl having 1 to 8, preferably 1 to 4 carbon atoms,
cycloalkyl having 3 to 12, preferably 3 to 8 carbon atoms, or
cycloalkylalkyl having 4 to 12, preferably 4 to 8 carbon atoms,
each of which is branched or unbranched and which is unsubstituted
or substituted one or more times with halogen, C.sub.1-4-alkyl,
C.sub.1-4-alkoxy, oxo, or combinations thereof (e.g., CHF.sub.2,
CF.sub.3), or [0098] a heterocyclic group, which is saturated,
partially saturated or unsaturated, having 5 to 10 ring atoms in
which at least 1 ring atom is an N, O or S atom, which is
unsubstituted or substituted one or more times by halogen, hydroxy,
aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g.,
trifluoromethyl), nitro, or combinations thereof (e.g., substituted
or unsubstituted morpholinyl, substituted or unsubstituted
pyrrolyl, substituted or unsubstituted pyrrolidinyl, substituted or
unsubstituted piperidinyl, substituted or unsubstituted pyridyl),
[0099] R.sup.5 is amino(NH.sub.2), alkylamino, dialkylamino (e.g.,
NMe.sub.2), NR.sup.6C(O)R.sup.8 (e.g., --NHC(O)CH.sub.3,
--N(CH.sub.3)C(O)CH.sub.3)) or [0100] a heterocyclic group, which
is saturated, partially saturated or unsaturated, having 5 to 10
ring atoms in which at least 1 ring atom is an N, O or S atom,
which is unsubstituted or substituted one or more times by halogen,
hydroxy, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g.,
trifluoromethyl), nitro, or combinations thereof (e.g., substituted
or unsubstituted morpholinyl, substituted or unsubstituted
pyrimidinyl, substituted or unsubstituted pyrrolidinyl), [0101]
R.sup.6 is H or alkyl having 1 to 8, preferably 1 to 4 carbon
atoms, which is branched or unbranched and which is unsubstituted
or substituted one or more times with halogen, C.sub.1-4-alkyl,
C.sub.1-4-alkoxy, oxo, or combinations thereof; [0102] R.sup.7 is,
in each case, independently [0103] H, halogen (e.g., F, Cl, Br),
C(O)R.sup.8 (e.g., COCH.sub.3), CO.sub.2R.sup.8 (e.g.,
CO.sub.2CH.sub.3), NR.sup.6COR.sup.8 (e.g., NHCOCH.sub.3), [0104]
alkyl having 1 to 12, preferably 1 to 8 carbon atoms, which is
branched or unbranched and which is unsubstituted or substituted
one or more times by halogen, hydroxy, cyano, C.sub.1-4-alkoxy, oxo
or combinations thereof, and wherein optionally one or more
--CH.sub.2CH.sub.2-- groups is replaced in each case by
--CH.dbd.CH-- or C.ident.C--(e.g., CH.sub.3, CH.sub.2CH.sub.3,
CHF.sub.2, CF.sub.3, etc.), [0105] alkoxy having 1 to 8, preferably
1 to 4 carbon atoms, which is branched or unbranched and which is
unsubstituted or substituted one or more times by halogen (e.g.,
OCHF.sub.2, OCF.sub.3), [0106] cycloalkyl having 3 to 10,
preferably 3 to 8 carbon atoms, which is unsubstituted or
substituted one or more times by halogen, hydroxy, oxo, cyano,
alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon
atoms, or combinations thereof (e.g., cyclopentyl), [0107]
cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms,
which is unsubstituted or substituted in the cycloalkyl portion
and/or the alkyl portion one or more times by halogen, oxo, cyano,
hydroxy, C.sub.1-4-alkyl, C.sub.1-4-alkoxy or combinations thereof
(e.g., cyclopentylmethyl, cyclopropylmethyl, etc.), [0108] aryl
having 6 to 14 carbon atoms, which is unsubstituted or substituted
one or more times by halogen, CF.sub.3, OCF.sub.3, alkyl, hydroxy,
alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or
combinations thereof (e.g., substituted or unsubstituted phenyl,
substituted or unsubstituted pyridinyl, etc.), [0109] arylalkyl in
which the aryl portion has 6 to 14 carbon atoms and the alkyl
portion, which is branched or unbranched, has 1 to 5 carbon atoms,
wherein the arylalkyl radical is unsubstituted, substituted in the
aryl portion one or more times by halogen, CF.sub.3, OCF.sub.3,
alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy,
ethylenedioxy, or combinations thereof, and/or substituted in the
alkyl portion one or more times by halogen, oxo, hydroxy, cyano, or
combinations thereof, and wherein in the alkyl portion one or more
--CH.sub.2CH.sub.2-- groups are each optionally replaced by
--CH.dbd.CH-- or --C.ident.C--, and one or more --CH.sub.2-- groups
are each optionally replaced by --O-- or --NH-- (e.g., phenylethyl,
phenylpropyl, phenylbutyl, methoxyphenylethyl, methoxyphenylpropyl,
chlorophenylethyl, chlorophenylpropyl, phenylethenyl, phenoxyethyl,
phenoxybutyl, chlorophenoxyethyl, chlorophenylaminoethyl, etc.),
[0110] a heterocyclic group, which is saturated, partially
saturated or unsaturated, having 5 to 10 ring atoms in which at
least 1 ring atom is an N, O or S atom, which is unsubstituted or
substituted one or more times by halogen, hydroxy, aryl, alkyl,
alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof
(e.g., substituted or unsubstituted morpholinyl), or [0111] a
heterocycle-alkyl group, wherein the heterocyclic portion is
saturated, partially saturated or unsaturated, and has 5 to 10 ring
atoms in which at least 1 ring atom is an N, O or S atom, and the
alkyl portion is branched or unbranched and has 1 to 5 carbon
atoms, the heterocycle-alkyl group is unsubstituted, substituted
one or more times in the heterocyclic portion by halogen,
OCF.sub.3, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl,
nitro, oxo, or combinations thereof, and/or cyano, or combinations
thereof, and wherein in the alkyl portion one or more
--CH.sub.2CH.sub.2-groups are each optionally replaced by
--CH.dbd.CH-- or --C.ident.C--, and one or more --CH.sub.2-- groups
are each optionally replaced by --O-- or --NH--; [0112] R.sup.8 is
in each case, independently, H or alkyl having 1 to 8, carbon
atoms, preferably 1 to 4 carbon atoms, which is branched or
unbranched and which is unsubstituted or substituted one or more
times by halogen (e.g., CH.sub.3, CH.sub.2CH.sub.3, CHF.sub.2,
CF.sub.3, etc.);
[0113] and pharmaceutically acceptable salts or solvates (e.g.,
hydrates) thereof, or solvates of pharmaceutically acceptable salts
thereof;
with the following provisos: [0114] (i) when Ar is represented by
formula (j), then at least one of A, B, D, or E represents CR.sup.4
in which R.sup.4 is other than H, halogen, alkyl, or halogenated
alkyl; [0115] (ii) when A, B, D, E and G are CH, and Ar is
represented by formula (b), and each X is O, then d is 3; [0116]
(iii) when one of A, B, D, or E represents N and the rest are CH, G
is CH, and Ar is represented by one of formulas (d)-(i), then at
least one R.sup.7 substituent on said formula (d)-(i) is other than
H, halogen, hydroxyl, alkyl, alkoxy, halogenated alkyl, halogenated
alkoxy; [0117] (iv) when G is N and A, B, and D are CH or CR.sup.4,
then: [0118] (a) R.sub.2 is alkyl having 1 to 8 carbon atoms,
[0119] (b) Q is N, [0120] (c) Ar is selected from formulas (d)-(g)
(preferably formula (d)), or [0121] (d) a combination of at least
two of (a)-(c) (preferably a combination of (a) and (c); [0122] (v)
said compound is not: [0123]
1-[(4-aminophenyl)sulfonyl]-5-nitro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H
indole, [0124]
1-[(4-aminophenyl)sulfonyl]-5-bromo-3-(1,2,3,6-tetrahydro-4-pyridinyl)-11-
1 indole, [0125]
1-[(4-aminophenyl)sulfonyl]-5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1-
H indole, [0126]
1-[(4-aminophenyl)sulfonyl]-6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1-
H indole, [0127]
1-[(4-aminophenyl)sulfonyl]-6-nitro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H
indole, [0128]
1-[(4-aminophenyl)sulfonyl]-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H
indole, [0129]
5-(4-methyl-2-thiazolyl)-1-(phenylsulfonyl)-3-(1,2,3,6-tetrahydro--
4-pyridinyl)-1H indole, [0130]
1-[(4-aminophenyl)sulfonyl]-5-fluoro-3-(4-piperidinyl)-1H indole,
[0131] 1-[(4-aminophenyl)sulfonyl]-6-chloro-3-(4-piperidinyl)-1H
indole, or [0132]
3,6-dihydro-4-[5(4-methyl-2-thiazolyl)-1-(phenylsulfonyl)-1H-indol-
-3-yl)-1,1-dimethylethylester;
[0133] or a pharmaceutically acceptable salt thereof, or a solvate
thereof, or a solvate of a pharmaceutically acceptable salt
thereof.
[0134] According to a further embodiment, the compound of formula
(I) is represented by subformulas (Ia)-(Ix):
##STR00008## ##STR00009## ##STR00010## ##STR00011##
##STR00012##
[0135] According to a preferred embodiment, the compound of formula
(I) is represented by subformulas Ib, Ic, Id, If, Ig, Ih, Ij, Ik,
Il, In, Io, Ip, Iq, Ir, Is, It, Iu, Iv, Iw or Ix, for example,
subformulas Ib, Ic, Id, If, Ij, Ik, or In.
[0136] In another preferred embodiment, the compound of formula (I)
is represented by one or more of the following subformulas:
##STR00013##
According to a further aspect of the present invention, when
R.sup.1 is aminophenyl, then at least one of A, B, D, or E is
CR.sup.4 in which R.sup.4 is other than H, halogen or nitro.
[0137] According to a further aspect of the present invention, when
R.sup.1 is unsubstituted phenyl or unsubstituted pyridinyl, then at
least one of A, B, D, or E is CR.sup.4 in which R.sup.4 is nitro or
a substituted or unsubstituted heterocyclic group.
[0138] According to a further aspect of the present invention, when
R.sup.1 is unsubstituted phenyl or unsubstituted pyridinyl, then at
least one of A, B, D, or E is CR.sup.4 in which R.sup.4 is nitro or
a substituted or unsubstituted heterocyclic group other than
thiazolyl (e.g., substituted or unsubstituted pyridyl, substituted
or unsubstituted pyrrolyl (e.g., 2,5-dimethylpyrrol-1-yl).
[0139] According to a further aspect of the present invention, when
A, B, D, E and G are CH, and Ar is represented by formula (b), then
d is 3.
[0140] In a preferred embodiment R.sub.2 is H.
[0141] In another preferred embodiment, the bond between Q and CH
(i.e., - - - - - in Formula I) represents a single bond and Q is CH
or N.
[0142] Halogen herein refers to F, Cl, Br, and I. Preferred
halogens are F and Cl.
[0143] Alkyl means a straight-chain or branched-chain aliphatic
hydrocarbon radical. Suitable alkyl groups include, but are not
limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,
tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,
and dodecyl. Other examples of suitable alkyl groups include, but
are not limited to, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or
2,2-dimethylpropyl, 1-ethylpropyl, 1-, 2-, 3- or 4-methylpentyl,
1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or
2-ethylbutyl, ethylmethylpropyl, trimethylpropyl, methylhexyl,
dimethylpentyl, ethylpentyl, ethylmethylbutyl, dimethylbutyl, and
the like.
[0144] These alkyl radicals can optionally have one or more
--CH.sub.2CH.sub.2-- groups replaced in each case by CH.dbd.CH-- or
--C.ident.C-- groups. Suitable alkenyl or alkynyl groups include,
but are not limited to, 1-propenyl, 2-propenyl, 1-propynyl,
1-butenyl, 2-butenyl, 3-butenyl, 1-butynyl, 1,3-butadienyl, and
3-methyl-2-butenyl.
[0145] The alkyl groups include cycloalkyl groups, e.g.,
monocyclic, bicyclic or tricyclic saturated hydrocarbon radical
having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms.
Suitable cycloalkyl groups include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, and norbornyl. Other suitable cycloalkyl groups
include, but are not limited to, spiropentyl, bicyclo[2.1.0]pentyl,
bicyclo[3.1.0]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl,
bicyclo[5.1.0]octyl, spiro[2.6]nonyl, bicyclo[2.2.0]hexyl,
spiro[3.3]heptyl, and bicyclo[4.2.0]octyl.
[0146] The alkyl groups also include cycloalkylalkyl in which the
cycloalkyl portions have preferably 3 to 8 carbon atoms, preferably
4 to 6 carbon atoms and alkyl the portions have preferably 1 to 8
carbon atoms, preferably 1 to 4 carbon atoms. Suitable examples
include, but are not limited to, cyclopentylethyl and
cyclopropylmethyl.
[0147] In the arylalkyl groups and heteroalkyl groups, "alkyl"
refers to a divalent alkylene group preferably having 1 to 4 carbon
atoms.
[0148] In the cases where alkyl is a substituent (e.g., alkyl
substituents on aryl and heteroaryl groups) or is part of a
substituent (e.g., in the alkylamino, dialkylamino, hydroxyalkyl,
hydroxyalkoxy, alkylthio, alkylsulphinyl, and alkylsulphonyl
substituents), the alkyl portion preferably has 1 to 12 carbon
atoms, especially 1 to 8 carbon atoms, in particular 1 to 4 carbon
atoms.
[0149] Aryl, as a group or substituent per se or as part of a group
or substituent, refers to an aromatic carbocyclic radical
containing 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms,
especially 6 to 10 carbon atoms. Suitable aryl groups include, but
are not limited to, phenyl, naphthyl and biphenyl. Substituted aryl
groups include the above-described aryl groups which are
substituted one or more times by, for example, halogen, alkyl,
hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,
alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy,
cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl,
alkylsulphonyl, phenoxy, and acyloxy (e.g., acetoxy).
[0150] Arylalkyl refers to an aryl-alkyl-radical in which the aryl
and alkyl portions are in accordance with the previous
descriptions. Suitable examples include, but are not limited to,
benzyl, 1-phenethyl, 2-phenethyl, phenpropyl, phenbutyl,
phenpentyl, and naphthalenemethyl.
[0151] Heteroaryl groups refer to unsaturated heterocyclic groups
having one or two rings and a total number of 5 to 10 ring atoms
wherein at least one of the ring atoms is preferably an N, O or S
atom. Preferably, the heteroaryl group contains 1 to 3, especially
1 or 2, hetero-ring atoms selected from N, O and S. Suitable
heteroaryl groups include, for example, furyl, benzothienyl,
benzofuranyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl,
pyrimidinyl, isoxazolyl, quinolinyl, azaindolyl, naphthyridinyl,
thiazolyl, and the like. Preferred heteroaryl groups include, but
are not limited to, furyl, benzothienyl, benzofuranyl, pyrrolyl,
pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, isoxazolyl, and
thiazolyl.
[0152] Substituted heteroaryl groups refer to the heteroaryl groups
described above which are substituted in one or more places by
preferably halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl
(e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, and
dialkylamino.
[0153] Hetereocycles are non-aromatic, saturated or partially
unsaturated, cyclic groups containing at least one hetero-ring
atom, preferably selected from N, S, and O, for example,
1,2,3,4,-tetrahydroquinolyl, dihydrobenzofuranyl,
dihydrobenzodioxepinyl, dihydrobenzodioxinyl, dihydroindolyl,
benzodioxolyl, 3-tetrahydrofuranyl, piperidinyl, imidazolinyl,
imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, piperazinyl,
oxazolidinyl, and indolinyl.
[0154] Heteroarylalkyl refers to a heteroaryl-alkyl-group wherein
the heteroaryl and alkyl portions are in accordance with the
previous discussions. Suitable examples include, but are not
limited to, pyridylmethyl, thienylmethyl, pyrimidinylmethyl,
pyrazinylmethyl, isoquinolinylmethyl, pyridylethyl and
thienylethyl.
[0155] Carbocyclic structures are non-aromatic mono cyclic or
bicyclic structures containing 5 to 14 carbon atoms, preferably 6
to 10 carbon atoms, wherein the ring structure(s) optionally
contain at least one C.dbd.C bond.
[0156] Acyl refers to alkanoyl radicals having 2 to 4 carbon atoms.
Suitable acyl groups include, but are not limited to, formyl,
acetyl, propionyl, and butanoyl.
[0157] Substituted radicals preferably have 1 to 3 substituents,
especially 1 or 2 substituents.
[0158] R.sup.2 is preferably H or alkyl having 1 to 4 carbon atoms,
e.g., methyl, ethyl, propyl, isopropyl, n-butyl, especially
methyl.
[0159] R.sup.3 is preferably H or alkyl having 1 to 4 carbon atoms,
e.g., methyl, ethyl, propyl, isopropyl, n-butyl, especially methyl.
More preferably, R.sup.3 is H.
[0160] R.sup.4 is preferably halogen (e.g., F, Cl, Br, more
preferably F), nitro, alkyl having 1 to 4 carbon atoms, which is
branched or unbranched and which is unsubstituted or substituted
one or more times with halogen, C.sub.1-4-alkyl, C.sub.r4-alkoxy,
oxo, or any combination thereof (e.g., CF.sub.3) or heterocyclic
group (e.g., substituted or unsubstituted pyrrolyl, pyridinyl,
pyrrolidinyl, morpholinyl, piperidinyl). In one preferred
embodiment, R.sup.4 is halogen, fluorinated C.sub.1-4-alkyl, or
heterocyclic group. In another preferred embodiment, R.sup.4 is
halogen (e.g., F), or fluorinated C.sub.1-4-alkyl (e.g.
CF.sub.3).
[0161] When R.sup.5 is a heterocyclic group, it is preferably
unsubstituted or substituted pyrrolyl (e.g.,
2,5-dimethyl-1H-pyrrol-1-yl), pyridinyl (e.g., pyridin-4-yl,
pyridine-3-yl, pyridine-2-yl), pyrrolidinyl (e.g.,
pyrrolidin-1-yl), or morpholinyl (e.g., morpholin-4-yl).
[0162] R.sup.6 is preferably H or alkyl having 1 to 4 carbon atoms,
e.g., methyl, ethyl, propyl, isopropyl, n-butyl, especially H or
methyl.
[0163] R.sup.7 is preferably C.sub.1-4-alkyl (e.g., methyl, ethyl),
halogenated C.sub.1-4-alkyl (e.g., CHF.sub.2, CF.sub.3), aryl
(e.g., unsubstituted or substituted phenyl), CO.sub.2R.sub.8 (e.g.,
CO.sub.2CH.sub.3), NR.sup.6COR.sub.8 (e.g., NHCOCH.sub.3,
N(CH.sub.3)COCH.sub.3), halogen (e.g., F, Cl), or C(O)R.sup.8
(e.g., COCH.sub.3).
[0164] R.sup.8 is preferably alkyl having 1 to 4 carbon atoms,
e.g., CH.sub.3, CH.sub.2CH.sub.3, especially CH.sub.3.
[0165] Q is preferably C or CH or N.
[0166] Y is preferably O or NR.sup.7.
[0167] W is preferably absent, or when present, is preferably
O.
[0168] Preferred examples of Ar represented by formulas (a)-(r)
include, but are not limited to, phenyl substituted at least once
by amino, dialkylamino (e.g. N(CH.sub.3).sub.2), NR.sup.6COR.sup.8
(e.g., NHCOCH.sub.3), N(CH.sub.3)COCH.sub.3), or substituted or
unsubstituted heterocyclic group (e.g., pyrimidinyl, pyrrolidinyl,
morpholinyl); pyridinyl substituted at least once by substituted or
unsubstituted heterocyclic group (e.g., morpholinyl); unsubstituted
or substituted dihydrobenzofuranyl (e.g.,
2,3-dihydrobenzofuran-5-yl); unsubstituted or substituted
dihydrobenzodioxepinyl (e.g.,
3,4-dihydro-2H-1,5-benzodioxepin-7-yl); unsubstituted or
substituted thiazolyl (e.g., 4-alkyl-2-aryl-substituted thiazolyl);
unsubstituted or substituted pyrazolyl (e.g.,
5-methyl-1-phenyl-1H-pyrazol-4-yl,
1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl,
1,3,5-trimethyl-1-H-pyrazol-4-yl, 1-ethyl-3-methyl-1H-pyrazol-4-yl,
1-difluoromethyl-5-methyl-1H-pyrazol-4-yl,
1-difluoromethyl-3-methyl-1H-pyrazol-4-yl,
1-ethyl-5-methyl-1H-pyrazol-4-yl, 1-ethyl-1H-pyrazol-4-yl,
1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl,
1,5-dimethyl-1H-pyrazol-4-yl); unsubstituted or substituted
benzothienyl (e.g., 1-benzothien-2-yl, 1-benzothien-3-yl);
unsubstituted or substituted furanyl (e.g., 5-acetoxy-furan-2-yl,
2,5-dimethyl-furan-3-yl); unsubstituted or substituted benzofuranyl
(e.g., 1-benzofuran-2-yl); unsubstituted or substituted oxazolyl
(e.g., 3,5-dimethyloxazol-4-yl); unsubstituted or substituted
benzothiazolyl (e.g., 1,3-benzothiazol-6-yl); unsubstituted or
substituted pyrrolyl (e.g., 4-chloro-1,2-dimethyl-1-H-pyrrol-3-yl);
unsubstituted or substituted imidazolyl (e.g.,
1-methyl-1H-imidazol-4-yl, 1,2-dimethyl-1H-imidazol-4-yl);
unsubstituted or substituted dihydroindolyl (e.g.,
2,3,dihydro-1-H-indol-5-yl, 1-acetyl-2,3,dihydro-1-H-indol-5-yl,
1-methyl-2,3,dihydro-1-H-indol-5-yl,
1-ethyl-2,3,dihydro-1-H-indol-5-yl); unsubstituted or substituted
indazolyl (e.g., 1-(2,2-dimethylpropanoyl)indazol-5-yl); and
unsubstituted or substituted tetrahydroisoquinolinyl (e.g.,
1,2,3,4-tetrahydroisoquinolin-7-yl,
1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl,
1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl).
[0169] In addition, preferred compounds in accordance with the
invention are described by subformulas (i)-(xix), which correspond
to formula I, but exhibit the following preferred groups:
[0170] (i) A, D, E, and G are CH, [0171] B is CR.sup.4 wherein
R.sup.4 is H, halogen or halogenated alkyl, and [0172] R.sup.1 is
SO.sub.2Ar wherein Ar is phenyl substituted at least once by amino,
dialkylamino (e.g. N(CH.sub.3).sub.2), NR.sup.6COR.sup.8 (e.g.,
NHCOCH.sub.3), N(CH.sub.3)COCH.sub.3), or substituted or
unsubstituted heterocyclic group (e.g., pyrimidinyl, pyrrolidinyl,
morpholinyl), [0173] pyridinyl substituted at least once by
substituted or unsubstituted heterocyclic group (e.g.,
morpholinyl), [0174] unsubstituted or substituted
dihydrobenzofuranyl (e.g., 2,3-dihydrobenzofuran-5-yl), [0175]
unsubstituted or substituted dihydrobenzodioxepinyl (e.g.,
3,4-dihydro-2H-1,5-benzodioxepin-7-yl), [0176] unsubstituted or
substituted thiazolyl (e.g., 4-alkyl-2-aryl-substituted thiazolyl),
[0177] unsubstituted or substituted pyrazolyl (e.g.,
5-methyl-1-phenyl-1H-pyrazol-4-yl,
1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl,
1,3,5-trimethyl-1-H-pyrazol-4-yl, 1-ethyl-3-methyl-1H-pyrazol-4-yl,
1-difluoromethyl-5-methyl-1H-pyrazol-4-yl,
1-difluoromethyl-3-methyl-1H-pyrazol-4-yl,
1-ethyl-5-methyl-1H-pyrazol-4-yl, 1-ethyl-1H-pyrazol-4-yl,
1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl,
1,5-dimethyl-1H-pyrazol-4-yl), [0178] unsubstituted or substituted
benzothienyl (e.g., 1-benzothien-2-yl, 1-benzothien-3-yl), [0179]
unsubstituted or substituted furanyl (e.g., 5-acetoxy-furan-2-yl,
2,5-dimethyl-furan-3-yl), [0180] unsubstituted or substituted
benzofuranyl (e.g., 1-benzofuran-2-yl), [0181] unsubstituted or
substituted oxazolyl (e.g., 3,5-dimethyloxazol-4-yl), [0182]
unsubstituted or substituted benzothiazolyl (e.g.,
1,3-benzothiazol-6-yl), [0183] unsubstituted or substituted
pyrrolyl (e.g., 4-chloro-1,2-dimethyl-1-H-pyrrol-3-yl), [0184]
unsubstituted or substituted dihydroindolyl (e.g.,
2,3,dihydro-1-H-indol-5-yl, 1-acetyl-2,3,dihydro-1-H-indol-5-yl,
1-methyl-2,3,dihydro-1-H-indol-5-yl,
1-ethyl-2,3,dihydro-1-H-indol-5-yl), [0185] unsubstituted or
substituted indazolyl (e.g., 1-(2,2-dimethylpropanoyl)
indazol-5-yl), or [0186] unsubstituted or substituted
tetrahydroisoquinolinyl (e.g., 1,2,3,4-tetrahydroisoquinolin-7-yl,
1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl,
1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl).
[0187] (ii) A, D, E, and G are CH, [0188] B is CR.sup.4 wherein
R.sup.4 is H, halogen or halogenated alkyl, and [0189] R.sup.1 is
SO.sub.2Ar wherein Ar is phenyl substituted at least once by amino,
dimethylamino, NHCOCH.sub.3, N(CH.sub.3)COCH.sub.3, unsubstituted
or substituted pyrimidinyl, unsubstituted or substituted
pyrrolidinyl or unsubstituted or substituted morpholinyl, [0190]
pyridinyl substituted at least once by substituted or unsubstituted
heterocyclic group, [0191] unsubstituted or substituted
dihydrobenzofuranyl, [0192] unsubstituted or substituted
dihydrobenzodioxepinyl, [0193] unsubstituted thiazolyl or thiazolyl
substituted by one or more alkyl and/or aryl groups, [0194]
unsubstituted pyrazolyl or pyrazolyl substituted by one or more
alkyl, aryl, halogenated alkyl groups, [0195] unsubstituted or
substituted benzothienyl, [0196] unsubstituted furanyl or furanyl
substituted by one or more acetoxy and/or alkyl groups, [0197]
unsubstituted or substituted benzofuranyl, [0198] unsubstituted
oxazolyl or oxazolyl substituted by one or more alkyl groups,
[0199] unsubstituted or substituted benzothiazolyl, [0200]
unsubstituted pyrrolyl or pyrrolyl substituted by one or more
halogen and/or alkyl groups, [0201] unsubstituted dihydroindolyl or
dihydroindolyl substituted by one or more acetyl, and/or alkyl
groups, [0202] unsubstituted indazolyl or indazolyl substituted by
one or more C(O)R.sup.8 groups, or [0203] unsubstituted
tetrahydroisoquinolinyl or tetrahydroisoquinolinyl substituted by
one or more alkyl groups.
[0204] (iii) A, D, E, and G are CH, [0205] B is CR.sup.4 wherein
R.sup.4 is H, F, or CF.sub.3, and [0206] R.sup.1 is SO.sub.2Ar
wherein Ar is 4-aminophenyl, 4-dimethylaminophenyl,
3-dimethylaminophenyl, p-C.sub.6H.sub.4(NHCOCH.sub.3),
p-C.sub.6H.sub.4(N(CH.sub.3)COCH.sub.3),
3-(2-methylpyrimidin-4-yl)phenyl, 4-morpholin-4-ylphenyl,
4-pyrrolidin-1-ylphenyl, 3-pyrrolidin-1-ylphenyl,
4-morpholin-4-yl-pyridin-3-yl, 2,3-dihydrobenzofuran-5-yl,
3,4-dihydro-2H-1,5-benzodioxepin-7-yl,
4-methyl-2-phenyl-1,3-thiazol-5yl,
5-methyl-1-phenyl-1H-pyrazol-4-yl,
1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl,
1,3,5-trimethyl-1-H-pyrazol-4-yl, 1-ethyl-3-methyl-1H-pyrazol-4-yl,
1-difluoromethyl-5-methyl-1H-pyrazol-4-yl,
1-difluoromethyl-3-methyl-1H-pyrazol-4-yl,
1-ethyl-5-methyl-1H-pyrazol-4-yl, 1-ethyl-1H-pyrazol-4-yl,
1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl,
1,5-dimethyl-1H-pyrazol-4-yl, 1-benzothien-2-yl, 1-benzothien-3-yl,
5-acetoxy-furan-2-yl, 2,5-dimethyl-furan-3-yl, 1-benzofuran-2-yl,
3,5-dimethyloxazol-4-yl), 1,3-benzothiazol-6-yl),
4-chloro-1,2-dimethyl-1-H-pyrrol-3-yl), 2,3,dihydro-1-H-indol-5-yl,
1-acetyl-2,3,dihydro-1-H-indol-5-yl,
1-methyl-2,3,dihydro-1-H-indol-5-yl,
1-ethyl-2,3,dihydro-1-H-indol-5-yl),
1,2,3,4-tetrahydroisoquinolin-7-yl,
1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl,
1-(2,2-dimethylpropanoyl)indazol-5-yl, or
1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl.
[0207] (iv) A, B, D, and E are CH or CR.sup.4, [0208] R.sup.1 is
SO.sub.2Ar wherein Ar is an unsubstituted phenyl, and [0209] at
least one of A, B, D and E is CR.sup.4 in which R.sup.4 is NO.sub.2
or heterocyclic group (e.g., substituted or unsubstituted pyrrolyl,
pyridinyl, pyrrolidinyl, morpholinyl).
[0210] (v) A, and E are CH, [0211] R.sup.1 is SO.sub.2Ar wherein Ar
is an unsubstituted phenyl, and [0212] at least one of B or D is
CR.sup.4 in which R.sup.4 is NO.sub.2 or heterocyclic group (e.g.,
substituted or unsubstituted pyrrolyl, pyridinyl, pyrrolidinyl,
morpholinyl).
[0213] (vi) A, and E are CH, [0214] R.sup.1 is SO.sub.2Ar wherein
Ar is an unsubstituted phenyl, and [0215] at least one of B or D is
CR.sup.4 in which R.sup.4 is NO.sub.2, 2,5-dimethylpyrrol-1-yl,
pyridin-4-yl, pyridine-3-yl, pyridine-2-yl, pyrroldin-1-yl, or
morpholin-4-yl.
[0216] (vii) A, D, and G are CH, [0217] E is N, [0218] B is
CR.sup.4 wherein R.sup.4 is H, halogen (e.g., F) or halogenated
alkyl (e.g., CF.sub.3), and [0219] R.sup.1 is SO.sub.2Ar wherein Ar
is phenyl substituted at least once by amino, dialkylamino (e.g.
N(CH.sub.3).sub.2), NR.sup.6COR.sup.8 (e.g., NHCOCH.sub.3),
N(CH.sub.3)COCH.sub.3), or substituted or unsubstituted
heterocyclic group (e.g., pyrimidinyl, pyrrolidinyl, morpholinyl),
[0220] pyridinyl substituted at least once by substituted or
unsubstituted heterocyclic group (e.g., morpholinyl) [0221]
unsubstituted or substituted dihydrobenzofuranyl (e.g.,
2,3-dihydrobenzofuran-5-yl), [0222] unsubstituted or substituted
dihydrobenzodioxepinyl (e.g.,
3,4-dihydro-2H-1,5-benzodioxepin-7-yl), [0223] thiazolyl
substituted at least once by aryl (e.g., 4-alkyl-2-aryl-substituted
thiazolyl), [0224] unsubstituted or substituted dihydroindolyl
(e.g., 2,3,dihydro-1-H-indol-5-yl,
1-acetyl-2,3,dihydro-1-H-indol-5-yl,
1-methyl-2,3,dihydro-1-H-indol-5-yl,
1-ethyl-2,3,dihydro-1-H-indol-5-yl), or [0225] unsubstituted or
substituted tetrahydroisoquinolinyl (e.g.,
1,2,3,4-tetrahydroisoquinolin-7-yl,
1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl,
1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl).
[0226] (viii) A, D, and G are CH, [0227] E is N, [0228] B is
CR.sup.4 wherein R.sup.4 is H, halogen (e.g., F) or halogenated
alkyl (e.g., CF.sub.3), and [0229] R.sup.1 is SO.sub.2Ar wherein Ar
is phenyl substituted at least once by amino, dialkylamino (e.g.
N(CH.sub.3).sub.2), NR.sup.6COR.sup.8 (e.g., NHCOCH.sub.3),
N(CH.sub.3)COCH.sub.3), or substituted or unsubstituted
heterocyclic group (e.g., pyrimidinyl, pyrrolidinyl, morpholinyl),
[0230] pyridinyl substituted at least once by substituted or
unsubstituted heterocyclic group, [0231] unsubstituted or
substituted dihydrobenzofuranyl, [0232] unsubstituted or
substituted dihydrobenzodioxepinyl, [0233] thiazolyl substituted at
least once by aryl, [0234] unsubstituted dihydroindolyl or
dihydroindolyl substituted by one or more acetyl and/or alkyl
groups, or [0235] unsubstituted tetrahydroisoquinolinyl or
tetrahydroisoquinolinyl substituted by one or more alkyl
groups.
[0236] (ix) A, B, D, and G are CH, [0237] E is N, and [0238]
R.sup.1 is SO.sub.2Ar wherein Ar is 4-aminophenyl,
4-dimethylaminophenyl, 3-dimethylaminophenyl,
p-C.sub.6H.sub.4(NHCOCH.sub.3),
p-C.sub.6H.sub.4(N(CH.sub.3)COCH.sub.3),
3-(2-methylpyrimidin-4-yl)phenyl, 4-morpholin-4-ylphenyl,
4-pyrrolidin-1-ylphenyl, 3-pyrrolidin-1-ylphenyl,
4-morpholin-4-yl-pyridin-3-yl, 2,3-dihydrobenzofuran-5-yl,
3,4-dihydro-2H-1,5-benzodioxepin-7-yl,
4-methyl-2-phenyl-1,3-thiazol-5yl, 2,3,dihydro-1-H-indol-5-yl,
1-acetyl-2,3,dihydro-1-H-indol-5-yl,
1-methyl-2,3,dihydro-1-H-indol-5-yl,
1-ethyl-2,3,dihydro-1-H-indol-5-yl),
1,2,3,4-tetrahydroisoquinolin-7-yl,
1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl, or
1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl.
[0239] (x) A, D, and E are CH, [0240] G is N, [0241] B is CR.sup.4
wherein R.sup.4 is H, halogen or halogenated alkyl, and [0242]
R.sup.1 is SO.sub.2Ar wherein Ar is unsubstituted or substituted
imidazolyl (e.g., 1,2-dimethyl-1H-imidazol-4-yl), or unsubstituted
or substituted furyl (e.g., 2,5-dimethylfur-3-yl).
[0243] (xi) A, B and D are CH or CR.sup.4, [0244] E and G are N,
[0245] R.sup.1 is SO.sub.2Ar wherein Ar is unsubstituted or
substituted imidazolyl (e.g., 1,2-dimethyl-1H-imidazol-4-yl), or
unsubstituted or substituted furyl (e.g.,
2,5-dimethylfur-3-yl).
[0246] (xii) A, D and G are CH, [0247] B is CR.sup.4 wherein
R.sup.4 is H, halogen, halogenated alkyl, nitro, pyridine, dimethyl
pyrrole, tetrahydropyrrole, tetrahydropyridine, or
tetrahydrooxazine, [0248] E is CH or N, [0249] R.sub.2 is CH.sub.3,
[0250] R.sub.3 is H, [0251] - - - is a double bond and Q is C.
[0252] (xiii) Ar is a heterocycle selected from formulas (b)-(i)
and (k)-(l).
[0253] (xiv) G is CH or CR.sup.4.
[0254] (xv) R.sup.4 is halogen (e.g., F), nitro, [0255] alkyl
having 1 to 8, preferably 1 to 4 carbon atoms, cycloalkyl having 3
to 12, preferably 3 to 8 carbon atoms, or cycloalkylalkyl having 4
to 12, preferably 4 to 8 carbon atoms, each of which is branched or
unbranched and which is unsubstituted or substituted one or more
times with halogen, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, oxo, or any
combination thereof, or [0256] a heterocyclic group, which is
saturated, partially saturated or unsaturated, having 5 to 10 ring
atoms in which at least 1 ring atom is an N, O or S atom, which is
unsubstituted or substituted one or more times by halogen, hydroxy,
aryl, alkyl, alkoxy, cyano, halogenated alkyl, nitro, or any
combination thereof.
[0257] (xvi) Q is N, [0258] A, B, and D are CH, [0259] E is CH or
NH, [0260] R.sub.2 is H or CH.sub.3, [0261] R.sub.3 is H, and
[0262] R.sup.1 is SO.sub.2Ar wherein Ar is a heterocycle selected
from formulas (a), (c) and (n).
[0263] (xvii) A, D, and E are CH, [0264] B is CR.sup.4 and R.sup.4
is F [0265] R.sup.1 is SO.sub.2Ar wherein Ar is a heterocycle
having the formula (o), [0266] R.sub.2 is H or CH.sub.3, and [0267]
R.sub.3 is H.
[0268] (xviii) R.sup.1 is SO.sub.2Ar wherein Ar is
2,3-dihydrobenzo[b][1,4]dioxine, 3,4-dihydroquinolin-2(1H)-one,
4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, or
2H-benzo[b][1,4]oxazin-3(4H)-one.
[0269] (xix) Q is N
[0270] A, B, D, E and G are CH, [0271] R.sup.1 is SO.sub.2Ar
wherein Ar is 2H-benzo[b][1,4]oxazin-3(4H)-one, [0272] R.sub.2 is
H, [0273] R.sub.3 is H, [0274] and - - - - - represents a single
bond.
[0275] According to a compound and/or method aspect of the present
invention, the compounds are selected from: [0276] 2)
N-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl-1H-indol-1-yl]sulfonyl}-
phenyl)acetamide, [0277] 3)
N-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyrid-
in-1-yl]sulfonyl}phenyl)acetamide, [0278] 4)
N-(4-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl-
]sulfonyl}phenyl)acetamide, [0279] 5)
N-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-
-indol-1-yl]sulfonyl}phenyl)acetamide, [0280] 6)
1-(2,3-dihydro-1-benzofuran-5-ylsulfonyl)-3-methyl-1,2,3,6-tetrahydropyri-
din-4-yl)-1H-indole, [0281] 7)
1-(2,3-dihydro-1-benzofuran-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydrop-
yridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0282] 8)
1-(2,3-dihydro-1-benzofuran-5-ylsulfonyl)-5-fluoro-3-(1-methyl-1,2,3,6-te-
trahydropyridin-4-yl)-1H-indole, [0283] 9)
1-(2,3-dihydro-1-benzofuran-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydrop-
yridin-4-yl)-5-(trifluoromethyl)-1H-indole, [0284] 10)
1-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylsulfonyl)-3-(1-methyl-1,2,3,6-tet-
rahydropyridin-4-yl)-1H-indole, [0285] 11)
1-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylsulfonyl)-3-(1-methyl-1,2,3,6-tet-
rahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0286] 12)
1-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylsulfonyl)-5-fluoro-3-(1-methyl-1,-
2,3,6-tetrahydropyridin-4-yl)-1H-indole, [0287] 13)
1-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylsulfonyl)-3-(1-methyl-1,2,3,6-tet-
rahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, [0288] 14)
1-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-indole, [0289] 15)
1-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0290] 16)
5-fluoro-1-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)sulfonyl]-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-indole, [0291] 17)
1-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, [0292] 18)
1-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetra-
hydropyridin-4-yl)-1H-indole, [0293] 19)
1-[(5-Methyl-1-phenyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetra-
hydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0294] 20)
5-fluoro-1-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,-
3,6-tetrahydropyridin-4-yl)-1H-indole, [0295] 21)
1-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetra-
hydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, [0296] 22)
1-(1-benzothien-2-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-indole, [0297] 23)
1-(1-benzothien-2-ylsulfonyl)-5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyri-
din-4-yl)-1H-indole, [0298] 24)
1-(1-benzothien-2-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-5-(trifluoromethyl)-1H-indole, [0299] 25)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-{[1-methyl-3-(trifluorometh-
yl)-1H-pyrazol-4-yl]sulfonyl}-1H-indole, [0300] 26)
5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-{[1-methyl-3-(trif-
luoromethyl)-1H-pyrazol-4-yl]sulfonyl}-1H-indole, [0301] 27)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-{[1-methyl-3-(trifluorometh-
yl)-1H-pyrazol-4-yl]sulfonyl}-5-(trifluoromethyl)-1H-indole, [0302]
28) Methyl
5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-A]sulfo-
nyl}-2-furoate, [0303] 29) Methyl
5-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-2-furoate, [0304] 30) Methyl
5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-in-
dol-1-yl]sulfonyl}-2-furoate, [0305] 31) Methyl
5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin--
1-yl]sulfonyl}-2-furoate, [0306] 32)
1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyr-
idin-4-yl)-1H-indole, [0307] 33)
5-fluoro-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-indole, [0308] 34)
1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyr-
idin-4-yl)-5-(trifluoromethyl)-1H-indole, [0309] 35)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0310] 36)
1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydr-
opyridin-4-yl)-1H-indazole, [0311] 37)
1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2,3,6--
tetrahydropyridin-4-yl)-1H-indazole, [0312] 38)
1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydr-
opyridin-4-yl)-5-(trifluoromethyl)-1H-Indazole, [0313] 39)
1-[(2,5-dimethyl-3-furyl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyridin--
4-yl)-1H-indole, [0314] 40)
1-[(2,5-dimethyl-3-furyl)sulfonyl]-5-fluoro-3-(1-methyl-1,2,3,6-tetrahydr-
opyridin-4-yl)-1,1-indole, [0315] 41)
1-[(2,5-dimethyl-3-furyl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyridin--
4-yl)-5-(trifluoromethyl)-1H-indole, [0316] 42)
1-(1-benzothien-3-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-indole, [0317] 43)
1-(1-benzothien-3-ylsulfonyl)-5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyri-
din-4-yl)-1H-indole, [0318] 44)
1-(1-benzothien-3-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-5-(trifluoromethyl)-1H-indole, [0319] 45)
1-(1,3-benzodioxol-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4--
yl)-1H-pyrrolo[2,3-b]pyridine, [0320] 46)
1-(1-benzofuran-2-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-indole, [0321] 47)
1-(1-benzofuran-2-ylsulfonyl)-5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyri-
din-4-yl)-1H-indole, [0322] 48)
1-(1-benzofuran-2-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-5-(trifluoromethyl)-1H-indole, [0323] 49)
1-{[3-(2-methylpyrimidin-4-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3,6-tetrah-
ydropyridin-4-yl)-1H-indole, [0324] 50)
5-fluoro-1-{[3-(2-methylpyrimidin-4-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3-
,6-tetrahydropyridin-4-yl)-1H-indole, [0325] 51)
1-{[3-(2-methylpyrimidin-4-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3,6-tetrah-
ydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, [0326] 52)
1-{[3-(2-methylpyrimidin-4-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3,6-tetrah-
ydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0327] 53)
1-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyr-
idin-4-yl)-1H-indole, [0328] 54)
1-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-indole, [0329] 55)
1-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyr-
idin-4-yl)-5-(trifluoromethyl)-1H-indole, [0330] 56)
6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]sulfonyl}-1-
,3-benzothiazole, [0331] 57)
6-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-1,3-benzothiazole, [0332] 58)
6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-in-
dol-1-yl]sulfonyl}-1,3-benzothiazole, [0333] 59)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(1,3,5-trimethyl-1H-pyrazo-
l-4-yl)sulfonyl]-1H-indole, [0334] 60)
5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(1,3,5-trimethyl--
1H-pyrazol-4-yl)sulfonyl]-1H-indole, [0335] 61)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1-[(1,3,5-
-trimethyl-1H-pyrazol-4-yl)sulfonyl]-1H-indole, [0336] 62)
1-[(4-chloro-1,2-dimethyl-1H-pyrrol-3-yl)sulfonyl]-3-(1-methyl-1,2,3,6-te-
trahydropyridin-4-yl)-1H-indole, [0337] 63)
1-[(4-chloro-1,2-dimethyl-1H-pyrrol-3-yl)sulfonyl]-5-fluoro-3-(1-methyl-1-
,2,3,6-tetrahydropyridin-4-yl)-1H-indole, [0338] 64)
1-[(4-chloro-1,2-dimethyl-1H-pyrrol-3-yl)sulfonyl]-3-(1-methyl-1,2,3,6-te-
trahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, [0339] 65)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-indole, [0340] 66)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-indole, [0341] 67)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, [0342] 68)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0343] 69)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(6-morpholin-4-ylpyridin-3-
-yl)sulfonyl]-1H-indole, [0344] 70)
5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(6-morpholin-4-yl-
pyridin-3-yl)sulfonyl]-1H-indole, [0345] 71)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(6-morpholin-4-ylpyridin-3-
-yl)sulfonyl]-5-(trifluoromethyl)-1H-indole, [0346] 72)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(6-morpholin-4-ylpyridin-3-
-yl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine, [0347] 73)
1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-
in-4-yl)-1H-indole, [0348] 74)
1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-5-fluoro-3-(1-methyl-1,2,3,6-tetrah-
ydropyridin-4-yl)-1H-indole, [0349] 75)
1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-
in-4-yl)-5-(trifluoromethyl)-1H-indole, [0350] 76)
1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-
in-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0351] 77)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1-(phenylsulfonyl)-1H-
-indole, [0352] 78)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitro-1-(phenylsulfonyl)-1H-
-indole, [0353] 79)
5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-y-
l)-1-(phenylsulfonyl)-1H-indole, [0354] 80)
6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-y-
l)-1-(phenylsulfonyl)-1H-indole, [0355] 81)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-5-pyridin--
4-yl-1H-indole, [0356] 82)
4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-in-
dol-1-yl]sulfonyl}aniline, [0357] 83)
4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin--
1-yl]sulfonyl}aniline, [0358] 84)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-5-pyridin--
3-yl-1H-indole, [0359] 85)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-6-pyridin--
3-yl-1H-indole, [0360] 86)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-6-pyridin--
4-yl-1H-indole, [0361] 87)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-morpholin-4-ylphenyl)su-
lfonyl]-1H-indole, [0362] 88)
5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-morpholin-4-yl-
phenyl)sulfonyl]-1H-indole, [0363] 89)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-morpholin-4-ylphenyl)su-
lfonyl]-5-(trifluoromethyl)-1H-indole, [0364] 90)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-morpholin-4-ylphenyl)su-
lfonyl]-1H-pyrrolo[2,3-b]pyridine, [0365] 91)
N,N-dimethyl-4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-y-
l]sulfonyl}aniline, [0366] 92)
4-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-N,N-dimethylaniline, [0367] 93)
N,N-dimethyl-4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoro-
methyl)-1H-indol-1-yl]sulfonyl}aniline, [0368] 94)
N,N-dimethyl-4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2-
,3-b]pyridin-1-yl]sulfonyl}aniline, [0369] 95)
N,N-dimethyl-3-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-y-
l]sulfonyl}aniline, [0370] 96)
3-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-N,N-dimethylaniline, [0371] 97)
N,N-dimethyl-3-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoro-
methyl)-1H-indol-1-yl]sulfonyl}aniline, [0372] 98)
N,N-dimethyl-3-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2-
,3-b]pyridin-1-yl]sulfonyl}aniline, [0373] 99)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-5-pyrrolid-
in-1-yl-1H-indole, [0374] 100)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-6-pyrrolid-
in-1-yl-1H-indole, [0375] 101)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-5-piperidi-
n-1-yl-1H-indole, [0376] 102)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-6-piperidi-
n-1-yl-1H-indole, [0377] 103)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-morpholin-4-yl-1-(phenylsul-
fonyl)-1H-indole, [0378] 104)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-morpholin-4-yl-1-(phenylsul-
fonyl)-1H-indole, [0379] 105)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-5-pyridin--
2-yl-1H-indole dihydrochloride, [0380] 106)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-6-pyridin--
2-yl-1H-indole dihydrochloride, [0381] 107)
1-[(1-methyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-indole, [0382] 108)
5-fluoro-1-[(1-methyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-indole, [0383] 109)
1-[(1-methyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, [0384] 110)
1-[(1-methyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0385] 111)
1-[(1-ethyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetra-
hydropyridin-4-yl)-1H-indole, [0386] 112)
1-[(1-ethyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2,-
3,6-tetrahydropyridin-4-yl)-1H-indole, [0387] 113)
1-[(1-ethyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetra-
hydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, [0388] 114)
1-[(1-ethyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetra-
hydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0389] 115)
N-methyl-N-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl-
]sulfonyl}phenyl)acetamide, [0390] 116)
N-(4-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl-
]sulfonyl}phenyl)-N-methylacetamide, [0391] 117)
N-methyl-N-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluorom-
ethyl)-1H-indol-1-yl]sulfonyl}phenyl)acetamide, [0392] 118)
N-methyl-N-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,-
3-b]pyridin-1-yl]sulfonyl}phenyl)acetamide, [0393] 119)
7-([3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]sulfonyl)-1-
,2,3,4-tetrahydroquinoline, [0394] 120)
7-([5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl)-1,2,3,4-tetrahydroquinoline, [0395] 121)
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-in-
dol-1-yl]sulfonyl}-1,2,3,4-tetrahydroquinoline, [0396] 122)
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin--
1-yl]sulfonyl}-1,2,3,4-tetrahydroquinoline, [0397] 123)
1-methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-1,2,3,4-tetrahydroquinoline, [0398] 124)
7-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-1-methyl-1,2,3,4-tetrahydroquinoline, [0399] 125)
1-methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluorometh-
yl)-1H-indol-1-yl]sulfonyl}-1,2,3,4-tetrahydroquinoline, [0400]
126)
1-methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b-
]pyridin-1-yl]sulfonyl}-1,2,3,4-tetrahydroquinoline, [0401] 127)
1-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-1,2,3,4-tetrahydroquinoline, [0402] 128)
6-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-1-methyl-1,2,3,4-tetrahydroquinoline,
[0403] 129)
1-methyl-6-([3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluorometh-
yl)-1H-indol-1-yl]sulfonyl)-1,2,3,4-tetrahydroquinoline, [0404]
130)
1-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b-
]pyridin-1-yl]sulfonyl}-1,2,3,4-tetrahydroquinoline, [0405] 131)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-pyrrolidin-1-ylphenyl)s-
ulfonyl]-1H-indole, [0406] 132)
5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-pyrrolidin-1-y-
lphenyl)sulfonyl]-1H-indole, [0407] 133)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-pyrrolidin-1-ylphenyl)s-
ulfonyl]-5-(trifluoromethyl)-1H-indole, [0408] 134)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-pyrrolidin-1-ylphenyl)s-
ulfonyl]-1H-pyrrolo[2,3-b]pyridine, [0409] 135)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(3-pyrrolidin-1-ylphenyl)s-
ulfonyl]-1H-indole, [0410] 136)
5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(3-pyrrolidin-1-y-
lphenyl)sulfonyl]-1H-indole, [0411] 137)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(3-pyrrolidin-1-ylphenyl)s-
ulfonyl]-5-(trifluoromethyl)-1H-indole, [0412] 138)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(3-pyrrolidin-1-ylphenyl)s-
ulfonyl]-1H-pyrrolo[2,3-b]pyridine, [0413] 139)
1-[(1-ethyl-3-methyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrah-
ydropyridin-4-yl)-1H-indole, [0414] 140)
1-[(1-ethyl-3-methyl-1H-pyrazol-4-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2,3-
,6-tetrahydropyridin-4-yl)-1H-indole, [0415] 141)
1-[(1-ethyl-3-methyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrah-
ydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, [0416] 142)
1-{[1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]sulfonyl}-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-indole, [0417] 143)
1-{[1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]sulfonyl}-5-fluoro-3-(1-m-
ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, [0418] 144)
1-{[1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]sulfonyl}-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, [0419]
145)
1-[(1-ethyl-5-methyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrah-
ydropyridin-4-yl)-1H-indole, [0420] 146)
1-[(1-ethyl-5-methyl-1H-pyrazol-4-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2,3-
,6-tetrahydropyridin-4-yl)-1H-indole, [0421] 147)
1-[(1-ethyl-5-methyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrah-
ydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, [0422] 148)
1-[(1-ethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyrid-
in-4-yl)-1H-indole [0423] 149)
1-[(1-ethyl-1H-pyrazol-4-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2,3,6-tetrah-
ydropyridin-4-yl)-1H-indole, [0424] 150)
1-[(1-ethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyrid-
in-4-yl)-5-(trifluoromethyl)-1H-indole, [0425] 151)
1-[(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-te-
trahydropyridin-4-yl)-1H-indole, [0426] 152)
1-[(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-5-fluoro-3-(1-methyl-1-
,2,3,6-tetrahydropyridin-4-yl)-1H-indole, [0427] 153)
1-[(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6
[0428] 154)
1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyri-
din-4-yl)-1,4-indole, [0429] 155)
5-fluoro-1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetra-
hydropyridin-4-yl)-1H-indole, [0430] 156)
1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyri-
din-4-yl)-5-(trifluoromethyl)-1H-indole, [0431] 157)
1-[(1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydro-
pyridin-4-yl)-1H-indole, [0432] 158)
1-[(1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2,3,6-t-
etrahydropyridin-4-yl)-1H-indole, [0433] 159)
1-[(1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydro-
pyridin-4-yl)-5-(trifluoromethyl)-1H-indole, [0434] 160)
1-[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydro-
pyridin-4-yl)-1H-indole, [0435] 161)
1-[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2,3,6-t-
etrahydropyridin-4-yl)-1H-indole, [0436] 162)
1-[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydro-
pyridin-4-yl)-5-(trifluoromethyl)-1H-indole, [0437] 163)
1-[(1-methyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-indole, [0438] 164)
5-fluoro-1-[(1-methyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-indole, [0439] 165)
1-[(1-methyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, [0440] 166)
1-[(1-methyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyri dine, [0441] 167)
1-(2,2-dimethylpropanoyl)-5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-indol-1-yl]sulfonyl}-1H-indazole, [0442] 168)
1-(2,2-dimethylpropanoyl)-5-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyri-
din-4-yl)-1H-indol-1-yl]sulfonyl}-1H-indazole, [0443] 169)
1-(2,2-dimethylpropanoyl)-5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-5-(trifluoromethyl)-1H-indol-1-yl]sulfonyl}-1H-indazole, [0444]
170)
1-{[1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl]sulfonyl}-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-indole, [0445] 171)
1-{[1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl]sulfonyl}-5-fluoro-3-(1-m-
ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, [0446] 172)
1-{[1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl]sulfonyl}-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, [0447]
173)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-1H-indole, [0448] 174)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-5-fluoro-3-(1-methyl-1,2,3,6-
-tetrahydropyridin-4-yl)-1H-indole, [0449] 175)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, [0450] 176)
4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]sulfonyl}an-
iline, [0451] 177)
4-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}aniline, [0452] 178)
1-(2,2-dimethylpropanoyl)-5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-pyrrolo[2,3-b]pyridin-1-yl]sulfonyl}-1H-indazole [0453] 179)
6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin--
1-yl]sulfonyl}-3,4-dihydroquinolin-2(1H)-one, [0454] 180)
1-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b-
]pyridin-1-yl]sulfonyl}-3,4-dihydroquinolin-2(1H)-one, [0455] 181)
1-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluorometh-
yl)-1H-indol-1-yl]sulfonyl}-3,4-dihydroquinolin-2(1H)-one, [0456]
182)
6-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-1-methyl-3,4-dihydroquinolin-2(1H)-one, [0457] 183)
1-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-3,4-dihydroquinolin-2(1H)-one, [0458] 184)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methylpiperidin-4-yl)-1-
H-pyrrolo[2,3-b]pyridine, [0459] 185)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1,2,3,6-tetrahydropyridin-
-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0460] 186)
5-fluoro-1-[(1-methyl-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahy-
dropyridin-4-yl)-1H-indole, [0461] 187)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(1,3-oxazol-2-yl)-1-(pyridi-
n-3-ylsulfonyl)-1H-indole, [0462] 188)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-6-(1,3-oxazol-2-yl)-1H-indole, [0463] 189)
1-[(1-ethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyrid-
in-4-yl)-6-(1,3-oxazol-2-yl)-1H-indole, [0464] 190)
1-[(1-ethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyrid-
in-4-yl)-5-(1,3-oxazol-2-yl)-1H-indole, [0465] 191)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-5-(1,3-oxazol-2-yl)-1H-indole, [0466] 192)
5-(3,6-dihydro-2H-pyran-4-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1-(phenylsulfonyl)-1H-indole, [0467] 193)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-6-(1,3-thi-
azol-2-yl)-1H-indole, [0468] 194)
5-fluoro-1-{[6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]sulfonyl}-3-(1-meth-
yl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, [0469] 195
1-{[6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]sulfonyl}-3-(1-methyl-1,2,3,-
6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0470] 196)
7-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-2H-1,4-benzoxazin-3(4H)-one, [0471] 197)
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin--
1-yl]sulfonyl}-2H-1,4-benzoxazin-3(4H)-one, [0472] 198)
1-[(1-acetyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-indole, [0473] 199)
1-[(1-acetyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0474] 200)
4-methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b-
]pyridin-1-yl]sulfonyl}-3,4->dihydro-2H-1,4-benzoxazine, [0475]
201)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-5-fluoro-3-(1-methylpiperidi-
n-4-yl)-1H-indole hydroformate, [0476] 202)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine, [0477] 203)
4-methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b-
]pyridin-1-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine, [0478] 204)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(1,3-oxazol-2-yl)-1-(pyridi-
n-3-ylsulfonyl)-1H-indole, [0479] 205)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-5-(1,3-thiazol-2-yl)-1H-indole, [0480] 206)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(pyridin-3-ylsulfonyl)-5-(1-
,3-thiazol-2-yl)-1,1-indole, [0481] 207)
1-[(1-ethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyrid-
in-4-yl)-5-(1,3-thiazol-2-yl)-1H-indole, [0482] 208)
1-[(1-methyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine, [0483] 209)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine, [0484] 210)
1-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyrid-
in-1-yl]sulfonyl}phenyl)pyrrolidin-2-one, [0485] 211)
3-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b-
]pyridin-1-yl]sulfonyl}-1,3-benzoxazol-2(3H)-one, [0486] 212)
1-[(1-methyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0487] 213)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0488] 214)
1-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyrid-
in-1-yl]sulfonyl}phenyl)pyrrolidin-2-one, [0489] 215)
3-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b-
]pyridin-1-yl]sulfonyl}-1,3-benzoxazol-2(3H)-one, [0490] 216)
7-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine; compound with
formic acid, [0491] 217)
7-{[5-fluoro-3-(1-methylpiperidin-4-yl)-1H-indol-1-yl]sulfonyl}-4-methyl--
3,4-dihydro-2H-1,4-benzoxazine; compound with formic acid, [0492]
218)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-5-fluoro-3-(1,2,3,6-tetrahyd-
ropyridin-4-yl)-1H-indole hydroformate, [0493] 219)
6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin--
1-yl]sulfonyl}-2H-1,4-benzoxazin-3(4H)-one, [0494] 220)
5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridin--
1-yl]sulfonyl}-1,3-dihydro-2H-benzimidazol-2-one, [0495] 221)
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridin--
1-yl]sulfonyl}-2H-1,4-benzoxazin-3(4H)-one, [0496] 222)
6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridin--
1-yl]sulfonyl}-2H-1,4-benzoxazin-3(4H)-one, [0497] 223)
6-{[S-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-2H-1,4-benzoxazin-3(4H)-one; compound with formic acid,
[0498] 224)
6-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1--
yl]sulfonyl}-3-methyl-1,3-benzoxazol-2(3H)-one; compound with
formic acid, [0499] 225)
7-{[6-(3-methoxypyrrolidin-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4--
yl)-1H-indol-1-yl]sulfonyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine,
[0500] 226)
6-(3-methoxypyrrolidin-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)--
1-(pyridin-3-ylsulfonyl)-1H-indole, [0501] 227)
6-(3-methoxypyrrolidin-1-yl)-1-[(1-methyl-1H-indol-5-yl)sulfonyl]-3-(1-me-
thyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, [0502] 228)
7-{[4-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine; compound with
formic acid, [0503] 229)
7-[5-Fluoro-3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-indole-1-sulfony-
l]-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine, [0504] 230)
7-{[6-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine; compound with
formic acid, [0505] 231)
7-{[7-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine; compound with
formic acid, [0506] 232)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1,2,3,6-tetrahydropyr-
idin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0507] 233)
1-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylsulfonyl)-3-(1-methyl-1,2,3,6-tet-
rahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine, [0508] 234)
4-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b-
]pyridin-1-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine, [0509] 235)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methylpiperidin-4-y-
l)-1H-pyrrolo[2,3-b]pyridine, [0510] 236)
7-{[3,5-bis(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]sulfon-
yl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine, [0511] 237)
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl]sulfonyl}-
-4-benzoxazin-3(4H)-one, [0512] 238)
1-[(1-methyl-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyridi-
n-4-yl)-1H-indazole, [0513] 239)
1-[(1-methyl-1H-indol-5-yl)sulfonyl]-3,5-bis(1-methyl-1,2,3,6-tetrahydrop-
yridin-4-yl)-1H-indole, [0514] 240)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-piperidin-4-yl-1H-pyrrolo[-
2,3-b]pyridine; compound with formic acid, [0515] 241)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-5-fluoro-3-piperidin-4-yl-1H-
-indole hydroformate, [0516] 242)
7-{[3,5-bis(1-methylpiperidin-4-yl)-1H-indol-1-yl]sulfonyl}-4-methyl-3,4--
dihydro-2H-1,4-benzoxazine, [0517] 243)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0518] 244)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-piperidin-4-yl-1H-pyrr-
olo[2,3-b]pyridine, [0519] 245)
4-methyl-7-{[3-(1-methylpiperidin-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl]sul-
fonyl}-3,4-dihydro-2H-1,4-benzoxazine; compound with formic acid,
[0520] 246)
4-methyl-7-{[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyr-
idin-1-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine; compound with
formic acid, [0521] 247)
4-methyl-7-[(3-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridin-1-yl)sulfonyl]-3,4-
-dihydro-2H-1,4-benzoxazine; compound with formic acid,
[0522] 248)
4-methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl]-
sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine; compound with formic
acid, [0523] 249)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0524] 250)
1-(3-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyrid-
in-1-yl]sulfonyl}phenyl)pyrrolidin-2-one, [0525] 251)
1-[(5-bromo-2,3-dihydro-1-benzofuran-7-yl)sulfonyl]-3-(1-methyl-1,2,3,6-t-
etrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0526] 252)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine, [0527] 253)
1-(3-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyrid-
in-1-yl]sulfonyl}phenyl)pyrrolidin-2-one, [0528] 254)
1-[(5-bromo-2,3-dihydro-1-benzofuran-7-yl)sulfonyl]-3-(1-methyl-1,2,3,6-t-
etrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine,
[0529] 255)
6-ethyl-1-[(1-methyl-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0530] 256)
6-ethyl-1-[(1-methyl-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0531] 257)
6-ethyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(3-pyrrolidin-1-yl-
phenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine, [0532] 258)
6-ethyl-1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,-
3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0533] 259)
1-(3-{[6-ethyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-
-b]pyridin-1-yl]sulfonyl}phenyl)pyrrolidin-2-one, [0534] 260)
1-[(5-bromo-2,3-dihydro-1-benzofuran-7-yl)sulfonyl]-6-ethyl-3-(1-methyl-1-
,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0535]
261)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(1H-pyrazol-1-yl)-1-(pyridi-
n-3-ylsulfonyl)-1H-indole; compound with formic acid, [0536] 262)
4-methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(1H-pyrazol-1--
yl)-1H-indol-1-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine;
compound with formic acid, [0537] 263)
5-(1H-imidazol-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(pyrid-
in-3-ylsulfonyl)-1H-indole; compound with formic acid, [0538] 264)
7-{[5-(1H-imidazol-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-i-
ndol-1-yl]sulfonyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine;
compound with formic acid, [0539] 265)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-indazole, [0540] 266)
4-acetyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl]-
sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine, [0541] 267)
5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl]sulfonyl}-
-1,2-benzisoxazole, [0542] 268)
1-(1-benzothien-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-indazole, [0543] 269)
1-(1-benzofuran-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-indazole, [0544] 270)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-6-ethyl-3-(1-methyl-1,2,-
3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0545] 271)
6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl]sulfonyl}-
-2H-1,4-benzoxazin-3 (4H)-one, [0546] 272)
1-(1-benzofuran-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-pyrazolo[4,3-b]pyridine, [0547] 273)
1-(1-benzothien-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-pyrazolo[4,3-b]pyridine, [0548] 274)
1-(1-benzofuran-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-pyrazolo[3,4-b]pyridine, [0549] 275)
1-(1-benzothien-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-pyrazolo[3,4-b]pyridine, [0550] 276)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-indazole; compound with formic
acid, [0551] 277)
5-fluoro-1-[(1-methyl-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahy-
dropyridin-4-yl)-1H-indazole; compound with formic acid, [0552]
278)
5-fluoro-1-[(1-methyl-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahy-
dropyridin-4-yl)-1H-indazole; compound with formic acid, [0553]
279)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrazolo[4,3-b]pyridine, [0554] 280)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine, [0555] 281)
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-
-1-yl]sulfonyl}-2H-1,4-benzoxazin-3(4H)-one, [0556] 282)
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-
-1-yl]sulfonyl}-2H-1,4-benzoxazin-3(4H)-one, [0557] 283)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine, [0558] 284)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrazolo[4,3-b]pyridine, [0559] 285)
4-Methyl-7-(3-piperidin-4-yl-pyrrolo[3,2-b]pyridine-1-sulfonyl)-3,4-dihyd-
ro-2H-benzo[1,4]oxazine, [0560] 286)
1-(3-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyrid-
in-1-yl]sulfonyl}phenyl)pyrrolidin-3-ol, [0561] 287)
1-[(1-acetyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, [0562] 288)
1-[(6-morpholin-4-ylpyridin-3-yl)sulfonyl]-3-(1,2,3,6-tetrahydropyridin-4-
-yl)-1H-pyrrolo[3,2-b]pyridine; compound with formic acid, [0563]
289)
1-{[6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]sulfonyl}-3-(1,2,3,6-tetrahy-
dropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine; compound with formic
acid, [0564] 290)
1-[(5-methoxypyridin-3-yl)sulfonyl]-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-
-pyrrolo[3,2-b]pyridine; compound with formic acid, [0565] 291)
1-{[5-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]sulfonyl}-3-(1,2,3,6-tetrahy-
dropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine; compound with formic
acid, [0566] 292)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1,2,3,6-tetrahydropyr-
idin-4-yl)-1H-pyrrolo[3,2-b]pyridine, [0567] 293)
5-methoxy-1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1-methyl-1,-
2,3,6-tetrahydropyridin-4-yl)-1H-indole, [0568] 294)
7-{[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl]sulf-
onyl}-2H-1,4-benzoxazin-3(4H)-one, [0569] 295)
7-{[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl]sulf-
onyl}-3,4-dihydroquinolin-2(1H)-one, [0570] 296)
4-methyl-6-{[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridin--
1-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine, [0571] 297)
6-{[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl]sulf-
onyl}-2H-1,4-benzoxazin-3(4H)-one, [0572] 298)
7-{[5-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]s-
ulfonyl}-2H-1,4-benzoxazin-3(4H)-one, [0573] 299)
7-{[5-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]s-
ulfonyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine, [0574] 300)
5-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(pyridin-3-ylsulf-
onyl)-1H-indole, [0575] 301)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(4-methylpiperazin-1-y-
l)-1H-indazole, [0576] 302)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-piperazin-1-yl-1H-inda-
zole, [0577] 303)
7-[(3-piperazin-1-yl-1H-indazol-1-yl)sulfonyl]-2H-1,4-benzoxazin-3(4H)-on-
e, [0578] 304)
7-{[3-(4-methylpiperazin-1-yl)-1H-indazol-1-yl]sulfonyl}-2H-1,4-benzoxazi-
n-3(4H)-one, [0579] 305)
7-{[3-(4-methylpiperazin-1-yl)-1H-indol-1-yl]sulfonyl}-2H-1,4-benzoxazin--
3(4H)-one, [0580] 306)
7-[(3-piperazin-1-yl-1H-indol-1-yl)sulfonyl]-2H-1,4-benzoxazin-3
(4H)-one, [0581] 307)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(4-methylpiperazin-1-y-
l)-1H-indole, [0582] 308)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-piperazin-1-yl-1H-indo-
le, [0583] 309)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-piperazin-1-yl-1H-pyrr-
olo[2,3-b]pyridine; compound with formic acid, [0584] 310)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-piperazin-1-yl-1H-pyrr-
olo[2,3-b]pyridine; compound with formic acid, [0585] 311)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(4-methylpiperazin-1-y-
l)-1H-indazole, [0586] 312)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-piperazin-1-yl-1H-inda-
zole, [0587] 313)
3-piperazin-1-yl-1-(pyridin-3-ylsulfonyl)-1H-indazole, [0588] 314)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(4-methylpiperazin-1-y-
l)-1H-indole, [0589] 315)
4-methyl-7-{[3-(4-methylpiperazin-1-yl)-1H-indazol-1-yl]sulfonyl}-3,4-dih-
ydro-2H-1,4-benzoxazine, [0590] 316)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-piperazin-1-yl-1H-indo-
le, [0591] 317)
7-[(3-piperazin-1-yl-1H-indol-1-yl)sulfonyl]-2H-1,4-benzoxazin-3(4H)-one,
[0592] 318)
4-methyl-7-[(3-piperazin-1-yl-1H-indol-1-yl)sulfonyl]-3,4-dihydro-2H-1,4--
benzoxazine; compound with formic acid, [0593] 319)
4-methyl-7-[(3-piperazin-1-yl-1H-indazol-1-yl)sulfonyl]-3,4-dihydro-2H-1,-
4-benzoxazine, [0594] 320)
7-[(3-piperazin-1-yl-1H-indol-1-yl)sulfonyl]-2H-1,4-benzoxazin-3(4H)-one,
[0595] 321)
7-[(3-piperazin-1-yl-1H-indazol-1-yl)sulfonyl]-2H-1,4-benzoxazin-3(4H)-on-
e, [0596] 322)
5-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}isoquinoline hydroformate, [0597] 323)
5-{[5-fluoro-3-(1-methylpiperidin-4-yl)-1H-indol-1-yl]sulfonyl}isoquinoli-
ne hydroformate, [0598] 324)
5-{[5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]sulfonyl}is-
oquinoline hydroformate, [0599] 325)
8-[5-Fluoro-3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-indole-1-sulfony-
l]-isoquinoline; compound with formic acid, [0600] 326)
1-(1,2-benzisoxazol-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-
-yl)-1H-pyrazolo[4,3-b]pyridine, [0601] 327)
1-(1,2-benzisoxazol-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-
-yl)-1H-pyrazolo[3,4-b]pyridine, [0602] 328)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(6-phenoxypyridin-3-yl)sul-
fonyl]-1H-pyrrolo[3,2-b]pyridine, [0603] 329)
2-methyl-8-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b-
]pyridin-1-yl]sulfonyl}-1,2,3,4-tetrahydroisoquinoline, [0604] 330)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-methoxy-3-(1-methyl-1,-
2,3,6-tetrahydropyridin-4-yl)-1H-indole,
[0605] wherein salts listed above can also be in free base form or
in the form of another pharmaceutically acceptable salt, and free
base forms listed above can also be in the form of a
pharmaceutically acceptable salt,
[0606] wherein a compound listed above (either in a free base form
or in the form of a pharmaceutically acceptable salt) can also be
in the form of a solvate (such as a hydrate),
[0607] wherein a compound listed above (in a free base form or
solvate thereof, or in the form of a pharmaceutically acceptable
salt or solvate thereof) can also be in the form of a polymorph,
and
[0608] wherein if the compound exhibits chirality it can be in the
form of a mixture of enantiomers such as a racemate or a mixture of
diastereomers, or can be in the form of a single enantiomer or a
single diastereomer.
[0609] The following table presents structures for selected
compounds of the present invention:
##STR00014## ##STR00015## ##STR00016## ##STR00017## ##STR00018##
##STR00019## ##STR00020## ##STR00021## ##STR00022## ##STR00023##
##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028##
##STR00029## ##STR00030## ##STR00031## ##STR00032## ##STR00033##
##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038##
##STR00039## ##STR00040## ##STR00041## ##STR00042## ##STR00043##
##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048##
##STR00049## ##STR00050## ##STR00051## ##STR00052## ##STR00053##
##STR00054## ##STR00055## ##STR00056## ##STR00057## ##STR00058##
##STR00059## ##STR00060## ##STR00061## ##STR00062## ##STR00063##
##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068##
##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073##
##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078##
##STR00079## ##STR00080## ##STR00081## ##STR00082## ##STR00083##
##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088##
##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093##
##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098##
##STR00099## ##STR00100## ##STR00101## ##STR00102## ##STR00103##
##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108##
##STR00109## ##STR00110## ##STR00111##
[0610] Additional aspects of the present invention include
pharmaceutical compositions comprising a compound of this invention
and a pharmaceutically acceptable carrier and, optionally, one or
more additional active agent(s) as discussed below. Further aspects
include methods of treating a disease state related to or modulated
by the 5HT6 receptor, in a patient, such as a mammal, e.g., a
human, e.g., those disease states mentioned herein.
[0611] The compounds of the present invention are effective in
inhibiting, or modulating the activity of the 5HT6 receptor in
animals, e.g., mammals, especially humans. These compounds exhibit
activity, especially where such activity affects states associated
with CNS disorders including motor, mood, personality, behavioral,
psychiatric, cognitive, and neurodegenerative disorders, such as,
but not limited to, Alzheimer's disease (enhancement of cognitive
memory), Parkinson's disease, Huntington's disease, anxiety,
depression, manic depression, epilepsy, obsessive compulsive
disorders, migraine, sleep disorders, feeding disorders such as
anorexia and bulimia, panic attacks, attention deficit
hyperactivity disorder (ADHD), attention deficit disorder (ADD),
withdrawal from drug abuse such as cocaine, ethanol, nicotine and
benzodiazepines, psychoses, such as schizophrenia, bipolar
disorder, and also disorders associated with spinal trauma and/or
head injury such as hydrocephalus. Such compounds are also useful
for the treatment of memory/cognitive impairment associated with
Alzheimer's disease, schizophrenia, Parkinson's disease,
Huntington's disease Pick's disease, Creutzfeld Jakob disease, HIV,
cardiovascular disease, head trauma or age-related cognitive
decline. In addition, such compounds are also expected to be of use
in the treatment of certain gastrointestinal (GI) disorders such
as, but not limited to, functional bowel disorder, constipation,
including chronic constipation, gastroesophageal reflux disease
(GERD), nocturnal-GERD, and irritable bowel syndrome (IBS),
including diarrhea-predominant IBS (IBS-c),
constipation-predominant IBS (IBS-c) and alternating
constipation/diarrhea IBS.
[0612] All methods comprise administering to the patient in need of
such treatment an effective amount of one or more compounds of the
invention.
[0613] A subject or patient in whom administration of the
therapeutic compound is an effective therapeutic regimen for a
disease or disorder is preferably a human, but can be any animal,
including a laboratory animal in the context of a clinical trial or
screening or activity experiment. Thus, as can be readily
appreciated by one of ordinary skill in the art, the methods,
compounds and compositions of the present invention are
particularly suited to administration to any animal, particularly a
mammal, and including, but by no means limited to, humans, domestic
animals, such as feline or canine subjects, farm animals, such as
but not limited to bovine, equine, caprine, ovine, and porcine
subjects, wild animals (whether in the wild or in a zoological
garden), research animals, such as mice, rats, rabbits, goats,
sheep, pigs, dogs, cats, etc., avian species, such as chickens,
turkeys, songbirds, etc., i.e., for veterinary medical use.
[0614] The compounds of the present invention may be prepared using
conventional synthetic methods analogous to those established in
the art, and, if required, standard separation or isolation
techniques. Suitable synthetic procedures that may be used to
prepare the compounds of the present invention are described in,
for example, U.S. Pat. Nos. 6,133,217, 6,191,141, and 6,903,112.
All starting materials are either commercially available, or can be
conventionally prepared from known starting materials without undue
experimentation.
[0615] One of ordinary skill in the art will recognize that some of
the compounds of Formula I can exist in different geometrical
isomeric forms. In addition, some of the compounds of the present
invention possess one or more asymmetric atoms and are thus capable
of existing in the form of optical isomers, as well as in the form
of racemic or nonracemic mixtures thereof, and in the form of
diastereomers and diastereomeric mixtures inter alia. All of these
compounds, including cis isomers, trans isomers, diastereomeric
mixtures, racemates, nonracemic mixtures of enantiomers,
substantially pure, and pure enantiomers, are within the scope of
the present invention. Substantially pure enantiomers contain no
more than 5% w/w of the corresponding opposite enantiomer,
preferably no more than 2%, most preferably no more than 1%.
[0616] The optical isomers can be obtained by resolution of the
racemic mixtures according to conventional processes, for example,
by the formation of diastereomeric salts using an optically active
acid or base or formation of covalent diastereomers.
[0617] Examples of appropriate acids include, but are not limited
to, tartaric, diacetyltartaric, dibenzoyltartaric,
ditoluoyltartaric and camphorsulfonic acid. Mixtures of
diastereomers can be separated into their individual diastereomers
on the basis of their physical and/or chemical differences by
methods known to those skilled in the art, for example, by
chromatography or fractional crystallization. The optically active
bases or acids are then liberated from the separated diastereomeric
salts.
[0618] A different process for separation of optical isomers
involves the use of chiral chromatography (e.g., chiral HPLC or SFC
columns), with or without conventional derivation, optimally chosen
to maximize the separation of the enantiomers. Suitable chiral HPLC
or SFC columns are manufactured by Diacel, e.g., Chiracel OD and
Chiracel OJ among many others, all routinely selectable. Enzymatic
separations, with or without derivatization, are also useful. The
optically active compounds of Formulas I-II can likewise be
obtained by utilizing optically active starting materials in chiral
syntheses processes under reaction conditions which do not cause
racemization.
[0619] In addition, one of ordinary skill in the art will recognize
that the compounds can be used in different enriched isotopic
forms, e.g., enriched in the content of .sup.2H, .sup.3H, .sup.11C,
.sup.13C and/or .sup.14C. In one particular embodiment, the
compounds are deuterated. Such deuterated forms can be made by the
procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997. As
described in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration
can improve the efficacy and increase the duration of action of
drugs.
[0620] Deuterium substituted compounds can be synthesized using
various methods such as described in: Dean, Dennis C.; Editor.
Recent Advances in the Synthesis and Applications of Radiolabeled
Compounds for Drug Discovery and Development. [In: Curr., Pharm.
Des., 2000; 6(10)] (2000), 110 pp. CAN 133:68895 AN 2000:473538
CAPLUS; Kabalka, George W.; Varma, Rajender S. The Synthesis of
Radiolabeled Compounds via Organometallic Intermediates.
Tetrahedron (1989), 45(21), 6601-21, CODEN: TETRAB ISSN:0040-4020.
CAN 112:20527 AN 1990:20527 CAPLUS; and Evans, E. Anthony.
Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981),
64(1-2), 9-32. CODEN: JRACBN ISSN:0022-4081, CAN 95:76229 AN
1981:476229 CAPLUS.
[0621] The present invention also relates to useful forms of the
compounds as disclosed herein, including free base forms, as well
as pharmaceutically acceptable salts or prodrugs of all the
compounds of the present invention for which salts or prodrugs can
be prepared. Pharmaceutically acceptable salts include those
obtained by reacting the main compound, functioning as a base, with
an inorganic or organic acid to form a salt, for example, but not
limited to, salts of hydrochloric acid, sulfuric acid, phosphoric
acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid,
maleic acid, succinic acid and citric acid. Pharmaceutically
acceptable salts also include those in which the main compound
functions as an acid and is reacted with an appropriate base to
form, e.g., sodium, potassium, calcium, magnesium, ammonium, and
choline salts. Those skilled in the art will further recognize that
acid addition salts of the claimed compounds may be prepared by
reaction of the compounds with the appropriate inorganic or organic
acid via any of a number of known methods. Alternatively, alkali
and alkaline earth metal salts are prepared by reacting the
compounds of the invention with the appropriate base via a variety
of known methods.
[0622] The following are further non-limiting examples of acid
salts that can be obtained by reaction with inorganic or organic
acids: acetates, adipates, alginates, citrates, aspartates,
benzoates, benzenesulfonates, bisulfates, butyrates, camphorates,
digluconates, cyclopentanepropionates, dodecylsulfates,
ethanesulfonates, glucoheptanoates, glycerophosphates,
hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides,
hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates,
methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates,
palmoates, pectinates, persulfates, 3-phenylpropionates, picrates,
pivalates, propionates, succinates, tartrates, thiocyanates,
tosylates, mesylates and undecanoates.
[0623] For example, the pharmaceutically acceptable salt can be a
hydrochloride, hydroformate, hydrobromide, or maleate.
[0624] Preferably, the salts formed are pharmaceutically acceptable
for administration to mammals. However, pharmaceutically
unacceptable salts of the compounds are suitable as intermediates,
for example, for isolating the compound as a salt and then
converting the salt back to the free base compound by treatment
with an alkaline reagent. The free base can then, if desired, be
converted to a pharmaceutically acceptable acid addition salt.
[0625] One of ordinary skill in the art will also recognize that
some of the compounds of Formula I can exist in different
polymorphic forms. As known in the art, polymorphism is an ability
of a compound to crystallize as more than one distinct crystalline
or "polymorphic" species. A polymorph is a solid crystalline phase
of a compound with at least two different arrangements or
polymorphic forms of that compound molecule in the solid state.
Polymorphic forms of any given compound are defined by the same
chemical formula or composition and are as distinct in chemical
structure as crystalline structures of two different chemical
compounds.
[0626] One of ordinary skill in the art will further recognize that
compounds of Formula I can exist in different solvate forms.
Solvates of the compounds of the invention may also form when
solvent molecules are incorporated into the crystalline lattice
structure of the compound molecule during the crystallization
process. For example, suitable solvates include hydrates, e.g.,
monohydrates, dihydrates, sesquihydrates, and hemihydrates.
[0627] The compounds of the invention can be administered alone or
as an active ingredient of a formulation. Thus, the present
invention also includes pharmaceutical compositions of one or more
compounds of Formula I containing, for example, one or more
pharmaceutically acceptable carriers.
[0628] Numerous standard references are available that describe
procedures for preparing various formulations suitable for
administering the compounds according to the invention. Examples of
potential formulations and preparations are contained, for example,
in the Handbook of Pharmaceutical Excipients, American
Pharmaceutical Association (current edition); Pharmaceutical Dosage
Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current
edition, published by Marcel Dekker, Inc., as well as Remington's
Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current
edition).
[0629] In view of their high degree of selective 5HT6 receptor
activity, the compounds of the present invention can be
administered to anyone requiring modulation of the 5HT6 receptor.
Administration may be accomplished according to patient needs, for
example, orally, nasally, parenterally (subcutaneously,
intravenously, intramuscularly, intrasternally and by infusion) by
inhalation, rectally, vaginally, topically and by ocular
administration.
[0630] Various solid oral dosage forms can be used for
administering compounds of the invention including such solid forms
as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk
powders. The compounds of the present invention can be administered
alone or combined with various pharmaceutically acceptable
carriers, diluents (such as sucrose, mannitol, lactose, starches)
and excipients known in the art, including but not limited to
suspending agents, solubilizers, buffering agents, binders,
disintegrants, preservatives, colorants, flavorants, lubricants and
the like. Time release capsules, tablets and gels are also
advantageous in administering the compounds of the present
invention.
[0631] Various liquid oral dosage forms can also be used for
administering compounds of the inventions, including aqueous and
non-aqueous solutions, emulsions, suspensions, syrups, and elixirs.
Such dosage forms can also contain suitable inert diluents known in
the art such as water and suitable excipients known in the art such
as preservatives, wetting agents, sweeteners, flavorants, as well
as agents for emulsifying and/or suspending the compounds of the
invention. The compounds of the present invention may be injected,
for example, intravenously, in the form of an isotonic sterile
solution. Other preparations are also possible.
[0632] Suppositories for rectal administration of the compounds of
the present invention can be prepared by mixing the compound with a
suitable excipient such as cocoa butter, salicylates and
polyethylene glycols. Formulations for vaginal administration can
be in the form of a pessary, tampon, cream, gel, paste, foam, or
spray formula containing, in addition to the active ingredient,
such suitable carriers as are known in the art.
[0633] For topical administration, the pharmaceutical composition
can be in the form of creams, ointments, liniments, lotions,
emulsions, suspensions, gels, solutions, pastes, powders, sprays,
and drops suitable for administration to the skin, eye, ear or
nose. Topical administration may also involve transdermal
administration via means such as transdermal patches.
[0634] Aerosol formulations suitable for administering via
inhalation also can be made. For example, for treatment of
disorders of the respiratory tract, the compounds according to the
invention can be administered by inhalation in the form of a powder
(e.g., micronized) or in the form of atomized solutions or
suspensions. The aerosol formulation can be placed into a
pressurized acceptable propellant.
[0635] The compounds of the present invention are effective in
inhibiting, or modulating the activity of the 5HT6 receptor in
animals, e.g., mammals, especially humans. These compounds exhibit
activity, especially where such activity affects states associated
with CNS disorders including motor, mood, personality, behavioral,
psychiatric, cognitive, and neurodegenerative disorders, such as,
but not limited to, Alzheimer's disease (enhancement of cognitive
memory), Parkinson's disease, Huntington's disease, anxiety,
depression, manic depression, epilepsy, obsessive compulsive
disorders, migraine, sleep disorders, feeding disorders such as
anorexia and bulimia, panic attacks, attention deficit
hyperactivity disorder (ADHD), attention deficit disorder (ADD),
withdrawal from drug abuse such as cocaine, ethanol, nicotine and
benzodiazepines, psychoses, such as schizophrenia, bipolar
disorder, and also disorders associated with spinal trauma and/or
head injury such as hydrocephalus. Such compounds are also useful
for the treatment of memory/cognitive impairment associated with
Alzheimer's disease, schizophrenia, Parkinson's disease,
Huntington's disease, Pick's disease, Creutzfeld Jakob disease,
HIV, cardiovascular disease, head trauma or age-related cognitive
decline. In addition, such compounds are also expected to be of use
in the treatment of certain gastrointestinal (GI) disorders such as
functional bowel disorder and irritable bowel syndrome.
[0636] Assays for determining 5HT6 receptor activity, and
selectivity of 5HT6 receptor activity are known within the art.
See, for example, U.S. Pat. Nos. 6,133,287, 6,686,374, and
6,903,112, and Example 13 described below. Compounds of the
invention show 5-HT6 binding activity with receptor Ki values of
typically less than 1-100 nM. Preferably, the binding activity will
be less than 1-50 nM, and more preferably, the activity will be
less than 1-10 nM. Compounds of the invention show 5-HT6 functional
activity with pA2 values of greater than 6 (IC.sub.50 less than 1
.mu.M). Preferably, the pA2 value will be greater than 7 (IC.sub.50
Less than 500 nM), and more preferably the pA2 value will be
greater than 8 (IC.sub.50 less than 100 nM).
[0637] The preferred pharmacokinetic profile of the compounds may
be further shown with measurements to determine hERG and Cyp3A4
inhibition. The hERG inhibition may be measured as described by
Dubin, A. (2004). HERG Potassium Channel Activity Assayed with the
PatchXpress Planar Patch Clamp. Inaugural PatchXpress User's
Meeting, Feb. 12, 2004 (Baltimore, Md.). The Cyp inhibition may be
measured as described by Miller V P, Stresser D M, Blanchard A P,
Turner S, Crespi C L: Fluorometric high-throughput screening for
inhibitors of cytochrome P450. Ann N Y Acad Sci 200; 919:26-32. In
one preferred embodiment, the compounds show hERG inhibition with
an IC.sub.50 greater than 1 .mu.M, preferably greater than 3 .mu.M,
and more preferably greater than 10 .mu.M. In another preferred
embodiment, the compounds show Cyp3A4 inhibition with an IC.sub.50
greater than 1 .mu.M, preferably greater than 3 .mu.M, and more
preferably greater than 10 .mu.M.
[0638] High hERG inhibition and Cyp3A4 inhibition is potentially
linked with adverse cardiac action potential and drug metabolism,
respectively.
[0639] According to a method aspect, the invention includes a
method for the treatment of a disorder of the central nervous
system (CNS) related to or affected by the 5HT6 receptor in a
patient in need thereof by administering to the patient a
therapeutically effective amount of a compound selected from
formula I, as described herein above.
[0640] The compounds can be administered as the sole active agent
or in combination with other pharmaceutical agents such as other
agents used in the treatment of CNS disorders, such as psychoses,
especially schizophrenia and bipolar disorder, obsessive-compulsive
disorder, Parkinson's disease, cognitive impairment and/or memory
loss, e.g., nicotinic .alpha.-7 agonists, PDE4 inhibitors, PDE10
inhibitors, other 5HT6 receptor ligands, calcium channel blockers,
muscarinic m1 and m2 modulators, adenosine receptor modulators,
ampakines, NMDA-R modulators, mGluR modulators, dopamine
modulators, serotonin modulators, canabinoid modulators, and
cholinesterase inhibitors (e.g., donepezil, rivastigimine, and
galanthanamine). In such combinations, each active ingredient can
be administered either in accordance with their usual dosage range
or in accordance with a dose below their usual dosage range.
[0641] The compounds can be administered in combination with other
pharmaceutical agents used in the treatment of schizophrenia, e.g.,
Clozaril, Zyprexa, Risperidone, and Seroquel. Thus, the invention
also includes methods for treating schizophrenia, including memory
impairment associated with schizophrenia, comprising administering
to a patient, simultaneously or sequentially, the compound of the
invention and one or more additional agents used in the treatment
of schizophrenia such as, but not limited to, Clozaril, Zyprexa,
Risperidone, and Seroquel. In methods using simultaneous
administration, the agents can be present in a combined composition
or can be administered separately. As a result, the invention also
includes compositions comprising a compound according to Formula I
and one or more additional pharmaceutical agents used in the
treatment of schizophrenia, e.g., Clozaril, Zyprexa, Risperidone,
and Seroquel. Similarly, the invention also includes kits
containing a composition comprising a compound according to Formula
I and another composition comprising one or more additional
pharmaceutical agents used in the treatment of schizophrenia, e.g.,
Clozaril, Zyprexa, Risperidone, and Seroquel.
[0642] In addition, the compounds can be administered in
combination with other pharmaceutical agents used in the treatment
bipolar disorder such as Lithium, Zyprexa, Depakote, and Zyprexa.
Thus, the invention also includes methods for treating bipolar
disorder, including treating memory and/or cognitive impairment
associated with the disease, comprising administering to a patient,
simultaneously or sequentially, the compound of the invention and
one or more additional agents used in the treatment of bipolar
disorder such as, but not limited to, Lithium, Zyprexa, and
Depakote. In methods using simultaneous administration, the agents
can be present in a combined composition or can be administered
separately. As a result, the invention also includes compositions
comprising a compound according to Formula I and one or more
additional pharmaceutical agents used in the treatment of bipolar
disorder such as, but not limited to, Lithium, Zyprexa, and
Depakote. Similarly, the invention also includes kits containing a
composition comprising a compound according to Formula I and
another composition comprising one or more additional
pharmaceutical agents used in the treatment of bipolar disorder
such as Lithium, Zyprexa, and Depakote.
[0643] In one preferred embodiment, the compounds of the invention
can be administered in combination with a nicotinic acetylcholine
subtype .alpha.-7 receptor ligand (.alpha.-7 receptor ligand).
Nicotinic acetylcholine subtype .alpha.-7 receptor ligands modulate
the function of nicotinic acetylcholine subtype .alpha.-7 receptors
by altering the activity of the receptor. Suitable compounds also
can be partial agonists that partially block or partially activate
the .alpha.-7 receptor or agonists that activate the receptor.
Positive allosteric modulators are compounds that potentiate the
receptor response to acetylcholine without themselves triggering
receptor activation or desensitization, or either, of the receptor.
Nicotinic acetylcholine subtype .alpha.7 receptor ligands that can
be combined with the 5HT6 ligand of the present invention can
include full agonists, partial agonists, or positive allosteric
modulators.
[0644] .alpha.-7 receptor ligands typically demonstrate K.sub.i
values from about 1 nM to about 10 .mu.M when tested by the
[.sup.3H]-MLA assay. Many having a binding value ("K.sub.i MLA") of
less than 1 .mu.M. According to one embodiment, [.sup.3H]-Cytisine
binding values ("K.sub.i Cyt") of the .alpha.-7 receptor ligand
range from about 50 nM to greater than 100 .mu.M. According to
another embodiment, preferred .alpha.-7 receptor ligands have K,
MLA value (as measured by MLA assay in view of the K.sub.i Cyt
value as measured by [.sup.3H]-cytisine binding, such that in the
formula D=K.sub.i Cyt/K.sub.i MLA) of at least 50. For example,
preferred compounds typically exhibit greater potency at .alpha.-7
receptors compared to .alpha.4.beta.2 receptors. Although the MLA
and [.sup.3H]-cytisine binding assays are well known, further
details for carrying out the assays are provided in International
Publication Nos. WO 2005/028477; WO 2005/066168; US 20050137184;
US20050137204; US20050245531; WO 2005/066166; WO 2005/066167; and
WO 2005/077899.
[0645] Positive allosteric modulators, at concentrations ranging
from 1 nM to 10 .mu.M, enhance responses of acetylcholine at
.alpha.-7 nicotinic receptors expressed endogenously in neurons or
cell lines, or via expression of recombinant protein in Xenopus
oocytes or in cell lines. .alpha.-7 receptor ligands can be used to
improve efficacy of 5HT6 ligands without exaggerating the side
effect profile of such agents.
[0646] Accordingly, .alpha.-7 receptor ligands that may be combined
with the 5HT6 ligand can be compounds of various chemical classes.
Particularly, some examples of .alpha.-7 receptor ligands suitable
for the invention include, but are not limited to,
diazabicycloalkane derivatives, for example as described in
International Publication No. WO 2005/028477; spirocyclic
quinuclidinic ether derivatives, for example as described in
International Publication No. WO 2005/066168; fused
bicycloheterocycle substituted quinuclidine derivatives, for
example as described in US Publication Nos. US20050137184;
US20050137204; and US20050245531; 3-quinuclidinyl aminosubstituted
biaryl derivatives, for example as described in International
Publication No. WO 2005/066166; 3-quinuclidinyl heteroatom-bridged
biaryl derivatives, for example as described in International
Publication No. WO 2005/066167; and aminosubstituted tricyclic
derivatives, for example as described in International Publication
No. WO 2005/077899, all of which are hereby incorporated by
reference in their entirety.
[0647] Examples of compounds reported as .alpha.-7 agonists or
partial agonists are quinuclidine derivatives, for example as
described in WO 2004/016608 and WO 2004/022556; and tilorone
derivatives, for example also as described in WO 2004/016608.
[0648] Examples of compounds reported as positive allosteric
modulators are 5-hydroxyindole analogs, for example as described in
WO 01/32619, WO 01/32620, and WO 01/32622; tetrahydroquinoline
derivatives, for examples as described in WO 04/098600;
amino-thiazole derivatives; and diarylurea derivatives, for example
as described in WO 04/085433.
[0649] Specific examples of compounds that are suitable neuronal
nicotinic subtype .alpha.-7 receptor ligands include, for example,
5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl)-1H-indole;
2-(6-phenylpyridazine-3-yl)octahydropyrrolo[3,4-c]pyrrole;
5-[5-{(1R,5R)-6-methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl}-pyridin-2-yl]-1-
H-indole; and
5-[6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl-1H-
-indole. Other suitable .alpha.-7 ligands are described in
WO2006/101745, which is hereby incorporated by reference.
[0650] Compounds modulating activity of nicotinic acetylcholine
receptor .alpha.-7 subtype are suitable for the invention
regardless of the manner in which they affect the receptor. Other
compounds reported as demonstrating .alpha.-7 activity include, but
are not limited to, quinuclidine amide derivatives, for example
PNU-282987, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide
TC-5619, varanicline, and others as described in WO 04/052894, and
MEM-3454. Additional compounds can include, but are not limited to,
AR R17779, AZD0328, WB-56203, SSR-180711A, GTS21, and OH-GTS-21,
which are all described in the publicly available literature.
[0651] The invention also includes methods for treating Parkinson's
disease, including treating memory and/or cognitive impairment
associated with Parkinson's disease, comprising administering to a
patient, simultaneously or sequentially, the compound of the
invention and one or more additional agents used in the treatment
of Parkinson's disease such as, but not limited to, Levodopa,
Parlodel, Permax, Mirapex, Tasmar, Contan, Kemadin, Artane, and
Cogentin. In methods using simultaneous administration, the agents
can be present in a combined composition or can be administered
separately. As a result, the invention also includes compositions
comprising a compound according to Formula I and one or more
additional pharmaceutical agents used in the treatment of
Parkinson's disease, such as, but not limited to, Levodopa,
Parlodel, Permax, Mirapex, Tasmar, Contan, Kemadin, Artane, and
Cogentin. Similarly, the invention also includes kits containing a
composition comprising a compound according to Formula I and
another composition comprising one or more additional
pharmaceutical agents gent used in the treatment of Parkinson's
disease such as, but not limited to, Levodopa, Parlodel, Permax,
Mirapex, Tasmar, Contan, Kemadin, Artane, and Cogentin.
[0652] In addition, the invention includes methods for treating
memory and/or cognitive impairment associated with Alzheimer's
disease comprising administering to a patient, simultaneously or
sequentially, the compound of the invention and one or more
additional agents used in the treatment of Alzheimer's disease such
as, but not limited to, Reminyl, Cognex, Aricept, Exelon, Akatinol,
Neotropin, Eldepryl, Estrogen and Cliquinol. In methods using
simultaneous administration, the agents can be present in a
combined composition or can be administered separately. As a
result, the invention also includes compositions comprising a
compound according to Formula I and one or more additional
pharmaceutical agents used in the treatment of Alzheimer's disease
such as, but not limited to, Reminyl, Cognex, Aricept, Exelon,
Akatinol, Neotropin, Eldepryl, Estrogen and Cliquinol. Similarly,
the invention also includes kits containing a composition
comprising a compound according to Formula I and another
composition comprising one or more additional pharmaceutical agents
used in the treatment of Alzheimer's disease such as, but not
limited to Reminyl, Cognex, Aricept, Exelon, Akatinol, Neotropin,
Eldepryl, Estrogen and Cliquinol.
[0653] Another aspect of the invention includes methods for
treating memory and/or cognitive impairment associated with
dementia comprising administering to a patient, simultaneously or
sequentially, the compound of the invention and one or more
additional agents used in the treatment of dementia such as, but
not limited to, Thioridazine, Haloperidol, Risperidone, Cognex,
Aricept, and Exelon. In methods using simultaneous administration,
the agents can be present in a combined composition or can be
administered separately. As a result, the invention also includes
compositions comprising a compound according to Formula I and one
or more additional pharmaceutical agents used in the treatment of
dementia such as, but not limited to, Thioridazine, Haloperidol,
Risperidone, Cognex, Aricept, and Exelon. Similarly, the invention
also includes kits containing a composition comprising a compound
according to Formula I and another composition comprising one or
more additional pharmaceutical agents used in the treatment of
dementia such as, but not limited to, Thioridazine, Haloperidol,
Risperidone, Cognex, Aricept, and Exelon.
[0654] A further aspect of the invention includes methods for
treating memory and/or cognitive impairment associated with
epilepsy comprising administering to a patient, simultaneously or
sequentially, the compound of the invention and one or more
additional agents used in the treatment of epilepsy such as, but
not limited to, Dilantin, Luminol, Tegretol, Depakote, Depakene,
Zarontin, Neurontin, Barbita, Solfeton, and Felbatol. In methods
using simultaneous administration, the agents can be present in a
combined composition or can be administered separately. As a
result, the invention also includes compositions comprising a
compound according to Formula I and one or more additional
pharmaceutical agents used in the treatment of epilepsy such as,
but not limited to, Dilantin, Luminol, Tegretol, Depakote,
Depakene, Zarontin, Neurontin, Barbita, Solfeton, and Felbatol.
Similarly, the invention also includes kits containing a
composition comprising a compound according to Formula I and
another composition comprising one or more additional
pharmaceutical agents used in the treatment of epilepsy such as,
but not limited to, Dilantin, Luminol, Tegretol, Depakote,
Depakene, Zarontin, Neurontin, Barbita, Solfeton, and Felbatol.
[0655] A further aspect of the invention includes methods for
treating memory and/or cognitive impairment associated with
multiple sclerosis comprising administering to a patient,
simultaneously or sequentially, the compound of the invention and
one or more additional agents used in the treatment of multiple
sclerosis such as, but not limited to, Detrol, Ditropan XL,
OxyContin, Betaseron, Avonex, Azothioprine, Methotrexate, and
Copaxone. In methods using simultaneous administration, the agents
can be present in a combined composition or can be administered
separately. As a result, the invention also includes compositions
comprising a compound according to Formula I and one or more
additional pharmaceutical agents used in the treatment of multiple
sclerosis such as, but not limited to, Detrol, Ditropan XL,
OxyContin, Betaseron, Avonex, Azothioprine, Methotrexate, and
Copaxone. Similarly, the invention also includes kits containing a
composition comprising a compound according to Formula I and
another composition comprising one or more additional
pharmaceutical agents used in the treatment of multiple sclerosis
such as, but not limited to, Detrol, Ditropan XL, OxyContin,
Betaseron, Avonex, Azothioprine, Methotrexate, and Copaxone.
[0656] The invention further includes methods for treating
Huntington's disease, including treating memory and/or cognitive
impairment associated with Huntington's disease, comprising
administering to a patient, simultaneously or sequentially, the
compound of the invention and one or more additional agents used in
the treatment of Huntington's disease such as, but not limited to,
Amitriptyline, Imipramine, Despiramine, Nortriptyline, Paroxetine,
Fluoxetine, Setraline, Terabenazine, Haloperidol, Chloropromazine,
Thioridazine, Sulpride, Quetiapine, Clozapine, and Risperidone. In
methods using simultaneous administration, the agents can be
present in a combined composition or can be administered
separately. As a result, the invention also includes compositions
comprising a compound according to Formula I and one or more
additional pharmaceutical agents used in the treatment of
Huntington's disease such as, but not limited to, Amitriptyline,
Imipramine, Despiramine, Nortriptyline, Paroxetine, Fluoxetine,
Setraline, Terabenazine, Haloperidol, Chloropromazine,
Thioridazine, Sulpride, Quetiapine, Clozapine, and Risperidone.
Similarly, the invention also includes kits containing a
composition comprising a compound according to Formula I and
another composition comprising one or more additional
pharmaceutical agents used in the treatment of Huntington's disease
such as, but not limited to, Amitriptyline, Imipramine,
Despiramine, Nortriptyline, Paroxetine, Fluoxetine, Setraline,
Terabenazine, Haloperidol, Chloropromazine, Thioridazine, Sulpride,
Quetiapine, Clozapine, and Risperidone.
[0657] Indications that may be treated with 5HT6 ligands, either
alone or in combination with other drugs, include, but are not
limited to, those diseases thought to be mediated in part by the
basal ganglia, prefrontal cortex and hippocampus. These indications
include psychoses, Parkinson's disease, dementias, obsessive
compulsion disorder, tardive dyskinesia, choreas, depression, mood
disorders, impulsivity, drug addiction, attention
deficit/hyperactivity disorder (ADHD), depression with parkinsonian
states, personality changes with caudate or putamen disease,
dementia and mania with caudate and pallidal diseases, and
compulsions with pallidal disease.
[0658] Psychoses are disorders that affect an individual's
perception of reality. Psychoses are characterized by delusions and
hallucinations. The present invention includes methods for treating
patients suffering from all forms of psychoses, including but not
limited to schizophrenia, late-onset schizophrenia, schizoaffective
disorders, prodromal schizophrenia, and bipolar disorders.
Treatment may be for the positive symptoms of schizophrenia as well
as for the cognitive deficits and negative symptoms. Other
indications for 5HT6 ligands include psychoses resulting from drug
abuse (including amphetamines and PCP), encephalitis, alcoholism,
epilepsy, Lupus, sarcoidosis, brain tumors, multiple sclerosis,
dementia with Lewy bodies, or hypoglycemia. Other psychiatric
disorders, like posttraumatic stress disorder (PTSD), and schizoid
personality may also be treated with 5HT6 ligands.
[0659] Dementias are diseases that include memory loss and
additional intellectual impairment separate from memory. The
present invention includes methods for treating patients suffering
from memory impairment in all forms of dementia. Dementias are
classified according to their cause and include: neurodegenerative
dementias (e.g., Alzheimer's, Parkinson's disease, Huntington's
disease, Pick's disease), vascular (e.g., infarcts, hemorrhage,
cardiac disorders), mixed vascular and Alzheimer's, bacterial
meningitis, Creutzfeld-Jacob Disease, multiple sclerosis, traumatic
(e.g., subdural hematoma or traumatic brain injury), infectious
(e.g., HIV), genetic (Down syndrome), toxic (e.g., heavy metals,
alcohol, some medications), metabolic (e.g., vitamin B12 or folate
deficiency), CNS hypoxia, Cushing's disease, psychiatric (e.g.,
depression and schizophrenia), and hydrocephalus.
[0660] The condition of memory impairment is manifested by
impairment of the ability to learn new information and/or the
inability to recall previously learned information. The present
invention includes methods for dealing with memory loss separate
from dementia, including mild cognitive impairment (MCI) and
age-related cognitive decline. The present invention includes
methods of treatment for memory impairment as a result of disease.
Memory impairment is a primary symptom of dementia and can also be
a symptom associated with such diseases as Alzheimer's disease,
schizophrenia, Parkinson's disease, Huntington's disease, Pick's
disease, Creutzfeld-Jakob disease, HIV, cardiovascular disease, and
head trauma as well as age-related cognitive decline. In another
application, the invention includes methods for dealing with memory
loss resulting from the use of general anesthetics, chemotherapy,
radiation treatment, post-surgical trauma, and therapeutic
intervention. Thus, in accordance with a preferred embodiment, the
present invention includes methods of treating patients suffering
from memory impairment due to, for example, Alzheimer's disease,
multiple sclerosis, amylolaterosclerosis (ALS), multiple systems
atrophy (MSA), schizophrenia, Parkinson's disease, Huntington's
disease, Pick's disease, Creutzfeld-Jakob disease, depression,
aging, head trauma, stroke, spinal cord injury, CNS hypoxia,
cerebral senility, diabetes associated cognitive impairment, memory
deficits from early exposure of anesthetic agents, multiinfarct
dementia and other neurological conditions including acute neuronal
diseases, as well as HIV and cardiovascular diseases. The invention
also relates to agents and/or methods to stimulate the formation of
memory in "normal" subjects (i.e., subjects who do not exhibit an
abnormal or pathological decrease in a memory function), e.g.,
ageing middle-aged subjects.
[0661] The invention is also suitable for use in the treatment of a
class of disorders known as polyglutamine-repeat diseases. These
diseases share a common pathogenic mutation. The expansion of a CAG
repeat, which encodes the amino acid glutamine, within the genome
leads to production of a mutant protein having an expanded
polyglutamine region. For example, Huntington's disease has been
linked to a mutation of the protein huntingtin. In individuals who
do not have Huntington's disease, huntingtin has a polyglutamine
region containing about 8 to 31 glutamine residues. For individuals
who have Huntington's disease, huntingtin has a polyglutamine
region with over 37 glutamine residues. Aside from Huntington's
disease (HD), other known polyglutamine-repeat diseases and the
associated proteins are: dentatorubral-pallidoluysian atrophy,
DRPLA (atrophin-1); spinocerebellar ataxia type-1 (ataxin-1);
spinocerebellar ataxia type-2 (ataxin-2); spinocerebellar ataxia
type-3 also called Machado-Joseph disease, MJD (ataxin-3);
spinocerebellar ataxia type-6 (alpha 1a-voltage dependent calcium
channel); spinocerebellar ataxia type-7 (ataxin-7); and spinal and
bulbar muscular atrophy, SBMA, also know as Kennedy disease
(androgen receptor). Thus, in accordance with a further aspect of
the invention, there is provided a method of treating a
polyglutamine-repeat disease or CAG repeat expansion disease
comprising administering to a patient, such as a mammal, especially
a human, a therapeutically effective amount of a compound. In
accordance with a further embodiment, there is provided a method of
treating Huntington's disease (HD), dentatorubral-pallidoluysian
atrophy (DRPLA), spinocerebellar ataxia type-1, spinocerebellar
ataxia type-2, spinocerebellar ataxia type-3 (Machado-Joseph
disease), spinocerebellar ataxia type-6, spinocerebellar ataxia
type-7, or spinal and bulbar muscular atrophy, comprising
administering to a patient, such as a mammal, especially a human, a
therapeutically effective amount of a compound of the
invention.
[0662] The basal ganglia are important for regulating the function
of motor neurons; disorders of the basal ganglia result in movement
disorders. Most prominent among the movement disorders related to
basal ganglia function is Parkinson's disease (Obeso J A et al.,
Neurology., 2004 Jan. 13; 62(1 Suppl 1):S17-30). Other movement
disorders related to dysfunction of the basla ganglia include
tardive dyskinesia, progressive supranuclear palsy and cerebral
palsy, corticobasal degeneration, multiple system atrophy, Wilson
disease, and dystonia, tics, and chorea. In one embodiment, the
compounds of the invention may be used to treat movement disorders
related to dysfunction of basal ganglia neurons.
[0663] The dosages of the compounds of the present invention depend
upon a variety of factors including the particular syndrome to be
treated, the severity of the symptoms, the route of administration,
the frequency of the dosage interval, the particular compound
utilized, the efficacy, toxicology profile, pharmacokinetic profile
of the compound, and the presence of any deleterious side-effects,
among other considerations. One of ordinary skill in the art of
treating such diseases will be able, without undue experimentation
and in reliance upon personal knowledge and the disclosure of this
Application, to ascertain a therapeutically effective amount of the
compounds of the present invention for a given disease.
[0664] The compounds of the invention are typically administered at
dosage levels and in a mammal customary for 5HT6 ligands, such as
those known compounds mentioned above. For example, the compounds
can be administered, in single or multiple doses, by oral
administration at a dosage level of generally 0.001-100 mg/kg/day,
for example, 0.01-100 mg/kg/day, preferably 0.1-70 mg/kg/day,
especially 0.5-10 mg/kg/day. Unit dosage forms can contain
generally 0.01-1000 mg of active compound, for example, 0.1-50 mg
of active compound. For intravenous administration, the compounds
can be administered, in single or multiple dosages, at a dosage
level of, for example, 0.001-50 mg/kg/day, preferably 0.001-10
mg/kg/day, especially 0.01-1 mg/kg/day. Unit dosage forms can
contain, for example, 0.1-10 mg of active compound.
[0665] In carrying out the procedures of the present invention, it
is of course to be understood that reference to particular buffers,
media, reagents, cells, culture conditions and the like are not
intended to be limiting, but are to be read so as to include all
related materials that one of ordinary skill in the art would
recognize as being of interest or value in the particular context
in which that discussion is presented. For example, it is often
possible to substitute one buffer system or culture medium for
another and still achieve similar, if not identical, results. Those
of skill in the art will have sufficient knowledge of such systems
and methodologies so as to be able, without undue experimentation,
to make such substitutions as will optimally serve their purposes
in using the methods and procedures disclosed herein.
[0666] The present invention will now be further described by way
of the following non-limiting examples. In applying the disclosure
of these examples, it should be kept clearly in mind that other and
different embodiments of the methods disclosed according to the
present invention will no doubt suggest themselves to those of
skill in the relevant art.
[0667] In the foregoing and in the following examples, all
temperatures are set forth uncorrected in degrees Celsius; and,
unless otherwise indicated, all parts and percentages are by
weight.
[0668] The entire disclosures of all applications, patents and
publications, cited above and below, are hereby incorporated by
reference in their entirety.
EXAMPLES
[0669] All spectra were recorded at 300 MHz on a Bruker Instruments
NMR unless otherwise stated. Coupling constants (J) are in Hertz
(Hz) and peaks are listed relative to TMS (.delta. 0.00 ppm).
[0670] Analytical HPLC was performed on 4.0 mm.times.50 mm WATERS
YMC ODS-A Cartridge 120A S3u 4 column using (i) a gradient of 0/100
to 100/0 acetonitrile (0.05% TFA)/water (0.05% TFA) over 4 min (for
all compounds except
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3-
,6-tetrahydropyridin-4-yl)-1H-indole, or (ii) a 4.6 mm.times.100 mm
Waters Sunfire RP C18 5 mm column using a gradient of 20/80 to
80/20 acetonitrile (0.1% formic acid)/water (0.1% formic acid) over
8 min (for
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-indole).
[0671] Preparative HPLC was performed on 30 mm.times.100 mm Xterra
Prep RP.sub.18 5.mu. columns using an 8 min gradient of 95/5 to
20/80 water (0.1% formic acid)/acetonitrile (0.1% formic acid).
General Procedure A
Synthesis of
5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-
-indole
##STR00112##
[0672] 1) Synthesis of
5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole
[0673] A solution of KOH (6.7 g, 118.45 mmol) in methanol (60 mL)
was added to 5-bromo-1H-indole (10 g, 50.51 mmol) in a 250 mL
3-necked round bottom flask. 1-methylpiperidin-4-one (7.7 g, 67.46
mmol) was then added dropwise with stirring, while cooling to a
temperature of 20.degree. C. The resulting solution was allowed to
react, with stirring, for 4 hours while the temperature was
maintained at 73.degree. C. The reaction mixture was then cooled to
15.degree. C. and filtered. The filter cake was washed with water
(3.times.50 mL). The product was purified by recrystallization from
ethanol to afford 12.3 g (83%) of
5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole as a
white solid.
2) Synthesis of
5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-
-indole
[0674] NaH (600 mg, 15.00 mmol) was added (in several batches) to a
solution of
5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (3 g,
9.79 mmol) in DMF (60 mL) while cooling to a temperature of
0-5.degree. C. The resulting solution was stirred for 1 hour while
the temperature was maintained at room temperature. Benzenesulfonyl
chloride (2.3 g, 12.89 mmol) was then added dropwise and the
reaction was stirred for an additional 4 hours at room temperature.
After filtration, the filter cake was washed with ethanol
(2.times.50 mL) and the resulting solid was dried to afford 0.4 g
(10%) of
5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-
-indole as a white solid. .sup.1H NMR (DMSO) .delta. 8.04 (4H),
7.95 (1H), 7.73 (1H), 7.32-7.63 (3H), 6.29 (s, 1H), 3.98 (2H), 3.68
(2H), 2.72-2.89 (511). m/z 434.1 (M.sup.++1)
Split Patterns Needed Above
[0675] Using this general procedure, the following compounds were
prepared using different starting materials:
[0676] 2)
N-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl-
]sulfonyl}phenyl)acetamide, LC/MS (EI) t.sub.R 1.87, m/z 410.2
(M.sup.++1)
[0677] 3)
N-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,-
3-b]pyridin-1-yl]sulfonyl}phenyl)acetamide, LC/MS (EI) t.sub.R
1.69, m/z 411.2 (M.sup.++1)
[0678] 4)
N-(4-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-i-
ndol-1-yl]sulfonyl}phenyl)acetamide, LC/MS (EI) t.sub.R 1.87, m/z
428.1 (M.sup.++1)
[0679] 5)
N-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluorom-
ethyl)-1H-indol-1-yl]sulfonyl}phenyl)acetamide, LC/MS (EI) t.sub.R
1.94, m/z 178.2 (M.sup.++1)
[0680] 6)
1-(2,3-dihydro-1-benzofuran-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-te-
trahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 1.97, m/z 395.2
(M.sup.++1)
[0681] 7)
1-(2,3-dihydro-1-benzofuran-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-te-
trahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, LC/MS (EI) t.sub.R
1.83, m/z 396.2 (M.sup.++1)
[0682] 8)
1-(2,3-dihydro-1-benzofuran-5-ylsulfonyl)-5-fluoro-3-(1-methyl-1-
,2,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 1.97,
m/z 413.2 (M.sup.++1)
[0683] 9)
1-(2,3-dihydro-1-benzofuran-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-te-
trahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI)
t.sub.R 2.04, m/z 463.2 (M.sup.++1)
[0684] 10)
1-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylsulfonyl)-3-(1-methyl-1-
,2,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 1.97,
m/z 425.2 (M.sup.++1)
[0685] 11)
1-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylsulfonyl)-3-(1-methyl-1-
,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, LC/MS
(EI) t.sub.R 1.81, m/z 426.2 (M.sup.++1)
[0686] 12)
1-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylsulfonyl)-5-fluoro-3-(1-
-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI)
t.sub.R 2.01, m/z 443.2 (M.sup.++1)
[0687] 13)
1-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylsulfonyl)-3-(1-methyl-1-
,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS
(EI) t.sub.R 2.08, m/z 493.2 (M.sup.++1)
[0688] 14)
1-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)sulfonyl]-3-(1-methyl-1,-
2,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.11,
m/z 450.2 (M.sup.++1)
[0689] 15)
1-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)sulfonyl]-3-(1-methyl-1,-
2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, LC/MS (EI)
t.sub.R 2.01, m/z 451.2 (M.sup.++1)
[0690] 16)
5-fluoro-1-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)sulfonyl]-3-(1--
methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI)
t.sub.R 2.11, m/z 468.2 (M.sup.++1)
[0691] 17)
1-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)sulfonyl]-3-(1-methyl-1,-
2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS
(EI) t.sub.R 2.22, m/z 518.2 (M.sup.++1)
[0692] 18)
1-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 1.97,
m/z 433.3 (M.sup.++1)
[0693] 19)
1-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, LC/MS (EI)
t.sub.R 1.87, m/z 434.2 (M.sup.++1)
[0694] 20)
5-fluoro-1-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-m-
ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R
2.01, m/z 451.2 (M.sup.++1)
[0695] 21)
1-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS
(EI) t.sub.R 2.08, m/z 501.2 (M.sup.++1)
[0696] 22)
1-(1-benzothien-2-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyr-
idin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.04, m/z 409.1
(M.sup.++1)
[0697] 23)
1-(1-benzothien-2-ylsulfonyl)-5-fluoro-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.04, m/z 427.1
(M.sup.++1)
[0698] 24)
1-(1-benzothien-2-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyr-
idin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI) t.sub.R 2.11,
m/z 477.1 (M.sup.++1)
[0699] 25)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-([1-methyl-3-(tri-
fluoromethyl)-1H-pyrazol-4-yl]sulfonyl)-1H-indole, LC/MS (EI)
t.sub.R 1.94, m/z 425.2 (M.sup.++1)
[0700] 26)
5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-{[1-meth-
yl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}-1H-indole, LC/MS
(EI) t.sub.R 1.97, m/z 443.2 (M.sup.++1)
[0701] 27)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-{[1-methyl-3-(tri-
fluoromethyl)-1H-pyrazol-4-yl]sulfonyl}-5-(trifluoromethyl)-1H-indole,
LC/MS (EI) t.sub.R 2.01, m/z 493.2 (M.sup.++1)
[0702] 28) methyl
5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]sulfonyl}-2-
-furoate, LC/MS (EI) t.sub.R 1.90, m/z 401.2 (M.sup.++1)
[0703] 29) methyl
5-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-2-furoate, LC/MS (EI) t.sub.R 1.94, m/z 419.1
(M.sup.++1)
[0704] 30) methyl
5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-in-
dol-1-yl]sulfonyl}-2-furoate, LC/MS (EI) t.sub.R 2.01, m/z 469.2
(M.sup.++1)
[0705] 31) methyl
5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin--
1-yl]sulfonyl}-2-furoate, LC/MS (EI) t.sub.R 1.80, m/z 402.1
(M.sup.++1)
[0706] 32)
1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tet-
rahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 1.83, m/z 357.2
(M.sup.++1)
[0707] 33) 5-fluoro-1-[(1-methyl-1H-imidazol-4-yl)
sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole,
LC/MS (EI) t.sub.R 1.83, m/z 375.2 (M.sup.++1)
[0708] 34)
1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tet-
rahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI)
t.sub.R 1.90, m/z 425.2 (M.sup.++1)
[0709] 35)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methyl-1,2,3,-
6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, LC/MS (EI)
t.sub.R 1.83, m/z 412.2 (M.sup.++1)
[0710] 36)
1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-
-tetrahydropyridin-4-yl)-1H-indazole, LC/MS (EI) t.sub.R 1.83, m/z
372.2 (M.sup.++1)
[0711] 37)
1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-5-fluoro-3-(1-methy-
l-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole, LC/MS (EI) t.sub.R
1.83, m/z 390.2 (M.sup.++1)
[0712] 38)
1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-
-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indazole, LC/MS
(EI) t.sub.R 1.94, m/z 440.4 (M.sup.++1)
[0713] 39)
1-[(2,5-dimethyl-3-furyl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 1.97, m/z 371.1
(M.sup.++1)
[0714] 40)
1-[(2,5-dimethyl-3-furyl)sulfonyl]-5-fluoro-3-(1-methyl-1,2,3,6-
-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 1.97, m/z
389.1 (M.sup.++1)
[0715] 41)
1-[(2,5-dimethyl-3-furyl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI) t.sub.R
2.04, m/z 439.7 (M.sup.++1)
[0716] 42)
1-(1-benzothien-3-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyr-
idin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.01, m/z 409.0
(M.sup.++1)
[0717] 43)
1-(1-benzothien-3-ylsulfonyl)-5-fluoro-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.01, m/z 427.4
(M.sup.++1)
[0718] 44)
1-(1-benzothien-3-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyr-
idin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI) t.sub.R 2.08,
m/z 477.0 (M.sup.++1)
[0719] 45)
1-(1,3-benzodioxol-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydro-
pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, LC/MS (EI) t.sub.R 1.83,
m/z 398.4 (M.sup.++1)
[0720] 46)
1-(1-benzofuran-2-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyr-
idin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.08, m/z 393.4
(M.sup.++1)
[0721] 47)
1-(1-benzofuran-2-ylsulfonyl)-5-fluoro-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.08, m/z 411.4
(M.sup.++1)
[0722] 48)
1-(1-benzofuran-2-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyr-
idin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI) t.sub.R 2.15,
m/z 461.4 (M.sup.++1)
[0723] 49)
1-{[3-(2-methylpyrimidin-4-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,-
3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.01, m/z
445.5 (M.sup.++1)
[0724] 50)
5-fluoro-1-{[3-(2-methylpyrimidin-4-yl)phenyl]sulfonyl}-3-(1-me-
thyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R
2.01, m/z 463.5 (M.sup.++1)
[0725] 51)
1-{[3-(2-methylpyrimidin-4-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,-
3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS
(EI) t.sub.R 2.08, m/z 513.4 (M.sup.++1)
[0726] 52)
1-{[3-(2-methylpyrimidin-4-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,-
3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, LC/MS (EI)
t.sub.R 1.90, m/z 446.4 (M.sup.++1)
[0727] 53)
1-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tet-
rahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 1.95, m/z 372.0
(M.sup.++1)
[0728] 54)
1-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,-
2,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 1.98,
m/z 390.4 (M.sup.++1)
[0729] 55)
1-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tet-
rahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI)
t.sub.R 2.08, m/z 440.0 (M.sup.++1)
[0730] 56)
6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]s-
ulfonyl}-1,3-benzothiazole, LC/MS (EI) t.sub.R 1.95, m/z 410.0
(M.sup.++1)
[0731] 57)
6-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-ind-
ol-1-yl]sulfonyl}-1,3-benzothiazole, LC/MS (EI) t.sub.R 1.97, m/z
428 (M.sup.++1)
[0732] 58)
6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromet-
hyl)-1H-indol-1-yl]sulfonyl}-1,3-benzothiazole, LC/MS (EI) t.sub.R
2.04, m/z 478.6 (M.sup.++1)
[0733] 59)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(1,3,5-trimethyl-
-1H-pyrazol-4-yl)sulfonyl]-1H-indole, LC/MS (EI) t.sub.R 1.90, m/z
385.5 (M.sup.++1)
[0734] 60)
5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(1,3,5--
trimethyl-1H-pyrazol-4-yl)sulfonyl]-1H-indole, LC/MS (EI) t.sub.R
1.94, m/z 403.4 (M.sup.++1)
[0735] 61)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-
-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]-1H-indole, LC/MS
(EI) t.sub.R 2.01, m/z 453.4 (M.sup.++1)
[0736] 62)
1-[(4-chloro-1,2-dimethyl-1H-pyrrol-3-yl)sulfonyl]-3-(1-methyl--
1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R
X1.94, m/z 404.7 (M.sup.++1)
[0737] 63)
1-[(4-chloro-1,2-dimethyl-1H-pyrrol-3-yl)sulfonyl]-5-fluoro-3-(-
1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI)
t.sub.R 1.97, m/z 422.6 (M.sup.++1)
[0738] 64)
1-[(4-chloro-1,2-dimethyl-1H-pyrrol-3-yl)sulfonyl]-3-(1-methyl--
1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole,
LC/MS (EI) t.sub.R 2.04, m/z 472.8 (M.sup.++1)
[0739] 65)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,-
2,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 3.60,
m/z 436 (M.sup.++1)
[0740] 66)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-fluoro-3-(1--
methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI)
t.sub.R 3.12, m/z 454.0 (M.sup.++1)
[0741] 67)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,-
2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS
(EI) t.sub.R 3.13, m/z 504.0 (M.sup.++1)
[0742] 68)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,-
2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, LC/MS (EI)
t.sub.R 2.85, m/z 437.0 (M.sup.++1)
[0743] 69)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(6-morpholin-4-y-
lpyridin-3-yl)sulfonyl]-1H-indole, LC/MS (EI) t.sub.R 2.30, m/z
439.0 (M.sup.++1)
[0744] 70)
5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(6-morp-
holin-4-ylpyridin-3-yl)sulfonyl]-1H-indole, LC/MS (EI) t.sub.R
2.32, m/z 457.0 (M.sup.++1)
[0745] 71)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(6-morpholin-4-y-
lpyridin-3-yl)sulfonyl]-5-(trifluoromethyl)-1H-indole, LC/MS (EI)
t.sub.R 2.48, m/z 507.0 (M.sup.++1)
[0746] 72)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(6-morpholin-4-y-
lpyridin-3-yl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine, LC/MS (EI)
t.sub.R 1.95, m/z 440.0 (M.sup.++1)
[0747] 73)
1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetra-
hydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.06, m/z 394.0
(M.sup.++1)
[0748] 74)
1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-5-fluoro-3-(1-methyl-1,2,-
3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.09, m/z
412.0 (114'41)
[0749] 75)
1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetra-
hydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI)
t.sub.R 2.13, m/z 395.0 (M.sup.++1)
[0750] 76)
1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetra-
hydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, LC/MS (EI) t.sub.R
1.92, m/z 395.0 (M.sup.++1)
[0751] 82)
4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromet-
hyl)-1H-indol-1-yl]sulfonyl}aniline, LC/MS (EI) t.sub.R 2.09, m/z
436.0 (M.sup.++1)
[0752] 83)
4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3--
b]pyridin-1-yl]sulfonyl}aniline, LC/MS (EI) t.sub.R 1.85, m/z 369.0
(M.sup.++1)
[0753] 87)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-morpholin-4-y-
lphenyl)sulfonyl]-1H-indole, LC/MS (EI) t.sub.R 2.06, m/z 438.0
(M.sup.++1)
[0754] 88)
5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-morp-
holin-4-ylphenyl)sulfonyl]-1H-indole, LC/MS (EI) t.sub.R 2.06, m/z
456.0 (M.sup.++1)
[0755] 89)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-morpholin-4-y-
lphenyl)sulfonyl]-5-(trifluoromethyl)-1H-indole, LC/MS (EI) t.sub.R
2.16, m/z 506.0 (M.sup.++1)
[0756] 90)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-morpholin-4-y-
lphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine, LC/MS (EI) t.sub.R
1.95, m/z 439.0 (M.sup.++1)
[0757] 91)
N,N-dimethyl-4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-
-indol-1-yl]sulfonyl}aniline, LC/MS (EI) t.sub.R 2.13, m/z 396.0
(M.sup.++1)
[0758] 92)
4-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-ind-
ol-1-yl]sulfonyl}-N,N-dimethylaniline, LC/MS (EI) t.sub.R 2.13, m/z
414.0 (M.sup.++1)
[0759] 93)
N,N-dimethyl-4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5--
(trifluoromethyl)-1H-indol-1-yl]sulfonyl}aniline, LC/MS (EI)
t.sub.R 2.16, m/z 464.0 (M.sup.++1)
[0760] 94)
N,N-dimethyl-4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-
-pyrrolo[2,3-b]pyridin-1-yl]sulfonyl}aniline, LC/MS (EI) t.sub.R
1.99, m/z 397.0 (M.sup.++1)
[0761] 95)
N,N-dimethyl-3-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-
-indol-1-yl]sulfonyl}aniline, LC/MS (EI) t.sub.R 2.13, m/z 396.0
(M.sup.++1)
[0762] 96)
3-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-ind-
ol-1-yl]sulfonyl}-N,N-dimethylaniline, LC/MS (EI) t.sub.R 2.16, m/z
414.0 (M.sup.++1)
[0763] 97)
N,N-dimethyl-3-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5--
(trifluoromethyl)-1H-indol-1-yl]sulfonyl}aniline, LC/MS (EI)
t.sub.R 2.20, m/z 464.0 (M.sup.++1)
[0764] 98)
N,N-dimethyl-3-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-
-pyrrolo[2,3-b]pyridin-1-yl]sulfonyl}aniline, LC/MS (EI) t.sub.R
1.99, m/z 397.0 (M.sup.++1)
[0765] 107)
1-[(1-methyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.14, m/z 408.0
(M.sup.++1)
[0766] 108)
5-fluoro-1-[(1-methyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.13,
ink 426.0 (M.sup.++1)
[0767] 109)
1-[(1-methyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI)
t.sub.R 2.23, m/z 476.0 (M.sup.++1)
[0768] 110)
1-[(1-methyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, LC/MS (EI) t.sub.R
1.99, m/z 409.0 (M.sup.++1)
[0769] 111)
1-[(1-ethyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetra-
hydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.16, m/z 422.0
(M.sup.++1)
[0770] 112)
1-[(1-ethyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2,-
3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.20, m/z
440.0 (M.sup.++1)
[0771] 113)
1-[(1-ethyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetra-
hydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI)
t.sub.R 2.27, m/z 490.0 (M.sup.++1)
[0772] 114)
1-[(1-ethyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetra-
hydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, LC/MS (EI) t.sub.R
2.06, m/z 423.0 (M.sup.++1)
[0773] 115)
N-methyl-N-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl-
]sulfonyl}phenyl)acetamide, LC/MS (EI) t.sub.R 2.02, m/z 424
(M.sup.++1)
[0774] 116)
N-(4-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl-
]sulfonyl}phenyl)-N-methylacetamide, LC/MS (EI) t.sub.R 2.02, m/z
441.5 (M.sup.++1)
[0775] 117)
N-methyl-N-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluorom-
ethyl)-1H-indol-1-yl]sulfonyl}phenyl)acetamide, LC/MS (EI) t.sub.R
2.13, m/z 492 (M.sup.++1)
[0776] 118)
N-methyl-N-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,-
3-b]pyridin-1-yl]sulfonyl}phenyl)acetamide, LC/MS (EI) t.sub.R
1.95, m/z 425 (M.sup.++1)
[0777] 119)
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]sulfonyl}-1-
,2,3,4-tetrahydroquinoline, LC/MS (EI) t.sub.R 2.13, m/z 408
(M.sup.++1)
[0778] 120)
7-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-1,2,3,4-tetrahydroquinoline, LC/MS (EI) t.sub.R 2.20, m/z
426 (M.sup.++1)
[0779] 121)
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-in-
dol-1-yl]sulfonyl}-1,2,3,4-tetrahydroquinoline, LC/MS (EI) t.sub.R
2.23, m/z 476 (M.sup.++1)
[0780] 122)
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin--
1-yl]sulfonyl}-1,2,3,4-tetrahydroquinoline, LC/MS (EI) t.sub.R
2.09, m/z 409 (M.sup.++1)
[0781] 123)
1-methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-1,2,3,4-tetrahydroquinoline, LC/MS (EI) t.sub.R 2.27, m/z
422 (M.sup.++1)
[0782] 124)
7-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-1-methyl-1,2,3,4-tetrahydroquinoline, LC/MS (EI) t.sub.R
2.27, m/z 440 (M.sup.++1)
[0783] 125)
1-methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluorometh-
yl)-1H-indol-1-yl]sulfonyl}-1,2,3,4-tetrahydroquinoline, LC/MS (EI)
t.sub.R 2.34, m/z 490 (M.sup.++1)
[0784] 126)
1-methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b-
]pyridin-1-yl]sulfonyl}-1,2,3,4-tetrahydroquinoline, LC/MS (EI)
t.sub.R 2.13, m/z 423 (M.sup.++1)
[0785] 127)
1-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-1,2,3,4-tetrahydroquinoline, LC/MS (EI) t.sub.R 2.20, m/z
422 (M.sup.++1)
[0786] 128)
6-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-1-methyl-1,2,3,4-tetrahydroquinoline, LC/MS (EI) t.sub.R
2.20, m/z 440 (M.sup.++1)
[0787] 129)
1-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluorometh-
yl)-1H-indol-1-yl]sulfonyl}-1,2,3,4-tetrahydroquinoline, LC/MS (EI)
t.sub.R 2.27, m/z 490 (M.sup.++1)
[0788] 130)
1-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b-
]pyridin-1-yl]sulfonyl}-1,2,3,4-tetrahydroquinoline, LC/MS (EI)
t.sub.R2.06, m/z 423 (M.sup.++1)
[0789] 131)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-pyrrolidin-1-ylphenyl)s-
ulfonyl]-1H-indole, LC/MS (EI) t.sub.R 2.20, m/z 422
(M.sup.++1)
[0790] 132)
5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-pyrrolidin-1-y-
lphenyl)sulfonyl]-1H-indole, LC/MS (EI) t.sub.R 2.20, m/z 440
(M.sup.++1)
[0791] 133)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-pyrrolidin-1-ylphenyl)s-
ulfonyl]-5-(trifluoromethyl)-1H-indole, LC/MS (EI) t.sub.R 2.27,
m/z 490 (M.sup.++1)
[0792] 134)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(4-pyrrolidin-1-ylphenyl)s-
ulfonyl]-1,1-Pyrrolo[2,3-b]pyridine, LC/MS (EI) t.sub.R 2.09, m/z
423 (M.sup.++1)
[0793] 135)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(3-pyrrolidin-1-ylphenyl)s-
ulfonyl]-1H-indole, LC/MS (EI) t.sub.R 2.23, m/z 422
(M.sup.++1)
[0794] 136)
5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(3-pyrrolidin-1-y-
lphenyl)sulfonyl]-1H-indole, LC/MS (EI) t.sub.R 2.20, m/z 440
(M.sup.++1)
[0795] 137)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(3-pyrrolidin-1-ylphenyl)s-
ulfonyl]-5-(trifluoromethyl)-1H-indole, LC/MS (EI) t.sub.R 2.30,
m/z 490 (M.sup.++1)
[0796] 138)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(3-pyrrolidin-1-ylphenyl)s-
ulfonyl]-1H-pyrrolo[2,3-b]pyridine, LC/MS (EI) t.sub.R 2.09, m/z
423 (M.sup.++1)
[0797] 139)
1-[(1-ethyl-3-methyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrah-
ydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.06, m/z 385
(M.sup.++1)
[0798] 140)
1-[(1-ethyl-3-methyl-1H-pyrazol-4-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2,3-
,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.09, m/z
403 (M.sup.++1)
[0799] 141)
1-[(1-ethyl-3-methyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrah-
ydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI) t.sub.R
2.16, m/z 453 (M.sup.++1)
[0800] 142)
1-{[1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]sulfonyl}-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.09,
m/z 407 (M.sup.++1)
[0801] 143)
1-{[1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]sulfonyl}-5-fluoro-3-(1-m-
ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R
2.09, m/z 425 (M.sup.++1)
[0802] 144)
1-{[1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]sulfonyl}-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS
(EI) t.sub.R 2.13, m/z 475 (M.sup.++1)
[0803] 145)
1-[(1-ethyl-5-methyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrah-
ydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.09, m/z 385
(M.sup.++1)
[0804] 146)
1-[(1-ethyl-5-methyl-1H-pyrazol-4-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2,3-
,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.09, m/z
403 (M.sup.1+1)
[0805] 147)
1-[(1-ethyl-5-methyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrah-
ydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI) t.sub.R
2.13, m/z 453 (M.sup.++1)
[0806] 148)
1-[(1-ethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyrid-
in-4-yl)-1H-indole, LC/MS (EI) t.sub.R 1.99, m/z 371
(M.sup.++1)
[0807] 149)
1-[(1-ethyl-1H-pyrazol-4-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2,3,6-tetrah-
ydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.it 2.02, m/z 389
(M.sup.1+1)
[0808] 150)
1-[(1-ethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyrid-
in-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI) t.sub.R 2.09,
m/z 439 (M.sup.++1)
[0809] 151)
1-[(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-te-
trahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.03, m/z 399
(M.sup.++1)
[0810] 152)
1-[(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-5-fluoro-3-(1-methyl-1-
,2,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.09,
m/z 417 (M.sup.1+1)
[0811] 153)
1-[(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-te-
trahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI)
t.sub.R 2.16, m/z 467 (M.sup.++1)
[0812] 154)
1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyri-
din-4-yl)-1H-indole, LC/MS (EI) t.sub.R 1.95, m/z 357
(M.sup.1+1)
[0813] 155)
5-fluoro-1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetra-
hydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.02, m/z 375
(M.sup.++1)
[0814] 156)
1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyri-
din-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI) t.sub.R 2.06,
m/z 425 (M.sup.++1)
[0815] 157)
1-[(1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydro-
pyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 1.99, m/z 371
(M.sup.++1)
[0816] 158)
1-[(1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2,3,6-t-
etrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.02, m/z 389
(M.sup.1+1)
[0817] 159)
1-[(1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydro-
pyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI) t.sub.R
2.09, m/z 439 (M.sup.++1)
[0818] 160)
1-[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydro-
pyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.02, m/z 371
(M.sup.++1)
[0819] 161)
1-[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2,3,6-t-
etrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.02, m/z 389
(M.sup.++1)
[0820] 162)
1-[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydro-
pyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI) t.sub.R
2.09, m/z 439 (M.sup.4+1)
[0821] 163)
1-[(1-methyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.13, m/z 408
(M.sup.++1)
[0822] 164)
5-fluoro-1-[(1-methyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.13,
m/z 426 (M.sup.++1)
[0823] 165)
1-[(1-methyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS (EI)
t.sub.R 2.18, m/z 476 (M.sup.++1)
[0824] 166)
1-[(1-methyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, LC/MS (EI) t.sub.R
2.02, m/z 409 (M.sup.++1)
[0825] 167)
1-(2,2-dimethylpropanoyl)-5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-indol-1-yl]sulfonyl}-1H-indazole, LC/MS (EI) t.sub.R 2.3, m/z
477 (M.sup.++1)
[0826] 168)
1-(2,2-dimethylpropanoyl)-5-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyri-
din-4-yl)-1H-indol-1-yl]sulfonyl}-1H-indazole, LC/MS (EI) t.sub.R
2.3, m/z 495 (M.sup.++1)
[0827] 169)
1-(2,2-dimethylpropanoyl)-5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-5-(trifluoromethyl)-1H-indol-1-yl]sulfonyl}-1H-indazole, LC/MS
(EI) t.sub.R 2.37, m/z 545 (M.sup.++1)
[0828] 170)
1-{[1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl]sulfonyl}-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R 2.09,
m/z 407 (M.sup.++1)
[0829] 171)
1-{[1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl]sulfonyl}-5-fluoro-3-(1-m-
ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, LC/MS (EI) t.sub.R
2.13, m/z 425 (M.sup.++1)
[0830] 172)
1-{[1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl]sulfonyl}-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-indole, LC/MS
(EI) t.sub.R 2.16, m/z 475 (M.sup.++1)
[0831] Similarly, using this general procedure, with different
starting materials, and where the 1-methylpiperidin-4-one can be
replaced with 1-methyl-1,4-piperazine, additional compounds of the
present invention wherein Q is N can be synthesized.
General Procedure B
81)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-5-(pyri-
din-4-yl)-1H-indole
##STR00113##
[0833] Into a 100 mL 3-necked round bottom flask was placed
pyridin-3-ylboronic acid (200 mg, 1.63 mmol),
5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-
-indole (470 mg, 1.08 mmol), and n-propanol (140 mL). The mixture
was stirred at room temperature for 30 min during which time the
solids dissolved. A solution of Na.sub.2CO.sub.3 (430 mg, 4.06
mmol) in water (5 mL) was then added, followed by the addition of
Pd(PPh.sub.3).sub.4 (130 mg, 0.108 mmol). The resulting solution
was stirred at reflux temperature overnight, and then concentrated.
The residue was dissolved in water (10 mL), and the resulting
solution was extracted diethylether (2.times.50 mL). The organic
layers were combined and the residue was purified by column
chromatography using a 1:5 dichloromethane/methanol solvent system
to afford 200 mg (42.5%) of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-5-(pyridin-
-4-yl)-1H-indole as a deep yellow solid. .sup.1H NMR (CDCl.sub.3)
.delta. 8.69 (d, 2H), 8.12 (d, 1H), 7.93 (t, 31H), 7.60 (d, 3H),
7.48 (dxd, 4H), 6.18 (s, 1H), 2.85 (2H), 1.52 (2H), 1.25 (3H), 0.87
(2H). LC/MS (EI) t.sub.R 2.18, m/z 430.0 (M.sup.++1)
[0834] Using this general procedure, the following compounds were
prepared using different starting materials:
[0835] 84)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)--
5-pyridin-3-yl-1H-indole, LC/MS (EI) t.sub.R 1.92, m/z 430.0
(M.sup.++1)
[0836] 85)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)--
6-pyridin-3-yl-1H-indole, LC/MS (EI) t.sub.R 1.88, m/z 430.0
(M.sup.++1)
[0837] 86)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)--
6-pyridin-4-yl-1H-indole, LC/MS (EI) t.sub.R 1.85, m/z 430.0
(M.sup.++1)
[0838] 105) 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenyl
sulfonyl)-5-pyridin-2-yl-1H-indole dihydrochloride, LC/MS (EI)
t.sub.R 1.99, m/z 444.0 (M.sup.++1)
[0839] 106)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-6-pyridin--
2-yl-1H-indole dihydrochloride, LC/MS (EI) t.sub.R 1.99, m/z 444.0
(M.sup.++1)
General Procedure C
79)
5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin--
4-yl)-1-(phenylsulfonyl)-1H-indole
##STR00114##
[0840] 1) Synthesis of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole
[0841] A solution of KOH (12 g, 213.21 mmol) in methanol (100 mL)
was added to 5-nitro-1H-indole (15 g, 92.04 mmol) in a 250 mL
flask. 1-methylpiperidin-4-one (13.7 g, 120.46 mmol) was then added
dropwise with stirring, while cooling the reaction to 20.degree. C.
The resulting solution was stirred for 4 hours, while the
temperature was maintained at 72.degree. C. The reaction mixture
was then cooled to 15.degree. C., and the product was precipitated
by the addition of water (100 mL). Filtration, followed by
recrystallization of the residue from ethanol afforded 11 g (46%)
of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole as
a yellow solid.
2) Synthesis of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1-(phenylsulfonyl)-1H-
-indole
[0842] NaH (330 mg, 8.25 mmol) was added in several batches, to a
solution of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole (1.4
g, 5.42 mmol) in DMF (25 mL) while cooling to 0-5.degree. C. The
resulting solution was stirred at room temperature for 0.5 hours,
and then benzenesulfonyl chloride (1.5 g, 8.41 mmol) was added
dropwise. The reaction was stirred for an additional 4 hours at
room temperature, and then filtered. The filter cake was washed
with ethanol (3.times.50 mL) and dried to afford 1.2 g (55%) of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1-(phenylsulfonyl)-1H-
-indole as a light yellow solid. .sup.1H NMR (DMSO) .delta. 8.62
(s, 1H), 8.17-8.27 (3H), 8.10 (d, 2H), 7.74 (1H), 7.61 (2H), 6.32
(s, 1H), 3.84 (s, 2H), 3.38 (2H), 2.83-2.87 (5H).
3) Synthesis of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indol-5-
-amine
[0843] Zinc (3.28 g, 50.46 mmol) was added to a solution of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1-(phenylsulfonyl)-1H-
-indole (2 g, 5.04 mmol) in ethanol (500 mL). Acetic acid (30 mL)
was then added dropwise with stirring while the reaction was cooled
in a ice water bath. The resulting solution was stirred for 2 hours
at room and then filtered. The filtrate cake was washed with
ethanol, and the collected filtrate was concentrated in vacuo. The
residue was purified by column chromatography using a 10:1
methanol/ammonia solvent system to afford 1 g (54%) of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1-
H-indol-5-amine as a yellow solid.
4) Synthesis of
5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-y-
l)-1-(phenylsulfonyl)-1H-indole
[0844] Hexane-2,5-dione (2 mL) was added to a solution of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indol-5-
-amine (300 mg, 0.82 mmol) in ethanol (50 mL). Acetic acid (2 mL)
was added, and the resulting solution was stirred at room
temperature overnight. The solvent was concentrated, followed by
column chromatography purification using a 1:10
methanol/dichloromethane solvent system provided 30 mg (8%) of
5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-y-
l)-1-(phenylsulfonyl)-1H-indole as a yellow solid. NMR (CDCl.sub.3)
.delta. 8.05 (d, 1H), 7.95 (d, 2H), 7.62 (s, 1H), 7.50 (d, 2H),
7.26 (2H), 6.84 (d, 2H), 6.11 (s, 1H), 5.90 (s, 2H), 3.46 (d, 2H),
3.07 (t, 2H), 2.74 (s, 2H), 2.62 (s, 2H), 1.98 (s, 6H). LC/MS (EI)
t.sub.R 2.46, m/z 446.0 (M.sup.++1)
[0845] Using this general procedure the following compound was
prepared using different starting materials:
[0846] 77)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1-(phenylsu-
lfonyl)-1H-indole, LC/MS (EI) t.sub.R 2.27, m/z 398.0
(M.sup.++1).
General Procedure D
80)
6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin--
4-yl)-1-(phenylsulfonyl)-1H-indole
##STR00115##
[0847] 1) Synthesis of
3-(1-methylpiperidin-4-yl)-6-nitro-1H-indole
[0848] KOH (3.96 g, 70.71 mmol) was added to a solution of
6-nitro-1H-indole (5 g, 30.86 mmol) in methanol (50 mL).
1-methylpiperidin-4-one (4.53 g, 40.09 mmol) was then added, and
the resulting solution was stirred for 6 hours at 90.degree. C.
After cooling, the mixture was concentrated and the residue was
recrystallized from ethanol (20 mL) to afford 3.0 g (36%) of
3-(1-methylpiperidin-4-yl)-6-nitro-1H-indole as a yellow
powder.
2) Synthesis of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitro-1-(phenylsulfonyl)-1H-
-indole
[0849] Sodium hydride (50 mg, 2.08 mmol) was added in several
batches to a solution of
3-(1-methyl-1,3,6-tetrahydropyridin-4-yl)-6-nitro-1H-indole (300
mg, 1.11 mmol) in DMF (30 mL) chilled in an ice water bath. The
reaction was then placed under an atmosphere of nitrogen and
maintained at 0.degree. C. for 1 hour. Benzenesulfonyl chloride
(214 mg, 1.21 mmol) was then added at 0.degree. C., and the
resulting solution was stirred for 2 hours at room temperature. The
mixture was quenched by the addition of 35 mL of ice water (with
external cooling by ice/water). After filtration, the residue was
purified by column chromatography using a 50:1
dichloromethane/methanol solvent system to afford 0.13 g (30%) of
3-(1-methyl-1,
tetrahydropyridin-4-yl)-6-nitro-1-(phenylsulfonyl)-1H-indole as a
light yellow solid. .sup.1H NMR (CDCl.sub.3) .delta. 9.3 (s, 1H),
7.93 (d, 2H), 7.9 (d, 2H), 7.54 (d, 1H), 7.3 (s, 1H), 6.13 (s, 1H),
2.83 (t, 2H), 2.45 (t, 2H), 2.27 (t, 3H), 2.07 (t, 2H).
3) Synthesis of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indol-6-
-amine
[0850] Tin (II) chloride (2 g, 9.35 mmol) was added to a solution
of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitro-1-(phenylsulfonyl)-1H-
-indole (100 mg, 0.25 mmol) in methanol (30 mL). The resulting
solution was stirred for 2 hours at reflux temperature After
cooling to room temperature, the mixture was concentrated by
evaporation to provide
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indol-6-
-amine, which was used in the next stage without further
purification.
4) Synthesis of
6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-y-
l)-1-(phenylsulfonyl)-1H-indole
[0851] Hexane-2,5-dione (930 mg, 8.16 mmol) was added to a solution
of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indol-6-
-amine (1.66 g, 1.13 mmol) in toluene (80 mL). Para-toluenesulfonic
acid (30 mg, 0.17 mmol) was then added, and the resulting solution
was stirred for 4 hours at 130.degree. C. After filtration, the
filtrate was concentrated and the residue was purified by column
chromatography using a 30:1 dichloromethane/methanol solvent
system. The product was washed with petroleum ether to afford 170
mg (32%) of
6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-y-
l)-1-(phenylsulfonyl)-1H-indole as a yellow solid. .sup.1H NMR
(DMSO) .delta. 8.3 (s, 1H), 8.3 (s, 1H), 8.1 (s, 1H), 8.0 (s, 1H),
7.8 (s, 1H), 7.6 (s, 1H), 7.4 (s, 1H), 7.4 (s, 1H), 7.1 (s, 1H),
6.3 (s, 1H), 5.8 (s, 1H), 5.8 (s, 1H), 3.0 (s, 2H), 2.27 (s, 3H),
2.6 (d, 2H), 2.6 (d, 2H), 1.8 (d, 3H), 1.8 (d, 3H). LC/MS (EI)
t.sub.R 2.48, m/z 446.0 (M.sup.++1)
[0852] Using this general procedure the following compound was
prepared using different starting materials:
[0853] 78)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitro-1-(phenylsu-
lfonyl)-1H-indole, LC/MS (EI) t.sub.R 2.17, m/z 398.0
(M.sup.++1).
General Procedure E
Synthesis of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indole--
5-carbonitrile
##STR00116##
[0854] 1) Synthesis of 1H-indole-5-carbonitrile
[0855] CuCN (3.7 g, 40.70 mmol) was added to a solution of
5-bromo-1H-indole (5 g, 25.26 mmol) in 1-methylpyrrolidin-2-one (25
mL), and the resulting solution was stirred at reflux for 18 hours.
The reaction mixture was then added to 200 g of ice and the mixture
was filtered. The filter cake was washed with ammonium hydroxide
(3.times.50 mL). The residue was dissolved in chloroform (600 mL)
and then filtered. The organic layer was washed with water (200
mL), and dried (MgSO.sub.4). After a further filtration, the
filtrate was concentrated to yield 3.7 g (82%) of
1H-indole-5-carbonitrile as brown oil.
2) Synthesis of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carboxamide
[0856] A solution of KOH (1.0 g, 17.68 mmol) in methanol (20 mL)
was added to 1H-indole-5-carbonitrile (1.0 g, 6.96 mmol).
1-methylpiperidin-4-one (1.0 g, 8.75 mmol) was then added dropwise
with stirring, while cooling to 0-5.degree. C. and the resulting
solution was stirred for 1 hour at 50.degree. C. The reaction
mixture was then cooled to room temperature, concentrated, and the
residue was purified by column chromatography using ethanol solvent
system to give 200 mg of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carboxamide
as a white solid.
3)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carbonitrile
[0857] H.sub.2SO.sub.4 (0.1 mL) was added to a solution of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carboxamide
(130 mg, 0.41 mmol) in ethanol (4 mL) and the resulting solution
was stirred at room temperature for 1 hour. Filtration and
subsequent concentration afforded 20 mg (18.6%) of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carbonitrile
as a white solid.
4) Synthesis of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indole--
5-carbonitrile
[0858] Nah (26 mg, 1.07 mmol) was added in several batches to a
solution of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carbonitrile
(200 mg, 0.76 mmol) in DMF (2 mL) at 0-5.degree. C., and the
mixture was maintained for 1 hour at room temperature.
Benzenesulfonyl chloride (222 mg, 1.24 mmol) was then added, and
the resulting solution was maintained at room temperature for an
additional 4 hours. The mixture was filtered, and the filter cake
was washed with ethanol (2.times.10 mL) and diethylether
(2.times.10 mL) to afford 250 mg (86%) of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indole--
5-carbonitrile as a white solid. .sup.1H NMR (DMSO) .delta. 8.41
(s, 1H), 8.14 (d, 2H), 8.07 (d, 2H), 7.78 (d, 1H), 7.71 (d, 2H),
7.61 (t, 1H), 6.35 (s, 1H), 3.79 (2H), 3.34 (s, 2H), 2.80-2.87 (m,
5H).
General Procedure F
Synthesis of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(pyrro-lidin-1-yl)-1H-indol-
e
##STR00117##
[0859] 1) Synthesis of tert-butyl
5-bromo-1H-indole-1-carboxylate
[0860] (Boc).sub.2O (23.35 g, 107.11 mmol) was added to a solution
of 5-bromo-1H-indole (20 g, 102.04 mmol) in dichloromethane (120
mL). Et.sub.3N (10.302 g, 102.00 mmol) was then added, and the
resulting solution was stirred at room temperature overnight, then
for 6 hours at reflux temperature. The residue was purified by
column chromatography using petroleum ether solvent to afford 7.21
g (23%) of tert-butyl 5-bromo-1H-indole-1-carboxylate as a white
solid.
2) Synthesis of 5-(pyrrolidin-1-yl)-1H-indole
[0861] t-Butyl 5-bromo-1H-indole-1-carboxylate (200 mg, 0.68 mmol)
was placed in a 10 mL sealed tube. Cs.sub.2CO.sub.3 (440 g, 1.35
mol) was then added, followed by CuI (13 mg, 0.07 mmol), L-proline
(16 mg, 0.14 mmol), DMSO (3 mL), and pyrrolidine (480 g, 6.75 mol).
After sparging with nitrogen, the resulting solution was stirred at
95.degree. C. for 18 hours. The mixture was extracted with ethyl
acetate (3.times.40 mL), and the organic layers were combined and
washed with brine. The residue was purified by column
chromatography using 1:5 and 1:2 ethyl acetate/petroleum ether
solvent systems. The collected fractions were combined and
concentrated to give 100 mg (80%) of 5-(pyrrolidin-1-yl)-1H-indole
as brown oil.
3) Synthesis of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(pyrro-lidin-1-yl)-1H-indol-
e
[0862] 1-methylpiperidin-4-one (1.2 g, 10.62 mmol) was added to a
solution of 5-(pyrrolidin-1-yl)-1H-indole (200 mg, 1.08 mmol) in
methanol (20 mL). KOH (600 mg, 10.71 mmol) was then added, and the
resulting solution was stirred at reflux temperature overnight. The
mixture was concentrated, quenched by the addition of water and
filtered. The filter cake was washed with water and ether to afford
120 mg (37%) of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(pyrrolidin-1-yl)-1H-indole
as a yellow solid. .sup.1H NMR (CDCl.sub.3) .delta. 7.85 (s, 1H),
7.09 (d, 1H), 6.98 (s, 1H), 6.69 (d, 1H), 6.12 (s, 1H), 3.32 (t,
4H), 3.25 (s, 2H), 2.75 (t, 2H), 2.66 (t, 2H), 2.47 (s, 3H), 1.71
(t, 4H).
[0863] Using this general procedure, followed by procedure A (2),
the following compounds were prepared using different starting
materials:
[0864] 99)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)--
5-pyrrolidin-1-yl-1H-indole, LC/MS (EI) t.sub.R 2.02, m/z 422.0
(M.sup.++1)
[0865] 101)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-5-piperidi-
n-1-yl-1H-indole, LC/MS (EI) t.sub.R 1.88, m/z 436.0
(M.sup.++1)
[0866] 103)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-morpholin-4-yl-1-(phenylsul-
fonyl)-1H-indole, LC/MS (EI) t.sub.R 2.02, m/z 438.0
(M.sup.++1)
General Procedure G
Synthesis of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(pyrrolidin-1-yl)-1H-indole
##STR00118##
[0867] 1). Synthesis of 6-(pyrrolidin-1-yl)-1H-indole
[0868] A solution of 6-bromo-1H-indole (300 mg, 1.53 mmol) in DMSO
(2 mL) was placed in a 10 mL sealed tube and sparged with nitrogen.
Pyrrolidine (1.09 g, 15.33 mmol) was then added, followed by the
addition of cesium carbonate (1 g, 3.07 mmol), copper (I) iodide
(30 mg, 0.16 mmol), and L-proline (200 mg, 1.74 mmol). The
resulting solution was stirred for 20 hours at 94.degree. C. The
reaction mixture was then quenched by the addition of iced water
(30 mL). The resulting solution was extracted with ethyl acetate
(3.times.100 mL) and the organic layers were combined, dried
(MgSO.sub.4) and concentrated. The residue was purified by column
chromatography using a 1:2 ethyl acetate/petroleum ether solvent
system to give 160 mg (47%) of 6-(pyrrolidin-1-yl)-1H-indole as a
tan crystalline solid.
2) Synthesis of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(pyrrolidin-1-yl)-1H-indole
[0869] 6-(pyrrolidin-1-yl)-1H-indole (500 mg, 2.68 mmol) was added
to a solution of potassium hydroxide (1.55 g, 27.62 mmol) in
methanol (20 mL). 1-methylpiperidin-4-one (610 mg, 5.39 mmol) was
then added, and the resulting solution was stirred at 72.degree. C.
overnight. The mixture was concentrated and the residue was poured
into water (40 mL). After filtration, the filter cake was washed
with water (1.times.50 mL) and diethylether (1.times.50 mL), to
afford 400 mg (47.6%) of
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(pyrrolidin-1-yl)-1H-indole
as a white solid.
[0870] Using this general procedure, followed by procedure A (2),
the following compounds were prepared using different starting
materials:
[0871] 100)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-6-pyrrolid-
in-1-yl-1H-indole, LC/MS (EI) t.sub.R 2.13, m/z 422.0
(M.sup.++1)
[0872] 102)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-6-piperidi-
n-1-yl-1H-indole, LC/MS (EI) t.sub.R 1.88, m/z 436.0
(M.sup.++1)
[0873] 104)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-morpholin-4-yl-1-(phenylsul-
fonyl)-1H-indole, LC/MS (EI) t.sub.R 2.03, m/z 438.0
(M.sup.++1).
General Procedure H
##STR00119##
[0874] Ha: (319) Synthesis of
4-methyl-7-[(3-piperazin-1-yl-1H-indazol-1-yl)sulfonyl]-3,4-dihydro-2H-1,-
4-benzoxazine
[0875] Into a vial, tert-butyl
4-(1H-indazol-3-yl)piperazine-1-carboxylate (85 mg, 0.00028 mol)
was added to tetrahydrofuran (2 mL, 0.03 mol) and
N,N-dimethylformamide (2 mL, 0.03 mol). The flask was cooled at
5.degree. C. and 1.0 M of sodium bis(trimethylsilyl)amide in
tetrahydrofuran (422 .mu.L) was added and was stirred under an
atmosphere of nitrogen for 30 minutes. The solution was drawn up
and was added at 5.degree. C. with
4-methyl-3,4-dihydro-2h-1,4-benzoxazine-7-sulfonyl chloride (104
mg, 0.000422 mol) and N,N-dimethylethylamine (45.7 .mu.L, 0.000422
mol) and tetrahydrofuran (2 mL, 0.03 mol) into a 1-neck
round-bottom flask. The reaction was stirred for 30 minutes and was
extracted with ethyl acetate and then was washed with water twice
and brine once. The solvent was rotovaped to 190 mg of crude
material.
[0876] The crude was adsorbed onto silica gel and was flash
chromatographed on silica gel on a 12 g cartridge using a
hexane:ethyl acetate gradient (10-50%) over 8 minutes at a flow
rate of 20 mL/min and UV detection at 240 nm. 50 mg was
recovered.
[0877] Alternatively, if the Boc group is methyl group, the residue
was purified on a C18 Sunfire column (30.times.100 mm) using a
gradient of (5-80%)acetonitrile:water (with 0.1% formic acid) and a
flow rate of 45 mL/min, gave the corresponding formic salt, or the
crude was adsorbed onto silica gel and was flash chromatographed on
silica gel on a 12 g cartridge using a ethyl
acetate:methanol:Et.sub.3N gradient (70:30:1) over 8 minutes at a
flow rate of 20 mL/min and UV detection at 240 nm, gave the
corresponding free base).
[0878] Using this general procedure the following compound s were
prepared using different starting materials: [0879] 174)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-5-fluoro-3-(1-methyl-1,2,3,6-
-tetrahydropyridin-4-yl)-1H-indole [0880] 187)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(1,3-oxazol-2-yl)-1-(pyridi-
n-3-ylsulfonyl)-1H-indole, [0881] 200)
4-methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin->4-yl)-1H-pyrrolo[2-
,3-b]pyridin-1-yl]sulfonyl}-3,4->dihydro-2H-1,4-benzoxazine
[0882] 203)
4-methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b-
]pyridin-1-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine [0883] 204)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(1,3-oxazol-2-yl)-1-(pyridi-
n-3-ylsulfonyl)-1H-indole [0884] 206)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(pyridin-3-ylsulfonyl)-5-(1-
,3-thiazol-2-yl)-1H-indole [0885] 217)
7-{[5-fluoro-3-(1-methylpiperidin-4-yl)-1H-indol-1-yl]sulfonyl}-4-methyl--
3,4-dihydro-2H-1,4-benzoxazine, [0886] 225)
7-{[6-(3-methoxypyrrolidin-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4--
yl)-1H-indol-1-yl]sulfonyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine,
[0887] 226)
6-(3-methoxypyrrolidin-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)--
1-(pyridin-3-ylsulfonyl)-1H-indole [0888] 228)
7-{[4-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine, [0889] 229)
7-[5-Fluoro-3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-indole-1-sulfony-
l]-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine [0890] 230)
7-{[6-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine; compound with
formic acid [0891] 231)
7-{[7-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine; compound with
formic acid [0892] 234)
4-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b-
]pyridin-1-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine [0893] 236)
7-{[3,5-bis(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1,1-indol-1-yl]sulfo-
nyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine, [0894] 242)
7-{[3,5-bis(1-methylpiperidin-4-yl)-1H-indol-1-yl]sulfonyl}-4-methyl-3,4--
dihydro-2H-1,4-benzoxazine [0895] 245)
4-methyl-7-{[3-(1-methylpiperidin-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl]sul-
fonyl}-3,4-dihydro-2H-1,4-benzoxazine; compound with formic acid
[0896] 248)
4-methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol--
1-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine; compound with formic
acid [0897] 261)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(1H-pyrazol-1-yl)-1-(pyridi-
n-3-ylsulfonyl)-1H-indole; compound with formic acid [0898] 262)
4-methyl-7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(1H-pyrazol-1--
yl)-1H-indol-1-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine;
compound with formic acid [0899] 263)
5-(1H-imidazol-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(pyrid-
in-3-ylsulfonyl)-1H-indole; compound with formic acid [0900] 264)
7-{[5-(1H-imidazol-1-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-i-
ndol-1-yl]sulfonyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine;
compound with formic acid [0901] 279)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrazolo[4,3-b]pyridine [0902] 299)
7-{[5-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]s-
ulfonyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine, [0903] 300)
5-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(pyridin-3-ylsulf-
onyl)-1H-indole, [0904] 318)
4-methyl-7-[(3-piperazin-1-yl-1H-indol-1-yl)sulfonyl]-3,4-dihydro-2H-1,4--
benzoxazine; compound with formic acid [0905] 322)
5-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl} isoquinoline hydroformate, [0906] 323)
5-{[5-fluoro-3-(1-methylpiperidin-4-yl)-1H-indol-1-yl]sulfonyl}
isoquinoline hydroformate [0907] 325)
8-[5-Fluoro-3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-indole-1-sulfony-
l]-isoquinoline; compound with formic acid [0908] 329)
2-methyl-8-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b-
]pyridin-1-yl]sulfonyl}-1,2,3,4-tetrahydroisoquinoline
Hb:
Tert-butyl-4-{1-[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfonyl-
]-1H-indazol-3-yl}piperazine-1-carboxylate (50 mg, 0.0001 mol) was
used in one of three ways
[0909] 1). The carboxylate was stirred in acetonitrile (2 mL, 0.04
mol) and iodotrimethylsilane (28 uL, 0.00019 mol) was added and was
stirred for 10 minutes. LC-MS (1080.sub.--8 min) shows M+H=414. The
reaction was diluted with water/acetonitrile (1.0 mL) and filtered
through a 0.45 um filter. The filtrate was purified on a C18
Sunfire column (30.times.100 mm) using a gradient of (10-80%)
acetonitrile:water (with 0.1% formic acid) and a flow rate of 45
ml/min. Detection was performed by m/z=413.2. Fractions of interest
were pooled and lyophilized. 20 mg was recovered as a an amorphous
white solid. LC-MS (2080.sub.--8 min) M+H 414.1 at 4.36 minutes.
.sup.1H NMR (CD.sub.3OD) .delta. 2.82 (3H, s), 3.22 (6H, m),
3.4-3.6 (4H, m), 4.25 (2H, m), 6.56 (1H, d), 6.95 (1H, d), 7.08
(1H, m), 7.35 (1H, t), 7.58 (1H, t), 7.80 (1H, d), 8.15 (1H, d),
8.53 (111, br s).
[0910] 2). The carboxylate was treated with CF.sub.3CO.sub.2H and
concentrated to form the corresponding CF.sub.3CO.sub.2H salt,
[0911] 3) The carboxylate was treated with HCl in dioxane and
concentrated to form the corresponding HCl salt.
[0912] Using the synthesis described in Ha and Hb the following
compound was prepared using different starting materials: [0913]
246)
4-methyl-7-{[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridin--
1-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine; compound with formic
acid [0914] 247)
4-methyl-7-[(3-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridin-1-yl)sulfonyl]-3,4-
-dihydro-2H-1,4-benzoxazine; compound with formic acid [0915] 285)
4-Methyl-7-(3-piperidin-4-yl-pyrrolo[3,2-b]pyridine-1-sulfonyl)-3,4-dihyd-
ro-2H-benzo[1,4]oxazine [0916] 296)
4-methyl-6-[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-
-yl]sulfonyl)-3,4-dihydro-2H-1,4-benzoxazine [0917] 313)
3-piperazin-1-yl-1-(pyridin-3-ylsulfonyl)-1H-indazole [0918] 318)
4-methyl-7-[(3-piperazin-1-yl-1H-indol-1-yl)sulfonyl]-3,4-dihydro-2H-1,4--
benzoxazine; compound with formic acid [0919] 319)
4-methyl-7-[(3-piperazin-1-yl-1H-indazol-1-yl)sulfonyl]-3,4-dihydro-2H-1,-
4-benzoxazine [0920] 324)
5-{[5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]sulfonyl}
isoquinoline hydroformate
General Procedure I
##STR00120##
[0921] Ia: Synthesis of tert-butyl
4-(1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-1H-pyrrolo[3,2-b]pyri-
din-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate
[0922] Into a 1-Neck round-bottom flask tert-butyl
4-(1H-pyrrolo[3,2-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate
(100 mg, 0.000334 mol) was stirred in tetrahydrofuran (3 mL, 0.04
mol) and N,N-dimethylformamide (3 mL, 0.04 mmol) at 5.degree. C.
and 1.0 M of sodium bis(trimethylsilyl)amide in tetrahydrofuran
(0.50 mL) was added. The reaction was stirred for 20 minutes at
5.degree. C. 3-(3-Methoxypyrrolidin-1-yl)benzenesulfonyl chloride
(138 mg, 0.000501 mol) in tetrahydrofuran (3 mL, 0.04 mop was added
by syringe at 5.degree. C. and the reaction was stirred for 30
minutes. The reaction was extracted with ethyl acetate and was
washed with water and brine. The solvent was rotovaped.
[0923] The crude was adsorbed onto silica gel and was flash
chromatographed on silica gel on a 12 g cartridge using a
hexane:ethyl acetate gradient (10-50%) over 10 minutes at a flow
rate of 20 mL/min and UV detection at 254 nm. 137 mg recovered as
an oil. LC-MS (80% acetonitrile/water with 0.1% formic acid)
M+H=539 at 8.00 minutes
[0924] If the Boo group was a methyl group, the residue was
purified on a C18 Sunfire column (30.times.100 mm) using a gradient
of (5-80%) acetonitrile:water (with 0.1% formic acid) and a flow
rate of 45 mL/min, gave the corresponding formic salt, or the crude
was adsorbed onto silica gel and was flash chromatographed on
silica gel on a 12 g cartridge using a ethyl acetate: methanol:
Et.sub.3N gradient (70:30:1) over 8 minutes at a flow rate of 20
mL/min and UV detection at 240 nm, gave the corresponding free
base.
[0925] Using this general procedure the following compound was
prepared using different starting materials: [0926] 173)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-1H-indole [0927] 175)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-5-(trifluoromethyl)-1H-indole [0928] 176)
4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]sulfonyl}an-
iline [0929] 178)
1-(2,2-dimethylpropanoyl)-5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-pyrrolo[2,3-b]pyridin-1-yl]sulfonyl}-1H-indazole [0930] 179)
6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin--
1-yl]sulfonyl}-3,4-dihydroquinolin-2(1H)-one [0931] 180)
1-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b-
]pyridin-1-yl]sulfonyl}-3,4-dihydroquinolin-2(1H)-one [0932] 181)
1-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluorometh-
yl)-1H-indol-1-yl]sulfonyl}-3,4-dihydro quinolin-2(1H)-one [0933]
182)
6-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-1-methyl-3,4-dihydroquinolin-2(1H)-one [0934] 183)
1-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-3,4-dihydroquinolin-2(1H)-one [0935] 184)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methylpiperidin-4-yl)-1-
H-pyrrolo[2,3-b]pyridine [0936] 186)
5-fluoro-1-[(1-methyl-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahy-
dropyridin-4-yl)-1H-indole [0937] 189)
1-[(1-ethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyrid-
in-4-yl)-6-(1,3-oxazol-2-yl)-1H-indole [0938] 190)
1-[(1-ethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyrid-
in-4-yl)-5-(1,3-oxazol-2-yl)-1H-indole [0939] 191)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-5-(1,3-oxazol-2-yl)-1H-indole [0940] 192)
5-(3,6-dihydro-2H-pyran-4-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1-(phenylsulfonyl)-1H-indole [0941] 193)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-6-(1,3-thi-
azol-2-yl)-1H-indole [0942] 194)
5-fluoro-1-{[6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]sulfonyl}-3-(1-meth-
yl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole [0943] 195
1-{[6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]sulfonyl}-3-(1-methyl-1,2,3,-
6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine [0944] 196)
7-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-2H-1,4-benzoxazin-3(4H)-one [0945] 197)
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin--
1-yl]sulfonyl}-2H-1,4-benzoxazin-3(4H)-one [0946] 198)
1-[(1-acetyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-indole [0947] 199)
1-[(1-acetyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine [0948] 201)
1-(2,3-dihydro-1,4-benzo
dioxin-6-ylsulfonyl)-5-fluoro-3-(1-methylpiperidin-4-yl)-1H-indole
hydroformate [0949] 202)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine [0950] 205)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-5-(1,3-thiazol-2-yl)-1H-indole [0951] 207)
1-[(1-ethyl-1H-pyrazol-4-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyrid-
in-4-yl)-5-(1,3-thiazol-2-yl)-1H-indole [0952] 208)
1-[(1-methyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine [0953] 209)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine [0954] 210)
1-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyrid-
in-1-yl]sulfonyl}phenyl)pyrrolidin-2-one [0955] 211)
3-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b-
]pyridin-1-yl]sulfonyl}-1,3-benzoxazol-2(3H)-one [0956] 212)
1-[(1-methyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine [0957] 213)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine [0958] 214)
1-(4-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyrid-
in-1-yl]-sulfonyl}phenyl)pyrrolidin-2-one [0959] 215)
3-methyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b-
]pyridin-1-yl]sulfonyl}-1,3-benzoxazol-2(3H)-one [0960] 219)
6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin--
1-yl]sulfonyl}-2H-1,4-benzoxazin-3(4H)-one [0961] 220)
5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridin--
1-yl]sulfonyl}-1,3-dihydro-2H-benzimidazol-2-one [0962] 221)
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridin--
1-yl]sulfonyl}-2H-1,4-benzoxazin-3(41-1)-one [0963] 222)
6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridin--
1-yl]sulfonyl}-2H-1,4-benzoxazin-3(4H)-one [0964] 227)
6-(3-methoxypyrrolidin-1-yl)-1-[(1-methyl-1H-indol-5-yl)sulfonyl]-3-(1-me-
thyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole [0965] 233)
1-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylsulfonyl)-3-(1-methyl-1,2,3,6-tet-
rahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine [0966] 235)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methylpiperidin-4-y-
l)-1H-pyrrolo[2,3-b]pyridine [0967] 237)
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl]sulfonyl}-
-2H-1,4-benzoxazin-3 (414)-one [0968] 238)
1-[(1-methyl-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyridi-
n-4-yl)-1H-indazole [0969] 239)
1-[(1-methyl-1H-indol-5-yl)sulfonyl]-3,5-bis(1-methyl-1,2,3,6-tetrahydrop-
yridin-4-yl)-1H-indole [0970] 243)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine [0971] 249)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine [0972] 250)
1-(3-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyrid-
in-1-yl]sulfonyl}phenyl)pyrrolidin-2-one [0973] 251)
1-[(5-bromo-2,3-dihydro-1-benzofuran-7-yl)sulfonyl]-3-(1-methyl-1,2,3,6-t-
etrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine [0974] 252)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine [0975] 253)
1-(3-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyrid-
in-1-yl]sulfonyl}phenyl)pyrrolidin-2-one [0976] 254)
1-[(5-bromo-2,3-dihydro-1-benzo
furan-7-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrro-
lo[3,2-b]pyridine [0977] 255)
6-ethyl-1-[(1-methyl-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine [0978] 256)
6-ethyl-1-[(1-methyl-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine [0979] 257)
6-ethyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(3-pyrrolidin-1-yl-
phenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine [0980] 258)
6-ethyl-1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,-
3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine [0981] 259)
1-(3-{[6-ethyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-
-b]pyridin-1-yl]sulfonyl}phenyl)pyrrolidin-2-one [0982] 260)
1-[(5-bromo-2,3-dihydro-1-benzofuran-7-yl)sulfonyl]-6-ethyl-3-(1-methyl-1-
,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine [0983]
265)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-indazole [0984] 266)
4-acetyl-6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl]-
sulfonyl}-3,4-dihydro-2H-1,4-benzoxazine [0985] 267)
5-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl]sulfonyl}-
-1,2-benzisoxazole [0986] 268)
1-(1-benzothien-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-indazole [0987] 269)
1-(1-benzofuran-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-indazole [0988] 270)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-6-ethyl-3(1-methyl-1,2,3-
,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine [0989] 271)
6-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl]sulfonyl}-
-2H-1,4-benzoxazin-3(4H)-one [0990] 272)
1-(1-benzofuran-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-pyrazolo[4,3-b]pyridine [0991] 273)
1-(1-benzothien-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-pyrazolo[4,3-b]pyridine [0992] 274)
1-(1-benzofuran-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-pyrazolo[3,4-b]pyridine [0993] 275)
1-(1-benzothien-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-
-1H-pyrazolo[3,4-b]pyridine [0994] 276)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-fluoro-3-(1-methyl-1,2-
,3,6-tetrahydropyridin-4-yl)-1H-indazole; compound with formic acid
[0995] 277)
5-fluoro-1-[(1-methyl-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-te-
trahydropyridin-4-yl)-1H-indazole; compound with formic acid [0996]
278)
5-fluoro-1-[(1-methyl-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetrahy-
dropyridin-4-yl)-1H-indazole; compound with formic acid [0997] 279)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrazolo[4,3-b]pyridine [0998] 280)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine [0999] 281)
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-
-1-yl]sulfonyl}-2H-1,4-benzoxazin-3 (4H)-one [1000] 282)
7-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-
-1-yl]sulfonyl}-2H-1,4-benzoxazin-3(4H)-one [1001] 283)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine [1002] 284)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin [1003] 286)
1-(3-{[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyrid-
in-1-yl]sulfonyl}phenyl)pyrrolidin-3-ol [1004] 287)
1-[(1-acetyl-2,3-dihydro-1H-indol-6-yl)sulfonyl]-3-(1-methyl-1,2,3,6-tetr-
ahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine [1005] 293)
5-methoxy-1-[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl)-3-(1-methyl-tet-
rahydropyridin-4-yl)-1H-indole [1006] 298)
7-{[5-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]s-
ulfonyl}-2H-1,4-benzoxazin-3(4H)-one [1007] 301)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(4-methylpiperazin-1-y-
l)-1H-indazole [1008] 304)
7-{[3-(4-methylpiperazin-1-yl)-1H-indazol-1-yl]sulfonyl}-2H-1,4-benzoxazi-
n-3(4H)-one [1009] 305)
7-{[3-(4-methylpiperazin-1-yl)-1H-indol-1-yl]sulfonyl}-2H-1,4-benzoxazin--
3(4H)-one [1010] 306)
7-[(3-piperazin-1-yl-1H-indol-1-yl)sulfonyl]-2H-1,4-benzoxazin-3(4H)-one
[1011] 307)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(4-methylpiperazin-1-y-
l)-1H-indole [1012] 311)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(4-methylpiperazin-1-y-
l)-1H-indazole [1013] 314)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(4-methylpiperazin-1-y-
l)-1H-indole [1014] 315)
4-methyl-7-{[3-(4-methylpiperazin-1-yl)-1H-indazol-1-yl]sulfonyl}-3,4-dih-
ydro-2H-1,4-benzoxazine [1015] 326)
1-(1,2-benzisoxazol-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-
-yl)-1H-pyrazolo[4,3-b]pyridine [1016] 327)
1-(1,2-benzisoxazol-5-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-
-yl)-1H-pyrazolo[3,4-b]pyridine [1017] 328)
3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-[(6-phenoxypyridin-3-yl)sul-
fonyl]-1H-pyrrolo[3,2-b]pyridine [1018] 330)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-methoxy-3-(1-methyl-1,-
2,3,6-tetrahydropyridin-4-yl)-1H-indole
Ib: Synthesis of
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-(1,2,3,6-tetrahydropyr-
idin-4-yl)-1H-pyrrolo[3,2-b]pyridine
[1019] Tert-butyl
4-(1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-1H-pyrrolo[3,2-b]pyri-
din-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.137 g, 0.000254
mol) was put into a 1-neck round-bottom flask in one of the two
reactions.
[1020] 1.) The carboxylate was combined with acetonitrile (4 mL,
0.08 mol) and stirred and iodotrimethylsilane (72 .mu.L, 0.00051
mol) was added and was stirred for 20 minutes. The solvent was
rotovaped. The reaction was diluted with water/acetonitrile (3.0
mL) and filtered through a 0.45 um filter. The filtrate was
purified on a C18 Sunfire column (30.times.100 mm) using a gradient
of (10-80%) acetonitrile:water (with 0.1% formic acid) and a flow
rate of 45 mL/min. Detection was performed by m/z=439. Fractions of
interest were pooled and concentrated on a freeze drier. 48.5 mg
recovered as a white amorphous solid. LC-MS (10-80%
acetonitrile/water with 0.1% formic acid over 8 min) M+H=439.0 at
4.86 minutes .sup.1H NMR (CD.sub.3OD) .delta. 2.12 (m, 2H), 2.81
(m, 2H), 3.4-3.5 (m, 6H), 3.60 (m, 3H), 3.82 (m, 2H), 4.14 (m, 1H),
6.22 (m, 1H), 6.99 (s, 1H), 7.15 (m, 1H), 7.42 (m, 3H), 8.03 (s,
1H), 8.41 (m, 1H), 8.62 (m, 2H),
[1021] 2) The carboxylate was treated with CF.sub.3CO.sub.2H and
concentrated to form the corresponding CF.sub.3CO.sub.2H salt, 3)
or was treated with HCl in dioxane and concentrated to form the
corresponding HCl salt.
[1022] Using the synthesis described in Ia and Ib, the following
compound was prepared using different starting materials: [1023]
177)
4-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}aniline, [1024] 185)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1,2,3,6-tetrahydropyridin-
-4-yl)-1H-pyrrolo[2,3-b]pyridine [1025] 188)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-(1-methyl-1,2,3,6-tetrahyd-
ropyridin-4-yl)-6-(1,3-oxazol-2-yl)-1H-indole [1026] 218)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-5-fluoro-3-(1,2,3,6-tetrahyd-
ropyridin-4-yl)-1H-indole hydroformate [1027] 223)
6-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-2H-1,4-benzoxazin-3(4H)-one; compound with formic acid
[1028] 224)
6-{[5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]su-
lfonyl}-3-methyl-1,3-benzoxazol-2(3H)-one; compound with formic
acid [1029] 232)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1,2,3,6-tetrahydropyr-
idin-4-yl)-1H-pyrrolo[2,3-b]pyridine [1030] 240)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-3-piperidin-4-yl-1H-pyrrolo[-
2,3-b]pyridine; compound with formic acid [1031] 241)
1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-5-fluoro-3-piperidin-4-yl-1H-
-indole hydroformate [1032] 244)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-piperidin-4-yl-1H-pyrr-
olo[2,3-b]pyridine [1033] 288)
1-[(6-morpholin-4-ylpyridin-3-yl)sulfonyl]-3-(1,2,3,6-tetrahydropyridin-4-
-yl)-1H-pyrrolo[3,2-b]pyridine; compound with formic acid [1034]
289)
1-{[6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]sulfonyl}-3-(1,2,3,6-tetrahy-
dropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine; compound with formic
acid [1035] 290)
1-[(5-methoxypyridin-3-yl)sulfonyl]-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-
-pyrrolo[3,2-b]pyridine; compound with formic acid [1036] 291)
1-{[5-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]sulfonyl}-3-(1,2,3,6-tetrahy-
dropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine; compound with formic
acid [1037] 292)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-(1,2,3,6-tetrahydropyr-
idin-4-yl)-1H-pyrrolo[3,2-b]pyridine [1038] 294)
7-{[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl]sulf-
onyl}-2H-1,4-benzoxazin-3(4H)-one [1039] 295)
7-{[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl]sulf-
onyl}-3,4-dihydroquinolin-2(1H)-one [1040] 297)
6-{[3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl]sulf-
onyl}-2H-1,4-benzoxazin-3(41-1)-one [1041] 302)
1-([3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl)-3-piperazin-1-yl-1H-inda-
zole [1042] 303)
7-[(3-piperazin-1-yl-1H-indazol-1-yl)sulfonyl]-2H-1,4-benzoxazin-3
(4H)-one [1043] 308)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-piperazin-1-yl-1H-indo-
le [1044] 309)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-piperazin-1-yl-1H-pyrr-
olo[2,3-b]pyridine; compound with formic acid [1045] 310)
1-{[3-(3-methoxypyrrolidin-1-yl)phenyl]sulfonyl}-3-piperazin-1-yl-1H-pyrr-
olo[2,3-b]pyridine; compound with formic acid [1046] 312)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-piperazin-1-yl-1H-inda-
zole [1047] 316)
1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-3-piperazin-1-yl-1H-indo-
le [1048] 317)
7-[(3-piperazin-1-yl-1H-indol-1-yl)sulfonyl]-2H-1,4-benzoxazin-3(4H)-one
[1049] 320)
7-[(3-piperazin-1-yl-1H-indol-1-yl)sulfonyl]-2H-1,4-benzoxazin-3(4H)-one
[1050] 321)
7-[(3-piperazin-1-yl-1H-indazol-1-yl)sulfonyl]-2H-1,4-benzoxazin-3(4H)-on-
e
##STR00121##
[1050] Ia and II) (306) Synthesis of
7-[(3-piperazin-1-yl-1H-indol-1-yl)sulfonyl]-2H-1,4-benzoxazin-3(4H)-one
[1051] In a vial was placed a solution of tert-butyl
4(1H-indol-3-yl)piperazine-1-carboxylate (70 mg, 0.0002 mol)
N,N-Dimethylformamide (1.5 mL, 0.019 mol). Sodium
bis(trimethylsilyl)amide (0.08 mL, 0.0005 mol) was then added. The
mixture was allowed to stir at 5.degree. C. for 30 min.
3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonyl chloride (76.5 mg,
0.000309 mol) in tetrahydrofuran (1 mL) was then added, and the
resulting mixture was stirred at room temperature for 60 minutes,
and was concentrated followed by FCC, the obtained fraction was
treated with 4.0 M HCl in dioxane. The obtained residue was
purified by HPLC. The reaction mixture was diluted with
water/acetonitrile (1.0 mL) and filtered through a 0.45 um filter.
The filtrate was purified on a C18 Sunfire column (30.times.100 mm)
using a gradient of (5-80%) acetonitrile:water (with 0.1% formic
acid) and a flow rate of 45 mL/min. Detection was performed by
m/z=413. Fractions of interest were pooled and concentrated on a
Genevac. A tan solid was recovered. LC-MS (2080.sub.--8 min)
M+H=413 at 4.13 minutes. .sup.1H NMR (CD.sub.3OD) .delta. 3.3 (4H,
m), 3.7 (4H, m), 4.7 (2H, s), 7.0 (1H, t), 7.2 (1H, d), 7.4 (1H,
t), 7.5 (1H, d), 7.6 (1H, t), 7.9 (1H, d), 8.1 (1H, d), 8.5 (1H, br
s).
Synthesis of
tert-butyl-4-(1H-indol-3-yl)-piperazine-1-carboxylate
##STR00122##
[1052] 1. Synthesis of 3-iodo-1H-indole
[1053] Into a 500 mL 3-necked round bottom flask, was placed a
solution of 1H-indole (10 g, 85.40 mmol) in MeOH/H.sub.2O (150/30
mL). To this was added potassium iodide (15.6 g, 93.98 mmol). To
the mixture was added sodium hydroxide (3.76 g, 94.00 mmol). To the
above was added I.sub.2 (23.88 g, 94.02 mmol) in several batches.
The resulting solution was allowed to react, with stirring, for 3
hours while the temperature was maintained at room temperature. The
reaction progress was monitored by TLC (ethyl acetate/petroleum
ether=1:10). The reaction mixture was then quenched by the adding
100 mL of H.sub.2O. A filtration was performed. The filter cake was
washed 3 times with 200 mL of water. This resulted in 18 g (84%) of
3-iodo-1H-indole as a light yellow solid.
2. Synthesis of 1H-indol-3-yl acetate
[1054] Into a 500 nth round bottom flask was placed a solution of
3-iodo-1H-indole (23 g, 94.65 mmol) in acetic acid (300 mL). To the
mixture was added CH3COOAg (31.6 g, 189.22 mmol). The resulting
solution was allowed to react, with stirring, for 1 hour while the
temperature was maintained at 90.degree. C. in a bath of oil. The
reaction progress was monitored by TLC (ethyl acetate/petroleum
ether=1:1). A filtration was performed. The filtrate was
concentrated by evaporation under vacuum using a rotary evaporator.
The resulting solution was dissolved with 100 mL of ethyl acetate.
The resulting mixture was washed 2 times with 100 mL of NaCl(aq.).
The final product was purified by recrystallization from
MeOH/H.sub.2O in the ratio 2:3. This resulted in 8.5 g (41%) of
1H-indol-3-yl acetate as a dark purple solid.
3. Synthesis of 1-acetyl-1H-indol-3-yl acetate
[1055] Into a 500 mL round bottom flask was placed a solution of
1H-indol-3-yl acetate (8 g, 45.69 mmol) in tetrahydrofuran (150
mL). To this was added acetic anhydride (46.6 g, 456.86 mmol).
Addition of triethylamine (9.25 g, 91.49 mmol) was next. To the
mixture was added DMAP (1.11 g, 9.10 mmol). The resulting solution
was allowed to react, with stirring, for 3 hours while the
temperature was maintained at reflux in a bath of oil. The reaction
progress was monitored by TLC (ethyl acetate/petroleum ether=1:2).
The mixture was concentrated by evaporation under vacuum using a
rotary evaporator. The resulting solution was diluted with 300 mL
of ethyl acetate The resulting mixture was washed 2 times with 150
mL of NaCl(aq.). The mixture was dried over Na.sub.2SO.sub.4. The
residue was purified by eluting through a column with a 20:1
petroleum ether/ethyl acetate solvent system. This resulted in 6.6
g (67%) of 1-acetyl-1H-indol-3-yl acetate as a white solid.
4. Synthesis of tert-butyl
4-(1-acetyl-1H-indol-3-yl)piperazine-1-carboxylate
[1056] Into a 150 mL sealed tube was placed a solution of
1-acetyl-1H-indol-3-yl acetate (2.5 g, 11.51 mmol) in toluene (80
mL). To this was added tert-butyl piperazine-1-carboxylate (10.71
g, 57.55 mmol). To the mixture was added p-toluenesulfonic acid
(400 mg, 2.33 mmol). The resulting solution was allowed to react,
with stirring, overnight while the temperature was maintained at
120.degree. C. in a bath of oil. The reaction progress was
monitored by TLC (ethyl acetate/petroleum ether=1:1). The mixture
was concentrated by evaporation under vacuum using a rotary
evaporator. The resulting solution was diluted with 200 mL of ethyl
acetate. The resulting mixture was washed 3 times with 200 mL of
NaCl(aq.). The mixture was dried over Na.sub.2SO.sub.4. The residue
was purified by eluting through a column with a 10:1 petroleum
ether/ethyl acetate solvent system. This resulted in 2.9 g (72%) of
tert-butyl 4-(1-acetyl-1H-indol-3-yl)piperazine-1-carboxylate as a
purple solid.
5. tert-butyl-4-(1H-indol-3-yl)-piperazine-1-carboxylate
[1057] Into a 250 mL round bottom flask was placed a solution of
tert-butyl 4-(1-acetyl-1H-indol-3-yl)piperazine-1-carboxylate (2.6
g, 7.58 mmol) in methanol (80 mL). To the mixture was added
Et.sub.3N (2.3 g, 22.73 mmol). The resulting solution was allowed
to react, with stirring, for 1 hour while the temperature was
maintained at reflux in a bath of oil. The reaction progress was
monitored by LCMS and TLC (ethyl acetate/petroleum ether=1:1). The
mixture was concentrated by evaporation under vacuum using a rotary
evaporator. The resulting solution was diluted with 200 mL of ethyl
acetate. The resulting mixture was washed 3 times with 150 mL of
NaCl(aq.). The residue was purified by eluting through a column
with a 10:1 petroleum ether/ethyl acetate solvent system. This
resulted in 2.1 g (89%) of tert-butyl
4-(1H-indol-3-yl)piperazine-1-carboxylate as a light pink
solid.
[1058] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.55 (9H, s), 3.1
(4H, s), 3.7 (4H, s), 6.7 (1H, s), 7.21 (1H, t), 7.32 (1H, t), 7.34
(1H, d), 7.68 (1H, d), 7.7 (1H, d). m/z 302 (M.sup.++1).
Synthesis of tert-butyl
4-(1H-indazol-3-yl)piperazine-1-carboxylate
##STR00123##
[1059] 1. Synthesis of 2-chlorobenzoyl chloride
[1060] Into a 500 mL round bottom flask was placed a solution of
2-chlorobenzoic acid (20 g, 127.80 mmol) in toluene (150 mL). To
the mixture was added SOCl.sub.2 (16 g, 134.45 mmol). The resulting
solution was allowed to react, with stirring, overnight while the
temperature was maintained at 75.degree. C. in a bath of oil. The
mixture was concentrated by evaporation under vacuum using a rotary
evaporator. This resulted in 22.3 g (100%) of 2-chlorobenzoyl
chloride as yellow oil.
2. Synthesis of 2-chloro-N'-tosylbenzohydrazide
[1061] Into a 500 mL round bottom flask was placed a solution of
2-chlorobenzoyl chloride (22.3 g, 127.43 mmol) in toluene (200 mL).
To the mixture was added 4-methylbenzenesulfonohydrazide (23.3 g,
125.27 mmol). The resulting solution was allowed to react, with
stirring, overnight while the temperature was maintained at
75.degree. C. in a bath of oil. A filtration was performed. The
filter cake was dried in an oven under reduced pressure. This
resulted in 37.7 g (91%) of 2-chloro-N'-tosylbenzohydrazide as a
white solid.
3. Synthesis of
N'-(chloro(2-chlorophenyl)methylene)-4-methylbenzenesulfonohydrazide
[1062] Into a 500 mL round bottom flask was placed
2-chloro-N'-tosylbenzohydrazide (10 g, 30.79 mmol). To this was
added SOCl.sub.2 (36.6 g, 307.56 mmol). The resulting solution was
allowed to react, with stirring, for 1.5 hours while the
temperature was maintained at 75.degree. C. in a bath of oil. To
the mixture was added 2-chloro-N'-tosylbenzohydrazide (10 g, 30.79
mmol), while cooling to a temperature of 60.degree. C. The
resulting solution was allowed to react, with stirring, for an
additional 2 hours while the temperature was maintained at
75.degree. C. in a bath of oil. The reaction mixture was then
quenched by the adding 100 mL of n-hexane. A filtration was
performed. The filter cake was washed with n-hexane. The solid was
dried in an oven under reduced pressure. This resulted in 19.6 g
(74%) of
N'-(chloro(2-chlorophenyl)methylene)-4-methylbenzene-sulfonohydrazide
as a white solid.
4. Synthesis of tert-butyl
4-(1-tosyl-1H-indazol-3-yl)piperazine-1-carboxylate
[1063] Into a 500 mL round bottom flask was placed a solution of
tert-butyl piperazine-1-carboxylate (11.9 g, 63.98 mmol) in NMP
(100 mL). This was followed by the addition of a solution of
N'-(chloro(2-chlorophenyl)methylene)-4-methylbenzenesulfonohydrazide
(11 g, 32.07 mmol) in NMP (100 mL), which was added dropwise with
stirring. The resulting solution was allowed to react, with
stirring, for 40 minutes while the temperature was maintained at
room temperature. To the mixture was added K.sub.2CO.sub.3 (6.2 g,
44.93 mmol). The resulting solution was allowed to react, with
stirring, for an additional 4 hours while the temperature was
maintained at 40.degree. C. in a bath of oil. The reaction progress
was monitored by TLC (ethyl acetate/petroleum ether=1:1). The
reaction mixture was then quenched by the adding 100 mL of
H.sub.2O/ice. The reaction was filtered. The filter cake was washed
with water. This resulted in 13.8 g (87%) of piperazine analog as a
white solid.
[1064] Into a 500 mL round bottom flask was placed the obtained
piperazine analog (13.8 g, 27.99 mmol). To this was added Cu (900
mg, 14.06 mmol). Addition of K.sub.2CO.sub.3 (3.8 g, 27.54 mmol)
was next. To the mixture was added DMF (200 mL). The resulting
solution was allowed to react, with stirring, for 1.5 hours while
the temperature was maintained at reflux in a bath of oil. The
reaction progress was monitored by TLC (ethyl acetate/petroleum
ether=1:2). The reaction mixture was then quenched by the adding
100 mL of H.sub.2O. The resulting solution was extracted one time
with 200 mL of ethyl acetate and the organic layers combined and
dried over MgSO.sub.4 and concentrated by evaporation under vacuum
using a rotary evaporator. This resulted in 7 g (55%) of tert-butyl
4-(1-tosyl-1H-indazol-3-yl)piperazine-1-carboxylate as a white
solid.
5. Synthesis of tert-butyl
4-(1H-indazol-3-yl)piperazine-1-carboxylate
[1065] Into a 500 mL 3-necked round bottom flask purged and
maintained with an inert atmosphere of nitrogen was placed
tert-butyl 4-(1-tosyl-1H-indazol-3-yl)piperazine-1-carboxylate (6
g, 13.16 mmol). To this was added NaOH (1.3 g, 32.50 mmol).
Addition of methanol (100 mL) was next. To the mixture was added
H.sub.2O (40 mL). The resulting solution was allowed to react, with
stirring, for 4 hours while the temperature was maintained at
90.degree. C. in a bath of oil. The reaction progress was monitored
by TLC (ethyl acetate/petroleum ether=1:1). The mixture was
concentrated by evaporation under vacuum using a rotary evaporator.
The resulting solution was extracted one time with 200 mL of ethyl
acetate and the organic layers combined and dried over
Na.sub.2SO.sub.4. The residue was purified by eluting through a
column with a 1:5 ethyl acetate/petroleum ether solvent system.
This resulted in 3.0 g (60%) of tert-butyl
4-(1H-indazol-3-yl)piperazine-1-carboxylate as a white solid.
[1066] .sup.1HNMR (400 Hz, CDCl.sub.3) .delta. 1.5 (s, 9H) 3.4 (m,
4H) 3.6 (m, 4H) 7.10 (m, 1H) 7.39 (m, 2H) 7.73 (m, 1H). m/z: 303
(M.sup.++1).
Synthesis of tert-butyl
4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperazine-1-carboxylate
##STR00124##
[1067] 1. Synthesis of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde
[1068] Into a 250 mL round bottom flask was placed
1H-pyrrolo[2,3-b]pyridine (10 g, 84.75 mmol). To this was added
HMTA (hexamethylenetetramine) (17.8 g, 126.99 mmol). Addition of
acetic acid (36 mL) was next. To the mixture was added H.sub.2O (70
mL). The resulting solution was bath of oil. The resulting solution
was diluted with 200 mL of H.sub.2O. The reaction mixture was
cooled. A filtration was performed and the filtrate cake was washed
with H.sub.2O. This resulted in 7.5 g (61%) of
1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde as a white solid.
2. Synthesis of
1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde
[1069] Into a 100 mL 3-necked round bottom flask was placed
tetrahydrofuran (50 mL). To the above was added NaH (2.19 g, 54.75
mmol) in several batches, while cooling to a temperature of
0.degree. C. This was followed by the addition of a solution of
1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2 g, 13.70 mmol) in
tetrahydrofuran (400 mL), which was added dropwise with stirring,
while cooling to a temperature of 0.degree. C. The resulting
solution was allowed to react, with stirring, for 30 minutes while
the temperature was maintained at room temperature. This was
followed by the addition of a solution of benzenesulfonyl chloride
(3.63 g, 20.55 mmol) in tetrahydrofuran (50 mL), which was added
dropwise with stirring, while cooling to a temperature of 0.degree.
C. The resulting solution was allowed to react, with stirring, for
3 hours while the temperature was maintained at room temperature.
The reaction mixture was then quenched by the adding of H.sub.2O.
The mixture was concentrated by evaporation under vacuum using a
rotary evaporator. The residue was dissolved in 300 mL of ethyl
acetate. The resulting mixture was washed two times with 200 mL of
brine and the organic layers combined. The mixture was dried over
Na.sub.2SO.sub.4 and concentrated by evaporation under vacuum using
a rotary evaporator. The resulting mixture was washed with ethyl
acetate/petroleum ether=1:40. This resulted in 3.4 g (82%) of
1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde as a
light yellow solid.
3. Synthesis of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl
formate
[1070] Into a 250 mL 3-necked round bottom flask was placed
dichloromethane (30 mL). To the mixture was added mCPBA
(m-chloroperbenzoic acid) (2.78 g, 13.69 mmol), while cooling to a
temperature of 0.degree. C. This was followed by the addition of a
solution of
1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (3 g,
10.49 mmol) in dichloromethane (100 mL), which was added dropwise
with stirring, while cooling to a temperature of 0.degree. C. The
resulting solution was allowed to react, with stirring, 2 hours
while the temperature was maintained at 0.degree. C. Then the
resulting solution was allowed to react, with stirring, overnight
while the temperature was maintained at 30.degree. C. in a bath of
oil. The reaction progress was monitored by LC-MS. The residue was
purified by eluting through a column with a 1:10 ethyl
acetate/petroleum ether solvent system. This resulted in 2 g (63%)
of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl formate as a
light yellow solid.
4. Synthesis of tert-butyl
4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperazine-1-carboxyl-
ate
[1071] Into a 150 mL sealed tube was placed
1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl formate (1.5 g,
4.97 mmol). To this was added tert-butyl piperazine-1-carboxylate
(9.24 g, 49.68 mmol). Addition of p-toluenesulfonic acid (171 mg,
0.99 mmol) was next. To the mixture was added toluene (70 mL).
After nitrogen bubbled, the resulting solution was allowed to
react, with stirring, overnight while the temperature was
maintained at 120.degree. C. in a bath of oil. The mixture was
concentrated by evaporation under vacuum using a rotary evaporator.
The residue was dissolved in 300 mL of ethyl acetate. The resulting
mixture was washed 2 times with 150 mL of brine. The mixture was
dried over Na.sub.2SO.sub.4. The residue was purified by eluting
through a column with a 1:2 ethyl acetate/petroleum ether solvent
system. This resulted in 420 mg (18%) of tert-butyl
4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperazine-1-carboxyl-
ate as a yellow solid.
5. Synthesis of tert-butyl
4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperazine-1-carboxylate
[1072] Into a 50 mL round bottom flask purged and maintained with
an inert atmosphere of nitrogen was placed tert-butyl
4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperazine-1-carboxyl-
ate (400 mg, 0.90 mmol). To this was added NaOH (90 mg, 2.25 mmol).
Addition of methanol (20 mL) was next. To the mixture was added
H.sub.2O (8 mL). The resulting solution was allowed to react, with
stirring, for 4 hours while the temperature was maintained at
90.degree. C. in a bath of oil. The mixture was concentrated by
evaporation under vacuum using a rotary evaporator. A filtration
was performed and the filter cake was washed with H.sub.2O. This
resulted in 180 mg (66%) of tert-butyl
4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperazine-1-carboxylate as a
light yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.40
(s, 9H), 2.96 (m, 4H), 3.56 (m, 4H), 6.73 (s, 1H), 6.97 (d, 1H),
7.88 (d, 1H), 8.22 (d, 1H), 8.97 (s, 1H). m/z 303 (M.sup.++1).
Example 1
Synthesis of 1-methylindoline-6-sulfonyl chloride
##STR00125##
[1073] 1) Synthesis of 1-methylindoline
[1074] NaH (15 g, 375.00 mmol) was added in several batches to a
chilled (0.degree. C.) solution of indoline (30 g, 252.10 mmol) in
tetrahydrofuran (400 mL). Methyl iodide (53 g, 373.24 mmol) was
then added dropwise with stirring, while maintaining the
temperature of 0.degree. C. The resulting solution was stirred at
room temperature for 15 hours, then quenched by the addition of
ethanol (200 mL). The mixture was concentrated, water (400 mL) was
added, and the product was extracted with methylene chloride
(3.times.200 mL). The organics were combined, dried
(Na.sub.2SO.sub.4), filtered and concentrated to provide 20.4 g
(60%) of 1-methylindoline as a brown liquid.
2) Synthesis of 1-methylindoline-6-sulfonyl chloride
[1075] ClSO.sub.3H (400 g, 3.45 mol) was cooled to 0.degree. C. and
1-methylindoline (35 g, 263.16 mmol) was added dropwise with
stirring, maintaining the temperature at 0.degree. C. The resulting
solution was then warmed to room temperature and stirred for 20
hours. The reaction mixture was added carefully then dropwise to 3
L of iced water and the resulting solution was extracted using
dichloromethane (3.times.400 mL). The organic layers were combined,
dried (Na.sub.2SO.sub.4) and concentrated. The resulting residue
was purified by column chromatography using a 1:30 ethyl
acetate/petroleum ether solvent system. The collected fractions
were combined and concentrated to give 4.2 g (7%) of
1-methylindoline-6-sulfonyl chloride as a brown solid. .sup.1H NMR
(CDCl.sub.3) .delta. 7.34 (d, 1H), 7.20 (d, 1H), 6.95 (s, 1H), 3.52
(t, 2H), 3.08 (t, 2H), 2.86 (s, 3H).
Example 2
Synthesis of 3-(Dimethylamino)benzene-1-sulfonyl chloride
##STR00126##
[1077] Sulfurochloridic acid (100 g, 862.07 mmol) was cooled to
0.degree. C. and N,N-dimethylbenzenamine (20 g, 165.29 mmol) was
added dropwise with stirring, maintaining a temperature of
0.degree. C. The resulting solution was then heated to 120.degree.
C. and stirred for 3 hours. After cooling to room temperature,
dichloromethane (40 mL) was added and the resulting mixture was
added dropwise to 100 mL of ice/salt water. The resulting solution
was extracted with dichloromethane (3.times.500 mL) and the organic
layers combined, dried (Na.sub.2SO.sub.4) and filtered. The
filtrate was concentrated and the residue was purified by column
chromatography using a 1:100 ethyl acetate/petroleum ether solvent
system. The collected fractions were combined and concentrated to
give 4.1 g (11%) of 3-(dimethylamino) benzene-1-sulfonyl chloride
as a yellow solid. .sup.1H NMR (CDCl.sub.3) .delta. 7.41 (t, 1H),
7.31 (d, 1H), 7.23 (s, 1H), 6.98 (m, 1H), 3.05 (s, 6H).
Example 3
Synthesis of 4-morpholinobenzene-1-sulfonyl chloride
##STR00127##
[1078] 1) Synthesis of 4-phenylmorpholine
[1079] 1-iodobenzene (28.12 g, 137.84 mmol) was added to morpholine
(12.0 g, 137.93 mmol). L-Proline (3.12 g, 27.13 mmol) was then
added, followed by the addition of CuI (2.6 g, 13.68 mmol) and DMSO
(120 mL). The resulting solution was stirred at 90.degree. C. for 4
hours, and then the reaction mixture was then quenched by the
addition of 300 mL of iced water. The resulting solution was
extracted using dichloromethane (2.times.200 mL), and the organic
layers combined, dried (Na.sub.2SO.sub.4) and concentrated. The
residue was purified by column chromatography using a petroleum
ether solvent system. The collected fractions were combined and
concentrated to give 10 g (42%) of 4-phenylmorpholine as a white
solid.
2) Synthesis of 4-morpholinobenzene-1-sulfonyl chloride
[1080] Sulfurochloridic acid (71.0 g, 612.07 mmol) was cooled to
0.degree. C. and 4-phenylmorpholine (20.0 g, 122.53 mmol) was added
in several batches, while keeping the temperature at 0.degree. C.
The resulting solution was then stirred at 90.degree. C. for 20
hours. The reaction mixture was then added dropwise to 200 mL of
ice/salt. The resulting solution was extracted with ethyl acetate
(2.times.200 mL) and the organic layers were combined, dried
(MgSO.sub.4) and filtered. The filtrate was concentrated, and the
residue was purified by column chromatography using a 20:1 ethyl
acetate/petroleum ether solvent system to give 4.7 g of
4-morpholinobenzene-1-sulfonyl chloride as a yellow solid. .sup.1H
NMR (CDCl.sub.3) .delta. 7.9 (d, 2H), 6.9 (d, 1H), 7.5 (d, 2H),
3.87 (t, 2H), 3.4 (t, 2H).
Example 4
Synthesis of 1-ethylindoline-5-sulfonyl chloride
##STR00128##
[1081] 1) Synthesis of 1-ethylindoline
[1082] NaH (10 g) was added to a chilled (0.degree. C.) solution of
indoline (30 g, 252.10 mmol) in tetrahydrofuran (300 mL). The
resulting solution was then stirred at room temperature for 30
minutes. Iodoethane (50 g, 322.58 mmol) was then added dropwise and
the resulting solution was maintained at room temperature for an
additional 3 hours. The reaction mixture was then quenched by
adding ethanol (100 mL). The resulting solution was extracted with
dichloromethane (3.times.500 mL), and the organic layers were
combined and concentrated. The residue was purified by column
chromatography using a 100:1 ethyl acetate/petroleum ether solvent
system to give 29 g (78%) of 1-ethylindoline as yellow oil.
2) Synthesis of 1-ethylindoline-5-sulfonyl chloride
[1083] 1-ethylindoline (15 g, 102.04 mmol) was added at 0.degree.
C. to ClSO.sub.1H (60 g). The resulting solution was stirred at
50.degree. C. overnight, then the reaction was quenched by adding
300 g iced water. The resulting solution was extracted with
dichloromethane (3.times.600 mL) and the organic layers were
combined, dried (MgSO.sub.4) and concentrated. The residue was then
purified by column chromatography using a 1:100 ethyl
acetate/petroleum ether solvent system to give 1.5 g (6%) of
1-ethylindoline-5-sulfonyl chloride as a yellow solid. 1H NMR
(CDCl.sub.3) .delta. 7.28 (d, 1H), 7.18 (d, 1H), 7.11 (s, 1H), 3.39
(q, 2H), 3.52 (t, 2H), 3.06 (t, 2H), 1.23 (t, 3H).
Example 5
Synthesis of 2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonyl
chloride
##STR00129##
[1084] 1) Synthesis of benzo[d]oxazol-2(3H)-one
[1085] Triethylamine (27.0 mL) was added to a mixture of
2-aminophenol (10 g, 91.74 mmol) in dichloromethane (200 mL) at
5.degree. C. This was followed by the addition of a solution of
bis(trichloromethyl) carbonate (9.35 g, 31.48 mmol) in
dichloromethane (40 mL), while maintaining the temperature below
10.degree. C. The resulting solution was then maintained below
10.degree. C. for 6 hours. The reaction mixture was then quenched
by the addition of water (50 mL) and ethanol (20 mL). After 0.5
hours, the mixture was concentrated and then poured into 400 mL of
water. After filtration, the filter cake was washed with
hydrochloric acid (10%) and water to afford 10 g (48%) of
benzo[d]oxazol-2(3H)-one as an off-white solid.
2) Synthesis of 2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonyl
chloride
[1086] Sulfurochloridic acid (70 g, 603.45 mmol) was cooled to
0.degree. C. and benzo[d]oxazol-2(3H)-one (1.8 g, 13.33 mmol) was
added in several batches, maintaining the temperature at about
0.degree. C. The resulting solution was stirred at room temperature
for 3 hours, then quenched by the addition 400 mL of iced water.
The resulting solution was extracted with ethyl acetate
(3.times.100 mL) and the organic layers were combined, dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue was
purified by column chromatography using a 1:10 ethyl
acetate/petroleum ether solvent system to afford 0.8 g (26%) of
2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonyl chloride as a white
solid. .sup.1H NMR (CDCl.sub.3) .delta. 8.26 (s, 1H), 8.00 (d, 1H),
7.98 (d, 1H), 7.32 (s, 1H).
Example 6
Synthesis of 3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonyl
chloride
##STR00130##
[1087] 1) Synthesis of benzo[d]oxazol-2(3H)-one
[1088] Triethylamine (27.0 mL) was added to a mixture of
2-aminophenol (10 g, 91.74 mmol) in CH.sub.2Cl.sub.2 (200 mL) at
5.degree. C. A solution of bis(trichloromethyl) carbonate (9.35 g,
31.48 mmol) in dichloromethane (40 mL) was then added, maintaining
the temperature below 10.degree. C. The resulting solution was then
maintained below 10.degree. C. for 6 hours. The reaction mixture
was then quenched by the addition of water (50 mL) and ethanol (20
mL). After 0.5 hours, the mixture was concentrated and then poured
into 400 mL of H.sub.2O. After filtration, the filter cake was
washed with hydrochloric acid (10%) and water to afford 10 g (48%)
of benzo[d]oxazol-2(3H)-one as an off-white solid.
2) Synthesis of 3-methylbenzo[d]oxazol-2-(3H)-one
[1089] NaH (280 mg, 7.00 mmol) was added to a chilled (0.degree.
C.) solution of benzo[d]oxazol-2(3H)-one (650 mg, 4.81 mmol) in
tetrahydrofuran (20 mL). After 0.5 hours, methyl iodide (1.03 g,
7.25 mmol) was added dropwise with stirring, maintaining a
temperature of 0.degree. C. The resulting solution was then stirred
for 6 hours at room temperature. The reaction mixture was then
quenched by the addition of ethanol (10 mL), and the mixture was
concentrated. Water (50 mL) was then added and the resulting
solution was extracted with dichloromethane (3.times.20 mL). The
organic layers were combined, dried (Na.sub.2SO.sub.4), filtered
and concentrated to afford 0.62 g (82%) of 3-methylbenzo[d]oxazol-2
(3H)-one as a light red solid.
3) Synthesis of
3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonyl chloride
[1090] 3-methylbenzo[d]oxazol-2(3H)-one (620 mg, 4.16 mmol) was
added, in several batches, to chilled sulfurochloridic acid (17.5
g, 150.86 mmol) at 0.degree. C. The resulting solution was stirred
at room temperature for 3 hours, then quenched by adding it slowly
to 200 mL of ice/salt. The resulting solution was extracted with
ethyl acetate (3.times.40 mL). The organic layers were combined,
dried (Na.sub.2SO.sub.4), filtered and concentrated to afford 0.5 g
(46%) of 3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonyl
chloride as a light brown solid. .sup.1H NMR (CDCl.sub.3) .delta.
8.00 (d, 1H), 7.97 (s, 1H), 7.16 (d, 1H), 3.52 (s, 3H).
Example 7
Synthesis of 4-(pyrrolidin-1-yl)benzene-1-sulfonyl chloride
##STR00131##
[1091] 1) Synthesis of 1-phenylpyrrolidine
[1092] Pyrrolidine (21.6 g, 304.23 mmol), L-proline (1.12 g, 9.74
mmol), and CuI (960 mg, 5.05 mmol) were added sequentially to
1-iodobenzene (10.0 g, 49.02 mmol). DMSO (40 mL) was then added,
and the resulting solution was stirred at 60.degree. C. for 20
hours. The reaction mixture was then quenched by adding 400 mL of
iced water. The resulting solution was extracted with ethyl acetate
(3.times.150 mL), and the organic layers were combined, dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue was
purified by column chromatography using a 1:100 ethyl
acetate/petroleum ether solvent system to afford 4.3 g (57%) of
1-phenylpyrrolidine as brown oil.
2) Synthesis of 4-(pyrrolidin-1-yl)benzenesulfonic acid
[1093] A solution of H.sub.2SO.sub.4 (6.8 g, 68.00 mmol) in
diethylether (80 mL) was added to 1-phenylpyrrolidine (10 g, 68.03
mmol) in diethylether (20 mL) at 0.degree. C. The diethylether was
decanted, and the resulting solution was stirred for 3 hours at
170.degree. C., then concentrated in vacuo to afford 7.3 g (43%) of
4-(pyrrolidin-1-yl)benzenesulfonic acid as a white solid.
3) Synthesis of 4-(pyrrolidin-1-yl)benzene-1-sulfonyl chloride
[1094] DMF (0.5 mL) was added to solution of
4-(pyrrolidin-1-yl)benzenesulfonic acid (7.3 g, 32.16 mmol) in
dichloromethane (40 mL). Oxalyl chloride (10 g, 78.74 mmol) was
then dropwise and the resulting solution was maintained at room
temperature for 1 hour. The reaction mixture was then quenched by
the addition of 40 mL of iced water. The resulting solution was
extracted using dichloromethane (3.times.20 mL), and the organic
layers were combined, dried (Na.sub.2SO.sub.4), filtered and
concentrated. The residue was purified by column chromatography
using a 1:100 ethyl acetate/petroleum ether solvent system to
afford 1.5 g (19%) of 4-(pyrrolidin-1-yl)benzene-1-sulfonyl
chloride as a yellow solid. .sup.1H NMR (CDCl.sub.3) .delta. 7.78
(d, 2H), 6.55 (d, 2H), 3.41 (t, 4H), 2.03 (t, 4H).
Example 8
Synthesis of 3-(pyrrolidin-1-yl)benzene-1-sulfonyl chloride
##STR00132##
[1095] 1) Synthesis of 1-phenylpyrrolidine
[1096] Pyrrolidine (21.6 g, 304.23 mmol), L-proline (1.12 g, 9.74
mmol), and CuI (960 mg, 5.05 mmol) were added sequentially to
1-iodobenzene (10.0 g, 49.02 mmol). Dimethyl sulfoxide (40 mL) was
then added, and the resulting solution was stirred at 60.degree. C.
for 20 hours. The reaction mixture was then quenched by adding 400
mL of iced water. The resulting solution was extracted with ethyl
acetate (3.times.150 mL), and the organic layers were combined,
dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue
was purified by column chromatography using a 1:100 ethyl
acetate/petroleum ether solvent system to afford 4.3 g (57%) of
1-phenylpyrrolidine as brown oil.
2) Synthesis of 3-(pyrrolidin-1-yl)benzene-1-sulfonyl chloride
[1097] 1-phenylpyrrolidine (4.3 g, 29.25 mmol) was added dropwise
to sulfurochloridic acid (20 mL) at 0.degree. C. and the resulting
solution was then maintained at 60.degree. C. overnight. The
reaction mixture was then quenched by adding 200 mL of ice/salt.
The resulting solution was extracted with ethyl acetate
(3.times.100 mL), and the organic layers were combined, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by column chromatography using a 1:500 ethyl
acetate/petroleum ether solvent system. The collected fractions
were combined and concentrated to give 0.5 g (7%) of
3-(pyrrolidin-1-yl)benzene-1-sulfonyl chloride as a yellow solid.
NMR (CDCl.sub.3) .delta. 7.36 (m, 1H), 7.24 (d, 1H), 7.07 (s, 1H),
6.82 (d, 1H), 3.34 (t, 4H), 2.05 (t, 4H).
Example 9
Synthesis of 4-(N-methylacetamido)benzene-1-sulfonyl chloride
##STR00133##
[1098] 1) Synthesis of N-methyl-N-phenylacetamide
[1099] (CH.sub.3C0).sub.2O (50 g, 480.77 mmol) was added to
N-methylbenzenamine (10.7 g, 100.00 mmol), and the resulting
solution was stirred at room temperature for 15 hours. The reaction
mixture was then quenched by adding 200 mL of iced water. The
resulting solution was extracted with dichloromethane (2.times.100
mL), and the organic layers were combined and concentrated to
afford 11 g (70%) of N-methyl-N-phenylacetamide as a white
solid.
2) Synthesis of 4-(N-methylacetamido)benzene-1-sulfonyl
chloride
[1100] A solution of N-methyl-N-phenylacetamide (11 g, 73.83 mmol)
in dichloromethane (20 mL) was added dropwise to HSO.sub.3Cl (80 g,
689.66 mmol) at 5.degree. C. The resulting solution was then
stirred at room temperature overnight. The reaction mixture was
then quenched by adding 100 mL of iced water. The resulting
solution was extracted using dichloromethane (2.times.50 mL) and
the organic layers were combined. The residue was purified by
column chromatography using a 10:1 ethyl acetate/petroleum ether
solvent system to give 2.2 g (11%) of
4-(N-methylacetamido)benzene-1-sulfonyl chloride as a white solid.
.sup.1H NMR (CDCl.sub.3) .delta. 8.09 (d, 2H), 7.48 (d, 2H), 3.38
(s, 3H), 2.17 (s, 3H).
Example 10
Synthesis of
1-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroquinoline-6-sulfonyl
chloride
##STR00134##
[1101] 1) Synthesis
1-(3,4-dihydroquinolin-1(2H)-yl)-2,2,2-trifluoroethanone
[1102] A solution of O(COCF.sub.3).sub.2 (6.3 g, 29.95 mmol) in
CHCl.sub.3 (30 mL) was added dropwise to a solution of
1,2,3,4-tetrahydroquinoline (2.66 g, 19.97 mmol) in chloroform (20
mL) at 5.degree. C., and the resulting mixture was stirred for 2
hours at room temperature. The mixture was concentrated, and the
residue was purified by column chromatography using a 1:10 ethyl
acetate/petroleum ether solvent system to afford 4 g (87%) of
1-(3,4-dihydroquinolin-1(2H)-yl)-2,2,2-trifluoroethanone as a
yellow liquid.
2) Synthesis of
1-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroquinoline-6-sulfonyl
chloride
[1103] 1-(3,4-dihydroquinolin-1(2H)-yl)-2,2,2-trifluoroethanone (4
g, 17.45 mmol) was added to HSO.sub.3Cl (30 g, 258.62 mmol) at
0.degree. C. The resulting solution was maintained at room
temperature overnight. The reaction mixture was then quenched by
adding 100 mL of iced water and the resulting solution was
extracted with dichloromethane (3.times.50 mL). The residue was
purified by column chromatography using a 1:10 ethyl
acetate/petroleum ether solvent system to afford 1.2 g (21.4%) of
1-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroquinoline-6-sulfonyl
chloride as a white solid. .sup.1H NMR (CDCl.sub.3) .delta. 8.01
(d, 1H), 7.89 (s, 1H), 7.87 (s, 1H), 3.91 (t, 2H), 3.01 (t, 2H),
2.16 (m, 2H).
Example 11
Synthesis of 1-methyl-1,2,3,4-tetrahydroquinoline-7-sulfonyl
chloride
##STR00135##
[1104] 1) Synthesis of 1-methyl-1,2,3,4-tetrahydroquinoline
[1105] NaH (12 g, 60%, 300.00 mmol) was added in several batches,
to a solution of 1,2,3,4-tetrahydroquinoline (26.6 g, 199.70 mmol)
in tetrahydrofuran (150 mL) at 0-5.degree. C. The resulting
solution was maintained at 0-5.degree. C. for 30 minutes, then
iodomethane (50 g, 352.11 mmol) was added dropwise (at 0-5.degree.
C.). The resulting solution was then stirred at room temperature
overnight. The mixture was filtered, and the filtrate was purified
by column chromatography using a 1:100 ethyl acetate/petroleum
ether solvent system to afford 19 g (61%) of
1-methyl-1,2,3,4-tetrahydroquinoline as a yellow liquid.
2) Synthesis of 1-methyl-1,2,3,4-tetrahydroquinoline-7-sulfonyl
chloride
[1106] A solution of 1-methyl-1,2,3,4-tetrahydroquinoline (10 g,
68.03 mmol) in dichloromethane (20 mL) was added dropwise to
HSO.sub.3Cl (80 g, 689.66 mmol) at 0-5.degree. C., and the
resulting solution was maintained at room temperature overnight.
The reaction mixture was then quenched by adding 300 mL of iced
water. The resulting solution was extracted using ethyl acetate
(3.times.150 mL). The organic layers were combined, concentrated,
and the residue was purified by column chromatography using a 1:20
ethyl acetate/petroleum ether solvent system to afford
1-methyl-1,2,3,4-tetrahydroquinoline-7-sulfonyl chloride as a
yellow liquid in 8% yield. .sup.1H NMR (CDCl.sub.3) .delta. 7.19
(d, 1H), 7.10 (d, 1H), 7.06 (s, 1H), 3.33 (t, 2H), 2.97 (s, 3H),
2.81 (d, 2H), 1.99 (m, 2H).
Example 12
Synthesis of 1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonyl
chloride
##STR00136##
[1107] 1) Synthesis of 1-methyl-1,2,3,4-tetrahydroquinoline
[1108] NaH (12 g, 60%, 300.00 mmol) was added in several batches,
to a solution of 1,2,3,4-tetrahydroquinoline (26.6 g, 199.70 mmol)
in tetrahydrofuran (150 mL) at 0-5.degree. C. The resulting
solution was maintained at 0-5.degree. C. for 30 minutes, then
iodomethane (50 g, 352.11 mmol) was added dropwise (at 0-5.degree.
C.). The resulting solution was stirred at room temperature
overnight. The mixture was filtered, and the filtrate was purified
by column chromatography using a 1:100 ethyl acetate/petroleum
ether solvent system to give 19 g (61%) of
1-methyl-1,2,3,4-tetrahydroquinoline as a yellow liquid.
2) Synthesis of 1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonic
acid
[1109] A solution of H.sub.2SO.sub.4 (6 g, 60.00 mmol) in ether (40
mL) was added dropwise to a solution of
1-methyl-1,2,3,4-tetrahydroquinoline (9 g, 61.14 mmol) in
diethylether (10 mL) at 5.degree. C. The resulting solution was
maintained at room temperature for 30 minutes, then under vacuum,
with stirring, for an additional 3 hours at 170.degree. C. The
resulting mixture was washed with methanol (1.times.100 mL) and
filtered to afford 5 g (34%) of
1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonic acid as a white
solid.
3) Synthesis of 1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonyl
chloride
[1110] Oxalyl chloride (20 g, 157.60 mmol) was added dropwise at
room temperature to a solution of
1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonic acid (5 g, 22.00
mmol) in dichloromethane (100 mL) and DMF (10 mL). The resulting
solution was stirred for 2 hours, then quenched by adding 200 mL of
iced water. The resulting solution was extracted using
dichloromethane (2.times.100 mL), and the combined organics were
dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue
was purified by column chromatography using a 1:4 ethyl
acetate/petroleum ether solvent system to afford 1.1 g (20.1%) of
1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonyl chloride as a
yellow solid. NMR (CDCl.sub.3) .delta. 7.69 (d, 1H), 7.51 (s, 1H),
6.54 (d, 1H), 3.57 (t, 2H), 3.02 (s, 3H), 2.78 (d, 2H), 1.98 (m,
2H).
Example 13
Synthesis of 2-methyl-1,2,3,4-tetrahydroisoquinoline-8-sulfonyl
chloride
##STR00137##
[1111] 1. Synthesis of 5-bromoisoquinoline
[1112] Into a 250 mL 3-necked round bottom flask was placed
H.sub.2SO.sub.4 (150 mL). To the above was added isoquinoline (17
g, 131.62 mmol) in several batches, while cooling to a temperature
of 0.degree. C. To the above was added NBS (29.2 g, 164.04 mmol) in
several batches, while cooling to a temperature of -25--22.degree.
C. The resulting solution was allowed to react, with stirring, for
2 hours while the temperature was maintained at -25--22.degree. C.
The resulting solution was allowed to react, with stirring,
overnight while the temperature was maintained at room temperature.
The reaction progress was monitored by TLC (ethyl acetate/petroleum
ether=1:5). The reaction mixture was then quenched by the adding
1000 mL of H.sub.2O/ice. Adjustment of the pH to 8-10 was
accomplished by the addition of NH.sub.3. H.sub.2O (30%). The
resulting solution was extracted four times with 500 mL of ethyl
acetate and the organic layers combined and dried over
Na.sub.2SO.sub.4. The residue was purified by eluting through a
column with a 1:5 ethyl acetate/petroleum ether solvent system.
This resulted in 22.24 g (81%) of 5-bromoisoquinoline as a white
solid.
2. Synthesis of 5-bromo-8-nitroisoquinoline
[1113] Into a 500 mL 3-necked round bottom flask was placed a
solution of 5-bromoisoquinoline (22.24 g, 106.87 mmol) in
H.sub.2SO.sub.4 (120 mL). This was followed by the addition of a
solution of KNO.sub.3 (15.1 g, 149.36 mmol) in H.sub.2SO.sub.4 (100
mL), which was added dropwise with stirring, while cooling to a
temperature of 20.degree. C. over a time period of 1 hour. The
resulting solution was allowed to react, with stirring, for 1 hour
while the temperature was maintained at room temperature. The
reaction progress was monitored by TLC (ethyl acetate/petroleum
ether=1:5). The reaction mixture was then quenched by the adding
600 mL of H.sub.2O/ice. Adjustment of the pH to 8-10 was
accomplished by the addition of NH.sub.3. H.sub.2O (30%). A
filtration was performed. The filter cake was washed 2 times with
500 mL of H.sub.2O. The solid was dried in an oven under reduced
pressure. This resulted in 25.59 g (90%) of
5-bromo-8-nitroisoquinoline as a yellow solid.
3. Synthesis of 5-bromo-8-nitro-N-methylisoquinolinium iodide
[1114] Into a 500 mL round bottom flask, was placed a solution of
5-bromo-8-nitroisoquinoline (25.59 g, 101.11 mmol) in DMF (200 mL).
To the mixture was added iodomethane (71.8 g, 505.99 mmol). The
resulting solution was allowed to react, with stirring, overnight
while the temperature was maintained at 40.degree. C. A filtration
was performed. The filter cake was washed 2 times with 250 mL of
ether. This resulted in 33.33 g (83%) of
5-bromo-8-nitro-N-methylisoquinolinium iodide as a red solid.
4. Synthesis of
5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline
[1115] Into a 500 mL 3-necked round bottom flask was placed a
solution of Ni(NO.sub.3).sub.2.6H.sub.2O (12.6 g, 43.33 mmol) in
CH.sub.3OH (200 mL). To the mixture was added
5-bromo-8-nitro-N-methylisoquinolinium iodide (33.33 g, 84.38
mmol). To the above was added NaCNBH.sub.3 (10.6 g, 168.68 mmol) in
several batches. The resulting solution was allowed to react, with
stirring, for 5 hours while the temperature was maintained at room
temperature. The reaction progress was monitored by TLC (ethyl
acetate/petroleum ether=1:5). The resulting solution was
concentrated by evaporation under vacuum using a rotary evaporator.
The residue was dissolved with 800 mL of H.sub.2O. Adjustment of
the pH to 8-10 was accomplished by the addition of NaOH (5%). A
filtration was performed. The resulting solution was extracted 2
times with 800 mL of ethyl acetate and the organic layers combined
and dried over Na.sub.2SO.sub.4. The residue was purified by
eluting through a column with a 1:5 ethyl acetate/petroleum ether
solvent system. This resulted in 19.3 g (83%) of
5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline as a yellow
solid.
5. Synthesis of 2-methyl-1,2,3,4-tetrahydroisoquinolin-8-amine
[1116] Into a 250 mL 3-necked round bottom flask was added a
solution of 5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline
(4.85 g, 17.89 mmol) in CH.sub.3OH/Et.sub.3N(anhydrous) (150/15
mL). To the mixture was added Pd/C (4.5 g). Hydrogen gas was
bubbled into the mixture The resulting solution was allowed to
react, with stirring, for 3 hours while the temperature was
maintained at room temperature. The reaction progress was monitored
by TLC (ethyl acetate/petroleum ether=1:1). A filtration was
performed. The filtrate was concentrated by evaporation under
vacuum using a rotary evaporator. The resulting solution was
diluted with 50 mL of Na.sub.2CO.sub.3(10%). The resulting solution
was extracted four times with 50 mL of ethyl acetate and the
organic layers combined and dried over Na.sub.2SO.sub.4. The
residue was purified by eluting through a column with a 50:1
CH.sub.2Cl.sub.2/MeOH solvent system. This resulted in 2.57 g (89%)
of 2-methyl-1,2,3,4-tetrahydroisoquinolin-8-amine as a light yellow
oil.
6. Synthesis of 8-bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline
[1117] Into a 50 mL 3-necked round bottom flask (named A), was
placed 2-methyl-1,2,3,4-tetrahydroisoquinolin-8-amine (500 mg, 3.08
mmol). This was followed by the addition of a solution of HBr (5
mL) in H.sub.2O (5 mL), which was added dropwise with stirring,
while cooling to a temperature of 0.degree. C. To the above was
added NaNO.sub.2 (230 mg, 3.33 mmol) in several batches, while
cooling to a temperature of 0.degree. C. and the mixture was
stirred for 30 mins at that temperature. Then into another 50 mL
3-necked round bottom flask (named B), was purged and maintained
with an inert atmosphere of nitrogen, was placed a solution of CuBr
(550 mg, 3.83 mmol) in HBr/H.sub.2O (3 mol/L) (10 mL), while
cooling to a temperature of 0.degree. C. The mixture was stirred
for 10 minutes. Then was followed by the addition of the reaction
solution of flask A with dropwise while the temperature was
maintained at 0.degree. C. The resulting solution was allowed to
react, with stirring, for 30 minutes while the temperature was
maintained at 0.degree. C. The resulting solution was allowed to
react, with stirring, for an additional 2 hours at room
temperature. The reaction progress was monitored by TLC(ethyl
acetate:petroleum ether=1:1). Adjustment of the pH to 9 was
accomplished by the addition of NaOH (10%). The resulting solution
was extracted three times with 50 mL of CH.sub.2Cl.sub.2 and the
organic layers combined and dried over K.sub.2CO.sub.3. A
filtration was performed. The filtrate was concentrated by
evaporation under vacuum using a rotary evaporator. The residue was
purified by eluting through a column with a 1:1 ethyl acetate;
petroleum ether solvent system. This resulted in 0.45 g (65%) of
8-bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline as light yellow
oil.
7. Synthesis of 2-methyl-1,2,3,4-tetrahydroisoquinoline-8-sulfonyl
chloride
[1118] Into a 100 mL 3-necked round bottom flask purged and
maintained with an inert atmosphere of nitrogen was placed a
solution of 8-bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline (3 g,
13.27 mmol) in tetrahydrofuran (30 mL). To the above was added 2.5M
n-BuLi/hexane (6.9 mL), while cooling to a temperature of
-78.degree. C. over a time period of 15 minutes. The resulting
solution was allowed to react, with stirring, for 40 minutes while
the temperature was maintained at -78.degree. C. Addition of
SO.sub.2 (890 mg, 13.91 mmol) was next, while cooling to a
temperature of -100.degree. C. The resulting solution was allowed
to react, with stirring, for 20 minutes while the temperature was
maintained at -78.degree. C. The resulting solution was allowed to
react, with stirring, for an additional 1 hour while the
temperature was maintained at room temperature. This was followed
by the addition of n-hexane (60 mL). Then a filtration was
performed. A light yellow solid was obtained. In another 250 mL
3-necked round bottom flask was placed the above filter cake and
CH.sub.2Cl.sub.2 (80 mL). To the above was added NCS (2.7 g, 20.22
mmol) in several batches, while cooling to a temperature of
-10-0.degree. C. The resulting solution was allowed to react, with
stirring, for an additional 1 hour while the temperature was
maintained at room temperature. The reaction progress was monitored
by TLC(ethyl acetate:petroleum ether=3:2). The resulting mixture
was washed 2 times with 100 mL of saturated NaHSO.sub.3 and 2 times
with 50 mL of saturated NaCl. The mixture was dried over
Na.sub.2SO.sub.4. A filtration was performed. The filtrate was
concentrated by evaporation under vacuum using a rotary evaporator.
This resulted in 1.44 g (44%) of
2-methyl-1,2,3,4-tetrahydroisoquinoline-8-sulfonyl chloride as a
light yellow solid.
[1119] .sup.1HNMR (300 MHz, DMSO) .delta. 7.63 (d, 1H), 7.22 (m,
2H), 5.03 (d, 1H), 4.4 (m, 1H), 3.6 (d, 1H), 3.34 (d, 1H), 2.94 (m,
2H), 2.49 (s, 3H). m/z 246 [M+1].sup.+
Example 14
Synthesis of
4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl
chloride
##STR00138##
[1120] 1. Synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazine
[1121] Into a 250 mL 3-necked round bottom flask was placed a
solution of lithium aluminum hydride (3.6 g, 94.74 mmol) in
tetrahydrofuran (80 mL). The mixture was stirred for 15 minutes.
This was followed by the addition of a solution of
2H-benzo[b][1,4]oxazin-3(4H)-one (5.7 g, 38.22 mmol) in
tetrahydrofuran (21 mL), which was added dropwise with stirring.
The resulting solution was allowed to react, with stirring,
overnight while the temperature was maintained at reflux in a bath
of oil. The reaction progress was monitored by TLC (ethyl
acetate/petroleum ether=1:1). The reaction mixture was then
quenched by the adding 3.6 mL of H.sub.2O and 10.8 mL 15% NaOH. A
filtration was performed. The filter cake was washed with 30 mL of
tetrahydrofuran. The resulting solution was extracted two times
with 100 mL of ethyl acetate and the organic layers combined and
dried over Na.sub.2SO.sub.4 and concentrated by evaporation under
vacuum using a rotary evaporator. This resulted in 4.8 g (79%) of
3,4-dihydro-2H-benzo[b][1,4]oxazine as red oil.
2. Synthesis of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine
[1122] Into a 250 mL 3-necked round bottom flask was placed a
solution of 3,4-dihydro-2H-benzo[b][1,4]oxazine (4.8 g, 35.51 mmol)
in tetrahydrofuran (50 mL). To the above was added NaH (2.3 g,
57.50 mmol) in several batches, while cooling to a temperature of
0-5.degree. C. The mixture was stirred for 30 minutes at
0-5.degree. C. To the above was added iodomethane (9.0 g, 63.41
mmol) dropwise with stirring, while cooling to a temperature of
0-5.degree. C. The resulting solution was allowed to react, with
stirring, overnight while the temperature was maintained at room
temperature. The reaction progress was monitored by TLC (ethyl
acetate/petroleum ether=1:2). A filtration was performed. The
filtrate was concentrated by evaporation under vacuum using a
rotary evaporator. The residue was purified by eluting through a
column with a 1:100 ethyl acetate/petroleum ether solvent system.
This resulted in 3.0 g (50%) of
4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine as yellow oil.
3. Synthesis of
4-methyl-3,4-dihydro-21:1-benzo[b][1,4]oxazine-6-sulfonyl
chloride
[1123] Into a 250 mL 3-necked round bottom flask was placed
HSO.sub.3Cl (25 mL). To the above was added
4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (5.8 g, 38.93 mmol)
dropwise with stirring, while cooling to a temperature of
0-5.degree. C. The resulting solution was allowed to react, with
stirring, for 120 minutes while the temperature was maintained at
room temperature. The reaction progress was monitored by TLC (ethyl
acetate/petroleum ether=1:2). The reaction mixture was then
quenched by the adding of H.sub.2O/ice. The resulting solution was
extracted three times with 200 mL of ethyl acetate and the organic
layers combined and dried over Na.sub.2SO.sub.4 and concentrated by
evaporation under vacuum using a rotary evaporator. The resulting
mixture was washed 3 times with 15 mL of hexane. This resulted in
2.9 g (27%) of
4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride as
a light yellow solid.
[1124] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.98 (s, 3H), 3.36
(m, 2H), 4.38 (m. 2H), 6.87 (d, 1H), 7.19 (s, 1H), 7.34 (d, 1H).
m/z 319 [M+BnNH+H].sup.+
Example 15
Synthesis of 2-oxo-1,2,3,4-tetrahydroquinoline-7-sulfonyl
chloride
##STR00139##
[1125] 1. Synthesis of ethyl 3-phenylpropanoate
[1126] A 500 mL 3-necked round bottom flask was added a solution of
ethyl cinnamate (10 g, 56.75 mmol) in methanol (200 mL). To the
mixture was added Pd/C (2 g) followed by addition of hydrogen gas.
The resulting solution was allowed to react, with stirring,
overnight while the temperature was maintained at 35.degree. C. in
a bath of oil. A filtration was performed. The filtrate was
concentrated by evaporation under vacuum using a rotary evaporator.
This resulted in 10 g (99%) of ethyl 3-phenylpropanoate as a
colorless oil.
2. Synthesis of ethyl 3-(2,4-dinitrophenyl)propanoate
[1127] Into a 250 mL 3-necked round bottom flask was placed a
solution of fuming HNO.sub.3 (25 mL) in conc. H.sub.2SO.sub.4 (50
mL). To the mixture was added ethyl 3-phenylpropanoate (5 g, 28.09
mmol) while cooling to a temperature of 0.degree. C. The resulting
solution was allowed to react, with stirring, for 1 hour while the
temperature was maintained at 0.degree. C. The resulting solution
was allowed to react, with stirring, overnight while the
temperature was maintained at 60.degree. C. The reaction progress
was monitored by TLC (ethyl acetate/petroleum ether=1:3). The
reaction mixture was then quenched by the adding of H.sub.2O/ice.
The resulting solution was extracted two times with 50 mL of ethyl
acetate and the organic layers combined. The resulting mixture was
washed 2 times with 50 mL of NaHCO.sub.3(aq.). The mixture was
dried over MgSO.sub.4 and concentrated by evaporation under vacuum
using a rotary evaporator. This resulted in 2 g (27%) of ethyl
3-(2,4-dinitrophenyl)propanoate as a yellow solid.
3. Synthesis of 7-amino-3,4-dihydroquinolin-2(1H)-one
[1128] Into a 100 mL 3-necked round bottom flask was placed a
solution of ethyl 3-(2,4-dinitrophenyl)propanoate (1.5 g, 5.60
mmol) in methanol (20 mL). To the mixture was added Pd/C (0.5 g).
Hydrogen gas was passed through. The resulting solution was allowed
to react, with stirring, overnight while the temperature was
maintained at 30.degree. C. A filtration was performed. The
filtrate was concentrated by evaporation under vacuum using a
rotary evaporator. This resulted in 0.5 g (55%) of
7-amino-3,4-dihydroquinolin-2(1H)-one as a green-yellow solid.
4. Synthesis of 2-oxo-1,2,3,4-tetrahydroquinoline-7-sulfonyl
chloride
[1129] Into a 50 mL 3-necked round bottom flask was placed a
solution of 7-amino-3,4-dihydroquinolin-2(1H)-one (350 mg, 2.16
mmol) in conc.HCl (6 mL). This was followed by the addition of a
solution of sodium nitrite (200 mg, 2.90 mmol) in H.sub.2O (2 mL)
at -5-0.degree. C. The mixture was stirred for 30 minutes. Then the
resulting solution was added into a solution of copper chloride
(200 mg, 2.02 mmol) in CH.sub.3COOH (10 mL) that was saturated with
SO.sub.2 gas. The resulting solution was allowed to react, with
stirring, for 1 hour while the temperature was maintained at
10-30.degree. C. The reaction progress was monitored by
TLC(CH.sub.2Cl.sub.2/MeOH=10:1). The reaction mixture was then
quenched by the adding of H.sub.2O/ice. The resulting solution was
extracted two times with 20 mL of ethyl acetate and the organic
layers combined. The resulting mixture was washed 2 times with 10
mL of H.sub.2O and 1 time with 10 mL of NaHCO.sub.3/H.sub.2O. The
mixture was dried over Na.sub.2SO.sub.4. A filtration was
performed. The filtrate was concentrated by evaporation under
vacuum using a rotary evaporator. This resulted in 0.24 g (45%) of
2-oxo-1,2,3,4-tetrahydroquinoline-7-sulfonyl chloride as a brown
solid.
[1130] .sup.1HNMR (300 MHz, CDCl.sub.3)) .delta. 2.89 (m, 2H), 2.95
(m, 2H), 7.41 (m, 1H), 7.43 (m, 1H), 7.47 (m, 1H). m/z 315
[M-H].sup.-
Example 16
Synthesis of 3-(3-methoxypyrrolidin-1-yl)benzene-1-sulfonyl
chloride
##STR00140##
[1131] 1. Synthesis of 1-(3-bromophenyl)-3-methoxypyrrolidine
[1132] Into a 250 mL 3-necked round bottom flask purged and
maintained with an inert atmosphere of nitrogen, was placed a
solution of 1,3-dibromobenzene (11.9 g, 50.42 mmol) in toluene (100
mL). To this was added 3-methoxypyrrolidine (6.1 g, 60.40 mmol).
Addition of Pd(OAc).sub.2 (113 mg, 0.50 mmol) was next. This was
followed by the addition of BINAP (940 mg, 1.51 mmol). To the
mixture was added Cs.sub.2CO.sub.3 (40.9 g, 125.54 mmol). The
resulting solution was allowed to react, with stirring, overnight
while the temperature was maintained at reflux in a bath of oil.
The reaction progress was monitored by TLC (ethyl acetate/petroleum
ether=1:5). A filtration was performed. The filtrate was
concentrated by evaporation under vacuum using a rotary evaporator.
The residue was purified by eluting through a column with a 1:30
ethyl acetate/petroleum ether solvent system. This resulted in 8.3
g (64.3%) of 1-(3-bromophenyl)-3-methoxypyrrolidine as yellow
oil.
2. Synthesis of lithium
3-(3-methoxypyrrolidin-1-yl)benzenesulfinate
[1133] Into a 250 mL 3-necked round bottom flask purged and
maintained with an inert atmosphere of nitrogen, was placed a
solution of 1-(3-bromophenyl)-3-methoxypyrrolidine (8.3 g, 32.42
mmol) in tetrahydrofuran (100 mL). To this was added BuLi (15.6
mL). The resulting solution was allowed to react, with stirring,
for 1 hour while the temperature was maintained at -78.degree. C.
in a bath of liquid nitrogen. To the mixture was added SO.sub.2 (4
mL). The resulting solution was allowed to react, with stirring,
for an additional 2 hours while the temperature was maintained at
-78.degree. C. in a bath of liquid nitrogen. The reaction progress
was monitored by TLC (ethyl acetate/petroleum ether=1:1). The
mixture was concentrated by evaporation under vacuum using a rotary
evaporator. The product was precipitated by the addition of hexane.
A filtration was performed. The filter cake was washed 2 times with
50 mL of hexane. The solid was dried in an oven under reduced
pressure. This resulted in 12 g (90%) of lithium
3-(3-methoxypyrrolidin-1-yl)benzenesulfinate as a yellow solid.
3. Synthesis of 3-(3-methoxypyrrolidin-1-yl)benzene-1-sulfonyl
chloride
[1134] Into a 250 mL round bottom flask was placed a solution of
lithium 3-(3-methoxypyrrolidin-1-yl)benzenesulfinate (12 g, 29.15
mmol) in dichloromethane (100 mL). To the above was added NCS (4.48
g, 33.56 mmol) in several batches, while cooling to a temperature
of 0.degree. C. over a time period of 10 minutes. The resulting
solution was allowed to react, with stirring, for 15 minutes while
the temperature was maintained at 0.degree. C. in a bath of
H.sub.2O/ice, then the ice bath was removed and the solution was
allowed to react for an additional 25 minutes at room temperature.
The reaction progress was monitored by TLC (ethyl acetate/petroleum
ether=1:1). The resulting mixture was washed 2 times with 50 mL of
NaHSO.sub.3 and 2 times with 50 mL of brine. The mixture was dried
over Na.sub.2SO.sub.4 and concentrated by evaporation under vacuum
using a rotary evaporator. The residue was purified by eluting
through a column with a 2:3 ethyl acetate/petroleum ether solvent
system. This resulted in 6.6 g (82.5%) of
3-(3-methoxypyrrolidin-1-yl)benzene-1-sulfonyl chloride as yellow
oil.
[1135] .sup.1HNMR (400 Hz, CDCl.sub.3) .delta. 2.24 (1H, m), 2.30
(m, 1H); 3.54-3.45 (m, 2H) 3.61-3.56 (m, 2H), 4.2 (s, 3H), 6.90 (d,
1H, J=8 Hz), 7.34 (s, 1H, J=8 Hz), 7.367 (dd, 1H, J=8 Hz), 7.485
(dd, 1H, J=8.8 Hz). m/z 347 [M+BnNH+H].sup.+
Example 17
Synthesis of 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl
chloride
##STR00141##
[1136] 1. Synthesis of 211-benzo[b][1,4]oxazin-3(4H)-one
[1137] Into a 100 mL round bottom flask was placed a solution of
2-aminophenol (5.45 g, 49.98 mmol) in CHCl.sub.3 (30 mL). To this
was added TEBA (11.4 g, 50.00 mmol). To the mixture was added
NaHCO.sub.3 (16.8 g, 200.00 mmol). This was followed by the
addition of a solution of 2-chloroacetyl chloride (8.16 g, 72.21
mmol) in CHCl.sub.3 (5 mL), which was added dropwise with stirring,
while cooling to a temperature of 0.degree. C. over a time period
of 20 minutes. The resulting solution was allowed to react, with
stirring, for 1 hour while the temperature was maintained at
0-5.degree. C. The resulting solution was allowed to react, with
stirring, overnight while the temperature was maintained at
55.degree. C. The mixture was concentrated by evaporation under
vacuum using a rotary evaporator. The product was precipitated by
the addition of H.sub.2O. A filtration was performed. The filter
cake was washed 2 times with 50 mL of H.sub.2O. The final product
was purified by recrystallization from ethanol. This resulted in
4.5 g (60%) of 2H-benzo[b][1,4]oxazin-3(4H)-one as a white
solid.
2. Synthesis of
3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride
[1138] Into a 100 mL round bottom flask, was placed HSO.sub.3Cl (10
mL). To the above was added 2H-benzo[b][1,4]oxazin-3(4H)-one (2 g,
13.42 mmol) in several batches, while cooling to a temperature of
0-5.degree. C. over a time period of 20 minutes. The resulting
solution was allowed to react, with stirring, for 1 hour while the
temperature was maintained at 5-10.degree. C. The reaction mixture
was poured into 100 g of ice carefully. The resulting solution was
extracted one time with 100 mL of CH.sub.2Cl.sub.2 and the organic
layers combined and dried over Na.sub.2SO.sub.4. A filtration was
performed. The filtrate was concentrated by evaporation under
vacuum using a rotary evaporator. This resulted in 2.2 g (66%) of
3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride as a
white solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.29 (s, 1H),
7.71 (d, 2H), 7.52 (s, 1H), 7.16 (d, 2H), 4.80 (s, 21-1). m/z 317
[M+BnNH-H].sup.-
Example 18
Synthesis of
3-(3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidin-1-yl)benzene-1-sulfonyl
chloride
##STR00142##
[1139] 1. Synthesis of pyrrolidin-3-ol hydrochloride
[1140] Into a 500 mL 3-necked round bottom flask was placed a
solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (41 g,
218.97 mmol) in ethyl ether (300 mL). To the above was bubbled HCl
(g), while maintaining at room temperature over a time period of 3
hours. The resulting solution was allowed to react, with stirring,
overnight while the temperature was maintained at room temperature.
The mixture was concentrated by evaporation under vacuum using a
rotary evaporator. This resulted in 27 g (crude) of pyrrolidin-3-ol
hydrochloride as a white solid.
2. Synthesis of benzyl 3-hydroxypyrrolidine-1-carboxylate
[1141] Into a 500 mL 3-necked round bottom flask was placed a
solution of pyrrolidin-3-ol hydrochloride (20.2 g, 163.43 mmol) in
H.sub.2O (60 mL) while cooling to 5.degree. C. Adjustment of the pH
to 7 was accomplished by the NaOH (10%). This was followed by the
addition of a solution of benzyl chloroformate (36.8 g, 216.47
mmol), which was added dropwise with stirring, while cooling to a
temperature of 5.degree. C. The resulting solution was allowed to
react, with stirring, for 2 hours at 5.degree. C. Then the
resulting solution was allowed to react, with stirring, for 1 hour
while the temperature was maintained at room temperature. The
reaction progress was monitored by TLC (ethyl acetate/petroleum
ether=1:2). The resulting solution was extracted three times with
100 mL of ethyl acetate and the organic layers combined and dried
over MgSO.sub.4 and concentrated by evaporation under vacuum using
a rotary evaporator. This resulted in 30 g (crude) of benzyl
3-hydroxypyrrolidine-1-carboxylate as brown oil.
3. Synthesis of benzyl
3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-1-carboxylate
[1142] Into a 250 mL 3-necked round bottom flask was placed a
solution of benzyl 3-hydroxypyrrolidine-1-carboxylate (10 g, 45.23
mmol) in CH.sub.2Cl.sub.2 (100 mL). To this was added
3,4-dihydro-2H-pyran (19 g, 226.19 mmol). To the mixture was added
p-toluenesulfonic acid (389 mg, 2.26 mmol) and the resulting
solution was allowed to react, with stirring, for 10 minutes while
the temperature was maintained at 0.degree. C. The resulting
solution was allowed to react, with stirring, for an additional 1
hour at room temperature. The reaction progress was monitored by
TLC (ethyl acetate/petroleum ether=1:2). The reaction mixture was
then quenched by the adding 100 mL of NaHCO.sub.3. The resulting
mixture was washed with 100 mL of NaHCO.sub.3 and 100 mL of brine.
The mixture was dried over MgSO.sub.4 and concentrated under vacuum
using a rotary evaporator. This resulted in 15 g (98%) of benzyl
3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-1-carboxylate as yellow
oil.
4. Synthesis of 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine
[1143] Into a 250 mL round bottom flask was placed a solution of
benzyl 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-1-carboxylate (15
g, 44.26 mmol) and Pd/C (2.3 g) in CH.sub.3OH (absolute) (100 mL).
Hydrogen gas was bubbled. The resulting solution was allowed to
react, with stirring, for 2 hours while the temperature was
maintained at room temperature. A filtration was performed. The
filtrate was concentrated by evaporation under vacuum using a
rotary evaporator. This resulted in 5.6 g (67%) of
3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine as a yellow liquid.
5. Synthesis of
1-(3-bromophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine
[1144] Into a 250 mL 3-necked round bottom flask purged and
maintained with an inert atmosphere of nitrogen, was placed a
solution of 1,3-dibromobenzene (7.0 g, 29.91 mmol) in toluene (100
mL). To this was added 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine
(5.6 g, 32.75 mmol). Addition of Pd(OAc).sub.2 (66.9 mg, 0.30 mmol)
was next. This was followed by the addition of Cs.sub.2CO.sub.3
(24.27 g, 74.49 mmol). To the mixture was added BINAP (556 mg, 0.89
mmol). The resulting solution was allowed to react, with stirring,
overnight while the temperature was maintained at reflux in a bath
of oil. The reaction progress was monitored by TLC (ethyl
acetate/petroleum ether=1:5). A filtration was performed. The
filter cake was washed 3 times with 100 mL of brine. The mixture
was dried over MgSO.sub.4. The residue was purified by eluting
through a column with a 1:100 ethyl acetate/petroleum ether solvent
system. This resulted in 1.36 g (13%) of
1-(3-bromophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine as a
yellow liquid.
6. Synthesis of
3-(3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidin-1-yl)benzene-1-sulfonyl
chloride
[1145] Into a 100 mL 3-necked round bottom flask purged and
maintained with an inert atmosphere of nitrogen, was placed a
solution of
1-(3-bromophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine (1.4
g, 0.00429 mol) in tetrahydrofuran (50 mL). To the above was added
n-BuLi (2.16 mL) dropwise with stirring, while cooling to a
temperature of -78.degree. C. The resulting solution was allowed to
react, with stirring, for 40 minutes at -78 degree C. To the
mixture was added SO.sub.2 (450 mg, 0.00703 mol). The resulting
solution was allowed to react, with stirring, for 60 minutes at
-78.about.40 degree C. Then 50 mL of n-hexane was added, and the
solid was collected by filtration. Then the solid was suspended in
50 mL of CH.sub.2Cl.sub.2. To the above was added NCS (930 mg,
0.00697 mol) in several batches, while cooling to a temperature of
0.degree. C. The resulting solution was allowed to react, with
stirring, for 40 minutes while the temperature was maintained at
room temperature. The resulting mixture was washed 3 times with 100
mL of NaHSO.sub.3(2M) and 1 time with 100 mL of brine. The mixture
was dried over MgSO.sub.4. A filtration was performed. The filtrate
was concentrated by evaporation under vacuum using a rotary
evaporator. This resulted in 1.0 g (61%) of
3-(3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidin-1-yl)benzene-1-sulfonyl
chloride as yellow oil.
[1146] .sup.1HNMR (300 MHz, CDCl.sub.3) .delta. 7.38 (m, 1H), 7.30
(m, 1H), 7.10 (s, 1H), 6.82 (d, 1H), 4.75 (m, 1H), 4.52 (m, 1H),
3.90 (m, 1H) 3.38-3.57 (m, 5H), 2.18 (m, 1H), 2.05 (m, 1H),
1.70-1.80 (m, 2H), 1.55 (d, 4H). m/z 417 [M+BnNH2+H].sup.+.
Example 19
Synthesis of benzo[d]isoxazole-5-sulfonyl chloride
##STR00143##
[1147] 1. Synthesis of (E)-2-hydroxybenzaldehyde oxime
[1148] Into a 500 mL round bottom flask was placed a solution of
2-hydroxybenzaldehyde (20 g, 163.93 mmol) in ethanol (200 mL). To
this was added (H.sub.2NOH HCl) hydroxylamine hydrochloride (14 g,
197.18 mmol). To the mixture was added triethylamine (19.2 g,
190.10 mmol) slowly. The resulting solution was allowed to react,
with stirring, for 5 hours while the temperature was maintained at
95.degree. C. in a bath of oil. The reaction progress was monitored
by TLC (ethyl acetate/petroleum ether=1:2). The mixture was
concentrated by evaporation. The resulting solution was extracted
two times with 150 mL of ethyl acetate and water. The resulting
mixture was washed 3 times with 150 mL of water. The mixture was
dried over MgSO.sub.4 and concentrated by evaporator. The residue
was purified by eluting through a column with a 1:100 ethyl
acetate/petroleum ether solvent system. This resulted in 10 g (43%)
of (E)-2-hydroxybenzaldehyde oxime as a white solid.
2. Synthesis of benzo[d]isoxazole
[1149] Into a 1 L 3-necked round bottom flask purged and maintained
with an inert atmosphere of nitrogen, was placed a solution of
(E)-2-hydroxybenzaldehyde oxime (3 g, 21.90 mmol) in
tetrahydrofuran (300 mL). To the mixture was added PPh.sub.3 (6.024
g, 22.99 mmol), while cooling to a temperature of 4.degree. C. This
was followed by the addition of a solution of DEAD (4 g, 22.99
mmol) in tetrahydrofuran (150 mL), while cooling to a temperature
of 4.degree. C. over a time period of 4 hours. The resulting
solution was allowed to react, with stirring, for 1 hour while the
temperature was maintained at 4.degree. C. in a bath of
H.sub.2O/ice. The reaction progress was monitored by TLC (ethyl
acetate/petroleum ether=1:2). The mixture was concentrated by
evaporation under vacuum using a rotary evaporator. The residue was
purified by eluting through a column with a 1:100 ethyl
acetate/petroleum ether solvent system. This resulted in 1.8 g
(66%) of benzo[d]isoxazole as yellow oil.
3. Synthesis of benzo[d]isoxazole-5-sulfonyl chloride
[1150] Into a 50 mL round bottom flask was placed ClSO.sub.3H (2.8
mL). To the mixture was added benzo[d]isoxazole (500 mg, 4.20)
dropwise at 0.degree. C. The resulting solution was allowed to
react, with stirring, for 27 hours while the temperature was
maintained at 100.degree. C. in a bath of oil. The reaction
progress was monitored by TLC (ethyl acetate/petroleum ether=1:5).
The reaction mixture was diluted by CH.sub.2Cl.sub.2 and poured
into 50 mL of H.sub.2O/ice cautiously. The aqueous layer was
extracted two times with 50 mL of CH.sub.2Cl.sub.2 and the organic
layers combined. The resulting mixture was washed 2 times with 50
mL of water. The mixture was dried over MgSO.sub.4 and concentrated
by evaporation under vacuum using a rotary evaporator. This
resulted in 500 mg (48%) of benzo[d]isoxazole-5-sulfonyl chloride
as a red solid.
[1151] .sup.1HNMR (300 MHz, CDCl.sub.3) .delta. 8.93 (s, 1H), 8.54
(s, 1H), 8.26 (d, 1H), 7.87 (d, 1H). m/z 287 [M+BnNH-H].sup.-
Example 20
Synthesis of isoquinoline-8-sulfonyl chloride
##STR00144##
[1152] 1. Synthesis of isoquinoline-8-sulfonyl chloride
[1153] Into a 500 mL 4-necked round bottom flask, was placed a
solution of isoquinolin-8-amine (2.9 g, 16.09 mmol) in CH.sub.3CN
(100 mL). To this was added acetic acid (12 g, 199.67 mmol), while
cooling to a temperature of -5-0.degree. C. To the above was added
HCl (6.1 g, 60.16 mmol) dropwise with stirring, while cooling to a
temperature of -5-0.degree. C. This was followed by the addition of
a solution of NaNO.sub.2 (1.67 g, 24.20 mmol) in H.sub.2O (2 mL)
and the mixture was stirred for 45 mins, while cooling to a
temperature of -5-0.degree. C. SO.sub.2 gas was introduced for
about 2 hours. This was followed by the addition of a solution of
CuCl.sub.2.2H.sub.2O (3.6 g, 21.11 mmol) in H.sub.2O (5 mL), while
cooling to a temperature of -5-0.degree. C. To the mixture was
introduced with SO.sub.2 gas for about 1 hour. The resulting
solution was allowed to react, with stirring, overnight while the
temperature was maintained at 0-5.degree. C. in a bath of
H.sub.2O/ice. The reaction progress was monitored by TLC (ethyl
acetate/petroleum ether=1:2). The reaction mixture was then
quenched by the adding 400 mL of H.sub.2O/ice. The resulting
solution was extracted three times with 200 mL of CH.sub.2Cl.sub.2
and the organic layers combined and washed with brine and dried
over Na.sub.2SO.sub.4 and concentrated by evaporation under vacuum
using a rotary evaporator. The resulting mixture was washed 2 times
with 10 mL of CH.sub.2Cl.sub.2. A filtration was performed. This
resulted in 0.74 g (12%) of isoquinoline-8-sulfonyl chloride as a
brown solid. m/z 228 [M+H].sup.+
Example 21
Synthesis of 4-(2-oxopyrrolidin-1-yl)benzene-1-sulfonyl
chloride
##STR00145##
[1154] 1. Synthesis of 1-phenylpyrrolidin-2-one
[1155] Into a 150 mL sealed tube purged and maintained with an
atmosphere of nitrogen, was placed 1-bromobenzene (4 g, 25.48
mmol). To this was added pyrrolidin-2-one (2.18 g, 25.65 mmol).
Addition of Pd(OAc).sub.2 (57 mg, 0.25 mmol) was next. This was
followed by the addition of BINAP (240 mg, 0.39 mmol). This was
followed by the addition of Cs.sub.2CO.sub.3 (12.5 g, 38.34 mmol).
To the mixture was added toluene (50 mL). The resulting solution
was allowed to react, with stirring, overnight while the
temperature was maintained at 120.degree. C. in a bath of oil. The
mixture was concentrated by evaporation under vacuum using a rotary
evaporator. The residue was purified by eluting through a column
with a 1:10 ethyl acetate/petroleum ether solvent system. This
resulted in 1 g (24%) of 1-phenylpyrrolidin-2-one as yellow
oil.
2. Synthesis of 4-(2-oxopyrrolidin-1-yl)benzene-1-sulfonyl
chloride
[1156] Into a 50 mL round bottom flask was placed HSO.sub.3Cl (10
mL). To the mixture was added 1-phenylpyrrolidin-2-one (1 g, 6.21
mmol). The resulting solution was allowed to react, with stirring,
overnight while the temperature was maintained at room temperature.
The reaction mixture was then quenched by the adding 100 mL of
H.sub.2O/ice. The resulting solution was extracted one time with
100 mL of CH.sub.2Cl.sub.2 and the organic layers and dried over
MgSO.sub.4 and concentrated by evaporation under vacuum using a
rotary evaporator. This resulted in 0.7 g (43%) of
4-(2-oxopyrrolidin-1-yl)benzene-1-sulfonyl chloride as a yellow
solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 2.22 (m, 2H), 2.71
(t, 2H), 3.95 (t, 2H), 7.88 (t, 2H), 8.05 (t, 21-1). m/z
[M+H].sup.+
Example 22
Synthesis of
4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl
chloride
##STR00146##
[1157] 1. Synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazine
[1158] Into a 250 mL 3-necked round bottom flask was placed a
solution of lithium aluminum hydride (3.6 g, 94.74 mmol) in
tetrahydrofuran (80 mL). The mixture was stirred for 15 minutes.
This was followed by the addition of a solution of
2H-benzo[b][1,4]oxazin-3(4H)-one (5.7 g, 38.22 mmol) in
tetrahydrofuran (21 mL), which was added dropwise with stirring.
The resulting solution was allowed to react, with stirring,
overnight while the temperature was maintained at reflux in a bath
of oil. The reaction progress was monitored by TLC (ethyl
acetate/petroleum ether=1:1). The reaction mixture was then
quenched by the adding 3.6 mL of H.sub.2O and 10.8 mL 15% NaOH. A
filtration was performed. The filter cake was washed 1 time with 30
mL of tetrahydrofuran. The resulting solution was extracted two
times with 100 mL of ethyl acetate and the organic layers combined
and dried over Na.sub.2SO.sub.4 and concentrated by evaporation
under vacuum using a rotary evaporator. This resulted in 4.8 g
(79%) of 3,4-dihydro-2H-benzo[b][1,4]oxazine as red oil.
2. Synthesis of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine
[1159] Into a 250 mL 3-necked round bottom flask was placed a
solution of 3,4-dihydro-2H-benzo[b][1,4]oxazine (4.8 g, 35.51 mmol)
in tetrahydrofuran (50 mL). To the above was added NaH (2.3 g,
57.50 mmol) in several batches, while cooling to a temperature of
0-5.degree. C. The mixture was stirred for 30 minutes at
0-5.degree. C. To the above was added iodomethane (9.0 g, 63.41
mmol) dropwise with stirring, while cooling to a temperature of
0-5.degree. C. The resulting solution was allowed to react, with
stirring, overnight while the temperature was maintained at room
temperature. The reaction progress was monitored by TLC (ethyl
acetate/petroleum ether=1:2). A filtration was performed. The
filtrate was concentrated by evaporation under vacuum using a
rotary evaporator. The residue was purified by eluting through a
column with a 1:100 ethyl acetate/petroleum ether solvent system.
This resulted in 3.0 g (50%) of
4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine as yellow oil.
3. Synthesis of
4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl
chloride
[1160] Into a 250 mL 3-necked round bottom flask was placed
HSO.sub.3Cl (25 mL). To the above was added
4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (5.8 g, 38.93 mmol)
dropwise with stirring, while cooling to a temperature of
0-5.degree. C. The resulting solution was allowed to react, with
stirring, for 120 minutes while the temperature was maintained at
room temperature. The reaction progress was monitored by TLC (ethyl
acetate/petroleum ether=1:2). The reaction mixture was then
quenched by the adding of H.sub.2O/ice. The resulting solution was
extracted three times with 200 mL of ethyl acetate and the organic
layers combined and dried over Na.sub.2SO.sub.4 and concentrated by
evaporation under vacuum using a rotary evaporator. The resulting
mixture was washed 3 times with 15 mL of hexane. This resulted in
2.9 g (27%) of
4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride as
a light yellow solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
2.98 (s, 3H), 3.36 (m, 2H), 4.38 (m, 2H), 6.87 (d, 1H), 7.19 (s,
1H), 7.34 (d, 1H). m/z 319 [M+BnNH+H].sup.+
Example 23
Synthesis of 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl
chloride
##STR00147##
[1161] 1. Synthesis of 7-amino-2H-benzo[b][1,4]oxazin-3(4H)-one
[1162] Into 500 mL 3-necked round bottom flask was added a solution
of 7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (12 g, 61.86 mmol) in
DMF (150 mL). To the mixture was added Pd/C (5 g) followed by
addition of hydrogen gas. The resulting solution was allowed to
react, with stirring, overnight while the temperature was
maintained at room temperature. The reaction progress was monitored
by TLC (ethyl acetate/petroleum ether=1:1). A filtration was
performed. The filtrate was concentrated by evaporation under
vacuum using a rotary evaporator. The product was precipitated by
the addition of H.sub.2O. A filtration was performed. The filter
cake was washed 3 times with 300 mL of hexane. This resulted in 7.3
g (68%) of 7-amino-2H-benzo[b][1,4]oxazin-3(4H)-one as a yellow
solid.
2. Synthesis of
3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride
[1163] Into a 500 mL 3-necked round bottom flask was placed a
solution of 7-amino-2H-benzo[b][1,4]oxazin-3(4H)-one (5 g, 28.96
mmol) in CH.sub.3CN (200 mL). To the above was added acetic acid
(24.9 g) dropwise with stirring, while cooling to a temperature of
0.degree. C. To the above was added HCl (16.2 g) dropwise with
stirring, while cooling to a temperature of 0.degree. C. This was
followed by the addition of a solution of NaNO.sub.2 (2.52 g, 36.52
mmol) in H.sub.2O (2 mL), which was added dropwise with stirring,
while cooling to a temperature of 0.degree. C. The resulting
solution was allowed to react, with stirring, for 30 minutes while
the temperature was maintained at 0-5.degree. C. in a bath of
H.sub.2O/ice. This was followed by and maintained with an
atmosphere of sulfur dioxide, the resulting solution was allowed to
react, with stirring, for an additional 2 hours while the
temperature was maintained at 0-5.degree. C. in a bath of
H.sub.2O/ice. To the mixture was added CuCl.sub.2.2H.sub.2O (5.11
g, 29.97 mmol), while cooling to a temperature of 0-5.degree. C.
The resulting solution was allowed to react, with stirring,
maintained with an atmosphere of sulfur dioxide for an additional 2
hours while the temperature was maintained at 0-5.degree. C. in a
bath of H.sub.2O/ice. The resulting solution was allowed to react,
with stirring, overnight while the temperature was maintained at
room temperature. The reaction progress was monitored by TLC
(petroleum ether/ethyl acetate=1:1). The reaction mixture was then
quenched by the adding 200 mL of H.sub.2O/ice. The resulting
solution was extracted one time with 500 mL of ethyl acetate and
the organic layers combined. Then the mixture was washed 3 times
with 200 mL of brine. The mixture was dried over MgSO.sub.4 and
concentrated by evaporation under vacuum using a rotary evaporator.
The residue was dissolved in 100 mL of CH.sub.2Cl.sub.2. A
filtration was performed. The filtrate was concentrated by
evaporation under vacuum using a rotary evaporator. This resulted
in 0.9 g (11%) of
3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride as a
yellow solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 4.73 (s,
2H), 7.00 (m, 1H), 7.28 (d, 1H), 7.71 (d, 1H), 8.27 (s, 1H).
Example 24
[1164] Assays for determining 5HT.sub.6 receptor activity, and
selectivity of 5HT.sub.6 receptor activity are known within the art
(see. e.g., Example 58 of U.S. Pat. No. 6,903,112).
[1165] The assay protocol for determining 5-HT.sub.6 receptor
activity generally entailed the incubation of membrane homogenates
prepared from HeLa cells expressing the human 5-HT6 receptor with
the radioligand .sup.3H-lysergic acid diethylamide (.sup.3H-LSD) at
a concentration of 1.29 nM. Concentrations ranging from 10.sup.-10
M to 10.sup.-5 M of test compound were incubated with the
radioligand and the membrane homogenates. After 60 minutes
incubation at 37.degree. C. the reaction was terminated by vacuum
filtration. The filters were washed with buffer and were counted
for radioactivity using a liquid scintillation counter. The
affinity of the test compound was calculated by determining the
amount of the compound necessary to inhibit 50% of the binding of
the radioligand to the receptor. Ki values were determined based
upon the following equation:
K.sub.i=IC.sub.50/(1+L/K.sub.D)
[1166] where L is the concentration of the radioligand used and
K.sub.D is the dissociation constant of the ligand for the receptor
(both expressed in nM).
[1167] Compounds of the invention show 5-HT6 binding activity with
receptor Ki values of typically less than 1-100 nM. In addition,
compounds of the invention show 5-HT6 functional activity with pA2
values of greater than 6 (IC.sub.50 less than 1 .mu.M).
[1168] In terms of selectivity, affinity for other serotonin
receptors, specifically the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B,
5-HT2C, 5-HT5A, and 5HT7 receptors, is expressed as the amount (in
percent) of binding of the radioligand that is inhibited in the
presence of 100 nM test compound. A lower percent inhibition
indicates lower affinity for the serotonin receptor. Selected
compounds show a percent inhibition of less than 50% for other
serotonin receptors. In one embodiment, the compounds show a
percent inhibition of less than 25% for other serotonin
receptors
[1169] The preceding procedures and examples can be repeated with
similar success by substituting the generically or specifically
described reactants and/or operating conditions of this invention
for those used in the preceding procedures and examples.
[1170] While the invention has been illustrated with respect to the
production and of particular compounds, it is apparent that
variations and modifications of the invention can be made without
departing from the spirit or scope of the invention. Upon further
study of the specification, further aspects, objects and advantages
of this invention will become apparent to those skilled in the
art.
* * * * *