Note: Descriptions are shown in the official language in which they were submitted.
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Novel benzofuran derivative , which can be used in prophylaxis
or treatment of 5-HT6 receptor-related disorder
TECHNICAL FIELD
S The present invention relates to novel compounds, to pharmaceutical
compositions
comprising the compounds, to processes for their preparation, as well as to
the use of the
compounds for the preparation of a medicament against 5-HT6 receptor-related
disorders.
BACKGROUND OF THE INVENTION
Obesity is a condition characterized by an increase in body fat content
resulting in
excess body weight above accepted norms. Obesity is the most important
nutritional
disorder in the western world and represents a major health problem in all
industrialized
countries. This disorder leads to increased mortality due to increased
incidences of diseases
1 S such as cardiovascular disease, digestive disease, respiratory disease,
cancer and type 2
diabetes. Searching for compounds, which reduce body weight has been going on
for many
decades. One line of research has been activation of serotoninergic systems,
either by
direct activation of serotonin receptor subtypes or by inhibiting serotonin
reuptake. The
exact receptor subtype profile required is however not known.
Serotonin (5-hydroxytryptamine or 5-HT), a key transmitter of the peripheral
and
central nervous system, modulates a wide range of physiological and
pathological
functions, including anxiety, sleep regulation, aggression, feeding and
depression. Multiple
serotonin receptor subtypes have been identified and cloned. One of these, the
S-HT6
receptor, was cloned by several groups in 1993 (Ruat, M. et al. (1993)
Biochem. Biophys.
Res. Commun.193: 268-276; Sebben, M. et al. (1994) NeuroReport 5: 2553-2557).
This
receptor is positively coupled to adenylyl cyclase and displays affinity for
antidepressants
such as clozapine. Recently, the effect of 5-HT6 antagonist and 5-HT6
antisense
oligonucleotides to reduce food intake in rats has been reported (Bentley,
J.C. et al. (1999)
Br J Pharmacol. Suppl. 126, P66; Bentley, J.C. et al. (1997) J.
Psychopharmacol. Suppl.
A64, 255; Woolley M.L. et al. (2001) Neuropharmacology 41: 210-219).
Compounds with enhanced affinity and selectivity for the 5-HT6 receptor have
been
identified, e.g. in WO 00/34242 and by Isaac, M. et al. (2000) 6-
Bicyclopiperazinyl-1-
arylsulphonylindoles and 6-Bicyclopiperidinyl-1-arylsulphonylindoles
derivatives as novel,
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potent afzd selective 5-HT6 receptor antagonists. Bioorganic & Medicinal
Chemistry
Letters 10: 1719-1721 (2000), Bioorganic & Medicinal Chemistry Letters 13:
3355-3359
(2003), Expert Opinion Therapeutic Patents 12(4) 513-527 (2002).
It has surprisingly been found that the compounds according to the present
invention
show affinity for the 5-HT6 receptor as antagonists at nanomolar range.
Compounds
according to the present invention and their pharmaceutically acceptable salts
have 5-HT6
receptor antagonist, agonist and partial agonist activity and are believed to
be of potential
use in the treatment or prophylaxis of obesity and type 2 diabetes, to achieve
reduction of
body weight and of body weight gain, as well as in the treatment or
prophylaxis of
disorders of the central nervous system such as anxiety, depression, panic
attacks, memory
disorders, cognitive disorders, epilepsy, sleep disorders, migraine, anorexia,
bulimia, binge
eating disorders, obsessive compulsive disorders, psychoses, Alzheimer's
disease,
Parkinson's disease, Huntington's chorea and/or schizophrenia, panic attacks,
Attention
Deficit Hyperactive Disorder (ADHD), withdrawal from drug abuse,
neurodegenerative
diseases characterized by impaired neuronal growth, and pain. The reduction of
body
weight and of body weight gain (e.g. treating body-weight disorders) is
achieved ihte~ alia
by reduction of food intake. As used herein, the term "body weight disorders"
refers to the
disorders caused by an imbalance between energy intake and energy expenditure,
resulting
in abnormal (e.g., excessive) body weight. Such body weight disorders include
obesity.
DISCLOSURE OF THE INVENTION
One object of the present invention is a compound of the Formula (I):
P
,,
,,
,,. W2
W~
~O
,,
,,
R3
(I)
wherein:
P is selected from a substituent of Formula (II)-(VII):
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R12 13
O N-R~ R \S(O)x R14 R2
O
Rz N~; O~~Sy ~~Y ~N~,
. . J
> > > >
(II) (III) (IV) (V)
O O
R1 \ ~ ' R14
N N%~, N ,
Ro li~ R~ ,
R or ,
(VI) (VII)
wherein:
x, y and j are each independently selected from 0, 1, and 2 ;
wherein the dashed bonds denote that P and R3, respectively, may be attached
to
either the A or B ring at any carbon atom that allows the substitution,
provided that P and
R3 are not both simultaneously attached to ring B;
Rl is selected from:
(a) C1-6-alkyl,
(b) C 1 _6-alkoxy-C 1 _6-alkyl,
(c) C3_6-alkenyl,
(d) hydroxy-C 1 _6-alkyl,
(e) halo-C1_6-alkyl,
(f) aryl,
(g) arylcarbonyhnethyl,
(h) aryl-C3_6-alkenyl,
(i) aryl-C1_6-alkyl,
(j) C3_~-cycloalkyl,
(k) heteroaryl,
(1) 4-piperidinyl,
(m) N-substituted 4-piperidinyl, wherein the substituents are selected from
C 1 _6-alkyl and aryl-C 1-6-alkyl,
(o) heteroaryl-C,_6-alkyl,
wherein any heteroaryl or aryl residue, alone or as part of another group may
be
substituted, independently, in one or more positions with a substituent
selected from:
(a) hydrogen,
3
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(b) halogen,
(c) C1_s-alkyl,
(d) hydroxy,
(e) C1_s-alkoxy,
(~ Cz-s-alkenyl,
(g) Cz_3-alkynyl,
(h) phenyl,
(i ) phenoxy,
(j) benzyloxy,
(k) benzoyl,
(1) benzyl,
(m) -OCF3,
(n) -CN,
(o) hydroxy-C1_s-alkyl,
(p) CI-s-alkoxy-C1_s-alkyl,
(~ halo-CI_s-alkyl,
(r) NR9R9,
(s) -NOz,
(t) -CONR9R9,
(u) NR~CORIO,
(v) -C(=O)Rio~
(x) C1_6-alkoxycarbonyl,
(y) C1_g-alkylthio,
(z) -SCF3,
(aa) -CHF=CHz,
(ab) methylsulfonyl, or
(ac) -COOH
with the proviso that when the substituent on the said aryl or heteroaryl
residue is
selected from phenyl, phenoxy, benzyloxy, benzoyl and benzyl, the phenyl ring
thereof
may be optionally substituted by one or more of halogen, C1-4-alkyl, C1-4-
alkylthio, C1-a
alkoxy, cyano, or trifluoromethyl;
Rz is selected from:
(a) hydrogen,
4
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(b) C 1 _6-alkyl,
(c) Cl_6-alkoxy-C2_g alkyl,
(d) hydroxy-C2_g -alkyl,
(e) -(CHZ)m CHZ-F, wherein m is 2-4,
(f) 3,3,3-trifluoropropyl, or
(g) C1-4-alkylsulfonyl, provided that P is selected from a substituent of
formula (V);
Wl and WZ are each independently selected from:
(a) hydrogen,
(b) halogen,
(c) C1_6-alkyl,
(d) hydroxy,
(e) C1_6-alkoxy,
(fj C1_6-alkylthio,
(g) Cz-s-alkenyl,
(h) phenyl,
(i) phenoxy,
(j) benzyloxy,
(k) benzoyl,
(1) benzyl,
(m) -OCF3,
(n) -CN,
(o) hydroxy-C1_6-alkyl,
(p) C1_6-alkoxy-C1_6 alkyl,
(c~ halo-C1_6-alkyl,
(r) -CONRgR9,
(s) -C(=O)Rio
(t) C1_6-alkoxycarbonyl,
(u) -SCF3, or
(v) -CHF=CH2,
with the proviso that when Wl and W2 are selected from phenyl, phenoxy,
benzoyl,
benzyloxy and benzyl, the phenyl ring thereof may be optionally substituted by
one or
more of halogen, C~-4-alkyl, C1-4-alkoxy, cyano, or trifluoromethyl, and with
the further
s
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proviso that, when W~ and W2 are not selected from methoxy, methyl and
halogen, at least
one of Wi and W2 is selected from hydrogen;
R3 is H when P is a substituent of Formula (II) wherein Rl is N-substituted 4-
piperidinyl, or R3 is a group selected from:
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R~_ __ ', , ,,, __~__ F Crl~,
r O N ~ r L O N ~ p N F Rzs N Rzs
f~ t~ ~ ~P N
N
r N7 ~ p Ra N Ra Ra
R R
_ _ Oy' L Xj' ~ ,~Xz?,
OH l O I Js
R~5 OL 'r N N
R~8 ~~ ~Rzo R'1~N ~O~ ~Rzo
NJ N~ N tz O I a L ] z~O
4
Ra Ra R'~~N.R~' R R
- -
_r__ -- o
N ~N R'e ~N ~p Jp
~-- 23 ~ ~
C ~R RZa-~ N~R~S N~ ~. NCR Rs ,
N N / / - R's
I a R~ R~ R~ N ~ J P
R r R'
_ __
X3 [ NwR~ [ , .~..
p n '
J
R~ a ~ r R~ Rs Rs N n ~Xa
zz 1 1 N
Rzi NL~R a~N Jo a'N ~ ~ Jf Rs
H ~ H R R f~ f
Ra
O '' ~
" R~N~O O '. _
L s R " H ~ H s
N N\\ R r z' Rzz O/~NiR
/ N~ Rzt Rzz R /\~ ~ s
Rs N R5 ~ ~N- ~ R
Ra H Ra H R~~iN~Ro
N R~~ ~ t
J
~, ~Z N R1~ "Rts
R \ L ~1 N C ~Z R
R"iN~R'~ R~~N ' O R"N R Ra Na RsiN~Rs
R
R\ /', -- _
', _ _ _
N.R'~ N ~ ~~ w I ~ R" N
~o R" ~ R i R" N ~_
R"
N N
~N J
R" R"iN~R" NJ r
R"
_ ' N\ , '' I \ ~ , ,
i ~ i
N
N N
N
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__ _ , ,
, ,
_N__ N P ,
N
R8~ ~ R8 ~ ~ R11 N
N N
Rzs Rzs Ra Ra N
__~_ Ra
y,
Oi; O
F R~-N ~ P
NCR'
R11
N~ ~P Jr
R'
R3 may also be a group selected from:
HN O HN O HN O HN O 1
HN O
~ N
11 / \ 9
R N9 R ~ C ~ O R1~ N
R N N R~~N J R,i
R' R'
and further from a group selected from
-O-(C=NH)NR11R11, or
-(CH2)ri O-~(C=~)-NRI 1R~ ~
wherein
n=0, l,2or3
r is each independently 0, 1 or 2,
0=1,2,or3,
p is each independently 1 or 2,
s=2or3,
t=Oorl,
t1 = 1 or 2,
t2 = 0 or 1,
f = 1, 2, 3 or 4, and
f~=l,2or4;
with the proviso that when t1 and p simultaneously are l, r is not 0;
X is selected from O, NR' and S;
X1 is selected from NR' and S;
s
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X2 is selected from O, NR' and S, provided that X2 is selected from NR' and S
when
ta=0;
X3 is selected from NR' and S, provided that X3 is selected from S when r = 1;
X4 is selected from O, NR' and S, provided that X4 is selected from S and NR'
when
f is selected from 2, 3, and 4;
Q is selected from CH2, S02 and oxygen, provided that when Q is SOZ or oxygen,
p is
1;
Z is selected from S02 and oxygen;
when P is a group selected from a substituent of Formula (V) - (VII), R3 is
additionally selected from the following groups:
p _t__
. _~__ OJ',, . ~ O
N
~n N N
R
R6 R2~ 6~ J o
~r N ~p 4~N~ ~f O
R
R
0
N p
\N~H
N4 NJ R11
Ra
wherein:
n=0,1,2or3
r = 0, 1 or 2,
0=1,2,or3,
p = 1 or 2,
s = 2 or 3, and
f = 1, 2, 3 or 4;
R4 is a group selected from:
(a) hydrogen,
(b) C1-6-alkyl,
(c) 2-cyanoethyl,
(d) hydroxy-C2-6_alkyl,
(e) C3-6-alkenyl,
9
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(f) C3-6-alkynyl,
(g) C3-~-cycloalkyl,
(h) C3-~-cycloalkyl-C1-a-alkyl,
(i) C1-6-alkoxy-CZ-6-alkyl
G) -C(=NH)-N-RnRy
(k) -C(=O)-N-R11R11,
(1) -CHZ-CO-N-R'IRI1, or
(m) 3,3,3-trifluoropropyl;
RS is selected from:
(a) hydrogen,
(b) C1-4-alkyl,
(c) hydroxy-C1-4-alkyl,
(d) C1-ø-alkoxymethyl,
(e) halo-C1-ø-alkyl,
(f) NRlIRy
(g) -CO-NRl i Ri y
(h) hydroxy, provided that the said hydroxy group is not attached to a carbon
atom adjacent to a ring nitrogen atom, or
(i) fluorine, provided that the said fluorine atom is not attached to a carbon
atom adjacent to a ring nitrogen atom;
R6 is selected from:
(a) hydrogen,
(b) C1-4-alkyl,
(c) hydroxy-C1-4-alkyl,
(d) C1-4-alkoxy-CI-4-alkyl,
(e) hydroxy, provided that the said hydroxy group is not attached to a carbon
atom adj acent to a heterocyclic ring nitrogen atom, and further provided that
the said
heterocyclic ring is not substituted with oxo,
(f) fluorine, provided that the said fluorine atom is not attached to a carbon
atom adjacent to a ring nitrogen atom, or
(g) halo-C~-4-alkyl;
R' is each independently selected from:
(a) hydrogen, provided that R' is not hydrogen when present simultaneously
with r
and said r is 1 or 2,
to
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(b) C1-4-alkyl,
(c) hydroxy-C2-4-alkyl, or
(d) methoxy-CZ-4-alkyl;
R$ is each independently selected from:
(a) hydrogen, or
(b) C1-4-alkyl, and
when both R8 simultaneously are selected from C1-ø-alkyl,said C1-4-alkyls may
be attached to the same or different carbon atoms, or when two groups are
present at
the same carbon atom they may together form a cyclopropane ring;
R9 is each independently selected from:
(a) hydrogen,
(b) C1-6-alkyl
(c) C3-~-cycloalkyl, or
wherein the two R9 groups together with the nitrogen to which they are
attached
form a heterocyclic ring; and provided that when the two R9 groups form a
piperazine ring,
the nitrogen of the said piperazine ring that allows the substitution is
substituted with C1-4-
alkyl, and further provided that when the two R9 groups form a piperidine
ring, any ring
carbon atom in the said piperidine ring may be optionally substituted with
methyl;
RI° is selected from:
(a) C1-6-alkyl,
(c) aryl, or
(d) heteroaryl,
wherein heteroaryl or aryl may be substituted in one or more positions with
substituents selected from halogen, Cl-ø-alkyl, Cl-4-alkoxy, cyano,
trifluoromethyl;
Rl l is each independently selected from: °
(a) hydrogen,
(b) methyl, or
(c) ethyl, provided that Rl l is present in a group R4 or R26 selected from
-CHa-CO-N-RllRi I;
Rl2 is selected from:
(a) hydrogen,
(b) C 1 _6-alkyl,
(c) aryl,
(d) aryl-C,_6-alkyl,
11
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(e) C3_~-cycloalkyl,
(f) C3_~-cycloalkyl-C1-4-alkyl,
(g) heteroaryl, or
(h) heteroaryl-CI_6-alkyl,
wherein any heteroaryl or aryl residue, alone or as part of another group, is
optionally
substituted, independently, in one or more positions with substituents
selected from:
(a) hydrogen,
(b) halogen,
(c) C1_6-alkyl,
(d) hydroxy,
(e) C ~ _6-alkoxy,
(f) C2_6-alkenyl,
(g) C2-6-alkynyl,
(h) phenyl,
(i) phenoxy,
(j) benzyloxy,
(k) benzoyl,
(1) benzyl,
(m) -OCF3,
(n) -CN,
(o) hydroxy-C1_6-alkyl,
(p) CI-6-alkoxy-C1_6-alkyl,
(q) halo-C1_6-alkyl,
(r) ~9R9~ .
(s) -N02,
(t) -CONR9R9,
(u) NR~CORIO,
(v) -C(=O)Rio
(x) C1_6-alkoxycarbonyl,
(y) C1_6-alkylthio,
(z) -SCF3,
(aa) -CHF=CHZ,
(ab) methylsulfonyl, or
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(ac) -COOH;
with the proviso that when the substituent on the said aryl or heteroaryl
residue is
selected from phenyl, phenoxy, benzyloxy, benzoyl, and benzyl, the phenyl ring
thereof
may be optionally substituted by one or more of halogen, C1-4-alkyl, C1-4-
alkoxy, cyano, or
trifluoromethyl;
R13 is selected from:
(a) C I-6-alkyl,
(b) C3-6-cycloalkyl,
(c) aryl,
(d) heteroaryl,
(e) aryl-C1-2-alkyl, or
(f) heteroaryl-C~-2-alkyl,
wherein any heteroaryl or aryl residue may be substituted in one or more
positions
with substituents selected from halogen, C1-4-alkyl, C1-ø-alkoxy, cyano,
trifluoromethyl,
and acetyl;
R14 is selected from:
(a) aryl,
(b) heteroaryl,
(c) aryl-C1-3-alkyl, or
(d) heteroaryl-C1-3-alkyl,
wherein any heteroaryl or aryl residue may be substituted in one or more
positions
with substituents selected from halogen, C1-4-alkyl, C1-4-alkoxy, cyano, and
trifluoromethyl;
R15 is selected from:
(a) fluorine, or
(b) hydroxy;
R16 is selected from:
(a) hydrogen, provided that r = 0,
(b) amino,
(c) dimethylamino,
(d) F, or
(e) OH;
Rl' is selected from:
(a) hydrogen,
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(b) C,-4-alkyl,
(c) hydroxy, provided that the said hydroxy group is not attached to a carbon
atom adj acent to a ring nitrogen atom;
Rl8 is selected from:
(a) hydrogen, or
(b) fluorine;
R19 is selected from:
(a) hydrogen,
(b) methyl,
(c) trifluoromethyl, or
(d) CI-2-alkoxymethyl;
and provided that at least one of R'9 and Rl l, when present simultaneously,
is
selected from a non-hydrogen substituent, and further provided that when R19
is selected
from trifluoromethyl or C1-2-alkoxymethyl, each Rl' is selected from hydrogen;
R2° is selected from:
(a) hydrogen,
(b) C1-4-alkyl,
(c) hydroxy-C1-4-alkyl,
(d) C1-4-alkoxy-C1-4-alkyl, or
(e) fluoromethyl;
with the proviso that when t2 is 1, RZ° is H;
RZ1 and R22 are each independently selected from:
(a) hydrogen, or
(b) methyl,
provided that, when present at the same time as Rl l, at least two of Rl l,
Rai and R2a
are selected from hydrogen;
Rz3 is selected from:
(a) hydroxy-C1-4-alkyl,
(b) C1-4-alkoxymethyl,
(c) halo-C~-4-alkyl, or
(d) -CO-NRIIRy provided that R4 is not selected from -C(=NH)-N-R11RI1,
-C(=O)-N-RllRy and -CH2-CO-N-RllRn
R24 is selected from:
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(a) hydroxymethyl,
(b) methoxymethyl, or
(c) fluoromethyl;
R25 is each independently selected from
(a) hydrogen,
(b) C1-~-alkyl,
(c) hydroxy-C1-4-alkyl,
(d) C1-4-alkoxy-C1-~-alkyl, or
(e) fluoromethyl;
with the proviso that when both R25 simultaneously are selected from C1_4-
alkyl, said CI_4-
alkyls may be attached to the same or different carbon atoms, and with the
further proviso
that when one R25 is selected from hydroxy-C1_4-alkyl, C1_4-alkoxy-C~_4-alkyl,
and
fluoromethyl, the other RZS represents hydrogen; and
R26 is selected from
(a) 2-cyanoethyl,
(b) C3_6-alkenyl,
(c) C3_6-alkynyl,
(d) C3_~-cycloalkyl,
(e) C3_~-cycloalkyl-C1_4-alkyl,
(f) -CH2-CO-NRlIRy or
(g) 3,3,3-trifluoropropyl;
with the proviso that R2 and R12 in Formula (III) are not simultaneously
selected from
hydrogen; and with the further proviso that the said RZ and R12 together may
for a
heterocyclic ring selected from piperidine, pyrrolidine, morpholine,
piperazine
thiomorpholine, and provided that when Rz and R12 together form a piperazine
ring, the
distal piperazine nitrogen may be optionally substituted by C1-4 alkyl or
aryl, and wherein
said aryl is substituted in one or more positions with substituents selected
from halogen,
C1-4-alkyl, CI-4-alkoxy, cyano, trifluoromethyl; or RZ and R12 together form a
heteroaromatic ring of Formula (VIII):
' \
N
(CH2)v
(VIII)
wherein v is 0, 1 or 2; and
is
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further provided that when R15 is selected from hydroxy, Rl8 is selected from
hydrogen; and
pharmaceutically acceptable salts, hydrates, solvates, geometrical isomers,
tautomers,
optical isomers, and prodrug forms thereof.
Preferred is a compound of the Formula (Ib):
P
~O
,
,,
"3
R
(Ib)
wherein:
P is selected from a substituent of Formula (II)-(VII):
R~ R~~ ~s
R ~ R2
O O\ N R~ S(O)S ~ R~4 N ,
R-N~; O%S~, ~,Y
> > > >
(II) (III) (IV) (V)
O O
R~ \ ~ ,,
R14
or R
(VI) (VII)
wherein:
x, y and j are each independently selected from 0, 1, and 2 ;
wherein the dashed bonds denote that R3 may be attached to either the A or B
ring at
any carbon atom that allows the substitution;
Rl is selected from:
(a) C1_6-alkyl,
(b) C1_6-alkoxy-C2_6-alkyl,
(c) C3_6-alkenyl,
(d) hydroxy-C2_6-alkyl,
(e) halo-C~-6-alkyl,
(fj aryl,
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(g) arylcarbonylmethyl,
(h) aryl-C3_s-alkenyl,
(i) aryl-CI_6-alkyl,
(j) C3_~-cycloalkyl,
(k) heteroaryl,
(o) heteroaryl-C1_6-alkyl,
wherein any heteroaryl or aryl residue, alone or as part of another group may
be
optionally substituted, independently, in one or more positions with a
substituent selected
from
(b) halogen,
(c) C1_6-alkyl,
(d) hydroxy,
(e) C 1 _6-alkoxy,
(f) Cz_6-alkenyl,
(g) C2_3-alkynyl,
(h) phenyl,
(i) phenoxy,
(j) benzyloxy,
(k) benzoyl,
(1) benzyl,
(m) -OCF3,
(n) -CN,
(o) hydroxy-C1_6-alkyl,
(p) C1-6-alkoxy-C,_6-alkyl,
(q) halo-C1_6-alkyl,
(r) NR9R9,
(s) -NO2,
(t) -CONR9R9,
(u) NR~CORIO,
(v) -C(=O)Rlo,
(x) C1_6-alkoxycarbonyl,
(y) C1_6-alkylthio,
(z) -SCF3,
1~
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(aa) -CHF=CHa,
(ab) methylsulfonyl, or
(ac) -COOH,
with the proviso that when the substituent on the said aryl or heteroaryl
residue is
selected from phenyl, phenoxy, benzyloxy, benzoyl and benzyl, the phenyl ring
thereof
may be optionally substituted by one or more of halogen, C1-~-alkyl, C1-4-
alkylthio, C1-4
alkoxy, cyano, or trifluoromethyl;
R2 is selected from:
(a) hydrogen,
(b) C1_6-alkyl,
(c) C1-6-alkoxy-C2_6 alkyl,
(d) hydroxy-C2_6 -alkyl,
(e) -(CHZ)m CHZ-F, wherein m is 2-4, or
(g) C1-4-alkylsulfonyl, provided that P is selected from a substituent of
formula (V);
Wl and Wz are each independently selected from:
(a) hydrogen,
(b) halogen,
(c) C1_6-alkyl,
(d) hydroxy,
(e) C1_6-alkoxy,
(f) C1_6-alkylthio,
(g) Cz_6-alkenyl,
(m) -OCF3,
(n) -CN,
(o) hydroxy-CI_6-alkyl,
(p) C 1-6-alkoxy-C 1 _s alkyl,
(q) halo-C1_6-alkyl,
(r) -CONR9R9,
(s) -C(=O)Rlo,
(t) C1_6-alkoxycarbonyl,
(u) -SCF3, or
(v) -CHF=CH2,
18
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WO 2005/058858 PCT/SE2004/001949
with the proviso that when Wl and WZ are not selected from hydroxy, methoxy,
methyl and halogen, at least one of Wl and W2 is selected from hydrogen;
R3 is a group selected from:
iy
O ' _i__ N__ __
Rzs r~Rzs Rs R8 ~ ~Rza
C~ N
N~ NQ N
R' R Rzs R Rzs
P '~ s sr
N N / N
R11 ~O~ ~Rzo ~O~ ~Rzo
N N 2~0 L 'j 2 O N
Ra Ra Ra
__~__
o , O O R~_N
F [ P [ p _
J
~R~ tt ~ ERs
N Rtt N R ~ O N N P
R4 N Rs R'
_ __
' X
r 3
N~Rtt ~ ~~ 5 N n' X~~ Rtt
Rtt R~ N
l zz
s~~ Rzt R
R4~N ~o Ra>N ~f Jf R~ ~f
1 R
_ _. Xt Rt\N~' . _.
C ~/ /O Rtt [ t ~ ~ ~ Rtt
~ ti
N S''O R1t ttRtt Ry R N N Rtt N /
R4 siN. sR N Rtt R11.N.Rtt
R R
N , ' _1__
N ~ ~ ~~ O
N~ N ~~ N
N N N
wherein
n=0, l,2or3,
r = 0, 1 or 2,
0=l,2or3,
p= 1 or2,
s=2or3,
t=Oorl,
t2 = 0 or 1,
19
CA 02545506 2006-05-10
WO 2005/058858 PCT/SE2004/001949
f = 1, 2, 3 or 4, and
fl=l,2or4;
X1 is selected from NR' and S;
XZ is selected from O, NR' and S, provided that when t2 = 0 and s = 2 then XZ
is
selected from NR' and S;
X3 is selected from NR' and S, provided that X3 is selected from S when r = 1;
X4 is selected from O, NR' and S, provided that X4 is selected from S and NR'
when
f is selected from 2 and 3, and R6 simultaneously is selected from hydrogen
and C1-4 alkyl;
when P is a group selected from a substituent of Formula (V) - (VII), R3 is
additionally selected from the following groups:
_N__ -N-- ' _N _
R R
N N
Ra
R" ~ R"
N ~H N
s~ ~ N
R4~N ~f R o R~~ ~ Rzo
'O
wherein:
r = 0, 1 or 2,
0=l,2or3,
p is each independently 1 or 2,
s=2or3,and
f=1,2,3or4;
Rø is selected from:
(a) hydrogen,
(b) C1-6-alkyl,
(c) 2-cyanoethyl,
(d) hydroxy-CZ-6_alkyl,
(e) C3-6-alkenyl,
(f) C3-6-alkynyl,
(g) C3-~-cycloalkyl,
CA 02545506 2006-05-10
WO 2005/058858 PCT/SE2004/001949
(h) C3-~-cycloalkyl-C,-4-alkyl,
(i) C1-6-alkoxy-Cz-6-alkyl
(1) -CHz-CO-N-RllRy or
(m) 3,3,3-trifluoropropyl;
RS is selected from:
(a) hydrogen,
(b) C I -4-alkyl,
(c) hydroxy-C1-4-alkyl,
(d) C1-4-alkoxymethyl,
(e) halo-C1-4-alkyl,
(~ -NR' IRi i
(h) hydroxy, provided that the said hydroxy group is not attached to a carbon
atom adjacent to a ring nitrogen atom, or
(i) fluorine, provided that the said fluorine atom is not attached to a carbon
atom adjacent to a ring nitrogen atom;
R6 is selected from:
(a) hydrogen,
(b) C1-4-alkyl,
(c) hydroxy-C1-4-alkyl,
(d) C1-4-alkoxy-C1-4-alkyl,
(e) hydroxy, provided that the said hydroxy group is not attached to a carbon
atom adjacent to a heterocyclic ring nitrogen atom,
(f) fluorine, provided that the said fluorine atom is not attached to a carbon
atom adjacent to a ring nitrogen atom, or
(g) halo-CI-4-alkyl;
R' is each independently selected from:
(a) hydrogen, provided that R' is not hydrogen when present simultaneously
with r and said r is 1 or 2,
(b) C,-4-alkyl,
(c) hydroxy-Cz-4-alkyl, or
(d) methoxy-Cz-4-alkyl;
R$ is each independently selected from:
(a) hydrogen, or
21
CA 02545506 2006-05-10
WO 2005/058858 PCT/SE2004/001949
(b) C1-4-alkyl, with the proviso that when both R8 simultaneously are selected
from C1-4-alkyl, said C1-ø-alkyl may be attached to the same or different
carbon
atoms, or when two groups are present at the same carbon atom they may
together
form a cyclopropane ring;
R9 is each independently selected from:
(a) hydrogen,
(b) Ci-6-alkyl
(c) C3-~-cycloalkyl, or
the two R9 groups together with the nitrogen to which they are attached form a
heterocyclic ring; and provided that when the two R9 groups form a piperazine
ring,
the nitrogen of the said piperazine ring that allows the substitution may be
optionally
substituted with C1-4-alkyl; and further provided that when the two R9 groups
form a
piperidine ring, any ring carbon atom in the said piperidine ring may be
optionally
substituted with methyl;
Rl° is selected from:
(a) C1-6-alkyl,
(c) aryl, or
(d) heteroaryl,
wherein heteroaryl or aryl may be optionally substituted in one or more
positions
with substituents selected from halogen, C1-4-alkyl, C1-4-alkoxy, cyano,
trifluoromethyl;
Rl' is each independently selected from:
(a) hydrogen,
(b) methyl, or
(c) ethyl, provided that RI1 is present in a group R4 or Rz6 selected from -
CH2-
CO-N-RllRy
R12 is selected from:
(a) hydrogen,
(b) C1-6-alkyl,
(c) aryl,
(d) aryl-CI_6-alkyl,
(e) C3_~-cycloalkyl,
(f) C3_~-cycloalkyl-C1-4-alkyl,
(g) heteroaryl, or
(h) heteroaryl-C1_6-alkyl,
22
CA 02545506 2006-05-10
WO 2005/058858 PCT/SE2004/001949
wherein any heteroaryl or aryl residue, alone or as part of another group, may
be
optionally substituted, independently, in one or more positions with
substituents selected
from:
(b) halogen,
(c) C1_6-alkyl,
(d) hydroxy,
(e) C1_6-alkoxy,
(f) C2_6-alkenyl,
(g) C2-s-alkynyl,
(h) phenyl,
(i) phenoxy,
(j) benzyloxy,
(k) benzoyl,
(1) benzyl,
(m) -OCF3,
(n) -CN,
(o) hydroxy-C1_6-alkyl,
(p) C 1-6-alkoxy-C ~ _6-alkyl,
(q) halo-C1_6-alkyl,
(r) NR9R9,
(s) -N02,
(t) -CONR9R9,
(u) NR~CORIO,
(v) -C(=O)Rio~
(x) C1_g-alkoxycarbonyl,
(y) C 1 _6-alkylthio,
(z) -SCF3,
(aa) -CHF=CH2,
(ab) methylsulfonyl, or
(ac) -COOH,
with the proviso that when the substituent on the said aryl or heteroaryl
residue is
selected from phenyl, phenoxy, benzyloxy, benzoyl, and benzyl, the phenyl ring
thereof
23
CA 02545506 2006-05-10
WO 2005/058858 PCT/SE2004/001949
may be optionally substituted by one or more of halogen, C1-4-alkyl, C1-4-
alkoxy, cyano, or
trifluoromethyl;
R'3 is selected from:
(a) C1-6-alkyl,
(b) C3-6-cycloalkyl,
(c) aryl,
(d) heteroaryl,
(e) aryl-C1-2-alkyl, or
(f) heteroaryl-C1-Z-alkyl,
wherein any heteroaryl or aryl residue may be optionally substituted in one or
more
positions with substituents selected from halogen, C1-4-alkyl, C1-4-alkoxy,
cyano,
trifluoromethyl, and acetyl;
R14 is selected from:
(a) aryl,
(b) heteroaryl,
(c) aryl-C~-3-alkyl, or
(d) heteroaryl-Cl-3-alkyl,
wherein any heteroaryl or aryl residue may be substituted in one or more
positions
with substituents selected from halogen, C1-4-alkyl, C1-4-alkoxy, cyano, and
trifluoromethyl;
R2° is each independently selected from:
(a) hydrogen,
(b) methyl,
with the proviso that when t2 is 1, R2° is H;
R21 and R22 are each independently selected from:
(a) hydrogen, or
(b) methyl,
provided that, when present simultaneously with Rl l, at least two of Rll, Rai
and RZz
are selected from hydrogen;
Rz3 is selected from:
(a) hydroxy-C1-4-alkyl,
(b) C1-4-alkoxymethyl, or
(c) halo-CI-4-alkyl;
R25 is each independently selected from:
24
CA 02545506 2006-05-10
WO 2005/058858 PCT/SE2004/001949
(a) hydrogen,
(b) C1_4-alkyl,
(c) hydroxy-C1_4-alkyl,
(d) C1_4-alkoxy-C1_4-alkyl, or
e) fluoromethyl,
with the proviso that when both R25 simultaneously are selected from C1_4-
alkyl, said
C1_4-alkyl may be attached to the same or different carbon atoms, and with the
further
proviso that when one R25 is selected from hydroxy-C1_4-alkyl, C1_4-alkoxy-
CI_4-alkyl, and
fluoromethyl, the other R25 represents hydrogen;
R26 is selected from: -
(a) 2-cyanoethyl,
(b) C3-6-alkenyl,
(c) C3-6-alkynyl,
(d) C3-~-cycloalkyl,
(e) C3-~-cycloalkyl-C1-4-alkyl,
(f) -CHZ-CO-NRlIRy or
(g) 3,3,3-trifluoropropyl;
with the proviso that RZ and R12 in Formula (III) are not simultaneously
selected from
hydrogen; and with the further proviso that the said R2 and R12 together may
form a
heterocyclic ring selected from piperidine, pyrrolidine, morpholine,
piperazine
thiomorpholine, and provided that when R2 and Rlz together form a piperazine
ring, the
distal piperazine nitrogen may be optionally substituted by C1-4 alkyl or
aryl, and wherein
said aryl may be optionally substituted in one or more positions with
substituents selected
from halogen, C1-4-alkyl, C1-ø-alkoxy, cyano, trifluoromethyl; or R2 and R12
together form
a heteroaromatic ring of Formula (VIII):
N
(CH2)v /
(VIII)
wherein v is 0 or 1.
It is further preferred that:
P is selected from a substituent of Formula (II)-(V)
2s
CA 02545506 2006-05-10
WO 2005/058858 PCT/SE2004/001949
1 R12 R13 2
R R
R~ N;o o\ ~ s~o~x ]y R,4 N~,
N-R~
~s~, ,. ,
' or > >
> >
(II) (III) (IV) (V)
wherein x is 2, y is 0 and j is 1;
R' is selected from:
(f) aryl,
(i) aryl_C1_3_alkyl,
(k) heteroaryl,
(o) heteroaryl-C1_3-alkyl,
wherein any heteroaryl or aryl residue, alone or as part of another group may
be
optionally substituted, independently, in one or more positions with a
substituent selected
from:
(b) halogen,
(c) C1_4-alkyl,
(d) hydroxy,
(e) C1_4-alkoxy,
(m) -OCF3,
(n) -CN,
(o) hydroxy-C1_4-alkyl,
(p) C1-2-alkoxy-C1_2-alkyl,
(c~ halo-C1_3-alkyl,
(r) NR9R9,
(t) -CONR9R9,
(u) NR~CORIO,
(~) -C(_O)Rio~
(x) C1_3-alkoxycarbonyl,
(y) C1_3-alkylthio, or
(ab) methylsulfonyl,
R2 is selected from:
(a) hydrogen,
(b) C1_q-alkyl,
26
CA 02545506 2006-05-10
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Wl and Wz are each independently selected from:
(a) hydrogen,
(b) halogen,
(c) C1_4-alkyl,
(d) hydroxy,
(e) C1_4-alkoxy,
(f) C1_4-alkylthio,
(m) -OCF3,
(n) -CN,
(o) hydroxy-C1_z-alkyl,
(p) C1_z-alkoxy-CI-z-alkyl,
(c~ -CF3,
(r) -CONR9R9,
(s) acetyl,
(t) C1_q.-alkoxycarbonyl, or
with the proviso that when Wl and Wz are not selected from hydroxy, methoxy,
methyl and halogen, at least one of Wl and Wz is selected from hydrogen;
R3 is a group selected from:
2~
CA 02545506 2006-05-10
WO 2005/058858 PCT/SE2004/001949
N Rzs~ l-Rzs ~ ~Rzs R8~ 1Rs
NT N NN
Ra Ra Ra Rzs
,, _
R" ~ ,~ ~ xz'~ ~ R\ ,
P ~ ~S N N
N
~ °~ ~-R"
HH i H H tz O N N N
Ra la Rai Rai
R
--~-
0
° [ p0 . [ p __~_
N~ R'1 N~R~ R~~ ~N~
Ra l N O
Jr I
R
,fix
j 3
N~R~~ 5 N n' x~'~ R,1 ]r
R~ ~ R ~ zz
N ~R
N ~ ° ~f Rs~ ~f Rz, H i H
Ra' 4
R
__X1 R'\N~'' __
R" [ t ~ ~.~ R" ~ \ '' ~ \
R~~ J R~~ R" \ N
1,
N
R9~N\R9R ~ NJ R"~N.R" N
N
.
C ~' N \ '' / ~ O
N N N N
N
wherein:
n = 0, 1, 2 or 3
r is 0, 1 or 2,
0=1,2,or3,
p is 1 or 2,
s=2or3,
t=Oorl,
t2 = 0 or 1, and
28
CA 02545506 2006-05-10
WO 2005/058858 PCT/SE2004/001949
f=1,2,3or4;
Xl is selected from NR' and S;
XZ is selected from O, NR~ and S, provided that XZ is selected from NR~ and S
when
t=Oands=2;
X3 is selected from NR' and S, provided that X3 is selected from S when r = 1;
X~. is selected from O, NR' and S, provided that X4 is selected from S and NR'
when
f is selected from 2 and 3, and R6 simultaneously is selected from hydrogen
and C1-4 alkyl;
or;
when P is a group selected from formula (V) wherein j = 1, R3 is additionally
selected
from the following group;
N
Ra
N
R'
Rø is selected from:
(a) hydrogen,
(b) C1-4-alkyl,
(d) hydroxy-CZ-ø_alkyl,
(g) C3-6-cycloalkyl,
(h) C3-6-cycloalkyl-C1-4-alkyl,
(i)C 1-4-alkoxy-C2-4-alkyl
(m) 3,3,3-trifluoropropyl;
RS is selected from:
(a) hydrogen,
(b) C1-4-alkyl,
(c) hydroxy-C1-4-alkyl,
(d) C1-ø-alkoxymethyl,
(e) halo-C1-4-alkyl,
(fj NR11811
(g) hydroxy, provided that the said hydroxy group is not attached to a carbon
atom adjacent to a ring nitrogen atom, or
(h) fluorine, provided that the said fluorine atom is not attached to a carbon
atom adjacent to a ring nitrogen atom;
R6 is selected from:
29
CA 02545506 2006-05-10
WO 2005/058858 PCT/SE2004/001949
(a) hydrogen,
(b) C1-4-alkyl,
(c) hydroxy-C~-4-alkyl,
(d) C1-4-alkoxy-CI-4-alkyl,
(e) hydroxy, provided that the said hydroxy group is not attached to a carbon
atom adjacent to a heterocyclic ring nitrogen atom,
(f) fluorine, provided that the said fluorine atom is not attached to a carbon
atom adjacent to a ring nitrogen atom, or
(g) halo-C1-4-alkyl;
R' is each independently selected from:
(a) hydrogen, provided that R' is not hydrogen when present simultaneously
with r and said r is 1 or 2,
(b) C1-4-alkyl,
(c) hydroxy-C2-4-alkyl, or
(d) methoxy-Cz-4-alkyl;
R8 is each independently selected from:
(a) hydrogen, or
(b) C1-4-alkyl, with the proviso that when both R8 simultaneously are selected
from C1-4-alkyl, said C1-4-alkyl may be attached to the same or different
carbon
atoms, or when two groups are present at the same carbon atom they rnay
together
form a cyclopropane ring;
R9 is each independently selected from:
(a) hydrogen,
(b) C1-6-alkyl, or
the two R9 groups together with the nitrogen to which they are attached form a
heterocyclic ring; and provided that when the two R9 groups form a piperazine
ring,
the nitrogen of the said piperazine ring that allows the substitution is
optionally
substituted with C1-4-alkyl;
R'° is selected from:
(a) C,-6-alkyl,
(c) aryl, or
(d) heteroaryl,
wherein heteroaryl or aryl may be substituted in one or more positions with
substituents selected from halogen, C1-4-alkyl, C1-4-alkoxy, cyano,
trifluoromethyl;
CA 02545506 2006-05-10
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R11 is each independently selected from:
(a) hydrogen, or
(b) methyl,
(c) ethyl, provided that Rl l is present in a group R26 selected from -CHz-CO-
~uRu;
R12 is selected from:
(a) hydrogen,
(c) aryl,
(d) aryl-C1-3-alkyl,
(g) heteroaryl, or
(h) heteroaryl-C1-3-alkyl,
wherein any heteroaryl or aryl residue, alone or as part of another group, may
be
optionally substituted, independently, in one or more positions with
substituents selected
from
(b) halogen,
(c) C 1 _4-alkyl,
(d) hydroxy,
(e) C1_4-alkoxy,
(m) -OCF3,
(n) -CN,
(o) hydroxy-C1_3-alkyl,
(p) C~-3-alkoxy-C1_3-alkyl,
(q) halo-C1_4-alkyl,
(r) NR9R9,
(t) -CONR9R9,
(u) NR~CORIO,
(v) -C(=O)Rio~
(x) C1_3-alkylthio, or
(ab) methylsulfonyl;
R'3 is selected from:
(c) aryl,
(d) heteroaryl,
(e) aryl-C~-2-alkyl, or
(f) heteroaryl-C1-2-alkyl,
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CA 02545506 2006-05-10
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wherein any heteroaryl or aryl residue may be optionally substituted in one or
more positions with substituents selected from halogen, Cl-4-alkyl, C1-4-
alkoxy,
cyano, trifluoromethyl and acetyl;
R14 is selected from:
(a) aryl,
(b) heteroaryl,
(c) aryl-C1-3-alkyl, or
(d) heteroaryl-C1-3-alkyl;
wherein any heteroaryl or aryl residue may be optionally substituted in one or
more positions with substituents selected from halogen, C1-4-alkyl, C1-ø-
alkoxy,
cyano, and trifluoromethyl;
R2° is selected from:
(a) hydrogen, or
(b) methyl,
with the proviso that when t2 is 1, RZ° is H;
RZ1 and R2z are each independently selected from:
(a) hydrogen, or
(b) methyl,
provided that, when present simultaneously with Rl l, at least two of R' 1,
R21 and RZa
are selected from hydrogen;
Rz3 is selected from:
(a) hydroxy-C1-4-alkyl,
(b) C1-4-alkoxymethyl, or
(c) halo-C1-4-alkyl;
R25 is selected from:
(a) hydrogen,
(b) C1-4-alkyl,
(c) hydroxy-Cl-4-alkyl,
(d) C1-~-alkoxy-C,-4-alkyl, or
(e) fluoromethyl;
with the proviso that when both R25 simultaneously are selected from C1-4-
allcyl, said CI-~-
alkyl may be attached to the same or different carbon atoms, and with the
further proviso
that when one R25 is selected from hydroxy-CI-4-alkyl, CI-4-alkoxy-C1-4-alkyl,
and
fluoromethyl;the other R25 represents hydrogen;
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CA 02545506 2006-05-10
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Rz6 is selected from:
(e) C3-~-cycloalkyl-C1-a-alkyl,
(f) -CHz-CO-NR11R11, or
(g) 3,3,3-trifluoropropyl;
with the proviso that R2 and R12 in Formula (III) are not simultaneously
selected from
hydrogen; and with the further proviso that the said RZ and R12 together may
for a
heterocyclic ring selected from piperidine, pyrrolidine, morpholine,
piperazine
thiomorpholine, and provided that when RZ and Rl2 together form a piperazine
ring, the
distal piperazine nitrogen may be optionally substituted by C1-4 alkyl or
aryl, and wherein
said aryl may be optionally substituted in one or more positions with
substituents selected
from halogen, C1-4-alkyl, C1-4-alkoxy, cyano, trifluoromethyl; or RZ and R12
together form
a heteroaromatic ring of Formula (VIII):
' N
(CH2)v /
(VIII)
wherein v is 0 or 1.
A set of preferred compounds within this invention are those of the general
Formula
(XII):
W2
(XII)
wherein Wl, W2, P and R3 are as defined for formula (Ib).
Further preferred compounds of Formula (XII) are compounds wherein
P is selected from a substituent of Formula (II) -(IV);
xis2andyis0;
R' is selected from aryl and heteroaryl, wherein any heteroaryl or aryl
residue may be
optionally substituted, independently, in one or more positions with a
substituent selected
from halogen, C1_4-alkyl, CI_4-alkoxy and trifluoromethyl;
RZ is selected from hydrogen;
W~ and WZ are hydrogen;
R3 is a group selected from
33
CA 02545506 2006-05-10
WO 2005/058858 PCT/SE2004/001949
', C -t-- Ro
N ~,, N N ~ N
Rzs~N~RzS ~ ~ c
N N CF3 N
Ra Ra Ra Rzs a~N~
R
' ' ',
'
N N
H
H N H W
Ra N ~ N
Ra HzN Ray
__N _ __N_ ' __N_ _ _
O'
C ~ ~ ,N
p
R P NHz
_ Ri\N~' __
\ N~ ,
c~ ,, N.
N N NJ NH
z
\ ,,, / _ __O_.
N N
N
wherein
p = 1 or 2,
R4 is selected from:
(a) hydrogen, or
(b) C1-4-alkyl;
Rl l is each independently selected from:
(a) hydrogen, or
(b) methyl,
(c) ethyl, provided that Rl1 is present in a group R26 selected from -CH2-CO-
yiRii,
R12 and R13 are each independently selected from aryl and heteroaryl,
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CA 02545506 2006-05-10
WO 2005/058858 PCT/SE2004/001949
wherein any heteroaryl or aryl residue may be optionally substituted,
independently,
in one or more positions with a substituent selected from halogen, CI_4-alkyl,
C1_4-alkoxy,
and CF3;
R25 is selected from:
(a) hydrogen, or
(b) C1-4-alkyl;
R26 is selected from:
(e) C3-~-cycloalkyl-C1-4-alkyl,
(f) -CH2-CO-NRlIRy or
(g) 3,3,3-trifluoropropyl.
In more preferred compounds of Formula (XII),
P is selected from a substituent of Formula (II) -(IV);
x is 2 and y is 0;
Rl, R12 and R13 are each independently selected from phenyl or substituted
phenyl
selected from 2-methoxy-5-methylphenyl, 2-methylphenyl, 4-methylphenyl, 4-
fluorophenyl, 3,4-dimethoxyphenyl, 2-chlorophenyl, 2-trifluoromethylphenyl,
2,6-
dichlorophenyl, 3-chloro-4-methylphenyl, 3-methylphenyl, 3,6-dichloro-2-
methylphenyl,
and 2-chloro-5-fluorophenyl; or heteroaryl or substituted heteroaryl selected
from 2-
thienyl, 5-chloro-2-thienyl, 5-chloro-and 1,3-dimethyl-1H-pyrazol-4-yl;
RZ is selected from hydrogen;
Wl and W2 are hydrogen;
R3 is a group selected from:
CA 02545506 2006-05-10
WO 2005/058858 PCT/SE2004/001949
, ,
, ,
. ~ R~~ ~' ,
N
R25~ ~ R25 N
4,N~ R4/N
R
.
.
N N
HH I H H
a N
R
R4 H2N
. F _ _
O~ -
N~ N
R4 N
R4 is each independently selected from:
(a) hydrogen, or
(b) methyl,
Rl1 is each independently selected from:
(a) hydrogen, or
(b) methyl;
R25 is each independently selected from:
(a) hydrogen, or
(b) methyl.
A yet further set of preferred compounds within this invention are those of
the
general Formula (XIII):
R'
2
(XIII)
wherein Wl, Wa, P and R3 are as defined for Formula (Ib).
Further preferred compounds of Formula (XIII) are compounds wherein:
P is selected from a substituent of Formula (II) -(IV);
xis2andyis0;
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Rl is selected from aryl and heteroaryl, wherein any heteroaryl or aryl
residue may be
optionally substituted, independently, in one or more postions with a
substituent selected
from halogen, C~-4-alkyl, trifluoromethoxy, and C1-4-alkoxy;
R2 is selected from hydrogen;
Wl and W2 are hydrogen;
R3 is a group selected from:
' ,
'
N
~H R2s~ ~RZs
R4
R4
wherein:
R4 is each independently selected from:
(a) hydrogen, or
(b) C1-4-alkyl;
R25 is each independently selected from:
(a) hydrogen, or
(b) C1-4-alkyl, with the proviso that when both R25 represent C1-4-alkyl, said
C1-
4-alkyl may be attached to the same or different carbon atoms;
R12 and R13 are each independently selected from aryl and heteroaryl, wherein
any
heteroaryl or aryl residue may be optionally substituted, independently, in
one or more
postions with a substituent selected from halogen, C1-4-alkyl,
trifluoromethyl, and C1-4-
alkoxy.
In more preferred compounds of Formula (XIII),
P is selected from a substituent of Formula (II);
Rl is selected from 2-methoxy-5-methylphenyl;
RZ is selected from hydrogen;
W1 and WZ are hydrogen;
R3 is a group selected from:
' ,
R2s N~Ras
N
R4 Ra
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R4 is each independently selected from
a) hydrogen, or
b) methyl;
R25 is each independently selected from:
a) hydrogen, or
b) methyl.
Preferred compounds are
N-(7- f Methyl[3-(methylamino)propyl]amino}-1-benzofuran-5-
yl)benzenesulfonamide hydrochloride,
N-(7-Piperidin-1-yl-1-benzofuran-5-yl)benzenesulfonamide,
4-Fluoro-N-(7-piperidin-1-yl-1-benzofuran-5-yl)benzenesulfonamide,
3 ,4-D imethoxy-N-(7-piperidin-1-yl-1-benzofuran-5-yl)benzenesulfonamide
hydrochloride,
3 ,4-Dimethoxy-N-(7-pyrrolidin-1-yl-1-benzofuran-5-yl)b enzenesulfonamide,
N-(7-Pyrrolidin-1-yl-1-benzofuran-5-yl)benzenesulfonamide,
4-Fluoro-N-(7-pyrrolidin-1-yl-1-b enzofuran-5-yl)benzenesulfonamide
hydrochloride,
4-Fluoro-N-(7-morpholin-4-yl-1-benzofuran-5-yl)benzenesulfonamide
hydrochloride,
N-(7-Morpholin-4-yl-1-benzofuran-5-yl)benzenesulfonamide hydrochloride,
3,4-Dimethoxy-N-(7-morpholin-4-yl-1-benzofuran-5-yl)benzenesulfonamide,
2-Methoxy-5-methyl-N (7-pyridin-4-yl-1-benzofuran-5-yl)benzenesulfonamide,
N (7-Pyridin-3-yl-1-benzofuran-5-yl)benzenesulfonamide trifluoroacetate,
2-Methoxy-5-methyl-N (7-pyridin-3-yl-1-benzofuran-5-yl)benzenesulfonamide
trifluoroacetate,
N (7-Pyrazin-2-yl-1-benzofuran-5-yl)benzenesulfonamide trifluoroacetate,
N-(7-Pyrimidine-5-yl-1-benzofuran-5-yl)benzenesulfonamide hydrochloride, and,
N [7-(1-Aza-bicyclo[2.2.2]oct-2-en-3-yl)-benzofuran-5-yl]-2-methoxy-5-methyl-
benzenesulfonamide hydrochloride,
2-[4-(5-~[(2-Chlorophenyl)sulfonyl]amino}-1-benzofuran-7-yl)piperazin-1-yl]-
N,N-diethylacetamide hydrochloride,
N,N-diethyl-2-[4-(5- f [(2-methoxy-5-methylphenyl)sulfonyl]amino}-1-
benzofuran-7-yl)piperazin-1-yl]acetamide hydrochloride,
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N-[7-(1-Azabicyclo[2.2.2.]oct-3-yloxy)-1-benzofuran-5-yl]benzenesulfonamide
hydrochloride,
N-[7-(1-Azabicyclo[2.2.2.]oct-3-yloxy)-1-benzofuran-5-yl]-2-
chlorobenzenesulfonamide hydrochloride,
N-[7-( 1-Azabicyclo [2.2.2. ] oct-3 -yloxy)-1-benzofuran-5-yl]-2-methoxy-5-
benzenesulfonamide hydrochloride,
N- { 7-[(2-Morpholin-4-ylethyl) amino]-1-benzofuran-5-yl ] benzenesulfonamide
hydrochloride,
2-Methoxy-5-methyl-N- ~7-[(2-morpholin-4-ylethyl)amino]-1-benzofuran-5-
yl~benzenesulfonamide hydrochloride,
N- { 7-[(2-Morpholin-4-ylethyl) amino]-1-benzofuran-5-yl } -2-
(trifluoromethyl)benzenesulfonamide hydrochloride,
2,6-Dichloro-N- { 7-[(2-morpholin-4-ylethyl)amino]-1-benzofuran-5-
yl}benzenesulfonamide hydrochloride,
N-(7- f [2(Dimethylamino)ethyl]amino-1-benzofuran-5-yl)-2-methoxy-5-
benzenesulfonamide hydrochloride,
2-Chloro-N(7- { [2-(dimethylamino) } -1-benzofuran-5-yl)b enzenesulfonamide
hydrochloride,
N-[7-(Pyridin-4-ylamino)-1-benzofuran-5-yl]benzenesulfonamide hydrochloride,
2-Chloro-N-[7-(pyridin-4-ylamino)-1-benzofuran-5-yl]benzenesulfonamide
hydrochloride,
2-Methoxy-5-methyl-N-[7-(pyridin-4-ylamino)-1-benzofuran-5-
yl]benzenesulfonamide hydrochloride,
2-Methoxy-5-methyl-N-[7-(piperazin-1-ylcarbonyl)-1-benzofuran-5-
yl]benzenesulfonamide hydrochloride,
2-Methoxy-5-methyl-N-[7-(piperazin-1-ylmethyl)-1-benzofuran-S-
yl]benzenesulfonamide hydrochloride,
N- { 7-[(3-Aminopyrrolidin-1-yl)methyl]-1-benzofuran-5-yl ] -2-methoxy-5-
methylbenzenesulfonamide hydrochloride,
N-[7(6,6-Dioxidohexahydrothieno[3,4-b]pyrazin-1(2H)-yl)-1-benzofuran-5-yl]-2-
methoxy-5-methylbenzenesulfonamide hydrochloride,
N-[7(6, 6-Dioxidohexahydrothieno [3 ,4-b]pyrazin-1 (2H)-yl)-1-benzofuran-5-
yl]benzenesulfonamide hydrochloride,
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N- { 7-[(2-Pyrrolidin-1-ylethyl) amino]-1-b enzofuran-5-yl } b
enzenesulfonamide
hydrochloride,
2-Methoxy-5-methyl-N- { 7- [(2-pyrrolidin-1-ylethyl) amino]-1-b enzofuran-5-
yl}benzenesulfonamide hydrochloride,
N-{7-[(2-Pyrrolidin-1-ylethyl)amino]-1-benzofuran-5-yl}-2-
(trifluoromethyl)benzenesulfonamide hydrochloride,
3-Chloro-4-methyl-N-{7-[(2-pyrrolidin-1-ylethyl)amino]-1-benzofuran-5-
yl}benzenesulfonamide hydrochloride,
2-Methoxy-5-methyl-N- {7-[(3-morpholin-4-ylpropyl)amino]-1-benzofuran-5-
yl}benzenesulfonamide hydrochloride,
N- { 7-[(3 -Morpholin-4-ylpropyl)amino]-1-b enzofuran-5-yl } -2-
(trifluoromethyl)benzenesulfonamide hydrochloride,
3-Chloro-4-methyl-N-{7-[(3-morpholin-4-ylpropyl)amino]-1-benzofuran-5-
yl}benzenesulfonamide hydrochloride,
N-[7-({[(2R)-1-Ethylpyrrolidin-2-yl]methyl}amino)-1-benzofuran-5-
yl]benzenesulfonamide hydrochloride,
N-[7-( { [(2R)-1-Ethylpyrrolidin-2-yl]methyl } amino)-1-benzofuran-5-yl]-2-
methoxy-5-methylbenzenesulfonamide hydrochloride,
N-[7-( { [(2R)-1-Ethylpyrrolidin-2-yl]methyl } amino)-1-benzofuran-5-yl]-2-
(trifluoromethyl)benzenesulfonamide hydrochloride,
N-[7-( { [(2R)-1-Ethylpyrrolidin-2-yl]methyl } amino)-1-benzofuran-5-yl]-3 -
methylbenzenesulfonamide hydrochloride,
N-[7-( { [(2R)-1-Ethylpyrrolidin-2-yl] methyl } amino)-1-b enzofuran-5-yl]
thiophene-
2-sulfonamide hydrochloride,
5-Chloro-N-[7-({[(2R)-1-ethylpyrrolidin-2-yl]methyl}amino)-1-benzofuran-5-
yl]thiophene-2-sulfonamide hydrochloride,
5-Chloro-N-[7-( { [(2R)-1-ethylpyrrolidin-2-yl]methyl } amino)-1-benzofuran-5-
yl]-
1,3-dimethyl-1H-pyrazole-4-sulfonamide hydrochloride,
N-(7- { [3-(2-Methylpiperidin-1-yl)propyl] amino } -1-benzofuran-5 -
yl)benzenesulfonamide hydrochloride,
2-Methoxy-5-methyl-N-(7- { [3 -(2-methylpiperidin-1-yl)propyl] amino } -1-
benzofuran-5-yl)benzenesulfonamide hydrochloride,
N-(7-{[3-(2-Methylpiperidin-1-yl)propyl]amino} -1-benzofuran-5-yl)-2-
(trifluoromethyl)benzenesulfonamide hydrochloride,
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5-Chloro-1,3-dimethyl-N-(7- { [3 -(2-methylpiperidin-1-yl)propyl] amino } -1-
benzofuran-5-yl)-1H-pyrazole-4-sulfonamide hydrochloride,
N-[7-(6-Aminopyridin-3-yl)-1-benzofuran-5-yl]-2-methoxy-5-
methylbenzenesulfonamide,
N-{7-[4-(Cyclopropyhnethyl)piperazin-1-yl]-1-benzofuran-5-yl}-2-methoxy-5-
methylbenzenesulfonamide hydrochloride,
2-Methoxy-5-methyl-N- { 7-[4-(3, 3, 3-trifluoropropyl)piperazin-1-yl]-1-b
enzofuran-
5-yl}benzenesulfonamide hydrochloride,
2-Methoxy-5-methyl-N- { 7- [3 -(trifluoromethyl)piper azin-1-yl]-1-benzofuran-
5-
yl}benzenesulfonamide hydrochloride,
N-[7-(Aminopiperidin-1-yl)-1-benzofuran-5-yl]-2-
(trifluoromethyl)benzenesulfonamide hydrochloride,
N-[7-(Aininopiperidin-1-yl)-1-benzofuran-5-yl]-benzenesulfonamide
hydrochloride,
N-[7-(Aminopiperidin-1-yl)-1-benzofuran-5-yl]-2-chlorobenzenesulfonamide
hydrochloride,
N-[7-(Aminopiperidin-1-yl)-1-b enzofuran-5-yl]-2-methoxy-5 -
methylbenzenesulfonamide hydrochloride,
N-(7- { [cis-3-Fluoropiperidin-4-yl] oxy } -1-benzofuran-5-yl)-2-methoxy-5-
methylbenzenesulfonamide hydrochloride,
N-(7- {traps-3-Fluoropiperidin-4-yl] oxy} -1-b enzofuran-5-yl)-2-methoxy-5-
methylbenzenesulfonamide hydrochloride ,
N-(7- { [cis-3-Fluoropiperidin-4-yl] oxy } -1-benzofuran-5-yl)-2-
(trifluoromethyl)benzenesulfonamide hydrochloride,
N-(7-{[traps-3-Fluoropiperidin-4-yl]oxy}-1-benzofuran-5-yl)-2-
(trifluoromethyl)benzenesulfonamide hydrochloride,
2-Chloro-N-(7- { [traps-3-fluoropiperidin-4-yl] oxy } -1-b enzofuran-5-
yl)benzenesulfonamide hydrochloride,
N-(7- { [traps-3-Fluoropiperidin-4-yl] oxy } -1-b enzofuran-5-yl)-3-
methylbenzenesulfonamide hydrochloride,
3, 6-Dichloro-N-(7- { [traps-3 -fluoropiperidin-4-yl] oxy} -1-benzofuran-5-yl)-
2-
methylbenzenesulfonamide hydrochloride,
2-Chloro-5-fluoro-N-(7- { [traps-3-fluoropiperidin-4-yl]oxy}-1-benzofuran-5-
yl)benzenesulfonamide hydrochloride,
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N-(2-Methoxy-5-methylphenyl)-7-[(3 -methylpiperazin-1-yl)methyl]-1-b enzofuran-
5-sulfonamide hydrochloride,
N-(2-Methylphenyl)-7-(piperazin-1-ylmethyl)-1-b enzofuran-5-sulfonamide,
trifluoroacetate,
7-[(3,5-Dimethylpiperazin-1-yl)methyl]-N-(2-methylphenyl)-1-benzofuran-5-
sulfonamide, trifluoroacetate,
N-(2-Methylphenyl)-7-[(3-methylpiperazin-1-yl)methyl]-1-benzofuran-5-
sulfonamide, trifluoroacetate,
7-( 1,4-Diazepan-1-ylmethyl)-N-(2-methylphenyl)-1-benzofuran-5-sulfonamide,
trifluoroacetate,
7- ~ (trans-2, 5-Dimethylpiperazin-1-yl)methyl } -N-(2-methylphenyl)-1-
benzofuran-
5-sulfonamide, trifluoroacetate,
N-(2-Methylphenyl)-7- ~ [(2R)-2-methylpiperazin-1-yl]methyl } -1-benzofuran-5-
sulfonamide, trifluoroacetate,
N-(2-Methoxy-5-methylphenyl)-7-[(3-methylpiperazin-1-yl)methyl]-1-benzofuran-
5-sulfonamide, trifluoroacetate,
7-( 1,4-D iazepan-1-ylmethyl)-N-(2-methoxy-5-methylphenyl)-1-b enzofuran-5-
sulfonamide, trifluoroacetate,
N-(2-Methoxy-5-methylphenyl)-7-(piperazin-1-ylmethyl)-1-benzofuran-5-
sulfonamide, trifluoroacetate,
7- f (cis-3,5-Dimethylpiperazin-1-yl)methyl}-N-(2-methoxy-5-methylphenyl)-1-
benzofuran-5-sulfonamide, trifluoroacetate,
7- f [trans-2,5-Dimethylpiperazin-1-yl]methyl}-N-(2-methoxy-5-methylphenyl)-1-
benzofuran-5-sulfonamide, trifluoroacetate"
7-[(1S,4,S~-2,5-Diazabicyclo[2.2.1]hept-2-ylmethyl]-N-(2-methoxy-5-
methylphenyl)-1-benzofuran-5-sulfonamide, trifluoroacetate"
N-(2-Methoxy-5-methylphenyl)-7-[(2-methylpiperazin-1-yl)methyl]-1-benzofuran-
5-sulfonamide, trifluoroacetate;
2-Chloro-N-[7-(piperazin-1-ylmethyl)-1-benzofuran-5-yl]b enzenesulfonamide
dihydrochloride,
2-Methyl-N-[7-(piperazin-1-ylmethyl)-1-benzofuran-5-yl]benzenesulfonamide,
dihydrochloride,
N-[7-(Piperazin-1-ylmethyl)-1-benzofuran-5-yl]thiophene-2-sulfonamide,
dihydrochloride,
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2-Chloro-N-[7-( 1,4-diazepan-1-ylmethyl)-1-benzofuran-5-yl]benzenesulfonamide
dihydrochloride,
N-[7-( 1,4-Diazepan-1-ylmethyl)-1-benzofuran-5-yl]-2-methylbenzenesulfonamide,
dihydrochloride,
N-[7-(1,4-Diazepan-1-ylmethyl)-1-benzofuran-5-yl]thiophene-2-sulfonamide
dihydrochloride,
2-Methoxy-5-methyl-N- { 7-[(2-methylpiperazin-1-yl)methyl]-1-b enzofuran-5-
yl}benzenesulfonamide, dihydrochloride,
2-Methyl-N- { 7- [(2-methylpiperazin-1-yl)methyl]-1-benzofuran-5-
yl}benzenesulfonamide dihydrochloride,
2, 5-Dichloro-N- { 7- [(2-methylpiperazin-1-yl)methyl]-1-benzofuran-5-yl }
thiophene-
3-sulfonamide dihydrochloride,
2-Methoxy-5-methyl-N- { 7- [(3 -methylpiperazin-1-yl)methyl]-1-benzofuran-5-
yl}benzenesulfonamide, dihydrochloride,
N-{7-[(3-Methylpiperazin-1-yl)methyl]-1-benzofuran-5-yl}-2-
(trifluoromethyl)benzenesulfonamide, dihydrochloride,
2-Chloro-N- { 7- [(3 -methylpiperazin-1-yl)methyl]-1-benzofuran-5-
yl}benzenesulfonamide, dihydrochloride,
N {7-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-ylmethyl]-1-benzofuran-5-yl}-2-
methoxy-5-methylbenzenesulfonamide, dihydrochloride,
N {7-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-ylmethyl]-1-benzofuran-5-yl}-2-
(trifluoromethyl)benzenesulfonamide, dihydrochloride,
N {7-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-ylmethyl]-1-benzofuran-5-yl}-2-
methylbenzenesulfonamide, dihydrochloride,
2-Methoxy-5-methyl-N-{7-[(trans-2,5-dimethylpiperazin-1-yl)methyl]-1-
benzofuran-5-yl}benzenesulfonamide, bistrifluoroacetate,
2-Methyl-N- { 7-[(trans-2, 5-dimethylpiperazin-1-yl)methyl]-1-benzofuran-5-
yl}benzenesulfonamide, bistrifluoroacetate,
2-Chloro-N- { 7- [(trans-2, 5-dimethylpiperazin-1-yl)methyl]-1-benzofuran-5-
yl}benzenesulfonamide, bistrifluoroacetate,
1-( { 5- [(2-Methoxy-5-methylphenyl) sulfonyl]-1-b enzofuran-7-
yl}methyl)piperazine, trifluoroacetate,
1-{[5-(Phenylsulfonyl)-1-benzofuran-7-yl]methyl}piperazine, trifluoroacetate,
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1-( { 5 -[(4-Methylphenyl) sulfonyl]-1-benzofuran-7-yl } methyl)piperazine,
trifluoroacetate,
1-( f 5-[(2-Methoxy-5-methylphenyl)sulfonyl]-1-benzofuran-7-yl}methyl)-1,4-
diazepane, trifluoroacetate,
1- f [5-(Phenylsulfonyl)-1-benzofuran-7-yl]methyl}-1,4-diazepane,
trifluoroacetate,
1-( f 5-[(4-Methylphenyl)sulfonyl]-1-benzofuran-7-yl}methyl)-1,4-diazepane,
trifluoroacetate,
1-( { 5- [(2-Methoxy-5-methylphenyl) sulfonyl]-1-benzofuran-7-yl } methyl)-2-
methylpiperazine, trifluoroacetate,
1-( { 5- [(2-Methoxy-5-methylphenyl) sulfonyl]-1-benzofuran-7-yl } methyl)-3 -
methylpiperazine, trifluoroacetate,
N-(2-Methylphenyl)-7- f [(3R)-pyrrolidin-3-ylamino]methyl}-1-benzofuran-5-
sulfonamide, trifluoroacetate,
N-(2-Methylphenyl)-7-(piperidin-4-ylmethyl)-1-benzofuran-5-sulfonamide,
trifluoroacetate,
N-(2-Methylphenyl)-7-(pyrrolidin-3-ylmethyl)-1-benzofuran-5-sulfonamide,
trifluoroacetate,
N-(2-Methylphenyl)-7-(piperidin-3-ylmethyl)-1-benzofuran-5-sulfonamide,
trifluoroacetate,
2-Methoxy-5-methyl-N-[7-(piperidin-4-ylmethyl)-1-benzofuran-5-
yl]benzenesulfonamide, trifluoroacetate,
3-( f 5-[(4-Methylphenyl)sulfonyl]-1-benzofuran-7-yl}methyl)pyrrolidine,
trifluoroacetate"
2-Methoxy-5 -methyl-N-[S-(piperidin-4-ylmethyl)-1-benzofuran-7-
yl]benzenesulfonamide, trifluoroacetate,
2-Methoxy-5-methyl-N- { 5-[(3 -methylpiperazin-1-yl)methyl]-1-b enzofuran-7-
yl}benzenesulfonamide, bis(trifluoroacetate"
2-Methoxy-5-methyl-N-[5-(piperidin-4-ylmethyl)-1-benzofuran-7-
yl]benzenesulfonamide, trifluoroacetate.
Another object of the present invention is a process for the preparation of a
compound as mentioned above, comprising the following steps:
(a) halogenation of 4-nitrophenol to give a dihalogenated 4-nitrophenol,
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(b) ring closure of a dihalogenated 4-nitrophenol using
trimethylsilylacetylene to give
a halogenated nitrobenzofuran,
(c) nucleophilic displacement of a halogenated nitrobenzofuran with an amine
to give
an amine-substituted nitrobenzofuran,
(d) BOG-protection of an amine-substituted benzofuran to give a BOC-protected
amine-substituted nitrobenzofuran,
(e) reduction of a BOC-protected amine-substituted nitrobenzofuran to give a
BOC-
protected amine-substituted aminobenzofuran,
(f) coupling of a halogenated nitrobenzofuran with a
tributylstannylheterocycle,
tributylstannylheteroaryl compound, or heteroaryl boronic acid or heteroaryl
boronic ester
to give a heterocycle-substituted or heteroaryl-substituted nitrobenzofuran,
(g) reduction of a heterocycle-substituted or aryl-substituted nitrobenzofuran
to give
a heterocycle-substituted or heteroaryl-substituted aminobenzofuran,
(h) arylsulfonylation of a heterocycle-substituted or heteroaryl-substituted
aminobenzofuran to give a heterocycle-substituted or heteroaryl-substituted
arylsulfonylaminobenzofuran,
(i) arylsulfonylation of a BOC-protected amine-substituted aminobenzofuran to
give
a BOC-protected amine-substituted arylsulfonylaminobenzofuran,
(j) removal of the BOC-protecting group from a BOC-protected amine-substituted
arylsulfonylaminobenzofuran,
(lc) benzylation of a BOC-protected amine-substituted aminobenzofuran to give
a
BOC-protected amine-substituted benzylaminobenzofuran,
(1) removal of the BOC-protecting group from a BOC-protected amine-substituted
benzylaminobenzofuran,
(m) benzoylation of a BOC-protected amine-substituted aminobenzofuran to give
a
BOC-protected amine-substituted benzoylaminobenzofuran,
(n) removal of the BOC-protecting group from a BOC-protected amine-substituted
benzoylaminobenzofuran,
(o) reaction of a BOC-protected amine-substituted aminobenzofuran with an aryl
isocyanate to give a BOG-protected amine-substituted
phenylaminocarbonylaminobenzofuran, and
(p) removal of the BOC-protecting group from a BOC-protected amine-substituted
phenylaminocarbonylaminobenzofuran.
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Additional synthetic steps to reach the compounds of the present invention are
outlined in Schemes 7-14.
Another object of the present invention is a compound as mentioned above for
use in
therapy, especially for use in the treatment or prophylaxis of a 5-HT6
receptor-related
disorder, to achieve reduction of body weight and of body weight gain.
Another object of the present invention is a pharmaceutical formulation
comprising a
compound as mentioned above as active ingredient, in combination with a
pharmaceutically acceptable diluent or carrier, especially for use in the
treatment or
prophylaxis of a 5-HT6 receptor-related disorder, to achieve reduction of body
weight and
of body weight gain.
Another object of the present invention is a method for treating a human or
animal
subject suffering from a 5-HT6 receptor-related disorder, to achieve reduction
of body
weight and of body weight gain. The method can include administering to a
subject (e.g., a
human or an animal, dog, cat, horse, cow) in need thereof an effective amount
of one or
more compounds of any of the formulae herein, their salts, or compositions
containing the
compounds or salts.
The methods delineated herein can also include the step of identifying that
the subject
is in need of treatment of the 5-HT6 receptor-related disorder, to achieve
reduction of body
weight and of body weight gain. Identifying a subject in need of such
treatment can be in
the judgment of a subject or a health care professional and can be subjective
(e.g., opinion)
or objective (e.g., measurable by a test or diagnostic method).
Another object of the present invention is a method for the treatment or
prophylaxis
of a 5-HTg receptor-related disorder, to achieve reduction of body weight and
of body
weight gain, which comprises administering to a subject in need of such
treatment an
effective amount of a compound as mentioned above.
Another object of the present invention is a method for modulating (e g
inhibiting or
promoting) 5-HT6 receptor activity, which comprises administering to a subject
in need of
such treatment an effective amount of a compound as mentioned above.
Another object of the present invention is the use of a compound as mentioned
above
for the manufacture of a medicament for use in the prophylaxis or treatment of
a 5-HT6
receptor-related disorder, to achieve reduction of body weight and of body
weight gain.
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The compounds as mentioned above may be agonists, partial agonists or
antagonists
for the 5-HT6 receptor. Preferably, the compounds act as partial agonists or
antagonists for
the 5-HT6 receptor.
Another object of the present invention is a cosmetic composition comprising a
compound as mentioned above as active ingredient, in combination with a
cosmetically
acceptable diluent or carrier, especially for use in the prophylaxis or
treatment of a 5-HT6
receptor-related disorder, to achieve reduction of body weight and of body
weight gain.
Examples of 5-HT6 receptor-related disorders are obesity; type II diabetes;
disorders
of the central nervous system such as anxiety, depression, panic attacks,
memory disorders,
cognitive disorders, epilepsy, sleep disorders, migraine, anorexia, bulimia,
binge eating
disorders, obsessive compulsive disorders, psychoses, Alzheimer's disease,
Parkinson's
disease, Huntington's chorea, schizophrenia, attention deficit hyperactive
disorder
(ADHD), withdrawal from drug abuse, neurodegenerative diseases characterized
by
impaired neuronal growth, and pain.
The compounds and compositions are useful for treating diseases, to achieve
reduction of body weight and of body weight gain. The diseases include
obesity; type II
diabetes; disorders of the central nervous system such as anxiety, depression,
panic attacks,
memory disorders, cognitive disorders, epilepsy, sleep disorders, migraine,
anorexia,
bulimia, binge eating disorders, obsessive compulsive disorders, psychoses,
Alzheimer's
disease, Parkinson's disease, Huntington's chorea, schizophrenia, attention
deficit
hyperactive disorder (ADHD), withdrawal from drug abuse, neurodegenerative
diseases
characterized by impaired neuronal growth, and pain. In one aspect, the
invention relates to
a method for treating or preventing an aforementioned disease comprising
administering to
a subject in need of such treatment an effective amount or composition
delineated herein.
Definitions
The following definitions shall apply throughout the specification and the
appended
claims.
Unless otherwise stated or indicated, the term "C~_6-alkyl" denotes a straight
or
branched alkyl group having from 1 to 6 carbon atoms. Examples of said C1_6-
alkyl include
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl
and straight- and
branched-chain pentyl and hexyl. For parts of the range "C1_6-alkyl" all
subgroups thereof
47
CA 02545506 2006-05-10
WO 2005/058858 PCT/SE2004/001949
are contemplated such as C1_5-alkyl, C~_4-alkyl, C1_3-alkyl, C1_2-alkyl, CZ_s-
alkyl, C2_5-alkyl,
Cz_4-alkyl, C2_3-alkyl, C3_6-alkyl, C4_5-alkyl, etc. "Halo-C1_6-alkyl" means a
C1_6-alkyl group
substituted by one or more halogen atoms. Examples of said halo-C1_6-alkyl
include 2-
fluoroethyl, fluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl. Likewise,
"aryl-C1_s-
alkyl" means a C1_6-alkyl group substituted by one or more aryl groups.
Unless otherwise stated or indicated, the term "hydroxy-C1_6-alkyl" denotes a
straight
or branched alkyl group that has a hydrogen atom thereof replaced with OH.
Examples of
said hydroxy-C1_6-alkyl include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl
and 2-
hydroxy-2-methylpropyl.
Unless otherwise stated or indicated, the term "C1_6-alkoxy" denotes a
straight or
branched alkoxy group having from 1 to 6 carbon atoms. Examples of said C1_g-
alkoxy
include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-
butoxy, t-
butoxy and straight- and branched-chain pentoxy and hexoxy. For parts of the
range "C1-6-
alkoxy" all subgroups thereof are contemplated such as C1_5-alkoxy, C1_4-
alkoxy, C1_3-
alkoxy, C1_2-alkoxy, CZ_6-alkoxy, C2_5-alkoxy, C2_4-alkoxy, CZ_3-alkoxy, C3_6-
alkoxy, C4_s-
alkoxy, etc.
Unless otherwise stated or indicated, the term C1_6-alkoxy-C1_6-alkyl denotes
a
straight or branched alkoxy group having from 1 to 6 carbon atoms connected to
an alkyl
group having from 1 to 6 carbon atoms. Examples of said C1_6-alkoxy-C1_6-alkyl
include
methoxymethyl, ethoxymethyl, iso-propoxymethyl, n-butoxymethyl, t-butoxymethyl
and
straight- and branched-chain pentoxymethyl. For parts of the range "C1_6-
alkoxy-C1-s-
alkyl" all subgroups thereof are contemplated such as C1_5-alkoxy-C1_6-alkyl,
CI_4-alkoxy-
CI_6-alkyl, C1_3-alkoxy-C1_6-alkyl, C1_2-alkoxy-C1_6-alkyl, C2_6-alkoxy-C1_6-
alkyl, C2_5_
alkoxy-CI_6-alkyl, Cz_4-alkoxy-C1_6-alkyl, CZ_3-alkoxy-C,_6-alkyl, C3_6-alkoxy-
C1_6-alkyl,
C4_5-alkoxy-C1_6-alkyl, C1_6-alkoxy-CI_5-alkyl, C1_6-alkoxy-C1_~-alkyl, etc.
Unless otherwise stated or indicated, the term "CZ_6-alkenyl" denotes a
straight or
branched alkenyl group having from 2 to 6 carbon atoms. Examples of said Cz_6-
alkenyl
include vinyl, allyl, 2,3-dimethylallyl, 1-butenyl, 1-pentenyl, and 1-hexenyl.
For parts of
the range "CZ_6-alkenyl" all subgroups thereof are contemplated such as CZ_5-
alkenyl, CZ_4-
alkenyl, CZ_3-alkenyl, C3_6-alkenyl, C4_5-alkenyl, etc. Likewise, "aryl-C2_6-
alkenyl" means a
C2_6-alkenyl group substituted by one or more aryl groups. Examples of said
aryl-C2_6
alkenyl include styryl and cinnamyl.
The term "oxo" denotes
48
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Unless otherwise stated or indicated, the term "CZ_6-alkynyl" denotes a
straight or
branched alkynyl group having from 2 to 6 carbon atoms. Examples of said CZ_6-
alkynyl
include ethynyl, 1-propynyl, 1-butynyl, and 1-hexynyl. For parts of the range
"CZ_6-
alkynyl" all subgroups thereof are contemplated such as CZ_5-alkynyl, CZ_4-
alkynyl, C2_3-
alkynyl, C3_6-alkynyl, C4_5-alkynyl, etc.
Unless otherwise stated or indicated, the term "C3_~-cycloalkyl" denotes a
cyclic alkyl
group having a ring size from 3 to 7 carbon atoms. Examples of said cycloalkyl
include
cyclopropyl, cyclobutyl, cyclopentyl,.cyclohexyl, methylcyclohexyl, and
cycloheptyl. For
parts of the range "C3_~-cycloalkyl" all subgroups thereof are contemplated
such as C3_s-
cycloalkyl, C3_5-cycloalkyl, C3_4-cycloalkyl, C4_~-cycloalkyl, C4_6-
cycloalkyl, C4_s-
cycloalkyl, CS_~-cycloalkyl, C6_~-cycloalkyl, etc.
Unless otherwise stated or indicated, the term "aryl" refers to a hydrocarbon
ring
system having at least one aromatic ring. Examples of aryls are phenyl,
indenyl, indanyl,
1,2,3,4-tetrahydronaphthyl, 1-naphthyl, 2-naphthyl, and fluorenyl.
Likewise, aryloxy refers to an aryl group bonded to an oxygen atom.
The term "heteroaryl" refers to a mono- or bicyclic aromatic ring system, only
one
ring need be aromatic, and the said heteroaryl moiety can be linked to the
remainder of the
molecule via a carbon or nitrogen atom in any ring, and having from 5 to 10
ring atoms
(mono- or bicyclic), in which one or more of the ring atoms are other than
carbon, such as
nitrogen, sulphur, oxygen and selenium. Examples of such heteroaryl rings
include furyl,
pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl,
pyridinyl,
pyrimidinyl, pyrazinyl, chromanyl, quinazolinyl, indolyl, isoindolyl,
indolinyl,
isoindolinyl, indazolyl, pyrazolyl, pyridazinyl, quinolinyl, isoquinolinyl,
benzofuranyl, 2,3-
dihydrobenzofuranyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-
tetrahydroisoquinolinyl,
benzodioxolyl, benzodioxinyl, benzothienyl, benzimidazolyl, benzothiazolyl,
benzothiadiazolyl, benzotriazolyl, and 2,1,3-benzoxadiazolyl groups. If a
bicyclic
heteroaryl ring is substituted, it may be substituted in any ring.
Unless otherwise stated or indicated, the term "heterocyclic" refers to a non-
aromatic
(i.e., partially or fully saturated) mono- or bicyclic ring system having 4 to
10 ring atoms
with at least one heteroatom such as O, N, or S, and the remaining ring atoms
are carbon.
Examples of heterocyclic groups include piperidyl, tetrahydropyranyl,
tetrahydrofuranyl,
azepinyl, azetidinyl, pyrrolidinyl, morpholinyl, imidazolinyl,
thiomorpholinyl, pyranyl,
dioxanyl, piperazinyl, octahydrofuro[3,4b]pyrazinyl, and 1-
azabicyclo[2.2.2]oct-2-en-3-yl
groups. When present, the sulfur atom may be in an oxidized form (i.e., S=O or
O=S=O).
49
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Examples of heterocyclic groups containing sulfur in oxidized form include
octahydrothieno[3,4b]pyrazine 6,6-dioxide and thiomorpholine l,l-dioxide.
Unless otherwise stated or indicated, the term "halogen" shall mean fluorine,
chlorine, bromine or iodine.
The term -S(O)X in Formula (IV) , wherein x is 0, 1 or 2, has the meaning as
illustrated by Formula (IX) - (XI):
O
_ ' _'
' ~ '
II ' II
O ' O
(X) (
The term "leaving group" refers to a group to be displaced from a molecule
during a
nucleophilic displacement reaction. Examples of leaving groups are iodide,
bromide,
chloride, methanesulphonate, hydroxy, methoxy, thiomethoxy, tosyl, or suitable
protonated
forms thereof (e.g., HBO, MeOH), especially bromide and methanesulphonate.
"Optional" or "optionally" means that the subsequently described event or
circumstance may but need not occur, and that the description includes
instances where the
event or circumstance occurs and instances in which it does not.
"Pharmaceutically acceptable" means being useful in preparing a pharmaceutical
composition that is generally safe, non-toxic and neither biologically nor
otherwise
undesirable and includes being useful for veterinary use as well as human
pharmaceutical
use.
"Treatment" as used herein includes prophylaxis of the named disorder or
condition,
or amelioration or elimination of the disorder once it has been established.
"An effective amount" refers to an amount of a compound that confers a
therapeutic
effect on the treated subject. The therapeutic effect may be objective (i.e.,
measurable by
some test or marker) or subjective (i.e., subject gives an indication of or
feels an effect).
The term "prodrug forms" means a pharmacologically acceptable derivative, such
as
an ester or an amide, which derivative is biotransformed in the body to form
the active
drug. Reference is made to Goodman and Gilman's, The Pharmacological basis of
Therapeutics, 8th ed., Mc-Graw-Hill, Int. Ed. 1992, "Biotransformation of
Drugs", p. 13-
15; and "The Organic Chemistry of Drug Design and Drug Action" by Richard B.
Silverman. Chapter 8, p 352. (Academic Press, Inc. 1992. ISBN 0-12-643730-0).
The following abbreviations have been used:
BINAP means 2,2'-bis(diphenylphosphino)1-1'-binaphthyl,
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CA 02545506 2006-05-10
WO 2005/058858 PCT/SE2004/001949
BOC means tert-butyloxycarbonyl,
CV means Coefficient of Variation,
DCM means dichloromethane,
DME means 1,2-dimethoxyethane,
DMSO means dimethyl sulphoxide,
EDTA means ethylenediamine tetraacetic acid,
EtOH means ethanol,
EtOAc means ethyl acetate,
EGTA means ethylenebis(oxyethylenenitrilo)tetraacetic acid,
HEPES means 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid,
HPLC means high performance liquid chromatography,
LSD means lysergic acid, diethylamide,
MeCN means acetonitrile,
SPA means Scintillation Proximity Assay,
t-BuOK means potassium tert-butoxide,
TEA means triethylamine,
TFA means trifluoroacetic acid,
THF means tetrahydrofuran, and
Xantphos means 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
All isomeric forms possible (pure enantiomers, diastereomers, tautomers,
racemic
mixtures and unequal mixtures of two enantiomers) for the compounds delineated
are
within the scope of the invention. Such compounds can also occur as cis- or
trans-, E- or Z-
double bond isomer forms. All isomeric forms are contemplated.
The compounds of the formula (I) may be used as such or, where appropriate, as
pharmacologically acceptable salts (acid or base addition salts) thereof. The
pharmacologically acceptable addition salts mentioned above are meant to
comprise the
therapeutically active non-toxic acid and base addition salt forms that the
compounds are
able to form. Compounds that have basic properties can be converted to their
pharmaceutically acceptable acid addition salts by treating the base form with
an
appropriate acid. Exemplary acids include inorganic acids, such as hydrogen
chloride,
hydrogen bromide, hydrogen iodide, sulphuric acid, phosphoric acid; and
organic acids
such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic
acid, pyruvic
acid, glycolic acid, malefic acid, malonic acid, oxalic acid, benzenesulphonic
acid,
toluenesulphonic acid, methanesulphonic acid, trifluoroacetic acid, fumaric
acid, succinic
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WO 2005/058858 PCT/SE2004/001949
acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic
acid, pamoic acid,
benzoic acid, ascorbic acid and the like. Exemplary base addition salt forms
are the
sodium, potassium, calcium salts, and salts with pharmaceutically acceptable
amines such
as, for example, ammonia, alkylamines, benzathine, and amino acids, such as,
e.g. arginine
and lysine.
For example, sulfonamide derivatives of Formula (I) wherein P is selected from
a
substituent of Formula (II) and (III) and wherein RZ is hydrogen may be
converted into
their corresponding potassium, sodium or calcium salts, or salts of other
alkali metals or
alkaline earth metals. The term addition salt as used herein also comprises
solvates which
the compounds and salts thereof are able to form, such as, for example,
hydrates,
alcoholates and the like.
For clinical use, the compounds of the invention are formulated into
pharmaceutical
formulations for oral, rectal, parenteral or other mode of administration.
Pharmaceutical
formulations are usually prepared by mixing the active substance, or a
pharmaceutically
acceptable salt thereof, with conventional pharmaceutical excipients. Examples
of
excipients are water, gelatin, gum arabicum, lactose, microcrystalline
cellulose, starch,
sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate,
talcum,
colloidal silicon dioxide, and the like. Such formulations may also contain
other
pharmacologically active agents, and conventional additives, such as
stabilizers, wetting
agents, emulsifiers, flavouring agents, buffers, and the like. Usually, the
amount of active
compounds is between 0.1-95% by weight of the preparation, preferably between
0.2-20%
by weight in preparations for parentral use and more preferably between 1-50%
by weight
in preparations for oral administration.
The formulations can be further prepared by known methods such as
granulation, compression, microencapsulation, spray coating, etc. The
formulations may be prepared by conventional methods in the dosage form of
tablets, capsules, granules, powders, syrups, suspensions, suppositories or
inj ections. Liquid formulations may be prepared by dissolving or suspending
the
active substance in water or other suitable vehicles. Tablets and granules may
be
coated in a conventional manner.
In a further aspect the invention relates to methods of making compounds of
any of
the formulae herein comprising reacting any one or more of the compounds of
the
formulae delineated herein, including any processes delineated herein. The
compounds of
the formula (I) above may be prepared by, or in analogy with, conventional
methods.
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The processes described above may be carried out to give a compound of the
invention in the form of a free base or as an acid addition salt. A
pharmaceutically
acceptable acid addition salt may be obtained by dissolving the free base in a
suitable
organic solvent and treating the solution with an acid, in accordance with
conventional
procedures for preparing acid addition salts from base compounds. Examples of
addition
salt forming acids are mentioned above.
The compounds of formula (I) may possess one or more chiral carbon atoms, and
they may therefore be obtained in the form of optical isomers, e.g. as a pure
enantiomer, or
as a mixture of enantiomers (racemate) or as a mixture containing
diastereomers. The
separation of mixtures of optical isomers to obtain pure enantiomers is well
known in the
art and may, for example, be achieved by fractional crystallization of salts
with optically
active (chiral) acids or by chromatographic separation on chiral columns.
The chemicals used in the synthetic routes delineated herein may include, for
example, solvents, reagents, catalysts, and protecting group and deprotecting
group
reagents. The methods described above may also additionally include steps,
either before
or after the steps described specifically herein, to add or remove suitable
protecting groups
in order to ultimately allow synthesis of the compounds. In addition, various
synthetic
steps may be performed in an alteniate sequence or order to give the desired
compounds.
Synthetic chemistry transformations and protecting group methodologies
(protection and
deprotection) useful in synthesizing applicable compounds are known in the art
and
include, for example, those described in R. Larock, Comprehensive Organic
Transfof°mations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts,
Protective
Groups in Organic Synthesis, 3'd Ed., John Wiley and Sons (1999); L. Fieser
and M.
Fieser, Fieser° and Fieser's Reagents fof° Organic Synthesis,
John Wiley and Sons (1994);
and L. Paquette, ed., Encyclopedia of Reagents for' Organic Synthesis, John
Wiley and
Sons (1995) and subsequent editions thereof.
The necessary starting materials for preparing the compounds of formula (I)
are
either known or may be prepared in analogy with the preparation of known
compounds.
The dose level and frequency of dosage of the specific compound will vary
depending on a
variety of factors including the potency of the specific compound employed,
the metabolic
stability and length of action of that compound, the patient's age, body
weight, general
health, sex, diet, mode and time of administration, rate of excretion, drug
combination, the
severity of the condition to be treated, and the patient undergoing therapy.
The daily
dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of
body
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WO 2005/058858 PCT/SE2004/001949
weight, administered singly or multiply in doses, e.g. from about 0.01 mg to
about 25 mg
each. Normally, such a dosage is given orally but parenteral administration
may also be
chosen.
The invention will now be further illustrated by the following non-limiting
Examples.
The specific examples below are to be construed as merely illustrative, and
not
limitative of the remainder of the disclosure in any way whatsoever. Without
further
elaboration, it is believed that one skilled in the art can, based on the
description herein,
utilize the present invention to its fullest extent. All publications cited
herein are hereby
incorporated by reference in their entirety.
Methods
1H nuclear magnetic resonance (NMR) and 13C NMR were recorded on Bruker
Advance
DPX 400, Bruker DRX-500, JEOL JNM-EX 270 or Varian MERCURY plus 400 MHz
spectrometers. All spectra were recorded using residual solvent or
tetramethylsilane (TMS)
as internal standard. Ionspray mass spectrometry (MS) spectra were obtained on
a Perkin-
Elmer API 150EX mass spectrometer. Preparative HPLC/MS was performed on a
Waters/Micromass Platform ZQ system equipped with System A: ACE 5 C8 column
(19x50mm) or System B: Xterra MS C18, 5 ~,m column (19x50mm). The following
HPLC
setups have also been used: System C: Gilson/YMC AQ C18; 150x30 mm; System D:
Gilson Finnigan/YMC ODS AQ Sp,m column (20x50mm); System E: Gyncotech HPLC-
UV "SYS-2"; Ace C8, 5 ~m column (21x50mm) and System F: Gyncotech HPLC-UV
"SYS-2"; Ace C8, 5 pm column (30x150mm). Eluents used for System A, C-F: MeCN
in
milliQ-water with 0.1% TFA. Eluents used for System B: MilliQ water, MeCN and
NH4HCO3 (100 mM). Analytical HPLC were performed on Agilent 1100, column: ACE
3
C8 (System A) or column: YMC ODS-AQ (System B) or column: Chromolith C18
(SOx4.6mm) (System C), eluents: MilliQ/0.1%TFA and MeCN. Preparative flash
chromatography was performed on Merck silica gel 60 (230-400 mesh). Reactions
conducted under controlled microwave energy were performed with a Personal
Chemistry
Smith Creator using 0.5-2 mL, 2-5 mL or 20 mL Smith Process Vials fitted with
aluminium caps and septa.
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Table 1
P
~O
R3
EXAMPLE P
N-(7- f Methyl[3-(methylamino)propyl]amino}-1-o= -o
benzofuran-5-yl)benzenesulfonamideN H
hydrochloride NH
N-(7-Piperidin-1-yl-1-benzofuran-5-o- -o -
yl)benzenesulfonamide N H
F
I~
N
4-Fluoro-N-(7-piperidin-1-yl-1-benzofuran-5- U
yl)benzenesulfonamide
NH
_ __
O
O
3,4-Dimethoxy-N-(7-piperidin-1-yl-1-benzofuran-o I ~ o N
5-yl)benzenesulfonamide hydrochloride
NH
_ __
O
~ O
3,4-Dimethoxy-N-(7-pyrrolidin-1-yl-1-benzofuran-I
o= =p
5-yl)benzenesulfonamide
NH
_ __
I~
N-(7-Pyrrolidin-1-yl-1-benzofuran-5-o- -o N
yl)benzenesulfonamide NH
CA 02545506 2006-05-10
WO 2005/058858 PCT/SE2004/001949
_~S,NH
4-Fluoro-N-(7-pyrrolidin-1-yl-1-benzofuran-5- O
yl)benzenesulfonamide hydrochloride
F
_~S,NH
4-Fluoro-N-(7-morpholin-4-yl-1-benzofuran-5- O ~ \ N
8
yl)benzenesulfonamide hydrochloride
F
~~ ,NH
N-(7-Morpholin-4-yl-1-benzofuran-5- O % S N
yl)benzenesulfonamide hydrochloride
Co~
_~S,NH
3,4-Dimethoxy-N-(7-morpholin-4-yl-1-benzofuran- O / ~ N
to , /
5-yl)benzenesulfonamide
O
~O
11 N-(3,5-Dimethylbenzyl)-7-piperazin-1-yl-1-
H
zofuran-5-amine h drochloride
ben y
N-(3,4-Difluorobenzyl)-7-piperazin-1-yl-1- F ~ ~ H
1~ benzofuran-5-amine hydrochloride F i N~
H
13 N-(3,5-Dimethoxybenzyl)-7-piperazin-1-yl-1-
benzofuran-5-amine hydrochloride
H
N-Benzyl-7-piperazin-1-yl-1-benzofuran-5-amine ~ \
~ ~ '
14 h drochloride
y ' H
__F_
N-(7-piperazin-1-yl-1-benzofuran-5-yl)benzamide ~ ~ N ,
15 '
hydrochloride o
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4-Methoxy-N-(7-piperazin-1-yl-1-benzofuran-5- o ~
,' CND
16 yl)benzamide hydrochloride
H
Q
i
2-Bromo-5-methoxy-N-(7-piperazin-1-yl-1- - N
" C~
1 ~ benzofuran-5-yl)benzamide hydrochloride I ~ N ;< N
Br H
O
3-Methyl-N-(7-piperazin-1-yl-1-benzofuran-5- I ~ H '
1 g yl)benzamide hydrochloride N
O H
N-(7-Piperazin-1-yl-1-benzofuran-5-yl)-3- ~ ~ N '
CND
19 (~iluoromethyl)benzamide hydrochloride ~F3 N
O H
2,4-Dichloro-N-(7-piperazin-1-yl-1-benzofuran-5- of
2o I % N~ C
yl)benzamide hydrochloride N
Q H
3,5-Dimethoxy-N-(7-piperazin-1-yl-1-benzofuran-
"- C ~
21 g_yl)benzamide hydrochloride ~o I ~ N ;~ rN,
0
N-(3,5-Dimethoxyphenyl)-N'-(7- o' o _
22 piperazin-1-yl-benzofuxan-5-yl)urea ~o ~ ~ N~N',',
hydrochloride " " "
N-(2 4-Dichlorophenyl)-N'-(7-piperazin-1-yl- ~ ~ . N
23
benzofuran-5-yl)urea hydrochloride G H H
\ O
N-(2-Methoxyphenyl)-N'-(7-piperazin-1-
24 benzofuran-5-yl)urea hydrochloride / N N~
O H
N-Phenyl-N'-(7-piperazin-1-yl-1-benzofuran-5- ~ \ O
25 yl)urea hydrochloride ~ N~N~
N-(3-Fluorophenyl)-N'-(7-piperazin-1-yl- \ O
26
benzofuran-5-yl)urea hydrochloride I / ~ ;< N
F N N~ H
N-(7-Piperazin-1-yl-1-benzofuran-5-yl-)-N'- F I ~ O
N
27
[trifuoromethyl)phenyl]urea hydrochloride F / N N~ ~ N
H
F
I~
o, _ _
2-Methoxy-5-methyl-N (7-pyridin-4-yl-1- o- =o w
28
benzofuran-5-yl)benzenesulfonamide N H '
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i
N (7-Pyridin-3-yl-1-benzofuran-5- o= =o
yl)benzenesulfonamide trifluoroacetate NH NI i
2-Methoxy-5-methyl-N (7-pyridin-3-yl-1- I ~ O'
3 0 benzofuran-5-yl)benzenesulfonamide o o I
trifluoroacetate - ~ H- N i
i
N 7-P razin-2-yl-1-benzofuran-5- ~
31 ( y ~ NI '1
yl)benzenesulfonamide trifluoroacetate NH
I~ _
N- 7-P rimidin-5-yl-1-benzofuran-5- o='=o
32 ( y
yl)benzenesulfonamide hydrochloride NH
N [7-(1-Aza-bicyclo[2.2.2]oct-2-en-3-yl)- ~ ~ O'
33 benzofuran-5-yl]-2-methoxy-5-methyl- o= =o /
drochloride NH N
benzenesulfonamide by
2-[4-(5-{[(2-Chlorophenyl)sulfonyl]amino}-1- ~ S , N H
34 benzofuran-7-yl)piperazin-1-yl]-N,N- ~ C I O
diethylacetamide hydrochloride I \ ~ N ~
N,N-diethyl-2-[4-(5-{[(2-methoxy-5- O g' N hi
o~ CND
35 methylphenyl)sulfonyl]amino}-1-benzofuran-7- ~ C w O _ J
yl)piperazin-1-yl]acetamide hydrochloride ~ / ~~1N'~
N-[7-(1-Azabicyclo[2.2.2.]oct-3-yloxy)-1- O S ~ N H
38
benzofuran-5-yl]benzenesulfonamide hydrochloride
/
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N-[7-(1-Azabicyclo[2.2.2.]oct-3-yloxy)-1-~\ N H
~S~ oY
9 benzofuran-5-yl]-2- O C I
chlorobenzenesulfonamidehydrochloride
O
N-[7-(1-Azabicyclo[2.2.2.]oct-3-yloxy)-1-S ~ N H
O ' '-
o,
~ enzofuran-5-yl]-2-methoxy-5-benzenesulfonamide
hydrochloride ~ /
N {7-[(2-Morpholin-4-ylethyl)amino]-1-~\ , N H
,S
41 benzofuran-5-yl} benzenesulfonamideO
hydrochloride
~\ ,NH HN';
2-Methoxy-5-methyl-N {7-[(2-morpholin-4-, S
O'
42 ylethyl)amino]-1-benzofuran-5-
yl}benzenesulfonamide hydrochloride~ /
N f 7-[(2-Morpholin-4-ylethyl)amino]-1-~\ N H H N''
O
~SJ F
43 benzofuran-5-yl}-2- F
(trifluoromethyl)benzenesulfonamideI / \ F
hydrochloride
2,6-Dichloro-N {7-[(2-morpholin-4-ylethyl)amino]-~\ , N H H N ~'
S
44 1-benzofuran-5-yl}benzenesulfonamide,
C I O
C I
hydrochloride \ ~ o
~ /
2-Methoxy-5-methyl-N [7-(2-morpholin-4-O g ' N H o''
O'
45 ylethoxy)-1-benzofuran-5-yl]benzenesulfonamide
hydrochloride I /
O
3-Methyl-N [7-(2-morpholin-4-ylethoxy)-1-O ~ S ~ N H
46 benzofuran-5-yl]benzenesulfonamide
hydrochloride i , Cod
59
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3-Chloro-4-methyl-N [7-(2-morpholin-4-ylethoxy)- O ~ S ' N H o
4~ 1-benzofuran-5-yl]benzenesulfonamide \
hydrochloride I / o
~C I
N-(7-{[2(Dimethylamino)ethyl]amino}-1- O S' N H
4g benzofuran-5-yl)-2-methoxy-5- \
O O
benzenesulfonamide hydrochloride I / , N ~
2-Chloro-N(7-{[2-(dimethylamino)}-1-benzofuran- O ,S ~ N H ~' N H
49 5_yl)benzenesulfonamide hydrochloride \ C I
I / /N~
~~ ,NH HN
N-[7-(Pyridin-4-ylamino)-1-benzofuran-5- O ,S
50 yl]benzenesulfonamide hydrochloride \
I
/ N
,,
2-Chloro-N-[7-(pyridin-4-ylamino)-1-benzofuran- O , S ~ N H ~ HN'~
51 5-yl]benzenesulfonamide hydrochloride \ C I
I
/ N
~~ ,NH ,,
2-Methoxy-5-methyl-N-[7-(pyridin-4-ylamino)-I- O ' S HN'~
52 benzofuran-5-yl]benzenesulfonamide hydrochloride I \
N
2-Methoxy-5-methyl-N-[7-(piperazin-1- O S ' N H
O'
53. ylcarbonyl)-1-benzofuran-5-yl]benzenesulfonamide \
HNJ
hydrochloride /
2-Methoxy-5-methyl-N-[7-(piperazin-1-ylmethyl)- O g' N H
O'
54 1-benzofuran-5-yl]benzenesulfonamide I \ O ~
hydrochloride /
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WO 2005/058858 PCT/SE2004/001949
~\ ~NH
l]-1-
th
l
i
y g
)me O'
n-1-y
N-{7-[(3-Aminopyrrolid
benzofuran-5-yl}-2-methoxy-5-
methylbenzenesulfonamide hydrochlorideI / N H 2
N-[7(6,6-Dioxidohexahydrothieno[3,4-b]pyrazin-O g' N H -+--
N
56 1(2H)-yl)-1-benzofuran-5-yl]-2-methoxy-5-O
N
methylbenzenesulfonamide hydrochloride/
O
N-[7(6,6-Dioxidohexahydrothieno[3,4-b]pyrazin-\ S , N H N -
, o
1(2H)-yl)-1-benzofuran-5-yl]benzenesulfonamideO
N
hydrochloride I
O\
N {7-[(2-Pyrrolidin-1-ylethyl)amino]-1-, N H
xNH
benzofuran-5-yl}benzenesulfonamide
\ U
hydrochloride I
O
2-Methoxy-5-methyl-N {7-[(2-pyrrolidin-1-S ~ N H
_ ~N
O /
59
ylethyl)amino]-1-benzofuran-5-~ O ~ ,
~
yl}benzenesulfonamide hydrochlorideI /
N {7-[(2-Pyrrolidin-1-ylethyl)amino]-1-O\ , N H
S F xNH
60 benzofuran-5-yl}-2- ~
O F
(trifluoromethyl)benzenesulfonamideI \ \ F U
hydrochloride
O
3-Chloro-4-methyl-N {7-[(2-pyrrolidin-1-\ , N H ,
O iS ~N
~
61 ylethyl)amino]-1-benzofuran-5-
N
yl}benzenesulfonamide hydrochloride/ . U
CI
2-Methoxy-S-methyl-N {7-[(3-morpholin-4-O S ~ N H
;~NH
5 O ~
f
i
1
b
62 - ~ N~
uran- ~
enzo I
no]-
-
ylpropyl)am
yl}benzenesulfonamide hydrochloride/
61
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N {7-[(3-Morpholin-4-ylpropyl)amino]-1- ~ S , N H F ,
63 benzofuran-5-yl}-2- O F
(trifluoromethyl)benzenesulfonamide hydrochloride I \ \ F
O _.
NH
3-Chloro-4-methyl-N {7-[(3-morpholin-4- ~S , N H
64 ylpropyl)amino]-1-benzofuran-5- ~ N
yl}benzenesulfonamide hydrochloride
CI
N [7-({[(2R)-1-Ethylpyrrolidin-2- ~ S , N H
O'
65 yl]methyl}amino)-1-benzofuran-5-
1 benzenesulfonamide h drochloride ~ r '-
Y] Y
N 7 2R -1-Eth 1 rrolidin-2-
[ -(}[( ) YpY O~S,NH
66 yl]methyl}amino)-1-benzofuran-5-yl]-2-methoxy-
5-methylbenzenesulfonamide hydrochloride
N [7-({[(2R)-1-Ethylpyrrolidin-2- ~~ , N H
yl]methyl}amino)-1-benzofuran-S-yl]-2- O'S F F N,,
67
trifluorometh 1 benzenesulfonamide h drochloride \ F
( Y) Y
N [7-({[(2R)-1-Ethylpyrrolidin-2- ~~ ~ N H H
O ~S
6g yl]methyl}amino)-1-benzofuran-5-yl]-3-
methylbenzenesulfonamide hydrochloride
/
N [7-({[(2R)-1-Ethylpyrrolidin-2- ~~ ~ H ,
S,NH NT
69 yl]methyl}amino)-1-benzofuran-5-yl]thiophene-2- O'
sulfonamide hydrochloride / g
O
5-Chloro-N [7-({[(2R)-1-ethylpyrrolidin-2- ~S , N H
O'
yl]methyl} amino)-1-benzofuran-5-yl]thiophene-2-
/ S
sulfonamide hydrochloride
CI
62
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5-Chloro-N [7-({[(2R)-1-ethylpyrrolidin-2- ~ S ~ N H
71 yl]methyl}amino)-1-benzofuran-5-yl]-13-
' ~~ C I
dimethyl-1H-pyrazole-4-sulfonamide hydrochloride
N-N
~\ , N H
N(7-{[3-(2-Methylpiperidin-1-yl)propyl]amino}-1- C,S
72 benzofuran-5-yl)benzenesulfonamide hydrochloride
/
2-Methoxy-5-methyl-N (7-{[3-(2-methylpiperidin- O S ~ N H
O N
73 1-yl)propyl]amino}-1-benzofuran-5-
yl)benzenesulfonamide hydrochloride /
N (7-{[3-(2-Methylpiperidin-1-yl)propyl]amino}-1- ~ S , N H F
74 benzofuran-5-yl)-2- C F ~~
(trifluoromethyl)benzenesulfonamide hydrochloride ~ F N
5-Chloro-1,3-dimethyl-N (7-{[3-(2-
methylpiperidin-1-yl)propyl]amino}-1-benzofuran- ~I N'
75 ,, \ /
5-yl)-1H pyrazole-4-sulfonamide hydrochloride
~S,NH _
N [7-(6-Aminopyridin-3-yl)-1-benzofuran-5-yl]-2- O
76 methoxy-5-methylbenzenesulfonamide ~ O \ I ~N
/ NHZ
N- 7- 4- C clo ro lmeth 1 i erazin-1- 1-1 O\ , N H N
{ [ ( Y p pY Y)pp Y] - p~S
77 benzofuran-5-yl}-2-methoxy-5- \ ~ ~ N
methylbenzenesulfonamide hydrochloride
N
2-Methoxy-5-methyl-N-{7-[4-(3,3,3- O S ~ N H
O o CND
7g trifluoropropyl)piperazin-1-yl]-1-benzofuran-5-
yl}benzenesulfonamide hydrochloride
F I 'F
F
63
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O _~__
2-Methoxy-5-methyl-N-{7-[3- O \S , N H --N -
(trifluoromethyl)piperazin-1-yl]-1-benzofuran-5-
C
drochloride I N"CF
yl}benzenesulfonamide by /
H a
~\ ,NH F -
N-[7-(Aminopiperidin-1-yl)-1-benzofuran-5-yl]-2-O ,S
F
(trifluoromethyl)benzenesulfonamide~
hydrochloride _ F
I NNZ
~\ , N H __I__
N-[7-(Aminopiperidin-1-yl)-1-benzofuran-5-yl]-O , S
benzenesulfonamide hydrochloride
NHz
/
~\ , N H _
l S
2
]- O ,
-
N-[7-(Aminopiperidin-1-yl)-1-benzofuran-5-y
id
hl
d
or
e
roc
chlorobenzenesulfonamide hy
NHz
N-[7-(Aminopiperidin-1-yl)-1-benzofuran-5-yl]-2-O S ' N H _ _I_
O' _
methoxy-5-methylbenzenesulfonamide
hydrochloride I / NH
z
N (7-{[cis-3-Fluoropiperidin-4-yl]oxy}-1-_O S , N H
O
benzofuran-5-yl)-2-methoxy-5- N
methylbenzenesulfonamide hydrochlorideI / H
N (7-{traps-3-Fluoropiperidin-4-yl]oxy}-1-O g' N H
O _____
,
F
benzofuran-5-yl)-2-methoxy-5- I
Ibenzenesulfonamide h drochloride/ H
methy Y
O
N (7-{[cis-3-Fluoropiperidin-4-yl]oxy}-1-\S , N H F O-',,
6 benzofuran-5-yl)-2- O F YF
8 ' C
(trifluoromethyl)benzenesulfonamideI \ H
hydrochloride F
64
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O
N (7-{[tr~ans-3-Fluoropiperidin-4-yl]oxy}-1- \S , N H F O',
benzofuran-5-yl)-2- O F ~F
87
(trifluoromethyl)benzenesulfonamide hydrochloride I ~ ' F
O
2-Chloro-N (7-{[traps-3-fluoropiperidin-4-yl]oxy}- \S , N H
1-benzofuran-5-yl)benzenesulfonamide O ~ C I ' F
hydrochloride
H
N (7-{[traps-3-Fluoropiperidin-4-yl]oxy}-1- _\S, N H O-'.
benzofuran-5-yl)-3-methylbenzenesulfonamide O ~ ' F
89
hydrochloride I \ N
H
O _
3,6-Dichloro-N (7-{[traps-3-fluoropiperidin-4- _\\ , N H
yl]oxy}-1-benzofuran-5-yl)-2- O ~S CI ~F
N
methylbenzenesulfonamide hydrochloride
H
CI
2-Chloro-5-fluoro-N (7-{[tr~ans-3-fluoropiperidin- \\ , N H
91 4-yl]oxy}-1-benzofuran-5-yl)benzenesulfonamide O ~S C I ~F
JN
hydrochloride
H
F
-~ ,,O
N-(2-Methoxy-5-methylphenyl)-7-[(3- H N ~ S ~ O
92 methylpiperazin-1-yl)methyl]-1-benzofixran-5
sulfonamide hydrochloride I / N
O ~ ',
N-(2-Methylphenyl)-7-(piperazin-1-ylmethyl)-1- , S ~ ~ N
93 benzofuran-5-sulfonamide, trifluoroacetate %r I I ~ N
O H
O
7-[(3,5-Dimethylpiperazin-1-yl)methyl]-N-(2- ISI I N
94 methylphenyl)-1-benzofuran-5-sulfonamide, '~ ~
trifluoroacetate ~ I I N
O H
O
N-(2-Methylphenyl)-7-[(3-methylpiperazin-1- II w
95 yl)methyl]-1-benzofuran-5-sulfonamide, '~S~N ~ ~ N
trifluoroacetate 0 H
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7- 1 4-Diaze an-1- lmeth 1 -N-(2-meth 1 hen 1
p Y Y) Yp Y)- ', S~ ~ ~ N
96 1-benzofuran-5-sulfonamide, trifluoroacetate ''~ I I N
O H N
O
7-{(traps-2,5-Dimethylpiperazin-1-yl)methyl}-N- '~ ISI N I ~ N '
9'7 (2-methylphenyl)-1-benzofuran-5-sulfonamide,
trifluoroacetate O H
O ~,
N-(2-Methylphenyl)-7-{[(2R)-2-methylpiperazin-1- ,
9$ yl]methyl}-1-benzofuran-5-sulfonamide, ~S~N I ~ N
trifluoroacetate O H
~N~
H
N-(2-Methoxy-5-methylphenyl)-7-[(3- O ~ ,
I I
99 methylpiperazin-1-yl)methyl]-1-benzofuran-5- ~~S~N ~ ~ N
sulfonamide, trifluoroacetate O H O~ N
H
7-(1,4-Diazepan-1-ylmethyl)-N-(2-methoxy-5
100 methylphenyl)-1-benzofuran-5-sulfonamide, '%~ I I N
trifluoroacetate O H O~ N
H
N-(2-Methoxy-5-methylphenyl)-7-(piperazin-1
101 ylmethyl)-1-benzofuran-5-sulfonamide, '~ I I ~N
trifluoroacetate O H O~ ~N~
H
-{( Ypp Y) Y} ( _ S I N
7 cis-3,5-Dimeth 1 i erazin-1- 1 meth 1 -N- 2 O
102 methoxy-5-methylphenyl)-1-benzofixran-5- ~~ I I N
sulfonamide, trifluoroacetate O H O~ ~N~
H
O
7-{[traps-2,5-Dimethylpiperazin-1-yl]methyl}-N- , II ~ N
103 (2-methoxy-5-methylphenyl)-1-benzofuran-5- :ro~H I / N
sulfonamide, trifluoroacetate O
H
7-(2,5-Diazabicyclo[2.2.1 ]hept-2-ylmethyl)-N-(2-
104 methoxy-5-methylphenyl)-1-benzofuran-5- ':'~ I I \N
sulfonamide, trifluoroacetate O H O~ N
H
N-(2-Methoxy-5-methylphenyl)-7-[(2-
105 methylpiperazin-1-yl)methyl]-1-benzofuran-5- '!~ I I \N ~ N
sulfonamide, trifluoroacetate
O H O, N
H
66
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H O y '
2-Chloro-N-[7-(piperazin-1-ylmethyl)-1-'~N~II ~
d S
106 e '
benzofuran-5- 1 benzenesulfonamiCI C
y ] '
dihydrochloride O N
H
- H O y '
2-Methyl-N-[7-(piperazin-1-ylmethyl)-1-'~N~ I I ~
07 benzofuran-5-yl]benzenesulfonamide,' S ,
C
dihydrochloride ~ N'
H
S
N-[7-(Piperazin-1-ylmethyl)-1-benzofuran-5-o N%r
log ~ ~
H
yl]thiophene-2-sulfonamide, N
dihydrochloride
H
H O \ ~;
2-Chloro-N-[7-(1,4-diazepan-1-ylmethyl)-1-'~N~ I I J~~~ N
09 benzofuran-5-yl]benzenesulfonamide
S
CI
dihydrochloride ~ N
H
O I N
'
N
110 N-[7-(1,4-Diazepan-1-ylmethyl)-1-benzofuran-5-~
drochloride %~
mide ~
dih I I
1f
h
1b
, N
y
ona
yl]-2-met
enzenesu
y
O H
% N
~
N-[7-(1,4-Diazepan-1-ylmethyl)-1-benzofixran-5-f ~
111 chloride N ~
d ~ ~ O (
dih H
id
2
lf
h
ro N
e
y
onam
ene-
-su
yl]thiop
H
2-Methoxy-5-methyl-N-{7-[(2-methylpiperazin-1-
'
12 l)methyl]-1-benzofuran-5-yl}benzenesulfonamide,:r N ~O I
y
dihydrochloride II Q, H
O
H O
2-Methyl-N-{7-[(2-methylpiperazin-1-yl)methyl]-'~N~II ~ , Y
13 1-benzofuran-5-yl}benzenesulfonamide' S
C
dihydrochloride I I N'
O H
ci ~ ci
i ~ ~
-1-
th
l
i
2
N
7
l
peraz yH N
n -N
y
p
-me
-{
-[(
2,5-Dich
oro-
114 yl)methyl]-1-benzofuran-5-yl}thiophene-3-l,
Os C
sulfonamide dihydrochloride N'
H
2-Methoxy-5-methyl-N-{7-[(3-methylpiperazin-1-
';r N ~~ ~
15 l)methyl]-1-benzofuran-5-yl}benzenesulfonamide,
y
dihydrochloride S Q, H
O
N-{7-[(3-Methylpiperazin-1-yl)methyl]-1-'
O I
N
benzofuran-5-yl}-2- i
116 ~ ~
:r ~
(nifluoromethyl)benzenesulfonamide,II CF3 N
dihydrochloride O H
67
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H O
2-Chloro-N-{7-[(3-methylpiperazin-1-yl)methyl]-1- '~N~II ~
benzofuran-5- 1 benzenesulfonamide, ' S
117 Y } ~
dihydrochloride ~ CI CH' \
N-[7-(2,5-Diazabicyclo[2.2.1]hept-2-ylmethyl)-1-
'
11 ~ benzofuran-5-yl]-2-methoxy-5- %r N ~O I
methylbenzenesulfonamide, dihydrochloride I I O,
O
N-[7-(2,5-Diazabicyclo[2.2.1]hept-2-ylmethyl)-1- '
benzofuran-5-yl]-2- :,~ N ~ ISQI ~
119 (trifluoromethyl)benzenesulfonamide,
dih drochloride O
Y H
H O w
N-[7-(2,5-Diazabicyclo[2.2.1]kept-2-ylmethyl)-1- '~N~II ~ ,
120 benzofuran-5-yl]-2-methylbenzenesulfonamide, ' S
dihydrochloride O
2-Methoxy-5-methyl-N-{7-[(traps-2,5- ' N 0 I ~ N
121 dimethylpiperazin-1-yl)methyl]-1-benzofuran-5- :~ ~S ~ "",.
yl}benzenesulfonamide, bistrifluoroacetate I I O,
O
H O
2-Methyl-N-{7-[(trams-2,5-dimethylpiperazin-1- '~N~ I I ~ ~ N
122 yl)methyl]-1-benzofuran-5-yl}benzenesulfonamide, ' S
bishifluoroacetate I I '"°~~~N~
O H
H O
2-Chloro-N-{7-[(traps-2,5-dimethylpiperazin-1- '' N ~ I I J~~~ N
123 yl)methyl]-1-benzofuran-5-yl}benzenesulfonamide, 'r S
bistrifluoroacetate II CI ~°"°~N~
O H
'
O w
124 1-({5-[(2-Methoxy-5-methylphenyl)sulfonyl]-1- ~ ISI
benzofuran-7-yl}methyl)piperazine, trifluoroacetate
O O_
125 1-{[5-(Phenylsulfonyl)-1-benzofuran-7-
yl]methyl}piperazine, trifluoroacetate
126 1-( {5-[(4-Methylphenyl)sulfonyl]-1-benzofuran-7-
yl}methyl)piperazine, trifluoroacetate
'
1-({5-[(2-Methoxy-5-methylphenyl)sulfonyl]-1- ~ I ~
127 benzofuran-7-yl}methyl)-1,4-diazepane, -S i
trifluoroacetate ' ~ O, H
68
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128 1-{[5-(Phenylsulfonyl)-1-benzofuran-7-yl]methyl}- ~ $ ~ N
1,4-diazepane, trifluoroacetate O N
H
129 1-({5-[(4-Methylphenyl)sulfonyl]-I-benzofuran-7- ; $ ~ N
y1} methyl)-1,4-diazepane, trifluoroacetate ~ O N
H
1 5 2-Methox -5-meth 1 hen 1 sulfon 1 -1 O I
-( { -[( Y Y P Y ) Y ] - , N
130 benzofuran-7-yl}methyl)-2-methylpiperazine, :rO~H O\ N
trifluoroacetate
H
O ~;~
1-({5-[(2-Methoxy-5-methylphenyl)sulfonyl]-1- II ~ N
131 benzofuran-7-yl}methyl)-3-methylpiperazine, ~:rS~N I ~
CNI \
trifluoroacetate O .H O~ H
N-(2-Methylphenyl)-7-{[(3R)-pyrrolidin-3- -
O I ~ ~~
134 ylamino]methyl}-I-benzofuran-5-sulfonamide, '%r I ~ ~N
trifluoroacetate O H
H
O
II ~
N-(2-Methylphenyl)-7-(piperidin-4-ylmethyl)-1- '~S~ (
135 benzofixran-5-sulfonamide, trifluoroacetate ' ~ H N
H
O
II ~
136 N-(2-Methylphenyl)-7-(pyrrolidin-3-ylmethyl)-1- ~, $~ . I ,
benzofuran-5-sulfonamide, trifluoroacetate '~O H N
H
O
N- 2-Meth 1 hen 1 -7 i eridin-3- Imeth 1 -1 I I w
137 ( yp Y) -(hp Y Y) - ~~$~ I
benzofuran-5-sulfonamide, trifluoroacetate . I I N N
O H H
2-Methoxy-5-methyl-N-[7-(piperidin-4-ylmethyl)- O I
13 8 1-benzofuran-5-yl]benzenesulfonamide,
trifluoroacetate O H O~ N
H
O I ~ ,, .
139 3-({5-[(4-Methylphenyl)sulfonyl]-1-benzofuran-7- ',-$
yl}methyl)pyrrolidine, trifluoroacetate
N
H
Table 2
69
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R2
O
R'
EXAMPLE R~
O _~I__
1)-1- \
3- N H
t
2
2
2
2
l
y S ,
-en-
-
]oc
.
.
o[
N-[2-(1-Azabicyc
36
benzofuran-7-yl]benzenesulfonamidei
hydrochloride
NH '
~\
N-[2-(1-Azabicyclo[2.2.2]oct-2-en-3-yl)-1-
,
O'
3 ~ benzofuran-7-yl]-2-methoxy-5-
methylbenzenesulfonamide hydrochloride
Table 3
R5
O
R'
EXAMPLE R R
O
132 2-Methoxy-5-methyl-N-[5-(piperidin-4-ylmethyl)-1-~ J
benzofuran-7-yl]benzenesulfonamide,HN ~ N
trifluoroacetate H
2-Methoxy-5-methyl-N-{5-[(3-methylpiperazin-1-y I ,
l}benzenesulfonamide O'
an-7-
f
1
b
l
h
l
133 , N ~'
ur
y
enzo
-
]-
)met
y
y
bis(trifluoroacetate H H
l)-1- O
lmeth
idin-4-
i
5
l
N
h
140 y O J
y
per
-(p
-
-[
y
2-Methoxy-5-met
benzofuran-7-yl]benzenesulfonamide,HN O, N
trifluoroacetate H
The preparation of the compounds of Formula (I) according to the Examples may
in
particular be illuminated by the following Schemes 1-6, wherein steps (a) to
(s) are
detailed below.
~o
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The experimental details are given for each of the specific synthetic
examples.
Schemes 1-6 are merely illustrative of some methods by which the compounds of
the
present invention may be synthesisized, and various modifications to to these
synthetic
reaction schemes may be made. Any primary or seconday amine nitrogen, if
present, in R3
may optionally be protected with a nitrogen protecting group, such as tert-
butoxycarbonyl
(t-BOC) or benzyl, in reactions targeting a compound of Formula (I).
Subsequent N-
deprotection is carried out by conventional methods such as those described in
Protective
Groups in Organic Synthesis, John Wiley & Sons, 1991.
Scheme 1
OzN ~ i Via) OzN ~ w I fib) 02N ~ w ~ ~c)
i
OH OH ~ O~R
Hal Hal
ozN ~ w ~ (d) ozN ~ w ~ (e) H2N ~ w
O~R ~ O~R ~ O~R
R3 R3 3
R
R = H or SiMe3
Hal = Cl, Br, or I
R3 is as defined for Formula (I).
Scheme Z
02N I ~ I y02N I \ I C9) H2N ~ ~h~ R~SO~HN
/ / I/ I/
O R O R O R O R
Hal Het Het Het
R = H or SiMe3
Hal = Cl, Br, or I
Het = a heteroaryl group or a heterocyclic group within the scope of R3 as
defined for
Formula (I). Exemplary heteroaryl or heterocyclic groups are selected from 3-
pyridyl, 4-
pyridyl, pyrazinyl, 5-pyrimidyl, and 1-azabicyclo[2.2.2]oct-3-en-2-yl
R' is as defined for Formula (I).
~1
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Scheme 3
(I) Clso~ ~ U> CISO2 ~ (k)
-~ I ~ o I
i o o~
Hal
CISOZ I / I (I) R~~NHS02 I ~ I (m) R~2NHS02
I, J
Hal o
Hal R3
Hal = Cl, Br, or I
R3 and RlZ are as defined for Formula (I)
Scheme 4
HEN I ~ I (n) R~aCH2NH ~ (O) R~'4CHZNH
I~
o R ~ o R ~ o R
Rs Rs Rs
R = H or SiMe3
R3 and R14 are as defined for Formula (I).
Scheme 5
H2N ~ (p) R~aCONH ~ (a) R~4CONH
I~ ~ ~ I I ~ I
o R ~ o~R ~ o~R
Rs Rs Rs
R = H or SiMe3
R3 and R14 are as defined for Formula (I).
Scheme 6
HEN I ~ I (r) _ R'''NHCONH ~ (S) R'4NHCONH
I I
R ~ I ~ ~I ~ ~ o~R
O"R
R R3 Ra
R = H or SiMe3
R3 and R14 are as defined for Formula (I).
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Scheme 7
02N ~ 02N w OZN ~ \ OaN ~ \
\ ~ \
O / O O O
I ~Ha Br Am
O
H2N W Rv.N RvI.N
S ~ \ S ~ \
o ii I ~ ~ o , o
0
Am Am Am
Rl is as defined for formula (I) and Am is attached to the remainder of the
molecule
via a nitrogen atom. Exemplary Am groups are depicted in Figure 1.
Figure 1
_1__ --N- R,~N~~, --.~- -
N / N
R11~ ~ R11 N
N N
I 11 N
11
R R Rai~N R~~ H2N
wherein R11 is each independently selected from hydrogen or methyl.
Scheme 8
Cr~O2S ~ 12 O~~O 12 O~~O
R~ .S ~ R~ ,S
I / oI H I , I H I /
o- -o-
Ri\ OSO
N ~ I R'~ ~So
H I / of ~ H I ~ I
i / OJ
O
Am
R'Z is as defined for formula (I) and Am is attached to the remainder of the
molecule
via a nitrogen atom. Exemplary Am groups are shown in Figure 1.
73
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Scheme 9
0 0
\ \ R13iO \ Ri3iO ~ \
/ O / O / ~ /
O OH O~o~ O p~ O O~
O
Rl3is \ Rl3iS \ 13is \
m ~ m ~>~R of O
/o /o /o
OH CI Am
R12 is as defined for formula (I) and Am is attached to the remainder of the
molecule
via a nitrogen atom. Exemplary Am groups are shown i Figure 1.
Scheme 10
O O B R19 O\ /O 1z ~\ i~
1z \\ i~ R .
R ~ .S
H ~ / \ + N~ J z
~O
I P
N-L ~~
P
RI2 is as defined for formula (I);
P is a suitable protecting group such as t-BOC
and z = 0, 1 or 2
74
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Scheme 11
O O HO O
Br , CHO gr / , gr / Br / \
\
OH \ O ~ O O
l
NOZ NOZ NOZ NOZ
Br /
Br , I \
O OS. NH
NHS
Br
\ B
+ .N ~ ' HN
O .NH P ~ ~O l Jz O
N~ ~z ~~ .NH O~ .NH
R'
R
N~ ~z
P
R' is as defined for formula (I);
P is a suitable protecting group such as t-BOC; and
z=0, 1 or2
Scheme 12
Br / \ ~ , ~ Am
\ ~ ~ \
O O
~S.NH ~~ .NH \ O ~ \ O
O'-R~ ~S.NH ~S~NH
O. R1 O. I ~
R
Rl is as defined for formula (I) and Am is attached to the remainder of the
molecule
via a nitrogen atom. Exemplary Am groups are shown in Figure 1.
~s
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Scheme 13
H
O
ON
~SI(CH3)3 HzN I \ ~ Si(CH3)3 ~ RW~~-N I \ ~ SI(CH3)3
/ p ~ / p O / p
Br gr Br
p\ H H H
-N \ O~ -N O I
R~iO I / O Si(CH3)3 Rii~l I / ~ ~ Riil~-N I
O O p O
Am O Am O Am
H
O~ -N \
RiiO ~ / O
Am
R1 is as defined for formula (I) and Am is attached to the remainder of the
molecule
via a nitrogen atom. Exemplary Am groups are shown in Figure 1.
Scheme 14
/% H O H O
R~zi O S I \ \ ~ RiziN~s~ \ \ R~zrN~g~ \
/ O O I / O
'O
I
Am p Am
R1z is as defined for formula (I) and Am is attached to the remainder of the
molecule
via a nitrogen atom. Exemplary Am groups are shown in Figure 1.
INTERMEDIATE 1
N,N'-Dimethyl-N-(5-nitro-1-benzofuran-7-yl)-propyl-1,3-diamine
To a mixture of 7-iodo-5-nitro-1-benzofuran (prepared according to the
following
procedures Castro, C. E.; Stephens, R. D. J. Org. Chern. 1963, 28, 2163 and
Doad, G. J. S.;
Barltrop, J. A.; Petty, C. M.; Owen, T. C. Tetrahedron Lett. 1989, 30, 1597-
1590 (300 mg,
1.0 mmol), Xantphos (60 mg, 0.1 mmol), Pd2(dba)3 (23 mg, 25 mmol), sodium tert
butoxide (125 mg, 1.3 mmol) in xylene (10 mL) was added N,N'-dimethylpropane-
1,3-
diamine (540 ~.L, 5 mmol). The mixture was stirred at 120 °C for 2 h,
allowed to cool and
76
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filtered through a Celite pad. The filtrate was concentrated in vacuo to give
the crude title
compound. MS m/z 264 (M+H)+.
INTERMEDIATE 2
tert-Butyl3-[(5-amino-1-benzofuran-7-yl)(methyl)amino]propyl(methyl)carbamate
The crude N,N'-dimethyl-N-(5-nitro-1-benzofuran-7-yl)propyl-1,3-diamine
(Intermediate
1) was dissolved in DCM (10 mL) and di-tert-butyl dicarbonate (327 mg, 1.5
mmol) in
DCM (5 mL) was added at 0 °C. The mixture was stirred at 0 °C
for 15 min, after which
time the ice-bath was removed and the mixture was stirred for 2 h at room
temperature.
Water was added. The organic material was extracted with chloroform (2x), the
combined
organic layers were dried (MgS04) and filtered. The volatiles were evaporated
to give a
yellow oil which was filtered through silica gel eluting with EtOAc. The
volatiles were
evaporated and the crude material of tert-butyl methyl[3-(methyl f 5-nitro-1-
benzofuran-7-
yl~amino)]propyl]carbamate was dissolved in EtOH and an excess of Raney Ni as
a
suspension in EtOH (4 mL) was added followed by the addition of hydrazine
hydrate (300
~,L, 6 mmol). The reaction mixture was stirred at room temperature for 2 h
followed by
filtration through a Celite pad pre-treated with water. The Celite pad was
washed with
MeOH and the filtrate was concentrated in vacuo to give the title compound
(250 mg) as a
crude, which was used directly in the next step.
INTERMEDIATE 3
tert-Butyl methyl[3-(methyl{5-[(phenylsulfonyl)amino]-1-benzofuran-7-
yl)amino)propyl] carbamate
Benzenesulfonyl chloride (115 pL, 0.9 mmol) was added to a mixture of tert-
butyl 3-[(5-
amino-1-benzofuran-7-yl)(methyl)amino]propyl(methyl)carbamate (Intermediate 2;
250
mg, 0.75 mmol) in DCM (2 mL) followed by addition of pyridine (1 mL). The
reaction
mixture was stirred at room temperature for 4 h. The volatiles were evaporated
in vacuo
and the residue obtained was purified using RP-HPLC (Gilson/YMC AQ C18; 150x30
mm) to give the title compound as a beige oil (202 mg, 43% over 4 steps); HPLC
93%, RT:
2.49 min (System A); 95%, RT: 2.27 min (System B); IH NMR (CDCl3) b ppm 1.41
(s,
9H), 1.60-1.75 (m, 2H), 2.74 (s, 3H), 2.93 (s, 3H), 3.13-3.25 (m, 2H), 3.42-
3.53 (m, 2H),
6.19-6.69 (m, 2H), 6.87-7.06 (m, 1H), 7.33-7.58 (m, 4H), 7.71-7.79 (m, 2H); MS
m/z 474
(M+H)+.
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EXAMPLE 1
N-(7- f Methyl[3-(methylamino)propyl] amino}-1-benzofuran-5-
yl)benzenesulfonamide
hydrochloride
tert-Butyl methyl[3-(methyl{5-[(phenylsulfonyl)amino]-1-benzofuran-7-
yl~amino)propyl]carbamate (Intermediate 3; 202 mg, 0.43 mmol) in DCM (2 mL)
was
treated with TFA (2 mL) at 0 °C for 10 min and was stirred for an
additional 30 min at
room temperature. After concentration in vacuo, the residue was re-dissolved
in MeOH
and treated with an excess of 1M HCl in diethyl ether. Removal of the solvents
gave the
title compound (173 mg, 98%) as a white solid; HPLC 100%, RT: 1.65 min (System
A);
100%, RT: 0.630 min (System B); 1H NMR (methanol-d4) 8 ppm 1.85-2.00 (m, 2H),
2.67
(s, 3H), 3.04-3.17 (m, SH), 3.64-3.73 (m, 2H), 6.81-6.84 (m, 1H), 6.95-6.98
(m, 1H), 7.06-
7.09 (m, 1H), 7.43-7.60 (m, 3H), 7.72-7.78 (m, 2H), 7.81-7.85 (m, 1H); MS n~/z
374
(M+H)+.
INTERMEDIATE 4
1-(5-Nitro-1-benzofuran-7-yl)piperidine
Step 1. 2-By~omo-6-iodo-4-nit~ophenol. A solution of 4-nitrophenol (130 g,
0.96 mol) in
acetonitrile (500 mL) was cooled to 0 °C. While keeping the temperature
below 5 °C,
chlorosulfonic acid (120 g, 1.03 mol) was added. The resulting mixture was
stirred for 30
min at 0-5 °C. N-bromosuccinimide (181 g, 1.01 mol) was added
portionwise to the
mixture during 7 h, while keeping the temperature below 8 °C. The
reaction was then
quenched by addition of a solution of NaHS03 (250 g, 2.4 mol) in water (600
mL) while
the temperature was kept below 20 °C. The water phase was removed and
the remaining
organic phase was concentrated to 300 mL by distillation. The residue was
diluted with
acetic acid (381 mL, 6.6 mol) and potassium acetate (212 g, 2.16 mol) was
added. The
temperature was adjusted to 50 °C and ICl (152 g, 0.936 mol) was added
while the
temperature was maintained between 50 and 80 °C. When the addition was
completed, the
product was precipitated by addition of water (1000 mL). After cooling to 10
°C, the
product was isolated by filtration, to yield 290 g (90%) of 2-bromo-6-iodo-4-
nitrophenol.
IH NMR (270 MHz, CDC13) 8 ppm 6.53 (s, 1 H) 8.42 (d, J--2.72 Hz, 1 H) 8.58 (d,
J--2.72
Hz, 1 H).
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Step 2. 7-Bf°omo-5-nitf°o-2-(trirnethylsilyl)benzofur-an. To a
solution of 2-bromo-6-iodo-4-
nitrophenol (200 g, 581.56 mmol; obtained in Step 1) in acetonitrile (2800 mL)
were added
CuI (2.22 g, 11.63 mmol) and Et3N (117.70 g, 1163.12 mmol). N2 atmosphere was
established and PdCl2(PPh3)2 (4.08 g, 5.82 mmol) was added followed by slow
addition of
(trimethylsilyl)acetylene (59.98 g, 610.64 mmol) during 2 h. The reaction
mixture was
stirred overnight until complete formation of intermediate 2-bromo-4-nitro-6-
[(trimethylsilyl)ethynyl]phenol and then heated to 85 °C for 8 h. The
mixture was diluted
with acetonitrile (1500 mL) and activated carbon (6 g) was added followed by
water (600
mL). The resulting suspension was heated to 85 °C and the carbon was
removed by
filtration. The volume was adjusted to 1950 mL by distillation followed by the
addition of
water (1600 mL). The product was obtained as an oily precipitation that
solidified upon
cooling. The liquid was decanted off and the solid residue was dissolved in
acetonitrile
(500 mL). The volatiles were eliminated to give 149.7 g (82%) of 7-bromo-5-
nitro-2-
(trimethylsilyl)-benzofuran. 1H NMR (270 MHz, CDCl3) 8 ppm 0.39 (s, 9 H) 7.12
(s, 1 H)
8.38 (d, J=2.23 Hz, 1 H) 8.42 (d, J=2.23 Hz, 1 H).
Step 3. 1-(5-Nit~o-1-benzofuran-7 yl)piperidine. A mixture of 7-bromo-5-nitro-
2-
(trimethylsilyl)benzofuran (1.57 g, 5 mmol; obtained in Step 2), piperidine
(0.47 g, 5.5.
mmol), Pd(OAc)2 (56 mg, 0.25 mmol), BINAP (0.31 g, 0.5 nnnol) and NaOtBu (0.96
g, 10
mmol) in xylene (15 mL) was stirred at 110 °C for 6 h. The cooled
mixture was filtered
through Celite and concentrated to give an oil that was put on a Si02-column
and eluted
with EtOAc/hexane (25:75) to give 1-(5-nitro-1-benzofuran-7-yl)piperidine.
Yield: 650 mg
(53%). 1H NMR (400 MHz, CDCl3) 8 ppm 1.62-1.70 (m, 2 H), 1.77-1.85 (m, 4 H),
3.36 (t,
4 H), 6.86 (d, 1 H), 7.64 (d, 1 H), 7.73 (d, 1 H), 8.09 (d, 1 H); GC-MS (EI+)
for
2S C13H14NaOs ~z 246 M+.
INTERMEDIATE 5
4-(5-Nitro-1-benzofuran-7-yl)morpholine
Prepared according to the procedure of Intermediate 4 (Step 3) starting from
morpholine.
Yield: 460 mg (37%); 1H NMR (400 MHz, CDC13) b ppm 3.40-3.45 (m, 4 H), 3.94-
3.98
(m, 4 H), 6.90 (d, 1 H), 7.64 (d, 1 H), 7.74 (d, 1 H), 8.15 (d, 1 H); GC-MS
(EI+) for
C12H12N2~4 jn~~ 248 (M) .
INTERMEDIATE 6
79
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7-Piperidin-1-yl-1-benzofuran-5-amine
1-(5-Nitro-1-benzofuran-7-yl)piperidine (630 mg, 2.56 mmol; Intermediate 4)
was
dissolved in EtOAc (50 mL), Pt02 added and the mixture stirred under HZ for 36
h.
Filtration through Celite and concentration of the filtrate furnished 7-
piperidin-1-yl-1-
benzofuran-5-amine. Yield: 540 mg (98%). 1H NMR (400 MHz, CDC13) 8 ppm 1.59-
1.65
°(m, 2 H), 1.71-1.83 (m, 4 H), 3.21-3.26 (m, 4 H), 3.55 (br s, 2 H),
6.19 (d, 1 H), 6.45 (d, 1
H), 6.56 (d, 1 H), 7.51 (d, 1 H); GC-MS (EI+) for C13Hi6Nz0 m/z 216 M+.
INTERMEDIATE 7
7-Morpholin-4-yl-1-benzofuran-5-amine
Prepared according to the procedure of Intermediate 6 starting from 4-(5-nitro-
1-
benzofuran-7-yl)morpholine (Intermediate 5). Yield: 520 mg (98%); 1H NMR (400
MHz,
CDC13) 8 ppm 3.28-3.32 (m, 4 H), 3.56 (br s, 2 H), 3.91-3.95 (m, 4 H), 6.17
(d, 1 H), 6.50
(d, 1 H), 6.58 (d, 1 H), 7.50 (d, 1 H); GC-MS (EI+) for C12H1øN202 rnlz 218
(M)+.
EXAMPLE 2
N-(7-Piperidin-1-yl-1-benzofuran-5-yl)benzenesulfonamide
The synthesis was performed according to the procedure of Intermediate 3
starting from 7-
piperidin-1-yl-1-benzofuran-5-amine (Intermediate 6). Yield: 70 mg (39%). 1H
NMR (400
MHz, CDC13) 8 ppm 1.57-1.62 (m, 2 H), 1.70-1.78 (m, 4 H), 3.16 (t, 4 H), 6.39
(br s, 1 H),
6.41 (d, 1 H), 6.63 (d, 1 H), 6.83 (d, 1 H), 7.37-7.43 (m, 2 H), 7.49-7.54 (m,
1 H), 7.57 (d,
1 H), 7.68-7.72 (m, 2 H); MS (ESI+) for Cl9HzoNa03S mlz 357 (M+H)+; HPLC 97%
(System A).
EXAMPLE 3
4-Fluoro-N-(7-piperidin-1-yl-1-benzofuran-5-yl)benzenesulfonamide
The synthesis was performed according to the procedure of Intermediate 3
starting from 7-
piperidin-1-yl-1-benzofuran-5-amine (Intermediate 6). Yield: 55 mg (29%).1H
NMR (400
MHz, CDC13) 8 ppm 1.56-1.65 (m, 2 H), 1.70-1.79 (m, 4 H), 3.19 (t, 4 H), 6.43
(d, 1 H),
6.48 (br s, 1 H), 6.63 (d, 1 H), 6.81 (d, 1 H), 7.04-7.10 (m, 2 H), 7.58 (d, 1
H), 7.68-7.74
(m, 2 H); 13C NMR (100 MHz, CDC13) 8 24.30, 25.88, 50.90, 107.00, 108.11,
108.42,
115.96, 116.19, 128.67, 130.01, 131.52, 134.89, 138.76, 144.80, 145.16,
163.85, 166.39;
MS (ESI+) for C19Hi9FNz03S m/z 375 (M+H)+. HPLC 100% (System A).
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EXAMPLE 4
3,4-Dimethoxy-N-(7-piperidin-1-yl-1-benzofuran-5-yl)benzenesulfonamide
hydrochloride
The synthesis was performed according to the procedure of Intermediate 3
starting from 7-
piperidin-1-yl-1-benzofuxan-5-amine (Intermediate 6). Yield: 100 mg (48%).1H
NMR (400
MHz, CDCl3) 8 ppm 1.52-1.57 (m, 2 H), 1.62-1.66 (m, 4 H), 3.09-3.15 (m, 4 H),
3.69 (s, 3
H), 3.75 (s, 3 H), 6.50-6.55 (m, 1 H), 6.82 (d, 1 H), 6.88 (d, 1 H), 7.01 (d,
1 H), 7.20-7.26
(m, 2 H), 7.87 (d, 1 H), 9.80 (br s, 1 H); MS (ESI+) for CzlHa4NzOsS m/z 417
(M+H)+;
HPLC 100% (System A).
INTERMEDIATE 8
1-(5-Nitro-1-benzofuran-7-yI)pyrrolidine
The synthesis was performed as described fox Intermediate 4 (Step 3). Yield
26%. 1H
NMR (400 MHz, CDC13) 8 ppm 2.03-2.08 (m, 4 H), 3.66-3.72 (m, 4 H), 6.82 (d, 1
H), 7.23
(d, 1 H), 7.67 (d, 1 H), 7.81 (d, 1 H); GC-MS (EI+) for Cl2HiaNa03 m/z 232 M~.
INTERMEDIATE 9
7-Pyrrolidin-1-yl-1-benzofuran-5-amine
The synthesis was performed as described for Intermediate 6. Yield 48%. MS
(ESI+) for
C12H14N2~ m/Z 203 (M+H)+.
EXAMPLE 5
3,4-Dimethoxy-N-(7-pyrrolidin-1-yl-1-benzofuran-5-yl)benzenesulfonamide
The title compound was prepared according to the procedure of Intermediate 3
starting
from 7-pyrrolidin-1-yl-1-benzofuran-5-amine (Intermediate 9). Yield: 70 mg
(43%). 1H
NMR (400 MHz, DMSO-d6) 8 ppm 1.88-1.93 (m, 4 H), 3.38-3.43 (m, 4 H), 3.71 (s,
3 H),
3.75 (s, 3 H), 6.16 (d, 1 H), 6.60 (d, 1 H), 6.75 (d, 1 H), 7.01 (d, 1 H),
7.24-7.29 (m, 2 H),
7.80 (d, 1 H), 9.71 (s, 1 H); 13C NMR (100 MHz, DMSO-d6) 8 24.72, 48.82,
55.62, 55.71,
100.66, 101.57, 106.96, 109.54, 110.91, 120.58, 128.29, 131.10, 134.01,
134.58, 140.65,
145.37, 148.33, 151.89; MS (ESI+) for CzaH22N2O5S m/z 403 (M+H)+; HPLC 98%
(System A).
s1
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EXAMPLE 6
N-(7-Pyrrolidin-1-yl-1-benzofuran-5-yl)benzenesulfonamide
The title compound was prepared according to the procedure of Intermediate 3
starting
from 7-pyrrolidin-1-yl-1-benzofuran-5-amine (Intermediate 9). Yield: 30 mg
(22%). 1H
NMR (400 MHz, DMSO-d6) b ppm 1.86-1.93 (m, 4 H), 3.36-3.43 (m, 4 H), 6.13 (br
s, 1
H), 6.59 (br s, 1 H), 6.73 (d, 1 H), 7.45-7.60 (m, 3 H), 7.73 (d, 2 H), 7.79
(d, 1 H), 9.92 (s,
1 H); 13C NMR (100 MHz, DMSO-d6) 8 ppm 24.73, 48.79, 100.68, 101.51, 106.97,
126.74, 128.33, 129.05, 132.58, 133.70, 134.62, 139.67, 140.68, 145.40; MS
(ESI+) for
C18H18Na03S m/z 343 (M+H)+; HPLC 95% (System A).
EXAMPLE 7
4-Fluoro-N-(7-pyrrolidin-1-yl-1-benzofuran-5-yl)benzenesulfonamide
hydrochloride
The title compound was prepared according to the procedure of Intermediate 3
starting
from 7-pyrrolidin-1-yl-1-benzofuran-5-amine (Intermediate 9). Yield: 65 mg
(41%). 1H
NMR (400 MHz, DMSO-d6) 8 ppm 1.87-1.94 (m, 4 H), 3.38-3.44 (m, 4 H), 6.13 (d,
1 H),
6.58 (d, 1 H), 6.75 (d, 1 H), 7.34-7.40 (m, 2 H), 7.74-7.80 (m, 2 H), 7.81 (d,
1H), 9.94 (s, 1
H); 13C NMR (100 MHz, DMSO-d6) b 24.73, 48.85, 100.97, 101.73, 106.99, 116.13,
116.36, 128.38, 129.71, 1129.80, 133.51, 134.59, 135.99, 140.77, 145.48,
162.88, 165.38;
MS (ESI+) for C18H1~FN203S m/z 361.0 (M+H)+; HPLC 98%.
EXAMPLE 8
4-Fluoro-N-(7-morpholin-4-yl-1-benzofuran-5-yl)benzenesulfonamide
hydrochloride
The title compound was prepared according to the procedure of Intermediate 3
starting
fiom Intermediate 7. Yield: 100 mg (53%); 1H NMR (400 MHz, DMSO-d6) 8 ppm 3.08-
3.14 (m, 4 H), 3.72-3.78 (m, 4 H), 6.47 (d, 1 H), 6.83 (d, 1 H), 6.88 (d, 1
H), 7.32-7.40 (m,
2 H), 7.74-7.78 (m, 2 H), 7.88 (d, 1 H), 10.07 (s, 1 H); 13C NMR (100 MHz,
DMSO-d6) 8
ppm 49.31, 65.98, 105.45, 106.13, 107.14, 116.20, 116.43, 128.52, 129.85,
133.24, 135.70,
137.00, 143.09, 145.74, 162.96, 165.46; MS (ESI+) for CIBHl~FN204S m/z 377.2
(M+H)+;
HPLC 100 %.
EXAMPLE 9
N-(7-Morpholin-4-yl-1-benzofuran-5-yl)benzenesulfonamide hydrochloride,
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WO 2005/058858 PCT/SE2004/001949
The title compound was prepared according to the procedure of Intermediate 3
starting
from Intermediate 7. Yield: 75 mg (42%); 1H NMR (400 MHz, DMSO-d6) 8 ppm 3.06-
3.12 (m, 4 H), 3.71-3.78 (m, 4 H), 6.46 (d, 1 H), 6.82 (d, 1 H), 6.88 (d, 1
H), 7.48-7.54 (m,
2 H), 7.54-7.60 (m, 1 H), 7.71 (d, 2 H), 7.87 (d, 1 H), 10.03 (s, 1 H); 13C
NMR (100 MHz,
DMSO-d6) ~ 49.29, 65.98, 105.30, 105.90, 107.10, 126.75, 128.46, 129.11,
132.71,
133.40, 136.93, 139.37, 142.99, 145.67; MS (ESI+) for C18H18Nz04S nalz 359.2
(M+H)+;
HPLC 97 %.
EXAMPLE 10
3,4-Dimethoxy-N-(7-morpholin-4-yl-1-benzofuran-5-yl)benzenesulfonamide
The title compound was prepared according to the procedure of Intermediate 3
starting
from Intermediate 7. Yield: 45 mg (21%); 1H NMR (400 MHz, CDC13) 8 ppm 3.23-
3.28
(m, 4 H), 3.75 (s, 3 H), 3.89 (s, 3 H), 3.89-3.93 (m, 4 H), 6.53 (br s, 1 H),
6.65 (d, 1 H),
6.76 (br s, 1 H), 6.82 (d, 1 H), 6.89 (br s, 1 H), 7.18 (d, 1 H), 7.35 (dd, 1
H), 7.57 (d, 1 H);
MS (ESI+) for CzoHzzNzOsS m/z 419.0 (M+H)+; HPLC 88 %.
INTERMEDIATE 10
tent-Butyl 4-(5-amino-1-benzofuran-7-yl)piperazine-1-carboxylate
tent-Butyl 4-(5-vitro-1-benzofuran-7-yl)piperazine-1-carboxylate* (1 g, 2.9
mmol) was
dissolved in THF/EtOH (1:4). An excess of Raney-Ni (slurry in ethanol) was
added
followed by hydrazine-hydrate (0.58 g, 11.5 mmol). The reaction mixture was
stirred at
room temperature overnight. Filtration and evaporation afforded 1.19 g of the
title product
that was used in the next step without further purification. HPLC purity 93%,
RT=1.71 min
(System A; 10-97% MeCN over 3 min). *Previously described in WO 2002100822.
General procedure A: Alkylation of ter~t-butyl 4-(5-amino-1-benzofuran-7-
yl)piperazine-
1-carboxylate.
A stock solution of tent-butyl 4-(5-amino-1-benzofuran-7-yl)piperazine-1-
carboxylate
(0.12 g, 0.378 mmol; Intermediate 10) in acetonitrile was added together with
KZC03 (52
mg, 0.378 mmol) to respective benzyl bromide (0.378 mmol). The mixtures were
shaken at
room temperature for 3 h. The reaction progress was controlled with LC-MS.
Workup:
filtration
and purification by preparative HPLC using acetonitrile-water gradients
containing 0.1%
trifluoroacetic acid. N deprotection was carried out according to the
procedure of Example
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1 and the target hydrochloride salt was obtained following treatment with 2 M
HCl in
ether.
EXAMPLE 11
N-(3,5-Dimethylbenzyl)-7-piperazin-1-yl-1-benzofuran-5-amine hydrochloride
Prepared by general procedure A from 1-(bromomethyl)-3,5-dimethylbenzene (75
mg,
0.378 mmol). Yield: 8 mg (6%). HPLC 93%, RT: 1.240 (System A; 10-97% MeCN over
3
min).1H NMR (270 MHz, methanol-d4) 8 ppm 2.30 (s, 6 H) 3.47-3.64 (m, 8 H) 4.52
(s, 2
H) 6.86-6.95 (m, 2 H) 7.08-7.09 (m, 3 H) 7.32 (s, 1 H) 7.93 (s, 1 H). LC-MS
336 (M+H)+.
EXAMPLE 12
N-(3,4-Difluorobenzyl)-7-piperazin-1-yl-1-benzofuran-5-amine hydrochloride
Prepared by general procedure A from 4-(bromomethyl)-1,2-difluorobenzene (78
mg,
0.378 mmol). Yield: 6 mg (5%). HPLC 97%, RT: 1.499 (System A; 10-97% MeCN over
3
min). 1H NMR (270 MHz, methanol-d4) ~ ppm 3.46-3.63 (m, 8 H) 4.73 (s, 2 H)
6.86-6.94
(m, 2 H) 7.36 (s, 1 H) 7.49-7.64 (m, 2 H) 7.91-8.00 (m, 2 H). LC-MS 344
(M+H)+.
EXAMPLE 13
N-(3,5-Dimethoxybenzyl)-7-piperazin-1-yl-1-benzofuran-5-amine hydrochloride
Prepared by general procedure A from 1-(bromomethyl)-3,5-dimethoxybenzene (87
mg,
0.378 mmol). Yield: 8 mg (6%). HPLC 93%, RT: 1.355 (System A; 10-97% MeCN over
3
min). 1H NMR (270 MHz, methanol-d4) 8 ppm 3.47-3.65 (m, 8 H) 3.76 (s, 6H) 4.56
(s, 2
H) 6.54 (s, 1H) 6.64 (s, 2H) 6.89 (s, 1H) 6.95 (s, 1H) 7.35 (s, 1 H) 7.92 (s,
1 H). LC-MS
368 (M+H)+.
EXAMPLE 14
N-Benzyl-7-piperazin-1-yl-1-benzofuran-5-amine hydrochloride
A stock solution of tef°t-butyl 4-(5-amino-1-benzofuran-7-yl)piperazine-
1-carboxylate
(0.12 g, 0.378 mmol; Intermediate 10) in acetonitrile was added, together with
K2C03 (52
mg, 0.378 mmol), to benzyl bromide (65 mg, 0.378 mmol). The mixture was shaken
at
room temperature for 3 h. The product was controlled with LC-MS, filtered and
purified by
' preparative HPLC using acetonitrile-water gradients containing 0.1 %
trifluoroacetic acid.
N-deprotection and conversion into the hydrochloride salt was performed by
treatment
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with with 2 M HCl in ether. Yield: 19 mg (16.4%). HPLC 92%, RT: 1.240 (System
A; 10-
97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) 8 ppm 3.56 (d, 8 H) 4.65
(s, 2
H) 6.94 (s, 2 H) 7.43 (s, 6 H) 7.92 (s, 1 H). LC-MS 308 (M+H)+.
General procedure B: Amidation of test-butyl 4-(5-amino-1-benzofuran-7-
yl)piperazine-
1-carboxylate.
Pyridine (274 p.1, 3.40 mmol) and a stock solution of tef°t-butyl 4-(5-
amino-1-benzofuran-
7-yl)piperazine-1-carboxylate (0.12 g, 0.378 mmol; Intermediate 10) in DCM (2
mL) were
added to the respective benzoyl chloride (0.454 mmol). The mixtures were
shaken at room
temperature for 2 h. The products were controlled with LC-MS and the solvent
was
removed. Purification of the products was done by preparative HPLC using
acetonitrile-
water gradients containing 0.1% trifluoroacetic acid. The final products were
obtained
following N deprotection according to the procedure of Example 1 and
conversion into the
corresponding hydrochloride salt by treatment with 2 M HCl in ether.
EXAMPLE 15
N-(7-Piperazin-1-yl-1-benzofuran-5-yl)benzamide hydrochloride
Prepared by general procedure B from tent-butyl 4-(5-amino-1-benzofuran-7-
yl)piperazine-
1-carboxylate (64 mg, 0.454 mmol; Intermediate 10). Yield: 3 mg (3%). HPLC
94%, RT:
1.534 (System A; 10-97% MeCN over 3 min). 1H NMR (270 MHz methanol-d4) ~ ppm
3.46-3.61 (m, 8 H) 6.85 (d, J=2.23 Hz, 1 H) 7.28 (d, J=1.24 Hz, 1 H) 7.52-7.59
(m, 4 H)
7.78 (d, J=1.98 Hz, 1 H) 7.95 (d, J=6.68 Hz, 2 H). LC-MS 322 (M+H)+.
EXAMPLE 16
4-Methoxy-N-(7-piperazin-1-yl-1-benzofuran-5-yl)benzamide hydrochloride
Prepared by general procedure B from 4-methoxybenzoyl chloride (77 mg, 0.454
mmol).
Yield: 2 mg (1.5%). HPLC 99%, RT: 1.568 (System A; 10-97% MeCN over 3 min). 1H
NMR (270 MHz, methanol-d4) b ppm 3.44-3.61 (m, 8 H) 3.87 (s, 2 H) 6.84 (d, J
2.23 Hz,
1 H) 7.04 (d, J--8.91 Hz, 2 H) 7.27 (d, J--1.48 Hz, 1 H) 7.52 (d, J--1.73 Hz,
1 H) 7.77 (d,
J--1.98 Hz, 1 H) 7.93 (d, J 8.91 Hz, 2 H). LC-MS 352 (M+H)+.
EXAMPLE 17
2-Bromo-5-methoxy-N-(7-piperazin-1-yl-1-benzofuran-5-yl)benzamide
hydrochloride
8s
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Prepared by general procedure B from 2-bromo-5-methoxybenzoyl chloride (113
mg,
0.454 mmol). Yield: 10 mg (6.2%). HPLC 85%, RT: 1.685 (System A; 10-97% MeCN
over 3 min). 1H NMR (270 MHz, methanol-d~) 8 ppm 3.46-3.48 (m, 4 H) 3.59-3.61
(m, 4
H) 3.84 (s, 3 H) 6.84 (d, J--1.98 Hz, 1 H) 6.97 (dd, J--8.66, 2.72 Hz, 1 H)
7.10 (d, J--2.97
Hz, 1 H) 7.23 (s, 1 H) 7.54-7.59 (m, 2 H) 7.78 (d, J 1.98 Hz, 1 H). LC-MS 430
(M+H)+.
EXAMPLE 18
3-Methyl-N-(7-piperazin-1-yl-1-benzofuran-5-yl)benzamide hydrochloride
Prepared by general procedure B from 3-methylbenzoyl chloride (70 mg, 0.454
mmol).
Yield: 14 mg (11.1%). HPLC 93%, RT: 1.666 (System A; 10-97% MeCN over 3 min).
1H
NMR (270 MHz, methanol-d4) 8 ppm 2.43 (s, 3 H) 3.46-3.62 (m, 8 H) 6.84 (d, J
1.73 Hz,
1 H) 7.39 (d, J--4.21 Hz, 2 H) 7.76 (d, J--10.14 Hz, 3 H). LC-MS 336 (M+H)+.
EXAMPLE 19
N-(7-Piperazin-1-yl-1-benzofuran-5-yl)-3-(trifluoromethyl)benzamide
hydrochloride
Prepared by general procedure B from 3-(trifluoromethyl)benzoyl chloride (95
mg, 0.454
mmol). Yield: 12 mg (8.2%). HPLC 88%, RT: 1.779 (System A; 10-97% MeCN over 3
min). 1H NMR (270 MHz, methanol-d4) ~ ppm 3.45-3.63 (m, 8 H) 6.86 (d, J--2.23
Hz, 1
H) 7.31 (d, J--1.73 Hz, 1 H) 7.58 (s, 1 H) 7.75-7.79 (m, 2 H) 7.92 (s, 1 H)
8.24 (m, 2 H).
LC-MS 390.1 (M+H)+.
EXAMPLE 20
2,4-Dichloro-N-(7-piperazin-1-yl-1-benzofuran-5-yl)benzamide hydrochloride
Prepared by general procedure B from 2,4-dichlorobenzoyl chloride (95 mg,
0.454 mmol).
Yield: 19 mg (12.9%). HPLC 93%, RT: 1.803 (System A; 10-97% MeCN over 3 min).
1H
NMR (270 MHz, methanol-d4) 8 ppm 3.47-3.62 (m, 8 H) 6.84 (d, J--2.23 Hz, 1 H)
7.21 (d,
J--2.23 Hz, 1 H) 7.44-7.78 (m, 5 H). LC-MS 390 (M+H)+.
EXAMPLE 21
3,5-Dimethoxy-N-(7-piperazin-1-yl-1-benzofuran-5-yl)benzamide hydrochloride
Prepared by general procedure B from 3,5-dimethoxybenzoyl chloride (91 mg,
0.454
mmol). Yield: 18.3 mg (12.7%). HPLC 91%, RT: 1.666 (System A; 10-97% MeCN over
3
min). 1H NMR (270 MHz, methanol-d4) 8 ppm 2.76-7.82 (m, 8 H) 3.04 (s, 6 H)
5.87 (s, 1
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H) 6.02 (d, J--1.57 Hz, 1 H) 6.30 (d, J 1.57 Hz, 2 H) 6.41-6.49 (m, 1 H) 6.78-
6.79 (m, 1
H) 6.98-6.69 (m, 1 H). LC-MS 382 (M+H)+.
General procedure C: Synthesis of urea derivatives from test-butyl 4-(5-amino-
1-
benzofuran-7-yl)piperazine-1-carboxylate. Method A.
A stock solution of teat-butyl 4-(5-amino-1-benzofuran-7-yl)piperazine-1-
carboxylate
(0.12 g, 0.378 mmol; Intermediate 10) in acetonitrile (2 mL) and pyridine (274
p.1, 3.4
mmol) were added to the respective aryl isocyanate (0.416 mmol). The mixtures
were
shaken at room temperature over night. The reaction progress was controlled
with LC-MS.
Workup: filtration and purification by preparative HPLC using acetonitrile-
water gradients
containing 0.1 % trifluoroacetic acid. The final products were obtained
following N
deprotection according to the procedure of Example 1 and conversion into the
hydrochloride salt by treatment with 2 M HCl in ether.
EXAMPLE 22
N-(3,5-Dimethoxyphenyl)-N°-(7-piperazin-1-yl-benzofuran-5-yl)urea
hydrochloride.
Prepared by general procedure C (method A) from 1-isocyanato-3,5-
dimethoxybenzene
(75 mg, 0.416 mmol). Yield: 11 mg (8 %). HPLC 100%, RT: 1.673 (System A; 10-
97%
MeCN over 3 min). 'H NMR (270 MHz, methanol-d4) 8 ppm 3.44-3.46 (m, 4 H) 3.56-
3.57
(m, 4 H) 3.75 (s, 6 H) 6.78 (d, J=1.98. Hz, 2 H) 7.03 (s, 2 H) 7.27 (d, J=1.48
Hz, 1 H) 7.72
(d, J=1.98 Hz, 2 H). LC-MS 397 (M+H)+.
EXAMPLE 23
N-(2,4-Dichlorophenyl)-N'-(7-piperazin-1-yl-benzofuran-5-yl)urea
hydrochloride.
Prepared by general procedure C (method A) from 2,4-dichloro-1-
isocyanatobenzene (78
mg, 0.416 mmol). Yield: 9 mg (6%). HPLC 100%, RT: 1.775 (System A; 10-97% MeCN
over 3 min). 1H NMR (270 MHz, methanol-d4) 8 ppm 3.46-3.47 (m, 4 H) 3.58-3.59
(m,
4H) 6.80 (d, J=1.98 Hz, 1 H) 7.06-7.07 (m, 1 H) 7.26 (d, J--2.23 Hz, 1 H) 7.29
(d, J--2.47
Hz, 1 H) 7.46 (d, J=2.47 Hz, 1 H) 7.74 (d, J=1.98 Hz, 1 H) 8.13 (d, J=8.91 Hz,
1 H). LC-
MS 405 (M+H)+.
General procedure C: Synthesis of urea derivatives from test-butyl 4-(5-amino-
1-
benzofuran-7-yl)piperazine-1-carboxylate. Method B.
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A stock solution of tent-butyl 4-(5-amino-1-benzofuran-7-yl)piperazine-1-
carboxylate
(0.12 g, 0.378 mmol; Intermediate 10) in acetonitrile was added, together with
triethylamine (158 ~L, 1.13 mmol), to respective isocyanate (0.416 mmol). The
mixtures
were shaken at room temperature overnight. The reaction progress was
controlled with LC-
MS. Workup: filtration and purification by preparative HPLC using acetonitrile-
water
gradients containing 0.1% trifluoroacetic acid. The final products were
obtained following
N deprotection according to the procedure of Example 1 and conversion into the
corresponding hydrochloride salt by treatment with 2 M HCl in ether.
EXAMPLE 24
N-(2-Methoxyphenyl)-N'-(7-piperazin-1-yl-1-benzofuran-5-yl)urea hydrochloride
Prepared by the general procedure above (Method B) from 1-isocyanato-2-
methoxybenzene (60 mg, 0.416 mmol). Yield: 33 mg (23.8%). HPLC 93%, RT: 1.673
(System A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) ~ ppm 3.44-
3.60 (m, 8 H) 3.92 (s, 3 H) 6.79-6.99 (m, 5 H) 7.12-7.21 (m, 1 H) 7.73 (d, J--
2.23 Hz, 1 H)
8.05 (d, J 7.67 Hz, 1 H). LC-MS 367.1 (M+H)+.
EXAMPLE 25
N-Phenyl-N'-(7-piperazin-1-yl-1-benzofuran-5-yl)urea hydrochloride
Prepared by the general procedure above (Method B) from isocyanatobenzene (50
mg,
0.416 mmol). Yield: 31 mg (24.4%). HPLC 93%, RT: 1.583 (System A; 10-97% MeCN
over 3 min). 1H NMR (270 MHz, methanol-d4) 8 ppm 3.43-3.47 (m, 4 H) 3.56-3.60
(m, 4
H) 6.80 (d, J--2.23 Hz, 1 H) 7.09-7.21 (m, 2 H) 7.22-7.31 (m, 3 H) 7.43 (d, J--
8.41 Hz, 2
H) 7.74 (d, .I--2.23 Hz, 1 H). LC-MS 337 (M+H)+.
EXAMPLE 26
N-(3-Fluorophenyl)-N°-(7-piperazin-1-yl-benzofuran-5-yl)urea
hydrochloride
Prepared by the general procedure above (Method B) from 1-fluoro-3-
isocyanatobenzene
(57 mg, 0.416 mmol). Yield: 5 mg (3.7%). HPLC 93%, RT: 1.700 (System A; 10-97%
MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) 8 ppm 3.46-3.47 (m, 4 H) 3.57-
3.60
(m, 4 H) 6.77-6.81 (m, 2 H) 7.08-7.09 (m, 2 H) 7.22-7.28 (m, 2 H) 7.42-7.47
(m, 1 H) 7.74
(d, J--1.98 Hz, 1 H). LC-MS 355 (M+H)+.
EXAMPLE 27
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N-(7-Piperazin-1-yl-1-benzofuran-5-yl-)-N'-[trifluoromethyl)phenyl]urea
hydrochloride
Prepared by the general procedure above (Method B) from 1-isocyanato-3-
(trifluoromethyl)benzene (78 mg, 0.416 mmol). Yield: 27 mg (17.7%). HPLC 91%,
RT:
1.932 (System A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) 8 ppm
3.44-3.47 (m, 4 H) 3.57-3.61 (m, 4 H) 6.81 (d, J 2.23 Hz, 1 H) 7.12-7.30 (m, 3
H) 7.51
(m, 2 H) 7.74 (d, J--2.23 Hz, 1 H) 7.96 (s, 1 H). LC-MS 405 (M+H)+.
INTERMEDIATE 11
4-(5-Nitro-1-benzofuran-7-yl)pyridine
7-Iodo-5-nitrobenzofuran (2.00 g, 0.00692 mol), 4-tributylstannylpyridine
(2.80 g, 0.00761
mol), copper(I)iodide (132 mg, 0.692 mmol) and dichlorobis(triphenylphosphine)
palladium(II) (49 mg, 0.0692 mmol) were added to a 50 mL test tube followed by
DMF
(20 mL). The mixture was heated at 100 °C overnight in a StemBlock.
After cooling to
room temperature, aqueous sodium hydroxide (2 M; 4 mL) was added and the
solution was
stirred for 15 min. Chloroform (20 mL) was added and the mixture was filtered
through
Celite. The aqueous layer was then extracted with chloroform (3x) and the
combined
organic phases were evaporated. The residue was then triturated with ether and
the
precipitate was dried in vacuo overnight to yield a light brown solid. Yield:
686 mg (41%);
HLPC (System A) purity = 99%, m/z = 241 (M+H)+, 1H NMR (270 MHz, DMSO-d6) 8
ppm 7.33 (d, J=2.23 Hz, 1 H) 7.98 (m, 2 H) 8.38 (d, J=2.23 Hz, 1 H) 8.50 (d,
J=2.47 Hz, 1
H) 8.75 (d, J=2.23 Hz, 1 H) 8.79 (m, 2 H).
INTERMEDIATE 12
3-(5-Nitro-1-benzofuran-7-yl)pyridine
The title compound was prepared according to the procedure described for
Intermediate 11
using 3-tributylstannylpyridine. Yield:145 mg (35%); HLPC (System A) purity =
97%,
m/z = 241 (M+H)+, 1H NMR (270 MHz, DMSO-d6) 8 ppm 7.32 (d, J=2.23 Hz, 1 H)
7.63
(dd, J=7.79, 4.82 Hz, 1 H) 8.33 (m, 1 H) 8.36 (d, J=2.23 Hz, 1 H) 8.44 (d,
J=2.47 Hz, 1 H)
8.72 (m, 2 H) 9.14 (d, J=1.73 Hz, 1 H).
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INTERMEDIATE 13
2-(5-Nitro-1-benzofuran-7-yl)pyridine
The title compound was prepared according to the procedure described for
Intermediate 11
using 2-tributylstannylpyridine.. Yield: 282 mg (42%); HLPC (System A) purity
= 98%,
m/z = 241 (M+H)+, 1H NMR (270 MHz, DMSO-d6) 8 ppm 7.33 (d, J=2.23 Hz, 1 H)
7.53
(m, 1 H) 8.06 (m, 1 H) 8.41 (m, 2 H) 8.72 (d, J=2.47 Hz, 1 H) 8.84 (m, 1 H)
8.99 (d,
J=2.47 Hz, 1 H).
INTERMEDIATE 14
2-(5-Nitro-1-benzofuran-7-yl)pyrazine
The title compound was prepared according to the procedure described for
Intermediate 11
using 2-tributylstannylpyrazine. Yield: 238 mg (57%); HLPC (System A) purity =
97%,
m/z = 242 (M+H)+, 1H NMR (270 MHz, DMSO-d6) 8 ppm 7.35 (d, J=2.23 Hz, 1 H)
8.43
(d, J=2.23 Hz, 1 H) 8.78 (m, 2 H) 8.92 (m, 2 H) 9.58 (s, 1 H).
INTERMEDIATE 15
2-(5-Nitro-1-benzofuran-7-yl)pyrimidine
The title compound was prepared according to the procedure described for
Intermediate 11
using 2-tributylstannylpyrimidine. Yield: 219 mg (52%); HLPC (System A) purity
= 97%,
m/z = 242 (M+H)+, 1H NMR (270 MHz, DMSO-d6) 8 ppm 7.32 (d, J=2.23 Hz, 1 H)
7.61
(t, J=4.95 Hz, 1 H) 8.40 (d, J=2.23 Hz, 1 H) 8.81 (d, J=2.47 Hz, 1 H) 9.07
(m,' 3 H).
INTERMEDIATE 16
4-(5-Amino-1-benzofuran-7-yl)pyridine
4-(5-Nitro-1-benzofuran-7-yl)pyridine (125 mg, 0.520 mmol; Intermediate 11)
was
dissolved in 1,4-dioxane (15 mL). After addition of ethanol (20 mL), Raney-
nickel (slurry
in ethanol; 2 mL) and hydrazine hydrate (4 mL) were added and the mixture was
left
stirring at room temperature overnight. The product was used directly in the
subsequent
reaction after filtration through Celite and evaporation of solvent.
EXAMPLE 28
2-Methoxy-5-methyl-N-(7-pyridin-4-yl-1-benzofuran-5-yl)benzenesulfonamide
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4-(5-Amino-1-benzofuran-7-yl)pyridine (55 mg, 0.260 mmol; Intermediate 16) and
6-
methoxy-m-toluenesulfonyl chloride (69 mg, 0.312 mmol) was dissolved in
dichloromethane (5 mL). Triethylamine (73 ~,L, 0.520 mmol) was added and the
mixture
was shaken for 2 h. After concentration, the residue was triturated with cold
acetonitrile
and the precipitate was collected and dried in vacuo. Yield: 56 mg (55%); HLPC
(System
A) purity = 98%, m/z = 395 (M+H)+, 1H NMR (270 MHz, DMSO-d6) 8 ppm 2.21 (s, 3
H)
3.87 (s, 3 H) 7.09 (m, 2 H) 7.35 (dd, J=8.54, 2.10 Hz, 1 H) 7.56 (m, 2 H) 8.14
(d, J=2.23
Hz, 1 H) 8.25 (d, J=6.68 Hz, 2 H) 8.98 (d, J=6.68 Hz, 2 H) 10.13 (s, 1 H).
EXAMPLE 29
N-(7-Pyridin-3-yl-1-benzofuran-5-yl)benzenesulfonamide trifluoroacetate
The title compound was prepared according to the procedure described for
Example 28
using 3-(5-amino-1-benzofuran-7-yl)pyridine* and purified by preparative HPLC.
Yield:
63 mg (51%); HLPC (System A) purity = 95%, m/z = 351 (M+H)+, 1H NMR (270 MHz,
methanol-d4) 8 ppm 6.90 (d, J=2.23 Hz, 1 H) 7.49 (m, 5 H) 7.74 (m, 2 H) 7.89
(d, J=2.23
Hz, 1 H) 8.01 (m, 1 H) 8.77 (m, 2 H) 9.19 (d, J=1.73 Hz, 1 H). *Prepared
according to the
procedure of Intermediate 16 using 3-(5-nitro-1-benzofuran-7-yl)pyridine
(Intermediate
12).
EXAMPLE 30
2-Methoxy-5-methyl-N-(7-pyridin-3-yl-1-benzofuran-5-yl)benzenesulfonamide
trifluoroacetate
The title compound was prepared according to the procedure described for
Example 28,
using 3-(5-amino-1-benzofuran-7-yl)pyridine* and purified by preparative HPLC
(System
D). Yield: 67 mg (50%); HLPC (System A) purity = 97%, m/z = 395 (M+H)+, 1H NMR
(270 MHz, methanol-d4) 8 ppm 2.17 (s, 3 H) 3.95 (s, 3 H) 6.88 (d, J=2.23 Hz, 1
H) 7.01 (d,
J=8.41 Hz, 1 H) 7.29 (m, 1 H) 7.48 (d, J=2.23 Hz, 2 H) 7.54 (m, 1 H) 7.86 (d,
J=2.23 Hz, 1
H) 8.10 (m, 1 H) 8.84 (m, 2 H) 9.24 (d, J=1.98 Hz, 1 H). *Prepared according
to the
procedure of Intermediate 16 using 3-(5-nitro-1-benzofuran-7-yl)pyridine
(Intermediate
12).
EXAMPLE 31
91
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N-(7-Pyrazin-2-yl-1-benzofuran-5-yl)benzenesulfonamide trifluoroacetate
The title compound was prepared according to the procedure described for
Example 28
using 2-(5-amino-1-benzofuran-7-yl)pyrazine* and purified by preparative HPLC
(System
D). Yield: 20 mg (17%), HLPC (System A) purity = 98%, m/z = 352 (M+H)+, 1H NMR
(270 MHz, DMSO-d6) 8 ppm 7.07 (d, J=2.23 Hz, 1 H) 7.53 (m, 3 H) 7.76 (m, 2 H)
7.91 (d,
J=1.98 Hz, 1 H) 8.14 (d, J=2.23 Hz, 1 H) 8.67 (d, J=2.47 Hz, 1 H) 8.82 (m, 1
H) 9.45 (d,
J=1.73 Hz, 1 H) 10.39 (s, 1 H). *Prepared according to the procedure of
Intermediate 16
using 2-(5-nitro-1-benzofuran-7-yl)pyrazine (Intermediate 14).
INTERMEDIATE 17
5-(5-Nitro-1-benzofuran-7-yl)pyrimidine
Pd(PPh3)4 (240 mg, 209 mmol) was added to 7-iodo-5-nitro-1-benzofurane (1.00
g, 3.45
mmol) in DME ( 11 mL) and the resulting mixture was stirred for 10 min. The
color went
from dark red to mustard yellow. Pyrimidine-5-boronic acid (0.24 g, 0.21 mmol)
and 1 M
Na2C03 (5 mL) were added and the reaction mixture was refluxed at 100
°C for 2.5 h. The
mixture was concentrated i~2 vacuo and the residue was dissolved in 1 M HCl
(50 mL) and
washed with diethyl ether (50 mL). The aqueous layer was made basic (pH 8), by
addition
of K2C03, and extracted with chloroform (3x). The combined organic layers were
dried
with K2C03, filtered and concentrated to afford 0.455 g (55%) of a yellow
solid. HPLC
100%, RT: 1.870 min (System A; 10-97% over 3 min). 1H NMR (270 MHz, CDC13) 8
ppm
7.06 (d, J=2.47 Hz, 1 H) 7.90 (d, J=2.23 Hz, 1 H) 8.45 (d, J=2.23 Hz, 1 H)
8.63 (d, J=2.23
Hz, 1 H) 9.28-9.31 (m, 3 H). LC-MS 242 (M+H)+.
INTERMEDIATE 18
7-Pyrimidin-5-yl-1-benzofuran-5-amine
Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (0.378 g, 7.55 mmol) were
added to
5-(5-nitro-1-benzofuran-7-yl)pyrimidine (0.455 g, 1.87 mmol, Intermediate 17)
in
ethanol/THF (100 mL:25 mL). The mixture was stirred at room temperature for 3
h,
filtered through Celite and concentrated in vacuo to afford 0.317 g (80%) of
the title
compound as a yellow solid. HPLC 100%, RT: 0.957 min (System A; 10-97% over 3
min).
1H NMR (270 MHz, methanol-dø) 8 ppm 6.77 (d, J=2.23 Hz, 1 H) 7.05 (q, J=2.23
Hz, 2 H)
7.76 (d, J=2.23 Hz, 1 H) 9.14 (s, 1 H) 9.26 (s, 2 H). LC-MS 212 (M+H)+.
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EXAMPLE 32
N-(7-Pyrimidin-5-yl-1-benzofuran-5-yl)benzenesulfonamide hydrochloride
Benzenesulfonyl chloride (0.093 g, 0.524 mmol) and pyridine (347 ~L, 430 mmol)
were
added to 7-pyrimidin-5-yl-1-benzofuran-5-amine (0.100 g, 0.473 mmol;
Intermediate 18)
in dichloromethane (2 mL). The mixture was shaken at room temperature for 1 h
and the
solvent was removed. The crude product was purified by preparative HPLC using
acetonitrile-water gradients containing 0.1 % trifluoroacetic acid and then
converted into
the hydrochloride salt by treatment with 2 M HCL in diethyl ether. This gave
0.071 g
(43%) of the title compound as a yellow solid. HPLC 97%, RT: 1.863 min (System
A; 10-
97% over 3 min). 1H NMR (500 MHz, DMSO-d6) 8 ppm 6.98 (d, J=2.20 Hz, 1 H) 7.34
(d,
J=2.20 Hz, 1 H) 7.50-7.54 (m, 3 H) 7.58-7.60 (m, 1 H) 7.80-7.82 (m, 1 H) 7.97
(d, J=2.20
Hz, 1 H) 9.10 (s, 2 H) 9.20 (s, 1 H) 9.87 (s, 1 H). GC-MS 351 (M+).
EXAMPLE 33
N [7-(1-Aza-bicyclo[2.2.2]oct-2-en-3-yl)-benzofuran-5-yl]-2-methoxy-5-methyl-
benzenesulfonamide hydrochloride
3-Tributylstannanyl-1-aza-bicyclo[2.2.2]oct-2-ene (2.14 g, 5.36 mmol; prepared
according
to Bioo~g. Med. Chefy~.. Lett. 1994, 4, 2837-2840) was added to a mixture of 7-
iodo-5-nitro-
benzofuran (0.52 g, 1.79 mmol), Pd(PPh3)4 (0.206 g, 0.17 mmol) in DMF (10 mL).
The
mixture was heated at 160 °C for 10 min in a sealed reaction vessel
using controlled
microwave energy. The reaction mixture was diluted with CHCl3 and then
filtered through
a pad of Celite and concentrated under reduced pressure. The residue was
purified by
repetitive chromatography on silica using gradient elution, (CHCl3 -~CHCl3 +
10% MeOH
+ 0.4% NH3) followed by CHC13 + 10% MeOH + 0.4 % NH3 to give 399.5 mg of 3-(5-
nitro-benzofuran-7-yl)-1-aza-bicyclo[2.2.2]oct-2-ene. This intermediate was
dissolved in a
solvent system of EtOH:THF (4:1; 20 mL) and Raney-Ni (~ 1.0 mL suspension in
EtOH)
was added followed by hydrazine monohydrate (6 equiv). The mixtures are
stirred
vigorously for 3 h and then filtered through Celite pre-treated with water.
The filtrate was
concentrated, followed by the addition of toluene and re-evaporation to yield
340 mg of the
crude intermediate (7-(1-aza-bicyclo[2.2.2]oct-2-en-3-yl)-benzofuran-5-
ylamine). Most of
this material (325 mg; 1.35 mm01) was dissolved in DCM (5 mL). Pyridine (1.05
mL) was
added followed by 2-methoxy-5-methyl-benzenesulfonyl chloride (267 mg, 1.20
mmol).
The resultant mixture was stirred at room temperature for 16 h and then
concentrated under
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reduced pressure. The residue was purified by column chromatography on silica
using
gradient elution (CHC13~CHC13 + 10% MeOH + 0.4 % NH3) to give 230 mg of the
free
base of the title compound. The free base was dissolved in MeOH and 1 M HCl in
ether
was added to the solution. More ether was added and the precipitate was
collected by
filtration to give 182 mg of the HCl-salt. The product was dissolved in
CH3CN:MeOH
(2:1) and then purified by preparative reversed phase HPLC. The pure HPLC
fractions was
pooled and then concentrated to give the TFA-salt of the final product. The
TFA-salt was
converted to the HCl-salt: yield 100 mg of N [7-(1-aza-bicyclo[2.2.2]oct-2-en-
3-yl)-
benzofuran-5-yl]-2-methoxy-5-methyl-benzenesulfonamide hydrochloride; 1H NMR
(270
MHz, DMSO-d6) 8 ppm 1.57-1.76 (m, 2H), 2.00-2.20 (m, 3H), 2.21 (s, 3H), 3.00-
3.17 (m,
2H), 3.27-3.66 (m, obscured in part by solvent signal, 3H), 3.86 (s, 3H), 6.99-
7.09 (m, 2H),
7.20-7.42 (m, 4H), 7.53-7.60 (m, 1H), 8.05-8.10 (m, 1H), 9.98 (m, s, 1H ); GC-
MS (EI+)
for C23Hz4N2O4S nalz 425 (M)~.
INTERMEDIATE 19
tent-Butyl 4-(5-{ [(2-chlorophenyl)sulfonyl] amino}-1-benzofuran-7-
yl)piperazine-1-
carboxylate
test-Butyl 4-(5-amino-1-benzofuran-7-yl)piperazine-1-carboxylate (0.59 g, 1.87
mmol;
Intermediate 10) was dissolved in DCM. 2-Chlorobenzenesulfonyl chloride (0.59
g, 2.8
mmol) was added followed by pyridine (0.45 mL, 5.6 mmol). The reaction mixture
was
stirred at room temperature overnight. Filtration through a silica plug
afforded 0.66 g
(72%) of the title product. HPLC purity 92%, RT=2.56 min (System A; 10-97%
MeCN
over 3 min). 1H NMR (400 MHz, CDC13) 8 ppm 1.48 (s, 9 H) 3.07 - 3.21 (m, 4 H)
3.51 -
3.65 (m, 4 H) 6.51 (d, J--2.0 Hz, 1 H) 6.62 (d, J--2.3 Hz, 1 H) 6.93 (d, J 2.0
Hz, 1 H) 7.00
(s, 1 H) 7.18 - 7.31 (m, 2 H) 7.36 - 7.47 (m, 1 H) 7.47 - 7.57 (m, 2 H) 7.90
(dd, J--7.9, 1.6
Hz, 1 H). MS (ESI+) nz/z 492.2 (M+H)+.
INTERMEDIATE 20
2-Chloro-N-(7-piperazin-1-yl-1-benzofuran-5-yl)benzenesulfonamide
tef~t-Butyl4-(5-{[(2-chlorophenyl)sulfonyl]amino-1-benzofuran-7-yl)piperazine-
1-
carboxylate (0.66 g, 1.34 mmol; Intermediate 19) was dissolved in DCM (5 mL)
and TFA
was added (30% solution of TFA in DCM; 5 mL) and the mixture was stirred for
30 min.
The solvents were evaporated. The residue was dissolved in water, pH adjusted
to pH 8
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and extracted with EtOAc. The organic layer was dried and evaporated to give
0.41 g
(80%) of the title product that was used in the next step without further
purification. HPLC
purity 93%, RT=1.61 min (System A; 10-97% MeCN over 3 min).
INTERMEDIATE 21
1-(5-Nitro-1-benzofuran-7-yl)piperazine
Removal of the N-t-BOC group in text-butyl 4-(5-nitro-1-benzofuran-7-
yl)piperazine-1-
carboxylate* was performed according to the procedure of Intermediate 20
giving 2.3 g
(80%) of the title compound as a yellow solid. HPLC purity 94%, RT=1.37 min
(System A;
10-97% MeCN over 3 min). *Previously described in WO 2002100822.
INTERMEDIATE 22
N,N-Diethyl-2-[4-(5-nitro-1-benzofuran-7-yl)piperazin-1-yl] acetamide
A mixture of 1-(5-nitro-1-benzofuran-7-yl)piperazine (0.4 g, 1.6 mmol;
Intermediate 21)
and 2-chloro-N,N diethylacetamide (0.48 g, 3.2 mmol) in the presence of K2C03
(0.45 g,
3.2 mmol) in DMF was heated at 225 °C for 5 min using controlled
microwave energy.
The solvent was evaporated and the residue triturated with MeCN to give 0.31 g
(54%) of
the title compound as a yellow solid. HPLC purity 80%, RT=1.63 min (System A;
10-97%
MeCN over 3 min). 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.02 (t, J--7.0 Hz, 3 H)
1.14 (t,
J 7.0 Hz, 3 H) 2.58 - 2.77 (m, 4 H) 3.14 - 3.50 (m, 10 H) 7.14 (d, J 2.3 Hz, 1
H) 7.53 (d,
J--2.3 Hz, 1 H) 8.18 (dd, J--12.5, 2.3 Hz, 2 H).
INTERMEDIATE 23
2-[4-(5-Amino-1-benzofuran-7-yl)piperazin-1-yl]-N,N-diethylacetamide
Reduction of the nitro group in N,N-diethyl-2-[4-(5-nitro-1-benzofuran-7-
yl)piperazin-1-
yl]acetamide (0.3 g, 0.83 mmol; Intermediate 22) was performed according to
the
procedure of Intermediate 10. Yield: 0.19 g (70%). This material was used in
the next step
without further purification. MS (ESI+) rnlz 331.2 (M+H)+.
EXAMPLE 34
2-[4-(5-~ [(2-Chlorophenyl)sulfonyl] amino-1-benzofuran-7-yl)piperazin-1-yl]-
N,N-
diethylacetamide hydrochloride
2-[4-(5-Amino-1-benzofuran-7-yl)piperazin-1-yl]-N,N-diethylacetamide (0.095 g,
0.29
mmol; Intermediate 23) was reacted with 2-chlorobenzenesulfonyl chloride
according to
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the procedure of Intermediate 19. Yield: 0.06 g (41%) after purification by
preparative
HPLC (System E; 20-50% MeCN). 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.08 (t, J--6.9
Hz, 3 H) 1.15 (t, J--6.9 Hz, 3 H) 3.09 - 3.43 (m, 7 H) 3.55 - 3.65 (m, 2 H)
3.67 - 3.76 (m, 2
H) 4.39 (s, 2 H) 6.62 (d, J 1.0 Hz, 1 H) 6.86 (d, J 1.3 Hz, 1 H) 6.93 (d, J
1.5 Hz, 1 H)
7.47 (t, J--7.0 Hz, 1 H) 7.60 (q, J 7.7 Hz, 2 H) 7.91 (d, J--1.3 Hz, 1 H) 8.01
(d, J--7.8 Hz, 1
H) 10.08 (s, 1 H) 10.46 (s, 1 H). HPLC purity 92%, RT=1.85 min (System A; 10-
97%
MeCN over 3 min). MS (ESI+) rnlz 505.2 (M+H)+.
EXAMPLE 35
N,N-Diethyl-2-[4-(5-~[(2-methoxy-5-methylphenyl)sulfonyl]amino)-1-benzofuran-7-
yl)piperazin-1-yl]acetamide hydrochloride
2-[4-(5-Amino-1-benzofuran-7-yl)piperazin-1-yl]-N,N-diethylacetamide (0.095 g,
0.29
mmol; Intermediate 23) was reacted with 2-methoxy-5-methylphenylsulfonyl
chloride
according to the procedure of Intermediate 19. Yield: 0.05 g (33%) after
preparative HPLC
(System F; 10-50% MeCN). HPLC purity 93%, RT=1.87 min (System A; 10-97% MeCN
over 3 min). 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.08 (t, J--7.0 Hz, 3 H) 1.16 (t,
J--7.0
Hz, 3 H) 2.20 (s, 3 H) 3.08 - 3.45 (m, 7 H) 3.58-3.73 (m, 4 H) 3.87 (s, 3 H)
4.40 (s, 2 H)
6.61 (d, J--1.8 Hz, 1 H) 6.85 (d, J--2.0 Hz, 1 H) 6.93 (d, J--1.8 Hz, 1 H)
7.04 (d, J--8.5 Hz,
1 H) 7.32 (dd, J 8.8, 2.0 Hz, 1 H) 7.52 (d, J--1.8 Hz, 1 H) 7.89 (d, J--2.3
Hz, 1 H) 9.75 (s,
1 H) 10.07 (s, 1 H) MS (ESI+) m/z 515.4 (M+H)+.
INTERMEDIATE 24
3-(7-Bromo-1-benzofuran-2-yl)quinuclidin-3-of
Step 1. 3-~(Trimethylsilyl)ethynylJquinuclidin-3-ol.
A mixture of 3-quinuclidinone hydrochloride (24.12 g, 0.149 mol) and Na2C03
(27 g, 0.25
mol), in water. (500 mL) was extracted with dichloromethane (500 mL). The
organic phase
was evaporated to dryness. The residue was dissolved in THF (200 g) and slowly
added to
a solution of TMS-Li-acetylide (1.1 equiv) in THF (200 g) at 0-5 °C.
When the addition
was completed, a solution of NaHC03 in water (500 mL) was added. The organic
phase
was washed with additional water (500 mL) and evaporated to dryness to yield
20.89 g
(63%) of the title compound as a white solid. 1H NMR (270 MHz, CDCl3) 8 ppm
0.15 (s, 9
H) 1.27 - 1.46 (m, 1 H) 1.47 - 1.73 (m, 1 H) 1.80 - 2.14 (m, 3 H) 2.61 - 3.02
(m, 5 H) 3.17
(dd, J 13.86, 1.73 Hz, 1 H) 4.14 (br s, 1 H).
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Step 2. 3-(7-B~omo-1-benzofu~an-2 yl)quinuclidin-3-ol.
2,6-Dibromonitrophenol (3.0 g, 0.0119 mol), 3-
[(trimethylsilyl)ethynyl]quinuclidin-3-of
(2.66 g, 0.0119 mol; obtained in Step 1), Cu20 (1.70 g, 0.0119 mol) and
pyridine (200 mL)
were added to a round bottom flask. The resulting mixture was heated at reflux
overnight,
filtered through Celite, and the solvent was evaporated. The residue was
purified by
chromatography on silica gel using ethyl acetate (250 mL) and methanol (500
mL) as
eluents. The methanol fraction was evaporated to yield 1.12 g (29%) of the
title compound.
HPLC purity = 90%, m/z = 322 (M+H)+.
INTERMEDIATE 25
3-(7-Bromo-1-benzofuran-2-yl)-1-azabicyclo [2.2.2] oct-2-ene
3-(7-Bromo-1-benzofizran-2-yl)quinuclidin-3-of (600 mg, 1.86 mmol;
Intermediate 24,
Step 2) was dissolved in methanol (2 mL) and formic acid (40 mL) was added to
the flask.
The resulting mixture was heated at reflux overnight. Concentration in vacuo
furnished
562 mg (99%) of the title product. HPLC purity = 90%, m/z = 305 (M+H)+.
INTERMEDIATE 26
[2-(1-Azabicyclo[2.2.2]oct-2-en-3-yl)-1-benzofuran-7-yl]amine
3-(7-Bromo-1-benzofuran-2-yl)-1-azabicyclo[2.2.2]oct-2-ene (300 mg, 0.986
mmol;
Intermediate 25) was dissolved in methanol (2 mL). A solution of concentrated
aqueous
ammonia (25%; 10 mL) and CuCl2 (15 mg) were added and the resulting mixture
was
heated at 120 °C for 48 h. The mixture was run through a silica plug
using
methanol/ammonia solution (9:1) as eluent. Concentration in vacuo furnished
236 mg of
the crude title product. This material was used directly in subsequent
experiments.
EXAMPLE 36
N (2-(1-Azabicyclo[2.2.2]oct-2-en-3-yl)-1-benzofuran-7-yl]benzenesulfonamide
hydrochloride
[2-(1-Azabicyclo[2.2.2]oct-2-en-3-yl)-1-benzofuran-7-yl]amine (118 mg, 0.493
mmol;
Intermediate 26), benzenesulfonyl chloride (104 mg, 0.592 mmol) and
triethylamine (137
~.1, 0.986 mmol) were dissolved in ethanol (5 mL). The mixture was shaken for
2 hours.
Purification was carried out by preparative HPLC (20-90% acetonitrile/TFA-
water
gradient). Evaporated to yield 47 mg TFA salt, which was converted to the HCl
salt by
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stirring it in HCl/ether. Yield: 37 mg (18%), HPLC purity = 99%, m/z = 381
(M+H)+, 'H
NMR (270 MHz, methanol-d4) 8 ppm 1.74 - 1.91 (m, 2 H) 2.10 - 2.26 (m, 2 H)
3.15 - 3.29
(m, 2 H) 3.49 - 3.57 (m, 1 H) 3.64 - 3.78 (m, 2 H) 6.97 - 7.01 (m, 1 H) 7.13 -
7.28 (m, 3 H)
7.38-7.57(m,4H)7.70-7.76(m,2H).
EXAMPLE 37
N [2-(1-Azabicyclo[2.2.2]oct-2-en-3-yl)-1-benzofuran-7-yl]-2-methoxy-5-
methylbenzenesulfonamide hydrochloride
The title compound was prepared according to the same procedure as Example 36.
Yield:
56 mg (25%), HPLC purity = 99%, m/z = 425 (M+H)+, IH NMR (270 MHz, CDCl3) 8
ppml.77-1.96(m,2H)2.06-2.20(m,2H)2.22(s,3H)3.14-3.32(m,2H)3.39-3.48
(m, 1H)3.55-3.71 (m,2H)3.97(s,3H)6.89-6.95(m,2H)7.06-7.29(m,SH)7.41
(dd, J 7.92, 0.99 Hz, 1 H).
EXAMPLE 3 8
N-[7-(1-Azabicyclo [2.2.2.] oct-3-yloxy)-1-benzofuran-5-yl]benzenesulfonamide
hydrochloride
Step 1. 3-~(S-vitro-1-beyazofur~ah-7 yl)oxyJquinuclidi~2e.
7-Iodo-5-vitro-1-benzofuran (1.00 g, 3.46 mmol), quinuclidin-3-of (1.10 g,
8.65 mmol),
1,10-phenanthroline (0.25 g, 1.38 mmol), CuI (0.13 g, 0.69 mmol) and toluene
(20 mL)
were mixed together and heated at 140 °C overnight. The solvent was
removed in vacuo
and the crude product was purifed by flash chromatography (eluent: hexane and
chloroform:MeOHariethylamine; 9:0.9:0.1) to give 3-[(5-vitro-1-benzofuran-7-
yl)oxy]quinuclidine (3.46 mmol).
Step 2. 7-(1-Azabicyclo(2.2.2Joct-3-yloxy)-1-benzofuran-S-amine.
3-[(5-Nitro-1-benzofuran-7-yl)oxy]quinuclidine (1.38 g, 4.79 mmol; obtained in
Stepl)
was dissolved in ethanol:THF (100 mL: 25 mL) and Raney-nickel (slurry in
ethanol; 6 mL)
and hydrazine (891 ~L, 0.18 mmol) were added. The mixture was stirred at room
temperature for 3 h and then filtered through Celite and the solvent was
removed in vacuo.
The crude product was purified by flash chromatography [eluent: DCM:methanol
(6:1) and
chloroform:MeOHariethylamine (9:1:0.1)] to give 7-(1-azabicyclo[2.2.2]oct-3-
yloxy)-1-
benzofuran-S-amine (500 mg; 40%).
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Step 3. N ~7-(1-Azabicyclo~2.2.2.Joct-3 yloxy)-1-benzofuran-5
ylJbenzeyzesulfonamide
hydrochloride.
Benzenesulfonyl chloride (30 ~L, 0.232 mmol) and pyridine (141 ~,L, 1.74 mmol)
were
added to 7-(1-azabicyclo[2.2.2]oct-3-yloxy)-1-benzofuran-5-amine (0.50 g,
0.194 mmol;
obtained in Step 2) in DCM (2 mL). The mixture was shaken at room temperature
for 2 h
and then the solvent was removed in vacuo. Purification of the product was
done by
preparative HPLC using acetonitrile-water gradients containing 0.1 %
trifluoroacetic acid.
The obtained TFA salt was converted into the hydrochloride salt by treatment
with 2 M
HCl in ether. Yield: 11.0 mg (11.8%). HPLC 100%, RT: 1.680 (System B; 10-97%
MeCN
over 3 min). 1H NMR (270 MHz, methanol-d4) b ppm 0.91 (t, J--7.05 Hz, 1 H)
1.31 (m, 1
H) 1.89-2.36 (m, 5 H) 3.32-3.46 (m, 4 H) 3.77-3.87 (m, 1 H) 6.68-6.74 (m, 2 H)
6.94 (s, 1
H) 7.43-7.56 (m, 3 H) 7.68-7.73 (m, 3 H). LC-MS 399 (M+H)+.
EXAMPLE 39
N-[7-(1-Azabicyclo [2.2.2.] oct-3-yloxy)-1-benzofuran-5-yl]-2-
chlorobenzenesulfonamide hydrochloride
The title compound was prepared according to the procedure of Example 38, Step
3,
starting from 7-(1-azabicyclo[2.2.2]oct-3-yloxy)-1-benzofuran-5-amine
(obtained in
Example 38, Step 2) and 2-chlorobenzenesulfonyl chloride (0.49 g, 0.232 mmol).
Yield: 55
mg (54%). HPLC 100%, RT: 1.760 (System B; 10-97% MeCN over 3 min). 1H NMR (270
MHz, methanol-d4) 8 ppm 1.80-2.35 (m, 5 H) 2.18 (d, J--7.42 Hz, 1 H) 2.25 (s,
1 H) 3.29-
3.30 (m, 2 H) 3.41 (t, J--8.04 Hz, 2 H) 3.83 (dd, J--13.61, 7.92 Hz, 1 H) 3.97
(s, 1 H) 6.73-
6.76 (m, 2 H) 6.99-7.05 (m, 2 H) 7.33-7.36 (m, 1 H) 7.50-7.54 (m, 1 H) 7.70
(t, J 2.60 Hz,
1 H) 7.96 (d, J--7.67 Hz, 1 H). LC-MS 433 (M+H)+.
EXAMPLE 40
N-[7-(1-Azabicyclo[2.2.2.]oct-3-yloxy)-1-benzofuran-5-yl]-2-methoxy-5-
methylbenzenesulfonamide hydrochloride
The title compound was prepared according to the procedure of Example 38, Step
3,
starting from 7-(1-azabicyclo[2.2.2]oct-3-yloxy)-1-benzofuran-5-amine
(obtained in
Example 38, Step 2) and 2-methoxy-5-methylbenzenesulfonyl chloride (0.51 g,
0.232
mmol). Yield: 80 mg (77%). HPLC 100%, RT: 1.794 (System B; 10-97% MeCN over 3
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min). 1H NMR (270 MHz, methanol-d4) S ppm 0.92 (d, J--7.92 Hz, 1 H) 1.28-1.37
(m, 1
H) 1.99 (d, J--11.13 Hz, 3 H) 2.21 (s, 3 H) 2.36 (s, 1 H) 3.46-3.48 (m, 4 H)
3.85 (d, J--7.18
Hz, 1 H) 3.96 (s, 3 H) 5.02-5.04 (m, 1 H) 6.73-6.77 (m, 2 H) 6.96 (s, 1 H)
7.03 (d, J 8.41
Hz, 1 H) 7.32 (d, .I--7.42 Hz, 1 H) 7.49 (s, 1 H) 7.70 (d, J--1.48 Hz, 1 H).
LC-MS 443
(M+H)+.
INTERMEDIATE 27
(2-Morpholin-4-ylethyl)(5-nitro-1-benzofuran-7-yl)amine
7-Iodo-5-nitrobenzofuran (1.00 g, 3.46 mmol), 4-(2-aminoethyl)morpholine (0.54
g, 4.15
mmol), NaOt-Bu (0.47 g, 0.00484 mol), Xantphos (0.20 g, 0.346 mmol) and
Pd2dba3 (80
mg, 0.0865 mol) were heated in xylene (20 mL) at 120 °C for 1.5 hours.
The reaction
mixture was filtered through Celite and the solvent evaporated. The residue
was run
through a silica plug using dichloromethane (DCM) and then a 90:9:1 mixture of
DCM/MeOH/NH3 (aqueous 25%) as eluents. The product-containing fractions were
concentrated to yield 0.978 g (97%) of the title compound as a dark yellow
oil. HPLC
purity = 97 %, m/z = 292 (M+H)+, 1H NMR (270 MHz, CDC13) 8 ppm 2.44 - 2.61 (m,
4 H)
2.75 (t, J--5.81 Hz, 2 H) 3.31 - 3.43 (m, 2 H) 3.69 - 3.82 (m, 4 H) 6.85 (d, J-
-1.98 Hz, 1 H)
7.36 (d, J 1.98 Hz, 1 H) 7.70 (d, J--1.98 Hz, 1 H) 7.90 (d, J--2.23 Hz, 1 H).
INTERMEDIATE 28
N'-(2-Morpholin-4-ylethyl)-1-benzofuran-5,7-diamine
(2-Morpholin-4-ylethyl)(5-nitro-1-benzofuran-7-yl)amine (450 mg, 1.545 mmol;
Intermediate 27) was dissolved in THF (5 mL). After addition of ethanol ( 100
mL), Raney-
nickel (cat.) and hydrazine hydrate (2 mL), the mixture was left stirring at
room
temperature for 2 h. The product was used directly in the subsequent reaction
after
filtration through Celite and evaporation of solvent.
INTERMEDIATE 29
4-~2-[(5-Nitro-1-benzofuran-7-yl)oxy] ethyl~morpholine
To a test tube was added 7-iodo-5-nitrobenzofuran (1.0 g, 0.00346 mol), 4-(2-
hydroxyethyl)morpholine (0.91 g, 0.00692 mol), cesium carbonate (2.25 g,
0.00692 mol),
1,10-phenanthroline (0.25 g, 0.00138 mol) and CuI (130 mg, 0.692 mmol).
Toluene (15
mL) was added and the solution was heated in a StemBlock for 72 h. After
filtration
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WO 2005/058858 PCT/SE2004/001949
through Celite, the crude material was purified by flash chromatography
(EtOAc/DCM;
l: l). Yield: 32%, HPLC purity = 90%, m/z = 293 (M+H)+.
INTERMEDIATE 30
[7-(2-Morpholin-4-ylethoxy)-1-benzofuran-5-yl]amine
The title compound was prepared according to the same procedure as
Intermediate 28
starting from Intermediate 29. The product was used directly in the subsequent
reaction
(Example 45).
EXAMPLE 41
N {7-[(Z-Morpholin-4-ylethyl)amino]-1-benzofuran-5-yl}benzenesulfonamide
hydrochloride
To a solution of N~-(2-Morpholin-4-ylethyl)-1-benzofuran-5,7-diamine (58 mg,
0.221
mmol; Intermediate 28) in dichloromethane (2 mL) were added triethylamine (62
~,L,
0.442 mmol) and benzenesulfonyl chloride (39 mg, 0.221 mmol). The mixture was
stirred
at room temperature for 1 h and evaporated. The residue was purified by
preparative HPLC
(System D), evaporated pure fractions, and converted the resulting TFA salt to
a HCl salt.
Yield: 32%, HPLC purity = 100%, m/z = 402 (M+H)+, 'H NMR (270 MHz, methanol-
d4)
8 ppm 3.43 (t, J--6.06 Hz, 2 H) 3.40 - 3.61 (m, J--6.06, 6.06 Hz, 4 H) 3.68
(t, J--6.06 Hz, 2
H)3.75-4.14(m,4H)6.48-6.55(m,2H)6.64(d,J--2.23Hz,1H)7.41-7.59(m,3H)
7.65-7.74(m,3H).
EXAMPLE 42
2-Methoxy-5-methyl-N {7-[(2-morpholin-4-ylethyl)amino]-1-benzofuran-5-
yl}benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure of Example 41.
Yield: 37%,
HPLC purity = 100%, m/z = 446 (M+H)+, 1H NMR (270 MHz, methanol-d4) 8 ppm 2.18
-
2.24 (s, 3 H) 3.35 - 3.60 (m, 4 H) 3.43 (t, J--5.94 Hz, 2 H) 3.67 (t, J--5.94
Hz, 2 H) 3.74 -
4.07 (m, 4 H) 3.94 - 3.99 (m, 3 H) 6.51 (d, J 1.98 Hz, 1 H) 6.63 (dd, J--4.08,
2.10 Hz, 2 H)
7.03 (d, J--8.41 Hz, 1 H) 7.32 (dd, J--8.78, 2.60 Hz, 1 H) 7.49 (d, J--2.23
Hz, 1 H) 7.64 (d,
J--2.23 Hz, 1 H).
EXAMPLE 43
lol
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N {7-[(2-Morpholin-4-ylethyl)amino]-1-benzofuran-5-yl~-2-
(trifluoromethyl)benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure of Example 41.
Yield: 38%,
HPLC purity = 100%, m/z = 470 (M+H)+, 1H NMR (270 MHz, methanol-d4) ~ ppm 3.15
-
3.63 (m, 4 H) 3.43 (t, J 5.94 Hz, 2 H) 3.67 (t, J--6.06 Hz, 2 H) 3.72 - 4.14
(m, 4 H) 6.49
(d, J--1.73 Hz, 1 H) 6.64 (dd, J 7.42, 1.98 Hz, 2 H) 7.60 - 7.75 (m, 3 H) 7.88
- 7.94 (m, 1
H) 8.00 - 8.04 (m, 1 H).
EXAMPLE 44
2,6-Dichloro-N ~7-[(2-morpholin-4-ylethyl)amino]-1-benzofuran-5-
yl~benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure of Example 41.
Yield: 19%,
HPLC purity = 100%, m/z = 470 (M+H)~, 1H NMR (270 MHz, methanol-d4) 8 ppm 3.22
-
3.60 (m, 4 H) 3.45 (t, J--5.94 Hz, 2 H) 3.69 (t, J--5.94 Hz, 2 H) 3.72 - 4.13
(m, 4 H) 6.58
(d, J 1.98 Hz, 1 H) 6.67 (dd, J 9.65, 1.98 Hz, 2 H) 7.33 - 7.41 (m, 1 H) 7.45 -
7.52 (m, 2
H) 7.66 (d, J--1.98 Hz, 1 H).
EXAMPLE 45
2-Methoxy-5-methyl-N [7-(2-morpholin-4-ylethoxy)-1-benzofuran-5-
yl]benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure of Example 41
starting from
[7-(2-morpholin-4-ylethoxy)-1-benzofuran-5-yl]amine (Intermediate 30). Yield:
32%,
HPLC purity = 99%, m/z = 447 (M+H)+, 1H NMR (270 MHz, methanol-d4) 8 ppm 2.20
(s,
3H)3.26-3.74(m,4H)3.66-3.72(m,2H)3.75-4.15(m,4H)3.96(s,3H)4.49-4.57
(m, 2 H) 6.73 (d, J--2.23 Hz, 1 H) 6.85 (d, J--1.98 Hz, 1 H) 6.96 (d, J--1.98
Hz, 1 H) 6.99
7.04 (m, 1 H) 7.27 - 7.34 (m, 1 H) 7.51 (d, J 2.23 Hz, 1 H) 7.70 (d, J 2.23
Hz, 1 H).
EXAMPLE 46
3-Methyl-N [7-(2-morpholin-4-ylethoxy)-1-benzofuran-5-yl]benzenesulfonamide
hydrochloride
The title compound was prepared according to the procedure of Example 41
starting from
[7-(2-morpholin-4-ylethoxy)-1-benzofuran-5-yl]amine (Intermediate 30). Yield:
28%,
HPLC purity = 98%, m/z = 417 (M+H)+, 'H NMR (270 MHz, methanol-d~) 8 ppm 2.28 -
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2.36(m,3H)3.24-3.69(m,4H)3.67-3.73(m,2H)3.76-4.17(m,4H)4.51-4.59 (m,
2 H) 6.74 (d, J 2.23 Hz, 1 H) 6.82 (d, J--1.98 Hz, 1 H) 6.89 (d, J--1.98 Hz, 1
H) 7.27 - 7.40
(m, 2 H) 7.46 - 7.57 (m, 2 H) 7.73 (d, J--2.23 Hz, 1 H).
EXAMPLE 47
3-Chloro-4-methyl-N [7-(2-morpholin-4-ylethoxy)-1-benzofuran-5-
yl]benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure of Example 41
starting from
[7-(2-morpholin-4-ylethoxy)-1-benzofuran-5-yl]amine (Intermediate 30). Yield:
11%,
HPLC purity = 99%, m/z = 451 (M+H)+, 1H NMR (270 MHz, methanol-dø) 8 ppm 2.36 -
2.39(m,3H)3.31-3.71 (m,4H)3.68-3.74(m,2H)3.75-4.22(m,4H)4.54-4.61 (m,
2 H) 6.77 (d, J--1.98 Hz, 1 H) 6.87 (q, J--1.98 Hz, 2 H) 7.35 - 7.40 (m, 1 H)
7.48 - 7.54 (m,
1 H) 7.66 (d, J--1.73 Hz, 1 H) 7.75 (d, J--1.98 Hz, 1 H).
INTERMEDIATE 31
[2-(Dimethylamino)ethyl] (5-vitro-1-benzofuran-7-yl)amine
Xylene (75 mL) was added to 7-iodo-5-vitro-1-benzofuran (1.00 g, 3.46 mmol),
N,N
dimethylethane-1,2-diamine (0.37 g, 4.15 mmol), Pdz(dba)3 (0.08 g, 0.87 mmol),
Xantphos
(0.20 g, 0.35 mmol) and Cs2C03 (1.59 g, 4.84 mmol). The mixture was stirred at
120 °C
overnight, filtered through Celite and the solvent was removed in vacuo. The
crude product
was purified by flash chromatography [eluent: DCM:MeOH (6:1) and DCM:MeOH:Et3N
(9:1:0.1)] to afford 0.378 g (44%) of the title compound. HPLC 90%, RT: 1.430
(System
A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) 8 ppm 2.44 (d, J--
3.22
Hz, 6 H) 2.81 (t, J 6.56 Hz, 2 H) 3.52 (t, J 6.56 Hz, 2 H) 6.97 (d, J--2.23
Hz, 1 H) 7.40 (d,
J 2.23 Hz, 1 H) 7.89 (t, J--1.98 Hz, 2 H). LC-MS 250 (M+H)+.
EXAMPLE 48
N-(7-{ [2(Dimethylamino)ethyl] amino]-1-benzofuran-5-yl)-2-methoxy-5-
benzenesulfonamide
Step 1. N'-~2-(Dimethylamiho)ethylJ-1-benzofur~an-5,7-diamine.
Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (295 ~L, 6.08 mmol) were
added to
[2-(dimethylamino)ethyl](5-vitro-1-benzofuran-7-yl)amine (0.378 g, 1.52 mmol;
Intermediate 31) in a mixture of ethanol (100 mL) and THF (25 mL). The
reaction mixture
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was stirred at room temperature for 2 h. Additional Raney-nickel (slurry in
ethanol; 2 mL)
and hydrazine (295 ~L, 6.08 mmol) were added and stirring was continued
overnight. The
mixture was filtered through Celite and the solvent was removed. The crude
product was
used in the next step without further purification.
Step 2. N (7-~~2(Dimethylamino)ethylJamifao~-1-behzofuran-S yl)-2-methoxy-5-
benzehesulfonamide.
2-methoxy-5-methylbenzenesulfonyl chloride (0.145 g, 0.657 mmol) and pyridine
(398
~,L, 4.93 mmol) were added to N'-[2-(dimethylamino)ethyl]-1-benzofuran-5,7-
diamine
(0.120 g, 0.547 mmol; from Step 1) in DCM (1 mL). The mixture was shaken at
room
temperature for 1 h, solvent was removed in vacuo and the product was purified
by
preparative HPLC using acetonitrile-water gradients containing 0.1%
trifluoroacetic acid.
The obtained TFA salt was converted into the hydrochloride salt by treatment
with 2 M
HCl in ether to afford 13.3 mg (6%) of the title product. HPLC 99%, RT: 1.692
(System A;
10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) ~ ppm 2.21 (s, 3 H)
2.94 (s,
6 H) 3.40 (t, J--5.69 Hz, 2 H) 3.60-3.64 (m, 2 H) 3.97 (s, 3 H) 6.52 (s, 1 H)
6.64 (t, J--2.10
Hz, 1 H) 7.03 (d, J--8.41 Hz, 1 H) 7.32 (d, J 6.19 Hz, 1 H) 7.50 (d, J 1.98
Hz, 1 H) 7.65
(d, J 2.23 Hz, 2 H). LC-MS 404 (M+H)+.
EXAMPLE 49
2-Chloro-N-(7- f [2-(dimethylamino)]-1-benzofuran-5-yl)benzenesulfonamide
hydrochloride
2-Chlorobenzenesulfonyl chloride (0.139 g, 0.657 mmol) and pyridine (398 ~L,
4.93
mmol) were added to N'-[2-(dimethylamino)ethyl]-1-benzofuran-5,7-diamine
(0.120 g,
0.547 mmol; Example 48, Step 1) in DCM (1 mL). The mixture was shaken at room
temperature for 1 h, solvent removed in vacuo, and the product was purified by
preparative
HPLC using acetonitrile-water gradients containing 0.1 % trifluoroacetic acid.
The obtained
TFA salt was converted into the hydrochloride salt by treatment with 2 M HCl
in ether to
afford 22.8 mg (10%) of the title product. HPLC 99%, RT: 1.651 (System A; 10-
97%
MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) ~ ppm 2.94 (s, 6 H) 3.40 (s, 2
H)
3.65 (d, J--1.48 Hz, 2 H) 6.65 (d, J 1.73 Hz, 1 H) 7.36 (t, J 7.18 Hz, 2 H)
7.50-7.56 (m, 3
H) 7.66 (d, J--1.73 Hz, 1 H) 7.97 (d, J 7.67 Hz, 1 H). LC-MS 394 (M+H)+.
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INTERMEDIATE 32
N-(5-Nitro-1-benzofuran-7-yl)pyridin-4-yl-amine
A mixture of 7-iodo-5-nitro-1-benzofuran (1.00 g, 3.46 mmol), 4-aminopyridine
(0.39 g,
4.15 mmol), Xantphos (0.20 g, 0.36 mmol), Pd2(dba)3 (0.08 g, 0.09 mmol),
NaOtBu (0.47
g, 4.84 mmol) in xylene (200 mL) was heated at 120 °C overnight. The
reaction mixture
was filtered through Celite and a yellow precipitate was formed which was
collected by
filtration to yield 0.52 g (60%) of the title product. HPLC 96%, RT: 1.344
(System A; 10-
97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) 8 ppm 6.91-7.12 (m, 4 H)
8.00
(d, J--2.23 Hz, 1 H) 8.15-8.24 (m, 2 H) 8.37 (d, J--2.23 Hz, 1 H). LC-MS 256
(M+H)+.
INTERMEDIATE 33
5-Amino-1-benzofuran-7-yl)pyridin-4-yl-amine
Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (404 ~,L, 8.33 mmol) were
added to
N-(5-nitro-1-benzofuran-7-yl)pyridin-4-yl-amine (0.52 g, 2.08 mmol;
Intermediate 32) in
ethanol (40 mL) and THF (10 mL). The mixture was stirred at room temperature
for 3 h,
filtered through Celite and the solvent was removed in vacuo to yield 0.27 g
(53%) of the
title product. HPLC 96%, RT: 0.964 (System A; 10-97% MeCN over 3 min). 1H NMR
(270
MHz, methanol-d4) 8 ppm 6.69 (d, J 2.23 Hz, 1 H) 6.72 (d, J 2.23 Hz, 1 H) 6.77
(d,
J--1.98 Hz, 1 H) 6.83 (dd, J--4.95, 1.48 Hz, 2 H) 7.62 (d, J--1.98 Hz, 1 H)
8.08 - 8.10 (m, 2
H). LC-MS 226 (M+H)+.
EXAMPLE 50
N-[7-(Pyridin-4-ylamino)-1-benzofuran-5-yl]benzenesulfonamide hydrochloride
Benzenesulfonyl chloride (65 ~,L, 0.48 mmol) and pyridine (289 ~L, 3.58 mmol)
were
added to (5-amino-1-benzofuran-7-yl)pyridin-4-yl-amine (90 mg, 0.40 mmol;
Intermediate
33) in DCM (2 mL). The mixture was heated at 40 °C for 10 min, shaken
at room
temperature for 1 h, and solvent was removed in vacuo. The residue was
purified by
preparative HPLC using acetonitrile-water gradients containing 0.1%
trifluoroacetic acid.
The obtained TFA salt was converted into the hydrochloride salt by treatment
with 2 M
HCl in ether to afford 78.7 mg (45%) of the title product. HPLC 100%, RT:
1.560 (System
A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) 8 ppm 6.91 (s, 1 H)
7.04
(d, J 2.23 Hz, 2 H) 7.36 (d, J--1.98 Hz, 1 H) 7.51-7.65 (m, 3 H) 7.74-7.77 (m,
2 H) 8.03
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(d, J--1.98 Hz, 1 H) 8.32 (d, J--6.93 Hz, 2 H) 10.43 (s, 1 H) 10.84 (s, 1 H).
LC-MS 366
(M+H)+.
EXAMPLE 51
2-Chloro-N-[7-(pyridin-4-ylamino)-1-benzofuran-5-yl]benzenesulfonamide
hydrochloride
Prepared by the same method as for N-[7-(pyridin-4-ylamino)-1-benzofuran-5-
yl]benzenesulfonamide hydrochloride (Example 50) from 2-chlorobenzenesulfonyl
chloride (101 mg, 0.48 mmol). This furnished 60.3 mg (32%) of 2-chloro-N-[7-
(pyridin-4-
ylamino)-1-benzofuran-5-yl]benzenesulfonamide hydrochloride. HPLC 100%, RT:
1.639
(System A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) 8 ppm 6.92
(s,
1 H) 7.03 (d, J 2.23 Hz, 1 H) 7.09 (d, J--1.98 Hz, 1 H) 7.36 (d, J--2.23 Hz, 1
H) 7.48-7.53
(m, 1 H) 7.60-7.68 (m, 2 H) 8.02-8.06 (m, 2 H) 8.33 (d, J--7.18 Hz, 2 H) 10.74
(s, 1 H)
10.86 (s, 1 H). LC-MS 400 (M+H)~.
EXAMPLE 52
2-Methoxy-5-methyl-N-[7-(pyridin-4-ylamino)-1-benzofuran-5-
yl]benzenesulfonamide hydrochloride
Prepared by the same method as for N-[7-(pyridin-4-ylamino)-1-benzofuran-5-
yl]benzenesulfonamide hydrochloride (Example 50) from 2-methoxy-5-
methylbenzenesulfonyl chloride (105 mg, 0.48 mmol). This furnished 50.9 mg
(26%) of 2-
methoxy-5-methyl-N-[7-(pyridin-4-ylamino)-1-benzofuran-5 -
yl]benzenesulfonamide
hydrochloride. HPLC 100%, RT: 1.692 (System A; 10-97% MeCN over 3 min). 1H NMR
(270 MHz, methanol-d4) S ppm 2.21 (s, 3 H) 3.86 (s, 3 H) 6.91 (s, 1 H) 7.02-
7.09 (m, 3 H)
7.33-7.38 (m, 2 H) 7.55 (d, J--1.73 Hz, 1 H) 8.00 (d, J--1.98 Hz, 1 H) 8.32
(d, J 6.93 Hz, 2
H) 10.04 (s, 1 H) 10.78 (s, 1 H). LC-MS 410 (M+H)+.
EXAMPLE 53
2-Methoxy-5-methyl-N-[7-(piperazin-1-ylcarbonyl)-1-benzofuran-5-
yl]benzenesulfonamide hydrochloride
Step 1. 7-Br~omo-2-tr~itnethylsilanyl-bertzofuran-5 ylamine.
7-Bromo-5-nitro-2-trimethysilylbenzofuran (5.0 g, 15.9 mmol; Intermediate 4,
Step 2) was
reduced with PtOa (363 mg, 1.6 mmol) in EtOAc (100 mL) over 2.5 bar HZ
overnight. The
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resulting mixture was filtered through wetted Celite to yield 4.5 g
(quantitative) of 7-
bromo-2-trimethylsilanyl-benzofuran-5-ylamine.
Step 2. N (7-Bromo-2-t>~imethylsilanyl-benzofur~an-5 yl)-2-znethoxy-5-methyl-
benzenesulfonamide.
Coupling of the amine (4.5 g, 15.9 mmol) from Step 1 with 2-methoxy-5-
methylphenylsulfonyl chloride (3.5 g, 15.9 mmol) in dichloromethane (200 mL)
using
pyridine as a base (3.2 mL, 40 mmol) required 2.5 hours at ambient
temperature. Washing
the resulting mixture with water, drying and concentration yielded 7.4 g
(100%) of N-(7-
bromo-2-trimethylsilanyl-benzofuran-5-yl)-2-methoxy-5-methyl-
benzenesulfonamide as a
dark orange solid.
Step 3. 4-~S-(2-Methoxy-5-n2ethyl-benzenesulfonylamino)-benzofu>"an-7-
carbonylJ-
pipe>"azine-1-caf°boxylic acid tent-butyl estez°.
The Heck carbonylation was performed under controlled microwave heating at
150°C/15
min by mixing the above bromide (168 mg, 0.36 mmol) from Step 2, (tez°t-
butoxycarbonyl)piperazine (134 mg, 0.72 mmol), Mo(CO)6 (48 mg, 0.18 mmol),
trans-
di(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II) (Herrmann's
catalyst, 36 mg,
0.04 mmol), aqueous I~2CO3 (4 M; 300 ~L, 1.3 mmol) and diglyme (1 mL). This
yielded
about 50% of product with TMS remaining (4-[5-(2-methoxy-5-methyl-
benzenesulfonylamino)-2-trimethylsilanyl-benzofuran-7-carbonyl]-piperazine-1-
carboxylic
acid tert-butyl ester) and about 7% product with TMS absent, i.e., the title
product. Both
products were isolated pure by preparative HPLC (Gilson; using a gradient of
30-70%
MeCN). Yield TMS product: 53 mg (24%) yellow oil. HPLC 100% RT=2.06 (System C;
2-
95% MeCN over 2 min). The TMS group was removed by allowing to stir in t-BuN+F-
(0.5
mL, 1 M in THF) in THF (3 mL) at ambient temperature for 1 h 20 min.
Purification using
preparative HPLC (gradient of 30-70% MeCN) gave additional material of the
title product
as a yellow oil.
Step 4. 2-Methoxy-5-methyl-N ~7-(pipe~azirz-1 ylcarbonyl)-1-benzofuran-S-
ylJbenzenesulfonamide hydf~ochloride. Deprotection of the N-t-BOC group in 4-
[5-(2-
methoxy-5-methyl-b enzenesulfonylamino)-benzofuran-7-carbonyl]-piperazine-1-
carboxylic acid tert-butyl ester (Step 3) was performed by adding HCl/ether to
a solution of
the said substrate in ethyl acetate and allowed to stir overnight at ambient
temperature.
log
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Concentration of the solution gave the title product as a white solid. Yield:
31 mg. HPLC
96% RT=2.73 min (System A; 30-80% MeCN over 3 min), 1.05 min (System C; 2-95%
MeCN over 2 min). 1H NMR (400 Mz, methanol-d4) 8 ppm 2.17 (s, 3H), 3.19 (m,
2H),
3.34 (m, 2H), 3.49 (m, 2H), 3.91 (s, 3H), 4.01 (m, 2H), 6.80 (d, J--2.2 Hz,
1H), 6.99 (d,
J 8.6 Hz, 1H), 7.20 (d, J 2.2 Hz, 1H), 7.28 (dd, J--8.6, 2.0 Hz, 1H), 7.45 (d,
J 2.2 Hz,
1H), 7.49 (d, J 2.O Hz, 1H), 7.76 (d, J--2.0 Hz, 1H). 13C NMR (400 Mz, MeOH-
d4) b ppm
19.15, 55.60, 94.55, 106.86, 112.31, 116.62, 118.32, 118.44, 125.90, 129.07,
129.89,
130.51, 133.47, 135.37, 140.33, 147.22, 147.92, 154.75, 166.24 (C=O). MS (ESI)
for
~21H23N3~Ss ~Z 430 (M+H).
EXAMPLE 54
2-Methoxy-5-methyl-N-[7-(piperazin-1-ylmethyl)-1-benzofuran-5-
yl]benzenesulfonamide hydrochloride
To a solution of 4-[5-(2-methoxy-5-methyl-benzenesulfonylamino)-2-
trimethylsilanyl-
benzofuran-7-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (94 mg,
0.16 mmol;
obtained in Example 53, Step 3) in THF was added LiAlH4 (22 mg, 0.56 mmol) and
allowed to stir overnight at 80 °C (only 50% conversion to t-BOC- and
TMS-deprotected
bisamine product after 3 hours). The solution was made neutral by addition of
aqueous 1 M
HCl and extracted with ethyl acetate, but little product in organic phase. The
resulting
aqueous phase was therefore made acidic, and then concentrated. Purification
by
preparative HPLC (Gilson; gradient of 20-50% MeCN) gave 14 mg of pure product
as the
TFA salt. Conversion to the HCl salt was done with aqueous 6 M HCI.
Concentration gave
the final product as a white solid. Yield: 15 mg. HPLC 100% RT=2.51 min
(System A; 30-
80% MeCN over 3 min), 0.94 min (System C; 2-95% MeCN over 2 min). 1H NMR (400
Mz, MeOH-d4) 8 ppm 2.14 (s, 3H), 2.98 (s, 3H), 3.66 (br m, 9H), 4.69 (s, 2H),
6.80 (d,
J--8.3 Hz, 1H), 6.82 (d, J 2.2 Hz, 1H), 7.14 (dd, J--8.3, 2.2 Hz, 1H), 7.38
(d, J 2.0 Hz,
1H), 7.40 (d, J 2.0 Hz, 1H), 7.52 (d, J--2.2 Hz, 1H), 7.82 (d, J--2.2 Hz, 1H).
MS(ESI) for
C21H25N3~4S ~Z 416 (M+H).
EXAMPLE 55
N-{7-[(3-Aminopyrrolidin-1-yl)methyl]-1-benzofuran-5-yl~-2-methoxy-5-
methylbenzenesulfonamide hydrochloride
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To a solution of {1-[5-(2-methoxy-5-methyl-benzenesulfonylamino)-2-
trimethylsilanyl-
benzofuran-7-carbonyl]-pyrrolidin-3-yl}-carbamic acid tart-butyl ester* (84
mg, 0.14
mmol) in THF was added LiAlH4 (22 mg, 0.56 mmol) and the resulting mixture was
allowed to stir for 4 h at 80 °C. Ethyl acetate was added and the
mixture was washed with
1 M aqueous HCl and then with water, dried and concentrated to yield 37 mg of
the mono
boc-protected diamine. (According to HPLC, 34% was reduced at the furan ring).
Purification by preparative HPLC (Gilson; gradient of 40-80% MeCN) gave pure
boc-
protected diamine. N-Deprotection was performed cleanly overnight in 6 M
aqueous HCl
(attempts with HCl/ether at 60 °C overnight gave only 25% product and
some biproducts)
to give the product after evaporation as a yellow solid. Yield: 16 mg. HPLC
92% RT=1.30
min (System A; 30-80% MeCN over 3 min), 1.03 min (System C; 2-95% MeCN over 2
min). The peaks in the proton NMR spectrum are broad due to the conformational
flexibility of the pyrrolidine ring. 1H NMR (400 Mz, methanol-d4) 8 ppm 1.44
(br s, 1H),
2.17 (s, 3H), 2.38 (br s, 1H), 3.37-3.83 (br m, 4H), 3.97 (s, 3H), 4.08-4.73
(br m, 3H), 6.82
(br s, 1H), 7.03 (m, 1H), 7.22-7.34 (br m, SH), 7.48 (m, 3H), 7.81 (br s, 1H).
MS(ESI) for
CZ~H25N3O4S m/z 416 (M+H). *Prepared from pyrrolidin-3-yl-carbamic acid tart-
butyl
ester according to the procedure of Example 53 (Step 3).
INTERMEDIATE 34
Octahydrothieno[3,4-b]pyrazine 6,6-dioxide*
cis-3,4-Dichlorotetrahydrothiophene 1,1-dioxide (5.0 g, 26.0 mmol) in dioxane
(40 mL)
was added dropwise to ethane-1,2-diamine (10.4 g, 173.0 mmol) in dioxane (25
mL) at 0
°C. The mixture was heated at 100 °C for 3 h, followed by
cooling to room temperature
and continued stirring overnight. The two layers were separated and the bottom
layer,
containing ethylene diamine and amine salt, was washed twice with dioxane. The
dioxane
layers were combined and the solvent was removed in vacuo. The crude product
was
recrystallized from toluene to afford 2.7 g (59%) of the title compound as
white crystals.
HPLC 98%, RT: 0.292 (System B; 10-97% MeCN over 3 min). 1H NMR (270 MHz,
methanol-d4) 8 ppm 2.67-2.76 (m, 2 H) 2.86-2.96 (m, 2 H) 3.13-3.20 (m, 2 H)
3.33-3.44
(m, 2 H) 3.63-3.70 (m, 2 H). LC-MS 177 (M+H)+. *Previously described in U.S.
Patent
3,882,122.
INTERMEDIATE 35
109
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1-(5-Nitro-1-benzofuran-7-yl)octahydrothieno[3,4-b]pyrazine 6,6-dioxide
Xylene (150 mL) was added to 7-iodo-5-nitro-1-benzofuran (1.00 g, 3.46 mmol),
octahydrothieno[3,4-b]pyrazine 6,6-dioxide (0.73 g, 4.15 mmol; Intermediate
34),
Pdz(dba)3 (0.08 g, 0.87 mmol), Xantphos (0.20 g, 0.35 mmol) and Cs2C03 (1.59
g, 4.84
mmol). The resulting mixture was stirred at 120 °C overnight, filtered
through Celite and
the solvent was removed in vacuo. The crude product was purified by flash
chromatography [eluent: DCM and DCM:MeOH (1:l)] and then recrystallized from
MeOH to afford 0.354 g (8%) of the title product. HPLC 90%, RT: 1.390 (System
A; 10-
97% MeCN over 3min). 1H NMR (270 MHz, CDC13) 8 ppm 2.85 (dd, J 12.62, 7.42 Hz,
1
H) 3.16-3-49 (m, 6 H) 3.71 (t, J--11.63 Hz, 1 H) 4.02-4.05 (m, 1 H) 5.17-5.25
(m, 1 H)
6.93 (d, J--2.23 Hz, 1 H) 7.62 (t, J--2.72 Hz, 1 H) 7.77 (d, J 1.98 Hz, 1 H)
8.19 (d, .l--1.98
Hz, 1 H). LC-MS 338 (M+H)+.
INTERMEDIATE 36
7-(6,6-Dioxidohexahydrothieno[3,4-b]pyrazine-1(2H)-yl-1-benzofuran-5-amine
Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (204 mL, 4.20 mmol) were
added to
1-(5-nitro-1-benzofuran-7-yl)octahydrothieno[3,4-b]pyrazine 6,6-dioxide (0.354
g, 1.05
mmol; Intermediate 35) in a mixture of THF (20 mL) and EtOH (80 mL). The
resulting
mixture was stirred at room temperature overnight and then more Raney-nickel
(slurry in
ethanol; 2 mL) and hydrazine (204 mL, 4.20 mmol) were added and stirring was
continued
overnight. The mixture was filtered through Celite and the solvent was removed
in vacuo
to afford 0.338 g (quantitative). HPLC 90%, RT: 0.782 (System A; 10-97% MeCN
over 3
min). 1H NMR (270 MHz, methanol-d~) 8 ppm 2.79 (dd, J--12.49, 7.30 Hz, 1 H)
2.90-3.25
(m, 4 H) 3.43-3.64 (m, 3 H) 3.91-3.94 (m, 1 H) 5.01-5.07 (m, 1 H) 6.33 (d, J--
1.98 Hz, 1
H) 6.61 (dd, J--12.99, 2.10 Hz, 2 H) 7.62 (d, ~ 1.98 Hz, 1 H). LC-MS 308
(M+H)+.
EXAMPLE 56
N-[7(6,6-Dioxidohexahydrothieno [3,4-b] pyrazin-1(2H)-yl)-1-benzofuran-5-yl]-2-
methoxy-5-methylbenzenesulfonamide hydrochloride
2-Methoxy-5-methylbenzenesulfonyl chloride (0.094 g, 0.428 mmol) and pyridine
(259
~,L, 3.21 mmol) were added to 7-(6,6-dioxidohexahydrothieno[3,4-b]pyrazine-
1(2H)-yl-1-
benzofuran-5-amine (0.110 g, 0.357 mmol; Intermediate 36) in DCM (1 rnL). The
mixture
was shaken at room temperature for 1 h, solvent removed in vacuo, and the
residue was
llo
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purified by preparative HPLC using acetonitrile-water gradients containing 0.1
trifluoroacetic acid. The obtained TFA salt was converted into the
hydrochloride salt by
treatment with 2 M HCl in ether to afford 20.0 mg (11%) of the title product.
HPLC 98%,
RT: 1.483 (System A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) 8
ppm 3.08-3.12 (m, 2 H) 3.37-3.79 (m, 6 H) 3.96 (s, 3 H) 4.55 (d, J--3.96 Hz, 1
H) 6.77 (d,
J--2.23 Hz, 1 H) 6.84 (d, J--1.98 Hz, 1 H) 7.03 (d, J--8.41 Hz, 1 H) 7.12 (d,
J--1.98 Hz, 1
H) 7.31 (dd, J 8.78, 1.86 Hz, 1 H) 7.51 (d, J--1.73 Hz, 1 H) 7.74 (d, J--2.23
Hz, 1 H). LC-
MS 492 (M+H)+.
EXAMPLE 57
N-[7(6,6-Dioxidohexahydrothieno(3,4-b]pyrazin-1(2I~-yl)-1-benzofuran-5-
yl]benzenesulfonamide hydrochloride
Benzenesulfonyl chloride (0.076 g, 0.428 mmol) and pyridine (259 mL, 3.21
mmol) were
added to 7-(6,6-dioxidohexahydrothieno[3,4-b]pyrazine-1(2H)-yl-1-benzofuran-5-
amine
(0.110 g, 0.357 mmol; Intermediate 36) in DCM (1 mL). The mixture was shaken
at room
temperature for 1 h, solvent removed in vacuo, and the residue was purified by
preparative
HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid.
The
obtatined TFA salt was converted into the hydrochloride salt by treatment with
2 M HCl in
ether to afford 27.0 mg (17%) of the title product. HPLC 99%, RT: 1.556
(System A; 10-
97% MeCN over 3 min). 'H NMR (270 MHz, methanol-d4) 8 ppm 3.17 (d, J--6.68 Hz,
2
H) 3.47-3.85 (m, 6 H) 4.52-4.56 (m, 1 H) 4.95-4.99 (m, 1 H) 6.77-6.79 (m, 2 H)
7.07 (d,
J 1.98 Hz, 1 H) 7.42-7.54 (m, 3 H) 7.69-7.77 (m, 3 H). LC-MS 448 (M+H)~.
EXAMPLE 58
N ~7-[(2-Pyrrolidin-1-ylethyl)amino]-1-benzofuran-5-yl~benzenesulfonamide
hydrochloride
To a test tube containing benzenesulfonyl chloride (42 mg, 0.235 mmol) was
added a
solution of N'-(2-pyrrolidin-1-ylethyl)-1-benzofuran-5,7-diamine* (48 mg,
0.195 mmol) in
dichloromethane (3 mL). After addition of triethylamine (55 ~1, 0.391 mmol),
the mixture
was shaken for 1 h and then concentrated. The residue was purified by
preparative HPLC.
The resulting TFA-salt was treated with HCllether and evaporated to provide
the title
compound. Yield: 5%, HPLC purity = 99%, m/z = 386 (M+H)+, 1H NMR (270 MHz,
methanol-d4) 8 ppm 1.95 - 2.26 (m, 4 H) 3.03 - 3.24 (m, 2 H) 3.38 - 3.47 (m, 2
H) 3.58 -
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3.65 (m, 2 H) 3.64 - 3.77 (m, 2 H) 6.45 - 6.48 (m, 1 H) 6.55 - 6.57 (m, 1 H)
6.65 (d, J--2.23
Hz, 1 H) 7.40 - 7.59 (m, 3 H) 7.67 (d, J 2.23 Hz, 1 H) 7.68 - 7.73 (m, 2 H).
*Prepared in
two steps starting from 2-pyrrolidin-1-yl-ethylamine: i) Pd-catalysed
amination of 7-iodo-
5-nitro-benzofuran according to the procedure of Intermediate 31 to provide (5-
nitro-
benzofuran-7-yl)-(2-pyrrolidin-1-yl-ethyl)-amine and ii) reduction of the
nitro group of (5-
nitro-benzofuran-7-yl)-(2-pyrrolidin-1-yl-ethyl)-amine to provide N'-(2-
pyrrolidin-1-
ylethyl)-1-benzofuran-5,7-diamine according to the procedure of Example 48
(Step 1).
EXAMPLE 59
2-Methoxy-5-methyl N {7-[(2-pyrrolidin-1-ylethyl)amino]-1-benzofuran-5-
yl~benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure described for
Example 58.
Yield: 18%, HPLC purity = 98%, m/z = 430 (M+H)+, 1H NMR (500 MHz, DMSO-d6) 8
ppm1.81-1.92(m,2H) 1.96-2.08(m,2H)2.18-2.22(m,3H)3.00-3.12(m,2H)
3.31-3.37(m,2H)3.39-3.45(m,2H)3.55-3.63(m,2H)3.87-3.90(m,3H)6.34-
6.37 (m, 1 H) 6.59 - 6.63 (m, 1 H) 6.77 (d, J 2.20 Hz, 1 H) 7.03 - 7.07 (m, 1
H) 7.32 (m, 1
H) 7.48 - 7.50 (m, 1 H) 7.83 (d, J--1.88 Hz, 1 H).
EXAMPLE 60
N f 7-[(2-Pyrrolidin-1-ylethyl)amino]-1-benzofuran-5-yl}-2-
(trifluoromethyl)benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure described for
Example 58.
Yield: 31%, HPLC purity = 99%, m/z = 454 (M+H)+, 1H NMR (270 MHz, methanol-d4)
8
ppml.92-2.26(m,4H)3.07-3.22(m,2H)3.39-3.48(m,2H)3.56-3.64(m,2H)
3.61 - 3.75 (m, 2 H) 6.49 (d, J--1.98 Hz, 1 H) 6.63 (d, J 1.98 Hz, 1 H) 6.66
(d, J--2.23 Hz,
1 H) 7.60 - 7.76 (m, 3 H) 7.88 - 7.95 (m, 1 H) 7.99 - 8.05 (m, 1 H).
EXAMPLE 61
3-Chloro-4-methyl-N {7-[(2-pyrrolidin-1-ylethyl)amino]-1-benzofuran-5-
yl~benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure described for
Example 58.
Yield: 32%, HPLC purity = 99%, m/z = 433 (M+H)+, 1H NMR (270 MHz, methanol-d4)
8
ppml.93-2.25(m,4H)2.35-2.40(m,3H)3.11-3.24(m,2H)3.42-3.50(m,2H)
3.61-3.68(m,2H)3.65-3.76(m,2H)6.47-6.50(m,lH)6.56-6.60(m,lH)6.67(d,
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J 2.23 Hz, 1 H) 7.35 - 7.40 (m, 1 H) 7.48 - 7.54 (m, 1 H) 7.67 (d, J 1.98 Hz,
1 H) 7.68 (d,
J 1.98 Hz, 1 H).
EXAMPLE 62
2-Methoxy-5-methyl-N ~7-[(3-morpholin-4-ylpropyl)amino]-1-benzofuran-5-
yl}benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure described for
Example 58
using N~-(3-morpholin-4-yl-propyl)-benzofuran-5,7-diamine.* Yield: 5%, HPLC
purity =
98%, m/z = 460 (M+H)+, 1H NMR (270 MHz, methanol-d4) 8 ppm 1.99 - 2.15 (m, 2
H)
2.18-2.27(m,3H)3.17-3.40(m,6H)3.61-4.OS(m,6H)3.94-3.98(m,3H)6.46(d,
J--1.73 Hz, 1 H) 6.53 - 6.57 (m, 1 H) 6.61 (d, J--2.23 Hz, 1 H) 6.99 - 7.06
(m, 1 H) 7.27 -
7.34 (m, 1 H) 7.47 - 7.52 (m, 1 H) 7.60 (d, J--2.23 Hz, 1 H). * Prepared in
two steps
starting from 3-morpholin-4-yl-propylamine: i) Pd-catalysed amination of 7-
iodo-5-nitro-
benzofuran according to the procedure of Intermediate 31 to provide (3-
morpholin-4-yl-
propyl)-(5-nitro-benzofuran-7-yl)-amine and ii) reduction of the nitro group
of (3-
morpholin-4-yl-propyl)-(5-nitro-benzofuran-7-yl)-amine to provide N~-(3-
morpholin-4-yl-
propyl)-benzofuran-5,7-diamine according to the procedure of Example 48 (Step
1).
EXAMPLE 63
N ~7-[(3-Morpholin-4-ylpropyl)amino]-1-benzofuran-5-yl~-2-
(trifluoromethyl)benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure described for
Example 58
using N'-(3-morpholin-4-yl-propyl)-benzofuran-5,7-diamine. Yield: 13%, HPLC
purity =
99%, m/z = 484 (M+H)~, IH NMR (270 MHz, methanol-d4) 8 ppm 1.99 - 2.15 (m, 2
H)
3.03-3.38(m,6H)3.38-3.57(m,2H)3.62-3.85(m,2H)3.89-4.14(m,2H)6.44(d,
J--1.98 Hz, 1 H) 6.53 (d, J--1.98 Hz, 1 H) 6.62 (d, J--2.23 Hz, 1 H) 7.60 -
7.75 (m, 3 H)
7.89 - 7.94 (m, 1 H) 7.99 - 8.05 (m, 1 H).
EXAMPLE 64
3-Chloro-4-methyl-N f 7-[(3-morpholin-4-ylpropyl)amino]-1-benzofuran-5-
yl~benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure described for
Example 58
using N'-(3-morpholin-4-yl-propyl)-benzofuran-5,7-diamine. Yield: 15%, HPLC
purity =
113
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99%, m/z = 464 (M+H)+, 1H NMR (270 MHz, methanol-d4) 8 ppm 2.04 - 2.18 (m, 2
H)
2.35-2.40(m,3H)3.06-3.24(m,2H)3.27-3.41 (m,4H)3.44-3.57(m,2H)3.65-
3.81 (m,2H)3.98-4.13(m,2H)6.43-6.49(m,2H)6.63(d,.I--1.98 Hz, 1H)7.34-7.40
(m, 1 H) 7.47 - 7.52 (m, 1 H) 7.65 (d, J 1.98 Hz, 1 H) 7.66 (d, J--1.98 Hz, 1
H).
INTERMEDIATE 37
~ [(2R)-1-Ethylpyrrolidin-2-yl] methyl} (5-nitro-1-benzofuran-7-yl)amine
The title compound was prepared according to the procedure described for
Intermediate 27
using (R)-2-aminomethyl-1-ethylpyrrolidine. Yield: 100%, HPLC purity = 90%,
m/z = 290
(M+H)+.
INTERMEDIATE 3 8
N'-f [(2R)-1-Ethylpyrrolidin-2-yl]methyl}-1-benzofuran-5,7-diamine
The title compound was prepared according to the procedure described for
Intermediate 28
using {[(2R)-1-ethylpyrrolidin-2-yl]methyl}(5-nitro-1-benzofuran-7-yl)amine
(Intermediate 37). The obtained product was used directly in the subsequent
reaction.
EXAMPLE 65
N [7-(~[(2R)-1-Ethylpyrrolidin-2-yl]methyl}amino)-1-benzofuran-5-
yl]benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure of Example 41 using
N~-
f [(2R)-1-ethylpyrrolidin-2-yl]methyl}-1-benzofuran-5,7-diamine. Yield: 7 mg
(8%),
HPLC purity = 95%, m/z = 400 (M+H)+, 1H NMR (270 MHz, methanol-d4) 8 ppm 1.29
(t,
J--7.30Hz,3H) 1.83-2.39(m,4H)3.05-3.28(m,2H)3.37-3.54 (m, 1 H)3.54-3.61
(m, J 6.06, 3.34 Hz, 2 H) 3.63 - 3.77 (m, 2 H) 6.47 (d, J--1.73 Hz, 1 H) 6.57
(d, J--1.98
Hz, 1 H) 6.65 (d, J 2.23 Hz, 1 H) 7.39 - 7.59 (m, 3 H) 7.65 - 7.73 (m, 3 H).
EXAMPLE 66
N [7-({[(2R)-1-Ethylpyrrolidin-2-yl]methyl}amino)-1-benzofuran-5-yl]-2-methoxy-
5-
methylbenzenesulfonamide hydrochloride '
The title compound was prepared according to the procedure of Example 41 using
N~-
f [(2R)-1-ethylpyrrolidin-2-yl]methyl}-1-benzofuran-5,7-diamine. Yield: 16 mg
(17%),
HPLC purity = 97%, m/z = 444 (M+H)+, 1H NMR (270 MHz, methanol-d4) 8 ppm 1.27
(t,
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J 7.18Hz,3H) 1.85-2.20(m,2H)2.19-2.23 (s,3H)2.24-2.42 (m, 1H)3.01-3.28
(m, 3 H) 3.38 - 3.53 (m, 1 H) 3.54 - 3.60 (m, 2 H) 3.63 - 3.81 (m, 2 H) 3.94 -
3.98 (s, 3 H)
6.53 (d, J--1.73 Hz, 1 H) 6.64 (dd, J--3.84, 1.86 Hz, 2 H) 7.00 - 7.06 (m, 1
H) 7.28 - 7.35
(m, 1 H) 7.45 - 7.51 (m, 1 H) 7.64 (d, J--1.98 Hz, 1 H).
EXAMPLE 67
N [7-({[(2R)-1-Ethylpyrrolidin-2-yl]methyl]amino)-1-benzofuran-5-yl]-2-
(trifluoromethyl)benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure of Example 41 using
N~-
{[(2R)-1-ethylpyrrolidin-2-yl]methyl}-1-benzofuran-5,7-diamine. Yield: 21 mg
(21%),
HPLC purity = 99%, m/z = 468 (M+H)~, 1H NMR (270 MHz, methanol-d4) 8 ppm 1.29
(t,
J--7.30Hz,3H) 1.82-2.39(m,4H)3.05-3.28(m,2H)3.40-3.53 (m, 1H)3.53-3.61
(m, 2 H) 3.63 - 3.78 (m, 2 H) 6.50 (d, J--1.98 Hz, 1 H) 6.66 (dd, J 5.57, 2.10
Hz, 2 H) 7.58
- 7.77 (m, 3 H) 7.88 - 7.95 (m, 1 H) 7.97 - 8.05 (m, 1 H).
EXAMPLE 68
N [7-({[(2R)-1-Ethylpyrrolidin-2-yl]methyl}amino)-1-benzofuran-5-yl]-3-
methylbenzenesulfonamide hydrochloride
The title compound was prepared according to the procedure of Example 41 using
N~-
{[(2R)-1-ethylpyrrolidin-2-yl]methyl}-1-benzofuran-5,7-diamine. Yield: 15 mg
(16%),
HPLC purity = 96%, m/z = 414 (M+H)+, IH NMR (270 MHz, methanol-d4) 8 ppm 1.29
(t,
J 7.30 Hz,3H)1.81-2.38(m,4H)2.30-2.34(s,3H)3.02-3.27(m,2H)3.39-3.54
(m, 1 H) 3.54 - 3.61 (m, 2 H) 3.64 - 3.79 (m, 2 H) 6.47 (d, J--1.98 Hz, 1 H)
6.57 (d, J--1.73
Hz, 1 H) 6.66 (d, J 2.23 Hz, 1 H) 7.26 - 7.41 (m, 2 H) 7.44 - 7.55 (m, 2 H)
7.67 (d, J--1.98
Hz, 3 H).
EXAMPLE 69
N [7-({[(2R)-1-Ethylpyrrolidin-2-yl]methyl}amino)-1-benzofuran-5-yl]thiophene-
2-
sulfonamide hydrochloride
The title compound was prepared according to the procedure of Example 41 using
N~-
{[(2R)-1-ethylpyrrolidin-2-yl]methyl}-1-benzofuran-5,7-diamine. Yield: 17 mg
(19%),
HPLC purity = 99%, m/z = 406 (M+H)+, 1H NMR (270 MHz, methanol-d4) 8 ppm 1.30
(t,
J--7.30Hz,3H) 1.82-2.42(m,4H)3.02-3.28(m,2H)3.39-3.57 (m, 1H)3.57-3.64
lls
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(m, 2 H) 3.64 - 3.82 (m, 2 H) 6.49 - 6.54 (m, J--1.98 Hz, 1 H) 6.64 (d, J--
1.98 Hz, 1 H)
6.69 (d, J--1.98 Hz, 1 H) 7.04 (dd, J--4.95, 3.71 Hz, 1 H) 7.43 (dd, J--3.71,
1.24 Hz, 1 H)
7.63 - 7.72 (m, 2 H).
EXAMPLE 70
5-Chloro-N [7-(~[(2R)-1-ethylpyrrolidin-2-yl]methyl]amino)-1-benzofuran-5-
yl]thiophene-2-sulfonamide hydrochloride
The title compound was prepared according to the procedure of Example 41 using
N~-
{[(2R)-1-ethylpyrrolidin-2-yl]methyl]-1-benzofuran-5,7-diamine. Yield: 5 mg
(5%),
HPLC purity = 99%, m/z = 440 (M+H)+, 1H NMR (270 MHz, methanol-d4) 8 ppm 1.32
(t,
J--7.30 Hz, 3 H) 1.84 - 2.42 (m, 4 H) 3.06 - 3.28 (m, 2 H) 3.44 - 3.58 (m, 1
H) 3.59 - 3.65
(m, 2 H) 3.65 - 3.82 (m, 2 H) 6.52 (d, J--1.73 Hz, 1 H) 6.68 (d, J 1.98 Hz, 1
H) 6.73 (d,
J--2.23 Hz, 1 H) 6.95 - 6.99 (m, 1 H) 7.22 - 7.26 (m, 1 H) 7.72 (d, J--2.23
Hz, 1 H).
EXAMPLE 71
5-Chloro-N [7-(~[(2R)-1-ethylpyrrolidin-2-yl]methyl}amino)-1-benzofuran-5-yl]-
1,3-
dimethyl-1H-pyrazole-4-sulfonamide hydrochloride
The title compound was prepared according to the procedure of Example 41 using
N~-
f [(2R)-1-ethylpyrrolidin-2-yl]methyl]-1-benzofuran-5,7-diamine. Yield: 12 mg
(12%),
HPLC purity = 98%, m/z = 452 (M+H)+, IH NMR (270 MHz, methanol-d4) 8 ppm 1.33
(t,
J--7.30 Hz, 3 H) 1.87 - 2.41 (m, 4 H) 2.17 - 2.20 (m, 3 H) 3.07 - 3.28 (m, 2
H) 3.44 - 3.65
(m, 3 H) 3.66 - 3.82 (m, 2 H) 3.70 - 3.73 (m, 3 H) 6.53 (d, J 1.98 Hz, 1 H)
6.64 (d, J--1.98
Hz, 1 H) 6.70 (d, J--1.98 Hz, 1 H) 7.70 (d, J 2.23 Hz, 1 H).
EXAMPLE 72
N (7-~[3-(2-Methylpiperidin-1-yl)propyl]amino-1-benzofuran-5-
yl)benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure described for
Example 58
using N'-[3-(2-methyl-piperidin-1-yl)-propyl]-benzofuran-5,7-diamine.* Yield:
9%, HPLC
purity = 97%, m/z = 428 (M+H)+, 1H NMR (270 MHz, methanol-d4) 8 ppm 1.29 (d,
J--6.43 Hz, 0.3 H, rotamers) 1.32 (d, J--6.43 Hz, 3 H) 1.45 - 2.17 (m, 8 H)
2.91 - 3.07 (m, 1
H)3.13-3.27(m,3H)3.35(t,J--6.43Hz,2H)3.39-3.56 (m, 1H)6.43-6.49(m,2H)
6.61 (d, J 2.23 Hz, 1 H) 7.40 - 7.58 (m, 3 H) 7.63 (d, J 1.98 Hz, 1 H) 7.68 -
7.74 (m, 2
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H). *Prepared in two steps starting from 3-(2-methyl-piperidin-1-yl)-
propylamine: i) Pd-
catalysed amination of 7-iodo-5-nitro-benzofuran according to the procedure of
Intermediate 31 to provide [3-(2-methyl-piperidin-1-yl)-propyl]-(5-nitro-
benzofuran-7-yl)-
amine, and ii) reduction of the nitro group of (3-morpholin-4-yl-propyl)-(5-
nitro-
benzofuran-7-yl)-amine to provide N~-[3-(2-methyl-piperidin-1-yl)-propyl]-
benzofuran-
5,7-diamine according to the procedure of Example 48 (Step 1).
EXAMPLE 73
2-Methoxy-5-methyl-N (7-{[3-(2-methylpiperidin-1-yl)propyl]amino-1-benzofuran-
5-yl)benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure described for
Example 58
using N'-[3-(2-methyl-piperidin-1-yl)-propyl]-benzofuran-5,7-diamine. Yield:
7%, HPLC
purity = 98%, m/z = 472 (M+H)+, 1H NMR (270 MHz, methanol-d4) 8 ppm 1.29 (d,
J--6.43 Hz, 0.3 H, rotamers) 1.31 (d, J 6.43 Hz; 3 H) 1.48 - 2.16 (m, 8 H)
2.18 - 2.22 (m, 3
H)2.88-3.OS(m,lH)3.11-3.27(m,3H)3.31-3.39(m,2H)3.38-3.55(m,lH)3.94
- 3.98 (m, 3 H) 6.46 - 6.49 (m, 1 H) 6.58 (d, J--1.98 Hz, 1 H) 6.61 (d, J--
1.98 Hz, 1 H) 6.99
- 7.05 (m, 1 H) 7.27 - 7.34 (m, 1 H) 7.48 - 7.52 (m, 1 H) 7.60 (d, J--1.98 Hz,
1 H).
EXAMPLE 74
N (7-{[3-(2-Methylpiperidin-1-yl)propyl]amino-1-benzofuran-5-yl)-2-
(trifluoromethyl)benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure described for
Example 58
using N'-[3-(2-methyl-piperidin-1-yl)-propyl]-benzofuran-5,7-diamine. Yield:
1%, HPLC
purity = 97%, m/z = 496 (M+H)+, 1H NMR (270 MHz, methanol-d4) 8 ppm 1.29 (d,
J--6.43 Hz, 0.3 H, rotamers) 1.33 (d, J--6.43 Hz, 3 H) 1.45 - 2.20 (m, 8 H)
2.94 - 3.08 (m, 1
H)3.12-3.28(m,3H)3.32-3.39(m,2H)3.44-3.59(m,lH)6.46-6.49 (m,lH)6.53
(d, J--1.98 Hz, 1 H) 6.63 (d, J--2.23 Hz, 1 H) 7.60 - 7.76 (m, 3 H) 7.88 -
7.94 (m, 1 H) 7.99
- 8.06 (m, 1 H).
EXAMPLE 75
5-Chloro-1,3-dimethyl N (7-~[3-(2-methylpiperidin-1-yl)propyl]amino}-1-
benzofuran-
5-yl)-1H pyrazole-4-sulfonamide hydrochloride
The title compound was prepared according to the procedure described for
Example 58
using N'-[3-(2-methyl-piperidin-1-yl)-propyl]-benzofuran-5,7-diamine. Yield:
10%, HPLC
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purity = 97%, m/z = 480 (M+H)+, 'H NMR (270 MHz, methanol-d4) 8 ppm 1.30 (d,
J--6.43 Hz, 0.4 H, rotamers) 1.35 (d, J--6.43 Hz, 3 H) 1.50 - 2.16 (m, 8 H)
2.17 - 2.21 (m, 3
H) 2.93 - 3.08 (m, 1 H) 3.15 - 3.27 (m, 3 H) 3.38 (t, J--6.43 Hz, 2 H) 3.41 -
3.58 (m, 1 H)
3.70 - 3.73 (m, 3 H) 6.46 - 6.49 (m, 1 H) 6.56 (d, J--1.73 Hz, 1 H) 6.66 (d, J-
-1.98 Hz, 1 H)
7.66 (d, J--1.98 Hz, 1 H).
INTERMEDIATE 39
5-(5-Nitro-benzofuran-7-yl)-pyridin-2-ylamine
7-Iodo-5-nitrobenzofuran (289 mg, 1.0 mmol), pinacolborane (192 mg, 1.5 mmol)
and
PdCl2(dppf)~DCM were added to a test tube together with dioxane (4 mL).
Triethylamine
(304 mg, 3.0 mmol) was added carefully to the solution, and the mixture was
heated in a
StemBlock at 70 °C overnight to form 5-nitro-7-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-
yl)-1-benzofuran in situ. Then 2-amino-5-iodopyridine (220 mg, 1.0 mmol) and
aqeous
barium hydroxide (1 mL; 2 M) were added. The resulting mixture was stirred at
70 °C
overnight and then filtered through Celite and evaporated. The residue was
extracted with
chloroform/water and evaporated to give the title product. Yield: 82%, HPLC
purity =
82%, m/z = 256 (M+H)~.
INTERMEDIATE 40
5-(5-Amino-1-benzofuran-7-yl)pyridin-2-amine
The title compound was prepared from 5-(5-nitro-benzofuran-7-yl)-pyridin-2-
ylamine
(Intermediate 39) according to the procedure of Intermediate 28. The product
was used
directly in the subsequent reaction.
EXAMPLE 76
N [7-(6-Aminopyridin-3-yl)-1-benzofuran-5-yl]-2-methoxy-5-
methylbenzenesulfonamide
The title compound was prepared from 5-(5-amino-1-benzofuran-7-yl)pyridin-2-
amine
(Intermediate 40) according to the procedure of Example 41, except the
purification step
where flash chromatography (eluent: 30% EtOAc in hexane) was employed. Yield:
7%,
HPLC purity = 93%, m/z = 410 (M+H)+, 1H NMR (270 MHz, methanol-d4) 8 ppm 2.20
(s,
3 H) 3.96 (s, 3 H) 6.84 (d, J--2.23 Hz, 1 H) 6.99 - 7.05 (m, J--8.41 Hz, 1 H)
7.10 - 7.17 (m,
J--9.90 Hz, 1 H) 7.27 - 7.36 (m, 3 H) 7.51 - 7.55 (m, 1 H) 7.82 (d, J--2.23
Hz, 1 H) 8.27 -
8.34 (m, 2 H).
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INTERMEDIATE 41
2-Methoxy-5-methyl-N-(7-piperazin-1-yl-1-benzofuran-5-yl)benzenesulfonamide
teat-Butyl 4-(5- { [(2-methoxy-5-methylphenyl) sulfonyl] amino } -1-b
enzofuran-7-
yl)piperazine-1-carboxylate* (1.5 g, 2.99 mmol) was reacted according to the
procedure of
Intermediate 20 and the product was used in the next step without further
purification.
Yield: 1.2 g (100%). HPLC purity 99%, RT=1.60 min (System A; 10-97% MeCN over
3
min). *Prepared from tent-butyl 4-(5-amino-1-benzofuran-7-yl)piperazine-1-
carboxylate
(Intermediate 10) according to the procedure of Intermediate 19.
EXAMPLE 77
N-{7-[4-(Cyclopropylmethyl)piperazin-1-yl]-1-benzofuran-5-yl}-2-methoxy-5-
methylbenzenesulfonamide hydrochloride
Cyclopropanecarbaldehyde (0.087 g, 1.25 mmol) was added to a solution of 2-
methoxy-5-
methyl-N-(7-piperazin-1-yl-1-benzofuran-5-yl)benzenesulfonamide (0.1 g, 0.25
mmol;
Intermediate 41) in methanol. After being stirred at room temperature for 5
min, sodium
cyanoborohydride (0.156 g, 2.5 mmol) was added and the resulting mixture was
stirred at
room temperature for 5 days. Precipitation from the reaction mixture was
collected by
filtration giving the free base of the title compound (0.063 g; 55%). The free
base was
dissolved in MeOH and treated with HCl/ether 1 M to give the title compound.
Yield:
0.029 g (43%). HPLC 100%, RT=1.82 min (System A; 10-97% MeCN over 3 min). 1H
NMR (400 MHz, DMSO-d6) 8 ppm 0.37 - 0.48 (m, 2 H) 0.59 - 0.72 (m, 2 H) 1.09 -
1.22
(m, 1 H) 2.20 (s, 3 H) 3.03 (dd, J--6.7, 5.4 Hz, 2 H) 3.12 - 3.26 (m, 4 H)
3.59 - 3.75 (m, 4
H) 3.87 (s, 3 H) 6.59 (d, J--1.8 Hz, 1 H) 6.85 (d, J--2.0 Hz, 1 H) 6.95 (d, J--
1.8 Hz, 1 H)
7.03 (d, J 8.5 Hz, 1 H) 7.32 (dd, J--8.4, 2.1 Hz, 1 H) 7.51 (d, J--2.0 Hz, 1
H) 7.89 (d, J 2.3
Hz, 1 H) 9.74 (s, 1 H). MS (ESI+) for Cz4Ha9Ns04S m/z 456.2 (M+H)+.
EXAMPLE 78
2-Methoxy-5-methyl-N-~7-[4-(3,3,3-trifluoropropyl)piperazin-1-yl]-1-benzofuran-
5-
yl}benzenesulfonamide hydrochloride
The title compound was prepared from 2-methoxy-5-methyl-N-(7-piperazin-1-yl-1-
benzofuran-S-yl)benzenesulfonamide (0.1 g, 0.25 mmol; Intermediate 41) and
3,3,3-
trifluoropropanal according to the procedure of Example 77. Precipitation from
the
reaction mixture was collected by filtration giving the free base of the title
compound
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(0.075 g; 60%). The free base was dissolved in MeOH and treated with HCl/ether
1 M to
give the title compound. Yield: 0.078 g (96%). HPLC 98%, RT=1.84 min (System
A; 10-
97% MeCN over 3 min). 1H NMR (400 MHz, DMSO-d6) 8 ppm 2.20 (s, 3 H) 2.93 -
3.10
(m,2H)3.15(s,2H)3.16-3.30(m,4H)3.36-3.50(m,2H)3.60-3.77(m,3H)3.87
(s, 3 H) 6.58 (d, J--1.8 Hz, 1 H) 6.85 (d, J--2.3 Hz, 1 H) 6.95 (d, J 1.8 Hz,
1 H) 7.03 (d,
J 8.5 Hz, 1 H) 7.25 (s, .2 H) 7.31 (dd, J--8.5, 2.3 Hz, 1 H) 7.38 (s, 2 H)
7.51 (s, 3 H) 7.89
(d, J--2.3 Hz, 1 H) 9.74 (s, 1 H). MS (ESI+) for C23H26F3N3O4S m/z 498.2
(M+H)+.
INTERMEDIATE 42
3,3-Dibromo-1,1,1-trifluoroacetone*
1,1,1-Trifluoropropanone (50.0 g, 446.2 mmol) was dissolved in concentrated
sulphuric
acid (250 g). Br2 (81.69 g, 510.1 mmol) was added dropwise, at room
temperature, during
2 h and the mixture was stirred overnight. After this time, additional Br2
(40.85 g, 255.6
mmol) was added and the mixture stirred overnight. Separated the two phases
formed
when allowed to stand and distilled the bottom layer to yield 3,3-dibromo-
1,1,1-
trifluoroacetone as a yellow oil (10.37 g, 8.6 %). 1H NMR (270 MHz, CDC13) 8
ppm 6.23
(s, 1 H). *Previously described in Rec. Trav. Chim. Pays-Bas 1995, 114, 97-
102.
INTERMEDIATE 43
3,3,3-Trifluoro-2-oxopropanal*
3,3-Dibromo-l,l,l-trifluoroacetone (10.37 g, 38.43 mmol; Intermediate 42) was
dissolved
in water (51.85 g). NaOAc (12.61 g, 153.72 mmol) was added and the resulting
mixture
was stirred at 100 °C overnight. Extracted the mixture with EtOAc (50
mL) and evaporated
the solvents from the organic phase. The residue was redissolved in EtOAc (20
mL) and
filtration yielded 3,3,3-trifluoro-2-oxopropanal (1.35 g, 24 %). *Previously
described in
Rec. Trav. Chim. Pays-Bas 1995, 114, 97-102.
INTERMEDIATE 44
1-Benzyl-3-(trifluoromethyl)piperazine*
A solution of 3,3,3-trifluoro-2-oxopropanal (0.31 g, 2.3 mmol; Intermediate
43) in DMF
(10 mL) was cooled to 0 °C and a solution of N-benzylethane-1,2-diamine
(0.37 g, 2.72
mmol) in DMF (10 mL) was added. After being stirred at room temperature
overnight, the
mixture was concentrated in vacuo. The residue was redissolved in THF (5 mL)
and citrate
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buffer (5.3 mL; 0.4 M), followed by NaBH3CN (0.31 g, 4.9 mmol), were added.
The
resulting mixture was stirred at room temperature overnight. The mixture was
made basic
(pH 8) with aqueous NaOH (8 mL; 1 M) and the aqueous layer was extracted twice
with
DCM (15 mL). The combined organic layers were dried (Na2S04) and concentated.
The
residue was purified by LC-MS prep to give 1-benzyl-3-
(trifluoromethyl)piperazine (66
mg, 12 %). HPLC 94 %, RT=1.25 min (System A; 10-97 % MeCN over 3 min). 1H NMR
(270 MHz, CDCl3) 8 ppm 2.77 (s, 2 H) 3.17 - 3.31 (m, 1 H) 3.32 - 3.64 (m, 3 H)
3.83 -
4.02 (m, 1 H) 4.13 - 4.31 (m, 2 H) 6.68 (s, 1 H) 7.30 - 7.55 (m, 5 H). MS
(ESI+) mlz 245.
*Previously described in Rec. Trav. Chim. Pays-Bas 1995, 114, 97-102.
INTERMEDIATE 45
2-(Trifluoromethyl)piperazine*
1-Benzyl-3-(trifluoromethyl)piperazine (0.74 g, 3.0 mmol; Intermediate 44) was
dissolved
in acetic acid (70 mL) and water (5 mL). Pd, 5 % on carbon, (0.074 g) was
added and
hydrogenatation was performed at 3 bar and 70 °C overnight. The
reaction mixture was
filtered through Celite and the pad was rinsed with water (5 mL). Solvents
were removed
in vacuo, toluene (20 mL) added to the residue, followed by re-concentration
in vacuo to
remove residual water. The desired product sublimated on the evaporator and
0.15 g (32
%) was collected as a white powder. 1H NMR (270 MHz, methanol-d4) 8 ppm 2.67 -
2.87
(m, 3 H) 2.91 - 3.05 (m, 2 H) 3.12 - 3.21 (m, 1 H). MS (ESI+) m/z 155.
*Previously
described in Rec. Trav. Chim. Pays-Bas 1995, 114, 97-102.
INTERMEDIATE 46
1-(5-Nitro-1-benzofuran-7-yl)-3-(trifluoromethyl)piperazine
To 7-iodo-5-nitro-1-benzofuran (231.4 mg, 0.08 mmol) the following was added:
Xantphos (92.6 mg, 0.16 mmol), Pd2dba3 (36.6 mg, 0.04 mmol), sodium tert-
butoxide
(215.4 mg, 2.24 mmol), 2-(trifluoromethyl)piperazine (148.1 mg, 0.96 mmol;
Intermediate
45) and xylene (23 mL). The resulting mixture was stirred at 100 °C for
3 days. Filtration
through Celite and purification by flash chromatography, using EtOAc:heptane
(1:1) as
eluent, furnished 1-(5-nitro-1-benzofuran-7-yl)-3-(trifluoromethyl)piperazine
(112 mg, 44
yield). HPLC 90 %, RT=1.648 min (System A; 10-97 % MeCN over 3 min), MS
(ESI+) m/z 316 (M+H)+.
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INTERMEDIATE 47
7-[3-(Trifluoromethyl)piperazin-1-yl]-1-benzofuran-5-amine
1-(5-Nitro-1-benzofuran-7-yl)-3-(trifluoromethyl)piperazine (96.6 mg, 0.31
mmol;
Intermediate 46) was dissolved in THF (6 mL) and EtOH (25 mL). Raney nickel
(slurry in
ethanol; 1 mL) and H2NNH2 (61.4 mg, 1.23 mmol) were added and the mixture was
stirred
at room temperature overnight. Filtration through Celite and concentration
gave 7-[3-
(trifluoromethyl)piperazin-1-yl]-1-benzofuran-5-amine (55 mg, 63 %). This
material was
used in the next reaction step without further purification.
EXAMPLE 79
2-Methoxy-5-methyl-N-~7-[3-(trifluoromethyl)piperazin-1-yl]-1-benzofuran-5-
yl}benzenesulfonamide hydrochloride
A mixture of 7-[3-(trifluoromethyl)piperazin-1-yl]-1-benzofuran-5-amine (59
mg, 0.19
mmol; Intermediate 47), pyridine (155 ~L, 1.93 mmol) and 6-metoxy-m-toluene-
sulfonyl
chloride (42.6 mg, 0.19 mmol) in DCM (2 mL) was stirred at room temperature
overnight.
Volatiles were removed in vacuo. The residue was redissolved in MeOH (1.5 mL)
and the
solution was filtered. Addition of MeOH (100 p.L), HCl in ether (500 p,L) and
ether (500
~,L), followed by removal of solvents in vacuo furnished 2-methoxy-5-methyl-N-
f 7-[3-
(trifluoromethyl)piperazin-1-yl]-1-benzofuran-5-yl}benzenesulfonamide
hydrochloride as
a brown oil (44.1 mg, 47 %). HPLC 100 %, RT= 1.861 min (System A; 10-97 % MeCN
over 3 min). 1H NMR (270 MHz, methanol-d4) ~ ppm 2.23 (s, 3 H) 2.28 (s, 1 H)
2.98 -
3.24 (m, 1 H) 3.46 - 3.71 (m, 2 H) 3.85 (s, 1 H) 3.96 (s, 3 H) 4.09 - 4.19 (m,
1 H) 4.56 -
4.70 (m, 1 H) 6.75 (d, J--1.98 Hz, 2 H) 6.98 (d, J--1.73 Hz, 1 H) 7.02 (s, 1
H) 7.05 (s, 1 H)
7.33 (dd, J--8.04, 2.60 Hz, 1 H) 7.52 (d, J 1.73 Hz, 1 H) 7.73 (d, J 2.23 Hz,
1 H) 8.10 -
8.19 (m, 1 H) 8.64 - 8.74 (m, 1 H) 8.90 (d, J--5.20 Hz, 1 H). MS (ESI+) m/z
470 (M+H)+.
INTERMEDIATE 48
teat-Butyl [1-(5-nitro-1-benzofuran-7-yl)piperidin-4-yl]carbamate
Xylene (200 mL) was added to 7-iodo-5-nitro-1-benzofuran (2.78 g, 9.61 mmol),
tent-butyl
piperidin-4-ylcarbamate (2.31 g, 12.0 mmol), Pd2(dba)3 (0.22 g, 0.24 mmol),
Xantphos
(0.56 g, 0.96 mmol) and sodium teat-butoxide (1.29 g, 13.0 mmol). The mixture
was
heated at 120 °C with stirring for 16 h. The reaction mixture was
allowed to reach room
termperature, filtered through a pad of Celite, and concentrated in vacuo. The
crude
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product was purified by flash chromatography, using DCM as eluent, to afford
1.03 g
(84%) of the title product. HPLC 94%, RT: 2.770 (System B; 10-97% MeCN over
3min).
1H NMR (270 MHz, methanol-d4) 8 ppm 1.45 (s, 9 H) 1.62 - 1.72 (m, 2 H) 1.75 -
2.03 (m,
2 H) 2.94 - 3.02 (m, 2 H) 3.55 - 3.57 (m, 1 H) 3.88 - 3.93 (m, 2 H) 7.01 (d, J-
-2.23 Hz, 1
H) 7.64 (d, J--2.23 Hz, 1 H) 7.93 (d, J--2.23 Hz, 1 H) 8.13 (d, J--2.23 Hz, 1
H). LC-MS 362
(M+H)+.
INTERMEDIATE 49
tent-Butyl [1-(5-amino-1-benzofuran-7-yl)piperidin-4-yl]carbamate
Hydrazine (1.038 mL, 28 mmol) and raney-nickel (slurry in ethanol; 10 mL) were
added to
tent-butyl [1-(5-nitro-1-benzofuran-7-yl)piperidine-4-yl]carbamate (1.03 g,
2.85 mmol;
Intermediate 48) in a mixture of THF (50 mL) and ethanol (150 mL). The mixture
was
stirred at room temperature for 16 h, filtered through a pad of Celite and
concentrated in
vacuo to afford 1.02 g (quantitative) of the title product. HPLC 95%, RT:
1.746 (System A;
10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) ~ ppm 1.45 (s, 9 H)
1.65 -
1.69(m,2H) 1.72-1.96(m,2H)2.76-2.85 (m,2H)3.50-3.54 (m, 1 H)3.76(d,
J 12.62 Hz, 2 H) 6.33 (d, J--1.98 Hz, 1 H) 6.54 (d, J 1.98 Hz, 1 H) 6.60 (d, J-
-2.23 Hz, 1
H) 7.59 (d, J--1.98 Hz, 1 H). LC-MS 332 (M+H)+.
EXAMPLE 80
N-[7-(Aminopiperidin-1-yl)-1-benzofuran-5-yl]-2-(trifluoromethyl)-
benzenesulfonamide hydrochloride
2-(Trifluoromethyl)benzenesulfonyl chloride (89.0 mg, 0.36 mmol) and pyridine
(219 mL)
were added to test-butyl [1-(5-amino-1-benzofuran-7-yl)piperidin-4-
yl]carbamate (100.0
mg, 0.30 mmol; Intermediate 49) in DCM (1 mL). The mixture was shaken at room
temperature for 1 h, solvent removed in vacuo and the residue was purified by
preparative
HPLC using acetonitrile-water gradients containing 0.1 % trifluoroacetic acid.
N-
deprotection and conversion into the hydrochloride salt was performed by
treatment with 2
M HCl in ether. This furnished 76.1 mg (57%) of the title product. HPLC 100%,
RT: 1.834
(System A; 10-97% MeCN over 3 min). 1H NMR (500 MHz, DMSO-d6) 8 ppm 1.70 -
1.72
(m, 2 H) 2.00-2.02 (m, 2 H) 2.78 (t, J 11.30 Hz, 2 H) 3.21 (s, 1 H) 3.71 (d, J-
-12.56 Hz, 2
H) 6.60 (d, J--1.88 Hz, 1 H) 6.83 (d, J 2.20 Hz, 1 H) 6.85 - 6.91 (m, J--1.88
Hz, 1 H) 7.80
- 7.81 (m, 2 H) 7.88 - 7.89 (m, 1 H) 7.96 - 7.98 (m, 1 H) 8.08 - 8.10 (m, 4 H)
10.40 (s, 1
H). LC-MS 440 (M+H)+.
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EXAMPLE 81
N-[7-(Aminopiperidin-1-yl)-1-benzofuran-5-yl]-benzenesulfonamide hydrochloride
Benzenesulfonyl chloride (64.0 mg, 0.36 mmol) and pyridine (219 ~L) were added
to tert-
butyl [1-(5-amino-1-benzofuran-7-yl)piperidin-4-yl]carbamate (100.0 mg, 0.30
mmol;
Intermediate 49) in DCM (1 mL). The mixture was shaken at room temperature for
1 h,
solvent was removed in vacuo and the residue was purified by preparative HPLC
using
acetonitrile-water gradients containing 0.1 % trifluoroacetic acid. N-
deprotection and
conversion into the hydrochloride salt was performed by treatment with 2 M HCl
in ether.
This furnished 31.3 mg (28%) of the title product. HPLC 100%, RT: 1.612
(System A; 10-
97% MeCN over 3 min). 1H NMR (500 MHz, DMSO-d6) 8 ppm 1.69 - 1.70 (m, 2 H)
2.00
- 2.01 (m, 2 H) 2.76 (t, J--11.30 Hz, 2 H) 3.18 - 3.26 (m, 1 H) 6.54 (d, ~J--
1.88 Hz, 1 H)
6.82 (d, J--2.20 Hz, 1 H) 6.86 (d, J--1.88 Hz, 1 H) 7.52 (t, J--7.54 Hz, 2 H)
7.57 - 7.68 (m,
1 H) 7.71 - 7.72 (m, 2 H) 7.88 (d, J 2.20 Hz, 1 H) 8.14 (s, 3 H) 10.03 (s, 1
H). LC-MS 372
(M+H)+.
EXAMPLE 82
N-[7-(Aminopiperidin-1-yl)-1-benzofuran-5-yl]-2-chlorobenzenesulfonamide
hydrochloride
2-Chlorobenzenesulfonyl chloride (76.0 mg, 0.36 mmol) and pyridine (219 mL)
were
added to test-butyl [1-(5-amino-1-benzofuran-7-yl)piperidin-4-yl]carbamate
(100.0 mg,
0.30 mmol; Intermediate 49) in DCM (1 mL). The mixture was shaken at room
temperature for 1 h, solvent was removed in vacuo and the residue was purified
by
preparative HPLC using acetonitrile-water gradients containing 0.1 %
trifluoroacetic acid.
N-deprotection and conversion into the hydrochloride salt was performed by
treatment
with 2 M HCl in ether. This furnished to 60.6 mg (50%) of the title product.
HPLC 100%,
RT: 1.702 (System A; 10-97% MeCN over 3 min). 1H NMR (500 MHz, DMSO-d6) 8 ppm
1.69 - 1.72 (m, 2 H) 2.01- 2.02 (m, 2 H) 2.76 (t, J--11.62 Hz, 2 H) 3.21 (s, 1
H) 3.68 (d,
J--12.56 Hz, 2 H) 6.58 (s, 1 H) 6.82 (d, J--2.20 Hz, 1 H) 6.88 (s, 1 H) 7.47
(t, J--7.54 Hz, 1
H) 7.62 - 7.63 (m, 2 H) 7.87 (d, J 1.88 Hz, 1 H) 7.99 (d, J--7.54 Hz, 1 H)
8.23 (s, 3 H)
10.33 (s, 1 H). LC-MS 406 (M+H)+.
EXAMPLE 83
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N-[7-(Aminopiperidin-1-yl)-1-benzofuran-5-yl]-2-methoxy-5-
methylbenzenesulfonamide hydrochloride
2-Methoxy-5-methylbenzenesulfonyl chloride (80.0 mg, 0.36 mmol) and pyridine
(219
mL) were added to tent-butyl [1-(5-amino-1-benzofuran-7-yl)piperidin-4-
yl]carbamate
(100.0 mg, 0.30 mmol; Intermediate 49) in DCM (1 mL). The mixture was shaken
at room
temperature for 1 h, solvent was removed in vacuo and the residue was purified
by
preparative HPLC using acetonitrile-water gradients containing 0.1%
trifluoroacetic acid.
N-deprotection and conversion into the hydrochloride salt was performed by
treatment
with 2 M HCl in ether. This furnished 59.0 mg (47%) of the title product. HPLC
100%, RT:
1.731 (System A; 10-97% MeCN over 3 min). 'H NMR (500 MHz, DMSO-d6) 8 ppm 1.70
- 1.76 (m, 2 H) 2.05 (d, J--10.05 Hz, 2 H) 2.20 (s, 3 H) 2.76 (t, J--11.46 Hz,
2 H) 3.19- 3.21
(m, 1 H) 3.65 (d, J--12.56 Hz, 2 H) 3.87 (s, 3 H) 6.58 (d, J 1.88 Hz, 1 H)
6.81 (d, J 2.20
Hz, 1 H) 6.89 (d, J--1.88 Hz, 1 H) 7.04 (d, J--8.48 Hz, 1 H) 7.32 (dd, J--
8.48, 2.20 Hz, 1 H)
7.51 (d, J--2.20 Hz, 1 H) 7.86 (d, J--1.88 Hz, 1 H) 8.35 (d, J--3.45 Hz, 3 H)
9.65 (s, 1 H).
LC-MS 416 (M+H)+.
INTERMEDIATE 50
teat-Butyl cis-3-fluoro-4-[(5-nitro-1-benzofuran-7-yl)oxy]piperidine-1-
carboxylate
and
INTERMEDIATE 51
tent-Butyl tr~afzs-3-fluoro-4-[(5-nitro-1-benzofuran-7-yl)oxy]piperidine-1-
carboxylate
7-Iodo-5-nitrobenzofuran (2.0 g, 6.9 mmol), test-butyl 3-fluoro-4-
hydroxypiperidine-1-
carboxylate* (3.8 g, 17.3 mmol; mixture of cisltnayas isomers), 1,10-
phenanthroline (0.50 g,
2.8 mmol), CuI (0.26 g, 1.4 mmol) and Cs2C03 (4.5 g, 13.8 mmol) were heated in
toluene
(20 mL) at 120 °C for 72 h. The reaction mixture was filtered through
Celite and
evaporated. The resulting diastereomers were separated by flash chromatography
using
heptane/EtOAc [(4:1) -~ (2:1)] to yield 255 mg of the cis-isomer and 919 mg of
the trans-
isomer.
cis-isomer (Intermediate 50): Yield: 10%, HPLC purity = 70%, m/z = 381 (M+H)+.
tr~ans-isomer (Intermediate 51): Yield: 35%, HPLC purity = 94%, m/z = 381
(M+H)+.
*Prepared according to the procedure described in W02001085728.
INTERMEDIATE 52
tent-Butyl cis-4-[(5-amino-1-benzofuran-7-yl)oxy]-3-fluoropiperidine-1-
carboxylate
12s
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To a solution of tef°t-butyl cis-3-fluoro-4-[(5-nitro-1-benzofuran-7-
yl)oxy]piperidine-1-
carboxylate (200 mg, 0.526 mmol; Intermediate 50) dissolved in THF (10 mL) and
ethanol
(40 mL), was added Raney-nickel (as a slurry in ethanol) and hydrazine hydrate
(0.2 mL).
The mixture was stirred at room temperature for 30 min and then filtered
through Celite
and evaporated. The residue was re-dissolved in toluene and evaporated again.
This
material was used directly in the subsequent experiment.
INTERMEDIATE 53
tent-Butyl traszs-4-[(5-amino-1-benzofuran-7-yl)oxy]-3-fluoropiperidine-1-
carboxylate
The title compound was prepared from Intermediate 51 according to the
procedure of
Intermediate 52 and was used directly in the subsequent experiment.
EXAMPLE 84
N (7-{[cis-3-Fluoropiperidin-4-yl]oxy~-Z-benzofuran-5-yl)-2-methoxy-5-
methylbenzenesulfonamide hydrochloride
To a solution of tef°t-butyl cis-4-[(5-amino-1-benzofuran-7-yl)oxy]-3-
fluoropiperidine-1-
carboxylate (92 mg, 0.263 mmol; Intermediate 52) in dichloromethane (3 mL) was
added
6-methoxy-rn-toluenesulfonyl chloride (70 mg, 0.315 mmol) and triethylamine
(73 ~.1,
0.525 mmol). The mixture was shaken at room temperature for 1 h and then
evaporated.
Purified by preparative HPLC (gradient 50-85% MeCN in TFA/water). The residue
was
dissolved in methanol (0.5 mL) and HCl/ether (2 mL). After the solution had
been stirred
for 2 h, the solvent was evaporated to furnish the title compound. Yield: 25
mg (20%),
HPLC purity = 95%, m/z = 435 (M+H)+, 1H NMR (270 MHz, methanol-d4) 8 ppm 1.90 -
2.37(m,2H)2.16-2.26(m,3H)3.14-3.46(m,2H)3.48-3.74(m,2H)3.92-3.98 (m,
3 H) 4.73 - 4.88 (m, 1 H) 4.89 - 5.12 (m, 1 H) 6.72 (d, J--2.23 Hz, 0.2 H,
rotamers) 6.75 (d,
J--1.98 Hz, 1 H) 6.80 (d, J--1.98 Hz, 0.2 H, rotamers) 6.87 (d, J 1.98 Hz, 1
H) 6.95 (d,
J--1.98 Hz, 0.2 H, rotamers) 6.98 - 7.05 (m, 2 H) 7.27 - 7.35 (m, 1 H) 7.50 -
7.53 (m, 1 H)
7.72 (d, J--2.23 Hz, 1 H).
EXAMPLE 85
N (7-f [trams-3-Fluoropiperidin-4-yl]oxy}-1-benzofuran-5-yl)-2-methoxy-5-
methylbenzenesulfonamide hydrochloride
The title compound was prepared according to the same procedure as Example 84
starting
from teat-butyl trams-4-[(5-amino-1-benzofuran-7-yl)oxy]-3-fluoropiperidine-1-
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carboxylate (Intermediate 53) and 6-methoxy-m-toluenesulfonyl chloride. Yield:
8 mg
(5%), HPLC purity = 92%, m/z = 435 (M+H)+, 1H NMR (270 MHz, methanol-d4) 8 ppm
2.12-2.30(m,2H)2.21 (s,3H)3.14-3.34(m,2H)3.37-3.53 (m, 1 H)3.63-3.79 (m,
1 H) 3.95 (s, 3 H) 4.72 - 4.83 (m, 1 H) 4.95 - 5.20 (m, 1 H) 6.73 (d, J--2.23
Hz, 1 H) 6.84
(d, J--1.73 Hz, 1 H) 6.99 (d, J--1.98 Hz, 1 H) 7.00 - 7.05 (m, 1 H) 7.28 -
7.35 (m, 1 H) 7.50
(d, J--1.98 Hz, 1 H) 7.70 (d, J--1.98 Hz, 1 H).
EXAMPLE 86
N (7-{[cis-3-Fluoropiperidin-4-yl]oxy~-1-benzofuran-5-yl)-2-
(trifluoromethyl)benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure described for
Example 84
using 2-(trifluoromethyl)benzenesulfonyl chloride. Yield: 27 mg (21 %), HPLC
purity =
100%, m/z = 459 (M+H)+, 1H NMR (270 MHz, methanol-d4) 8 ppm 1.94 - 2.37 (m, 2
H)
3.14-3.49(m,3H)3.53-3.70(m,lH)4.78-5.16(m,2H)6.74(d,J--2.23Hz,0.3 H,
rotamers) 6.77 (d, J 2.23 Hz, 1 H) 6.79 (d, J--1.98 Hz, 0.3 H, rotamers) 6.87
(d, J--1.98
Hz, 1 H) 6.95 (d, J--1.98 Hz, 0.3 H, rotamers) 7.02 (d, J--1.98 Hz, 1 H) 7.61 -
7.74 (m, 3 H)
7.75 (d, J--2.23 Hz, 1 H) 7.88 - 7.95 (m, 1 H) 7.98 - 8.06 (m, 1 H).
EXAMPLE 87
N (7-~[tratZS-3-Fluoropiperidin-4-yl]oxy~-1-benzofuran-5-yl)-2-
(trifluoromethyl)benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure described for
Example 84
starting from tent-butyl traps-4-[(5-amino-1-benzofuran-7-yl)oxy]-3-
fluoropiperidine-1-
carboxylate (Intermediate 53) and 2-(trifluoromethyl)benzenesulfonyl chloride.
Yield: 49
mg (25%), HPLC purity = 100%, m/z = 459 (M+H)+, 1H NMR (270 MHz, methanol-d4)
b
ppm 2.13 - 2.31 (m, 2 H) 3.15 - 3.56 (m, 3 H) 3.64 - 3.79 (m, 1 H) 4.77 - 4.97
(m, 1 H)
5.00 - 5.24 (m, 1 H) 6.75 (d, J--1.98 Hz, 1 H) 6.81 - 6.84 (m, 1 H) 6.99 (d, J-
-1.73 Hz, 1 H)
7.60 - 7.77 (m, 3 H) 7.87 - 7.95 (m, 1 H) 7.98 - 8.05 (m, 1 H).
EXAMPLE 88
2-Chloro N (7-f [tyasas-3-fluoropiperidin-4-yl]oxy~-1-benzofuran-5-
yl)benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure described for
Example 84
starting from teat-butyl tr~ans-4-[(5-amino-1-benzofuran-7-yl)oxy]-3-
fluoropiperidine-1-
12~
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carboxylate (Intermediate 53) and 2-chlorobenzenesulfonyl chloride. Yield: 40
mg (22%),
HPLC purity = 100%, m/z = 425 (M+H)+, IH NMR (270 MHz, methanol-d4) 8 ppm 2.09
-
2.35 (m, 2 H) 3.10 - 3.57 (m, 3 H) 3.62 - 3.79 (m, 1 H) 4.73 - 4.96 (m, 1 H)
4.97 - 5.23 (m,
1 H) 6.74 (d, J 2.23 Hz, 1 H) 6.85 (d, J--1.98 Hz, 1 H) 7.05 (d, J--1.73 Hz, 1
H) 7.31 - 7.40
(m, 1 H) 7.45 - 7.58 (m, 2 H) 7.71 (d, J--2.23 Hz, 1 H) 7.96 (dd, J 7.79, 1.61
Hz, 1 H).
EXAMPLE 89
N (7-f [tracts-3-Fluoropiperidin-4-yl]oxy)-1-benzofuran-5-yl)-3-
methylbenzenesulfonamide hydrochloride
The title compound was prepared according to the procedure described for
Example 84
starting from tef°t-butyl traps-4-[(5-amino-1-benzofuran-7-yl)oxy]-3-
fluoropiperidine-1-
carboxylate (Intermediate 53) and 3-methylbenzenesulfonyl chloride. Yield: 47
mg (27%),
HPLC purity = 100%, m/z = 405 (M+H)+, 1H NMR (270 MHz, methanol-d4) ~ ppm 2.12
-
2.34(m,2H)2.28-2.34(m,3H)3.15-3.57(m,3H)3.64-3.78(m,lH)4.73-4.97 (m,
1 H) 4.98 - 5.21 (m, 1 H) 6.71 - 6.79 (m, 2 H) 7.25 - 7.57 (m, 4 H) 7.70 -
7.74 (m, 1 H).
EXAMPLE 90
3,6-Dichloro-N (7-{[tr~a~zs-3-fluoropiperidin-4-yl]oxy~-1-benzofuran-5-yl)-2-
methylbenzenesulfonamide hydrochloride
The title compound was prepared according to the procedure described for
Example 84
starting from teat-butyl trams-4-[(5-amino-1-benzofuran-7-yl)oxy]-3-
fluoropiperidine-1-
carboxylate (Intermediate 53) and 3,6-dichloro-2-W ethylbenzenesulfonyl
chloride. Yield:
39 mg (19%), HPLC purity = 98%, m/z = 473 (M+H)+, 1H NMR (270 MHz, methanol-
d4)
8ppm2.11-2.34(m,2H)2.47-2.54(m,3H)3.14-3.56(m,3H)3.63-3.79 (m, 1H)
4.76 - 4.97 (m, 1 H) 4.97 - 5.22 (m, 1 H) 6.77 (d, J 1.98 Hz, 1 H) 6.83 (d, J--
1.73 Hz, 1 H)
7.06 (d, J--1.98 Hz, 1 H) 7.26 (d, J 1.98 Hz, 1 H) 7.50 (d, J--1.98 Hz, 1 H)
7.74 (d, J--2.23
Hz, 1 H).
EXAMPLE 91
2-Chloro-5-fluoro-N (7-{[trafis-3-fluoropiperidin-4-yl]oxy)-1-benzofuran-5-
yl)benzenesulfonamide hydrochloride
The title compound was prepared according to the procedure described for
Example 84
starting from tent-butyl traps-4-[(5-amino-1-benzofuran-7-yl)oxy]-3-
fluoropiperidine-1-
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carboxylate (Intermediate 53) and 2-chloro-5-fluorobenzenesulfonyl chloride.
Yield: 34
mg (18%), HPLC purity = 100%, m/z = 443 (M+H)+, 1H NMR (270 MHz, methanol-d4)
8
ppm 2.11 - 2.36 (m, 2 H) 3.15 - 3.58 (m, 3 H) 3.63 - 3.81 (m, 1 H) 4.77 - 4.98
(m, 1 H)
5.00 - 5.24 (m, 1 H) 6.75 (d, J 2.23 Hz, 1 H) 6.85 (d, J--1.98 Hz, 1 H) 7.05
(d, J--1.98 Hz,
1 H) 7.09 - 7.20 (m, 1 H) 7.42 (dd, J 8.66, 2.47 Hz, 1 H) 7.72 (d, J--2.23 Hz,
1 H) 7.97 -
8.06 (m, 1 H).
INTERMEDIATE 54
2,3-Dihydro-benzofuran-5-sulfonyl chloride
Chlorosulphonic acid (43.4 g, 0.366 mol) in DCM (10 mL) was added to a cold
solution (5
°C) of 2,3-dihydrobenzofuran (20 g, 0.166 mol) in DCM (200 mL). After
the addition the
reaction was left with stirring at room temperature overnight. The reaction
mixture was
quenched with water (150 mL) keeping the temperature below 10 °C. The
organic phase
was separated and washed with an aqueous solution of NaHC03 (13,9 g dissolved
in 150
mL of water). The organic solvents were evaporated to yield the title compound
as a solid
residue 3.3 g (23 %). 1H NMR 270 MHz (CDC13) 8 ppm 3.32 (t, J--8.91 Hz, 2 H)
4.75 (t,
J--8.91 Hz, 2 H) 6.90 (d, J--9.15 Hz, 1 H) 7.78 - 7.90 (m, 2 H)
INTERMEDIATE 55
7-Iodo-2,3-dihydro-benzofuran-5-sulfonyl chloride
A solution of ICl (7.7 g, 47 mmol) in DCM (100 mL) was added dropwise to a
solution of
2,3-dihydro-benzofuran-5-sulfonyl chloride (5 g, 23 mmol; Intermediate 54) in
DCM (100
mL) at reflux temperature under nitrogen atmosphere. The reaction was heated
at reflux
overnight. The reaction mixture was cooled at room temperature and
acetonitrile (50 mL)
was added. The resultant mixture was washed with a saturated solution of
NaHC03 and
the organic phase was separated followed by elimination of the volatiles under
vacuum to
give 8 g of brown oil which was used to the next step without further
purification. 1H NMR
270 MHz (CDC13) 8 ppm 3.45 (t, J 8.91 Hz, 2 H) 4.82 (t, J--8.91 Hz, 2 H) 7.79
(d, J--1.48
Hz, 1 H) 8.16 (d, J--1.98 Hz, 1 H).
INTERMEDIATE 56
7-Iodo-benzofuran-5-sulfonyl chloride
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AIBN (270 mg, 1.3 mmol) and NBS (2.5 g, 14 mmol) were added to 7-iodo-2,3-
dihydro-
benzofuran-5-sulfonyl chloride (4.4 g , 13 mmol; Intermediate 55) in
chlorobenzene (30
mL) at 70 °C. The heating was turned off one hour after the addition.
Acetonitrile (30 mL)
was added and the organic phase was washed with sodium sulphite in water. The
organic
phase was separated and the volatiles were evaporated to give 4 g (90%) of the
title
compound as yellow crystals. 1H NMR 270 MHz (CDC13) 8 ppm 7.07 (d, J--2.23 Hz,
1 H)
7.90 (d, J--2.23 Hz, 1 H) 8.29 - 8.37 (m, 1 H).
INTERMEDIATE 57
7-Iodo-N-(2-methoxy-5-methylphenyl)-1-benzofuran-5-sulfonamide
To a solution of 7-iodo-1-benzofuran-5-sulfonyl chloride (10.75 g, 31 mmol;
Intermediate
56) in dichloromethane (200 mL) was added 5-methyl-2-methoxyaniline (4.25 g,
31 mmol)
and pyridine (7.4 mL, 93 mmol) and allowed to stir at ambient temperature
overnight. The
dark red solution was washed with water, separated, dried and filtered through
a plug of
silica to remove most of the red impurity, and finally concentrated. Yield:
13.51 g (99%)
red solid. HPLC 90% RT=2.58 min (System A; 30-80% MeCN over 3 min), 1.75 min
(System C; 2-95% MeCN over 2 min). 1H NMR (400 MHz, CDC13) S ppm 2.23 (m, 3 H)
3.52 (s, 3 H) 6.54 (d, J--8.30 Hz, 1 H) 6.79 (dd, J 8.42, 1.59 Hz, 1 H) 6.86
(d, J--2.20 Hz,
1 H) 6.96 (s, 1 H) 7.31 (d, J 1.71 Hz, 1 H) 7.71 (d, J--2.20 Hz, 1 H) 7.95 (d,
J--1.71 Hz, 1
H) 8.04 (d, J--1.71 Hz, 1 H). MS(ESI) for Cl6HiaIN04S m/z 444 (M+H).
EXAMPLE 92
N-(2-Methoxy-5-methylphenyl)-7-[(3-methylpiperazin-1-yl)methyl]-1-benzofuran-5-
sulfonamide hydrochloride
Step 1. 7-(3-Methyl piper~azin-1-cap~bonyl)-benzofurara-5-sulfonic acid (2-
rnethoxy-5-
methyl phenyl)-amide.
To 7-iodo-N-(2-methoxy-5-methylphenyl)-1-benzofuran-5-sulfonamide (100 mg,
0.23
mmol; Intermediate 57) was added 2-methylpiperazine (45 mg, 0.46 mmol),
Herrmann's
catalyst (25 mg, 0.02 mmol), Mo(CO)6 (30 mg, 0.12 mmol) and KZC03 (112 mg,
0.81
mmol) in diglyme (3 mL) and warmed in the StemBlock at 120 °C. After 20
minutes, the
mixture was filtered, diluted with ethyl acetate and washed with water. After
concentration, the crude mixture was purified by preparative HPLC (Gilson;
gradient 30-
70% MeCN) to give, after making basic with NaOH and washing with water, the
title
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amide product. Yield: 36 mg (36%). HPLC 88% RT=1.09 (System C; 2-95% MeCN over
2
min). MS(ESI) for CzzHzsNsGsS ~z 444 (M+H).
Step 2. N (2-Methoxy-5-rnethylpherayl)-7-~(3-methylpiperazin-1 yl)methylJ-1-
benzofuran-
5-sulfonamide hydrochloride.
To the obtained 7-(3-methyl-piperazin-1-carbonyl)-benzofuran-5-sulfonic acid
(2-
methoxy-5-methyl-phenyl)-amide (30 mg, 0.07 mmol; Step 1) was added LiAIHø
(9.0 mg,
0.24 mmol) in dry THF (4 mL) and the mixture was warmed to reflux. After 1 h,
HPLC
analysis showed 15% product and the remaining impurities. Added mixture to 2 M
HCI,
concentrated and purified by preparative HPLC (Gilson; gradient of 30-70%
MeCN). The
pure fractions were stripped, HCl/ether added and concentrated to give the
title compound
as a colourless solid. Yield: 1.3 mg (5%). HPLC 90% RT=1.17 min (System A; 30-
80%
MeCN over 3 min), 1.13 min (System C; 2-95% MeCN over 2 min). 1H NMR (400 MHz,
methanol-d4) 8 ppm 1.29 (d, J--7.0 Hz, 2 H) 2.21 (s, 3 H) 2.72 (m, 1 H) 2.86
(m, 1 H) 3.38
(s, 4 H) 3.43-3.64 (m, 4 H) 4.30 (d, J--6.59 Hz, 2 H) 6.62 (d, J--8.30 Hz, 1
H) 6.81 - 6.88
(m, 1 H) 6.99 (d, J--2.44 Hz, 1 H) 7.25 (d, J 1.95 Hz, 1 H) 7.76 (br s, 1 H)
7.94 (d, J 2.20
Hz, 1 H) 8.08 (d, J--1.71 Hz, 1 H). MS (ESI) for CzzHz~N3O4S mlZ 430 (M+H).
INTERMEDIATE 58
7-Iodo-N (2-methylphenyl)-1-benzofuran-5-sulfonamide
7-Iodo-1-benzofuran-5-sulfonyl chloride (10 g, 29.2 mmol; Intermediate 56) and
2-methyl
aniline (3.43 mL, 32.1 mmol) were dissolved in dichloromethane (150 mL) and
pyridine
(3.53 mL, 43.8 mmol) was added. The solution was stirred overnight and washed
with 1 M
HCl (2 x 100 mL), dried over sodium sulfate and evaporated to give the crude
solid
product that was recrystallized from methanol. Yield: 5.32 g (44%) of a beige
solid.
'H NMR (400 MHz, CDC13) ~ ppm 2.05 (s, 3 H) 6.36 (s, 1 H) 6.95 (d, J 2.3 Hz, 1
H) 7.11
- 7.19 (m, 3 H) 7.28 (d, J 7.5 Hz, 1 H) 7.81 (d, J--2.3 Hz, 1 H) 7.99 (d, J--
1.8 Hz, 1 H)
8.08 (d, J 1.8 Hz, 1 H).
INTERMEDIATE 59
N (2-Methylphenyl)-7-vinyl-1-benzofuran-5-sulfonamide
7-Iodo-N (2-methylphenyl)-1-benzofuran-5-sulfonamide (0.41 g, 1 mmol;
Intermediate
58), tributylvinyltin (0.32 mL, 1.1 mmol), bis(triphenylphosphine)palladium
diacetate (10
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mg) and acetonitrile (3 mL) were heated under microwave irradiation to 180
°C for 5 min.
The mixture was cooled, filtered and evaporated. The resulting oil was washed
with
hexane (2 x 50 mL), dissolved in diethyl ether (50 mL), filtered and
evaporated to give the
crude product which was crystallized from ethanol:water (3:1). Yield 0.19 g
(61%) of an
off white solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.93 (s, 3 H) 5.57 (dd, J--
11.3, 1.0
Hz, 1 H) 6.12 (dd, J--17.8, 1.0 Hz, 1 H) 6.84 - 7.07 (m, 6 H) 7.62 (d, J--1.8
Hz, 1 H) 7.84
(d, J 1.8 Hz, 1 H) 8.14 (d, J--2.3 Hz, 1 H) 9.43 (s, 1 H).
INTERMEDIATE 60
7-Formyl-N (2-methylphenyl)-1-benzofuran-5-sulfonamide
N (2-Methylphenyl)-7-vinyl-1-benzofuxan-5-sulfonamide (1.03 g, 3.3 mmol;
Intermediate
59) was dissolved in dioxane (30 mL) and 2,6-lutidine (0.8 mL). Osmium
tetroxide (84
mg, 0.33 mmol) was added with stirring followed by a solution of sodium
periodate (2.82
g, 13.2 mmol) in water (10 mL). After stirring for 90 minutes, 1 M HCl (40 mL)
was
added followed by water (200 mL). The precipitated product was collected by
filtration,
washed with water and dried under vacuo. Yield: 0.95 g (91%) of an off white
solid.
1H NMR (400 MHz, CDC13) ~ ppm 2.05 (s, 3 H) 6.38 (s, 1 H) 6.95 (d, J--2.3 Hz,
1 H) 7.11
(dd, J 5.1, 1.1 Hz, 2 H) 7.13 - 7.19 (m, 2 H) 7.91 (d, J--2.3 Hz, 1 H) 8.25
(dd, J 15.8, 1.8
Hz, 2 H) 10.42 (s, 1 H).
EXAMPLE 93
N-(2-Methylphenyl)-7-(piperazin-1-ylmethyl)-1-benzofuran-5-sulfonamide,
trifluoroacetate
7-Formyl-N (2-methylphenyl)-1-benzofuran-5-sulfonamide (20 mg, 0.06 mmol;
Intermediate 60), N-(tent-butoxycarbonyl)piperazine (13 mg, 0.07 mmol), acetic
acid (36
~,L, 0.63 mmol), sodium triacetoxyborohydride (27 mg, 0.13 mmol) were combined
with
dry THF (3 mL) and heated under microwave irradiation to 130 °C for 5
min. The solution
was cooled, altered and evaporated. The residue was dissolved in methanol (3
mL) and
treated with concentrated hydrochloric acid (0.3 mL). This solution was heated
under
microwave irradiation to 100 °C for 5 min. The solvent was evaporated
to give the crude
product which was purified by preparative HPLC (Gilson system equipped with an
ACE 5
C8 column (30x150 mm), Flow: 35 mL/min. Eluent: gradient 15-40% MeCN in 0.1%
TFA
in MilliQ water. Yield: 16 mg (50%). Analytical HPLC were performed on Agilent
1100,
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column: ACE 3 C8 (system A) or column: YMC-Pack (system B), eluents:
MilliQl0.1%TFA and MeCN. HPLC 99% RT=1.48 (System A; 10-97% MeCN over 3
min) 99% RT=1.31 (System B; 10-90% MeCN over 3 min). MS (ESI+) for C2oHa3N3O3S
nalz 386 (M+1). 1H NMR (400 MHz, methanol-d4) 8 ppm 1.89 (s, 3 H) 2.65 - 2.72
(m, 4 H)
3.10 - 3.17 (m, 4 H) 3.95 (s, 2 H) 6.92 (d, J 2.3 Hz, 1 H) 6.96 - 6.99 (m, 2
H) 6.99 - 7.02
(m, J 3.2, 1.8, 1.8 Hz, 2 H) 7.51 (d, J--1.8 Hz, 1 H) 7.87 (d, J--2.3 Hz, 1 H)
7.96 (d, J 1.8
Hz, 1 H).
EXAMPLE 94
7-((3,5-Dimethylpiperazin-1-yl)methyl]-N-(2-methylphenyl)-1-benzofuran-5-
sulfonamide, trifluoroacetate
The title compound was prepared according to the procedure described for
Example 93,
using 7-formyl-N (2-methylphenyl)-1-benzofuran-5-sulfonamide (40 mg, 0.12
mmol;
Intermediate 60) and 3,5-dimethylpiperazine (16 mg, 0.14 mmol) [Note: no HCl
deprotection step]. Yield: 21.5 mg (40%). HPLC 97% RT=1.57 (System A; 10-97%
MeCN over 3 min) 99% RT=1.39 (System B; 10-90% MeCN over 3 min). MS (ESI+) for
C22Hz~N3O3S m/z 414 (M+1). 1H NMR (400 MHz, methanol-d~) 8 ppm 1.19 (d, J--6.8
Hz,
6 H) 1.91 (s, 3 H) 2.11 (dd, J 12.7, 11.4 Hz, 2 H) 2.96 (dd, J--12.9, 2.4 Hz,
2 H) 3.27 (ddd,
.l--11.1, 6.7, 3.3 Hz, 2 H) 3.91 (s, 2 H) 6.90 (d, J 2.3 Hz, 1 H) 6.95 - 7.03
(m, 4 H) 7.57 (d,
.I--1.5 Hz, 1 H) 7.86 (d, J--2.3 Hz, 1 H) 7.91 (d, J--1.8 Hz, 1 H).
EXAMPLE 95
N-(2-Methylphenyl)-7-[(3-methylpiperazin-1-yl)methyl]-1-benzofuran-5-
sulfonamide,
trifluoroacetate
The title compound was prepared according to the procedure described for
Example 93,
using 7-formyl-N (2-methylphenyl)-1-benzofuran-5-sulfonamide (40 mg, 0.12
mmol;
Intermediate 60) and 2-methylpiperazine ( 14 mg, 0.14 mmol). [Note: no HCl
deprotection
step]. Yield: 31.6 mg (59%). HPLC 99% RT=1.50 (System A; 10-97% MeCN over 3
min)
99% RT=1.33 (System B; 10-90% MeCN over 3 min). MS (ESI+) for C21HZSN3O3S rnlz
400 (M+1). 1H NMR (400 MHz, methanol-d4) 8 ppm 1.20 (d, J--6.8 Hz, 3 H) 1.90
(s, 3 H)
2.33 (dd, J--12.7, 10.7 Hz, 1 H) 2.47 (td, J--12.4, 3.1 Hz, 1 H) 2.87 - 2.94
(m, J--12.8 Hz, 1
H) 3.00 - 3.09 (m, 2 H) 3.26 - 3.34 (m, J 10.0, 6.8, 6.8, 3.0 Hz, 2 H) 3.94 -
4.04 (m, 2 H)
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6.92 (d, J--2.3 Hz, 1 H) 6.97 (dt, J--5.0, 2.2 Hz, 2 H) 7.01 (td, J 3.6, 2.0
Hz, 2 H) 7.55 (d,
J--1.8 Hz, 1 H) 7.87 (d, J--2.0 Hz, 1 H) 7.95 (d, J--1.8 Hz, 1 H).
EXAMPLE 96
7-(1,4-Diazepan-1-ylmethyl)-N-(2-methylphenyl)-1-benzofuran-5-sulfonamide,
trifluoroacetate
The title compound was prepared according to the procedure described for
Example 93,
using 7-formyl-N (2-methylphenyl)-1-benzofuran-5-sulfonamide (40 mg, 0.12
mmol;
Intermediate 60) and N-(tent-butoxycarbonyl)homopiperazine (28 mg, 0.14 mmol).
Yield:
21.0 mg (31%). HPLC 99% RT=1.34 (System A; 10-97% MeCN over 3 min) 99%
RT=1.18 (System B; 10-90% MeCN over 3 min). MS (ESI+) for CZ~H25N3O3S fnlz 400
(M+1). 1H NMR (400 MHz, methanol-d4) 8 ppm 1.94 (s, 3 H) 2.10 - 2.17 (m, 2 H)
3.28 -
3.35 (m, 4 H) 3.49 - 3.59 (m, 4 H) 4.60 (s, 2 H) 6.92 - 7.04 (m, 5 H) 7.72 (d,
J--1.8 Hz, 1
H) 7.94 (d, J--2.3 Hz, 1 H) 8.09 (d, J--1.8 Hz, 1 H).
EXAMPLE 97
7-~(trafZS-2,5-Dimethylpiperazin-1-yl)methyl-N-(2-methylphenyl)-1-benzofuran-5-
sulfonamide, trifluoroacetate
The title compound was prepared according to the procedure described for
Example 93,
using 7-formyl-N (2-methylphenyl)-1-benzofuran-5-sulfonamide (80 mg, 0.24
mmol;
Intermediate 60) and tf°a~zs-2,5-dimethylpiperazine (58 mg, 0.48 mmol).
[Note: no HCl
deprotection step]. Yield: 32.2 mg (30%). HPLC 99% RT=1.58 (System A; 10-97%
MeCN over 3 min) 99% RT=1.40 (System B; 10-90% MeCN over 3 min). MS (ESI+) for
CZZHZ~N3O3S r~alz 414 (M+1). 1H NMR (400 MHz, methanol-d4) 8 ppm 1.12 (d, J--
6.5 Hz,
3 H) 1.22 (d, J--5.8 Hz, 3 H) 1.91 (s, 3 H) 2.23 (dd, J 13.1, 11.3 Hz, 1 H)
2.75 - 2.86 (m, 3
H) 3.14 - 3.21 (m, 1 H) 3.27 (dd, J 12.2, 2.4 Hz, 1 H) 3.72 (d, J 14.3 Hz, 1
H) 4.37 (d,
J 14.3 Hz, 1 H) 6.91 (d, J--2.3 Hz, 1 H) 6.97 - 7.03 (m, 4 H) 7.58 (d, J--1.8
Hz, 1 H) 7.86
(d, J--2.3 Hz, 1 H) 7.91 (d, J--1.8 Hz, 1 H).
EXAMPLE 98
N-(2-Methylphenyl)-7-f [(2R)-2-methylpiperazin-1-yl]methyl-1-benzofuran-5-
sulfonamide, trifluoroacetate
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The title compound was prepared according to the procedure described for
Example 93,
using 7-formyl-N (2-methylphenyl)-1-benzofuran-5-sulfonamide (40 mg, 0.12
mmol;
Intermediate 60) and (3R)-3-methyl-1-tritylpiperazine (48 mg, 0.14 mmol).
Yield: 22.8 mg
(35%). HPLC 96% RT=1.49 (System A; 10-97% MeCN over 3 min) 96% RT=1.31
(System B; 10-90% MeCN over 3 min). MS (ESI+) for CzlHzsN30sS nalz 400 (M+1).
1H NMR (400 MHz, methanol-d4) 8 ppm 1.32 (d, J 6.3 Hz, 3 H) 1.90 (s, 3 H) 2.58
- 2.66
(m, 1 H) 2.87 - 2.97 (m, 2 H) 2.99 - 3.08 (m, 2 H) 3.24 - 3.27 (m, 1 H) 3.33
(dt, J--11.9, 1.8
Hz, 1 H) 3.91 (d, J--14.1 Hz, 1 H) 4.50 (d, J 14.1 Hz, 1 H) 6.94 (d, J--2.3
Hz, 1 H) 6.96 -
6.99 (m, 2 H) 7.01 (dd, J--4.0, 2.8 Hz, 2 H) 7.56 (d, J--1.8 Hz, 1 H) 7.88 (d,
J--2.0 Hz, 1 H)
7.99 (d, J 1.8 Hz, 1 H).
INTERMEDIATE 61
N-(2-Methoxy-5-methylphenyl)-7-vinyl-1-benzofuran-5-sulfonamide
Five batches each consisting of a mixture of N-(2-methoxy-5-methylphenyl)-7-
iodo-1-
benzofuran-5-sulfonamide (443 mg, 1.0 mmol; Intermediate 57),
tributyl(vinyl)tin (350
mg, 1.1 mmol) and bis(triphenylphosphine)palladium diacetate ( 15 mg, 0.02
mmol) in
acetonitrile (3 mL) was heated in a Smith Creator microwave oven to 180
°C for 5 min.
The combined reaction mixtures were filtered and concentrated to give 2.0 g of
crystalline
crude material that was put through a SiOz column using EtOAc/hexane (gradient
5:95
25:75) as eluent giving 1.3 g (75 %) of off white crystalline product. 1H NMR
(400 MHz,
CDC13) 8 2.26 (s, 3 H), 3.53 (s, 3 H), 5.56 (dd, 1 H), 6.16 (dd, 1 H), 6.57
(d, 1 H), 6.79-
6.98 (m, 4 H), 7.38 (d, 1 H), 7.71-7.74 (m, 2 H), 7.94 (d, 1 H); MS (ESI+) for
C18H1~NO~S
m/z 344 (M+H)+.
INTERMEDIATE 62
7-Formyl-N (2-methoxy-5-methylphenyl)-1-benzofuran-5-sulfonamide
Osmium tetroxide (84 mg, 0.33 mmol) was added to a solution of N-(2-methoxy-5-
methylphenyl)-7-vinyl-1-benzofuran-5-sulfonamide (1.25 g, 3.3 mmol;
Intermediate 61)
and lutidine (0.71 g, 6.6 mmol) in dioxane (30 mL). A solution of sodium
periodate (2.82
g, 13.2 mmol) in water (10 mL) was added under stirring. After 90 min, aqueous
HCl (2
M; 40 mL) was added to give a clear solution. Addition of water (200 mL) gave
a
precipitate that was collected by filtration. This material was washed with
water and dried
to give 1.12 g (88 %) of the title product. 1H NMR (400 MHz, CDC13) 8 2.27 (s,
3 H), 3.55
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(s, 3 H), 6.57 (d, 1 H), 6.80-6.85 (m, 1 H), 6.92 (d, 1 H), 7.02 (br s, 1 H),
7.38 (d, 1 H),
7.85 (d, 1 H), 8.22. (d, 1 H), 8.28 (d, 1 H), 10.38 (s, 1 H).
EXAMPLE 99
N-(2-Methoxy-5-methylphenyl)-7-[(3-methylpiperazin-1-yl)methyl]-1-benzofuran-5-
sulfonamide, trifluoroacetate
A mixture of 7-formyl-N (2-methoxy-5-methylphenyl)-1-benzofuran-5-sulfonamide
(100
mg, 0,29 mmol; Intermediate 62), 2-methylpiperazine (32 mg, 0,32 mmol) and
sodium
triacetoxyborohydride (245 mg, 1,16 mmol) in 1,2-dichloroethane (3 mL) was
stirred
overnight. Filtration and concentration provided 100 mg of crude material that
was purified
by preparative HPLC to after concentration give 30 mg (19 %) of the title
product. 1H
NMR (400 MHz, methanol-d4) 8 1.27 (d, 3 H), 2.24 (s, 3 H), 2.33-2.40 (m, 1 H),
2.46-2.55
(m, 1 H), 2.91-2.98 (m, 1 H), 3.05-3.17 (m, 2 H), 3.32-3.38 (m, 1 H), 3.39 (s,
3 H), 3.96
4.08 (m, 2 H), 6.64 (d, 1 H), 6.87 (dd, 1 H), 6.97 (d, 1 H), 7.28 (d, 1 H),
7.66 (d, 1 H), 7.91
(d, 1 H), 8.04 (d, 1 H); MS (ESI+) for C22HZ~N3O4S m/z 430 (M+H)+; HPLC 99 %,
RT=1.66 in (System A; 10-97% MeCN over 3 min), 99% RT=1.46 (System B; 10-97%
MeCN over 3 min).
EXAMPLE 100
7-(1,4-Diazepan-1-ylmethyl)-N-(2-methoxy-5-methylphenyl)-1-benzofuran-5-
sulfonamide, trifluoroacetate
The title product was prepared according to the procedure of Example 99.
Yield: 55 mg
(69%). 1H NMR (400 MHz, methanol-d4) 8 2.16-2.23 (m, 2 H), 2.23 (s, 3 H), 3.35-
3.42
(m, 4 H), 3.39 (s, 3 H), 3.58-3.67 (m, 4 H), 4.66 (s, 2 H), 6.64 (d, 1 H),
6.88 (dd, 1 H), 7.05
(d, 1 H), 7.28 (d, 1 H), 7.84 (d, 1 H), 7.98 (d, 1 H), 8.18 (d, 1 H); MS
(ESI+) for
~22H27N3~4s jnlz 430 (M+H)+; HPLC 99 %, RT=1.50 in (System A; 10-97% MeCN over
3
min), 99% RT=1.33 (System B; 10-97% MeCN over 3 min).
EXAMPLE 101
N-(2-Methoxy-5-methylphenyl)-7-(piperazin-1-ylmethyl)-1-benzofuran-5-
sulfonamide, trifluoroacetate
The title product was prepared according to the procedure of Example 99.
Yield:
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26 mg (34%). 1H NMR (400 MHz, methanol-d4) 8 2.24 (s, 3 H), 2.91-2.96 (m, 4
H), 3.26-
3.32 (m, 4 H), 3.38 (s, 3 H), 4.17 (s, 2 H), 6.63 (d, 1 H), 6.87 (dd, 1 H),
6.99 (d, 1 H), 7.28
(d, 1 H), 7.68 (d, 1 H), 7.92 (d, 1 H), 8.08 (d, 1 H); MS (ESI+) for
CalHasNs04S ynlz 416
(M+H)+; HPLC 99 %, RT=1.58 in (System A; 10-97% MeCN over 3 min), 99% RT=1.39
(System B; 10-97% MeCN over 3 min).
EXAMPLE 102
7- f (cis-3,5-Dimethylpiperazin-1-yl)methyl-N-(2-methoxy-5-methylpheny1)-1-
benzofuran-5-sulfonamide, trifluoroacetate
The title product was prepared according to the procedure of Example 99.
Yield: 39 mg
(48%). 1H NMR (400 MHz, methanol-d4) 8 1.26 (d, 6 H), 2.20-2.28 (m, 2 H), 2.23
(s, 3 H),
3.03-3.08 (m, 2 H), 3.32-3.39 (m, 2 H), 3.41 (s, 3 H), 4.01 (s, 2 H), 6.65 (d,
1 H), 6.86 (dd,
1 H), 6.96 (d, 1 H), 7.27 (d, 1 H), 7.69 (d, 1 H), 7.90 (d, 1 H), 8.02 (d, 1
H); MS (ESI+) for
C23H29N3~4S m/z 444 (M+H)+; HPLC 99 %, RT=1.70 in (System A; 10-97% MeCN over
3
min), 99% RT=1.50 (System B; 10-97% MeCN over 3 min).
EXAMPLE 103
7-{[trafZS-2,5-Dimethylpiperazin-1-yl]methyl-N-(2-methoxy-5-methylphenyl)-1-
benzofuran-5-sulfonamide, trifluoroacetate.
The title product was prepared according to the procedure of Example 99.
Yield: 11 mg
(13%). 'H NMR (400 MHz, methanol-d4) 8 1.17 (d, 3 H), 1.26 (d, 3 H), 2.16-2.24
(m, 1
H), 2.24 (s, 3 H), 2.72-2.78 (m, 1 H), 2.82-2.91 (m, 2 H), 3.19-3.25 (m, 1 H),
3.30-3.35 (m,
1 H), 3.41 (s, 3 H), 3.71 (d, 1 H), 4.36 (d, 1 H), 6.66 (d, 1 H), 6.87 (dd, 1
H), 6.97 (d, 1 H),
7.29 (d, 1 H), 7.67 (d, 1 H), 7.91 (d, 1 H), 8.02 (d, 1 H); MS (ESI+) for
Cz3H29N304s m/z
444 (M+H)+; HPLC 99 %, RT=1.70 in (System A; 10-97% MeCN over 3 min), 99%
R-r=1.49 (System B; 10-97% MeCN over 3 min).
EXAMPLE 104
7-[(1S,4S)-2,5-Diazabicyclo [2.2.1 ] hept-2-ylmethyl]-N-(2-methoxy-5-
methylphenyl)-1-
benzofuran-5-sulfonamide, trifluoroacetate
The title product was prepared according to the procedure of Example 99.
Yield: 46 mg
(73%). 1H NMR (400 MHz, CD30D) 8 2.20 (d, 1 H), 2.23 (s, 3 H), 2.54 (d, 1 H),
3.38 (s, 3
H), 3.44-3.50 (m, 2 H), 3.56 (dd, 1 H), 3.78 (dd, 1 H), 4.28 (br s, 1 H), 4.54
(br s, 1 H),
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4.61 (d, 1 H), 4.71 (d, 1 H), 6.64 (d, 1 H), 6.88 (dd, 1 H), 7.04 (d, 1 H),
7.28 (d, 1 H), 7.83
(d, 1 H), 7.97 (d, 1 H), 8.16 (d, 1 H); MS (ESI+) for C22HasN3O4S m/z 428
(M+H)+; HpLC
99 %, RT=1.50 in (System A; 10-97% MeCN over 3 min), 99% RT=1.32 (System B; 10-
97% MeCN over 3 min).
EXAMPLE 105
N-(2-Methoxy-5-methylphenyl)-7-[(2-methylpiperazin-1-yl)methyl]-1-benzofuran-5-
sulfonamide, trifluoroacetate
The title product was prepared according to the procedure of Example 99.
Yield: 31 mg
(49%). 1H NMR (400 MHz, methanol-d4) 8 1.35 (d, 3 H), 2.24 (s, 3 H), 2.56-2.65
(m, 1 H),
2.87-3.11 (overlapping m, 4 H), 3.25-3.28 (m, 1 H), 3.33-3.37 (m, 1 H), 3.38
(s, 3 H), 3.88
(d, 1 H), 3.48 (d, 1 H), 6.64 (d, 1 H), 6.87 (dd, 1 H), 6.98 (d, 1 H), 7.29
(d, 1 H), 7.66 (d, 1
H), 7.92 (d, 1 H), 8.07 (d, 1 H); MS (ESI+) for C22H2~N3OøS m/z 430 (M+H)+;
HpLC 99
%, RT=1.58 in (System A; 10-97% MeCN over 3 min), 99% RT=1.40 (System B; 10-
97%
MeCN over 3 min).
INTERMEDIATE 63
7-Methyl-5-nitro-1-benzofuran
7-Iodo-5-nitro-benzofuran (6.5 g, 22.1 mmol), Pd(OAc)2 (1 g, 3.9 mmol), P(o-
tolyl)3 (5.5
g, 18. 2 mmol), Me4Sn (8.05 g, 42 mmol), and Et3N (3.16 mL, 20.4 mmol) were
dissolved
in DMF (40 mL) and portioned out in 13 tubes and heated at 100 °C for
10 min each using
controlled microwave energy. The reaction mixtures were combined and filtered
and the
solvent was evaporated. The crude material was purified using flash
chromatography
(using a gradient of isohexane - 10% EtOAc in isohexane). Yield: 2.82 g (70%)
of 7-
methyl-5-nitro-1-benzofuran. 1H NMR (400 MHz, CDCl3) 8 ppm 2.51 - 2.64 (m, 3
H) 6.90
(d, J--2.3 Hz, 1 H) 7.77 (d, J--2.3 Hz, 1 H) 8.04 (d, J--1.3 Hz, 1 H) 8.37 (d,
J--2.3 Hz, 1 H);
HPLC 96% Rt=2.31 min (System A; 10-97% in 3 min ACE column). MS (ESI+) for
C9H~N03 m/z 178 (M+H)+.
INTERMEDIATE 64
7-(Bromomethyl)-5-nitro-benzofuran
7-Methyl-5-nitro-1-benzofuran (2.1 g, 12 mmol; Intermediate 63) was dissolved
in CCl4
and heated to 80 °C. Benzoyl peroxide (0.43 g, 1,6 mmol) was added
followed by NBS
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(2.1 g, 12 mmol) that was added in small portions. The reaction mixture was
heated at
reflux overnight with stirring. Additional benzoyl peroxide (0.08 mmol) and
NBS (0.2
mmol) were added and the reaction mixture was stirred for one additional
night. After this
time, the mixture was filtered and concentrated. The crude was redissolved in
DCM and
washed with water. The organic solvent was dried (MgSOa) and evaporated. The
residue
was purified using preparative HPLC with a gradient of 45-70% MeCN. This
afforded 0.7
g (22%) of 7-(bromomethyl)-5-nitro-benzofuran as a solid. 1H NMR (400 MHz,
CDC13) 8
ppm 4.78 (s, 2 H) 6.96 (d, J 2.3 Hz, 1 H) 7.84 (d, J--2.3 Hz, 1 H) 8.28 (d, J--
2.3 Hz, 1 H)
8.49 (d, J 2.3 Hz, 1 H). HPLC Rt=1.9 min (System A; 30-80% MeCN over 3 min ACE
column).
EXAMPLE 106
2-Chloro-N-[7-(piperazin-1-ylmethyl)-1-benzofuran-5-yl]benzenesulfonamide
dihydrochloride
Step 1: tent-Butyl 4-[(5-nitro-1-benzofuran-7-yl)methyl]piperazine-1-
carboxylate
7-(Bromomethyl)-5-nitro-1-benzofuran (145 mg, 70 mol % pure, 0.44 mmol;
Intermediate
64), I~ZC03 (181 mg, 1.31 mmol) and 1-boc-piperazine (98 mg, 0.53 mmol)
were mixed in dry MeCN (5 mL) and heated to 80 °C while stirring for 2
h using a
StemBlock. The solvent was evaporated under reduced pressure and the residue
was
partitioned between water and DCM (x2). The organic layers were combined,
dried
(Na2S04) and purified using flashtube (10% MeOH in DCM). This afforded the
title
product (123 mg, 78%) as a light yellow solid. HPLC 98%, RT=1.70 min (System
A; 10-
97% MeCN over 3 min), 99%, RT=1.55 min (System B; 10-97% MeCN over 3 min). MS
(ESI+) for C18H23N305 m/z 362 (M+H)+.
Step 2: 4-(5-Amino-benzofuran-7-ylmethyl)-piperazine-1-carboxylic acid tent-
butyl
ester
Raney nickel (slurry in ethanol) and hydrazine hydrate (66 ~,L, 1.36 mmol)
were added to
tert-butyl 4-[(5-nitro-1-benzofuran-7-yl)methyl]piperazine-1-carboxylate (123
mg, 0.34
mmol; obtained in Step 1) in ethanol:THF (4:1; 10 mL). The mixture was stirred
at room
temperature for 1 h. Unreacted starting material was still present and
additional Raney
nickel and hydrazine hydrate (33 ~.L, 0.68 mmol) were added with continous
stirring for 1
h. The mixture was filtered through a pad of Celite, which was rinsed several
times with
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ethanol. Evaporation of the solvent gave 119 mg (quantitative) of the title
amine as a green
sticky oil which was used directly in the next step.
Step 3: 2-Chloro-N-[7-(piperazin-1-ylmethyl)-1-benzofuran-5-
yl]benzenesulfonamide
dihydrochloride
Dry pyridine (20 ~,L, 0.24 mmol) and 2-chlorobenzenesulfonyl chloride (25 ~.L,
0.18
mmol) were added to a solution of 4-(5-amino-benzofuran-7-ylmethyl)-piperazine-
1-
carboxylic acid ter°t-butyl ester (40 mg, 0,12 mmol; obtained in Step
2) in a mixture of dry
DCM:THF (2:1; 3 mL). The resulting mixture was stirred for 3 h and volatiles
were then
evaporated. The product was purified using flashtube (15% MeOH in DCM). The
residue
was dissolved in TFA:water (9:1; 2 mL) and the mixture was stirred at room
temperature
for 30 min to accomplish removal of the N-t-BOC group. The reaction mixture
was made
basic by addition of saturated aqueous Na2C03 (pH 8-9) and extracted with DCM
(x2).
The organic layers were combined, dried (Na2S04) and concentrated. The crude
product
was purified with preperative HPLC (System A; 10-40% MeCN). Pure fractions
were
combined and concentrated. The obtained TFA salt was dissolved in MeOH and 1 M
HCl
in ether was added, followed by concentration to give the title compound (10
mg, 18%) as
a light yellow solid. HPLC 100%, RT=1.38 min (System A; 10-97% MeCN over 3
min),
100%, RT=1.23 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz,
methanol-d4) b ppm 2.86 - 2.92 (m, 4 H) 3.25 - 3.28 (m, 4 H) 4.04 - 4.08 (m, 2
H) 6.73 (d,
J 2.26 Hz, 1 H) 7.15 (d, J--2.01 Hz, 1 H) 7.26 - 7.31 (m, 1 H) 7.32 (d, J--
2.26 Hz, 1 H)
7.42 - 7.47 (m, 1 H) 7.47 - 7.52 (m, 1 H) 7.70 (d, J 2.26 Hz, 1 H) 7.90 (dd, J-
-8.03, 1.51
Hz, 1 H). MS (ESI+) for C19H2oC1N3O3S rnlz 406 (M+H).
EXAMPLE 107
2-Methyl-N-[7-(piperazin-1-ylmethyl)-1-benzofuran-5-yl]benzenesulfonamide,
dihydrochloride
The title compound was prepared according to the procedure of Example 106,
Step 3,
starting from 4-(5-amino-benzofuran-7-ylmethyl)-piperazine-1-carboxylic acid
tent-butyl
ester (40 mg, 0,12 mmol; obtained in Example 106, Step 2) and 2-
methylbenzenesulfonyl
chloride (26 ~.L, 0.18 mmol). The crude product was purified with preperative
HPLC
(System B; 10-40% MeCN). The title compound (10 mg, 19%) was obtained as a
colorless
solid. HPLC 99%, RT=1.41 min (System A; 10-97% MeCN over 3 min), 99%, RT=1.26
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min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, methanol-dd) 8 ppm
2.66
(s, 3 H) 3.50 - 3.65 (m, 8 H) 4.67 (s, 2 H) 6.86 (d, J--2.01 Hz, 1 H) 7.22 -
7.29 (m, 1 H)
7.30 - 7.37 (m, 2 H) 7.40 - 7.48 (m, 2 H) 7.81 - 7.90 (m, 2 H). MS (ESI+) for
C2oH23NsOsS
m/z 386 (M+H)+.
EXAMPLE 108
N-[7-(Piperazin-1-ylmethyl)-1-benzofuran-5-yl]thiophene-2-sulfonamide,
dihydrochloride
The title compound was prepared according to the procedure of Example 106,
Step 3,
starting from 4-(5-amino-benzofuran-7-ylmethyl)-piperazine-1-carboxylic acid
test-butyl
ester (40 mg, 0,12 mmol; obtained in Example 106, Step 2) and 2-
thiophenesulfonyl
chloride (33 mg, 0.18 mmol). Additional 2-thiophenesulfonyl chloride (10 mg,
0.05 mmol)
was added with continued stirring for 1 h. The crude product was purified with
preperative
HPLC (System B; 10-40% MeCN). The title compound (3 mg, 6%) was obtained as a
colorless solid. HPLC 95%, RT=1.25 rnin (System A; 10-97% MeCN over 3 min),
95%,
RT=1.11 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, methanol-d4)
~
ppm 3.43 - 3.49 (m, 4 H) 3.50 - 3.57 (m, 4 H) 4.59 (s, 2 H) 6.90 (d, J--2.26
Hz, 1 H) 7.05
(dd, J 5.02, 3.76 Hz, 1 H) 7.35 (d, J 2.26 Hz, 1 H) 7.45 - 7.50 (m, 2 H) 7.70
(dd, J--5.02,
1.51 Hz, 1 H) 7.88 (d, J--2.26 Hz, 1 H). MS (ESI+) for C1~H19N303S2 m/z 378
(M+H)+.
EXAMPLE 109
2-Chloro-N-[7-(1,4-diazepan-1-ylmethyl)-1-benzofuran-5-yl]benzenesulfonamide
dihydrochloride
Step 1: tent-Butyl 4-[(5-nitro-1-benzofuran-7-yl)methyl]-1,4-diazepane-1-
carboxylate
The title product, obtained as a light yellow solid, was prepared according to
the procedure
of Example 106, Step 1, starting from 1-boc-homopiperazine (103 ~.L, 0.53
mmol). Yield:
109 mg (66%). HPLC 98%, RT=1.73 min (System A; 10-97% MeCN over 3 min), 100%,
RT=1.57 min (System B; 10-97% MeCN over 3 min). MS (ESI+) for C19Hz5N305 rialz
376
(M+H)+.
Step 2: 4-(5-Amino-benzofuran-7-ylmethyl)-1,4-diazepane-1-carboxylic acid tert-
butyl ester
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The title compound was prepared according to the procedure of Example 106,
Step 2,
starting from tent-butyl 4-[(5-nitro-1-benzofuran-7-yl)methyl]-1,4-diazepane-1-
carboxylate
(obtained in Step 1).
Step 3: 2-Chloro-N-[7-(1,4-diazepan-1-ylmethyl)-1-benzofuran-5-
yl]benzenesulfonamide dihydrochloride
The title compound was prepared according to the procedure of Example 106,
Step 3,
starting from 4-(5-amino-benzofuran-7-ylmethyl)-1,4-diazepane-1-carboxylic
acid tert-
butyl ester (36 mg, 0.10 mmol; obtained in Step 2) and 2-chlorobenzenesulfonyl
chloride
(21 ~.L, 0.16 mmol). The crude material was purified with preperative HPLC
(System B;
10-40% MeCN). The title compound (16 mg, 33%) was obtained as a colorless
solid.
HPLC 95%, RT=1.31 min (System A; 10-97% MeCN over 3 min), 96%, RT=1.17 min
(System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, methanol-d4) 8 ppm 2.25 -
2.37(m,2H)3.41-3.48(m,2H)3.48-3.59(m,J--4.52Hz,2H)3.69-3.75 (m,J--3.51
Hz, 2 H) 3.74 - 3.83 (m, 2 H) 4.70 (s, 2 H) 6.86 (d, J--2.26 Hz, 1 H) 7.36 -
7.41 (m, 1 H)
7.42 (d, J--2.01 Hz, 1 H) 7.51 - 7.59 (m, 3 H) 7.85 (d, J--2.01 Hz, 1 H) 8.00 -
8.04 (m,
J 7.91, 1.13 Hz, 1 H). MS (ESI+) for C2oH22C1N303S rnlz 420 (M+H)+.
EXAMPLE 110
N-[7-(1,4-Diazepan-1-ylmethyl)-1-benzofuran-5-yl]-2-methylbenzenesulfonamide,
dihydrochloride
The title compound was prepared according to the procedure of Example 106,
Step 3,
starting from 4-(5-amino-benzofuran-7-ylmethyl)-1,4-diazepane-1-carboxylic
acid tert-
butyl ester (36 mg, 0.10 mmol; obtained in Example 109, Step 2) and 2-
methylbenzenesulfonyl chloride (23 ~.L, 0.16 mmol). The title compound (13 mg,
28%)
was obtained as a colorless solid. HPLC 99%, RT=1.35 min (System A; 10-97%
MeCN
over 3 min), 100%, RT=1.22 min (System B; 10-97% MeCN over 3 min). 1H NMR (400
MHz, methanol-d4) 8 ppm 2.26 - 2.32 (m, 2 H) 2.66 (s, 3 H) 3.40 - 3.60 (m, 4
H) 3.69 -
3.83 (m, 4 H) 4.69 (s, 2 H) 6.86 (d, .I--2.26 Hz, 1 H) 7.23 - 7.29 (m, 1 H)
7.32 - 7.38 (m, 2
H) 7.41 - 7.46 (m, 1 H) 7.47 (d, J--2.26 Hz, 1 H) 7.84 - 7.90 (m, 2 H). MS
(ESI+) for
CziHzsNsC3S jnlz 400 (M+H)+.
EXAMPLE 111
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N-[7-(1,4-Diazepan-1-ylmethyl)-1-benzofuran-5-yl]thiophene-2-sulfonamide
dihydrochloride
The title compound was prepared according to the procedure of Example 106,
Step 3,
starting from 4-(5-amino-benzofuran-7-ylmethyl)-1,4-diazepane-1-carboxylic
acid tert-
butyl ester (36 mg, 0.10 mmol; obtained in Example 109, Step 2) and 2-
thiophenesulfonyl
chloride (29 mg, 0.16 mmol). Additional 2-thiophenesulfonyl chloride (10 mg,
0.06 mmol)
was added with continous stirring for 1 h. The title compound (10 mg, 22%) was
obtained
as a colorless solid. HPLC 100%, RT=1.20 min (System A; 10-97% MeCN over 3
min),
100%, RT=1.06 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz,
methanol-d4) 8 ppm 2.20 - 2.29 (m, 2 H) 3.34 - 3.41 (m, 2 H) 3.41 - 3.55 (m, 2
H) 3.63 -
3.69 (m, 2 H) 3.69 - 3.77 (m, 2 H) 4.66 (s, 2 H) 6.84 (d, J--2.26 Hz, 1 H)
6.98 (dd, J--5.02,
3.76 Hz, 1 H) 7.32 (d, J 2.01 Hz, 1 H) 7.42 (dd, J 3.76, 1.25 Hz, 1 H) 7.47
(d, J--2.26 Hz,
1 H) 7.63 (dd, J--5.02, 1.25 Hz, 1 H) 7.82 (d, J--2.26 Hz, 1 H). MS (ESI+) for
C18H21N3~3S2 3n~~ 392 (M+H)+.
EXAMPLE 112
2-Methoxy-5-methyl-N-~7-[(2-methylpiperazin-1-yl)methyl]-1-benzofuran-5-
yl,~benzenesulfonamide, dihydrochloride
Step 1: tent-Butyl 3-methyl-4-[(5-nitro-1-benzofuran-7-yl)methyl]piperazine-1-
carboxylate
A mixture of 7-(bromomethyl)-5-nitro-1-benzofuran (120 mg, 70 mol %, 0.39
mmol;
Intermediate 64), K2C03 (162 mg, 1.17 mmol) and tert-butyl 3-methylpiperazine-
1-
carboxylate (94 mg, 0.47 mmol) in dry MeCN (5 mL) was heated at 80 °C
while stirring
for 1 h 45 min using a StemBlock. The solvent was evaporated under reduced
pressure and
the residue was partitioned between water and DCM (x2). The organic layers
were
combined, dried (Na2S04) and purified using flashtube (10% MeOH in DCM). This
afforded the title product (115 mg, 78%) as a light yellow sticky oil. HPLC
99%, RT=2.47
min (System A; 5-60% MeCN over 3 min), 99%, RT=2.27 min (System B; 5-60% MeCN
over 3 min). MS (ESI+) for C19H25N3O5 nZ~z 376 (M+H)+.
Step 2: test Butyl 4-[(5-amino-1-benzofuran-7-yl)methyl]-3-methylpiperazine-1-
carboxylate
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Raney nickel (slurry in ethanol) and hydrazine hydrate (97 ~L, 2.0 mmol) were
added to
tert-butyl 3-methyl-4-[(5-nitro-1-benzofuran-7-yl)methyl]piperazine-1-
carboxylate (115
mg, 0.31 mmol; obtained in Step 1) in ethanol:THF (4:1; 5 mL). The resulting
mixture was
stirred at room temperature for 1.5 h, followed by filtration through Celite.
The Celite pad
was rinsed several times with ethanol. The solvent was evaporated to give the
crude
product (136 mg) as a light green solid. This material was used in the next
step without
further purification. HPLC 98%, RT=1.77 min (System A; 5-60% MeCN over 3 min),
100%, RT=1.50 min (System B; 5-60% MeCN over 3 min). MS (ESI+) for C19H2~N3O3
m/z 346 (M+H)+.
Step 3: 2-Methoxy-5-methyl-N- f 7-[(2-methylpiperazin-1-yl)methyl]-1-
benzofuran-5-
yl~benzenesulfonamide, dihydrochloride
Pyridine (17 ~L, 0.20 mmol) and 6-methoxy-m-toluenesulfonyl chloride (34 mg,
0.15
mmol) were added to a solution of tert-butyl 4-[(5-amino-1-benzofuran-7-
yl)methyl]-3
methylpiperazine-1-carboxylate (45 mg crude material, 0.10 mmol; obtained in
Step 2) in
dry DCM:THF (2:1; 3 mL). The reaction mixture was stirred at room temperature
for 2 h
and the solvent was evaporated under reduced pressure followed by purification
by
flashtube (15% MeOH in DCM). The residue was dissolved in TFA:water (9:1; 4.5
mL)
and the mixture was stirred at room temperature for 1 h to accomplish removal
of the N-t-
BOC group. The reaction mixture was diluted with DCM (10 mL) and saturated
aqueous
Na2C03 was added to reach pH 8-9 (~15 mL). The phases were separated using
"phase
separator" filters and the organic phase was concentrated. The crude product
was purified
by preparative HPLC (System B; 10-40% MeCN). Pure fractions were combined and
concentrated to give the product as the free base, which was dissolved in MeOH
and 1 M
HCl in ether (200 ~,L, 0.2 mmol) was added. The solvent was evaporated to give
the title
compound (19 mg, 38%) as an off white solid. HPLC 99%, RT=1.46 min (System A;
10-
97% MeCN over 3 min), 100%, RT=1.29 min (System B; 10-97% MeCN over 3 min). 1H
NMR (400 MHz, methanol-d4) 8 ppm 1.72 (d, J--6.53 Hz, 3 H) 2.20 (s, 3 H) 3.39 -
3.62
(m, 5 H) 3.67 - 3.74 (m, 1 H) 3.87 - 3.96 (m, 1 H) 3.98 (s, 3 H) 4.60 (d, J--
13.55 Hz, 1 H)
4.93 (d, J--13.80 Hz, 1 H) 6.87 (d, J--2.26 Hz, 1 H) 7.04 (d, J 8.53 Hz, 1 H)
7.28 - 7.37
(m, 2 H) 7.52 (d, J--2.26 Hz, 1 H) 7.54 (d, J--2.01 Hz, 1 H) 7.85 (d, J--2.01
Hz, 1 H). MS
(ESI+) for CZZHZ~N3O4S m/z 430 (M+H)+.
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EXAMPLE 113
2-Methyl-N-{7-[(2-methylpiperazin-1-yl)methyl]-1-benzofuran-5-
yl~benzenesulfonamide dihydrochloride
The title product was prepared according to the procedure of Example 112, Step
3, starting
from tert-butyl 4-[(5-amino-1-benzofuran-7-yl)methyl]-3-methylpiperazine-1-
carboxylate
(45 mg crude material, 0.10 mmol; obtained in Example 112, Step 2) and o-
toluenesulfonyl
chloride (22 pL, 0.15 mmol). The title compound (17 mg, 35%) was obtained as
an off
white solid. HPLC 99%, RT=1.42 min (System A; 10-97% MeCN over 3 min), 100%,
RT=1.26 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, methanol-d4)
8
ppm 1.69 - 1.74 (m, 3 H) 2.67 (s, 3 H) 3.37 - 3.62 (m, 5 H) 3.67 - 3.75 (m, 1
H) 3.84 - 3.95
(m, 1 H) 4.57 - 4.65 (m, 1 H) 4.90 - 4.97 (m, J--13.55 Hz, 1 H) 6.86 (d, J--
2.26 Hz, 1 H)
7.23 - 7.29 (m, J 7.65, 7.65 Hz, 1 H) 7.31 (d, J--2.01 Hz, 1 H) 7.32 - 7.36
(m, 1 H) 7.40 -
7.46 (m, 1 H) 7.50 (d, J 2.01 Hz, 1 H) 7.85 - 7.90 (m, 2 H). MS (ESI+) for
C2lHasNs03S
m/z 400 (M+H)+.
EXAMPLE 114
2,5-Dichloro-N-(7-[(2-methylpiperazin-1-yl)methyl]-1-benzofuran-5-yl)thiophene-
3-
sulfonamide dihydrochloride
The title product was prepared according to the procedure of Example 112, Step
3, starting
from tert-butyl 4-[(5-amino-1-benzofuran-7-yl)methyl]-3-methylpiperazine-1-
carboxylate
(45 mg crude material, 0.10 mmol; obtained in Example 112, Step 2) and 2,5-
dichlorothiophene-3-sulphonyl chloride (38 mg, 0.15 mmol). The title compound
(23 mg,
43%) was obtained as an off white solid. HPLC 98%, RT=1.61 min (System A; 10-
97%
MeCN over 3 min), 100%, RT=1.43 min (System B; 10-100% MeCN over 3 min). 1H
NMR (400 MHz, methanol-d4) 8 ppm 1.53 (d, J--6.27 Hz, 3 H) 2.87 - 3.02 (m, 1
H) 3.14 -
3.27 (m, 2 H) 3.39 - 3.47 (m, 1 H) 3.47 - 3.54 (m, 1 H) 4.12 - 4.24 (m, 1 H)
4.62 - 4.71 (m,
1 H) 6.89 (d, J--2.26 Hz, 1 H) 7.13 (s, 1 H) 7.30 - 7.32 (m, J--1.76 Hz, 1 H)
7.45 (d, J--2.26
Hz, 1 H) 7.85 (d, J 2.26 Hz, 1 H). *Two hydrogens are not visible in the
spectrum.
Probably "hidden" behind the HZO- and the MeOH signals. MS (ESI+) for
~18H19C12N303S2 YI2/2 460 (M+H)+.
EXAMPLE 115
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2-Methoxy-5-methyl-N-~7-[(3-methylpiperazin-1-yl)methyl]=1-benzofuran-5-
yl~benzenesulfonamide, dihydrochloride
Step'1: 3-Methyl-1-[(5-nitro-1-benzofuran-7-yl)methyl]piperazine
The title compound was prepared according to the procedure of Example 112,
Step 1,
starting from 7-(bromomethyl)-5-nitro-1-benzofuran (120 mg, 70 mol%, 0.39
mmol;
Intermediate 64) and 2-methylpiperazine (196 mg, 1.95 mmol). The crude product
was
purified by flash chromatography (eluent: 4% MeOH, 1% NEt3 in DCM). The title
compound (102 mg, 87%) was obtained as a light yellow sticky oil. HPLC 99%,
RT=1.60
min (System A; 5-60% MeCN over 3 min), 100%, RT=1.40 min (System B; 5-60% MeCN
10~ over 3 min). MS (ESI+) for C14H1~N303 rnlz 276 (M+H)~.
Step 2: tent-Butyl 2-methyl-4-[(5-nitro-1-benzofuran-7-yl)methyl]piperazine-1-
carboxylate
Di-tert-butyl Bicarbonate (89 mg, 0.41 mmol) in dry DCM (2 mL) was added, with
a
15 syringe, under NZ to 3-methyl-1-[(5-nitro-1-benzofuran-7-
yl)methyl]piperazine (102 mg,
0.37 mmol; obtained in Step 1) and NEt3 (77 ~L, 0.77 mmol) in dry DCM (5 mL)
at 0 °C.
The resulting mixture was allowed to attain room temperature and stirred for
1.5 h. The
reaction mixture was diluted with DCM and saturated aqueous NaaC03 was added.
The
organic layer was dried (NaZS04) and concentrated followed by purification
with flash
20 chromatography (eluent: 1.5% MeOH in DCM). This gave the title compound
(124 mg,
89%) as a white foam. HPLC 90%, RT=2.53 min (System A; 5-60% MeCN over 3 min),
90%, RT=2.35 min (System B; 5-60% MeCN over 3 min). MS (ESI+) for Cl9HasN30s
m~z
376 (M+H)+.
25 Step 3: tent-Butyl 4-[(5-amino-1-benzofuran-7-yl)methyl]-2-methylpiperazine-
1-
carboxylate
The title compound was prepared according to the procedure of Example 112,
Step 2,
using tert-butyl 2-methyl-4-[(5-nitro-1-benzofuran-7-yl)methyl]piperazine-1-
carboxylate
('124 mg, 0.33 mmol; obtained in Step 2). The crude title compound (124 mg)
was obtained
30 as a light green solid. This material was used in the next step without
further purification.
HPLC 100%, RT=1.82 min (System A; 5-60% MeCN over 3 min), 100%, RT=1.57 min
(System B; 5-60% MeCN over 3 min). MS (ESI+) for C19H2~N3O3 fYl~2 346 (M+H)+.
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Step 4: 2-Methoxy-5-methyl-N- f 7-[(3-methylpiperazin-1-yl)methyl]-1-
benzofuran-5-
yl)benzenesulfonamide, dihydrochloride
tent-Butyl 4-[(5-amino-1-benzofuran-7-yl)methyl]-2-methylpiperazine-1-
carboxylate (41
mg crude starting material, 0.11 mmol; obtained in Step 3) was dissolved in
dry DCM:THF
(2:1; 3 mL). Pyridine (18 ~L, 0.22 mmol) and 6-methoxy-m-toluenesulfonyl
chloride (36
mg, 0.17 mmol) were added. The resultant mixture was stirred at room
temperature for 2 h
and the solvent was evaporated under reduced pressure followed by purification
by
flashtube (11% MeOH in DCM). The residue was dissolved in TFA:water (9:1; 4.5
mL)
and the mixture was stirred at room temperature for 1 h to accomplish removal
of the N-t-
BOC group. The reaction mixture was diluted with DCM (10 mL) and saturated
aqueous
Na2C03 was added to reach pH 8-9 (~15 mL). The phases were separated using
"phase
separator" filters and the organic phase was concentrated. The crude product
was purified
by preparative HPLC (System B; 10-40% MeCN). Pure fractions were combined and
concentrated to give the product as the free base, which was dissolved in MeOH
and 1 M
HCl in ether (200 ~L, 0.2 mmol) was added. The solvent was evaporated to give
the title
compound (16 mg, 29%) as an off white solid. HPLC 99%, RT=1.48 min (System A;
10-
97% MeCN over 3 min), 100%, RT=1.30 min (System B; 10-97% MeCN over 3 min). 1H
NMR (400 MHz, methanol-d4) ~ ppm 1.38 - 1.45 (m, J--6.53 Hz, 3 H) 2.20 (s, 3
H) 3.34 -
3.42 (m, J--13.30 Hz, 1 H) 3.46 - 3.78 (m, 5 H) 3.79 - 3.91 (m, 1 H) 3.98 (s,
3 H) 4.71 (s, 2
H) 6.87 (d, J 2.26 Hz, 1 H) 7.04 (d, J 8.53 Hz, 1 H) 7.29 - 7.34 (m, J 8.78,
2.01 Hz, 1 H)
7.37 (d, J--2.26 Hz, 1 H) 7.51 - 7.53 (m, J--2.01 Hz, 1 H) 7.54 (d, J--2.26
Hz, 1 H) 7.85 (d,
J--2.01 Hz, 1 H). MS (ESI+) for Cz2HZ~N3O4S m/z 430 (M+H)+.
EXAMPLE 116
N- f 7-[(3-Methylpiperazin-1-yl)methyl]-1-benzofuran-5-yl]-2
(trifluoromethyl)benzenesulfonamide, dihydrochloride
The title compound was prepared according to the procedure of Example 115,
Step 4,
starting from tert-butyl 4-[(5-amino-1-benzofuran-7-yl)methyl]-2-
methylpiperazine-1-
carboxylate (41 mg crude starting material, 0.11 mmol; obtained in Example
115, Step 3)
and 2-(trifluoromethyl)benzenesulfonyl chloride (25 ~,L, 0.17 mmol). The title
compound
(24 mg, 44%) was obtained as an off white solid. HPLC 98%, RT=1.56 min (System
A;
10-97% MeCN over 3 min), 97%, RT=1.37 min (System B; 10-97% MeCN over 3 min).
'H NMR (400 MHz, methanol-d4) 8 ppm 1.41 (d, J--6.53 Hz, 3 H) 3.36 - 3.44 (m,
J 13.30,
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12.05 Hz, 1 H) 3.47 - 3.78 (m, 5 H) 3.81 - 3.94 (m, 1 H) 4.74 (s, 2 H) 6.88
(d, J 2.26 Hz, 1
H) 7.41 (d, J--2.01 Hz, 1 H) 7.53 (d, J 2.26 Hz, 1 H) 7.68 - 7.76 (m, 2 H)
7.88 (d, J--2.01
Hz, 1 H) 7.90 - 7.95 (m, J--6.90, 2.13 Hz, 1 H) 8.09 - 8.13 (m, 1 H). MS
(ESI+) for
C21H22f3N3~3S m/z 454 (M+H)+.
EXAMPLE 117
2-Chloro-N- f 7-[(3-methylpiperazin-1-yl)methyl]-1-benzofuran-5-
yl~benzenesulfonamide, dihydrochloride
The title compound was prepared according to the procedure of Example 115,
Step 4,
starting from tent-butyl 4-[(5-amino-1-benzofuran-7-yl)methyl]-2-
methylpiperazine-1-
carboxylate (41 mg crude starting material, 0.11 mmol; obtained in Example
115, Step 3)
and 2-chlorobenzenesulfonyl chloride (22 pL, 0.17 mmol). The title compound
(21 mg,
39%) was obtained as an off white solid. HPLC 100%, RT=1.42 min (System A; 10-
97%
MeCN over 3 min), 100%, RT=1.26 min (System B; 10-97% MeCN over 3 min). 1H NMR
(400 MHz, methanol-d4) 8 ppm 1.41 (d, J 6.53 Hz, 3 H) 3.32 - 3.37 (m, 1 H)
3.45 - 3.59
(m,2H)3.63-3.76(m,3H)3.78-3.89 (m, 1H)4.70(s,2H)6.86(d,J--2.26 Hz, 1H)
7.36 - 7.41 (m, 1 H) 7.42 (d, J 2.01 Hz, 1 H) 7.49 - 7.54 (m, 1 H) 7.54 - 7.58
(m, 2 H) 7.86
(d, J--2.01 Hz, 1 H) 8.02 (dd, J--7.91, 1.63 Hz, 1 H). MS (ESI+) for
CZOHz2C1N303S m/z
420 (M+H)+.
EXAMPLE 118
N {7-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-ylmethyl]-1-benzofuran-5-yl~-2-
methoxy-
5-methylbenzenesulfonamide, dihydrochloride
Step 1: tent-Butyl (1S,4S)-5-[(5-nitro-1-benzofuran-7-yl)methyl]-2,5-
diazabicyclo[2.2.1]heptane-2-carboxylate
The title compound was prepared according to the procedure of Example 112,
Step l,
starting from 7-(bromomethyl)-5-nitro-1-benzofuran (120 mg, 70 mol%, 0.39
mmol;
Intermediate 64) and tert-butyl (1S,4S)-(-)-2,5-diazabicyclo-(2.2.1)heptane-2-
carboxylate
(93 mg, 0.47 mmol). The title compound (115 mg, 79%) was obtained as a light
yellow
sticky oil. HPLC 99%, RT=2.34 min (System A; 5-60% MeCN over 3 min), 99%,
RT=2.15
min (System B; 5-60% MeCN over 3 min). MS (ESI+) for C19Hz3N30s m/z 374
(M+H)+.
Step 2: tent-Butyl (1S,4S)-5-[(5-amino-1-benzofuran-7-yl)methyl]-2,5-
diazabicyclo [2.2.1] heptane-2-carboxylate
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The title compound was prepared according to.the procedure of Example 112,
Step 2,
using using tent-butyl (1S,4S)-5-[(5-nitro-1-benzofuran-7-yl)methyl]-2,5-
diazabicyclo[2.2.1]heptane-2-carboxylate (116 mg, 0.31 mmol; obtained in Step
1). The
title compound (133 mg) was obtained as a light green solid.. This material
was used in the
next step without further purification. HPLC 99%, RT=1.69 min (System A; 5-60%
MeCN
over 3 min), 100%, RT=1.45 min (System B; 5-60% MeCN over 3 min). MS (ESI+)
for
C19H25N3~3 n2/Z 344 (M+H)+.
Step 3: N ~7-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-ylmethyl]-1-benzofuran-5-
yl~-2-
methoxy-5-methylbenzenesulfonamide, dihydrochloride
The title compound was prepared according to the procedure of Example 112,
Step 3,
starting from test-butyl (1S,4S)-5-[(5-amino-1-benzofuran-7-yl)methyl]-2,5-
diazabicyclo[2.2.1]heptane-2-carboxylate (44 mg crude starting material, 0.10
mmol;
obtatined in Step 2) and 6-methoxy-m-toluenesulfonyl chloride (34 mg, 0.15
mmol). The
title compound (11 mg, 20%) was obtained as an off white solid. HPLC 100%,
RT=1.39
min (System A; 10-97% MeCN over 3 min), 100%, RT=1.24 min (System B; 10-97%
MeCN over 3 min). 1H NMR (400 MHz, methanol-d4) 8 ppm 2.20 (s, 3 H) 2.28 -
2.34 (m,
J--12.80 Hz, 1 H) 2.61 - 2.70 (m, 1 H) 3.52 - 3.58 (m, J--13.80, 2.76 Hz, 1 H)
3.64 - 3.72
(m, J--13.30, 2.51 Hz, 1 H) 3.85 - 3.93 (m, 1 H) 3.98 (s, 3 H) 4.48 (s, 1 H)
4.65 (s, 1 H)
4.70 - 4.76 (m, 1 H) 4.77 - 4.82 (m, 2 H) 6.87 (d, J--2.01 Hz, 1 H) 7.04 (d, J-
-8.53 Hz, 1 H)
7.30 - 7.34 (m, J--8.53, 2.26 Hz, 1 H) 7.41 (d, J--2.26 Hz, 1 H) 7.50 (d, J--
2.01 Hz, 1 H)
7.51 - 7.53 (m, J--2.26 Hz, 1 H) 7.85 (d, J--2.26 Hz; 1 H). MS (ESI+) for
C22H25N3~4S ynlz
428 (M+H)+.
EXAMPLE 119
N ~7-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-ylmethyl]-1-benzofuran-5-yl~-2-
(trifluoromethyl)benzenesulfonamide, dihydrochloride
The title compound was prepared according to the procedure of Example 112,
Step 3,
starting from tef°t-butyl (1S,4S~-5-[(5-amino-1-benzofuran-7-yl)methyl]-
2,5-
diazabicyclo[2.2.1]heptane-2-carboxylate (44 mg crude starting material, 0.10
mmol;
obtained in Example 118, Step 2) and 2-(trifluoromethyl)benzenesulfonyl
chloride (24 ~.L,
0.15 mmol). The title compound (18 mg, 34%) was obtained as an off white
solid. HPLC
99%, RT=1.46 min (System A; 10-97% MeCN over 3 min), 100%, RT=1.29 min (System
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B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, methanol-d4) 8 ppm 2.31 - 2.37
(m,
J--13.05 Hz, 1 H) 2.65 - 2.78 (m, J--6.27 Hz, 1 H) 3.53 - 3.60 (m, J--13.43,
2.89 Hz, 1 H)
3.67 - 3.76 (m, 1 H) 3.88 - 3.96 (m, J 12.80 Hz, 1 H) 4.51 (s, 1 H) 4.66 (s, 1
H) 4.72 - 4.79
(m, 1 H) 4.84 (d, 2 H) 6.88 (d, J--2.01 Hz, 1 H) 7.46 (d, J--2.01 Hz, 1 H)
7.51 (d, J--2.01
Hz, 1 H) 7.68 - 7.75 (m, 2 H) 7.88 (d, J--2.26 Hz, 1 H) 7.89 - 7.94 (m, 1 H)
8.09 - 8.13 (m,
1 H). MS (ESI+) for C21H20F3N3~3S m/z 452 (M+H)+.
EXAMPLE 120
N {7-[(1S,4.S~-2,5-Diazabicyclo[2.2.1]hept-2-ylmethyl]-1-benzofuran-5-yl~-2-
methylbenzenesulfonamide, dihydrochloride
The title compound was prepared according to the procedure of Example 112,
Step 3,
starting from test-butyl (1S,4S~-5-[(5-amino-1-benzofuran-7-yl)methyl]-2,5-
diazabicyclo[2.2.1]heptane-2-carboxylate (44 mg crude starting material, 0.10
mmol;
obtained in Example 118, Step 2) and o-toluenesulfonyl chloride (22 ~,L, 0.15
mmol). The
title compound (15 mg, 31%) was obtained as an off white solid. HPLC 98%,
RT=1.37 min
(System A; 10-97% MeCN over 3 min), 97%, RT=1.21 min (System B; 10-97% MeCN
over 3 min). 1H NMR~ (400 MHz, methanol-d4) 8 ppm 2.28 - 2.34 (m, 1 H) 2.66
(s, 3 H)
2.67 - 2.72 (m, 1 H) 3.52 - 3.59 (m, J--13.68, 2.64 Hz, 1 H) 3.63 - 3.76 (m, 1
H) 3.85 - 3.93
(m, J 12.80 Hz, 1 H) 4.45 - 4.51 (m, 1 H) 4.65 (s, 1 H) 4.69 - 4.78 (m, 1 H)
4.78 - 4.83 (m,
2 H) 6.86 (d, J--2.26 Hz, 1 H) 7.23 - 7.29 (m, 1 H) 7.31 - 7.36 (m, J--7.53
Hz, 1 H) 7.37 -
7.46 (m, 2 H) 7.48 (d, J--2.26 Hz, 1 H) 7.84 - 7.88 (m, 2 H). MS (ESI+) for
CZ1H23N3O3S
m/z 398 (M+H)+.
EXAMPLE 121
2-Methoxy-5-methyl-N-~7-[(tra~zs-2,5-dimethylpiperazin-1-yl)methyl]-1-
benzofuran-
5-yl~benzenesulfonamide, bis(trifluoroacetate)
Step 1: trafzs-2,5-Dimethyl-1-[(5-nitro-1-benzofuran-7-yl)methyl]piperazine
The title compound was prepared according to the procedure of Example 112,
Step 1,
starting from 7-(bromomethyl)-5-nitro-1-benzofuran (0.16 g, 0.6 mmol) and
trans-2,5
dimethylpiperazine (0.36 g, 3.1 mmol). This afforded the title product (0.11
g, 60%) as a
light yellow solid. HPLC 98% RT=1.26 min (System A; 10-97% MeCN over 3 min).
1H
NMR (400 MHz, CDC13) 8 ppm 0.93 (d, J--6.3 Hz, 3 H) 1.17 (d, J--6.0 Hz, 3 H)
1.48 (br s,
1H) 1.79 (dd, J--11.0, 10.3 Hz, 1 H) 2.29 - 2.41 (m, 1 H) 2.63 - 2.75 (m, 2 H)
2.80 - 2.89
(m, 1 H) 2.93 (dd, J--12.0, 3.3 Hz, 1 H) 3.61 (d, J--14.6 Hz, 1 H) 4.28 (d, J--
14.3 Hz, 1 H)
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6.91 (d, J--2.3 Hz, 1 H) 7.76 (d, J--2.3 Hz, 1 H) 8.29 (d, J--2.3 Hz, 1 H)
8.41 (d, J 2.3 Hz,
1 H). MS (ESI+) m/z 290.1 (M+H)+.
Step 2: tent-Butyl trafZS-2,5-dimethyl-4-[(5-vitro-1-benzofuran-7-
yl)methyl]piperazine-
1-carboxylate
trans-2,5-Dimethyl-1-[(5-vitro-1-benzofuran-7-yl)methyl]piperazine (0.11 g,
0.4 mmol;
obtained in Step 1) was dissolved in MeOH. Boc-anhydride (0.114 g, 0.5 mmol)
was added
and the reaction was stirred at ambient temperature overnight. The solvent was
evaporated
and the residue was dissolved in DCM and washed with citric acid. The organic
layer was
dried (MgS04) and evaporated to give 0.135 g (91%) of the title product. HPLC
96%
Rt=1.79 min (System A; 10-97% MeCN over 3 min). 1H NMR (400 MHz, CDCl3) 8 ppm
1.07 (d, J 6.5 Hz, 3 H) 1.27 (d, J--6.8 Hz, 3 H) 1.46 (s, 9 H) 2.18 - 2.27 (m,
1 H) 2.82 (dd,
J--11.5, 4.3 Hz, 1 H) 2.98 - 3.06 (m, 1 H) 3.37 (dd, J 13.1, 3.5 Hz, 1 H) 3.65
- 3.75 (d,
J 13.1 Hz, 1 H) 3.83 - 3.95 (m, 2 H) 4.16 - 4.27 (m, 1 H) 6.91 (d, J--2.3 Hz,
1 H) 7.76 (d,
J 2.3 Hz, 1 H) 8.25 - 8.55 (m, 2 H). MS (ESI+) m/z 390.2 (M+H)'~.
Step 3: tent-Butyl trafZS-4-[(5-amino-1-benzofuran-7-yl)methyl]-2,5-
dimethylpiperazine-1-carboxylate
test-Butyl tans-2,5-dimethyl-4-[(5-vitro-1-benzofuran-7-yl)methyl]piperazine-1-
carboxylate (0.14 g, 0.35 mmol; obtained in Step 2) was dissolved in THF/EtOH
(4:1; 5
mL). Excess Raney-Ni (slurry in EtOH) was added followed by hydrazine hydrate
(0.07 g,
1.39 mmol). The reaction mixture was stirred overnight at ambient temperature.
After
filtration and evaporation of solvent, a crude oil (0.11 g, 87%) was obtained
that was used
in the next step without further purification. HPLC 86% RT=1.15 min (System B;
10-97%
MeCN over 3 min). MS (ESI+) m/z 360.2 (M+H)+.
Step 4: test-Butyl trams-4-[(5-f [(2-methoxy-5-methylphenyl)sulfonyl]amino}-1-
benzofuran-7-yl)methyl]-2,5-dimethylpiperazine-1-carboxylate
tent-Butyl trans-4-[(5-amino-1-benzofuran-7-yl)methyl]-2,5-dimethylpiperazine-
1-
carboxylate (0.037 g, 0.1 mmol; obtained in Step 3) was dissolved in DCM and
reacted
with 2-methoxy-5-methylbenzenesulfonyl chloride (0.045 g, 0.2 mmol) and
pyridine
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(0.024 g, 0.3 mmol) overnight. The mixture was washed with 1 M HCl and the
organic
layer was dried (MgS04) and evaporated. The crude was purified using flashtube
(10%
MeOH in DCM) and afforded the title product (0.026 g, 48%). HPLC 93% RT=2.01
min
(System A; 10-97% MeCN over 3 min), 93% RT=1.85 min (System B; 10-97% MeCN
over 3 min). MS (ESI+) m/z 544.2 (M+H)+.
Step 5: 2-Methoxy-5-methyl-N- f 7-[(traps-2,5-dimethylpiperazin-1-yl)methyl]-1-
benzofuran-5-yl}benzenesulfonamide, bis(trifluoroacetate)
A solution of tent-butyl traps-4-[(5- f [(2-methoxy-5-
methylphenyl)sulfonyl]amino}-1-
benzofuran-7-yl)methyl]-2,5-dimethylpiperazine-1-carboxylate (0.026 g, 0.047
mmol;
obtained in Step 4) in TFA:water (9:1) was stirred at ambient temperature for
1 h. The
solvent was evaporated and the residue was purified by preparative HPLC
(System A; 20-
40% MeCN). Pure fractions were combined and concentrated to give the title
compound
as a colorless TFA-salt (0.020 mg, 63%). HPLC 100%, RT=1.52 min (System A; 10-
97%
MeCN over 3 min), 100%, RT=1.25 min (System B; 10-97% MeCN over 3 min). 1H NMR
(400 MHz, methanol-d4) 8 ppm 1.24 (d, J--6.53 Hz, 3 H) 1.48 (d, J--6.27 Hz, 3
H) 2.20 (s,
3 H) 2.61 (dd, J--13.30, 11.54 Hz, 1 H) 3.05 - 3.23 (m, 3 H) 3.39 - 3.47 (m, 1
H) 3.50 (dd,
J--12.92, 2.64 Hz, 1 H) 3.97 (s, 3 H) 4.07 (d, J--13.80 Hz, 1 H) 4.60 (d, J--
13.80 Hz, 1 H)
6.80 (d, J--2.26 Hz, 1 H) 7.03 (d, J--8.53 Hz, 1 H) 7.24 (d, J--2.01 Hz, 1 H)
7.29 - 7.33 (m,
J--8.78, 2.01 Hz, 1 H) 7.35 (d, J--2.01 Hz, 1 H) 7.48 - 7.51 (m, J--1.51 Hz, 1
H) 7.76 (d,
J 2.01 Hz, 1 H). MS (ESI+) for C23H29N3O~.S m/z 444 (M+H)+.
EXAMPLE 122
2-Methyl-N- f 7-[(trafas-2,5-dimethylpiperazin-1-yl)methyl]-1-benzofuran-5-
yl}benzenesulfonamide, bis(trifluoroacetate)
Step 1: tent-Butyl trasas-2,5-dimethyl-4-[(5-~[(2-methylphenyl)sulfonyl]amino}-
1-
benzofuran-7-yl)methyl]piperazine-1-carboxylate
The title product was prepared according to the procedure of Example 121, Step
4, starting
from tent-butyl trams-4-[(5-amino-1-benzofuran-7-yl)methyl]-2,5-
dimethylpiperazine-1-
carboxylate (obtained in Example 121, Step 3) and 2-methylbenzenesulfonyl
chloride
(0.039 g, 0.2 mmol). Yield: 0.022 g (43%). HPLC 95% RT=1.99 min (System A; 10-
97%
MeCN over 3 min), 93% RT=1.85 min (System B; 10-97% MeCN over 3 min). MS
(ESI+)
m/z 514.2(M+H)+.
1s2
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Step 2: 2-Methyl-N-]7-[(traszs-2,5-dimethylpiperazin-1-yl)methyl]-1-benzofuran-
5-
yl}benzenesulfonamide, bis(trifluoroacetate)
The title product was prepared according to the procedure of Example 121, Step
5, starting
from tent-butyl trans-2,5-dimethyl-4-[(5-{[(2-methylphenyl)sulfonyl]amino}-1-
benzofuran-7-yl)methyl]piperazine-1-carboxylate (0.022 g, 0.043 mmol; obtained
in Step
1) . Yield: 0.017 g (62%). HPLC 100%, RT=1.49 min (System A; 10-97% MeCN over
3
min), 100%, RT=1.22 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz,
methanol-d4) 8 ppm 1.20 - 1.27 (m, 3 H) 1.43 - 1.51 (m, 3 H) 2.51 - 2.65 (m, 1
H) 2.63 (s,
3 H) 3.02 - 3.25 (m, 3 H) 3.38 - 3.45 (m, 1 H) 3.45 - 3.53 (m, 1 H) 4.00 -
4.11 (m, 1 H)
4.53 - 4.64 (m, 1 H) 6.79 (d, J--2.26 Hz, 1 H) 7.15 - 7.35 (m, 4 H) 7.40 -
7.46 (m, 1 H) 7.75
- 7.80 (m, 1 H) 7.82 - 7.87 (m, J--8.03, 1.25 Hz, 1 H). MS (ESI+) for
CzzH2~N3O3S m/z 414
(M+H)+.
EXAMPLE 123
2-Chloro-N-{7-[(trasZS-2,5-dimethylpiperazin-1-yl)methyl]-1-benzofuran-5-
yl}benzenesulfonamide, bis(trifluoroacetate)
Step 1: tent-Butyl trafzs-4-[(5-~[(2-chlorophenyl)sulfonyl]amino}-1-benzofuran-
7-
yl)methyl]-2,5-dimethylpiperazine-1-carboxylate
The title product was prepared according to the procedure of Example 121, Step
4, starting
from tef°t-butyl trans-4-[(5-amino-1-benzofuran-7-yl)methyl]-2,5-
dimethylpiperazine-1-
carboxylate (obtained in Example 121, Step 3) and 2-chlorobenzenesulfonyl
chloride
(0.043 g, 0.2 mmol). Yield: 0.017 g (26%). HPLC 94% RT=2.01 min (System A; 10-
97%
MeCN over 3 min), 98% RT=1.85 min (System B; 10-97% MeCN over 3 min). MS
(ESI+)
m/z 534.2 (M+H)+.
Step 2: 2-Chloro-N- f 7-[(trarls-2,5-dimethylpiperazin-1-yl)methyl]-1-
benzofuran-5-
yl}benzenesulfonamide, bis(trifluoroacetate)
The title compound was prepared according to the procedure of Example 121,
Step 5,
starting from teat-butyl trans-4-[(5-{[(2-chlorophenyl)sulfonyl]amino}-1-
benzofuran-7-
yl)methyl]-2,5-dimethylpiperazine-1-carboxylate (0.017 g, 0.032 mmol; obtained
in Step
1). Yield: 0.016 g (76%). HPLC 99%, RT=1.47 min (System A; 10-97% MeCN over 3
min), 100%, RT=1.20 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz,
methanol-d4) 8 ppm 1.23 (d, J--6.53 Hz, 3 H) 1.43 (d, J 5.77 Hz, 3 H) 2.48
(dd, J--13.18,
11.42 Hz, 1 H) 3.00 - 3.06 (m, 2 H) 3.10 (dd, J--13.30, 3.26 Hz, 1 H) 3.34 -
3.42 (m, 1 H)
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3.42 - 3.47 (m, 1 H) 3.96 (d, J 14.05 Hz, 1 H) 4.51 (d, J--14.05 Hz, 1 H) 6.79
(d, J--2.01
Hz, 1 H) 7.24 (d, J--2.01 Hz, 1 H) 7.33 - 7.39 (m, 2 H) 7.47 - 7.53 (m, 1 H)
7.53 - 7.57 (m,
1 H) 7.76 (d, J 2.26 Hz, 1 H) 7.94 - 7.99 (m, J--7.78, 1.51 Hz, 1 H). MS
(ESI+) for
CztHa4C1N3O3S rnlz 434 (M+H)+.
INTERMEDIATE 65
Methyl 2,3-dihydro-1-benzofuran-7-carboxylate
2,3-Dihydrobenzofuran-7-carboxylic acid (8 g, 48.7 mmol) was dissolved in
methanol
(39.6 mL, 975 mmol) and concentrated sulfuric acid (2.6 mL, 48.7 mmol) was
slowly
added. The mixture was refluxed at 80 °C for 17 h. The solvent was
evaporated and the
residue was dissolved in ethyl acetate and washed with brine. The organic
layer was
evaporated to give the title compound as a beige solid. Yield: 8.6 g (99%).
HPLC purity
93%, RT=1.72 min (System A; 10-97% MeCN over 3 min); 96%, RT=1.67 min (System
B;
10-97% MeCN over 3 min). MS (ESI+) for CIOHio03 m/z 179 (M+H)+.
INTERMEDIATE 66
Methyl 5-[(2-methoxy-5-methylphenyl)sulfonyl]-2,3-dihydro-1-benzofuran-7-
carboxylate
To methyl 2,3-dihydro-1-benzofuran-7-carboxylate (1 g, 5.6 mmol; Intermediate
65) were
2-methoxy-5-methylbenzenesulfonic acid (1.13 g, 5.6 mmol) and phosphorus
pentoxide-
methanesulfonic acid solution (1:10; 13.5 mL) added. The mixture was stirred
at room
temperature for 48 h. Additional 2-methoxy-5-methylbenzenesulfonic acid (0.56
g, 2.8
mmol) was added and the reaction mixture was stirred at 50 °C for 15 h.
The mixture was
poured onto water/ice and the formed precipitate was filtrated off, dissolved
in DCM and
evaporated. The crude product was purified using flash chromatography (eluent:
isohexane:EtOAc 1:1) yielding the title compound. Yield: 1.07 g (53%). MS
(ESI+) for
C18H1806S nalz 363 (M+H)+.
INTERMEDIATE 67
Methyl5-[(2-methoxy-5-methylphenyl)sulfonyl]-1-benzofuran-7-carboxylate
Methyl 5-[(2-methoxy-5-methylphenyl)sulfonyl]-2,3-dihydro-1-benzofuran-7-
carboxylate
(879 mg, 2.4 mmol; Intermediate 66) was dissolved in chlorobenzene (6 mL). N-
bromosuccinimide (432 mg, 2.4 mmol) and benzoyl peroxide (58 mg, 0.24 mmol)
were
added and the mixture was stirred at 100 °C for 17 h. The mixture was
washed with
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saturated aqueous NaHC03 and the organic layer was concentrated. Yield: 405 mg
(46%)
after purification by preparative HPLC (System F; 40-60% MeCN). MS (ESI+) for
CI8H16O6S m/z 361 (M+H)~.
INTERMEDIATE 68
~5-[(2-Methoxy-5-methylphenyl)sulfonyl]-1-benzofuran-7-yl]methanol
Methyl 5-[(2-methoxy-5-methylphenyl)sulfonyl]-1-benzofuran-7-carboxylate (400
mg, 1.1
mmol; Intermediate 67) was dissolved in dry THF (3 mL) and 1 M lithium
aluminiumhydride in THF (0.3 mL) was slowly added. The mixture was stirred at
room
temperature overnight. After this time, water (0.15 mL) was added and stirring
was
continued for 10 min, followed by the addition of 2 M aqueous NaOH (0.15 mL)
and
water (0.45 mL). The precipitate formed was filtered off and the solvent was
evaporated.
The crude product was used in the next step without further purification. MS
(ESI+) for
Ci~H1605S m/z 333 (M+H)+.
INTERMEDIATE 69
7-(Chloromethyl)-5-[(2-methoxy-5-methylphenyl)sulfonyl]-1-benzofuran
Oxalyl chloride (0.1 mL, 1.1 mmol) was dissolved in dry DCM (2 mL) and DMF
(0.9 mL,
1.1 mmol) was added (very exothermic reaction). f 5-[(2-Methoxy-5-
methylphenyl)sulfonyl]-1-benzofuran-7-yl]methanol (370 mg, 1.1 mmol;
Intermediate 68)
was added and the resultant mixture was stirred at room temperature for 17 h.
The mixture
was washed with 2 M NaOH (2x) and the organic layer was concentrated yielding
the
crude product. This material was used in the next step without further
purification. MS
(ESI+) for C1~H15C104S m/z 351 (M+H)~.
EXAMPLE 124
1-(~5-[(2-Methoxy-5-methylphenyl)sulfonyl]-1-benzofuran-7-
yl]methyl)piperazine,
trifluoroacetate
7-(Chloromethyl)-5-[(2-methoxy-5-methylphenyl)sulfonyl]-1-benzofuran (35 mg,
O.lmmol; Intermediate 69) was dissolved in ethanol (2 mL) and N-t-Boc-
piperazine (28
mg, 0.1 mmol) and sodium bicarbonate (13 mg, 0.1 mmol) were added. The mixture
was
heated at 80 °C in a StemBlock overnight. The mixture was extracted
with chloroform (x2)
and the chloroform-layers were evaporated. Purification was done by
preparative
HPLC/MS (System A; 10-40% MeCN). The obtained N-t-BOC derivative of the title
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compound was dissolved in DCM (1 mL) and TFA (1 mL) was added. After being
stirred
at room temperature overnight, the solvent was evaporated to provide the title
compound.
Yield: 11 mg (27%) after purification by preparative HPLC/MS (System A; 10-40%
MeCN). HPLC purity 98%, RT=1.50 min (System A; 10-97% MeCN over 3 min); 99%,
RT=1.30 min (System B; 10-90% MeCN over 3 min). 1H NMR (400 MHz, CDC13) 8 ppm
2.35 (s, 3 H) 3.26 - 3.46 (m, 8 H) 3.70 (s, 3 H) 4.34 (s, 2 H) 6.78 (d, J--
8.53 Hz, 1 H) 6.90
(d, J 2.01 Hz, 1 H) 7.32 (dd, J 8.41, 1.63 Hz, 1 H) 7.75 (d, J--1.25 Hz, 1 H)
7.89 - 7.98
(m, 2 H) 8.30 (d, J--1.25 Hz, 1 H). MS (ESI+) for C21H24N2~4S m/z 401 (M+H)+.
EXAMPLE 125
1-f [5-(Phenylsulfonyl)-1-benzofuran-7-yl]methyl~piperazine, trifluoroacetate
Step 1: Methyl 5-(phenylsulfonyl)-2,3-dihydro-1-benzofuran-7-carboxylate
The title compound was prepared according to the procedure of Intermediate 66
starting from methyl 2,3-dihydro-1-benzofuran-7-carboxylate (1 g, 5.6 mmol;
Intermediate
65) and benzenesulfonic acid (0.89 g, 5.6 mmol). Yield: 882 mg (49%). MS
(ESI+) for
C16H14~SS m/z 319 (M+H)+.
Step 2: Methyl 5-(phenylsulfonyl)-1-benzofuran-7-carboxylate
The title compound was prepared according to the procedure of Intermediate 67
starting
from methyl 5-(phenylsulfonyl)-2,3-dihydro-1-benzofuran-7-carboxylate (198 mg,
0.6
mmol; obtained in Step 1). Yield: 80 mg (41%) after purification by
preparative HPLC
(System F; 40-70% MeCN). MS (ESI+) for C16H140sS m/z 317 (M+H)+.
Step 3: [5-(Phenylsulfonyl)-1-benzofuran-7-yl]methanol
The title compound was prepared according to the procedure of Intermediate 68
starting
from methyl 5-(phenylsulfonyl)-1-benzofuran-7-carboxylate (80 mg, 0.25 mmol;
obtained
in Step 2). The crude material was used directly in the subsequent reaction.
MS (ESI+) for
C15H12~4S m/z 289 (M+H)+.
Step 4: 7-(Chloromethyl)-5-(phenylsulfonyl)-1-benzofuran
The title compound was prepared according to the procedure of Intermediate 69
starting
from [5-(phenylsulfonyl)-1-benzofuran-7-yl]methanol (73 mg, 0.3 mmol; obtained
in Step
3). The crude material was used directly in the subsequent reaction. MS (ESI+)
for
Cl5HaC10sS rnlz 307 (M+H)+.
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Step 5: 1-~[5-(Phenylsulfonyl)-1-benzofuran-7-yl]methyl]piperazine,
trifluoroacetate
N-t-BOC-piperazine (24 mg, 0.13 mmol) and sodium bicarbonate (11 mg, 0.13
mmol)
were added to a solution of 7-(chloromethyl)-5-(phenylsulfonyl)-1-benzofuran
(26 mg,
0.08 mmol; obtained in Step 4) in ethanol (2 mL). The mixture was stirred at
80 °C in a
STEM-block overnight and the solvent was evaporated. The obtained N-t-BOC
derivative
of the title compound was dissolved in DCM (1 mL) and TFA (1 mL) was added.
After the
mixture had been stirred at room temperature for 2 h, the solvent was
evaporated to
provide the title compound. Yield: 6.1 mg (12%) after purification by
preparative
HPLC/MS (System A; 10-40% MeCN). HPLC purity 99%, RT=1.39 min (System A; 10-
97% MeCN over 3 min); 96%, RT=1.16 min (System B; 10-90% MeCN over 3 min). 1H
NMR (400 MHz, CDC13) 8 ppm 3.10 - 3.17 (m, 4 H) 3.34 - 3.39 (m, 4 H) 4.20 (s,
2 H)
6.87 - 6.92 (m, 1 H) 7.46 - 7.58 (m, 3 H) 7.75 (d, J 2.26 Hz, 1 H) 7.92 - 7.97
(m, 3 H) 8.26
(d, J--1.76 Hz, 1 H). MS (ESI+) for C19H2oN2O3S m/z 357 (M+H)+.
EXAMPLE 126
1-({5-[(4-Methylphenyl)sulfonyl]-1-benzofuran-7-yl]methyl)piperazine,
trifluoroacetate
Step 1: Methyl 5-[(4-methylphenyl) sulfonyl]-2,3-dihydro-1-benzofuran-7-
carboxylate
The title compound was prepared according to the procedure of Intermediate 66
starting
from methyl 2,3-dihydro-1-benzofuran-7-carboxylate (1 g, 5.6 mmol;
Intermediate 65) and
4-methylbenzenesulfonic acid (0.97 g, 5.6 mmol). Yield: 405 mg (22%). MS
(ESI+) for
C1~H1605S rnlz 333 (M+H)+.
Step 2: Methyl 5-[(4-methylphenyl)sulfonyl]-1-benzofuran-7-carboxylate
The title compund was prepared according to the procedure of Intermediate 67
starting
from methyl 5-[(4-methylphenyl) sulfonyl]-2,3-dihydro-1-benzofuran-7-
carboxylate (117
mg, 0.4 mmol; obtained in Step 1). Yield: 62 mg (53%) after purification by
preparative
HPLC (System F; 40-60% MeCN). MS (ESI+) for C1~H160sS rnlz 331 (M+H)+.
Step 3: {5-[(4-Methylphenyl)sulfonyl]-1-benzofuran-7-yl~methanol
The title compound was prepared according to the procedure of Intermediate 68
starting
from methyl 5-[(4-methylphenyl)sulfonyl]-1-benzofuran-7-carboxylate (62 mg,
0.19
mmol; obtained in Step 2). MS (ESI+) for CI6Hia04S nalz 303 (M+H)+.
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Step 4: 7-(Chloromethyl)-5-[(4-methylphenyl)sulfonyl]-1-benzofuran
The title compound was prepared according to the procedure of Intermediate 69
starting
from {5-[(4-methylphenyl)sulfonyl]-1-benzofuran-7-yl}methanol (57 mg, 0.2
mmol;
obtained in Step 3). MS (ESI+) for Cl6HisC1O3S nz/z 321 (M+H)+.
Step 5: 1-({5-[(4-Methylphenyl)sulfonyl]-1-benzofuran-7-yl~methyl)piperazine,
trifluoroacetate
The title compound was prepared according to the procedure of Example 125,
Step 5,
starting from 7-(chloromethyl)-5-[(4-methylphenyl)sulfonyl]-1-benzofuran (20
mg, 0.06
mmol; obtained in Step 4). Yield: 5.8 mg (15%) after purification by
preparative
HPLC/MS (System A; 5-20% MeCN). HPLC purity 99%, RT=1.52 min (System A; 10-
97% MeCN over 3 min); 99%, RT=1.28 min (System B; 10-90% MeCN over 3 min). 1H
NMR (400 MHz, CHLOROFORM-D) 8 ppm 2.37 (s, 3 H) 3.33 - 3.37 (m, 4 H) 3.44 -
3.50
(m, 4 H) 4.37 (s, 2 H) 6.90 (d, J 2.26 Hz, 1 H) 7.28 (d, J--8.03 Hz, 2 H) 7.75
(d, J 2.26
Hz, 1 H) 7.81 (d, J--8.28 Hz, 2 H) 7.97 (d, J--1.51 Hz, 1 H) 8.26 (d, J 1.76
Hz, 1 H). MS
(ESI+) for C2pH22N2~3s jnlz 371 (M+H)~.
EXAMPLE 127
1-({5-[(2-Methoxy-5-methylphenyl)sulfonyl]-1-benzofuran-7-yl)methyl)-1,4-
diazepane, trifluoroacetate
7-(Chloromethyl)-5-[(2-methoxy-5-methylphenyl)sulfonyl]-1-benzofuran (66 mg,
0.19
mmol; Intermediate 69) was dissolved in ethanol (2 mL) and 1-boc-
homopiperazine (57
mg, 0.28 mmol) and sodium bicarbonate (24 mg, 0.28 mmol) were added. The
mixture was
heated to 80 °C in a StemBlock overnight. The mixture was extracted
with chloroform (x2)
and the chloroform-layers were evaporated. The obtained N-t-BOC derivative of
the title
compound was dissolved in DCM (1 mL) and TFA (1 mL) was added. After being
stirred
at room temperature for 2 h, the solvent evaporated to provide the title
compound. Yield:
39 mg (32%) after purification by preparative HPLC/MS (System A; 10-40% MeCN).
HPLC purity 99%, RT=1.41 min (System A; 10-97% MeCN over 3 min); 99%, RT=1.19
min (System B; 10-90% MeCN over 3 min). 1H NMR (400 MHz, CDC13) 8 ppm 2.16
(bs,
2H)2.24(s,3H)3.30(bs,2H)3.39(bs,2H)3.54(bs,2H)3.57-3.67(m,SH)4.50 (s,
1s8
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2 H) 6.69 (d, J--8.78 Hz, 1 H) 6.81 (d, J 1.76 Hz, 1 H) 7.23 (d, J--8.53 Hz, 1
H) 7.66 (s, 1
H) 7.81 (s, 1 H) 7.94 (s, 1 H) 8.22 (s, 1 H). MS (ESI+) for C22H26N2~4S m/z
415 (M+H)+.
EXAMPLE 128
1-~[5-(Phenylsulfonyl)-1-benzofuran-7-yl]methyl]-1,4-diazepane,
trifluoroacetate
The title compound was prepared according to the procedure of Example 127
starting from
7-(chloromethyl)-5-(phenylsulfonyl)-1-benzofuran (37 mg, 0.12 mmol; obtained
in
Example 125, Step 4). Yield: 9.4 mg (13%) after purification by preparative
HPLC/MS
(System A; 10-40% MeCN). HPLC purity 99%, RT=1.29 min (System A; 10-97% MeCN
over 3 min); 99%, RT=1.16 min (System B; 10-90% MeCN over 3 min). 1H NMR (400
MHz, CDC13) ~ ppm 2.28 - 2.35 (m, 2 H) 3.42 - 3.52 (m, 4 H) 3.65 - 3.77 (m, 4
H) 4.60 (s,
2 H) 6.93 (d, J--2.26 Hz, 1 H) 7.46 - 7.53 (m, 2 H) 7.53 - 7.59 (m, 1 H) 7.77
(d, J--2.26 Hz,
1 H) 7.92 - 7.97 (m, 2 H) 8.09 (d, J--1.76 Hz, 1 H) 8.32 (d, J 1.76 Hz, 1 H).
MS (ESI+) for
C20H22N2~3s nalz 371 (M+H)+.
EXAMPLE 129
1-(~5-[(4-Methylphenyl)sulfonyl]-1-benzofuran-7-ylj~methyl)-1,4-diazepane,
trifluoroacetate
The title compound was prepared according to the procedure of Example 127
starting from
7-(chloromethyl)-S-[(4-methylphenyl)sulfonyl]-1-benzofuran (32 mg, 0.10 mmol;
obtained
in Example 126, Step 4). Yield: 8.1 mg (13%) after purification by preparative
HPLC/MS
(System A; 10-40% MeCN). HPLC purity 99%, RT=1.42 min (System A; 10-97% MeCN
over 3 min); 99%, RT=2.94 min (System B; 10-90% MeCN over 3 min). 1H NMR (400
MHz, CDCl3) 8 ppm 2.31 (bs, 2 H) 2.37 (s, 3 H) 3.41 - 3.54 (m, 4 H) 3.66 -
3.79 (m, 4 H)
4.61 (s, 2 H) 6.91 (d, J--2.26 Hz, 1 H) 7.26 - 7.31 (m, 2 H) 7.75 (d, J--2.26
Hz, 1 H) 7.81
(d, J--8.28 Hz, 2 H) 8.07 (d, J--1.51 Hz, 1 H) 8.29 (d, J--1.76 Hz, 1 H). MS
(ESI+) for
C21H24N2~3s m/z 385 (M+H)+.
EXAMPLE 130
1-( f 5-[(2-Methoxy-5-methylphenyl)sulfonyl]-1-benzofuran-7-yl}methyl)-2-
methylpiperazine, trifluoroacetate
7-(Chloromethyl)-5-[(2-methoxy-5-methylphenyl)sulfonyl]-1-benzofuran (60 mg,
0.17
mmol; Intermediate 69) was dissolved in ethanol (2 mL) and tert-butyl 3-
methylpiperazine-1-carboxylate (41 mg, 0.21 mmol) and sodium bicarbonate (22
mg, 0.26
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mmol) were added. The resulting mixture was heated at 80 °C in a
StemBlock overnight.
The mixture was extracted with chloroform (x2) and the chloroform layers were
concentrated. The obtained N-t-BOC derivative of the title compound was
dissolved in
DCM (1 mL) and TFA (1 mL) was added. After the mixture had been stirred at
room
temperature for 2 h, the solvent was evaporated. Yield: 33 mg (36%) after
purification by
preparative HPLCIMS (System A; 10-40% MeCN). HPLC purity 99%, RT=1.55 min
(System A; 10-97% MeCN over 3 min); 99%, RT=1.37 min (System B; 10-97% MeCN
over 3 min). 1H NMR (400 MHz, CDC13) 8 ppm 1.65 (d, J--6.27 Hz, 3 H) 2.34 (s,
3 H)
3.35 - 3.61 (m, 6 H) 3.68 (s, 3 H) 3.90 - 3.99 (m, 1 H) 4.46 (d, J--13.55 Hz,
1 H) 4.82 (d,
J--13.55 Hz, 1 H) 6.77 (d, J--8.53 Hz, 1 H) 6.92 (d, J--2.26 Hz, 1 H) 7.32
(dd, J--8.53, 1.76
Hz, 1 H) 7.75 (d, J--2.26 Hz, 1 H) 7.87 (d, J--2.01 Hz, 1 H) 7.97 (d, J 1.25
Hz, 1 H) 8.34
(d, .l--1.51 Hz, 1 H). MS (ESI+) for C22Hz6Na04S m/z 414 (M+H)+.
EXAMPLE 131
1-(~5-((Z-Methoxy-5-methylphenyl)sulfonyl]-1-benzofuran-7-yl}methyl)-3-
methylpiperazine, trifluoroacetate
7-(Chloromethyl)-5-[(2-methoxy-5-methylphenyl)sulfonyl]-1-benzofuran (60 mg,
0.17
mmol; Intermediate 69) was dissolved in ethanol (2 mL) and 2-methylpiperazine
(21 mg,
0.21 mmol) and sodium bicarbonate (22 mg, 0.26 mmol) were added. The mixture
was
heated at 80 °C in a StemBlock overnight. The mixture was extracted
with chloroform (x2)
and the chloroform layers were evaporated. The obtained N-t-BOC derivative of
the title
compound was dissolved in DCM (1 mL) and TFA (1 mL) was added. After the
mixture
had been stirred at room temperature for 2 h, the solvent was evaporated.
Yield: 28 mg
(31 %) after purification by preparative HPLC/MS (System A; 10-40% MeCN). HPLC
purity 99%, RT=1.57 min (System A; 10-97% MeCN over 3 min); 99%, RT=1.35 min
(System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, CDC13) 8 ppm 0.80 - 0.90
(m, 2 H) 1.30 (d, J 6.27 Hz, 3 H) 2.35 (s, 3 H) 3.14 (t, J 12.05 Hz, 1 H) 3.27
- 3.45 (m, 4
H) 3.70 (s, 3 H) 4.40 (s, 2 H) 6.78 (d, J 8.53 Hz, 1 H) 6.91 (d, J 2.26 Hz, 1
H) 7.32 (dd,
J 8.41, 1.88 Hz, 1 H) 7.76 (d, J--2.01 Hz, 1 H) 7.88 - 7.99 (m, 2 H) 8.32 (d,
J--1.51 Hz, 1
H). MS (ESI+) for C22Hz6NzOaS m/z 414 (M+H)+.
INTERMEDIATE 70
(5-Bromo-1-benzofuran-7-yl)amine
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Step 1: Ethyl 5-bromo-7-nitro-1-benzofuran-3-carboxylate
A mixture of 5-bromo-2-hydroxy-3-nitrobenzaldehyde (8.9 g, 36.2 mmol), diethyl
bromomalonate (6.3 mL, 37.3 mmol) and potassium carbonate (4.6 g) in butanone
(50 mL)
was heated a reflux for 4 h. The mixture was cooled, filtered and evaporated
to give the
crude product which was recrystallized from ethanol. Yield: 6.6 g (58%) of a
pale yellow
solid. 1H NMR (400 MHz, DMSO-d6) ~ ppm 1.29 (t, J--7.0 Hz, 3 H) 4.35 (q, J--
7.1 Hz, 2
H) 7.83 (s, 1 H) 8.39 (d, J--2.0 Hz, 1 H) 8.43 (d, J--2.0 Hz, 1 H).
Step 2: 5-Bromo-7-nitro-1-benzofuran-3-carboxylic acid
Ethyl 5-bromo-7-nitro-1-benzofuran-3-carboxylate (5.5 g, 17.5 mmol; obtained
in Step 1)
was suspended in ethanol (20 mL). 2 M NaOH (20 mL) was added and the mixture
was
heated at reflux for 2 h. The ethanol was removed by evaporation and the
remaining
solution acidified with concentrated HCl (4 mL), diluted with water and the
product
collected by filtration, washed with water and dried in a vacuum oven. Yield:
4.65 g
(93%). 1H NMR (400 MHz, DMSO-d6) 8 ppm 7.43 (s, 1 H) 8.26 (d, J--1.8 Hz, 1 H)
8.34
(d, J--2.0 Hz, 1 H).
Step 3: 5-Bromo-7-nitro-1-benzofuran
5-Bromo-7-nitro-1-benzofuran-3-carboxylic acid (4.65 g, 16 mmol; obtained in
Step 2)
was suspended in quinoline (25 mL), 0.1 g Cu0 was added and the mixture heated
to 190
°C for 30 minutes. The warm reaction mixture was diluted with hot
toluene (100 mL),
filtered and the filter cake washed with hot toluene (total 400 mL). The
combined toluene
extracts were washed with 1 M HCl (2x100 mL) and brine, evaporated and the
solid
product washed with hexane, collected by filtration and dried. Yield: 1.9 g
(48%). 1H NMR
(400 MHz, DMSO-d6) 8 ppm 7.13 (d, J--2.3 Hz, 1 H) 8.20 (d, J 2.0 Hz, 1 H) 8.28
(d,
J--2.3 Hz, 1 H) 8.32 (d, J--2.0 Hz, 1 H).
Step 4: (5-Bromo-1-benzofuran-7-yl)amine
A mixture of 5-bromo-7-nitro-1-benzofuran (1.9 g, 7.9 mmol; obtained in Step
3), iron
powder (2.3 g) methanol (20 mL), 1,4-dioxane (20 mL) and ammonium chloride
(2.3 g
dissolved in 10 mL of water), was refluxed overnight. The warm mixture was
filtered
through wetted Celite, which was further washed with hot methanol and the
solvents were
evaporated. The crude product was dissolved in hot ethanol/water (100 mL) and
then water
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added so that product began to crystallize out. The product was collected by
filtration,
washed with water and dried in a vacuum oven. Yield: 1.1 g (65%). 1H NMR (400
MHz,
DMSO-d6) 8 ppm 5.63 (s, 2 H) 6.68 (d, J 2.0 Hz, 1 H) 6.81 (d, J--2.3 Hz, 1 H)
6.96 (d,
J 2.0 Hz, 1 H) 7.92 (d, J--2.3 Hz, 1 H).
EXAMPLE 132
2-Methoxy-5-methyl-N-[5-(piperazin-1-ylmethyl)-1-benzofuran-7-
yl]benzenesulfonamide, bis(trifluoroacetate)
Step 1: N-(5-Bromo-1-benzofuran-7-yl)-2-methoxy-5-methylbenzenesulfonamide
A mixture of (5-bromo-1-benzofuran-7-yl)amine (500 mg, 2.4 mmol; Intermediate
70,
Step 4), pyridine (0.38 mL, 4.7 mmol) and 6-methoxy-m-toluenesulfonyl chloride
(0,78 g,
3.5 mmol) in dry DCM (20 mL) was stirred at room temperature for 2.5 h.
Additional 6-
methoxy-m-toluenesulfonyl chloride (0,26 g, 1.2 mmol) was added with continous
stirring
over night. The reaction mixture was diluted with DCM and extracted with
water. The
organic layer was concentrated. The product precipitated from a mixture of
DCM/isohexane/MeOH (80:20:20) and was collected by filtration to give the
title
compound 580 mg (61%) as a light brown solid. HPLC 94%, RT=2.32 min (System A;
30-
80% MeCN over 3 min). MS (ESI+) for C16Hi4BrN04S m/z 396 (monoisotop.mass+H)+.
Step 2: 2-Methoxy-5-methyl-N-[5-(piperazin-1-ylmethyl)-1-benzofuran-7-
yl]benzenesulfonamide, bis(trifluoroacetate)
Pd(PPh3)20Ac2 (189 mg, 0.25 mmol) and vinyltributyltin (295 ~,L, 1.01 mmol)
were added
to N (5-bromo-1-benzofuran-7-yl)-2-methoxy-5-methylbenzenesulfonamide (200 mg,
0.51
mmol; obtained in Step 1) in dry toluene under argon. The mixture was stirred
at 110 °C
over weekend (62 h). The reaction mixture was filtered and concentrated. The
crude
mixture was stirred with isohexane for 10 min. The isohexane was decanted off
and the
residue was dried under reduced pressure. The alkene intermediate was
dissolved in
dioxane (6 mL) and lutidine (120 ~L, 1.0 mmol). Osmium tetroxide (26 mg, 0.10
mmol)
was added and a color change from light brown to dark brown/black was noticed.
Sodium
periodate (432 mg, 2.02 mmol) in water (1.5 mL, warmed to dissolve) was added
while
stirring. A light brown precipitation was formed after 1 min. The mixture was
stirred for 2
h, and partitioned between 2 M aqueous HCl and DCM. The organic layer was
dried
(Na2S04), filtered and concentrated to give the crude aldehyde as a black
solid. Half of the
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material was suspended in dry THF (4 mL) and N-t-BOC-piperazine (50 mg, 0.27
mmol),
acetic acid (140 pL, 2.5 mmol) and sodium triacetoxyborohydride (104 mg, 0.49
mmol)
were added. The reaction mixture was irradiated using microwaves, 300 s at 130
°C. The
mixture was filtered, dissolved in MeOH (2 mL) and concentrated HCl (0.5 mL)
and
irradiated using microwaves, 300 s 100 °C. The solvent was evaporated,
the residue
dissolved in MeOH and purified by preparative HPLC (System A; 19-40% MeCN).
Pure
fractions were combined and concentrated to give the title compound (31 mg,
20%) as a
brown gum. HPLC 100%, RT=1.35 min (System A; 10-97% MeCN over 3 min), 99%,
RT=1.15 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, methanol-d4)
8
ppm2.22(s,3H)3.30-3.36(m,4H)3.43-3.50(m,4H)3.81 (s,3H)4.29(s,2H)6.82
(d, J--2.26 Hz, 1 H) 6.95 (d, J--8.53 Hz, 1 H) 7.28 - 7.33 (m, J--8.53, 2.26
Hz, 1 H) 7.43 (d,
J 1.51 Hz, 1 H) 7.48 (d, J 1.51 Hz, 1 H) 7.56 - 7.59 (m, J--2.26 Hz, 1 H) 7.77
(d, J 2.26
Hz, 1 H). MS (ESI+) for CZ1H25N3O4S ynlz 416 (M+H)+.
EXAMPLE 133
Z-Methoxy-5-methyl-N-}5-[(3-methylpiperazin-1-yl)methyl]-1-benzofuran-7-
yl}benzenesulfonamide, bis(trifluoroacetate)
The title compound was prepared according to the procedure of Example 132,
Step 2,
using 2-methylpiperazine (27 mg, 0.27 mmol). The title compound (18 mg, 11%)
was
obtained as a brown gum. HPLC 97%, RT=1.38 min (System A; 10-97% MeCN over 3
min), 98%, RT=1.18 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz,
methanol-d4) 8 ppm 1.33 (d, J--6.53 Hz, 3 H) 2.22 (s, 3 H) 2.82 (dd, J 13.18,
11.42 Hz, 1
H) 2.94 - 3.04 (m, 1 H) 3.31 - 3.44 (m, 2 H) 3.51 - 3.59 (m, 2 H) 3.79 - 3.87
(m, 1 H) 3.81
(s, 3 H) 4.18 (s, 2 H) 6.81 (d, J--2.01 Hz, 1 H) 6.95 (d, J 8.53 Hz, 1 H) 7.27
- 7.32 (m,
J--8.53, 2.26 Hz, 1 H) 7.41 (d, J 1.76 Hz, 1 H) 7.45 (d, J--1.76 Hz, 1 H) 7.55
- 7.58 (m,
J 1.51 Hz, 1 H) 7.75 (d, J 2.26 Hz, 1 H). MS (ESI+) for C22H2~N304S m/z 430
(M+H)+.
EXAMPLE 134
N-(2-Methylphenyl)-7-~[(3R)-pyrrolidin-3-ylamino]methyl}-1-benzofuran-5-
sulfonamide, trifluoroacetate
The title compound was prepared according to the procedure of Example 93
starting from
7-formyl-N (2-methylphenyl)-1-benzofuran-5-sulfonamide (80 mg, 0.24 mmol;
Intermediate 60) and (R)-(+)-3-aminopyrolidine (50 mg, 0.6 mmol). [Note: no
HCl
deprotection step]. Yield: 17.8 mg (28%). HPLC 97% RT=1.39 (System A; 10-97%
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MeCN over 3 min) 98% RT=1.22 (System B; 10-90% MeCN over 3 min). MS (ESI+) for
CZOH23N3O3S rnlz 386 (M+1). 1H NMR (400 MHz, methanol-d4) ~ ppm 1.94 (s, 3 H)
2.02 -
2.12 (m, 1 H) 2.44 - 2.54 (m, 1 H) 3.24 - 3.31 (m, 1 H) 3.40 - 3.52 (m, 2 H)
3.72 (dd,
J--12.8, 8.3 Hz, 1 H) 4.04 (tt, J 8.3, 5.5 Hz, 1 H) 4.68 (d, J--2.5 Hz, 2 H)
6.92 - 7.03 (m, 5
H) 7.73 (d, J--1.5 Hz, 1 H) 7.94 (d, J 2.3 Hz, 1 H) 8.08 (d, J--1.8 Hz, 1 H).
EXAMPLE 135
N-(2-Methylphenyl)-7-(piperidin-4-ylmethyl)-1-benzofuran-5-sulfonamide,
trifluoroacetate
9-Borabicyclo[3.3.1]-nonane (9-BBN; 0.5 M in THF, 2.2 mL, 2.2 mmol) was added
to a
solution of 1-(4-methylidenepiperidino)ethan-1-one (Maybridge Chemical
Company, 140
mg, 1 mmol) in dry THF (2 mL) under a nitrogen atmosphere at 0 °C.
After stirring for 1 h
at 0 °C, the solution was allowed to warm to room temperature for 3 h.
Next, a microwave
reaction tube was charged with 7-iodo-N (2-methylphenyl)-1-benzofuran-5-
sulfonamide
(40 mg, 0.1 mmol; Intermediate 58), Herrmann's catalyst (5 mg), dry THF (3
mL), 4 M
aqueous NaOH (0.1 mL) and the above solution of in situ generated 1-[4-(9-
borabicyclo[3.3.1]non-9-ylmethyl)-piperidin-1-yl]-ethanone (0.75 mL, 0.17
mmol). The
mixture was heated under microwave irradiation to 140 °C for 5 minutes.
This reaction
mixture and three similar mixtures were combined, filtered and evaporated. The
residue
was dissolved in DCM (20 mL) and washed with 1 M HCI. After evaporation of the
solvent, the crude acetylated derivative of the title product was purified by
preparative
HPLC-MS (System A 30-60% MeCN 0.1% TFA). The purified material was N-
deprotected by dissolving in methanol (3 mL), adding concentrated aqueous HCl
(1 mL)
and heating under microwave irradiation to 120 °C for 1 hour. The final
product was
purified by preparative HPLC-MS (System A 30-60% MeCN 0.1% TFA) to give 5.9 mg
(3%) of the title compound. HPLC 95% RT=1.75 (System A; 10-97% MeCN over 3
min)
95% RT=1.58 (System B; 10-90% MeCN over 3 min). MS (ESI+) for C21Hz4Na03S rnlz
385 (M+1). 1H NMR (400 MHz, methanol-d4) 8 ppm 1.26 - 1.38 (m, 2 H) 1.60 -
1.71 (m,
J--14.1Hz,2H)1.87(s,2H)1.89-1.97(m,2H)2.76-2.85(m,4H)3.11-3.19(m,1H)
3.26 - 3.30 (m, 2 H) 6.88 (d, J--2.3 Hz, 1 H) 6.96 - 7.03 (m, 4 H) 7.27 (d, J--
1.5 Hz, 1 H)
7.83 (d, J--2.3 Hz, 1 H) 7.86 (d, J 1.8 Hz, 1 H).
INTERMEDIATE 71
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tent Butyl 4-methylenepiperidine-1-carboxylate*
To a solution of methyl triphenylphosphonium bromide (2.69 g, 7.5 mmol) in THF
(20
mL) was n-butyllithium (1.8 M; 4.2 mL, 7.5 mmol) in hexane slowly added at-78
°C. The
mixture was stirred for 1 h. After this time, a solution of tent-butyl 4-
oxopiperidine-1-
carboxylate (1 g, 5.0 mmol) in THF (10 mL) was added dropwise to the mixture.
The
resultant mixture was stirred at room temperature overnight. The reaction
mixture was
quenched with water and extracted with isohexane (x3). The combined isohexane
layers
were evaporated and filtrated through a silica-plug. The crude product was
purified using
flash chromatography with DCM as eluent yielding 0.58 g (59%) of the title
compound.
HPLC purity 91%, RT=2.47 min (System A; 10-97% MeCN over 3 min); 86%, RT=2.43
min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, CDC13) 8 ppm 1.46 (s,
9
H) 2.12 - 2.22 (m, 4 H) 3.35 - 3.46 (m, 4 H) 4.73 (s, 2 H). MS (ESI+) for
C11H19NO2 m/z
142 (M-C4H8)+.
*Previously reported in J. Med. Chem. 2002, 45, 3143-3160.
INTERMEDIATE 72
tent-Butyl 3-methylenepyrrolidine-1-carboxylate*
The title compound was prepared according to the procedure of Intermediate 71
starting
from test-butyl 3-oxopyrrolidine-1-carboxylate (0.8 g, 4.3 mmol),
triphenylphosphonium
bromide (2.31 g, 6.5 mmol) and n-BuLi ( 1.8 M; 2.4 mL, 6.5 mmol). Yield: 0.23
g (29%)
after purification by flash chromatography with DCM as eleuent. HPLC purity
99%,
RT=2.28 min (System A; 10-97% MeCN over 3 min); 99%, RT=2.21 min (System B; 10-
97% MeCN over 3 min). 1H NMR (400 MHz, CDC13) 8 ppm 1.23 - 1.40 (m, 9 H) 2.42
(t,
J--6.78 Hz, 2 H) 3.31 (t, .I--7.40 Hz, 2 H) 3.71 - 3.85 (m, 2 H) 4.74 - 4.91
(m, 2 H). MS
(ESI+) for CIOH1~N02 rnlz 128 (M-C4Hg)+.
*Previously reported in Tetrahedron 1997, 53, 539-556.
INTERMEDIATE 73
tent-Butyl 3-methylenepiperidine-1-carboxylate
The title compound was prepared according to the procedure of Intermediate 71
starting
from tent-butyl 3-oxopiperidine-1-carboxylate (1 g, 5.0 mmol),
triphenylphosphonium
bromide (2.69 g, 7.5 mmol) and n-BuLi (1.8 M; 4.2 mL, 7.5 mmol). Yield: 0.28 g
(28%)
after purification by flash chromatography with 10% isohexane in DCM as
eluent. HPLC
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purity 95%, RT=2.43 min (System A; 10-97% MeCN over 3 min); 90%, RT=2.38 min
(System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, CDC13) ~ ppm 1.41 - 1.48
(m,9H)1.56-1.65(m,2H)2.20-2.30(m,2H)3.38-3.47(m,2H)3.86(s,2H)4.74
(s, 1 H) 4.80 (s, 1 H). MS (ESI+) for ClHI9NOz m/z 142 (M-C4H8)+.
*Previously reported in Tetrahedron 2002, 58, 7165-7175.
EXAMPLE 136
N-(2-Methylphenyl)-7-(pyrrolidin-3-ylmethyl)-1-benzofuran-5-sulfonamide,
trifluoroacetate
9 BBN (0.5 M in THF; 1.5 mL, 0.75 mmol) was added to a solution of teat-butyl
3-
methylenepyrrolidine-1-carboxylate (110 mg, 0.6 mmol; Intermediate 72) in dry
THF (1
mL) under a nitrogen atmosphere at 0 °C. After stirring for 1 h at 0
°C, the solution was
allowed to warm to room temperature for 3 h. A microwave reaction tube was
charged
with 7-iodo-N (2-methylphenyl)-1-benzofuran-5-sulfonamide (90 mg, 0.2 mmol;
Intermediate 58), Herrmann's catalyst (10 mg), dry THF (2.5 mL), 4 M aqueous
NaOH
(0.2 mL) and half of the above solution of in situ generated 3-(9-
borabicyclo[3.3.1]non-9-
ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.1 mL, 0.3 mmol).
The mixture
was heated under microwave irradiation at 140 °C for 5 min. This
reaction mixture and a
similar mixture were combined, filtered and evaporated. The residue was
dissolved in
methanol (3 mL), concentrated HCl (0.5 mL) was added and the mixture heated
under
microwave irradiation at 100 °C for 5 min to accomplish deprotection of
the N-t-BOC
group. Purification by preparative HPLC (System F 20-45% MeCN 0.1% TFA)
provided
31 mg (13%) of the title compound. HPLC 98% RT=1.69 (System A; 10-97% MeCN
over
3 min) 98% RT=1.53 (System B; 10-90% MeCN over 3 min). MS (ESI+) for
2S CZOH22N203S m/z 371 (M+1). 1H NMR (400 MHz, methanol-d4) 8 ppm 1.57 (dq, J--
13.3,
8.8 Hz, 1 H) 1.87 (s, 3 H) 1.88 - 1.95 (m, 1 H) 2.58 - 2.70 (m, 1 H) 2.81 (dd,
J--11.4, 8.9
Hz, 1 H) 2.96 (ddd, J 18.1, 14.0, 7.5 Hz, 2 H) 3.10 - 3.21 (m, 2 H) 3.30 (ddd,
J--11.9, 8.2,
4.3 Hz, 1 H) 6.89 (d, J--2.3 Hz, 1 H) 6.97 - 7.02 (m, 4 H) 7.32 (d, J--1.8 Hz,
1 H) 7.85 (d,
J 2.0 Hz, 1 H) 7.87 (d, J 1.8 Hz, 1 H).
EXAMPLE 137
N-(2-Methylphenyl)-7-(piperidin-3-ylmethyl)-1-benzofuran-5-sulfonamide,
trifluoroacetate
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The title compound was prepared according to the procedure of Example 136
starting from
from tent-butyl 3-methylenepiperidine-1-carboxylate (120 mg, 0.6 mmol;
Intermediate 73)
and 7-iodo-N (2-methylphenyl)-1-benzofuran-5-sulfonamide (180 mg, 0.4 mmol;
Intermediate 58). Yield: 40 mg (21%). HPLC 99% RT=1.74 (System A; 10-97% MeCN
over 3 min) 100% RT=1.58 (System B; 10-90% MeCN over 3 min). MS (ESI+) for
C21H24N203s j~z/z 385 (M+1). 1H NMR (400 MHz, methanol-d4) ~ ppm 1.60 - 1.72
(m, 3
H)1.85-1.95(m,2H)1.99(s,3H)2.15-2.26(m,J--11.3,7.6,7.6,3.8,3.8Hz,1H)2.73
(t, J 12.3 Hz, 1 H) 2.86 - 2.97 (m, 3 H) 3.24 (dd, J--12.5, 3.5 Hz, 1 H) 3.34 -
3.37 (m, 1 H)
6.98 (d, J--2.3 Hz, 1 H) 7.05 - 7.09 (m, 2 H) 7.09 - 7.12 (m, 2 H) 7.41 (d, J--
1.8 Hz, 1 H)
7.94 (d, J--2.3 Hz, 1 H) 7.96 (d, J--1.8 Hz, 1 H).
INTERMEDIATE 74
7-Iodo-1-benzofuran-5-amine
7-Iodo-5-nitro-1-benzofuran (2.5 g, 8.6 mmol) and iron (2.51 g, 45.0 mmol)
were added to
a round bottom flask. Methanol (25 mL), 1,4-dioxane (25 mL) and ammonium
chloride
(2.5 g, 46.7 mmol), dissolved in water (50 mL); were added and the mixture was
heated at
100 °C for 16 h. The reaction mixture was filtered through Celite and
volatiles were
evaporated off. The residue was dissolved in a mixture of methanol (10 mL) and
DCM (90
mL). This mixture was filtered through a silica plug and the solvent was
evaporated
yielding 2.22 g (99%) of the title compound as a brown oil. HPLC purity 70%,
RT=1.26
min (System A; 10-97% MeCN over 3 min). MS (ESI+) for C$H61N0 m/z 260 (M+H)+.
INTERMEDIATE 75
N-(7-Iodo-1-benzofuran-5-yl)-2-methoxy-5-methylbenzenesulfonamide
To a mixture of 7-iodo-1-benzofuran-5-amine (2.22 g, 8.6 mmol; Intermediate
74) in dry
DCM/THF (5:1; 50 mL, starting material partly dissolved), were added pyridine
(1.43 mL,
17.1 mmol) and 6-methoxy-m-toluenesulfonyl chloride (2.64 g, 12.8 mmol). The
resultant
mixture was stirred at ambient temperature overnight for 21 h. The solvent was
evaporated
under reduced pressure and the crude product was purified using flash
chromatography
(eluent: 20% isohexane in DCM). Pure fractions were combined and concentrated
to give
the product (1.62 g, 42%) as a light brown fluffy solid. HPLC 81%, RT=2.26 min
(System
A; 30-80% MeCN over 3 min), 86%, RT=2.27 min (System B; 10-97% MeCN over 3
min).
1H NMR (400 MHz, CDC13) 8 ppm 2.22 (s, 3 H) 4.04 (s, 3 H) 6.77 (d, J--2.01 Hz,
1 H)
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6.92 (d, J--8.28 Hz, 1 H) 7.25 - 7.29 (m, 1 H) 7.32 (d, J 2.01 Hz, 1 H) 7.36
(d, J--2.01 Hz,
1 H) 7.53 - 7.55 (m, J--2.26 Hz, 1 H) 7.62 (d, J--2.26 Hz, 1 H). MS (ESI+) for
C16Hi4TNO4
m/z 444 (M+H)~.
EXAMPLE 138
2-Methoxy-5-methyl-N-[7-(piperidin-4-ylmethyl)-1-benzofuran-5-
yl]benzenesulfonamide, trifluoroacetate
The title compound was prepared according to the procedure of Example 136
starting from
tent-butyl 4-methylenepiperidine-1-carboxylate (120 mg, 0.6 mmol; Intermediate
71) and
N (7-iodo-1-benzofuran-5-yl)-2-methoxy-5-methylbenzenesulfonamide (180 mg,
0.42
mmol; Intermediate 75). Yield: 69 mg (33%). HPLC 96% RT=1.75 (System A; 10-97%
MeCN over 3 min) 99% RT=1.58 (System B; 10-90% MeCN over 3 min). MS (ESI+) for
C22H26N2~4s m/z 415 (M+1). 1H NMR (400 MHz, methanol-d4) 8 ppm 1.22 - 1.34 (m,
2
H) 1.61 (d, J--13.6 Hz, 2 H) 1.80 - 1.91 (m, J--11.3, 7.6, 7.6, 3.6, 3.6 Hz, 1
H) 2.10 (s, 3 H)
2.69 (d, J--7.3 Hz, 2 H) 2.78 (td, J 12.9, 2.6 Hz, 2 H) 3.24 (d, J--2.0 Hz, 2
H) 3.87 (s, 3 H)
6.62 (d, J--2.3 Hz, 1 H) 6.79 (d, J--2.0 Hz, 1 H) 6.93 (d, J 8.5 Hz, 1 H) 7.10
(d, J--2.0 Hz,
1 H) 7.21 (dd, 1 H) 7.38 (d, J--2.0 Hz, 1 H) 7.58 (d, .I--2.3 Hz, 1 H).
INTERMEDIATE 76
2-(2,6-Dibromophenoxy)ethyl bromide*
A mixture of 2,6-dibromophenol (10.2 g, 40 mmol), 1,2-dibromoethane (7.6 g, 40
mmol)
and NaOH (1.76 g, 44 mmol) in water was heated at reflux overnight under
stirring. The
mixture was cooled, extracted with diethyl ether (2x100 mL), the extract
washed with
aqueous NaOH, brine, dried (MgSOø) and concentrated to give the product as a
pale
yellow oil. Yield: 10.0 g (70 %). 1H NMR (400 MHz, CDC13) 8 3.73 (t, 2 H),
4.31 (t, 2 H),
6.88 (t, 1 H), 7.50 (d, 2 H).
*Previously reported in Tetrahedron Lett. 1998, 39, 2219-2222.
INTERMEDIATE 77
7-Bromo-2,3-dihydrobenzofuran*
A solution of 2-(2,6-dibromphenoxy)ethyl bromide (1.08 g, 3 mmol; Intermediate
76) in a
mixture of THF (12 mL) and hexane (3 mL) was cooled in a ethanol/dry ice bath
for 30
min. n-BuLi in hexane (2 mL of 1.5 M solution) was added dropwise over 15 min.
The
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reaction mixture was stirred at-78 °C for another 30 min after which
time the bath was
allowed to slowly warm to 0 °C. The mixture was poured onto water and
extracted with
diethyl ether (2x100 mL). The combined extract was dried and concentrated to
give a pale
brown oil (0.5 g) containing the product contaminated with approximately 25 %
2,3-
dihydrobenzofuran. This material was used as such for further synthesis but
could if
necessary be purified by flash chromatography [eluent: hexane -~ EtOAc/hexane
(5:95)].
1H NMR (400 MHz, CDC13) 8 3.30 (t, 2 H), 4.65 (t, 2 H), 6.71 (t, 1 H), 7.11
(dd, 1 H), 7.25
(dd, 1 H).
*Previously reported in Tetrahedron Lett. 1998, 39, 2219-2222.
INTERMEDIATE 78
7-Bromo-5-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1-benzofuran
7-Bromo-1,2-dihydrobenzofuran (64 mg, 0.3 mmol; Intermediate 77) and para-
toluensulfonic acid monohydrate (62 mg, 0.3 mmol) were mixed and then a 1:10
mixture
(by weight) of methanesulfonic and phosphorous pentoxide (1 mL) was added. The
resultant mixture was stirred over night at room temperature and was then
poured onto
ice/water. The obtained crystalline material was filtered and dried to give
120 mg of the
title product. 1H NMR (400 MHz, CDCl3) 8 2.40 (s, 3 H), 3.33 (t, 2 H), 4.73
(t, 2 H), 7.29
(d, 2 H), 7.65 (d, 1 H), 7.79 (d, 2 H), 7.89 (d, 1 H); GC-MS (EI+) for
ClSHisBrS03 m/z 354
(M+H)+.
INTERMEDIATE 79
7-Bromo-5-[(4-methylphenyl)sulfonyl]-1-benzofuran
A mixture of 7-bromo-5-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1-benzofuran
(353 mg, 1
mmol; Intermediate 78), NBS (178 mg, 1 mmol) and dibenzoylperoxide (24 mg, 0.1
mmol) in carbon tetrachloride (20 mL) was heated to 80 °C for 2 h. TEA
(2 mL) was added
and the mixture was heated for another 2 h. Flash chromatography using
EtOAc/hexane
10:9025:75 as eluent gave the title product as a white crystalline material.
Yield: 130 mg
(37%). 1H NMR (400 MHz, CDC13) 8 2.39 (s, 3 H), 6.93 (d, 1 H), 7.30 (d, 2 H),
7.78 (d, 1
H), 7.84 (d, 2 H), 8.02 (d, 1 H), 8.19 (d, 1 H).
EXAMPLE 139
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3-( f 5-[(4-Methylphenyl)sulfonyl]-1-benzofuran-7-yl~methyl)pyrrolidine,
trifluoroacetate
The title compound was prepared according to the procedure of Example 136
starting from
tent-butyl 3-methylenepiperidine-1-carboxylate (60 mg, 0.3 mmol; Intermediate
73) and 7-
bromo-5-[(4-methylphenyl)sulfonyl]-1-benzofuran (70 mg, 0.21 rmnol;
Intermediate 79).
Yield: 3 mg (3%). HPLC 97% RT=1.79 (System A; 10-97% MeCN over 3 min) 97%
RT=1.61 (System B; 10-90% MeCN over 3 min). MS (ESI+) for C21H23NO3S m/z 356
(M+1).
EXAMPLE 140
2-Methoxy-5-methyl-N-[5-(piperidin-4-ylmethyl)-1-benzofuran-7-
yl]benzenesulfonamide, trifluoroacetate
The title compound was prepared according to the procedure of Example 136
starting from
from tent-butyl 4-methylenepiperidine-1-carboxylate (120 mg, 0.6 mmol;
Intermediate 71)
and N (5-bromo-1-benzofuran-7-yl)-2-methoxy-5-methylbenzenesulfonamide (150
mg,
0.42 mmol; obtained in Example 132, Step 1). Yield: 27 mg (12%). HPLC 97%
RT=1.68
(System A; 10-97% MeCN over 3 min) 97% RT=1.52 (System B; 10-90% MeCN over 3
min). MS (ESI+) for CZZHzsNa04S nz/z 415 (M+1). 1H NMR (400 MHz, methanol-d4)
8
ppm 1.22 - 1.33 (m, 2 H) 1.62 - 1.73 (m, 3 H) 2.13 (s, 3 H) 2.51 (d, J--7.0
Hz, 2 H) 2.80
(td, J--12.7, 2.4 Hz, 2 H) 3.24 - 3.28 (m, 2 H) 3.77 (s, 3 H) 6.63 (d, J--2.0
Hz, 1 H) 6.87 (d,
J 8.5 Hz, 1 H) 6.98 (d, J--1.5 Hz, 1 H) 7.05 (d, .l--1.5 Hz, 1 H) 7.21 (dd, J--
8.2, 1.9 Hz, 1
H) 7.46 (d, J 2.3 Hz, 1 H) 7.59 (d, J--2.3 Hz, 1 H).
BIOLOGICAL TESTS
The ability of a compound according to the invention to bind to the human 5-
HT6
receptor, and to be pharmaceutically useful, can be determined using in vivo
and in vitro
assays known in the art.
(a) S-HT6 binding Assay
Binding affinity experiment for the 5-HT6 receptor are performed in HEK293
cells
transfected with the human 5-HT6 receptor using [3H]-LSD as labeled ligand
according to
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the general method as described by Boess F.G et al. Neuropharmacology 36(4/5)
713-720,
1997.
Materials
Cell culture
The HEK-293 cell line transfected with the human 5-HT6 receptor was cultured
in
Dulbeccos Modified Eagles Medium containing 5 % dialyzed foetal bovine serum,
(Gibco
BRL 10106-169), 0.5 mM sodium pyruvate and 400 ~g/mL Geneticin (G-418) (Gibco
BRL10131-019). The cells were passaged 1:10, twice a week.
Chemicals
The radioligand [3H~ LSD 60-240 Ci/mmol, obtained from Amersham Pharmacia
Biotech, (Buckinghamshire, England) was in ethanol and stored at -20°C.
The compounds
were dissolved in 100% DMSO and diluted with binding buffer.
Disposable
Compounds were diluted in Costar 96 well V-bottom polypropylene plates
(Corning Inc. Costar, NY, USA). Samples were incubated in Packard Optiplate
(Packard
Instruments B.V., Groningen, The Netherlands). The total amount of added
radioligand
was measured in Packard 24-well Barex plates (Packard Instruments B.V.,
Groningen, The
Netherlands) in the presence of MicroscintTM 20 scintillation fluid (Packard
Bioscience,
Meriden, CT, USA).
Buffer
The binding buffer consisted of 20 mM HEPES, 150 mM NaCI, 10 mM MgCl2, and
1 mM, EDTA, pH 7.4.
Methods
Membrane preparation
Cells were grown to approximately 90% confluence on 24.5 x 24.5 mm culture
dishes. The medium was aspirated, and after rinsing with ice-cold PBS, the
cells were
scraped off using 25 mL Tris buffer (50 mM Tris-HCI, 1 mM EDTA, 1 mM EGTA, pH
7.4) and a window scraper. The cells were then broken with a Polytron
homogeniser, and
remaining particulate matter was removed by low-speed centrifugation, 1000x g
for 5 min.
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Finally, the membranes were collected by high-speed centrifugation (20 OOOx
g),
suspended in binding buffer, and frozen in aliquots at -70°C.
Radioli~;and binding
Frozen cell membranes were thawed, immediately rehomogenized with a Polytron
homogenizer, and coupled to SPA wheat germ agglutinin beads (Amersham Life
Sciences,
Cardiff, England) for 30 min under continuous shaking of the tubes. After
coupling, the
beads were centrifuged for 10 minutes at 1000 g, and subsequently suspended in
20 mL of
binding buffer per 96-well plate The binding reaction was then initiated by
adding
radioligand and test compounds to the bead-membrane suspension. Following
incubation
at room temperature, the assay plates were subjected to scintillation
counting.
The original SPA method was followed except for that membranes were prepared
from HEK293 cells expressing the human 5-HT6 receptor instead of from HeLa
cells
(Dinh DM, Zaworski PG, Gill GS, Schlachter SK, Lawson CF, Smith MW. Validation
of
human 5-HT6 receptors expressed in HeLa cell membranes: saturation binding
studies,
pharmacological profiles of standard CNS agents and SPA development. (The
Upjohn
Company Technical Report 7295-95-064 1995;27 December). The specific binding
of
[3H]-LSD was saturable, while the non-specific binding increased linearly with
the
concentration of added radioligand. [3H]-LSD bound with high affinity to 5-HT6
receptors. The Kd value was estimated to 2.6~ 0.2 nM based on four separate
experiments.
The total binding at 3 nM of [3H]-LSD, the radioligand concentration used in
the
competition experiments, was typically 6000 dpm, and the specific binding more
than
70%. 5-HT caused a concentration dependent inhibition of [3H]-LSD binding with
an over
all average Ki value of 236 nM when tested against two different membrane
preparations.
The inter assay variability over three experiments showed a CV of 10% with an
average K;
values of 173 nM (SD 30) and a Hill coefficient of 0.94 (SD 0.09). The infra
assay
variation was 3% (n=4). All unlabelled ligands displaced the specific binding
of [3H]-LSD
in a concentration-dependent manner, albeit at different potencies. The rank
order of
affinity for the 5-HT6 receptor of reference compounds was methiothepin (Ki 2
nM)
>mianserin (190 nM) ~ 5-HT (236 nM) >methysergide (4~2 nM) > mesulergine (1970
nM).
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Protein determination
Protein concentrations were determined with BioRad Protein Assay (Bradford MM.
A rapid and sensitive method for the quantitation of microgram quantities of
protein
utilizing the principle of protein-dye binding. Anal. Biochem. 1976;72:248-
54). Bovine
serum albumin was used as standard.
Scintillation counting
The radioactivity was determined in a Packard TopCountTM scintillation counter
(Packard Instruments, Meriden, CT, USA) at a counting efficiency of
approximately 20 %.
The counting efficiency was determined in separate sets of experiments.
Saturation experiments
At least 6 concentrations in duplicates of radioligand (0.1-20 nM of [3H]-LSD)
were used in saturation experiments. The specific binding was calculated as
the difference
between total binding and non-specific binding, which was determined as the
binding of
radioligand in the presence of 5 ~,M lisuride. BmaX and the dissociation
constant, Kd, were
determined from the non-linear regression analysis using equation 1. L" is the
unbound
concentration of radioligand, and is y is the amount bound.
B max. Lu
y = (equation 1)
Lu + Kd
Competition experiments
Total- and non-specific binding of radioligand was defined in eight replicates
of
each. Samples containing test compound were run in duplicate at 11
concentrations.
Incubations were carried out at room temperature for 3 hours. The ICSO value,
i.e. the
concentration of test compound that inhibited 50% of the specific binding of
radioligand,
was determined with non linear regression analysis and the K; value was
calculated using
equation 2 [Cheng Y.C. Biochem. Pharmacol. 22, 3099-3108, 1973].
ICso
Ki = L (equation 2)
1 + Kd
L = concentration of radioligand
Kd= Affinity of radioligand
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WO 2005/058858 PCT/SE2004/001949
(b) 5-HT6 Intrinsic Activity Assay
Antagonists to the 5-HT6 receptor were characterized by measuring inhibition
of 5-
HT induced increase in cAMP in HEK 293 cells expressing the human 5-HT6
receptor (see
Boers et al. (1997) Neuropharmacology 36: 713-720). Briefly, HEK293/5-HT6
cells were
seeded in polylysine coated 96-well plates at a density of 25,000 / well and
grown in
DMEM (Dulbecco's Modified Eagle Medium) (without phenol-red) containing 5%
dialyzed Foetal Bovine Serum for 48 h at 37°C in a 5% C02 incubator.
The medium was
then aspirated and replaced by 0.1 mL assay medium (Hanks Balance Salt
Solution
containing 20 mM HEPES, 1.5 mM isobutylmethylxanthine and 1 mg/mL bovine serum
albumin). After addition of test substances, 50 ~,1 dissolved in assay medium,
the cells were
incubated for 10 min at 37°C in a 5% C02 incubator. The medium was
again aspirated and
the cAMP content was determined using a radioactive cAMP kit (Amersham
Pharmacia
Biotech, BIOTR.AK RPA559). The potency of antagonists was quantified by
determining
the concentration that caused 50% inhibition of 5-HT (at [5-HT]= 8 times ECso)
evoked
increase in cAMP, using the formula fKi=ICso/(1+[SHT]/ECso).
The compounds in accordance with the invention have a selective affinity to 5-
HT6
receptors with Ki and ICso,°°,.,. values between 0.5 nM and 5
~uM or display a % inhibition
of [3H]-LSD >_ 20 % at 50 nM and are antagonists, agonists or partial agonists
at 5-HT6 .
The compounds show good selectivity over 5-HTIa, 5-HTIb, 5-HT2a, 5-HT2b, 5-
HT2~.
(c) Ih vivo assay of f°eduction of food intake
For a review on serotonin and food intake, see Blundell, J.E. and Halford,
J.C.G.
(1998) Serotonin and Appetite Regulation. Implications for the Pharmacological
Treatment
of Obesity. CNS Drugs 9:473-495.
Obese (ob/ob) mouse is selected as the primary animal model for screening as
this
mutant mouse consumes high amounts of food resulting in a high signal to noise
ratio. To
further substantiate and compare efficacy data, the effect of the compounds on
food
consumption is also studied in wild type (C57BL/6J) mice. The amount of food
consumed
during 15 hours of infusion of compounds is recorded.
Male mice (obese C57BL/6JBom-Lep b and lean wild-type C57BL/6JBom;
Bomholtsgaard, Denmark) 8-9 weeks with an average body weight of 50 g (obese)
and 25
g (lean) are used in all the studies. The animals are housed singly in cages
at 23~1°C, 40-
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WO 2005/058858 PCT/SE2004/001949
60 % humidity and have free access to water and standard laboratory chow. The
12/12-h
light/dark cycle is set to lights off at 5 p.m. The animals are conditioned
for at least one
week before start of study.
The test compounds are dissolved in solvents suitable for each specific
compound
such as cyclodextrin, cyclodextrin/methane sulphonic acid, polyethylene
glycol/methane
sulphonic acid, saline. Fresh solutions are made for each study. Doses of 30,
50 and 100
mg kg lday I are used. The purity of the test compounds is of analytical
grade.
The animals are weighed at the start of the study and randomized based on body
weight. Alzet osmotic minipumps (Model 2001D; infusion rate 8 ~1/h) are used
and loaded
essentially as recommended by the Alzet technical information manual (Alza
Scientific
Products, 1997; Theeuwes, F. and Yam, S.I. Ann. Biomed. Eng. 4(4). 343-353,
1976).
Continuous subcutaneous infusion with 24 hours duration is used. The minipumps
are
either filled with different concentrations of test compounds dissolved in
vehicle or with
only vehicle solution and maintained in vehicle pre-warmed to 37°C
(approx. 1h). The
minipumps are implanted subcutaneously in the neck/back region under short
acting
anesthesia (metofane/enflurane). This surgical procedure lasts approximately 5
min.
The weight of the food pellets are measured at 5 p.m. and at 8 p. m. for two
days
before (baseline) and one day after the implantation of the osmotic minipumps.
The weigh-
in is performed with a computer assisted Mettler Toledo PR 5002 balance.
Occasional
spillage is corrected for. At the end of the study the animals are killed by
neck dislocation
and trunk blood sampled for later analysis of plasma drug concentrations.
The plasma sample proteins are precipitated with methanol, centrifuged and the
supernatant is transferred to HPLC vials and injected into the liquid
chromatography /mass
spectrometric system. The mass spectrometer is set for electrospray positive
ion mode and
Multiple Reaction Monitoring. A linear regression analysis of the standards
forced through
the origin is used to calculate the concentrations of the unknown samples.
Food consumption for 1 S hours is measured for the three consecutive days and
the
percentage of basal level values is derived for each animal from the day
before and after
treatment. The values are expressed as mean ~ SD and ~ SEM from eight animals
per dose
group. Statistical evaluation is performed by Kruskal-Wallis one-way ANOVA
using the
percent basal values. If statistical significance is reached at the level of
p<0.05, Mann-
Whitney U-test for statistical comparison between control and treatment groups
is
performed.
1~5
CA 02545506 2006-05-10
WO 2005/058858 PCT/SE2004/001949
The compounds according to the invention show an effect (i.e., reduction of
food
intake) in the range of 5-200 mglkg/d.
Table 4. Functional in vitro data at the h-5-HT receptor (fKi). Data are
expressed as
fKi, =ICSO/(1+[SHT]/ECso). The potency of antagonists was quantified by
determining the
concentration that caused 50% inhibition of 5-HT (at [5-HT]= 8 times ECso)
evoked
increase in cAMP, using the formula fKi =ICso/(1+[SHT]/ECso).
Table 4.
EXAMPLE fKi (nM)
1 87
12 87
28 66
32 54
33 20
Table 5. Competitive binding in vitro data at the h-5-HT receptor (Ki). The
ICso value,
i.e. the concentration of test compound that inhibited 50% of the specific
binding of
radioligand ([3H]-LSD), was determined with non linear regression analysis and
the K;
ICso
value was calculated using the equation Ki =
1 + Kd
Table 5.
Exam 1e Ki (nM)
92 5.56
36 20
67 13
84 7.5
85 7
86 7
87 5.3
89 14
91 56
54 17.4
176
