U.S. patent application number 13/222045 was filed with the patent office on 2011-12-29 for pyrazine derivatives and use as pi3k inhibitors.
This patent application is currently assigned to MERCK SERONO SA. Invention is credited to Dennis Church, PASCALE GAILLARD, Jasna Klicic, Vincent Pomel, Anna Quattropani, Thomas Rueckle.
Application Number | 20110319410 13/222045 |
Document ID | / |
Family ID | 35276409 |
Filed Date | 2011-12-29 |
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United States Patent
Application |
20110319410 |
Kind Code |
A1 |
GAILLARD; PASCALE ; et
al. |
December 29, 2011 |
PYRAZINE DERIVATIVES AND USE AS PI3K INHIBITORS
Abstract
The present invention is related to pyrazine derivatives of
Formula (I) in particular for the treatment and/or prophylaxis of
autoimmune disorders and/or inflammatory diseases, cardiovascular
diseases, neurodegenerative diseases, bacterial or viral
infections, kidney diseases, platelet aggregation, cancer,
transplantation, graft rejection or lung injuries.
Inventors: |
GAILLARD; PASCALE;
(Collonges Sous Saleve, FR) ; Quattropani; Anna;
(Geneva, CH) ; Pomel; Vincent; (Groisy, FR)
; Rueckle; Thomas; (Geneva, CH) ; Klicic;
Jasna; (Biberach, DE) ; Church; Dennis;
(Commugny, CH) |
Assignee: |
MERCK SERONO SA
Coinsins, Vaud
CH
|
Family ID: |
35276409 |
Appl. No.: |
13/222045 |
Filed: |
August 31, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12064284 |
Feb 20, 2008 |
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PCT/EP06/65688 |
Aug 25, 2006 |
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13222045 |
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60711873 |
Aug 26, 2005 |
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Current U.S.
Class: |
514/234.8 ;
514/249 |
Current CPC
Class: |
C07D 405/12 20130101;
A61P 37/08 20180101; C07D 417/12 20130101; C07D 409/12 20130101;
A61P 9/00 20180101; A61P 17/06 20180101; A61P 9/04 20180101; A61P
19/04 20180101; A61P 31/04 20180101; A61P 9/12 20180101; A61P 19/02
20180101; C07D 401/12 20130101; A61P 1/04 20180101; A61P 9/08
20180101; A61P 11/06 20180101; A61P 7/06 20180101; A61P 11/00
20180101; C07D 403/12 20130101; A61P 1/18 20180101; A61P 15/08
20180101; A61P 35/04 20180101; A61P 25/14 20180101; A61P 35/00
20180101; C07D 241/44 20130101; A61P 7/00 20180101; A61P 13/12
20180101; A61P 7/02 20180101; A61P 21/00 20180101; C07D 407/12
20130101; A61P 1/00 20180101; A61P 9/10 20180101; A61P 29/00
20180101; A61P 37/06 20180101; A61P 37/00 20180101; A61P 25/28
20180101; A61P 15/00 20180101; A61P 25/00 20180101; A61P 31/12
20180101; A61P 43/00 20180101; C07D 471/04 20130101; C07D 413/12
20130101 |
Class at
Publication: |
514/234.8 ;
514/249 |
International
Class: |
A61K 31/498 20060101
A61K031/498; A61P 19/02 20060101 A61P019/02; A61P 37/00 20060101
A61P037/00; A61P 29/00 20060101 A61P029/00; A61P 1/00 20060101
A61P001/00; A61P 25/28 20060101 A61P025/28; A61P 31/04 20060101
A61P031/04; A61P 31/12 20060101 A61P031/12; A61P 11/06 20060101
A61P011/06; A61P 35/00 20060101 A61P035/00; A61K 31/5377 20060101
A61K031/5377; A61P 9/00 20060101 A61P009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 26, 2005 |
EP |
05107838.4 |
Claims
1. A method of treating autoimmune disorders and/or inflammatory
diseases, cardiovascular diseases, neurodegenerative diseases,
bacterial or viral infections, allergy, asthma, pancreatitis,
multi-organ failure, kidney diseases, platelet aggregation, cancer,
transplantation, sperm motility, erythrocyte deficiency, graft
rejection or lung injuries comprising administering to a subject in
need of treatment a composition comprising a pharmaceutically
acceptable carrier, diluent or excipient and a compound according
to Formula (I), ##STR00251## wherein: A, B, D and E, each of which
may be optionally substituted, are C, such that the ring R is an
aromatic ring; R.sup.1 is selected from H, halogen, nitro,
optionally substituted C.sub.1-C.sub.6-alkyl, optionally
substituted C.sub.2-C.sub.6-alkenyl or optionally substituted
C.sub.2-C.sub.6-alkynyl; R.sup.2 is selected from H, optionally
substituted C.sub.1-C.sub.6-alkyl, optionally substituted
C.sub.2-C.sub.6-alkenyl or optionally substituted
C.sub.2-C.sub.6-alkynyl; R.sup.3 is selected from H, halo,
optionally substituted C.sub.1-C.sub.6-alkyl, optionally
substituted C.sub.2-C.sub.6-alkenyl, optionally substituted
C.sub.2-C.sub.6-alkynyl, optionally substituted alkoxy, optionally
substituted aryl or optionally substituted heteroaryl; R.sup.4 is
selected from optionally substituted C.sub.1-C.sub.6-alkyl,
optionally substituted C.sub.2-C.sub.6-alkenyl, optionally
substituted C.sub.2-C.sub.6-alkynyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted
C.sub.3-C.sub.8 cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl
C.sub.1-C.sub.6-alkyl, optionally substituted heteroaryl
C.sub.1-C.sub.6-alkyl, optionally substituted C.sub.3-C.sub.8
cycloalkyl optionally substituted C.sub.1-C.sub.6-alkyl, optionally
substituted heterocycloalkyl C.sub.1-C.sub.6-alkyl, optionally
substituted aryl C.sub.2-C.sub.6-alkenyl or optionally substituted
heteroaryl C.sub.2-C.sub.6-alkenyl; n is an integer selected from
0, 1, 2, 3 and 4; an optionally substituted group may be
substituted with from 1 to 5 substituents selected from the group
consisting of C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, cycloalkyl, heterocycloalkyl,
C.sub.1-C.sub.6-alkyl aryl, C.sub.1-C.sub.6-alkyl heteroaryl,
C.sub.1-C.sub.6-alkyl cycloalkyl, C.sub.1-C.sub.6-alkyl
heterocycloalkyl, amino, ammonium, acyl, acyloxy, acylamino,
aminocarbonyl, alkoxycarbonyl, ureido, aryl, carbamate, heteroaryl,
sulfinyl, sulfonyl, alkoxy, sulfanyl, halogen, carboxy,
trihalomethyl, cyano, hydroxy, mercapto and nitro; with the first
proviso that when R.sup.4 is thiophenyl, it is not selected from
the group consisting of: unsubstituted thiophenyl, unsubstituted
chloro-5-thiophenyl and unsubstituted bromo-5-thiophenyl; with the
second proviso that when R.sup.4 is a phenyl, it is a
mono-substituted phenyl that is not selected from the group
consisting of: p-bromo phenyl; p-methoxy phenyl; p-ethoxy phenyl;
o-, m- or p-chloro phenyl; m- or p-methyl phenyl; o- or p-fluoro
phenyl; o-CF3-phenyl; p- or m-nitro phenyl; p-NHAc-phenyl and
p-amino phenyl; or it is a multi-substituted phenyl, that is not an
unsubstituted bi-substituted phenyl selected from the group
consisting of: m-, p-dimethyl phenyl; m-, m-dimethyl phenyl; o-,
p-dimethyl phenyl; o-, m-dimethyl phenyl; o-methyl p-fluoro phenyl;
m-, m-dichloro phenyl; o-, m-dichloro phenyl; p-chloro m-nitro
phenyl and o-ethoxy m-bromo phenyl; with the final proviso that
wherein R.sup.4 is a 1,4 benzodioxin it is a substituted
benzodioxin; or an optically active form or a pharmaceutically
acceptable salt thereof.
2. The method according to claim 1, wherein R.sup.1 is selected
from H or halogen.
3. The method according to claim 1, wherein R.sup.2 is methyl,
which may be optionally substituted.
4. The method according to claim 1, wherein R.sup.3 is selected
from H or alkoxy, which may be optionally substituted.
5. The method according to claim 1, wherein R.sup.3 is selected
from halo, optionally substituted aryl or optionally substituted
heteroaryl.
6. The method according to claim 1, wherein R.sup.4 is selected
from optionally substituted C.sub.1-C.sub.6-alkyl, optionally
substituted C.sub.2-C.sub.6-alkenyl, optionally substituted
C.sub.2-C.sub.6-alkynyl, optionally substituted aryl
C.sub.1-C.sub.6-alkyl or optionally substituted heteroaryl
C.sub.1-C.sub.6-alkyl.
7. The method according to claim 1, wherein R.sup.4 is selected
from optionally substituted aryl or optionally substituted
heteroaryl.
8. The method according to claim 1, wherein R.sup.1 is selected
from H and halogen; R.sup.2 is substituted methyl; and R.sup.3 is
selected from H or substituted alkoxy.
9. The method according to claim 1, wherein R.sup.1 is selected
from H and halogen; R.sup.2 is methyl; R.sup.3 is selected from H
or alkoxy.
10. The method according to claim 1, wherein said compound is
selected from:
4-cyano-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzenesul-
fonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzenesulfonam-
ide;
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]ben-
zoic acid;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1-methyl-1H-i-
midazole-4-sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-methylbenzene
sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-methylbenzene
sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-methylbenzene
sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-methylbenzene
sulfonamide;
5-bromo-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}thiophene-2-sulf-
onamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1-pyridin-3-ylm-
ethane sulfonamide; Methyl
3-{4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phen-
yl}propanoate; Methyl
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoat-
e;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-fluorobenzene
sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(methylsulfonyl)benze-
ne sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2,3-dihydro-1,4-benzodi-
oxine-6-sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(pyrrolidin-1-yl
sulfonyl)benzenesulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-(methylsulfonyl)benze-
ne sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-(methylsulfonyl)benze-
ne sulfonamide;
2-cyano-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
2-cyano-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
2-chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}pyridine-3-sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1-methyl-1H-imidazole-4-
-sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluorobenzene
sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluorobenzene
sulfonamide;
4-cyano-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}methanesulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}thiophene-3-sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}methanesulfonamide;
3-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoic
acid; Methyl
4-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoat-
e; Methyl
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfony-
l]thiophene-2-carboxylate;
5-chloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1,3-dimethyl-1-
H-pyrazole-4-sulfonamide;
4-chloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
3-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]thiophe-
ne-2-carboxylic acid;
3-{4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phen-
yl}propanoic acid;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-methyl-2-oxo-2,3-dihy-
dro-1,3-benzothiazole-6-sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2,1,3-benzothiadiazole--
4-sulfonamide;
4-chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-methyl-2-oxo-2,3-dihy-
dro-1,3-benzothiazole-6-sulfonamide;
4-bromo-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
4-bromo-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
4-acetyl-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}propane-1-sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}thiophene-3-sulfonamide;
4-acetyl-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1,2-dimethyl-1H-imidazo-
le-5-sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2,1,3-benzoxadiazole-4--
sulfonamide;
3-chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
3-cyano-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
N-{3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phen-
yl}acetamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}propane-1-sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(trifluoromethyl)benz-
ene sulfonamide;
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]butanoi-
c acid;
3-chloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
N-{6-chloro-3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1-pyridin-2-ylmethane
sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-methoxybenzene
sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]pyrido[2,3-b]pyrazin-2-yl}ethane
sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-methoxybenzene
sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1-pyridin-2-ylmethane
sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1-pyridin-3-ylmethane
sulfonamide; Methyl
3-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]thiophe-
ne-2-carboxylate;
N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
4-chloro-N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-methoxybenzene
sulfonamide;
4-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]butanoi-
c acid;
N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}methanesulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-iodobenzene
sulfonamide;
4-bromo-N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
4-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoic
acid; Methyl
4-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]butanoa-
te;
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benz-
oic acid;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2-fluorobenzen- e
sulfonamide;
N-(3-{[5-methoxy-2-(1H-pyrrol-1-yl)phenyl]amino}quinoxalin-2-yl)benzene
sulfonamide; Methyl
3-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoat-
e;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-morpholin-4-yl
pyridine-3-sulfonamide;
4-methoxy-N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; Methyl
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoat-
e;
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]thiop-
hene-2-carboxylic acid;
N-{3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2-(methylsulfonyl)benze-
ne sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2-fluorobenzene
sulfonamide;
4,5-dichloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}thiophene-2-
-sulfonamide;
N-{3-[(5-methoxy-2-methylphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-fluorobenzene
sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2-(methylsulfonyl)
benzenesulfonamide;
N-{3-[(2,3-dihydro-1,4-benzodioxin-5-ylmethyl)amino]quinoxalin-2-yl}benze-
ne sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]-6-nitroquinoxalin-2-yl}benzene
sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(pyrrolidin-1-ylsulfo-
nyl)benzene sulfonamide; methyl
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)
sulfonyl]butanoate; methyl
5-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-4-meth-
ylthiophene-2-carboxylate; methyl
5-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-1-meth-
yl-1H-pyrrole-2-carboxylate; methyl
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-1-meth-
yl-1H-pyrrole-2-carboxylate;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}thiophene-2-sulfonamide;
2-chloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluorobenzen-
e sulfonamide;
2-chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluorobenzen-
e sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}pyridine-3-sulfonamide;
3-cyano-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluorobenzene
sulfonamide;
3-cyano-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluorobenzene
sulfonamide;
6-chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}pyridine-3-sulf-
onamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-(dimethylamin-
o)pyridine-3-sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-[(3-methoxypropyl)ami-
no]pyridine-3-sulfonamide;
N-{3-[(5-methoxy-2-methylphenyl)amino]quinoxalin-2-yl}pyridine-3-sulfonam-
ide; N-{3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2-yl}-4-cyano
benzene sulfonamide;
N-{3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2-yl}pyridine-3-sulfonam-
ide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-methoxypyridine-3-
-sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-oxo-1,6-dihydropyridi-
ne-3-sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-methylpyridine-3-sulf-
onamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluoro-2-meth-
ylbenzene sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-methylpyridine-3-sulf-
onamide;
4-cyano-N-{3-[(5-methoxy-2-methylphenyl)amino]quinoxalin-2-yl}ben-
zene sulfonamide;
N-{3-[(5-methoxy-2-methylphenyl)amino]quinoxalin-2-yl}-6-methylpyridine-3-
-sulfonamide;
N-{3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2-yl}-6-methylpyridine-3-
-sulfonamide; methyl
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]pyridin-
e-2-carboxylate;
N-{3-[(2-bromo-5-methoxyphenyl)amino]quinoxalin-2-yl}-1-methyl-1H-imidazo-
le-4-sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-(morpholin-4-ylcarbon-
yl)benzenesulfonamide;
5-{([3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-4-meth-
yl thiophene-2-carboxylic acid;
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-4-meth-
yl thiophene-2-carboxylic acid;
5-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-1-meth-
yl-1H-pyrrole-2-carboxylic acid;
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-1-meth-
yl-1H-pyrrole-2-carboxylic acid;
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]pyridin-
e-2-carboxylic acid;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-(morpholin-4-ylmethyl-
)benzene sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-[(4-methylpiperazin-1-
-yl)methyl]benzenesulfonamide;
4-(aminomethyl)-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-(hydroxymethyl)benzen-
esulfonamide;
3-(aminomethyl)-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzenes-
ulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(hydroxymethyl)benzen-
esulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-(hydroxymethyl)pyridi-
ne-3-sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(morpholin-4-ylmethyl-
)benzenesulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-[(4-methylpiperazin-1-
-yl)methyl]benzenesulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-[(dimethylamino)methy-
l]benzenesulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-[(dimethylamino)methy-
l]benzenesulfonamide;
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzami-
de;
4-[({3-[(5-methoxy-2-methylphenyl)amino]quinoxalin-2-yl}amino)sulfonyl-
]benzamide;
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-N-(3-m-
ethoxypropyl)benzamide;
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-N-[3-(-
dimethylamino)propyl]benzamide;
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-N-[3-(-
dimethylamino)propyl]benzamide;
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-N,N-di-
methylpyridine-2-carboxamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-[(4-methylpiperazin-1-
-yl)carbonyl]benzenesulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-(morpholin-4-ylcarbon-
yl)pyridine-3-sulfonamide;
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-[(4-methylpiperazin-1-
-yl)methyl]pyridine-3-sulfonamide; or
5-(aminomethyl)-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}thiophen-
e-2-sulfonamide.
11. The method according to claim 1, wherein said compound is
selected from:
4-cyano-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzenesul-
fonamide;
2-chloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzen- e
sulfonamide;
5-chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1,3-dimethyl-1-
H-pyrazole-4-sulfonamide;
N-{3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phen-
yl}acetamide;
3-cyano-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide;
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(trifluoromethyl)benz-
ene sulfonamide; or
4-fluoro-N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
and N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-iodobenzene
sulfonamide.
12. The method according to claim 1, wherein said autoimmune
disorder and/or inflammatory disease is selected from the group
consisting of multiple sclerosis, psoriasis, rheumatoid arthritis,
systemic lupus erythematosis, inflammatory bowel disease, lung
inflammation, thrombosis and brain infection/inflammation.
13. The method according to claim 1, wherein said neurodegenerative
disease is selected in the group consisting of Alzheimer's disease,
Huntington's disease, CNS trauma, stroke or ischemic
conditions.
14. The method according to claim 1, wherein said cardiovascular
disease is selected from the group consisting of atherosclerosis,
heart hypertrophy, cardiac myocyte dysfunction, elevated blood
pressure or vasoconstriction.
15. The method according to claim 1, wherein said autoimmune and/or
inflammatory disease, cardiovascular diseases, neurodegenerative
diseases, bacterial or viral infections, allergy, asthma,
pancreatitis, multi-organ failure, kidney diseases, platelet
aggregation, cancer, transplantation, sperm motility, erythrocyte
deficiency, graft rejection or lung injuries is selected from the
group consisting of chronic obstructive pulmonary disease,
anaphylactic shock fibrosis, psoriasis, allergic diseases, asthma,
stroke or ischemic conditions, ischemia-reperfusion, platelets
aggregation/activation, skeletal muscle atrophy/hypertrophy,
leukocyte recruitment in cancer tissue, angiogenesis, invasion
metastasis, melanoma, Karposi's sarcoma, acute and chronic
bacterial and viral infections, sepsis, graft rejection, glomerulo
sclerosis, glomerulo nephritis, progressive renal fibrosis,
endothelial and epithelial injuries in the lung and general lung
airway inflammation.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. Ser. No.
12/064,284, filed Feb. 20, 2008, which is the U.S. national stage
application of International Patent Application No.
PCT/EP2006/065688, filed Aug. 25, 2006, which claims the benefit of
U.S. Provisional Patent Application No. 60/711,873, filed Aug. 26,
2005, the disclosures of which are hereby incorporated by reference
in their entireties, including all figures, tables and amino acid
or nucleic acid sequences.
FIELD OF THE INVENTION
[0002] This present invention is related to the use of pyrazine
derivatives of Formula (I) for the treatment and/or prophylaxis of
autoimmune disorders and/or inflammatory diseases, cardiovascular
diseases, neurodegenerative diseases, bacterial or viral
infections, allergy, asthma, pancreatitis, multi-organ failure,
kidney diseases, platelet aggregation, cancer, transplantation,
sperm motility, erythrocyte deficiency, graft rejection or lung
injuries. Specifically, the present invention is related to
pyrazine derivatives for the modulation, notably the inhibition of
the activity or function of the phosphoinositide-3-kinases,
PI3Ks.
BACKGROUND OF THE INVENTION
[0003] Phosphoinositide 3-kinases (PI3Ks) have a critical
signalling role in cell proliferation, cell survival,
vascularization, membrane trafficking, glucose transport, neurite
outgrowth, membrane ruffling, superoxide production, actin
reorganization and chemotaxis (Cantley, 2000, Science, 296,
1655-1657).
[0004] The term PI3K is given to a family of lipid kinases which,
in mammals, consists in eight identified PI3Ks that are divided
into three sub-families according to their structure and their
substrate specificity.
[0005] Class I group of PI3Ks consists in two sub-groups, Class IA
and Class IB.
[0006] Class IA are a family of heterodimeric lipid kinases
consisting in a 85 kDa regulatory unit (responsible for
protein-protein interactions via the interaction of Src homology 2
(SH2) domain with phosphotyrosine residues of other proteins) and a
catalytic sub-unit of 110 kDa that generate second messenger
signals downstream of tyrosine kinases, thereby controlling cell
metabolism, growth, proliferation, differentiation, motility and
survival. Three catalytic forms (p110.alpha., p110.beta. and
p110.delta.) and five regulatory isoforms (p85.alpha., p85.beta.,
p55.gamma., p55.alpha. and p50.alpha.) exist for this class.
[0007] Class IB are stimulated by G protein .beta..gamma. sub-units
of heterodimeric G proteins. The only characterized member of Class
IB is PI3K.gamma. (p110.gamma. catalytic sub-unit complex with a
101-kDa regulatory protein, p101).
[0008] Class II PI3Ks comprises .alpha., .beta. and .gamma.
isoforms, which are approximately of 170 kDa and characterized by
the presence of a C-terminal C2 domain.
[0009] Class III PI3Ks includes the phosphatidylinositol specific
3-kinases.
[0010] The evolutionary conserved isoforms p110.alpha. and .beta.
are ubiquitously expressed, while .delta. and .gamma. are more
specifically expressed in the haematopoetic cell system, smooth
muscle cells, myocytes and endothelial cells (Vanhaesebroeck et
al., 2001, Annu. Rev. Biochem., 70, 535-602). Their expression
might also be regulated in an inducible manner depending on the
cellular-, tissue type and stimuli as well as disease context.
[0011] PI3Ks are enzymes involved in phospholipid signalling and
are activated in response to a variety of extra-cellular signals
such as growth factors, mitogens, integrins (cell-cell
interactions) hormones, cytokines, viruses and neurotransmitters
and also by intra-cellular cross regulation by other signalling
molecules (cross-talk, where the original signal can activate some
parallel pathways that in a second step transmit signals to PI3Ks
by intra-cellular signalling events), such as small GTPases,
kinases or phosphatases for example.
[0012] Phosphatidylinositol (PtdIns) is the basic building block
for the intracellular inositol lipids in eukaryotic cells,
consisting of D-myo-inositol-1-phosphate (Ins1P) linked via its
phosphate group to diacylglycerol. The inositol head group of
PtdIns has five free hydroxy groups and three of these are found to
be phosphorylated in cells in different combinations. PtdIns and
its phosphorylated derivatives are collectively referred as
inositol phospholipids or phosphoinositides (PIs). Eight PI species
have been documented in eukaryotic cells (Vanhaesebroeck et al.,
2001, above). PIs all reside in membranes and are substrates for
kinases, phosphatases and lipases.
[0013] In vitro, PI3Ks phosphorylate the 3-hydroxyl group of the
inositol ring in three different substrates: phosphatidylinositol
(PtdIns), phosphatidylinositol-4-phosphate (PI(4)P) and
phosphatidylinositol-4,5-biphosphate (PI(4,5)P.sub.2), respectively
generating three lipid products, namely phosphatidylinositol
3-monophosphate (PI(3)P), phosphatidylinositol 3,4-bisphosphate
(PI(3,4)P.sub.2) and phosphatidylinositol 3,4,5-trisphosphate
(PI(3,4,5)P.sub.3 (see Scheme A below).
##STR00001##
[0014] The preferred substrate for Class I PI3Ks is PI(4,5)P.sub.2.
Class II PIKs have a strong preference for PtdIns as substrate over
PI(4)P and PI(4,5)P.sub.2. Class III PI3Ks can only use PtdIns as
substrate in vivo and are likely to be responsible for the
generation of most PI(3)P in cells (Vanhaesebroeck et al., 2001,
above).
[0015] The phosphoinositides intracellular signalling pathway
begins with the binding of a signalling molecule (extracellular
ligands, stimuli, receptor dimidiation, transactivation by
heterologous receptor (e.g. receptor tyrosine kinase)) to a
G-protein linked transmembrane receptor integrated into the plasma
membrane resulting in the activation of PI3Ks.
[0016] Once activated, PI3Ks convert the membrane phospholipid
PI(4,5)P.sub.2 into PI(3,4,5)P.sub.3 which in turn can be further
converted into another 3' phosphorylated form of phosphoinositides
by 5'-specific phosphoinositide phosphatases, thus PI3K enzymatic
activity results either directly or indirectly in the generation of
two 3'-phosphoinositide sub-types that function as second
messengers in intra-cellular signal transduction (Taker et al.,
2002, Cell Mol. Life Sci. 59(5) 761-79).
[0017] The role as second messengers of phosphorylated products of
PtdIns act is involved in a variety of signal transduction
pathways, including those essential to cell proliferation, cell
differentiation, cell growth, cell size, cell survival, apoptosis,
adhesion, cell motility, cell migration, chemotaxis, invasion,
cytoskeletal rearrangement, cell shape changes, vesicle trafficking
and metabolic pathway (Stein, 2000, Mol. Med. Today 6(9) 347-57).
Chemotaxis--the directed movement of cells toward a concentration
gradient of chemical attractants, also called chemokines is
involved in many important diseases such as
inflammation/auto-immunity, neurodegeneration, angiogenesis,
invasion/metastasis and wound healing (Wyman et al., 2000, Immunol
Today 21(6) 260-4 and Gerard et al., 2001, Nat Immunol. 2(2)
108-15).
[0018] PI3-kinase activation, is therefore believed to be involved
in a range of cellular responses including cell growth,
differentiation, migration and apoptosis (Parker et al., 1995,
Current Biology, 5, 577-99; Yao et al., 1995, Science, 267,
2003-05).
[0019] Recent biochemical studies revealed that, Class I PI3Ks
(e.g. Class IB isoform PI3K.gamma.) are dual-specific kinase
enzymes, i.e. they display both lipid kinase activity
(phosphorylation of phospho-inositides) as well as protein kinase
activity, as they are able to induce the phosphorylation of other
protein as substrates, including auto-phosphorylation as
intra-molecular regulatory mechanism.
[0020] PI3Ks appear to be involved in a number of aspects of
leukocyte activation. A p85-associated PI3-kinase activity has been
shown to physically associate with the cytoplasmic domain of CD28,
which is an important co-stimulatory molecule for the activation of
T-cells in response to antigen. These effects are linked to
increases in the transcription of a number of genes including
interleukin-2 (IL-2), an important T cell growth factor (Fraser et
al., 1991, Science, 251, 313-16). Mutation of CD28 such that it can
longer interact with PI3-kinase leads to a failure to initiate IL-2
production, suggesting a critical role for PI3-kinase in T cell
activation.
[0021] Cellular processes in which PI3Ks play an essential role
include suppression of apoptosis, reorganization of the actin
skeleton, cardiac myocyte growth, glycogen synthase stimulation by
insulin, TNF.alpha.-mediated neutrophil priming and superoxide
generation, and leukocyte migration and adhesion to endothelial
cells.
[0022] Recently, it has been described that PI3K.gamma. relays
inflammatory signals through various G(i)-coupled receptors
(Laffargue et al., 2002, Immunity 16(3) 441-51) and its central to
mast cell function, stimuli in context of leukocytes, immunology
includes cytokines, chemokines, adenosines, antibodies, integrins,
aggregation factors, growth factors, viruses or hormones for
example (Lawlor et al., 2001, J. Cell. Sci., 114 (Pt 16)
2903-1).
[0023] Two compounds, LY294002 and Wortmannin (cf. hereinafter),
have been widely used as PI3-kinase inhibitors. These compounds are
non-specific PI3K inhibitors, as they do not distinguish among the
four members of Class I PI3-kinases.
##STR00002##
[0024] IC.sub.50 values of Wortmannin against each of the various
Class I PI3-kinases are in the range of 1-10 nM and IC.sub.50
values for LY294002 against each of these PI3-kinases are about
15-20 .mu.M (Fruman et al., 1998, Ann. Rev. Biochem., 67, 481-507),
also 5-10 mM on CK2 protein kinase and some inhibitory activity on
phospholipases.
[0025] Wortmannin is a fungal metabolite which irreversibly
inhibits PI3K activity by binding covalently to the catalytic
domain of this enzyme. Inhibition of PI3K activity by wortmannin
eliminates the subsequent cellular response to the extracellular
factor (Thelen et al., 1994, Proc. Natl. Acad. Sci. USA, 91,
4960-64). Experiments with wortmannin, show that PI3K activity in
cells of hematopoietic lineage, particularly neutrophils,
monocytes, and other types of leukocytes, is involved in many of
the non-memory immune response associated with acute and chronic
inflammation.
[0026] Based on studies using Wortmannin, there is evidence that
PI3-kinase function is also required for some aspects of leukocyte
signalling through G-protein coupled receptors (Thelen et al.,
1994, above). Moreover, it has been shown that Wortmannin and
LY294002 block neutrophil migration and superoxide release.
[0027] Some results have indicated that PI3K inhibitors, for
example, LY294002, can increase the in vivo antitumor activity of
certain cytotoxic agents (e.g. paclitaxel) (Grant, 2003, Current
Drugs, 6(10), 946-948).
[0028] However, in as much as these compounds do not distinguish
among the various isoforms of PI3K, it remains unclear which
particular PI3K isoform or isoforms are involved in these
phenomena. Specific inhibitors against individual members of a
family of enzymes provide valuable tools for deciphering functions
of each enzyme as depending on the disease application, varying the
degree of selectivity for PI3K isoforms can be of interest.
[0029] p110.delta. is expressed predominantly in cells of
hemopoeitic origin such as leukocytes.
[0030] To assess the role of the .delta. isoform of the p110
catalytic subunit of PI3Ks, PI3K.delta.-null mice have been
recently developed (Jou et al., 2002, Molecular and Cellular
biology, 22(4), 8580-8591) and their specific immunological
phenotype has been well characterized (Vanhaesebroeck et al., 2005,
Trends in Biochemical Sciences, 30(4), 194-204). These experiments
show that the PI3K.delta.-null animals are viable and that a
deficiency in PI3K.delta. results in a very specific loss of the
function of the B-cell antigen specific receptor complex, while
signalling through the cytokine receptor complexes is unaffected
(Jou et al., 2002, above).
[0031] It has been also shown that the inactivation of the
p110.delta. isoform of PI3K in mast cells leads to defective stem
cell factor-mediated in vitro proliferation, adhesion and migration
and to impaired allergen-IgE-induced degranulation and cytokine
release. Inactivation of p110.delta. protects mice against
anaphylactic allergic responses, suggesting p110.delta. as a target
for therapeutic intervention in allergy and mast-cell-related
pathologies (Ali. et al., 2004, Nature, 431, 1007-1010).
[0032] Mast cells have emerged as a unique immune cell that could
participate in a variety of inflammatory diseases in the nervous
system (e.g. multiple sclerosis), skin, joints as well as
cardiopulmonary, intestinal and urinary systems (Theoharides et
al., 2004, J. of Neuroimmunology, 146, 1-12).
[0033] The high relevance of the PI3K pathway in some widely spread
diseases stresses the need to develop inhibitors, including
selective inhibitors, of PIK isozymes, in order that the functions
of each isozyme can be better characterized.
[0034] Recently, PI3K inhibitors have been developed: thiazole
derivatives (WO 2005/021519; and WO 04/078754), thiazolidine
derivatives (WO 2004/007491 and WO 2004/056820) and Quinazolinones
derivatives (WO 03/035075).
SUMMARY OF THE INVENTION
[0035] According to one aspect of the invention, are provided
substances which are suitable for the treatment and/or prevention
of disorders related to phosphoinositide-3-kinases, PI3Ks, such as
PI3K alpha or PI3K gamma or PI3K delta.
[0036] According to another aspect of the invention, are provided
substances which are suitable for the treatment and/or prevention
of auto-immune and/or inflammatory disorders.
[0037] According to another aspect of the invention, are provided
substances which are suitable for the treatment and/or prevention
of cardiovascular diseases.
[0038] According to another aspect of the invention, are provided
substances which are suitable for the treatment and/or prevention
of neurodegenerative disorders.
[0039] According to another aspect of the invention, are provided
substances which are suitable for the treatment and/or prevention
of cancers.
[0040] According to another aspect of the invention, are provided
substances which are suitable for the treatment and/or prevention
of a disorder selected from bacterial and viral infections,
allergy, asthma, pancreatitis, multi-organ failure, kidney
diseases, platelet aggregation, cancer, transplantation, sperm
motility, erythrocyte deficiency, graft rejection, lung injuries,
respiratory diseases and ischemic conditions.
[0041] According to another aspect of the invention, are provided
chemical compounds which are able to modulate, especially inhibit
the activity or function of phosphoinositide-3-kinases, PI3Ks in
disease states in mammals, especially in humans.
[0042] According to another aspect of the invention, are provided a
new category of pharmaceutical formulations for the treatment of
and/or diseases mediated selected from auto-immune, inflammatory
disorders, cardiovascular diseases, neurodegenerative disorders,
bacterial and viral infections, allergy, asthma, pancreatitis,
multi-organ failure, kidney diseases, platelet aggregation, cancer,
transplantation, sperm motility, erythrocyte deficiency, graft
rejection, lung injuries, respiratory diseases and ischemic
conditions.
[0043] According to another aspect of the invention, are provided a
method for the treatment and/or prevention of disorders selected
from auto-immune, inflammatory disorders, cardiovascular diseases,
neurodegenerative disorders, bacterial and viral infections,
allergy, asthma, pancreatitis, multi-organ failure, kidney
diseases, platelet aggregation, cancer, transplantation, sperm
motility, erythrocyte deficiency, graft rejection, lung injuries,
respiratory diseases and ischemic conditions.
[0044] In a first aspect, the invention provides pyrazine
derivatives of Formula (I):
##STR00003##
wherein n, A, B, D, E, R, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
defined in the detailed description below.
[0045] In a second aspect, the invention provides a compound
according to Formula (I) for use as a medicament.
[0046] In a third aspect, the invention provides a use of a
compound according to Formula (I) for the preparation of a
pharmaceutical composition for the treatment of a disorder selected
from auto-immune, inflammatory disorders, cardiovascular diseases,
neurodegenerative disorders, bacterial and viral infections,
allergy, asthma, pancreatitis, multi-organ failure, kidney
diseases, platelet aggregation, cancer, transplantation, sperm
motility, erythrocyte deficiency, graft rejection, lung injuries,
respiratory diseases and ischemic conditions and other diseases and
disorders associated with the phosphoinositide-3-kinases, PI3Ks,
comprising PI3K .alpha., .gamma. or .delta..
[0047] In a fourth aspect, the invention provides a pharmaceutical
composition comprising at least one a compound according to Formula
(I) and a pharmaceutically acceptable carrier, diluent or excipient
thereof.
[0048] In a fifth aspect, the invention provides a method for
treating a patient suffering from a disorder selected from
auto-immune, inflammatory disorders, cardiovascular diseases,
neurodegenerative disorders, bacterial and viral infections,
allergy, asthma, pancreatitis, multi-organ failure, kidney
diseases, platelet aggregation, cancer, transplantation, sperm
motility, erythrocyte deficiency, graft rejection, lung injuries,
respiratory diseases and ischemic conditions and other diseases and
disorders associated with the phosphoinositide-3-kinases, PI3Ks.
The method comprises administering a compound according to Formula
(I).
[0049] In a sixth aspect, the invention provides methods of
synthesis of a compound according to Formula (I).
[0050] In a seventh aspect, the invention provides compounds
according to Formula (II).
[0051] In an eighth aspect, the invention provides compounds
according to Formula (XI).
DETAILED DESCRIPTION OF THE INVENTION
[0052] The following paragraphs provide definitions of the various
chemical moieties that make up the compounds according to the
invention and are intended to apply uniformly through-out the
specification and claims unless an otherwise expressly set out
definition provides a broader definition.
[0053] "C.sub.1-C.sub.6-alkyl" refers to monovalent alkyl groups
having 1 to 6 carbon atoms. This term is exemplified by groups such
as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
tert-butyl, n-hexyl and the like. By analogy,
"C.sub.1-C.sub.12-alkyl" refers to monovalent alkyl groups having 1
to 12 carbon atoms, including "C.sub.1-C.sub.6-alkyl" groups and
heptyl, octyl, nonyl, decanoyl, undecanoyl and dodecanoyl groups
and "C.sub.1-C.sub.10-alkyl" refers to monovalent alkyl groups
having 1 to 10 carbon atoms, "C.sub.1-C.sub.8-alkyl" refers to
monovalent alkyl groups having 1 to 8 carbon atoms and
"C.sub.1-C.sub.5-alkyl" refers to monovalent alkyl groups having 1
to 5 carbon atoms.
[0054] "Heteroalkyl" refers to C.sub.1-C.sub.12-alkyl, preferably
C.sub.1-C.sub.6-alkyl, wherein at least one carbon has been
replaced by a heteroatom selected from O, N or S, including
2-methoxy ethyl.
[0055] "Aryl" refers to an unsaturated aromatic carbocyclic group
of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or
multiple condensed rings (e.g., naphthyl). Aryl include phenyl,
naphthyl, phenantrenyl and the like.
[0056] "C.sub.1-C.sub.6-alkyl aryl" refers to aryl groups having a
C.sub.1-C.sub.6-alkyl substituent, including methyl phenyl, ethyl
phenyl and the like.
[0057] "Aryl C.sub.1-C.sub.6-alkyl" refers to C.sub.1-C.sub.6-alkyl
groups having an aryl substituent, including 3-phenylpropanoyl,
benzyl and the like.
[0058] "Heteroaryl" refers to a monocyclic heteroaromatic, or a
bicyclic or a tricyclic fused-ring heteroaromatic group. Particular
examples of heteroaromatic groups include optionally substituted
pyridyl, pyrrolyl, pyrimidinyl, furyl, thienyl, imidazolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadia-zolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,
[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl,
benzothiazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl,
benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl,
benzoxazolyl, quinolizinyl, quinazolinyl, pthalazinyl,
quinoxalinyl, cinnolinyl, napthyridinyl, pyrido[3,4-b]pyridyl,
pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl,
tetrazolyl, 5,6,7,8-tetrahydroquinolyl,
5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,
xanthenyl or benzoquinolyl.
[0059] "C.sub.1-C.sub.6-alkyl heteroaryl" refers to heteroaryl
groups having a C.sub.1-C.sub.6-alkyl substituent, including methyl
furyl and the like.
[0060] "Heteroaryl C.sub.1-C.sub.6-alkyl" refers to
C.sub.1-C.sub.6-alkyl groups having a heteroaryl substituent,
including furyl methyl and the like.
[0061] "C.sub.2-C.sub.6-alkenyl" refers to alkenyl groups
preferably having from 2 to 6 carbon atoms and having at least 1 or
2 sites of alkenyl unsaturation. Preferable alkenyl groups include
ethenyl (--CH.dbd.CH.sub.2), n-2-propenyl (allyl,
--CH.sub.2CH.dbd.CH.dbd.CH.sub.2) and the like.
[0062] "C.sub.2-C.sub.6-alkenyl aryl" refers to an aryl groups
having a C.sub.2-C.sub.6-alkenyl substituent, including vinyl
phenyl and the like.
[0063] "Aryl C.sub.2-C.sub.6-alkenyl" refers to a
C.sub.2-C.sub.6-alkenyl groups having an aryl substituent,
including phenyl vinyl and the like.
[0064] "C.sub.2-C.sub.6-alkenyl heteroaryl" refers to heteroaryl
groups having a C.sub.2-C.sub.6-alkenyl substituent, including
vinyl pyridinyl and the like.
[0065] "Heteroaryl C.sub.2-C.sub.6-alkenyl" refers to
C.sub.2-C.sub.6-alkenyl groups having a Heteroaryl substituent,
including pyridinyl vinyl and the like.
[0066] "C.sub.2-C.sub.6-alkynyl" refers to alkynyl groups
preferably having from 2 to 6 carbon atoms and having at least 1-2
sites of alkynyl unsaturation, preferred alkynyl groups include
ethynyl (--C.ident.CH), propargyl (--CH.sub.2C.ident.CH), and the
like.
[0067] "C.sub.3-C.sub.8-cycloalkyl" refers to a saturated
carbocyclic group of from 3 to 8 carbon atoms having a single ring
(e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl).
C.sub.3-C.sub.8-cycloalkyl include cyclopentyl, cyclohexyl,
norbornyl and the like.
[0068] "Heterocycloalkyl" refers to a C.sub.3-C.sub.8-cycloalkyl
group according to the definition above, in which up to 3 carbon
atoms are replaced by heteroatoms chosen from the group consisting
of O, S, NR, R being defined as hydrogen or methyl.
Heterocycloalkyl include pyrrolidine, piperidine, piperazine,
morpholine, tetrahydrofurane and the like.
[0069] "C.sub.1-C.sub.6-alkyl cycloalkyl" refers to
C.sub.3-C.sub.8-cycloalkyl groups having a C.sub.1-C.sub.6-alkyl
substituent, including methyl cyclopentyl and the like.
[0070] "Cycloalkyl C.sub.1-C.sub.6-alkyl" refers to
C.sub.1-C.sub.6-alkyl groups having a C.sub.3-C.sub.8-cycloalkyl
substituent, including 3-cyclopentyl propyl and the like.
[0071] "C.sub.1-C.sub.6-alkyl heterocycloalkyl" refers to
heterocycloalkyl groups having a C.sub.1-C.sub.6-alkyl substituent,
including 1-methylpiperazine and the like.
[0072] "Heterocycloalkyl C.sub.1-C.sub.6-alkyl" refers to
C.sub.1-C.sub.6-alkyl groups having a heterocycloalkyl substituent,
including 4-methyl piperidyl and the like.
[0073] "Carboxy" refers to the group --C(O)OH.
[0074] "Carboxy C.sub.1-C.sub.6-alkyl" refers to
C.sub.1-C.sub.6-alkyl groups having a carboxy substituent,
including 2-carboxyethyl and the like.
[0075] "Acyl" refers to the group --C(O)R where R includes H,
"C.sub.1-C.sub.12-alkyl", preferably "C.sub.1-C.sub.6-alkyl",
"aryl", "heteroaryl", "C.sub.3-C.sub.8-cycloalkyl",
"heterocycloalkyl", "aryl C.sub.1-C.sub.6-alkyl", "heteroaryl
C.sub.1-C.sub.6-alkyl", "C.sub.3-C.sub.8-cycloalkyl
C.sub.1-C.sub.6-alkyl" or "heterocycloalkyl
C.sub.1-C.sub.6-alkyl".
[0076] "Acyl C.sub.1-C.sub.6-alkyl" to C.sub.1-C.sub.6-alkyl groups
having an acyl substituent, including acetyl, 2-acetylethyl and the
like.
[0077] "Acyl aryl" refers to aryl groups having an acyl
substituent, including 2-acetylphenyl and the like.
[0078] "Acyloxy" refers to the group --OC(O)R where R includes H,
"C.sub.1-C.sub.6-alkyl", "C.sub.2-C.sub.6-alkenyl",
"C.sub.2-C.sub.6-alkynyl", "C.sub.3-C.sub.8-cycloalkyl",
"heterocycloalkyl", "aryl", "heteroaryl", "aryl
C.sub.1-C.sub.6-alkyl" or "heteroaryl C.sub.1-C.sub.6-alkyl", "aryl
C.sub.2-C.sub.6-alkenyl", "heteroaryl C.sub.2-C.sub.6-alkenyl",
"aryl C.sub.2-C.sub.6-alkynyl", "heteroaryl
C.sub.2-C.sub.6-alkynyl", "cycloalkyl C.sub.1-C.sub.6-alkyl",
"heterocycloalkyl C.sub.1-C.sub.6-alkyl".
[0079] "Acyloxy C.sub.1-C.sub.6-alkyl" refers to
C.sub.1-C.sub.6-alkyl groups having an acyloxy substituent,
including propionic acid ethyl ester and the like.
[0080] "Alkoxy" refers to the group --O--R where R includes
"C.sub.1-C.sub.6-alkyl" or "aryl" or "hetero-aryl" or "aryl
C.sub.1-C.sub.6-alkyl" or "heteroaryl C.sub.1-C.sub.6-alkyl".
Preferred alkoxy groups include for example, methoxy, ethoxy,
phenoxy and the like.
[0081] "Alkoxy C.sub.1-C.sub.6-alkyl" refers to alkoxy groups
having a C.sub.1-C.sub.6-alkyl substituent, including methoxy,
methoxyethyl and the like.
[0082] "Alkoxycarbonyl" refers to the group --C(O)OR where R
includes H, "C.sub.1-C.sub.6-alkyl" or "aryl" or "heteroaryl" or
"aryl C.sub.1-C.sub.6-alkyl" or "heteroaryl C.sub.1-C.sub.6-alkyl"
or "heteroalkyl".
[0083] "Alkoxycarbonyl C.sub.1-C.sub.6-alkyl" refers to
C.sub.1-C.sub.5-alkyl groups having an alkoxycarbonyl substituent,
including 2-(benzyloxycarbonyl)ethyl and the like.
[0084] "Aminocarbonyl" refers to the group --C(O)NRR' where each R,
R' includes independently hydrogen or C.sub.1-C.sub.6-alkyl or aryl
or heteroaryl or "aryl C.sub.1-C.sub.6-alkyl" or "heteroaryl
C.sub.1-C.sub.6-alkyl", including N-phenyl formamide.
[0085] "Aminocarbonyl C.sub.1-C.sub.6-alkyl" refers to
C.sub.1-C.sub.6-alkyl groups having an aminocarbonyl substituent,
including 2-(dimethylaminocarbonyl)ethyl, N-ethyl acetamide,
N,N-Diethyl-acetamide and the like.
[0086] "Acylamino" refers to the group --NRC(O)R' where each R, R'
is independently hydrogen, "C.sub.1-C.sub.6-alkyl",
"C.sub.2-C.sub.6-alkenyl", "C.sub.2-C.sub.6-alkynyl",
"C.sub.3-C.sub.8-cycloalkyl", "heterocycloalkyl", "aryl",
"heteroaryl", "aryl C.sub.1-C.sub.6-alkyl" or "heteroaryl
C.sub.1-C.sub.6-alkyl", "aryl C.sub.2-C.sub.6-alkenyl", "heteroaryl
C.sub.2-C.sub.6-alkenyl", "aryl C.sub.2-C.sub.6-alkynyl",
"heteroaryl C.sub.2-C.sub.6-alkynyl", "cycloalkyl
C.sub.1-C.sub.6-alkyl", "heterocycloalkyl
C.sub.1-C.sub.6-alkyl".
[0087] "Acylamino C.sub.1-C.sub.6-alkyl" refers to
C.sub.1-C.sub.6-alkyl groups having an acylamino substituent,
including 2-(propionylamino)ethyl and the like,
[0088] "Ureido" refers to the group --NRC(O)NR'R'' where each R,
R', R'' is independently hydrogen, "C.sub.1-C.sub.6-alkyl",
"C.sub.2-C.sub.6-alkenyl", "C.sub.2-C.sub.6-alkynyl",
"C.sub.3-C.sub.8-cycloalkyl", "heterocycloalkyl", "aryl",
"heteroaryl", "aryl C.sub.1-C.sub.6-alkyl" or "heteroaryl
C.sub.1-C.sub.6-alkyl", "aryl C.sub.2-C.sub.6-alkenyl", "heteroaryl
C.sub.2-C.sub.6-alkenyl", "aryl C.sub.2-C.sub.6-alkynyl",
"heteroaryl C.sub.2-C.sub.6-alkynyl", "cycloalkyl
C.sub.1-C.sub.6-alkyl", "heterocycloalkyl C.sub.1-C.sub.6-alkyl",
and where R' and R'', together with the nitrogen atom to which they
are attached, can optionally form a 3-8-membered heterocycloalkyl
ring.
[0089] "Ureido C.sub.1-C.sub.6-alkyl" refers to
C.sub.1-C.sub.6-alkyl groups having an ureido substituent,
including 2-(N'-methylureido)ethyl and the like,
[0090] "Carbamate" refers to the group --NRC(O)OR' where each R, R'
is independently hydrogen, "C.sub.1-C.sub.6-alkyl",
"C.sub.2-C.sub.6-alkenyl", "C.sub.2-C.sub.6-alkynyl",
"C.sub.3-C.sub.8-cycloalkyl", "heterocycloalkyl", "aryl",
"heteroaryl", "C.sub.1-C.sub.6-alkyl aryl" or "heteroaryl
C.sub.1-C.sub.6-alkyl", "aryl C.sub.2-C.sub.6-alkenyl", "heteroaryl
C.sub.2-C.sub.6-alkenyl", "aryl C.sub.2-C.sub.6-alkynyl",
"heteroaryl C.sub.2-C.sub.6-alkynyl", "cycloalkyl
C.sub.1-C.sub.6-alkyl", "heterocycloalkyl
C.sub.1-C.sub.6-alkyl".
[0091] "Amino" refers to the group --NRR' where each R, R' is
independently hydrogen or "C.sub.1-C.sub.6-alkyl" or "aryl" or
"heteroaryl" or "C.sub.1-C.sub.6-alkyl aryl" or
"C.sub.1-C.sub.6-alkyl heteroaryl", or "cycloalkyl", or
"heterocycloalkyl", and where R and R', together with the nitrogen
atom to which they are attached, can optionally form a 3-8-membered
heterocycloalkyl ring.
[0092] "Amino C.sub.1-C.sub.6-alkyl" refers to
C.sub.1-C.sub.5-alkyl groups having an amino substituent, including
2-(1-pyrrolidinyl)ethyl and the like.
[0093] "Ammonium" refers to a positively charged group
--N.sup.+RR'R'', where each R, R', R'' is independently
"C.sub.1-C.sub.6-alkyl" or "C.sub.1-C.sub.6-alkyl aryl" or
"C.sub.1-C.sub.6-alkyl heteroaryl", or "cycloalkyl", or
"heterocycloalkyl", and where R and R', together with the nitrogen
atom to which they are attached, can optionally form a 3-8-membered
heterocycloalkyl ring.
[0094] "Ammonium C.sub.1-C.sub.6-alkyl" refers to
C.sub.1-C.sub.6-alkyl groups having an ammonium substituent,
including 1-ethylpyrrolidinium and the like.
[0095] "Halogen" refers to fluoro, chloro, bromo and iodo
atoms.
[0096] "Sulfonyloxy" refers to a group --OSO.sub.2--R wherein R is
selected from H, "C.sub.1-C.sub.6-alkyl", "C.sub.1-C.sub.6-alkyl"
substituted with halogens, e.g., an --OSO.sub.2--CF.sub.3 group,
"C.sub.2-C.sub.6-alkenyl", "C.sub.2-C.sub.6-alkynyl",
"C.sub.3-C.sub.8-cycloalkyl", "heterocycloalkyl", "aryl",
"heteroaryl", "aryl C.sub.1-C.sub.6-alkyl" or "heteroaryl
C.sub.1-C.sub.6-alkyl", "aryl C.sub.2-C.sub.6-alkenyl", "heteroaryl
C.sub.2-C.sub.6-alkenyl", "aryl C.sub.2-C.sub.6-alkynyl",
"heteroaryl C.sub.2-C.sub.6-alkynyl", "cycloalkyl
C.sub.1-C.sub.6-alkyl", "heterocycloalkyl
C.sub.1-C.sub.6-alkyl".
[0097] "Sulfonyloxy C.sub.1-C.sub.6-alkyl" refers to
C.sub.1-C.sub.6-alkyl groups having a sulfonyloxy substituent,
including 2-(methylsulfonyloxy)ethyl and the like.
[0098] "Sulfonyl" refers to group "--SO.sub.2--R" wherein R is
selected from H, "aryl", "heteroaryl", "C.sub.1-C.sub.6-alkyl",
"C.sub.1-C.sub.6-alkyl" substituted with halogens, e.g., an
--SO.sub.2--CF.sub.3 group, "C.sub.2-C.sub.6-alkenyl",
"C.sub.2-C.sub.6-alkynyl", "C.sub.3-C.sub.8-cycloalkyl",
"heterocycloalkyl", "aryl", "heteroaryl", "aryl
C.sub.1-C.sub.6-alkyl" or "heteroaryl C.sub.1-C.sub.6-alkyl", "aryl
C.sub.2-C.sub.6-alkenyl", "heteroaryl C.sub.2-C.sub.6-alkenyl",
"aryl C.sub.2-C.sub.6-alkynyl", "heteroaryl
C.sub.2-C.sub.6-alkynyl", "cycloalkyl C.sub.1-C.sub.6-alkyl",
"heterocycloalkyl C.sub.1-C.sub.6-alkyl".
[0099] "Sulfonyl C.sub.1-C.sub.6-alkyl" refers to
C.sub.1-C.sub.5-alkyl groups having a sulfonyl substituent,
including 2-(methylsulfonyl)ethyl and the like.
[0100] "Sulfinyl" refers to a group "--S(O)--R" wherein R is
selected from H, "C.sub.1-C.sub.6-alkyl", "C.sub.1-C.sub.6-alkyl"
substituted with halogens, e.g., a --SO--CF.sub.3 group,
"C.sub.2-C.sub.6-alkenyl", "C.sub.2-C.sub.6-alkynyl",
"C.sub.3-C.sub.8-cycloalkyl", "heterocycloalkyl", "aryl",
"heteroaryl", "aryl C.sub.1-C.sub.6-alkyl" or "heteroaryl
C.sub.1-C.sub.6-alkyl", "aryl C.sub.2-C.sub.6-alkenyl", "heteroaryl
C.sub.2-C.sub.6-alkenyl", "aryl C.sub.2-C.sub.6-alkynyl",
"heteroaryl C.sub.2-C.sub.6-alkynyl", "cycloalkyl
C.sub.1-C.sub.6-alkyl", "heterocycloalkyl
C.sub.1-C.sub.6-alkyl".
[0101] "Sulfinyl C.sub.1-C.sub.6-alkyl" refers to
C.sub.1-C.sub.6-alkyl groups having a sulfonyl substituent,
including 2-(methylsulfinyl)ethyl and the like.
[0102] "Sulfinyl" refers to groups --S--R where R includes H,
"C.sub.1-C.sub.6-alkyl", "C.sub.1-C.sub.6-alkyl" substituted with
halogens, e.g., a --SO--CF.sub.3 group, "C.sub.2-C.sub.6-alkenyl",
"C.sub.2-C.sub.6-alkynyl", "C.sub.3-C.sub.8-cycloalkyl",
"heterocycloalkyl", "aryl", "heteroaryl", "aryl
C.sub.1-C.sub.6-alkyl" or "heteroaryl C.sub.1-C.sub.6-alkyl", "aryl
C.sub.2-C.sub.6-alkenyl", "heteroaryl C.sub.2-C.sub.6-alkenyl",
"aryl C.sub.2-C.sub.6-alkynyl", "alkynylheteroaryl
C.sub.2-C.sub.6", "cycloalkyl C.sub.1-C.sub.6-alkyl",
"heterocycloalkyl C.sub.1-C.sub.6-alkyl". Preferred sulfanyl groups
include methylsulfanyl, ethylsulfanyl, and the like.
[0103] "Sulfanyl C.sub.1-C.sub.6-alkyl" refers to
C.sub.1-C.sub.5-alkyl groups having a sulfanyl substituent,
including 2-(ethylsulfanyl)ethyl and the like,
[0104] "Sulfonylamino" refers to a group --NRSO.sub.2--R' where
each R, R' includes independently hydrogen,
"C.sub.1-C.sub.6-alkyl", "C.sub.2-C.sub.6-alkenyl",
"C.sub.2-C.sub.6-alkynyl", "C.sub.3-C.sub.8-cycloalkyl",
"heterocycloalkyl", "aryl", "heteroaryl", "aryl
C.sub.1-C.sub.6-alkyl" or "heteroaryl C.sub.1-C.sub.6-alkyl", "aryl
C.sub.2-C.sub.6-alkenyl", "heteroaryl C.sub.2-C.sub.6-alkenyl",
"aryl C.sub.2-C.sub.6-alkynyl", "heteroaryl
C.sub.2-C.sub.6-alkynyl", "cycloalkyl C.sub.1-C.sub.6-alkyl",
"heterocycloalkyl C.sub.1-C.sub.6-alkyl".
[0105] "Sulfonylamino C.sub.1-C.sub.6-alkyl" refers to
C.sub.1-C.sub.6-alkyl groups having a sulfonylamino substituent,
including 2-(ethylsulfonylamino)ethyl and the like.
[0106] "Aminosulfonyl" refers to a group --SO.sub.2--NRR' where
each R, R' includes independently hydrogen,
"C.sub.1-C.sub.6-alkyl", "C.sub.2-C.sub.6-alkenyl",
"C.sub.2-C.sub.6-alkynyl", "C.sub.3-C.sub.8-cycloalkyl",
"heterocycloalkyl", "aryl", "heteroaryl", "aryl
C.sub.1-C.sub.6-alkyl" or "heteroaryl C.sub.1-C.sub.6-alkyl", "aryl
C.sub.2-C.sub.6-alkenyl", "heteroaryl C.sub.2-C.sub.6-alkenyl",
"aryl C.sub.2-C.sub.6-alkynyl", "heteroaryl
C.sub.2-C.sub.6-alkynyl", "cycloalkyl C.sub.1-C.sub.6-alkyl",
"heterocycloalkyl C.sub.1-C.sub.6-alkyl".
[0107] "Aminosulfonyl C.sub.1-C.sub.6-alkyl" refers to
C.sub.1-C.sub.6-alkyl groups having an aminosulfonyl substituent,
including 2-(cyclohexylaminosulfonyl)ethyl and the like.
[0108] "Substituted or unsubstituted": Unless otherwise constrained
by the definition of the individual substituent, the above set out
groups, like "alkenyl", "alkynyl", "aryl", "heteroaryl",
"cycloalkyl", "heterocycloalkyl" etc. groups can optionally be
substituted with from 1 to 5 substituents selected from the group
consisting of "C.sub.1-C.sub.6-alkyl", "C.sub.2-C.sub.6-alkenyl",
"C.sub.2-C.sub.6-alkynyl", "cycloalkyl", "heterocycloalkyl",
"C.sub.1-C.sub.6-alkyl aryl", "C.sub.1-C.sub.6-alkyl heteroaryl",
"C.sub.1-C.sub.6-alkyl cycloalkyl", "C.sub.1-C.sub.6-alkyl
heterocycloalkyl", "amino", "ammonium", "acyl", "acyloxy",
"acylamino", "aminocarbonyl", "alkoxycarbonyl", "ureido", "aryl",
"carbamate", "heteroaryl", "sulfanyl", "sulfonyl", "alkoxy",
"sulfanyl", "halogen", "carboxy", trihalomethyl, cyano, hydroxy,
mercapto, nitro, and the like.
[0109] "Substituted" refers to groups substituted with from 1 to 5
substituents selected from the group consisting of
"C.sub.1-C.sub.6-alkyl", "C.sub.2-C.sub.6-alkenyl",
"C.sub.2-C.sub.6-alkynyl", "cycloalkyl", "heterocycloalkyl",
"C.sub.1-C.sub.6-alkyl aryl", "C.sub.1-C.sub.6-alkyl heteroaryl",
"C.sub.1-C.sub.6-alkyl cycloalkyl", "C.sub.1-C.sub.6-alkyl
heterocycloalkyl", "amino", "aminosulfonyl", "ammonium", "acyl
amino", "amino carbonyl", "aryl", "heteroaryl", "sulfinyl",
"sulfonyl", "alkoxy", "alkoxy carbonyl", "carbamate", "sulfonyl",
"halogen", trihalomethyl, cyano, hydroxy, mercapto, nitro, and the
like.
[0110] "Pharmaceutically acceptable salts or complexes" refers to
salts or complexes of the below-identified compounds of Formula (I)
that retain the desired biological activity. Examples of such salts
include, but are not restricted to acid addition salts formed with
inorganic acids (e.g., hydrochloric acid, hydrobromic acid,
sulfuric acid, phosphoric acid, nitric acid, and the like), and
salts formed with organic acids such as acetic acid, oxalic acid,
tartaric acid, succinic acid, malic acid, fumaric acid, maleic
acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid,
alginic acid, polyglutamic acid, naphthalene sulfonic acid,
naphthalene disulfonic acid, and poly-galacturonic acid. Said
compounds can also be administered as pharmaceutically acceptable
quaternary salts known by a person skilled in the art, which
specifically include the quarternary ammonium salt of the formula
--NR, R', R''.sup.+Z.sup.-, wherein R, R', R'' is independently
hydrogen, alkyl, or benzyl, C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl,
C.sub.1-C.sub.6-alkyl aryl, C.sub.1-C.sub.6-alkyl heteroaryl,
cycloalkyl, heterocycloalkyl, and Z is a counterion, including
chloride, bromide, iodide, --O-alkyl, toluenesulfonate,
methylsulfonate, sulfonate, phosphate, or carboxylate (such as
benzoate, succinate, acetate, glycolate, maleate, malate, fumarate,
citrate, tartrate, ascorbate, cinnamoate, mandeloate, and
diphenylacetate).
[0111] Also comprised are salts formed by reaction of compounds of
Formula (I) with organic or inorganic bases such as hydroxide,
carbonate or bicarbonate of a metal cation such as those selected
in the group consisting of alkali metals (sodium, potassium or
lithium), alkaline earth metals (e.g. calcium or magnesium), or
with an organic primary, secondary or tertiary alkyl amine. Amine
salts derived from methyl amine, dimethylamine, trimethylamine,
ethylamine, diethylamine, triethylamine, morpholine, ammonium,
N-methyl-D-glucamine, N,N'-bis(phenylmethyl)-1,2-ethanediamine,
tromethamine, ethanolamine, diethanolamine, ethylenediamine,
N-methylmorpholine, procaine, piperidine, piperazine and the like
are contemplated being within the scope of the instant
invention.
[0112] "Pharmaceutically active derivative" refers to any compound
that upon administration to the recipient, is capable of providing
directly or indirectly, the activity disclosed herein. The term
"indirectly" also encompasses prodrugs which may be converted to
the active form of the drug via endogenous enzymes or
metabolism.
[0113] It has now been found that compounds of the present
invention are modulators of the Phosphatoinositides 3-kinases
(PI3Ks), comprising PI3K .alpha., .gamma. or .delta.. When the
phosphatoinositides 3-kinase (PI3K) enzyme is inhibited by the
compounds of the present invention, PI3K is unable to exert its
enzymatic, biological and/or pharmacological effects.
[0114] The compounds of the present invention are therefore useful
in the treatment and prevention of autoimmune disorders and/or
inflammatory diseases, cardiovascular diseases, neurodegenerative
diseases, bacterial or viral infections, allergy, asthma,
pancreatitis, multi-organ failure, kidney diseases, platelet
aggregation, cancer, transplantation, sperm motility, erythrocyte
deficiency, graft rejection or lung injuries.
[0115] General Formula (I) according to the present invention also
comprises its tautomers, its geometrical isomers, its optically
active forms as enantiomers, diastereomers and its racemate forms,
as well as pharmaceutically acceptable salts thereof. Preferred
pharmaceutically acceptable salts of the Formula (I) are base
addition salts formed by reaction of compounds of formula (I) with
pharmaceutically acceptable bases like sodium, potassium or calcium
of hydroxides, ammonium or N-methyl-D-glucamine.
[0116] The compounds according to Formula (I) are suitable for the
modulation, notably the inhibition of the activity of
phosphatoinositides 3-kinases (PI3K). It is therefore believed that
the compounds of the present invention are also particularly useful
for the treatment and/or prevention of disorders, which are
mediated by PI3Ks, particularly PI3K .alpha. and/or PI3K .gamma.
and/or PI3K .delta.. Said treatment involves the
modulation--notably the inhibition or the down regulation--of the
phosphatoinositides 3-kinases.
[0117] The compounds according to Formula (I) are suitable for use
as a medicament.
[0118] In one embodiment, the invention provides pyrazine
derivatives of Formula (I):
##STR00004##
[0119] wherein:
[0120] A, B, D and E are independently selected from C and N, such
that the ring R is a stable aromatic ring, including optionally
substituted phenyl and optionally substituted pyridinyl;
[0121] R.sup.1 is selected from H; halogen, including chloro;
nitro; optionally substituted C.sub.1-C.sub.6-alkyl, including
methyl; optionally substituted C.sub.2-C.sub.6-alkenyl and
optionally substituted C.sub.2-C.sub.6-alkynyl;
[0122] R.sup.2 is selected from H; optionally substituted
C.sub.1-C.sub.6-alkyl, including methyl; optionally substituted
C.sub.2-C.sub.6-alkenyl and optionally substituted
C.sub.2-C.sub.6-alkynyl;
[0123] R.sup.3 is selected from H; halo, including chloro;
optionally substituted C.sub.1-C.sub.6-alkyl; optionally
substituted C.sub.2-C.sub.6-alkenyl; optionally substituted
C.sub.2-C.sub.6-alkynyl, optionally substituted alkoxy, including
methoxy; optionally substituted aryl; optionally substituted
heteroaryl, including pyrrolyl;
[0124] R.sup.4 is selected from optionally substituted
C.sub.1-C.sub.6-alkyl, including methyl, ethyl, butyl, propyl,
carboxy C.sub.1-C.sub.6-alkyl (e.g. butanoic acid), alkoxycarbonyl
C.sub.1-C.sub.6-alkyl (e.g. methyl-4-butanoate); optionally
substituted C.sub.2-C.sub.6-alkenyl; optionally substituted
C.sub.2-C.sub.6-alkynyl; optionally substituted aryl, including
optionally substituted phenyl such as cyano phenyl (e.g. 4-cyano
phenyl, 2-cyano phenyl, 3-cyano phenyl), phenyl, halo phenyl such
as fluoro phenyl (e.g. 3-fluorophenyl, 4-fluorophenyl,
2-fluorophenyl), chloro phenyl (e.g. 2-chloro phenyl, 3-chloro
phenyl), 4-chloro phenyl), iodo phenyl (e.g. 4-iodo phenyl) and
bromo phenyl (e.g. 4-bromo phenyl), sulfonyl phenyl (e.g. 4-methyl
sulfonyl phenyl, 3-methyl sulfonyl phenyl), optionally substituted
C.sub.1-C.sub.6-alkyl phenyl (e.g. 4-methyl phenyl, 3-methyl
phenyl, 4-trifluoromethyl phenyl), carboxy phenyl (e.g. 3-benzoic
acid, 4-benzoic acid, 3-propanoic acid phenyl), optionally
substituted acyl amino phenyl (3-methyl acetamide phenyl),
optionally substituted alkoxy phenyl (e.g. 4-methoxy phenyl,
3-methoxy phenyl), optionally substituted acyl phenyl (eg. 4-acetyl
phenyl), alkoxycarbonyl C.sub.1-C.sub.6-alkyl phenyl (e.g. methyl
3-propanoate phenyl, methyl-4-benzoate, methyl-3-benzoate,
optionally substituted heteroaryl, including optionally substituted
imidazolyl (e.g. 1-methyl imidazolyl, 1,2-dimethyl-imidazol-5-yl),
optionally substituted thiophenyl such as halo thiophenyl (e.g.
5-bromo-thiophenyl, 4,5-dichloro thiophenyl), thiophen-3-yl,
carboxy thiophenyl (e.g. thiophene-2-carboxylic acid),
alkoxycarbonyl C.sub.1-C.sub.6-alkyl thiophenyl (e.g.
methyl-3-thiophene-2-carboxylate) and alkoxycarbonyl thiophenyl
(e.g. methyl 3-thiophen-2-yl), optionally substituted pyridinyl
(e.g. 6-morpholin-4-yl-pyridin-3-yl), optionally substituted
pyrazolyl such as halo pyrazolyl (e.g. 5-chloro-1,3
dimethyl-pyrazol-4-yl), optionally fused heteroaryl ring such as
optionally substituted dihydro-benzodioxinyl (e.g.
2,3-dihydro-1,4-benzodioxinyl), optionally substituted oxo
dihydro-benzothiazolyl (e.g.
3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazolyl), optionally
substituted dihydro-benzothiadiazolyl (e.g.
2,1,3-benzothiadiazolyl), optionally substituted benzoxadiazolyl
(e.g. 2,1,3-benzoxadiazol-4-yl); optionally substituted
C.sub.3-C.sub.8 cycloalkyl; optionally substituted
heterocycloalkyl, including optionally substituted pyrrolidinyl;
optionally substituted aryl C.sub.1-C.sub.6-alkyl; optionally
substituted heteroaryl C.sub.1-C.sub.6-alkyl, including optionally
substituted C.sub.1-C.sub.6-alkyl pyridinyl such as pyridinyl
methyl (e.g. pyridinyl-3-methyl, pyridinyl-2-methyl); optionally
substituted C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.6-alkyl;
optionally substituted heterocycloalkyl C.sub.1-C.sub.6-alkyl;
optionally substituted aryl C.sub.2-C.sub.6-alkenyl, including
phenyl ethylenyl; optionally substituted heteroaryl
C.sub.2-C.sub.6-alkenyl;
[0125] n is an integer selected from 0, 1, 2, 3 and 4;
[0126] as well as its geometrical isomers, its optically active
forms as enantiomers, diastereomers, tautomers and its racemate
forms, as well as pharmaceutically acceptable salts thereof for use
as a medicament.
[0127] In another embodiment, the invention provides pyrazine
derivatives of Formula (I):
##STR00005##
[0128] wherein:
[0129] A, B, D and E are independently selected from C and N, such
that the ring R is a stable aromatic ring, including optionally
substituted phenyl and optionally substituted pyridinyl;
[0130] R.sup.1 is selected from H; halogen, including chloro;
nitro; optionally substituted C.sub.1-C.sub.6-alkyl, including
methyl; optionally substituted C.sub.2-C.sub.6-alkenyl and
optionally substituted C.sub.2-C.sub.6-alkynyl;
[0131] R.sup.2 is selected from H; optionally substituted
C.sub.1-C.sub.6-alkyl, including methyl; optionally substituted
C.sub.2-C.sub.6-alkenyl and optionally substituted
C.sub.2-C.sub.6-alkynyl;
[0132] R.sup.3 is selected from H; halo, including chloro;
optionally substituted C.sub.1-C.sub.6-alkyl; optionally
substituted C.sub.2-C.sub.6-alkenyl; optionally substituted
C.sub.2-C.sub.6-alkynyl, optionally substituted alkoxy, including
methoxy; optionally substituted aryl; optionally substituted
heteroaryl, including pyrrolyl;
[0133] R.sup.4 is selected from optionally substituted
C.sub.1-C.sub.6-alkyl, including methyl, ethyl, butyl, propyl,
carboxy C.sub.1-C.sub.6-alkyl (e.g. butanoic acid), alkoxycarbonyl
C.sub.1-C.sub.6-alkyl (e.g. methyl-4-butanoate); optionally
substituted C.sub.2-C.sub.6-alkenyl; optionally substituted
C.sub.2-C.sub.6-alkynyl; optionally substituted aryl, including
optionally substituted phenyl such as cyano phenyl (e.g. 4-cyano
phenyl, 2-cyano phenyl, 3-cyano phenyl), phenyl, halo phenyl such
as fluoro phenyl (e.g. 3-fluorophenyl, 4-fluorophenyl,
2-fluorophenyl), chloro phenyl (e.g. 2-chloro phenyl, 3-chloro
phenyl), 4-chloro phenyl), iodo phenyl (e.g. 4-iodo phenyl) and
bromo phenyl (e.g. 4-bromo phenyl), sulfonyl phenyl (e.g. 4-methyl
sulfonyl phenyl, 3-methyl sulfonyl phenyl), optionally substituted
C.sub.1-C.sub.6-alkyl phenyl (e.g. 4-methyl phenyl, 3-methyl
phenyl, 4-trifluoromethyl phenyl), carboxy phenyl (e.g. 3-benzoic
acid, 4-benzoic acid, 3-propanoic acid phenyl), optionally
substituted acyl amino phenyl (3-methyl acetamide phenyl),
optionally substituted alkoxy phenyl (e.g. 4-methoxy phenyl,
3-methoxy phenyl), optionally substituted acyl phenyl (eg. 4-acetyl
phenyl), alkoxycarbonyl C.sub.1-C.sub.6-alkyl phenyl (e.g. methyl
3-propanoate phenyl, methyl-4-benzoate, methyl-3-benzoate);
optionally substituted heteroaryl, including optionally substituted
imidazolyl (e.g. 1-methyl imidazolyl, 1,2-dimethyl-imidazol-5-yl),
optionally substituted thiophenyl such as halo thiophenyl (e.g.
5-bromo-thiophenyl, 4,5-dichloro thiophenyl), thiophen-3-yl,
carboxy thiophenyl (e.g. thiophene-2-carboxylic acid),
alkoxycarbonyl C.sub.1-C.sub.6-alkyl thiophenyl (e.g.
methyl-3-thiophene-2-carboxylate) and alkoxycarbonyl thiophenyl
(e.g. methyl 3-thiophen-2-yl), optionally substituted pyridinyl
(e.g. 6-morpholin-4-yl-pyridin-3-yl), optionally substituted
pyrazolyl such as halo pyrazolyl (e.g. 5-chloro-1,3
dimethyl-pyrazol-4-yl), optionally fused heteroaryl ring such as
optionally substituted dihydro-benzodioxinyl (e.g.
2,3-dihydro-1,4-benzodioxinyl), optionally substituted
dihydro-benzothiazolyl (e.g. 3-methyl-2,3-dihydro-1,3
benzothiazolyl), optionally substituted dihydro-benzothiadiazolyl
(e.g. 2,1,3-benzothiadiazolyl), optionally substituted
benzoxadiazolyl (e.g. 2,1,3-benzoxadiazol-4-yl); optionally
substituted C.sub.3-C.sub.8 cycloalkyl; optionally substituted
heterocycloalkyl, including optionally substituted pyrrolidinyl;
optionally substituted aryl C.sub.1-C.sub.6-alkyl; optionally
substituted heteroaryl C.sub.1-C.sub.6-alkyl, including optionally
substituted C.sub.1-C.sub.6-alkyl pyridinyl such as pyridinyl
methyl (e.g. pyridinyl-3-methyl, pyridinyl-2-methyl); optionally
substituted C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.6-alkyl;
optionally substituted heterocycloalkyl C.sub.1-C.sub.6-alkyl;
optionally substituted aryl C.sub.2-C.sub.6-alkenyl, including
phenyl ethylenyl; optionally substituted heteroaryl
C.sub.2-C.sub.6-alkenyl;
[0134] n is an integer selected from 0, 1, 2, 3 and 4;
[0135] with the first proviso that when R.sup.4 is thiophenyl, it
is not a group selected from unsubstituted thiophenyl,
unsubstituted chloro-5-thiophenyl or unsubstituted
bromo-5-thiophenyl;
[0136] with the second proviso that when R.sup.4 is a phenyl, it is
a mono-substituted phenyl that is not selected from the group
consisting of: p-bromo phenyl, p-methoxy phenyl, p-ethoxy phenyl,
o-, m- or p-chloro phenyl; m- or p-methyl phenyl; o- or p-fluoro
phenyl; o-CF3-phenyl; p- or m-nitro phenyl; p-NHAc-phenyl and
p-amino phenyl; or it is a multi-substituted phenyl, that is not an
unsubstituted bi-substituted phenyl selected from the group
consisting of: m-, p-dimethyl phenyl; m-, m-dimethyl phenyl; o-,
p-dimethyl phenyl; o-, m-dimethyl phenyl; o-methyl p-fluoro phenyl;
m-, m-dichloro phenyl; o-, m-dichloro phenyl; p-chloro m-nitro
phenyl; o-ethoxy m-bromo-phenyl;
[0137] with the final proviso that wherein R.sup.4 is a 1,4
benzodioxin it is a substituted benzodioxin;
[0138] as well as its geometrical isomers, its optically active
forms as enantiomers, diastereomers, tautomers and its racemate
forms, as well as pharmaceutically acceptable salts thereof:
[0139] In a specific embodiment, the invention provides pyrazine
derivatives of Formula (I) wherein R.sup.1 selected from H and
halogen, including chloro.
[0140] In another specific embodiment, the invention provides
pyrazine derivatives of Formula (I) wherein R.sup.2 is methyl.
[0141] In another specific embodiment, the invention provides
pyrazine derivatives of Formula (I) wherein R.sup.3 is selected
from H and optionally substituted alkoxy, including methoxy.
[0142] In another specific embodiment, the invention provides
pyrazine derivatives of Formula (I) wherein R.sup.3 is selected
from halo, including chloro, optionally substituted aryl and
optionally substituted heteroaryl, including pyrrolyl.
[0143] In another specific embodiment, the invention provides
pyrazine derivatives of Formula (I) wherein R.sup.4 is selected
from optionally substituted C.sub.1-C.sub.6-alkyl, optionally
substituted C.sub.2-C.sub.6-alkenyl, optionally substituted
C.sub.2-C.sub.6-alkynyl, optionally substituted aryl
C.sub.1-C.sub.6-alkyl and optionally substituted heteroaryl
C.sub.1-C.sub.6-alkyl.
[0144] In another specific embodiment, the invention provides
pyrazine derivatives of Formula (I) wherein R.sup.4 is selected
from optionally substituted aryl and optionally substituted
heteroaryl.
[0145] In another specific embodiment, the invention provides
pyrazine derivatives of Formula (I) wherein A, B, D and E are
C.
[0146] In another further specific embodiment, the invention
provides pyrazine derivatives of Formula (I) wherein A is N; B, D
and E are C.
[0147] In another further specific embodiment, the invention
provides pyrazine derivatives of Formula (I) wherein A, B and E are
C; D is N.
[0148] In another specific embodiment, the invention provides
pyrazine derivatives of Formula (I) wherein R.sup.1 selected from H
and halogen; R.sup.2 is methyl; R.sup.3 is selected from H and
optionally substituted alkoxy; R, n, R.sup.4, A, B, D and E are as
defined above.
[0149] In another specific embodiment, the invention provides
pyrazine derivatives of Formula (I) wherein R.sup.1 selected from H
and halogen; R.sup.2 is methyl; R.sup.3 is selected from H and
optionally substituted alkoxy; A, B, D and E are C; R, n and
R.sup.4 are as defined above.
[0150] In another specific embodiment, the invention provides
pyrazine derivatives of Formula (I) wherein R.sup.1 is H; R.sup.2
is methyl; R.sup.3 is selected from H and alkoxy; n is 3; A, B, D
and E are independently selected from C and N, such that the ring R
is optionally substituted pyridinyl; R.sup.4 is as defined
above.
[0151] Compounds of the present invention include in particular
those of the group consisting of:
TABLE-US-00001 Example No. Name 1
4-cyano-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}
benzenesulfonamide; 2
4-cyano-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}
benzenesulfonamide; 3
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
4
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoi-
c acid; 5
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1-methyl-1H-imidazole-
4-sulfonamide; 6
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-methylbenzene
sulfonamide; 7
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-methylbenzene
sulfonamide; 8
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-methylbenzene
sulfonamide; 9
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-methylbenzene
sulfonamide 10
5-bromo-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}thiophene-2-
sulfonamide; 11
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1-pyridin-3-ylmethane
sulfonamide; 12 methyl
3-{4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)
sulfonyl]phenyl}propanoate; 13 methyl
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfony-
l] benzoate; 14
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-fluorobenzene
sulfonamide; 15
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(methylsulfonyl)
benzenesulfonamide; 16
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2,3-dihydro-1,4-
benzodioxine-6-sulfonamide; 17
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(pyrrolidin-1-yl
sulfonyl)benzenesulfonamide; 18
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-(methylsulfonyl)
benzenesulfonamide; 19
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-(methylsulfonyl)
benzenesulfonamide; 20
2-cyano-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 21
2-cyano-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 22
2-chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 23
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}pyridine-3-sulfonamide-
; 24
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1-methyl-1H-imidazole-
- 4-sulfonamide; 25
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluorobenzene
sulfonamide; 26
N-{3-[(2,5-dimethoxyphenyl)amino]pyrido[2,3-b]pyrazin-2-yl}benzene
sulfonamide; 27
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluorobenzene
sulfonamide; 28
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;
29
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}methanesulfonamide;
30
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}thiophene-3-sulfonamid-
e; 31
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}methanesulfonamide;
32
3-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzo-
ic acid; 33 methyl
4-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfony-
l] benzoate; 34 methyl
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfony-
l] thiophene-2-carboxylate; 35
5-chloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1,3-dimethyl-
- 1H-pyrazole-4-sulfonamide; 36
4-chloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 37
3-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]
thiophene-2-carboxylic acid; 38
3-{4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]
phenyl}propanoic acid; 39
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-methyl-2-oxo-2,3-
dihydro-1,3-benzothiazole-6-sulfonamide; 40
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2,1,3-benzothiadiazol-
e-4- sulfonamide; 41
4-chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 42
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-methyl-2-oxo-2,3-
dihydro-1,3-benzothiazole-6-sulfonamide; 43
4-bromo-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 44
N-{3-[(3,5-dimethoxyphenyl)amino]pyrido[2,3-b]pyrazin-2-yl}benzene
sulfonamide; 45
4-bromo-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 46
4-acetyl-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 47
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}propane-1-sulfonamide;
48
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}thiophene-3-sulfonamid-
e; 49
4-acetyl-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 50
2-chloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 51
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1,2-dimethyl-1H-
imidazole-5-sulfonamide; 52
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2,1,3-benzoxadiazole--
4- sulfonamide; 53
3-chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 54
5-chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1,3-dimethyl-
- 1H-pyrazole-4-sulfonamide; 55
3-cyano-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 56
N-{3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]
phenyl}acetamide; 57
3-cyano-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 58
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}propane-1-sulfonamide;
59
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(trifluoromethyl)
benzenesulfonamide; 60
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]butan-
oic acid; 61
3-chloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 62
4-fluoro-N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamid-
e; 63
N-{6-chloro-3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 64
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1-pyridin-2-ylmethane
sulfonamide; 65
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-methoxybenzene
sulfonamide; 66
N-{3-[(3,5-dimethoxyphenyl)amino]pyrido[2,3-b]pyrazin-2-yl}ethane
sulfonamide; 67
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-methoxybenzene
sulfonamide; 68
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1-pyridin-2-ylmethane
sulfonamide; 69
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1-pyridin-3-ylmethane
sulfonamide; 70 methyl
3-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfony-
l] thiophene-2-carboxylate; 71
N-{2-[(2,5-dimethoxyphenyl)amino]pyrido[3,4-b]pyrazin-3-yl}benzene
sulfonamide; 72
N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamide; 73
4-chloro-N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamid-
e; 74
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-methoxybenzene
sulfonamide; 75
4-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]butan-
oic acid; 76
N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}methanesulfonamide; 77
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-iodobenzene
sulfonamide; 78
4-bromo-N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 79
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-iodobenzene
sulfonamide; 80
4-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzo-
ic acid; 81 methyl
4-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfony-
l] butanoate; 82
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzo-
ic acid; 83
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2-fluorobenzene
sulfonamide; 84
N-(3-{[5-methoxy-2-(1H-pyrrol-1-yl)phenyl]amino}quinoxalin-2-yl)benzene
sulfonamide; 85 methyl
3-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfony-
l] benzoate; 86
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-morpholin-4-yl
pyridine-3-sulfonamide; 87
4-methoxy-N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 88 methyl
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfony-
l] benzoate; 89
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]thiop-
hene- 2-carboxylic acid; 90
N-{3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamid-
e; 91
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2-(methylsulfonyl)
benzenesulfonamide; 92
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2-fluorobenzene
sulfonamide; 93
4,5-dichloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}thiophene-
-2- sulfonamide; 94
N-{3-[(5-methoxy-2-methylphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide; 95
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-fluorobenzene
sulfonamide; 96
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2-(methylsulfonyl)
benzenesulfonamide; 97
N-{3-[(2,3-dihydro-1,4-benzodioxin-5-ylmethyl)amino]quinoxalin-2-yl}
benzenesulfonamide; 98
N-{3-[(3,5-dimethoxyphenyl)amino]-6-nitroquinoxalin-2-yl}benzene
sulfonamide; 99
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(pyrrolidin-1-
ylsulfonyl)benzenesulfonamide; 100 methyl
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)
sulfonyl]butanoate; 101 methyl
5-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfon-
yl]- 4-methylthiophene-2-carboxylate; 102 methyl
5-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfon-
yl]- 1-methyl-1H-pyrrole-2-carboxylate; 103 methyl
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfon-
yl]- 1-methyl-1H-pyrrole-2-carboxylate; 104
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}thiophene-2-sulfonami-
de; 105
2-chloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluoroben-
zene sulfonamide; 106
2-chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluoroben-
zene sulfonamide; 107
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}pyridine-3-sulfonamid-
e; 108
3-cyano-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluorobenz-
ene sulfonamide; 109
3-cyano-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluorobenz-
ene sulfonamide;
110
6-chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}pyridine-3-
sulfonamide; 111
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-(dimethylamino)
pyridine-3-sulfonamide; 112
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-[(3-methoxypropyl)
amino]pyridine-3-sulfonamide; 113
N-{3-[(5-methoxy-2-methylphenyl)amino]quinoxalin-2-yl}pyridine-3-
sulfonamide; 114
N-{3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2-yl}-4-
cyanobenzenesulfonamide; 115
N-{3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2-yl}pyridine-3-
sulfonamide; 116
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-methoxypyridine-3-
sulfonamide; 117
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-oxo-1,6-
dihydropyridine-3-sulfonamide; 118
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-methylpyridine-3-
sulfonamide; 119
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluoro-2-methyl
benzenesulfonamide; 120
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-methylpyridine-3-
sulfonamide; 121
4-cyano-N-{3-[(5-methoxy-2-methylphenyl)amino]quinoxalin-2-yl}
benzene sulfonamide; 122
N-{3-[(5-methoxy-2-methylphenyl)amino]quinoxalin-2-yl}-6-methylpyridin-
e- 3-sulfonamide; 123
N-{3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2-yl}-6-methylpyridin-
e-3- sulfonamide; 124 methyl
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfon-
yl] pyridine-2-carboxylate; 125
N-{3-[(2-bromo-5-methoxyphenyl)amino]quinoxalin-2-yl}-1-methyl-1H-
imidazole-4-sulfonamide; 126
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-(morpholin-4-
ylcarbonyl)benzenesulfonamide; 127
5-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-4-
methylthiophene-2-carboxylic acid; 128
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-4-
methylthiophene-2-carboxylic acid; 129
5-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-1-
methyl-1H-pyrrole-2-carboxylic acid; 130
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-1-
methyl-1H-pyrrole-2-carboxylic acid; 131
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]pyri-
dine- 2-carboxylic acid; 132
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-(morpholin-4-ylmet-
hyl) benzene sulfonamide; 133
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-[(4-methylpiperazi-
n-1- yl) methyl]benzenesulfonamide; 134
4-(aminomethyl)-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}
benzene sulfonamide; 135
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-(hydroxymethyl)
benzenesulfonamide; 136
3-(aminomethyl)-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}
benzenesulfonamide; 137
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(hydroxymethyl)
benzenesulfonamide; 138
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-(hydroxymethyl)
pyridine-3-sulfonamide; 139
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(morpholin-4-ylmet-
hyl) benzenesulfonamide; 140
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-[(4-methylpiperazi-
n-1- yl)methyl]benzenesulfonamide; 141
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-[(dimethylamino)
methyl]benzenesulfonamide; 142
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-[(dimethylamino)
methyl]benzenesulfonamide; 143
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino) sulfonyl]
benzamide; 144
4-[({3-[(5-methoxy-2-methylphenyl)amino]quinoxalin-2-yl}amino)
sulfonyl]benzamide; 145
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-N-(-
3- methoxypropyl)benzamide; 146
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-N-[-
3- (dimethylamino)propyl]benzamide; 147
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-N-[-
3- (dimethylamino)propyl]benzamide; 148
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-N,N-
- dimethylpyridine-2-carboxamide; 149
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-[(4-methylpiperazi-
n-1- yl)carbonyl]benzenesulfonamide; 150
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-(morpholin-4-yl
carbonyl)pyridine-3-sulfonamide; 151
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-[(4-methylpiperazi-
n-1- yl)methyl]pyridine-3-sulfonamide; 152
5-(aminomethyl)-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-
yl}thiophene-2-sulfonamide.
[0152] The compounds of the present invention are useful as
medicaments. They may be used for the preparation of a medicament
for the prophylaxis and/or treatment of autoimmune disorders and/or
inflammatory diseases, cardiovascular diseases, neurodegenerative
diseases, bacterial or viral infections, kidney diseases, platelet
aggregation, cancer, transplantation, erythrocyte deficiency, graft
rejection or lung injuries.
[0153] In one embodiment, the compounds of Formula (I) are useful
for the treatment and/or prophylaxis of autoimmune diseases or
inflammatory diseases such as multiple sclerosis, psoriasis,
rheumatoid arthritis, systemic lupus erythematosis, inflammatory
bowel disease, lung inflammation, thrombosis or brain
infection/inflammation such as meningitis or encephalitis.
[0154] In another embodiment, the compounds of Formula (I) are
useful for the treatment and/or prophylaxis of neurodegenerative
diseases including Alzheimer's disease, Huntington's disease, CNS
trauma, stroke or ischemic conditions.
[0155] In still a further embodiment according to the invention,
the compounds of Formula (I) are useful for the treatment and/or
prophylaxis of cardiovascular diseases such as atherosclerosis,
heart hypertrophy, cardiac myocyte dysfunction, elevated blood
pressure or vasoconstriction.
[0156] In still a further embodiment according to the invention,
the compounds of Formula (I) are useful for the treatment and/or
prophylaxis of erythrocyte deficiency such as an anaemia, including
haemolytic anaemia, aplastic anaemia and pure red cell anaemia.
[0157] In still a further embodiment according to the invention,
the compounds of Formula (I) are useful for the treatment and/or
prophylaxis of cancers including non-small cell lung (NSCL) cancer,
pancreatic cancer, endometrial cancer, ovarian cancer, bladder
cancer, seminomas, thyroid cancer, breast cancer, glioblastoma
multiforme, mammary carcinoma, gastric cancers, and lymphomas,
cancers of the lung, prostate, liver, colon, breast, kidney, brain,
skin including malignant melanoma, testes or ovaries, or leukemias,
including myeloid and lymphocytic leukemias, acute myeloid leukemia
(AML), multiple myeloma-related bone disorder, mestatic melanoma
and malignant melanoma and Kaposi's sarcoma.
[0158] In still another embodiment according to the invention, the
compounds of Formula (I) are useful for the treatment and/or
prophylaxis of chronic obstructive pulmonary disease, anaphylactic
shock fibrosis, psoriasis, allergic diseases, asthma, stroke or
ischemic conditions, ischemia-reperfusion, platelets
aggregation/activation, skeletal muscle atrophy/hypertrophy,
leukocyte recruitment in cancer tissue, angiogenesis, invasion
metastisis, in particular melanoma, Karposi's sarcoma, acute and
chronic bacterial and viral infections, sepsis, transplantation,
graft rejection, glomerulo sclerosis, glomerulo nephritis,
progressive renal fibrosis, endothelial and epithelial injuries in
the lung or in general lung airways inflammation.
[0159] In another embodiment according to the invention, is
provided a process for the preparation of pyrazine derivative
according to Formula (I), comprising the step of reacting a chloro
derivative of Formula (II) with an aniline of Formula (III) in an
appropriate solvent such as EtOH or MeOH in absence of base, either
by traditional thermic methods or using microwave technology such
as those described hereinafter in the Examples:
##STR00006##
wherein n, A, B, D, E, R, R.sup.1, R.sup.2, R.sup.3, R.sup.4 are as
above defined.
[0160] In another embodiment according to the invention, is
provided a process for the preparation of pyrazine derivative
according to Formula (I) comprising the step of reacting an amino
derivative of Formula (XI) and a sulfonylchloride of Formula (IX)
in the presence of base such as triethylamine, isopropylamine, DIEA
(diisopropylethylamine), with the optional presence of a co-solvent
such as 1,2-dichlorobenzene. A preferred base is pyridine.
##STR00007##
wherein n, A, B, D, E, R, R.sup.1, R.sup.2, R.sup.3, R.sup.4 are as
above defined.
[0161] In another embodiment according to the invention, is
provided a compound of Formula (II)
##STR00008##
wherein n, A, B, D, E, R, R.sup.1, R.sup.4 are as defined above and
wherein the compounds of Formula (II) are selected from the list
below: [0162]
4,5-dichloro-N-(3-chloroquinoxalin-2-yl)thiophene-2-sulfonamide;
[0163] 4-acetyl-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide;
[0164] 4-cyano-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide;
[0165] 5-bromo-N-(3-chloroquinoxalin-2-yl)thiophene-2-sulfonamide;
[0166]
5-chloro-N-(3-chloroquinoxalin-2-yl)-1,3-dimethyl-1H-pyrazole-4-sulfonami-
de; [0167] methyl
3-(4-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}phenyl)propanoate;
[0168] methyl
4-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}butanoate; [0169]
N-(2-chloropyrido[3,4-b]pyrazin-3-yl)benzenesulfonamide; [0170]
N-(3,6-dichloroquinoxalin-2-yl)benzenesulfonamide; [0171]
N-(3-chloro-6-nitroquinoxalin-2-yl)benzenesulfonamide; [0172]
N-(3-chloro-7-methoxyquinoxalin-2-yl)benzenesulfonamide; [0173]
N-(3-chloropyrido[2,3-b]pyrazin-2-yl)benzenesulfonamide; [0174]
N-(3-chloroquinoxalin-2-yl)-2,2-dimethylchromane-7-sulfonamide;
[0175] N-(3-chloroquinoxalin-2-yl)-3-fluorobenzenesulfonamide;
[0176] N-(3-chloroquinoxalin-2-yl)-3-methylbenzenesulfonamide;
[0177]
N-(3-chloroquinoxalin-2-yl)-4-(trifluoromethyl)benzenesulfonamide;
[0178] N-(3-chloroquinoxalin-2-yl)-4-cyanobenzenesulfonamide;
[0179] N-(3-chloroquinoxalin-2-yl)-4-iodobenzenesulfonamide; [0180]
N-(3-chloroquinoxalin-2-yl)-4-methoxybenzenesulfonamide; [0181]
N-(3-chloroquinoxalin-2-yl)biphenyl-4-sulfonamide; [0182]
N-(3-chloroquinoxalin-2-yl)methanesulfonamide; [0183]
N-(3-chloroquinoxalin-2-yl)propane-1-sulfonamide; and [0184]
N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide; [0185] methyl
5-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}-4-methylthiophene-2-carboxyl-
ate; [0186] methyl
5-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}-1-methyl-1H-pyrrole-2-carbox-
ylate; [0187] N-(3-chloroquinoxalin-2-yl)thiophene-2-sulfonamide;
[0188]
2-chloro-N-(3-chloroquinoxalin-2-yl)-4-fluorobenzenesulfonamide;
[0189]
N-(3-chloroquinoxalin-2-yl)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)me-
thyl]thiophene-2-sulfonamide; [0190]
N-(3-chloroquinoxalin-2-yl)-3-cyano-4-fluorobenzenesulfonamide;
[0191] 6-chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide;
[0192]
N-(3-chloroquinoxalin-2-yl)-6-(dimethylamino)pyridine-3-sulfonamide;
[0193]
N-(3-chloroquinoxalin-2-yl)-6-[(3-methoxypropyl)amino]pyridine-3-s-
ulfonamide; [0194]
N-(3-chloroquinoxalin-2-yl)-6-methoxypyridine-3-sulfonamide; [0195]
N-(3-chloroquinoxalin-2-yl)-6-methylpyridine-3-sulfonamide; [0196]
methyl
5-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}pyridine-2-carboxylate;
[0197]
N-(3-chloroquinoxalin-2-yl)-3-(morpholin-4-ylcarbonyl)benzenesulfo-
namide; [0198]
N-(3-chloroquinoxalin-2-yl)-1-methyl-1H-imidazole-4-sulfonamide.
[0199] In another embodiment according to the invention, is
provided a compound of Formula (XI):
##STR00009##
wherein n, A, B, D, E, R, R.sup.1, R.sup.2, R.sup.3, R.sup.4 are as
defined above with the proviso that the compound of Formula (XI) is
not N-(3-methoxyphenyl)-2,3-Quinoxalinediamine (RN 165058-49-1) nor
3-[(3-amino-2-quinoxalinyl)amino]-Phenol (165058-51-5).
[0200] In a further embodiment according to the invention, is
provided a compound of Formula (XI) selected from the following
group: [0201] N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine;
[0202] N-(5-methoxy-2-methyl-phenyl)quinoxaline-2,3-diamine; [0203]
N-(5-methoxy-2-pyrrol-1-yl-phenyl)quinoxaline-2,3-diamine; [0204]
N-(5-methoxy-2-chloro-phenyl)quinoxaline-2,3-diamine; [0205]
N-(3-methoxy-phenyl)quinoxaline-2,3-diamine; [0206]
N-(5-methoxy-2-bromo-phenyl)quinoxaline-2,3-diamine; [0207]
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine.
[0208] The pyrazine derivatives exemplified in this invention may
be prepared from readily available starting materials using the
following general methods and procedures. It will be appreciated
that where typical or preferred experimental conditions (i.e.
reaction temperatures, time, moles of reagents, solvents etc.) are
given, other experimental conditions can also be used unless
otherwise stated. Optimum reaction conditions may vary with the
particular reactants or solvents used, but such conditions can be
determined by the person skilled in the art, using routine
optimisation procedures.
[0209] When employed as pharmaceuticals, the compounds of the
present invention are typically administered in the form of a
pharmaceutical composition. Hence, pharmaceutical compositions
comprising a compound of Formula (I) and a pharmaceutically
acceptable carrier, diluent or excipient therefore are also within
the scope of the present invention. A person skilled in the art is
aware of a whole variety of such carrier, diluent or excipient
compounds suitable to formulate a pharmaceutical composition.
[0210] The compounds of the invention, together with a
conventionally employed adjuvant, carrier, diluent or excipient may
be placed into the form of pharmaceutical compositions and unit
dosages thereof, and in such form may be employed as solids, such
as tablets or filled capsules, or liquids such as solutions,
suspensions, emulsions, elixirs, or capsules filled with the same,
all for oral use, or in the form of sterile injectable solutions
for parenteral (including subcutaneous use). Such pharmaceutical
compositions and unit dosage forms thereof may comprise ingredients
in conventional proportions, with or without additional active
compounds or principles, and such unit dosage forms may contain any
suitable effective amount of the active ingredient commensurate
with the intended daily dosage range to be employed.
[0211] Pharmaceutical compositions containing pyrazine derivatives
of this invention can be prepared in a manner well known in the
pharmaceutical art and comprise at least one active compound.
Generally, the compounds of this invention are administered in a
pharmaceutically effective amount. The amount of the compound
actually administered will typically be determined by a physician,
in the light of the relevant circumstances, including the condition
to be treated, the chosen route of administration, the actual
compound administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms, and the
like.
[0212] The pharmaceutical compositions of the present invention can
be administered by a variety of routes including oral, rectal,
transdermal, subcutaneous, intravenous, intramuscular and
intranasal. The compositions for oral administration can take the
form of bulk liquid solutions or suspensions, or bulk powders. More
commonly, however, the compositions are presented in unit dosage
forms to facilitate accurate dosing. The term "unit dosage forms"
refers to physically discrete units suitable as unitary dosages for
human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect, in association with a suitable
pharmaceutical excipient. Typical unit dosage forms include
prefilled, premeasured ampoules or syringes of the liquid
compositions or pills, tablets, capsules or the like in the case of
solid compositions. In such compositions, the pyrazine derivative
is usually a minor component (from about 0.1 to about 50% by weight
or preferably from about 1 to about 40% by weight) with the
remainder being various vehicles or carriers and processing aids
helpful for forming the desired dosing form.
[0213] Liquid forms suitable for oral administration may include a
suitable aqueous or nonaqueous vehicle with buffers, suspending and
dispensing agents, colorants, flavors and the like. Solid forms may
include, for example, any of the following ingredients, or
compounds of a similar nature: a binder such as microcrystalline
cellulose, gum tragacanth or gelatine; an excipient such as starch
or lactose, a disintegrating agent such as alginic acid, Primogel,
or corn starch; a lubricant such as magnesium stearate; a glidant
such as colloidal silicon dio-xide; a sweetening agent such as
sucrose or saccharin; or a flavoring agent such as pepper-mint,
methyl salicylate, or orange flavoring.
[0214] Injectable compositions are typically based upon injectable
sterile saline or phosphate-buf-fered saline or other injectable
carriers known in the art. As above mentioned, the pyrazine
derivatives of Formula (I) in such compositions is typically a
minor component, frequently ranging between 0.05 to 10% by weight
with the remainder being the injectable carrier and the like.
[0215] The above described components for orally administered or
injectable compositions are merely representative. Further
materials as well as processing techniques and the like are set out
in Part 5 of Remington's Pharmaceutical Sciences, 20.sup.th
Edition, 2000, Marck Publishing Company, Easton, Pa., which is
incorporated herein by reference.
[0216] The compounds of this invention can also be administered in
sustained release forms or from sustained release drug delivery
systems. A description of representative sustained release
materials can also be found in the incorporated materials in
Remington's Pharmaceutical Sciences.
Synthesis of Compounds of the Invention:
[0217] The pyrazine derivatives according to Formula (I) may be
prepared from readily available starting materials using the
following general methods and procedures. It will be appreciated
that where typical or preferred experimental conditions (i.e.
reaction temperatures, time, moles of reagents, solvents etc.) are
given, other experimental conditions can also be used unless
otherwise stated. Optimum reaction conditions may vary with the
particular reactants or solvents used, but such conditions can be
determined by the person skilled in the art, using routine
optimisation procedures.
[0218] The following abbreviations refer respectively to the
definitions below: min (min-ute), hr (hour), g (gram), mmol
(millimole), m.p. (melting point), eq. (equivalents), mL
(milliliter), .mu.L (microliters), ACN (Acetonitrile), AcOH,
(acetic acid), CDCl.sub.3 (deuterated chloroform), CsCO.sub.3
(Cesium carbonate), CuI (Copper iodide), DCM (Dichloromethane), DMA
(Dimethylacetamide), DMF (Dimethylformamide), DMSO
(Dimethyl-sulfoxide), DMSO-d.sub.6 (deuterated dimethylsulfoxide),
Et.sub.3N (Triethylamine), EtOAc (ethyl acetate), EtOH (Ethanol),
Et.sub.2O (Diethyl ether), HPLC (High Performance Liquid
Chromatography), K.sub.2CO.sub.3 (Potassium carbonate), MS (mass
spectrometry), MgSO.sub.4 (Magnesium sulfate), NMP
(N-methylpyrrolidone), NMR (Nuclear Magnetic Resonance), MeOH
(methanol), NaI (Sodium iodide), NaHCO.sub.3 (Sodium bicarbonate),
NH.sub.4Cl (Ammonium chloride), (NH.sub.4).sub.2CO.sub.3 (Ammonium
carbonate), PIs (Phosphoinositides), PI3Ks (Phosphoinositide
3-kinases), PI(3)P (Phosphatidylinositol 3-monophosphate),
PI(3,4)P.sub.2 (Phosphatidylinositol 3,4-bisphosphate),
PI(3,4,5)P.sub.3 (Phosphatidylinositol 3,4,5-trisphosphate), PI(4)P
(Phosphatidylinositol-4-phosphate), PI(4,5)P.sub.2) (Phosphatidyl
inositol-4,5-biphosphate), POCl.sub.3 (phosphorus oxychloride),
PtdIns (Phosphatidylinositol), TDB pol
(7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene on polystyrene), THF
(Tetrahydrofuran), TLC (Thin Layer Chromatography), rt (room
temperature), Rt (retention time).
[0219] Depending on the nature of A, B, D, F, R, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 different synthetic
strategies may be selected for the synthesis of compounds of
Formula (I). In the process illustrated in the following schemes A,
B, D, E, R, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 as
above-defined in the description.
[0220] Generally, the quinoxaline sulfonamide and the
azaquinoxaline sulfonamide derivatives according to the general
Formula (I) may be obtained by several processes using
solution-phase chemistry protocols.
[0221] According to one process, quinoxaline sulfonamide and
azaquinoxaline sulfonamide derivatives according to the general
Formula (I), whereby the substituents A, B, D, E and R, R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are as above defined, are prepared
from the chloro derivatives of Formula (II) and anilines of Formula
(III), by well known solution-phase chemistry protocols, such as
those shown in Scheme 1 below. In a typical procedure, the
nucleophilic substitution is performed in an appropriate solvent
such as EtOH or MeOH in absence of base or presence of acid such as
AcOH, either by traditional thermic methods or using microwave
technology such as those described hereinafter in the Examples.
##STR00010##
[0222] The aniline derivatives of Formula (III) may be obtained
either from commercial sources or they may be prepared from known
compounds using procedures such as those described hereinafter in
the examples, or conventional procedures, known by one skilled in
the art.
[0223] The chloro derivatives of Formula (II), whereby the
substituents A, B, D, E and R, R.sup.1, R.sup.2, R.sup.3, R.sup.4
are as above defined, are prepared from the dichloro derivatives of
Formula (IV) and sulfonamides of Formula (V), by well known
solution-phase chemistry protocols such as shown in Scheme 2 below
(Litvinenko et al., 1994, Chemistry of heterocyclic compounds, 30
(3), 340-344). In a typical procedure, the nucleophilic
substitution is performed in an appropriate solvent such as DMF or
DMA in presence of a base such as K.sub.2CO.sub.3, Cs.sub.2CO.sub.3
or TDB pol. Depending on the intrinsic reactivity of dichloro
derivatives of Formula (IV) and sulphonamide derivatives of Formula
(V), the reaction can be performed at various temperatures in the
presence or absence of NaI or CuI, either by traditional thermic
methods or using microwave technology such as those described
hereinafter in the Examples.
##STR00011##
[0224] The dichloro derivatives of Formula (IV) may be obtained
either from commercial sources or they may be prepared from the
corresponding bis amino derivatives of Formula (VI) using
conventional procedures, known by one skilled in the art as shown
in the Scheme 3 below. In a typical procedure, the first step is
performed in aqueous HCl under reflux. In a subsequent step, a
dione of Formula (VIII) is treated with POCl.sub.3 in the presence
of an organic base such as Et.sub.3N to give the expected dichloro
derivatives of Formula (IV), such as those described hereinafter in
the Examples.
##STR00012##
[0225] Sulfonamides of Formula (V) may be obtained either from
commercial sources or they may be prepared from the corresponding
sulfonylchlorides of Formula (IX) using conventional procedures
known by one skilled in the art, as shown in the Scheme 4 below. In
a typical procedure, the reaction is performed in the presence of
ammonia of Formula (X), in a solvent such as EtOH, MeOH, dioxane or
water, such as those described hereinafter in the Examples.
##STR00013##
[0226] According to another process, quinoxaline sulfonamide and
the azaquinoxaline sulfonamide derivatives according to the general
Formula (I), whereby the substituents A, B, D, E and R.sup.1,
R.sup.2, R.sup.3, R.sup.4 are as above defined, are prepared from
the amino derivatives of Formula (XI) and sulfonylchlorides of
Formula (IX), by well known solution-phase chemistry protocols, as
shown in Scheme 5, below. In a typical procedure, the sulfonylation
is performed in the presence of pyridine, with or without a
co-solvent such as 1,2-dichlorobenzene. Depending on the intrinsic
reactivity of the sulfonylchlorides of Formula (IX), the reaction
can be performed at various temperatures, either by traditional
thermic methods or using microwave technology such as those
described hereinafter in the Examples.
##STR00014##
[0227] Amino derivatives of Formula (XI) are prepared from the
2-amino 3-chloro derivatives of Formula (XII) and anilines of
Formula (III), by well-known solution-phase chemistry protocols, as
shown in Scheme 6 below. In a typical procedure, the nucleophilic
substitution is performed in absence of base using an appropriate
solvent such as NMP, DMF or DMA, such as those described
hereinafter in the Examples.
##STR00015##
[0228] 2-Amino 3-chloro derivatives of Formula (XII) are prepared
from the dichloro derivatives of Formula (IV), by well-known
solution-phase chemistry protocols, as shown in Scheme 7 below. In
a typical procedure, the reaction is performed using
(NH.sub.4).sub.2CO.sub.3 (XIII) or aqueous ammonia in an
appropriate solvent such as DMF, DMA or dioxane, such as those
described hereinafter in the Examples.
##STR00016##
[0229] If the above set out general synthetic methods are not
applicable for the obtention of compounds of Formula (I), suitable
methods of preparation known by a person skilled in the art should
be used.
[0230] The pharmaceutically acceptable cationic salts of compounds
of the present invention are readily prepared by reacting the acid
forms with an appropriate base, usually one equivalent, in a
co-solvent. Typical bases are sodium hydroxide, sodium methoxide,
sodium ethoxide, sodium hydride, potassium hydroxide, potassium
methoxide, magnesium hydroxide, calcium hydroxide, benzathine,
choline, diethanolamine, ethylenediamine, meglumine, benethamine,
diethylamine, piperazine and tromethamine. The salt is isolated by
concentration to dryness or by addition of a non-solvent. In some
cases, salts can be prepared by mixing a solution of the acid with
a solution of the cation (sodium ethylhexanoate, magnesium oleate),
employing a solvent in which the desired cationic salt
precipitates, or can be otherwise isolated by concentration and
addition of a non-solvent.
[0231] According to a further general process, compounds of Formula
(I) can be converted to alternative compounds of Formula (I),
employing suitable interconversion techniques well known by a
person skilled in the art.
[0232] If the above set of general synthetic methods is not
applicable to obtain compounds according to Formula (I) and/or
necessary intermediates for the synthesis of compounds of Formula
(I), suitable methods of preparation known by a person skilled in
the art should be used. In general, the synthesis pathways for any
individual compound of Formula (I) will depend on the specific
substitutents of each molecule and upon the ready availability of
intermediates necessary; again such factors being appreciated by
those of ordinary skill in the art. For all the protection and
deprotection methods, see Philip J. Kocienski, in "Protecting
Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and,
Theodora W. Greene and Peter G. M. Wuts in "Protective Groups in
Organic Synthesis", Wiley Interscience, 3.sup.rd Edition 1999.
[0233] Compounds of this invention can be isolated in association
with solvent molecules by crys-tallization from evaporation of an
appropriate solvent. The pharmaceutically acceptable acid addition
salts of the compounds of Formula (I), which contain a basic
center, may be prepared in a conventional manner. For example, a
solution of the free base may be treated with a suitable acid,
either neat or in a suitable solution, and the resulting salt
isolated either by filtration or by evaporation under vacuum of the
reaction solvent. Pharmaceutically acceptable base addition salts
may be obtained in an analogous manner by treating a solution of
compound of Formula (I) with a suitable base. Both types of salts
may be formed or interconverted using ion-exchange resin
techniques.
[0234] In the following the present invention shall be illustrated
by means of some examples, which are not construed to be viewed as
limiting the scope of the invention.
EXAMPLES
[0235] The commercially starting materials used in the following
experimental description were purchased from Aldrich or Fluka
unless otherwise reported.
[0236] The HPLC, NMR and MS data provided in the examples described
below are obtained as followed: HPLC: column Waters Symmetry C8
50.times.4.6 mm, Conditions: MeCN/H.sub.2O, 5 to 100% (8 min), max
plot 230-400 nm; LC/MS spectra: Waters ZMD (ES); .sup.1H-NMR:
Bruker DPX-300 MHz.
[0237] The preparative HPLC purifications are performed with HPLC
Waters Prep LC 4000 System equipped with columns XTERRAPrepMS C18
10 .mu.m, 50.times.300 mm. All the purifications were performed
with a gradient of ACN/H.sub.2O 0.1% TFA.
[0238] The microwave chemistry is performed on a single mode
microwave reactor EMRYS Optimiser from Personal Chemistry.
Intermediate 1: 3-chloroquinoxalin-2-amine (Formula XII)
##STR00017##
[0240] 2,3-dichloroquinoxaline (4 g, 20 mmol, commercially
available from Aldrich) is dissolved in dry DMF (20 ml) and treated
with solid (NH.sub.4).sub.2CO.sub.3 (9.7 g, 101 mmol). The
resulting mixture is stirred at 60.degree. C. for 3 days (reaction
showed 60% completion). The reaction mixture is diluted with water
and the product is extracted with EtOAc. The organic layer is dried
and the solvent was removed under reduced pressure. The crude
residue obtained is purified via column chromatography by eluting
with petroleum ether: EtOAc to afford 1.9 g (53%) of the title
compound as a pale yellow solid. LC/MS: (ES+): 180.1.
Intermediate 2: N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine
(Formula XI)
##STR00018##
[0242] 3-chloroquinoxalin-2-amine (1.8 g, 10 mmol) and
3,5-dimethoxyaniline (4.6 g, 30 mmol, commercially available from
Aldrich) are taken up in NMP (4.5 ml) and heated to 145.degree. C.
in the sealed tube for 3 h under N.sub.2. When TLC confirms the
total consumption of the starting material, the reaction is cooled
to rt and treated with EtOAc (4 ml). The first crop of solid is
filtered followed by the 2.sup.nd crop. The first is recrystallised
from CHCl.sub.3:EtOAc and the 2.sup.nd crop is washed with EtOAc,
to afford 1.8 g (60%) of pure title compound. LC/MS: (ES+): 297.1,
(ES-): 295.1.
Intermediate 3: N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine
(Formula XI)
##STR00019##
[0244] Following the procedure outlined for the synthesis of 2,
N-(2,5-dimethoxyphenyl) quinoxaline-2,3-diamine is obtained from
3-chloroquinoxalin-2-amine (1.6 g, 8.9 mmol) and
2,5-dimethoxyaniline (4.1 g, 26.8 mmol, commercially available from
Aldrich). The title compound is extracted with EtOAc and the
organic layer is consequently washed with water (4.times.20 ml) and
brine (25 ml) then dried. The solvent is removed under reduced
pressure and the residue obtained is purified via column
chromatography by eluting with DCM: MeOH to afford 1.1 g (42%) of
the title compound as a yellow solid. 1H NMR (DMSO-d6) .delta.
9.40-8.50 (brs, 2H), 7.95-7.20 (m, 5H), 7.15-6.95 (m, 1H),
6.85-6.55 (m, 1H), 3.77 (s, 3H), 3.73 (s, 3H). HPLC (max plot) 98%;
Rt 2.56 min. LC/MS: (ES+): 297.1, (ES-): 295.1.
Procedure A
Intermediate 4: Benzene sulfonamide (Formula V)
##STR00020##
[0246] 200 ml of aq. NH.sub.3 is cooled to -10.degree. C. and
treated with benzenesulfonylchloride (13 g, 73 mmol). The resulting
mixture is stirred at this temperature for 3 h. When TLC confirmed
the completion of the reaction, the reaction mixture is warmed to
rt, and the resulting solid is filtered, washed with water and
dried under vacuum to afford the title compound (11.1 g, 96%).
LC/MS: (ES+): 158.2, (ES-): 156.2.
Intermediate 5: Propane-1-sulfonamide (Formula V)
##STR00021##
[0248] Following the protocol outlined in procedure A,
propane-1-sulfonamide is obtained from propane-1-sulfonyl chloride
(0.3 g, 2.1 mmol) and aqueous NH.sub.3 to afford 230 mg (88%) of
the title compound. LC/MS: (ES+): 124.2, (ES-): 122.2.
Procedure B
Intermediate 6: Methyl 3-[4-(aminosulfonyl)phenyl]propanoate methyl
(Formula V)
##STR00022##
[0250] To a solution of methyl 3-(4-chlorosulphonyl)phenypropionate
(1000 mg; 3.81 mmol; 1 eq., commercially available from Lancaster)
in THF (5 ml) is added ammonia 0.5 M in dioxane (38.1 ml, 0.5 M, 19
mmol, 5 eq.). The resulting suspension was stirred at r.t for 1 h.
The solvent is removed and the residue is taken up in DCM. The
organic phase was washed with a saturated aqueous solution of
NH.sub.4Cl then brine and the DCM was removed under reduced
pressure to afford, after drying under vacuum at 40.degree. C.,
831.4 mg (90%) of the title compound as a off white powder. 1H NMR
(DMSO-d6) .delta. 7.72 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H),
7.31 (s, 2H), 3.56 (s, 3H), 2.90 (t, J=7.6 Hz, 2H), 2.66 (t, J=7.6
Hz, 2H). HPLC (max plot) 98%; Rt 1.80 min.
Intermediate 7: 3-Methylbenzenesulfonamide (Formula V)
##STR00023##
[0252] Following the protocol outlined in procedure B, intermediate
7 is obtained from m-toluene sulfonyl chloride (761 .mu.l, 5.25
mmol, 1 eq.) and ammonia 2M in EtOH (13.1 ml, 2 M, 26.2 mmol, 5
eq.) in THF (5 ml) under stirring at r.t. for 2 h to afford 898 mg
(100%) of the title compound. 1H NMR (DMSO-d6) .delta. 7.67-7.59
(m, 2H), 7.50-7.38 (m, 2H), 7.29 (s, 2H), 2.39 (s, 3H). HPLC (max
plot) 99%; Rt 1.29 min. LC/MS: (ES-): 170.2.
Intermediate 8: 4-Acetylbenzenesulfonamide (Formula V)
##STR00024##
[0254] Following the protocol outlined in procedure B, intermediate
8 is obtained from 4-acetylbenzensulphonyl chloride (1000 mg, 4.57
mmol, 1 eq.) and ammonia 0.5 M in dioxane (45.7 ml, 0.5 M, 22.9
mmol, 5 eq.) in THF (5 ml) under stirring at r.t. for 1 h, to
afford 715 mg (78%) of the title compound. 1H NMR (DMSO-d6) .delta.
8.13-8.10 (m, 2H), 7.95-7.92 (m, 2H), 7.53 (br s, 2H), 2.62 (s,
3H). HPLC (max plot) 99%; Rt 1.04 min. LC/MS: (ES-): 198.2.
Intermediate 9: 4,5-Dichlorothiophene-2-sulfonamide (Formula V)
##STR00025##
[0256] Following the protocol outlined in procedure B, intermediate
9 is obtained from 2,3-dichlorothiophene-5-sulphonyl chloride (1000
mg, 3.98 mmol, 1 eq., commercially available from Lancaster) and
ammonia 0.5 M in dioxane (39.7 ml, 0.5 M, 19.9 mmol, 5 eq.) in THF
(5 ml) under stirring at rt for 1 h, to afford 802 mg (87%) of the
title compound. 1H NMR (DMSO-d6) .delta. 7.80 (br s, 2H), 7.44 (s,
1H). HPLC (max plot) 98%; Rt 2.50 min. LC/MS: (ES-): 230.0.
Intermediate 10: 4-Iodobenzenesulfonamide (Formula V)
##STR00026##
[0258] Following the protocol outlined in procedure B, intermediate
10 is obtained from pipsyl chloride (2000 mg, 6.61 mmol, 1 eq.) and
ammonia 2M in EtOH (66.1 ml, 0.5 M, 33.1 mmol, 5 eq.) in THF (8 ml)
under stirring at rt for 3 h, to afford 1336.3 mg (71%) of the
title compound. 1H NMR (DMSO-d6) .delta. 7.97 (d, J=8.3 Hz, 2H),
7.59 (d, J=8.3 Hz, 2H), 7.43 (s, 2H). HPLC (max plot) 100%; Rt 2.19
min. LC/MS: (ES+): 116.2, (ES-): 282.0.
Intermediate 11: Pyridine-3-sulfonamide (Formula V)
##STR00027##
[0260] Following the protocol outlined in procedure B, intermediate
11 is obtained from pyridine-3-sulphonyl chloride (1000 mg, 5.6
mmol, 1 eq., commercially available from Davos) and ammonia 0.5 M
in dioxane (23.9 ml, 2 M, 47.9 mmol, 8.5 eq.) in THF (5 ml) under
stirring at rt for 1 h, to afford 636.6 mg (71%) of the title
compound as a yellowish powder. 1H NMR (DMSO-d6) .delta. 9.20-8.90
(m, 1H), 8.85-8.75 (m, 1H), 8.40-8.05 (m, 1H), 7.80-7.40 (m,
3H).
Intermediate 12: 5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide
(Formula V)
##STR00028##
[0262] Following the protocol outlined in procedure B, intermediate
12 is obtained from 5-chloro-1,3-dimethypyrazole-4-sulphonyl
chloride (1000 mg, 4.4 mmol, 1 eq, commercially available from
Maybridge) and ammonia 0.5 M in dioxane (43.6 ml, 0.5 M, 21.8 mmol,
5 eq.) in THF (5 ml) under stirring at rt for 1 h, to afford 345.3
mg (38%) of the title compound as a off white powder. 1H NMR
(DMSO-d6) .delta. 7.39 (s, 2H), 3.74 (s, 3H), 2.28 (s, 3H). HPLC
(max plot) 100%; Rt 0.98 min.
Intermediate 13: 5-Bromothiophene-2-sulfonamide (Formula V)
##STR00029##
[0264] Following the protocol outlined in procedure B, Intermediate
13 is obtained from 5-bromothiophene-2-sulphonyl chloride (1000 mg,
3.82 mmol, 1 eq., commercially available from Maybridge) and
ammonia 0.5M in dioxane (38.2 ml, 0.5 M, 19,1 mmol, 5 eq.) in THF
(5 ml) under stirring at rt for 1 h, to afford 904 mg (98%) of the
title compound. 1H NMR (DMSO-d6) .delta. 7.73 (br s, 2H), 7.37 (d,
J=4.1 Hz, 1H), 7.29 (d, J=4.1 Hz, 1H). HPLC (max plot) 98%; Rt 1.60
min. LC/MS: (ES-): 240.0.
Intermediate 14: methyl
5-(aminosulfonyl)-4-methylthiophene-2-carboxylate (Formula V)
##STR00030##
[0266] Following the protocol outlined in Procedure B, Intermediate
14 is obtained from methyl
5-(chlorosulfonyl)-4-methyl-2-thiophenecarboxylate (600 mg; 2.36
mmol; 1 eq), commercially available (Acros), and ammonia 2M in MeOH
(5.89 ml; 2M; 11.78 mmol; 5 eq) in THF (3 ml) under stirring at
r.t. for 3 h, to afford 413.7 mg (75%) of the title compound. 1H
NMR (DMSO-d6) .delta. 7.90 (brs, 2H), 7.68 (s, 1H), 3.84 (s, 3H),
2.41 (s, 3H). HPLC (max plot) 96.66%; Rt 1.79 min. LC/MS: (ES-)
234.1.
Intermediate 15: thiophene-2-sulfonamide (Formula V)
##STR00031##
[0268] Following the protocol outlined in Procedure B, Intermediate
15 is obtained from 2-thiophenesulfonyl chloride (100 0 mg; 5.47
mmol; 1 eq), commercially available (Aldrich), and ammonia 2M in
EtOH (13.7 ml; 2M; 27.4 mmol; 5 eq) in THF (10 ml) under stirring
at r.t. for 3 h, to afford 540 mg (60%) of the title compound as a
grey powder. 1H NMR (DMSO-d6) .delta. 7.83 (dd, J=1.5, 4.9 Hz, 1H),
7.54 (dd, J=1.5, 3.8 Hz, 1H), 7.13 (dd, J=3.8, 4.9 Hz, 1H). HPLC
(max plot) 92%; Rt 1.56 min. LC/MS: (ES-) 162.1
Intermediate 16: 2-chloro-4-fluorobenzenesulfonamide (Formula
V)
##STR00032##
[0270] Following the protocol outlined in Procedure B, Intermediate
16 is obtained from 2-chloro-4-fluorobenzenesulfonyl chloride (1000
mg; 4.37 mmol; 1 eq), commercially available (ABCR), and ammonia 2M
in MeOH (10.91 ml; 2M; 21.83 mmol; 5 eq) in THF (4 ml) under
stirring at r.t. for 3 h, to afford 784 mg (86%) of the title
compound. 1H NMR (DMSO-d6) .delta. 8.03 (dd, J=9.0, 6.0 Hz, 1H),
7.68 (dd, J=9.7, 2.7 Hz, 1H), 7.64 (br s, 2H), 7.40 (dt, J=8.7, 2.7
Hz, 1H). HPLC (max plot) 98%; Rt 1.29 min. LC/MS: (ES-): 208.2.
Intermediate 17:
5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]thiophene-2-sulfonamide
(Formula V)
##STR00033##
[0272] Following the protocol outlined in Procedure B, Intermediate
17 is obtained from
5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-thiophene-2-sulfonyl
chloride (2000 mg; 5.85 mmol; 1 eq) and ammonia 2M in EtOH (14.63
ml; 2M; 29.26 mmol; 5 eq) in THF (10 ml) under stirring at r.t. for
2 h, to afford 1428 mg (76%) of the title compound. 1H NMR
(DMSO-d6) .delta. 7.93-7.84 (m, 4H), 7.37 (d, J=3.8 Hz, 1H), 7.30
(s, 2H), 7.09 (d, J=3.8 Hz, 1H), 4.96 (s, 2H). HPLC (max plot) 96%;
Rt 2.65 min. LC/MS: (ES-): 321.1.
Intermediate 18: 3-cyano-4-fluorobenzenesulfonamide (Formula V)
##STR00034##
[0274] Following the protocol outlined in Procedure B, Intermediate
18 is obtained from 4-fluoro-3-cyanobenzenesulfonyl chloride (2000
mg; 9.11 mmol; 1 eq), commercially available (Aldrich), and ammonia
2M in EtOH (22.77 ml; 2M; 45.53 mmol; 5 eq) in THF (8 ml) under
stirring at -10.degree. C. for 30 min, to afford 1625.5 mg (89%) of
the title compound as a white solid. 1H NMR (DMSO-d6) .delta. 8.32
(dd, J=6.0, 2.3 Hz, 1H), 8.22-8.15 (m, 1H), 7.76 (t, J=9.0 Hz, 1H),
7.59 (br s, 2H). HPLC (max plot) 99%; Rt 1.10 min. LC/MS: (ES-):
199.2.
Intermediate 19: 6-methoxypyridine-3-sulfonamide (Formula V)
##STR00035##
[0276] Following the protocol outlined in Procedure B, Intermediate
19 is obtained from 6-methoxy-pyridine-3-sulfonyl chloride (1000
mg; 4.82 mmol; 1 eq), commercially available (Anichem), and ammonia
2M in MeOH (12.04 ml; 2M; 24.08 mmol; 5 eq) in THF (8 ml) under
stirring at rt for 3 h, to afford 474.5 mg (52%) of the title
compound. 1H NMR (DMSO-d6) .delta. 8.56 (d, J=2.6 Hz, 1H), 8.05
(dd, J=2.6, 8.7 Hz, 1H), 7.34 (s, 3H), 6.98 (d, J=8.7 Hz, 1H). HPLC
(max plot) 100%; Rt 0.88 min. LC/MS: (ES+): 189.1, (ES-):
187.2.
Procedure C
Intermediate 20: 3-(Aminosulfonyl)benzoic acid (Formula V)
##STR00036##
[0278] To ice-cold solution of ammonium hydroxide (25%, 250 ml) is
added 3-(chlorosulfonyl)benzoic acid (25 g, commercially available,
Aldrich) portionwise and the mixture is stirred at room temperature
for 15 h. The solvent is removed under vacuum to about 50 ml and
the mixture is acidified with conc. HCl. The precipitate is
collected by filtration and dried under vacuum to afford 22 g (96%)
of the title compound as a white solid. 1H NMR (DMSO-d6) .delta.
13.44 (br s, 1H), 8.38 (s, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.04 (d,
J=7.9 Hz, 1H), 7.72 (t, J=7.9 Hz, 1H), 7.49 (s, 2H), HPLC (max
plot) 97%; Rt 0.68 min. LC/MS: (ES-): 199.8.
Intermediate 21: 6-Chloropyridine-3-sulfonamide (Formula V)
##STR00037##
[0280] Following the protocol outlined in Procedure C, Intermediate
21 is obtained from ammonium hydroxide (150 ml, 25% w/v) and
6-chloropyridine-3-sulfonyl chloride (19.3 g, commercially
available, Aldrich) at rt for 12 h to afford 14.5 g (83%) of the
title compound as an off-white solid. mp: 151-154.degree. C., HPLC
(max plot) 99%. Rt 4.77 min, LC/MS: (ES-): 190.7, 1H NMR (DMSO-d6:
400 MHz) .delta. 8.80 (1H, s), 8.20-8.23 (1H, d), 7.76-7.78 (1H,
d), 7.72 (2H, bs).
Intermediate 22: 6-Methylpyridine-3-sulfonamide (Formula V)
##STR00038##
[0282] Following the protocol outlined in Procedure C, Intermediate
22 is obtained from ammonium hydroxide (25 ml, 25% w/v) and
6-methylpyridine-3-sulfonyl chloride (2.5 g) at rt for 3 h to
afford 1 g (41%) of the title compound as an off-white solid. mp:
151-155.degree. C., LC/MS: (ES+): 172.9, HPLC (max plot) 95%, Rt:
4.05 min, 1H NMR (DMSO-d6: 400 MHz) .delta. 9.10 (1H, m), 8.04-8.06
(1H, m), 7.53 (2H, bs), 7.45-7.47 (1H, m), 2.54 (3H, s).
Procedure D
Intermediate 23: 6-Cyanopyridine-3-sulfonyl chloride (Formula
IX)
##STR00039##
[0284] Thionylchloride (34.1 ml, 0.467 mol) is added to water (182
ml) at 0.degree. C. over a period of 1 h maintaining the reaction
temperature below 5.degree. C. The reaction mixture is allowed to
warm to 18.degree. C. over a period of 20 h. To this mixture is
added copper (1) chloride (0.143 g, 0.0014 mol) and the resulting
yellow-green solution is cooled to -5.degree. C.
[0285] In parallel, 5-amino-2-cyano pyridine (10 g, 0.084 mol) is
dissolved in concentrated HCl (98 ml) and the mixture is cooled to
-5.degree. C. To this mixture is added dropwise over a period of 1
h a solution of NaNO.sub.2 (8.2 g, 0.118 mol) in water (50 ml),
maintaining the reaction temperature between -5.degree. C. and
0.degree. C. This slurry is then added dropwise over a period of 1
h to the above reaction mixture (thionylchloride/water mixture),
maintaining the reaction temperature between -5.degree. C. and
0.degree. C. (Note: The diazotized mixture should be also kept at
-5.degree. C. through out the addition). As the addition proceeds,
a white solid precipitates. When the addition is over, the reaction
mixture is stirred for an additional hour. The precipitate is
collected by filtration, washed with cold water and dried under
vacuum to afford the title compound as light yellow solid (12.5 g,
Yield 73.5%). 1H NMR (DMSO-d6: 400 MHz) .delta. 14.49 (1H, s), 8.87
(1H, s), 8.11-8.14 (1H, d), 8.0-8.03 (1H, d); HPLC (max plot) 97%
Rt 1.155 min; LCMS: m/z, M+, 202.8.
Intermediate 24: 6-Chloropyridine-3-sulfonyl chloride (Formula
IX)
##STR00040##
[0287] Following the protocol outlined in Procedure D, Intermediate
24 is obtained from thionyl chloride (42 ml, 0.575 mol) and copper
(I) chloride (0.151 g, 0.00152 mol) in water (250 ml) at 0.degree.
C. to which is added, over a period of 2 h, a slurry obtained from
5-amino-2-chloro pyridine (17.3 g, 0.134 mol) in concentrated HCl
(135 ml) and NaNO.sub.2 (10 g, 0.1449 mol) in water (40 ml) at
-5.degree. C., to afford 19.7 g (70%) of the title compound as a
solid. mp: 48.3-49.3.degree. C., LC/MS: (ES-): 192 which
corresponds to the sulfonic acid, 1H NMR (CDCl.sub.3: 400 MHz)
.delta. 9.05 (1H, s), 8.26-8.29 (1H, d), 7.62-7.64 (1H, d).
Intermediate 25: 6-Methylpyridine-3-sulfonyl chloride (Formula
IX)
##STR00041##
[0289] Following the protocol outlined in Procedure D, Intermediate
25 is obtained from thionyl chloride (46.1 ml, 0.39 mol) and copper
(I) chloride (0.118 g, 0.0012 mol) in water (160 ml) at 0.degree.
C. to which is added, over a period of 2 h, a slurry obtained from
3-amino-6-picoline (10 g, 0.094 mol) in concentrated HCl (80 ml)
and NaNO.sub.2 (6.8 g, 0.0988 mol) in water (20 ml) at -5.degree.
C., to afford 2.5 g (14%) of the title compound as a liquid, which
is used in the next step without storage. LC/MS: (ES-): 172 which
corresponds to the sulfonic acid.
Intermediate 26: methyl
5-(aminosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate (Formula V)
##STR00042##
[0291] 5-(Aminosulfonyl)-1-methyl-1H-pyrrole-2-carboxylic acid
(1310 mg; 6.42 mmol; 1 eq.), commercially available (ASDI), is
dissolved in MeOH (24 ml), then toluene (8 ml) is added followed by
the dropwise addition of (trimethylsilyl)diazomethane (9.62 ml; 2M;
19.25 mmol; 3 eq). The solution is stirred at r.t. for 2 hr and
another equivalent of (trimethylsilyl)diazomethane (3.21 ml; 2 M;
6.42 mmol; 1 eq) is added to reaction mixture. After 1 hr stirring,
the solvent is concentrated to dryness and the resulting off white
solid is recrystallized in MeOH to afford 851.1 mg (61%) of the
title compound. 1H NMR (DMSO-d6) .delta. 7.58 (d, J=1.5 Hz, 1H),
7.13 (s, 2H), 7.06 (d, J=1.9 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H).
HPLC (max plot) 100%; Rt 1.19 min. LC/MS: (ES-) 217.1.
Intermediate 27: 6-Cyanopyridine-3-sulfonamide (Formula V)
##STR00043##
[0293] To an ice-cold solution of ammonium hydroxide (75 ml, 25%
w/v) is added 6-cyanopyridine-3-sulfonyl chloride (12.5 g)
portionwise and the mixture is stirred for 30 minutes at
0-5.degree. C. The reaction mixture is then concentrated to
1/5.sup.th of its original volume and cooled. The precipitate is
filtered and dried under vacuum to afford the title compound as
light brown solid (9 g, Yield 80%). 1H NMR (DMSO-d6: 400 MHz)
.delta. 9.10 (1H, s), 8.33-8.35 (1H, m), 8.23-8.25 (1H, d);
7.88-8.03 (2H, bs); HPLC (max plot) 98%, Rt 4.67 min; LCMS: (ES+)
183.8.
Intermediate 28: Methyl 5-(aminosulfonyl)pyridine-2-carboxylate
(Formula V)
##STR00044##
[0295] 6-Cyanopyridine-3-sulfonamide (10 g, 0.0545 mol) is
dissolved in dry HCl in methanol (400 ml) at 25-26.degree. C. under
nitrogen atmosphere. Reaction mixture is heated to 50.degree. C.
and stirred for 15 h at 50.degree. C. The reaction mixture is
concentrated under vacuum and the residue obtained is diluted with
water (100 ml) and basified with solid sodium bicarbonate to pH
6-7. The reaction mixture is stirred for 15 minutes and filtered.
The resulting solid obtained is washed with water (50 ml) and dried
under vacuum to afford the title compound (9 g, 76%) as light
yellow solid. 1H NMR (DMSO-d6) .delta. 9.08 (d, J=3 Hz, 1H), 8.38
(dd, J=9 and 3 Hz, 1H), 8.26 (d, J=9 Hz, 1H), 7.79 (m, 2H), 3.93
(s, 3H). HPLC (max plot) 94%; Rt 3.45 min; LC/MS: (ES+) 216.9.
Intermediate 29: Methyl 4-(aminosulfonyl)benzoate (Formula V)
##STR00045##
[0297] To a suspension of 4-(aminosulfonyl)benzoic acid (500 mg,
2.5 mmol) in MeOH (2 ml) at 0.degree. C. is added thionylchloride
(0.2 ml, 7.4 mmol). The reaction mixture is stirred at rt
overnight. When TLC confirms the total consumption of the starting
acid, the solvent and excess thionyl chloride are removed under
reduced pressure to afford 400 mg (75%) of the title compound,
which was used in the next step without any further purification.
LC/MS: (ES+): 215.9, (ES-): 214.1.
Intermediate 30: Methyl 3-(chlorosulfonyl)benzoate (Formula IX)
##STR00046##
[0299] To a suspension of 3-(chlorosulphonyl)benzoic acid (300 mg,
1.4 mmol) in DCM (2 ml) at 0.degree. C. is added thionylchloride
(0.3 ml, 4.1 mmol), the reaction mixture is stirred at rt
overnight. When TLC confirms the total consumption of the starling
acid, the solvent and excess thionyl chloride are removed under
reduced pressure to obtain the corresponding acid chloride. A
suspension of the acid chloride in MeOH (2 ml) at -5.degree. C. is
stirred for 2 hr and the solvent is removed under reduced pressure
to afford 200 mg (63%) of the title compound, which is used in the
next step without any further purification. LC/MS: (ES-):
233.1.
Intermediate 31: Methyl 3-(aminosulfonyl)benzoate (Formula V)
##STR00047##
[0301] To a solution of 3-(aminosulfonyl)benzoic acid (22 g, 0.109
mol) in MeOH (250 ml) is added thionyl chloride (25 ml, 0.328 mol)
and the mixture is refluxed for 16 h. The solvent is removed and
the residue is diluted with EtOAc (200 ml), washed with a 10%
solution of sodium bicarbonate, water and brine. The solvent was
removed under vacuum to afford 17 g (73%) of the title compound as
a solid. 1H NMR (DMSO-d6) .delta. 8.39 (t, J=1.5 Hz, 1H), 8.16-8.13
(m, 1H), 8.09-8.05 (m, 1H), 7.76 (t, J=7.9 Hz, 1H), 7.53 (s, 2H),
3.90 (s, 3H). HPLC (max plot) 99%; Rt 1.49 min. LC/MS: (ES+):
215.9, (ES-): 214.1.
Intermediate 32: 3-(Morpholin-4-ylcarbonyl)benzenesulfonamide
(Formula V)
##STR00048##
[0303] To a solution of 3-(aminosulfonyl)benzoic acid (6 g, 0.029
mol) in THF (100 ml) at 0.degree. C. is added CDI (5.8 g, 0.035
mol) and the mixture is stirred for 4 h. To this mixture morpholine
(7.8 ml, 0.089 mol) is added dropwise and the mixture is stirred at
room temperature for 15 h. The solvent is removed under vacuum and
the residue is diluted with EtOAc (100 ml), washed with a 10%
solution of sodium bicarbonate, water and brine. The solvent is
removed under vacuum and the residue is taken up with small amount
of water (15 ml) and stirred for 15 min. The solid is collected by
filtration to afford 4 g (50%) of the title compound as a solid. 1H
NMR (DMSO-d6, 400 MHz) .delta. 7.88-7.90 (1H, m), 7.83 (1H, s),
7.64-7.65 (2H, m), 7.47 (2H, bs), 3.56-3.64 (6H, m), 3.28-3.34 (2H,
m); HPLC (Max polt) 98%, Rt, 4.09 min; LCMS: (ES+): 206.2.
Intermediate 33: 6-(Dimethylamino)pyridine-3-sulfonamide (Formula
V)
##STR00049##
[0305] A mixture of 6-chloropyridine-3-sulfonamide (5 g, 0.0259
mol) and aqueous dimethylamine (100 ml, 40%) is stirred at rt for
13 h. The mixture is concentrated to 1/5.sup.th of its original
volume and cooled. The precipitate is collected by filtration,
washed with ice-cold water (10 ml) and dried under vacuum to afford
4.5 g (95%) of the title compound as a solid. mp: 133-138.degree.
C., LC/MS: (ES+) 201.9.
Intermediate 34: 6-[(3-Methoxypropyl)amino]pyridine-3-sulfonamide
(Formula V)
##STR00050##
[0307] A mixture of 6-chloropyridine-3-sulfonamide (5 g, 0.025 mol)
and 3-methoxy propylamine (50 ml) is stirred at 100.degree. C. for
12 h. The mixture is cooled and excess reagent is removed by
distillation. The residue is suspended in DCM (25 ml) and cooled.
The precipitate is filtered, washed with cold ammonium hydroxide
(2.times.50 ml) and dried under vacuum to afford 5 g (78%) of the
titled compound as a white solid. mp: 129-132.degree. C., LC/MS:
(ES+) 246.
Procedure E
Intermediate 35:
N-(3-Chloro-quinoxalin-2-yl)-3-fluoro-benzenesulfonamide (Formula
II)
##STR00051##
[0309] 3-fluorobenzenesulfonamide (250 mg, 1.4 mmol),
2,3-dichloroquinoxaline (284.1 mg, 1.4 mmol) and dry
K.sub.2CO.sub.3 (198.4 mg, 1.4 mmol) are dissolved in dry DMF (0.8
ml) and heated up to 135.degree. C. in a sealed tube for 2.5 h.
When TLC confirms the completion of the reaction, the reaction
mixture is cooled down to rt and quenched by addition of water (4
ml) and AcOH (0.03 ml). The residue obtained is triturated and the
resulting solid is filtered and washed with water until neutral pH
then dried under vacuum to afford 400 mg (83%) of the title
compound as an off white solid. 1H NMR (DMSO-d6) .delta. 12.8-10.9
(br s, 1H), 8.05-7.62 (m, 7H), 7.54 (td, J=2.0, 8.5 Hz, 1H). HPLC
(max plot) 94%; Rt 3.79 min. LC/MS: (ES+): 338.1, (ES-): 336.1.
Intermediate 36: N-(3-chloro-2-quinoxalinyl)benzenesulfonamide
(Formula II)
##STR00052##
[0311] Following the protocol outlined in Procedure E, Intermediate
36 is obtained from 2,3-dichloroquinoxaline (1 000 mg, 5.0 mmol, 1
eq.) and benzenesulfonamide (789.8 mg, 5.0 mmol; 1 eq.) in the
presence of K.sub.2CO.sub.3 (694.4 mg, 5.0 mmol; 1 eq.) in DMA (10
ml), to afford 1291 mg (80%) of the title compound as a yellow
powder. 1H NMR (DMSO-d6) .delta. 12.5-10-5 (br s, 1H), 8.25-8.08
(m, 2H), 7.95-7.50 (m, 7H). HPLC (max plot) 90%; Rt 3.54 min.
LC/MS: (ES+): 320.03, (ES-): 318.02.
Intermediate 37: N-(3-chloroquinoxalin-2-yl)propane-1-sulfonamide
(Formula II)
##STR00053##
[0313] Following the protocol outlined in Procedure E, Intermediate
37 is obtained from 2,3-dichloroquinoxaline (0.2 g, 1 mmol, 1 eq.)
and propane-1-sulfonamide (123.8 mg, 1 mmol, 1 eq.) in the presence
of K.sub.2CO.sub.3 (138.8 mg, 1 mmol, 1 eq.) in DMF (2 ml), to
afford 187 mg (65%) of the title compound as a yellow powder.
LC/MS: (ES+): 286.7.
Intermediate 38: Methyl
4-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}butanoate (Formula
II)
##STR00054##
[0315] Following the protocol outlined in Procedure E, Intermediate
38 is obtained from 2,3-dichloroquinoxaline (0.2 g, 1 mmol, 1 eq.)
and methyl 4-sulfamido butanoate (181.2 mg, 1 mmol, 1 eq.) in the
presence of K.sub.2CO.sub.3 (138.8 mg, 1 mmol, 1 eq.) in DMF (2
ml), to afford 307 mg (87%) of the title compound as a yellow
powder. LC/MS: (ES+): 344.6.
Intermediate 39: Methyl
4-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}benzoate (Formula
II)
##STR00055##
[0317] Following the protocol outlined in Procedure E, Intermediate
39 is obtained from 2,3-dichloroquinoxaline (500 mg, 2.5 mmol, 1
eq.) and methyl 4-(aminosulfonyl)benzoate (538.1 mg, 2.5 mmol, 1
eq.) in the presence of K.sub.2CO.sub.3 (347.2 mg, 2.5 mmol, 1 eq.)
in DMF (5 ml), to afford 757 mg (80%) of the title compound as a
yellow powder. LC/MS: (ES+): 378.8.
Procedure F
Intermediate 40:
N-(3-chloroquinoxalin-2-yl)-3-methylbenzenesulfonamide (Formula
II)
##STR00056##
[0319] A suspension of 2,3-dichloroquinoxaline (500 mg; 2.5 mmol; 1
eq), 3-methylbenzene sulfonamide (430.1 mg, 2.5 mmol, 1 eq.), dry
K.sub.2CO.sub.3 (347.2 mg, 2.5 mmol, 1 eq.) in DMA (5 ml) is heated
up at 170.degree. C. in the microwave for 30 min under normal
absorption. The solvent is evaporated to dryness. Water (20 ml) is
added then AcOH until acidic pH. The residual suspension is left at
4.degree. C. for 1 h and the precipitate formed is filtered off,
washed with water until neutral, then ACN and dried under vacuum at
40.degree. C. overnight, to afford 548.3 mg (65%) of the title
compound. 1H NMR (DMSO-d6) .delta. 11.53 (brs, 1H), 7.99 (m, 2H),
7.87 (t, J=8.6 Hz, 2H), 7.77 (dt, J=1.5, 7.5 Hz, 1H), 7.67 (t,
J=8.0 Hz, 1H), 7.56-7.43 (m, 2H), 2.42 (s, 3H). HPLC (max plot)
99%; Rt 3.70 min. LC/MS: (ES+): 334.2, (ES-): 332.2.
Intermediate 41:
4-Chloro-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (Formula
II)
##STR00057##
[0321] Following the protocol outlined in procedure F, intermediate
41 is obtained from 2,3-dichloroquinoxaline (1000 mg, 5.0 mmol, 1
eq.) and 4-chlorobenzenesulfonamide (962.8 mg, 5.0 mmol, 1 eq.) in
the presence of K.sub.2CO.sub.3 (694.3 mg, 5.0 mmol, 1 eq.) in DMA
(10 ml), to afford 1.69 g (95%) of the title compound as a yellow
solid. 1H NMR (DMSO-d6) .delta. 8.16 (d, J=8.7 Hz, 2H), 7.89-7.88
(m, 2H), 7.78-7.63 (m, 2H), 7.69 (d, J=8.7 Hz, 2H). HPLC (max plot)
90%; Rt 4.15 min. LC/MS: (ES+): 354.2, (ES-): 352.1.
Intermediate 42:
N-(3-chloroquinoxalin-2-yl)-4-fluorobenzenesulfonamide (Formula
II)
##STR00058##
[0323] Following the protocol outlined in Procedure F, Intermediate
42 is obtained from 2,3-dichloroquinoxaline (1000 mg, 5.02 mmol, 1
eq.) and 4-fluorobenzenesulfonamide (880.1 mg, 5.0 mmol, 1 eq.) in
the presence of K.sub.2CO.sub.3 (694.3 mg, 5 mmol, 1 eq.) in DMA (5
ml), to afford 540 mg (32%) of the title compound as a yellow
solid. 1H NMR (DMSO-d6) .delta. 8.24 (dd, J=5.28, 9.05 Hz, 2H),
7.88 (br dd, 2H), 7.79-7.74 (m, 1H), 7.69-7.64 (m, 1H), 7.49-7.43
(m, 2H). HPLC (max plot) 89%; Rt 3.87 min. LC/MS: (ES+): 338.1,
(ES-): 336.1.
Intermediate 43:
N-(3-chloroquinoxalin-2-yl)-4-methoxybenzenesulfonamide (Formula
II)
##STR00059##
[0325] Following the protocol outlined in Procedure F, Intermediate
43 is obtained from 2,3-dichloroquinoxaline (1000 mg, 5.0 mmol, 1
eq.) and 4-methoxybenzenesulfonamide (940.6 mg, 5.0 mmol, 1 eq.) in
the presence of K.sub.2CO.sub.3 (694.3 mg, 5.0 mmol, 1 eq.) in DMA
(10 ml), to afford 782 mg (44%) of the title compound as a yellow
solid. 1H NMR (DMSO-d6) .delta. 8.11 (d, J=8.4 Hz, 2H), 7.88 (d,
J=8.4 Hz, 2H), 7.79-7.74 (m, 1H), 7.68-7.63 (m, 1H), 7.15-7.10 (m,
2H), 3.81 (s, 3H). HPLC (max plot) 92%; Rt 3.54 min. LC/MS: (ES+):
350.1; (ES-): 348.1.
Intermediate 44:
N-(3-chloroquinoxalin-2-yl)-4-methylbenzenesulfonamide (Formula
II)
##STR00060##
[0327] Following the protocol outlined in procedure F, intermediate
44 is obtained from 2,3-dichloroquinoxaline (500 mg, 2.51 mmol, 1
eq.) and p-toluenesulfonamide (430.1 mg, 2.5 mmol, 1 eq.) in the
presence of K.sub.2CO.sub.3 (347.2 mg, 2.5 mmol, 1 eq.) in DMA (5
ml), to afford 680.6 mg (81%) of the title compound. 1H NMR
(DMSO-d6) .delta. 11.51 (brs, 1H), 8.05 (d, J=7.9 Hz, 2H),
7.92-7.84 (m, 2H), 7.81-7.73 (m, 1H), 7.72-7.63 (m, 1H), 7.42 (d,
J=8.3 Hz, 2H), 2.37 (s, 3H). HPLC (max plot) 88%; Rt 3.70 min.
LC/MS: (ES+): 334.0, (ES-): 332.0.
Intermediate 45:
4-Bromo-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (Formula
II)
##STR00061##
[0329] Following the protocol outlined in Procedure F, Intermediate
45 is obtained from 2,3-dichloroquinoxaline (1000 mg, 5.0 mmol, 1
eq.) and 4-bromobenzenesulfonamide (1186 mg, 5.0 mmol, 1 eq.) in
the presence of K.sub.2CO.sub.3 (694.3 mg, 5.0 mmol, 1 eq.) in DMA
(10 ml), to afford 1800 mg (90%) of the title compound as a yellow
solid. 1H NMR (DMSO-d6) .delta. 8.08 (d, J=8.67 Hz, 2H), 7.88-7.82
(m, 2H), 7.84 (d, J=8.67 Hz, 2H), 7.78-7.73 (m, 1H), 7.68-7.63 (m,
1H). HPLC (max plot) 90%; Rt 4.21 min. LC/MS: (ES+): 400.0, (ES-):
398.0.
Intermediate 46: N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide
(Formula II)
##STR00062##
[0331] Following the protocol outlined in Procedure F, Intermediate
46 is obtained from 2,3-dichloroquinoxaline (165 mg, 0.8 mmol, 1
eq.) and pyridine-3-sulfonamide (131.1 mg, 0.8 mmol, 1 eq.) in the
presence of K.sub.2CO.sub.3 (114.6 mg, 0.8 mmol, 1 eq.) in DMA
(1.60 ml), to afford 200 mg (75%) of the title compound as an
orange powder. 1H NMR (DMSO-d6) .delta. 9.28 (s, 1H), 8.80 (d,
J=4.1 Hz, 1H), 8.57 (d, J=8.0 Hz, 1H), 7.95-7.55 (m, 5H). HPLC (max
plot) 91%; Rt 2.54 min.
Intermediate 47:
N-(3-chloroquinoxalin-2-yl)-4-cyanobenzenesulfonamide (Formula
II)
##STR00063##
[0333] Following the protocol outlined in Procedure F, Intermediate
47 is obtained from 2,3-dichloroquinoxaline (600 mg, 3.0 mmol, 1
eq.) and 4-cyanobenzenesulfonamide (549.2 mg, 3.0 mmol, 1 eq.,
commercially available from Maybridge) in the presence of
K.sub.2CO.sub.3 (416.6 mg, 3.0 mmol, 1 eq.) in DMA (6.0 ml), to
afford 660.3 mg (64%) of the title compound as a yellowish solid.
1H NMR (DMSO-d6) .delta. 8.29 (d, J=8.2 Hz, 2H), 8.09 (d, J=8.3 Hz,
2H), 7.92-7.57 (m, 4H). HPLC (max plot) 93%; Rt 3.68 min. LC/MS:
(ES+): 345.1, (ES-): 343.1.
Intermediate 48: N-(3-chloroquinoxalin-2-yl)methanesulfonamide
(Formula II)
##STR00064##
[0335] Following the protocol outlined in Procedure F, Intermediate
48 is obtained from 2,3-dichloroquinoxaline (300 mg, 1.5 mmol, 1
eq.) and methanesulfonamide (143.4 mg, 1.5 mmol; 1 eq.) in the
presence of K.sub.2CO.sub.3 (208.3 mg, 1.5 mmol, 1 eq.) in DMA (3.0
ml), to afford 234.2 mg (60%) of the title compound as a yellow
powder. 1H NMR (DMSO-d6) .delta. 11.05 (br s, 1H), 8.04-7.88 (m,
2H), 7.85-7.61 (m, 2H), 3.49 (s, 3H). HPLC (max plot) 90% Rt 2.35
min. LC/MS: (ES+): 258.0; (ES-): 256.0,
Intermediate 49:
N-(3-chloroquinoxalin-2-yl)-4-(trifluoromethyl)benzenesulfonamide
(Formula II)
##STR00065##
[0337] Following the protocol outlined in Procedure F, Intermediate
49 is obtained from 2,3-dichloroquinoxaline (500 mg, 2.5 mmol, 1
eq.) and (trifluoromethyl)benzenesulfonamide (565.7 mg, 2.5 mmol, 1
eq., commercially available from ABCR) in the presence of
K.sub.2CO.sub.3 (347.2 mg; 2.5 mmol; 1 eq.) in DMA (5 ml), to
afford 892.5 mg (92%) of the title compound. 1H NMR (DMSO-d6)
.delta. 8.38 (d, J=8.3 Hz, 2H), 8.02 (d, J=8.6 Hz, 2H), 7.90-7.84
(m, 2H), 7.79-7.71 (m, 1H), 7.69-7.62 (m, 1H). HPLC (max plot) 83%;
Rt 4.35 min. LC/MS: (ES+): 388.1, (ES-): 386.2.
Intermediate 50:
N-(3-chloroquinoxalin-2-yl)-4-iodobenzenesulfonamide (Formula
II)
##STR00066##
[0339] Following the protocol outlined in procedure F, intermediate
50 is obtained from 2,3-dichloroquinoxaline (500 mg, 2.5 mmol, 1
eq.) and 4-iodobenzenesulfonamide (711.1 mg, 2.5 mmol, 1 eq.,
commercially available from Apollo) in the presence of
K.sub.2CO.sub.3 (347.2 mg, 2.5 mmol, 1 eq.) in DMA (5 ml), to
afford 989.6 mg (88%) of the title compound. 1H NMR (DMSO-d6)
.delta. 8.03 (d, J=8.3 Hz, 2H), 7.93 (d, J=8.6 Hz, 2H), 7.89 (d,
J=8.7 Hz, 2H), 7.77 (m. 1H), 7.67 (m, 1H). HPLC (max plot) 91%; Rt
4.26 min. LC/MS: (ES+): 446.1, (ES-): 444.0.
Intermediate 51:
4,5-dichloro-N-(3-chloroquinoxalin-2-yl)thiophene-2-sulfonamide
(Formula II)
##STR00067##
[0341] Following the protocol outlined in Procedure F, Intermediate
51 is obtained from 2,3-dichloroquinoxaline (250 mg, 1.3 mmol. 1
eq.) and 4,5-dichlorothiophene-2-sulfonamide (291.5 mg, 1.3 mmol, 1
eq.) in the presence of K.sub.2CO.sub.3 (173.6 mg, 1.3 mmol, 1 eq.)
in DMA (3 ml), to afford 439 mg (89%) of the title compound. 1H NMR
(DMSO-d6) .delta. 7.93-7.89 (m, 1H), 7.84-7.81 (m, 1H), 7.83 (s,
1H), 7.76-7.70 (m, 1H), 7.59-7.54 (m, 1H). HPLC (max plot) 95%; Rt
4.25 min. LC/MS: (ES+): 395.9, (ES-): 393.9.
Intermediate 52:
5-chloro-N-(3-chloroquinoxalin-2-yl)-1,3-dimethyl-1H-pyrazole-4-sulfonami-
de (Formula II)
##STR00068##
[0343] Following the protocol outlined in Procedure F, Intermediate
52 is obtained from 2,3-dichloroquinoxaline (300 mg, 1.5 mmol, 1
eq.) and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide (316 mg,
1.5 mmol, 1 eq.) in the presence of K.sub.2CO.sub.3 (208.3 mg, 1.5
mmol, 1 eq.) in DMA (3 ml), to afford 374.1 mg (67%) of the title
compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 8.00-7.5 (m,
4H), 3.75 (s, 3H), 2.46 (s, 3H). HPLC (max plot) 96%; Rt 3.09
min.
Intermediate 53:
4-acetyl-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (Formula
II)
##STR00069##
[0345] Following the protocol outlined in procedure F, intermediate
53 is obtained from 2,3-dichloroquinoxaline (250 mg, 1.3 mmol, 1
eq.) and 4-acetylbenzenesulfonamide (250.24 mg, 1.3 mmol, 1 eq.) in
the presence of K.sub.2CO.sub.3 (173.59 mg, 1.3 mmol, 1 eq.) in DMA
(3 ml), to afford 330 mg (73%) of the title compound. 1H NMR
(DMSO-d6) .delta. 8.28 (d, J=8.7 Hz, 2H), 8.15 (d, J=8.7 Hz, 2H),
7.89-7.84 (m, 2H), 7.78-7.72 (m, 1H), 7.68-7.62 (m, 1H), 2.61 (s,
3H). HPLC (max plot) 94%; Rt 3.34 min. LC/MS: (ES+): 362.1, (ES-):
360.1.
Intermediate 54: methyl 3-(4-{[(3-chloroquinoxalin-2
yl)amino]sulfonyl}phenyl) propanoate (Formula II)
##STR00070##
[0347] Following the protocol outlined in Procedure F, Intermediate
54 is obtained from 2,3-dichloroquinoxaline (200 mg, 1 mmol, 1 eq.)
and methyl 3-[4-(aminosulfonyl)phenyl] propanoate (244.5 mg, 1
mmol, 1 eq.) in the presence of K.sub.2CO.sub.3 (138.9 mg, 1 mmol,
1 eq.) in DMA (2 ml), to afford 278.7 mg (68%) of the title
compound as a yellow solid. 1H NMR (DMSO-d6) .delta. 11.50 (br s,
1H), 8.07 (d, J=7.9 Hz, 2H), 8-7.58 (m, 4H), 7.47 (d, J=7.9 Hz,
2H), 3.52 (s, 3H), 2.91 (t, J=7.5 Hz, 2H), 2.65 (t, J=7.5 Hz, 2H).
HPLC (max plot) 81%; Rt 3.65 min.
Intermediate 55:
5-bromo-N-(3-chloroquinoxalin-2-yl)thiophene-2-sulfonamide (Formula
II)
##STR00071##
[0349] Following the protocol outlined in Procedure F, Intermediate
55 is obtained from 2,3-dichloroquinoxaline (740 mg, 3.7 mmol, 1
eq.) and 5-bromothiophene-2-sulfonamide (900.2 mg, 3.7 mmol, 1 eq.)
in the presence of K.sub.2CO.sub.3 (513.8 mg, 3.7 mmol, 1 eq.) in
DMA (7 ml), to afford 235 mg (16%) of the title compound. 1H NMR
(DMSO-d6) .delta. 7.92-7.89 (m, 1H), 7.85-7.82 (m, 1H), 7.76-7.71
(m, 1H), 7.67 (d, J=4.1 Hz, 1H), 7.61-7.55 (m, 1H), 7.26 (d, J=4.1
Hz, 1H). HPLC (max plot) 97%; Rt 3.91 min. LC/MS: (ES+): 405.9,
(ES-): 403.8.
Intermediate 56:
2-chloro-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (Formula
II)
##STR00072##
[0351] Following the protocol outlined in Procedure F, Intermediate
56 is obtained from 2,3-dichloroquinoxaline (700 mg, 3.5 mmol, 1
eq.), 2-chlorobenzenesulfonamide (674 mg, 3.5 mmol, 1 eq.) in the
presence of K.sub.2CO.sub.3 (486 mg, 3.52 mmol, 1 eq.) in DMA (7
ml), to afford 1184.9 mg (95%) of the title compound as a white
solid. 1H NMR (DMSO-d6) .delta. 8.32-8.26 (m, 1H), 7.87 (d, J=7.9
Hz, 1H), 7.75-7.57 (m, 7H). HPLC (max plot) 90%; Rt 3.64 min.
LC/MS: (ES+): 354.2, (ES-): 352.2.
Intermediate 57:
3-chloro-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (Formula
II)
##STR00073##
[0353] Following the protocol outlined in Procedure F, Intermediate
57 is obtained from 2,3-dichloroquinoxaline (500 mg, 2.5 mmol, 1
eq.) and 3-chlorobenzenesulfonamide (481.4 mg, 2.5 mmol, 1 eq.,
commercially available from Lancaster) in the presence of
K.sub.2CO.sub.3 (347.2 mg, 2.5 mmol, 1 eq.) in DMA (5 ml), to
afford 782 mg (88%) of the title compound as a yellow powder. 1H
NMR (DMSO-d6) .delta. 8.18 (t, J=1.9 Hz, 1H), 8.12-8.09 (m, 1H),
7.89-7.87 (m, 1H), 7.83-7.71 (m, 3H), 7.68-7.63 (m, 2H). HPLC (max
plot) 93%; Rt 4.15 min. LC/MS: (ES+): 354.1, (ES-): 3521
Intermediate 58: N-(3,6-dichloroquinoxalin-2-yl)benzenesulfonamide
(Formula II)
##STR00074##
[0355] Following the protocol outlined in Procedure F, Intermediate
58 is obtained from 2,3,6-trichloroquinoxaline (300 mg, 1.3 mmol, 1
eq., commercially available from Acros) and benzenesulfonamide (202
mg, 1.3 mmol, 1 eq.) in the presence of K.sub.2CO.sub.3 (177.6 mg,
1.3 mmol, 1 eq.) in DMA (9 ml), then washing with hot ACN to afford
97.6 mg (21%) of the title compound as a beige solid. 1H NMR
(DMSO-d6) .delta. 8-30-8.10 (m, 2H), 8-7.75 (m, 2H), 7.70-7.50 (m,
4H), Rt 3.85 min. HPLC (max plot) 99%; Rt 3.86 min.
Intermediate 59: methyl
5-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}-4-methylthiophene-2-carboxyl-
ate (Formula II)
##STR00075##
[0357] Following the protocol outlined in procedure F, intermediate
59 is obtained from 2,3-dichloroquinoxaline (295 mg; 1.48 mmol; 1
eq) and methyl 5-(aminosulfonyl)-4-methylthiophene-2-carboxylate
(348.22 mg; 1.48 mmol; 1 eq) in the presence of K.sub.2CO.sub.3
(204.54 mg; 1.48 mmol; 1 eq) in DMA (4 ml), to afford 426.2 mg
(72%) of the title compound. 1H NMR (DMSO-d6) .delta. 7.90-7.58 (m,
5H), 3.84 (s, 3H), 2.51 (s, 3H). HPLC (max plot) 99%; Rt 4.05 min.
LC/MS: (ES+): 398.1, (ES-): 396.1.
Intermediate 60: methyl
5-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}-1-methyl-1H-pyrrole-2-carbox-
ylate (Formula II)
##STR00076##
[0359] Following the protocol outlined in procedure F, intermediate
60 is obtained from 2,3-dichloroquinoxaline (500 mg; 2.51 mmol;
leg) and methyl 5-(aminosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate
(548.22 mg; 2.51 mmol; leg) in the presence of K.sub.2CO.sub.3
(347.18 mg; 2.51 mmol; leg) in DMA (5 ml), to afford 545.3 mg (57%)
of the title compound. 1H NMR (DMSO-d6) .delta. 11.21 (br s, 1H),
8.08 (d, J=7.9 Hz, 1H), 8.04 (s, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.82
(t, J=7.4 Hz, 1H), 7.69 (t, J=7.4 Hz, 1H), 731 (d, J=1.9 Hz, 1H),
3.92 (s, 3H), 3.76 (s, 3H). HPLC (max plot) 99%; Rt 3.32 min.
LC/MS: (ES+): 381.2, (ES-): 379.2.
Intermediate 61: N-(3-chloroquinoxalin-2-yl)thiophene-2-sulfonamide
(Formula II)
##STR00077##
[0361] Following the protocol outlined in procedure F, intermediate
61 is obtained from 2,3-dichloroquinoxaline (650.00 mg; 3.27 mmol;
1.00 eq) and thiophene-2-sulfonamide (533.03 mg; 3.27 mmol; 1.00
eq) in the presence of K.sub.2CO.sub.3 (451.33 mg; 3.27 mmol; 1.00
eq) in DMA (7 ml), to afford 693 mg (65.13%) of the title compound.
1H NMR (DMSO-d6) .delta. 7.99-7.97 (m, 3H), 7.91-7.88 (m, 1H),
7.82-7.75 (m, 1H), 7.70-7.65 (m, 1H), 7.19-7.16 (m, 1H). HPLC (max
plot) 87.42%; Rt 3.51 min. LC/MS: (ES+): 326.1, (ES-): 324.1.
Intermediate 62:
2-chloro-N-(3-chloroquinoxalin-2-yl)-4-fluorobenzenesulfonamide
(Formula II)
##STR00078##
[0363] Following the protocol outlined in procedure F, intermediate
62 is obtained from 2,3-dichloroquinoxaline (300.00 mg; 1.5
.mu.mol; 1 eq) and 2-chloro-4-fluorobenzenesulfonamide (315.96 mg;
1.51 mmol; leg) in the presence of K.sub.2CO.sub.3 (208.31 mg; 1.51
mmol; 1 eq) in DMA (3 ml), to afford 479.8 mg (85.5%) of the title
compound as a beige solid. 1H NMR (DMSO-d6) .delta. 8.35 (dd,
J=9.0, 3.0 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.71 (d, J=4.9 Hz, 2H),
7.69-7.56 (m, 2H), 7.48 (dt, J=8.4, 2.4 Hz, 1H), (, H). HPLC (max
plot) 90.5%; Rt 3.76 min. LC/MS: (ES+): 372.2, (ES-): 370.2.
Intermediate 63:
N-(3-chloroquinoxalin-2-yl)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)me-
thyl]thiophene-2-sulfonamide (Formula II)
##STR00079##
[0365] Following the protocol outlined in procedure F, intermediate
63 is obtained from 2,3-dichloroquinoxaline (800 mg; 4.02 mmol; 1
eq) and
5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]thiophene-2-sulfonamide
(1295.68 mg; 4.02 mmol; leg) in the presence of K.sub.2CO.sub.3
(555,48 mg; 4.02 mmol; 1 eq) in DMA (8 ml), to afford 647 mg (33%)
of the title compound, 1H NMR (DMSO-d6) .delta. 7.92-7.79 (m, 7H),
7.72-7.61 (m, 2H), 7.14 (d, J=3.8 Hz, 1H), 4.98 (s, 2H). HPLC (max
plot) 88%; Rt 3.95 min. LC/MS: (ES+): 485.2, (ES-): 483.2.
Intermediate 64:
N-(3-chloroquinoxalin-2-yl)-3-cyano-4-fluorobenzenesulfonamide
(Formula II)
##STR00080##
[0367] Following the protocol outlined in procedure F, intermediate
64 is obtained from 2,3-dichloroquinoxaline (1000 mg; 5.02 mmol; 1
eq) and 3-cyano-4-fluorobenzenesulfonamide (1005.79 mg; 5.02 mmol;
1 eq) in the presence of K.sub.2CO.sub.3 (694.35 mg; 5.02 mmol; 1
eq) in DMA (40 ml), to afford 541 mg (30%) of the title compound as
a yellow solid. 1H NMR (DMSO-d6) .delta. 8.65 (dd, J=6.0, 2.2 Hz,
1H), 8.54-8.47 (m, 1H), 7.89-7.83 (m, 2H), 7.79-7.71 (m, 2H),
7.67-7.59 (m, 1H). HPLC (max plot) 97%; Rt 3.57 min. LC/MS: (ES+):
363.2, (ES-): 361.2.
Intermediate 65:
6-chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide (Formula
II)
##STR00081##
[0369] Following the protocol outlined in procedure F, intermediate
65 is obtained from 2,3-dichloroquinoxaline (200 mg; 1 mmol; 1 eq)
and 6-Chloropyridine-3-sulfonamide (193.55 mg; 1 mmol; 1 eq) in the
presence of K.sub.2CO.sub.3 (138.87 mg; 1 mmol; 1 eq) in DMA (2
ml), to afford 292 mg (82%) of the title compound as a powder. 1H
NMR (DMSO-d6) .delta. 9.09 (d, J=2.3 Hz, 1H), 8.52 (dd, J=2.6, 8.3
Hz, 1H), 7.85 (dd, J=1.1, 8.3 Hz, 2H), 7.77-7.71 (m, 2H), 7.65-7.60
(m, 1H). HPLC (max plot) 97%; Rt 3.45 min. LC/MS: (ES+): 355.2,
(ES-): 353.2.
Intermediate 66:
N-(3-chloroquinoxalin-2-yl)-6-(dimethylamino)pyridine-3-sulfonamide
(Formula II)
##STR00082##
[0371] Following the protocol outlined in procedure F, intermediate
66 is obtained from 2,3-dichloroquinoxaline (250 mg; 1.26 mmol; 1
eq) and 6-dimethylamino-pyridine-3-sulfonic acid amide (252.77 mg;
1.26 mmol; 1 eq) in the presence of K.sub.2CO.sub.3 (173.59 mg;
1.26 mmol; 1 eq) in DMA (3 ml), to afford 252 mg (55%) of the title
compound as a powder. 1H NMR (DMSO-d6) .delta. 11.26 (br s, 1H),
8.76 (d, J=2.3 Hz, 1H), 8.14 (dd, J=2.3, 9.0 Hz, 1H), 7.90-7.87 (m,
2H), 7.81-7.76 (m, 1H), 7.66 (t, J=7.5 Hz, 1H), 6.74 (d, J=9.0 Hz,
1H), 3.08 (s, 6H). HPLC (max plot) 89.63%; Rt 2.39 min. LC/MS:
(ES+): 364.3, (ES-): 362.3.
Intermediate 67:
N-(3-chloroquinoxalin-2-yl)-6-[(3-methoxypropyl)amino]pyridine-3-sulfonam-
ide (Formula II)
##STR00083##
[0373] Following the protocol outlined in procedure F, intermediate
67 is obtained from 2,3-dichloroquinoxaline (250 mg; 1.26 mmol; 1
eq) and 6-[(3-methoxypropyl)amino]pyridine-3-sulfonamide (308.11
mg; 1.26 mmol; 1 eq) in the presence of K.sub.2CO.sub.3 (173.59 mg;
1.26 mmol; 1 eq) in DMA (3 ml), to afford 388 mg (76%) of the title
compound as a powder. 1H NMR (DMSO-d6) .delta. (, H), 11.29 (br s,
1H), 8.68 (d, J=1.9 Hz, 1H), 8.04 (d, J=8.7 Hz, 1H), 7.90-7.85 (m,
2H), 7.79-7.74 (m, 1H), 7.67-7.62 (m, 2H), 6.56 (d, J=9.0 Hz, 1H),
3.35-3.27 (m, 4H), 3.19 (s, 3H), 1.76-1.67 (m, 2H). HPLC (max plot)
84.5%; Rt 2.44 min. LC/MS: (ES+): 408.3, (ES-): 406.3.
Intermediate 68:
N-(3-chloroquinoxalin-2-yl)-6-methoxypyridine-3-sulfonamide
(Formula II)
##STR00084##
[0375] Following the protocol outlined in procedure F, intermediate
68 is obtained from 2,3-dichloroquinoxaline (250.00 mg; 1.26 mmol;
1 eq) and 6-methoxypyridine-3-sulfonamide (236.39 mg; 1.26 mmol; 1
eq) in the presence of K.sub.2CO.sub.3 (173.59 mg; 1.26 mmol; 1 eq)
in DMA (3 ml), to afford 230 mg (52%) of the title compound as a
powder. 1H NMR (DMSO-d6) .delta. 8.92 (d, J=2.26 Hz, 1H), 8.43-8.39
(m, 1H), 7.91-7.86 (m, 2H), 7.80-7.75 (m, 1H), 7.69-7.64 (m, 1H),
7.02 (d, J=9.04 Hz. 1H). 3.91 (s, 3H). HPLC (max plot) 80%; Rt 3.28
min. LC/MS: (ES+): 351.1, (ES-): 349.2.
Intermediate 69:
N-(3-chloroquinoxalin-2-yl)-6-methylpyridine-3-sulfonamide (Formula
II)
##STR00085##
[0377] Following the protocol outlined in procedure F, intermediate
69 is obtained from 2,3-dichloroquinoxaline (500 mg; 2.51 mmol; 1
eq.), 6-methyl-pyridine-3-sulfonic acid pyridine (432.59 mg; 2.51
mmol; 1 eq.) in the presence of K.sub.2CO.sub.3 (347.18 mg; 2.51
mmol; 1 eq.) in DMA (5 ml), to afford 451 mg (54%) of the title
compound as a red powder. HPLC (max plot) 94%; Rt 2.72 min. LC/MS:
(ES+): 335.1, (ES-): 333.1.
Intermediate 70: methyl
5-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}pyridine-2-carboxylate
(Formula II)
##STR00086##
[0379] Following the protocol outlined in procedure F, intermediate
70 is obtained from 2,3-dichloroquinoxaline (92.06 mg; 0.46 mmol; 1
eq.) and methyl 5-(aminosulfonyl)pyridine-2-carboxylate (100 mg;
0.46 mmol; 1 eq.) in the presence of K.sub.2CO.sub.3 (63.92 mg;
0.46 mmol; 1 eq.) in DMA (1.5 ml), to afford 112 mg (65%) of the
title compound as a brown powder. 1H NMR (DMSO-d6) .delta. 9.30 (d,
J=3 Hz, 1H), 8.70 (dd, J=9 and 3 Hz, 1H), 8.25 (d, J=9 Hz, 1H),
7.76 (m, 2H), 7.60 (m, 2H), 3.90 (s, 3H). HPLC (max plot) 83%; Rt
3.22 min. LC/MS: (ES+): 379 and (ES-): 377.
Intermediate 71:
N-(3-chloroquinoxalin-2-yl)-3-(morpholin-4-ylcarbonyl)benzenesulfonamide
(Formula II)
##STR00087##
[0381] Following the protocol outlined in procedure F, intermediate
71 is obtained from 2,3-dichloroquinoxaline (800 mg; 4.02 mmol; 1
eq.) and 3-(morpholine-4-carbonyl)-benzenesulfonamide (1086.45 mg;
4.02 mmol; 1 eq.) in the presence of K.sub.2CO.sub.3 (555.48 mg;
4.02 mmol; 1 eq.) in DMA (8 ml), to afford 1267 mg (73%) of the
title compound as a yellow solid. 1H NMR (DMSO-d6) .delta.
8.22-8.18 (m, 2H), 7.89-7.83 (m, 2H), 7.78-7.73 (m, 1H), 7.70-7.63
(m, 3H), 3.63-3.27 (m, 8H). HPLC (max plot) 92%; Rt 3.13 min.
LC/MS: (ES+): 433.2, (ES-): 431.2.
Intermediate 72:
N-(3-chloroquinoxalin-2-yl)-1-methyl-1H-imidazole-4-sulfonamide
(Formula II)
##STR00088##
[0383] Following the protocol outlined in procedure F, intermediate
72 is obtained from 2,3-dichloroquinoxaline (500 mg; 2.51 mmol; 1
eq.) and 1-methyl-1H-imidazole-4-sulfonamide (404.9 mg; 2.51 mmol;
1 eq.) in the presence of K.sub.2CO.sub.3 (347.18 mg; 2.51 mmol; 1
eq.) in DMA (5 ml), to afford 3516 mg (65.5%) of the title
compound. 1H NMR (DMSO-d6) .delta. 8.15 (s, 1H), 7.87 (m, 3H), 7.74
(m, 1H), 7.61 (m, 1H), 3.73 (s, 3H). HPLC (max plot) 92%; Rt 2.41
min. LC/MS: (ES+): 324.0, (ES-): 321.9.
Intermediate 73: 1,4-Dihydropyrido[3,4-b]pyrazine-2,3-dione
(Formula VIII)
##STR00089##
[0385] To a suspension of 3,4-diaminopyridine (10 g, 0.068 mol) in
4N aqueous HCl (100 ml) is added oxalic acid (10.4 g, 0.082 mol)
and the reaction mixture is refluxed for 20 h. The reaction mixture
is cooled down and the solid precipitated is filtered, washed with
water then dried under vacuum to afford 9 g (80%) of the title
compound as a solid. HPLC (max plot) 98%. LC/MS: (ES+): 164.3.
Intermediate 74: 2,3-Dichloro-pyrido(3,4-b)pyrazine (Formula
IV)
##STR00090##
[0387] To a solution of 1,4-dihydropyrido[3,4-b]pyrazine-2,3-dione
(9 g, 0.055 mol) in POCl.sub.3 (90 ml) is added Et.sub.3N (6.7 g,
0.066 mol) and the reaction mixture is refluxed for 20 h under
N.sub.2. The reaction mixture is cooled down and carefully quenched
with ice-water (1 kg) and the product is extracted with EtOAc
(3.times.150 ml). The combined organic layer is washed with water,
dried over MgSO.sub.4 and evaporated under reduced pressure to
afford 6 g (54%) of the title compound as a solid.
TLC--Chloroform/methanol (9/1): R.sub.f=0.8, HPLC (max plot)
98%.
Intermediate 75: 1,4-Dihydropyrido[2,3-b]pyrazine-2,3-dione
(Formula VIII)
##STR00091##
[0389] To a suspension of 2,3-diaminopyridine (20 g, 0.136 mol) in
4N aqueous HCl (200 ml) is added oxalic acid (20.7 g, 0.164 mol)
and the reaction mixture is refluxed for 20 h. The reaction mixture
is cooled and the solid precipitated is filtered, washed with water
and dried under vacuum to afford 20 g (89%) of the title compound
as a solid. HPLC (max plot) 98%.
Intermediate 76: 2,3-Dichloro-pyrido(2,3-b)pyrazine (Formula
IV)
##STR00092##
[0391] To a solution of 1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
(10 g, 0.0613 mol) in POCl.sub.3 (100 ml) was added Et.sub.3N (9 g,
0.092 mol) and the reaction mixture refluxed for 18 h under
nitrogen. The reaction mixture is cooled and carefully quenched
with ice-water (1 kg) and the product was extracted with EtOAc
(3.times.150 ml). The combined organic layer is washed with water,
dried over MgSO4 and evaporated under reduced pressure to afford 8
g (65%) of the title compound as a solid. TLC--Chloroform/methanol
(9/1): R.sub.f=0.8, HPLC (max plot) 98%.
Intermediate 77:
N-(2-chloropyrido[3,4-b]pyrazin-3-yl)benzenesulfonamide (Formula
II)
##STR00093##
[0393] 2,3-dichloro-pyrido(3,4-b)pyrazine (300 mg, 1.5 mmol, 1
eq.), benzenesulfonamide (235.8 mg, 1.5 mmol, 1 eq.) and
K.sub.2CO.sub.3 (207.3 mg, 1.5 mmol, 1 eq.) are taken up in
anhydrous DMA (10 ml) under argon. The reaction mixture is stirred
at room temperature for 3 days, then water (15 ml) is added. The
aqueous phase is washed with EtOAc (4.times.10 ml) then
lyophilized. The solid residue obtained is extracted with DCM and
the solvent is evaporated to near dryness then purified by
preparative HPLC using a gradient of H2O, TFA 0.1%/ACN, TFA 0.1%,
to afford 21.7 mg (5%) of the title compound. 1H NMR (DMSO-d6)
.delta. 9.13 (s, 1H). 8.42 (d, J=6.7 Hz, 1H). 8.03-7.97 (m, 2H),
7.56 (d, J=6.8 Hz, 1H), 7.51-7.45 (m, 3H). HPLC (max plot) 95%; Rt
1.71 min. LC/MS: (ES+): 321.0, (ES-): 319.0.
Intermediate 78:
N-(3-chloropyrido[2,3-b]pyrazin-2-yl)benzenesulfonamide (Formula
II)
##STR00094##
[0395] 2,3-dichloro-pyrido(2,3-b)pyrazine (300 mg; 1.5 mmol; 1
eq.), benzenesulfonamide (235.8 mg, 1.5 mmol, 1 eq.) and
K.sub.2CO.sub.3 (207.3 mg, 1.5 mmol, 1 eq.) are taken up in
anhydrous DMA (10 ml) under argon. The reaction mixture is stirred
at room temperature for 7 days. The solvent is evaporated and the
residue obtained is purified by prep HPLC using a gradient of H2O,
TEA 0.1%/ACN, TFA 0.1%, to afford 82.1 mg (17%) of the title
compound. 1H NMR (DMSO-d6) .delta. 8.67 (dd, J=5.7, 1.5 Hz, 1H),
8.57 (dd, J=7.9, 1.5 Hz, 1H), 8.08 (dd, J=8.0 Hz, 1.8 Hz, 2H), 7.57
(dd, J=7.9, 5.7 Hz, 1H), 7.54-7.46 (m, 4H). HPLC (max plot) 94%; Rt
1.96 min. LC/MS: (ES+): 321.0, (ES-): 319.0.
Procedure G
Intermediate 79:
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-[(4-methylpiperazin-1-
-yl)carbonyl]benzenesulfonamide (Formula I)
##STR00095##
[0397]
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]b-
enzoic acid (162 mg; 0.34 mmol; 1 eq.), EDC-HCl (71.10 mg; 0.37
mmol; 1.10 eq.) and HOBT (50.11 mg; 0.37 mmol; 1.10 eq.) were taken
up in DCM (6 ml) then DIEA (84.89 .mu.l; 0.51 mmol; 1.50 eq.) and
1-methylpiperazine (37.52 .mu.l; 0.34 mmol; 1 eq.) were added. The
mixture was stirred at rt for 5 h. The solution was washed
successively with a saturated solution of NaHCO.sub.3, NH.sub.4Cl
and NaCl. The organic phase was dried over MgSO.sub.4 and
concentrated to near dryness to afford 171 mg (90%) of the title
compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 10.06 (br s,
1H), 8.80 (s, 1H), 8.13 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.3 Hz, 2H),
7.44-7.41 (m, 1H), 7.39-7.34 (m, 1H), 7.31 (br d, 2H), 7.21-7.14
(m, 2H), 6.15 (t, J=2.3 Hz, 1H), 3.76 (s, 6H), 3.65-3.35 (m, 4H),
3.10-2.85 (m, 4H), 2.63 (s, 3H). HPLC (max plot) 97.1%; Rt 3.55
min. LC/MS: (ES+): 563.4, (ES-): 561.2.
Intermediate 80:
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(morpholin-4-ylcarbon-
yl)benzenesulfonamide) (Formula I)
##STR00096##
[0399] Following the protocol outlined in Procedure G, Example 80
is obtained from
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoic
acid (160 mg; 0.33 mmol; 1 eq.), EDC-HCl (70.22 mg; 0.37 mmol; 1.10
eq.), HOBT (49.49 mg; 0.37 mmol; 1.10 eq.), DIEA (83.84 .mu.l; 0.5
mmol; 1.50 eq.) and morpholine (29.01 .mu.l; 0.33 mmol; 1 eq.) in
DCM (6 ml) to afford the title compound as a parent. Treatment of
the parent with HCl in MeOH affords 165 mg (90%) of the title
compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 12.34 (s,
1H), 8.94 (s, 1H), 8.16 (d, J=8.3 Hz, 2H), 7.90 (br s, 1H),
7.61-7.55 (m, 3H), 7.40-7.34 (m, 4H), 6.23 (t, J=2.3 Hz, 1H), 3.75
(s, 6H), 3.62-3.27 (m, 8H). HPLC (max plot) 98.4%; Rt 4.19 min.
LC/MS: (ES+): 550.2, (ES-): 548.8.
Intermediate 81:
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)
sulfonyl]-N,N-dimethylbenzamide (Formula I)
##STR00097##
[0401] Following the protocol outlined in Procedure G, Example 81
is obtained from
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoic
acid (166 mg; 0.35 mmol; 1 eq.), EDC-HCl (72.85 mg; 0.38 mmol; 1.1
eq.), HOBT (51.35 mg; 0.38 mmol; 1.1 eq.), DIEA (86.98 .mu.l; 0.52
mmol; 1.50 eq.) and dimethylamine (172.74 .mu.l; 2 M; 0.35 mmol; 1
eq.) in DCM (6 ml) to afford 155 mg (88%) of the title compound as
a parent (yellow powder). 1H NMR (DMSO-d6) .delta. 12.36 (br s,
1H), 8.94 (s, 1H), 8.15 (d, J=8.3 Hz, 2H), 7.90 (br s, 1H), 7.58
(d, J=8.3 Hz, 2H), 7.57-7.55 (m, 1H), 7.38-7.34 (m, 4H), 6.22 (t,
J=2.3 Hz, 1H), 3.75 (s, 6H), 2.97 (s, 3H), 2.86 (s, 3H). HPLC (max
plot) 98%; Rt 4.38 min. LC/MS: (ES+): 508.1, (ES-): 506.1.
Intermediate 82:
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-N,N-di-
methylbenzamide (Formula I)
##STR00098##
[0403] Following the protocol outlined in Procedure G, Example 82
is obtained from
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoic
acid (110 mg; 0.23 mmol; 1 eq.), EDC-HCl (48.28 mg; 0.25 mmol; 1.1
eq.), HOBT (34.03 mg; 0.25 mmol; 1.1 eq.), DIEA (57.64 .mu.l; 0.34
mmol; 1.5 eq.) and dimethylamine (114.46 .mu.l; 2 M; 0.23 mmol; 1
eq.) in DCM (4.5 ml) to afford 102 mg (88%) of the title compound
as a parent (yellow powder). 1H NMR (DMSO-d6) .delta. 12.34 (br s,
1H), 8.95 (s, 1H), 8.17-8.12 (m, 2H), 7.90 (br s, 1H), 7.66-7.63
(m, 2H), 7.58-7.55 (m, 1H), 7.41-7.34 (m, 4H), 6.22 (t, J=2.3 Hz,
1H), 3.75 (s, 6H), 2.97 (s, 3H), 2.87 (s, 3H). HPLC (max plot) 98%;
Rt 4.34 min. LC/MS: (ES+): 508.3, (ES-): 506.1.
Intermediate 83:
6-(chloromethyl)-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}pyridin-
e-3-sulfonamide (Formula I)
##STR00099##
[0405]
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-(hydroxymethyl)-
pyridine-3-sulfonamide (90 mg; 0.19 mmol; 1 eq.) is dissolved in
CHCl.sub.3 (10 ml) at rt. Thionyl chloride (0.05 ml; 0.39 mmol; 2
eq.) is added and reaction mixture is stirred for 1 h30. Water and
aqueous NaHCO.sub.3 are added and the product is extracted with
DCM. The organic phase is dried over magnesium sulfate and the
solvent is evaporated under reduced pressure to afford 100 mg
(108%) of the title compound as a powder. It was used as such in
the next step. HPLC (max plot) 35%; Rt 4.78 min, LC/MS: (ES+)
486.22, (ES-) 484.22.
Intermediate 84: methyl
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-4-meth-
ylthiophene-2-carboxylate (Formula I)
##STR00100##
[0407] Methyl
5-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}-4-methylthiophene-2-carboxyl-
ate (100 mg; 0.25 mmol; 1 eq) and 3,5-dimethoxyaniline (42.35 mg;
0.28 mmol; 1.1 eq) are taken up in EtOH (2 ml) and the resulting
suspension is heated up to 170.degree. C. for 6 min on high
absorption in the microwave. The precipitate formed is filtered off
and washed with EtOH then dried under vacuum at 40.degree. C. for 1
day. The solid is washed with hot EtOH then THF to afford, after
cooling at 4.degree. C., 103.6 mg (80%) of the title compound as a
powder. 1H NMR (DMSO-d6) .delta. 12.64 (brs, 1H), 8.91 (s, 1H),
7.89 (brs, 1H), 7.71 (s, 1H), 7.60 (dd, J=7.7, 1.7 Hz, 1H),
7.46-7.34 (m, 2H), 7.32 (d, J=1.9 Hz, 2H), 6.26 (t, J=1.9 Hz, 1H),
3.83 (s, 3H), 3.77 (s, 6H), 2.48 (s, 3H). HPLC (max plot) 95%; Rt
4.93 min. LC/MS: ES+ 515.2, ES- 512.9.
Procedure H
Example 1
N-[3-(3,5-Dimethoxy-phenylamino)-quinoxalin-2-yl]-3-methanesulfonyl-benzen-
esulfonamide (1) (Scheme 5)
##STR00101##
[0409] N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine (50 mg, 0.17
mmol), 3-(methylsulfonyl)benzenesulfonyl chloride (64 mg, 0.26
mmol, commercially available from Matrix) are dissolved in a 1 to 1
mixture of pyridine and 1,2-dichlorobenzene (0.4 ml) and the
reaction mixture is heated at 100.degree. C. in the microwave for
20 min. When TLC confirms the total consumption of the starting
material, the reaction mixture is cooled down to rt. The
precipitate formed is filtered and purified by column
chromatography, using CHCl3:MeOH as eluent, to afford 18 mg (21%)
of the title compound as a light brown solid. HPLC (max plot) 84%,
rt. 4.2 min. LC/MS: (ES+): 515.
Example 2
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}thiophene-3-sulfonamide
(2) (Scheme 5)
##STR00102##
[0411] Following the general protocol outlined in Procedure H,
Example 2 is obtained from
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
thiophene-3-sulfonyl chloride (commercially available from ABCR) in
a 1 to 2 mixture of pyridine:dichlorobenzene (yellow solid, 8 mg,
11%). HPLC (max plot) 94%, rt. 4.51 min. LC/MS: (ES+): 443.
Example 3
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-morpholin-4-yl
pyridine-3-sulfonamide (3) (Scheme 5)
##STR00103##
[0413] Following the general protocol outlined in Procedure H,
Example 3 is obtained from
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine (65 mg, 0.22 mmol, 1
eq.) and 6-morpholin-4-sulfonyl chloride (86.4 mg, 0.33 mmol, 1.5
eq., commercially available from ASDI) in a 1 to 2 mixture of
pyridine:dichloro-benzene to afford 12.2 mg (11%) of the title
compound as a brown solid. 1H NMR (DMSO-d6) .delta. 12.40-12.20 (br
s, 1H), 9.15 (s, 1H), 8.75-8.65 (m, 1H). 8.58-8.45 (m, 1H),
8.15-7.83 (m, 2H), 7.70-750 (m, 1H), 7.45-7.25 (m, 2H), 7.10-6.75
(m, 2H), 6.68-6.5 (m, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.70-3.54
(m, 8H). HPLC (max plot) 95%; Rt 4.36 min. LC/MS: (ES+): 523.3;
(ES-): 521.3.
Procedure I
Example 4
N-{3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]pheny-
l}acetamide (4) (Scheme 5)
##STR00104##
[0415] N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine (50 mg, 0.168
mmol), 3-Acetylamino benzene sulfonylchloride (59 mg, 0.5 mmol,
commercially available from INTERCHIM) are dissolved in a 1 to 2
mixture of pyridine: dichlorobenzene (0.3 ml) and the reaction
mixture is heated to 150.degree. C. overnight in an orbital shaker.
When TLC confirms the total consumption of the starting material,
the reaction mixture is cooled down to rt. The precipitate formed
is filtered and purified by column chromatography, using
Pet.Ether:EtOAc as eluent, to afford 20 mg (24%) of the title
compound as a yellow solid. HPLC (max plot) 89%, rt. 4.08 min.
LC/MS: (ES+): 494.
Example 5
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2-(methylsulfonyl)benzen-
esulfonamide (5) (Scheme 5)
##STR00105##
[0417] Following the general protocol outlined in Procedure I,
Example 5 is obtained from
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
2-(methylsulfonyl)benzenesulfonyl chloride (commercially available
from Acros) in a 1 to 2 mixture of pyridine:dichlorobenzene (dark
yellow solid, 10 mg, 14%). HPLC (max plot) 96%, rt. 4.48 min.
LC/MS: (ES+): 515.
Example 6
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2-(methylsulfonyl)benzen-
esulfonamide (6) (Scheme 5)
##STR00106##
[0419] Following the general protocol outlined in Procedure I,
Example 6 is obtained from
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
2-(methylsulfonyl)benzenesulfonyl chloride in pyridine (yellow
solid, 20 mg, 24%). HPLC (max plot) 89%, rt. 4.47 min. to LC/MS:
(ES+): 515.
Example 7
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2,3-dihydro-1,4-benzodio-
xine-6-sulfonamide (7) (Scheme 5)
##STR00107##
[0421] Following the general protocol outlined in Procedure I,
Example 7 is obtained from
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
2,3-dihydro-1,4-benzodioxine-6-sulfonyl chloride (commercially
available from Acros) in a 1 to 2 mixture of
pyridine:dichlorobenzene (brown solid, 30 mg, 36%). HPLC (max plot)
98%, rt. 4.71 min. LC/MS: (ES+): 495.2.
Example 8
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(pyrrolidin-1-yl
sulfonyl)benzenesulfonamide (8) (Scheme 5)
##STR00108##
[0423] Following the general protocol outlined in Procedure I,
Example 8 is obtained from
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine and 4-(pyrrolidin-1
ylsulfonyl)benzene sulfonyl chloride (commercially available from
Acros) in a 1 to 2 mixture of pyridine:dichlorobenzene (dark brown
solid, 18 mg, 19%). HPLC (max plot) 94%, rt. 4.73 min. LC/MS:
(ES+): 570.
Example 9
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}thiophene-3-sulfonamide
(9) (Scheme 5)
##STR00109##
[0425] Following the general protocol outlined in Procedure I,
Example 9 is obtained from
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
thiophene-3-sulfonyl chloride in a 1 to 2 mixture of
pyridine:dichlorobenzene (yellow solid, 15 mg, 20%). HPLC (max
plot) 98%, rt. 4.64 min. LC/MS: (ES+): 443.
Example 10
2-Cyano-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide (10) (Scheme 5)
##STR00110##
[0427] Following the general protocol outlined in Procedure 1,
Example 10 is obtained from
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
2-cyanobenzenesulfonyl chloride in a 1 to 2 mixture of
pyridine:dichlorobenzene (yellow solid, 15 mg, 19%). HPLC (max
plot) 95%, rt. 4.56 min. LC/MS: (ES+): 462.2.
Example 11
3-Cyano-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide (11) (Scheme 5)
##STR00111##
[0429] Following the general protocol outlined in Procedure I,
Example 11 is obtained from
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
3-cyanobenzenesulfonyl chloride in a 1 to 2 mixture of
pyridine:dichlorobenzene (brown solid, 20 mg, 26%). HPLC (max plot)
93%, rt. 4.65 min. LC/MS: (ES+): 462.2.
Example 12
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-methoxybenzene
sulfonamide (12) (Scheme 5)
##STR00112##
[0431] Following the general protocol outlined in Procedure 1,
Example 12 is obtained from
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
3-methoxybenzenesulfonyl chloride in a 1 to 2 mixture of
pyridine:dichlorobenzene (brown solid, 20 mg, 25%). HPLC (max plot)
88%, rt. 4.84 min. LC/MS: (ES+): 467.1.
Procedure J
Example 13
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1-methyl-1H-imidazole-4--
sulfonamide (13) (Scheme 5)
##STR00113##
[0433] N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine (50 mg, 0.17
mmol), 1-methylimidazole-4-sulfonylchloride (91.4 mg, 0.51 mmol,
commercially available from Acros) are dissolved in pyridine (0.3
ml) and the reaction mixture was stirred at rt, overnight. When TLC
confirms the total consumption of N-(2,5-dimethoxyphenyl)
quinoxaline-2,3-diamine, the product is extracted with CHCl.sub.3.
The organic layer is washed with water, 1.5N HCl and brine then
dried over Na.sub.2SO.sub.4. The solvent is removed under reduced
pressure and the residue obtained is purified by recrystallization
from MeOH to afford 47 mg (64%) of the title compound as a yellow
solid. HPLC (max plot) 95%, rt. 3.91 min. LC/MS: (ES+): 441.2.
Example 14
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2-fluorobenzene
sulfonamide (14) (Scheme 5)
##STR00114##
[0435] Following the general protocol outlined in Procedure J,
Example 14 is obtained from
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
2-fluorobenzenesulfonyl chloride in pyridine (light brown solid,
18.3 mg, 30%). HPLC (max plot) 91%, rt. 4.79 min. LC/MS: (ES+):
455.5.
Example 15
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2-fluorobenzene
sulfonamide (15) (Scheme 5)
##STR00115##
[0437] Following the general protocol outlined in Procedure J,
Example 15 is obtained from
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
2-fluorobenzenesulfonyl chloride in pyridine (light brown solid, 20
mg, 30%). HPLC (max plot) 98%, rt. 4.65 min. LC/MS: (ES+):
455.2.
Example 16
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(methylsulfonyl)benzen-
esulfonamide (16) (Scheme 5)
##STR00116##
[0439] Following the general protocol outlined in Procedure J,
Example 16 is obtained from
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
4-(methylsulfonyl)benzenesulfonyl chloride in pyridine (yellow
solid, 5 mg, 9%). HPLC (max plot) 98%, rt. 6.21 min. LC/MS: (ES+):
515.
Example 17
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(pyrrolidin-1-yl
sulfonyl)benzenesulfonamide (17) (Scheme 5)
##STR00117##
[0441] Following the general protocol outlined in Procedure J,
Example 17 is obtained from
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
4-(pyrrolidin-1-ylsulfonyl)benzene sulfonyl chloride in pyridine
(yellow solid, 32 mg, 33%). HPLC (max plot) 89%, rt. 4.6 min.
LC/MS: (ES+): 570.
Example 18
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-(methylsulfonyl)benzen-
esulfonamide (18) (Scheme 5)
##STR00118##
[0443] Following the general protocol outlined in Procedure J,
Example 18 is obtained from
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
3-(methylsulfonyl)benzenesulfonyl chloride in pyridine (dark yellow
solid, 27 mg, 31%). HPLC (max plot) 94%, rt. 4.31 min. LC/MS:
(ES+): 515.
Example 19
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2,1,3-benzo
thiadiazole-4-sulfonamide (19) (Scheme 5)
##STR00119##
[0445] Following the general protocol outlined in Procedure J,
Example 19 is obtained from
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
2,1,3-benzothiadiazole-4-sulfonyl chloride (commercially available
from ACROS) in pyridine (yellow solid, 40 mg, 48%). HPLC (max plot)
89%, rt 4.79 min. LC/MS: (ES+): 495.1.
Example 20
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1-methyl-1H-imidazole-4--
sulfonamide (20) (Scheme 5)
##STR00120##
[0447] Following the general protocol outlined in Procedure J,
Example 20 is obtained from
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
1-methyl-1H-imidazole-4-sulfonyl chloride in pyridine (yellow
solid, 53 mg, 67%). HPLC (max plot) 99%, rt. 3.81 min. LC/MS:
(ES+): 441.2.
Example 21
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-2,1,3-benzoxadiazole-4-s-
ulfonamide (21) (Scheme 5)
##STR00121##
[0449] Following the general protocol outlined in Procedure J,
Example 21 is obtained from
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
2,1,3-benzoxadiazole-4-sulfonyl chloride (commercially available
from ACROS) in pyridine (yellow solid, 20 mg, 25%). HPLC (max plot)
90%, rt. 4.57 min. LC/MS: (ES+): 479.
Example 22
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1-pyridin-2-yl
methanesulfonamide (22) (Scheme 5)
##STR00122##
[0451] Following the general protocol outlined in Procedure J,
Example 22 is obtained from
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
pyridin-2-ylmethanesulfonyl chloride triflate (commercially
available from ARRAY) in pyridine (yellow solid, 11 mg, 14%). HPLC
(max plot) 94%, rt. 3.85 min. LC/MS: (ES+): 452.
Example 23
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1-pyridin-2-yl
methanesulfonamide (23) (Scheme 5)
##STR00123##
[0453] Following the general protocol outlined in Procedure J,
Example 23 is obtained from
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
pyridin-2-ylmethanesulfonyl chloride triflate (commercially
available from ARRAY) in pyridine (yellow solid, 10 mg, 13%). HPLC
(max plot) 94%, rt. 3.75 min. LC/MS: (ES+): 452.
Example 24
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-pyridin-3-yl
methanesulfonamide (24) (Scheme 5)
##STR00124##
[0455] Following the general protocol outlined in Procedure J,
Example 24 is obtained from
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
pyridin-3-ylmethanesulfonyl chloride triflate (commercially
available from ARRAY) in pyridine (yellow solid, 30 mg, 39%). HPLC
(max plot) 97%, rt. 3.57 min. LC/MS: (ES+): 452.
Example 25
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1-pyridin-3-yl
methanesulfonamide (25) (Scheme 5)
##STR00125##
[0457] Following the general protocol outlined in Procedure J,
Example 25 is obtained from
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
pyridin-3-ylmethanesulfonyl chloride triflate (commercially
available from ARRAY) in pyridine (yellow solid, 30 mg, 20%). HPLC
(max plot) 96%, rt. 3.49 min. LC/MS: (ES+): 452.5.
Example 26
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1,2-dimethyl-1H-imidazol-
e-5-sulfonamide (26) (Scheme 5)
##STR00126##
[0459] Following the general protocol outlined in Procedure J,
Example 26 is obtained from
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
1,2-dimethyl-1H-imidazole-5-sulfonyl chloride (commercially
available from Apollo) in pyridine (yellow solid, 10 mg, 13%). HPLC
(max plot) 95%, rt. 3.77 min. LC/MS: (ES+): 455.2.
Example 27
methyl 3-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)
sulfonyl]thiophene-2-carboxylate (27) (Scheme 5)
##STR00127##
[0461] Following the general protocol outlined in Procedure J,
Example 27 is obtained from
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine and methyl
3-(chlorosulfonyl)thiophene-2-carboxylate in pyridine (yellow
solid, 20 mg, 24%). HPLC (max plot) 94%, rt. 4.72 min. LC/MS:
(ES+): 501.
Example 28
methyl 3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)
sulfonyl]thiophene-2-carboxylate (28) (Scheme 5)
##STR00128##
[0463] Following the general protocol outlined in Procedure J,
Example 28 is obtained from
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine and methyl
3-(chlorosulfonyl)thiophene-2-carboxylate in pyridine (yellow
solid, 7 mg, 8%). HPLC (max plot) 91%, rt. 4.61 min. LC/MS: (ES+):
501.5.
Example 29
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-methyl-2-oxo-2,3-dihyd-
ro-1,3-benzothiazole-6-sulfonamide (29) (Scheme 5)
##STR00129##
[0465] Following the general protocol outlined in Procedure J,
Example 29 is obtained from
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazole-6-sulfonyl chloride
(commercially available from CBI) in pyridine (yellow solid, 22 mg,
28%). HPLC (max plot) 98%, rt. 4.62 min. LC/MS: (ES+): 524.5.
Example 30
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-methyl-2-oxo-2,3-dihyd-
ro-1,3-benzothiazole-6-sulfonamide (30) (Scheme 5)
##STR00130##
[0467] Following the general protocol outlined in Procedure J,
Example 30 is obtained from
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
3-methyl-2-oxo-2,3-dihydro-1,3-benzo thiazole-6-sulfonyl chloride
in pyridine (yellow solid, 110 mg, 62%). HPLC (max plot) 92%, rt.
4.47 min. LC/MS: (ES+): 524.5.
Example 31
2-cyano-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide (31) (Scheme 5)
##STR00131##
[0469] Following the general protocol outlined in Procedure J,
Example 31 is obtained from
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
2-cyanobenzenesulfonyl chloride in pyridine (yellow solid, 10 mg,
13%). HPLC (max plot) 94%, rt. 4.5 min. LC/MS: (ES+): 462.2.
Example 32
3-cyano-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene to
sulfonamide (32) (Scheme 5)
##STR00132##
[0471] Following the general protocol outlined in Procedure J,
Example 32 is obtained from
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
3-cyanobenzenesulfonyl chloride in pyridine (yellow solid, 15 mg,
19%). 1H NMR (DMSO-d6) .delta. 12.45 (br s, 1H), 8.97 (s, 1H), 8.63
(t, J=1.5 Hz, 1H), 8.39 (dt, J=8.3, 1.5 Hz, 1H), 8.11 (dt, J=7.9,
1.5 Hz, 1H), 7.89 (br d, J=6.7 Hz, 1H), 7.81 (t, J=7.9 Hz, 1H),
7.60-7.57 (m, 1H), 7.44-7.35 (m, 2H), 7.35 (d, J=2.3 Hz, 2H), 6.24
(t, J=2.3 Hz, 1H), 3.76 (s, 6H); HPLC (max plot) 86%, rt. 4.5 min.
LC/MS: (ES+): 462.5.
Example 33
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-methoxybenzene
sulfonamide (33) (Scheme 5)
##STR00133##
[0473] Following the general protocol outlined in Procedure J,
Example 33 is obtained from
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine and
3-methoxybenzenesulfonyl chloride in pyridine (dark yellow solid,
10 mg, 13%). HPLC (max plot) 92%, rt. 4.71 min. LC/MS: (ES+):
467.1
Example 34
methyl 3-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)
sulfonyl]benzoate (34) (Scheme 5)
##STR00134##
[0475] Following the general protocol outlined in Procedure J,
Example 34 is obtained from
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine and methyl
3-(chlorosulfonyl)benzoate in pyridine (brown solid, 8 mg, 27%).
HPLC (max plot) 90%, rt. 4.79 min. LC/MS: (ES+): 495.1.
Example 35
methyl 3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)
sulfonyl]benzoate (35) (Scheme 5)
##STR00135##
[0477] Following the general protocol outlined in Procedure J,
Example 35 is obtained from
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine and methyl
3-(chlorosulfonyl)benzoate in pyridine (yellow solid, 5 mg, 17%).
HPLC (max plot) 99%, rt. 4.65 min. LC/MS: (ES+): 495.1.
Procedure K
Example 36
N-[3-(2,5-Dimethoxy-phenylamino)-quinoxalin-2-yl]-3-fluorobenzene
sulfonamide (36) (Scheme 1)
##STR00136##
[0479] N-(3-chloroquinoxalin-2-yl)-3-fluorobenzenesulfonamide (125
mg, 0.4 mmole) and 2,5-dimethoxyaniline (170.4 mg, 1.1 mmole) are
taken in 0.5 ml of EtOH and the resulting suspension is stirred at
100.degree. C. in an orbital shaker, overnight. The precipitate
obtained is filtered and washed with EtOH then ether to afford the
title compound as a dark green solid (163 mg, 97%). HPLC (max plot)
96%, rt. 4.88 min. LC/MS: (ES+): 455.2.
Example 37
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-fluorobenzene
sulfonamide (37) (Scheme 1)
##STR00137##
[0481] Following the general protocol outlined in Procedure K,
example 37 is obtained from
N-(3-chloroquinoxalin-2-yl)-3-fluorobenzenesulfonamide and
3,5-dimethoxyaniline in EtOH (yellow solid, 105 mg, 90%). HPLC (max
plot) 96%, rt. 4.71 min. LC/MS: (ES+): 455.2.
Example 38
2-chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide (38) (Scheme 1)
##STR00138##
[0483] Following the general protocol outlined in Procedure K,
Example 38 is obtained from
2-chloro-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide and
3,5-dimethoxyaniline in EtOH (yellow solid, 52 mg, 78%). HPLC (max
plot) 93%, rt. 4.82 min. LC/MS: (ES+): 471.
Example 39
4-cyano-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide (39) (Scheme 1)
##STR00139##
[0485] Following the general protocol outlined in Procedure K,
Example 39 is obtained from
4-cyano-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide and
3,5-dimethoxyaniline in EtOH (yellow solid, 22 mg, 50%). 1H NMR
(DMSO-d6) .delta. 12.44 (br s, 1H), 8.95 (s, 1H), 8.27 (d, J=8.3
Hz, 2H), 8.06 (d, J=8.3 Hz, 2H), 7.95-7.80 (m, 1H), 7.62-7.50 (m,
1H), 7.45-7.25 (m, 4H), 6.23 (s, 1H), 3.75 (s, 6H). HPLC (max plot)
87%, rt. 4.45 min. LC/MS: (ES+): 462.5.
Example 40
3-chloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide (40) (Scheme 1)
##STR00140##
[0487] Following the general protocol outlined in Procedure K,
Example 40 is obtained from
3-chloro-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide and
2,5-dimethoxyaniline in EtOH (greenish black solid, 66 mg, 83%).
HPLC (max plot) 97%, rt. 5.1 min. LC/MS: (ES+): 471.5.
Example 41
3-chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide (41) (Scheme 1)
##STR00141##
[0489] Following the general protocol outlined in Procedure K,
Example 41 is obtained from
3-chloro-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide and
3,5-dimethoxyaniline in EtOH (yellow solid, 66 mg, 83%). HPLC (max
plot) 99%, rt 4.89 min. LC/MS: (ES+): 471.5.
Example 42
2-chloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide (42)
##STR00142##
[0491] Following the general protocol outlined in Procedure K,
Example 42 is obtained from
2-chloro-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide and
3,5-dimethoxyaniline in EtOH (greenish black solid, 50 mg, 98%).
HPLC (max plot) 94%, rt. 4.94 min. LC/MS: (ES+): 471.5.
Example 43
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}propane-1-sulfonamide
(43) (Scheme 1)
##STR00143##
[0493] Following the general protocol outlined in Procedure K,
example 43 is obtained from
N-(3-chloroquinoxalin-2-yl)propane-1-sulfonamide and
2,5-dimethoxyaniline in EtOH (light green solid, 12 mg, 40%). HPLC
(max plot) 97%, rt. 4.62 min. LC/MS: (ES+): 403.5.
Example 44
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}propane-1-sulfonamide
(44) (Scheme 1)
##STR00144##
[0495] Following the general protocol outlined in Procedure K,
Example 44 is obtained from N-(3-chloroquinoxalin-2-yl)propane-1-
and 3,5-dimethoxyaniline in EtOH (yellow solid, 15 mg 43%). HPLC
(max plot) 98%, rt. 4.47 min. LC/MS: (ES+): 403.5.
Example 45
N-(3-{[5-methoxy-2-(1H-pyrrol-1-yl)phenyl]amino}quinoxalin-2-yl)
Benzenesulfonamide (45) (Scheme 1)
##STR00145##
[0497] Following the general protocol outlined in Procedure K,
Example 45 is obtained from
N-(3-chloroquinoxalin-2-yl)-benzenesulfonamide and
5-methoxy-2-(1H-pyrrol-1-yl)aniline (commercially available from
Bionet) in EtOH (yellow solid, 25 mg, 34%). HPLC (max plot) 99%,
rt. 5.11 min. LC/MS: (ES+): 472.
Example 46
N-{3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide (46) (Scheme 1)
##STR00146##
[0499] Following the general protocol outlined in Procedure K,
Example 46 is obtained from
N-(3-chloroquinoxalin-2-yl)-benzenesulfonamide and
2-chloro-5-methoxyaniline (commercially available from Pflatz
Bauer) in EtOH (light green solid, 10 mg, 10%). HPLC (max plot)
100%, rt. 5.09 min. LC/MS: (ES+): 441.2.
Example 47
N-{3-[(5-methoxy-2-methylphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide (47) (Scheme 1)
##STR00147##
[0501] Following the general protocol outlined in Procedure K,
Example 47 is obtained from
N-(3-chloroquinoxalin-2-yl)-benzenesulfonamide and
5-methoxy-2-methylaniline in EtOH (yellow solid, 35 mg, 53%). HPLC
(max plot) 99%, rt, 12.2 min, LC/MS: (ES+): 421.
Example 48
Methyl 4-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)
sulfonyl]benzoate (48) (Scheme 1)
##STR00148##
[0503] Following the general protocol outlined in Procedure K,
Example 48 is obtained from methyl
4-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}benzoate and
2,5-dimethoxyaniline in EtOH (greenish black solid, 57 mg, 60%).
HPLC (max plot) 96%, rt. 4.8 min. LC/MS: (ES+): 495.5.
Example 49
Methyl 4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)
sulfonyl]benzoate (49) (Scheme 1)
##STR00149##
[0505] Following the general protocol outlined in Procedure K,
Example 49 is obtained from methyl
4-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}benzoate and
3,5-dimethoxyaniline in EtOH (yellow solid, 8 mg, 35%). HPLC (max
plot) 89%, rt. 4.64 min. LC/MS: (ES+): 495.5.
Example 50
Methyl 4-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)
sulfonyl]butanoate (50) (Scheme 1)
##STR00150##
[0507] Following the general protocol outlined in Procedure K,
Example 50 is obtained from methyl
4-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}butanoate and
2,5-dimethoxyaniline in EtOH (greenish black solid, 10 mg, 45%).
HPLC (max plot) 98%, rt. 4.32 min. LC/MS: (ES+): 460.5.
Example 51
Methyl 4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)
sulfonyl]butanoate (51) (Scheme 1)
##STR00151##
[0509] Following the general protocol outlined in Procedure K,
Example 51 is obtained from methyl
4-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}butanoate and
3,5-dimethoxyaniline in EtOH (yellow solid, 10 mg, 23%). HPLC (max
plot) 94%, rt. 4.2 min. LC/MS: (ES+): 460.5.
Procedure L
Example 52
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamide
(52)-potassium salt (Scheme 1)
##STR00152##
[0511] N-(3-chloro-2-quinoxalinyl)benzenesulfonamide (500 mg, 1.6
mmol, 1 eq.) and 3,5-dimethoxyaniline (263.5 mg, 1.7 mmol, 1.1 eq.)
are taken up in EtOH (7 ml) and the resulting suspension is heated
up to 170.degree. C. for 6 min on high absorption in the microwave.
The precipitate formed is filtered off and washed with EtOH then
dried under vacuum at 40.degree. C. for 1 day. The solid is washed
with hot EtOH then THF to afford, after cooling at 4.degree. C.,
397 mg (58%) of the title compound as parent. The parent (397 mg,
0.9 mmol, 1 eq.) is suspended in water (8 ml) then potassium
hydroxide (0.18 ml, 0.5 M, 0.9 mmol, 1 eq.) is added and the
mixture is lyophilised to afford 453 mg (100%) of the title
compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 8.79 (s, 1H),
8.05-8.01 (m, 2H), 7.40-7.35 (m, 4H), 7.30 (br s, 2H), 7.26-7.23
(m, 1H), 7.16-7.06 (m, 2H), 6.12 (t, J=2.3 Hz, 1H), 3.77 (s, 6H).
HPLC (max plot) 97%; Rt 4.61 min. LC/MS: (ES+): 437.3, (ES-):
435.3.
Example 53
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3 methylbenzene
sulfonamide (53)-potassium salt (Scheme 1)
##STR00153##
[0513] Following the protocol outlined in Procedure L, Example 53
is obtained from
N-(3-chloroquinoxalin-2-yl)-3-methylbenzenesulfonamide (100 mg, 0.3
mmol, 1 eq.) and 2,5-dimethoxyaniline (50.5 mg, 0.33 mmol, 1.10
eq.) in EtOH (2 ml), to afford 108 mg (80%) of the title compound
as a parent. Treatment of the parent (97.4 mg, 0.2 mmol, 1 eq.)
with an aqueous solution of potassium hydroxide (432 .mu.l, 0.5 M,
0.2 mmol, 1 eq.) affords 106.5 mg (100%) of the title compound as a
yellow powder. 1H NMR (DMSO-d6) .delta. 9.25 (s, 1H), 8.80 (s, 1H),
7.89 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.43 (d, J=7.5 Hz, 1H), 7.29
(t, J=7.3 Hz, 2H), 7.24-7.10 (m, 3H), 6.94 (d, J=8.7 Hz, 1H), 6.49
(dd, J=9.1, 3.0 Hz, 1H), 3.86 (s, 3H), 3.76 (s, 3H), 2.35 (s, 3H).
HPLC (max plot) 98%; Rt 4.74 min. LC/MS: (ES+): 451.4, (ES-):
449.2.
Example 54
4-Chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
Sulfonamide (54)-potassium salt (Scheme 1)
##STR00154##
[0515] Following the protocol outlined in Procedure L, Example 54
is obtained from
4-chloro-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (200 mg,
0.56 mmol, 1 eq.) and 3,5-dimethoxyaniline (95.1 mg, 0.62 mmol, 1.1
eq.) in EtOH (3 ml), to afford 179 mg (67.3%) of the title compound
as a parent. Treatment of the parent (179 mg, 0.4 mmol, 1 eq.) with
an aqueous solution of potassium hydroxide (760.2 .mu.l, 0.5 M, 0.4
mmol, 1 eq.) affords 184 mg (95%) of the title compound as a beige
solid. 1H NMR (DMSO-d6) .delta. 8.74 (s, 1H), 8.04-8.01 (m, 2H),
7.44-7.38 (m, 3H), 7.31-7.25 (m, 3H), 7.15-7.08 (m, 2H), 6.13 (t,
J=2.3 Hz, 1H), 3.77 (s, 6H). HPLC (max plot) 98%; Rt 4.77 min.
LC/MS: (ES+): 471.3, (ES-): 469.3.
Example 55
4-fluoro-N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide (55)-potassium salt (Scheme 1)
##STR00155##
[0517] Following the protocol outlined in Procedure L, Example 55
is obtained from
N-(3-chloroquinoxalin-2-yl)-4-fluorobenzenesulfonamide (170 mg, 0.5
Mmol, 1 eq.) and m-anisidine (62 .mu.l, 0.55 mmol, 1.10 eq.) in
EtOH (3 ml), to afford 149 mg (70%) of the title compound as a
parent. Treatment of the parent (140 mg, 0.3 mmol, 1 eq.) with an
aqueous solution of potassium hydroxide (659.7 .mu.l, 0.5 M, 0.3
mmol, 1 eq.) affords 149 mg (98%) of the title compound as an
orange solid. 1H NMR (DMSO-d6) .delta. 8.77 (s, 1H), 8.11-8.06 (m,
2H), 7.84-7.83 (m, 1H), 7.46-7.39 (m, 2H), 7.29-7.04 (m, 6H), 6.55
(dd, J=1.9, 7.9 Hz, 1H), 3.79 (s, 3H). HPLC (max plot) 100%; Rt
4.51 min. LC/MS: (ES+): 425.3, (ES-): 423.3.
Example 56
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluorobenzene
Sulfonamide (56)-potassium salt (Scheme 1)
##STR00156##
[0519] Following the protocol outlined in Procedure L, Example 56
is obtained from
N-(3-chloroquinoxalin-2-yl)-4-fluorobenzenesulfonamide (170 mg, 0.5
Mmol, 1 eq.) and 3,5-dimethoxyaniline (84.8 mg, 0.55 mmol, 1.1 eq.)
in EtOH (3 ml), to afford 157 mg (69%) of the title compound as a
parent. Treatment of the parent (145 mg, 0.32 mmol, 1 eq.) with an
aqueous solution of potassium hydroxide (638.1 .mu.l, 0.5 M, 0.32
mmol, 1 eq.) affords 161 mg (100%) of the title compound as a light
brown. 1H NMR (DMSO-d6) .delta. 8.76 (s, 1H), 8.10-8.06 (m, 2H),
7.41-7.38 (m, 1H), 7.31-7.08 (m, 7H), 6.13-6.12 (m, 1H), 3.77 (s,
6H). HPLC (max plot) 97%; Rt 4.54 min. LC/MS: (ES+): 455.3, (ES-):
453.2.
Example 57
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-methoxybenzene
Sulfonamide (57)-potassium salt (Scheme 1)
##STR00157##
[0521] Following the protocol outlined in Procedure L, Example 57
is obtained from
N-(3-chloroquinoxalin-2-yl)-4-methoxybenzenesulfonamide (200 mg,
0.57 mmol, 1 eq.) and 2,5-dimethoxyaniline (96.3 mg, 0.63 mmol, 1.1
eq.) in EtOH (3 ml), to afford 173 mg (65%) of the title compound
as a parent. Treatment of the parent (173 mg, 0.37 mmol, 1 eq.)
with an aqueous solution of potassium hydroxide (0.74 ml, 0.5 M,
0.37 mmol, 1 eq.) affords 160 mg (86%) of the title compound as a
green solid. 1H NMR (DMSO-d6) .delta. 9.24 (s, 1H), 8.80 (d, 3.4
Hz, 1H), 7.98-7.95 (m, 2H), 7.44-7.39 (m, 1H), 7.29-7.26 (m, 1H),
7.17-7.02 (m, 2H), 6.94-6.89 (m, 3H), 6.47 (dd, J=3.0, 8.7 Hz, 1H),
3.87 (s, 3H), 3.75 (s, 3H), 3.74 (s, 3H). HPLC (max plot) 98%; Rt
4.82 min. LC/MS: (ES+): 467.4, (ES-): 465.3.
Example 58
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-methylbenzene
Sulfonamide (58)-potassium salt (Scheme 1)
##STR00158##
[0523] Following the protocol outlined in Procedure L, Example 58
is obtained from
N-(3-chloroquinoxalin-2-yl)-4-methylbenzenesulfonamide (100 mg, 0.3
mmol, 1 eq.) and 2,5-dimethoxyaniline (50.5 mg, 0.33 mmol, 1.1 eq.)
in EtOH (2 ml), to afford 105.6 mg (78%) of the title compound as a
parent. Treatment of the parent (75.6 mg; 0.17 mmol; 1 eq.) with an
aqueous solution of potassium hydroxide (335.6 .mu.l, 0.5 M, 0.17
mmol, 1 eq.) affords 82.4 mg (100%) of the title compound as a
yellow powder. 1H NMR (DMSO-d6) .delta. 9.26 (s, 1H), 8.80 (d,
J=3.1 Hz, 1H). 7.93 (d, J=8.3 Hz, 2H), 7.41 (dd, J=7.6, 1.9 Hz,
1H), 7.27 (dd, J=7.5, 1.9 Hz, 1H), 7.19 (d, 2H), 7.18-7.06 (m, 2H),
6.95 (d, J=9.0 Hz, 1H), 6.48 (dd, J=8.6, 3.0 Hz, 1H), 3.88 (s, 3H),
3.76 (s, 3H), 2.29 (s, 3H). HPLC (max plot) 98%; Rt 4.75 min.
LC/MS: (ES+): 451.3, (ES-): 449.3.
Example 59
4-Bromo-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
Sulfonamide (59)-potassium salt (Scheme 1)
##STR00159##
[0525] Following the protocol outlined in Procedure L, Example 59
is obtained from
4-bromo-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (200 mg, 0.5
Mmol, 1 eq.) and 2,5-dimethoxyaniline (84.5 mg, 0.55 mmol, 1.1 eq.)
in EtOH (3 ml), to afford 184 mg (71%) of the title compound as a
parent. Treatment of the parent (192 mg; 0.37 mmol; 1 eq.) with an
aqueous solution of potassium hydroxide (745.1 .mu.l, 0.5 M, 0.37
mmol, 1 eq.) affords 193 mg (94%) of the title compound as an
orange solid. 1H NMR (DMSO-d6) .delta. 9.18 (s, 1H), 8.74 (br s,
1H), 7.97-7.94 (m, 2H), 7.64-7.19 (m, 6H), 6.95 (d, J=9.1 Hz, 1H),
6.52-6.48 (m, 1H), 3.84 (s, 3H), 3.75 (s, 3H). HPLC (max plot) 97%;
Rt 5.12 min. LC/MS: (ES+): 515.3, (ES-): 513.3.
Example 60
4-chloro-N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide (60)-potassium salt (Scheme 1)
##STR00160##
[0527] Following the protocol outlined in Procedure L, Example 60
is obtained from
4-chloro-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (200 mg,
0.56 mmol, 1 eq.) and m-anisidine (69.5 .mu.l, 0.62 mmol, 1.1 eq.)
in EtOH (3 ml), to afford 186 mg (75%) of the title compound as a
parent. Treatment of the parent (186 mg; 0.42 mmol; 1 eq.) with an
aqueous solution of potassium hydroxide (843.7 .mu.l, 0.5 M, 0.42
mmol, 1 eq.) affords 200 mg (99%) of the title compound as a beige
solid. 1H NMR (DMSO-d6) .delta. 8.76 (s, 1H), 8.04-8.02 (m, 2H),
7.84 (t, J=2.3 Hz, 1H), 7.47-7.39 (m, 4H), 7.29-7.09 (m, 4H),
6.56-6.53 (m, 1H), 3.79 (s, 3H). HPLC (max plot) 98%; Rt 4.72 min.
LC/MS: (ES+): 441.1, (ES-): 439.3.
Example 61
4-Chloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
Sulfonamide (61)-potassium salt (Scheme 1)
##STR00161##
[0529] Following the protocol outlined in Procedure L, Example 61
is obtained from
4-chloro-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (200 mg,
0.56 mmol, 1 eq.) and 2,5-dimethoxy aniline (95.1 mg, 0.62 mmol,
1.10 eq.) in EtOH (3 ml), to afford 184 mg (69%) of the title
compound as a parent. Treatment of the parent (184 mg, 0.39 mmol, 1
eq.) with an aqueous solution of potassium hydroxide (781.4 .mu.l,
0.5 M, 0.39 mmol, 1 eq.) affords 183 mg (92%) of the title compound
as a green solid. 1H NMR (DMSO-d6) .delta. 9.20 (s, 1H), 8.80 (d,
J=3.0 Hz, 1H), 8.04-8.01 (m, 2H), 7.45-7.40 (m, 3H), 7.29-7.25 (m,
1H), 7.18-7.09 (m, 2H), 6.94 (d, J=8.6 Hz, 1H), 6.48 (dd, J=3.0,
8.6 Hz, 1H), 3.87 (s, 3H), 3.75 (s, 3H). HPLC (max plot) 97%; Rt
4.85 min. LC/MS: (ES+): 471.3, (ES-): 469.2.
Example 62
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluorobenzene
sulfonamide (62)-potassium salt (Scheme 1)
##STR00162##
[0531] Following the protocol outlined in Procedure L, Example 62
is obtained from N-(3-chloro
quinoxalin-2-yl)-4-fluorobenzenesulfonamide (170 mg, 0.5 Mmol, 1
eq.) and 2,5-dimethoxy aniline (84.8 mg, 0.55 mmol, 1.1 eq.) in
EtOH (3 ml), to afford 167 mg (73%) of the title compound as a
parent. Treatment of the parent (161 mg, 0.35 mmol, 1 eq.) with an
aqueous solution of potassium hydroxide (708.5 .mu.l, 0.5 M, 0.35
mmol, 1 eq.) affords 144 mg (83%) of the title compound as a beige
solid. 1H NMR (DMSO-d6) .delta. 9.22 (s, 1H), 8.79 (d, J=3.0 Hz,
1H), 8.10-8.05 (m, 2H), 7.43-7.40 (m, 1H), 7.29-7.08 (m, 5H), 6.94
(d, J=9.1 Hz, 1H), 6.48 (dd, J=3.0, 8.6 Hz, 1H), 3.87 (s, 3H), 3.75
(s, 3H). HPLC (max plot) 99.64%; Rt 4.65 min. LC/MS: (ES+): 455.3,
(ES-): 453.3.
Example 63
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide (63)-potassium salt (Scheme 1)
##STR00163##
[0533] Following the protocol outlined in procedure L, example 63
is obtained from N-(3-chloro quinoxalin-2-yl)benzenesulfonamide
(500 mg, 1.56 mmol, 1 eq.) and 2,5-dimethoxy aniline (263.5 mg,
1.72 mmol, 1.1 eq.) in EtOH (6 ml), to afford 477.6 mg (70%) of the
title compound as a parent. Treatment of the parent (372.8 mg, 0.85
mmol, 1 eq.) with an aqueous solution of potassium hydroxide (1.7
ml, 0.5 M, 0.85 mmol, 1 eq.) affords 483.8 mg (97%) of the title
compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 9.25 (s, 1H),
8.80 (d, J=3 Hz, 1H), 8.10-7.93 (m, 2H), 7.50-7.32 (m, 4H),
7.31-720 (m, 1H), 7.19-7.02 (m, 2H), 6.93 (d, J=8.7 Hz, 1H), 6.48
(dd, J=9, 3 Hz, 1H), 3.86 (s, 3H), 3.75 (s, 3H). HPLC (max plot)
99%; Rt 4.71 min. LC/MS: (ES+): 437.0, (ES-): 435.1. CHN analysis:
Calc: C, 54.58%; H, 4.19%; N, 11.51%. Exp.: C, 54.80%; H, 3.73%; N,
11.50%.
Example 64
N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}benzene sulfonamide
(64)-potassium salt (Scheme 1)
##STR00164##
[0535] Following the protocol outlined in Procedure L, Example 64
is obtained from N-(3-chloro quinoxalin-2-yl)benzenesulfonamide
(150 mg; 0.47 mmol; 1 eq.) and m-anisidine (58 .mu.l, 0.52 mmol,
1.10 eq.) in EtOH (2.5 ml), to afford 127 mg (67%) of the title
compound as a parent. Treatment of the parent (126 mg, 0.31 mmol, 1
eq.) with an aqueous solution of potassium hydroxide (620 .mu.l,
0.5 M, 0.31 mmol, 1 eq.) affords 142 mg (100%) of the title
compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 8.83 (s, 1H),
8.06-8.03 (m, 2H), 7.82 (s, 1H), 7.47-7.15 (m, 9H), 6.56 (d, J=7.9
Hz, 1H), 3.76 (s, 3H). HPLC (max plot) 99%; Rt 4.58 min. LC/MS:
(ES+): 407.2, (ES-): 405.2.
Example 65
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}pyridine-3-sulfonamide
(65)-potassium salt (Scheme 1)
##STR00165##
[0537] Following the protocol outlined in Procedure L, Example 65
is obtained from N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide
(200 mg, 0.62 mmol, 1 eq.) and 2,5-dimethoxyaniline (105.1 mg, 0.69
mmol, 1.1 eq.) in EtOH (2.50 ml), to afford 186.1 mg (68%) of the
title compound as a parent. Treatment of the parent (186 mg, 0.43
mmol, 1 eq.) with an aqueous solution of potassium hydroxide (850.3
.mu.l, 0.5 M, 0.43 mmol, 1 eq.) affords 200.9 mg (99%) of the title
compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 9.19 (s, 1H),
9.15 (d, J=1.9 Hz, 1H), 8.79 (d, J=3.1 Hz, 1H), 8.53 (dd, J=4.9,
1.9 Hz, 1H), 8.36 (dt, J=7.9, 1.9 Hz, 1H), 7.48-7.35 (m, 2H),
7.29-1.21 (m, 1H), 7.20-7.07 (m, 2H), 6.94 (d, J=9 Hz, 1H), 6.48
(dd, J=9, 3 Hz, 1H), 3.88 (s, 3H), 3.75 (s, 3H). HPLC (max plot)
98%; Rt 4.03 min. LC/MS: (ES+): 438.7, (ES-): 436.2. CHN analysis:
Calc: C, 50.54%; H, 3.64%; N, 14.03%. Found: C, 50.49%; H, 3.59%;
N, 13.94%.
Example 66
4-Cyano-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
Sulfonamide (66)-potassium salt (Scheme 1)
##STR00166##
[0539] Following the protocol outlined in Procedure L, Example 66
is obtained from
N-(3-chloroquinoxalin-2-yl)-4-cyanobenzenesulfonamide (200 mg, 0.58
mmol, 1 eq.) and 2,5-dimethoxyaniline (97.8 mg, 0.64 mmol, 1.1 eq.)
in EtOH (3 ml), to afford 196.5 mg (73%) of the title compound as a
parent. Treatment of the parent (80 mg, 0.17 mmol, 1 eq.) with an
aqueous solution of potassium hydroxide (346.7 .mu.l, 0.5 M, 0.17
mmol, 1 eq.) affords 87.8 mg (100%) of the title compound as a
yellow fluffy solid. 1H NMR (DMSO-d6) .delta. 9.18 (s, 1H), 8.78
(d, J=3 Hz, 1H), 8.17 (d, J=8.3 Hz, 2H), 7.86 (d, J=8.6 Hz, 2H),
7.45-7.35 (m, 1H), 7.28-7.18 (m, 1H), 7.17-7.06 (m, 2H), 6.95 (d,
J=8.6 Hz, 1H), 6.49 (dd, J=8.7, 3 Hz, 1H), 3.87 (s, 3H), 3.75 (s,
3H). HPLC (max plot) 98.51%; Rt 4.77 min. LC/MS: (ES+): 4.62,
(ES-): 460.3.
Example 67
N-{3-[(3,5-Dimethoxyphenyl)amino]quinoxalin-2-yl}methane
sulfonamide (67)-potassium salt (Scheme 1)
##STR00167##
[0541] Following the protocol outlined in Procedure L, Example 67
is obtained from N-(3-chloroquinoxalin-2-yl)methanesulfonamide (100
mg, 0.39 mmol, 1 eq.) and 3,5-dimethoxyaniline (65.4 mg, 0.43 mmol,
1.1 eq.) in EtOH (1.5 ml), to afford 86.8 mg (60%) of the title
compound as a parent. Treatment of the parent (86.8 mg, 0.23 mmol,
1 eq.) with an aqueous solution of potassium hydroxide (0.46 ml,
0.5 M, 0.23 mmol, 1 eq.) affords 91.5 mg (96%) of the title
compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 8.81 (s, 1H),
7.44 (dd, J=7.5, 1.5 Hz, 1H), 7.35 (dd, J=7.9, 1.5 Hz, 1H), 7.30
(d, J=1.5 Hz, 2H), 7.23-7.08 (m, 2H), 6.12 (t, J=2.3 Hz, 1H), 3.77
(s, 6H), 3.06 (s, 3H). HPLC (max plot) 96%; Rt 3.96 min. LC/MS:
(ES+): 375.2, (ES-): 373.3.
Example 68
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}methane
sulfonamide (68)-potassium salt (Scheme 1)
##STR00168##
[0543] Following the protocol outlined in Procedure L, Example 68
is obtained from N-(3-chloroquinoxalin-2-yl)methanesulfonamide (100
mg, 0.39 mmol, 1 eq.) and 2,5-dimethoxyaniline (65.4 mg, 0.43 mmol,
1.10 eq.) in EtOH (1.5 ml), to afford 87.7 mg (60%) of the title
compound as a parent. Treatment of the parent (87.7 mg, 0.23 mmol,
1 eq.) with an aqueous solution of potassium hydroxide (0.47 ml,
0.5 M, 0.23 mmol, 1 eq.) affords 92 mg (95%) of the title compound
as a yellow powder. 1H NMR (DMSO-d6) .delta. 9.26 (s, 1H), 8.84 (d,
J=2.6 Hz, 1H), 7.46 (dd, J=7.6, 1.1 Hz, 1H), 7.42-7.25 (m, 1H),
7.23-7.05 (m, 2H), 6.93 (d, J=9 Hz, 1H), 6.48 (dd, J=9, 3 Hz, 1H),
3.85 (s, 3H), 3.77 (s, 3H), 3.06 (s, 3H). HPLC (max plot) 95%; Rt
4.12 min. LC/MS: (ES+): 375.3, (ES-): 373.2.
Example 69
N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}methane sulfonamide
(69)-potassium salt (Scheme 1)
##STR00169##
[0545] Following the protocol outlined in Procedure L, Example 69
is obtained from N-(3-chloroquinoxalin-2-yl)methanesulfonamide (30
mg, 0.12 mmol, 1 eq.) and m-anisidine (14.4 .mu.l, 0.13 mmol, 1.1
eq.) in EtOH (1.0 ml), to afford 25 mg (62%) of the title compound
as a parent. Treatment of the parent (25 mg, 0.07 mmol, 1 eq.) with
an aqueous solution of potassium hydroxide (145 .mu.l, 0.5 M; 0.07
mmol, 1 eq.) affords 26.9 mg (97%) of the title compound as a
yellow powder. 1H NMR (DMSO-d6) .delta. 8.83 (s, 1H), 7.84 (t,
J=2.2 Hz, 1H), 7.50-7.39 (m, 2H), 7.34 (dd, J=7.9, 1.9 Hz, 1H),
7.27-7.06 (m, 3H), 6.55 (dd, =7.5, 1.8 Hz, 1H), 3.79 (s, 3H), 3.06
(s, 3H). HPLC (max plot) 99.54%; Rt 3.65 min. LC/MS: (ES+): 345.2,
(ES-): 343.2.
Example 70
4-Methoxy-N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide (70)-potassium salt (Scheme 1)
##STR00170##
[0547] Following the protocol outlined in Procedure L, Example 70
is obtained from
N-(3-chloroquinoxalin-2-yl)-4-methoxybenzenesulfonamide (200 mg,
0.57 mmol, 1 eq.) and m-anisidine (0.07 ml, 0.63 mmol, 1.10 eq.) in
EtOH (3.0 ml), to afford 162 mg (65%) of the title compound as a
parent. Treatment of the parent (162 mg, 0.37 mmol, 1 eq.) with an
aqueous solution of potassium hydroxide (0.74 ml, 0.5 M, 0.37 mmol,
1 eq.) affords 171 mg (97%) of the title compound as a beige solid.
1H NMR (DMSO-d6) .delta. 8.80 (s, 1H), 8.01-7.96 (m, 2H), 7.84 (t,
J=2.3 Hz, 1H), 7.45-7.38 (m, 2H), 7.29-7.06 (m, 4H), 6.91-6.87 (m,
2H), 6.54 (dd, J=1.8, 7.9 Hz, 1H), 3.79 (s, 3H), 3.73 (s, 3H). HPLC
(max plot) 99%; Rt 4.77 min. LC/MS: (ES+): 437.2, (ES-): 435.2.
Example 71
4-Bromo-N-{3-[(3-methoxyphenyl)amino]quinoxalin-2-yl}benzene
sulfonamide (71)-potassium salt (Scheme 1)
##STR00171##
[0549] Following the protocol outlined in Procedure L, Example 71
is obtained from
4-bromo-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (200 mg, 0.5
mmol, 1 eq.) and m-anisidine (61.78 .mu.l, 0.55 mmol, 1.10 eq.) in
EtOH (3.0 ml), to afford 178 mg (73%) of the title compound as a
parent. Treatment of the parent (178 mg, 0.37 mmol, 1 eq.) with an
aqueous solution of potassium hydroxide (733.47 .mu.l, 0.5 M, 0.37
mmol, 1 eq.) affords 183 mg (95%) of the title compound as a beige
solid. 1H NMR (DMSO-d6) .delta. 8.76 (s, 1H), 7.98-7.95 (m, 2H),
7.84-7.83 (m, 1H), 7.59-7.56 (m, 2H), 7.47-7.39 (m, 2H), 7.29-7.09
(m, 4H), 6.57-6.53 (m, 1H), 3.79 (s, 3H). HPLC (max plot) 98%; Rt
4.78 min. LC/MS: (ES+): 487.2, (ES-): 485.2.
Example 72
4-Bromo-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
Sulfonamide (72)-potassium salt (Scheme 1)
##STR00172##
[0551] Following the protocol outlined in Procedure L, Example 72
is obtained from
4-bromo-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (200 mg, 0.5
mmol, 1 eq.) and 3,5-dimethoxyaniline (84.53 mg, 0.55 mmol, 1.10
eq.) in EtOH (3.0 ml), to afford 176 mg (68%) of the title compound
as a parent. Treatment of the parent (176 mg, 0.34 mmol, 1 eq.)
with an aqueous solution of potassium hydroxide (683 .mu.l, 0.5 M,
0.34 mmol, 1 eq.) affords 176 mg (93%) of the title compound as a
yellow solid. 1H NMR (DMSO-d6) .delta. 8.74 (s, 1H), 7.96 (dt,
J=1.9, 8.3 Hz, 2H), 7.57 (dt, J=1.9, 8.3 Hz, 2H), 7.42-7.38 (m,
1H), 7.31-7.26 (m, 3H), 7.18-7.09 (m, 2H). 6.13-6.12 (m, 1H). 3.77
(s, 3H). HPLC (max plot) 97%; Rt 4.82 min. LC/MS: (ES+): 515.3,
(ES-): 513.2.
Example 73
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(trifluoromethyl)
Benzenesulfonamide (73)-potassium salt (Scheme 1)
##STR00173##
[0553] Following the protocol outlined in Procedure L, Example 73
is obtained from
N-(3-chloroquinoxalin-2-yl)-4-(trifluoromethyl)benzenesulfonamide
(100 mg, 0.26 mmol, 1 eq.) and 2,5-dimethoxyaniline (43.5 mg, 0.28
mmol, 1.1 eq.) in EtOH (2.0 ml), to afford 108.1 mg (83%) of the
title compound as a parent. Treatment of the parent (101.70 mg,
0.20 mmol, 1 eq.) with an aqueous solution of potassium hydroxide
(403.2 .mu.l, 0.5 M, 0.20 mmol, 1 eq.) affords 101.4 mg (99%) of
the title compound as a yellow solid. 1H NMR (DMSO-d6) .delta. 9.22
(s, 1H), 8.81 (d, J=3.0 Hz, 1H), 8.24 (d, J=8.3 Hz, 2H), 7.78 (d,
J=8.3 Hz, 2H), 7.46-7.41 (m, 1H), 7.30-7.25 (m, 1H), 7.20-7.10 (m,
2H), 6.96 (d, J=9.0 Hz, 1H), 6.50 (dd, J=9.1, 3.0 Hz. 1H), 3.88 (s,
3H), 3.76 (s, 3H). HPLC (max plot) 98%; Rt 5.21 min. LC/MS: (ES+):
505.4, (ES-): 503.4.
Example 74
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-iodobenzene
Sulfonamide (74)-potassium salt (Scheme 1)
##STR00174##
[0555] Following the protocol outlined in Procedure L, Example 74
is obtained from
N-(3-chloroquinoxalin-2-yl)-4-iodobenzenesulfonamide (100 mg, 0.22
mmol, 1 eq.) and 3,5-dimethoxyaniline (37.8 mg, 0.25 mmol, 1.1 eq.)
in EtOH (2.0 ml), to afford 95.2 mg (75%) of the title compound as
a parent. Treatment of the parent (74.2 mg, 0.13 mmol, 1 eq.) with
an aqueous solution of potassium hydroxide (263.9 .mu.l, 0.5 M,
0.13 mmol, 1 eq.) affords 78.1 mg (98%) of the title compound as a
yellow powder. 1H NMR (DMSO-d6) .delta. 8.76 (s, 1H), 7.84-7.73 (m,
4H), 7.44-7.39 (m, 1H), 7.34-7.24 (m, 3H), 7.21-7.09 (m, 2H), 6.14
(t, J=2.2 Hz, 1H), 3.78 (s, 6H). HPLC (max plot) 98%; Rt 5.09 min.
LC/MS: (ES+): 563.3, (ES-): 561.2.
Example 75
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-iodobenzene
sulfonamide (75)-potassium salt (Scheme 1)
##STR00175##
[0557] Following the protocol outlined in Procedure L, Example 75
is obtained from
N-(3-chloroquinoxalin-2-yl)-4-iodobenzenesulfonamide (100 mg, 0.22
mmol, 1 eq.) and 2,5-dimethoxyaniline (37.8 mg, 0.25 mmol, 1.1 eq.)
in EtOH (2.0 ml), to afford 100.4 mg (80%) of the title compound as
a parent. Treatment of the parent (98 mg, 0.17 mmol, 1 eq.) with an
aqueous solution of potassium hydroxide (348.5 .mu.l, 0.5 M, 0.17
mmol, 1 eq.) affords 103.5 mg (99%) of the title compound as an
orange powder. 1H NMR (DMSO-d6) .delta. 9.21 (s, 1H), 8.80 (d,
J=3.0 Hz, 1H), 7.84-7.73 (m, 4H), 7.45-7.40 (m, 1H), 7.30-7.25 (m,
1H), 7.20-7.09 (m, 2H), 6.95 (d, J=9.1 Hz, 1H), 6.49 (dd, J=8.6,
3.0 Hz, 1H), 3.88 (s, 3H), 3.76 (s, 3H). HPLC (max plot) 98%; Rt
5.20 min. LC/MS: (ES+): 563.2, (ES-): 561.3.
Example 76
4,5-Dichloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}thiophene-2--
sulfonamide (76)-potassium salt (Scheme 1)
##STR00176##
[0559] Following the protocol outlined in Procedure L, Example 76
is obtained from
4,5-dichloro-N-(3-chloroquinoxalin-2-yl)thiophene-2-sulfonamide
(100 mg, 0.25 mmol, 1 eq.) and 2,5-dimethoxyaniline (42.7 mg, 0.28
mmol, 1.1 eq.) in EtOH (2 ml), to afford 96 mg (74%) of the title
compound as a parent. Treatment of the parent (96 mg, 0.19 mmol, 1
eq.) with an aqueous solution of potassium hydroxide (375.4 .mu.l,
0.5 M, 0.19 mmol; 1 eq.) affords 108 mg (100%) of the title
compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 9.07 (s, 1H),
8.75 (s, 1H), 7.66-7.53 (m, 3H), 7.30-7.28 (m, 2H), 6.97 (d, J=8.7
Hz, 1H), 6.54-6.51 (m, 1H), 3.86 (s, 3H), 3.76 (s, 3H). HPLC (max
plot) 99%; Rt 5.34 min. LC/MS: (ES+): 511.1, (ES-): 509.3.
Example 77
4-Acetyl-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
Sulfonamide (77)-potassium salt (Scheme 1)
##STR00177##
[0561] Following the protocol outlined in Procedure L, Example 77
is obtained from
4-acetyl-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (100 mg,
0.28 mmol, 1 eq.) and 3,5-dimethoxyaniline (46.6 mg, 0.30 mmol, 1.1
eq.) in EtOH (2 ml), to afford 90 mg (68%) of the title compound as
a parent. Treatment of the parent (90 mg, 0.19 mmol, 1 eq.) with an
aqueous solution of potassium hydroxide (376.1 .mu.l, 0.5 M. 0.19
mmol, 1 eq.) affords 100 mg (100%) of the title compound as a
yellow powder. 1H NMR (DMSO-d6) .delta. 8.76 (s, 1H), 8.14 (d,
J=8.3 Hz, 2H), 7.95 (d, J=8.3 Hz, 2H), 7.41-7.38 (m, 1H), 7.31 (d,
J=2.2 Hz, 2H), 7.27-7.24 (m, 1H), 7.17-7.08 (m, 2H), 6.14-6.12 (m,
1H), 3.77 (s, 6H), 2.55 (s, 3H). HPLC (max plot) 94%; Rt 4.53 min.
LC/MS: (ES+): 479.3, (ES-): 477.3.
Example 78
4-Acetyl-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
Sulfonamide (78)-potassium salt (Scheme 1)
##STR00178##
[0563] Following the protocol outlined in Procedure L, Example 78
is obtained from
4-acetyl-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (100 mg,
0.28 mmol, 1 eq.) and 2,5-dimethoxyaniline (46.6 mg; 0.30 mmol; 1.1
eq.) in EtOH (2.0 ml), to afford 78 mg (59%) of the title compound
as a parent. Treatment of the parent (78 mg; 0.16 mmol, 1 eq.) with
an aqueous solution of potassium hydroxide (326 .mu.l, 0.5 M, 0.16
mmol, 1 eq.) affords 81 mg (96%) of the title compound as a beige
powder. 1H NMR (DMSO-d6) .delta. 9.22 (s, 1H), 8.80 (d, J=3.0 Hz,
1H), 8.13 (d, J=8.7 Hz, 2H), 7.96 (d, J=8.7 Hz, 2H), 7.43-7.39 (m,
1H), 7.27-7.24 (m, 1H). 7.17-7.08 (m, 2H), 6.95 (d, J=9.0 Hz, 1H),
6.50-6.46 (m, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 2.56 (s, 3H). HPLC
(max plot) 93%; Rt 4.62 min. LC/MS: (ES+): 479.4, (ES-): 477.3.
Example 79
Methyl 3-{4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)
sulfonyl]phenyl}propanoate (79) (Scheme 1)
##STR00179##
[0565] Following the protocol outlined in Procedure L, Example 79
is obtained from methyl
3-(4-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}phenyl)propanoate
(270 mg, 0.67 mmol, 1 eq.) and 3,5-dimethoxyaniline (112.1 mg, 0.73
mmol, 1.1 eq.) in MeOH (3.0 ml), to afford 192.8 mg (55%) of the
title compound as a parent (yellow powder). 1H NMR (DMSO-d6)
.delta. 12.21 (br s, 1H), 8.91 (s, 1H), 8.02 (d, J=7.9 Hz, 2H),
7.95-7.8 (m, 1H), 7.65-7.20 (m, 7H), 6.23 (t, J=2.2 Hz, 1H), 3.75
(s, 6H), 3.54 (s, 3H), 2.91 (t, J=7.5 Hz, 2H), 2.66 (t, 2H). HPLC
(max plot) 96%; Rt 4.56 min. LC/MS: (ES+): 523.4; (ES-): 521.4.
Example 80
5-Chloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1,3-dimethyl-1H-
-pyrazole-4-sulfonamide (80)-potassium salt (Scheme 1)
##STR00180##
[0567] Following the protocol outlined in Procedure L, Example 80
is obtained from
5-chloro-N-(3-chloroquinoxalin-2-yl)-1,3-dimethyl-1H-pyrazole-4-sulfonami-
de (100 mg, 0.27 mmol, 1 eq) and 2,5-dimethoxyaniline (45.3 mg,
0.30 mmol, 1.1 eq.) in EtOH (1.5 ml), to afford 88.1 mg (67%) of
the title compound as a parent. Treatment of the parent (88.1 mg,
0.18 mmol, 1 eq.) with an aqueous solution of potassium hydroxide
(0.36 ml, 0.5M, 0.18 mmol, 1 eq.) affords 92 mg (97%) of the title
compound as a greenish powder. 1H NMR (DMSO-d6) .delta. 9.22 (s,
1H), 8.78 (d, J=3 Hz, 1H), 7.41 (dd, J=7.1, 2.9 Hz, 1H), 7.23 (dd,
J=7.6, 2.2 Hz, 1H), 7.17-7.05 (m, 2H), 6.93 (d, J=9 Hz, 1H), 6.48
(dd, J=8.6, 3 Hz, 1H), 3.86 (s, 3H), 3.75 (s, 3H), 3.64 (s, 3H),
2.44 (s, 3H). HPLC (max plot) 98%; Rt 4.43 min. LC/MS: (ES+) 489.4;
(ES-): 487.5.
Example 81
5-Chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-1,3-dimethyl-1H-
-pyrazole-4-sulfonamide (81)-potassium salt (Scheme 1)
##STR00181##
[0569] Following the protocol outlined in Procedure L, Example 81
is obtained from
5-chloro-N-(3-chloroquinoxalin-2-yl)-1,3-dimethyl-1H-pyrazole-4-sulfonami-
de (100 mg, 0.27 mmol, 1 eq.) and 3,5-dimethoxyaniline (45.3 mg,
0.30 mmol, 1.1 eq.) in EtOH (1.5 ml), to afford 93.1 mg (71%) of
the title compound as a parent. Treatment of the parent (93.1 mg,
0.19 mmol, 1 eq.) with an aqueous solution of potassium hydroxide
(380.8 .mu.l, 0.5M, 0.19 mmol, 1 eq.) affords 100 mg (99%) of the
title compound as a yellow solid. 1H NMR (DMSO-d6) .delta. 8.77 (s,
1H), 7.39 (dd, J=7.2, 2.0 Hz, 1H), 7.29 (d, J=2.3 Hz, 2H), 7.23 (d,
J=7.9, 2.7 Hz, 1H), 7.15-7.05 (m, 2H), 6.13 (t, J=2.2 Hz, 1H), 3.77
(s, 6H), 3.64 (s, 3H), 2.45 (s, 3H). HPLC (max plot) 94%; Rt 4.30
min. LC/MS: (ES+): 489.3; (ES-): 487.3.
Example 82
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-methylbenzene
Sulfonamide (82)-potassium salt (Scheme 1)
##STR00182##
[0571] Following the protocol outlined in Procedure L, Example 82
is obtained from
N-(3-chloroquinoxalin-2-yl)-4-methylbenzenesulfonamide (100 mg,
0.30 mmol, 1 eq.) and 3,5-dimethoxyaniline (50.5 mg, 0.33 mmol, 1.1
eq.) in EtOH (2.0 ml), to afford 113.9 mg (84%) or the title
compound as a parent, Treatment of the parent (84.5 mg, 0.19 mmol,
1 eq.) with an aqueous solution of potassium hydroxide (375.1
.mu.l, 0.5M, 0.19 mmol, 1 eq.) affords 85.3 mg (100%) of the title
compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 8.80 (s, 1H),
7.93 (d, J=8.3 Hz, 2H), 7.39 (dd, J=7.8, 1.7 Hz, 1H), 7.30 (d,
J=1.8 Hz, 2H), 7.26 (dd, J=7.7, 1.7 Hz, 1H), 7.20-7.13 (m, 4H),
6.13 (t, J=2.3 Hz, 1H), 3.78 (s, 6H), 2.28 (s, 3H). HPLC (max plot)
97%; Rt 4.64 min. LC/MS: (ES+): 451.4, (ES-): 449.3.
Example 83
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-methylbenzene
Sulfonamide (83)-potassium salt (Scheme 1)
##STR00183##
[0573] Following the protocol outlined in Procedure L, Example 83
is obtained from
N-(3-chloroquinoxalin-2-yl)-3-methylbenzenesulfonamide (100 mg,
0.30 mmol, 1 eq.) and 3,5-dimethoxyaniline (50.5 mg, 0.33 mmol, 1.1
eq.) in EtOH (2.0 ml), to afford 102.1 mg (76%) of the title
compound as a parent. Treatment of the parent (91.4 mg, 0.20 mmol,
1 eq.) with an aqueous solution of potassium hydroxide (405.7
.mu.l; 0.5M; 0.20 mmol; 1 eq) affords 100.3 mg (100%) of the title
compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 8.80 (s, 1H),
7.91 (s, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.40 (dd, J=7.6, 1.5 Hz, 1H),
7.30 (d, J=12 Hz, 2H), 7.26 (t, J=7.7 Hz, 2H), 7.20-7.06 (m, 3H),
6.13 (t, J=2.2 Hz, 1H), 3.78 (s, 6H), 2.34 (s, 3H). HPLC (max plot)
99%; Rt 4.63 min. LC/MS: (ES+): 451.4, (ES-): 449.4.
Example 84
5-Bromo-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}thiophene-2-sulfo-
namide (84)-potassium salt (Scheme 1)
##STR00184##
[0575] Following the protocol outlined in procedure L, example 84
is obtained from
5-bromo-N-(3-chloroquinoxalin-2-yl)thiophene-2-sulfonamide (230 mg,
0.57 mmol, 1 eq.) and 3,5-dimethoxy aniline (95.8 mg, 0.63 mmol,
1.1 eq.) in EtOH (4.0 ml), to afford 238 mg (80%) of the title
compound as a parent. Treatment of the parent (35 mg, 0.07 mmol, 1
eq.) with an aqueous solution of potassium hydroxide (134.2 .mu.l,
0.5M, 0.07 mmol, 1 eq.) affords 36 (96%) of the title compound as a
yellow powder. 1H NMR (DMSO-d6) .delta. 8.65 (s, 1H), 7.51-7.46 (m,
3H), 7.32-7.17 (m, 4H), 7.10-7.09 (m, 1H), 6.14-6.13 (m, 1H), 3.76
(s, 6H). HPLC (max plot) 95%; Rt 5.09 min. LC/MS: (ES+): 523.2,
(ES-): 521.1.
Example 85
N-{3-[(3,5-dimethoxyphenyl)amino]pyrido[2,3-b]pyrazin-2-yl}benzene
Sulfonamide (85)-potassium salt (Scheme 1)
##STR00185##
[0577] Following the protocol outlined in Procedure L, Example 85
is obtained from
N-(3-chloropyrido[2,3-b]pyrazin-2-yl)benzenesulfonamide (100 mg,
0.31 mmol, 1 eq.) and 3,5-dimethoxyaniline (52.5 mg, 0.34 mmol, 1.1
eq.) in EtOH (2 ml), to afford 74 mg (54%) of the title compound as
a yellow solid. Treatment of the parent (63.1 mg, 0.14 mmol, 1 eq.)
with an aqueous solution of potassium hydroxide (288.5 .mu.l, 0.5M,
0.14 mmol, 1 eq.) affords 67.3 mg (98%) of the title compound as a
yellow powder. 1H NMR (DMSO-d6) .delta. 8.98 (s, 8.33 (m, 1H),
8.12-8.05 (m, 2H), 7.94 (d, J=7.9 Hz, 1H), 7.45-7.40 (m, 3H), 7.32
(d, J=1.9 Hz, 2H), 7.23 (dd, J=7.9, 4.9 Hz, 1H), 6.20 (m, 1H), 3.78
(s, 6H). HPLC (max plot) 100%; Rt 3.54 min. LC/MS: (ES+): 438.4,
(ES-): 436.3.
Example 86
N-{3-[(2,5-dimethoxyphenyl)amino]pyrido[2,3-b]pyrazin-2-yl}benzene
sulfonamide (86) (Scheme 1)
##STR00186##
[0579] Following the protocol outlined in Procedure L, Example 86
is obtained from
N-(2-chloropyrido[2,3-b]pyrazin-2-yl)benzenesulfonamide (73.6 mg,
0.23 mmol, 1 eq.) and 2,5-dimethoxyaniline (38.7 mg, 0.25 mmol; 1.1
eq.) in EtOH (1 ml), to afford 53.5 mg (53%) of the title compound
as parent (yellow solid). 1H NMR (DMSO-d6) .delta. 14.89 (brs, 1H),
9.46 (singulet, 1H), 8.58 (d, J=3.0 Hz, 1H), 8.34 (dd, J=7.9, 1.1
Hz, 1H), 8.29 (d, J=6.0 Hz, 1H), 8.10 (dd, J=7.3, 2.1 Hz, 2H),
7.55-7.49 (m, 3H), 7.46 (dd, J=6.1, 7.9 Hz, 1H), 7.01 (d, J=9.0 Hz,
1H), 6.63 (dd, J=9.1, 3.0 Hz, 1H), 3.84 (s, 3H), 3.77 (s, 3H). HPLC
(max plot) 97%; Rt 3.73 min. LC/MS: (ES+): 438.3, (ES-): 436.1.
Example 87
N-{2-[(2,5-dimethoxyphenyl)amino]pyrido[3,4-b]pyrazin-3-yl}benzene
Sulfonamide (87) (Scheme 1)
##STR00187##
[0581] Following the protocol outlined in Procedure L, Example 87
is obtained from
N-(2-chloropyrido[3,4-b]pyrazin-3-yl)benzenesulfonamide (17.3 mg,
0.05 mmol, 1 eq.) and 2,5-dimethoxyaniline (9.1 mg, 0.06 mmol, 1.1
eq.) in EtOH (0.3 ml), to afford 12.5 mg (53%) of the title
compound as parent (yellow solid). 1H NMR (DMSO-d6) .delta. 14.43
(br s, 1H), 9.47 (s, 1H), 8.91 (s, 1H), 8.55 (d, J=2.7 Hz, 1H),
8.27 (d, J=6.4 Hz, 1H), 8.06-8.01 (m, 2H), 7.54-7.48 (m, 4H), 7.02
(d, J=9.0 Hz, 1H), 6.63 (dd, J=9.0, 2.8 Hz, 1H), 3.86 (s, 3H), 3.77
(s, 3H). HPLC (max plot) 85%; Rt 3.17 min. LC/MS: (ES+): 438.3,
(ES-): 436.2.
Example 88
N-{7-chloro-3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzene
Sulfonamide (88)-potassium salt (Scheme 1)
##STR00188##
[0583] Following the protocol outlined in Procedure L, Example 88
is obtained from N-(3,7-dichloroquinoxalin-2-yl)benzenesulfonamide
(50 mg, 0.14 mmol, 1 eq.) and 3,5-dimethoxyaniline (23.8 mg, 0.16
mmol, 1.1 eq.) in EtOH (0.75 ml), to afford 38.6 mg (58%) of the
title compound as a parent. Treatment of the parent (38.6 mg, 0.08
mmol, 1 eq.) with an aqueous solution of potassium hydroxide (163.9
.mu.l; 0.50M; 0.08 mmol; 1 eq) affords 38.6 mg (93%) of the title
compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 8.85 (s, 1H),
8.10-7.95 (m, 2H), 7.50-6.95 (m, 8H), 6.18-6.10 (m, 1H), 3.76 (s,
6H). HPLC (max plot) 98%; Rt 4.69 min. LC/MS: (ES+): 471.4, (ES-):
469.2.
Example 89
methyl
5-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]--
4-methylthiophene-2-carboxylate (89)-potassium salt (Scheme 1)
##STR00189##
[0585] Following the protocol outlined in Procedure L, Example 89
is obtained from methyl
5-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}-4-methylthiophene-2-carboxyl-
ate (100 mg; 0.25 mmol; 1 eq) and 2,5-dimethoxyaniline (42.35 mg;
0.28 mmol; 1.1 eq) in EtOH (2 ml) to afford 105.1 mg (81%) of the
title compound as a parent. Treatment of the parent (30.80 mg; 0.06
mmol; 1 eq) with an aqueous solution of potassium hydroxide (118.43
.mu.l, 0.50 M; 0.06 mmol; 1 eq) affords 33.6 mg (100%) of the title
compound as a yellow greenish powder. 1H NMR (DMSO-d6) .delta. 9.18
(s, 1H), 8.80 (s, 1H), 7.52-7.44 (m, 2H), 7.25-7.15 (m. 3H), 6.97
(d, J=9.0 Hz, 1H), 6.51 (dd, J=9.0, 2.3 Hz, 1H), 3.89 (s, 3H), 3.81
(s, 3H), 3.77 (s, 3H), 2.41 (s, 3H). HPLC (max plot) 91%; Rt 5.06
min. LC/MS: ES+ 515.3, ES- 513.3.
Example 90
methyl
5-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]--
1-methyl-1H-pyrrole-2-carboxylate (90) (Scheme 1)
##STR00190##
[0587] Following the protocol outlined in Procedure L, Example 90
is obtained from methyl
5-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}-1-methyl-1H-pyrrole-2-carbox-
ylate (200 mg; 0.53 mmol; 1 eq) and 2,5-dimethoxyaniline (88.49 mg,
0.58 mmol; 1.1 eq) in MeOH (4 ml) to afford 188.8 mg (72%) of the
title compound as a green powder. 1H NMR (DMSO-d6) .delta. 12.26
(br s, 1H), 9.19 (s, 1H), 8.57 (d, J=3.0 Hz, 1H), 7.96 (br d, J=6.7
Hz, 1H), 7.88 (d, J=1.9 Hz, 1H), 7.65-7.59 (m, 1H), 7.43-7.32 (m,
2H), 7.29 (d, J=2.3 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.61 (dd,
J=8.7, 3.0 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.77 (s, 6H). HPLC
(max plot) 99%; Rt 4.44 min. LC/MS: (ES+): 498.6, (ES-): 496.4.
Example 91
methyl
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]--
1-methyl-1H-pyrrole-2-carboxylate (91) (Scheme 1)
##STR00191##
[0589] Following the protocol outlined in Procedure L, Example 91
is obtained from methyl
5-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}-1-methyl-1H-pyrrole-2-carbox-
ylate (200 mg; 0.53 mmol; 1 eq) and 3,5-dimethoxyaniline (88.49 mg;
0.58 mmol; 1.1 eq) in MeOH (4 ml) to afford 181 mg (69%) of the
title compound as yellow powder. 1H NMR (DMSO-d6) .delta. 12.02 (br
s, 1H), 8.89 (s, 1H), 7.92 (br s, 2H), 7.59-7.54 (m, 1H), 7.40-7.33
(br m, 5H), 6.24 (t, J=2.2 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 6H),
3.75 (s, 3H). HPLC (max plot) 96%; Rt 4.35 min. LC/MS: (ES+):
498.4, (ES-): 496.4.
Example 92
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}thiophene-2-sulfonamide
(92)-potassium salt (Scheme 1)
##STR00192##
[0591] Following the protocol outlined in Procedure L, Example 92
is obtained from N-(3-chloroquinoxalin-2-yl)thiophene-2-sulfonamide
(200 mg; 0.61 mmol; 1 eq) and 2,5-dimethoxyaniline (94.03 mg; 0.61
mmol; 1 eq) in EtOH (3 ml) to afford 150 mg (55%) of the title
compound as a parent (yellow powder). Treatment of the parent (150
mg; 0.34 mmol; 1 eq) with an aqueous solution of potassium
hydroxide (677.94 .mu.l; 0.5 M; 0.34 mmol; 1 eq) affords 163 mg
(100%) of the title compound as a yellow powder. 1H NMR (DMSO-d6)
.delta. 9.16 (s, 1H), 8.81 (d, J=3.0 Hz, 1H), 7.70-7.68 (m, 1H),
7.57-7.55 (m, 1H), 7.48-7.43 (m, 2H), 7.24-7.14 (m, 2H), 6.98-6.92
(m, 1H), 6.94 (d, J=9.0 Hz, 1H), 6.48 (dd, J=3.0, 9.0 Hz, 1H), 3.87
(s, 3H), 3.76 (s, 3H). HPLC (max plot) 99%; Rt 4.49 min. LC/MS:
(ES+): 443.4, (ES-): 441.3.
Example 93
2-chloro-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluorobenzene-
sulfonamide (93)-potassium salt (Scheme 1)
##STR00193##
[0593] Following the protocol outlined in Procedure L, Example 93
is obtained from
2-chloro-N-(3-chloroquinoxalin-2-yl)-4-fluorobenzenesulfonamide
(150 mg; 0.4 mmol; 1 eq) and 2,5-dimethoxyaniline (67.91 mg; 0.44
mmol; 1.1 eq) in EtOH (3 ml) to afford 146.8 mg (74%) of the title
compound as a parent (yellow powder). Treatment of the parent
(137.5 mg; 0.28 mmol; 1 eq) with an aqueous solution of potassium
hydroxide (562.46 .mu.l; 0.50 M; 0.28 mmol; 1 eq) affords 157.8 mg
(100%) of the title compound as a yellow powder. 1H NMR (DMSO-d6)
.delta. 9.26 (s, 1H), 8.78 (d, J=3.0 Hz, 1H), 8.26 (dd, J=8.3, 6.4
Hz, 1H), 7.44-7.39 (m, 1H), 7.34-7.26 (m, 2H), 7.13-7.02 (m, 3H),
6.96 (d, J=9.1 Hz, 1H), 6.49 (dd, J=8.9, 3.2 Hz, 1H), 3.86 (s, 3H),
3.77 (s, 3H). HPLC (max plot) 99.5%; Rt 4.76 min. LC/MS: (ES+):
489.4, (ES-): 487.4.
Example 94
2-chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluorobenzene-
sulfonamide (94)-potassium salt (Scheme 1)
##STR00194##
[0595] Following the protocol outlined in Procedure L, Example 94
is obtained from
2-chloro-N-(3-chloroquinoxalin-2-yl)-4-fluorobenzenesulfonamide
(150 mg; 0.4 mmol; 1 eq) and 3,5-dimethoxyaniline (67.91 mg; 0.44
mmol; 1.1 eq) in EtOH (3 ml) to afford 145 mg (74%) of the title
compound as a parent (yellow powder). Treatment of the parent (133
mg; 0.27 mmol; 1 eq) with an aqueous solution of potassium
hydroxide (544.05 .mu.l; 0.50 M; 0.27 mmol; 1 eq) affords 154.9 mg
(100%) of the title compound as a yellow powder. 1H NMR (DMSO-d6)
.delta. 8.80 (s, 1H), 8.28 (dd, J=9.4, 6.4 Hz, 1H), 7.43-7.37 (m,
1H), 7.33-7.26 (m, 4H), 7.13-7.08 (m, 2H), 7.05-7 (m, 1H), 6.15 (t,
J=2.3 Hz, 1H), 3.78 (s, 6H). HPLC (max plot) 97%; Rt 4.67 min,
LC/MS: (ES+): 489.3, (ES-): 487.4.
Example 95
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}pyridine-3-sulfonamide
(95)-potassium salt (Scheme 1)
##STR00195##
[0597] Following the protocol outlined in Procedure L, Example 95
is obtained from N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide
(150 mg; 0.47 mmol; 1 eq) and 3,5-dimethoxyaniline (78.80 mg; 0.51
mmol; 1.1 eq) in EtOH (2 ml) to afford 112 mg (55%) of the title
compound as a parent (yellow powder). Treatment of the parent (112
mg; 0.26 mmol; 1 eq) with an aqueous solution of potassium
hydroxide (512.02 .mu.l; 0.50 M; 0.26 mmol; 1 eq) affords 120 mg
(98.5%) of the title compound as a yellow powder. 1H NMR (DMSO-d6)
.delta. 9.13 (d, J=1.5 Hz, 1H), 8.73 (s, 1H), 8.52 (dd, J=1.9, 4.9
Hz, 1H), 8.37 (dt, J=1.9, 7.9 Hz, 1H), 7.44-7.38 (m, 2H), 7.31 (d,
J=2.3 Hz, 2H), 7.28-7.24 (m, 1H), 7.18-7.09 (m, 2H), 6.13 (t, J=2.3
Hz, 1H), 3.77 (s, 6H). HPLC (max plot) 99%; Rt 3.94 min. LC/MS:
(ES+): 438.4, (ES-): 436.4.
Example 96
3-cyano-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluorobenzenes-
ulfonamide (96)-potassium salt (Scheme 1)
##STR00196##
[0599] Following the protocol outlined in Procedure L, Example 96
is obtained from
N-(3-chloroquinoxalin-2-yl)-3-cyano-4-fluorobenzenesulfonamide (541
mg; 1.49 mmol; 1 eq) and 3,5-dimethoxyaniline (251.28 mg; 1.64
mmol; 1.10 eq) in EtOH (8 ml) to afford 425 mg (59.44%) of the
title compound as a parent (yellow powder). Treatment of the parent
(100 mg; 0.21 mmol; 1 eq) with an aqueous solution of potassium
hydroxide (417.11 .mu.l; 0.50 M; 0.21 mmol; 1 eq) affords 99 mg
(91.71%) of the title compound as a yellow powder. 1 .mu.l NMR
(DMSO-d6) .delta. 8.71 (br s, 1H), 8.57 (br d, 1H), 8.40-8.35 (m,
1H), 7.57-7.51 (m, 1H), 7.44-7.42 (m, 1H), 7.35-7.30 (br s, 1H),
7.31 (d, J=1.9 Hz, 2H), 7.23-7.16 (m, 2H), 6.14 (br d, 1H), 3.76
(s, 6H). HPLC (max plot) 95%; Rt 4.48 min. LC/MS: (ES+): 480.4,
(ES-): 478.4.
Example 97
3-cyano-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluorobenzenes-
ulfonamide (97)-potassium salt (Scheme 1)
##STR00197##
[0601] Following the protocol outlined in Procedure L, Example 97
is obtained from
N-(3-chloroquinoxalin-2-yl)-3-cyano-4-fluorobenzenesulfonamide
(84.1 mg; 0.23 mmol; 1 eq) and 2,5-dimethoxyaniline (39.06 mg; 0.26
mmol; 1.1 eq) in EtOH (2 ml) to afford 88.5 mg (80%) of the title
compound as a parent (green powder). Treatment of the parent (80
mg; 0.17 mmol; 1 eq) with an aqueous solution of potassium
hydroxide (333.7 .mu.l; 0.5 M; 0.17 mmol; 1 eq) affords 87.4 mg
(100%) of the title compound as a green powder. 1H NMR (DMSO-d6)
.delta. 9.16 (s, 1H), 8.79 (d, J=3.0 Hz, 1H). 8.56 (dd, J=6.5, 2.3
Hz, 1H), 8.43-8.35 (m, 1H), 7.54 (t, J=9.0 Hz, 1H), 7.45 (dd,
J=7.4, 1.7 Hz, 1H), 7.31 (dd, J=7.8, 1.7 Hz, 1H), 7.24-7.12 (m,
2H), 6.96 (d, J=8.7 Hz, 1H), 6.50 (dd, J=8.7, 3.0 Hz, 1H), 3.89 (s,
3H), 3.76 (s, 3H). HPLC (max plot) 99%; Rt 4.59 min. LC/MS: (ES+):
480.4, (ES-): 478.5.
Example 98
6-chloro-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}pyridine-3-sulfo-
namide (98)-potassium salt (Scheme 1)
##STR00198##
[0603] Following the protocol outlined in Procedure L, Example 98
is obtained from
6-chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide (237 mg;
0.67 mmol; 1 eq) and 3,5-dimethoxyaniline (107.32 mg; 0.70 mmol;
1.05 eq) in EtOH (6 ml) to afford 59 mg (19%) of the title compound
as a parent (yellow powder). Treatment of the parent (58 mg; 0.12
mmol; 1 eq) with an aqueous solution of potassium hydroxide (245.8
.mu.l; 0.5 M; 0.12 mmol; 1 eq) affords 63 mg (100%) of the title
compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 8.97 (d,
J=2.3 Hz, 1H), 8.69 (s, 1H), 8.41 (dd, J=8.3, 2.3 Hz, 1H), 7.54 (d,
J=8.6 Hz, 1H), 7.44-7.41 (m, 1H), 7.31 (d, J=2.3 Hz, 2H), 7.31-7.28
(br s, 1H), 7.21-7.13 (m, 2H), 6.14-6.13 (m, 1H), 3.77 (s, 6H).
HPLC (max plot) 95%; Rt 4.49 min. LC/MS: (ES+): 472.4, (ES-):
470.4.
Example 99
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-(dimethylamino)pyridin-
e-3-sulfonamide (99)-potassium salt (Scheme 1)
##STR00199##
[0605] Following the protocol outlined in Procedure L, Example 99
is obtained from
N-(3-chloroquinoxalin-2-yl)-6-(dimethylamino)pyridine-3-sulfonamide
(150 mg; 0.41 mmol; 1 eq) and 3,5-dimethoxyaniline (69.47 mg; 0.45
mmol; 1.1 eq) in EtOH (2 ml) to afford 144 mg (73%) of the title
compound as a parent (yellow powder). Treatment of the parent (144
mg; 0.3 mmol; 1 eq) with an aqueous solution of potassium hydroxide
(599.32 .mu.l; 0.5 M; 0.3 mmol; 1 eq) affords 142.6 mg (92%) of the
title compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 8.78
(s, 1H), 8.66 (s, 1H), 8.10 (dd, J=9.0, 2.6 Hz, 1H), 7.41-7.30 (m,
4H), 7.07-6.93 (m, 2H), 6.56 (br d, 1H), 6.13 (s, 1H), 3.77 (s,
6H), 3.01 (s, 6H). HPLC (max plot) 98%; Rt 3.54 min. LC/MS: (ES+):
481.5, (ES-): 479.4.
Example 100
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-[(3-methoxypropyl)amin-
o]pyridine-3-sulfonamide (100)-HCl salt (Scheme 1)
##STR00200##
[0607] Following the protocol outlined in Procedure L, Example 100
is obtained from
N-(3-chloroquinoxalin-2-yl)-6-[(3-methoxypropyl)amino]pyridine-3-sulfonam-
ide (100 mg; 0.25 mmol; 1 eq) and 3,5-dimethoxyaniline (41.31 mg;
0.27 mmol; 1.1 eq) in EtOH (1.5 ml) to afford 79.5 mg (62%) of the
title compound as a parent (yellow powder). Treatment of the parent
(79.5 mg; 0.15 mmol; 1 eq) in solution in DCM (3 ml) with
hydrochloric acid in MeOH (1 ml; 1.25 M; 1.25 mmol; 8.25 eq)
affords 79.6 mg (94%) of the title compound as a yellow powder. 1H
NMR (DMSO-d6) .delta. 12.03 (br s, 1H), 8.93 (s, 1H), 8.62 (d,
J=1.9 Hz, 1H), 8.10-7.76 (m, 3H), 7.63-7.50 (m, 1H), 7.47-7.25 (m,
4H), 6.67 (d, J=9.4 Hz, 1H), 6.23 (t, J=1.9 Hz, 1H), 3.75 (s, 6H),
3.40-2.27 (m, 4H), 3.20 (s, 3H), 1.82-1.68 (m, 2H). HPLC (max plot)
98%; Rt 3.48 min. LC/MS: ES+ 525.6, ES- 523.6, 1.73 min,
98.37%.
Example 101
N-{3-[(5-methoxy-2-methylphenyl)amino]quinoxalin-2-yl}pyridine-3-sulfonami-
de (101) (Scheme 1)
##STR00201##
[0609] Following the protocol outlined in Procedure L, Example 101
is obtained from N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide
(150 mg; 0.47 mmol; 1 eq) and 5-methoxy-2-methylaniline (70.57 mg;
0.51 mmol; 1.1 eq) in EtOH (2 ml) to afford 87 mg (44%) of the
title compound as a parent (yellow powder), 1H NMR (DMSO-d6)
.delta. 12.65 (br s, 1H), 9.23 (d, J=2.3 Hz, 1H), 8.83-8.81 (m,
1H), 8.71 (br s, 1H), 8.48-8.44 (m, 1H), 7.96-7.91 (m, 2H),
7.67-7.62 (m, 1H), 7.55-7.52 (m, 1H), 7.41-7.32 (m, 2H), 7.13 (d,
J=8.7 Hz, 1H), 6.66-6.63 (m, 1H), 3.75 (s, 3H), 2.05 (s, 3H). HPLC
(max plot) 99%; Rt 3.72 min. LC/MS: (ES+): 422.4, (ES-): 420.4.
Example 102
N-{3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2-yl}-4-cyanobenzenesulfo-
namide (102)-potassium salt (Scheme 1)
##STR00202##
[0611] Following the protocol outlined in Procedure L, Example 102
is obtained from
N-(3-chloroquinoxalin-2-yl)-4-cyanobenzenesulfonamide (150 mg; 0.44
mmol; 1 eq) and 2-chloro-5-methoxyaniline (75.42 mg; 0.48 mmol; 1.1
eq) in EtOH (2.50 ml) to afford 72.8 mg (36%) of the title compound
as a parent (yellow powder). Treatment of the parent (55.2 mg; 0.12
mmol; 1 eq) with an aqueous solution of potassium hydroxide (0.24
ml; 0.5 M; 0.12 mmol; 1 eq) affords 44.4 mg (74%) of the title
compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 9.35 (s, 1H),
8.88 (s, 1H), 8.18 (d, J=7.9 Hz, 2H), 7.89 (d, J=7.2 Hz, 2H),
7.60-7.05 (m, 5H), 6.61 (dd, J=8.7, 2.7 Hz, 1H), 3.82 (s, 3H). HPLC
(max plot) 98%; Rt 4.64 min. LC/MS: (ES+): 466.3, (ES-): 464.3,
1.89 min, 99%.
Example 103
N-{3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2-yl}pyridine-3-sulfonami-
de (103)-potassium salt (Scheme 1)
##STR00203##
[0613] Following the protocol outlined in Procedure L, Example 103
is obtained from N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide
(200 mg; 0.62 mmol; 1 eq.) and 2-chloro-5-methoxyaniline (108.09
mg; 0.69 mmol; 1.1 eq.) in EtOH (3 ml) to afford 69 mg (25%) of the
title compound as a parent (yellow powder). Treatment of the parent
(69 mg; 0.16 mmol; 1 eq.) with an aqueous solution of potassium
hydroxide (312.29 .mu.l; 0.5 M; 0.16 mmol; 1 eq.) affords 70 mg
(93%) of the title compound as a yellow powder. 1H NMR (DMSO-d6)
.delta. 9.34 (s, 1H), 9.16 (d, J=1.9 Hz, 1H), 8.86 (br s, 1H), 8.59
(br s, 1H), 8.38 (dt, J=1.9, 7.9 Hz, 1H), 7.51-7.44 (m. 3H), 7.40
(d, J=8.7 Hz. 1H), 7.25-7.20 (m, 2H), 6.63-6.59 (m, 1H), 3.81 (s,
3H). HPLC (max plot) 100%; Rt 4.11 min, LC/MS: (ES+): 442.1, (ES-):
440.2.
Example 104
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-methoxypyridine-3-sulf-
onamide (104)-potassium salt (Scheme 1)
##STR00204##
[0615] Following the protocol outlined in Procedure L, Example 104
is obtained from
N-(3-chloroquinoxalin-2-yl)-6-methoxypyridine-3-sulfonamide (228
mg; 0.65 mmol; 1 eq.) and 3,5-dimethoxyaniline (109.52 mg; 0.71
mmol; 1.1 eq.) in EtOH (3 ml) to afford 46 mg (15%) of the title
compound as a parent (yellow powder) after preparative HPLC.
Treatment of the parent (46 mg; 0.1 mmol; 1 eq.) with an aqueous
solution of potassium hydroxide (196.79 .mu.l; 0.50 M; 0.1 mmol; 1
eq.) affords 48 mg (96.5%) of the title compound as a yellow
powder. 1H NMR (DMSO-d6) .delta. 8.79 (br d, 2H), 8.31 (dd, J=2.3,
8.7 Hz, 1H), 7.44-7.21 (m, 6H), 6.84 (br d, 1H), 6.15 (s, 1H), 3.85
(s, 3H), 3.76 (s, 6H). HPLC (max plot) 98%; Rt 4.38 min. LC/MS:
(ES+): 468.4, (ES-): 466.2.
Example 105
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-oxo-1,6-dihydropyridin-
e-3-sulfonamide (105) (Scheme 1)
##STR00205##
[0617] Following the protocol outlined in Procedure L, Example 105
is obtained from
N-(3-chloroquinoxalin-2-yl)-6-methoxypyridine-3-sulfonamide (228
mg; 0.65 mmol; 1 eq.) and 3,5-dimethoxyaniline (109.52 mg; 0.71
mmol; 1.10 eq.) in EtOH (3 ml) to afford 32 mg, (12%) of the title
compound as a parent (yellow powder) after preparative HPLC. 1H NMR
(DMSO-d6) .delta. 8.94 (s, 1H), 8.21 (s, 1H), 7.93 (dd, J=2.6, 9.8
Hz, 2H), 7.58-7.55 (m, 1H), 7.38-7.35 (m, 4H), 6.41 (d, J=9.8 Hz,
1H), 6.23 (t, 1H), 3.76 (s, 6H), 3.15 (s, 2H). HPLC (max plot)
100%; Rt 3.60 min. LC/MS: (ES+): 454.3, (ES-): 452.2.
Example 106
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-methylpyridine-3-sulfo-
namide (106)-potassium salt (Scheme 1)
##STR00206##
[0619] Following the protocol outlined in Procedure L, Example 106
is obtained from
N-(3-chloroquinoxalin-2-yl)-6-methylpyridine-3-sulfonamide (150 mg;
0.45 mmol; 1 eq.) and 3,5-dimethoxyaniline (75.50 mg; 0.49 mmol;
1.10 eq.) in EtOH (2 ml) to afford 110 mg (54%) of the title
compound as a parent (yellow powder). Treatment of the parent (108
mg; 0.24 mmol; 1 eq.) with an aqueous solution of potassium
hydroxide (0.48 ml; 0.50 M; 0.24 mmol; 1 eq.) affords 121.6 mg
(100%) of the title compound as a yellow powder. 1H NMR (DMSO-d6)
.delta. 9.01 (d, J=1.9 Hz, 1H), 8.72 (s, 1H), 8.26-8.23 (m. 1H),
7.41-7.38 (m, 1H). 7.31-7.24 (m, 4H), 7.19-7.09 (m, 2H), 6.12 (t,
J=2.3 Hz, 1H), 2.43 (s, HPLC (max plot) 98%; Rt 4.02 min. LC/MS:
(ES+): 452.0, (ES-): 450.2.
Example 107
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-fluoro-2-methylbenzene-
sulfonamide (107)-potassium salt (Scheme 1)
##STR00207##
[0621] Following the protocol outlined in Procedure L, Example 107
is obtained from
N-(3-chloroquinoxalin-2-yl)-4-fluoro-2-methylbenzenesulfonamide
(100 mg; 0.28 mmol; 1 eq.) and 3,5-dimethoxyaniline (43.54 mg; 0.28
mmol; 1 eq.) in EtOH (2 ml) to afford 58 mg (43.5%) of the title
compound as a parent (yellow powder). Treatment of the parent (58
mg; 0.12 mmol; 1 eq.) with an aqueous solution of potassium
hydroxide (247.59 .mu.l; 0.50 M; 0.12 mmol; 1 eq.) affords 58 mg
(100%) of the title compound as a yellow powder. 1H NMR (DMSO-d6)
.delta. 8.82 (s, 1H), 8.13 (dd, J=6.4, 8.4 Hz, 1H), 7.34-7.35 (m,
1H), 7.30 (d, J=2.3 Hz, 2H), 7.10-7.02 (m, 4H), 6.96-6.91 (m, 1H),
6.13 (t, J=2.3 Hz, 1H), 3.77 (s, 6H), 2.57 (s, 3H). HPLC (max plot)
99%; Rt 5.24 min. LC/MS: MS- (ES+): 469.4, (ES-): 467.3.
Example 108
N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-methylpyridine-3-sulfo-
namide (108)-potassium salt (Scheme 1)
##STR00208##
[0623] Following the protocol outlined in Procedure L, Example 108
is obtained from
N-(3-chloroquinoxalin-2-yl)-6-methylpyridine-3-sulfonamide (150 mg;
0.45 mmol; 1 eq.) and 2,5-dimethoxyaniline (75.5 mg; 0.49 mmol; 1.1
eq.) in EtOH (2 ml) to afford 104 mg (51%) of the title compound as
a parent (green powder). Treatment of the parent (104 mg; 0.23
mmol; 1 eq.) with an aqueous solution of potassium hydroxide
(460.68 .mu.l; 0.50 M; 0.23 mmol; 1 eq.) affords 114 mg (100%) of
the title compound as a green powder. 1H NMR (DMSO-d6) .delta. 9.19
(s, 1H), 9.02 (s, 1H), 8.78 (br d, 1H), 8.25 (d, J=7.9 Hz, 1H),
7.43 (d, J=7.5 Hz, 1H), 7.27-7.12 (m, 4H), 6.95 (d, J=8.67 Hz, 1H),
6.49-6.47 (m, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 2.44 (s, 3H). HPLC
(max plot) 98%; Rt 4.20 min. LC/MS: (ES+): 452.3, (ES-): 450.6.
Example 109
4-cyano-N-{3-[(5-methoxy-2-methylphenyl)amino]quinoxalin-2-yl}benzenesulfo-
namide (109) (Scheme 1)
##STR00209##
[0625] Following the protocol outlined in Procedure L, Example 109
is obtained from
N-(3-chloroquinoxalin-2-yl)-4-cyanobenzenesulfonamide (536 mg; 1.55
mmol; 1 eq.) and 5-methoxy-2-methylaniline (234.59 mg; 1.71 mmol;
1.10 eq.) in EtOH (10 ml) to afford 417 mg (60%) or the title
compound as a parent (yellow powder). 1H NMR (DMSO-d6) .delta. 2.04
(s, 3H), 3.75 (s, 3H), 6.64 (dd, J=2.6 Hz, J=8.3 Hz, 1H), 7.13 (d,
J=8.3 Hz, 1H), 7.37 (m, 2H), 7.54 (m, 1H), 7.90 (m, 1H), 8.02 (m,
1H), 8.07 (d, J=8.3 Hz, 2H), 8.24 (d, J=8.3 Hz, 2H), 8.64 (br s,
1H), 12.70 (br s, 1H). HPLC (max plot) 99%; Rt 4.92 min. LC/MS: MS
(ES+): 446.4, (ES-): 444.2.
Example 110
N-{3-[(5-methoxy-2-methylphenyl)amino]quinoxalin-2-yl}-6-methylpyridine-3--
sulfonamide (110)-potassium salt (Scheme 1)
##STR00210##
[0627] Following the protocol outlined in Procedure L, Example 110
is obtained from
N-(3-chloroquinoxalin-2-yl)-6-methylpyridine-3-sulfonamide (531 mg;
1.59 mmol; 1 eq.) and 5-methoxy-2-methylaniline (326.37 mg; 2.38
mmol; 1.5 eq.) in EtOH (7 ml) to afford 557 mg (80%) of the title
compound as a parent. Treatment of the parent (557 mg; 1.28 mmol; 1
eq.) with an aqueous solution of potassium hydroxide (2563.78
.mu.l; 0.50 M; 1.28 mmol; 1 eq.) affords 598 mg (98%) of the title
compound as a brown powder. 1H NMR (DMSO-d6) .delta. 9.02 (s, 1H),
8.88 (s, 1H), 8.60 (s, 1H), 8.25 (dd, J=9 et 3 Hz, 1H), 7.42 (dd,
J=9 et 3 Hz, 1H), 7.30 (m, 2H), 7.15 (m, 3H), 6.50 (dd, J=9 et 3
Hz, 1H), 3.76 (s, 3H), 2.55 (s, 3H), 2.09 (s, 3H). HPLC (max plot)
99%; Rt 3.88 min. LC/MS: (ES+): 436.2, (ES-): 434.0.
Example 111
N-{3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2-yl}-6-methylpyridine-3--
sulfonamide (111)-potassium salt (Scheme 1)
##STR00211##
[0629] Following the protocol outlined in Procedure L, Example 111
is obtained from
N-(3-chloroquinoxalin-2-yl)-6-methylpyridine-3-sulfonamide (474 mg;
1.42 mmol; 1 eq.) and 2-chloro-5-methoxyaniline (334.7 mg; 2.12
mmol; 1.5 eq.) in EtOH (7 ml) to afford 308 mg (47%) of the title
compound as a parent. Treatment of the parent (308 mg; 0.678 mmol;
1 eq.) with an aqueous solution of potassium hydroxide (1358.
.mu.l; 0.5 M; 0.678 mmol; 1 eq.) affords 330 mg (98%) of the title
compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 9.40 (s, 1H),
9.03 (s, 1H), 8.92 (s, 1H), 8.25 (dd, J=9 et 3 Hz, 1H), 7.47 (dd,
J=9 et 3 Hz, 1H), 7.40 (d, J=9 Hz, 1H), 7.23 (m, 3H), 6.59 (dd, J=9
et 3 Hz, 1H), 3.76 (s, 3H), 2.55 (s, 3H). HPLC (max plot) 99%; Rt
4.38 min. LC/MS: (ES+): 456.2, (ES-): 454.1.
Example 112
methyl
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]p-
yridine-2-carboxylate (112) (Scheme 1)
##STR00212##
[0631] Following the protocol outlined in Procedure L, Example 112
is obtained from Methyl
5-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}pyridine-2-carboxylate
(720 mg; 1.9 mmol; 1 eq.) and 3,5-dimethoxyaniline (727.9 mg; 4.75
mmol; 2.5 eq.) in EtOH (5 ml) to afford 650 mg (69%) of the title
compound as a parent (yellow powder). 1H NMR (DMSO-d6) .delta. 9.37
(d, J=3 Hz, 1H), 8.98 (m, 1H), 8.63 (dd, J=9 and 3 Hz, 1H), 8.21
(d, J=9 Hz, 1H), 7.85 (m, 1H), 7.59 (m, 1H), 7.35 (m, 4H), 6.24 (m,
1H), 3.90 (s, 3H), 3.75 (s, 6H); HPLC (max plot) 86%; Rt 4.43 min.
LC/MS: MS: (ES+): 496.2, (ES-): 494.2.
Example 113
N-{3-[(2-bromo-5-methoxyphenyl)amino]quinoxalin-2-yl}-1-methyl-1H-imidazol-
e-4-sulfonamide (113) (Scheme 1)
##STR00213##
[0633] Following the protocol outlined in Procedure L, Example 113
is obtained from
N-(3-chloroquinoxalin-2-yl)-1-methyl-1H-imidazole-4-sulfonamide (50
mg; 0.15 mmol; 1 eq.), 2-bromo-5-methoxyaniline (31.52 mg; 0.16
mmol; 1.01 eq.) and sodium hydroxyde (20 .mu.l; 1 M; 0.02 mmol;
0.13 eq.) in water (1.50 ml) to afford 21.8 mg (29%) of the title
compound as a parent (yellow powder). 1H NMR (DMSO-d6) .delta. 11.9
(s, 0.13H), 9.19 (s, 1H), 8.60 (s, 1H), 8.10-7.76 (m, 3H),
7.74-7.20 (m, 5H), 6.80-6.58 (m, 1H), 3.82 (s, 3H), 3.71 (s, 3H).
HPLC (max plot) 99%; Rt 4.32 min. LC/MS: ES+ 491.2, ES- 489.1.
Example 114
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-(morpholin-4-ylcarbony-
l)benzenesulfonamide (114)-potassium salt (Scheme 1)
##STR00214##
[0635] Following the protocol outlined in Procedure L, Example 114
is obtained from
N-(3-chloroquinoxalin-2-yl)-3-(morpholin-4-ylcarbonyl)benzenesulfonamide
(600 mg; 1.39 mmol; 1 eq.) and 3,5-dimethoxyaniline (212.31 mg;
1.39 mmol; 1 eq.) in EtOH (7 ml) to afford 237 mg (31%) of the
title compound as a parent. Treatment of the parent (237 mg; 0.43
mmol; 1 eq.) with an aqueous solution of potassium hydroxide
(862.43 .mu.l; 0.50 M; 0.43 mmol; 1 eq.) affords 215 mg (85%) of
the title compound as a yellow powder. 1H NMR (DMSO-d6) .delta.
8.78 (s, 1H), 8.05-8.02 (m, 2H), 7.49-7.38 (m, 3H), 7.31 (d, J=2.3
Hz, 2H), 7.20-7.08 (m, 3H), 6.14-6.12 (m, 1H), 3.77 (s, 6H),
3.65-3.10 (m, 8H). HPLC (max plot) 95%; Rt 4.25 min. LC/MS: LC/MS:
(ES+): 550.1, (ES-): 548.2.
Procedure M
Example 115
3-[3-(2,5-Dimethoxy-phenylamino)-quinoxalin-2-ylsulfamoyl]-benzoic
acid (115)
##STR00215##
[0637] Methyl
3-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoat-
e (30 mg, 0.061 mmol), NaOH pellets (3.6 mg, 0.91 mmol) are
dissolved in a 1 to 1 mixture of MeOH and H2O (4 ml) and the
reaction mixture is stirred at rt overnight. When TLC confirms the
total consumption of the starting ester, the reaction mixture was
acidified with 1.5N HCl and precipitate was filtered and dried
under vacuum to obtain example 6 as a white solid (26 mg, 89%).
HPLC (max plot) 90%, rt, 4.15 min. LC/MS: (ES+): 481.1.
Example 116
3-[({3-[(3,5-Dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoic
acid (116)
##STR00216##
[0639] Following the general protocol outlined in Procedure M,
Example 116 is obtained from methyl
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoat-
e in a 1 to 1 mixture of MeOH and H.sub.2O in the presence of NaOH
(yellow solid, 10 mg, 15%). 1H NMR (DMSO-d6) .delta. 13.43 (s, 1H),
12.40 (s, 1H), 8.94 (s, 1H), 8.58 (s, 1H), 8.37 (d, J=7.9 Hz, 1H),
8.16 (d, J=7.5 Hz, 1H), 7.90 (s, 1H), 7.75-7.70 (m, 1H), 7.58-7.55
(m, 1H), 7.41-7.32 (m, 4H), 6.23-6.22 (m, 1H), 3.75 (s, 6H). HPLC
(max plot) 93%, rt. 4.07 min. LC/MS: (ES+): 481.1.
Example 117
4-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoic
acid (117)
##STR00217##
[0641] Following the general protocol outlined in Procedure M,
Example 117 is obtained from methyl
4-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoat-
e in a 1 to 1 mixture of MeOH and H.sub.2O in the presence of NaOH
(dark green solid, 10 mg, 23%). HPLC (max plot) 96%, rt. 4.17 min.
LC/MS: (ES+): 481.5.
Example 118
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoic
acid (118)
##STR00218##
[0643] Following the general protocol outlined in Procedure M,
Example 118 is obtained from methyl
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoat-
e in a 1 to 1 mixture of MeOH and H.sub.2O in the presence of NaOH
(yellow solid, 10 mg, 15%). HPLC (max plot) 97%, rt. 4.06 min.
LC/MS: (ES+): 481.5.
Example 119
4-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]butanoic
acid (119)
##STR00219##
[0645] Following the general protocol outlined in Procedure M,
Example 119 is obtained from methyl
4-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]butanoa-
te in a 1 to 1 mixture of MeOH and H.sub.2O in the presence of NaOH
(dark green solid, 10 mg, 30%). HPLC (max plot) 99%, rt. 3.82 min.
LC/MS: (ES+): 447.1.
Example 120
4-[({3-[(3,5-Dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]butanoic
acid (120)
##STR00220##
[0647] Following the general protocol outlined in Procedure M,
Example 120 is obtained from methyl
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]butanoa-
te in a 1 to 1 mixture of MeOH and H.sub.2O in the presence of NaOH
(yellow solid, 10 mg, 20%). HPLC (max plot) 99%, rt. 3.71 min.
LC/MS: (ES+): 447.1.
Example 121
3-[({3-[(2,5-Dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]thiophen-
e-2-carboxylic acid (121)
##STR00221##
[0649] Following the general protocol outlined in Procedure M,
Example 121 is obtained from methyl
3-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]thiophe-
ne-2-carboxylate in a 1 to 1 mixture of MeOH and H.sub.2O in the
presence of NaOH (yellow solid, 8 mg, 28%). HPLC (max plot) 97%,
rt. 4.07 min. LC/MS: (ES+): 485.
Example 122
3-[({3-[(3,5-Dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]thiophen-
e-2-carboxylic acid (122)
##STR00222##
[0651] Following the general protocol outlined in Procedure M,
Example 122 is obtained from methyl
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]thiophe-
ne-2-carboxylate in a 1 to 1 mixture of MeOH and H.sub.2O in the
presence of NaOH (yellow solid, 14 mg, 59%) HPLC (max plot) 94%,
rt. 3.95 min. LC/MS: (ES+): 487.5.
Procedure N
Example 123
3-{4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]pheny-
l}propanoic acid (123)
##STR00223##
[0653]
Methyl-3-{4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)-
sulfonyl]phenyl}propanoate (50 mg, 0.10 mmol, 1 eq.) and lithium
hydroxide monohydrate (20.1 mg, 0.48 mmol, 5 eq.) are dissolved in
THF (1 ml) and water (1 ml) and the yellow solution is heated up to
50.degree. C. for 1 h. Aqueous HCl 1N is added until reaching
acidic pH and the precipitate formed is filtered off then washed
with water until neutral. The solid is dried under vacuum at
40.degree. C. overnight, affording 38.1 mg (78%) of the title
compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 12.30-11.95
(m, 2H), 8.91 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7-95-7.82 s, 1H),
7.60-7.50 (m, 1H), 7.48-7.23 (m, 6H), 6.23 (s, 1H), 3.75 (s, 6H),
2.88 (t, J=7.2 Hz, 2H), 2.56 (t, J=7.5 Hz, 2H). HPLC (max plot)
100%; Rt 4.10 min. LC/MS: (ES+): 509.4; (ES-): 507.4.
Example 124
5-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-4-methy-
lthiophene-2-carboxylic acid (124)
##STR00224##
[0655] Following the protocol outlined in Procedure N, Example 124
is obtained from methyl
5-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-4-meth-
ylthiophene-2-carboxylate (64 mg; 0.12 mmol; 1 eq) and lithium
hydroxide monohydrate (26.1 mg; 0.62 mmol; 5 eq) in THF (1 ml) and
water (1 ml) to afford 62.6 mg (100%) of the title compound as a
yellow powder 1H NMR (DMSO-d6) .delta. 13.62 (brs, 1H), 12.76 (brs,
1H), 9.15 (s, 1H), 8.62 (d, J=2.7 Hz, 1H), 7.97 (d, J=7.5 Hz, 1H),
7.68 (s, 1H), 7.65 (m, 1H), 7.47-7.34 (m, 2H), 7.02 (d, J=8.7 Hz,
1H), 6.62 (dd, J=8.7, 2.7 Hz, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 2.55
(s, 3H). HPLC (max plot) 99%; Rt 4.51 min. LC/MS: (ES+): 501.3,
(ES-): 499.3.
Example 125
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-4-methy-
lthiophene-2-carboxylic acid (125)
##STR00225##
[0657] Following the protocol outlined in Procedure N, Example 125
is obtained from methyl
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-4-meth-
ylthiophene-2-carboxylate (99.4 mg; 0.18 mmol; 1 eq) and lithium
hydroxide monohydrate (37.74 mg; 0.90 mmol; 5 eq) in THF (1.5 ml)
and water (1.5 ml) to afford 82.1 mg (91%) of the title compound as
a yellow powder. 1H NMR (DMSO-d6) .delta. 13.56 (br s, 1H), 12.58
(br s, 1H), 8.90 (s, 1H), 7.89 (br s, 1H), 7.63-7.57 (m, 2H),
7.45-7.33 (m, 2H), 7.32 (d, J=2.2 Hz, 2H), 6.26 (t, J=2.2 Hz, 1H),
3.77 (s, 6H), 2.47 (s, 3H). HPLC (max plot) 98%; Rt 4.20 min.
LC/MS: (ES+): 501.4, (ES-): 499.3.
Example 126
5-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-1-methy-
l-1H-pyrrole-2-carboxylic acid (126)-dipotassium salt
##STR00226##
[0659] Following the protocol outlined in Procedure N, Example 126
is obtained from methyl
5-[({3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-1-meth-
yl-1H-pyrrole-2-carboxylate (108.3 mg; 0.22 mmol; 1 eq) and lithium
hydroxide monohydrate (45.67 mg; 1.09 mmol; 5 eq) in THF (2 ml) and
water (1.5 ml) to afford 102.3 mg (97%) of the title compound as a
green powder. Treatment of the parent (91.2 mg; 0.19 mmol; 1 eq)
with an aqueous solution of potassium hydroxide (754.5 .mu.l; 0.5
M; 0.38 mmol; 2 eq) affords 108.1 mg (100%) of the title compound
as a green powder. 1H NMR (DMSO-d6) .delta. 9.31 (s, 1H), 8.83 (d,
J=3.0 Hz, 1H), 7.43-7.35 (t, J=8.9 Hz, 2H), 7.20-7.05 (m, 3H), 6.93
(d, J=9.0 Hz, 1H), 6.65 (d, J=1.9 Hz, 1H), 6.46 (dd, J=8.7, 3.0 Hz,
1H), 3.89 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H). HPLC (max plot) 99%;
Rt 3.96 min. LC/MS: (ES+): 484.4, (ES-): 482.4.
Example 127
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-1-methy-
l-1H-pyrrole-2-carboxylic acid (127)-dipotassium salt
##STR00227##
[0661] Following the protocol outlined in Procedure N, Example 127
is obtained from methyl
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-1-meth-
yl-1H-pyrrole-2-carboxylate (94.2 mg; 0.19 mmol; 1 eq) and lithium
hydroxide monohydrate (39.72 mg; 0.95 mmol; 5 eq) in THF (2 ml) and
water (1.5 ml) to afford 87.1 mg (95%) of the title compound as a
yellow powder. Treatment of the parent (76.9 mg; 0.16 mmol; 1 eq)
with an aqueous solution of potassium hydroxide (636.19 .mu.l; 0.5
M; 0.32 mmol; 2 eq) affords 87.1 mg (98%) of the title compound as
a yellow powder. 1H NMR (DMSO-d6) .delta. 8.85 (s, 1H), 7.40 (d,
J=8.3 Hz, 2H), 7.28 (d, J=2.3 Hz, 2H), 7.21-7.13 (m, 2H), 7.09 (dt,
J=7.5, 1.5 Hz, 1H), 6.62 (d, J=1.9 Hz, 1H), 6.11 (t, J=2.3 Hz, 1H),
3.79 (s, 3H), 3.78 (s, 6H). HPLC (max plot) 97%; Rt 3.88 min.
LC/MS: (ES+): 484.5, (ES-): 482.5.
Example 128
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]pyridine-
-2-carboxylic acid (128)
##STR00228##
[0663] Following the protocol outlined in Procedure N, Example 128
is obtained from Methyl
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]pyridin-
e-2-carboxylate (200 mg; 0.4 mmol; 1 eq.) and hydroxide monohydrate
(84.68 mg; 2.02 mmol; 5 eq.) in THF (15 ml) and water (5 ml) to
afford 185 mg (95%) of the title compound as a yellow powder. 1H
NMR (DMSO-d6) .delta. 9.36 (d, J=3 Hz, 1H), 8.99 (m, 1H), 8.62 (dd,
J=9 and 3 Hz, 1H), 8.20 (d, J=9 Hz, 1H), 7.87 (m, 1H), 7.59 (m,
1H), 7.35 (m, 4H), 6.24 (m, 1H), 3.76 (s, 6H). HPLC (max plot)
98.5%; Rt 4.04 min. LC/MS: (ES+): 482.2, (ES-): 480.2.
Procedure O
Example 129
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-(morpholin-4-ylmethyl)-
benzenesulfonamide (129)
##STR00229##
[0665]
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-(morpholin-4-yl-
carbonyl)benzenesulfonamide (184 mg; 0.33 mmol; 1 eq.) was
suspended in THF (8 ml) and lithium aluminum hydride (669.57 .mu.l;
1 M; 0.67 mmol; 2 eq.) was added dropwise. The solution was stirred
at rt for 1 h30. The reaction was quenched by addition of 25.4
.mu.l of water, 25.4 .mu.l of NaOH 1N then 3 times 25.4 .mu.l of
water and the precipitate formed was filtered through celite. The
filtrate was evaporated then the oily residue was taken up in water
and was neutralised with HCl 0.1N. After 1 h at 4.degree. C. the
precipitate formed was filtered and dried at 40.degree. C. under
vacuum overnight, affording 50 mg (28%) of the parent as a yellow
solid. Treatment of the parent (50 mg; 0.09 mmol; 1 eq.) with HCl
in MeOH (373.40 .mu.l; 1.25 M; 0.47 mmol; 5 eq.) affords 38 mg
(71%) of the title compound as a yellow powder. 1H NMR (DMSO-d6)
.delta. 12.38 (br s, 1H), 10.66 (br s, 1H), 8.90 (s, 1H), 8.29 (s,
1H), 8.20-8.17 (m, 1H), 7.90 (s, 1H), 7.82-7.79 (m, 1H), 7.71-7.66
(m, 1H), 7.59-7.56 (m, 1H), 7.41-7.34 (m, 4H), 6.24-6.23 (m, 1H),
4.43 (s, 2H), 3.90-3.77 (m, 2H), 3.75 (s, 6H), 3.71-3.56 (m, 2H),
3.31-2.96 (m, 4H). HPLC (max plot) 98%; Rt 3.54 min. LC/MS: (ES+):
536.3, (ES-): 534.4.
Example 130
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-[(4-methylpiperazin-1--
yl)methyl]benzenesulfonamide (130)-di HCl salt
##STR00230##
[0667] Following the protocol outlined in Procedure O, Example 130
is obtained from
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-[(4-methylpiperazin-1-
-yl)carbonyl]benzenesulfonamide (171 mg; 0.3 mmol; 1 eq.) and
lithium aluminum hydride (607.84 .mu.l; 1 M; 0.61 mmol; 2 eq.) in
THF (7 ml)) to afford 74 mg (44.38%) of the title compound as a
parent. Treatment of the parent (74 mg; 0.13 mmol; 1 eq.) with HCl
in MeOH (647.39 .mu.l; 1.25 M; 0.81 mmol; 6 eq.) affords 72 mg
(86%) of the title compound as a yellow powder. 1H NMR (DMSO-d6)
.delta. 12.28 (br s, 1H), 10.02 (br s, 1H), 8.93 (s, 1H), 8.12 (d,
J=7.9 Hz, 2H), 7.91 (s, 1H), 7.64-7.56 (m, 3H), 7.41-7.34 (m, 4H),
6.24-6.23 (m, 1H), 3.90-3.60 (m, 4H), 3.75 (s, 6H), 3.45-3.32 (m,
2H), 3.20-2.90 (m, 4H), 2.74 (s, 3H). HPLC (max plot) 99.5%; Rt
3.34 min. LC/MS: (ES+): 549.3, (ES-): 547.2. CHN analysis:
[C28H32N6O4S-2.0 HCl-H20] Calculated: C, 52.58%; H, 5.67%; N,
13.14%. Found: C, 52.23%; H, 5.52%; N, 12.98%.
Example 131
4-(aminomethyl)-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzenesu-
lfonamide (131)-HCl salt
##STR00231##
[0669] Following the protocol outlined in Procedure O, Example 131
is obtained from
4-cyano-N-{3-[(2,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzenesulfonami-
de (110 mg; 0.24 mmol; 1 eq) and lithium aluminum hydride (0.48 ml;
1 M; 0.48 mmol; 2 eq) in THF (3) to afford the title compound as a
parent. Treatment of the parent with HCl in MeOH affords 75 mg
(63%) of the title compound as a yellow powder. 1H NMR (DMSO-d6)
.delta. 12.59 (br s, 1H), 9.15 (s, 1H), 8.63-8.48 (m, 1H),
8.40-8.15 (m, 1H), 8.10 (d, J=7.9 Hz, 2H), 7.94 (br s, 1H),
7.80-7.55 (m, 3H), 7.48-7.30 (m, 2H), 7 (d, J=8.7 Hz, 2H), 6.59
(dd, J=9.1, 2.6 Hz, 1H), 4.20-4.90 (m, 2H), 3.80 (s, 3H), 3.76 (s,
3H). 1H NMR (DMSO-d6) .delta. 5 exchangeable protons. HPLC (max
plot) 98%; Rt 3.25 min. LC/MS: (ES+): 466.5, (ES-): 464.4; 1.48
min; 100%.
Example 132
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-(hydroxymethyl)benzene-
sulfonamide (132)
##STR00232##
[0671] Following the protocol outlined in Procedure O, Example 132
is obtained from Methyl
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoat-
e (150 mg; 0.30 mmol; 1 eq) and lithium aluminum hydride (333.65
.mu.l; 1 M; 0.33 mmol; 1.10 eq) in THF (8 ml) to afford 139 mg
(98%) of the title compound as a parent (pale yellow powder). 1H
NMR (DMSO-d6) .delta. 8.79 (s, 1H), 8.03 (s, 1H), 7.91 (dt, J=1.9,
7.2 Hz, 1H), 7.40-7.26 (m, 6H), 7.16-7.06 (m, 2H), 6.13-6.12 (m,
1H), 5.24 (t, J=5.7 Hz, 1H), 4.51 (d, J=5.7 Hz, 2H), 3.77 (s, 6H).
HPLC (max plot) 98.5%; Rt 3.93 min. LC/MS: (ES+): 467.4, (ES-):
465.4.
Example 133
3-(aminomethyl)-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzenesu-
lfonamide (133)-HCl salt
##STR00233##
[0673] Following the protocol outlined in Procedure O, Example 133
is obtained from
3-cyano-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzenesulfonami-
de (300 mg; 0.65 mmol; 1 eq) and lithium aluminum hydride (1300.11
.mu.l; 1 M; 1.3 mmol; 2 eq in THF (8 ml) to afford 150 mg (50%) of
the title compound as a parent. Treatment of the parent (150 mg;
0.32 mmol; 1 eq.) with HCl in MeOH (1.29 ml; 1.25 M; 1.61 mmol; 5
eq.) affords 64 mg (40%) of the title compound as a yellow powder.
1H NMR (DMSO-d6) .delta. 12.37 (br s, 1H), 8.85 (s, 1H), 8.27-8.12
(m, 4H), 7.91 (s, 1H), 7.70-7.56 (m, 3H), 7.37-7.32 (m, 4H), 6.23
(s, 1H), 4.17-4.11 (m, 2H), 3.75 (s, 6H). HPLC (max plot) 98.5%; Rt
3.12 min. LC/MS: (ES+): 466.4, (ES-): 464.4.
Example 134
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(hydroxymethyl)benzene-
sulfonamide (134)
##STR00234##
[0675] Following the protocol outlined in Procedure O, Example 134
is obtained from Methyl
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoat-
e (150 mg; 0.30 mmol; 1 eq.) and lithium aluminum hydride (333.65
.mu.l; 1 M; 0.33 mmol; 1.1 eq.) in THF (8 ml) to afford 64 mg (45%)
of the title compound as a parent (yellow powder). 1H NMR (DMSO-d6)
.delta. 12.23 (s, 1H), 8.90 (s, 1H), 8.06 (d, J=8.3 Hz, 2H), 7.92
(s, 1H), 7.51-7.48 (m, 1H), 7.44 (d, J=8.3 Hz, 2H), 7.37-7.33 (m,
4H), 6.17-6.16 (m, 1H), 5.36 (s, 1H), 4.55 (s, 2H), 3.75 (s, 6H).
HPLC (max plot) 100%; Rt 3.88 min. LC/MS: (ES+): 467.3, (ES-):
465.3.
Example 135
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-(hydroxymethyl)pyridin-
e-3-sulfonamide (135)
##STR00235##
[0677] Following the protocol outlined in Procedure O, Example 135
is obtained from methyl
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]pyridin-
e-2-carboxylate (220 mg; 0.44 mmol; 1 eq.) and lithium aluminum
hydride (0.49 ml; 1 M; 0.49 mmol; 1.1 eq.) in THF (8 ml) at
-78.degree. C. to afford 120 mg (58%) of the title compound as a
parent (yellow powder). 1H NMR (DMSO-d6) .delta. 8.25 (m, 2H), 7.64
(d, J=3 Hz, 1H), 7.50 (m, 4H), 7.05 (s, 2H), 6.18 (s, 1H), 4.78 (s,
2H), 3.76 (s, 6H). HPLC (max plot) 71%; Rt 3.88 min. LC/MS: MS:
(ES+): 468.5 and (ES-): 466.5.
Example 136
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(morpholin-4-ylmethyl)-
benzenesulfonamide (136)-HCl salt
##STR00236##
[0679] Following the protocol outlined in Procedure O, Example 136
is obtained from
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-(morpholin-4-ylcarbon-
yl)benzenesulfonamide (165 mg; 0.3 mmol; 1 eq.) and lithium
aluminum hydride (600.43 .mu.l; 1 M; 0.6 mmol; 2 eq.) in THF (7 ml)
to afford 98 mg (61%) of the title compound as a parent. Treatment
of the parent benzenesulfonamide (97 mg; 0.18 mmol; 1 eq.) with HCl
in MeOH (724.39 .mu.l; 1.25 M; 0.91 mmol; 5 eq.) affords 96 mg
(93%) of the title compound as a yellow powder. 1H NMR (DMSO-d6)
.delta. 12.32 (br s, 1H), 10.54 (br s, 1H), 8.94 (s, 1H), 8.21 (d,
J=7.9 Hz, 2H), 7.90 (s, 1H), 7.75 (d, J=7.9 Hz, 2H), 7.59-7.56 (m,
1H), 7.42-7.34 (m, 4H), 6.23 (t, J=2.3 Hz, 1H), 4.40 (s, 2H),
3.97-3.85 (m, 2H), 3.75 (s, 6H), 3.71-3.60 (m, 2H), 3.28-3.01 (m,
4H). HPLC (max plot) 99%; Rt 3.61 min. LC/MS: (ES+): 536.3, (ES-):
534.2,
Example 137
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-[(4-methylpiperazin-1--
yl)methyl]benzenesulfonamide (137)-di HCl salt
##STR00237##
[0681] Following the protocol outlined in Procedure O, Example 137
is obtained from
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-[(4-methylpiperazin-1-
-yl)carbonyl]benzenesulfonamide (267 mg; 0.47 mmol; 1 eq.) and
lithium aluminum hydride (949.08 .mu.l; 1 M; 0.95 mmol; 2 eq.) in
THF (10 ml) to afford 211 mg (81%) of the title compound as a
parent. Treatment of the parent benzenesulfonamide (211 mg; 0.38
mmol; 1 eq.) with HCl in MeOH (1845.93 .mu.l; 1.25 M; 2.31 mmol; 6
eq.) affords 184 mg (77%) of the title compound as a yellow powder.
1H NMR (DMSO-d6) .delta. (, H), 12.31 (br s, 1H), 9.91 (br s, 1H),
8.91 (s, 1H), 8.12-8.05 (m, 2H), 7.91 (s, 1H), 7.61-7.56 (m, 3H),
7.42-7.33 (m, 4H), 6.25-6.23 (m, 1H), 3.75 (s, 6H), 3.75-3.25 (m,
6H), 3.10-2.85 (m, 4H), 2.71 (s, 3H). HPLC (max plot) 100%; Rt 3.33
min. LC/MS: (ES+): 549.4, (ES-): 547.3. CHN analysis:
[C28H32N6O4S-2.0 HCl-0.8 H20] Calculated: C, 52.88%; H, 5.64%; N,
13.21%. Found: C, 52.94%; H, 5.63%; N, 13.21%.
Example 138
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-4-[(dimethylamino)methyl-
]benzenesulfonamide (138)-HCl salt
##STR00238##
[0683] Following the protocol outlined in Procedure O, Example 138
is obtained from
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-N,N-di-
methylbenzamide (155 mg; 0.31 mmol; 1 eq.) and lithium aluminum
hydride (610.75 .mu.l; 1 M; 0.61 mmol; 2 eq.) in THF (5 ml) to
afford 84 mg (56%) of the title compound as a parent. Treatment of
the parent benzenesulfonamide (84 mg; 0.17 mmol; 1 eq.) with HCl in
MeOH (680.73 .mu.l; 1.25 M; 0.85 mmol; 5 eq.) affords 93 mg (103%)
of the title compound as a yellow powder. 1H NMR (DMSO-d6) .delta.
12.35 (s, 1H), 10.36 (s, 1H), 8.95 (s, 1H), 8.21 (d, J=8.3 Hz, 2H),
7.91 (s, 1H), 7.75 (d, J=8.3 Hz, 2H), 7.59-7.56 (m, 1H), 7.42-7.34
(m, 4H), 6.24-6.23 (m, 1H), 4.33 (d, J=5.3 Hz, 2H), 3.75 (s, 6H),
2.69 (d, J=4.9 Hz, 6H). HPLC (max plot) 98%; Rt 3.53 min. LC/MS:
(ES+): 494.3, (ES-): 492.2.
Example 139
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-[(dimethylamino)methyl-
]benzenesulfonamide (139)-1-HCl salt
##STR00239##
[0685] Following the protocol outlined in Procedure O Example 139
is obtained from
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-N,N-di-
methylbenzamide (102 mg; 0.2 mmol; 1 eq.) and lithium aluminum
hydride (401.91 .mu.l; 1 M; 0.4 mmol; 2 eq.) in THF (5 ml) to
afford 56 mg (56.5%) of the title compound as a parent. Treatment
of the parent benzenesulfonamide (56 mg; 0.11 mmol; 1 eq.) with HCl
in MeOH (453.82 .mu.l; 1.25 M; 0.57 mmol; 5 eq.) affords 52 mg
(86.5%) of the title compound as a yellow powder. 1H NMR (DMSO-d6)
.delta. 12.39 (s, 1H), 10.23 (s, 1H), 8.90 (s, 1H), 8.28 (s, 1H),
8.19 (d, J=8.3 Hz, 1H), 7.90 (s, 1H), 7.78 (d, J=7.9 Hz, 1H),
7.71-7.66 (m, 1H), 7.59-7.56 (m, 1H), 7.41-7.33 (m, 4H), 6.24-6.22
(m, 1H), 4.37 (br d, 2H), 3.75 (s, 6H), 2.70 (br d, 6H). HPLC (max
plot) 98%; Rt 3.53 min. LC/MS: (ES+): 494.2, (ES-): 492.2.
Procedure P
Example 140
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzamid-
e (140)-sodium salt
##STR00240##
[0687]
4-cyano-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}benzenesul-
fonamide (101.2 mg; 0.22 mmol; 1 eq.) was dissolved in aqueous
sodium hydroxide (0.5 ml) 5N and EtOH (0.5 ml) and the solution was
heated up to 80.degree. C. Over Night. The solution was cooled down
and the solvent was removed. The solid residue was taken up in a
small volume of EtOH and refluxed. After cooling at 4.degree. C.,
the precipitate formed was filtered off, washed with EtOH and dried
at 40.degree. C. overnight. Recrystallization in ACN affords 45.4
mg (41%) of the title compound as a sodium salt (light yellow
powder). 1H NMR (DMSO-d6) .delta. 8.80 (s, 1H), 7.90 (d, J=8.2 Hz,
2H), 7.78 (d, J=8.2 Hz, 2H), 7.37 (dd, J=7.5, 1.8 Hz, 1H), 7.29 (d,
J=1.9 Hz, 2H), 7.23 (dd, J=7.9, 1.5 Hz, 1H), 7.17-7.01 (m, 2H),
6.12 (t, J=1.9 Hz, 1H), 3.77 (s, 6H). HPLC (max plot) 98.5%; Rt
4.06 min. LC/MS: (ES+): 481.2, (ES-): 479.2, 1.35 min, 99.5%.
Example 141
4-[({3-[(5-methoxy-2-methylphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]ben-
zamide (141)-sodium salt
##STR00241##
[0689] Following the protocol outlined in Procedure P, Example 141
is obtained from
4-cyano-N-{3-[(5-methoxy-2-methyl-phenyl)amino]quinoxalin-2-yl}benzenesul-
fonamide (113 mg; 0.25 mmol; 1 eq.) aqueous sodium hydroxide (0.5
ml) 5N in EtOH (1 ml) to afford 97 mg (79%) of the title compound
as a yellow powder. 1H NMR (DMSO-d6) .delta. 8.75 (s, 1H), 8.43 (d,
J=2.6 Hz, 1H), 7.70 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H),
7.19-7.16 (m, 1H), 7.07-7.04 (m, 1H), 6.95-6.86 (m, 3H), 6.29 (dd,
J=2.6, 8.3 Hz, 1H), 3.56 (s, 3H), 2.03 (s, 3H). HPLC (max plot)
98%; Rt 4.39 min. LC/MS: (ES+): 465.3, (ES-): 463.1.
Procedure Q
Example 142
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-N-(3-me-
thoxypropyl)benzamide (142)
##STR00242##
[0691]
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]b-
enzoic acid (100 mg; 0.21 mmol; 1 eq.), EDC-HCl (51.87 mg; 0.27
mmol; 1.3 eq.) and HOBT (36.56 mg; 0.27 mmol; 1.3 eq.) were taken
up in DMA (5 ml) then DIEA (106.88 .mu.l; 0.62 mmol; 3 eq.) and
3-methoxypropylamine (21.23 .mu.l; 0.21 mmol; 1 eq.) were added.
The solution was stirred at rt for 3 h. The DMA was evaporated and
the residue was taken up in DCM. The organic phase was washed with
a saturated solution of NaHCO.sub.3 then a saturated solution of
NH4Cl and brine. It was dried over MgSO.sub.4 and concentrated to
near dryness. The residue obtained was taken up in ACN and
refluxed. After cooling at 4.degree. C., the precipitate was
filtered off then washed with ACN to afford 76 mg (66%) of the
title compound as a parent. Treatment of the parent (74 mg; 0.13
mmol; 1 eq.) with an aqueous solution of potassium hydroxide
(268.30 .mu.l; 0.5 M; 0.13 mmol; 1 eq.) affords 76 mg (96%) of the
title compound as a yellow powder. 1H NMR (DMSO-d6) .delta. 8.77
(s, 1H), 8.49-8.45 (m, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.80 (d, J=8.3
Hz, 2H), 7.41-7.38 (m, 1H), 7.31 (d, J=2.3 Hz, 2H), 7.27-7.24 (m,
1H), 7.17-7.08 (m, 2H), 6.13-6.12 (m, 1H), 3.77 (s, 6H), 3.35-3.31
(m, 2H), 3.28-3.22 (m, 2H), 3.20 (s, 3H), 1.75-1.66 (m, 2H). HPLC
(max plot) 97%; Rt 4.17 min. LC/MS: (ES+): 552.4, (ES-): 550.3.
Example 143
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-N-[3-(d-
imethylamino)propyl]benzamide (143)-HCl salt
##STR00243##
[0693] Following the protocol outlined in Procedure Q, Example 143
is obtained from
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoic
acid (100 mg; 0.21 mmol; 1 eq.) EDC-HCl (51.87 mg; 0.27 mmol; 1.3
eq.), HOBT (36.56 mg; 0.27 mmol; 1.3 eq.), DIEA (106.88 .mu.l; 0.62
mmol; 3 eq.) and N,N-dimethyl-1,3-propanediamine (26.25 .mu.l; 0.21
mmol; 1 eq.) in DMA (5 ml) to afford 81 mg (69%) of the title
compound as a parent. Treatment of the parent (81 mg; 0.14 mmol; 1
eq.) with HCl in MeOH (0.5 ml; 1.25 M; 0.62 mmol; 4.36 eq.) affords
80 mg (93%) of the title compound as a dark yellow powder. 1H NMR
(DMSO-d6) .delta. 9.90-9.50 (m, 1H), 9-8.60 (m, 2H), 8.25-8.10 (m,
2H), 8.05-7.80 (m, 2H), 7.55-7.10 (m, 6H), 6.25-6.10 (m, 1H), 3.80
(s, 6H), 3.45-3 (m, 4H), 2.76 (s, 6H). 2-1.80 (m, 2H). HPLC (max
plot) 98%; Rt 3.24 min. LC/MS: (ES+): 565.4, (ES-): 563.4.
Example 144
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-N-[3-(d-
imethylamino)propyl]benzamide (144)-HCl salt
##STR00244##
[0695] Following the protocol outlined in Procedure Q, Example 144
is obtained from
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoic
acid (90 mg; 0.19 mmol; 1 eq.), EDC-HCl (46.68 mg; 0.24 mmol; 1.30
eq.), HOBT (32.90 mg; 0.24 mmol; 1.3 eq.), DIEA (96.19 .mu.l; 0.56
mmol; 3 eq.) and N,N-dimethyl-1,3-propanediamine (23.63 .mu.l; 0.19
mmol; 1 eq.) in DMA (5 ml) to afford the title compound as a
parent. Treatment of the parent with HCl in MeOH affords 57 mg
(54%) of the title compound as a yellow powder. 1H NMR (DMSO-d6)
.delta. 12.39 (br s, 1H), 9.57 (br s, 1H), 8.90-8.88 (m, 2H), 8.55
(s, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.10-8.08 (m, 1H), 7.91 (br s,
1H), 7.72-7.67 (m, 7.58-7.55 (m, 1H), 7.38-7.32 (m, 4H), 6.24-6.22
(m, 1H), 3.75 (s, 6H), 3.40-3.30 (m, 2H), 3.10-3.03 (m, 2H), 2.74
(s, 6H), 1.90-1.85 (m, 2H). HPLC (max plot) 98%; Rt 3.29 min.
LC/MS: (ES+): 565.5, (ES-): 563.5.
Example 145
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]-N,N-dim-
ethylpyridine-2-carboxamide (145)
##STR00245##
[0697] Following the protocol outlined in Procedure Q, Example 145
is obtained from
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]pyridin-
e-2-carboxylic acid (100 mg; 0.21 mmol; 1 eq.), EDC-HCl (43.80 mg;
0.23 mmol; 1.1 eq.), HOBT (30.87 mg; 0.23 mmol; 1.1 eq.), DIEA
(52.29 .mu.l; 0.31 mmol; 1.5 eq.) and dimethylamine (103.84 .mu.l;
2 M; 0.21 mmol; 1 eq.) in THF (4.5 ml) to afford 102 mg (96.5%) of
the title compound as a parent (yellow powder). 1H NMR (DMSO-d6)
.delta. 12.41 (br s, 1H), 9.21 (s, 1H), 8.94 (s, 1H), 8.56-8.53 (m,
1H), 7.85-7.53 (m, 3H), 7.35-7.30 (m, 4H), 6.21 (br t, 1H), 3.75
(s, 6H), 3.00 (s, 3H), 2.89 (s, 3H). HPLC (max plot) 99%; Rt 4.13
min. LC/MS: (ES+): 509.2, (ES-): 507.1.
Example 146
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-3-[(4-methylpiperazin-1--
yl)carbonyl]benzenesulfonamide-potassium salt (146)
##STR00246##
[0699] Following the protocol outlined in Procedure Q, Example 146
is obtained from
3-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoic
acid (300 mg; 0.62 mmol; 1 eq.), EDC-HCl (131.66 mg; 0.69 mmol; 1.1
eq.), HOBT (92.80 mg; 0.69 mmol; 1.1 eq.), DMA (157.20 .mu.l; 0.94
mmol; 1.5 eq.) and 1-methylpiperazine (69.49 .mu.l; 0.62 mmol; 1
eq.) in DCM (12 ml) to afford 278 mg (79%) of the title compound as
a parent. Treatment of the parent (275 mg; 0.49 mmol; 1 eq.) with
and aqueous solution of potassium hydroxide (977.52 .mu.l; 0.50 M;
0.49 mmol; 1 eq.) affords 301 mg (100%) of the title compound as a
yellow powder. 1H NMR (DMSO-d6) .delta. 8.79 (s, 1H), 8.09-8.08 (m,
2H), 7.52-7.40 (m, 3H), 7.31 (d, J=2.3 Hz, 2H), 7.25 (br s, 1H),
7.16-7.14 (m, 2H), 6.14 (t, J=2.3 Hz, 1H), 3.77 (s, 6H), 3.52-3.25
(m, 4H), 3.05-2.30 (m, 7H). HPLC (max plot) 99%; Rt 3.45 min.
LC/MS: (ES+): 563.6, (ES-): 561.1.
Example 147
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-(morpholin-4-ylcarbony-
l)pyridine-3-sulfonamide (147)
##STR00247##
[0701] Following the protocol outlined in Procedure Q, Example 147
is obtained from
5-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]pyridin-
e-2-carboxylic acid (110 mg; 0.23 mmol; 1 eq.), EDC-HCl (55.43 mg;
0.28 mmol; 1.5 eq.), HOBT (39.07 mg; 0.28 mmol; 1.5 eq.), DIEA
(118.52 .mu.l; 0.69 mmol; 3 eq.) and morpholine (20.22 .mu.l; 0.23
mmol; 1 eq.) in DCM (20 ml) to afford 140 mg (111.3%) of the title
compound as a pale yellow oil. 1H NMR (DMSO-d6) .delta. 9.30 (d,
J=3 Hz, 1H), 8.55 (m, 2H), 7.57 (d, J=9 Hz, 1H), 7.47 (m, 1H), 7.35
(m, 1H), 7.23 (d, J=3 Hz, 2H), 7.10 (m, 2H), 6.15 (m, 1H), 6.08 (m,
1H), 3.75 (s, 6H), 3.52 (m, 4H), 2.92 (m, 4H). HPLC (max plot)
91.5%; Rt 4.08 min. LC/MS: (ES+): 551.2, (ES-): 549.3.
Example 148
N-{3-[(3,5-dimethoxyphenyl)amino]pyrido[2,3-b]pyrazin-2-yl}ethane
Sulfonamide (148)-potassium salt
##STR00248##
[0703] A suspension of 2,3-dichloro-pyrido[2,3-b]pyrazine (200 mg;
1 mmol; 1 eq), ethane sulfonamide (109.1 mg, 1 mmol, 1 eq.),
7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene on polystyrene.hl (862
mg, 2.5 mmol, 2.5 eq.) and NaI (149.87 mg, 1 mmol, 1 eq.) in DMA (5
ml) is heated at 100.degree. C. in the microwave for 1 hour under
high absorbance. HCl in dioxane (374.9 .mu.l, 4M; 1.5 mmol, 1.5
eq.) then 3,5-dimethoxyaniline (765.8 mg, 5 mmol, 5 eq.) are added,
and the resulting reaction mixture is heated at 170.degree. C. in
the microwave for 30 min. The polymer is filtered off, washed with
DMA, and the solvent evaporated under reduced pressure. The product
was extracted with EtOAc, the organic layer is washed with brine
and dried under MgSO4 then conecentrated to near dryness. The
residue is purified by preparative HPLC to afford 69.4 mg (18%) of
the title compound as a parent. The parent (58.6 mg, 0.15 mmol, 1
eq.) is suspended in water (2 ml) then potassium hydroxide (300.9
.mu.l, 0.50 M, 0.15 mmol, 1 eq.) is added and the mixture is
lyophilised to afford 64 mg (99%) of the title compound as a yellow
powder. 1H NMR (DMSO-d6) .delta. 8.92 (s, 1H), 8.34 (dd, J=4.5, 1.7
Hz, 1H), 7.79 (dd, J=7.9, 1.7 Hz, 1H), 7.31 (d, J=2.3 Hz, 2H), 7.14
(dd, J=7.9, 4.5 Hz, 1H), 6.16 (t, J=2.3 Hz, 1H), 3.78 (s, 6H), 3.40
(q, J=7.5 Hz, 2H), 1.15 (t, J=7.5 Hz, 3H). HPLC (max plot) 99%; Rt
2.87 min. LC/MS: (ES+): 390.3, (ES-): 388.3.
Example 149
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-6-[(4-methylpiperazin-1--
yl)methyl]pyridine-3-sulfonamide (149)
##STR00249##
[0705]
6-(chloromethyl)-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}p-
yridine-3-sulfonamide (100 mg; 0.12 mmol; 1 eq.) and
N-ethyl-N-isopropylpropan-2-amine (0.03 ml; 0.25 mmol; 2 eq.) are
dissolved in ACN (25 ml) at room temperature then
1-methylpiperazine (0.06 ml; 0.62 mmol; 5 eq.) is added. The
reaction mixture is stirred at room temperature for 2 hours. The
reaction is quenched by addition of water and neutralized by
addition of aqueous Na.sub.2CO.sub.3. The mixture is concentrated
under reduced pressure. The residue obtained is taken up in DCM.
The product is extracted with DCM, the organic phase is washed with
citric acid 10% then dried over MgSO.sub.4. After evaporation of
the solvent, the crude residue obtained is purified by flash
chromatography to afford 6 mg (9%) of the title compound as a white
powder. 1H NMR (DMSO-d6) .delta. 9.17 (d, J=3 Hz, 1H), 8.30 (m,
1H), 8.24 (dd, J=9 and 3 Hz, 1H), 7.72 (dd, J=9 and 3 Hz, 1H), 7.63
(d, J=9 Hz, 1H), 7.44-7.38 (m, 3H), 7.15 (d, J=3 Hz, 2H), 6.27 (m,
1H), 3.85 (s, 6H), 3.75 (s, 2H), 2.57 (m, 8H), 2.52 (s, 3H). HPLC
(max plot) 90%, Rt 3.34 min. LC/MS: MS: (ES+): 550.5, (ES-):
548.5.
Example 150
5-(aminomethyl)-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}thiophene-
-2-sulfonamide (150)-HCl salt
##STR00250##
[0707]
N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}-5-[(1,3-dioxo-1,3-
-dihydro-2H-isoindol-2-yl)methyl]thiophene-2-sulfonamide (584 mg;
0.97 mmol; 1 eq) is suspended in EtOH (10 ml) then hydrazine
hydrate (0.14 ml; 2.91 mmol; 3 eq) is added. The reaction mixture
is stirred at rt for 5 days. The mixture is filtered off and washed
with ACN then recrystallised in EtOH to afford, after drying under
vacuum, 184 mg (40%) of the title compound as a parent. Treatment
of the parent (50 mg; 0.11 mmol; 1 eq) with HCl in MeOH (84.82
.mu.l; 1.25 M; 0.11 mmol; 1 eq) affords 20 mg (37%) of the title
compound as a yellow solid. 1H NMR (DMSO-d6) .delta. 12.28 (br s,
1H), 8.88 (s, 1H), 8.27 (br s, 2H), 7.94-7.85 (m, 1H), 7.84 (d,
J=3.8 Hz, 1H), 7.54-7.51 (m, 1H), 7.37-7.28 (m, 4H), 7.19 (d, J=3.8
Hz, 1H), 6.18 (t, J=2.3 Hz, 1H), 4.23-4.16 (m, 2H), 3.70 (s, 6H).
HPLC (max plot) 95.99%; Rt 3.16 min. LC/MS: (ES+): 472.5, (ES-):
470.4.
Example A
Biological Assays
[0708] The efficacy of compounds of the invention in inhibiting the
PI3K induced-lipid phosphorylation may be tested in the following
binding assay.
[0709] The assay combines the scintillation proximity assay
technology (SPA, Amersham) with the capacity of neomycin (a
polycationic antibiotic) to bind phospholipids with high affinity
and specificity. The Scintillation Proximity Assay is based on the
properties of weakly emitting isotopes (such as .sup.3H, .sup.125I,
.sup.33P). Coating SPA beads with neomycin allows the detection of
phosphorylated lipid substrates after incubation with recombinant
PI3K and radioactive ATP in the same well, by capturing the
radioactive phospholipids to the SPA beads through their specific
binding to neomycin.
[0710] To a 96 wells MTP containing 10 .mu.l of the test compound
of Formula (I) (solubilized in 10% DMSO; to yield a concentration
of 100, 25, 5.0, 1.25, 0.312, 0.078, 0.0195, 0.00488, 0.00122 and
0.0003 .mu.M of the test compound), the following assay components
are added: 1) 10 .mu.l of lipid micelles 2) 20 .mu.l of Kinase
buffer ([.sup.33P].gamma.-ATP 162 .mu.M/300 nCi, MgCl.sub.2 2.5 mM,
DTT 2.5 mM, Na.sub.3VO.sub.4 25 .mu.M in Hepes 40 mM, pH 7.4) and
3) 10 .mu.l (100 ng) of Human recombinant GST-PI3.delta. (in Hepes
40 mM, pH 7.4, ethylenglycol 4%). After incubation at room
temperature for 120 minutes, with gentle agitation, the reaction is
stopped by addition of 200 .mu.l of a solution containing 250 .mu.g
of neomycin-coated PVT SPA beads, ATP 60 mM and EDTA 6.2 mM in PBS.
The assay is further incubated at room temperature for 60 minutes
with gentle agitation to allow binding of phospholipids to
neomycin-SPA beads. After precipitation of the neomycin-coated PVT
SPA beads for 5 minutes at 1500.times.g, radioactive PtdIns(3)P is
quantified by scintillation counting in a Wallac MicroBeta.TM.
plate counter.
[0711] The values indicated in Table I below refer to the IC.sub.50
(.mu.M) with respect to PI3K, i.e. the amount necessary to achieve
50% inhibition of said target. Said values show a considerable
inhibitory potency of pyrazine compounds with regard to PI3K.
[0712] Examples of inhibitory activities for compounds of the
invention are set out in Table I below.
TABLE-US-00002 TABLE I IC.sub.50 values of pyrazine derivatives
against PI3K. PI3K Example No. IC.sub.50 (.mu.M) 29 0.240 13 0.080
11 0.430 86 0.073 65 0.056 144 0.030 138 0.027
Example B
SCF-Induced PKB/Akt Phosphorylation in Mast Cells
[0713] Protocol: Primary bone marrow cells were isolated from 4-8
weeks old wild type mice and derived to mast cells by incubation
with medium containing 20 ng/mL of stem cell factor (SCF)
(PeproTech, Switzerland) and 20 ng/mL of IL-3 (PeproTech,
Switzerland) for at least 4 weeks. Confirmation of the expression
of mast cell specific surface markers was done by FACS analysis
using antibodies against c-kit (cKit-PE mouse antibody;
Pharmingen). Cells were maintained in culture in the presence of
SCF and IL-3. To induce PKB/Akt phosphorylation, mast cells were
resuspended at 2.5.times.10.sup.6 cells/mL and starved in medium
containing no SCF or IL-3 for 24 h. After preincubation with
compounds or 1% DMSO for 20 minutes, cells were activated with 20
ng/mL of SCF for 15 minutes at 37.degree. C., fixed in 1.5%
paraformaldehyde for 20 minutes and permeabilised with 0.2% Triton
X-100 for 10 minutes, at room temperature. PKB/Akt phosphorylation
was visualized using phospho-Ser-473 specific Akt antibodies (Cell
Signaling) and standard FACS protocols.
[0714] Results: Inhibition of SCF-Induced Akt Phosphorylation
[0715] Examples of inhibitory activities for compounds of the
invention are set out in Table II below.
TABLE-US-00003 TABLE II Example No. IC50 .mu.M 150 0.09 130 0.13
131 0.15 138 0.18 134 0.21 139 0.27 39 0.35 149 0.39 137 0.40 20
0.41 135 0.54 132 0.68 109 0.82 65 1.19 106 1.22 136 1.22 95 1.60
38 1.89 56 2.42
Example C
IgM-Induced Akt Phosphorylation in B Cell
[0716] Protocol:
[0717] In vitro stimulation:
[0718] Human PBMC were prepared from a Buffy coat (Geneve Hospital)
after a Ficoll gradient (FICOLL-PAQUE Plus PHARMACIA ref:
17-1440-03).
[0719] Cell concentration was adjusted to 10.sup.6 cells per ml in
RPMI (GIBCO Ref: 72400-21) without serum. Before stimulation, 90
.mu.l of PBMC suspension was incubated with 10 .mu.l of diluted
compound in a 96 well round bottom plate for 20 minutes at
37.degree. C.
[0720] For B cell activation, 30 .mu.l of Fab'2 Goat anti IgM
(Jackson Immuno-research) at 10 .mu.g/ml was added to each well.
After 5 minutes, cell activation was stopped with 4%
paraformaldehyde (10 minutes at room temperature).
[0721] Fixed PBMC were then treated for 20 minutes with 0.15%
Triton, washed twice with PBS and permeabilized with 50% methanol
for 15 minutes.
[0722] Surface staining:
[0723] PBMC were washed twice in PBS, resuspended in: PBS-4% FCS
and incubated with anti P-Akt (1/100 dilution) for one hour at room
temperature.
[0724] After one wash, PBMC were further stained for 30 minutes
with a mixture of anti --CD19-PE (BD Biosciences), anti-IgM-FITC
(BD Biosciences) and goat anti rabbit IgG-Alexa 647 (Molecular
probe).
[0725] Flow Cytometry Analysis
[0726] After washing, PBMC (Peripheral Blood Mononuclear Cells)
were analysed on a FACSCalibur instrument (BD Biosciences) equipped
with a 633 helium-neon laser, or stored at 4.degree. C. for further
analysis. 510.sup.3 B cells events were gathered per sample in the
CD19 positive region.
[0727] For the analysis, a threshold was applied on P-Akt histogram
of CD19+ IgM+ lymphocytes cells from the non stimulated samples and
the percentage of cells above this threshold was determined for
each sample.
[0728] Results: Inhibition of IgM-induced Akt phosphorylation.
[0729] Examples of inhibitory activities for compounds of the
invention are set out in Table III below.
TABLE-US-00004 TABLE III Example No. IC50 .mu.M 150 0.007 39 0.011
131 0.013 138 0.016 65 0.021 20 0.024 15 0.026 111 0.026 139 0.027
13 0.03 14 0.034 137 0.04 38 0.04 130 0.06 42 0.11 110 0.14 101
0.15 129 0.29 136 0.37
Example D
Passive Cutaneous Anaphylaxis (PCA)
[0730] Protocol:
[0731] Female Balb/c mice (Elevage Janvier) (8 week old) were
intradermally injected by anti-DNP IgE (50 ng in 20 .mu.l, id, 2
sites of injection) on their shaved backs. Twenty four hours later
they received an intravenous injection of DNP-human serum albumin
(50 .mu.g/mouse) and Evans blue (25 mg/kg) by retroorbital
injection. Thirty minutes later, the animals were sacrificed. The
skin of the back was removed. The extravasated dye (punch diameter:
5 mm) was extracted from 2 punches by 0.4 ml of formamide and was
quantified by fluorescence (E1: 585 nm, E2: 660 nm).
[0732] Inhibitors are administered by oral route at the dose of 30
mg/kg 2 hours before the challenge of DNP-human serum albumin and
Evans blue.
[0733] Results:
[0734] Using this protocol, Example 65 exhibits 84% inhibition of
vascular permeability at 30 mg/kg.
Example E
Preparation of a Pharmaceutical Formulation
[0735] Formulation 1--Tablets
[0736] A compound of Formula (I) is admixed as a dry powder with a
dry gelatin binder in an approximate 1:2 weight ratio. A minor
amount of magnesium stearate is added as a lubricant. The mixture
is formed into 240-270 mg tablets (80-90 mg of active pyrazine
compound per tablet) in a tablet press.
[0737] Formulation 2--Capsules
[0738] A compound of Formula (I) is admixed as a dry powder with a
starch diluent in an approximate 1:1 weight ratio. The mixture is
filled into 250 mg capsules (125 mg of active pyrazine compound per
capsule).
[0739] Formulation 3--Liquid
[0740] A compound of Formula (I) (1250 mg), sucrose (1.75 g) and
xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S.
sieve, and then mixed with a previously prepared solution of
microcrystalline cellulose and sodium carboxymethyl cellulose
(11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color
are diluted with water and added with stirring. Sufficient water is
then added to produce a total volume of 5 ml.
[0741] Formulation 4--Tablets
[0742] A compound of Formula (I) is admixed as a dry powder with a
dry gelatin binder in an approximate 1:2 weight ratio. A minor
amount of magnesium stearate is added as a lubricant. The mixture
is formed into 450-900 mg tablets (150-300 mg of active pyrazine
compound) in a tablet press.
[0743] Formulation 5--Injection
[0744] A compound of Formula (I) is dissolved in a buffered sterile
saline injectable aqueous medium to a concentration of
approximately 5 mg/ml.
* * * * *