U.S. patent application number 13/377745 was filed with the patent office on 2012-11-01 for compounds useful for treating cancer.
This patent application is currently assigned to SOCIETE SPLICOS. Invention is credited to Carsten Brock, Nathalie Cahuzac, Gilles Gadea, Florence Mahuteau, Romain Najman, Pierre Roux, Didier Scherrer, Jamal Tazi.
Application Number | 20120277230 13/377745 |
Document ID | / |
Family ID | 43309298 |
Filed Date | 2012-11-01 |
United States Patent
Application |
20120277230 |
Kind Code |
A1 |
Roux; Pierre ; et
al. |
November 1, 2012 |
COMPOUNDS USEFUL FOR TREATING CANCER
Abstract
The present invention relates to compound (I) wherein: means a
pyridazine, a pyrimidine or a pyrazine group, R independently
represent a hydrogen atom, a halogen atom or a group chosen among a
CN group, a hydroxyl group, a COOR.sub.1 group, a
(C.sub.1-C.sub.3)fluoroalkyl group, a (C.sub.1-C.sub.3)fluoroalkoxy
group, a NO.sub.2 group, a NR.sub.1R.sub.2 group, a
(C.sub.1-C.sub.4)alkoxy group, a phenoxy group and a
(C.sub.1-C.sub.3)alkyl group, said alkyl being optionally
mono-substituted by a hydroxyl group, n is 1, 2 or 3, n is 1 or 2,
R is a hydrogen atom, a halogen atom or a group chosen among a
(C.sub.1-C.sub.3)alkyl group, a hydroxyl group, a COOR.sub.1 group,
a NO.sub.2 group, a NR.sub.1R.sub.2 group, a morpholinyl or a
morpholino group, a N-methylpiperazinyl group, a
(C.sub.1-C.sub.3)fluoroalkyl group, a (C1-C4)alkoxy group and a CN
group, Z is N or C, Y is N or C, X is N or C, W is N or C, T is N
or C, U is N or C, for use as an agent for preventing, inhibiting
or treating cancer. Some of said compounds are new and also form
part of the invention. ##STR00001##
Inventors: |
Roux; Pierre;
(Saint-Gely-Du-Fesc, FR) ; Mahuteau; Florence;
(Saint Remy Les Chevreuse, FR) ; Najman; Romain;
(L'Hay-Les-Roses, FR) ; Tazi; Jamal; (Clapiers,
FR) ; Gadea; Gilles; (Matelles, FR) ;
Scherrer; Didier; (Castelnau Le Lez, FR) ; Brock;
Carsten; (Montpellier, FR) ; Cahuzac; Nathalie;
(Jacou, FR) |
Assignee: |
SOCIETE SPLICOS
MONTPELLIER
FR
UNIVERSITE MONTPELLIER 2
MONTPELLIER
FR
INSTITUT CURIE
PARIS
FR
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
PARIS
FR
|
Family ID: |
43309298 |
Appl. No.: |
13/377745 |
Filed: |
June 14, 2010 |
PCT Filed: |
June 14, 2010 |
PCT NO: |
PCT/IB10/52650 |
371 Date: |
July 5, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61186552 |
Jun 12, 2009 |
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61186544 |
Jun 12, 2009 |
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Current U.S.
Class: |
514/235.2 ;
435/375; 514/249; 514/255.05; 514/272; 514/313; 544/128; 544/331;
544/356; 544/405; 546/159; 546/160; 546/162 |
Current CPC
Class: |
C07D 215/46 20130101;
A61P 9/10 20180101; C07D 213/74 20130101; A61P 35/00 20180101; A61P
31/18 20180101; A61K 31/4709 20130101; A61P 37/04 20180101; A61P
3/10 20180101; A61P 17/18 20180101; C07D 403/12 20130101; C07D
215/42 20130101; A61K 31/4985 20130101; A61P 19/10 20180101; C07D
401/12 20130101; C07D 241/44 20130101; A61P 17/00 20180101; A61P
21/00 20180101; C07D 215/38 20130101; A61P 31/12 20180101; A61P
39/06 20180101; A61P 25/28 20180101; A61P 27/12 20180101; A61P
43/00 20180101 |
Class at
Publication: |
514/235.2 ;
546/162; 514/313; 546/160; 544/405; 514/255.05; 544/356; 514/249;
544/331; 514/272; 546/159; 544/128; 435/375 |
International
Class: |
A61K 31/4709 20060101
A61K031/4709; C07D 215/38 20060101 C07D215/38; A61K 31/497 20060101
A61K031/497; C07D 241/44 20060101 C07D241/44; C12N 5/09 20100101
C12N005/09; A61K 31/506 20060101 A61K031/506; C07D 215/42 20060101
C07D215/42; C07D 413/04 20060101 C07D413/04; A61K 31/5377 20060101
A61K031/5377; A61P 35/00 20060101 A61P035/00; C07D 401/12 20060101
C07D401/12; A61K 31/498 20060101 A61K031/498 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 12, 2009 |
EP |
09162630.9 |
Jun 12, 2009 |
EP |
09305540.8 |
Claims
1. A method of preventing, inhibiting, or treating cancer
comprising contacting a cell with at least one compound of formula
(I): ##STR00197## wherein: ##STR00198## is an aromatic ring wherein
V is C or N and when V is N, V is in an ortho, meta or para
position with respect to Z such that the ring respectively forms a
pyridazine, a pyrimidine, or a pyrazine, R independently represents
a hydrogen atom, a halogen atom or a group chosen among a --CN
group, a hydroxyl group, a --COOR.sub.1 group, a
(C.sub.1-C.sub.3)fluoroalkyl group, a (C.sub.1-C.sub.3)fluoroalkoxy
group, a --NO.sub.2 group, a --NR.sub.1R.sub.2 group, a
(C.sub.1-C.sub.4)alkoxy group, a phenoxy group and a
(C.sub.1-C.sub.3)alkyl group, said alkyl group being optionally
mono-substituted by a hydroxyl group, R.sub.1 and R.sub.2 are
independently a hydrogen atom or a (C.sub.1-C.sub.3)alkyl group, n
is 1, 2 or 3, n' is 1 or 2, R' is a hydrogen atom, a halogen atom
or a group chosen among a (C.sub.1-C.sub.3)alkyl group, a hydroxyl
group, a --COOR.sub.1 group, a --NO.sub.2 group, a
--NR.sub.1R.sub.2 group, a morpholinyl or a morpholino group, a
N-methylpiperazinyl group, a (C.sub.1-C.sub.3)fluoroalkyl group, a
(C.sub.1-C.sub.4)alkoxy group and a --CN group, R'' is a hydrogen
atom or a (C.sub.1-C.sub.4)alkyl group, Z is N or C, Y is N or C, X
is Nor C, W is N or C, T is N or C, U is N or C, and wherein at
most four of the groups V, T, U, Z, Y, X and W are N, and at least
one of the groups T, U, Y, X and W is N, or a pharmaceutically
acceptable salt thereof.
2. The method of claim 1, wherein Z is N, V is C, Y is N, X is C, T
is C, U is C and W is C, Z is C, V is C, Y is N, X is C, T is C, U
is C and W is C, Z is N, V is C, Y is C, X is N, T is C, U is C and
W is C, Z is N, V is C, Y is C, X is C, T is C, U is C and W is N,
Z is N, V is N and is in the para position with respect to Z, Y is
N, X is C, T is C, U is C and W is C Z is C, V is N and is in the
para position with respect to Z, Y is C, X is N, T is C, U is C and
W is C, Z is C, V is N and is in the meta position with respect to
Z and is in a para position with respect to the bond linked to
NR'', Y is N, X is C, T is C, U is C and W is C, Z is C, V is N and
is in the meta position with respect to Z and is in the para
position with respect to of the bond linked to NR'', Y is C, X is
N, T is C, U is C and W is C, Z is C, V is C, Y is C, X is N, T is
C, U is C and W is C, Z is C, V is C, Y is N, X is N, T is C, U is
C and W is C, Z is N, V is N and is in the meta position with
respect to Z and in an ortho position with respect to the bond
linked to NR'', Y is N, X is C, T is C, U is C and W is C, Z is N,
V is N and is in the para position with respect to Z, Y is C, X is
C, T is C, U is C and W is N, Z is N, V is N and is in the para
position with respect to Z, Y is C, X is N, T is C, U is C and W is
C, Z is N, V is C, Y is N, X is N, T is C, U is C and W is C, Z is
N, V is N and is in the meta position with respect to Z and is in
the ortho position with respect to of the bond linked to NR'', Y is
N, X is N, T is C, U is C and W is C, Z is C, V is C, Y is C, X is
C, T is N, U is C and W is C, Z is N, V is C, Y is C, X is C, T is
N, U is C and W is C, or Z is N, V is C, Y is C, X is C, T is C, U
is N and W is C.
3. The method of claim 1, wherein Z is N, V is C, Y is N, X is C, T
is C, U is C and W is C, Z is N, V is N and is in the para position
with respect to Z, Y is N, X is C, T is C, U is C and W is C, Z is
C, V is C, Y is C, X is C, T is N, U is C and W is C, or Z is N, V
is C, Y is C, X is C, T is C, U is N and W is C.
4. The method of claim 1, wherein the compound of formula (I) is
selected from the group consisting of ##STR00199## wherein: R
independently represents a hydrogen atom, a halogen atom or a group
chosen among a (C.sub.1-C.sub.3)alkyl group, a --CN group, a
hydroxyl group, a --COOR.sub.1 group, a
(C.sub.1-C.sub.3)fluoroalkyl group, a --NO.sub.2 group, a
--NR.sub.1R.sub.2 group and a (C.sub.1-C.sub.3)alkoxy group, R' is
a hydrogen atom, a halogen atom or a group chosen among a
(C.sub.1-C.sub.3)alkyl group, a --NO.sub.2 group, a
(C.sub.1-C.sub.3)alkoxy group and a --NR.sub.1R.sub.2 group,
R.sub.1 and R.sub.2 are a hydrogen atom or a (C.sub.1-C.sub.3)alkyl
group, ##STR00200## wherein: R independently represents a hydrogen
atom, a halogen atom or a group chosen among a
(C.sub.1-C.sub.3)alkyl group, a --NR.sub.1R.sub.2 group, a
(C.sub.1-C.sub.3)fluoroalkoxy group, a --NO.sub.2 group, a phenoxy
group and a (C.sub.1-C.sub.4)alkoxy group, R.sub.1 and R.sub.2 are
independently a hydrogen atom or a (C.sub.1-C.sub.3)alkyl group, R'
is a hydrogen atom, a halogen atom or a group chosen among a
(C.sub.1-C.sub.3)alkyl group and a (C.sub.1-C.sub.4)alkoxy group,
##STR00201## wherein: R independently represents a hydrogen atom or
a group chosen among a (C.sub.1-C.sub.3)alkyl group, a
(C.sub.1-C.sub.3)fluoroalkyl group, a --NR.sub.1R.sub.2 group, a
--COOR.sub.1 group, a--NO.sub.2 group and a (C.sub.1-C.sub.3)alkoxy
group, R' is a hydrogen atom, R.sub.1 and R.sub.2 are independently
a hydrogen atom or a (C.sub.t--C.sub.3)alkyl group, ##STR00202##
wherein: R independently represents a hydrogen atom or a group
chosen among a (C.sub.1-C.sub.3)alkyl group, a
(C.sub.1-C.sub.3)fluoroalkyl group and a (C.sub.1-C.sub.3)alkoxy
group, R' is a hydrogen atom, ##STR00203## wherein: R is a hydrogen
atom, R' is a hydrogen atom, a halogen atom or a group chosen among
a (C.sub.1-C.sub.3)alkyl group and a (C.sub.1-C.sub.3)alkoxy group,
##STR00204## wherein: R is a hydrogen atom, R' is a hydrogen atom,
##STR00205## wherein: R is a hydrogen atom, R' is a hydrogen atom
or a halogen atom, ##STR00206## wherein: R is a hydrogen atom, R'
is a hydrogen atom, ##STR00207## wherein: R independently
represents a hydrogen atom or a group chosen among a
(C.sub.1-C.sub.3)fluoroalkoxy group and a (C.sub.1-C.sub.3)alkoxy
group, R' is a hydrogen atom, ##STR00208## wherein: R independently
represents a hydrogen atom or a group chosen among a
(C.sub.1-C.sub.3)fluoroalkoxy group and a (C.sub.1-C.sub.3)alkyl
group, R' is a hydrogen atom, ##STR00209## wherein: R is a hydrogen
atom, R' is a hydrogen atom, a halogen atom or a
(C.sub.1-C.sub.3)alkyl group, ##STR00210## wherein: R is a hydrogen
atom, R' is a hydrogen atom, ##STR00211## wherein: R is a hydrogen
atom, R' is a hydrogen atom, ##STR00212## wherein: R independently
represents a hydrogen atom, a halogen atom or a group chosen among,
a --NO.sub.2 group, a --CN group and a (C.sub.1-C.sub.3)alkyl
group, said alkyl being optionally mono-substituted by a hydroxyl
group, R' is a hydrogen atom, a halogen atom or a
(C.sub.1-C.sub.3)fluoroalkyl group, ##STR00213## wherein: R is a
hydrogen atom, R' is a hydrogen atom, ##STR00214## wherein: R
independently represents a hydrogen atom, a (C.sub.1-C.sub.3)alkoxy
group or a (C.sub.1-C.sub.3)fluoroalkoxy group, R' is a hydrogen
atom or a group chosen among a --NR.sub.1R.sub.2 group, a
N-methylpiperazinyl group, a (C.sub.1-C.sub.3)alkoxy group and a
morpholino group, R.sub.1 and R.sub.2 are independently a hydrogen
atom or a (C.sub.1-C.sub.3)alkyl group, ##STR00215## wherein: R
independently represents a hydrogen atom or a
(C.sub.1-C.sub.3)alkyl group, R' is a hydrogen atom or a group
chosen among a --NR.sub.1R.sub.2 group, a morpholino group and a
(C.sub.1-C.sub.3)alkoxy group, R.sub.1 and R.sub.2 are
independently a hydrogen atom or a (C.sub.1-C.sub.3)alkyl group,
##STR00216## wherein: R independently represents a hydrogen atom, a
(C.sub.1-C.sub.3)alkyl group or a (C.sub.1-C.sub.3)fluoroalkyl
group, R' is a hydrogen atom or a (C.sub.1-C.sub.3)alkyl group, or
(19) a pharmaceutically acceptable salt thereof.
5. The method of claim 1 wherein the compound of formula (I) is
selected from the group consisting of: ##STR00217## wherein: R
independently represents a hydrogen atom, a halogen atom or a group
chosen among a (C.sub.1-C.sub.3)alkyl group, a--CN group, a
--COOR.sub.1 group and a (C.sub.1-C.sub.3)fluoroalkyl group,
R.sub.1 is a hydrogen atom or a (C.sub.1-C.sub.3)alkyl group, R' is
a hydrogen atom, a halogen atom or a (C.sub.1-C.sub.3)alkyl group,
##STR00218## wherein: R is a hydrogen atom, R' is a hydrogen atom
or a halogen atom, ##STR00219## wherein: R is a
(C.sub.1-C.sub.3)fluoroalkoxy group, ##STR00220## wherein: R is
independently a hydrogen atom or a (C.sub.1-C.sub.4)alkyl group, or
(5) a pharmaceutically acceptable salt thereof.
6. The method of claim 1, wherein the compound of formula (I) has
the formula (Iq) ##STR00221## wherein n is 1 or 2, with the proviso
that R' and R are not simultaneously a hydrogen atom, when R' is a
hydrogen atom, R is not a --NO.sub.2 group or a --NH.sub.2 group,
when n is 2 and R' is a hydrogen atom, R is not a COOC.sub.2H.sub.5
group or a chlorine atom, or a pharmaceutically acceptable salt
thereof.
7. The method of claim 1, wherein the compound of formula (I) has
the formula (Iee) ##STR00222## or a pharmaceutically acceptable
salt thereof, with the exclusion of the following compound
##STR00223## and with the exclusion of compounds wherein R is a
--NO.sub.2 group or a --NH.sub.2 group when R' is a hydrogen or a
methyl group.
8. A method of preventing, inhibiting, or treating cancer
comprising contacting a cell with at least one compound chosen
from: (1) (8-Chloro-quinolin-2-yl)-pyridin-2-yl-amine (2)
2-(Quinolin-2-ylamino)-isonicotinic acid (3)
(4-Methyl-pyridin-2-yl)-quinolin-2-yl-amine (4)
Pyridin-2-yl-quinolin-2-yl-amine (5)
2-(8-Chloro-quinolin-2-ylamino)-isonicotinic acid (6)
(8-Chloro-quinolin-2-yl)-(4-methyl-pyridin-2-yl)-amine (7)
6-(Quinolin-2-ylamino)-nicotinonitrile (8)
Quinolin-2-yl-(4-trifluoromethoxy-phenyl)-amine (9)
Pyridin-2-yl-quinolin-3-yl-amine (10)
(3-Methoxy-pyridin-2-yl)-quinolin-3-yl-amine (11)
Quinolin-3-yl-(5-trifluoromethyl-pyridin-2-yl)-amine (12)
(5-Nitro-pyridin-2-yl)-quinolin-3-yl-amine (13)
(5-Methyl-pyridin-2-yl)-quinolin-3-yl-amine (14)
2-(Quinolin-3-ylamino)-isonicotinic acid (15)
Quinolin-6-yl-(5-trifluoromethyl-pyridin-2-yl)-amine (16)
(6-Methyl-pyridin-2-yl)-quinolin-6-yl-amine (17)
N-(6-methylpyridin-2-yl)quinolin-2-amine (18)
8-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine (19)
4-methyl-N-(pyridin-2-yl)quinolin-2-amine (20)
4-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine (21)
3-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine (22)
3-methyl-N-(pyridin-2-yl)quinolin-2-amine (23)
6-((4-methylquinolin-2-yl)amino)nicotinonitrile (24)
6-((3-methylquinolin-2-yl)amino)nicotinonitrile (25)
6-chloro-N-(4-methylpyridin-2-yl)quinolin-2-amine (26)
6-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine (27)
4-methyl-N-(5-nitropyridin-2-yl)quinolin-2-amine (28)
N-(3-nitropyridin-2-yl)quinolin-2-amine (29)
8-chloro-N-(3-nitropyridin-2-yl)quinolin-2-amine (30)
2-((4-methylquinolin-2-yl)amino)nicotinonitrile (31)
N-(3-methylpyridin-2-yl)quinolin-2-amine (32)
N-(5-methylpyridin-2-yl)quinolin-2-amine (33)
2-(quinolin-2-ylamino)isonicotinonitrile (34)
N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine (35)
8-chloro-N-(3-methylpyridin-2-yl)quinolin-2-amine (36)
8-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine (37)
8-chloro-N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine (38)
N-(3-methoxypyridin-2-yl)quinolin-2-amine (39)
N-(5-nitropyridin-2-yl)quinolin-2-amine (40)
6-((8-chloroquinolin-2-yl)amino)nicotinonitrile (41)
N-(5-fluoropyridin-2-yl)quinolin-2-amine (42)
N-(6-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine (43)
8-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine (44)
2-((8-chloroquinolin-2-yl)amino)nicotinic acid (45)
4-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine (46)
3-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine (47)
5-cyano-2-(quinolin-2-ylamino)pyridin-1-ium chloride (48)
2-((8-chloroquinolin-2-yl)amino)-4-methylpyridin-1-ium chloride
(49) 8-chloro-N-(4-ethylpyridin-2-yl)quinolin-2-amine (50)
8-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine (51)
8-chloro-N-(4,6-dimethylpyridin-2-yl)quinolin-2-amine (52)
6-((8-chloroquinolin-2-yl)amino)-2-methylnicotinonitrile (53)
8-chloro-N-(4-chloropyridin-2-yl)quinolin-2-amine (54)
8-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine (55)
N-(5-bromo-4-methylpyridin-2-yl)-8-chloroquinolin-2-amine (56)
8-chloro-N-(3-ethyl-6-methylpyridin-2-yl)quinolin-2-amine (57)
8-fluoro-N-(4-methylpyridin-2-yl)quinolin-2-amine (58)
8-bromo-N-(4-methylpyridin-2-yl)quinolin-2-amine (59) methyl
6-(quinolin-2-ylamino)nicotinate (60) methyl
6-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate (61) methyl
6-[(3-methylquinolin-2-yl)amino]pyridine-3-carboxylate (62) methyl
2-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate (63)
8-methoxy-N-(4-methylpyridin-2-yl)quinolin-2-amine (64)
N-(4-methylpyridin-2-yl)-5-nitroquinolin-2-amine (65)
2-N-(4-methylpyridin-2-yl)quinoline-2,8-diamine (66)
2-N-(4-methylpyridin-2-yl)quinoline-2,5-diamine (67) methyl
6-[(4-methylquinolin-2-yl)amino]pyridine-3-carboxylate (68)
8-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine (69)
2-[(8-chloroquinolin-2-yl)amino]pyridin-3-ol (70)
8-chloro-N-[6-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine (71)
6-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine (72)
N-(6-ethylpyridin-2-yl)-3-methylquinolin-2-amine (73)
N-(5-fluoropyridin-2-yl)-3-methylquinolin-2-amine (74)
3-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine (75)
4-N-(8-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine
(76) N-(4-methoxyphenyl)quinolin-2-amine (77)
8-chloro-N-(4-methoxyphenyl)quinolin-2-amine (78)
4-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine (79)
N-(4-methoxyphenyl)-3-methylquinolin-2-amine (80)
3-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine (81)
1-N,1-N-dimethyl-4-N-(3-methylquinolin-2-yl)benzene-1,4-diamine
(82) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine (83)
N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine (84)
N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine (85)
N-(4-nitrophenyl)quinolin-2-amine (86)
N-(3-fluorophenyl)quinolin-2-amine (87)
8-chloro-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine (88)
8-chloro-N-(3-fluorophenyl)quinolin-2-amine (89)
2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride (90)
8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine (91)
3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine
(92) 3-methyl-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine (93)
3-methyl-N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine (94)
8-chloro-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine
(95) 3-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium
chloride (96)
6-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine (97)
4-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium
chloride (98)
8-bromo-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine (99)
8-fluoro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine (100)
8-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine (101)
N-(4-butoxyphenyl)-8-chloroquinolin-2-amine (102)
N-(4-phenoxyphenyl)quinolin-2-amine (103)
8-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine (104)
8-chloro-N-[3-chloro-4-(trifluoromethoxy)phenyl]quinolin-2-amine
(105) N-(6-methylpyridin-2-yl)quinolin-3-amine (106)
N-(3-nitropyridin-2-yl)quinolin-3-amine (107)
N-(5-methylpyridin-2-yl)quinolin-6-amine (108)
N-(3-methoxypyridin-2-yl)quinolin-6-amine (109)
6-chloro-N-(pyrazin-2-yl)quinolin-2-amine (110)
8-bromo-N-(pyrazin-2-yl)quinolin-2-amine (111)
8-methyl-N-(pyrazin-2-yl)quinolin-2-amine (112)
8-chloro-N-(pyrazin-2-yl)quinolin-2-amine (113)
N-(pyrazin-2-yl)quinolin-2-amine (114)
4-methyl-N-(pyrazin-2-yl)quinolin-2-amine (115)
3-methyl-N-(pyrazin-2-yl)quinolin-2-amine (116)
8-fluoro-N-(pyrazin-2-yl)quinolin-2-amine (117)
8-methoxy-N-(pyrazin-2-yl)quinolin-2-amine (118)
N-(pyridin-3-yl)quinolin-3-amine (119)
8-chloro-N-(pyridin-4-yl)quinolin-2-amine (120)
N-(pyridin-4-yl)quinolin-2-amine (121)
N-(pyridin-4-yl)quinolin-3-amine (122)
N-[4-(trifluoromethoxy)phenyl]quinolin-3-amine (123)
N-(4-methoxyphenyl)quinolin-3-amine (124)
N-[4-(trifluoromethoxy)phenyl]quinoxalin-2-amine (125)
N-[2-methyl-4-(trifluoromethoxy)phenyl]quinoxalin-2-amine (126)
N-[3-(trifluoromethoxy)phenyl]quinoxalin-2-amine (127)
N-[2-(trifluoromethoxy)phenyl]quinoxalin-2-amine (128)
N-(pyrimidin-2-yl)quinolin-2-amine (129)
8-chloro-N-(pyrimidin-2-yl)quinolin-2-amine (130)
4-methyl-N-(pyrimidin-2-yl)quinolin-2-amine (131)
N-(pyrazin-2-yl)quinolin-6-amine (132)
N-(pyrazin-2-yl)quinolin-3-amine (133)
6-methyl-N-(naphthalen-2-yl)pyridin-2-amine (134)
N-(naphthalen-2-yl)pyridin-2-amine (135)
N-(pyridin-2-yl)quinoxalin-2-amine (136)
N-(4-methylpyridin-2-yl)quinoxalin-2-amine (137)
6-(quinoxalin-2-ylamino)pyridine-3-carbonitrile (138)
N-(6-methylpyridin-2-yl)quinoxalin-2-amine (139)
N-(4-methylpyridin-2-yl)-3-(trifluoromethyl)quinoxalin-2-amine
(140) N-(3,5-dichloro-4-methylpyridin-2-yl)quinoxalin-2-amine (141)
N-(4-methyl-3-nitropyridin-2-yl)quinoxalin-2-amine (142)
N-(pyrimidin-2-yl)quinoxalin-2-amine (143)
4-N,4-N-dimethyl-7-N-[4-(trifluoromethoxy)phenyl]quinoline-4,7-diamine
(144)
4-(morpholin-4-yl)-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine
(145) 4-methoxy-N-(pyridin-2-yl)quinolin-7-amine (146)
4-methoxy-N-(4-methylpyridin-2-yl)quinolin-7-amine (147)
4-N,4-N-dimethyl-7-N-(4-methylpyridin-2-yl)quinoline-4,7-diamine
(148) 5,8-dimethyl-N-(5-methylpyridin-2-yl)isoquinolin-6-amine
(149) 5,8-dimethyl-N-(5-methylpyridin-2-yl)isoquinolin-6-amine
(150) N-(4-methylpyridin-2-yl)-8-nitroquinolin-2-amine (151)
6-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine (152)
6-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine (153)
6-chloro-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine (154)
N2-(8-chloroquinolin-2-yl)-4-methylpyridine-2,3-diamine (155)
N-(4-butoxyphenyl)-3-methylquinolin-2-amine (156)
4-N-(6-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine
(157) 8-chloro-N-(3-chloro-4-methoxyphenyl)quinolin-2-amine (158)
N1-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine
(159) 2-{4-[(8-chloroquinolin-2-yl)amino]phenoxy}ethan-1-ol (160)
6-chloro-N-(4-methylpyridin-2-yl)quinoxalin-2-amine (161)
N-(4-ethylpyridin-2-yl)quinoxalin-2-amine (162)
N-(5-bromo-4-methylpyridin-2-yl)quinoxalin-2-amine (163)
N-(4,6-dimethylpyridin-2-yl)quinoxalin-2-amine (164)
[2-(quinoxalin-2-ylamino)pyridin-4-yl]methanol (165)
N-(4-methyl-5-nitropyridin-2-yl)quinoxalin-2-amine (166)
N-(4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)quinolin-7-amine
(167) 4-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine
(168) N-(4-methylpyridin-2-yl)-4-(morpholin-4-yl)quinolin-7-amine
and a pharmaceutically acceptable salt thereof.
9. The method of claim 8, wherein the compound is chosen among the
compounds (1), (2), (5)-(7), (10)-(16), (18), (21)-(44), (46)-(74),
(105)-(108), (124)-(130), (135)-(141), (145)-(147), (150)-(154),
(159), (160)-(165), and (168) and the pharmaceutically acceptable
salts are hydrobromide, tartrate, citrate, trifluoroacetate,
ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate,
formate, acetate and fumarate.
10. The method of claim 1, wherein compound is in a pharmaceutical
composition.
11. The method of claim 9, wherein the compound is in a
pharmaceutical composition.
12. The method of claim 1, further comprising a step of
administering the compound to a patient in need of cancer
treatment.
13. The method of claim 12, comprising orally administering the
compound.
14. The method of claim 8, further comprising a step of
administering the compound to a patient in need of cancer
treatment.
15. The method of claim 14, comprising orally administering the
compound.
16. A compound selected from the group consisting of: ##STR00224##
wherein R independently represents a hydrogen atom, a halogen atom
or a group chosen among a --CN group, a hydroxyl group, a
--COOR.sub.1 group, a (C.sub.1-C.sub.3)fluoroalkyl group, a
(C.sub.1-C.sub.3)fluoroalkoxy group, a --NO.sub.2 group, a
--NR.sub.1R.sub.2 group, a (C.sub.1-C.sub.4)alkoxy group, a phenoxy
group and a (C.sub.1-C.sub.3)alkyl group, said alkyl group being
optionally mono-substituted by a hydroxyl group, R.sub.1 and
R.sub.2 are independently a hydrogen atom or a
(C.sub.1-C.sub.3)alkyl group, n is 1 or 2, n' is 1 or 2, R' is a
hydrogen atom, a halogen atom or a group chosen among a
(C.sub.1-C.sub.3)alkyl group, a hydroxyl group, a --COOR.sub.1
group, a --NO.sub.2 group, a --NR.sub.1R.sub.2 group, a morpholinyl
or a morpholino group, a N-methylpiperazinyl group, a
(C.sub.1-C.sub.3)fluoroalkyl group, a (C.sub.1-C.sub.4)alkoxy group
and a --CN group, R'' is a hydrogen atom or a
(C.sub.1-C.sub.4)alkyl group, with the proviso that R' and R are
not simultaneously a hydrogen atom, when R' is a hydrogen atom, R
is not a --NO.sub.2 group or a --NH.sub.2 group, when n is 2 and R'
is a hydrogen atom, R is not a COOC.sub.2H.sub.5 group or a
chlorine atom, ##STR00225## wherein: R independently represents a
hydrogen atom, a halogen atom or a group chosen among a --CN group,
a hydroxyl group, a --COOR.sub.1 group, a
(C.sub.1-C.sub.3)fluoroalkyl group, a (C.sub.1-C.sub.3)fluoroalkoxy
group, a --NO.sub.2 group, a --NR.sub.1R.sub.2 group, a
(C.sub.1-C.sub.4)alkoxy group, a phenoxy group and a
(C.sub.1-C.sub.3)alkyl group, said alkyl group being optionally
mono-substituted by a hydroxyl group, R.sub.1 and R.sub.2 are
independently a hydrogen atom or a (C.sub.1-C.sub.3)alkyl group, n
is 1, 2 or 3, n' is 1 or 2, R' is a hydrogen atom, a halogen atom
or a group chosen among a (C.sub.1-C.sub.3)alkyl group, a hydroxyl
group, a --COOR.sub.1 group, a --NO.sub.2 group, a
--NR.sub.1R.sub.2 group, a morpholinyl or a morpholino group, a
N-methylpiperazinyl group, a (C.sub.1-C.sub.3)fluoroalkyl group, a
(C.sub.1-C.sub.4)alkoxy group and a --CN group, R'' is a hydrogen
atom or a (C.sub.1-C.sub.4)alkyl group, with the exclusion of the
following compound ##STR00226## and with the exclusion of compounds
wherein R is a --NO.sub.2 group or a --NH.sub.2 group when R' is a
hydrogen or a methyl group, and (3) a pharmaceutically acceptable
salt thereof.
17. A compound selected from the group consisting of: (1)
(8-Chloro-quinolin-2-yl)-pyridin-2-yl-amine (2)
2-(Quinolin-2-ylamino)-isonicotinic acid (5)
2-(8-Chloro-quinolin-2-ylamino)-isonicotinic acid (6)
(8-Chloro-quinolin-2-yl)-(4-methyl-pyridin-2-yl)-amine (7)
6-(Quinolin-2-ylamino)-nicotinonitrile (18)
8-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine (46)
3-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine (47)
5-cyano-2-(quinolin-2-ylamino)pyridin-1-ium chloride (48)
2-((8-chloroquinolin-2-yl)amino)-4-methylpyridin-1-ium chloride
(49) 8-chloro-N-(4-ethylpyridin-2-yl)quinolin-2-amine (50)
8-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine (51)
8-chloro-N-(4,6-dimethylpyridin-2-yl)quinolin-2-amine (52)
6-((8-chloroquinolin-2-yl)amino)-2-methylnicotinonitrile (53)
8-chloro-N-(4-chloropyridin-2-yl)quinolin-2-amine (54)
8-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine (55)
N-(5-bromo-4-methylpyridin-2-yl)-8-chloroquinolin-2-amine (56)
8-chloro-N-(3-ethyl-6-methylpyridin-2-yl)quinolin-2-amine (57)
8-fluoro-N-(4-methylpyridin-2-yl)quinolin-2-amine (58)
8-bromo-N-(4-methylpyridin-2-yl)quinolin-2-amine (59) methyl
6-(quinolin-2-ylamino)nicotinate (60) methyl
6-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate (61) methyl
6-[(3-methylquinolin-2-yl)amino]pyridine-3-carboxylate (62) methyl
2-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate (63)
8-methoxy-N-(4-methylpyridin-2-yl)quinolin-2-amine (64)
N-(4-methylpyridin-2-yl)-5-nitroquinolin-2-amine (65)
2-N-(4-methylpyridin-2-yl) quinoline-2,8-diamine (66)
2-N-(4-methylpyridin-2-yl)quinoline-2,5-diamine (67) methyl
6-[(4-methylquinolin-2-yl)amino]pyridine-3-carboxylate (68)
8-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine (69)
2-[(8-chloroquinolin-2-yl)amino]pyridin-3-.beta.1 (70)
8-chloro-N-[6-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine (71)
6-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine (72)
N-(6-ethylpyridin-2-yl)-3-methylquinolin-2-amine (73)
N-(5-fluoropyridin-2-yl)-3-methylquinolin-2-amine (74)
3-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine (150)
N-(4-methylpyridin-2-yl)-8-nitroquinolin-2-amine (151)
6-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine (152)
6-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine (153)
6-chloro-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine and
(154) N2-(8-chloroquinolin-2-yl)-4-methylpyridine-2,3-diamine and a
pharmaceutically acceptable salt, wherein the pharmaceutically
acceptable salt is selected from hydrobromide, tartrate, citrate,
trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate,
maleate, mesylate, formate, acetate and fumarate.
Description
FIELD OF THE INVENTION
[0001] The present invention is generally dedicated to the use of
compounds for the manufacture of compositions useful to treat
cancer.
BACKGROUND OF THE INVENTION
[0002] In most of the cancers, mortality is not due to the primary
tumor but rather to the derived metastases. This malignant
progression which leads to tumor invasion and is clinically defined
by the appearance of metastases is the final outcome of the primary
loss of cell adhesion and increase of cell motility which together
allow invasive cell to leave the initial tumor site and colonize
various target tissues.
[0003] Metastases are considered as a recurrent feature of
uncontrolled malignant progression of cancer. During this process,
tumor cells complete their malignant transformation by increasing
their migratory capacity. Cancer cells can then disseminate and
establish tumor foci in far away sites. Spreading of cancer cells
in the organism is the outcome of a series of events called
<<metastatic cascade>>: invasion of the tissues around
the tumor, venous or lymphatic intravasation, migration and
establishment in a distant place of a new colony that escapes from
all the defence mechanisms of the organism.
[0004] Metastatic invasion, against which there is no efficient
therapeutic option available at this time, is by far the major
cause of death. Due to the frequency of cancers diagnosed at the
metastatic stage and to the therapeutic impasse they represent, the
development of molecules that specifically target metastatic
invasion is thus a crucial requirement for a major breakthrough in
cancer treatments.
[0005] The present invention is in keeping with the evidence as
published during the last twenty years of a link between changes in
RNA alternative splicing and metastatic invasion which has opened
to new therapeutic strategies.
SUMMARY OF THE INVENTION
[0006] It has now been found that derivatives of formula (I) as
defined in formula (I) hereinafter are able to correct defects of
alternative splicing, as illustrated in the experimental data
hereinafter, a mechanism closely associated with the invasive
progression of metastatic cancers, and on the basis of such
activity, the compounds are useful in the treatment of cancer.
[0007] The present invention therefore relates to compounds of
formula (I) as defined below for use as agents for preventing,
inhibiting or treating cancer.
[0008] The present invention moreover relates to a method of
preventing, inhibiting or treating cancer, which comprises at least
one step consisting in administering to a patient suffering
therefrom an effective amount of a compound as defined in formula
(I) below or one of its pharmaceutically acceptable salts.
[0009] The present invention further relates to some particular
derivatives as such, as defined below.
[0010] The present invention also provides pharmaceutical
compositions comprising at least one of said particular
compounds.
DETAILED DESCRIPTION OF THE INVENTION
[0011] According to a first aspect, a subject-matter of the present
invention relates to a compound of formula (I)
##STR00002## [0012] wherein:
##STR00003##
[0013] means an aromatic ring wherein V is C or N and when V is N,
V is in ortho, meta or para of Z, i.e. forms respectively a
pyridazine, a pyrimidine or a pyrazine group,
[0014] R independently represent a hydrogen atom, a halogen atom or
a group chosen among a --CN group, a hydroxyl group, a --COOR.sub.1
group, a (C.sub.1-C.sub.3)fluoroalkyl group, a
(C.sub.1-C.sub.3)fluoroalkoxy group, a --NO.sub.2 group, a
--NR.sub.1R.sub.2 group, a (C.sub.1-C.sub.4)alkoxy group, a phenoxy
group and a (C.sub.1-C.sub.3)alkyl group, said alkyl being
optionally mono-substituted by a hydroxyl group,
[0015] R.sub.1 and R.sub.2 are independently a hydrogen atom or a
(C.sub.1-C.sub.3)alkyl group,
[0016] n is 1, 2 or 3,
[0017] n' is 1 or 2,
[0018] R' is a hydrogen atom or a group chosen among a
(C.sub.1-C.sub.3)alkyl group, a halogen atom, a hydroxyl group, a
--COOR.sub.1 group, a --NO.sub.2 group, a --NR.sub.1R.sub.2 group,
a morpholinyl or a morpholino group, a N-methylpiperazinyl group, a
(C.sub.1-C.sub.3)fluoroalkyl group, a (C.sub.1-C.sub.4)alkoxy group
and a --CN group,
[0019] R'' is a hydrogen atom or a (C.sub.1-C.sub.4)alkyl
group,
[0020] Z is N or C,
[0021] Y is N or C,
[0022] X is N or C,
[0023] W is N or C,
[0024] T is N or C,
[0025] U is N or C,
[0026] and wherein at most four of the groups V, T, U, Z, Y, X and
W are N,
[0027] and at least one of the groups T, U, Y, X and W is N,
[0028] or anyone of its pharmaceutically acceptable salt,
[0029] for use as an agent for preventing, inhibiting or treating
cancer.
[0030] According to one aspect, the present invention relates to a
compound of formula (I) as defined above, wherein Z is N, V is C, Y
is N, X is C, T is C, U is C and W is C, for use as an agent for
preventing, inhibiting or treating cancer.
[0031] According to another aspect, the present invention relates
to a compound of formula (I) as defined above, wherein Z is C, V is
C, Y is N, X is C, T is C, U is C and W is C, for use as an agent
for preventing, inhibiting or treating cancer.
[0032] According to another aspect, the present invention relates
to a compound of formula (I) as defined above, wherein Z is N, V is
C, Y is C, X is N, T is C, U is C and W is C, for use as an agent
for preventing, inhibiting or treating cancer.
[0033] According to another aspect, the present invention relates
to a compound of formula (I) as defined above, wherein Z is N, V is
C, Y is C, X is C, T is C, U is C and W is N, for use as an agent
for preventing, inhibiting or treating cancer.
[0034] According to another aspect, the present invention relates
to a compound of formula (I) as defined above, wherein Z is N, V is
N and is in para of Z, Y is N, X is C, T is C, U is C and W is C,
for use as an agent for preventing, inhibiting or treating
cancer.
[0035] According to another aspect, the present invention relates
to a compound of formula (I) as defined above, wherein Z is C, V is
N and is in para of Z, Y is C, X is N, T is C, U is C and W is C,
for use as an agent for preventing, inhibiting or treating
cancer.
[0036] According to another aspect, the present invention relates
to a compound of formula (I) as defined above, wherein Z is C, V is
N and is in meta of Z and is in para of the bond linked to NR'', Y
is N, X is C, T is C, U is C and W is C, for use as an agent for
preventing, inhibiting or treating cancer.
[0037] According to another aspect, the present invention relates
to a compound of formula (I) as defined above, wherein Z is C, V is
N and is in meta of Z and is in para of the bond linked to NR'', Y
is C, X is N, T is C, U is C and W is C, for use as an agent for
preventing, inhibiting or treating cancer.
[0038] According to another aspect, the present invention relates
to a compound of formula (I) as defined above, wherein Z is C, V is
C, Y is C, X is N, T is C, U is C and W is C, for use as an agent
for preventing, inhibiting or treating cancer.
[0039] According to another aspect, the present invention relates
to a compound of formula (I) as defined above, wherein Z is C, V is
C, Y is N, X is N, T is C, U is C and W is C, for use as an agent
for preventing, inhibiting or treating cancer.
[0040] According to another aspect, the present invention relates
to a compound of formula (I) as defined above, wherein Z is N, V is
N and is in meta of Z and in ortho of the bond linked to NR'', Y is
N, X is C, T is C, U is C and W is C, for use as an agent for
preventing, inhibiting or treating cancer.
[0041] According to another aspect, the present invention relates
to a compound of formula (I) as defined above, wherein Z is N, V is
N and is in para of Z, Y is C, X is C, T is C, U is C and W is N,
for use as an agent for preventing, inhibiting or treating
cancer.
[0042] According to another aspect, the present invention relates
to a compound of formula (I) as defined above, wherein Z is N, V is
N and is in para of Z, Y is C, X is N, T is C, U is C and W is C,
for use as an agent for preventing, inhibiting or treating
cancer.
[0043] According to another aspect, the present invention relates
to a compound of formula (I) as defined above, wherein Z is N, V is
C, Y is N, X is N, T is C, U is C and W is C, for use as an agent
for preventing, inhibiting or treating cancer.
[0044] According to another aspect, the present invention relates
to a compound of formula (I) as defined above, wherein Z is N, V is
N and is in meta of Z and is in ortho of the bond linked to NR'', Y
is N, X is N, T is C, U is C and W is C, for use as an agent for
preventing, inhibiting or treating cancer.
[0045] According to another aspect, the present invention relates
to a compound of formula (I) as defined above, wherein Z is C, V is
C, Y is C, X is C, T is N, U is C and W is C, for use as an agent
for preventing, inhibiting or treating cancer.
[0046] According to another aspect, the present invention relates
to a compound of formula (I) as defined above, wherein Z is N, V is
C, Y is C, X is C, T is N, U is C and W is C, for use as an agent
for preventing, inhibiting or treating cancer.
[0047] According to another aspect, the present invention relates
to a compound of formula (I) as defined above, wherein Z is N, V is
C, Y is C, X is C, T is C, U is N and W is C, for use as an agent
for preventing, inhibiting or treating cancer.
[0048] According to one preferred aspect, the present invention
relates to a compound of formula (I) as defined above, wherein Z is
N, V is C, Y is N, X is C, T is C, U is C and W is C, for use as an
agent for preventing, inhibiting or treating cancer.
[0049] According to another preferred aspect, the present invention
relates to a compound of formula (I) as defined above, wherein Z is
N, V is N and is in para of Z, Y is N, X is C, T is C, U is C and W
is C, for use as an agent for preventing, inhibiting or treating
cancer.
[0050] According to another preferred aspect, the present invention
relates to a compound of formula (I) as defined above, wherein Z is
C, V is C, Y is C, X is C, T is N, U is C and W is C, for use as an
agent for preventing, inhibiting or treating cancer.
[0051] According to another preferred aspect, the present invention
relates to a compound of formula (I) as defined above, wherein Z is
N, V is C, Y is C, X is C, T is C, U is N and W is C, for use as an
agent for preventing, inhibiting or treating cancer.
[0052] The compounds of the invention may exist in the form of free
bases or of addition salts with pharmaceutically acceptable
acids.
[0053] Suitable physiologically acceptable acid addition salts of
compounds of formula (I) include hydrobromide, tartrate, citrate,
trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate,
maleate, mesylate, formate, acetate and fumarate.
[0054] The compounds of formula (I) and or salts thereof may form
solvates (e.g. hydrates) and the invention includes all such
solvates.
[0055] In the context of the present invention, the term:
[0056] "halogen" is understood to mean chlorine, fluorine, bromine,
or iodine, and in particular denotes chlorine, fluorine or
bromine,
[0057] "(C.sub.1-C.sub.3)alkyl" as used herein respectively refers
to C.sub.1-C.sub.3 normal, secondary or tertiary saturated
hydrocarbon. Examples are, but are not limited to, methyl, ethyl,
1-propyl, 2-propyl,
[0058] "(C.sub.1-C.sub.3)alkoxy" as used herein respectively refers
to O--(C.sub.1-C.sub.3)alkyl moiety, wherein alkyl is as defined
above. Examples are, but are not limited to, methoxy, ethoxy,
1-propoxy, 2-propoxy,
[0059] "fluoroalkyl group" and "fluoroalkoxy group" refers
respectively to alkyl group and alkoxy group as above-defined, said
groups being substituted by at least one fluorine atom. Examples
are perfluoroalkyl groups, such as trifluoromethyl or
perfluoropropyl, and
[0060] "patient" may extend to humans or mammals, such as cats or
dogs.
[0061] According to a particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(Ia)
##STR00004##
[0062] wherein:
[0063] R independently represent a hydrogen atom, a halogen atom or
a group chosen among a (C.sub.1-C.sub.3)alkyl group, a --CN group,
a hydroxyl group, a --COOR.sub.1 group, a
(C.sub.1-C.sub.3)fluoroalkyl group, a --NO.sub.2 group, a
--NR.sub.1R.sub.2 group and a (C.sub.1-C.sub.3)alkoxy group,
[0064] R'' is as defined above and is advantageously a hydrogen
atom,
[0065] n is as defined above and is advantageously 1,
[0066] n' is as defined above and is advantageously 1,
[0067] R' is a hydrogen atom, a halogen atom or a group chosen
among a (C.sub.1-C.sub.3)alkyl group, a --NO.sub.2 group, a
(C.sub.1-C.sub.3)alkoxy group and a --NR.sub.1R.sub.2 group,
[0068] R.sub.1 and R.sub.2 are a hydrogen atom or a
(C.sub.1-C.sub.3)alkyl group,
[0069] or one of its pharmaceutically acceptable salt,
[0070] for use as an agent for preventing, inhibiting or treating
cancer.
[0071] According to another particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(Ib)
##STR00005##
[0072] wherein:
[0073] R independently represent a hydrogen atom, a halogen atom or
a group chosen among a (C.sub.1-C.sub.3)alkyl group, a
--NR.sub.1R.sub.2 group, a (C.sub.1-C.sub.3)fluoroalkoxy group, a
--NO.sub.2 group, a phenoxy group and a (C.sub.1-C.sub.4)alkoxy
group,
[0074] R.sub.1 and R.sub.2 are independently a hydrogen atom or a
(C.sub.1-C.sub.3)alkyl group,
[0075] R'' is as defined above and is advantageously a hydrogen
atom,
[0076] n is as defined above and is preferably 1 or 2,
[0077] n' is as defined above and is preferably 1,
[0078] R' is a hydrogen atom, a halogen atom or a group chosen
among a (C.sub.1-C.sub.3)alkyl group and a (C.sub.1-C.sub.4)alkoxy
group,
[0079] or one of its pharmaceutically acceptable salt,
[0080] for use as an agent for preventing, inhibiting or treating
cancer.
[0081] According to another particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(Ic)
##STR00006##
[0082] wherein:
[0083] R independently represent a hydrogen atom or a group chosen
among a (C.sub.1-C.sub.3)alkyl group, a
(C.sub.1-C.sub.3)fluoroalkyl group, a --NR.sub.1R.sub.2 group, a
--COOR.sub.1 group, a --NO.sub.2 group and a
(C.sub.1-C.sub.3)alkoxy group,
[0084] R'' is as defined above and is advantageously a hydrogen
atom,
[0085] n is as defined above and is advantageously 1,
[0086] n' is as defined above and is advantageously 1,
[0087] R' is a hydrogen atom,
[0088] R.sub.1 and R.sub.2 are independently a hydrogen atom or a
(C.sub.1-C.sub.3)alkyl group,
[0089] or one of its pharmaceutically acceptable salt,
[0090] for use as an agent for preventing, inhibiting or treating
cancer.
[0091] According to another particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(Id)
##STR00007##
[0092] wherein:
[0093] R independently represent a hydrogen atom or a group chosen
among a (C.sub.1-C.sub.3)alkyl group, a
(C.sub.1-C.sub.3)fluoroalkyl group and a (C.sub.1-C.sub.3)alkoxy
group,
[0094] R'' is as defined above and is advantageously a hydrogen
atom,
[0095] n is as defined above and is advantageously 1,
[0096] n' is as defined above and is advantageously 1,
[0097] R' is a hydrogen atom,
[0098] or one of its pharmaceutically acceptable salt,
[0099] for use as an agent for preventing, inhibiting or treating
cancer.
[0100] According to another particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(Ie)
##STR00008##
[0101] wherein:
[0102] R represents a hydrogen atom,
[0103] R'' is as defined above and is advantageously a hydrogen
atom,
[0104] n is as defined above and is advantageously 1,
[0105] n' is as defined above and is advantageously 1,
[0106] R' is a hydrogen atom, a halogen atom or a group chosen
among a (C.sub.1-C.sub.3)alkyl group and a (C.sub.1-C.sub.3)alkoxy
group,
[0107] or one of its pharmaceutically acceptable salt,
[0108] for use as an agent for preventing, inhibiting or treating
cancer.
[0109] According to another particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(If)
##STR00009##
[0110] wherein:
[0111] R represents a hydrogen atom,
[0112] R'' is as defined above and is advantageously a hydrogen
atom,
[0113] n is as defined above and is advantageously 1,
[0114] n' is as defined above and is advantageously 1,
[0115] R' is a hydrogen atom,
[0116] or one of its pharmaceutically acceptable salt,
[0117] for use as an agent for preventing, inhibiting or treating
cancer.
[0118] According to another particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(Ig)
##STR00010##
[0119] wherein:
[0120] R represents a hydrogen atom,
[0121] R'' is as defined above and is advantageously a hydrogen
atom,
[0122] n is as defined above and is advantageously 1,
[0123] n' is as defined above and is advantageously 1,
[0124] R' is a hydrogen atom or a halogen atom,
[0125] or one of its pharmaceutically acceptable salt,
[0126] for use as an agent for preventing, inhibiting or treating
cancer.
[0127] According to another particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(Ii)
##STR00011##
[0128] wherein:
[0129] R represents a hydrogen atom,
[0130] R'' is as defined above and is advantageously a hydrogen
atom,
[0131] n is as defined above and is advantageously 1,
[0132] n' is as defined above and is advantageously 1,
[0133] R' is a hydrogen atom,
[0134] or one of its pharmaceutically acceptable salt,
[0135] for use as an agent for preventing, inhibiting or treating
cancer.
[0136] According to another particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(Ii)
##STR00012##
[0137] wherein:
[0138] R independently represent a hydrogen atom or a group chosen
among a (C.sub.1-C.sub.3)fluoroalkoxy group and a
(C.sub.1-C.sub.3)alkoxy group,
[0139] R'' is as defined above and is advantageously a hydrogen
atom,
[0140] n is as defined above and is advantageously 1,
[0141] n' is as defined above and is advantageously 1,
[0142] R' is a hydrogen atom,
[0143] or one of its pharmaceutically acceptable salt,
[0144] for use as an agent for preventing, inhibiting or treating
cancer.
[0145] According to another particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(Ij)
##STR00013##
[0146] wherein:
[0147] R independently represent a hydrogen atom or a group chosen
among a (C.sub.1-C.sub.3)fluoroalkoxy group and a
(C.sub.1-C.sub.3)alkyl group,
[0148] R'' is as defined above and is advantageously a hydrogen
atom,
[0149] n is as defined above and is advantageously 1,
[0150] n' is as defined above and is advantageously 1,
[0151] R' is a hydrogen atom,
[0152] or one of its pharmaceutically acceptable salt,
[0153] for use as an agent for preventing, inhibiting or treating
cancer.
[0154] According to another particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(Ik)
##STR00014##
[0155] wherein:
[0156] R represents a hydrogen atom,
[0157] R'' is as defined above and is advantageously a hydrogen
atom,
[0158] n is as defined above and is advantageously 1,
[0159] n' is as defined above and is advantageously 1,
[0160] R' is a hydrogen atom, a halogen atom or a
(C.sub.1-C.sub.3)alkyl group,
[0161] or one of its pharmaceutically acceptable salt,
[0162] for use as an agent for preventing, inhibiting or treating
cancer.
[0163] According to another particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(Il)
##STR00015##
[0164] wherein:
[0165] R represents a hydrogen atom,
[0166] R'' is as defined above and is advantageously a hydrogen
atom,
[0167] n is as defined above and is advantageously 1,
[0168] n' is as defined above and is advantageously 1,
[0169] R' is a hydrogen atom,
[0170] or one of its pharmaceutically acceptable salt,
[0171] for use as an agent for preventing, inhibiting or treating
cancer.
[0172] According to another particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(Im)
##STR00016##
[0173] wherein:
[0174] R represents a hydrogen atom,
[0175] R'' is as defined above and is advantageously a hydrogen
atom,
[0176] n is as defined above and is advantageously 1,
[0177] n' is as defined above and is advantageously 1,
[0178] R' is a hydrogen atom,
[0179] or one of its pharmaceutically acceptable salt,
[0180] for use as an agent for preventing, inhibiting or treating
cancer.
[0181] According to another particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(Io)
##STR00017##
[0182] wherein:
[0183] R independently represent a hydrogen atom or a halogen atom
or a group chosen among, a --NO.sub.2 group, a --CN group and a
(C.sub.1-C.sub.3)alkyl group, said alkyl being optionally
mono-substituted by a hydroxyl group,
[0184] R'' is as defined above and is advantageously a hydrogen
atom,
[0185] n is as defined above and is advantageously 1,
[0186] n' is as defined above and is advantageously 1,
[0187] R' is a hydrogen atom, a halogen atom or a
(C.sub.1-C.sub.3)fluoroalkyl group,
[0188] or one of its pharmaceutically acceptable salt,
[0189] for use as an agent for preventing, inhibiting or treating
cancer.
[0190] According to another particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(Ip)
##STR00018##
[0191] wherein:
[0192] R represents a hydrogen atom,
[0193] R'' is as defined above and is advantageously a hydrogen
atom,
[0194] n is as defined above and is advantageously 1,
[0195] n' is as defined above and is advantageously 1,
[0196] R' is a hydrogen atom,
[0197] or one of its pharmaceutically acceptable salt,
[0198] for use as an agent for preventing, inhibiting or treating
cancer.
[0199] According to another particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(Iq)
##STR00019##
[0200] wherein:
[0201] R independently represent a hydrogen atom, a
(C.sub.1-C.sub.3)alkoxy group or a (C.sub.1-C.sub.3)fluoroalkoxy
group,
[0202] R'' is as defined above and is advantageously a hydrogen
atom,
[0203] n is as defined above and is advantageously 1,
[0204] n' is as defined above and is advantageously 1,
[0205] R' is a hydrogen atom or a group chosen among a
--NR.sub.1R.sub.2 group, a N-methylpiperazinyl group, a
(C.sub.1-C.sub.3)alkoxy group and a morpholino group,
[0206] R.sub.1 and R.sub.2 are independently a hydrogen atom or a
(C.sub.1-C.sub.3)alkyl group,
[0207] or one of its pharmaceutically acceptable salt,
[0208] for use as an agent for preventing, inhibiting or treating
cancer.
[0209] According to another particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(Ir)
##STR00020##
[0210] wherein:
[0211] R independently represent a hydrogen atom or a
(C.sub.1-C.sub.3)alkyl group,
[0212] R'' is as defined above and is advantageously a hydrogen
atom,
[0213] n is as defined above and is advantageously 1,
[0214] n' is as defined above and is advantageously 1,
[0215] R' is a hydrogen atom or a group chosen among a
--NR.sub.1R.sub.2 group, a morpholino group and a
(C.sub.1-C.sub.3)alkoxy group,
[0216] R.sub.1 and R.sub.2 are independently a hydrogen atom or a
(C.sub.1-C.sub.3)alkyl group,
[0217] or one of its pharmaceutically acceptable salt,
[0218] for use as an agent for preventing, inhibiting or treating
cancer.
[0219] According to another particular embodiment, an additional
subject-matter of the present invention is a compound of formula
(Iee)
##STR00021##
[0220] wherein:
[0221] R independently represent a hydrogen atom, a
(C.sub.1-C.sub.3)alkyl group or a (C.sub.1-C.sub.3)fluoroalkyl
group,
[0222] R'' is as defined above and is advantageously a hydrogen
atom,
[0223] n is as defined above and is advantageously 1,
[0224] n' is as defined above and is advantageously 2,
[0225] R' is a hydrogen atom or a (C.sub.1-C.sub.3)alkyl group,
[0226] or one of its pharmaceutically acceptable salt,
[0227] for use as an agent for preventing, inhibiting or treating
cancer.
[0228] Among the previous defined families of compounds of formulae
(Ia) to (Iee), some are more particularly preferred for their use
as an agent for preventing, inhibiting or treating cancer. These
preferred compounds particularly belong to formulae (Ia), (Ie),
(Iq) and (Iee), as defined above or one of its pharmaceutically
acceptable salts.
[0229] Accordingly the present invention further relates to a
compound chosen among compounds of formulae (Ia), (Ie), (Iq) and
(Iee), and their pharmaceutically acceptable salts for use as an
agent for preventing, inhibiting or treating cancer.
[0230] According to a particular embodiment, the present invention
more particularly focuses on a compound of formula (Ia)
[0231] wherein:
[0232] R independently represent a hydrogen atom, a halogen atom or
a group chosen among a (C.sub.1-C.sub.3)alkyl group, a --CN group,
a --COOR.sub.1 group and a (C.sub.1-C.sub.3)fluoroalkyl group,
[0233] R'' is as defined above and more preferably is a hydrogen
atom,
[0234] R.sub.1 is as defined above,
[0235] n is as defined above,
[0236] n' is as defined above,
[0237] R' is a halogen atom, a (C.sub.1-C.sub.4)alkyl group, a
(C.sub.1-C.sub.4)alkoxy group or a --NO.sub.2 group,
[0238] or one of its pharmaceutically acceptable salt,
[0239] for use as an agent for preventing, inhibiting or treating
cancer.
[0240] According to another particular embodiment, the present
invention more particularly focuses on a compound of formula
(Ie)
[0241] wherein:
[0242] R represents a hydrogen atom or a (C.sub.1-C.sub.4)alkyl
group,
[0243] R'' is as defined above and more preferably is a hydrogen
atom,
[0244] n is as defined above,
[0245] n' is as defined above,
[0246] R' is a halogen atom,
[0247] or one of its pharmaceutically acceptable salt,
[0248] for use as an agent for preventing, inhibiting or treating
cancer.
[0249] According to another particular embodiment, the present
invention more particularly focuses on a compound of formula
(Iq)
[0250] wherein:
[0251] R', R'', n and n' are as defined in formula (I), and
[0252] R is a (C.sub.1-C.sub.3)fluoroalkoxy group,
[0253] or one of its pharmaceutically acceptable salt,
[0254] for use as an agent for preventing, inhibiting or treating
cancer.
[0255] According to another particular embodiment, the present
invention more particularly focuses on a compound of formula
(Iee)
[0256] wherein:
[0257] R is independently a hydrogen atom or a
(C.sub.1-C.sub.4)alkyl group,
[0258] R', R'', n and n' are as defined in formula (I),
[0259] or one of its pharmaceutically acceptable salt,
[0260] for use as an agent for preventing, inhibiting or treating
cancer.
[0261] In a particular embodiment, the present invention relates to
a compound of formula (Ia) or (Ie) as defined above or one of its
pharmaceutically acceptable salts, for use as an agent for
preventing, inhibiting or treating cancer.
[0262] According to a preferred embodiment of the present
invention, the compound for use as an agent for preventing,
inhibiting or treating cancer, is chosen from: [0263] (1)
(8-Chloro-quinolin-2-yl)-pyridin-2-yl-amine [0264] (2)
2-(Quinolin-2-ylamino)-isonicotinic acid [0265] (3)
(4-Methyl-pyridin-2-yl)-quinolin-2-yl-amine [0266] (4)
Pyridin-2-yl-quinolin-2-yl-amine [0267] (5)
2-(8-Chloro-quinolin-2-ylamino)-isonicotinic acid [0268] (6)
(8-Chloro-quinolin-2-yl)-(4-methyl-pyridin-2-yl)-amine [0269] (7)
6-(Quinolin-2-ylamino)-nicotinonitrile [0270] (8)
Quinolin-2-yl-(4-trifluoromethoxy-phenyl)-amine [0271] (9)
Pyridin-2-yl-quinolin-3-yl-amine [0272] (10)
(3-Methoxy-pyridin-2-yl)-quinolin-3-yl-amine [0273] (11)
Quinolin-3-yl-(5-trifluoromethyl-pyridin-2-yl)-amine [0274] (12)
(5-Nitro-pyridin-2-yl)-quinolin-3-yl-amine [0275] (13)
(5-Methyl-pyridin-2-yl)-quinolin-3-yl-amine [0276] (14)
2-(Quinolin-3-ylamino)-isonicotinic acid [0277] (15)
Quinolin-6-yl-(5-trifluoromethyl-pyridin-2-yl)-amine [0278] (16)
(6-Methyl-pyridin-2-yl)-quinolin-6-yl-amine [0279] (17)
N-(6-methylpyridin-2-yl)quinolin-2-amine [0280] (18)
8-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine [0281] (19)
4-methyl-N-(pyridin-2-yl)quinolin-2-amine [0282] (20)
4-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine [0283] (21)
3-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine [0284] (22)
3-methyl-N-(pyridin-2-yl)quinolin-2-amine [0285] (23)
6-((4-methylquinolin-2-yl)amino)nicotinonitrile [0286] (24)
6-((3-methylquinolin-2-yl)amino)nicotinonitrile [0287] (25)
6-chloro-N-(4-methylpyridin-2-yl)quinolin-2-amine [0288] (26)
6-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine [0289] (27)
4-methyl-N-(5-nitropyridin-2-yl)quinolin-2-amine [0290] (28)
N-(3-nitropyridin-2-yl)quinolin-2-amine [0291] (29)
8-chloro-N-(3-nitropyridin-2-yl)quinolin-2-amine [0292] (30)
2-((4-methylquinolin-2-yl)amino)nicotinonitrile [0293] (31)
N-(3-methylpyridin-2-yl)quinolin-2-amine [0294] (32)
N-(5-methylpyridin-2-yl)quinolin-2-amine [0295] (33)
2-(quinolin-2-ylamino)isonicotinonitrile [0296] (34)
N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine [0297] (35)
8-chloro-N-(3-methylpyridin-2-yl)quinolin-2-amine [0298] (36)
8-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine [0299] (37)
8-chloro-N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine [0300]
(38) N-(3-methoxypyridin-2-yl)quinolin-2-amine [0301] (39)
N-(5-nitropyridin-2-yl)quinolin-2-amine [0302] (40)
6-((8-chloroquinolin-2-yl)amino)nicotinonitrile [0303] (41)
N-(5-fluoropyridin-2-yl)quinolin-2-amine [0304] (42)
N-(6-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine [0305] (43)
8-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine [0306] (44)
2-((8-chloroquinolin-2-yl)amino)nicotinic acid [0307] (45)
4-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine [0308] (46)
3-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine [0309] (47)
5-cyano-2-(quinolin-2-ylamino)pyridin-1-ium chloride [0310] (48)
2-((8-chloroquinolin-2-yl)amino)-4-methylpyridin-1-ium chloride
[0311] (49) 8-chloro-N-(4-ethylpyridin-2-yl)quinolin-2-amine [0312]
(50) 8-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine [0313] (51)
8-chloro-N-(4,6-dimethylpyridin-2-yl)quinolin-2-amine [0314] (52)
6-((8-chloroquinolin-2-yl)amino)-2-methylnicotinonitrile [0315]
(53) 8-chloro-N-(4-chloropyridin-2-yl)quinolin-2-amine [0316] (54)
8-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine [0317] (55)
N-(5-bromo-4-methylpyridin-2-yl)-8-chloroquinolin-2-amine [0318]
(56) 8-chloro-N-(3-ethyl-6-methylpyridin-2-yl)quinolin-2-amine
[0319] (57) 8-fluoro-N-(4-methylpyridin-2-yl)quinolin-2-amine
[0320] (58) 8-bromo-N-(4-methylpyridin-2-yl)quinolin-2-amine [0321]
(59) methyl 6-(quinolin-2-ylamino)nicotinate [0322] (60) methyl
6-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate [0323] (61)
methyl 6-[(3-methylquinolin-2-yl)amino]pyridine-3-carboxylate
[0324] (62) methyl
2-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate [0325] (63)
8-methoxy-N-(4-methylpyridin-2-yl)quinolin-2-amine [0326] (64)
N-(4-methylpyridin-2-yl)-5-nitroquinolin-2-amine [0327] (65)
2-N-(4-methylpyridin-2-yl)quinoline-2,8-diamine [0328] (66)
2-N-(4-methylpyridin-2-yl)quinoline-2,5-diamine [0329] (67) methyl
6-[(4-methylquinolin-2-yl)amino]pyridine-3-carboxylate [0330] (68)
8-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine [0331]
(69) 2-[(8-chloroquinolin-2-yl)amino]pyridin-3-ol [0332] (70)
8-chloro-N-[6-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine [0333]
(71) 6-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine [0334] (72)
N-(6-ethylpyridin-2-yl)-3-methylquinolin-2-amine [0335] (73)
N-(5-fluoropyridin-2-yl)-3-methylquinolin-2-amine [0336] (74)
3-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine [0337]
(75)
4-N-(8-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine
[0338] (76) N-(4-methoxyphenyl)quinolin-2-amine [0339] (77)
8-chloro-N-(4-methoxyphenyl)quinolin-2-amine [0340] (78)
4-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine [0341] (79)
N-(4-methoxyphenyl)-3-methylquinolin-2-amine [0342] (80)
3-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine [0343] (81)
1-N,1-N-dimethyl-4-N-(3-methylquinolin-2-yl)benzene-1,4-diamine
[0344] (82) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine
[0345] (83) N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine [0346]
(84) N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine [0347] (85)
N-(4-nitrophenyl)quinolin-2-amine [0348] (86)
N-(3-fluorophenyl)quinolin-2-amine [0349] (87)
8-chloro-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine [0350] (88)
8-chloro-N-(3-fluorophenyl)quinolin-2-amine [0351] (89)
2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride [0352]
(90) 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine [0353]
(91)
3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine
[0354] (92) 3-methyl-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine
[0355] (93) 3-methyl-N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine
[0356] (94)
8-chloro-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine
[0357] (95)
3-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium
chloride [0358] (96)
6-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine [0359] (97)
4-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium
chloride [0360] (98)
8-bromo-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine [0361] (99)
8-fluoro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine [0362]
(100) 8-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine
[0363] (101) N-(4-butoxyphenyl)-8-chloroquinolin-2-amine [0364]
(102) N-(4-phenoxyphenyl)quinolin-2-amine [0365] (103)
8-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine [0366]
(104)
8-chloro-N-[3-chloro-4-(trifluoromethoxy)phenyl]quinolin-2-amine
[0367] (105) N-(6-methylpyridin-2-yl)quinolin-3-amine [0368] (106)
N-(3-nitropyridin-2-yl)quinolin-3-amine [0369] (107)
N-(5-methylpyridin-2-yl)quinolin-6-amine [0370] (108)
N-(3-methoxypyridin-2-yl)quinolin-6-amine [0371] (109)
6-chloro-N-(pyrazin-2-yl)quinolin-2-amine [0372] (110)
8-bromo-N-(pyrazin-2-yl)quinolin-2-amine [0373] (111)
8-methyl-N-(pyrazin-2-yl)quinolin-2-amine [0374] (112)
8-chloro-N-(pyrazin-2-yl)quinolin-2-amine [0375] (113)
N-(pyrazin-2-yl)quinolin-2-amine [0376] (114)
4-methyl-N-(pyrazin-2-yl)quinolin-2-amine [0377] (115)
3-methyl-N-(pyrazin-2-yl)quinolin-2-amine [0378] (116)
8-fluoro-N-(pyrazin-2-yl)quinolin-2-amine [0379] (117)
8-methoxy-N-(pyrazin-2-yl)quinolin-2-amine [0380] (118)
N-(pyridin-3-yl)quinolin-3-amine [0381] (119)
8-chloro-N-(pyridin-4-yl)quinolin-2-amine [0382] (120)
N-(pyridin-4-yl)quinolin-2-amine [0383] (121)
N-(pyridin-4-yl)quinolin-3-amine [0384] (122)
N-[4-(trifluoromethoxy)phenyl]quinolin-3-amine [0385] (123)
N-(4-methoxyphenyl)quinolin-3-amine [0386] (124)
N-[4-(trifluoromethoxy)phenyl]quinoxalin-2-amine [0387] (125)
N-[2-methyl-4-(trifluoromethoxy)phenyl]quinoxalin-2-amine [0388]
(126) N-[3-(trifluoromethoxy)phenyl]quinoxalin-2-amine [0389] (127)
N-[2-(trifluoromethoxy)phenyl]quinoxalin-2-amine [0390] (128)
N-(pyrimidin-2-yl)quinolin-2-amine [0391] (129)
8-chloro-N-(pyrimidin-2-yl)quinolin-2-amine [0392] (130)
4-methyl-N-(pyrimidin-2-yl)quinolin-2-amine [0393] (131)
N-(pyrazin-2-yl)quinolin-6-amine [0394] (132)
N-(pyrazin-2-yl)quinolin-3-amine [0395] (133)
6-methyl-N-(naphthalen-2-yl)pyridin-2-amine [0396] (134)
N-(naphthalen-2-yl)pyridin-2-amine [0397] (135)
N-(pyridin-2-yl)quinoxalin-2-amine [0398] (136)
N-(4-methylpyridin-2-yl)quinoxalin-2-amine [0399] (137)
6-(quinoxalin-2-ylamino)pyridine-3-carbonitrile [0400] (138)
N-(6-methylpyridin-2-yl)quinoxalin-2-amine [0401] (139)
N-(4-methylpyridin-2-yl)-3-(trifluoromethyl)quinoxalin-2-amine
[0402] (140)
N-(3,5-dichloro-4-methylpyridin-2-yl)quinoxalin-2-amine [0403]
(141) N-(4-methyl-3-nitropyridin-2-yl)quinoxalin-2-amine [0404]
(142) N-(pyrimidin-2-yl)quinoxalin-2-amine [0405] (143)
4-N,4-N-dimethyl-7-N-[4-(trifluoromethoxy)phenyl]quinoline-4,7-diamine
[0406] (144)
4-(morpholin-4-yl)-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine
[0407] (145) 4-methoxy-N-(pyridin-2-yl)quinolin-7-amine [0408]
(146) 4-methoxy-N-(4-methylpyridin-2-yl)quinolin-7-amine [0409]
(147)
4-N,4-N-dimethyl-7-N-(4-methylpyridin-2-yl)quinoline-4,7-diamine
[0410] (148)
5,8-dimethyl-N-(5-methylpyridin-2-yl)isoquinolin-6-amine [0411]
(149) 5,8-dimethyl-N-(5-methylpyridin-2-yl)isoquinolin-6-amine
[0412] (150) N-(4-methylpyridin-2-yl)-8-nitroquinolin-2-amine
[0413] (151) 6-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine
[0414] (152) 6-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine
[0415] (153)
6-chloro-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine [0416]
(154) N2-(8-chloroquinolin-2-yl)-4-methylpyridine-2,3-diamine
[0417] (155) N-(4-butoxyphenyl)-3-methylquinolin-2-amine [0418]
(156)
4-N-(6-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine
[0419] (157) 8-chloro-N-(3-chloro-4-methoxyphenyl)quinolin-2-amine
[0420] (158)
N1-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine
[0421] (159) 2-{4-[(8-chloroquinolin-2-yl)amino]phenoxy}ethan-1-ol
[0422] (160) 6-chloro-N-(4-methylpyridin-2-yl)quinoxalin-2-amine
[0423] (161) N-(4-ethylpyridin-2-yl)quinoxalin-2-amine [0424] (162)
N-(5-bromo-4-methylpyridin-2-yl)quinoxalin-2-amine [0425] (163)
N-(4,6-dimethylpyridin-2-yl)quinoxalin-2-amine [0426] (164)
[2-(quinoxalin-2-ylamino)pyridin-4-yl]methanol [0427] (165)
N-(4-methyl-5-nitropyridin-2-yl)quinoxalin-2-amine [0428] (166)
N-(4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)quinolin-7-amine
[0429] (167)
4-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine [0430]
(168) N-(4-methylpyridin-2-yl)-4-(morpholin-4-yl)quinolin-7-amine
[0431] and their pharmaceutically acceptable salts.
[0432] Among said compounds, compounds (6), (18), (30), (35), (36),
(37), (45), (48), (51), (52), (53), (55), (56), (58), (61), (63),
(64), (109), (110), (112), (143), (144) and (148) are of particular
interest.
[0433] The present invention therefore extends to compounds (6),
(18), (30), (35), (36), (37), (45), (48), (51), (52), (53), (55),
(56), (58), (61), (63), (64), (109), (110), (112), (143), (144) and
(148) or one of its pharmaceutically acceptable salts for use as an
agent for preventing, inhibiting or treating cancer.
[0434] Some of said preceding compounds are new and form part of
the present invention: (6), (18), (30), (35), (36), (37), (48),
(51), (52), (53), (55), (56), (58), (61), (63), (64), (109), (110),
(112), (143) and (144).
[0435] The compounds of formulae (I), (Ia), (Ib), (Ic), (Id), (Ie),
(If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io), (Ip), (Iq),
(Ir) and (Iee) can comprise one or more asymmetric carbon atoms.
They can thus exist in the form of enantiomers or of
diastereoisomers. These enantiomers, diastereoisomers and their
mixtures, including the racemic mixtures, are encompassed within
the scope of the present invention.
[0436] Among the compounds of formula (I), some of them are new and
form part of the invention, as well as their pharmaceutically
acceptable salts, such as hydrobromide, tartrate, citrate,
trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate,
maleate, mesylate, formate, acetate and fumarate.
[0437] According to a particular embodiment, the present invention
encompasses compounds of formula (Ig)
[0438] wherein:
[0439] R independently represent a hydrogen atom, a halogen atom or
a group chosen among a (C.sub.1-C.sub.3)alkyl group, a --CN group,
a hydroxyl group, a --COOR.sub.1 group, a
(C.sub.1-C.sub.3)fluoroalkyl group, a (C.sub.1-C.sub.3)fluoroalkoxy
group, a --NO.sub.2 group, a --NR.sub.1R.sub.2 group, and a
(C.sub.1-C.sub.3)alkoxy group,
[0440] n is 1 or 2,
[0441] n' is 1 or 2,
[0442] R' is a hydrogen atom or a group chosen among a
(C.sub.1-C.sub.3)alkyl group, a halogen atom, a hydroxyl group, a
--COOR.sub.1 group, a --NO.sub.2 group, a --NR.sub.1R.sub.2 group,
a (C.sub.1-C.sub.3)alkoxy group and a --CN group,
[0443] R'' is a hydrogen atom or a (C.sub.1-C.sub.4)alkyl
group,
[0444] R.sub.1 and R.sub.2 are independently a hydrogen atom or a
(C.sub.1-C.sub.3)alkyl group,
[0445] with the proviso that R and R' are not simultaneously a
hydrogen atom,
[0446] and when n and n' are 1 and R is a hydrogen atom then R' is
not a --COOH group,
[0447] or anyone of its pharmaceutically acceptable salt.
[0448] According to another particular embodiment, the present
invention encompasses compounds of formula (If)
[0449] wherein:
[0450] R independently represent a hydrogen atom, a halogen atom or
a group chosen among a (C.sub.1-C.sub.3)alkyl group, a --CN group,
a hydroxyl group, a --COOR.sub.1 group, a
(C.sub.1-C.sub.3)fluoroalkyl group, a (C.sub.1-C.sub.3)fluoroalkoxy
group, a --NO.sub.2 group, a --NR.sub.1R.sub.2 group, and a
(C.sub.1-C3)alkoxy group,
[0451] n is 1 or 2,
[0452] n' is 1 or 2,
[0453] R' is a hydrogen atom or a group chosen among a
(C.sub.1-C.sub.3)alkyl group, a halogen atom, a hydroxyl group, a
--COOR.sub.1 group, a --NO.sub.2 group, a --NR.sub.1R.sub.2 group,
a (C.sub.1-C.sub.3)alkoxy group and a --CN group,
[0454] R'' is a hydrogen atom or a (C.sub.1-C.sub.4)alkyl
group,
[0455] R.sub.1 and R.sub.2 are independently a hydrogen atom or a
(C.sub.1-C.sub.3)alkyl group,
[0456] or anyone of its pharmaceutically acceptable salt.
[0457] According to another particular embodiment, the present
invention encompasses compounds of formula (Ih)
[0458] wherein:
[0459] R independently represent a hydrogen atom, a halogen atom or
a group chosen among a (C.sub.1-C.sub.3)alkyl group, a --CN group,
a hydroxyl group, a --COOR.sub.1 group, a
(C.sub.1-C.sub.3)fluoroalkyl group, a (C.sub.1-C.sub.3)fluoroalkoxy
group, a --NO.sub.2 group, a --NR.sub.1R.sub.2 group, and a
(C.sub.1-C.sub.3)alkoxy group,
[0460] n is 1 or 2,
[0461] n' is 1 or 2,
[0462] R' is a hydrogen atom or a group chosen among a
(C.sub.1-C.sub.3)alkyl group, a halogen atom, a hydroxyl group, a
--COOR.sub.1 group, a --NO.sub.2 group, a --NR.sub.1R.sub.2 group,
a (C.sub.1-C.sub.3)alkoxy group and a --CN group,
[0463] R'' is a hydrogen atom or a (C.sub.1-C.sub.4)alkyl
group,
[0464] R.sub.1 and R.sub.2 are independently a hydrogen atom or a
(C.sub.1-C.sub.3)alkyl group,
[0465] or anyone of its pharmaceutically acceptable salt.
[0466] According to another particular embodiment, the present
invention encompasses compounds of formula (II)
[0467] wherein:
[0468] R independently represent a hydrogen atom, a halogen atom or
a group chosen among a (C.sub.1-C.sub.3)alkyl group, a --CN group,
a hydroxyl group, a --COOR.sub.1 group, a
(C.sub.1-C.sub.3)fluoroalkyl group, a (C.sub.1-C.sub.3)fluoroalkoxy
group, a --NO.sub.2 group, a --NR.sub.1R.sub.2 group, and a
(C.sub.1-C.sub.3)alkoxy group,
[0469] n is 1 or 2,
[0470] n' is 1 or 2,
[0471] R' is a hydrogen atom or a group chosen among a
(C.sub.1-C.sub.3)alkyl group, a halogen atom, a hydroxyl group, a
--COOR.sub.1 group, a --NO.sub.2 group, a --NR.sub.1R.sub.2 group,
a (C.sub.1-C.sub.3)alkoxy group and a --CN group,
[0472] R'' is a hydrogen atom or a (C.sub.1-C.sub.4)alkyl
group,
[0473] R.sub.1 and R.sub.2 are independently a hydrogen atom or a
(C.sub.1-C.sub.3)alkyl group,
[0474] with the proviso that R and R' are not simultaneously a
hydrogen atom,
[0475] or anyone of its pharmaceutically acceptable salt.
[0476] According to another particular embodiment, the present
invention encompasses compounds of formula (Im)
[0477] wherein:
[0478] R independently represent a hydrogen atom, a halogen atom or
a group chosen among a (C.sub.1-C.sub.3)alkyl group, a --CN group,
a hydroxyl group, a --COOR.sub.1 group, a
(C.sub.1-C.sub.3)fluoroalkyl group, a (C.sub.1-C.sub.3)fluoroalkoxy
group, a --NO.sub.2 group, a --NR.sub.1R.sub.2 group, and a
(C.sub.1-C.sub.3)alkoxy group,
[0479] n is 1 or 2,
[0480] n' is 1 or 2,
[0481] R' is a hydrogen atom or a group chosen among a
(C.sub.1-C.sub.3)alkyl group, a halogen atom, a hydroxyl group, a
--COOR.sub.1 group, a --NO.sub.2 group, a --NR.sub.1R.sub.2 group,
a (C.sub.1-C.sub.3)alkoxy group and a --CN group,
[0482] R'' is a hydrogen atom or a (C.sub.1-C.sub.4)alkyl
group,
[0483] R.sub.1 and R.sub.2 are independently a hydrogen atom or a
(C.sub.1-C.sub.3)alkyl group,
[0484] with the proviso that when n and n' are 1 and R is a
hydrogen atom, R' is not a chlorine atom,
[0485] or anyone of its pharmaceutically acceptable salt.
[0486] For a sake of simplification, the following compounds and
their corresponding definitions are called "new compounds".
[0487] According to another particular embodiment, the present
invention encompasses compounds of formula (Ia), as such,
##STR00022##
[0488] wherein:
[0489] R'' and n are as defined in formula (Ia),
[0490] n' is 1,
[0491] R independently represent a hydrogen atom, a halogen atom or
a group chosen among a (C.sub.1-C.sub.3)alkyl group, a --CN group,
a hydroxyl group, a --COOR.sub.1 group, a
(C.sub.1-C.sub.3)fluoroalkyl group, a --NO.sub.2 group, a
(C.sub.1-C.sub.3)fluoroalkoxy group and a (C.sub.1-C.sub.3)alkoxy
group,
[0492] R' is a hydrogen atom or a halogen atom or a group chosen
among a (C.sub.1-C.sub.3)alkyl group, a --COOR.sub.1 group, and a
--CN group,
[0493] R.sub.1 is a hydrogen atom or a (C.sub.1-C.sub.3)alkyl
group:
[0494] with the proviso that
[0495] when R and R' are not simultaneously a hydrogen atom,
[0496] when n is 1, R is not a methyl group in ortho or para
position with respect to Z, Z being N,
[0497] when R' is a hydrogen atom, R is not a bromine atom or a
chlorine atom,
[0498] when R is a hydrogen atom, R' is not a methyl or ethyl
group, a --COOH group, a COOC.sub.2H.sub.5 group or a bromine atom,
said bromine atom being in ortho position of the bond linked to
NR'',
[0499] or one of its pharmaceutically acceptable salt.
[0500] Still according to this particular embodiment, the present
invention more particularly focuses on compounds of formula (Ia),
as such, wherein,
[0501] R independently represent a hydrogen atom or a
(C.sub.1-C.sub.3)alkyl group,
[0502] R'' is as defined in formula (Ia),
[0503] R' is a hydrogen atom, a halogen atom, a
(C.sub.1-C.sub.3)alkoxy group or a --NO.sub.2 group,
[0504] n' is 1,
[0505] n is 1,
[0506] with the proviso that
[0507] when n is 1, R is not a methyl group in ortho or para
position with respect to Z, Z being N,
[0508] or one of its pharmaceutically acceptable salt.
[0509] Still according to this particular embodiment, the present
invention more preferably focuses on compounds of formula (Ia'), as
such,
##STR00023##
[0510] wherein,
[0511] R independently represent a hydrogen atom, a
(C.sub.1-C.sub.3)alkyl group, a (C.sub.1-C.sub.3)fluoroalkyl group,
a halogen atom or a hydroxyl group,
[0512] R'' is as defined in formula (Ia),
[0513] n is 1 or 2,
[0514] or one of its pharmaceutically acceptable salt.
[0515] According to another particular embodiment, the present
invention encompasses compounds of formula (Ie)
##STR00024##
[0516] wherein:
[0517] R, R', R'' n and n' are as defined in formula (I),
[0518] with the proviso that
[0519] when R is a hydrogen atom, R' is not a bromine atom,
[0520] or one of its pharmaceutically acceptable salt.
[0521] The present invention further relates to a compound of
formula (Iq) as defined above, as such
##STR00025##
[0522] wherein:
[0523] R, R', R'' and n' are as defined in formula (I),
[0524] n is 1 or 2,
[0525] with the proviso that
[0526] R' and R are not simultaneously a hydrogen atom,
[0527] when R' is a hydrogen atom, R is not a --NO.sub.2 group or a
--NH.sub.2 group,
[0528] when n is 2 and R' is a hydrogen atom, R is not a
COOC.sub.2H.sub.5 group or a chlorine atom,
[0529] or one of its pharmaceutically acceptable salt.
[0530] Still according to this particular embodiment, the present
invention more particularly focuses on compounds of formula (Iq),
as such, wherein
[0531] R', R'', n and n' are as defined in formula (I), and
[0532] R is a (C.sub.1-C.sub.3)fluoroalkoxy group,
[0533] or one of its pharmaceutically acceptable salt.
[0534] Still according to this particular embodiment, the present
invention more particularly focuses on compounds of formula (Iq),
as such, wherein
[0535] R, R'', n and n' are as defined in formula (I), and
[0536] R' is a --NR.sub.1R.sub.2 group,
[0537] R.sub.1 and R.sub.2 are independently a hydrogen atom or a
(C.sub.1-C.sub.3)alkyl group,
[0538] or one of its pharmaceutically acceptable salt.
[0539] Still according to this particular embodiment, the present
invention more particularly focuses on compounds of formula (Iq),
as such, wherein
[0540] R, R'', n and n' are as defined in formula (I), and
[0541] R' is a morpholinyl group, a morpholino group or a
N-methylpiperazinyl group,
[0542] or one of its pharmaceutically acceptable salt.
[0543] The present invention further relates to a compound of
formula (Iee) as defined above, as such
##STR00026##
[0544] wherein:
[0545] R, R', R'', n and n' are as defined in formula (I),
[0546] or one of its pharmaceutically acceptable salt,
[0547] with the exclusion of the following compound
##STR00027##
[0548] and with the exclusion of compounds wherein R is a
--NO.sub.2 group or a --NH.sub.2 group when R' is a hydrogen or a
methyl group.
[0549] Still according to this particular embodiment, the present
invention more particularly focuses on compounds of formula (Iee),
as such, wherein
[0550] R', R'', n and n' are as defined in formula (I), and
[0551] R is a (C.sub.1-C.sub.3)fluoroalkyl group,
[0552] or one of its pharmaceutically acceptable salt.
[0553] Among said compounds as such, compounds (1), (2), (5)-(8),
(10)-(16), (18), (21)-(44), (46)-(75), (77)-(84), (86)-(119),
(121), (124)-(130), (132), (135)-(141), (143)-(147), (149)-(168)
and their pharmaceutically acceptable salts are of particular
interest.
[0554] The present invention therefore extends to compounds (1),
(2), (5)-(8), (10)-(16), (18), (21)-(44), (46)-(75), (77)-(84),
(86)-(119), (121), (124)-(130), (132), (135)-(141), (143)-(147),
(149)-(168) and their pharmaceutically acceptable salts, as
such.
[0555] More preferably, compounds (143), (144), (149), (166), (167)
and their pharmaceutically acceptable salts are of particular
interest.
[0556] The present invention therefore extends to compounds (143),
(144), (149), (166), (167) and their pharmaceutically acceptable
salts, such as hydrobromide, tartrate, citrate, trifluoroacetate,
ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate,
formate, acetate and fumarate.
[0557] Still more preferably, the present invention extends to
compounds (143), (144) and their pharmaceutically acceptable salts,
such as hydrobromide, tartrate, citrate, trifluoroacetate,
ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate,
formate, acetate and fumarate.
[0558] The new compounds of the present invention, i.e. compounds
of formulae (Ia), (Ie), (Iq) and (Iee) and the specific compounds
as listed above, are not only useful as agent for inhibiting,
preventing or treating cancer but can also be useful for
inhibiting, preventing or treating premature aging or progeria and
for inhibiting, preventing or treating AIDS.
[0559] According to an aspect of the invention, said compounds may
be useful to inhibit, prevent and/or treat diseases with premature
aging and that are likely related to an aberrant splicing of the
nuclear lamin A gene. Among all, said disease may include
Hutchinson Guilford Progeria Syndrome (HGPS), progeria, premature
aging associated with HIV infection, muscular dystrophy,
Charcot-Marie-Tooth disorder, Werner syndrome, but also
atherosclerosis, insulin resistant type II diabetes, cataracts,
osteoporosis and aging of the skin such as restrictive
dermopathy.
[0560] The compounds of the present invention can be prepared by
conventional methods of organic synthesis practiced by those
skilled in the art. The general reaction sequences outlined below
represent a general method useful for preparing the compounds of
the present invention and are not meant to be limiting in scope or
utility.
[0561] The compounds of general formula (I) can be prepared
according to scheme 1 below.
##STR00028##
As appears in said scheme two routes are available for recovering a
compound of formula (I) according to the present invention.
[0562] The synthesis is based on a coupling reaction alternatively
starting from a halogeno-bicycle of formula (III), wherein X, Y, W,
T, U, n', R' and R'' are as defined above and X' is a chlorine atom
or a bromine atom or from a chloro-monocycle of formula (V),
wherein Z, V, n and R are as defined above and X' is a chlorine
atom or a bromine atom.
[0563] According to route (A), the compound of formula (III) is
placed in a protic solvent such as tert-butanol. The compound of
formula (IV) is then added in a molar ratio ranging from 1 to 1.5
with respect to the compound of formula (III) in presence of an
inorganic base, such as Cs.sub.2CO.sub.3 or K.sub.2CO.sub.3 in a
molar ratio ranging from 1 and 2, in the presence of a diphosphine,
such as Xantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)
or X-Phos (2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl)
in an amount ranging from 2 mol % to 10 mol % relative to the total
amount of compound of formula (III), and in the presence of a
catalyst, such as Pd(OAc).sub.2 or Pd.sub.2dba.sub.3 in an amount
ranging from 2 mol % to 10 mol % relative to the total amount of
compound of formula (III). The reaction mixture can then be heated
at a temperature ranging from 80 to 120.degree. C., for example at
90.degree. C. and stirred for a time ranging form 15 to 25 hours,
for example during 20 hours under inert gas and for example argon.
The reaction mixture can be concentrated under reduced
pressure.
[0564] According to route (B) the compound of formula (V) is placed
in a protic solvent such as tert-butanol. The compound of formula
(VI) is then added in a molar ratio ranging from 1 to 1.5 with
respect to the compound of formula (V) in presence of an inorganic
base, such as Cs.sub.2CO.sub.3 or K.sub.2CO.sub.3 in a molar ratio
ranging from 1 to 2, in the presence of a diphosphine, such as
Xantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) or
X-Phos (2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) in
an amount ranging from 2 mol % to 10 mol % relative to the total
amount of compound of formula (V), and in the presence of a
catalyst, such as Pd(OAc).sub.2 or Pd.sub.2 dba.sub.3 in an amount
ranging from 2 mol % to 10 mol % relative to the total amount of
compound of formula (V). The reaction mixture can then be heated at
a temperature ranging from 80 to 120.degree. C., for example at
90.degree. C. and stirred for a time ranging form 15 to 25 hours,
for example during 20 hours under inert gas and for example argon.
The reaction mixture can be concentrated under reduced
pressure.
[0565] The starting compounds of formula (III), (IV), (V) and (VI)
are commercially available or can be prepared according to methods
known to the person skilled in the art.
[0566] The chemical structures and spectroscopic data of some
compounds of formula (I) of the invention are illustrated
respectively in the following Table I and Table II.
TABLE-US-00001 TABLE I (I) ##STR00029## Formula (Ia) ##STR00030## 1
##STR00031## 2 ##STR00032## 3 ##STR00033## 4 ##STR00034## 5
##STR00035## 6 ##STR00036## 7 ##STR00037## 17 ##STR00038## 18
##STR00039## 19 ##STR00040## 20 ##STR00041## 21 ##STR00042## 22
##STR00043## 23 ##STR00044## 24 ##STR00045## 25 ##STR00046## 26
##STR00047## 27 ##STR00048## 28 ##STR00049## 29 ##STR00050## 30
##STR00051## 31 ##STR00052## 32 ##STR00053## 33 ##STR00054## 34
##STR00055## 35 ##STR00056## 36 ##STR00057## 37 ##STR00058## 38
##STR00059## 39 ##STR00060## 40 ##STR00061## 41 ##STR00062## 42
##STR00063## 43 ##STR00064## 44 ##STR00065## 45 ##STR00066## 46
##STR00067## 47 ##STR00068## 48 ##STR00069## 49 ##STR00070## 50
##STR00071## 51 ##STR00072## 52 ##STR00073## 53 ##STR00074## 54
##STR00075## 55 ##STR00076## 56 ##STR00077## 57 ##STR00078## 58
##STR00079## 59 ##STR00080## 60 ##STR00081## 61 ##STR00082## 62
##STR00083## 63 ##STR00084## 64 ##STR00085## 65 ##STR00086## 66
##STR00087## 67 ##STR00088## 68 ##STR00089## 69 ##STR00090## 70
##STR00091## 71 ##STR00092## 72 ##STR00093## 73 ##STR00094## 74
##STR00095## 150 ##STR00096## 151 ##STR00097## 152 ##STR00098## 153
##STR00099## 154 Formula (Ib) ##STR00100## 8 ##STR00101## 75
##STR00102## 76 ##STR00103## 77 ##STR00104## 78 ##STR00105## 79
##STR00106## 80 ##STR00107## 81 ##STR00108## 82 ##STR00109## 83
##STR00110## 84 ##STR00111## 85 ##STR00112## 86 ##STR00113## 87
##STR00114## 88 ##STR00115## 89 ##STR00116## 90 ##STR00117## 91
##STR00118## 92 ##STR00119## 93 ##STR00120## 94 ##STR00121## 95
##STR00122## 96 ##STR00123## 97 ##STR00124## 98 ##STR00125## 99
##STR00126## 100 ##STR00127## 101 ##STR00128## 102 ##STR00129## 103
##STR00130## 104 ##STR00131## 155 ##STR00132## 156 ##STR00133## 157
##STR00134## 158 Formula (Ic) ##STR00135## 9 ##STR00136## 10
##STR00137## 11 ##STR00138## 12 ##STR00139## 13 ##STR00140## 14
##STR00141## 105 ##STR00142## 106 ##STR00143## 159 Formula (Id)
##STR00144## 15 ##STR00145## 16 ##STR00146## 107 ##STR00147## 108
Formula (Ie) ##STR00148## 109 ##STR00149## 110
##STR00150## 111 ##STR00151## 112 ##STR00152## 113 ##STR00153## 114
##STR00154## 115 ##STR00155## 116 ##STR00156## 117 Formula (If)
##STR00157## 118 Formula (Ig) ##STR00158## 119 ##STR00159## 120
Formula (Ih) ##STR00160## 121 Formula (Ii) ##STR00161## 122
##STR00162## 123 Formula (Ij) ##STR00163## 124 ##STR00164## 125
##STR00165## 126 ##STR00166## 127 Formula (Ik) ##STR00167## 128
##STR00168## 129 ##STR00169## 130 Formula (Il) ##STR00170## 131
Formula (Im) ##STR00171## 132 Formula (Io) ##STR00172## 135
##STR00173## 136 ##STR00174## 137 ##STR00175## 138 ##STR00176## 139
##STR00177## 140 ##STR00178## 141 ##STR00179## 160 ##STR00180## 161
##STR00181## 162 ##STR00182## 163 ##STR00183## 164 ##STR00184## 165
Formula (Ip) ##STR00185## 142 Formula (Iq) ##STR00186## 143
##STR00187## 144 ##STR00188## 166 ##STR00189## 167 Formula (Ir)
##STR00190## 145 ##STR00191## 146 ##STR00192## 147 ##STR00193## 168
Formula (Iee) ##STR00194## 148 ##STR00195## 149
TABLE-US-00002 TABLE II Ex Characterizations 1 MS (ESI) [M + H]
.sup.+ = 256 2 .sup.1H NMR (300 MHz, D.sub.2O) .delta. 8.31 (d, J =
5.1, 1H), 8.21 (d, J = 9.3, 1H), 7.60 (d, J = 7.5, 3H), 7.34 (dd, J
= 6.2, 15.6, 2H), 7.18 (s, 1H), 6.99 (d, J = 9.1, 1H) MS (ESI) [M +
H] .sup.+ = 266 5 MS (ESI) [M + H] .sup.+ = 300 6 .sup.1H NMR (300
MHz, DMSO) .delta. 10.23 (s, 1H), 8.96 (s, 1H), 8.18 (d, J = 8.8,
2H), 7.78 (dd, J = 7.7, 13.7, 2H), 7.46 (d, J = 8.9, 1H), 7.31 (t,
J = 7.8, 1H), 6.86 (d, J = 4.3, 1H), 2.37 (s, 3H). .sup.13C NMR (75
MHz, DMSO) .delta. 153.63, 153.61, 148.37, 147.32, 142.65, 137.52,
129.68, 129.47, 126.82, 125.06, 123.26, 118.36, 115.10, 113.31,
21.24. MS (ESI) [M + H] .sup.+ = 270 7 .sup.1H NMR (300 MHz, DMSO)
.delta. 10.71 (s, 1H), 8.71 (d, J = 1.4, 1H), 8.62 (d, J = 8.9,
1H), 8.24 (d, J = 8.9, 1H), 8.17 (dd, J = 1.9, 8.9, 1H), 7.89 -
7.74 (m, 2H), 7.66 (dd, J = 7.9, 14.2, 2H), 7.42 (t, J = 7.3, 1H).
.sup.13C NMR (75 MHz, DMSO) .delta. 156.09, 152.40, 152.11, 146.24,
141.07, 137.83, 129.87, 127.67, 126.78, 124.50, 124.21, 118.04,
114.49, 111.67, 100.12. MS (ESI) [M + H] .sup.+ = 247 8 .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.92 (d, J = 8.9, 1H), 7.79 (d, J =
8.4, 1H), 7.65 (t, J = 7.7, 3H), 7.59 (dd, J = 7.1, 8.3, 1H), 7.31
(t, J = 7.0, 1H), 7.20 (d, J = 8.5, 2H), 6.88 (d, J = 8.9, 1H),
6.80 (s, 1H) .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 153.88,
147.62, 144.35, 139.26, 138.11, 130.13, 127.65, 127.12, 124.43,
123.70, 122.20, 120.95, 112.25. MS (ESI) [M + H] .sup.+ = 305 10
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.10 (d, J = 2.5, 1H),
8.83 (d, J = 2.6, 1H), 8.02 (d, J = 7.9, 1H), 7.94 (dd, J = 1.3,
5.0, 1H), 7.85 - 7.79 (m, 1H), 7.52 (pd, J = 1.5, 6.9, 2H), 7.33
(s, 1H), 7.04 (dd, J = 1.2, 7.9, 1H), 6.81 (dd, J = 5.1, 7.9, 1H),
3.95 (s, 3H) 11 MS (ESI) [M + H].sup.+ = 290 12 .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 9.18 (d, J = 2.7, 1H), 8.86 (d, J = 2.5,
1H), 8.56 (d, J = 2.3, 1H), 8.33 (dd, J = 2.7, 9.2, 1H), 8.08 (d, J
= 8.5, 1H), 7.83 (d, J = 8.5, 1H), 7.71 - 7.63 (m, 2H), 7.57 (t, J
= 7.4, 2H), 6.82 (d, J = 9.1, 1H) 13 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.83 (d, J = 2.6, 1H), 8.37 (d, J = 2.3, 1H),
8.00 (d, J = 8.2, 1H), 7.71 (d, J = 7.7, 1H), 7.59 - 7.51 (m, 1H),
7.46 (dd, J = 7.3, 15.1, 2H), 6.71 (d, J = 8.3, 1H), 6.67 (d, J =
7.4, 1H), 2.49 (s, 3H) .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.
157.13, 154.59, 145.81, 144.43, 138.78, 134.54, 129.22, 128.86,
127.41, 127.27, 121.48, 115.41, 106.50, 24.18. MS (ESI) [M + H]
.sup.+ = 236 14 MS (ESI) [M + H].sup.+ = 266 15 MS (ESI) [M +
H].sup.+ = 290 16 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.77
(dd, J = 1.5, 4.2, 1H), 8.04 (dd, J = 4.7, 8.7, 2H), 7.92 (d, J =
2.4, 1H), 7.59 (dd, J = 2.5, 9.1, 1H), 7.47 (t, J = 7.8, 1H), 7.35
(dd, J = 4.2, 8.3, 1H), 6.87 (s, 1H), 6.81 (d, J = 8.2, 1H), 6.70
(d, J = 7.4, 1H), 2.50 (s, 3H) MS (ESI) [M + H] .sup.+ = 236 18
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.53 (d, J = 59.9, 2H),
7.76 (d, J = 8.6, 1H), 7.58 (t, J = 8.3, 2H), 7.42 (d, J = 7.8,
1H), 7.09 (t, J = 7.7, 1H), 6.95 (d, J = 8.7, 1H), 6.71 (d, J =
7.3, 1H), 2.38 (s, 3H) 21 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.78 (s, 1H), 8.13 (d, J = 5.1, 1H), 7.89 (d, J = 8.3, 1H), 7.79
(s, 1H), 7.63 (d, J = 8.0, 1H), 7.56 (d, J = 7.3, 1H), 7.38 (s,
1H), 7.33 (t, J = 7.5, 1H), 6.79 (d, J = 4.9, 1H), 2.44 (s, 6H) 22
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.95 (d, J = 8.4, 1H),
8.28 (d, J = 5.7, 1H), 7.87 (d, J = 8.3, 1H), 7.78 (s, 1H), 7.76 -
7.70 (m, 1H), 7.62 (d, J = 8.0, 1H), 7.60 - 7.52 (m, 1H), 7.42 (s,
1H), 7.32 (t, J = 7.4, 1H), 6.95 (dd, J = 5.1, 6.5, 1H), 2.45 (s,
3H) 23 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.64 (d, J = 8.4,
1H), 8.55 (d, J = 2.1, 1H), 8.03 (s, 1H), 7.90 (d, J = 8.5, 4H),
7.66 (t, J = 7.6, 1H), 7.44 (t, J = 7.6, 1H), 7.06 (s, 1H), 2.67
(s, 4H) 24 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.09 (d, J =
8.9, 1H), 8.53 (d, J = 1.7, 1H), 7.94 (dd, J = 2.2, 8.9, 1H), 7.92
- 7.84 (m, 2H), 7.67 (d, J = 8.6, 2H), 7.65 - 7.58 (m, 1H), 7.40
(t, J = 7.4, 1H), 2.49 (s, 3H) 25 .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.16 (d, J = 5.2, 1H), 8.10 (s, 1H), 7.90 (d, J = 8.8, 1H),
7.79 (d, J = 9.0, 1H), 7.66 (d, J = 2.2, 1H), 7.55 (dd, J = 2.3,
8.9, 1H), 7.39 (d, J = 9.0, 1H), 6.79 (d, J = 5.2, 1H), 2.42 (s,
3H) MS (ESI) [M + H] .sup.+ = 270 26 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.06 (d, J = 8.3, 1H), 7.70 (d, J = 9.0, 1H),
7.64 (d, J = 8.9, 1H), 7.49 (t, J = 7.9, 2H), 7.40 (dd, J = 2.3,
8.9, 1H), 7.18 (d, J = 8.9, 1H), 6.68 (d, J = 7.4, 1H), 2.38 (s,
3H) MS (ESI) [M + H] .sup.+ = 270 27 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 9.17 (d, J = 2.5, 1H), 8.71 (s, 1H), 8.49 (dd,
J = 2.6, 9.0, 1H), 7.99 (s, 1H), 7.93 (d, J = 8.9, 2H), 7.74 - 7.64
(m, 1H), 7.48 (dd, J = 4.2, 11.4, 1H), 7.09 (s, 1H), 2.71 (s, 3H)
28 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.64 - 8.51 (m, 3H),
8.18 (d, J = 9.0, 1H), 7.93 (d, J = 8.4, 1H), 7.79 (d, J = 8.1,
1H), 7.73 - 7.64 (m, 1H), 7.51 - 7.41 (m, 1H), 7.00 (dd, J = 4.6,
8.2, 1H), 6.75 (dd, J = 4.6, 8.3, 0H) 29 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 10.77 (s, 1H), 8.60 (s, 3H), 8.19 (d, J = 8.2,
1H), 7.76 (dd, J = 6.6, 25.5, 2H), 7.38 (d, J = 7.2, 1H), 7.04 (d,
J = 4.4, 1H) 30 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.46 (dd,
J = 1.9, 5.0, 1H), 7.87 (dd, J = 2.0, 7.6, 1H), 7.82 (d, J = 7.3,
1H), 7.60 (t, J = 7.3, 2H), 7.43 - 7.33 (m, 1H), 6.90 (dd, J = 5.0,
7.6, 1H), 2.64 (s, 3H) 31 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.44 (d, J = 9.1, 1H), 8.17 (d, J = 4.8, 1H), 8.03 (d, J = 9.1,
1H), 7.78 (d, J = 8.4, 1H), 7.68 (d, J = 8.0, 1H), 7.62 - 7.54 (m,
1H), 7.39 (d, J = 7.3, 1H), 7.32 (t, J = 7.5, 1H), 6.82 (dd, J =
5.0, 7.3, 1H), 2.31 (s, 3H) MS (ESI) [M + H] .sup.+ = 236 32
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.23 (d, J = 8.5, 1H),
8.10 (s, 1H), 7.91 (d, J = 8.9, 1H), 7.82 (d, J = 8.4, 1H), 7.62
(d, J = 8.3, 1H), 7.56 (d, J = 7.3, 1H), 7.50 (dd, J = 1.8, 8.5,
1H), 7.37 - 7.24 (m, 2H), 2.26 (s, 3H) MS (ESI) [M + H] .sup.+ =
236 33 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.87 (s, 1H), 8.32
(d, J = 5.0, 1H), 7.95 (d, J = 8.8, 1H), 7.84 (d, J = 8.3, 1H),
7.60 (dd, J = 7.4, 14.1, 2H), 7.32 (t, J = 7.5, 1H), 7.04 (dd, J =
5.0, 9.0, 2H) MS (ESI) [M + H] .sup.+ = 247 34 .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.52 (s, 1H), 8.45 (d, J = 8.6, 1H), 8.01
(d, J = 8.8, 1H), 7.87 (dd, J = 2.5, 8.5, 2H), 7.72 - 7.56 (m, 2H),
7.39 (d, J = 9.0, 2H) MS (ESI) [M + H] .sup.+ = 290 35 .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 8.32 (d, J = 9.1, 1H), 8.07 (d, J =
4.8, 1H), 7.93 (d, J = 9.1, 1H), 7.59 (t, J = 7.9, 1H), 7.52 (d, J
= 8.0, 1H), 7.36 (d, J = 7.2, 1H), 7.14 (t, J = 7.8, 1H), 6.77 (dd,
J = 5.0, 7.3, 1H), 2.29 (s, 3H) MS (ESI) [M + H] .sup.+ = 270 36
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.70 (d, J = 7.2, 1H),
8.01 (s, 1H), 7.82 (d, J = 8.9, 1H), 7.62 (d, J = 7.6, 1H), 7.53
(dd, J = 1.8, 8.6, 1H), 7.46 (d, J = 7.9, 1H), 7.12 (t, J = 7.8,
1H), 7.05 (d, J = 8.8, 1H), 2.21 (s, 3H) MS (ESI) [M + H] .sup.+ =
270 37 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.08 (d, J = 8.5,
1H), 8.55 (s, 1H), 8.36 (s, 1H), 8.02 (d, J = 8.1, 2H), 7.77 (d, J
= 7.2, 1H), 7.62 (d, J = 7.6, 1H), 7.35 - 7.24 (m, 1H), 7.12 (d, J
= 8.8, 1H) MS (ESI) [M + H] .sup.+ = 324 38 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.69 (d, J = 9.1, 1H), 7.97 (d, J = 9.1, 1H),
7.80 - 7.74 (m, 1H), 7.70 (d, J = 8.4, 1H), 7.59 (d, J = 8.0, 1H),
7.54 - 7.45 (m, 1H), 7.22 (t, J = 7.5, 1H), 6.87 (d, J = 7.9, 1H),
6.68 (dd, J = 5.0, 7.9, 1H), 3.73 (s, 3H) MS (ESI) [M + H] .sup.+ =
252 39 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.57 (d, J = 29.4,
1H), 7.80 (d, J = 8.8, 1H), 7.66 (t, J = 6.7, 2H), 7.46 (d, J =
7.9, 1H), 7.14 (t, J = 7.8, 1H), 7.06 (d, J = 8.8, 1H), 6.79 (d, J
= 7.3, 1H), 2.73 (dd, J = 7.6, 15.2, 2H), 1.28 (t, J = 7.7, 3H) 40
.sup.1H NMR (300 MHz, DMSO) .delta. 9.75 (s, 1H), 9.12 (d, J = 2.3,
1H), 8.50 (d, J = 2.2, 1H), 8.48 (s, 1H), 8.13 (s, 1H), 7.83 (s,
1H), 7.80 (s, 1H), 7.64 (t, J = 7.7, 1H), 7.45 (t, J = 7.8, 1H) 41
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.52 (dd, J = 2.8, 8.6,
1H), 8.35 (s, 1H), 8.15 (d, J = 2.3, 1H), 7.94 (d, J = 8.8, 1H),
7.84 (d, J = 8.2, 1H), 7.65 (d, J = 7.8, 1H), 7.59 (d, J = 7.2,
1H), 7.50 - 7.40 (m, 1H), 7.33 (t, J = 7.4, 1H), 7.11 (d, J = 8.9,
1H) MS (ESI) [M + H] .sup.+ = 240 42 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.55 (d, J = 6.8, 1H), 8.01 (d, J = 8.9, 2H),
7.82 (dd, J = 9.1, 17.3, 2H), 7.69 (d, J = 8.0, 1H), 7.63 (t, J =
7.6, 1H), 7.37 (t, J = 7.5, 1H), 7.32 - 7.18 (m, 2H) MS (ESI) [M +
H] .sup.+ = 290 43 .sup.1H NMR (300 MHz, DMSO) .delta. 10.41 (s,
1H), 9.08 (dd, J = 4.1, 9.3, 1H), 8.31 (d, J = 2.9, 1H), 8.20 (d, J
= 8.9, 1H), 7.88 - 7.70 (m, 3H), 7.44 (d, J = 8.9, 1H), 7.32 (t, J
= 7.8, 1H) .sup.13C NMR (75 MHz, DMSO) .delta. 156.30, 153.32,
153.04, 150.17, 142.55, 137.73, 135.06, 134.74, 129.58, 129.49,
126.86, 125.29, 125.14, 125.04, 123.36, 114.91, 113.36. MS (ESI) [M
+ H] .sup.+ = 274 44 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
11.09 (s, 1H), 8.78 (d, J = 9.0, 1H), 8.42 (dd, J = 1.9, 4.7, 1H),
8.28 (dd, J = 1.9, 7.8, 1H), 8.11 (d, J = 9.1, 1H), 7.73 (d, J =
7.5, 1H), 7.65 (d, J = 8.1, 1H), 7.27 (dd, J = 6.4, 9.2, 1H), 6.88
(dd, J = 4.8, 7.8, 1H) MS (ESI) [M + H] .sup.+ = 300 46 .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 8.59 (d, J = 8.3, 1H), 7.73 (d, J =
8.3, 1H), 7.57 (s, 1H), 7.51 (t, J = 7.9, 1H), 7.43 (t, J = 9.2,
2H), 7.17 (t, J = 7.4, 1H), 6.67 (d, J = 7.4, 1H), 2.36 (s, 3H),
2.28 (s, 3H) 47 .sup.1H NMR (300 MHz, MeOD) .delta. 8.99 (s, 1H),
8.76 (d, J = 9.2, 1H), 8.32 (d, J = 8.7, 1H), 8.22 (d, J = 8.6,
1H), 8.11 (d, J = 7.8, 1H), 8.01 (t, J = 7.1, 1H), 7.76 (t, J =
7.4, 1H), 7.55 - 7.43 (m, 2H) MS (ESI) [M + H] .sup.+ = 247 48
.sup.1H NMR (300 MHz, MeOD) .delta. 8.48 (d, J = 9.1, 1H), 8.40 (d,
J = 6.7, 1H), 7.94 (d, J = 8.4, 1H), 7.90 (d, J = 7.8, 1H), 7.54
(t, J = 8.0, 1H), 7.38 (d, J = 8.6, 1H), 7.30 (s, 2H), 2.58 (s, 3H)
MS (ESI) [M + H] .sup.+ = 270 49 .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 9.34 (s, 1H), 8.95 (s, 1H), 8.21 (d, J = 5.1, 1H), 7.87 (d,
J = 8.9, 1H), 7.71 (d, J = 7.5, 1H), 7.52 (d, J = 7.9, 1H), 7.19
(t, J = 7.8, 1H), 7.05 (d, J = 8.9, 1H), 6.84 (d, J = 5.1, 1H),
2.76 (q, J = 7.6, 2H), 1.37 (t, J = 7.6, 3H) 50 .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.57 (d, J = 29.4, 1H), 7.80 (d, J = 8.8,
1H), 7.66 (t, J = 6.7, 2H), 7.46 (d, J = 7.9, 1H), 7.14 (t, J =
7.8, 1H), 7.06 (d, J = 8.8, 1H), 6.79 (d, J = 7.3, 1H), 2.73 (dd, J
= 7.6, 15.2, 2H), 1.28 (t, J = 7.7, 3H) 51 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.64 (s, 1H), 8.06 (s, 1H), 7.89 (d, J = 8.7,
1H), 7.71 (d, J = 7.4, 1H), 7.54 (d, J = 7.8, 1H), 7.20 (t, J =
7.7, 1H), 7.02 (d,
J = 8.8, 1H), 6.67 (s, 1H), 2.43 (s, 3H), 2.39 (s, 3H) .sup.13C NMR
(75 MHz, CDCl.sub.3) .delta. 156.15, 153.17, 152.82, 150.16,
143.70, 137.92, 131.34, 129.89, 126.49, 125.47, 123.43, 118.62,
114.47, 111.02, 24.13, 21.70. MS (ESI) [M + H] .sup.+ = 284 52
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.89 (d, J = 8.8, 1H),
8.05 (d, J = 8.8, 1H), 8.01 (s, 1H), 7.93 (d, J = 8.8, 1H), 7.79
(d, J = 7.5, 1H), 7.64 (d, J = 8.0, 1H), 7.32 (t, J = 7.8, 1H),
7.13 (d, J = 8.8, 1H), 2.67 (s, 3H) 53 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 9.27 (s, 1H), 8.33 (d, J = 5.7, 1H), 8.13 (d, J
= 5.2, 1H), 8.00 (d, J = 8.8, 1H), 7.76 (d, J = 7.4, 1H), 7.60 (d,
J = 8.0, 1H), 7.29 (d, J = 7.9, 1H), 7.07 (d, J = 8.9, 1H), 6.97
(d, J = 4.8, 1H) 54 MS (ESI) [M + H] .sup.+ = 250 55 .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 8.19 (s, 1H), 7.90 (d, J = 9.0, 1H),
7.63 (d, J = 7.5, 1H), 7.52 (d, J = 7.9, 1H), 7.33 (d, J = 7.4,
1H), 7.14 (t, J = 7.8, 1H), 6.69 (d, J = 7.5, 1H), 2.70 (dd, J =
7.3, 14.8, 2H), 2.47 (s, 3H), 1.26 (t, J = 7.7, 3H) 56 .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 8.20 (s, 1H), 7.90 (d, J = 9.0, 1H),
7.63 (d, J = 7.5, 1H), 7.52 (d, J = 7.9, 1H), 7.33 (d, J = 7.4,
1H), 7.14 (t, J = 7.8, 1H), 6.69 (d, J = 7.5, 1H), 2.70 (dd, J =
7.3, 14.8, 2H), 2.47 (s, 3H), 1.25 (dd, J = 7.5, 15.5, 3H) 57 MS
(ESI) [M + H] .sup.+ = 253 58 MS (ESI) [M + H] .sup.+ = 314-316 59
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.91 (d, J = 1.7, 1H),
8.46 (d, J = 8.8, 1H), 8.28 (dd, J = 2.0, 8.8, 1H), 8.23 (s, 1H),
8.03 (d, J = 8.8, 1H), 7.88 (d, J = 8.3, 1H), 7.70 (d, J = 8.0,
1H), 7.67 - 7.58 (m, 1H), 7.38 (t, J = 7.4, 1H), 7.32 (d, J = 8.8,
2H), 3.91 (s, 3H) 60 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.94
(d, J = 8.9, 1H), 8.91 (d, J = 1.8, 1H), 8.37 (dd, J = 2.2, 8.8,
1H), 8.04 (d, J = 8.9, 2H), 7.77 (d, J = 7.5, 1H), 7.62 (d, J =
7.2, 1H), 7.30 (t, J = 7.8, 2H), 7.19 (d, J = 8.8, 2H), 3.92 (s,
3H) 61 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.96 (d, J = 8.8,
1H), 8.85 (d, J = 1.3, 1H), 8.28 (d, J = 9.9, 1H), 7.84 (d, J =
8.0, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.59 (d, J = 8.4, 2H), 7.53
(d, J = 8.4, 1H), 7.31 (t, J = 7.4, 1H), 3.88 (s, 4H), 2.42 (s, 4H)
MS (ESI) [M + H] .sup.+ = 294 62 .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 11.02 (s, 1H), 8.75 (d, J = 9.2, 1H), 8.44 (d, J = 3.7,
1H), 8.31 (d, J = 7.9, 1H), 8.10 (d, J = 9.0, 1H), 7.72 (d, J =
7.5, 1H), 7.64 (d, J = 8.2, 1H), 7.27 (d, J = 8.1, 1H), 6.88 (dd, J
= 4.7, 7.8, 1H), 3.97 (s, 3H) MS (ESI) [M + H] .sup.+ = 314 63 MS
(ESI) [M + H] .sup.+ = 266 64 .sup.1H NMR (300 MHz, DMSO) .delta.
10.38 (s, 1H), 8.56 (s, 1H), 8.28 (d, J = 9.1, 1H), 8.20 - 8.03 (m,
3H), 7.50 (d, J = 8.7, 1H), 7.45 (d, J = 8.0, 1H), 6.88 (d, J =
4.4, 1H), 2.37 (s, 3H) 65 MS (ESI) [M + H] .sup.+ = 314-316 66 MS
(ESI) [M + H] .sup.+ = 250 67 .sup.1H NMR (300 MHz, DMSO) .delta.
10.51 (s, 1H), 8.83 (d, J = 2.3, 1H), 8.62 (d, J = 9.3, 1H), 8.24
(dd, J = 2.7, 9.1, 1H), 7.96 (d, J = 8.9, 1H), 7.81 (d, J = 7.8,
1H), 7.67 (t, J = 7.6, 1H), 7.45 (d, J = 11.2, 2H), 3.86 (s, 3H),
2.62 (s, 3H) MS (ESI) [M + H] .sup.+ = 294 68 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 9.57 (s, 1H), 8.44 (d, J = 4.8, 1H), 8.05 (d, J
= 8.8, 1H), 7.86 (s, 1H), 7.80 (d, J = 7.5, 1H), 7.64 (d, J = 8.0,
1H), 7.31 (t, J = 7.8, 1H), 7.19 (d, J = 4.3, 1H), 7.04 (d, J =
8.8, 1H) 69 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.12 (s, 1H),
7.94 (d, J = 8.6, 1H), 7.71 (d, J = 7.5, 1H), 7.57 (d, J = 7.8,
1H), 7.40 (s, 1H), 7.25 (d, J = 10.2, 2H), 7.17 (s, 1H), 7.05 (s,
1H) 70 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.07 (d, J = 8.5,
1H), 7.97 (d, J = 8.8, 1H), 7.90 (t, J = 8.0, 1H), 7.84 (s, 1H),
7.75 (dd, J = 1.1, 7.5, 1H), 7.62 - 7.55 (m, 1H), 7.31 (d, J = 7.6,
1H), 7.27 (t, J = 7.8, 1H), 7.08 (d, J = 8.8, 1H) MS (ESI) [M + H]
.sup.+ = 274 71 MS (ESI) [M + H] .sup.+ = 274 72 .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.67 (d, J = 7.9, 1H), 7.83 (d, J = 8.3,
1H), 7.71 (s, 1H), 7.69 - 7.61 (m, 1H), 7.57 (d, J = 7.9, 2H), 7.52
(d, J = 7.1, 1H), 7.28 (t, J = 7.4, 1H), 2.74 (q, J = 7.6, 2H),
2.42 (s, 3H), 1.31 (t, J = 7.6, 3H) MS (ESI) [M + H] .sup.+ = 264
73 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.91 (dd, J = 3.8,
9.0, 1H), 8.11 (d, J = 2.9, 1H), 7.81 (d, J = 8.3, 1H), 7.71 (s,
1H), 7.56 (dd, J = 7.4, 14.1, 2H), 7.51 - 7.42 (m, 1H), 7.29 (d, J
= 7.2, 1H), 2.38 (s, 3H) MS (ESI) [M + H] .sup.+ = 254 74 .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.96 (d, J = 8.3, 1H), 8.49 (s,
1H), 7.89 (dd, J = 1.9, 9.0, 1H), 7.82 (d, J = 8.2, 1H), 7.72 (s,
1H), 7.57 (t, J = 8.7, 3H), 7.33 (t, J = 7.4, 1H), 2.37 (s, 3H) MS
(ESI) [M + H] .sup.+ = 304 75 .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.83 (d, J = 9.0, 1H), 7.69 (dd, J = 1.3, 7.6, 1H), 7.53
(dd, J = 1.2, 8.0, 1H), 7.42 (d, J = 8.9, 2H), 7.15 (t, J = 7.8,
1H), 6.89 (d, J = 8.9, 2H), 6.79 (d, J = 8.9, 2H), 2.97 (s, 6H) 77
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.83 (d, J = 8.8, 1H),
7.70 (d, J = 7.6, 1H), 7.59 (d, J = 8.6, 2H), 7.52 (d, J = 7.3,
1H), 7.16 (t, J = 7.7, 1H), 6.94 (d, J = 8.4, 3H), 6.86 (d, J =
8.8, 1H), 3.82 (s, 3H) .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.
156.40, 155.54, 144.29, 138.09, 132.96, 130.44, 129.99, 126.61,
125.22, 123.29, 122.66, 114.73, 112.16, 55.74. MS (ESI) [M + H]
.sup.+ = 285 78 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.80 (t,
J = 7.6, 2H), 7.64 (d, J = 8.9, 2H), 7.61 - 7.55 (m, 1H), 7.33 (t,
J = 7.6, 1H), 7.19 (d, J = 8.7, 2H), 2.59 (s, 3H) 79 .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.78 (d, J = 8.4, 1H), 7.76 - 7.71
(m, 2H), 7.69 (s, 1H), 7.57 (dd, J = 1.1, 8.0, 1H), 7.51 (ddd, J =
1.5, 7.0, 8.4, 1H), 7.29 - 7.21 (m, 1H), 6.96 - 6.90 (m, 2H), 3.82
(s, 3H), 2.35 (s, 3H) 80 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.92 (d, J = 8.9 Hz, 2H), 7.84 (d, J = 8.3 Hz, 1H), 7.78 (s, 1H),
7.62 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.32 (t, J =
7.4 Hz, 1H), 7.24 (d, J = 8.7 Hz, 2H), 6.53 (s, 1H), 2.42 (s, 3H)
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 152.46, 146.25, 143.86,
139.33, 136.83, 128.93, 126.96, 126.71, 124.75, 123.56, 121.88,
120.44, 119.95, 17.77. MS (ESI) [M + H] .sup.+ = 319 81 .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.75 (d, J = 8.3, 1H), 7.66 (d, J =
8.5, 3H), 7.55 (d, J = 7.8, 1H), 7.48 (t, J = 7.6, 1H), 7.20 (d, J
= 7.2, 1H), 6.80 (d, J = 8.8, 2H), 6.32 (s, 1H), 2.93 (s, 7H), 2.35
(s, 3H) 82 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.92 (d, J =
8.9, 1H), 7.82 - 7.70 (m, 2H), 7.66 (d, J = 7.8, 1H), 7.59 (t, J =
7.6, 1H), 7.30 (dd, J = 6.0, 13.5, 1H), 7.14 (s, 1H), 7.11 (s, 1H),
6.84 (d, J = 8.9, 1H), 2.32 (s, 3H) MS (ESI) [M + H] .sup.+ = 319
83 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.93 - 7.86 (m, 1H),
7.85 (s, 1H), 7.82 (d, J = 8.4, 1H), 7.59 (dd, J = 8.2, 15.5, 2H),
7.44 - 7.38 (m, 1H), 7.29 (dd, J = 8.3, 16.8, 2H), 6.91 (d, J =
9.0, 1H), 6.87 (d, J = 8.3, 1H) MS (ESI) [M + H] .sup.+ = 305 84
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.67 (d, J = 8.1, 1H),
7.92 (d, J = 8.9, 1H), 7.85 (d, J = 8.4, 1H), 7.63 (d, J = 7.6,
1H), 7.58 (d, J = 7.3, 1H), 7.30 (dd, J = 6.8, 14.8, 3H), 7.02 (t,
J = 7.8, 1H), 6.89 (d, J = 8.9, 1H) MS (ESI) [M + H] .sup.+ = 305
86 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.93 (d, J = 8.9, 1H),
7.83 (d, J = 8.3, 1H), 7.70 (d, J = 12.0, 1H), 7.61 (dd, J = 7.9,
18.1, 2H), 7.32 (d, J = 7.9, 1H), 7.31 - 7.25 (m, 1H), 7.21 (t, J =
6.5, 1H), 6.92 (d, J = 8.9, 1H), 6.79 - 6.68 (m, 1H) MS (ESI) [M +
H] .sup.+ = 239 87 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.27
(s, 1H), 7.76 (d, J = 8.9, 1H), 7.67 (d, J = 7.5, 1H), 7.51 (d, J =
8.2, 1H), 7.45 (d, J = 7.9, 1H), 7.28 (d, J = 8.2, 1H), 7.14 (t, J
= 7.8, 1H), 6.86 (d, J = 10.1, 1H), 6.76 (d, J = 8.9, 1H) MS (ESI)
[M + H] .sup.+ = 339 88 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.11 (dt, J = 2.1, 12.1, 1H), 7.76 (d, J = 8.9, 1H), 7.66 (dd, J =
1.2, 7.6, 1H), 7.45 (dd, J = 1.1, 8.0, 1H), 7.22 (dd, J = 1.4, 7.2,
2H), 7.18 (d, J = 7.6, 1H), 7.12 (d, J = 7.8, 1H), 6.75 (d, J =
8.9, 1H), 6.69 (d, J = 7.9, 1H) MS (ESI) [M + H] .sup.+ = 273 89
.sup.1H NMR (300 MHz, DMSO) .delta. 11.38 (s, 1H), 8.41 (d, J =
9.1, 1H), 7.93 (d, J = 7.8, 1H), 7.80 (dt, J = 8.1, 20.9, 4H), 7.50
(d, J = 7.8, 3H), 7.36 (d, J = 9.3, 1H) 90 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.84 (d, J = 9.1, 2H), 7.79 (d, J = 8.9, 1H),
7.67 (dd, J = 1.2, 7.6, 1H), 7.48 (dd, J = 1.1, 8.0, 1H), 7.18 (s,
3H), 6.89 (s, 1H), 6.75 (d, J = 8.9, 1H) .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 153.88, 144.30, 143.91, 139.00, 138.25, 131.13,
130.13, 126.55, 125.42, 123.45, 122.50, 122.17, 120.49, 119.10,
113.24. MS (ESI) [M + H] .sup.+ = 339 91 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.74 (s, 1H), 8.54 (s, 1H), 8.46 (d, J = 8.8,
1H), 7.91 (dd, J = 5.5, 14.5, 2H), 7.79 (d, J = 8.9, 1H), 7.67 (d,
J = 2.1, 1H), 7.56 (dd, J = 2.3, 8.9, 1H), 7.35 (d, J = 8.9, 1H) 92
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.67 (d, J = 7.9, 1H),
7.83 (d, J = 8.3, 1H), 7.71 (s, 1H), 7.69 - 7.61 (m, 1H), 7.55 (dd,
J = 7.5, 14.4, 2H), 7.29 (d, J = 7.8, 1H), 6.80 (d, J = 7.4, 1H) 93
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.21 (dd, J = 1.5, 8.4,
1H), 7.85 (d, J = 8.4, 1H), 7.73 (s, 1H), 7.58 (d, J = 7.8, 1H),
7.53 (dd, J = 1.3, 8.3, 1H), 7.40 - 7.35 (m, 1H), 7.32 (dd, J =
1.1, 4.6, 1H), 7.31 - 7.24 (m, 2H), 7.04 (s, 1H), 7.02 - 6.94 (m,
1H), 2.38 (s, 3H) 94 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.16
(d, J = 8.7, 1H), 7.83 (d, J = 8.9, 1H), 7.63 (d, J = 7.6, 1H),
7.48 (d, J = 8.0, 1H), 7.13 (t, J = 7.8, 1H), 7.08 (s, 1H), 7.04
(s, 2H), 6.81 (d, J = 8.9, 2H), 2.27 (s, 3H) MS (ESI) [M + H]
.sup.+ = 353 95 .sup.1H NMR (300 MHz, MeOD) .delta. 8.42 (s, 1H),
7.94 (d, J = 7.9, 1H), 7.83 (d, J = 8.1, 1H), 7.78 (d, J = 7.1,
1H), 7.72 (d, J = 8.7, 2H), 7.58 (d, J = 8.2, 3H), 2.60 (s, 3H) MS
(ESI) [M + H] .sup.+ = 319 96 .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.79 (d, J = 8.9, 1H), 7.70 (d, J = 8.9, 1H), 7.64 (d, J =
8.9, 2H), 7.59 (d, J = 2.1, 1H), 7.50 (dd, J = 2.3, 8.9, 1H), 7.19
(d, J = 8.6, 2H), 6.85 (d, J = 8.9, 1H) MS (ESI) [M + H] .sup.+ =
281 97 .sup.1H NMR (300 MHz, MeOD) .delta. 8.11 (d, J = 8.4, 1H),
7.81 (s, 2H), 7.62 (d, J = 8.7, 3H), 7.51 (d, J = 8.3, 2H), 7.12
(s, 1H), 2.77 (s, 3H) MS (ESI) [M + H] .sup.+ = 319 98 MS (ESI) [M
+ H] .sup.+ = 383-385 99 MS (ESI) [M + H] .sup.+ = 320 100 MS (ESI)
[M + H] .sup.+ = 316 101 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.82 (d, J = 8.9, 1H), 7.70 - 7.63 (m, 1H), 7.51 (dd, J = 5.3, 7.6,
3H), 7.14 (t, J = 7.8, 1H), 6.91 (d, J = 8.8, 3H), 6.85 (d, J =
9.0, 2H), 3.96 (t, J = 6.5, 2H), 1.84 - 1.68 (m, 3H), 1.49 (dd, J =
7.4, 15.0, 3H), 0.97 (t, J = 7.4, 3H) MS (ESI) [M + H] .sup.+ = 327
102 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.89 (d, J = 8.9,
1H), 7.76 (d, J = 8.5, 1H), 7.63 (d, J = 8.1, 1H), 7.59 (s, 1H),
7.54 (d, J = 8.8, 2H), 7.38 - 7.24 (m, 3H), 7.09 (d, J = 7.4, 1H),
7.02 (dd, J = 2.4, 8.8, 4H), 6.90 (d, J = 8.9, 1H) MS (ESI) [M + H]
.sup.+ = 313 103 MS (ESI) [M + H] .sup.+ = 334 104 .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.49 (d, J = 2.5, 1H), 7.89 (d, J = 8.8,
1H), 7.72 (d, J =
7.6, 1H), 7.63 (dd, J = 2.5, 8.9, 1H), 7.53 (d, J = 8.0, 1H), 7.23
(dd, J = 6.2, 14.0, 2H), 7.04 (s, 1H), 6.81 (d, J = 8.8, 1H) MS
(ESI) [M + H] .sup.+ = 373 105 .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.85 (d, J = 2.6, 1H), 8.45 (d, J = 2.3, 1H), 8.01 (d, J =
8.1, 1H), 7.71 (d, J = 7.8, 1H), 7.58 (s, 1H), 7.53 (d, J = 7.6,
1H), 7.51 - 7.45 (m, 2H), 7.45 - 7.36 (m, 1H), 6.72 - 6.62 (m, 2H),
2.48 (s, 3H) .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 157.18,
154.80, 145.42, 143.80, 138.17, 135.04, 128.88, 128.76, 127.17,
127.04, 120.69, 115.22, 106.73, 24.38 106 .sup.1H NMR (300 MHz,
DMSO) .delta. 10.24 (s, 1H), 9.06 (d, J = 2.3, 1H), 8.65 (d, J =
1.8, 1H), 8.60 (d, J = 8.3, 1H), 8.56 (d, J = 4.5, 1H), 7.97 (dd, J
= 8.2, 14.4, 2H), 7.69 (t, J = 6.9, 1H), 7.59 (t, J = 7.4, 1H),
7.08 (dd, J = 4.6, 8.3, 1H) MS (ESI) [M + H] .sup.+ = 267 107
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.77 (dd, J = 1.5, 4.3,
1H), 8.06 (dd, J = 10.8, 18.4, 3H), 7.93 (d, J = 2.4, 1H), 7.57
(dd, J = 2.4, 9.0, 1H), 7.39 (ddd, J = 3.1, 8.3, 12.5, 3H), 6.93
(d, J = 8.4, 1H), 6.89 (s, 1H), 2.29 (s, 3H) 108 .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.72 (dd, J = 1.6, 4.2, 1H), 8.61 (d, J =
2.4, 1H), 8.11 (d, J = 8.3, 1H), 8.00 (d, J = 9.0, 1H), 7.91 (dd, J
= 1.2, 5.0, 1H), 7.69 (dd, J = 2.4, 9.1, 1H), 7.35 - 7.26 (m, 2H),
7.01 (dd, J = 1.2, 7.9, 1H), 6.77 (dd, J = 5.1, 7.8, 1H), 3.93 (s,
3H) 109 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.68 (s, 1H),
8.21 (s, 2H), 7.94 (d, J = 8.9, 1H), 7.79 (d, J = 9.2, 1H), 7.67
(d, J = 2.3, 1H), 7.56 (dd, J = 2.3, 8.9, 1H), 7.34 (d, J = 8.9,
1H) MS (ESI) [M + H] .sup.+ = 257 110 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 10.32 (s, 1H), 8.33 - 8.21 (m, 2H), 8.05 (d, J
= 8.9, 1H), 8.00 (dd, J = 1.2, 7.6, 1H), 7.69 (dd, J = 1.1, 7.8,
1H), 7.61 (s, 1H), 7.30 - 7.22 (m, 3H), 7.16 (d, J = 8.8, 1H). MS
(ESI) [M + H] .sup.+ = 301-303 111 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.82 (d, J = 8.9, 1H), 7.70 - 7.63 (m, 1H),
7.51 (dd, J = 5.3, 7.6, 3H), 7.14 (t, J = 7.8, 1H), 6.91 (d, J =
8.8, 3H), 6.85 (d, J = 9.0, 2H), 3.96 (t, J = 6.5, 2H), 1.84 - 1.68
(m, 3H), 1.49 (dd, J = 7.4, 15.0, 3H), 0.97 (t, J = 7.4, 3H) 112
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.89 (d, J = 8.9, 1H),
7.76 (d, J = 8.5, 1H), 7.63 (d, J = 8.1, 1H), 7.59 (s, 1H), 7.54
(d, J = 8.8, 2H), 7.38 - 7.24 (m, 3H), 7.09 (d, J = 7.4, 1H), 7.02
(dd, J = 2.4, 8.8, 4H), 6.90 (d, J = 8.9, 1H) .sup.13C NMR (75 MHz,
DMSO) .delta. 152.94, 150.19, 142.48, 142.18, 138.20, 137.55,
135.74, 129.71, 126.99, 125.35, 123.84, 114.75. MS (ESI) [M + H]
.sup.+ = 255 113 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.74 (s,
1H), 8.20 (s, 2H), 8.03 (d, J = 8.6, 1H), 7.87 (d, J = 7.6, 1H),
7.80 (s, 1H), 7.70 (d, J = 8.0, 1H), 7.63 (t, J = 7.7, 1H), 7.37
(t, J = 7.4, 1H), 7.30 (d, J = 8.7, 1H) 114 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 9.67 (s, 1H), 8.34 - 8.12 (m, 2H), 7.84 (d, J =
8.0, 2H), 7.70 - 7.54 (m, 1H), 7.38 (t, J = 7.6, 1H), 7.17 (s, 1H),
2.61 (s, 3H) MS (ESI) [M + H] .sup.+ = 237 115 .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 10.15 (s, 1H), 8.24 - 8.12 (m, 2H), 7.79
(s, 1H), 7.71 (s, 1H), 7.55 (t, J = 8.3, 2H), 7.30 (t, J = 7.9,
1H), 2.38 (s, 3H) MS (ESI) [M + H] .sup.+ = 237 116 MS (ESI) [M +
H] .sup.+ = 240 117 MS (ESI) [M + H] .sup.+ = 253 118 MS (ESI) [M +
H] .sup.+ = 222 119 MS (ESI) [M + H] .sup.+ = 256 121 MS (ESI) [M +
H] .sup.+ = 222 124 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.42
(s, 1H), 7.95 (dd, J = 1.3, 8.2, 1H), 7.87 - 7.78 (m, 3H), 7.70 -
7.61 (m, 1H), 7.55 - 7.47 (m, 1H), 7.26 (dd, J = 2.4, 6.5, 3H),
6.90 (s, 1H) MS (ESI) [M + H] .sup.+ = 306 125 .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.42 (s, 1H), 8.03 (d, J = 9.5, 1H), 7.92
(d, J = 8.2, 1H), 7.73 (d, J = 8.2, 1H), 7.61 (t, J = 7.3, 1H),
7.46 (t, J = 7.2, 1H), 7.13 (s, 2H), 6.84 (s, 1H), 2.35 (s, 3H) 126
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.40 (s, 1H), 8.03 (s,
1H), 7.94 (d, J = 8.2, 1H), 7.84 (d, J = 8.2, 1H), 7.65 (t, J =
7.4, 1H), 7.53 (d, J = 7.1, 1H), 7.48 (d, J = 7.2, 1H), 7.35 (t, J
= 8.2, 1H), 7.22 (s, 1H), 6.94 (d, J = 8.1, 1H) 127 .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 8.85 (dd, J = 1.0, 8.3, 1H), 8.47 (s,
1H), 7.96 (d, J = 8.2, 1H), 7.85 (d, J = 8.3, 1H), 7.72 - 7.61 (m,
1H), 7.57 - 7.47 (m, 1H), 7.42 - 7.36 (m, 1H), 7.33 (d, J = 10.0,
1H), 7.14 (s, 1H), 7.13 - 7.04 (m, 1H) 128 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 9.17 (s, 1H), 8.68 (d, J = 9.1, 1H), 8.64 (d, J
= 4.8, 2H), 8.15 (d, J = 9.1, 1H), 7.87 (d, J = 8.4, 1H), 7.76 (d,
J = 8.1, 1H), 7.64 (t, J = 7.7, 1H), 7.39 (t, J = 7.5, 1H), 6.87
(t, J = 4.8, 1H) .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 158.34,
138.07, 129.85, 127.63, 127.31, 124.34, 114.20, 113.90. 129 .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 9.14 (s, 1H), 8.73 (d, J = 21.2,
3H), 8.17 (s, 1H), 7.73 (d, J = 20.3, 2H), 7.28 (d, J = 9.6, 2H),
6.91 (s, 1H) 130 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.05 (s,
1H), 8.64 (d, J = 4.8, 2H), 8.52 (s, 1H), 7.89 (dd, J = 8.5, 14.6,
2H), 7.63 (t, J = 7.5, 1H), 7.41 (t, J = 7.4, 1H), 6.86 (t, J =
4.8, 1H), 2.74 (s, 3H) MS (ESI) [M + H] .sup.+ = 237 132 .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.86 (d, J = 2.6, 1H), 8.70 (d, J
= 2.5, 1H), 8.32 (d, J = 1.1, 1H), 8.25 - 8.21 (m, 1H), 8.10 (d, J
= 2.7, 1H), 8.06 (d, J = 8.3, 1H), 7.82 (dd, J = 1.2, 7.9, 1H),
7.66 - 7.51 (m, 3H), 6.89 (s, 1H) 135 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 9.09 (s, 1H), 8.71 (s, 1H), 8.54 (d, J = 8.4,
1H), 8.37 (dd, J = 1.0, 4.9, 1H), 7.96 (d, J = 8.2, 1H), 7.85 (d, J
= 8.3, 1H), 7.82 - 7.74 (m, 1H), 7.66 (t, J = 7.6, 1H), 7.52 (dd, J
= 7.0, 8.1, 1H), 7.02 (dd, J = 5.0, 7.2, 1H) MS (ESI) [M + H]
.sup.+ = 223 136 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.02 (s,
1H), 8.70 (s, 1H), 8.30 (s, 1H), 8.20 (d, J = 5.1, 1H), 7.94 (d, J
= 8.1, 1H), 7.84 (d, J = 8.2, 1H), 7.64 (t, J = 7.6, 1H), 7.49 (t,
J = 8.1, 1H), 6.83 (d, J = 5.0, 1H), 2.43 (s, 3H) .sup.13C NMR (75
MHz, CDCl.sub.3) .delta. 153.28, 150.20, 148.55, 147.40, 140.93,
139.83, 138.35, 130.44, 129.16, 127.18, 126.28, 119.70, 113.75,
21.87. MS (ESI) [M + H] .sup.+ = 237 137 .sup.1H NMR (300 MHz,
DMSO) .delta. 11.10 (s, 1H), 9.03 (s, 1H), 8.82 - 8.75 (m, 1H),
8.56 (d, J = 8.9, 1H), 8.24 (dd, J = 2.3, 8.9, 1H), 7.96 (dd, J =
1.2, 8.2, 1H), 7.87 (dd, J = 1.0, 8.3, 1H), 7.79 - 7.71 (m, 1H),
7.61 (ddd, J = 1.4, 7.0, 8.3, 1H) MS (ESI) [M + H] .sup.+ = 248 138
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.72 (s, 1H), 8.53 (s,
1H), 8.20 (d, J = 8.3, 1H), 7.93 (d, J = 8.2, 1H), 7.81 (d, J =
8.3, 1H), 7.62 (td, J = 3.4, 8.1, 2H), 7.53 - 7.43 (m, 1H), 6.83
(d, J = 7.4, 1H), 2.48 (s, 3H) .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta. 156.86, 152.27, 148.40, 140.92, 139.70, 139.00, 138.35,
130.42, 129.13, 127.14, 126.27, 117.76, 110.01, 24.15. MS (ESI) [M
+ H] .sup.+ = 237 139 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.53 (s, 1H), 8.20 (d, J = 4.8, 1H), 8.04 (d, J = 8.3, 1H), 7.92
(d, J = 8.4, 1H), 7.87 (s, 1H), 7.79 (t, J = 7.6, 1H), 7.60 (t, J =
7.6, 1H), 6.88 (d, J = 4.7, 1H), 2.46 (s, 3H) 140 .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 9.93 (s, 1H), 8.19 (s, 1H), 8.05 (d, J =
8.1, 1H), 7.99 (s, 1H), 7.82 (d, J = 8.2, 1H), 7.69 (t, J = 7.6,
1H), 7.59 (t, J = 8.2, 1H), 2.53 (s, 4H) 141 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 9.72 (s, 1H), 9.35 (s, 1H), 8.30 (d, J = 5.0,
1H), 8.05 (d, J = 7.7, 1H), 7.87 (d, J = 7.0, 1H), 7.66 (dd, J =
7.4, 16.9, 3H), 6.92 (d, J = 4.9, 1H), 2.58 (s, 3H) 143 .sup.1H NMR
(300 MHz, DMSO) .delta. 8.85 (s, 1H), 8.42 (d, J = 5.3, 1H), 7.96
(d, J = 9.1, 1H), 7.44 (s, 1H), 7.30 (s, 4H), 7.28 - 7.21 (m, 2H),
6.66 (d, J = 5.3, 1H), 2.99 (s, 6H) .sup.13C NMR (75 MHz, DMSO)
.delta. 156.82, 150.25, 149.69, 143.79, 141.71, 125.95, 122.33,
118.88, 117.37, 115.95, 109.39, 104.92, 43.57 MS (ESI) [M + H]+ =
348 144 MS (ESI) [M + H] .sup.+ = 390 145 MS (ESI) [M + H] .sup.+ =
252 146 .sup.1H NMR (300 MHz, DMSO) .delta. 9.34 (s, 1H), 8.59 (d,
J = 5.2, 1H), 8.53 (s, 1H), 8.13 (d, J = 5.1, 1H), 7.98 (d, J =
9.0, 1H), 7.66 (d, J = 9.1, 1H), 6.80 (d, J = 5.2, 1H), 6.76 (s,
1H), 6.69 (d, J = 4.9, 1H), 4.00 (s, 3H), 2.26 (s, 3H) .sup.13C NMR
(75 MHz, DMSO) .delta. 161.31, 155.67, 151.63, 150.25, 147.77,
147.01, 142.97, 121.56, 119.16, 116.61, 114.75, 112.60, 111.41,
98.91, 55.78, 20.66. MS (ESI) [M + H].sup.+ = 266 147 MS (ESI) [M +
H] .sup.+ = 279 149 MS (ESI) [M + H] .sup.+ = 318 150 MS (ESI) [M +
H] .sup.+ = 280 151 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.35
(s, 1H), 8.04 (d, J = 8.3, 1H), 7.82 (d, J = 8.9, 1H), 7.74 (d, J =
8.9, 1H), 7.60 (t, J = 7.8, 2H), 7.50 (dd, J = 2.3, 8.9, 1H), 7.36
(d, J = 8.9, 1H), 6.79 (d, J = 7.4, 1H), 2.75 (q, J = 7.6, 2H),
1.30 (t, J = 7.6, 3H). MS (ESI) [M + H].sup.+ = 284 152 .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 8.30 (d, J = 8.5, 1H), 8.08 (s, 1H),
7.90 (d, J = 9.0, 1H), 7.77 (d, J = 8.9, 1H), 7.65 (d, J = 2.2,
1H), 7.55 (td, J = 2.0, 8.8, 2H), 7.39 (d, J = 9.0, 1H), 2.31 (s,
3H). MS (ESI) [M + H].sup.+ = 270 153 .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.75 (s, 1H), 8.54 (s, 1H), 8.46 (d, J = 8.8,
1H), 7.91 (dd, J = 5.5, 14.5, 2H), 7.79 (d, J = 8.9, 1H), 7.67 (d,
J = 2.1, 1H), 7.56 (dd, J = 2.3, 8.9, 1H), 7.35 (d, J = 8.9, 1H).
MS (ESI) [M + H].sup.+ = 324 154 .sup.1H NMR (300 MHz, DMSO)
.delta. 9.08 (s, 1H), 8.12 (d, J = 8.4, 1H), 7.73 (d, J = 8.2, 2H),
7.66 (d, J = 10.0, 1H), 7.53 (s, 1H), 7.25 (s, 1H), 6.82 (s, 1H),
5.10 (s, 2H), 2.16 (s, 4H). MS (ESI) [M + H].sup.+ = 285 155
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.68 (d, J = 8.3, 1H),
7.61 (s, 1H), 7.56 (d, J = 11.5, 2H), 7.44 (d, J = 8.3, 1H), 7.38
(d, J = 7.8, 1H), 7.13 (t, J = 7.4, 1H), 6.80 (d, J = 8.7, 2H),
3.85 (t, J = 6.5, 2H), 2.18 (s, 3H), 1.73 - 1.58 (m, 2H), 1.48 -
1.31 (m, 2H), 0.88 (t, J = 7.3, 3H) MS (ESI) [M + H].sup.+ = 307
156 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.75 (d, J = 9.1,
1H), 7.62 (d, J = 8.9, 1H), 7.58 (d, J = 2.2, 1H), 7.48 (dd, J =
2.4, 8.9, 1H), 7.30 (d, J = 8.9, 2H), 6.86 (d, J = 9.0, 1H), 6.77
(d, J = 8.9, 2H), 6.71 (s, 1H), 2.97 (s, 6H) MS (ESI) [M + H].sup.+
= 298 157 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.98 (d, J =
2.6, 1H), 7.89 (d, J = 8.9, 1H), 7.72 (d, J = 7.5, 1H), 7.62 (dd, J
= 2.6, 8.8, 1H), 7.55 (d, J = 7.8, 1H), 7.20 (t, J = 7.8, 1H), 6.95
(d, J = 8.9, 1H), 6.84 (d, J = 8.9, 1H), 6.79 (s, 1H), 3.91 (s, 3H)
MS (ESI) [M + H].sup.+ = 319 158 .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.89 (d, J = 9.0, 1H), 7.70 (dd, J = 1.2, 7.5, 1H), 7.56
(dd, J = 1.1, 8.0, 1H), 7.30 (d, J = 8.6, 1H), 7.20 (t, J = 7.8,
1H), 6.71 (t, J = 5.9, 2H), 6.64 (d, J = 9.5, 1H). MS (ESI) [M +
H].sup.+ = 354 159 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.80
(d, J = 2.6, 1H), 8.37 (d, J = 2.6, 1H), 8.01 (d, J = 8.1, 1H),
7.91 (dd, J = 1.6, 4.9, 1H), 7.78 - 7.70 (m, 1H), 7.58 - 7.43 (m,
2H), 7.09 (dd, J = 1.6, 7.6, 1H), 6.84 (dd, J = 4.9, 7.6, 1H), 6.69
(s, 1H), 3.82 - 3.07 (m, 2H). 160 .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 9.68 - 8.90 (m, 1H), 8.77 (s, 1H), 8.35 (s, 1H), 8.14
(d, J = 5.0, 1H), 7.96 (s, 1H), 7.79 (d, J = 8.8, 1H), 7.61 (d, J =
8.5, 1H), 6.88 (d, J = 4.8, 1H), 2.46 (s, 3H) 161 .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 9.98 (s, 1H), 8.70 (s, 1H), 8.45 (s, 1H),
8.27 (d, J = 5.2, 1H), 7.94 (d, J = 8.1, 1H), 7.84 (d, J = 8.2,
1H), 7.63 (t, J = 7.5, 1H), 7.48 (t, J = 7.5, 1H), 6.87 (d, J =
5.0, 1H), 2.74 (q, J = 7.6, 2H), 1.34 (t, J = 7.6, 3H). MS (ESI) [M
+ H].sup.+ = 251 162 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.73
(s, 1H), 8.70 - 8.60 (m, 1H), 8.48 (s, 1H), 8.31 (s, 1H), 7.98 (d,
J = 8.1, 1H), 7.86 (d, J = 7.9, 1H), 7.68 (t, J = 8.2, 1H), 7.54
(t, J = 8.1, 1H), 2.49 (s, 3H) MS (ESI) [M + H].sup.+ = 315 163
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.75 (s, 1H), 8.68 (s,
1H), 8.01 (s, 1H), 7.95 (d, J = 8.2, 1H), 7.84 (d, J = 8.3, 1H),
7.64 (t, J = 8.2, 1H), 7.49 (t, J = 7.0, 1H), 6.69 (s, 1H), 2.45
(s, 3H), 2.38 (s, 3H) MS (ESI) [M + H].sup.+ = 251 164 .sup.1H NMR
(300 MHz, DMSO) .delta. 10.46 (s, 1H), 9.00 (s, 1H), 8.41 (s, 1H),
8.24 (d, J = 3.0, 1H), 7.90 (d, J = 8.2, 1H), 7.79 (d, J = 8.3,
1H), 7.69 (t, J = 7.0, 1H), 7.52 (t, J = 7.4, 1H), 6.98 (d, J =
4.8, 1H), 5.45 (q, J = 5.6, 1H), 4.58 (d, J = 5.7, 2H). MS (ESI) [M
+ H].sup.+ = 253 165 .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.07
(s, 1H), 8.79 (s, 1H), 8.51 (s, 1H), 8.18 (s, 1H), 8.09 - 8.01 (m,
1H), 7.94 (d, J = 8.4, 1H), 7.81 - 7.71 (m, 1H), 7.69 - 7.59 (m,
1H), 2.80 (s, 3H) MS (ESI) [M + H].sup.+ = 282 166 .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.49 (d, J = 5.0, 1H), 7.77 (d, J = 9.0,
1H), 7.32 (d, J = 2.0, 1H), 7.12 (d, J = 9.0, 2H), 6.99 (dd, J =
2.0, J = 9.0, 1H), 6.82 (d, J = 9.0, 2H), 6.57 (d, J = 5.0, 1H),
5.78 (s, 1H), 3.74 (s, 3H), 3.17 (s, 4H), 2.62 (s, 4H), 2.34 (s,
3H) 167 MS (ESI) [M + H] .sup.+ = 335 168 MS (ESI) [M + H] .sup.+ =
321
[0567] The following examples illustrate in detail the preparation
of compounds (51), (64), (110), (143) and (148) according to the
invention. The structures of the products obtained have been
confirmed at least by NMR spectra.
EXAMPLES
[0568] According to route (A), the compound of formula (III) is
placed in a protic solvent such as tert-butanol. The compound of
formula (IV) is then added in a 1.1 molar ratio with respect to the
compound of formula (III) in presence of an inorganic base, such as
Cs.sub.2CO.sub.3 or K.sub.2CO.sub.3, in a 2.8 molar ratio, in the
presence of a diphosphine, such as Xantphos
(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene), or X-Phos
2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl in a 2 mol %
amount relative to the total amount of compound of formula (III),
and in the presence of a catalyst, such as Pd(OAc).sub.2 or
Pd.sub.2 dba.sub.3 in a 2 mol % amount relative to the total amount
of compound of formula (III). The reaction mixture is then heated
at 90.degree. C., and stirred during 20 hours, under argon. The
reaction mixture is concentrated under reduced pressure and the
resulting residue is diluted with ethyl acetate. The organic phase
is then washed twice with water, dried on magnesium sulphate,
filtered and concentrated under reduced pressure. The residue could
then be purified by column chromatography on silica gel to yield
pure compounds (51), (64), (110), and (143).
[0569] According to route (B), the compound of formula (V) is
placed in a protic solvent such as tert-butanol. The compound of
formula (VI) is then added in a 1.1 molar ratio with respect to the
compound of formula (V) in presence of Cs.sub.2CO.sub.3 in a 2.8
molar ratio, in the presence of Xantphos
(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) in a 2 mol %
amount relative to the total amount of compound of formula (V), and
in the presence of a Pd(OAc).sub.2, in a 2 mol % amount relative to
the total amount of compound of formula (V). The reaction mixture
is then heated at 90.degree. C., and stirred during 20 hours, under
argon. The reaction mixture is concentrated under reduced pressure
and the resulting residue is diluted with ethyl acetate. The
organic phase is then washed twice with water, dried on magnesium
sulphate, filtered and concentrated under reduced pressure. The
residue could then be purified by column chromatography on silica
gel to yield pure compound (148).
Example 1
Compound (51) of Table I
[0570] According to route (A), a mixture of 2,8-dichloroquinoline
(98.5 mg) and 2-amino-4,6-dimethylpyridine (67.1 mg), Pd(OAc).sub.2
(2.2 mg), XantPhos (5.8 mg) and Cs.sub.2CO.sub.3 (456 mg) in 2 mL
of t-BuOH gave compound (51) (99.7 mg).
Example 2
Compound (64) of Table I
[0571] According to route (A), a mixture of
2-chloro-5-nitroquinoline (100.0 mg) and 2-amino-4-methylpyridine
(57.6 mg), Pd.sub.2 dba.sub.3 (20 mg), XantPhos (30 mg) and
K.sub.2CO.sub.3 (270 mg) in 3 mL of t-BuOH gave compound (64) (14.0
mg).
[0572] The preparation of 2-chloro-5-nitroquinoline is described in
Patent application WO2009/23844.
Example 3
Compound (110) of Table I
[0573] According to route (A), a mixture of
8-bromo-2-chloroquinoline (500 mg) and aminopyrazine (216 mg),
Pd.sub.2 dba.sub.3 (95 mg), XantPhos (120 mg) and K.sub.2CO.sub.3
(1.15 g) in 12 mL of t-BuOH gave compound (110) (245 mg).
[0574] The preparation of 8-bromo-2-chloroquinoline is described in
Cottet, F. et al. Eur. J. Org. Chem. 2003, 8, 1559.
Example 4
Compound (143) of Table I
[0575] According to route (A), a mixture of
7-chloro-4-(N,N-dimethylamino)quinoline (500 mg),
4-trifluoromethoxyaniline (0.257 mL), Pd.sub.2dba.sub.3 (110 mg),
XPhos (115 mg) and K.sub.2CO.sub.3 (1g) in 10 mL of t-BuOH gave
compound (143) (410 mg).
[0576] The preparation of 7-chloro-4-(N,N-dimethylamino)quinoline
is described in Sanchez-Martin, R. et al. J. Med. Chem. 2005, 48,
3354.
Example 5
Compound (148) of Table I
[0577] According to route (B), a mixture of
5,8-dimethylisoquinolin-6-amine (59 mg) and
2-bromo-5-methylpyridine (86 mg), Pd(OAc).sub.2 (2.2 mg), XantPhos
(5.8 mg) and Cs.sub.2CO.sub.3 (456 mg) in 2 mL of t-BuOH gave
compound (148) (48 mg).
[0578] The preparation of 5,8-dimethylisoquinolin-6-amine is
described in Australian Journal of Chemistry 1969, 22, 2489.
[0579] 1H NMR (300 MHz, CDCl.sub.3) .delta. 9.32 (s, 1H), 8.52 (d,
J=6.0, 1H), 8.07 (s, 1H), 7.72 (d, J=6.0, 1H), 7.51 (s, 1H), 7.36
(dd, J=2.1, 8.4, 1H), 6.69 (d, J=8.3, 2H), 2.72 (s, 3H), 2.48 (s,
3H), 2.26 (s, 3H)
[0580] MS (ESI) [M+H]+=264
Example 6
Pharmacological Data
[0581] Standard operating procedure:
[0582] Effect of drug compounds on invasion
[0583] of MDA-MB231-D3H2LN cells into collagen
[0584] Background:
[0585] A key step in the generation of tumor metastasis is the
invasion of tumor cells into the extracellular matrix, a major
component of which is collagen. Therefore, the invasion of tumor
cells into collagen in vitro may be indicative of the generation of
metastasis in vivo. E. g., MDA-MB231-luc-D3H2LN mouse breast cancer
cells display indeed both higher invasion into collagen in vitro
and a higher metastatic potential in vivo as compared to MDA-MB231
cells (from which they were derived). Using these
MDA-MB231-luc-D3H2LN cells as a model, the aim of the experiment
described here is to identify drug compounds that inhibit the
invasion of tumor cells into collagen in vitro, therefore
potentially inhibiting also the generation of tumor metastasis in
vivo.
[0586] Assay Principle:
[0587] Step 1: Preparation of cells at the bottom of a collagen
gel: Cells are suspended in a liquid collagen solution (4.degree.
C.), distributed into BSA-coated wells, and then collected at the
bottom of the wells by centrifugation. The collagen is then
solidified by incubation at 37.degree. C. The BSA coating improves
the adhesion of the collagen gel.
[0588] Step 2: Pre-treatment with the compounds to be tested:
Concentrated drug solutions are then added on top of the collagen,
and cells are pre-incubated for 24 h with the drugs at low serum
conditions (0.025% FBS).
[0589] Step 3: Stimulation of invasion: Medium with 5% FBS is then
added in order to stimulate invasion of the cells into the collagen
gel.
[0590] Step 4: Fixation and staining: Following another 24 h
incubation, cells are fixed and nuclei are stained.
[0591] Step 5: Analysis: Finally, plates are analyzed using an
automated microscope. Fluorescent beads that have been included
into the BSA coating serve to detect the bottom of the wells.
Pictures of the stained nuclei are taken at the same level (0
.mu.m) as well as 25 .mu.m and 50 .mu.m above.
[0592] Note:
[0593] In order to detect possible toxic effects, all compounds are
tested in parallel in a viability assay. The viability assay is
performed in parallel on serum-starved cells (as in the invasion
assay) vs. cells under normal culture conditions (10% FBS).
[0594] Materials:
[0595] General equipment: Freezer (-20.degree. C.), refrigerator
(4.degree. C.), ice machine, water bath (37.degree. C.), incubator
(37.degree. C./5% CO.sub.2), cell culture hood, vortex, vacuum
pump, microscope, Malassez cell, Pipet aid, micropipettes (for
pipetting 1-1000 .mu.l), multichannel pipettes (for pipetting
20-200 .mu.l), standard cell culture centrifuge, refrigerated
centrifuge for 96 well plates
[0596] General consumables: Sterile 96 well cell culture plates
(for the viability assay), sterile tubes (1.5/15/50 ml), sterile
pipettes (5/10/25 ml), sterile micropipette tips (for pipetting
1-1000 .mu.l), sterile Pasteur pipettes, sterile reagent
reservoirs
[0597] General products: Sterile PBS, sterile Milli-Q water, DMSO,
decomplemented FBS (frozen aliquots), 0.1 N NaOH, 1 M Hepes, MEM
without serum (not older than 1 month), 2.5.times.MEM without serum
(not older than 1 month), MEM with 10% FBS (not older than one
month), 0.25% trypsin/1 mM EDTA solution, 37% formaldehyde
solution
[0598] Specific Equipment:
[0599] plate reader: Tecan Infinite F200
[0600] automated microscope: Cellomics ArrayScan VTI HCS Reader
[0601] Specific Consumables:
[0602] sterile black 96 well plates (for the invasion assay):
Perkin Elmer ViewPlate-96 F TC, ref. 6005225
[0603] sterile 96 deep well polypropylene plates (for drug
preparation): Starlab, ref S1896-5110
[0604] Specific Products:
[0605] rat tail collagen, type 1: BD Biosciences, ref. 354236
(note: each new lot has to be validated)
[0606] red fluorescent beads (1 .mu.m diameter): Invitrogen, ref.
F13083
[0607] Y-27632 (5 mM aqueous solution): Calbiochem, ref. 688001 (in
solution) or 688000 (dry powder)
[0608] BSA without fatty acids (sterile-filtered 4% aqueous
solution): Sigma, ref A8806 (dry powder)
[0609] Hoechst 33342 nuclear stain (10 mg/ml): Invitrogen, ref.
H3570
[0610] MTS reagent: Promega CellTiter CellTiter 96.RTM. AQueous One
Solution Reagent, ref. G3581
[0611] drug compounds to be tested: generally 25 or 50 mM in 100%
DMSO (aliquots stored at -20.degree. C., then at 4.degree. C. for
max. 3 months)
[0612] MDA-MB231-luc-D3H2LN cells:
[0613] Limits for the cell cultures to be used in the assays:
[0614] total passage number: max. 30
[0615] last passage: between 2 and 4 days before, between 1:3 and
1:20
[0616] cell density: between 50 and 90% (optimally 70%) (between 1
and 2.times.106 cells per 100 mm dish)
[0617] Experimental Procedures:
[0618] General considerations: Controls and plate maps:
[0619] Invasion assay: Negative control: No drug (just DMSO at
equivalent concentration). Positive control: 10 .mu.M Y-27632. To
avoid edge effects, only the 60 central wells B2-G11 are used;
lines A and H as well as columns 1 and 12 remain free. Each drug is
tested at least in triplicate. The positive and negative controls
should be tested in double triplicates at different positions on
each plate. Typical plate map (-=negative control, +=positive
control, 1-16=16 different drug compounds):
TABLE-US-00003 1 2 3 4 5 6 7 8 9 10 11 12 A B - 1 2 3 4 5 6 7 8 + C
- 1 2 3 4 5 6 7 8 + D - 1 2 3 4 5 6 7 8 + E + 9 10 11 12 13 14 15
16 - F + 9 10 11 12 13 14 15 16 - G + 9 10 11 12 13 14 15 16 -
H
[0620] Viability assays: No additional controls. The MTS viability
assay is based on colorimetric detection of a product generated by
the mitochondrial activity of the cells. Each drug is tested at
least in duplicate. To detect potential direct interactions with
the assay substrate, each drug is also tested in absence of cells
(background signals). Typical plate map (controls and drug
compounds as in the invasion assay, lines A-B and E-F: with cells,
lines C-D and G-H: without cells; each 1 plate with 10% vs. 0.025%
FBS):
TABLE-US-00004 1 2 3 4 5 6 7 8 9 10 11 12 A - 1 2 3 4 5 6 7 8 + B -
1 2 3 4 5 6 7 8 + C - 1 2 3 4 5 6 7 8 + D - 1 2 3 4 5 6 7 8 + E + 9
10 11 12 13 14 15 16 - F + 9 10 11 12 13 14 15 16 - G + 9 10 11 12
13 14 15 16 - H + 9 10 11 12 13 14 15 16 -
[0621] The volumes or other quantities indicated in the following
are required for testing 16 drug compounds per 96 wells-plate at 5
.mu.M each (+controls) in an invasion assay and each one viability
assay on serum-starved cells vs. cells under normal culture
conditions according to the plate maps above. According to the
number of tested compounds, the volumes and other quantities should
be adapted for testing more or less compounds or different
concentrations.
[0622] Day 1: Preparation and treatment of the cells (all steps are
performed under a cell culture hood):
[0623] Preparation of 100.times. concentrated drug solutions in 10%
DMSO:
[0624] prepare 10% DMSO in sterile PBS: 1.8 ml sterile PBS+0.2 ml
DMSO
[0625] prepare 100 .mu.l/well 10% DMSO in PBS in 16 wells of a
sterile 96 well polypropylene plate
[0626] add each 1 or 2 .mu.l of the 50 or 25 mM compound stock
solutions, respectively
[0627] mix by pipetting up and down
[0628] Preparation of 4.times. concentrated drug and control
solutions in 0.4% DMSO in MEM+0.1% FBS:
[0629] prepare MEM+0.1% FBS: 12 ml MEM without serum+12 .mu.l FBS
(freshly thawed aliquot)
[0630] prepare 480 .mu.l/well MEM+0.1% FBS in 20 wells of a sterile
96 deep well polypropylene plate
[0631] negative controls (no drug): add each 20 .mu.l 110% DMSO in
sterile PBS
[0632] positive controls (Y-27632): add each 14 .mu.l sterile PBS+2
.mu.l DMSO+4 .mu.l 5 mM Y-27632 (freshly thawed aliquot)
[0633] drug compounds: add each 20 .mu.l of the 100.times.
concentrated drug solutions in 10% DMSO
[0634] mix by pipetting up and down
[0635] store at RT until use
[0636] Coating of the Plates for the Invasion Assay:
[0637] mix 9.5 ml MEM without serum+0.5 ml 4% BSA without fatty
acids+1 .mu.l vortexed fluorescent beads (i.e. dilute 1:10000),
vortex, distribute 100 .mu.l/well into the plate for the invasion
assay
[0638] centrifuge 30' with 1800.times.g at 4.degree. C. (e.g. 3000
rpm in a Jouan GR412 centrifuge)
[0639] remove supernatants by aspiration
[0640] Preparation of a 10.times.106 Cells/ml Cell Suspension
(During the Centrifugation of the Plates):
[0641] remove medium, wash cells with .about.10 ml/dish PBS, add 1
ml/dish 0.25% trypsin/1 mM EDTA
[0642] incubate 30-60 s at 37.degree. C.
[0643] add 5-10 ml/dish pre-warmed MEM+10% FBS
[0644] homogenize by pipetting up and down using a 10 ml pipette,
pool all
[0645] count cells using a Malassez cell
[0646] centrifuge 2.times.106 (or more) cells for 5' with
150.times.g at RT (850 rpm in a std. cell culture centrifuge)
[0647] remove supernatant, resuspend cell pellet in 0.2 ml (or
more, respectively) MEM without serum, yielding 10.times.106
cells/ml
[0648] Preparation of the Invasion Assay (on Ice; Start During the
Centrifugation of the Cells):
[0649] mix on ice in a pre-chilled tube: example for a 3.4 mg/ml
collagen stock solution; volumes of collagen and water to be
adapted according to the stock concentration of each collagen
lot:
[0650] 2.8 ml 2.5.times.MEM
[0651] 441 .mu.l water
[0652] 140 .mu.l M Hepes
[0653] 49 .mu.l 1 N NaOH
[0654] 3.5 ml 3.4 mg/ml collagen stock solution (yielding 1.7 mg/ml
collagen in 7 ml)
[0655] homogenize by pipetting gently up and down (keep on ice)
[0656] add 70 .mu.l of the 10.times.106 cells/ml cell suspension,
homogenize by pipetting gently up and down (yields 0.1.times.106
cells/ml in 1.7 mg/ml collagen in 7 ml 1.times.MEM+20 .mu.M Hepes)
(keep on ice)
[0657] distribute 100 .mu.l/well (i.e. 10000 cells/well) into the
coated wells of the plate for the invasion assay (all on ice)
[0658] centrifuge 5' with 200.times.g at 4.degree. C. (e.g. 1000
rpm in a Jouan GR412 centrifuge)
[0659] add 200 .mu.l/well PBS to all free wells
[0660] incubate 30' at 37.degree. C./5% CO.sub.2 (solidification of
the collagen)
[0661] Preparation of the Viability Assay on Serum-Starved
Cells:
[0662] add 50 .mu.l of the 10.times.106 cells/ml cell suspension to
5 ml MEM without serum (yields 0.1.times.106 cells/ml)
[0663] distribute 100 .mu.l/well of this suspension (i.e. 10000
cells/well) or MEM without serum without cells, respectively, into
a standard 96 well tissue culture plate, according to the plate map
above
[0664] add 200 .mu.l/well PBS to all free wells
[0665] incubate 30' at 37.degree. C./5% CO.sub.2
[0666] Preparation of the Viability Assay on Cells Under Normal
Culture Conditions:
[0667] add 30 .mu.l of the 10.times.106 cells/ml cell suspension to
5 ml MEM+10% FBS (yields 0.06.times.106 cells/ml)
[0668] distribute 100 .mu.l/well of this suspension (i.e. 6000
cells/well) or MEM+10% FBS without cells, respectively, into a
standard 96 well tissue culture plate, according to the plate map
above
[0669] add 200 .mu.l/well PBS to all free wells
[0670] incubate 30' at 37.degree. C./5% CO.sub.2
[0671] Treatment with the Drugs:
[0672] add each 33 .mu.l/well of the 4.times. concentrated drug
solutions in MEM+0.1% FBS to the corresponding wells in all three
plates, according to the plate maps above
[0673] incubate 24 h at 37.degree. C./5% CO.sub.2
[0674] Day 2: Addition of FBS to stimulate the invasion:
[0675] Microscopic observation after 24 h of treatment:
[0676] examine the cells of the viability assays
[0677] Addition of FBS (under a cell culture hood):
[0678] prepare MEM+5% FBS: 7.2 ml MEM without serum+0.8 ml FBS
(freshly thawed aliquot or rest of the aliquot thawed the day
before if kept at 4.degree. C.)
[0679] add 33 .mu.l/well to all wells of invasion and viability
assays
[0680] incubate 24 h at 37.degree. C./5% CO.sub.2
[0681] Day 3: Stop:
[0682] Microscopic observation after 48 h of treatment:
[0683] examine the cells of the viability assays
[0684] Viability assays: MTS assay:
[0685] add each 33 .mu.l/well of the MTS reagent, incubate 2.5 h at
37.degree. C./5% CO.sub.2
[0686] shake and read absorbance at 490 nm (proportional to the
viability)
[0687] calculate the background-corrected signals by subtracting
the means of the background signals in absence of cells from the
corresponding signals in presence of cells
[0688] normalize the background-corrected signals with respect to
the mean signal of the negative controls (no drug) (viabilities are
thus expressed in "% of control")
[0689] Invasion assays: fixation and staining (formaldehyde must be
manipulated under a fume cupboard):
[0690] freshly prepare 1 .mu.g/ml Hoechst 33342 in 18.5%
formaldehyde: 5 ml PBS (not necessarily sterile)+5 ml 37%
formaldehyde+1 .mu.l 10 mg/ml Hoechst 33342 (note: for one plate, a
smaller volume would be sufficient, but the minimal pipetted volume
should not be below 1 .mu.l)
[0691] add 50 .mu.l/well to all wells of the invasion assay (yields
4.3% formaldehyde final)
[0692] seal with black film (provided with the plates)
[0693] incubate at least 7 h at RT
[0694] Day 3: 17 (min. 7 h/max. 2 weeks after fixation and
staining): Analysis of the invasion assay:
[0695] Lecture using the Cellomics ArrayScan VTI HCS Reader:
[0696] BioApplication: SpotDetector.V3
[0697] Plate type: Perkin Elmer 96 well
[0698] Parameters of the Assay Protocol:
[0699] objective: 10.times.(NA 0.45)
[0700] apotome: yes (resulting optical slice: 11.7 .mu.M)
[0701] fields per well: 8
[0702] autofocus in each field
[0703] autofocus channel: 1
[0704] channel 1 (autofocus on, and photo of the fluorescent beads
at the bottom of the wells): filter: XF93-TRITC; exposure time:
usually between 0.002 and 0.01 s
[0705] channel 2 (photo of the stained cells at the same level as
the fluorescent beads): filter: XF100-Hoechst; exposure time:
usually between 0.02 and 0.1 s; z offset: 0 .mu.M
[0706] channel 3 (photo of the stained cells 25 .mu.M above the
fluorescent beads): filter: XF100-Hoechst; exposure time: usually
between 0.02 and 0.1 s; z offset: -25 .mu.M
[0707] channel 4 (photo of the fluorescent cells 50 .mu.M above the
fluorescent beads): filter: XF100-Hoechst; exposure time: usually
between 0.02 and 0.1 s; z offset: -50 .mu.M
[0708] object identification: method: fixed threshold:
100-32767
TABLE-US-00005 object selection parameters: min. max. SpotArea: 20
1000000000000 SpotShapeBFR: 0.2 1000 SpotShapeBAR: 0 1000
SpotAvgInten: 200 32767 SpotTotalInten: .ltoreq.4000 (thus not
limiting) 1000000000000 TargetAvgInten: 0 32767 TargetTotalInten: 0
1000000000000
[0709] Analysis of the results of the scan using vHCS Viewer:
[0710] export the results: for each well:
[0711] number of valid fields
[0712] number of objects in each valid field in each of the
channels 2, 3 and 4 ("field details")
[0713] mean numbers of objects per valid field for each well, in
each of the channels 2, 3 and 4
[0714] exclude wells with less than 6 valid fields per well from
further analysis
[0715] visually check all photos for any apparent problems, such as
bad focusing or obviously inhomogeneous collagen structure
("bubbles", . . . ), . . . ; in case of apparent problems:
document, then exclude the corresponding wells from further
analysis
[0716] Further analysis of the results of the invasion assay (using
e.g. Excel):
[0717] for each well, calculate the mean invasion distance of the
counted cells: (25 .mu.m.times.number of cells at 25 .mu.m+50
.mu.m.times.number cells at 50 .mu.m)/sum of cells at 0, 25 and 50
.mu.m
[0718] for all four parameters (number of cells at 0 .mu.m, number
of cells at 25 .mu.m, number of cells at 50 .mu.m, mean invasion
distance of the counted cells), calculate means, SD and CV of the
replicates (n=6 for the controls; n=3 for the samples)
[0719] invalidate any replicate with a CV.gtoreq.50% (compound to
be re-tested, or assay to be repeated if CV.gtoreq.50% for the
untreated negative control or the compound Y-27632-treated positive
control). Y27632 is a selective inhibitor of the Rho-associated
protein kinase p160ROCK of the following formula
##STR00196##
[0720] validate the assay only if the mean invasion distance of the
cells treated with 10 .mu.M Y-27632 (positive control) is decreased
by .gtoreq.40% as compared to the untreated negative control
[0721] plot graphs of all four parameters (number of cells at 0
.mu.m, number of cells at 25 .mu.m, number of cells at 50 .mu.m,
mean invasion distance of the counted cells)
[0722] Results
[0723] Anti-invasive effect at 5 .mu.M on MDA-MB231 breast cancer
cells (fold effect compared to 10 .mu.M Y-27632 ref compound)
TABLE-US-00006 Compound Invasion of MDA MB231 cells at 5 mM
(family) (fold effect of positive control) 148 (Iee) 0.54 109 (Ie)
0.41 110 (Ie) 0.64 112 (Ie) 0.26 143 (Iq) 0.8 144 (Iq) 0.73 63 (Ia)
0.69 64 (Ia) 1.16 6 (Ia) 0.63 18 (Ia) 0.52 45 (Ia) 0.50 30 (Ia)
0.33 35 (Ia) 0.26 36 (Ia) 0.43 37 (Ia) 0.34 48 (Ia) 0.63 53 (Ia)
0.27 51 (Ia) 1.06 52 (Ia) 0.27 58 (Ia) 0.33 61 (Ia) 0.34 58 (Ia)
0.33 55 (Ia) 0.27 56 (Ia) 0.26
[0724] The compounds according to the present invention demonstrate
an anti-invasive effect predictive for their activity against
cancer.
[0725] Therefore, the result of the tests carried out on the
compounds disclosed in the present invention show that said
compounds may be useful to inhibit, prevent and/or treat cancer.
The following type of cancer may more particularly be treated by
the compounds according to the present invention: colorectal
cancer, pancreatic cancer, lung cancer including non-small cell
lung cancer, breast cancer, bladder cancer, gall bladder cancer,
thyroid cancer, melanoma, liver cancer, uterine/cervical cancer,
oesophageal cancer, kidney cancer, ovarian cancer, prostate cancer,
head and neck cancer, and stomach cancer, etc.
[0726] For this purpose an effective amount of a said compound may
be administered to a patient suffering from cancer.
[0727] The present invention is also related to the use of at least
a compound chosen among a compound of anyone of formula (I), (Ia),
(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il),
(Im), (Io), (Ip), (Iq), (Ir) or (Iee) as defined above, and
compounds (I) to (168) as defined above, or one of its
pharmaceutically acceptable salts according to the present
invention for the manufacture of a pharmaceutical composition
intended for the treatment of cancer.
[0728] The present invention also encompasses pharmaceutical
compositions comprising at least a compound chosen among new
compounds of formula (Iq) or (Iee) as defined above and compounds
(143), (144), (149), (166) and (167) as defined above or any
pharmaceutically acceptable salt thereof.
[0729] Thus, these pharmaceutical compositions contain an effective
amount of said compound, and one or more pharmaceutical
excipients.
[0730] The aforementioned excipients are selected according to the
dosage form and the desired mode of administration.
[0731] In this context they can be present in any pharmaceutical
form which is suitable for enteral or parenteral administration, in
association with appropriate excipients, for example in the form of
plain or coated tablets, hard gelatine, soft shell capsules and
other capsules, suppositories, or drinkable, such as suspensions,
syrups, or injectable solutions or suspensions, in doses which
enable the daily administration of from 0.1 to 1000 mg of active
substance.
[0732] The present invention is also related to the use of a
compound of anyone of formula (I), (Ia), (Ib), (Ic), (Id), (Ie),
(If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io), (Ip), (Iq),
(Ir) or (Iee) as defined above, and compounds (I) to (168) as
defined above, or one of its pharmaceutically acceptable salts
according to the present invention for the manufacture of a
pharmaceutical composition intended for inhibiting, preventing
and/or treating cancer.
[0733] The present invention further relates to a method of
treatment of patients suffering form cancer, which comprises at
least a step of administration to a patient suffering thereof of an
effective amount of a compound of anyone of formula (I), (Ia),
(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il),
(Im), (Io), (Ip), (Iq), (Ir) or (Iee) as defined above and (1) to
(168) or one of its pharmaceutically acceptable salts.
* * * * *