Note: Descriptions are shown in the official language in which they were submitted.
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SUBSTITUTED DIHYDRO-BENZIMIDAZOLE COMPOUNDS AS ROR
GAMMA MODULATORS
Related Applications
This application claims the benefit of Indian Provisional Application No.
3207/MUM/2013 filed on October 10, 2013; which is hereby incorporated by
reference in its
entirety.
Technical Field
The present patent application is directed to substituted dihydro-
benzimidazole
compounds which may be useful as retinoid-related orphan receptor gamma t
(RORyt)
modulators.
Background of the invention
Retinoid-related orphan receptors (RORs) are transcription factors which
belong to the
steroid hormone nuclear receptor super family. The ROR family consists of
three members,
ROR alpha (RORa), ROR beta (RORP) and ROR gamma (RORy), also known as NRIF I,
NR1F2 and NR1F3 respectively (and each encoded by a separate gene RORA, RORB
and
RORC, respectively). RORs contain four principal domains shared by the
majority of nuclear
receptors: an N-terminal A/B domain, a DNA-binding domain, a hinge domain, and
a ligand
binding domain. Each ROR gene generates several isoforms which differ only in
their N-
terminal A/B domain. Two isoforms of RORy, RORyl and RORyt (also known as
RORy2)
have been identified.
RORyt is a truncated form of RORy, lacking the first N-terminal 21 amino acids
and is
exclusively expressed in cells of the lymphoid lineage and embryonic lymphoid
tissue
inducers (Sun et al., Science, 2000, 288, 2369-2372; Eberl et al., Nat
Immunol., 2004, 5: 64-
73) in contrast to RORy which is expressed in multiple tissues (heart, brain,
kidney, lung,
liver and muscle).
RORyt has been identified as a key regulator of Th17 cell differentiation.
Th17 cells are
a subset of T helper cells which produce IL-17 and other proinflammatory
cytokines and have
been shown to have key functions in several mouse autoimmune disease models
including
experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis
(CIA). In
addition, Th17 cells have also been associated in the pathology of a variety
of human
inflammatory and autoimmune disorders including multiple sclerosis, rheumatoid
arthritis,
psoriasis, Crohn's disease and asthma (Jetten et al., Nucl. Recept. Signal,
2009, 7:e003; Manel
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et al., Nat. Immunol., 2008, 9, 641-649). The pathogenesis of chronic
autoimmune diseases
including multiple sclerosis and rheumatoid arthritis arises from the break in
tolerance
towards self-antigens and the development of auto-aggressive effector T cells
infiltrating the
target tissues. Studies have shown that Th17 cells are one of the important
drivers of the
inflammatory process in tissue-specific autoimmunity (Steinman et al., J. Exp.
Med., 2008,
205: 1517-1522; Leung et al., Cell. Mol. Immunol., 2010 7: 182-189). Th17
cells are activated
during the disease process and are responsible for recruiting other
inflammatory cells types,
especially neutrophils, to mediate pathology in the target tissues (Korn et
al., Annu. Rev.
Immunol., 2009, 27:485-517) and RORyt has been shown to play a critical role
in the
pathogenic responses of Th17 cells (Ivanov et al., Cell, 2006 126: 1121-1133).
RORyt
deficient mice have shown no Th17 cells and also resulted in amelioration of
EAE. The
genetic disruption of RORy in a mouse colitis model also prevented colitis
development
(Buonocore et al., Nature, 2010, 464: 1371-1375). The role of RORyt in the
pathogenesis of
autoimmune or inflammatory diseases has been well documented in the
literature. ( Jetten et
al., Adv. Dev. Biol., 2006, 16:313-355; Meier et al. Immunity, 2007, 26:643-
654; Aloisi et al.,
Nat. Rev. Immunol., 2006, 6:205-217; Jager et al., J. Immunol., 2009, 183:7169-
7177; Serafmi
et al., Brain Pathol., 2004, 14: 164-174; Magliozzi et al., Brain, 2007, 130:
1089-1104;
Barnes et al., Nat. Rev. Immunol., 2008, 8: 183-192).
In addition, RORyt is also shown to play a crucial role in other non-Th17
cells, such as
mast cells (Hueber et al., J Immunol., 2010, 184: 3336-3340). RORyt expression
and secretion
of Th17-type of cytokines has also been reported in NK T-cells (Eberl et al.,
Nat. Immunol.,
2004, 5: 64-73) and gamma-delta T-cells (Sutton et al, Nat. Immunol., 2009,
31: 331-341;
Louten et al., J Allergy Clin. Immunol., 2009, 123: 1004-1011), suggesting an
important
function for RORyt in these cells.
In view of the above, a need exists for therapeutic agents that could modulate
the
activity of RORyt and thus will open new methods for treating diseases or
condition
associated with the modulation of RORyt.
PCT publication numbers W02012/139775, W02012/027965, W02012/028100,
W02012/100732, W02012/100734, W02012/064744 and W02013/171729 disclose
numerous heterocyclic compounds which are shown to be modulators of retinoid-
related
orphan receptor gamma (RORy) receptor activity.
The present application is directed to compounds that may be modulators of the
RORyt receptor. Thus in light of the role RORyt plays in the pathogenesis of
diseases, it is
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desirable to prepare compounds that modulate RORyt activity, which can be used
in the
treatment of diseases mediated by RORyt.
Summary of the Invention
In one aspect, the present invention relates to compound of formula (I)
(R5) n
R4 R3
M ¨ L¨ N N ____________________________________ )¨ R1
Y3¨
?7-4yi
y2/
(R2) m
(I)
or a pharmaceutically acceptable salt thereof,
wherein,
L is selected from -C(0)-, -CH2-, -S(0)2- and -5(0)-;
M is C6-14 aryl, 5 to 14-membered heteroaryl or 3 to 15 membered heterocyclyl,
each
being optionally substituted with one or more R6;
Y1 and Y2 are each independently selected from CH and N;
Y3 is selected from CH and N;
R1 is selected from cyano, -C(0)0R9, -C(0)NR7R8, -S(0)2NR7R8, -S(0)2R1 , -
P(0)(0R11)2, 5 to 14 membered heteroaryl and 3 to 15 membered heterocyclyl;
each occurrence of R2 is independently selected from cyano, halogen, hydroxyl,
C1.
8alkyl, Ci.8alkoxy, haloCi.8alkyl, hydroxyCi_8alkyl, Ci.8alkoxyCi.8alkyl,
C3.12cycloalkyl, -
NRYItz and -CH2NRYRz;
R3 and R4 are each independently selected from hydrogen, hydroxyl, Ci.8alkyl
and
haloCi.8alkyl; or R3 and R4 together with the carbon atom to which they are
attached, form a
cyclic ring which is substituted or unsubstituted and wherein the cyclic ring
optionally
contains one or more hetero atoms selected from 0, N or S; or R3 and R4
togetherform a oxo
(=0) group;
each occurrence of R5 is independently selected from cyano, halogen, hydroxyl,
C1.
8alkyl, Ci.8alkoxy, haloCi.8alkyl, C3.12cycloalkyl and -C(0)0H;
each occurrence of R6 is independently selected from cyano, halogen, hydroxyl,
Ci.
8alkyl, Ci.8alkoxy, haloCi.8alkyl and C3.12cycloalkyl;
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R7 and R8 are each independently selected from hydrogen, Ci_galkyl and C3_
6cycloalkyl;
R9 is selected from hydrogen, Ci_galkyl, haloCi_galkyl, C3_6cycloalkyl,
C6.14ary1C1-
8alkyl and -(CH2)qCOORx;
5R' =
is selected from Ci_galkyl and haloCi_galkyl;
is selected from hydrogen and Ci_galkyl;
Rx is selected from hydrogen and Ci_4alkyl;
RY and Itz are each independently selected from hydrogen, Ci_4alkyl and C3-
6cycloalkyl;
'm' is an integer ranging from 0 to 2, both inclusive;
'n' is an integer ranging from 0 to 3, both inclusive; and
'q' is an integer ranging from 1 to 4, both inclusive.
The compounds of formula (I) may involve one or more embodiments. Embodiments
of formula (I) includes compounds of formula (Ia) as described hereinafter. It
is to be
understood that the embodiments below are illustrative of the present
invention and are not
intended to limit the claims to the specific embodiments exemplified. It is
also to be
understood that the embodiments defined herein may be used independently or in
conjunction
with any definition, any other embodiment defined herein. Thus the invention
contemplates
all possible combinations and permutations of the various independently
described
embodiments. For example, the invention provides compounds of formula (I) as
defined
above wherein L is -C(0)- (according to an embodiment defined below), Yl and
Y2 are CH
(according to another embodiment defined below), 'm' is 0 or 1 (according to
yet another
embodiment defined below) and 'n' is 0 or 1 (according to yet another
embodiment defined
below).
According to one embodiment, specifically provided are compounds of formula
(I), in
which L is -C(0)-.
According to another embodiment, specifically provided are compounds of
formula
(I), in which L is -C(0)-, -CH2- or -S(0)2-.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which M is C6.14ary1 (e.g. phenyl or naphthyl) or 5- to 14-
membered
heteroaryl (e.g. pyridinyl).
According to yet another embodiment, specifically provided are compounds of
formula (I), in which M is phenyl, naphthyl or pyridinyl; each being
optionally substituted
with one or more of R6.
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According to yet another embodiment, specifically provided are compounds of
formula (I), in which M is phenyl.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which each occurrence of R6 is independently halogen (e.g. F,
Cl or Br), Ci.
g alkyl (e.g. methyl or ethyl), C i_galkoxy (e.g. methoxy), haloC i_g alkyl
(e.g. CHF2 or CF3) or
C3.12cycloalkyl (e.g. cyclopropyl).
According to yet another embodiment, specifically provided are compounds of
formula (I), in which M is phenyl optionally substituted with one or two R6
substituent(s)
independently selected from halogen (e.g. F, Cl or Br), Ci.4alkyl (e.g. methyl
or ethyl), C1.
8alkoxy (e.g. methoxy), haloCi.8alkyl (e.g. CHF2 or CF3) and C3.6cycloalkyl
(e.g.
cyclopropyl).
According to yet another embodiment, specifically provided are compounds of
formula (I), in which M is phenyl or pyridine, each being optionally
substituted with one or
two R6 substituent(s) independently selected from F, Cl, Br, OCH3, CHF2, CF3
and
cyclopropyl.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which M is phenyl or pyridin-4-yl, each being optionally
substituted at 2 or 6
position with one or more of R6 substituent(s) independently selected from F,
Cl, Br, OCH3,
CHF2, CF3 and cyclopropyl.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which M is 2,6-dichlorophenyl, 2-bromo-6-chlorophenyl, 2-
chloro-6-
methoxyphenyl, 2-fluoro-6-methoxyphenyl, 2-chloro-6-(difluoromethyl)phenyl, 2-
chloro-6-
(trifluoromethyl)phenyl, 2-(trifluoromethyl)phenyl, 2-chloro-6-
cyclopropylphenyl, 1-naphthyl
or 3, 5 -di chl oropyri di n-4-yl.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which L-M is 2,6-dichlorobenzoyl, 2-bromo-6-chlorobenzoyl, 2-
chloro-6-
methoxybenzoyl, 2-fluoro-6-methoxybenzoyl, 2-chloro-6-(difluoromethyl)benzoyl,
2-chloro-
6-(trifluoromethyl)benzoyl, 2-chloro-6-cyclopropylbenzoyl, 1-naphthoyl,
(3,5 -
dichloropyridin-4-yl)carbonyl, 2,6-dichlorobenzyl or [2-
(trifluoromethyl)phenyl]sulfonyl.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which is -C(0)0H.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which
is -C(0)0R9. In this embodiment R9 is hydrogen or Ci.4alkyl (e.g.
methyl, ethyl, propyl or tert-butyl).
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According to yet another embodiment, specifically provided are compounds of
formula (I), in which R1 is -C(0)NR7R8 or -S(0)2NR7R8. In this embodiment R7
is hydrogen
or C3-6cycloalkyl (e.g. cyclopropyl) and R8 is hydrogen.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which RI-is -P(0)(0R11)2. In this embodiment is hydrogen or
Ci_4alkyl (e.g.
methyl or ethyl).
According to yet another embodiment, specifically provided are compounds of
formula (I), in which RI-is 5- to 14-membered heteroaryl (e.g. tetrazolyl or
oxadiazolyl).
According to yet another embodiment, specifically provided are compounds of
formula (I), in which R1 is cyano, -C(0)0H, -C(0)0CH3, -C(0)0C2H5, -
C(0)0C(CH3)3, -
C(0)NH2, -C(0)NH-cyclopropyl, -S(0)2NH-cycl opropyl, -P(0)(0C2H5)2, 2H-tetraz
01-5 -yl
or 5-oxo-4,5-dihydro-1,2,4-oxadi azol -3 -yl
According to yet another embodiment, specifically provided are compounds of
formula (I), in which `m' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which Y1 and Y2 are CH.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which one of the Y1 and Y2 is N and other is CH.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which R2 is optional substituent present on Y1 or Y2 when Y1
or Y2 is CH.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which R2 is cyano, halogen (e.g. Cl or F), hydroxyCi_galkyl
(e.g.
hydroxymethyl or 2-hydroxy-1,1-dimethyl-ethyl), Ci_galkoxyCi_galkyl (e.g. 2-
methoxy-1,1-
dimethyl-ethyl), Ci-galkoxy (e.g. 3-methyl-oxetan-3-ylmethoxy), -NRYRz and -
CH2NRYRz
In this embodiment RY and Rz are each independently selected from Ci_4alkyl
(e.g. methyl or
ethyl) or C3.6cycloalkyl (e.g. cyclopropyl or cyclobutyl).
According to yet another embodiment, specifically provided are compounds of
formula (I), in which R2 is CN, halogen (e.g. Cl or F), hydroxyCi_galkyl (e.g.
hydroxymethyl
or
2-hydroxy-1, 1-di m ethyl -ethyl), Ci_galkoxyCi_galkyl (e.g. 2-m ethoxy-1, 1-
di m ethyl -ethyl),
Ci_galkoxy (e.g. 3-methyl -oxetan-3-ylmethoxy), -CH2N(CH3)2, -N(CH3)2 or
.3; and
`m' is 0 or 1.
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According to yet another embodiment, specifically provided are compounds of
H3c>OH (.../...cH3 H3C>C3.õ
OCH3 h0"-Co
formula (I), in which R2 is CN, F, -CH2OH, H3C
/cH3 Nro
\
C H3 C H3 or -CH2N(CH3)2
According to yet another embodiment, specifically provided are compounds of
H3c>coHC H3
H3 C H3
o'N/Co
formula (I), in which R2 is CN, F, -CH2OH, H3C
,C H3 k
\
CrI3 CH3 or -CH2N(CH3)2; and 'm' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which Yl is N, C-H or C-F.
According to yet another embodiment, specifically provided are compounds of
H3C>4!:::õ..OH C H3
OC H3
formula (I), in which Y2 is N, C-H, C-F, C-CN, C-CH2OH, C , C
C H3
C 0 C ¨Kr
H3C CH3 C H3 or C-CH2N(CH3)2.
According to yet another embodiment, specifically provided are compounds of
H3c>(..,cH3
OH
formula (I), in which Yl is N, C-H or C-F; Y2 is N, C-H, C-F, C-CN, C-CH2OH, C
H3c C H3 H3
C C-1\1
H3C CH3 CH3, or C-CH2N(CH3)2; and m is 0 or
1.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which R3 and R4 togetherform a oxo (=0) group.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which R3 is hydrogen and R4 is Ci_4alkyl (e.g. methyl or
ethyl).
According to yet another embodiment, specifically provided are compounds of
formula (I), in which 'n' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which R5 is halogen (e.g. Cl or F).
According to yet another embodiment, specifically provided are compounds of
formula (I), in which R5 is F or Cl.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which R5 is optional substituent present on Y3, when Y3 isCH.
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According to yet another embodiment, specifically provided are compounds of
formula (I), in which R5 is F or Cl; and 'n' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which Y3 is N, C-H or C-F.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which Y3 is N, C-H or C-F; and 'n' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of
(R5)n
Ri =
i
formula (I), in which y3¨/ is COOH ¨O¨COOH , N¨ F COOH
= COOH
COOH I * F CO0C2H5 =
, ,
CO0C2H5 COOC(C H3)3 ¨0¨CON H2
CON H¨<1
CI
0
N
\)¨SO2NH ¨µ1
.5/2 0
¨ or
According to yet another embodiment, specifically provided are compounds of
formula (I), in which
Yl and Y2 are each independently selected from CH and N;
Y3 is selected from CH and N;
le is cyano, -C(0)0H, -C(0)0CH3, -C(0)0C2H5, -C(0)0C(CH3)3, -C(0)NE12, -
C(0)NH-cyclopropyl, -S(0)2NH-cyclopropyl, -P(0)(0C2H5)2, 2H-tetrazol-5-y1 or 5-
oxo-4,5-
dihydro-1,2,4-oxadiazol-3-y1;
R2 is CN, halogen, hydroxyCl-galkyl, Cl-galkoxyCl-galkyl, Cl-galkoxy, -
CH2N(CH3)2,
-0
i¨N
-N(CH3)2 or cH3=
Lis -C(0)-;
M is phenyl, naphthyl or pyridinyl; each being optionally substituted with one
or two
R6;
R3 and R4 togetherform a oxo (=0) group;
R5 is F or Cl;
R6 is F, Cl, Br, OCH3, CHF2, CF3 or cyclopropyl;
'm' is 0 or 1; and 'n' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which
Yl and Y2 are each independently selected from CH and N;
Y3 is selected from CH and N;
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R1 is cyano, -C(0)0H, -C(0)0CH3, -C(0)0C2H5, -C(0)0C(CH3)3, -C(0)NE12, -
C(0)NH-cyclopropyl, -S (0)2NH-cycl op ropyl, -P(0)(0C2H5)2, 2H-tetrazol -5-y1
or 5-oxo-4,5-
dihydro-1,2,4-oxadiazol -3-y1;
H3c>4.....vcH3 /cH3
OH H3C
>COCH3
R2 is CN, F, -CH2OH, H3c \C H3 N\ C H3
or -CH2N(CH3)2,
R3 and R4 togetherform a oxo (=0) group;
R5 is F or Cl; 'm' is 0 or 1; 'n' is 0 or 1; and
L-M is 2,6-dichlorobenzoyl, 2-bromo-6-chlorobenzoyl, 2-chloro-6-
methoxybenzoyl,
2-fluoro-6-m ethoxyb enzoyl, 2-chloro-6-(difluoromethyl)b enzoyl,
2-chl oro-6-
(trifluoromethyl)benzoyl, 2-chloro-6-cyclopropylb enzoyl, 1 -naphthoyl, (3,5-
di chl oropyri din-
4-yl)carb onyl, 2, 6-di chl orob enzyl or [2-(trifluoromethyl)phenyl] sulfonyl
.
According to yet another embodiment, specifically provided are compounds of
formula (I), in which
Yl and Y2 are each independently selected from CH and N;
H3cxõ...õ
cH3 0H H3c> ,CH3 .11)
OCH3
R2 is CN, F, -CH2OH, H3c \C H3 N\ C H3
or -CH2N(CH3)2,
'm' is 0 or 1;
(R5)n
Ri 40, COOH COOH
=COOH
= COOH ¨e-3¨COOH
Y3=7 1S N CI
41 CO0C2H5
CO0C2H5 COOC(CH3)3 CON H2 4. CON H¨<1
= S02NH
/ 0
) N.¨NH ,N
41 P0(0C2H52 = 20 N or H =
R3 and R4 togetherform a oxo (=0) group; and
L-M is 2,6-dichlorobenzoyl, 2-bromo-6-chlorobenzoyl, 2-chloro-6-
methoxybenzoyl,
2-fluoro-6-m ethoxyb enzoyl, 2-chloro-6-(difluoromethyl)b enzoyl,
2-chloro-6-
(trifluoromethyl)benzoyl, 2-chloro-6-cyclopropylb enzoyl, 1 -naphthoyl, (3,5-
di chl oropyri din-
4-yl)carbonyl, 2, 6-di chl orob enzyl or [2-(trifluoromethyl)phenyl] sulfonyl
.
According to an embodiment, specifically provided are compounds of formula (I)
with
an IC50 value of less than 500 nM, preferably less than 100 nM, more
preferably less than 50
nM with respect to RORyt activity.
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Further embodiments relating to groups RI-, R2, R3, R4, R5, L, M,
Y2, Y3, m and n
(and groups defined therein) are described hereinafter in relation to the
compounds of formula
(Ia) or formula (lb). It is to be understood that these embodiments are not
limited to use in
conjunction with formula (Ia) or formula (lb), but apply independently and
individually to the
compounds of formula (I). For example, in an embodiment described hereinafter,
the
invention specifically provides compounds of formula (Ia) or formula (lb), in
which 'n' is 0 or
1 and consequently there is also provided a compound of formula (I) in which
'n' is 0 or 1.
The invention also provides a compound of formula (Ia), which is an embodiment
of a
compound of formula (I).
Accordingly the invention provides compound of formula (Ia)
0 (R5),
0
N A N
(R6)19 ______________________________________ y3 __
\ 1
r y2
(R2)m
(Ia)
or a pharmaceutically acceptable salt thereof,
wherein,
Yl and Y2 are each independently selected from CH and N;
Y3 is selected from CH and N;
Y4 is selected from CH and N;
R' is selected from cyano, -C(0)0R9, -C(0)NH2, -C(0)NH-cyclopropyl, -S(0)2NH-
cyclopropyl, -P(0)(0C2H5)2, 2H-tetrazol-5-y1 and 5-oxo-4,5-dihydro-1,2,4-
oxadiazol-3-y1;
each occurrence of R2 is independently selected from cyano, halogen,
H3c>(...voltC H3 /C H3 N.4.)
OH H3C>4.,..,70C H3 -1\j
-CH2OH, z H3C H3 ,
cH3 and -
,
CH2N(CH3)2,
each occurrence of R5 is independently selected from cyano, halogen, hydroxyl,
Ci.
8alkyl and haloCi_8alkyl;
each occurrence of R6 is independently selected from halogen, Ci_8alkyl,
Ci_8alkoxY,
haloCi_8alkyl and C3_6cycloalkyl;
R9 is selected from hydrogen and Ci_8alkyl;
'm' is an integer ranging from 0 to 2, both inclusive;
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'n' is an integer ranging from 0 to 3, both inclusive; and
p' is an integer ranging from 1 to 4, both inclusive.
The compound of formula (Ia) may involve one or more embodiments. It is to be
understood that the embodiments below are illustrative of the present
invention and are not
intended to limit the claims to the specific embodiments exemplified. It is
also to be
understood that the embodiments defined herein may be used independently or in
conjunction
with any definition of any other embodiment defined herein. Thus, the
invention contemplates
all possible combinations and permutations of the various independently
described
embodiments. For example, the invention provides compounds of formula (Ia) as
defined
above wherein Yl and Y2 are CH (according to an embodiment defined below), 'm'
is 0 or 1
(according to another embodiment defined below) and 'n' is 0 or 1 (according
to yet another
embodiment defined below).
According to one embodiment, specifically provided are compounds of formula
(Ia),
in which RI- is -C(0)0H.
According to another embodiment, specifically provided are compounds of
formula
(Ia), in which RI- is -C(0)0R9. In this embodiment R9 is hydrogen or Ci_galkyl
(e.g. methyl,
ethyl, propyl or tert-butyl).
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which RI- is -C(0)N}{2, -C(0)NH-cyclopropyl, -S(0)2NH-
cyclopropyl, -
P(0)(0C2H5)2, 2H-tetrazol-5-y1 and 5-oxo-4,5-dihydro-1,2,4-oxadi azol -3 -yl
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which le is cyano, -C(0)0H, -C(0)0CH3, -C(0)0C2H5, -
C(0)0C(CH3)3, -
C(0)NH2, -C(0)NH-cyclopropyl, -S(0)2NH-cycl opropyl, -P(0)(0C2H5)2, 2H-
tetrazol-5-y1
or 5-oxo-4,5-dihydro-1,2,4-oxadi azol-3 -yl
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which 'm' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which YI- and Y2 are CH.
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which one of the Yl and Y2 is N and other is CH.
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which R2 is optional substituent present on Yl or Y2 when Yl
or Y2 is CH.
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According to yet another embodiment, specifically provided are compounds of
H3c>0H H3C>4,õ/õCH3 oc H3 h nC,o
formula (Ia), in which R2 is CN, F, -CH2OH, H3C
,c H3 k N
\
CH3 CH3 or -CH2N(CH3)2
According to yet another embodiment, specifically provided are compounds of
H3c>coHC H3
H3\C>4,,...,õ, 0 C H3 ¨0-"N/Co
formula (Ia), in which R2 is CN, F, -CH2OH, H3C
,C H3 k N1:7
\
CrI3 CH3 or -CH2N(CH3)2; and 'm' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which Yl is N, C-H or C-F.
According to yet another embodiment, specifically provided are compounds of
HC CF-I3 r
CF-I3"3 ->4....õ"
OC H3
formula (Ia), in which Y2 is N, C-H, C-F, C-CN, C-CH2OH, C , C
c ¨o'N/OD C_K(C H3
H3C CH3 CH3 or C-CH2N(CH3)2.
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which Yl is N, C-H or C-F; Y2 is N, C-H, C-F, C-CN, C-CH2OH,
H3c CH3 H3c CH3
>4õ...,OCH3 C-000 C¨N
C H3C
CH3 , C-N(CH3)2, or C-CH2N(CH3)2; and m
is 0 or 1.
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which 'n' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which R5 is halogen (e.g. Cl or F).
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which R5 is F or Cl.
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which R5 is an optional substituent present on Y3, when Y3 is
CH.
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which R5 is F or Cl; and 'n' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which Y3 is N, C-H or C-F.
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According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which Y3 is N, C-H or C-F; and 'n' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which each occurrence of R6 is independently halogen (e.g. F,
Cl or Br), C1.
g alkyl (e.g. methyl or ethyl), Ci.8alkoxy (e.g. methoxy), haloC i_g alkyl
(e.g. CHF2 or CF3) or
C3.6cycloalkyl (e.g. cyclopropyl).
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which each occurrence of R6 is independently halogen (e.g. F,
Cl or Br), C1.
galkyl (e.g. methyl or ethyl), Ci-galkoxy (e.g. methoxy), haloC i-galkyl (e.g.
CHF2 or CF3) or
C3.6cycloalkyl (e.g. cyclopropyl); and 'ID' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which R6 is independently selected from F, Cl, Br, OCH3,
CHF2, CF3 and
cyclopropyl.
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which R6 is independently selected from F, Cl, Br, OCH3,
CHF2, CF3 and
cyclopropyl; and 'ID' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of
Y4µ\
formula (Ia), in which \\
ring is optionally substituted at 2 or 6 position with one or
two R6 substituent(s) independently selected from F, Cl, Br, OCH3, CHF2, CF3
and
cyclopropyl.
According to yet another embodiment, specifically provided are compounds of
6 ),...(:<4 R6T-T-R6
formula (Ia), in which (R )P is y4
. In this embodiment R6 is independently
halogen (e.g. F, Cl or Br), Ci-galkyl (e.g. methyl or ethyl), Ci-galkoxy (e.g.
methoxy), haloC
8alkyl (e.g. CHF2 or CF3) or C3.6cycloalkyl (e.g. cyclopropyl).
According to yet another embodiment, specifically provided are compounds of
6 R6
R6
formula (Ia), in which (R)1334k(1-1¨\ 1S Y4
. In this embodiment R6 is independently
selected from F, Cl, Br, OCH3, CHF2, CF3 and cyclopropyl.
According to yet another embodiment, specifically provided are compounds of
.¨
6 y4
formula (Ia), in which (R )P
is 2,6-dichlorophenyl, 2-bromo-6-chlorophenyl, 2-chloro-
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6-methoxyphenyl, 2-fluoro-6-methoxyphenyl, 2-chloro-6-(difluoromethyl)phenyl,
2-chloro-
6-(trifluoromethyl)phenyl, 2-chloro-6-cyclopropylphenyl or 3,5-dichloropyridin-
4-yl.
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which R9 is hydrogen or Ci_4alkyl (e.g. methyl, ethyl, propyl
or tert-butyl).
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which R9 is hydrogen, methyl, ethyl, propyl or tert-butyl.
According to yet another embodiment, specifically provided are compounds of
(R5)n
COOH =COOH
i
formula (Ia), in which y3¨ is = O¨COOH ¨
COOH N¨ F
COOH * CO0C2H5
\CON H2 FC
CO0C2H5 COOC (C H3)3
ON H¨<1
CI F
0
N."'NH 41 = I
\)¨S02NH
/
kv-A-,2. .5/2 I
N0
1 0 N
N or
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which
Yl and Y2 are each independently selected from CH and N;
Y3 is selected from CH and N;
Y4 is selected from CH and N;
R' is cyano, -C(0)0H, -C(0)0CH3, -C(0)0C2H5, -C(0)0C(CH3)3, -C(0)NE12, -
C(0)NH-cyclopropyl, -S(0)2NH-cyclopropyl, -P(0)(0C2H5)2, 2H-tetrazol-5-y1 or 5-
oxo-4,5-
dihydro-1,2,4-oxadiazol-3-y1;
C H3 0H H3c>C. /CH3
N _127
OCH3 N\
R2 is CN, F, -CH2OH, H3c \C H3
\ CH3
or -CH2N(CH3)2;
R5 is F or Cl;
R6 is F, Cl, Br, OCH3, CHF2, CF3 or cyclopropyl;
'm' is 0 or 1; 'n' is 0 or 1; and 'ID' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which
Yl and Y2 are each independently selected from CH and N;
Y3 is selected from CH and N;
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R' is cyano, -C(0)0H, -C(0)0CH3, -C(0)0C2H5, -C(0)0C(CH3)3, -C(0)NH2, -
C(0)NH-cyclopropyl, -S (0)2NH-cycl op ropyl, -P(0)(0C2H5)2, 2H-tetrazol -5 -yl
or 5 -ox o-4, 5 -
dihydro-1,2,4-oxadi azol -3 -yl ;
H3cxõ...7.cH3 /cH3
OH H3C
>COCH3
R2 is CN, F, -CH2OH, H3c
CH3 \ CH3
or -CH2N(CH3)2;
(R )p _______________ S 2,6-di chl orophenyl ,
2-bromo-6-chlorophenyl, 2-chloro-6-
methoxyphenyl, 2-fluoro-6-methoxyphenyl, 2-chloro-6-(difluoromethyl)phenyl, 2-
chloro-6-
(trifluoromethyl)phenyl, 2-chloro-6-cyclopropylphenyl or 3,5-dichloropyridin-4-
y1;
R5 is F or Cl;
'm' is 0 or 1; and
'n' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of
formula (Ia), in which
Yl and Y2 are each independently selected from CH and N;
HC
CH3 HcCõ ,CH3
3>(..,0H 3 >
OCH3 i_N
R2 is CN, F, -CH2OH, H3c
CH3 \ CH3
or -CH2N(CH3)2;
'm' is 0 or 1;
(R6 5
s 2,6-di chl orophenyl ,
2-bromo-6-chlorophenyl, 2-chloro-6-
methoxyphenyl, 2-fluoro-6-methoxyphenyl, 2-chloro-6-(difluoromethyl)phenyl, 2-
chloro-6-
(trifluoromethyl)phenyl, 2-chloro-6-cyclopropylphenyl or 3,5-dichloropyridin-4-
y1; and
(R5)n
COOH 473-COOH = COOH 41 00H =COOH
Y3- i S F CI
41 COOC 2H5
= C00C2H5 =
COOC(CH3)3 afr CON H2 = CON H-(1 )-SO2NH
N
=
PO(0C2H5)2 = /
N or N 0
According to an embodiment, specifically provided are compounds of formula
(Ia)
with an IC50 value of less than 500 nM, preferably less than 100 nM, more
preferably less
than 50 nM with respect to RORyt activity.
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Further embodiments relating to groups R1, R2, R5, R6, R9, yl, Y-2,
Y3, Y4, m, n and p
(and groups defined therein) are described hereinafter in relation to the
compounds of formula
(lb). It is to be understood that these embodiments are not limited to use in
conjunction with
formula (lb), but apply independently and individually to the compounds of
Formula (I) or
Formula (Ia). For example, in an embodiment described hereinafter, the
invention
specifically provides compounds of formula (lb), in which 'n' is 0 or 1 and
consequently there
is also provided a compound of Formula (I) or Formula (Ia) in which 'n' is 0
or 1.
The invention also provides a compound of formula (lb), which is an embodiment
of a
compound of formula (I).
Accordingly the invention provides compound of formula (lb)
0
0
N i-COOR9
(R6)p, _________________________
//
(R2)õ
(Ib)
or a pharmaceutically acceptable salt thereof,
wherein,
H3C>(.7CH3
OH
each occurrence of R2 is independently selected from cyano, F, -CH2OH,
H3c>OCH3
,cH3 Nra
H3C CH3
CH3 and -CH2N(CH3)2,
each occurrence of R5 is independently selected from cyano, halogen, hydroxyl,
Ci.
8alkyl and haloCi_8alkyl;
each occurrence of R6 is independently selected from halogen, Ci_8alkyl,
Ci_8alkoxY,
haloCi_8alkyl and C3_6cycloalkyl;
R9 is selected from hydrogen and Ci_8alkyl;
'm' is an integer ranging from 0 to 2, both inclusive;
'n' is an integer ranging from 0 to 3, both inclusive; and
p' is an integer ranging from 1 to 4, both inclusive.
The compounds of formula (lb) may involve one or more embodiments. It is to be
understood that the embodiments below are illustrative of the present
invention and are not
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intended to limit the claims to the specific embodiments exemplified. It is
also to be
understood that the embodiments defined herein may be used independently or in
conjunction
with any definition of any other embodiment defined herein. Thus, the
invention contemplates
all possible combinations and permutations of the various independently
described
embodiments. For example, the invention provides compounds of formula (Ib) as
defined
above wherein R5 is F or Cl (according to an embodiment defined below), 'm' is
0 or 1
(according to another embodiment defined below) and 'n' is 0 or 1 (according
to yet another
embodiment defined below).
According to one embodiment, specifically provided are compounds of formula
(Ib),
in which 'm' is 0 or 1.
According to another embodiment, specifically provided are compounds of
formula
CH3 0H H3C>C.
NN CH
/ 3
OCH3
(lb), in which R2 is CN, F, -CH2OH, H3c
C H3
CH3 or -CH2N(CH3)2; and 'm' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of
formula (lb), in which 'n' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of
formula (lb), in which R5 is halogen (e.g. Cl or F).
According to yet another embodiment, specifically provided are compounds of
formula (lb), in which R5 is F or Cl.
According to yet another embodiment, specifically provided are compounds of
formula (lb), in which R5 is F or Cl; and 'n' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of
formula (lb), in which each occurrence of R6 is independently halogen (e.g. F,
Cl or Br), C1.
galkyl (e.g. methyl or ethyl), Ci_galkoxy (e.g. methoxy), haloC i-galkyl (e.g.
CHF2 or CF3) or
C3.6cycloalkyl (e.g. cyclopropyl).
According to yet another embodiment, specifically provided are compounds of
formula (lb), in which each occurrence of R6 is independently halogen (e.g. F,
Cl or Br), C1.
galkyl (e.g. methyl or ethyl), C i_galkoxy (e.g. methoxy), haloC i_galkyl
(e.g. CHF2 or CF3) or
C3.6cycloalkyl (e.g. cyclopropyl); and 'ID' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of
formula (lb), in which R6 is independently selected from F, Cl, Br, OCH3,
CHF2, CF3 and
cyclopropyl.
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According to yet another embodiment, specifically provided are compounds of
formula (lb), in which R6 is independently selected from F, Cl, Br, OCH3,
CHF2, CF3 and
cyclopropyl; and 'ID' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of
_________________________________________________________________________
formula (lb), in which ring is optionally substituted at 2 or 6 position
with one or two
R6 substituent(s) independently selected from F, Cl, Br, OCH3, CHF2, CF3 and
cyclopropyl.
According to yet another embodiment, specifically provided are compounds of
R6 R6
/ s
formula (lb), in which v /P ____ is 40
. In this embodiment R6 is independently
selected from F, Cl, Br, OCH3, CHF2, CF3 and cyclopropyl.
According to yet another embodiment, specifically provided are compounds of
ix-
formula (lb), in which 1P
is 2,6-dichlorophenyl, 2-bromo-6-chlorophenyl, 2-chloro-
6-methoxyphenyl, 2-fluoro-6-methoxyphenyl, 2-chloro-6-(difluoromethyl)phenyl,
2-chloro-
6-(trifluoromethyl)phenyl or 2-chloro-6-cyclopropylphenyl.
According to yet another embodiment, specifically provided are compounds of
formula (lb), R9 ishydrogen or Ci_8alkyl (e.g. methyl, ethyl, propyl or tert-
butyl).
According to yet another embodiment, specifically provided are compounds of
formula (lb), R9 ishydrogen, methyl, ethyl, propyl or tert-butyl.
According to yet another embodiment, specifically provided are compounds of
formula (lb), in which
CH3 0H IA3õ
..r
CH3 0H
,CH3
0 3
R2 is CN, F, -CH2OH, H3c C H3 N \ C H3
or -CH2N(CH3)2;
R5 is F or Cl;
R6 is F, Cl, Br, OCH3, CHF2, CF3 or cyclopropyl;
R9 ishydrogen, methyl, ethyl, propyl or tert-butyl;
'm' is 0 or 1;
'n' is 0 or 1; and
'ID' is 1 or 2.
According to yet another embodiment, specifically provided are compounds of
formula (lb), in which
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H3C> ,CH3
CH3 oFi
OH H3C>(.../..,.0 3
R2 is CN, F, -CH2OH, H3c C H3
\ CH3
or -CH2N(CH3)2;
"R6'
s 2,6-dichlorophenyl, 2-bromo-6-chlorophenyl, 2-chloro-6-
methoxyphenyl, 2-fluoro-6-methoxyphenyl, 2-chloro-6-(difluoromethyl)phenyl, 2-
chloro-6-
(trifluoromethyl)phenyl, or 2-chloro-6-cyclopropylphenyl;
R5 is F or Cl;
R9 ishydrogen, methyl, ethyl, propyl or tert-butyl;
'm' is 0 or 1;
and 'n' is 0 or 1.
According to an embodiment, specifically provided are compounds of formula
(Ia)
with an IC50 value of less than 500 nM, preferably less than 100 nM, more
preferably less
than 50 nM with respect to RORyt activity.
Compounds of the present invention include the compounds in Examples 1-44.
It should be understood that the formulas (I), (Ia) and (lb) (structurally
encompasses
all geometrical isomers, stereoisomers, enantiomers and diastereomers, N-
oxides, and
pharmaceutically acceptable salts that may be contemplated from the chemical
structure of the
genera described herein.
As disclosed herein, esters of the compounds of present invention refer to a
modified
version or a precursor of a parent compound, designed to enhance the delivery
properties and
be converted to the parent compound in the body.
Ester of the compounds of present invention are entities structurally related
to parent
acidic drug compound (-COOH), which, after administration, release the parent
drug in vivo
as the result of some metabolic process, such as enzymatic or chemical
hydrolysis of a
susceptible functionality.
le is ¨COOR9 Ester (wherein R9 is Ci_galkyl) of the compounds of present
invention
are entities structurally related to parent acidic drug compound (R9 is -
COOH), which, after
administration, release the parent drug in vivo as the result of some
metabolic process, such as
enzymatic or chemical hydrolysis of a susceptible functionality.
The present application also provides a pharmaceutical composition that
includes at
least one compound described herein and at least one pharmaceutically
acceptable excipient
(such as a pharmaceutically acceptable carrier or diluent). Preferably, the
pharmaceutical
composition comprises a therapeutically effective amount of at least one
compound described
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herein. The compounds described in the present patent application may be
associated with a
pharmaceutically acceptable excipient (such as a carrier or a diluent) or be
diluted by a
carrier, or enclosed within a carrier which can be in the form of a capsule,
sachet, paper or
other container.
The compounds and pharmaceutical compositions of the present invention are
useful
for inhibiting the activity of RORyt, which is believed to be related to a
variety of disease
states.
The present patent application further provides a method of inhibiting RORyt
in a
subject in need thereof by administering to the subject one or more compounds
described
herein in the amount effective to cause inhibition of such receptor.
Detailed Description of the Invention
Definitions
The terms "halogen" or "halo" means fluorine (fluoro), chlorine (chloro),
bromine
(bromo), or iodine (iodo).
The term "alkyl" refers to a hydrocarbon chain radical that includes solely
carbon and
hydrogen atoms in the backbone, containing no unsaturation, having from one to
eight carbon
atoms (i.e. Ci_galkyl), and which is attached to the rest of the molecule by a
single bond, e.g.,
methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-
dimethylethyl (t-
butyl). The term "Ci.6 alkyl" refers to an alkyl chain having 1 to 6 carbon
atoms. The term
"Ci_4alkyl" refers to an alkyl chain having 1 to 4 carbon atoms. Unless set
forth or recited to
the contrary, all alkyl groups described or claimed herein may be straight
chain or branched,
substituted or unsubstituted.
The term "alkenyl" refers to a hydrocarbon chain containing from 2 to 10
carbon
atoms (i.e. C2.10alkenyl) and including at least one carbon-carbon double
bond. Non-limiting
examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl),
iso-propenyl, 2-
methyl-1-propenyl, 1-butenyl, and 2-butenyl. Unless set forth or recited to
the contrary, all
alkenyl groups described or claimed herein may be straight chain or branched,
substituted or
unsubstituted.
The term "alkynyl" refers to a hydrocarbyl radical having at least one carbon-
carbon
triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to
about 10 carbon
atoms being preferred i.e. C2.10alkyny1). Non-limiting examples of alkynyl
groups include
ethynyl, propynyl, and butynyl. Unless set forth or recited to the contrary,
all alkynyl groups
described or claimed herein may be straight chain or branched, substituted or
unsubstituted.
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The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the
rest of
the molecule (i.e. C18 alkoxy). Representative examples of such groups are -
OCH3 and -
0C2H5. Unless set forth or recited to the contrary, all alkoxy groups
described or claimed
herein may be straight chain or branched, substituted or unsubstituted.
The term "alkoxyalkyl" or "alkyloxyalkyl" refers to an alkoxy or alkyloxy
group as
defined above directly bonded to an alkyl group as defined above (i.e.
Ci_galkoxyCi_galkyl or
Ci_galkyloxyCi_galkyl). Example of such alkoxyalkyl moiety includes, but are
not limited to, -
CH2OCH3 and -CH20C2H5. Unless set forth or recited to the contrary, all
alkoxyalkyl groups
described herein may be straight chain or branched, substituted or
unsubstituted.
The term "haloalkyl" refers to at least one halo group (selected from F, Cl,
Br or I),
linked to an alkyl group as defined above (i.e. haloCi_galkyl). Examples of
such haloalkyl
moiety include, but are not limited to, trifluoromethyl, difluoromethyl and
fluoromethyl
groups. Unless set forth or recited to the contrary, all haloalkyl groups
described herein may
be straight chain or branched, substituted or unsubstituted.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more
halogen
atoms (i.e. haloCi_galkoxy). Examples of "haloalkoxy" include but are not
limited to
fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,
pentafluoroethoxy,
pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-
bromoethoxy.
Unless set forth or recited to the contrary, all haloalkoxy groups described
herein may be
straight chain or branched, substituted or unsubstituted.
The term "hydroxyalkyl" refers to an alkyl group as defined above wherein one
to
three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl
groups (i.e.
hydroxyCi_galkyl). Examples of hydroxyalkyl moieties include, but are not
limited to -
CH2OH, -C2H4OH and ¨CH(OH)C2H4OH.
The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system
of 3 to
about 12 carbon atoms, (i.e.C3_12cycloalkyl). Examples of monocyclic
cycloalkyl include but
are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
Examples of
multicyclic cycloalkyl groups include, but are not limited to,
perhydronapthyl, adamantyl and
norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g.,
spiro(4,4)non-2-yl. The
term "C3_6cycloalkyl" refers to the cyclic ring having 3 to 6 carbon atoms.
Unless set forth or
recited to the contrary, all cycloalkyl groups described or claimed herein may
be substituted
or unsubstituted.
The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3
to about
8
carbon atoms directly attached to an alkyl group (i.e. C 3 -8cycloalkylC 1-
galkyl). The
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cycloalkylalkyl group may be attached to the main structure at any carbon atom
in the alkyl
group that results in the creation of a stable structure. Non-limiting
examples of such groups
include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. Unless set
forth or recited
to the contrary, all cycloalkylalkyl groups described or claimed herein may be
substituted or
unsubstituted.
The term "cycloalkenyl" refers to a cyclic ring-containing radical having 3 to
about 8
carbon atoms with at least one carbon-carbon double bond, (i.e.
C3.8cycloalkeny1). Examples
of "cycloalkenyl" include but are not limited to cyclopropenyl, cyclobutenyl,
and
cyclopentenyl. Unless set forth or recited to the contrary, all cycloalkenyl
groups described or
claimed herein may be substituted or unsubstituted.
The term "cycloalkenylalkyl" refers to a cyclic ring-containing radical having
3 to
about 8 carbon atoms with at least one carbon-carbon double bond, directly
attached to an
alkyl group, (i.e. C3-8cycloalkenylCi-8alkyl). The cycloalkenylalkyl group may
be attached to
the main structure at any carbon atom in the alkyl group that results in the
creation of a stable
structure. Unless set forth or recited to the contrary, all cycloalkenylalkyl
groups described or
claimed herein may be substituted or unsubstituted.
The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms
(i.e. C6-
14ary1), including monocyclic, bicyclic and tricyclic aromatic systems, such
as phenyl,
naphthyl, tetrahydronapthyl, indanyl, and biphenyl. Unless set forth or
recited to the contrary,
all aryl groups described or claimed herein may be substituted or
unsubstituted.
The term "aryloxy" refers to an aryl group as defined above attached via an
oxygen
linkage to the rest of the molecule (i.e. C6_14aryloxy). Examples of aryloxy
moieties include,
but are not limited to phenoxy and naphthoxy. Unless set forth or recited to
the contrary, all
aryloxy groups described herein may be substituted or unsubstituted.
The term "arylalkyl" refers to an aryl group as defined above directly bonded
to an
alkyl group as defined above, i.e. C6.14arylCi_8alkyl, such as -CH2C6H5 and -
C2H4C6H5.
Unless set forth or recited to the contrary, all arylalkyl groups described or
claimed herein
may be substituted or unsubstituted.
The term "heterocyclic ring" or "heterocycly1" unless otherwise specified
refers to
non-aromatic 3 to 15 membered ring radical (i.e. 3 to 15 membered
heterocycly1) which
consists of carbon atoms and from one to five hetero atoms selected from
nitrogen,
phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-,
bi- or tricyclic
ring system, which may include fused, bridged or spiro ring systems, and the
nitrogen,
phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical
may be optionally
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oxidized to various oxidation states. In addition, the nitrogen atom may be
optionally
quaternized; also, unless otherwise constrained by the definition the
heterocyclic ring or
heterocyclyl may optionally contain one or more olefinic bond(s). Examples of
such
heterocyclic ring radicals include, but are not limited to azepinyl,
azetidinyl, benzodioxolyl,
benzodioxanyl, chromanyl, di oxol anyl, di oxaphosphol anyl, decahydroi
soquinolyl, indanyl,
indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl,
morpholinyl,
oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-
oxopyrrolidinyl, 2-
oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl,
piperazinyl, 4-
piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl,
quinuclidinyl,
tetrahydroisquinolyl, tetrahydrofuryl or tetrahydrofuranyl, tetrahydropyranyl,
thiazolinyl,
thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl
sulfone. The
heterocyclic ring radical may be attached to the main structure at any
heteroatom or carbon
atom that results in the creation of a stable structure. Unless set forth or
recited to the
contrary, all heterocyclyl groups described or claimed herein may be
substituted or
unsubstituted.
The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly
bonded to an
alkyl group (i.e. 3 to 15 membered heterocycly1C1.8alkyl). The
heterocyclylalkyl radical may
be attached to the main structure at any carbon atom in the alkyl group that
results in the
creation of a stable structure. Unless set forth or recited to the contrary,
all heterocyclylalkyl
groups described or claimed herein may be substituted or unsubstituted.
The term "heteroaryl" unless otherwise specified refers 5 to 14 membered
aromatic
heterocyclic ring radical with one or more heteroatom(s) independently
selected from N, 0 or
S (i.e. 5 to 14 membered heteroaryl). The heteroaryl may be a mono-, bi- or
tricyclic ring
system. The heteroaryl ring radical may be attached to the main structure at
any heteroatom or
carbon atom that results in the creation of a stable structure. Examples of
such heteroaryl ring
radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl,
furyl, indolyl,
isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadiazolyl,
thiazolyl, isothiazolyl,
pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl,
benzothiazolyl,
benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl,
quinolinyl,
isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl,
quinoxalinyl,
quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl and
phthalazinyl. Unless
set forth or recited to the contrary, all heteroaryl groups described or
claimed herein may be
substituted or unsubstituted.
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The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded
to an
alkyl group (i.e. 5 to 14 membered heterarylCi_galkyl). The heteroarylalkyl
radical may be
attached to the main structure at any carbon atom in the alkyl group that
results in the creation
of a stable structure. Unless set forth or recited to the contrary, all
heteroarylalkyl groups
described or claimed herein may be substituted or unsubstituted.
Unless otherwise specified, the term "substituted" as used herein refers to
substitution
with any one or any combination of the following substituents: hydroxy,
halogen, carboxyl,
cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl,
substituted or
unsubstituted haloalkyl, substituted or unsubstituted hydroxyl alkyl,
substituted or
unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or
unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted
cycloalkyl,
substituted or unsubstituted cycloalkenyl alkyl, substituted or unsubstituted
cycloalkenyl,
substituted or unsubstituted amino, substituted or unsubstituted aryl,
substituted or
unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted
heteroarylalkyl, substituted or unsubstituted heterocyclylalkyl ring,
substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring,
substituted or
unsubstiuted guanidine, -COORx', -C(0)R', -C(S)R', -C(0)NRxitY', -
C(0)0NRxitY', -
NRx'CONRY'Rz', -N(Rx')SORY', -N(Rx')S02RY', -(=N-N(Rx')RY'), -NRx'C(0)ORY
XY -
NRx'C(0)RY -NRx'C(S)R -NRx'C(S)NRY'Rz', -SONRxitY', -S02NRxitY', -0Rx', -
OC(0)NRY'Rz', -0C(0)0RY', -0C(0)Rx', -0C(0)NRxitY', -SRx', -SORx', -S02Rx',
and -0NO2,
wherein each occurrence of Rx', RY' and Rz' are independently selected from
hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,
substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or unsubstituted
cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or
unsubstituted
aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl
ring, substituted or
unsubstituted heteroarylalkyl, and substituted or unsubstituted heterocyclic
ring. The
substituents in the aforementioned "substituted" groups cannot be further
substituted. For
example, when the substituent on "substituted alkyl" is "substituted aryl",
the substituent on
"substituted aryl" can be unsubstituted alkenyl but cannot be "substituted
alkenyl".
The term "pharmaceutically acceptable salt" includes salts prepared from
pharmaceutically acceptable bases or acids including inorganic or organic
bases and inorganic
or organic acids.
Examples of such salts include, but are not limited to, acetate,
benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,
bromide, camsylate,
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carbonate, chloride, clavulanate, citrate, di hydrochl ori de, edetate, edi
syl ate, e stol ate, esyl ate,
fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,
hexylresorcinate,
hydrab amine, hydrob romi de, hydrochloride, hydroxynaphthoate, iodide, i
sothionate, lactate,
lactobionate, laurate, m al ate, m al eate, m andel ate, m e syl ate, m ethylb
romi de, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt,
oleate, oxalate,
pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate,
polygalacturonate,
salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate,
teoclate, tosylate,
triethiodide and valerate. Examples of salts derived from inorganic bases
include, but are not
limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium,
magnesium,
manganic, mangamous, potassium, sodium, and zinc.
The term "treating" or "treatment" of a state, disorder or condition includes:
(a)
preventing or delaying the appearance of clinical symptoms of the state,
disorder or condition
developing in a subject that may be afflicted with or predisposed to the
state, disorder or
condition but does not yet experience or display clinical or subclinical
symptoms of the state,
disorder or condition; (b) inhibiting the state, disorder or condition, i.e.,
arresting or reducing
the development of the disease or at least one clinical or subclinical symptom
thereof; or (c)
relieving the disease, i.e., causing regression of the state, disorder or
condition or at least one
of its clinical or subclinical symptoms.
The term "subject" includes mammals (especially humans) and other animals,
such as
domestic animals (e.g., household pets including cats and dogs) and non-
domestic animals
(such as wildlife).
A "therapeutically effective amount" means the amount of a compound that, when
administered to a subject for treating a state, disorder or condition, is
sufficient to effect such
treatment. The "therapeutically effective amount" will vary depending on the
compound, the
disease and its severity and the age, weight, physical condition and
responsiveness of the
subject to be treated.
Pharmaceutical Compositions
The compounds of the invention are typically administered in the form of a
pharmaceutical composition. Such compositions can be prepared using procedures
well
known in the pharmaceutical art and comprise at least one compound of the
invention. The
pharmaceutical composition of the present patent application comprises one or
more
compounds described herein and one or more pharmaceutically acceptable
excipients.
Typically, the pharmaceutically acceptable excipients are approved by
regulatory authorities
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or are generally regarded as safe for human or animal use. The
pharmaceutically acceptable
excipients include, but are not limited to, carriers, diluents, glidants and
lubricants,
preservatives, buffering agents, chelating agents, polymers, gelling agents,
viscosifying
agents, solvents and the like.
Examples of suitable carriers include, but are not limited to, water, salt
solutions,
alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra
alba, sucrose,
dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc,
gelatin, agar, pectin,
acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty
acids, fatty acid amines,
fatty acid monoglycerides and diglycerides, fatty acid esters, and
polyoxyethylene.
The pharmaceutical composition may also include one or more pharmaceutically
acceptable auxiliary agents, wetting agents, suspending agents, preserving
agents, buffers,
sweetening agents, flavouring agents, colorants or any combination of the
foregoing.
The pharmaceutical compositions may be in conventional forms, for example,
capsules, tablets, solutions, suspensions, injectables or products for topical
application.
Further, the pharmaceutical composition of the present invention may be
formulated so as to
provide desired release profile.
Administration of the compounds of the invention, in pure form or in an
appropriate
pharmaceutical composition, can be carried out using any of the accepted
routes of
administration of pharmaceutical compositions. The route of administration may
be any route
which effectively transports the active compound of the patent application to
the appropriate
or desired site of action. Suitable routes of administration include, but are
not limited to, oral,
nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal,
subcutaneous, intravenous,
intraurethral, intramuscular, or topical.
Solid oral formulations include, but are not limited to, tablets, capsules
(soft or hard
gelatin), dragees (containing the active ingredient in powder or pellet form),
troches and
lozenges.
Liquid formulations include, but are not limited to, syrups, emulsions, and
sterile
injectable liquids, such as suspensions or solutions.
Topical dosage forms of the compounds include ointments, pastes, creams,
lotions,
powders, solutions, eye or ear drops, impregnated dressings, and may contain
appropriate
conventional additives such as preservatives, solvents to assist drug
penetration.
The pharmaceutical compositions of the present patent application may be
prepared by
conventional techniques, e.g., as described in Remington: The Science and
Practice of
Pharmacy, 20th Ed., 2003 (Lippincott Williams & Wilkins).
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Suitable doses of the compounds for use in treating the diseases and disorders
described herein can be determined by those skilled in the relevant art.
Therapeutic doses are
generally identified through a dose ranging study in humans based on
preliminary evidence
derived from the animal studies. Doses must be sufficient to result in a
desired therapeutic
benefit without causing unwanted side effects. Mode of administration, dosage
forms, and
suitable pharmaceutical excipients can also be well used and adjusted by those
skilled in the
art. All changes and modifications are envisioned within the scope of the
present patent
application.
Methods of Treatment
Compounds of the present invention are particularly useful because they may
inhibit
the activity of Retinoid-related orphan receptor gamma {and particularly
Retinoid-related
orphan receptor gamma t (RORyt)}, i.e., they prevent, inhibit, or suppress the
action of
RORyt, and/or may elicit RORyt modulating effect. Compounds of the invention
are thus
useful in the treatment of those conditions in which inhibition of a ROR gamma
activity, and
particularly RORyt, is required.
The compounds of the present patent application are modulators of RORyt and
can be
useful in the treatment of diseases/disorder mediated by RORyt. Accordingly,
the compounds
and the pharmaceutical compositions of this invention may be useful in the
treatment of
inflammatory, metabolic and autoimmune diseases mediated by RORyt.
The term "autoimmune diseases" will be understood by those skilled in the art
a
condition that occurs when the immune system mistakenly attacks and destroys
healthy body
tissue. An autoimmune disorder may result in the destruction of one or more
types of body
tissue, abnormal growth of an organ, and changes in organ function. An
autoimmune disorder
may affect one or more organ or tissue types which include blood vessels,
connective tissues,
endocrine glands such as the thyroid or pancreas, joints, muscles, red blood
cells, and skin.
Examples of autoimmune (or autoimmune-related) disorders include multiple
sclerosis,
arthritis, rheumatoid arthritis, psoriasis, Crohn's disease, gastrointestinal
disorder,
inflammatory bowel disease, irritable bowel syndrome, colitis, ulcerative
colitis, Sjorgen's
syndrome, atopic dermatitis, optic neuritis, respiratory disorder, chronic
obstructive
pulmonary disease (COPD), asthma, type I diabetes, neuromyelitis optica,
Myasthenia Gavis,
uveitis, Guillain- Barre syndrome, psoriatic arthritis, Gaves' disease,
allergy, osteoarthritis,
Kawasaki disease, mucosal lei shmaniasis, Hashimoto's thyroiditis, Pernicious
anemia,
Addison's disease, Systemic lupus erythematosus, Dermatomyositis, Sjogren
syndrome,
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Lupus erythematosus, Myasthenia gravis, Reactive arthritis, Celiac disease -
sprue (gluten-
sensitive enteropathy), Graves's disease, thymopoiesis and Lupus.
Compounds of the present patent application may be useful in the treatment of
inflammation. The term "inflammation" will be understood by those skilled in
the art to
include any condition characterized by a localized or a systemic protective
response, which
may be elicited by physical trauma, infection, chronic diseases, and/or
chemical and/or
physiological reactions to external stimuli (e.g. as part of an allergic
response). Any such
response, which may serve to destroy, dilute or sequester both the injurious
agent and the
injured tissue, may be manifest by, for example, heat, swelling, pain,
redness, dilation of
blood vessels and/or increased blood flow, invasion of the affected area by
white.
The term "inflammation" is also understood to include any inflammatory
disease,
disorder or condition per se, any condition that has an inflammatory component
associated
with it, and/or any condition characterized by inflammation as a symptom,
including inter alia
acute, chronic, ulcerative, specific, allergic, infection by pathogens, immune
reactions due to
hypersensitivity, entering foreign bodies, physical injury, and necrotic
inflammation, and
other forms of inflammation known to those skilled in the art. The term thus
also includes, for
the purposes of this present patent application, inflammatory pain, pain
generally and/or fever.
The compounds of the present invention may be used for treatment of arthritis,
including rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic
arthritis,
spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and
juvenile arthritis,
osteoarthritis, and other arthritic conditions.
The compounds of the present invention may be used for treatment of
respiratory
disorders such as chronic obstructive pulmonary disease (COPD), asthma,
bronchospasm, and
cough.
Other respiratory disorders include bronchitis, bronchiolitis, bronchiectasis,
acute
nasoparyngitis, acute and chronic sinusitis, maxillary sinusitis, pharyngitis,
tonsillitis,
laryngitis, tracheitis, epiglottitis, croup, chronic disease of tonsils and
adenoids, hypertrophy
of tonsils and adenoids, peritonsillar abscess, rhinitis, abscess or ulcer and
nose, pneumonia,
viral and bacterial pneumonia, bronchopneumonia, influenza, extrinsic allergic
alveolitis, coal
workers' pneumoconiosis, asbestosis, pneumoconiosis, pneumonopathy,
respiratory
conditions due to chemical fumes, vapors and other external agents, emphysema,
pleurisy,
pneumothorax, abscess of lung and mediastinum, pulmonary congestion and
hypostasis,
postinflammatory pulmonary fibrosis, other alveolar and parietoalveolar
pneumonopathy,
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idiopathic fibrosing alveolitis, Hamman-Rich syndrome, atelectasis, ARDS,
acute respiratory
failure, mediastinitis.
The compounds of the present invention may be used for treatment of pain
conditions.
The pain can be acute or chronic pain. Thus, the compounds of the present
invention may be
used for treatment of inflammatory pain, arthritic pain, neuropathic pain,
post-operative pain,
surgical pain, visceral pain, dental pain, premenstrual pain, central pain,
cancer pain, pain due
to burns; migraine or cluster headaches, nerve injury, neuritis, neuralgias,
poisoning, ischemic
injury, interstitial cystitis, viral, parasitic or bacterial infection, post-
traumatic injury, or pain
associated with irritable bowel syndrome.
The compounds of the present invention may be used for treatment of
gastrointestinal
disorder such as irritable bowel syndrome, inflammatory bowel disease,
colitis, ulcerative
colitis, biliary colic and other biliary disorders, renal colic, diarrhea-
dominant IBS, and pain
associated with gastrointestinal distension.
In addition, the compounds of the present invention may be useful in the
treatment of
cancer, and pain associated with cancer. Such cancers include multiple myeloma
and bone
disease associated with multiple myeloma, melanoma, medulloblastoma, acute
myelogenous
leukemia (AML), head and neck squamous cell carcinoma, hepatocellular
carcinoma, gastric
cancer, bladder carcinoma and colon cancer.
The compounds of the present invention may be useful in a treatment of
disease,
disorder, syndrome or condition selected from the group consisting of chronic
obstructive
pulmonary disease (COPD), asthma, cough, pain, inflammatory pain, chronic
pain, acute pain,
arthritis, osteoarthritis, multiple sclerosis, rheumatoid arthritis, colitis,
ulcerative colitis and
inflammatory bowel disease.
The methods of treatment of the present patent application comprise
administering a
safe and effective amount of a compound according to Formula I or a
pharmaceutically-
acceptable salt thereof to a patient (particularly a human) in need thereof.
The present patent application relates to the use of the compounds in the
preparation
of a medicament for the treatment of diseases mediated by RORyt.
Compounds of the invention are indicated both in the therapeutic and/or
prophylactic
treatment of the above-mentioned conditions. For the above-mentioned
therapeutic uses the
dosage administered will, of course, vary with the compound employed, the mode
of
administration, the treatment desired and the disorder indicated.
Compounds of the present invention are indicated both in the therapeutic
and/or prophylactic
treatment of the above-mentioned conditions. For the above-mentioned
therapeutic uses the
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dosage administered will, of course, vary with the compound employed, the mode
of
administration, the treatment desired and the disorder indicated. The daily
dosage of the
compound of the invention may be in the range from 0.05 mg/kg to 100 mg/kg.
General Methods of Preparation
The compounds, described herein, are prepared according to general formula
(I), (Ia)
and (Ib). Suitable synthetic methods are depicted in schemes 1 to 11.
Furthermore, in the
following schemes, where specific acids, bases, reagents, coupling agents,
solvents, etc. are
mentioned, it is understood that other suitable acids, bases, reagents,
coupling agents, solvents
etc. may be used and are included within the scope of the present invention.
The
modifications to reaction conditions, for example, temperature, duration of
the reaction or
combinations thereof, are envisioned as part of the present invention. The
compounds
obtained using the general reaction sequences may be of insufficient purity.
These compounds
can be purified using any of the methods for purification of organic compounds
known to
persons skilled in the art, for example, crystallization or silica gel or
alumina column
chromatography using different solvents in suitable ratios. All possible
geometrical isomers
and stereoisomers are envisioned within the scope of this invention.
The starting materials used herein are commercially available or were prepared
by
methods known in the art to those of ordinary skill or by methods disclosed
herein. In general,
the intermediates and compounds of the present invention can be prepared
through the
reaction schemes as follows.
A general approach for the synthesis of compound of general formula (I)
(wherein L,
1\4, yl, y2, y3, R1, R2, R3, R4, K5,
'm' and 'n' are as defined with respect to a compound of
formula (I)) is shown in scheme 1. Thus benzimidazole compound of formula (1)
on coupling
with compound of formula (2) (wherein X is halogen (e.g. F, Cl, Br or I)) in
the presence of
base such as potassium carbonate, cesium carbonate, sodium hydride, etc. gives
the final
compound of general formula (I).
Scheme 1
R4 R3 (175)n R4 R3 (R5)n
HN
Y3 M¨L¨X (2)
Y3 ¨
base e)T4y1
Y2:1j y2:/
1
(R-7 )m (R2)m
(1)
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A general approach for the synthesis of compound of general formula (Ia)
(wherein
R2, R5, R6, Y2, Y3, Y4,
'm', 'n' and 'ID' are as defined with respect to a compound of
formula (Ia)) is shown in scheme 2. Thus, 2-halo nitrobenzene of formula (3)
(wherein X is
halogen (e.g. F, Cl, Br or I)) on aromatic nucleophilic substitution reaction
with aniline of
general formula (4) using base such as sodium hydride or cesium carbonate
gives nitro
intermediate (5). Alternatively, the Buchwald coupling reaction of 2-halo
nitrobenzene
derivative (3) with aniline derivative (4) using palladium catalyst such as
palladium acetate in
the presence of a base such as cesium carbonate also affords Intermediate (5).
The reduction
of the nitro intermediate (5) to amine of general formula (6) followed by
cyclization using
1,1-carbodiimidazole (CDI) yields benzimidazolone Intermediate of formula (7).
The
coupling reaction of compound of formula (7) with the compound of formula (8)
yields the
compound of formula (Ia). The compound of formula (7) may be reacted with
compound of
formula (8) in the presence of a suitable base. The suitable base may be
sodium hydride. The
reaction may be carried out in a suitable solvent or mixture of solvents. The
suitable solvent
may be DNIF. The compound of formula (Ia) may be optionally further converted
to
pharmaceutically acceptable salt.
Scheme 2
,
(R6) (R5)
n
02N x (R6)n AyR1
H2N FIN
Y + H2N4N_Ri base.. 02N HN¨/3_)-\ reductionõ
Y2t7
(Rim Y2 H/ (R2)m
(3) (4) (R )m(5) (6)
(R% 5
/
0 (R5)n COC I 0 (RI NI
HN-1114¨( 5\ _Ri / I \
1-7cY3¨ (8) (R% N
1 /--c(v1
Y2-V base
Y4 / Y2
(R2), (R-)m
(7) (la)
Intermediate of formula (6) (RI-, R2, R5,
Y2, Y3, 'm' and 'n' are as defined with
respect to a compound of formula (Ia)) can be prepared from o- diamine
compound of
formula (9) and compound of formula (10) as depicted in scheme 3. The reaction
may be
carried out in the presence of base such as N,N-diisoporpylethylamine (DIPEA)
or
triethylamine (TEA).
Scheme 3
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(R5)fl
\
n
H2N NH2 (R)
rc 1 x_OL 4 ly Ri
Y3¨
y / R1 base H2N HN
y2:11
Y
(R2)m v2:6,
' 2
(R )m (6)
(9) (10)
Similarly, Intermediate (7) can also be prepared from compound of general
formula
(11) and substituted phenyl halide of formula (12) as shown in scheme 4. The
reaction may
be carried out in the presence of base such as ethylene diamine and potassium
hydrogen
5 sulphate. The reaction may be carried out in the presence of catalyst
such as copper iodide.
Scheme 4
0
5 0 (175)n
\
(R )n
HNANH
+
base HNAN_CD_Ri
ih(yi X-13-yi R1 v3 /
Y2 V, 1=( Y 1 '
(R-), Y
21I
(11) (12) (R2)m
(7)
A general approach for the synthesis of compound of general formula (14)
(wherein
R2, R5, R6, 'm', 'n' and 'ID' are as defined with respect to a compound of
formula (Ia)) and
(16) (wherein R2, R5, R6, R7, R8, 'm', 'n' and 'ID' are as defined with
respect to a compound of
formula (Ia)) is shown in scheme 5.
Scheme 5
(IR5)n (R5)n
0
0 0 NAN j.k_10H
dAN \ I OC(CH3)3
deprotection
¨ 0
16 -I. 1
(R )p (R2) m (R6 )p (R2)rn
(13) (14)
1 NHR7R8 (15)
Coupling agents
(R5)n
8
N N II NR
c-3----,1 0
(R) (R2)rn
(16)
The Intermediate (13) (obtained as described in scheme 2, wherein It' is
COOC(CH3)3)
undergoes deprotection of tert-butyl group using acid such as trifluoroacetic
acid (TFA) to
yield the compound of general formula (14). The acid of general formula (14)
on coupling
with the amine of formula (15) using appropriate reagent such as 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimi de (ED C I), or
b enzotri azol -1-
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yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) affords the
amide
compound of the formula (16).
An approach for the synthesis of compound of general formula (18) (wherein R2,
R5,
R6, 'm', 'n' and 'ID' are as defined with respect to a compound of formula
(Ia)) and (19)
(wherein R2, R5, R6, 'm', 'n' and 'ID' are as defined with respect to a
compound of formula
(Ia)) is described in scheme 6. Thus, the Intermediate (17) (prepared as
described in Scheme
2, wherein Ri- is CN) on reaction with hydroxylamine hydrochloride followed by
cyclization
using 1,1-carbodiimidazole yields the compound of the formula (18). On the
other hand, the
cyano intermediate (17) on reaction with sodium azide in the presence of
ammonium chloride,
yields final compound of the formula (19).
Scheme 6
(R5)n (R5)n
0 0
0 0
_}
9¨NAN¨e¨CN 1. NH2OH.HCI
(R )p (R2)m (R 6)p (R2)m
(17) (18)
1 NaN3, NH4CI
(R5)n
0
d_NAN4¨)Nr
Y 61
-.-
(R6)p (R2)m
(19)
An approach for the synthesis of compound of general formula (Ia-1) (wherein
RI-, R5,
R6, 'n' and 'ID' are as defined with respect to a compound of formula (Ia); RY
is CH3 or
cyclobutyl; and Rz is CH3) is described in scheme 7. Thus, the Buchwald
coupling reaction of
4-halo-3-nitrobenzaldehyde (20) (wherein X is halogen (e.g. F, Cl, Br or I))
with aniline
derivative (4A) using palladium catalyst such as palladium acetate in the
presence of a base
such as cesium carbonate yields the Intermediate (21). The Intermediate (21)
on reductive
amination using sodium triacetoxy borohydride (STAB) with amine of formula
(15) affords
the Intermediate (22). The reduction of nitro group of the intermediate (22)
followed by
cyclization using CDI gives the Intermediate (23). The coupling of the acid
chloride
intermediate (8A) with the amine of formula (23) yields the compound of the
formula (Ia-1).
The compound of formula (23) is reacted with compound of formula (8A) in the
presence of a
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suitable base. The suitable base may be sodium hydride. The reaction may be
carried out in a
suitable solvent or mixture thereof The suitable solvent may be DMF.
Scheme 7
(R5)n (R5)
02N X 5\
(R in02N HN-0¨\-1./. R1
\¨R
¨01 N RYRz
+ H2N¨O¨R=
base 02N HN
(15) base
OHC OHC
NRYRz
(20) (4A) (21) (22)
COCI
o (R5 )n 0 0 (R5)n
HNAN-0-
1.1
1. reduction (R6)p.o(8A) N N¨O¨R
2 CD! base __ (R6)pep
N RYRz N RYRz
(23) (Ia-1)
Similarly, compound of general formula (Ia-2) (wherein R5, R6, 'n' and 'ID'
are as defined
with respect to a compound of formula (Ia)) can be prepared as depicted in
scheme 8. Thus,
the aldehyde group of the Intermediate (21) is reduced to corresponding
alcohol (24) using
sodium borohydride followed by the reaction with 3,4-dihydro-2H-pyran (DHP) to
give the
THP protected Intermediate (25). The nitro group reduction of the Intermediate
(25) followed
by cyclization yields the Intermediate (26). The coupling of the Intermediate
(26) with the
acid chloride of formula (8A) followed by deprotection affords the final
compound of formula
(Ia-2).
Scheme 8
5\
(R )n5\
(R )n (R5)n
02N HN-0¨R
\-1./. 1 DHP 02N HN-0¨
reduction \-1"/ Ri
02N HN R1
OHC
OH OTH P
(21) (24) (25)
0
_b_R5)n p 0(C0)C 0 , base
ase 0 (75)n
¨
1. reduction HN N Ri 1 8A
. NAN¨(
_____________________________________________________________ 6 )L
2. CDI p 2.deprotection (R 0
pr"1-.
OTH P OH
(26) (Ia-2)
An approach for the synthesis of compounds of general formula (I-1) (wherein
RI-, R2, R3, R4,
R5, R6, 'm', 'n' and 'ID' are as defined with respect to a compound of formula
(I)) is described
in scheme 9. Thus, the Intermediate (6) obtained as described in scheme 2, on
coupling with
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the acid chloride derivative (8) using base such as N,N-diisopropylethylamine
(DIPEA) gives
the amide Intermediate (27). The cyclization of the Intermediate (27) with the
dimethoxy
alkyl derivative (28) using acid such as PTSA gives the final compound of
general formula (I-
1).
Scheme 9
C oc
4
(R5)n 1 (R6)p .1 6Y D\r, /. (R5)n R4R3C(OCH3)2
ipp5A
4 3 n
ya
R R I (R
H2N HN-1113¨R1 I- N 3¨R1
ihty3¨ (8) HN
HN¨%r _)¨/ R
1 V\yi
Y2'Id2 base
Y2 Id PTSA
Y4 Y211
(R-)m(R2)m (R2)m
(6) (27) (I-1)
A general approach for the synthesis of compound of general formula (Ia)
(wherein
R', R2, R5, R6, Y2, Y3, Y4, 'm', 'n' and 'ID' are as defined with respect
to a compound of
formula (Ia)) is shown in scheme 10.
Scheme 10
(R6)p
0 5\
(R ) n r\Dõ...COCI
I 0 5\
(R )n
(R6)p 1-\_
JN713=r\ R1
Y3¨
Y
YT Y4 Y2:111
(R2)m (R2)m
(7) (Ia)
The process for the preparation of compound of formula (Ia) or a
pharmaceutically
acceptable salt thereof, which comprises:
reacting a compound of formula (7) with a compound of formula (8); and
optionally
converting the compound of formula (Ia) to a pharmaceutically acceptable salt
thereof
In an embodiment, the compound of formula (7) is reacted with compound of
formula
(8) in the presence of a suitable base. The suitable base may be sodium
hydride.
In another embodiment, the reaction may be carried out in a suitable solvent.
The
suitable solvent may be DMF.
In yet another embodiment, the compound of formula (7) is reacted with a
compound
of formula (8) in the presence of sodium hydride in DMF.
A general approach for the synthesis of compound of general formula (Ib)
(wherein
R2, R5, R6, R9, 'm', 'n' and 'ID' are as defined with respect to a compound of
formula (Ib)) is
shown in scheme 11.
Scheme 11
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(R6)p
0 (R5)n
I \ \ I N N _ 0 (R5)n
A
HNIA N-0¨/ COOR9 (8A) (R6)p COOR9
(Rim (R2)m
(29) (Ia)
The process for the preparation of compound of formula (Ib) or a
pharmaceutically
acceptable salt thereof which comprises:
reacting a compound of formula (29) with a compound of formula (8A); and
optionally converting the compound of formula (Ib) to a pharmaceutically
acceptable salt
thereof
In an embodiment, the compound of formula (29) is reacted with compound of
formula (8A) in the presence of a suitable base. The suitable base may be
sodium hydride.
In another embodiment, the reaction may be carried out in a suitable solvent.
The
suitable solvent may be DMF.
In yet another embodiment, the compound of formula (29) is reacted with a
compound
of formula (8A) in the presence of sodium hydride in DNIF.
Experimental
Unless otherwise stated, work-up includes distribution of the reaction mixture
between
the organic and aqueous phase indicated within parentheses, separation of
layers and drying
the organic layer over sodium sulphate, filtration and evaporation of the
solvent. Purification,
unless otherwise mentioned, includes purification by silica gel
chromatographic techniques,
generally using ethyl acetate/petroleum ether mixture of a suitable polarity
as the mobile
phase. Use of a different eluent system is indicated within parentheses.
The abbreviations, symbols and terms used in the examples and assays have the
following meanings throughout: DCM: dichloromethane; DMSO-d6:
Hexadeuterodimethyl
sulfoxide; 1E1 NMR: Proton Nuclear Magnetic Resonance; DMF: N,N-dimethyl
formamide;
DMSO: Dimethyl sulfoxide; CDI: 1, 1-carb odiimidazol e; BOP: (B enzotri azol-1-
yl oxy)tri s(dimethylamino)phosphonium hexafluorophosphate; EDCI: 1-
Ethy1-3 -(3 -
dimethyl aminopropyl)c arb odiimi de; STAB: Sodium tri acetoxyb orohydri de;
DMAP : 4-
Dimethyl aminopyri dine; Xphos :
2-Di cycl ohexylphosphino-2 1,4 ',6 '-trii sopropylbiphenyl;
DHP: 3,4-dihydro-2H-pyran; THP: Tetrahydropyran; EDC: ethylene dichloride;
DIPEA: N,N-
di i s opropyl ethyl amine; DEAD: diethyl az adi c ab oxyl ate; THF :
Tetrahydofuran; TF A:
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trifluoroacetic acid; Na2SO4: Sodium sulfate; PTSA: p-Toluenesulfonic acid; J:
Coupling
constant in units of Hz; h: hour(s); RT or rt: Room temperature (22-26 C);
APCI-MS:
Atmospheric Pressure Chemical Ionization Mass Spectrometry; Pd: Palladium;
MHz:
Megahertz.
Intermediates
Intermediate 1
tert-Butyl 4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)benzoate
0
HNAN =CO2C(CH3)3
Step 1: tert-Butyl 4-[(2-nitrophenyl)amino]benzoate:
To a stirred and cooled (0 C) mixture of tert-butyl 4-amino benzoate (1 g,
5.175 mmol) in
dry DMF (10 mL) was added sodium hydride (248 mg, 6.211 mmol) and the reaction
mixture
was stirred at the same temperature for 10 minutes. 1-Fluoro-2-nitrobenzene
(0.5 mL, 5.175
mmol) was added to the reaction mixture and it was stirred at RT overnight.
The reaction
mass was diluted with water (100 mL) and the product was extracted with ethyl
acetate (3 x
100 mL). The combined organic layers were washed with water (2 x 100 mL),
brine (50 mL)
and dried over anhydrous Na2504. The solvent was recovered under reduced
pressure and the
residue obtained was purified by column chromatography to afford 800 mg of the
title product
as off-white solid. 11-1 NMR (300 MHz, DMSO-d6) 6 1.53 (s, 9H), 7.07 (t, J=
7.8 Hz, 1H),
7.29 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 6.9 Hz, 1H), 7.59 (t, J= 7.8 Hz, 1H),
7.84 (d, J= 7.8 Hz,
2H), 8.10 (d, J= 8.4 Hz, 1H), 9.31 (s, 1H).
Step 2: tert-Butyl 4-[(2-aminophenyl)amino]benzoate:
To the stirred solution of Step 1 intermediate (500 mg, 1.592 mmol) in
methanol (10 mL) was
added catalytic amount of 10% palladium on carbon and the mixture was stirred
for 5 h under
hydrogen atmosphere. The reaction mixture was filtered through celite pad and
the filtrate
was concentrated to yield 370 mg of the desired product as off white solid. 11-
1 NMR (300
MHz, DMSO-d6) 6 1.49 (s, 9H), 4.83 (br s, 2H), 6.56 (t, J= 6.9 Hz, 1H), 6.65
(d, J = 8.1 Hz,
2H), 6.76 (d, J= 7.8 Hz, 1H), 6.92 (t, J= 7.8 Hz, 1H), 6.99 (d, J = 7.8 Hz,
1H), 7.65 (d, J =
8.4 Hz, 2H), 7.82 (s, 1H).
Step 3: tert-Butyl 4-(2-oxo-2,3 -dihydro-1H-b enzimi daz ol -1-yl)b enzoate :
To a stirred solution of Step 2 intermediate (360 mg, 1.266 mmol) in THF (10
mL) was added
CDI (313 mg, 1.90 mmol) and the reaction mixture was heated at 60 C for 1 h.
The reaction
mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x
20 mL). The
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combined organic layers were washed with water (2 x 20 mL), brine (20 mL) and
dried over
anhydrous Na2SO4. The solvent was distilled off under reduced pressure. The
residue obtained
was purified by column chromatography to afford 310 mg of the title product as
off-white
solid. 1-H NMR (300 MHz, DMSO-d6) 6 1.57 (s, 9H), 7.03-7.09 (m, 2H), 7.10-7.15
(m, 2H),
7.70 (d, J = 7.8 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 11.27 (br s, 1H); APCI-MS
(m/z) 311
(M+H)+.
Intermediate 2
tert-Butyl 2 -chl oro-4-(2-oxo-2,3 -di hydro-1H-b enzimi dazol -1-yl)b enzoate
0
HNAN CO2C(CH3)3
CI
Step 1: tert-Butyl 2-chloro-4-[(2-nitrophenyl)amino]benzoate:
To a well stirred mixture of 1-iodo-2-nitro benzene (200 mg, 0.803 mmol) in
1,4-dioxane (10
mL) were added tert-butyl 4-amino-2-chlorobenzoate (218 mg, 0.963 mmol),
palladium
acetate (18 mg, 0.080 mmol), XPhos (56 mg, 0.090 mmol) and cesium carbonate
(391 mg,
1.204 mmol). The reaction mixture was heated at 100 C for 2h. The reaction
mixture diluted
with ethyl acetate (20 mL) and filtered through celite. The filtrate was
concentrated under
reduced pressure and residue thus obtained was purified by silica gel column
chromatography
to afford 300 mg of the title product as yellow oil. 1E1 NMR (300 MHz, DMSO-
d6) 6 1.53 (s,
9H), 7.11-7.20 (m, 2H), 7.20 (s, 1H), 7.49 (d, J= 8.4 Hz, 1H), 7.63 (t, J =
7.5 Hz, 1H), 7.72
(d, J= 8.1 Hz, 1H), 8.09 (d, J= 8.4 Hz, 1H), 9.27 (s, 1H).
Step 2: tert-Butyl 2-chl oro-4-(2-oxo-2,3 -di hydro-1H-b enzimi dazol -1-yl)b
enzoate :
The title compound was prepared by platinum catalysed hydrogenation of Step 1
intermediate
(280 mg, 0.8027 mmol) in a mixture of ethyl acetate (15 mL) and ethanol (3 mL)
followed by
cyclization of the corresponding diamine derivative (240 mg, 0.7528 mmol) in
the presence of
CDI (186 mg, 1.1292 mmol) in THF (10 mL) as per the process described in step
2 and 3 of
the Intermediate 1 respectively to yield 140 mg of the product as off white
solid. 1E1 NMR
(300 MHz, DMSO-d6) 6 1.57 (s, 9H), 7.02-7.09 (m, 1H), 7.15 (d, J= 7.5 Hz, 2H),
7.65 (d, J=
8.4 Hz, 1H), 7.78 (br s, 1H), 7.89 (d, J= 7.8 Hz, 1H), 11.31 (br s, 1H).
Intermediate 3
tert-Butyl 2 -fluoro-4-(2-ox o-2,3 -di hydro-1H-b enzimi dazol-1-yl)b enzoate
0
HNAN CO2C(CH3)3
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Step 1: tert-Butyl 2-fluoro-4-[(2-nitrophenyl)amino]benzoate:
The title compound was prepared by the reaction of 1-iodo-2-nitro benzene (800
mg, 3.212
mmol) with tert-butyl 4-amino-2-fluorobenzoate (678 mg, 3.212 mmol) in the
presence of
palladium acetate (72 mg, 0.3212 mmol), XPhos (223 mg, 0.321 mmol) and cesium
carbonate
(1.56 g, 4.819 mmol) in 1,4-dioxane (10 mL) as per the process described in
step 1 of the
Intermediate 2 to yield 710 mg of the product as yellow solid. 111 NMR (300
MHz, DMSO-
d6) 6 1.51 (s, 9H), 6.97-7.04 (m, 2H), 7.17 (t, J= 7.8 Hz, 1H), 7.55 (d, J=
8.4 Hz, 1H), 7.56-
7.76 (m, 2H), 8.10 (d, J = 8.4 Hz, 1H), 9.30 (s, 1H).
Step 2: tert-Butyl 2-fluoro-4-(2-ox o-2,3 -di hydro-1H-b enzimi dazol-1-yl)b
enz oate
The title compound was prepared by palladium catalyzed hydrogenation of step 1
intermediate (650 mg, 1.155 mmol) in methanol (15 mL) followed by cyclization
of the
corresponding diamine derivative (450 mg, 1.4883 mmol) in the presence of CDI
(368 mg,
2.232 mmol) in THF (10 mL) as per the process described in step 2 and 3 of
Intermediate 1
respectively to yield 220 mg of the product as yellow solid. 111NWIR (300 MHz,
DMSO-d6) 6
1.55 (s, 9H), 7.03-7.10 (m, 3H), 7.20 (d, J = 7.2 Hz, 1H), 7.52-7.60 (m, 2H),
7.98 (t, J = 8.1
Hz, 1H), 11.34 (br s, 1H).
Intermediate 4
tert-Butyl 3 -fluoro-4-(2-ox o-2,3 -di hydro-1H-b enzimi dazol-1-yl)b enzoate
0
HNAN CO2C(CH3)3
F
Step 1: tert-Butyl 3-fluoro-4-[(2-nitrophenyl)amino]benzoate:
To a well stirred mixture of 1-iodo-2-nitro benzene (300 mg, 1.204 mmol) in
degassed 1,4-
dioxane (10 mL) were added tert-butyl 4-amino-3-fluorobenzoate (328 mg, 1.445
mmol),
palladium acetate (27 mg, 0.1204 mmol), XPhos (84 mg, 0.1445 mmol) and cesium
carbonate
(588 mg, 1.807 mmol). The reaction mixture was heated at 100 C for 2h. The
reaction
mixture was diluted with ethyl acetate (30 mL) and filtered through celite.
The filtrate was
concentrated under reduced pressure and the residue thus obtained was purified
by silica gel
column chromatography to afford 410 mg of the product as yellow oil. 111 NMR
(300 MHz,
DMSO-d6) 6 1.54 (s, 9H), 7.07 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H),
7.48 (t, J = 8.4
Hz, 1H), 7.57 (t, J= 7.5 Hz, 1H), 7.71-7.74 (m, 2H), 8.12 (d, J = 8.4 Hz, 1H),
9.25 (s, 1H).
Step 2: tert-Butyl 4-[(2-aminophenyl)amino]-3-fluorobenzoate:
A solution of step 1 intermediate (400 mg, 1.203 mmol) in methanol (10 mL) was
hydrogenated in the presence of 10% palladium on carbon in a Parr apparatus
for 3 hours at
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RT. The reaction mixture was filtered through celite and the filtration bed
was thoroughly
rinsed with methanol (2 x 20 mL). The mother liquor and washings were combined
and
concentrated under reduced pressure to obtain 350 mg of the title product as
light yellow oil.
1-H NMR (300 MHz, DMSO-d6) 6 1.50 (s, 9H), 5.26 (br s, 2 H), 6.48 (t, J= 8.7
Hz, 1H), 6.62
(t, J= 7.2 Hz, 1H), 6.82 (d, J= 7.8 Hz, 1H), 6.96-7.01 (m, 2H), 7.47-7.55 (m,
2H), 7.73 (s,
1H).
Step 3: tert-Butyl 3 -fluoro-4-(2-ox o-2,3 -di hydro-1H-b enzimi dazol-1-yl)b
enz oate
To a stirred solution of Step 2 intermediate (350 mg, 1.157 mmol) in THF (10
mL) was added
CDI (286 mg, 1.736 mmol) and the reaction mixture was stirred at RT for 15 h.
The reaction
mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x
20 mL). The
combined organic layers were washed with water (2 x 15 mL), brine (20 mL) and
dried over
anhydrous Na2504. The solvent was distilled off under reduced pressure. The
residue obtained
was purified by column chromatography to yield 300 mg of the product as brown
solid. 1E1
NMR (300 MHz, DMSO-d6) 6 1.63 (s, 9H), 6.84 (d, J= 7.5 Hz, 1H), 7.05-7.15 (m,
3H), 7.62
(t, J= 7.8 Hz, 1H), 7.91-7.98 (m, 2H), 9.93 (br s, 1H).
Intermediate 5
tert-Butyl 6-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)pyri dine-3 -carboxyl ate
0
HNAN-0-co2c(cH3)3
N
Step 1: tert-Butyl 6-[(2-nitrophenyl)amino]pyridine-3-carboxylate:
The title compound was prepared by the reaction of 2-nitroaniline (200 mg,
1.448 mmol) and
tert-butyl 6-chloropyridine-3-carboxylate (309 mg, 1.448 mmol) in the presence
of palladium
acetate (33 mg, 0.1448 mmol), XPhos (100 mg, 0.1737 mmol) and cesium carbonate
(706 mg,
2.172 mmol) in 1,4-dioxane (10 mL) as per the process described in step 1 of
Intermediate 2
to yield 150 mg of the product as orange solid. 1-H NMR (300 MHz, CDC13) 6
1.60 (s, 9H),
6.92 (d, J= 8.7 Hz, 1H), 7.08 (t, J= 7.8 Hz, 1H), 7.63 (t, J= 7.8 Hz, 1H),
8.15 (d, J= 9.0 Hz,
1H), 8.25 (d, J= 9.0 Hz, 1H), 8.83 (d, J= 8.4 Hz, 1H), 10.35 (br s, 1H).
Step 2: tert-Butyl 6-(2-oxo-2,3 -dihydro-1H-b enzimi daz ol -1-yl)pyri dine-3 -
carb oxyl ate :
The title compound was prepared by palladium catalyzed hydrogenation of step 1
intermediate (600 mg, 1.9028 mmol) in methanol (10 mL) followed by the
cyclization of the
corresponding diamine derivative (510 mg, 1.787 mmol) in the presence of CDI
(442 mg,
2.681 mmol) in THF (10 mL) as per the process described in step 2 and 3 of
Intermediate 1
respectively to yield 400 mg of the product as off white solid. 1H NMR (300
MHz, DMSO-d6)
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6 1.58 (s, 9H), 7.09-7.15 (m, 3H), 8.14 (d, J= 8.1 Hz, 1H), 8.30-8.40 (m, 2H),
9.02 (s, 1H),
11.45 (br s, 1H).
Intermediate 6
tert-Butyl 3 -fluoro-4-(2-oxo-2,3 -dihydro-1H-imi dazo [4,5-c] pyri din-l-yl)b
enzoate
F
HNAN CO2C(CH3)3
Step 1: tert-Butyl 3-fluoro-4-[(3-nitropyridin-4-yl)amino]benzoate:
The title compound was prepared by the reaction of 4-chloro-3-nitropyridine
(450 mg, 2.840
mmol) and tert-butyl 4-amino-3-fluorobenzoate (600 mg, 2.8407 mmol) in the
presence of
palladium acetate (64 mg, 0.284 mmol), XPhos (198 mg, 0.341 mmol) and cesium
carbonate
(1.38 g, 4.26 mmol) in 1,4-dioxane (15 mL) as per the process described in
step 1 of
Intermediate 2 to yield 610 mg of the product as yellow solid. 111 NMR (300
MHz, CDC13) 6
1.61 (s, 9H), 6.95 (br s, 1H), 7.80 (t, J= 6.6 Hz, 1H), 7.47 (t, J= 8.4 Hz,
1H), 7.84-7.90 (m,
2H), 8.38 (br s, 1H), 9.34 (s, 1H), 9.67 (br s, 1H).
Step 2: tert-Butyl 3 -fluoro-4-(2-ox o-2,3 -di hydro-1H-imi daz o [4, 5-c]
pyri din-l-yl)b enzoate :
The title compound was prepared by palladium catalyzed hydrogenation of step 1
intermediate (600 mg, 1.801 mmol) in methanol (10 mL) followed by the
cyclization of the
corresponding diamine derivative (500 mg, 1.648 mmol) in the presence of CDI
(408 mg,
2.472 mmol) in THF (10 mL) as per the process described in step 2 and 3 of
Intermediate 1
respectively to yield 400 mg of the product as light brown solid. 1-HNMR (300
MHz, DMS0-
d6) 6 1.57 (s, 9H), 6.95 (br s, 1H), 7.80 (t, J= 6.6 Hz, 1H), 7.92 (d, J= 9.3
Hz, 1H), 8.20 (br s,
1H), 8.33 (s, 1H), 11.63 (br s, 1H).
Intermediate 7
tert-Butyl 3 -fluoro-4-(2-oxo-1,2-dihydro-3H-imi dazo [4,5-b] pyri din-3 -yl)b
enzoate
F
HNAN = CO2C(CH3)3
Step 1: tert-Butyl 3-fluoro-4-[(3-nitropyridin-2-yl)amino]benzoate:
The title compound was prepared by the reaction of 2-chloro-3-nitropyridine
(250 mg, 1.5768
mmol) and tert-butyl-4-amino-3-fluorobenzoate (332 mg, 1.5760 mmol) in the
presence of
palladium acetate (35 mg, 0.157 mmol), XPhos (109 mg, 0.189 mmol) and cesium
carbonate
(772 mg, 2.37 mmol) in 1,4-dioxane (10 mL) as per the process described in
step 1 of
Intermediate 2 to yield 410 mg of the product as yellow solid. 1-HNMR (300
MHz, DMSO-d6)
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6 1.55 (s, 9H), 7.13 (br s, 1H), 7.71-7.79 (m, 2H), 8.40 (t, J = 7.8 Hz, 1H),
8.60 (br s, 2H),
10.27 (br s, 1H).
Step 2: tert-Butyl 3 -fluoro-4-(2-ox o-1,2-di hydro-3H-imi daz o [4, 5 -1)]
pyri din-3 -yl)b enz oate
The title compound was prepared by palladium catalyzed hydrogenation of step 1
intermediate (400 mg, 1.200 mmol) in methanol (10 mL) followed by the
cyclization of the
corresponding diamine derivative (380 mg, 1.254 mmol) in the presence of CDI
(269 mg,
1.6303 mmol) in THF (10 mL) as per the process described in step 2 and 3 of
Intermediate 1
respectively to yield 300 mg of the product as off white solid. 1H NMIR (300
MHz, DMSO-d6)
6 1.61 (s, 9H), 7.09 (t, J= 7.5 Hz, 1H), 7.39 (d, J= 7.8 Hz, 1H), 7.64 (t, J=
7.8 Hz, 1H),
7.91-7.99 (m, 2H), 8.06 (br s, 1H), 10.41 (br s, 1H).
Intermediate 8
tert-Butyl 4-(6-fluoro-2-ox o-2,3 -di hydro-1H-b enzimi dazol-1-yl)b enzoate
0
HNAN =CO2C(CH3)3
Step 1: tert-Butyl 4-[(5-fluoro-2-nitrophenyl)amino]benzoate:
The title compound was prepared by the reaction of tert-butyl 4-amino benzoate
(384 mg,
2.727 mmol) with 2-bromo-4-fluoro-1-nitrobenzene (500 mg, 2.272 mmol) in the
presence of
palladium acetate (51 mg, 0.227 mmol), XPhos (157 mg, 0.272 mmol) and cesium
carbonate
(1.12 g, 3.409 mmol) in 1,4-dioxane (10 mL) as per the process described in
step 1 of
Intermediate 2 to yield 520 mg of the product as yellow oil. 111 NMR (300 MHz,
CDC13) 6
1.61 (s, 9H), 6.57 (br s, 1H), 7.01 (d, J= 11.1 Hz, 1H), 7.27-7.32 (m, 2H),
8.05 (d, J= 8.1 Hz,
2H), 8.25-8.31 (m, 1H), 9.70 (s, 1H).
Step 2: tert-Butyl 4-(6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-
yl)benzoate:
The title compound was prepared by palladium catalyzed hydrogenation of step 1
intermediate (500 mg, 1.504 mmol) in methanol (10 mL) followed by the
cyclization of the
corresponding diamine derivative (350 mg, 1.157 mmol) in the presence of CDI
(286 mg,
1.736 mmol) in THF (10 mL) as per the process described in step 2 and 3 of
Intermediate 1
respectively to yield 230 mg of the product as off white solid. 1H NMIR (300
MHz, DMSO-d6)
6 1.63 (s, 9H), 6.84 (br s, 2H), 7.04-7.10 (m, 1H), 7.62 (d, J= 8.4 Hz, 2H),
8.18 (d, J= 8.4
Hz, 2H), 10.21 (br s, 1H).
Intermediate 9
tert-Butyl-3 -fluoro-4-(7-fluoro-2-ox o-2,3 -di hydro-1H-b enzimi dazol-1-yl)b
enz oate
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0 F
HNANCO2C(CH3)3
F
Step 1: tert-Butyl 3-fluoro-4-[(2-fluoro-6-nitrophenyl)amino]benzoate:
To a well stirred mixture of 2-bromo-1-fluoro-3-nitrobenzene (300 mg, 1.363
mmol) in 1,4-
dioxane (10 mL) were added tert-butyl 4-amino-3-fluorobenzoate (287 mg, 1.3636
mmol),
acetate (31 mg, 0.136 mmol), XPhos (94 mg, 0.1036 mmol) and cesium carbonate
(666 mg,
2.045 mmol). The reaction mixture was heated at 100 C for 3 h. The reaction
mixture diluted
with ethyl acetate (20 mL) and filtered through celite pad. The filtrate was
concentrated
under reduced pressure and residue thus obtained was purified by silica gel
column
chromatography to afford 320 mg of the title product as yellow oil. 111 NMR
(300 MHz,
CDC13) 6 1.58 (s, 9H), 6.84-6.89 (m, 1H), 7.10-7.13 (m, 1H), 7.41 (t, J= 10.2
Hz, 1H), 7.69-
7.74 (m, 2H), 8.00 (d, J = 8.1 Hz, 1H), 8.45 (s, 1H).
Step 2: tert-Butyl 3 -fluoro-4-(7-fluoro-2-oxo-2,3 -di hydro- 1H-b enzimi
dazol -1-yl)b enzoate :
To the stirred solution of Step 1 intermediate (300 mg, 0.8571 mmol) in
methanol (10 mL)
was added catalytic amount of 10% palladium on carbon and the mixture was
stirred for 5 h
under hydrogen atmosphere. The reaction mixture was filtered through celite
pad and the
filtrate was concentrated. The obtained solid was dissolved in THF (10 mL) and
CDI (201
mg, 1.212 mmol) was added and the reaction mixture was refluxed for 18 h. The
reaction
mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x
20 mL). The
combined organic layers were washed with water (2 x 20 mL), brine (20 mL) and
dried over
anhydrous Na2504. The solvent was distilled off under reduced pressure. The
residue obtained
was purified by column chromatography to afford 200 mg of the product as off
white solid.
111 NMR (300 MHz, DMSO-d6) 6 1.57 (s, 9H), 6.89 (d, J = 9.0 Hz, 1H), 6.96 (d,
J = 8.4 Hz,
1H), 7.09 (m, 1H), 7.79 (t, J= 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 2H), 11.61
(br s, 1H).
Intermediate 10
tert-Butyl 4-(5-cyano-2-oxo-2,3 -di hydro- 1H-b enzimi dazol -1-y1)-3 -fluorob
enz oate
0 F
HNAN =CO2C(CH3)3
Nc
Step 1: tert-Butyl 4-[(4-cyano-2-nitrophenyl)amino]-3-fluorobenzoate:
The title compound was prepared by the reaction of 4-bromo-3-nitrobenzonitrile
(374 mg,
1.65 mmol) with tert-butyl 4-amino-3-fluorobenzoate (350 mg, 1.65 mmol) in the
presence of
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palladium acetate (18 mg, 0.082 mmol), XPhos (57 mg, 0.099 mmol) and cesium
carbonate
(804 mg, 2.47 mmol) in 1,4-dioxane (20 mL) as per the process described in
step 1 of
Intermediate 2 to yield 513 mg of the product as brown solid. 1-H NMR (300
MHz, CDC13) 6
1.61 (s, 9H), 7.18 (d, J= 7.5 Hz, 1H), 7.44 (t, J= 7.8 Hz, 1H), 7.64 (d, J=
7.2 Hz, 1H), 7.86
(t, J= 9.3 Hz, 2H), 8.59 (s, 1H), 9.73 (br s, 1H); APCI-MS (m/z) 355 (M+H)+.
Step 2: tert-Butyl 4-[(2-amino-4-cyanophenyl)amino]-3-fluorobenzoate:
To a stirred suspension of step 1 intermediate (504 mg, 1.411 mmol) and
ammonium chloride
(754 mg, 14.11 mmol) in water (8 mL) and ethanol (16 mL) was added iron powder
(236 mg,
4.23 mmol) at 60 C and it was stirred at the same temperature for 2 hours.
The reaction
mixture was cooled to RT and diluted with ethyl acetate (50 mL). The organic
mixture was
washed with saturated aqueous solution of sodium bicarbonate (20 mL), brine
(20 mL), the
organic layer was separated and dried over anhydrous sodium sulfate. The
solvent was
recovered under reduced pressure to yield 448 mg of the title product as
yellow oil. 1-H NMR
(300 MHz, CDC13) 6 1.57 (s, 9H), 6.21 (br s, 1H), 6.87-6.93 (m, 1H), 7.13-7.25
(m, 3H),
7.65-7.69 (m, 2H); APCI-MS (m/z) 326 (M+H)+.
Step 3: tert-Butyl 4-(5-cy ano-2-ox o-2,3 -di hydro-1H-b enzimi dazol-1-y1)-3 -
fluorob enzoate
The title compound was prepared by the cyclization of step 2 intermediate (441
mg, 1.348
mmol) in the presence of CDI (327 mg, 2.022 mmol) in THF (10 mL) as per the
process
described in step 3 of Intermediate 1 to yield 324 mg of the product as pale
yellow solid. 1E1
NMR (300 MHz, DMSO-d6) 6 1.57 (s, 9H), 7.01 (d, J= 7.8 Hz, 1H), 7.49 (d, J=
8.4 Hz, 1H),
7.53 (s, 1H), 7.80 (t, J= 8.1 Hz, 1H), 7.92 (t, J= 9.3 Hz, 2H), 11.79 (br s,
1H).
Intermediate 11
tert-Butyl 4-[5-(dim ethyl amino)-2-ox o-2,3 -di hydro-1H-b enzimi dazol-l-yl]
-3 -fluorob enz oate
F
HNAN 410. CO2C(CH3)3
(H3C)2N
Step 1: tert-Butyl 4- [4-(dimethyl amino)-2-nitrophenyl] amino } -3 -fluorob
enzoate
The title compound was prepared by the reaction of 4-fluoro-N,N-dimethy1-3-
nitroaniline
(694 mg, 3.030 mmol) with tert-butyl 4-amino-3-fluorobenzoate (767 mg, 3.636
mmol) in the
presence of sodium hydride (60% w/w, 242 mg, 6.060 mmol) in DIVIF (20 mL) as
per the
process described in step 1 of Intermediate 1 to yield 700 mg of the product
as brown oil; 1-H
NMR (300 MHz, CDC13) 6 1.59 (s, 9H), 3.01 (s, 6H), 7.13 (br s, 1H), 7.31-7.39
(m, 1H), 7.52
(br s, 1H), 7.61-7.75 (m, 2H), 8.78 (s, 1H), 11.48 (br s, 1H); APCI-MS (m/z)
376 (M+H)+.
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Step 2: tert-Butyl 4-[5-(dim ethyl amino)-2-ox o-2,3 -di hydro- 1H-
b enzimi daz ol-1-yl] -3 -
fluorob enz oate
The title compound was prepared by palladium catalyzed hydrogenation of step 1
intermediate (700 mg, 1.865 mmol) in methanol (15 mL) followed by the
cyclization of the
corresponding diamine derivative (226 mg, 0.650 mmol) in the presence of CDI
(159 mg,
0.984 mmol) in THF (10 mL) as per the process described in step 2 and 3 of
Intermediate 1
respectively to yield 231 mg of the product as white solid. 111NWIR (300 MHz,
DMSO-d6) 6
1.57 (s, 9H), 2.85 (s, 6H), 6.42 (d, J= 8.7 Hz, 1H), 6.45 (s, 1H), 6.68 (d, J=
8.1 Hz, 1H), 7.72
(t, J = 7.8 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 11.05 (br s, 1H).
Intermediate 12
tert-Butyl 4-[5 -(cycl butyl -methyl-amino)-2-oxo-2,3 -di hydro-b enzoimi
dazol -1-yl] -benzoate
0
HNAN * CO2C(CH3)3
01\)
C H3
Step 1: N-Cyclobuty1-4-fluoro-3-nitroaniline
A mixture of 4-fluoro-3-nitroaniline (200 mg, 1.280 mmol) and cyclobutanone
(0.13 mL,
1.923 mmol) in dichloroethane (10 mL) with catalytic amount of acetic acid was
stirred for 2
hours at RT. To the reaction mixture, sodium triacetoxy borohydride (542 mg,
2.560 mmol)
was added and stirred for 15 hours at RT. The reaction mixture was diluted
with ethyl acetate
(30 mL) and washed with saturated aqueous solution of sodium bicarbonate (20
mL), water
(20 mL) and brine (20 mL). The organic solution was dried over anhydrous
sodium sulfate,
filtered, concentrated and the residue thus obtained was purified by silica
gel column
chromatography to yield 107 mg of the title product as yellow oil. 111 NMR
(300 MHz,
CDC13) 6 1.77-1.94 (m, 4H), 2.40-2.45 (m, 2H), 3.85-3.92 (m, 1H), 6.88 (br s,
1H), 7.10 (t, J
= 9.9 Hz, 1H), 7.23-7.25 (m, 1H); APCI-MS (m/z) 210 (M+H)+.
Step 2: N-Cycl butyl -4 -fluoro-N-m ethy1-3 -nitroaniline
A mixture of step 1 intermediate (573 mg, 2.728 mmol), potassium carbonate
(564 mg, 4.092
mmol) and methyl iodide (0.25 mL, 4.092 mmol) in DMF (5 mL) was heated to 50
C for 15
hours in a sealed tube. The reaction mixture was cooled to RT and diluted with
ethyl acetate
(25 mL). The organic mixture was washed with water (2 x 20 mL) followed by
brine (20 mL)
and dried over anhydrous sodium sulfate. The solution was filtered,
concentrated and the
residue thus obtained was purified by silica gel column chromatography to
yield 547 mg of
the title product as yellow solid. 111NWIR (300 MHz, CDC13) 6 1.74-1.79 (m,
2H), 2.07-2.14
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(m, 2H), 2.25-2.30 (m, 2H), 2.86 (s, 3H), 3.89-4.00 (m, 1H), 7.00 (br s, 1H),
7.11 (t, J= 9.9
Hz, 1H), 7.33 (br s, 1H).
Step 3: tert-Butyl 4- [(4- { cycl obutyl-m ethyl-amino } -2-
nitrophenyl)amino]benzoate
The title compound was synthesized by the reaction of step 2 intermediate (354
mg, 1.955
mmol) and tert-butyl 4-aminobenzoate (465 mg, 1.955 mmol) in the presence of
sodium
hydride (60% w/w, 117 mg, 2.932 mmol) in DMF (7 mL) as per the process
described in step
1 of Intermediate 1 to yield 404 mg of the product as brown solid. APCI-MS
(m/z) 398
(M+H)+.
Step 4: tert-Butyl 4-[5-(cycl obutyl-m ethyl-amino)-2-oxo-2,3 -dihydro-b
enzoimi daz ol-1-yl] -
benzoate
The title compound was synthesized by the catalytic hydrogenation reaction of
step 3
intermediate (422 mg, 1.062 mmol) followed by the cyclization of the
corresponding diamine
derivative (303 mg, 0.825 mmol) by using CDI (200 mg, 1.237 mmol) in THF (10
mL) as per
the process described in respective step 2 and 3 of Intermediate 1 to yield
142 mg of the
product as white solid. 1-H NMR (300 MHz, DMSO-d6) 6 1.56 (s, 9H), 1.60-1.65
(m, 2H),
2.00-2.03 (m, 2H), 2.12-2.15 (m, 2H), 2.73 (s, 3H), 3.86-3.90 (m, 1H), 6.52
(br s, 2H), 7.02
(d, J = 9.3 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 8.05 (d, J= 8.7 Hz, 2H), 11.02
(br s, 1H).
Intermediate 13
tert-Butyl 4- { 5- [(dimethylamino)methyl] -2-oxo-2,3 -dihydro-1H-b enzo[d]
imidazol-1-
yl }benzoate
0 C 02C(C H3)3
HNAN
N (C H3)2
Step 1: tert-Butyl 4-[(4-formy1-2-nitrophenyl)amino]benzoate
To a stirred mixture of 4-bromo-3-nitrobenzaldehyde (2 g, 8.66 mmol) in 1,4-
dioxane (30
mL) were added tert-butyl 4-aminobenzoate (1.84 g, 9.53 mmol), palladium
acetate (97 mg,
0.433 mmol), XPhos (299 mg, 0.519 mmol) and cesium carbonate (4 g, 12.99
mmol). The
reaction mixture was heated at 100 C for 2h. The reaction mixture was diluted
with water
(100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic
layers were
washed with water (2 x 50 mL), brine (50 mL) and dried over anhydrous Na2504.
The solvent
was removed under reduced pressure and the residue thus obtained was purified
by column
chromatography to afford 2.5 g of the title product as off-white solid. 1-H
NMR (300 MHz,
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CDC13) 6 1.61 (s, 9H), 7.33-7.38 (m, 3H), 7.86 (d, J= 8.7 Hz, 1H), 8.09 (d, J=
7.8 Hz, 2H),
8.73 (s, 1H), 9.86 (s, 1H), 10.02 (br s, 1H).
Step 2: tert-Butyl 4-( 4-[(dimethyl amino)m ethyl] -2-nitrophenyl }
amino)benzoate:
To a stirred solution of Step 1 intermediate (500 mg, 1.460 mmol) in EDC (10
mL) was added
dimethylamine hydrochloride (238 mg, 2.920 mmol) and the reaction mixture was
stirred at
RT for 2 h. STAB (618 mg, 2.920 mmol) was added to the reaction mixture and it
was further
stirred for 15 hours at RT. The reaction mixture was diluted with ethyl
acetate (50 mL) and
washed with aqueous solution of sodium bicarbonate (2 x 25 mL) and brine (20
mL). The
solution was dried over anhydrous Na2504 and concentrated under reduced
pressure. The
residue thus obtained was purified by column chromatography to afford 660 mg
of the title
product as off-white solid. 11-1 NMR (300 MHz, CDC13) 6 1.53 (s, 9H), 2.15 (s,
6H), 3.38 (s,
2H), 7.28 (d, J= 8.4 Hz, 2H), 7.44 (d, J= 7.8 Hz, 1H), 7.51 (d, J = 9.0 Hz,
1H), 7.84 (d, J=
8.4 Hz, 2H), 7.98 (s, 1H), 9.28 (s, 1H).
Step 3: tert-Butyl 4-({2-amino-4-[(dimethylamino)methyl]phenyl}amino)
benzoate:
To the stirred solution of Step 2 intermediate (658 mg, 1.77 mmol) in methanol
(10 mL) was
added catalytic amount of 10% palladium on carbon and the reaction mixture was
stirred for 5
h under hydrogen atmosphere. The reaction mixture was filtered and the
filtrate was
concentrated to yield 570 mg of the product. 1E1 NMR (300 MHz, CDC13) 6 1.56
(s, 9H), 2.29
(s, 6H), 3.40 (s, 2H), 3.48 (s, 2H), 5.56 (s, 1H), 6.60-6.70 (m, 3H), 6.83 (s,
1H), 7.07 (d, J =
7.8 Hz, 1H), 7.82 (d, J= 8.4 Hz, 2H).
Step 4: tert-Butyl 4-{5-[(dimethylamino)methyl]-2-oxo-2,3-dihydro-1H-
benzo[d]imidazol-1-
y1 }benzoate:
To a stirred solution of Step 3 intermediate (555 mg, 1.626 mmol) in THF (10
mL) was added
CDI (395 mg, 2.43 mmol) and the reaction mixture was heated at 60 C for 1 h.
The reaction
mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x
20 mL). The
combined organic layers were washed with water (2 x 50 mL), brine (50 mL) and
dried over
anhydrous Na2504. The solvent was distilled out under reduced pressure and the
residue thus
obtained was purified by column chromatography to afford 250 mg of the title
product as
white solid. 111NMR (300 MHz, DMSO-d6) 6 1.57 (s, 9H), 2.25 (s, 6H), 3.56 (s,
2H), 6.98 (br
s, 1H), 7.07 (m, 2H), 7.70 (d, J= 8.4 Hz, 2H), 8.06 (d, J= 8.1 Hz, 2H), 11.28
(br s, 1H).
Intermediate 14
tert-Butyl 4-(2-oxo-5-{ [(tetrahydro-2H-pyran-2-yl)oxy]methyl } -2,3 -dihydro-
1H-
b enzo[d]imidazol-1-yl)b enzoate
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0
HNAN 10. CO2C(CH3)3
00
Step 1: tert-Butyl 4-[(4-formy1-2-nitrophenyl)amino]benzoate:
To a well stirred mixture of 4-bromo-3-nitrobenzaldehyde (2 g, 8.66 mmol) in
1,4-dioxane
(20 mL) were added tert-butyl 4-aminobenzoate (1.84 g, 9.53 mmol), palladium
acetate (97
mg, 0.433 mmol), XPhos (299 mg, 0.519 mmol) and cesium carbonate (4 g, 12.99
mmol).
The reaction mixture was heated at 100 C for 2h. The reaction mixture was
diluted with
water (50 ml) and product was extracted in ethyl acetate (2 x 100 mL). The
combined organic
layers were washed with water (2 x 50 mL), brine (25 mL) and dried over
anhydrous Na2504.
The solvent was distilled off under reduced pressure. The obtained product was
purified by
column chromatography to afford 1.8 g of the title product as off-white solid.
1-14 NMR (300
MHz, CDC13) 6 1.61 (s, 9H), 7.33-7.38 (m, 3H), 7.86 (d, J= 8.7 Hz, 1H), 8.09
(d, J = 7.8 Hz,
2H), 8.73 (s, 1H), 9.86 (s, 1H), 10.02 (br s, 1H).
Step 2: tert-Butyl 4- { [4-(hydroxym ethyl)-2-nitrop henyl] amino } b enzoate
:
To the stirred solution of step 1 intermediate (1 g, 2.92 mmol) in methanol
(10 mL) was added
sodium borohydride (143 mg, 3.79 mmol) at 0 C and the reaction mixture was
stirred at the
same temperature for 30 minutes. The reaction mixture was diluted with ethyl
acetate (50
mL), washed with saturated solution of ammonium chloride (50 mL) and brine (25
mL). The
solvent was distilled under reduced pressure and the residue thus obtained was
purified by
silica gel column chromatography to yield 750 mg of the product as off white
solid. 11-INMR
(300 MHz, CDC13) 6 1.60 (s, 9H), 4.67 (br s, 1H), 4.78 (br s, 2H), 7.29-7.35
(m, 2H), 7.47 (br
s, 1H), 7.86 (d, J= 7.8 Hz, 1H), 8.02 (d, J= 8.4 Hz, 2H), 9.86 (br s, 1H),
11.78 (br s, 1H).
Step 3: tert-Butyl 4-[(2-nitro-4-{ [(tetrahydro-2H-pyran-2-
yl)oxy]methyl }phenyl)
amino]benzoate:
To a stirred solution of Step 2 intermediate (200 mg, 0.580 mmol) in DCM (5
mL) were
added DHP (0.6 mL, 0.696 mmol) and catalytic amount of PTSA. The reaction
mixture was
stirred at RT for 2h. The reaction mixture was diluted with water (20 mL) and
extracted with
ethyl acetate (3 x 20 mL). The combined organic layers were washed with water
(2 x 50 mL),
brine (25 mL) and dried over anhydrous Na2504. The solvent was distilled out
under reduced
pressure and the residue thus obtained was purified by column chromatography
to afford 200
mg of the title product as off-white solid. 1H NMR (300 MHz, CDC13) 6 1.60 (s,
9H), 1.75 (br
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s, 5H), 3.55 (br s, 1H), 3.90 (br s, 1H), 4.45 (d, J= 11.7 Hz, 1H), 4.71 (br
s, 2H), 7.29 (br s,
3H), 7.45 (br s, 2H), 8.00 (d, J= 8.4 Hz, 2H), 8.21 (s, 1H), 9.48 (br s, 1H).
Step 4: tert-Butyl 4-[(2-amino-4-{ [(tetrahydro-2H-pyran-2-
yl)oxy]methylI
phenyl)aminoThenzoate:
To the stirred solution of Step 3 intermediate (200 mg, 0.467 mmol) in
methanol (5 mL) was
added catalytic amount of 10% palladium on carbon and the reaction was stirred
for 5 h under
hydrogen atmosphere. The reaction mixture was filtered through celite and the
filtrate was
concentrated to yield 155 mg of the title product. 111 NMR (300 MHz, CDC13) 6
1.56 (br s,
9H), 1.75-1.86 (m, 3H), 3.56 (br s, 4H), 3.93 (br s, 2H), 4.42 (d, J= 11.7 Hz,
1H), 4.70 (br s,
2H), 5.68 (br s, 1H), 6.67 (d, J= 7.8 Hz, 2H), 6.81 (br s, 1H), 6.89 (br s,
2H), 7.11 (br s, 1H),
7.81 (d, J= 7.8 Hz, 2H).
Step 5: tert-Butyl 4-(2-oxo-5- { [(tetrahydro-2H-pyran-2-yl)oxy]methyl 1-2,3 -
dihydro-1H-
b enzo[d]imidazol-1-yl)b enzoate :
To a well stirred solution of Step 4 intermediate (150 mg, 0.376) in THF (5
mL) was added
1,1-carbodiimidazole (CDI) (91 mg, 0.565 mmol) and the reaction mixture was
heated to 60
C. The reaction mixture was stirred at the same temperature for 1 hour. The
reaction mixture
was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL).
The combined
organic layers were washed with water (2 x 25 mL), brine (25 mL) and dried
over anhydrous
Na2504. The solvent was recovered under reduced pressure and the residue
obtained was
purified by column chromatography to afford 100 mg of the title product as off-
white solid.
111 NMR (300 MHz, DMSO-d6) 6 1.49 (br s, 6H), 1.57 (s, 9H), 3.50 (br s, 1H),
3.80 (br s,
1H), 4.46 (d, J= 11.1 Hz, 1H), 4.66 (br s, 2H), 7.02 (br s, 1H), 7.06 (br s,
2H), 7.71 (d, J= 8.0
Hz, 2H), 8.07 (d, J= 8.0 Hz, 2H), 11.26 (br s, 1H).
Intermediate 15
tert-Butyl 3 -fluoro-4-(2-ox o-5- { [(tetrahydro-2H-pyran-2-yl)oxy]methylI-2,3-
dihydro-1H-
benzo[d]imidazol-1-yl)benzoate
()
HNz N CO2C(C1-13)3
_
0 c)
Step 1: tert-Butyl 3-fluoro-4-[(4-formy1-2-nitrophenyl)amino]benzoate
The title compound was prepared by the reaction of 4-bromo-3-nitrobenzaldehyde
(1 g, 4.340
mmol) with tert-butyl 4-amino-3-fluorobenzoate (1 g, 4.78 mmol) in the
presence of
palladium acetate (48 mg, 0.217 mmol), XPhos (150 mg, 0.260 mmol) and cesium
carbonate
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(2.12 g, 6.51 mmol) in 1,4-dioxane (20 mL) as per the process described in
step 1 of
Intermediate 14 to yield 1.4 g of the product as yellow solid. 1-H NMR (300
MHz, CDC13) 6
1.61 (s, 9H), 7.22 (br s, 2H), 7.47 (t, J= 7.8 Hz, 1H), 7.83-7.89 (m, 2H),
7.96 (d, J= 9.0 Hz,
1H), 8.74 (br s, 1H), 9.89 (br s, 2H).
Step 2: tert-Butyl 3 -fluoro-4- [4-(hydroxym ethyl)-2-nitrophenyl]
amino}benzoate
The title compound was prepared by the aldehyde reduction of step 1
intermediate (800 mg,
2.22 mmol) by using sodium borohydride (109 mg, 2.88 mmol) in methanol (10 mL)
as per
the process described in step 2 of Intermediate 14 to yield 625 mg of the
product as brown oil.
1-H NMR (300 MHz, CDC13) 6 1.60 (s, 9H), 4.69 (s, 2H), 7.33 (d, J= 8.7 Hz,
1H), 7.41-7.53
(m, 2H), 7.78 (br s, 2H), 8.22 (s, 1H), 9.36 (s, 1H).
Step 3: tert-Butyl 3-fluoro-442-nitro-4-(tetrahydro-pyran-2-yloxymethyl)-
phenylamino]-
benzoate
The title compound was prepared by the reaction of Step 2 intermediate (200
mg, 0.580
mmol) with DHP (0.18 mL, 2.04 mmol) in the presence of catalytic amount of
PTSA in DCM
(15 mL) as per the process described in step 3 of Intermediate 14 to afford
620 mg of the
product as colorless oil. 1-H NMR (300 MHz, CDC13) 6 1.60 (s, 9H), 1.63-1.73
(m, 3H), 1.74-
7.85 (m, 2H), 3.55 (br s, 1H), 3.90 (br s, 1H), 4.45 (d, J= 12.0 Hz, 1H), 4.71
(br s, 2H), 7.27-
7.34 (m, 1H), 7.42-7.51 (m, 2H), 7.80 (d, J= 9.3 Hz, 2H), 8.23 (s, 1H), 9.36
(br s, 1H).
Step 4: tert-Butyl 4-[2-amino-4-(tetrahydro-pyran-2-yloxymethyl)-phenylamino]-
3-fluoro-
benzoate
The title compound was prepared by palladium catalysed hydrogenation of step 3
intermediate in methanol (20 mL) as per the process described in step 4 of
Intermediate 14 to
afford 475 mg of the product as off white solid. 1-H NMR (300 MHz, CDC13) 6
1.56 (s, 9H),
1.60-1.70 (m, 5H), 3.58 (br s, 2H), 3.92 (br s, 1H), 4.45 (d, J= 12.0 Hz, 1H),
4.71 (br s, 2H),
6.02 (br s, 1H), 6.67 (br s, 1H), 6.92 (d, J= 7.8 Hz, 1H),7.03 (br s, 1H),
7.16 (d, J= 8.4 Hz,
1H), 7.58 (br s, 2H).
Step 5: tert-Butyl 3 -fluoro-4-(2-ox o-5- [(tetrahydro-2H-pyran-2-
yl)oxy]methylI-2,3-dihydro-
1H-benzo[d]imidazol-1-yl)benzoate
The title compound was prepared by cyclization reaction of step 4 intermediate
(475 mg,
1.141 mmol) in the presence of CDI (277 mg, 1.712 mmol) in THF (10 mL) as per
the process
described in step 5 of Intermediate 14 to yield 420 mg of the product as white
solid. 1E1 NMR
(300 MHz, DMSO-d6) 6 1.63 (s, 9H), 1.78 (br s, 7H), 3.58 (br s, 1H), 3.92 (br
s, 1H), 4.50 (d,
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J= 11.7 Hz, 1H), 4.71 (s, 1H), 4.79 (d, J = 11.7 Hz, 1H), 6.80 (d, J = 7.5 Hz,
1H), 7.07 (d, J =
8.4 Hz, 1H), 7.21 (s, 1H), 7.61 (t, J= 7.5 Hz, 1H), 7.91-7.98 (m, 2H), 9.84
(br s, 1H).
Intermediate 16
tert-Butyl 3 -fluoro-4- [5-(2-methoxy-1,1-dim ethyl -ethyl)-2-ox o-2,3 -di
hydro-b enzoimi dazol-1-
A -benzoate
= c o2c (c H3)3
HNm
F
H3C0 CH3
C H3
Step 1: 1-Fluoro-4-(1-methoxy-2-methylpropan-2-yl)benzene
To a cooled (0 C) suspension of sodium hydride (60% w/w, 618 mg, 15.46 mmol)
in THF
(20 mL) was added a solution of 2-(4-fluoropheny1)-2-methylpropan-1-ol (1.3 g,
7.728 mmol)
in THF (20 mL). After the complete addition, the resulting suspension was
warmed up to RT
and stirred for 1 hour under the same conditions. Methyl iodide (2.4 mL,
38.642 mmol) was
added drop-wise and the mixture was continued to stir for 3 hours at RT. The
reaction mixture
was quenched with water (20 mL) and the aqueous solution was extracted with
ethyl acetate
(3 x 20 mL). The combined organic extracts were washed with brine (25 mL) and
dried over
anhydrous sodium sulfate. The solution was filtered, concentrated and the
residue thus
obtained was purified by silica gel column chromatography to yield 1.23 g of
the title product
as yellow oil. 111NMR (300 MHz, CDC13) 6 6.41 (s, 6H), 3.30 (s, 3H), 3.37 (s,
2H), 6.98 (t, J
= 9.0 Hz, 2H), 7.31-7.35 (m, 2H)
Step 2: 1-Fluoro-4-(1-m ethoxy-2-m ethyl prop an-2-y1)-2-nitrob enzene
To a cooled (-30 C) solution of step 1 intermediate (300 mg, 1.650 mmol) was
added conc.
sulphuric acid (2.7 mL, 50.84 mmol). To the above mixture was slowly added
fuming nitric
acid (0.3 mL, 6.75 mmol) in duration of 10 minutes. The resulting solution was
stirred at ¨20
C for 30 minutes. The reaction mixture was poured in to crushed ice and
extracted with ethyl
acetate (2 x 20 mL). The combined organic extracts were washed with water (25
mL), brine
(25 mL) and dried over anhydrous sodium sulfate. The solution was filtered,
concentrated and
the residue thus obtained was purified by silica gel column chromatography to
yield 211 mg
of the title product as pale yellow oil; 111 NMR (300 MHz, CDC13) 6 1.36 (s,
6H), 1.30 (s,
3H), 3.38 (s, 2H), 7.18-7.25 (m, 1H), 7.62-7.67 (m, 1H), 8.02-8.07 (m, 1H).
Step 3: tert-Butyl 3 -fluoro-4-[4-(2-m ethoxy-1,1 -dim ethyl-ethyl)-2-nitro-
phenyl amino] -
benzoate
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The title compound was synthesized by the reaction of step 2 intermediate (500
mg, 2.200
mmol) and tert-butyl 4-amino-3-fluorobenzoate (511 mg, 2.42 mmol) in the
presence of
sodium hydride (60% w/w, 132 mg, 3.30 mmol) in DMF (40 mL) as per the process
described
in step 1 of Intermediate 1 to yield 752 mg of the product as bright orange
liquid. 1-H NMR
(300 MHz, DMSO-d6) 6 1.26 (s, 6H), 1.54 (s, 9H), 3.22 (s, 3H), 3.39 (s, 2H),
7.22 (d, J = 8.7
Hz, 1H), 7.43 (d, J= 8.4 Hz, 1H), 7.65-7.72 (m, 3H), 8.02 (br s, 1H), 9.14 (s,
1H); APCI-MS
(m/z) 417 (M+H)+.
Step 4: tert-Butyl 4-[2-amino-4-(2-m ethoxy-1, 1-dim ethyl -
ethyl)-phenyl amino] -3 -
fluorobenzoate
The title compound was synthesized by the palladium catalyzed hydrogenation of
step 3
intermediate (746 mg, 1.780 mmol) in methanol (10 mL) as per the process
described in step
2 of Intermediate 1 to yield 566 mg of the product as white solid. 1-H NMR
(300 MHz,
DMSO-d6) 6 1.22 (s, 6H), 1.50 (s, 9H), 3.22 (s, 3H), 3.31 (s, 2H), 4.77 (br s,
2H), 6.42-6.45
(m, 1H), 6.60 (d, J= 8.4 Hz, 1H), 6.80 (br s, 1H), 6.90 (d, J = 8.1 Hz, 1H),
7.46-7.53 (m, 2H),
7.62 (br s, 1H); APCI-MS (m/z) 387 (M+H)+.
Step 5: tert-Butyl 3 -fluoro-4- [5-(2-m ethoxy-1, 1-di m ethyl-ethyl)-2-oxo-
2,3 -di hydro-
b enzoimidazol-1-y1]-b enzoate
The title compound was synthesized by the reaction of step 4 intermediate (560
mg, 1.442
mmol) and CDI (351 mg, 2.16 mmol) in THF (20 mL) as per the process described
in step 3
of Intermediate 1 to yield 522 mg of the product as off white solid. 1-H NMR
(300 MHz,
DMSO-d6) 6 1.26 (s, 6H), 1.57 (s, 9H), 3.21 (s, 3H), 3.34 (s, 2H), 6.76 (d, J=
7.8 Hz, 1H),
7.01-7.05 (m, 2H), 7.75-7.79 (m, 1H), 7.91 (d, J = 9.0 Hz, 2H), 11.18 (br s,
1H); APCI-MS
(m/z) 415 (M+H)+.
Intermediate 17
tert-Buty1-3-fluoro-4-[5-(3-methyl-oxetan-3-ylmethoxy)-2-oxo-2,3-dihydro-
benzoimidazol-1-
y1]-benzoate
c 02c (c H3)3
HNAN 11110
CH
F
Step 1: 3- [(4-Iodo-3 -nitrophenoxy)m ethyl] -3 -m ethyl ox etane
To a stirred mixture of 4-iodo-3-nitrophenol (1.02 g, 3.849 mmol), 3-methyl-3-
oxetane
30 methanol (393 mg, 3.849 mmol) and triphenylphosphine (1.51 g, 5.773
mmol) in THF (20
mL) was added a diethyl azadicaboxylate (DEAD) (0.91 mL, 5.773 mmol) at 0 C.
The
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reaction mixture was stirred at RT for 18 hours. The reaction mixture was
concentrated under
reduced pressure and the residue thus obtained was purified by silica gel
column
chromatography to yield 971 mg of the title product as yellow solid. 1-H NMR
(300 MHz,
CDC13) 6 1.44 (s, 3H), 4.07 (s, 2H), 4.48 (d, J = 6.0 Hz, 2H), 4.60 (d, J= 6.0
Hz, 2H), 6.89-
6.93 (m, 1H), 7.45-7.47 (m, 1H), 7.91 (d, J= 8.7 Hz, 1H).
Step 2: tert-Butyl
3 -fluoro-4-[4-(3 -methyl -ox etan-3 -ylm ethoxy)-2-nitro-phenyl amino]
benzoate
The title compound was synthesized by the reaction of step 1 intermediate (612
mg, 1.752
mmol) and tert-butyl 4-amino-3-fluorobenzoate (370 mg, 1.7529 mmol) in the
presence of
palladium acetate (39 mg, 0.1752 mmol), XPhos (121 mg, 0.210 mmol) and cesium
carbonate
(856 mg, 2.629 mmol) in 1,4-dioxane (10 mL) as per the process described in
step 1 of
Intermediate 2 to yield 692 mg of the title product as yellow solid. 1-H NMR
(300 MHz,
CDC13) 6 1.45 (s, 3H), 1.59 (s, 9H), 4.06 (s, 2H), 4.49 (d, J= 6.0 Hz, 2H),
4.64 (d, J= 6.0 Hz,
2H), 7.21-7.22 (m, 1H), 7.34-7.37 (m, 2H), 7.70-7.78 (m, 3H), 9.08 (br s, 1H);
APCI-MS
(m/z) 431 (M+H)+.
Step 3: tert-Butyl
4- [2-amino-4-(3 -m ethyl-oxetan-3 -ylm ethoxy)-phenyl amino] -3 -
fluorobenzoate
The title compound was synthesized by the catalytic hydrogenation of step 2
intermediate
(673 mg, 1.556 mmol) in methanol (10 mL) as per the process described in step
2 of
Intermediate 1 to yield 463 mg of the product as off white solid. 1-H NMR (300
MHz, DMSO-
d6) 6 1.35 (s, 3H), 1.49 (s, 9H), 3.96 (s, 2H), 4.30 (d, J= 6.0 Hz, 2H), 4.48
(d, J = 6.0 Hz,
2H), 4.91 (br s, 2H), 6.23 (d, J = 8.7 Hz, 1H), 6.31-6.40 (m, 2H), 6.87 (d, J
= 8.4 Hz, 1H),
7.44-7.51 (m, 2H), 7.58 (br s, 1H); APCI-MS (m/z) 401 (M+H)+.
Step 4: tert-Butyl 3 -fluoro-4- [5-(3-m ethyl-ox etan-3 -ylm ethoxy)-2-oxo-2,3
-di hydro-
benzoimidazol-1-y1]-benzoate
The title compound was synthesized by the reaction of step 3 intermediate (443
mg, 1.100
mmol) and CDI (272 mg, 1.65 mmol) in THF (10 mL) as per the process described
in step 3
of Intermediate 1 to yield 409 mg of the product as off white solid. 1-H NMR
(300 MHz,
DMSO-d6) 6 1.35 (s, 3H), 1.57 (s, 9H), 4.02 (s, 2H), 4.30 (d, J= 6.0 Hz, 2H),
4.49 (d, J= 6.0
Hz, 2H), 6.66 (d, J= 9.0 Hz, 1H), 6.73-6.76 (m, 2H), 7.74 (t, J= 8.4 Hz, 1H),
7.90 (d, J= 8.4
Hz, 2H), 11.28 (br s, 1H).
Intermediate 18
Ethyl 4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)benzoate
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0
HNAN CO CH CH
_ _2 _ 2 _ 3
Step 1: Ethyl 4[(2-nitrophenyl)aminoThenzoate
A mixture of ethyl 4-amino benzoate (1 g, 6.050 mmol) and 1-fluoro-2-
nitrobenzene (0.64
mL, 6.050 mmol) was heated at 160 C in a sealed tube for 15 hours. The
reaction mixture
was cooled down to RT and purified by silica gel column chromatography to
yield 500 mg of
the title product as yellow solid. 111 NMR (300 MHz, CDC13) 6 1.40 (t, J= 6.9
Hz, 3H), 4.35
(q, J= 6.9 Hz, 2H), 6.89-6.91 (m, 1H), 7.27-7.31 (m, 2H), 7.74 (br s, 2H),
8.06 (d, J = 8.7 Hz,
2H), 8.21 (d, J= 8.4 Hz, 1H), 9.49 (br s, 1H).
Step 2: Ethyl 4 -(2-ox o-2,3 -di hydro-1H-b enzimidazol-1-yl)benzoate
The title compound was prepared by palladium catalyzed hydrogenation of step 1
intermediate (500 mg, 1.746 mmol) in methanol (10 mL) followed by the
cyclization of the
corresponding diamine derivative (370 mg, 1.444 mmol) in the presence of CDI
(351 mg,
2.166 mmol) in THF (10 mL) as per the process described in step 2 and 3 of
Intermediate 1
respectively to yield 300 mg of the product as off white solid. 1H NMR (300
MHz, DMSO-d6)
6 1.34 (t, J= 7.2 Hz, 3H), 4.35 (q, J= 6.9 Hz, 2H), 7.06-7.15 (m, 4H), 7.74
(d, J = 7.8 Hz,
2H), 8.12 (d, J= 8.4 Hz, 2H), 11.28 (br s, 1H).
Intermediate 19
4-(2-0xo-2,3 -di hydro-1H-b enzimi dazol-1-yl)b enzonitrile
0
HNAN CN
Step 1: 44(2-Nitrophenyl)aminoThenzonitrile
The title compound was prepared by the reaction of 4-aminobenzonitrile (1 g,
8.47 mmol)
with 1-fluoro-2-nitrobenzene (892 mg, 8.47 mmol) in the presence of sodium
hydride (60%
w/w, 406 mg, 10.16 mmol) in DMF (10 mL) as described in step 1 of Intermediate
1 to yield
810 mg of the product as off white solid. 1-H NMR (300 MHz, DMSO-d6) 6 7.17
(t, J = 7.8
Hz, 1H), 7.30 (br s, 2H), 7.53 (d, J = 7.8 Hz, 1H), 7.61-7.73 (m, 3H), 8.10
(d, J = 8.7 Hz, 1H),
9.30 (s, 1H); APCI-MS (m/z) 238 (M+H)+.
Step 2: 4-(2-0xo-2,3-dihydro-1H-benzimidazol-1-y1)benzonitrile
The title compound was prepared by palladium catalyzed hydrogenation of step 1
intermediate (800 mg, 3.344 mmol) in methanol (10 mL) followed by the
cyclization of the
corresponding diamine derivative (600 mg, 2.87 mmol) in the presence of CDI
(697 mg, 4.30
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mmol) in THF (10 mL) as per the process described in step 2 and 3 of
Intermediate 1
respectively to yield 240 mg of the product as pale yellow solid. 1-H NMR (300
MHz, DMSO-
d6) 6 7.04 (br s, 1H), 7.10 (br s, 2H), 7.15 (d, J= 7.8 Hz, 1H), 7.81 (d, J=
8.1 Hz, 2H), 8.02
(d, J= 7.8 Hz, 2H), 11.32 (br s, 1H); APCI-MS (m/z) 236 (M+H)+.
Intermediate 20
N-Cyclopropy1-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-y1)benzenesulfonamide
HN-Cicl =SO2NH
1>
Step 1: N-Cyclopropy1-44(2-nitrophenyl)aminoThenzenesulfonamide
The title compound was prepared by the reaction of 1-iodo-2-nitrobenzene (495
mg, 1.987
mmol) with 4-amino-N-cyclopropylbenzenesulfonamide (600 mg, 2.204 mmol) in the
presence of palladium acetate (45 mg, 0.198 mmol), XPhos (137 mg, 0.238 mmol)
and
cesium carbonate (1.95 g, 5.963 mmol) in 1,4-dioxane (15 mL) as per the
process described
in step 1 of Intermediate 2 to yield 230 mg of the product as yellow solid. 1-
H NMR (300
MHz, DMSO-d6) 6 0.39-0.49 (s, 4H), 2.10 (br s, 1H), 7.10 (t, J= 7.5 Hz, 1H),
7.37 (d, J= 8.4
Hz, 2H), 7.50 (d, J= 8.7 Hz, 1H), 7.61 (t, J= 7.2 Hz, 1H), 7.72 (d, J= 8.7 Hz,
2H), 8.11 (d, J
= 8.4 Hz, 1H), 9.31 (s, 1H); APCI-MS (m/z) 333 (M+H)+.
Step 2: N-Cycl opropy1-4-(2-oxo-2,3 -di hydro-1H-b enzimi dazol -1-yl)b enz
ene sul fonami de
The title compound was prepared by palladium catalyzed hydrogenation of step 1
intermediate (230 mg, 0.688 mmol) in methanol (8 mL) followed by the
cyclization of the
corresponding diamine derivative (180 mg, 0.594 mmol) in the presence of CDI
(145 mg,
0.891 mmol) in THF (8 mL) as per the process described in step 2 and 3 of
Intermediate 1
respectively to yield 90 mg of the product as off white solid. 1-H NMR (300
MHz, DMSO-d6)
6 0.43 (br s, 2H), 0.53 (br s, 2H), 2.16 (br s, 1H), 7.07-7.10 (m, 3H), 7.16
(d, J= 7.8 Hz, 1H),
7.83 (d, J= 8.4 Hz, 2H), 7.97 (d, J= 8.1 Hz, 2H), 8.05 (br s, 1H), 11.31 (br
s, 1H).
Intermediate 21
Diethyl [4-(2-oxo-2,3-dihydro-1H-b enzimidazol-1-yl)phenyl]phosphonate
HN5)&N PO(OCH2CH3)2
Step 1: Ethyl propyl {4-[(2-nitrophenyl)amino]phenylIphosphonate
The title compound was prepared from 1-iodo-2-nitro benzene (482 mg, 1.94
mmol) and
diethyl (4-aminophenyl)phosphonate (370 mg, 1.614 mmol) in the presence of
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acetate (36 mg, 0.161 mmol), XPhos (112 mg, 0.194 mmol) and cesium carbonate
(789 mg,
2.42 mmol) in 1,4-dioxane (10 mL) as per the process described in step 1 of
Intermediate 2 to
yield 416 mg of the product as brown solid. 1-H NMR (300 MHz, DMSO-d6) 6 1.23
(t, J = 6.9
Hz, 6H), 3.99 (q, J= 6.9 Hz, 4H), 7.07 (br s, 2H), 7.36 (br s, 2H), 7.48 (d, J
= 8.1 Hz, 2H),
7.60-7.68 (m, 2H), 8.09 (br s, 1H), 9.27 (br s, 1H); APCI-MS (m/z) 351 (M+H)+.
Step 2: Diethyl [4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)phenyl]phosphonate
The title compound was prepared by the nitro reduction of step 1 intermediate
(416 mg, 1.187
mmol) in the presence of iron powder (198 mg, 3.560 mmol) and ammonium
chloride (663
mg, 11.875 mmol) in water (3.0 mL) and methanol (15 mL) as per the process
described in
step 2 of Intermediate 10 followed by cyclization of the diamine derivative
(360 mg, 1.124
mmol) by using CDI (273 mg, 1.68 mmol) in THF (10 mL) to yield 300 mg of the
product as
off white solid. 1-H NMR (300 MHz, DMSO-d6) 6 1.26 (t, J= 6.9 Hz, 6H), 4.02-
4.09 (m, 4H),
7.03-7.09 (m, 3H), 7.14 (d, J = 7.5 Hz, 1H), 7.76 (br s, 2H), 7.85-7.92 (m,
2H), 11.27 (br s,
1H).
Intermediate 22
Ethyl 4-[(2-{ [(2,6-dichlorophenyl)carbonyl]amino}phenyl)aminoThenzoate
* ci
0
c I
HN HN CO2CH2CH3
Step 1: Ethyl 4-[(2-nitrophenyl)amino]benzoate:
A stirred solution of ethyl 4-amino benzoate (1 g, 6.053 mmol) in 1-fluoro-2-
nitrobenzene
(0.64 mL, 6.053 mmol) was heated at 160 C in sealed tube for 16 hours. The
reaction
mixture was cooled to RT and the residue was purified by silica gel column
chromatography
to yield 500 mg of the product as off white solid. 1-H NMR (300 MHz, CDC13) 6
1.40 (t, J =
7.2 Hz, 3H), 4.38 (d, J = 7.2 Hz, 2H), 6.80 (br s, 1H), 7.30 (d, J= 8.4 Hz,
2H), 7.45 (br s,
2H), 8.06 (d, J= 8.7 Hz, 2H), 8.22 (d, J= 8.4 Hz, 1H), 9.49 (br s, 1H).
Step 2: Ethyl 4-[(2-aminophenyl)amino]benzoate:
To the stirred solution of Step 1 intermediate (300 mg, 1.048 mmol) in
methanol (10 mL) was
added catalytic amount of 10% palladium on carbon and the reaction was stirred
for 5 h under
hydrogen atmosphere. The reaction mixture was filtered through celite and the
filtrate was
concentrated to yield 200 mg of the product. 1-H NMR (300 MHz, CDC13) 6 1.35
(t, J = 7.5
Hz, 3H), 4.33 (q, J= 7.2 Hz, 2H), 5.81 (br s, 1H), 6.69 (d, J = 8.1 Hz, 2H),
6.85 (t, J = 7.8 Hz,
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1H), 6.91 (d, J = 7.8 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz,
1H), 7.85 (d, J =
8.7 Hz, 2H).
Step 3: Ethyl 44(2-{[(2,6-dichlorophenyl)carbonyl]amino}phenyl)amino]
benzoate:
To a well stirred solution of Step 2 intermediate (350 mg, 1.365 mmol) in DCM
(10 ml) was
added DIPEA (0.7 mL, 4.09 mmol) and the reaction mixture was cooled to 0 C
followed by
the addition of 2,6-dichlorobenzoyl chloride (0.3 mL, 2.047 mmol). The
reaction mixture was
stirred overnight at RT. The reaction mixture was diluted with water (10 mL)
and the
precipitate thus obtained was filtered. The obtained product was purified by
silica gel column
chromatography to yield 450 mg of the title product as off white solid. 111
NMR (300 MHz,
CDC13) 6 1.35 (t, J = 6.6 Hz, 3H), 4.30 (q, J = 7.2 Hz, 2H), 6.81 (q, J= 8.1
Hz, 2H), 7.20-7.33
(m, 4H), 7.43 (d, J= 7.8 Hz, 1H), 7.82-7.90 (m, 4H).
Examples
Example 1
443 -(2,6-Di chl orob enzoy1)-2-oxo-2,3 -dihydro-1H-b enzo[d]imi dazol -1-y1
]b enzoi c acid
CI 0 * CO2H
*NN
Step 1: tert-Butyl 4- [3 -(2, 6-di chl orob enzoy1)-2-oxo-2,3 -di hydro-1H-b
enz o [d] imi dazol
yl]b enzoate :
To a stirred and cooled (0 C) solution of Intermediate 1 (150 mg, 0.483 mmol)
in DMF (5
mL) was added sodium hydride (60% w/w, 25 mg, 0.628 mmol) and the reaction
mixture was
stirred for 10 minutes at the same temperature. 2,6-Dichlorobenzoyl chloride
(0.08 mL, 0.580
mmol) was added to the reaction mixture and it was stirred at RT for 2 h. The
reaction
mixture was diluted with water (10 mL) and product was extracted in ethyl
acetate (2 x 10
mL). The layers were separated. The combined organic layer was washed with
water (2 x 15
mL), brine (20 ml) and dried over anhydrous Na2504. The solvent was recovered
under
reduced pressure. The residue was purified by column chromatography to afford
150 mg of
the product as off-white solid. 111 NMR (300 MHz, DMSO-d6) 6 1.56 (s, 9H),
7.17 (s, 1H),
7.36 (br s, 2H), 7.55-7.61 (m, 3H), 7.84 (s, 1H), 8.29 (s, 1H)
Step 2: 443-(2,6-Dichlorobenzoy1)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-
yl]benzoic
acid:
To a well stirred and cooled (0 C) solution of Step 1 product (100 mg, 0.206
mmol) in
dichloromethane (3 mL) was added trifluoroacetic acid (3 mL) and the reaction
mixture was
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stirred at RT for 4h. The solvents were recovered under reduced pressure and
the residue
obtained was washed with water, triturated with diethyl ether and dried to
yield 60 mg of the
product as off white solid. 1-H NMR (300 MHz, DMSO-d6) 6 7.20 (br s, 1H), 7.36
(br s, 2H),
7.54-7.61 (m, 3H), 7.68 (d, J = 8.1 Hz, 2H), 8.07 (d, J= 8.1 Hz, 2H), 8.29 (br
s, 1H); APCI-
MS (m/z) 427 (M+H)+.
Example 2
4- 3 [2-Chl oro-6-(trifluoromethyl)b enzoyl] -2-oxo-2,3 -dihydro-1H-b enzo [d]
imi dazol-1-
yl }benzoic acid
F3C 0 * CO2H
*NN
CIO
The title compound was prepared by the reaction of Intermediate 1 (138 mg,
0.411 mmol) and
2-chloro-6-(trifluoromethyl)benzoyl chloride (100 mg, 0.445 mmol) in the
presence of
sodium hydride (60% w/w, 24 mg, 0.5788 mmol) in DMF (5 mL) followed by the
hydrolysis
of the corresponding ester derivative (110 mg, 0.212 mmol) by using TFA (3 mL)
in DCM (3
mL) as per the process described in Example 1 to yield 55 mg of the product as
off white
solid. 1H NIVIR (300 MHz, DMSO-d6) 6 7.21 (br s, 1H), 7.36 (br s, 2H), 7.66
(t, J= 8.4 Hz,
2H), 7.76 (t, J = 7.8Hz, 1H), 7.89-7.96 (m, 2H), 8.10 (t, J = 8.1 Hz, 2H),
8.28 (br s, 1H),
13.23 (br s, 1H); APCI-MS (m/z) 458 (M-H)+.
Example 3
2-Chloro-443-(2,6-dichlorobenzoy1)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-
yl]benzoic
acid
0
CI * co2H
N A N
CI
110 CIO
The title compound was prepared by the reaction of Intermediate 2 (130 mg,
0.377 mmol)
with 2,6-dichlorobenzoyl chloride (0.06 mL, 0.452 mmol) in the presence of
sodium hydride
(60% w/w, 20 mg, 0.490 mmol) in DMF (5 mL) followed by the hydrolysis of the
corresponding ester derivative (120 mg, 0.231 mmol) by using TFA (3 mL) in DCM
(3 mL)
as per the process described in Example 1 to yield 20 mg of the product as off
white solid. 1E1
NMR (300 MHz, DMSO-d6) 6 7.21 (br s, 1H), 7.37 (br s, 2H), 7.55-7.64 (m, 4H),
7.79 (s,
1H), 7.96 (d, J= 8.4 Hz, 1H), 8.28 (br s, 1H), 13.20 (br s, 1H); APCI-MS (m/z)
461 (M+H)+.
Example 4
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443 -(2,6-Di chl orob enzoy1)-2-oxo-2,3 -dihydro-1H-b enzo[d]imidazol -1-yl] -
2-fluorob enzoi c
acid
0 0
NN 4/k co2H
ci
CIO F
The title compound was prepared by the reaction of Intermediate 3 (200 mg,
0.609 mmol) and
5 2,6-dichlorobenzoyl chloride (0.12 mL, 0.731 mmol) in the presence of
sodium hydride (60%
w/w, 32 mg, 0.7921 mmol) in DNIF (5 mL) followed by the hydrolysis of the
corresponding
ester derivative (160 mg, 0.319 mmol) by using TFA (2 mL) in DCM (4 mL) as per
the
process described in Example 1 to yield 35 mg of the product as white solid. 1-
H NMR (300
MHz, CDC13) 6 7.20-7.27 (m, 2H), 7.33-7.39 (m, 5H), 7.48 (br s, 1H), 8.17 (br
s, 1H), 8.48
10 (br s, 1H); APCI-MS (m/z) 445 (M)+.
Example 5
443 -(2,6-Di chl orob enzoy1)-2-oxo-2,3 -dihydro-1H-b enzo[d]imidazol -1-yl] -
3 -fluorob enzoi c
acid
ci
o 0 ''co2H
NAN
10 CIO
The title compound was prepared by the reaction of Intermediate 4 (150 mg,
0.456 mmol) and
2,6-dichlorobenzoyl chloride (0.08 mL, 0.548 mmol) in the presence of sodium
hydride (60%
w/w, 24 mg, 0.593 mmol) in DMF (5 mL) followed by the hydrolysis of the
corresponding
ester derivative (120 mg, 0.239 mmol) by using TFA (3 mL) in DCM (3 mL) as per
the
process described in Example 1 to yield 65 mg of the product as off white
solid. 1-H NMR
(300 MHz, DMSO-d6) 6 7.03 (br s, 1H), 7.35 (s, 2H), 7.51-7.61 (m, 3H), 7.85
(t, J= 7.2 Hz,
1H), 7.95 (d, J= 8.7 Hz, 2H), 8.29 (m, 1H), 13.16 (br s, 1H); APCI-MS (m/z)
442 (M¨H)-.
Example 6
443 -(2-Bromo-6-chl orob enzoy1)-2-oxo-2,3 -dihydro-1H-b enzo[d]imidazol -1-
yl] -3 -
fluorobenzoic acid
Br 0 0 FCO2H
NAN lir
110 ctc)\-1
The title compound was prepared by the reaction of Intermediate 4 (300 mg,
0.914 mmol)
with 2-bromo-6-chlorobenzoyl chloride (536 mg, 1.005 mmol) in the presence of
sodium
hydride (60% w/w, 48 mg, 1.188 mmol) in DMF (5 mL) followed by the hydrolysis
of the
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corresponding ester derivative (123 mg, 0.225 mmol) by using TFA (2 mL) in DCM
(4 mL)
as per the process described in Example 1 to yield 57 mg of the product as
white solid. 1E1
NMR (300 MHz, CDC13) 6 6.91 (br s, 1H), 7.29-7.40 (m, 3H), 7.41 (d, J= 8.4 Hz,
1H), 7.53
(d, J = 8.4 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H), 8.01 (t, J= 8.4 Hz, 2H), 8.45
(d, J= 6.9 Hz, 1H);
APCI-MS (m/z) 490 (M+H)+.
Example 7
443 -(2-Chloro-6-methoxyb enzoy1)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl] -
3-
fluorobenzoic acid
H3C0 co2H
N N
110 c10
The title compound was prepared by the reaction of Intermediate 4 (750 mg,
2.285 mmol)
with 2-chloro-6-methoxybenzoyl chloride (200 mg, 1.078 mmol) in the presence
of sodium
hydride (60% w/w, 43 mg, 1.078 mmol) in DMF (5 mL) followed by the hydrolysis
of the
corresponding ester derivative (210 mg, 0.4226 mmol) by using TFA (2 mL) in
DCM (4 mL)
as per the process described in Example 1 to yield 55 mg of the product as
white solid. 1E1
NMR (300 MHz, DMSO-d6) 6 3.77 (br s, 3H), 7.00 (br s, 1H), 7.13 (d, J = 8.4
Hz, 2H), 7.33
(br s, 2H), 7.46 (t, J = 8.4 Hz, 2H), 7.83 (t, J = 7.2 Hz, 1H), 7.94 (d, J=
9.3 Hz, 2H), 8.26 (br
s, 1H); APCI-MS (m/z) 441 (M+H)+.
Example 8
3 -Fluoro-443 -(2-fluoro-6-methoxyb enzoy1)-2-oxo-2,3 -dihydro-1H-b enzo[d]
imidazol-1-
yl]benzoic acid
H300 (..iZ * co2H
N N
q-75.
The title compound was prepared by the reaction of Intermediate 4 (150 mg,
0.457 mmol)
with 2-fluoro-6-methoxybenzoyl chloride (0.08 mL, 0.594 mmol) in the presence
of sodium
hydride (60% w/w, 15 mg, 0.594 mmol) in DMF (5 mL) followed by the hydrolysis
of the
corresponding ester derivative (160 mg, 0.332 mmol) by using TFA (2 mL) in DCM
(4 mL)
as per the process described in Example 1 to yield 70 mg of the product as
white solid. 1E1
NMR (300 MHz, DMSO-d6) 6 3.78 (s, 3H), 6.90-7.00 (m, 3H), 7.32 (br s, 2H),
7.50 (q, J =
7.8 Hz, 1H), 7.82 (t, J = 7.2 Hz, 1H), 7.94 (d, J= 9.3 Hz, 2H), 8.22 (br s,
1H), 13.62 (br s,
1H); AP C I-M S (m/z) 425 (M+H)+.
Example 9
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4- {3 -[2-Chloro-6-(difluoromethyl)b enzoy1]-2-oxo-2,3-dihydro-1H-benzo[d]
imidazol-1-y1 } -
3-fluorobenzoic acid
*
F2Hc a co, AC)
N N
CI
The title compound was prepared by the reaction of Intermediate 4 (200 mg,
0.609 mmol)
5 with 2-chloro-6-(difluoromethyl)benzoyl chloride (230 mg, 1.022 mmol) in
the presence of
sodium hydride (60% w/w, 32 mg, 0.792 mmol) in DMF (5 mL) followed by the
hydrolysis
of the corresponding ester derivative (200 mg, 0.386 mmol) by using TFA (2 mL)
in DCM (4
mL) as per the process described in Example 1 to yield 110 mg of the product
as white solid.
111 NMR (300 MHz, DMSO-d6) 6 6.79 (t, J= 54.6 Hz, 1H), 6.91 (br s, 1H), 7.32
(br s, 2H),
10 7.53-7.61 (m, 4H), 8.01 (d, J = 8.7 Hz, 2H), 8.42 (br s, 1H), 13.52 (br
s, 1H); APCI-MS (m/z)
461 (M+H)+.
Example 10
4- { 3 [2-Chl oro-6-(trifluoromethyl)b enzoyl] -2-oxo-2,3 -dihydro-1H-b enzo
[d] imidazol-1-y1 } -
3-fluorobenzoic acid
0 "',
F3C
co
NAN
15
Step 1: tert-Butyl-4 - { 3- [2-chl oro-6-(tri fluorom ethyl)b enzoyl] -2-oxo-
2,3-dihydro-1H-benzo[d]
imidazol-1-y1} -3 -fluorob enzoate
To a stirred solution of 2-chloro-6-(trifluoromethyl)benzoic acid (100 mg,
0.446 mmol) in dry
THF (5 mL) was added DMF (20 ilL) followed by 2.0 M solution of oxalyl
chloride (0.33
0.667 mmol) in DCM (5 mL). The resulting mixture was stirred at RT for 2
hours. The
solvents were removed under reduced pressure and the residue obtained was
dried completely
under vaccuo. The sticky mass obtained was dissolved in DMF (5 mL) and slowly
added to a
precooled (0 C) suspension of sodium hydride (60% w/w, 23 mg, 0.5781 mmol)
and
Intermediate 4 (146 mg, 0.446 mmol) in DNIF (5 mL). The resulting mixture was
warmed up
to RT and stirred for 2 hours. The reaction mixture was quenched with water (5
mL) and
extracted with ethyl acetate (2 x 10 mL). The combined organic layers were
washed with
water (2 x 10 mL) and brine (10 mL). The solution was dried over anhydrous
sodium
sulphate, filtered and concentrated under reduced pressure. The residue
obtained was purified
by silica gel column chromatography to yield 115 mg of the title product as
off white solid.
111 NMR (300 MHz, DMSO-d6) 6 1.25 (s, 9H), 6.86 (d, J= 6.3 Hz, 1H), 7.30 (br
s, 2H), 7.50-
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7.56 (m, 2H), 7.63-7.68 (m, 2H), 7.87 (t, J= 8.7 Hz, 2H), 8.41 (d, J= 7.8 Hz,
1H); APCI-MS
(m/z) 535 (M+H)+.
Step 2: 4-{342-Chloro-6-(trifluoromethyl)benzoy1]-2-oxo-2,3-dihydro-1H-
benzo[d] imidazol-
1-y11-3 -fluorob enzoi c acid
A precooled (0 C) solution of step 1 intermediate (110 mg, 0.205 mmol) in DCM
(3 mL) was
treated with TFA (1 mL) and the resulting mixture was stirred at RT for 4
hours. The solvent
and excess of reagent were removed under reduced pressure and the residue
obtained was
diluted with water (10 mL). The aqueous mixture was extracted with ethyl
acetate (2 x 10
mL). The combined organic layers were washed with brine (10 mL) and dried over
anhydrous
sodium sulfate. The solution was filtered and concentrated under reduced
pressure. The
residue thus obtained was purified by silica gel column chromatography to
obtain 25 mg of
the title product as white solid. 1E1 NMR (300 MHz, DMSO-d6) 6 6.89 (d, J =
6.3 Hz, 1H),
7.32 (br s, 1H), 7.50-7.60 (m, 2H), 7.63-7.68 (m, 2H), 8.00 (t, J= 8.7 Hz,
2H), 8.43 (d, J= 7.8
Hz, 1H); APCI-MS (m/z) 479 (M+H)+.
Example 11
Sodium 4-(3 - { [2-chloro-6-(trifluoromethyl)phenyl] carbonyl I-2-oxo-2,3 -
dihydro-1H-
b enzimi dazol-1-y1)-3 -fluorob enzoate
F3C 0 e CO2Na
/NN
#
To a well stirred and cooled (0 C) solution of Example 10 (60 mg, 0.125 mmol)
in
methanol (2 mL) was added 1N aqueous solution of sodium hydroxide (0.13 mL,
0.125
mmol) and the reaction mixture was stirred at the same temperature for lh. The
solvent was
recovered under reduced pressure and the residue obtained was triturated with
diethyl ether to
yield 38 mg of the product as white solid. 111 NMR (300 MHz, CD30D) 6 6.92 (br
s, 1H),
7.33 (br s, 2H), 7.50 (br s, 1H), 7.64-7.69 (m, 1H), 7.76 (br s, 2H), 7.83-
7.92 (m, 2H), 8.30 (br
s, 1H); APCI-MS (m/z) 479 [(M+H)-Na)]+.
Example 12
Ethyl 4-(3- { [2-chl oro-6-(trifluorom ethyl)phenyl] carbonyl I-2-ox o-2,3 -
dihydro-1H-
b enzimi dazol-1-y1)-3 -fluorob enzoate
F3c0 _ _2_2 5
* CO C H
NAN
#
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To a well stirred solution of Example 10 (203 mg, 0.4263 mmol) in ethanol (10
mL) was
added conc. sulphuric acid (0.3 mL) and the reaction mixture was refluxed for
18 h. The
solvent was recovered under reduced pressure and the residue obtained was
diluted with ethyl
acetate (20 mL) and washed with saturated aqueous solution of sodium
bicarbonate (2 x 10
mL). The solution was dried over anhydrous sodium sulphate, concentrated under
reduced
pressure and triturated the residue with n-pentane to yield 182 mg of the
product as white
solid. 1H NMR (300 MHz, CDC13) 6 1.40 (t, J= 6.9 Hz, 3H), 4.40 (q, J= 6.9 Hz,
2H), 6.86
(d, J = 7.2 Hz, 1H), 7.31 (br s, 2H), 7.50-7.56 (m, 2H), 7.63-7.68 (m, 2H),
7.94 (t, J= 9.9 Hz,
2H), 8.42 (d, J= 7.8 Hz, 1H); ESI-MS (m/z) 507 (M+H)+.
Example 13
443 -(2-Chl oro-6-cycl opropylb enzoy1)-2-oxo-2,3 -dihydro-1H-b
enzo[d]imidazol-1-yl] -3 -
fluorobenzoic acid
o 0 F CO2H
NAN 1111V
The title compound was prepared by the reaction of Intermediate 4 (143 mg,
0.435 mmol)
with 2-chloro-6-cyclopropylbenzoyl chloride (102 mg, 0.478 mmol) in the
presence of
sodium hydride (60% w/w, 23 mg, 0.5665 mmol) in DNIF (3 mL) followed by the
hydrolysis
of the corresponding ester derivative (157 mg, 0.309 mmol) by using TFA (2 mL)
in DCM (4
mL) as per the process described in Example 1 to yield 32 mg of the product as
off white
solid. 1H NMR (300 MHz, CDC13) 6 0.74 (br s, 1H), 0.82-0.88 (m, 3H), 1.91 (br
s, 1H), 6.90
(br s, 1H), 6.97 (d, J= 7.2 Hz, 1H), 7.28-7.35 (m, 5H), 7.62 (br s, 1H), 7.97-
8.04 (m, 2H),
8.48 (d, J = 6.9 Hz, 1H).
Example 14
[(3,5-Di chl oropyridin-4-yl)carb onyl] -2-oxo-2,3 -di hydro-1H-b enzimi dazol
-1-y11-3 -
fluorobenzoic acid
co2H
ci
e.NN
N CIO
The title compound was prepared by the reaction of Intermediate 4 (100 mg,
0.304 mmol)
with 3,5-dichloropyridine-4-carbonyl chloride (75 mg, 0.357 mmol) in the
presence of sodium
hydride (60% w/w, 18 mg, 0.456 mmol) in DMF (5 mL) followed by the hydrolysis
of the
corresponding ester derivative (65 mg, 0.129 mmol) by using TFA (1 mL) in DCM
(4 mL) as
per the process described in Example 1 to yield 30 mg of the product as white
solid. 1E1 NMR
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(300 MHz, DMSO-d6) 6 7.07 (br s, 1H), 7.40 (br s, 2H), 7.84-7.89 (m, 1H), 7.95
(d, J= 8.7
Hz, 2H), 8.27 (br s, 1H), 8.84 (s, 2H), 13.58 (br s, 1H); APCI-MS (m/z) 446
(M+H)+.
Example 15
643-(2,6-Dichlorobenzoy1)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl]
nicotinic acid
ci o 0 -n-CO2H
N
cin5
The title compound was prepared by the reaction of Intermediate 5 (200 mg,
0.642 mmol)
with 2,6-dichlorobenzoyl chloride (0.110 mL, 0.770 mmol) in the presence of
sodium hydride
(60% w/w, 34 mg, 0.835 mmol) in DNIF (3 mL) followed by the hydrolysis of the
corresponding ester derivative (150 mg, 0.309 mmol) by using TFA (3 mL) in DCM
(3 mL)
as per the process described in Example 1 to yield 70 mg of the product as off
white solid. 1E1
NMR (300 MHz, DMSO-d6) 6 7.42 (s, 2H), 7.57-7.63 (m, 3H), 7.96 (q, J= 8.4 Hz,
1H), 8.05
(br s, 1H), 8.30 (br s, 1H), 8.44 (d, J= 8.1 Hz, 1H), 9.09 (s, 1H), 13.56 (br
s, 1H); APCI-MS
(m/z) 428 (M+H)+.
Example 16
443 -(1-Naphthoy1)-2-oxo-2,3 -dihydro-1H-b enzo[d]imidazol-1-yl] -3 -fluorob
enzoic acid
o 0 * c 02H
N"N
The title compound was prepared by the reaction of Intermediate 4 (100 mg,
0.304 mmol)
with naphthalene-l-carbonyl chloride (0.06 mL, 0.396 mmol) in the presence of
sodium
hydride (60% w/w, 16 mg, 0.396 mmol) in DMF (5 mL) followed by the hydrolysis
of the
corresponding ester derivative (130 mg, 0.269 mmol) by using TFA (1 mL) in DCM
(3 mL)
as per the process described in Example 1 to yield 65 mg of the product as
white solid. 1E1
NMR (300 MHz, DMSO-d6) 6 6.98 (br s, 1H), 7.35 (br s, 2H), 7.59 (br s, 3H),
7.76 (d, J = 7.8
Hz, 1H), 7.86-7.93 (m, 3H), 7.95-8.04 (m, 2H), 8.11 (d, J= 8.7 Hz, 1H),8.21
(br s, 1H), 13.58
(br s, 1H); APCI-MS (m/z) 427 (M+H)+.
Example 17
443 -(2,6-Dichlorob enzoy1)-2-oxo-2,3 -dihydro-1H-imidazo[4,5-c]pyridin-1-y1]-
3 -
fluorobenzoic acid
o 0 NAN * co2H
ci
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The title compound was prepared by the reaction of Intermediate 6 (400 mg,
1.214 mmol)
with 2,6-dichlorobenzoyl chloride (0.209 mL, 1.457 mmol) in the presence of
sodium hydride
(60% w/w, 63 mg, 1.579 mmol) in DNIF (5 mL) followed by the hydrolysis of the
corresponding ester derivative (200 mg, 0.398 mmol) by using TFA (2 mL) in DCM
(4 mL)
as per the process described in Example 1 to yield 110 mg of the product as
white solid. 1E1
NMR (300 MHz, DMSO-d6) 6 7.52 (br s, 1H), 7.59-7.65 (m, 4H), 7.86 (t, J = 7.8
Hz, 1H),
7.97 (d, J= 8.4 Hz, 1H), 8.56 (br s, 1H), 9.37 (s, 1H), 13.68 (br s, 1H); APCI-
MS (m/z) 446
(M+H)+.
Example 18
441-(2,6-Dichlorob enzoy1)-2-oxo-1H-imidazo[4,5-b]pyridin-3 (21/)-y1]-3 -
fluorobenzoic acid
o 0 NN * co2H
ci
CIC\ N
The title compound was prepared by the reaction of Intermediate 7 (150 mg,
0.454 mmol) and
2,6-dichlorobenzoyl chloride (0.09 mL, 0.638 mmol) in the presence of sodium
hydride (60%
w/w, 24 mg, 0.592 mmol) in DMF (4 mL) followed by the hydrolysis of the
corresponding
ester derivative (170 mg, 0.338 mmol) by using TFA (2 mL) in DCM (4 mL) as per
the
process described in Example 1 to yield 75 mg of the product as white solid. 1-
H NMR (300
MHz, DMSO-d6) 6 7.09 (br s, 1H), 7.23-7.30 (m, 3H), 7.41 (br s, 1H), 7.70-7.76
(m, 2H),
8.03 (br s, 1H), 8.37 (s, 1H), 13.50 (br s, 1H); APCI-MS (m/z) 446 (M+H)+.
Example 19
443 -(2,6-Dichlorob enzoy1)-6-fluoro-2-oxo-2,3 -dihydro-1H-b enzo[d]imidazol-1-
yl]benzoic
acid
CI 0 0 4, co2H
NN
Pc
The title compound was prepared by the reaction of Intermediate 8 (210 mg,
0.639 mmol)
with 2,6-dichlorobenzoyl chloride (0.12 mL, 0.766 mmol) in the presence of
sodium hydride
(60% w/w, 33 mg, 0.8314 mmol) in DNIF (5 mL) followed by the hydrolysis of the
corresponding ester derivative (220 mg, 0.4388 mmol) by using TFA (4 mL) in
DCM (4 mL)
as per the process described in Example 1 to yield 90 mg of the product as off
white solid. 1E1
NMR (300 MHz, DMSO-d6) 6 7.11 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H),
7.51-7.61
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(m, 3H), 7.68 (d, J = 8.4 Hz, 2H), 8.10 (d, J = 8.1 Hz, 2H), 8.26-8.32 (m,
1H), 13.11 (br s,
1H); AP C I-M S (m/z) 445 (M+H)+.
Example 20
443 -(2,6-Dichlorob enzoy1)-7-fluoro-2-oxo-2,3 -dihydro-1H-b enzo[d]imidazol -
1-y1]-3 -
fluorobenzoic acid
0 NAN F CO2H
CI 111111
C F
The title compound was prepared by the reaction of Intermediate 9 (150 mg,
0.433 mmol)
with 2,6-dichlorobenzoyl chloride (0.09 mL, 0.606 mmol) in the presence of
sodium hydride
(60% w/w, 23 mg, 0.5630 mmol) in DNIF (4 mL) followed by the hydrolysis of the
corresponding ester derivative (170 mg, 0.327 mmol) by using TFA (2 mL) in DCM
(4 mL)
as per the process described in Example 1 to yield 50 mg of the product as off
white solid. 1E1
NMR (300 MHz, DMSO-d6) 6 7.31-7.37 (m, 2H), 7.55-7.64 (m, 3H), 7.89-7.93 (m,
3H), 8.15
(d, J = 7.8 Hz, 1H), 13.61 (br s, 1H); APCI-MS (m/z) 463 (M+H)+.
Example 21
4- { 3 [2-Chl oro-6-(di fluoromethyl)b enzoyl] -7-fluoro-2-ox o-2,3 -di hydro-
1H-b enzo
[d]imidazol-1-y1 -3 -fluorob enzoic acid
F2HC o F C 02H
N N 111111
PCIF
The title compound was prepared by the reaction of Intermediate 9 (200 mg,
0.578 mmol)
with 2-chloro-6-(difluoromethyl)benzoyl chloride (143 mg, 0.635 mmol) in the
presence of
sodium hydride (60% w/w, 18 mg, 0.7514 mmol) in DNIF (5 mL) followed by the
hydrolysis
of the corresponding ester derivative (180 mg, 0.337 mmol) by using TFA (2 mL)
in DCM (4
mL) as per the process described in Example 1 to yield 78 mg of the product as
white solid.
1-H NMR (300 MHz, CDC13) 6 6.77 (dt, J= 10.2 Hz, J = 55.8 Hz, 1H), 7.07 (t, J
= 10.2 Hz,
1H), 7.28 (br s, 1H), 7.53-7.63 (m, 4H), 7.96 (t, J= 9.6 Hz, 2H), 8.23 (t, J=
7.8 Hz, 1H);
APCI-MS (m/z) 479 (M+H)+.
Example 22
4- { 3 [2-Chl oro-6-(trifluorom ethyl)b enz oyl] -7-fluoro-2-oxo-2,3 -dihydro-
1H-
b enzo[d]imidazol-1-y1} -3 -fluorob enzoic acid
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F
F3C NAN 00 =-= C 2H
11111
PCIF
The title compound was prepared by the reaction of Intermediate 9 (200 mg,
0.577 mmol)
with 2-chloro-6-(trifluoromethyl)benzoyl chloride (0.13 mL, 0.808 mmol) in the
presence of
sodium hydride (60% w/w, 30 mg, 0.7507 mmol) in DMF (5 mL) followed by the
hydrolysis
of the corresponding ester derivative (300 mg, 0.542 mmol) by using TFA (3 mL)
in DCM (6
mL) as per the process described in Example 1 to yield 150 mg of the product
as white solid.
111 NMR (300 MHz, CDC13) 6 7.08 (d, J = 9.3 Hz, 1H), 7.29 (br s, 2H), 7.51-
7.57 (m, 2H),
7.60 (br s, 2H), 7.97 (t, J = 9.3 Hz, 2H), 8.28 (d, J = 8.1 Hz, 1H); APCI-MS
(m/z) 497
(M+H)+.
Example 23
443 -(2-Chl oro-6-cycl opropylb enzoy1)-7-fluoro-2-oxo-2,3 -dihydro-IH-b
enzo[d]imi dazol-1-
yl] -3 -fluorob enz oi c acid
o 0 F CO2H
NAN WI/
PCF
Step 1: tert-Butyl 443 -(2-Chl oro-6-cycl opropylb enzoy1)-7-fluoro-2-oxo-2,3 -
dihydro- 1H-
benzo[d]imidazol-1-yl] -3 -fluorobenzoate :
To a stirred and cooled (0 C) solution of Intermediate 9 (183 mg, 0.528 mmol)
in DMF (3
mL) was added sodium hydride (60% w/w, 28 mg, 0.686 mmol) and the reaction
mixture was
stirred for 10 minutes at the same temperature. A cooled solution of 2-chloro-
6-
cyclopropylbenzoyl chloride (183 mg, 0.851 mmol) and DIPEA (0.46 mL, 2.642
mmol) in
THF (3 mL) was added to the reaction mixture and it was stirred at RT for 2 h.
The reaction
mixture was diluted with water (10 mL) and product was extracted with ethyl
acetate (2 x 10
mL). The layers were separated. The combined organic layers were washed with
water (2 x 15
mL), brine (20 ml) and dried over anhydrous Na2504. The solvent was recovered
under
reduced pressure. The residue was purified by column chromatography to afford
173 mg of
the title product as white solid. 111 NMR (300 MHz, CDC13) 6 0.83-0.90 (m,
4H), 1.59 (s,
9H), 1.89 (br s, 1H), 6.95-7.08 (m, 2H), 7.28 (br s, 4H), 7.48-7.56 (m, 1H),
7.83 (t, J= 12.3
Hz, 2H), 8.28 (d, J = 9.0 Hz, 1H).
Step 2: 4- [3 -(2-C hl oro-6-cycl opropylb enzoy1)-7-fl uoro-2-ox o-2,3 -di
hydro- IH-
benzo[d]imidazol-1-yl] -3 -fluorobenzoi c acid:
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To a well stirred and cooled (0 C) solution of Step 1 intermediate (168 mg,
0.3200 mmol) in
dichloromethane (4 mL) was added trifluoroacetic acid (2 mL) and the reaction
mixture was
stirred at RT for 3h. The solvents were recovered under reduced pressure and
the residue
obtained was washed with water, triturated with diethyl ether and dried to
yield 54 mg of the
title product as white solid. 111 NMR (300 MHz, CDC13) 6 0.64-0.73 (m, 1H),
0.81-0.97 (m,
3H), 1.84-1.93 (m, 1H), 6.97 (d, J= 6.6 Hz, 1H), 7.06 (t, J= 9.3 Hz, 1H), 7.29-
7.34 (m, 4H),
7.54-7.64 (m, 1H), 7.92-7.99 (m, 2H), 8.29 (d, J= 7.8 Hz, 1H); APCI-MS (m/z)
469 (M+H)+.
Example 24
4[5-Cyano-3 -(2,6-di chl orob enzoy1)-2-oxo-2,3 -dihydro-1H-b enzo[d]imi dazol
-1-yl] -3 -
fluorobenzoic acid
0 0 F
CI c o2H
NAN 11111/
# CIO
NC
The title compound was prepared by the reaction of Intermediate 10 (168 mg,
0.475 mmol)
with 2,6-dichlorobenzoyl chloride (0.08 mL, 0.570 mmol) in the presence of
sodium hydride
(60% w/w, 28 mg, 0.712 mmol) in DNIF (5 mL) followed by the hydrolysis of the
corresponding ester derivative (202 mg, 0.384 mmol) by using TFA (2 mL) in DCM
(6 mL)
as per the process described in Example 1 to yield 112 mg of the product as
off white solid.
111 NMR (300 MHz, DMSO-d6) 6 7.25 (d, J= 8.4 Hz, 1H), 7.62 (br s, 2H), 7.84-
7.89 (m, 3H),
7.96 (d, J= 8.4 Hz, 2H), 8.60 (br s, 1H), 13.66 (br s, 1H); ESI-MS (m/z) 467
(M-H)+.
Example 25
4-[3 -(2,6-Di chl orob enzoy1)-5 -(dim ethyl amino)-2-oxo-2,3 -di hydro-1H-b
enz o [d] imidazol-1-
y1]-3-fluorobenzoic acid
ci
o 0 4, co2H
NAN
10 CIO
(H3C)2N
The title compound was prepared by the reaction of Intermediate 11(100 mg,
0.269 mmol)
and 2,6-dichlorobenzoyl chloride (0.05 mL, 0.323 mmol) in the presence of
sodium hydride
(60% w/w, 16 mg, 0.403 mmol) in DNIF (5 mL) followed by the hydrolysis of the
corresponding ester derivative (130 mg, 0.239 mmol) by using TFA (1 mL) in DCM
(4 mL)
as per the process described in Example 1 to yield 80 mg of the product as off
white solid. 1E1
NMR (300 MHz, DMSO-d6) 6 2.95 (br s, 6H), 6.72 (d, J= 8.7 Hz, 1H), 6.87 (d, J=
9.0 Hz,
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1H), 7.50-7.60 (m, 3H), 7.37 (s, 1H), 7.79 (d, J= 7.2 Hz, 1H), 7.92 (d, J= 8.7
Hz, 2H), 13.58
(br s, 1H); APCI-MS (m/z) 488 (M+H)+.
Example 26
4- [5 -(Cycl obutyl-m ethyl-amino)-3 -(2, 6-di chl oro-b enzoy1)-2-ox o-2,3 -
di hydro-b enz oimi dazol-
1-y1]-benzoic acid
0 0 =c o2H
CI
NAN
cic)\-1
,N
C H3
The title compound was prepared by the reaction of Intermediate 12 (130 mg,
0.331 mmol)
and 2,6-dichlorobenzoyl chloride (0.06 mL, 0.397 mmol) in the presence of
sodium hydride
(60% w/w, 19 mg, 0.496 mmol) in DMF (5 mL) followed by the the hydrolysis of
the ester
derivative (143 mg, 0.253 mmol) by using TFA (1.5 mL) in DCM (4.5 mL) as per
the process
described in Example 1 to yield 70 mg of the product as off white solid. 1-H
NMR (300 MHz,
CDC13) 6 1.75-1.79 (m, 2H), 1.89-2.48 (m, 5H), 2.94 (br s, 3H), 4.00-4.01 (m,
1H), 6.74 (br s,
1H), 7.07 (br s, 1H), 7.38 (d, J= 4.8 Hz, 3H), 7.63 (d, J= 8.7 Hz, 2H), 8.04-
8.10 (m, 1H),
8.23 (d, J= 8.1 Hz, 2H); APCI-MS (m/z) 510 (M+H)+.
Example 27
4- { 3 -(2,6-Di chl orob enz oy1)-5 -[(dim ethyl amino)m ethyl] -2-ox o-2,3 -
di hydro-1H-
benzo[d]imidazol-1-ylIbenzoic acid
0 * c o2H
ci
NN
C1,11
(H3C)2N
The title compound was prepared by the reaction of Intermediate 13 (230 mg,
0.626 mmol)
with 2,6-dichlorobenzoyl chloride (0.11 mL, 0.751 mmol) in the presence of
sodium hydride
(60% w/w, 38 mg, 0.939 mmol) in DNIF (5 mL) followed by the hydrolysis of the
corresponding ester derivative (80 mg, 0.148 mmol) by using TFA (1 mL) in DCM
(4 mL) as
per the process described in Example 1 to yield 60 mg of the product as off
white solid. 1E1
NMR (300 MHz, DMSO-d6) 6 2.76 (s, 6H), 4.43 (s, 2H), 7.30 (d, J = 8.7 Hz, 1H),
7.51 (d, J =
8.4 Hz, 1H), 7.56-7.64 (m, 2H), 7.68 (d, J= 8.7 Hz, 2H), 8.12 (d, J= 9.0 Hz,
2H), 8.54 (s,
1H), 9.95 (br s, 1H), 13.57 (br s, 1H); APCI-MS (m/z) 484 (M+H)+.
Example 28
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4-[3 -(2,6-Di chl orob enzoy1)-5 -(hydroxym ethyl)-2-oxo-2,3 -di hydro-1H-b
enz o [d] imi dazol-1-
yl]b enzoic acid
ci a0 * c o2H
NAN
HO
The title compound was prepared by the reaction of Intermediate 14 (150 mg,
0.353 mmol)
5 with 2,6-dichlorobenzoyl chloride (0.06 mL, 0.424 mmol) in the presence
of sodium hydride
(60% w/w, 18 mg, 0.455 mmol) in DNIF (5 mL) followed by the hydrolysis of the
corresponding ester derivative (100 mg, 0.167 mmol) by using TFA (1 mL) in DCM
(4 mL)
as per the process described in Example 1 to yield 25 mg of the product as
white solid. 1E1
NMR (300 MHz, DMSO-d6) 6 5.56 (s, 2H), 7.25 (br s, 1H), 7.52-7.60 (m, 4H),
7.69 (d, J=
10 7.8 Hz, 2H), 8.11 (d, J = 9.0 Hz, 2H), 8.45 (br s, 1H), 13.25 (br s,
1H); APCI-MS (m/z) 455
(M+H)+.
Example 29
4- { 3 [2-Chl oro-6-(trifluorom ethyl)b enz oyl] -(hydroxym ethyl)-2-ox 0-2,3 -
dihydro-1H-
b enzo[d]imidazol-1-y1} -fluorob enzoic acid
* CO2H
F3C a
NAN
C .1*
HO
The title compound was prepared by the reaction of Intermediate 15 (420 mg,
0.949 mmol)
with 2-chloro-6-(trifluoromethyl)benzoyl chloride (0.17 mL, 1.04 mmol) in the
presence of
sodium hydride (60% w/w, 56 mg, 1.421 mmol) in DMF (10 mL) followed by the
hydrolysis
and deprotection of the corresponding ester derivative (600 mg, 0.925 mmol) by
using TFA (6
mL) in DCM (15 mL) as per the process described in Example 1 to yield 120 mg
of the
product as white solid. 111 NMR (300 MHz, DMSO-d6) 6 4.60 (s, 2H), 5.40 (br s,
1H), 6.99
(d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.74-7.83 (m, 2H), 7.85-7.95
(m, 4H), 8.28 (s,
1H), 13.61 (br s, 1H); APCI-MS (m/z) 509 (M+H)+.
Example 30
4- [3 -(2-C hl oro-6-trifluorom ethyl -b enzoy1)-5 -(2-hydroxy-1,1-dim ethyl -
ethyl)-2 -oxo-2,3 -
dihydro-b enzoimi dazol-1-y1]-3 -fluoro-b enzoi c acid
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0
F3C
NAN C 02H
CI
HO
C H3
H3C
Step 1: tert-Butyl 4- [3 -(2-chl oro-6-tri fluorom ethyl-b enz oy1)-5 -(2-m
ethoxy-1, 1-dim ethyl-
ethyl)-2-oxo-2,3 -dihydro-b enzoimi daz ol-1-yl] -3 -fluorob enzoate
The title compound was prepared by the reaction of Intermediate 16 (321 mg,
0.774 mmol)
with 2-chloro-6-(trifluoromethyl)benzoyl chloride (0.15 mL, 0.929 mmol) in the
presence of
sodium hydride (60% w/w, 46.5 mg, 1.160 mmol) in DIVIF (10 mL) as per the
process
described in step 1 of Example 1
to yield 573
mg of the product as white solid. 1E1 NMIR (300 MHz, DMSO-d6) 6 1.32 (s, 6H),
1.56 (s, 9H),
3.24 (s, 3H), 3.42 (s, 2H), 6.97 (d, J = 8.4 Hz, 1H), 7.41 (d, J= 8.4 Hz, 1H),
7.73-8.05 (m,
6H), 8.28 (s, 1H); APCI-MS (m/z) 622 (M+H)+.
Step 2: 4- 3 -(2-C hl oro-6-trifluorom ethyl-b enzoy1)-5-(2-hydroxy-1, 1-dim
ethyl-ethyl)-2-ox o-
2,3 -di hydro-b enz oimi daz ol-1-y1I-3 -fluoro-b enzoi c acid
To a cooled (-78 C) solution of step 1 intermediate (72 mg, 0.116 mmol) in
DCM (5 mL)
was slowly added a solution of boron tribromide (1M in DCM, 1.2 mL) in DCM (5
mL). The
reaction mixture was allowed to warm up to RT and it was stirred for 1 hour at
RT. The
reaction mixture was poured into crushed ice and extracted with ethyl acetate
(2 x 10 mL).
The combined organic extracts were washed with brine (20 mL), dried over
anhydrous
sodium sulfate and concentrated under reduced pressure. The residue thus
obtained was
purified by silica gel column chromatography to yield 23 mg of the title
product as yellow
solid.lEINIVIR (300 MHz, DMSO-d6) 6 1.50 (s, 6H), 3.47 (s, 2H), 4.79 (br s,
1H), 6.97 (d, J=
8.4 Hz, 1H), 7.40 (d, J= 8.4 Hz, 1H), 7.74-7.79 (m, 2H), 7.89-7.96 (m, 4H),
8.31 (s, 1H);
AP C I-M S (m/z) 550 (M)+.
Example 31
4- [3 -(2-C hl oro-6-trifluorom ethyl -b enzoy1)-5 -(2-m ethoxy-1, 1-dim ethyl
-ethyl)-2-ox o-2,3-
dihydro-benzoimidazol-1-y1]-3-fluoro-benzoic acid
F3C 0 co2H
=NAN
CI
H3C"
L, n3
H3C
The title compound was prepared by the ester hydrolysis of tert-butyl 4-[3-(2-
chloro-6-
trifluorom ethyl-b enzoy1)-5-(2-m ethoxy-1,1-dim ethyl-ethyl)-2-ox o-2,3 -di
hydro-
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benzoimidazol-1-y1]-3-fluorobenzoate (80 mg, 0.129 mmol) (Step 1 product of
Example 30)
by using TFA (1.0 mL) in DCM (3 mL) as per the process described in step 2 of
Example 1 to
yield 65 mg of the product as off white solid. 1H NIVIR (300 MHz, DMSO-d6) 6
1.32 (s, 6H),
3.23 (s, 3H), 3.34 (s, 2H), 6.98 (d, J = 8.1 Hz, 1H), 7.42 (d, J= 7.8 Hz, 1H),
7.76-7.79 (m,
2H), 7.83-7.95 (m, 4H), 8.28 (s, 1H), 13.60 (br s, 1H); APCI-MS (m/z) 562
(M+H)+.
Example 32
4- [3 -(2-C hl oro-6-tri fluorom ethyl -b enzoy1)-5 -(3 -m ethyl-oxetan-3 -ylm
ethoxy)-2-oxo-2,3 -
dihydro-b enzoimi dazol-1-yl] -3 -fluoro-b enzoi c acid
F3C 0 * co2H
=NAN
CI
0
H3C
0
The title compound was prepared by the reaction of Intermediate 17 (203 mg,
0.474 mmol)
and 2-chloro-6-(trifluoromethyl)benzoyl chloride (161 mg, 0.663 mmol) in the
presence of
sodium hydride (60% w/w, 25 mg, 0.616 mmol) in DMF (5 mL) followed by the
hydrolysis
of the corresponding ester derivative (211 mg, 0.332 mmol) by using TFA (2.0
mL) in DCM
(5 mL) as per the process described in step 1 and 2 of Example 1 respectively
to yield 63 mg
of the product as off white solid. 1H NMIR (300 MHz, CDC13) 6 1.48 (s, 3H),
4.13 (br s, 5H),
4.53 (d, J = 5.7 Hz, 2H), 4.72 (d, J = 5.7 Hz, 2H), 6.82 (d, J= 9.0 Hz, 1H),
6.92 (d, J= 9.0
Hz, 1H), 7.50-7.68 (m, 4H), 7.99 (t, J = 10.2 Hz, 2H), 8.11 (s, 1H); APCI-MS
(m/z) 579
(M+H)+.
Example 33
443 -(2,6-Di chl orob enzy1)-2-oxo-2,3 -dihydro-1H-b enzo [d] imi dazol-1-yl] -
3 -fluorob enzoi c
acid
0 * co2H
CI
NN
IP 10
The title compound was prepared by the reaction of Intermediate 4 (100 mg,
0.304 mmol)
with 2-(bromomethyl)-1,3-dichlorobenzene (102 mg, 0.426 mmol) in the presence
of sodium
hydride (60% w/w, 16 mg, 0.3959 mmol) in DMF (5 mL) followed by the hydrolysis
of the
corresponding ester derivative (130 mg, 0.205 mmol) by using TFA (1.5 mL) in
DCM (5 mL)
as per the process described in Example 1 to yield 65 mg of the product as
white solid. 1E1
NMR (300 MHz, DMSO-d6) 6 5.38 (br s, 2H), 6.88 (br s, 2H), 7.00-7.06 (m, 2H),
7.42 (t, J=
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7.8 Hz, 1H), 7.55 (d, J= 7.8 Hz, 2H), 7.76 (t, J= 7.8 Hz, 1H), 7.97 (br s,
2H), 13.51 (br s,
1H); APCI-MS (m/z) 431 (M+H)+.
Example 34
4-(2-0xo-3-{ [2-(trifluoromethyl)phenyl] sulfony1{-2,3-dihydro-1H-benzo[d] imi
dazol-1-
yl)benzoic acid
* cO2H
F3c 0%to N N
* (-5
The title compound was prepared by the reaction of Intermediate 1 (150 mg,
0.483 mmol)
with 2-(trifluoromethyl)benzenesulfonyl chloride (0.12 mL, 0.725 mmol) in the
presence of
sodium hydride (60% w/w, 27 mg, 0.6766 mmol) in DNIF (5 mL) followed by the
hydrolysis
of the corresponding ester derivative (170 mg, 0.327 mmol) by using TFA (3 mL)
in DCM (3
mL) as per the process described in Example 1 to yield 95 mg of the product as
off white
solid. NMR (300 MHz, DMSO-d6) 6 7.14 (d, J= 7.5 Hz, 1H), 7.27-7.31 (m,
2H), 7.65 (d,
J= 8.1 Hz, 2H), 7.82 (d, J= 7.2 Hz, 1H), 8.04-8.11 (m, 5H), 8.50 (br s, 1H),
13.14 (br s, 1H);
APCI-MS (m/z) 463 (M+H)+.
Example 35
Ethyl 4-[3 -(2,6-di chl orob enzoy1)-2-ox o-2,3 -di hydro-1H-b enz o [d]imi
dazol -1-yl]b enz oate
ci0 _ _2 _ 2 _ 3
* CO CH CH
NAN
ci0
The title compound was prepared by the reaction of Intermediate 18 (90 mg,
0.318 mmol)
with 2,6-dichlorobenzoyl chloride (0.06 mL, 0.446 mmol) in the presence of
sodium hydride
(60% w/w, 17 mg, 0.414 mmol) in DMF (5 mL) as per the process described in
Step 1 of
Example 1 to yield 22 mg of the product as white solid. 111 NMR (300 MHz, DMSO-
d6) 6
1.40 (t, J= 6.9 Hz, 3H), 4.40 (q, J= 6.9 Hz, 2H), 7.13 (br s, 1H), 7.31-7.38
(m, 5H), 7.59 (d, J
= 8.4 Hz, 2H), 8.18 (d, J= 8.4 Hz, 2H), 8.44 (br s, 1H); APCI-MS (m/z) 455
(M+H)+.
Example 36
tert-Butyl 4-[3 -(2, 6-di chl orob enzoy1)-2-oxo-2,3 -dihydro-1H-b
enzo[d]imidazol-1-yl]benzoate
ci0 _ -2-,- 3,3
* no nrcH
NAN
IP CIO
The title compound was prepared by the reaction of Intermediate 1 (80 mg,
0.251 mmol) with
2,6-dichlorobenzoyl chloride (0.05 mL, 0.309 mmol) in the presence of sodium
hydride (60%
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w/w, 14 mg, 0.335 mmol) in DMF (5 mL) as per the process described in step 1
of Example 1
to yield 55 mg of the product as white solid. 1E1 NMR (300 MHz, DMSO-d6) 6
1.55 (br s,
9H), 7.18 (br s, 1H), 7.36 (br s, 2H), 7.54-7.61 (m, 3H), 7.68 (d, J= 7.8 Hz,
2H), 8.06 (d, J =
8.1 Hz, 2H), 8.28 (br s, 1H); APCI-MS (m/z) 483 (M+H)+.
Example 37
443 -(2,6-Di chl orob enzoy1)-2-oxo-2,3 -dihydro-1H-b enzo[d]imidazol -1-y1 ]b
enzamide
0 0 =
a NN
* coNH2
*CIO
To a well stirred solution of Example 1 (80 mg, 0.187 mmol) in DMSO (3 mL)
were added
BOP (124 mg, 0.281 mmol) and ammonium chloride (100 mg, 1.877 mmol) followed
by
DIPEA (0.01 mL, 0.563 mmol) and the reaction mixture was stirred at RT
overnight. The
reaction mixture was diluted with water (10 mL) and the precipitate thus
obtained was
filtered. The obtained product was purified by silica gel column
chromatography to yield 20
mg of the title product as white solid. 111 NMR (300 MHz, DMSO-d6) 6 7.15 (br
s, 1H), 7.36
(br s, 2H), 7.50-7.56 (m, 2H), 7.59-7.65 (m, 2H), 8.05 (d, J = 8.4 Hz, 2H),
8.12 (br s, 1H),
8.28 (br s, 1H); APCI-MS (m/z) 426 (M+H)+.
Example 38
N-Cyclopropy1-443-(2,6-dichlorobenzoy1)-2-oxo-2,3-dihydro-1H-b enzo[d]imidazol-
1-
yl]benzamide
CI 0 0 *
A N
10N N H
CIO
To a well stirred and cooled (0 C) solution of Example 1(100 mg, 0.234 mmol)
in DMF (5
mL) were added EDCI (69 mg, 0.351 mmol) and DMAP (9 mg, 0.070 mmol) and the
reaction
mixture was stirred for 10 minutes. Cyclopropylamine (100 mL, 0.234 mmol) was
added to
the reaction mixture and it was stirred at RT overnight. The reaction mixture
was diluted with
water (10 mL) and the precipitate obtained was filtered and purified by silica
gel column
chromatography to yield 21 mg of the title product as white solid. 111 NMR
(300 MHz,
DMSO-d6) 6 0.58 (br s, 2H), 0.71 (d, J= 5.7 Hz, 2H), 2.85 (br s, 1H), 7.12 (br
s, 1H), 7.36 (br
s, 2H), 7.51-7.61 (m, 5H), 7.99 (d, J= 8.4 Hz, 2H), 8.28 (br s, 1H), 8.60 (br
s, 1H); APCI-MS
(m/z) 466 (M+H)+.
Example 39
443 -(2,6-Di chl orob enzoy1)-2-oxo-2,3 -dihydro-1H-b enzo[d]imidazol -1-y1 ]b
enzonitril e
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CI0 * CN
NN
* Gib
The title compound was prepared by the reaction of Intermediate 19 (230 mg,
0.978 mmol)
with 2,6-dichlorobenzoyl chloride (0.16 mL, 1.173 mmol) in the presence of
sodium hydride
(60% w/w, 51 mg, 1.270 mmol) in DMF (5 mL) as per the process described in
step 1 of
Example 1 to yield 300 mg of the product as white solid. 111 NMR (300 MHz,
DMSO-d6) 6
7.14 (d, J= 6.3 Hz, 1H). 7.37 (br s, 5H), 7.67 (d, J= 8.4 Hz, 2H), 7.81 (d, J=
8.7 Hz, 2H),
8.47 (d, J= 8.1 Hz, 1H); APCI-MS (m/z) 408 (M)+.
Example 40
1- [4-(2H-T etrazol-5 -yl)phenyl] -3 -(2, 6-di chl orob enz oy1)-1H-b enz o[d]
imi daz ol-2(31/)-one
N-NH
CI 0 *
A NPN
N N
C
To a well stirred solution of Example 39 (168 mg, 0.411 mmol) in DMF (5 mL)
were added
sodium azide (34 mg, 0.534 mmol) and ammonium chloride (28 mg, 0.534 mmol) and
the
reaction mixture was heated at 80 C overnight. The reaction mixture was
diluted with water
(20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic
layers were
washed with water (3 x 25 mL), brine (25 mL) and dried over anhydrous Na2SO4.
The solvent
was distilled off under reduced pressure. The residue obtained was purified by
column
chromatography to afford 60 mg of the title product as white solid. 111 NMR
(300 MHz,
DMSO-d6) 6 7.22 (br s, 1H), 7.37 (br s, 2H), 7.57-7.61 (m, 3H), 7.79 (d, J=
8.4 Hz, 2H), 8.22
(d, J= 7.8 Hz, 2H), 8.29 (br s, 1H); APCI-MS (m/z) 451 (M)+.
Example 41
3-{ 443 -(2,6-Dichlorob enzoy1)-2-oxo-2,3 -dihydro-1H-b enzo[d]imidazol-1-
yl]pheny1}-1,2,4-
oxadiazol-5(41/)-one
N-0
CI 0 0 40
A N
NN
* Clo
Step 1: 4- { 3 -[(2,6-Di chl orophenyl)carb ony1]-2-oxo-2,3 -dihydro-1H-b
enzimi dazol-1-y11-N-
hydroxy benzenecarboximidamide:
To a well stirred solution of Example 39 (100 mg, 0.244 mmol) in dry DMSO (3
mL) was
added hydroxylamine hydrochloride (63 mg, 0.906 mmol) followed by DIPEA (0.15
mL,
0.906 mmol) and the reaction mixture was heated at 80 C overnight. The
reaction mixture
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was diluted with water and the precipitate thus obtained was filtered and
dried to obtain 65
mg of the title product as white solid. APCI-MS (m/z) 441 (M)+.
Step 2: 3-{ 443 -(2,6-Dichlorob enzoy1)-2-oxo-2,3 -dihydro-1H-b
enzo[d]imidazol -1-yl]pheny1}-
1,2,4-oxadiazol-5(41/)-one: To the well stirred solution of Step 1
intermediate (65 mg, 0.147
mmol) in dry DNIF (2 mL) was added CDI (36 mg, 0.220 mmol) and the reaction
mixture was
heated at 80 C overnight. The reaction mixture was diluted with water (25 mL)
and product
was extracted in ethyl acetate (2 x 100 mL). The combined organic layers were
washed with
water (2 x 50 mL), brine (50 mL) and dried over anhydrous Na2504. The solvent
was
recovered under reduced pressure. The residue obtained was purified by column
chromatography to afford 30 mg of the title product as off-white solid. 1-H
NMR (300 MHz,
DMSO-d6) 6 7.14 (br s, 1H), 7.36 (br s, 5H), 7.70 (br s, 2H), 7.99 (br s, 2H),
8.47 (d, J = 6.3
Hz, 1H), 11.67 (br s, 1H); APCI-MS (m/z) 467 (M)+.
Example 42
N-Cyclopropy1-443-(2,6-dichlorobenzoy1)-2-oxo-2,3-dihydro-1H-b enzo[d]
imidazol-1-
yl]benzenesulfonamide
0
ci NAN 0, so2s,
*00
The title compound was prepared by the reaction of Intermediate 20 (80 mg,
0.242 mmol)
with 2,6-dichlorobenzoyl chloride (0.05 mL, 0.364 mmol) in the presence of
sodium hydride
(60% w/w, 20 mg, 0.532 mmol) in DMF (5 mL) as per the process described in
step 1 of
Example 1 to yield 10 mg of the product as white solid. 1-H NMR (300 MHz, DMSO-
d6) 6
0.81 (br s, 4H), 2.95 (br s, 1H), 7.22 (br s, 1H), 7.38 (br s, 2H), 7.56-7.62
(m, 5H), 7.88 (d, J =
8.4 Hz, 2H), 8.22 (br s, 1H), 8.30 (br s, 1H); APCI-MS (m/z) 503 (M+H)+.
Example 43
Diethyl { 443 -(2,6-di chl orob enzoy1)-2-oxo-2,3 -dihydro-1H-b
enzo[d]imidazol-1-
yl]phenylIphosphonate
ci a0 * 0(_ .2- P ionH cH3, )2
10
NAN .
The title compound was prepared by the reaction of Intermediate 21(300 mg,
0.866 mmol)
with 2,6-dichlorobenzoyl chloride (0.15 mL, 1.039 mmol) in the presence of
sodium hydride
(60% w/w, 52 mg, 1.299 mmol) in DMF (10 mL) as per the process described in
Step 1 of
Example 1 to yield 370 mg of the product as white solid. 1-H NMR (300 MHz,
DMSO-d6) 6
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1.24 (t, J= 6.9 Hz, 6H), 4.01-4.08 (m, 4H), 7.22 (br s, 1H), 7.36 (br s, 2H),
7.54-7.61 (m,
3H), 7.74 (m, 2H), 7.84-7.93 (m, 2H), 8.28 (br s, 1H); APCI-MS (m/z) 519
(M+H)+.
Example 44
443-(2,6-Dichlorobenzoy1)-2-methy1-2,3-dihydro-1H-benzo[d]imidazol-1-yl]
benzoic acid
ci H3c ,
N...1.N CO2H
CI
5
Step 1: Ethyl 4-(3 -(2,6-di chl orob enzoy1)-2-m ethy1-2,3 -di hydro-1H-b enzo
[d] imi dazol-1-
yl)benzoate:
To the stirred solution of Intermediate 22 (150 mg, 0.349 mmol) in DCM (10 mL)
was added
acetaldehyde dimethyl acetal (157 mg, 1.74 mmol) followed by catalytic amount
of PTSA
10 (6.6 mg, 0.035 mmol) and the reaction mixture was stirred at RT for 15
hours. The solvent
was recovered under reduced pressure and the residue thus obtained was
purified by silica gel
column chromatography to yield 100 mg of the title product as colourless oil.
111 NMR (300
MHz, CDC13) 6 1.44 (t, J= 6.9 Hz, 3H), 1.73 (d, J= 5.4 Hz, 3H), 4.35 (q, J =
7.2 Hz, 2H),
5.79 (d, J = 8.4 Hz, 1H), 6.55-6.60 (m, 2H), 7.01 (br s, 1H), 7.15 (br s, 1H),
7.29-7.40 (m,
3H), 7.47 (br s, 1H), 8.04 (d, J= 8.1 Hz, 2H).
Step 2: 443-(2,6-Dichlorobenzoy1)-2-methy1-2,3-dihydro-1H-benzo[d]imidazol-1-
yl] benzoic
acid:
To the well stirred solution of Step 1 intermediate (100 mg, 0.219 mmol) in a
mixture of THF
(2 mL), methanol (2 mL) and water (1 mL) was added lithium hydroxide (27 mg,
0.658
mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture
was diluted
with water (20 mL) and acidified by using 1N HC1. The product was extracted
with ethyl
acetate (2 x 20 ml) and the layers were separated. The combined organic layers
were washed
with water (2 x 20 mL), brine (20 mL) and dried over anhydrous Na2504. The
solvent was
removed under reduced pressure. The residue thus obtained was purified by
column
chromatography to afford 60 mg of the title product as off-white solid. 111
NMR (300 MHz,
DMSO-d6) 6 1.61 (d, J= 5.4 Hz, 3H), 5.67 (d, J= 7.8 Hz, 1H), 6.51 (br s, 1H),
6.67 (t, J= 7.8
Hz, 1H), 7.05 (t, J= 7.8 Hz, 1H), 7.32-7.39 (m, 2H), 7.47 (d, J= 8.1 Hz, 2H),
7.63 (br s, 1H),
7.88 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H), 12.71 (br s, 1H); APCI-MS
(m/z) 427
(M+H)+.
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Pharmacological Activity
Biological Assay
The illustrative examples of the present patent application were screened for
ROR gamma
modulator activity using the TR-FRET assay by Lantha Screen as described in
JBC 2011,
286, 26: 22707-10; Drug Metabolism and Disposition 2009, 37, 10: 2069-78.
TR-FRET assay for ROR gamma:
The assay is based on the principle that binding of the agonist to the ROR
gamma
causes a conformational change around helix 12 in the ligand binding domain,
resulting in
higher affinity for the co-activator peptide. ROR gamma being constitutively
active, the
Fluorescein-D22 co-activator peptide used in the assay is recruited in the
absence of a ligand.
Binding of the co-activator peptide, causes an increase in the TR-FRET signal
while binding
of an antagonist decreases the recruitment of the co-activator peptide,
causing a decrease in
the TR-FRET signal compared to control with no compound. The assay was
performed using
a two-step procedure, pre-incubation step with the compound followed by the
detection step
on addition of the anti-GST tagged terbium (Tb) and fluorescein tagged
fluorophores as the
acceptor.
Test compounds or reference compounds such as T0901317 (Calbiochem) were
dissolved in dimethylsulfoxide (DMSO) to prepare 10.0 mM stock solution and
diluted
suitably to get the desired concentration. Final concentration of DMSO in the
reaction was 4%
(v/v). Assay mixture was prepared by mixing 1 OnM of the GST-tagged ROR gamma
ligand
binding domain (LBD) in the assay buffer containing 25 mM HEPES, 100 mM NaC1,
5mM
DTT and 0.01% BSA with or without the desired concentration of the compound.
The
reaction was incubated at 22 C for lhr. The pre-incubation step was terminated
by addition of
the detection mixture containing 300nM Fluorescein-D22 co-activator peptide
and 1 OnM
lantha screen Tb-anti GST antibody into the reaction mixture. After shaking
for 5 minutes the
reaction was further incubated for 2 hr at room temperature and read the next
day at 4 C on an
Infinite F500 reader as per the kit instructions (Invitrogen). The inhibition
of test compound is
calculated based on the TR-FRET ratio of 520/495. The activity was calculated
as a percent of
control reaction. IC50 values were calculated from dose response curve by
nonlinear
regression analysis using GraphPad Prism software.
The compounds prepared were tested using the above assay procedure and the
results
obtained are given in Table 1. Percentage inhibition at concentrations of 1.0
tM and 10.0 tM
are given in the table along with IC50 (nM) details for selected examples. The
compounds
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prepared were tested using the above assay procedure and were found to have
IC50 less than
500nM, preferably less than 100nM or more preferably less than 50nM.
The IC50 (nM) values of the compounds are set forth in Table 1 wherein "A"
refers to
an IC50 value of less than 50 nM, "B" refers to IC50 value in range of 50.01
to 100.0 nM and
"C" refers to IC50 values more than 100 nM.
Table 1: In-vitro screening results of compounds of present invention
Sr No. % inhibition at IC50 Value
Example
1 uM 10 uM (nM)
1. Example 1 93.39 97.7
A
2. Example 2 91.13 97.79
A
3. Example 3 4.85 62.19
-
4. Example 4 86.37 93.44
C
5. Example 5 96.13 98.11
A
6. Example 6 93.7 96.41
A
7. Example 7 95.93 99.23
A
8. Example 8 87.41 96.63
A
9. Example 9 99.3 100.0
A
10. Example 10 100.00
100.00 A
11. Example 11 99.26 -
A
12. Example 12 78.78 93.78
C
13. Example 13 98.88 99.56
A
14. Example 14 76.38 94.45
C
15. Example 15 94.64 94.80
A
16. Example 16 48.56 80.75
-
17. Example 17 68.77 93.48
-
18. Example 18 84.39 96.37
A
19. Example 19 81.2 95.61
C
20. Example 20 97.25 98.52
A
21. Example 21 98.36 100
A
22. Example 22 98.31 99.39
A
23. Example 23 96.59 96.99
A
24. Example 24 40.88 80.30
-
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25. Example 25 59.36
92.25 -
26. Example 26 51.54
84.10 -
27. Example 27 17.03
16.01 -
28. Example 28 87.04
92.52 A
29. Example 29 97.85 100.0 A
30. Example 30 0 1.8 -
31. Example 31 36.01
38.47 -
32. Example 32 8.4 32.4
-
33. Example 33 19.57
71.88 -
34. Example 34 74.22
91.6 C
35. Example 35 0.00 8.52
-
36. Example 36 11.02
10.42 -
37. Example 37 0.57
12.64 -
38. Example 38 0.00 8.93 -
39. Example 39 0.08 6.02
-
40. Example 40 12.28
72.73 -
41. Example 41 3.60
52.19 -
42. Example 42 18.89
14.9 -
43. Example 43 0.0 17.70 -
44. Example 44 69.03 91.48 C
(-): Not determined
