NZ721993B2 - Bicyclic heterocyclic derivatives as bromodomain inhibitors - Google Patents
Bicyclic heterocyclic derivatives as bromodomain inhibitors Download PDFInfo
- Publication number
- NZ721993B2 NZ721993B2 NZ721993A NZ72199315A NZ721993B2 NZ 721993 B2 NZ721993 B2 NZ 721993B2 NZ 721993 A NZ721993 A NZ 721993A NZ 72199315 A NZ72199315 A NZ 72199315A NZ 721993 B2 NZ721993 B2 NZ 721993B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- dimethylisoxazolyl
- methoxy
- quinolin
- benzo
- pyridinylmethyl
- Prior art date
Links
- 102000001805 Bromodomains Human genes 0.000 title claims abstract description 48
- 108050009021 Bromodomains Proteins 0.000 title claims abstract description 45
- 239000003112 inhibitor Substances 0.000 title abstract description 30
- 230000002401 inhibitory effect Effects 0.000 title abstract description 30
- 125000002618 bicyclic heterocycle group Chemical group 0.000 title abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 183
- 201000010099 disease Diseases 0.000 claims abstract description 52
- 239000011780 sodium chloride Substances 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 239000003937 drug carrier Substances 0.000 claims abstract description 5
- -1 4-(4-chlorobenzyl)(3,5-dimethylisoxazolyl)methoxy-3,4-dihydro-2H- benzo[b][1,4]oxazine Chemical compound 0.000 claims description 373
- 125000000217 alkyl group Chemical group 0.000 claims description 68
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 62
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2(1H)-one Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 53
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- 125000001188 haloalkyl group Chemical group 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 125000005842 heteroatoms Chemical group 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 25
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 125000002950 monocyclic group Chemical group 0.000 claims description 14
- 125000006513 pyridinyl methyl group Chemical group 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000002619 bicyclic group Chemical group 0.000 claims description 10
- 229910020008 S(O) Inorganic materials 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 9
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 7
- 150000002367 halogens Chemical group 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
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- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 241001465754 Metazoa Species 0.000 claims description 3
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- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- YZMVLKJJJCMVGX-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline-2,4-dione Chemical compound C1=CC=C2NC(=O)CC(=O)C2=C1 YZMVLKJJJCMVGX-UHFFFAOYSA-N 0.000 claims description 2
- QJMNHQKKCOHTDO-UHFFFAOYSA-N 1,2-dihydroquinoline-2-carbonitrile Chemical compound C1=CC=C2C=CC(C#N)NC2=C1 QJMNHQKKCOHTDO-UHFFFAOYSA-N 0.000 claims description 2
- JODCYFSRILIGHF-UHFFFAOYSA-N 1-pyridin-3-ylpyrrolidin-3-ol Chemical compound C1C(O)CCN1C1=CC=CN=C1 JODCYFSRILIGHF-UHFFFAOYSA-N 0.000 claims description 2
- 125000000586 2-(4-morpholinyl)ethoxy group Chemical group [H]C([H])(O*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 2
- FICAQKBMCKEFDI-UHFFFAOYSA-N 3,5-dimethyl-1,2-oxazole Chemical group CC=1C=C(C)ON=1 FICAQKBMCKEFDI-UHFFFAOYSA-N 0.000 claims description 2
- 125000001137 3-hydroxypropoxy group Chemical group [H]OC([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000005044 dihydroquinolinyl group Chemical group N1(CC=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
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- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention provides bicyclic heterocyclic derivatives of formula (I), which may be therapeutically useful, more particularly as bromodomain inhibitors; (I), in which R1, R2, R3, R4, L1, L2, Cy1, Cy2, X, n and dotted line are have the same meaning given in the specification, and pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof that are useful in the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder associated as bromodomain inhibitors. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of bicyclic heterocyclic derivatives of formula (I), together with a pharmaceutically acceptable carrier, diluent or excipient therefor. ically acceptable salts or pharmaceutically acceptable stereoisomers thereof that are useful in the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder associated as bromodomain inhibitors. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of bicyclic heterocyclic derivatives of formula (I), together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
Description
BICYCLIC HETEROCYCLIC DERIVATIVES AS BROMODOMAIN INHIBITORS
This application claims the benefit of Indian provisional application number
125/CHE/2014 filed on 10 January 2014, which hereby incorporated by reference.
FIELD OF THE INVENTION
The present invention relates to bicyclic heterocyclic derivatives of formula (I) which are
useful as bromodomain inhibitors.
The invention also relates to process for preparation thereof, pharmaceutical
compositions comprising them, and their use for treatment and prevention in diseases or
disorder, in particular their use in treatment of diseases or disorder associated with bromodomain
inhibition.
BACKGROUND OF THE INVENTION
The acetylation of histone lysine is central to providing the dynamic regulation of
chromatin-based gene transcription. The bromodomain (BRD), which is the conserved structural
module in chromatin-associated proteins and histone acetyltranferases, is the sole protein domain
known to recognize acetyl-lysine residues on proteins.
The BET family of bromodomain containing proteins comprises 4 proteins (BRD2,
BRD3, BRD4 and BRD-t) which contain tandem bromodomains capable of binding to two
acetylated lysine residues in close proximity, increasing the specificity of the interaction. BRD2
and BRD3 are reported to associate with histones along actively transcribed genes and may be
involved in facilitating transcriptional elongation (Leroy et al, Mol. Cell. 2008 30(1):51 -60),
while BRD4 appears to be involved in the recruitment of the pTEF-[beta] complex to inducible
genes, resulting in phosphorylation of RNA polymerase and increased transcriptional output
(Hargreaves et al, Cell, 2009 138(1): 129-145). It has also been reported that BRD4 or BRD3
may fuse with NUT (nuclear protein in testis) forming novel fusion oncogenes, BRD4-NUT or
BRD3-NUT, in a highly malignant form of epithelial neoplasia (French et al. Cancer Research,
2003, 63, 304-307 and French et al. Journal of Clinical Oncology, 2004, 22 (20), 4135-4139).
Data suggests that BRD-NUT fusion proteins contribute to carcinogenesis (Oncogene, 2008, 27,
2237-2242). BRD-t is uniquely expressed in the testes and ovary. All family members have been
reported to have some function in controlling or executing aspects of the cell cycle, and have
been shown to remain in complex with chromosomes during cell division suggesting a role in the
maintenance of epigenetic memory. In addition some viruses make use of these proteins to tether
their genomes to the host cell chromatin, as part of the process of viral replication (You et al
Cell, 2004 117(3):349-60).
Japanese patent application JP2008156311 discloses a benzimidazole derivative which is
said to be a BRD2 bromodomain binding agent has utility with respect to virus infection /
proliferation.
International patent application WO2009084693A1 discloses a series of
thienotriazolodiazepiene derivatives that are said to inhibit the binding between an acetylated
histone and a bromodomain containing protein which are said to be useful as anti-cancer agents.
International patent application WO2011054846A1 discloses a series of quinoline
derivatives that inhibit the binding of BET family bromodomains with acetylated lysine residues.
However, there remains a need for potent bromodomain inhibitors with desirable
pharmaceutical properties. It is any object of the present invention to go some way towards
meeting this need, and/or to at least provide the public with a useful choice. Certain bicyclic
heterocyclic derivatives have been found in the context of this invention to have a class of
compounds that inhibit the binding of BET family bromodomains to acetylated lysine residues
for controlling the gene expressions in human health and disease. Such compounds will hereafter
be referred to as "bromodomain inhibitors".
SUMMARY OF THE INVENTION
The present invention relates to bicyclic heterocyclic derivatives of the formula (I) that
inhibit the binding of BET family bromodomains to acetylated lysine residues.
or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof;
wherein,
dotted line[---] represents a single or a double bond;
X is selected from C, C(O), N or O; wherein C and N are substituted with one or more R
to meet the desired valency requirements;
L is a direct bond or a linker selected from -NH-, -NHC(O)- or -NHS(O) -;
L is a linker selected from -(CHR ) -, -C(O)- or -S(O) -;
2 6 n 2
Cy is an optionally substituted 5-6 membered monocyclic ring containing 1-4 hetero
atoms/ hetero groups independently selected form N, NH, O or –C(O)-; wherein the optional
substituent at each occurrence is independently selected from one or more R ;
Cy is an optionally substituted 4-12 membered monocyclic or bicyclic ring containing 0-
3 hetero atoms/groups independently selected form N, NH, O or S; wherein the optional
substituent at each occurrence is independently selected from one or more R ;
R is selected from hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,
aminoalkyl, heterocyclyl or heterocyclylalkyl;
R and R independently are hydrogen, alkyl or together form an oxo group;
R at each occurrence is independently selected from hydrogen, alkyl, cycloalkyl,
cyanoalkyl, hydroxyalkyl, or optionally substituted haloalkyl; wherein the optional substituent is
one or more hydroxyl;
R at each occurrence is independently selected from hydrogen, alkyl, haloalkyl,
cycloalkyl or cyano;
R is hydrogen or alkyl;
R is selected from alkyl, hydroxy or cycloalkyl;
R is selected from alkyl, alkoxy, amino, cyano, halogen, haloalkyl, hydroxy, -C(O)alkyl
or optionally substituted heterocyclyl; wherein the optional substituent is selected from one or
more alkyl or hydroxy; and
n is an integer selected from 1 or 2.
The present invention also relates to pharmaceutical composition comprising bicyclic
heterocyclic derivatives of formula (I) and processes for preparing thereof.
The present invention also relates to use of bicyclic heterocyclic derivatives of formula
(I) for the treatment and prevention in diseases or disorder, in particular their use in diseases or
disorder for which a bromodomain inhibitor is indicated.
The invention relates to use of novel bicyclic heterocyclic derivatives of formula (I) or a
pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof,
including mixtures thereof in all ratios as a medicament for which a bromodomain inhibitor is
indicated.
Accordingly, in a first aspect, the invention provides a compound of formula (I):
(I)
or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof;
wherein,
dotted line[---] represents a single or a double bond;
X is selected from C, C(O), N or O; wherein C and N are substituted with one or more R
to meet the desired valency requirements;
L is a direct bond or a linker selected from -NH-, -NHC(O)- or -NHS(O) -;
L is a linker selected from -(CHR ) -, -C(O)- or -S(O) -;
2 6 n 2
Cy is an optionally substituted 5-6 membered monocyclic ring containing 1-4 hetero
atoms/ hetero groups independently selected form N, NH, O or –C(O)-; wherein the optional
substituent at each occurrence is independently selected from one or more R ;
Cy is an optionally substituted 4-12 membered monocyclic or bicyclic ring containing 0-
3 hetero atoms/groups independently selected from N, NH, O or S; wherein the optional
substituent at each occurrence is independently selected from one or more R ;
R is selected from hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,
aminoalkyl, heterocyclyl or heterocyclylalkyl;
R and R independently are hydrogen, alkyl or together form an oxo group;
R4 at each occurrence is independently selected from hydrogen, alkyl, cycloalkyl,
cyanoalkyl, hydroxyalkyl, or optionally substituted haloalkyl; wherein the optional substituent is
one or more hydroxyl;
R at each occurrence is independently selected from hydrogen, alkyl, haloalkyl,
cycloalkyl or cyano;
R is hydrogen or alkyl;
R is selected from alkyl, hydroxy or cycloalkyl;
R is selected from alkyl, alkoxy, amino, cyano, halogen, haloalkyl, hydroxy, -C(O)alkyl
or optionally substituted heterocyclyl; wherein the optional substituent is selected from one or
more alkyl or hydroxy; and
n is an integer selected from 1 or 2.
In a second aspect, the invention provides a pharmaceutical composition comprising a
therapeutically effective amount of at least one compound of formula (I) according to the first
aspect, or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer
thereof, in admixture with at least one pharmaceutically acceptable carrier or excipient including
mixtures thereof in all ratios.
In a third aspect, the invention provides a pharmaceutical combination comprising a
therapeutically effective amount of at least one compound of formula (I) according to the first
aspect, or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer
thereof, and at least one therapeutically further active ingredient.
In a fourth aspect, the invention provides a compound according to the first aspect, or a
pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof, for use
in therapy.
In a fifth aspect, the invention provides use of a compound according to the first aspect,
in manufacture of a medicament for use in treatment of diseases associated with bromodomain in
animals including humans.
DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the present invention provides bicyclic heterocyclic derivatives of
formula (I) useful as bromodomain inhibitors.
One of the embodiments of the present invention relates to compounds of formula (I):
(I),
or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof;
wherein,
dotted line[---] represents a single or a double bond;
X is selected from C, C(O), N or O; wherein C and N are substituted with one or more R
to meet the desired valency requirements;
L is a direct bond or a linker selected from -NH-, -NHC(O)- or -NHS(O) -;
L is a linker selected from -(CHR ) -, -C(O)- or -S(O) -;
2 6 n 2
Cy is an optionally substituted 5-6 membered monocyclic ring containing 1-4 hetero
atoms/ hetero groups independently selected form N, NH, O or –C(O)-; wherein the optional
substituent at each occurrence is independently selected from one or more R ;
Cy is an optionally substituted 4-12 membered monocyclic or bicyclic ring containing 0-
3 hetero atoms/groups independently selected form N, NH, O or S; wherein the optional
substituent at each occurrence is independently selected from one or more R ;
R is selected from hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,
aminoalkyl, heterocyclyl or heterocyclylalkyl;
R and R independently are hydrogen, alkyl or together form an oxo group;
R at each occurrence is independently selected from hydrogen, alkyl, cycloalkyl,
cyanoalkyl, hydroxyalkyl, or optionally substituted haloalkyl; wherein the optional substituent is
one or more hydroxyl;
R at each occurrence is independently selected from hydrogen, alkyl, haloalkyl,
cycloalkyl or cyano;
R is hydrogen or alkyl;
R is selected from alkyl, hydroxy or cycloalkyl;
R is selected from alkyl, alkoxy, amino, cyano, halogen, haloalkyl, hydroxy, -C(O)alkyl
or optionally substituted heterocyclyl; wherein the optional substituent is selected from one or
more alkyl or hydroxy; and
n is an integer selected from 1 or 2.
The embodiments below are illustrative of the present invention and are not intended to
limit the claims to the specific embodiments exemplified.
According to one embodiment, specifically provided are compounds of the formula (I), in
which X is selected from O, N, C(O), CH , CH, C(R ) or CR .
2 5 2 5
According to above embodiment, R is selected from alkyl, haloalkyl, cycloalkyl or
cyano; in particular alkyl is methyl, haloalkyl is –CF and cycloalkyl is cyclopropyl.
According to other embodiment, specifically provided are compounds of the formula (I),
in which L is a direct bond.
According to yet another embodiment, specifically provided are compounds of the
formula (I), in which L is a linker selected from -NH-, -NHC(O)- or -NHS(O) -.
According to further yet another embodiment, specifically provided are compounds of the
formula (I), in which Cy is selected from optionally substituted 5- or 6- membered monocyclic
ring containing 1-3 hetero atoms/ hetero groups independently selected form N, NH, O or –C(O)-
.
According to preceding embodiment, Cy is selected from the group consisting of
, , , , , , ,
or .
According to further yet another embodiment, specifically provided are compounds of the
formula (I), in which L is selected from -(CHR ) -, -C(O)- or -S(O) -; in which ‘n’ is an integer
2 6 n 2
selected from 1 or 2 and R is selected from hydrogen or alkyl; in particular alkyl is methyl.
According to further yet another embodiment, specifically provided are compounds of the
formula (I), in which Cy is selected from optionally substituted 5- or 6- membered monocyclic
ring or 12 membered bicyclic ring containing 0-3 hetero atoms/groups independently selected
from N, N(H), O or S.
According to preceding embodiment, Cy is selected from the group consisting of
thiazole, pyrazine, tetrahydro-2H-pyran, morpholine, pyrimidine, quinoline, optionally
substituted piperidine, optionally substituted phenyl or optionally substituted pyridyl.
According to preceding embodiments, optional substituents are selected from halogen,
alkoxy, amino, cyano, alkyl, haloalkyl, hydroxy, -C(O)alkyl and heterocyclyl; in particular alkyl
is methyl, halogen is fluoro, chloro or bromo, alkoxy is methoxy, -C(O)alkyl is propanone,
and heterocyclyl is pyrrolidinol, 3,5-dimethyl-1H-pyrazole and 1-methyl-1H-pyrazole.
According to further yet another embodiment, specifically provided are compounds of the
formula (I), in which R is hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or
alkyl substituted aminoalkyl; in particular alkyl is methyl or butyl, alkenyl is propene,
hydroxyalkyl is –(CH ) OH or –(CH ) OH, haloalkyl is –CF or –CH CF , alkoxyalkyl is
2 2 2 3 3 2 3
methoxyethyl, and aminoalkyl is dimethylaminoethyl.
According to further yet another embodiment, specifically provided are compounds of the
formula (I), in which R is heterocyclyl or heterocyclylalkyl; in particular heterocyclyl is
piperidine, and heterocyclylalkyl is morpholinyl-ethyl, piperdinyl-methyl, piperdinyl-ethyl,
piperazinyl-ethyl, pyridyl-methyl, tetrahydropyran-methyl and pyrrolidinyl-ethyl.
According to further yet another embodiment, specifically provided are compounds of the
formula (I), in which R is hydrogen, alkyl, cycloalkyl, cyanoalkyl, hydroxyalkyl or optionally
substituted haloalkyl; in particular alkyl is methyl, cycloalkyl is cyclohexyl, cyanoalkyl is –
CH CN, hydroxyalkyl is –CH OH; and optionally substituted haloalkyl is –CH F, -CH(OH)CF
2 2 2 3
or –C(OH)(OH)CF .
According to yet another embodiment of the present invention, the compound of formula
(I) is a compound of formula (Ia):
(Ia);
wherein,
R , R , R , R , Cy , Cy , L , L and ‘n’ are same as defined in formula (I);
1 2 3 4 1 2 1 2
or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof.
According to yet another embodiment of the present invention, the compound of formula
(I) is a compound of formula (Ib):
(Ib);
wherein,
R , R , R , R , Cy , Cy , L , L and ‘n’ are same as defined in formula (I);
1 2 3 4 1 2 1 2
or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof.
According to yet another embodiment of the present invention, the compound of formula
(I) is a compound of formula (Ic):
(Ic);
wherein,
R , R , R , R , Cy , Cy , L , L and ‘n’ are same as defined in formula (I);
1 2 3 4 1 2 1 2
or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof.
In yet another particular embodiment of the present invention, the compound of formula
(I) is selected from the group consisting of:
Compoun
IUPAC Name
d. No
4-(4-chlorobenzyl)(3,5-dimethylisoxazolyl)methoxy-3,4-dihydro-2H-
benzo[b][1,4]oxazine;
6-(3,5-dimethylisoxazolyl)methoxy((5-methoxypyridin
yl)methyl)quinolin-2(1H)-one;
6-(3,5-dimethyl-4H-1,2,4-triazolyl)methoxy(pyridin
ylmethyl)quinolin-2(1H)-one;
1-(4-chlorobenzyl)(3,5-dimethylisoxazolyl)methoxyquinoxalin-2(1H)-
one;
1-(4-chlorobenzyl)(3,5-dimethylisoxazolyl)methoxy-3,4-
dihydroquinolin-2(1H)-one;
4-(1-(4-chlorophenyl)ethyl)(3,5-dimethylisoxazolyl)methoxy-3,4-
dihydro-2H-benzo[b][1,4]oxazine;
7-(3,5-dimethylisoxazolyl)methoxy(1-(pyridinyl)ethyl)-3,4-dihydro-
2H-benzo[b][1,4]oxazine;
6-(3,5-dimethylisoxazolyl)methoxy(pyrazinylmethyl)quinolin-2(1H)-
one;
6-(3,5-dimethylisoxazolyl)((3-fluoropyridinyl)methyl)
methoxyquinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)-3,4-
dihydroquinolin-2(1H)-one;
4-((3-chlorophenyl)sulfonyl)(3,5-dimethylisoxazolyl)methoxy-3,4-
dihydro-2H-benzo[b][1,4]oxazine;
7-(3,5-dimethylisoxazolyl)methoxy(pyridinylsulfonyl)-3,4-dihydro-
2H-benzo[b][1,4]oxazine;
N-(4-(4-chlorobenzyl)methoxyoxo-3,4-dihydro-2H-benzo[b][1,4]oxazin
yl)-3,5-dimethylisoxazolesulfonamide;
14. 1-((4-chlorophenyl)sulfonyl)(3,5-dimethylisoxazolyl)methoxyquinolin-
2(1H)-one;
1-(4-chlorobenzoyl)(3,5-dimethylisoxazolyl)methoxyquinolin-2(1H)-
one;
2-((7-(3,5-dimethylisoxazolyl)methoxy-2H-benzo[b][1,4]oxazin-4(3H)-
yl)methyl)aniline;
7-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)-2H-
benzo[b][1,4]oxazin-3(4H)-one;
4-(4-chlorobenzyl)(3,5-dimethylisoxazolyl)methoxy-2H-
benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazolyl)methoxy(1-(pyridinyl)ethyl)-2H-
benzo[b][1,4]oxazin-3(4H)-one (Isomer-1);
7-(3,5-dimethylisoxazolyl)methoxy(1-(pyridinyl)ethyl)-2H-
benzo[b][1,4]oxazin-3(4H)-one (Isomer-2);
7-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)-2H-
benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)-2H-
benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazolyl)methoxy((tetrahydro-2H-pyranyl)methyl)-
2H-benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazolyl)methoxy(1-(pyridinyl)ethyl)-2H-
benzo[b][1,4]oxazin-3(4H)-one (Isomer-1);
7-(3,5-dimethylisoxazolyl)methoxy(1-(pyridinyl)ethyl)-2H-
benzo[b][1,4]oxazin-3(4H)-one (Isomer-2);
7-(3,5-dimethylisoxazolyl)methoxy((6-methoxy pyridinyl)methyl)-
2H-benzo[b][1,4]oxazin-3(4H)-one;
6-((7-(3,5-dimethylisoxazolyl)methoxyoxo-2H-benzo[b][1,4]oxazin-
4(3H)-yl)methyl)nicotinonitrile;
4-((5-chloropyridinyl)methyl)(3,5-dimethylisoxazolyl)methoxy-2H-
benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazolyl)((5-fluoropyridinyl)methyl)methoxy-2H-
benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazolyl)methoxy((5-methoxy pyridinyl)methyl)-
2H-benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazolyl)methoxy(1-(pyridinyl)ethyl)-2H-
benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazolyl)methoxy((6-methylpyridinyl)methyl)-2H-
benzo[b][1,4]oxazin-3(4H)-one;
4-(1-(4-chlorophenyl)ethyl)(3,5-dimethylisoxazolyl)methoxy-2H-
benzo[b][1,4]oxazin-3(4H)-one (Isomer-1);
4-(1-(4-chlorophenyl)ethyl)(3,5-dimethylisoxazolyl)methoxy-2H-
benzo[b][1,4]oxazin-3(4H)-one (Isomer-2);
7-(3,5-dimethylisoxazolyl)methoxy(2-(pyridinyl)ethyl)-2H-
benzo[b][1,4]oxazin-3(4H)-one;
6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)quinolin-2(1H)-
one;
1-((5-chloropyridinyl)methyl)(3,5-dimethylisoxazolyl)
methoxyquinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)methoxy(2-morpholinoethyl)quinolin-2(1H)-
one;
6-(3,5-dimethylisoxazolyl)methoxy(thiazolylmethyl)quinolin-2(1H)-
one;
6-(3,5-dimethylisoxazolyl)methoxy(1-(pyridinyl)ethyl)quinolin-
2(1H)-one;
6-(3,5-dimethylisoxazolyl)methoxy(1-(pyridinyl)ethyl)quinolin-
2(1H)-one;
6-(3,5-dimethylisoxazolyl)methoxy(2-(pyridinyl)ethyl)quinolin-
2(1H)-one;
6-(3,5-dimethylisoxazolyl)methoxy(pyrimidinylmethyl)quinolin-
2(1H)-one;
6-(3,5-dimethylisoxazolyl)methoxy(pyrimidinylmethyl)quinolin-
2(1H)-one;
45. 6-(3,5-dimethylisoxazolyl)((5-fluoropyridinyl)methyl)
methoxyquinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)quinolin-2(1H)-
one;
6-(3,5-dimethylisoxazolyl)methoxy((5-(trifluoromethyl)pyridin
yl)methyl)quinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)methoxy-4,4-dimethyl(pyridinylmethyl)-
3,4-dihydroquinolin-2(1H)-one;
7-(3,5-dimethylisoxazolyl)methoxy-2,2-dimethyl(pyridinylmethyl)-
2H-benzo[b][1,4]oxazin-3(4H)-one;
6-(3,5-dimethylisoxazolyl)methoxymethyl(pyridin
ylmethyl)quinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)methoxy-3,3-dimethyl(pyridin
ylmethyl)quinoline-2,4(1H,3H)-dione;
6-(3,5-dimethylisoxazolyl)methoxy-3,3-dimethyl(pyridinylmethyl)-
3,4-dihydroquinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)methoxymethyl(pyridin
ylmethyl)quinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)
(trifluoromethyl)quinolin-2(1H)-one;
4-cyclopropyl(3,5-dimethylisoxazolyl)methoxy(pyridin
ylmethyl)quinolin-2(1H)-one;
56. 1-(4-chlorobenzyl)(3,5-dimethylisoxazolyl)methoxyquinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)methoxy(quinolinylmethyl)quinolin-
2(1H)-one;
1-((5-chloropyridinyl)methyl)(3,5-dimethylisoxazolyl)methoxy
methylquinolin-2(1H)-one;
1-(4-chlorophenethyl)(3,5-dimethylisoxazolyl)methoxy
methylquinolin-2(1H)-one;
7-(3,5-dimethylisoxazolyl)methoxy(piperidinylmethyl)-2H-
benzo[b][1,4]oxazin-3(4H)-one;
61. 6-(6-hydroxypyridinyl)methoxy(pyridinylmethyl)quinolin-2(1H)-one;
6-(3-cyclopropylmethylisoxazolyl)methoxy(pyridin
ylmethyl)quinolin-2(1H)-one;
63. 7-methoxy(5-methylisoxazolyl)(pyridinylmethyl)quinolin-2(1H)-one;
64. 7-methoxy(3-methylisoxazolyl)(pyridinylmethyl)quinolin-2(1H)-one;
4-(4-chlorobenzyl)(3,5-dimethyl-1H-pyrazolyl)methoxy-2H-
benzo[b][1,4]oxazin-3(4H)-one;
6-(3,5-dimethyl-1H-pyrazolyl)methoxy(pyridinylmethyl)quinolin-
2(1H)-one;
1-((6-chloropyridinyl)methyl)(3,5-dimethylisoxazolyl)
methoxyquinolin-2(1H)-one;
3-cyclohexyl(3,5-dimethylisoxazolyl)methoxy(pyridin
ylmethyl)quinolin-2(1H)-one;
3-cyclohexyl(3,5-dimethylisoxazolyl)methoxy(pyridin
ylmethyl)quinolin-2(1H)-one;
7-(3,5-dimethylisoxazolyl)((6-hydroxypyridinyl)methyl)methoxy-2H-
benzo[b][1,4]oxazin-3(4H)-one;
7-(3,5-dimethylisoxazolyl)(2-methoxyethoxy)(pyridinylmethyl)-2H-
benzo[b][1,4]oxazin-3(4H)-one;
6-(3,5-dimethylisoxazolyl)hydroxy(pyridinylmethyl)quinolin-2(1H)-
one;
1-((5-chloropyridinyl)methyl)(3,5-dimethylisoxazolyl)
hydroxyquinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)(pyridinylmethyl)(2,2,2-
trifluoroethoxy)quinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)(2-morpholinoethoxy)(pyridin
ylmethyl)quinolin-2(1H)-one;
7-(2-(dimethylamino)ethoxy)(3,5-dimethylisoxazolyl)(pyridin
ylmethyl)quinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)(piperidinylmethoxy)(pyridin
ylmethyl)quinolin-2(1H)-one;
78. 7-butoxy(3,5-dimethylisoxazolyl)(pyridinylmethyl)quinolin-2(1H)-
one;
7-(allyloxy)(3,5-dimethylisoxazolyl)(pyridinylmethyl)quinolin-
2(1H)-one;
6-(3,5-dimethylisoxazolyl)(2-hydroxyethoxy)(pyridin
ylmethyl)quinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)(pyridinylmethyl)(2-(pyrrolidin
yl)ethoxy)quinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)(2-(piperazinyl)ethoxy)(pyridin
ylmethyl)quinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)(pyridinylmethyl)(pyridin
ylmethoxy)quinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)(3-hydroxypropoxy)(pyridin
ylmethyl)quinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)(pyridinylmethyl)
(trifluoromethoxy)quinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)(piperidinyloxy)(pyridin
ylmethyl)quinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)(pyridinylmethyl)((tetrahydro-2H-pyran
yl)methoxy)quinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)(2-(piperidinyl)ethoxy)(pyridin
ylmethyl)quinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)(pyridinylmethyl)(2-(pyrrolidin
yl)ethoxy)quinolin-2(1H)-one hydrochloride;
7-(3,5-dimethylisoxazolyl)methoxy((1-propionylpiperidinyl)methyl)-
2H-benzo[b][1,4]oxazin-3(4H)-one;
7-methoxy(5-methyloxo-2,3-dihydro-1H-imidazolyl)(pyridin
ylmethyl)quinolin-2(1H)-one;
3-(7-methoxyoxo(pyridinylmethyl)-1,2-dihydroquinolinyl)methyl-
1H-pyrrole-2,5-dione;
6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)quinoxalin-
2(1H)-one;
N-(4-(4-chlorobenzyl)methoxyoxo-3,4-dihydro-2H-benzo [b][1,4]oxazin
yl)-3,5-dimethylisoxazolecarboxamide;
4-(4-chlorobenzyl)((3,5-dimethylisoxazolyl)amino)methoxy-2H-
benzo[b][1,4]oxazin-3(4H)-one;
6-(3,5-dimethylisoxazolyl)(hydroxymethyl)methoxy(pyridin
ylmethyl)quinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)(fluoromethyl)methoxy(pyridin
ylmethyl)quinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)methoxy((5-(1-methyl-1H-pyrazol
yl)pyridinyl)methyl)quinolin-2(1H)-one;
1-((5-bromopyridinyl)methyl)(3,5-dimethylisoxazolyl)methoxy
quinolin-2(1H)-one;
1-((5-(3,5-dimethyl-1H-pyrazolyl)pyridinyl)methyl)(3,5-
dimethylisoxazolyl)methoxyquinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)((5-(3-hydroxypyrrolidinyl)pyridin
100.
yl)methyl)methoxyquinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)methoxy(pyridinyl methyl)(2,2,2-
101.
trifluorohydroxyethyl)quinolin-2(1H)-one;
6-(3,5-dimethylisoxazolyl)methoxy(pyridinyl methyl)(2,2,2-
102.
trifluorohydroxyethyl)quinolin-2(1H)-one (Isomer-1);
6-(3,5-dimethylisoxazolyl)methoxy(pyridinyl methyl)(2,2,2-
103.
trifluorohydroxyethyl)quinolin-2(1H)-one (Isomer-2);
6-(3,5-dimethylisoxazolyl)methoxy(pyridinyl methyl)(2,2,2-
104.
trifluoro-1,1-dihydroxyethyl)quinolin-2(1H)-one;
1-(4-chlorophenethyl)(3,5-dimethylisoxazolyl)methoxymethyloxo-
105.
1,2-dihydroquinolinecarbonitrile; and
2-(1-(4-chlorophenethyl)(3,5-dimethylisoxazolyl)methoxyoxo-1,2-
106.
dihydroquinolinyl)acetonitrile,
or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof.
In a further embodiment, the present invention relates to processes for preparing novel
bicyclic heterocyclic derivatives of formula (I).
It should be understood that the compounds of formula (I), (Ia), (Ib) and (Ic) structurally
encompasses all stereoisomers, enantiomers and diastereomers, and pharmaceutically acceptable
salts that may be contemplated from the chemical structure of the general formula (I) described
herein.
The absolute configuration at an asymmetric atom is specified by either R or S. Resolved
compounds whose absolute configuration is not known can be designated by (+) or (-) depending
on the direction in which they rotate plane polarized light. When a specific stereoisomer is
identified, this means that said stereoisomer is substantially free, i.e. associated with less than
50%, preferably less than 20%, more preferably less than 5%, in particularly less than 2% or 1%
of the other isomers. Thus when a compound of formula (1) is for instance specified as (R), this
means that the compound is substantially free of (S) isomer; when the compound of formula (1)
is for instance specified as E, this means that the compound is free of the Z isomer; when the
compound of formula (1) is for instance specified as cis isomer, this means that the compound is
free of the trans isomer.
In yet another embodiment according to the present invention, it provides a
pharmaceutical composition comprising the compound of formula (I) of the present invention
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 herein.
In yet another embodiment of the present invention relates to the pharmaceutical
combination comprising the compound of formula (I) of the present invention and at least one
additional pharmaceutically acceptable therapeutic agent. Preferably, the additional
pharmaceutically acceptable therapeutic agent can be anticancer agent, autoimmune agent,
cardiovascular agents and/or inflammatory agents.
Unless defined otherwise, all technical and scientific terms used herein have the same
meaning as is commonly understood by one of skill in art to which the subject matter herein
belongs. As used herein, the following definitions are supplied in order to facilitate the
understanding of the present invention.
"Alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain,
containing the indicated number of carbon atoms, for example, a C -C alkyl group may have
from 1 to 6 (inclusive) carbon atoms in it. Examples of C -C alkyl groups include, but are not
limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl,
isopentyl, neopentyl, and isohexyl.
"Alkenyl" refers to a hydrocarbon chain that may be a straight chain or branched chain,
containing the indicated number of carbon atoms having at least one –C=C-, for example, a C2
C alkenyl group may have from 2 to 6 (inclusive) –C=C- atoms in it. Examples of C -C alkenyl
6 2 6
groups include, but are not limited to ethylene, propene, butene, butene, pentene,
pentene, hexene, hexene and the like.
"Alkoxy" refers to the group Ak-O- or –O-Ak, where Ak is an alkyl group, as defined
above. Exemplary C -C alkyl group containing alkoxy groups include but are not limited to
methoxy, ethoxy, n-propoxy, 1-propoxy, isopropoxy, n-butoxy and t-butoxy.
“Alkoxyalkyl” refers to an alkyl group substituted with one or more alkoxy groups; the
alkyl group and alkoxy groups are same as defined above. Representative examples of an
alkoxyalkyl group include but are not limited to –CH OCH , -CH CH OCH , -CH OCH CH , -
2 3 2 2 3 2 2 3
CH CH OCH CH and the like.
2 2 2 3
"Cyanoalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl
group's hydrogen atoms have been replaced with -CN. Representative examples of an cyanoalkyl
group include, but are not limited to -CH2CN, -CH2CH2CN, -C(CH2)2CN, -CH2CH2CH2CN and
the like.
"Aryl" refers to an optionally substituted monocyclic, bicyclic or polycyclic aromatic
hydrocarbon ring system of about 6 to 14 carbon atoms. Examples of a C -C aryl group include,
6 14
but are not limited to phenyl, naphthyl, biphenyl, anthryl, biphenylenyl, and acenaphthyl.
"Cycloalkyl" refers to a C -C non-aromatic, saturated, monocyclic, bicyclic or
3 10
polycyclic hydrocarbon ring system. Representative examples of a C -C cycloalkyl include, but
3 10
are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl and the like.
"Cyano" refers to –CN group.
"Hydroxy" refers to -OH group.
"Amino" refers to an –NH2 group.
"Aminoalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl
group’s hydrogen atom has been replaced with amino group. Moreover one or more hydrogen
atoms on the amino group can be replaced by one or more alkyl group. Representative examples
of a aminoalkyl group include, but are not limited to –CH NH , -CH N(H)CH , -CH N(CH ) , –
2 2 2 3 2 3 2
(CH ) NH , -(CH ) N(H)CH , -(CH ) N(CH ) and the like.
2 2 2 2 2 3 2 2 3 2
"Hydroxyalkyl" refers to an alkyl group, as defined above, wherein one or more of the
alkyl group’s hydrogen atom has been replaced with -OH group. Representative examples of a
hydroxylalkyl group include, but are not limited to methanol, ethanol, propanol, isopropanol,
butanol, butanol and hexanol.
"Halo" or “halogen” refers to -F, -Cl, -Br and -I.
"Haloalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl
group's hydrogen atoms has been replaced with - F,- Cl,- Br or -I. Representative examples of an
haloalkyl group include, but are not limited to -CH F, -CCl , -CF , -CH Cl, -CH CH Br, -
2 3 3 2 2 2
CH CH I, -CH CH CHF, - CH CH CH Cl, -CH CH CH CH Br, -CH CH CH CH I, -
2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2
CH CH CH CH CH Br, -CH CH CH CH CH I, -CH CH(Br)CH , -CH CH(Cl)CH CH , and -
2 2 2 2 2 2 2 2 2 2 2 3 2 2 3
CH(F)CH CH .
The term "Heterocyclyl" includes the definitions of “heterocycloalkyl” and “heteroaryl”.
The term “Heterocycloalkyl” refers to a non-aromatic, saturated, monocyclic ring system
of 5 to 10 member having at least one heteroatom or heterogroup selected from O, N, S, S(O),
S(O) , NH and C(O). Exemplary heterocycloalkyl groups include piperdinyl, piperazinyl,
pyrrolidinyl, morpholinyl, thiomorpholinyl, 1,3-dioxolanyl, 1,4-dioxanyl,tetrahydro-2H-pyran
and the like.
"Heteroaryl" refers to an unsaturated, monocyclic, bicyclic, or polycyclic aromatic ring
system containing at least one heteroatom selected from oxygen, sulfur and nitrogen. Examples
of C -C heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole,
12
thiadiazole, isoxazole, isothiazole, imidazole, imidazolone, N-methylimidazole, pyridine,
pyrimidine, pyrazine, pyrrole, pyrrole-2,5-dione, N-methylpyrrole, pyrazole, N-methylpyrazole,
1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole,
benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole,
azabenzimidazole, indazole, quinazoline, quinoline and isoquinoline. Bicyclic heteroaryl groups
include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-
membered monocyclic heterocyclyl ring having one or two heteroatoms atoms in the ring, one
nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring
atom.
"Heterocyclylalkyl" refers to an alkyl group, as defined above, wherein one or more of
the alkyl group’s hydrogen atom has been replaced with heterocyclyl group. Representative
examples of a heterocyclylalkyl group include, but are not limited to pyrrolidinylethyl-,
morpholinylethyl-, piperazinylethyl-, pyridinylmethyl-, piperidinyl-methyl, or 1-
propylpyrrolidine and the like.
The term "heteroatom" as used herein designates a sulfur, nitrogen, or oxygen atom.
“Monocyclic ring” or “Bicyclic ring” refers to a saturated, partially saturated or
unsaturated 3-12 membered cyclic ring, in which 0 to 4 ring carbon atoms can be replaced with
a heteroatom/heterogroups such as N, O, S, -C(O)-, -S(O), -NH and S(O) . Representative
examples of a 3 to 12 membered ring include, but are not limited to cyclopropyl, cyclohexyl,
isoxazole, triazole, imidazolone, oxirane, phenyl, pyridyl, pyrazole, pyrimidine, piperdine,
piperazine, thiazole, furan, pyrrolidinyl, pyrazine, pyrrole-2,5-dione, quinoline, morpholine,
1,2,3,6-tetrahydropyridine, tetrahydro-2H-pyran, 2,3-dihydrobenzo[b][1,4] dioxine, 1H-indazole
and the like.
The term "comprise" or "comprising" is generally used in the sense of include, that is to
say permitting the presence of one or more features or components.
The use of the term "including" as well as other forms, such as “include”, “includes”, and
“included”, is not limiting.
As used herein, the terms "treat", "treating" or "treatment" encompass either or both
responsive and prophylaxis measures, e.g., measures designed to inhibit or delay the onset of the
disease or disorder, achieve a full or partial reduction of the symptoms or disease state, and/or to
alleviate, ameliorate, lessen, or cure the disease or disorder and/or its symptoms. The terms
"treat”, "treating" or "treatment", include, but are not limited to, prophylactic and/or therapeutic
treatments.
As used herein the terms "subject" or "patient" are well-recognized in the art, and, are
used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow,
horse, goat, sheep, pig, camel, and, most preferably, a human. In some embodiments, the subject
is a subject in need of treatment or a subject with a disease or disorder. However, in other
embodiments, the subject can be a normal subject. The term does not denote a particular age or
sex. Thus, adult and new-born subjects, whether male or female, are intended to be covered.
As used herein the term "therapeutically effective amount", refers to a sufficient amount
of a compound or a composition being administered which will relieve to some extent one or
more of the symptoms of the disease or condition being treated. The result can be reduction
and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration
of a biological system. The term “therapeutically effective amount” includes, for example, a
prophylactically effective amount.
"Pharmaceutically acceptable" means that, which is useful in preparing a pharmaceutical
composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable
and includes that which is acceptable for veterinary as well as human pharmaceutical use.
“Pharmaceutically acceptable salt” refers to the salts of the compounds, that is
pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent
compound. Pharmaceutically acceptable salts of the compounds of this invention include those
derived from suitable inorganic and organic acids and bases. Such salts include: acid addition
salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid,
nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid,
propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic
acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,
benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methane sulfonic
acid, ethane sulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzene
sulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid,
camphor sulfonic acid, 4-methylbicyclo[2.2.2]-octenecarboxylic acid, glucoheptonic acid,
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid,
gluconic acid, glutamic acid, hydroxyl naphthoic acid, salicylic acid, stearic acid, muconic acid,
and the like.
In further yet another particular embodiment, the compounds and pharmaceutically
compositions of the present invention are used in the treatment and/or prevention of diseases
and/or disorders in which aberrant, abnormal or deregulated activity of bromodomain containing
proteins contribute to the pathology and/or symptomology of such diseases and/or disorders.
Such diseases and/or disorders mediated by one or more of these kinases are provided herein.
In further yet another particular embodiment, the compounds and pharmaceutically
compositions of the present invention are useful in treatment and/or prevention of diseases
and/or disorders in which aberrant, abnormal or deregulated activity of BET family of
bromodomain containing proteins; in particular BRD2, BRD3, BRD4 and BRD-t proteins.
In further yet another particular embodiment, the compounds and pharmaceutically
compositions of the present invention are useful in manufacture of a medicament for use in the
treatment of diseases associated with bromodomain in animals including humans.
In further yet another particular embodiment, the method of treatment of diseases or
disease conditions for which bromodomain inhibitor is indicated comprises administering an
effective amount of compound of formula (I) according to the present invention.
In further yet another particular embodiment, the disease or disease condition for which
bromodomain inhibitor is indicated is autoimmune, inflammatory or cancer.
Bromodomain inhibitors are believed to be useful in the treatment of a variety of diseases
or conditions related to systemic or tissue inflammation, inflammatory responses to infection or
hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis and in the prevention
and treatment of viral infections.
Bromodomain inhibitors may be useful in the treatment of a wide variety of chronic
autoimmune and inflammatory conditions such as rheumatoid arthritis, osteoarthritis, acute gout,
psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's
disease and Ulcerative colitis), asthma, chronic obstructive airways disease, pneumonitis,
myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases,
nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis,
hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease,
hypophysitis, thyroiditis, type I diabetes and acute rejection of transplanted organs.
Bromodomain inhibitors may be useful in the treatment of a wide variety of acute
inflammatory conditions such as acute gout, giant cell arteritis, nephritis including lupus
nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including
giant cell arteritis, Wegener's granulomatosis, Polyarteritisnodosa, Behcet's disease, Kawasaki
disease, Takayasu's Arteritis, vasculitis with organ involvement and acute rejection of
transplanted organs.
Bromodomain inhibitors may be useful in the prevention or treatment of diseases or
conditions which involve inflammatory responses to infections with bacteria, viruses, fungi,
parasites or their toxins, such as sepsis, sepsis syndrome, septic shock, endotoxaemia, systemic
inflammatory response syndrome (SIRS), multi-organ dysfunction syndrome, toxic shock
syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure,
fulminant hepatitis, burns, acute pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimer
reactions, encephalitis, myelitis, meningitis, malaria and SIRS associated with viral infections
such as influenza, herpes zoster, herpes simplex and coronavirus.
Bromodomain inhibitors may be useful in the prevention or treatment of conditions
associated with ischaemia-reperfusion injury such as myocardial infarction, cerebro- vascular
ischaemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation,
coronary artery bypass grafting, cardio-pulmonary bypass procedures, pulmonary, renal, hepatic,
gastro-intestinal or peripheral limb embolism.
Bromodomain inhibitors may be useful in the treatment of disorders of lipid metabolism
via the regulation of APO-A1 such as hypercholesterolemia, atherosclerosis and Alzheimer's
disease.
Bromodomain inhibitors may be useful in the treatment of fibrotic conditions such as
idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation,
scleroderma and cardiac fibrosis.
Bromodomain inhibitors may be useful in the prevention and treatment of viral infections
such as herpes virus, human papilloma virus, adenovirus and poxvirus and other DNA viruses.
Bromodomain inhibitors may be useful in the treatment of cancer, including hematological,
epithelial including lung, breast and colon carcinomas, midline carcinomas, mesenchymal,
hepatic, renal and neurological tumors.
In one embodiment the disease or condition for which a bromodomain inhibitor is
indicated is selected from diseases associated with systemic inflammatory response syndrome,
such as sepsis, burns, pancreatitis, major trauma, haemorrhage and ischaemia. In this
embodiment the bromodomain inhibitor would be administered at the point of diagnosis to
reduce the incidence of: SIRS, the onset of shock, multi-organ dysfunction syndrome, which
includes the onset of acute lung injury, ARDS, acute renal, hepatic, cardiac and gastro-intestinal
injury and mortality.
In another embodiment the bromodomain inhibitor would be administered prior to
surgical or other procedures associated with a high risk of sepsis, haemorrhage, extensive tissue
damage, SIRS or MODS (multiple organ dysfunction syndrome).
In a particular embodiment the disease or condition for which a bromodomain inhibitor is
indicated is sepsis, sepsis syndrome, septic shock and endotoxaemia. In another embodiment, the
bromodomain inhibitor is indicated for the treatment of acute or chronic pancreatitis. In another
embodiment the bromodomain is indicated for the treatment of burns. In one embodiment the
disease or condition for which a bromodomain inhibitor is indicated is selected from herpes
simplex infections and reactivations, cold sores, herpes zoster infections and reactivations,
chickenpox, shingles, human papilloma virus, cervical neoplasia, adenovirus infections,
including acute respiratory disease, poxvirus infections such as cowpox and smallpox and
African swine fever virus. In one particular embodiment a bromodomain inhibitor is indicated
for the treatment of Human papilloma virus infections of skin or cervical epithelia.
The term "diseases or conditions for which a bromodomain inhibitor is indicated", is
intended to include each of or all of the above disease states.
While it is possible that for use in therapy, a compound of formula (I) as well as
pharmaceutically acceptable salts thereof may be administered as the raw chemical, it is common
to present the active ingredient as a pharmaceutical composition.
The term "therapeutically effective amount" means the amount of the subject compound
that will elicit the biological or medical response of a tissue, system, animal or human that is
being sought by the researcher, veterinarian, medical doctor or other clinician.
The compounds and pharmaceutical compositions of the present invention may be used
in combination with other drugs that are used in the treatment/prevention/suppression or
amelioration of the diseases or conditions for which compounds of the present invention may be
useful. Such other drugs may be administered, by a route and in an amount commonly used there
for, contemporaneously or sequentially with a compound of the present invention. When a
compound of the present invention is used contemporaneously with one or more other drugs, a
pharmaceutical composition containing such other drugs in addition to the compound of the
present invention may also be preferred. Accordingly, the pharmaceutical compositions of the
present invention include those that also contain one or more other active ingredients, in addition
to a compound of the present invention.
A pharmaceutical composition of the invention may be formulated as being compatible
with its intended route of administration, which may preferably be an oral administration. For
example the pharmaceutical compositions of the invention may be formulated for administration
by inhalation, such as aerosols or dry powders; for oral administration, such in the form of
tablets, capsules, gels, syrups, suspensions, emulsions, elixirs, solutions, powders or granules; for
rectal or vaginal administration, such as suppositories; or for parenteral injection (including
intravenous, subcutaneous, intramuscular, intravascular, or infusion) such as a sterile solution,
suspension or emulsion.
The compounds of the present invention may also be entrapped in microcapsules
prepared, for example, by coacervation techniques or by interfacial polymerization, for example,
hydroxymethyl cellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules,
respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres,
microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are
disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).
The bicyclic heterocyclic derivatives of formula (I) according to the present invention
may be prepared from readily available starting materials using the following general methods
and procedures. It will be appreciated that where typical or preferred experimental conditions
(i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental
conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with
the particular reactants or solvents used, but such conditions can be determined by the person
skilled in the art, using routine optimization procedures. The specifics of the processes according
to the present invention are detailed in the example section mentioned below.
In a further aspect, the compounds of the present invention can also contain unnatural
proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For
example, the present invention also embraces isotopically-labeled variants of the present
invention which are identical to those recited herein, but for the fact that one or more atoms of
the compound are replaced by an atom having the atomic mass or mass number different from
the predominant atomic mass or mass number usually found in nature for the atom. All isotopes
of any particular atom or element as specified are contemplated within the scope of the
compounds of the invention, and their uses. Exemplary isotopes that can be incorporated in to
compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
2 3 11 13 14 13 15
phosphorous, sulfur, fluorine, chlorine and iodine, such as H (“D”), H, C, C, C, N, N,
17 18 32 33 35 18 36 123 125
O, O, O, P, P, S, F, Cl, I and I. Isotopically labeled compounds of the present
inventions can generally be prepared by following procedures analogous to those disclosed in the
Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for
a non-isotopically labeled reagent.
The abbreviations used in the entire specification may be summarized herein below with
their particular meaning.
MeOH–Methanol; EtOH–Ethanol; DME–1,2-dimethoxyethane; CHCl -Chloroform;
DCM–Dichloromethane; DMF–N,N-Dimethylformamide; DMSO–Dimethylsulfoxide; CDCl –
Deuterated chloroform; EtOAc–Ethylacetate; CH CN-Acetonitrile; THF–Tetrahydrofuran; TEA
–Triethylamine; DIPEA-Diisopropylethylamine; TFA-Trifluoroacetic acid; AcOH-Acetic acid;
AlCl -Aluminium chloride; AlBr -Aluminium bromide; Br -Bromine; NBS-N-
3 3 2
bromosuccinimide; NCS-N-chlorosuccinimide; MeI-Methyl iodide; KI-Potassium iodide; TPP-
Triphenyl phosphene; NaOAc-Sodiumacetate; KOAc-Potassiumacetate; Na SO -Sodium
sulphate; H SO –Sulfuric acid; HNO -Nitric acid; HBr-Hydrobromic acid; NaHCO -Sodium
2 4 3 3
bicarbonate; KHCO -Potassium bicarbonate; Na CO –Sodium carbonate; K CO –Potassium
3 2 3 2 3
carbonate; Cs CO -Cesiumcarbonate; NaH-Sodium hydride; t-BuOK-Potassium tert-butoxide;
LDA-lithium diisopropylamide; n-BuLi-n-Butyllithium; DIAD-Diisopropylazodicarboxylate;
BBr -Boron tribromide; NMP-N-Methyl pyrrolidine; DAST-Diethylaminosulfurtrifluoride;
AgBF -Silver tetrafluoroborate; NaN -Sodium azide; CuI-Copper(I)iodide; SnCl .2H O–
4 3 2 2
Stannous chloride dihydrate; NaBH -Sodium borohydride; NaCNBH -Sodium
cyanoborohydride; (BOC) O-Di-tert-butyldicarbonate; EDC.HClEthyl(3-
dimethylaminopropyl)carbodiimide hydrochloride; HOBthydroxybenzotriazole; POCl –
Phosphorous oxychloride; SOCl -Thionyl chloride; AcCl-Acetyl chloride; Ac O-Acetic
anhydride; NH Cl-Ammonium chloride; NiCl -Nickel chloride; H O -Hydrogen peroxide;
4 2 2 2
NaOEt-Sodium ethoxide; NaOMe-Sodium methoxide; NaOH–Sodium hydroxide; KOH-
potassium hydroxide; HCl–Hydrochloric acid; Pd(pph ) –Tetrakis
(triphenylphosphine)palladium(0); Pd(dppf)Cl2-[1,1′-Bis(diphenyl
phosphino)ferrocene]dichloropalladium (II), complex with dichloromethane; Pd(OAc) -
Palladium(II)acetate; BINAP-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene; TMS-CF -
(Trifluoromethyl)trimethylsilane; TBAF-Tetrabutylammonium fluoride; KCN-Potassium
cyanide; Pd/C–Palladium on activated carbon; H O–Water; Fe–Iron powder; ML–Milliliter;
TLC–Thin layer chromatography; RT-Room temperature; h-Hour; N–Normality; M-Molarity; s-
Singlet; d-Doublet; t-Triplet; m-Multiplet; HNMR–Proton nuclear magnetic resonance; MS–
Mass spectroscopy; LC–Liquid chromatography; H–Proton; MHz–Mega hertz; Hz–Hertz; ppm–
Parts per million; Bs–Broad singlet; ES–Electro spray; Conc–Concentrated; g-Gram and Mmol–
Milli mol.
General Scheme:
In one aspect the present invention relates to the preparation of bicyclic heterocyclic
derivatives of formula (I). Herein disclosed the general process for preparation of the compound
of formula (I).
Scheme-I:
In Scheme-I, the compounds of formula-I are prepared in two methods:
Method-I: N-alkylation/sulfonamide formation followed by Suzuki coupling.
Method-II: Suzuki coupling followed by N-alkylation/sulfonamide formation.
N-alkylation/sulfonamide formation:
The compound of formula-1.0 and 1.2 can undergo N-alkylation/sulfonylation with
sulfonyl chloride/sulfonates/alkylhalide derivatives in presence of a suitable solvent (e.g., ACN,
DMF, DCM, THF, Dioxane, and the like) and a suitable base (e.g., Cs CO , t-BuOK, K CO ,
2 3 2 3
Na2CO3, Pyridine, and the like) at a temperature of about 0ºC to 50ºC for about 2-48 h to provide
compound of formula-1.1 and compound of formula (I) respectively.
Suzuki Coupling:
A compound of formula (I) and a compound of formula-1.2 can be prepared by reacting a
compound of formula-1.1 and a compound of formula-1.0 with Cy -boronic acid/ester
respectively in presence of a suitable solvent (e.g., DME/H O, 1,4-Dioxane/H O, DMF, DMSO,
and the like), a suitable base (e.g., Na CO , K CO , KOAc, and the like) and a suitable Pd
2 3 2 3
catalyst (e.g., Pd(OAc) , Pd(PPh ) Cl , Pd(PPh ) , Pd(dppf) Cl , and the like) at a temperature of
2 3 2 2 3 4 2 2
about 60°C to 150°C for about 2 to 24 h.
Scheme-II:
Method-III: (De-alkylation):
The compound of formula-I (2.0) can be treated with strong acid (e.g., BBr , HCl, HBr,
and the like) in presence of a suitable solvent (e.g., DCM, CHCl , DCE or 1,4-Dioxane, and the
like) at a temperature of about -78°C to 35°C for about 2 to 24 h to provide the compound of
formula-I (2.1).
Method-IV: This method can be carried out in any of the alternative procedures given below.
O-alkylation: The compound of formula- I (2.1) can undergo O-alkylation with R -Br in
presences of a suitable solvent (e.g., DMF, ACN, THF, Dioxane, and the like) and a suitable
base (e.g., NaH, Cs CO , t-BuOK, K CO , Na CO , Pyridine, and the like) at a temperature of
2 3 2 3 2 3
about 20°C to 120°C for about 2 to 48 h to provide the compound of formula (I).
Mitsunobu or Mitsunobu-type reaction: The compound of formula-I (2.1) can be treated with R -
OH in presence of triphenylphosphine, and suitable reagent like DIAD or DEAD in a suitable
solvent (e.g., Diethyl ether, THF, and the like) at a temperature of about 0°C to 35°C for about 8
to 24 h to provide the compound of formula (I).
EXAMPLES
Although the invention has been illustrated by certain of the preceding examples, it is not
to be construed as being limited thereby; but rather, the invention encompasses the generic area
as hereinbefore disclosed. Various modifications and embodiments can be made without
departing from the spirit and scope thereof.
The MS data provided in the examples described below were obtained as follows:
Mass spectrum: LC/MS Agilent 6120 Quadrapole LC/MS.
The NMR data provided in the examples described below were obtained as follows:
H-NMR: Varian 400 MHz.
The microwave chemistry was performed on a CEM Explorer.
The procedure for the compounds of Formula (I) are detailed herein below stepwise
including the general Synthesis of various intermediates involved in process of manufacture of
the compounds according to the present invention.
Intermediate-1: Synthesis of 7-(3,5-dimethylisoxazolyl)methoxy-3,4-dihydro-2H-
benzo[b][1,4]oxazine
Step-a: Synthesis of 2-aminomethoxyphenol
To a solution of 4-methoxynitrophenol (5.0 g, 29.58 mmol) in MeOH (50 mL) was
added 10% Pd-C (2.5 g) and stirred under H balloon pressure at RT for 16 h. After completion
of the reaction, the reaction mixture was filtered through celite bed, washed with methanol. The
filtrate was concentrated to afford the title product as an off white solid (4.0 g, 97%). The crude
product was as such taken forward for next step without further purification. H NMR (400
MHz, CDCl ): δ 6.75–6.60 (m, 1H), 6.40–6.28 (m, 1H), 6.25–6.15 (m, 1H), 3.75–3.60 (bs, 3H);
LC-MS: m/z 140.1 (M+1) .
Step-b: Synthesis of 2-acetamidomethoxyphenylacetate
To an ice-cooled solution of 2-aminomethoxyphenol (5 g, 35.97 mmol) in THF (130
mL) was added triethylamine (25 mL, 179.85 mmol) and stirred for 10 min before acetyl
chloride (7.7 mL, 107.91 mmol) was added. Then the reaction mixture allowed to stir at RT for
16 h. After completion of the reaction, the reaction mixture was quenched with NaHCO solution
(up to pH ~8) and extracted with EtOAc (200 mL X 2). The combined organic layers were
washed with water (200 mL), brine (100 mL), dried over sodium sulphate and concentrated to
get residue. The residue was directly used for next step without further purification (5.0 g, 62%).
H NMR (400 MHz, CDCl ): δ 7.90–7.75 (bs, 1H), 7.25–7.10 (m, 1H), 7.05–6.95 (m, 1H), 6.70–
6.60 (m, 1H), 3.79 (s, 3H), 2.34 (s, 3H), 2.17 (s, 3H); LC-MS: m/z 224.1 (M+1) .
Step-c: Synthesis of 2-acetamidobromomethoxyphenylacetate
To an ice cooled solution of 2-acetamidomethoxyphenyl acetate (5.0 g, 22.42 mmol)
in DMF (65 mL) was add N-bromosuccinimide (4.79 g, 26.90 mmol) portion wise and stirred at
RT for 16 h. After completion of the reaction, the reaction mixture was poured over crushed ice,
separated solids were filtered, washed with water and dried under reduced pressure. The residue
was directly used for next step without further purification (4.0 g, 59%). H NMR (400 MHz,
CDCl ): δ 7.99 (s, 1H), 7.33 (s, 1H), 7.20–7.10 (bs, 1H), 3.89 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H);
LC-MS: m/z 302.0 (M+1) .
Step-d: Synthesis N-(4-bromohydroxymethoxyphenyl)acetamide
To a solution of 2-acetamidobromomethoxyphenyl acetate (1.0 g, 3.29 mmol) in
MeOH (10 mL) was add potassium carbonate (1.36 g, 9.86 mmol) portion wise and stirred at RT
for 16 h. After completion of the reaction, the reaction mixture was poured over crushed ice,
separated solids were filtered, washed with water and dried under vacuum. The residue was
directly used for the next step without further purification (0.7 g, 81%). H NMR (400 MHz,
DMSO-d ): δ 9.70 (s, 1H), 9.31 (s, 1H), 7.69 (s, 1H), 7.02 (s, 1H), 3.71 (s, 3H), 2.09 (s, 3H); LC-
MS: m/z 262.0 (M+1) .
Step-e: Synthesis 1-(7-bromomethoxy-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanone
To a solution of N-(4-bromohydroxymethoxyphenyl)acetamide (0.60 g, 2.30 mmol)
in DCM (7.5 mL) and CH CN (4.5 mL) were added 1,2-dibromoethane (0.8 mL, 9.23), NaOH
(037 g, 9.23 mmol), benzyltriethylammonium chloride (0.12 g) and stirred at RT for 16 h. After
completion of the reaction, the reaction mixture was diluted with water (80 mL) and extracted
with EtOAc (200 mL). The organic layer was washed with water (200 mL), brine (100 mL),
dried over sodium sulphate and concentrated to afford the title compound as an off white solid
(0.5 g, 75%). H NMR (400 MHz, DMSO-d ): δ 8.05–7.80 (bs, 1H), 7.12 (s, 1H), 4.21 (t, J=4.4
Hz, 2H), 3.83 (t, J=4.6 Hz, 2H), 3.74 (s, 3H), 2.27 (s, 3H); LC-MS: m/z 288.0 (M+1) .
Step-f: Synthesis 1-(7-(3, 5-dimethylisoxazolyl)methoxy-2H-benzo[b][1,4]oxazin-4(3H)-
yl)ethanone
To a solution of 1-(7-bromomethoxy-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanone
(0.45 g, 1.57 mmol) in 1,2-DME (4.5 mL) and H O (1.5 mL) were added 3,5-dimethylisoxazole
boronic acid (0.66 g, 4.72 mmol), sodium carbonate (0.42 g, 3.93 mmol) and degassed with
nitrogen purging for 20 min. Then tetrakistriphenylphosphinepalladium(0) (0.09 g, 0.078 mmol)
was added and heated at 100°C for 16 h. After completion of the reaction, the reaction mixture
was diluted with EtOAc (50 mL), washed with water (50 mL), brine (50 mL), dried over sodium
sulphate and concentrated to get residue. The obtained residue was directly used for next step,
without further purification (0.3 g, 66%). H NMR (400 MHz, DMSO-d ): δ 8.00–7.80 (bs, 1H),
6.76 (s, 1H), 4.23 (t, J=4.4 Hz, 2H), 3.87 (t, J=4.6 Hz, 2H), 3.68 (s, 3H), 2.30 (s, 3H), 2.25 (s,
3H), 2.07 (s, 3H); LC-MS: m/z 303.1 (M+1) .
Step-g: Synthesis 7-(3, 5-dimethylisoxazolyl)methoxy-3,4-dihydro-2H-benzo[b][1,4]
oxazine
To a solution of 1-(7-(3,5-dimethylisoxazolyl)methoxy-2H-benzo[b][1,4]oxazin-
4(3H)-yl)ethanone (0.3 g, 0.99 mmol) in MeOH (3 mL) and H O (1 mL) was added KOH (0.35
g, 6.35 mmol) and stirred at RT for 2 h. Reaction mixture was diluted with EtOAc (50 mL),
washed with water (50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The
obtained residue was directly used for next step, without further purification (0.2 g, 77%); LC-
MS: m/z 261.1 (M+1) .
Intermediate-2: Synthesis of 7-bromomethoxy-2H-benzo[b][1,4]oxazin-3(4H)-one
Step-a: Synthesis of 6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one
To an ice-cooled solution of 2-aminomethoxyphenol (4 g, 28.77 mmol) in CH CN (50
mL) was added K CO (12.0 g, 86.33 mmol) and stirred for 10 min before 2-chloroacetyl
chloride (3.43 g, 57.55 mmol) was added. Then the reaction mixture was allowed stirred at
100°C for 2 h. After completion of the reaction, the reaction was concentrated and treated with
ice-cold water to crash out the solids. The separated solids were filtered, washed with water and
dried under vacuum (4.1 g, 78%). H NMR (400 MHz, DMSO-d ): δ 10.61 (bs, 1H), 6.87–6.85
(m, 1H), 6.50–6.47 (m, 2H), 4.48 (s, 2H), 3.68 (s, 3H); LC-MS: m/z 178.2 (M-1) .
Step-b: Synthesis of 7-bromomethoxy-2H-benzo[b][1,4]oxazin-3(4H)-one
To an ice cooled solution of 6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (4.0 g, 22.9
mmol) in DMF (50 mL) was add N-bromosuccinimide (10.17 g, 58.0 mmol) portion wise and
stirred at RT for 3 h. After completion of the reaction, the reaction mixture was poured over ice
water, separated solids were filtered, washed with water and dried under vacuum (4.0 g, 70%).
H NMR (400 MHz, DMSO-d ): δ 10.72 (bs, 1H), 7.19 (s, 1H), 6.62 (s, 1H), 4.53 (s, 2H), 3.76
(s, 3H); LC-MS: m/z 257.0 (M-1) .
Intermediate-3: Synthesis of 7-bromomethoxy-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-
O NH
O N O
2 O N O
OH Br O
Intermediate-3
The process for preparation is similar to the one depicted in intermediate-2. The desired
compound obtained as a white solid (0.09 g, 60%). H NMR (400 MHz, DMSO-d ): δ 10.64 (bs,
1H), 7.15 (s, 1H), 6.61 (s, 1H), 3.76 (s, 3H), 1.37 (s, 6H).
Intermediate-4: Synthesis of 7-amino(4-chlorobenzyl)methoxy-2H-benzo[b][1,4]oxazin-
3(4H)-one
Step-a: Synthesis of 6-methoxynitro-2H-benzo[b][1,4]oxazin-3(4H)-one
To an ice cooled solution of 6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (0.60 g, 3.35
mmol) in AcOH (1.8 mL) was added drop wise 70% HNO (0.6 mL) and stirred at RT for 15
min. After completion of the reaction, the reaction mixture was poured into ice water (100 g),
separated solids were filtered, washed with water and dried under reduced pressure. The residue
was directly used for the next step without further purification (0.60 g, 80%). H NMR (400
MHz, DMSO-d ) δ 11.14 (bs, 1H), 7.60 (s, 1H), 6.75 (s, 1H), 4.64 (s, 2H), 3.85 (s, 3H). LC-MS:
m/z 223.1 (M-1) .
Step-b: Synthesis of 4-(4-chlorobenzyl)methoxynitro-2H-benzo[b][1,4]oxazin-3(4H)-one
To an solution of 6-methoxynitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.60 g, 2.67
mmol) in DMF (6 mL) were added K CO (1.06 g, 7.68 mmol), followed by addition of 4-chloro
benzyl bromide (0.41 g, 2.00 mmol), and stirred at 80ºC for 16 h. After completion of the
reaction, the reaction mixture was poured into ice water (100 g), separated solids were filtered,
washed the solid thoroughly with water and dried under reduced pressure. The residue was
directly used for the next step without further purification (0.48 g, 51%). H NMR (400 MHz,
DMSO-d ) δ 7.63 (s, 1H), 7.43–7.37 (m, 4H), 6.89 (s, 1H), 5.29 (s, 2H), 4.86 (s, 2H), 3.78 (s,
3H).
Step-c: Synthesis of 7-amino(4-chlorobenzyl)methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one
To a solution of 4-(4-chlorobenzyl)methoxynitro-2H-benzo[b][1,4]oxazin-3(4H)-
one (0.48 g, 1.38 mmol) in EtOH (5 mL) and water (2.5 mL) at RT were added NH Cl (0.22 g,
4.14 mmol) followed by Fe powder (0.39 g, 7.00 mmol) and refluxed at 100ºC for 2 h. Then the
reaction mixture was cooled to RT, filtered through celite pad and washed with EtOAc (200
mL). The organic layer was washed with aq. sodium bicarbonate solution (50 mL), water (50
mL), brine (50 mL), dried over sodium sulphate and concentrated. The residue was purified by
column chromatography on silica gel (100-200 mesh) to afford the title compound (0.20 g, 46%);
H NMR (400 MHz, DMSO-d ) δ 7.39 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 6.54 (s, 1H),
6.31 (s, 1H), 5.10 (s, 2H), 4.66 (s, 2H), 4.58 (s, 2H), 3.60 (s, 3H); LC-MS: m/z 319.1 (M+1) .
Intermediate-5: Synthesis of 6-bromomethoxyquinolin-2(1H)-one
Step-a: Synthesis of 3,3-diethoxypropanoic acid
To a stirred suspension of ethyl 3,3-diethoxypropanoate (15.0 g, 78.88 mmol) in water
(32 mL) was added NaOH (4.10 g, 102.6 mmol) and heated to 110ºC for 1.5 h. After completion
of the reaction, the reaction mixture was cooled, acidified to pH~3 with aq. 3N HCl and
extracted with EtOAc (500 mL x 2). The organic layer was washed with water (200 mL), brine
(100 mL), dried over sodium sulphate and concentrated. The residue was used for next step
without further purification (11.50 g, 91%). H NMR (400 MHz, DMSO-d ): δ 12.20 (s, 1H),
4.81 (t, J=5.9 Hz, 1H), 3.58–3.59 (m, 2H), 3.48–3.40 (m, 2H), 2.60–2.40 (m, 2H), 1.09 (t, J=7.3
Hz, 6H).
Step-b: Synthesis of 3-ethoxyacryloyl chloride
To an ice cooled compound of 3,3-diethoxypropanoic acid (5.00 g, 31.05 mmol) was
added thionyl chloride (10.0 mL, 142.9 mmol) over a period of 10 min., and stirred at 80ºC for
1.5 h. After completion of the reaction, the reaction mixture was concentrated and dried under
reduced pressure to afford the title product as a dark brown liquid (3.0 g, 73%). H NMR (400
MHz, DMSO-d ): δ 7.50 (d, J=12.2 Hz, 1H), 5.14 (d, J=12.2 Hz, 1H), 3.94 (q, J=7.3 Hz, 2H),
1.24 (t, J=7.3 Hz, 3H).
Step-c: Synthesis of (E/Z)-N-(4-bromomethoxyphenyl)ethoxyacrylamide
To an ice cooled solution of 4-bromomethoxyaniline (3.00 g, 14.85 mmol) in pyridine
(20 mL) was added (E/Z)ethoxyacryloyl chloride (2.98 g, 22.27 mmol) over a period of 5 min.
and stirred at RT for 16 h. After completion of the reaction, the reaction mixture was diluted with
ice cooled water and extracted with EtOAC (150 mL x 2). The combined organic layer was
washed with aq. 1N HCl (100 mL), water (150 mL), brine (100 mL), dried over sodium sulphate
and concentrated. The residue was used for next step without further purification (3.20 g, 72%).
H NMR (400 MHz, DMSO-d ): δ 9.86 (s, 1H), 7.54–7.42 (m, 3H), 7.12–7.08 (m, 1H), 5.50 (d,
J=12.7 Hz, 1H), 3.95 (q, J=6.9 Hz, 2H), 3.80 (s, 3H), 1.27 (t, J=7.3 Hz, 3H); LC-MS: m/z 301.1
(M+1) .
Step-d: Synthesis of 6-bromomethoxyquinolin-2(1H)-one
A solution of (E/Z)-N-(4-bromomethoxyphenyl)ethoxyacrylamide (3.0 g, 10.0
mmol) in Conc. H SO (30 mL) was stirred at RT for 1 h. After completion of the reaction, the
reaction mixture was poured over ice water; separated solids were filtered, washed the solid
thoroughly with water and dried under reduced pressure. The residue was directly used for the
next step without further purification (2.08 g, 82%). H NMR (400 MHz, DMSO-d ): δ 12.70
(bs, 1H), 7.94 (s, 1H), 7.80 (d, J=9.8 Hz, 1H), 6.92 (s, 1H), 6.36 (d, J=9.8 Hz, 1H), 3.88 (s, 3H);
LC-MS: m/z 256.0 (M+1) .
Intermediate-6: Synthesis of 6-(3, 5-dimethylisoxazolyl)methoxyquinolin-2(1H)-one
Step-a: Synthesis of 4-(3,5-dimethylisoxazolyl)methoxyaniline
The process of this step was adopted from step-f of intermediate-1. The desired
compound obtained as a pale yellow solid (0.6 g, 60%). H NMR (400 MHz, DMSO-d ): δ 6.78
(d, J=7.8 Hz, 1H), 6.30–6.19 (m, 2H), 5.26 (s, 2H), 3.66 (s, 3H), 2.19 (s, 3H), 2.02 (s, 3H); LC-
MS: m/z 219.2 (M+1) .
Step-b: Synthesis of (E)-N-(4-(3,5-dimethylisoxazolyl)methoxyphenyl)ethoxyacryl
amide
The process of this step was adopted from step-c of intermediate-5. The desired
compound obtained as a pale yellow solid (0.4 g, 46%). H NMR (400 MHz, DMSO-d ): δ 9.85
(s, 1H), 7.52–7.48 (m, 2H), 7.22–7.21 (m, 1H), 7.11–7.09 (m, 1H), 5.53 (d, J=12.2 Hz, 2H),
3.98–3.93 (m, 2H), 3.73 (s, 3H), 2.23 (s, 3H), 2.05 (s, 3H), 1.30–1.22 (m, 2H); LC-MS: m/z
317.2 (M+1) .
Step-c: Synthesis of 6-(3,5-dimethylisoxazolyl)methoxyquinolin-2(1H)-one
The process of this step was adopted from step-d of intermediate-5. The desired
compound obtained as an off white solid (0.2 g, 59%); H NMR (400 MHz, DMSO-d ): δ 11.76
(bs, 1H), 7.82 (d, J=9.3 Hz, 1H), 7.53 (s, 1H), 6.94 (s, 1H), 6.35 (d, J=9.8 Hz, 1H), 3.81 (s, 3H),
2.26 (s, 3H), 2.07 (s, 3H); LC-MS: m/z 271.1 (M+1) .
Intermediate-7: Synthesis of 6-bromomethoxymethylquinolin-2(1H)-one
Step-a: Synthesis of (E)-ethyl 3-(4-methoxynitrophenyl)methylacrylate
To a stirred suspension of sodium hydride (0.44 g, 11.04 mmol) in THF (20 mL) at 0°C
were added 4-methoxynitrobenzaldehyde (1.0 g, 5.52 mmol) and ethyl(triphenyl
phosphoranylidene)propanoate (2.0 g, 5.52 mmol), allowed to stir at RT for 4 h. After
completion of the reaction, the reaction mixture diluted with water and extracted with EtOAc
(200 mL X 2). The combined organic layers were washed with water (200 mL), brine (100 mL),
dried over sodium sulphate and concentrated. The residue was purified on silica gel (100–200
mesh) to afford the title product as a brown solid (0.33 g, 22%). H NMR (400 MHz, CDCl ): δ
7.83 (s, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.26 (s, 1H), 7.20–7.17 (m, 1H), 4.28 (q, J=7.3 Hz, 2H),
3.90 (s, 3H), 1.91 (s, 3H), 1.35 (t, J=7.4 Hz, 3H).
Step-b: Synthesis of (E)-ethyl 3-(2-aminomethoxyphenyl)methylacrylate
To a solution of (E)-ethyl 3-(4-methoxynitrophenyl)methylacrylate (0.33 g, 1.23
mmol) in MeOH (10 mL) were added Conc. HCl (2.0 mL) and SnCl .2H O (1.46 g, 6.05 mmol)
stirred at 80ºC for 4 h. After completion of the reaction, the reaction mixture was filter through
celite, the filtrate was concentrated. The residue was diluted with water and extracted with
EtOAc (200 mL X 2). The combined organic layers were washed with water (200 mL), brine
(100 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was
purified by column chromatography by using silica gel (100–200 mesh) to afford the title
product as a brown solid (0.2 g, 69%). H NMR (400 MHz, DMSO-d ): δ 7.50 (s, 1H), 7.01 (d,
J=8.3 Hz, 1H), 6.29 (d, J=2.3 Hz, 1H), 6.19 (dd, J=8.8, 2.4 Hz, 1H), 5.24 (bs, 2H), 4.20–4.10 (m,
2H), 3.68 (s, 3H), 1.95 (s, 3H), 1.25 (d, J=6.8 Hz, 3H); LC-MS: m/z 236.2 (M+1) .
Step-c: Synthesis of 7-methoxymethylquinolin-2(1H)-one
A solution of (E)-ethyl 3-(2-aminomethoxyphenyl)methylacrylate (0.13 g, 0.55
mmol) in dioxane.HCl (4 mL) was heated at 100ºC in a sealed tube for 16 h. After completion of
the reaction, the reaction mixture was allowed to RT and concentrated, neutralized with cold aq.
NaHCO solution. The residue was extracted with EtOAc (200 mL X 2) twice. The combined
organic layers were washed with water (200 mL), brine (100 mL), dried over sodium sulphate
and concentrated under reduced pressure to afford the title product as an off white solid (0.06 g,
58 %). H NMR (400 MHz, DMSO-d ): δ 11.59 (bs, 1H), 7.67 (s, 1H), 7.48 (d, J=8.3 Hz, 1H),
6.79–6.75 (m, 2H), 3.79 (s, 3H), 2.04 (s, 3H); LC-MS: m/z 190.2 (M+1) .
Step-d: Synthesis of 6-bromomethoxymethylquinolin-2(1H)-one
The process of this step was adopted from step-b of Intermediate-2. The desired
compound obtained as an off white solid (0.06 g, 53%); H NMR (400 MHz, DMSO-d ): δ 11.72
(bs, 1H), 7.84 (s, 1H), 7.66 (s, 1H), 6.91 (s, 1H), 3.87 (s, 3H), 2.04 (s, 3H); LC-MS: m/z 268.0
(M+1) .
Alternative procedure: Synthesis of 6-bromomethoxymethylquinolin-2(1H)-one
Step-a: Synthesis of N-(3-methoxyphenyl)acetamide
To an ice-cooled solution of 3-methoxyaniline (40 g, 325.0 mmol) in AcOH (40 mL) was
added aceticanhydride (40 mL) drop wise and stirred at RT for 2 h. Reaction mixture was poured
into ice water; solid was filtered off and washed with water, dried under reduced pressure for
overnight to give title compound as off white solid (60 g). H NMR (400 MHz, DMSO-d ) δ
9.89 (s, 1H), 7.27 (s, 1H), 7.18 (t, J=8.0 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 6.60 (dd, J=2.2 Hz, 8.2
Hz, 1H), 3.71 (s, 3H), 2.02 (s, 3H); LC-MS: m/z 166.2 (M+1) .
Step-b: Synthesis of 2-chloromethoxyquinolinecarbaldehyde
POCl (339 mL, 3636.0 mmol) was added drop wise to DMF (112 mL, 1454.4 mmol) at
0 C, after stirred for 5 min, N-(3-methoxyphenyl)acetamide (60 g, 363.6 mmol) was added and
resulting solution was heated to 100 C for 3 h. The reaction mixture was cooled to room
temperature and poured into ice water; solid was filtered off and washed with water, dried under
reduced pressure for overnight to give title compound as pale yellow solid (88 g). H NMR (400
MHz, DMSO-d ) δ 10.34 (s, 1H), 8.88 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.45 (d, J=2.5 Hz, 1H),
7.39 (dd, J=2.5 Hz, 9.3 Hz, 1H), 3.98 (s, 3H); LC-MS: m/z 222.1 (M+1) .
Step-c: Synthesis of 7-methoxyoxo-1,2-dihydroquinolinecarbaldehyde
A suspension of 2-chloromethoxyquinolinecarbaldehyde (8.0g, 36.2 mmol) in 70%
acetic acid (370 mL) was heated to 110 ºC for 16h. Upon cooling the reaction mixture to room
temperature and poured into crushed ice;solid was filtered off and washed with water, dried
under reduced pressure for overnight to give title compound as pale yellow solid (5.6 g, 76%). H
NMR (400 MHz, DMSO-d ) δ 12.07 (s, 1H), 10.18 (s, 1H), 8.43 (s, 1H), 7.84 (d, J=8.9 Hz, 1H),
6.89 (dd, J=2.5 Hz, 8.8 Hz, 1H), 6.82 (d, J=1.9 Hz, 1H), 3.86 (s, 3H); LC-MS: m/z 204.1
(M+1) .
Step-d: Synthesis of 7-methoxymethylquinolin-2(1H)-one
To an ice-cooled solution of 7-methoxyoxo-1,2-dihydroquinolinecarbaldehyde (6 g,
29.55 mmol) in TFA (110 mL) was added triethyl silane (13.2 mL) drop wise and stirred at RT
for 16h. Reaction mixture was poured into ice water; solid was filtered off and washed with
water, dried under reduced pressure for overnight to give title compound as pale yellow solid
crude (6 g). H NMR (400 MHz, DMSO-d ) δ 11.59 (s, 1H), 7.67 (s, 1H), 7.48 (d, J=8.8 Hz,
1H), 6.78-6.75 (m, 2H), 3.78 (s, 3H), 2.04 (s, 3H); LC-MS: m/z 190.1 (M+1) .
Step-e: Synthesis of 6-bromomethoxymethylquinolin-2(1H)-one
The process of this step was adopted from step-b of Intermediate-2.
Intermediate-7.1: Synthesis of 6-bromocyclohexylmethoxyquinolin-2(1H)-one:
Step-a: Synthesis of methyl 3-(5-bromomethoxynitrophenyl)cyclohexylhydroxy
propanoate
To a solution of methyl 2-cyclohexylacetate (0.39 g, 2.49 mmol) in THF (20 mL) at -
78 C was added LDA 2.0 M in THF (2.4 mL, 4.80 mmol) and stirred for 1 h at same conditions,
then added 5-bromomethoxynitrobenzaldehyde (0.5 g, 1.92 mmol) in THF and stirred at -
78 C for 2h. The reaction mixture quenched with sat NH Cl and extracted with EtOAc (150 mL)
and washed with water (150 mL), dried over sodium sulphate and concentrated under reduced
pressure. The residue was used for further step without purification (0.07 g crude).
Step-b: Synthesis of 6-bromocyclohexylmethoxyquinolin-2(1H)-one
To a solution of methyl 3-(5-bromomethoxynitrophenyl)cyclohexylhydroxy
propanoate (0.5 g, 1.29 mmol) in AcOH (10 mL) was added iron powder (0.2 g, 3.88 mmol) and
C for 1 h. Reaction mixture filtered through celite, washed with EtOAc combined
stirred at 80
filtrate was concentrated, the residue was diluted with water and extracted with EtOAc (100 mL),
washed with brine (100 mL), dried over sodium sulphate and concentrated. The residue was used
for further step without purification (crude-0.4 g). H NMR (400 MHz, DMSO-d6): δ 11.70 (s,
1H), 7.89 (s, 1H), 7.59 (s, 1H), 6.89 (s, 1H), 3.86 (s, 3H), 2.67-2.55 (m, 1H), 1.83-1.77 (m, 6H),
1.34-1.23 (m, 4H); LC-MS: m/z 336.1 (M+1) .
Intermediate-8: Synthesis of 6-bromomethoxymethylquinolin-2(1H)-one
Step-a: Synthesis of N-(4-bromomethoxyphenyl)oxobutanamide
To a stirred solution of 4-bromomethoxyaniline (0.5 g, 2.47 mmol) in toluene (5 mL)
were added ethylacetoacetate (0.5 mL, 3.71), sodium ethoxide (0.34 g, 4.94 mmol), and heated to
110ºC for 16 h. After completion of the reaction, the reaction mixture was diluted with EtOAC
(100 mL), washed with water (100 mL), brine (100 mL), dried over sodium sulphate and
concentrated. The residue was purified by column chromatography by using silica gel (60-120
mesh) to afford the title product as yellow solid (0.4 g, 90%). H NMR (400 MHz, DMSO-d ): δ
.21 (s, 1H), 7.48–7.43 (m, 2H), 7.11–7.08 (m, 1H), 3.83 (s, 3H), 3.54 (s, 2H), 2.20 (s, 3H); ES-
MS: m/z 286.1 (M+1) .
Step-b: Synthesis of 6-bromomethoxymethylquinolin-2(1H)-one
The process of this step was adopted from step-d of intermediate-5. The desired
compound obtained as a pale yellow solid (0.33 g, 90%); H NMR (400 MHz, DMSO-d6): δ
11.56 (bs, 1H), 7.86 (s, 1H), 6.93 (s, 1H), 6.26 (s, 1H), 3.88 (s, 3H), 2.37 (s, 3H); LC-MS: m/z
268.1 (M+1) .
The below Intermediates 9 and 10 were prepared according to the above protocol.
Int Characterization Int Characterization
Structure Structure
No. data No. data
LC-MS: m/z LC-MS: m/z
9 10
323.3 (M+1) . 297.0 (M+1) .
Intermediate-11: Synthesis of 6-bromomethoxy-4,4-dimethyl-3,4-dihydroquinolin-2(1H)-
one:
Step-a: Synthesis of N-(4-bromomethoxyphenyl)methylbutenamide
A solution of 4-bromomethoxyaniline (2.0 g, 9.90 mmol) in chloroform (20 mL) was
added 3-methylbutenoyl chloride and refluxed for 3 h. After completion of the reaction, the
reaction mixture was poured over cold aq. NaHCO solution and extracted with EtOAC (50 mL),
washed with water (50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The
residue was used for next step without further purification (1.7 g). H NMR (400 MHz, DMSO-
d ): δ 9.95 (s, 1H), 7.56 (d, J=2.5 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.11 (dd, J=2.2, 8.4 Hz, 1H),
.84 (s, 1H), 3.80 (s, 3H), 2.14 (s, 3H), 1.84 (s, 3H); LC-MS: m/z 284.0 (M+1) .
Step-b: Synthesis of 6-bromomethoxy-4,4-dimethyl-3,4-dihydroquinolin-2(1H)-one
N-(4-bromomethoxyphenyl)methylbutenamide (0.5 g, 1.76 mmol) was heated at
130°C before aluminum chloride (0.35 g, 2.64 mmol) was added portion wise over a period of
1.5 h. After completion of the reaction, the reaction mixture was diluted with H O (50 mL),
extracted with EtOAc (100 mL X 2). The combined organic layers were washed with water (50
mL), brine (50 mL), dried over sodium sulphate and concentrated. The residue was purified by
column chromatography by using silica gel (100-200 mesh) to afford the title product as a off-
white solid. (0.15 g, 31%). H NMR (400 MHz, DMSO-d6): δ 10.14 (bs, 1H), 7.38 (s, 1H), 6.62
(s, 1H), 3.77 (s, 3H), 2.32 (s, 2H), 1.19 (s, 6H); ES-MS: m/z 285.0 (M+1) .
Intermediate-12: Synthesis of 6-bromomethoxy-3,3-dimethylquinoline-2,4(1H,3H)-dione
Step-a: Synthesis of 3-((3-methoxyphenyl)amino)-2,2-dimethyloxopropanoicacid
A solution of 2,2-dimethylmalonic acid (5.3 g, 40.65 mmol) and thionyl chloride (3.5
mL, 48.78 mmol) in THF (20 mL) was refluxed for 2 h and then concentrated. The residue was
dissolved in THF (20 mL) and solution was slowly added into a solution of 3-methoxy aniline (5
g, 40.65 mmol) and triethylamine (5.6 mL, 40.65 mmol) in THF (20 mL) at 0°C, then the
reaction mixture allowed to stir at RT for 1h. After completion of the reaction, the reaction
mixture concentrated and diluted with 5N NaOH solution (p ~9-11), washed with EtOAc. The
aqueous layer was acidified with Conc. HCl and the resulting precipitate was collected and
washed with water to afford the title product as a white solid (2.5 g, 29%). H NMR (400 MHz,
DMSO-d ): δ 12.65 (bs, 1H), 9.41 (s, 1H), 7.33 (t, J=1.9 Hz, 1H), 7.24–715 (m, 2H), 6.63–6.60
(m, 1H), 3.71 (s, 3H), 1.40 (s, 6H); ES-MS: m/z 236.1 (M-1) .
Step-b: Synthesis of 7-methoxy-3,3-dimethylquinoline-2,4(1H,3H)-dione
A solution of 3-((3-methoxyphenyl) amino)oxopropanoic acid (0.5 g, 2.39 mmol) in
poly phosphoric acid (5 mL) was heated to 130ºC for 4 h. After completion of the reaction, the
reaction mixture was poured into ice water and extracted with EtOAc (100 mL). The organic
layer was washed with brine (100 mL), dried over sodium sulphate and concentrated. The
residue was purified on silica gel (60-120 mesh) to afford the title product as a yellow solid (0.25
g, 54 %); ES-MS: m/z 220.1 (M+1) .
Step-c: Synthesis of 6-bromomethoxy-3,3-dimethylquinoline-2,4(1H,3H)-dione
The process of this step was adopted from step-b of intermediate-2. The desired
compound obtained as white solid 0.15 g (73%); H NMR (400 MHz, DMSO-d ): δ 10.80 (s,
1H), 7.84 (s, 1H), 6.74 (s, 1H), 3.91 (s, 3H), 1.33 (s, 6H); LC-MS: m/z 299.1 (M+1) .
Intermediate-13: Synthesis of 6-bromomethoxy-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-
one
Step-a: Synthesis of 7-methoxy-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one
To a stirred solution of 7-methoxy-3,3-dimethylquinoline-2,4(1H,3H)-dione (0.25 g, 1.14
mmol) in AcOH (28 mL), were added Ac O (0.12 mL), Conc. H SO (0.02 mL), 10% Pd-C then
2 2 4
hydrogenated using hydrogen bladder pressure at RT for 16 h. Then the reaction mixture filtered,
powdered NaHCO was added to the filtrate and extracted with EtOAc (100 mL) and organic
layer washed with water (100 mL), dried over sodium sulphate and concentrated. The residue
was purified by column chromatography by using silica gel (60-120 mesh) to afford the title
product as a pale yellow solid (0.15 g, 65%). H NMR (400 MHz, DMSO-d ): δ 9.91 (s, 1H),
7.04 (d, J=8.3 Hz, 1H), 6.50–6.43 (m, 2H), 3.68 (s, 3H), 2.65 (s, 2H), 1.03 (s, 6H); LC-MS: m/z
206.2 (M+1) .
Step-b: Synthesis of 6-bromomethoxy-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one
The process of this step was adopted from step-b of intermediate-2. The desired
compound obtained as a white solid (0.09 g, 60%). H NMR (400 MHz, DMSO-d ): δ 10.03 (s,
1H), 7.34 (s, 1H), 6.60 (s, 1H), 3.76 (s, 3H), 2.68 (s, 2H), 1.03 (s, 6H); LC-MS: m/z 286.1
(M+1) .
Intermediate-14: Synthesis of 6-(3, 5-dimethylisoxazolyl)methoxy-3,4-dihydroquinolin-
2(1H)-one
Step-a: Synthesis of 6-bromohydroxy-3, 4-dihydroquinolin-2(1H)-one
The process of this step was adopted from step-b of intermediate-2. The desired
compound obtained as a white solid (2.2 g, 75%); H NMR (400 MHz DMSO-d ) δ 9.46 (bs,
1H), 9.39 (bs, 1H), 7.18 (s, 1H), 6.56 (s, 1H), 2.82 (t, J=7.3 Hz, 2H), 2.52 (t, J=7.3 Hz, 2H); ES-
MS m/z 244.1 (M+1) .
Step-b: Synthesis of 6-bromomethoxy-3, 4-dihydroquinolin-2(1H)-one
To a stirred suspension of 6-bromohydroxy-3, 4-dihydroquinolin-2(1H)-one (2.2 g, 9
mmol) in ethanol was added K CO (2.49 g, 18.1 mmol). The resulting mixture was refluxed for
2 h, then reaction mixture cooled to 0°C and methyl iodide (2.5 g, 18.1 mmol), KI (0.075 g, 18.1
mmol) were added. The reaction mixture was refluxed for 12 h, filtered, concentrated under
reduced pressure. The residue was purified by chromatography on silica (10 % EtOAc in
hexanes) to give the desired product as a off-white solid (1.7 g, 73%). H NMR (400 MHz
DMSO-d ) δ 10.07 (bs, 1H), 7.30 (s, 1H), 6.60 (s, 1H), 3.76 (s, 3H), 2.81- 2.78 (m, 2H), 2.43-
2.40 (m, 2H); ES-MS m/z 256.1 (M+1) .
Step-c: Synthesis of 6-(3, 5-dimethylisoxazolyl)methoxy-3,4-dihydroquinolin-2(1H)-one
The process of this step was adopted from step-f of intermediate-1. The desired
compound obtained as an off white solid (0.150 g, 47 %). H NMR (400 MHz DMSO-d ) δ
10.09 (s, 1H), 6.99 (s, 1H), 6.62 (s, 1H), 3.69 (s, 3H), 3.82 (t, J=7.6 Hz, 2H), 2.45 (t, J=7.6 Hz,
2H), 2.23 (s, 3H), 2.05 (s, 3H); ES-MS m/z 273.1 (M+1) .
Intermediate-15: Synthesis of 1-(pyridinyl)ethylmethanesulfonate
Step-a: To an ice cooled solution of 1-(pyridinyl)ethanol (0.25 g, 2.07 mmol) in DCM (5 mL)
were added triethylamine (0.58 mL, 4.14 mmol) followed by methanesulfonylchloride (0.32 mL,
4.14 mmol) and stirred at RT for 4 h. After completion of the reaction, the reaction mixture was
diluted with DCM (50 mL) and washed with water (50 mL), brine (20 mL), dried over sodium
sulphate and concentrated. The residue was used for next step without further purification (0.42
g, 100%). H NMR (400 MHz, DMSO-d ): δ 8.61 (d, J=6.0 Hz, 2H), 7.44 (d, J=6.0 Hz, 2H),
5.80 (qt, J=6.8 Hz, 1H), 3.20 (s, 3H), 1.60 (d, J =6.8 Hz, 3H); LC-MS: m/z 202.1 (M+1) .
The below Intermediates 16 to 26, 26a, 26b, 26c and 26d were prepared according to the
above protocol.
Int Characterization Int Characterization
Structure Structure
No. data No. data
LC-MS: m/z
16 - 17
202.1 (M+1) .
LC-MS: m/z
18 19 -
221.1 (M+1) .
LC-MS: m/z
21 -
206.1 (M+1) .
ES-MS: m/z
22 - 23
202.1 (M+1) .
ES-MS: m/z
24 - 25
189.1 (M+1) .
LC-MS: m/z
ES-MS: m/z
26 26a 218.1 (M+1) .
194.1 (M+1) .
26b - 26c -
26d -
Intermediate-27: Synthesis of 2-(iodomethyl)(trifluoromethyl)pyridine
To a stirred solution of (5-(trifluoromethyl)pyridinyl)methanol (0.9 g, 5.02 mmol) in
anhydrous THF (10 mL), triphenylphosphine (1.97 g, 7.54 mmol), imidazole (1.02 g, 15.08
mmol) and iodine (1.92 g, 7.54 mmol) were added sequentially at RT. The reaction mixture was
stirred for 30 min at room temperature. After complete of the reaction, the reaction mixture was
quenched with an aqueous sodium thiosulfate (20 mL). The organic solvent was separated and
aqueous layer was extracted with diethyl ether. The combined organic layer were washed with
brine solution and dried over anhydrous Na SO . The solvents were removed under reduced
pressure. The residue was purified by column chromatography (60-120 silica gel and 2% EtOAc
in hexane as eluent) to yield the title compound (0.30 g, 20%). H NMR, CDCl , 300 MHz: δ
8.82 (s, 1H), 7.86 (dd, J=8.1 & 1.8 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 4.55 (s, 2H); LC-MS: m/z
287.8 (M+1) .
Intermediate-28: Synthesis of 7-bromomethoxy(pyridinylmethyl)-2H-benzo[b][1,4]
oxazin-3(4H)-one (Method-A)
To a solution of intermediate-2 (0.5 g, 1.98 mmol) in CH CN (20 mL) were added
cesium carbonate (1.58 g, 4.85 mmol) followed by 4-(bromomethyl)pyridine.HBr (0.73 g, 2.91
mmol) and stirred at 60ºC for 6h. After completion of the reaction, the reaction mixture was
concentrated, diluted with water and extracted with EtOAc (200 mL X 2) twice. The combined
organic layers were washed with water (200 mL), brine (100 mL), dried over sodium sulphate
and concentrated under reduced pressure. The residue was purified on silica gel (100-200 mesh)
to afford the titled product as off-white solid (0.52 g, 74%). H NMR (400 MHz, DMSO-d ) δ
8.52 (d, J=4.4 Hz, 2H), 7.31–7.30 (m, 3H), 6.89 (s, 1H), 5.26 (s, 2H), 4.78 (s, 2H), 3.66 (s, 3H).
Intermediate-29: Synthesis of 6-bromo((6-chloropyridinyl) methyl)methoxyquinolin-
2(1H)-one (Method-B)
To a solution of intermediate-5 (0.2 g, 0.78 mmol) in DMF (5 mL) were add potassium
carbonate (0.32 g, 0.99 mmol) followed by 2-chloro(chloromethyl)pyridine (0.33 g, 2.36
mmol) and stirred at RT for 16 h. After completion of the reaction, the reaction mixture was
diluted with water and extracted with EtOAc (200 mL X 2). The combined organic layers were
washed with water (200 mL), brine (100 mL), dried over sodium sulphate and concentrated. The
residue was purified by preparative TLC to afford the title product as an off white solid (0.05 g,
17%). H NMR (400 MHz, DMSO-d ): δ 8.44 (d, J=2.5 Hz, 1H), 8.04 (s, 1H), 7.90 (d, J=9.3 Hz,
1H), 7.67 (dd, J=5.9 & 2.4 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 6.98 (s, 1H), 6.60 (d, J=9.3 Hz, 1H),
.60 (s, 2H), 3.86 (s, 3H); LC-MS: m/z 379.0 (M+1) .
Intermediate-30: Synthesis of 6-bromomethoxy(pyrimidinylmethyl)quinolin-2(1H)-
one (Method-C)
To a stirred solution of intermediate-5 (0.15 g, 0.59 mmol) in DMF (5 mL) were added
60% NaH (0.035 g, 0.088 mmol), 4-(chloromethyl)pyrimidine (0.113 g, 0.88 mmol), and stirred
at RT for 16 h. After completion of the reaction, the reaction mixture was poured on ice water,
diluted with EtOAC (30 mL), washed with water (50 mL), brine (50 mL), dried over sodium
sulphate and concentrated. The residue was purified on silica gel (100-200 mesh) to afford the
titled product as off-white solid (0.08 g, 39%). H NMR (400 MHz, DMSO-d ): δ 9.07–9.06 (m,
1H), 8.73 (d, J=4.8 Hz, 1H), 8.04 (s, 1H), 7.94–7.90 (m, 1H), 7.41–7.39 (m. 1H), 6.94 (s, 1H),
6.57 (d, J=9.8 Hz, 1H), 5.66 (s, 2H), 3.80 (s, 3H); LC-MS: m/z 346.1 (M+1) .
The below intermediates were prepared by using the above three different methods. This
N-alkylation reaction can be carried out by using the appropriate reactant having
alkylhalide/mesylate in presence of suitable base.
Int Meth
Structure Characterization data
No. od
H NMR (400 MHz, CDCl ) δ 7.40 – 7.10 (m, 5H), 6.39
(s, 1H), 5.12 (s, 2H), 4.67(s, 2H), 3.67 (s, 3H); ES-MS:
31 A
O N O
m/z 382.1 (M+H) .
Br O
H NMR (400 MHz, DMSO-d ): δ 8.56 (d, J=6.0 Hz,
2H), 7.36 (d, J=5.2 Hz, 2H), 7.32 (s, 1H), 6.37 (s, 1H),
32 A
6.15–60.5 (m, 1H), 4.74–4.65 (m, 2H), 3.52 (s, 3H), 1.79
(d, J=6.8 Hz, 3H); LC-MS: m/z 364.1.0 (M+1) .
H NMR (400 MHz, CDCl ): δ 8.63–8.56 (m, 2H), 7.59
(d, J=8.0 Hz, 1H), 7.31–7.29 (m, 1H), 7.21 (s, 1H), 6.41
33 A
(s, 1H), 5.18 (s, 2H), 4.68 (s, 2H), 3.69 (s, 3H); LC-MS:
m/z 351.0 (M+1) .
H NMR (400 MHz, CDCl ) δ 8.56 (d, J=4.0 Hz, 1H),
7.66 (td, J=7.6 & 2.0 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H),
34 A 7.23–7.20 (m, 1H), 7.17 (s, 1H), 6.89 (s, 1H), 5.26 (s,
2H), 4.66 (s, 2H), 3.74 (s, 3H); LC-MS: m/z 349.0
(M+1) .
H NMR (400 MHz, DMSO-d ): δ 7.26 (s, 1H), 6.94 (s,
1H), 4.60 (s, 2H), 3.92 (d, J=7.2 Hz, 2H), 3.86 (s, 3H),
A 3.81 (dd, J=11.6 & 2.8 Hz, 2H), 3.21 (t, J=5.8 Hz, 2H),
1.94 – 1.89 (m, 1H), 1.52–1.48 (m, 2H), 1.30-1.18 (m,
2H); LC-MS: m/z 358.1 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.60 (d, J=2.4 Hz,
1H), 8.50 (d, J=4.4 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.40
36 A (dd, J=8.4 & 3.6 Hz, 1H), 7.30 (s, 1H), 6.45 (s, 1H), 6.14
(q, J=7.6 Hz, 1H), 4.73-4.63 (m, 2H), 3.54 (s, 3H), 1.83
(d, J=7.6 Hz, 3H); LC-MS: m/z 364.0 (M+1) .
1H NMR (400 MHz, CDCl ): δ 8.13 (d, J=2.4 Hz, 1H),
7.50 (dd, J=8.8 & 2.8 Hz, 1H), 7.19 (s, 1H), 6.72 (d,
37 A
J=8.4 Hz, 1H), 6.51 (s, 1H), 5.08 (s, 2H), 4.64 (s, 2H),
3.91 (s, 3H), 3.74 (s, 3H). LC-MS: m/z 381.0 (M+1) .
H NMR (400 MHz, CDCl ): δ 8.84 (d, J=2.0 Hz, 1H),
7.95 (dd, J=7.6 & 2.0 Hz, 1H), 7.49 (d, J=6.0 Hz, 1H),
38 A
O N O
7.21 (s, 1H), 6.76 (s, 1H), 5.29 (s, 2H), 4.66 (s, 2H), 3.77
(s, 3H); LC-MS: m/z 376.0 (M+1) .
H NMR (400 MHz, CDCl ): δ 8.51 (d, J=2.4 Hz, 1H),
7.64 (dd, J=8.8 & 2.4 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H),
39 A
7.17 (s, 1H), 6.90 (s, 1H), 5.21 (s, 2H), 4.64 (s, 2H), 3.70
(s, 3H); LC-MS: m/z 384.0 (M+1) .
H NMR (400 MHz, CDCl ) δ 8.41 (s, 1H), 7.45-7.35
(m, 2H), 7.17 (s, 1H), 6.95 (s, 1H), 5.23 (s, 2H), 4.64 (s,
40 A
2H), 3.79 (s, 3H); LC-MS: m/z 367.0 (M+1) .
H NMR (400 MHz, CDCl ) δ 8.23 (d, J=2.8 Hz, 1H),
7.29 (d, J=8.8 Hz, 1H), 7.18–7.15 (m, 2H), 7.03 (s, 1H),
41 A
.19 (s, 2H), 4.63 (s, 2H), 3.84 (s, 3H), 3.79 (s, 3H); LC-
MS: m/z 381.0 (M+1) .
H NMR (400 MHz, CDCl3) δ 8.59–8.58 (m, 1H), 7.81–
7.77 (m, 1H), 7.43–7.41 (m, 1H), 7.33–7.26 (m, 1H),
42 A 7.13 (s, 1H), 6.61 (s, 1H), 6.23–6.18 (m, 1H), 4.66 (s,
2H), 3.54 (s, 3H), 1.80 (d, J=6.9 Hz, 3H); LC-MS: m/z
365.0 (M+1) .
43 A LC-MS: m/z 363.0 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 7.45–7.35 (m, 4H),
6.40 (s, 1H), 6.13–6.11 (m, 1H), 4.72–4.63 (m, 2H),
44 A
4.04–4.02 (m, 1H), 3.51 (s, 3H), 1.78 (d, J=6.9 Hz, 3H);
ES-MS: m/z 398.1 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.52 (d, J=4.4 Hz,
1H), 7.71–7.67 (m, 1H), 7.29–7.21 (m, 3H), 6.94 (s, 1H),
45 A
4.57 (s, 2H), 4.30 (t, J= 7.0 Hz, 2H), 3.86 (s, 3H), 3.05 (t,
J=7.0 Hz, 2H); LC-MS: m/z 363.0 (M+1) .
H NMR (400 MHz, CDCl ) δ 7.32 (s, 1H), 6.59 (s, 1H),
4.60 (s, 2H), 4.25–4.14 (m, 2H), 4.15–3.80 (m, 5H),
46 A
2.75–2.60 (m, 2H), 2.00–1.90 (m, 1H), 1.75–1.70 (m,
2H), 1.47 (s, 9H), 1.40–1.25 (m, 2H).
H NMR (400 MHz, DMSO-d ): δ 8.59 (d, J = 1.5 Hz,
1H), 8.46 (dd, J=3.9 & 1.0 Hz, 1H), 8.04 (s, 1H), 7.90 (d,
47 A J=8.1 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.35–7.32 (m,
1H), 6.99 (s, 1H), 6.60 (d, J=9.8 Hz, 1H), 5.61 (s, 2H),
3.84(s, 3H); LC-MS: m/z 346.0 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.57–8.55 (m, 1H),
8.18–8.15 (m, 2H), 7.79–7.75 (m, 1H), 7.49 (d, J=7.6 Hz,
48 A 1H), 7.32–7.27 (m, 1H), 7.18 (s, 1H), 6.99 (d, J=8.8 Hz,
1H), 6.45-6.44 (m, 1H), 3.95 (s, 3H), 1.67 (d, J=6.8 Hz,
3H); LC-MS: m/z 361.0 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.75 (s, 1H), 8.50–
8.48 (m, 1H), 8.18–8.14 (m, 2H), 7.93–7.90 (m, 1H),
49 A 7.41–7.38 (m, 1H), 7.22 (s, 1H), 6.95 (d, J=8.8 Hz, 1H),
6.48-6.42 (m, 1H), 3.97 (s, 3H), 1.68 (d, J=6.4 Hz, 3H);
LC-MS: m/z 359.0 (M+1) .
50 A LC-MS: m/z 359.1 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.49 (d, J=3.0 Hz,
1H), 8.01 (s, 1H), 7.87 (d, J=9.6 Hz, 1H), 7.72–7.67 (m,
51 A 1H), 7.42–7.38 (m, 1H), 7.07 (s, 1H), 6.57 (d, J=9.6 Hz,
1H), 5.63 (s, 2H), 3.82 (s, 3H); LC-MS: m/z 365.0
(M+1) .
H NMR (400 MHz DMSO-d ): δ 8.41 (d, J=8.8 Hz,
1H), 8.23–8.21 (m, 2H), 8.01 (t, J=9.3 Hz, 2H), 7.80-
52 A 7.78 (m, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.63 (m, 1H), 7.27
(s, 1H), 7.08 (d, J=8.8 Hz, 1H), 5.76 (s, 2H), 3.97 (s,
3H); LC-MS: m/z 395.0 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.50 (d, J=2.5 Hz,
1H), 8.01 (s, 1H), 7.90–7.87 (m, 2H), 7.36 (d, J=8.8 Hz,
53 B
1H), 7.04 (s, 1H), 6.57 (d, J=9.8 Hz, 1H), 5.63 (s, 2H),
3.81 (s, 3H); LC-MS: m/z 380.1 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.74–8.73 (m, 1H),
8.02 (s, 2H), 7.86 (d, J=9.2 Hz, 1H), 7.41– 7.38 (m, 1H),
54 B
6.88 (s, 1H), 6.54 (d, J=8.8 Hz, 1H), 5.73 (s, 2H), 3.75 (s,
3H); LC-MS: m/z 348.0 (M+1) .
55 B ES-MS: m/z 367.1 (M+1) .
56 B LC-MS: m/z 353.0 (M+1) .
H NMR (CDCl , 300 MHz): δ 8.82 (s, 1H), 7.85 (d,
J=7.2 Hz, 1H), 7.71 (s, 1H), 7.59 (d, J=9.6 Hz, 1H ), 7.47
57 B
(d, J=8.1 Hz, 1H), 7.11 (s, 1H), 6.66 (d, J=9.6 Hz, 1H),
.71 (bs, 2H), 3.91 (s, 3H); LC-MS: m/z 414.8 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.50 (d, J=7.2 Hz,
1H), 7.77–7.73 (m, 1H), 7.40 (s, 1H), 7.34–7.25 (m, 2H),
58 B
6.81 (s, 1H), 5.28 (s, 2H), 3.67 (s, 3H), 2.55 (s, 2H),
1.23 (s, 6H); LC-MS: m/z 377.1 (M+1) .
59 B ES-MS: m/z 377.0 (M+1) .
H NMR (400 MHz, CDCl ): δ 8.56 (d, J=4.9 Hz, 1H),
7.63–7.58 (m, 2H), 7.46 (s, 1H), 7.26–7.24 (m, 1H),
60 B
7.20–7.18 (m, 1H), 7.12 (s, 1H), 5.68 (s, 2H), 3.86 (s,
3H), 2.29 (s, 3H); LC-MS: m/z 361.0 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.55 (d, J=2.0 Hz,
1H), 7.91-7.87 (m, 2H), 7.75 (d, J=1.0 Hz, 1H), 7.35 (d,
61 B
J=8.8 Hz, 1H), 7.02 (s, 1H), 5.65 (s, 2H), 3.80 (s, 3H),
2.13 (s, 3H); LC-MS: m/z 393.0 (M+1) .
H NMR (400 MHz, CDCl ): δ 7.67 (s, 1H), 7.43 (s, 1H),
7.30-7.26 (m, 2H), 7.22 (d, J=8.3 Hz, 2H), 6.66 (s, 1H),
62 B
4.45 (t, J=7.9 Hz, 2H), 3.93 (s, 3H), 3.02 (t, J=7.8 Hz,
2H), 2.24 (s, 3H); LC-MS: m/z 406.0 (M+1) .
63 B LC-MS: m/z 427.1 (M+H, 97.56%).
64 B LC-MS: m/z 429.1 (M+2) .
H NMR (400 MHz, DMSO-d ): δ 8.50 (d, J=4.4 Hz,
1H), 7.92 (s, 1H), 7.79–7.75 (m, 1H), 7.39–7.37 (m, 1H),
65 B
7.31–7.28 (m, 1H), 6.90 (s, 1H), 5.38 (s, 2H), 3.80 (s,
3H), 2.40 (s, 6H); LC-MS: m/z 391.0 (M+1) .
66 B LC-MS: m/z 375.1 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.50 (d, J=4.4 Hz,
1H), 7.92 (s, 1H), 7.76–7.72 (m, 1H), 7.29–7.24 (m, 2H),
67 B
7.07 (s, 1H), 6.50 (s, 1H), 5.61 (s, 2H), 3.78 (s, 3H), 2.42
(s, 3H); LC-MS: m/z 359.1 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.49–8.48 (m, 1H),
7.81–7.77 (m, 2H), 7.42–7.40 (m, 1H), 7.31–7.29 (m,
68 B
1H), 7.22 (s, 1H), 7.10 (s, 1H), 5.71 (s, 2H), 3.84 (s, 3H);
LC-MS: m/z 413.0 (M+1) .
H NMR (400 MHz, CDCl ): δ 8.55 (d, J=4.5 Hz, 1H),
8.18 (s, 1H), 7.59 (dt, J=7.8, 1.8 Hz, 1H), 7.25 (s, 1H),
69 B 7.20–7.17 (m, 2H), 7.15 (s, 1H), 5.64 (bs, 2H), 3.87 (s,
3H), 2.10–2.00 (m, 1H), 1.23–1.07 (m, 2H), 0.83–0.78
(m, 2H); LC-MS: m/z 385.1 (M+1) .
H NMR (400MHz, DMSO-d ): δ 8.49 (d, J=4.4 Hz,
1H), 8.01 (s, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.78-7.77 (m,
70 C 1H), 7.29-7.26 (m, 2H), 7.08 (s, 1H), 6.58 (d, J=9.2 Hz,
1H), 5.62 (s, 2H), 3.79 (s, 3H); MS (ES) m/e 347.0
(M+2) .
HNMR 400 MHz (DMSO-d ) δ 8.02 (s, 1H), 7.96 (S,
1H), 7.40-7.39 (m, 2H), 7.38-7.30 (m, 2H), 6.93 (S, 1H),
71 C
6.60 (d, J=9.2 Hz, 1H), 5.56 (s, 2H), 3.82 (S, 3H); MS
(LC) m/e 378.0 (M+1) .
Intermediate-72: Synthesis of tert-butyl 3, 5-dimethyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazolecarboxylate
To a stirred solution of 3,5-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazole (0.5 g, 2.25 mmol) in 1,4-dioxane (10.0 mL) and 2M Na CO solution (2.5 mL) was
added Boc-anhydride (0.62 mL, 2.70 mmol) and stirred at RT for 48 h. After completion of the
reaction, the reaction mixture was diluted with EtOAc (200 mL), washed with water (100 mL),
brine (50 mL), dried over sodium sulphate and concentrated. The residue was purified on silica
gel (100-200 mesh) to isolate the title compound as off-white solid (0.45 g, 62%). H NMR (400
MHz, DMSO-d ) δ 3.31 (s, 3H), 2.21 (s, 3H), 1.55 (s, 9H), 1.26 (s, 12H); LC-MS: m/z 323.2
(M+1) .
Intermediate-73: Synthesis of 3-bromo(3,4-dimethoxybenzyl)methyl-1H-pyrrole-2,5-
dione
Step-a: Synthesis of 3-bromomethylfuran-2,5-dione
A stirred mixture of 3-methyl-2,5-furandione (2.0 g, 17.85 mmol), AlBr (0.11 g, 3.18
mmol) and Br (1.6 mL, 71.4mmol) was heated overnight at 120ºC. Upon completion of
reaction, the reaction mixture was cooled to RT and diluted with ethyl acetate (100 mL). The
organic phase was washed with 0.1% HCl and brine. The organic phase were dried over
anhydrous Na SO and concentrated under reduced pressure to obtain crude compound, which
was used in next step without any purification (3.20 g, crude). H NMR (300 MHz, CDCl ): δ
2.21 (s, 3H).
Step-b: Synthesis of 3-bromo(3,4-dimethoxybenzyl)methyl-1H-pyrrole-2,5-dione
A stirred solution of 3-bromomethyl-2,5-furandione (1.0 g, 5.29 mmol) in acetic acid
(10 mL) was treated with 1-[3,4-bis(methyloxy)phenyl]methanamine (0.8 g, 5.29 mmol) at RT.
The resulting mixture was heated overnight at 100ºC. Upon completion of the reaction (TLC),
the reaction mixture was concentrated under reduced pressure. The obtained residue was taken in
AcOH (20 mL) and AcONa (0.315 g, 4.23 mmol) was added to the above solution. The reaction
mixture was refluxed for 2 h. The reaction mixture was cooled to RT and diluted with cold
water, before extracting with DCM (3 x 50 mL). The combined organic phase was dried over
anhydrous Na SO and concentrated under reduced pressure. The obtained residue was purified
by silica gel column chromatography (elution 10% EtOAc/hexanes) to give the title compound
as off-white solid (1.0 g, 55.8%). H NMR (300 MHz, CDCl ): δ 6.95–6.92 (m, 2H), 6.81–6.77
(m, 1H), 4.62 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 2.03 (s, 3H); LC-MS: m/z 341.8 (M+1) .
Intermediate-74: Synthesis of 3-cyclopropylmethyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)isoxazole
Step-a: Synthesis of cyclopropanecarbaldehydeoxime
To a stirred solution of hydroxylamine hydrochloride (3.0 g, 45 mmol) in water (10 mL)
were added Na CO (2.4 g, 18 mmol) and a solution of cyclopropanecarboxaldehyde (2.1 g, 30
mmol) in ethyl alcohol (9 mL) at RT. Then the reaction mixture was stirred at room temperature
for 2 h and was extracted with ethyl acetate. The combined organic extracts were washed with
brine, dried over anhydrous sodium sulfate and concentrated. The product was re-crystalyzed
with hexane as white crystalline needles (2.20 g, 99%). H NMR (400 MHz, CDCl ): δ 8.60 (bs,
1H), 6.03 (d, J=8.8 Hz, 1H), 2.31–2.27 (m, 1H), 0.97–0.83 (m, 2H), 0.65–0.61 (m, 2H); LC-MS:
.
m/z 86.2 (M+1)
Step-b: Synthesis of N-hydroxycyclopropanecarbimidoyl chloride
To a stirred solution of cyclopropanecarbaldehyde oxime (1.0 g, 11.75 mmol) in DMF
(10 mL) maintained at RT, NCS (1.50 g, 27.74 mmol) was added under argon atmosphere at RT
and stirred for 2 h. The reaction mixture was diluted with water and extracted with DCM (3 x 50
mL). The combined organic extract was washed with brine and concentrated under reduced
pressure. The residue obtained was used in next step without further purification (1.00 g, crude);
H NMR (400 MHz, CDCl ): δ 9.92 (bs, 1H), 1.91–1.87 (m, 1H), 0.94–0.90 (m, 2H), 0.80–0.75
(m, 2H).
Step-c: Synthesis of 3-cyclopropylmethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)isoxazole
A stirred solution of N-hydroxycyclopropanecarbimidoyl chloride (0.5 g, 4.20 mmol) in
DME (16 mL) was treated with 4,4,5,5-tetramethyl(propynyl)-1,3,2-dioxaborolane (0.69
g, 4.2 mmol) and KHCO3 (0.84 g, 8.4 mmol) at RT under a nitrogen atmosphere. The reaction
mixture was heated at 50ºC for 12 h. The mixture was cooled to room temperature and filtered
through celite pad. The filtrate was concentrated under reduced pressure. The obtained oily
residue was purified by silica gel (100-200 mesh) column chromatography (using 10-20%
EtOAc/Hexane as eluent) to give the title compound as a white solid (0.5 g); LC-MS: m/z 249.8
(M+1) .
Intermediate-75: Synthesis of 3-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)
(trimethylsilyl)isoxazole
Step-a: Synthesis of trimethyl((4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)ethynyl)silane
To a stirred solution of trimethylsilylacetylene (5.27 g, 53.76 mmol) in THF (100 mL) at
-78ºC, 2.5 M of n-BuLi in n-hexane (35.3 mL, 53.76 mmol) was added drop wise under nitrogen
atmosphere. After 15 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.0 g, 53.76
mmol) was slowly added and the reaction mixture was stirred at -78ºC. After 2 h, the reaction
mixture was allowed to warm to -30ºC, and the p was adjusted to 3 using anhydrous HCl. The
reaction mixture was filtered, and the filtrate was distilled to give the title product (10.00 g,
crude). H NMR (400 MHz, DMSO-d ): δ 1.17 (s, 12H), 0.14 (s, 9H).
Step-b: Synthesis of 3-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)(trimethylsilyl)
isoxazole
A solution of chloroacetaldoxime (0.5 g, 4.62 mmol), trimethyl((4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)ethynyl)silane (0.833 g, 3.73 mmol) and KHCO3 (0.934 g, 9.35 mmol)
in DME (16 mL) was heated at 50ºC for 12 h. After completion of the reaction, the reaction
mixture was cooled to room temperature, solids were filtered through celite. The filtrate was
concentrated under reduced pressure to give yellow oil, which was purified by flash column
chromatography (10% EtOAc/Hexane as eluent) to give the title compound as a white solid (0.60
g, 45.5%). H NMR (CDCl , 300 MHz): δ2.40 (s, 3 H), 1.31 (s, 12 H), 0.37 (s, 9 H); LC-MS: m/z
282.3 (M+1) .
Intermediate-76: Synthesis of 7-methoxy(pyridinylmethyl)(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)quinolin-2(1H)-one
In a resealable reaction tube, to a solution of 6-bromomethoxy(pyridin
ylmethyl)quinolin-2(1H)-one (1.0 g, 2.90 mmol) in 1, 4-dioxane, was added 4,4,4',4',5,5,5',5'-
octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.1 g, 4.30 mmol), Pd(dppf)Cl .DCM (0.23 g, 0.29
mmol), and KOAc (0.85 g, 8.7 mmol) under nitrogen atmosphere. The solution was degassed
with nitrogen gas for 15 min, later gradually heated to 100ºC and stirred at same temperature
until the completion of reaction. The reaction mixture was cooled to room temperature, was
diluted with cold water and extracted with ethyl acetate (3 x 30 mL). The combined organic
layers were washed with brine and concentrated under reduced pressure. The residue obtained
was purified by column chromatography (60-120 mesh, 50-100% EtOAc-hexanes as eluent) to
yield the title compound as a pale brown solid (0.80 g, 70.7%). H NMR (400 MHz, DMSO-d ):
δ 8.50 (s, 1H), 7.94–7.90 (m, 2H), 7.78 (m, 1H), 7.3–7.19 (m, 2H), 6.87 (s, 1H), 6.56-6.45 (m,
1H), 5.60 (d, J=18.8 Hz, 2H), 3.93 (s, 3H), 1.26 (s, 12H); LC-MS: m/z 393.2 (M+1) .
Intermediate-77: Synthesis of 6-(3,5-dimethylisoxazolyl)methoxyquinoxalin-2(1H)-one
Step-a: Synthesis of ethyl 2-((5-bromomethoxynitrophenyl)amino)acetate
To a suspension of 5-bromomethoxynitroaniline (1 g, 4.0 mmol) in ethylbromo
acetate (8 g, 4.7 mmol) was added K CO (0.838 g, 6.1 mmol). The reaction mixture was heated
to 150 °C and maintained for 3 h at same temperature. The reaction mixture was diluted with
ethyl acetate and washed with water (50 mLx3) and dried over Na SO and concentration. The
obtained residue was purified by column chromatography on silica (2-5% EtOAc in hexane) to
give the desired product as an off white solid (0.600 g, 45%). HNMR (400 MHz, DMSO-d ) δ
8.25 (bs, 1H), 7.63 (s, 1H), 7.32 (s, 1H), 4.29 (d, J=6.0 Hz, 2H), 4.17 (q, J=7.0 Hz, 2H), 3.84 (s,
3H), 1.22 (t, J=7.0 Hz, 3H). MS (ES) m/e 333.1 (M+1) .
Step-b: Synthesis of ethyl 2-((5-(3,5-dimethylisoxazolyl)methoxynitrophenyl)amino)
acetate
To a stirred solution of ethyl 2-((5-bromomethoxynitrophenyl) amino) acetate (1 g,
3.0 mmol) in 10 mL of 1,4-Dioxane:H O (7:3) was added 3,5-dimethylisoxazoleboronicacid
(0.847 g, 6.0 mmol), K CO (1.243 g, 9.0 mmol), followed by Pd(PPh ) Cl (0.210 g, 0.3 mmol).
2 3 3 2 2
The reaction mixture was heated to 100°C and maintained for 1.5 h at same temperature. Then
allowed to RT and reaction mixture was diluted with ethyl acetate and washed with water (50
mL x 3), dried over Na SO and concentration to gave the desired product as a white solid (0.7 g,
67%); MS (ES) m/e 350.2 (M+1) .
Step-c: Synthesis of 6-(3, 5-dimethylisoxazolyl)methoxy-3,4-dihydroquinoxalin-2(1H)-
A stirred solution of ethyl 2-((5-(3,5-dimethylisoxazolyl)methoxynitrophenyl)
amino)acetate(0.07 g, 2.0057 mmol) in 10 mL of ethanol was added SnCl .2H O (2.25 g, 10.028
mmol). The reaction mixture was heated to reflux and maintained for 1 h. The reaction mixture
was basified with aq. Na CO , extracted with ethyl acetate and dried under reduced pressure to
afford the title compound (0.500 g, 97%) as pale brown solid. HNMR (400 MHz, DMSO-d ) δ
12.4 (bs, 1H), 10.3 (s, 1H), 8.03 (s, 1H), 7.64 (s, 1H), 3.85 (s, 3H), 3.63 (s, 2H), 2.28 (s, 3H),
2.23 (s, 3H). MS (ES) m/e 274.2 (M+1) .
Step-d: Synthesis of 6-(3, 5-dimethylisoxazolyl)methoxyquinoxalin-2(1H)-one
A stirred solution of 6-(3, 5-dimethylisoxazolyl)methoxy-3,4-dihydroquinoxalin-
2(1H)-one (0.200 g, 0.7782 mmol) in 8 % NaOH (2.64 mL) solution was added 30 % H O (2.34
mL) at room temperature. The reaction mixture was heated to 80°C and maintained for 4 h at
same temperature. The reaction mixture was cooled and acetic acid (0.3 mL) was added drop
wise. The suspension was stirred over night at room temperature and the precipitated solid was
collected by filtration to afford the title compound as an off white solid (0.117 g, 59%). HNMR
(400 MHz, DMSO-d ) δ 12.4 (s, 1H), 8.03 (s, 1H), 7.64 (s, 1H), 6.90 (s, 1H), 3.85 (s, 3H), 2.27
(s, 3H), 2.08 (s, 3H). MS (ES) m/e 272.1 (M+1) .
Intermediate-78: Synthesis of 6-(3,5-dimethylisoxazolyl)methoxyoxo(pyridin
ylmethyl)-1,2-dihydroquinolinecarbaldehyde
Step-a: Synthesis of N-(4-bromomethoxyphenyl)acetamide
To an ice-cooled solution of 4-bromomethoxyaniline (2.0 g, 9.90 mmol) in DCM (25
mL) was added triethylamine (4.1 mL, 29.7 mmol), after stirred for 5 min, acetyl chloride (1.05
mL, 14.85 mmol) was added. After completion of reaction, the reaction mixture was quenched
with aq. NaHCO solution (up to pH~8) extracted with DCM (200 mL X 2). The combined
organic layers were washed with water (200 mL), brine (200 mL), dried over sodium sulphate
and concentrated. The residue was directly used for the next step without further purification (2.5
g). H NMR (400 MHz, DMSO-d ) δ 10.06 (s, 1H), 7.45–7.43 (m, 2H), 7.10 (dd, J =2.0 Hz,
J =8.3 Hz, 1H), 3.79 (s, 3H), 2.04 (s, 3H); LC-MS: m/z 244.1 (M+1) .
Step-b: Synthesis of 6-bromochloromethoxyquinolinecarbaldehyde
POCl (7.6 mL, 81.96 mmol) was added drop wise to DMF (2.5 mL, 32.78 mmol) at 0 C,
after stirred for 5 min, N-(4-bromomethoxyphenyl) acetamide (2.0 g, 8.19 mmol) was added
and resulting solution was heated to 80 C for 6 h. The reaction mixture was cooled to room
temperature and poured into crushed ice and extracted with EtOAc (200 mL X 2) twice. The
combined organic layers were washed with water (200 mL), brine (200 mL), dried over sodium
sulphate and concentrated. The residue was directly used for the next step without further
purification (2.0 g). H NMR (400 MHz, DMSO-d ) δ 10.33 (s, 1H), 8.88 (s, 1H), 8.64 (s, 1H),
7.59 (s, 1H), 4.07 (s, 3H); LC-MS: m/z 300 (M+1) .
Step-c: Synthesis of 6-bromomethoxyoxo-1,2-dihydroquinolinecarbaldehyde
A suspension of 6-bromochloromethoxyquinolinecarbaldehyde (2.0 g, 6.65
mmol) in 70% acetic acid (40 mL) was heated to reflux for 6 h. Upon cooling the reaction
mixture to room temperature a solid product was precipitated out which was filtered and washed
with water and dried invacuo to afford the title compound as brown solid (1.5 g, 80%). H NMR
(400 MHz, DMSO-d ) δ 12.18 (s, 1H), 10.17 (s, 1H), 8.42 (s, 1H), 8.22 (s, 1H), 6.93 (s, 1H),
3.94 (s, 3H); LC-MS: m/z 284 (M+1) .
Step-d: Synthesis of 6-bromomethoxyoxo(pyridinylmethyl)-1,2-dihydroquinoline
carbaldehyde
To a solution of 6-bromomethoxyoxo-1, 2-dihydroquinolinecarbaldehyde (9 g,
31.91 mmol) in DMF (80 mL) were added potassium carbonate (13.2 g, 95.73 mmol) followed
by 2-(chloromethyl) pyridine hydrochloride (6.4 g, 35.1 mmol) and stirred at 80ºC for 16 h. After
completion of reaction, the reaction mixture was diluted with water and extracted with EtOAc
(400 mL X 2). The combined organic layers were washed with water (400 mL), brine (300 mL),
dried over sodium sulphate and concentrated. The residue was directly used for the next step
without further purification (7.5 g, 63%). H NMR (400 MHz, DMSO-d ) δ 10.25 (s, 1H), 8.51–
8.48 (m, 2H), 8.31 (s, 1H), 7.78 (t, J=7.9 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.31–7.28 (m, 1H),
7.13 (s, 1H), 5.70 (s, 2H), 3.86 (s, 3H); LC-MS: m/z 373.0 (M) .
Step-e: Synthesis of 6-(3,5-dimethylisoxazolyl)methoxyoxo(pyridinylmethyl)-
1,2-dihydroquinolinecarbaldehyde
To a stirred solution of 6-bromomethoxyoxo(pyridinylmethyl)-1,2-
dihydroquinolinecarbaldehyde (4.0 g, 10.72 mmol) in 1,4-dioxane (40 mL) and H O (10 mL)
were added 3,5-dimethylisoxazoleboronic acid (2.30 g, 16.08 mmol), sodium carbonate (3.41 g,
32.16 mmol) and degassed with nitrogen purging for 20 min. Then tetrakis triphenylphosphine
palladium (2.47 g, 2.14 mmol) was added and heated at 100°C for 8 h. After completion of
reaction, the reaction mixture was concentrated and the residue was diluted with EtOAc (200
ml), washed with water (200 mL), brine (200 mL), dried over sodium sulphate and concentrated.
The residue was washed with hexane to give title compound as yellow solid (3.2 g, 76%). H
NMR (400 MHz, DMSO-d ) δ 10.28 (s, 1H), 8.54 (s, 1H), 8.52 (d, J=4.4 Hz, 1H), 7.94 (s, 1H),
7.82-7.77 (m, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.33 – 7.29 (m, 1H), 7.17 (s, 1H), 5.72 (s, 2H), 3.81
(s, 3H), 2.27 (s, 3H), 2.08 (s, 3H); LC-MS: m/z 390.1 (M+1) .
Intermediate-79: Synthesis of 6-(3,5-dimethyl-4H-1,2,4-triazolyl)methoxyquinolin-
2(1H)-one
Step-a: Synthesis of 1-fluoromethoxynitrobenzene
To a solution of 2-fluoronitrophenol (5.0 g, 31.84 mmol) in DMF(50 mL) was added
K CO (5.27 g, 38.1 mmol), after stirring at room temperature for 15 min was added methyl
iodide (3 mL, 47.7 mmol) and the reaction mixture stirred at room temperature for 2h. Reaction
mixture was poured into ice water, separated solids were filtered, washed the solid thoroughly
with water and vacuum dried to afford an off white solid (4.0 g, 73.5%). H NMR (300 MHz,
CDCl3) 7.89-7.84 (m, 2H), 7.25-7.17 (m, 1H), 3.98 (s, 3H).
Step-b: Synthesis of 4-(2-methoxynitrophenyl)-3,5-dimethyl-4H-1,2,4-triazole
To a solution of 3,5-dimethyl-4H-1,2,4-triazole (0.44 g, 4.49 mmol) in DMF (10 mL)
was added NaH (60%)(0.33 g, 8.18 mmol), after stirring at room temperature for 15 min, was
added 1-fluoromethoxynitrobenzene (0.7 g, 4.09 mmol) and heated at 80 C for 3h. The
reaction mixture diluted with cold water and extracted with ethyl acetate (100 mL), and washed
with water (50 mL), brine (50 mL), dried over sodium sulphate and concentrated invacuo to
afford yellow oil which was used further step without purification (0.8 g); LC-MS: m/z 249.0
(M+H).
Step-c: Synthesis of 4-(3,5-dimethyl-4H-1,2,4-triazolyl)methoxyaniline
In a 50 mL round bottom flask, a stirred solution of 4-(2-methoxynitrophenyl)-3,5-
dimethyl-4H-1,2,4-triazole (800 mg , 3.22 mmol) in Ethanol (20 mL) was added Fe powder
(1.26 g, 22.5 mmol) and NH Cl (1.2 g, 22.5 mmol) the reaction mixture and heated at 90 C for
2h. .After completion of the reaction, the reaction mixture was diluted with ethyl acetate and
filtered over celite bed and bed was washed with ethyl acetate (2x50 mL). The filtrate was
washed sequentially with water, dried over Na2SO4 and concentrated to give title compound as a
brown color solid .The crude product was taken to next step without any purification. (600 mg,
crude). LC-MS m/z: 219.1 (M+1)
Step-d: Synthesis of (E)-N-(4-(3,5-dimethyl-4H-1,2,4-triazolyl)methoxyphenyl)
ethoxyacrylamide
The process of this step was adopted from step-b of intermediate-2 . LC-MS: m/z 317.0
(M+1)
Step-e: Synthesis of 6-(3,5-dimethyl-4H-1,2,4-triazolyl)methoxyquinolin-2(1H)-one
The process of this step was adopted from intermediate-2 of step-c. LC-MS: m/z 271.1
(M+1) .
The present invention is further exemplified, but not limited, by the following examples
that illustrate the preparation of compounds according to the invention.
Example-I: Synthesis of 4-(4-chlorobenzyl)(3,5-dimethylisoxazolyl)methoxy-3,4-
dihydro-2H-benzo[b][1,4]oxazine (Compound-1)
To a solution of intermediate-1 (0.04 g, 0.15 mmol) in DMF (5 mL) were added K CO
(0.064 g, 0.46 mmol), 4-chloro benzyl bromide (0.038 g, 0.18 mmol), and stirred at RT for 24 h.
After completion of the reaction, the reaction mixture was diluted with EtOAC (50 mL), washed
with water (50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The residue
was purified on preparative TLC plate to afford the title product as off-white semisolid (0.010 g,
72%). H NMR (400 MHz, DMSO-d ): δ 7.44–7.39 (m, 4H), 6.53 (s, 1H), 6.39 (s, 1H), 4.55 (s,
2H), 4.17 (t, J=4.4 Hz, 2H), 3.55 (s, 3H), 3.40 (s, 2H), 2.19 (s, 3H), 2.02 (s, 3H); ES-MS: m/z
385.2 (M+1) .
The below compounds were prepared using the procedure similar to that for Compound-1
(Example-I).
Comp
ound Structure Characterization data
H NMR (400 MHz, DMSO-d ): δ 8.24 (d, J=2.9 Hz, 1H),
7.88 (d, J=9.8 Hz, 1H), 7.60 (s, 1H), 7.39-7.36 (m, 1H), 7.31-
2 7.29 (m, 1H), 7.22 (s, 1H), 6.57 (d, J=9.3 Hz, 1H), 5.57 (s,
2H), 3.79 (s, 3H), 3.78 (s, 3H), 2.24 (s, 3H), 2.05 (s, 3H); LC-
MS: m/z 392.1 (M+1) .
1H NMR (300 MHz , CDCl3) : 8.63 (m, 1H), 8.03-7.96 (m,
2H) 7.86 (s, 1H), 7.52-7.49 (m,2H),7.26 (s, 1H), 6.74 (d,
J=9.6Hz, 1H),5.83 (s, 2H),3.85 (s, 3H), 2.43 (s, 3H) ,2.36 (s,
3H); LC-MS: m/z 362.0 (M+1) .
Example-II: Synthesis of 1-(4-chlorobenzyl)(3,5-dimethylisoxazolyl)methoxy
quinoxalin-2(1H)-one (Compound-4)
To a stirred solution of 6-(3,5-dimethylisoxazolyl)methoxyquinoxalin-2(1H)-one
(0.117 g, 0.4317 mmol) in 2 mL of DMF at 0°C was added 60% NaH (0.025 g, 1.0869 mmol),
followed by 4-chlorobenzylbromide (0.098 g, 0.4780 mmol). Then the reaction mixture was
allowed to stir for 1 h at room temperature. After completion of reaction, the reaction mixture
was quenched with methanol and diluted with ethyl acetate and water. Layers were separated,
washed with water (50 mL x 3), dried over Na SO and concentration. The obtained crude was
purified by column chromatography on silica (2% MeOH in DCM) to give the desired product as
an off white solid (0.017 g, 11%). HNMR (400 MHz, DMSO-d ) δ 8.21 (s, 1H), 7.72 (s, 1H),
7.43 (s, 4H), 7.01 (s, 1H), 5.56 (s, 2H), 3.81 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H); MS (ES) m/z
396.1 (M+1) .
Example-III: Synthesis of 1-(4-chlorobenzyl)(3, 5-dimethylisoxazolyl)methoxy-3,4-
dihydroquinolin-2(1H)-one (Compound-5)
To a stirred suspension of 6-(3,5-dimethylisoxazolyl)methoxy-3,4-dihydroquinolin-
2(1H)-one (0.180 g, 0.629 mmol) in DMF (8 mL) was added potassium t-butoxide (0.140 g,
1.25 mmol). The resulting mixture was refluxed for 2 h, was cooled to 0°C and 1-(bromo
methyl)chlorobenzene (0.194 g, 0.94 mmol) and KI (0.005 g, 0.031 mmol) were added.
Subsequently, the reaction mixture was refluxed for 12 h, diluted with ethyl acetate and washed
with water (50 mL), dried over Na2SO4 and concentration under reduced pressure,followed by
chromatography on silica gel (10% EtOAc in hexane) to give the desired product as a white solid
(0.020 g, 8 %); H NMR (400 MHz DMSO-d ) δ 7.41-7.34 (m, 4H), 7.07 (s, 1H), 6.64 (s, 1H),
5.21 (s, 2H), 3.59 (s, 3H), 2.89 (t, J=7.2 Hz, 2H), 2.20 (t, J=7.1 Hz, 2H), 2.21 (s, 3H), 2.03 (s,
3H). MS (ES) m/e 397.3 (M+1) .
Example-IV: Synthesis of 4-(1-(4-chlorophenyl) ethyl)(3,5-dimethylisoxazolyl)
methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine (Compound-6)
To a solution of intermediate-1 (0.020 g, 0.076 mmol) in CH CN (10 mL) were added
Cs CO (0.050 g, 0.15mmol), benzyltriethylammoniumchloride (0.017 mg, 0.007 mmol)
followed by 1-(4-chlorophenyl)ethylmethanesulfonate (0.018 g, 0.076 mmol), and stirred at
65°C for 16 h. After completion of reaction, the reaction mixture was diluted with EtOAC (50
mL), washed with water (50 mL), brine (50 mL), dried over sodium sulphate and concentrated.
The residue was purified on preparative HPLC plate to afford the title product as brown solid
(0.003 g, 11%). H NMR (400 MHz, DMSO-d ): δ 7.50–7.30 (m, 4H), 6.53 (s, 1H), 6.52 (s, 1H),
.22–5.18 (m, 1H), 4.18–3.95 (m, 2H), 3.60 (s, 3H), 3.35–3.28 (m, 1H), 3.15–3.05 (m, 1H), 2.20
(s, 3H), 1.98 (s, 3H), 1.53 (d, J=6.8 Hz, 3H); LC-MS: m/z 399.2 (M+1) .
The below compounds were prepared according to the above protocol by using the given
starting intermediate and reactant at suitable reaction conditions.
Comp
ound Structure Characterization data
H NMR (400 MHz, CDCl ): δ 8.68 (s, 1H), 8.56 (d, J=4.4 Hz,
1H), 7.71 (d, J=7.6 Hz, 1H), 7.34-30 (m, 1H), 6.58 (s, 1H), 6.39
7 (s, 1H), 5.20–5.10 (m, 1H), 4.22-4.17 (m, 2H), 3.63 (s, 3H),
3.40-3.25 (m, 1H), 3.18-3.05 (m, 1H), 2.30 (s, 3H), 2.17 (s,
3H), 1.66 (d, J=6.8 Hz, 3H); LC-MS: m/z 366.2 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.74 (s, 1H), 8.56 (s, 2H),
7.91 (d, J=9.3 Hz, 1H), 7.63 (s, 1H), 7.12 (s, 1H), 6.56 (d, J=9.3
Hz, 1H), 5.74 (s, 2H), 3.77 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H);
LC-MS: m/z 363.2 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.27 (d, J=4.4 Hz, 1H), 7.89
(d, J=9.2 Hz 1H), 7.80–7.60 (m, 1H), 7.62 (s, 1H), 7.41–7.39
(m, 1H), 7.03 (s, 1H), 6.52 (d, J=9.2 Hz, 1H), 5.74 (s, 2H), 3.74
(s, 3H), 2.26 (s, 3H), 2.07 (s, 3H); LC-MS: m/z 380.2 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.54–8.53 (m, 1H), 7.78–
7.76 (m, 1H), 7.33–7.27 (m, 2H), 7.07 (s, 1H), 6.78 (s, 1H),
O N O
.25 (s, 2H), 3.57 (s, 3H), 2.92–2.88 (m, 2H), 2.70–2.67 (m,
2H), 2.21 (s, 3H), 2.03 (s, 3H); LC-MS: m/z 364.2 (M+1) .
* Compound-10 was prepared from intermediate-14 and 2-(chloromethyl)pyridine hydrochloride
using the procedure similar to the one depicted for Compound-6 (Example-IV).
Example-V: Synthesis of 4-((3-chlorophenyl) sulfonyl)(3,5-dimethylisoxazolyl)
methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine (Compound-11)
To a solution of 3-chlorobenzenesulfonyl chloride (0.052 g, 0.25 mmol) in DCM (3
mL) were added pyridine (0.03 mL, 0.38 mmol) followed by intermediate-1 (0.050 g, 0.19
mmol), and stirred at RT for 5 h. After completion of reaction, the reaction mixture was diluted
with EtOAc (50 mL), washed with water (50 mL), brine (50 mL), dried over sodium sulphate
and concentrated. The residue was purified on preparative TLC plate to afford the title product
(0.020 g, 24%). H NMR (400 MHz, DMSO-d ): δ 7.83–7.80 (m, 1H), 7.75–7.63 ( m, 3H), 7.38
(s, 1H), 6.77 (s, 1H), 3.98–3.95 (m, 2H), 3.78–3.74 ( m, 2H), 3.74 (s, 3H), 2.23 (s, 3H), 2.05 (s,
3H); LC-MS: m/z 435.1 (M+1) .
The below compounds were prepared according to the above protocol by using the given
starting intermediate and reactant at suitable reaction conditions.
Comp
ound Structure Characterization data
H NMR (400 MHz, DMSO-d ): δ 8.96 (d, J=2.0 Hz, 1H),
8.89–8.88 (m, 1H), 8.20 (d, J=8.4 Hz, 1H), 7.69–7.65 (m, 1H),
12 7.40 (s, 1H), 6.76 (s, 1H), 4.01-3.99 (m, 2H), 3.81–3.79 (m,
2H), 3.75 (s, 3H), 2.23 (s, 3H), 1.99 (s, 3H); LC-MS: m/z
402.1 (M+1) .
H NMR (400 MHz, DMSO-d ); δ 9.74 (bs, 1H), 7.40 (d,
J=8.3 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 6.87 (s, 1H), 6.64 (s,
1H), 5.20 (s, 2H), 4.72 (s, 2H), 3.34 (s, 3H), 2.14 (s, 3H), 2.09
(s, 3H); LC-MS: m/z 479.1 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.45 (d, J=8.8 Hz, 1H),
8.16 (d, J=8.3 Hz, 2H), 7.94 (s, 1H), 7.81 (d, J=8.4 Hz, 2H),
O S O
7.33 (s, 1H), 7.19 (d, J=8.4 Hz, 1H), 3.95 (s, 3H), 2.30 (s, 3H),
O N O
2.10 (s, 3H); LC-MS: m/z 445.1 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.50 (d, J=8.3 Hz, 1H),
8.21(d, J=8.3 Hz, 2H), 7.98 (s, 1H), 7.73 (d, J=8.3 Hz 2H),
7.50 (s, 1H), 7.41 (d, J=8.8 Hz, 1H), 3.94 (s, 3H), 2.33 (s, 3H),
2.13 (s, 3H); LC-MS: m/z 409 (M+1) .
Example-VI: Synthesis of 2-((7-(3,5-dimethylisoxazolyl)methoxy-2H-benzo[b][1,4]
oxazin-4(3H)-yl)methyl)aniline (Compound-16)
Step-i: Synthesis of 7-bromomethoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine
To a solution of intermediate-1e (2.00 g, 6.99 mmol) in MeOH (10 mL) and H O (5 mL)
was added KOH (1.17 g, 20.9 mmol) and stirred at reflux temperature for 2 h. After completion
of reaction, the reaction mixture was diluted with EtOAC (50 mL), washed with water (50 mL),
brine (50 mL), dried over sodium sulphate and concentrated. The residue was as such taken
forward for the next step without further purification (1.2 g, 70%). LC-MS: m/z 246.0 (M+2) .
Step-ii: Synthesis of 7-bromomethoxy(2-nitrobenzyl)-3,4-dihydro-2H-benzo[b][1,4]
oxazine
To a solution of 7-bromomethoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.00 g, 4.09
mmol) in DMF (10 mL) were added K CO (1.13 g, 8.18 mmol), 2-nitro benzylbromide (1.32 g,
6.14 mmol) and stirred at RT for 24 h. After completion of reaction, the reaction mixture was
diluted with EtOAC (100 mL), washed with water (50 mL), brine (50 mL), dried over sodium
sulphate and concentrated. The residue was as such taken forward for next step without further
purification (0.60 g, 37%). H NMR (400 MHz, DMSO-d ): δ 8.09-8.07 (m, 1H), 7.73-7.69 (m,
1H), 7.57-7.48 (m, 2H), 6.88 (s, 1H), 6.23 (s, 1H), 4.86 (s, 2H), 4.17–4.15 (m, 2H), 3.53 (s, 3H),
3.38–3.36 (m, 2H); LC-MS: m/z 379.1 (M+1) .
Step-iii: Synthesis of 2-((7-bromomethoxy-2H-benzo[b][1,4]oxazin-4(3H)-yl)methyl)aniline
To a ice cooled solution of 7-bromomethoxy(2-nitrobenzyl)-3,4-dihydro-2H-
benzo[b][1,4]oxazine (0.5 g, 1.26 mmol) in MeOH (20 mL) were added NiCl .6H O (0.3 g, 1.26
mmol) followed by NaBH (0.23 g, 6.32 mmol) and stirred at the same temperature for 2 h. After
completion of reaction, the reaction mixture was concentrated, the residue was treated with aq.
saturated ammonium chloride solution and extracted with ethyl acetate (100 mL). The organic
layer was washed with water (50 mL), brine (50 mL), dried over sodium sulphate and
concentrated. The residue was taken forward for next step without further purification (0.2 g,
44%). H NMR (400 MHz, DMSO-d ): δ 7.00–6.90 (m, 2H), 6.88 (s, 1H), 6.75–6.68 (m, 1H),
6.58–6.50 (m, 1H), 6.24 (s, 1H), 4.92 (s, 2H), 4.29 (s, 2H), 4.20–4.10 (m, 2H), 3.62 (s, 3H),
3.30–3.20 (m, 2H); LC-MS: m/z 349.0 (M+1) .
Step-iv: Synthesis of compound-16d
To a solution of 2-((7-bromomethoxy-2H-benzo[b][1,4]oxazin-4(3H)-yl)methyl)
aniline (0.2 g, 0.27 mmol) in DCM (2 mL) and DIPEA (0.08 mL, 0.54 mmol) was added Boc
anhydride (0.071 mL, 0.33 mmol) and stirred at RT for 4 h. After completion of reaction, the
reaction mixture was diluted with EtOAC (50 mL), washed with water (50 mL), brine (50 mL),
dried over sodium sulphate and concentrated. The residue was taken forward to next step without
further purification (0.1 g, 32%). H NMR (400 MHz, DMSO-d ): δ 7.40–7.25 (m, 3H), 7.22–
7.18 (m, 1H), 6.87 (s, 1H), 6.20 (s, 1H), 4.29 (s, 2H), 4.20–4.15 (m, 2H), 3.53 (s, 3H), 3.35–3.25
(m, 2H), 1.36 (s, 18H).
Step-v: Synthesis of tert-butyl (2-((7-(3,5-dimethylisoxazolyl)methoxy-2H-benzo[b][1,4]
oxazin-4(3H)-yl)methyl)phenyl)carbamate
To a solution of compound-16d (0.1 g, 1.17 mmol) in toluene (3 mL), EtOH (1.0 mL)
and H O (1.0 mL) were added 3,5-dimethylisoxazoleboronic acid (0.099 g, 0.35 mmol), sodium
carbonate (0.056 g, 0.53 mmol). The resulting suspension was degassed with nitrogen purging
for 20 min. Then tetrakis triphenylphosphine palladium (0.02 g, 0.01 mmol) was added and
heated at 100°C for 16 h. After completion of reaction, the reaction mixture was diluted with
EtOAc (50 mL), washed with water (50 mL), brine (50 mL), dried over sodium sulphate and
concentrated. The residue was directly used for next step, without further purification 0.1 g
(crude). H NMR (400 MHz, DMSO-d ): δ 8.73 (bs, 1H), 7.36–7.12 (m, 4H), 6.53 (s, 1H), 6.27
(s, 1H), 4.48 (s, 2H), 4.19 (bs, 2H), 3.50 (s, 3H), 3.39 (bs, 2H), 2.19 (s, 3H), 2.06 (s, 3H), 1.49 (s,
9H); LC-MS: m/z 466.3 (M+1) .
Step-vi: Synthesis of 2-((7-(3,5-dimethylisoxazolyl)methoxy-2H-benzo[b][1,4]oxazin-
4(3H)-yl)methyl)aniline
To an ice-cooled solution of tert-butyl (2-((7-(3,5-dimethylisoxazolyl)methoxy-2H-
benzo[b][1,4]oxazin-4(3H)-yl)methyl)phenyl)carbamate (0.1 g, 0.21 mmol) was added
methanolic HCl (2 mL) and stirred at RT for 3 h. After completion of reaction, the reaction
mixture was diluted with EtOAC (50 mL), neutralized with aq. NaHCO solution, washed with
water (50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The residue was
purified on preparative TLC plate to afford the title product as brown solid (0.020 g, 39%). H
NMR (400 MHz, DMSO-d + D O): δ 7.06–6.99 (m, 2H), 6.72–6.70 (m, 1H), 6.60–6.58 (m,
1H), 6.57 (s, 1H), 6.42 (s, 1H), 4.32 (s, 2H), 4.19–4.17 (m, 2H), 3.54 (s, 3H), 3.28 -3.26 (m, 2H),
2.20 (s, 3H), 2.03 (s, 3H); LC-MS: m/z 366.2 (M+1) .
Example-VII: Synthesis of 7-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)-
2H-benzo[b][1,4]oxazin-3(4H)-one (Compound-17)
To a stirred solution of intermediate-28 (0.10 g, 0.29 mmol) in 1,2-DME (4.0 mL) and
H O (1.0 mL) were added 3,5-dimethylisoxazoleboronic acid (0.123 g, 0.87 mmol), sodium
carbonate (0.077 g, 0.73 mmol) and degassed with nitrogen purging for 20 min. Then tetrakis
triphenylphosphine palladium (0.017 g, 0.015 mmol) was added and heated at 90°C for 16 h.
After completion of reaction, the reaction mixture was diluted with EtOAc (50 mL), washed with
water (50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The residue was
purified by prep. TLC to afford the title compound as a brown solid (0.04 g, 38%). H NMR (400
MHz, DMSO-d ) δ 8.55 (d, J=4.9 Hz, 2H), 7.36 (d, J=4.9 Hz, 2H), 6.96 (s, 1H), 6.66 (s, 1H),
.27 (s, 2H), 4.80 (s, 2H), 3.58 (s, 3H), 2.22 (s, 3H), 2.04 (s, 3H); LC-MS: m/z 366.1 (M+1) .
The below compounds were prepared by procedure similar to the one described in
Example-VII with appropriate variations in reactants, quantities of reagents and reaction
conditions. The physiochemical characteristics of the compounds are summarized herein below
table.
Comp
ound Structure Characterization Data
H NMR (400 MHz, DMSO-d ) δ 7.45–7.38 (m, 4H), 6.93
(s, 1H), 6.75 (s, 1H), 5.23 (s, 2H), 4.77(s, 2H), 3.62 (s, 3H),
2.21 (s, 3H), 2.03 (s, 3H); ES-MS: m/z 399.1 (M+1) .
Compound 19 (Isomer-1): H NMR (400 MHz, CDCl ): δ
8.63 (dd, J=4.4 & 2.4 Hz, 2H), 7.30 (d, J=4.8 Hz, 2H), 6.79
(s, 1H), 6.40–6.30 (m, 1H), 6.14 (s, 1H), 4.75–4.60 (m, 2H),
3.37 (s, 3H), 2.26 (s, 3H), 2.11 (s, 3H), 1.88 (d, J=7.2 Hz,
3H); LC-MS: m/z 380.2 (M+1) .
Compound 20 (Isomer-2): H NMR (400 MHz, CDCl ): δ
8.64 (d, J=5.6 Hz, 2H), 7.30 (d, J=4.8 Hz, 2H), 6.79 (s, 1H),
6.42–6.30 (m, 1H), 6.14 (s, 1H), 4.80–4.60 (m, 2H), 3.37 (s,
3H), 2.26 (s, 3H), 2.12 (s, 3H), 1.88 (d, J=7.2 Hz, 3H); LC-
MS: m/z 380.2 (M+1) .
H NMR (400 MHz, DMSO-d ) δ 8.66 (s, 1H), 8.57 (d,
J=4.4 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.33-7.30 (m, 1H),
6.78 (s, 1H), 6.47 (s, 1H), 5.22 (s, 2H), 4.72 (s, 2H), 3.60 (s,
3H), 2.27 (s, 3H), 2.13 (s, 3H); LC-MS: m/z 366.2 (M+1) .
H NMR (400 MHz, CDCl ) δ 8.59 (d, J=4.8 Hz, 1H), 8.69
(td, J=8.0 & 2.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.24-7.22
22 (m, 1H), 6.95 (s, 1H), 6.75 (s, 1H), 5.30 (s, 2H), 4.71 (s, 2H),
3.66 (s, 3H), 2.27 (s, 3H), 2.13 (s, 3H); LC-MS: m/z 366.1
(M+1) .
H NMR (400 MHz, CDCl ) δ 6.79 (s, 1H), 6.60 (s, 1H),
4.60 (s, 2H), 4.00 (dd, J=4.2 & 2.4 Hz, 2H), 3.90 (d, J=7.2
23 Hz, 2H), 3.77 (s, 3H), 3.36 (t, J=11.2 Hz, 2H), 2.31 (s, 3H),
2.18 (s, 3H), 2.08-2.00 (m, 1H), 1.64-1.60 (m, 2H), 1.58-
1.40 (m, 2H); LC-MS: m/z 373.2 (M+1) .
Compound 24 (Isomer-1): H NMR (400 MHz, CDCl ): δ
8.69 (s, 1H), 8.58 (d, J=4.4 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H),
24 7.35-7.31 (m, 1H), 6.78 (s, 1H), 6.41 (q, J=7.2 Hz, 1H), 6.25
O N O
& (s, 1H), 4.72-4.62 (m, 2H), 3.40 (s, 3H), 2.26 (s, 3H), 2.12 (s,
3H), 1.93 (d, J=6.8 Hz, 3H). LC-MS: m/z 380.2 (M+1) .
Compound 25 (Isomer-2): 1H NMR (400 MHz, CDCl ): δ
8.70 (s, 1H), 8.58 (d, J=4.4 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H),
7.35-7.32 (m, 1H), 6.78 (s, 1H), 6.41 (q, J=7.2 Hz, 1H), 6.25
(s, 1H), 4.72-4.62 (m, 2H), 3.40 (s, 3H), 2.26 (s, 3H), 2.11 (s,
3H), 1.93 (d, J=6.8 Hz, 3H); LC-MS: m/z 380.2 (M+1) .
H NMR (400 MHz, CDCl ): δ 8.18 (d, J=2.4 Hz, 1H), 7.57
(dd, J=8.8 & 2.4 Hz, 1H), 6.76 (s, 1H), 6.74 (s, 1H), 6.57 (s,
1H), 5.12 (s, 2H), 4.69 (s, 2H), 3.92 (s, 3H), 3.65 (s, 3H),
2.27 (s, 3H), 2.13 (s, 3H); LC-MS: m/z 396.1 (M+1)
H NMR (400 MHz, CDCl ): δ 8.86 (d, J=1.6 Hz, 1H), 7.97
(dd, J=8.0 & 2.0 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 6.81 (s,
1H), 6.78 (s, 1H), 5.33 (s, 2H), 4.70 (s, 2H), 3.67 (s, 3H),
2.27 (s, 3H), 2.13 (s, 3H); LC-MS: m/z 391.2 (M+1) .
H NMR (400 MHz, CDCl ) δ 8.54 (d, J=2.0 Hz, 1H), 7.67
(dd, J=8.0, 2.4 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 6.96 (s, 1H),
6.75 (s, 1H), 5.26 (s, 2H), 4.69 (s, 2H), 3.69 (s, 3H), 2.27 (s,
3H), 2.13 (s, 3H); LC-MS: m/z 400.2 (M+1) .
H NMR (400 MHz, CDCl ) δ 8.43 (d, J=2.0 Hz, 1H), 7.45-
7.26 (m, 2H), 7.00 (s, 1H), 6.75 (s, 1H), 5.27 (s, 2H), 4.69 (s,
2H), 3.69 (s, 3H), 2.27 (s, 3H), 2.13 (s, 3H); LC-MS: m/z
384.2 (M+1) .
H NMR (400 MHz, CDCl3) δ 8.25 (d, J=2.8 Hz, 1H), 7.36
(d, J=8.8 Hz, 1H), 7.19 (dd, J=8.8 & 2.0 Hz, 1H), 7.10 (s,
1H), 6.73 (s, 1H), 5.23 (s, 2H), 4.68 (s, 2H), 3.70 (s, 3H),
3.58 (s, 3H), 2.27 (s, 3H), 2.13 (s, 3H); LC-MS: m/z 396.2
(M+1) .
H NMR (400 MHz, CDCl ) δ 8.60 (bs, 1H), 7.82–7.79 (m,
1H), 7.62 (d, J=8.4 Hz, 1H), 7.34–7.31 (m, 1H), 6.92 (s, 1H),
31 6.63 (s, 1H), 6.24–6.22 (m, 1H), 4.67 (s, 2H), 3.43 (s, 3H),
2.21 (s, 3H), 1.97 (s, 3H), 1.84 (d, J=6.9 Hz, 3H); LC-MS:
m/z 380.2 (M+1) .
H NMR (400 MHz, CDCl ): δ 8.58 (s, 1H), 7.56 (d, J=7.4
Hz, 1H), 7.17 (d, J=7.6 Hz, 1H), 6.77 (s, 1H), 6.51 (s, 1H),
.17 (s, 2H), 4.70 (s, 2H), 3.61 (s, 3H), 2.55 (s, 3H), 2.26 (s,
3H), 2.12 (s, 3H); ES-MS: m/z 380.2 (M+1) .
Compound 33 (Isomer-1): H NMR (400 MHz, CDCl ): δ
7.37–7.30 (m, 4H), 6.76 (s, 1H), 6.45-6.35 (m, 1H), 6.27 (s,
1H), 4.72–4.60 (m, 2H), 3.38 (s, 3H), 2.25 (s, 3H), 2.12 (s,
3H), 1.84 (d, J=7.4 Hz, 3H); LC-MS: m/z 413.0 (M+1) .
Compound 34 (Isomer-2): H NMR (400 MHz, CDCl ): δ
7.31–7.27 (m, 4H), 6.69 (s, 1H), 6.35-6.28 (m, 1H), 6.20 (s,
1H), 4.65–4.54 (m, 2H), 3.32 (s, 3H), 2.19 (s, 3H), 2.05 (s,
3H), 1.78 (d, J=6.9 Hz, 3H); LC-MS: m/z 413.0 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.57 (d, J=3.4 Hz, 1H),
7.61 (t, J=6.9 Hz, 1H), 7.26 (s, 1H), 7.21–7.14 (m, 1H), 6.89
(s, 1H), 6.74 (s, 1H), 4.60 (s, 2H), 4.37 (t, J=7.3 Hz, 2H),
3.79 (s, 3H), 3.20 (t, J=7.6 Hz, 2H), 2.30 (s, 3H), 2.15 (s,
3H); LC-MS: m/z 380.1 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.64 (d, J=2.0 Hz, 1H),
8.47 (d, J=3.5 Hz, 1H), 7.92 (d, J=9.3 Hz , 1H), 7.68 (d,
36 J=7.8 Hz, 1H), 7.64 (s, 1H), 7.36 (dd, J=4.9 & 3.0 Hz , 1H),
7.01 (s, 1H), 6.60 (d, J=9.3 Hz, 1H), 5.63 (s, 2H), 3.78 (s,
3H), 2.24 (s, 3H), 2.05 (s, 3H); LC-MS: m/z 362.2 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.57 (d, J=2.0 Hz, 1H),
7.90–7.78 (m, 2H), 7.62 (s, 1H), 7.41 (d, J=7.3 Hz, 1H), 7.07
(s, 1H), 6.57 (d, J=9.3 Hz, 1H), 5.65 (s, 2H), 3.76 (s, 3H),
2.25 (s, 3H), 2.06 (s, 3H); LC-MS: m/z 396.1 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 7.83 (d, J=9.0 Hz, 1H),
7.61 (s, 1H), 7.07 (s, 1H), 6.47 (d, J=9.7 Hz, 1H), 4.43 (t,
38 J=7.3 Hz, 2H), 3.94 (s, 3H), 3.58 (t, J=4.4 Hz, 4H), 2.61–
2.54 (m, 6H), 2.49 (s, 3H), 2.09 (s, 3H); LC-MS: m/z 384.2
(M+1) .
H NMR (400 MHz, DMSO-d ): δ 7.92-7.90 (m, 1H), 7.78–
7.77 (m, 1H), 7.71–7.70 (m, 1H), 7.63 (s, 1H), 7.36 (s, 1H),
6.57 (d, J=9.7 Hz, 1H), 5.85 (s, 2H), 3.86 (s, 3H), 2.25 (s,
3H), 2.06 (s, 3H); LC-MS: m/z 368.1 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.57–8.56 (m, 1H), 8.19–
8.14 (m, 1H), 7.78 (dt, J=7.8, 1.9 Hz, 1H), 7.73 (s, 1H), 7.49
(d, J=8.0 Hz, 1H), 7.31–7.29 (m, 1H), 7.18 (s, 1H), 6.98 (d,
J=8.8 Hz, 1H), 6.49-6.44 (m, 1H), 3.88 (s, 3H), 2.32 (s, 3H),
2.08 (s, 3H), 1.67 (d, J= 6.4 Hz, 3H); LC-MS: m/z 376.2
(M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.76 (s, 1H), 8.50–8.48
(m, 1H), 8.16 (d, J=8.8 Hz, 1H), 7.94–7.91 (m, 1H), 7.73 (s,
41 1H), 7.41–7.38 (m, 1H), 7.23 (s, 1H), 6.94 (d, J=8.8 Hz, 1H),
6.51-6.46 (m, 1H), 3.89 (s, 3H), 2.27 (s, 3H), 2.08 (s, 3H),
1.69 (d, J=6.0 Hz, 3H); LC-MS: m/z 376.2 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.53–8.50 (m, 1H), 8.13
(d, J=8.8 Hz, 1H), 7.76–7.70 (m, 1H), 7.72 (s, 1H), 7.39–
7.35 (m, 1H), 7.30 (s, 1H), 7.28–7.22 (m, 1H), 6.82 (d, J=8.8
Hz, 1H), 4.79 (t, J=6.8 Hz, 2H), 3.41 (s, 3H), 3.27 (t, J=6.8
Hz, 2H), 2.29 (s, 3H), 2.08 (s, 3H); LC-MS: m/z 376.2
(M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.76–8.73 (m, 2H), 7.90
(d, J=9.2 Hz, 1H), 7.62 (s, 1H), 7.43–7.40 (m, 1H), 6.90 (s,
1H), 6.54 (d, J=9.2 Hz, 1H), 5.75 (s, 2H), 3.69 (s, 3H), 2.25
(s, 3H), 2.06 (s, 3H); LC-MS: m/z 363.2 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 9.10 (d, J=2.0 Hz, 1H),
8.75 (d, J=7.2 Hz, 1H), 7.93 (d, J=9.2 Hz, 1H), 7.65 (s, 1H),
44 7.45–7.43 (m, 1H), 6.97 (s, 1H), 6.57 (d, J=9.4 Hz, 1H),
.68 (s, 2H), 3.74 (s, 3H), 2.26 (s, 3H), 2.06 (s, 3H); LC-MS:
m/z 363.2 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.53 (d, J=3.0 Hz, 1H),
7.90 (d, J=9.2 Hz, 1H), 7.74–7.69 (m, 1H), 7.62 (s, 1H),
45 7.46–7.43 (m, 1H), 7.11 (s, 1H), 6.57 (d, J=9.2 Hz, 1H), 5.65
(s, 2H), 3.77 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H); LC-MS: m/z
380.2 (M+1) .
H NMR (400MHz, DMSO-d ): δ 8.52 (d, J=4.4 Hz, 1H),
7.90 (d, J=9.6 Hz, 1H), 7.79-7.75 (m, 1H), 7.62 (s, 1H),
46 7.33-7.28 (m, 2H), 7.12 (s, 1H), 6.58 (d, J=9.6 Hz, 1H), 5.65
(s, 2H), 3.74 (s, 3H), 2.24 (s, 3H), 2.05 (s, 3H). MS (ES) m/z
362.3 (M+ 1) .
H NMR (CDCl , 400 MHz): δ 8.83 (s, 1H), 7.85 (d, J=7.6
Hz, 1H), 7.65 (d, J=9.2 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.26
47 (s, 1H), 7.15 (s, 1H), 6.67 (d, J=9.6 Hz, 1H), 5.73 (bs, 2H),
3.80 (s, 3H), 2.26 (s, 3H), 2.11 (s, 3H); LC-MS: m/z 430.1
(M+1) ,
H NMR (400 MHz, DMSO-d ) δ 8.53–8.52 (m, 1H), 7.77–
7.73 (m, 1H), 7.37–7.25 (m, 2H), 7.11 (s, 1H), 6.81 (s, 1H),
.29 (s, 2H), 3.59 (s, 3H), 2.59 (s, 2H), 2.22 (s, 3H), 2.04 (s,
3H), 1.25 (s, 6H); LC-MS: m/z 392.2 (M+1) .
H NMR (400 MHz, DMSO-d6): δ 8.62 (s, 1H), 8.56 (d,
J=3.9 Hz, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.32–7.29 (m, 1H),
O N O
6.75 (s, 1H), 6.42 (s, 1H), 5.18 (s, 2H), 3.59 (s, 3H), 2.27 (s,
3H), 2.13 (s, 3H), 1.58 (s, 6H); LC-MS: m/z 394.2 (M+1) .
H NMR (400 MHz, CDCl ): δ 8.58 (s, 1H), 7.64–7.61 (m,
1H), 7.54 (s, 1H), 7.34–7.32 (m, 1H), 7.20–7.17 (m, 3H),
.71 (s, 2H), 3.77 (s, 3H), 2.31 (s, 3H), 2.31 (s, 3H), 2.26 (s,
3H); LC-MS: m/z 376.2 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.50 (d, J=4.4 Hz, 1H),
7.79–7.75 (m, 1H), 6.55 (s, 1H), 7.41 (d, J=7.9 Hz, 1H),
51 7.35–7.25 (m, 1H), 6.94 (s, 1H), 5.41 (s, 2H), 3.74 (s, 3H),
2.22 (s, 3H), 2.02 (s, 3H), 1.42 (s, 6H); LC-MS: m/z 406.2
(M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.50 (d, J=7.8 Hz, 1H),
7.66–7.62 (m, 1H), 7.30–7.18 (m, 2H), 6.84 (s, 1H), 6.78 (s,
1H), 5.30 (s, 2H), 3.63 (s, 3H), 2.79 (s, 2H), 2.26 (s, 3H),
2.12 (s, 3H), 1.27 (s, 6H); LC-MS: m/z 392.2 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.50 (d, J=3.9 Hz, 1H),
7.78-7.74 (m, 1H), 7.59 (s, 1H), 7.36–7.27 (m, 2H), 7.10 (s,
1H), 6.50 (s, 1H), 5.63 (s, 2H), 3.73 (s, 3H), 2.44 (s, 3H),
2.25 (s, 3H), 2.05 (s, 3H); LC-MS: m/z 376.2 (M+1) .
H NMR (400 MHz, CDCl ) δ 8.59 (d, J=4.4 Hz, 1H), 7.67
(dt J=8.0, 0.8 Hz, 1H), 7.54 (d, J=0.8 Hz, 1H), 7.42–7.38 (m,
2H), 7.25–7.20 (m, 1H), 7.08 (s, 1H), 5.71 (bs, 2H), 3.85 (s,
3H), 2.28 (s, 3H), 2.14 (s, 3H); LC-MS: m/z 430.2 (M+1) .
H NMR (400 MHz, DMSO-d ) δ 8.54–8.52 (m, 1H), 7.94
(s, 1H), 7.77 (dt, J=7.8, 2.0 Hz, 1H), 7.31-7.28 (m, 2H), 7.13
55 (s, 1H), 6.27 (s, 1H), 5.63 (s, 2H), 3.74 (s, 3H), 2.32–2.29
(m, 1H), 2.27 (s, 3H), 2.08 (s, 3H), 1.06–1.01 (m, 2H), 0.81–
0.77 (m, 2H); LC-MS: m/z 402.2 (M+1) .
HNMR 400 MHz (DMSO-d ) δ 7.91 (d, J=9.2 Hz, 1H),
7.63 (s, 1H), 7.40-7.36 (m, 4H), 6.96 (s, 1H), 6.60 (d, J=9.2
Hz, 1H), 5.58 (s, 2H), 3.77 (s, 3H), 2.24 (s, 3H), 2.05 (s, 3H).
MS (ES) m/e 395.3 (M+1) .
H NMR (400 MHz DMSO-d ): δ 8.41 (d, J=8.8 Hz, 1H),
8.24 (d, J=8.8Hz, 1H), 8.01-7.98 (m, 2H), 7.81-7.77 (m, 2H),
57 7.69 (d, J=8.3 Hz, 1H), 7.62 (t, J=7.8Hz, 1H), 7.27 (s, 1H),
7.08 (d, J=8.8 Hz, 1H), 5.79 (s, 2H), 3.89 (s, 3H), 2.30 (s,
3H), 2.10 (s, 3H); LC-MS: m/z 412.2 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.58 (d, J=2.4 Hz, 1H),
7.91 (dd, J1=2.4 Hz, J2=8.8 Hz, 1H), 7.79 (s, 1H), 7.53 (s,
1H), 7.39 (d, J=8.8 Hz, 1H), 7.05 (s, 1H), 5.67 (s, 2H), 3.75
(s, 3H), 2.25 (s, 3H), 2.15 (s, 3H), 2.06 (s, 3H); LC-MS: m/z
410.2 (M+1) .
H NMR (400 MHz, CDCl ): δ 7.52 (s, 1H), 7.35-7.23 (m,
5H), 6.72 (s, 1H), 4.50 (t, J=7.8 Hz, 2H), 3.88 (s, 3H), 3.07
(t, J=7.9 Hz, 2H), 2.27 (s, 3H), 2.26 (s, 3H), 2.16 (s, 3H);
LC-MS: m/z 423.1 (M+1) .
H NMR (400 MHz, DMSO-d ) δ 8.34 (bs, 1H), 6.93 (s,
1H), 6.89 (s, 1H), 4.63 (s, 2H), 3.94 (d, J=7.7 Hz, 2H), 3.80
60* (s, 3H), 3.14 (d, J=11.7 Hz, 2H), 2.75–2.60 (m, 2H), 2.33 (s,
3H), 2.08 (s, 3H), 2.05–1.80 (m, 1H), 1.75–1.55 (m, 2H),
1.42–1.28 (m, 2H); LC-MS: m/z 372.2 (M+1) ;
H NMR (300 MHz, CD3OD): δ 8.53 (d, J=5.1 Hz, 1H), 7.95
(d J=9.6Hz, 1H), 7.82–7.74 (m, 2H), 7.64 (s, 1H), 7.85 (d,
61* J=2.7 Hz, 1H), 7.34–7.25 (m, 2H), 7.04 (s, 1H), 6.6 (d, J=9.3
Hz, 1H), 6.56 (d, J=9.6 Hz, 1H), 5.74 (s, 2H), 3.78 (s, 3H);
LC-MS: m/z 360.10 (M+1) .
H NMR (300 MHz, CDCl ): δ8.82 (s, 1H), 7.76-7.68 (m,
2H), 7.41-7.38 (m, 1H), 7.34-7.30 (m, 1H), 7.15 (s, 1H), 6.71
62 (d, J=6.6 Hz, 2H), 5.78 (s, 2H), 3.80 (s, 3H), 2.24 (s, 3H),
1.55-1.50 (m, 1H), 1.02-0.96 (m, 2H), 0.88-0.81 (m, 2H).
LCMS (ESI, m/z): 388.0 (M+1) .
H NMR (CDCl , 300 MHz): δ 8.58 (d, J=4.2 Hz, 1H), 8.31
(s, 1H), 7.65 (d, J=9.3 Hz, 1H), 7.59 (dd, J=7.8 Hz, J=1.8
63 Hz, 1H), 7.35 (s, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.26–7.20 (m,
2H), 6.68 (d, J=9.3 Hz, 1H), 5.70 (bs, 2H), 3.83 (s, 3H), 2.45
(s, 3H). LC-MS: m/z 348.1 (M+1) .
H NMR (CDCl , 300 MHz): δ 8.85–8.78 (m, 1H), 8.46 (s,
1H), 7.97 (dt, J=8.1 & 1.5 Hz, 1H), 7.75 (d, J=9.3 Hz, 1H),
64 7.56 (t, J=6.0 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.48 (s, 1H),
6.99 (s, 1H), 6.74 (d, J=9.3 Hz, 1H), 5.98 (s, 2H), 3.83 (s,
3H), 2.32 (s, 3H); LC-MS: m/z 348.2 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 12.30–12.10 (bs, 1H),
7.44–7.39 (m, 4H), 6.75 (s, 1H), 6.68 (s, 1H), 5.21 (s, 2H),
4.74 (s, 2H), 3.56 (s, 3H), 1.98 (s, 6H); LC-MS: m/z 398.2
(M+1) .
H NMR (400 MHz, DMSO-d ): δ 12.19 (s, 1H), 8.53 (d,
J=3.4, 1H), 7.89 (d, J=9.8 Hz,1H), 7.76 (t, J=7.8 Hz, 1H),
66 7.47 (s, 1H), 7.30 (d, J=7.4 Hz, 2H), 7.05 (s, 1H), 6.54 (d,
J=9.3 Hz, 1H), 5.63 (s, 2H), 3.69 (s, 3H), 2.00 (s, 6H); LC-
MS: m/z 361.2 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.50 (d, J=8.5 Hz, 1H),
7.92 (d, J=9.3 Hz, 1H), 7.74 (d, J=6.9 Hz, 1H), 7.65 (s, 1H),
67 7.49 (d, J=8.4 Hz, 1H), 7.00 (s, 1H), 6.60 (d, J=9.2 Hz, 1H),
.63 (s, 2H), 3.81 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H); LC-MS:
m/z 396.2 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.53 (d,J=4.4Hz, 1H),
7.78-7.74(m, 1H), 7.72 (s, 1H), 7.58 (s, 1H), 7.31-7.27 (m,
68 2H), 7.10 (s, 1H), 5.66 (s, 2H), 3.72 (s, 3H), 2.86-2.81 (m,
1H), 2.24 (s, 3H), 2.05 (s, 3H), 1.90-1.72(m, 6H), 1.41-1.28
(m, 4H); LC-MS: m/z 444.3 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.63 (s, 1H), 8.47 (bs,
1H), 7.73 (s, 1H), 7.68-7.66 (m, 1H), 7.60 (s, 1H), 7.38-7.36
69 (m, 1H), 7.0 (s, 1H), 5.66 (s, 2H), 3.77 (s, 3H), 2.85-2.62 (m,
1H), 2.24 (s, 3H), 2.05 (s, 3H), 1.91-1.72(m, 6H), 1.45-1.29
(m, 4H); LC-MS: m/z 444.3 (M+1) .
NOTE: Synthesis of Compound 60 comprises deprotection reaction according to the procedure
depicted in below step:
Deprotection (for Compound-60): 7-(3,5-dimethylisoxazolyl)methoxy(piperidin
ylmethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one
To an ice-cooled solution of tert-butyl 4-((7-(3,5-dimethylisoxazolyl)methoxy
oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)methyl)piperidinecarboxylate (0.20 g, 0.42 mmol) in
DCM (10 mL) was add TFA (6.0 mL, 39.20 mmol) and stirred at same temperature for 1h.
Reaction mixture was concentrated in vacuo, and residue was triturated with hexane to afford a
white solid. The solid was suspended in DCM (5 mL) and at 0ºC was added saturated aq.
NaHCO solution (1.0 mL), stirred for 1 h at same temperature. The organic layer separated,
dried over Na SO , concentrated in vacuo to afford the title product as an off white semi solid
(0.01 g, 6%).
Similarly synthesis Compound-61 comprises debenzylation reaction according to the procedure
depicted hereinafter.
Debenzylation (for Compound-61): N-(4-(6-hydroxypyridinyl)methoxymethylphenyl)-
N-(pyridinylmethyl) acetamide
In a 25 mL single neck round bottom flask, a stirred solution 6-(6-(benzyloxy)pyridinyl)
methoxy(pyridinylmethyl)quinolin-2(1H)-one (0.040 g, 0.08 mmol) in MeOH (3 mL) was
treated with Pd/C (10%, 0.050 g) at RT under nitrogen atmosphere. The suspension was
hydrogenated (balloon pressure) at RT for 30 min. Upon completion of reaction (TLC), the
reaction mixture was filtered and filtrate was concentrated under reduced pressure to give title
compound as an off white solid (0.010 g, 30.3%).
Example-VIII: Synthesis of 7-(3,5-dimethylisoxazolyl)((6-hydroxypyridinyl)methyl)-
6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound-70)
A solution of compound-26 (0.04 g, 0.10 mmol) in 33% HBr in AcOH (3.0 mL) was
heated at 100°C in a sealed tube for 6 h. After completion of reaction, the reaction was quenched
by the addition of water (10 mL) followed by saturated aq. sodium bicarbonate solution (20 mL)
and extracted with 10% MeOH:DCM (100 mL). The organic layer was washed with water (50
mL), brine (50 mL), dried over sodium sulphate and concentrated under reduced pressure. The
residue was purified by preparative TLC to isolate the title product as a brown solid (5 mg,
13%). H NMR (400 MHz, CDCl ): δ 7.52 (m, 1H), 7.32 (s, 1H), 6.79 (s, 1H), 6.60 (d, J=9.6 Hz,
1H), 6.49 (s, 1H), 4.94 (s, 2H), 4.66 (s, 2H), 3.67 (s, 3H), 2.29 (s, 3H), 2.15 (s, 3H); LC-MS: m/z
382.1 (M+1) .
Example-IX: Synthesis of 7-(3,5-dimethylisoxazolyl)(2-methoxyethoxy)(pyridin
ylmethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound-71)
Step-(i): Synthesis of 7-(3,5-dimethylisoxazolyl)hydroxy(pyridinylmethyl)-2H-
benzo[b][1,4]oxazin-3(4H)-one
To an ice cooled solution of compound-17 (0.10 g, 0.27 mmol) in DCM (4.0 mL) was
added BBr (1.0M in DCM, 1 mL) and stirred at 100°C for 16 h. After completion of reaction,
the reaction was quenched by the addition of aq. sodium bicarbonate solution and extracted with
DCM (50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over
sodium sulphate and concentrated. The residue was purified by prep. TLC to afford the title
compound as off-white solid (0.080 g, 84%). H NMR (400 MHz, CDCl ) δ 8.46-8.44 (m, 2H),
7.20-7.19 (m, 2H), 6.77 (s, 1H), 6.39 (s, 1H), 5.14 (s, 2H), 4.74 (s, 2H), 2.32 (s, 3H), 2.18 (s,
3H); ES-MS: m/z 350.2 (M-1) .
Step-(ii): Synthesis of 7-(3,5-dimethylisoxazolyl)(2-methoxyethoxy)(pyridin
ylmethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one
To a solution of compound-71a (0.08 g, 0.23 mmol) in DMF (3.0 mL) were added K CO
(0.095 g, 0.069 mmol) followed by 1-bromomethoxyethane (0.064 g, 0.46 mmol) and stirred
at 50°C for 16 h. After completion of reaction, the reaction was diluted with water (10 mL) and
extracted with EtOAc (50 mL). The organic layer was washed with water (50 mL), brine (50
mL), dried over sodium sulphate and concentrated. The residue was purified by prep. TLC to
afford the title compound as white solid (0.010 g, 11%). H NMR (400 MHz, CDCl ) δ 8.61 (d,
J=5.4 Hz, 2H), 7.22 (d, J=5.8 Hz, 2H), 6.80 (s, 1H), 6.44 (s, 1H), 5.17 (s, 2H), 4.75 (s, 2H), 3.78
(t, J=4.6 Hz, 2H), 3.50 (t, J=4.4 Hz, 2H), 3.27 (s, 3H), 2.29 (s, 3H), 2.16 (s, 3H); LC-MS: m/z
410.2 (M+1) .
The below compounds were prepared by procedure similar to any or both of the steps
depicted in Example-IX with appropriate variations in reactants, quantities of reagents and
reaction conditions. The physiochemical characteristics of the compounds are summarized herein
below table.
Comp
ound Structure Characterization Data
H NMR (300 MHz, CDCl ): δ 9.8 (bs, 1H), 8.16-814 (m, 1H),
7.71–7.65 (m, 2H), 7.32 (s, 1H), 7.17–7.14 (m, 2H), 6.94 (s,
1H), 6.55 (d, J=9.0 Hz, 1H), 5.65 (s, 2H), 3.34 (s, 3H), 3.20 (s,
3H); LC-MS: m/z 348.1 (M+1) .
H NMR (400 MHz, DMSO-d6): δ 10.45 (s, 1H), 8.59 (d,
J=2.4 Hz, 1H), 7.90 (dd, J =2.4 Hz, J =8.8 Hz, 1H), 7.87 (d,
J=9.8 Hz, 1H), 7.56 (s, 1H), 7.24 (d, J=8.3 Hz, 1H), 6.81 (s,
1H), 6.50 (d, J=9.8 Hz, 1H), 5.48 (s, 2H), 2.25 (s, 3H), 2.09 (s,
3H); LC-MS: m/z 382.1 (M+1) .
H NMR (300 MHz, CDCl ): δ 8.58 (d, J=4.2 Hz, 1H), 7.69–
7.63 (m, 2H), 7.45 (s, 1H), 7.42–7.41 (m, 1H), 7.31 (s, 1H),
74 7.25–7.22 (m, 1H), 6.74 (d, J=9.3 Hz, 1H), 5.66 (s, 2H), 4.41–
4.33 (m, 2H), 2.27 (s, 3H), 2.13 (s, 3H); LC-MS: m/z 430.1
(M+1) .
H NMR ( 300 MHz, CDCl ): δ 8.57 (d, J= 4.8 Hz, 1H), 7.67-
7.61 (m, 2H), 7.34 (d, J=7.8 Hz, 1H), 7.23-7.20 (m, 3H ), 6.69
(d, J=9.3 Hz, 1H), 5.67 (s, 2H), 4.07 (t, J= 5.4 Hz,2H), 3.74 -
3.64 (m, 4H), 2.68 (t, J= 6.3 Hz, 2H), 2.45–2.42 (m, 4H), 2.27
(s, 3H), 2.14 (s, 3H); LC-MS: m/z 461.2 (M+1) .
H NMR (300 MHz, CDCl ): δ 8.57 (d, J= 4.8 Hz, 1H), 7.67-
7.60 (m, 2H), 7.34 (d, J=7.8 Hz, 1H), 7.23-7.18 (m, 3H), 6.69
(d, J=9.3 Hz, 1H), 5.67 (s, 2H), 4.04 (t, J= 5.7 Hz, 2H), 2.62
(t, J= 5.7 Hz, 2H), 2.27 (s, 3H), 2.23 (s, 6H ), 2.13 (s, 3H);
LC-MS: m/z 419.3 (M+1) .
H NMR (CD OD, 300 MHz): δ 8.83 (s, 1H), 8.48-8.44 (m,
1H), 8.03 (d, J= 9.6 Hz, 1 H), 7.94 (bs, 1H), 7.76 (d, J= 7.6
Hz, 1 H), 7.65 (s, 1H), 7.21 (s, 1H), 6.66 (d, J= 9.6 Hz, 1 H),
6.00 (s, 2H), 4.05 (s, 2H),3.73-3.66 (m, 1H) 3.39-3.34 (m, 2H),
3.01-2.95 (m, 2H), 2.29 (s, 3H), 2.12 (s, 3H), 1.92-1.88 (m,
2H),1.52-1.49 (m, 2H); LC-MS: m/z 445.05 (M+1)
HNMR (300 MHz, CDCl ): δ 8.57 (d, J=4.2 Hz, 1H), 7.67–
7.60 (m, 2H), 7.34 (d, J=8.1 Hz, 1H), 7.26–7.17 (m, 3H), 6.68
78 (d, J=9.6 Hz, 1H), 5.68 (s, 2H), 3.93 (t, J=6.9 Hz, 2H), 2.26 (s,
3H), 2.12 (s, 3H), 1.68 (t, J=6.9 Hz, 2H), 1.39–1.32 (m, 2H),
0.90 (t, J= 6.9 Hz, 3H); LC-MS: m/z 404.1 (M+1) .
HNMR (300 MHz, CDCl ): δ 8.61 (d, J=3.0 Hz, 1H), 7.97–
7.90 (m, 2H), 7.58 (s, 1H), 7.46 (t, J=3.0 Hz, 6.0 Hz, 1H),
79 7.37 (d, J=6.0 Hz, 1H), 7.05 (s, 1H), 6.65 (d, J=9.0 Hz, 1H),
.88–5.85 (m, 1H), 5.77 (s, 2H), 5.22–5.10 (m, 2H), 4.56–4.54
(m, 2H), 2.27 (s, 3H), 2.11 (s, 3H); LC-MS: m/z 388.2 (M+1) .
H NMR (400 MHz, DMSO-d ) δ 8.52 (d, J=3.9 Hz, 1H), 7.90
(d, J=9.8 Hz, 1H), 7.77–7.75 (m, 1H), 7.61 (s, 1H), 7.31–7.28
80 (m, 2H), 7.09 (s, 1H), 6.59 (d, J=9.3 Hz, 1H), 5.63 (s, 2H),
4.83 (t, J=5.3 Hz, 1H), 3.96 (t, J=4.9 Hz, 2H), 3.64–3.60 (m,
2H), 2.27 (s, 3H), 2.10 (s, 3H); ES-MS: m/z 392.2 (M+1)
H NMR (300 MHz, CDCl ) δ 8.57 (d, J=4.2 Hz, 1H), 7.67–
7.59 (m, 2H), 7.33–7.18 (m, 4H), 6.68 (d, J=9.6 Hz, 1H), 5.67
81 (s, 2H), 4.07 (t, J=5.7 Hz, 2H), 2.80 (t, J=5.4 Hz, 2H), 2.47 (m,
4H), 2.27 (s, 3H), 2.14 (s, 3H), 1.74 (m, 4H); LC-MS: m/z
445.2 (M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.51 (d, J=4.0 Hz, 1H),
7.90 (d, J=9.2 Hz, 1H), 7.77 (t, J=7.6 Hz, 1H), 7.61 (s, 1H),
7.31–7.28 (m, 2H), 7.10 (s, 1H), 6.57 (d, J=9.6 Hz, 1H), 5.64
(s, 2H), 4.04 (t, J=5.6 Hz, 2H), 2.68 -2.64 (m, 5H), 2.61-2.59
(m, 2H), 2.28–2.26 (m, 7H), 2.10 (s, 3H); LC-MS: m/z 460.3
(M+1) .
H NMR (400 MHz, DMSO-d ): δ 8.46 (d, J=5.4 Hz, 2H),
8.41 (d, J=4.4 Hz, 1H), 7.91 (d, J=9.3 Hz, 1H), 7.71-7.69 (m,
83 1H), 7.67 (s, 1H), 7.26-7.12 (m, 5H), 6.58 (d, J=9.3 Hz, 1H),
.57 (s, 2H), 5.22 (s, 2H), 2.26 (s, 3H), 2.07 (s, 3H); LC-MS:
m/z 439.2 (M+1) .
H NMR (400 MHz, DMSO-d6): δ 8.51 (d, J=4.4 Hz, 1H),
7.90 (d, J=9.8 Hz, 1H), 7.76 (t, J=7.8 Hz, 1H), 7.60 (s, 1H),
7.30 (d, J=7.8 Hz, 2H), 7.11 (s, 1H), 6.57 (d, J=9.3 Hz, 1H),
.63 (s, 2H), 4.51 (t, J=4.8 Hz, 1H), 4.0 (t, J=6.4 Hz, 2H),
3.42-3.38 (m, 2H), 2.24 (s, 3H), 2.06 (s, 3H), 1.77-1.72 (m,
2H); LC-MS: m/z 406.2 (M+1) .
Note: Synthesis of Compound 77 comprises deprotection reaction according to the procedure
depicted in below step:
Deprotection reaction (for Compound-77): 6-(3,5-dimethylisoxazolyl)(piperidin
ylmethoxy)(pyridinylmethyl)quinolin-2(1H)-one hydrochloride
A solution of tert-butyl 4-(((6-(3,5-dimethylisoxazolyl)oxo(pyridinylmethyl)-
1,2-dihydroquinolinyl)oxy)methyl)piperidinecarboxylate (0.05 g, 0.0919 mmol) in 1,4-
dioxane. HCl (2 mL) was stirred at room temperature for 4 h. After completion of reaction, the
solvent was removed under reduced pressure, residue was triturated with ether and hexane to
give the title compound (0.01 g, 22.6%).
Similarly synthesis of Compound 82 comprises deprotection reaction according to the
preocedure depicted herein after.
Deprotection reaction (for Compound-82): 6-(3, 5-dimethylisoxazolyl)(2-(piperazinyl)
ethoxy)(pyridinylmethyl) quinolin-2(1H)-one
To a cooled solution of tert-butyl 4-(2-((6-(3,5-dimethylisoxazolyl)oxo(pyridin-
2-ylmethyl)-1,2-dihydroquinolinyl)oxy)ethyl)piperazinecarboxylate (0.05 g, 0.09 mmol) in
DCM(3 mL) was added TFA (0.5 mL) and stirred at room temperature for 2h. The reaction
mixture concentrated, residue was diluted with DCM (50 mL) and washed with sat NaHCO (50
mL), water (50 mL), dried over sodium sulphate and concentrated invacuo. The residue was
washed with diethyl ether to afford the title compound as brown solid (0.015 g, 37%).
Example-X: Synthesis of 6-(3,5-dimethylisoxazolyl)(pyridinylmethyl)(trifluoro
methoxy)quinolin-2(1H)-one (Compound-85)
Step-(i): Synthesis of 7-(bromodifluoromethoxy)(3,5-dimethylisoxazolyl)(pyridin
ylmethyl)quinolin-2(1H)-one
The process of this adopted from step-(ii) of compound-71 (Example-IX) to give the
titled compound as pale yellow solid (0.05 g, 36 %). H NMR (300 MHz, CDCl ): δ 8.58 (d,
J=4.8 Hz, 1H), 7.74–7.63 (m, 3H), 7.42 (s, 1H), 7.29 (d, J=5.1 Hz, 1H), 7.20–7.19 (m, 1H), 6.87
(d, J=9.6 Hz, 1H), 5.66 (s, 2H), 2.29 (s, 3H), 2.15 (s, 3H); F NMR (300 MHz, CDCl ): δ 15.9;
LC-MS: m/z 477.9 (M+1) .
Step-(ii): Synthesis of 6-(3,5-dimethylisoxazolyl)(pyridinylmethyl)(trifluoro
methoxy)quinolin-2(1H)-one
In a 50 mL polypropylene flask, a stirred solution of 7-(bromodifluoromethoxy)(3,5-
dimethylisoxazolyl)(pyridinylmethyl)quinolin-2(1H)-one (0.05 g, 0.105 mmol) in
DCM(5 mL) was treated with AgBF (0.061 g, 0.315 mmol), at -78ºC for 30 min. The reaction
mixture was stirred at RT for 12 h. The reaction mixture was diluted with cold saturated
NaHCO and extracted with DCM. The organic extract was washed with water and brine. The
organic layer was separated and dried over Na SO . The solution was concentrated under
reduced pressure to give crude compound. The residue obtained was purified by silica gel
preparative TLC (50% EtOAc/Hexane) to yield the title compound as an off white solid (0.016 g,
37%). H NMR (300 MHz, CDCl3): δ 8.58 (d, J=4.2 Hz, 1H), 7.72–7.61 (m, 3H), 7.41 (s, 1H),
7.33 (d, J=8.1 Hz, 1H), 7.23–7.19 (m, 1H), 6.84 (d, J=9.6 Hz, 1H), 5.64 (s, 2H), 2.28 (s, 3H),
19 +
2.14 (s, 3H); F NMR (300 MHz, CDCl ): δ -57.95; LC-MS: m/z 416.4 (M+1) .
Example-XI: Synthesis of 6-(3,5-dimethylisoxazolyl)(piperidinyloxy)(pyridin
ylmethyl)quinolin-2(1H)-one hydrochloride (Compound-86)
Step-(i): Synthesis of tert-butyl 4-((6-(3,5-dimethylisoxazolyl)oxo(pyridinylmethyl)-
1,2-dihydroquinolinyl)oxy)piperidinecarboxylate
To a solution of compound-72 (0.07 g, 0.20mmol) in dry THF (8 mL) was added tert-
butyl 4-hydroxypiperidinecarboxylate (0.05 g, 0.22 mmol), triphenylphosphine (0.16 g, 0.6
mmol), and DIAD (0.12 mL, 0.6 mmol), and stirred at room temperature 16 h. The reaction
mixture diluted with water and extracted with EtOAc (50 mL x2), combined organic layer
washed with brine (50 mL), dried over sodium sulphate and concentrated. The residue was
purified by silica gel (60-120 mesh) column chromatography (elution 20-40% EtOAc-hexane) to
afford title compound (0.05 g, 47 %); LC-MS: m/z 531.3 (M+1) .
Step-(ii): Synthesis of 6-(3,5-dimethylisoxazolyl)(piperidinyloxy)(pyridin
ylmethyl)quinolin-2(1H)-one hydrochloride
The process of this adopted from deprotection reaction of compound-77 (Example-IX).
H NMR (400 MHz, CD OD): δ 8.69 (d, J= 5.6 Hz, 1H), 8.16 (m, 1H), 7.98 (d, J=12.0 Hz, 1H),
7.67-7.65 (m, 2H), 7.57 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 6.66 (d, J=8.0 Hz, 1H), 5.86 (s, 2H),
.00–4.80 (m, 1H), 3.18-3.11 (m, 2H), 3.05-3.01 (m, 2H), 2.29 (s, 3H), 2.13 (s, 3H), 2.05-2.03
(m, 2H), 1.84-1.82 (m, 2H); LC-MS: m/z 431.1 (M+1) .
The below compounds were prepared by procedure similar to any or both of the steps
depicted in Example XI with appropriate variations in reactants, quantities of reagents and
reaction conditions. The physiochemical characteristics of the compounds are summarized herein
below table.
Comp
ound Structure Characterization Data
H NMR (300 MHz, CDCl ): δ 8.56 (d, J= 4.2 Hz, 1H), 7.66-
7.61 (m, 2H), 7.34 (d, J=7.8 Hz, 1H), 7.23-7.20 (m, 3H), 6.68
87 (d, J=9.6 Hz, 1H), 5.68 (s, 2H), 3.98–3.93 (m, 2H), 3.76 (d,
J=6.9 Hz, 2H), 3.35 (m, 2H), 2.25 (s, 3H), 2.11 (s, 3H), 1.95-
1.91 (m, 1H), 1.39-1.25 (m, 4H); LC-MS: m/z 446.3 (M+1) .
H NMR (400 MHz, CDCl ): δ 8.78 (d, J=5.6 Hz, 1H) ,8.35
(m, 1H), 8.00 (d, J=10 Hz, 1H), 7.85 (m,1H), 7.70 (d, J=8.0
Hz, 1H), 7.63 (s, 1H), 7.15 (s, 1H) ,6.64 (d, J=9.6 Hz, 1H),
.92 (s, 2H), 4.19-4.14 (m, 2H), 2.88 (t, J=12.8 Hz, 2H), 2.27
(s, 3H), 2.11 (s,3H), 1.85 (d, J=14 Hz, 2H) ,1.71-1.66 (m, 2H),
1.66-1.33(m, 2H), 1.26 (m, 3H); LC-MS: m/z 459.0 (M+1) .
1H NMR (300 MHz ,CD3OD) : 8.82 (d, J=5.7 Hz, 1H), 8.45-
8.40 (m, 1H), 8.03 (d, J=9.6 Hz, 1H), 7.96-7.90 (m, 1H),7.76
(d, J=8.1Hz,1H), 7.67(s, 1H), 7.19 (s, 1H), 6.66 ( d, J=9.6Hz,
89 1H), 5.99 (s, 2H), 4.30-4.20 (m, 2H), 3.80-3.60 (m, 2H), 3.25-
3.10 (m, 1H), 2.75-2.65 (m, 1H), 2.40-2.30 (m, 1H), 2.31
(s,3H), 2.14 (s, 3H), 2.15-2.05 (m, 1H), 1.98-1.85 (m, 2H),
1.70-1.55 (m, 1H); LC-MS: m/z 445.2 (M+1) .
Example-XII: Synthesis of 7-(3, 5-dimethylisoxazolyl)methoxy((1-propionylpiperidin-
4-yl) methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound-90)
To an ice cooled solution of compound-60 (0.10 g, 0.27 mmol) in DCM (5 mL) were
added triethyl amine (0.1 mL, 0.8 mmol) followed by addition of propionyl chloride (0.04 g,
0.40 mmol) drop wise and stirred at RT for 3 h. After completion of reaction, the reaction
mixture was diluted with DCM (50 mL) and washed with aq. NaHCO solution (20 mL), water
(50 mL), brine (20 mL), dried over sodium sulphate and concentrated. The obtained residue was
purified by preparative HPLC to afford the title product as an off-white solid (0.08 g, 8%). H
NMR (400 MHz, DMSO-d ): δ 6.92 (s, 1H), 6.90 (s, 1H), 4.62 (s, 2H), 4.40–4.32 (m, 1H), 3.90–
3.80 (m, 2H), 3.80–3.75 (m, 4H), 2.80–2.75 (m, 1H), 2.47–2.40 (m, 5H), 2.20–1.80 (m, 5H),
1.72–1.60 (m, 2H), 1.30–1.10 (m, 2H), 0.97 (t, J=7.3 Hz, 3H); LC-MS: m/z 428.3 (M+1) .
Example-XIII: Synthesis of 7-methoxy(5-methyloxo-2,3-dihydro-1H-imidazolyl)
(pyridinylmethyl)quinolin-2(1H)-one (Compound-91)
Step-(i): Synthesis of 6-aminomethoxy(pyridinylmethyl)quinolin-2(1H)-one
In a 100 mL resealable tube, a solution of 6-bromomethoxy(pyridin
ylmethyl)quinolin-2(1H)-one (1.0 g, 2.99 mmol) in DMSO (10 mL), was treated sequentially
with sodium azide (0.28g, 4.2mmol), CuI (0.54 g, 2.99 mmol) and L-proline (0.50 g, 4.3 mmol)
at RT under a nitrogen atmosphere. The resulting mixture was heated overnight at 100ºC. Upon
completion of the reaction (TLC), the reaction mixture was diluted with cold water and extracted
with EtOAc (3 x 50 mL). The combined organic layers were washed with brine and concentrated
under reduced pressure to afford the title compound as pale brown solid (0.60 g, 74%), which
was used in the next step without further purification. H NMR (400 MHz, CDCl ): δ 8.53 (d,
J=3.6 Hz, 1H), 7.56-7.51 (m, 2H), 7.20–7.13 (m, 2H), 6.95 (s, 1H), 6.77 (s, 1H), 6.62 (d, J=8.8
Hz, 1H), 5.64 (s, 2H), 3.8 (s, 3H); LC-MS: m/z 282.1 (M+1) .
Step-(ii): Synthesis of 6-isocyanatomethoxy(pyridinylmethyl)quinolin-2(1H)-one
To a solution of triphosgene (0.35 g, 1.24 mmol) in DCM (2 mL) was added drop wise a
solution of 6-aminomethoxy(pyridinylmethyl)quinolin-2(1H)-one (0.35 g , 1.24 mmol)
in DCM (10 mL) followed by the drop wise addition of triethylamine (0.1 mL, 2.48 mmol)) at
RT. The reaction mixture was stirred at RT for 4 h. After completion of the reaction (TLC), the
solvent was distilled off under reduced pressure. The residue obtained was used to next step
without any purification (0.30 g, crude); LC-MS: m/z 308.1 (M+1) .
Step-(iii): Synthesis of 1-(7-methoxyoxo(pyridinylmethyl)-1,2-dihydroquinolinyl)
(propynyl)urea
To a stirred solution of 6-isocyanatomethoxy(pyridinylmethyl)quinolin-2(1H)-
one (0.3 g, 0.97 mmol ) in dry THF (10mL) was added propargyl amine (0.059 g, 0.97 mmol)
in THF (1mL) under argon atmosphere at RT. The reaction mixture was stirred for 12 h at RT.
The reaction mixture was diluted with water and extracted with EtOAc (3x30 mL). The
combined organic extract was washed with brine and concentrated under reduced pressure. The
residue obtained was purified by silica gel (60-120 mesh) column chromatography and eluting
with 20% EtOAc/Hexane afforded the title compound as a pale yellow solid (0.32 g, crude). LC-
MS: m/z 363.4 (M+1) .
Step-(iv): Synthesis of 7-methoxy(5-methyloxo-2,3-dihydro-1H-imidazolyl)(pyridin-
2-ylmethyl)quinolin-2(1H)-one
To a stirred solution of 1-(7-methoxyoxo(pyridinylmethyl)-1,2-dihydroquinolin-
6-yl)(propynyl)urea (0.3 g, 0.82 mmol ) in MeOH (15 mL) was added 5 N sodium
methoxide in MeOH (0.5 mL) at RT under nitrogen atmosphere. The reaction mixture was
stirred at reflux temperature for 24 h. After completion of the reaction, was cooled to room
temperature and solvent was removed under reduced pressure. The residue obtained was purified
by silica gel preparative TLC (5% MeOH/CHCl ) to give the compound as an off white solid
(0.01 g, 3.3%). H NMR (400 MHz, CDCl ): δ 9.79 (s, 1H), 8.51–8.50 (d, J=4.8Hz, 1H), 7.92 (d,
J=9.6 Hz, 1H), 7.76–7.74 (m, 1H), 7.63 (s, 1H), 7.31–7.26 (m, 2H), 7.11 (s, 1H), 6.58 (d, J=8.4
Hz, 1H), 6.18 (s, 1H), 7.74 (d, J=16.8 Hz, 1H), 7.55 (d, 16.8Hz, 1H), 3.69 (s, 3H), 1.69 (3H);
LC-MS: m/z 363.0 (M+1) .
Example-XIV: Synthesis of 3-(7-methoxyoxo(pyridinylmethyl)-1,2-dihydroquinolin
yl)methyl-1H-pyrrole-2,5-dione (Compound-92)
Step-(i): Synthesis of 1-(3,4-dimethoxybenzyl)(7-methoxyoxo(pyridinylmethyl)-1,2-
dihydroquinolinyl)methyl-1H-pyrrole-2,5-dione
The process of this step was adopted from example-VII (Compound-17). The desired
compound obtained as a crude material (0.10 g); LC-MS: m/z 526.1 (M+1) .
Step-(ii): Synthesis of 3-(7-methoxyoxo(pyridinylmethyl)-1,2-dihydroquinolinyl)
methyl-1H-pyrrole-2,5-dione
A solution of 1-(3,4-dimethoxybenzyl)(7-methoxyoxo(pyridinylmethyl)-1,2-
dihydroquinolinyl)methyl-1H-pyrrole-2,5-dione (0.10 g, 0.19 mmol ), anisole (0.1 mL)
and H2SO4 (catalytic amount) in TFA (4 mL) was heated over night at 90ºC. Upon completion of
the reaction (TLC), the reaction mixture was cooled to RT and diluted with DCM. The organic
layer was washed with saturated NaHCO solution and dried over anhydrous sodium sulfate,
before evaporating under reduced pressure. The obtained residue was purified by silica gel (60-
120 mesh) column chromatography and eluting with 5% DCM/MeOH gave the title compound
as an off-white solid (0.004 g, 5.6%). H NMR (400 MHz, CDCl ): δ 8.54–8.53 (m, 1H), 7.95–
7.90 (m, 1H), 7.77–7.74 (m, 1H), 7.62 (s, 1H), 7.34–7.27 (m, 2H), 7.07 (s, 1H), 6.67 (d, J=9.3
Hz, 1H), 5.74 (s, 2H), 3.78 (s, 3H), 1.90 (s, 3H); LC-MS: m/z 376.1 (M+1) .
Example-XV: Synthesis of 6-(3, 5-dimethylisoxazolyl)methoxy(pyridinylmethyl)
quinoxalin-2(1H)-one (Compound-93)
Step-(i): Synthesis of 5-(3,5-dimethylisoxazolyl)methoxynitroaniline
The process of this step was adopted from Example-VII (compound-17). The desired
compound obtained as a pale yellow solid. HNMR (400 MHz, DMSO-d ) δ 7.49 (s, 1H), 7.26
(bs, 2H), 6.95 (s, 1H), 3.75 (s, 3H), 2.30 (s, 3H), 2.11 (s, 3H); LC-MS: m/e 264.2 (M+1) .
Step-(ii): Synthesis of tert-butyl (5-(3,5-dimethylisoxazolyl)methoxynitrophenyl)
carbamate
A stirred suspension of 60% NaH (0.091 g, 2.28 mmol) in 5 mL of DMF at 0°C was
added 5-(3,5-dimethylisoxazolyl)methoxynitroaniline (0.5 g, 1.90 mmol). Stirred at
same conditions for 30 min then added Boc-anhydride (0.48 mL, 2.09 mmol). The reaction
mixture was stirred for 3h at room temperature. The reaction mixture was diluted with ethyl
acetate and washed with water (100 mL), dried over Na SO and concentration. The obtained
residue was purified by column chromatography on silica (20 % EtOAc in hexane) to give the
desired product as a yellow solid (0.45 g, 65%). H NMR (400 MHz, DMSO-d ) δ 9.38 (bs, 1H),
7.61 (s, 1H), 7.41 (s, 1H), 3.85 (s, 3H), 2.30 (s, 3H), 2.11 (s, 3H), 1.43 (s, 9H); LC-MS: m/e
364.2 (M+1) .
Step-(iii): Synthesis of tert-butyl (2-amino(3,5-dimethylisoxazolyl)methoxyphenyl)
carbamate
A stirred solution of tert-butyl (5-(3,5-dimethylisoxazolyl)methoxynitrophenyl)
carbamate (0.45 g, 1.23 mmol) in 10 mL of MeOH was added 10% Pd-C (0.1 g) and stirred
under H balloon pressure at RT for 2 h. After completion of reaction, the reaction mixture was
filtered through celite pad, washed with methanol. The filtrate was concentrated to afford the title
product as pale yellow solid (0.5 g). The crude product was as such taken forward for next step
without further purification. H NMR (400 MHz, DMSO-d ) δ 8.31 (s, 1H), 6.87 (bs, 1H), 6.44
(s, 1H), 5.01 (bs, 2H), 3.65 (s, 3H), 2.21 (s, 3H), 2.03 (s, 3H), 1.43 (s, 9H); LC-MS: m/e 334.2
(M+1) .
Step-(iv): Synthesis of tert-butyl (5-(3,5-dimethylisoxazolyl)methoxy((pyridin
ylmethyl)amino)phenyl)carbamate
To an ice-cooled solution of tert-butyl (2-amino(3,5-dimethylisoxazolyl)
methoxyphenyl)carbamate (0.15 g, 0.45 mmol) in MeOH (10 mL) were add pyridine
carboxaldehyde (0.06 mL, 0.67 mmol) and stirred at RT for 2 h. Then the reaction mixture was
again cooled to 0ºC and added sodium cyanoborohydride (0.057 g, 0.9 mmol) followed by
AcOH (0.02 mL) and stirred at RT for 16 h. After completion of reaction, the reaction mixture
was concentrated, diluted with water and extracted with EtOAc (100 mL X 2). The combined
organic layers were washed with aq. sodium bicarbonate (20 mL), water (200 mL), brine (100
mL), dried over sodium sulphate and concentrated. The residue was purified silica gel (100-200
mesh) to afford the title product (0.1 g, 52 %). H NMR (400 MHz, DMSO-d ): δ 8.54 (d, J=4.4
Hz, 1H), 8.31 (s, 1H), 7.80–7.76 (m, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.30–7.27 (m, 1H), 6.84 (s,
1H), 6.35–6.25 (m, 1H), 5.94 (t, J=5.6 Hz, 1H), 4.47 (d, J=5.4 Hz, 2H), 3.61 (s, 3H), 2.20 (s,
3H), 2.02 (s, 3H), 1.23 (s, 9H); LC-MS: m/z 425.3 (M+1) .
Step-(v): Synthesis of tert-butyl (2-(2-chloro-N-(pyridinylmethyl)acetamido)(3,5-dimethyl
isoxazolyl)methoxyphenyl)carbamate
To an ice-cooled solution of tert-butyl (5-(3,5-dimethylisoxazolyl)methoxy
((pyridinylmethyl)amino)phenyl)carbamate (0.1 g, 0.23 mmol) in DCM (10 mL) were add
NaHCO (0.197 g, 2.35 mmol) followed by 2-chloroacetyl chloride (0.022 g, 0.28 mmol) and
stirred at 0ºC for 10 min. Reaction mixture was diluted with DCM (100 mL), washed with water
(50 mL), brine (20 mL), dried over sodium sulphate and concentrated. The residue was as such
used for next step without further purification (0.1 g, 85%). H NMR (400 MHz, DMSO-d ): δ
11.05–10.80 (bs, 1H), 8.54 (d, J=4.4 Hz, 1H), 7.89–7.85 (m, 1H), 7.70 (s, 1H), 7.49–7.41 (m,
1H), 7.39–7.37 (m, 1H), 7.22 (s, 1H), 4.35–4.20 (m, 4H), 3.75 (s, 3H), 2.30 (s, 3H), 2.07 (s, 3H),
1.23 (s, 9H); LC-MS: m/z 502.2 (M+1) .
Step-(vi): Synthesis of tert-butyl 7-(3,5-dimethylisoxazolyl)methoxyoxo(pyridin
ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate
To an ice-cooled solution of tert-butyl (5-(3,5-dimethylisoxazolyl)methoxy
((pyridinylmethyl)amino)phenyl)carbamate (0.1 g, 0.20 mmol) in DMF (5 mL) was add NaH
(0.0.12 g, 0.29 mmol) and stirred at 0ºC for 15 min. After completion of reaction, the reaction
mixture was quenched with MeOH, diluted with H2O (10 mL) and extracted with EtOAc (50 mL
X 2). The organic layer was washed with water (50 mL), brine (20 mL), dried over sodium
sulphate and concentrated. The residue was as such used for next step without further
purification (0.093 g, 100%); LC-MS: m/z 465.3 (M+1) .
Step-(vii): Synthesis of 6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)
quinoxalin-2(1H)-one
To an ice-cooled solution of tert-butyl 7-(3,5-dimethylisoxazolyl)methoxyoxo-
4-(pyridinylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.1 g, 0.21 mmol) in DCM
(5 mL) was add TFA (0.016 mL, 2.15 mmol) and stirred at RT for 3 h. After completion of
reaction, the reaction mixture was diluted with DCM (100 mL), washed with aq. sodium
bicarbonate solution (20 mL), water (50 mL), brine (20 mL), dried over sodium sulphate and
concentrated. The residue was purified by preparative TLC to afford the title compound as pale
brown solid (0.015 g, 19%). H NMR (400 MHz, DMSO-d ): δ 8.50 (d, J=4.0 Hz, 1H), 8.20 (s,
1H), 7.80 (t, J=7.1 Hz, 1H), 7.12 (s, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.33–7.29 (m, 1H), 7.13 (s,
1H), 5.64 (s, 2H), 3.77 (s, 3H), 2.26 (s, 3H), 2.06 (s, 3H); LC-MS: m/z 363.2 (M+1) .
Example-XVI: Synthesis of N-(4-(4-chlorobenzyl)methoxyoxo-3, 4-dihydro-2H-benzo
[b][1,4]oxazinyl)-3,5-dimethylisoxazolecarboxamide (Compound-94)
Step-(i): Synthesis of N-(4-(4-chlorobenzyl)methoxyoxo-3,4-dihydro-2H-
benzo[b][1,4]oxazinyl)-3,5-dimethylisoxazolecarboxamide
To a solution of 7-amino(4-chlorobenzyl)methoxy-2H-benzo[b][1,4]oxazin-3(4H)-
one (0.10 g, 0.31 mmol) in DCM (5 mL) were added 3,5-dimethylisoxazolecarboxylic acid
(0.05 g, 0.33 mmol), HOBt (0.02, 0.15 mmol), EDC.HCl (0.12 g, 0.63 mmol), Triethylamine
(0.11 ml, 0.77 mmol) and stirred at RT for 16 h. After completion of reaction, the reaction
mixture was diluted with DCM (100 mL), washed with water (50 mL), brine (50 mL), dried over
sodium sulphate and concentrated. The residue was purified by preparative TLC to afford title
product as a yellow solid (0.03 g 22%). H NMR (400 MHz, DMSO-d ): δ 9.08 (bs, 1H), 7.63 (s,
1H), 7.40 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.3 Hz, 2H), 6.80 (s, 1H), 5.22 (s, 2H), 4.73 (s, 2H), 3.70
(s, 3H), 3.56 (s, 3H), 2.34 (s, 3H); LC-MS: m/z 442.1 (M+1) .
Example-XVII: Synthesis of 4-(4-chlorobenzyl)((3,5-dimethylisoxazolyl)amino)
methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound-95)
To a solution of 7-bromo(4-chlorobenzyl)methoxy-2H-benzo[b][1,4]oxazin-3(4H)-
one (0.10 g, 0.26 mmol) in toluene (5.0 mL) in a sealed tube were added 3,5-dimethylisoxazol
amine (0.03 g, 0.26 mmol), cesium carbonate (0.20 g, 0.65 mmol), xantphos (0.02 g, 0.025
mmol) and degassed with nitrogen purging for 20 min. Then palladium(II)acetate (0.015 g, 0.065
mmol) was added and heated at 100°C for 16 h. After completion of reaction, the reaction
mixture was allowed RT, diluted with EtOAc (50 mL), washed with water (50 mL), brine (50
mL), dried over sodium sulphate and concentrated. The residue was purified by preparative TLC
to afford the title product as pale brown solid (6 mg, 0.5%). H NMR (400 MHz, DMSO-d ) δ
7.41 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.3 Hz, 2H), 6.66 (s, 1H), 6.57 (s, 1H), 5.14 (bs, 2H), 4.59 (s,
2H), 3.70 (s, 3H), 2.18 (s, 3H), 1.98 (s, 3H); LC-MS: m/z 414.1 (M+1) .
Example-XVIII: Synthesis of 6-(3,5-dimethylisoxazolyl)(hydroxymethyl)methoxy
(pyridinylmethyl)quinolin-2(1H)-one (Compound-96) & 6-(3,5-dimethylisoxazolyl)
(fluoromethyl)methoxy(pyridinylmethyl)quinolin-2(1H)-one (Compound-97)
(i) (ii) O N O
O N O
O N O
Compound-97
O Intermediate-78 O
Compound-96
Step-(i): Synthesis of 6-(3, 5-dimethylisoxazolyl)(hydroxymethyl)methoxy(pyridin-
2-ylmethyl) quinolin-2(1H)-one
To an ice cooled solution of 6-(3,5-dimethylisoxazolyl)methoxyoxo(pyridin-
2-ylmethyl)-1,2-dihydroquinolinecarbaldehyde (0.07 g, 0.18 mmol) in MeOH (3 mL) was
added NaBH4 (0.007 g, 0.18 mmol) pinch wise and stirred at 0 C for 1 h. After completion of
reaction, the reaction mixture concentrated, the residue was diluted with water and extracted with
EtOAc (50 mL x 2). The organic layer was washed brine (100 mL), dried over sodium sulphate
and concentrated under reduced pressure and column purified to afford the title product as white
solid (0.02 g, 28%). H NMR (400 MHz, DMSO-d ): δ 8.52 (d, J=8.4 Hz, 1H), 7.91 (s, 1H), 7.77
(t, J=7.8 Hz, 1H), 7.62 (s, 1H), 7.32-7.28 (m, 2H), 7.11 (s, 1H), 5.75 (s, 2H), 5.27 (t, J=5.4 Hz,
1H), 4.46 (d, J=5.4 Hz, 2H), 3.73 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H); LC-MS: m/z 392.1 (M+1) .
Step-(ii): Synthesis of 6-(3,5-dimethylisoxazolyl)(fluoromethyl)methoxy(pyridin
ylmethyl)quinolin-2(1H)-one
To a cooled solution of 6-(3,5-dimethylisoxazolyl)(hydroxymethyl)methoxy
(pyridinylmethyl)quinolin-2(1H)-one (0.04 g, 0.102 mmol) in DCM(2 mL) was added DAST
(0.04 mL, 0.3 mmol) and stirred at room temperature for 2h. The reaction mixture diluted with
DCM (50 mL) and washed with water (50 mL), dried over sodium sulphate and concentrated
under reduced pressure and purified by preparative TLC to afford the title compound as an off
white solid (0.01 g, 25%). H NMR (300 MHz, CDCl ): δ 8.53 – 8.51 (m, 1H), 7.72 (s, 1H), 7.58
(t, J= 7.4 Hz, 1H), 7.29 (d, J= 7.8 Hz, 1H), 7.24 (s, 1H), 7.16 – 7.14 (m, 2H), 5.64 (bs, 2H), 5.51
(s, 1H), 5.40 (s, 1H), 3.74 (s, 3H), 2.20 (s, 3H), 2.06 (s, 3H); LC-MS: m/z 394.2 (M+1) .
Example-XIX: Synthesis of 6-(3,5-dimethylisoxazolyl)methoxy((5-(1-methyl-1H-
pyrazolyl) pyridinyl) methyl) quinolin-2(1H)-one (Compound-98)
Step-(i): 1-((5-bromopyridinyl) methyl)(3,5-dimethylisoxazolyl)methoxy quinolin-
2(1H)-one
The process of this adopted from step-d of Intermediate-78.
H NMR (400 MHz, DMSO-d ): δ 8.65 (d, J=2.0 Hz, 1H), 8.03 (dd, J =2.4 Hz, J =8.8 Hz, 1H),
6 1 2
7.91 (d, J=9.3 Hz, 1H), 7.63 (s, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.07 (s, 1H), 6.57 (d, J=9.3 Hz, 1H),
.63 (s, 2H), 3.76 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H); LC-MS: m/z 442 (M+2) .
Step-(ii): 6-(3, 5-dimethylisoxazolyl)methoxy((5-(1-methyl-1H-pyrazolyl) pyridin
yl) methyl) quinolin-2(1H)-one
The process of this was adopted from compound-17 (Example-VII). H NMR (400 MHz,
DMSO-d ): δ 8.77 (d, J= 2.0 Hz, 1H), 8.21 (s, 1H), 7.94 – 7.89 (m, 3H), 7.62 (s, 1H), 7.32 (d,
J= 8.3 Hz, 1H), 7.19 (s, 1H), 6.58 (d, J= 9.3 Hz, 1H), 5.63 (s, 2H), 3.86 (s, 3H), 3.77 (s, 3H),
2.24 (s, 3H), 2.05 (s, 3H); LC-MS: m/z 442.7 (M+1) .
Example-XX: Synthesis of 1-((5-(3,5-dimethyl-1H-pyrazolyl)pyridinyl)methyl)(3,5-
dimethylisoxazolyl)methoxyquinolin-2(1H)-one (Compound-99)
The process of this was adopted from compound-17 (Example-VII). H NMR (400 MHz,
DMSO-d ): δ 12.39 (bs, 1H), 8.47 (d, J=1.4 Hz, 1H), 7.91 (d, J=9.3 Hz, 1H), 7.14 (dd, J =2.4
Hz, J =8.3 Hz, 1H), 7.63 (s, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.23 (s, 1H), 6.59 (d, J=9.3 Hz, 1H),
.66 (s, 2H), 3.78 (s, 3H), 2.25 (s, 9H), 2.06 (s, 3H); LC-MS: m/z 456.2 (M+1) .
Example-XXI: Synthesis of 6-(3,5-dimethylisoxazolyl)((5-(3-hydroxypyrrolidin
yl)pyridinyl)methyl)methoxyquinolin-2(1H)-one (Compound-100)
To a solution of 1-((5-bromopyridinyl)methyl)(3,5-dimethylisoxazolyl)
methoxyquinolin-2(1H)-one (0.05 g, 0.11 mmol) in 1,4-dioxane (4 mL) in a sealed tube were
added pyrrolidinol (0.01 g , 0.13 mmol), cesium carbonate (0.11 g, 0.34 mmol) and BINAP
(0.004 g, 0.006 mmol) and degassed with nitrogen purging for 15 min then added palladium
acetate (0.003g, 0.011 mmol), then heated at 100°C for 16 h. After completion of the reaction,
the reaction mixture was diluted with EtOAc (50 mL), washed with water (50 mL), brine (50
mL), dried over sodium sulphate and concentrated. The residue was purified by preparative TLC
to afford the title compound as brown solid (0.02 g, 43%). H NMR (400 MHz, DMSO-d ): δ
7.91 (d, J=9.8 Hz, 1H), 7.85 (s, 1H), 7.60 (s, 1H), 7.30 (s, 1H), 7.20 (d, J=8.8 Hz, 1H), 6.99-6.97
(m, 1H), 6.59 (d, J=9.3 Hz, 1H), 5.53 (bs, 2H), 4.41-4.39 (m, 1H), 3.82 (s, 3H), 3.60-3.30 (m,
4H), 3.10 (d, J=10.3 Hz, 1H), 2.24 (s, 3H), 2.06 (s, 3H), 2.03-1.91 (m, 2H); LC-MS: m/z 447.1
(M+1) .
Example-XXII: Synthesis of 6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)-
3-(2,2,2-trifluorohydroxyethyl)quinolin-2(1H)-one (Compound-101)
To a cooled solution of 6-(3,5-dimethylisoxazolyl)methoxyoxo(pyridin
ylmethyl)-1,2-dihydroquinolinecarbaldehyde (0.02 g, 0.051 mmol) in THF (1 mL) were added
tetra butyl ammonium fluoride 1.0 M in THF (0.015 mL, 0.015 mmol) and TMS-CF (0.01 mL,
0.061 mmol), stirred at 0 C for 1 h. The reaction mixture quenched with sat. NH Cl, extracted
with EtOAc (50 mL), washed with water (50 mL), dried over sodium sulphate and concentrated.
The residue was purified on preparative TLC to afford the title compound as an off white solid
(0.01g, 43%). H NMR (400 MHz, DMSO-d ): δ 8.52 (d, J=3.9 Hz, 1H), 8.19 (s, 1H), 7.80–7.77
(m, 2H), 7.33–7.28 (m, 2H), 7.15 (s, 1H), 6.90 (d, J=7.4 Hz, 1H), 5.77–5.64 (m, 2H), 5.49–5.43
(m, 1H), 3.76 (s, 3H), 2.25 (s, 3H), 2.07 (s, 3H); LC-MS: m/z 460.2 (M+1) .
The above compound-101 (racemate) was purified by chiral HPLC. The characterization
data of desired isomers was given below.
Comp
ound Structure Characterization Data
Compound 102 (Isomer-1): H NMR (400 MHz,
DMSO-d ): δ 8.52 (d, J=4.4 Hz, 1H), 8.18 (s, 1H),
7.80 (s, 1H), 7.79–7.77 (m, 1H), 7.33–7.29 (m, 2H),
7.15 (s, 1H), 6.90 (d, J=6.0 Hz, 1H), 5.77–5.64 (m,
2H), 5.49–5.44 (m, 1H), 3.76 (s, 3H), 2.25 (s, 3H),
O N O +
2.06 (s, 3H); LC-MS: m/z 460.1 (M+1) .
Compound 103 (Isomer-2): H NMR (400 MHz,
DMSO-d ): δ 8.52 (d, J=4.4 Hz, 1H), 8.19 (s, 1H),
7.80 (s, 1H), 7.79–7.77 (m, 1H), 7.33–7.29 (m, 2H)
7.15 (s, 1H), 6.90 (d, J=5.6 Hz, 1H), 5.77–5.64 (m,
2H), 5.48–5.45 (m, 1H), 3.76 (s, 3H), 2.25 (s, 3H),
2.06 (s, 3H); LC-MS: m/z 460.1 (M+1) .
Example-XXIII: Synthesis of 6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)-
3-(2,2,2-trifluoro-1,1-dihydroxyethyl)quinolin-2(1H)-one (Compound-104)
To cooled solution of 6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)-
3-(2,2,2-trifluorohydroxyethyl)quinolin-2(1H)-one (0.2 g, 0.43 mmol) in DCM (5 mL) was
added dess-martin per iodinane (0.28 g, 0.65 mmol) and stirred at room temperature for 16 h.
After completion of the reaction, the reaction mixture was diluted with DCM (100 mL) and
washed with mixture of aqueous NaHCO and Na S O in 5:1 ratio dried over sodium sulphate
3 2 2 5
and concentrated. The residue was purified by preparative HPLC to afford title compound as
white solid (0.015 g, 8%). H NMR (400 MHz, DMSO-d ): δ 8.55 (s, 2H), 8.50 (d, J=4.9 Hz,
1H), 8.40 (s, 1H), 7.94 (s, 1H), 7.82 (t, J=6.9 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.32-7.29 (m,
1H), 7.23 (s, 1H), 5.77 (s, 2H), 3.79 (s, 3H), 2.26 (s, 3H), 2.07 (s, 3H); ES-MS: m/z 476.1
(M+1) .
Example-XXIV: Synthesis of 1-(4-chlorophenethyl)(3,5-dimethylisoxazolyl)methoxy-
3-methyloxo-1,2-dihydroquinolinecarbonitrile (Compound-105) & 2-(1-(4-
chlorophenethyl)(3,5-dimethylisoxazolyl)methoxyoxo-1,2-dihydroquinolin
yl)acetonitrile: (Compound-106)
Step-(i): Synthesis of 6-bromo(4-chlorophenethyl)methoxyoxo-1,2-dihydroquinoline
carbaldehyde
The process of this was adopted from step-(i) of compound-1 (Example-I). H NMR (400
MHz, CDCl ): δ 10.42 (s, 1H), 8.24 (s, 1H), 7.89 (s, 1H), 7.30 (d, J=8.3 Hz, 2H), 7.20 (d, J=8.3
Hz, 2H), 6.63 (s, 1H), 4.48 (t, J=7.8 Hz, 2H), 3.96 (s, 3H), 3.06 (t, J=7.8 Hz, 2H); LC-MS: m/z
421.0 (M+1) .
Step-(ii): Synthesis of 1-(4-chlorophenethyl)(3,5-dimethylisoxazolyl)methoxyoxo-
1,2-dihydroquinolinecarbaldehyde
The process of this was adopted from compound-17 (Example-VII). H NMR (400 MHz,
CDCl ): δ 10.45 (s, 1H), 8.33 (s, 1H), 7.46 (s, 1H), 7.30 (d, J=8.3 Hz, 2H), 7.22 (d, J=8.3 Hz,
2H), 6.67 (s, 1H), 4.53 (t, J=7.9 Hz, 2H), 3.89 (s, 3H), 3.10 (t, J=7.8 Hz, 2H), 2.31 (s, 3H), 2.15
(s, 3H); LC-MS: m/z 437.1 (M+1) .
Step-(iii): Synthesis of 1-(4-chlorophenethyl)(3,5-dimethylisoxazolyl)(hydroxymethyl)-
7-methoxyquinolin-2(1H)-one
The process of this was adopted from compound-97 (Example-XVIII-). The desired
compound obtained as a white solid (0.2 g, 67%). H NMR (400 MHz, CDCl ): δ 7.64 (s, 1H),
7.32-7.21 (m, 5H), 6.67 (s, 1H), 4.66-4.64 (m, 2H), 4.52 (t, J=7.8 Hz, 2H), 3.86 (s, 3H), 3.35-
3.30 (m, 1H), 3.08 (t, J=7.8 Hz, 2H), 2.31 (s, 3H), 2.16 (s, 3H); LC-MS: m/z 439.1 (M+1) .
Step-(iv): Synthesis of 1-(4-chlorophenethyl)(3,5-dimethylisoxazolyl)methoxyoxo-
1,2-dihydroquinolinyl)methylmethanesulfonate
The process of this step was adopted from intermediate-15. The obtained crude was used
in the next step without any purification.
Step-(v): Synthesis of 1-(4-chlorophenethyl)(3,5-dimethylisoxazolyl)methoxy
methyloxo-1,2-dihydroquinolinecarbonitrile & 2-(1-(4-chlorophenethyl)(3,5-
dimethylisoxazolyl)methoxyoxo-1,2-dihydroquinolinyl)acetonitrile
To a cooled solution of (1-(4-chlorophenethyl)(3,5-dimethylisoxazolyl)methoxy-
2-oxo-1,2-dihydroquinolinyl)methyl methanesulfonate (0.22 g, 0.43 mmol) in DMF (5 mL)
was added potassium cyanide (0.042 g, 0.64 mmol) and stirred at room temperature for 16 h.
After completion of the reaction, the reaction mixture poured into ice water and extracted with
EtOAc (100 x 2), dried over sodium sulphate, concentrated under reduced pressure and column
purified to afford title compound as pale yellow solid (A) (0.02 g, 10%). H NMR (400 MHz,
CDCl ): δ 7.64 (s, 1H), 7.30 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 6.73 (s, 1H), 4.51 (t,
J=7.4 Hz, 2H), 3.86 (s, 3H), 3.07 (t, J=7.8 Hz, 2H), 2.53 (s, 3H), 2.33 (s, 3H), 2.17 (s, 3H); LC-
MS: m/z 448.1 (M+1) . & (B) (0.065 g, 34%). H NMR (400 MHz, CDCl ): δ 7.89 (s, 1H), 7.37
(s, 1H), 7.30-7.28 (m, 2H), 7.21 (d, J=8.8 Hz, 2H), 6.72 (s, 1H), 4.52 (t, J=7.3 Hz, 2H), 3.87 (s,
3H), 3.75 (d, J=1.5 Hz, 2H), 3.07 (t, J=7.9 Hz, 2H), 2.32 (s, 3H), 2.17 (s, 3H); LC-MS: m/z 448.1
(M+1) .
BIOLOGICAL DATA:
In-Vitro Biochemical Data of bicyclic heterocyclic derivatives in time-resolved
fluorescence resonance energy transfer (TR-FRET) assay.
The Bet bromodomain TR-FRET assay has been used to identify compounds that bind to
bet bromodomain and prevent its interaction with acetylated histone peptides.
In the assay, optimized concentration of in-house Bet bromodomain protein (BRD4) and
300 nM of acetyl histone peptide substrate were diluted in assay buffer (50 mM HEPES, pH: 7.5,
50 mM NaCl, 500 µM CHAPS) and were added to the positive control and test control wells in a
384 well plate. Substrate control wells have 300 nM of acetyl histone peptide substrate diluted in
assay buffer. Buffer blank wells were added with assay buffer. The reaction mixture was allowed
for incubation at room temperature for 30 mins. Stock solutions of test compounds at 20mM
DMSO are prepared. Compounds are serially diluted and added to the test wells in 384-well
polypropylene plates. The reaction mixture was further incubated for 30 mins at room
temperature on a plate shaker. 2 nM of Europium labeled streptavidn and 10nM of XL-665
labeled antibody diluted in detection buffer (50mM HEPES, pH: 7.5, 50mM NaCl, 500µM
CHAPS and 800mM KF) were added to all the wells excluding the buffer blank wells. The
reaction plate was incubated for additional 30mins at room temperature on plate shaker. The
plate was read in Perkin Elmer WALLAC 1420 Multilabel Counter Victor 3 (Ex: 340 nm Em:
615 and 665 nm). The amount of displacement of the peptide was measured as ratio of specific
665nm energy transfer signal to 615 nm signals. The compounds IC was determined by fitting
the dose response data to sigmoid curve fitting equation using Graph Pad Prism software V5.
The compounds were screened in the above mentioned assay and the results (IC50) are
summarized in the table below; wherein “A” refers to an IC value of less than or equal to 1000
nM, “B” refers to IC value in range of 1000.01 to 3000 nM and “C” refers to IC value of
50 50
greater than 3000 nM.
Group Compound No
1, 2, 4, 5, 7, 8, 9, 10, 16, 17, 18, 20, 21, 22, 23, 24, 26, 28, 29, 32, 34, 36, 37, 38,
A 39, 40, 41, 43, 44, 45, 46, 47, 49, 50, 55, 56, 58, 59, 62, 64, 65, 66, 67, 68, 69,
72, 73, 74, 77, 78, 79, 80, 83, 84, 89, 90, 93, 96, 97, 98, 101, 102, 103, 104, 106.
B 11, 12, 25, 27, 30, 31, 33, 35, 42, 51, 53, 57, 75, 81, 82, 85, 87, 88.
C 3, 6, 13, 14, 15, 19, 48, 52, 54, 60, 61, 63, 70, 71, 76, 86, 91, 92, 94, 95, 105.
In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission that such
documents, or such sources of information, in any jurisdiction, are prior art, or form part of the
common general knowledge in the art.
In the description in this specification reference may be made to subject matter which is
not within the scope of the appended claims. That subject matter should be readily identifiable by
a person skilled in the art and may assist in putting into practice the invention as defined in the
appended claims.
Claims (1)
- We Claim : 1. A compound of formula (I): or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof; 5 wherein, dotted line[---] represents a single or a double bond; X is selected from C, C(O), N or O; wherein C and N are substituted with one or more R to meet the desired valency requirements; L is a direct bond or a linker selected from -NH-, -NHC(O)- or -NHS(O) -; 10 L is a linker selected from -(CHR ) -, -C(O)- or -S(O) -; 2 6 n 2 Cy is an optionally substituted 5-6 membered monocyclic ring containing 1-4 hetero atoms/ hetero groups independently selected form N, NH, O or –C(O)-; wherein the optional substituent at each occurrence is independently selected from one or more R ; Cy is an optionally substituted 4-12 membered monocyclic or bicyclic ring containing 0- 15 3 hetero atoms/groups independently selected from N, NH, O or S; wherein the optional substituent at each occurrence is independently selected from one or more R ; R is selected from hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclyl or heterocyclylalkyl; R and R independently are hydrogen, alkyl or together form an oxo group; 20 R at each occurrence is independently selected from hydrogen, alkyl, cycloalkyl, cyanoalkyl, hydroxyalkyl, or optionally substituted haloalkyl; wherein the optional substituent is one or more hydroxyl; R at each occurrence is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl or cyano; 25 R is hydrogen or alkyl; R is selected from alkyl, hydroxy or cycloalkyl; R is selected from alkyl, alkoxy, amino, cyano, halogen, haloalkyl, hydroxy, -C(O)alkyl or optionally substituted heterocyclyl; wherein the optional substituent is selected from one or more alkyl or hydroxy; and n is an integer selected from 1 or 2. 5 2. The compound according to claim 1, wherein X is CH or O. 3. The compound according to claim 1, wherein Cy is 3,5-dimethylisoxazole. 4. The compound according to claim 1, wherein L1 is direct bond. 5. The compound according to claim 1, wherein L is –CH -. 6. The compound according to claim 1, wherein Cy is optionally substituted pyridyl or 10 optionally substituted phenyl. 7. The compound according to claim 6, wherein the optional substituent is halogen, haloalkyl, alkoxy, amino or cyano. 8. The compound according to claim 1, wherein R is alkyl, cyanoalkyl, hydroxyalkyl and optionally substituted haloalkyl; wherein the optional substituent is hydroxy. 15 9. The compound according to claim 1, wherein the compound is of formula (Ia): (Ia); wherein, R , R , R , R , Cy , Cy , L , L and n are same as defined in claim 1; or a pharmaceutically 1 2 3 4 1 2 1 2 acceptable salt or a pharmaceutically acceptable stereoisomer thereof. 20 10. The compound according to claim 1, wherein the compound is of formula (Ib): (Ib); wherein, the dotted line, R , R , R , R , Cy , Cy , L , L and n are same as defined in claim 1; or a 1 2 3 4 1 2 1 2 pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof. 11. The compound according to 1, wherein the compound is of formula (Ic): (Ic); 5 wherein, the R , R , R , R , Cy , Cy , L and L are same as defined in claim 1; or a pharmaceutically 1 2 3 4 1 2 1 2 acceptable salt or a pharmaceutically acceptable stereoisomer thereof. 12. A compound according to claim 1 selected from the group consisting of: Compou IUPAC Name nd No. 4-(4-chlorobenzyl)(3,5-dimethylisoxazolyl)methoxy-3,4-dihydro-2H- benzo[b][1,4]oxazine; 6-(3,5-dimethylisoxazolyl)methoxy((5-methoxypyridin yl)methyl)quinolin-2(1H)-one; 6-(3,5-dimethyl-4H-1,2,4-triazolyl)methoxy(pyridinylmethyl)quinolin- 2(1H)-one; 1-(4-chlorobenzyl)(3,5-dimethylisoxazolyl)methoxyquinoxalin-2(1H)- one; 1-(4-chlorobenzyl)(3,5-dimethylisoxazolyl)methoxy-3,4-dihydroquinolin- 2(1H)-one; 4-(1-(4-chlorophenyl)ethyl)(3,5-dimethylisoxazolyl)methoxy-3,4- dihydro-2H-benzo[b][1,4]oxazine; 7-(3,5-dimethylisoxazolyl)methoxy(1-(pyridinyl)ethyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine; 6-(3,5-dimethylisoxazolyl)methoxy(pyrazinylmethyl)quinolin-2(1H)- one; 6-(3,5-dimethylisoxazolyl)((3-fluoropyridinyl)methyl) methoxyquinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)-3,4- dihydroquinolin-2(1H)-one; 4-((3-chlorophenyl)sulfonyl)(3,5-dimethylisoxazolyl)methoxy-3,4- dihydro-2H-benzo[b][1,4]oxazine; 7-(3,5-dimethylisoxazolyl)methoxy(pyridinylsulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine; N-(4-(4-chlorobenzyl)methoxyoxo-3,4-dihydro-2H-benzo[b][1,4]oxazin yl)-3,5-dimethylisoxazolesulfonamide; 1-((4-chlorophenyl)sulfonyl)(3,5-dimethylisoxazolyl)methoxyquinolin- 2(1H)-one; 15. 1-(4-chlorobenzoyl)(3,5-dimethylisoxazolyl)methoxyquinolin-2(1H)-one; 2-((7-(3,5-dimethylisoxazolyl)methoxy-2H-benzo[b][1,4]oxazin-4(3H)- yl)methyl)aniline; 7-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)-2H- benzo[b][1,4]oxazin-3(4H)-one; 4-(4-chlorobenzyl)(3,5-dimethylisoxazolyl)methoxy-2H- benzo[b][1,4]oxazin-3(4H)-one; 7-(3,5-dimethylisoxazolyl)methoxy(1-(pyridinyl)ethyl)-2H- benzo[b][1,4]oxazin-3(4H)-one (Isomer-1); 7-(3,5-dimethylisoxazolyl)methoxy(1-(pyridinyl)ethyl)-2H- benzo[b][1,4]oxazin-3(4H)-one (Isomer-2); 7-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)-2H- benzo[b][1,4]oxazin-3(4H)-one; 7-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)-2H- benzo[b][1,4]oxazin-3(4H)-one; 7-(3,5-dimethylisoxazolyl)methoxy((tetrahydro-2H-pyranyl)methyl)- 2H-benzo[b][1,4]oxazin-3(4H)-one; 7-(3,5-dimethylisoxazolyl)methoxy(1-(pyridinyl)ethyl)-2H- benzo[b][1,4]oxazin-3(4H)-one (Isomer-1); 7-(3,5-dimethylisoxazolyl)methoxy(1-(pyridinyl)ethyl)-2H- benzo[b][1,4]oxazin-3(4H)-one (Isomer-2); 7-(3,5-dimethylisoxazolyl)methoxy((6-methoxypyridinyl)methyl)-2H- benzo[b][1,4]oxazin-3(4H)-one; 6-((7-(3,5-dimethylisoxazolyl)methoxyoxo-2H-benzo[b][1,4]oxazin- 4(3H)-yl)methyl)nicotinonitrile; 4-((5-chloropyridinyl)methyl)(3,5-dimethylisoxazolyl)methoxy-2H- benzo[b][1,4]oxazin-3(4H)-one; 7-(3,5-dimethylisoxazolyl)((5-fluoropyridinyl)methyl)methoxy-2H- benzo[b][1,4]oxazin-3(4H)-one; 7-(3,5-dimethylisoxazolyl)methoxy((5-methoxypyridinyl)methyl)-2H- benzo[b][1,4]oxazin-3(4H)-one; 7-(3,5-dimethylisoxazolyl)methoxy(1-(pyridinyl)ethyl)-2H- benzo[b][1,4]oxazin-3(4H)-one; 7-(3,5-dimethylisoxazolyl)methoxy((6-methylpyridinyl)methyl)-2H- benzo[b][1,4]oxazin-3(4H)-one; 4-(1-(4-chlorophenyl)ethyl)(3,5-dimethylisoxazolyl)methoxy-2H- benzo[b][1,4]oxazin-3(4H)-one (Isomer-1); 4-(1-(4-chlorophenyl)ethyl)(3,5-dimethylisoxazolyl)methoxy-2H- benzo[b][1,4]oxazin-3(4H)-one (Isomer-2); 7-(3,5-dimethylisoxazolyl)methoxy(2-(pyridinyl)ethyl)-2H- benzo[b][1,4]oxazin-3(4H)-one; 6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)quinolin-2(1H)- one; 1-((5-chloropyridinyl)methyl)(3,5-dimethylisoxazolyl) methoxyquinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)methoxy(2-morpholinoethyl)quinolin-2(1H)- one; 6-(3,5-dimethylisoxazolyl)methoxy(thiazolylmethyl)quinolin-2(1H)- one; 40. 6-(3,5-dimethylisoxazolyl)methoxy(1-(pyridinyl)ethyl)quinolin-2(1H)- one; 6-(3,5-dimethylisoxazolyl)methoxy(1-(pyridinyl)ethyl)quinolin-2(1H)- one; 6-(3,5-dimethylisoxazolyl)methoxy(2-(pyridinyl)ethyl)quinolin-2(1H)- one; 6-(3,5-dimethylisoxazolyl)methoxy(pyrimidinylmethyl)quinolin- 2(1H)-one; 6-(3,5-dimethylisoxazolyl)methoxy(pyrimidinylmethyl)quinolin- 2(1H)-one; 6-(3,5-dimethylisoxazolyl)((5-fluoropyridinyl)methyl) methoxyquinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)quinolin-2(1H)- one; 6-(3,5-dimethylisoxazolyl)methoxy((5-(trifluoromethyl)pyridin yl)methyl)quinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)methoxy-4,4-dimethyl(pyridinylmethyl)- 3,4-dihydroquinolin-2(1H)-one; 7-(3,5-dimethylisoxazolyl)methoxy-2,2-dimethyl(pyridinylmethyl)- 2H-benzo[b][1,4]oxazin-3(4H)-one; 6-(3,5-dimethylisoxazolyl)methoxymethyl(pyridin ylmethyl)quinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)methoxy-3,3-dimethyl(pyridin ylmethyl)quinoline-2,4(1H,3H)-dione; 6-(3,5-dimethylisoxazolyl)methoxy-3,3-dimethyl(pyridinylmethyl)- 3,4-dihydroquinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)methoxymethyl(pyridin ylmethyl)quinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl) (trifluoromethyl)quinolin-2(1H)-one; 4-cyclopropyl(3,5-dimethylisoxazolyl)methoxy(pyridin ylmethyl)quinolin-2(1H)-one; 56. 1-(4-chlorobenzyl)(3,5-dimethylisoxazolyl)methoxyquinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)methoxy(quinolinylmethyl)quinolin-2(1H)- one; 1-((5-chloropyridinyl)methyl)(3,5-dimethylisoxazolyl)methoxy methylquinolin-2(1H)-one; 1-(4-chlorophenethyl)(3,5-dimethylisoxazolyl)methoxy methylquinolin-2(1H)-one; 7-(3,5-dimethylisoxazolyl)methoxy(piperidinylmethyl)-2H- benzo[b][1,4]oxazin-3(4H)-one; 61. 6-(6-hydroxypyridinyl)methoxy(pyridinylmethyl)quinolin-2(1H)-one; 6-(3-cyclopropylmethylisoxazolyl)methoxy(pyridin ylmethyl)quinolin-2(1H)-one; 63. 7-methoxy(5-methylisoxazolyl)(pyridinylmethyl)quinolin-2(1H)-one; 64. 7-methoxy(3-methylisoxazolyl)(pyridinylmethyl)quinolin-2(1H)-one; 4-(4-chlorobenzyl)(3,5-dimethyl-1H-pyrazolyl)methoxy-2H- benzo[b][1,4]oxazin-3(4H)-one; 6-(3,5-dimethyl-1H-pyrazolyl)methoxy(pyridinylmethyl)quinolin- 2(1H)-one; 1-((6-chloropyridinyl)methyl)(3,5-dimethylisoxazolyl) methoxyquinolin-2(1H)-one; 3-cyclohexyl(3,5-dimethylisoxazolyl)methoxy(pyridin ylmethyl)quinolin-2(1H)-one; 3-cyclohexyl(3,5-dimethylisoxazolyl)methoxy(pyridin ylmethyl)quinolin-2(1H)-one; 7-(3,5-dimethylisoxazolyl)((6-hydroxypyridinyl)methyl)methoxy-2H- benzo[b][1,4]oxazin-3(4H)-one; 7-(3,5-dimethylisoxazolyl)(2-methoxyethoxy)(pyridinylmethyl)-2H- benzo[b][1,4]oxazin-3(4H)-one; 6-(3,5-dimethylisoxazolyl)hydroxy(pyridinylmethyl)quinolin-2(1H)- one; 73. 1-((5-chloropyridinyl)methyl)(3,5-dimethylisoxazolyl) hydroxyquinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)(pyridinylmethyl)(2,2,2- trifluoroethoxy)quinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)(2-morpholinoethoxy)(pyridin ylmethyl)quinolin-2(1H)-one; 7-(2-(dimethylamino)ethoxy)(3,5-dimethylisoxazolyl)(pyridin ylmethyl)quinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)(piperidinylmethoxy)(pyridin ylmethyl)quinolin-2(1H)-one; 7-butoxy(3,5-dimethylisoxazolyl)(pyridinylmethyl)quinolin-2(1H)- one; 7-(allyloxy)(3,5-dimethylisoxazolyl)(pyridinylmethyl)quinolin-2(1H)- one; 6-(3,5-dimethylisoxazolyl)(2-hydroxyethoxy)(pyridin ylmethyl)quinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)(pyridinylmethyl)(2-(pyrrolidin yl)ethoxy)quinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)(2-(piperazinyl)ethoxy)(pyridin ylmethyl)quinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)(pyridinylmethyl)(pyridin ylmethoxy)quinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)(3-hydroxypropoxy)(pyridin ylmethyl)quinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)(pyridinylmethyl) (trifluoromethoxy)quinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)(piperidinyloxy)(pyridin ylmethyl)quinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)(pyridinylmethyl)((tetrahydro-2H-pyran yl)methoxy)quinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)(2-(piperidinyl)ethoxy)(pyridin ylmethyl)quinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)(pyridinylmethyl)(2-(pyrrolidin yl)ethoxy)quinolin-2(1H)-one hydrochloride; 7-(3,5-dimethylisoxazolyl)methoxy((1-propionylpiperidinyl)methyl)- 2H-benzo[b][1,4]oxazin-3(4H)-one; 7-methoxy(5-methyloxo-2,3-dihydro-1H-imidazolyl)(pyridin ylmethyl)quinolin-2(1H)-one; 3-(7-methoxyoxo(pyridinylmethyl)-1,2-dihydroquinolinyl)methyl- 1H-pyrrole-2,5-dione; 6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)quinoxalin- 2(1H)-one; N-(4-(4-chlorobenzyl)methoxyoxo-3,4-dihydro-2H-benzo[b][1,4]oxazin yl)-3,5-dimethylisoxazolecarboxamide; 4-(4-chlorobenzyl)((3,5-dimethylisoxazolyl)amino)methoxy-2H- benzo[b][1,4]oxazin-3(4H)-one; 6-(3,5-dimethylisoxazolyl)(hydroxymethyl)methoxy(pyridin ylmethyl)quinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)(fluoromethyl)methoxy(pyridin ylmethyl)quinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)methoxy((5-(1-methyl-1H-pyrazol yl)pyridinyl)methyl)quinolin-2(1H)-one; 1-((5-bromopyridinyl)methyl)(3,5-dimethylisoxazolyl)methoxy quinolin-2(1H)-one; 1-((5-(3,5-dimethyl-1H-pyrazolyl)pyridinyl)methyl)(3,5- dimethylisoxazolyl)methoxyquinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)((5-(3-hydroxypyrrolidinyl)pyridin 100. yl)methyl)methoxyquinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)(2,2,2- 101. trifluorohydroxyethyl)quinolin-2(1H)-one; 6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)(2,2,2- 102. trifluorohydroxyethyl)quinolin-2(1H)-one (Isomer-1); 103. 6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)(2,2,2- trifluorohydroxyethyl)quinolin-2(1H)-one (Isomer-2); 6-(3,5-dimethylisoxazolyl)methoxy(pyridinylmethyl)(2,2,2- 104. trifluoro-1,1-dihydroxyethyl)quinolin-2(1H)-one; 1-(4-chlorophenethyl)(3,5-dimethylisoxazolyl)methoxymethyloxo- 105. 1,2-dihydroquinolinecarbonitrile; and 2-(1-(4-chlorophenethyl)(3,5-dimethylisoxazolyl)methoxyoxo-1,2- 106. dihydroquinolinyl)acetonitrile, or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof. 13. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I) according to any of claims 1 to 12, or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof, in admixture with at least one pharmaceutically acceptable carrier or excipient including mixtures thereof in all ratios. 14. A pharmaceutical combination comprising a therapeutically effective amount of at least one compound of formula (I) according to any of claims 1 to 12, or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof, and at least one therapeutically further active ingredient. 10 15. A compound according to any of the claims 1 to 12, or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof, for use in therapy. 16. Use of a compound according to any of claims 1 to 12, in manufacture of a medicament for use in treatment of diseases associated with bromodomain in animals including humans. 17. The use of claim 16; wherein the bromodomain protein is BRD-2, BRD-3 or BRD-4 protein. 18. The use of claim 16 or 17, wherein the disease is autoimmune, inflammatory or cancer. 19. A compound according to any one of claims 1 to 12 and 15, substantially as herein described with reference to any example thereof. 20. The pharmaceutical composition according to claim 13, substantially as herein described 20 with reference to any example thereof. 21. The pharmaceutical combination according to claim 14, substantially as herein described with reference to any example thereof. 22. Use according to any one of claims 16 to 18, substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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IN125CH2014 | 2014-01-09 | ||
IN125/CHE/2014 | 2014-01-09 | ||
PCT/IB2015/050090 WO2015104653A1 (en) | 2014-01-09 | 2015-01-06 | Bicyclic heterocyclic derivatives as bromodomain inhibitors |
Publications (2)
Publication Number | Publication Date |
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NZ721993A NZ721993A (en) | 2021-05-28 |
NZ721993B2 true NZ721993B2 (en) | 2021-08-31 |
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