BICYCLIC HETEROCYCLE DERIVATIVES AS BROMODOMAIN
INHIBITORS
Technical field
The present invention relates to novel bicyclic heterocycle derivatives of
formula (I) which are useful as bromodomain inhibitors and to pharmaceutical
compositions thereof.

The invention relates also to the use of compounds of formula (I) for the
treatment or prevention of diseases or disorders, in particular those where
bromodomain inhibition is desired.
Background of the invention
The acetylation of histone lysine is central for 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 1 17(3):349-60).
Japanese patent application JP 2008-156311 discloses a benzimidazole
derivative which is said to be a BRD2 bromodomain binding agent which has utility
with respect to virus infection / proliferation.
International patent application WO 2009/084693 discloses a series of
thienotriazolodiazepiene derivatives that are said to inhibit the binding between an
acetylated histone and a bromodomain containing protein and are said to be useful as
anti-cancer agents
International patent application WO 2011/054846 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. Certain bicyclic heterocycle derivatives have
been found according to the present invention which inhibit the binding of BET
family bromodomains to acetylated lysine residues. Such compounds will hereafter
be referred to as bromodomain inhibitors.

Summary of the invention
The present invention provides new bicyclic heterocycle derivatives which are
able to inhibit the binding of BET family bromodomains to acetylated lysine
residues. The present invention provides a compound of formula (I)

wherein
Cy1 is an optionally substituted 5-6 membered monocyclic heterocyclyl ring
containing 1-3 hetero atoms independently selected from N or O, which ring is
optionally substituted by 1-3 C1-7 alkyl groups;
Cy2 is an optionally substituted aryl, optionally substituted C3-10 cycloalkyl or
optionally substituted 5-12 membered monocyclic or bicyclic heterocyclyl ring
containing 1-3 hetero atoms independently selected fromN, O or S; wherein the
optional substitution at each occurrence is, independently, selected from 1-3
substituents selected from C1-7 alkyl, C1-7 alkoxy, halogen and -C(O)C1-7 alkyl;
L1 is-(CR3R3a)n;
Ri is C1-7 alkyl or halo C1.7 alkyl;
R2 is an optionally substituted aryl, optionally substituted aryl C1-7 alkyl,
optionally substituted heterocyclyl, optionally substituted heterocyclyl C1-7 alkyl,
-N(Ra)Rb, -(CH2)mC(O)Ral, -(CH2)m1C(O)ORa2, -(CH2)m2C(O)N(Ra3)Rb1,
-CH(CF3)R4, -S(O)2N(Ra4)Rb2, -(CRa5Rb3)m3C(O)ORa6) -CH(CF3)ORc and
-CH(CF3)N(Ra7)Rb4, wherein the optional substitution at each occurrence is,
independently, selected from 1-3 substituents selected from C1-7 alkyl, halo C1-7 alkyl,
-NHC(O)C1-7 alkyl, amino, halogen, hydroxy, oxo, hydroxy C1-7 alkyl, aryl,
-N(H)C(O)C1-7 alkyl, -(CH2)m4C(O)OH or -(CH2)m5C(O)NH(hydroxy C1-7 alkyl);

Ra, Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, Ra7, Rb, Rb1, Rb2, Rb3 and Rb4 are independently
selected from hydrogen, C1-.7 alkyl, hydroxy, C1-7 alkoxy, hydroxy C1-7 alkyl, halo C1-7
alkyl, -S(O)2C1-7 alkyl, optionally substituted aryl, optionally substituted C3.10 cyclo-
alkyl, optionally substituted heterocyclyl or optionally substituted heterocyclyl C1-7
alkyl; wherein the optional substitution at each occurrence is independently selected
from 1-3 substituents selected from C1-7 alkyl, halogen, hydroxy, hydroxy C1-7 alkyl,
C1-7 alkoxy, cyano, halo C1-7 alkyl and amino;
Re is selected from C1-7 alkyl or aryl, wherein aryl is optionally substituted by
1-3 halogen atoms;
Rd is selected from optionally substituted heterocyclyl or optionally
substituted aryl, wherein the optional substitution at each occurrence is independently
selected from 1-3 substituents selected from C1-7 alkyl and halogen;
R3 and R3a independently are selected from hydrogen, C1-7 alkyl, hydroxy and
halogen, or alternatively R3 and R3a together with the carbon atom to which they are
attached form a carbonyl (C=O) group;
m, m1i, m2, m3; 1114 and ms are, independently, an integer selected from 0, 1 or
2; and
n is an integer selected from 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
In a further aspect, the present invention provides a pharmaceutical
composition, comprising a compound of formula (I) or a pharmaceutically acceptable
salt thereof.
In yet further aspect of the present invention, it provides a compound of
formula (I) or a pharmaceutically acceptable thereof for use in the treatment or
prevention of diseases or disorders where bromodomain inhibition is desired, in
particular for the treatment or prevention of an autoimmune disease, inflammatory
disease or cancer.
Detailed description of the invention

An embodiment of the present application provides compounds of formula (I)
or pharmaceutically acceptable salts thereof which are useful as bromodomain
inhibitors. -
One of the embodiments of the present invention provides a compound of
formula (I)

wherein,
Cyi is an optionally substituted 5-6 membered monocyclic heterocyclyl ring
containing 1-3 hetero atoms independently selected from N or O, which ring is
optionally substituted by 1-3 C1-7 alkyl groups;
Cy2 is an optionally substituted aryl, optionally substituted C3.10 cycloalkyl or
optionally substituted 5-12 membered monocyclic or bicyclic heterocyclyl ring
containing 1-3 hetero atoms independently selected from N, O or S; wherein the
optional substitution at each occurrence is, independently, selected from 1-3
substituents selected from C1-7 alkyl, C1-7 alkoxy, halogen and -C(O)C1-7 alkyl;
L1 is-(CR3R3a)n-;
R1 is C1-7 alkyl or halo C1-7 alkyl;
R2 is an optionally substituted aryl, optionally substituted aryl C1-7 alkyl,
optionally substituted heterocyclyl, optionally substituted heterocyclyl C4.7 alkyl,
-N(Ra)Rb, -(CH2)mC(O)Ra1, -(CH2)m1C(O)ORa2, -(CH2)m2C(O)N(Ra3)Rb1,
-CH(CF3)Rd, -S(O)2N(Ra4)Rb2, -(CRa5Rb3)m3C(O)ORa6, -CH(CF3)ORc and
-CH(CF3)N(Ra7)Rb4, wherein the optional substitution at each occurrence is,
independently, selected from 1-3 substituents selected from C1-7 alkyl, halo C1-7 alkyl,
-NHC(O)C1-7 alkyl, amino, halogen, hydroxy, oxo, hydroxy C1-7 alkyl, aryl,
-N(II)C(O)Ci.7 alkyl, -(CH2)m4C(O)OH or -(CH2)m5C(O)NH(hydroxy C1-7 alkyl);

Ra, Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, Ra7, Rb, Rb1, Rb2, Rb3 and Rb4 are independently
selected from hydrogen, C1-7 alkyl, hydroxy, C1-7 alkoxy, hydroxy C1-7 alkyl, halo C1-7
alkyl, -S(O)2C1-7 alkyl, optionally substituted aryl, optionally substituted C3.10 cyclo-
alkyl, optionally substituted heterocyclyl or optionally substituted heterocyclyl C1-7
alkyl; wherein the optional substitution at each occurrence is independently selected
from 1-3 substituents selected from C1-7 alkyl, halogen, hydroxy, hydroxy C1-7 alkyl,
C1-7 alkoxy, cyano, halo C1-7 alkyl and amino;
Re is selected from C1-7 alkyl or aryl wherein aryl is optionally substituted by
1-3 halogen atoms;
Rd is selected from optionally substituted heterocyclyl or optionally
substituted aryl, wherein the optional substitution at each occurrence is independently
selected from 1-3 substituents selected from C1-7 alkyl and halogen;
R3 and R3a independently are selected from hydrogen, C1-7 alkyl, hydroxy and
halogen, or alternatively R3 and R3a together with the carbon atom to which they are
attached form a carbonyl (C=O) group;
m, m1, m2, m3; 1114 and ms are, independently, an integer selected from 0,1 or
2; and
n is an integer selected from 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
It is to be understood that in case n is 2 or 3, each R3 and R3a substituent in
the Li chain can be selected independently of each other.
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
formula (I), in which Cyi is 3,5-dimethylisoxazole.
According to another embodiment, specifically provided are compounds of
formula (I), or according to any other embodiment or subclass referred to above,
wherein R1 is C1-7 alkyl. As a subclass of this embodiment are compounds wherein Ris methyl.

According to another embodiment, specifically provided are compounds of
formula (I), or according to any other embodiment or subclass referred to above, in
which Cy2 is a 5-12 membered monocyclic or bicyclic ring containing 0-2 hetero
atoms independently selected from N and O, which ring is optionally substituted by
1-3 substituents selected from C1-7 alkyl, C1-7 alkoxy, halogen and -C(6)C1-7 alkyl.
In a subclass of the above embodiment are compounds of formula (I), wherein
Cy2 is selected from optionally substituted pyridyl, optionally substituted phenyl,
cyclohexyl, morpholinyl, optionally substituted piperazinyl or optionally substituted
chromanyl; wherein the optional substitution at each occurrence is independently
selected from 1-3 substituents selected from C1-7 alkyl, C1-7 alkoxy, halogen and
-C(O)C1-7 alkyl.
According to another embodiment, specifically provided are compounds of
formula (I), or according to any other embodiment or subclass referred to above,
wherein Cy2 is optionally substituted by 1-2 substituents selected from C1-7 alkoxy
and halogen.
According to another embodiment, specifically provided are compounds of
formula (I), or according to any other embodiment or subclass referred to above,
wherein Cy2 is selected from optionally substituted pyridyl or optionally substituted
phenyl, wherein the optional substitution at each occurrence is independently selected
from 1-2 substituents selected from C4.7 alkoxy and halogen.
According to another embodiment, specifically provided are compounds of
formula (I), or according to any other embodiment or subclass referred to above,
wherein L1 is -CH2-, -(CH2)2-, -CH2CH(OH)-, -CH2CH(CH3)- or -CH2C(O)-,wherein
the left bond is attached to the quinolin-2(lH)-one ring of formula (I).
According to another embodiment, specifically provided are compounds of
formula (I), or according to any other embodiment or subclass referred to above,
wherein R2 is an optionally substituted 5312 membered monocyclic or bicyclic ring

containing 0-4 hetero atoms independently selected from N and O, which ring is
optionally substituted by 1-3 substituents selected from C1-7 alkyl, halogen, amino,
hydroxy, -NHC(O)C1-7 alkyl, halo C1-7 alkyl, phenyl, oxo, hydroxy C1-7 alkyl,
-(CH2)m5C(O)NH(hydroxy C1-7 alkyl) or -(CH2)m4C(O)OH.
In a subclass of the above embodiment are compounds of formula (I), wherein
R2 is phenyl, isoxazolyl, pyridinyl, pyrazolyl, imidazolyl, morpholinyl, 3,4-dihydro-
isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 2-oxoimidazolidinyl, piperidinyl,
pyrrolidinyl, indolinyl, l,2,4-oxadiazol-5-yl or lH-benzo[d]imidazole or azetidinyl;
and the optional substituents are selected froml-3 substituents selected from C4.7
alkyl, halogen, amino, hydroxy, NHC(O)C1-7 alkyl, halo C1-7 alkyl, phenyl, oxo,
hydroxy C1-7 alkyl,-(CH2)m5C(O)NH(hydroxy C1-7 alkyl) or -(CH2)m4C(O)0H.
According to yet another embodiment, specifically provided are compounds
of formula (I), or according to any other embodiment or subclass referred to above, in
which R.2 is -(CH2)mC(O)Ra1, in particular wherein Rai is a 5-12 membered
monocyclic or bicyclic ring containing 0-4 hetero atoms independently selected from
N and O, which ring is optionally substituted by one hydroxy group, and m is 0 or 1.
In a subclass of this embodiment are compounds wherein Rai is phenyl, piperidinyl,
pyrrolidinyl, azetidinyl or indolinyl which rings are optionally substituted by one
hydroxy group, and m is 0 or 1.
According to yet another embodiment, specifically provided are compounds
of formula (I), or according to any other embodiment or subclass referred to above,
wherein R2 is -(CH2)m2C(O)N(Ra3)Rbi; in particular wherein Ra3 is hydrogen or C1-7
alkyl, and Rbi is hydrogen, C1-7 alkyl, hydroxy C1-7 alkyl, halo C1-7 alkyl, optionally
substituted C3.10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted
phenyl and optionally substituted heterocyclyl C1-7 alkyl, wherein heterocyclyl at each
occurrence means a 5-12 membered monocyclic or bicyclic ring containing 1 -4 .
heteroatoms independently selected from N, O and S, and wherein the optional
substitution at each occurrence is, independently, selected from 1-3 substituents
selected from C1-7 alkyl, hydroxy, halogen, halo C1-7 alkyl, amino, cyano or C1-7
alkoxy and m2 is 0 or 1

In a subclass of the above embodiment are compounds of formula (I), wherein
Rbi is cyclohexyl, pyridinyl, piperidinyl, 1,3,4-thiadiazolyl, pyrazolyl, phenyl or
imidazolyl C1-7 alkyl, which groups are optionally substituted by 1-3 substituents
independently selected from C1-7 alkyl, hydroxy, halogen, halo C1-7 alkyl, amino,
cyano or C1-7 alkoxy.
According to yet another embodiment, specifically provided are compounds
of formula (I), or according to any other embodiment or subclass referred to above,
wherein Ra3 is hydrogen.
According to yet another embodiment, specifically provided are compounds
of formula (I), or according to any other embodiment or subclass referred to above,
wherein R2 is -N(Ra)R|,; in particular wherein Ra is hydrogen and Rb is hydrogen,
hydroxy C1-7 alkyl, -SCh-methyl or optionally substituted 5-12 membered monocyclic
or bicyclic ring containing 1-4 hetero atoms independently selected from N, O and S,
and wherein the optional substitution is selected from 1-3 substituents selected from
C1-7 alkyl, hydroxy, halogen, halo C1-7 alkyl or C1-7 alkoxy.
According to yet another embodiment, specifically provided are compounds
of formula (I), or according to any other embodiment or subclass referred to above,
wherein R2 is -CH(CF3)Rd, -CH(CF3)ORc or -CH(CF3)N(Ra7)Rb4; in particular those
wherein Rd is morpholinyl, Re of is 4-fluorophenyl or C1-7 alkyl, Ra7 is hydrogen and
Rb4 is hydroxy C1-7 alkyl or 4-fluorophenyl.
According to yet another embodiment, specifically provided are compounds
of formula (I), or according to any other embodiment or subclass referred to above,
wherein n is 1 or 2.
According to yet another embodiment of the present invention, the compound
of formula (I) is a compound of formula (IA):


wherein R2, L1 and Cy2 are same as defined in formula (I), or a pharmaceutically
acceptable salt thereof.
According to yet another embodiment of the present invention, the compound
of formula (I) is a compound of formula (IB):

wherein, R2 and L1 are same as defined in formula (I), or a pharmaceutically
acceptable salt thereof. In a subgroup of this embodiment are compounds wherein L1
is -CH2-.
According to yet another embodiment of the present invention, the compound
of formula (I) is a compound of formula (IC):

wherein R2 and L1 are same as defined in formula (I), and R4 is hydrogen, C1-7
alkoxy, or halogen, or a pharmaceutically acceptable salt thereof.

In yet another particular embodiment of the present invention, the compound
of formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt or tautomer thereof.
In yet another embodiment according to the present patent application, it
provides a pharmaceutical composition comprising a compound of formula (I), (IA),
(IB) or (IC) 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.
It should be understood that the compounds of the invention including those
according to formulas (I), (IA), (IB) or (IC) encompass all stereoisomers,
enantiomers, diastereomers or geometrical isomers that may be contemplated from
the chemical structure of the compounds.
The present compounds may also exist as tautomers or equilibrium mixtures
thereof wherein a proton of a compound shifts from one atom to another. Examples
of tautomers include, but are not limited to, amido-imido, keto-enol, phenol-keto,
oxime-nitroso, nitro-aci, imine-enamine and the like. All tautomeric forms of the
compounds are intended to be encompassed by their structural formula even though
only one tautomeric form may be depicted.
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.
The term "C1-7 alkyl", as employed herein as such or as part of another group,
refers to a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5,
6 or 7 carbon atom(s). Representative examples of C1-7 alkyl include, but are not
limited to, methyl, ethyl, ^-propyl, wo-propyl, «-butyl, wo-butyl, sec-butyl, tert-butyl,

H-pentyl, z'so-pentyl and «-hexyl. The term "C1-3 alkyl" refers to a preferred
embodiment of "C1-7 alkyl" having 1, 2 or 3 carbon atoms.
The term "C2-7 alkenyl", as employed herein as such or as part of another
group, refers to an aliphatic hydrocarbon group having 2 to 7 carbon atoms and
containing at least one carbon to carbon double bond. Representative examples
include, but are not limited to, ethenyl, prop-1-enyl, but-1-enyl, but-2-enyl, pent-1-
enyl, pent-2-enyl, hex-1-enyl and hex-2-enyl.
The term "C3-10 cycloalkyl", as employed herein as such or as part of another
group, refers to a saturated or partially saturated, monocyclic, bicyclic or polycyclic
hydrocarbon ring system having 3 to 10 carbon atoms. Representative examples of
C3-10 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl
and cyclohexyl, decahydronaphthalen-1-yl and octahydro-lH-inden-2-yl. The term
"C3.7 cycloalkyl", as employed herein as such or as part of another group, refers to a
saturated or partially saturated monocyclic hydrocarbon ring containing 3, 4, 5, 6 or 7
carbon atoms.
The term "C1-7 alkoxy", as employed herein as such or as part of another
group, refers to C1-7 alkyl, as defined herein, appended to the parent molecular moiety
through an oxygen atom. Representative examples of C 1.7 alkoxy include, but are not
limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy and ter?-butoxy.
The term "halo" or "halogen", as employed herein as such or as part of
another group, refers to chlorine, bromine, fluorine or iodine.
The term "amino", as employed herein as such or as part of another group,
refers to an -NH2 group. The term "hydroxy", as employed herein as such or as part
of another group, refers to an -OH group. The term "cyano", as employed herein as
such or as part of another group, refers to a -CN group. The term "carboxy", as
employed herein as such or as part of another group, refers to -COOH group. The
term "carbonyl", as employed herein as such or as part of another group; refers to a

herein as such or as part of another group, refers to oxygen atom linked to another
atom by a double bond (=0).
The term "hydroxy C1-7 alkyl", as employed herein, refers to at least one
hydroxy group, as defined herein, appended to the parent molecular moiety through a
C1-7 alkyl group, as defined herein. Representative examples include, but are not
limited to, hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-
hydroxypropyl, 1-methyl-1-hydroxyethyl and 1-methyl-1-hydroxypropyl.
The term "halo C1-7 alkyl", as employed herein, refers to at least one halogen,
as defined herein, appended to the parent molecular moiety through a C1-7 alkyl
group, as defined herein. Representative examples include, but are not limited to,
fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl and 3-bromopropyl.
The term "aryl", as employed herein, refers to a monocyclic, bicyclic or
polycyclic aromatic hydrocarbon ring system of 6 to 14 carbon atoms. Examples of
aryl groups include, but are not limited to phenyl* naphthyl, biphenyl, anthryl,
tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl and acenaphthyl. Preferred aryl
group is phenyl.
The term "aryl C4.7 alkyl", as employed herein, refers to at least one aryl group
appended to the parent molecular moiety through a C1-7 alkyl group, as defined
herein. Examples of aryl C1-7 alkyl groups include, but are not limited to benzyl,
benzhydryl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-
naphthylmethyl and 2-naphthylmethyl. Preferred aryl C1-7 alkyl group is phenyl C1-7
alkyl.
The term "heterocyclyl" includes the definitions of "heterocycloalkyl" and
"heteroaryl".
The term "heterocycloalkyl" refers to a non-aromatic, saturated or partially
saturated, monocyclic or polycyclic ring system with 3 to 10 ring atoms of which at

and S. One particular embodiment of "heterocycloalkyl" is a non-aromatic, saturated
or partially saturated, monocyclic or polycyclic ring system with 5 to 10 ring atoms
of which 1-4 are heteroatoms selected from the group consisting of N, O and S.
Examples of heterocycloalkyl groups include piperidinyl, piperazinyl, pyrrolidinyl,
morpholinyl, thiomorpholinyl, 1,3-dioxolanyl, tetrahydro-2H-pyran and 1,4-dioxanyl.
The term "heteroaryl" refers to a monocyclic, bicyclic, or polycyclic aromatic
ring system of 5-14 ring atoms containing at least one, preferably 1 to 4, heteroatom
selected from the group consisting of N, O and S. One particular embodiment of
"heteroaryl" is a monocyclic, bicyclic, or polycyclic aromatic ring with 5-10 ring
atoms of which 1-4 are heteroatoms selected from the group consisting of N, O and
S. Examples of 5-10 membered heteroaryl groups include furan, thiophene, indole,
azaindole, oxazole, thiazole, thiadiazole, isoxazole, isothiazole, imidazole, 1H-
indazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, 1,3,4-oxadiazole, 1,2,4-
triazole, lH-tetrazole, 1,2,3,4-tetrahydroisoquinoline, benzoxazole, benzothiazole,
benzofuran, benzisoxazole, benzimidazole, 3,4-dihydroisoquinolin-l(2H)-one,
azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Examples of
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 nitrogen atoms in the ring, one nitrogen atom together with either one
oxygen or one sulphur atom in the ring, or one O or S ring atom.
The term "heterocyclyl C1-7 alkyl" refers to at least one heterocyclyl group, as
defined above, appended to the parent molecular moiety through a C1-7 alkyl group,
as defined herein. Representative examples include, but are not limited to pyrroli-
dinyl-1-ethyl, pyrrolidinyl-1 propyl or piperidinyl-1 propyl.
The term "4-12 membered monocyclic or bicyclic ring containing 0-3
heteroatoms" refers to a monocyclic or bicyclic aromatic or non-aromatic cyclic ring
having 4-12 ring member atoms of which 0-3 have been independently replaced with
N or O. Representative examples of such rings include, but are not limited to phenyl,
pyridine, pyrimidine, morpholine, piperidine, piperazine, imidazole, pyrazole,

tetrahydroisoquinoline, quinoline, indazole, [l,2,4]triazolo[4,3-a]pyridine and
tetrahydroisoquinoline. A particular embodiment of "4-12 membered monocyclic or
bicyclic ring containing 0-3 heteroatoms" is a monocyclic or bicyclic aromatic or
non-aromatic cyclic ring with 5-10 ring atoms of which 0-3 are heteroatoms selected
from a group consisting of N or 0.
The term "5-10 membered heterocyclic ring having 1-4 heteroatoms selected
from O or N" refers to aromatic, saturated or partially saturated monocyclic, bicyclic
or polycyclic ring which have 5 to 10 ring member atoms of which 1 to 4 are
heteroatoms selected from a group consisting of O or N.
The term "optionally substituted", if not otherwise specified, means that one,
two or three hydrogen atoms of the optionally substituted group has been substituted
with suitable groups as exemplified but not limited to C1-7 alkyl, C2-7 alkenyl, C1-7
alkoxy, C2-7 alkynyl, aryl, amido, amino, carboxy, cyano, C3.10 cycloalkyl, halogen,
hydroxy, nitro, halo C1-7 alkyl, halo C1-7 alkoxy, heterocyclyl, oxo(=0), thio(=S),
-C(O)C1-7 alkyl, -C(O)(aryl), -C(O)C3-io cycloalkyl, -C(O)(heterocyclyl), or two
substituents on the same carbon atom is combined together to form an optionally
substituted 3-8 member ring containing 0-3 heteroatoms independently selected form
N, O and S. One particular embodiment of "optionally substituted" is 1-3 substituents
selected from the group consisting of C1-7 alkyl, C3-7 cycloalkyl, halogen, nitro,
cyano, amino, hydroxy, halo C1-7 alkyl, hydroxy C1-7 alkyl, C1-7 alkoxy and halo C1-7
alkoxy substituents.
The term "stereoisomers" refers to any enantiomers, diastereoisomers, or
geometrical isomers of the compounds of the invention including those according to
formula (I), (IA), (IB) or (IC), wherever they are chiral or when they bear one or more
double bonds. When the compounds of the invention are chiral, they can exist in
racemic or in optically active form Individual stereoisomers of compounds can be
prepared synthetically from commercially available starting materials which contain
chiral centers or by preparation of mixtures of enantiomeric products followed by
separation such as conversion to a mixture of diastereomers followed by separation

chiral chromatographic columns, or any other appropriate method known in the art.
Starting compounds of particular stereochemistry are either commercially available
or can be made and resolved by techniques known in the art. Additionally, the
compounds of the present invention may exist as geometric isomers. The present
invention includes all cis, trans, syn, anti, E and Z isomers as well as the appropriate
mixtures thereof. Additionally, compounds may exist as tautomers, including keto-
enol tautomers; all tautomeric isomers are provided by this invention.
The term "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, sulphuric 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-chloro-
benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphor
sulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic
acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl
sulphuric acid, gluconic acid, glutamic acid, hydroxyl naphthoic acid, salicylic acid,
stearic acid, muconic acid, and the like.
In one embodiment, the compounds 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.
In another particular embodiment, the compounds of the present invention are

aberrant, abnormal or deregulated activity of BET family of bromodomain containing
proteins; in particular BRD2, BRD3, BRD4 and BRD-t proteins, contribute to the
pathology and/or symptomology of such diseases and/or disorders.
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, chrome
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 glomeru-
lonephritis, 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,

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.
In yet another embodiment, compounds of the present invention inhibit one or
more of BRD2, BRD3, BRD4, BRDT, and/or another member of the bromodomain-
containing proteins, or a mutant thereof.
In yet another embodiment, compounds of the present invention inhibit two or
more of BRD2, BRD3, BRD4, BRDT, and/or another member of the bromodomain-
containing proteins, or a mutant thereof.
In yet another embodiment, compounds of the present invention are inhibitors
of one of more of the bromodomain-containing proteins, such as BRD2, BRD3,
BRD4, and/or BRDT and are therefore useful for treating one or more disorders
associated with activity of one or more of the bromodomain-containing proteins, such
as BRD2, BRD3, BRD4, and/or BRDT. Thus, in yet another embodiment, the present
invention provides a method for treating an bromodomain-containing protein-

BRD4-mediated disorder, and/or a BRDT-mediated disorder comprising the step of
inhibiting a bromodomain-containing protein, such as a BET protein, such as BRD2,
BRD3, BRD4, and/or BRDT, or a mutant thereof, by administering to a patient in
need thereof a provided compound, or a pharmaceutically acceptable composition
thereof.
The term "diseases or disorders where bromodomain inhibition is desired", 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 such, it is
common to present the active ingredient as a pharmaceutical composition.
The compounds and pharmaceutically 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, simultaneously
or sequentially with a compound of the present invention. When a compound of the
present invention is used simultaneously with one or more other drugs, a pharma-
ceutical 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, suchas 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 novel 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 details of the processes
according to the present invention are provided in the example section 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

fluorine, chlorine and iodine, such as 2H ("D"), 3H, nC, 13C, 14C, 13N, 15N, 150,170,
180,32P, 33P, 35S, 18F, 36C1,123I and 125I. 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-l,2-dimethoxyethane; DCM-
Dichloromethane; DMF-N,N-Dimethylformamide; DMSO-Dimethylsulfoxide;
CDCl3-Deuterated chloroform; EtOAc-Ethyl acetate; ACN-Acetonitrile; THF-
Tetrahydrofuran; TEA-Triethylamine; DIPEA-diisopropylethylamine; AcOH-acetic
acid; TBS-Cl-tert-Butyldimethylsilyl chloride; TBAF-Tetrabutylammonium fluoride;
TMS-Trimethylsilyl; KCN-Potassium cyanide; NBS-N-bromo succinimide; NCS-N-
chlorosuccinamide; NaOMe-sodium ethoxide; FkSC^-Sulfuric acid; NaHC03-
Sodium bicarbonate; Na2C03-Sodium carbonate; Cs2C03-cesium carbonate; NaBHU-
sodium borohydride; (BOC)20-Di-tert-butyldicarbonate; EDC.HCl-l-Ethyl-3-(3-
dimethylamino propyl)carbodiimide.HCl; HOBt-1-hydroxybenzotriazole; HATU-1-
[Bis(dimemylammo)memylene]-lH-l,2,3-triazolo[4,5-b]pyridinium-3-oxidhexa-
fluorophosphate; PyBOP-(Benzotriazol-1 -yloxy)tripyrrolidinophosphoniumhexa-
fluorophosphate; POCl3-Phosphorous oxychloride; AcCl-Acetyl chloride; NaOH-
Sodium hydroxide; HC1- Hydrochloric acid; Pd (pph3)4 -Tetrakis(triphenyl-
phosphine)palladium (O); Fe-Iron powder; Pd/C-Palladium on activated carbon;
H2O-Water; Fe-Iron powder; h-Hour; N-Normality; M-Molarity; s-Singlet; d-
Doublet; t-Triplet; m-Multiplet; TLC-Thin layer chromatography; 1HNMR-Proton
nuclear magnetic resonance; HPLC-High-performance liquid chromatography; MS—
Mass spectroscopy; LC-Liquid chromatography; H-Proton; MHz-Megahertz; Hz-
Hertz; Ppm-Parts per million; Bs-Broad singlet; ES-Electro spray; g-Gram; mmol-
Milli mol; mL-millilitre; RT - Room temperature; 5 - Chemical shift expressed in
ppm.

Although the invention has been illustrated by following examples, it is not to
be construed as being limited thereby. 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: ^-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 synthesis of the compounds according to the present invention.
Examples
Intermediate-1: 6-(3, 5-dimethylisoxazol-4-yl)-7-methoxy-2-oxo-l-(pyridin-2-yl-
methyi)-l, 2-dihydroquinoline-3-carboxylic acid

Step-a: N-(4-bromo-3-methoxvphenyl')acetamide (la)
To an ice-cooled solution of 4-bromo-3-methoxyaniline (2.0 g, 9.90 mmol) in
DCM (25 mL) was added triethylamine (4.1 mL, 29.7 mmol) and, after being stirred
for 5 min, acetylchloride (1.05 mL, 14.85 mmol). The reaction mixture was quenched
by addition of aqueous NaHC03 solution (pH~8) followed by extraction with DCM
(200 mL x 2). The combined organic layers were washed with water (200 mL) and
brine (200 mL), dried over sodium sulphate and concentrated under reduced pressure.
The residue was directly used for next step without 61111161' purification (2.5 g). lH

NMR (400 MHz, DMSO-d6) 8 10.06 (s, 1H), 7.45 - 7.43 (m, 2H), 7.10 (dd, Ji=2.0
Hz, J2=8.3 Hz, 1H), 3.79 (s, 3H), 2.04 (s, 3H); LC-MS: m/z 244.1 (M+H)+.
Step-b: 6-bromo-2-chloro-7-methoxvquinoline-3-carbaldehvde (lb)
P0C13 (7.6 mL, 81.96 mmol) was added dropwise to DMF (2.5 mL, 32.78
mmol) at 0 °C followed by stirring for 5 min. Intermediate-la (2.0 g, 8.19 mmol) was
added and resulting solution was heated to 80 °C for 6 h. The mixture was cooled to
RT, quenched with ice water and extracted with EtOAc (200 mL x 2). The combined
organic layers were washed with water (200 mL) and brine (200 mL), dried over
sodium sulphate and concentrated under reduced pressure. The residue was directly
used for next step without further purification (2.0 g). !H NMR (400 MHz, DMSO-
d6) 5 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+H)+.
Step-c: 6-bromo-7-methoxv-2-oxo-1,2-dihydroquinoline-3 -carbaldehyde (1 c)
A suspension of intermediate-lb (2.0 g, 6.65 mmol) in 70 % acetic acid (40
mL) was heated to reflux for 6 h. Upon cooling the mixture to RT a solid product
was precipitated out which was filtered and washed with water and dried under
reduced pressure to afford the title compound as brown solid (1.5 g, 80 %). *H NMR
(400 MHz, DMSO-de) 8 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+2H)2+.
Step-d: 6-bromo-7-methoxy-2-oxo-1 -(pyridin-2-vlmethvl)-1,2-dihvdro-
quinoline-3-carbaldehvde (Id)
To a solution of intermediate-lc (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). The mixture was stirred at 80 °C for 16 h.
The mixture was then diluted with water and extracted with EtOAc (400 mL x 2).
The combined organic layers were washed with water (400 mL) and brine (300 mL),
dried over sodium sulphate and concentrated under reduced pressure. The residue
was directly used for next step without further purification (7.5 g, 63 %). *H NMR
(400 MHz, DMSO-de) 8 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, .7=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+H)+.
Step-e: 6-C3.5-dimethylisoxazol-4-yl)-7-methoxv-2-oxo-l-(pvridin-2-yl-

To a solution of intermediate-Id (4.0 g, 10.72 mmol) in 1,4-dioxane (40 mL)
and H2O (10 mL) were added 3,5-dimethylisoxazoleboronic acid (2.30 g, 16.08
mmol), sodium carbonate (3.41 g, 32.16 mmol) followed by degassing with nitrogen
purging for 20 min. Then tetrakistriphenylphosphine palladium (2.47 g, 2.14 mmol)
was added and the mixture was heated at 100 °C for 8 h. The mixture was then
concentrated under reduced pressure and the residue was diluted with EtOAc (200
ml), washed with water (200 mL) and brine (200 mL), dried over sodium sulphate
and concentrated under reduced pressure. The residue was washed with hexane to
give the title compound as yellow solid (3.2 g, 76 %). *H NMR (400 MHz, DMSO-
d6) 8 10.28 (s, 1H), 8.54 (s, 1H), 8.52 (d, .7=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+H)+.
Step-f: Synthesis oft)-(3. 5-dimethylisoxazol-4-yl)-7-methoxy-2-oxo-l-
rpyridin-2-ylmethyl)-L 2-dihydroquinoline-3-carboxylic acid (intermediate-1)
To a solution of intermediate- le (1.2 g, 3.08 mmol) in mixture of acetonitrile
(12 mL) and H2O (6 mL) were added sodiumdihydrogenphosphate (1.6 g), hydrogen-
peroxide 30 % (1 mL) and sodiumchlorite (0.85 g). The mixture was stirred at RT for
4 h. The mixture was then quenched with ice water, solids were separated, filtered,
washed thoroughly with water and dried under reduced pressure to give the title
compound as yellow solid (0.85 g, 75 %). !H NMR (400 MHz, DMSO-d6) 5 14.36 (s,
1H), 8.99 (s, 1H), 8.50 (d, 7=4.4 Hz, 1H), 8.05 (s, 1H), 7.84-7.80 (m, 1H), 7.51 (d,
J=7.8 Hz, 1H), 7.34-7.31 (m, 1H), 7,28 (s, 1H), 5.84 (s, 2H), 3,84 (s, 3H)r2.28 (s,
3H), 2.09 (s, 3H); LC-MS: m/z 406.2 (M+H)+.
Intermediate-2: 3-Bromo-6-(3,5-dimethvlisoxazol-4-vl)-7-methoxv-l-rpvridin-2-
ylmethyl)quinolin-2(lH)-one


Step-a: 4-(3.5-dimemylisoxazol-4-ylV3-methoxyaniline (2a-)
To a solution of 4-bromo-3-methoxyaniline (1 g, 4.95 mmol) in DME (15 ml)
and water (5 ml) were added Na2CC>3 (1.6 g, 14.85 mmol) and 3,5-dimethyl-
isoxazole-4-boronic acid (1.4 g, 9.90 mmol). The mixture was degassed with
nitrogen for 15 min. Then Pd[PPh3]4 (0.29 g, 0.24 mmol) was added followed by
o
degassing with nitrogen for 5 min and heating to 90 C for 16 h. The mixture was
diluted with EtOAc (150 ml), washed with water (150 mL) and brine (150 mL), dried
over sodium sulphate and concentrated under reduced pressure. The residue was
purified on silica gel (60-120 mesh) to afford the title product as pale yellow solid
(0.6 g, 60 %). *H NMR (400 MHz, DMSO-dg): 8 6.78 (d, .7=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+H)+
Step-b: r-£^-N-(4-r3,5-dimethylisoxazol-4-yl)-3-methoxvphenyl)-3-ethoxv-
acrylamide (2b)
To a solution of intermediate-2a (0.6 g, 4.12 mmol) in pyridine (5 mL) at 0 °C
was added (£)-3-ethoxyacryloylchloride (0.83 g, 6.19 mmol). The mixture was
allowed to stir at RT for 16 h. The mixture was quenched with ice water and diluted
with EtOAc (100 ml), washed with IN HC1 (100 mL) and brine (100 mL), dried over
sodium sulphate and concentrated under reduced pressure. The residue was purified
by on silica gel (60-120 mesh) to afford the title product as pale yellow solid 0.4 g
(46 %). lH NMR (400 MHz, DMSO-d6): 5 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+H)+.
Step-c: 6-(3.5-dimethvlisoxazol-4-yl)-7-methoxyquinolin-2riH)-one(2c)

A solution of intermediate-2b (0.4 g, 2.16 mmol) in H2SO4 (3 mL) was stirred
at RT for 2 h. The mixture was quenched with ice water and the solid formed was
filtered off, washed with water and dried under reduced pressure to afford the title
product as off white solid (0.2 g, 59 %)}U NMR (400 MHz, DMSO-d6): 5 11.76 (bs,
1H), 7.82 (d, 7=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+H)+.
Step-d: 3-bromo-6-r3,5-dimethvlisoxazol-4-yl')-7-methoxvquinolin-2(lH)-one
(2d)
To a cooled solution of intermediate-2c (3.5 g, 12.96 mmol) in DMF (30 mL)
was added N-bromosuccinimide (2.8 g, 15.55 mmol) portion wise. The mixture was
stirred at RT for 1 h. The mixture was quenched with ice water, solids were
separated, filtered, washed thoroughly with water and dried under reduced pressure to
afford the title compound (3.5 g, 78 %); !H NMR (400 MHz, DMSO-d6): 8 12.25 (s,
1H), 8.40 (s, 1H), 7.56 (s, 1H), 6.96 (s, 1H), 3.83 (s, 3H), 2.26 (s, 3H), 2.07 (s, 3H);
LC-MS: m/z 351.1 (M+2H)2+.
Step-e: 3-bromo-6-('3.5-dimethvlisoxazol-4-yl')-7-methoxy-l-(pyridin-2-
ylmethyl>)quinolin-2('l HVone (intermediate-2)
To a solution of intermediate-2d (3.5 g, 10.02 mmol) in DMF (30 mL) were
added potassium carbonate (4.2 g, 30.06 mmol) followed by 2-(chloromethyl)-
pyridine hydrochloride (2.5 g, 15.64 mmol). The mixture was stirred at RT for 16 h.
The mixture was quenched with ice water, solids were separated, filtered, washed
. thoroughly with water and dried under reduced pressure to afford the title compound
(3.0 g, 68 %); 8 8.52 (s, 1H), 8.50 (s, 1H), 7.80-7.79 (m, 1H), 7.64 (s, 1H), 7.40 (d,
J=7.8 Hz, 1H), 7.32-7.30 (m, 1H), 7.13 (s, 1H), 5.72 (s, 2H), 3.75 (s, 3H), 2.25 (s,
3H), 2.06 (s, 3H); LC-MS: m/z 440.1 (M+H)+.
The below intermediate was prepared according to the step-e of the above
procedure by using suitable reactant and reagents in the presence of suitable reaction
conditions.



Intermediate-4: (3-Memyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) isoxazol-
5-yl)methyl acetate

To a 200 mL flask (under N2) was added dichlorobis(acetonitrile)-
palladium(II) (0.22 g, 0.85 mmol) and dicyclohexyl(2\6'-dimethoxybiphenyl-2-yl)-
phosphine (1.40 g, 3.41 mmol). To the solid were sequentially added a solution of (4-
bromo-3-methylisoxazol-5yl)methyl acetate (10.0 g, 42.73 mmol) in dry 1,4-dioxane
(100 mL), dry Et3N (17.82 mL, 128.20 mmol), and 4,4,5,5-tetramethyl-l,3,2-dioxa-
borolane (15.50 mL, 106.83 mmol). The flask was sequentially evacuated, purged
under N2, and repeated for 20 min. The mixture was heated to 110 °C (under N2) for
16 h. The mixture was cooled to RT and filtered through celite pad followed by
washing with EtOAc. The filtrate was concentrated under reduced pressure. The.
residue was used for further step without further purification (12.0 g). !.H NMR (400
MHz, CDCI3): 8 5.31 (s, 2H), 2.37 (s, 3H), 2.11 (s, 12H).
Intermediate-5: 2-Morpholinoethylmethanesulfonate

To an ice cooled solution of 2-morpholinoethan-l-ol (0.3 g, 2.28 mmol) in
DCM (10 mL) were added triethylamine (1 mL, 6.86 mmol) followed by methane-
sulfonylchloride (0.21 mL, 2.74 mmol). The mixture was stirred at RT for 2 h. The

mL), dried over sodium sulphate and concentrated under reduced pressure. The
residue (0.35 g) was used for further step without purification.
The below intermediates was prepared according to the above described
procedure by using suitable reactant and reagents and in presence of suitable reaction
conditions.

Intermediate-12: Synthesis of 6-bromo-3-rhvdroxvdiphenvlmethylV7-methoxy-1 -
(pyridin-2-vlmethyDquinolin-2( 1 HVone


Step-a: 6-Bromo-7-methoxy-2-oxo-1 -(pvridin-2-ylmethvO-1.2-dihydro-
quinoline-3-carboxylic acid (12a^)
To a solution of intermediate-Id (0.2 g, 0.71 mmol) in a mixture of
acetonitrile (3 mL) and H2O (1 mL) were added sodiumdihydrogenphosphate (0.28
g), hydrogenperoxide 30 % (0.2 mL) and sodiumchlorite (0.14 g). The mixture was
stirred at RT for 16 h. The mixture was then quenched with ice water, solids were
separated, filtered, washed thoroughly with water and vacuum dried to give the title
compound as a yellow solid (0.15 g). !H NMR (400 MHz, DMSO-de) 5 14.26 (bs,
1H), 8.93 (s, 1H), 8.47 (d, J=4.4 Hz, 1H), 8.42 (s, 1H), 7.82-7.78 (m, 1H), 7.46 (d,
J=7.8 Hz, 1H), 7.32-7.29 (m, 1H), 7.24 (s, 1H), 5.81 (s, 2H), 3.88 (s, 3H); LC-MS:
m/z 389.2 (M+H)+.
Step-b: Methyl 6-bromo-7-memoxv-2-oxo-l-(pyridm-2-vlmemyl)-L2-di-
hydroquinoline-3-carboxylate (12b-)
To a solution of intermediate-12a (1.0 g, 2.57 mmol) in DMF (20 mL) were
added potassium carbonate (0.71 g, 5.14 mmol) followed by methyl iodide (0.31 mL,
5.14 mmol). The mixture was stirred at RT for 4 h. The mixture was diluted with
water and extracted with EtOAc (200 mL x 2). The combined organic layers were
washed with water (200 mL) and brine (100 mL), dried over sodium sulphate and
concentrated under reduced pressure. The residue was directly used for next step
without further purification (0.8 g). *H NMR (400 MHz, DMSO-d6) 5 8.52 (s, 1H),
8.49 (d, 7=5.4 Hz, 1H), 8.48 (s, 1H), 7.79-7.74 (m, 1H), 7.34-7.27 (m, 2H), 7.09 (s,
1H), 5.65 (s, 2H), 3.83 (s, 3H), 3.81 (s, 3H); LC-MS: m/z 405.2 (M+2H)2+.
Step-c: 6-Bromo-3 -flivdroxvdiphenvlmethyl)-7-methoxv-1 -fpyridin-2-yl-
methvDquinolin-2( 1 HVone (Intermediate-12)
To an ice-cooled solution of intermediate-12b (0.5 g, 1.24 mmol) in THF (15
mL) was added phenyl magnesium bromide (3.7 mL, 3.72 mmol). The reaction

aqueous ammonium chloride and extracted with EtOAc (100 mL x 2). The combined
organic layers were washed with water (100 mL) and brine (100 mL), dried over
sodium sulphate and concentrated under reduced pressure. The residue obtained was
purified by silica gel (60-120 mesh) column chromatography (elution 1% MeOH-
DCM) to give the title compound (0.08 g, 12 %). *H NMR (400 MHz, DMSO-d6) 5
8.49 (d, J=4.9 Hz, 1H), 8.0 (s, 1H), 7.77-7.76 (m, 1H), 7.35-7.26 (m, 12H), 7.21 (d,
J=7.8 Hz, 1H), 7.15 (s, 1H), 6.73 (s, 1H), 5.65 (s, 2H), 3.81 (s, 3H).
Intermediate-13: 5-Bromo-4-methoxy-2-nitrobenzaldehyde

Step-a: 5-Bromo-4-fluoro-2-nitrobenzaldehvde 13a
To a cooled solution of 3-bromo-4-fluorobenzaldehyde (15.0 g, 73.8 rnmol)
in H2SO4 (150 mL) was added HNO3 (10 mL) dropwise followed by stirring at RT
for 3 h. The mixture was poured into crushed ice. The solids were filtered, washed
thoroughly with water and dried under reduced pressure to afford the title compound
(11 g, 61%); !H NMR (400 MHz, DMSO-de): 5 10.15 (s, 1H), 8.32 (d, J=8.3 Hz,
1H), 8.26 (d, .7=6.9 Hz, 1H).
Step-b: 5-Bromo-4-methoxv-2-nitrobenzaldehydeintermediate (intermediate-
13}
To an ice cooled solution of intermediate-13a (2.5 g, 10.08 rnmol) in MeOH
(30 mL) was added sodium methoxide (0.8 g, 15.1 rnmol) followed by stirring at RT
for 8 h. The mixture was quenched with ice water. Solids were separated, filtered,
washed thoroughly with water and dried under reduced pressure. The product was
further recrystallized by using 10 % EtOAc-hexane to afford the title compound (1.0
g, 40 %). JH NMR (400 MHz, DMSO-d6): 8 10.04 (s, 1H), 8.17 (s, 1H), 7.80 (s, 1H),
4.06 (s, 3H); LC-MS: m/z 260 (M+H)+.
Intermediate-14: 4-((tert-Butyldimethylsilyl)oxy)-3-fluoroaniline


Step-a: tert-Butyl (2-fluoro-4-riitrophenoxyMimethylsilane 14a
To a cooled solution of 2-fluoro-4-nitrophenol (1.0 g, 6.36 mmol) in DCM
(15 mL) was added imidazole (1.4 g, 9.54 mmol) followed by TBS-C1 (0.9 g, 12.72
mmol). The mixture was stirred at RT for 5 h. The mixture was diluted with DCM
(250 mL), washed with water (250 mL) and brine (250 mL), dried over sodium
sulphate and concentrated under reduced pressure. The residue was used in next step
without purification (0.5 g, 30 %). *H NMR (400 MHz, CDC13): 5 8.0-7.95 (m, 2H),
7.02-6.97 (m, 1H), 1.01 (s, 9H), 0.25 (s, 6H).
Step-b: 4-((tert-ButyldimethvlsilyO oxy)-3-fluoroaniline (Intermediate-14)
To a solution of intermediate-14a (0.4 g, 1.47 mmol) in EtOH (5 mL), THF
(2.5 mL) and H2O (1 mL) were added iron powder (0.2 g, 3.67 mmol) and NH4CI
(0.22 g, 4.41 mmol). The mixture was heated to reflux for 1 h. The mixture was
cooled to RT, filtered through celite followed by washing with EtOAc. The combined
filtrate was concentrated under reduced pressure. The residue was diluted with water,
extracted with EtOAc (100 mL), washed with brine (100 mL), dried over sodium
sulphate and concentrated under reduced pressure to afford the title compound as
brown oil (0.2 g). LC-MS: m/z 242.1 (M+H)+.
The below intermediates were prepared according to the procedure depicted
above by using suitable reactants and reagents and appropriate reaction conditions.



Intermediate-18: 3-(Azetidine-1 -carbonyl)-6-bromo-7-methoxyquinolin-2( 1 H)-one

Step-a: 6-Bromo-7-methoxv-2-oxo-l.,2-dihvdroquinoline-3-carboxvlicacid
18a
The process of this step was adopted from step-f of intermediate-l^HNMR
(400 MHz, DMSO-de) 5 13.80 (bs, 2H), 8.83 (s, 1H), 8.33 (s, 1H), 7.04 (s, 1H), 3.96
(s, 3H); LC-MS: m/z 300.0 (M+2H)2+.
Step-b: 3-Cazetidine-1 -carbonvlV 6-bromo-7-memoxyquinolin-2( 1 HVone
(Intermediate-18)
To a solution of intermediate-18a (3.0 g, 10.1 mmol) in DMF (30 mL) were
added azetidine hydrochloride (1.42 g, 15.15 mmol), HOBt (2.7 g, 20.2 mmol),
EDC.HC1 (3.9 g, 20.2 mmol) and triethylamine (2.7 mL, 20.2 mmol). The mixture
was stirred at RT for 16 h. The mixture was then diluted with EtOAc (100 mL),
washed with water (100 mL) and brine (100 mL), dried over sodium sulphate and
concentrated under reduced pressure to afford the title compound as off white solid
(2.5 g). *H NMR (400 MHz, DMSO-ds) 5 11.98 (s, 1H), 8.04 (d, .7=2.9 Hz, 2H), 6.91
(s, 1H), 4.04 (t, .7=7.4 Hz, 2H), 3.98 (t, 7=7.8 Hz, 2H), 3.90 (s, 3H), 2.22 (t, .7=7.8 Hz,
2H); LC-MS: m/z 339.0 (M+2H)2+.
Intermediate-19: l-(6-(3,5-Dimethvlisoxazol-4-vl)-7-methoxv-2-oxo-l-(pvridin-2-
ylmethyl)-1,2-dihydroquinolin-3 -yl)-2,2,2-trifluoroethyl methanesulfonate


Step-a: 6-(3,S-Dimethylisoxazol-4-yl)-7-metfao?cy-l-(pyridin-2-ylmethyl)-3-
f 2.2.2-trifluoro-1 -hvdxoxvethvllquinolin^riHP-one (19a)
To a cooled solution of intermediate-le (0.02 g, 0.051 mmol) in THF (1 mL)
were added telrabutylarnrnoniumfluoride 1.0 M in THF (0.015 mL, 0.015 mmol) and
TMS-CF3 (0.01 mL, 0.061 mmol) followed by stirring at 0 °C for 1 h. The mixture
was quenched with saturated NH4CI and extracted with EtOAc (50 mL), washed with
water (50 mL), dried over sodium sulphate and concentrated under reduced pressure.
The residue was purified on preparative TLC to afford the title compound as an off
white solid 0.01 g (43 %). *H NMR (400 MHz, DMSO-d6): 5 8.52 (d, 7=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+H)+.
Step-b: l-(6-(3,5-Dimethvlisoxazol-4-ylV7-methoxy-2-oxo-l-(pyridin-2-
ylmethylV 1.2-dihvdro quinolin-3 -vlV2,2,2-trifluoroethyl methanesulfonate
(Intermediate-19)
The process of this step was adopted from step-a of intermediate-5. !H NMR
(400 MHz, DMSO-de): 5 8.51 (d, J=4.4 Hz, 1H), 8.34 (s, 1H), 7.86 (s, 1H), 7.80-7.79
(m, 1H), 7.35-7.30 (m, 2H), 7.18 (s, 1H), 6.48-6.46 (m, 1H), 5.73 (s, 2H), 3.78 (s,
3H), 3.39 (s, 3H), 2.26 (s, 3H), 2.06 (s, 3H); LC-MS: m/z 538.1 (M+Hf.
Intermediate-20: 6-(3, 5-Dimethylisoxazol-4-yl)-3-(hydroxymethyl)-7-methoxy-l-
(pyridin-2-ylmethyl) quinolin-2( 1 H)-one


To an ice cooled solution of 6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-2-oxo-
1 -(pyridin-2-ylmethyl)-1,2-dihydroquinoline-3-carbaldehyde (intermediate-1 e) (0.07
g, 0.18 mmol) in MeOH (3 mL) was added NaBH4 (0.007 g, 0.18 mmol) pinch wise
followed by stirring at 0 °C for 1 h. The mixture was concentrated in vacuum. The
residue was diluted with aqueous ammonium chloride and extracted with EtOAc (50
mL x 2). The organic layer was washed with water (100 mL) and 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 title product as white solid
0.02 g (28 %). *H NMR (400 MHz, DMSO-d6): 8 8.52 (d, .7=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=5A Hz, 2H), 3.73 (s, 3H), 2.25 (s, 3H), 2.06
(s, 3H); LC-MS: m/z 392.1 (M+H)+.
The below intermediates were prepared according to the procedure depicted
above by using suitable reactants and reagents at appropriate reaction conditions.



The starting compounds 21.1&21a.l were prepared according to the
procedure depicted in step-d and step-e of intermediate-1 by using 4-chlorophen-
ethylmethanesulfonate and l-(chloromethyl)-4-methoxybenzene as the reactant by
using suitable reagents and solvents under appropriate reaction conditions. The
characterization data for intermediate 21.1 &21a.l are given below. Intermediate-
21.1: ^NMR^OO MHz, CDC13) 5 10.45 (s, 1H), 8.33 (s, 1H), 7.31 (s, 1H), 7.28-
7.21 (m, 4H), 6.67 (s, 1H), 4.53 (t, .7=7.9 Hz, 2H), 3.88 (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+H)+.
Intermediate-21a.l: ^NMR (400 MHz, DMSO-d6): 8 10.31 (s, 1H), 8.52 (s, 1H),
7.92 (s, 1H), 7.37 (d, J=8.8 Hz, 2H), 7.07 (s, 1H), 6.91 (d, J=8.8 Hz, 2H), 5.58 (s,
2H), 3.85 (s, 3H), 3.71 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H); LC-MS: m/z 419.2
(M+H)+.
Intermediate-22: 6-(3,5-Dimethylisoxazol-4-yl')-7-methoxv-l-('pyridin-2-vlmethvl)
quinolin-2( 1 H)-one

Step-a: 3, 3-Diethoxypropanoic acid (22a)
To a 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) followed by stirring at 110 °C
for 1.5 h. The mixture was cooled, acidified to pH ~3 with 3 N HC1 and extracted
with EtOAc (500 ml x 2). The organic layer was washed with water (200 mL) and
brine (100 mL), dried over sodium sulphate and concentrated under reduced pressure.
The residue was used for next step without further purification (11.50 g, 91 %). lH

NMR (400 MHz, DMSO-d6): 5 12.20 (s, 1H), 4.81 (t, .7=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, .7=7.3 Hz, 6H).
Step-b: 3-Ethoxvacryloyl chloride ('22b')
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
followed by stirring at 80 °C for 1.5 h. The mixture was concentrated and dried under
reduced pressure to afford the title product as a clear dark brown liquid (3.0 g, 73 %).
JH NMR (400 MHz, DMSO-d6): 5 7.50 (d, .7=12.2 Hz, 1H), 5.14 (d, .7=12.2 Hz, 1H),
3.94 (q, .7=7.3 Hz, 2H), 1.24 (t, .7=7.3 Hz, 3H).
Step-c: ("£'/Z)-N-(4-bromo-3-methoxvphenvlV3-ethoxvacrvlamide (22c)
To an ice cooled solution of 4-bromo-3-methoxyaniline (3.00 g, 14.85 mmol)
in pyridine (20 mL) was added (£/Z)-3-ethoxyacryloyl chloride (2.98 g, 22.27 mmol)
over a period of 5 min followed by stirring at RT for 16 h. The mixture was diluted
with ice cooled water and extracted with EtOAc (150 ml x 2). The combined organic
layer was washed with IN HC1, water (150 mL) and brine (100 mL), dried over
sodium sulphate and concentrated under reduced pressure. The residue was used for
next step without further purification (3.20 g, 72 %). *H NMR (400 MHz, DMSO-
d6): 5 9.86 (s, 1H), 7.54-7.42 (m, 3H), 7.12-7.08 (m, 1H), 5.50 (d, .7=12.7 Hz, 1H),
3.95 (q, 7=6.9 Hz, 2H), 3.80 (s, 3H), 1.27 (t, .7=7.3 Hz, 3H); LC-MS: m/z 301.1
(M+H)+.
Step-d: 6-Bromo-7-methoxyquinolin-2(lHVone (22d")
A solution of (E/Z)-N-(4-bromo-3-methoxyphenyl)-3-ethoxyacrylamide (3.0
g, 10.0 mmol) in concentrated H2SO4 (30 mL) was stirred at RT for 2 h. The mixture
was poured over crushed ice and the solids were filtered, washed thoroughly with
water and vacuum dried. The residue was directly used for the next step without
further purification (2.08 g, 82 %). 'HNMR (400 MHz, DMSO-d6): 8 12.70 (brs,
1H), 7.94 (s, 1H), 7.80 (d, .7=9.8 Hz, 1H), 6.92 (s, 1H), 6.36 (d, .7=9.8 Hz, 1H), 3.88
(s, 3H); LC-MS: m/z 256.0 (M+H)+.
Step-e: 6-Bromo-7-methoxy-1 -fpyridin-2-ylmethyDquinolin-2(" 1 HVone (22e^
To a cold solution of 6-bromo-7-methoxyquinolin-2(lH)-one (0.300 g, 1.18
mmol) in dry DMF (5 ml) at 0 °C was added NaH (0.034 g, 1.42 mmol). After 15
min, 2-(bromomethyl)-pyridine hydro bromide (0.36 g, 1.42 mmol) was added and

water and solids were separated, filtered, washed thoroughly with water and dried
under reduced pressure to afford the title compound (0.2 g).*H NMR (400MHz,
DMSO-d6): 8 8.49 (d, J=4.4 Hz, 1H), 8.01 (s, 1H), 7.87 (d, J=9.2 Hz, 3H), 7.78-7.77
(m, 1H), 7.29-7.26 (m, 2H), 7.08 (s, 1H), 6.58 (d, .7=9.2 Hz, 1H), 5.62 (s, 2H), 3.79
(s, 3H). MS (ES) m/e 347.0 (M+2H)2+.
Step-f: 6-f3,5-Dimethylisoxazol-4-ylV7-methoxy-1 -(pyridin-2-ylmethyl)-
quinolin-2dH)-one (intermediate-22)
To a stirred solution of 6-bromo-7-methoxy-l-(pyridin-2-ylmethyl) quinolin-
2(lH)-one (0.200 g, 0.58 mmol) in 10 ml of 1,4 dioxane:water (7:3) mixture was
added 3,5-dimethylisoxazol-4-yl) boronic acid (0.164 g, 1.16 mmol) and K2CO3
(0.240 g, 1.74 mmol). The resulting mixture was degassed with nitrogen for 15 min
and Pd (PPh3)4 (0.033 g, 0.029 mmol) was added. The mixture was stirred at 90 °C
for 2 h. The mixture was then diluted with DCM and washed with water (50 ml) and
dried over Na2SC>4. Filtration and then concentration in vacuum was followed by
chromatography on silica (20 % EtOAc in hexanes) to give the title product as a solid
(0.142 g, 67 %). *H NMR (400MHz, DMSO-de): 5 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), 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/e
362.3 (M+H)+.

Step-a: Intermediate 23.1
To a solution of 3-methyl-5-nitropyridin-2-amine (0.1 g, 0.65 mmol) in DCM
(10 mL) was added di tert butyl dicarbonate (0.33 mL, 1.43 mmol) and DMAP
(0.016 g, 0.13 mmol) followed by stirring at RT for 2 h. The mixture was
concentrated under reduced pressure and purified by combi flash to afford

intermediate 21.1 as white solid (0.23 g, 99 %). *HNMR (400 MHz, DMSO-d6): 8
9.15 (d, J=2.9 Hz, 1H), 8.67 (d, .7=3.0 Hz, 1H), 2.29 (s, 3H), 1.37 (s, 18H).
Step-b: Intermediate 23
To a solution of Intermediate 21.1 (2.1 g, 5.94 mmol) in MeOH (20 mL) was
added 10 % Pd-C (0.3 g) followed by stirring under H2 bladder pressure at RT for 2
h. The mixture was filtered through celite followed by washing with EtOAc. The
filtrate was concentrated under reduced pressure to afford the title compound as pale
yellow solid (1.5 g^H NMR (400 MHz, DMSO-d6): 5 7.57 (d, J=2.9 Hz, 1H), 6.81
(d, 7=2.4 Hz, 1H), 5.32 (s, 2H), 1.97 (s, 3H), 1.35 (s, 18H); LC-MS: m/z 324.3
(M+H).
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: 3,6-Bisf3,5 -dimethylisoxazol-4-yP-7-methoxy-1 -(pvridin-2-vlmethyl')
quinolin^riHVone (Compound-1)

Step-i: 3,6-dibromo-7-methoxvquinolin-2flH)-one (1.1)
To a cooled solution of 7-methoxyquinolin-2(lH)-one (2.0 g, 11.36 mmol) in
DMF (10 mL) was added N-bromosuccinimide (2.0 g, 11.93 mmol) portion wise
followed by stirring at RT for 16 h. The mixture was quenched with ice water,
separated, filtered, washed thoroughly with water and dried under reduced pressure to
afford the title compound (2.3 g, mixture with mono bromo compound); LC-MS: m/z
334 (M+H)+.
Step-ii: 3,6-Dibromo-7-methoxv-l-(pvridin-2-vlmethynquinolin-2nH')-one
CL2)
The process of this step was adopted from step-e of intermediate-2. *H NMR
(400 MHz, DMSO-d6): 5 8.48 (s, 2H), 8.02 (s, 1H), 7.78 (t, J=7.8 Hz, 1H), 7.36 (d,

J=7.8 Hz, 1H), 7.31-7.28 (m, 1H), 7.09 (s, 1H), 5.71(s, 2H), 3.81 (s, 3H); LC-MS:
m/z 425.0 (M+H)+.
Step-iii: 3,6-bis (3,5-dimethylisoxazol-4-yl)-7-methoxy-l-(pyridiii-2-yl-
methyl)quinolin-2( 1 H)-one (Compound-1)
The process of this step was adopted from step-e of intermediate-1. The
desired di substituted compound was isolated by preparative HPLC from the mixture
of mono and di substituted compounds. *H NMR (400 MHz, DMSO-d6): 8 8.54 (d,
J=4.4 Hz, 1H), 8.01 (s, 1H), 7.79 (t, J=6.4 Hz, 1H), 7.66 (s, 1H), 7.36 (d, J=7.2 Hz,
1H), 7.33-7.32 (m, 1H), 7.19 (s,lH), 5.72 (s, 2H), 3.77 (s, 3H), 2.37 (s, 3H), 2.26 (s,
3H), 2.19 (s, 3H), 2.06 (s, 3H); LC-MS: m/z 457.2 (M+H)+.
ExampIe-II; N-(3-(6-(3,5-dimethylisoxazol-4-vl')-7-methoxv-2-oxo-1 -
(pyridin-2-ylmethyl)-1 ,2-dihvdroqumolin-3-vDphenvDacetarnide (Compound^

To a solution of 3-bromo-6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-l-
(jpyridm-2-yhnethyl)quinolin-2(lH)-one (intermediate-2) (0.11 g, 0.23 mmol) in 1,2-
DME (3 mL) and H2O (1 mL) were added pyridin-4-ylboronic acid (0.09 g, 0.69
mmol) and sodium carbonate (0.06 g, 0.57 mmol) followed by degassing with
nitrogen purging for 20 min. Then tetrakistriphenylphosphine palladium (0.03 g,
0.023 mmol) was added and the mixture was heated at 90 °C for 16 h. The mixture
was then diluted with EtOAc (50 mL), washed with water (50 mL) and brine (50
mL), dried over sodium sulphate and concentrated under reduced pressure. The
residue was purified by preparative TLC to afford the title compound as a pale green
solid (0.03 g, 30 %); XH NMR (400 MHz, DMSO-d6) 8 8.65-8.63 (m, 2H), 8.53 (d,
J=4.4Hz, 1H), 7.36 (s, 1H), 7.83-7.77 (m, 3H), 7.73 (s, 1H), 7.41 (d, J=8.0 Hz, 1H),
7.32-7.29 (m, 1H), 7.71 (s, 1H), 5.75 (s, 2H), 3.78 (s, 3H), 2.27 (s, 3H), 2.08 (s, 3H);
LC-MS: m/z 439.2 (M+H)+.

The below compounds were prepared by a procedure similar to the one
described in Example-II by using appropriate bromo compounds and reacting with
suitable boronic acids or esters in presence of suitable palladium catalyst and
reagents in the presence of suitable solvents at appropriate reaction conditions. The
physiochemical characteristics of the compounds are also summarized.


49

6 HO^OH
F 5 8.54 (d, .7=4.4 Hz, IH), 8.05 (s,
IH), 7.81-7.76 (m, IH), 7.68 (s,
IH), 7.64-7.58 (m, IH), 7.37-7.30
(m, 3H), 7.21-7.16 (m, 2H), 5.72
(s, 2H), 3.78 (s, 3H), 2.26 (s, 3H),
2.07 (s, 3H); LC-MS: m/z 474.1
(M+H)+.
7 HO^.OH
OH 5 9.57 (s, IH), 8.53 (d, .7=4.4 Hz,
IH), 8.02 (s, IH), 7.78 (t, J=7.3 Hz,
IH), 7.65 (s, IH), 7.61 (d, J=8.3
Hz, 2H), 7.36 (d, J=7.8 Hz, IH),
7.32-7.28 (m, IH), 7.13 (s, IH),
7.62 (d, J=8.3 Hz, IH), 5.72 (s,
2H), 3.76 (s, 3H), 2.26 (s, 3H), 2.07
(s, 3H); LC-MS: m/z 452.2 (M-H)".
8 HO^OH
6rCF3 OA F3C^^ 5 8.56 (d, .7=4.4 Hz, IH), 7.88 (s,
IH), 7.84-7.72 (m, 3H), 7.67 (s,
IH), 7.66-7.62 (m, IH), 7.50 (d,
7=7.3 Hz, IH), 7.33-7.26 (m, 2H ),
7.20 (s, IH), 5.71-5.67 (m, 2H),
3.78 (s, 3H), 2.25 (s, 3H), 2.06 (s,
3H); LC-MS: m/z 506.1 (M+H)+.
9 HO.g.OH
N-N
/ '0-\ Htf
\ 5 8.60 (d, .7=4.4 Hz, IH), 8.40 (s,
IH), 7.97 (s, IH), 7.93 (s, IH),
7.63-7.61 (m, IH), 7.35 (d, J=7.8
Hz, IH), 7.31 (s, IH), 7.23 (d,
.7=5.9 Hz, IH), 7.20 (s, IH), 5.97
(bs, 2H), 3.97 (s, 3H), 3.80 (s, 3H),
2.29 (s, 3H), 2.14 (s, 3H); LC-MS:
m/z 442.2 (M+H)+.

Example-Ill: 6-r3,5-dimethylisoxazol-4-yl')-7-methoxy-3-('lH-pyrazol-l-vl')-l-
(pyridin-2-ylmemvDquinolin-2f lHVone (Compound-15)

To a solution of 3-bromo-6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-l-(pyri-
din-2-ylmethyl)quinolin-2(lH)-one (intermediate-2) (0.1 g, 0.22 mmol) in DMSO (3
mL) in a sealed tube were added imidazole (0.03 g, 0.45 mmol), L-proline (0.005 g,
0.04 mmol), copper (I) iodide (0.009 g, 0.04 mmol) and potassium carbonate (0.1 g,
0.68 mmol) followed by heating at 110 °C for 16 h. The mixture was diluted with
EtOAc (50 mL), washed with water (50 mL) and brine (50 mL), dried over sodium
sulphate and concentrated under reduced pressure. The residue was purified by
preparative HPLC to afford the title compound as an off white solid (0.02 g, 20 %).
JH NMR (400 MHz, DMSO-d6): 5 8.53 (d, .7=4.4 Hz, 1H), 8.12 (s, 1H), 7.82-7.80
(m, 1H), 7.68 (s, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.33-7.32 (m, 1H), 7.27 (s, 1H), 7.20
(s, 1H), 7.08 (s, 1H), 6.73 (s, 1H), 5.73 (s, 2H), 3.78 (s, 3H), 2.21 (s, 3H), 2.0 (s, 3H);
LC-MS: m/z 428.2 (M+H)+.
The below compounds were prepared by a procedure similar to the one
described in Example-Ill by using appropriate bromo compounds reacting with
suitable reactants in the presence of suitable reagents, catalysts and solvents at

appropriate reaction conditions. The physiochemical characteristics of the
compounds are also summarized.

ExampIe-IV: 6-(3,5-Dimethvlisoxazol-4-vl)-3-(4-hvdroxypiperidine-l-carbonvlV7-
methoxy-1 -(pyridin-2-ylmethyl)quinolin-2( 1 H)-one (Compound-25)

To a solution of 6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-2-oxo-l-(pyridin-
2-ylmethyl)-l,2-dihydroquinoline-3-carboxylicacid (intermediate-1) (0.1 g, 0.25
mmol) in DMF (5 mL) were added piperidin-4-ol (0.04 g, 0.37 mmol), HOBt (0.1 g,
0.74 mmol), EDC.HC1 (0.14 g, 0.74 mmol) and triethylamine (0.1 mL, 0.74 mmol)
followed by stirring RT for 4 h. The mixture was diluted with EtOAc (50 mL),
washed with water (50 mL) and brine (50 mL), dried over sodium sulphate and
concentrated under reduced pressure. The residue was purified by preparative TLC to
afford the title compound as an off white solid (0.025 g, 20 %); *H NMR (400 MHz,

1H), 7.36-7.29 (m, 2H), 7.16 (s, 1H), 5.68 (s, 2H), 4.76 (s, 1H), 4.1-4.0 (m, 1H),
3.77 (s, 3H), 3.44-3.09 (m, 4H), 2.25 (s, 3H), 2.05 (s, 3H), 1.76-1.70 (m, 2H), 1.38-
1.35 (m, 2H); LC-MS: m/z 489.2 (M+H)+.
The below compounds were prepared by a procedure similar to the one
described in Example-IV by using intermediate-1 or compound-77 prepared
according to Example-XH as starting compounds and reacting with suitable reactants
in the presence of suitable reagents and solvents at appropriate reaction conditions.
The physiochemical characteristics of the compounds are also summarized.

Notes:
* Compounds 51-55 undergoes further deprotection step by using reagents
such as TBAF (in 1M THF) and in the presence of suitable solvents at appropriate
reaction conditions to give the respective compounds.
** Compounds 64 & 65 were prepared according to the protocol depicted in
Example-IY with their appropriate starting compounds depicted below. Starting
compounds for compound 64 & 65 are prepared according to the protocol described
in intermediate-1.



Example-V: 6-(3,5-Dimemylisoxazol-4-yl)-3-(lH-imidazol-2-yl)-7-methoxy-l -
(pyridin-2-ylmethyl)quinolin-2(lH)-one (Compound-66)

Step-i: 6-Bromo-3-('lH-iniidazol-2-vl)-7-methoxv-l-('pvridin-2-vlmethvl')
quinolin-2(TL0-one
To a solution of 6-bromo-7-methoxy-2-oxo-l-(pyridin-2-ylmethyl)-l,2-di-
hydroquinoline-3-carbaldebyde (intermediate-Id) (0.3 g, 0.8 mmol) in EtOH (10 mL)
were added glyoxal 40 % (1.2 mL) and ammonium hydroxide (2.5 mL) followed by
stirring at RT for 16 h. The mixture was diluted with EtOAc (100 ml), washed with
water (100 mL) and brine (100 mL), dried over sodium sulphate and concentrated
under reduced pressure. The residue was purified by column chromatography (60-
120 silica gel and 2 % MeOH in DCM as eluent) to afford the title compound as
brown solid (0.2 g, 60%). !H NMR (400 MHz, DMSO-d6) 5 12.27 (bs, 1H), 8.73 (s,
1H), 8.50 (d, J=4.4 Hz, 1H), 8.24 (s, 1H), 7.79-7.74 (m, 1H), 7.36 (d, J=8.3 Hz, 1H),
7.31-7.28 (m, 1H), 7.16 (s, 1H), 7.15 (s, 2H), 5.78 (s, 2H), 3.84 (s, 3H); LC-MS: m/z
411.0 (M+H)+.
Step-ii: 6-(3,5-dimethvlisoxazol-4-vlV3-nH-imidazol-2-vlV7-methoxv-l-
fpyridin-2-ylmethyl) quinolin-2nH)-one (compound-66)
The process of this step was adopted from step-(i) of Compound-2. *HNMR
(400 MHz, DMSO-d6): 5 12.26 (s, 1H), 8.79 (s, 1H), 8.53 (d, .7=4.4 Hz, 1H), 7.86 (s,
1H), 7.81-7.76 (m, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.33-7.76 (m, 1H), 7.19 (s, 1H),

7.17 (bs, 1H), 7.08 (s, 1H), 5.82 (s, 2H), 3.79 (s, 3H), 2.28 (s, 3H), 2.09 (s3 3H); LC-
MS: m/z 428.2 (M+H)+.
Example-VI: 6-(3,5-dimethylisoxazol-4-yl)-7-metlioxy-3-(l -phenyl-lH-
imidazol-2-yl)-1 -(pyridin-2-ylmethyl)quinolin-2( 1 H)-one (Compound-67)

The process of this step was adopted from step (i) of compound-15. H NMR
(400 MHz, DMSO-de) 5 8.51 (d, .7=4.4 Hz, 1H), 8.31 (s, 1H), 7.75 (s, 1H), 7.68 (t,
.7=7.9 Hz, 1H), 7.63-7.61 (m, 1H), 7.43-7.23 (m, 7H), 7.16 (s, 1H), 6.73 (d, J=7.9
Hz, 1H), 5.46 (s, 2H), 3.78 (s, 3H), 2.26 (s, 3H), 2.08 (s, 3H); LC-MS: m/z 504.3
(M+H)+.
Example-VII: 6-(3,5-Dimethylisoxazol-4-yl)-3-(hydroxydiphenylmethyl)-7-
methoxy-1 -(pyridin-2-ylmethyl)quinolin-2(l H)-one (Compound-68)

To a solution of 6-bromo-3-(hydroxydiphenylmethyl)-7-methoxy-l-(pyridin-
2-ylmethyl)quinolin-2(lH)-one (intermediate-12) (0.08 g, 0.15 mmol) in 1,2-DME
(4.0 mL) and H2O (1.0 mL) were added 3,5-dimethylisoxazoleboronic acid (0.04 g,
0.30 mmol), sodium carbonate (0.05 g, 0.45 mmol) followed by degassing with
nitrogen purging for 20 min. Then tetrakis triphenylphosphinepalladium (0.009 g,
0.015 mmol) was added followed by heating at 90 °C for 16 h. The mixture was
diluted with EtOAc (50 ml), washed with water (50 mL) and brine (50 mL), dried
over sodium sulphate and concentrated under reduced pressure. The residue obtained

MeOH-DCM) to afford the title compound as white solid (0.02 g, 24 %). JH NMR
(400 MHz, DMSO-d6) 5 8.52 (d, J=4.3 Hz, 1H), 7.77-7.75 (m, 1H), 7.57 (s, 1H),
7.36-7.24 (m, 13H), 7.18 (s, 1H), 6.80 (s, 1H), 5.68 (s, 2H), 3.75 (s, 3H), 2.20 (s,
3H), 2.01 (s, 3H).
Example-VIII: 6-(3,5-Dimethylisoxazol-4-yl)-7-methoxy-1 -(pyridin-2-ylmethyl)-3-
(2,2,2-trifluoro-l-(4-fluorophenoxy)ethyl)quinoliri-2(lH)-one(Compound-69)

To a solution of l-(6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-2-oxo-l-(pyri-
din-2-ylmethyl)-1,2-dihydroquinolin-3 -yl)-2,2,2-trifluoroethylmethanesulfonate
(intermediate-19) (0.15 g, 0.27 mmol) in DMF (3 mL) were added potassium
carbonate (0.12 g, 0.83 mmol) and 4-fluorophenol (0.05 g, 0.41 mmol) followed by
stirring at RT for 16 h. The mixture was diluted with EtOAc (50 mL), washed with
water (50 mL) and brine (50 mL), dried over sodium sulphate and concentrated under
reduced pressure. The residue was purified by preparative TLC to afford the title
compound as off white solid (0.012 g, 8 %). lR NMR (400 MHz, DMSO-d6): 8 8.51
(d, J=3.9 Hz, 1H), 8.29 (s, 1H), 7.81 (s, 1H), 7.82-7.80 (m, 1H), 7.34-7.31 (m, 2H),
7.18-7.13 (m, 3H), 7.04-7.0 (m, 2H), 6.23-6.21 (m, 1H), 5.75 (s, 2H), 3.76 (s, 3H),
2.22 (s, 3H), 2.03 (s, 3H); LC-MS: m/z 554.2 (M+H)+.
The below compounds were prepared by a procedure similar to the one
described in Example-VIII by using intermediate-19 as starting compound in the
presence of suitable reagents and solvents at appropriate reaction conditions. The
physiochemical characteristics of the compounds are also summarized.



ExampIe-IX; 6-(3,5-Dimethvlisoxazol-4-ylV3-ri-ethoxv-2,2,2-trifluoroethvlV7-
methoxy-l-(pyridin-2-ylmethyl)quinolin-2(lH)-one (Compound-73)


To a cooled solution of 6-(3,5-dimemylisoxazol-4-yl)-7-memoxy-l-(pyridin-
2-ylmethyl)-3-(2,2,2-trifIuoro-1 -hydroxyethyl)quinolin-2( 1 H)-one (intermediate-19a)
(0.15 g, 0.32 mmol) in DMF (5 mL) was added sodium hydride 60 % (0.06 g, 0.98
mmol) followed by stirring at RT for 30 min. Then iodoethane (0.04 mL, 0.65 mmol)
was added followed by stirring at RT for 16 h. The mixture was quenched with ice
water and extracted with EtOAc (50 mL x 2). Combined organic phase was washed
with brine (50 mL), dried over sodium sulphate and concentrated under reduced
pressure. The residue was purified by silica gel (60-120 mesh) column
chromatography (elution 20 % EtOAc-hexane) to afford the title compound as pale
brown solid (0.015 g, 10 %). *H NMR (400 MHz, DMSO-d6): 5 8.52 (d, .7=4.4 Hz,
1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.80-7.76 (m, 1H), 7.32-7.29 (m, 2H), 7.15 (s, 1H),
5.70 (s, 2H), 5.37-5.35 (m, 1H), 3.76 (s, 3H), 3.67-3.63 (m, 2H), 2.25 (s, 3H), 2.06
(s, 3H), 1.20-1.17 (m, 3H); LC-MS: m/z 488.2 (M+H)+.
The below compound was prepared by a procedure similar to the one
described in Example-IX by using intermediate-19a in presence of appropriate .
reactants and solvents at appropriate reaction conditions. The physiochemical
characteristic of the compound is also summarized.



Example-X: 6-(3,5-dimethylisoxazol-4-vl)-3-(3-ethyl-l,2,4-oxadiazol-5-yl')-7-
methoxy-l-(pyridin-2-ylmethyl)quinolin-2(lH)-one (Compound-75)

To a solution of 6-(3,5-dimemylisoxazol-4-yl)-7-methoxy-2-oxo-l-(pyridin-
2-ylmethyl)-l,2-dihydroquinoline-3-carboxylic acid (intermediate-1) (0.05 g, 0.12
mmol) in DMF (3 mL) were added HATU (0.05 g, 0.135 mmol) and diisopropyl
ethyl amine (0.025 mL, 0.18 mmol) followed by stirring at RT for 10 min. Then (Z)-
N'-hydxoxypropionimidamide was added followed by stirring at RT for 16 h. The
mixture was diluted with EtOAc (50 mL), washed with water (50 mL) and brine (50
mL), dried over sodium sulphate and concentrated under reduced pressure. The
residue was purified by preparative TLC to afford the title compound as off white
solid (0.015 g, 13 %). 'HNMR (400 MHz, DMSO-d6) 5 8.93 (s, 1H), 8.52 (d, J=4.4
Hz, 1H), 7.95 (s, 1H), 7.82-7.78 (m, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.33-7.30 (m, 1H),
7.19 (s, 1H), 5.80 (s, 2H), 3.82 (s, 3H), 2.80 (q, J=7.8 Hz, 2H), 2.26 (s, 3H), 2.09 (s,
3H), 1.30 (t, J=7.& Hz, 3H); LC-MS: m/z 458.2 (M+H)+.


Step-i: 5-(3,5-dimethylisoxazol-4-viy4-methoxy-2-rritrobenzaldehyde (16.1)
The process of this step was adopted from step-(i) of compound-2. *H NMR
(400 MHz, DMSO-d6): 5 10.09 (s, 1H), 7.86 (s, 1H), 7.83 (s, 1H), 3.99 (s, 3H), 2.31
(s, 3H), 2.11 (s, 3H); LC-MS: m/z 277.1 (M+H)+.
Step-ii: 2-arnino-5-(3,5-dimethvlisoxazol-4-yl')-4-rnethoxvbenzaldehvde
£762}
To a solution of 5-(355-dimethylisoxazol-4-yl)-4-methoxy-2-nitrobenz-
aldehyde (2.0 g, 7.24 mmol) in EtOH (20 mL) was added sodium dithionate (7.46 g,
36.2 mmol) followed by stirring at 80 °C for 3 h. The mixture was filtered and
' washed with EtOAc and concentrated under reduced pressure. The residue was used
in the further step without purification (1.2 g). LC-MS: m/z 247.1 (M+H)+.
Step-iii: (6-(3,5-dimemylisoxazol-4-ylV2-ethoxv-7-methoxyquinolin-3-yO-
(phenvDmethanone (76.3')
To a solution of 2-amino-5-(3,5-dimethylisoxazol-4-yl)-4-methoxybenz-
aldehyde (1.0 g, 4.06 mmol) in EtOH (10 mL) was added ethyl 3-oxo-3-phenyl-
propanoate (1.56 mL, 8.13 mmol) and piperidine (0.04 mL, 0.41 mmol) followed by
refiuxing for 16 h. The mixture was concentrated under reduced pressure. The
residue was used further without purification (0.7 g, 43 %); LC-MS: m/z 402.8
(M+H)+.
Step-iv: 3-benzovl-6-(3.5-dirnethylisoxazol-4-yl)-7-methoxyquinolin-2(lH)-
one (76.4)
To a solution of (6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-7-methoxyquinolin-
3-yl)(phenyl)methanone (0.7 g, 1.74 mmol) in 1,4-dioxane (10 mL) was added 3 N •
HC1 (3 mL) followed by refiuxing for 16 h. The mixture was poured into saturated
NaHCC>3, extracted with EtOAc (100 mL), washed with water (100 mL) and brine
(100 mL), dried over sodium sulphate and concentrated under reduced pressure. The
residue was used further without purification (0.4 g).
Step-v: 3-benzoyl-6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-l-(pyridin-2-
ylmethyl)quinolin-2(lH)-one (76.5)
The process of this was adopted from step-e of intermediate-2. *H NMR (400
MHz, DMSO-d6) 5 8.89 (s, 1H), 8.54 (d, .7=4.9 Hz, 1H), 8.12 (s, 1H), 7.50-7.49 (m,
1H), 7.63-7.61 (m, 3H), 7.45-7.44 (m, 3H), 7.40-7.35 (m, 1H), 7.09 (d, J=7.9 Hz,

1H), 5.28 (s, 2H), 3.99 (s, 3H), 2.35 (s, 3H), 2.15 (s, 3H); LC-MS: m/z 466.2
(M+H)+.
Example-XII: 2-(6-(3,5-Dimethylisoxazol-4-yl)-7-methoxy-2-oxo-l-(pyridin-2-
ylmethyl)-l, 2-dihydroquinolin-3-yl) acetic acid (compound-77)

Step-i: (6-(3,5-Dimethvlisoxazol-4-vD-7-methoxv-2-oxo-1 -(pyridin-2-yl-
methvl)-l,2-dihydro quinolin-3-vl)methyl methanesulfonate (77.1)
The process of this step was adopted from step-a of intermediate-5.
Step-ii: 2-r6-n,5-Dirnethylisoxazol-4-yl')-7-methoxy-2-oxo-l-('pvridin-2-yl-
methvl)-1.2-dihvdro qumolin-3-yl')acetonitrile (77.2)
To a cooled solution of (6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-2-oxo-l-
(pyridm-2-ylmethyl)-l52-dihydroquinolm-3-yl)methylmethanesulfonate (1.08 g, 2.30
mmol) in DMF (10 mL) was added potassium cyanide (0.3 g, 4.60 mmol) followed
by stirring at RT for 16 h. The mixture was poured into ice water and extracted with
EtOAc (100 x 2), dried over sodium sulphate and concentrated under reduced
pressure. The residue was purified by silica gel (60-120 mesh) column
chromatography (elution 30-40 % EtOAc-hexane) to afford the title compound as off
white solid, (0.6 g). JHNMR (400 MHz, DMSO-d6) 5 8.51 (d, .7=3.9 Hz, 1H), 8.06
(s, 1H), 7.89-7.76 (m, 1H), 7.72 (s, 1H), 7.36 (d, >7.8 Hz, 1H), 7.32-7.29 (m, 1H),
7.14 (s, 1H), 5.71 (s, 2H), 3.89 (s, 2H), 3.75 (s, 3H), 2.26 (s, 3H), 2.07 (s, 3H); LC-
MS: m/z 401.1 (M+H)+.
Step-iii: 2-(6-(3,5-Dimethvlisoxazol-4-yl)-7-methoxy-2-oxo-l-(pyridin-2-
ylmethvl)-l,2-dihydro quinolin-3-yl)acetic acid (Compound-77)
A solution of 2-(6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-2-oxo-l-(pyridin-

heated at 100 °C for 6 h. The mixture was poured into saturated NaHCC>3 (pH~8),
acidified with citric acid solution, extracted with EtOAc (100 x 2), dried over sodium
sulphate and concentrated in vacuo. The residue was purified by silica gel (60-120
mesh) column chromatography (elution 2-4 % MeOH-DCM) to afford the title
compound as off white solid (0.1 g, 27 %). 'HNMR (400 MHz, DMSO-d6) 5 12.29
(bs, III), 8.53 (d, J=4.4 Hz, 1H), 7.86 (s, 1H), 7.80-7.75 (m, 1H), 7.60 (s, 1H), 7.32-
7.27 (m, 2H), 7.13 (s, 1H), 5.67 (s, 2H), 3.74 (s, 3H), 3.53 (s, 2H), 2.25 (s, 3H), 2.09
(s, 3H); LC-MS: m/z 420.2 (M+H)+.
The below compound was prepared by a procedure similar to the one
described in Example-XH by using intermediates 21 and 21a as starting compound in
the presence of suitable reagents and solvents at appropriate reaction conditions. The
physiochemical characteristic of the compound is also summarized.



Example-XHI: 2-(4-(6-(3,5-Dimethvlisoxazol-4-yl)-7-methoxy-2-oxo-1 -(pyridin-2-
ylmethyl)-1,2-dihydroquinolin-3 -yl)-1 H-pyrazol-1 -yl)-N-(2-hydroxyethyl)acetamide
(Compound-80) and 2-(4-(6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-2-oxo-1 -
(pyridin-2-ylmethyl) -1,2-dihydroquinolin-3 -yl)-1 H-pyrazol-1 -yl)acetic acid
(Compound-81)

Step-i: Ethyl 2-(4-(6-f3.5-dimemylisoxazol-4-vlV7-methoxy-2-oxo-l-
(pyridin-2-ylmethyD-l.2-dmydroquinolin-3-vl)-lH-pyrazol-l-yl)acetate C80.1)
The process of this step was adopted from step-e of intermediate-2. *H NMR
(400 MHz, DMSO-d6) 5 8.53-8.51 (m, 2H), 8.34 (s, 1H), 8.11 (s, 1H), 7.85-7.75 (m, .
1H), 7.60 (s, 1H), 736 (d, J=7.8 Hz, 1H), 7.35-7.25 (m, 1H), 7.15 (s, 1H), 5.76 (s,
2H), 5.13 (s, 2H), 4.74-4.16 (m, 2H), 3.76 (s, 3H), 2.27 (s, 3H), 2.08 (s, 3H), 1.25-
1.22 (m, 3H); LC-MS: m/z 514.2 (M+H)+.
Step-ii: 2-(4-(6-(3,5-Dimethylisoxazol-4-ylV7-methoxy-2-oxo-l-('pyridiri-2-
ylmethyl)-1,2-dihydroquinolin-3 -yl)-1 H-pyrazol-1 -vll-N-f 2-hydroxyethyDacetamide
(compound-80)
A solution of ethyl 2-(4-(6-(3, 5-dimethylisoxazol-4-yl)-7-methoxy-2-oxo-l-
(pyridin-2-ylmethyl)-l,2-dihydroquinolin-3-yl)-lH-pyrazol-l-yl)acetate (0.06 g) in2-
aminoethane-1-ol (0.5 mL) in a sealed tube was heated at 90 °C for 4 h. The mixture
was poured into crushed ice, the solids were filtered, washed thoroughly with water,
and dried under reduced pressure to afford the title compound as off white solid (0.02

1H), 8.20-8.10 (m, 1H), 8.06 (s, 1H), 7.85-7.75 (m, 1H), 7.58 (s, 1H), 7.40-7.20 (m,
2H), 7.13 (s, 1H), 5.74 (s, 2H), 4.83 (s, 2H), 4.80-4.73 (m, 1H), 3.74 (s, 3H), 3.41-
3.40 (m, 2H), 3.15-3.14 (m, 2H), 2.25 (s, 3H), 2.06 (s, 3H); LC-MS: m/z 529.4
(M+H)+.
Step-iii: 2-(4-r6-(,3,5-Dimethvlisoxazol-4-vlV7-methoxv-2-oxo-l-fpyridm-2-
ylmethyl)-1,2-dihydroquinulin-3 -yl)-1 H-pyrazol-1 -vQacetic acid (Compound-81)
To a solution of ethyl 2-(4-(6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-2-oxo-
1 -(pyridin-2-ylmethyl)-1,2-dihydroquinolin-3 -yl)-1 H-pyrazol-1 -yl)acetate (0.1 g, 0.19
mmol) in MeOH (4 mL) were added sodium hydroxide (0.02g, 0.39 mmol) in water
(lmL) followed by stirring at RT for lh. The mixture was concentrated to remove
methanol, diluted with water, acidified with IN HC1 and then extracted with EtOAc .
(50 ml). The organic layer was washed with brine (50 mL), dried over sodium
sulphate and concentrated under reduced pressure. The obtained solid was washed
with diethyl ether and EtOAc and filtered off to afford the title product as brown
solid (0.08 g, 85 %). *H NMR (400 MHz, DMSO-d6): 5 13.08 (bs, 1H), 8.53 (d,
J=4.4 Hz; 1H), 8.49 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 7.79-7.74 (m, 1H), 7.60 (s,
1H), 7.36 (d, 7=7.8 Hz, 1H), 7.31-7.28 (m, lH),7.15(s, 1H), 5.76 (d, J=1.9Hz, 2H),
5.03(s, 2H), 3.76 (s, 3H), 2.27 (s, 3H), 2.08 (s, 3H); LC-MS: m/z 486.2 (M+H)+.
Example-XTV: 6-(3,5-Dimethvlisoxazol-4-vl)-7-methoxv-2-oxo-N-rpvridin-2-vn-1 -
(pyridin-2-ylmethyl)-l ,2-dihydroquinoline-3 -sulfonamide (Compound-82)

Step-i: 6-(3,5-Dimethylisoxazol-4-vl)-7-methoxy-2-oxo-l-(pvridin-2-yl-
methyl)-1.2-dihydro quinoline-3-sulfonyl chloride (82.1)
A solution of 6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-l-(pyridin-2-yl-
methyl)quinolin-2(lH)-one (intermediate-22) (0.3 g) in chlorosulfonic acid (3 mL)
was heated at 70 °C for 2 h. The mixture was poured into crushed ice, solids were

compound as brown solid (O.lg). !H NMR (400 MHz, DMSO-d6) 5 8.78 (d, J=5.4
Hz, 1H), 8.39 (s, 1H), 8.20-8.16 (m, 1H), 7.80 (s, 1H), 7.72-7.68 (m, 1H), 7.51 (d,
J=7.9 Hz, 1H), 7.10 (s, 1H), 5.78 (s, 2H), 3.80 (s, 3H), 2.27 (s, 3H), 2.09 (s, 3H); LC-
MS:m/z 459.8 (M+H)+.
Step-ii: 6-r3.5-Dimethvlisoxazol-4-ylV7-methoxy-2-oxo-N-rpyridin-2-yn-l-
(pyiidin-2-ylmethyl) -1,2-dihydroquinoline-3-sulfonamide (Compound-82)
To a cold solution of 6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-2-oxo-l-
(pyridin-2-ylmethyl)-l,2-dihydroquinoline-3-sulfonyl chloride (O.lg, 0.22 mmol) in
DCM (2 mL) were added triethyl amine (0.09 mL, 0.65 mmol) and 2-amino pyridine
(0.03 g, 0.33 mmol) followed by stirring at RT for 3 h. The mixture was diluted with
DCM (50 ml), washed with water (50 mL) and brine (50 mL), dried over sodium
sulphate and concentrated under reduced pressure. The residue was purified on
preparative TLC plate to afford the title product as brown solid (0.006 g, 5 %). *H
NMR (400 MHz, DMSO-d6): 5 8.76 (s, 1H) 8.50-8.48 (m, 1H), 8.06-8.04 (m, 1H),
7.96-7.90 (m, 2H), 7.77-7.69 (m, 2H), 7.33-7.30 (m, 1H), 7.23-7.21 (m, 1H), 7.1 l(s,
1H), 7.69 (d, J=7.4 Hz, 1H), 6.87-6.85 (m, 1H), 5.65 (s, 2H), 3.83 (s, 3H), 2.27 (s,
3H), 2.09 (s, 3H); LC-MS: m/z 518.5 (M+H)+.
Example-XV: 6-(3,5-Dimethylisoxazol-4-yl)-3-(6-hydroxy-lH-benzo[d] imidazol-2-
yl)-7-memoxy-l-(pyridin-2-ylmemyl)quinolin-2(lH)-one (Compound-83)

To a stirred solution of 6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-2-oxo-l-
(pyridin-2-ylmemyl)-l,2-dihydroquinoline-3-carbaldehyde (intermediate-le) (0.1 g,
0.25 mmol) in acetic acid (5 mL) was added 3,4-diaminophenol (0.04 g, 0.3 mmol)
followed by heating to reflux for 16h. The mixture was concentrated to remove acetic
acid. The residue was diluted with EtOAc and washed with water (50 mL), saturated
NaHC03 (50 ml) and brine (50 mL), dried over sodium sulphate and concentrated
under, reduced pressure. The residue was purified by preparative TLC to afford the

title compound as a brown solid (0.01 g, 8 %). !H NMR (400 MHz, DMSO-d6) 5
12.14-12.33 (m, 1H), 9.17-9.0 (m, 2H), 8.53 (d, 7=4.9 Hz, 1H), 7.94 (s, 1H), 7.81 (t,
.7=7.4 Hz, 1H), 7.47-7.40 (m, 2H), 7.33-7.30 (m, 1H), 7.23 (s, 1H), 7.04-6.95 (m,
1H), 6.69 (d, J=8.3 Hz, 1H), 5.85 (s, 2H), 3.82 (s, 3H), 2.30 (s, 3H), 2.11 (s, 3H);
LC-MS: m/z 494.2 (M+H)+.
Example-XVI: 3-(Azetidine-1 -carbonyl)-1 -(4-chlorobenzyl)-6-(3,5-dimethyl
isoxazol-4-yl)-7-methoxyquinolin-2(lH)-one (Compound-84)

Step-i: 3-(Azetidine-l-carbonvlV6-bromo-l-(4-chlorobenzyl')-7-methoxy-
quinolin-2(TH>one f84.n
The process of this step was adopted from step-e of intermediate-2. lH NMR
(400 MHz, DMSO-d6): 8 8.12 (d, J=2.9 Hz, 2H), 7.39 (d, 7=8.3 Hz, 2H), 7.30 (d,
7=9.7 Hz, 2H), 6.95 (s, 1H), 5.75 (s, 2H), 4.07-3.99 (m, 4H), 3.85 (s, 3H), 2.23 (t,
J=7.8 Hz, 2H); LC-MS: m/z 463.0 (M+2H)2+.
Step-ii: 3-rAzetidine-l-carbonylVl-(4-chlorobenzylV6-(3,5-dimethyl-
isoxazol-4-yl)-7-methoxy quinolin-2('lH^-one (compound 84^
The process of this step was adopted from step-a of intermediate-2 .*H NMR.
(400 MHz, DMSO-cfe): 5 8.13 (s, 1H), 7.72 (s, 1H), 7.41-7.35 (m, 4H), 6.96 (s, 1H),
5.60 (s, 2H), 4.06 (t, J=7.4 Hz, 2H), 4.0 (t, J=7.4 Hz, 2H), 3.76 (s, 3H), 2.26-2.18 (m,
2H), 2.26 (s, 3H), 2.04 (s, 3H); LC-MS: m/z 478.2 (M+H)+.
The below compounds were prepared by a procedure similar to the one
described in Example-XVI by using intermediate-18 as starting compound and
reacting with appropriate reactants B in the presence of suitable reagents, catalysts
and solvents at appropriate reaction conditions. The physiochemical characteristics of
the compounds are also summarized.

Example-XVTI: 6-(3,5-Dimethylisoxazol-4-yl')-N-(4-hvdroxy-3,5-dimethvlphenvl')-
7-methoxy-N-methyl-2-oxo-1 -(pyridin-2-ylmethyl)-1,2-dihydroquinoline-3 -
carboxamide (Componnd-98)

Step4:N-f4-(ftert-butvldimetfaylsilvnoxvV3.5-dimetfavlphenvlV6-f3.S-di-
methylisoxazol-4-vlV7-methoxv-N-methvl-2-oxo-1 -(pyridin-2-ylmethvlV 1,2-di-
hvdroquinoline-3-carboxamide (98.1)
To a cooled solution of N-(4-((tert-butyldimethylsilyl)oxy)-3,5-dimethyl-
phenyl)-6-(3,5 -dimethylisoxazol-4-yl)-7-methoxy-2-oxo-1 -(pyridin-2-ylmethyl)-1,2-
dihydroquinoline-3-carboxamide (TBS protected Compound-55 from Example-IV)
(0.1 g, 0.156 rnrnol) in THF (20 mL) were added sodium hydride (60 %) (0.007 g,
0.187 mmol) and methyl iodide (0.05 mL, 0.78 mmol) followed by stirring at RT for
6 h. The mixture was quenched with ice water and extracted with EtOAc (50 mL x
2). The combined organic layers were washed with water (50 mL) and brine (50 mL),

title compound (0.07g). *H NMR (400 MHz, CDC13) 5 8.52 (d, .7=4.4 Hz, 1H), 7.59-
7.50 (m, 2H), 7.18-7.15 (m, 2H), 7.08 (s, 1H), 6.90 (s, 2H), 6.95-6.90 (m, 1H), 5.60-
5.55 (m, 2H), 3.76 (s, 3H), 3.45 (s, 3H), 2.23 (s, 3H), 2.09 (s, 3H), 2.06 (s, 6H), 0.92
(s, 9H), 0.12 (s, 6H); LC-MS: m/z 653.2 (M+H)+.
Step-ii: 6-(3,5-dimethvlisoxazol-4-ylVN-r4-hvdroxy-3,5-dimethylphenylV7-
methoxv-N-methyl-2-oxo-1 -fpvridin-2-ylmethylV1,2-dihydroquinoline-3 -
carboxamide ('Compound-98')
To a cooled solution of step-(i) compound (98.1) (0.07 g, 0.107 mmol) in
THF (3 mL) was added tetra butyl ammonium fluoride 1.0 M in THF (0.16 ml)
followed by stirring at RT for 2 h. The mixture was quenched with saturated NH4CI
and extracted with EtOAc (50 mL), washed with water (50 mL), dried over sodium
sulphate and concentrated under reduced pressure. The residue was purified by
column chromatography (60-120 silica gel and 2 % MeOH in DCM as eluent) to
afford the title compound (0.025 g). *H NMR (400 MHz, DMSO-d6): 5 8.52 (d,
7=4.9 Hz, 1H), 8.05 (s, 1H), 7.80 (bs, 1H), 7.69-7.60 (m, 1H), 7.52 (s, 1H), 7.30 (t,
J=7.5 Hz, 1H), 7.07 (s, 1H), 6.85 (s, 3H), 5.53 (s, 2H), 3.73 (s, 3H), 3.27 (s, 3H),
2.32 (s, 3H), 2.04 (s, 9H); LC-MS: m/z 539.2 (M+H)+.
Example-XVIII: 6-(3,5-Dimethvlisoxazol-4-vl)-3-((5-hvdroxyindorin-l-vl)methvl)-
7-methoxy-l -(pyridin-2-ylmethyl)quinolin-2(lH)-one (Compound-99)

To a stirred solution of 6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-2-oxo-l-
(pyridin-2-ylmethyl)-l,2-dihydroquinoline-3-carbaldehyde (intermediate-le) (0.2 g,
0.51 mmol) in titanium isopropoxide (5 mL) was added indolin-5-ol (0.1 g, 0.77
mmol) followed by stirring at RT for 16 h. After stirring, methanol (20 mL) was
added to the mixture at 0 °C followed by NaCNBBU (0.16 g, 2.56 mmol). The
mixture was stirred at RT for 2 h. The mixture was then quenched with ammonium
hydroxide and the solids were filtered off. The filtrate was extracted with EtOAc

sulphate and concentrated under reduced pressure. The residue was purified to get the
title compound as pale brown solid (0.016 g, 6 %). *H NMR (400 MHz, CDC13) 5
8.60 (d, J=4.8 Hz, 1H), 7.86 (s, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H),
7.27 (s, 1H), 7.23-7.20 (m, 2H), 6.69 (s, 1H), 6.60-6.48 (m, 2H), 5.74 (s, 2H), 4.29
(s, 2H), 3.79 (s, 3H), 3.61-3.59 (m, 2H), 3.10-3.00 (m, 2H), 2.25 (s, 3H), 2.11 (s,
311); LC-MS: m/z 509.3 (M+H)+.
Example-XIX: 3-((lH-Tetrazol-5-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-7-
methoxy-1 -(pyridin-2-ylmethyl)quinolin-2( 1 H)-one (Compound-100)

To a solution of 2-(6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-2-oxo-l-
(pyridm-2-ymiethyl)-l,2-dmydroquinolin-3-yl)acetonitrile (compound-77.2) (0.05 g,
0.12 mmol) in DMF (1 mL) was added sodium azide (0.024 g, 0.37 mmol) and
ammonium chloride (0.02 g, 0.37) portion wise followed by stirring at 120 °C for 16
h. The mixture was diluted with EtOAc (50 mL) and washed with water. The organic
layer was dried over Na2SC>4, concentrated under reduced pressure and column
purified to obtain the title compound as greenish solid (0.015 g, 14 %).1H NMR (400
MHz, DMSO-de) 5 16.5 (bs, 1H), 8.52 (d, J=4.4 Hz, 1H), 7.89 (s, 1H), 7.78-7.75
(m,lH), 7.62 (s, 1H), 7.30 (d, J=7.4 Hz, 2H), 7.13 (s, 1H), 5.66 (s, 2H), 4.20 (s, 2H),
3.74 (s, 3H), 2.24 (s, 3H), 2.05 (s, 3H); LC-MS: m/z 444.2 (M+H).
Example-XX: 2-(6-(3,5-Dimethylisoxazol-4-yl)-7-methoxy-2-oxo-1 -(pyridin-2-
ylmethyl)-l,2-dihydroquinolin-3-yl)-2-methylpropanoic acid (Compound-101)


Step-i: 2-r6-(3,5-Dimethvlisoxa2ol-4-vlV7-methoxy-2-oxo-l-('pyridiii-2-
ylmethvD-1,2-dihydroquinolin-3 -vl)-2-methvlpropanenitrile (101.1)
To a cold suspension of sodium hydride (0.03 g, 0.75) in THF (4 mL) was
added slowly 2-(6-(3,5-dimethylisoxazol-4-yi)-7-methoxy-2-oxo-1 -(pyridin-2-yl-
methyl)-l,2-dihydroquinolin-3-yl)acetonitrile (compound-77.2) (0.1 g, 0.25 mmol) in
THF (1 mL) followed by stirring for 10 min. Methyl iodide (0.03mL, 0.5 mmol) was
then added followed by stirring at RT for 16 h. The mixture was quenched with ice
water and extracted with EtOAc (50 mL). The organic layer was dried over Na2SC>4,
concentrated under reduced pressure and column purified to afford the title
compound as white solid (0.06 g, 56 %). *H NMR (400 MHz, DMSO-de) 5 8.52 (d,
J=4.0 Hz, 1H), 8.04 (s, 1H), 7.82-7.77 (m, 1H), 7.71 (s, 1H), 7.34-7.29 (m, 2H), 7.13
(s, 1H), 5.71 (s, 2H), 3.75 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H), 1.75 (s, 6H); LC-MS:
m/z 429.2 (M+H)+.
Step-ii: 2-f6-f3.5-Dimemylisoxazol-4-yl)-7-memoxy-2-oxo-l-(pyridin-2-
vlmethvlV1.2-dihydro quinolin-3-vlV2-methylpropanoic acid (101)
The process of this step was adopted from step-iii of Example-XII. !H NMR
(400 MHz, DMSO-de) 5 11.9 (bs, 1H), 8.54 (d, J=4.4 Hz, 1H), 7.85 (s, 1H), 7.77-
7.73 (m, 1H), 7.64 (s, 1H), 7.31-7.28 (m, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.11 (s, 1H),
5.65 (s, 2H), 3.74 (s, 3H), 2.25 (s, 3H), 2.05 (s, 3H), 1.46 (s, 6H); LC-MS: m/z 448.3
(M+H)+.
The below compound was prepared by a procedure similar to the one
described in Example-XX by using appropriate starting compound (prepared
according to Example-XII (step-ii)) and in the presence of suitable reagents and
solvents at appropriate reaction conditions. The physiochemical characteristics of the
compounds are also summarized.



Example-XXI: 3-(Azetidme-l-carbonylH-(2-(4-cMorophenyl)-2-oxoethyr)-6-(3,5-
dimethylisoxazol-4-yl)-7-methoxyquinolin-2(lH)-one(Compound-103)

To a solution of 3-(azetidine-l-carbonyl)-l-(2-(4-chlorophenyl)-2-hydroxy-
ethyl)-6-(3,5-dimethylisoxazol-4-yl)-7-methoxyquinolin-2(lH)-one (0.2 g, 0.39
mmol) in 1,4-dioxane (5 mL) was added manganese dioxide (0.1 g, 1.18 mmol),
followed by stirring at 110 °C for 3 h. The mixture cooled to RT, filtered-on celite
bed and washed with EtOAc (50 mL). The combined organic layer was concentrated
under reduced pressure and purified by combiflash to afford the title compound as
white solid (0.015 g, 7 %).JH NMR (400 MHz, DMSO-de): 5 8.18 (d, J=8.4 Hz, 2H),
8.17 (s, 1H), 7.77 (s, 1H), 7.72 (d, .7=8.8 Hz, 2H), 7.02 (s, 1H), 5.96 (s, 2H), 3.97 (t,
J=7.8 Hz, 4H), 3.81 (s, 3H), 2.28 (s, 3H), 2.23-2.16 (m, 2H), 2.09 (s, 3H); LC-MS:
m/z 506.2 (M+H).
Example-XXII:6-("3,5-Dimethvlisoxazol-4-vl)-N-(4,6-dimethvlpyridin-2-vlV7-
methoxy-2-oxo-1 -(pyridin-2-ylmethyl)-1,2-dihydroquinoline-3 -carboxamide hydro-
chloride (Compound-104)


To a solution of 6-(3,5-dimethylisoxazol-4-yl)-N-(4,6-dimethylpyridin-2-yl)-
7-methoxy-2-oxo-l-(pyridin-2-ylmethyl)-l,2-dihyo!roquinoline-3-carboxamide(0.08
g, 0.16 mmol) in methanol (4 mL) was added 6 N HC1 (1.5 mL) followed by stirring
at RT for 3 h. The mixture was concentrated under reduced pressure to afford the title
compound as yellow solid (0.06 g, 75 %)}n NMR (400 MHz, DMSO-d6): 6 12.45
(s, 1H), 9.07 (s, 1H), 8.64 (d, J= 4.9 Hz, 1H), 8.10 (s, 1H), 8.09 (s, 1H), 8.02 (t, J=
7.4 Hz, 1H), 7.59 (d, J= 7.8 Hz, 1H), 7.53 (t, J= 6A Hz, 1H), 7.27 (s, 1H), 7.05 (s,
1H), 5.94 (s, 2H), 3.87 (s, 3H), 2.44 (s, 3H), 2.39 (s, 3H), 2.29 (s, 3H), 2.10 (s, 3H);
LCMSrWz 510.3 (M+H)+.
Example-XXIH: 3-(6-Arnmopyridin-3-vl')-6-(3,5-dimethvlisoxazol-4-vlV7-
memoxy-l-(pyridm-2-ylmemyl)quinolin-2(lH)-one (Compound 105)

Step-i: tert-Butyl (5-(6-n,5-dimethvlisoxazol-4-ylV7-methoxv-2-oxo-l-
(pyridin-2-vlmethvl)-1,2-dihydroquinolin-3 -vDpyridin-2-vl)carbamate
To a solution of 3-bromo-6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-l-
(pyridin-2-ylmethyl)quinolin-2(lH)-one (0.05 g, 0.11 mmol) in 1,2-DME (8 mL) and
H2O (2 mL) were added tert-butyl (5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-
pyridin-2-yl)carbamate (0.054 g, 0.17 mmol) and sodium carbonate (0.04 g, 0.34
mmol). The mixture was degassed with nitrogen purging for 20 min. Then tetrakis
triphenylphosphine palladium (0.013 g, 0.011 mmol) was added followed by heating
at 90 °C for 16 h. The mixture was diluted with EtOAc (50 mL), washed with water
(50 mL) and brine (50 mL), dried over sodium sulphate and concentrated under

reduced pressure. The residue was purified by combi flash to afford the title
compound as a pale yellow solid (0.05 g); LC-MS: m/z 554.3 (M+H).
Step-ii: 3-(6-Ammopvridin-3-ylV6-r3,5-dirnethvlisoxazol-4-vlV7-rnethoxy-l-
(pyridin-2-ylmethyl)quinolin-2( 1 HVone
To a solution of tert-butyl (5-(6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-2-
oxo-l-(pyridin-2-ylmemyl)-l,2-dUiychoqiunolin-3-yl)pyridin-2-yl)carbamate (0.05 g,
0.09 mmol) in DCM (5 mL) was added TFA (0.07 mL, 0.9 rnmol) followed by
stirring at RT for 3 h. The mixture was concentrated and the residue was diluted with
EtOAc, washed with aqueous NaHCC>3, dried over sodium sulphate, concentrated
under reduced pressure and purified by combi flash to afford title compound as off
white solid (0.02 g, 50 %). *H NMR (400 MHz, DMSO-d6) 5 8.52 (d, .7=3.9Hz, 1H),
8.34 (d, .7=1.9 Hz, 1H), 8.04 (s, 1H), 7.83 - 7.76 (m, 2H), 7.64 (s, 1H), 7.35 (d, J=7.9
Hz, 1H), 7.32 - 7.29 (m, 1H), 7.12 (s, 1H), 6.49 (d, J=8.8 Hz, 1H), 6.09 (s, 2H), 5.72
(s, 2H), 3.75 (s, 3H), 2.26 (s, 3H), 2.07 (s, 3H); LC-MS: m/z 454.2 (M+H).
Example-XXTV: N-f6-amino-5-memvlpvridm-3-yl)-6-(3,5-dimethvlisoxazol-
4-yl)-7-methoxy-2-oxo-1 -(pyridin-2-ylmethyl)-1,2-dihydroquinoline-3 -carboxamide
(Compound 106)
Step-i: Compound 1U6.1
To a solution of 6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-2-oxo-l-(pyridin-2-
ylmethyl)-l,2-dihydroquinoline-3-carboxylic acid (0.15 g, 0.37 mmol) in DMF (4
mL) were added Intermediate-23 (0.18 g, 0.55 mmol), HOBt (0.15 g, 1.11 mmol),
EDC.HC1 (0.21 g, 1.11 mmol) andtriethyl amine (0.15 mL, 1.11 mmol) followed by
stirring at RT for 16 h. The mixture was diluted with EtOAc (50 mL), washed with
water (50 mL) and brine (50 mL), dried over sodium sulphate, concentrated under
reduced pressure and purified by combi flash to afford the title compound as yellow
solid (0.17 g, 65 %); *H NMR (400 MHz, DMSO-d6): 5 12.13 (s, 1H), 9.04 (s, 1H),
8.70 (d, J=2.5 Hz, 1H), 8.52 (d, J=4.9 Hz, 1H), 8.18 (d, J=2.4 Hz, 1H), 8.04 (s, 1H),

7.83-7:79 (m, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.34-7.31 (m, 1H), 7.24 (s, 1H), 5.85 (s,
2H), 3.83 (s, 3H), 2.29 (s, 3H), 2.17 (s, 3H), 2.10 (s, 3H), 1.35 (s, 18H).
Step-ii: N-(6-amino-5-methvlpyridin-3-ylV6-n,5-dimethylisoxa2ol-4-ylV7-
methoxy-2-oxo-1 -(pyridin-2-ylmethyl)-1,2-dihydroquinoline-3 -carboxamide
(Compound 106)
To a cold solution of Compound 106.1 (0.17 g, 0.24 mmol) in DCM (5 mL)
was added TFA (0.5 mL) followed by stirring at RT for 4 h. The mixture was
concentrated, diluted with DCM and washed with aqueous NaHCCb. The organic
layer was dried over sodium sulphate and concentrated. The residue was purified by
combi flash to afford the title compound as yellow solid (0.045 g, 38 %). JH NMR
(400 MHz, DMSO-d6): 5 11.62 (s, 1H), 8.97 (s, 1H), 8.51 (d, .7=4.4 Hz, 1H), 8.19 (d,
J=2.5 Hz, 1H), 8.01 (s, 1H), 7.83-7.78 (m, 1H), 7.64 (d, .7=2.0 Hz, 1H), 7.46 (d,
.7=7.8 Hz, 1H), 7.33-7.30 (m, 1H ), 7.22 (s, 1H), 5.83 (s, 2H), 5.65 (s, 2H), 3.81 (s,
3H), 2.28 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H); LC-MS: m/z 511.2 (M+H).
Example-XXV:6-(3,5-Dimemvlisoxazol-4-vl)-3-(r2.6-dimethvbvridin-4-
yl)arru^o)-7-methoxy-l-(pyridin-2-ylmethyl)quinolin-2(lH)-one (Compound 107)

To a solution of 3-bromo-6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-l-
(pyridin-2-ylmethyl)quinolin-2(lH)-one (0.15 g, 0.34 mmol) in 1,4-dioxane (6 mL)
were added 2,6-dimethylpyridin-4-amine (0.062 g, 0.51 mmol) and cesium carbonate
(0.33 g, 1.02 mmol). The mixture was degassed with nitrogen purging for 15 min.
Then tris(dibenzylideneacetone)di palladium (O) (0.031 g, 0.034 mmol) and xantphos
(0.010 g, 0.017 mmol) were added followed by heating at 100 °C for 16 h. The
mixture was diluted with EtOAc (50 mL), washed with water (50 mL) and brine (50
mL), dried over sodium sulphate, concentrated under reduced pressure and purified
by combi flash to afford the title compound as pale yellow solid (0.05 g, 37 %).lH
NMR (400 MHz, DMSO-d6) 5 8.51 (d, J= 4.4 Hz, 1H), 8.32 (bs, 1H), 7.83 (s, 1H),

1H), 6.94 (s, 2H), 5.76 (s, 2H), 3.73 (s, 3H), 2.34 (s, 6H), 2.26 (s, 3H), 2.07 (s, 3H);
LC-MS: m/z 482.3 (M+H).
Example-XXVI: 3-(6-Amino-5-methylpyridiii-3-vl)-6-('3,5-dimethvl-
isoxazol-4-yl)-7-methoxy-1 -(pyridin-2-ylmethyl)quinolin-2( 1 H)-one (Compound
108)

Step-i: tert-Butyl (5-(6-f 3,5-dimethylisoxazol-4-yl)-7-methoxy-2-oxo-1 -
rpyridin-2-vlmethylV 1,2-dihydroquinolin-3 -yl)-3 -methylpyridin-2-yl)carbamate
To a solution of 3-bromo-6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-l-
(pyridha-2-ylmethyl)quinolin-2(lH)-one (0.12 g, 0.27 mmol) in 1,4-dioxane (6 mL)
and H20 (2 mL) were added tert-butyl (3-memyl-5-(4,4,5,5-tetramethyl-l,3,2-
dioxaborolan-2-yl)pyridin-2-yl)carbamate (0.13 g, 0.40 mmol) and sodium carbonate
(0.086 g, 0.81 mmol) followed by degassing with nitrogen purging for 20 min. Then
tetrakis triphenylphosphine palladium (0.031 g, 0.027 mmol) was added followed by
heating at 90 °C for 16 h. The mixture was diluted with EtOAc (50 mL), washed with
water (50 mL) and brine (50 mL), dried over sodium sulphate, concentrated under
reduced pressure and purified by combi flash to afford the title compound as a pale
yellow gummy mass (0.09 g, 58 % ). *H NMR (400 MHz, DMSO-d6): 8 8.68 (d,
J=1.5 Hz, 1H), 8.54 (d, .7=4.4 Hz, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 7.80-7.77 (m, 1H),
7.71 (s, 1H), 7.41 (d, 7=7.4 Hz, 2H), 7.33-7.29 (m, 1H ), 7.16 (s, 1H), 5.75 (s, 2H),
3.78 (s, 3H), 2.27 (s, 3H), 2.21 (s, 3H), 2.08 (s, 3H), 1.39 (s, 9H).
Step-ii: 3-(6-Ammo-5-memylpyridin-3-vl')-6-n.5-dimethvlisoxazol-4-yl)-7-
methoxy-l-(pyridin-2-ylmethyl)quinolin-2riH)-one
To a cold solution of tert-butyl (5-(6-(3,5-dimethylisoxazol-4-yl)-7-methoxy-
2-oxo-1 -(pyridin-2-ylmethyl)-1,2-dihydroquinolin-3 -yl)-3 -methylpyridin-2-yl)-
carbamate (0.09 g, 0.158 mmol) in DCM (5 mL) was added TFA (2 mL) followed by
stirring at RT for 4 h. The mixture was concentrated and the residue was diluted with

under reduced pressure and purified by combi flash to afford the title compound as
white solid (0.02 g, 27 %). *H NMR (400 MHz, DMSO-d6): 8 8.53 (d, J=4A Hz,
1H), 8.24 (d, .7=1.9 Hz, 1H), 8.04 (s, 1H), 7.79-7.75 (m, 1H), 7.69 (s, 1H), 7.64 (s,
1H), 7.35 (d, J=7.8 Hz, 1H), 7.31-7.28 (m, 1H), 7.12 (s, 1H), 5.89 (s, 2H), 5.71 (s,
2H), 3.75 (s, 3H), 2.26 (s, 3H), 2.10 (s, 3H), 2.07 (s, 3H); LC-MS: m/z 468.2 (M+H).
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 BRD4 bromodomain and prevent its interaction with acetylated
histone peptides (Chung, C. et aL, J. Med. Chern., 54, 3827-3838, 2011).
In the assay, optimized concentration of in-house Bet BRD4 bromodomain
protein and 300 nM of acetyl histone peptide substrate were diluted in assay buffer
(50 mM HEPES, pH: 7.5, 50 mM NaCl, 500 uM 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 RT for 30 min. Stock solutions of test compounds at 20 mM DMSO were
prepared. Compounds were serially diluted and added to the test wells in 384-well
polypropylene plates. The reaction mixture was further incubated for 30 min at RT
on a plate shaker. 2 nM of Europium labeled streptavidin and 10 nM of XL-665
labeled antibody diluted in detection buffer (50 mM HEPES, pH: 7.5, 50 mM NaCl,
500 uM CHAPS and 800 mM KF) were added to all the wells excluding the buffer
blank wells. The reaction plate was incubated for additional 30 min at RT 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 665 nm energy transfer signal to 615 nm
signals. The IC50 of the compounds was determined by fitting the dose response data

The compounds were screened in the above mentioned assay and the results
(IC50) are summarized in the table below. The IC50 values of the compounds are set
forth in below Table wherein "A" refers to an IC50 value of less than 600 nM, "B"
refers to IC50 value in range of 600.01 to 1000 nM and "C" refers to IC50 value of in
the range of 1000.01 to 10000 nM.


Claims
1. A compound of formula (I)

wherein,
Cy1 is an optionally substituted 5-6 membered monocyclic heterocyclyl ring
containing 1-3 hetero atoms independently selected from N or O, which ring is
optionally substituted by 1-3 C1-7 alkyl groups;
Cy2 is an optionally substituted aryl, optionally substituted C3.10 cycloalkyl or
optionally substituted 5-12 membered monocyclic or bicyclic heterocyclyl ring
containing 1-3 hetero atoms independently selected from N, O or S; wherein the
optional substitution at each occurrence is, independently, selected from 1-3
substituents selected from C1-7 alkyl, C1-7 alkoxy, halogen and -C(O)C1-7 alkyl;
L1 is-(CR3R3a)n;
R1 is C1-7 alkyl or halo C1-7 alkyl;
R2 is an optionally substituted aryl, optionally substituted aryl C1-7 alkyl,
optionally substituted heterocyclyl, optionally substituted heterocyclyl C1-7 alkyl,
-N(Ra)Rb, -(CH2)mC(O)Ra1, -(CH2)m1C(O)ORa2, -(CH2)m2C(O)N(Ra3)Rb1,
-CH(CF3)Rd, -S(O)2N(Ra4)Rb2, -(CRa5Rb3)m3C(O)ORa6, -CH(CF3)ORc and
-CH(CF3)N(Ra7)Rb4, wherein the optional substitution at each occurrence is,
independently, selected from 1-3 substituents selected from C1-7 alkyl, halo C1-7 alkyl,
-NHC(O)C1-7 alkyl, amino, halogen, hydroxy, oxo, hydroxy C1-7 alkyl, aryl,
-N(H)C(O)C1-7 alkyl, -(CH2)m4C(O)OH or -(CH2)m5C(O)NH(hydroxy C1-7 alkyl);
Ra, Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, Ra7, Rb, RB1, Rb2, Rb3 and Rb4 are independently
selected from hydrogen, C1-7 alkyl, hydroxy, C1-7 alkoxy, hydroxy C1-7 alkyl, halo C1-7
alkyl, -S(O)2C1-7 alkyl, optionally substituted aryl, optionally substituted C3.10 cyclo-
alkyl, optionally substituted heterocyclyl or optionally substituted heterocyclyl C1-7

alkyl; wherein the optional substitution at each occurrence is independently selected
from 1-3 substituents selected from C1-7 alkyl, halogen, hydroxy, hydroxy C1-7 alkyl,
C1-7 alkoxy, cyano, halo C4-7 alkyl and amino;
Rc is selected from C1-7 alkyl or aryl wherein aryl is optionally substituted by
1-3 halogen atoms;
Rd is selected from optionally substituted heterocyclyl or optionally
substituted aryl, wherein the optional substitution at each occurrence is independently
selected from 1-3 substituents selected from C1-7 alkyl and halogen;
R3 and R3a independently are selected from hydrogen, C1-7 alkyl, hydroxy and
halogen, or alternatively R3 and R3a together with the carbon atom to which they are
attached form a carbonyl (C=O) group;
m, m1, m2, 1113,1114 andms are, independently, an integer selected from 0, 1 or
2; and
n is an integer selected from 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein Cy1 is 3,5-dimethylisoxazole.
3. A compound according to claim 1 or 2, wherein R1 is C1-7 alkyl.
4. A compound according to claim 3, wherein R1 is methyl.
5. A compound according to any of claims 1 to 4, wherein Cy2 is a 5-12
membered monocyclic or bicyclic ring containing 0-2 hetero atoms independently
selected from N and O, which ring is optionally substituted by 1-3 substituents
selected from C1-7 alkyl, C1-7 alkoxy, halogen and -C(O)C1-7 alkyl.
6. A compound according to claim 5, wherein Cy2 is selected from optionally
substituted pyridyl, optionally substituted phenyl, cyclohexyl, morpholinyl,
optionally substituted piperazinyl or optionally substituted chromanyl; wherein the
optional substitution at each occurrence is independently selected from 1-3
substituents selected from C1-7 alkyl, C1-7 alkoxy, halogen and -C(O)C1-7 alkyl.

7. A compound according to claim 5 or 6, wherein Cy2 is optionally,
substituted by 1-2 substituents selected from C1-7 alkoxy and halogen.
8. A compound according to claim 6 or 7, wherein Cy2 is selected from
optionally substituted pyridyl or optionally substituted phenyl, wherein the optional
substitution at each occurrence is independently selected from 1-2 substituents
selected from C1-7 alkoxy and halogen.
9. A compound according to any of claims 1 to 8, wherein L1 is -CH2-,
-(CH2)2-, -CH2CH(OH)-, -CH2CH(CH3)- or -CH2C(O)-, wherein the left bond is
attached to the quinolin-2(lH)-one ring of formula (I).

10. A compound according to any of claims 1 to 9, wherein R2 is an
optionally substituted 5-12 membered monocyclic or bicyclic ring containing 0-4
hetero atoms independently selected from N and O, which ring is optionally
substituted by 1-3 substituents selected from C1-7 alkyl, halogen, amino, hydroxy,
-NHC(O)C1-7 alkyl, halo C1-7 alkyl, phenyl, oxo, hydroxy C1-7 alkyl,
-(CH2)m5C(O)NH(hydroxy C1-7 alkyl) or -(CH2)m4C(O)OH.
11. A compound according to claim 10, wherein R2 is phenyl, isoxazolyl,
pyridinyl, pyrazolyl, imidazolyl, morpholinyl, 3,4-dihydroisoquinolinyl, 1,2,3,4-
tetrahydroisoquinolinyl, 2-oxoimidazolidinyl, piperidinyl, pyrrolidinyl, indolinyl,
l,2,4-oxadiazol-5-yl or lH-benzo[d]imidazole or azetidinyl; and the optional
substituents are selected from 1-3 substituents selected from C1-7 alkyl, halogen,
amino, hydroxy, NHC(O)C1-7 alkyl, halo C1-7 alkyl, phenyl, oxo, hydroxy C1-7 alkyl,
-(CH2)m5C(O)NH(hydroxy C1-7 alkyl) or -(CH2)m4C(O)OH.
12. A compound according to any of claims 1 to 9, wherein R2 is
-(CH2)mC(O)Ra1.
13. A compound according to claim 12, whereinRa1 is a 5-12 membered
monocyclic or bicyclic ring containing 0-4 hetero atoms independently selected from
N and Q, which ring is optionally substituted by one hydroxy group, and m is 0 or 1.

14. A compound according to claim 13, whereinRa1 is phenyl, piperidinyl,
pyrrolidinyl, azetidinyl or indolinyl which rings are optionally substituted by one
hydroxy group, and m is 0 or 1.
15. A compound according to any of claims 1 to 9, wherein R.2 is
-(CH2)m2C(O)N(Ra3)Rb1.
16. A compound according to claim 15, wherein Ra3 is hydrogen or C1-7 alkyl,
and Rb1 is hydrogen, C1-7 alkyl, hydroxy C1-7 alkyl, halo C1-7 alkyl, optionally
substituted C3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted
phenyl or optionally substituted heterocyclyl C1-7 alkyl, wherein heterocyclyl at each
occurrence means a 5-12 membered monocyclic or bicyclic ring containing 1-4
hetero atoms independently selected from N, O and S, and wherein the optional
substitution at each occurrence is, independently, selected from 1-3 substituents
selected from C1-7 alkyl, hydroxy, halogen, halo C1-7 alkyl, amino, cyano or C1-7
alkoxy; and m2 is 0 or 1.
17. A compound according to claim 15 or 16, wherein Rb1 is cyclohexyl,
pyridinyl, piperidinyl, 1,3,4-thiadiazolyl, pyrazolyl, phenyl or imidazolyl C1-7 alkyl,
which groups are optionally substituted by 1-3 substituents independently selected
from C1-7 alkyl, hydroxy, halogen, halo C1-7 alkyl, amino, cyano or C1-7 alkoxy.
18. A compound according any of claims 15 to 17, wherein Ra3 is hydrogen.
19. A compound according to any of claims 1 to 9, wherein R2 is -N(Ra)Rb-
20. A compound according to claim 19, wherein Ra is hydrogen and Rb is
hydrogen, hydroxy C1-7 alkyl, -S02-methyl or optionally substituted 5-12 membered
monocyclic or bicyclic ring containing 1-4 hetero atoms independently selected from
N, O and S, and wherein the optional substitution is selected from 1-3 substituents
selected from C1-7 alkyl, hydroxy, halogen, halo C1-7 alkyl or C1-7 alkoxy.

21. A compound according to any of claims 1 to 9, wherein R.2 is
-CH(CF3)Rd, -CH(CF3)ORc or -CH(CF3)N(Ra7)Rb4.
22. A compound according to claim 21, wherein Rd is morpholinyl, Rc of is 4-
fluorophenyl or C1-7 alkyl, R47 is hydrogen and Rb4 is hydroxy C1-7 alkyl or 4-fluoro-
phenyl.
23. A compound according to any of claims 1 to 22, wherein n is 1 or 2.
24. A compound according to any of claims 1 to 23, wherein the compound of
formula (I) is a compound of formula (IA):

or a pharmaceutically acceptable salt thereof.
25. A compound according to any of claims 1 to 24, wherein the compound of
formula (I) is a compound of formula (IB):

or a pharmaceutically acceptable salt thereof.
26. A compound according to any of claims 1 to 24, wherein the compound of
formula (I) is a compound of formula (IC):


R4 is hydrogen, C1-7 alkoxy, or halogen, or a pharmaceutically acceptable salt thereof.
27. A compound according to any of claims 1 to 26, wherein L1 is -CH2-.
28. A compound according to claim 1 selected from the group consisting of

or a pharmaceutically acceptable salt or tautomer thereof.
29. A pharmaceutical composition comprising a compound according to any
of claims 1-28 together with a pharmaceutically acceptable carrier.
30. A method for the treatment or prevention of diseases or disorders, where
bromodpmain inhibition is desired comprising administering to a subject in need
thereof a therapeutically effective amount of a compound according to any of claims
1-28.
31. A method according to claim 30, wherein the disease or disorder is an
autoimmune disease, an inflammatory disease or cancer.
32. Use of a compound according to any of claims 1-28 in the manufacture of
a medicament for the treatment or prevention of diseases or disorders where
bromodomain inhibition is desired.
33. Use according to claim 32, where the disease or disorder is an
autoimmune disease, inflammatory disease or cancer.