Specification
SPIRO[CYCLOBUTANE-1,3'-INDOLIN]-2'-ONE DERIVATIVES AS
BROMODOMAIN INHIBITORS
Technical field
The present invention relates to novel spiro[cyclobutane-1,3'-indolin]-2'-one
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 acetyl-
tranferases, 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 spiro[cyclobutane-1,3'-indolin]-2'-one
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 spiro[cyclobutane-1,3'-indolin]-2'-one
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
Cy is a 4-12 membered monocyclic or bicyclic ring containing 0-4 hetero-
atoms independently selected form N, O or S;
L is a linker selected from -N(R3a)S(O)2-, -S(O)2N(R3b)-, -C(R3c)(OR3d)-,
-N(R3e)C(O)-, -N(R3f)C(O)N(R3g)- or -N(R3h)C(O)CH(R3i)-;
R3a, R3b,R3c,R3d,R3e, R3f, R3g, R3h, and R3i are selected, independently, from
hydrogen or C1-7alkyl;
R2 is halogen, C1-7 alkoxy, amino, cyano, oxo, -C(O)O-C1-7 alkyl,
optionally substituted aryl or optionally substituted heterocyclyl, wherein the optional
substitution at each occurrence is, independently, selected from 1-3 substituents
selected from halogen or C1-7 alkoxy;
in case wherein
L is -S(O)2N(R3b)-, -C(R3c)(OR3d)-, -N(R3e)C(O)-, -N(R3f)C(O)N(R3g)- or
-N(R3h)C(O)CH(R3i)-;
then
R1 is hydrogen, C1-7 alkyl, halogen, hydroxy C1-7 alkyl, C3-10 cycloalkyl,
optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted
heterocyclyl C1-7 alkyl, optionally substituted aryl C1-7 alkyl, optionally substituted
aryl C2-7 alkenyl, -NRaRb; -C(O)NRcRd, -C(O)ORe, -C(O)Rf, -C(ORs)-aryl,
-C(ORh)(Ri)-aryl or -ORj; wherein the optional substitution at each occurrence is,
independently, selected from 1-3 substituents selected from halogen, hydroxy, C1-7
alkyl or C1-7 alkoxy; except that R1 is not hydrogen when L is -S(O)2NH- or
-CH(OH)-, and R1 is not hydrogen or halogen when L is -NHC(O)CH(CH3)-;
in case wherein
L is -N(R3a)S(O)2-
then
R1 is -NRaRb, -C(O)NRcRd, -C(O)ORe, -C(O)Rf,-C(ORg)-aryl,
-C(ORh)(Ri)-aryl or -ORj, -CH(CH3)-aryl, hydroxy C1-7 alkyl, aryl halo C1-7 alkyl,
optionally substituted heterocyclyl C1-7alkyl3 optionally substituted aryl, optionally
substituted aryl C2-7alkenyl, optionally substituted 9-12 membered heterocyclic ring
having 1-3 heteroatoms selected from N or O, pyridinyl having 1-2 substituents
selected from halogen, hydroxy or C1-7alkoxy, 2-oxopiperidinyl, fluorophenyl C1-7
alkyl, 1-methylpiperidinyl (when at least one of R2 is halogen), piperidinyl (when at
least two of R2 is C1-7alkoxy), phenyl C1-7alkyl (when at least one of R2 is halogen
and at least one another of R2 is C1-7alkoxy); wherein the optional substitution at each
occurrence is, independently, selected from 1-3 substituents selected from halogen,
hydroxy, oxo, C1-7 alkyl or C1-7 alkoxy;
Ra, Rb, Re and Rd are, independently, selected from hydrogen, C1-7 alkyl, C2-7
alkenyl, -C(O)-C 1-7 alkyl, optionally substituted heterocyclyl, optionally substituted
C3-10cycloalkyl, optionally substituted heterocyclyl C1-7 alkyl, optionally substituted
aryl, optionally substituted aryl C1-7 alkyl, optionally substituted C3-10 cycloalkyl C1-7
alkyl, optionally substituted -C(O)heterocyclyl; wherein the optional substitution at
each occurrence is, independently, selected from 1-3 substituents selected from C1-7
alkyl, -C(O)-C 1-7 alkyl, -C(O)O-C1-7 alkyl, halogen, aryl C1-7 alkyl, C 1-7 alkoxy, oxo or.
hydroxy C 1-7 alkyl;
Re, Rf, Rg, Rh, Ri and Rj are, independently, selected from hydrogen, C1-7 alkyl,
optionally substituted aryl or optionally substituted heterocyclyl wherein the optional
substitution at each occurrence is, independently, selected from 1-3 substituents
selected from C1-7 alkyl or hydroxy C1-7 alkyl; and
'm' is selected from 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
1 In a further aspect, the present invention provides a pharmaceutical
composition comprising spiro[cyclobutane-1,3'-indolin]-2'-one derivative of
formula (I) or a pharmaceutically acceptable salt thereof.
In yet further aspect of the present invention, it provides spiro[cyclo-
butane-1,3'-ihdolin]-2'-one derivatives 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 novel spiro[cyclobutane-
1,3'-indolin]-2'-one derivatives 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
Cy is a 4-12 membered monocyclic or bicyclic ring containing 0-4 hetero-
atoms independently selected form N, O or S;
L is a linker selected from -N(R3a)S(O)r, -S(O)2N(R3b)-, -C(R3c)(OR3d)-,
-N(R3e)C(O)-, -N(R3f)C(O)N(R3g)- or -N(R3h)C(O)CH(R3i)-;
R3a, R3b,R3c,R3d.R3<;, R3f, R3g, R3h and R3i are selected, independently, from
hydrogen or C1-7 alkyl;
R2 is halogen, C1-7alkoxy, amino, cyano, oxo, -C(O)O-C1-7 alkyl,
optionally substituted aryl or optionally substituted heterocyclyl, wherein the optional
substitution at each occurrence is, independently, selected from 1-3 substituents
selected from halogen or C1-7 alkoxy;
in case wherein
L is -S(O)2N(R3b)-, -C(R3c)(OR3d)-, -N(R3e)C(O)-, -N(R3f)C(O)N(R3g)- or
-N(R3h)C(O)CH(R3,)-;
then
Ri is hydrogen, C1-7alkyl, halogen, hydroxy C1-7alkyl, C3-10cycloalkyl,
optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted
heterocyclyl C1-7alkyl, optionally substituted aryl C1-7 alkyl, optionally substituted
aryl C2-7alkenyl, -NRaRb) -C(O)NRcRd, -C(O)ORe, -C(O)Rf,-C(ORg)-aryl,
-C(ORh)(Ri)-aryl or -OR,; wherein the optional substitution at each occurrence is,
independently, selected from 1-3 substituents selected from halogen, hydroxy, C1-7
alkyl or C1-7 alkoxy; except that R1 is not hydrogen when L is -S(O)2NH- or
-CH(OH)-, and R1 is not hydrogen or halogen when L is -NHC(O)CH(CH3)-;
in case wherein
L is -N(R3a)S(O)2-
then
R1 is -NRaRb, -C(O)NRcRd, -C(O)OR, -C(O)Rf,-C(ORg)-aryl,
-C(ORh)(Ri)-aryl or -ORj, -CH(CH3)-aryl, hydroxy C1-7 alkyl, aryl halo d.7 alkyl,
optionally substituted heterocyclyl C1-7 alkyl, optionally substituted aryl, optionally
substituted aryl C2.7alkenyl, optionally substituted 9-12 membered heterocyclic ring
having 1-3 heteroatoms selected from N or O, pyridinyl having 1-2 substituents
selected from halogen, hydroxy or C1-7 alkoxy, 2-oxopiperidinyl, fluorophenyl C1-7
alkyl, 1-methylpiperidinyl (when at least one of R2 is halogen), piperidinyl (when at
least two of R2 is C1-7 alkoxy), phenyl C1-7 alkyl (when at least one of R2 is halogen
and at least one another of R2 is C1-7 alkoxy); wherein the optional substitution at each
occurrence is, independently, selected from 1-3 substituents selected from halogen,
hydroxy, oxo, C1-7 alkyl or C1-7 alkoxy;
Ra, Rb, Re and Rd are, independently, selected from hydrogen, C1-7 alkyl, C2.7
alkenyl, -C(O)-C1-7 alkyl, optionally substituted heterocyclyl, optionally substituted
C3-10cycloalkyl, optionally substituted heterocyclyl C1-7 alkyl, optionally substituted
aryl, optionally substituted aryl C1-7 alkyl, optionally substituted C3-10cycloalkyl C1-7
alkyl, optionally substituted -C(O)heterocyclyl; wherein the optional substitution at
each occurrence is, independently, selected from 1-3 substituents selected from C1-7
alkyl, -C(O)-C 1.7 alkyl, -C(O)O-C1-7 alkyl, halogen, aryl C1-7 alkyl, C1-7 alkoxy, oxo or
hydroxy C1-7 alkyl;
Re, Rf, Rg, Rh, R; and Rj are, independently, selected from hydrogen, C1-7 alkyl,
optionally substituted aryl or optionally substituted heterocyclyl wherein the optional
substitution at each occurrence is, independently, selected from 1-3 substituents
selected from C1-7 alkyl or hydroxy C1-7 alkyl; and
1 'm' is selected from 0, 1,2 or 3;
or a pharmaceutically acceptable salt thereof.
It is to be understood that the left bond in each linker L is attached to the
indolinone ring of formula (I).
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 of the present invention, the compound of
formula (I) is a compound of formula (IA)
wherein R1, R2, Cy, L and 'm' 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 R1, R2,R3a, Cy and 'm' 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 (IC)
wherein R1, R2, R3f, R.3g, Cy and 'm' 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 (ID)
wherein R1, R2,R3e, Cy and 'm' are same as defined in formula (I), or a
pharmaceutically acceptable salt thereof.
According to one embodiment, specifically provided are compounds of
formula (I ) wherein Cy is phenyl, C3-10 cycloalkyl or a 5-6 membered heterocyclic
ring having 1-3 heteroatoms selected from N or O;
L is a linker selected from -N(R3a)S(O)2-, -N(R3e)C(O)- or
-N(R3f)C(O)N(R3g)-;
R3a, R3=, R3f and R3g, are selected, independently, from hydrogen or C1-7alkyl;
R2 is halogen, C1-7alkoxy, cyano, -C(O)O-C1-7alkyl or a 5-6 membered
heterocyclic ring having 1-3 heteroatoms selected from N or O;
in case wherein
L is -N(R3e)C(O)- or -N(R3f)C(O)N(R3g)-
then
R1 is hydrogen, C1-7alkyl, halogen, hydroxy C1-7alkyl, C3-10cycloalkyl,
optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted
heterocyclyl C1-7 alkyl, optionally substituted aryl C1-7 alkyl, optionally substituted
aryl C1-7 alkenyl, -NRaRb, -C(O)NRcRd, -C(O)ORe, -C(O)Rf,-C(ORg)-aryI,
-C(ORh)(R)-aryl or -ORJ; wherein the optional substitution at each occurrence is,
independently, selected from 1-3 substituents selected from halogen, hydroxy, C1-7
alkyl or C1-7 alkoxy;
in case wherein
L is -N(R3a)S(O)2-
then
R1 is -NRaRb, -C(O)NRcRd, -C(O)ORe, -C(O)Rf,-C(ORg)-aryl,
-C(ORh)(Ri)-aryl or -ORj, -CH(CH3)-aryl, hydroxy C1-7 alkyl, aryl halo C1-7 alkyl,
optionally substituted heterocyclyl C1-7 alkyl, optionally substituted aryl, optionally
substituted aryl C2-7 alkenyl, optionally substituted 9-12 membered heterocyclic ring
having 1-3 heteroatoms selected from N or O, pyridinyl having 1-2 substituents
selected from halogen, hydroxy or C1-7 alkoxy, 2-oxopiperidinyl, fluorophenyl C1-7
alkyl, 1-methylpiperidinyl (when at least one of R2 is halogen), piperidinyl (when at
least two of R2 is C1-7 alkoxy), phenyl C1-7 alkyl (when at least one of R2 is halogen
and at least one another of R2 is C1-7 alkoxy); wherein the optional substitution at each
occurrence is, independently, selected from 1-3 substituents selected from halogen,
hydroxy, oxo, C 1-7 alkyl or C1-7 alkoxy;
Ra, Rb, Re and Ri are, independently, selected from hydrogen, C1-7 alkyl, C2.7
alkenyl, -C(O)-C1-7 alkyl, optionally substituted heterocyclyl, optionally substituted
G-10 cycloalkyl, optionally substituted heterocyclyl C1-7 alkyl, optionally substituted
aryl, optionally substituted aryl C1-7 alkyl, optionally substituted G-10 cycloalkyl C1-7
alkyl, optionally substituted-C(O)heterocyclyl; wherein the optional substitution at
each occurrence is, independently, selected from 1-3 substituents selected from C1-7
alkyl, -C(O)-C1-7 alkyl, -C(O)0-C1-7 alkyl, halogen, aryl C1-7 alkyl, C1-7 alkoxy, oxo or
hydroxy C 1.7 alkyl;
Re, Rf, Rg, Rh, R and Rj are, independently, selected from hydrogen, C1-7 alkyl,
optionally substituted aryl or optionally substituted heterocyclyl wherein the optional
substitution at each occurrence is, independently, selected from 1-3 substituents
selected from C1-7 alkyl or hydroxy C1-7 alkyl; and
'm' is selected from 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof. •
According to one embodiment, specifically provided are compounds of
formula (I), (IA), (IB), (IC) or (ID), wherein Cy is aromatic or non-aromatic cyclic
ring with 5-10 ring atoms of which 0-4 are heteroatoms selected from a group
consisting of N, 0 and S. In a subclass of the above embodiment are compounds
wherein Cy is phenyl, C3-10 cycloalkyl or a 5-6 membered heterocyclic ring having
1-3 heteroatoms selected from N or O. In yet another subclass of the above
embodiment are compounds wherein Cy is phenyl, cyclohexyl or piperidinyl.
According to one embodiment, specifically provided are compounds of
formula (I), (IA), (IB), (IC) or (ID), or according to any other embodiment, or
subclass referred to above, wherein L is a linker selected from -NHS(O)2-, -NHC(O)-
or -NHC(O)NH-. In a subclass of the above embodiment are compounds wherein L is
-NHS(O)2-.
According to yet one embodiment, specifically provided are compounds of
formula (I), (IA) or (IB), wherein
Cy is phenyl; L is -NHS(O)2-;
R2 is halogen or C1-7 alkoxy, R1 is -NHRa, -C(O)NHRc, -C(O)OR^, -C(O)Rf,-
C(OH)phenyl, -C(OH)( C1-7alkyl)phenyl or -ORj, -CH(CH3)phenyl, hydroxy d.7
alkyl, aryl halo C1-7alkyl, optionally substituted heterocyclyl C1-7alkyl, optionally
substituted phenyl, optionally substituted phenyl C2.7 alkenyl, optionally substituted
9-12 membered heterocyclic ring having. 1-3 heteroatoms selected from N or O,
pyridinyl having 1-2 substituents selected from halogen, hydroxy or C1-7alkoxy, 2-
oxopiperidinyl, fluorophenyl C1-7alkyl, 1-methylpiperidinyl (when at least one of R2
is halogen), piperidinyl (when at least two of R2 is C1-7alkoxy), phenyl C1-7 alkyl
(when at least one of R2 is halogen and at least one another of R2 is C1-7alkoxy);
wherein the optional substitution at each occurrence is, independently, selected from
1-3 substituents selected from halogen, hydroxy, oxo, C1-7alkyl or C|.7alkoxy;
1 Ra and Re are, independently, selected from hydrogen, C1-7 alkyl, C2.7 alkenyl,
-C(O)-C|.7 alkyl, optionally substituted C3.|0 cycloalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclyl C1-7 alkyl, optionally substituted C3.10
cycloalkyl C1-7 alkyl, optionally substituted-C(O)heterocycly 1; wherein the optional
substitution at each occurrence is, independently, selected from 1-3 substituents
selected from C,.7allcyl, -C(O)-C1-7alkyl, -C(O)0-C1-7 alkyl, halogen, phenyl C1-7
alkyl, C1-7alkoxy, oxo or hydroxy C1-7 alkyl;
Re is hydrogen or C1-7 alkyl;
i Rf and Rj are independently optionally substituted phenyl or optionally
substituted heterocyclyl wherein the optional substitution at each occurrence is,
independently, selected from 1-3 substituents selected from C1-7 alkyl or hydroxy C1-7
alkyl;
wherein heterocyclyl at each occurrence is a 5-10 membered heterocyclic ring
having 1-4 heteroatoms selected from O, N, or S; and
'm' is selected from 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
In one subclass of any of the above embodiments are compounds of formula
(I), (IA), (IB), (IC) or (ID), wherein Cy-(R2)m is selected from one of the following
groups or tautomers thereof
According to one embodiment, specifically provided are compounds of
formula (I), (IA), (IB), (IC) or (ID) wherein R, is -NRaRb) -C(O)NRcRd, -C(O)ORe,
-C(O)Rf,-C(ORg)-aryl, -C(ORh)(Ri)-aryl or -ORj, -CH(CH3)-aryl, hydroxy C1-7 alkyl,
aryl halo C1-7alkyl, optionally substituted heterocyclyl C1-7alkyl, optionally
substituted aryl, optionally substituted aryl C2-7alkenyl, optionally substituted 9-12
membered heterocyclic ring having 1-3 heteroatoms selected from N or O, pyridinyl
having 1-2 substituents selected from halogen, hydroxy or C1-7alkoxy, 2-oxo-
piperidinyl, fluorophenyl C1-7 alky 1, 1-methylpiperidinyl (when at least one of R2 is
halogen), piperidinyl (when at least two of R2 is C1-7alkoxy), phenyl C1-7 alkyl (when
at least one of R2 is halogen and at least one another of R2 is C1-7alkoxy); wherein the
optional substitution at each occurrence is, independently, selected from 1-3
substituents selected from halogen, hydroxy, oxo, C1-7alkyl or C1-7alkoxy.
In one subclass of the above embodiment are compounds wherein Ri is
-NRaRb or -C(O)NRcRd, and Ra, Rb, Rc and Rj are, independently, selected from
hydrogen, optionally substituted heterocyclyl, optionally substituted heterocyclyl C1-7
alkyl, optionally substituted C3.10 cycloalkyl C1-7 alkyl, wherein the optional
substitution at each occurrence is, independently, selected from 1-3 substituents
selected from C,.7 alkyl, -C(O)-C,.7 alkyl, -C(O)0-C1-7 alkyl, halogen, aryl C1-7alkyl,
C1-7alkoxy, oxo or hydroxy C 1.7 alkyl.
According to one embodiment are compounds of formula (I), (IA), (IB), (IC)
or (ID), or according to any embodiment or subclass referred to above, wherein Ri is
optionally substituted heterocyclyl or optionally substituted heterocyclyl C1-7 alkyl; in
particular selected from one of the following groups or tautomers thereof
According to one embodiment, provided are compounds according to any
embodiment or subclass referred to above, wherein R1 is -NRaRb or -C(O)NRcRd; in
particular Ra, Rb, Re and Rd being independently selected from hydrogen, C1-7 alkyl
(such as methyl), C2-7 alkenyl (such as but-1-ene), -C(O)-C1-7 alkyl (such as
-C(O)CH3), or from one of the following groups or tautomers thereof
According to one embodiment, specifically provided are compounds
according to any embodiment or subclass referred to above, wherein heterocyclyl at
each occurrence is a 5-10 membered heterocyclic ring having 1-4 heteroatoms
selected from O, N, or S.
In yet another particular embodiment of the present invention, the compound
of formula (I) is selected from the group consisting of:
or pharmaceutically acceptable salts thereof.
In yet another embodiment according to the present patent application, it
provides a pharmaceutical composition comprising a compound of formula (I), (TA),
(IB) (IC) or (ID) of the present invention and at least one pharmaceutically acceptable
excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the
pharmaceutical composition comprises a therapeutically effective amount of at least
one compound described herein.
It should be understood that formulas (I), (IA), (IB) (IC) and (ID) encompass
all stereoisomers, enantiomers and diastereomers that may be contemplated from the
chemical structure of the compounds according to above formulas.
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 "C1-7alkyl", 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 C1-7alkyl include, but are not
limited to, methyl, ethyl, rc-propyl, wo-propyl, rc-butyl, wo-butyl, sec-butyl, ter/-butyl,
n-pentyl, wo-pentyl and n-hexyl. The term "C 1-3 alky 1" refers to an preferred
embodiment of "C1-7alkyl" 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 one or several double bonds. Representative examples include, but are not
limited to, ethylene, prop-J-ene, but-1-ene, but-2-ene, pent-1-ene, pent-2-ene, hex-1-
ene and hex-2-ene.
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. Examples of C3-10 cycloalkyl
groups are include those where saturated 5 or 6 membered cycloalkyl ring is fused to
a phenyl ring. 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. Representative examples of C3-10
cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl.
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 "C1-7 alkoxy", as employed herein as such or as part of another
group, refers to C1-7alkyl, as defined herein, appended to the parent molecular moiety
through an oxygen atom. Representative examples of C1-7 alkoxy include, but are not
limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
The term "hydroxy", as employed herein as such or as part of another group,
refers to an —OH group. The term "amino", as employed herein as such or as part of
another group, refers to an -NH2 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
carbon atom double-bonded to an oxygen atom (C^O). The term "oxo", as employed
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 of hydroxyl C1-7 alkyl
include, but are not limited to, hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl,
3-hydroxypropyl, 1-hydroxypropyl, 1-methyl-1-hydroxyethyl and 1-methyl-l-
hydroxypropyl.
The term "halo C1-7 alkyl", as employed herein, refers to at least one halogen,
ias defined herein, appended to the parent molecular moiety through a C1-7 alkyl
group, as defined herein. Representative examples of halo C1-7 alkyl include, but are
not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl and 3-
bromopropyl.
1 The term "C3-10 cycloalkyl C1-7 alkyl", as employed herein refers to a C3-10
cycloalkyl group, as defined herein, appended to the parent molecular moiety through
a C1-7 alkyl group, as defined herein.
The term "phenyl C1-7 alkyl", as employed herein, refers to at least one phenyl
group appended to the parent molecular moiety through a C1-7 alkyl group, as defined
herein. The term "halo phenyl C1-7 alkyl", as employed herein, refers to at least one
halo group appended to the parent molecular moiety through a phenyl C1-7 alkyl
group, as defined herein.
1 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,
biphenylenyl, and acenaphthyl. Preferred aryl group is phenyl.
1 The term "aryl C 1.7 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
lalkyl. The term "aryl C2-7alkenyl", as employed herein, refers to an aryl group
appended to the parent molecular moiety through a C2-7alkenyl group, as defined
herein. Examples of aryl C1-7alk.enyl groups include, but are not limited to 1-phenyl-
ethenyl, 2-phenylethenyl and 2-phenylprop-l-enyl.
The term "aryl halo C1-7 alkyl", as employed herein, refers to at least one aryl
group, as defined herein, appended to the parent molecular moiety through a halo
C1-7 alkyl group, as defined herein. Examples of aryl halo C1-7 alkyl groups include,
but are not limited to phenyl fluoro methyl and 1-phenyl 2-chloro ethyl.
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
least one, preferably 1-4, is a heteroatom selected from the group consisting of O, N,
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 piperdinyl, piperazinyl, morpholinyl,
thiomorpholinyl, 1,3-dioxolanyl 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 N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methyl-
pyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-
triazole, lH-tetrazole, 1,2,3,4-tetrahydroisoquinoline 1-methyltetrazole, benzoxazole,
benzothiazole, benzofuran, benzisoxazole, benzimidazole, 3-quinuclidine, 3,4-
dihydroisoquinolin-l(2H)-one, N-methylbenzimidazole, 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 sulfur atom in the
ring, or one 0 or S ring atom.
The term "4-12 membered monocyclic or bicyclic ring containing 0-4
iheteroatoms" refers to a 4-12 membered monocyclic or bicyclic aromatic or non-
aromatic cyclic ring in which 0-4 of the ring carbon atoms have been independently
replaced with N, O or S. Representative examples of such rings include, but are not
limited to phenyl, pyridine, pyrimidine, morpholine, piperidine, piperazine, imida-
zole, pyrazole, pyrrole, thiophene, cyclopropyl, 2,3dihydrobenzo[b][l,4]dioxine,
1,2,3,4-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 0-4 heteroatoms" are a monocyclic or bicyclic aromatic or
non-aromatic cyclic ring with 5-10 ring atoms of which 0-4 are heteroatoms selected
from a group consisting of N, O and S.
The term "5-10 membered heterocyclic ring having 1-4 heteroatoms selected
from O, N, or S" 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, N, and S.
The term "9-12 membered heterocyclic ring having 1-3 heteroatoms selected
from N or O" refers to aromatic, saturated or partially saturated monocyclic, bicyclic ...
or polycyclic ring which have 9 to 12 ring member atoms of which 1 to 3 are
heteroatoms selected from a group consisting of N and O.
The term "optionally substituted or substituted", if not otherwise specified,
means that at least one hydrogen atom of the optionally substituted group has been
substituted with suitable groups as exemplified but not limited to halogen, nitro,
cyano, hydroxy, oxo (=0), thio (=S), -N(C,-3alkyl)C(O)(Cr7alkyl), -NHC(O)(C,-7
lalkyl), -NHC(O)(cycloalkyl), -NHC(O)(aryl), -NHC(O)(heterocyciyl),
-NHC(O)(heteroaryl), -NHC(O)H, -C(O)NH2, -C(O)NH(C,-7alkyl),
-C(O)NH(cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(heteroaryl), -C(O)N(C,-7
alkyl)(Cr7alkyl),.-S(O)NH(Cr7alkyl)!-S(O)2NH(C1-7alkyl),-S(O)NH(cycloalkyl),
-S(O)2NH(cycloalkyl), carboxy, -C(O)0(C,-7alkyl),.-C(O)(C,-7alkyl), =N-OH,
alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,
cycloalkenylalkyl, cycloalkenyl, amino, heteroaryl, heterocyclyl, heteroarylalkyl or
heterocyclic ring. One particular embodiment of "optionally substituted or
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 Cr7 alkyl,
C1-7 alkoxy and halo C1-7 alkoxy substituents.
As used herein, the terms "treat", "treating" or "treatment" encompass either
or both responsive and prophylaxis measures, e.g. measures designed to inhibit or
delay the onset of the disease or disorder, achieve a full or partial reduction of the
symptoms or disease state, and/or to alleviate, ameliorate, lessen, or cure the disease
or disorder and/or its symptoms. The terms "treat," "treating" or "treatment", include,
but are not limited to, prophylactic and/or therapeutic treatments.
As used herein the terms "subject" or "patient" are well-recognized in the art,
and, are used interchangeably herein to refer to a mammal, including dog, cat,-rat,
mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human.
In some embodiments, the subject is a subject in need of treatment or a subject with a
disease or disorder. However, in other embodiments, the subject can be a normal
subject. The term does not denote a particular age or sex. Thus, adult and new-born
subjects, whether male or female, are intended to be covered.
As used herein the term "therapeutically effective amount," refers to a
sufficient amount of a compound or a composition being administered which will
relieve to some extent one or more of the symptoms of the disease or condition being
treated. The result can be reduction and/or alleviation of the signs, symptoms, or
causes of a disease, or any other'desired alteration of a biological system. The term
"therapeutically effective amount" includes, for example, a prophylactically effective
amount.
"Pharmaceutically acceptable" means that, which is useful in preparing a
pharmaceutical composition that is generally safe, non-toxic, and neither biologically
nor otherwise undesirable and includes that which is acceptable for veterinary as well
as human pharmaceutical use.
"Pharmaceutical ly 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 hydro-
chloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the
like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid,
cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid,
succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic
acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methane
sulfonic acid, ethane sulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethane-
sulfonic acid, benzene sulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalene-
sulfonic acid, 4-toluenesulfonic acid, camphor sulfonic acid, 4-methylbicyclo[2.2.2]-
oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethyl-
acetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxyl naphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.
The term "stereoisomers" refers to any enantiomers, diastereomers, or
geometrical isomers of the compounds of formula (I) wherever they are chiral or
when they bear one or more double bond. When the compounds of the formula (I)
and related formulae are chiral, they can exist in racemic or in optically active form.
Since the pharmaceutical activity of the racemates or stereoisomers of the
compounds according to the invention may differ, it may be desirable to use the
enantiomers. In these cases, the end product or even the intermediates can be
separated into enantiomeric compounds by chemical or physical measures known to
the person skilled in the art or even employed as such in the synthesis. In the case of
racemic amines, diastereomers are formed from the mixture by reaction with an
optically active resolving agent. Examples of suitable resolving agents are optically
active acids, such as the R and S forms of tartaric acid, diacetyl tartaric acid,
dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected
amino acids (for example N-benzoylproline or N-benzenesulfonylproline), or the
various optically active camphorsulfonic acids. Also advantageous is
chromatographic enantiomer resolution with the aid of an optically active resolving
agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other
derivatives of carbohydrates or chirally derivatised methacrylate polymers
immobilised on silica gel). Suitable eluents for this purpose are aqueous or alcoholic
solvent mixtures, such as, for example, hexane/isopropanol/ acetonitrile, for example
in the ratio 82:15:3.
Bromodomain inhibitors are believed to be useful in the treatment of a variety
of diseases or conditions related to systemic or tissue inflammation, inflammatory
responses to infection or hypoxia, cellular activation and proliferation, lipid
metabolism, fibrosis and in the prevention and treatment of viral infections.
Bromodomain inhibitors may be useful in the treatment of a wide variety of
chronic autoimmune and inflammatory conditions such as rheumatoid arthritis,
osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis,
inflammatory bowel disease (Crohn's disease and Ulcerative colitis), asthma, chronic
obstructive airways disease, pneumonitis, myocarditis, pericarditis, myositis, eczema,
dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, athero-
sclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis,
pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease,
hypophysitis, thyroiditis, type Idiabetes 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 glomerulo-
nephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis,
Polyarteritisnodosa, Behcet's disease, Kawasaki disease, Takayasu's Arteritis,
'vasculitis with organ involvement and acute rejection of transplanted organs.
Bromodomain inhibitors may be useful in the prevention or treatment of
diseases or conditions which involve inflammatory responses to infections with
bacteria, viruses, fungi, parasites or their toxins, such as sepsis, sepsis syndrome,
septic shock, endotoxaemia, systemic inflammatory response syndrome (SIRS),
multi-organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS
(adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns,
acute pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimer reactions,
encephalitis, myelitis, meningitis, malaria and SIRS associated with viral infections
such as influenza, herpes zoster, herpes simplex and coronavirus.
Bromodomain inhibitors may be useful in the prevention or treatment of
conditions associated with ischaemia-reperfusion injury such as myocardial
infarction, cerebro- vascular ischaemia (stroke), acute coronary syndromes, renal
reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-
pulmonary bypass procedures, pulmonary, renal, hepatic, gastro-intestinal or
peripheral limb embolism.
Bromodomain inhibitors may be useful in the treatment of disorders of lipid
metabolism via the regulation of APO-A1 such as hypercholesterolemia,
atherosclerosis and Alzheimer's disease.
Bromodomain inhibitors may be useful in the treatment of fibrotic conditions
such as idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid
formation, scleroderma and cardiac fibrosis.
Bromodomain inhibitors may be useful in the prevention and treatment of
viral infections such as herpes virus, human papilloma virus, adenovirus and pox-
virus 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
tumours.
In one embodiment the disease or condition for which a bromodomain
inhibitor is indicated is selected from diseases associated with systemic inflammatory
response syndrome, such as sepsis, burns, pancreatitis, major trauma, haemorrhage
and ischaemia. In this embodiment the bromodomain inhibitor would be
administered at the point of diagnosis to reduce the incidence of: SIRS, the onset of
shock, multi-organ dysfunction syndrome, which includes the onset of acute lung
injury, ARDS, acute renal, hepatic, cardiac and gastro-intestinal injury and mortality.
In another, embodiment the bromodomain inhibitor would be administered
prior to surgical or other procedures associated with a high risk of sepsis,
haemorrhage, extensive tissue damage, SIRS or MODS (multiple organ dysfunction
syndrome).
In a particular embodiment the disease or condition for which a bromodomain
inhibitor is indicated is sepsis, sepsis syndrome, septic shock and endotoxaemia. In
another embodiment, the bromodomain inhibitor is indicated for the treatment of
acute or chronic pancreatitis. In another embodiment the bromodomain is indicated
for the treatment of burns. In one embodiment the disease or condition for which a
bromodomain inhibitor is indicated is selected from herpes simplex infections and
reactivations, cold sores, herpes zoster infections and reactivations, chickenpox,
shingles, human papilloma virus, cervical neoplasia, adenovirus infections, including
acute respiratory disease, poxvirus infections such as cowpox and smallpox and
African swine fever virus. In one particular embodiment a bromodomain inhibitor is
indicated for the treatment of Human papilloma virus infections of skin or cervical
epithelia.
The term "diseases or 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, such as suppositories; or for parenteral injection (including
intravenous, subcutaneous, intramuscular, intravascular, or infusion) such as a sterile
solution, suspension or emulsion.
The compounds of the present invention may also be entrapped in
microcapsules prepared, for example, by coacervation techniques or by interfacial
polymerization, for example, hydroxymethyl cellulose or gelatin-microcapsules and
poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery
systems (for example, liposomes, albumin microspheres, microemulsions, nano-
particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in
Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).
The novel spiro[cyclobutane-1,3'-indolin]-2'-one 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 given in the example section
mentioned below.
In a further aspect, the compounds of the present invention can also contain
unnatural proportions of atomic isotopes at one or more of the atoms that constitute
such compounds. For example, the present invention also embraces isotopically-
labeled variants of the present invention which are identical to those recited herein,
but for the fact that one or more atoms of the compound are replaced by an atom
having the atomic mass or mass number different from the predominant atomic mass
or mass number usually found in nature for the atom. All isotopes of any particular
atom or element as specified are contemplated within the scope of the compounds of
the invention, and their uses.
Exemplary isotopes that can be incorporated in to compounds of the invention
include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur,
fluorine, chlorine and iodine, such as 2H ("D"), 3H, UC, 13C, 14C, 13N, 15N, 150,170,
180,32P, 33P, 3SS, 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, DCM - Dichloromethane, DMF - N,
N-Dimethyl formamide, DMSO -DimethySulfoxide, CDC13-Deuterated
chloroform, EtOAc - Ethyl acetate, CH3CN-Acetonitrile, TH.F - Tetrahydrofuran,
TEA - Triethylamine, DIPEA-Diisopropylethylamine, TFA-Trifluoroacetic acid,
AcOH-Acetic acid, AlCl3-Aluminium chloride, NBS-N-bromosuccinimide, PyBOP-
(Benzotriazol-l-yloxy)tripyrrolidino phosphonium hexafluorophosphate, HATU-(1-
[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid
hexafiuorophosphate), DMF.DMA-N,N-Dimethylformamide dimethyl acetal, NMO-
N-methyl morpholine N-oxide, DCE-1.2-Dichloro ethane, CFL-Compact fluorescent
lamp, KOAc-Potassium acetate, Na2S04-Sodium sulphate, H2SO4 - Sulfuric acid,
HN03-Nitric acid, NaHC03-Sodiumbicarbonate, Na2C03 - Sodium carbonate, K2CO3
- Potassium carbonate, Cs2C03-Cesium carbonate, NaH-Sodium hydride, DAST-
Diethyl amino sulfur trifluoride, NaBH4-Sodiumborohydride, NaCNBH3-Sodium
cyanoborohydride, (BOC) 20-Di-tert-butyl dicarbonate, EDC.HCl-l-Ethyl-3-(3-
dimethylaminopropyl) carbodiimide hydrochloride, HOBt-1-hydroxybenzotriazole,
AcCl-Acetyl chloride, Ac20-Acetic anhydride, NH4Cl-Ammonium chloride, H20-
water, NaOMe-Sodium methoxide, NaOH - Sodium hydroxide, HC1 - Hydrochloric
acid, Pd (pph3)4 -Tetrakis (triphenylphosphine) palladium (O), Pd (dppf) Cl2- [1,1-
Bis(diphenyl phosphino)ferrocene]dichloropalladium(II), complex with
dichloromethane, Pd(OAc)2-Palladium (II) acetate, Pd/C - Palladium on activated
carbon, TLC - Thin layer chromatography, RT-Room temperature, N - Normality,
M- Molarity, s- Singlet, d- Doublet, t- Triplet, m- Multiple:, 1HNMR - Proton
nuclear magnetic resonance, MS - Mass spectroscopy, HPLC-High-performance
liquid chromatography, LC - Liquid chromatography, H - Proton, MHz - Mega
hertz, Hz - Hertz, Ppm - Parts per million, Bs - Broad singlet, ES - Electro spray.
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: 'H-NMR: Varian 400 MHz.
The microwave chemistry was performed on a CEM Explorer.
The procedure for the compounds of formula (I) are detailed herein below
stepwise including the general synthesis of various intermediates involved in
process of synthesis of the compounds according to the present invention.
Examples
Step-a: N'-phenylcyclobutanecarbohydrazide (la):
i To a solution of phenyl hydrazine hydrochloride (60 g, 416.6 mmol) in DMF
(200 mL) at -30 °C were added pyridine (100 mL, 1249.8 mmol) followed by
cyclobutanecarbonylchloride (47.3 mL, 416.6 mmol) dropwise. The mixture was
stirred at -30 °C for 2 h. The mixture was poured into ice cooled water and the solid
formed was filtered off, washed with water and dried under reduced pressure to
'afford the title product as white solid. Yield 50.0 g (63%).'H NMR (400 MHz,
DMSO-A): 5 9.47 (s, 1H), 7.13-7.09 (m, 2H), 6.70-6.63 (m, 3H), 3.12-3.08 (m, 1H),
2.20-2.06 (m, 4H), 1.96-1.77 (m, 2H); LC-MS: m/zl9l.2 (M+H)+.
Step-b: Spiro[cyclobutane-1.3'-indolin]-2'-one (lb):
To a solution of N'-phenylcyclobutanecarbohydrazide (15 g, 78.9 mmol) in
quinoline (15 mL) was added calcium oxide (44.2 g, 789.0 mmol). The mixture was
heated to 260 °C on pre-heated sand bath and stirred for. 4 h. The mixture was cooled
to RT and quenched with 6 N HC1 dropwise. The mixture was extracted with EtOAc
(250 ml x 2). The combined organic layer was washed with water (200 mL), brine
(200 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 yellow
solid 8.0 g (58%).'H NMR (400 MHz, DMSO-^): 5 10.20 (s, 1H), 7.54 (d,J=7.4 Hz,
1H), 7.15 (t, J=7.3 Hz, 1H), 6.99 (t, J=7.4 Hz, 1H), 6.77 (d, J =7.8 Hz, 1H), 2.44-
2.38 (m, 2H), 2.30-2.22 (m, 4H); LC-MS: m/z 174.1 (M+H)+.
Step-c: 5'-nitrospiro[cyclobutane-1.3'-indolin]-2'-one (lc):
i To a stirring suspension of spiro[cyclobutane-1,3'-indolin]-2'-one (4.0 g,
23.12 mmol) in sulphuric acid (40 mL) at -20 °C was added potassium nitrate (2.3 g,
23.12 mmol) portion wise. The mixture was stirred at -20 °C for 30 min. The mixture
was poured into ice cooled water and the solid formed was filtered off, washed with
water and dried under reduced pressure and purified under column to afford title
compound as yellow solid 2.0 g (40 %).'H NMR (400 MHz, DMSO-d6): 5 10.95 (s,
1H), 8.44 (d, J=2.5 Hz, 1H), 8.15(dd, J=2.1 Hz & 8.5 Hz, 1H), 6.97 (d, J=8.3 Hz,
1H), 2.46-2.38 (m, 4H), 2.27-2.17 (m, 2H ); LC-MS: m/z 217.1 (M-H)".
Step-d: 7'-bromo-5'-nitrospiro[cvclobutane-1.3'-indolin]-2'-one (Id):
To a stirring suspension of 5'-nitrospiro[cyclobutane-1,3'-indolin]-2'-one (3.0
g, 13.76 mmol) in sulphuric acid (20 mL) at RT was added N-bromosuccinimide (2.9
g, 16.51 mmol) portion wise. The mixture was stirred at RT for 16 h. The mixture
was poured into ice cooled water and the solid formed was filtered off, washed with
water and dried under reduced pressure to afford title compound as pale brown solid
2.8 g (70 %).lU NMR (400 MHz, DMSO-^s) 5 11.27 (s, 1H), 8.46 (d, .7=2.1 Hz, 1H),
8.30 (d, J=1.9 Hz, 1H), 2.48-2.41 (m, 4H), 2.25-2.19 (m, 2H); LC-MS: m/z 297
(M+H)+.
Step-e: 5'-amino-7'-bromospiro[cyclobutane-1.3'-indolin]-2'-one (le):
To a solution of 7'-bromo-5'-nitrospiro[cyclobutane-1,3'-indolin]-2'-one (2.8
g, 9.45 mmol) in EtOH (30 mL) and H20 (15 mL) were added iron powder (2.6 g,
47.25 mmol) and NH4C1 (2.5 g, 47.25 mmol). The mixture was heated to 100 °C for
3 h. The mixture was cooled to RT, filtered through celite and washed with EtOAc.
The combined filtrate was concentrated. 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
yellow solid 2.5 g (49%);'H NMR (400 MHz, DMSO-^) 5 10.04 (s, 1H), 6.82 (d,
J=2.0 Hz, 1H), 6.55 (d, J=2.0 Hz, 1H), 4.98 (s, 2H), 2.44-2.39 (m, 2H), 2.22-2.07 (m
4H); LC-MS: m/z 267.5 (M+H)+.
Step-f: N-(7'-bromo-2'-oxospiro[cyclobutane-1.3'-indolin]-5'-yl)-2.4-difluoro
benzenesulfonamide (Intermediate 1):
To an ice cooled solution of 5'-amino-7'-bromospiro[cyclobutane-1,3'-
indolin]-2'-one(2.3 g, 8.61 mmol) in DCM (30 mL) were added pyridine (4.2 mL,
51.66 mmol) followed by 2,4-difluorobenzenesulfonyl chloride (1.3 mL,9.47 mmol)
dropwise. The mixture was stirred at RT for 2 h. The mixture was diluted with DCM
(100 mL), washed with water (100 mL) and brine (100 mL), dried over sodium
sulphate and concentrated under reduced pressure and column purified to afford the
title compound as off white solid (1.8 g, 48%).1HNMR (400 MHz, DMSO-d6): 5
10.54 (s, 1.H), 10.51 (s; 1H), 7.89- 7.83 (m, 1H), 7.59-7.53 (m, 1H), 7.28-7.23 (m,
2H), 7.02 (d, J=l.5 Hz, 1H), 2.44-2.33 (m, 2H), 2.23-2.03 (m, 4H); LC-MS: m/z
445.0 (M+3H)3+.
The below intermediates 2 and 3 were prepared according to the procedure
depicted in step-f of intermediate-1 by using 5'-amino-7'-bromospiro[cyclobutane-
1,3'-indolin]-2'-one as a starting compound and in presence of appropriate reactants,
reagents, solvents and in appropriate conditions. The characterization data for the
intermediates are detailed in below table.
Intermediate-4: 2.4-difluoro-N-f7'-nitro-2'-oxospiro[cyclobutaiie-13'-indolin]-5'-
yl)benzenesulfonamide:
Step-a: Synthesis of 5'-aminospiro[cyclobutane-1.3'-indolin]-2'-one (4a):
The compound was prepared using the procedure of step-e of Intermediate-1.
'H NMR (400 MHz, DMSO-&): 5 9.77 (s, 1H), 6.82 (d, J=2.0 Hz, 1H), 6.47 (d,
7=7.8 Hz, 1H), 6.39-6.36 (m, 1H), 4.69 (s, 2H), 2.44-2.37 (m, 2H), 2.20-2.00 (m,
4H); LC-MS: m/z 189.2 (M+l)+.
Step-b: 2-(2'-oxospiro[cyclobutane-1.3'-indolin]-5'-yl)isoindoline-1.3-dione
(Mi
To a solution of 5'-aminospiro[cyclobutane-1,3'-indolin]-2'-one (3.6 g, 18.99
mmol) in AcOH (35 mL) was added pthalic anhydride (4.2 g, 20.48 mmol). The
mixture was heated to 100 °C for 2 h. The mixture was poured into crushed ice and
the solid formed was filtered off, washed with water and dried under reduced
pressure to afford the title product as brown solid (4.5 g, 75%).'H NMR (400 MHz,
DMSO-J*): 5 10.43 (s, 1H), 7.98-7.90 (m, 4H), 7.33 (d, 7=1.9 Hz, 1H), 7.24-7.21 (m,
1H), 6.92 (d, J=8.3 Hz, 1H), 2.48-2.43 (m, 2H), 2.32-2.14 (m, 4H); LC-MS: m/z
319.1 (M+l)+.
Step-c: 2-(7'-nitro-2'-oxospiro[cyclobutane-1.3'-indolin]-5'-yl)isoindoline-1.3-
dione (4c):
To a solution of 2-(2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)isoindoline-
1,3-dione (9.2 g, 28.93 mmol) in AcOH (100 mL) at RT was added nitric acid (9.0
m.L) dropwise. The mixture was heated to 110 °C for 2 h. The mixture was poured
into ice cooled water and the solid formed was filtered off, washed with water and
dried under reduced pressure to afford title compound as brown solid (10.5 g). 'H
NMR(400 MHz, DMSO-40: 5 10.19 (s, 1H), 8.15 (d, J=1.5 Hz, 1H), 8.13 (d, J=1.5
Hz, 1H), 8.02-7.93 (m, 4H), 2.51-2.48 (m, 2H), 2.39-2.37 (m, 4H); LC-MS: m/z
364.1 (M+l)+.
Step-d: 5'-amino-7'-nitrospiro[cyclobutane-1.3'-indolin]-2'-one (4dV
To a solution of 2-(7'-nitro-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)iso-
indoline-1,3-dione (10.5 g, 28.92 mmol) in EtOH (100 mL) was added hydrazine
hydrate (21 mL) and then heated to 100 °C for 2h. Reaction mixture was poured into
ice cooled water and the solid formed was filtered off, washed with water and dried
under reduced pressure to afford the title compound (5.5 g). 'H NMR (400 MHz,
DMSO-J5): 5 10.52 (s, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.11 (d, J=1.9 Hz, 1H), 5.38 (s,
2H), 2.54-2.48 (m, 2H), 2.48-2.14 (m, 4H); LC-MS: m/z234.\ (M+l)+.
Step-e: Synthesis of2.4-difluoro-N-f7'-nitro-2'-oxospiro[cyclobutane-l .3'-
indolin]-5'-yl)benzenesulfonamide (Intermediate-4):
To an ice cooled solution of 5'-amino-7'-nitrospiro[cyclobutane-1,3'-indolin]-
2'-one (2.0 g, 8.58 mmol) in DCM (20 mL) were added pyridine (1.4 mL, 17.16
mmol) followed by 2,4-difluorobenzenesulfonyl chloride (1.7 mL, 12.87 mmol)
dropwise. The mixture was at RT for 3 h. The mixture was diluted with DCM (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 yellow solid
(2.5 g, 89 %.).'HNMR(400 MHz, DMSO-^): 5 11.0 (s, 1H), 10.86 (s, 1H), 7.95-
7.83 (m, 1H), 7.68 (d, J=1.5 Hz, 1H), 7.62 (d, 7=1.5 Hz, 1H), 7.56 (t, J=8.8 Hz, 1H), .
7.30-7.25 (m, 1H), 2.47-2.40 (m, 2H), 2.35-2.12 (m, 4H).
Intermediate-5: Methyl 5'-amino-2'-oxospiro[cyclobutane-L3'-indoline]-7'-
carboxylate:
Step-(a): Methyl 5'-nitro-2'-oxospiro[cyclobutane-1.3'-indoline]-7'-
carboxylate f5a):
To a solution of 7'-bromo-5'-nitrospiro[cyclobutane-1,3'-mdolin]-2'-one (1.0
g, 3.37 mmol) in triethyl amine (30 mL) were added xantphos (0.19 g, 0.337 mmol),
palladium(ll)acetate (0.15 g, 0.674) and methanol (4 mL). The mixture was purged
with carbon monoxide gas for 10 min and then heated to 80 °C for 16 h under carbon
monoxide atmosphere. The mixture was diluted with EtOAc (100 mL) and washed
with IN HC1 (100 mL), water (100 mL) and brine (100 mL), dried over sodium
sulphate and concentrated under reduced pressure and column purified to afford the
title compound as yellow solid (0.45 g, 48%.). 'H NMR (400 MHz, DMSO-ck): 5
10.87 (s, 1H), 8.66 (d, J=2A Hz, 1H), 8.53(d, J=2.5 Hz, 1H), 3.90 (s, 3H), 2.45-2.32
(m, 4H), 2.28-2.16 (m, 2H); LC-MS: m/z 277.1 (M+H)+.
Step-(bV Methyl 5'-amino-2'-oxospiro[cyclobutane-1.3'-indoline]-7'-
carboxylate (Intermediate 5):
The compound was prepared using the procedure of step-e of Intermediate-1.
'H NMR (400 MHz, DMSO-4s): 5 9.67 (s, 1H), 7.11 (d, J=2.5 Hz, 1H), 6.93(d, .7=2.4
Hz, 1H), 5.03 (s, 2H), 3.80 (s, 3H), 2.46-2.40 (m, 2H), 2.26-2.12 (m, 4H); LC-MS:
m/z 247.2 (M+H)+.
Intermediate-6: 5'-amino-N-(l-methylpiperidin-4-ylV2'-oxospiro[cyclobutane-1.3'-
indoline]-7'-carboxamide
Step a: 5'-nitro-2'-oxospiro[cvclobutane-1.3'-indo]ine]-7'-carboxylic acid (6a)
To a solution of methyl 5'-nitro-2'-oxospiro[cyclobutane-1,3'-indoline]-7'-
carboxylate (0.35 g, 1.27 mmol) in THF (4 mL) was added lithium hydroxide
monohydrate (0.21 g, 5.08 mmol) in 2 mL of water. The mixture was stirred at RT
for 16 h. The mixture was concentrated, diluted with water, acidified with IN HC1
and extracted with EtOAc (100 mL), washed with brine (100 mL), dried over sodium
sulphate and concentrated under reduced pressure to afford the solid title compound
(0.2 g, 60%). 'HNMR (400 MHz, DMSO-Jd): 5 13.80 (bs, 1H), 10.56 (s, 1H), 8.63
(d, J=2.4 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H), 2.56-2.50 (m, 2H), 2.49-2.41 (m,. 2H),
2.31-2.20 (m, 2H); LC-MS: m/z 263.1 (M+H)+.
Step-b: N-(l-methylpiperidin-4-ylV5'-nitro-2'-6xospiro[cyclobutane-1.3'-
indoline]-7'-carboxamide (6bV
To a solution of 5'-nitro-2'-oxospiro[cyclobutane-1,3'-indoline]-7'-carboxylic
acid (0.2 g, 0.76 mmol) in DCM (10 mL) were added l-methylpiperidin-4-amine
(0.14 mL, 1.14 mmol), HOBt (0.15 g, 1.14 mmol), EDC.HC1 (0.22 g, 1.14 mmol)
and diisopropyl ethylamine (0.4 mL, 2.29 mmol). The mixture was stirred at RT for
16 h. The mixture was poured into ice water and solids were filtered off. The mixture
was then washed with water and dried under reduced pressure to afford the solid title
compound (0.18 g, 66%). 'HNMR (400 MHz, DMSO-^6): 5 10.19 (bs, 1H), 8.86 (bs,
1H), 8.65 (d, J=2.0 Hz, 1H), 8.54 (d, J=1.9 Hz, 1H), 3.81-3.70 (m, 1H), 2.86-2.82
(m, 2H), 2.47-2.42 (m, 4H), 2.38-2.24 (m, 2H), 2.23 (s, 3H), 2.18-2.03 (m, 2H),
1.83-1.80 (m32H), 1.66-1.55 (m, 2H); LC-MS: m/z 359.1 (M+H)+.
Step-c: 5'-amino-N-fl-methylpiperidin-4-ylV2'-oxospiro[cyclobutane-1.3'-
indoline]-7'-carboxamide (Intermediate-6).
The compound was prepared using the procedure of step-e of Intermediate-1.
'H NMR (400 MHz, DMSO-4,): 5 9.23 (s, 1H), 8.17 (d, J=7.8 Hz, 1H), 7.01 (d,
7=1.9 Hz, 1H), 6.78 (d, J=1.9 Hz, 1H), 4.95 (bs, 2H), 3.76-3.66 (m, 1H), 2.85-2.82
(m, 2H), 2.45-2.39 (m, 2H), 2.23 (s, 3H), 2.23-2.07 (m, 6H), 1.78-1.74 (m, 2H),
1.63-1.57 (m,2H); LC-MS: m/z 329.2 (M+H)+.
Intertnediate-7: 7'-amino-5'-bromospiro[cyclobutane-1.3'-indolin]-2'-one
Step-(a): 5'-bromospiro[cyclobutane-L3'-indolin]-2'-one (7a):
To a solution of spiro[cyclobutane-1,3'-indolin]-2'-one (5.0 g, 28.73 mmol) in
acetonitrile (50 mL) at RT was added N-bromo succinimide (6.1 g, 34.47 mmol)
portion wise. The mixture was stirred at RT for 2 h. The mixture was poured into
crushed ice and the solid formed was filtered off. The mixture was washed with
water and dried under reduced pressure to afford the title compound as off white
solid (6.1 g). 'H NMR (400 MHz, DMSO-^j): 510.34 (s, 1H), 7.75 (d, J=2.0 Hz, 1H),
7.33 (dd, J;=2.0 Hz, J2=83 Hz, 1H), 6.74 (d, .7=8.1 Hz, 1H), 2.40-2.31 (m, 4H),
2.28-2.16 (m, 2H); LCMS: m/z 253.0 (M+H)+.
Step-(b): 5'-bromo-7'-nitrospiro[cyclobutane-1.3'-indolin]-2'-one f7b):
The compound was prepared using the procedure of step-c of Intermediate-1.
'HNMR (400 MHz, DMSO-^): 511.15 (s, 1H), 8.22 (d, J=1.4 Hz, 1H), 8.09 (d,
7=1.9 Hz, 1H), 2.46-2.42 (m, 4H),.2.24-2.20 (m, 2H); LCMS: m/z 296.0 (M+H)+.
Step-(c): 7'-amino-5'-bromospiro[cyclobutane-1.3'-indolin]-2'-one
(Intermediated:
The compound was prepared using the procedure of step-e of Intermediate-1.
'H NMR (400 MHz, DMSO-Jtf): 5 9.81 (s, 1H), 6.96 (d, J=l .5 Hz, 1H), 6.68 (d,
/=2.0 Hz, 1H), 5.08 (s, 2H), 2.41-2.35 (m, 2H), 2.28-2.22 (m, 2H), 2.19-2.11 (m,
2H); LCMS: m/z 267.0 (M + H)+.
Intermediate-8: 5'-amino-7'-cyclopropylspiro[cyclobutane-1.3'-indolin]-2'-one
Step-a: 7'-cyclopropyl-5'-nitrospiro[cyclobutane-l.3'-indolin]-2'-one (8a):
To a stirred solution of 7'-bromo-5'-nitrospiro[cyclobutane-1,3'-indolin]-2'-
one (0.200 g, 0.673 mmol) in mixture of solvents 1,4-dioxane (10 mL): water (3 mL)
was added potassium phosphate (0.285 g, 1.34 mmol), Pd(amphos)Cl2 (0.047 g,
0.067 mmol) and cyclopropylboronic acid (0.069 g, 0.807 mmol). The mixture was
purged with nitrogen gas for 10-15 min and heated to 100-110°C for 12 h under
nitrogen atmosphere or in a sealed tube. The mixture was poured into ice cold water
(10 mL) and extracted with ethyl acetate. The combined extracts were washed with
water, dried over MgSC>4 and evaporated. The obtained crude product was purified by
silica gel chromatography using a mixture of 70 % ethyl acetate/hexane as an eluent
to get the title compound as a pale yellow solid (0.120 g, 69.36%); LC-MS: 257.0
[M-H]
Step-b: 5'-amino-7'-cyclopropylspiro[cyclobutane-1.3'-indolin]-2'-one
fIntermediate-8):
The process of this, step was adopted from step-c of Intermediate-7 (0.050 g,
51.55%); LC-MS: 229.1 [M+H]+.
Intermediate-9: 5'-nitro-7'-(4.4.5.5-tetramethyl-1.3.2-dioxaborolari-2-yl)spiro[cyclo-
butane-1.3'-indolin]-2'-one
To a solution of 7'-bromo-5,-nitrospiro[cyclobutane-1,3'-indolin]-2'-one (1.0
g, 3.38 mmol) and 4,4,4',4,,5,535,J5'-octamethyl-2,2,-bi(1,3;2-dioxaborolane) (1.76 g,
7.76 mmol) in 1,4-dioxane (20 mL) in sealed tube was added potassium acetate (1.0
g, 10.14 mmol). The reaction mixture was purged with nitrogen gas for 10 min and
then Pd(dppf)2Cl2«DCM (0.28 g, 0.39 mmol) was added. The mixture was again
purged with nitrogen gas for 5 min and then heated to 100 °C for 16 h. The mixture
was diluted with EtOAc (150 mL) and washed with water (150 mL) and brine (150
-40 °C and stirred for 1 h. The mixture was again cooled to -78 °C and 1,1,1-
trifluoro-N-phenyl-N-((trifIuoromethyl)sulfonyl)methanesulfonamide (2.9 g, 8.26
mmol) in THF (5 mL)was added over a period of 5 min. The mixture was slowly
brought to 0 °C followed by stirring for 4 h, cooling to -78 °C and quenching with 1
mL of MeOH in 10 mL of EtOAc. The mixture was slowly brought to RT and
concentrated under reduced pressure. The residue was dissolved in 20 mL of diethyl
ether and 20 mL of pentane was added. This organic layer was concentrated under
reduced pressure and purified by combi flash to afford the title compound as
colorless oil (1.20 g, 57 %). 'HNMR (400 MHz, DMSO-d6): 5 8.88 (d, J=l.9 Hz,
1H), 8.70-8.69 (m, 1H), 8.06-8.04 (m, 1H), 7.59-7.55 (m, 1H), 6.29 (d, J=4.9 Hz,
1H), 5.72 (d, J=4.9 Hz, 1H); LC-MS: m/z 254.1 (M+H)+.
Intermediate-11: l-(Pyridin-2-yl)vinyl trifluoromethanesulfonate
The process of this step was adopted from Intermediate-10. 'H NMR (400
MHz, DMSO-Jtf): 5 8.68 (d, J=4.4 Hz, 1H), 7.99-7.94 (m, 1H), 7.89-7.87 (m, 1H),
7.52-7.49 (m, 1H), 6.45 (d, J=4.4 Hz, 1H), 5.77 (d, J=4.4 Hz, 1H); LC-MS: m/z
254.1 (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: 2.4-difluoro-N-(7'-(3-hydroxyphenyl)-2'-oxospiro[cyclobutane-1.3'-
indolin]-5'-yl)benzenesulfonamide: (Compound-D
lntermediate-1 Compound-1
To a solution of N-(7'-bromo-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-2,4-
difluoro benzenesulfonamide (intermediate-1) (0.15 g, 0.34 mmol) in 1,4-dioxane (8
mL) and H20 (2 mL) were added (3-hydroxyphenyl)boronic acid (0.057 g, 0.41
mmol), potassium phosphate (0.22 g, 1.02 mmol). The mixture was degassed with
nitrogen purging for 20 min. Then Pd(Amphos)Cl2(0.024 g, 0.034 mmol) was added
and the mixture was heated at 100°C for 16 h. The mixture was concentrated under
ireduced pressure and the residue was diluted with EtOAc (100 ml), washed with
water (100 mL), brine (100 mL), dried over sodium sulphate and concentrated under
reduced pressure and column purified to afford the title compound as white solid
(0.07 g, 45%).'1HNMR(400 MHz, DUSO-d6): 5 10.39 (s,lH), 10.04 (s, 1H), 9.51
(s, 1H), 7.88-7.82 (m, 1H), 7.58-7.53 (m, 1H), 7.27-7.19 (m, 3H), 6.82 (d, J=2.0 Hz,
HH), 6.75 (dd, Ji=7.8 Hz, J2=1.5 Hz, 1H), 6.69-6.66 (m, 2H), 2.44-2.38 (m, 2H), .
2.24-2.06 (m, 4H); LC-MS: m/z 457.1 (M+H)+.
The below compounds were prepared by procedure similar to the one
described in Example-I with appropriate variations in reactants, quantities of reagents
land reaction conditions. The physiochemical characteristics of the compounds are
also summarized.
Example-II: N-(7'-amino-2'-oxospiro[cvclobutane-13'-indolin]-5'-yiy2-methoxy-
benzenesulfonamide: (Compound-12)
To a solution of N-(7'-bromo-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yi)-2-
methoxybenzenesulfonamide (intermediate-2) (0.2 g, 0.46 mmol) in DMSO (1 mL)
were added copper(l)iodide (0.009 g, 0.046), L-proline (0.01 g, 0.09 mmol), NaOH
(0.03 g, 0.69 mmol) followed by aqueous ammonia (1 mL). The mixture was stirred
at 100 °C in sealed tube for 16 h. The mixture was diluted with EtOAc (100 mL) and
washed with water (100 mL) and brine (50 mL), dried over sodium sulphate and
concentrated under reduced pressure and purified by preparative HPLC to afford the
title compound as pale brown solid (0.03 g, 17%.).'H NTvlR (400 MHz, DMSO-tf,,): 5
9.56 (s, 1H), 9.44 (s, 1H), 7.66 (dd, J=1.5 Hz & 7.9 Hz, 1H), 7.54 (t, J=6.9 Hz, 1H),
7.17 (d, .7=7.8 Hz, 1H), 6.98 (t, J=7.3 Hz, 1H), 6.55 (d, J=1.5 Hz, 1H), 6.35 (d, J=1.4
Hz, 1H), 5.0 (bs, 2H), 3.93 (s, 3H), 2.36-2.31 (m, 2H), 2.20-2.00 (m, 4H); LC-MS:
m/z374.1(M+H)+.
Example-Ill: N-(7'-((cvclopropylmethynamino)-2'-oxospiro[cyclobutane-1.3'-
indolin]-5'-yl)-2-methoxybenzenesulfonamide (PI): (Compound-13) and N-(7'-(but-
3-en-l-ylamino)-2'-oxospiro[cyclobutane-1.3'-indolin]-5'-yl)-2-
methoxvbenzenesulfonamide (P2): (Compound-14)
To a solution of N-(7'-amino-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-2-
methoxy benzenesulfonamide (Compound-12) (0.15 g, 0.4 mmol) in isopropyl
alcohol (0.3 mL) was added(bromomethyl)cyclopropane (0.08 mL, 0.8 mmol). The
mixture was stirred at 120 °C for 16 h. The mixture was diluted with EtOAc (100
mL), washed with water (100 mL) and brine (50 mL), dried over sodium sulphate
and concentrated under reduced pressure and purified by preparative HPLC to afford
the title compounds as off white solids PI (0.006 g, 4 %.) & P2 (0.004 g, 2 %).
Compound-13 (PI): 'H NMR (400 MHz, DMSO-^): 5 9.71 (s, 1H), 9.41 (s, 1H),
7.68-7.66 (m, 1H), 7.53 (t, J=7.9 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 6.97 (t, J=7.8 Hz,
1H), 6.55 (s, 1H), 6.20 (s, 1H), 4.95 (bs, 1H), 3.92 (s, 3H), 2.77-2.75 (m, 2H), 2.33-
2.22 (m, 2H), 2.14-2.0 (m, 4H), 0.93-0.85 (m, 1H), 045 (d, J=7.3 Hz, 2H), 0.17 (d,
J=4.4, 2H); ES-MS: m/z 426.5 (M-H)\ Compound-14 (P2): 'H NMR (400 MHz,
DMSO-4,): 5 9.64 (s, 1H), 9.43 (s, 1H), 7.67 (dd, .7=1.5 Hz & 7.8 Hz, 1H), 7.55-7.51
(m, 1H), 7.16 (d, .7=7.8 Hz, 1H), 6.98 (t, J=7.4, 1H), 6.56 (d, J=1.4 Hz, 1H), 6.20 (d,
.7=1.4 Hz, 1H), 5.86-5.80 (m, 1H), 5.11-5.04 (m, 2H), 4.86 - 4.80 (m, 1H), 3.92 (s,
3H), 2.97-2.95 (m, 2H), 2.33-2.30 (m, 2H), 2.23-2.04 (m, 4H), 2.02-2.00 (m, 2H);
ES-MS: m/z 428.3 (M+H)+.
Example-IV: N-(7'-amino-2'-oxospiro[cyclobutane-1.3'-indolin]-5'-yl)-2.4-difluoro-
benzenesulfonamide: (Compound-15^)
To a solution of 2,4-difluoro-N-(7'-nitro-2'-oxospiro[cyclobutane-1,3'-ind6-
lin]-5'-yl)benzenesulfonamide (intermediate-4) (6.7 g, 16.38 mmol) in EtOH (70 mL)
and H20 (35 mL) were added iron powder (4.6 g, 81.90 mmol) and NH4CI (2.6 g,
49.18 mmol). The mixture was heated to 100 °C for 2 h. The mixture was cooled to
RT, filtered through celite and washed with EtOAc. The combined filtrate was
concentrated, the residue was diluted with water and extracted with EtOAc (200 mL),
washed with brine (200 mL), dried over sodium sulphate and concentrated under
reduced pressure and purified to afford the title compound as brown solid (5.8 g,
93%). 'H NMR (400 MHz, DMSO-^s): 5 10.07 (s, 1H), 9.67 (s, 1H), 7.82-7.76 (m,
1H), 7.55-7.50 (m, 1H), 7.25-7.20 (m, 1H), 6.51 (d, J=1.5 Hz, 1H), 6.28 (d, J=2.0
Hz, 1H), 4.93 (s; 2H), 2.38-2.31 (m, 2H), 2.20-1.99 (m, 4H); ES-MS: m/z 378.1 (M-
H)".
Example-V: 2.4-difluoro-N-(7'-((l-methylpiperidin-3-yl)aminoV2'-oxospiro
[cyclobutane-13'-indolin]-5'-y0benzenesulfonamide f Compound-16)
i To a suspension of N-(7'-amino-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-
2,4-difluorobenzenesulfonamide (compound-15) (0.15 g, 0.39 ramol) in titanium
isopropoxide (1.5 mL) was added l-methylpiperidine-3-one (0.07 g, 0.59 mmol). The
mixture was stirred at RT for 16 h. The mixture was cooled to 0 °C, MeOH (3 mL)
was added followed by NaBHt (0.03 g, 0.78 mmol). The mixture was stirred at RT
ifor 3 h. The mixture was diluted with EtOAc (100 mL), washed with aqueous
ammonia (100 mL) and water (100 mL), dried over sodium sulphate and
concentrated under reduced pressure and column purified to afford the title
compound as off white solid (0.07 g, 37 %). 'H NMR (400 MHz, DMSO-^j): 5 10.06
(bs, 1H), 9.81 (s, 1H), 7.82-7.76 (in, 1H), 7.53 (t, J=8.8 Hz, 1H), 7.22 (t, J=7.8 Hz,
>1H), 6.55 (s, 1H), 6.17(s, 1H), 4.77 (d, J=7.8 Hz, 1H), 3.20-3.15 (m, 1H), 2.70-2.67
(m, 1H), 2.37-2.34 (m, 2H), 2.14 (s, 3H), 2.10-2.05 (m, 4H), 1.98-1.90 (m, 2H), 1.69-
1.65 (m, 3H), 1.49-1.46 (m, 1H), 1.07-1.04 (m, 1H); LC-MS: m/z All.2 (M+H)+.
The below compounds were prepared by procedure similar to the one
idescribed in Example-V with appropriate variations in reactants, quantities of
reagents and reaction conditions. The physiochemical characteristics of the
compounds are also summarized.
Example-VI: Methyl S'-((2.4-difluorophenyl)sulfonamidoV2'-oxospiro [cyclo-
butane-L3'-indoline]-7'-carboxylate (Compound-41') and 5'-ff2.4-difluoro
>phenyl)sulfonamido)-2'-oxospiro[cyclobutane-13'-indoline]-7'-carboxylic acid
(Compound-42^
Step-fiV Methyl 5'-f(7.4-difluorophenyDsulfonamidoV2'-oxospiro[cyclo-
butane-1.3'-indoline]-7'-carboxylate (compound-4P
To a solution of N-(7'-bromo-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-2,4-
difluorobenzenesulfonamide (intermediate-1) (0.1 g, 0.23 mmol) in triethyl amine (5
mL) were added xantphos (0.013 g, 0.023 mmol), palladium(ll)acetate (0.01 g, 0.046
mmol) and methanol (0.09 mL, 2.3 mmol). The mixture was purged with carbon
monoxide gas for 10 min and then heated to 70 °C for 4 h under carbon monoxide
atmosphere. The mixture was diluted with EtOAc (50 mL) and washed with IN HCl
(50 mL), water (50 mL) and brine (50 mL). The mixture was dried over sodium
sulphate, concentrated under reduced pressure and column purified to afford the title
compound as off white solid (0.05 g, 52%). 'HNMR (400 MHz, DMSO-de): 5 10.52
(s, 1H), 10.14 (s, 1H), 7.85-7.81 (m, 1H), 7.57-7.52 (m, 1H), 7.51 (d, 7=2.2 Hz, 1H),
7.38 (d, 7=1.9 Hz, 1H), 7.26-7.23 (m, 1H), 3.81 (s, 3H), 2.42-2.36 (m, 2H), 2.24-2.08
(m, 4H); LC-MS: m/z 423.1 (M+H)+.
Step-(ii): 5'-((2.4-difluorophenyl)sulfonamido)-2'-oxospiro[cyclobutane-1.3'-
indoline]-7'-carboxylic acid (compound-42^
To a solution of methyl 5'-((2,4-difluorophenyl)sulfonamido)-2'-oxo-
spiro[cyclobutane-1,3'-indoline]-7'-carboxylate (0.15 g, 0.35 mmol) in THF (4 mL)
was added lithium hydroxide monohydrate (0.044 g, 1.05 mmol) in 1 mL of water.
The mixture was stirred at RT for 16 h, concentrated, diluted with water, acidified
with IN HCl, extracted with EtOAc (50 mL) and washed with brine (50 mL). The
product was dried over sodium sulphate and concentrated under reduced pressure to
afford the title compound as off white solid (0.12 g, 82%).'H NMR (400 MHz,
DMSO-^s): 5 13.32 (bs, 1H), 10.48 (s, 1H), 9.78 (s, 1H), 7.86-7.78 (m, 1H), 7.58-
7.52 (m, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.26-7.18 (m, 1H),
2.42-2.38 (m, 2H), 2.22-2.10 (m, 4H); LC-MS: m/z 407.1 (M-H)".
Example-VII (Method-A): N-(5'-((2.4-difluorophenyl)sulfonamidoV2'-oxospiro
[cyclobutane-1.3'-indolin]-7'-yl)-l-methylpiperidine-4-carboxamide fCompound-43)
0
NH COOH T
Compound-15 Compound-43
To a solution of N-(7'-amino-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-2,4-
difluorobenzenesulfonamide (compound-15) (0.1 g, 0.26 mmol) in DMF (2 mL)
were added l-methylpiperidine-4-carboxylic acid (0.074 g, 0.52 mmol), triethylamine
(0.14 mL, 1.04 mmol) and PyBOP (0.27 g, 0.52 mmol). The mixture was stirred 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 and column purified to afford the title compound as off white solid (0.01 g,
8%).^ NMR (400 MHz, DMSO-d6) 5 10.22 (bs, 1H), 9.81 (s, 1H), 9.19 (s, 1H),
7.84-7.79 (m, 1H), 7.53 (t, J=8.6 Hz, 1H), 7.27 (s, 1H), 7.24-7.20 (m, 1H), 7.03(d,
J=1.5 Hz,lH), 3.17-3.16 (m, 1H), 2.88-2.85 (m, 2H), 2.41-2.35 (m, 2H), 2.29-1.91
(m, 9H), 1.79-1.76 (m, 2H), 1.68-1.60 (m, 2H): LC-MS: m/z 505.2 (M+H)+.
The below compounds were prepared by procedure similar to the one
described in Example-VII (method-A) with appropriate variations in reactants,
quantities of reagents and reaction conditions. The physiochemical characteristics of
the compounds are also summarized.
(Method-B): 2.4-difluoro-N-(7'-(4-methylpiperazine-l-carbonvl)-2'-ox6spiro
[cyclobutane-1.3'-indolin]-5'-yl)benzenesulfonamide (Compound-47)
To a solution of 5'-((2,4-difluorophenyl)sulfonamido)-2'-oxospiro[cyclo-
butane-1.3'-indoline]-7'-carboxylic acid (compound-42) (0.1 g, 0.24 mmol) inDMF
(3 mL) were added 1-methylpiperazine (0.032 mL, 0.29 mmol), HOBt (0.05 g, 0.36
mmol), EDC.HC1 (0,07 g, 0.36 mmol) and diisopropylethylamine (0.13 mL, 0.72
mmol. The mixture was stirred at RT for 16 h, diluted with EtOAc (50 mL), washed
with water (50 mL) and brine (50 mL), dried over sodium sulphate and concentrated
under reduced pressure and column purified to afford the title compound as white
solid (0.03 g, 25%); 'H NMR (400 MHz, DMSO-d6): 5 10.37 (s, 1H), 10.32 (s, 1H),
7.80-7.78 (m, 1H), 7.57-7.52 (m, 1H), 7.32 (s, 1H), 7.23 (t, J=7.3 Hz, 1H), 6.67 (d,
J=1.5 Hz, 1H), 3.60-3.54 (m, 2H), 3.15-3.04 (m, 2H), 2.44-2.30 (m, 4H), 2.17 (s,
3H), 2.20-2.12 (m, 6H); LC-MS: m/z 491.1 (M+H)+. '
The below compounds were prepared by procedure similar to the one
described in Example-VII (method-B) with appropriate variations in reactants,
quantities of reagents and reaction conditions. The physiochemical characteristics of
the compounds are also summarized.
Exam pie-VIH: 4-Fluoro-N-(7'-(morpholine-4-carbonvl)-2'-oxospiro[cyclobutarie-
1.3'-indo]in]-5'-yl):2-morpholinoben2enesulfonamide: (Compound-61)
To a solution of N-(7'-bromo-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-2,4-
difluorobenzenesulfonamlde (intermediate-1) (0.1 g, 0.23 mmol) in toluene (10 mL)
were added xantphos (0.013g, 0.023 mmol), palladium(ll)acetate (0.01 g, 0.046
mmol), potassium phosphate (0.15 g, 0.69 mmol) and morpholine (0.024 mL, 0.28
mmol). The reaction mixture was purged with carbon monoxide gas for 10 min and
then heated to 110 °C for 6 h under carbon monoxide atmosphere. 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 and purified by
preparative HPLC to afford the title compound as brown solid (0.03 g, 27%). 'H
NMR (400 MHz, DMSO-dfi): 5 10.30 (s, 1H), 9.58 (s, III), 7.94-7.91 (m, 1H), 7.29
(dd, J=2.6 Hz & 10.8 Hz, 1H), 7.20 (d, J=2.1 Hz, 1H), 7.12-7.08 (m, 1H), 6.67 (d,
.7=2.1 Hz, 1H), 3.82-3.80 (m, 4H), 3.65-3.37 (m, 6H), 3.10-3.03 (m, 2H), 2.90-2.88
(m, 4H), 2.42-2.36 (m, 2H), 2.20-2.07 (m, 4H); LC-MS: m/z 545.2 (M+H)+.
Example-IX: 2.4-Difluoro-N-(2'-oxo-7'-(pyridin-4-ylamino)spiro[cyclobutane-1.3'-
indolin]-5'-yl)benzenesulfonamide (Compound-62)
To a solution of N-(7'-amino-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-2,4-
difluorobenzenesulfonamide (compound-1.5) (0.1 g, 0.26 mmol) in HC1 in 1,4-
dioxane (10 mL) was added 4-chloropyridine (0.025 mL, 0.26 mmol) in a sealed
tube. The mixture was heated to 110 °C for 16 h. The mixture was diluted with DCM
(50 mL), washed with aqueous sodium bicarbonate (50 m,L) and brine (50 mL), dried
over sodium sulphate, concentrated under reduced pressure and purified by
preparative HPLC to afford the title compound as white solid (0.025 g, 21%). 'H
NMR (400 MHz, DMSO-&): 5 10.38 (bs, 1H), 10.01 (s, 1H), 8.13 (d, .7=6.3 Hz, 2H),
8.08 (s, 1H), 7.85-7.79 (m, 1H), 7.61-7.55 (m, 1H), 7.29-7.25 (m, 1H), 7.10 (d, J=1.5
Hz, 1H), 6.77 (d, J=1.5 Hz, 1H), 6.47 (d, J=5.8 Hz, 2H), 2.45-2.33 (m, 2H), 2.20-
2.08 (m, 4H); LC-MS: m/z 457.1 (M+H)+.
Example-X: N-(5'-((2.4-difluorophenyl)sulfonamidoV2'-oxospiro[cyclobutane-1.3'-
indolin]-7'-yl)acetamide (Compound-63)
A solution of N-(7'-amino-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-2,4-
difluorobenzenesulfonamide (compound-15) (0.15 g, 0.39 mmol) in acetic anhydride
(1 mL) was stirred at RT for 48 h. The mixture was poured into ice water and the
solid formed was filtered off. The product was washed with water and dried under
reduced pressure to afford the title compound as white solid (0.08 g, 48 %). 'H NMR
(400 MHz, DMSO-d6): 5 10.35 (s, 1H), 9.78 (s, 1H), 9.32 (s, 1H), 7.85-7.78 (m, 1H),
7.56-7.50 (m, 1H), 7.25-7.20 (m, 1H), 7.14 (s, 1H), 7.05 (d, .7=1.5 Hz, 1H), 2.43-2.33
(m, 2H), 2.17-2.00 (m, 4H), 1.98 (s, 3H); LC-MS: m/z 422.1 (M+H)+.
Example-XI: 5'-((2-methoxyphenyl)sulfonamido)-2'-oxo-N-(piperidin-4-ynspiro
[cyclobutane-1.3'-indoline]-7'-carboxamide (Compound-64)
Step-(i): Methyl 5'-((2-methoxypheny0sulfonamido)-2'-oxospiro[cyclo-
butane-1.3'-indoline]-7'-carboxylate (64.11
The process of this step was adopted from step-(i) of Example-VI. 'H NMR
(400 MHz, DMSO-^0: 5 10.05 (s, 1H), 9.90 (s, 1H), 7.72-7.69 (m, 1H), 7.55-7.48
(m, 1H), 7.42 (s, 1H), 7.40 (s, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.01-6.98 (m, 1H), 3.90
(s, 3H), 3.79 (s, 3H), 2.39-2.32 (m, 2H), 2.19-2.11 (m, 4H); LC-MS: m/z 417.0
(M+H)+.
Step-(ii): 5'-((2-Methoxyphenyl)sulfonamido)-2'-oxospiro[cyclobutane-1.3'-
indoline]-7'-carboxylicacid (64.21
The process of this step was adopted from step-(ii) of Example-VI. 1HNMR
(400 MHz, DMSO-rf«): 5 12.02 (bs, 1H), 9.86 (s, 1H), 9.68 (s, 1H), 7.71-7.69 (m,
1H), 7.52-7.50 (m, 1H), 7.46 (d, J=1.9 Hz, 1H), 7.38 (d, J=2.5 Hz, 1H), 7.16 (d,
J-8.3 Hz, 1H), 7.02-6.98 (m, 1H), 3.90 (s, 3H), 2.45-2.32 (m, 2H), 2.25-2.16 (m,
4H); LC-MS: m/z 403.0 (M+H)+.
Step-(iii): tert-Butyl 4-f5'-ff2-memoxvphenyl)sulfonamido>2'-oxospiro
[cyclobutane-13'-indoline]-7'-carboxamido')piperidine-l-carboxylate (64.3s)
The process of this step was adopted from Example-VII (Method-B). lH
NMR (400 MHz, DMSO-rfs): 5 9.76 (s, 1H), 9.68 (s, 1H), 8.32 (d, J=7.9 Hz, 1H),
7.64 (dd, J=\ ,5 Hz & 7.8 Hz, 1H), 7.59-7.54 (m, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.21
(d, J=8.3 Hz, 1H), 7.13 (d, J=1.5 Hz, 1H), 6.99 (t, .7=7.6 Hz, 1H), 3.92 (s, 3H), 3.87-
3.85 (m, 1H), 2.82-2.78 (m, 2H), 2.39-2.33 (m, 2H), 2.19-2.14 (m, 2H), 2.08-1.94
(m, 4H), 1.78-1.76 (m, 2H), 1.41 (s, 9H), 1.39-1.27 (m, 2H); LC-MS: m/z 583.2 (M-
H)-.
Step-(ivV 5'-((2-Methoxyphenyflsulfonamido)-2'-oxo-N-(piperidin-4-yl)spiro
[cyciobutane-1.3'-indoUne]-7'-carboxamide (compound-64)
To a solution of tert-butyl 4-(5'-((2-methoxyphenyl)sulfonamido)-2'-oxo-
spiro[cyclobutane-1,3'-indoline]-7'-carboxamido)piperidine-l-carboxylate (0.08 g,
0.136 mmol) in DCM (2 mL) wasadded TFA (0.05 mL, 0.68 mmol) at RT for 3 h.
The mixture was diluted with DCM and washed with saturated NaHC03. The organic
layer was dried over sodium sulphate, concentrated under reduced pressure and
washed with diethyl ether to afford the title compound as pale yellow solid (0.03 g,
45%). 'H NMR (400 MHz, DMSO-^): 5 8.34 (d, J=7.3 Hz, 1H), 7.64 (dd, J=1.4 Hz
& 7.8 Hz, 1H), 7.58-7.54 (m, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H),
7.11 (d, J=2.0 Hz, 1H), 6.98 (t, J=7.9 Hz, 1H), 3.92 (s, 3H), 3.79-3.72 (m, 1H), 2.95
(d, J=12.2 Hz, 2H), 2.67-2.47 (m, 3H), 2.50-2.48 (m, 2H), 2.40-1.94 (m, 4H)1.72 (d,
J=9.8 Hz, 2H), 1.44-1.24 (m, 2H); LC-MS: m/z 485.2 (M+H)+.
The below compounds were prepared by procedure similar to the one
described in Example-XI with appropriate variations in reactants, quantities of
reagents and reaction conditions. The physiochemical characteristics of the
compounds are also summarized.
* Isomer-1 and 2 were separated by using Chiral HPLC under below conditioi
Column: Chiralpak-IA(250*4.6*5.0u)
Mobile phase-A: 0.1% DEA in n-Hexane; Mobile phase-B:Ethanol
Isocratic: 70:30(A:B); Flow rate: 1.0 ml/min
Column temp: Ambient
Diluent: Mobile phase
Exarnple-XH: 2.4-Difluoro-N-(7'-(hydroxymethyn-2'-oxospiro[cyclobutane-13'-
indolin]-5'-yl)benzenesulfonamide (Compound-69^
To a cooled solution of methyl 5'-((2,4-difluorophenyl)sulfonamido)-2'-oxo-
spiro[cyclobutane-1,3'-indoline]-7'-carbdxylate (compound-41) (0.15 g, 0.35 mmol)
in THF (5 mL) was added Red-Al 60 % in toluene (0.21 g, 1.05 mmol). The mixture
was stirred at RT for 16 h. The reaction mixture was then quenched with rochelle
salt, extracted with EtOAc (50 mL) and washed with water (50 mL) and brine (50
mL), dried over sodium sulphate, concentrated under reduced pressure and purified
by preparative TLC to afford the title compound as off white solid (0.08 g, 57 %).'H
NMR (400 MHz, DMSO-2.2 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H),
3.09-3.06 (m, 2H), 2.67-2.56 (m, 2H), 2.42-2.32 (m, 4H), 2.19-2.03 (m, 4H), 1.70-
1.67 (m, 2H), 1.35-1.23 (m, 3H), 1.13-1,01 (m, 2H); LC-MS: m/z 476.2 (M+H)+.
Step-iv: 2.4-Difluoro-N-(7'-r2-(l-methy]piperidin-4-yl)ethyl)-2'-oXospiro
[cyclo butane-1.3'-indolin]-5'-yl)benzenesulfonamide (116)
The process of this step was adopted from Example-XX (compound-89)
alkylation. *HNMR (400 MHz, DMSO-ek): 5 10.27 (s, 1H), 10.10 (bs, 1H), 7.80-
7.74 (m, 1H), 7.55-7.50 (m, 1H), 7.23-7.18 (m, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.62 (d,
.7=1.9 Hz, 1H), 2.76-2.73 (m, 2H), 2.42-2.32 (m, 4H), 2.16 (s, 3H), 2.14-2.04 (m,
4H), 1.85-1.78 (m, 2H), 1.63-1.57 (m, 2H), 1.24-1.22 (m, 3H), 1.18-1.04 (m, 2H);
LC-MS: m/z 490.2 (M+H)+.
Step-i: N-(7'-(1.2-dihydroxy-l-phenylethyl)-2'-oxospiro[cyclobutane-1.3'-
indolin]-5'-ylV2-methoxybenzenesulfonarnide (117.1)
To a solution of 2-methoxy-N-(2'-oxo-7,-(l-phenylvinyl)spiro[cyclobutane-
1,3'-indolin]-5'-yl)benzenesulfonamide (0.6 g, 1.30 mmol) in acetone (6 mL) were
added NMO (0.27 mL, 2.6 mmol) and osmium tetroxide 4 % in water (0.03 mL)
followed by stirring at RT for 16 h. The reaction mixture was quenched with aqueous
sodium metabisulfite and extracted with EtOAc. The organic layer was dried over
sodium sulphate, concentrated under reduced pressure and purified by combi flash to
afford the title compound as off white solid (0.48 g, 75%).
Step-ii: N-(7'-benzoyl-2'-oxospiro[cyclobutane-1.3'-indolin]-5'-ylV2-
methoxybenzenesulfonamide (117)
To a solution of N-(7'-(l,2-dihydroxy-l-phenylethyl)-2'-oxospiro[cyclo-
butane-1,3'-indolin]-5'-yl)-2-methoxybenzenesulfonamide (0.48 g, 0.97 mmol) in
mixture of THF (8 mL) and water (1 mL) was added sodium meta periodate (2.06 g,
9.70 mmol) followed by stirring at 80 °C for 2 h. The mixture was diluted with water
and extracted with EtOAc. The organic layer was dried over sodium sulphate,
concentrated under reduced pressure and purified by combi flash to afford the title
compound as white solid (0.24 g, 55 %).
Example-XXXI: N-(7'-(hydroxy(phenyl)methyl)-2'-oxospiro[cyclobutane-1.3'-
indolin]-5'-yl)-2-methoxybenzenesulfonamide Compound-118
To a cold solution of N-(7'-benzoyl-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-
yl)-2-methoxybenzenesulfonamide (0.1 g, 0.216 mmol) in MeOH (4 mL) was added
sodium borohydride (0.025 g, 0.65 mmol) followed by stirring at RT for 16 h. The
mixture was concentrated under reduced pressure, diluted with water and extracted
with EtOAc (50 ml x 2). The organic layer was dried over sodium sulphate,
concentrated under reduced pressure and purified by combi flash to afford the title
icompound as white solid (0.03 g, 30 %); 'H NMR (400 MHz, DMSO-J6): 5 10.15 (s,
1H), 9.57 (s, 1H), 7.62 (dd, J=1.5 Hz, 7.9 Hz, 1H), 7.55-7.51 (m, 1H), 7.26-7.21 (m,
5H), 7.19-7.09 (m, 2H), 7.00-6.94 (2H), 5.76 (d, J=3.4 Hz, 1H), 5.69 (d, .7=3.4 Hz,
1H), 3.83 (s, 3H), 2.39-2.32 (m, 2H), 2.18-2.00 (m, 4H); LCMS: m/z 463.1 (M-H)".
lExample-XXXII: N-(7'-( 1 -hydroxy-1 -phenylethyl)-2'-oxospiro[cyclobutane-1.3'-
indolin]-5'-ylV2-methoxybenzenesulfonamide (Compound-120)
To a stirring suspension of ZnCl2 (0.0003 g, 0.022 mmol) in THF was added
imethyl magnesium bromide (0.47 mL, 0.66 mmol) followed by stirring at RT for 1 h.
The mixture was cooled to 0 °C and N-(7'-benzoyl-2'-oxospiro [cyclobutane-1,3'-
indolin]-5'-yl)-2-methoxy benzenesulfonamide (0.1 g, 0.22) in THF was added
followed by stirring at 0 °C for 2 h. The reaction mixture was quenched with
saturated ammonium chloride and extracted with EtOAc. The organic layer was dried
lover sodium sulphate, concentrated under reduced pressure and purified by combi
flash to afford the title compound as white solid (0.02 g, 20 %). 'H NMR (400 MHz,
DMSO-J6): 5 9.57 (s, 1H), 8.69 (s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.58 (t, J=6.8 Hz,
1H), 7.22 (d, J=6.9 Hz, 2H), 7.17-7.15 (m, 5H), 7.00 (t, J=7:8Hz, 1H), 6.83 (d, J=1.9
Hz, 1H), 6.09 (s, 1H), 3.88 (s, 3H), 2.37-2.31 (m, 2H), 2.15-2.05 (m, 4H), 1.64 (s,
i3H); LCMS: m/z 477.1 (M-H)".
Example-XXXHI: i-(7'-Cyclopropyl-2'-oxospiro[cyclobutane-K3'-indolin]-5'-ylV3-
(2-methoxyphenyl)urea (Compound-121.)
5 -
A mixture of intermediate-8 (0.1 g, 0.43 mmol) and pyridine (0.113 g, 1.31
mmol) in DCM (10 mL) was cooled to 0 °C. l-Isocyanato-2-methoxybenzene
(0.0065 g, 0.43 mmol) was then added. The mixture was gradually warmed to RT
5and stirred for 2 h. The solid formed was filtered, washed with ether and hexanes to
get the title compound (0.07 g, 42 %). 1H-NMR (400MHz DMSO-^): 10.18 (s, 1H),
9.14 9s, 1H), 8.13-8.10 (m, 2H), 7.53 9s, 1H), 7.01 (d, 1H), 6.94-6.86 (m, 2H), 6.63
(s, 1H), 3.87 (s, 3H), 2.50-2.41 (m, 4H), 2.26-2.14 (m, 4H), 1.93-1.92 (m, 1H), 0.92
(d, 2H), 0.59 (d, 2H). LC-MS: m/z 378.1 (M+H)+.
10
Example-XXXIV: 2-Methoxy-N-(2'-oxo-7'-( 1 -(pyridin-3 -yl)ethyl)spiro [cyclo-
butane-1,3'-indolin]-5'-yl)benzenesulfonamide (Compound 122)
Step-i: 5'-Nitro-7'-ri-(pyridin-3-vnvinyl)spiro[cyclobutane-1.3'-indolin]-2'-
15one
To a solution of 5'-nitro-7'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro-
[cyclobutane-1,3'-indolin]-2'-one (intermediate-9) (0.5 g, 1.45 mmol) in 1,4-dioxane
(10 mL) and H20 (3 mL) in a sealed tube were added l-(pyridin-3-yl)vinyl trifluoro
methanesulfonate (intermediate-10) (0.73 g, 2.90 mmol) and sodium carbonate (0.38
20g, 3.62 mmol). The mixture was degassed with nitrogen purging for 20 min. Then Pd
(PPh3)4 (0.17 g, 0.145 mmol) was added followed by heating at 100 °C for 16 h. The
mixture was concentrated under reduced pressure and the residue was diluted with
EtOAc (100 ml), washed with water (100 mL) and brine (100 mL), dried over
sodium sulphate, concentrated under reduced pressure and purified by combi flash to
25afford the title compound as yellow solid (0.4 g). 'H NMR (400 MHz, DMSO-tf6): 5
10.72 (s, 1H), 8.57 (d, J=2.5 Hz, 1.H), 8.54 (d, .7=1.5 Hz, 1H), 8.53 (dTJ=1.0 Hz, 1H),
7.90 (d, J= 2.4 Hz, 1H), 7.68-7.53 (m, 1H), 7.40-7.36 (m, 1H), 6.10 (s, 1H), 5.56 (s,
1H), 2.48-2.41 (m, 4H), 2.28-2.22 (m, 2H); LCMS: m/z 322.2 (M+H).
Step-ii: 5'-Amino-7'-(l-rpyridin-3-ynethynspiro[cyclobutane-1.3'-indolin]-2'-
one
i To a solution of 5'-nitro-7'-(l-(pyridin-3-yl)vinyl)spiro[cyclobutane-1,3'-
indolin]-2'-one (0.4 g, 1.51 mmol) in MeOH (5 mL) was added Palladium hydroxide
(0.2 g) followed by stirring under H2 bladder pressure at RT for 6 h. The mixture was
filtered through celite bed and washed with EtOAc. The organic layer was
concentrated under reduced pressure and purified by combi flash to afford the title
^compound as white solid (0.18 g). 'H NMR (400 MHz, DMSO-d«): 5 10.01 (s, 1H),
8.52 (d, J=2.4 Hz,.lH), 8.38 (dd, J-1.4 Hz, 4.9 Hz, 1H), 7.64 (d, J=7.9 Hz, 1H),
7.32-7.29 (m, 1H), 6.69 (d, J=2.0 Hz, 1H), 6.32 (d, J = 2.0 Hz, 1H), 4.69 (bs, 2H),
4.23 (q, J=7.4 Hz, 1H), 2.44-2.33 (m, 2H), 2.20-2.08 (m, 4H), 1.49 (d, J=7.4 Hz,
3H); LCMS: m/z 294.2 (M+H).
Step-iii: Synthesis of 2-methoxy-N-(2'-oxo-7'-(l-(pyridin-3-yl)ethyl)spiro-
[cyclobutane-1.3'-indolin]-5'-yDbenzenesulfonamide
To an ice cooled solution of 5'-amino-7'-(l-(pyridin-3-yl)ethyl)spiro[cyclo-
butane-1,3'-indolin]-2'-one (0.15 g, 0.51 mmol) in DCM (6 mL) were added pyridine
(0.2 mL, 2.55 mmol) and 2-methoxy benzenesulfonyl chloride (0.13 g, 0.61 mmol)
folloed by stirring at RT for 3 h. The mixture was diluted with DCM (100 mL) and
washed with water (100 mL) and brine (100 mL), dried over sodium sulphate and
concentrated under reduced pressure and purified by preparative HPLC to afford the
title compound as white solid (0.05 g, 21 %). 'H NMR (400 MHz, DMSO-rf6): 8
10.33 (s, 1H), 9.55 (s, 1H), 8.40-8.37 (m, 2H), 7.61 (dd, 7=1.5 Hz, 7.8 Hz, 1H), 7.56-
17.52 (m, 1H), 7.35-7.32 (m, 1H), 7.29-7.26 (m, 1H), 7.13-7.11 (m, 2H), 6.97 (t, J=7.4
Hz, 1H), 6.74 (d, J=1.9 Hz, 1H), 4.20 (q, J=6.9 Hz, 1H), 3.84 (s, 3H), 2-40-2.32 (m,
2H), 2.20-2.05 (m, 4H), 1.38 (d, J=6.8 Hz, 3H); LCMS: m/z 464.2 (M+H)+.
Exatnple-XXXV: 2-Methoxy-N-(2'-oxo-7'-n-(pyridin-2-yl)ethyl)spiro [cvclobutane- '
iL3'-indolin]-5'-yl)benzenesulfonamide (Compound 123)
Step-i: 5'-Nitro-7'-ri-fpyridin-2-ynvinvnspiro[cyclobutane-13'-indolin]-2'-
one
The process of this step was adopted from Example-XXXIV of step-i.
'H NMR (400 MHz, DMSO-d6): 5 10.73 (s, 1H), 8.53 (d, 7=4.9 Hz, 1H), 8.47 (d,
7=2.5 Hz, 1H), 7.90 (d, .7=2.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.53 (d, J = 7.9 Hz, 1H),
7.35-7.32 (m, 1H), 6.43 (s, 1H), 5.65 (s, 1H), 2.46-2.41 (m, 2H), 2.28-2.19 (m, 4H);
LCMS:m/z 322.1 (M+H)+.
Step-ii: 5'-Amino-7'-ri-(pyridin-2-vnethyl)spiro[cyclobutane-1.3'-indolin]-2'-
one
The process of this step was adopted from Example-XXXIV of step-ii.
'HNMR (400 MHz, DMSO-J6): 5 10.0 (s, 1H), 8.57 (d, J=3.9 Hz, 1H), 7.70-7.66
(m, 1H), 7.29 (d, 7=7.8 Hz, 1H), 7.21-7.18 (m, 1H), 6.65 (d, 7=2.4 Hz, 1H), 6.28 (d,
J= 1.9 Hz, 1H), 4.64 (bs, 2H), 4.31 (q, 7=6.8 Hz, 1H), 2.42-2.33 (m, 2H), 2.17-2.06
(m, 4H), 1.50 (d, J=7.4 Hz, 3H); LCMS: m/z 294.0 (M+H)+.
Step-iii: 2-Methoxy-N-(2'-oxo-7'-(l-(pyridin-2-yl)ethyl)spiro[cyclobutane-
1.3'-indolin]-5'-ynbenzenesulfonamide
The process of this step was adopted from Example- XXXIV of step-iii.
'H NMR (400 MHz, DMSO-J6): 5 10.35 (s, 1H), 9.48 (s, 1H), 8.50 (d, .7=3.9 Hz,
1H), 7.68-7.64 (m, 1H), 7.57-7.54 (m, 1H), 7.53-7.48 (m, 1H), 7.22-7.19 (m, 1H),
7.14-7.08 (m, 3H), 6.93 (t, 7=7.8 Hz, 1H), 6.73 (d, .7=2.0 Hz, 1H), 4.28 (q, .7=6.9 Hz,
1H), 3.83 (s, 3H), 2.40-2.33 (m, 2H), 2.20-2.05 (m, 4H), 1.38 (d, 7=6.8 Hz, 3H);
LCMS: m/z 464.2 (M+H)+.
Example-XXXVI: 2-Methoxy-N-(2'-oxo-7'-(pyridin-2-yloxy)spiro[cyclobutane-1.3'-
indolinl-5'-yl)benzenesulfonamide (Compound 124)
Step-i: 7'-Hydroxy-5'-nitrospiro[cyclobutane-1.3'-indolin]-2'-one
To a cold solution of 5'-nitro-7'-(4,4,5,5-teframethyl-1,3,2-dioxaborolan-2-yl)-
spiro[cyclobutane-1,3'-indolin]-2'-one (0.45 g, 1.31 mmol) in THF (10 mL) was
added hydrogen peroxide 30 % in water (2.5 mL) followed by stirring at RT for 6 h.
The mixture was diluted with water and extracted with EtOAc. The organic layer was
dried over sodium sulphate and concentrated under reduced pressure. The obtained
solid was washed with diethyl ether to afford the title compound as yellow solid
(0.35 g). 'HNMR (400 MHz, DMSO-d&): 5 10.78 (s, 1H), 10.54 (s, 1H), 8.01 (d,
7=2.0 Hz, 1H), 7.61 (d, 7=1.9 Hz, 1H), 2.43-2.39 (m, 4H), 2.25-2.16 (m, 2H).
Step-ii: 5'-Nitro-7Wpyridin-2-yloxy)spiro[cvclobutanc-1.3'-indolin]-2'-one
To a solution of 7'-hydroxy-5'-nitrospiro[cyclobutane-1,3'-indolin]-2'-one
(0.18 g, 0.72 mmol) in DMF (2 mL) was added potassium carbonate (0.3 g, 2.16
mmol) and 2-fluoro pyridine (0.14 g, 1.44 mmol) followed by heating to 150 °C for
16 h. The mixture was diluted with EtOAc and washed with water. The organic layer
was dried over sodium sulphate, concentrated under reduced pressure and purified by
combi flash to afford the title compound as yellow solid (0.11 g, 50 %). 'HNMR
(400 MHz, DMSO-rf6): 5 11.20 (s, 1H), 8.40 (d, .7=1.9 Hz, 1H), 8.11 (dd, J=1.5 Hz,
4.9 Hz, 1H), 7.97 (d, J=1.9 Hz, 1H), 7.92-7.88 (m, 1H), 7.18-7.14 (m, 2H), 2.47-2.42
(m, 4H), 2.26-1.98 (m, 2H); LCMS: m/z 312.1 (M+H)+.
Step-iii: 5'-Amino-7'-(pyridin-2-yloxy)spiro[cyclobutane-L3'-indolin]-2'-one:
The process of this step was adopted from step-e of Intermediate-1. 'H NMR
(400 MHz, DMSO-rf6): 5 9.95 (s, 1H), 8.11 (dd, 7=1.4 Hz, 4.9 Hz, 1H), 7.82-7.78 (m,
1H), 7.09-7.06 (m, 1H), 6.94 (d, .7=8.3 Hz, 1H), 6.72 (d, .7=1.9 Hz, 1H), 6.14 (d,
J=2.0, 1H), 4.89-4.88 (bs, 2H), 2.46-2.40 (m, 2H), 2.33-2.14 (m, 4H); LCMS: m/z
282.2 (M+H)+.
Step-iv: 2-Methoxy-N-(2'-oxo-7'-(pvridin-2-yloxy)spiro[cyclobutane-1.3'-
indolin]-5'-yl)benzenesulfonamide
The process of this step was adopted from step-f of Intermediate-1. 'H NMR
(400 MHz, DMSO-ck): 5 10.32 (s, 1H), 9.75 (s, 1H), 8.06 (d, 7= 4.4 Hz, 1H), 7.81 (t,
J=8.4 Hz, 1H), 7.69 (d, 7=7.8 Hz, 1H), 7.56 (t, 7=8.3 Hz, 1H), 7.17-7.09 (m, 3H),
7.01 (t, 7=7.3 Hz, 1H), 6.92 (d, J=8.3 Hz, 1H), 6.63 (s, 1H), 3.85 (s, 3H), 2.42-2.32
(m, 2H), 2.19-2.07 (m, 4H); LCMS: m/z 452.2 (M+H)+.
Example-XXXVH: N-(7'-ffluorofphenyl)memyl)-2'-oxospiro[cyclobutane-1.3'-
indolin]-5'-yl)-2-methoxybenzenesulfonaimide (Compound .125)
To a cold solution of N-(7'-(hydroxy(phenyl)methyl)-2'-
oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-2-methoxybenzenesulfonamide (0.09 g,
0.19 mmol) in DCM (4 mL) was added DAST (0.025 mL, 0.19 mmol) followed by
stirring at RT for 30 min. The mixture was diluted with DCM and washed with
saturated NaHCO3. The organic layer was dried over sodium sulphate, concentrated
and purified by combi flash to afford the title compound as brick red solid (0.03 g, 33
%). 1H NMR (400 MHz, DMSO-d6): δ 10.48 (s, 1H), 9.66 (s, 1H), 7.60 (d, 7= 7.8
Hz, 1H), 7.54 (t, 7=7.3 Hz, 1H), 7.38-7.37 (m, 3H), 7.26 (s, 1H), 7.18 (d, 7=6.4 Hz,
2H), 7.10 (d, 7=8.3 Hz, 1H), 6.97 (t, 7=7.4 Hz, 1H), 6.80 (s, 1H), 6.69-6.58 (m, 1H), .
3.79 (s, 3H), 2.40-2.32 (m, 2H), 2.20-2.09 (m, 4H); LCMS: m/z 467.2 (M+H)+.
Example-XXXVIII: 2.4-Difluoro-N-C2'-oxo-7'-ri-phenylethyl)spiro[cyclobutane-
l.,3'-indolin]-5'-yl)benzenesulfonamide (Compound 126)
Step-i: 2.4-Difluoro-N-f2'-oxo-7'-(l-phenyIvinyl)spiro[cyclobutane-1.3'-
indolin]-5'-yl)benzenesulfonamide
The process of this step was adopted from Example-I. 'H NMR (400 MHz,
DMSO-J5): 5 10.22 (s, 1H), 9.94 (s, 1H), 7.76-7.70 (m, 1H), 7.53-7.48 (m, 1H), 7.31-
7.29 (m, 4H), 7.24-7.20 (m, 1H), 7.12-7.08 (m, 2H), 6.51 (d, J-2.0 Hz, 1H), 5.77 (s,
1H), 5.20 (s, 1H), 2.43-2.32 (m, 2H), 2.21-2.12 (m, 4H); LC-MS: m/z 467.1 (M+H)+.
Step-ii: 2.4-Difluoro-N-(2'-oxo-7'-(l-phenylethyl)spiro[cyclobutane-1.3'-
indolin]-5'-yl)benzenesulfonamide
The process of this step was adopted from Example-XXVTfl. 'H NMR (400
MHz, DMSO-d6): 5 10.37 (s, 1H), 10.16 (s, 1H), 7.72-7.66 (m, 1H), 7.52-7.47 (m,
1H), 7.26-7.19 (m, 4H), 7.17-7.07 (m3 3H), 6.66 (d, J=1.9 Hz, 1H), 4.20 (q, J=6.8
Hz, 1H), 2.40-2.33 (m, 2H), 2.20-2.07 (m, 4H), 1.35 (d, J=7.4 Hz, 3H); LC-MS: m/z
469.1 (M+H)+.
Biological Data
In-Vitro biochemical data of spiro[cyclobutane-1,3'-indolin]-2'-one
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. Chem., 54, 3827-3838, 2011).
In the assay, optimized concentration of in-house BetBRD4 bromo-
domain protein and 300 nM of acetyl histone peptide substrate were diluted in
assay buffer (50 mM HEPES, pH: 7.5, 50 raM NaCI, 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 to sigmoid curve fitting equation using Graph Pad
Prism software V5.
The compounds were screened in the above mentioned assay and the
results (IC50) are summarized in the table below. 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
greater than 1000 nM.
Claims
1. A compound of formula (I)
wherein
Cy is a 4-12 membered monocyclic or bicyclic ring containing 0-4 hetero-
atoms independently selected form N, O or S;
L is a linker selected from -N(R3a)S(O)2-, -S(O)2N(R3b)-, -C(R3c)(OR3d)-,
-N(R3e)C(O)-, -N(R3f)C(O)N(R3g)- or -N(R3h)C(O)CH(R3i)-;
R3a, R3b,R3c,R3d,R3c, R3f, R3g, R3h and R3i are selected, independently, from
hydrogen or C1-7 alkyl;
R2 is halogen, C1-7 alkoxy, amino, cyano, oxo, -C(O)O-C1-7 alkyl,
optionally substituted aryl or optionally substituted heterocyclyl, wherein the optional
substitution at each occurrence is, independently, selected from 1-3 substituents
selected from halogen or C1-7 alkoxy;
in case wherein
L is -S(O)2N(R3b)-, -C(R3c)(OR3d)-, -N(R3c)C(O)-, -N(R3f)C(O)N(R3g)- or
-N(R3h)C(O)CH(R3i)-;
then
R1 is hydrogen, C1-7 alkyl, halogen, hydroxy C1-7 alkyl, C3-10 cycloalkyl,
optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted
heterocyclyl C1-7 alkyl, optionally substituted aryl C 1.7 alkyl, optionally substituted
aryl C2-7alkenyl, -NRaRb, -C(O)NRcRd, -C(O)ORe, -C(O)Rf,-C(ORg)-aryl,
-C(ORh)(Ri)-aryl or -ORj; herein the optional substitution at each occurrence is,
independently, selected from 1-3 substituents selected from halogen, hydroxy, C1-7
alkyl or C1-7alkoxy; except that R1 is not hydrogen when L is -S(O)2NH- or
-CH(OHT)-, and R, is not hydrogen or halogen when L is -NHC(O)CH(CH3)-;
in case wherein
L is -N(R3a)S(O)2-
then
R1 is-NRaRb3-C^NRcRd,-C(O)ORe, -C(O)Rf,-C(ORg)-aryl,
-C(ORh)(Ri)-aryl or -ORj, -CH(CH3)-aryl, hydroxy C1-7 alkyl, aryl halo C1-7 alkyl,
optionally substituted heterocyclyl C1-7 alkyl, optionally substituted aryl, optionally
substituted aryl C2-7 alkenyl, optionally substituted 9-12 membered heterocyclic ring
having 1-3 heteroatoms selected from N or O, pyridinyl having 1-2 substituents
selected from halogen, hydroxy or C1-7alkoxy, 2-oxopiperidinyl, fluorophenyl C1-7
alkyl, 1-methylpiperidinyl (when at least one of R2 is halogen), piperidinyl (when at
least two of R2 is C1-7alkoxy), phenyl C1-7 alkyl (when at least one of R2 is halogen
and at least one another of R2 is C1-7alkoxy); wherein the optional substitution at each
occurrence is, independently, selected from 1-3 substituents selected from halogen,
hydroxy, oxo, C1-7 alkyl or C1-7alkoxy;
Ra, Rb, Rc and Rd are, independently, selected from hydrogen, C1-7 alkyl, C2-7
alkenyl, -C(O)-C1-7 alkyl, optionally substituted heterocyclyl, optionally substituted
C3-10 cycloalkyl, optionally substituted heterocyclyl C1-7 alkyl, optionally substituted
aryl, optionally substituted aryl C1-7 alkyl, optionally substituted C3-10 cycloalkyl C1-7
alkyl, optionally substituted -C(O)heterocyclyl; wherein the optional substitution at
each occurrence is, independently, selected from 1-3 substituents selected from C1-7
alkyl, -C(O)-C1-7alkyl, -C(O)O-C1-7 alkyl, halogen, aryl C1-7alkyl, C1-7alkoxy, oxo or
hydroxy C1-7 alkyl;
Re, Rf, Rg, Rh, Ri and Rj are, independently, selected from hydrogen, C1-7 alkyl,
optionally substituted aryl or optionally substituted heterocyclyl wherein the optional
substitution at each occurrence is, independently, selected from 1-3 substituents
selected from C1-7alkyl or hydroxy C1-7alkyl; and
'm' is selected from 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim I, wherein the compound is represented by
formula (IA):
wherein R1, R.2,Cy, L and 'm' are as defined in claim 1, or a pharmaceutically
acceptable salt thereof.
3. A compound according to claim 1 or 2, wherein the compound is
represented by formula (IB):
wherein R1, R2, R3a, Cy and 'm' are as defined in claim 1, or a pharmaceutically
acceptable salt thereof.
4. A compound according to claim 1 or 2, wherein the compound is
represented by formula (IC):
wherein R1, R2, R3f, R3g, Cy and 'm' are as defined in claim 1, or a pharmaceutically
acceptable salt thereof.
5. A compound according to claim 1 or 2, wherein the compound is
represented by formula (ID):
wherein R1, R2, R3e, Cy and 'm' are are as defined in claim 1, or a pharmaceutically
acceptable salt thereof.
6. A compound according to any of claims 1 to 5, wherein Cy is aromatic or
non-aromatic cyclic ring with 5-10 ring atoms of which 0-4 are heteroatoms selected
from a group consisting of N, O and S.
7. A compound according to claim 6, wherein Cy is phenyl, C3-10cycloallcyl or
a 5-6 membered heterocyclic ring having 1-3 heteroatoms selected from N or O.
8. A compound according to any of claims 1 to 7, wherein Cy is phenyl, C3-10
cycloalkyl or a 5-6 membered heterocyclic ring having 1-3 heteroatoms selected from
N or O;
L is a linker selected from -N(R3a)S(O)2-, -N(R3c)C(O)- or
-N(R3f)C(O)N(R3g)-;
R3a, R3e,, R3f and R3g, are selected, independently, from hydrogen or C1-7 alkyl;
R2 is halogen, C1-7alkoxy, cyano, -C(O)O-C1-7 alky 1 or a 5-6 membered
heterocyclic ring having 1-3 heteroatoms selected from N or O;
in case wherein
L is -N(R3e)C(O)- or -N(R3f)C(O)N(R3g)-
then
R1 is hydrogen, C1-7alkyl, halogen, hydroxy C1-7alkyl, C3-10 cycloalkyl,
optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted
heterocyclyl C1-7alkyl, optionally substituted aryl C1-7alkyl, optionally substituted
aryl C2-7alkenyl, -NRaRb, -C(O)NRcRd, -C(O)ORe, -C(O)Rf,-C(ORs)-aryl,
-C(ORh)(R,)-aryl or -ORj; wherein the optional substitution at each occurrence is,
independently, selected from 1-3 substituents selected from halogen, hydroxy, C1-7
alkyl or C1-7alkoxy;
in case wherein
L is-N(R3a)S(O)2-
then
R1 is -NRaRb, -C(O)NRcRd) -C(O)ORe, -C(O)Rfj-C(ORg)-aryl;
-C(ORh)(Ri)-aryl or -ORj, -CH(CH3)-aryl, hydroxy C1-7alkyl, aryl halo C1-7 alkyl,
optionally substituted heterocyclyl C1-7 alkyl, optionally substituted aryl, optionally
substituted aryl C2-7alkenyl, optionally substituted 9-12 membered heterocyclic ring
having 1-3 heteroatoms selected from N or O, pyridinyl having 1-2 substituents
selected from halogen, hydroxy or C1-7alkoxy, 2-oxopiperidinyl, fluorophenyl C1-7
alkyl, 1-methylpiperidinyl (when at least one of R2 is halogen), piperidinyl (when at
least two of R2 is C1-7 alkoxy), phenyl C1-7 alkyl (when at least one of R2 is halogen
and at least one another of R2 is C1-7 alkoxy); wherein the optional substitution at each
occurrence is, independently, selected from 1-3 substituents selected from halogen,
hydroxy, oxo, C1-7 alkyl or C1-7 alkoxy;
Ra, Rb, Rc and Rd are, independently, selected from hydrogen, C1-7 alkyl, C2-7
alkenyl, -C(O)-C1-7 alkyl, optionally substituted heterocyclyl, optionally substituted
C3-10 cycloalkyl, optionally substituted heterocyclyl C1-7 alkyl, optionally substituted
aryl, optionally substituted aryl C1-7 alkyl, optionally substituted C3-10 cycloalkyl C1-7
alkyl, optionally substituted -C(O)heterocyclyl; wherein the optional substitution at
each occurrence is, independently, selected from 1-3 substituents selected from C1-7
alkyl, -C(O)-C1-7 alkyl, -C(O)O-C1-7 alkyl, halogen, aryl C1-7 alkyl, C1-7 alkoxy, oxo or
hydroxy C1-7 alkyl;
Re, Rf, Rg, Rh, Ri and Rj are, independently, selected from hydrogen, C1-7 alkyl,
optionally substituted aryl or optionally substituted heterocyclyl wherein the optional
substitution at each occurrence is, independently, selected from 1-3 substituents
selected from C1-7 alkyl or hydroxy C1-7 alkyl; and
'm' is selected from 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
9. A compound according to any of claims 1 to 8, wherein L is a linker
selected from -NHS(O)2-, -NHC(O)- or-NHC(O)NH-. .
1.0. A compound according to any of claims 1 to 9, wherein L is -NHS(O)2-.
11. A compound according to any of claims 1-3 or 6-10, wherein
Cy is phenyl,
L is-NHS(O)2-,
R2 is halogen or C1-7alkoxy,
R1 is -NHRa, -C(O)NHRC, -C(O)ORe, -C(O)Rf,-C(OH)phenyl,
-C(OH)( C1-7alkyl)phenyl or -ORj, -CH(CH3)phenyl, hydroxy C1-7alkyl, aryl halo C1-7
alkyl, optionally substituted heterocyclyl C1-7alkyl, optionally substituted phenyl,
optionally substituted phenyl C2-7 alkenyl, optionally substituted 9-12 membered
heterocyclic ring having 1-3 heteroatoms selected from N or O, pyridinyl having 1-2
substituents selected from halogen, hydroxy or C1-7 alkoxy, 2-oxopiperidinyl,
fluorophenyl C1-7 alkyl, 1-methylpiperidinyl (when at least one of R2 is halogen),
piperidinyl (when at least two of R2 is C1-7alkoxy), phenyl C1-7 alkyl (when at least
one of R2 is halogen and at least one another of R2 is C1-7alkoxy); wherein the
optional substitution at each occurrence is, independently, selected from 1-3
substituents selected from halogen, hydroxy, oxo, C1-7 alkyl or C1-7 alkoxy;
Ra and Rc are, independently, selected from hydrogen, C1-7 alkyl, C2-7 alkenyl,
-C(O)-C1-7 alkyl, optionally substituted C3-10 cycloalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclyl C1-7 alkyl, optionally substituted C3-10
cycloalkyl C1-7 alkyl, optionally substituted -C(O)heterocyclyl; wherein the optional
substitution at each occurrence is, independently, selected from 1-3 substituents
selected from C1-7 alkyl, -C(O)-C1-7 alkyl, -C(O)0-C1-7 alkyl, halogen, phenyl C1-7
alkyl, C1-7 alkoxy, oxo of hydroxy C1-7 alkyl;
Re is hydrogen or C1-7 alkyl;
Rf and Rj are independently optionally substituted phenyl or optionally
substituted heterocyclyl wherein the optional substitution at each occurrence is,
independently, selected from 1-3 substituents selected from C1-7alkyl or hydroxy C1-7
alkyl;
wherein heterocyclyl at each occurrence is a 5-10 membered heterocyclic ring
having 1-4 heteroatoms selected from O, N, or S; and
'm' is selected from 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
12. A compound according to any of claims 1-11, wherein Cy-(R2)m is
selected from one of the following groups or tautomers thereof
13. A compound according to any of claims 1-12, wherein R1 is selected from
one of the following groups or tautomers thereof
14. A compound according to any of claims 1-12, wherein R1 is -NHRa or
-C(O)NHRc, wherein Ra, and Re are, independently, selected from one of the
following groups or tautomers thereof
15. A compound according to any of claims 1 to 14, wherein R2 is halogen or
C1-7 alkoxy and m is selected from 0, 1, 2 or 3.
16. A compound according to claim 15, wherein R2 is fluoro or methoxy and
m is selected from 1 or 2.
17. A compound according to claim 1 selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
18. A pharmaceutical composition comprising a compound according to any
of claims 1-17 together with a pharmaceutically acceptable carrier.
19. A method for the treatment or prevention of diseases or disorders where
bromodomain inhibition is desired comprising administering to a subject in need.,.,
thereof a therapeutically effective amount of a compound according to any of claims
1-17.
20. A method according to claim 19, wherein the disease or disorder is an
autoimmune disease, an inflammatory disease or cancer.
21. Use of a compound according to any of claims 1-17 in the manufacture of
a medicament for the treatment or prevention of diseases or disorders where
bfomodomain inhibition is desired.
22. Use according to claim 21, where the disease or disorder is an
autoimmune disease, inflammatory disease or cancer.