Note: Descriptions are shown in the official language in which they were submitted.
1
SUBSTITUTED PHENYLAMINO-OXAZOLE-4-CARBOXYLIC ACID AMIDES AS TYK2
KINASE INHIBITORS
This invention relates to compounds that inhibit or modulate the activity of
JAK kinases, in
particular TYK2 kinase, and to the use of the compounds in the treatment or
prophylaxis of
disease states or conditions mediated by the kinases.
Background of the Invention
Protein kinases constitute a large family of structurally related enzymes that
are responsible
for the control of a wide variety of signal transduction processes within the
cell (Hardie and
Hanks (1995) The Protein Kinase Facts Book. I and II, Academic Press, San
Diego, CA).
The kinases may be categorized into families by the substrates they
phosphorylate (e.g.,
protein-tyrosine, protein-serine/threonine, lipids, etc.). Sequence motifs
have been identified
that generally correspond to each of these kinase families (e.g., Hanks and
Hunter, FASEB
J., (1995) 9. 576-596; Knighton, etal., Science, (1991) 253, 407-414; Hiles,
etal., Cell, (1992)
70, 419-429; Kunz, etal., Cell, (1993) 73, 585-596; Garcia-Bustos, et al.,
EMBO J., (1994)
13, 2352-2361).
Protein kinases may be characterized by their regulation mechanisms. These
mechanisms
include, for example, autophosphorylation, transphosphorylation by other
kinases, protein-
protein interactions, protein-lipid interactions, and protein-polynucleotide
interactions. An
individual protein kinase may be regulated by more than one mechanism.
Kinases regulate many different cell processes including, but not limited to,
proliferation,
differentiation, apoptosis, motility, transcription, translation and other
signalling processes, by
adding phosphate groups to target proteins. These phosphorylation events act
as molecular
on/off switches that can modulate or regulate the target protein biological
function.
Phosphorylation of target proteins occurs in response to a variety of
extracellular signals
(hormones, neurotransmitters, growth and differentiation factors, etc.), cell
cycle events,
environmental or nutritional stresses, etc. The appropriate protein kinase
functions in
signalling pathways to activate or inactivate (either directly or indirectly),
for example, a
metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion
channel or pump, or
transcription factor. Uncontrolled signalling due to defective control of
protein phosphorylation
has been implicated in a number of diseases, including, for example,
inflammation, cancer,
allergy/asthma, disease and conditions of the immune system, disease and
conditions of the
central nervous system, and angiogenesis.
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The Janus kinase (JAK) family is a family of intracellular non-receptor
tyrosine kinases,
ranging in size from 120-140 kDa, that transduce cytokine-mediated signals via
the JAK-
STAT pathway. The JAK family plays a role in the cytokine-dependent regulation
of
proliferation and function of cells involved in immune response. Currently,
there are four
known mammalian JAK family members: JAK1, JAK2, JAK3 and TYK2. JAK1, JAK2 and
TYK2 are ubiquitously expressed whereas JAK3 is expressed in the myeloid and
lymphoid lineages. The JAK family members are non-receptor tyrosine kinases
that
associate with many hematopoietin cytokines, receptor tyrosine kinases and
GPCR's.
Each JAK kinase protein has a kinase domain and a catalytically inactive
pseudo-kinase
domain. The JAK proteins bind to cytokine receptors through their amino-
terminal FERM
(Band-4.1, ezrin, radixin, moesin) domains. After the binding of cytokines to
their
receptors, JAKs are activated and phosphorylate the receptors, thereby
creating docking
sites for signalling molecules, especially for members of the signal
transducer and
activator of transcription (STAT) family (Yamaoka et al, 2004. The Janus
kinases (Jaks).
Genome Biology 5(12): 253).
In mammals, JAK1, JAK2 and TYK2 are ubiquitously expressed. The role of TYK2
in the
biological response to cytokines has been characterized using a mutant human
cell line
that was resistant to the effects of Type I interferons (IFNs) and by
demonstrating that
IFNa responsiveness could be restored by genetic complementation of TYK2
(Velazquez et al, 1992. Cell 70, 313-322). Further in vitro studies have
implicated TYK2
in the signalling pathways of multiple other cytokines involved in both innate
and
adaptive immunity. However, analysis of TYK2-/- mice revealed less profound
immunological defects than were anticipated (Karaghiosoff et al, 2000.
Immunity 13,
549-560; Shimoda et al, 2000. Immunity 13, 561-671). Surprisingly, TYK2
deficient mice
display merely reduced responsiveness to I FNa/11 and signal normally to
interleukin 6
(IL-6) and interleukin 10 (IL- 10), both of which activate TYK2 in vitro. In
contrast, TYK2
was shown to be essential for IL-12 signalling with the absence of TYK2
resulting in
defective STAT4 activation and the failure of T cells from these mice to
differentiate into
IFNy- producing Thl cells. Consistent with the involvement of TYK2 in
mediating the
biological effects of Type I IFNs and IL-12, TYK2-1- mice were more
susceptible to viral
and bacterial infections.
Thus far only a single patient with an autosomal recessive TYK2 deficiency has
been
described (Minegishi et al, 2006. Immunity 25, 745-755). The homozygous
deletion of
four base pairs (GCTT at nucleotide 550 in the TYK2 gene) and consequent
frameshift
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mutation in the patient's coding DNA introduced a premature stop codon and
resulted in
the truncation of the TYK2 protein at amino acid 90. The phenotype of this
null mutation
in human cells was much more severe than predicted by the studies in murine
cells
lacking TYK2. The patient displayed clinical features reminiscent of the
primary
immunodeficiency hyper-IgE syndrome (HIES) including recurrent skin abscesses,
atopic dermatitis, highly elevated serum IgE levels and susceptibility to
multiple
opportunistic infections.
Contrary to reports in TYK2' - mice, signalling by a wide variety of cytokines
was found to
be impaired thus highlighting non-redundant roles for human TYK2 in the
function of
Type I IFNs, IL-6, IL-10, IL-12 and IL- 23. An imbalance in T helper cell
differentiation
was also observed, with the patient's T cells exhibiting an extreme skew
towards the
development of IL-4 producing Th2 cells and impaired Thl differentiation.
Indeed, these
cytokine signalling defects could be reponsible for many of the clinical
manifestations
described, for example atopic dermatitis and elevated IgE levels (enhanced
Th2),
increased incidence of viral infections (IFN defect), infection with
intracellular bacteria
(IL-12/Thl defect) and extracellular bacteria (IL-6 and IL-23/Th17 defect).
Emerging
evidence from genome-wide association studies suggests that single nucleotide
polymorphisms (SNPs) in the TYK2 gene significantly influence autoimmune
disease
susceptibility.
Less efficient TYK2 variants are associated with protection against systemic
lupus
erythematosus (SLE) (TYK2 rs2304256 and rsI2720270, Sigurdsson et al, 2005.
Am. J.
Hum. Genet. 76, 528-537; Graham et al, 2007. Rheumatology 46, 927-930;
Hellquist et
al, 2009. J. Rheumatol. 36, 1631-1638; Jarvinen et al, 2010. Exp. Dermatol.
19, 123-
131) and multiple sclerosis (MS) (rs34536443, Ban et al, 2009. Eur. J. Hum.
Genet. 17,
1309-1313; Mero et al, 2009. Eur. J. Hum. Genet. 18, 502-504), whereas
predicted gain-
of- function mutations increase susceptibility to inflammatory bowel disease
(IBD)
(rs280519 and rs2304256, Sato et al, 2009. J. Olin. lmmunol. 29, 815-825).
In support of the involvement of TYK2 in immunopathologic disease processes,
it has
been shown that B10.D1 mice harbouring a missense mutation in the pseudokinase
domain of TYK2 that results in the absence of encoded TYK2 protein are
resistant to
both autoimmune arthritis (CIA) and experimental autoimmune encephalomyelitis
(EAE)
(Shaw et al, 2003. PNAS 100, 11594- 11599; Spach et al, 2009. J. lmmunol. 182,
7776-
7783). Furthermore, a recent study showed that TYK2 4- mice were completely
resistant
to MOG-induced EAE (Oyamada et al, 2009. J. Immunol. 183, 7539-7546). In these
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mice resistance was accompanied by a lack of CD4 T cells infiltrating the
spinal cord, a
failure to signal through IL-12R and IL-23R and hence the inability to
upregulate
encephalitogenic levels of IFNy and IL-17.
The non-receptor tyrosine kinase TYK2 plays essential roles in both innate and
adaptive
immunity. A lack of TYK2 expression manifests in the attenuated signalling of
multiple
proinflammatory cytokines and a profound imbalance in T helper cell
differentiation.
Furthermore, evidence from genetic association studies supports that TYK2 is a
shared
autoimmune disease susceptibility gene. Taken together, these reasons suggest
TYK2
as a target for the treatment of inflammatory and auto-immune diseases.
Overexpression of TYK2 kinase has been implicated in the development of some
disease states. For example, elevated levels of TYK2 were found in patients
suffering
from progressive pulmonary sarcoidosis (Schischmanoff et al., Sarcoidosis
Vasc.
Diffuse., 2006, 23(2), 101-7).
Several JAK family inhibitors have been reported in the literature which may
be useful in
the medical field (Ghoreschi et al, 2009. Immunol Rev, 228:273-287). It is
expected that
a selective TYK2 inhibitor that inhibits TYK2 with greater potency than JAK2
may have
advantageous therapeutic properties, because inhibition of JAK2 can cause
anemia
(Ghoreschi et al, 2009. Nature lmmunol. 4, 356-360).
Even though TYK2 inhibitors are known in the art there is a need for providing
additional
TYK2 inhibitors having at least partially more effective pharmaceutically
relevant
properties, like activity, selectivity especially over JAK2 kinase, and ADMET
properties.
Thus, an object of the present invention is to provide a new class of
compounds as
TYK2 inhibitors which preferably show selectivity over JAK2 and may be
effective in the
treatment or prophylaxis of disorders associated with TYK2.
W02012/000970 (Cellzome) discloses a series of triazolopyridines as TYK2
kinase
inhibitors. W02011/113802 (Roche) discloses a series of imidazopyridines as
TYK2
kinase inhibitors. The properties of JAK kinases and their relevance as
therapeutic
targets are also disclosed in W02008/156726, W02009/155156, W02010/005841 and
W02010/011375, all in the name of Merck.
W02010/055304 (Sareum) discloses a family of substituted oxazole carboxamides
for
use in the prophylaxis or treatment of autoimmune diseases and in particular
multiple
sclerosis. The compounds disclosed in W02010/055304 are described as being
FLT3
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kinase inhibitors. The kinase inhibiting effect of oxazole carboxamides is
also disclosed
in International patent application W02008/139161 (Sareum).
Summary of the Invention
It has now been found that a subgroup of compounds of the type disclosed in
5 W02008/139161 and W02010/055304 are particularly effective inhibitors of
TYK2
kinase and, furthermore, demonstrate selectivity against TYK2 compared to the
other
three JAK kinases JAK1, JAK2 and JAK3. Such compounds therefore provide a
means
of treating inflammatory conditions and diseases whilst exhibiting reduced or
substantially no side effects associated with JAK1, JAK2 or JAK3 inhibition.
Accordingly, in a first embodiment (Embodiment 1.0), the invention provides a
method of
inhibiting a TYK2 kinase, which method comprises bringing into contact with
the TYK2
kinase an effective TYK2 kinase-inhibiting amount of a compound having the
formula
(0):
Q¨A¨R1
0 (F)n
I N
N
NH2
0 (0)
or a salt or stereoisomer thereof; wherein:
n is 0, 1 or 2;
Arl is selected from phenyl, pyridyl, thienyl and furanyl, each of which is
optionally
substituted with one, two or three substituents independently selected from
halogen, C1-4
alkyl, hydroxyl-C1_4 alkyl, C1-2alkoxy-01_4 alkyl, C1-4 alkoxy, C1_2alkoxy-
C1.4 alkoxy, C2-4
alkenyl, C2_4 alkenyloxy, C2_4 alkynyl, C2_4 alkynyloxy, cyano, 01_4 alkanoyl,
hydroxy and
Ci_4 alkanoyloxy, wherein the C1_4 alkyl and C1_4alkoxy moieties are each
optionally
substituted with one or more fluorine atoms;
Q1 is selected from C(=0), S(=0) and SO2;
A is absent or is NR2;
R1 is selected from:
hydrogen;
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a 01_6 non-aromatic hydrocarbon group optionally substituted with one or more
substituents selected from hydroxyl, C1_2 alkoxy, amino, mono-C1_4 alkylamino,
alkylamino, 3- to 7-membered non-aromatic carbocyclic and heterocyclic rings
containing one or two heteroatom ring members selected from 0, N and S, and
bridged
bicyclic heterocyclic rings of seven to nine ring members of which one or two
are
nitrogen atoms, the carbocyclic and heterocyclic rings and bridged bicyclic
heterocyclic
rings being optionally substituted with one or more hydroxy, C1_4 alkyl, C1-4
alkoxy, C1-4
alkanoyl, CiA alkanoyloxy, C1.4 alkoxycarbonyl or hydroxyl-C1_3 alkyl groups;
and
3- to 7-membered non-aromatic carbocyclic and heterocyclic rings containing
.. one or two heteroatom ring members selected from 0, N and S, and bridged
bicyclic
heterocyclic rings of seven to nine ring members of which one or two are
nitrogen atoms,
the carbocyclic and heterocyclic rings and bridged bicyclic heterocyclic rings
being
optionally substituted with one or more hydroxy, C1.4 alkyl, C1_4 alkoxy, Ci.4
alkanoyl, C1-4
alkanoyloxy, 01-4 alkoxycarbonyl, mono-
01_2 alkylamino-C13 alkyl, di-01-2
alkylamino-Ci_salkyl or hydroxyl-01_3 alkyl groups;
R2 is selected from hydrogen and C1-4 alkyl; or
NR1R2 forms a 4- to 7-membered non-aromatic nitrogen-containing heterocyclic
ring
optionally containing a second heteroatom ring member selected from nitrogen
and
oxygen, the heterocyclic ring being optionally substituted with one or more
hydroxy, C1-4
alkyl, 01_4 alkanoyl, Ci.4 alkanoyloxy, C1.4 alkoxy, Ci_4 alkoxycarbonyl amino-
C1_3alkyl,
mono-C1_2 alkylamino-C1.3 alkyl,
alkylamino-013 alkyl or hydroxy-C1.3 alkyl groups.
Within formula (0), n may be selected from 0 and 1 (Embodiment 1.0A), or n may
be 0
(Embodiment 1.0B) or n may be 1 (Embodiment 1.0C).
In a second embodiment (Embodiment 1.1), the invention provides a method of
inhibiting
a TYK2 kinase, which method comprises bringing into contact with the TYK2
kinase an
effective TYK2 kinase-inhibiting amount of a compound having the formula (1):
QL_A_R1
Ari
I N
N)
NH
NH2
(1)
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or a salt or stereoisomer thereof; wherein:
Arl is selected from phenyl, pyridyl, thienyl and furanyl, each of which is
optionally
substituted with one, two or three substituents independently selected from
halogen, C1-4
alkyl, hydroxyl-01_4 alkyl, C1-2 alkoxy-C14 alkyl, C1_4 alkoxy, C1_2alkoxy-C14
alkoxy, C24
alkenyl, C2_4 alkenyloxy, 02_4 alkynyl, C2.4 alkynyloxy, cyano, C4 alkanoyl,
hydroxy and
01_4 alkanoyloxy, wherein the C1_4 alkyl and 014 alkoxy moieties are each
optionally
substituted with one or more fluorine atoms;
Q1 is selected from C(=0), S(=0) and SO2;
A is absent or is NR2;
R1 is selected from:
hydrogen;
a Ci_e non-aromatic hydrocarbon group optionally substituted with one or more
substituents selected from hydroxyl, C1_2 alkoxy, amino, mono-014 alkylamino,
di-C14
alkylamino, 3- to 7-membered non-aromatic carbocyclic and heterocyclic rings
containing one or two heteroatom ring members selected from 0, N and S, and
bridged
bicyclic heterocyclic rings of seven to nine ring members of which one or two
are
nitrogen atoms, the carbocylic and heterocyclic rings and bridged bicyclic
heterocyclic
rings being optionally substituted with one or more hydroxy, C1_4 alkyl, 01_4
alkoxy, C1-4
alkanoyl, C1.4 alkanoyloxy, C1_4 alkoxycarbonyl or hydroxyl-C1.3 alkyl groups;
and
- 3- to 7-membered non-aromatic carbocyclic and heterocyclic rings
containing
one or two heteroatom ring members selected from 0, N and S, and bridged
bicyclic
heterocyclic rings of seven to nine ring members of which one or two are
nitrogen atoms,
the carbocyclic and heterocyclic rings and bridged bicyclic heterocyclic rings
being
optionally substituted with one or more hydroxy, C1_4 alkyl, C1_4 alkoxy, 01-4
alkanoyl, C1-4
alkanoyloxy, C1_4alkoxycarbonyl, amino-C1_3alkyl, mono-01_2 alkylamino-C1_3
alkyl, di-01.2
alkylamino-C1_3alkyl or hydroxyl-C1_3 alkyl groups;
R2 is selected from hydrogen and C14 alkyl; or
NR1R2 forms a 4-to 7-membered non-aromatic nitrogen-containing heterocyclic
ring
optionally containing a second heteroatom ring member selected from nitrogen
and
oxygen, the heterocyclic ring being optionally substituted with one or more
hydroxy, C14
alkyl, C1_4 alkanoyl, C alkanoyloxy, C1_4 alkoxy, C1.4 alkoxycarbonyl amino-
C1_3alkyl,
mono-C1_2 alkylamino-C1_3alkyl, alkylamino-C1_3 alkyl or hydroxy-C1_3 alkyl
groups.
Particular and preferred aspects and embodiments of the invention are set out
below in
Embodiments 1.2 to 2.26 and 3.1 to 3.3.
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1.2 A method according to any one of Embodiments 1.0 to 1.1 wherein Ari
is
optionally substituted phenyl.
1.3 A method according to any one of Embodiments 1.0 to 1.1 wherein Ari
is
optionally substituted pyridyl.
1.4 A method according to any one of Embodiments 1.0 to 1.1 wherein Arl is
optionally substituted thienyl.
1.5 A method according to any one of Embodiments 1.0 to 1.1 wherein Arl
is
optionally substituted furanyl
1.6 A method according to any one of Embodiments 1.0 to 1.5 wherein the
optional
substituents for Arl are independently selected from halogen, C1_4 alkyl,
hydroxy-C1-4
alkyl, C1_2alkoxy-C1_4 alkyl, C1-4 alkoxy, C1.2 alkoxy-C1.4 alkoxy, C2_4
alkenyl, C2-4
alkenyloxy, 024 alkyhyl, 02-4 alkynyloxy, cyano, C1_4 alkanoyl, hydroxy and C1-
4
alkanoyloxy, wherein the 01_4 alkyl and C1.4 alkoxy moieties are each
optionally
substituted with one or more fluorine atoms.
1.7 A method according to Embodiment 1.6 wherein the optional substituents
for Arl
are independently selected from halogen, C1_3 alkyl, hydroxy-C1_3 alkyl, 01.2
alkoxy-C1-3
alkyl, C1_3 alkoxy, 01-2 alkoxy-C1_3 alkoxy, cyano, Ci.3 alkanoyl and C1.3
alkanoyloxy,
wherein the C1.3 alkyl and C13 alkoxy moieties are each optionally substituted
with one or
more fluorine atoms.
1.8 A method according to Embodiment 1.7 wherein the optional substituents
for Arl
are independently selected from fluorine, chlorine, bromine, C1.3 alkyl,
hydroxy-C1_3 alkyl,
methoxy-C1_3 alkyl, C1_3-alkoxy, methoxy-C1_3 alkoxy, cyano, Ci_3 alkanoyl and
C1-3
alkanoyloxy, wherein the C1.3 alkyl and 01_3 alkoxy moieties are each
optionally
substituted with one or more fluorine atoms.
1.9 A method according to Embodiment 1.8 wherein the optional substituents
for Arl
are independently selected from fluorine, chlorine, bromine, methyl, ethyl,
isopropyl,
hydroxymethyl, hydroxyethyl, methoxyethyl, methoxy, ethoxy, isopropoxy,
methoxyethoxy, cyano, acetyl, acetoxy, trifluoromethyl, trifluoromethoxy,
difluoromethyl
and difluoromethoxy.
1.10 A method according to Embodiment 1.9 wherein the optional substituents
for Arl
are independently selected from fluorine, chlorine, methyl, ethyl, isopropyl,
hydroxymethyl, methoxy, ethoxy, isopropoxy, cyano, acetyl, acetoxy,
trifluoromethyl,
trifluoromethoxy, difluoromethyl and difluoromethoxy.
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1.11 A method according to Embodiment 1.10 wherein the optional substituents
for
Arl are independently selected from fluorine, chlorine, methyl, ethyl,
methoxy, cyano,
acetyl and trifluoromethyl.
1.12 A method according to Embodiment 1.11 wherein the optional substituents
for
Arl are independently selected from fluorine and chlorine.
1.13 A method according to Embodiment 1.12 wherein each substituent is
fluorine.
1.14 A method according to any one of Embodiments 1.1 to 1.13 wherein Arl is
unsubstituted or has 1, 2 or 3 substituents.
1.15 A method according to Embodiment 1.14 wherein Arl is unsubstituted.
1.16 A method according to Embodiment 1.14 wherein Ar' has 1 substituent.
1.17 A method according to Embodiment 1.14 wherein Arl has 2 substituents.
1.18 A method according to Embodiment 1.14 wherein Arl has 3 substituents.
1.19 A method according to Embodiment 1.14 wherein Arl is unsubstituted or has
1 or
2 substituents.
1.20 A method according to any one of Embodiments 1.0 to 1.1, 1.2 and 1.6 to
1.17
wherein Arl is an unsubstituted phenyl group or a 2-monosubstituted, 3-
monosubstituted, 4-monosubstituted, 2,3 disubstituted, 2,4 disubstituted, 2,5
disubstituted or 2,6 disubstituted phenyl group.
1.21 A method according to Embodiment 1.20 wherein Arl is selected from
unsubstituted phenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 2-
methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 2,6-difluorophenyl, 2-fluoro-3-
methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-6-methoxyphenyl, 2-fluoro-6-
methoxyphenyl, 2,6-dichlorophenyl, 2-chloro-6-fluorophenyl, and 5-fluoro-2-
methoxyphenyl.
1.22 A method according to Embodiment 1.21 wherein Arl is selected from 2,6-
difluorophenyl, 2-chloro-6-fluorophenyl and 2,6-dichlorophenyl.
1.23 A method according to Embodiment 1.22 wherein Arl is 2,6-difluorophenyl.
1.23A A method according to Embodiment 1.22 wherein Arl is 2-chloro-6-
fluorophenyl.
1.23B A method according to Embodiment 1.22 wherein Arl is 2,6-dichlorophenyl.
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1.24 A method according to any one of Embodiments 1.0 to 1.23B wherein Q1 is
C(=0).
1.25 A method according to any one of Embodiments 1.0 to 1.23B wherein Q1 is
S(=0).
5 1.26 A method according to any one of Embodiments 1.0 to 1.23B wherein Q1
is SO2.
1.27 A method according to any one of Embodiments 1.0 to 1.26 wherein A is
absent
(i.e. the moieties R1 and Q1 are directly joined together)
1.28 A method according to any one of Embodiments 1.0 to 1.23B wherein A is
absent and Q1 is SO2.
10 1.29 A method according to any one of Embodiments 1.0 to 1.26 wherein A
is NR2.
1.30 A method according to any one of Embodiments 1.0 to 1.29 wherein R1 is
selected from:
hydrogen;
a C1_6 saturated hydrocarbon group optionally substituted with one or more
substituents selected from hydroxy, C1_2 alkoxy, amino, mono-C1_4 alkylamino,
di-C1_4
alkylamino, 3- to 6-membered saturated carbocyclic rings and 4 to 7 membered
heterocyclic rings containing one or two heteroatom ring members selected from
0, N
and S, and bridged bicyclic heterocyclic rings of seven to nine ring members
of which
one or two are nitrogen atoms, the carbocylic and heterocyclic rings and
bridged bicyclic
heterocyclic rings being optionally substituted with one or more hydroxy, 01_4
alkyl, 01-4
alkoxy, C1-4 alkanoyl, C1-4 alkanoyloxy, C1_4alkoxycarbonyl, amino-C1_3alkyl,
mono-01-2
alkylamino-C13alkyI, di-012 alkylamino-C1_3alkyl or hydroxy-01_3 alkyl groups;
and
3- to 6-membered saturated carbocyclic rings and 4 to 7 membered heterocyclic
rings containing one or two heteroatom ring members selected from 0, N and S,
and
bridged bicyclic heterocyclic rings of seven to nine ring members of which one
or two are
nitrogen atoms, the carbocylic and heterocyclic rings and bridged bicyclic
heterocyclic
rings being optionally substituted with one or more hydroxy, C1_4 alkyl, 01_4
alkoxy, C1-4
alkanoyl, C1_4 alkanoyloxy, C14alkoxycarbonyl, mono-C1_2
di-C1_2 alkylamino-Ci_s alkyl or hydroxy-01_3 alkyl groups;
R2, when present, is selected from hydrogen and Ci_4 alkyl; or
NR1R2 forms a 4- to 7-membered saturated nitrogen-containing heterocyclic ring
optionally containing a second heteroatom ring member selected from nitrogen
and
oxygen, the heterocyclic ring being optionally substituted with one or more
hydroxy, C1-4
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alkyl, C1_4 alkanoyl, C1_4 alkanoyloxy, 01_4 alkoxy, 01_4alkoxycarbonyl or
hydroxy-01_3 alkyl
groups.
1.31 A method according to Embodiment 1.30 wherein R1 is selected from:
hydrogen;
- a C1_4 alkyl group optionally substituted with one or more substituents
selected
from hydroxyl, C1_3 alkoxy, amino, mono-C1_3 alkylamino, di-C1_3 alkylamino, 3-
to 5-
membered saturated carbocyclic rings and 4- to 6- membered heterocyclic rings
containing one or two heteroatom ring members selected from 0, N and S, the
carbocylic and heterocyclic rings being optionally substituted with one or
more hydroxy,
C1_3 alkyl, C1_3 alkoxy, C3 alkanoyl, C1.3 alkanoyloxy, C1_3alkoxycarbonyl, or
hydroxy-
C1_3 alkyl groups; and
3- to 5-membered saturated carbocyclic rings and 4 to 6 membered heterocyclic
rings containing one or two heteroatom ring members selected from 0, N and S,
the
carbocylic and heterocyclic rings being optionally substituted with one or
more hydroxy,
C1-3 alkyl, C1_3 alkoxy, C1-3 alkanoyl, C1_3 alkanoyloxy, C1_4alkoxycarbonyl
or hydroxy-01-3
alkyl groups;
R2, when present, is selected from hydrogen and C1_2 alkyl; or
NR1R2 forms a 4- to 7-membered saturated nitrogen-containing heterocyclic ring
optionally containing a second heteroatom ring member selected from nitrogen
and
oxygen, the heterocyclic ring being optionally substituted with one or more
hydroxy, C1-3
alkyl, 01_3 alkanoyl, C1.3 alkanoyloxy, 013 alkoxy, C1_4alkoxycarbonyl or
hydroxy-01_3 alkyl
groups.
1.31 A method according to Embodiment 1.30 wherein R1 is selected from:
hydrogen;
- a C1_4 alkyl group optionally substituted with one or more substituents
selected
from hydroxy, amino, mono-01_3 alkylamino and di-01_3 alkylamino; and
5 to 6-membered heterocyclic rings containing a nitrogen ring member and
optionally a second ring member selected from N and 0, the heterocyclic rings
being
optionally substituted with one or more C1_3 alkyl or hydroxy-01_3 alkyl
groups;
R2, when present, is selected from hydrogen and C1.2 alkyl; or
NR1R2 forms a 5 to 6-membered heterocyclic ring containing a nitrogen ring
member
and optionally a second ring member selected from N and 0, the heterocyclic
rings
being optionally substituted with one or more 01_3 alkyl or hydroxy-01_3 alkyl
groups.
1.32 A method according to Embodiment 1.31 wherein R1 is selected from:
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- hydrogen;
- a C1.4 alkyl group optionally substituted with one or more substituents
selected
from hydroxy, amino and mono-C1.3 alkylamino; and
to 6-membered heterocyclic rings selected from pyrrolidine, piperidine,
5 piperazine and morpholine, the heterocyclic rings being optionally
substituted with one or
more Ci.3 alkyl or hydroxy-01_3 alkyl groups;
R2, when present, is selected from hydrogen and C1_2 alkyl; or
NR1R2 forms a 5 to 6-membered heterocyclic ring selected from pyrrolidine,
piperidine,
piperazine and morpholine, the heterocyclic ring being optionally substituted
with one or
more Ci.3 alkyl or hydroxy-C1_3 alkyl groups.
1.33 A method according to Embodiment 1.32 wherein R1 is selected from:
hydrogen;
a C1_3 alkyl group optionally substituted with one or more substituents
selected
from hydroxy, amino and methylamino; and
- 5 to 6-membered heterocyclic rings selected from pyrrolidine, piperidine,
piperazine and morpholine, the heterocyclic rings being optionally substituted
with one or
more C1.3 alkyl or hydroxy-C1_3 alkyl groups;
R2, when present, is selected from hydrogen and C1.2 alkyl; or
NR1R2 forms a 5 to 6-membered heterocyclic ring selected from pyrrolidine,
piperidine,
piperazine and morpholine, the heterocyclic ring being optionally substituted
with one or
more C1_3 alkyl or hydroxy-C1_3 alkyl groups.
1.34 A method according to Embodiment 1.33 wherein R1 is selected from:
hydrogen;
a C1_3 alkyl group optionally substituted with one or more substituents
selected
from hydroxy, amino and methylamino; and
5 to 6-membered heterocyclic rings selected from pyrrolidine and piperidine,
the
heterocyclic rings being optionally substituted with a methyl group;
R2, when present, is selected from hydrogen and methyl; or
NR1R2 forms a 5 to 6-membered heterocyclic ring selected from pyrrolidine and
morpholine, the heterocyclic ring being optionally substituted with a
hydroxymethyl
group.
1.35 A method according to Embodiment 1.34 wherein Q1-A-R1 is selected from
groups AA to AR in the table below:
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0 0 0 OH3
II II II /
¨S¨CH *¨S¨NH * __ S N
II 3 II 2 II \
0 AA 0 AB 0 CH3
AC
0 0 is.H 0
I I /<
* S¨N-CH3 ,...,. .3 *
II H N N-(CH2)s-NH2
0 AD 613 AE H AF
0 0 0
*
*
/.
H rla¨K
/
N N
H H
AG AH 0 Al
0 0 0
* *
/. '/ ..._CH
N-(CH2)TN-CH3 NICH2) * s-N-CH3 N
H H H H H
AJ AK AL
/ /
0 "OH
0
*
' CH -----N *
H '
/0 N-(CH2)0H
H
AM AN AO
*
0
0 0
*
/. /.
* __
./ \ *
N ( \
/
AP AQ AR /N¨CH3
N-(CH2)0H N __ K NH H
H H
wherein the point of attachment to the phenyl group is indicated by the
asterisk.
1.36 A method according to Embodiment 1.35 wherein Q1-A-R1 is the group AA.
1.37 A method according to Embodiment 1.0 or 1.1 wherein the compound of
formula
(0) or (1) is selected from:
2-(2,6-difluorophenyI)-5-(4-(methylsulfonyl)phenylamino)oxazole-4-carboxamide;
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2-(2,6-difluorophenyI)-5-(4-sulfamoylphenylamino)oxazole-4-carboxamide;
2-(2,6-difluorophenyI)-5-(4-(N,N-dimethylsulfamoyl)phenylamino)oxazole-4-
carboxamide;
2-(2,6-difluorophenyI)-5-(4-(N'-methylsulfamoyl)phenylamino)oxazole-4-
carboxamide;
2-(2,6-difluorophenyI)-5-(4-(dimethylcarbamoyl)phenylamino)oxazole-4-
carboxamide;
5-(4-((3-aminopropyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4-
carboxamide;
(R)-2-(2,6-difluorophenyI)-5-(4-(piperidin-3-ylcarbamoyl)phenylamino)oxazole-4-
carboxamide;
(S)-2-(2,6-difluorophenyI)-5-(4-(piperidin-3-ylcarbamoyl)phenylamino)oxazole-4-
carboxamide;
2-(2,6-difluorophenyI)-5-(4-(morpholine-4-carbonyl)phenylamino)oxazole-4-
carboxamide;
5-(4-((2-(methylamino)ethyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)
oxazole-4-
carboxamide;
5-(4-((3-(methylamino)propyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)
oxazole-4-
carboxamide;
(R)-2-(2,6-difluorophenyI)-5-(4-(pyrrolidin-3-ylcarbamoyl)phenylamino)oxazole-
4-
carboxamide;
(S)-2-(2,6-difluorophenyI)-5-(4-(pyrrolidin-3-ylcarbamoyl)phenylamino)oxazole-
4-
carboxamide;
(R)-2-(2,6-difluorophenyI)-5-(4-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)
phenylamino)oxazole-4-carboxamide;
5-(4-((2-hydroxyethyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4-
carboxamide;
5-(4-((3-hydroxypropyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4-
carboxamide;
2-(2,6-difluorophenyI)-5-(4-(piperidin-4-ylcarbamoyl)phenylamino)oxazole-4-
carboxamide; and
5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)
oxazole-4-
carboxamide;
and salts thereof.
In another aspect, the invention provides a novel group of compounds within
formula (0)
of Embodiment 1Ø The novel compounds per se of the invention are as defined
in
Embodiments 1.38 to 1.96
1.38 A compound of the formula (2):
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R5 Q¨A¨R1
R4
R6
R3 0 (F)n
R7 Ni HN
NH2
0 (2)
or a salt or stereoisomer thereof; wherein:
R7 is selected from chlorine and fluorine;
R3, R4, R5 and R6 are each independently selected from hydrogen, fluorine and
chlorine;
5 n is 0, 1 or 2;
Ql is selected from C(=0), S(=0) and SO2;
A is absent or is NR2;
R1 is selected from:
hydrogen;
10 - a C1_6 non-aromatic hydrocarbon group optionally substituted with
one or more
substituents selected from hydroxyl, C1_2 alkoxy, amino, mono-01_4 alkylamino,
alkylamino, 3- to 7-membered non-aromatic carbocyclic and heterocyclic rings
containing one or two heteroatom ring members selected from 0, N and S, and
bridged
bicyclic heterocyclic rings of seven to nine ring members of which one or two
are
15 nitrogen atoms, the carbocylic and heterocyclic rings and bridged
bicyclic heterocyclic
rings being optionally substituted with one or more hydroxy, C1_4 alkyl, 01_4
alkoxy, 01-4
alkanoyl, C1_4 alkanoyloxy, C1_4 alkoxycarbonyl or hydroxyl-C1_3 alkyl groups;
and
3- to 7-membered non-aromatic carbocyclic and heterocyclic rings containing
one or two heteroatom ring members selected from 0, N and S, and bridged
bicyclic
heterocyclic rings of seven to nine ring members of which one or two are
nitrogen atoms,
the carbocyclic and heterocyclic rings and bridged bicyclic heterocyclic rings
being
optionally substituted with one or more hydroxy, C1_4 alkyl, Ci_4 alkoxy, C1_4
alkanoyl, C1-4
alkanoyloxy, Ci_4 alkoxycarbonyl, amino-C1_3alkyl, mono-C1_2 alkylamino-C13
alkyl,
alkylamino-C1_3alkyl or hydroxyl-01_3 alkyl groups;
R2 is selected from hydrogen and C1_4 alkyl; or
NR1R2 forms a 4- to 7-membered non-aromatic nitrogen-containing heterocyclic
ring
optionally containing a second heteroatom ring member selected from nitrogen
and
oxygen, the heterocyclic ring being optionally substituted with one or more
hydroxy, C1-4
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alkyl, C1_4 alkanoyl, C1_4 alkanoyloxy, C1_4alkoxy, C14alkoxycarbonyl amino-
C1_3alkyl,
mono-C1_2 alkylamino-C1_3alkyl,
alkylamino-C1_3alkyl or hydroxy-01_3 alkyl groups;
with the provisos that:
(i) no more than two of R3 to R6 are other than hydrogen; and
(ii) when R7 and R6 are both fluorine, then one of R3 to R6 is chlorine or
fluorine
and/or R1-A-Q1 is selected from ethylsulfonyl and isopropylsulfonyl.
1.38A A compound according to Embodiment 1.38 provided that when R7 and R6 are
both fluorine, then one of R3 to R6 is chlorine or fluorine.
1.39 A compound according to Embodiment 1.38 or Embodiment 1.38A wherein R7 is
chlorine.
1.40 A compound according to Embodiment 1.39 wherein R7 is chlorine and R6 is
fluorine.
1.41 A compound according to Embodiment 1.39 wherein R7 and R6 are both
chlorine.
1.42 A compound according to any one of Embodiments 1.38 to 1.41 wherein at
least
one of R3 and R6 is hydrogen.
1.43 A compound according to Embodiment 1.42 wherein both of R3 and R6 are
hydrogen.
1.44 A compound according to any one of Embodiments 1.38 to 1.43 wherein R4 is
hydrogen.
1.45 A compound according to any one of Embodiments 1.38 to 1.43 wherein R4 is
fluorine.
1.46 A compound according to any one of Embodiments 1.38 to 1.43 wherein R4 is
chlorine.
1.47 A compound according to any one of Embodiments 1.38 to 1.46 wherein Q1 is
C(=0).
1.48 A compound according to any one of Embodiments 1.38 to 1.46 wherein Q1 is
S(=0).
1.49 A compound according to any one of Embodiments 1.38 to 1.46 wherein Q1 is
S02.
1.50 A compound according to any one of Embodiments 1.38 to 1.49 wherein A is
absent (i.e. the moieties R1 and Q1 are directly joined together)
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1.51 A compound according to Embodiment 1.50 wherein A is absent and Q1 is
SO2.
1.52 A compound according to any one of Embodiments 1.38 to 1.49 wherein A is
NR2.
1.53 A compound according to any one of Embodiments 1.38 to 1.52 wherein:
R1 is selected from:
hydrogen;
a C1_6 saturated hydrocarbon group optionally substituted with one or more
substituents selected from hydroxy, C1_2 alkoxy, amino, mono-C1_4 alkylamino,
alkylamino, 3- to 6-membered saturated carbocyclic rings and 4 to 7 membered
heterocyclic rings containing one or two heteroatom ring members selected from
0, N
and S, and bridged bicyclic heterocyclic rings of seven to nine ring members
of which
one or two are nitrogen atoms, the carbocylic and heterocyclic rings and
bridged bicyclic
heterocyclic rings being optionally substituted with one or more hydroxy, C1_4
alkyl, C1-4
alkoxy, 01.4 alkanoyl, 014 alkanoyloxy, C1-4 alkoxycarbonyl, amino-C1.3 alkyl,
mono-01-2
alkylamino-C1_3alkyl, alkylamino-C1.3alkyl or hydroxy-C1_3 alkyl groups;
and
3- to 6-membered saturated carbocyclic rings and 4 to 7 membered heterocyclic
rings containing one or two heteroatom ring members selected from 0, N and S,
and
bridged bicyclic heterocyclic rings of seven to nine ring members of which one
or two are
nitrogen atoms, the carbocylic and heterocyclic rings and bridged bicyclic
heterocyclic
rings being optionally substituted with one or more hydroxy, C1_4 alkyl, C1_4
alkoxy, C1-4
alkanoyl, C1_4 alkanoyloxy, C1_4 alkoxycarbonyl, amino-C1.3 alkyl, mono-C1_2
alkylamino-
01.3 alkyl, di-C1.2 alkylamino-01_3alkyl or hydroxy-01.3 alkyl groups;
R2, when present, is selected from hydrogen and 01.4 alkyl; or
NR1R2 forms a 4- to 7-membered saturated nitrogen-containing heterocyclic ring
optionally containing a second heteroatom ring member selected from nitrogen
and
oxygen, the heterocyclic ring being optionally substituted with one or more
hydroxy, 01-4
alkyl, Ci _4 alkanoyl, C1_4 alkanoyloxy, C1_4 alkoxy, C1_4 alkoxycarbonyl or
hydroxy-C1.3 alkyl
groups.
1.54 A compound according to Embodiment 1.53 wherein:
R1 is selected from:
hydrogen;
a 01.4 alkyl group optionally substituted with one or more substituents
selected
from hydroxyl, C1-3 alkoxy, amino, mono-C1_3 alkylamino, alkylamino, 3- to
5-
membered saturated carbocyclic rings and 4- to 6- membered heterocyclic rings
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containing one or two heteroatom ring members selected from 0, N and S, the
carbocylic and heterocyclic rings being optionally substituted with one or
more hydroxy,
C1_3 alkyl, 01_3 alkoxy, 01_3 alkanoyl, Ci alkanoyloxy, C1_3alkoxycarbonyl, or
hydroxy-
C1_3 alkyl groups; and
- 3- to 5-membered saturated carbocyclic rings and 4 to 6 membered non-
aromatic
heterocyclic rings containing one or two heteroatom ring members selected from
0, N
and S, the carbocylic and heterocyclic rings being optionally substituted with
one or
more hydroxy, C1_3 alkyl, C1_3 alkoxy, C1_3 alkanoyl, C1-3 alkanoyloxy,
C1_4alkoxycarbonyl
or hydroxy-01_3 alkyl groups;
R2, when present, is selected from hydrogen and C1_2 alkyl; or
NR1R2 forms a 4- to 7-membered saturated nitrogen-containing heterocyclic ring
optionally containing a second heteroatom ring member selected from nitrogen
and
oxygen, the heterocyclic ring being optionally substituted with one or more
hydroxy, 01.3
alkyl, C1_3 alkanoyl, C1_3 alkanoyloxy, C1_3 alkoxy, 01_4alkoxycarbonyl or
hydroxy-C1_3 alkyl
groups.
1.55 A compound according to Embodiment 1.54 wherein:
R1 is selected from:
hydrogen;
a C1.4 alkyl group optionally substituted with one or more substituents
selected
from hydroxy, amino, mono-C1_3 alkylamino and di-C1_3 alkylamino; and
5 to 6-membered non-aromatic heterocyclic rings containing a nitrogen ring
member and optionally a second ring member selected from N and 0, the
heterocyclic
rings being optionally substituted with one or more Ci_3 alkyl or hydroxy-C1_3
alkyl
groups;
R2, when present, is selected from hydrogen and C1.2 alkyl; or
NR1R2 forms a 5 to 6-membered heterocyclic ring containing a nitrogen ring
member
and optionally a second ring member selected from N and 0, the heterocyclic
rings
being optionally substituted with one or more Ci.3 alkyl or hydroxy-C1.3 alkyl
groups.
1.56 A compound according to Embodiment 1.55 wherein:
R1 is selected from:
hydrogen;
a 01.4 alkyl group optionally substituted with one or more substituents
selected
from hydroxy, amino and mono-C1_3 alkylamino; and
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to 6-membered non-aromatic heterocyclic rings selected from pyrrolidine,
piperidine, piperazine and morpholine, the heterocyclic rings being optionally
substituted
with one or more C1_3 alkyl or hydroxy-C1_3 alkyl groups;
R2, when present, is selected from hydrogen and C1.2 alkyl; or
5 NR1R2 forms a 5 to 6-membered heterocyclic ring selected from
pyrrolidine, piperidine,
piperazine and morpholine, the heterocyclic ring being optionally substituted
with one or
more C1.3 alkyl or hydroxy-C1_3 alkyl groups.
1.57 A compound according to Embodiment 1.56 wherein:
R1 is selected from:
- hydrogen;
a C1_3 alkyl group optionally substituted with one or more substituents
selected
from hydroxy, amino and methylamino; and
5 to 6-membered heterocyclic rings selected from pyrrolidine, piperidine,
piperazine and morpholine, the heterocyclic rings being optionally substituted
with one or
more C1_3 alkyl or hydroxy-01_3 alkyl groups;
R2, when present, is selected from hydrogen and C1.2 alkyl; or
NR1R2 forms a 5 to 6-membered heterocyclic ring selected from pyrrolidine,
piperidine,
piperazine and morpholine, the heterocyclic ring being optionally substituted
with one or
more C1_3 alkyl or hydroxy-C1.3 alkyl groups.
1.58 A compound according to Embodiment 1.57 wherein:
R1 is selected from:
- hydrogen;
- a 01.3 alkyl group optionally substituted with one or more substituents
selected
from hydroxy, amino and methylamino; and
- 5 to 6-membered heterocyclic rings selected from pyrrolidine and
piperidine, the
heterocyclic rings being optionally substituted with a methyl group;
R2, when present, is selected from hydrogen and methyl; or
NR1R2 forms a 5 to 6-membered heterocyclic ring selected from pyrrolidine and
morpholine, the heterocyclic ring being optionally substituted with a
hydroxymethyl
group.
1.59 A compound according to any one of Embodiments 1.38 to 1.52 wherein R1 is
selected from:
- hydrogen; and
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- a Ci.6 non-aromatic hydrocarbon group optionally substituted with one or
more
substituents selected from hydroxyl, C1.2 alkoxy, amino, mono-C1_4 alkylamino,
di-01.4
alkylamino, 3- to 7-membered non-aromatic carbocyclic and heterocyclic rings
containing one or two heteroatom ring members selected from 0, N and S, and
bridged
5 bicyclic heterocyclic rings of seven to nine ring members of which one or
two are
nitrogen atoms, the carbocylic and heterocyclic rings and bridged bicyclic
heterocyclic
rings being optionally substituted with one or more hydroxy, 01.4 alkyl, C1_4
alkoxy, C1-4
alkanoyl, C1_4 alkanoyloxy, C1.4 alkoxycarbonyl or hydroxyl-C1_3 alkyl groups.
1.60 A compound according to any one of Embodiments 1.38 to 1.52 wherein R1 is
10 selected from:
hydrogen; and
- a C1.4 alkyl group optionally substituted with one or more substituents
selected
from hydroxyl, C1_3 alkoxy, amino, mono-C1_3 alkylamino, di-C1_3 alkylamino, 3-
to 5-
membered saturated carbocyclic rings and 4- to 6- membered heterocyclic rings
15 .. containing one or two heteroatom ring members selected from 0, N and S,
the
carbocylic and heterocyclic rings being optionally substituted with one or
more hydroxy,
C1.3 alkyl, 01_3 alkoxy, 01_3 alkanoyl, C1.3 alkanoyloxy, C1_3alkoxycarbonyl,
or hydroxy-
C1_3 alkyl groups.
1.61 A compound according to any one of Embodiments 1.38 to 1.52 wherein R1 is
20 selected from:
hydrogen; and
- a C1_4 alkyl group optionally substituted with one or more substituents
selected
from hydroxy, amino, mono-C1_3 alkylamino and di-C1_3 alkylamino.
1.62 A compound according to any one of Embodiments 1.38 to 1.52 wherein R1 is
.. selected from:
hydrogen; and
a 01.4 alkyl group optionally substituted with one or more substituents
selected
from hydroxy, amino and mono-C1_3 alkylamino.
1.63 A compound according to any one of Embodiments 1.38 to 1.52 wherein R1 is
selected from:
hydrogen; and
a C1_3 alkyl group optionally substituted with one or more substituents
selected
from hydroxy, amino and methylamino.
1.64 A compound according to Embodiment 1.63 wherein R1 is a C1.3 alkyl group.
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1.65 A compound according to Embodiment 1.64 wherein R1 is selected from
methyl,
ethyl and isopropyl.
1.66 A compound according to Embodiment 1.65 wherein R1 is methyl.
1.67 A compound according to Embodiment 1.65 wherein R1 is ethyl.
1.68 A compound according to Embodiment 1.65 wherein R1 is isopropyl.
1.69 A compound according to Embodiment 1.63 wherein R1 is a C1_3 alkyl group
optionally substituted with one or more substituents selected from hydroxy,
amino and
methylamino.
1.70 A compound according to Embodiment 1.69 wherein R1 is a C2.3 alkyl group
substituted with one or more substituents selected from hydroxy, amino and
methylamino.
1.71 A compound according to Embodiment 1.70 wherein R1 is selected from 3-
aminopropyl, 3-methylaminopropyl, 2-methylaminoethyl, 3-hydroxypropyl and 2-
hydroxyethyl.
1.73 A compound according to Embodiment 1.63 wherein R1 is hydrogen.
1.74 A compound according to any one of Embodiments 1.38 to 1.52 wherein R1 is
selected from 3- to 6-membered saturated carbocyclic rings and 4 to 7 membered
heterocyclic rings containing one or two heteroatom ring members selected from
0, N
and S, and bridged bicyclic heterocyclic rings of seven to nine ring members
of which
.. one or two are nitrogen atoms, the carbocylic and heterocyclic rings and
bridged bicyclic
heterocyclic rings being optionally substituted with one or more hydroxy, C1_4
alkyl, C1-4
alkoxy, C1_4 alkanoyl, C alkanoyloxy, C14alkoxycarbonyl, amino-C1_3alkyl, mono-
C1-2
alkylamino-C13alkyl, di-C12 alkylamino-C1_3alkyl or hydroxy-C1_3 alkyl groups.
1.75 A compound according to any one of Embodiments 1.38 to 1.52 wherein R1 is
selected from 3- to 5-membered saturated carbocyclic rings and 4 to 6 membered
non-
aromatic heterocyclic rings containing one or two heteroatom ring members
selected
from 0, N and S, the carbocylic and heterocyclic rings being optionally
substituted with
one or more hydroxy, C1_3 alkyl, C1_3 alkoxy, 01_3 alkanoyl, C1.3 alkanoyloxy,
C1-4
alkoxycarbonyl or hydroxy-C1_3 alkyl groups.
1.76 A compound according to any one of Embodiments 1.38 to 1.52 wherein R1 is
selected from 5 to 6-membered non-aromatic heterocyclic rings containing a
nitrogen
ring member and optionally a second ring member selected from N and 0, the
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heterocyclic rings being optionally substituted with one or more Ci_3 alkyl or
hydroxy-C1_3
alkyl groups.
1.77 A compound according to any one of Embodiments 1.38 to 1.52 wherein R1 is
a
5- or 6-membered non-aromatic heterocyclic ring selected from pyrrolidine,
piperidine,
piperazine and morpholine, the heterocyclic ring being optionally substituted
with one or
more C1.3 alkyl or hydroxy-C1_3 alkyl groups.
1.78 A compound according to Embodiment 1.57 wherein R1 is a 5 to 6-membered
heterocyclic ring selected from pyrrolidine and piperidine, the heterocyclic
ring being
optionally substituted with a methyl group.
.. 1.79 A compound according to any one of Embodiments 1.38 to 1.49 wherein A
is
NR2 and NR1R2 forms a 4-to 7-membered saturated nitrogen-containing
heterocyclic
ring optionally containing a second heteroatom ring member selected from
nitrogen and
oxygen, the heterocyclic ring being optionally substituted with one or more
hydroxy, C1-4
alkyl, Ci.4 alkanoyl, C1_4 alkanoyloxy, C1_4alkoxy, C1_4alkoxycarbonyl or
hydroxy-C1_3 alkyl
.. groups.
1.80 A compound according to any one of Embodiments 1.38 to 1.49 wherein A is
NR2 and NR1R2 forms a 4- to 7-membered saturated nitrogen-containing
heterocyclic
ring optionally containing a second heteroatom ring member selected from
nitrogen and
oxygen, the heterocyclic ring being optionally substituted with one or more
hydroxy, C1-3
alkyl, Ci_3 alkanoyl, C1.3 alkanoyloxy, Ci_3alkoxy, C1-4 alkoxycarbonyl or
hydroxy-01_3 alkyl
groups.
1.81 A compound according to any one of Embodiments 1.38 to 1.49 wherein A is
NR2 and NR1R2 forms a 5 to 6-membered heterocyclic ring containing a nitrogen
ring
member and optionally a second ring member selected from N and 0, the
heterocyclic
rings being optionally substituted with one or more C1_3 alkyl or hydroxy-C1_3
alkyl groups.
1.82 A compound according to any one of Embodiments 1.38 to 1.49 wherein A is
NR2 and NR1R2 forms a 5 to 6-membered heterocyclic ring selected from
pyrrolidine,
piperidine, piperazine and morpholine, the heterocyclic ring being optionally
substituted
with one or more C1_3 alkyl or hydroxy-C1_3 alkyl groups.
1.83 A compound according to any one of Embodiments 1.38 to 1.49 wherein A is
NR2 and NR1R2 forms a 5 to 6-membered heterocyclic ring selected from
pyrrolidine and
morpholine, the heterocyclic ring being optionally substituted with a
hydroxymethyl
group.
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1.84 A compound according to any one of Embodiments 1.38 to 1.49 and 1.52 to
1.78
wherein R2 is selected from hydrogen and methyl.
1.85 A compound according to any one of Embodiments 1.38 to 1.49 and 1.52 to
1.78
wherein R2 is hydrogen.
1.86 A compound according to any one of Embodiments 1.38 to 1.49 and 1.52 to
1.78
wherein R2 is methyl.
1.87 A compound according to any one of Embodiments 1.38 to 1.46 wherein Q1-A-
R1
is selected from groups AA to AT in the table below:
0
0 I I 0 CH
I I *¨S¨NH II / 3
¨S¨CH II *¨S¨N
I I I I
3 2
0 \
0 AB 0 CH3
AA AC
O //0 /. 0
I I
*¨S¨N-CH, \ CH3 *
H H ' IV
N-(CH2)S-NFI2
O AD 6E13 AE H AF
O 0 0
*
*
Ir( il
H
N N
H AG H AH \ 0 Al
O 0 0
* ____
/. ......CNH
I NICH2)TN-CH3
H H N-(CH2)TN-CH3 *
H H N
H
AJ AK AL
0 /OH
/0
/
* . CH ----N * __
N-(CH2)TOH
H /0 H
AM AN AO
*
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0 0 0
* ____________________________
N-(CH2)i- OH N \NH N __ ( \N¨CH3
H ____________________________________
AP AQ AR
0 0 CH
* ¨ S ¨ C H -- CH S¨CH
I I 2 3 I
0 AS 0 CH3 AT
wherein the point of attachment to the phenyl group is indicated by the
asterisk.
1.88 A compound according to Embodiment 1.87 wherein Q1-A-R1 is selected from
groups AA, AG, AN, Al, AR, AS and AT.
.. 1.89 A compound according to Embodiment 1.88 wherein Q1-A-R1 is selected
from
groups AA, AS and AT.
1.90 A compound according to Embodiment 1.89 wherein Q1-A-R1 is a group AA.
1.91 A compound according to Embodiment 1.88 wherein 01-A-R1 is selected from
groups AG, AH, Al and AR.
1.92 A compound according to any one of Embodiments 1.38 to 1.91 wherein n is
selected from 0 and 1.
1.93 A compound according to Embodiment 1.92 wherein n is 0.
1.94 A compound according to Embodiment 1.92 wherein n is 1.
1.95 A compound according to Embodiment 1.94 wherein the fluorine atom is
attached to the benzene ring at a position ortho with respect to the moiety
Q1.
1.96 A compound according to Embodiment 1.38 wherein the compound of formula
(2) is selected from:
2-(2,6-dichloro-phenyl)-5-(4-methanesulfonyl-phenylamino)-oxazole-4-carboxylic
acid
amide;
2-(2-chloro-6-fluoro-phenyl)-5-(4-methanesulfonyl-phenylamino)-oxazole-4-
carboxylic
acid amide;
5-(4-methanesulfonyl-phenylamino)-2-(2,4,6-trifluoro-phenyl)-oxazole-4-
carboxylic acid
amide;
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2-(2,5-difluoro-phenyI)-5-(4-methanesulfonyl-phenylamino)-oxazole-4-carboxylic
acid
amide;
(S) 2-(2-chloro-6-fluoro-phenyl)-5-[4-(piperidin-3-ylcarbamoy1)-phenylamino]-
oxazole-4-
carboxylic acid amide;
5 (R) 2-(2-chloro-6-fluoro-phenyl)-544-(piperidin-3-ylcarbamoy1)-
phenylamino]-oxazole-4-
carboxylic acid amide;
2-(2-chloro-6-fluoro-phenyl)-544-(morpholine-4-carbonyl)-phenylamino]-oxazole-
4-
carboxylic acid amide;
2-(2-chloro-6-fluoro-phenyl)-544-(1-methyl-piperidin-4-ylcarbamoy1)-
Phenylamino]-
10 oxazole-4-carboxylic acid amide;
(S) 2-(2,6-dichloro-phenyl)-544-(piperidin-3-ylcarbamoy1)-phenylamino]-oxazole-
4-
carboxylic acid amide;
(R) 2-(2,6-dichloro-phenyl)-5-[4-(piperidin-3-ylcarbamoy1)-phenylamino]-
oxazole-4-
carboxylic acid amide;
15 2-(2,6-dichloro-phenyl)-544-(morpholine-4-carbonyl)-phenylamino]-oxazole-
4-carboxylic
acid amide;
2-(2,6-dichloro-phenyl)-5-[4-(1-methyl-piperidin-4-ylcarbamoy1)-phenylamino]-
0xaz0le-4-
carboxylic acid amide;
2-(2,6-difluoro-phenyl)-5-(4-ethanesulfonyl-phenylamino)-oxazole-4-carboxylic
acid
20 amide;
2-(2,6-difluoro-phenyl)-5-(4-methanesulfonyl-phenylamino)-oxazole-4-carboxylic
acid
amide; and
2-(2,6-difluoro-phenyl)-5-[4-propane-2-sulfony1)-henylamino]-oxazole-4-
carboxylic acid
amide;
25 and salts and stereoisomers thereof.
1.97 A method according to any one of Embodiments 1.0 to 1.37 or a compound
according to any one of Embodiments 1.38 to 1.96 wherein the compound of
formula (0),
(1) or (2) is in the form of a salt.
1.98 A method or a compound according to Embodiment 1.97 wherein the salt is
an
acid addition salt.
1.99 A method or compound according to Embodiment 1.97 or Embodiment 1.98
wherein the acid addition salt is a pharmaceutically acceptable salt.
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1.100 A method according to any one of Embodiments 1.0 to 1.37 or a compound
according to any one of Embodiments 1.38 to 1.96 wherein the compound of
formula (0),
(1) or (2) is in the form of a free base.
Definitions
References to formula (1) below include formulae (0) and (2) as well as
formula (1)
unless the context indicates otherwise.
The term "non-aromatic hydrocarbon group", as in "Cl_6 non-aromatic
hydrocarbon
group", as used herein refers to a structural group consisting of carbon and
hydrogen
and which does not have aromatic character.
Unless indicated otherwise, the non-aromatic hydrocarbon group can be acyclic
or cyclic
and can be saturated or unsaturated. Thus the term covers alkyl, alkenyl,
alkynyl,
cycloalkyl and cycloalkenyl groups and combinations thereof.
Where specified, non-aromatic hydrocarbon groups can be substituted; i.e. a
hydrogen
atom may be replaced by another atom or functional group.
References to "non-aromatic carbocyclic and heterocyclic rings" as used herein
refer to
both saturated and unsaturated ring systems provided that any such unsaturated
ring
systems do not have aromatic character,
The term "bridged bicyclic heterocyclic rings" as used herein refers to non-
aromatic
heterocyclic ring systems in which two rings share more than two atoms, see
for
example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley
Interscience,
pages 131-133, 1992. The bridged bicyclic ring systems can be, for example,
[3.2.1]
bicyclic ring systems such as an 8-aza-bicyclo[3.2.1]octane-3-y1 group, or
[2.2.2] biyclic
ring systems such as a quinuclidin-3-ylgroup.
Salts
The compounds of formulae (0), (1) and (2) may be presented in the form of
salts.
The salts (as defined in Embodiments 1.97 to 1.99) are typically acid addition
salts.
The salts can be synthesized from the parent compound by conventional chemical
methods such as methods described in Pharmaceutical Salts: Properties,
Selection, and
Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-
026-8,
Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by
reacting
the free base form of the compound with the acid in water or in an organic
solvent, or in
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a mixture of the two; generally, nonaqueous media such as ether, ethyl
acetate, ethanol,
isopropanol, or acetonitrile are used.
Acid addition salts (as defined in Embodiment 1.98) may be formed with a wide
variety
of acids, both inorganic and organic. Examples of acid addition salts include
salts
formed with an acid selected from the group consisting of acetic, 2,2-
dichloroacetic,
adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulphonic,
benzoic, 4-
acetamidobenzoic, butanoic, (+) camphoric, camphor-sulphonic, (+)-(1S)-camphor-
10-
sulphonic, capric, caproic, caprylic, cinnamic, citric, cyclamic,
dodecylsulphuric, ethane-
1,2-disulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, formic, fumaric,
galactaric,
gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic
(e.g. L-
glutamic), a-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric,
hydriodic,
isethionic, (+)-L-lactic, ( )-DL-lactic, lactobionic, maleic, malic, (-)-L-
malic, malonic, ( )-
DL-mandelic, methanesulphonic, naphthalene-2-sulphonic, naphthalene-1,5-
disulphonic,
1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic,
pamoic, phosphoric,
propionic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic,
succinic,
sulphuric, tannic, (+)-L-tartaric, thiocyanic, p-toluenesulphonic, undecylenic
and valeric
acids, as well as acylated amino acids and cation exchange resins.
The salt forms of the compounds of the invention are typically
pharmaceutically
acceptable salts, and examples of pharmaceutically acceptable salts are
discussed in
Berge etal., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sc., Vol.
66, pp. 1-
19. However, salts that are not pharmaceutically acceptable may also be
prepared as
intermediate forms which may then be converted into pharmaceutically
acceptable salts.
Such non-pharmaceutically acceptable salts forms, which may be useful, for
example, in
the purification or separation of the compounds of the invention, also form
part of the
invention.
Isotopes
The compounds of the invention as defined in any one of Embodiments 1.0 to
1.100 may
contain one or more isotopic substitutions, and a reference to a particular
element
includes within its scope all isotopes of the element. For example, a
reference to
hydrogen includes within its scope 1H, 2H (D), and 3H (T). Similarly,
references to
carbon and oxygen include within their scope respectively 120, 130 and 140 and
160 and
180.
In an analogous manner, a reference to a particular functional group also
includes within
its scope isotopic variations, unless the context indicates otherwise.
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For example, a reference to an alkyl group such as an ethyl group also covers
variations
in which one or more of the hydrogen atoms in the group is in the form of a
deuterium or
tritium isotope, e.g. as in an ethyl group in which all five hydrogen atoms
are in the
deuterium isotopic form (a perdeuteroethyl group).
The isotopes may be radioactive or non-radioactive. In one embodiment of the
invention
(Embodiment 1.101), the compound of any one of Embodiments 1.0 to 1.100
contains
no radioactive isotopes. Such compounds are preferred for therapeutic use. In
another
embodiment (Embodiment 1.102), however, the compound of any one of Embodiments
1.0 to 1.100 may contain one or more radioisotopes. Compounds containing such
radioisotopes may be useful in a diagnostic context.
Solvates
Compounds of the formulae (0), (1) or (2) as defined in any one of Embodiments
1.0 to
1.102 may form solvates.
Preferred solvates are solvates formed by the incorporation into the solid
state structure
(e.g. crystal structure) of the compounds of the invention of molecules of a
non-toxic
pharmaceutically acceptable solvent (referred to below as the solvating
solvent).
Examples of such solvents include water, alcohols (such as ethanol,
isopropanol and
butanol) and dimethylsulphoxide. Solvates can be prepared by recrystallising
the
compounds of the invention with a solvent or mixture of solvents containing
the solvating
solvent. Whether or not a solvate has been formed in any given instance can be
determined by subjecting crystals of the compound to analysis using well known
and
standard techniques such as thermogravimetric analysis (TGE), differential
scanning
calorimetry (DSC) and X-ray crystallography.
The solvates can be stoichiometric or non-stoichiometric solvates.
Particularly preferred solvates are hydrates, and examples of hydrates include
hemihydrates, monohydrates and dihydrates.
Accordingly, in further embodiments 1.103 and 1.104, the invention provides:
1.103 A method or compound according to any one of Embodiments 1.0 to 1.102
wherein the compound of formula (0), (1) or (2) is in the form of a solvate.
.. 1.104 A method or compound according to Embodiment 1.103 wherein the
solvate is a
hydrate.
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For a more detailed discussion of solvates and the methods used to make and
characterise them, see Bryn et al., Solid-State Chemistry of Drugs, Second
Edition,
published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.
Alternatively, rather than existing as a hydrate, the compound of the
invention may be
anhydrous. Therefore, in another embodiment (Embodiment 1.105), the compound
of
formula (1) as defined in any one of Embodiments 1.0 to 1.102 is in an
anhydrous form.
Inhibition of TYK2 kinase and therapeutic uses arising therefrom
In Embodiments 1.0 to 1.37, there is provided a method of inhibiting a TYK2
kinase,
which method comprises bringing into contact with the TYK2 kinase an effective
TYK2
kinase-inhibiting amount of a compound having the formula (0) or formula (1).
The inhibition of the TYK2 kinase may take place either in vitro or in vivo.
Accordingly, the invention provides:
2,1 A method according to any one of Embodiments 1.0 to 1.37 and 1.97 to
1.105
wherein the inhibition of the TYK2 kinase takes place in vitro.
2.2 A method according to any one of Embodiments 1.1 to 1.37 and 1.97 to
1.105
wherein the inhibition of the TYK2 kinase takes place in vivo.
The novel compounds of Embodiments 1.38 to 1.105 can also be used for
inhibiting
TYK2 kinase. Accordingly, the invention further provides:
2.3 A method of inhibiting a TYK2 kinase, which method comprises bringing
into
contact with the TYK2 kinase an effective TYK2 kinase-inhibiting amount of a
compound
having the formula (2) or a salt or stereoisomer thereof as defined in any one
of
Embodiments 1.38 to 1.105.
2.4 A method according to Embodiment 2.3 wherein the inhibition of the
TYK2 kinase
takes place in vitro.
2.5 A method according to Embodiment 2.4 wherein the inhibition of the TYK2
kinase
takes place in vivo.
2.6 A compound of the formula (0), (1) or (2) as defined in any one of
Embodiments
1.0 to 1.105 for use as an inhibitor of TYK2 kinase.
2.7 A compound of the formula (2) as defined in any one of Embodiments
1.38 to
1.105 for use in medicine.
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The inhibition of TYK2 kinase preferably takes place in vivo as part of a
therapeutic
treatment of a disease or condition in which TYK2 kinase is implicated.
The method of the invention is particularly applicable in the context of
treating a disease
or condition selected from an inflammatory disease or condition, an
immunological
5 disease or condition, an allergic disease or disorder, a transplant
rejection and Graft-
versus host disease. The method is also applicable in the context of treating
sepsis and
septic shock.
Accordingly, in further aspects, the invention provides:
2.8 A
method of treating a disease or condition in a subject in need thereof,
wherein
10 the disease is selected from an inflammatory disease or condition, an
immunological
disease or condition, an allergic disease or disorder, a transplant rejection
and Graft-
versus host disease, or a disease or condition selected from sepsis and septic
shock,
wherein the disease or condition is susceptible to TYK2 inhibition, which
method
comprises administering to the subject an effective TYK2 inhibiting amount of
a
15 compound of the formula (0), (1) or (2) or a salt thereof as defined in
any one of
Embodiments 1.0 to 1.105.
2.9 A
compound of the formula (0), (1) or (2), or a salt thereof, as defined in any
one
of Embodiments 1.0 to 1.105 for use in the treatment of an inflammatory
disease or
condition, an immunological disease or condition, an allergic disease or
disorder, a
20 transplant rejection and Graft-versus host disease; or for use in the
treatment of sepsis
or septic shock, wherein the disease or condition is susceptible to TYK2
inhibition.
2.10 The use of a compound of the formula (0), (1) or (2), or a salt thereof,
as defined
in any one of Embodiments 1.0 to 1.105 for the manufacture of a medicament for
the
treatment of an inflammatory disease or condition, an immunological disease or
25 condition, an allergic disease or disorder, a transplant rejection and
Graft-versus host
disease; or for use in the treatment of sepsis or septic shock, wherein the
disease or
condition is susceptible to TYK2 inhibition.
Autoimmune Diseases
The TYK2 inhibitory activity of the compounds of formulae (0), (1) and (2) can
be made
30 use of in treating autoimmune diseases. Thus, in further aspects, the
invention provides:
2.11 A method of treating an autoimnnune disease in a subject in need thereof,
which
method comprises administering to the subject an effective TYK2 inhibiting
amount of a
compound of the formula (0), (1) or (2), as defined in any one of Embodiments
1.0 to
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1.105, so as to inhibit TYK2 kinase in the subject and thereby block or reduce
the extent
of an inflammatory process associated with the autoimmune disease.
2.12 A compound of the formula (0), (1) or (2), as defined in any one of
Embodiments
1.0 to 1.105, for use in a method of treating an autoimmune disease in a
subject in need
thereof, which method comprises administering to the subject an effective TYK2
inhibiting amount of the said compound, so as to inhibit TYK2 kinase in the
subject and
thereby block or reduce the extent of an inflammatory process associated with
the
autoimmune disease.
2.13 The use of a compound of the formula (0), (1) or (2), as defined in any
one of
Embodiments 1.0 to 1.105, for the manufacture of a medicament for treating an
autoimmune disease in a subject in need thereof by administering to the
subject an
effective TYK2 inhibiting amount of the said compound, so as to inhibit TYK2
kinase in
the subject and thereby block or reduce the extent of an inflammatory process
associated with the autoimmune disease.
2.14 A method, compound for use or use according to any one of Embodiments
2.11
to 2.13 wherein the autoimmune disease is multiple sclerosis.
Experimental autoimmune encephalomyelitis (EAE) and Theiler's murine
encephalitis
virus-induced demyelinating disease (TMEV-IDD) are two clinically relevant
murine
models of multiple sclerosis (MS) (see (i) Raine CS: Biology of disease. The
analysis of
autoimmune demyelination: its impact upon multiple sclerosis. Lab Invest 1984,
50:608-
635; (ii) Steinman L: Assessment to the utility of animal models for MS and
demyelinating disease in the design of rational therapy. Neuron 1999, 24:511-
514; and
(iii) Kevin G. Fuller et al.,Mouse Models of Multiple Sclerosis: Experimental
Autoimmune
Encephalomyelitis and Theiler's Virus-Induced Demyelinating Disease,
Autoimmunity:
Methods and Protocols, (Series: Methods in Molecular Medicine), Volume: 102 ,
2004,
339-361)
The usefulness of the compounds of formulae (0), (1) or (2) in treating
multiple sclerosis
can be demonstrated using either of the above models and in particular the
experimental
autoimmune encephalomyelitis (EAE) model described in the examples below.
The terms "treating" and "treatment" as used herein in the context of multiple
sclerosis
include any one or more of:
= halting the progression of the disease;
= slowing the progression of the disease;
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= modifying the progression of the disease;
= providing symptomatic relief, e.g. by eliminating or reducing the
severity of one or
more symptoms;
= extending periods of remission;
= preventing relapses;
= reducing the severity of relapses; and
= preventing or slowing the progression from an initial period of relapsing-
remitting
MS to secondary progressive MS.
Symptoms of multiple sclerosis that may be eliminated or reduced in severity
in
accordance with the invention include any one or more symptoms, in any
combination,
selected from:
= weakness and/or numbness in one or more extremities;
= tingling of the extremities;
= tight band-like sensations around the trunk or limbs;
= tremor of one or more extremities;
= dragging or poor control of one or both legs;
= spastic or ataxic paraparesis;
= paralysis of one or more extremities;
= hyperactive tendon reflexes;
= disappearance of abdominal reflexes;
= Lhermitte's sign;
= retrobulbar or optic neuritis;
= unsteadiness in walking;
= problems with balance,
= increased muscle fatigue;
= brain stem symptoms (diplopia, vertigo, vomiting);
= disorders of micturition;
= hemiplegia;
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= trigeminal neuralgia;
= other pain syndromes;
= nystagmus and ataxia;
= cerebellar-type ataxia;
= Charcot's triad; diplopia;
= bilateral internuclear ophthalmoplegia;
= myokymia or paralysis of facial muscles;
= deafness;
= tinnitus;
= unformed auditory hallucinations (because of involvement of cochlear
connections);
= transient facial anesthesia or of trigeminal neuralgia;
= urinary and/or faecal incontinence
= bladder dysfunction euphoria;
= depression;
= fatigue;
= dementia;
= dull, aching pain in the lower back;
= sharp, burning, poorly localized pains in a limb;
= abrupt attacks of neurologic deficit;
= dysarthria and ataxia;
= paroxysmal pain and dysesthesia in a limb;
= flashing lights;
= paroxysmal itching;
= tonic seizures;
= changes in sensation;
= visual problems;
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= muscle weakness;
= difficulties with coordination and speech;
= cognitive impairment;
= overheating; and
= impaired mobility and disability.
The compound may be used in a prophylactic sense during periods of remission
in order
to prevent or reduce the likelihood or severity of relapses or it may be used
to treat
patients who are suffering from a relapse. Preferably it is used in a
prophylactic sense.
The compound of the formulae (0), (1) or (2) or a pharmaceutically acceptable
salt
thereof may be used as the sole therapeutic agent or it may be used in
conjunction with
other therapeutic agents such as steroids or interferons.
In one general embodiment of the invention, the compound of the formula (0),
(1) or (2)
or pharmaceutically acceptable salt thereof is used as the sole therapeutic
agent.
Use in treating diseases and conditions other than multiple sclerosis
Whilst the TYK2 inhibitory activity of the compounds of formula (1) can be
made use of
in the treatment of autoimmune diseases, it can also be put to good use in the
treatment
of a range of other inflammatory diseases, as well as immunological and
allergic
diseases. Accordingly, the invention also provides:
2.15 A method of treating a disease or condition in a subject in need thereof,
wherein
the disease is other than an autoimmune disease and is selected from an
inflammatory
disease or condition, an immunological disease or condition, an allergic
disease or
disorder, a transplant rejection and Graft-versus host disease wherein the
disease or
condition is susceptible to TYK2 inhibition, which method comprises
administering to the
subject an effective TYK2 inhibiting amount of a compound of the formula (0),
(1) or (2)
or a salt thereof as defined in any one of Embodiments 1.0 to 1.105.
2.16 A method of treating a disease or condition in a subject in need thereof,
wherein
the disease is other than multiple sclerosis and is selected from an
inflammatory disease
or condition, an immunological disease or condition, an allergic disease or
disorder, a
transplant rejection and Graft-versus host disease wherein the disease or
condition is
susceptible to TYK2 inhibition, which method comprises administering to the
subject an
effective TYK2 inhibiting amount of a compound of the formula (0), (1) or (2)
or a salt
thereof as defined in any one of Embodiments 1.0 to 1.105.
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2.17 A method of treating a disease or condition in a subject in need thereof,
wherein
the disease is any one or more diseases or conditions selected from:
(a) skin inflammation due to radiation exposure;
(b) asthma;
5 (c) allergic inflammation;
(d) chronic inflammation;
(e) an inflammatory ophthalmic disease;
(f) dry eye syndrome (DES, also known as keratoconjunctivitis sicca or
dysfunctional tear syndrome);
10 (g) uveitis (e.g. chronic progressive or relapsing forms of non-
infectious uveitis);
(h) insulin- dependent diabetes (Type I);
(i) Hashimoto's thyroiditis;
(i) Graves' disease;
(k) Cushing's disease;
15 (I) Addison's disease (which affect the adrenal glands)
(m) chronic active hepatitis (which affects the liver);
(n) polycystic ovary syndrome (PCOS);
(o) coeliac disease;
(p) psoriasis;
20 (q) inflammatory bowel disease (IBD);
(r) ankylosing spondylitis;
(s) rheumatoid arthritis;
(t) systemic lupus erythematosus;
(u) myasthenia gravis;
25 (v) transplant rejection (allograft transplant rejection); and
(w) graft-versus-host disease (GVDH);
which method comprises administering to the subject an effective TYK2
inhibiting
amount of a compound of the formula (0), (1) or (2) or a salt thereof as
defined in any
one of Embodiments 1.0 to 1.105.
30 2.18 A compound of the formula (0), (1) or (2) as defined in any one of
Embodiments
1.0 to 1.105 for use in a method as defined in any one of Embodiments 2.15,
2.16 and
2.17.
2.19 The use of a compound of the formula (0), (1) or (2) as defined in any
one of
Embodiments 1.0 to 1.105 for the manufacture of a medicament for use in a
method as
35 .. defined in any one of Embodiments 2.15, 2.16 and 2.17.
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In the context of the present invention, an autoimmune disease is a disease
which is at
least partially provoked by an immune reaction of the body against its own
components,
for example proteins, lipids or DNA. Examples of organ-specific autoimmune
disorders
are insulin- dependent diabetes (Type I) which affects the pancreas,
Hashimoto's
thyroiditis and Graves' disease which affect the thyroid gland, pernicious
anemia which
affects the stomach, Cushing's disease and Addison's disease which affect the
adrenal
glands, chronic active hepatitis which affects the liver; polycystic ovary
syndrome
(PCOS), celiac disease, psoriasis, inflammatory bowel disease (IBD) and
ankylosing
spondylitis. Examples of non-organ-specific autoimmune disorders are
rheumatoid
arthritis, multiple sclerosis, systemic lupus and myasthenia gravis. Type I
diabetes
ensues from the selective aggression of autoreactive T-cells against insulin
secreting
beta-cells of the islets of Langerhans.
Rheumatoid arthritis (RA) is a chronic progressive, debilitating inflammatory
disease that
affects approximately 1% of the world's population. RA is a symmetric
polyarticular
arthritis that primarily affects the small joints of the hands and feet. In
addition to
inflammation in the synovium, the joint lining, the aggressive front of tissue
called
pannus invades and destroys local articular structures (Firestein 2003, Nature
423:356-
361).
Inflammatory bowel disease (IBD) is characterized by a chronic relapsing
intestinal
inflammation. IBD is subdivided into Crohn's disease and ulcerative colitis
phenotypes.
Crohn's disease involves most frequently the terminal ileum and colon, is
transmural and
discontinuous. In contrast, in ulcerative colitis, the inflammation is
continuous and limited
to rectal and colonic mucosal layers. In approximately 10% of cases confined
to the
rectum and colon, definitive classification of Crohn's disease or ulcerative
colitis cannot
be made and are designated 'indeterminate colitis'. Both diseases include
extraintestinal
inflammation of the skin, eyes, or joints. Neutrophil-induced injuries may be
prevented by
the use of neutrophil migration inhibitors (Asakura et al., 2007, World J.
Gastroenterol.
13(15):2145-9).
Psoriasis is a chronic inflammatory dermatosis that affects approximately 2%
of the
population. It is characterized by red, scaly skin patches that are usually
found on the
scalp, elbows, and knees, and may be associated with severe arthritis. The
lesions are
caused by abnormal keratinocyte proliferation and infiltration of inflammatory
cells into
the dermis and epidermis (Schon et al, 2005, New Engl. J. Med. 352: 1899-
1912).
Systemic lupus erythematosus (SLE) is a chronic inflammatory disease generated
by T
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cell-mediated B-cell activation, which results in glomerulonephritis and renal
failure.
Human SLE is characterized at early stages by the expansion of long-lasting
autoreactive CD4+ memory cells (D'Cruz et al, 2007, Lancet 369(9561):587-596).
Transplant rejection (allograft transplant rejection) includes, without
limitation, acute and
chronic allograft rejection following for example transplantation of kidney,
heart, liver,
lung, bone marrow, skin and cornea. It is known that T cells play a central
role in the
specific immune response of allograft rejection. Hyperacute, acute and chronic
organ
transplant rejection may be treated. Hyperacute rejection occurs within
minutes of
transplantation. Acute rejection generally occurs within six to twelve months
of the
transplant. Hyperacute and acute rejections are typically reversible where
treated with
immunosuppressant agents. Chronic rejection, characterized by gradual loss of
organ
function, is an ongoing concern for transplant recipients because it can occur
any time
after transplantation.
Graft-versus-host disease (GVDH) is a major complication in allogeneic bone
marrow
transplantation (BMT). GVDH is caused by donor T cells that recognize and
react to
recipient differences in the histocompatibility complex system, resulting in
significant
morbidity and mortality.
Compounds of the formulae (0), (1) and (2) can also be used in the treatment
of
diseases or conditions characterized or caused (at least in part) by or
associated with
overexpression (elevated expression) of TYK2 kinase. One disease which has
been
shown to be associated with elevated levels of TYK2 is pulmonary sarcoidosis.
Pulmonary sarcoidosis is a relatively rare inflammatory disorder of unknown
cause which
typically develops in adults of 20 to 50 years of age. Pulmonary sarcoidosis
is
characterised by small lumps, or granulomas in the lungs, which generally heal
and
disappear on their own. However, for those granulomas that do not heal, the
tissue can
remain inflamed and become scarred, or fibrotic. Pulmonary sarcoidosis can
develop
into pulmonary fibrosis, which distorts the structure of the lungs and can
interfere with
breathing.
Therefore, in further aspects, the invention provides:
2.20 A method of treating a disease or condition in a subject in need thereof,
wherein
the disease is one which is characterized or caused (at least in part) by or
associated
with overexpression (elevated expression) of TYK2 kinase, which method
comprises
administering to the subject an effective TYK2 inhibiting amount of a compound
of the
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formula (0), (1) or (2) or a salt thereof as defined in any one of Embodiments
1.0 to
1.105.
2.21 A method according to Embodiment 2.20 wherein the disease or condition is
pulmonary sarcoidosis.
2.22 A compound of the formula (0), (1) or (2) or a salt thereof as defined in
any one
of Embodiments 1.0 to 1,105 for use in a method as defined in Embodiment 2.20
or
2.21.
2.23 The use of compound of the formula (0), (1) or (2) or a salt thereof as
defined in
any one of Embodiments 1.0 to 1.105 for the manufacture of a medicament for
use in a
.. method as defined in Embodiment 2.20 or 2.21.
Other Aspects
In further aspects (Embodiments 2.24 to 2.26), the invention provides:
2.24 A compound of the formula (0), (1) or (2) or a salt thereof as defined in
any one
of Embodiments 1.0 to 1.105 for use in inhibiting TYK2 kinase.
2.25 A compound of the formula (0), (1) or (2) or a salt thereof as defined in
any one
of Embodiments 1.0 to 1.105 for use in treating a disease or condition
selected from an
inflammatory disease or condition, an immunological disease or condition, an
allergic
disease or disorder, a transplant rejection and Graft-versus host disease, as
defined
herein.
.. 2.26 The use of a compound of the formula (0), (1) or (2) or a salt thereof
as defined
in any one of Embodiments 1.0 to 1.105 for the manufacture of a medicament for
treating a disease or condition selected from an inflammatory disease or
condition, an
immunological disease or condition, an allergic disease or disorder, a
transplant
rejection and Graft-versus host disease, as defined herein.
The activity of the compounds of formulae (0), (1) and (2) as TYK2 inhibitors
can be
measured using the assay set forth in the examples below and the level of
activity
exhibited by a given compound can be defined in terms of the 1050 value.
Preferred
compounds of the present invention are compounds having an 1050 value of less
than
0.03 pM.
An advantage of compounds of the formulae (0), (1) and (2) as defined herein
is that
they exhibit selectivity for TYK2 kinase compared to other kinases of the JAK
family.
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For example, the majority of the compounds of formulae (0), (1) and (2)
exemplified
herein have at least a tenfold selectivity for TYK2 compared to JAK2 and JAK3
and at
least a fivefold selectivity for TYK2 versus JAK1.
Whilst selectivity for TYK2 is considered advantageous, it is envisaged that,
in some
.. circumstances, activity against other JAK kinases as well as TYK2 may be
beneficial.
Thus, for example, compounds of the formula (0), (1) or (2) as defined herein
may have
1050 values against TYK2 of less than 200 nanomolar (e.g. less than 50
nanomolar) and
IC50 values against JAK1, JAK2 and JAK3 of less than 500 nanomolar (e.g. less
than
200 nanomolar), but wherein the activity against TYK2 is greater than the
activity against
any of JAK1, JAK2 and JAK3.
Methods for the Preparation of Compounds of Formulae (0), (1) and (2)
The compounds of formula (0), (1) and (2) can be prepared by the methods
described in
International patent application W02008/139161 (Sareum): for example using the
methods described in Examples 0-3, 0-14, 0-20, 0-21, Q-22, Q-25, Q-26, 0-27, Q-
28,
.. 0-29, Q-50, 0-51, 0-52 0-53, 0-54, 0-55, 0-57, U-2, U-3, U-4, U-6, U-7, U-
8, U-9, U-
12, U-13, U-14, U-15, U-16, U-17, U-18, U-19, U-24, U-25, U-26 and U-27 and
methods
analogous thereto. Methods for the preparation of compounds of the formula (2)
are also
set out below in the Examples section.
Pharmaceutical Formulations
While it is possible for the active compound to be administered alone, it is
preferable to
present it as a pharmaceutical composition (e.g. formulation) comprising at
least one
active compound of the invention together with one or more pharmaceutically
acceptable
excipients such as carriers, adjuvants, diluents, fillers, buffers,
stabilisers, preservatives,
lubricants, or other materials well known to those skilled in the art, and
optionally other
therapeutic or prophylactic agents.
The term "pharmaceutically acceptable" as used herein refers to compounds,
materials,
compositions, and/or dosage forms which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of a subject (e.g.
human) without
excessive toxicity, irritation, allergic response, or other problems or
complication,
commensurate with a reasonable benefit/risk ratio. Each excipient must also be
"acceptable" in the sense of being compatible with the other ingredients of
the
formulation.
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The pharmaceutical compositions can be in any form suitable for oral,
parenteral,
topical, intranasal, ophthalmic, otic, rectal, intra-vaginal, or transdermal
administration.
Where the compositions are intended for parenteral administration, they can be
formulated for intravenous, intramuscular, intraperitoneal, subcutaneous
administration
5 or for direct delivery into a target organ or tissue by injection,
infusion or other means of
delivery.
Pharmaceutical dosage forms suitable for oral administration include tablets,
capsules,
caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and
suspensions,
sublingual tablets, wafers or patches and buccal patches.
10 Pharmaceutical compositions containing compounds of the formulae (0),
(1) and (2) can
be formulated in accordance with known techniques, see for example,
Remington's
Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.
Thus, tablet compositions can contain a unit dosage of active compound
together with
an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose,
sucrose, sorbitol
15 or mannitol; and/or a non-sugar derived diluent such as sodium
carbonate, calcium
phosphate, calcium carbonate, or a cellulose or derivative thereof such as
methyl
cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such
as corn
starch. Tablets may also contain such standard ingredients as binding and
granulating
agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked
polymers
20 such as crosslinked carboxymethylcellulose), lubricating agents (e.g.
stearates),
preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for
example
phosphate or citrate buffers), and effervescent agents such as
citrate/bicarbonate
mixtures. Such excipients are well known and do not need to be discussed in
detail
here.
25 Capsule formulations may be of the hard gelatin or soft gelatin variety
and can contain
the active component in solid, semi-solid, or liquid form. Gelatin capsules
can be formed
from animal gelatin or synthetic or plant derived equivalents thereof.
The solid dosage forms (e.g. tablets, capsules etc.) can be coated or un-
coated, but
typically have a coating, for example a protective film coating (e.g. a wax or
varnish) or a
30 .. release controlling coating. The coating (e.g. a Eudragit TM type
polymer) can be
designed to release the active component at a desired location within the
gastro-
intestinal tract. Thus, the coating can be selected so as to degrade under
certain pH
conditions within the gastrointestinal tract, thereby selectively releasing
the compound in
the stomach or in the ileum or duodenum.
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Instead of, or in addition to, a coating, the drug can be presented in a solid
matrix
comprising a release controlling agent, for example a release delaying agent
which may
be adapted to selectively release the compound under conditions of varying
acidity or
alkalinity in the gastrointestinal tract. Alternatively, the matrix material
or release
retarding coating can take the form of an erodible polymer (e.g. a maleic
anhydride
polymer) which is substantially continuously eroded as the dosage form passes
through
the gastrointestinal tract. As a further alternative, the active compound can
be
formulated in a delivery system that provides osmotic control of the release
of the
compound. Osmotic release and other delayed release or sustained release
formulations may be prepared in accordance with methods well known to those
skilled in
the art.
Compositions for topical use include ointments, creams, sprays, patches, gels,
liquid
drops and inserts (for example intraocular inserts). Such compositions can be
formulated in accordance with known methods.
Compositions for parenteral administration are typically presented as sterile
aqueous or
oily solutions or fine suspensions, or may be provided in finely divided
sterile powder
form for making up extemporaneously with sterile water for injection.
Compositions for parenteral administration may be formulated for
administration as
discrete dosage units or may be formulated for administration by infusion.
Examples of formulations for rectal or intra-vaginal administration include
pessaries and
suppositories which may be, for example, formed from a shaped moldable or waxy
material containing the active compound.
Compositions for administration by inhalation may take the form of inhalable
powder
compositions or liquid or powder sprays, and can be administrated in standard
form
using powder inhaler devices or aerosol dispensing devices. Such devices are
well
known. For administration by inhalation, the powdered formulations typically
comprise
the active compound together with an inert solid powdered diluent such as
lactose.
The compounds of the inventions will generally be presented in unit dosage
form and, as
such, will typically contain sufficient compound to provide a desired level of
biological
activity. For example, a formulation intended for oral administration may
contain from
0.1 milligrams to 2 grams of active ingredient, more usually from 10
milligrams to 1
gram, for example, 50 milligrams to 500 milligrams.
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The active compound will be administered to a patient in need thereof (for
example a
human or animal patient) in an amount sufficient to achieve the desired
therapeutic
effect.
Methods of Treatment
It is envisaged that the compounds of the formulae (0), (1) and (2) as defined
in any one
of Embodiments 1.0 to 1.105 will be useful in the prophylaxis or treatment of
inflammatory diseases or conditions, immunological diseases or conditions,
allergic
diseases or disorders, transplant rejections and Graft-versus host disease.
Examples of
such disease states and conditions are set out above.
The compounds will typically be administered in amounts that are
therapeutically or
prophylactically useful and which generally are non-toxic, However, in certain
situations
(for example in the case of life threatening diseases), the benefits of
administering a
compound of the formula (0), (1) or (2) may outweigh the disadvantages of any
toxic
effects or side effects, in which case it may be considered desirable to
administer
compounds in amounts that are associated with a degree of toxicity.
The compounds may be administered over a prolonged term to maintain beneficial
therapeutic effects or may be administered for a short period only.
Alternatively they
may be administered in a pulsatile or continuous manner.
The compound of formula (0), (1) or (2) will generally be administered to a
subject in
need of such administration, for example a human patient.
A typical daily dose of the compound can be up to 1000 mg per day, for example
in the
range from 0.01 milligrams to 10 milligrams per kilogram of body weight, more
usually
from 0.025 milligrams to 5 milligrams per kilogram of body weight, for example
up to 3
milligrams per kilogram of bodyweight, and more typically 0.15 milligrams to 5
milligrams
per kilogram of bodyweight although higher or lower doses may be administered
where
required.
By way of example, an initial starting dose of 12.5 mg may be administered 2
to 3 times
a day. The dosage can be increased by 12.5 mg a day every 3 to 5 days until
the
maximal tolerated and effective dose is reached for the individual as
determined by the
physician. Ultimately, the quantity of compound administered will be
commensurate with
the nature of the disease or physiological condition being treated and the
therapeutic
benefits and the presence or absence of side effects produced by a given
dosage
regimen, and will be at the discretion of the physician.
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The compounds of the formulae (0), (1) and (2) can be administered as the sole
therapeutic agent or they can be administered in combination therapy with one
of more
other compounds such as steroids or interferons.
Methods of Diagnosis
Prior to administration of a compound of the formula (0), (1) or (2) a patient
may be
screened to determine whether a disease or condition from which the patient is
or may
be suffering is one which would be susceptible to treatment with a compound
having
activity against TYK2.
Accordingly, in further embodiments (3.1 to 3.6), the invention provides:
3.1 A compound as defined in any one of Embodiments 1.0 to 1.105 herein or
any
sub-groups or examples thereof as defined herein for use in the treatment or
prophylaxis
of a disease state or condition in a patient who has been screened and has
been
determined as suffering from, or being at risk of suffering from, a disease or
condition
which would be susceptible to treatment with a compound having activity
against a TYK2
kinase.
3.2 The use of a compound as defined in any one of Embodiments 1.0 to
1.105
herein or any sub-groups or examples thereof as defined herein for the
manufacture of a
medicament for the treatment or prophylaxis of a disease state or condition in
a patient
who has been screened and has been determined as suffering from, or being at
risk of
suffering from, a disease or condition which would be susceptible to treatment
with a
compound having activity against TYK2 kinase.
3.3 A method for the diagnosis and treatment of a disease state or
condition
mediated by TYK2 kinase, which method comprises (i) screening a patient to
determine
whether a disease or condition from which the patient is or may be suffering
is one which
would be susceptible to treatment with a compound having activity against the
kinase;
and (ii) where it is indicated that the disease or condition from which the
patient is thus
susceptible, thereafter administering to the patient an effective TYK2
inhibiting amount of
a compound as defined in any one of Embodiments 1.0 to 1.105 herein or any sub-
groups or examples thereof as defined herein.
A subject (e.g. patient) may be subjected to a diagnostic test to detect a
marker
indicative of the presence of a disease or condition in which TYK2 is
implicated, or a
marker indicative of susceptibility to the said disease or condition. For
example, subjects
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may be screened for genetic markers indicative of a susceptibility to develop
an
autoimmune or inflammatory disease.
The genetic marker can comprise a particular allele or single nucleotide
polymorphism of
the TYK2 gene which is indicative of susceptibility to an autoimmune disease
such as
multiple sclerosis (see for example Ban etal., European Journal of Human
Genetics
(2009), 17, 1309-1313) or an inflammatory bowel disease such as Crohn's
disease (see
Sato etal., J. Clin. Immunol. (2009), 29:815-825). The genetic marker can, for
example,
be a single nucleotide polymorphism in the TYK2 gene, or it can be a haplotype
comprising a single nucleotide polymorphism in the TYK2 gene and a
polymorphism in
another gene.
The diagnostic tests are typically conducted on a biological sample selected
from blood
samples, biopsy samples, stool biopsies, sputum, chromosome analysis, pleural
fluid,
peritoneal fluid, or urine.
Methods of indentifying genetic markers such as single nucleotide
polymorphisms are
well known. Examples of suitable methods for identifying such markers are
described in
Ban et a/. and Sato et al. above.
EXAMPLES
The invention will now be illustrated, but not limited, by reference to the
specific
embodiments described in the following examples.
Enzyme Inhibition
Compounds of the invention were assayed for their ability to inhibit TYK2
kinase and
other JAK kin ases.
Substrates and kinases used in the assays are identified in Table 2 below.
Kinase assays were performed at Reaction Biology Corp., Malvern, Pennsylvania,
USA,
using the following general procedure:
1) Prepare indicated substrate in freshly prepared Base Reaction Buffer (20 mM
Hepes
pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/all BSA, 0.1 mM Na3VO4,
2 mM DTT, 1% DMSO).
2) Deliver cofactors (1.5mM CaCl2, 16 ug/mL Calmodulin, 2mM MnCl2) to the
substrate
solution above
3) Deliver indicated kinase into the substrate solution and gently mix
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4) Deliver varying concentrations of test compound in DMSO into the kinase
reaction
mixture
5) Deliver 33P-ATP (specific activity 0.01 Ci4r1.., final) into the reaction
mixture to initiate
the reaction
5 6) Incubate kinase reaction for 120 min at room temperature
7) Reactions are spotted onto P81 ion exchange filter paper (Whatman # 3698-
915)
8) Unbound phosphate is removed by washing filters extensively in 0.75%
Phosphoric
acid.
9) 33P signal was determined using Typhoon phosphorimagers (GE Healthcare).
After
10 subtraction of background derived from control reactions containing
inactive enzyme,
IC50 values were determined using the nonlinear regression function in Prism
(Graphpad software).
Table 2
Protein
Protein HUGO Genbank
Substrate Accession Clone Expression Tag
Name symbol Accession #
N-
Baculovirus
aa 866-
terminal
JAK1 JAK1 pEY NP 002218.2 P23458
1154 in Sf21
GST
insect cells
tag
N-
NP 004963 060674 aa 809- Baculovirus
JAK2 JAK2 pEY
1132 in Sf21
terminal
GST
+g insect cells
tag
1 NP 000206 P52333 aa 781- Baculovirus N-
JAK3 JAK3 JAK3tide 1124 in Sf21
terminal
GST
insect cells
tag
N-
Aa Baculovirus
terminal
TYK2 TYK2 AXLtide NP_003322.2 P29597 833- in Sf21
GST
1187 insect cells
tag
15 Substrates:
AXLtide = [KKSRGDYMTMQIG]
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JAK3tide = [Ac-GEEEEYFELVKKKK-NH2]
pEY = poly Glu-Tyr [Glu:Tyr (4:1), M.W. = 5,000¨ 20,000]
The results are shown in Table 3 below.
Table 3
Example STRUCTURE In Vitro Enzyme IC50 (nM)
Number
(and method of TYK2 JAK1 JAK2 JAK3
preparation)
p H3
So
Example 1
(Example Q-3 in 0 13.5 90.2 234.7 404.8
W02008/139161) F
NH2
0
0, NH2
Example 2
(Example Q-25 in iLo 14.6 78.2 146.6 418.8
W02008/139161) F
NH2
0
0,
Example 3
(Example Q-26 in 0 5.3 47.6 95.0 359.0
W02008/139161) F
NH2
0
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_________________________________ OP/ ___________________________
'S-NH
Example 4
(Example Q-27 in 0 13.8 65.6 109.0 387.2
W02008/139161) F NH
NH2
0
N 0
Example 5 F 0 NH2
(Example Q-20 in NH 9.2 88.6 112.1 218.9
W02008/139161)
H2N _______________________________________________________________
HN
Example 6 0
! (Example Q-51 inF 25.0 192.4 297.1 471.6
W02008/139161)
0
F N
0 NH2
CNH
HNI
0
Example 7
(Example Q-54 in 9.8 201.5 261.0 419.3 1
W02008/139161)
F N
0 NH2
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cNH
HN
0
Example 8
(Example Q-53 in 12.9 201.0 267.5 408.5
W02008/139161) 0
F N
NH2
o
0
Example 9
(Example U-2 in ' 22.7 75.6 267.4 423.4
W02008/139161) 0
1 F N
NH2
0
NH
HN
Example 10 0
(Example U-3 in F 20.5 183.3 311.4 1 397.2
W02008/139161) NH
0
F N
NH2
0
HN
HN
Example 11 0
(Example U-4 in 15.1 189.6 338.4 387.7
W02008/139161)
0
NH
F N
NH2
0
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HN
Example 12 0
(Example U-6 in F 23.41 168.6 292.4 346.2
W02008/139161)
0
FN NH
NH2
HN
Example 13 0
(Example U-7 in F 11.2 123.0 181.6 341.5
W02008/139161)
L0 <NH
F N
NH2
OH
0
Example 14
(Example U-12 in 9.6 67.22 36.0 125.9
W02008/139161)
F N
NH2
0
OH
HN
0
Example 15
(Example U-16 in F 7.5 41.1 101.3 194.9
W02008/139161) çIXO\
F N
NH2
0
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HO
HN
Example 16 0
(Example U-17 in 8.4 58.1 118.8 199.1
W02008/139161)
0
NH2
0
NH
HN
Example 17 0
(Example U-21 in 13.7 152.8 167.2 99.2
W02008/139161)
0
F
NH2
0E13
HN
Example 18 0
(Example U-18 in 13.8 118.3 191.8 164.6
W02008/139161)
0
F
NH2
0
The data set out in the table above illustrate that compounds of formula (1)
are potent
inhibitors of TYK2 kinase and show a pronounced selectivity for TYK2 kinase
compared
to other JAK kinases.
5 On the basis of their activity against TYK2 kinase, it is envisaged that
the compounds of
the formula (1) will be useful as therapeutic agents for treating a wide range
of
inflammatory, immunological and allergic diseases and conditions.
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EXAMPLES 19 TO 33
The compounds of Examples 19 to 33 in Table 4 below are novel compounds and
are
made using the methods described below or methods analogous thereto. The
starting
materials and synthetic intermediates used in the methods are shown in Table 5
and the
NMR and LCMS properties of the final products are set out in Table 6.
Table 4
0/'S'
0,'S/
NH NH
NF12
Cl 0--- _____________________________________ F 0-...S NH2
Cl CI
Example 19 Example 20
\ /0
\ ,0
es/
0/
NH
NH
F 0,,,,S ,NH2
µNH2
N 0
¨N 0
F F F
Example 21 Example 22
H H
0 N,,NH
NH
\-,-J
Cl T CI
o-NH 0 NH
\ I \ I
NO N-----yD
F F
H2N H2N
Example 23 Example 24
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0 H
0 N) 0 N
--,---
N,
F F
0 NH 0 NH
\ I \ I
N----Nr0 N----Nr0
Cl CI
H2N H2N
Example 25 Example 26
H H
0 NõNH 0 N,,-NH
CI I Cl
0 NH 0 NH
\ I \ I
N---Nr0 .
Cl Cl
H2N ,
. H2N
Example 27 Example 28
. ---'0 H
0 N
--CN,
Cl I Cl
0.___NH 0 NH
\ I \ I
N --Nr0 N--Nr0
CI CI
H2N H2N
Example 29 Exampe 30
'1 I
0=S=0 0=S=0
F
F F
0-----NH 0 NH
\ I \ I
N--Nr0 N---"Nr0
F F
H2N H2N
Example 31 Example 32
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0=S=0
0 NH
\ I
H2N
Example 33
Table 5 - Synthetic Intermediates and Starting Materials
Compound Structure Source or method of
preparation
CI
Br Prepared as described in steps a
¨ Iy and b from Example F-1 in
1-1 \o
NNCN W02008/139161,
using 2,6-
dichlorobenzoyl chloride in step a
CI
Prepared as described in steps a
and b from Example F-1 in
1-2
NNCN
W02008/139161, using 2-chloro-6-
--
CI fluorobenzoyl chloride in step a
Prepared as described in steps a
and b from Example F-1 in
1-3
N---"NCN W02008/139161, using 2,4,6-
trifluorobenzoyl chloride in step a
Prepared as described in steps a
and b from Example F-1 in
1-4 W02008/139161,
using 2,5-
difluorobenzoyl chloride in step a
1-5 \ I Example F-1
of W02008/139161
1-6 110
H2N s¨ Commercially available
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1-7 H2N Commercially available
\
0
1-8 H2N ( Commercially available
H2N S-
1-9 Commercially available
0
H2N
1-10 0¨ Commercially available
(Compound (13) in General
Method B)
N,H2
1-11 ( Commercially available
\N
\O
NH
2
1-12 C) \N .( ( Commercially available
\O
1-13 H2N ( N¨ Commercially available
General Method A
Step a ¨ Preparation of Intermediate Compound (12)
R5 R5
R4 R4
R6 R6
R3 0 R3 0 (F)n
R7 NBr R7 N__,se [1.1
H2N
ON ON
(10) (F), (12)
(11)
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In the reaction scheme, the group Rt in formulae (11) and (12) is either a
group R1 as
defined herein or a protected form of the group R1.
A solution of palladium acetate (0.025mm01) and ( )-2,2"-
bis(diphenylphosphino)-1,1"-
binaphthalene (0.024mm01) in DMF (7.1mL) is stirred at room temperature for 3
minutes.
5 Then compound (10) (0.35mm01), compound (11) (1.40mmo1) and potassium
phosphate
tribasic (0.70mm01) are added and the mixture heated in the microwave for 3
minutes at
180 C. The reaction is diluted with Et0Ac and washed with water. The organic
phase
is passed through a MP-SH resin cartridge, dried over MgSO4 and the solvent
removed
in vacuo. The residue is purified by silica gel column chromatography using a
gradient
10 10-100% Et0Ac in hexanes to afford Compound (12), the identity of which
can be
confirmed by 1H NMR (DMSO) and LCMS.
Step b ¨ Preparation of Compound (2)
R5 ()LA¨RI
R5 Q R4
R4 R6
R6
R3 0 (F)n
N / H
R7 NH
(12) ON NH2
(2) 0
A solution of Compound (12) (0.09mm01) in concentrated sulfuric acid (1.7mL)
is stirred
15 at room temperature for 1.5 hours. The solution is neutralised by
pouring into saturated
sodium bicarbonate solution. The aqueous phase is extracted with Et0Ac. The
combined organic phase is dried over MgSO4 and the solvent is removed in vacuo
to
afford Compound (2), the identity of which can be confirmed by 1H NMR (DMS0)
and
LCMS.
20 General Method B
Step a ¨ Preparation of Intermediate Compound (14)
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0
R5 0 R5
0
R4 1-1,N1 R4 \
R6 0¨ R6
(13)
R3 0 , R3 0
R7 NI,s,? ___________ Br R7
ON ON
(10) (14)
Compound (10) is reacted with compound (13) under the conditions set out in
step a of
General Method A to give Compound (14).
Step b ¨ Preparation of Intermediate Compound (15)
0 0
R5 R5
0 OH
R4 \ R4
R6 R6
R3 0 R3 0
R7 i\ ri _______________ 31.-
R7 r\ N
ON CN
(14) (15)
Compound (14) is hydrolysed using lithium hydroxide to give the carboxylic
acid
Compound (15).
Alternatively, Compound (15) can be prepared by the method of step a of
Example U-1
of W02008/139161 or methods analogous thereto.
Step c ¨ Preparation of Intermediate Compound (16)
0 Rx
0 R5 R6 Ni
R5 OH R4 \
R4 RY
R6
__________________________________________ R3
R3 0
R7 Nj___e 11.1 /
HN Rx R7 ,,e _____ ,
\ y
R ON
ON (16)
(15)
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To a solution of Compound (15) (0.059mmo1), 0-(7-azabenzotriazol-1-y1)-
N,N,N1,Nr-
tetramethyluronium hexafluorophosphate (0.059mm01), and diisopropylethylamine
(0.117mmol) in N,N-dimethylformamide (2mL) is added an amine of formula HNRxRY
(0.059mm01) and the reaction mixture is stirred at room temperature for 16
hours. The
reaction mixture is then diluted with Et0Ac washed with 1M HCI, water and
brine. The
organic phase is dried over MgSO4 and the solvent removed in vacuo. The
residue is
purified by preparative HPLC to afford Compound (16), the identity of which
can be
confirmed by LCMS.
Step d ¨ Preparation of Compound (17)
0 Rx
0 Rx
R R5 R R5
R4
4 \ R6 RY
6 R'
R3
0 (F)n
0 (F)n
N
N
N H
ON NH2
(16) (17) 0
A solution of Compound (16) (0.022mm01) in concentrated sulfuric acid (0.5mL)
is stirred
at room temperature for 1.5 hours. The solution is neutralised by pouring into
saturated
sodium bicarbonate solution. The aqueous phase is then basified to pH14 using
5M
NaOH and extracted with Et0Ac. The combined organic phase is dried over MgS0.4
and
the solvent removed in vacuo to afford Compound (17), the identity of which
can be
confirmed by 1H NMR (DMSO) and LCMS. Compounds (17) containing a basic
nitrogen,
such as those prepared from 1-11 or 1-12 which bear an acid-sensitive nitrogen
protecting group, are concomitantly deprotected during the final acid-mediated
reaction
.. step.
General Method B can be used to make compounds wherein NRxRY forms a cyclic
amine such as a morpholino, piperazino or piperidino group or compounds
wherein R2 is
hydrogen or a substituent and RY is hydrogen or a substituent.
Table 6 0
Ex, No. Name Synthetic method 1H
NMR LCMS
G=4
I
.6.
2-(2,6-Dichloro-phenyl)-5-
(4-methanesulfonyl- General Method A using
(DMSO) 6 9.86 (1H, s), 7.83 (2H, d),
19 7.73-7.65 (4H,
m), 7.48 (3H, d), 3.14 m/z (ES+) 426
phenylamino)-oxazole-4- intermediates 1-1 and 1-
6.
carboxylic acid amide (3H, s)
2-(2-Chloro-6-fluoro-
pheny1)-5-(4- (DMSO) 6 9.86 (1H, s), 7.83 (2H, d),
General Method A using
20 methanesulfonyl- 7.64 (1H, q),
7.58-7.48 (6H, m), 3.16 m/z (ES+) 410
1
phenylamino)-oxazole-4- intermediates 1-2 and -
6. (3H, s) p
carboxylic acid amide
N.
un
5-(4-Methanesulfonyl-
GO
phenylamino)-2-(2,4,6- General Method A using
(DMSO) 6 9.81 (1H, s), 7.81 (2H, d),
21
0,
trifluoro-phenyl)-oxazole-4- intermediates 1-3 and 1-
6. 7.54 (2H, d), 7.46-7.44 (4H, m), 3.15 m/z (ES+) 412
carboxylic acid amide (3H, s)
2-(2,5-Difluoro-pheny1)-5-(4-
methanesulfonyl- General Method A using
(DMSO) 6 9.84 (1H, s), 7.85 (2H, d),
22 phenylamino)-oxazole-4- intermediates 1-4 and 1-
6. 7.78 (1H, br. s), 7.63 (2H, d), 7.51- m/z (ES+) 394
carboxylic acid amide 7.45 (4H, m),
3.19 (3H, s)
(S) 2-(2-Chloro-6-fluoro-
phenyI)-5-[4-(piperidin-3-
23 ylcarbarnoy1)-phenylamino]-
General Method B using
oxazole-4-carboxylic acid
intermediates 1-2, 1-10 and 1-11
amide
ot
0
(Me0D) 6 7.87 (2H, d), 7.62-7.59
(R) 2-(2-Chloro-6-fluoro-
"
o
(1H, m), 7.49-7.46 (3H, m), 7.33 (1H,
,..,
phenyl)-5-[4-(piperidin-3-
u,
General Method B using t), 4.29-4.24
(1H, m), 3.53 (1H, dd), O
24 ylcarbamoyI)-phenylamino]- .
m/z (ES+) 458 (.4
intermediates 1-2, 1-10 and 1-12 3.39-3.35 (1H,
m), 3.02-2.92 (2H, "
oxazole-4-carboxylic acid
.1
amide m), 2.13-2.07
(2H, m), 1.89-1.74 (.4
(2H, m)
2-(2-Chloro-6-fluoro-
pheny1)-5-[4-(morpholine-4- General Method B using (DMSO) 6 9.50
(1H, s), 7.64 (1H,
25 carbonyl)-phenylamino]- intermediates 1-2, 1-10 and dd), 7.54
(1H, d), 7.47-7.45 (2H, m),
m/z (ES+) 445
7.39-7.34 (5H, m), 3.55 (4H, br. m),
oxazole-4-carboxylic acid morpholine
amide 3.36 (4H, br. m)
P
2-(2-Chloro-6-fluoro- (Me0D) 6 7.87
(2H, d), 7.62-7.58 ,,
phenyl)-5-[4-(1-methyl- (1H, m), 7.51-
7.47 (3H, m), 7.34 (1H, .
General Method B using ' 26 piperidin-4-
ylcarbamoyI)- intermediates 1-2, 1-10 and 1-13 t), 4.16 (1H, m), 3.59
(2H, m), 3.20 m/z (ES+) 472
phenylanninoFoxazole-4- (2H, m), 2.92
(3H, s), 2.24 (2H, m), .
c.,
'
carboxylic acid amide 1.92 (2H, m)
.
(S) 2-(2,6-Dichloro-phenyl)- (Me0D) 6 7.82
(2H, d), 7.59-7.52
5-[4-(piperidin-3- General Method B using (3H, m), 7.40
(2H, d), 4.23-4.18 (1H,
27 ylcarbamoy1)-phenylaminoF intermediates 1-1, 1-10 and 1-11 m),
3.49 (1H, dd), 3.34-3.29 (1H, m), m/z (ES+) 474
oxazole-4-carboxylic acid 2.97-2.86 (2H,
m), 2.09-2.03 (2H, m)
amide 1.84-1.69 (2H, m)
(R) 2-(2,6-Dichloro-phenyl)- (Me0D) 8 7.86
(2H, d), 7.64-7.60 Iv
5-[4-(piperidin-3- General Method B using (3H, m), 7.44
(2H, d), 4.25-4.23 (1H, n
28 ylcarbamoy1)-phenylaminol- intermediates 1-1, 1-10 and 1-12
m), 3.52 (1H, dd), 3.38-3.33 (1H, m), m/z (ES+)
474 le-it
oxazole-4-carboxylic acid 3.02-2.90 (2H,
m), 2.11-2.07 (2H, m) o
amide 1.88-1.74 (2H, m)
,--,
(.4
O
c,
ot
,-,
ot
2-(2,6-Dichloro-phenyl)-5-
0
General Method B using
[4-(morpholine-4-carbonyl)-
29 intermediates 1-1, 1-10 and
phenylamino]-oxazole-4-
morphol ine
(.4
carboxylic acid amide
(.4
2-(2,6-Dichloro-phenyl)-5-
[4-(1-methyl-piperidin-4-
(Me0D) 8 7.85 (2H, d), 7.62-7.59
General Method B using
30 ylcarbamoyI)-phenylamino]- (3H, m), 7.43
(2H, d), 4.15 (1H, m) m/z (ES+) 490
intermediates l-1, 1-10 and 1-13 3.58 (2H, m),
3.19 (2H, m), 2.91 (3H,
oxazole-4-carboxylic acid
amide s), 2.22 (2H, m),
1.93 (2H, m)
2-(2,6-Difluoro-phenyl)-5-(4- (DMSO) 8 9.82
(1H, s), 7.74 (2H, d),
31 ethanesulfonyl- General Method A using
7.62-7.60 (1H, m), 7.54 (2H, d), 7.44 m/z (ES+) 430 p
phenylamino)-oxazole-4- intermediates 1-5 and 1-
7. (2H, br s), 7.33-7.29 (2H, m), 3.20 (M+Na+)
carboxylic acid amide (2H, q), 1.06
(3H, t)
o
2-(2,6-Difluoro-phenyl)-5-(4-
methanesulfonyl- General Method A using
(DMSO) 610.07 (1H, s), 7.73-7.67 m/z (ES+) 434
32 (2H, m), 7.52-
7.45 (3H, m), 7.40-
phenylamino)-oxazole-4- intermediates 1-5 and 1-
6.
7.34 (3H, m), 3.27 (3H, s)
(M+Na+)
carboxylic acid amide
2-(2,6-Difluoro-phenyl)-5-[4- (DMSO) d 9.83
(1H, s), 7.71 (2H, d),
33 propane-2-sulfonyI)- General Method A using
7.63-7.60 (1H, m), 7.54 (2H, d), 7.44 m/z (ES+) 444
phenylamino]-oxazole-4- intermediates 1-5 and 1-
8. (2H, br s), 7.33-7.29 (2H, m), 3.35 (M+Na+)
carboxylic acid amide (1H, m), 1.11
(6H, d)
(.4
ot
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EXAMPLE 34
Enzyme Inhibitory Activities of Novel Compounds of Formula (2)
Novel compounds of formula (2) were tested in the TYK2 kinase inhibition assay
and the
other JAK kinase inhibition assays described above. The results are shown in
Table 7
below.
Table 7
In Vitro Enzyme IC50 (nM)
Compound of Example No.
TYK2 JAK1 JAK2 JAK3
19 2.3 21.9 87.7 214
20 2.7 28.7 72.6 165
21 68.3 241 412 2180
22 183 843 663 '
5500
23 1.89 63.3 61.9 240
24 5.11 157 125 167
25 0.564 28.9 30.9 43.2
26 2.98 100 87.8 132
27 1.21 72.2 93.3 233
28 1.77 108 122 194
29 0.617 16.8 40.3 90.8
30 1.52 83.4 106 164
31 4.41 222 213 390
32 31 1970 1590 5370 ,
33 5.47 135 153 516
The data set out in the table above illustrate that compounds of formula (2)
are potent
inhibitors of TYK2 kinase and show a pronounced selectivity for TYK2 kinase
compared
to other JAK kinases.
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On the basis of their activity against TYK2 kinase, it is envisaged that the
compounds of
the formula (2) will be useful as therapeutic agents for treating a wide range
of
inflammatory, immunological and allergic diseases and conditions.
EXAMPLE 35
PHARMACEUTICAL FORMULATIONS
(i) Tablet Formulation
A tablet composition containing a compound of the formula (0), (1) or (2) is
prepared by
mixing 50mg of the compound with 197mg of lactose (BP) as diluent, and 3mg
magnesium stearate as a lubricant and compressing to form a tablet in a known
manner.
.. (ii) Capsule Formulation
A capsule formulation is prepared by mixing 100mg of a compound of the formula
(0),
(1) or (2) with 100mg lactose and filling the resulting mixture into standard
opaque hard
gelatin capsules.
(iii) Injectable Formulation I
A parenteral composition for administration by injection can be prepared by
dissolving a
compound of the formula (0), (1) or (2) (e.g. in a salt form) in water
containing 10%
propylene glycol to give a concentration of active compound of 1.5% by weight.
The
solution is then sterilised by filtration, filled into an ampoule and sealed.
(iv) Injectable Formulation II
A parenteral composition for injection is prepared by dissolving in water a
compound of
the formula (0), (1) or (2) (e.g. in salt form) (2mg/mL) and mannitol
(50mg/mL), sterile
filtering the solution and filling into sealable 1mL vials or ampoules.
(iv) Sub-cutaneous Injection Formulation
A composition for sub-cutaneous administration is prepared by mixing a
compound of
.. the formula (0), (1) or (2) with pharmaceutical grade corn oil to give a
concentration of
5mg/mL. The composition is sterilised and filled into a suitable container.
Equivalents
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The foregoing examples are presented for the purpose of illustrating the
invention and
should not be construed as imposing any limitation on the scope of the
invention. It will
readily be apparent that numerous modifications and alterations may be made to
the
specific embodiments of the invention described above and illustrated in the
examples
without departing from the principles underlying the invention. All such
modifications
and alterations are intended to be embraced by this application.
