Note: Descriptions are shown in the official language in which they were submitted.
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PYRIDINE COMPOUNDS AND AZA ANALOGUES THEREOF AS TYK2
INHIBITORS
The present invention relates to a novel class of kinase inhibitors, including
pharmaceutically
acceptable salts, prodrugs and metabolites thereof, which are useful for
modulating protein
kinase activity for modulating cellular activities such as signal
transduction, proliferation, and
cytokine secretion. More specifically the invention provides compounds which
inhibit,
regulate and/or modulate kinase activity, in particular TYK2 activity, and
signal transduction
pathways relating to cellular activities as mentioned above. Furthermore, the
present
invention relates to pharmaceutical compositions comprising said compounds,
for example
for the treatment or prevention of an immunological, inflammatory, autoimmune,
or allergic
disorder or disease or a transplant rejection or a Graft-versus host disease.
Kinases catalyze the phosphorylation of proteins, lipids, sugars, nucleosides
and other cellular
metabolites and play key roles in all aspects of eukaryotic cell physiology.
Especially, protein
kinases and lipid kinases participate in the signaling events which control
the activation,
growth, differentiation and survival of cells in response to extracellular
mediators or stimuli
such as growth factors, cytokines or chemokines. In general, protein kinases
are classified in
two groups, those that preferentially phosphorylate tyrosine residues and
those that
preferentially phosphorylate serine and/or threonine residues. The tyrosine
kinases include
membrane-spanning growth factor receptors such as the epidermal growth factor
receptor
(EGFR) and cytosolic non-receptor kinases such as Janus kinases (JAK).
Inappropriately high protein kinase activity is involved in many diseases
including cancer,
metabolic diseases, autoimmune or inflammatory disorders. This effect can be
caused either
directly or indirectly by the failure of control mechanisms due to mutation,
overexpression or
inappropriate activation of the enzyme. In all of these instances, selective
inhibition of the
kinase is expected to have a beneficial effect.
One group of kinases that has become a recent focus of drug discovery is the
Janus kinase
(JAK) family of non-receptor tyrosine kinases. In mammals, the family has four
members,
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JAK1, JAK2, JAK3 and Tyrosine kinase 2 (TYK2). Each 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. By contrast, the
expression
of JAK3 is predominantly in hematopoietic cells and it is highly regulated
with cell
development and activation (Musso et al., 1995. J. Exp. Med. 181(4):1425-31).
The study of JAK-deficient cell lines and gene-targeted mice has revealed the
essential,
nonredundant functions of JAKs in cytokine signalling. JAK1 knockout mice
display a
perinatal lethal phenotype, probably related to the neurological effects that
prevent them from
sucking (Rodig et al., 1998. Cell 93(3):373-83). Deletion of the JAK2 gene
results in
embryonic lethality at embryonic day 12.5 as a result of a defect in
erythropoiesis (Neubauer
et al., 1998. Cell 93(3):397-409). Interestingly, JAK3 deficiency was first
identified in
humans with autosomal recessive severe combined immunodeficiency (SCID)
(Macchi et al.,
1995. Nature 377(6544):65-68). JAK3 knockout mice too exhibit SCID but do not
display
non-immune defects, suggesting that an inhibitor of JAK3 as an
immunosuppressant would
have restricted effects in vivo and therefore presents a promising drug for
immunosuppression
(Papageorgiou and Wikman 2004, Trends in Pharmacological Sciences 25(11):558-
62).
The role of TYK2 in the biological response to cytokines was first
characterized using a
mutant human cell line that was resistant to the effects of Type I interferons
(IFNs) and the
demonstration that IFNa responsiveness could be restored by genetic
complementation of
TYK2 (Velazquez et al, 1992. Cell 70, 313-322). Further in vitro studies
implicated TYK2 in
the signaling pathways of multiple other cytokines involved in both innate and
adaptive
immunity. Analysis of TYK-24- mice however 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 IFNa/f3 and signal normally to interleukin 6 (IL-6) and
interleukin 10 (IL-
IO), both of which activate TYK2 in vitro. In contrast, TYK2 was shown to be
essential for
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IL-12 signaling 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-/- 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
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,
signaling 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 signaling 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 rs12720270, 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. Clin. Immunol. 29, 815-825). In support of
the involvement of
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TYK2 in immunopathologic disease processes, it has been shown that B 10.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. Immunol. 182, 7776-7783). Furthermore, a recent
study showed
that TYK2 -/- mice were completely resistant to MOG-induced EAE (Oyamada et
al., 2009. J.
Immunol. 183, 7539-7546). In these 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 signaling of
multiple pro-
inflammatory 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.
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 Immunol. 4, 356-360).
TYK2 inhibitors are described in European patent application with application
N
10168056.9.
Phenylaminopyrimidines as JAK2 kinase selective compounds are known from WO-A
2008/109943. Pyrimidinyl-thiophene kinase modulators are known from WO-A
2007/053776.
TYK2 inhibitors are known from DE-A 102009001438, DE-A 102009015070 and WO-A
2011/113802.
Similar pyrimidine compounds are known from N. Hebert et al., Internationnal
Journal of
Mass Spectrometry and Ion Processes 79 (1986), 45-56 and K. Takagi et al.
Chimica
Therapeutica 1974-9, N 1, p. 14 to 18.
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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.
Accordingly, the present invention provides compounds of formula (I)
R3
X21
X
R2
or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein
R' is Tl; C(0)R4; C(0)N(R4a)R4; or C(0)0R4;
R4 is Tl; or C1_6 alkyl, wherein C1_6 alkyl is optionally substituted with one
or more R5, which
are the same or different;
R4a is H; or C1_6 alkyl, wherein C1_6 alkyl is optionally substituted with one
or more halogen,
which are the same or different;
R5 is T2; halogen; CN; C(0)0R6; OR6; C(0)R6; C(0)N(R6R6a); S(0)2N(R6R6a);
S(0)N(R6R6a); S(0)2R6; S(0)R6; N(R6)S(0)2N(R6aR6b); N(R6)S(0)N(R6aR6b); SR6;
N(R6R6a);
OC(0)R6; N(R6)C(0)R6a; N(R6)S(0)2R6a; N(R6)S(0)R6a; N(R6)C(0)N(R6aR6b);
N(R6)C(0)0R6a; or OC(0)N(R6R6a);
R6, K-6a,
R6b are independently selected from the group consisting of H; T2; and C1_6
alkyl,
wherein C1_6 alkyl is optionally substituted with one or more halogen, which
are the same or
different;
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Tl is C3,7 cycloalkyl; or 5 membered aromatic heterocyclyl, wherein Tl is
optionally
substituted with one or more R7, which are the same or different;
R7 is T2; halogen; CN; C(0)0R8; OR8; oxo (=0), where the ring is at least
partially saturated;
C(0)R8; C(0)N(R8R8a); S(0)2N(R8R8a); S(0)N(R8R8a);
S(0)2R8; S(0)R8;
N(R8)S(0)2N(R8aR8b); N(R8)S(0)N(R8aR8b); SR8; N(R8R8a); OC(0)R8; N(R8)C(0)R8a;
N(R8)S(0)2R8a; N(R8)S(0)R8a; N(R8)C(0)N(R8aR8b); N(R8)C(0)0R8a; OC(0)N(R8R8a);
or
Ch6 alkyl, wherein Ch6 alkyl is optionally substituted with one or more R9,
which are the
same or different;
R8, R8a, R8b are independently selected from the group consisting of H; T2; or
C1_6 alkyl,
wherein C1_6 alkyl is optionally substituted with one or more Ril), which are
the same or
different;
R9 is T2; halogen; CN; C(0)0R8c; 0R8c; C(0)R8c; C(0)N(R8cR8d); S(0)2N(R8cR8d);
S(0)N(R8cR8d); S(0)2R8c; S(0)R8c; N(R8c)S(0)2N(R8dR8e); N(R8c)S(0)N(R8dR8e);
SR8c;
N(R8cR8d); OC(0)R8c; N(R8c)C(0)R8d;
N(R8c)S(0)2R8d; N(R8c)S(0)R8d;
N(R8c)C(0)N(R8dR8e); N(R8c)C(0)0R8d; and OC(0)N(R8cR8d);
R8c, R8d, R8e are independently selected from the group consisting of H; T2;
or C1_6 alkyl,
wherein C1_6 alkyl is optionally substituted with one or more halogen, which
are the same or
different;
T2 is phenyl; C3,7 cycloalkyl; or 4 to 7 membered heterocyclyl, wherein T2 is
optionally
substituted with one or more R", which are the same or different;
R" is halogen; CN; C(0)0R12; OR12; oxo (=0), where the ring is at least
partially saturated;
C(0)R12; C(0)N(R2Ri2a); s(0)2N(R2Ri2a); s(0)N(R2Ri2a); s(0)2R12; "Au.;
N(R12)S(0)2N(Ri2aRi2); N(R12)s(0)N(RzaRa;
) SR12; N(R12R12a); OC(0)R12;
N(R12)C(0)R12a; N(R12)S(0)2R2a; N(R12)S(0)R2a;
N(R12)C(0)N(R12aR12);
MR12)C(0)0R12a; OC(0)N(R12R12a); or Ch6 alkyl, wherein C1_6 alkyl is
optionally substituted
with one or more R", which are the same or different;
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R10, K-13
are independently selected from the group consisting of halogen; CN;
C(0)140R14;
OR14; C(0)R14; C(0)N(Ri4R4a); s(0)2N(Ri4Ri4a); s(0)N(Ri4Ri4a); s(0)2R14;
s(0)R14;
N(R14)S(0)2N(R4aR4); N(R14)s(0)N(R4aR4);
SR14; N(R14R14a);
OC(0)R14;
N(R14)C(0)R14a; N(R14)S(0)2R4a; N(R14)S(0)R4a;
N(R14)C(0)N(R14aR14);
N(R14)C(0)0R14a; and OC(0)N(R14R14a);
R12, R12a, R12b, R14, R14a, ¨14b
are independently selected from the group consisting of H; and
Ch6 alkyl, wherein C1_6 alkyl is optionally substituted with one or more
halogen, which are
the same or different;
X1 is N and X2 is C(R15); or X1 is C(R16) and X2 is C(R15); or X1 is N and X2
is N;
R15 is C(R17)3;
R3, R16 are independently from the group consisting of H; and halogen;
each R17 is independently selected from the group consisting of H; and
halogen;
R2 is phenyl; or 4 to 7 membered aromatic heterocyclyl, wherein R2 is
optionally substituted
with one or more R18, which are the same or different;
R18 is T3; halogen; CN; C(0)0R19; OR19; C(0)R19; C(0)N(Ri9R9a);
s(0)2N(R9Ri9a);
S(0)N(Ri9Risia); s(0)2R19; S(0)R' 9; N(R19)s(0)2N(R19aR19);
N(R19)s(0)N(R19aR19); sR19;
N(Ri9R19a);
OC(0)R19; N(R19)C(0)R19a; N(R19)S(0)2R19a;
N(R19)S(0)R19a;
N(R19)C(0)N(R19aRl9b), N,-19)C(0)OR' 9a; OC(0)N(R19R19a); or C16 alkyl,
wherein C1-6
alkyl is optionally substituted with one or more R29, which are the same or
different;
R19, K ¨19a R19-
, b
are independently selected from the group consisting of H; T3; or Ch6 alkyl,
wherein C1_6 alkyl is optionally substituted with one or more R21, which are
the same or
different;
T3 is phenyl; C3_7 cycloalkyl; or 4 to 7 membered heterocyclyl, wherein T3 is
optionally
substituted with one or more R22, which are the same or different;
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R22 is halogen; CN; C(0)0R23; OR23; oxo (=0), where the ring is at least
partially saturated;
C(0)R23; C(0)N(R23R23a); S(0)2N(R23R23a); S(0)N(R23R23a); S(0)2R23; S(0)R23;
N(R23)S(0)2N(R23aR23b); N(R23)s(0)N(R23aR23b ;
) SR23; N(R23R23a); OC(0)R23;
N(R23)C(0)R23a; N(R23)S(0)2R23a; N(R23)S(0)R23a;
N(R23)C(0)N(R23aR23b);
N(R23)C(0)0R23a; OC(0)N(R23R23a); or C1_6 alkyl, wherein Ci_6 alkyl is
optionally substituted
with one or more R24, which are the same or different;
R20, R21, R24 are independently selected from the group consisting of halogen;
CN; C(0)0R25;
OR25; C(0)R25; C(0)N(R25R25a); S(0)2N(R25R25a); S(0)N(R25R25a); S(0)2R25;
S(0)R25;
N(R25)S(0)2N(R
25aR25b); N(R25)s(0)N(R25aR25b ;
) SR25; N(R25R25a); OC(0)R25;
N(R25)C(0)R25a; N(R25)S(0)2R25a; N(R25)S(0)R25a;
N(R25)C(0)N(R25aR25b);
N(R25)C(0)0R25a; and OC(0)N(R25R25a);
R23, R23a, R23b, R25, K ¨25a, R25- 1-)
are independently selected from the group consisting of H; T4;
and Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more
R26, which are the
same or different;
T4 is phenyl; C3_7 cycloalkyl; or 4 to 7 membered heterocyclyl, wherein T4 is
optionally
substituted with one or more R27, which are the same or different;
R27 is halogen; CN; C(0)0R28; OR28; oxo (=0), where the ring is at least
partially saturated;
C(0)R28; C(0)N(R28R28a); s(0)2N(R28R28a); s(0)N(R28R28a); s(0)2R28; s("28;
N(R28)S(0)2N(R28aR28b); N(R28)s(0)N(R28aR28b ;
) sR28; N(R28R28a);
OC(0)R28;
N(R28)C(0)R28a; N(R28)S(0)2R28a; N(R28)S(0)R28a;
N(R28)C(0)N(R28aR28);
N(R28)C(0)0R28a; OC(0)N(R28R28a); or C16 alkyl, wherein Ci_6 alkyl is
optionally substituted
with one or more R29, which are the same or different;
R26, R29 are independently selected from the group consisting of halogen; CN;
C(0)0R30;
OR30; C(0)R30; C(0)N(R3 R3 a); S(0)2N(R3 R3 a); S(0)N(R3 R3 a); S(0)2R30;
S(0)R30;
N(R30)S(0)2N(R
30aR30b); N(R30)s(0)N(R30aR3013);
SR30; N(R3 R3 a); OC(0)R30;
N(R30)C(0)R30a; N(R30)S(0)2R3 a; N(R30)S(0)R30a;
N(R30)C(0)N(R30aR30b);
N(R30)C(0)0R3 a; and OC(0)N(R3 R3 a);
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R28, R28a, R28b, R30, R30a, R30b
are independently selected from the group consisting of H; and
Ch6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more
halogen, which are
the same or different,
provided that the following compounds are excluded:
N
N NoI
eNS N
N=( Br N
N \
0
-S
'
(1) , (2) , (3) 01\0
CI N N
I
cN
I N 0
(4)
, (5) -N
N N
1\1 S-"µ
I --0O2Et I N 0
N N
OH
(6) F ,(7)
Compound (1) is known from EP 1 654 706 A as compound [165-1]. Compound (2) is
known
from WO 2010/055077 A as compound A41. Compound (3) is known from M.E.
Swarbrick
et al., Bioorganic & Medicinal Chemistry Letters 19 (2009), 4504-4508 as
compound 40.
Compound (4) is known from GB 2 056 449 A as compound of example 5. Compound
(5) is
described by the Chemical Abstracts Service with accession number 1185523-72-
1.
Compound (6) is described by the Chemical Abstracts Service with accession
number
861211-24-7.
Compound (7) excluded from the scope of the present invention is described in
N. Hebert et
al., International Journal of Mass Spectrometry and Ion Processes 79 (1986),
45-56; J.C. Blais
et al., International Journal of Mass Spectrometry and Ion Processes (1989),
88(1), 29-43
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In case a variable or substituent can be selected from a group of different
variants and such
variable or substituent occurs more than once the respective variants can be
the same or
different.
Within the meaning of the present invention the terms are used as follows:
"Alkyl" means a straight-chain or branched hydrocarbon chain. Each hydrogen of
an alkyl
carbon may be replaced by a substituent as further specified.
"C1_4 alkyl" means an alkyl chain having 1 - 4 carbon atoms, e.g. if present
at the end of a
molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, or e.g. -
CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-, when two
moieties
of a molecule are linked by the alkyl group. Each hydrogen of a Ci_4 alkyl
carbon may be
replaced by a substituent as further specified.
"C1_6 alkyl" means an alkyl chain having 1 - 6 carbon atoms, e.g. if present
at the end of a
molecule: C1-4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl; tert-butyl,
n-pentyl, n-hexyl, or e.g. -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -
CH(C2H5)-, -
C(CH3)2-, when two moieties of a molecule are linked by the alkyl group. Each
hydrogen of a
C1_6 alkyl carbon may be replaced by a substituent as further specified.
"C3_7 cycloalkyl" or "C3_7 cycloalkyl ring" means a cyclic alkyl chain having
3 - 7 carbon
atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,
cycloheptyl.
Preferably, cyloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, or
cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a
substituent as further
specified. The term "C3_5 cycloalkyl" or "C3_5 cycloalkyl ring" is defined
accordingly.
"Halogen" means fluor , chloro, bromo or iodo. It is generally preferred that
halogen is fluoro
or chloro.
"4 to 7 membered heterocycly1" or "4 to 7 membered heterocycle" means a ring
with 4, 5, 6
or 7 ring atoms that may contain up to the maximum number of double bonds
(aromatic or
non-aromatic ring which is fully, partially or un-saturated) wherein at least
one ring atom up
to 4 ring atoms are replaced by a heteroatom selected from the group
consisting of sulfur
(including -S(0)-, -S(0)2-), oxygen and nitrogen (including =N(0)-) and
wherein the ring is
linked to the rest of the molecule via a carbon or nitrogen atom. Examples for
a 4 to 7
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membered heterocycles are azetidine, oxetane, thietane, furan, thiophene,
pyrrole, pyrroline,
imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole,
isoxazoline,
thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline,
tetrahydrofuran,
tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine,
isoxazolidine,
thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran,
dihydropyran, tetrahydropyran,
imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine,
piperidine, morpholine,
tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine or
homopiperazine.
Accordingly, the term "4 to 7 membered aromatic heterocycly1" or "4 to 7
membered
aromatic heterocycle" refers to a 4 to 7 membered heterocyclic ring which is
aromatic.
"5 membered aromatic heterocycly1" or "5 membered aromatic heterocycle" means
a
heterocycle derived from cyclopentadienyl, where at least one carbon atom is
replaced by a
heteroatom selected from the group consisting of sulfur (including -S(0)-, -
S(0)2-), oxygen
and nitrogen (including =N(0)-). Examples for such heterocycles are furan,
thiophene,
pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole,
thiadiazole, triazole,
tetrazole.
Preferred compounds of formula (I) are those compounds in which one or more of
the
residues contained therein have the meanings given below, with all
combinations of preferred
substituent definitions being a subject of the present invention. With respect
to all preferred
compounds of the formula (I) the present invention also includes all
tautomeric and
stereoisomeric forms and mixtures thereof in all ratios, and their
pharmaceutically acceptable
salts.
In preferred embodiments of the present invention, the substituents mentioned
below
independently have the following meaning. Hence, one or more of these
substituents can have
the preferred or more preferred meanings given below.
Preferably, Xl is N and X2 is C(R15). Further preferred is X1=X2=N.
Preferably, le is Tl; or C(0)R4.
Preferably, R4 is Tl.
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Preferably, Tl is cyclopropyl; thiophenyl; isothiazolyl; or pyrazolyl, wherein
Tl is optionally
substituted with one or more R7 (preferably one R7), which are the same or
different.
Preferably, le is C(0)T1, Tl is C3_7 cycloalkyl, wherein Tl is optionally
substituted with one
or more R7 (preferably unsubstituted), which are the same or different. More
preferably, Tl
is cyclopropyl.
Preferably, le is Tl, Tl is 5 membered aromatic heterocyclyl, wherein Tl is
optionally
substituted with one or more R7 (preferably one R7), which are the same or
different.
Preferably, Tl is isothiazolyl; or pyrazolyl, wherein Tl is optionally
substituted with one or
more R7, which are the same or different.
Preferably, Tl is
R7 ,R7 ,R7
_cNN,
or
N
, more preferably,
wherein R7 is defined as indicated above.
Preferably, Tl is cyclopropyl; or pyrazolyl, wherein Tl is unsubstituted or
substituted with one
or more R7, which are the same or different.
Preferably, R7 is methyl; CH2CH2OR8c; CH2C(0)T2; or CH2C(0)N(R8cR8d). Also
preferably,
R7 is methyl; CH2CH2OR8c or CH2C(0)T2. R8c is preferably H. T2 is preferably
morpholin-4-
yl; pyrrolidin-lyl or piperidin-l-yl. Independent of each other, lec and R8d
are preferably H
or C1-4 alkyl. More preferably, T2 is morpholin-4-yl. More preferably, R8c is
H and R8d is
ethyl. Even more preferably, R7 is methyl. Even more preferably, R7 is
CH2C(0)N(R8cR8d).
Preferably, R15 is CH3.
Preferably, R3 is H.
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Preferably, R2 is phenyl; pyridyl; pyrimidyl; pyrazolyl; oxadiazolyl;
thiazolyl; or thiadiazolyl,
wherein R2 is substituted with one or more R18, which are the same or
different. More
preferably, R2 is phenyl, wherein R2 is substituted with one or more R18.
Preferably, R2 is substituted with one or two R18.
Preferably, R" is halogen; CN; S(0)2N(R9Ri9a); s(0)2R19; mis(0)2R9a;
OR19;
C(0)N(R19aR19); SR19; C1-4 alkyl, unsubstituted or substituted with one or
more halogen,
which are the same or different; NHC(0)R19; or C(0)R19. More preferably, R" is
halogen;
OCH3; S(0)2CH3; NHS(0)2CH3; or CH2NHS(0)2CH3. More preferably, R" is F; Cl;
CN;
OR19; S(0)2R19; C1_4 alkyl, unsubstituted or substituted with one R20;
S(0)2NHR19;
S(0)2N(CH3)R19; NHS(0)2R19; C(0)NHR19; C(0)N(CH3)R19; NHC(0)R19; CF3; SR19;
T3,
optionally substituted with one substituent selected from the group consisting
of methyl and
NH2; C(0)T3 or S(0)2T3, wherein T3 is optionally substituted with one
substituent selected
from the group consisting of methyl and methylcarbonyl; NHC(0)T3; or
NHC(0)NuR19a.
Even more preferably R" is F; Cl; CN; OH; 0C1_4 alkyl; S(0)2-Ch4 alkyl; C1_4
alkyl;
CH2S(0)2CH3; S(0)2NH2; S(0)2N(CH3)2; S(0)2NHCh4 alkyl; NH2; NHS(0)2CH3;
C(0)NH2;
C(0)NH-Ci_4 alkyl; C(0)N(CH3)2; NHC(0)CH3; CF3; SCH3; cyclohexyloxy;
hy droxy ethyl oxy; hy droxy ethyl ami nocarb onyl ;
m ethoxy ethyl oxy; pyrrol i di n-1-
ylcarbonylmethyloxy; aminocarbonylmethylaminocarbonyl; pyrrolidin-l-
ylcarbonyl;
morpholin-4-ylcarbonyl; cy clop entyl ami nocarb
onyl ; tetrahydrofuranami no carb onyl ;
hydroxyethylaminosulfonyl; methoxyethylaminosulfonyl; aminocarbonylmethylamino-
sulfonyl; S(0)2T3 or C(0)T3, wherein T3 is optionally substituted with methyl
or
methyl carb onyl ; aminoethylaminocarbonyl; NHC(0)NH-Ci_4
alkyl; pyrroli din-1-
ylcarbonylamino; aminoethyloxy; phenyl; cyclobutyloxy; cyclopentyloxy;
cyclopropyloxy;
cyclopropylaminocarbonyl; cylobutylaminocarbonyl;
3,3,3 -trifluorpropyl oxy; or
cyanomethylsulfonylamino. Even more preferably, R" is F; methyl; ethyl; iso-
propyl; OR19;
C(0)NHR19; or S(0)2NHR19, wherein R19 is methyl; ethyl; iso-propyl; propyl; or
CH2CH2OH.
Preferably, R2 is
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R18 or R18 ,
wherein R" is defined as indicated above.
More preferably, when R2 is
R18 , R" is OR19.
Compounds of formula (I) in which some or all of the above-mentioned groups
have the
preferred meanings are also an object of the present invention.
Further preferred compounds of the present invention are selected from the
group consisting
of
N-(4-(3-fluoropheny1)-5-methylpyrimidin-2-yl)cyclopropanecarboxamide;
4-(2-fluoro-4-methoxypheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-
amine;
N-(4-(2-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-
yl)cyclopropanecarboxamide;
N-(4-(4-chloropheny1)-5-methylpyrimidin-2-yl)cyclopropanecarboxamide;
N-(5-methy1-4-(4-(methylsulfonyl)phenyl)pyrimidin-2-
yl)cyclopropanecarboxamide;
N-(5-methy1-4-(p-tolyl)pyrimidin-2-yl)cyclopropanecarboxamide;
N-(4-(4-methoxypheny1)-5-methylpyrimidin-2-yl)cyclopropanecarboxamide;
N-(4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-
yl)cyclopropanecarboxamide;
4-(3-fluoro-4-methoxypheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-
amine;
5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-(4-(methylsulfonyl)phenyl)pyrimidin-2-
amine;
4-(3-fluoro-4-methoxypheny1)-5-methyl-N-(1H-pyrazol-4-yl)pyrimidin-2-amine;
5-methy1-4-(4-(methylsulfonyl)pheny1)-N-(1H-pyrazol-4-y1)pyrimidin-2-amine;
2-(44(4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)-1-
morpholinoethanone;
2-(44(5-methy1-4-(4-(methylsulfonyl)phenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)ethanol;
2-(44(4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)ethanol;
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2-(44(5-methy1-4-(4-(methylsulfonyl)phenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)-1-
morpholinoethanone;
N-(3 -(5-methyl-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
yl)benzyl)methane
sulfonamide;
N-methy1-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzenesulfonamide;
N-methy1-3-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzenesulfonamide;
4-(2-fluoro-4-(methylsulfonyl)pheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-
y1)pyrimidin-2-
amine;
N-(4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
yl)phenyl)methanesulfonamide;
4-(3-fluoropheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-amine;
4-(4-fluoropheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-amine;
4-(2-methoxypheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-amine;
4-(4-methoxypheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-amine;
3 -(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-y1)benzamide;
5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-(4-(trifluoromethyl)phenyl)pyrimidin-2-
amine;
5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-(3-(methylthio)phenyl)pyrimidin-2-
amine;
5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-(4-(methylthio)phenyl)pyrimidin-2-
amine;
5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-phenylpyrimidin-2-amine;
4-(3,4-difluoropheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-amine;
4-(3,5-difluoropheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-amine;
4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-y1)benzonitrile;
4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-y1)benzamide;
4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
y1)benzenesulfonamide;
5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-(3-(methylsulfonyl)phenyl)pyrimidin-2-
amine;
4-(4-(ethylsulfonyl)pheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-
amine;
4-(4-(isopropylsulfonyl)pheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-
2-amine;
4-(3,4-dimethoxypheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-
amine;
4-(3-chloro-4-methoxypheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-
amine;
4-(4-chloro-3-fluoropheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-
amine;
4-(4-methoxy-3 -(trifluoromethyl)pheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-
y1)pyrimidin-
2-amine;
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4-(3-fluoro-4-methylpheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-
amine;
N-(2-fluoro-4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
y1)phenyl)acetamide;
5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-(pyridin-4-y1)pyrimidin-2-amine;
2'-methoxy-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)44,5'-bipyrimidin]-2-amine;
5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-(1H-pyrazol-4-y1)pyrimidin-2-amine;
5-methy1-4-(4-(5-methy1-1,3,4-oxadiazol-2-yl)pheny1)-N-(1-methyl-1H-pyrazol-4-
yl)pyrimidin-2-amine;
4-(4-ethoxy-3-fluoropheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-
amine;
4-(3-fluoro-4-propoxypheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-
amine;
4-(3-fluoro-4-isopropoxypheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-
2-amine;
4-(4-(cyclohexyloxy)-3 -fluoropheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-
y1)pyrimidin-2-
amine;
2-(2-fluoro-4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
yl)phenoxy)ethanol;
4-(3 -fluoro-4-(2-methoxyethoxy)pheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-
y1)pyrimidin-
2-amine;
2-(2-fluoro-4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
y1)phenoxy)-1-
(pyrrolidin-1-y1)ethanone;
N-methyl-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzamide;
N,N-dimethy1-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzamide;
N-ethyl-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzamide;
N-isopropyl-4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
yl)benzamide;
4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-y1)-N-
propylbenzamide;
N-(2-hydroxyethyl)-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzamide;
N-(2-amino-2-oxoethyl)-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-
4-
y1)benzamide;
(4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
y1)phenyl)(pyrrolidin-1-
yl)methanone;
(4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
y1)phenyl)(morpholino)methanone;
N-cyclopenty1-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzamide;
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4-(5-methy1-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-y1)-N-
(tetrahydrofuran-3-
y1)benzamide;
2-fluoro-4-(5-methyl-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
y1)benzamide;
5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-(thiazol-2-y1)pyrimidin-2-amine;
5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-(thiazol-5-y1)pyrimidin-2-amine;
5-(4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-y1)pheny1)-1,3,4-
thiadiazol-
2-amine;
N,N-dimethy1-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzenesulfonamide;
N-ethy1-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzenesulfonamide;
N-isopropy1-4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
yl)benzenesulfonamide;
4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-y1)-N-
propylbenzenesulfonamide;
N-(2-hydroxyethyl)-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzenesulfonamide;
N-(2-methoxyethyl)-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimi din-4-
yl)benzenesulfonamide;
2-(4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
y1)phenylsulfonamido)acetamide;
5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-(4-(pyrroli din-l-yl
sulfonyl)phenyl)pyrimidin-2-
amine;
5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-(4-(morpholinosulfonyl)phenyl)pyrimi
din-2-
amine;
5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-(4-((4-methylpiperazin-1-
y1)sulfonyl)phenyl)pyrimidin-2-amine;
1-(44(4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
yl)phenyl)sulfonyl)piperazin-1-yl)ethanone;
N-cyclopenty1-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzenesulfonamide;
4-(5-methy1-2-((l-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-y1)-N-
(tetrahydrofuran-3-
y1)benzenesulfonamide;
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N-(2-methoxyethyl)-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
yl)benzamide;
N-(2-aminoethyl)-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzamide;
(4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-y1)phenyl)(4-
methylpiperazin-1-y1)methanone;
1-(4-(4-(5-methyl-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzoyl)piperazin-1-
yl)ethanone;
N-(4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-y1)-3-methylisothiazol-5-
amine;
2-(44(4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)-N-
isopropylacetamide;
N-cyclopropy1-2-(44(4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-yl)amino)-
1H-
pyrazol-1-yl)acetamide;
N-(2-aminoethyl)-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
yl)benzenesulfonamide;
2-(44(4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)acetamide;
2-(44(4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)-N-
methylacetamide;
N-ethy1-2-(44(4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-y1)amino)-1H-
pyrazol-1-
y1)acetamide;
2-(44(4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)-N,N-
dimethylacetamide;
2-(44(4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)-1-
(piperazin-l-yl)ethanone;
2-(44(4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)-1-
(piperidin-1-y1)ethanone;
2-(44(4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)-1-
(pyrrolidin-1-y1)ethanone;
1-ethy1-3-(4-(5-methy1-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
y1)phenyl)urea;
1-isopropy1-3-(4-(5-methy1-2-((l-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
y1)phenyl)urea;
1-(4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-y1)pheny1)-3-
propylurea;
1-(2-hydroxyethyl)-3 -(4-(5-methy1-2-((l-methyl-1H-pyrazol-4-yl)amino)pyrimi
din-4-
yl)phenyOurea;
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N-(4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
yl)phenyl)pyrrolidine-1-
carboxamide;
4-(3-fluoro-4-methoxypheny1)-5-methyl-N-(thiophen-3-yl)pyrimidin-2-amine;
N-(2-(2-fluoro-4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
yl)phenoxy)ethyl)acetamide;
4-(4-(2-aminoethoxy)-3 -fluoropheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-
y1)pyrimidin-2-
amine;
1-methy1-3-(4-(5-methy1-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
y1)phenyl)urea;
1,1-dimethy1-3 -(4-(5-methy1-2-((l-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
yl)phenyl)urea;
2-(3-(4-(5-methyl-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)phenyl)ureido)acetamide;
N-(4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
yl)phenyl)morpholine-4-
carboxamide;
5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-(p-toly1)pyrimidin-2-amine;
5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-(m-toly1)pyrimidin-2-amine;
4-([1,1'-bipheny1]-4-y1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-
amine;
4-(3 -fluoro-4-(methylsulfonyl)pheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-
y1)pyrimidin-2-
amine;
4-(4-ethoxypheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-amine;
2-(4-(5-methyl-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
y1)phenoxy)ethanol;
4-(3 -fluoro-4-(methylthio)pheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-
y1)pyrimidin-2-
amine;
2-(2-fluoro-4-(5-methy1-24(3-methylisothiazol-5-yl)amino)pyrimidin-4-
y1)phenoxy)ethanol;
N-cyclopenty1-4-(5-methy1-24(3-methylisothiazol-5-yl)amino)pyrimidin-4-
y1)benzenesulfonamide;
N-ethyl-4-(5-methy1-24(3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)benzamide;
3 -methyl-N-(5-methy1-4-(4-(methylsulfonyl)phenyl)pyrimidin-2-yl)i sothiazol-5-
amine;
4-(4-ethylpheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-amine;
4-(4-isopropylpheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-amine;
2-(44(4-(3-fluoro-4-(2-hydroxyethoxy)pheny1)-5-methylpyrimidin-2-yl)amino)-1H-
pyrazol-
1-y1)-1-morpholinoethanone;
N-cyclopenty1-4-(5-methy1-2-((1-(2-morpholino-2-oxoethyl)-1H-pyrazol-4-
y1)amino)pyrimidin-4-y1)benzenesulfonamide;
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N-ethy1-4-(5-methy1-24(1-(2-morpholino-2-oxoethyl)-1H-pyrazol-4-
yl)amino)pyrimidin-4-
y1)benzamide;
2-methoxy-5-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
y1)benzonitrile;
2-methoxy-5-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
y1)benzamide;
4-(3-fluoro-4-methoxypheny1)-5-methyl-N-(1-((methylsulfonyl)methyl)-1H-pyrazol-
4-
y1)pyrimidin-2-amine;
N-ethy1-2-fluoro-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzamide;
4-(4-(1H-pyrazol-3 -yl)pheny1)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-
2-amine;
2-(44(4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)-1-(4-
methylpiperazin-1-y1)ethanone;
1-(3,5-dimethylpiperazin-1-y1)-2-(44(4-(3-fluoro-4-methoxypheny1)-5-
methylpyrimidin-2-
yl)amino)-1H-pyrazol-1-y1)ethanone;
1-(1,4-diazepan-1-y1)-2-(44(4-(3 -fluoro-4-methoxypheny1)-5-methylpyrimidin-2-
yl)amino)-
1H-pyrazol-1-yl)ethanone;
2-(44(4-(4-ethylpheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-y1)-1-
morpholinoethanone;
2-(4-((4-(4-isopropylpheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-y1)-1-
morpholinoethanone;
N-isopropy1-4-(5-methy1-24(1-(2-morpholino-2-oxoethyl)-1H-pyrazol-4-
yl)amino)pyrimidin-
4-y1)benzamide;
N-isopropy1-4-(5-methy1-2-((1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-
y1)amino)pyrimidin-4-y1)benzamide;
4-(4-(sec-butoxy)-3 -fluoropheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-
y1)pyrimidin-2-
amine;
4-(3-fluoro-4-isobutoxypheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-
2-amine;
4-(4-cyclobutoxy-3 -fluoropheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-
y1)pyrimidin-2-
amine;
4-(4-(cyclop entyloxy)-3 -fluoropheny1)-5-methyl-N-(1-methyl-1H-pyrazol-4-
yl)pyrimidin-2-
amine;
N-(tert-butyl)-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzamide;
N-(sec-butyl)-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzamide;
N-isobuty1-4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
yl)benzamide;
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N-(2-hydroxypropy1)-4-(5-methy1-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimi din-
4-
yl)benzamide;
2-(44(4-(4-ethylpheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-y1)-1-
(piperidin-1-
y1)ethanone;
2-(44(4-(4-isopropylpheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-y1)-1-
(piperidin-
1-y1)ethanone;
N-ethy1-4-(5-methy1-24(1-(2-oxo-2-(piperidin-1-yl)ethyl)-1H-pyrazol-4-
y1)amino)pyrimidin-
4-y1)benzamide;
N-isopropy1-4-(5-methy1-24(1-(2-oxo-2-(piperidin-1-yl)ethyl)-1H-pyrazol-4-
yl)amino)pyrimidin-4-yl)benzamide;
2-(4-((4-(4-ethoxy-3-fluoropheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)-1-
morpholinoethanone;
2-(44(4-(3-fluoro-4-isopropoxypheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-
1-y1)-1-
morpholinoethanone;
N-ethy1-4-(5-methy1-2-((1-(2-oxo-2-(pyrrolidin-1-y1)ethyl)-1H-pyrazol-4-
y1)amino)pyrimidin-4-y1)benzamide;
1-(2-fluoro-4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
y1)phenoxy)propan-2-ol;
4-(4-cycl opropoxy-3 -fluoropheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-
y1)pyrimidin-2-
amine;
N-cyclopropy1-4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
yl)benzamide;
N-cyclobuty1-4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
yl)benzamide;
2-(44(4-(3-fluoro-4-propoxypheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)-1-
morpholinoethanone;
4-(3-fluoro-4-(3,3,3-trifluoropropoxy)pheny1)-5-methyl-N-(1-methy1-1H-pyrazol-
4-
y1)pyrimidin-2-amine;
N-ethyl-2-(44(4-(4-ethylpheny1)-5-methylpyrimidin-2-y1)amino)-1H-pyrazol-1-
y1)acetami de;
4-(5-methyl-2-((1-(2-oxo-2-(piperi din-1-yl)ethyl)-1H-pyrazol-4-
y1)amino)pyrimi din-4-
yl)benzenesulfonamide;
4-(5-methy1-24(1-(2-morpholino-2-oxoethyl)-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzenesulfonamide;
N-ethy1-4-(24(1-(2-(ethylamino)-2-oxoethyl)-1H-pyrazol-4-y1)amino)-5-
methylpyrimidin-4-
y1)benzamide;
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4-(2-((1-(2-(ethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-
4-y1)-N-
isopropylbenzamide;
N-ethy1-2-(44(5-methyl-4-(4-sulfamoylphenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)acetamide;
N-ethy1-2-(44(5-methyl-4-(4-(morpholinosulfonyl)phenyl)pyrimidin-2-yl)amino)-
1H-
pyrazol-1-y1)acetamide;
N-ethyl-2-(4-((5-methy1-4-(4-(N-(tetrahydrofuran-3 -yl)sulfamoyl)phenyl)pyrimi
din-2-
yl)amino)-1H-pyrazol-1-yl)acetamide;
N-ethy1-2-(44(4-(4-isopropylpheny1)-5-methylpyrimidin-2-y1)amino)-1H-pyrazol-1-
yl)acetamide;
N-ethy1-2-(44(5-methyl-4-(3-(methylsulfonyl)phenyl)pyrimidin-2-yl)amino)-1H-
pyrazol-1-
y1)acetamide;
2-(4-((5 -methyl-4-(3 -(methylsulfonyl)phenyl)pyrimidin-2-yl)amino)-1H-pyrazol-
1 -y1)-1 -
(piperidin-1 -yl)ethanone;
2-(44(5-methy1-4-(4-(morpholino sulfonyl)phenyl)pyrimidin-2-yl)amino)-1H-
pyrazol-1 -y1)-1 -
morpholinoethanone;
4-(5-methy1-24(1-(2-morpholino-2-oxoethyl)-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)-N-
(tetrahydrofuran-3 -yl)b enzenesulfonami de;
2-(4-((5 -methyl-4-(3 -(methylsulfonyl)phenyl)pyrimidin-2-yl)amino)-1H-pyrazol-
1 -y1)-1 -
morpholinoethanone;
2-(4-((4-(4-ethoxy-3 -fluoropheny1)-5-methylpyrimi din-2-yl)amino)-1H-pyrazol-
1-y1)-N-
ethyl acetami de;
N-ethy1-2-(44(4-(3-fluoro-4-isopropoxypheny1)-5-methylpyrimidin-2-y1)amino)-1H-
pyrazol-
1-y1)acetamide;
N-ethy1-2-(44(4-(3-fluoro-4-propoxypheny1)-5-methylpyrimidin-2-y1)amino)-1H-
pyrazol-1-
y1)acetamide;
N-ethy1-2-(44(4-(3-fluoro-4-hydroxypheny1)-5-methylpyrimidin-2-y1)amino)-1H-
pyrazol-1-
y1)acetamide;
2-(44(5-methy1-4-(4-(morpholino sulfonyl)phenyl)pyrimidin-2-yl)amino)-1H-
pyrazol-1 -y1)-1 -
(piperidin-l-yl)ethanone;
4-(5-methyl-2-((1-(2-oxo-2-(piperi din-1-yl)ethyl)-1H-pyrazol-4-
y1)amino)pyrimi din-4-y1)-N-
(tetrahydrofuran-3 -yl)b enzenesulfonami de;
2-(4-((4-(4-ethoxy-3-fluoropheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)-1-
(piperidin-1-y1)ethanone;
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2-(44(4-(3-fluoro-4-isopropoxypheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-
1-y1)-1-
(piperidin-1-y1)ethanone;
2-(4-((4-(4-ethoxy-3-fluoropheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)-1-
(pyrrolidin-1-y1)ethanone;
2-(44(4-(3-fluoro-4-isopropoxypheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-
1-y1)-1-
(pyrrolidin-1-y1)ethanone;
4-(3 -fluoro-4-(2-methoxypropoxy)pheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-
y1)pyrimidin-
2-amine;
4-(4-ethoxy-3-fluoropheny1)-N-(1-isopropy1-1H-pyrazol-4-y1)-5-methylpyrimidin-
2-amine;
5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-(4-methyl-3 -(methyl
sulfonyl)phenyl)pyrimi din-2-
amine;
N-(4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
yl)phenyl)ethanesulfonamide;
N-(4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propane-
1-
sulfonamide;
N-(4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propane-
2-
sulfonamide;
(R)-N-(sec-buty1)-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzamide;
(S)-N-(sec-buty1)-4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)benzamide;
(R)-1-(2-fluoro-4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
y1)phenoxy)propan-2-ol;
(S)-1-(2-fluoro-4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
yl)phenoxy)propan-2-ol;
(S)-4-(4-(sec-butoxy)-3 -fluoropheny1)-5-methyl-N-(1-methyl-1H-pyrazol-4-
yl)pyrimidin-2-
amine;
(R)-4-(4-(sec-butoxy)-3 -fluoropheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-
y1)pyrimidin-2-
amine;
2-(44(4-(3-fluoro-4-hydroxypheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)-1-
(pyrrolidin-1-y1)ethanone;
2-(44(4-(3-fluoro-4-hydroxypheny1)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-
y1)-1-
(piperidin-1-y1)ethanone;
4-(4-ethoxy-3-fluoropheny1)-5-methyl-N-(1H-pyrazol-4-yl)pyrimidin-2-amine;
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N-(4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-y1)-2-methylthiazol-5-
amine;
4-(4-(tert-butoxy)-3 -fluoropheny1)-5-methyl-N-(1-methyl-1H-pyrazol-4-
yl)pyrimidin-2-
amine;
N-(2-methoxypropy1)-4-(5-methy1-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimi din-
4-
yl)benzamide;
4-(4-ethoxy-3 -fluoropheny1)-5-methyl-N-(1-(2-morpholinoethyl)-1H-pyrazol-4-
y1)pyrimidin-
2-amine;
3 -(4-((4-(4-ethoxy-3 -fluoropheny1)-5-methylpyrimi din-2-yl)amino)-1H-pyrazol-
1-y1)propan-
1-ol;
4-(4-ethoxy-3-fluoropheny1)-N-(1-ethy1-1H-pyrazol-4-y1)-5-methylpyrimidin-2-
amine;
4-(4-ethoxy-3-fluoropheny1)-5-methyl-N-(1-propy1-1H-pyrazol-4-y1)pyrimidin-2-
amine;
2-(4-((4-(4-ethoxy-3 -fluoropheny1)-5-methylpyrimi din-2-yl)amino)-1H-pyrazol-
1-
yl)acetonitrile;
4-(4-ethoxy-3 -fluoropheny1)-N-(1-(2-methoxyethyl)-1H-pyrazol-4-y1)-5-
methylpyrimi din-2-
amine;
(S)-3-(4-((4-(4-ethoxy-3-fluoropheny1)-5-methylpyrimidin-2-yl)amino)-1H-
pyrazol-1-
yl)propane-1,2-diol;
(R)-3 -(4-((4-(4-ethoxy-3 -fluoropheny1)-5-methylpyrimidin-2-yl)amino)-1H-
pyrazol-1-
yl)propane-1,2-diol;
4-(3,5-difluoro-4-methoxypheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-
y1)pyrimidin-2-
amine;
4-(4-methoxy-3-(methyl sulfonyl)pheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-
y1)pyrimidin-
2-amine;
4-(4-ethoxy-3 -fluoropheny1)-N-(1-(4-methoxybenzy1)-1H-pyrazol-4-y1)-5-
methylpyrimidin-
2-amine;
N-(4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
yl)phenyl)benzenesulfonamide;
N-(1-(2-aminoethyl)-1H-pyrazol-4-y1)-4-(4-ethoxy-3 -fluoropheny1)-5-
methylpyrimidin-2-
amine;
3 -(4-((4-(4-ethoxy-3 -fluoropheny1)-5-methylpyrimi din-2-yl)amino)-1H-pyrazol-
1-y1)-N-
ethylpropanamide;
3 -(4-((4-(4-ethoxy-3 -fluoropheny1)-5-methylpyrimi din-2-yl)amino)-1H-pyrazol-
1-y1)-1-
morpholinopropan-l-one;
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1-(4-((4-(4-ethoxy-3 -fluoropheny1)-5-m ethyl pyrimi din-2-yl)amino)-1H-pyraz
ol-1-y1)-2-
methylpropan-2-ol;
1-cyano-N-(4-(5-methy1-24(1-methy1-1H-pyrazol-4-y1)amino)pyrimidin-4-
y1)phenyl)methanesulfonamide; and
2-hydroxy-N-(4-(5-methy1-24(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-
y1)phenyl)ethanesulfonamide.
Prodrugs of the compounds of the present invention are also within the scope
of the present
invention.
"Prodrug" means a derivative that is converted into a compound according to
the present
invention by a reaction with an enzyme, gastric acid or the like under a
physiological
condition in the living body, e.g. by oxidation, reduction, hydrolysis or the
like, each of which
is carried out enzymatically. Examples of a prodrug are compounds, wherein the
amino group
in a compound of the present invention is acylated, alkylated or
phosphorylated to form, e.g.,
eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl
group is
acylated, alkylated, phosphorylated or converted into the borate, e.g.
acetyloxy, palmitoyloxy,
pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carboxyl group
is esterified
or amidated. These compounds can be produced from compounds of the present
invention
according to well-known methods.
Metabolites of compounds of formula (I) are also within the scope of the
present invention.
The term "metabolites" refers to all molecules derived from any of the
compounds according
to the present invention in a cell or organism, preferably mammal.
Preferably the term relates to molecules which differ from any molecule which
is present in
any such cell or organism under physiological conditions.
The structure of the metabolites of the compounds according to the present
invention will be
obvious to any person skilled in the art, using the various appropriate
methods.
Where tautomerism, e.g. keto-enol tautomerism, of compounds of general formula
(I) may
occur, the individual forms, e.g. the keto and enol form, are comprised
separately and together
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as mixtures in any ratio. The same applies for stereoisomers, e.g.
enantiomers, cis/trans
isomers, conformers and the like.
If desired, isomers can be separated by methods well known in the art, e.g. by
liquid
chromatography. The same applies for enantiomers by using e.g. chiral
stationary phases.
Additionally, enantiomers may be isolated by converting them into
diastereomers, i.e.
coupling with an enantiomerically pure auxiliary compound, subsequent
separation of the
resulting diastereomers and cleavage of the auxiliary residue. Alternatively,
any enantiomer of
a compound of formula (I) may be obtained from stereoselective synthesis using
optically
pure starting materials.
The compounds of formula (I) may exist in crystalline or amorphous form.
Furthermore,
some of the crystalline forms of the compounds of formula (I) may exist as
polymorphs,
which are included within the scope of the present invention. Polymorphic
forms of
compounds of formula (I) may be characterized and differentiated using a
number of
conventional analytical techniques, including, but not limited to, X-ray
powder diffraction
(XPD) patterns, infrared (IR) spectra, Raman spectra, differential scanning
calorimetry
(DSC), thermogravimetric analysis (TGA) and solid state nuclear magnetic
resonance
(s sNMR).
In case the compounds according to formula (I) contain one or more acidic or
basic groups,
the invention also comprises their corresponding pharmaceutically or
toxicologically
acceptable salts, in particular their pharmaceutically utilizable salts. Thus,
the compounds of
the formula (I) which contain acidic groups can be used according to the
invention, for
example, as alkali metal salts, alkaline earth metal salts or as ammonium
salts. More precise
examples of such salts include sodium salts, potassium salts, calcium salts,
magnesium salts
or salts with ammonia or organic amines such as, for example, ethylamine,
ethanolamine,
triethanolamine or amino acids. Compounds of the formula (I) which contain one
or more
basic groups, i.e. groups which can be protonated, can be present and can be
used according
to the invention in the form of their addition salts with inorganic or organic
acids. Examples
for suitable acids include hydrogen chloride, hydrogen bromide, phosphoric
acid, sulfuric
acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid,
naphthalenedisulfonic acids,
oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic
acid, formic acid,
propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid,
pimelic acid,
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fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid,
gluconic acid,
ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids
known to the person
skilled in the art. If the compounds of the formula (I) simultaneously contain
acidic and basic
groups in the molecule, the invention also includes, in addition to the salt
forms mentioned,
inner salts or betaines (zwitterions). The respective salts according to the
formula (I) can be
obtained by customary methods which are known to the person skilled in the art
like, for
example by contacting these with an organic or inorganic acid or base in a
solvent or
dispersant, or by anion exchange or cation exchange with other salts. The
present invention
also includes all salts of the compounds of the formula (I) which, owing to
low physiological
compatibility, are not directly suitable for use in pharmaceuticals but which
can be used, for
example, as intermediates for chemical reactions or for the preparation of
pharmaceutically
acceptable salts.
Throughout the invention, the term "pharmaceutically acceptable" means that
the
corresponding compound, carrier or molecule is suitable for administration to
humans.
Preferably, this term means approved by a regulatory agency such as the EMEA
(Europe)
and/or the FDA (US) and/or any other national regulatory agency for use in
animals,
preferably in humans.
The present invention furthermore includes all solvates of the compounds
according to the
invention.
According to the present invention "JAK" comprises all members of the JAK
family (e.g.
JAK1, JAK2, JAK3, and TYK2).
According to the present invention, the expression "JAK1" or "JAK1 kinase"
means "Janus
kinase 1". The human gene encoding JAK1 is located on chromosome 1p31.3.
According to the present invention, the expression "JAK2" or "JAK2 kinase"
means "Janus
kinase 2".The human gene encoding JAK2 is located on chromosome 9p24.
According to the present invention, the expression "JAK3" or "JAK3 kinase"
means "Janus
kinase 3". The gene encoding JAK3 is located on human chromosome 19p13.1 and
it is
predominantly in hematopoietic cells.
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According to the present invention, the expression "TYK2" or "TYK2 kinase"
means
"Protein-Tyrosine kinase 2".The JAK3 and TYK2 genes are clustered on
chromosome
19p13.1 and 19p13.2, respectively.
As shown in the examples, compounds of the invention were tested for their
selectivity for
TYK2 over JAK2 kinase. As shown, all tested compounds bind TYK2 more
selectively than,
JAK2 (see table 9 below).
Consequently, the compounds of the present invention as mentioned above are
considered to
be useful for the prevention or treatment of diseases and disorders associated
with TYK2, for
example immunological, inflammatory, autoimmune, or allergic disorders,
transplant
rejection, Graft-versus-Host-Disease or proliferative diseases such as cancer.
In a preferred embodiment, the compounds of the present invention are
selective TYK2
inhibitors.
The compounds of the present invention may be further characterized by
determining whether
they have an effect on TYK2, for example on its kinase activity (Fridman et al
2010. J.
Immunology 2010 184(9):5298-307).
A cell-based assay was described to assess the inhibitory activity of small
molecule drugs
toward TYK2-dependent signal transduction (Bacon et al 1995. PNAS 92, 7307-
7311;
W02009155551).
The present invention provides pharmaceutical compositions comprising a
compound of
formula (I) or a pharmaceutically acceptable salt thereof as active ingredient
together with a
pharmaceutically acceptable carrier, optionally in combination with one or
more other
pharmaceutical compositions.
"Pharmaceutical composition" means one or more active ingredients, and one or
more inert
ingredients that make up the carrier, as well as any product which results,
directly or
indirectly, from combination, complexation or aggregation of any two or more
of the
ingredients, or from dissociation of one or more of the ingredients, or from
other types of
reactions or interactions of one or more of the ingredients. Accordingly, the
pharmaceutical
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compositions of the present invention encompass any composition made by
admixing a
compound of the present invention and a pharmaceutically acceptable carrier.
The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with
which the
therapeutic is administered. Such pharmaceutical carriers can be sterile
liquids, such as water
and oils, including those of petroleum, animal, vegetable or synthetic origin,
including but not
limited to peanut oil, soybean oil, mineral oil, sesame oil and the like.
Water is a preferred
carrier when the pharmaceutical composition is administered orally. Saline and
aqueous
dextrose are preferred carriers when the pharmaceutical composition is
administered
intravenously. Saline solutions and aqueous dextrose and glycerol solutions
are preferably
employed as liquid carriers for injectable solutions. Suitable pharmaceutical
excipients
include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,
silica gel, sodium
stearate, glycerol monostearate, talc, sodium chloride, dried skim milk,
glycerol, propylene,
glycol, water, ethanol and the like. The composition, if desired, can also
contain minor
amounts of wetting or emulsifying agents, or pH buffering agents. These
compositions can
take the form of solutions, suspensions, emulsions, tablets, pills, capsules,
powders, sustained-
release formulations and the like. The composition can be formulated as a
suppository, with
traditional binders and carriers such as triglycerides. Oral formulation can
include standard
carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium
stearate,
sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable
pharmaceutical
carriers are described in "Remington's Pharmaceutical Sciences" by E.W.
Martin. Such
compositions will contain a therapeutically effective amount of the
therapeutic, preferably in
purified form, together with a suitable amount of carrier so as to provide the
form for proper
administration to the patient. The formulation should suit the mode of
administration.
A pharmaceutical composition of the present invention may comprise one or more
additional
compounds as active ingredients like one or more compounds of formula (I) not
being the
first compound in the composition or other JAK inhibitors. Further bioactive
compounds may
be steroids, leukotriene antagonists, cyclosporine or rapamycin.
The compounds of the present invention or pharmaceutically acceptable salt(s)
thereof and the
other pharmaceutically active agent(s) may be administered together or
separately and, when
administered separately, this may occur separately or sequentially in any
order. When
combined in the same formulation it will be appreciated that the two compounds
must be
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stable and compatible with each other and the other components of the
formulation. When
formulated separately they may be provided in any convenient formulation,
conveniently in
such manner as are known for such compounds in the art.
It is further included within the present invention that the compound of
formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutical composition
comprising a
compound of formula (I) is administered in combination with another drug or
pharmaceutically active agent and/or that the pharmaceutical composition of
the invention
further comprises such a drug or pharmaceutically active agent.
In this context, the term "drug or pharmaceutically active agent" includes a
drug or
pharmaceutical agent that will elicit the biological or medical response of a
tissue, system,
animal or human that is being sought, for instance, by a researcher or
clinician.
"Combined" or "in combination" or "combination" should be understood as a
functional
coadministration, wherein some or all compounds may be administered
separately, in
different formulations, different modes of administration (for example
subcutaneous,
intravenous or oral) and different times of administration. The individual
compounds of such
combinations may be administered either sequentially in separate
pharmaceutical
compositions as well as simultaneously in combined pharmaceutical
compositions.
For example, in rheumatoid arthritis therapy, combination with other
chemotherapeutic or
antibody agents is envisaged. Suitable examples of pharmaceutically active
agents which may
be employed in combination with the compounds of the present invention and
their salts for
rheumatoid arthritis therapy include: immunosuppresants such as amtolmetin
guacil,
mizoribine and rimexolone; anti-TNFa agents such as etanercept, infliximab,
Adalimumab,
Anakinra, Abatacept, Rituximab; tyrosine kinase inhibitors such as
leflunomide; kallikrein
antagonists such as subreum; interleukin 11 agonists such as oprelvekin;
interferon beta 1
agonists; hyaluronic acid agonists such as NRD-101 (Aventis); interleukin 1
receptor
antagonists such as anakinra; CD8 antagonists such as amiprilose
hydrochloride; beta amyloid
precursor protein antagonists such as reumacon; matrix metalloprotease
inhibitors such as
cipemastat and other disease modifying anti-rheumatic drugs (DMARDs) such as
methotrexate, sulphasalazine, cyclosporin A, hydroxychoroquine, auranofin,
aurothioglucose,
gold sodium thiomalate and penicillamine.
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In particular, the treatment defined herein may be applied as a sole therapy
or may involve, in
addition to the compounds of the invention, conventional surgery or
radiotherapy or
chemotherapy. Accordingly, the compounds of the invention can also be used in
combination
with existing therapeutic agents for the treatment proliferative diseases such
as cancer.
Suitable agents to be used in combination include:
(i) antiproliferative/antineoplastic drugs and combinations thereof, as used
in medical
oncology such as alkylating agents (for example cis-platin, carboplatin,
cyclophosphamide,
nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas);
antimetabolites (for
example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur,
raltitrexed,
methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumour
antibiotics (for
example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,
epirubicin,
idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents
(for example
vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and
taxoids like
paclitaxel and taxotere); and topoisomerase inhibitors (for example
epipodophyllotoxins like
etoposide and teniposide, amsacrine, topotecan and camptothecins);
(ii) cytostatic agents such as antioestrogens (for example tamoxifen,
toremifene, raloxifene,
droloxifene and iodoxyfene), oestrogen receptor down regulators (for example
fulvestrant),
antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone
acetate),
LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and
buserelin),
progestogens (for example megestrol acetate), aromatase inhibitors (for
example as
anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-
reductase such as
finasteride;
(iii) anti-invasion agents (for example c-Src kinase family inhibitors like 4-
(6-chloro- 2,3 -
methylenedioxyanilino)-7- [2-(4-methylpiperazin- 1 -ypethoxy] -5 -
tetrahydropyran- 4-yloxy-
quinazoline (AZD0530) and
N-(2-chloro-6-methylpheny1)-2- { 6- [4-(2-
hydroxyethyl)piperazin-l-y1]-2-methylpyrimidin- 4-
ylamino}thiazole-5-carboxamide
(dasatinib, BMS-354825), and metalloproteinase inhibitors like marimastat and
inhibitors of
urokinase plasminogen activator receptor function);
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(iv) inhibitors of growth factor function: for example such inhibitors include
growth factor
antibodies and growth factor receptor antibodies (for example the anti-erbB2
antibody
trastuzumab [HerceptinTM] and the anti-erbB1 antibody cetuximab [C225]); such
inhibitors
also include, for example, tyrosine kinase inhibitors, for example inhibitors
of the epidermal
growth factor family (for example EGFR family tyrosine kinase inhibitors such
as N-(3-
chl oro-4-fluoropheny1)-7-methoxy-6-(3 -morphol inoprop oxy)quinazol in-4-
amine (gefitinib,
ZD 1839), A/-(3-ethynylpheny1)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
(erlotinib,
OSI-774) and 6-acrylamido-A/-(3-chloro-4-fluoropheny1)-7-(3-
morpholinopropoxy)-
quinazolin-4-amine (CI 1033) and erbB2 tyrosine kinase inhibitors such as
lapatinib),
inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-
derived growth
factor family such as imatinib, inhibitors of serine/threonine kinases (for
example Ras/Raf
signalling inhibitors such as farnesyl transferase inhibitors, for example
sorafenib (BAY 43-
9006)) and inhibitors of cell signalling through MEK and/or Akt kinases;
(v) antiangiogenic agents such as those which inhibit the effects of vascular
endothelial
growth factor, for example the anti-vascular endothelial cell growth factor
antibody
bevacizumab (AvastinTM) and VEGF receptor tyrosine kinase inhibitors such as 4-
(4-bromo-
2-fiuoroanilino)-6-methoxy-7-( 1 -methylpiperidin-4-ylmethoxy)quinazoline
(ZD6474;
Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindo1-5-yloxy)-6-methoxy-7-
(3-
pyrrolidin-l-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212),
vatalanib
(PTK787; WO 98/35985) and SU1 1248 (sunitinib; WO 01/60814), and compounds
that work
by other mechanisms (for example linomide, inhibitors of integrin avf33
function and
angio statin);
(vi) vascular damaging agents such as combretastatin A4 and compounds
disclosed in
International Patent Application WO 99/02166;
(vii) antisense therapies, for example those which are directed to the targets
listed above, such
as ISIS 2503, an anti-ras antisense agent;
(viii) gene therapy approaches, including approaches to replace aberrant genes
such as
aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug
therapy) approaches such as those using cytosine deaminase, thymidine kinase
or a bacterial
nitroreductase enzyme and approaches to increase patient tolerance to
chemotherapy or
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radiotherapy such as multi-drug resistance gene therapy; and (ix)
immunotherapeutic
approaches, including ex-vivo and in-vivo approaches to increase the
immunogenicity of
patient tumour cells, such as transfection with cytokines such as interleukin
2, interleukin 4 or
granulocyte-macrophage colony stimulating factor, approaches to decrease T-
cell anergy,
approaches using transfected immune cells such as cytokine-transfected
dendritic cells,
approaches using cytokine-transfected tumour cell lines and approaches using
anti-idiotypic
antibodies.
Further combination treatments are described in WO-A 2009/008992 and WO-A
2007/107318, incorporated herein by reference.
Accordingly, the individual compounds of such combinations may be administered
either
sequentially in separate pharmaceutical compositions as well as simultaneously
in combined
pharmaceutical compositions.
The pharmaceutical compositions of the present invention include compositions
suitable for
oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and
intravenous),
ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal
administration, although
the most suitable route in any given case will depend on the nature and
severity of the
conditions being treated and on the nature of the active ingredient. They may
be conveniently
presented in unit dosage form and prepared by any of the methods well-known in
the art of
pharmacy.
In practical use, the compounds of formula (I) can be combined as the active
ingredient in
intimate admixture with a pharmaceutical carrier according to conventional
pharmaceutical
compounding techniques. The carrier may take a wide variety of forms depending
on the form
of preparation desired for administration, e.g., oral or parenteral (including
intravenous). In
preparing the compositions for oral dosage form, any of the usual
pharmaceutical media may
be employed, such as water, glycols, oils, alcohols, flavoring agents,
preservatives, coloring
agents and the like in the case of oral liquid preparations, such as, for
example, suspensions,
elixirs and solutions; or carriers such as starches, sugars, microcrystalline
cellulose, diluents,
granulating agents, lubricants, binders, disintegrating agents and the like in
the case of oral
solid preparations such as powders, hard and soft capsules and tablets, with
the solid oral
preparations being preferred over the liquid preparations.
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Because of their ease of administration, tablets and capsules represent the
most advantageous
oral dosage unit form in which case solid pharmaceutical carriers are
obviously employed. If
desired, tablets may be coated by standard aqueous or non-aqueous techniques.
Such
compositions and preparations should contain at least 0.1 percent of active
compound. The
percentage of active compound in these compositions may, of course, be varied
and may
conveniently be between about 2 percent to about 60 percent of the weight of
the unit. The
amount of active compound in such therapeutically useful compositions is such
that an
effective dosage will be obtained. The active compounds can also be
administered
intranasally, for example, as liquid drops or spray.
The tablets, pills, capsules, and the like may also contain a binder such as
gum tragacanth,
acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a
disintegrating agent
such as corn starch, potato starch, alginic acid; a lubricant such as
magnesium stearate; and a
sweetening agent such as sucrose, lactose or saccharin. When a dosage unit
form is a capsule,
it may contain, in addition to materials of the above type, a liquid carrier
such as fatty oil.
Various other materials may be present as coatings or to modify the physical
form of the
dosage unit. For instance, tablets may be coated with shellac, sugar or both.
A syrup or elixir
may contain, in addition to the active ingredient, sucrose as a sweetening
agent, methyl and
propylparabens as preservatives, a dye and a flavoring such as cherry or
orange flavor.
Compounds of formula (I) may also be administered parenterally. Solutions or
suspensions of
these active compounds can be prepared in water suitably mixed with a
surfactant such as
hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid
polyethylene
glycols and mixtures thereof in oils. Under ordinary conditions of storage and
use, these
preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous
solutions or
dispersions and sterile powders for the extemporaneous preparation of sterile
injectable
solutions or dispersions. In all cases, the form must be sterile and must be
fluid to the extent
that easy syringability exists. It must be stable under the conditions of
manufacture and
storage and must be preserved against the contaminating action of
microorganisms such as
bacteria and fungi. The carrier can be a solvent or dispersion medium
containing, for example,
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water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid
polyethylene glycol),
suitable mixtures thereof, and vegetable oils.
Any suitable route of administration may be employed for providing a mammal,
especially a
human, with an effective dose of a compound of the present invention. For
example, oral,
rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be
employed. Dosage
forms include tablets, troches, dispersions, suspensions, solutions, capsules,
creams,
ointments, aerosols, and the like. Preferably compounds of formula (I) are
administered
orally.
The effective dosage of active ingredient employed may vary depending on the
particular
compound employed, the mode of administration, the condition being treated and
the severity
of the condition being treated. Such dosage may be ascertained readily by a
person skilled in
the art.
A therapeutically effective amount of a compound of the present invention will
normally
depend upon a number of factors including, for example, the age and weight of
the animal,
the precise condition requiring treatment and its severity, the nature of the
formulation, and
the route of administration. However, an effective amount of a compound of
formula (I) for
the treatment of an inflammatory disease, for example rheumatoid arthritis
(RA), will
generally be in the range of 0.1 to 100 mg/kg body weight of recipient
(mammal) per day and
more usually in the range of 1 to 10 mg/kg body weight per day. Thus, for a 70
kg adult
mammal, the actual amount per day would usually be from 70 to 700 mg and this
amount may
be given in a single dose per day or more usually in a number (such as two,
three, four, five or
six) of sub-doses per day such that the total daily dose is the same. An
effective amount of a
pharmaceutically acceptable salt, prodrug or metabolite thereof, may be
determined as a
proportion of the effective amount of the compound of formula (I) per se. It
is envisaged that
similar dosages would be appropriate for treatment of the other conditions
referred to above.
As used herein, the term "effective amount" means that amount of a drug or
pharmaceutical
agent that will elicit the biological or medical response of a tissue, system,
animal or human
that is being sought, for instance, by a researcher or clinician.
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Furthermore, the term "therapeutically effective amount" means any amount
which, as
compared to a corresponding subject who has not received such amount, results
in improved
treatment, healing, prevention, or amelioration of a disease, disorder, or
side effect, or a
decrease in the rate of advancement of a disease or disorder. The term also
includes within its
scope amounts effective to enhance normal physiological function.
Another aspect of the present invention is a compound of the present invention
or a
pharmaceutically acceptable salt thereof for use as a medicament as mentioned
above.
Another aspect of the present invention is a compound of the present invention
or a
pharmaceutically acceptable salt thereof for use in a method of treating or
preventing a
disease or disorder associated with TYK2 as mentioned above.
In the context of the present invention, a disease or disorder associated with
TYK2 is defined
as a disease or disorder where TYK2 is involved.
In a preferred embodiment, wherein the diseases or disorder is associated with
TYK2 is an
immunological, inflammatory, autoimmune, or allergic disorder or disease of a
transplant
rejection or a Graft-versus host disease.
Consequently, another aspect of the present invention is a compound or a
pharmaceutically
acceptable salt thereof of the present invention for use in a method of
treating or preventing
an immunological, inflammatory, autoimmune, or allergic disorder or disease of
a transplant
rejection or a Graft-versus host disease.
Inflammation of tissues and organs occurs in a wide range of disorders and
diseases and in
certain variations, results from activation of the cytokine family of
receptors. Exemplary
inflammatory disorders associated with activation of TYK2 include, in a non-
limiting manner,
skin inflammation due radiation exposure, asthma, allergic inflammation and
chronic
inflammation.
In a preferred embodiment, the inflammatory disease is an eye disease.
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Dry eye syndrome (DES, also known as keratoconjunctivitis sicca) is one of the
most
common problems treated by eye physicians. Sometimes DES is referred to as
dysfunctional
tear syndrome (Jackson, 2009. Canadian Journal Ophthalmology 44(4), 385-394).
DES
affects up to 10% of the population between the ages of 20 to 45 years, with
this percentage
increasing with age. Although a wide variety of artificial tear products are
available, these
products provide only transitory relief of symptoms. As such, there is a need
for agents,
compositions and therapeutic methods to treat dry eye.
As used herein, "dry eye disorder" is intended to encompass the disease states
summarized in
a recent official report of the Dry Eye Workshop (DEWS), which defined dry eye
as "a
multifactorial disease of the tears and ocular surface that results in
symptoms of discomfort,
visual disturbance, and tear film instability with potential damage to the
ocular surface. It is
accompanied by increased osmolality of the tear film and inflammation of the
ocular surface."
(Lemp, 2007. "The Definition and Classification of Dry Eye Disease: Report of
the Definition
and Classification Subcommittee of the International Dry Eye Workshop", The
Ocular
Surface, 5(2), 75-92). Dry eye is also sometimes referred to as
keratoconjunctivitis sicca. In
some embodiments, the treatment of the dry eye disorder involves ameliorating
a particular
symptom of dry eye disorder, such as eye discomfort, visual disturbance, tear
film instability,
tear hyperosmolarity, and inflammation of the ocular surface.
Uveitis is the most common form of intraocular inflammation and remains a
significant cause
of visual loss. Current treatments for uveitis employs systemic medications
that have severe
side effects and are globally immunosuppressive. Clinically, chronic
progressive or relapsing
forms of non-infectious uveitis are treated with topical and/or systemic
corticosteroids. In
addition, macrolides such as cyclosporine and rapamycin are used, and in some
cases
cytotoxic agents such as cyclophosphamide and chlorambucil, and
antimetabolites such as
azathioprine, methotrexate, and leflunomide (Srivastava et al., 2010. Uveitis:
Mechanisms
and recent advances in therapy. Clinica Chimica Acta,
doi:10.1016/j.cca.2010.04.017).
Further eye diseases, combination treatments and route of administration are
described for
example in WO-A 2010/039939, which is hereby incorporated herein by reference.
According to the present invention, an autoimmune disease is a disease which
is at least
partially provoked by an immune reaction of the body against own components,
for example
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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.
In a preferred embodiment, the autoimmune disease is selected from the group
consisting of
rheumatoid arthritis (RA), inflammatory bowel disease (IBD; Crohns's disease
and ulcerative
colitis), psoriasis, systemic lupus erythematosus (SLE), and multiple
sclerosis (MS).
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 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 neutrophils
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,
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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 (Scholl et al., 2005, New Engl. J. Med. 352:1899-1912).
Systemic lupus erythematosus (SLE) is a chronic inflammatory disease generated
by T 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).
Multiple sclerosis (MS) is an inflammatory and demyelating neurological
disease. It has bee
considered as an autoimmune disorder mediated by CD4+ type 1 T helper cells,
but recent
studies indicated a role of other immune cells (Hemmer et al., 2002, Nat. Rev.
Neuroscience
3, 291-301).
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 anytime 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.
In a further preferred embodiment, the disease or disorder associated with
TYK2 is a
proliferative disease, especially cancer as mentioned above.
Diseases and disorders associated especially with TYK2 are proliferative
disorders or
diseases, especially cancer.
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Therefore, another aspect of the present invention is a compound or a
pharmaceutically
acceptable salt thereof of the present invention for use in a method of
treating or preventing a
proliferative disease, especially cancer.
Cancer comprises a group of diseases characterized by uncontrolled growth and
spread of
abnormal cells. All types of cancers generally involve some abnormality in the
control of cell
growth, division and survival, resulting in the malignant growth of cells. Key
factors
contributing to said malignant growth of cells are independence from growth
signals,
insensitivity to anti-growth signals, evasion of apoptosis, limitless
replicative potential,
sustained angiogenesis, tissue invasion and metastasis, and genome instability
(Hanahan and
Weinberg, 2000. The Hallmarks of Cancer. Cell 100, 57-70).
Typically, cancers are classified as hematological cancers (for example
leukemias and
lymphomas) and solid cancers such as sarcomas and carcinomas (for example
cancers of the
brain, breast, lung, colon, stomach, liver, pancreas, prostate, ovary).
The TYK2 inhibitors of the present invention may also be useful in treating
certain
malignancies, including skin cancer and hematological malignancy such as
lymphomas and
leukemias.
Yet another aspect of the present invention is the use of a compound of the
present invention
or a pharmaceutically acceptable salt thereof for the manufacture of a
medicament for the
treatment or prophylaxis of diseases and disorders associated with TYK2.
Yet another aspect of the present invention is the use of a compound of the
present invention
or a pharmaceutically acceptable salt thereof for the manufacture of a
medicament for treating
or preventing an immunological, inflammatory, autoimmune, or allergic disorder
or disease or
a transplant rejection or a Graft-versus host disease.
Yet another aspect of the present invention is the use of a compound of the
present invention
or a pharmaceutically acceptable salt thereof for the manufacture of a
medicament for treating
or preventing a proliferative disease, especially cancer.
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In the context of these uses of the invention, diseases and disorders
associated with TYK2 are
as defined above.
Yet another aspect of the present invention is a method for treating,
controlling, delaying or
preventing in a mammalian patient in need thereof one or more conditions
selected from the
group consisting of diseases and disorders associated with TYK2, wherein the
method
comprises the administration to said patient a therapeutically effective
amount of a compound
according to present invention or a pharmaceutically acceptable salt thereof
Yet another aspect of the present invention is a method for treating,
controlling, delaying or
preventing in a mammalian patient in need thereof one or more conditions
selected from the
group consisting of an immunological, inflammatory, autoimmune, or allergic
disorder or
disease or a transplant rejection or a Graft-versus host disease, wherein the
method comprises
the administration to said patient a therapeutically effective amount of a
compound according
to present invention or a pharmaceutically acceptable salt thereof.
Yet another aspect of the present invention is a method for treating,
controlling, delaying or
preventing in a mammalian patient in need thereof a proliferative disease,
especially cancer,
wherein the method comprises the administration to said patient a
therapeutically effective
amount of a compound according to present invention or a pharmaceutically
acceptable salt
thereof
In the context of these methods of the invention, diseases and disorders
associated with TYK2
are as defined above.
As used herein, the term "treating" or "treatment" is intended to refer to all
processes, wherein
there may be a slowing, interrupting, arresting, or stopping of the
progression of a disease, but
does not necessarily indicate a total elimination of all symptoms.
Exemplary routes for the preparation of compounds of the present invention are
described
below. It is clear to a practitioner in the art to combine or adjust such
routes especially in
combination with the introduction of activating or protective chemical groups.
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A general route for the preparation of compounds according to present
invention is outlined in
Schemes 1 and 2.
CI CI NH2
ii
N N i N N N N
I 10.
__________________________________________________________ 11.
I
R3 jC I R3 R2 R3 R2
HN,R1
NH2
N N iii N N
I _________________ 1P
R3 R2
R3 - - R2
(i) R2B(01-)2, Pd(dPPO(C12).DCM, Et0H, 2M Na2CO3, Dioxane, 130 C, 30min; (ii)
ammonia, dioxane, 160 C,
lh; (iii) R1C(0)C1, triethylamine, ACN, lh.
Scheme 1
CI CI
N N 1 i N N
I
R3 -C1 _______________ N.-
R3 R2
CI H N 11
ii iii H N ;11¨R7
N N N N
1 ______________________________________________________ ¨ N N
R3 R2 R3 R2 1
R3 R2
(i) R2B(01-)2, Pd(dPPO(C12).DCM, Et0H, 2M Na2CO3, Dioxane, 130 C, 30min; (ii)
HN-14, IPA, HC1 (4M
dioxane), 150 C, lh, microwave; (iii) leC(0)C1, K2CO3, NaI, ACN, 80 C, lh.
Scheme 2
Examples
Analytical Methods
NMR spectra were obtained on a Brucker dpx400. LCMS (methods A and B) was
carried out
on an Agilent 1100 using a Gemini C18, 3 x 30 mm, 3 micron column. Solvents
used were
water and acetonitrile with 0.1% formic acid and with an injection volume of 3
L.
Wavelengths were 254 and 210 nm. LCMS method C was carried out on a Waters
uPLC-
SQD using the same solvents. Photodiode array detection was between 210 and
400 nm.
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Methods D-G were carried out on an Agilent 1200 series HPLC with detection at
254 nm.
Water (with 0.07% TFA) and methanol were the solvents used.
Method A
Column: Phenomenex Gemini-C18, 3 x 30mm, 3microns. Flow rate: 1.2 mL/min
Table 1
Time (min) Water (%) ACN (%)
0 95 5
3 5 95
4.5 5 95
4.6 95 5
5 STOP
Method B
Column: Phenomenex Gemini-C18, 4.6 x 150mm, 5microns. Flow rate: 1.0 mL/min
Table 2
Time (min) Water (%) ACN (%)
0.00 95.0 5.0
11.00 5.0 95.0
13.00 5.0 95.0
13.01 95.0 5.0
14.00 STOP
Method C
Column: Waters Acquity UPLC BEH C18, 2.1 x 30 mm, 1.7 microns. Flow rate: 0.5
mL/min
Table 3
Time (min) Water ACN (%)
(%)
0.00 95.0 5.0
0.20 95.0 5.0
1.00 5.0 95.0
1.50 5.0 95.0
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1.70 95.0 5.0
2.70 95.0 5.0
3.00 STOP
Method D
Column: Ultimate AQ-C18 column, 4.6x250 mm, 5 microns. Flow rate: 1.0 mL/min
at 30 C.
Table 4
Time (min) Methanol (%) Water (%)
0 40 60
3 40 60
5 60 40
7 80 20
8 95 5
95 5
17 STOP
Method E
Column: Ultimate AQ-C18 column, 4.6x250 mm, 5 microns. Flow rate: 1.0 mL/min
at 30 C.
10 Table 5
Time (min) Methanol (%) Water (%)
0 20 80
5 20 80
8 65 35
10 95 5
14 95 5
17 STOP
Method F
Column: Waters Novapak C18, 3.9 x 150 mm, 4 microns. Flow rate: 1.0 mL/min.
Gradient as described in Table 4 (Method D)
Method G
Column: Waters Novapak C18, 3.9 x 150 mm, 4 microns. Flow rate: 1.0 mL/min.
Gradient as described in Table 5 (Method E)
Table 6: Abbreviations
ACN Acetonitrile
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Ar Aryl
aq Aqueous
br Broad
Boc Tert-Butoxycarbonyl
BuLi Butyllithium
d Doublet
dba Dibenzylideneacetone
DCM Dichloromethane
dd Double doublet
ddd Double doublet of doublets
DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
DEAD Diethyl azodicarboxylate
DIAD Diisopropyl azodicarboxylate
DIPEA Diisopropylethylamine
DME 1,2-Dimethoxyethane
DMF N,N`-Dimethylformamide
DMF-DMA N,N `-dimethylformami de dimethylacetal
DMSO N,N`-dimethylsulfoxide
DP Drug pulldown
dppf 1,1`-Bis(diphenylphosphino)ferrocene
dt Doublet of triplets
DTT Dithiothreitol
EDC 1-Ethy1-3-(3-dimethylaminopropyl)carbodiimide
EDTA Ethylenediaminetetraacetic acid
Et0Ac Ethyl acetate
Et0H Ethanol
eq Equivalents
g Grams
h Hours
0-(7-Azabenzotriazol-1-y1)-N,N,N',N'-tetramethyluronium
HATU
hexafluorophosphate
HC1 Hydrochloric acid
H20 Water
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H2S Hydrogen sulfide
HOBt 1-Hydroxybenzotriazole
HPLC High performance liquid chromatography
ICso 50% inhibition concentration
IPA Isopropyl alcohol
iPr Isopropyl
L Litres
LC-MS Liquid chromatography mass spectroscopy
m Multiplet
M Molar
Me0H Methanol
Mesyl Methanesulfonyl chloride
mg Milligrams
MgSO4 Magnesium Sulphate
min Minutes
mL Millilitres
mm Millimetres
mmol Millimoles
mol% Molar percent
IAL Microlitres
nm Nanometres
NMR Nuclear magnetic resonance
PBS Phosphate buffered saline
Prep. Preparative
q Quartet
rpm Revolutions per minute
rt Room temperature
RT Retention time
s Singlet
sat. Saturated
t Triplet
td Triplet of doublets
tdd Triple doublet of doublets
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tert Tertiary
TFA Trifluoroacetic acid
THF Tetrahydrofuran
tt Triplet of triplets
Xantphos 4,5-Bi s(diphenylphosphino)-9,9-dimethylxanthene
Experimental
Procedure A
Step (i)
2,4-dichloro-5-methylpyrimidine (300 mg, 1.8 mmol), (4-
(methylsulfonyl)phenyl)boronic
acid (0.36 mL, 1.8 mmol), [1,11-
Bis(diphenylphosphino)ferrocene]dichloropalladium(H),
complex with dichloromethane (44 mg, 0.054 mmol) and sodium carbonate (2M
aqueous
solution, 2.7 mL, 5.4 mmol) in ethanol (1 mL) and dioxane (3 mL) were heated
to 130 C for
30 min. The residue was cooled to rt and partitioned between Et0Ac and water.
The phases
were separated and the aqueous phase was extracted with Et0Ac. The combined
organic
extracts were washed with brine, dried (Mg504) and the solvents removed in
vacuo to afford
a brown oil. This was purified by flash column chromatography to afford 2-
chloro-5-methy1-
4-(4-(methylsulfonyl)phenyl)pyrimidine.
Step (ii)
2-chloro-5-methy1-4-(4-(methylsulfonyl)phenyl)pyrimidine (112 mg, 0.4 mmol)
and ammonia
(5 mL, 0.06 mmol) in dioxane (0.75 mL) were heated to 160 C for 1 h. The
mixture was
concentrated in vacuo to afford 5-methy1-4-(4-(methylsulfonyl)phenyl)pyrimidin-
2-amine as
a white solid which was used in the next step without further purification.
Step (iii)
Cyclopropanecarbonyl chloride (84 L, 0.91 mmol) was added to a stirred
solution of 5-
methy1-4-(4-(methylsulfonyl)phenyl)pyrimidin-2-amine (120 mg, 0.46 mmol) and
triethylamine (53 L, 0.91 mmol) in ACN (10 mL). The mixture was stirred for a
further 1 h
then the solvent was removed in vacuo and water then DCM were added. The
organic phase
was separated and the solvent was removed in vacuo to afford a yellow oil
which was purified
by prep. HPLC to afford N-(5-methy1-4-(4-(methylsulfonyl)phenyl)pyrimidin-2-
yl)cyclopropanecarboxamide.
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Procedure B
General Procedure for the Synthesis of 4-Amino-1-N-alkylated-pyrazoles
Step (i)
A solution of 4-nitropyrazole (300mg, 2.65mmol), potassium carbonate (2eq) and
the
alkylating reagent (1.1eq) in acetonitrile (10mL) was heated to 60 C for 18 h.
After cooling
to rt the mixture was diluted with Et0Ac and washed with water. The organic
phase was
collected, dried (Mg504) and concentrated in vacuo.
Step (ii)
The crude residue was dissolved in methanol (10mL), palladium on carbon (50mg)
was added
and the reaction was stirred under a balloon of hydrogen for 18 h. The
resulting mixture was
filtered through Celite and the filtrate concentrated in vacuo to give the
desired product.
Procedure C
Step (i)
2,4-dichloro-5-methylpyrimidine (300 mg, 1.8 mmol), (4-
(methylsulfonyl)phenyl)boronic
acid (0.36 mL, 1.8 mmol), [1,11-
Bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (44 mg, 0.054 mmol) and sodium carbonate (2M
aqueous
solution, 2.7 mL, 5.4 mmol) in ethanol (1 mL) and dioxane (3 mL) were heated
to 130 C for
min. The residue was cooled to rt and partitioned between Et0Ac and water. The
phases
were separated and the aqueous phase was extracted with Et0Ac. The combined
organic
extracts were washed with brine, dried (Mg504) and the solvents removed in
vacuo to afford
a brown oil. This was purified by flash column chromatography to afford 2-
chloro-5-methyl-
25 4-(4-(methyl sulfonyl)phenyl)pyrimi dine .
Step (ii)
2-chloro-5-methy1-4-(4-(methylsulfonyl)phenyl)pyrimidine (70 mg, 0.25 mmol), 1-
methyl-
1H-pyrazol-4-amine (26 mg, 0.27 mmol), prepared according to Procedure B, IPA
(3 mL) and
30 HC1 (4M in dioxane, 100 L, 0.4 mmol) were heated to 150 C for 1 h in the
microwave. The
solvent was removed in vacuo and the brown oil purified by prep HPLC to afford
5-methyl-
N-(1-methy1-1H-pyrazol-4-y1)-4-(4-(methylsulfonyl)phenyl)pyrimidin-2-amine.
Procedure D
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General procedure for alkylation of N-(1H-pyrazol-4-yl)pyrimidin-2-amines
N-(1H-pyrazol-4-yl)pyrimidin-2-amine (1.1 eq), alkyl chloride (1 eq) potassium
carbonate
(2eq), sodium iodide (catalytic) and ACN were heated to 80 C for 1 h. The
mixture was
cooled to rt and Et0Ac then water were added. The organic phase was separated,
washed
with brine, dried (MgSO4) and concentrated in vacuo to afford a yellow oil.
Petrol was added
and the resulting precipitate was separated by filtration to give the desired
product as a white
solid.
Procedure E
Step (i)
HC1 (4M in dioxane, 200 mL) was added slowly to a stirred solution of 1-methy1-
1H-pyrazol-
4-amine (52 g, 0.53 mol, prepared according to Procedure B) and cyanamide (29
g, 0.69 mol)
in dioxane (50 mL) then the mixture was heated to 95 C overnight. The reaction
was cooled
to room temperature and the solvent removed in vacuo. The residue was washed
with ether
(100 mL) to afford 1-(1-methyl-1H-pyrazol-4-yl)guanidine hydrochloride (93 g,
¨ 100%) as
a yellow solid which was used in the next step without further purification.
Step (ii)
Ethyl propionate (35 mL, 0.31 mol) was added dropwise to a stirred solution of
sodium
methoxide (28 g, 0.51 mol) in anhydrous DMF (300 mL) then the mixture was
stirred for 20
min before the dropwise addition of methyl formate (14 mL, 0.23 mol). The
reaction was
stired for 30 min before 1-(1-methyl-1H-pyrazol-4-yl)guanidine hydrochloride
(38 g, 0.21
mol) was added and the reaction heated at 100 C overnight. The mixture was
concentrated in
vacuo, diluted with water and adjusted to pH6-7 by addition of 4M hydrochloric
acid. The
precipitate was collected and washed with H20 (100 mL) and ethyl acetate (50
mL) to afford
5-methy1-2-(1-methy1-1H-pyrazol-4-ylamino)pyrimidin-4-ol (35 g, 79%) as a grey
solid
which was used in next step without further purification.
Step (iii)
5-methy1-2-(1-methy1-1H-pyrazol-4-ylamino)pyrimidin-4-ol (35 g, 0.17 mol) was
dissolved
in POC13 (25 mL) and the mixture was heated at 95 C for 5 h then concentrated
in vacuo,
poured onto ice water (100 mL) and adjusted to pH7-8 by addition of saturated
aqueous
NaHCO3. The precipitate was collected by filtration, dried in vacuo and
purified by column
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chromatography (silica, 3-5% v/v Me0H in DCM) to afford 4-chloro-5-methyl-N-(1-
methyl-
1H-pyrazol-4-yl)pyrimidin-2-amine (15.0 g, 39%) as a white solid.
Procedure F
Step (i)
1M NaOH (aq) (0.93 mol) was added to a stirred solution of ethyl 2-(4-(4-(3-
fluoro-4-
m ethoxypheny1)-5-methylpyrimi din-2-ylamino)-1H-pyrazol-1-yl)ac etate (115
mg, 0.31
mmol, prepared according to procedure B step (i)) in Me0H (10 mL) and the
mixture was
stirred at rt for 3 h. After the reaction was complete, the solvent was
removed in vacuo and
the residue was acidified by addition of dilute HC1 and extracted with Et0Ac.
The combined
organic extracts were dried (Na2504) and concentrated in vacuo to afford 2-(4-
(4-(3-fluoro-4-
methoxypheny1)-5-methyl pyrimidin-2-ylamino)-1H-pyrazol-1-yl)acetic acid (100
mg, 91%)
as a white solid.
Step (ii)
HATU (99 mg, 0.26 mmol) and triethylamine (52 mg, 0.51 mmol) were added to a
stirred
solution of 2-(4-(4-(3-fluoro-4-methoxypheny1)-5-methyl pyrimidin-2-ylamino)-
1H-pyrazol-
1-yl)acetic acid (60 mg, 0.17 mmol, 1 eq) in ACN (25 mL) and the mixture was
stirred at rt
for 0.5 h before addition of cyclopropylamine (12 mg, 0.20 mmol). After 3 h
the solvent was
removed in vacuo, the residue was diluted with saturated aqueous Na2CO3 and
extracted with
Et0Ac. The combined organic extracts were dried (Na2504) ,concentrated in
vacuo and
purified by column chromatography (silica, 0-2%, v/v Me0H in DCM) to afford 2-
(4-(4-(3-
fluoro-4-methoxypheny1)-5-methylpyrimi din-2-y1 amino)-1H-pyrazol-1-y1)-N-
cyclopropylacetamide (21 mg, 31%) as a yellow solid.
Procedure G
A mixture of 2-fluoro-4-(5-methy1-2-(1-methy1-1H-pyrazol-4-ylamino)pyrimidin-4-
y1)phenol
(60 mg, 0.2 mmol), cyclobutyl bromide (32 mg, 0.24 mmol) and Cs2CO3 (130 mg,
0.4 mmol)
in acetonitrile (4 mL) was heated at 160 C in microwave reactor for 30 min.
The mixture was
partitioned between water and ethyl acetate, the organic layer was washed with
brine, dried
(Na2504), concentrated and purifed by preparative TLC (5% v/v Me0H in DCM) to
afford 4-
(4-cyclobutoxy-3 -fluoropheny1)-5-methyl-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-
2-amine
(40 mg, 56%) as a white solid.
Procedure H
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A mixture of 2-fluoro-4-(5-methy1-2-(1-methy1-1H-pyrazol-4-ylamino)pyrimidin-4-
y1)phenol
(60 mg, 0.2 mmol), propylene oxide (58 mg, 1.0 mmol), lithium chloride (25 mg,
0.6 mmol)
and triethylamine (2 mg, 0.02 mmol) in ethanol was heated at 60 C in a sealed
tube overnight.
The mixture was concentrated in vacuo, dissolved in ethyl acetate, washed with
brine, dried
(Na2SO4), concentrated and purifed by preparative TLC (5% v/v Me0H in DCM) to
obtain 1-
(2-fluoro-4-(5-methy1-2-(1-methy1-1H-pyrazol-4-ylamino)pyrimidin-4-
y1)phenoxy)propan-2-
ol (20 mg, 28%) as a light yellow solid.
Procedure I
Step (i)
TFA (2 mL) was added to a solution of tert-butyl 4-(5-methy1-2-(1-methy1-1H-
pyrazol-4-
ylamino)pyrimidin-4-y1)phenylcarbamate (420 mg, 1.1 mmol) in DCM (5 mL). The
mixture
was stirred at rt overnight then concentrated in vacuo. The residue was
suspended in 5%
NaHCO3(aq) and extracted twice with DCM. The combined organic layer was washed
with
brine, dried (Na2504), and concentrated to give the crude product which was
purifed by
column chromatography (silica, 5% v/v Me0H in DCM) to afford 4-(4-aminopheny1)-
5-
methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-amine (250 mg, 79%) as a white
solid.
Step (ii)
Ethylsulfonyl chloride (46 mg, 0.36 mmol) was added to a stirred solution of 4-
(4-
aminopheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-amine (100 mg,
0.36
mmol) in pyridine (4 mL) and the reaction was stirred at rt for 3 h. The
pyridine was removed
under reduced pressure and the residue was extracted with DCM, washed with
water and
brine, dried (Na2504) and concentrated to give the crude product which was
purified by
preparative TLC (5% v/v Me0H in DCM) to afford N-(4-(5-methy1-2-(1-methy1-1H-
pyrazol-
4-ylamino)pyrimidin-4-y1)phenyl) ethanesulfonamide (35 mg, 26%).
Procedure J
Step (i)
Phenylchloroformate (209 mg, 1.3 mmol) was added dropwise to a stirred mixture
of 4-(4-
aminopheny1)-5-methyl-N-(1-methy1-1H-pyrazol-4-y1)pyrimidin-2-amine (250 mg,
0.89
mmol, prepared according to Procedure I(i)) and NaHCO3 (224 mg, 2. 7 mmol) in
THF (10
mL) and the mixture was stirred at rt for 3 h. The solvent was removed in
vacuo and the
residue was purified by column chromatography (silica, 5% v/v Me0H in DCM) to
afford
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phenyl 4-(5-methy1-2-(1-methy1-1H-pyrazol-4-ylamino)pyrimidin-4-
y1)phenylcarbamate (320
mg, 90%) as a white solid.
Step (ii)
A mixture of 4-(5-methy1-2-(1-methy1-1H-pyrazol-4-ylamino)pyrimidin-4-
y1)phenylcarbamate (80 mg, 0.2 mmol) and 2-methoxyethanamine (30 mg, 0.4 mmol)
in THF
(3 mL) was heated to 120 C for 15 min in a microwave reactor. The solvent was
removed in
vacuo and the residue was extracted with ethyl acetate. The combined organic
layer was
washed with water, dried (Na2504) and the crude product was purifed by column
chromatography (silica, 3% v/v Me0H in DCM) to afford 1-(2-methoxyethyl)-3-(4-
(5-
methy1-2-(1-methy1-1H-pyrazol-4-ylamino)pyrimidin-4-y1)phenyl)urea (30 mg,
40%) as a
white solid.
Procedure K
A mixture of 2-chloro-4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidine (70 mg,
0.28
mmol), 3-methylisothiazol-5-amine (39 mg, 0.34 mmol), Cs2CO3 (182 mg, 0.56
mmol),
Pd2dba3 (28 mg, 0.03 mmol) and Xantphos (35 mg, 0.06 mmol) in dioxane (14 mL)
was
purged with nitrogen and then heated at 130 C for 5 min in a microwave
reactor. The solvent
was removed in vacuo and the residue was dissolved in Et0Ac. The organic layer
was washed
with water and brine, dried (Na2504) and concentrated to afford a crude
residue which was
purified by column chromatography (silica, 1-2% v/v Me0H in DCM) to afford 4-
(3-fluoro-
4-methoxypheny1)-5-methyl-N-(3-methylisothiazol-5-y1)pyrimidin-2-amine (18 mg,
20%) as
a brown solid.
Procedure L
Step (i)
To a solution of pentafluorophenol (5.0 g, 27 mmol) in DCM (220 mL) was added
triethylamine (11 mL, 82 mmol). A solution of 4-bromophenylsulfonyl chloride
(6.9 g, 27
mmol) in DCM (50 mL) was then added and the reaction stirred at rt overnight.
The mixture
was washed with 5% citric acid (2x100 mL) and brine (2x50 mL), dried (Na2504)
filtered
and concentrated to afford perfluorophenyl 4-bromobenzenesulfonate (10.2 g,
93.6%) as a
white solid.
Step (ii)
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A mixture of perfluorophenyl 4-bromobenzenesulfonate (3.3 g, 8.2 mmol),
bis(pinacolato)diboron (2.29 g, 9.0 mmol), Pd(dppf)C12 (669 mg, 0.82 mmol),
dppf (454 mg,
0.82 mmol), and sodium acetate (4.0 g, 49 mmol) in dioxane (116 mL) was heated
to reflux
under a nitrogen atmosphere for 16 h. The reaction was then cooled and the
solid precipitate
removed by filtration. The filtrate was concentrated to give a crude product
which was boiled
in hexane (40 mL). Any further solid that precipitated was removed by
filtration, then the
filtrate was collected and concentrated in vacuo to give perfluorophenyl
444,4,5,5-
tetramethy1-1,3,2-dioxaborolan-2-yl)benzenesulfonate (980 mg, 27%) as a pale
red solid.
Step (iii)
A mixture of perfluorophenyl
4-(4,4,5,5-tetramethy1-1,3 ,2-di oxab orol an-2-
yl)b enzenesulfonate (890 mg, 2.0 mmol), 4-chloro-5-methyl-N-(1-methy1-1H-
pyraz 01-4-
yl)pyrimidin-2-amine (340 mg, 1.5 mmol, prepared by Procedure E), Pd(dppf)C12
(163 mg,
1.5 mmol) and Na2B407 (2.4 g, 12 mmol) in dioxane (23 mL) and ethanol (4.5 mL)
was
heated to 120 C for 15 min in a microwave reactor. The resulting mixture was
concentrated
under reduced pressure to give a residue which was purifed by column
chromatography
(silica, 2% v/v Me0H in DCM) to afford perfluorophenyl 4-(5-methy1-2-(1-methy1-
1H-
pyrazol-4-ylamino)pyrimidin-4-y1)benzenesulfonate (700 mg, 91%).
Step (iv)
A mixture of perfluorophenyl 4-(5-methy1-2-(1-methy1-1H-pyrazol-4-
ylamino)pyrimidin-4-
y1)benzenesulfonate (30 mg, 0.087 mmol), morpholine (9 mg, 0.10 mmol) and
triethylamine
(2 mL) in dioxane (8 mL) was heated to 120 C for 15 min in a microwave
reactor. The
mixture was concentrated to give a residue which was purified by preparative
HPLC to
provide 5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-(4-
(morpholinosulfonyl)phenyl)pyrimidin-
2-amine (11.6 mg, 48%).
Procedure M
Step (i)
n-BuLi (2.0 M in hexane, 2.1 mL, 4.2 mmol) was added dropwise over 5 min to a
stirred
solution of 2-bromopyridine (675 mg, 4.2 mmol) in dry ether (15 mL) at -45 C
and the
reaction was stirred at this temperature for a further 1 h. A suspension of 2-
chloro-5-
methylpyrimidine (500 mg, 3.9 mmol) in ether (30 mL) was added dropwise over 5
min, the
reaction was stirred a further 15 min at -45 C, warmed to 0 C and stirred for
1 h. The reaction
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PCT/EP2011/069553
was quenched by addition of water (100 mg) in THF (3 mL) and then DDQ (1.32 g,
5.8
mmol) in THF (5 mL) was added. The reaction was warmed to rt and stirred for a
further 15
min. It was then cooled to 0 C and hexane (10 mL) was added followed by 3M
aqueous
sodium hydroxide (2.5 mL, 7.5 mmol). The suspension was stirred for 5 min,
extracted with
ethyl acetate, concentrated in vacuo then purified by column chromatography to
give a
mixture of the deisred 2-chloro-5-methyl-4-(pyridin-2-yl)pyrimidine and
starting material 2-
chloro-5-methylpyrimidine. The mixture was dissolved in Et0Ac and extracted
with 1M HC1.
The aqueous layer was collected and made basic by addition of NaOH solution
and extracted
with Et0Ac. The organics were concentrated in vacuo afford 2-chloro-5-methy1-4-
(pyridin-2-
yl)pyrimidine (220 mg, 28%) as a white solid.
Step (ii)
N-methyl-4-aminopyrazole (62 mg, 0.64 mmol) and 12M HC1 (0.15 mL, 1.7 mmol)
were
added to a stirred solution of 2-chloro-5-methyl-4-(pyridin-2-yl)pyrimidine
(100mg, 0.49
mmol), in IPA (3 mL) then the mixture was heated to 160 C for 45 min in a
microwave
reactor. The reaction was quenched by addition of water and made basic with
sodium
hydroxide solution. The resulting mixture was extracted with Et0Ac and the
combined
extracts were dried, concentrated and purified by preparative TLC (5% v/v Me0H
in DCM)
followed by an ethanol rinse to afford 5-methyl-N-(1-methy1-1H-pyrazol-4-y1)-4-
(pyridin-2-
yl)pyrimidin-2-amine (28 mg, 22%) as a yellow solid.
Procedure N
Step (i)
A mixture of 2-chloro-4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidine (300 mg,
1.2
mmol) and concentrated aqueous ammonia (2 mL) in Et0H (10 mL) was heated to
160 C in a
sealed tube overnight. The solvent was removed in vacuo and the residue
purified by column
chromatography (silica, 0-10% v/v Me0H in DCM) to afford 4-(3-fluoro-4-
methoxypheny1)-
5-methylpyrimidin-2-amine (150 mg, 54%) as a white solid.
Step (ii)
Perbromomethane (1.07 g, 3.2 mmol) was added to a stirred mixture of 2-
acetamidoacetic
acid (377 mg, 3.2 mmol) in pyridine (10 mL) at 0 C under N2. The reaction was
stirred for 10
min then triphenylphosphine (845 mg, 3.2 mmol) was added portionwise and the
whole
mixture was stirred for 1 h at rt. 4-(3-fluoro-4-methoxypheny1)-5-
methylpyrimidin-2-amine
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PCT/EP2011/069553
(150 mg, 0.64 mmol) was added and the whole mixture was stirred overnight. The
solvent
was removed in vacuo, the residue was diluted with water and extracted twice
with Et0Ac.
The combined organic layer was dried (Na2SO4), concentrated and purified by
column
chromatography (silica, 0-5%, v/v Me0H in DCM) to afford 2-acetamido-N-[4-(3-
fluoro-4-
methoxypheny1)-5-methylpyrimidin-2-yl]acetamide (60 mg, 28%) as a white solid.
Step (iii)
A mixture of 2-acetamido-N44-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-
yl]
acetamide (40 mg, 0.12 mmol) and Lawesson's Reagent (243 mg, 0.60 mmol) in
xylene (20
mL) was heated to 150 C overnight. The solvent was removed in vacuo and the
residue was
purified by preparative HPLC and then preparative TLC (5% v/v Me0H in DCM) to
afford 4-
(3 -fluoro-4-methoxypheny1)-5-methyl-N-(2-methyl- 1,3 -thiazol-5-yl)pyrimidin-
2-amine (2.0
mg, 5%) as a white solid.
Example 1: N-(4-(3-fluoropheny1)-5-methylpyrimidin-2-
yl)cyclopropanecarboxamide
0
N N
Synthesised according to Procedure A using (3-fluorophenyl)boronic acid. 11-1
NMR (400
MHz, CDC13) 6 8.62 (s, 1H), 8.54 (s, 1H), 7.49 (m, 2H), 7.38 ¨7.31 (m, 1H),
7.23 ¨7.12 (m,
1H), 2.35 (s, 3H), 1.74 (m, 1H), 1.25 ¨ 1.14 (m, 2H), 1.00 ¨0.83 (m, 2H); LCMS
method B,
(ES+) 272, RT = 8.37 min.
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Example 2: 4-(2-fluoro-4-methoxypheny1)-5-methyl-N-(1-methyl-IH-pyrazol-4-
Apyrimidin-2-
amine
HN
F N N
0
Synthesised according to Procedure C using (2-fluoro-4-methoxyphenyl)boronic
acid. 11-1
NMR (400 MHz, d6-DMS0) 6 9.36 (s, 1H), 8.34 (s, 1H), 7.80 (s, 1H), 7.46-7.43
(m, 2H), 7.00
¨ 6.94 (m, 2H), 3.85 (s, 3H), 3.78 (s, 3H), 2.02 (s, 3H); LCMS method B, (ES+)
314, RT =
8.79 min.
Example 3: N-(4-(2-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-yl)cyclopropane
carboxamide
0
FNN
0
Synthesised according to Procedure A using (2-fluoro-4-methoxyphenyl)boronic
acid. 11-1
NMR (400 MHz, d6-DMS0) 6 10.76 (s, 1H), 8.52 (s, 1H), 7.37 (s, 1H), 6.95 ¨
6.86 (m, 2H),
3.79 (s, 3H), 2.18 ¨ 1.89 (m, 4H), 1.32¨ 1.04 (m, 1H), 0.90 ¨ 0.54 (m, 4H);
LCMS method B,
(ES+) 302, RT = 8.47 min.
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Example 4: N-(4-(4-chloropheny1)-5-methylpyrimidin-2-
yl)cyclopropanecarboxamide
0
N N
CI =
Synthesised according to Procedure A using (4-chlorophenyl)boronic acid. 11-1
NMR (400
MHz, d6-DMS0) 6 10.81 (s, 1H), 8.58 (m, 1H), 7.73-7.71 (m, 2H), 7.60-7.58 (m,
2H), 2.29-
2.28 (m, 3H), 2.14-2.07 (m, 1H), 0.82-0.78 (m, 4H); LCMS method B, (ES+) 288,
RT = 9.09
min.
Example 5: N-(5-methy1-4-(4-(methylsulfonyl)phenyppyrimidin-2-
y1)cyclopropanecarboxamide
0
H11).
N N
'S
0
Synthesised according to Procedure A using (4-(methylsulfonyl)phenyl)boronic
acid. 11-INMR
(400 MHz, d6-DMS0) 6 10.86 (s, 1H), 8.64 (m, 1H), 8.07 (d, J= 8.6 Hz, 2H),
7.93 (d, J= 8.6
Hz, 2H), 3.29 (s, 3H), 2.29 (s, 3H), 2.13 ¨2.10 (m, 1H), 0.85 ¨ 0.77 (m, 4H);
LCMS method
A, (ES+) 332, RT = 0.89min.
Example 6: N-(5-methyl-4-(p-tolyppyrimidin-2-yl)cyclopropanecarboxamide
0
N N
Synthesised according to Procedure A using p-tolylboronic acid. 11-1 NMR (400
MHz, d6-
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DMSO) 6 10.74 (s, 1H), 8.53 (m, 1H), 7.59 (d, 2H), 7.32 (d, 2H), 2.38 (s, 3H),
2.29 (s, 3H),
2.16-2.10 (m, 1H), 0.82-0.77 (m, 4H); LCMS method B, (ES+) 268, RT = 8.70 min.
Example 7: N-(4-(4-methoxypheny1)-5-methylpyrimidin-2-
yl)cyclopropanecarboxamide
0
N
0
Synthesised according to Procedure A using (4-methoxyphenyl)boronic acid. 11-1
NMR (400
MHz, d6-DMS0) 6 10.73 (s, 1H), 8.51 (s, 1H), 7.71 (d, 2H), 7.06 (d, 2H), 3.84
(s, 3H), 2.32 (s,
3H), 2.14 (m, 1H), 0.91 ¨0.71 (m, 4H); LCMS method B, (ES+) 284, RT = 7.88
min.
Example 8: N-(4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-
yl)cyclopropanecarboxamide
0
H11).
N
Synthesised according to Procedure A using (3-fluoro-4-methoxyphenyl)boronic
acid. 11-1
NMR (400 MHz, d6-DMS0) 6 10.76 (s, 1H), 8.55-8.53 (m, 1H), 7.64-7.54 (m, 2H),
7.32-7.26
(m, 1H), 3.94-3.89 (m, 3H), 2.35-2.30 (m, 3H), 2.14-2.09 (m, 1H), 0.83-0.78
(m, 4H); LCMS
method B, (ES+) 302, RT = 8.26 min.
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Example 9: 4-(3-fluoro-4-methoxypheny1)-5-methyl-N-(1-methyl-IH-pyrazol-4-
Apyrimidin-2-
amine
C,:rsszµN
HN
N N
F
0
Synthesised according to Procedure C using (3-fluoro-4-methoxyphenyl)boronic
acid. 11-1
NMR (400 MHz, d6-DMS0) 6 9.32 (s, 1H), 8.32 (s, 1H), 7.83 (s, 1H), 7.59-7.49
(m, 3H),
7.33-7.28 (m, 1H), 3.93 (s, 3H), 3.79 (s, 3H), 2.23 (m, 3H); LCMS method B,
(ES+) 314, RT
= 8.53 min.
Example 10: 5-methyl-N-(1-methyl-1H-pyrazol-4-y1)-4-(4-
(methylsulfonAphenyOpyrimidin-2-
amine
;C:vsN
HN
N N
0%
0
Synthesised according to Procedure C using (4-(methylsulfonyl)phenyl)boronic
acid. 11-1 NMR
(400 MHz, d6-DMS0) 6 9.43 (s, 1H), 8.41 (s, 1H), 8.08 (d, 2H), 7.94 (d, 2H),
7.83 (s, 1H),
7.49 (s, 1H), 3.79 (s, 3H), 3.31(s, 3H), 2.20 (s, 3H); LCMS method B, (ES+)
344, RT = 7.10
min.
Example 11: 4-(3-fluoro-4-methoxypheny1)-5-methyl-N-(1H-pyrazol-4-Apyrimidin-2-
amine
HN
N N
F
0
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Synthesised according to Procedure C using (3-fluoro-4-methoxyphenyl)boronic
acid in step
(i) and 1H-pyrazol-4-amine hydrochloride in Step (ii). 11-1 NMR (400 MHz, d6-
DMS0) 6
12.40 (s, 1H), 9.30 (s, 1H), 8.32 (s, 1H), 7.87 (br s, 1H), 7.60 ¨ 7.53 (m,
3H), 7.31 (m, 1H),
3.93 (s, 3H), 2.23 (s, 3H); LCMS method A, (ES+) 300, RT = 0.97 min.
Example 12: 5-methyl-4-(4-(methylsulfonApheny1)-N-(1H-pyrazol-4-Apyrimidin-2-
amine
;c1;NH
HN
N N
O.
'S =
0
Synthesised according to Procedure C using (4-(methylsulfonyl)phenyl)boronic
acid in Step
(i) and 1H-pyrazol-4-amine hydrochloride in Step (ii). 11-1 NMR (400 MHz, d6-
DMS0) 6
12.41 (s, 1H), 9.41 (s, 1H), 8.41 (s, 1H), 8.09 ¨ 8.05 (m, 2H), 7.94 (br d,
2H), 7.87 ( br s, 1H),
7.58 (br s, 1H), 3.32 (s, 3H), 2.14 (s, 3H); LCMS method A, (ES+) 330, RT =
0.87 min.
Example 13: 2-(4-((4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-yl)amino)-
1H-pyrazol-
1-y1)-1-morpholinoethanone
0
N \
HNC-"/
N N
F
0
The title product was synthesised according to Procedure D using 4-(3-fluoro-4-
methoxypheny1)-5-methyl-N-(1H-pyrazol-4-y1)pyrimidin-2-amine (see Example 11)
and 2-
chloro-1-morpholinoethanone as alkylating agent. 11-1 NMR (400 MHz, d6-DMS0) 6
9.42 (s,
1H), 8.38 (s, 1H), 7.89 (s, 1H), 7.71 ¨ 7.48 (m, 3H), 7.35 (t, J= 8.7 Hz, 1H),
5.12 (s, 2H), 3.97
(s, 3H), 3.70 ¨ 3.43 (m, 8H), 2.28 (s, 3H); LCMS method B, (ES+) 428, RT =
7.72 min.
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Example 14: 2-(4-((5-methyl-4-(4-(methylsulfonyOphenyOpyrimidin-2-yDamino)-1H-
pyrazol-
1-yDethanol
NsN FON
N
õs
0
'0
0
Synthesised according to Procedures B and C. lEINMR (400 MHz, d6-DMS0) 6 9.43
(s, 1H),
8.41 (s, 1H), 8.14 ¨ 8.03 (m, 2H), 7.95 (d, J= 8.1 Hz, 2H), 7.89 (s, 1H), 7.53
(s, 1H), 4.87 (t, J
= 5.5 Hz, 1H), 4.08 (t, J = 5.5 Hz, 2H), 3.70 (m, 2H), 3.31 (s, 3H), 2.21 (s,
3H); LCMS method
A, (ES+) 374, RT = 0.82 min.
Example 15: 2-(4-((4-(3-fluoro-4-methoxypheny1)-5-methylpyrimidin-2-yDamino)-
1H-pyrazol-
1-yDethanol
FON
N
F
0 IW
Synthesised according to Procedures B and C. lEINMR (400 MHz, d6-DMS0) 6 9.31
(s, 1H),
8.32 (s, 1H), 7.95 ¨ 7.82 (m, 1H), 7.66 ¨ 7.46 (m, 3H), 7.29 (t, J= 8.7 Hz,
1H), 4.85 (br s, 1H),
4.07 (t, J = 5.6 Hz, 2H), 3.92 (s, 3H), 3.70 (t, J = 5.6 Hz, 2H), 2.22 (s,
3H); LCMS method B,
(ES+) 344, RT = 7.56 min.
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Example 16: 2-(4-((5-methyl-4-(4-(methylsulfonyl)phenyl)pyrimidin-2-yl)amino)-
1H-pyrazol-
1-y1)-1-morpholinoethanone
0
N 0
HN
N
I
0.
'S
0
The title product was synthesised according to Procedure D using 5-methy1-4-(4-
(methylsulfonyl)pheny1)-N-(1H-pyrazol-4-yl)pyrimidin-2-amine (see Example 12)
and 2-
chloro-1-morpholinoethanone as alkylating agent. 11-1 NMR (400 MHz, d6-DMS0) 6
9.48 (s,
1H), 8.42 (s, 1H), 8.07 (d, 2H), 7.94 (d, 2H), 7.83 (s, 1H), 7.56 (s, 1H),
5.08 (s, 2H), 3.66-3.52
(m, 4H), 3.52-3.39 (m, 4H), 3.31 (s, 3H), 2.20 (s, 3H); LCMS method B, (ES+)
458, RT =
6.64 min.
Example 17: N-(3-(5-methyl-2-(0-methyl-IH-pyrazol-4-yl)amino)pyrimidin-4-
yl)benzyl)methanesulfonamide
N¨N
N NH
,NH
Synthesised according to Procedure C using ((3-
(methylsulfonamidomethyl)phenyl)boronic
acid. 11-INMR (400 MHz, d6-DMS0) 6 9.37 (s, 1H), 8.35 (s, 1H), 7.87 (s, 1H),
7.67 ¨ 7.46 (m,
6H), 4.25 (d, 2H), 3.78 (s, 3H), 2.89 (s, 3H), 2.19 (s, 3H); LCMS method C,
(ES+) 374, RT =
0.87 min.
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Example 18: N-methyl-4-(5-methyl-2-(0-methyl-IH-pyrazol-4-yDamino)pyrimidin-4-
yObenzenesulfonamide
N j\I
N -N
S.
0'.1'0
NH
Synthesised according to Procedure C using (4-(N-
methylsulfamoyl)phenyl)boronic acid. 11-1
NMR (400 MHz, d6-DMS0) 6 9.42 (s, 1H), 8.39 (s, 1H), 7.90 (s, 4H), 7.83 (s,
1H), 7.60 ¨
7.56 (m, 1H), 7.48 (s, 1H), 3.78 (s, 3H), 2.48 (s, 3H), 2.19 (s, 3H); LCMS
method C, (ES+)
360, RT = 0.87 min.
Example 19: N-methyl-3-(5-methyl-2-(0-methyl-IH-pyrazol-4-yDamino)pyrimidin-4-
yObenzenesulfonamide
N
N -N
Si 0
&N-1
Synthesised according to Procedure C using (3-(N-
methylsulfamoyl)phenyl)boronic acid. 11-1
NMR (400 MHz, d6-DMS0) 6 9.46 (s, 1H), 8.40 (s, 1H), 8.10 ¨ 8.08 (m, 1H), 7.98
¨ 7.96 (m,
1H), 7.91 ¨ 7.88 (m, 2H), 7.76 ¨ 7.62 (m, 1H), 7.62 ¨ 7.58 (m, 1H), 7.47 (s,
1H), 3.78 (s, 3H),
2.47 (s, 3H), 2.22 (s, 3H); LCMS method C, (ES+) 360, RT = 0.88 min.
Examples 20-219 are given in Table 7 together with an indication of the
procedures used to
prepare them. The order of events is not implied and a person skilled in the
art would
understand that more than one order of events could lead to the desired
product.
Table 7
Synthetic Analytical RT MS
Example
Procedure Method (min) ES+
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/
' N ri-N,
I N
20 0 N H BC A 2.19 362
O.
'SF
il
0
r_N/
' N
I N
21 0 N H BC A 2.11 359
HN
'
-S.
0"0
N'
= I
HN N 40/
22 BCE E 15.27 284
N-N F
\
N '
= I
HN N 1
23 BCE D 12.80 284
F
N-N
\
N'
I
HN N 40/
24 BCE D 12.11 296
0
N-N I
\
N'
= I
HN N 40/
25 IBCE D 12.29 296
0
N-N I
\
N'
= I
HN N (00
26 BCE D 10.22 309
N-N\ 0 NH2
N'
= I
HN N 0
27 BCE D 13.49 334
CF3
N-N
\
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N'
HN
I
HN N 0
28 BCE D 13.37 312
N-N S
\
N'
HN
I
HN N 0
29 BCE D 13.23 312
S
N-N I
\
N'
HN
I
HN N 0
BCE D 12.54 266
30
N-N
\
N'
HN
I
HN N 0
31
F BCE D 13.19 302
N-N F
\
N'
HN
I
HN N
32 si F
BCE D 13.30 302
N-N F
\
N
HN Nr 0
33
CN BCE D 12.25 291
N-N
\
N 1
I
HN N 0
34 BCE D 10.10 309
0
N-N NH2
\
N'
HN
I
HN N 0
,NH2
S. BCE D 9.93 345
N-N 0
\
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N' 1
I
HN N 40
36 BCE B 7.25 344
N¨N 0=S¨
\
0
N ' 1
I
HN N 0
37 /¨ BCE D 11.54 358
S.
// '0
N¨N 0
\
N' 1
I
HN N 0
38 BCE D 12.05 372
n=,s,
0, 0
N¨N
N' 1
I
HN N 40)
39
0 BCE D 11.70 326
c\ )
N¨N 0 I
\
N ' 1
I
HN N 0
40 BCE D 13.22 330
0
N¨N CI
\
N ' 1
I
HN N 0
41 BCE D 13.62 318
CI
N¨N F
\
N' 1
I
HN N 0
42 IBCE D 13.36 364
0
N¨N CF3
\
N ' 1
I
HN N 0
43 BCE D 13.46 298
N¨N F
\
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N 1
I
HN N 0
44 ABCE D 11.43 341
N0
H
N-N F
\
N
I
HN N
45 C\I BCE D 4.75 267
N-N
\
N
I
HN NrN
46
BCE D 11.39 298
N (:)
N-N
1\1Xci
I
HN N
47 --- NH BCEI D 5.09 256
-NI
N-N
\
I\V 1
I
HN N 0
48 BCE D 12.30 348
0
I------
N-N N-N
\
N 1
I
HN N 0
49 BCG D 13.17 328
0
N-N F
\
N 1
I
HN 'N 0
50 BCG D 13.60 342
C)
N-N F
\
N 1
I
HN N 0
51 BCG D 13.41 342
C)
N-N F
\
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I\V
HNN1 0
52 BCG D 14.28 382
n 0
N-N F
I\V
1
HN N 0
53 BCG D 11.45 344
cy....-..õ,OH
N-N F
\
NI
I
HN N
54BCG D 12.56 358
N-N F
\
I\V
HNN 1 40
0- _I\FID BCFG D 12.16 411
y
N-N F 0
\
I\V
1
HN N 40/
56 H BCF D 10.84 323
N
n
N-N 0
/
I\V
1
HN N 10 1
57 1 BCF D 11.16 337
I\1
N-N 0
/
I\V
1
HN N 0
58 H BCF D 11.55 337
N
N-N 0
/
I\V
1
HN N 0
59 H BCF D 12.09 351
N
N-N 0
/
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N 1
I
HN N 0
60 H BCF D 12.20 351
N
N-N 0
/
N
HN Nr 0
61 H BCF D 10.17 353
N OH
N-N 0
/
N
HN N= r 40 0
62 ININH2 BCF D 9.16 366
N-N 0
/
N
HN N= r 40/
63 0 BCF D 12.06 363
N-N 0
/
N
HN N= r 40 r(:)
64 I\1) BCF D 11.03 379
n
N-N 0
/
N
HN Nr 0
65 H BCF D 12.84 377
N
N-N 0
/
N
HN Nr 0
66 H BCF D 11.40 379
N o
N-N 0
/
N 1
I
HN N el
67 0 BCEF D 10.82 327
N-N F NH2
\
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WO 2012/062704 70 PCT/EP2011/069553
N,,,
1
HN N --N
68 çJ S-- BEM D 12.76 273
N-N
Nc,,,,\
'
HN N ---' N
69 S-2/ BEM D 12.76 273
N-N
\
N 1
I
HN N 0
70S BCE D 11.58 365
N-N N-N
\
N
HN N 0
71 0 BCE D 11.95 373
6 N
N-N I
\
N
HN N Si
72 0 BEL D 11.78 373
re,NH
N-N c
\ )
N
HN N Si
73 /0 BEL D 12.28 387
N-N de,NH
\
N
HN N 0
74 I
0 BEL D 12.35 387
0
S,_.,....õ....õ.õ--
N-N 6 il
\
N
HN N 0 0
75 BEL D 10.64 389
0
S, OH
N-N 0/ H
\
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N
HN N 0
76 0 BEL D 11.55 403
,f, 0
0 N
N-N H
\
N
HN N 0 0
77 BEFL D 10.18 402
//
,SN
, ,NH2
01 1
N-N H
\ 0
N
HN N 40
78 I ,p BEL D 12.39 399
S,
e NO
N-N
/
N
HN N 0 0
79 BEL D 12.00 415
N-N 6 il 1
/ 0
N
HN N 0
80 ,p BEL D 10.00 428
P'N
N-N O 0
/ N
N
HN N 0
n p
81 ,
s,// N BEL D 11.55 456
N-N 0 N
/
1r
0
N
82 HN N 0 0
BEL D 12.86 413
e,
N-N di
/
N
HN N 0
83 I,p
s ZO BEL D 11.49 415
N-N 611
/
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N
HN N 0
84 H BCF D 11.36 367
n=Ne
N-N 0
/
N
HN N 40
85 H BCF D 7.23 352
NNH2
N-N 0
/
N
HN N 40/ (1\1
86 1\1) BCF D 5.58 392
N-N 0
/
N 0
HN N N
87 01\1) BCF D 10.43 420
n
N-N 0
/
N
HN N 0
88
OMe CK D 12.45 331
r,
F
N 1
I
HN N 0
89 n OMe
BCF D 12.54 399
N-N F
S----NH
N'
HN
I
HN N 40
OMe
n
90 BCF D 12.23 397
N-N F
/-NH
0
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N
HN Nr õI
91 p BEL E 13.13 388
'P'N N H2
N-N 0 H
\
N ' 1
I
HN N 0
92 OMe BCF D 11.43 357
N-N F
NH2
0
N ' 1
I
HN N 0
93 OMe BCF D 11.81 371
N-N F
NH
O \
N ' 1
I
HN N 40/
94 n OMe BCF D 12.18 385
N-N F
S-NH
O \¨
N ' 1
I
HN N 0
95 n OMe BCF D 11.77 385
N-N F
/
S. N
O \
N ' 1
I
HN N (00
96 n OMe BCF D 10.36 426
N-N F
j-1\1/--\NH
6 \¨
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N 1
I
HN N 0
97 n OMe BCF D 12.71 425
N¨N F
0
N 1
I
HN N 0
98 n OMe BCF D 12.30 411
N¨N F
S¨Nr---
0 \..---
N
HN N 0 0
99
NNH BCIJ D 11.16 352
N¨N H)
/
N
HN N 0 0
100 I BCIJ D 11.82 366
NNH
H
N¨N _õ----
/
N
HN N 0 0
101 BCIJD 11.88 366
-=,,,
N N
H H
N¨N
/
N
HN N0 0
102 BCIJ D 9.65 368
.---..õ-
n N N OH
H H
N¨N
/
N
HN N
=103 40 0
BCIJ D 11.67 378
H NON¨N
/
N
40 104 HN N CK D 13.77 316
0 OMe
F
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N
HN N
105BCG 11.61 385
oN/
N-N F 0
N
HN N
106 IBCGI E 13.09 343
NH2
N-N
N
HN N 0
107
N NH BCIJ D 10.29 338
H
N-N
N
HN N 0
108
NN BCIJ D 12.98 352
H
N-N
N
HN N 0
109 BCIJ E 12.82 381
NNH2
H H II
N-N 0
N
HN N NN 0
BCIJ 10.98 394
110
N-N H
N
HN N
111 BCE D 13.09 280
N-N
N
HN N
112 BCE D 13.12 280
N-N
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N
HN N
113 BCE D 13.91 342
N-N 401
N
HN N
114 IBCE D 11.38 362
SO2Me
N¨N
N
HN N
115 k BCG D 12.90 310
N-N
N
HN N
116 IBCG D 10.55 326
(:)0H
N¨N
N
HN N
117 BCE D 13.43 330
SMe
N¨N
N
HN N 40/
118 BCGK D 11.44 361
(:)0H
N
HN N
119 LK E 14.84 430
S-Nn(:)
N
HN N
120 CFK 14.12 354
¨1\1 0
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N
HN
121 S CK D 10.40 361
0/'
-1\1
N
HN N
122 5 BCE D 13.50 294
N-N
N
HN N
123 5 BCE E 15.88 308
N-N
N
HN
00H
124 N-N F BCFG D 10.48 457
(
-N
0-)
N
HN
125 N-N 0' \O BCFL D 12.20 526
c0
c-N
0-)
N
HN
126 N-N 0 BCF E 13.99 450
c-N
0-)
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N 1
I
HN N 0
127 BCE D 12.19 321
0
N¨N CN
\
N 1
I
HN N 0
128 BCEFL D 10.27 339
0
N¨N\ HN 0
N 1
I
HN N 0
129 OMe BC D 12.24 392
N¨N F
(
/SI-
0/ '0
N
HN N 10
130 H BCF E 14.62 355
N
N¨N F 0
/
N 1
I
HN 'N Si
N
131 BCEI D 12.21 332
-- 'NH
N¨N
\
N 1
I
HN N 0
132 n OMe BCF E 13.65 440
N¨N F
N/¨\N-
0 \¨
N 1
I
HN N 0
OMe
133 BCF E 13.69 454
N¨N / F
N/ NH
0 \
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N
I
HN N
134 OMe BCF C 0.87 440
N¨N
r-NNH
N\..õ)
0
N
HN
135 BCF D 12.88 407
N¨N
0
N
HN
136 BCF D 13.26 421
N¨N
0
N
HN
137 BCF D 11.31 464
N¨N 0
0
N
HN
138 BCF D 11.85 448
N¨N 0
N
HN
139 BCG D 13.73 356
C)
N¨N
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N
HN N
140 BCG D 13.89 356
N-N
N
HN N
141
BCG D 13.64 354
0
N-N
N
HN N
142 = BCG D 13.92 368
0
N-N
N
HN N 40/
143 BCF D 12.71 365
1\1<
N-N 0
N
HN N =
144 BCF D 12.49 365
N
N-N 0
N
HN N =
145 BCF D 12.66 365
N
N-N 0
N
HN N =
N
146 BCF 10.77 367
OH
N-N 0
N
HN N
147 BCF G 9.34 405
N-N
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N
HN N= r 0
148 n BCE G 9.46 419
N-N
O--NO
N
HN N= r .
H
N
149 n BCF G 8.64 448
N-N 0
O---NO
N
HN N= r 0
H
N
150 BCF G 8.79 462
N-N 0
----NO
0
N
HN Nr 0
0
151 BCFG D 12.48 441
N-N F
7-----\
---N
O })
N
HN Nr 0
0
152 BCFG D 12.86 455
N-N F
7-----\
---N
O })
N
HN N= r 0/
H
N
153 n BCF G 8.44 434
N-N 0
O.---NO
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N
HN N
154 BCH F 7.23 358
N-N F OH
N
HN N
155
BCG D 13.29 340
0
N-N
N
HN N
156 ij BCF G 8.55 349
V
N-N 0
N
HN N = 157ij BCF D 12.40 363
N-N 0
N
HN N
158 BCFG D 13.10 455
N-N
o
N
I
HN N
159 ) BCG 1.09 396
0-<F
N-N
N
HN N
160 BCF G 8.03 365
N-N
NH
0 \______
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N
HN N= r 40
s,NH2
161 BCF G 8.26 456
N-N 6, b
---- NO
0
N
HN N= r 40
162S'NH2
BCF G 7.69 458
N-N 6, b
----N7----\0
N
HN N= r 40
H
N
163 n BCF F 8.37 408
N-N 0
-----NH
0
N
HN N= r 0
H
N
164 BCF F 6.70 422
N-N 0
-----NH
0
N
HN N (00
165S'NH2
BCF G 7.83 416
N-N (3, \\0
-----NH
0
N
HN N 0 0
166 S'I\1)
BCFL G 8.51 486
N-N 00
---NH
0
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N
HN N
67r .
H
N
1 n s- o
N-N 6 BCFL F 8.33 486
"0
-----NH
O \______
N
HN Nr /00
168 n BCF G 8.22 379
N-N
-----NH
O \__
N
A
HN N 0
169 BCF G 8.19 415
N-N
S--NH
0
N
A
HN Nr 0/
170 n BCF G 8.53 455
N-N
O--NO
N
A
HN Nr 0 0
171 S'N)
BCFL G 8.43 528
N-N 00'
/----\
-----N
O \.......1)
N
A
HN N
72r 0
H
N
1 n s-
N-N d '0 0 BCFL G 8.24 528
S---/-%
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N
HN N= r 0
173 BCF F 8.13 457
N-N
----Nr----\
N
HN N= r 40
0
174 BCFG F 7.71 399
N-N F
-----NH
0
N
HN N= r 0
0
175 BCFG F 7.94 413
N-N F
-----NH
0
N
HN N= r 0
0
176 BCFG G 8.08 413
N-N F
-----NH
0 \______
N
HN N= r 40
177 n OH BCF G 8.27 371
N-N F
-----NH
0 \______
N
0 (C))
HN N= r
pi
178
6 0 BCFL G 8.73 526
N-N
----NO
0
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N
IS
HN H
179
N-N "
BCFL 8.56 526
00
NQ
N
HN
180 BCFG F 7.98 439
N-N
NQ0
N
HN
181 BCFG G 8.14 453
N-N
NQ0
N
HN
182 BCFG F 9.03 425
N-N
N
HN
183 BCFG F 8.00 439
N-N
N
HN N
184 BCG F 7.97 372
/N-N F 0
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N
HN N 5
185 BCDG G 8.32 356
0
N-N F
-----c
N
HN N 0
186 BC G 8.58 358
N-N 0=S
/ 6
N
HN N
187 5 0õ0
S BCEI G 8.39 373
N
H
N-N
/
N
HN N
188 5
NS BCEI G 8.62 387
H
N-N
/
N
HN N
189 5
S BCEI F 8.59 387
N
H
N-N
/
N
HN N 0
190 H BCF F 7.42 365
1\ln
N-N 0
/
N
HN N 0
191 H BCF G 7.41 365
N
N-N 0 =
/
N
HN N 0
192 BCH F 8.75 358
n Or
N-N F OH
/
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N
HN N 0
193 BCH F 7.20 358
0
n
N-N F OH
/
N
194 HN N 0
BCG F 8.40 356
n=0
N-N F
/
N
HN N 0 _
195 BCG G 8.42 356
0-
n
N-N F
/
N
HN N 40
196 n OH BCF G 8.37 397
N-N F
OS-NO
N
HN N .
197 n OH BCF G 8.56 411
N-N F
OS-NO
N
40 198 HN N BCG F 8.96 314
0
N-NH F
N
HN N 0
199 CN F 7.81 331
S' 0
)=N F
N
HN N i.
0-<
200 BCG G 8.36 356
n
N-N F
/
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N
HN N 0
201 H BCFG G 8.60 381
N....._õ,....0,--
n
N-N 0
/
N
HN N 0
202 n BCDG F 8.80 427
0
N_/N -N F
N
HN N 0
203 BCDG F 7.73 372
0
HO---v_p_N F
N
HN N 01
204 BCDG F 8.16 342
0
N-N F
--___/
N
HN N 0/
205 BCDG G 8.35 356
n 0
\21-N F
N
HN N 0
206
0 BCDG G 9.03 353
n
N-N F
NC-----/
N
HN N 0/
207
, 0
BCDG G 9.19 372
n
N-N F
N
HN N 0
208 0 BCDG G 8.81 388
N-N F
STh
HO OH
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N
HN N 0
209 0 BCDG F 8.81 388
N-N F
----\
HO OH
N
0
HN N F
210 BCE G 8.05 332
0
N-N F 1
/
N
HN N 40
211 BCE F 8.27 374
0
N-N 0=S
/ 6
N
HN N 40
212 o BCDG G 8.48 434
\o 11 N-N F
N
HN N (00 0\ /0
213
NS/ 40 BCEI F 8.74 421
n=
H
N-N
/
N
HN N 40
214 BCDG F 7.14 357
n 0
H2N N-N F
N
HN N 40
215 BCFG G 7.84 413
0 0
HN--/C/N_N F
N
HN N 0
216 BCFG F 9.07 455
07----\N o n0
F
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N
HN
217
0
BCDG G 7.91 386
F
HO
N
HN
218 0, //0 N
BCEI G
8.34 384
N-N
N
HNN0, //0
219 BCEI F
8.09 389
õ
N -OH
N-N
Biology Assays
Determination of the effect of the compounds according to the invention on
TYK2
The compounds of the present invention as described in the previous examples
were tested in a
KinobeadsTM assay as described for ZAP-70 (WO-A 2007/137867). Briefly, test
compounds
(at various concentrations) and the affinity matrix with the immobilized
aminopyrido-
pyrimidine ligand 24 were added to cell lysate aliquots and allowed to bind to
the proteins in
the lysate sample. After the incubation time the beads with captured proteins
were separated
from the lysate. Bound proteins were then eluted and the presence of TYK2 and
JAK2 was
detected and quantified using specific antibodies in a dot blot procedure and
the Odyssey
infrared detection system. Dose response curves for individual kinases were
generated and
IC50 values calculated. KinobeadsTM assays have been previously described (WO-
A
2007/137867; WO-A 2006/134056).
Protocols
Washing of affinity matrix
The affinity matrix was washed two times with 15mL of lx DP buffer containing
0.2% NP40
(IGEPAL CA-630, Sigma, #13021) and then resuspended in lxDP buffer containing
0.2%
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NP40 (3% beads slurry).
5xDP buffer: 250mM Tris-HC1 pH 7.4, 25% Glycerol, 7.5mM MgC12, 750mM NaC1, 5mM
Na3VO4; filter the 5xDP buffer through a 0.22[tm filter and store in aliquots
at -80 C. The
5xDP buffer is diluted with H20 to lxDP buffer containing 1mM DTT and 25mM
NaF.
Preparation of test compounds
Stock solutions of test compounds were prepared in DMSO. In a 96 well plate
304, solution
of diluted test compounds at 5mM in DMSO were prepared. Starting with this
solution a 1:3
dilution series (9 steps) was prepared. For control experiments (no test
compound) a buffer
containing 2% DMSO was used.
Cell culture and preparation of cell lysates
Molt4 cells (ATCC catalogue number CRL-1582) and Ramos cells (ATCC catalogue
number
CRL-1596) were grown in 1L Spinner flasks (Integra Biosciences, #182101) in
suspension in
RPMI 1640 medium (Invitrogen, #21875-034) supplemented with 10% Fetal Bovine
Serum
(Invitrogen) at a density between 0.15 x 106 and 1.2 x 106 cells/mL. Cells
were harvested by
centrifugation, washed once with 1 x PBS buffer (Invitrogen, #14190-094) and
cell pellets
were frozen in liquid nitrogen and subsequently stored at -80 C. Cells were
homogenized in a
Potter S homogenizer in lysis buffer: 50mM Tris-HC1, 0.8% NP40, 5% glycerol,
150mM
NaC1, 1.5mM MgC12, 25 mM NaF, 1mM sodium vanadate, 1mM DTT, pH 7.5. One
complete
EDTA-free tablet (protease inhibitor cocktail, Roche Diagnostics, 1873580) per
25mL buffer
was added. The material was dounced 10 times using a mechanized POTTER S,
transferred to
50mL falcon tubes, incubated for 30 minutes on ice and spun down for 10
minutes at 20,000 g
at 4 C (10,000 rpm in Sorvall SLA600, precooled). The supernatant was
transferred to an
ultracentrifuge (UZ)-polycarbonate tube (Beckmann, 355654) and spun for lhour
at 100.000g
at 4 C (33.500 rpm in Ti50.2, precooled). The supernatant was transferred
again to a fresh
50mL falcon tube, the protein concentration was determined by a Bradford assay
(BioRad) and
samples containing 50mg of protein per aliquot were prepared. The samples were
immediately
used for experiments or frozen in liquid nitrogen and stored frozen at -80 C.
Dilution of cell lysate
Cell lysate (approximately 50mg protein per plate) was thawed in a water bath
at room
temperature and then stored on ice. To the thawed cell lysate lxDP 0.8% NP40
buffer
containing protease inhibitors (1 tablet for 25mL buffer; EDTA-free protease
inhibitor
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cocktail; Roche Diagnostics 1873580) was added in order to reach a final
protein
concentration of 10mg/mL total protein. The diluted cell lysate was stored on
ice. Mixed
Molt4/Ramos lysate was prepared by combining one volume of Molt4 lysate and
two volumes
of Ramos lysate (ratio 1:2).
Incubation of lysate with test compound and affinity matrix
To a 96 well filter plate (Multiscreen HTS, BV Filter Plates, Millipore
#MSBVN1250) were
added per well: 100pL affinity matrix (3% beads slurry), 3 pL of compound
solution, and 50pL
of diluted lysate. Plates were sealed and incubated for 3 hours in a cold room
on a plate shaker
(Heidolph tiramax 1000) at 750rpm. Afterwards the plate was washed 3 times
with 230pL
washing buffer (1xDP 0.4% NP40). The filter plate was placed on top of a
collection plate
(Greiner bio-one, PP-microplate 96 well V-shape, 65120) and the beads were
then eluted with
20pL of sample buffer (100 mM Tris, pH 7.4, 4% SDS, 0.00025% bromophenol blue,
20%
glycerol, 50 mM DTT). The eluate was frozen quickly at -80 C and stored at -20
C.
Detection and quantification of eluted kinases
The kinases in the eluates were detected and quantified by spotting on
nitrocellulose
membranes and using a first antibody directed against the kinase of interest
and a fluorescently
labelled secondary antibody (anti-rabbit IRDyeTM antibody 800 (Licor, # 926-
32211). The
Odyssey Infrared Imaging system from LI-COR Biosciences (Lincoln, Nebraska,
USA) was
operated according to instructions provided by the manufacturer (Schutz-
Geschwendener et
at., 2004. Quantitative, two-color Western blot detection with infrared
fluorescence.
Published May 2004 by LI-COR Biosciences, www.licor.com).
After spotting of the eluates the nitrocellulose membrane (BioTrace NT; PALL,
#BTNT3OR)
was first blocked by incubation with Odyssey blocking buffer (LICOR, 927-
40000) for 1 hour
at room temperature. Blocked membranes were then incubated for 16 hours at the
temperature
shown in table 8 with the first antibody diluted in Odyssey blocking buffer
(LICOR #927-
40000). Afterwards the membrane was washed twice for 10 minutes with PBS
buffer
containing 0.2% Tween 20 at room temperature. The membrane was then incubated
for 60
minutes at room temperature with the detection antibody (anti-rabbit IRDyeTM
antibody 800,
Licor, # 926-32211) diluted in Odyssey blocking buffer (LICOR #927-40000).
Afterwards the
membrane was washed twice for 10 minutes each with 1 x PBS buffer containing
0.2% Tween
20 at room temperature. Then the membrane was rinsed once with PBS buffer to
remove
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WO 2012/062704 94 PCT/EP2011/069553
residual Tween 20. The membrane was kept in PBS buffer at 4 C and then scanned
with the
Odyssey instrument. Fluorescence signals were recorded and analysed according
to the
instructions of the manufacturer.
Table 8: Sources and dilutions of antibodies
Target kinase Primary antibody Temperature Secondary antibody
(dilution) of primary (dilution)
incubation
Jak2 Cell signaling #3230 Room Licor anti-rabbit 800
(1:100) temperature (1:15000)
TYK2 Upstate #06-638 Room Licor anti-rabbit 800
(1:1000) temperature (1:5000)
Results
Table 9: Inhibition values (IC50 in [tM) as determined in the KinobeadsTM
assay
Activity level: A < 0.1 [tM; 0.1 [tM < B < 1 [tM; 1 [tM < C < 10[tM; D >1
O[tM).
Example No. TYK2 IC50 (04) JAK2 ICso
1
2
3
4
6
7
8 A
9 A
A
11 A
12 A
13 A
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PCT/EP2011/069553
14 A
15 A
16 A
17
18 A
19
Furthermore, the following Examples inhibited TYK2 with activity level A and
JAK2 with
activity level B: 36, 37, 49, 50, 51, 53, 54, 58, 60, 61, 71, 72, 75, 76, 77,
79, 83, 84, 88, 89,
91, 93, 94, 95, 96, 106, 114, 116, 117, 118, 120, 124, 137, 144, 146, 152,
154, 158, 159, 166,
171, 175, 176, 178, 183, 184, 185, 187, 191, 192, 193, 195, 198, 202, 203,
204, 207, 208, 209,
216, 218, 219.
Furthermore, the following Examples inhibited TYK2 with activity level A and
JAK2 with
activity level C: 29, 35, 56, 59, 62, 64, 67, 85, 90, 92, 97, 98, 111, 115,
121, 122, 123, 125,
126, 129, 132, 133, 134, 135, 136, 138, 147, 148, 149, 150, 151, 153, 160,
161, 162, 163, 164,
167, 168, 172, 174, 179, 180, 181, 182, 188, 189, 190, 196, 206, 214, 215.
All other examples inhibited TYK2 with activity level B and typically
inhibited JAK2 with
activity level C or D.
