Title of Invention

PYRAZINES

Abstract The present invention relates to compounds useful as inhibitors of protein kinases, such as SYK, JAK-3, or GSK-3 protein kinases. These compounds have the general formula I: or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, X1, and X2 are as defined herein. The invention also provides processes for making said compounds, pharmaceutically acceptable compositions comprising said compounds, and methods of using the compositions in the treatment of various diseases, conditions, or disorders.
Full Text PYRAZINES
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates to compounds useful as inhibitors of protein kinases.
The invention also provides pharmaceutically acceptable compositions comprising the
compounds of the invention and methods of using the compositions in the treatment of
various disorders.
BACKGROUND OF THE INVENTION
[0002] The search for new therapeutic agents has been greatly aided in recent years by a •
better understanding of the structure of enzymes and other biomolecules associated with
diseases. One important class of enzymes that has been the subject of extensive study is
protein kinases.
[0003] Protein kinases constitute a large family of structurally related enzymes that are
responsible for the control of a variety of signal transduction processes within the cell. (See,
Hardie, G. and Hanks, S. The Protein Kinase Facts Book, I and II, Academic Press, San
Diego, CA: 1995). Protein kinases are thought to have evolved from a common ancestral
gene due to the conservation of their structure and catalytic function. Almost all kinases
contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into
families by the substrates they phosphorylate (e.g., protein-tyrosine, protem-serme/threonine,
lipids, etc.). Sequence motifs have been identified that generally correspond to each of these
kinase families (See, for example, Hanks, S.K., Hunter, T., FASEB J. 1995, 9, 576-596;
Knighton et al, Science 1991, 253,407-414; Hiles et al, Cell 1992, 70,419-429; Kunz et al,
Celll993, 73, 585-596; Garcia-Bustos etal, EMBOJ. 1994,13,2352-2361).
[0004] In general, protein kinases mediate intracellular signaling by effecting a
phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a
signaling pathway. These phosphorylation events act as molecular on/off switches that can
modulate or regulate the target protein biological function. These phosphorylation events are
ultimately triggered in response to a variety of extracellular and other stimuli. Examples of
such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat
shock, ultraviolet radiation, bacterial endotoxin, and H2O2), cytokines (e.g., interleukin-1 (IL-
1) and tumor necrosis factor a (TNF-a)), and growth factors (e.g., granulocyte macrophage-
colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF)). An extracellular
stimulus may affect one or more cellular responses related to cell growth, migration,
differentiation, secretion of hormones, activation of transcription factors, muscle contraction,
glucose metabolism, control of protein synthesis, and regulation of the cell cycle.
[0005] Many diseases are associated with abnormal cellular responses triggered by
protein kinase-mediated events as described above. These diseases include, but are not
limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases,
, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and
asthma, Alzheimer's disease, and hormone-related diseases. Accordingly, there has been a
substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as
therapeutic agents.
[0006] Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase
comprised of a and ß isoforms that are each encoded by distinct genes [Coghlan et al.,
Chemistry & Biology 2000, 7, 793-803; and Kim and Kimmel, Curr. Opinion Genetics Dev.,
2000 10, 508-514]. GSK-3 has been implicated in various diseases including diabetes,
Alzheimer's disease, CNS disorders such as manic depressive disorder and
neurodegenerative diseases, and cardiomyocyte hypertrophy [PCT Application Nos.: WO
99/65897 and WO 00/38675; and Haq et al, J. Cell Biol. 2000, 151, 117-130]. These
diseases are associated with the abnormal operation of certain cell signaling pathways in
which GSK-3 plays a role. GSK-3 has been found to phosphorylate and modulate the activity
of a number of regulatory proteins. These proteins include glycogen synthase, which is the
rate limiting enzyme necessary for glycogen synthesis, the microtubule associated protein
Tau, the gene transcription factor ß-catenin, the translation initiation factor elF2B, as well as
ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-myc, omyb, CREB, and CEPBa These
diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation,
differentiation, and development.
[0007] In a GSK-3 mediated pathway that is relevant for the treatment of type II diabetes,
insulin-induced signaling leads to cellular glucose uptake and glycogen synthesis. Along this
pathway, GSK-3 is a negative regulator of the insulin-induced signal. Normally, the presence
of insulin causes inhibition of GSK-3 mediated phosphorylation and deactivation of glycogen
synthase. The inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake.
[Klein et al, PNAS1996,93, 8455-8459; Cross et al, Biochem. J. 1994,303,21-26); Cohen,
Biochem. Soc. Trans. 1993, 21, 555-567; and Massillon et al, Biochem J. 1994, 299, 123-
128]. However, in a diabetic patient, where the insulin response is impaired, glycogen
synthesis and glucose uptake fail to increase despite the presence of relatively high blood
levels of insulin. This leads to abnormally high blood levels of glucose with acute and long-
term effects that may ultimately result in cardiovascular disease, renal failure and blindness.
In such patients, the normal insulin-induced inhibition of GSK-3 fails to occur. It has also
been reported that in patients with type II diabetes, GSK-3 is overexpressed [see, PCT
Application: WO 00/38675]. Therapeutic inhibitors of GSK-3 are therefore potentially useful
for treating diabetic patients suffering from an impaired response to insulin.
[0008] GSK-3 activity is associated with Alzheimer's disease. This disease is
characterized by the well-known P-arnyloid peptide and the formation of intracellular
neurofibrillary tangles.
[0009] Amyloid-ß plagues, formed by the aggregation of these |3-amyloid peptides, are
one of the pathological hallmarks of Alzheimer's disease. It has been shown that GSK-3 a
inhibition reduces amyloid-ß peptides in an animal model of Alzheimer's disease. See pages
435, 438. Phiel et. al., Nature 423, 435-439 (2003). Mice over-expressing amyloid precursor
protein (APP) treated with lithium (a GSK-3 a inhibitor) over a three-week period showed
over a 50% decrease in amyloid-ß peptide tissue levels.
[0010] The neurofibrillary tangles contain hyperphosphorylated Tau protein, in which
Tau is phosphorylated on abnormal sites. GSK-3 is known to phosphorylate these abnormal
sites in cell and animal models. Furthermore, inhibition of GSK-3 has been shown to prevent
hyperphosphorylation of Tau in cells [Lovestone et al., Current Biology 1994, 4, 1077-86;
and Brownlees et al, Neuroreport 1997, 8, 3251-55]. Therefore, GSK-3 activity promotes
generation of the neurofibrillary tangles and the progression of Alzheimer's disease.
[0011] Another substrate of GSK-3 is P-catenin, which is degradated after
phosphorylation by GSK-3. Reduced levels of p-catenin have been reported in schizophrenic
patients and have also been associated with other diseases related to increase in neuronal cell
death [Zhong et al, Nature 1998, 395, 698-702; Takashima et al, PNAS 1993, 90, 7789-93;
and Pei .et al, J. Neuropathol. Exp 1997,56,70-78].
[0012] GSK-3 activity is associated with stroke [Wang et al, Brain Res 2000, 859, 381-
5; Sasaki et al, Neurol Res 2001, 23, 588-92; Hashimoto et al, J. Biol. Chem 2002, 277,
32985-32991].
[0013] The Janus kinases (JAK) are a family of tyrosine kinases consisting of JAK1,
JAK2, JAK3 and TYK2. The JAKs play a critical role in cytokine signaling. The down-
stream substrates of the JAK family of kinases include the signal transducer and activator of
transcription (STAT) proteins. JAK/STAT signaling has been implicated in the mediation of
many abnormal immune responses such as allergies, asthma, autoimmune diseases such as
transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis
as well as in solid and hematologic malignancies such as leukemias and lymphomas. The
pharmaceutical intervention in the JAK/STAT pathway has been reviewed [Frank Mot Med.
1999, J, 432-456 and Seidel et al, Oncogene 2000,19, 2645-2656].
[0014] JAK1, JAK2, and TYK2 are ubiquitously expressed, while JAK3 is
predominantly expressed in hematopoietic cells. JAK3 binds exclusively to the common
cytokine receptor gamma chain (yc) and is activated by IL-2, IL-4, 1L-7, JX-9, and IL-15.
The proliferation and survival of murine mast cells induced by IL-4 and EL-9 have, in fact,
been shown to be dependent on JAK3- and %- signaling [Suzuki et al, Blood 2000,96, 2172-
2180].
[0015] Cross-linking of the high-affinity immunoglobulin (Ig) E receptors of sensitized
mast cells leads to a release of proinflammatory mediators, including a number of vasoactive
cytokines resulting in acute allergic, or immediate (type I) hypersensitivity reactions [Gordon
et al, Nature 1990, 346, 274-276 and Galli, N. Engl -J. Med. 1993, 328, 257-265]. A crucial
role for JAK3 in IgE receptor-mediated mast cell responses in vitro and in vivo has been
established [Malaviya et al, Biochem. Biophys. Res. Commun. 1999, 257, 807-813]. In
addition, the prevention of type I hypersensitivity reactions, including anaphylaxis, mediated
by mast cell-activation through inhibition of JAK3 has also been reported [Malaviya et al, J.
Biol. Chem. 1999 274, 27028-27038]. Targeting mast cells with JAK3 inhibitors modulated
mast cell degranulation in vitro and prevented IgE receptor/antigen-mediated anaphylactic
reactions in vivo.
[0016] A recent study described the successful targeting of JAK3 for immunosuppression
and allograft acceptance. The study demonstrated a dose-dependent survival of Buffalo heart
allograft in Wistar Furth recipients upon administration of inhibitors of JAK3 indicating the
possibility of regulating -unwanted immune responses in graft versus host disease [Kirken,
Transpl. Proc. 2001, 33, 3268-3270].
[0017] IL-4-mediated STAT-phosphorylation has been implicated as the mechanism
involved in early and late stages of rheumatoid arthritis (RA). Up-regulation of
proinflammatory cytokines in RA synovium and synovial fluid is a characteristic of the
disease. It has been demostrated that DL-4-mediated activation of IL-4/STAT pathway is
mediated through the Janus Kinases (JAK 1 & 3) and that IL-4-associated JAK kinases are
expressed in the RA synovium [Muller-Ladner et al, J. Immunol 2000,164, 3894-3901].
[0018] Familial amyotrophic lateral sclerosis (FALS) is a fatal neurodegenerative
disorder affecting about 10% of ALS patients. The survival rates of FALS mice were
increased upon treatment with a JAK3 specific inhibitor. This suggested that JAK3 plays a
role in FALS [Trieu et al, Biochem. Biophys. Res. Commun. 2000,267, 22-25].
[0019] Signal transducer and activator of transcription (STAT) proteins are activated by,
among others, the JAK family kinases. Results from a recent study suggested the possibility
of intervention in the JAK/STAT signaling pathway by targeting JAK family kinases with
specific inhibitors for the treatment of leukemia [Sudbeck et al, Clin. Cancer Res. 1999, 5,
1569-1582]. JAK3 specific compounds were shown to inhibit the clonogenic growth of
JAK3-expressing cell lines DAUDI, RAMOS, LC1-19, NALM-6, MOLT-3 and HL-60.
[0020] In animal models, TEL/JAK2 fusion proteins have induced myeloproliferative
disorders and in hematopoietic cell lines, and introduction of TEL/JAK2 resulted in
activation of STAT1, STAT3, STATS, and cytokine-independent growth [Schwaller et al,
EMBOJ. 1998,17, 5321-5333].
[0021] Inhibition of JAK3 and TYK2 abrogated tyrosine phosphorylation of STAT3, and
inhibited cell growth of mycosis fungoides, a form of cutaneous T-cell lymphoma. These
results implicated JAK family kinases in the constitutively activated JAK/STAT pathway
that is present in mycosis fungoides [Nielsen et al, Proc. Nat. Acad. Set U.SA. 1997, 94,
6764-6769]. Similarly, STAT3, STAT5, JAK1 and JAK2 were demonstrated to be
constitutively activated in mouse T-cell lymphoma characterized initially by LCK over-
expression, thus further implicating the JAK/STAT pathway in abnormal cell growth [Yu et
al, J. Immunol. 1997,159, 5206-5210]. In addition, IL-6-mediated STAT3 activation was
blocked by an inhibitor of JAK, leading to sensitization of myeloma cells to apoptosis
[Catlett-Falcone et al, Immunity 1999,10, 105-115].
[0022] Syk is a tyrosine kinase that plays a critical role in FcsRI mediated mast cell
degramilation and eosinophil activation. Accordingly, Syk kinase is implicated in various
allergic disorders, in particular asthma. It has been shown that Syk binds to the
phosphorylated gamma chain of the FcsRI receptor via N-terminal SH2 domains and is
essential for downstream signaling [Taylor et al, Mol. Cell. Biol. 1995,15,4149].
[0023] Inhibition of eosinophil apoptosis has been proposed as a key mechanism for the
development of blood and tissue eosinophilia in asthma. EL-5 and GM-CSF are upregulated
in asthma and are proposed to cause blood and tissue eosinophilia by inhibition of eosinophil
apoptosis. Inhibition of eosinophil apoptosis has been proposed as a key mechanism for the
development of blood and tissue eosinophilia in asthma. It has been reported that Syk kinase
is required for the prevention of eosinophil apoptosis by cytokines (using antisense)[Yousefi
et al, J. Exp. Med. 1996, 253,1407].
[0024] The role of Syk in FcyR dependent and independent response in bone marrow
derived macrophages has been determined by using irradiated mouse chimeras reconstituted
with fetal liver cells from Syk -/- embryos. Syk deficient macrophages were defective in
phagocytosis induced by FcyR but showed normal phagocytosis in response to complement
[Kiefer et al, Mol. Cell. Biol. 1998,18, 4209]. It has also been reported that aerosolized Syk
antisense suppresses Syk expression and mediator release from macrophages [Stenton et al,
J. Immunology 2000,164, 3790].
[0025] Accordingly, there is a great need to develop compounds useful as inhibitors of •
protein kinases. In particular, it would be desirable to develop compounds that are useful as
inhibitors of SYK, JAK-3, or GSK-3, particularly given the inadequate treatments currently
available for the majority of the disorders implicated in their activation.
SUMMARY OF THE INVENTION
[0026] It has now been found that compounds of this invention, and pharmaceutically
acceptable compositions thereof, are effective as inhibitors of protein kinases. In certain
embodiments, these compounds are effective as inhibitors of SYK, JAK-3, or GSK-3, protein
kinases. These compounds have the general formula I:

each occurrence of R is independently selected from hydrogen or an optionally
substituted C1-6 aliphatic group; and each occurrence of R' is independently hydrogen or an
optionally substituted group selected from C1-8 aliphatic; a 5-6 membered monocyclic or an 8-
10 membered bicyclic aryl group having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur; a 3-7-membered saturated or partially unsaturated monocyclic
ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-
10-membered saturated or partially unsaturated bicyclic ring system having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or wherein R and R' taken together,
or two occurrences of R' taken together, form a 3-8 membered cycloalkyL heterocyclyl, aryl,
or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur;
each independent occurrence of Q is a bond or is a C1-C6 alkylidene chain wherein up
to two methylene units of Q are optionally replaced by -C(O)-, -C(S)-, -C(O)C(O)-, -CONR-,
-CONRNR-, -CO2-, -OC(O)-, -NRCO2-, -O-, -NRCONR-, -OC(O)NR-, -NRNR, -NRCO-,
-S-, -SO-, -SO2-, -NR-, -SO2NR-, or -NRSO2-; and each occurrence of Rx is independently
R', halogen, NO2, or CN;
X1 is OO, S=O, SO2, or C=NR;
X2 is NR, S, O, or C(R)2; and
R3 is an optionally substituted group selected from: C1-6 aliphatic; a 5-6 membered
monocyclic or an 8-10 membered bicyclic aryl group having 0-5 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; a 3-8-membered saturated or partially unsaturated
monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur; or an 8-10-membered saturated or partially unsaturated bicyclic ring system having 0-
5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R3 is
optionally substituted with m independent occurrences of Z-RY, wherein m is 0-5; each
independent occurrence of Z is a bond or is a C1-C6 alkylidene chain, wherein up to two
methylene units of Z are optionally replaced by -C(O)-, -C(O)C(O)-, -CONR-, -CONRNR-,
-CO2-, -OC(O)-, -NRCO2-, -O-, -NRCONR-, -OC(O)NR-, -NRNR, -NRCO-, -S-, -SO-,
-SO2-, -NR-, -SO2NR-, or -NRSO2-; and each occurrence of RY is independently R', halogen,
NO2, or CN.
[0030] In certain embodiments, for compounds described directly above:
a) when X1 is CO, then R2 is not C(S)NH2 or CN;
b) when X1 is CO, X2 is NH, and R2 is 3,4-OMe-phenyl, then R3 is not n-butyl;
c) when X1 is CO and X2 is CH2, then R1 and R2 are not both hydrogen;
d) when X1 is SO2 and X2 is O, then R1 and R2 are not both hydrogen;
e) when R1 and R2 are both hydrogen, X1 is CO, and X2 is SO2 or NH, then R3 is not
unsubstituted benzyl, phenyl, or cyclohexyl;
f) when R1 and R2 are each methyl, then:
i) when X1 is CO and X2 is NH, then R3 is not unsubstituted cyclohexyl or
unsubstituted benzyl; and
ii) when X1 is CO and X2 is CH2, then R3 is not unsubstituted benzyl;
g) when R1 and R2, taken together, are unsubstituted phenyl, then:
i) when X1 is CO and X2 is CH2, then R3 is not substituted furyl, 2-Cl-phenyl,
3,5-dimethyl-2-benzofuranyl, 3,7-dimemyl-2-benzofuranyl, or 4-OMe-phenyl;
ii) when X1 is CO and X2 is NH, then R3 is not 2,4-dichloro-phenyl, 4-C1-
pheriyl, 4-Me-phenyl, or unsubstituted phenyl, cyclohexyl, or benzyl; and
iii) when X1 is CO and X2 is CHOH, then R1 is not unsubstituted phenyl or
-CHOHCH2OH;
h) when R1 and R2, taken together, are unsubstituted cyclohexyl, then:
i) when X1 is CO and X2 is CH2, then R3 is not unsubstituted phenyl; and
ii) when X1 is CO and X2 is NH, then R3 is not unsubstituted benzyl or
cyclohexyl; and
i) when R1 and R2, taken together, are 6,7-Me-phenyl, X1 is CO, and X2 is NH, then
R3 is not n-hexyl, n-butyl, n-propyl, or -CH2CH=CH2.
[0031] In other embodiments, for compounds described directly above:
a) when X1 is CO, then R2 is not C(S)NH2 or CN;
b) when X1 is CO, X2 is NH, and R2 is 3,4-OMe-phenyl, then R3 is not n-butyl;
c) when X1 is CO and X2 is CH2, then R1 and R2 are not both hydrogen;
d) when Xj is SO2 and X2 is O, then R1 and R2 are not both hydrogen;
e) when R1 and R2 are both hydrogen, X1 is CO, and X2 is SO2 or NH, then R3 is not
unsubstituted benzyl, phenyl, or cyclohexyl;
f) when R1 and R2 are each methyl, then:
i) when X1 is CO and X2 is NH, then R3 is not unsubstituted cyclohexyl or
unsubstituted benzyl; and
ii) when X1 is CO and X2 is CH2, then R3 is not unsubstituted benzyl;
g) when R1 and R2, taken together, are unsubstituted phenyl, then:
i) when X1 is CO and X2 is CH, then R3 is not unsubstituted phenyl or OH;
ii) when X1 is CO and X2 is CH2, then R3 is not methyl, unsubstituted phenyl,
substituted furyl, 2-Cl-phenyl, 3,5-dimethyl-2-benzofuranyl, 3,7-dimethyl-
2-benzofuranyl, or 4-OMe-phenyl;
iii) when X1 is CO and X2 is NH, then R3 is not methyl, -C(O)CH3,
C(O)0(Ci.3alkyl), C(O)C(O)OH, C(O)C(O)0(C1-3alkyl), unsubstituted
phenyl, cyclohexyl, benzyl, substituted benzofuranyl, 2,4-dichloro-phenyl,
4-Cl-phenyl, or 4-Me-phenyl;
iv) when X1 is CO and X2 is NMe, then R3 is not methyl;
v) when X1 is CO and X2 is O, then R3 is not methyl;
vi) when X1 is CO and X2 is CHOH, then R1 is not unsubstituted phenyl or
-CHOHCH2OH;
h) when R1 and R2, taken together, are unsubstituted cyclohexyl, then:
i) when X1 is CO and X2 is CH2, then R3 is not unsubstituted phenyl;
ii) when X1 is CO and X2 is NH, then R3 is not unsubstituted benzyl or
cyclohexyl; and
i) when X1 is CO and X2 is NH, then:
i) when R1 and R2, taken together, are 6,7-Me-phenyl, then R3 is not n-hexyl,
n-butyl, n-propyl, -CH2CH=CH2, -CH=N-CH2CH=CH2, C(=O)NR,
C(=O)OR wherein R is H or C1-3 alkyl;
ii) when R1 and R2, taken together, are 6-NHAc-7-Me-phenyl, then R3 is not
-C(=O)CH3;
iii) when R1 and R2, taken together, are 6,7-OMe-phenyl, then R3 is not
C(O)C(O)OH or C(O)C(O)0(Ci.3alkyl);
iv) when R1 and R2, taken together, are substituted pyrirnidine, then R3 is
not -C(=O)CH3;
j) when X1 is CO and X2 is O, then:
i) when R1 and R2, taken together, are 6,7-Cl-phenyl, then R3 is not methyl
or-CH2CH=CH2;
ii) when R1 and R2, taken together, are 6-NO2-7-F-phenyl, then R3 is not
methyl.
[0032] 2. Compounds and Definitions:
[0033] Compounds of this invention include those described generally above, and are
further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the
following definitions shall apply unless otherwise indicated. For purposes of this invention,
the chemical elements are identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles
of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University
Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.:
Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of
which are hereby incorporated by reference.
[0034] As described herein, compounds of the invention may optionally be substituted
with one or more substituents, such as are illustrated generally above, or as exemplified by
particular classes, subclasses, and species of the invention. It will be appreciated that the
phrase "optionally substituted" is used interchangeably with the phrase "substituted or
unsubstituted." La general, the term "substituted", whether preceded by the term "optionally"
or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a
specified substituent. Unless otherwise indicated, an optionally substituted group may have a
substituent at each substitutable position of the group, and when more than one position in
any given structure may be substituted with more than one substituent selected from a
specified group, the substituent may be either the same or different at every position.
Combinations of substituents envisioned by this invention are preferably those that result in
the formation of stable or chemically feasible compounds. The term "stable", as used herein,
refers to compounds that are not substantially altered when subjected to conditions to allow
for their production, detection, and preferably their recovery, purification, and use for one or
more of the purposes disclosed herein. In some embodiments, a stable compound or
chemically feasible compound is one that is not substantially altered when kept at a
temperature of 40°C or less, in the absence of moisture or other chemically reactive
conditions, for at least a week.
[0035] The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain
(i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is
completely saturated or that contains one or more units of unsaturation, or a monocyclic
hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more
units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle"
"cycloaliphatic" or "cycloalkyl"), that has a single point of attachment to the rest of the
molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms.
In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other
embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other
embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other
embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments,
"cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C8 hydrocarbon
or bicyclic C8-C12 hydrocarbon that is completely saturated or that contains one or more units
of unsaruration, but which is not aromatic, that has a single point of attachment to the rest of
the molecule wherein any individual ring in said bicyclic ring system has 3-7 members.
Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or
unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl,
(cycloalkenyl)alkyl or (cycloalkyl)atkenyl.
[0036] The term "heteroaHphatic", as used herein, means aliphatic groups wherein one or
two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen,
phosphorus, or silicon. Heteroaliphatic groups may be substituted or unsubstituted, branched
or unbranched, cyclic or acyclic, and include "heterocycle", "heterocyclyl",
"heterocycloaliphatic", or "heterocyclic" groups.
[0037] The term "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic"
as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which
one or more ring members are an independently selected heteroatom. In some embodiments,
the "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" group has three to
fourteen ring members in which one or more ring members is a heteroatom independently
selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3
to 7 ring members.
[0038] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen,
phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or
silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a
heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or
NR+ (as in N-substituted pyrrolidinyl)).
[0039] The term "unsaturated", as used herein, means that a moiety has one or more units
of unsaruration.
[0040] The term "alkoxy", or "thioalkyl", as used herein, refers to an alkyl group, as
previously defined, attached to the principal carbon chain through an oxygen ("alkoxy") or
sulfur ("thioalkyl") atom.
[0041] The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" means alkyl, alkenyl or
alkoxy, as the case may be, substituted with one or more halogen atoms. The term "halogen"
means F, C1, Br, or I.
[0042] The term "aryl" used alone or as part of a larger moiety as in "aralkyl",
"aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic, and tricyclic ring systems
having a total of five to fourteen ring members, wherein at least one ring in the system is
aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl"
may be used interchangeably with the term "aryl ring". The term "aryl" also refers to
heteroaryl ring systems as defined hereinbelow.
[0043] The term '"heteroaryl", used alone or as part of a larger moiety as in
"heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic, and tricyclic ring
systems having a total of five to fourteen ring members, wherein at least one ring in the
system is aromatic, at least one ring in the system contains one or more heteroatoms, and
wherein each ring in the system contains 3 to 7 ring members. The term "heteroaryl" may be
used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".
[0044] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl
(including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more
substituents. Suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl
group are selected from halogen; -R°; -OR°; -SR°; 1,2-methylenedioxy, 1,2-ethylenedioxy;
phenyl (Ph) optionally substituted with R°; -O(Ph) optionally substituted with R°;
-(CH2)i-2(Ph), optionally substituted with R°; -CH=CH(Ph), optionally substituted with R°;
-NO2; -CN; -N(R°)2; -NR°C(O)R°; -NR°C(S)R°; -NR°C(O)N(R°)2; -NR°C(S)N(R°)2;
-NR°CO2R°; -NR°NR°C(O)R°; -NR°NR°C(O)N(R°)2; -NR°NR°CO2R0; -C(O)C(O)R°;
-C(O)CH2C(O)R°; -CO2R°; -C(O)R°; -C(S)R°; -C(O)N(R°)2; -C(S)N(R°)2; -OC(O)N(R°)2;
-OC(O)R°; -C(O)N(OR°) R°; -C(NOR°) R°; -S(O)2R°; -S(O)3R°; -SO2N(R°)2; -S(O)R°; -
NR°SO2N(R°)2; -NR°SO2R°; -N(OR°)R°; -C(=NH)-N(R°)2; or -(CH2)0-2NHC(O)R° wherein
each independent occurrence of R° is selected from hydrogen, optionally substituted C1-4
aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or
-CH2(Ph), or, notwithstanding the definition above, two independent occurrences of R°, on
the same substituent or different substituents, taken together with the atom(s) to which each
R° group is bound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-
membered cycloalkyl ring having 0-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur. Optional substituents on the aliphatic group of R° are selected from NH2,
NH(C1-4aliphatic), N(C1-4aliphatic)2, halogen, C1-4aliphatic, OH, O(C1-4aliphatic), NO2, CN,
CO2H, CO2(C1-4aliphatic), 0(haloC1-4 aliphatic), or haloC1-4aliphatic, wherein each of the
foregoing C1-4aliphatic groups of R° is unsubstituted.
[0045] An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may
contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic
or heteroaliphatic group, or of a non-aromatic heterocyclic ring are selected from those listed
above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the
following: =O, =S, =NNHR*, =NN(R*)2, =NNHC(O)R*, =NNHCO2(alkyl),
=NNHSO2(alkyl), or =NR , where each R is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic. Optional substituents on the aliphatic group of R are
selected from NH2, NH(C1-4 aliphatic), N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, OH, 0(C1-4
aliphatic), NO2, CN, CO2H, CO2(C1-4 aliphatic), O(halo C1-4 aliphatic), or halo(C1-4 aliphatic),
wherein each of the foregoing C1-4aliphatic groups of R is unsubstituted.
[0046] Optional substituents on the nitrogen of a non-aromatic heterocyclic ring are
selected from -R+, -N(R+)2, -C(O)R+, -CO2R+, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+,
-SO2N(R% -C(=S)N(R+)2, -C(=NH)-N(R4)2, or -NR+SO2R+; wherein R+ is hydrogen, an
optionally substituted C1-6 aliphatic, optionally substituted phenyl, optionally substituted
-O(Ph), optionally substituted -CH2(Ph), optionally substituted -(CH2)i-2(Ph); optionally
substituted -CH=CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring
having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or,,
notwithstanding the definition above, two independent occurrences of R+, on the same
substituent or different substituents, taken together with the atom(s) to which each R+ group
is bound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered
cycloalkyl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur. Optional substituents on the aliphatic group or the phenyl ring of R+ are selected from
NH2, NH(C1-4 aliphatic), N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, OH, 0(C1-4 aliphatic),
NO2, CN, CO2H, CO2(C1-4 aliphatic), 0(halo C1-4 aliphatic), or halo(C1-4 aliphatic), wherein
each of the foregoing C1-4aliphatic groups of R+ is unsubstituted.
[0047] As described herein, a bond drawn from a substituent to the center of one ring
within a multiple-ring system (as shown below), represents substitution of the substituent at
any substitutable position in any of the rings within the multiple ring system. For example,
Figure a represents possible substitution in any of the positions shown in Figure b.

[0048] The term "alkylidene chain" refers to a straight or branched carbon chain that may
be fully saturated or have one or more units of unsaturation and has two points of attachment
to the rest of the molecule.
[0049] As detailed above, in some embodiments, two independent occurrences of R° (or
R+, or any other variable similarly defined herein), are taken together together with the
atom(s) to which each variable is bound to form a 5-8-membered heterocyclyl, aryl, or
heteroaryl ring or a 3-8-membered cycloalkyl ring having 0-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur. Exemplary rings that are formed when two
independent occurrences of R° (or R+, or any other variable similarly defined herein) are
taken together with the atom(s) to which each variable is bound include, but are not limited to
the following: a) two independent occurrences of R° (or R+, or any other variable similarly
defined herein) that are bound to the same atom and are taken together with that atom to form
a ring, for example, N(R°)2, where both occurrences of R° are taken together with the
nitrogen atom to form a piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two
independent occurrences of R° (or R , or any other variable similarly defined herein) that are
bound to different atoms and are taken together with both of those atoms to form a ring, for
example where a phenyl group is substituted with two occurrences of OR0
these two occurrences of R° are taken together with the oxygen atoms to which they are
bound to form a fused 6-membered oxygen containing ring: It will be
appreciated that a variety of other rings can be formed when two independent occurrences of
R° (or R+, or any other variable similarly defined herein) are taken together with the atom(s)
to which each variable is bound and that the examples detailed above are not intended to be
limiting.
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, Xi, and X2 are as
defined below.
[0027] These compounds and pharmaceutically acceptable compositions thereof are
useful for treating or preventing a variety of diseases, disorders or conditions, including, but
not limited to, immunodeficiency disorders, inflammatory diseases, allergic diseases,
autoimmune diseases, proliferative disorders, immunologically-mediated diseases, or
respiratory disorders, to name a few. The compounds provided by this invention are also
useful for the study of kinases in biological and pathological phenomena; the study of
intracellular signal transduction pathways mediated by such kinases; and the comparative
evaluation of new kinase inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
[0028] I. General Description of 'Compounds of'the Invention:
[0029] The present invention relates to a compound of formula I:
I
or a pharmaceutically acceptable salt thereof, wherein:
R1 and R2 are each independently halogen or -L-R'; or R1 and R2, taken together,
form an optionally substituted 5- or 6-membered monocyclic aryl ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or sulfur; or a 5-, 6-, or 7-
membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, wherein any ring formed by R1 and
R2 taken together is optionally substituted at one or more substituable carbon or nitrogen
atoms with n independent occurrences of Q-Rx, wherein n is 0-5;
L is a bond or is an optionally substituted C1-6 alkylidene chain wherein up to two
non-adjacent methylene units of L are optionally and independently replaced by -CO-, -CO2-,
-COCO-, -CONR-, -OCONR-, -NRNR-, -NRNRCO-, -NRCO-, -NRCO2-, -NRCONR-, -SO-,
-SO*-, -NRSO2-, -SO2NR-, -NRSO2NR-, -O-, -S-, or-NR-;
[0050] Unless otherwise stated, structures depicted herein are also meant to include all
isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the
structure; for example, the R and S configurations for each asymmetric center, (Z) and (E)
double bond isomers, and (Z) and (E) conformational isomers. Therefore, single
stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or
conformational) mixtures of the present compounds are within the scope of the invention.
Unless otherwise stated, all tautomeric forms of the compounds of the invention are within
the scope of the invention. Additionally, unless otherwise stated, structures depicted herein
are also meant to include compounds that differ only in the presence of one or more
isotopically enriched atoms. For example, compounds having the present structures except
for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a
13C- or 14C-enriched carbon are within me scope of this invention. Such compounds are
useful, for example, as analytical tools or probes in biological assays.
[0051] 3. Description of Exemplary Compounds:
[0052] As described generally above, R1 and R2 are each independently halogen or -L-R',
or R and R , taken together, form an optionally substituted 5- or 6-membered monocyclic
aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or a
5-, 6-, or 7-membered saturated or partially unsaturated monocyclic ring having 0-5
heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0053] In certain embodiments, R1 and R2 are each independently halogen or -L-R'. bi
other embodiments, R1 and R2 are each independently hydrogen, halogen, or an optionally
substituted group selected from C1-6alkyl, aryl, aryl(C1-6)alkyl, -N(R')2, -CH2N(R')2, -OR',
-CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -(CH2)2N(R')2, -(CH2)2OR', -(CH2)2SR',
-COR', -CON(R')2, -SO2R', or -SO2N(R')2. In yet other embodiments, R1 and R2 are each
independently H, CI, Br, F, CF3, Me, Et, -COOH, NH2, -N(CH3)2, -N(Et)2, -N(iPr)2,
-O(CH2)2OCH3, -CO(C1-C4alkyl), -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3,
-SO2(C1-C4alkyl), -SO2NH2, -SO2N(CH3)2, or an optionally substituted group selected from
C1-4alkoxy, phenyl, phenyloxy, benzyl, or benzyloxy.
[0054] In other embodiments, R1 and R2, taken together, form an optionally substituted 5-
or 6-membered monocyclic aryl ring having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or a 5-, 6-, 7-, or 8-membered saturated or partially unsaturated
monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur.
[0055] In certain embodiments, R1 and R2, taken together, form an optionally substituted
5- or 6-membered monocyclic aryl ring having 0-5 "heteroatoms independently selected from
nitrogen, oxygen, or sulfur.
[0056] In other embodiments, R1 and R2, taken together, form an optionally substituted 5-
, 6-, 7-, or 8-membered saturated or partially unsaturated monocyclic ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0057] hi another embodiment, R1 and R2, taken together, form an optionally substituted
6-membered monocyclic aryl ring having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur.
[0058] In preferred embodiments, R1 and R2 are taken together to form a ring and
compounds have one of the structures depicted below:
n n
[0059] In other embodiments, compounds of formula I-A, I-H, I-I, I-J, I-K, I-L, I-M, or
I-N are provided.
[0060] In other embodiments, compounds of formula I-A are provided.
[0061] It will also be appreciated that one or more hydrogen atoms on any substitutable
nitrogen or carbon atom may optionally be substituted with n independent occurrences of Q-
Rx, wherein n is 0-5.
[0062] In certain embodiments, each occurrence of Q is a bond or C1-C6 alkylidene chain,
wherein up to two methylene units of Q are optionally replaced by -C(O)-, -C(O)C(O)-,
-CONR-, -CONRNR-, -CO2-, -OC(O)-, -NRCO2-, -O-, -NRCONR-, -OC(O)NR-, -NRNR-,
-NRCO-, -S-, -SO-, -SO2-, -NR-, -SO2NR-, or -NRSO2-. In other embodiments, each
occurrence of Q is optionally substituted C1-C6alkyl wherein up to two methylene units of the
alkyl chain are optionally replaced by -C(O)-, -CONR-, -CO2-, -OC(O)-, -NRCO2-, -O-,
-NRCONR-, -NRCO-, -S-, -SO-, -SO2-, or -NR-.
[0063] In some embodiments, each R* is independently R'. In other embodiments, each
Rx is H. In other embodiments, each Rx is independently halogen, NO2, or CN.
[0064] In certain preferred embodiments, n is 0-4, and each ocurrence of Q-Rx, when
present, is independently halogen, CN, NO2, or an optionally substituted group selected from
C1-4alkyl, aryl, aralkyl, heteroaryl, a cycloalkyl or heterocycloalkyl group having 3-10 atoms,
-N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NRCOR', -CON(R% or
-S(O)2N(R')2.
[0065] In other preferred embodiments, each occurrence of Q-Rx, when present, is CI, Br,
F, CF3, methyl, ethyl, propyl, butyl, CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2,
-O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, ~OCH2CH2CH3,
-OCH2CH2CH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -NHCO(pyridyl), -NHCONH2, -NH2,
-NHCO(CH2)N(CH2)2, -NHCO(CH2)NH2, or an optionally substituted group selected from
piperidinyl, piperizinyl, morpholino, • phenyl, phenyloxy, benzyl, benzyloxy, pyridyl,
pyrimidinyl, pyridazinyl, thiophene, furan, thiazole, oxazole, thiadiazole, oxadiazole,
pyrazole, or pyrrole.
[0066] In some embodiments', each occurrence of Q-Rx, when present, is CI, Br, F, CF3,
methyl, ethyl, propyl, butyl, CN, -COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)20CH3,
-CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH2CH2CH3, -
CH2OH, -NHCOCH3, -SO2NH2, -NHCO(pyridyl), -NHCONH2, -NH2,
-NHCO(CH2)N(CH2)2, or -NHCO(CH2)NH2.
[0067] In other embodiments, each occurrence of Q-Rx, when present, is an optionally
substituted group selected from piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy,
benzyl, benzyloxy, pyridyl, pyrimidinyl, pyridazinyl, thiophene, furan, thiazole, oxazole,
thiadiazole, oxadiazole, pyrazole, or pyrrole.
[0068] In some embodiments each occurrence of Q-Rx, when present, is optionally
substituted aryl. In other embodiments, each occurrence of Q-Rx, when present, is optionally
substituted heteroaryl.
[0069] In other preferred embodiments, n is 2. In still other preferred embodiments, n is
1. In yet other preferred embodiments, n is 0.
[0070] In certain embodiments, any substitutable nitrogen atom on a ring formed by R1
and R2 taken together is substituted with hydrogen, or with an optionally substituted group
selected from C1-C6alkyl, aryl, aryl(C1-C6)alkyl, -N(R')2, -CH2N(R')2, -CH2OR', -CH2SR',
-(CH2)2N(R')2, -(CH2)2OR', -(CH2)2SR', -COR', -CON(R')2, SO2R', or -S(O)2N(R')2. In
more preferred embodiments, any substitutable nitrogen atom on a ring formed by R1 and R2,
taken together is substituted with H, Me, CF3, ethyl, propyl, butyl, pentyl, CO(C1-C4alkyl),
-CONH2, -COO(C1-C4alkyl), -CH2OH, -SO2(C1-C4alkyl), -SO2NH2, SO2N(CH3)2, or
optionally substituted phenyl or benzyl.
[0071] As described generally above, X1 is 0=O, S=O, SO2i or C=NR. In preferred
embodiments, X1 is C=O or SO2. In more preferred embodiments, X1 is C=O and
compounds have the structure:

wherein R3,R2,X2 and R3 are defined generally above, or in any of the classes and
subclasses described above and herein.
[0072] As described generally above, X2 is NR, S, O, or C(R)2. In some embodiments,
X2 is NR or C(R)2. In other embodiments, X2 is NR, O, or S. In yet other embodiments, X2
is NR and compounds have the structure:

[0073] la another embodiments, X1 is C=O and X2 is NR and compounds have the
structure:

[0074] As described generally above, R3 is an optionally substituted group selected from:
C1-6 aliphatic; a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl group having
0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3-8-membered
saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; or an 8-10-membered saturated or partially
unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, wherein R3 is optionally substituted with m independent
occurrences of Z-RY, wherein m is 0-5.
[0075] In certain preferred embodiments, R3 is a 5-6 membered monocyclic or an 8-10
membered bicyclic aryl group having 0-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur; a 3-8-membered saturated or partially unsaturated monocyclic ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-10-
membered saturated or partially unsaturated bicyclic ring system having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.
[0076] In other preferred embodiments, R3 is an optionally substituted C1-ealiphatic
group, wherein the C1-6aliphatic group is optionally substituted with a 5-6 membered
monocyclic or an 8-10 membered bicyclic aryl group having 0-5 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; a 3-8-membered saturated or partially unsaturated
monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur; or an 8-10-membered saturated or partially unsaturated bicyclic ring system having 0-
5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0077] In certain embodiments, the 5-6 membered monocyclic or 8-10 membered
bicyclic aryl group having 0-5 heteroatoms independently selected from nitrogen, oxygen, or
sulfur; the 3-8-membered saturated or partially unsaturated monocyclic ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or sulfur; or the 8-10-membered
saturated or partially unsaturated bicyclic ring system having 0-5 heteroatoms independently
selected from nitrogen, oxygen, or sulfur is selected from one of the following groups:
[0078] In some preferred embodiments, R3 is an optionally substituted group selected
from i, ii, xxxix, xL, xLi, or xLii. In other preferred embodiments, R is an optionally
substituted phenyl group (i).
[0079] It will also be appreciated that one or more hydrogen atoms on any substitutable
nitrogen or carbon atom may optionally be substituted with n independent occurrences of
Z-RY, wherein m is 0-5. In preferred embodiments, Z is a bond or is an optionally substituted
C1-6 alkylidene chain wherein one or two non-adjacent methylene units are optionally and
independently replaced by -O-, -NR-, -S-, -SO2-, or -C(O)0-5 -CO-, and RY is R' or halogen.
[0080] In other preferred embodiments, each occurrence of ZRY is independently
-C1-3alkyl, -O(C1-3alkyl), -OH, -S(C1-3alkyl), -SH, CF3, -OCF3, -SCF3, -F, -CI, -Br, -CN,
-COOR', -COR', -O(CH2)2N(R)CR'), -O(CH2)N(R)(R'), -CON(R)(R'), -NRCOR',
-(CH2)2OR', -(CH2)OR', -N(R)(R'), -(CH2)2N(R)(R'), -(CH2)N(R)(R')5 -SO2N(R)(R'),
-NRSO2R', or an optionally substituted group selected from pyrrolidinyl, morpholino,
piperazinyl, piperidinyl, phenyl, phenoxy, benzyl, benzyloxy, triazolyl, pyrazolyl, orpyridyl.
[0081] In some embodiments m is 0. In other embodiments m is 1. In still other
embodiments m is 2.
[0082] In preferred embodiments, any substitutable nitrogen atom is substituted with
hydrogen, or an optionally substituted group selected from C1-6alkyl, aryl, aryl(C1-6)alkyl,
-N(R')2, -CH2N(R')2, -CH2OR', -CH2SR', -(CH2)2N(R')2, -(CH2)2OR', -(CH2)2SR', -COR',
-CON(R')2, SO2R', or -S(O)2N(R')2. In more preferred embodiments, any substitutable
nitrogen atom is substituted with H, Me, CF3, ethyl, propyl, butyl, pentyl, CO(C1-C4alkyl),
-CONH2, -COO(C1-C4alkyl), -CH2OH, -SO1(C1-C4alkyl), -SO2NH2, SO2N(CH3)2, or
optionally substituted phenyl or benzyl.
[0083] In other preferred embodiments, compounds have the general formula I-A:
I-A
wherein Xi, X2, R3, QRX and n are as described generally and in subsets above.
[0084] In some embodiments, compounds have the general formula I-A provided that
a) when n is 0, then:
i) when X1 is CO and X2 is CH2, then R3 is not substituted furyl, 2-Cl-phenyl,
3,5-dimethyl-2-benzofuranyl, 3,7-dimethyl-2-benzofuranyl, or 4-OMe-phenyl;
ii) when X1 is CO and X2 is NH, then R3 is not 2,4-dichloro-phenyl, 4-C1-
phenyl, 4-Me-phenyl, or unsubstituted phenyl, cyclohexyl, orben2yl; and
iii) when X1 is CO and X2 is CHOH, then R1 is not unsubstituted phenyl or
-CHOHCH2OH; and
b) when n is 2, and the two occurrences of QRX are 6,7-Me-phenyl, then when X1 is
CO, and X2 is NH, then R3 is not n-hexyl, n-butyl, n-propyl, or -CH2CH=CH2.
[0085J In other embodiments, compounds have the general formula I-A provided that
a) when n is 0, then:
i) when X1 is CO, and X2 is CH, then R3 is not unsubstituted phenyl or OH;
ii) when X1 is CO, and X2 is CH2, then R3 is not methyl, 'unsubstituted
phenyl, substituted furyl, 2-Cl-phenyl, 3,5-dimethyl-2-benzoforanyl, 3,7-
dimethyl-2-benzofuranyl, or 4-OMe-phenyl;
iii) when X1 is CO, and X2 is NH, then R3 is not methyl, -C(O)CH3,
C(O)C(Ci_3alkyl), C(O)C(O)OH, C(O)C(O)0(C1.3alkyl), unsubstituted
phenyl, cyclohexyl, benzyl, substituted benzofuranyl, 2,4-dichloro-
phenyl, 4-Cl-phenyl, or 4-Me-phenyl;
iv) when X1 is CO, and X2 is NMe, then R3 is not methyl;
v) when X1 is CO, and X2 is O, then R3 is not methyl;
vi) when X1 is CO, and X2 is CHOH, then R1 is not unsubstituted phenyl or
-CHOHCH2OH;
b) when n is 2, then:
i.) when X1 is CO, and X2 is NH
a) and the two occurrences of QRX are 6,7-Me-phenyl, then R3 is not
n-hexyl, n-butyl, n-propyl, o-CH2CH=CH2, -CH=N~CH2CH=CH2,
C(=O)NR, C(=O)OR wherein R is H or Cj.3 alkyl;
b) and the two occurrences of QRX are 6-NHAc-7-Me-phenyl, then R3
isnot-C(=O)CH3
c) and the two occurrences of QRX are 6,7-OMe-phenyl, then R3 is not
C(O)C(O)OH or C(O)C(O)0(C!.3alkyl);
d) and the two occurrences of QRX are 6,7-Cl-phenyl, then R3 is not
methyl or -CH2CH=CH2;
ii.) when X1 is CO, and X2 is O,
a) and the two occurrences of QRX are 6-NO2-7-F-phenyl, then R3 is
not methyl.
[0086] In other preferred embodiments, for compounds of formula I-A, X1 is CO and X2
is NR and compounds have the general structure I-A-i:
I-A-i
wherein QRX, R, and R3 are described generally and in subsets above.
[0087] Representative examples of compounds of formula I are set forth below in Table
1.
[0089] 4. General Synthetic Methodology:
[0090] The compounds of this invention may be prepared in general by methods known
to those skilled in the art for analogous compounds or by those methods depicted in the
Examples below. In general, Example 1 depicts several methods for the preparation of
functionalized quinoxalines.
[0091] Although certain exemplary embodiments are depicted and described herein, it
will be appreciated that a compounds of the invention can be prepared according to the
methods described generally above using appropriate starting materials by methods generally
available to one of ordinary skill in the art.
[0092] 5, Uses, Formulation and Administration
[0093] Pharmaceutically acceptable compositions
[0094] As discussed above, the present invention provides compounds that are inhibitors
of protein kinases, and thus the present compounds are useful for the treatment of diseases,
dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,
gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate,
lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-
naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate,
sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium
and N+(C1-4alkyl)4 salts. This invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or
dispersable products may be obtained by such quaternization. Representative alkali or
alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the
like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic
ammonium, quaternary ammonium, and amine cations formed using counterions such as
halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl
sulfonate.
[0098] As described above, the pharmaceutically acceptable compositions of the present
invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle,
which, as used herein, includes any and all solvents, diluents, or other liquid vehicle,
dispersion or suspension aids, surface active agents, isotonic agents, thickening or
emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the
particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.
W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in
formulating pharmaceutically acceptable compositions and known techniques for the
preparation thereof. Except insofar as any conventional carrier medium is incompatible with
the compounds of the invention, such as by producing any undesirable biological effect or
otherwise interacting in a deleterious manner with any other component(s) of the
pharmaceutically acceptable composition, its use is contemplated to be within the scope of
this invention. Some examples of materials which can serve as pharmaceutically acceptable
carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, letithin,
serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine,
sofbic acid, or potassium sofbate, partial glyceride mixtures of saturated vegetable fatty acids,
water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate,
potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-
block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn
starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc;
excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil;
safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol
or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents
such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as
other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate,
as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be present in the composition,
according to the judgment of the formulator.
[0099] Uses of Compounds andPharmaceutically acceptable compositions
[00100] In yet another aspect, a method for the treatment or lessening the severity of a
proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune
disorder, a condition associated with organ transplant, an inflammatory disorder, or an
immunologically mediated disorder is provided comprising administering an effective
amount of a compound, or a pharmaceutically acceptable composition comprising a
compound to a subject in need thereof. In certain embodiments of the present invention an
"effective amount" of the compound or pharmaceutically acceptable composition is that
amount effective for treating or lessening the severity of a proliferative disorder, a cardiac
disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with
organ transplant, an inflammatory disorder, or an immunologically mediated disorder. The
compounds and compositions, according to the method of the present invention, may be
administered using any amount and any route of administration effective for treating or
lessening the severity of a proliferative disorder, a cardiac disorder, a neurodegenerative
disorder, an autoimmune disorder, a condition associated with organ transplant, an
inflammatory disorder, or an immunologically mediated disorder. The exact amount required
will vary from subject to subject, depending on the species, age, and general condition of the
subject, the severity of the infection, the particular agent, its mode of administration, and the
like. The compounds of the invention are preferably formulated in dosage unit form for ease
of administration and uniformity of dosage. The expression "dosage unit form" as used herein
refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be
understood, however, that the total daily usage of the compounds and compositions of the
present invention will be decided by the attending physician within the scope of sound
medical judgment. The specific effective dose level for any particular patient or organism
will depend upon a variety of factors including the disorder being treated and the severity of
the disorder; the activity of the specific compound employed; the specific composition
employed; the age, body weight, general health, sex and diet of the patient; the time of
administration, route of administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination or coincidental with the
specific compound employed, and like factors well known in the medical arts. The term
"patient", as used herein, means an animal, preferably a mammal, and most preferably a
human.
[00101] The pharmaceutically acceptable compositions of this invention can be
administered to humans and other animals orally, rectally, parenterally, intracisternally,
intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an
oral or nasal spray, or the like, depending on the severity of the infection being treated. In
certain embodiments, the compounds of the invention may be administered orally or
parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from
about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to
obtain the desired therapeutic effect.
[00102] Liquid dosage forms for oral administration include, but are not limited to,
pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and
elixirs. In addition to the active compounds, the liquid dosage forms may contain inert
diluents commonly used in the art such as, for example, water or other solvents, solubilizing
agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide,
oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),
glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan,
and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants
such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and
perfuming agents.
[00103] Injectable preparations, for example, sterile injectable aqueous or oleaginous
suspensions may be formulated according to the known art using suitable dispersing or
wetting agents and suspending agents. The sterile injectable preparation may also be a sterile
injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or
solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium
chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the
preparation of injectables.
[00104] The injectable formulations can be sterilized, for example, by filtration through a
bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water or other sterile injectable
medium prior to use.
[00105] In order to prolong the effect of a compound of the present invention, it is often
desirable to slow the absorption of the compound from subcutaneous or intramuscular
injection. This may be accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of absorption of the compound then
depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline
form. Alternatively, delayed absorption of a parenterally administered compound form is
accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot
forms are made by forming microencapsule matrices of the compound in biodegradable
polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate of compound release can
be controlled. Examples of other biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared by entrapping the
compound in liposomes or microemulsions that are compatible with body tissues.
[00106] Compositions for rectal or -vaginal administration are preferably suppositories
which can be prepared by mixing the compounds of this invention with suitable non-irritating
excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which
are solid at ambient temperature but liquid at body temperature and therefore melt in the
rectum or vaginal cavity and release the active compound.
[00107] Solid dosage forms for oral administration include capsules, tablets, pills,
powders, and granules. In such solid dosage forms, the active compound is mixed with at
least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or
dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose,
¦ mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d)
disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f)
absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as,
for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid
polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules,
tablets and pills, the dosage form may also comprise buffering agents.
[00108] Solid compositions of a similar type may also be employed as fillers in soft and
hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high
molecular weight polyethylene glycols and the like. The solid dosage forms of tablets,
dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric
coatings and other coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a composition that they release the
active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally,
in a delayed manner. Examples of embedding compositions that can be used include
polymeric substances and waxes. Solid compositions of a similar type may also be employed
as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar
as well as high molecular weight polethylene glycols and the like.
[00109] The active compounds can also be in micro-encapsulated form with one or more
excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and
granules can be prepared with coatings and shells such as enteric coatings, release controlling
coatings and other coatings well known in the pharmaceutical formulating art. In such solid
dosage forms the active compound may be admixed with at least one inert diluent such as
sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice,
additional substances other than inert diluents, e.g., tableting lubricants and other tableting
aids such a magnesium stearate and rmcrocrystalline cellulose. In the case of capsules, tablets
and pills, the dosage forms may also comprise buffering agents. They may optionally contain
opacifying agents and can also be of a composition that they release the active ingredient(s)
only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions that can be used include polymeric substances and
waxes.
[00110] Dosage forms for topical or transdermal administration of a compound of this
invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays,
inhalants or patches. The active component is admixed under sterile conditions with a
pharmaceuticalry acceptable carrier and any needed preservatives or buffers as may be
required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being
within the scope of this invention. Additionally, the present invention contemplates the use of
transdermal patches, which have the added advantage of providing controlled delivery of a
compound to the body. Such dosage forms can be made by dissolving or dispensing the
compound in the proper medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by either providing a rate
controlling membrane or by dispersing the compound in a polymer matrix or gel.
[00111] As described generally above, the compounds of the invention are useful as
inhibitors of protein kinases. In one embodiment, the compounds and compositions of the
invention are inhibitors of one or more of SYK, JAK-3, or GSK-3, and thus, without wishing
to be bound by any particular theory, the compounds and compositions are particularly useful
for treating or lessening the severity of a disease, condition, or disorder where activation of
one or more of SYK, JAK-3, or GSK-3 is implicated in the disease, condition, or disorder.
When activation of SYK, JAK-3, or GSK-3 is implicated in a particular disease, condition, or
disorder, the disease, condition, or disorder may also be referred to as "SYK, JAK-3, or
GSK-3-mediated disease" or disease symptom. Accordingly, in another aspect, the present
invention provides a method for treating or lessening the severity of a disease, condition, or
disorder where activation or one or more of SYK, JAK-3, or GSK-3 is implicated in the
disease state.
[00112] The activity of a compound utilized in this invention as an inhibitor of SYK,
JAK-3, or GSK-3, may be assayed in viti-o, in vivo or in a cell line. In vitro assays include
assays that determine inhibition of either the phosphorylation activity or ATPase activity of
activated SYK, JAK-3, or GSK-3. Alternate in vitro assays quantitate the ability of the
inhibitor to bind to SYK, JAK-3, or GSK-3. Inhibitor binding may be measured by
radiolabelling the inhibitor prior to binding, isolating the inhibitor/SYK, JAK-3, or GSK-3,
complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding
may be determined by running a competition experiment where new inhibitors are incubated
with SYK, JAK-3, or GSK-3 bound to known radioligands.
[00113] The term "measurably inhibit", as used herein means a measurable change in
SYK, JAK-3, or GSK-3 activity between a sample comprising said composition and a SYK,
JAK-3, or GSK-3 kinase and an equivalent sample comprising SYK, JAK-3, or GSK-3
kinase in the absence of said composition.
[00114] The term "GSK-3-mediated disease" as used herein, means any disease or other
deleterious condition or disease in which GSK-3 is known to play a role. Such diseases or
conditions include, without limitation, autoimmune diseases, inflammatory diseases,
metabolic, neurological and neurodegenerative diseases, cardiovascular diseases, allergy,
asthma, diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-
associated dementia, amyotrophic lateral sclerosis (AML, Lou Gehrig's disease), multiple
sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy, reperfusion/ischemia, stroke, and
baldness.
[00115] The term "JAK-mediated disease", as used herein means any disease or other
deleterious condition in which a JAK family kinase, in particular JAK-3, is known to play a
role. Such conditions include, without limitation, immune responses such as allergic or type I
hypersensitivity reactions, asthma, autoimmune diseases such as transplant rejection, graft
versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis,
neurodegenerative disorders such as Familial amyotrophic lateral sclerosis (FALS), as well as
in solid and hematologic malignancies such as leukemias and lymphomas.
[00116] The term "SYK-mediated disease" or "SYK-mediated condition", as used herein,
means any disease or other deleterious condition in which SYK protein kinase is known to
play a role. Such conditions include, without limitation, allergic disorders, especially
asthma.
[00117] In other embodiments, the invention relates to a method of enhancing glycogen
synthesis and/or lowering blood levels of glucose in a patient in need thereof, comprising
administering to said patient a therapeutically effective amount of a composition comprising
a compound of formula I. This method is especially useful for diabetic patients.
[00118] In yet another embodiment, the invention relates to a method of inhibiting the
production of hyperphosphorylated Tau protein in a patient in need thereof, comprising
administering to said patient a therapeutically effective amount of a composition comprising
a compound of formula I. This method is especially useful in halting or slowing the
progression of Alzheimer's disease.
[00119] In still another embodiments, the invention relates to a method of inhibiting the
phosphorylation of p-catenin in a patient in need thereof, comprising administering to said
patient a therapeutically effective amount of a composition comprising a compound of
formula I. This method is especially useful for treating schizophrenia.
[00120] It will also be appreciated that the compounds and pharmaceutically acceptable
compositions of the present invention can be employed in combination therapies, that is, the
compounds and pharmaceutically acceptable compositions can be administered concurrently
with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
The particular combination of therapies (therapeutics or procedures) to employ in a
combination regimen will take into account compatibility of the desired therapeutics and/or
procedures and the desired therapeutic effect to be achieved. It will also be appreciated that
the therapies employed may achieve a desired effect for the same disorder (for example, an
inventive compound may be administered concurrently with another agent used to treat the
same disorder), or they may achieve different effects (e.g., control of any adverse effects). As
used herein, additional therapeutic agents that are normally administered to treat or prevent a
particular disease, or condition, are known as "appropriate for the disease, or condition, being
treated".
[00121] The amount of additional therapeutic agent present in the compositions of this
invention will be no more than the amount that would normally be administered in a
composition comprising that therapeutic agent as the only active agent. Preferably the
amount of additional therapeutic agent in the presently disclosed compositions will range
from about 50% to 100% of the amount normally present in a composition comprising that
agent as the only therapeutically active agent.
[00122] The compounds of this invention or pharmaceutically acceptable compositions
thereof may also be incorporated into compositions for coating implantable medical devices,
such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the
present invention, in another aspect, includes a composition for coating an implantable device
comprising a compound of the present invention as described generally above, and in classes
and subclasses herein, and a carrier suitable for coating said implantable device. In still
another aspect, the present invention includes an implantable device coated with a
composition comprising a compound of the present invention as described generally above,
and in classes and subclasses herein, and a carrier suitable for coating said implantable
device.
[00123] Vascular stents, for example, have been used to overcome restenosis (re-
narrowing of the vessel wall after injury). However, patients using stents or other
implantable devices risk clot formation or platelet activation. These unwanted effects maybe
prevented or mitigated by pre-coating the device with a pharmaceutically acceptable
composition comprising a kinase inhibitor. Suitable coatings and the general preparation of
coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121.
The coatings are typically biocompatible polymeric materials such as a hydrogel polymer,
polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl
acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable
topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations
thereof to impart controlled release characteristics in the composition.
[00124] Another aspect of the invention relates to inhibiting SYK, JAK-3, or GSK-3
activity in a biological sample or a patient, which method comprises administering to the
patient, or contacting said biological sample with a compound of formula I or a composition
comprising said compound. The term, '^biological sample", as used herein, includes, without
limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or
extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts
thereof.
[00125] Inhibition of SYK, JAK-3, or GSK-3 kinase activity in a biological sample is
useful for a variety of purposes that are known to one of skill in the art. Examples of such
purposes include, but are not limited to, blood transfusion, organ-transplantation, biological
specimen storage, and biological assays.
EXAMPLES
[00128] Step A (Compound 1)
[00129] M-CPBA (6.0 g.) was added to a solution of 3-Bromo Quinoline (4.25 g. / 20.4
mmol) in CHCl3 (31.0 ml.). The reaction mixture was allowed to stir at room temperature
overnight. The reaction mixture was diluted with saturated sodium bicarbonate solution (25
ml.) and IN NaOH solution (7.5 ml.). The layers were separated and the aqueous layer was
re-extracted with (12.5 ml) CHC13. The combined organics were washed with 5% (by weight)
aqueous sodium bisulfite solution (25 ml.), saturated aqueous sodium bicarbonate solution
(12.5 ml.), water (20 ml.) and brine (25 ml.). The reaction mixture was then dried over
sodium sulfate, filtered and evaporated to dryness. No further purification, material used as
is. Yield: 5.61 g. (impure, theoretical yield is 4.57 g.) 1H NMR (500 MHz, CDC13) 5 8.75 (d,
1H), 8.69 (d, 1H), 7.97 (s, 1H), 7.82 - 7.77 (m, 2H), 7.71 - 7.67 (m, 1H).
[00130] Step B (Compound 2)
[00131] A mixture of Compound 2 (20.4 mmol) and dimethyl sulfate (2.8 ml, 29.6 mmol)
was heated at 70 degrees for two hours (under N2). Upon cooling to room temperature, added
was water (9.0 ml.) producing a precipitate. The reaction mixture was cooled to -10 degrees
via an isopropanol /dry ice bath. Added was a solution of sodium cyanide (2.56 g. / 52.2
mmol) in water (18.0 ml.) in a dropwise manner through an addition funnel. The precipitated
material was collected and recrystallized from ethyl acetate / hexane. Yield 2.33 g.,
approximately 50%. 1H NMR (500 MHz, CDCl3) 5 8.51 (s, 1H), 8.15 (d, 1H), 7.88 - 7.83 (m,
2H), 7.76-7.73 (m,lH).
[00132] Step C (Compound 3)
[00133] Compound 3 (800 mg., 3.45 mmol) was suspended in sulfuric acid (1.0 ml.,
concentrated). The reaction mixture was heated to 80 degrees where a solution occurs. After
30 minutes, the reaction mixture is allowed to cool to room temperature and is then basified
with 6 N sodium hydroxide solution (with a little solid NaOH added). The product was
extracted with methylene chloride, washed with water, dried over magnesium sulfate, filtered
and evaporated to dryness. This crude material was recrystallized from ethyl acetate /
methanol. Yield: 353.6 mg., approximately 40%. 1H NMR (500 MHz, CD3OD) 8 8.60 (s,
1H), 7.98 (d, 1H), 7.85'(4 1H), 7.76 - 7.71 (m, 1H), 7.59 (m, 1H).
[00134] Step D (Compound 4)
[00135] Compound 4 (125.6 mg. / 0.5 mmol) was dissolved in 1,4-dioxane (1.5 ml.).
Added was p-anisidine (67.8 mg. / 0.55 mmol) followed by potassium tert- butoxide (180 mg.
/ 1.6 mmol.), iris (dibenzylideneacetone) dipalladium (O) (4.6 mg. / 0.005 mmol.) and 1,3-bis
(2,6-diisopropylphenyl) imidazolium chloride (4.3 mg. / 0.01 mmol.). The reaction mixture
was heated to 100 degrees (sealed tube, under Ar) and allowed to stir there overnight. The
reaction mixture was allowed to cool to room temperature and was then diluted with ethyl
acetate. This organic phase was washed with water, brine, dried over magnesium sulfate,
filtered and evaporated to dryness. This crude material was chromatographed on 1.5 inches of
silica gel and eluted with 1% methanol / methylene chloride. Yield: 14.1 mg. JH NMR (500
MHz, CDCl3) 8 8.17 - 7.92 (m, 2H), 7.79 - 7.66 (m, 1H), 7.65 - 7.51 (m, 2H), 7.24 (d, 2H),
6.98 (d, 2H), 6.71 (s, broad, 1H), 3.89 (s, 3H).
[00136] Scheme B:

[00137] Step E (Compound 5)
[00138] 3-Hydroxy-2-quinoxalinecarboxylic acid (2.86 g. / 15.0 mmol.) was suspended in
ethanol (75 ml.). Added (slowly!) was concentrated sulfuric acid (5.0 ml.) and the reaction
mixture was allowed to stir at room temperature overnight. The precipitated product was
filtered off and dried under reduced pressure. No further purification, material used as is.
Yield: 2.15 g. LC / MS data - Retention time: 1.89 min. in 10 - 90 gradient MS+: 219.2.
[00139] Step F (Compound 6)
[00140] A mixture of compound 5 (4.5 g. / 20.6 mmol) and Phosphorous oxychloride was
heated to 115 degrees for ten minutes. The excess phosphorous oxychloride was removed at
reduced pressure and the residue was poured onto two hundred fifty grams of crushed ice.
The mixture was neutralized by the addition of ammonium hydroxide and then extracted with
ethyl ether. The organic layer was dried over magnesium sulfate, filtered and evaporated to
dryness. No further purification, material used as is. Yield: 3.74 g. approximately 77%. !H
NMR (500 MHz, CDC13) 8 8.22 (d, 1H), 8.11 (d, 1H), 7.95 - 7.86 (m, 2H), 4.60 (q, 2H), 1.50
(t,3H).
[00141] Step G (Compound 7)
[00142] Compound 6 (1.6 g.) was dissolved in ethanol (32.0 ml.). The reaction mixture
was cooled to approximately -50 degrees via an acetone / dry ice bath. Ammonia (g) was
bubbled into the solvent for approximately 30 seconds and the glass vessel was capped. The
bath was removed and the reaction mixture was allowed to gradually rise to room
temperature where it was stirred overnight The reaction mixture was re-cooled to -50
degrees (as above) and the glass vessel was opened. After allowing to warm to room
temperature, the solid product was collected by filtration. After washing with a small amount
of cool ethanol, the product was dried under reduced pressure. Yield: 720 mg., approximately
52%. 1H NMR (500 MHz, CDC13) 5 8.16 (d, 1H), 8.08 (d, 1H), 7.97 - 7.87 (m, 2H).
[00143] Step H (Compound 8)
[00144] Compound 7 (62.3 mg. / 0.30 rnmol.) and p-Anisidine (36.4 mg. / 0.296 mmol.)
were dissolved in pyridine (1.5 ml.). The reaction mixture was heated to 125 degrees (in a
sealed tube, under N2) and allowed to stir there overnight. The excess pyridine was removed
with heat and a stream of N2. The residue was chromatographed on a plug of silica gel (1.75
inches) and eluted with 10 - 25 % ethyl acetate / hexane. Yield: 25.4 mg., approximately
30%. 1H NMR (500 MHz, CDCl3) 8 10.97 (s, broad, 1H), 8.19 (s, broad, 1H), 7.82 (m, 3H),
7.75 (d, 1H), 7.69 (t, 1H), 7.44 (t, 1H), 6.96 (d, 2H), 5.72 (s, broad, 1H), 3.87 (s, 3H).
[00145] Step I (Compound 9):
[00146] Scheme C: •
[00147] Compound 7 (64.2 mg. / 0.31 mmol.) and 4-Morpholino aniline (57.8 mg. / 0.32
mmol.) were dissolved in 0.1M HCl/Isopropanol (total of 3.0 ml.). The reaction mixture was
heated to 85 degrees and allowed to stir there overnight. After cooling to room temperature,
the precipitated material was filtered, washed with ethyl ether, collected and dried under
reduced pressure. This crude material was then recrystallized from methanol / ethyl acetate to
give the HC1 salt of the product. Yield: 25.6 mg. approximately 22 %. 1H NMR (500 MHz,
DMSO d-6)
[00148] Scheme D:
Compound 10 Compound 11
[00149] Step J (Compound 10):
[00150] Compound 6 (77.7 mg. / 0.33 mmol.) was dissolved in ethanol. Added was 3,5-
Dimethyl aniline and the reaction mixture (in a sealed tube) was heated to 85 degrees. After
stirring overnight, the reaction was allowed to cool to room temperature. The precipitated
solid was diluted with ethanol and collected by filtration. Yield: 33.7 mg. approximately
30%. LC Data -retention time: 7.166 min., >95% pure, MS+ (FIA) Data: 322.1.
[00151] Step K (Compound 11)
[00152] Compound 10 (33.7 mg. / 0.10 mmol.) was suspended in ethanol. The reaction
mixture was cooled to approximately-50 degrees via an isopropanol / dry ice bath. Ammonia
(g) was bubbled in for approximately 30 seconds and the vessel was capped. The reaction
mixture was allowed to gradually warm to room temperature and stirred there for two hours.
After re-cooling to -50 degrees, the sealed vessel was opened. Upon reaching room
temperature, the precipitated solid was filtered and washed with ethanol. Yield: 24.5 mg.
approximately 84%. 1H NMR (500 MHz, CDC13).

[00154] This depicts introduction of functionality to the 8 position of the quinoxaline ring
system. The preparation of these compounds is analogous to those of Li and Yue in
Tetrahedron Letters, Volume 40 (1999) pp. 4507 - 4510 and preparations described herein.
The nitro group may be reduced at selected steps along the way to the amino compound,
which may be farther diversified by diazotization and subsequent replacement of the
diazonium salt.
[00155] Scheme F:

[00156] Step S (Compound 19)
[00157] 3-Hydroxy-2-quinoxaline carboxylic acid (15.0 g / 78.9 mmol) was dissolved in
concentrated sulfuric acid (225 ml). The reaction mixture was cooled in an ice - water bath
and added slowly was Potassium nitrate (24.0 g / 237.4 mmol). After completion of addition,
the cooling bath was removed and the reaction mixture was allowed to reach room
temperature where it was stirred overnight. The reaction mixture was poured onto ice (900 g)
and the resulting precipitate was filtered. The solid was dissolved in boiling water (2.4 L) and
filtered hot. Upon cooling to room temperature, the precipitated product was collected by
disorders, and conditions including, but not limited to immunodeficiency disorders,
inflammatory diseases, allergic diseases, autoimmune diseases, proliferative disorders,
immunologically-mediated diseases, or respiratory disorders. Accordingly, in another aspect
of the present invention, pharmaceutically acceptable compositions are provided, wherein
these compositions comprise any of the compounds as described herein, and optionally
comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments,
these compositions optionally further comprise one or more additional therapeutic agents.
[0095] It will also be appreciated that certain of the compounds of present invention can
exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable
derivative thereof. According to the present invention, a pharmaceutically acceptable
derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of
such esters, or any other adduct or derivative which upon administration to a patient in need
is capable of providing, directly or indirectly, a compound as otherwise described herein, or a
metabolite or residue thereof.
[0096] As used herein, the term "pharmaceutically acceptable salt" refers to those salts
which are, within the scope of sound medical judgement, suitable for use in contact with the
tissues of humans and lower animals without undue toxicity, irritation, allergic response and
the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically
acceptable salf' means any non-toxic salt or salt of an ester of a compound of this invention
that, upon administration to a recipient, is capable of providing, either directly or indirectly, a
compound of this invention or an inhibitorily active metabolite or residue thereof. As used
herein, the term "inhibitorily active metabolite or residue thereof means that a metabolite or
residue thereof is also an inhibitor of a SYK, JAK-3, or GSK-3 kinase.
[0097] Pharmaceutically acceptable salts are well known in the art. For example, S. M.
Berge et ah, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical
Sciences, 1977, 66,1-19, incorporated herein by reference. Pharmaceutically acceptable salts
of the compounds of this invention include those derived from suitable inorganic and organic
acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are
salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic
acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic
acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by
using other methods used in the art such as ion exchange. Other pharmaceutically acceptable
salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,
borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate,
filtration and washed with Et20. Yield: 11.40 g (62%, approximately) !H NMR (500 MHz,
DMSO-d6) 8 8.61 (s, 1H), 8.46 (d, 1H), 7.50 (s, 1H).
[00158] Step T (Compound 20)
[00159] Compound 19 (6.65 g / 28.3 mmol) was suspended in toluene (250 ml). Added
was thionyl chloride (25 ml / 342.7 mmol) and the resulting reaction mixture was heated to
reflux (under N2). After 2 hours all volatiles were removed at reduced pressure. The residue
was suspended in ethanol (250 ml) and brought to reflux (under N2), where it was allowed to
stir overnight. All volatiles were removed at reduced pressure and the residue was
recrystallized from ethanol. Yield: 2.85 g (38 %, approximately). !H NMR (500 MHz,
DMSO-d6) 5 8.62 (s, 1H), 8.48 (d, 1H), 7.49 (d, 1H), 4.39 (q, 2H), 1.33 (t, 3H).
[00160] Step U (Compound 21)
[00161] Compound 20 (2.85 g / 10.83 mmol) was suspended in toluene (45 ml). Added
was thionyl chloride (1.0 ml /13.7 mmol) followed by DMF (1.0 ml). The reaction mixture is
heated to reflux and allowed to stir there for 2 hours. All volatiles were removed at reduced
pressure and the residue was recrystallized from EtOAc / Hexane. Yield: 3.1 g (assume
quantitative, slightly impure). 1H NMR (500 MHz, DMSO-d6) 8 9.09 (s, 1H), 8.66 (d, 2H),
8.22 (d, 2H), 4.61 (q, 2H), 1.49 (t, 3H).
[00162] Step V (Compound 22)
[00163] Compound 21 (2.26 g./ 8.0 mmol) and 4-morpholino aniline (1.5 g / 8.4 mmol)
were suspended in 0.1 M HC1 / Isopropanol (80 ml). The reaction mixture was heated to
reflux and allowed to stir there for 1 hour. After cooling to room temperature, the product
was filtered and collected. The product was washed with Et20 and pumped down overnight.
The product was taken up in boiling methanol (approximately 100 ml) and allowed to cool to
room temperature. The product was then collected and washed with Et20. Yield: 1.70 g (50
%, approximately). *H NMR (500 MHz, DMSO-d6) 810.29 (s, br, 1H), 8.72 (s, 1H), 8.46 (d,
1H), 7.83 (m, 3H), 7.20 (s, br, 2H), 4.50 (q, 2H), 3.82 (s, br, 4H), 3.25 (s, br, 4H), 1.41 (t,
3H).
[00164] Step W (Compound 23)
[00165] Compound 22 (1.70 g / 4.0 mmol) and 10% Palladium on carbon (170 mg) were
suspended in ethanol (50 ml). Added via balloon was hydrogen gas. After 1 hour, TLC
indicates all of starting material to have been consumed. The reaction mixture was filtered
and all volatiles were removed at reduced pressure. No further purification, material used as
is. Yield: 1.39 g (88%, approximately). 1H NMR (500 MHz, DMSO-d6) 8 9.76 (s, br, 1H),
7.77 (d, 1H), 7.58 (d, 1H), 7.37 (d, 2H), 7.17 - 7.02 (m, 3H), 6.73 (s, br, 1H), 6.51 (s, br, 1H),
4.46 (q, 2H), 3.83 - 3.72 (m, 4H), 3.21 - 3.10 (m, 4H), 1.40 (t, 3H).
[00166] Step X (Compound 24)
[00167] Compound 23 (1.39 g / 3.5 mmol) was dissolved in MeOH (10 ml) and 7N NH3/
MeOH solution (10 ml). The reaction mixture was capped and heated to 70 degrees C. After
1 hour, TLC indicates some starting material still present. Added was another (10 ml) portion
of 7N NH3 / MeOH, the tube was recapped and heating at 70 degrees C was continued for 1
more hour. All volatiles were removed at reduced pressure. The residue was taken up in
boiling methanol and allowed to cool to room temperature. The product was filtered and
washed witfi Et20. Yield: 600 mg. (47 %, approximately). !H NMR (500 MHz, DMSO-d6)
[00168] Scheme G:
[00169] This scheme depicts the introduction of functionality to the 6 position of the
quinoxaline ring system. The preparation of these compounds is analogous to those of
Osdene and Timmis in the Journal of the Chemical Society (1955) pp. 2027 — 2031 and
preparations described herein. The 6 - amino compound may be further diversified by
diazotization and subsequent replacement of the diazonium salt.
[00170] Scheme H:
[00171] This scheme depicts the introduction of functionality to the 5 position of the
quinoxaline ring system. The preparation of these compounds is analogous to those of U. S.
Patent 4,264,600 and preparations described herein. The nitro group may be reduced at
selected steps along the way to the amino compound, which may be further diversified by
diazotization and subsequent replacement of the diazonium salt.
[00172] Example 2: GSK-3 Inhibition Assay:
[00173] Compounds of the present invention were screened for their ability to inhibit
GSK-3 P (AA 1-420) activity using a standard coupled enzyme system (Fox et al, Protein
Set 1998, 7, 2249). Reactions were carried out in a solution containing 100 mM HEPES (pH
7.5), 10 mM MgCl2, 25 mM NaCl, 300 µm NADH, 1 mM DTT and 1.5% DMSO. Final
substrate concentrations in the assay were 20 uM ATP (Sigma Chemicals, St Louis, MO) and
300 uM peptide (American Peptide, Sunnyvale, CA). Reactions were carried out at 30 °C
and 20 nM GSK-3ß. Final concentrations of the components of the coupled enzyme system
were 2.5 mM phosphoenolpyruvate, 300 µM NADH, 30 ug/ml pyruvate kinase and 10 ug/ml
lactate dehydrogenase.
[00174] An assay stock buffer solution was prepared containing all of the reagents listed
above with the exception of ATP and the test compound of the present invention. The assay
stock buffer solution (175 ul) was incubated in a 96 well plate with 5 ul of the test compound
of the present invention at final concentrations spanning 0.002 µM to 30 uM at 30°C for 10
min. Typically, a 12 point titration was conducted by preparing serial dilutions (from 10 mM
compound stocks) with DMSO of the test compounds of the present invention in daughter
plates. The reaction was initiated by the addition of 20 ul of ATP (final concentration 20
uM). Rates of reaction were obtained using a Molecular Devices Spectramax plate reader
(Sunnyvale, CA) over 10 min at 30°C. The Ki values were determined from the rate data as a
function of inhibitor concentration. Compounds of the invention were found to inhibit
GSK-3.
[00175] Example 3: JAK3 Inhibition Assay
[00176] Compounds were screened for their ability to inhibit JAK using the assay shown
below. Reactions were carried out in a kinase buffer containing 100 mM HEPES (pH 7.4), 1
mM DTT, 10 mM MgCl2,25 mM NaCl, and 0.01% BSA.
[00177] Substrate concentrations in the assay were 5- uM ATP (200 uCi/umole ATP) and 1
uM poly(Glu)4Tyr. Reactions were carried out at 25 °C and 1 nM JAK3.
[00178] To each well of a 96 well polycarbonate plate was added 1.5 ul of a candidate
JAK3 inhibitor along with 50 µl of kinase buffer containing 2 µM poly(Glu)4Tyr and 10 uM
ATP. This was then mixed and 50µl of kinase buffer containing 2 nM JAK3 enzyme was
added to start the reaction. After 20 minutes at room temperature (25C), the reaction was
stopped with 50ul of 20% trichloroacetic acid (TCA) that also contained 0.4 mM ATP. The
entire contents of each well were then transferred to a 96 well glass fiber filter plate using a
TomTek Cell Harvester. After washing, 60 µl of scintillation fluid was added and 33P
incorporation detected on a Perkin Elmer TopCount. Compounds of the invention were
found to inhibit JAK-3.
[00179] Example 4: JAK2 Inhibition Assay
[00180] As above (for JAK3) except that final poly(Glu)4Tyr concentration is 15 uM and
final ATP concentration is 12 uM.. Compounds of the invention were found to inhibit
JAK-2.
[00181] Example 5: SYK Inhibition Assay:
[00182] Compounds were screened for their ability to inhibit SYK using a standard
coupled enzyme assay (Fox et ah, Protein Sci. 1998, 7, 2249). Reactions were carried out in
100 mM HEPES (pH 7.5), 10 mM MgCl2, 25 mM NaCl, 1 mM DTT and 1.5% DMSO.
Final substrate concentrations in the assay were 200 µM ATP (Sigma chemical Co.) and 4
uM poly Gly-Tyr peptide (Sigma Chemical Co.). Assays were carried out at 30 °C and 200
nM SYK. Final concentrations of the components of the coupled enzyme system were 2.5
mM phosphoenolpyruvate, 300 uM NADH, 30 µg/ml pyruvate kinase and 10 µg/ml lactate
dehydrogenase.
[00183] An assay stock buffer solution was prepared containing all of the reagents listed
above, with the exception of SYK, DTT, and the test compound of interest of the present
invention. 56 ul of the test reaction was placed in a 96 well plate followed by the addition of
1 ul of 2 mM DMSO stock containing the test compound of the present invnetion (final
compound concentration 30 uM). The plate was pre-incubated for -10 minutes at 30 °C and
the reaction initiated by the addition of 10 µl of enzyme (final concentration 25 nM). Rates
of reaction were obtained using a BioRad Ultramark plate reader (Hercules, CA) over a 5
minute read time at 30°C, and K values for the compounds of the present invention were
determined according to standard methods. Compounds of the invention were found to
inhibit SYK.
WE CLAIM:
Quinoxalines of formula (I):
I
or a pharmaceutically acceptable salt thereof, wherein:
R1 and R2, taken together, form an optionally substituted 5- or 6-membered
monocyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen,
or sulfur or a 5-, 6-, or 7-membered saturated or partially unsaturated monocyclic ring having
0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein any ring
formed by R1 and R2 taken together is optionally substituted at one or more substituable
carbon or nitrogen atoms with n independent occurrences of Q-Rx, wherein n is 0-5;
each occurrence of R is independently selected from hydrogen or a C1-6 aliphatic group; and
each occurrence of R' is independently hydrogen or an optionally substituted group selected
from C1-8 aliphatic; a 5-6 membered monocyclic or an 8-10 mernbered bicyclic aryl group
having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3-7-
membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; or an 8-10-membered saturated or
partially unsaturated bicyclic ring system having 0-5 heteroatoms independently selected
from nitrogen, oxygen, or sulfur; or wherein R and R' taken together, or two occurrences of
R' taken together, form a 3-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring
having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein
each R' is optionally substituted with R° or N(R°)2 wherein R° is H or C1-6aliphatic;
each independent occurrence of Q is a bond or is a C1-C6 alkylidene chain wherein up
to two methylene units of Q are optionally replaced by -C(O)-, -C(S)-, -C(O)C(O)-,
-C(O)NR-, -C(O)NRNR-, -CO2-, -OC(O)-, -NRCO2-, -O-, -NRC(O)NR-, -OC(O)NR-,
-NRNR, -NRC(O)-, -S-, -SO-, -SO2-, -NR-, -SO2NR-, or -NRSO2-; and each occurrence of
Rx is independently R', halogen, NO?, or CN;
X1 is C=O, SO, SO2, or C=NR;
X2 is NR, S, O, or C(R)2; and
R3 is an optionally substituted group selected from: C1-6 aliphatic; a 5-6 membered
monocyclic or an 8-10 membered bicyclic aryl group having 0-5 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; a 3-8-membered saturated or partially unsaturated
monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur; or an 8-10-membered saturated or partially unsaturated bicyclic ring system having 0-
5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R3 is
optionally substituted with m independent occurrences of Z-RY, wherein m is 0-5; each
independent occurrence of Z is a bond or is a C1-C6 alkylidene chain, wherein up to two
methylene units of Z are optionally replaced by -C(O)-, -C(O)C(O)-, -C(O)NR-,
-C(O)NRNR-, -CO,-, -OC(O)-, -NRC(O)0-, -O-, -NRC(O)NR-, -OC(O)NR-, -NRNR,
-NRC(O)-, -S-, -SO-, -SO2-, -NR-, -SO2NR-, or -NRSO2-; and each, occurrence of RY is .
independently R', halogen, NO2, or CN,
provided that:
a) when R1 and R2, taken together, are unsubstituted phenyl, then:
i) when X] is CO, and X2 is CH2, then R3 is not methyl, unsubstituted
phenyl, substituted furyl, 2-Cl-phenyl, 3,5-dimethyl-2-benzofuranyl,
3,7-dimethyl-2-benzofuranyl, or 4-OMe-phenyl;
ii) when X, is CO, and X2 is NH, then R3 is not methyl, -C(O)CH3,
-C(O)0(Ci.3alkyl)r -C(O)C(O)OH. -C(O)C(O)0(C,-3alkyl),
unsubstituted phenyl, cyclohexyl, benzyl, substituted benzofuranyl,
2,4-dicMoro-phenyl, 4-Cl-phenyl, or 4-Me-phenyl;
iii) when X1 is CO and X2 is NMe, then R3 is not methyl;
iv) when X1 is CO and X2 is O, then R3 is not methyl;
v) when X1 is CO and X2 is CHOH, then R1 is not unsubstituted phenyl or
-CHOHCH2OH;
b) when R1 and R2, taken together are unsubstituted cyclohexyl, then:
i) when X1 is CO and X2 is CH2, then R3 is not unsubstituted phenyl; and
ii) when X1 is CO and X2 is NH, then R3 is not unsubstituted benzyl or
cyclohexyl; and
c) when X1 is CO, and X2 is NH, then:
i) when R1 and R2, taken together, are 6,7-Me-phenyl. then R3 is not n-hexyl,
n-butyl, n-propyl, -CH2CH=CH2] -CH=N-CH2CH=CH2, -C(=O)N(R)2,
-C(=O)OR wherein R is H or C1-3 alkyl;
ii) when R1 and R2, taken together, are 6-NHAc-7-Me-phenyl, then R3 is not
-C(=O)CH3;
iii) when R1 and R2, taken together, are 6,7-OMe-phenyl, then R3 is not
C(O)C(O)OH or C(O)C(O)0(C1.3alkyl);
iv) when R1 and R2, taken together, are substituted pyrimidine, then R3 is
not-C(=O)CH3;
d) when X1 is CO and X2 is O, then:
i) when R1 and R2, taken together, are 6,7-Cl-phenyl, then R3 is not methyl
or -CH2CH=CH2;
ii) when R1 and R2, taken together, are 6-NO2-7-F-phenyl, then R3 is not
methyl.
2. The compound as claimed in claim 1, wherein R1 and R2, taken together, form an
optionally substituted 5- or 6-membered monocyclic aryl ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or a 5-, 6-, 7-, or 8-membered
saturated or partially unsaturated monocyclic ring having 0-5 heteroatoms independently
selected from nitrogen, oxygen, or sulfur.
3. The compound as claimed in claim 1 or claim 2, wherein R1 and R2, taken together,
form an optionally substituted 5- or 6-membered monocyclic aryl ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or sulfur.
4. The compound as claimed in claim 3, wherein R1 and R2, taken together, form an
optionally substituted 6-membered monocyclic aryl ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur.
5. The compound as claimed in claim 1 or claim 2, wherein R1 and R1 are taken together
to form a ring and compounds have one of the' folio wing structures:
6. The compound as claimed in claim 5, wherein compounds have formula I-A, I-H, I-I,
I-J, I-KI-L, I-M, or I-N.
7. The compound as claimed in claim 6, wherein compounds have formula I-A.
8. The compound as claimed in claim 1 or claim 7, wherein n is 0-4, and each
occurrence of Q-Rx, when present, is independently halogen, CN, NO2, or an optionally
substituted group selected from C1-4alkyl, aryl, aralkyl, heteroaryl, a cycloalkyl or
heterocycloalkyl group having 3-10 atoms, N(R)R', -CH2N(R)R', -OR', -CH2OR', -SR',
-CH2SR', -C(O)OR', -NRCOR',-CON(R)R', or-S(O)2N(R)R'.
-CH2N(R% -CH2OR', -CH2SR', -(CH2)2N(R% -(CH2)2OR', -(CH2)2SR', -COR',
-CON(R')2, SO2R', or -S(O)2N(R')2.
16. The compound as claimed in claim 15, wherein any substitutable nitrogen atom on a
ring formed by R1 and R2, taken together is substituted with H, Me, CF3, ethyl, propyl, butyl,
pentyl, CO(C1-C4alkyl), -CONH2, -COO(C1-C4alkyl), -CH2OH, -SO2(C1-C4alkyl), -SO2NH2,
-SO2N(CH3)2, or optionally substituted phenyl or benzyl.
17. The compound as claimed in claim 1, wherein X1 is C=O, S=O, SO2, or C=NR.
18. The compound as claimed in claim 1, wherein X1 is C=O or SO2.
19. The compound as claimed in claim 1, wherein X1 is C=O and compounds have the
structure:
20. The compound as claimed in claim 1, wherein X2 is NR, S, O, or C(R)2.
21. The compound as claimed in claim 1, wherein X2 is NR or C(R)2.
22. The compound as claimed in claim 1, wherein X2 is NR and compounds have the
structure:
23. The compound as claimed in claim 1, wherein X1 is C=O and X2 is NR and
compounds have the structure:
9. The compound as claimed in claim 8 wherein each occurrence of Q-Rx, when present,
is independently halogen, CN, NO2, or a group selected from C1-4alkyl, -N(R')2, -CH2N(R')2,
-OR', -CH2OR'3 -SR', -CH2SR', -C(O)OR', -NRCOR', or -CON(R')2.
10. The compound as claimed in claim 8 wherein n is 0.
11. The compound as claimed in claim 8 wherein nisi.
12. The compound as claimed in claim 1 or claim 7, wherein n is 0,1, or 2, wherein each
occurrence of Q-Rx, when present, is CL Br, F, CF3, methyl, ethyl, propyl, butyl, CN,
-COOH, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3,
-OCH2CH3, -OCH2CH2CH3, -OCH2CH2CH2CH3, -CH2OH, -NHCOCH3, -SO2NH2,
-NHCO(pyridyl), -NHCONH,, -NH2, -NHCO(CH2)N(CH2)2, -NHC0(CH2)NH2, or a group
selected from piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, benzyloxy,
pyridyl, pyrimidinyl, pyridazinyl, thiophene, furan, thiazole, oxazole, thiadiazole, oxadiazole,
pyrazole, or pyrrole.
13. The compound as claimed in claim 12 wherein each occurrence of Q-Rx, when
present, is CI, Br, F, CF3, methyl, ethyl, propyl, butyl, CN, -COOH, -N(CH3)2, -N(Et)2,
-N(iPr)2, -O(CH2)2OCH3, -CONH2, -COOCH3, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3,
-OCH2CH2CH2CH3, -CH2OH, -NHCOCH3, -SO2NH2, -NHCO(pyridyl), -NHCONH2, -NH2,
-NHCO(CH2)N(CH2)2, or-NHCO(CH2)NH2.
14. The compound as claimed in claim 12 wherein each occurrence of Q-Rx, when
present, is a group selected from piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy,
benzyl benzyloxy, pyridyl, pyrimidinyl, pyridazinyl, thiophene, furan, thiazole, oxazole,
thiadiazole, oxadiazole, pyrazole, or pyrrole.
15. The compound as claimed in claim 1 or claim 2, wherein any substitutable nitrogen
atom on a ring formed by R1 and R2, taken together, is substituted with hydrogen, or with an
optionally substituted group selected from C1-6alkyl, aryl, aryl(C1-6)alkyi, -N(R')2,

24. The compound as claimed in claim 7, wherein X1 is C=O and X1 is NR and
compounds have the structure:
I-A-i.
25. The compound as claimed in claim 1, 7 or 24 wherein R3 is a 5-6 membered
monocyclic or an 8-10 membered bicyclic aryl group having 0-5 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; a 3-8-membered saturated or partially unsaturated
monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur; or an 8-10-membered saturated or partially unsaturated bicyclic ring system having 0-
5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
26. The compound as claimed in claim 1, 7 or 24, wherein R3 is an optionally
substituted C1-6aliphatic group, wherein the C1-6aliphatic group is optionally substituted with
a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl group having 0-5
heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3-8-membered
saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; or an 8-10-membered saturated or partially
unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur.
27. The compound as claimed in claim 25 or claim 26, wherein the 5-6 membered
monocyclic or 8-10 membered bicyclic aryl group having 0-5 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; the 3-8-membered saturated or partially
unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur; or the 8-10-membered saturated or partially unsaturated bicyclic ring
system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur is
selected from one of the following groups:
28. The compound as claimed in claim 27, wherein R3 is an optionally substituted group
selected from i, ii, xxxix, xl, xii, or xiii.
29. The compound as claimed in claim 27. wherein R3 is an optionally substituted phenyl
group (i).
30. The compound as claimed in any one of claims 1, 7, or 24, wherein Z is a bond or is a
C1-6 alkylidene chain wherein one or two non-adjacent methylene units are optionally and
independently replaced by -O-, -NR-, -S-, -SO2-, or -C(O)0-, -CO-, and RY is R' or halogen.
31. The compound as claimed in any one of claims 1, 7, or 24, wherein each occurrence
of ZRY, when present, is independently -C1-2alkyl, -O(C1-3alkyl), -OH, -S(C1-3alkyl), -SH, CF3,
-OCF3, -SCF3, -F, -CI, -Br, -CN, -COOR', -COR', -O(CH2)2N(R)(R'), -O(CH2)N(R)(R'),
-CON(R)(R'), -NRCOR', -(CH2)2OR', -(CH2)OR', -N(R)(R'), -(CH2)2N(R)(R'), -(CH2)N(R)
(R'), -SO2N(R)(R'), -NRSO2R', or an optionally substituted group selected from
pyrrolidinyl, morpholino, piperazinyl, piperidinyl, phenyl, phenoxy, benzyl, benzyloxy,
triazolyl, pyrazolyl, or pyridyl.
32. The compound as claimed in any one of claims 1, 7, or 24, wherein any substitutable
nitrogen atom in an R3 group is substituted with hydrogen, or an optionally substituted group
selected from C1-6alkyl, aryl, aryl(C1-6)alkyl, N(R)R', -CH2N(R)R',-CH2OR', -CH2SR', -
(CH2)2N(R')2, -(CH2)2OR', -(CH2)2SR', -COR', -CON(R)R', SO2R', or -S(O)2N(R')2.
33. The compound as claimed in claim 32, wherein any substitutable nitrogen atom is
substituted with H, Me, CF3, ethyl, propyl, butyl, pentyl, CO(C1-C4alkyl), -CONH2,
-COO(C1-C4alkyl), -CH2OH, -SO2(C1-C4alkyl), -SO2NH2; SO2N(CH3)2, or optionally
substituted phenyl or benzyl.
34. The compound as claimed in claim 1 selected from:
35. A pharmaceutical!}-' acceptable composition comprising an effective amount of
compound as claimed in claim 1. and a pharmaceutically acceptable carrier, adjuvant or
vehicle.
36. The composition as claimed in claim 35, wherein the compound is in an amount to
detectably inhibit SYK, JAK-3, or GSK-3 protein kinase activity.
37. The composition as claimed in claim 35, additionally comprising a therapeutic agent
selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an
immunomodulatory or immunosuppressive agent a neurotrophic factor, an agent for treating
cardiovascular disease, an agent for treating diabetes, or an agent for treating
immunodeficiency disorders.
38. A pharmaceutical composition as claimed in claim 35, for inhibiting SYK, JAK-3, or
GSK-3 kinase activity in:
(a) a patient; or
(b) a biological sample.
39. The composition as claimed in claim 38, wherein the kinase activity is SYK activity.
40. A pharmaceutical composition as claimed in claim 35, for treating or lessening the
severity of a disease of condition selected from a proliferative disorder, a cardiac disorder, a
. neurodegenerative disorder, an autoimmune disorder, a condition associated with organ
transplant, an inflammatory disorder, or an immunologically mediated disorder.
41. The composition as claimed in claim 40, in combination with an additional
therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-
inflammatory agent, an immunomodulatory or immunosuppressive agent a neurotrophic
factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent
for treating immunodeficiency disorders, wherein:
said additional therapeutic agent is appropriate for the disease being treated
42. The composition as claimed in claim 40. wherein the disease or disorder is allergic or
type I hypersensitivity reactions, asthma, diabetes, Alzheimer's disease, Huntington's
disease, Parkinson's disease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML,
Lou Gehrig's disease), multiple sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy,
reperfusion/ischeniia, stroke, baldness, transplant rejection, graft versus host disease,
rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis, and solid and
hematologic malignancies such as leukemias and lymphomas.
43. The composition as claimed in claim 40, wherein the disease or disorder is asthma.


The present invention relates to compounds useful as inhibitors of protein kinases,
such as SYK, JAK-3, or GSK-3 protein kinases. These compounds have the general formula
I:

or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, X1, and X2 are as defined
herein. The invention also provides processes for making said compounds, pharmaceutically
acceptable compositions comprising said compounds, and methods of using the
compositions in the treatment of various diseases, conditions, or disorders.

Documents:

01556-kolnp-2006-abstract.pdf

01556-kolnp-2006-claims.pdf

01556-kolnp-2006-correspondence other.pdf

01556-kolnp-2006-correspondence.pdf

01556-kolnp-2006-description complete.pdf

01556-kolnp-2006-form 1.pdf

01556-kolnp-2006-form 3.pdf

01556-kolnp-2006-form 5.pdf

01556-kolnp-2006-form-18.pdf

01556-kolnp-2006-international publication.pdf

01556-kolnp-2006-international search report.pdf

01556-kolnp-2006-pct form.pdf

01556-kolnp-2006-priority document.pdf

1556-KOLNP-2006-CORRESPONDENCE-1.1.pdf

1556-KOLNP-2006-CORRESPONDENCE-1.2.pdf

1556-kolnp-2006-correspondence.pdf

1556-kolnp-2006-examination report.pdf

1556-kolnp-2006-form 13.pdf

1556-kolnp-2006-form 18.pdf

1556-kolnp-2006-form 3.pdf

1556-kolnp-2006-form 5.pdf

1556-KOLNP-2006-FORM-27-1.pdf

1556-KOLNP-2006-FORM-27.pdf

1556-kolnp-2006-gpa.pdf

1556-kolnp-2006-granted-abstract.pdf

1556-kolnp-2006-granted-claims.pdf

1556-kolnp-2006-granted-description (complete).pdf

1556-kolnp-2006-granted-form 1.pdf

1556-kolnp-2006-granted-form 2.pdf

1556-kolnp-2006-granted-specification.pdf

1556-kolnp-2006-others.pdf

1556-kolnp-2006-reply to examination report.pdf


Patent Number 248227
Indian Patent Application Number 1556/KOLNP/2006
PG Journal Number 26/2011
Publication Date 01-Jul-2011
Grant Date 28-Jun-2011
Date of Filing 06-Jun-2006
Name of Patentee VERTEX PHARMACEUTICALS INCORPORATED
Applicant Address 130 WAVERLY STREET, CAMBRIDGE, MA 02139
Inventors:
# Inventor's Name Inventor's Address
1 BEMIS, GUY, W. 256 APPLETON STREET, ARLINGTON, MA 02476
2 DUFFY, JOHN, P. 174 CARRIAGE HILL ROAD, NORTH-BOROUGH, MA 01532
PCT International Classification Number C07D 403/12
PCT International Application Number PCT/US2004/040777
PCT International Filing date 2004-12-03
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/526,843 2003-12-04 U.S.A.