Note: Descriptions are shown in the official language in which they were submitted.
CA 02689117 2009-11-30
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5-HETEROARYL SUBSTITUTED INDAZOLES AS KINASE INHIBITORS
Technical Field
The present invention relates to 5-substituted indazole containing compounds,
methods of making the compounds, compositions containing the compounds which
are useful
for inhibiting kinases such as Glycogen Synthase kinase 3 (GSK-3), Rho kinase
(ROCK),
Janus Kinases (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNKl, aurora, pim 1 and
nek 2.
Background of the Invention
Protein kinases are a class of enzymes that catalyze the transfer of a
phosphate group
from ATP to a tyrosine, serine, threonine, or histidine residue located on a
protein substrate.
Protein kinases clearly play a role in normal cell growth. Many of the growth
factor receptor
proteins have intracellular domains that function as protein kinases and it is
through this
function that they effect signaling. The interaction of growth factors with
their receptors is a
necessary event in the normal regulation of cell growth, and the
phosphorylation state of
substrate proteins often is related to the modulation of cell growth.
It is widely known that abnormal protein phosphorylation may be directly
linked to
certain disease states or may be a contributing factor in the onset of such
diseases. As a
result, protein kinases have become the targets of new pharmaceutical research
(Cohen, P.
Nature Reviews Drug Discovery, 1:309-315, 2002). Various protein kinase
inhibitors have
been used clinically in the treatment of a wide variety of diseases, such as
cancer, chronic
inflammatory diseases, diabetes and stroke.
The protein kinases are a large and diverse family of enzymes that catalyze
protein
phosphorylation and play a key role in cellular signaling. Protein kinases may
exert positive
or negative regulatory effects, depending upon their target protein. Protein
kinases are
involved in specific signaling pathways which regulate cell functions such as,
but not limited
to, metabolism, cell cycle progression, cell adhesion, vascular function,
apoptosis, and
angiogenesis. As a result, malfunctions of cellular signaling have been
associated with many
diseases, the most characterized of which include cancer and diabetes. The
regulation of
signal transduction by cytokines and the association of signal molecules with
proto-
oncogenes and tumor suppressor genes have been well documented. Similarly, the
connection between diabetes, viral infections and the conditions related
thereto has also been
associated with the regulation of protein kinases.
Because protein kinases regulate nearly every cellular process, including
metabolism,
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cell proliferation, cell differentiation, and cell survival, they are
attractive targets for
therapeutic intervention for various disease states. For example, cell-cycle
control and
angiogenesis, in which protein kinases play a pivotal role are cellular
processes associated
with numerous disease conditions such as, but not limited to, cancer,
inflammatory diseases,
abnormal angiogenesis and diseases related thereto, atherosclerosis, macular
degeneration,
diabetes, obesity, and pain.
The elucidation of the intricacy of protein kinase pathways and the complexity
of the
relationship and interaction among and between the various protein kinases and
kinase
pathways highlights the importance of developing pharmaceutical agents capable
of acting as
protein kinase modulators, regulators or inhibitors that have beneficial
activity on multiple
kinases or multiple kinase pathways.
It has therefore been suggested that due to the complexity of intracellular
signaling
cascades of protein kinase pathways, agents that affect multiple pathways
simultaneously
may be required for meaningful clinical activity. Although it has been
suggested that a single
agent that provides combinatorial effects is an attractive notion, there is a
need to identify and
use single agents that target the right combination of multiple pathways that
are clinically
effective in a particular disease setting.
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase encoded by two
isoforms, GSK-3a and GSK-3(3 with molecular weights of 51 and 47 kDa,
respectively.
These share 97% sequence similarity in their kinase catalytic domains. The GSK-
3a isoform
has an extended glycine-rich N-terminal tail. A minor splice variant of GSK-3
(3 has been
identified (expressed at - 15% of total) with a 13 amino acid insert within
the kinase domain.
This variant had a reduced activity towards tau. GSK-3 is highly conserved
throughout
evolution, and found in all mammals thus far with high homology in the kinase
domain. Both
isoforms are ubiquitously expressed in mammalian tissues, including the brain.
Pharmacological GSK-3 inhibitors are not able to selectively inhibit one of
the isoforms.
GSK-3 (3 plays an important role in the control of metabolism, differentiation
and
survival. It was initially identified as an enzyme able to phosphorylate and
hence inhibit
glycogen synthase. Subsequently, it was recognized that GSK-3(3 was identical
to tau protein
kinase 1(TPKl), an enzyme that phosphorylates tau protein in epitopes that are
also found to
be hyperphosphorylated in Alzheimer's disease and in several taupathies.
Interestingly, protein kinase B (AKT) phosphorylation of GSK-3(3 results in a
loss of
kinase activity, and it has been proposed that this inhibition may mediate
some of the effects
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of neurotrophic factors. Moreover, phosphorylation of (3-catenin (a protein
involved in cell
survival) by GSK-3(3, results in its degradation by an ubiquitinilation
dependent proteasome
pathway.
Therefore it appears that inhibition of GSK-3(3 activity may result in
neurotrophic
activity. There is evidence that lithium, an uncompetitive inhibitor of GSK-
3(3, enhances
neuritogenesis in some models and can also increase neuronal survival, through
the induction
of survival factors such as Bcl-2 and the inhibition of the expression of
proapoptotic factors
such as P53 and Bax.
Further studies have shown that (3-amyloid increases GSK-3 (3 activity and tau
protein
phosphorylation. Moreover, this hyperphosphorylation as well as the neurotoxic
effects of (3-
amyloid are blocked by lithium chloride and by a GSK-3(3 antisense mRNA. These
observations taken together suggest that GSK-3(3 may be the link between the
two major
pathological processes in Alzheimer's disease: abnormal APP (Amyloid Precursor
Protein)
processing and tau protein hyperphosphorylation.
These experimental observations indicate that GSK-3(3 may find application in
the
prevention and treatment of the neuropathological consequences and the
cognitive and
attention deficits associated with Alzheimer's disease, as well as other acute
and chronic
neurodegenerative diseases. These include, but are not limited to: Parkinson's
disease,
tauopathies (e.g. frontotemporoparietal dementia, corticobasal degeneration,
Pick's disease,
progressive supranuclear palsy) and other dementia including vascular
dementia; acute stroke
and other traumatic injuries; cerebrovascular accidents (e.g. age related
macular
degeneration); brain and spinal cord trauma; peripheral neuropathies;
retinopathies and
glaucoma.
GSK-3 (3 may also have utility in the treatment of other diseases such as: non-
insulin
dependent diabetes and obesity; manic depressive illness; schizophrenia;
alopecia;
inflammation; cancers such as breast cancer, non-small cell lung carcinoma,
thyroid cancer, T
or B-cell leukemia and several virus-induced tumors.
Rho kinases (ROCKs), the first Rho effectors to be described, are
serine/threonine
kinases that are important in fundamental processes of cell migration, cell
proliferation and
cell survival. Abnormal activation of the Rho/ROCK pathway has been observed
in various
disorders. Examples of disease states in which compounds of the present
invention have
potentially beneficial therapeutic effects due to their anti vasospasm
activity includes
cardiovascular diseases such as hypertension, chronic and congestive heart
failure, cardiac
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hypertrophy, restenosis, chronic renal failure, cerebral vasospasm after
subarachnoid
bleeding, pulmonary hypertension and atherosclerosis. The muscle relaxing
property is also
beneficial for treating asthma, male erectile dysfunctions, female sexual
dysfunction, and
over-active bladder syndrome. Injury to the adult vertebrate brain and spinal
cord activates
ROCKs, thereby inhibiting neurite growth and sprouting. Inhibition of ROCKs
results in
induction of new axonal growth, axonal rewiring across lesions within the CNS,
accelerated
regeneration and enhanced functional recovery after acute neuronal injury in
mammals
(spinal-cord injury, traumatic brain injury). Inhibition of the Rho/ROCK
pathway has also
proved to be efficacious in other animal models of neurodegeneration like
stroke,
inflammatory and demyelinating diseases, Alzheimer's disease as well as the
treatment of
pain. Rho/ROCK pathway inhibitors therefore have potential for preventing
neurodegeneration and stimulating neuroregeneration in various neurological
disorders,
including spinal-cord injury, Alzheimer's disease, stroke, multiple sclerosis,
amyotrophic
lateral sclerosis, as well as the treatment of pain. ROCK inhibitors have been
shown to
possess anti-inflammatory properties. Thus, compounds of the invention can be
used as
treatment for neuroinflammatory diseases such as stroke, multiple sclerosis,
Alzheimer's
disease, Huntington's disease, Parkinson's disease, amyotrophic lateral
sclerosis, and
inflammatory pain, as well as other inflammatory diseases such as rheumatoid
arthritis,
osteoarthritis, asthma, irritable bowel syndrome, Crohn's disease, psoriasis,
ulcerative colitis,
Lupus, and inflammatory bowel disease. Since ROCK inhibitors reduce cell
proliferation and
cell migration, they could be useful in treating cancer and tumor metastasis.
Further more,
there is evidence suggesting that ROCK inhibitors suppress cytoskeletal
rearrangement upon
virus invasion, thus they also have potential therapeutic value in anti-viral
and anti-bacterial
applications. ROCK inhibitors are also useful for the treatment of insulin
resistance and
diabetes. Further, ROCK inhibitors have been shown to ameliorate progression
of cystic
fibrosis (Abstract S02.3, 8th World Congress on Inflammation, Copenhagen,
Denmark, June
16-20, 2007).
In addition, Rho-associated coiled-coil forming protein kinases (ROCK)-1 and -
2,
have been shown to enhance myosin light chain (MLC) phosphorylation by
inhibiting MLC
phosphatase as well as phosphorylating MLC. This results in the regulation of
actin-myosin
contraction. Recent reports have demonstrated that inhibition of ROCK results
in disruption
of inflammatory cell chemotaxis as well as inhibition of smooth muscle
contraction in models
of pulmonary inflammation associated with asthma. Therefore, the inhibitors of
the
Rho/ROCK pathway should be useful for the treatment of asthma.
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The Janus kinases (JAKs) are an important family of intracellular protein
tyrosine
kinases (PTKs), with 4 mammalian members, JAKl, JAK2, JAK3, and TYK2, as well
as
homologs in chicken, fish, and Drosophila. The JAKs play critical roles in
several important
intracellular signaling pathways, including the eponymous JAK/STAT pathway,
central to the
mediation of cytokine signaling. It is this pivotal role in cytokine signaling
that underpins
the notion that specific JAK inhibitors may be therapeutically deployed in
situations where
cytokine activity results in disease. Important examples of this include
autoimmune diseases
such as rheumatoid arthritis and psoriasis, myeloproliferative syndromes such
as, leukemias,
lymphomas, and cardiovascular diseases.
JAK2, a member of the Janus kinase (JAK) family of protein tyrosine kinases
(PTKs),
is an important intracellular mediator of cytokine signaling. Mutations of the
JAK2 gene are
associated with hematologic cancers, and aberrant JAK activity is also
associated with a
number of immune diseases, including rheumatoid arthritis.
Aurora kinases are a family of multigene mitotic serine-threonine kinases that
functions as a class of novel oncogenes. These kinases comprise aurora-A,
aurora-B, and
aurora-B members. These are hyperactivated and/or over-expressed in several
solid tumors
including but not limited to breast, ovary, prostate, pancreas, and colorectal
cancers. In
particular aurora-A is a centrosome kinase, and its localization depends on
the cell cycle and
plays an important role cell cycle progression and cell proliferation. Aurora-
A is located in
the 20q13 chromosome region that is frequently amplified in several different
types of
malignant tumors such as colorectal, breast and bladder cancers. Inhibition of
aurora kinase
activity could help to reduce cell proliferation, tumor growth and potentially
tumorigenesis.
Accordingly, there remains a need for the development of methods comprising
the use
of a single agent drug capable of targeting specific sets of kinases or kinase
pathways. In
particular such methods affect the right combination of multiple targets
thereby achieving
clinical efficacy.
Summary Of The Invention
In the principle embodiment, the present invention provides compounds of
Formula
(I),
R~
A
N
(R3)m/ N
R2
(I)~
5
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or a pharmaceutically acceptable salt thereof, wherein
A is
(Ri)a (Rii)b (Riii)c (Riv)c (Rv)b
N, NI N N, I N ~IN~ Q I ~ I N~ ' N
(i) (ii) (iii) (iv) (v)
(Rvi)b (Rvii)b (Rviii)a (Rix)a
N
I ~ ~ I,N~ I ~ ~
O Ol ~ O~ ~ 0 (vi) (vii) (viii) (ix)
(Rx)b (Rxi)b (Rxii)a (Rxiii)a
N N
I,l `I, I
S S S S
(x) (xi) (xii) (xiii)
(Rxiv)c ^ ^ ~ N (Rxv)d (Rxvi)d (Rxvii)d
~ ~ ~~- N^iz+~ r\ N~j~ N
S N
N N N ~ N N~
(xiv) (xv) (xvi) (xvii)
(RN )c (Rxix)cN (Rxx)N` l (Rxxi)d\~
, T~ C TI
N~ N , N N
(xviii) (xix) (xx) (xxi)
(Rxxii)c (Rxxiii)c
~I% or ~I%~ ;
S
(xxii) (xxiii)
Ri is hydrogen, alkyl, aryl, heterocycle, heteroaryl, RRbN-, RRdN-C(O)- or
RRdN-S(O)z-;
R2 is hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl,
heterocyclecarbonyl or ReRfN-alkyl-C(O)-;
R3 is alkyl, alkoxy, aryl, cyano, cycloalkyl, halogen, haloalkyl, heteroaryl,
nitro, or
RgRhN-;
R4 is alkyl, alkoxyalkyl, aryl, cycloalkyl, heteroaryl, heterocycle,
heterocyclealkyl,
RjRkN- or RjRkN-alkyl-;
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R5 is alkyl, aryl, or heteroaryl;
R6 is alkyl, alkoxyalkyl, RjRkN-alkyl-, aryl, cycloalkyl or heteroaryl;
R7 is alkyl, aryl or heteroaryl;
Ra and Rb are each independently hydrogen, alkyl, arylalkyl, cycloalkyl,
cycloalkylalkyl, heteroarylalkyl, R4-C(O)-, or RS-S(O)z-;
R, and Rd are each independently hydrogen, alkyl or heteroaryl;
Re and Rf are each independently hydrogen, alkyl, arylalkyl, heteroarylalkyl,
R6-C(O)-, or R7-S(O)2-;
R. and Rh are each independently hydrogen, alkyl, or alkylcarbonyl;
Rj and Rk are each independently hydrogen, alkyl, aryl, arylalkyl, cycloalkyl,
heteroaryl, or heterocycle;
Ri, Rij, Ri , Ri,, R,, Rj, Rji, Ri , RiX, RX, RXi, RXii, RXiii, RXi,, RX,,
RX,j, RXjj, RXvjjj, RXjX,
RXX, RXõ RXxiõ and RXX,;; are each independently alkyl, alkoxy, alkoxyalkyl,
alkoxycarbonyl,
alkoxycarbonylalkyl, aryl, arylalkyl, aryl(hydroxy)alkyl, aryloxyalkyl,
arylcarbonyl,
arylthioalkyl, carboxy, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkylcarbonyl, halogen, heteroaryl, heteroarylalkyl, heterocycle,
heterocyclealkyl,
heterocyclecarbonyl, hydroxyalkyl, trialkylsilylalkyl, H2NC(O)-alkyl, ZaZbN-,
ZaZbNalkyl,
Z,ZdNC(O)- or ZZdNS(O)z- wherein RX,v, RX,, RXv,, and RXv;; may occur at any
open valence
on compounds (xiv), (xv), (xvi) or (xvii);
Za and Zb are each independently hydrogen, alkyl, alkoxycarbonylalkyl, aryl,
arylalkyl, cycloalkyl, H2NC(O)-, H2NalkylC(O)-, H2NC(O)-alkyl, dialkylNC(O)-
or
dialkylNC(O)-alkyl-;
Z, and Zd are each independently hydrogen, alkyl, alkoxyalkyl, aryl,
arylalkyl,
aryl(hydroxy)alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycle,
heterocyclealkyl, hydroxyalkyl, H2NC(O)-alkyl-, dialkylNC(O)-alkyl-, dialkylN-
alkyl-, or
CHZeZ f;
Ze is aryl or heteroaryl;
Zf is heteroarylalkyl, heterocyclealkyl, or ZiZzN-alkyl-;
m is 0, 1 or 2;
ais0orl;
b is 0, 1, or 2;
c is 0, 1, 2 or 3; and
d is 0, 1, 2, 3 or 4.
Also provided are pharmaceutically acceptable compositions comprising a
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therapeutically effective amount of a compound of formula (I) in combination
with a
pharmaceutically suitable carrier.
The object of the present invention is to provide compounds that are useful
for the
preventive of or treatment of diseases caused by abnormal protein kinase
activity. In
addition, the invention also provides pharmaceutically effective compositions
of the
compounds of the present invention that are useful for the prevention of or
treatment of said
diseases.
The present invention also relates to a pharmaceutical composition which
comprises
at least one 5-substituted indazole compound of the formula (I) which may
exist as a
pharmaceutically acceptable salt or prodrug thereof, in the presence or
absence of
pharmaceutically acceptable carriers, dragees, adjuvants or other auxiliary
substances.
The compounds of the present invention have inhibitory activity against GSK-3,
ROCK-l, ROCK-2, JAK2 as well as other kinases and are useful for the
inhibition of such
kinases. Certain compounds of the present invention are selective toward one
or more
kinases and may be useful for the selective inhibition of such kinases.
Accordingly, the
compounds of the present invention are useful as an active ingredient for the
preparation of a
composition, which enables preventive and/or therapeutic treatment of a
disease caused by
abnormal GSK-3 activity and more particularly, of neurodegenerative diseases
such as
Alzheimer's disease. In addition, the compounds of the present invention are
also useful as an
active ingredient for the preparation of a composition for preventive and/or
therapeutic
treatment of neurodegenerative diseases such as Parkinson's disease,
tauopathies (e.g.
frontotemporoparietal dementia, corticobasal degeneration, Pick's disease,
progressive
supranuclear palsy) and other dementia including vascular dementia; acute
stroke and other
traumatic injuries; cerebrovascular accidents (e.g. age related macular
degeneration); brain
and spinal cord trauma; peripheral neuropathies; retinopathies and glaucoma;
and other
diseases such as non-insulin dependent diabetes (such as diabetes type II) and
obesity; manic
depressive illness; schizophrenia; alopecia; cancers such as breast cancer,
non-small cell lung
carcinoma, thyroid cancer, T or B-cell leukemia and several virus-induced
tumors.
Detailed Description of the Invention
Compounds of the present invention have the formula (I) as described above.
More
particularly, compounds of formula (I) can include, but are not limited to,
compounds
wherein A is (ii), (iii), (iv), (vii), (x), (xiv), (xv), (xvi), (xvii),
(xviii), (xix), (xx), (xxi), (xxii),
or (xxiii).
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In another embodiment of the present invention there is disclosed a compound
of
formula (I), wherein A is (ii),
(Rii)b
N I,NA
N
(ii);
Ri is hydrogen, aryl, heteroaryl, heterocycle, RaRbN- or RRdN-C(O)-; R2 is
hydrogen,
alkoxycarbonyl, heterocyclecarbonyl, alkylcarbonyl, or RRfN-alkyl-C(O)-; R4 is
alkyl,
alkoxyalkyl, aryl, cycloalkyl, heterocycle, heterocyclealkyl, RjRkN-, or RjRkN-
alkyl-; R5 is
alkyl, aryl, or heteroaryl; Ra and Rb are each independently hydrogen,
arylalkyl,
cycloalkylalkyl, R4-C(O)-, or RS-S(O)2-; R, and Rd are each independently
hydrogen or
heteroaryl, R. and Rf are each independently hydrogen or alkyl, Rj and Rk are
each
independently hydrogen, alkyl, aryl, cycloalkyl, or heterocycle; R;; is alkyl,
alkoxyalkyl,
alkoxycarbonyl, aryl, arylalkyl, aryl(hydroxy)alkyl, aryloxyalkyl,
arylcarbonyl,
alkoxycarbonylalkyl, arylthioalkyl, carboxy, carboxyalkyl, cycloalkyl,
cycloalkylalkyl,
cycloalkylcarbonyl, halogen, heteroaryl, heteroarylalkyl, heterocycle,
heterocyclealkyl,
heterocyclecarbonyl, hydroxyalkyl, trialkylsilylalkyl, ZaZbN-, ZaZbNalkyl-, or
ZcZdNC(O)-;
Za and Zb are each independently hydrogen, alkyl, or H2NalkylC(O)-; Zc and Zd
are each
independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, cycloalkyl,
cycloalkylalkyl,
heteroarylalkyl, heterocyclealkyl, hydroxyalkyl, or dialkyLN-alkyl-; m is 0;
and b is 0, 1, or 2.
In another embodiment of the present invention, there is disclosed a compound
of
formula (I), wherein A is (iii),
(Riii)c
N
(iii)
Ri is hydrogen or RaRbN-; R2 is hydrogen; R4 is RjRkN-alkyl-; Ra and Rb are
each
independently hydrogen or R4-C(O)-; Rj and Rk are each alkyl; R;;, is
alkoxycarbonylalkyl,
alkyl, arylalkyl, cyanoalkyl, heterocyclealkyl, or H2NC(O)-alkyl-; c is 0, 1,
or 2; and m is 0.
In another embodiment of the present invention, there is disclosed a compound
of
formula (I), wherein A is (iv),
(Riv)c
'-N
~
N
(iv)
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Ri is hydrogen or RaRbN-; R2 is hydrogen; Ra and Rb are each hydrogen; R,, is
aryl,
arylalkyl, heterocycle, heterocyclealkyl, ZaZbNalkyl or Z,ZaNS(O)z-; Za and Zb
are each
independently hydrogen or alkyl; Zc and Zd are each alkyl; c is 0, 1, or 2;
and m is 0.
In another embodiment of the present invention, there is disclosed a compound
of
formula (I), wherein A is (vii),
(Rvii)b
,N
O
(vii)
Ri is hydrogen, alkyl, or RaRbN; R2 is hydrogen; Ra and Rb are each hydrogen;
Rv,; is
alkyl, alkoxycarbonyl, aryl, arylalkyl, cycloalkyl, heterocyclealkyl,
heterocyclecarbonyl,
hydroxyalkyl, or Z,ZdNC(O)-; Z, and Zd are each independently hydrogen, alkyl,
alkoxyalkyl, aryl, arylalkyl, aryl(hydroxy)alkyl, cycloalkyl, cycloalkylalkyl,
heteroarylalkyl,
heterocycle, heterocyclealkyl, hydroxyalkyl, or CHZeZf; Ze is aryl or
heteroaryl, Zf is
heteroarylalkyl, heterocyclealkyl, or ZiZzN-alkyl-; b is 1; and m is 0.
In another embodiment of the present invention, there is disclosed a compound
of
formula (I), wherein A is (x),
(Rx)b
N-I--\\
S>
(x)
Ri is hydrogen; R2 is hydrogen; RX is alkyl, aryl, or ZaZliN-; Za and Zb are
each
independently hydrogen, alkyl, aryl, or arylalkyl; b is 1 or 2; and m is 0.
In another embodiment of the present invention, there is disclosed a compound
of
formula (I), wherein A is (xiv),
(RXiv), '\-N
S-J" N
(xiv)
Ri is hydrogen; R2 is hydrogen; RX,v is ZaZbN-; Za and Zb are each
independently
hydrogen or cycloalkyl; c is 1; and m is 0.
In another embodiment of the present invention, there is disclosed a compound
of
formula (I), wherein A is (xv),
(Rxv)d
=\ N\
N
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WO 2008/154241 PCT/US2008/065727
(xv)
Ri is hydrogen or RaRbN-; R2 is hydrogen; Ra and Rb are each hydrogen; Rx, is
ZaZbN-; Za and Zb are each independently hydrogen, alkoxycarbonylalkyl, aryl,
arylalkyl, or
cycloalkyl; d is 0 or 1; and m is 0.
In another embodiment of the present invention, there is disclosed a compound
of
formula (I), wherein A is (xvi),
(Rxvi)(~^
I N
N~N
(xvi)
R, is hydrogen; R2 is hydrogen; RX,; is ZaZbN-; Za and Zb are each
independently
hydrogen or cycloalkyl; d is 1; and m is 0.
In another embodiment of the present invention, there is disclosed a compound
of
formula (I), wherein A is (xvii),
(Rxvii)d
N
~J,N
N
(xvii)
Ri is hydrogen; R2 is hydrogen; Rx,; is aryl or ZaZbN-; Za and Zb are each
independently hydrogen, alkyl, alkoxycarbonylalkyl, aryl, arylalkyl,
cycloalkyl, or
H2NC(O)-alkyl-; d is 0 or 1; and m is 0.
In another embodiment of the present invention, there is disclosed a compound
of
formula (I), wherein A is (xviii),
(Rxvui)c
N7/J~
O1 N/ %
(xviii)
Ri is RaRbN-; R2 is hydrogen; Ra and Re are each hydrogen; c is 0; and m is 0.
In another embodiment of the present invention, there is disclosed a compound
of
formula (I), wherein A is (xix),
(Rxix)c
i
CN~
N
(xix)
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Ri is RaRbN-; R2 is hydrogen; Ra and Re are each independently hydrogen; c is
0; and
m is 0.
In another embodiment of the present invention, there is disclosed a compound
of
formula (I), wherein A is (xx),
~Rxx)o
N
N
(xx)
Ri is RaRbN-; R2 is hydrogen; R4 is RjRkN-alkyl-; Ra and Rb are each hydrogen
or
R4-C(O)-; Rj and Rk are independently alkyl; RXX is ZaZbN- or heterocycle; Za
and Zb are
independently hydrogen or alkyl; c is 0 or 1; and m is 0.
In another embodiment of the present invention, there is disclosed a compound
of
formula (I), wherein A is (xxi),
(RXXj)d
N
(xxi)
Ri is RaRbN-; R2 is hydrogen; Ra and Rb are each hydrogen; RXX; is alkoxy; d
is 1; and
mis0.
In another embodiment of the present invention, there is disclosed a compound
of
formula (I), wherein A is (xxii),
~Rxxu)o
(xxii)
Ri is RaRbN-; R2 is hydrogen; R4 is RjRkN-alkyl-; Ra and Rb are each
independently
hydrogen or R4-C(O)-; Rj and Rk are each alkyl; c is 0 and m is 0.
In another embodiment of the present invention, there is disclosed a compound
of
formula (I), wherein A is (xxiii),
(Rxxui )c
S
(xxiii)
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Ri is RaRbN-; R2 is hydrogen; Ra and Re are each hydrogen; c is 0; and m is 0.
Specific embodiments contemplated as part of the invention include, but are
not
limited to, compounds of formula (I), for example:
5-(1-benzyl-lH-1,2,3-triazol-5-yl)-1H-indazole compound with 5-(1-benzyl-lH-
1,2,3-triazol-4-yl)-1H-indazole;
5 -(1 H-1,2,3-triazol-5-yl)-1 H-indazole;
5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazole;
5 -[ 1-(2-methylbenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
5-[1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;
5 -[ 1-(4-methylbenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
5-[ 1-(3-methoxybenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
5-[ 1-(2-fluorob enzyl)-1 H-1,2, 3-triazol-4-yl] -1 H-indazole;
5-[ 1-(3 -fluorob enzyl)-1 H-1,2, 3-triazol-4-yl] -1 H-indazole;
5-[1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;
5-[ 1-(2-chlorobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
5-[ 1-(3-chlorobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
5-[ 1-(4-chlorobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
5-[ 1-(2-bromobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
5-[1-(2-nitrobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;
5-[ 1-(3-nitrobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
5-[ 1-(4-nitrobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
2- {[4-(1 H-indazol-5 -yl)-1 IH- 1,23-triazol-l-yl]methyl} b enzonitrile;
3- {[4-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-l-yl]methyl}benzonitrile;
4-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-l-yl]methyl}benzonitrile;
5-{ 1-[2-(trifluoromethyl)benzyl] -1 H-1,2, 3-triazol-4-yl} -1 H-indazole;
5- { 1-[3-(trifluoromethyl)benzyl]-1 H-1,2,3-triazol-4-yl}-1 H-indazole;
5-{ 1 -[4-(trifluoromethyl)benzyl] -1 H-1,2, 3-triazol-4-yl} -1 H-indazole;
5- {1-[3-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;
5-{1-[4-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;
5-[ 1-(4-tert-butylbenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
methyl 3- { [4-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-l-yl]methyl}benzoate;
methyl 4- { [4-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-l-yl]methyl}benzoate;
5-[ 1-(2,4-dimethylbenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
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5-[ 1-(3,5-dimethylbenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
5- [ 1-(2,3-dichlorobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
5- [ 1-(2,4-dichlorobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
5- [ 1-(2,5-dichlorobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
5-[1-(3,5-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole;
5- {1-[2,4-bis(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole;
N-cyclohexyl-6-(1 H-indazol-5 -yl)imidazo [2,1-b] [ 1, 3] thiazol-5 -amine;
N-cyclohexyl-2-(1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-amine;
N-cyclohexyl-2-(1H-indazol-5-yl)imidazo[1,2-a]pyrazin-3-amine;
5-[1-benzyl-4-(4-fluorophenyl)-1H-imidazol-5-yl]-1H-indazole;
N- {3 -[4-(4-fluorophenyl)-5-(1 H-indazol-5-yl)-1 H-imidazol-l-yl]propyl} -N,N-
dimethylamine;
N-cyclohexyl-2-(1 H-indazol-5 -yl)imidazo [ 1,2-a]pyrimidin-3 -amine;
5-[4-(4-fluorophenyl)-1-(1-phenylethyl)-1H-imidazol-5-yl]-1H-indazole;
2-(1H-indazol-5-yl)-N-isopropylimidazo[1,2-a]pyrimidin-3-amine;
4-(1 H-indazol-5-yl)-N-phenyl-1,3-thiazol-2-amine;
5-(2-methyl-1,3-thiazol-4-yl)-1H-indazole;
N-ethyl-4-(1H-indazol-5-yl)-1,3-thiazol-2-amine;
N-benzyl-4-(1H-indazol-5-yl)-1,3-thiazol-2-amine;
4-(1H-indazol-5-yl)-1,3-thiazol-2-amine;
4-(1 H-indazol-5 -yl)-N-(2-phenylethyl)-1,3-thiazol-2-amine;
N-benzyl-2-(1 H-indazol-5-yl)imidazo [ 1,2-a]pyrimidin-3 -amine;
N-butyl-2-(1 H-indazol-5 -yl)imidazo [ 1, 2-a]pyrimidin-3 -amine;
N-(4-chlorophenyl)-2-(1 H-indazol-5-yl)imidazo[ 1,2-a]pyrimidin-3-amine;
2-(1H-indazol-5-yl)-N-(4-methoxyphenyl)imidazo[1,2-a]pyrimidin-3-amine;
2-(1H-indazol-5-yl)imidazo[1,2-a]pyrimidine;
methyl N-[2-(1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-yl]glycinate;
N-b enzyl-2-(1 H-indazol-5 -yl)imidazo [ 1, 2-a]pyridin-3 -amine;
N-(4-chlorophenyl)-2-(1 H-indazol-5-yl)imidazo[ 1,2-a]pyridin-3-amine;
2-(1H-indazol-5-yl)-N-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-amine;
tert-butyl4-[4-(4-fluorophenyl)-5-(1 H-indazol-5-yl)-1 H-imidazol-1-
yl]piperidine-l-
carboxylate;
3,5-bis(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazole;
5 -(1-benzyl-1 H-1,2,3-triazol-4-yl)-3-phenyl-1 H-indazole;
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5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-amine;
5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1-[(1-methylpiperidin-4-yl)carbonyl]-1 H-
indazol-
3-amine;
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-methoxyacetamide;
Ni-[5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N2,N2-
dimethylglycinamide;
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]butanamide;
5-[4-(4-fluorophenyl)-1-piperidin-4-yl-lH-imidazol-5-yl]-1H-indazole;
5- {4-(4-fluorophenyl)-1-[2-(1-methylpyrrolidin-2-yl)ethyl]-1 H-imidazol-5-yl}-
1 H-
indazole;
5-{4-(4-fluorophenyl)-1-[3-(4-methylpiperazin-l-yl)propyl]-1H-imidazol-5-yl}-
1H-
indazole;
ethyl 5-(1 H-indazol-5-yl)isoxazole-3-carboxylate;
5-(1 H-indazol-5-yl)-N-methylisoxazole-3-carboxamide;
5-(3-benzylisoxazol-5-yl)-1 H-indazole;
N-[5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzamide;
5-(3-propylisoxazol-5-yl)-1H-indazole;
N-benzyl-4-(1H-indazol-5-yl)-5-phenyl-1,3-thiazol-2-amine;
4-(1 H-indazol-5-yl)-N,5-diphenyl-1,3-thiazol-2-amine;
5 -(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazole;
5-(1-benzyl-4-cyclopropyl-lH-1,2,3-triazol-5-yl)-1H-indazole;
2-(1 H-indazol-5-yl)-3-phenylimidazo [ 1,2-a]pyrimidine;
5-[ 1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
5- [3 -(pip eridin-1-ylcarbonyl)isoxazol-5 -yl] -1 H-indazole;
5-(1 H-indazol-5-yl)-N-phenylisoxazole-3-carboxamide;
N-cyclohexyl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;
5-[3-(piperidin-1-ylmethyl)isoxazol-5-yl]-1H-indazole;
[5-(1 H-indazol-5-yl)isoxazol-3-yl]methanol;
5 -(1 H-indazol-5 -yl)-N-(2-methoxyethyl)isoxazole-3 -carboxamide;
5 -(1-benzyl-5-phenyl-1 H-1,2,3-triazol-4-yl)-1 H-indazole;
5-(4-benzyl-lH-1,2,3-triazol-1-yl)-1H-indazole;
5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-amine;
5-(1-benzyl-4-cyclopropyl-1 H-1,2,3-triazol-5-yl)-1 H-indazol-3-amine;
5-(3-isobutylisoxazol-5-yl)-1 H-indazol-3-amine;
5-(3-benzylisoxazol-5-yl)-1 H-indazol-3-amine;
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N- {2-[4-(4-fluorophenyl)-5-(1 H-indazol-5-yl)-1 H-imidazol-l-yl] ethyl} -N,N-
dimethylamine;
- [4-(4-fluorophenyl)-1-(3 -morpho lin-4-ylpropyl)-1 H-imidazol-5 -yl] -1 H-
indazole;
5-[4-(4-fluorophenyl)-1-(3-pyrrolidin-1-ylpropyl)-1 H-imidazol-5-yl]-1 H-
indazole;
5 5-{4-(4-fluorophenyl)-1-[2-(4-methylpiperidin-l-yl)ethyl]-1H-imidazol-5-yl}-
1H-
indazole;
5-[ 1-(1-benzylpiperidin-4-yl)-4-(4-fluorophenyl)-1 H-imidazol-5-yl]-1 H-
indazole;
5-[4-(4-fluorophenyl)-1-(2-morpholin-4-ylethyl)-1 H-imidazol-5-yl]-1 H-
indazole;
5 - [ 1-(1-benzylpyrrolidin-3-yl)-4-(4-fluorophenyl)-1 H-imidazol-5-yl]-1 H-
indazole;
2-{4-[4-(4-fluorophenyl)-5-(1H-indazol-5-yl)-1H-imidazol-1-yl]piperidin-1-yl}-
2-
oxoethanol;
5 -(1-benzyl-5-phenyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-amine;
2-[ 1-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-4-yl]propan-2-ol;
5- [4-(methoxymethyl)-1 H-1,2,3-triazol-l-yl]-1 H-indazole;
1-[ 1-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-4-yl]-1-phenylethanol;
5-(4-propyl-lH-1,2,3-triazol-1-yl)-1H-indazole;
1-[ 1-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-4-yl]propan-2-ol;
3-[ 1-(1 H-indazol-5 -yl)-1 H-1,2, 3-triazol-4-yl]prop an-l-ol;
1- {[ 1-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-4-yl]methyl}-1 H-1,2,3-
benzotriazole;
5-{4-[(phenylthio)methyl]-1H-1,2,3-triazol-l-yl}-1H-indazole;
5 -(4-cyclopropyl-1 H-1,2,3-triazol-l-yl)-1 H-indazole;
5-[4-(2-phenylethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole;
5-[4-(cyclohexylmethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole;
5-(4-cyclopentyl-lH-1,2,3-triazol-1-yl)-1H-indazole;
1-[ 1-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-4-yl]cyclohexanol;
5- [4-(phenoxymethyl)-1 H-1,2,3-triazol-1-yl]-1 H-indazole;
5- {4-[(1,1-dioxidothiomorpholin-4-yl)methyl]-1 H-1,2,3-triazol-l-yl} -1 H-
indazole;
5- [4-(3-phenylpropyl)-1 H-1,2,3-triazol-l-yl]-1 H-indazole;
[ 1-benzyl-4-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-5-yl] (phenyl)methanone;
N,N-diethyl-N-{[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]methyl}amine;
ethyl N-[2-(1H-indazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl]-beta-alaninate;
5 -(1-benzyl-5-methyl-1 H-1,2,3-triazol-4-yl)-1 H-indazole;
5 -(1-benzyl-5-methyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-amine;
N3-[2-(1H-indazol-5-yl)imidazo [ 1,2-a]pyrimidin-3-yl]-(3-alaninamide;
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5-(1-benzyl-5-iodo-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-amine;
N- {3-[4-(3-amino-1 H-indazol-5-yl)-1-benzyl-1 H-1,2,3-triazol-5-yl]phenyl} -
N'-(3-
methylphenyl)urea;
5-(1 H-indazol-5-yl)-N-(2-isopropoxyethyl)isoxazole-3-carboxamide;
5-[3-(morpholin-4-ylcarbonyl)isoxazol-5-yl]-1H-indazole;
5-(1 H-indazol-5-yl)-N-(3-morpholin-4-ylpropyl)isoxazole-3-carboxamide;
N-[2-(1H-imidazol-4-yl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;
(3R)-1- { [5-(1 H-indazol-5-yl)isoxazol-3-yl]carbonyl}piperidin-3-ol;
1- {[5-(1H-indazol-5-yl)isoxazol-3-yl]carbonyl}piperidine-3-carboxamide;
2-[2-(4-{[5-(1H-indazol-5-yl)isoxazol-3-yl]carbonyl}piperazin-l-
yl)ethoxy]ethanol;
5- {3-[(4-methyl-1,4-diazepan-1-yl)carbonyl]isoxazol-5-yl} -1 H-indazole;
N-(3-hydroxypropyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;
N-[(1 R)-2-hydroxy-l-phenylethyl]-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide;
N-[3-(1 H-imidazol-1-yl)propyl]-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide;
5-(1H-indazol-5-yl)-N-[3-(2-oxopyrrolidin-1-yl)propyl]isoxazole-3-carboxamide;
N- {2-[4-(aminosulfonyl)phenyl]ethyl} -5-(1 H-indazol-5-yl)isoxazole-3-
carboxamide;
[ 1-benzyl-4-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-5-yl] (3-
chlorophenyl)methanone;
[ 1-benzyl-4-(1 H-indazol-5-yl)-1 H-1,2, 3 -triazol-5 -yl]
(cyclopropyl)methanone;
5-[5-cyclopropyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-1,2,3-triazol-4-yl]-1
H-
indazole;
N'- {[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]methyl} glycinamide;
(4-fluorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-
1,2,3-
triazol-5-yl]methanone;
(4-chlorophenyl) [4-(1 H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-
1,2,3-
triazol-5-yl]methanone;
(3-chlorophenyl) [4-(1 H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-
1,2,3-
triazol-5-yl]methanone;
(2-chlorophenyl) [4-(1 H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-
1,2,3-
triazol-5-yl]methanone;
cyclopentyl[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-
triazol-5-yl]methanone;
1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxylic acid;
5- {5-(4-fluorophenyl)-1-[4-(trifluoromethyl)benzyl]-1 H-1,2,3-triazol-4-yl} -
1 H-
indazol-3-amine;
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5-[ 1-b enzyl-5 -(4-fluorophenyl)-1 H- 1,2, 3-triazol-4-yl] -1 H-indazo l-3 -
amine;
[4-(1 H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-1,2,3-triazol-5-
yl] (tetrahydro-2H-pyran-4-yl)methanone;
5-[ 1-benzyl-5-(2-methylphenyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
5-{1-benzyl-5-[(4-methylpiperazin-1-yl)carbonyl]-1H-1,2,3-triazol-4-yl}-1H-
indazole;
1- {[ 1-benzyl-4-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-5-yl] carbonyl}piperidin-
4-ol;
1-acetyl-5-[5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-
triazol-
4-yl]-1H-indazole;
1-benzyl-4-(1H-indazol-5-yl)-N,N-dimethyl-lH-1,2,3-triazole-5-carboxamide;
N,1-dibenzyl-4-(1 H-indazol-5-yl)-1 H-1,2,3-triazole-5-carboxamide;
N-(2-hydroxy-2-phenylethyl)-5-(1H-indazol-5-yl)-N-methylisoxazole-3-
carboxamide;
N-[(1 S)-2-hydroxy-l-phenylethyl]-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide;
N-benzyl-N-(2-hydroxyethyl)-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide;
5-[1-benzyl-5-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]-3-methyl-lH-indazole;
5-[ 1-benzyl-5-(2-methylphenyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-3-amine;
2- {2-[ 1-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-4-yl] ethyl} -1 H-isoindole-
1,3(2H)-dione;
5- {4-[(2,4-dichlorophenoxy)methyl]-1H-1,2,3-triazol-l-yl}-1H-indazole;
5- {4-[(2,6-dichlorophenoxy)methyl]-1 H-1,2,3-triazol-l-yl}-1 H-indazole;
5-[5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-
yl]-1H-
indazole;
1- {[ 1-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-4-yl]methyl}-1 H-indazole;
5-[1-benzyl-5-(piperidin-l-ylcarbonyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole;
5-[5-(2-methylphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-
yl]-
1 H-indazole;
5-[5-(2-methylphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-
yl]-
1H-indazol-3-amine;
5-[ 1-b enzyl-5 -(morpholin-4-ylcarbonyl)-1 H- 1,2,3-triazol-4-yl] -1 H-
indazole;
5-[ 1-benzyl-5-(4-methoxyphenyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-3-amine;
N-[(1S)-1-benzyl-2-hydroxyethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;
N-[(1 S,2R)-2-hydroxy-2,3-dihydro-1 H-inden-l-yl]-5-(1 H-indazol-5-
yl)isoxazole-3-
carboxamide;
5- {3-[(3-phenylmorpholin-4-yl)carbonyl]isoxazol-5-yl} -1 H-indazole;
N-benzyl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;
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((1 S)-2- { [5-(1 H-indazol-5-yl)isoxazol-3-yl]carbonyl} -6,7-dimethoxy-
1,2,3,4-
tetrahydroisoquinolin-l-yl)methanol;
N-[(1R)-3-hydroxy-l-phenylpropyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;
N-[(1 S)-3-hydroxy-l-phenylpropyl]-5-(1 H-indazol-5 -yl)isoxazole-3 -
carboxamide;
N-2,3-dihydro-lH-inden-l-yl-5-(lH-indazol-5-yl)isoxazole-3-carboxamide;
N-2,3-dihydro-lH-inden-2-yl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;
5 -(1 H-indazol-5-yl)-N-(1-phenylpropyl)isoxazole-3-carboxamide;
5- {1-benzyl-5-[3-(dimethylamino)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-
amine;
5-{1-benzyl-5-[4-(dimethylamino)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-
amine;
N-{3-[4-(3-amino-lH-indazol-5-yl)-1-benzyl-lH-1,2,3-triazol-5-
yl]phenyl} acetamide;
N-{4-[4-(3-amino-lH-indazol-5-yl)-1-benzyl-lH-1,2,3-triazol-5-
yl]phenyl} acetamide;
5- { 1-benzyl-5-[3-(1 H-pyrazol-l-yl)phenyl]-1 H-1,2,3-triazol-4-yl} -1 H-
indazol-3-
amine;
5-[ 1-benzyl-5-(1-methyl-1 H-pyrazol-4-yl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-
3 -
amine;
3-[4-(3-amino-lH-indazol-5-yl)-1-benzyl-lH-1,2,3-triazol-5-yl]-N-
phenylbenzamide;
3-[4-(3-amino-1 H-indazol-5-yl)-1-benzyl-1 H- 1,2,3 -triazol-5-yl]-N-
benzylbenzamide;
5-[ 1-benzyl-5-(1-methyl-1 H-indol-5-yl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-3-
amine;
5-[1-benzyl-5-(3-methoxyphenyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-3 -amine;
5-[ 1-benzyl-5-(3-morpholin-4-ylphenyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-3-
amine;
5-[3-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)isoxazol-5-yl]-1H-indazole;
5- {3-[(4-methyl-2-phenylpiperazin-l-yl)carbonyl]isoxazol-5-yl}-1 H-indazole;
1- {[ 1-benzyl-4-(1 H-indazol-5-yl)-1 H- 1,2,3 -triazol-5-yl]
carbonyl}piperidin-4-amine;
N- [5 -(1 -benzyl-5 -phenyl-1 H-1,2, 3-triazol-4-yl)-1 H-indazol-3-
yl]benzamide;
N-[5-(1-benzyl-5-phenyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-
yl]benzenesulfonamide;
N-[5-(1-benzyl-5-phenyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N'-(4-
methoxyphenyl)urea;
N- [5 -(1 -benzyl-5 -phenyl-1 H-1,2, 3-triazol-4-yl)-1 H-indazol-3-
yl]butanamide;
N-[5-(1-benzyl-5-phenyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-
methylpropanamide;
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N-[5-(1-benzyl-5-phenyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-
yl] cyclopropanecarboxamide;
N-[1-benzoyl-5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-
yl]benzamide;
N-[5-(1-benzyl-5-cyclopropyl-IH-1,2,3-triazol-4-yl)-IH-indazol-3-yl]-3-
fluorobenzamide;
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-
yl]benzamide;
N-benzyl-5-(1-benzyl-5-cyclopropyl-IH-1,2,3-triazol-4-yl)-IH-indazol-3-amine;
N-[(1 R)-1-benzyl-2-hydroxyethyl]-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide;
5-(1-benzyl-IH-pyrazol-4-yl)-IH-indazole;
N-[(IR)-3-hydroxy-l-phenylpropyl]-5-(3-methyl-lH-indazol-5-yl)isoxazole-3-
carboxamide;
3-[4-(3-amino-1 H-indazol-5-yl)-1-benzyl-1 H- 1,2,3 -triazol-5-yl]phenol;
3-[4-(3 -amino-1 H-indazol-5 -yl)- I-b enzyl-1 H- 1,2,3-triazol-5 -
yl]benzamide;
5-{1-benzyl-5-[4-(methylsulfonyl)phenyl]-IH-1,2,3-triazol-4-yl}-IH-indazol-3-
amine;
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-
chlorobenzamide;
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-4-
chlorobenzamide;
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-
yl] ethanesulfonamide;
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-
yl]benzenesulfonamide;
N-[5-(1-benzyl-5-cyclopropyl-IH-1,2,3-triazol-4-yl)-IH-indazol-3-yl]-2-
chlorobenzenesulfonamide;
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-3-
chlorobenzenesulfonamide;
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-4-
chlorobenzenesulfonamide;
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2,5-
dimethylfuran-3-sulfonamide;
5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-N-(2-chlorobenzyl)-1 H-
indazol-3-
amine;
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5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-N-(3-chlorobenzyl)-1 H-
indazol-3-
amine;
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-3-
chlorobenzamide;
N-[5-(1-benzyl-5-cyclopropyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-
furamide;
5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-N-ethyl-1 H-indazol-3-amine;
5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-N-(4-chlorobenzyl)-1 H-
indazol-3-
amine;
5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-N-(3-furylmethyl)-1 H-
indazol-3-
amine;
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N'-[5-
methyl-
2-(trifluoromethyl)-3-furyl]urea;
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-3-
furamide;
5 -(1 H-indazol-5 -yl)-N- [(1 S)-1-phenylpropyl]isoxazole-3 -carboxamide;
5-(1H-indazol-5-yl)-N-[(1R)-1-phenylpropyl]isoxazole-3-carboxamide;
5 -(1-b enzyl-1 H-pyrazol-4-yl)-1 H-indazol-3 -amine;
1-benzyl-4-(1 H-indazol-5-yl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-1 H-1,2,3-
triazole-
5-carboxamide;
1-benzyl-4-(1 H-indazol-5-yl)-N-(2-isopropoxyethyl)-1 H-1,2,3-triazole-5-
carboxamide;
1-benzyl-4-(1 H-indazol-5 -yl)-N- [(2R)-tetrahydrofuran-2-ylmethyl]-1 H-1,2,3 -
triazole-
5-carboxamide;
1-benzyl-4-(1 H-indazol-5-yl)-N-(tetrahydrofuran-3-ylmethyl)-1 H-1,2,3-
triazole-5-
carboxamide;
1-benzyl-N-cyclopentyl-4-(1 H-indazol-5-yl)-1 H-1,2,3-triazole-5-carboxamide;
1-benzyl-N-(cyclopentylmethyl)-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-
carboxamide;
1-benzyl-N-ethyl-4-(1 H-indazol-5 -yl)-N-methyl-1 H-1,2,3 -triazole-5-
carboxamide;
1-benzyl-4-(1 H-indazol-5-yl)-N-isopropyl-N-methyl-1 H-1,2,3-triazole-5-
carboxamide;
1-benzyl-4-(1 H-indazol-5-yl)-N-(2-methoxyethyl)-N-methyl-1 H-1,2,3-triazole-5-
carboxamide;
1-benzyl-4-(1 H-indazol-5-yl)-N-phenyl-1 H-1,2,3-triazole-5-carboxamide;
1-benzyl-N-(4-chlorophenyl)-4-(1 H-indazol-5-yl)-1 H-1,2,3-triazole-5-
carboxamide;
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1-benzyl-4-(1 H-indazol-5-yl)-N-(2-morpholin-4-ylethyl)-1 H-1,2,3-triazole-5-
carboxamide;
1-benzyl-N-[2-(dimethylamino)ethyl] -4-(1 H-indazol-5 -yl)-N-methyl-1 H-1,2,3-
triazole-5-carboxamide;
1-benzyl-N-(2-hydroxyethyl)-4-(1 H-indazol-5-yl)-N-propyl-1 H-1,2,3-triazole-5-
carboxamide;
1-benzyl-N-[3-(dimethylamino)propyl]-4-(1H-indazol-5-yl)-N-methyl-lH-1,2,3-
triazole-5-carboxamide;
1-benzyl-N-[2-(diethylamino)ethyl]-4-(1 H-indazol-5 -yl)-N-methyl-1 H-1,2,3-
triazole-
5-carboxamide;
N,1-dibenzyl-N-ethyl-4-(1 H-indazol-5-yl)-1 H- 1,2,3 -triazole-5-carboxamide;
N,1-dibenzyl-N-(2-hydroxyethyl)-4-(1 H-indazol-5-yl)-1 H-1,2,3-triazole-5-
carboxamide;
(3R)-1- { [ 1-benzyl-4-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-5-
yl]carbonyl}piperidin-3-ol;
1- {[ 1-benzyl-4-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-5-yl]
carbonyl}piperidine-4-
carboxamide;
5- {1-benzyl-5-[(2,6-dimethylmorpholin-4-yl)carbonyl]-1H-1,2,3-triazol-4-yl}-
1H-
indazole;
5- {5-[(4-acetylpiperazin-1-yl)carbonyl]-1-benzyl-lH-1,2,3-triazol-4-yl}-1H-
indazole;
5-{1-benzyl-5-[(4-phenylpiperazin-1-yl)carbonyl]-1H-1,2,3-triazol-4-yl}-1H-
indazole;
1-benzyl-N-[(1 R)-1-(hydroxymethyl)-2-methylpropyl]-4-(1 H-indazol-5-yl)-1 H-
1,2,3-
triazole-5-carboxamide;
1-benzyl-N-[(1 S)-1-(hydroxymethyl)-2-methylpropyl]-4-(1 H-indazol-5-yl)-1 H-
1,2,3 -
triazole-5-carboxamide;
1-benzyl-N-[3-(1H-imidazol-l-yl)propyl]-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-
5-
carboxamide;
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N'-
ethylurea;
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N'-
phenylurea;
N-benzyl-N'-[5-(1-benzyl-5-cyclopropyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-
yl]urea;
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N'-(2-
chlorophenyl)urea;
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N'-(3-
chlorophenyl)urea;
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N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N'-(4-
chlorophenyl)urea;
N-[5-(1-benzyl-5-iodo-lH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]benzamide;
3-[4-(3-amino-1 H-indazol-5-yl)-1 H-pyrazol-l-yl]propanenitrile;
2-[4-(3-amino-lH-indazol-5-yl)-1H-pyrazol-l-yl]acetamide;
methyl 3-[4-(3-amino-1 H-indazol-5-yl)-1 H-pyrazol-l-yl]propanoate;
3-[4-(3-amino-1 H-indazol-5-yl)-1 H-pyrazol-l-yl]propanamide;
[4-(3 -amino-1 H-indazol-5 -yl)-1 H-pyrazol-l-yl] acetonitrile;
4-(3-amino-1 H-indazol-5-yl)-N,N-dimethyl-1 H-imidazole-l-sulfonamide;
5-pyrazin-2-yl-lH-indazol-3-amine;
5-thien-2-yl-1 H-indazol-3-amine;
5-(2-aminopyrimidin-4-yl)-1 H-indazol-3-amine;
5-(2-methoxypyridin-3-yl)-1H-indazol-3-amine;
5 -imidazo [ 1, 2-a]pyridin-3 -yl-1 H-indazol-3 -amine;
N2,N2 -dimethyl-N1-[5-(1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]glycinamide;
5 -(1 H-pyrazol-5-yl)-1 H-indazol-3-amine;
5 -(4-methyl-1 H-imidazol-5-yl)-1 H-indazol-3-amine;
5-(1 H-imidazol-4-yl)-1H-indazol-3-amine;
N2,N2 -dimethyl-N1- {5-[ 1-(3-methylbenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-
indazol-3-
yl}glycinamide;
5-(1-benzyl-1 H-imidazol-4-yl)-1 H-indazol-3 -amine;
Ni- {5-[ 1-(4-tert-butylbenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-3-yl} -
N2,N2-
dimethylglycinamide;
N2,N2 -dimethyl-N1- {5-[ 1-(2-piperidin-1-ylethyl)-1 H-1,2,3-triazol-4-yl]-1 H-
indazol-3-
yl}glycinamide;
N2,N2 -dimethyl-N1- {5-[ 1-(2-morpholin-4-ylethyl)-1 H-1,2,3-triazol-4-yl]-1 H-
indazol-
3-yl}glycinamide;
Ni-(5- { 1-[2-(3,5-dimethylisoxazol-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl} -1 H-
indazol-3-
yl)-N2,N2 -dimethylglycinamide;
Ni-(5-{1-[2-(3,5-dimethyl-lH-pyrazol-4-yl)ethyl]-1H-1,2,3-triazol-4-yl}-1H-
indazol-
3-yl)-N2,N2 -dimethylglycinamide;
2-(4- {3-[(N,N-dimethylglycyl)amino]-1 H-indazol-5-yl} -1 H-1,2,3-triazol-l-
yl)-2-
methylpropanoic acid;
ethyl (4-{3-[(N,N-dimethylglycyl)amino]-1H-indazol-5-yl}-1H-1,2,3-triazol-1-
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yl)acetate;
N2,N2 -dimethyl-N1-(5- { 1-[(trimethylsilyl)methyl]-1 H-1,2,3-triazol-4-yl} -1
H-indazol-
3-yl)glycinamide;
Ni-[5-(3-furyl)-1 H-indazol-3-yl]-N2,N2 -dimethylglycinamide;
N2,N2 -dimethyl-N1-[5-(1H-pyrazol-5-yl)-1H-indazol-3-yl]glycinamide;
N2,N2 -dimethyl-N 1-(5 -pyrimidin-5 -yl-1 H-indazol-3 -yl) glycinamide;
Ni-[5-(2,1,3-benzoxadiazol-5-yl)-1H-indazol-3-yl]-N2,N2 -dimethylglycinamide;
N2,N'-dimethyl-N1-[5-(1 H-pyrazol-4-yl)-1 H-indazol-3-yl]glycinamide;
N2,N2 -dimethyl-N1-[5-(1-methyl-1 H-pyrazol-4-yl)-1 H-indazol-3-
yl]glycinamide;
Ni-[5-(3,5-dimethyl-lH-pyrazol-4-yl)-1H-indazol-3-yl]-N2,N2 -
dimethylglycinamide;
Ni- {5-[2-(dimethylamino)pyrimidin-5-yl]-1 H-indazol-3-yl} -N2,N2-
dimethylglycinamide;
N2,N2 -dimethyl-N 1- [5 -(2-morpholin-4-ylpyrimidin-5 -yl)-1 H-indazol-3 -
yl] glycinamide;
N2,N2 -dimethyl-N1-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]-1H-indazol-3-
yl} glycinamide;
Ni-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N2,N2-
dimethylglycinamide;
Ni-[5-(1-benzyl-1 H-pyrazol-4-yl)-1 H-indazol-3-yl]-N2,N2 -
dimethylglycinamide;
Ni-[5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N2-methylglycinamide;
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-pyrrolidin-l-
ylacetamide;
Ni-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3 -yl] -N2-
cyclopentylglycinamide;
Ni-[5-(1-benzyl-1 H-1,2,3 -triazol-4-yl)-1 H-indazol-3 -yl]-N2 -
cyclopropylglycinamide;
Ni-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3 -yl] -N 2 -tetrahydro-2H-
pyran-4-
ylglycinamide;
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-(3-
hydroxypyrrolidin-l-
yl)acetamide;
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-(3-hydroxypiperidin-
l-
yl)acetamide;
Ni-[5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N3,N3-dimethyl-beta-
alaninamide;
N-[5 -(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-morpholin-4-
ylacetamide;
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-(4-methylpiperazin-
l-
yl)acetamide;
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N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-(3-oxopiperazin-l-
yl)acetamide;
Ni-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N2 -
isopropylglycinamide;
Ni-[5-(1-benzyl-1 H-1,2,3 -triazol-4-yl)-1 H-indazol-3 -yl]-N2 -
cyclohexylglycinamide;
N-[5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]acetamide;
Ni-[5-(1-benzyl-1 H-1,2,3 -triazol-4-yl)-1 H-indazol-3 -yl]-N2 -
cyclobutylglycinamide;
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N'-propylurea;
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]ethanesulfonamide;
5-(1-b enzyl-1 H-1,2, 3-triazol-4-yl)-N-(cyclopropylmethyl)-1 H-indazol-3 -
amine;
N-[5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N'-ethylurea;
1-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]pyrrolidin-2-one;
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-4-
(dimethylamino)butanamide;
N-3,4-dihydro-lH-isochromen-4-yl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;
N-(cyclohexylmethyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;
N-(3-chlorobenzyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;
5-(1 H-indazol-5-yl)-N-(2-methoxybenzyl)isoxazole-3-carboxamide;
5-(1 H-indazol-5-yl)-N-[2-(trifluoromethyl)benzyl]isoxazole-3-carboxamide;
5-(1 H-indazol-5-yl)-N-[3-(trifluoromethyl)benzyl]isoxazole-3-carboxamide;
5-(1H-indazol-5-yl)-N-[4-(trifluoromethyl)benzyl]isoxazole-3-carboxamide;
5-(1 H-indazol-5-yl)-N-(pyridin-2-ylmethyl)isoxazole-3-carboxamide;
5-(1 H-indazol-5-yl)-N-(pyridin-3-ylmethyl)isoxazole-3-carboxamide;
5-(1 H-indazol-5-yl)-N-(pyridin-4-ylmethyl)isoxazole-3-carboxamide;
N-(2-chlorobenzyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;
N-(4-chlorobenzyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;
5 -(1 H-indazol-5 -yl)-N-(1-phenyl-2-pip eridin-l-ylethyl)isoxazo le-3 -
carboxamide;
N-[2-(1 H-imidazol-l-yl)-1-phenylethyl]-5-(1 H-indazol-5-yl)isoxazole-3-
carboxamide;
5-(1 H-indazol-5-yl)-N-(2-morpholin-4-yl-l-phenylethyl)isoxazole-3-
carboxamide;
5-(1H-indazol-5-yl)-N-[2-(4-methylpiperazin-l-yl)-1-phenylethyl]isoxazole-3-
carboxamide;
5-(1 H-indazol-5-yl)-N-(1-phenyl-2-pyrrolidin-l-ylethyl)isoxazole-3-
carboxamide;
tert-butyl 2-({ [5-(1 H-indazol-5-yl)isoxazol-3-yl]carbonyl} amino)-2-
phenylethylcarbamate;
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-(1 H-indazol-5-yl)-N-(1-naphthylmethyl)isoxazole-3-carboxamide;
5 -(1 H-indazol-5-yl)-N-(2-phenylethyl)isoxazole-3-carboxamide;
5 -(1 H-indazol-5 -yl)-N-(2-pyridin-2-ylethyl)isoxazole-3 -carboxamide;
5 -(1 H-indazol-5 -yl)-N-(2-pyridin-3-ylethyl)isoxazole-3 -carboxamide;
5 5-(1H-indazol-5-yl)-N-(2-pyridin-4-ylethyl)isoxazole-3-carboxamide;
N-[2-(2-chlorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;
N-[2-(3-chlorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;
N-[2-(4-chlorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;
N-benzyl-N-ethyl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;
5-(1H-indazol-5-yl)-N-methyl-N-(1-naphthylmethyl)isoxazole-3-carboxamide;
5 -(1 H-indazol-5-yl)-N-methyl-N-(2-phenylethyl)isoxazole-3-carboxamide;
5 -(1 H-indazol-5 -yl)-N-methyl-N-(2-pyridin-2-ylethyl)isoxazole-3 -
carboxamide;
5-(1 H-indazol-5-yl)-N-[(1 R)-1-phenylethyl]isoxazole-3-carboxamide;
5-(1 H-indazol-5-yl)-N-1,2,3,4-tetrahydronaphthalen-l-ylisoxazole-3-
carboxamide;
5-(1H-indazol-5-yl)-N-[(1S)-1-(1-naphthyl)ethyl]isoxazole-3-carboxamide;
5-(1 H-indazol-5-yl)-N-[(1 R)-1-(1-naphthyl)ethyl]isoxazole-3-carboxamide;
N- [3 -(dimethylamino)-1-phenylpropyl]-5-(1 H-indazol-5-yl)isoxazole-3-
carboxamide;
N-(2,3-dihydro-1,4-benzodioxin-5-ylmethyl)-5-(1 H-indazol-5-yl)isoxazole-3-
carboxamide;
N-(3,4-dihydro-2H-1,5-benzodioxepin-6-ylmethyl)-5-(1H-indazol-5-yl)isoxazole-3-
carboxamide;
5 -(1 H-indazol-5 -yl)-N- [(1-methyl-1 H-indol-4-yl)methyl] isoxazole-3 -
carboxamide;
5- {3-[(3-phenylpyrrolidin-l-yl)carbonyl]isoxazol-5-yl}-1 H-indazole;
5- {3-[(2-phenylpyrrolidin-l-yl)carbonyl]isoxazol-5-yl} -1 H-indazole;
5-{3-[(2-phenylpiperidin-l-yl)carbonyl]isoxazol-5-yl}-1H-indazole;
5-(1H-indazol-5-yl)-N-[(1 S)-1-phenylethyl]isoxazole-3-carboxamide;
5-(1 H-indazol-5-yl)-N-[(1 R)-1-(4-methylphenyl)ethyl]isoxazole-3-carboxamide;
5-(1 H-indazol-5-yl)-N-[(1 S)-1-(4-methylphenyl)ethyl]isoxazole-3-carboxamide;
N-[(1 R,2S)-2-hydroxy-2,3-dihydro-1 H-inden-l-yl]-5-(1 H-indazol-5-
yl)isoxazole-3-
carboxamide;
N-[(1 R,2R)-2-hydroxy-2,3-dihydro-1 H-inden-l-yl]-5-(1 H-indazol-5-
yl)isoxazole-3-
carboxamide;
N-[(1 R)-1-(4-bromophenyl)ethyl]-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide;
N-[(1 S)-1-(4-bromophenyl)ethyl]-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide;
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N-[(1 R)-1-(4-chlorophenyl)ethyl]-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide;
N-[(1 S)-1-(4-chlorophenyl)ethyl]-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide;
5-(1 H-indazol-5-yl)-N-[(1 S)-1-(2-naphthyl)ethyl]isoxazole-3-carboxamide;
N-[1-(4-ethoxyphenyl)-2-hydroxyethyl]-5-(1 H-indazol-5-yl)isoxazole-3-
carboxamide;
N- [2-hydroxy-l-(4-isopropylphenyl) ethyl] -5 -(1 H-indazol-5 -yl)isoxazole-3 -
carboxamide;
N-[1-(3,4-dimethylphenyl)-2-hydroxyethyl]-5-(1 H-indazol-5-yl)isoxazole-3-
carboxamide;
N-[2-hydroxy-l-(2-methoxyphenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-
carboxamide;
N-[2-hydroxy-l-(4-methylphenyl)ethyl]-5-(1 H-indazol-5-yl)isoxazole-3-
carboxamide;
5-(1 H-indazol-5-yl)-N-[(1 R)-1-(2-methoxyphenyl)ethyl]isoxazole-3-
carboxamide;
N-[(1S)-1-(3,4-difluorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-
carboxamide;
5-(1 H-indazol-5-yl)-N-[(1 R)-1-(3-methoxyphenyl)ethyl]isoxazole-3-
carboxamide;
5-(1 H-indazol-5-yl)-N- {(1 R)-1-[3-(trifluoromethyl)phenyl]ethyl}isoxazole-3-
carboxamide;
N-[1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]-5-(1 H-indazol-5-yl)isoxazole-3-
carboxamide;
N-[1-(3,5-dichlorophenyl)-2-hydroxyethyl]-5-(1H-indazol-5-yl)isoxazole-3-
carboxamide;
teNt-butyl5 -(1-benzyl-lH-1,2,3-triazol-4-yl)-3-[( { [6-
(trifluoromethyl)pyridin-2-
yl]amino}carbonyl)amino]-1H-indazole-l-carboxylate;
5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1-[(1-methylpiperidin-2-yl)carbonyl]-1H-
indazol-
3-amine;
5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1-[(dimethylamino)acetyl]-1H-indazol-3-
amine;
teNt-butyl3-amino-5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1H-indazole-l-
carboxylate;
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-piperidin-l-
ylacetamide;
N-[5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-morpholin-4-
ylacetamide;
and
N-[5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-1-methylpiperidine-2-
carboxamide.
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All patents, patent applications, and literature references cited in the
specification are
herein incorporated by reference in their entirety. In the case of
inconsistencies, the present
disclosure, including definitions, will prevail.
As used throughout this specification and the appended claims, the following
terms
have the following meanings:
The term "alkenyl" as used herein, means a straight or branched chain
hydrocarbon
containing from 2 to 10 carbons and containing at least one carbon-carbon
double bond
formed by the removal of two hydrogens. Representative examples of alkenyl
include, but
are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-
pentenyl, 5-
hexenyl, 2-heptenyl, 2-methyl-I-heptenyl, and 3-decenyl.
The term "alkoxy" as used herein, means an alkyl group, as defined herein,
appended
to the parent molecular moiety through an oxygen atom. Representative examples
of alkoxy
include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,
tert-butoxy,
pentyloxy, and hexyloxy.
The term "alkoxyalkoxy" as used herein, means an alkoxy group, as defined
herein,
appended to the parent molecular moiety through another alkoxy group, as
defined herein.
Representative examples of alkoxyalkoxy include, but are not limited to, tert-
butoxymethoxy,
2-ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy.
The term "alkoxyalkoxyalkyl" as used herein, means an alkoxyalkoxy group, as
defined herein, appended to the parent molecular moiety through an alkylene
group, as
defined herein. Representative examples of alkoxyalkoxyalkyl include, but are
not limited to,
tert-butoxymethoxymethyl, ethoxymethoxymethyl, (2-methoxyethoxy)methyl, and 2-
(2-
methoxyethoxy)ethyl.
The term "alkoxyalkyl" as used herein, means an alkoxy group, as defined
herein,
appended to the parent molecular moiety through an alkylene group, as defined
herein.
Representative examples of alkoxyalkyl include, but are not limited to, tert-
butoxymethyl, 2-
ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
The term "alkoxycarbonyl" as used herein, means an alkoxy group, as defined
herein,
appended to the parent molecular moiety through a carbonyl group, as defined
herein.
Representative examples of alkoxycarbonyl include, but are not limited to,
methoxycarbonyl,
ethoxycarbonyl, and tert-butoxycarbonyl.
The term "alkoxycarbonylalkyl" as used herein, means an alkoxycarbonyl group,
as
defined herein, appended to the parent molecular moiety through an alkylene
group, as
defined herein. Representative examples of alkoxycarbonylalkyl include, but
are not limited
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to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and 2-tert-
butoxycarbonylethyl.
The term "alkyl" as used herein, means a straight or branched chain
hydrocarbon
containing from 1 to 10 carbon atoms. Representative examples of alkyl
include, but are not
limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-
butyl, tert-butyl, n-
pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-
dimethylpentyl,
n-heptyl, n-octyl, n-nonyl, and n-decyl.
The term "alkylcarbonyl" as used herein, means an alkyl group, as defined
herein,
appended to the parent molecular moiety through a carbonyl group, as defined
herein.
Representative examples of alkylcarbonyl include, but are not limited to,
acetyl, 1-oxopropyl,
2,2-dimethyl-l-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
The term "alkylcarbonylalkyl" as used herein, means an alkylcarbonyl group, as
defined herein, appended to the parent molecular moiety through an alkylene
group, as
defined herein. Representative examples of alkylcarbonylalkyl include, but are
not limited
to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.
The term "alkylcarbonyloxy" as used herein, means an alkylcarbonyl group, as
defined herein, appended to the parent molecular moiety through an oxygen
atom.
Representative examples of alkylcarbonyloxy include, but are not limited to,
acetyloxy,
ethylcarbonyloxy, and tert-butylcarbonyloxy.
The term "alkylene" means a divalent group derived from a straight or branched
chain
hydrocarbon of from 1 to 10 carbon atoms. Representative examples of alkylene
include, but
are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH2CH2-,
-CH2CH2CH2CH2-, and -CHzCH(CH3)CHz-.
The term "alkylene-NRg-" as used herein, means an alkylene group, as defined
herein,
appended to the parent molecular moiety through a-NRg group, as defined
herein.
The term "alkylsulfinyl" as used herein, means an alkyl group, as defined
herein,
appended to the parent molecular moiety through a sulfinyl group, as defined
herein.
Representative examples of alkylsulfinyl include, but are not limited to,
methylsulfinyl and
ethylsulfinyl.
The term "alkylsulfinylalkyl" as used herein, means an alkylsulfinyl group, as
defined
herein, appended to the parent molecular moiety through an alkylene group, as
defined
herein. Representative examples of alkylsulfinylalkyl include, but are not
limited to,
methylsulfinylmethyl and ethylsulfinylmethyl.
The term "alkylsulfonyl" as used herein, means an alkyl group, as defined
herein,
appended to the parent molecular moiety through a sulfonyl group, as defined
herein.
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Representative examples of alkylsulfonyl include, but are not limited to,
methylsulfonyl and
ethylsulfonyl.
The term "alkylsulfonylalkyl" as used herein, means an alkylsulfonyl group, as
defined herein, appended to the parent molecular moiety through an alkylene
group, as
defined herein. Representative examples of alkylsulfonylalkyl include, but are
not limited to,
methylsulfonylmethyl and ethylsulfonylmethyl.
The term "alkylthio" as used herein, means an alkyl group, as defined herein,
appended to the parent molecular moiety through a sulfur atom. Representative
examples of
alkylthio include, but are not limited to, methylthio, ethylthio, tert-
butylthio, and hexylthio.
The term "alkylthioalkyl" as used herein, means an alkylthio group, as defined
herein,
appended to the parent molecular moiety through an alkylene group, as defined
herein.
Representative examples of alkylthioalkyl include, but are not limited to,
methylthiomethyl
and 2-(ethylthio)ethyl.
The term "alkynyl" as used herein, means a straight or branched chain
hydrocarbon
group containing from 2 to 10 carbon atoms and containing at least one carbon-
carbon triple
bond. Representative examples of alkynyl include, but are not limited to,
acetylenyl, 1-
propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
The term "aryl," as used herein, means phenyl, a bicyclic aryl or a tricyclic
aryl. The
bicyclic aryl is naphthyl, or a phenyl fused to a cycloalkyl, or a phenyl
fused to a
cycloalkenyl, or a phenyl fused to a monocyclic heteroaryl ring as defined
herein, or a phenyl
fused to a monocyclic heterocycle as defined herein. The bicyclic aryl of the
present
invention must be attached to the parent molecular moiety through any
available carbon atom
contained within the phenyl ring. Representative examples of the bicyclic aryl
include, but
are not limited to, 2,3 -dihydro- 1,4-benzodioxin-5 -yl, 2,3 -dihydro- 1,4-
benzodioxin-6-yl, 3,4-
dihydro-2H-1,5-benzodioxepin-6-yl, dihydroindenyl, indenyl, indol-4-yl,
naphthyl,
dihydronaphthalenyl, and tetrahydronaphthalenyl. The tricyclic aryl is
anthracene or
phenanthrene, or a bicyclic aryl fused to a cycloalkyl, or a bicyclic aryl
fused to a
cycloalkenyl, or a bicyclic aryl fused to a phenyl. The tricyclic aryl is
attached to the parent
molecular moiety through any carbon atom contained within the tricyclic aryl.
Representative examples of tricyclic aryl ring include, but are not limited
to, azulenyl,
dihydroanthracenyl, fluorenyl, and tetrahydrophenanthrenyl.
The aryl groups of this invention are optionally substituted with 1, 2, 3, 4
or 5
substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy,
alkoxyalkoxyalkyl,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,
alkylcarbonylalkyl,
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alkylcarbonyloxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl,
alkylsulfonylalkyl,
alkylthio, alkylthioalkyl, alkynyl, aryl*NC(O)-, aryl*NHC(O)NH-, carboxy,
carboxyalkyl,
cyano, cyanoalkyl, formyl, formylalkyl, halogen, haloalkyl, heteroaryl,
hydroxy,
hydroxyalkyl, mercapto, morpholino, nitro, Z1Z2N-, or (Z3Z4N)carbonyl. Aryl*
is optionally
substituted with 1, 2 or 3 substituents independently selected from alkyl,
halo, eyano or nitro.
Z1 and Z2 are each independently selected from hydrogen, alkyl or
alkylcarbonyl.
The term "aryloxy" as used herein, means an aryl group, as defined herein,
appended
to the parent molecular moiety through an oxygen atom. Representative examples
of aryloxy
include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-
chlorophenoxy, 4-
methylphenoxy, and 3,5-dimethoxyphenoxy.
The term "aryloxyalkyl" as used herein, means an aryloxy group, as defined
herein,
appended to the parent molecular moiety through an alkyl group, as defined
herein.
Representative examples of aryloxyalkyl include, but are not limited to, 2-
phenoxyethyl, 3-
naphth-2-yloxypropyl and 3-bromophenoxymethyl.
The term "arylalkyl" as used herein, means an aryl group, as defined herein,
appended
to the parent molecular moiety through an alkylene group, as defined herein.
Representative
examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl,
3-phenylpropyl,
and 2-naphth-2-ylethyl.
The term "aryl(hydroxy)alkyl" as used herein, means an aryl group, as defined
herein,
appended to the parent molecular moiety through an alkylene group bearing one
hydroxy
group, as defined herein. Representative examples of aryl(hydroxy)alkyl
include, but are not
limited to, 2-phenylethanol-2-yl and 2-hydroxy-2-phenylethanyl.
The term "arylcarbonyl" as used herein, means an aryl group, as defined
herein,
appended to the parent molecular moiety through a carbonyl group, as defined
herein.
Representative examples of arylcarbonyl include, but are not limited to,
benzoyl and
naphthoyl.
The term "arylthio" as used herein, means an aryl group, as defined herein,
appended
to the parent molecular moiety through a sulfur atom. Representative examples
of arylthio
include, but are not limited to, phenylthio and 2-naphthylthio.
The term "arylthioalkyl" as used herein, means an arylthio group, as defined
herein,
appended to the parent molecular moiety through an alkylene group, as defined
herein.
Representative examples of arylthioalkyl include, but are not limited to,
phenylthiomethyl, 2-
naphth-2-ylthioethyl, and 5-phenylthiomethyl.
The term "azido" as used herein, means a -N3 group.
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The term "azidoalkyl" as used herein, means an azido group, as defined herein,
appended to the parent molecular moiety through an alkylene group, as defined
herein.
The term "carbonyl" as used herein, means a -C(O)- group.
The term "carboxy" as used herein, means a-COzH group.
The term "carboxyalkyl" as used herein, means a carboxy group, as defined
herein,
appended to the parent molecular moiety through an alkylene group, as defined
herein.
Representative examples of carboxyalkyl include, but are not limited to,
carboxymethyl, 2-
carboxyethyl, and 3-carboxypropyl.
The term "cyano" as used herein, means a -CN group.
The term "cyanoalkyl" as used herein, means a cyano group, as defined herein,
appended to the parent molecular moiety through an alkylene group, as defined
herein.
Representative examples of cyanoalkyl include, but are not limited to,
cyanomethyl, 2-
cyanoethyl, and 3-cyanopropyl.
The term "cycloalkenyl" as used herein, means a monocyclic or bicyclic ring
system
containing from 3 to 10 carbons and containing at least one carbon-carbon
double bond
formed by the removal of two hydrogens. Representative examples of monocyclic
ring
systems include, but are not limited to, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl,
2,4-
cyclohexadien-l-yl and 3-cyclopenten-l-yl. Bicyclic ring systems are
exemplified by a
monocyclic cycloalkenyl ring system which is fused to another monocyclic
cycloalkyl ring as
defined herein, a monocyclic aryl ring as defined herein, a monocyclic
heterocycle as defined
herein or a monocyclic heteroaryl as defined herein. The bicyclic ring systems
of the present
invention must be appended to the parent molecular moiety through an available
carbon atom
within the cycloalkenyl ring. Representative examples of bicyclic ring systems
include, but
are not limited to, 4,5-dihydro-benzo[1,2,5]oxadiazole, 3a, 4, 5, 6, 7, 7a-
hexahydro-lH-
indenyl, 1, 2, 3, 4, 5, 6-hexahydro-pentalenyl, 1, 2, 3, 4, 4a, 5, 6, 8a-
octahydro-pentalenyl.
The term "cycloalkyl" as used herein, means a monocyclic, bicyclic, or
spirocyclic
ring system. Monocyclic ring systems are exemplified by a saturated cyclic
hydrocarbon
group containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems
include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
Bicyclic
cycloalkyl groups of the present invention are exemplified by a monocyclic
cycloalkyl ring
fused to another monocyclic cycloalkyl ring, or a monocyclic cycloalkyl ring
fused
cycloalkenyl, or a monocyclic cycloalkyl ring fused to a phenyl ring, or a
monocyclic
cycloalkyl ring fused to a monocyclic heteroaryl ring as defined herein, or a
monocyclic
cycloalkyl ring fused to a monocyclic heterocycle as defined herein. The
bicyclic cycloalkyl
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ring systems of the present invention must be appended to the parent molecular
moiety
through an available carbon atom within the monocycloalkyl ring.
The cycloalkyl groups of the present invention are optionally substituted with
1, 2, 3,
or 4 substituents selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,
alkoxycarbonyl,
alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl,
alkylthio,
alkylthioalkyl, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl,
halogen, hydroxy,
hydroxyalkyl, mercapto, oxo, ZiZzN-, or (Z3Z4N)carbonyl.
The term "cycloalkylalkyl," as used herein, means a cycloalkyl group appended
to the
parent molecular moiety through an alkyl group, as defined herein.
The term "cycloalkylcarbonyl" as used herein, means cycloalkyl group, as
defined
herein, appended to the parent molecular moiety through a carbonyl group, as
defined herein.
Representative examples of cycloalkylcarbonyl include, but are not limited to,
cyclopropylcarbonyl, 2-cyclobutylcarbonyl, and cyclohexylcarbonyl.
The term "formyl" as used herein, means a -C(O)H group.
The term "formylalkyl" as used herein, means a formyl group, as defined
herein,
appended to the parent molecular moiety through an alkylene group, as defined
herein.
Representative examples of formylalkyl include, but are not limited to,
formylmethyl and 2-
formylethyl.
The term "halo" or "halogen" as used herein, means -Cl, -Br, -I or -F.
The term "haloalkoxy" as used herein, means at least one halogen, as defined
herein,
appended to the parent molecular moiety through an alkoxy group, as defined
herein.
Representative examples of haloalkoxy include, but are not limited to,
chloromethoxy, 2-
fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
The term "haloalkyl" as used herein, means at least one halogen, as defined
herein,
appended to the parent molecular moiety through an alkylene group, as defined
herein.
Representative examples of haloalkyl include, but are not limited to,
chloromethyl, 2-
fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
The term "heteroaryl," as used herein, means a monocyclic heteroaryl or a
bicyclic
heteroaryl. The monocyclic heteroaryl is a 5 or 6 membered ring containing at
least one
heteroatom independently selected from 0, N, or S. The 5 membered ring
contains two
double bonds may contain one, two, three or four heteroatoms. The 6 membered
ring
contains three double bonds may contain one, two, three or four heteroatoms.
The 5 or 6
membered heteroaryl is connected to the parent molecular moiety through any
carbon atom
or any nitrogen atom contained within the heteroaryl. Representative examples
of
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monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl,
isoxazolyl,
isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl,
pyrazinyl, pyrazolyl,
pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and
triazinyl. The bicyclic
heteroaryl consists of a monocyclic heteroaryl fused to a monocyclic aryl ring
as defined
herein, a monocyclic cycloalkyl ring as defined herein, a monocyclic
cycloalkenyl ring as
defined herein, another monocyclic heteroaryl or a monocyclic heterocycle ring
as defined
herein. The bicyclic heteroaryl ring systems of the present invention must be
appended to the
parent molecular moiety through an available carbon atom within the heteroaryl
ring. The
bicyclic heteroaryl is connected to the parent molecular moiety through any
carbon atom or
any nitrogen atom contained within the bicyclic heteroaryl. Representative
examples of
bicyclic heteroaryl include, but are not limited to, benzofuranyl,
benzoxadiazolyl, 1,3-
benzothiazolyl, benzimidazolyl, benzodioxolyl, benzothiophenyl, chromenyl,
cinnolinyl,
furopyridine, indolyl, indazolyl, isoindolyl, isoquinolinyl, naphthyridinyl,
oxazolopyridine,
quinolinyl, thienopyridine and thienopyridinyl.
The heteroaryl groups of the present invention are optionally substituted with
1, 2, 3,
or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy,
alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl,
alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl,
benzyl, carboxy,
carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen,
hydroxy,
hydroxyalkyl, mercapto, nitro, ZiZzN-, or (Z3Z4N)carbonyl. Heteroaryl groups
of the present
invention that are substituted may be present as tautomers. The present
invention
encompasses all tautomers including non-aromatic tautomers.
The term "heteroarylalkyl," as used herein, means a heteroaryl group appended
to the
parent molecular moiety through an alkyl group, as defined herein.
The term "heterocycle" or "heterocyclic" as used herein, refers to a
monocyclic,
bicyclic, tricyclic or a spirocyclic ring system that contains at least one
heteroatom. The
monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least
one heteroatom
independently selected from the group consisting of 0, N, and S. The 3 or 4
membered ring
contains 1 heteroatom selected from the group consisting of 0, N and S. The 5
membered
ring contains zero or one double bond and one, two or three heteroatoms
selected from the
group consisting of 0, N and S. The 6 or 7 membered ring contains zero, one or
two double
bonds and one, two or three heteroatoms selected from the group consisting of
0, N and S.
The monocyclic heterocycle is connected to the parent molecular moiety through
any carbon
atom or any nitrogen atom contained within the monocyclic heterocycle.
Representative
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examples of monocyclic heterocycle include, but are not limited to,
azetidinyl, azepanyl,
aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-
dithianyl,
imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,
isoxazolidinyl,
isoindoline-1,3-dione, morpholinyl, oxadiazolinyl, oxadiazolidinyl,
oxazolinyl, oxazolidinyl,
piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,
pyrrolidinyl,
tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl,
thiazolinyl,
thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine
sulfone),
thiopyranyl, and trithianyl. The bicyclic heterocycle of the present invention
is defined as a
monocyclic heterocycle fused to a phenyl group, a cycloalkylgroup as defined
herein, a
cycloalkenyl group as defined herein, another monocyclic heterocycle group as
defined
herein, or a spirocyclic ring wherein one carbon atom of the monocyclic
heterocycle is
bridged by two ends of an alkylene chain. The bicyclic heterocycle of the
present invention
is connected to the parent molecular moiety through any carbon atom or any
nitrogen atom
contained within the heterocyclic ring. Representative examples of bicyclic
heterocycle
include, but are not limited to, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-
dihydro-1,4-
benzodioxinyl, 2,3-dihydro-l-benzofuranyl, 2,3-dihydro-l-benzothienyl, 3,4-
dihydro-lH-
isochromen-4-yl, 2,3-dihydro-lH-indolyl, succinmimidyl, and 1,2,3,4-
tetrahydroquinolinyl.
The tricyclic heterocycle is a bicyclic heterocycle fused to a phenyl, or a
bicyclic heterocycle
fused to a cycloalkyl, or a bicyclic heterocycle fused to a cycloalkenyl, or a
bicyclic
heterocycle fused to a monocyclic heterocycle. The tricyclic heterocycle is
connected to the
parent molecular moiety through any carbon atom or any nitrogen atom contained
within the
tricyclic heterocycle. Representative examples of tricyclic heterocycle
include, but are not
limited to, 2,3,4,4a,9,9a-hexahydro-lH-carbazolyl, 5a,6,7,8,9,9a-
hexahydrodibenzo[b,d]furanyl, and 5a,6,7,8,9,9a-hexahydrodibenzo[b,d]thienyl.
The heterocycles of this invention are optionally substituted with 1, 2,or 3
substituents
independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,
alkoxycarbonyl,
alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,
alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, aryl, benzyl, carboxy,
carboxyalkyl,
cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy,
hydroxyalkyl,
hydroxyalkylcarbonyl, hydroxyalkoxyalkyl, mercapto, oxo, ZiZ2N-, or
(Z3Z4N)carbonyl.
The term "heterocyclealkyl," as used herein, means a heterocycle group
appended to
the parent molecular moiety through an alkyl group, as defined herein.
The term "heterocyclecarbonyl" as used herein, means a heterocycle, as defined
herein, appended to the parent molecular moiety through a carbonyl group, as
defined herein.
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The term "hydroxy" as used herein, means an -OH group.
The term "hydroxyalkyP" as used herein, means at least one hydroxy group, as
defined
herein, is appended to the parent molecular moiety through an alkylene group,
as defined
herein. Representative examples of hydroxyalkyl include, but are not limited
to,
hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-
ethyl-4-
hydroxyheptyl.
The term "hydroxyalkylcarbonyl" as used herein, means a hydroxyalkyl group, as
defined herein, as appended to the parent molecular moiety through a carbonyl
group, as
defined herein. Representative examples include, but are not limited to, 2-
hydroxyacetyl, and
4-hydroxybutanoyl.
The term "hydroxyalkoxyalkyl" as used herein, means a hydroxyalkoxy group, as
defined herein, appended to the parent molecular moiety through an alkylene
group, as
defined herein. Representative examples of hydroxyalkoxyalkyl include, but are
not limited
to, (2-hydroxy-ethoxy)-ethyl, and (3-hydroxyl-propoxyl)-ethyl.
The term "hydroxy-protecting group" or "O-protecting group" means a
substituent
that protects hydroxyl groups against undesirable reactions during synthetic
procedures.
Examples of hydroxy-protecting groups include, but are not limited to,
substituted methyl
ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-
(trimethylsilyl)-ethoxymethyl, benzyl, and triphenylmethyl; tetrahydropyranyl
ethers;
substituted ethyl ethers, for example, 2,2,2-trichloroethyl and t-butyl; silyl
ethers, for
example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclic
acetals and
ketals, for example, methylene acetal, acetonide and benzylidene acetal;
cyclic ortho esters,
for example, methoxymethylene; cyclic carbonates; and cyclic boronates.
Commonly used
hydroxy-protecting groups are disclosed in T.W. Greene and P.G.M. Wuts,
Protective Groups
in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
The term "mercapto" as used herein, means a -SH group.
The term "nitrogen protecting group" as used herein, means those groups
intended to
protect an amino group against undesirable reactions during synthetic
procedures. Preferred
nitrogen protecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl
(Cbz), formyl,
phenylsulfonyl, tert-butoxycarbonyl (Boc), tert-butylacetyl, trifluoroacetyl,
and
triphenylmethyl (trityl).
The term "nitro" as used herein, means a-NOz group.
The term "trialkylsilyl" as used herein, means three independently selected
alkyl
groups, as defined herein, appended to the parent molecular moiety through a
silicon atom.
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Representative examples of trialkylsilyl include, but are not limited to,
trimethylsilyl,
triethylsilyl, t-butyldimethylsilyl and triisopropylsilyl.
The term "trialkylsilylalkyl" as used herein, means a trialkylsilyl group, as
defined
herein, appended to the parent molecular through an alkylene group, as defined
herein.
Representative examples of trialkylsilylalkyl include, but are not limited to,
trimethylsilylmethyl, 2-trimethylsilylethyl, and 2-t-butyldimethylsilylethyl.
The term "Z1Z2N" as used herein, means two groups, Zi and Z2, which are
appended
to the parent molecular moiety through a nitrogen atom. Zi and Z2 are each
independently
hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl and formyl. In
certain
instances within the present invention, Zi and Z2 taken together with the
nitrogen atom to
which they are attached form a heterocyclic ring. Representative examples of
Z1Z2N include,
but are not limited to, amino, methylamino, acetylamino, acetylmethylamino,
phenylamino,
benzylamino, azetidinyl, pyrrolidinyl and piperidinyl.
The term " Z3Z4N" as used herein, means two groups, Z3 and Z4, which are
appended
to the parent molecular moiety through a nitrogen atom. Z3 and Z4 are each
independently
hydrogen, alkyl, aryl and arylalkyl. Representative examples of Z3Z4N include,
but are not
limited to, amino, methylamino, phenylamino and benzylamino.
The term "( Z3Z4N)carbonyl" as used herein, means a NZ3Z4 group, as defined
herein,
appended to the parent molecular moiety through a carbonyl group, as defined
herein.
Representative examples of (Z3Z4N)carbonyl include, but are not limited to,
aminocarbonyl,
(methylamino)carbonyl, (dimethylamino)carbonyl, and
(ethylmethylamino)carbonyl.
The term "oxo" as used herein, means a =0 moiety.
The term "sulfinyl" as used herein, means a -S(O)- group.
The term "sulfonyl" as used herein, means a-SO2- group.
The term "sulfonamide" as used herein means a-SO2NHz group.
The term "tautomer" as used herein means a proton shift from one atom of a
compound to another atom of the same compound wherein two or more structurally
distinct
compounds are in equilibrium with each other.
Compounds of the present invention may exist as stereoisomers wherein,
asymmetric
or chiral centers are present. These stereoisomers are "R" or "S" depending on
the
configuration of substituents around the chiral carbon atom. The terms "R" and
"S" used
herein are configurations as defined in IUPAC 1974 Recommendations for Section
E,
Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The present
invention
contemplates various stereoisomers and mixtures thereof and these are
specifically included
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within the scope of this invention. Stereoisomers include enantiomers and
diastereomers, and
mixtures of enantiomers or diastereomers. Individual stereoisomers of
compounds of the
present invention may be prepared synthetically from commercially available
starting
materials that contain asymmetric or chiral centers or by preparation of
racemic mixtures
followed by resolution which is well known to those of ordinary skill in the
art. These
methods of resolution are exemplified by (1) attachment of a mixture of
enantiomers to a
chiral auxiliary, separation of the resulting mixture of diastereomers by
recrystallization or
chromatography and liberation of the optically pure product from the
auxiliary; or (2) direct
separation of the mixture of optical enantiomers on chiral chromatographic
columns.
The compounds and processes of the present invention will be better understood
by
reference to the following Examples, which are intended as an illustration of
and not a
limitation upon the scope of the invention. Further, all citations herein are
incorporated by
reference.
Compound names are assigned by using Name Pro naming software, which is
provided by ACD/Labs. Alternatively, compound names are assigned using AuTONoM
naming software, which is provided by MDL Information Systems GmbH (formerly
known
as Beilstein Informationssysteme) of Frankfurt, Germany, and is part of the
CHEMDRAW
ULTRA v. 6Ø2 software suite and ISIS Draw v. 2.5. Also, compound names are
assigned
using Struct=Name naming algorithm, which is part of the CHEMDRAW ULTRA v.
9Ø7
software suite.
Abbreviations
Abbreviations which have been used in the descriptions of the Schemes and the
Examples that follow are: DMF for N,N-dimethylformamide, DMSO for dimethyl
sulfoxide,
EtOAc for ethyl acetate, CHC13 for chloroform, CH2C12 for dichloromethane,
CH3CN for
acetonitrile, THF for tetrahydrofuran, HATU for O-(7-azabenzotriazol-l-yl)-
N,N,N',N'-
tetramethyluronium hexafluorophosphate, EDC or EDCI for 1-(3-
dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride, LC/MS for liquid chromatography/mass
spectroscopy,
NH4OAc for ammonium acetate, NaBH(OAc)3 for sodium triacetoxyborohydride, PBS
for
bovine serum albumin, PBS for phosphate buffered saline, TMS for
trimethylsilyl, MW for
microwave, DMAP for 4-(dimethylamino)pyridine, dppf for 1,1'-
bis(diphenylphosphino)ferrocene, TFA for trifluoroacetic acid, BINAP for 2,2'-
bis(diphenylphosphino)-1,1'-binaphyl, TBAF for tetrabutylammonium fluoride,
Tween for
polyoxoethylenesorbitan monolaurate HPLC for high pressure liquid
chromatography, DME
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for 1,2-dimethoxyethane, Boc for tert-butoxycarbonyl, BSA for bovine serum
albumin, DTT
for dithiothreitol, ATP for adenosine triphosphate, EDTA for
ethylenediaminetetraacetic acid,
HPMC for hydroxypropylmethylcellulose, TMB for 3,3',5,5'-tetramethylbenzidine
and
HEPES for 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid.
Preparation of Compounds of the Present Invention
The compounds and processes of the present invention will be better understood
in
connection with the following synthetic Schemes and Examples that illustrate a
means by
which the compounds of the present invention can be prepared.
Scheme 1
Ri R,
X1 A
~N A-M, I\ ~N
N Pd catalyst
R2 2 R2
As shown in Scheme 1, compounds of formula 2 which are representative of
compounds of formula (I), may be made accordingly. Compounds of formula 1
wherein Rl
and R2 are as defined in formula (I), and X1 is iodo, bromo or chloro, and
which may be
obtained from commercial sources or may be synthesized according to methods
known in the
literature, when treated with reagent A-Mi, wherein A is defined in formula
(I) and Mi is
-Sn(Rz)3 or -B(ORy)z, wherein Rz is alkyl or aryl, and Ry is hydrogen, alkyl,
aryl or the two
Ry groups together with the boron atom to which they are attached form a 1,3-
dioxoborolane,
in the presence of a palladium catalyst will provide compounds of formula 2.
Such reactions
between compounds of formula 1 and compounds of formula A-Sn(Rz)3, commonly
known
as Stille couplings, utilize a palladium catalyst such as, but not limited to,
tetrakis(triphenylphosphine)palladium(0),
dichlorobis(triphenylphosphine)palladium(II),
tris(dibenzylidineacetone)dipalladium or palladium diacetate, in the presence
or absence of a
ligand such as tri(2-furyl)phosphine or triphenylarsine in a solvent such as
toluene or DMF at
a temperature from about 25 C to about 150 C. In addition, Li(I), Cu(I), or
Mn(II) salts
may be added to improve reactivity or specificity. Reactions between compounds
of formula
1 and compounds of formula A-B(ORy)z, commonly known as Suzuki couplings
utilize
palladium catalysts such as, but not limited to,
tetrakis(triphenylphosphine)palladium(0),
dichlorobis(triphenylphosphine)palladium(II),
tris(dibenzylidineacetone)dipalladium or
palladium diacetate. A palladium ligand may be added such as 2-
(dicyclohexylphosphino)biphenyl, tri-t-butylphosphine, or tris(2-
furyl)phosphine and a base
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such as, but not limited to, aqueous K3P04, cesium carbonate, potassium
carbonate or
Na2CO3 in solvents such as toluene, dimethoxyethane, dioxane, water or DMF at
a
temperature from about 25 C to about 150 C. The reaction may also be
achieved with
heating in a microwave reactor oven.
Although many organo stannanes are commercially available or described in the
literature, it is also possible to prepare additional stannanes from A-halides
or A-triflates by
treatment with a hexa-alkyldistannane of formula ((Rz,)3Sn)z in the presence
of Pd(Ph3P)4.
Similarly, in the absence of commercially available organoboron reagents, A-
B(ORy)z may
be prepared from the corresponding halides or triflates (A-halo or A-triflate)
via metal
exchange with an organolithium followed by the addition of the alkyl borate.
Scheme 2
R, R,
X1 A
N A-H I~ ~N
N `
R2 2 R2
Compounds of formula 2, wherein Ri and R2 are as defined in formula (I) and A
is a
heteroaryl ring linked to the parent moiety through a nitrogen atom may be
prepared as
illustrated in Scheme 2. The treatment of compounds of formula 1 with a
reagent of formula
A-H, wherein the H is a hydrogen on a nitrogen atom contained within the
heteroaryl ring A,
in the presence of a base such as, but not limited to, sodium t-butoxide or
cesium carbonate
and a metal catalyst such as, but not limited to, copper metal, Cul or
palladium diacetate and
optionally with a ligand such as, but not limited to, BINAP, or tri-
tertbutylphosphine will
provide compounds of formula 2.
Scheme 3
R;; R;;
N R;; N R;;
N; N; I
R;; N R, N R,
R~j,, NSnBu3 + ~ NN N N
N Pj
N' N'
3 4 P1 6 H
As previously mentioned in Scheme 1, compounds of formula (I) may be
synthesized
utilizing Stille couplings as described in Scheme 3. Compounds of formula 3,
wherein R;; is
defined in formula (I), when treated with compounds of formula 4, wherein Ri
is defined in
formula (I) and Pi is a nitrogen protecting group such as, but not limited to,
tert-
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butyloxycarbonyl or acetyl, in the presence of
dichlorobis(triphenylphosphine)palladium(II)
and (thiophene-2-carbonyloxy)copper in toluene under heated conditions will
provide
compounds of formula 5. Compounds of formula 5 when treated with conditions
known to
remove the protecting group such as hydrochloric acid or trifluoroacetic acid
in a solvent
such as acetic acid or dioxane when the protecting group is tert-
butyloxycarbonyl or sodium
hydroxide, lithium hydroxide, or potassium hydroxide in an aqueous mixture of
THF,
isopropanol, or dioxane when the protecting group is acetyl will provide
compounds of
formula 6 which are representative of compounds of formula (I) wherein A is
(ii).
Scheme 4
R",- N R
H Bu3SnNMe2 SnBu3 g 3 R;;, N
` 1
/\-o~ / SnBu3
dioxane N~N
Rij Bu3SnN(Et)C(O)OMe R~~ heat
7 8 3
Compounds of formula 3 utilized in Scheme 3 to generate compounds of formula
(I)
may be prepared as outlined in Scheme 4. Compounds of formula 7, which are
obtained from
commercial sources or may be prepared according to methods known to one
skilled in the art,
when treated with either 1,1,1-tributyl-N,N-dimethylstannamine or methyl
ethyl(tributylstannyl)carbamate will provide compounds of formula 8. Alkynes
of formula 8
when heated in the presence of compounds of formula 9, wherein R;; is defined
in formula (1)
and N3 is an azide, will provide compounds of formula 3.
Scheme 5
1. - TMS Rij
Cul, (Ph3)2CI2Pd, R CI, N
R~ DMF, ET3N ~ R~ NaN3, N\~ R
X~ 95 C, ON CuSO4, Cu N
N N am
N H 2. TBAF, THF H N H
10 11 12
As outlined in Scheme 5, compounds of formula 12 which are representative of
compounds of formula (I), wherein A is (ii) may be prepared accordingly.
Compounds of
formula 10 wherein Ri is defined in formula (1) and Xi is iodo, bromo, chloro,
or triflate,
when treated with TMS acetylene in the presence of copper iodide,
dichlorobis(triphenylphosphine)palladium(II) and triethylamine followed by
treatment with
tetrabutylammonium fluoride or potassium hydroxide will provide compounds of
formula 11.
The reaction may be done in a solvent such as, but not limited to, DMF at
ambient
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temperature or under heated conditions. Compounds of formula 11 when treated
with R;;-Cl,
sodium azide, copper sulfate, and metallic copper under heated conditions in a
solvent such
as dioxane, will provide compounds of formula 12 which are representative of
compounds of
formula (I) wherein A is (ii).
Scheme 6
1) ~TMS Rij~N Rij,
~ Cul 9 3 N
X, \ CN PdCl2(PPh3)2 CN or NaN3 N~ I \ CN NZH4
Et3N Cu2SO4 N
2 TBAF F Cu wire EtOH
) F heat
13 14 15
R;; Rii,
NN NH2 Boc O NN NH2
N \ N ~ N N
I / N DMAP / N
16 H 17
O O~/
O ~
1) R4 CI
18 2) TFA
pyr, CH2CI2
Rij
N Rij, O
N` ~ NH2 N
HN-J/\
N R N
N
19A / RZ 19 H
Alternatively, compounds of formula 13 when treated with TMS-acetylene in the
presence of copper iodide, dichlorobis(triphenylphosphine)palladium(II) and
triethylamine
followed by treatment with tetrabutylammonium fluoride or potassium hydroxide
will
provide compounds of formula 14. The reaction may be done in a solvent such
as, but not
limited to, DMF at ambient temperature or under heated conditions. Compounds
of formula
14, when treated with compounds of formula 9 wherein R;; is defined in formula
(I), or
sodium azide, copper sulfate and metallic copper under heated conditions will
provide
compounds of formula 15. Compounds of formula 15, when heated in the presence
of
hydrazine in ethanol, will provide compounds of formula 16. Compounds of
formula 16
when treated with di-tert-butyldicarbonate and a catalytic amount of DMAP in a
solvent such
as THF or acetonitrile will provide compounds of formula 17. Compounds of
formula 17
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WO 2008/154241 PCT/US2008/065727
when treated with compounds of formula 18 in the presence of a base such as,
but not limited
to, pyridine in a solvent such as dichloromethane followed by treatment with
trifluoroacetic
acid will provide compounds of formula 19. Compounds of formula 16 when
treated with a
carboxylic acid using carboxylic acid-amine coupling conditions known to one
skilled in the
art will provide compounds of formula 19A. Standard carboxylic acid amine
coupling
conditions include adding a coupling reagent such as, but not limited to, 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),
1,3dicyclohexylcarbodiimide (DCC), Bis(2-oxo-3-oxazolidinyl)phosphinic
chloride
(BOPCI), O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate
(HATU) or O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU)
with or without an auxiliary reagent such as, but not limited to, 1-hydroxy-7-
azabenzotriazole
(HOAT) or 1-hydroxybenzotriazole hydrate (HOBT) in a solvent such as, but not
limited to,
dichloromethane.
Scheme 7
R;;\
X, XNH2 Ac20, KOAc, X, Z 23 ~
I 70 oC I rN N NaN3, CuSO4,
00 Na2CO3
N
O~ ~O O
21 22
R;; ~
N~~ ~N
N
\
N
~
N
24
Compounds of formula 24 which are representative of compounds of formula (I)
may
be prepared accordingly. Compounds of formula 20 wherein Xi is halo or
triflate, when
treated with the compound of formula 21, acetic anhydride and a base such as,
but not limited
to, potassium acetate under heated conditions will provide compounds of
formula 22.
Compounds of formula 22 when treated with sodium azide, copper sulfate, a base
such as
sodium carbonate and compounds of formula 23, wherein R;; is defined in
formula (I) and are
either available from commercial sources or may be prepared by one skilled in
the art, will
provide compounds of formula 24.
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Scheme 8
Rij R;; Rij 9 - X R 23 R1 1) N3
1 N ~N
/ N PdC12(PPh3)2 2) TFA
Boc Cu I Boc
25 Et3N 27
Rij ` R N Rij
N " N' I R1
R, N N + RIN NN
N H
29 H 30
As outlined in Scheme 8, compounds of formula 29 and 30, which are
representative
of compounds of formula (I), may be prepared accordingly. Compounds of formula
25,
wherein Ri is defined in formula (I) and Xi is halo or triflate, when treated
with compounds
of formula 23 copper iodide, dichlorobis(triphenylphosphine)palladium(II) and
triethylamine
in DMF at ambient temperature or under heated conditions will provide
compounds of
formula 27. Compounds of formula 27 when treated with compounds of formula 9
under
heated conditions, and either neat or in a solvent such as, but not limited
to, dioxane, will
provide compounds of formula 29 and 30.
Scheme 9
1) NH2OH HCI, NaOH Rvu
Rv",_ CHO 2) Chloramine-T 3H2O
Ny R,
31 3) CuSO4, Cu wireR 0 \ N
4)
~ \ \ 32 H
N
11 H
Compounds of formula 32 which are representative of compounds of formula (I),
wherein A is (vii), and Ri and R,; are defined in formula (I), may be prepared
accordingly.
Aldehydes of formula 31, wherein R,; is defined in formula (I) which may be
obtained from
commercial sources, when treated with hydroxylamine hydrochloride and aqueous
sodium
hydroxide will provide an oxime intermediate which when oxidized with
Chloramine T
trihydrate, followed by treatment with copper sulfate and copper wire and
compounds of
formula I l will provide compounds of formula 32.
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Scheme 10
CI
0 R1 N 0 R~ Mg
HO p' N ~ /
NN N N
H H
33 34
O R1 / I p R,
\ \ \
N \
N N
H 36 %
35 P1
Za-NH Za-NH
oy36A p R1 S~NH2 ~N R37 VNN N
2) deprotection H
% P, 38
Compounds of formula 38 which are representative of compounds of formula (I)
wherein A is (x), are prepared accordingly. Compounds of formula 33, wherein
Ri is defined
in formula (I) which may be obtained from commercial sources or prepared by
one skilled in
the art, when treated with N,O-dimethylhydroxylamine using acid coupling
conditions known
to one skilled in the art will provide compounds of formula 34. Standard
carboxylic acid-
amine coupling conditions include adding a coupling reagent such as, but not
limited to, 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1,3-
dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinic chloride
(BOPC1), 0-
(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
(HATU) or O-
benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) with
or without
an auxiliary reagent such as, but not limited to, I-hydroxy-7-azabenzotriazole
(HOAT) or I-
hydroxybenzotriazole hydrate (HOBT) in a solvent such as, but not limited to,
dichloromethane. Compounds of formula 34 when treated with a Grignard reagent
such as
benzylmagnesium bromide in a solvent such as tetrahydrofuran below ambient
temperature
will provide compounds of formula 35. Compounds of formula 35 when treated
with a
protecting group reagent such as, but not limited to, di-tert-butyldicarbonate
and a catalytic
amount of DMAP in a solvent such as THF or acetonitrile will provide compounds
of
formula 36. Compounds of formula 36 when treated with pyridinium tribromide in
a solvent
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such as, but not limited to, THF with or without the use of heat will provide
compounds of
formula 36A. Compounds of formula 36A when treated with compounds of formula
37 with
or without the use of heat followed by treating the product with conditions
that will remove
the nitrogen protecting group will provide compounds of formula 38. Commonly
used
nitrogen-protecting groups as well as methods to remove them are disclosed in
T.W. Greene
and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John
Wiley & Sons,
New York (1999).
Scheme I I
N
CN NHZ ~N
O R1 N 39 N R,
\ I \
N \N
2) deprotection H
36 Pj 40
Compounds of formula 36, wherein Ri is defined in formula (I) and Pi is a
nitrogen
protecting group, when treated with compounds of formula 39 under heated
conditions
followed by treating the product with conditions known to one skilled in the
art that will
remove a nitrogen protecting group or as outlined in the literature, will
provide compounds of
formula 40 which are representative of compounds of formula (I) wherein A is
(xvii).
Scheme 12
OEt
Br Boc2O Br 43 pyr HBr3
R, R, SnBu3 jlC'~N R1
DMA
CP PdCl2(PPh3)2 THF
N H CH
41 2 2 42 O>_OtBu 4 O/OtBu
S
O R1 R 'J~NH2 S
Br 46 Rx ~ R~
N EtOH ~/ \ N
45 O/OtBu 47 H
As outlined in Scheme 12, compounds of formula 47 which are representative of
compounds of formula (I), wherein A is (x) may be prepared accordingly.
Compounds of
formula 41, wherein Rt is defined in formula (I), when treated with di-tert-
butyldicarbonate
and a catalytic amount of DMAP in a solvent such as THF or acetonitrile will
provide
compounds of formula 42. Treatment of compounds of formula 42 with tributyl(1-
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ethoxyvinyl)stannane and dichlorobis(triphenylphosphine)palladium(II) will
provide
compounds of formula 44. Compounds of formula 44 when treated with pyridinium
tribromide in THF will provide compounds of formula 45. Compounds of formula
45 when
treated with compounds of formula 46 in a solvent such as, but not limited to,
ethanol,
wherein RX is defined in formula (I), will provide compounds of formula 47.
Scheme 13
Tol\
2
N Riv
Ri Riv N: R1
OHC \N 49 N I\ N
H RIVNH2 Riv H
48 50 51
As shown in Scheme 13, compounds of formula 51 which are representative of
compounds of formula (I), wherein A is (iv), may be prepared accordingly.
Compounds of
formula 48, wherein Ri is defined in formula (I), and which are either
available through
commercial sources or may be prepared according to literature procedures or as
outlined
herein, when heated in the presence of both compounds of formula 49 and
compounds of
formula 50, both of which are either commercially available or may be prepared
by one
skilled in the art using procedures described in the literature, will provide
compounds of
formula 51.
Scheme 14
N
),
X NH H
R~ R1 53 Z N N-Za R
Br
~
N 1=. Bu i OHC I~ ~ N Sc(OTf)3 X N ~ \ \ ~
H DMF ~ H 2) _C=N+_Za I N N
52 48 54 5 H
X = CH, N, S
Y = CH, N, bond
As outlined in Scheme 14, compounds of formula 55 which are representative of
compounds of formula (I) wherein A is (xiv), (xv), (xvi) or (xvii), may be
prepared
accordingly. Compounds of formula (52), wherein Ri is defined in formula (I),
when treated
with butyllithium followed by treatment with DMF followed by an acidic work up
will
provide compounds of formula 48. Compounds of formula 48 when treated with
compounds
of formula 53, wherein X is -CH-, -N- or -S-, Y is -CH-, -N- or a bond, and
scandium
tri(triflate) followed by treatment with compounds of formula 54, wherein Za
is define in
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formula (I) will provide compounds of formula 55.
Scheme 15
(R,ji)a
R, N~ I R,
N
NN
H H
11 56
As outlined in Scheme 15, compounds of formula 56, which are representative of
compounds of formula (I) wherein A is (vii) may be prepared accordingly.
Compounds of
formula (11), wherein Ri is defined in formula (I), when treated with a
reagent such as, but
not limited to, ethyl 2-chloro-2-(hydroxyimino)acetate with a base such as,
but not limited to,
triethylamine will provide compounds of formula 56. The reaction may be
performed in a
solvent such as but limited to toluene and may require the use of heat.
Scheme 16
H R1 R;;C(O)CI R" N R;;
RjjN3 (9) N N R,
NN T~ . N
Boc Cul N
27 29 H
As outlined in Scheme 16, compounds of formula 29 which are representative of
compounds of formula (I) wherein A is (ii) may be prepared accordingly.
Compounds of
formula (27), wherein Ri is defined in formula (I), when treated with a
compound of formula
9, R;;C(O)Cl or IC1, CuI, and triethylamine in a solvent such as, but not
limited to,
tetrahydrofuran will provide compounds of formula 29. The reaction may be
performed at
ambient temperature or with the use of heat.
Scheme 17
Br O R, O 1 Rl
I ~ N ammonium formate N N
N formic acid H
45 O/OtBu 57
As outlined in Scheme 17, compounds of formula 57 which are representative of
compound of formula (I), wherein A is (vi), may be prepared accordingly.
Compounds of
formula 45, wherein Ri is defined in formula (I), when treated with ammonium
formate and
formic acid will provide compound of formula 57.
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Scheme 18
O R, N~ Rl
H CH3-NO2 ~ \ \
NN NN
I
H H
48 58
As outlined in Scheme 18, compounds of formula 58 which are representative of
compounds of formula (I), wherein A is (vii), may be prepared accordingly.
Compounds of
formula 48, wherein Ri is defined in formula (I), when treated with
nitromethane will provide
compounds of formula 58 (Organic Preparations and Procedures International,
2001, 33, 381-
386).
Scheme 19
Qõ0
\ S'O
+
O Rl 59 N//-O R,
H \N N
N N
H H
48 60
As outlined in Scheme 19, compounds of formula 60 which are representative of
compounds of formula (I), wherein A is (vi), may be prepared accordingly.
Compounds of
formula 48, wherein Ri is defined in formula (I), when treated with 1-
(isocyanomethyl
sulfonyl)-4-methylbenzene, 59, and a suitable base such as, but not limited
to, potassium
carbonate in a solvent such as methanol or tetrahydrofuran and subsequently
treated with a
suitable acid such as hydrochloric acid will provide compounds of formula 60.
Scheme 20
Si-
O R, O R, N,N 10N R
HO ~N CI I\ ~N VN 62 O \N N N H H H
33 61 63
As outlined in Scheme 20, compound of formula 63 which are representative of
compounds of formula (I), wherein A is (vi), may be prepared accordingly.
Compounds of
formula 33, wherein Ri is defined in formula (I), when treated with a suitable
chlorinating
agent such as thionyl chloride will provide compounds of formula 61. Compounds
of
formula 61, when treated with 2-(trimethylsilyl)-2H-1,2,3-triazole, 62, in a
solvent such as
sulfolane will provide compound of formula 63.
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Scheme 21
OCH3
O Rl H2N` VN ~ H3CO 5 OCH3 N~O R
CI I~ ~ N hyd razi ne H N\ N
N ~
61 H 64 H 66 H
As outlined in Scheme 21, compounds of formula 66 which are representative of
compounds of formula (I), wherein A is (ix), may be prepared accordingly.
Compounds of
formula 61, wherein Ri is defined in formula (I), when treated with hydrazine
in a suitable
solvent such as tetrahydrofuran will provide compounds of formula 64.
Compounds of
formula 64, when treated with trimethylorthoformate, 65, in the presence of a
catalytic
amount ofp-toluene sulfonic acid in a solvent such as tetrahydrofuran will
provide
compounds of formula 66.
Scheme 22
NH2
(RyO)2B CN A-I A ~ CN Scheme 6 A
' \N
I/ F Pd-catalyst I/ F N
H
67 68 69
As outlined in Scheme 22, compounds of formula 69 which are representative of
compounds of formula (I), wherein A is as defined in formula (I) can be made
accordingly.
Compounds of formula 67, wherein Ry is hydrogen, alkyl, aryl or the two Ry
groups together
with the boron atom to which they are attached form a 1,3-dioxoborolane, in
the presence of a
palladium catalyst using the Suzuki reaction conditions described in Scheme 1
in the
presence of a heteroaryl iodide (A-I) provide compounds of formula 68.
Compounds of
formula 68 are transformed to compounds of formula 69 upon treatment with
hydrazine as
described in Scheme 6.
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Scheme 23
R4C(O)CI H, O
NHZ
X, CN 1) HZNNHZ X, N 18 X, R4
2) Boc2O I/ N KTH~s N' N
70 71 O 72~OO
~
H O
~N-J~ NN H O
:c::me:r R;;-N3 H N
Scheme 6
73 74 H
As outlined in Scheme 23, compounds of formula 74 which are representative of
compounds of formula (I), wherein R;; and R4 are as defined for formula (I)
are prepared
starting with compounds of formula 70, wherein Xi is iodo, bromo, or chloro.
Treatment of
compounds of formula 70 first with hydrazine and then with di-tert-
butyldicarbonate as
described in Scheme 6 furnishes compounds of formula 71. Compounds of formula
71 upon
reaction with acid chlorides of formula 18 in the presence of a base such as
potassium
carbonate in tetrahydrofuran at ambient temperature over 2 to 8 hours provide
compounds of
formula 72. Alternatively, compounds of formula 72 can be made from compounds
of
formula 71 using the conditions described in Scheme 6. Compounds of formula 72
are
reacted with (trimethylsilyl)acetylene under the conditions described in
Schemes 5 and 6 to
give compounds of formula 73. Compounds of formula 74 are obtained from
compounds of
formula 73 upon treatment with R;;-N3 in aqueous t-butanol in the presence of
copper(II)
sulfate and sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-
dihydrofuran-3-
olate at 40-80 C over 1 to 6 hours.
Scheme 24
HN~ 0 0 HN-J~
Br ~N R4 A-B A I \ R4
N N N
H
75 O~- O 76
~
As outlined in Scheme 24, compounds of formula 76, which are representative of
compounds of formula (I), wherein A and R4 are as defined for formula (I) are
obtained from
compounds of formula 75. Compounds of formula 75 can be treated with A-B(ORy)z
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wherein A is defined as for formula (I) and Ry is hydrogen, alkyl, aryl or the
two Ry groups
together with the boron atom to which they are attached form a 1,3-
dioxoborolane, in the
presence of a palladium catalyst using the Suzuki reaction conditions
described in Scheme 1
to give compounds of formula 76.
Scheme 25
N= N
R;;SnBu3 I \ CN Scheme 3 Rii-N CN Scheme 6
+ I ~ ~
R;;- N, N-N F
F
77 78 79
~
N= N H`
R;;-N ~ N R4
R,' N
H
As outlined in Scheme 25, compounds of formula 80, which are representative of
compounds of formula (I), wherein R;; and R4 are as defined for formula (I)
are prepared
accordingly. Compounds of formula 77 and 78 reacted under Stille coupling
conditions
10 described in Scheme 3 supply compounds of formula 79. Compounds of formula
79 when
reacted as described in Scheme 6 provide compounds of formula 80.
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Scheme 26
0
NH2 1) R4C(O)CI HN-J~
'4 I\ ~ 18 A N R4
N \
N 2) TFA N
H
81 O O~/ 82
~~ O
HN~
N-Ri
A \ ~ H
RN O N
N
H
83
Q,O
HN-S.
R5SO2CI q R5
j \ ~
N
N
H
84
H N' Ra
RaCHO A
\N
N
H
As outlined in Scheme 26, compounds of formulas 82, 83, 84, and 85, which are
representative of compounds of formula (I), wherein A, R4, R5, Ra and Ri are
as defined for
5 formula (I), are prepared from compounds of formula 81. Compounds of formula
81 can be
treated with an acid chloride, 18, in solvent such as tetrahydrofuran in the
presence of a base
such as potassium carbonate or triethylamine to give compounds of formula 82.
An
alternative solvent is dichloromethane and an alternative base is pyridine.
The acid chlorides
can be prepared from the corresponding carboxylic acids by treatment with
oxalyl chloride
10 with a catalytic amount of N,N-dimethylformamide. To prepare compounds of
formula 83,
compounds of formula 81 can be treated with RiNCO in heated pyridine.
Compounds of
formula 84 are prepared from compounds of formula 81 by treatment with R5SO2C1
in
pyridine at or near room temperature. Compounds of formula 85 are also
prepared from
compounds of formula 81 in a reductive amination reaction with RaCHO in the
presence of a
15 reducing agent such as sodium triacetoxyborohydride or sodium
cyanoborohydride and acetic
acid in a solvent such as 1,2-dichloroethane at or near room temperature and
subsequent
treatment with trifluoroacetic acid in dichloromethane to remove the t-
butoxycarbonyl
protecting group.
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Scheme 27
0 O
HN HN~NRjRk
~Br HNRjRk A 11-~' \
N
H H
86 87
As outlined in Scheme 27, compounds of formula 87, wherein A, Rj and Rk are
defined for formula (I), can be prepared from compounds of formula 86.
Compounds of
formula 86 are prepared as described for compounds of formula 82 in Scheme 26.
Compounds of formula 86 can then be heated in the presence of an amine,
HNRjRk, and a
base such as triethylamine in a solvent such as acetonitrile to give compounds
of formula 87.
Alternatively, heterocycles such as pyrrolidine, piperidine, piperazine, and
morpholine can be
substituted for the amine.
Scheme 28
R~ Zc R,
HO A \ Z d N A
0 NN ~ ~ NN
~
(R3)m R2 (R3)m R2
88 89
As outlined in Scheme 28, compounds of formula 89, wherein A, Ri, R2, R3, m,
Z,
and Zd are as defined for formula (I), can be prepared form compound of
formula 88.
Compounds of formula 88 can be prepared as described in Schemesl-4, 7-9, 22,
24, and 26.
During the preparation of compounds of formula 88, the carboxylic acid moiety
pendant on A
can be protected as an ester and subsequently hydrolyzed to expose the
carboxylic acid by
methods known to one skilled in the art of organic synthesis. Compounds of
formula 88
when treated with an amine (HNZcZd) using carboxylic acid-amine coupling
conditions
known to one skilled in the art will provide compounds of formula 89. Standard
carboxylic
acid amine coupling conditions include adding a coupling reagent such as, but
not limited to,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),
1,3dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinic
chloride (BOPC1),
O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
(HATU) or
0-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU)
optionally in
the presence of a base such as triethylamine or diisopropylethylamine with or
without an
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auxiliary reagent such as, but not limited to, 1-hydroxy-7-azabenzotriazole
(HOAT) or 1-
hydroxybenzotriazole hydrate (HOBT) in a solvent such as, but not limited to,
dichloromethane or N,N-dimethylformamide.
EXAMPLES
The compounds and processes of the invention will be better understood by
reference
to the following examples, which are intended as an illustration of and not a
limitation upon
the scope of the invention.
Example 1
5 -(1 -benzyl- I H- 1,2,3 -triazol-5 -yl)- I H-indazole compound with 5-(1-
benzyl-lH-1,2,3-triazol-
4-yl)-1H-indazole
Example IA
tert-Butyl 5-iodo-lH-indazole-l-carboxylate
To an ice bath cooled solution of 4-iodo-2-methylaniline (20 g, 83.24 mmol) in
chloroform (250 mL) was added dropwise a solution of acetic anhydride (21.2 g,
208.11
mmol) in chloroform (50 mL). Upon completion of the addition, the mixture was
stirred at
room temperature for 1 hour. Potassium acetate (2.5 g, 24.97 mmol) and
isoamylnitrite (22.3
mL, 166.48 mmol) were added and the mixture was heated at 70 C for 20 hours.
The
mixture was cooled and quenched with saturated aqueous NaHCO3 to pH 7. The
mixture was
extracted with dichloromethane, and the organics were dried over sodium
sulfate and filtered.
The solvent was evaporated under reduced pressure. The crude solid was washed
with
methanol, dissolved in tetrahydrofuran (200 mL) and treated with a warm
solution of KOH
(60 g) in water (200 mL). The mixture was stirred for 15 minutes and was
treated with 6N
HC1 to pH 1. The layers were separated, the organic layer was dried over
sodium sulfate and
filtered, and the solvent was evaporated under reduced pressure. The crude
solid was
dissolved in dichloromethane (500 mL) and triethylamine (23 mL, 166.48 mmol),
and di-tert-
butyldicarbonate (23.6 g, 108.2 mmol) and a catalytic amount of
dimethylaminopyridine (- 5
mg) were added. The mixture was stirred at room temperature for 2 hours,
diluted with
water, extracted with dichloromethane, and dried with sodium sulfate and
filtered. The
solvent was evaporated under reduced pressure to afford the title compound. MS
(ESI+) m/z
344.9 (M+H)+.
Example 1B
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tert-Butyl 5-((trimethylsilyl)ethynyl)-1 H-indazole-l-carboxylate
Example lA (10.81 g, 31.4 mmol), dichlorobis(triphenylphosphine)palladium(II)
(1.1
g, 1.57 mmol), and copper (I) iodide (365 mg, 1.92 mmol) were combined in
triethylamine
(70 mL) under an inert atmosphere. Trimethylsilyl acetylene (5.0 mL, 36.0
mmol) was added
and the mixture was stirred at 60 C overnight. The solvent was removed under
reduced
pressure and the resulting residue was dissolved in methylene chloride and
washed with 1 N
hydrochloric acid. The mixture was absorbed on silica gel and purified by
silica gel
chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to
afford the title
compound. MS (ESI+) m/z 215.0 (M-99)+.
Example 1 C
5-Ethynyl-1 H-indazole
Example 1B (7.93 g, 25.2 mmol) was dissolved in methanol (150 mL). A solution
of
1 N potassium hydroxide (50 mL) was added, and the mixture was stirred at
ambient
temperature for 1 hour. The solvent was removed under reduced pressure, and
the resulting
slurry was dissolved in ethyl acetate and washed with water and brine. The
organic layer was
dried over sodium sulfate and filtered, and the solvent was removed under
reduced pressure
to afford the title compound. 'H NMR (300 MHz, DMSO-d6) 6 ppm 13.24 (s, 1 H)
8.10 (s, 1
H) 7.95 (s, 1 H) 7.55 (d, J=8.82 Hz, 1 H) 7.39 (dd, J=8.48, 1.36 Hz, 1 H) 4.03
(s, 1 H).
Example 1D
5-(1-benzyl-lH-1,2,3-triazol-5-yl)-IH-indazole compound with 5-(1-benzyl-lH-
1,2,3-triazol-
4-yl)-1H-indazole
Into a microwave vial were added 100.0 mg (0.70 mmol) of Example 1 C and 94 mg
(0.70 mmol) of benzyl azide. The mixture was heated at 160 C for 20 minutes
using
microwave irradiation (CEM-Discover, 100 Watts, 1 minute ramp time). The
mixture was
dissolved in ethyl acetate and purified by silica gel chromatography eluting
with 75% ethyl
acetate in hexane to afford the title compounds. 'H NMR (300 MHz, DMSO-d6) 6
ppm
13.28 (s, 1 H) 13.12 (s, 1 H) 8.61 (s, 1 H) 8.23 (s, 1 H) 8.13 (s, 1 H) 8.11
(s, 1 H) 7.94 (s, 1
H) 7.82 - 7.89 (m, 2 H) 7.56 - 7.70 (m, 2 H) 7.20 - 7.44 (m, 9 H) 6.97 - 7.02
(m, 2 H) 5.69 (s,
2 H) 5.65 (s, 2 H). MS (CI) m/z 276 (M+H)+.
Example 2
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5-(1H-1,2,3-triazol-5-yl)-1H-indazole
Into a microwave vial were added 100.0 mg (0.70 mmol) of Example 1 C, 81 mg
(0.7
mmol) of trimethylsilyl azide, Cul (4 mg), and dimethylformamide/methanol
(1mL, 9:1).
The mixture was heated at 160 C for 20 minutes using microwave irradiation
(CEM-
Discover, 100 Watts, 1 minute ramp time). The mixture was dissolved in ethyl
acetate, and
the organic layer was washed with water. The organic layer was dried over
anhydrous
MgSO4, filtered and concentrated under reduced pressure, and purified by
silica gel
chromatography eluting with 80% ethyl acetate in hexanes to afford the title
compound. 'H
NMR (300 MHz, DMSO-d6) 6 ppm 13.16 (s, 1 H) 8.31 (s, 1 H) 8.25 (s, 1 H) 8.13
(s, 1 H)
7.87 (d, J=8.82 Hz, 1 H) 7.62 (d, J=8.82 Hz, 1 H). MS (CI) m/z 186 (M+H)+.
Example 3
5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazole
Example 3A
tert-Butyl 5 -io do-1 H-indazole-l-carboxylate
To an ice bath cooled solution of 4-iodo-2-methylaniline (20 g, 83.24 mmol) in
chloroform (250 mL) was added dropwise with an addition funnel a solution of
acetic
anhydride (21.2 g, 208.11 mmol) in chloroform (50 mL). Upon completion of the
addition,
the mixture was stirred at room temperature for 1 hour. Potassium acetate (2.5
g, 24.97
mmol) and isoamylnitrite (22.3 mL, 166.48 mmol) were added, and the mixture
was heated at
70 C for 20 hour. The mixture was then cooled and quenched with saturated
aqueous
NaHCO3 to pH 7. The mixture was extracted with dichloromethane, dried over
sodium
sulfate, filtered, and the solvent was evaporated under reduced pressure. The
crude solid was
washed with methanol, dissolved in tetrahydrofuran (200 mL) and treated with a
warm
solution of KOH (60 g) in water (200 mL). The mixture was stirred for 15
minutes and was
treated with 6N HCl to pH 1. The layers were separated, the organic layer was
dried over
sodium sulfate and filtered, and the solvent was evaporated under reduced
pressure. The
crude material was dissolved in dichloromethane (500 mL) and triethylamine (23
mL, 166.48
mmol), and di-tert-butyldicarbonate (23.6 g, 108.2 mmol), and a catalytic
amount of
dimethylaminopyridine (- 5 mg) were added. The mixture was stirred at room
temperature
for 2 hours, quenched with water, extracted with dichloromethane, and dried
over sodium
sulfate and filtered. The solvent was evaporated under reduced pressure to
afford the title
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compound. MS (ESI+) m/z 344.9 (M+H)+.
Example 3B
tert-Butyl 5-((trimethylsilyl)ethynyl)-1 H-indazole-l-carboxylate
Example 3A, (10.81 g, 31.4 mmol), dichlorobis(triphenylphosphine)palladium(II)
(l.l
g, 1.57 mmol), and copper (I) iodide (365 mg, 1.92 mmol) were combined in
triethylamine
(70 mL) under an inert atmosphere. Trimethylsilyl acetylene (5.0 mL, 36.0
mmol) was added
and the mixture was stirred at 60 C overnight. The solvent was removed under
reduced
pressure and the resulting residue was dissolved in methylene chloride and
washed with 1 N
hydrochloric acid. The mixture was absorbed on silica gel and purified by
silica gel
chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to
afford the title
compound. MS (ESI+) m/z 215.0 (M-99)+.
Example 3C
5-Ethynyl-1 H-indazole
Example 3B (7.93 g, 25.2 mmol) was dissolved in methanol (150 mL). A solution
of
1 N potassium hydroxide (50 mL) was added and the mixture was stirred at
ambient
temperature for 1 hour. The solvent was removed under reduced pressure, and
the resulting
slurry was dissolved in ethyl acetate and washed with water and brine. The
organic layer was
dried over sodium sulfate, filtered, and the solvent was removed under reduced
pressure to
afford the title compound. 'H NMR (300 MHz, DMSO-d6) 8 ppm 13.24 (s, 1 H) 8.10
(s, 1
H) 7.95 (s, 1 H) 7.55 (d, J=8.82 Hz, 1 H) 7.39 (dd, J=8.48, 1.36 Hz, 1 H) 4.03
(s, 1 H).
Example 3D
5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazole
Example 3C (40 mg, 0.28 mmol), benzyl azide (37 mg, 0.28 mmol), CuSO4 (14 mg,
0.056 mmol) and Cu wire (14 mg) were combined in tert-butanol (0.5 mL) and
water (0.5
mL) and heated in a CEM-Discover microwave for 10 minutes at 125 C and 100
Watts. To
the mixture was added 1 M HCI and water, the product was extracted with
dichloromethane,
and purified by silica gel chromatography (50% ethyl acetate in hexanes) to
afford the title
compound. 'H NMR (400 MHz, DMSO-d6) b ppm 13.10 (s, 1 H) 8.60 (s, 1 H) 8.23
(s, 1 H)
8.11 (s, 1 H) 7.85 (d, J=8.59, 1.53 Hz, 1 H) 7.59 (d, J=8.59 Hz, 1 H) 7.26 -
7.49 (m, 5 H) 5.65
(s, 2 H). MS (ESI+) m/z 276.0 (M+H)+.
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Example 4
-[ 1-(2-methylbenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole
Into a 5 mL CEM Microwave reaction tube which contained a Teflon-coated micro-
5 flea stirring bar were added 17.6 mg (0.124 mmol) of Example 3C, 300 uL
aqueous solution
containing 7.80 mg (0.118 mmol) of sodium azide; followed by 15.79 L (0. 118
mmol;
21.80 mg 0.95 equivalents) of 2-methyl-benzyl bromide (added neat). To the
suspension
were then added 300 L of tert-butanol; 25 mg of copper wire; and finally 50
L of 1 N
aqueous copper sulfate pentahydrate solution. The microwave reaction vessel
was then
capped and heated with stirring for 10 minutes at 125 C at 100 Watts power on
a CEM-
Discover microwave. After cooling to ambient temperature, the mixture was
diluted with
0.25 N aqueous HCI; and the aqueous suspension was extracted with
dichloromethane. The
organic layer was washed with distilled water; saturated aqueous NaCI; and
then dried over
anhydrous sodium sulfate and filtered. The dried solution was diluted with
acetonitrile; and
the soluble organic material was then filtered thru a glass wool plug which
was overlaid with
additional anhydrous sodium sulfate. An aliquot of the filtrate was then
removed for
subsequent LC/MS analysis. Those solutions that contained the desired triazole
product were
then evaporated in-vacuo and then redissolved in 1.50 mL of 1:1 DMSO/methanol.
The
solution of the crude triazole product was then purified by reverse-phase HPLC
using an
acetonitrile/water 0.1% TFA gradient elution method to afford the title
compound. iH NMR
(500 MHz, DMSO-d6/D20) b ppm 2.37 (s, 3 H) 5.66 (s, 2 H) 7.16 - 7.34 (m, 4 H)
7.63 (d,
J=8.54 Hz, 1 H) 7.87 (d, J=8.70, 1.37 Hz, 1 H) 8.14 (s, 1 H) 8.25 (s, 1 H)
8.49 (s, 1 H). MS
(ESI+) m/z 289.9 (M+H)+.
Example 5
5-[ 1-(3-methylbenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methylbenzylbromide with 3-methyl-benzyl bromide. 'H NMR (500
MHz,
DMSO-d6/D20) 8 ppm 8.58 (s, 1 H) 8.25 (s, 1 H) 8.14 (s, 1 H) 7.87 (d, J=8.85,
1.53 Hz, 1 H)
7.64 (d, J=8.54 Hz, 1 H) 7.30 (t, J=7.63 Hz, 1 H) 7.14 - 7.24 (m, 3 H) 5.60
(s, 2 H) 2.31 (s, 3
H). MS (ESI+) m/z 289.8 (M+H)+.
Example 6
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-[1-(4-methylbenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methylbenzylbromide with 4-methyl-benzyl bromide. 'H NMR (500
MHz,
DMSO-d6/D20) 8 ppm 8.55 (s, 1 H) 8.24 (s, 1 H) 8.14 (s, 1 H) 7.86 (d, J=8.54,
1.53 Hz, 1 H)
5 7.63(d,J=8.85Hz,1H)7.25-7.33(m,2H)7.18-7.24(m,2H)5.59(s,2H)2.29(s,3H).
MS (ESI+) m/z 290.1 (M+H)+.
Example 7
5-[1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 3-methoxylbenzylbromide. 'H NMR (500
MHz,
DMSO-d6/D20) b ppm 8.59 (s, 1 H) 8.25 (s, 1 H) 8.14 (s, 1 H) 7.87 (d, J=8.54,
1.53 Hz, 1 H)
7.64 (d, J=8.85 Hz, 1 H) 7.33 (t, J=7.93 Hz, 1 H) 6.89 - 7.00 (m, 3 H) 5.62
(s, 2 H) 3.76 (s, 3
H). MS (ESI+) m/z 306.1 (M+H)+.
Example 8
5 -[ 1-(2-fluorobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 2-fluorobenzylbromide. 'H NMR (500
MHz,
DMSO-d6/D20) 8 ppm 8.57 (s, 1 H) 8.25 (s, 1 H) 8.12 - 8.17 (m, 1 H) 7.87 (d,
J=8.54, 1.53
Hz, 1 H) 7.64 (d, J=8.54 Hz, 1 H) 7.41 - 7.49 (m, J=7.32, 7.32 Hz, 2 H) 7.22 -
7.33 (m,
J=7.02 Hz, 2 H) 5.71 (s, 2 H). MS (ESI+) m/z 293.9 (M+H)+.
Example 9
5 -[ 1-(3-fluorobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 3-fluorobenzylbromide. 'H NMR (500
MHz,
DMSO-d6/D20) S ppm 8.61 (s, 1 H) 8.25 (s, 1 H) 8.15 (s, 1 H) 7.87 (d, J=8.85,
1.53 Hz, 1 H)
7.64 (d, J=8.54 Hz, 1 H) 7.41 - 7.51 (m, 1 H) 7.15 - 7.28 (m, 3 H) 5.68 (s, 2
H). MS (ESI+)
m/z 293.8 (M+H)+.
Example 10
5 -[ 1-(4-fluorobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole
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The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 4-fluorobenzylbromide. 'H NMR (500
MHz,
DMSO-d6/D20) 6 ppm 8.58 (s, 1 H) 8.24 (s, 1 H) 8.14 (s, 1 H) 7.86 (d, J=8.85,
1.53 Hz, 1 H)
7.64 (d, J=8.85 Hz, 1 H) 7.46 (d, J=8.85, 5.49 Hz, 2 H) 7.24 (t, J=9.00 Hz, 2
H) 5.64 (s, 2 H).
MS (ESI+) m/z 293.9 (M+H)+.
Example 11
5- [ 1-(2-chlorobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 2-chlorobenzylbromide. 'H NMR (500
MHz,
DMSO-d6/D20) 6 ppm 8.56 (s, 1 H) 8.26 (s, 1 H) 8.14 (s, 1 H) 7.88 (d, J=8.54,
1.53 Hz, 1 H)
7.64 (d, J=8.54 Hz, 1 H) 7.55 (d, J=7.63, 1.53 Hz, 1 H) 7.32 - 7.48 (m, 3 H)
5.76 (s, 2 H).
MS (ESI+) m/z 309.8 (M+H)+.
Example 12
5- [ 1-(3-chlorobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 3-chlorobenzylbromide. 'H NMR (500
MHz,
DMSO-d6/D20) 6 ppm 8.62 (s, 1 H) 8.26 (s, 1 H) 8.15 (s, 1 H) 7.87 (d, J=8.54,
1.53 Hz, 1 H)
7.64 (d, J=8.54 Hz, 1 H) 7.40 - 7.49 (m, J=7.63 Hz, 3 H) 7.35 (d, J=6.41 Hz, 1
H) 5.67 (s, 2
H). MS (ESI+) m/z 309.8 (M+H)+.
Example 13
5- [ 1-(4-chlorobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 4-chlorobenzylbromide. 'H NMR (500
MHz,
DMSO-d6/D20) 6 ppm 8.58 (s, 1 H) 8.24 (s, 1 H) 8.15 (s, 1 H) 7.86 (d, J=8.54,
1.53 Hz, 1 H)
7.64 (d, J=8.85 Hz, 1 H) 7.45 - 7.52 (m, 2 H) 7.38 - 7.44 (m, 2 H) 5.65 (s, 2
H). MS (ESI-)
m/z 307.7 (M-H)-.
Example 14
5-[ 1-(2-bromob enzyl)-1 H-1,2, 3-triazol-4-yl] -1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
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substituting 2-methyl-benzyl bromide with 2-bromobenzylbromide. 'H NMR (500
MHz,
DMSO-d6/D20) 8 ppm 8.55 (s, 1 H) 8.26 (s, 1 H) 8.14 (s, 1 H) 7.88 (d, J=8.54,
1.53 Hz, 1 H)
7.72 (d, J=7.93 Hz, 1 H) 7.64 (d, J=8.54 Hz, 1 H) 7.41 - 7.50 (m, 1 H) 7.27 -
7.40 (m, 2 H)
5.74 (s, 2 H). MS (ESI+) m/z 353.5 (M+H)
Example 15
5-[ 1-(2-nitrobenzyl)-1 H-1,2, 3-triazol-4-yl] -1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 2-nitrobenzylbromide. 'H NMR (500
MHz,
DMSO-d6/Dz0) 8 ppm 8.57 (s, 1 H) 8.27 (s, 1 H) 8.12 - 8.22 (m, 2 H) 7.88 (d,
J=8.54, 1.53
Hz, 1 H) 7.75 - 7.83 (m, 1 H) 7.60 - 7.72 (m, 2 H) 7.27 (d, J=7.63 Hz, 1 H)
6.02 (s, 2 H). MS
(ESI+) m/z 320.8 (M+H)+.
Example 16
5-[1-(3-nitrobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 3-nitrobenzylbromide. 'H NMR (500
MHz,
DMSO-d6/D20) 8 ppm 8.65 (s, 1 H) 8.21 - 8.28 (m, 3 H) 8.15 (s, 1 H) 7.80 -
7.91 (m, 2 H)
7.73 (t, J=7.78 Hz, 1 H) 7.65 (d, J=8.54 Hz, 1 H) 5.83 (s, 2 H). MS (ESI+) m/z
320.8
(M+H)+.
Example 17
5-[ 1-(4-nitrobenzyl)-1 H-1,2, 3-triazol-4-yl] -1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 4-nitrobenzylbromide. 'H NMR (500
MHz,
DMSO-d6/D20) 8 ppm 8.64 (s, 1 H) 8.22 - 8.31 (m, 3 H) 8.15 (s, 1 H) 7.88 (d,
J=8.70, 1.37
Hz, 1 H) 7.57 - 7.68 (m, 3 H) 5.83 (s, 2 H). MS (ESI+) m/z 320.7 (M+H)+.
Example 18
2- {[4-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-1-yl]methyl} benzonitrile
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 2-cyanobenzylbromide. 'H NMR (500
MHz,
DMSO-d6/D20) 8 ppm 8.61 (s, 1 H) 8.26 (s, 1 H) 8.15 (s, 1 H) 7.93 (d, J=7.63
Hz, 1 H) 7.88
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(d, J=8.54, 1.53 Hz, 1 H) 7.72 - 7.80 (m, 1 H) 7.57 - 7.68 (m, 2 H) 7.53 (d,
J=7.93 Hz, 1 H)
5.86 (s, 2 H). MS (ESI+) m/z 300.9 (M+H)+.
Example 19
3- {[4-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-1-yl]methyl} benzonitrile
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 3-cyanobenzylbromide. 'H NMR (500
MHz,
DMSO-d6/D20) 8 ppm 8.63 (s, 1 H) 8.26 (s, 1 H) 8.15 (s, 1 H) 7.85 - 7.93 (m, 2
H) 7.83 (d,
J=7.63 Hz, 1 H) 7.72 (d, J=8.24 Hz, 1 H) 7.56 - 7.68 (m, 2 H) 5.74 (s, 2 H).
MS (ESI+) m/z
300.9 (M+H)+.
Example 20
4- {[4-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-1-yl]methyl} benzonitrile
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 4-cyanobenzylbromide. 'H NMR (500
MHz,
DMSO-d6/Dz0) 8 ppm 8.62 (s, 1 H) 8.26 (s, 1 H) 8.15 (s, 1 H) 7.82 - 7.93 (m,
J=8.24 Hz, 3
H) 7.65 (d, J=8.54 Hz, 1 H) 7.54 (d, J=8.24 Hz, 2 H) 5.78 (s, 2 H). MS (ESI+)
m/z 300.7
(M+H)+.
Example 21
5- { 1- [2-(trifluoromethyl)benzyl] -1 H-1,2, 3-triazol-4-yl} -1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 2-trifluoromethylbenzylbromide. 'H
NMR (500
MHz, DMSO-d6/D20) b ppm 8.56 (s, 1 H) 8.27 (s, 1 H) 8.15 (s, 1 H) 7.89 (d,
J=8.85, 1.53
Hz, 1 H) 7.85 (d, J=7.93 Hz, 1 H) 7.72 (t, J=7.63 Hz, 1 H) 7.55 - 7.68 (m, 2
H) 7.33 (d,
J=7.93 Hz, 1 H) 5.85 (s, 2 H). MS (ESI+) m/z 300.7 (M+H)+.
Example 22
5- { 1-[3-(trifluoromethyl)benzyl]-1 H-1,2,3-triazol-4-yl} -1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 3-trifluoromethylbenzylbromide. 'H
NMR (500
MHz, DMSO-d6/D20) b ppm 8.65 (s, 1 H) 8.25 (s, 1 H) 8.14 (s, 1 H) 7.87 (d,
J=8.70, 1.37
Hz, 1 H) 7.77 (s, 1 H) 7.71 - 7.76 (m, 1 H) 7.61 - 7.69 (m, 3 H) 5.78 (s, 2
H). MS (ESI+) m/z
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344.0 (M+H)+.
Example 23
5- { 1- [4-(trifluoromethyl)benzyl] -1 H-1,2, 3-triazol-4-yl} -1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 4-trifluoromethylbenzylbromide. 'H
NMR (500
MHz, DMSO-d6/D20) b ppm 8.63 (s, 1 H) 8.25 (s, 1 H) 8.14 (s, 1 H) 7.87 (d,
J=8.54 Hz, 1 H)
7.78 (d, J=7.93 Hz, 2 H) 7.63 (d, J=8.54 Hz, 1 H) 7.58 (d, J=7.93 Hz, 2 H)
5.78 (s, 2 H). MS
(ESI+) m/z 344.2 (M+H)+.
Example 24
5- { 1 - [3 -(trifluoromethoxy)benzyl] -1 H-1,2, 3 -triazol-4-yl} -1 H-
indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 3-trifluoromethoxybenzylbromide. 'H
NMR (500
MHz, DMSO-d6/D20) 8 ppm 8.64 (s, 1 H) 8.25 (s, 1 H) 8.14 (s, 1 H) 7.87 (d,
J=8.54 Hz, 1 H)
7.64 (d, J=8.54 Hz, 1 H) 7.56 (t, J=8.24 Hz, 1 H) 7.31 - 7.45 (m, 3 H) 5.73
(s, 2 H). MS
(ESI+) m/z 359.9 (M+H)+.
Example 25
5- { 1-[4-(trifluoromethoxy)benzyl]-1 H-1,2,3-triazol-4-yl}-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 4-trifluoromethoxybenzylbromide. 'H
NMR (500
MHz, DMSO-d6/D20) 8 ppm 8.61 (s, 1 H) 8.25 (s, 1 H) 8.14 (s, 1 H) 7.87 (d,
J=8.70, 1.37
Hz, 1 H) 7.63 (d, J=8.54 Hz, 1 H) 7.52 (d, J=8.85 Hz, 2 H) 7.40 (d, J=8.24 Hz,
2 H) 5.70 (s, 2
H). MS (ESI+) m/z 359.9 (M+H)+.
Example 26
5-[ 1-(4-tert-butylbenzyl)-1 H-1,2,3 -triazol-4-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 4-tert-butylbenzylbromide. 'H NMR
(500 MHz,
DMSO-d6/D20) 6 ppm 8.58 (s, 1 H) 8.24 (s, 1 H) 8.13 (s, 1 H) 7.86 (d, J=8.85,
1.53 Hz, 1 H)
7.63 (d, J=8.54 Hz, 1 H) 7.42 (d, J=8.24 Hz, 2 H) 7.32 (d, J=8.24 Hz, 2 H)
5.60 (s, 2 H) 1.26
(s, 9 H). MS (ESI+) m/z 332.1 (M+H)+.
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Example 27
methyl 3- { [4-(1 H-indazol-5-yl)-l H-1,2,3-triazol-1-yl]methyl}benzoate
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 3-carbomethoxybenzylbromide. 'H NMR
(500
MHz, DMSO-d6/D20) 8 ppm 8.62 (s, 1 H) 8.25 (s, 1 H) 8.14 (s, 1 H) 7.92 - 7.99
(m, 2 H)
7.87 (d, J=8.54, 1.53 Hz, 1 H) 7.68 (d, J=7.63 Hz, 1 H) 7.63 (d, J=8.54 Hz, 1
H) 7.58 (t,
J=7.63 Hz, 1 H) 5.75 (s, 2 H) 3.86 (s, 3 H). MS (ESI+) m/z 333.9 (M+H)+.
Example 28
methyl 4- { [4-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-1-yl]methyl}benzoate
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 4-carbomethoxybenzylbromide. 'H NMR
(500
MHz, DMSO-d6/D20) 8 ppm 8.62 (s, 1 H) 8.25 (s, 1 H) 8.14 (s, 1 H) 7.99 (d,
J=8.24 Hz, 2 H)
7.87 (d, J=8.85 Hz, 1 H) 7.63 (d, J=8.54 Hz, 1 H) 7.49 (d, J=8.24 Hz, 2 H)
5.76 (s, 2 H) 3.85
(s, 3 H). MS (ESI+) m/z 333.9 (M+H)+.
Example 29
5-[ l -(2,4-dimethylbenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 2,4-dimethylbenzylchloride. 'H NMR
(500 MHz,
DMSO-d6/D20) 6 ppm 8.45 (s, 1 H) 8.24 (s, 1 H) 8.13 (s, 1 H) 7.86 (d, J=8.54
Hz, 1 H) 7.62
(d, J=8.54 Hz, 1 H) 7.12 (d, J=7.93 Hz, 1 H) 7.07 (s, 1 H) 7.04 (d, J=7.63 Hz,
1 H) 5.60 (s, 2
H) 2.32 (s, 3 H) 2.26 (s, 3 H). MS (ESI+) m/z 304.0 (M+H)+.
Example 30
5-[ 1-(3,5-dimethylbenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 3,5-dimethylbenzylbromide. 'H NMR
(500 MHz,
DMSO-d6/D20) 8 ppm 8.56 (s, 1 H) 8.24 (s, 1 H) 8.13 (s, 1 H) 7.87 (d, J=8.54
Hz, 1 H) 7.63
(d, J=8.54 Hz, 1 H) 6.95 - 7.01 (m, 3 H) 5.55 (s, 2 H) 2.26 (s, 6 H). MS
(ESI+) m/z 304.2
(M+H)+.
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Example 31
5- [ 1-(2,3-dichlorobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 2,3-dichlorobenzylchloride. 'H NMR
(500 MHz,
DMSO-d6/D20) 8 ppm 8.59 (s, 1 H) 8.26 (s, 1 H) 8.14 (s, 1 H) 7.88 (d, J=8.70,
1.37 Hz, 1 H)
7.69 (d, J=8.09, 1.37 Hz, 1 H) 7.63 (d, J=8.54 Hz, 1 H) 7.44 (t, J=7.78 Hz, 1
H) 7.31 (d,
J=7.78, 1.07 Hz, 1 H) 5.81 (s, 2 H). MS (ESI+) m/z 343.8 (M+H)+.
Example 32
5-[1-(2,4-dichlorobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 2,4-dichlorobenzylchloride. 'H NMR
(500 MHz,
DMSO-d6/Dz0) 8 ppm 8.56 (s, 1 H) 8.25 (s, 1 H) 8.13 (s, 1 H) 7.87 (d, J=8.54
Hz, 1 H) 7.72
(d, J=2.14 Hz, 1 H) 7.63 (d, J=8.54 Hz, 1 H) 7.50 (d, J=8.39, 1.98 Hz, 1 H)
7.40 (d, J=8.24
Hz, 1 H) 5.74 (s, 2 H). MS (ESI-) m/z 341.8 (M-H)-.
Example 33
5- [ 1-(2,5-dichlorobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 2,5-dichlorobenzylchloride. 'H NMR
(500 MHz,
DMSO-d6/D20) 8 ppm 8.59 (s, 1 H) 8.26 (s, 1 H) 8.14 (s, 1 H) 7.88 (d, J=8.85
Hz, 1 H) 7.63
(d, J=8.85 Hz, 1 H) 7.56 - 7.61 (m, 1 H) 7.49 - 7.55 (m, 1 H) 7.47 (d, J=2.44
Hz, 1 H) 5.75 (s,
2 H). MS (ESI+) m/z 343.8 (M+H)+.
Example 34
5- [ 1-(3,5-dichlorobenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 3,5-dichlorobenzylchloride. 'H NMR
(500 MHz,
DMSO-d6/D20) 8 ppm 8.64 (s, 1 H) 8.26 (s, 1 H) 8.15 (s, 1 H) 7.87 (d, J=8.85
Hz, 1 H) 7.57
- 7.71 (m, 2 H) 7.44 (d, J=1.53 Hz, 2 H) 5.69 (s, 2 H). MS (ESI+) m/z 344.1
(M+H)+.
Example 35
5- { 1-[2,4-bis(trifluoromethyl)benzyl]-1 H-1,2,3-triazol-4-yl} -1 H-indazole
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The title compound was prepared according to the procedure outlined in Example
4,
substituting 2-methyl-benzyl bromide with 2,4-bis(trifluoromethyl)bromide. 'H
NMR (500
MHz, DMSO-d6/D20) 8 ppm 8.62 (s, 1 H) 8.27 (s, 1 H) 8.07 - 8.18 (m, 3 H) 7.89
(d, J=8.70,
1.37 Hz, 1 H) 7.64 (d, J=8.54 Hz, 1 H) 7.49 (d, J=7.93 Hz, 1 H) 5.96 (s, 2 H).
MS (ESI+)
m/z 411.7 (M+H)+.
Example 36
N-cyclohexyl-6-(1 H-indazol-5 -yl)imidazo [2,1-b] [ 1,3 ]thiazol-5-amine
Example 36A
1H-indazole-5-carbaldehyde
To a solution of 5-bromoindazole (5 g, 25.38 mmol) in tetrahydrofuran (100 mL)
cooled at -50 C under argon was added dropwise a solution of 1.6 M n-
butyllithium in
hexanes (40 mL, 63.44 mmol). Dimethylformamide (3.9 mL, 50.75 mmol) was added,
and
the mixture was allowed to warm to room temperature and stirred for 15
minutes. The
mixture was then quenched with water, extracted with ethyl acetate,
preabsorbed onto silica
gel and purified by silica gel chromatography eluting with a gradient of 10-
30% ethyl acetate
in hexanes to afford the title compound. 'H NMR (500 MHz, DMSO-d6) 8 ppm 10.03
(s, 1
H) 8.45 (s, 1 H) 8.35 (s, 1 H) 7.85 (dd, J=8.70, 1.37 Hz, 1 H) 7.69 (d, J=8.54
Hz, 1 H).
Example 36B
N-cyclohexyl-6-(1 H-indazol-5 -yl)imidazo [2,1-b] [ 1,3 ]thiazol-5-amine
Example 36A (50 mg, 0.34 mmol) and 2-aminothiazole (28 mg, 0.34 mmol) were
combined with scandium triflate (8 mg, 0.0 17 mmol) in anhydrous methanol (1
mL) in a 4
mL vial. The vial was sealed and shaken at ambient temperature for 30 minutes.
Cyclohexyl
isocyanide (42 mL, 0.34 mmol) was added, and the mixture was shaken for 2 days
at room
temperature. The mixture was purified by reverse-phase HPLC using an
acetonitrile/water
0.1% TFA gradient elution method to afford the title compound as the TFA salt.
'H NMR
(500 MHz, DMSO-d6) 8 ppm 13.12 (s, 1 H) 8.32 (s, 1 H) 8.13 (s, 1 H) 8.05 (d,
J=8.85, 1.22
Hz, 1 H) 7.92 (d, J=4.27 Hz, 1 H) 7.60 (d, J=8.54 Hz, 1 H) 7.37 (d, J=3.66 Hz,
1 H) 4.89 (s, 1
H)2.78-2.94(m,1H)1.73-1.83(m,2H)1.58-1.68(m,2H)1.45-1.53(m,1H)1.16-
1.29 (m, 2 H) 1.04 - 1.14 (m, 3 H). MS (ESI+) m/z 338.1 (M+H)+.
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Example 37
N-cyclohexyl-2-(1 H-indazol-5-yl)imidazo [ 1,2-a]pyridin-3-amine
The title compound was prepared according to the procedure outlined in Example
36B, substituting 2-aminothiazole with 2-aminopyridine. 'H NMR (500 MHz, DMSO-
d6) 6 ppm 13.04 (s, 1 H) 8.57 (s, 1 H) 8.23 - 8.39 (m, 2 H) 8.11 (s, 1 H) 7.57
(d, J=8.54 Hz, 1
H) 7.46 (d, J=8.85 Hz, 1 H) 7.12 - 7.21 (m, 1 H) 6.88 (t, J=6.71 Hz, 1 H) 4.78
(d, J=5.80 Hz,
1H)2.78-2.91(m,1H)1.69-1.77(m,J=10.98Hz,2H)1.57-1.67(m,2H)1.45-1.53
(m, 1 H) 1.21 - 1.34 (m, 2 H) 1.01 - 1.16 (m, 3 H). MS (ESI+) m/z 332.1
(M+H)+.
Example 38
N-cyclohexyl-2-(1 H-indazol-5-yl)imidazo [ 1,2-a]pyrazin-3-amine
The title compound was prepared according to the procedure outlined in Example
36B, substituting 2-aminothiazole with 2-aminopyrazine. 1 H NMR (500 MHz, DMSO-
d6) 6 ppm 13.12 (s, 1 H) 8.90 (d, J=1.22 Hz, 1 H) 8.61 (s, 1 H) 8.37 (d,
J=4.58, 1.53 Hz, 1 H)
8.29 (d, J=8.70, 1.37 Hz, 1 H) 8.15 (s, 1 H) 7.85 (d, J=4.58 Hz, 1 H) 7.62 (d,
J=8.85 Hz, 1 H)
5.05 (d, J=6.71 Hz, 1 H) 2.81 - 2.99 (m, 1 H) 1.70 - 1.77 (m, J=10.68 Hz, 2 H)
1.58 - 1.67 (m,
2 H) 1.47 (s, 1 H) 1.24 - 1.38 (m, 2 H) 1.00 - 1.16 (m, 3 H). MS (ESI+) m/z
333.1 (M+H)+.
Example 39
5 -[ 1-benzyl-4-(4-fluorophenyl)-1 H-imidazol-5-yl]-1 H-indazole
Into a 20 mL scintillation vial was added 50.0 mg (0.34 mmol) of Example 36A.
To
the solid was added a 2.0 mL dimethylformamide solution containing 0.46 mmol
(49 mg) of
benzylamine and 50 mg of powdered activated 4,k molecular sieves. The vial was
then
capped and heated at 60 C for 4 hours on an orbital shaker. The vial was
allowed to cool to
ambient temperature; and was uncapped. To the suspension was added 32 mg (0.23
mmol) of
anhydrous potassium carbonate followed by 66 mg (0.23 mmol) a-(p-
toluenesulfonyl)-4-
fluorobenzylisonitrile. The vial was then capped and heated overnight at 60 C
on a shaker.
The vial was removed from the shaker; allowed to cool to ambient temperature;
and the
resulting suspension was filtered. The filtrate was evaporated under reduced
pressure at
medium heat on a Savant Speed Vac. The crude residues were redissolved in 1:1
DMSO/methanol and purified by reverse-phase HPLC using an acetonitrile/water
TFA
gradient elution method to afford the title compound as the TFA salt. 'H NMR
(300 MHz,
DMSO-d6) 6 ppm 9.01 (s, 1 H) 8.12 (s, 1 H) 7.76 (s, 1 H) 7.60 (d, J=8.48 Hz, 2
H) 7.32 - 7.45
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(m, 2 H) 7.09 - 7.30 (m, 6 H) 6.96 (d, J=6.61, 2.88 Hz, 2 H) 5.23 (s, 2 H). MS
(DCI) m/z 369
(M+H)+.
Example 40
N-{3-[4-(4-fluorophenyl)-5-(1H-indazol-5-yl)-1H-imidazol-1-yl]propyl}-N,N-
dimethylamine
The title compound was prepared as a TFA salt according to the procedure
outlined in
Example 39 substituting benzylamine with Ni,Ni-dimethylpropane-1,3-diamine. iH
NMR
(300 MHz, DMSO-d6) 6 ppm 9.49 (s, 1 H) 8.88 (s, 1 H) 8.19 (s, 1 H) 7.94 (s, 1
H) 7.73 (d,
J=8.81Hz,1H)7.29-7.44(m,3H)7.17(t,J=8.98Hz,2H)4.01(t,J=7.12Hz,2H)2.89-
3.04 (m, J=10.51 Hz, 2 H) 2.68 (s, 3 H) 2.67 (s, 3 H) 1.87 - 2.02 (m, 2 H). MS
(DCI) m/z
364 (M+H)+.
Example 41
N-cyclohexyl-2-(1 H-indazol-5-yl)imidazo [ 1,2-a]pyrimidin-3-amine
The title compound was prepared as a TFA salt according to the procedure
outlined in
Example 36B substituting pyrimidin-2-amine for thiazol-2-amine. 'H NMR (500
MHz,
DMSO-d6) 6 ppm 13.21 - 13.41 (m, 1 H) 9.07 (d, J=5.80 Hz, 1 H) 8.85 (d, J=3.05
Hz, 1 H)
8.51 (s, 1 H) 8.24 (s, 1 H) 8.14 (d, J=8.70, 1.37 Hz, 1 H) 7.73 (d, J=8.85 Hz,
1 H) 7.47 - 7.56
(m, 1 H) 5.25 - 5.41 (m, J=2.75 Hz, 1 H) 2.81 - 2.91 (m, J=10.53, 10.53 Hz, 1
H) 1.74 - 1.83
(m,2H)1.56-1.66(m,2H)1.43-1.50(m,IH)1.24(q,J=11.09Hz,2H)1.00-1.14(m,3
H). MS (ESI+) m/z 333.1 (M+H)+.
Example 42
5-[4-(4-fluorophenyl)-1-(1-phenylethyl)-1 H-imidazol-5-yl]-l H-indazole
The title compound was prepared according to the procedure outlined in Example
39
substituting 1-phenylethanamine for benzylamine. 'H NMR (300 MHz, CDCl3) 6 ppm
8.04
(s,IH)7.75-7.84(m,1H)7.35-7.55(m,4H)7.20-7.31(m,5H)6.76-7.01(m,4H)
5.09 (q, J=7.12 Hz, 1 H) 1.82 (d, 3 H). MS (DCI) m/z 383 (M+H)+.
Example 43
2-(1 H-indazol-5-yl)-N-isopropylimidazo [ 1,2-a]pyrimidin-3 -amine
Example 36A (42 mg, 0.287 mmol) and 2-aminopyrimidine (27 mg, 0.284 mmol)
were combined with scandium triflate (7 mg, 0.014 mmol) in anhydrous methanol
(2 mL) in
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a 4 mL vial. The vial was sealed and shaken at ambient temperature for 30
minutes.
Isopropyl isocyanide (27 mL, 0.286 mmol) was added and the mixture was shaken
at ambient
temperature overnight, followed by 40 C for 2 hours. The mixture was absorbed
on silica
gel and purified using silica gel chromatography eluting using a gradient of 0-
5% methanol in
dichloromethane to afford the title compound. 'H NMR (300 MHz, DMSO-d6) 6 ppm
13.08
(s, 1 H) 8.75 (d, J=6.95, 1.86 Hz, 1 H) 8.60 (s, 1 H) 8.31 (d, J=8.82, 1.36
Hz, 1 H) 8.20 (d,
J=4.75 Hz, 1 H) 8.14 (s, 1 H) 7.60 (d, J=8.82 Hz, 1 H) 7.03 (d, J=6.78, 4.07
Hz, 1 H) 6.54 (d,
J=4.75 Hz, 1 H) 4.86 (d, J=5.09 Hz, 1 H) 1.05 (d, J=6.10 Hz, 6 H). MS (ESI+)
m/z 293.0
(M+H)+.
Example 44
4-(1H-indazol-5-yl)-N-phenyl-1,3-thiazol-2-amine
Example 44A
tert-Butyl 5 -bromo-1 H-indazole- l-carboxylate
5-Bromoindazole (4.40 g, 22.3 mmol) and a catalytic amount of
dimethylaminopyridine (-50 mg) were dissolved in dichloromethane (100 mL). Di-
tert-butyl
dicarbonate (5.43 g, 24.9 mmol) was added, and the mixture was stirred at
ambient
temperature overnight. The mixture was absorbed on silica gel and purified by
silica gel
chromatography eluting with a gradient of 0-40% ethyl acetate in hexanes to
afford the title
compound. MS (ESI+) m/z 297.2 (M+H)+.
Example 44B
tert-Buty15 -acetyl-1 H-indazo le-l-carboxylate
Example 44A (5.12 g, 17.2 mmol), tributyl (1-ethoxyvinyl) tin (7.0 mL, 20.7
mmol),
and dichlorobis(triphenylphosphine)palladium(II) (672 mg, 0.957 mmol) were
combined in
toluene (85 mL). Nitrogen was bubbled into the mixture for 5 minutes, and the
mixture was
heated to 100 C in a sealed tube overnight. The mixture was absorbed on
silica gel and
purified by silica gel chromatography eluting with a gradient of 0-40% ethyl
acetate in
hexanes to afford the title compound. MS (ESI+) m/z 283.0 (M+Na)+.
Example 44C
tert-Butyl 5 -(2-bromoacetyl)-1 H-indazole-l-carboxylate
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Example 44B (1.60 g, 6.15 mmol) and pyridinium tribromide (1.98 g, 6.19 mmol)
were combined in tetrahydrofuran and heated to 40 C for 2 hours. The mixture
was
absorbed on silica gel and purified by silica gel chromatography eluting with
a gradient of 0-
40% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 360.9
(M+Na)
Example 44D
4-(1H-indazol-5-yl)-N-phenyl-1,3-thiazol-2-amine
Example 44C (71 mg, 0.208 mmol) and 1-phenyl-2-thiourea (33 mg, 0.217 mmol)
were combined in ethanol (300 mL) in a 4 mL vial. The vial was shaken at 80 C
overnight.
The mixture was absorbed on silica gel and purified by silica gel
chromatography eluting
with a gradient of methanol in dichloromethane (0-5%) to afford the title
compound. 'H
NMR (400 MHz, DMSO-d6) 6 ppm 13.08 (s, 1 H) 10.23 (s, 1 H) 8.32 (s, 1 H) 8.14
(s, 1 H)
7.93 (d, J=8.59, 1.53 Hz, 1 H) 7.75 (d, J=8.75, 1.07 Hz, 1 H) 7.58 (d, J=8.90
Hz, 1 H) 7.36 (d,
J=8.59, 7.36 Hz, 1 H) 7.25 (s, 1 H) 6.92 - 7.02 (m, 1 H). MS (ESI+) m/z 292.9
(M+H)+.
Example 45
5-(2-methyl-1,3-thiazol-4-yl)-1H-indazole
The title compound was prepared according to the procedure outlined in Example
44D substituting 1-phenyl-2-thiourea with thioacetamide. 'H NMR (300 MHz, DMSO-
d6) 6 ppm 13.10 (s, 1 H) 8.34 (s, 1 H) 8.12 (s, 1 H) 7.94 (d, J=8.82, 1.70 Hz,
1 H) 7.85 (s, 1
H) 7.57 (d, J=8.82 Hz, 1 H) 2.73 (s, 3 H). MS (ESI+) m/z 215.9 (M+H)+.
Example 46
N-ethyl-4-(1H-indazol-5-yl)-1,3-thiazol-2-amine
The title compound was prepared according to the procedure outlined in Example
44D substituting 1-phenyl-2-thiourea with ethylthiourea. 'H NMR (300 MHz, DMSO-
d6) 6 ppm 13.04 (s, 1 H) 8.21 (s, 1 H) 8.09 (s, 1 H) 7.83 (d, J=8.65, 1.53 Hz,
1 H) 7.58 (t,
J=5.43 Hz, 1 H) 7.51 (d, J=8.82 Hz, 1 H) 6.96 (s, 1 H) 3.22 - 3.34 (m, 2 H)
1.21 (t, J=7.29
Hz, 3 H). MS (ESI+) m/z 244.9 (M+H)+.
Example 47
N-benzyl-4-(1H-indazol-5-yl)-1,3-thiazol-2-amine
The title compound was prepared according to the procedure outlined in Example
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44D substituting 1-phenyl-2-thiourea with 1-benzyl-2-thiourea. 'H NMR (400
MHz, DMSO-
d6) 6 ppm 13.02 (s, 1 H) 8.21 (s, 1 H) 8.12 (t, J=5.83 Hz, 1 H) 8.08 (s, 1 H)
7.83 (d, J=8.90,
1.53Hz,1H)7.50(d,J=8.90Hz,1H)7.39-7.45(m,2H)7.35(t,J=7.52Hz,2H)7.26(t,
J=7.21 Hz, 1 H) 6.97 (s, 1 H) 4.54 (d, J=5.83 Hz, 1 H). MS (ESI+) m/z 306.9
(M+H)
Example 48
4-(1H-indazol-5-yl)-1,3-thiazol-2-amine
The title compound was prepared according to the procedure outlined in Example
44D substituting 1-phenyl-2-thiourea with thiourea. 'H NMR (300 MHz, DMSO-d6)
6 ppm
13.03 (s, 1 H) 8.17 (s, 1 H) 8.07 (s, 1 H) 7.81 (d, J=8.82, 1.36 Hz, 1 H) 7.50
(d, J=8.82 Hz, 1
H) 7.01 (s, 2 H) 6.92 (s, 1 H). MS (ESI+) m/z 216.9 (M+H)+.
Example 49
4-(1 H-indazol-5-yl)-N-(2-phenylethyl)-1,3-thiazol-2-amine
The title compound was prepared according to the procedure outlined in Example
44D substituting 1-phenyl-2-thiourea with 1-phenethylthiourea. 'H NMR (300
MHz,
DMSO-d6) 6 ppm 13.03 (s, 1 H) 8.23 (s, 1 H) 8.09 (s, 1 H) 7.85 (d, J=8.65,
1.53 Hz, 1 H)
7.71 (t, J=5.43 Hz, 1 H) 7.51 (d, J=8.82 Hz, 1 H) 7.26 - 7.36 (m, 4 H) 7.18 -
7.26 (m, 1 H)
6.97 (s, 1 H) 3.47 - 3.59 (m, 1 H) 2.94 (t, J=7.44 Hz, 1 H). MS (ESI+) m/z
321.0 (M+H)+.
Example 50
N-benzyl-2-(1 H-indazol-5 -yl)imidazo [ 1,2-a]pyrimidin-3-amine
The title compound was prepared according to the procedure outlined in Example
43
substituting benzylisocyanide for isopropyl isocyanide. 'H NMR (300 MHz, DMSO-
d6) 6 ppm 13.10 (s, 1 H) 8.50 - 8.58 (m, 2 H) 8.39 (d, J=4.07, 2.03 Hz, 1 H)
8.25 (d, J=8.81,
1.36 Hz, 1 H) 8.13 (s, 1 H) 7.61 (d, J=8.81 Hz, 1 H) 7.24 (s, 5 H) 6.92 (d,
J=6.78, 4.07 Hz, 1
H) 5.44 (t, J=6.27 Hz, 1 H) 4.13 (d, J=6.10 Hz, 2 H). MS (ESI+) m/z 341.0
(M+H)+.
Example 51
N-butyl-2-(1 H-indazol-5 -yl)imidazo [ 1,2-a]pyrimidin-3-amine
The title compound was prepared according to the procedure outlined in Example
43
substituting butylisocyanide for isopropyl isocyanide. 'H NMR (300 MHz, DMSO-
d6) 6 ppm
13.09 (s, 1 H) 8.70 (d, J=6.78, 2.03 Hz, 1 H) 8.55 (s, 1 H) 8.44 (d, J=4.07,
2.03 Hz, 1 H) 8.25
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(d, J=8.82, 1.36 Hz, 1 H) 8.14 (s, 1 H) 7.61 (d, J=8.82 Hz, 1 H) 7.03 (d,
J=6.78, 4.07 Hz, 1 H)
4.90 (t, J=5.93 Hz, 1 H) 2.96 (s, 2 H) 1.49 (s, 2 H) 1.34 (s, 2 H) 0.82 (t,
J=7.29 Hz, 3 H). MS
(ESI+) m/z 307.0 (M+H)+.
Example 52
N-(4-chlorophenyl)-2-(1 H-indazol-5 -yl)imidazo [ 1,2-a]pyrimidin-3-amine
The title compound was prepared according to the procedure outlined in Example
43
substituting 4-chlorophenylisocyanide for isopropyl isocyanide. 'H NMR (500
MHz,
DMSO-d6) 8 ppm 13.12 (s, 1 H) 8.58 (dd, J=4.12, 1.98 Hz, 1 H) 8.46 (d, J=15.87
Hz, 2 H)
8.40 (dd, J=6.71, 1.83 Hz, 1 H) 8.06 - 8.16 (m, 2 H) 7.58 (d, J=8.85 Hz, 1 H)
7.18 (d, J=8.85
Hz, 2 H) 7.05 (dd, J=6.71, 3.97 Hz, 1 H) 6.57 (d, J=8.85 Hz, 2 H). MS (ESI+)
m/z 361.0
(M+H)+.
Example 53
2-(1 H-indazol-5-yl)-N-(4-methoxyphenyl)imidazo [ 1,2-a]pyrimidin-3 -amine
The title compound was prepared according to the procedure outlined in Example
43
substituting 4-methoxyphenylisocyanide for isopropyl isocyanide. 'H NMR (500
MHz,
DMSO-d6) 8 ppm 13.10 (s, 1 H) 8.56 (dd, J=3.97, 2.14 Hz, 1 H) 8.47 (s, 1 H)
8.36 (dd,
J=6.56, 1.98 Hz, 1 H) 8.15 (dd, J=8.70, 1.37 Hz, 1 H) 8.10 (s, 1 H) 7.99 (s, 1
H) 7.57 (d,
J=8.54 Hz, 1 H) 7.03 (dd, J=6.71, 4.27 Hz, 1 H) 6.76 (d, J=8.85 Hz, 2 H) 6.50
(d, J=8.85 Hz,
2 H) 3.63 (s, 3 H). MS (ESI+) m/z 357.4 (M+H)+.
Example 54
2-(1 H-indazol-5 -yl)imidazo [ 1, 2-a]pyrimidine
The title compound was prepared according to the procedure outlined in Example
44D substituting 2-aminopyrimidine for 1-phenyl-2-thiourea. 'H NMR (300 MHz,
DMSO-
d6) 8 ppm 13.13 (s, 1 H) 8.96 (dd, J=6.78, 2.03 Hz, 1 H) 8.51 (dd, J=4.41,
2.03 Hz, 1 H) 8.42
(s, 1 H) 8.36 (s, 1 H) 8.15 (s, 1 H) 8.01 (dd, J=8.82, 1.70 Hz, 1 H) 7.62 (d,
J=8.48 Hz, 1 H)
7.04 (dd, J=6.61, 4.24 Hz, 1 H). MS (ESI+) m/z 236.1 (M+H)+.
Example 55
methyl N-[2-(1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-yl]glycinate
The title compound was prepared as a TFA salt according to the procedure
outlined in
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Example 36B substituting 2-aminopyridine for 2-aminothiazole and methyl 2-
isocyanoacetate
for cyclohexyl isocyanide. 'H NMR (400 MHz, DMSO-d6) 6 ppm 13.41 (s, 1 H) 8.90
(d,
J=6.75 Hz, 1 H) 8.38 (s, 1 H) 8.27 (s, 1 H) 7.84 - 7.98 (m, 3 H) 7.77 (d,
J=8.90 Hz, 1 H) 7.55
(td, J=6.75, 1.23 Hz, 1 H) 5.95 - 6.06 (m, 1 H) 3.87 (d, J=4.60 Hz, 2 H) 3.51
(s, 3 H). MS
(ESI+) m/z 340.1 (M+H)+.
Example 56
N-benzyl-2-(1 H-indazol-5-yl)imidazo [ 1,2-a]pyridin-3 -amine
The title compound was prepared according to the procedure outlined in Example
36B
substituting 2-aminopyridine for 2-aminothiazole and benzyl isocyanide for
cyclohexyl
isocyanide. The final product precipitated out of solution and was isolated
after filtration. 'H
NMR (400 MHz, DMSO-d6) d ppm 13.04 (s, 1 H) 8.49 (s, 1 H) 8.16 - 8.27 (m, 2 H)
8.09 (s, 1
H) 7.58 (d, J=8.90 Hz, 1 H) 7.44 (d, J=8.90 Hz, 1 H) 7.19 - 7.35 (m, 5 H) 7.13
(ddd, J=8.98,
6.67, 0.92 Hz, 1 H) 6.80 (td, J=6.75, 0.92 Hz, 1 H) 5.32 (t, J=6.14 Hz, 1 H)
4.12 (d, J=6.14
Hz, 2 H). MS (ESI+) m/z 322.1 (M+H)+.
Example 57
N-(4-chlorophenyl)-2-(1 H-indazol-5-yl)imidazo [ 1,2-a]pyridin-3 -amine
The title compound was prepared according to the procedure outlined in Example
36B
substituting 2-aminopyridine for 2-aminothiazole and 1-chloro-4-
isocyanobenzene for
cyclohexyl isocyanide. 'H NMR (400 MHz, DMSO-d6) 6 ppm 13.06 (s, 1 H) 8.39 (s,
2 H)
8.05 - 8.14 (m, 2 H) 7.94 (d, J=6.75 Hz, 1 H) 7.62 (d, J=8.90 Hz, 1 H) 7.55
(d, J=8.59 Hz, 1
H)7.28-7.34(m,1H)7.17(d,J=8.90Hz,2H)6.88-6.96(m,J=6.75,6.75Hz,1H)6.53
(d, J=8.59 Hz, 2 H). MS (ESI+) m/z 360.0 (M+H)+.
Example 58
2-(1 H-indazol-5 -yl)-N-(4-methoxyphenyl)imidazo [ 1,2-a]pyridin-3 -amine
The title compound was prepared according to the procedure outlined in Example
36B
substituting 2-aminopyridine for 2-aminothiazole and 1-isocyano-4-
methoxybenzene for
cyclohexyl isocyanide. 'H NMR (400 MHz, DMSO-d6) 6 ppm 13.04 (s, 1 H) 8.44 (s,
1 H)
8.14 (d, J=8.90, 1.23 Hz, 1 H) 8.06 (s, 1 H) 7.87 - 7.96 (m, 2 H) 7.59 (d,
J=8.90 Hz, 1 H) 7.54
(d, J=8.59 Hz, 1 H) 7.24 - 7.33 (m, 1 H) 6.86 - 6.93 (m, J=6.75, 6.75 Hz, 1 H)
6.75 (d, J=9.21
Hz, 2 H) 6.47 (d, J=9.21 Hz, 2 H) 3.63 (s, 3 H). MS (ESI+) m/z 356.1 (M+H)+.
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Example 59
tert-butyl4-[4-(4-fluorophenyl)-5-(1 H-indazol-5-yl)-1 H-imidazol-1-
yl]piperidine-l-
carboxylate
The title compound was prepared according to the procedure outlined in Example
39
substituting tert-butyl4-aminopiperidine-l-carboxylate for benzylamine. iH NMR
(400
MHz, DMSO-d6) 8 ppm 13.32 (s, 1 H) 8.14 (s, 1 H) 8.01 (s, 1 H) 7.79 (s, 1 H)
7.68 (d, J=8.59
Hz,2H)7.24-7.39(m,2H)6.97(t,J=8.90Hz,2H)3.91-4.05(m,2H)3.71-3.84(m,l
H) 2.53 - 2.69 (m, 2 H) 1.76 - 1.94 (m, 4 H) 1.35 - 1.40 (m, 9 H). MS (DCI)
m/z 462
(M+H)+.
Example 60
3 ,5-bis(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazole
Example 60A
tert-Buty15 -bromo-3-iodo-1 H-indazole-l-carboxylate
To a solution of 5-bromoindazole (10 g, 50.75 mmol) in dimethylformamide (100
mL) was added KOH (10 g, 177.63 mmol). Over a period of 2 hours, iodine (20 g,
78.80
mmol) was added. The mixture was treated with a solution of NazSzOs (20 g) in
water (200
mL), extracted with ethyl acetate, washed with brine, dried over sodium
sulfate and filtered,
and the solvent was removed under reduced pressure. The solid was dissolved in
dichloromethane (350 mL) and treated with di-tert-butyl dicarbonate (14.4 g,
65.98 mmol)
and dimethylaminopyridine (10 mg, 0.08 mmol). The mixture was stirred for 20
minutes at
room temperature and passed directly through a bed of silica gel to afford the
title compound.
MS (DCI/NH3) m/z 422.9 (M+H)+.
Example 60B
teNt-butyl5-bromo-3-phenyl-lH-indazole-l-carboxylate and tert-butyl 5-bromo-3-
iodo-lH-
indazole-l-carboxylate
To a solution of Example 60A (2.1 g, 5 mmol) in toluene (10 mL) was added
Pd(PPh3)4 (173 mg, 0.15 mmol), a solution of Na2CO3 (1.1 g, 10 mmol) in water
(5 mL), and
a solution of phenyl boronic acid (671 mg, 5.5 mmol) in methanol (3 mL). The
mixture was
stirred at room temperature for 5 days, quenched with water, extracted with
ethyl acetate and
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purified by silica gel chromatography eluting with 5% ethyl acetate / hexanes
to afford the
title compounds as a mixture. 'H NMR (500 MHz, DMSO-d6) 6 ppm 8.28 (d, J=1.53
Hz, 1
H)8.12(d,J=8.85Hz,1H)7.97-8.04(m,3H)7.80-7.86(m,2H)7.75(d,J=1.83Hz,1
H) 7.54 - 7.63 (m, 3 H) 1.68 (s, 9 H) 1.64 (s, 9 H). MS (ESI+) m/z 373.9
(M+H)+.
Example 60C
tert-Butyl 3,5-bis((trimethylsilyl)ethynyl)-1H-indazole-l-carboxylate and tert-
butyl5-bromo-
3-((trimethylsilyl)ethynyl)-1 H-indazole-l-carboxylate
Example 60B (1 g, 2.55 mmol), dichlorobis(triphenylphosphine)palladium(II) (89
mg,
0.13 mmol), triethylamine (1.78 mL, 12.75 mmol), trimethylsilyl acetylene
(0.432 mL, 3.06
mmol), and Cul (24 mg, 0.13 mmol) were combined in dimethylformamide (10 mL)
and
stirred at room temperature for 20 hours. The mixture was diluted with ethyl
acetate, washed
with water, and purified by silica gel chromatography to afford the title
compounds. 'H
NMR (500 MHz, DMSO-d6) 6 ppm 8.10 (d, J=8.85 Hz, 1 H) 8.07 (d, J=8.85 Hz, 1 H)
7.97
(d, J=1.83 Hz, 1 H) 7.84 (s, 1 H) 7.82 (dd, J=8.85, 1.83 Hz, 1 H) 7.71 (dd,
J=8.54, 1.53 Hz, 1
H) 1.65 (s, 18 H) 0.33 (d, J=0.92 Hz, 18 H).
Example 60D
tert-buty13,5-diethynyl-lH-indazole-l-carboxylate and tert-butyl 5-bromo-3-
ethynyl-lH-
indazole-l-carboxylate
To a solution of Example 60C (350 mg, 0.85 mmol) in tetrahydrofuran (5mL) was
added a 1M solution of TBAF in tetrahydrofuran (2 mL, 2 mmol). After 10
minutes, the
solvent was evaporated under reduced pressure and the crude mixture was
purified by silica
gel chromatography eluting with 5% ethyl acetate in hexanes to afford the
title compounds.
'H NMR (500 MHz, DMSO-d6) 6 ppm 8.12 (d, J=7.93 Hz, 1 H) 8.07 (d, J=8.85 Hz, 1
H)
8.01 (d, J=1.53 Hz, 1 H) 7.90 (s, 1 H) 7.83 (dd, J=8.85, 1.83 Hz, 1 H) 7.74
(dd, J=8.85, 1.53
Hz, 1 H) 4.91 (s, 1 H) 4.90 (s, 1 H) 4.29 (s, 1 H) 1.66 (s, 9 H) 1.65 (s, 9
H).
Example 60E
3 ,5-bis(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
3D
substituting Example 60D for Example 3C. 'H NMR (500 MHz, DMSO-d6) 6 ppm 13.35
(s,
1 H) 8.76 (s, 1 H) 8.71 (s, 1 H) 8.70 (s, 1 H) 7.92 (d, J=8.61, 1.28 Hz, 1 H)
7.64 (d, J=8.79
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Hz, 1 H) 7.38 - 7.43 (m, 8 H) 7.33 - 7.37 (m, 2 H) 5.73 (s, 2 H) 5.66 (s, 2
H). MS (ESI+) m/z
433.2 (M+H)+.
Example 61
5 -(1-benzyl-1 H-1,2,3-triazol-4-yl)-3-phenyl-1 H-indazole
Example 61A
tert-Butyl 3-phenyl-5-((trimethylsilyl)ethynyl)-1H-indazole-l-carboxylate and
tert-butyl5-
bromo-3-phenyl-1 H-indazole-l-carboxylate
Example 60B (1 g, 2.55 mmol), dichlorobis(triphenylphosphine)palladium(II)
(89mg,
0.13 mmol), triethylamine (1.78 mL, 12.75 mmol), trimethylsilyl acetylene
(0.432 mL, 3.06
mmol), and Cul (24 mg, 0.13 mmol) were combined in dimethylformamide (10 mL)
and
stirred at room temperature for 20 hours. The mixture was diluted with ethyl
acetate and
purified by silica gel chromatography to afford the title compound. 'H NMR
(500 MHz,
DMSO-d6) 6 ppm 8.29 (d, J=1.53 Hz, 1 H) 8.09 - 8.19 (m, 3 H) 7.96 - 8.03 (m, 4
H) 7.83 (dd,
J=8.85, 1.83 Hz, 1 H) 7.72 (dd, J=8.85, 1.53 Hz, 1 H) 7.50 - 7.65 (m, 6 H)
1.68 (s, 18 H) 0.26
-0.27(m,9H).
Example 61B
teYt-Butyl5-ethynyl-3-phenyl-lH-indazole-l-carboxylate and tert-butyl5-bromo-3-
phenyl-
1 H-indazole-l-carboxylate
The title compound was prepared according to the procedure outlined in Example
60D substituting Example 61A for Example 60C. 'H NMR (500 MHz, DMSO-d6) 6 ppm
8.28 (d, J=1.53 Hz, 1 H) 8.21 (s, 1 H) 8.16 (d, J=8.54 Hz, 1 H) 8.12 (d,
J=8.85 Hz, 1 H) 7.97
- 8.05 (m, 4 H) 7.83 (dd, J=8.85, 1.83 Hz, 1 H) 7.75 (dd, J=8.85, 1.53 Hz, 1
H) 7.53 - 7.64
(m, 6 H) 4.27 (s, 1 H) 1.68 (s, 9 H) 1.68 (s, 9 H).
Example 61C
5 -(1-benzyl-1 H-1,2,3-triazol-4-yl)-3-phenyl-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
3D
substituting Example 61B for Example 3C. 'H NMR (500 MHz, DMSO-d6) 6 ppm 13.38
(s,
1 H) 8.77 (s, 1 H) 8.52 (s, 1 H) 8.06 (d, J=7.33 Hz, 2 H) 7.98 (d, J=8.79 Hz,
1 H) 7.69 (d,
J=8.79Hz,1H)7.53-7.61(m,J=7.51,7.51Hz,2H)7.33-7.48(m,6H)5.68(s,2H). MS
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(ESI+) m/z 352.0 (M+H)+.
Example 62
-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-amine
5
Example 62A
2-Fluoro-5-((trimethylsilyl)ethynyl)benzonitrile
5-Bromo-2-fluorobenzonitrile (5.01 g, 25.0 mmol),
dichlorobis(triphenylphosphine)palladium(II) (652 mg, 0.929 mmol), and copper
(I) iodide
(413 mg, 2.17 mmol) were combined in triethylamine (15 mL) under an atmosphere
of
nitrogen. Trimethylsilyl acetylene (4.2 mL, 29.7 mmol) was added and the
mixture was
heated to 100 C. The mixture solidified and was monitored by LC/MS. After
completion,
the mixture was diluted with methylene chloride and washed with 1 N HC1. The
organic
layer was absorbed on silica gel and purified by silica gel chromatography
eluting with a
gradient of ethyl acetate in hexanes (5-45%) to afford the title compound. 'H
NMR (300
MHz, DMSO-d6) 6 ppm 8.09 (dd, J=6.10, 2.03 Hz, 1 H) 7.77 - 7.97 (m, 1 H) 7.54
(t, J=9.15
Hz,1H)0.15-0.32(m,9H).
Example 62B
5-Ethynyl-2-fluorobenzonitrile
Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 70 mL) was
added
to a solution of Example 62A (5.05 g, 23.2 mmol) in tetrahydrofuran (50 mL)
and allowed to
stir for 20 minutes. The mixture was diluted with methylene chloride and
washed with water.
The organic layer was absorbed on silica gel and purified by silica gel
chromatography
eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title
compound. 'H
NMR (300 MHz, DMSO-d6) 6 ppm 8.13 (dd, J=6.27, 2.20 Hz, 1 H) 7.82 - 7.95 (m, 1
H) 7.56
(t, J=8.99 Hz, 1 H) 4.40 (s, 1 H).
Example 62C
5-(1-Benzyl-1 H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile
Example 62B (1.68 g, 11.6 mmol) was dissolved in tert-butanol (14 mL). Benzyl
azide (2.14 g, 15.8 mmol) was added and the mixture was transferred to 14
microwave vials
(1.0 mL each). Water (0.5 mL), a small piece of copper wire, and a 1 M
solution of copper
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(II) sulfate (0.5 mL) were added to each microwave vial and the vials were
heated in a CEM-
Discover microwave at 125 C using 100 Watts for 10 minutes each. The vials
were
recombined, diluted with ethyl acetate, and washed with water and brine. The
organic
material was absorbed on silica gel and purified by silica gel chromatography
eluting with a
gradient of 5-50% ethyl acetate in hexanes to afford the title compound. 'H
NMR (300
MHz, DMSO-d6) 6 ppm 8.73 (s, 1 H) 8.33 - 8.44 (m, 1 H) 8.19 - 8.32 (m, 1 H)
7.56 - 7.70
(m,1H)7.28-7.47(m,5H)5.68(s,2H).
Example 62D
5 -(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-amine
Hydrazine hydrate (18 mL) was added to Example 62C (1.93 g, 6.94 mmoL) in
ethanol (10 mL). The mixture was heated to 95 C overnight. The mixture was
diluted with
ethyl acetate and washed with water. Some of the product precipitated in the
separatory
funnel and was filtered to afford the title compound. The ethyl acetate layer
was
concentrated under reduced pressure and the resulting solid was triturated
with methanol to
afford additional title compound. 'H NMR (300 MHz, DMSO-d6) 6 ppm 11.43 (s, 1
H) 8.42
(s, 1 H) 8.21 (s, 1 H) 7.67 (d, J=8.82, 1.70 Hz, 1 H) 7.38 (s, 5 H) 7.26 (d,
J=8.48 Hz, 1 H)
5.64 (s, 2 H) 5.38 (s, 2 H). MS (ESI+) m/z 291.0 (M+H)+.
Example 63
5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1-[(1-methylpiperidin-4-yl)carbonyl]-1 H-
indazol-3-amine
Example 62D (44 mg, 0.152 mmol), 1-methylpiperdine-4-carboxylic acid
hydrochloride (27 mg, 0.150 mmol), and HATU (61 mg, 0.160 mmol) were combined
in
tetrahydrofuran (2 mL). Diisopropylethylamine (110 mL, 0.631 mmol) was added
and the
mixture was heated to 90 C for 30 minutes. The mixture was diluted with
methylene
chloride and washed with 1 N sodium hydroxide. The organic layer was absorbed
on silica
gel and purified by silica gel chromatography eluting with a gradient of 5-15%
methanol in
dichloromethane to afford the title compound. 'H NMR (300 MHz, DMSO-d6) 8 ppm
8.58
(s, 1 H) 8.47 (s, 1 H) 8.26 (d, J=8.48 Hz, 1 H) 7.97 (d, J=8.48, 1.70 Hz, 1 H)
7.38 (s, 5 H)
6.58(s,2H)5.67(s,2H)3.35-3.47(m,1H)2.95(d,J=11.19Hz,2H)2.28(s,3H)2.03-
2.20 (m, 2 H) 1.92 (s, 2 H) 1.77 (s, 2 H). MS (ESI+) m/z 416.2 (M+H)+.
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Example 64
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-methoxyacetamide
Example 64A
tert-Butyl3-amino-5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1H-indazole-l-carboxylate
Example 62D (1.80 g, 6.20 mmol) was suspended in methylene chloride (100 mL)
with a catalytic amount of dimethylaminopyridine. A solution of di-tert-butyl
dicarbonate
(1.36 g, 6.23 mmol) in methylene chloride (50 mL) was added dropwise over 1
hour. The
mixture was absorbed on silica gel and purified by silica gel chromatography
eluting with a
gradient of 0-5% methanol in dichloromethane to afford the title compound. MS
(ESI+) m/z
391.1 (M+H)+.
Example 64B
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-methoxyacetamide
Example 64A (45 mg, 0.115 mmol) was dissolved in methylene chloride (1.5 mL)
and
pyridine (0.5 mL). Methoxy acetyl chloride (18 uL, 0.197 mmol) was added and
the mixture
was stirred at ambient temperature for 2 hours. The solvents were removed
using a warm
stream of nitrogen, the mixture was injected on a silica gel column, and the
product was
purified by silica gel chromatography eluting with a gradient of 0-5% methanol
in
dichloromethane to afford tert-butyl5-(1-benzyl-IH-1,2,3-triazol-4-yl)-3-(2-
methoxyacetamido)-1H-indazole-l-carboxylate (58 mg). The intermediate was
dissolved in
methylene chloride (2 mL) and trifluoroacetic acid (1 mL) and stirred at
ambient temperature
overnight. The solvents were removed under reduced pressure, and the mixture
was purified
by preparative HPLC on a C8 column using a gradient of 10% to 100%
acetonitrile/water
containing 0.1% trifluoroacetic acid to afford the title compound. iH NMR (300
MHz,
DMSO-d6) 8 ppm 12.79 (s, 1 H) 10.16 (s, 1 H) 8.59 (s, 1 H) 8.20 (s, 1 H) 7.83
(d, J=8.65,
1.53 Hz, 1 H) 7.51 (d, J=8.82 Hz, 1 H) 7.37 (s, 5 H) 5.64 (s, 2 H) 4.12 (s, 2
H) 3.42 (s, 3 H).
MS (ESI+) m/z 363.0 (M+H)+.
Example 65
Ni-[5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N2,N2-
dimethylglycinamide
Example 64A (81 mg, 0.207 mmol) was dissolved in methylene chloride (2 mL) and
pyridine (0.5 mL). Dimethylaminoacetylchloride hydrochloride, 80% (120 mg,
0.607 mmol)
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was added in three portions over 2 hours and the mixture was stirred at
ambient temperature
overnight. Trifluoroacetic acid (2 mL) was added and the mixture was stirred
for 3 hours.
The mixture was diluted with methylene chloride and washed with 1 N sodium
hydroxide.
The organic layer was absorbed on silica gel and purified using silica gel
chromatography
eluting with a gradient of 5-15% methanol in dichloromethane to afford the
title compound.
IH NMR (300 MHz, DMSO-d6) 6 ppm 12.77 (s, 1 H) 10.05 (s, 1 H) 8.58 (s, 1 H)
8.24 (s, 1
H) 7.82 (d, J=8.65, 1.53 Hz, 1 H) 7.50 (d, J=8.82 Hz, 1 H) 7.30 - 7.44 (m, 5
H) 5.64 (s, 2 H)
3.16 - 3.20 (m, 2 H) 2.34 (s, 6 H). MS (ESI+) m/z 376.1 (M+H)+.
Example 66
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]butanamide
Example 64A (76 mg, 0.195 mmol) was dissolved in methylene chloride (2 mL) and
pyridine (0.2 mL). Butyryl chloride (26 uL, 0.250 mmol) was added and the
mixture was
stirred at ambient temperature for 2 hours. Trifluoroacetic acid (1 mL) was
added and the
mixture was stirred for 3 hours. The mixture was diluted with methylene
chloride and
washed with water. The organic layer was absorbed on silica gel and purified
using silica gel
chromatography eluting with a gradient of 1-8% methanol in dichloromethane to
afford the
title compound. 'H NMR (300 MHz, DMSO-d6) 6 ppm 12.70 (s, 1 H) 10.30 (s, 1 H)
8.57 (s,
1 H) 8.23 (s, 1 H) 7.81 (d, J=8.82 Hz, 1 H) 7.49 (d, J=8.82 Hz, 1 H) 7.37 (s,
5 H) 5.64 (s, 2
H) 2.39 (t, J=7.29 Hz, 2 H) 1.67 (s, 2 H) 0.97 (t, J=7.46 Hz, 3 H). MS (ESI+)
m/z 361.1
(M+H)+.
Example 67
5-[4-(4-fluorophenyl)-1-pip eridin-4-yl-1 H-imidazo l-5 -yl] -1 H-indazole
The title compound was prepared according to the procedure outlined in Example
39
substituting piperidin-4-amine for benzylamine. 'H NMR (300 MHz, DMSO-d6) 6
ppm
13.28 (s, 1 H) 8.14 (s, 1 H) 7.94 (s, 1 H) 7.78 (s, 1 H) 7.63 - 7.72 (m, 2 H)
7.21 - 7.43 (m, 2
H) 6.90 - 7.04 (m, 2 H) 4.14 (d, J=5.59, 1.86 Hz, 1 H) 3.53 - 3.74 (m, J=5.76
Hz, 1 H) 2.94
(d, J=12.21 Hz, 2 H) 2.21 - 2.35 (m, 2 H) 1.74 - 1.88 (m, 3 H). MS (DCI) m/z
362 (M+H)+.
Example 68
5- {4-(4-fluorophenyl)-1-[2-(1-methylpyrrolidin-2-yl)ethyl]-1 H-imidazol-5-yl}
-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
39
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substituting 2-(1-methylpyrrolidin-2-yl)ethanamine for benzylamine. iH NMR
(300 MHz,
DMSO-d6) 6 ppm 13.30 (s, 1 H) 8.14 (s, 1 H) 7.86 (s, 1 H) 7.82 (s, 1 H) 7.68
(d, J=8.48 Hz, 1
H)7.24-7.47(m,3H)6.92-7.08(m,2H)3.83(t,J=7.80Hz,2H)2.71-2.93(m,1H)1.88
- 2.01 (m, 3 H) 1.74 - 1.88 (m, 1 H) 1.00 - 1.83 (m, 7 H). MS (DCI) m/z 390
(M+H)+.
Example 69
5- {4-(4-fluorophenyl)-1-[3-(4-methylpiperazin-1-yl)propyl]-1 H-imidazol-5-yl}-
1 H-indazole
The title compound was prepared according to the procedure outlined in Example
39
substituting 3-(4-methylpiperazin-1-yl)propan-l-amine for benzylamine. iH NMR
(300
MHz, DMSO-d6) 6 ppm 13.36 (s, 1 H) 8.13 (s, 1 H) 7.81 (s, 2 H) 7.67 (d, J=8.48
Hz, 1 H)
7.32-7.45(m,2H)7.27(d,J=8.48,1.36Hz,1H)6.87-7.06(m,2H)3.72-3.91(m,2H)
1.92 - 2.21 (m, 10 H) 1.91 - 2.20 (s, 3 H) 1.51 - 1.66 (m, 2 H). MS (ESI+) m/z
419 (M+H)+.
Example 70
ethyl 5-(1H-indazol-5-yl)isoxazole-3-carboxylate
Example 3C (1.83 g, 12.9 mmol) was dissolved in toluene (60 mL) and
triethylamine
(2.2 mL) and warmed to 90 C. Ethy12-chloro-2-(hydroxyimino)acetate (1.89 g,
12.5 mmol)
was dissolved in toluene (15 mL) and was added dropwise over 30 minutes.
Following the
addition, the mixture was diluted with ethyl acetate and washed with 1 N
hydrochloric acid.
The organic layer was concentrated under reduced pressure and the resulting
residue was
triturated with methanol to afford the title compound. 'H NMR (300 MHz, DMSO-
d6) 6 ppm
13.38 (s, 1 H) 8.43 (s, 1 H) 8.23 (s, 1 H) 7.92 (d, J=8.82, 1.36 Hz, 1 H) 7.70
(d, J=8.82 Hz, 1
H) 7.44 (s, 1 H) 4.41 (q, J=7.12 Hz, 2 H) 1.35 (t, J=7.12 Hz, 3 H). MS (ESI+)
m/z 257.9
(M+H)+.
Example 71
5-(1 H-indazol-5-yl)-N-methylisoxazole-3-carboxamide
Example 71A
5-(1H-indazol-5-yl)isoxazole-3-carboxylic acid
Example 70 (1.50 g, 5.83 mmol) was dissolved in tetrahydrofuran (100 mL),
methanol (10 mL), and water (10 mL). Potassium hydroxide (680 mg, 12.1 mmol)
was
added, and the mixture was stirred at ambient temperature for 2 hours. The
solvents were
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removed under reduced pressure, and the resulting residue was triturated with
a mixture of 1
N hydrochloric acid and methanol to provide a solid that was filtered to
afford the title
compound. 'H NMR (300 MHz, DMSO-d6) 8 ppm 13.37 (s, 1 H) 8.39 (s, 1 H) 8.22
(s, I H)
7.90 (dd, J=8.8I, 1.36 Hz, I H) 7.69 (d, J=8.82 Hz, 1 H) 7.30 (s, I H).
Example 71B
5-(1 H-indazol-5-yl)-N-methylisoxazole-3-carboxamide
Example 71A (46 mg, 0.201 mmol), HATU (88 mg, 0.231 mmol), and
diisopropylethylamine (133 uL, 0.764 mmol) were combined in tetrahydrofuran (2
mL).
Monomethylamine (40% solution in water) (50 uL) was added, and the reaction
was stirred at
50 C for 2 hours. The mixture was diluted with methylene chloride and washed
with 1 N
sodium hydroxide, 1 N hydrochloric acid, and brine. The organic layer was
absorbed on
silica gel and purified by silica gel chromatography eluting with a gradient
of 10-50% ethyl
acetate in hexanes to afford the title compound. 'H NMR (300 MHz, DMSO-d6) 8
ppm
13.36 (s, 1 H) 8.72 (q, J=4.30 Hz, 1 H) 8.39 (s, 1 H) 8.23 (s, I H) 7.89 (d,
J=8.65, 1.53 Hz, 1
H) 7.69 (d, J=8.82 Hz, 1 H) 7.28 (s, I H) 2.80 (d, J=4.75 Hz, 3 H). MS (ESI+)
m/z 243.0
(M+H)+.
Example 72
5-(3-benzylisoxazol-5-yl)-1 H-indazole
Phenylacetaldehyde (90+ %) (266 mg, 2.38 mmol) was dissolved in tert-butanol
(1
mL) and water (1 mL). Hydroxylamine hydrochloride (79 mg, 1.14 mmol) was added
followed by a 6N solution of sodium hydroxide (19 uL, 31.7 mmol). The mixture
was stirred
for 30 minutes. Chloramine-T trihydrate (308 mg, 1.09 mmol) was added slowly
over 5
minutes followed by the addition of copper (II) sulfate and a small piece of
copper wire.
Example 3C (154 mg, 1.08 mmol) was added and the mixture was stirred at 50 C
for 2 hours
then ambient temperature overnight. The mixture was diluted with methylene
chloride and
washed with water. The organic layer was absorbed on silica gel and purified
by silica gel
chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes to
afford the title
compound. 'H NMR (300 MHz, DMSO-d6) b ppm 13.31 (s, I H) 8.28 (s, 1 H) 8.18
(s, I H)
7.79 (dd, J=8.65, 1.53 Hz, I H) 7.64 (d, J=8.8I Hz, 1 H) 7.13 - 7.46 (m, 5 H)
6.83 (s, I H)
4.04 (s, 2 H). MS (ESI+) m/z 275.7 (M+H)+.
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Example 73
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]benzamide
Example 64A (72 mg, 0.184 mmol) was dissolved in methylene chloride (2 mL) and
pyridine (0.2 mL). Benzoyl chloride (36 uL, 0.310 mmol) was added, and the
mixture was
stirred at ambient temperature for 2 hours. Trifluoroacetic acid (1 mL) was
added and the
mixture was stirred for 3 hours. The mixture was diluted with methylene
chloride and
washed with water. The organic layer was absorbed on silica gel and purified
using silica gel
chromatography eluting with a gradient of 1-8% methanol in dichloromethane to
afford the
title compound. 'H NMR (300 MHz, DMSO-d6) 8 ppm 12.88 (s, 1 H) 10.81 (s, 1 H)
8.63 (s,
1 H) 8.16 (s, 1 H) 8.06 - 8.13 (m, 2 H) 7.88 (d, J=8.82, 1.36 Hz, 1 H) 7.59 -
7.64 (m, J=7.12
Hz, 1 H) 7.51 - 7.59 (m, 3 H) 7.31 - 7.42 (m, 5 H) 5.63 (s, 2 H). MS (ESI+)
m/z 395.1
(M+H)+.
Example 74
5-(3-propylisoxazol-5-yl)-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
72
substituting butyraldehyde for phenylacetaldehyde. 'H NMR (300 MHz, DMSO-d6) 8
ppm
13.31 (s, 1 H) 8.28 (s, 1 H) 8.20 (s, 1 H) 7.76 - 7.85 (m, 1 H) 7.63 - 7.70
(m, 1 H) 6.88 (s, 1
H) 2.63 (t, J=7.46 Hz, 2 H) 1.61 - 1.79 (m, 2 H) 0.96 (t, J=7.29 Hz, 3 H). MS
(ESI+) m/z
228.0 (M+H)+.
Example 75
N-benzyl-4-(1H-indazol-5-yl)-5-phenyl-1,3-thiazol-2-amine
Example 75A
1H-indazole-5-carboxylic acid
The title compound was prepared according to the procedure outlined in Example
3A,
substituting methyl 4-amino-3-methylbenzoate for 4-iodo-2-methylaniline.
During the final
workup, addition of 6 N HCl until pH 6 resulted in the formation of a solid,
which was
filtered, washed twice with water and dried in vacuo to afford the title
compound. 'H NMR
(300 MHz, DMSO-d6) 6 ppm 13.32 (s, 1 H) 12.83 (s, 1 H) 8.46 (s, 1 H) 8.24 (s,
1 H) 7.92
(dd, J=8.82, 1.70 Hz, 1 H) 7.60 (d, J=8.82 Hz, 1 H).
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Example 75B
N-Methoxy-N-methyl-1 H-indazole-5-carboxamide
To a suspension of Example 75A (1.6 g, 10 mmol) and N,O-dimethylhydroxylamine
(l.l g, 11 mmol) in dichloromethane (40 mL) and dimethylformamide (10 mL) was
added
triethylamine (1.67 mL, 12 mmol) and EDC (2.1 g, 11 mmol), and the mixture was
stirred at
room temperature for 24 hours. The solvents were evaporated under reduced
pressure, and
the resulting residue was diluted with ethyl acetate and washed with water.
The organic layer
was dried over sodium sulfate and purified by silica gel column chromatography
in ethyl
acetate to afford the title compound. MS (ESI+) m/z 206.0 (M+H)+.
Example 75C
1-(1H-indazol-5-yl)-2-phenylethanone
A solution of Example 75B (900 mg, 4.39 mmol) in tetrahydrofuran (10 mL) was
cooled under argon with an ice bath and treated with a 2M solution of benzyl
magnesium
chloride in tetrahydrofuran (6.6 mL, 13.16 mmol). The reaction was stirred
overnight at
room temperature followed by the addition of one more equivalent of benzyl
magnesium
chloride. The mixture was heated at 70 C for 9 hours. One more equivalent of
benzylmagnesium chloride was added, and the reaction was heated at 70 C for
another 90
minutes and was allowed to cool to room temperature. Aqueous saturated
ammonium
chloride was added, and the product was extracted with ethyl acetate and
purified by silica
gel column chromatography using 30% ethyl acetate in hexanes to afford the
title compound.
MS (ESI+) m/z 237.1 (M+H)+.
Example 75D
tert-Butyl 5 -(2-phenylacetyl)-1 H-indazole- I-carboxylate
To a suspension of Example 75C (236 mg, 1 mmol) in dichloromethane (2 mL) was
added di-tert-butyl dicarbonate (327 mg, 1.5 mmol) and a pinch of
dimethylaminopyridine
(-2 mg). The mixture was stirred for 15 minutes, and passed through a bed of
silica gel and
eluted with dichlormethane. The solvent was evaporated under reduced pressure
to afford the
title compound. MS (ESI+) m/z 337.0 (M+H)+.
Example 75E
2-Bromo-l-(1H-indazol-5-yl)-2-phenylethanone
To a solution of Example 75D (336 mg, 1 mmol) in tetrahydrofuran (20 mL)
heated at
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40 C with an oil bath was added dropwise with an addition funnel a solution
of pyridinium
tribromide (352 mg, 1.1 mmol) in tetrahydrofuran (20 mL) over 10 minutes. The
reaction
mixture was heated for an extra 2 hours, and was cooled, filtered, and the
filtrate was
evaporated to afford the title compound. MS (ESI-) m/z 212.9 (M-H)-.
Example 75F
N-benzyl-4-(IH-indazol-5-yl)-5-phenyl-1,3-thiazol-2-amine
A vial containing Example 75E (50 mg, 0.16 mmol) and 1-benzylthiourea (26 mg,
0.16 mmol) in ethanol (1 mL) was capped and heated in a heater shaker at 80 C
for 2 hours.
The solution of the crude product was purified by reverse-phase HPLC using an
acetonitrile/water 0.1 % TFA gradient elution method to afford the title
compound as a TFA
salt. 'H NMR (400 MHz, DMSO-d6) 6 ppm 12.99 (s, 1 H) 8.33 - 8.37 (m, 1 H) 8.01
(s, 1 H)
7.92-7.99(m,1H)7.82(s,1H)7.60-7.67(m,J=7.83,7.83Hz,1H)7.31-7.45(m,5H)
7.17 - 7.30 (m, 5 H) 4.53 (d, J=4.60 Hz, 2 H). MS (ESI+) m/z 383.0 (M+H)+.
Example 76
4-(1H-indazol-5-yl)-N,5-diphenyl-1,3-thiazol-2-amine
The title compound was prepared as a TFA salt according to the procedure
outlined in
Example 75F substituting 1-phenylthiourea for 1-benzylthiourea. 'H NMR (400
MHz,
DMSO-d6) 6 ppm 13.09 (s, 1 H) 10.29 (s, 1 H) 8.05 (d, J=0.92 Hz, 1 H) 7.89 (d,
J=1.53, 0.92
Hz, 1 H) 7.69 (d, J=8.59, 1.23 Hz, 2 H) 7.47 (dt, J=8.59, 0.92 Hz, 1 H) 7.40 -
7.44 (m, 1 H)
7.26 - 7.37 (m, 7 H) 6.94 - 7.02 (m, J=7.36, 7.36 Hz, 1 H). MS (ESI+) m/z
369.0 (M+H)+.
Example 77
5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazole
Example 77A
tert-butyl5-(cyclopropylethynyl)-1H-indazole-l-carboxylate
Example 44A (2.31 g, 7.77 mmol), cyclopropyl acetylene (620 mg, 9.37 mmol),
dichlorobis(triphenylphosphine)palladium(II) (170 mg, 0.242 mmol), and copper
(I) iodide
(92 mg, 0.483 mmol) were combined in triethylamine (10 mL) under an inert
atmosphere of
nitrogen. The mixture was heated to 100 C in a sealed tube for 4 hours. The
mixture was
diluted with methylene chloride and washed with 1 N hydrochloric acid. The
organic layer
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was absorbed onto silica gel and purified by silica gel chromatography eluting
with a gradient
of 5-50% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z
283.0
(M+H)+.
Example 77B
5-(1-benzyl-5 -cyclopropyl-1 H-1,2, 3-triazol-4-yl)-1 H-indazole
Example 77A (145 mg, 0.51 mmol) and benzyl azide (82 mg, 0.62 mmol) were
heated
neat in a CEM-Discover microwave at 150 C and 150 Watts, for 10 minutes. The
crude
mixture was dissolved in dichloromethane and purified by silica gel column
chromatography
using 50% ethyl acetate in hexanes as the eluent. 'H NMR (400 MHz, DMSO-d6) 6
ppm
13.12 (s, 1 H) 8.11 (d, J=5.52 Hz, 2 H) 7.79 (d, J=8.59, 1.53 Hz, 1 H) 7.60
(d, J=8.59 Hz, 1
H)7.26-7.45(m,5H)5.69(s,2H)1.78-1.92(m,1H)0.98-1.09(m,2H)0.31-0.45(m,
2 H). MS (ESI+) m/z 316.0 (M+H)+.
Example 78
5-(1-benzyl-4-cyclopropyl-1 H-1,2,3-triazol-5-yl)-1 H-indazole
The title compound was isolated as a by-product according to the procedure
outlined
in Example 77B. 'H NMR (500 MHz, DMSO-d6) 8 ppm 13.29 (s, 1 H) 8.14 (s, 1 H)
7.80 (s,
1 H) 7.65 (d, J=8.85 Hz, 1 H) 7.29 (d, J=8.54, 1.53 Hz, 1 H) 7.21 - 7.27 (m, 3
H) 6.93 (d,
J=7.48, 1.98 Hz, 2 H) 5.49 (s, 2 H) 1.70 - 1.80 (m, 1 H) 0.81 - 0.92 (m, 4 H).
MS (ESI+) m/z
316.0 (M+H)+.
Example 79
2-(1 H-indazol-5-yl)-3-phenylimidazo[ 1,2-a]pyrimidine
A vial containing Example 75E (80 mg, 0.25 mmol) and pyrimidin-2-amine (23 mg,
0.25 mmol) in ethanol (1 mL) was capped and heated in a heater shaker at 80 C
for 21 hours.
The solution of the crude product was purified by reverse-phase HPLC using an
acetonitrile/water 0.1% TFA gradient elution method to afford the title
compound. 1H NMR
(400 MHz, DMSO-d6) 8 ppm 8.69 (dd, J=4.30, 1.84 Hz, 1 H) 8.59 (dd, J=6.75,
1.84 Hz, 1 H)
8.07 (s, 1 H) 8.02 (s, 1 H) 7.46 - 7.65 (m, 7 H) 7.16 (dd, J=6.75, 3.99 Hz, 1
H). MS (ESI+)
m/z 312.0 (M+H)+.
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Example 80
-[ 1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-1,2,3 -triazol-4-yl]-1 H-indazole
Example 80A
5 4-(azidomethyl)tetrahydro-2H-pyran
4-(Iodomethyl)tetrahydro-2H-pyran (4.76 g, 21.1 mmol) was dissolved in
dimethyl
sulfoxide (25 mL). Sodium azide (2.70 g, 41.5 mmol) was added and the mixture
was stirred
at ambient temperature overnight. The resulting slurry was diluted with
diethyl ether and
washed with water. The organic layer was concentrated under reduced pressure
to afford the
title compound. The product was used directly in subsequent reactions without
characterization.
Example 80B
5 -[ 1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-1,2,3 -triazol-4-yl]-1 H-indazole
Example 80A (122 mg, 0.864 mmol) and Example 3C (150 mg, 0.619 mmol) were
combined in a microwave vial with tert-butanol (1 mL) and water (1 mL). A
small piece of
copper wire followed by copper(II) sulfate (5 mg, 0.02 mmol) was added, and
the vial was
stirred in a microwave (CEM-Discover) at 125 C at 100 W for 10 minutes. The
mixture was
diluted with methylene chloride and washed with 1 N hydrochloric acid. The
organic layer
was absorbed onto silica gel and purified by silica gel chromatography eluting
with a gradient
of 0-5% methanol in dichloromethane to afford the title compound. 'H NMR (300
MHz,
DMSO-d6) 8 ppm 13.11 (s, 1 H) 8.53 (s, 1 H) 8.22 (s, 1 H) 8.12 (s, 1 H) 7.85
(d, J=8.48, 1.36
Hz, 1 H) 7.60 (d, J=8.82 Hz, 1 H) 4.32 (d, J=7.12 Hz, 2 H) 3.85 (d, J=11.70,
2.54 Hz, 2 H)
3.21 - 3.36 (m, 2 H) 2.14 (s, 1 H) 1.47 (s, 2 H) 1.30 (s, 2 H). MS (ESI+) m/z
284.0 (M+H)+.
Example 81
5-[3-(piperidin-1-ylcarbonyl)isoxazol-5-yl]-1H-indazole
Example 81A
5-(IH-indazol-5-yl)isoxazole-3-carboxylic acid
Example 70 (1.50 g, 5.83 mmol) was dissolved in tetrahydrofuran (100 mL),
methanol (10 mL), and water (10 mL). Potassium hydroxide (680 mg, 12.1 mmol)
was
added and the mixture was stirred at ambient temperature for 2 hours. The
solvents were
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removed under reduced pressure, and the resulting residue was triturated with
a mixture of 1
N hydrochloric acid and methanol to provide a solid that was filtered to
afford the title
compound. 'H NMR (300 MHz, DMSO-d6) 8 ppm 13.36 (s, 1 H) 8.41 (s, 1 H) 8.23
(s, I H)
7.91 (dd, J=8.82, 1.70 Hz, I H) 7.70 (d, J=8.82 Hz, 1 H) 7.36 (s, I H).
Example 81B
5-[3-(piperidin-1-ylcarbonyl)isoxazol-5-yl]-IH-indazole
Example 81A (110 mg, 0.480 mmol), piperidine (55 uL, 0.556 mmol), and HATU
(101 mg, 0.266 mmol) were combined in dimethylformamide (2 mL).
Diisopropylethylamine (133 uL, 0.764 mmol) was added and the reaction was
stirred at 45 C
for 2 hours. The mixture was diluted with ethyl acetate and washed with 1 N
sodium
hydroxide, 1 N hydrochloric acid, water (3 times), and brine. The organic
layer was absorbed
on silica gel and purified by silica gel chromatography eluting with a
gradient of 0-5%
methanol in dichloromethane to afford the title compound. 'H NMR (300 MHz,
DMSO-
d6)8ppm13.37(s,IH)8.34-8.40(m,1H)8.21-8.25(m,IH)7.84-7.91(m,1H)7.66-
7.72(m,IH)7.20(s,1H)3.59-3.69(m,2H)3.48-3.58(m,2H)1.47-1.72(m,6H).
MS (ESI+) m/z 297.0 (M+H)+.
Example 82
5-(1 H-indazol-5 -yl)-N-phenylisoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting aniline for piperidine. iH NMR (500 MHz, DMSO-d6) 6 ppm 13.40 (s,
I H)
10.74 (s, 1 H) 8.44 (s, 1 H) 8.25 (s, 1 H) 7.93 (d, J=8.85, 1.53 Hz, 1 H) 7.82
(d, J=7.63 Hz, 2
H) 7.72 (d, J=8.85 Hz, 1 H) 7.44 (s, I H) 7.35 - 7.42 (m, 2 H) 7.16 (t, J=7.32
Hz, I H). MS
(ESI+) m/z 304.9 (M+H)+.
Example 83
N-cyclohexyl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide
Example 81A (53 mg, 0.231 mmol), cyclohexylamine (29 uL, 0.253 mmol), and
HATU (10I mg, 0.266 mmol) were combined in dimethyl formamide (2 mL).
Diisopropylethylamine (133 uL, 0.764 mmol) was added, and the reaction was
stirred at 45
C for 2 hours. The mixture was diluted with ethyl acetate and washed with 1 N
sodium
hydroxide, I N hydrochloric acid, water (3 times), and brine. The organic
layer was absorbed
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on silica gel and purified by silica gel chromatography eluting with a
gradient of 0-5%
methanol in dichloromethane to afford the title compound. 'H NMR (300 MHz,
DMSO-
d6) 6 ppm 13.36 (s, I H) 8.58 (d, J=8.14 Hz, I H) 8.38 (s, I H) 8.22 (s, 1 H)
7.88 (d, J=8.81,
1.70 Hz, 1 H) 7.69 (d, J=8.81 Hz, 1 H) 7.28 (s, I H) 3.69 - 3.86 (m, I H) 1.77
(s, 4 H) 1.60
(d, J=12.21 Hz, 1 H) 1.20 - 1.46 (m, 4 H) 1.06 - 1.20 (m, 1 H). MS (ESI+) m/z
311.0
(M+H)+.
Example 84
5-[3-(piperidin-1-ylmethyl)isoxazol-5-yl]-1 H-indazole
Example 81B (22 mg, 0.0742 mmol) was dissolved in tetrahydrofuran (2.5 mL)
under
an inert atmosphere of nitrogen. Lithium aluminum hydride (1.0 M solution in
tetrahydrofuran) (250 uL) was added and the mixture was heated to 70 C for 20
minutes.
Methanol was added, and the mixture was absorbed on silica gel and purified by
silica gel
chromatography eluting with a gradient of methanol in dichloromethane (0-7%)
to afford the
title compound. 'H NMR (400 MHz, DMSO-d6) 6 ppm 13.30 (s, I H) 8.31 (s, 1 H)
8.20 (s, 1
H) 7.84 (d, J=8.59, 1.53 Hz, I H) 7.66 (d, J=8.59 Hz, I H) 6.92 (s, I H) 3.54
(s, 2 H) 2.32 -
2.46 (m, 2 H) 1.47 - 1.59 (m, 4 H) 1.33 - 1.46 (m, 2 H). MS (ESI+) m/z 283.0
(M+H)+.
Example 85
[5-(1H-indazol-5-yl)isoxazol-3-yl]methanol
Example 70 (84 mg, 0.366 mmol) was dissolved in tetrahydrofuran (8 mL).
Lithium
aluminum hydride (1.0 M solution in tetrahydrofuran) (3.0 mL) was added in 1.0
mL portions
over 2 hours. After the final addition, the mixture was stirred for an
additiona130 minutes.
The mixture was diluted with methylene chloride and washed with water and the
organic
layer was absorbed on silica gel and purified by silica gel chromatography
eluting with a
gradient of 0-20% methanol in dichloromethane to afford the title compound. 'H
NMR (400
MHz, DMSO-d6) 6 ppm 13.31 (s, 1 H) 8.31 (s, I H) 8.21 (s, 1 H) 7.83 (d,
J=8.59, 1.53 Hz, I
H) 7.67 (d, J=8.90 Hz, 1 H) 6.93 (s, 1 H) 5.51 (s, 1 H) 4.56 (d, J=2.45 Hz, 1
H). MS (ESI+)
m/z 215.9 (M+H)+.
Example 86
5 -(1 H-indazol-5 -yl)-N-(2-methoxyethyl)isoxazole-3 -carboxamide
The title compound was prepared according to the procedure outlined in Example
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substituting 2-methoxyethyl amine for piperidine. 'H NMR (300 MHz, DMSO-d6) b
ppm
13.36 (s, 1 H) 8.74 (t, J=4.92 Hz, 1 H) 8.39 (s, 1 H) 8.23 (s, 1 H) 7.89 (d,
J=8.65, 1.53 Hz, 1
H) 7.69 (d, J=8.82 Hz, 1 H) 7.30 (s, 1 H) 3.38 - 3.53 (m, 4 H) 3.28 (s, 3 H).
MS (ESI+) m/z
287.0 (M+H)+.
Example 87
5 -(1-benzyl-5-phenyl-1 H-1,2,3-triazol-4-yl)-1 H-indazole
Example 87A
1-(5-Iodo-1 H-indazol-1-yl)ethanone
4-lodo-2-methylaniline (30.2 g, 130 mmol) was dissolved in chloroform (300 mL)
and cooled to 5 C. Acetic anhydride (35 mL, 343 mmol) was added dropwise, and
the
mixture was allowed to warm to ambient temperature. Potassium acetate (4.21 g,
42.9 mmol)
and isoamylnitrite (37 mL, 277 mmol) were added, and the mixture was heated to
70 C
overnight. The mixture was neutralized with saturated aqueous sodium
bicarbonate and
extracted with methylene chloride. The solvents were removed under reduced
pressure and
the resulting residue was triturated with methanol to afford the title
compound. 'H NMR
(300 MHz, DMSO-d6) 8 ppm 8.41 (s, 1 H) 8.33 (s, 1 H) 8.05 - 8.21 (m, 1 H) 7.90
(dd,
J=8.48, 1.70 Hz, 1 H) 2.71 (s, 3 H).
Example 87B
1-Benzyl-5-phenyl-4-(tributylstannyl)-IH-1,2,3-triazole
Phenylethynyltri-n-butyltin (8.25 g, 21.1 mmol) and benzyl azide (2.3 mL, 18.4
mmol) were combined and heated to 150 C overnight. The mixture was purified
by silica gel
chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to
afford the title
compound. MS (ESI+) m/z 526.3 (M+H)+.
Example 87C
1-(5-(1-Benzyl-5-phenyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-1-yl)ethanone
Example 87A (139 mg, 0.486 mmol), Example 87B (284 mg, 0.542 mmol),
dichlorobis(triphenylphosphine)palladium(II) (40 mg, 0.057 mmol) and copper
thiophene-2-
carboxylate (167 mg, 0.876 mmol) were combined in toluene (1.5 mL) in a
microwave vial
under an inert atmosphere of nitrogen. The vial was heated in a microwave (CEM-
Discover)
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to 150 C at 125 Watts for 20 minutes. The mixture was absorbed on silica gel
and purified
by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in
hexanes to
afford the title compound. MS (ESI+) m/z 394.1 (M+H)+.
Example 87D
5 -(1-benzyl-5-phenyl-1 H-1,2,3-triazol-4-yl)-1 H-indazole
Example 87C (95 mg, 0.242 mmol) was dissolved in tetrahydrofuran (2.0 mL),
methanol (1.0 mL) and water (1.0 mL), and potassium hydroxide (64 mg, 1.14
mmol) was
added. The mixture was stirred for 2 hours, and diluted with ethyl acetate and
washed with
water. The organic layer was absorbed on silica gel and purified by silica gel
chromatography eluting with a gradient of 0-5% methanol in dichloromethane to
afford the
title compound. 'H NMR (300 MHz, DMSO-d6) 8 ppm 13.08 (s, 1 H) 8.00 (s, 1 H)
7.79 (s, 1
H)7.44-7.56(m,5H)7.24-7.36(m,5H)6.95-7.03(m,2H)5.49(s,2H). MS (ESI+)
m/z 252.1 (M+H)+.
Example 88
5-(4-benzyl-1 H-1,2,3-triazol-1-yl)-1 H-indazole
Example 87A (969 mg, 3.39 mmol), 3-phenyl-l-propyne (392 mg, 3.37 mmol),
sodium azide (278 mg, 4.28 mmol), sodium ascorbate (68 mg, 3.43 mmol), sodium
carbonate
(75 mg, 0.708 mmol), and L-proline (78 mg, 8.98 mmol) were combined in a 1:1
mixture of
dimethyl sulfoxide and water (10 mL). Copper(II) sulfate pentahydrate (46 mg,
0.184 mmol)
was added and the mixture was stirred at 65 C for 3 hours. 6N Sodium
hydroxide (1 mL)
was added, and the mixture was stirred for 30 minutes to deprotect the
indazole. The mixture
was diluted with ethyl acetate and washed with 1 N hydrochloric acid. The
organic layer was
concentrated under reduced pressure, and the resulting residue was triturated
with methanol.
The remaining solids were absorbed on silica gel and purified by silica gel
chromatography
eluting with a gradient of 0-5% methanol in dichloromethane to afford the
title compound.
iH NMR (300 MHz, DMSO-d6) 8 ppm 13.35 (s, 1 H) 8.58 (s, 1 H) 8.17 - 8.27 (m, 1
H) 7.86
(d,J=8.82,2.03Hz,1H)7.67-7.77(m,1H)7.27-7.36(m,2H)7.18-7.27(m,1H)4.10
(s, 1 H). MS (ESI+) m/z 276.0 (M+H)+.
Example 89
5-(1-benzyl-5 -cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3 -amine
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Example 89A
5-(Cyclopropylethynyl)-2-fluorobenzonitrile
5-Bromo-2-fluorobenzonitrile (3.06 g, 15.3 mmol),
dichlorobis(triphenylphosphine)palladium(II) (478 mg, 0.681 mmol), and
copper(I) iodide
(165 mg, 0.866 mmol) were combined in triethylamine (15 mL) under an inert
atmosphere of
nitrogen. Cyclopropylacetylene (1.8 mL) was added, and the mixture was heated
to 60 C
until it turned to a black solid. The mixture was diluted with methylene
chloride and washed
with 1 N hydrochloric acid. The organic layer was absorbed on silica gel and
purified by
silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in
hexanes to afford
the title compound. MS (ESI+) m/z 319.0 (M+H)+.
Example 89B
5-(1-benzyl-5 -cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3 -amine
Example 89A (211 mg, 1.14 mmol) and benzyl azide (143 uL, 1.14 mmol) were
combined in a microwave (CEM-Discover) vial and heated to 160 C using 100
Watts for 26
minutes. The mixture was absorbed on silica gel and purified by silica gel
chromatography
eluting with a gradient of 20-60% ethyl acetate in hexanes to afford a mixture
of inseparable
triazole regiomers. The mixture of regiomers were treated with hydrazine
hydrate (3.0 mL)
and ethanol (3.0 mL) and heated to 90 C for 1 hour. The mixture was diluted
with
methylene chloride and washed with water. The organic layer was absorbed on
silica gel and
purified by silica gel chromatography eluting with a gradient of 1-6% methanol
in
dichloromethane to afford the title compound. 'H NMR (300 MHz, DMSO-d6) 8 ppm
11.43
(s, 1 H) 8.07 (s, 1 H) 7.63 (d, J=8.65, 1.53 Hz, 1 H) 7.32 - 7.45 (m, 3 H)
7.24 - 7.32 (m, 3 H)
5.68(s,2H)5.40(s,2H)1.69-1.83(m,1H)0.98-1.08(m,2H)0.32-0.42(m,2H). MS
(ESI+) m/z 331.1 (M+H)+.
Example 90
5-(1-benzyl-4-cyclopropyl-1 H-1,2,3-triazol-5 -yl)- I H-indazol-3 -amine
The title compound was isolated as a by-product according to the procedure
outlined
in Example 89B. 'H NMR (300 MHz, DMSO-d6) 8 ppm 11.62 (s, 1 H) 7.79 (s, 1 H)
7.32 (d,
J=8.48 Hz, 1 H) 7.20 - 7.27 (m, 3 H) 7.15 (d, J=8.65, 1.53 Hz, 1 H) 6.93 (d,
J=7.12, 2.37 Hz,
2 H) 5.49 (s, 2 H) 5.45 (s, 2 H) 1.71 - 1.82 (m, 1 H) 0.80 - 0.89 (m, 4 H). MS
(ESI+) m/z
331.1 (M+H)+.
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Example 91
5-(3-isobutylisoxazol-5-yl)-1H-indazol-3-amine
Example 91A
2-fluoro-5-(3-isobutylisoxazol-5-yl)benzonitrile
The title compound was prepared according to the procedure outlined in Example
72
substituting isovaleraldehyde for phenylacetaldehyde and Example 62B for
Example 3C. 'H
NMR (300 MHz, DMSO-d6) 6 ppm 8.47 (dd, J=6.10, 2.03 Hz, 1 H) 8.19 - 8.29 (m, 1
H) 7.71
(t, J=8.99 Hz, 1 H) 7.08 (s, 1 H) 2.56 (d, J=7.12 Hz, 2 H) 1.86 - 2.10 (m, 1
H) 0.94 (d, J=6.78
Hz, 6 H).
Example 91B
5-(3-isobutylisoxazol-5-yl)-1H-indazol-3-amine
To Example 91A (75 mg, 0.307 mmol) was added hydrazine hydrate (1.5 mL) in
ethanol (1.0 mL). The mixture was heated to 70 C overnight in a sealed vial.
The mixture
was diluted with methylene chloride and washed with water. The organic layer
was absorbed
on silica gel and purified by silica gel chromatography eluting with a
gradient of 0-5%
methanol in dichloromethane to afford the title compound. 'H NMR (300 MHz,
DMSO-d6) 6
ppm 11.67 (s, 1 H) 8.26 (s, 1 H) 7.66 (dd, J=8.82, 1.70 Hz, 1 H) 7.32 (d,
J=8.48 Hz, 1 H)
6.67 (s, 1 H) 5.56 (s, 2 H) 2.51 - 2.58 (m, 2 H) 1.89 - 2.11 (m, 1 H) 0.95 (d,
J=6.44 Hz, 6 H).
MS (ESI+) m/z 257.0 (M+H)+.
Example 92
5-(3-benzylisoxazol-5-yl)-1 H-indazol-3-amine
Example 92A
5-(3-benzylisoxazol-5-yl)-2-fluorobenzonitrile
The title compound was prepared according to the procedure outlined in Example
72
substituting Example 62B for Example 3C. The crude product was used in the
next step
without further purification or characterization.
Example 92B
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5-(3-benzylisoxazol-5-yl)-1 H-indazol-3-amine
To Example 92A (65 mg, 0.234 mmol) was added hydrazine hydrate (1.5 mL) in
ethanol (1.0 mL). The mixture was heated to 70 C ovemight in a sealed vial.
The mixture
was diluted with methylene chloride and washed with water. The organic layer
was absorbed
on silica gel and purified by silica gel chromatography eluting with a
gradient of 0-20%
methanol in dichloromethane to afford the title compound. 'H NMR (300 MHz,
DMSO-
d6) 8 ppm 11.67 (s, 1 H) 8.26 (s, 1 H) 7.66 (d, J=8.82, 1.70 Hz, 1 H) 7.32 (d,
J=8.48 Hz, 1 H)
6.67 (s, 1 H) 5.56 (s, 2 H) 2.45 - 2.57 (m, 2 H) 1.91 - 2.08 (m, 1 H) 0.95 (d,
J=6.44 Hz, 6 H).
MS (ESI+) m/z 291.0 (M+H)+.
Example 93
N- {2-[4-(4-fluorophenyl)-5-(1 H-indazol-5-yl)-1 H-imidazol-l-yl]ethyl} -N,N-
dimethylamine
The title compound was prepared according to the procedure outlined in Example
39
substituting 2-dimethylaminoethylamine for benzylamine. 'H NMR (500 MHz, c) 8
ppm
13.28(s,1H)8.14(s,1H)7.78-7.87(m,2H)7.68(d,J=8.54Hz,1H)7.33-7.41(m,2H)
7.28 (d, J=8.54, 1.53 Hz, 1 H) 6.95 - 7.05 (m, 2 H) 3.86 (t, J=6.56 Hz, 2 H)
2.31 (t, J=6.71
Hz, 2 H) 2.00 (s, 6 H).
Example 94
5-[4-(4-fluorophenyl)-1-(3-morpholin-4-ylpropyl)-1H-imidazol-5-yl]-1H-indazole
The title compound was prepared according to the procedure outlined in Example
39
substituting 3-morpholinopropylamine for benzylamine. 'H NMR (500 MHz, DMSO-d6
/
D20)8ppm13.28(s, 1 H) 8.14 (s, 1 H) 7.79 - 7.87 (m, 2 H) 7.68 (d, J=8.24 Hz, 1
H)7.34-
7.42(m,2H)7.28(d,J=8.54,1.53Hz,1H)6.92-7.03(m,2H)3.77-3.89(m,2H)3.24-
3.30 (m, 4 H) 2.10 (t, J=6.56 Hz, 2 H) 1.96 - 2.05 (m, 4 H) 1.54 - 1.66 (m, 2
H). MS (ESI+)
m/z 406.1 (M+H)+.
Example 95
5-[4-(4-fluorophenyl)-1-(3-pyrrolidin-1-ylpropyl)-1 H-imidazol-5-yl]-1 H-
indazole
The title compound was prepared according to the procedure outlined in Example
39
substituting 3-pyrrolidinopropylamine for benzylamine. 'H NMR (500 MHz, DMSO-
d6 /
D20) 6 ppm 8.13 (d, J=0.92 Hz, 1 H) 7.79 - 7.85 (m, 2 H) 7.68 (d, J=8.54 Hz, 1
H) 7.38 (d,
J=8.85, 5.49 Hz, 2 H) 7.27 (d, J=8.54, 1.53 Hz, 1 H) 6.99 (t, J=9.00 Hz, 2 H)
3.82 - 3.90 (m,
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2H)2.21(t,J=6.71Hz,2H)2.08-2.18(m,4H)1.56-1.65(m,2H)1.44-1.53(m,4H).
MS (ESI+) m/z 390.2 (M+H)+.
Example 96
5-{4-(4-fluorophenyl)-1-[2-(4-methylpiperidin-l-yl)ethyl]-1H-imidazol-5-yl}-1H-
indazole
The title compound was prepared according to the procedure outlined in Example
39
substituting 2-(4-methylpiperidin-l-yl)ethanamine for benzylamine. 'H NMR (500
MHz,
DMSO-d6 / D20) 8 ppm 13.29 (s, 1 H) 8.14 (s, 1 H) 7.83 (s, 1 H) 7.81 (s, 1 H)
7.67 (d,
J=8.54 Hz, 1 H) 7.32 - 7.40 (m, 2 H) 7.28 (dd, J=8.54, 1.53 Hz, 1 H) 6.93 -
7.04 (m, 2 H)
3.85(t,J=6.56Hz,2H)2.60(d,J=11.60Hz,2H)2.37(t,J=6.56Hz,2H)1.71-1.85(m,2
H)1.45(d,J=11.29Hz,2H)1.15-1.30(m,1H)0.95-1.07(m,2H)0.83(d,J=6.71Hz,3
H) MS (ESI+) m/z 404.1 (M+H)+.
Example 97
5-[1-(1-benzylpiperidin-4-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-IH-indazole
The title compound was prepared according to the procedure outlined in Example
39
substituting 4-amino-N-benzylpiperidine for benzylamine. 'H NMR (500 MHz, DMSO-
d6 /
D20) 8 ppm 13.32 (s, 1 H) 8.14 (s, 1 H) 8.02 (s, 1 H) 7.78 (s, 1 H) 7.69 (d,
J=8.54 Hz, 1 H)
7.17-7.40(m,8H)6.97(t,J=8.85Hz,2H)3.50-3.63(m,1H)3.40(s,2H)2.82(d,
J=1 1.90 Hz, 2 H) 1.90 - 2.05 (m, 2 H) 1.72 - 1.89 (m, 4 H). MS (ESI+) m/z
452.2 (M+H)+.
Example 98
5-[4-(4-fluorophenyl)-1-(2-morpholin-4-ylethyl)-1 H-imidazol-5-yl]-1 H-
indazole
The title compound was prepared according to the procedure outlined in Example
39
substituting 2-morpholinoethylamine for benzylamine. 'H NMR (500 MHz, DMSO-d6
/
D20) 8 ppm 13.27 (s, 1 H) 8.14 (s, 1 H) 7.86 (s, 1 H) 7.81 (s, 1 H) 7.67 (d,
J=8.54 Hz, 1 H)
7.33-7.42(m,2H)7.29(d,J=8.54Hz,1H)6.95-7.06(m,2H)3.87(t,J=6.41Hz,2H)
3.42 - 3.51 (m, 4 H) 2.40 (t, J=6.56 Hz, 2 H) 2.21 (d, J=3.97 Hz, 4 H). MS
(ESI+) m/z 392.1
(M+H)+.
Example 99
5-[ 1-(1-benzylpyrrolidin-3 -yl)-4-(4-fluorophenyl)-1 H-imidazol-5 -yl]-l H-
indazole
The title compound was prepared according to the procedure outlined in Example
39
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substituting 3-pyrrlidinobenzylamine for benzylamine. 'H NMR (500 MHz, DMSO-d6
/
D20) 8 ppm 13.29 (s, 1 H) 8.13 (s, 1 H) 8.03 (s, 1 H) 7.76 (s, 1 H) 7.67 (d,
J=8.54 Hz, 1 H)
7.29 - 7.38 (m, 6 H) 7.20 - 7.28 (m, 2 H) 6.98 (t, J=9.00 Hz, 2 H) 4.25 - 4.34
(m, I H) 3.53 -
3.69 (m, 2 H) 2.89 - 2.97 (m, 1 H) 2.84 (d, J=9.76, 3.05 Hz, 1 H) 2.55 (d,
J=10.07, 6.71 Hz, 1
H) 2.17 - 2.34 (m, 2 H) 1.92 - 2.03 (m, 1 H). MS (ESI+) m/z 438.1 (M+H)+.
Example 100
Example 100 has been removed and is not part of this document.
Example 101
2- {4-[4-(4-fluorophenyl)-5-(1 H-indazol-5-yl)-1 H-imidazol-1-yl]piperidin-1-
yl} -2-oxoethanol
The title compound was prepared according to the procedure outlined in Example
39
substituting 1-(4-aminopiperidin-l-yl)-2-hydroxyethanone for benzylamine. 'H
NMR (300
MHz, DMSO-d6 / DzO) 8 ppm 13.27 (s, 1 H) 8.14 (s, 1 H) 7.99 (s, 1 H) 7.81 (s,
1 H) 7.69 (d,
J=8.48Hz,1H)7.25-7.39(m,4H)6.91-7.03(m,2H)4.48(t,J=5.43Hz,IH)4.34-4.44
(m, 1 H) 4.07 (t, J=5.59 Hz, 1 H) 3.79 - 3.91 (m, 1 H) 3.64 - 3.77 (m, 1 H)
2.85 (m, 1H) 2.77
- 2.90 (m, 5 H). MS (DCI) m/z 420 (M+H)+.
Example 102
5 -(1-benzyl-5-phenyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-amine
Example 102A
5-(1-Benzyl-5-phenyl-1 H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile
Example 87B (415 mg, 0.792 mmol), 5-bromo-2-fluorobenzonitrile (158 mg, 0.790
mmol), dichlorobis(triphenylphosphine)palladium(II) (52 mg, 0.074 mmol), and
copper
thiophene-2-carboxylate (226 mg, 1.19 mmol) were combined in toluene (2 mL) in
a
microwave vial under an inert atmosphere of nitrogen. The vial was heated in a
microwave
(CEM-Discover) to 150 C at 125 Watts for 20 minutes. The mixture was absorbed
on silica
gel and purified by silica gel chromatography eluting with a gradient of ethyl
acetate in
hexanes (5-40%) to afford the title compound. MS (ESI+) m/z 355.1 (M+H)+.
Example 102B
5 -(1-benzyl-5-phenyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-amine
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Example 102A (120 mg, 0.339 mmol) was treated with hydrazine hydrate (1.0 mL)
in
ethanol (1.0 mL) and heated to 60 C overnight. The mixture was diluted with
methylene
chloride and washed with water. The organic layer was absorbed on silica gel
and purified
by silica gel chromatography eluting with a gradient of 0-5% methanol in
dichloromethane to
afford the title compound. 'H NMR (300 MHz, DMSO-d6) 6 ppm 11.40 (s, 1 H) 8.06
(s, 1
H) 7.42 - 7.5 5 (m, 3 H) 7.23 - 7.3 3 (m, 5 H) 7.02 - 7. 10 (m, 2 H) 6.94 -
7.02 (m, 2 H) 5.49 (s,
2 H) 5.34 (s, 2 H). MS (ESI+) m/z 367.1 (M+H)+.
Example 103
2-[ 1-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-4-yl]propan-2-ol
The title compound was prepared according to the procedure outlined in Example
88
substituting 2-methyl-3-butyn-2-ol for 3-phenyl-l-propyne except that the
crude reaction
mixture was quenched with 2 mL of 1 N aqueous NaOH; and stirred for 1.5 hours
at ambient
temperature. The suspension was then dried by heated forced nitrogen gas
evaporation prior
to extraction. 'H NMR (500 MHz, DMSO-d6 / D20) 8 ppm 8.51 (s, 1 H) 8.22 - 8.29
(m, 2 H)
7.88 (d, J=9.00, 1.98 Hz, 1 H) 7.77 (d, J=8.85 Hz, 1 H) 1.57 (s, 6 H). MS
(ESI+) m/z 244.0
(M+H)+.
Example 104
5 -[4-(methoxymethyl)-1 H-1,2,3-triazol-1-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
88
substituting methyl propargyl ether for 3-phenyl-l-propyne. iH NMR (500 MHz,
DMSO-d6 /
D20) 6 ppm 8.73 (s, 1 H) 8.23 - 8.29 (m, J=1.83 Hz, 2 H) 7.88 (d, J=8.85, 2.14
Hz, 1 H) 7.78
(d, J=9.15 Hz, 1 H) 4.57 (s, 2 H) 3.35 (s, 3 H). MS (ESI+) m/z 230.0 (M+H)+.
Example 105
1-[ 1-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-4-yl]-1-phenylethanol
The title compound was prepared according to the procedure outlined in Example
88
substituting 2-phenyl-3-butyn-2-ol for 3-phenyl-l-propyne. iH NMR (500 MHz,
DMSO-d6 /
D20) 6 ppm 8.52 (s, 1 H) 8.21 - 8.28 (m, 2 H) 7.87 (d, J=8.85, 2.14 Hz, 1 H)
7.76 (d, J=9.15
Hz, 1 H) 7.51 - 7.57 (m, 2 H) 7.34 (t, J=7.78 Hz, 2 H) 7.24 (t, J=7.32 Hz, 1
H) 1.92 (s, 3 H).
MS (ESI+) m/z 306.0 (M+H)+.
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Example 106
-(4-propyl-1 H-1,2,3-triazol-l-yl)-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
88
substituting 1-pentyne for 3-phenyl-l-propyne. iH NMR (500 MHz, DMSO-d6 / Dz0)
8 ppm
5 8.50 (s, 1 H) 8.20 - 8.30 (m, 2 H) 7.87 (d, J=9.00, 1.98 Hz, 1 H) 7.77 (d,
J=8.85 Hz, 1 H) 2.71
(t, J=7.48 Hz, 2 H) 1.64 - 1.78 (m, 2 H) 0.97 (t, J=7.32 Hz, 3 H). MS (ESI+)
m/z 228.0
(M+H)+.
Example 107
1-[ 1-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-4-yl]propan-2-ol
The title compound was prepared according to the procedure outlined in Example
88
substituting pent-4-yn-2-ol for 3-phenyl-l-propyne. 'H NMR (500 MHz, DMSO-d6 /
D20) b
ppm 8.49 (s, 1 H) 8.20 - 8.33 (m, 2 H) 7.88 (dd, J=9.00, 1.98 Hz, 1 H) 7.74 -
7.82 (m, 1 H)
3.95 - 4.08 (m, 1 H) 2.74 - 2.89 (m, 2 H) 1.16 (d, J=6.10 Hz, 3 H). MS (ESI+)
m/z 244.0
(M+H)+.
Example 108
3- [ 1-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-4-yl]propan-l-ol
The title compound was prepared according to the procedure outlined in Example
88
substituting 4-pentyn-l-ol for 3-phenyl-l-propyne. iH NMR (500 MHz, DMSO-d6 /
Dz0) 8
ppm 8.50 (s, 1 H) 8.28 (s, 1 H) 8.23 (d, J=1.83 Hz, 1 H) 7.83 - 7.91 (m, 1 H)
7.74 - 7.82 (m, 1
H) 4.50 (t, J=6.41 Hz, 1 H) 3.51 (t, J=6.41 Hz, 2 H) 2.77 (t, J=7.63 Hz, 2 H)
1.80 - 1.90 (m, 2
H)MS (ESI+) m/z 244.0 (M+H)+.
Example 109
1- {[ 1-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-4-yl]methyl} -1 H-1,2,3-
benzotriazole
The title compound was prepared according to the procedure outlined in Example
88
substituting 1-propargyl-lH-benzotriazole for 3-phenyl-l-propyne. 'H NMR (500
MHz,
DMSO-d6 / D20) 8 ppm 8.91 (s, 1 H) 8.21 - 8.29 (m, 2 H) 8.07 (d, J=8.54 Hz, 1
H) 7.99 (d,
J=8.54 Hz, 1 H) 7.84 (d, J=9.00, 1.98 Hz, 1 H) 7.72 - 7.81 (m, 1 H) 7.57 -
7.65 (m, 1 H) 7.41
- 7.52 (m, 1 H) 6.16 (s, 2 H). MS (ESI-) m/z 315.0 (M-H)-.
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Example 110
5- {4-[(phenylthio)methyl]-1 H-1,2,3-triazol-l -yl} -1 H-indazole
The title compound was prepared according to the procedure outlined in Example
88
substituting phenyl propargyl sulfide for 3-phenyl-l-propyne. 'H NMR (500 MHz,
DMSO-
d6 / D20) 8 ppm 8.59 (s, 1 H) 8.26 (s, 1 H) 8.21 (d, J=1.22 Hz, 1 H) 7.80 -
7.86 (m, 1 H) 7.72
- 7.79 (m, 1 H) 7.43 (d, J=8.39, 1.37 Hz, 2 H) 7.35 (t, J=7.78 Hz, 2 H) 7.22
(t, J=7.32 Hz, 1
H) 4.38 (s, 2 H). MS (ESI+) m/z 308.3 (M+H)+.
Example 111
5-(4-cyclopropyl-1 H-1,2,3-triazol-l-yl)-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
88
substituting cyclopropylacetylene for 3-phenyl-l-propyne. iH NMR (500 MHz,
DMSO-d6 /
D20) 8 ppm 8.46 (s, 1 H) 8.25 (s, 1 H) 8.20 (d, J=1.53 Hz, 1 H) 7.84 (d,
J=9.00, 1.98 Hz, 1
H)7.76(d,J=8.85Hz,1H)1.97-2.14(m,1H)0.93-1.06(m,2H)0.77-0.91(m,2H).
MS (ESI+) m/z 226.0 (M+H)+.
Example 112
5-[4-(2-phenylethyl)-1 H-1,2,3-triazol-l-yl]-l H-indazole
The title compound was prepared according to the procedure outlined in Example
88
substituting 1-phenyl-l-butyne for 3-phenyl-l-propyne. The product was a l:l
mixture of
starting material and title compound. 'H NMR (500 MHz, DMSO-d6 / D20) b ppm
8.48 (s, 1
H) 8.25 (s, 1 H) 8.21 (d, J=1.53 Hz, 1 H) 8.06 (s, 1 H) 7.81 - 7.89 (m, 1 H)
7.73 - 7.80 (m, 1
H) 7.61 (dd, J=8.85, 1.53 Hz, 1 H) 7.45 (d, J=8.54 Hz, 1 H) 7.25 - 7.36 (m, 4
H) 7.17 - 7.25
(m, 1 H) 3.04 (s, 4 H). MS (ESI+) m/z 290.1 (M+H)+.
Example 113
5-[4-(cyclohexylmethyl)-1 H-1,2,3-triazol-l-yl]-l H-indazole
The title compound was prepared according to the procedure outlined in Example
88
substituting 3-cyclohexyl-l-propyne for 3-phenyl-l-propyne. 'H NMR (500 MHz,
DMSO-d6
/ D20) 6 ppm 8.49 (s, 1 H) 8.21 - 8.29 (m, 2 H) 7.88 (d, J=9.00, 1.98 Hz, 1 H)
7.77 (d, J=8.85
Hz,1H)2.61(d,J=6.71Hz,2H)1.54-1.77(m,6H)1.08-1.30(m,3H)0.91-1.05(m,2
H). MS (ESI+) m/z 282.2 (M+H)+.
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Example 114
5-(4-cyclopentyl-1 H-1,2,3-triazol-l-yl)-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
88
substituting cyclopentylacetylene for 3-phenyl-l-propyne. 'H NMR (500 MHz,
DMSO-d6 /
D20) 8 ppm 8.52 (s, 1 H) 8.19 - 8.30 (m, 2 H) 7.88 (d, J=9.00, 1.98 Hz, 1 H)
7.77 (d, J=8.85
Hz, 1 H) 3.13 - 3.27 (m, 1 H) 1.98 - 2.15 (m, 2 H) 1.57 - 1.84 (m, 6 H). MS
(ESI+) m/z
254.0 (M+H)+.
Example 115
1-[1-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-4-yl]cyclohexanol
The title compound was prepared according to the procedure outlined in Example
88
substituting 1-ethynyl-l-cyclohexanol for 3-phenyl-l-propyne. 'H NMR (500 MHz,
DMSO-
d6 / Dz0) 8 ppm 8.52 (s, 1 H) 8.21 - 8.30 (m, J=1.53 Hz, 2 H) 7.89 (dd,
J=9.00, 1.98 Hz, 1 H)
7.77(d,J=8.85Hz,1H)2.16-2.46(m,1H)1.92-2.05(m,2H)1.77-1.86(m,2H)1.61-
1.77(m,2H)1.51-1.59(m,1H)1.42-1.51(m,2H)1.28-1.40(m,J=9.92,2.90Hz,1
H)MS (ESI+) m/z 284.0 (M+H)+.
Example 116
5 -[4-(phenoxymethyl)-1 H-1,2,3-triazol-l-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
88
substituting phenyl propargyl ether for 3-phenyl-l-propyne. iH NMR (500 MHz,
DMSO-d6 /
D20) 6 ppm 8.87 (s, 1 H) 8.22 - 8.34 (m, 2 H) 7.89 (d, J=8.85, 1.83 Hz, 1 H)
7.79 (d, J=9.15
Hz, 1 H) 7.29 - 7.41 (m, 2 H) 7.09 (d, J=7.63 Hz, 2 H) 6.99 (t, J=7.32 Hz, 1
H) 5.25 (s, 2 H).
MS (ESI+) m/z 292.0 (M+H)+.
Example 117
5- {4-[(1,1-dioxidothiomorpholin-4-yl)methyl]-1 H-1,2,3-triazol-l-yl} -1 H-
indazole
The title compound was prepared according to the procedure outlined in Example
88
substituting N-propargyl thiomorpholine-sulfone for 3-phenyl-l-propyne. iH NMR
(500
MHz, DMSO-d6 / D20) b ppm 8.81 (s, 1 H) 8.24 - 8.36 (m, 2 H) 7.89 (d, J=9.00,
1.98 Hz, 1
H) 7.80 (d, J=9.15 Hz, 1 H) 4.38 (s, 2 H) 3.30 - 3.56 (m, J=39.36 Hz, 8 H). MS
(ESI+) m/z
332.9 (M+H)+.
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Example 118
5-[4-(3-phenylpropyl)-1H-1,2,3-triazol-l-yl]-IH-indazole
The title compound was prepared according to the procedure outlined in Example
88
substituting 1-phenyl-l-pentyne for 3-phenyl-l-propyne. 'H NMR (500 MHz, DMSO-
d6 /
D20) 8 ppm 8.52 (s, 1 H) 8.26 (s, 1 H) 8.23 (d, J=1.53 Hz, 1 H) 7.87 (d,
J=9.00, 1.98 Hz, 1
H)7.76(d,J=9.15Hz,1H)7.31(t,J=7.32Hz,2H)7.23-7.28(m,2H)7.20(t,J=7.32Hz,1
H) 2.74 (t, J=7.63 Hz, 2 H) 2.65 - 2.72 (m, 2 H) 1.95 - 2.05 (m, 2 H). MS
(ESI+) m/z 304.2
(M+H)+.
Example 119
[ 1-benzyl-4-(1 H-indazol-5-yl)-l H-1,2,3-triazol-5-yl](phenyl)methanone
Example 119A
teYt-Butyl5-ethynyl-1 H-indazole-l-carboxylate
To a solution of Example 3C (230 mg, 1.62 mmol) in dichloromethane (10 mL) was
added di-tert-butyl dicarbonate (459 mg, 2.1 mmol) and a pinch of
dimethylaminopyridine
(-3 mg), and the mixture was stirred fro 30 minutes at room temperature. Water
was added,
and the product was extracted with dichloromethane, dried over sodium sulfate,
filtered, and
the solvent was evaporated under reduced pressure to afford the title
compound. MS (ESI+)
m/z 265.0 (M+Na)+.
Example 119B
[ 1-benzyl-4-(1 H-indazol-5-yl)-l H-1,2,3-triazol-5-yl](phenyl)methanone
A vial under argon containing Example 119A (90 mg, 0.37 mmol), benzyl azide
(0.047 mL, 0.37 mmol), tetrahydrofuran (3 mL), triethylamine (0.062 mL, 0.44
mmol), CuI
(71 mg, 0.37 mmol) and benzoyl chloride (0.059 mL, 0.51 mmol) was capped and
shaken for
16 hours. The solvents were evaporated, and the product was purified by silica
gel column
chromatography in 5-30% ethyl acetate in hexanes. The crude material was
treated with TFA
(0.5 mL) in dichloromethane (1 mL) and purified by reverse-phase HPLC using an
acetonitrile/water 0.1% TFA gradient elution method to afford the title
compound. 1H NMR
(500 MHz, DMSO-d6 / D20) 8 ppm 13.08 (s, 1 H) 7.98 (s, 1 H) 7.77 (s, 1 H) 7.54
(d, J=8.24,
1.22Hz,2H)7.43-7.48(m,1H)7.33-7.40(m,2H)7.22-7.30(m,5H)7.17-7.21(m,2
H) 5.74 (s, 2 H). MS (ESI+) m/z 380.1 (M+H)+.
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Example 120
N,N-diethyl-N- {[ 1-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-4-yl]methyl} amine
The title compound was prepared according to the procedure outlined in Example
88
substituting 1,1-diethylpropargylamine for 3-phenyl-l-propyne. iH NMR (300
MHz,
DMSO-d6) 6 ppm 8.98 (s, 1 H) 8.30 (d, J=1.36 Hz, 1 H) 8.27 (s, 1 H) 7.85 -
7.93 (m, 1 H)
7.75-7.83(m,1H)4.53(d,J=4.07Hz,2H)3.11-3.23(m,4H)1.31(t,J=7.12Hz,6H).
MS (ESI+) m/z 271.0 (M+H)+.
Example 121
ethyl N-[2-(1H-indazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl]-beta-alaninate
The title compound was prepared according to the procedure outlined in Example
43
substituting ethyl isocyanopropionate for isopropyl isocyanide. 'H NMR (300
MHz, DMSO-
d6) 6 ppm 13.09 (s, 1 H) 8.71 (d, J=6.78, 2.03 Hz, 1 H) 8.54 (s, 1 H) 8.46 (d,
J=4.24, 1.87 Hz,
1 H) 8.23 (d, J=8.82, 1.36 Hz, 1 H) 8.14 (s, 1 H) 7.61 (d, J=8.82 Hz, 1 H)
7.05 (d, J=6.78,
4.07 Hz, 1 H) 5.03 (t, J=5.93 Hz, 1 H) 3.96 (q, J=7.12 Hz, 2 H) 3.23 (q,
J=6.22 Hz, 2 H) 2.47
- 2.55 (m, 2 H) 1.08 (t, J=7.12 Hz, 3 H). MS (ESI+) m/z 351.1 (M+H)+.
Example 122
5 -(1-benzyl-5-methyl-1 H-1,2,3-triazol-4-yl)-1 H-indazole
Example 122A
1-Benzyl-5-methyl-4-(tributylstannyl)-1H-1,2,3-triazole
Tributyl(1-propynyl)tin (3.87 g, 11.8 mmol) and benzyl azide (2.2 mL, 17.6
mmol)
were combined and heated to 150 C overnight. The mixture was purified by
silica gel
chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to
afford the title
compound. MS (ESI+) m/z 464.2 (M+H)+.
Example 122B
1-(5-(1-Benzyl-5-methyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-1-yl)ethanone
Example 87A (235 mg, 0.821 mmol), Example 122A (380 mg, 0.822 mmol),
dichlorobis(triphenylphosphine)palladium(II) (60 mg, 0.085 mmol), and copper
thiophene-2-
carboxylate (325 mg, 1.23 mmol) were combined in toluene (2.0 mL) in a
microwave vial
under an inert atmosphere of nitrogen. The vial was heated in a microwave (CEM-
Discover)
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to 150 C at 125 Watts for 20 minutes. The mixture was absorbed on silica gel
and purified
by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in
hexanes to
afford the title compound. MS (ESI+) m/z 332.2 (M+H)+.
Example 122C
5 -(1-benzyl-5-methyl-1 H-1,2,3-triazol-4-yl)-1 H-indazole
Example 122B (109 mg, 0.329 mmol) was dissolved in tetrahydrofuran (3.0 mL)
and
water (0.5 mL), and potassium hydroxide (53 mg, 0.945 mmol) was added. The
mixture was
stirred for 2 hours, diluted with ethyl acetate, and washed with water. The
organic layer was
absorbed on silica gel and purified by silica gel chromatography eluting with
a gradient of 0-
5% methanol in dichloromethane to afford the title compound. 'H NMR (300 MHz,
DMSO-
d6) 6 ppm 13.13 (s, 1 H) 8.12 (s, 1 H) 8.01 (s, 1 H) 7.71 - 7.78 (m, 1 H) 7.59
- 7.66 (m, 1 H)
7.31 - 7.45 (m, 3 H) 7.23 - 7.29 (m, 2 H) 5.65 (s, 2 H) 2.43 (s, 3 H). MS
(ESI+) m/z 290.1
(M+H)+.
Example 123
5 -(1-benzyl-5-methyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-amine
Example 123A
5-(1-Benzyl-5-methyl-1 H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile
Example 122A (415 mg, 0.792 mmol), 5-bromo-2-fluorobenzonitrile (158 mg, 0.790
mmol), dichlorobis(triphenylphosphine)palladium(II) (52 mg, 0.074 mmol), and
copper
thiophene-2-carboxylate (226 mg, 1.19 mmol) were combined in toluene (2 mL) in
a
microwave vial under an inert atmosphere of nitrogen. The vial was heated in a
microwave
(CEM-Discover) at 150 C at 125 Watts for 20 minutes. The mixture was absorbed
on silica
gel and purified by silica gel chromatography eluting with a gradient of 5-40%
ethyl acetate
in hexanes to afford the title compound. MS (ESI+) m/z 293.0 (M+H)+.
Example 123B
5 -(1-benzyl-5-methyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-amine
Example 123A (120 mg, 0.339 mmol) was treated with hydrazine hydrate (1.0 mL)
in
ethanol (1.0 mL) and heated to 60 C overnight. The mixture was diluted with
methylene
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chloride and washed with water. The organic layer was absorbed on silica gel
and purified
by silica gel chromatography eluting with a gradient of methanol in
dichloromethane (0-5%)
to afford the title compound. 'H NMR (300 MHz, DMSO-d6) S ppm 11.43 (s, 1 H)
7.98 (s, 1
H)7.60(d,J=8.65,1.53Hz,1H)7.27-7.44(m,4H)7.21-7.27(m,2H)5.65(s,2H)5.41
(s, 2 H) 2.41 (s, 3 H). MS (ESI+) m/z 305.1 (M+H)+.
Example 124
N3-[2-(IH-indazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl]-(3-alaninamide
Example 121 (42 mg, 0.120 mmol) and a solution of 7 N ammonia in methanol (1.0
mL) were combined and heated to 60 C overnight. The mixture was absorbed on
silica gel
and purified by silica gel chromatography eluting with a gradient of methanol
in
dichloromethane (1-7%) to afford the title compound. iH NMR (300 MHz, DMSO-
d6) 8 ppm 13.09 (s, 1 H) 8.76 (d, J=6.78, 2.03 Hz, 1 H) 8.56 (s, 1 H) 8.45 (d,
J=4.07, 2.03 Hz,
1 H) 8.24 (d, J=8.82, 1.36 Hz, 1 H) 8.15 (s, 1 H) 7.61 (d, J=8.48 Hz, 1 H)
7.32 (s, 1 H) 7.03
(d, J=6.78, 4.07 Hz, 1 H) 6.85 (s, 1 H) 4.93 (t, J=6.10 Hz, 1 H) 3.11 - 3.23
(m, 2 H) 2.32 (t,
J=6.78 Hz, 2 H). MS (ESI+) m/z 322.0 (M+H)+.
Example 125
5-(1-benzyl-5-iodo-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-amine
Example 125A
5-(1-Benzyl-5-iodo-1 H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile
A mixture of Example 62B (200 mg, 1.38 mmol), benzyl azide (0.176 mL, 1.38
mmol), tetrahydrofuran (12 mL), triethylamine (0.230, 1.56 mmol), Cul (263 mg,
1.38 mmol)
and ICI (0.069 mL, 1.38 mmol) under argon was stirred at room temperature for
24 hours.
The solvent was evaporated and the crude mixture was dissolved in
dichloromethane, loaded
directly onto a silica gel column and eluted with ethyl acetate / hexanes (10-
20%) to afford
the title compound. MS (ESI+) m/z 404.9 (M+H)+.
Example 125B
5-(1-benzyl-5-iodo-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-amine
Example 125A (50 mg, 0.12 mmol) and hydrazine monohydrate (ImL) in ethanol (1
mL) were heated at 95 C for 2 hours. Water was added, and the solid was
collected by
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filtration and further purified by reverse-phase HPLC using an
acetonitrile/water 0.1 % TFA
gradient elution method to afford the title compound as a TFA salt. 'H NMR
(500 MHz,
DMSO-d6) 8 ppm 12.07 (s, 1 H) 8.30 (s, 1 H) 7.83 (d, J=8.85, 1.53 Hz, 1 H)
7.44 (d, J=8.54
Hz,1H)7.38-7.43(m,J=7.32,7.32Hz,2H)7.32-7.37(m,1H)7.23-7.27(m,J=7.02
Hz, 2 H) 5.74 (s, 2 H) 4.00 (s, 2 H). MS (ESI+) m/z 417.0 (M+H)+.
Example 126
N- {3-[4-(3-amino-1 H-indazol-5-yl)-1-benzyl-1 H- 1,2,3 -triazol-5-yl]phenyl }
-N'-(3-
methylphenyl)urea
Example 126A
1-(3-(1-Benzyl-4-(3-cyano-4-fluorophenyl)-1 H-1,2,3-triazol-5-yl)phenyl)-3-m-
tolylurea
A vial under argon containing Example 125A (94 mg, 0.23 mmol), 1-(3-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-m-tolylurea (prepared according
to a
procedure described in W02004/113304) (990 mg, 0.26 mmol),
PdClzdppf=dichloromethane
(19 mg, 0.02 mmol), potassium carbonate (64 mg, 0.46 mmol), DME (2 mL) and
water (0.2
mL) was capped and heated in a heater shaker at 80 C for 90 minutes. The
solvents were
evaporated and the product was extracted with methanol / dichloromethane.
Silica gel
column chromatography using 10% ethyl acetate in hexanes afforded the title
compound.
MS (ESI+) m/z 503.2 (M+H)+.
Example 126B
N- {3-[4-(3-amino-1 H-indazol-5-yl)-1-benzyl-1 H- 1,2,3 -triazol-5-yl]phenyl }
-N'-(3-
methylphenyl)urea
Example 126A (25 mg, 0.05 mmol) and hydrazine monohydrate (0.5mL) in ethanol
(2
mL) were heated at 80 C for 1 hour. The crude mixture was loaded onto a
silica gel column
and eluted with a gradient of 0-5% methanol in dichloromethane to afford the
title compound.
iH NMR (500 MHz, DMSO-d6) 8 ppm 11.40 (s, 1 H) 8.79 (s, 1 H) 8.63 (s, 1 H)
8.12 (s, 1 H)
7.57 (d, J=8.24, 1.22 Hz, 1 H) 7.43 (t, J=1.83 Hz, 1 H) 7.38 (t, J=7.93 Hz, 1
H) 7.23 - 7.34
(m, 4 H) 7.08 - 7.22 (m, 4 H) 7.03 (d, J=6.71 Hz, 2 H) 6.88 (d, J=7.63 Hz, 1
H) 6.78 (d,
J=7.32 Hz, 1 H) 5.50 (s, 2 H) 5.36 (s, 2 H) 2.26 (s, 3 H). MS (ESI+) m/z 515.3
(M+H)+.
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Example 127
5-(1H-indazol-5-yl)-N-(2-isopropoxyethyl)isoxazole-3-carboxamide
In a 20 mL vial a solution of 81A (37 mg, 0.18 mmol) dissolved in
dimethylformamide (0.8 mL) was added, followed by the addition of HATU (61 mg,
0.18
mmol) dissolved in dimethylformamide (0.8 mL). Then a solution of 2-
isopropoxyethanamine (20 mg, 0.20 mmol) dissolved in dimethylformamide (0.9
mL) was
added followed by diisopropylethylamine (42 mg, 0.36 mmol) dissolved in
dimethylformamide (0.8 mL). The mixture was then shaken at 40 C for three
hours. The
crude reaction mixture was filtered through a Si-carbonate cartridge (6 mL, 2
g) supplied by
Silicycle Chemical Division with methanol, checked with LC/MS, and
concentrated to
dryness. The residue was dissolved in 1:1 DMSO/methanol and purified by
reverse phase
HPLC (Agilent, 5%-100% TFA/water gradient, 8 minute run). 'H NMR (300 MHz,
DMSO-
d6 /D20) b ppm 8.38 - 8.43 (m, 1 H) 8.22 - 8.30 (m, 1 H) 7.90 (d, 1 H) 7.73
(d, 1 H) 7.21 -
7.29 (m, 1 H) 3.56 - 3.65 (m, 1 H) 3.52 (t, 2 H) 3.43 (t, 2 H) 1.10 (d, 6 H).
MS (ESI+) m/z
315 (M+H)+.
Example 128
5- [3 -(morpholin-4-ylcarbonyl)isoxazol-5 -yl] -1 H-indazole
The title compound was prepared according to the procedure outlined in Example
127
substituting morpholine for 2-isopropoxyethanamine. 'H NMR (300 MHz, DMSO-
d6/D20) 8 ppm 8.36 - 8.43 (m, 1 H) 8.22 - 8.29 (m, 1 H) 7.89 (d, 1 H) 7.72 (d,
1 H) 7.11 -
7.22 (m, 1 H) 3.68 - 3.72 (m, 4 H) 3.61 - 3.68 (m, 4 H). MS (ESI+) m/z 299
(M+H)+.
Example 129
5-(IH-indazol-5-yl)-N-(3-morpholin-4-ylpropyl)isoxazole-3-carboxamide
The title compound was prepared as a TFA salt according to the procedure
outlined in
Example 127 substituting 3-morpholinopropan-l-amine for 2-
isopropoxyethanamine. 'H
NMR (300 MHz, DMSO-d6/D20) 6 ppm 8.37 - 8.46 (m, 1 H) 8.20 - 8.31 (m, 1 H)
7.91 (d, 1
H)7.73(d,1H)7.17-7.36(m,IH)3.98-4.08(m,2H)3.57-3.73(m,2H)3.42-3.51(m,
2 H) 3.35 - 3.41 (m, 2 H) 3.14 - 3.22 (m, 2 H) 3.01 - 3.14 (m, 2 H) 1.88 -
2.06 (m, 2 H). MS
(ESI+) m/z 356 (M+H)+.
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Example 130
N-[2-(1 H-imidazol-4-yl)ethyl]-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
127
substituting 2-(1H-imidazol-4-yl)ethanamine for 2-isopropoxyethanamine. iH NMR
(300
MHz, DMSO-d6/D20) 6 ppm 8.90 - 8.97 (m, 1 H) 8.34 - 8.46 (m, 1 H) 8.20 - 8.32
(m, 1 H)
7.90(d,1H)7.72(d,1H)7.38-7.49(m,1H)7.14-7.28(m,1H)3.57(t,2H)2.96(t,2H).
MS (ESI+) m/z 323 (M+H)+.
Example 131
(3R)-1- {[5-(1 H-indazol-5-yl)isoxazol-3-yl] carbonyl}piperidin-3-ol
The title compound was prepared according to the procedure outlined in Example
127
substituting (R)-piperidin-3-ol hydrochloride for 2-isopropoxyethanamine. 'H
NMR (300
MHz, DMSO-d6/D20) 6 ppm 8.34 - 8.45 (m, 1 H) 8.19 - 8.30 (m, 1 H) 7.89 (d, 1
H) 7.72 (d,
1H)7.13(d,1H)4.03-4.19(m,1H)3.64-3.72(m,1H)3.54-3.62(m,1H)3.34-3.44
(m,1H)3.20-3.32(m,1H)2.99-3.10(m,1H)1.67-2.03(m,2H)1.36-1.61(m,2H).
MS (ESI+) m/z 313 (M+H)+.
Example 132
1- { [5-(1 H-indazol-5-yl)isoxazol-3-yl]carbonyl}piperidine-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
127
substituting piperidine-3-carboxamide for 2-isopropoxyethanamine. 'H NMR (300
MHz,
DMSO-d6/D20) 6 ppm 8.36 - 8.45 (m, 1 H) 8.22 - 8.32 (m, 1 H) 7.90 (d, 1 H)
7.72 (d, 1 H)
7.07-7.23(m,1H)4.27-4.56(m,1H)3.91-4.05(m,1H)3.09-3.37(m,1H)2.85-3.04
(m,1H)2.31-2.45(m,1H)1.89-2.05(m,1H)1.73-1.86(m,1H)1.60-1.72(m,1H)
1.36 - 1.55 (m, 1 H). MS (ESI-) m/z 338 (M-H)-.
Example 133
2- [2-(4- { [5 -(1 H-indazol-5-yl)isoxazol-3-yl]carbonyl}piperazin-l-
yl)ethoxy] ethanol
The title compound was prepared as a TFA salt according to the procedure
outlined in
Example 127 substituting 2-(2-(piperazin-l-yl)ethoxy)ethanol for 2-
isopropoxyethanamine.
iH NMR (300 MHz, DMSO-d6/D20) 8 ppm 8.39 - 8.48 (m, 1 H) 8.19 - 8.32 (m, 1 H)
7.92 (d,
1H)7.74(d,1H)7.17-7.27(m,1H)4.49-4.60(m,1H)3.94-4.01(m,1H)3.76-3.81
(m,4H)3.56-3.63(m,2H)3.51-3.56(m,2H)3.33-3.43(m,3H)3.13-3.23(m,1H)
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2.65 - 2.75 (m, 2 H). MS (ESI+) m/z 386 (M+H)+.
Example 134
5- {3-[(4-methyl-l,4-diazepan-1-yl)carbonyl]isoxazol-5-yl}-1 H-indazole
The title compound was prepared as a TFA salt according to the procedure
outlined in
Example 127 substituting 1-methyl-l,4-diazepane for 2-isopropoxyethanamine. 'H
NMR
(300 MHz, DMSO-d6/D20) 6 ppm 8.38 - 8.46 (m, 1 H) 8.22 - 8.32 (m, 1 H) 7.85 -
7.98 (m, 1
H) 7.75 (d, 1 H) 7.22 (d, 1 H) 4.07 - 4.19 (m, I H) 3.69 - 3.77 (m, 2 H) 3.59 -
3.67 (m, I H)
3.44-3.59(m,1H)3.35-3.44(m,1H)3.24-3.35(m,2H)2.84-2.95(m,3H)2.66-2.74
(m, I H) 2.10 - 2.26 (m, 2 H). MS (ESI+) m/z 326 (M+H)+.
Example 135
N-(3-hydroxypropyl)-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
127
substituting 3-aminopropan-l-ol for 2-isopropoxyethanamine. 'H NMR (300 MHz,
DMSO-
d6/Dz0) 8 ppm 8.36 - 8.45 (m, 1 H) 8.20 - 8.30 (m, I H) 7.84 - 7.94 (m, 1 H)
7.71 (d, I H)
7.18-7.28(m,1H)3.48(t,2H)3.35(t,2H)1.64-1.78(m,2H). MS (ESI+) m/z 387
(M+H)+.
Example 136
N-[(1 R)-2-hydroxy-l-phenylethyl]-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
127
substituting (R)-2-amino-2-phenylethanol for 2-isopropoxyethanamine. 'H NMR
(300 MHz,
DMSO-d6/D20) 6 ppm 9.1I (d, I H) 8.37 - 8.46 (m, 1 H) 8.23 - 8.28 (m, I H)
7.91 (d, I H)
7.73(d,1H)7.40-7.45(m,2H)7.32-7.39(m,2H)7.23-7.32(m,2H)5.05-5.13(m,l
H) 3.66 - 3.72 (m, 2 H). MS (ESI+) m/z 349 (M+H)+.
Example 137
N-[3-(1 H-imidazol-1-yl)propyl]-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
127
substituting 3-(1H-imidazol-1-yl)propan-l-amine for 2-isopropoxyethanamine. iH
NMR
(300 MHz, DMSO-d6/D20) b ppm 9.02 - 9.10 (m, 1 H) 8.40 - 8.44 (m, 1 H) 8.25 -
8.29 (m, 1
H)7.87-7.95(m,IH)7.71-7.82(m,2H)7.61-7.69(m,IH)7.20-7.29(m,1H)4.28(t,
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2 H) 3.33 (t, 2 H) 2.06 - 2.19 (m, 2 H). MS (ESI+) m/z 337 (M+H)
Example 138
5-(1 H-indazol-5-yl)-N-[3-(2-oxopyrrolidin-1-yl)propyl]isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
127
substituting 1-(3-aminopropyl)pyrrolidin-2-one for 2-isopropoxyethanamine. 'H
NMR (300
MHz, DMSO-d6/D20) b ppm 8.38 - 8.43 (m, 1 H) 8.24 - 8.30 (m, 1 H) 7.87 - 7.93
(m, 1 H)
7.73(d,1H)7.22-7.26(m,1H)3.39(t,2H)3.21-3.30(m,4H)2.26(t,2H)1.90-2.00
(m, 2 H) 1.70 - 1.79 (m, 2 H). MS (ESI+) m/z 354 (M+H)+.
Example 139
N- {2-[4-(aminosulfonyl)phenyl] ethyl} -5-(1 H-indazol-5 -yl)isoxazole-3 -
carboxamide
The title compound was prepared according to the procedure outlined in Example
127
substituting 4-(2-aminoethyl)benzenesulfonamide for 2-isopropoxyethanamine. 'H
NMR
(300 MHz, DMSO-d6/D20) 8 ppm 8.37 - 8.42 (m, 1 H) 8.24 - 8.29 (m, 1 H) 7.86 -
7.93 (m, 1
H)7.70-7.80(m,3H)7.47(d,2H)7.20-7.24(m,1H)3.57(t,2H)2.96(t,2H). MS
(ESI+) m/z 412 (M+H)+.
Example 140
[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl](3-chlorophenyl)methanone
The title compound was prepared according to the procedure outlined in Example
119B substituting 3-chlorobenzoyl chloride for benzoyl chloride. iH NMR (500
MHz,
DMSO-d6) 8 ppm 13.09 (s, 1 H) 7.99 (s, 1 H) 7.77 (s, 1 H) 7.38 - 7.51 (m, 4 H)
7.28 - 7.37
(m, 3 H) 7.20 - 7.27 (m, 4 H) 5.78 (s, 2 H). MS (ESI+) m/z 414.1 (M+H)+.
Example 141
[ 1-benzyl-4-(1 H-indazol-5-yl)-1 H-1,2,3 -triazol-5 -yl]
(cyclopropyl)methanone
The title compound was prepared according to the procedure outlined in Example
119B substituting cyclopropanecarbonyl chloride for benzoyl chloride. iH NMR
(500 MHz,
DMSO-d6) 8 ppm 13.26 (s, 1 H) 8.18 (s, 1 H) 8.08 (s, 1 H) 7.61 - 7.70 (m, 2 H)
7.29 - 7.40
(m,3H)7.24(d,J=7.02Hz,2H)5.79(s,2H)1.86-2.00(m,1H)0.98-1.12(m,2H)0.77
- 0.93 (m, 2 H). MS (ESI+) m/z 344.1 (M+H)+.
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Example 142
5-[5-cyclopropyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-
indazole
Example 142A
5-Cyclopropyl-l-((tetrahydro-2H-pyran-4-yl)methyl)-4-(tributylstannyl)-IH-
1,2,3-triazole
Cyclopropyl acetylene (142 mg, 2.15 mmol) was added to 1,1,1-tributyl-N,N-
dimethylstannanamine (716 mg, 2.14 mmol) in hexane (3.0 mL) and stirred in a
sealed vial at
70 C for 2 hours. The mixture was cooled to ambient temperature, and the vial
was stirred
unsealed for 10 minutes. Example 80A (455 mg, 3.22 mmol) was added, and the
vial was
resealed and heated to 130 C overnight. The mixture was purified by silica
gel
chromatography eluting with a gradient of ethyl acetate in hexanes (5-50%) to
afford the title
compound. MS (ESI+) m/z 498.3 (M+H)+.
Example 142B
1-(5-(5-Cyclopropyl-l -((tetrahydro-2H-pyran-4-yl)methyl)-1 H-1,2,3-triazol-4-
yl)-1 H-
indazol-l-yl)ethanone
Example 142A (220 mg, 0.444 mmol), Example 87A (128 mg, 0.447 mmol),
dichlorobis(triphenylphosphine)palladium(II) (33 mg, 0.047 mmol), and copper
thiophene-2-
carboxylate (127 mg, 0.666 mmol) were combined in toluene (2.0 mL) in a 4 mL
vial under
an inert atmosphere of nitrogen. The vial was sealed and heated 150 C for 20
minutes. The
mixture was absorbed on silica gel and purified by silica gel chromatography
eluting with a
gradient of 5-70% ethyl acetate in hexanes to afford the title compound. MS
(ESI+) m/z
366.0 (M+H)+.
Example 142C
5-[5-cyclopropyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-
indazole
Example 142B (46 mg, 0.126 mmol) was dissolved in tetrahydrofuran (2.0 mL) and
water (0.5 mL) and potassium hydroxide (80 mg, 1.43 mmol) was added. The
mixture was
stirred for 2 hours, and was diluted with methylene chloride and washed with
water. The
organic layer was absorbed on silica gel and purified by silica gel
chromatography eluting
with a gradient of 0-8% methanol in dichloromethane to afford the title
compound. 'H NMR
(300 MHz, CDC13) 6 ppm 8.19 (s, 1 H) 7.96 (d, J-8.82 Hz, 1 H) 7.61 (d, J-7.80
Hz, 1 H)
7.25-7.28(m,1H)4.34(d,J=6.44Hz,2H)4.02(d,J=11.36,3.56Hz,2H)3.42(t,J=11.53
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Hz,2H)2.33-2.46(m,1H)1.81-1.95(m,1H)1.59-1.70(m,2H)1.43-1.58(m,2H)
1.23-1.28(m,1H)1.10-1.20(m,2H)0.47-0.62(m,2H). MS (ESI+) m/z 324.1
(M+H)+.
Example 143
N1- { [ 1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]methyl} glycinamide
Example 143A
2-((1-Benzyl-4-(tributylstannyl)-1H-1,2,3-triazol-5-yl)methyl)isoindoline-1,3-
dione
N-Propargylphthalimide (2.35 g mg, 12.7 mmol) was added to 1,1,1-tributyl-N,N-
dimethylstannanamine (4.23 mg, 12.7 mmol) in hexane (3.0 mL) and stirred in a
sealed vial
at 70 C for 2 hours. The mixture was cooled to ambient temperature and the
vial was stirred
unsealed for 10 minutes. Benzyl azide (2.0 mL, 16.0 mmol) was added and the
vial was
resealed and heated to 130 C overnight. The mixture was purified by silica
gel
chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes to
afford the title
compound. MS (ESI+) m/z 609.3 (M+H)+.
Example 143B
2-((4-(1-Acetyl-1 H-indazol-5-yl)-1-benzyl-1 H-1,2,3-triazol-5-
yl)methyl)isoindoline-1,3-
dione
Example 143A (567 mg, 0.934 mmol), Example 87A (268 mg, 0.934 mmol),
dichlorobis(triphenylphosphine)palladium(II) (67 mg, 0.095 mmol), and copper
thiophene-2-
carboxylate (268 mg, 1.41 mmol) were combined in toluene (2.5 mL) in a
microwave vial
under an inert atmosphere of nitrogen. The vial was heated in a microwave (CEM-
Discover)
to 150 C at 125 Watts for 20 minutes. The mixture was absorbed on silica gel
and purified
by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate
in hexanes to
afford the title compound. MS (ESI+) m/z 477.2 (M+H)+.
Example 143C
(1-Benzyl-4-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-5-yl)methanamine
Example 143B (140 mg, 0.294 mmol) was treated with hydrazine hydrate (0.7 mL)
in
ethanol (0.7 mL) and stirred at ambient temperature overnight. The mixture was
absorbed on
silica gel and purified by silica gel chromatography eluting with a gradient
of 1-6% methanol
in dichloromethane to afford the title compound. MS (ESI+) m/z 305.0 (M+H)+.
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Example 143D
N1- { [ 1-benzyl-4-(IH-indazol-5-yl)-IH-1,2,3-triazol-5-yl]methyl} glycinamide
Example 143C (66 mg, 0.217 mmol), N-(tert-butoxycarbonyl)-glycine (39 mg,
0.223
mmol), and HATU (85 mg, 0.224 mmol) were combined in methylene chloride (2.5
mL).
Diisopropylethylamine (150 uL, 0.865 mmol) was added and the mixture was
stirred at
ambient temperature overnight. The mixture was absorbed on silica gel and
purified by silica
gel chromatography eluting with a gradient of 0-6% methanol in dichloromethane
to afford
tert-butyl 2-((1-benzyl-4-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-5-
yl)methylamino)-2-
oxoethylcarbamate. This carbamate was dissolved in tetrahydrofuran (2 mL) and
0.5 mL of a
solution of 1 N hydrochloric acid in diethyl ether was added and the mixture
was stirred for
minutes at room temperature. The solvents were removed under reduced pressure,
and
diethyl ether was added to the mixture and stirred at room temperature
overnight. The
solvent was decanted, and the resulting residue was dried under a stream of
nitrogen to afford
the title compound as a hydrochloride salt. 'H NMR (300 MHz, DMSO-d6) 6 ppm
13.21 (s,
15 1 H) 9.02 (t, J=5.09 Hz, 1 H) 8.11 - 8.16 (m, 2 H) 8.06 (s, 2 H) 7.75 -
7.82 (m, 1 H) 7.64 (d,
J=8.82Hz,1H)7.30-7.45(m,3H)7.23-7.31(m,2H)5.72(s,2H)4.57(d,J=5.09Hz,2
H) 3.41 (q, J=5.76 Hz, 2 H). MS (ESI+) m/z 362.1 (M+H)+.
Example 144
20 (4-fluorophenyl)[4-(IH-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-
1,2,3-triazol-
5-yl]methanone
The title compound was prepared according to the procedure outlined in Example
119B substituting 4-fluorobenzoyl chloride for benzoyl chloride and Example
80A for benzyl
azide. 'H NMR (300 MHz, DMSO-d6) 6 ppm 13.10 (s, 1 H) 8.00 (s, 1 H) 7.72 -
7.80 (m, 3
H)7.38-7.44(m,1H)7.30-7.36(m,IH)7.09-7.19(m,2H)4.41(d,J=7.12Hz,2H)
3.80(d,J=11.36,2.54Hz,2H)3.14-3.26(m,2H)2.04-2.19(m,1H)1.38-1.49(m,2H)
1.19 - 1.35 (m, 2 H). MS (ESI+) m/z 406.1 (M+H)+.
Example 145
(4-chlorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-IH-
1,2,3-triazol-
5-yl]methanone
The title compound was prepared according to the procedure outlined in Example
119B substituting 4-chlorobenzoyl chloride for benzoyl chloride and Example
80A for benzyl
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azide. 'H NMR (300 MHz, DMSO-d6) b ppm 13.10 (s, 1 H) 8.00 (s, 1 H) 7.77 (s, 1
H) 7.68
(d, J=8.48 Hz, 2 H) 7.29 - 7.45 (m, 4 H) 4.42 (d, J=7.12 Hz, 2 H) 3.81 (d,
J=11.19, 2.71 Hz, 2
H)3.14-3.27(m,2H)2.03-2.19(m,1H)1.38-1.51(m,2H)1.22-1.36(m,2H). MS
(ESI+) m/z 422.1 (M+H)+.
Example 146
(3-chlorophenyl)[4-(1 H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-
1,2,3-triazol-
5-yl]methanone
The title compound was prepared according to the procedure outlined in Example
11 9B substituting 3 -chlorobenzoyl chloride for benzoyl chloride and Example
80A for benzyl
azide. 'H NMR (300 MHz, DMSO-d6) b ppm 13.04 (s, 1 H) 7.95 (s, 1 H) 7.64 (s, 1
H) 7.48 -
7.54(m,1H)7.29-7.35(m,1H)7.22-7.28(m,1H)7.13-7.22(m,3H)4.58(d,J=7.12
Hz,2H)3.86(d,J=11.53,2.37Hz,2H)3.20-3.30(m,2H)2.11-2.24(m,1H)1.45-1.54
(m, 2 H) 1.33 - 1.44 (m, 2 H). MS (ESI+) m/z 422.1 (M+H)+.
Example 147
(2-chlorophenyl)[4-(1 H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-
1,2,3-triazol-
5-yl]methanone
The title compound was prepared according to the procedure outlined in Example
11 9B substituting 2-chlorobenzoyl chloride for benzoyl chloride and Example
80A for benzyl
azide. 'H NMR (300 MHz, DMSO-d6) b ppm 13.08 (s, 1 H) 7.99 (s, 1 H) 7.75 (s, 1
H) 7.66
(t, J=1.86 Hz, 1 H) 7.56 (d, J=7.80 Hz, 1 H) 7.47 - 7.53 (m, 1 H) 7.36 - 7.42
(m, 1 H) 7.23 -
7.34(m,2H)4.45(d,J=6.78Hz,2H)3.82(d,J=11.19,2.37Hz,2H)3.18-3.29(m,2H)
2.09-2.23(m,1H)1.41-1.53(m,2H)1.28-1.38(m,2H). MS (ESI+) m/z 422.1
(M+H)+.
Example 148
cyclopentyl[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-
triazol-5-
yl]methanone
The title compound was prepared according to the procedure outlined in Example
119B substituting cyclopentanecarbonyl chloride for benzoyl chloride and
Example 80A for
benzyl azide. 'H NMR (300 MHz, DMSO-d6) b ppm 13.27 (s, 1 H) 8.18 (s, 1 H)
7.95 (s, 1
H) 7.68 (d, J=8.48 Hz, 1 H) 7.52 (d, J=8.48, 1.70 Hz, 1 H) 4.47 (d, J=7.12 Hz,
2 H) 3.85 (d,
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J=11.53,2.37Hz,2H)3.18-3.30(m,2H)3.02-3.14(m,1H)2.00-2.17(m,IH)1.19-
1.76 (m, 12 H). MS (ESI+) m/z 380.1 (M+H)+.
Example 149
1-benzyl-4-(IH-indazol-5-yl)-IH-1,2,3-triazole-5-carboxylic acid
Example 149A
Methyl 1-benzyl-4-(tributylstannyl)-1 H-1,2,3-triazole-5-carboxylate
Methyl propiolate (5.75 g, 68.4 mmol) was added to methyl
ethyl(tributylstannyl)carbamate (26.9 g, 68.6 mmol) in a large sealed tube.
The mixture was
heated to 70 C overnight. The mixture was cooled to ambient temperature and
the vial was
stirred unsealed for 10 minutes. Benzyl azide (10.2 mL, 81.6 mmol) was added,
and the vial
was resealed and heated to 130 C overnight. The mixture was purified by
silica gel
chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to
afford the title
compound. MS (ESI+) m/z 508.3 (M+H)+.
Example 149B
Methyl4-(1-acetyl-1 H-indazol-5-yl)-1-benzyl-1 H-1,2,3-triazole-5-carboxylate
Example 149A (7.17 g, 14.1 mmol), Example 87A (4.02 g, 14.1 mmol),
dichlorobis(triphenylphosphine)palladium(II) (1.01 mg, 1.44 mmol), and copper
thiophene-2-
carboxylate (4.07 mg, 21.3 mmol) were combined in toluene (55 mL) in a large
sealed tube
under an inert atmosphere of nitrogen. The tube was sealed and heated at 150
C for 30
minutes. The mixture was absorbed on silica gel and purified by silica gel
chromatography
eluting with a gradient of 10-50% ethyl acetate in hexanes to afford the title
compound. MS
(ESI+) m/z 376.1 (M+H)+.
Example 149C
1-benzyl-4-(IH-indazol-5-yl)-IH-1,2,3-triazole-5-carboxylic acid
Example 149B (3.40 mg, 9.06 mmol) was dissolved in tetrahydrofuran (100 mL),
methanol (10 mL), and water (10 mL), and potassium hydroxide (1.63 g, 29.1
mmol) was
added. The mixture was stirred for 3 hours, was diluted with ethyl acetate and
washed with 1
N hydrochloric acid, washed with brine, and the combined organic layers were
dried over
sodium sulfate. After filtration, the solvents were removed under reduced
pressure to afford
the title compound. 'H NMR (300 MHz, DMSO-d6) 8 ppm 13.16 (s, 1 H) 8.11 - 8.18
(m, 2
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H)7.66-7.76(m,1H)7.54-7.62(m,1H)7.31-7.43(m,3H)7.22-7.29(m,2H)5.93(s,
2 H). MS (ESI+) m/z 320.0 (M+H)+.
Example 150
5-{5-(4-fluorophenyl)-1-[4-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-
indazol-3-
amine
Example 150A
1-(Azidomethyl)-4-(trifluoromethyl)benzene
Sodium azide (2.30 g, 35.4 mmol) was added to a solution of 4-
(trifluoromethyl)benzyl bromide (4.26 g, 17.8 mmol) dissolved in dimethyl
sulfoxide (15
mL) and stirred at ambient temperature overnight. The mixture was diluted with
ethyl
acetate, washed with water and brine, and dried over sodium sulfate. After
filtration, the
solvent was removed under reduced pressure to afford the title compound. The
crude product
was used in the next step without further characterization.
Example 150B
5-(4-Fluorophenyl)-4-(tributylstannyl)-1-(4-(trifluoromethyl)benzyl)-1 H-1,2,3-
triazole
4-Fluorophenyl acetylene (524 mg, 4.36 mmol) was added to 1,1,1-tributyl-N,N-
dimethylstannanamine (1.46 g, 4.37 mmol), and the mixture was stirred in a
sealed vial at 50
C for 30 minutes. The mixture was cooled to ambient temperature, and the vial
was stirred
unsealed for 10 minutes. Example 150A (1.28 g, 6.30 mmol) was added and the
vial was
resealed and heated to 130 C overnight. The mixture was purified by silica
gel
chromatography eluting with a gradient of 5-35% ethyl acetate in hexanes to
afford the title
compound. MS (ESI+) m/z 612.3 (M+H)+.
Example 150C
2-Fluoro-5-(5-(4-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-
4-
yl)benzonitrile
Example 150B (485 mg, 0.795 mmol), 5-bromo-2-fluorobenzonitrile (143 mg, 0.715
mmol), dichlorobis(triphenylphosphine)palladium(II) (49 mg, 0.070 mmol), and
copper
thiophene-2-carboxylate (205 mg, 1.08 mmol) were combined in toluene (2.0 mL)
in a 4 mL
vial under an inert atmosphere of nitrogen. The vial was sealed and heated at
150 C for 30
minutes. The mixture was absorbed onto silica gel and purified by silica gel
chromatography
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eluting with a gradient of 10-50% ethyl acetate in hexanes to afford the title
compound. MS
(ESI+) m/z 441.2 (M+H)+.
Example 150D
5-{5-(4-fluorophenyl)-1-[4-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-
indazol-3-
amine
Example 150C was treated with hydrazine hydrate (1.0 mL) in ethanol (1.0 mL),
and
the reaction mixture was stirred and heated to 65 C for 3 hours. The mixture
was diluted
with methylene chloride and washed with water. The organic layer was absorbed
on silica
gel and purified by silica gel chromatography eluting with a gradient of 0-6%
methanol in
dichloromethane to afford the title compound. 'H NMR (300 MHz, DMSO-d6) 6 ppm
11.42
(s, 1 H) 8.04 (s, 1 H) 7.67 (d, J=8.14 Hz, 2 H) 7.26 - 7.41 (m, 4 H) 7.22 (d,
J=8.48 Hz, 2 H)
7.03 - 7.15 (m, 2 H) 5.62 (s, 2 H) 5.36 (s, 2 H). MS (ESI+) m/z 453.1 (M+H)+.
Example 151
5-[ l -benzyl-5-(4-fluorophenyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-3 -amine
Example 151A
1-B enzyl-5 -(4-fluorophenyl)-4-(tributylstannyl)-1 H-1,2, 3 -triazole
4-Fluorophenyl acetylene (525 mg, 4.37 mmol) was added to 1,1,1-tributyl-N,N-
dimethylstannanamine (1.46 g, 4.37 mmol), and the mixture was stirred in a
sealed vial at 50
C for 2 hours. The mixture was cooled to ambient temperature, and the vial was
stirred
unsealed for 10 minutes. Benzyl azide (850 uL, 6.80 mmol) was added, and the
vial was
resealed and heated to 130 C overnight. The mixture was purified by silica
gel
chromatography eluting with a gradient of 5-35% ethyl acetate in hexanes to
afford the title
compound. MS (ESI+) m/z 544.4 (M+H)+.
Example 151B
5-(1-Benzyl-5-(4-fluorophenyl)-1 H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile
Example 151A (361 mg, 0.666 mmol), 5-bromo-2-fluorobenzonitrile (119 mg, 0.595
mmol), dichlorobis(triphenylphosphine)palladium(II) (45 mg, 0.064 mmol), and
copper
thiophene-2-carboxylate (193 mg, 1.01 mmol) were combined in toluene (2.0 mL)
in a 4 mL
vial under an inert atmosphere of nitrogen. The vial was sealed and heated 150
C for 30
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minutes. The mixture was absorbed on silica gel and purified by silica gel
chromatography
cluting with a gradient of 10-50% ethyl acetate in hexanes to afford the title
compound. MS
(ESI+) m/z 373.0 (M+H)+.
Example 151 C
5-[ 1-benzyl-5-(4-fluorophenyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-3 -amine
Example 151B (135 mg, 0.363 mmol) was treated with hydrazine hydrate (1.0 mL)
in
ethanol (1.0 mL) and stirred and heated to 65 C for 3 hours. The mixture was
diluted with
methylene chloride and washed with water. The organic layer was absorbed on
silica gel and
purified by silica gel chromatography eluting with a gradient of 0-6% methanol
in
dichloromethane to afford the title compound. 'H NMR (300 MHz, DMSO-d6) 6 ppm
11.40
(s,1H)8.02(s,1H)7.24-7.38(m,7H)7.03-7.14(m,2H)6.98(d,J=7.29,2.20Hz,2H)
5.50 (s, 2 H) 5.35 (s, 2 H). MS (ESI+) m/z 385.1 (M+H)+.
Example 152
[4-(1 H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-1,2,3 -triazol-5 -
yl] (tetrahydro-
2H-pyran-4-yl)methanone
The title compound was prepared according to the procedure outlined in Example
119B substituting Example 80A for benzyl azide and tetrahydro-2H-pyran-4-
carbonyl
chloride for benzoyl chloride. 'H NMR (300 MHz, DMSO-d6) 6 ppm 13.30 (s, 1 H)
8.18 (s,
1 H) 8.00 (s, 1 H) 7.69 (d, J=8.48 Hz, 1 H) 7.53 (d, J=8.65, 1.53 Hz, 1 H)
4.48 (d, J=7.12 Hz,
2H)3.79-3.90(m,2H)3.62-3.74(m,2H)3.18-3.30(m,2H)2.76-2.88(m,1H)2.64-
2.76 (m, 2 H) 2.00 - 2.17 (m, 1 H) 1.20 - 1.58 (m, 8 H). MS (ESI+) m/z 396.0
(M+H)+.
Example 153
5-[I-benzyl-5-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazole
Example 153A
1-Benzyl-5-o-tolyl-4-(tributylstannyl)-1 H-1,2,3-triazole
2-Ethynyl toluene (456 uL, 3.62 mmol) was added to 1, 1, 1 -tributyl-N,N-
dimethylstannanamine (1.21 g, 3.62 mmol), and the mixture was stirred in a
sealed vial at 70
C for 3 hours. The mixture was cooled to ambient temperature, and the vial was
stirred
unsealed for 10 minutes. Benzyl azide (678 uL, 5.42 mmol) was added, and the
vial was
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resealed and heated to 130 C overnight. The mixture was purified by silica
gel
chromatography eluting with a gradient of 5-45% ethyl acetate in hexanes to
afford the title
compound. MS (ESI+) m/z 539.8 (M+H)+.
Example 153B
1-(5 -(1-B enzyl-5 -o-tolyl-1 H-1, 2,3 -triazo l-4-yl)-1 H-indazol-1-
yl)ethanone
Example 153A (119 mg, 0.221 mmol), Example 87A (63 mg, 0.221 mmol),
dichlorobis(triphenylphosphine)palladium(II) (16 mg, 0.023 mmol), and copper
thiophene-2-
carboxylate (65 mg, 0.341 mmol) were combined in toluene (2.0 mL) in a 4 mL
vial under an
inert atmosphere of nitrogen. The vial was sealed and heated at 150 C for 20
minutes. The
mixture was absorbed on silica gel and purified by silica gel chromatography
eluting with a
gradient 5-45% of ethyl acetate in hexanes to afford the title compound. MS
(ESI+) m/z
408.7 (M+H)+.
Example 153C
5-[l-benzyl-5-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazole
Example 153B (42 mg, 0.103 mmol) was dissolved in tetrahydrofuran (2.0 mL) and
water (0.3 mL), and potassium hydroxide (48 mg, 0.856 mmol) was added. The
mixture was
stirred for 1 hour, was diluted with methylene chloride and washed with water.
The organic
layer was absorbed on silica gel and purified by silica gel chromatography
eluting with a
gradient of 1-6% methanol in dichloromethane to afford the title compound. 'H
NMR (300
MHz, DMSO-d6) 8 ppm 13.07 (s, 1 H) 7.97 (s, 1 H) 7.73 (s, 1 H) 7.44 - 7.53 (m,
3 H) 7.39 (t,
J=6.95Hz,1H)7.28-7.35(m,2H)7.21-7.29(m,3H)6.86-6.95(m,2H)5.28-5.45(m,
2 H) 1.59 (s, 3 H). MS (ESI+) m/z 366.1 (M+H)+.
Example 154
5- { 1-benzyl-5-[(4-methylpiperazin-1-yl)carbonyl]-1 H-1,2,3-triazol-4-yl}-1 H-
indazole
The title compound was prepared according to the procedure outlined in Example
81 B
substituting Example 149C for Example 81A and 1-methyl piperazine for
piperidine and
tetrahydrofuran for dimethylformamide. 'H NMR (300 MHz, DMSO-d6) 8 ppm 13.20
(s, 1
H)8.16(s,1H)7.96(s,1H)7.57-7.69(m,2H)7.31-7.44(m,3H)7.23-7.30(m,2H)
5.36 - 5.83 (m, 2 H) 3.40 - 3.65 (m, J=4.75 Hz, 2 H) 2.38 - 2.49 (m, 2 H) 2.10
- 2.22 (m, 2 H)
1.89 (s, 3 H) 1.40 (t, J=4.92 Hz, 2 H). MS (ESI+) m/z 402.2 (M+H)+.
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Example 155
1- {[ 1-benzyl-4-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-5-yl] carbonyl}piperidin-
4-ol
The title compound was prepared according to the procedure outlined in Example
81 B
substituting Example 149C for Example 81A and 4-hydroxy piperidine for
piperidine and
tetrahydrofuran for dimethylformamide. 'H NMR (300 MHz, DMSO-d6) 8 ppm 13.15 -
13.24(m,IH)8.16(s,1H)7.97(s,1H)7.55-7.68(m,2H)7.32-7.43(m,3H)7.23-7.30
(m, 2 H) 5.41 - 5.83 (m, J=65.10 Hz, 2 H) 4.58 (d, J=3.39 Hz, 1 H) 3.74 - 3.91
(m, 1 H) 3.37
-3.48(m,2H)2.66-2.79(m,1H)2.25-2.47(m,1H)1.54-1.68(m,IH)1.20-1.36(m,
1 H) 0.74 - 0.90 (m, 1 H) 0.40 - 0.60 (m, 1 H). MS (ESI+) m/z 403.1 (M+H)+.
Example 156
1-acetyl-5-[5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-IH-1,2,3-
triazol-4-yl]-
1 H-indazole
Example 156A
5-(4-Fluorophenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-4-(tributylstannyl)-1
H-1,2,3-
triazole
4-Fluorophenyl acetylene (440 uL, 3.88 mmol) was added to 1,1,1-tributyl-N,N-
dimethylstannanamine (1.30 g, 3.89 mmol), and the mixture was stirred in a
sealed vial at 50
C for 40 minutes. The mixture was cooled to ambient temperature, and the vial
was stirred
unsealed for 10 minutes. Example 80A (710 uL, 5.68 mmol) was added and the
vial was
resealed and heated to 130 C overnight. The mixture was purified by silica
gel
chromatography eluting with a gradient of 5-50% ethyl acetate in hexanes to
afford the title
compound. MS (ESI+) m/z 552.4 (M+H)+.
Example 156B
1-acetyl-5-[5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-IH-1,2,3-
triazol-4-yl]-
1 H-indazole
Example 156A (433 mg, 0.787 mmol), Example 87A (205 mg, 0.717 mmol),
dichlorobis(triphenylphosphine)palladium(II) (55 mg, 0.078 mmol), and copper
thiophene-2-
carboxylate (224 mg, 1.17 mmol) were combined in toluene (2.0 mL) in a 4 mL
vial under an
inert atmosphere of nitrogen. The vial was sealed and heated to 150 C for 20
minutes. The
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mixture was absorbed on silica gel and purified by silica gel chromatography
eluting with a
gradient of 5-45% ethyl acetate in hexanes, and was triturated with methanol
to afford the
title compound. 'H NMR (300 MHz, DMSO-d6) S ppm 8.40 - 8.48 (m, J=0.68 Hz, 1
H) 8.25
(d, J=8.82 Hz, 1 H) 7.82 - 7.91 (m, 1 H) 7.73 (d, J=8.48, 1.70 Hz, 1 H) 7.50 -
7.60 (m, 2 H)
7.38-7.49(m,2H)4.13(d,J=7.12Hz,2H)3.76(d,J=11.36,2.54Hz,2H)3.10-3.25(m,
2 H) 2.70 (s, 3 H) 1.86 - 2.08 (m, 1 H) 1.37 (d, J=12.55, 1.70 Hz, 2 H) 1.03 -
1.23 (m, 2 H).
MS (ESI+) m/z 420.2 (M+H)+.
Example 157
1-benzyl-4-(1H-indazol-5-yl)-N,N-dimethyl-lH-1,2,3-triazole-5-carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting Example 149C for Example 81A and dimethylamine for piperidine and
tetrahydrofuran for dimethylformamide. 'H NMR (300 MHz, DMSO-d6) 6 ppm 13.19
(s, 1
H) 8.15 (s, 1 H) 7.96 (t, J=1.19 Hz, 1 H) 7.62 (d, J=1.36 Hz, 2 H) 7.33 - 7.44
(m, 3 H) 7.24 -
7.33 (m, 2 H) 5.59 (s, 2 H) 2.92 (s, 3 H) 2.21 (s, 3 H). MS (ESI+) m/z 347.1
(M+H)+.
Example 158
N,1-dibenzyl-4-(1 H-indazol-5-yl)-1 H-1,2,3-triazole-5-carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting Example 149C for Example 81A and benzyl amine for piperidine and
tetrahydrofuran for dimethylformamide. 'H NMR (300 MHz, DMSO-d6) b ppm 13.15
(s, 1
H) 9.35 (t, J=6.10 Hz, 1 H) 8.01 (d, J=12.55 Hz, 2 H) 7.68 (d, J=8.82, 1.36
Hz, 1 H) 7.53 (d,
J=8.82 Hz, 1 H) 7.17 - 7.41 (m, 10 H) 5.66 (s, 2 H) 4.41 (d, J=6.10 Hz, 2 H).
MS (ESI+) m/z
409.1 (M+H)+.
Example 159
N-(2-hydroxy-2-phenylethyl)-5-(1 H-indazol-5-yl)-N-methylisoxazole-3-
carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting DL-alpha-(methylaminomethyl)benzyl alcohol for piperidine. 'H NMR
(300
MHz, DMSO-d6) 8 ppm 13.01 (s, 1 H) 8.29 (s, 1 H) 8.17 (s, 1 H) 7.73 - 7.85 (m,
1 H) 7.62 -
7.72 (m, 1 H) 7.16 - 7.43 (m, 5 H) 6.86 (s, 1 H) 5.17 (d, J=4.39 Hz, 1 H) 4.89
(s, 1 H) 3.71 (d,
J=5.49 Hz, 2 H) 3.10 (s, 3 H). MS (ESI+) m/z 363.1 (M+H)+.
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Example 160
N-[(1 S)-2-hydroxy-l-phenylethyl]-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting (S)-2-amino-2-phenylethanol for piperidine. 'H NMR (300 MHz, DMSO-
d6) 6 ppm 13.37 (s, 1 H) 9.05 (d, J=8.14 Hz, 1 H) 8.40 (s, 1 H) 8.23 (s, 1 H)
7.89 (d, J=8.65,
1.53 Hz, 1 H) 7.70 (d, J=8.82 Hz, 1 H) 7.20 - 7.46 (m, 6 H) 5.02 - 5.13 (m, 1
H) 4.98 (t,
J=5.59 Hz, 1 H) 3.61 - 3.82 (m, 2 H). MS (ESI+) m/z 349.0 (M+H)+.
Example 161
N-benzyl-N-(2-hydroxyethyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting 2-(benzylamino)ethanol for piperidine. 'H NMR (300 MHz, DMSO-d6)
6 ppm
13.37 (s, 1 H) 9.05 (d, J=8.48 Hz, 1 H) 8.40 (s, 1 H) 8.23 (s, 1 H) 7.89 (d,
J=8.65, 1.53 Hz, 1
H) 7.70 (d, J=8.82 Hz, 1 H) 7.22 - 7.45 (m, 6 H) 5.02 - 5.14 (m, 1 H) 4.98 (t,
J=5.76 Hz, 1 H)
3.61 - 3.81 (m, 2 H). MS (ESI+) m/z 349.0 (M+H)+.
Example 162
5-[ 1-benzyl-5-(2-methylphenyl)-1 H-1,2,3-triazol-4-yl]-3-methyl-1 H-indazole
Example 162A
1-(5-Bromo-3-methyl-1 H-indazol-1-yl)ethanone
5-Bromo-3-methyl-lH-indazole (838 mg, 3.97 mmol) was dissolved in methylene
chloride (15 rnL) and diisopropylethylamine (0.7 mL). Acetic anhydride (500
uL, 5.29
mmol) was added and the mixture was stirred at ambient temperature overnight.
The mixture
was diluted with ethyl acetate, washed with 1 N sodium hydroxide followed by 1
N
hydrochloric acid and then brine. The organic layer was dried over sodium
sulfate and the
solvent was removed under reduced pressure to afford the title compound. MS
(ESI+) m/z
252.7 (M+H)+.
Example 162B
1-(5-(1-Benzyl-5-o-tolyl-1 H-1,2,3-triazol-4-yl)-3-methyl-1 H-indazol-1-
yl)ethanone
Example 153A (436 mg, 0.808 mmol), Example 162A (205 mg, 0.810 mmol),
dichlorobis(triphenylphosphine)palladium(II) (56 mg, 0.080 mmol), and copper
thiophene-2-
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carboxylate (239 mg, 1.25 mmol) were combined in toluene (2.0 mL) in a 4 mL
vial under an
inert atmosphere of nitrogen. The vial was sealed and heated 150 C for 30
minutes. The
mixture was absorbed on silica gel and purified by silica gel chromatography
eluting with a
gradient of 10-50% ethyl acetate in hexanes to afford the title compound. MS
(ESI+) m/z
422.6 (M+H)+.
Example 162C
5-[ 1-benzyl-5-(2-methylphenyl)-1 H-1,2,3-triazol-4-yl]-3-methyl-1 H-indazole
Example 162B (202 mg, 0.548 mmol) was dissolved in tetrahydrofuran (5.0 mL),
methanol (0.5 mL) and water (0.5 mL) and potassium hydroxide (133 mg, 2.37
mmol) was
added. The mixture was stirred for 1 hour and then was diluted with methylene
chloride and
washed with water. The organic layer was absorbed on silica gel and purified
by silica gel
chromatography eluting with a gradient of 30-80% ethyl acetate in hexanes to
afford the title
compound. 'H NMR (300 MHz, DMSO-d6) 6 ppm 12.63 (s, 1 H) 7.70 (s, 1 H) 7.44 -
7.52
(m,1H)7.38-7.43(m,1H)7.29-7.38(m,4H)7.22-7.29(m,3H)6.89-6.96(m,J=6.44,
3.05 Hz, 2 H) 5.30 - 5.48 (m, 2 H) 2.32 (s, 3 H) 1.58 (s, 3 H). MS (ESI+) m/z
380.1 (M+H)+.
Example 163
5-[1-benzyl-5-(2-methylphenyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-3-amine
Example 163A
5 -(1-Benzyl-5 -o-tolyl-1 H-1, 2, 3 -triazol-4-yl)-2-fluorobenzonitrile
Example 153A (450 mg, 0.834 mmol), 5-bromo-2-fluorobenzonitrile (167 mg, 0.835
mmol), dichlorobis(triphenylphosphine)palladium(II) (56 mg, 0.080 mmol), and
copper
thiophene-2-carboxylate (242 mg, 1.27 mmol) were combined in toluene (2.0 mL)
in a 4 mL
vial under an inert atmosphere of nitrogen. The vial was sealed and heated at
150 C for 30
minutes. The mixture was absorbed on silica gel and purified by silica gel
chromatography
eluting with a gradient of 10-50% ethyl acetate in hexanes to afford the title
compound. MS
(ESI+) m/z 369.2 (M+H)+.
Example 163B
5-[ 1-benzyl-5-(2-methylphenyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-3-amine
Example 163A (202 mg, 0.548 mmol) was treated with hydrazine hydrate (1.0 mL)
in
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ethanol (1.0 mL) and stirred and heated to 60 C overnight. The mixture was
diluted with
methylene chloride and washed with water. The organic layer was absorbed on
silica gel and
purified by silica gel chromatography eluting with a gradient of 35-85% ethyl
acetate in
hexanes to afford the title compound. 'H NMR (300 MHz, DMSO-d6) 6 ppm 11.38
(s, 1 H)
8.11(s,1H)7.41-7.49(m,1H)7.33-7.40(m,J=6.95,6.95Hz,1H)7.28-7.32(m,2H)
7.21-7.28(m,3H)7.00-7.06(m,1H)6.86-6.95(m,3H)5.27-5.44(m,4H)1.58(s,3
H). MS (ESI+) m/z 381.1 (M+H)+.
Example 164
2-{2-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]ethyl}-1H-isoindole-1,3(2H)-
dione
The title compound was prepared according to the procedure outlined in Example
88
substituting 2-(but-3 -ynyl)isoindoline- 1,3 -dione for 3-phenyl-l-propyne.
The crude product
was subjected to 25% TFA / dichloromethane and purified by reverse-phase HPLC
using an
acetonitrile/water 0.1% TFA gradient elution method to afford the title
compound. 1H NMR
(400 MHz, DMSO-d6) 6 ppm 13.33 (s, 1 H) 8.65 (s, 1 H) 8.22 (s, 1 H) 8.18 (d,
J=1.53 Hz, 1
H) 7.78 - 7.90 (m, 5 H) 7.71 - 7.75 (m, 1 H) 3.92 (t, J=7.21 Hz, 2 H) 3.08 (t,
J=7.21 Hz, 2 H).
MS (ESI+) m/z 359.0 (M+H)+.
Example 165
5- {4-[(2,4-dichlorophenoxy)methyl]-1 H-1,2,3-triazol-1-yl}-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
88
substituting 2,4-dichloro-l-(prop-2-ynyloxy)benzene for 3-phenyl-l-propyne.
The crude
product was subjected to 25% TFA / dichloromethane and was purified by reverse-
phase
HPLC using an acetonitrile/water 0.1 % TFA gradient elution method to afford
the title
compound. 'H NMR (400 MHz, DMSO-d6) 6 ppm 13.38 (s, 1 H) 8.93 (s, 1 H) 8.28
(d,
J=1.53 Hz, 1 H) 8.23 (s, 1 H) 7.88 (d, J=8.90, 1.84 Hz, 1 H) 7.76 (d, J=8.90
Hz, 1 H) 7.59 (d,
J=2.46 Hz, 1 H) 7.39 - 7.49 (m, 2 H) 5.37 (s, 2 H). MS (ESI+) m/z 359.9
(M+H)+.
Example 166
5- {4-[(2,6-dichlorophenoxy)methyl]-1 H-1,2,3-triazol-1-yl} -1 H-indazole
The title compound was prepared according to the procedure outlined in Example
88
substituting 1,3-dichloro-2-(prop-2-ynyloxy)benzene for 3-phenyl-l-propyne.
The crude
product was subjected to 25% TFA / dichloromethane and purified by reverse-
phase HPLC
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using an acetonitrile/water 0.1 % TFA gradient elution method to afford the
title compound.
iH NMR (500 MHz, DMSO-d6) 8 ppm 13.39 (s, 1 H) 8.97 (s, 1 H) 8.29 (d, J=1.53
Hz, 1 H)
8.24 (s, 1 H) 7.89 (d, J=9.00, 1.98 Hz, 1 H) 7.76 (d, J=8.85 Hz, 1 H) 7.51 -
7.55 (m, 2 H) 7.19
- 7.26 (m, J=8.24, 8.24 Hz, 1 H) 5.23 (s, 2 H). MS (ESI+) m/z 359.9 (M+H)+.
Example 167
5-[5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 H-1,2,3-triazol-4-
yl]-1 H-
indazole
Example 156B (168 mg, 0.401 mmol) was dissolved in tetrahydrofuran (5.0 mL),
methanol (0.5 mL) and water (0.5 mL) and potassium hydroxide (138 mg, 2.46
mmol) was
added. The mixture was stirred for 1 hour, and was diluted with methylene
chloride and
washed with water. The organic layer was absorbed on silica gel and purified
by silica gel
chromatography eluting with a gradient of 0-7% methanol in dichloromethane to
afford the
title compound. 'H NMR (300 MHz, DMSO-d6) 8 ppm 13.08 (s, 1 H) 8.02 (s, 1 H)
7.77 (s, 1
H)7.50-7.58(m,2H)7.37-7.49(m,4H)4.11(d,J=7.12Hz,2H)3.76(d,J=11.53,2.71
Hz,2H)3.11-3.24(m,2H)1.88-2.03(m,1H)1.30-1.43(m,J=12.72,1.86Hz,2H)1.04
- 1.22 (m, 2 H). MS (ESI+) m/z 378.1 (M+H)+.
Example 168
1- {[ 1-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-4-yl]methyl} -1 H-indazole
Example 168A
1-(Prop-2-ynyl)-1 H-indazole
Indazole (530 mg, 4.49 mmol) was dissolved in dimethylformamide (4 mL). Sodium
hydride (60% suspension in mineral oil, 231 mg, 5.78 mmol) was added slowly,
and the
mixture was stirred for 10 minutes. Propargyl bromide (80% wt in toluene, 5.0
mL) was
added, and the mixture was stirred at ambient temperature overnight. The
mixture was
diluted with ethyl acetate, washed excessively with water, absorbed on silica
gel, and purified
by silica gel chromatography eluting with a gradient of 5-30% ethyl acetate in
hexanes to
afford the title compound. MS (ESI+) m/z 157.1 (M+H)+.
Example 168B
1- {[ 1-(1 H-indazol-5-yl)-I H-1,2,3-triazol-4-yl]methyl} -1 H-indazole
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The title compound was prepared according to the procedure outlined in Example
88
substituting Example 168A for 3-phenyl-l-propyne. 'H NMR (300 MHz, DMSO-d6) 6
ppm
13.36 (s, 1 H) 8.78 (s, 1 H) 8.22 (d, J=2.03, 0.68 Hz, 1 H) 8.20 (s, 1 H) 8.10
(d, J=1.02 Hz, 1
H)7.80-7.87(m,2H)7.75-7.80(m,1H)7.68-7.74(m,1H)7.39-7.46(m,1H)7.13-
7.19 (m, 1 H) 5.81 (s, 2 H). MS (ESI+) m/z 316.0 (M+H)+.
Example 169
5-[ 1-benzyl-5-(piperidin-1-ylcarbonyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
81 B
substituting Example 149C for Example 81A and tetrahydrofuran for
dimethylformamide.
iH NMR (300 MHz, DMSO-d6) 6 ppm 13.20 (s, 1 H) 8.16 (s, 1 H) 7.95 - 8.00 (m,
J=1.02 Hz,
1H)7.62-7.68(m,1H)7.57-7.63(m,IH)7.31-7.44(m,3H)7.24-7.30(m,2H)5.36-
5.84(m,J=69.17Hz,2H)3.43-3.59(m,2H)2.43-2.59(m,2H)1.17-1.46(m,J=39.67
Hz, 4 H) 0.49 - 0.65 (m, 2 H). MS (ESI+) m/z 387.1 (M+H)+.
Example 170
5-[5-(2-methylphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-IH-1,2,3-triazol-4-
yl]-1H-
indazole
Example 170A
1-((Tetrahydro-2H-pyran-4-yl)methyl)-5-o-tolyl-4-(tributylstannyl)-1 H-1,2,3-
triazole
2-Ethynyl toluene (576 mg, 4.57 mmol) was added to 1,1,1-tributyl-N,N-
dimethylstannanamine (1.53 g, 4.58 mmol), and the mixture stirred in a sealed
vial at 70 C
for 2 hours. The mixture was cooled to ambient temperature, and the vial was
stirred
unsealed for 10 minutes. Example 80A (648 mg, 4.59 mmol) was added and the
vial was
resealed and heated to 130 C overnight. The mixture was purified by silica
gel
chromatography eluting with a gradient of 5-50% ethyl acetate in hexanes to
afford the title
compound. MS (ESI+) m/z 548.4 (M+H)+.
Example 170B
1-(5-(1-((Tetrahydro-2H-pyran-4-yl)methyl)-5 -o-tolyl-1 H-1,2,3-triazol-4-yl)-
1 H-indazol-l-
yl)ethanone
Example 170A (432 mg, 0.791 mmol), Example 87A (222 mg, 0.776 mmol),
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dichlorobis(triphenylphosphine)palladium(II) (58 mg, 0.083 mmol), and copper
thiophene-2-
carboxylate (231 mg, 1.21 mmol) were combined in toluene (2.0 mL) in a 4 mL
vial under an
inert atmosphere of nitrogen. The vial was sealed and heated at 150 C for 20
minutes. The
mixture was absorbed on silica gel and purified by silica gel chromatography
eluting with a
gradient of 20-70% ethyl acetate in hexanes to afford the title compound. MS
(ESI+) m/z
416.2 (M+H)+.
Example 170C
5-[5-(2-methylphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-
yl]-1H-
indazole
Example 170B (184 mg, 0.443 mmol) was dissolved in tetrahydrofuran (3.0 mL),
methanol (0.3 mL), and water (0.3 mL) and potassium hydroxide (140 mg, 2.50
mmol) was
added. The mixture was stirred for 3 hours, and was diluted with methylene
chloride and
washed with water. The organic layer was absorbed on silica gel and purified
by silica gel
chromatography eluting with a gradient of 35-100% ethyl acetate in hexanes to
afford the title
compound. 'H NMR (300 MHz, DMSO-d6) b ppm 13.08 (s, 1 H) 7.98 (s, 1 H) 7.68 -
7.74
(m, J=1.02, 1.02 Hz, 1 H) 7.49 - 7.56 (m, 1 H) 7.45 - 7.49 (m, 3 H) 7.41 -
7.45 (m, J=7.46 Hz,
2 H) 4.10 (d, J=13.73, 6.95 Hz, 1 H) 3.89 (d, J=13.90, 7.80 Hz, 1 H) 3.77 (d,
J=10.51, 2.71
Hz,2H)3.10-3.24(m,2H)1.92(s,3H)1.88-1.98(m,1H)1.26-1.43(m,2H)1.04-
1.21 (m, 2 H). MS (ESI+) m/z 374.1 (M+H)+.
Example 171
5-[5-(2-methylphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-
yl]-1H-
indazol-3-amine
Example 171A
2-Fluoro-5-(1-((tetrahydro-2H-pyran-4-yl)methyl)-5-o-tolyl-lH-1,2,3-triazol-4-
yl)benzonitrile
Example 170A (411 mg, 0.752 mmol), 5-bromo-2-fluorobenzonitrile (151 mg, 0.755
mmol), dichlorobis(triphenylphosphine)palladium(II) (52 mg, 0.074 mmol), and
copper
thiophene-2-carboxylate (223 mg, 1.17 mmol) were combined in toluene (2.0 mL)
in a 4 mL
vial under an inert atmosphere of nitrogen. The vial was sealed and heated 150
C for 30
minutes. The mixture was absorbed on silica gel and purified by silica gel
chromatography
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eluting with a gradient of 10-50% ethyl acetate in hexanes to afford the title
compound. MS
(ESI+) m/z 377.6 (M+H)+.
Example 171B
5-[5-(2-methylphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-
yl]-IH-
indazol-3-amine
Example 171A (175 mg, 0.465 mmol) was treated with hydrazine hydrate (2.0 mL)
in
ethanol (2.0 mL), and the mixture was stirred and heated to 65 C for 2 hours.
The mixture
was diluted with methylene chloride and washed with water. The organic layer
was absorbed
on silica gel and purified by silica gel chromatography eluting with a
gradient of 1-8%
methanol in dichloromethane to afford the title compound. 'H NMR (300 MHz,
DMSO-
d6)8ppm11.39(s,1H)8.08(s,1H)7.45-7.55(m,IH)7.37-7.45(m,3H)7.01-7.08
(m, J=8.48 Hz, 1 H) 6.89 - 6.97 (m, 1 H) 5.34 (s, 2 H) 4.09 (d, J=13.73, 6.95
Hz, 1 H) 3.89
(d,J=13.73,7.63Hz,1H)3.70-3.81(m,2H)3.08-3.24(m,2H)1.91(s,3H)1.84-1.99
(m, 1 H) 1.22 - 1.41 (m, 2 H) 1.04 - 1.20 (m, 2 H). MS (ESI+) m/z 389.1
(M+H)+.
Example 172
5-[ I -benzyl-5-(morpholin-4-ylcarbonyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
81 B
substituting Example 149C for Example 81A, morpholine for piperidine, and
tetrahydrofuran
for dimethylformamide. 'H NMR (300 MHz, DMSO-d6) 8 ppm 13.22 (s, 1 H) 8.18 (s,
1 H)
7.95-8.03(m,1H)7.64-7.70(m,1H)7.57-7.64(m,1H)7.33-7.45(m,3H)7.24-7.31
(m,2H)5.76(s,1H)5.52(s,1H)3.33-3.59(m,4H)2.61-2.74(m,2H)2.45-2.59(m,2
H). MS (ESI+) m/z 389.1 (M+H)+.
Example 173
5-[ 1-benzyl-5-(4-methoxyphenyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-3-amine
A vial under argon containing Example 125B (50 mg, 0.12 mmol), 4-
methoxyphenylboronic acid (20 mg, 0.13 mmol), PdC12(dppf) dichloromethane (10
mg, 0.01
mmol) and potassium carbonate (33 mg, 0.24 mmol) in DME (2 mL) and water (0.2
mL) was
capped and heated at 80 C in a heater shaker for 48 hours. The solvent was
evaporated under
reduced pressure, and the product was purified by reverse-phase HPLC using an
acetonitrile/water 0.1% TFA gradient elution method to afford the title
compound. 1H NMR
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(400 MHz, DMSO-d6) 6 ppm 11.85 (s, 1 H) 8.18 (s, 1 H) 7.26 - 7.34 (m, 3 H)
7.19 - 7.25 (m,
2 H) 7.16 - 7.19 (m, 2 H) 7.02 (t, J=8.13 Hz, 4 H) 5.47 (s, 2 H) 3.80 (s, 3
H). MS (ESI+) m/z
397.1 (M+H)+.
Example 174
N-[(1 S)-1-benzyl-2-hydroxyethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting (S)-(-)-2-amino-3-phenyl-l-propanol for piperidine. 'H NMR (300
MHz,
DMSO-d6) 6 ppm 13.36 (s, 1 H) 8.47 (d, J=8.82 Hz, 1 H) 8.38 (s, 1 H) 8.22 (s,
1 H) 7.87 (d,
J=8.82, 1.70 Hz, 1 H) 7.69 (d, J=8.82 Hz, 1 H) 7.23 - 7.31 (m, 3 H) 7.22 (s, 1
H) 7.12 - 7.21
(m,1H)4.90(t,J=5.59Hz,1H)4.07-4.28(m,1H)3.40-3.58(m,2H)2.89-3.00(m,l
H) 2.75 - 2.86 (m, 1 H). MS (ESI+) m/z 363.0 (M+H)+.
Example 175
N-[(IS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl]-5-(lH-indazol-5-yl)isoxazole-3-
carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting (1 S,2R)-(-)-cis-l-amino-2-indanol for piperidine. iH NMR (300
MHz, DMSO-
d6) 6 ppm 13.38 (s, 1 H) 8.42 (s, 1 H) 8.24 (s, 1 H) 8.16 (d, J=8.48 Hz, 1 H)
7.91 (d, J=8.82,
1.70Hz,1H)7.71(d,J=8.48Hz,1H)7.45(s,1H)7.16-7.32(m,4H)5.36-5.47(m,2H)
4.50 - 4.61 (m, 1 H) 3.14 (d, J=15.43, 5.26 Hz, 1 H) 2.90 (d, J=16.28, 1.70
Hz, 1 H). MS
(ESI+) m/z 361.0 (M+H)+.
Example 176
5- {3-[(3-phenylmorpholin-4-yl)carbonyl]isoxazol-5-yl} -1 H-indazole
The title compound was prepared according to the procedure outlined in Example
81 B
substituting 3-phenylmorpholine hydrochloride for piperidine. 'H NMR (300 MHz,
DMSO-
d6) 6 ppm 13.38 (s, 1 H) 8.32 - 8.46 (m, 1 H) 8.24 (s, 1 H) 7.81 - 7.96 (m, 1
H) 7.70 (d,
J=8.82Hz,1H)7.37-7.55(m,4H)7.26-7.37(m,2H)5.34-5.71(m,1H)4.51(d,
J=13.22Hz,1H)3.78-4.39(m,3H)3.59(t,J=11.36Hz,1H)3.33-3.41(m,1H). MS
(ESI+) m/z 375.0 (M+H)+.
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Example 177
N-benzyl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting benzylamine for piperidine. 'H NMR (300 MHz, DMSO-d6) 8 ppm 13.36
(s, 1
H) 9.35 (t, J=6.27 Hz, 1 H) 8.40 (s, 1 H) 8.23 (s, 1 H) 7.89 (d, J=8.82, 1.70
Hz, 1 H) 7.69 (d,
J=8.82Hz,1H)7.33-7.40(m,4H)7.32(s,1H)7.22-7.30(m,1H)4.48(d,J=6.10Hz,2
H). MS (ESI+) m/z 319.0 (M+H)+.
Example 178
((1S)-2-{[5-(1H-indazol-5-yl)isoxazol-3-yl]carbonyl}-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinolin-l-yl)methanol
The title compound was prepared according to the procedure outlined in Example
81 B
substituting (S)-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol
for piperidine.
MS (ESI+) m/z 435.1 (M+H)+.
Example 179
N-[(1 R)-3-hydroxy-l-phenylpropyl]-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting (R)-3-amino-3-phenylpropanol for piperidine. 'H NMR (300 MHz,
DMSO-
d6) 8 ppm 13.37 (s, 1 H) 9.24 (d, J=8.48 Hz, 1 H) 8.39 (s, 1 H) 8.23 (s, 1 H)
7.88 (d, J=8.82,
1.70Hz,1H)7.69(d,J=8.82Hz,1H)7.38-7.46(m,2H)7.34(t,J=7.46Hz,2H)7.19-
7.30(m,2H)5.09-5.27(m,1H)4.62(t,J=4.92Hz,1H)3.37-3.52(m,2H)2.00-2.16
(m, 1 H) 1.84 - 2.00 (m, 1 H). MS (ESI+) m/z 363.1 (M+H)+.
Example 180
N-[(1 S)-3-hydroxy-l-phenylpropyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting (S)-3-amino-3-phenylpropanol for piperidine. 'H NMR (300 MHz,
DMSO-
d6) 8 ppm 13.36 (s, 1 H) 9.24 (d, J=8.14 Hz, 1 H) 8.39 (s, 1 H) 8.22 (s, 1 H)
7.88 (d, J=8.65,
1.53Hz,1H)7.69(d,J=8.81Hz,1H)7.37-7.45(m,2H)7.29-7.37(m,2H)7.19-7.29
(m,2H)5.08-5.30(m,1H)4.55-4.68(m,1H)3.37-3.51(m,2H)2.00-2.14(m,1H)
1.83 - 1.99 (m, 1 H). MS (ESI+) m/z 363.0 (M+H)+.
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Example 181
N-2,3-dihydro-lH-inden-l-yl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting 1-aminoindane for piperidine. 'H NMR (300 MHz, DMSO-d6) b ppm
13.37 (s, 1
H) 9.13 (d, J=8.14 Hz, 1 H) 8.39 (s, 1 H) 8.23 (s, 1 H) 7.89 (d, J=8.82, 1.36
Hz, 1 H) 7.70 (d,
J=8.82 Hz, 1 H) 7.35 (s, 1 H) 7.15 - 7.32 (m, 4 H) 5.55 (q, J=7.91 Hz, 1 H)
2.95 - 3.08 (m, 1
H) 2.76 - 2.94 (m, 1 H) 2.37 - 2.49 (m, 1 H) 2.01 - 2.15 (m, 1 H). MS (ESI+)
m/z 345.0
(M+H)+.
Example 182
N-2,3-dihydro-lH-inden-2-yl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting 2-aminoindane for piperidine. 'H NMR (300 MHz, DMSO-d6) 6 ppm
13.37 (s, 1
H) 9.08 (d, J=7.46 Hz, 1 H) 8.39 (s, 1 H) 8.23 (s, 1 H) 7.89 (d, J=8.82, 1.70
Hz, 1 H) 7.69 (d,
J=8.82 Hz, 1 H) 7.31 (s, 1 H) 7.10 - 7.28 (m, 4 H) 4.63 - 4.79 (m, 1 H) 3.24
(d, J=15.77, 7.63
Hz, 2 H) 2.96 - 3.08 (m, 2 H). MS (ESI+) m/z 345.0 (M+H)+.
Example 183
5-(1 H-indazol-5-yl)-N-(1-phenylpropyl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting alpha-ethylbenzylamine for piperidine. 'H NMR (300 MHz, DMSO-d6)
b ppm
13.36 (s, 1 H) 9.18 (d, J=8.82 Hz, 1 H) 8.38 (s, 1 H) 8.22 (s, 1 H) 7.88 (d,
J=8.82, 1.36 Hz, 1
H) 7.69 (d, J=8.48 Hz, I H) 7.39 - 7.48 (m, 2 H) 7.34 (t, J=7.29 Hz, 2 H) 7.19
- 7.29 (m, 2 H)
4.84 - 5.00 (m, 1 H) 1.69 - 2.04 (m, 2 H) 0.91 (t, J=7.29 Hz, 3 H). MS (ESI+)
m/z 347.1
(M+H)+.
Example 184
5- { 1-benzyl-5-[3-(dimethylamino)phenyl]-1 H-1,2,3-triazol-4-yl}-1 H-indazol-
3-amine
The title compound was prepared as a TFA salt according to the procedure
outlined in
Example 173 substituting 3-(dimethylamino)phenylboronic acid for 4-
methoxyphenylboronic
acid. iH NMR (500 MHz, DMSO-d6) 8 ppm 11.52 (s, 1 H) 8.17 (s, 1 H) 7.22 - 7.35
(m, 4 H)
7.08 - 7.15 (m, 2 H) 7.03 (d, J=6.71 Hz, 2 H) 6.82 (d, J=8.39,2.29 Hz, I H)
6.48 - 6.54 (m, 2
H) 5.47 (s, 2 H) 2.78 (s, 6 H). MS (ESI+) m/z 410.2 (M+H)+.
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Example 185
5- { 1-benzyl-5-[4-(dimethylamino)phenyl]-1 H-1,2,3-triazol-4-yl} -1 H-indazol-
3-amine
The title compound was prepared as a TFA salt according to the procedure
outlined in
Example 173 substituting 4-(dimethylamino)phenylboronic acid for 4-
methoxyphenylboronic
acid. iH NMR (500 MHz, DMSO-d6) 6 ppm 11.65 (s, 1 H) 8.17 (s, 1 H) 7.23 - 7.38
(m, 3 H)
7.12 - 7.16 (m, 2 H) 7.01 - 7.09 (m, 4 H) 6.74 - 6.78 (m, 2 H) 5.45 (s, 2 H)
2.95 (s, 6 H). MS
(ESI+) m/z 410.2 (M+H)+.
Example 186
N-{3-[4-(3-amino-lH-indazol-5-yl)-1-benzyl-lH-1,2,3-triazol-5-
yl]phenyl}acetamide
The title compound was prepared according to the procedure outlined in Example
173
substituting 3-acetamidophenylboronic acid for 4-methoxyphenylboronic acid. 'H
NMR
(500 MHz, DMSO-d6) 6 ppm 10.05 (s, 1 H) 8.14 (s, 1 H) 7.69 (d, J=8.54 Hz, 1 H)
7.54 (s, 1
H)7.41(t,J=7.93Hz,1H)7.24-7.32(m,3H)7.08-7.16(m,2H)6.93-7.04(m,3H)5.48
(s, 2 H) 2.01 (s, 3 H). MS (ESI+) m/z 424.2 (M+H)+.
Example 187
N- {4-[4-(3-amino-1 H-indazol-5-yl)-1-benzyl-1 H- 1,2,3 -triazol-5 -yl]phenyl
} acetamide
The title compound was prepared according to the procedure outlined in Example
173
substituting 4-acetamidophenylboronic acid for 4-methoxyphenylboronic acid. 'H
NMR
(500 MHz, DMSO-d6) 6 ppm 10.14 (s, 1 H) 8.07 (s, 1 H) 7.66 (d, J=8.85 Hz, 2 H)
7.24 - 7.32
(m, 3 H) 7.18 - 7.22 (m, 2 H) 7.04 - 7.11 (m, 2 H) 6.98 - 7.02 (m, 2 H) 5.48
(s, 2 H) 5.35 (s, 2
H) 2.04 - 2.10 (m, 3 H). MS (ESI+) m/z 424.1 (M+H)+.
Example 188
5- { 1-benzyl-5-[3-(1 H-pyrazol-1-yl)phenyl]-1 H-1,2,3-triazol-4-yl} -1 H-
indazol-3-amine
The title compound was prepared according to the procedure outlined in Example
173
substituting 3-(1H-pyrazol-1-yl)phenylboronic acid for 4-methoxyphenylboronic
acid. 'H
NMR (500 MHz, DMSO-d6) 6 ppm 11.40 (s, 1 H) 8.45 (d, J=2.75 Hz, 1 H) 8.09 (s,
1 H) 7.99
(d, J=8.24, 1.53 Hz, 1 H) 7.80 - 7.85 (m, 1 H) 7.74 (d, J=1.83 Hz, 1 H) 7.56
(t, J=7.93 Hz, 1
H)7.20-7.30(m,3H)7.06-7.16(m,3H)6.98-7.04(m,2H)6.53-6.54(m,1H)5.55(s,
2 H) 5.35 (s, 2 H). MS (ESI+) m/z 433.2 (M+H)+.
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Example 189
5-[ 1-benzyl-5-(1-methyl-1 H-pyrazol-4-yl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-
3-amine
The title compound was prepared according to the procedure outlined in Example
173
substituting 1-methyl-lH-pyrazol-4-ylboronic acid for 4-methoxyphenylboronic
acid. 'H
NMR (500 MHz, DMSO-d6) 6 ppm 11.78 (s, 1 H) 8.11 (s, 1 H) 7.87 (s, 1 H) 7.43
(s, 1 H)
7.27-7.41(m,4H)7.24(d,J=8.54Hz,1H)7.05-7.11(m,J=7.02Hz,2H)5.54(s,2H)
3.86 (s, 3 H). MS (ESI+) m/z 370.9 (M+H)+.
Example 190
3-[4-(3-amino-lH-indazol-5-yl)-1-benzyl-lH-1,2,3-triazol-5-yl]-N-
phenylbenzamide
The title compound was prepared according to the procedure outlined in Example
173
substituting 3-(phenylcarbamoyl)phenylboronic acid for 4-methoxyphenylboronic
acid. 'H
NMR (500 MHz, DMSO-d6) 6 ppm 11.41 (s, 1 H) 10.22 (s, 1 H) 8.07 - 8.12 (m, 2
H) 7.95 (s,
1 H) 7.73 (d, J=7.63 Hz, 2 H) 7.60 (t, J=7.78 Hz, 1 H) 7.43 (d, J=7.63 Hz, 1
H) 7.32 - 7.39
(m, 2 H) 7.21 - 7.30 (m, 3 H) 7.05 - 7.15 (m, 3 H) 7.00 (d, J=6.71 Hz, 2 H)
5.54 (s, 2 H) 5.36
(s, 2 H). MS (ESI+) m/z 486.2 (M+H)+.
Example 191
3-[4-(3-amino-1 H-indazol-5-yl)-1-benzyl-1 H- 1,2,3 -triazol-5-yl] -N-
benzylbenzamide
The title compound was prepared according to the procedure outlined in Example
173
substituting 3-(benzylcarbamoyl)phenylboronic acid for 4-methoxyphenylboronic
acid. 'H
NMR (500 MHz, DMSO-d6) 6 ppm 11.41 (s, 1 H) 9.04 (t, J=5.95 Hz, 1 H) 8.07 (s,
1 H) 8.01
(d, J=7.93 Hz, 1 H) 7.85 (s, 1 H) 7.56 (t, J=7.78 Hz, 1 H) 7.41 (d, J=7.63 Hz,
1 H) 7.21 - 7.35
(m, 8 H) 7.01 - 7. 11 (m, 2 H) 6.96 (d, J=7.3 2, 2.14 Hz, 2 H) 5.5 2 (s, 2 H)
5.3 5 (s, 2 H) 4.45
(d, J=5.80 Hz, 2 H). MS (ESI+) m/z 500.2 (M+H)+.
Example 192
5-[ 1-benzyl-5-(1-methyl-1 H-indol-5-yl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-3-
amine
The title compound was prepared as a TFA salt according to the procedure
outlined in
Example 173 substituting 1-methyl-lH-indol-5-ylboronic acid for 4-
methoxyphenylboronic
acid. 'H NMR (500 MHz, DMSO-d6) 6 ppm 11.35 (s, 1 H) 8.14 (s, 1 H) 7.54 (d,
J=8.54 Hz,
1 H) 7.50 (d, J=1.53 Hz, 1 H) 7.42 (d, J=3.05 Hz, 1 H) 7.24 - 7.33 (m, 3 H)
6.97 - 7.05 (m, 5
H) 6.44 (d, J=2.75 Hz, 1 H) 5.46 (s, 2 H) 5.33 (s, 2 H) 3.83 (s, 3 H). MS
(ESI+) m/z 420.1
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(M+H)+.
Example 193
5-[ 1-benzyl-5-(3-methoxyphenyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example
173
substituting 3-methoxyphenylboronic acid for 4-methoxyphenylboronic acid. 'H
NMR (500
MHz, DMSO-d6) 8 ppm 11.40 (s, 1 H) 8.08 (s, 1 H) 7.34 - 7.40 (m, 1 H) 7.24 -
7.32 (m, 3 H)
7.03 - 7.11 (m, 3 H) 6.98 - 7.02 (m, 2 H) 6.80 - 6.85 (m, 2 H) 5.49 (s, 2 H)
5.35 (s, 2 H) 3.66
(s, 3 H). MS (ESI+) m/z 397.1 (M+H)+.
Example 194
5-[1-benzyl-5-(3 -morpholin-4-ylphenyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-3-
amine
A vial under argon containing Example 125B (35 mg, 0.09 mmol), 3-
morpholinophenylboronic acid (21 mg, 0.09 mmol), PdC1z(dppf)-dichloromethane
(7 mg,
0.009 mmol) and potassium carbonate (24 mg, 0.18 mmol) in DME (1 mL) and water
(0.1
mL) was capped and heated at 80 C in a heater shaker for 3 days. The solvent
was
evaporated under reduced pressure, and the product was purified by reverse-
phase HPLC
using an acetonitrile/water 0.1 % TFA gradient elution method to afford the
title compound as
a TFA salt. 'H NMR (500 MHz, DMSO-d6) 6 ppm 11.52 (s, 1 H) 8.14 (s, 1 H) 7.26 -
7.34
(m, 4 H) 6.98 - 7.12 (m, 5 H) 6.67 - 6.75 (m, 2 H) 5.47 (s, 2 H) 3.57 - 3.73
(m, 4 H) 2.91 -
3.03 (m, 4 H). MS (ESI+) m/z 452.2 (M+H)+.
Example 195
5 - [3 -(1, 3 -dihydro-2H-isoindol-2-ylcarbonyl)isoxazol-5 -yl] -1 H-indazole
The title compound was prepared according to the procedure outlined in Example
81 B
substituting isoindoline for piperidine. 'H NMR (300 MHz, DMSO-d6) 8 ppm 13.38
(s, 1 H)
8.43 (s, 1 H) 8.25 (s, 1 H) 7.93 (d, J=8.82, 1.36 Hz, 1 H) 7.71 (d, J=8.48 Hz,
1 H) 7.30 - 7.47
(m, 5 H) 5.18 (s, 2 H) 4.92 (s, 2 H). MS (ESI+) m/z 331.0 (M+H)+.
Example 196
5- { 3 - [ (4-methyl-2-phenylpiperazin-1-yl)carbonyl] isoxazol-5 -yl} -1 H-
indazole
The title compound was prepared according to the procedure outlined in Example
81 B
substituting 1-methyl-3-phenylpiperazine for piperidine. 'H NMR (300 MHz, DMSO-
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d6) 6 ppm 13.12 (s, 1 H) 8.28 - 8.36 (m, 1 H) 8.18 (s, 1 H) 7.83 (d, J=8.79,
1.46 Hz, 1 H) 7.67
(d, J=8.79 Hz, 1 H) 7.48 (d, J=7.69 Hz, 2 H) 7.30 - 7.40 (m, 2 H) 7.21 - 7.29
(m, 1 H) 7.14 (s,
1H)5.56-5.73(m,J=5.86Hz,1H)3.99-4.19(m,J=8.42Hz,1H)3.38-3.47(m,1H)
3.05 - 3.21 (m, J=7.69 Hz, 1 H) 2.80 (d, J=11.72 Hz, 1 H) 2.41 (d, J=12.08,
4.39 Hz, 1 H)
2.24 (s, 3 H) 2.02 - 2.16 (m, 1 H). MS (ESI+) m/z 388.1 (M+H)+.
Example 197
1- { [ 1-benzyl-4-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-5-yl]carbonyl}piperidin-
4-amine
Example 197A
tert-Butyl 1-(1-benzyl-4-(1 H-indazol-5-yl)-1 H-1,2,3-triazole-5-
carbonyl)piperidin-4-
ylcarbamate
The title compound was prepared according to the procedure outlined in Example
81 B
substituting Example 149C for Example 81B and 4-Boc-aminopiperidine for
piperidine. MS
(ESI+) m/z 502.3 (M+H)+.
Example 197B
1- {[ 1-b enzyl-4-(1 H-indazol-5 -yl)-1 H-1,2,3 -triazol-5 -yl] carbonyl}pip
eridin-4-amine
Example 197A (101 mg, 0.201 mmol) was dissolved in 4 M hydrochloric acid in
dioxane (4 mL) and methanol (1 mL) and stirred at ambient temperature for 2
hours. The
solvents were removed under reduced pressure to afford the title compound as
an HC1 salt.
iH NMR (300 MHz, DMSO-d6) 6 ppm 8.18 (s, 1 H) 7.92 - 8.08 (m, J=1.36 Hz, 3 H)
7.53 -
7.70(m,2H)7.24-7.47(m,5H)5.40-5.73(m,J=3.39Hz,2H)4.34-4.63(m,1H)3.44-
3.53(m,J=3.39Hz,1H)2.95-3.17(m,2H)2.76-2.94(m,J=11.02,11.02Hz,1H)1.87-
2.03(m,J=11.87Hz,1H)1.30-1.52(m,J=10.85Hz,2H)0.66-0.91(m,J=10.17Hz,1H).
MS (ESI+) m/z 402.2 (M+H)+.
Example 198
N-[5-(1-benzyl-5-phenyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]benzamide
Example 198A
tert-butyl3 -amino-5-(1-benzyl-5-phenyl-1 H-1,2,3-triazol-4-yl)-1 H-indazole-l-
carboxylate
Example 102B (200 mg, 0.55 mmol) and N,N-dimethylpyridin-4-amine (5 mg, 0.04
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mmol) were dissolved in methylene chloride. The mixture was stirred at room
temperature
while a solution of di-tert-butyl dicarbonate (120 mg, 0.55 mmol) in 5 mL
methylene chloride
was added dropwise. The reaction mixture was allowed to stir at room
temperature for 8
hours, was concentrated under vacuum, dissolved in methylene chloride (10 mL)
and washed
with dilute aqueous HCl solution (1 N, 10 mL) and saturated NaHCO3 aqueous
solution (10
mL). The organic layer was concentrated and purified by reverse phase-HPLC
(CH3CN/ H20
/NHqOAc) to afford the title compound. 'H NMR (300 MHz, DMSO-d6) 6 ppm 8.29
(s, 2
H), 7.43 - 7.59 (m, 3 H), 7.23 - 7.38 (m, 6 H), 6.98 (d, J=7.17, 2.39 Hz, 2
H), 6.38 (s, 2 H),
5.52 (s, 2 H), 1.55 (s, 9 H). MS (ESI+) m/z 467 (M+H)+.
Example 198B
N-[5-(1-benzyl-5-phenyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]benzamide
Example 198A (37.5 mg, 0.08 mmol) and pyridine ( 12.7 mg, 0.16 mmol) were
dissolved in methylene chloride (2 mL). The mixture was allowed to stir at
room temperature.
Benzoyl chloride (14 mg, 0.1 mmol) was added to the mixture. The reaction
mixture was
allowed to stir at room temperature overnight, concentrated under vacuum and
purified by
reverse phase-HPLC (CH3CN/ H20 /NH4OAc) to afford the Boc-protected precursor.
The
precursor was treated with 1:1 TFA / dichloromethane (2 mL) for 1 hour and was
concentrated under vacuum to afford the title compound as a TFA salt. 'H NMR
(300 MHz,
DMSO-d6) 6 ppm 12.84 (s, 1 H), 10.70 (s, 1 H), 8.01 (d, J=6.99 Hz, 2 H), 7.87
(s, 1 H), 7.50 -
7.69 (m, 3 H), 7.36 - 7.48 (m, 5 H), 7.18 - 7.35 (m, 5 H), 6.92 - 7.03 (m, 2
H), 5.48 (s, 2 H).
MS (ESI+) m/z 471 (M+H)+.
Example 199
N-[5-(1-benzyl-5-phenyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-
yl]benzenesulfonamide
The title compound was prepared according to the procedure outlined in Example
198B substituting benzenesulfonyl chloride for benzoyl chloride. 'H NMR (300
MHz,
DMSO-d6) 6 ppm 12.69 (s, 1 H), 10.61 (s, 1 H), 7.99 (s, 1 H), 7.70 - 7.76 (m,
2 H), 7.45 -
7.62 (m, 6 H), 7.24 - 7.36 (m, 7 H), 6.99 (d, J=6.99, 2.21 Hz, 2 H), 5.50 (s,
2 H). MS (ESI+)
m/z 507 (M+H)+.
Example 200
N-[5-(1-benzyl-5-phenyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N'-(4-
methoxyphenyl)urea
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Example 198A (25 mg, 0.54 mmol) was dissolved in dioxane (2 mL) and 1-
isocyanato-4-methoxybenzene(24 mg, 0.16 mmol) was added to the solution. The
reaction
mixture was stirred at 80 C for 12 hours, concentrated, and purified by
reverse phase-HPLC
(CH3CN/ H20 /NHqOAc) to afford the Boc-protected precursor. The precursor was
treated
with 1:1 TFA / dichloromethane (2 mL) for 1 hour and concentrated under vacuum
to afford
the title compound as a TFA salt. 'H NMR (300 MHz, DMSO-d6) 8 ppm 12.54 (s, 1
H),
9.51 (s, 1 H), 9.42 (s, 1 H), 8.28 (s, 1 H), 7.45 - 7.51 (m, 3 H), 7.36 - 7.42
(m, 2 H), 7.24 -
7.35 (m, 7 H), 6.98 (d, J=7.17, 2.39 Hz, 2 H), 6.87 - 6.94 (m, 2 H), 5.50 (s,
2 H), 3.74 (s, 3
H). MS (ESI+) m/z 516 (M+H)+.
Example 201
N-[5-(1-benzyl-5-phenyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]butanamide
The title compound was prepared as a TFA salt according to the procedure
outlined in
Example 198B substituting butyryl chloride for benzoyl chloride. 'H NMR (300
MHz,
DMSO-d6) 8 ppm 10.77 - 10.84 (m, 1 H), 8.07 (s, 1 H), 7.97 (d, J=8.82 Hz, 1
H), 7.64 (d,
J=8.82, 1.47 Hz, 1 H), 7.43 - 7.57 (m, 3 H), 7.22 - 7.38 (m, 5 H), 6.91 - 7.06
(m, 2 H), 5.50
(s, 2 H), 2.33 (t, J=7.17 Hz, 2 H), 1.54 - 1.60 (m, 2 H), 0.91 (t, J=7.35 Hz,
3 H). MS (ESI+)
m/z 437 (M+H)+.
Example 202
N-[5-(1-benzyl-5-phenyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-
methylpropanamide
The title compound was prepared according to the procedure outlined in Example
198B substituting isobutyryl chloride for benzoyl chloride. 'H NMR (300 MHz,
DMSO-
d6) 6 ppm 12.66 (s, 1 H), 10.12 (s, 1 H), 7.80 (s, 1 H), 7.42 - 7.55 (m, 4 H),
7.33 - 7.39 (m, 1
H), 7.22 - 7.32 (m, 5 H), 6.97 (d, J=6.99, 2.57 Hz, 2 H), 5.48 (s, 1 H), 2.59 -
2.69 (m, 1 H),
1.07 (d, J=6.99 Hz, 6 H). MS (ESI+) m/z 437 (M+H)+.
Example 203
N-[5-(1-benzyl-5-phenyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-
yl]cyclopropanecarboxamide
The title compound was prepared according to the procedure outlined in Example
198B substituting cyclopropanecarbonyl chloride for benzoyl chloride. 'H NMR
(300 MHz,
DMSO-d6) 6 ppm 10.45 - 10.64 (s, 1 H), 7.91 (s, 1 H), 7.43 - 7.55 (m, 3 H),
7.31 - 7.43 (m, 2
H), 7.23 - 7.30 (m, 5 H), 6.97 (d, J=7.17, 2.39 Hz, 2 H), 5.48 (s, 2 H), 1.77 -
1.91 (m, 1 H),
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0.69 - 0.87 (m, 4 H). MS (ESI+) m/z 435 (M+H)+.
Example 204
N-[ 1-benzoyl-5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-
yl]benzamide
Example 89B (33mg, 0.1 mmol) was dissolved in tetrahydrofuran (0.6 mL) in a
CEM microwave tube. Benzoyl chloride (28 mg, 0.2 mmol) was added and the
mixture was
heated at 120 C for 15 minutes in the CEM-Discover microwave. The reaction
mixture was
cooled to room temperature, and concentrated. The residue was purified by
reverse phase-
HPLC (CH3CN/ H20 /NHqOAc) to afford the title compound. 'H NMR (300 MHz, DMSO-
d6) 6 ppm 11.35 (s, 1 H), 8.55 (d, J=8.82 Hz, 1 H), 8.36 (s, 1 H), 8.17 (d,
J=8.64, 1.65 Hz, 1
H), 8.06 (d, J=7.54, 2.39 Hz, 4 H), 7.51 - 7.72 (m, 6 H), 7.26 - 7.45 (m, 5
H), 5.71 (s, 2 H),
1.76 - 1.87 (m, 1 H), 1.11 (d, J=6.62 Hz, 2 H), 0.44 (d, J=4.41 Hz, 2 H). MS
(ESI+) m/z 539
(M+H)+.
Example 205
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-3-
fluorobenzamide
Example 205A
tert-Butyl 3-amino-5 -(1-b enzyl-5 -cyclopropyl-1 H-1, 2, 3-triazol-4-yl)-1 H-
indazo le-1-
carboxylate
The title compound was prepared according to the procedure outlined in Example
198A substituting Example 89B for Example 102A. 'H NMR (300 MHz, DMSO-d6) 8
ppm
8.26 (s, 1 H), 7.96 - 8.07 (m, 1 H), 7.86 - 7.95 (m, 1 H), 7.35 - 7.46 (m, 3
H), 7.28 - 7.35 (m,
2 H), 6.35 - 6.47 (m, 2 H), 5.70 (s, 2 H), 1.72 - 1.84 (m, 1 H), 1.60 (s, 9
H), 0.99 - 1.10 (d,
J=1.84 Hz, 2 H), 0.38 (d, J=3.68 Hz, 2 H). MS (ESI+) m/z 431 (M+H)+.
Example 205B
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-3-
fluorobenzamide
Example 205A (25 mg, 0.058 mmol) and pyridine (9.2 mg, 0.116 mmol) were
dissolved in methylene chloride (1 mL). The mixture was allowed to stir at
room temperature,
and 3-fluorobenzoyl chloride (11.1 mg, 0.58 mmol) was added to the mixture.
The reaction
mixture was allowed to stir at room temperature overnight, and was
concentrated and purified
by reverse phase-HPLC (CH3CN/ H20 /NH4OAc) to afford the Boc-protected
precursor. The
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precursor was treated with 1:1 TFA / dichloromethane (2 mL) for 1 hour and
concentrated
under vacuum to afford the title compound as a TFA salt. 'H NMR (300 MHz, DMSO-
d6) 6 ppm 10.58 (s, 1 H), 7.75 (s, 1 H), 7.51 - 7.60 (m, 1 H), 7.46 (d,
J=8.82, 1.47 Hz, 1 H),
7.15 - 7.28 (m, 2 H), 7.10 (d, J=2.21 Hz, 1 H), 6.88 - 7.05 (m, 6 H), 5.31 (s,
2 H), 1.35 - 1.47
(m, J=5.15 Hz, 1 H), 0.68 (d, J=8.27, 1.65 Hz, 2 H),0.03 (d, J=5.52 Hz, 2 H).
MS (ESI+) m/z
453 (M+H)+.
Example 206
N-[5-(1-benzyl-5 -cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3 -
yl]benzamide
The title compound was prepared according to the procedure outlined in Example
205B substituting benzoyl chloride for 3-fluorobenzoyl chloride. 'H NMR (300
MHz,
DMSO-d6) b ppm 12.89 (s, 1 H), 10.83 (s, 1 H), 8.02 - 8.15 (m, 3 H), 7.83 (d,
J=8.82, 1.47
Hz, 1 H), 7.50 - 7.66 (m, 4 H), 7.24 - 7.43 (m, 5 H), 5.67 (s, 2 H), 1.77 (m,
1 H), 0.99 - 1.10
(m, 2 H), 0.39 (m, 2 H). MS (ESI+) m/z 435 (M+H)+.
Example 207
N-benzyl-5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-amine
To a solution of Example 89B (18.3 mg, 0.05 mmol) in dimethylformamide (2 mL)
was added acetic acid (15 mg, 0.25 mmol) and benzaldehyde (6.4 mg, 0.06 mmol).
The
reaction mixture was stirred at room temperature overnight. Sodium
triacetoxyborohydride
(NaBH(OAc)3, 32 mg, 0.15 mmol) was added to the mixture. The reaction was
stirred at
room temperature for 3 hours, concentrated and purified by reverse phase-HPLC
(CH3CN/
H20 /NH4OAc) to afford the title compound. 'H NMR (300 MHz, DMSO-d6) 6 ppm
13.09
(s, 1 H), 9.24 (s, 1 H), 8.02 - 8.10 (m, 3 H), 7.84 - 7.90 (m, 1 H), 7.49 -
7.67 (m, 4 H), 7.25 -
7.45 (m, 5 H), 5.70 (s, 2 H), 3.30 (s, 2 H), 1.88 - 1.95 (m, 1 H), 1.01 - 1.09
(m, 2 H), 0.43 (d,
J=4.04 Hz, 2 H). MS (ESI+) m/z 421 (M+H)+.
Example 208
N-[(1R)-1-benzyl-2-hydroxyethyl]-5-(IH-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting (R)-(+)-2-amino-3-phenyl-l-propanol (37 mg, 0.245 mmol) for
piperidine. 'H
NMR (300 MHz, DMSO-d6) 6 ppm 13.36 (s, 1 H) 8.46 (d, J=8.82 Hz, 1 H) 8.37 (s,
1 H) 8.22
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(s, 1 H) 7.87 (dd, J=8.82, 1.36 Hz, 1 H) 7.69 (d, J=8.82 Hz, 1 H) 7.12 - 7.35
(m, 6 H) 4.89 (t,
J=5.59Hz,1H)4.13-4.25(m,1H)3.40-3.58(m,2H)2.90-2.99(m,1H)2.74-2.87(m,
1 H). MS (ESI+) m/z 363.0 (M+H)+.
Example 209
5-(1-benzyl-1 H-pyrazol-4-yl)-1 H-indazole
Example 209A
1-(5-Bromo-1 H-indazol-1-yl)ethanone
4-Bromo-2-methylaniline (25.0 g, 134 mmol) was dissolved in chloroform (250
mL),
and the mixture was cooled to 5 C. Acetic anhydride (35 mL, 343 mmol) was
added
dropwise, and the mixture was allowed to warm to ambient temperature.
Potassium acetate
(3.97 g, 40.4 mmol) and isoamylnitrite (35 mL, 262 mmol) were added, and the
mixture was
heated at 70 C overnight. The mixture was neutralized with saturated sodium
bicarbonate
and extracted with methylene chloride. The combined organic layers were
concentrated
under reduced pressure, and the resulting residue was triturated with methanol
to afford the
title compound. 'H NMR (300 MHz, DMSO-d6) 8 ppm 8.45 (s, 1 H) 8.26 (d, J=8.82
Hz, 1
H) 8.17 (d, J=1.70 Hz, 1 H) 7.77 (dd, J=8.82, 2.03 Hz, 1 H) 2.72 (s, 3 H).
Example 209B
5-(1-benzyl-1 H-pyrazol-4-yl)-1 H-indazole
Example 209A (425 mg, 1.78 mmol), 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-pyrazole (508 mg, 1.79 mmol),
dichlorobis(triphenylphosphine)palladium(II) (133 mg, 0.189 mmol), and
potassium
carbonate (742 mg, 5.37 mmol) were combined in a sealed vial with dioxane (10
mL) and
water (1 mL) under and inert atmosphere of nitrogen, and the mixture was
heated to 110 C
overnight. The mixture was diluted with methylene chloride and washed with
water. The
organic layer was absorbed on silica gel and purified by silica gel
chromatography eluting
with a gradient of 45-90% ethyl acetate in hexanes to afford the title
compound. 'H NMR
(300 MHz, DMSO-d6) 8 ppm 13.00 (s, 1 H) 8.25 (s, 1 H) 8.02 (s, 1 H) 7.92 (s, 2
H) 7.55 -
7.61 (m, 1 H) 7.48 - 7.54 (m, 1 H) 7.25 - 7.40 (m, 5 H) 5.35 (s, 2 H). MS
(ESI+) m/z 274.9
(M+H)+.
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Example 210
N-[(1 R)-3-hydroxy-l-phenylpropyl]-5-(3-methyl-1 H-indazol-5-yl)isoxazole-3-
carboxamide
Example 210A
tert-Butyl 5-bromo-3-methyl-lH-indazole-l-carboxylate
5-Bromo-3-methyl-lH-indazole (5.11 g, 24.2 mmol) and catalytic
dimethylaminopyridine (-30 mg) were dissolved in methylene chloride (100 mL).
Di-tert-
butyl dicarbonate (5.9 g, 27.0 mmol) was added, and the mixture was stirred at
ambient
temperature for 3 hours. The solvent was removed under reduced pressure, and
the resulting
residue was diluted with ethyl acetate and washed with 1 N sodium hydroxide
(twice), 0.1 N
hydrochloric acid, and brine. The organic layer was dried over sodium sulfate
and filtered.
The filtrate was concentrated under reduced pressure to afford the title
compound. MS
(ESI+) m/z 210.8 (M-Boe)+.
Example 210B
tert-Butyl3-methyl-5-((trimethylsilyl)ethynyl)-1 H-indazole-l-carboxylate
Example 210A (7.55 g, 24.3 mmol), dichlorobis(triphenylphosphine)palladium(II)
(870 mg, 1.24 mmol), and copper(I) iodide (250 mg, 1.31 mmol) were combined in
triethylamine (60 mL) under an inert atmosphere of nitrogen. Trimethylsilyl
acetylene (4.0
mL, 28.9 mmol) was added, and the mixture was heated at 60 C overnight. The
mixture was
diluted with methylene chloride and washed with 0.1 M hydrochloric acid. The
organic layer
was absorbed onto silica gel and purified by silica gel chromatography eluting
with a gradient
of 10-40% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z
228.9 (M-
Boc)+.
Example 210C
5-Ethynyl-3-methyl-1 H-indazole
Example 210B (7.26 g, 22.1 mmol) was dissolved in methanol (170 mL). A
solution
of 1 N potassium hydroxide (45 mL) was added, and the mixture was stirred at
ambient
temperature overnight. The solvent was removed under reduced pressure, and the
resulting
residue was diluted with ethyl acetate and washed with water and brine. The
organic layer
was dried over sodium sulfate and concentrated under reduced pressure to
afford the title
compound. MS (ESI+) m/z 157.1 (M+H)+.
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Example 210D
ethyl 5-(3-methyl-IH-indazol-5-yl)isoxazole-3-carboxylate
Example 210C (411 mg, 2.63 mmol) was dissolved in toluene (15 mL) and
triethylamine (478 uL) and warmed to 90 C. Ethyl chlorooximidoacetate (480
mg, 3.17
mmol) dissolved in toluene (15 mL) was added slowly dropwise over 30 minutes.
Following
the addition, the mixture was diluted with ethyl acetate and washed with 1 N
hydrochloric
acid. The organic layer was concentrated under reduced pressure and the
resulting residue
was triturated with methanol to afford the title compound. MS (ESI+) m/z 271.9
(M+H)+.
Example 210E
5-(3-methyl-lH-indazol-5-yl)isoxazole-3-carboxylic acid
Example 210D (325 mg, 1.20 mmol) was dissolved in tetrahydrofuran (10 mL),
methanol (1 mL), and water (1 mL) and potassium hydroxide (150 mg, 2.67 mmol)
was
added. The mixture was stirred at ambient temperature for 3 hours. The mixture
was diluted
with ethyl acetate and washed with 1 N hydrochloric acid. The product
precipitated in the
separatory funnel and was filtered to afford the title compound. MS (ESI+) m/z
243.9
(M+H)+.
Example 210F
N-[(IR)-3-hydroxy-l-phenylpropyl]-5-(3-methyl-IH-indazol-5-yl)isoxazole-3-
carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting Example 210E for Example 81A and (R)-3-amino-3-phenylpropan-l-ol
for
piperidine. 'H NMR (300 MHz, DMSO-d6) 8 ppm 12.93 (s, 1 H) 8.45 (d, J=8.82 Hz,
1 H)
8.33 (s, 1 H) 7.84 (d, J=8.82, 1.70 Hz, 1 H) 7.59 (d, J=9.16 Hz, 1 H) 7.21 -
7.29 (m, 5 H) 7.13
-7.21(m,1H)4.89(t,J=5.59Hz,1H)4.10-4.26(m,1H)3.42-3.56(m,2H)2.88-3.00
(m, 1 H) 2.75 - 2.87 (m, 1 H) 2.55 (s, 3 H). MS (ESI+) m/z 377.1 (M+H)+.
Example 211
3-[4-(3-amino-1 H-indazol-5-yl)-1-benzyl-1 H- 1,2,3 -triazol-5-yl]phenol
A vial under argon containing Example 125B (35 mg, 0.09 mmol), 3-
hydroxyphenylboronic acid (12 mg, 0.09 mmol), PdClz(dppf)=dichloromethane (7
mg, 0.009
mmol) and potassium carbonate (24 mg, 0.18 mmol) in DME (1 mL) and water (0.1
mL) was
capped and heated at 80 C in a heater shaker for 3 days. The solvent was
evaporated and the
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product was purified by reverse-phase HPLC using an acetonitrile/water 0.1 %
TFA gradient
elution method to afford the title compound. 'H NMR (500 MHz, DMSO-d6) 6 ppm
11.40 (s,
1H)9.68(s,1H)8.09(s,1H)7.24-7.35(m,5H)6.98-7.13(m,3H)6.88(d,J=8.09,1.98
Hz, 1 H) 6.73 (s, 1 H) 6.60 - 6.66 (m, 1 H) 5.47 (s, 2 H) 5.35 (s, 2 H). MS
(ESI+) m/z 383.1
(M+H)+.
Example 212
3-[4-(3-amino-1 H-indazol-5-yl)-1-benzyl-1 H- 1,2,3 -triazol-5-yl]benzamide
The title compound was prepared according to the procedure outlined in Example
173
substituting 3-carbamoylphenylboronic acid for 4-methoxyphenylboronic acid. 'H
NMR
(500 MHz, DMSO-d6) 6 ppm 11.41 (s, 1 H) 8.07 (s, 1 H) 7.97 - 8.03 (m, 2 H)
7.83 - 7.87 (m,
1 H) 7.53 (t, J=7.78 Hz, 1 H) 7.45 (s, 1 H) 7.38 (d, J=7.63 Hz, 1 H) 7.23 -
7.30 (m, 3 H) 7.00
- 7.10 (m, 2 H) 6.96 (d, J=7.48, 1.98 Hz, 2 H) 5.51 (s, 2 H) 5.35 (s, 2 H). MS
(ESI+) m/z
410.1 (M+H)+.
Example 213
5- { 1-benzyl-5-[4-(methylsulfonyl)phenyl]-1 H-1,2,3-triazol-4-yl}-1 H-indazol-
3-amine
The title compound was prepared according to the procedure outlined in Example
173
substituting 4-(methylsulfonyl)phenylboronic acid for 4-methoxyphenylboronic
acid. 'H
NMR (500 MHz, DMSO-d6) 6 ppm 11.44 (s, 1 H) 7.94 - 8.01 (m, 3 H) 7.58 (d,
J=8.54 Hz, 2
H) 7.22 - 7.30 (m, 3 H) 7.04 - 7.13 (m, 2 H) 6.98 (d, J=7.48, 1.98 Hz, 2 H)
5.56 (s, 2 H) 5.37
(s, 2 H) 3.28 (s, 3 H). MS (ESI+) m/z 445.2 (M+H)+.
Example 214
N-[5-(1-benzyl-5-cyclopropyl-lH-1,2,3-triazol-4-yl)-IH-indazol-3-yl]-2-
chlorobenzamide
The title compound was prepared according to the procedure outlined in Example
205B substituting 2-chlorobenzoyl chloride for 3-fluorobenzoyl chloride. 'H
NMR (300
MHz, DMSO-d6) 6 ppm 10.94 (s, 1 H), 8.24 (s, 1 H), 7.85 (d, J=8.82, 1.47 Hz, 1
H), 7.65 (d,
J=6.99, 1.84 Hz, 1 H), 7.43 - 7.61 (m, 4 H), 7.26 - 7.42 (m, 5 H), 5.68 (s, 2
H), 1.71 - 1.83
(m, 1 H), 1.04 - 1.12 (m, 2 H), 0.37 - 0.45 (m, 2 H). MS (ESI+) m/z 469
(M+H)+.
Example 215
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-4-
chlorobenzamide
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The title compound was prepared according to the procedure outlined in Example
205B substituting 4-chlorobenzoyl chloride for 3-fluorobenzoyl chloride. 'H
NMR (300
MHz, DMSO-d6) 8 ppm 10.53 (s, 1 H), 7.65 - 7.71 (m, 3 H), 7.42 (d, J=8.82,
1.47 Hz, 1 H),
7.18-7.24(m,2H),7.12-7.18(m,1H),6.93-7.02(m,3H),6.83-6.92(m,3H),5.27(s,
2 H), 1.30 - 1.44 (m, 1 H), 0.59 - 0.67 (m, 2 H), -0.07 - 0.04 (m, 2 H). MS
(ESI+) m/z 469
(M+H)+.
Example 216
N-[5-(1-benzyl-5 -cyclopropyl-1 H-1,2, 3-triazol-4-yl)-1 H-indazol-3-yl]
ethanesulfonamide
The title compound was prepared according to the procedure outlined in Example
205B substituting ethanesulfonyl chloride for 3-fluorobenzoyl chloride. 'H NMR
(300 MHz,
DMSO-d6) b ppm 10.19 (s, 1 H), 8.15 (s, 1 H), 7.82 (d, J=8.64, 1.65 Hz, 1 H),
7.53 (d, J=8.82
Hz, 1 H), 7.35 - 7.45 (m, 3 H), 7.27 - 7.35 (m, 2 H), 5.69 (s, 2 H), 3.30 (q,
J=7.35 Hz, 2 H),
1.74-1.87(m,1H),1.27-1.36(m,3H),1.02-1.12(m,2H),0.34-0.44(m,2H). MS
(ESI+) m/z 423 (M+H)+.
Example 217
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-
yl]benzenesulfonamide
The title compound was prepared according to the procedure outlined in Example
205B substituting benzenesulfonyl chloride for 3-fluorobenzoyl chloride. 'H
NMR (300
MHz, DMSO-d6) 8 ppm 12.75 (s, 1 H), 10.69 (s, 1 H), 8.02 (s, 1 H), 7.71 - 7.83
(m, 3 H),
7.43-7.60(m,4H),7.34-7.43(m,3H),7.27-7.34(m,2H),5.69(s,2H),1.69-1.83(m,
1 H), 0.99 - 1.11 (m, 2 H), 0.31 - 0.45 (m, 2 H). MS (ESI+) m/z 471 (M+H)+.
Example 218
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-
chlorobenzenesulfonamide
The title compound was prepared according to the procedure outlined in Example
205B substituting 2-chlorobenzene-l-sulfonyl chloride for 3-fluorobenzoyl
chloride. 'H
NMR (300 MHz, DMSO-d6) 6 ppm 12.36 (s, 1 H), 10.60 (s, 1 H), 7.67 (s, 1 H),
7.62 (d,
J=7.91, 1.65 Hz, 1 H), 7.40 (d, J=8.82, 1.47 Hz, 1 H), 7.14 - 7.27 (m, 2 H),
7.00 - 7.12 (m, 4
H), 6.96 - 7.00 (m, 1 H), 6.90 - 6.95 (m, 2 H), 5.31 (s, 2 H), 1.29 - 1.44 (m,
1 H), 0.61 - 0.74
(m, 2 H), -0.05 - 0.05 (m, 2 H). MS (ESI+) m/z 505 (M+H)+.
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Example 219
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-3-
chlorobenzenesulfonamide
The title compound was prepared as an HCI salt according to the procedure
outlined
in Example 205B substituting 3-chlorobenzene-l-sulfonyl chloride for 3-
fluorobenzoyl
chloride. 'H NMR (300 MHz, DMSO-d6) 8 ppm 12.84 (s, 1 H), 10.86 (s, 1 H), 8.00
(s, 1 H),
7.82 (s, 1 H), 7.72 (d, J=7.72 Hz, 1 H), 7.64 (d, J=1.84 Hz, 1 H), 7.57 (d,
J=7.72 Hz, 1 H),
7.50 (d, J=8.82 Hz, 1 H), 7.34 - 7.45 (m, 3 H), 7.28 - 7.34 (m, 2 H), 5.69 (s,
2 H), 1.71 - 1.83
(m, 1 H), 1.06 (m, 2 H), 0.37 (m, 2 H). MS (ESI+) m/z 505 (M+H)+.
Example 220
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-4-
chlorobenzenesulfonamide
The title compound was prepared as an HCI salt according to the procedure
outlined
in Example 205B substituting 4-chlorobenzene-l-sulfonyl chloride for 3-
fluorobenzoyl
chloride. 'H NMR (300 MHz, DMSO-d6) 6 ppm 12.80 (s, 1 H), 10.79 (s, 1 H), 8.00
(s, 1 H),
7.73-7.83(m,3H),7.56-7.64(m,2H),7.49(d,J=8.82Hz,1H),7.34-7.45(m,3H),7.28
-7.34(m,2H),5.69(s,2H),1.71-1.86(m,1H),0.99-1.12(m,2H),0.31-0.43(m,2H).
MS (ESI+) m/z 505 (M+H)+.
Example 221
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2,5-
dimethylfuran-3-
sulfonamide
The title compound was prepared as an HCI salt according to the procedure
outlined
in Example 205B substituting 2,5-dimethylfuran-3-sulfonyl chloride for 3-
fluorobenzoyl
chloride. 'H NMR (300 MHz, DMSO-d6) 6 ppm 12.82 (s, 1 H), 10.48 (s, 1 H), 8.00
(s, 1 H),
7.78 (d, J=8.64, 1.65 Hz, 1 H), 7.50 (d, J=9.19 Hz, 1 H), 7.34 - 7.45 (m, 3
H), 7.28 - 7.33 (m,
2 H), 6.20 (s, 1 H), 5.69 (s, 2 H), 2.11 (s, 6 H), 1.71 - 1.84 (m, 1 H), 1.01 -
l.l 11 (m2 H),
0.32 - 0.41 (m, 2 H). MS (ESI+) m/z 489 (M+H)+.
Example 222
5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-N-(2-chlorobenzyl)-1 H-
indazol-3-amine
The title compound was prepared according to the procedure outlined in Example
207
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substituting 2-chlorobenzaldehyde for benzaldehyde. 'H NMR (300 MHz, DMSO-d6)
8 ppm
11.55 (s, 1 H), 8.20 (s, 1 H), 7.69 (d, J=8.46, 1.47 Hz, 1 H), 7.49 (d, J=8.82
Hz, 1 H), 7.34 -
7.46(m,4H),7.23-7.33(m,5H),5.69(s,2H),4.56(s,2H),1.72-1.83(m,1H),0.99-
1.09 (m, 2 H), 0.35 - 0.42 (m, 2 H). MS (ESI+) m/z 455 (M+H)+.
Example 223
5 -(1-benzyl-5 -cyclopropyl-1 H-1,2, 3 -triazol-4-yl)-N-(3 -chlorobenzyl)-1 H-
indazol-3 -amine
The title compound was prepared according to the procedure outlined in Example
207
substituting 3-chlorobenzaldehyde for benzaldehyde. 'H NMR (300 MHz, DMSO-d6)
b ppm
11.53 (s, 1 H), 8.15 (s, 1 H), 7.59 - 7.77 (m, 1 H), 7.25 - 7.48 (m, 10 H),
5.68 (s, 2 H), 4.49 (s,
2 H), 1.71 - 1.80 (m, 1 H), 1.04 (s, 2 H), 0.38 (s, 2 H).
Example 224
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-3-
chlorobenzamide
The title compound was prepared according to the procedure outlined in Example
205B substituting 3-chlorobenzoyl chloride for 3-fluorobenzoyl chloride. 'H
NMR (300
MHz, DMSO-d6) 8 ppm 10.99 (s, 1 H), 8.12 (s, 2 H), 8.03 (d, J=7.72 Hz, 1 H),
7.83 (d,
J=8.46 Hz, 1 H), 7.68 (s, 1 H), 7.58 (t, J=8.09 Hz, 2 H), 7.33 - 7.44 (m, 3
H), 7.25 - 7.33 (m,
2 H), 5.68 (s, 2 H), 1.72 - 1.86 (m, 1 H), 0.99 - 1.12 (m, 2 H), 0.34 - 0.45
(m, 2 H). MS
(ESI+) m/z 470 (M+H)+.
Example 225
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-
furamide
The title compound was prepared according to the procedure outlined in Example
205B substituting furan-2-carbonyl chloride for 3-fluorobenzoyl chloride. 'H
NMR (300
MHz, DMSO-d6) 8 ppm 10.36 (s, 1 H), 7.71 (s, 1 H), 7.42 (d, J=8.82, 1.47 Hz, 1
H), 7.15 (d,
J=8.82 Hz, 1 H), 7.06 (d, J=3.31 Hz, 1 H), 6.93 - 7.03 (m, 3 H), 6.86 - 6.93
(m, 2 H), 6.31 (d,
J=3.49, 1.65 Hz, 1 H), 5.28 (s, 1 H), 1.31 - 1.45 (m, 1 H), 0.59 - 0.71 (m, 2
H), -0.05 - 0.05
(m, 2 H). MS (ESI+) m/z 425 (M+H)+.
Example 226
5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-N-ethyl-1 H-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example
207
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substituting acetaldehyde for benzaldehyde. 'H NMR (300 MHz, DMSO-d6) 6 ppm
8.56 (s,
1 H), 8.30 - 8.42 (m, 1 H), 7.90 - 8.17 (m, 2 H), 7.20 - 7.45 (m, 5 H), 5.70
(s, 2 H), 1.78 -
1.93 (m, 2 H), 1.67 (s, 1 H), 1.06 (m, 3 H), 0.95 (m, 2 H), 0.29 - 0.48 (m, 2
H). MS (ESI+)
m/z 359 (M+H)+.
Example 227
5 -(1-benzyl-5 -cyclopropyl-1 H-1,2, 3 -triazol-4-yl)-N-(4-chlorobenzyl)-1 H-
indazol-3 -amine
The title compound was prepared according to the procedure outlined in Example
207
substituting 4-chlorobenzaldehyde for benzaldehyde. 'H NMR (300 MHz, DMSO-d6)
b ppm
10.01 (s, 1 H), 9.25 (s, 1 H), 8.25 - 8.33 (m, 1 H), 8.09 (d, J=8.46 Hz, 1 H),
7.84 - 7.97 (m, 2
H),7.57-7.73(m,2H),7.26-7.51(m,6H),5.70(s,2H),1.71-1.84(m,1H),0.97-1.15
(m, 2 H), 0.36 - 0.47 (m, 2 H). MS (ESI+) m/z 455 (M+H)+.
Example 228
5-(1-benzyl-5-cyclopropyl-lH-1,2,3-triazol-4-yl)-N-(3-furylmethyl)-1H-indazol-
3-amine
The title compound was prepared according to the procedure outlined in Example
207
substituting furan-3-carbaldehyde for benzaldehyde. 'H NMR (300 MHz, DMSO-d6)
8 ppm
8.21 (s, 1 H), 7.90 (s, 1 H), 7.71 - 7.82 (m, 1 H), 7.55 - 7.68 (m, 2 H), 7.24
- 7.51 (m, 6 H),
5.68 (s, 2 H), 4.33 (s, 2 H), 1.67 - 1.85 (m, 1 H), 0.95 - 1.13 (m, 2 H), 0.30
- 0.42 (m, 2 H).
MS (ESI+) m/z 411 (M+H)+.
Example 229
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N'-[5-
methyl-2-
(trifluoromethyl)-3-furyl]urea
Example 205A (30 mg, 0.07 mmol) was dissolved in dioxane (2 mL) and 3-
isocyanato-5-methyl-2-(trifluoromethyl)furan (40 mg, 0.21 mmol) was added to
the solution.
The reaction mixture was stirred at 80 C for 12 hours, concentrated and
purified by reverse
phase-HPLC (CH3CN/ H20 /NH4OAc) to afford the Boc-protected precursor. The
precursor
was dissolved in methanol and treated with excess HC1 in dioxane (4 M, 0.5
mmol). The
reaction was allowed to stir for 5 hours and concentrated under vacuum to
afford the title
compound as an HC1 salt. 'H NMR (300 MHz, DMSO-d6) 6 ppm 12.73 (s, 1 H), 10.19
(s, 1
H), 8.40 (s, 1 H), 7.83 (d, J=8.82, 1.47 Hz, 1 H), 7.64 - 7.75 (m, 1 H), 7.49
(d, J=8.82 Hz, 1
H), 7.35 - 7.45 (m, 3 H), 7.27 - 7.35 (m, 2 H), 5.69 (s, 2 H), 2.33 (s, 3 H),
1.73 - 1.84 (m, 1
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H), 1.02 - 1.11 (m, 2 H), 0.35 - 0.43 (m, 2 H). MS (ESI+) m/z 522 (M+H)+.
Example 230
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-3-
furamide
The title compound was prepared as an HCI salt according to the procedure
outlined
in Example 205B substituting furan-3-carbonyl chloride for 3-fluorobenzoyl
chloride. iH
NMR (300 MHz, DMSO-d6) 8 ppm 10.64 (s, 1 H), 8.46 (s, 1 H), 8.13 (s, 1 H),
7.74 - 7.84 (m,
2H),7.52-7.58(m,1H),7.33-7.46(m,3H),7.24-7.33(m,3H),7.06(s,1H),5.68(s,2
H), 1.70 - 1.86 (m, 1 H), 0.99 - 1.09 (m, 2 H), 0.33 - 0.44 (m, 2 H). MS
(ESI+) m/z 425
(M+H)+.
Example 231
5-(1 H-indazol-5-yl)-N-[(1 S)-1-phenylpropyl]isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting (S)-(-)-1-phenylpropyl amine for piperidine. iH NMR (300 MHz,
DMSO-
d6) 6 ppm 13.37 (s, 1 H) 9.20 (d, J=8.48 Hz, 1 H) 8.39 (s, 1 H) 8.23 (s, 1 H)
7.88 (d, J=8.81,
1.70Hz,1H)7.69(d,J=8.81Hz,1H)7.38-7.49(m,2H)7.18-7.38(m,4H)4.83-5.02
(m, 1 H) 1.73 - 1.97 (m, 2 H) 0.86 - 0.97 (m, 3 H). MS (ESI+) m/z 347.0
(M+H)+.
Example 232
5-(1 H-indazol-5-yl)-N-[(1 R)-1-phenylpropyl]isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting (R)-(-)-1-phenylpropyl amine for piperidine. 'H NMR (300 MHz,
DMSO-
d6) 6 ppm 13.37 (s, 1 H) 9.20 (d, J=8.48 Hz, 1 H) 8.39 (s, 1 H) 8.23 (s, 1 H)
7.88 (d, J=8.65,
1.53Hz,1H)7.69(d,J=8.81Hz,1H)7.39-7.48(m,2H)7.18-7.38(m,4H)4.85-4.99
(m, 1 H) 1.74 - 1.97 (m, 2 H) 0.91 (t, J=7.29 Hz, 3 H). MS (ESI+) m/z 347.0
(M+H)+.
Example 233
5-(1-benzyl-1 H-pyrazol-4-yl)-1 H-indazol-3-amine
Example 233A
5 -(1-B enzyl-1 H-pyrazol-4-yl)-2-fluorob enzonitrile
5-Bromo-2-fluorobenzonitrile (484 mg, 2.42 mmol), 1-benzyl-4-(4,4,5,5-
tetramethyl-
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1,3,2-dioxaborolan-2-yl)-1H-pyrazole (736 mg, 2.59 mmol),
dichlorobis(triphenylphosphine)palladium(II) (174 mg, 0.248 mmol), and
potassium
carbonate (1.36 g, 9.84 mmol) were combined in a sealed vial with dioxane (10
mL) and
water (1 mL) under an inert atmosphere of nitrogen, and the mixture was heated
to 110 C
overnight. The mixture was diluted with methylene chloride and washed with
water. The
organic layer was absorbed on silica gel and purified by silica gel
chromatography eluting
with a gradient of 10-50% ethyl acetate in hexanes to afford the title
compound. MS (ESI+)
m/z 290.0 (M+H)+.
Example 233B
5-(1-benzyl-1 H-pyrazol-4-yl)-1 H-indazol-3-amine
Example 233A (591 mg, 2.13 mmol) was treated with hydrazine hydrate (4.0 mL)
in
ethanol (3.0 mL) and was stirred and heated to 70 C overnight. The mixture
was diluted
with methylene chloride and washed with water. The organic layer was
concentrated under
reduced pressure, and the resulting residue was triturated with methanol to
afford the title
compound. 'H NMR (300 MHz, DMSO-d6) b ppm 11.32 (s, 1 H) 8.10 (s, 1 H) 7.85
(s, 1 H)
7.80 (s, 1 H) 7.44 (d, J=8.48, 1.70 Hz, 1 H) 7.25 - 7.41 (m, 5 H) 7.21 (d,
J=8.82 Hz, 1 H) 5.35
(s, 2 H) 5.24 - 5.30 (m, 2 H). MS (ESI+) m/z 290.0 (M+H)+.
Example 234
1-benzyl-4-(1H-indazol-5-yl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-1H-1,2,3-
triazole-5-
carboxamide
Into a 20 mL vial, a solution of Example 149C (51 mg, 0.16 mmol) dissolved in
dimethylformamide (0.5 mL) was added, followed by the addition of (S)-(+)-
tetrahydrofurfurylamine (18.2 mg, 0.18 mmol) dissolved in dimethylformamide
(0.9 mL). A
solution of HATU (68 mg, 0.18mmo1) dissolved in dimethylformamide (0.5 mL) was
added
followed by a solution of diisopropylethylamine (0.087 mL, 0.5 mmol) dissolved
in
dimethylformamide (0.5 mL). The mixture was shaken at 50 C overnight. The
reaction was
filtered through a Si-Carbonate cartridge (6 mL-1 g) supplied by Silicycle
Chemical Division,
and the filtrate was transferred to 20 mL vials. The reaction was checked by
LC/MS and
concentrated to dryness. The residue was dissolved in 1:1 DMSO/methanol and
purified by
reverse phase HPLC (Agilent, 5%-100% TFA/water gradient, 8 minute run). 'H NMR
(300
MHz, DMSO-d6/D20) 8 ppm 1.35 - 1.54 (m, 1 H) 1.64 - 1.96 (m, 3 H) 3.17 - 3.26
(m, 1 H)
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3.32-3.38(m,1H)3.50-3.77(m,2H)3.81-4.00(m,1H)5.58-5.74(m,2H)7.21-7.41
(m,5H)7.54-7.66(m,1H)7.68-7.84(m,1H)8.01-8.19(m,2H). MS (ESI-) m/z 401
(M-H)-.
Example 235
1-benzyl-4-(1 H-indazol-5 -yl)-N-(2-isopropoxyethyl)-1 H-1, 2,3 -triazo le-5 -
carboxamide
The title compound was prepared according to the procedure outlined in Example
234
substituting 2-aminoethylisopropyl ether for (S)-(+)-tetrahydrofurfurylamine.
'H NMR (300
MHz, DMSO-d6/D20) S ppm 0.98 (d, 6 H) 3.31 - 3.45 (m, 4 H) 3.45 - 3.57 (m, 1
H) 5.61 -
5.74(m,2H)7.25-7.46(m,5H)7.57-7.65(m,1H)7.68-7.80(m,1H)8.04-8.13(m,2
H). MS (ESI+) m/z 405 (M+H)+.
Example 236
1-benzyl-4-(1 H-indazol-5-yl)-N-[(2R)-tetrahydrofuran-2-ylmethyl]-1 H-1,2,3-
triazole-5-
carboxamide
The title compound was prepared according to the procedure outlined in Example
234
substituting (R)-(-)-tetrahydrofurfurylamine for (S)-(+)-
tetrahydrofurfurylamine. 'H NMR
(300 MHz, DMSO-d6/D20) 8 ppm 1.34 - 1.60 (m, 1 H) 1.65 - 1.94 (m, 3 H) 3.16 -
3.26 (m, 1
H)3.33-3.39(m,1H)3.51-3.77(m,2H)3.78-4.00(m,1H)5.60-5.73(m,2H)7.26-
7.45(m,5H)7.56-7.68(m,1H)7.71-7.79(m,1H)8.01-8.15(m,2H). MS(ESI-)m/z
401 (M-H)-.
Example 237
1-benzyl-4-(1 H-indazol-5-yl)-N-(tetrahydrofuran-3-ylmethyl)-1 H-1,2,3-
triazole-5-
carboxamide
The title compound was prepared according to the procedure outlined in Example
234
substituting 3-aminomethyltetrahydrofuran for (S)-(+)-tetrahydrofurfurylamine.
'H NMR
(300 MHz, DMSO-d6/D20) 6 ppm 1.36 - 1.59 (m, 1 H) 1.67 - 2.00 (m, 1 H) 2.19 -
2.45 (m, 1
H) 3.11 - 3.23 (m, 2 H) 3.45 - 3.77 (m, 2 H) 5.45 - 6.14 (m, 2 H) 7.16 - 7.44
(m, 5 H) 7.50 -
7.84 (m, 2 H) 7.96 - 8.25 (m, 2 H). MS (ESI+) m/z 403 (M+H)+.
Example 238
1-b enzyl-N-cyclop entyl-4-(1 H-indazol-5 -yl)-1 H-1,2, 3-triazole-5 -
carboxamide
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The title compound was prepared according to the procedure outlined in Example
234
substituting cyclopentylamine for (S)-(+)-tetrahydrofurfurylamine. 'H NMR (300
MHz,
DMSO-d6/D20) 6 ppm 1.19 - 1.63 (m, 6 H) 1.71 - 1.99 (m, 2 H) 3.99 - 4.37 (m, 1
H) 5.52 -
5.77(m,2H)7.22-7.45(m,5H)7.55-7.83(m,2H)7.95-8.20(m,2H). MS(ESI-)m/z
385 (M-H)-.
Example 239
1-benzyl-N-(cyclopentylmethyl)-4-(1 H-indazol-5-yl)-1 H-1,2,3 -triazole-5 -
carboxamide
The title compound was prepared according to the procedure outlined in Example
234
substituting aminomethylcyclopentane for (S)-(+)-tetrahydrofurfurylamine. 'H
NMR (300
MHz, DMSO-d6/D20) 6 ppm 1.02 - 1.28 (m, 2 H) 1.34 - 1.73 (m, 6 H) 1.83 - 2.17
(m, 1 H)
3.03-3.17(m,2H)5.51-5.80(m,2H)7.20-7.42(m,5H)7.52-7.81(m,2H)7.93-8.19
(m, 2 H). MS (ESI+) m/z 401 (M+H)+.
Example 240
1-benzyl-N-ethyl-4-(1 H-indazol-5-yl)-N-methyl-1 H-1,2,3-triazole-5-
carboxamide
The title compound was prepared according to the procedure outlined in Example
234
substituting N-methylethylamine hydrochloride for (S)-(+)-
tetrahydrofurfurylamine. 'H
NMR (300 MHz, DMSO-d6/D20) 6 ppm 0.33 - 0.56 (m, 1 H) 0.90 - 1.14 (m, 2 H)
2.15 - 2.25
(m,2H)2.58-2.69(m,1H)2.82-3.01(m,1H)3.35-3.52(m,1H)5.40-5.67(m,2H)
7.14 - 7.48 (m, 5 H) 7.56 - 7.79 (m, 2 H) 7.90 - 8.24 (m, 2 H). MS (ESI+) m/z
361 (M+H)+.
Example 241
1-benzyl-4-(1 H-indazol-5-yl)-N-isopropyl-N-methyl-1 H-1,2,3-triazole-5-
carboxamide
The title compound was prepared according to the procedure outlined in Example
234
substituting methylisopropylamine for (S)-(+)-tetrahydrofurfurylamine. 'H NMR
(300 MHz,
DMSO-d6/D20) 6 ppm 0.22 - 0.51 (m, 2 H) 0.84 - 1.09 (m, 4 H) 1.96 - 2.13 (m, 2
H) 2.74 -
2.87(m,1H)4.44-4.92(m,1H)5.43-5.67(m,2H)7.20-7.44(m,5H)7.51-7.73(m,2
H) 7.84 - 8.14 (m, 2 H). MS (ESI+) m/z 375 (M+H)
Example 242
1-benzyl-4-(1 H-indazol-5-yl)-N-(2-methoxyethyl)-N-methyl-1 H-1,2,3 -triazole-
5-
carboxamide
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The title compound was prepared according to the procedure outlined in Example
234
substituting N-(2-methoxyethyl)methylamine for (S)-(+)-
tetrahydrofurfurylamine. 'H NMR
(300 MHz, DMSO-d6/D20) 6 ppm 2.25 - 2.42 (m, 2 H) 2.74 - 3.06 (m, 4 H) 3.40 -
3.75 (m, 3
H)5.38-5.73(m,2H)7.18-7.45(m,5H)7.53-7.74(m,2H)7.85-8.19(m,2H). MS
(ESI+) m/z 391 (M+H)+.
Example 243
1-benzyl-4-(1 H-indazol-5-yl)-N-phenyl-1 H-1,2,3 -triazole-5-carboxamide
The title compound was prepared according to the procedure outlined in Example
234
substituting aniline for (S)-(+)-tetrahydrofurfurylamine. 'H NMR (300 MHz,
DMSO-
d6/D20)8ppm5.65-5.79(m,2H)7.04-7.55(m,10H)7.54-7.84(m,2H)7.95-8.21 (m,
2 H). MS (ESI+) m/z 395 (M+H)+.
Example 244
1-benzyl-N-(4-chlorophenyl)-4-(1 H-indazol-5-yl)-l H-1,2,3-triazole-5-
carboxamide
The title compound was prepared according to the procedure outlined in Example
234
substituting 4-chloroaniline for (S)-(+)-tetrahydrofurfurylamine. 'H NMR (300
MHz,
DMSO-d6/D20)8ppm5.70-5.74(m,2H)7.25-7.42(m,7H)7.43-7.52(m,2H)7.54-
7.66 (m, 1 H) 7.68 - 7.77 (m, 1 H) 8.03 - 8.15 (m, 2 H). MS (ESI-) m/z 427 (M-
H)-.
Example 245
1-benzyl-4-(1 H-indazol-5 -yl)-N-(2-morpholin-4-ylethyl)-1 H-1, 2,3 -triazo le-
5 -carboxamide
The title compound was prepared according to the procedure outlined in Example
234
substituting N-(3-aminopropyl)morpholine for (S)-(+)-tetrahydrofurfurylamine.
'H NMR
(300 MHz, DMSO-d6/D20) 6 ppm 2.94 - 3.13 (m, 6 H) 3.46 - 3.61 (m, 2 H) 3.63 -
3.79 (m, 4
H)5.61-5.88(m,2H)7.19-7.46(m,5H)7.56-7.88(m,2H)7.88-8.30(m,2H). MS
(ESI-) m/z 430 (M-H)-.
Example 246
1-benzyl-N-[2-(dimethylamino)ethyl]-4-(1 H-indazol-5-yl)-N-methyl-1 H-1,2,3-
triazole-5-
carboxamide
The title compound was prepared as a TFA salt according to the procedure
outlined in
Example 234 substituting N,N,N-trimethylethylenediamine for (S)-(+)-
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tetrahydrofurfurylamine. 'H NMR (300 MHz, DMSO-d6/D20) 6 ppm 2.28 - 2.42 (m, 3
H)
2.73 - 3.00 (m, 6 H) 3.07 - 3.19 (m, 2 H) 3.56 - 3.80 (m, 2 H) 5.55 - 5.68 (m,
2 H) 7.24 - 7.47
(m,5H)7.56-7.78(m,2H)7.91-8.02(m,1H)8.10-8.17(m,1H). MS (ESI+) m/z 404
(M+H)+.
Example 247
1-benzyl-N-(2-hydroxyethyl)-4-(1 H-indazol-5-yl)-N-propyl-1 H-1,2,3-triazole-5-
carboxamide
The title compound was prepared according to the procedure outlined in Example
234
substituting 2-(propylamino)ethanol for (S)-(+)-tetrahydrofurfurylamine. 'H
NMR (300
MHz, DMSO-d6/D20) 6 ppm 0.22 - 0.39 (m, 1 H) 0.80 - 1.06 (m, 3 H) 1.50 - 1.75
(m, 1 H)
2.65-2.78(m,1H)2.80-2.94(m,IH)2.97-3.09(m,1H)3.37-3.50(m,1H)3.51-3.63
(m,1H)3.61-3.73(m,1H)5.39-5.74(m,2H)7.20-7.44(m,5H)7.50-7.85(m,2H)
7.86 - 8.25 (m, 2 H). MS (ESI+) m/z 405 (M+H)+.
Example 248
1-benzyl-N-[3-(dimethylamino)propyl]-4-(1 H-indazol-5-yl)-N-methyl-1 H-1,2,3-
triazole-5-
carboxamide
The title compound was prepared as a TFA salt according to the procedure
outlined in
Example 234 substituting N,N,N-trimethyl-1,3-propanediamine for (S)-(+)-
tetrahydrofurfurylamine. 'H NMR (300 MHz, DMSO-d6/D20) 6 ppm 8.06 - 8.23 (m, 1
H)
7.85-8.05(m,1H)7.57-7.73(m,2H)7.19-7.48(m,5H)5.41-5.74(m,2H)3.36-3.45
(m,2H)2.88-3.10(m,3H)2.60-2.86(m,5H)2.24-2.42(m,4H)1.73-1.91(m,1H).
MS (ESI+) m/z 418 (M+H)+.
Example 249
1-benzyl-N-[2-(diethylamino)ethyl]-4-(1 H-indazol-5-yl)-N-methyl-1 H-1,2,3-
triazole-5-
carboxamide
The title compound was prepared as a TFA salt according to the procedure
outlined in
Example 234 substituting N,N-diethyl-N-methylethylenediamine for (S)-(+)-
tetrahydrofurfurylamine. 'H NMR (300 MHz, DMSO-d6/D20) 8 ppm 7.82 - 8.24 (m, 2
H)
7.56-7.76(m,2H)7.15-7.49(m,5H)5.54-5.71(m,2H)3.60-3.77(m,2H)3.20-3.24
(m, 2 H) 3.13 - 3.18 (m, 2 H) 3.03 - 3.11 (m, 2 H) 2.32 - 2.44 (m, 3 H) 0.63 -
1.41 (m, 6 H).
MS (ESI+) m/z 432 (M+H)+.
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Example 250
N,1-dibenzyl-N-ethyl-4-(1 H-indazol-5-yl)-1 H-1,2,3-triazole-5-carboxamide
The title compound was prepared according to the procedure outlined in Example
234
substituting N-ethylbenzylamine for (S)-(+)-tetrahydrofurfurylamine. 'H NMR
(300 MHz,
DMSO-d6/D20)6 ppm7.81-8.20(m,2H)7.49-7.71(m,2H)7.24-7.51(m,9H)6.39-
7.18(m,2H)5.41-5.74(m,2H)4.53-4.84(m,1H)3.82-4.00(m,1H)3.37-3.54(m,1
H) 2.61 - 2.78 (m, 1 H) 0.91 - 1.08 (m, 1 H) 0.27 - 0.45 (m, 2 H). MS (ESI+)
m/z 437
(M+H)+.
Example 251
N,1-dib enzyl-N-(2-hydroxyethyl)-4-(1 H-indazol-5 -yl)-1 H-1,2, 3-triazole-5 -
carboxamide
The title compound was prepared according to the procedure outlined in Example
234
substituting N-benzylethanolamine for (S)-(+)-tetrahydrofurfurylamine. MS
(ESI+) m/z 453
(M+H)+.
Example 252
(3R)-1- {[ 1-benzyl-4-(1 H-indazol-5-yl)-1 H-1,2,3-triazol-5-
yl]carbonyl}piperidin-3-ol
The title compound was prepared according to the procedure outlined in Example
234
substituting (R)-(+)-3-hydroxypiperidine hydrochloride for (S)-(+)-
tetrahydrofurfurylamine.
iH NMR (300 MHz, DMSO-d6/D20) 6 ppm 7.83 - 8.22 (m, 2 H) 7.51 - 7.78 (m, 2 H)
7.23 -
7.45(m,5H)5.46-5.75(m,2H)3.80-4.31(m,1H)3.40-3.68(m,1H)2.58-3.15(m,2
H) 2.19 - 2.49 (m, 1 H) 0.31 - 2.14 (m, 4 H). MS (ESI+) m/z 403 (M+H)+.
Example 253
1- {[ 1-b enzyl-4-(1 H-indazol-5 -yl)-1 H-1, 2,3 -triazo l-5 -yl] carbonyl}pip
eridine-4-carboxamide
The title compound was prepared according to the procedure outlined in Example
234
substituting isonipecotamide for (S)-(+)-tetrahydrofurfurylamine. 'H NMR (300
MHz,
DMSO-d6/D20)6 ppm7.86-8.24(m,2H)7.53-7.70(m,2H)7.22-7.46(m,5H)5.42-
5.77(m,2H)4.19-4.48(m,1H)2.65-3.10(m,2H)2.27-2.47(m,1H)2.05-2.24(m,1
H)1.65-1.89(m,1H)1.29-1.55(m,1H)0.98-1.27(m,1H)0.52-0.87(m,1H). MS
(ESI+) m/z 430 (M+H)+.
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Example 254
5- { 1-benzyl-5-[(2,6-dimethylmorpholin-4-yl)carbonyl]-1 H-1,2,3-triazol-4-yl}
-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
234
substituting 2,6-dimethylmorpholine for (S)-(+)-tetrahydrofurfurylamine. 'H
NMR (300
MHz, DMSO-d6/D20) 6 ppm 7.87 - 8.27 (m, 2 H) 7.50 - 7.76 (m, 2 H) 7.12 - 7.45
(m, 5 H)
5.46-5.68(m,2H)4.16-4.43(m,1H)2.61-2.98(m,1H)2.16-2.41(m,2H)1.77-2.13
(m, 1 H) 0.86 - 1.39 (m, 3 H) 0.38 - 0.83 (m, 3 H). MS (ESI+) m/z 417 (M+H)+.
Example 255
5-{5-[(4-acetylpiperazin-1-yl)carbonyl]-1-benzyl-lH-1,2,3-triazol-4-yl}-1H-
indazole
The title compound was prepared according to the procedure outlined in Example
234
substituting 1-acetylpiperazine for (S)-(+)-tetrahydrofurfurylamine. 'H NMR
(300 MHz,
DMSO-d6/Dz0)8ppm7.89-8.41(m,2H)7.55-7.86(m,2H)7.07-7.51(m,5H)5.44-
5.82(m,2H)3.46-3.70(m,3H)3.35-3.49(m,2H)2.57-2.93(m,3H)1.61-2.03(m,3
H). MS (ESI+) m/z 430 (M+H)+.
Example 256
5- { 1-benzyl-5-[(4-phenylpiperazin-1-yl)carbonyl]-1 H-1,2,3-triazol-4-yl} -1
H-indazole
The title compound was prepared according to the procedure outlined in Example
234
substituting 1-phenylpiperazine for (S)-(+)-tetrahydrofurfurylamine. 'H NMR
(300 MHz,
DMSO-d6/D20)8ppm7.79-8.38(m,2H)7.53-7.73(m,2H)7.22-7.46(m,5H)7.05-
7.19(m,2H)6.64-6.79(m,3H)5.54-5.68(m,2H)3.50-3.90(m,2H)2.93-3.15(m,2
H) 2.62 - 2.89 (m, 2 H) 2.19 - 2.43 (m, 2 H). MS (ESI-) m/z 462 (M-H)-.
Example 257
1-benzyl-N-[(1 R)-1-(hydroxymethyl)-2-methylpropyl]-4-(1 H-indazol-5-yl)-1 H-
1,2,3-
triazole-5-carboxamide
The title compound was prepared according to the procedure outlined in Example
234
substituting (R)-(+)-2-amino-3-methyl-l-butanol for (S)-(+)-
tetrahydrofurfurylamine. 'H
NMR (300 MHz, DMSO-d6/D20) 8 ppm 7.95 - 8.31 (m, 2 H) 7.52 - 7.96 (m, 2 H)
7.18 - 7.46
(m, 5 H) 5.42 - 5.86 (m, 2 H) 3.68 - 3.94 (m, I H) 3.38 - 3.59 (m, 2 H) 1.49 -
2.08 (m, I H)
0.50 - 1.20 (m, 6 H). MS (ESI+) m/z 405 (M+H)+.
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Example 258
1-benzyl-N-[(1 S)-1-(hydroxymethyl)-2-methylpropyl]-4-(1 H-indazol-5-yl)-1 H-
1,2,3-triazole-
5-carboxamide
The title compound was prepared according to the procedure outlined in Example
234
substituting (S)-(-)-2-amino-3-methyl-l-butanol for (S)-(+)-
tetrahydrofurfurylamine. 'H
NMR (300 MHz, DMSO-d6/D20) 8 ppm 7.94 - 8.36 (m, 2 H) 7.52 - 7.84 (m, 2 H)
7.18 - 7.51
(m,5H)5.57-5.76(m,2H)3.75-3.94(m,IH)3.35-3.54(m,2H)1.70-1.94(m,1H)
0.54 - 1.09 (m, 6 H). MS (ESI+) m/z 405 (M+H)+.
Example 259
1-benzyl-N-[3-(1 H-imidazol-1-yl)propyl]-4-(1 H-indazol-5-yl)-1 H-1,2,3-
triazole-5-
carboxamide
The title compound was prepared according to the procedure outlined in Example
234
substituting 1-(3-aminopropyl)imidazole for (S)-(+)-tetrahydrofurfurylamine.
'H NMR (300
MHz, DMSO-d6/D20) 8 ppm 8.57 - 8.85 (m, 1 H) 7.92 - 8.16 (m, 2 H) 7.60 - 7.80
(m, 2 H)
7.47 - 7.55 (m, 2 H) 7.19 - 7.40 (m, 5 H) 5.54 - 5.75 (m, 2 H) 3.83 - 4.21 (m,
2 H) 3.19 - 3.26
(m, 2 H) 1.79 - 2.06 (m, 2 H). MS (ESI+) m/z 427 (M+H)+.
Example 260
N-[5-(1-benzyl-5-cyclopropyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N'-
ethylurea
The title compound was prepared as a hydrochloric acid salt according to the
procedure outlined in Example 229 substituting isocyanatoethane for 3-
isocyanato-5-methyl-
2-(trifluoromethyl)furan. 'H NMR (300 MHz, DMSO-d6) 8 ppm 12.38 (s, 1 H), 9.47
(s, I
H), 8.38 (s, I H), 7.85 - 7.97 (m, 1 H), 7.78 (d, J=8.82, 1.47 Hz, 1 H), 7.34 -
7.50 (m, 4 H),
7.24 - 7.33 (m, 2 H), 5.69 (s, 2 H), 3.17 - 3.29 (m, 2 H), 1.70 - 1.83 (m, I
H), 1.12 (t, J=7.17
Hz, 3 H), 1.00 - 1.08 (m, 2 H), 0.37 (d, J=3.68 Hz, 2 H). MS (ESI+) m/z 402
(M+H)+.
Example 261
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N'-
phenylurea
The title compound was prepared as a hydrochloric acid salt according to the
procedure outlined in Example 229 substituting isocyanatobenzene for 3-
isocyanato-5-
methyl-2-(trifluoromethyl)furan. 'H NMR (300 MHz, DMSO-d6) b ppm 12.47 - 12.78
(m, 1
H), 9.64 (s, I H), 8.39 (s, I H), 7.70 - 7.95 (m, I H), 7.45 - 7.60 (m, 3 H),
7.27 - 7.45 (m, 7
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H), 7.02 (m, 1 H), 5.69 (s, 2 H), 1.79 (m, 1 H), 1.07 (m, 2 H), 0.40 (m, 2 H).
MS (ESI+) m/z
450 (M+H)+.
Example 262
N-benzyl-N'-[5-(1-benzyl-5-cyclopropyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-
yl]urea
The title compound was prepared as a hydrochloric acid salt according to the
procedure outlined in Example 229 substituting (isocyanatomethyl)benzene for 3-
isocyanato-
5-methyl-2-(trifluoromethyl)furan. 'H NMR (300 MHz, DMSO-d6) 8 ppm 12.42 (s, 1
H),
9.61 (s, 1 H), 8.37 (s, 1 H), 8.23 - 8.33 (m, 1 H), 7.79 (d, J=8.82, 1.47 Hz,
1 H), 7.36 - 7.50
(m, 4 H), 7.28 - 7.36 (m, 6 H), 7.21 - 7.27 (m, 1 H), 5.69 (s, 2 H), 4.45 (d,
J=5.88 Hz, 2 H),
1.65 - 1.79 (t, J=8.27, 8.27 Hz, 1 H), 0.99 - 1.08 (m, 2 H), 0.30 - 0.43 (m, 2
H). MS (ESI+)
m/z 464 (M+H)+.
Example 263
N-[5-(1-benzyl-5-cyclopropyl-IH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N'-(2-
chlorophenyl)urea
The title compound was prepared as a hydrochloric acid salt according to the
procedure outlined in Example 229 substituting 1-chloro-2-isocyanatobenzene
for 3-
isocyanato-5-methyl-2-(trifluoromethyl)furan. 'H NMR (300 MHz, DMSO-d6) b ppm
12.74
(s, 1 H), 10.23 (s, 1 H), 8.44 (s, 1 H), 8.34 (d, J=8.09 Hz, 1 H), 7.83 (d,
J=8.82, 1.47 Hz, 1 H),
7.46 - 7.55 (m, 2 H), 7.35 - 7.45 (m, 3 H), 7.28 - 7.35 (m, 3 H), 7.03 - 7.12
(m, I H), 5.70 (s,
2 H), 1.70 - 1.86 (m, 1 H), 1.00 - 1.12 (m, 2 H), 0.33 - 0.45 (m, 2 H). MS
(ESI+) m/z 484
(M+H)+.
Example 264
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N'-(3-
chlorophenyl)urea
The title compound was prepared as a hydrochloric acid salt according to the
procedure outlined in Example 229 substituting 1-chloro-3-isocyanatobenzene
for 3-
isocyanato-5-methyl-2-(trifluoromethyl)furan. 'H NMR (300 MHz, DMSO-d6) b ppm
12.66
(s, 1 H), 10.02 (s, 1 H), 9.71 (s, 1 H), 8.22 - 8.48 (m, 1 H), 7.71 - 7.91 (m,
2 H), 7.51 (d,
J=8.46 Hz, 1 H), 7.37 - 7.46 (m, 2 H), 7.26 - 7.37 (m, 5 H), 7.02 - 7.11 (m, 1
H), 5.69 (s, 2
H),1.73-1.89(m,1H),0.99-1.11(m,2H),0.33-0.48(m,2H). MS (ESI+) m/z 484
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(M+H)+.
Example 265
N-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N'-(4-
chlorophenyl)urea
The title compound was prepared as a hydrochloric acid salt according to the
procedure outlined in Example 229 substituting 1-chloro-4-isocyanatobenzene
for 3-
isocyanato-5-methyl-2-(trifluoromethyl)furan. 'H NMR (300 MHz, DMSO-d6) 6 ppm
12.65
(s, 1 H), 9.96 (s, 1 H), 9.68 (s, 1 H), 8.37 (s, 1 H), 7.81 (d, J=8.82, 1.47
Hz, 1 H), 7.53 - 7.60
(m, 2 H), 7.50 (d, J=8.82 Hz, 1 H), 7.39 - 7.44 (m, 1 H), 7.33 - 7.40 (m, 4
H), 7.27 - 7.32 (m,
2 H), 5.69 (s, 2 H), 1.71 - 1.87 (m, 1 H), 1.00 - 1.12 (m, 2 H), 0.34 - 0.44
(m, 2 H). MS
(ESI+) m/z 484 (M+H)+.
Example 266
N-[5-(1-benzyl-5-iodo-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]benzamide
Example 266A
tert-butyl3-amino-5-(1-benzyl-5-iodo-1 H-1,2,3-triazol-4-yl)-1 H-indazole-l-
carboxylate
The title compound was prepared according to the procedure outlined in Example
198A substituting Example 125B for Example 102B. The product was used directly
in
subsequent reactions without characterization.
Example 266B
N-[5-(1-benzyl-5-iodo-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]benzamide
The title compound was prepared as a TFA salt according to the procedure
outlined in
Example 205B substituting Example 266A for Example 205A. 'H NMR (300 MHz, DMSO-
d6) 6 ppm 12.97 (s, 1 H), 10.89 (s, 1 H), 8.28 (s, 1 H), 8.05 - 8.14 (m, 2 H),
7.88 (d, J=8.82,
1.47 Hz, 1 H), 7.58 - 7.67 (m, 2 H), 7.54 (t, J=7.35 Hz, 2 H), 7.29 - 7.45 (m,
3 H), 7.23 (d,
J=6.99 Hz, 2 H), 5.73 (s, 2 H). MS (ESI+) m/z 521 (M+H)+.
Example 267
3-[4-(3-amino-1 H-indazol-5-yl)-1 H-pyrazol-l-yl]propanenitrile
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Example 267A
3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1-
yl)propanenitrile
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(5.00 g,
25.8 mmol) in acetonitrile (50 mL) was added acrylonitrile (3.4 mL, 52 mmol)
followed by
1,8-diazabicyclo[5.4.0]undec-7-ene (1.94 mL, 12.9 mmol). After about 2 hours,
the reaction
mixture was concentrated under reduced pressure. The crude material was then
dissolved in
a minimal amount of dichloromethane and purified via silica gel chromatography
eluting with
a gradient of 10-50% ethyl acetate in heptane to afford the title compound. 'H
NMR (400
MHz, DMSO-d6) 8 ppm 8.03 (s, 1H), 7.64 (s, IH), 4.40 (t, J = 6.4 Hz, 2H), 3.06
(t, J = 6.4
Hz, 2H), 1.26 (s, 12H). MS (ESI+) m/z 247.3 (M+H)+.
Example 267B
3-[4-(3-amino-1 H-indazol-5-yl)-1 H-pyrazol-l-yl]propanenitrile
To a microwave vial was added 5-bromo-lH-indazol-3-amine (0.14 g, 0.66 mmol),
tetrakis(triphenylphosphine)palladium(0) (0.076 g, 0.066 mmol), and sodium
carbonate
(0.147 g, 1.39 mmol) followed by a solution of Example 267A (0.212 g, 0.858
mmol) in 1,2-
dimethoxyethane (2.50 mL) and then water (1.25 mL). The mixture was heated in
a CEM
microwave at about 150 C for about 20 minutes (275 psi maximum pressure,
about 2
minutes ramp, 200 maximum watts) and then the mixture was concentrated under
reduced
pressure. Methanol (20 mL) was added and the resulting mixture was stirred for
about 1
hour. The insoluble material was removed by filtration. The filtrate was
concentrated under
reduced pressure onto silica gel and purified via silica gel chromatography
eluting with a
stepwise gradient of dichloromethane/methanol/ ammonium hydroxide (990:9:1 to
985:13.5:1.5 to 980:18:2) to afford a solid. This solid was dissolved in a
minimum amount of
hot acetonitrile (-2 mL), filtered to remove minor amount of insolubles, while
washing with
methanol (<0.5 mL), and left to sit at ambient temperature. The resulting
solid that formed
overnight was collected by filtration, while washing with additional
acetonitrile, and dried in
a vacuum oven at about 60 C for about 2 hours to afford the title compound.
'H NMR (400
MHz, DMSO-d6) 6 ppm 11.35 (s, IH), 8.10 (s, 1H), 7.86 (s, 1H), 7.84 (s, 1H),
7.44 (dd, J =
8.54, 1.26 Hz, 1H), 7.23 (d, J = 8.62 Hz, IH), 5.32 (s, 2H), 4.42 (t, J = 6.36
Hz, 2H), 3.10 (t, J
= 6.43 Hz, 2H). MS (ESI+) m/z 253.2 (M+H)+.
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Example 268
2- [4-(3 -amino- I H-indazol-5-yl)-1 H-pyrazol-l-yl]acetamide
Example 268A
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1-yl)acetamide
A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(2.00 g,
10.3 mmol), 2-bromoacetamide (2.14 g, 15.5 mmol), and potassium carbonate
(2.14 g, 15.5
mmol) in acetone (60 mL) was heated at about 50 C for about 3.5 days. The
reaction
mixture was then cooled to ambient temperature, filtered through diatomaceous
earth, while
washing with additional acetone, and then concentrated under reduced pressure.
The crude
material was then dissolved in a minimal amount of dichloromethane and
purified via silica
gel chromatography eluting with a gradient of 80-100% ethyl acetate in heptane
to afford the
title compound. 'H NMR (400 MHz, DMSO-d6) 8 ppm 7.88 (s, 1H), 7.57 (s, IH),
7.46 (s,
IH), 7.24 (s, 1H), 4.77 (s, 2H), 1.26 (s, 12H). MS (ESI+) m/z 252.2 (M+H)+.
Example 268B
2- [4-(3 -amino- I H-indazol-5 -yl)- I H-pyrazol-l-yl]acetamide
The title compound was prepared according to the procedure outlined in Example
267B substituting Example 268A for Example 267A and heating at about 120 C
for about 10
minutes. 'H NMR (400 MHz, DMSO-d6) 8 ppm 11.32 (s, IH), 7.98 (s, IH), 7.87 (s,
1H),
7.77 (s, 1 H), 7.48 (s, 1 H), 7.45 (d, J = 8.6 Hz, 1 H), 7.26 (s, 1 H), 7.22
(d, J = 8.7 Hz, 1 H), 5.28
(s, 2H), 4.78 (s, 2H). MS (ESI+) m/z 257.2 (M+H)+.
Example 269
methyl 3 - [4-(3 -amino- I H-indazol-5-yl)-1 H-pyrazol-l-yl]propanoate
Example 269A
methyl3-(4-(4,4,5,5-tetramethyl-].,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-
yl)propanoate
The title compound was prepared according to the procedure outlined in Example
267A substituting methyl acrylate for acrylonitrile. 'H NMR (400 MHz, DMSO-d6)
8 ppm
7.91 (s, 1H), 7.57 (s, IH), 4.35 (t, J- 6.73 Hz, 2H), 2.87 (t, J- 6.75 Hz,
2H), 3.59 (s, 3H),
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1.24 (s, 12H). MS (ESI+) m/z 281.2 (M+H)+.
Example 269B
methyl3-[4-(3-amino-1 H-indazol-5-yl)-1 H-pyrazol-l-yl]propanoate
The title compound was prepared according to the procedure outlined in Example
267B substituting Example 269A for Example 267A and heating at about 120 C
for about 20
minutes. 'H NMR (400 MHz, DMSO-d6) 8 ppm 11.32 (s, 1H), 8.00 (s, 1H), 7.85 (s,
1H),
7.76 (s, 1H), 7.42 (d, J = 8.50 Hz, 1H), 7.21 (d, J = 8.61 Hz, 1H), 5.28 (s,
2H), 4.37 (t, J
6.71 Hz, 2H), 3.61 (s, 3H), 2.92 (t, J = 6.69 Hz, 2H). MS (ESI+) m/z 286.2
(M+H)+.
Example 270
3 - [4-(3 -amino -1 H-indazol-5 -yl)-1 H-pyrazol-l-yl]propanamide
Example 270A
3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanamide
The title compound was prepared according to the procedure outlined in Example
267A substituting acrylamide for acrylonitrile (0.72 g, 53%). 'H NMR (400 MHz,
DMSO-
d6) 8 ppm 7.84 (s, 1H), 7.56 (s, 1H), 7.37 (s, 1H), 6.88 (s, 1H), 4.30 (t, J =
6.80 Hz, 2H), 2.60
(t, J = 6.79 Hz, 2H), 1.24 (s, 12H). MS (ESI+) m/z 266.2 (M+H)+.
Example 270B
3-[4-(3-amino-1 H-indazol-5-yl)-1 H-pyrazol-l-yl]propanamide
The title compound was prepared according to the procedure outlined in Example
267B substituting Example 270A for Example 267A and heating at about 120 C
for about 15
minutes (0.056 g, 22%). 'H NMR (400 MHz, DMSO-d6) b ppm 11.32 (s, 1H), 7.94
(d, J
0.53 Hz, 1 H), 7.84 (s, 1 H), 7.75 (d, J = 0.54 Hz, 1 H), 7.42 (m, 2H), 7.20
(d, J = 8.26 Hz,
1H), 6.89 (s, 1H), 5.27 (s, 2H), 4.32 (t, J = 6.89 Hz, 2H), 2.65 (t, J = 6.89
Hz, 2H). MS
(ESI+) m/z 271.0 (M+H)+.
Example 271
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[4-(3 -amino-1 H-indazol-5 -yl)-1 H-pyrazol-l-yl] acetonitrile
Example 271A
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-l-
yl)acetonitrile
The title compound was prepared according to the procedure outlined in Example
268A substituting 2-bromoacetonitrile for 2-bromoacetamide. 'H NMR (400 MHz,
DMSO-
d6) 6 ppm 7.99 (s, 1H), 7.66 (s, 1H), 5.45 (s, 2H), 1.25 (s, 12H).
Example 271B
tert-butyl 3-(bis(tert-butoxycarbonyl)amino)-5-bromo-1 H-indazole-l-
carboxylate
To 5-bromo-lH-indazol-3-amine (2.00 g, 9.43 mmol) in tetrahydrofuran (20 mL)
was
added 4-(dimethylamino)pyridine (0.230 g, 1.886 mmol) and di-tert-butyl
dicarbonate (6.18
g, 28.3 mmol). The reaction was heated at 50 C for about 2 hours, cooled to
ambient
temperature, and concentrated under reduced pressure. The residue was
dissolved in diethyl
ether (100 mL) and then washed sequentially with 1 N hydrochloric acid (2 x 25
mL), 1 N
sodium hydroxide (2 x 25 mL) and brine (25 mL). The organic layer was then
dried over
sodium sulfate, filtered, concentrated under reduced pressure, and dried in a
vacuum oven at
about 60 C to afford the title compound. 'H NMR (400 MHz, DMSO-d6) 8.05 (d, J
= 8.95
Hz, 1H), 7.99 (d, J = 1.90 Hz, 1H), 7.81 (dd, J = 8.94, 1.89 Hz, 1H), 1.65 (s,
9H), 1.40 (s,
18H). MS (ESI+) m/z 512.2 (M+H)+.
Example 271C
teNt-butyl3-(bis(tert-butoxycarbonyl)amino)-5-(1-(cyanomethyl)-1H-pyrazol-4-
yl)-1H-
indazole-l-carboxylate
A vial was charged with Example 271A (0.682 g, 2.93 mmol), Example 271B (1.25
g,
2.44 mmol), cesium carbonate (1.99 g, 6.10 mmol), 1,4-dioxane (12.5 mL) and
water (2.50
mL). After a vacuum/nitrogen purge through a septa,
tris(dibenzylideneacetone)dipalladium(0) (0.112 g, 0.122 mmol) and tri-t-
butylphosphonium
tetrafluoroborate (0.085 g, 0.29 mmol) were added and a cap was put on the
vial after
flushing with nitrogen. After about 6 hours at ambient temperature, the
reaction was
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partitioned between saturated aqueous sodium bicarbonate and dichloromethane
(50 mL
each). The layers were separated and the aqueous layer was extracted with
additional
dichloromethane (2 x 50 mL). The combined organic layers were washed with
brine, dried
over magnesium sulfate, filtered, and concentrated under reduced pressure. The
crude oil
was dissolved in a minimal amount of dichloromethane and purified via silica
gel
chromatography eluting with a gradient of 20-60% ethyl acetate in heptane to
afford the title
compound. 'H NMR (400 MHz, DMSO-d6) b ppm 8.43 (s, IH), 8.19 (s, 1H), 8.08 (d,
J =
9.22 Hz, IH), 7.93 (m, 2H), 5.53 (s, 2H), 1.67 (s, 9H), 1.39 (s, 18H). MS
(ESI+) m/z 539.3
(M+H)+.
Example 271D
[4-(3 -amino-1 H-indazol-5 -yl)-1 H-pyrazol-l-yl] acetonitrile
To a solution of tert-butyl 3-(bis(tert-butoxycarbonyl)amino)-5-(1-
(cyanomethyl)-1H-
pyrazol-4-yl)-1H-indazole-l-carboxylate (0.30 g, 0.557 mmol) in
dichloromethane (4.0 mL)
was added trifluoroacetic acid (2.0 mL). After about 45 minutes, the reaction
was slowly
quenched with saturated aqueous sodium bicarbonate. The resulting mixture was
extracted
with dichloromethane (3 x 25 mL). The combined organic layers were washed with
brine,
dried over magnesium sulfate, filtered, and concentrated under reduced
pressure to give a
crude solid. A white precipitate that was suspended in both the initial
aqueous layer and the
brine layer was filtered and added to the crude solid. The resulting solid was
triturated with
dichloromethane/methanol (19:1). The remaining solid was collected by vacuum
filtration
and dried in a vacuum oven at about 70 C to afford the title compound. 'H NMR
(400 MHz,
DMSO-d6) 8 ppm 11.37 (s, 1H), 8.12 (s, 1H), 7.92 (s, IH), 7.89 (s, 1H) 7.49-
7.41 (m, IH),
7.24 (d, J = 8.71 Hz, IH), 5.52 (s, 2H), 5.31 (s, 2H). MS (ESI+) m/z 239.1
(M+H)
Example 272
4-(3 -amino-1 H-indazol-5 -yl)-N,N-dimethyl-1 H-imidazo le-l-sulfonamide
3-Cyano-4-fluorophenylboronic acid (0.083 g, 0.503 mmol), 4-iodo-N,N-dimethyl-
1H-imidazole-l-sulfonamide (0.167 g, 0.554 mmol), sodium carbonate (0.128 g,
1.208
mmol) and tetrakis(triphenylphosphine)palladium(0) (0.035 g, 0.030 mmol) were
combined
in dimethoxyethane (4 mL) and water (1.5 mL). The reaction mixture was heated
in a
microwave (CEM-Discover) at about 150 C for about 25 minutes. The organic
layer was
separated and the solvent was removed under reduced pressure. To the residue
was added
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ethanol (0.7 mL) and hydrazine monohydrate (1 mL). The reaction mixture was
heated at
about 80 C for about 20 hours. The reaction mixture was partitioned between
water (5 mL)
and dichloromethane (100 mL). The organic layer was separated and concentrated
under
reduced pressure. The residue was purified by reverse phase HPLC using
acetonitrile/water
(0.05 M ammonium acetate) gradient elution method to afford the title
compound. 'H NMR
(400 MHz, DMSO-d6) 6 ppm 11.42 (s, IH), 8.25 (s, 1H), 8.21 (d, J = 1.36 Hz,
IH), 7.92 (d, J
= 1.37 Hz, 1H), 7.74 (dd, J= 8.66, 1.58 Hz, 1H), 7.23 (d, J= 8.68 Hz, 1H),
5.35 (s, 2H),
2.87 (s, 6H). MS (ESI+) m/z 307.2 (M+H)+.
Example 273
5 -pyrazin-2-yl-1 H-indazol-3 -amine
The title compound was prepared according to the procedure outlined in Example
272
substituting 2-iodopyrazine for 4-iodo-N,N-dimethyl-IH-imidazole-l-
sulfonamide. 'H NMR
(400 MHz, DMSO-d6) 6 ppm 11.61 (s, 1H), 9.18 (d, IH, J 1.6), 8.66 (dd, 1H, J =
1.7, 2.4),
8.59 (d, IH, J = 1.0), 8.51 (d, 1H, J = 2.5), 8.04 (dd, 1H, J 1.8, 8.8), 7.35
(d, IH, J = 9.2),
5.54 (s, 2H). MS (ESI+) m/z 212.2 (M+H)+.
Example 274
5-thien-2-yl-1 H-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example
272
substituting 2-iodothiophene for 4-iodo-N,N-dimethyl-IH-imidazole-l-
sulfonamide. 'H
NMR (400 MHz,DMSO-d6) 6 ppm 11.47 (s, 1H), 7.99 (d, 1H, J = 1.4), 7.55 (dd,
1H, J = 1.8,
8.8), 7.43 (dd, 1H, J = 1.0, 5.1), 7.35 (dd, 1H, J = 1.1, 3.6), 7.26 (d, 1H, J
= 8.6), 7.10 (dd,
1H, J = 3.5, 5.1), 5.42 (d, 2H, J = 8.8). MS (ESI+) m/z 216.1 (M+H)+.
Example 275
5 -(2-aminopyrimidin-4-yl)-1 H-indazol-3 -amine
The title compound was prepared according to the procedure outlined in Example
272
substituting 5-iodopyrimidin-2-amine for 4-iodo-N,N-dimethyl-IH-imidazole-l-
sulfonamide.
iH NMR (400 MHz, DMSO-d6) 6 ppm 11.40 (s, 1H), 8.53 (s, 2H), 7.91 (dd, 1H, J =
0.7, 1.5),
7.47 (dd, 1H, J = 1.8, 8.6), 7.28 (dd, 1H, J = 0.7, 8.7), 6.64 (s, 2H), 5.36
(s, 2H). 1H NMR
(400 MHz, DMSO-d6 )6 ppm 11.41 (s, 1H), 8.53 (s, 2H), 7.92 (m, IH), 7.47 (dd,
J = 8.66,
1.74 Hz, 1H), 7.28 (dd, J = 8.63, 0.65 Hz, IH), 6.64 (s, 2H), 5.36 (s, 2H). MS
(ESI+) m/z
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227.2 (M+H)+.
Example 276
5-(2-methoxypyridin-3-yl)-1H-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example
272
substituting 3-iodo-2-methoxypyridine for 4-iodo-N,N-dimethyl-lH-imidazole-l-
sulfonamide. iH NMR (400 MHz, DMSO-d6) 8 ppm 11.43 (s, IH), 8.14 (dd, 1H, J =
1.9,
5.0), 7.86 (s, I H), 7.71 (dd, I H, J= 2.0, 7.2), 7.42 (dd, 1 H, J= 1.7, 8.7),
7.26 (d, I H, J= 8.6),
7.09 (dd, 1H, J = 5.0, 7.3), 5.38 (s, 2H), 3.89 (s, 3H). MS (ESI+) m/z 241.2
(M+H)+.
Example 277
5-imidazo[1,2-a]pyridin-3-yl-lH-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example
272
substituting 3-bromoimidazo[1,2-a]pyridine for 4-iodo-N,N-dimethyl-lH-
imidazole-l-
sulfonamide. iH NMR (400 MHz, DMSO-d6) 6 ppm 8.52 (dt, IH, J 1.2, 7.0), 7.99
(dd, IH,
J = 0.7, 1.7), 7.68 (s, IH), 7.65 (dt, 2H, J = 1.2, 9.0), 7.46 (dd, 1H, J 1.8,
8.6), 7.39 (dd, 1H,
J = 0.8, 8.6), 7.28 (ddd, 1H, J = 1.2, 6.6, 9.2), 6.96 (td, IH, J = 1.3, 6.7),
5.47 (s, 2H). MS
(ESI+) m/z 250.2 (M+H)+.
Example 278
N2,N2 -dimethyl-N'-[5-(1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl]glycinamide
Example 65 (257 mg, 0.685 mmol) was dissolved in ethanol (15 mL). The reaction
mixture was hydrogenated in an H-Cube apparatus with palladium hydroxide (20%)
on
carbon at about 80 C and about 60 psi for about 8 hours. The solvent was
removed under
reduced pressure and the residue was purified by reverse phase HPLC using
acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford
the title
compound. 'H NMR (400 MHz, DMSO-d6) 6 ppm 8.16-8.37 (m, 1H), 7.10-7.46 (bs,
2H),
7.00-7.34 (bs, 2H), 6.87-7.24 (bs, 2H), 3.33-3.34 (m, 2H). MS (ESI+) m/z 286.2
(M+H)+.
Example 279
5 -(1 H-pyrazol-5-yl)-1 H-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example
272
substituting 5-iodo-lH-pyrazole for 4-iodo-N,N-dimethyl-lH-imidazole-l-
sulfonamide. 'H
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NMR (400 MHz, DMSO-d6) 8 ppm 7.87-7.94 (m, 3H), 7.60-7.63 (m, 1H), 7.48 (dd, J
= 8.55,
1.62 Hz, 1H), 7.19-7.32 (m, 2H), 5.25-5.28 (m, 2H). MS (ESI+) m/z 200.1
(M+H)+.
Example 280
5-(4-methyl-1 H-imidazol-5-yl)-I H-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example
272
substituting 5-iodo-4-methyl-lH-imidazole for 4-iodo-N,N-dimethyl-lH-imidazole-
l-
sulfonamide. 'H NMR (400 MHz, DMSO-d6) 6 ppm 7.85 (s, 1H), 7.52 (d, 2H, J =
6.6), 7.22
(m, 1H), 5.3 2 (bs, 2H). 2.37 (s, 3H). MS (ESI+) m/z 214.1 (M+H)+.
Example 281
5 -(1 H-imidazol-4-yl)-1 H-indazol-3 -amine
The title compound was prepared according to the procedure outlined in Example
272
substituting 4-iodo-lH-imidazole for 4-iodo-N,N-dimethyl-lH-imidazole-l-
sulfonamide. 'H
NMR (400 MHz, DMSO-d6) 8 ppm 8.07 (s, 1H), 7.66 (s, 1H), 7.63 (d, 1H, J =
8.6), 7.37 (s,
1H), 7.20 (d, 1H, J = 8.8), 5.28 (s, 2H). MS (ESI+) m/z 200.1 (M+H)+.
Example 282
N2,N2 -dimethyl-N1- {5-[1-(3-methylbenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-
3-
yl} glycinamide
Example 282A
5-bromo-lH-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example
62D substituting 5-bromo-2-fluorobenzonitrile for Example 62C. 'H NMR (400
MHz,
DMSO-d6) 8 ppm 11.55 (s, 1H), 7.92 (d, J = 1.87 Hz, 1H), 7.30 (dd, J = 8.79,
1.89 Hz, IH),
7.19 (d, J = 8.78 Hz, 1H), 5.41 (s, 2H).
Example 282B
tert-butyl3-amino-5-bromo-lH-indazole-I-carboxylate
The title compound was prepared according to the procedure outlined in Example
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64A substituting Example 282A for Example 62D. 'H NMR (400 MHz, DMSO-d6) b ppm
8.12 (d, J = 1.93 Hz, 1H), 7.95-7.81 (m, 1H), 7.65 (dd, J = 8.85, 1.96 Hz,
1H), 6.39 (d, J
4.44 Hz, 1 H), 1.5 8(m, 9H)
Example 282C
tert-butyl 5-bromo-3-(2-(dimethylamino)acetamido)-1 H-indazole-l-carboxylate
To a mixture of Example 282B (24.43 g, 78 mmol), potassium carbonate (81 g,
587
mmol) and 2-(dimethylamino)acetyl chloride hydrochloride (43.3 g, 274 mmol)
was added
tetrahydrofuran (200 mL). The reaction mixture was stirred at room temperature
for about 2
hours. The reaction mixture was filtered and the filtrate was washed with
water (50 mL).
The organic layer was separated and the aqueous layer was extracted with
dichloromethane
(3 x 100 mL). The combined organic extracts were dried over magnesium sulfate,
filtered
and concentrated under reduced pressure. The residue was purified by silica
gel
chromatography eluting with methanol in dichloromethane (5%) to afford the
title compound.
iH NMR (400 MHz, DMSO-d6) 8 ppm 10.72 (s, 1H), 8.19 (d, IH, J = 1.6), 8.03 (d,
1H, J
9.0), 7.76 (dd, 1H, J = 2.0, 9.0), 3.22 (s, 2H), 2.32 (s, 6H), 1.63 (s, 9H).
Example 282 D
tert-butyl 3-(2-(dimethylamino)acetamido)-5-((trimethylsilyl)ethynyl)-1 H-
indazole-l-
carboxylate
To a mixture of Example 282C (2.56 g, 6.44 mmol),
bis(triphenylphosphine)palladium(II) chloride (0.225 g, 0.321 mmol), and
copper(I) iodide
(0.073 g, 0.383 mmol) was added triethylamine (20 mL, 144 mmol) followed by
ethynyltrimethylsilane (0.760 g, 7.73 mmol). The reaction mixture was heated
at about 60 C
for about 3 hours. The reaction mixture was diluted with dichloromethane (100
mL), washed
with water (20 mL) and brine (20 mL), dried over magnesium sulfate, filtered
and
concentrated under reduced pressure. The residue was purified by silica gel
chromatography
eluting with ethyl acetate in dichloromethane (10%) to give the title
compound. 'H NMR
(400 MHz, DMSO-d6) 6 ppm 10.69 (s, IH), 8.08 (s, 1H), 8.04 (d, 1H, J = 9.0),
7.62 (d, 1H, J
= 8.8), 3.21 (s, 2H), 2.30 (s, 6H), 1.61 (s, 9H), 0.23 (s, 9H).
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Example 282E
2-(dimethylamino)-N-(5-ethynyl-1 H-indazol-3-yl)acetamide
To Example 282D (0.303 g, 0.731 mmol) in methanol (5 mL) was added aqueous
potassium hydroxide (1.46 mL, 1.46 mmol, 1.ON solution). The reaction mixture
was stirred
at room temperature for about 1 hour. The solvent was removed under reduced
pressure and
the residue was dissolved in ethyl acetate (80 mL). The organic layer was
separated and
washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate,
filtered and
concentrated under reduced pressure to afford the title compound. 'H NMR (400
MHz,
DMSO-d6) 8 ppm 12.89 (s, 1H), 10.14 (s, 1H), 8.00 (d, 1H, J = 12.1), 7.44 (s,
2H), 7.38 (d,
1H, J = 8.6), 4.02 (s, 1H), 3.17 (s, 2H), 2.33 (s, 6H).
Example 282F
N2,N2 -dimethyl-N1- {5-[ 1-(3-methylbenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-
indazol-3-
yl} glycinamide
To a suspension of Example 282E (0.16 g, 0.660 mmol) in tert-butanol (1.2 mL)
was
added 1-(azidomethyl)-3-methylbenzene (0.098 g, 0.667 mmol), then water (1.2
mL). A
solution of sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-
dihydrofuran-3-olate
(0.057 mL, 0.066 mmol, 1.6 M in water) and an aqueous solution of copper (II)
sulfate
pentahydrate (0.019 ml, 6.6 gmol, 0.34M) was added. The reaction mixture was
heated at
about 60 C for about 2 hours. The solvent was removed under reduced pressure
and the
residue was purified by reverse phase HPLC using acetonitrile/water (0.05 M
ammonium
acetate) gradient elution method to afford the title compound. 'H NMR (400
MHz, DMSO-
d6) 8 ppm 12.77 (s, 1 H), 10.05 (s, 1 H), 8.56 (s, 1 H), 8.24 (s, 1 H), 7.82
(d, 1 H, J = 8.6), 7.50
(d, 1H, J = 8.8), 7.28 (t, 1H, J = 7.6), 7.16 (m, 4H), 5.59 (s, 2H), 3.18 (s,
2H), 2.34 (s, 6H),
2.30 (s, 3H). MS (ESI+) m/z 390.3 (M+H)+.
Example 283
5 -(1-benzyl-1 H-imidazol-4-yl)-1 H-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example
272
substituting 1-benzyl-4-iodo-lH-imidazole for 4-iodo-N,N-dimethyl-lH-imidazole-
l-
sulfonamide. 'H NMR (400 MHz, DMSO-d6) 6 ppm 11.29 (s, 1H), 8.07 (s, 1H), 7.79
(s,
1H), 7.61 (d, 1H, J = 8.6), 7.46 (s, 1H), 7.36 (m, 5H), 7.17 (d, 1H, J = 8.8),
5.28 (s, 2H), 5.22
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(s, 2H). MS (ESI+) m/z 290.2 (M+H)+.
Example 284
Ni- {5-[ 1-(4-tert-butylbenzyl)-1 H-1,2,3-triazol-4-yl]-1 H-indazol-3-yl} -N2
,N2-
dimethylglycinamide
The title compound was prepared according to the procedure outlined in Example
282F
substituting 1-(azidomethyl)-4-tert-butylbenzene for 1-(azidomethyl)-3-
methylbenzene. 'H
NMR (400 MHz, DMSO-d6) 6 ppm 12.88 (s, 1H), 10.05 (s, 1H), 8.57 (s, 1H), 8.23
(s, 1H),
7.81 (d, 1H, J = 8.8), 7.50 (d, 1H, J = 8.8), 7.41 (d, 2H, J = 8.2), 7.30 (d,
2H, J = 8.2), 3.18 (s,
2H), 2.34 (s, 6H), 1.26 (s, 9H). MS (ESI+) m/z 432.2 (M+H)
Example 285
N2,N2 -dimethyl-Ni- {5-[1-(2-piperidin-1-ylethyl)-1 H-1,2,3-triazol-4-yl]-1 H-
indazol-3-
yl} glycinamide
The title compound was prepared according to the procedure outlined in Example
282F substituting 1-(2-azidoethyl)piperidine for 1-(azidomethyl)-3-
methylbenzene. 'H NMR
(400 MHz, DMSO-d6) 6 ppm 12.91 (s, 1H), 10.07 (s, 1H), 8.47 (s, 1H), 8.22 (s,
1H), 7.80
(dd, 1H, J = 1.2, 8.7), 7.52 (d, 1H, J = 8.8), 4.49 (t, 2H, J = 6.4), 3.19 (s,
2H), 2.76 (t, 2H, J
6.4), 2.41 (s, 4H), 2.35 (s, 6H), 1.69 (s, 3H), 1.47 (m, 4H), 1.37 (dd, 2H, J
= 5.2, 10.2). MS
(ESI-) m/z 395.3 (M-H)-.
Example 286
N2,N2 -dimethyl-Ni- {5-[ 1-(2-morpholin-4-ylethyl)-1 H-1,2,3-triazol-4-yl]-1 H-
indazol-3-
yl} glycinamide
The title compound was prepared according to the procedure outlined in Example
282F substituting 4-(2-azidoethyl)morpholine for 1-(azidomethyl)-3-
methylbenzene. 'H
NMR (400 MHz, DMSO-d6) 6 ppm 12.83 (s, 1H), 10.07 (s, 1H), 8.49 (s, 1H), 8.23
(s, 1H),
7.81 (dd, 1H, J = 1.3, 8.7), 7.52 (d, 1H, J = 8.8), 4.53 (t, 2H, J = 6.3),
3.55 (m, 4H), 3.19 (s,
2H), 2.80 (t, 2H, J = 6.3), 2.45 (m, 4H), 2.35 (s, 6H). MS (ESI-) m/z 397.3 (M-
H)-.
Example 287
Ni-(5- { 1-[2-(3,5-dimethylisoxazol-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl} -1 H-
indazol-3-yl)-
N2,N2 -dimethylglycinamide
The title compound was prepared according to the procedure outlined in Example
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282F substituting 4-(2-azidoethyl)-3,5-dimethylisoxazole for 1-(azidomethyl)-3-
methylbenzene. 'H NMR (400 MHz, DMSO-d6) 8 ppm 12.90 (s, 1H), 10.07 (s, 1H),
8.44 (s,
1H), 8.21 (s, 1H), 7.78 (dd, 1H, J = 1.3, 8.7), 7.52 (d, 1H, J = 8.8), 4.51
(t, 2H, J = 6.7), 3.19
(s, 2H), 2.93 (t, 2H, J = 6.7), 2.35 (s, 6H), 2.08 (d, 6H, J = 4.3). MS (ESI-)
m/z 407.2 (M-H)-.
Example 288
Ni-(5- { 1-[2-(3,5-dimethyl-1 H-pyrazol-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}-1
H-indazol-3-yl)-
N2,N2 -dimethylglycinamide
The title compound was prepared according to the procedure outlined in Example
282F substituting 4-(2-azidoethyl)-3,5-dimethyl-lH-pyrazole for 1-
(azidomethyl)-3-
methylbenzene. 'H NMR (400 MHz, DMSO-d6) 6 ppm 12.85 (s, 1H), 10.06 (s, 1H),
8.37 (s,
1H), 8.21 (s, 1H), 7.78 (d, 1H, J = 8.8), 7.51 (d, 1H, J = 8.8), 4.42 (t, 2H,
J = 6.9), 3.19 (s,
2H), 2.89 (t, 2H, J = 7.0), 2.35 (s, 6H), 1.97 (s, 6H). MS (ESI-) m/z 406.2 (M-
H)-.
Example 289
2-(4- {3-[(N,N-dimethylglycyl)amino]-1 H-indazol-5-yl} -1 H-1,2,3-triazol-l-
yl)-2-
methylpropanoic acid
The title compound was prepared according to the procedure outlined in Example
282F substituting 2-azido-2-methylpropanoic acid for 1-(azidomethyl)-3-
methylbenzene. 'H
NMR (400 MHz, DMSO-d6) 8 ppm 12.77 (s, 1H), 10.03 (s, 1H), 8.47 (s, 1H), 8.22
(s, 1H),
7.85 (dd, 1H, J = 0.9, 8.7), 7.49 (d, 1H, J = 8.6), 3.21 (s, 2H), 2.36 (s,
6H), 1.77 (s, 6H). MS
(ESI-) m/z 370.2 (M-H)-.
Example 290
ethyl (4-{3-[(N,N-dimethylglycyl)amino]-1H-indazol-5-yl}-1H-1,2,3-triazol-l-
yl)acetate
The title compound was prepared according to the procedure outlined in Example
282F substituting ethyl 2-azidoacetate for 1-(azidomethyl)-3-methylbenzene. 'H
NMR (400
MHz, DMSO-d6) 8 ppm 12.87 (s, 1H), 10.08 (s, 1H), 8.51 (s, 1H), 8.26 (s, 1H),
7.82 (dd, 1H,
J = 1.4, 8.7), 7.53 (d, 1H, J = 8.8), 5.44 (s, 2H), 4.21 (q, 2H, J = 7.0),
3.19 (s, 2H), 2.35 (s,
6H), 1.24 (t, 3H, J = 7.1). MS (ESI+) m/z 372.2 (M+H)+.
Example 291
N2,N2 -dimethyl-N'-(5- { 1-[(trimethylsilyl)methyl]-1 H-1,2,3-triazol-4-yl} -1
H-indazol-3-
yl)glycinamide
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The title compound was prepared according to the procedure outlined in Example
282F substituting (azidomethyl)trimethylsilane for 1-(azidomethyl)-3-
methylbenzene. 'H
NMR (400 MHz, DMSO-d6) 6 ppm 13.04 (s, 1H), 10.20 (s, 1H), 8.46 (s, 1H), 8.36
(s, 1H),
7.94 (dd, 1H, J = 1.3, 8.7), 7.65 (d, 1H, J = 8.8), 4.18 (s, 2H), 3.33 (s,
2H), 2.49 (s, 6H), 0.25
(m, 9H). MS (ESI+) m/z 372.2 (M+H)+.
Example 292
Ni-[5-(3-furyl)-1 H-indazol-3-yl]-N2,N2 -dimethylglycinamide
The title compound was prepared according to the procedure outlined in Example
233A substituting Example 282C for 5-bromo-2-fluorobenzonitrile and furan-3-
ylboronic
acid for l-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
iH NMR
(600 MHz, DMSO-d6) 6 ppm 12.70 (s, 1H), 9.98 (s, 1H), 8.08 (s, 1H), 7.90 (s,
1H), 7.72 (t,
1H, J = 1.6), 7.59 (dd, 1H, J = 1.4, 8.7), 7.45 (d, 1H, J = 8.8), 6.87 (s,
1H), 3.17 (s, 2H), 2.33
(s, 6H). MS (ESI+) m/z 285.2 (M+H)+.
Example 293
N2,N2 -dimethyl-Ni-[5-(1 H-pyrazol-5 -yl)-1 H-indazol-3-yl]glycinamide
The title compound was prepared according to the procedure outlined in Example
233A substituting Example 282C for 5-bromo-2-fluorobenzonitrile and 1H-pyrazol-
5-
ylboronic acid for 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
pyrazole. 'H
NMR (400 MHz, DMSO-d6) 6 ppm 12.68 (s, 1H), 10.01 (s, 1H), 8.12 (s, 1H), 7.80
(d, 1H, J
= 9.0), 7.69 (s, 1 H), 7.46 (d, 1 H, J = 8.6), 6.60 (d, 1 H, J = 2.0), 3.17
(d, 2H, J = 6.4), 2.34 (s,
6H). MS (ESI+) m/z 285.2 (M+H)+.
Example 294
N2,N2 -dimethyl-Ni-(5-pyrimidin-5-yl-lH-indazol-3-yl)glycinamide
The title compound was prepared according to the procedure outlined in Example
233A substituting Example 282C for 5-bromo-2-fluorobenzonitrile and pyrimidin-
5-
ylboronic acid for 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
pyrazole. 'H
NMR (600 MHz, DMSO-d6) 8 ppm 12.87 (s, 1H), 10.11 (s, 1H), 9.16 (s, 1H), 9.09
(s, 2H),
8.16 (s, 1H), 7.75 (dd, 1H, J= 1.5, 8.8), 7.60 (d, 1H, J= 8.8), 3.18 (s, 2H),
2.33 (s, 6H). MS
(ESI+) m/z 297.2 (M+H)+.
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Example 295
Ni-[5-(2,1,3-benzoxadiazol-5-yl)-1 H-indazol-3-yl]-N2,N2 -dimethylglycinamide
The title compound was prepared according to the procedure outlined in Example
233A substituting Example 282C for 5-bromo-2-fluorobenzonitrile and
benzo[c][1,2,5]oxadiazol-5-ylboronic acid for 1-benzyl-4-(4,4,5,5-tetramethyl-
1,3,2-
dioxaborolan-2-yl)-1H-pyrazole. 'H NMR (600 MHz, DMSO-d6) 6 ppm 12.87 (s, IH),
10.15
(s, 1 H), 8.29 (s, 1 H), 8.21 (s, 1 H), 8.16 (d, 1 H, J = 9.4), 7.99 (dd, 1 H,
J = 1.1, 9.4), 7.85 (m,
1H), 7.59 (d, 1H, J= 8.8), 3.19 (s, 2H), 2.34 (s, 6H). MS (ESI+) m/z 337.2
(M+H)
Example 296
N2,N2 -dimethyl-Ni-[5-(1 H-pyrazol-4-yl)-1 H-indazol-3-yl]glycinamide
The title compound was prepared according to the procedure outlined in Example
233A substituting Example 282C for 5-bromo-2-fluorobenzonitrile and 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-benzyl-4-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-pyrazole. 'H NMR (600 MHz, DMSO-d6) 6 ppm 12.62 (s, IH),
9.94
(s, 1 H), 7.95 (s, 2H), 7.87 (s, 1 H), 7.5 8 (d, 1 H, J = 8.8), 7.42 (d, 1 H,
J= 8.8), 3.16 (s, 2H),
2.34 (s, 6H). MS (ESI+) m/z 285.2 (M+H)+.
Example 297
N2,N2 -dimethyl-Ni-[5-(1-methyl-lH-pyrazol-4-yl)-IH-indazol-3-yl]glycinamide
The title compound was prepared according to the procedure outlined in Example
233A substituting Example 282C for 5-bromo-2-fluorobenzonitrile and 1-methyl-4-
(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole or 1-benzyl-4-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-pyrazole. 'H NMR (600 MHz, DMSO-d6) 6 ppm 12.64 (s, IH),
9.98
(s, 1 H), 8.04 (s, 1 H), 7.86 (s, 1 H), 7.76 (s, 1 H), 7.55 (dd, 1 H, J = 1.6,
8.6), 7.43 (d, 1 H, J
8.8), 3.87 (s, 3H), 3.17 (s, 2H), 2.35 (s, 6H). MS (ESI+) m/z 299.2 (M+H)+.
Example 298
Nl-[5-(3,5-dimethyl-lH-pyrazol-4-yl)-1H-indazol-3-yl]-N2,N2 -
dimethylglycinamide
The title compound was prepared according to the procedure outlined in Example
233A substituting Example 282C for 5-bromo-2-fluorobenzonitrile and 3,5-
dimethyl-4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-benzyl-4-
(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 'H NMR (600 MHz, DMSO-d6) 6
ppm
12.63 (s, 1 H), 10.02 (s, 1 H), 7.63 (s, 1 H), 7.46 (m, 1 H), 7.27 (dd, 1 H, J
= 1.6, 8.6), 3.16 (s,
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2H), 2.32 (s, 6H), 2.18 (s, 6H). MS (ESI+) m/z 323.2 (M+H)
Example 299
Ni- {5-[2-(dimethylamino)pyrimidin-5-yl]-1 H-indazol-3-yl} -N2,N2 -
dimethylglycinamide
The title compound was prepared according to the procedure outlined in Example
233A substituting Example 282C for 5-bromo-2-fluorobenzonitrile and N,N-
dimethyl-5-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine for 1-benzyl-4-
(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 'H NMR (600 MHz, DMSO-d6) 6
ppm
12.72 (s, 1 H), 10.03 (s, 1 H), 8.62 (s, 2H), 7.91 (s, 1 H), 7.5 8(dd, 1 H, J
= 1.6, 8.6), 7.51 (d,
1H, J = 8.5), 3.16 (s, 8H), 2.33 (s, 6H). MS (ESI+) m/z 340.2 (M+H)+.
Example 300
N2,N2 -dimethyl-Ni - [ 5 -(2-morpholin-4-ylpyrimidin-5 -yl)-1 H-indazol-3 -yl]
glycinamide
The title compound was prepared according to the procedure outlined in Example
233A substituting Example 282C for 5-bromo-2-fluorobenzonitrile and 4-(5-
(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine for 1-benzyl-4-
(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 'H NMR (600 MHz, DMSO-d6) b
ppm
12.74 (s, 1H), 10.03 (s, 1H), 8.67 (s, 2H), 7.94 (s, 1H), 7.60 (dd, 1H, J =
1.8, 8.8), 7.52 (d,
1H, J = 8.5), 3.74 (m, 4H), 3.67 (m, 4H), 3.17 (s, 2H), 2.33 (s, 6H). MS
(ESI+) m/z 382.2
(M+H)+.
Example 301
N2,N2 -dimethyl-N1- {5-[ 1-(2-morpholin-4-ylethyl)-1 H-pyrazol-4-yl]-1 H-
indazol-3-
yl} glycinamide
The title compound was prepared according to the procedure outlined in Example
233A substituting Example 282C for 5-bromo-2-fluorobenzonitrile and 4-(2-(4-
(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine for 1-
benzyl-4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. iH NMR (600 MHz,
DMSO-d6)
b ppm 12.63 (s, 1 H), 9.96 (s, 1 H), 8.09 (s, 1 H), 7.85 (s, 1 H), 7.77 (s, 1
H), 7.54 (dd, 1 H, J =
1.5, 8.8), 7.43 (d, 1H, J = 8.5), 4.24 (t, 2H, J = 6.6), 3.54 (m, 4H), 3.16
(s, 2H), 2.73 (t, 2H, J
= 6.6), 2.41 (s, 4H), 2.34 (s, 6H). MS (ESI+) m/z 398.3 (M+H)+.
Example 302
Ni-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N2,N2-
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dimethylglycinamide
Example 302A
1-benzyl-5-cyclopropyl-4-(tributylstannyl)-1 H-1,2,3-triazole
The title compound was prepared according to the procedure outlined in Example
142A substituting toluene for hexane and (azidomethyl)benzene for Example 80A.
The
crude product was used in the next step without purification.
Example 302B
5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile
The title compound was prepared according to the procedure outlined in Example
142B substituting Examp1e302A for Example 142A and 2-fluoro-5-iodobenzonitrile
for 87A.
MS (ESI+) m/z 319.2 (M+H)+.
Example 302C
5-(1-benzyl-5 -cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3 -amine
The title compound was prepared according to the procedure outlined in Example
62D substituting Example 302B for Example 62C. MS (ESI-) m/z 299.2 (M-H)-.
Example 302D
tert-butyl3-amino-5-(1-benzyl-5-cyclopropyl-lH-1,2,3-triazol-4-yl)-1H-indazole-
l-
carboxylate
The title compound was prepared according to the procedure outlined in Example
64A substituting Example 302C for Example 62D.
Example 302E
Ni-[5-(1-benzyl-5-cyclopropyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N2,N2-
dimethylglycinamide
The title compound was prepared according to the procedure outlined in Example
64B
substituting Example 302D for Example 64A and dimethylaminoacetylchloride
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hydrochloride for methoxy acetyl chloride. 'H NMR (400 MHz, DMSO-d6) 8 ppm
12.76 (s,
1H), 10.06 (s, 1H), 8.18 (s, 1H), 7.79 (d, 1H, J = 8.8), 7.50 (d, 1H, J 8.8),
7.34 (m, 5H),
5.68 (s, 2H), 3.16 (s, 2H), 2.32 (s, 6H), 1.76 (m, 1H), 1.05 (q, 2H, J 6.1),
0.39 (q, 2H, J
5.4). MS (ESI+) m/z 416.3 (M+H)+. MS (ESI+) m/z 416.3 (M+H)
Example 303
Nl-[5-(1-benzyl-lH-pyrazol-4-yl)-1H-indazol-3-yl]-N2,N2 -dimethylglycinamide
Example 303A
3-amino-5-(1-benzyl-lH-pyrazol-4-yl)-indazole-l-carboxylic acid tert-butyl
ester
The title compound was prepared according to the procedure outlined in Example
64A substituting Example 233B for Example 62D (0.925 g, 100%). 'H NMR (400
MHz,
DMSO-d6) 6 ppm 8.19 (s, 1H), 8.04 (s, 1H), 7.90-7.95 (m, 1H), 7.87 (s, 1H),
7.74 (d, J = 1.6
Hz, 1H), 7.28-7.36 (m, 5 H), 6.27 (s, 2H), 5.37 (s, 2H), 1.58 (s, 9H). MS
(ESI+) m/z 390
(M+H)+.
Example 303B
Ni-[5-(1-benzyl-lH-pyrazol-4-yl)-1H-indazol-3-yl]-N2,N2 -dimethylglycinamide
A suspension of 2-(dimethylamino)acetic acid (32 mg, 0.308 mmol) and oxalyl
chloride (0.31 mL, 0.61 mmol) in dichloromethane (5 mL) and dimethylformamide
(2 drops)
was stirred at ambient temperature for about 1 hour then concentrated under
reduced
pressure. The residue was suspended in tetrahydrofuran (3 mL) and added to a
suspension of
Example 303A (40 mg, 0.103 mmol) and potassium carbonate (43 mg, 0.308 mmol)
in
tetrahydrofuran (5 mL). The reaction mixture was stirred at ambient
temperature for about
30 minutes then trifluoroacetic acid (4 mL) was added and the reaction mixture
was heated at
about 60 C for about 20 hours. The reaction mixture was cooled to ambient
temperature and
concentrated under reduced pressure, diluted with dichloromethane (20 mL) and
washed with
15% aqueous sodium hydroxide solution (20 mL). The organic extract was
separated, dried
over magnesium sulfate, filtered and concentrated under reduced pressure. The
crude
material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M
ammonium
acetate) gradient elution method to afford the title compound as the acetate
salt. 'H NMR
(400 MHz, DMSO-d6) 6 ppm 9.97 (s, 1H), 8.21 (s, 1H), 7.83 (s, 1H), 7.82 (s,
1H), 7.56 (d, J
= 8.7 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.32-7.40 (m, 2H), 7.25-7.32 (m, 3H),
5.35 (s, 2H),
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3.16 (s, 2H), 2.33 (s, 6H), 1.91 (s, 3H). MS (ESI+) m/z 375 (M+H)+.
Example 304
Ni-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N2 -
methylglycinamide
The title compound was prepared according to the procedure outlined in Example
303B substituting 2-(tert-butoxycarbonyl(methyl)amino)acetic acid for 2-
(dimethylamino)acetic acid and Example 64A for Example 303A. 'H NMR (400 MHz,
DMSO-d6) 6 ppm 8.56 (s, 1H), 8.28 (s, 1H), 7.78-7.88 (m, 1H), 7.45-7.56 (m,
1H), 7.28-7.45
(5H, m), 5.64 (2H, s), 2.37 (s, 2H), 1.89 (s, 3H). MS (ESI+) m/z 362 (M+H)+.
Example 305
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-pyrrolidin-1-
ylacetamide
Example 305A
tert-butyl 5-(1-benzyl-lH-1,2,3-triazol-4-yl)-3-(2-bromoacetamido)-1H-indazole-
l-
carboxylate
To a suspension of Example 64A (500 mg, 1.28 mmol) in tetrahydrofuran (12 mL)
was added diisopropylethylamine (0.22 mL, 1.28 mmol). The reaction mixture was
stirred at
ambient temperature for about 15 minutes then 2-bromoacetyl chloride (0.11 mL,
1.2 mmol)
was added. The reaction mixture was stirred at ambient temperature for about
16 hours then
additional 2-bromoacetyl chloride (0.11 mL, 1.2 mmol) was added. The reaction
mixture
was stirred for an additional 15 minutes then concentrated under reduced
pressure to provide
the title compound as a brown solid. This material was used without further
purification.
Example 305B
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-pyrrolidin-1-
ylacetamide
To a solution of Example 305A (44 mg, 0.086 mmol) and diisopropylethylamine
(0.015 mL, 0.086 mmol) in acetonitrile (1 mL) was added pyrrolidine (0.021 mL,
0.25 mmol)
and the reaction mixture was heated at about 60 C for about 15 minutes. The
reaction
mixture was cooled to ambient temperature and trifluoroacetic acid (1 mL) was
added. The
reaction mixture was heated at about 60 C for about 48 hours. The reaction
mixture was
concentrated under reduced pressure, diluted with dichloromethane (20 mL) and
washed with
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15% aqueous sodium hydroxide solution (20 mL). The organic layer was
separated, dried
over magnesium sulfate, filtered and concentrated under reduced pressure. The
crude
material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M
ammonium
acetate) gradient elution method to afford the title compound. 'H NMR (400
MHz, DMSO-
d6) 6 ppm 8.5 8(s, 1 H), 8.24 (s, I H), 7.81 (d, J = 8.7 Hz, I H), 7.50 (d, J
= 8.7 Hz, I H), 7.27-
7.45 (m, 5H), 5.64 (s, 2H), 3.35 (s, 2H), 2.65 (s, 4H), 1.76 (s, 4H). MS
(ESI+) m/z 402
(M+H)+.
Example 306
N'-[5-(I-benzyl-IH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N2-
cyclopentylglycinamide
The title compound was prepared according to the procedure outlined in Example
305B substituting cyclopentanamine for pyrrolidine (0.004 g, 12%). 'H NMR (400
MHz,
DMSO-d6) 6 ppm 8.56 (s, IH), 8.31 (s, IH), 7.73-7.86 (d, J = 8.8 Hz, IH), 7.49
(d, J = 8.7
Hz, 1H), 7.29-7.45 (m, 5H), 5.64 (s, 2H), 3.37 (s, 2H), 2.99-3.14 (m, IH),
1.60-1.80 (m, 4H),
1.30-1.50 (m, 4H). MS (ESI+) m/z 416 (M+H)+.
Example 307
Ni-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N2 -
cyclopropylglycinamide
To a solution of Example 305A (100 mg, 0.196 mmol) and diisopropylethylamine
(0.034 mL, 0.19 mmol) in acetonitrile (1 mL) was added cyclopropanamine (11
mg, 0.19
mmol) and the reaction mixture was heated at about 60 C for about 1 hour. The
reaction
mixture was cooled to ambient temperature and hydrochloric acid (4 N in
dioxane, I mL) was
added. The reaction mixture was stirred at ambient temperature for about 16
hours. The
reaction mixture was concentrated under reduced pressure and the crude
material was
purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium
acetate)
gradient elution method to afford the title compound as the acetate salt. 'H
NMR (400 MHz,
DMSO-d6) 6 ppm 10.18 (s, IH), 8.28 (s, IH), 8.56 (s, 1H), 7.81 (d, J = 8.6 Hz,
IH), 7.49 (d, J
= 8.7 Hz, IH), 7.30-7.45 (m, 5H), 5.64 (s, 2H), 3.45 (s, 2H), 2.18-2.26 (m,
1H), 1.89 (s, 3H),
0.37-0.45 (m, 2H), 0.29-0.37 (m, 2H). MS (ESI+) m/z 388 (M+H)
Example 308
Ni-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N2 -tetrahydro-2H-
pyran-4-
ylglycinamide
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The title compound was prepared as the acetate salt according to the procedure
outlined in Example 307 substituting tetrahydro-2H-pyran-4-amine for
cyclopropanamine.
iH NMR (400 MHz, DMSO-d6) 6 ppm 8.56 (s, 1H), 8.31 (s, 1H), 7.81 (d, J = 8.7
Hz, 1H),
7.50 (d, J= 8.7 Hz, 1H), 7.31-7.45 (m, 5H), 5.64 (s, 2H), 3.84 (d, J= 11.2 Hz,
2H), 3.43 (s,
2H), 3.30 (t, J = 10.8 Hz, 2H), 2.62-2.74 (m, 1H), 1.88 (s, 3H), 1.75-1.85 (m,
2H), 1.24-1.39
(m, 2H). MS (ESI+) m/z 432 (M+H)+.
Example 309
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-(3-
hydroxypyrrolidin-l-
yl)acetamide
The title compound was prepared as the diacetate salt according to the
procedure
outlined in Example 307 substituting pyrrolidin-3-ol for cyclopropanamine. 'H
NMR (400
MHz, DMSO-d6) 6 ppm 10.09 (s, 1H), 8.22 (s, 1H), 8.58 (s, 1H), 7.82 (d, J =
8.7 Hz, 1H),
7.50 (d, J = 8.7 Hz, 1H), 7.28-7.45 (m, 5H), 5.64 (s, 2H), 4.16-4.26 (m, 1H),
3.34 (s, 2H),
2.77-2.93 (m, 2H), 2.52-2.65 (m, 2H), 1.98-2.13 (m, 1H), 1.87 (s, 6H), 1.56-
1.69 (m, 1H).
MS (ESI+) m/z 418 (M+H)+.
Example 310
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-(3-hydroxypiperidin-
l-
yl)acetamide
The title compound was prepared as the acetate salt according to the procedure
outlined in Example 307 substituting piperidin-3-ol for cyclopropanamine. 'H
NMR (400
MHz, DMSO-d6) 6 ppm 10.05 (s, 1H), 8.56 (s, 1H), 8.23 (s, 1H), 7.82 (d, J =
8.7 Hz, 1H),
7.50 (d, J = 8.7 Hz, 1H), 7.29-7.44 (m, 5H), 5.64 (s, 2H), 3.55-3.67 (m, 1H),
3.20 (s, 2H),
2.77-2.88 (m, IH), 2.60-2.70 (m, 1H), 2.22-2.35 (m, 1H), 2.12-2.23 (m, 1H),
1.88 (s, 3H),
1.66-1.78 (m, 2H), 1.43-1.59 (m, 1H), 1.13-1.27 (m, 1H). MS (ESI+) m/z 432
(M+H)+.
Example 311
Ni -[ 5-(1-b enzyl-1 H-1,2, 3-triazol-4-yl)-1 H-indazol-3 -yl] -N3,N3-dimethyl-
beta-alaninamide
The title compound was prepared as the acetate salt according to the procedure
outlined in Example 307 substituting dimethylamine for cyclopropanamine. 'H
NMR (400
MHz, DMSO-d6) 6 ppm 10.48 (s, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 7.80 (d, J =
8.7 Hz, 1H),
7.48 (d, J = 8.7 Hz, 1H), 7.30-7.44 (m, 5H), 5.64 (s, 2H), 2.60 (d, J = 6.1
Hz, 2H), 2.54 (d, J
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6.3 Hz, 2H), 2.21 (s, 6H), 1.90 (s, 3H). MS (ESI+) m/z 390 (M+H)
Example 312
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-morpholin-4-
ylacetamide
The title compound was prepared according to the procedure outlined in Example
307
substituting morpholine for cyclopropanamine. iH NMR (400 MHz, DMSO-d6) 8 ppm
I0.10
(s, 1 H), 8.57 (s, I H), 8.23 (s, 1 H), 7.81 (d, J = 8.7 Hz, 1 H), 7.50 (d, J
= 8.7 Hz, 1 H), 7.29-
7.46 (m, 5H), 5.64 (s, 2H), 3.59-3.71 (m, 4H), 3.22-3.28 (m, 2H), 2.54 -2.64
(m, 4H). MS
(ESI+) m/z 418 (M+H)+.
Example 313
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-(4-methylpiperazin-
l-
yl)acetamide
The title compound was prepared as the diacetate salt according to the
procedure
outlined in Example 307 substituting 1-methylpiperazine for cyclopropanamine.
'H NMR
(400 MHz, DMSO-d6) 6 ppm 8.57 (s, 1H), 8.25 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H),
7.50 (d, J
8.7 Hz, IH), 7.32-7.43 (m, 5H), 5.64 (s, 2H), 3.22 (s, 2H), 2.53-2.65 (m, 4H),
2.31-2.45 (m,
4H), 2.17 (s, 3H), 1.85 (s, 6 H). MS (ESI+) m/z 431 (M+H)+.
Example 314
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-2-(3-oxopiperazin-l-
yl)acetamide
The title compound was prepared according to the procedure outlined in Example
307
substituting piperazine-2-one for cyclopropanamine. 'H NMR (400 MHz, DMSO-d6)
8 ppm
10.21 (s, 1 H), 8.5 7(s, 1 H), 8.22 (s, I H), 7.81 (d, J = 8.7 Hz, I H), 7.50
(d, J = 8.7 Hz, I H),
7.31 - 7.46 (m, 5H), 5.64 (s, 2H), 3.36 (s, 2H), 3.24 (s, 2H), 3.17 (s, 2H),
2.78 (s, 2H). MS
(ESI+) m/z 431 (M+H)+.
Example 315
Nl-[5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-N2-
isopropylglycinamide
The title compound was prepared as the acetate salt according to the procedure
outlined in Example 307 substituting propan-2-amine for cyclopropanamine. 'H
NMR (400
MHz, DMSO-d6) 8 ppm 8.56 (s 1H), 8.31 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.49
(d, J = 8.7
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Hz, 1H), 7.31-7.44 (m, 5H), 5.64 (s, 2H), 3.39 (s, 2H), 2.73-2.86 (m, IH),
1.90 (s, 3H), 1.04
(d, J = 6.1 Hz, 6H). MS (ESI+) m/z 390 (M+H)+.
Example 316
Ni-[5-(1-benzyl-lH-1,2,3-triazol-4-yl)-IH-indazol-3-yl]-N2-
cyclohexylglycinamide
The title compound was prepared as the acetate salt according to the procedure
outlined in Example 307 substituting cyclohexanamine for cyclopropanamine. 'H
NMR (400
MHz, DMSO-d6) 8 ppm 8.55 (s, 1H), 8.31 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.49
(d, J = 8.7
Hz, 1H), 7.30-7.44 (m, 5H), 5.64 (s, 2H), 3.40 (s, 2H), 1.90 (s, 3H), 1.80-
1.88 (m, 2H), 1.63-
1.73 (m, 2H), 1.50-1.60 (m, 1H), 1.02-1.29 (m, 5H). MS (ESI+) m/z 430 (M+H)+.
Example 317
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl] acetamide
To a mixture of Example 64A (20 mg, 0.051 mmol) and diisopropylethylamine
(0.063
mL, 0.35 mmol) in tetrahydrofuran (1.5 mL) was added acetyl chloride (0.013
mL, 0.17
mmol) and the reaction mixture was stirred at ambient temperature for about
1.5 hours.
Hydrochloric acid (4 N in dioxane, 1.5 mL) was added and the mixture stirred
at ambient
temperature for about 16 hours. The solvent was removed under reduced pressure
and the
crude material was purified by reverse-phase HPLC using acetonitrile/water
(0.05 M
ammonium acetate) gradient elution method to afford the title compound as the
acetate salt.
iH NMR (400 MHz, DMSO-d6) 6 ppm 10.35 (s, 1H), 8.57 (s, 1H), 8.22 (s, 1H),
7.81 (d, J
8.7 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.33-7.42 (m, 5H), 5.64 (s, 2H), 2.13
(s, 3H). MS
(ESI-) m/z 331 (M-H)-.
Example 318
Ni-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N2-
cyclobutylglycinamide
The title compound was prepared according to the procedure outlined in Example
307
substituting cyclobutanamine for cyclopropanamine. 'H NMR (400 MHz, DMSO-d6) 6
ppm
8.56 (s, 1 H), 8.29 (s, 1 H), 7.81 (d, J = 8.7 Hz, 1 H), 7.49 (d, J = 8.7 Hz,
1 H), 7.31-7.45 (m,
5H), 5.64 (s, 2H), 3.31 (s, 2H), 2.01-2.20 (m, 2H), 1.48-1.83 (m, 5H). MS
(ESI+) m/z 402
(M+H)+.
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Example 319
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N'-propylurea
To a solution of Example 64A (75 mg, 0.19 mmol) in pyridine (2 mL) was added 1-
isocyanatopropane (16 mg, 0.19 mmol) and the reaction mixture was stirred at
ambient
temperature for about 3 hours. Additional isocyanate (0.1 mL) was added and
the mixture
was heated at about 80 C for about 16 hours. The reaction mixture was cooled
to ambient
temperature and water (5 mL) was added. The resulting precipitate was
collected by
filtration then treated with hydrochloric acid (4 N solution in dioxane, 3 mL)
and stirred at
room temperature for about 4.5 hours. Diethyl ether (5 mL) was added and the
precipitate
collected by filtration. The crude material was purified by reverse-phase HPLC
using
acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford
the title
compound as the acetate salt. 'H NMR (400 MHz, DMSO-d6) S ppm 9.34 (s, 1H),
8.50 (s,
1H), 8.42 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.31-
7.48 (m, 5H), 5.65
(s, 2H), 3.18 (dd, J = 6.6, 12.7 Hz, 2H), 1.51 (dd, J = 7.1, 14.3 Hz, 2H),
0.91 (t, J = 7.3 Hz,
3H). MS (ESI+) m/z 376 (M+H)+.
Example 320
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl] ethanesulfonamide
To a solution of Example 64A (75 mg, 0.19 mmol) in pyridine (2 mL) was added
ethanesulfonyl chloride (25 mg, 0.19 mmol) and the reaction mixture was
stirred at room
temperature for about 3 hours. Additional sulfonyl chloride (25 mg, 0.19 mmol)
was added
and the reaction mixture was stirred for about 48 hours. The reaction mixture
was
concentrated under reduced pressure and the residue dissolved in
dichloromethane (10 mL)
and washed with 1 N aqueous hydrochloric acid (10 mL). The organic portion was
separated,
dried under reduced pressure, and treated with hydrochloric acid (4 N in
dioxane, 5 mL) and
stirred at room temperature for about 12 hours. The reaction mixture was
concentrated under
reduced pressure and the crude material was purified by reverse-phase HPLC
using
acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford
the title
compound as the acetate salt. 'H NMR (400 MHz, DMSO-d6) 6 ppm 10.12 (s, 1H),
8.61 (s,
1H), 8.24 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.29-
7.48 (m, 5H), 5.64
(s, 2H), 3.29 (d, J = 9.2 Hz, 2H), 1.31 (t, J = 7.3 Hz, 3H). MS (ESI+) m/z 383
(M+H)+.
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Example 321
5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-N-(cyclopropylmethyl)-1 H-indazol-3-amine
A mixture of Example 64A (100 mg, 0.256 mmol), cyclopropanecarbaldehyde (0.057
mL, 0.76 mmol), sodium triacetoxyborohydride (163 mg, 0.76 mmol) and acetic
acid (0.044
mL, 0.76 mmol) in 1,2-dichloroethane (5 mL) was stirred at ambient temperature
for about
2.5 hours. Hydrochloric acid (4 N in dioxane, 4 mL) was added and the reaction
mixture was
stirred for about 16 hours. The precipitate was collected by filtration,
rinsing with ether (10
mL). The solid was dissolved in dichloromethane (10 mL) and treated with
trifluoroacetic
acid (0.1 mL) and the reaction mixture was stirred at room temperature for
about 2 hours.
The reaction mixture was neutralized by the addition of 15% aqueous sodium
hydroxide
solution (about 15 mL) and the organic layer was separated, dried over
magnesium sulfate,
filtered and concentrated under reduced pressure. The crude material was
purified by
reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient
elution
method to afford the title compound as the acetate salt. 'H NMR (400 MHz, DMSO-
d6) 8
ppm 11.43 (s, IH), 8.41 (s, 1H), 8.28 (s, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.32-
7.45 (m, 5H),
7.26 (d, J = 8.6 Hz, 1H), 6.08 (t, J = 5.7 Hz, IH), 5.64 (s, 2H), 3.12 (t, J =
6.2 Hz, 2 H), 1.04-
1.22 (m, 1H), 0.35-0.53 (m, 2H), 0.17-0.32 (m, 2H). MS (ESI+) m/z 345 (M+H)+.
Example 322
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-N'-ethylurea
The title compound was prepared according to the procedure outlined in Example
319
substituting isocyanatoethane for 1-isocyanatopropane. 'H NMR (400 MHz, DMSO-
d6) b
ppm 9.32 (s, 1 H), 8.49 (s, 1 H), 8.42 (s, 1 H), 7.81 (d, J = 8.7 Hz, 1 H),
7.70 (d, J = 8.7 Hz,
1H), 7.31-7.49 (m, 5H), 5.65 (s, 2H), 3.23 (d, J = 6.9 Hz, 2H), 1.12 (t, J =
7.1 Hz, 3 H). MS
(ESI+) m/z 362 (M+H)+.
Example 323
1-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]pyrrolidin-2-one
A suspension of Example 64A (200 mg, 0.51 mmol) and diisopropylethylamine
(0.089 mL, 0.51 mmol) in tetrahydrofuran (5 mL) was stirred for about 15
minutes at ambient
temperature then 4-bromobutanoyl chloride (0.059 mL, 0.51 mmol) was added. The
reaction
mixture was stirred for about 16 hours. The precipitate was removed by
filtration and the
filtrate concentrated under reduced pressure. The residue was taken up in
acetonitrile (5 mL)
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and treated with diisopropylethylamine (0.089 mL, 0.51 mmol) and heated at
about 60 C for
about 16 hours. The reaction mixture was cooled to room temperature and
concentrated
under reduced pressure. The residue was treated with hydrochloric acid (4 N in
dioxane, 5
mL) and the reaction mixture stirred at room temperature for about 2 hours.
The reaction
mixture was concentrated under reduced pressure and the crude material was
purified by
reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient
elution
method to afford the title compound as the acetate salt. 'H NMR (400 MHz, DMSO-
d6) 6
ppm 12.84 (s, 1 H), 8.5 6(s, 1 H), 8.49 (s, 1 H), 7.84 (d, J = 8.6 Hz, 1 H),
7.51 (d, J = 8.7 Hz,
1H), 7.29-7.46 (m, 5H), 5.64 (s, 2H), 3.96 (t, J = 6.9 Hz, 2H), 2.56 (t, J =
7.9 Hz, 2H), 2.25-
2.12 (m, 2H). MS (ESI+) m/z 359 (M+H)+.
Example 324
N-[5-(1-benzyl-1 H-1,2,3-triazol-4-yl)-1 H-indazol-3-yl]-4-
(dimethylamino)butanamide
The title compound was prepared as the diacetate salt according to the
procedure
outlined in Example 303B substituting 4-(dimethylamino)butanoic acid for 2-
(dimethylamino)acetic acid and substituting Example 64A for Example 303A. 'H
NMR (400
MHz, DMSO-d6) 6 ppm 10.34 (s, 1H), 8.53 (s, 1H), 8.22 (s, 1H), 7.78 (d, J =
8.7 Hz, 1H),
7.47 (d, J = 8.7 Hz, 1H), 7.30-7.41 (m, 5H), 5.62 (s, 2H), 2.41 (t, J = 7.2
Hz, 2H), 2.28 (t, J
6.8 Hz, 2H), 2.14 (s, 6H), 1.84 (s, 6H), 1.74-1.77 (m, 2H). MS (ESI-) m/z 462
(M-H)-.
Example 325
N-3,4-dihydro-lH-isochromen-4-yl-5-(1H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81 B
substituting 3,4-dihydro-lH-isochromen-4-amine for piperidine. 'H NMR (300
MHz,
DMSO-d6) 6 ppm 13.4 (br s, 1 H), 9.02 (d, 1 H), 8.4 (m, 1 H), 8.22 (m, 1 H),
7.75 (m, 2 H),
7.2-7.4 (m, 5 H), 5.24 (m, 1 H), 4.75 (m, 2 H), 4.02 (m, 1 H), 3.8 (m, 1 H).
MS m/z (ESI+)
361 (M+H)+.
Example 326
N-(cyclohexylmethyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide
5-(1H-Indazol-5-yl)isoxazole-3-carboxylic acid (35 mg, 0.15 mmol, Example
71A),
was dissolved in N,1V-dimethylformamide (0.8 mL) followed by the addition of
HATU (60
mg, 0.15 mmol) dissolved in N,N-dimethylformamide (0.8 mL). Then a solution of
1-
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cyclohexylmethanamine (17 mg, 0.17 mmol), dissolved in N,N-dimethylformamide
(0. 8mL)
was added, followed by diisopropylethylamine (56 gL,0..31 mmol) dissolved in
N,N-
dimethylformamide (0.8 mL). The resulting mixture was shaken for 3 hours at 40
C. The
reaction was filtered, checked by LC/MS and concentrated to dryness. The
residues were
dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase
HPLC
(Phenomenex Luna C8(2) 5 m 100A AXIATM column (30 mm X 75 mm), 50 mL/min,
10-100% acetonitrile/0.1% trifluoroacetic acid in water) to provide the title
product. 'H
NMR (500 MHz, DMSO-d6/D20) 8 ppm 0.91 - 0.97 (m, 2 H), 1.12 - 1.27 (m, 4 H),
1.61 -
1.75(m,5H),3.08-3.16(m,2H),7.22-7.24(m,1H),7.71-7.75(m,1H),7.87-7.92(m,
1 H), 8.23 - 8.27 (m, 1 H), 8.38 - 8.41 (m, 1 H). MS (ESI+) m/z 325 (M+H)+;
(ESI-) m/z 323
(M-H)-.
Example 327
N-(3-chlorobenzyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 1-(3-chlorophenyl)methanamine was substituted for 1-
cyclohexylmethanamine. iH
NMR (500 MHz, DMSO-d6/D20) 8 ppm 4.47 - 4.52 (m, 2 H), 7.27 - 7.29 (m, 1 H),
7.30 -
7.42 (m, 4 H), 7.72 - 7.75 (m, 1 H), 7.89 - 7.93 (m, 1 H), 8.25 - 8.28 (m, 1
H), 8.41 - 8.42 (m,
1 H). MS (ESI+) m/z 353 (M+H)+; (ESI-) m/z 351 (M-H)-.
Example 328
5-(1 H-indazol-5-yl)-N-(2-methoxybenzyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 1-(2-methoxyphenyl)methanamine was substituted for 1-
cyclohexylmethanamine. 1H
NMR (500 MHz, DMSO-d6/D20) 8 ppm 3.82 - 3.86 (m, 3 H), 4.45 - 4.50 (m, 2 H),
6.92 -
6.97(m,1H),7.01-7.04(m,1H),7.19-7.24(m,1H),7.26-7.31(m,2H),7.69-7.77(m,
1 H), 7.88 - 7.93 (m, 1 H), 8.24 - 8.28 (m, 1 H), 8.38 - 8.44 (m, 1 H). MS
(ESI+) m/z 349
(M+H) (ESI-) m/z 347 (M-H)-.
Example 329
5-(IH-indazol-5-yl)-N-[2-(trifluoromethyl)benzyl]isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 1-[2-(trifluoromethyl)phenyl]methanamine was substituted for 1-
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cyclohexylmethanamine. 'H NMR (500 MHz, DMSO-d6/D20) b ppm 4.66 - 4.73 (m, 2
H),
7.29 - 7.33 (m, 1 H), 7.49 - 7.60 (m, 2 H), 7.67 - 7.79 (m, 3 H), 7.91 - 7.94
(m, 1 H), 8.26 -
8.28 (m, 1 H), 8.41 - 8.45 (m, 1 H). MS (ESI+) m/z 387 (M+H)+; (ESI-) m/z 385
(M-H)-.
Example 330
5-(IH-indazol-5-yl)-N-[3-(trifluoromethyl)benzyl]isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 1-[3-(trifluoromethyl)phenyl]methanamine was substituted for 1-
cyclohexylmethanamine. 'H NMR (500 MHz, DMSO-d6/D20) b ppm 4.57 - 4.61 (m, 2
H),
7.28-7.31(m,1H),7.59-7.77(m,5H),7.90-7.94(m,1H),8.27-8.28(m,1H),8.40-
8.43 (m, 1 H). MS (ESI-) m/z 385 (M-H)-.
Example 331
5-(IH-indazol-5-yl)-N-[4-(trifluoromethyl)benzyl]isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 1-[4-(trifluoromethyl)phenyl]methanamine was substituted for 1-
cyclohexylmethanamine. 'H NMR (500 MHz, DMSO-d6/D20) 8 ppm 4.55 - 4.60 (s, 2
H),
7.27-7.30(m,1H),7.54-7.59(m,2H),7.70-7.76(m,3H),7.88-7.94(m,1H),8.24-
8.28 (m, 1 H), 8.40 - 8.44 (m, 1 H). MS (ESI+) m/z 387 (M+H)+; (ESI-) m/z 385
(M-H)-.
Example 332
5-(1 H-indazol-5-yl)-N-(pyridin-2-ylmethyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 1-pyridin-2-ylmethanamine was substituted for 1-cyclohexylmethanamine.
'H NMR
(500 MHz, DMSO-d6/D20) 8 ppm 4.74 - 4.84 (s, 2 H), 7.30 - 7.34 (m, 1 H), 7.68 -
7.81 (m, 3
H), 7.89 - 7.97 (m, 1 H), 8.22 - 8.33 (m, 2 H), 8.40 - 8.45 (m, 1 H), 8.67 -
8.76 (m, 1 H). MS
(ESI+) m/z 320 (M+H)+; (ESI-) m/z 318 (M-H)-.
Example 333
5-(1 H-indazol-5-yl)-N-(pyridin-3-ylmethyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 1-pyridin-3-ylmethanamine was substituted for 1-cyclohexylmethanamine.
iH NMR
(500 MHz, DMSO-d6/D20) 8 ppm 4.61 - 4.68 (s, 2 H), 7.27 - 7.31 (m, 1 H), 7.70 -
7.75 (m, 1
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H), 7.83 - 7.94 (m, 2 H), 8.24 - 8.28 (m, 1 H), 8.31 - 8.37 (m, 1 H), 8.40 -
8.44 (m, 1 H), 8.69
- 8.74 (m, 1 H), 8.77 - 8.82 (m, 1 H). MS (ESI+) m/z 320 (M+H)+; (ESI-) m/z
318 (M-H)-.
Example 334
5-(1 H-indazol-5-yl)-N-(pyridin-4-ylmethyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 1-pyridin-4-ylmethanamine was substituted for 1-cyclohexylmethanamine.
iH NMR
(500 MHz, DMSO-d6/D20) 6 ppm 4.73 - 4.80 (s, 2 H), 7.30 - 7.33 (m, 1 H), 7.73 -
7.78 (m, 1
H),7.89-7.97(m,3H),8.25-8.30(m,1H),8.40-8.46(m,1H),8.76-8.83(m,2H). MS
(ESI-) m/z 318 (M-H)-.
Example 335
N-(2-chlorobenzyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 1-(2-chlorophenyl)methanamine was substituted for 1-
cyclohexylmethanamine. 'H
NMR (500 MHz, DMSO-d6/D20) 6 ppm 4.54 - 4.58 (s, 2 H), 7.27 - 7.32 (m, 1 H),
7.33 - 7.42
(m,3H),7.47-7.49(m,1H),7.71-7.77(m,1H),7.88-7.98(m,1H),8.24-8.27(m,1
H), 8.41 - 8.44 (m, 1 H). MS (ESI+) m/z 353 (M+H)+; (ESI-) m/z 351(M-H)-.
Example 336
N-(4-chlorobenzyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 1-(4-chlorophenyl)methanamine was substituted for 1-
cyclohexylmethanamine. 'H
NMR (500 MHz, DMSO-d6/D20) 6 ppm 4.42 - 4.49 (m, 2 H), 7.22 - 7.31 (m, 1 H),
7.34 -
7.49(m,4H),7.70-7.76(m,1H),7.84-7.92(m,1H),8.17-8.30(m,1H),8.35-8.47(m,
1 H). MS (ESI-) m/z 351 (M-H)-.
Example 337
5-(1H-indazol-5-yl)-N-(1-phenyl-2-piperidin-l-ylethyl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81B
substituting 1-phenyl-2-piperidin-1-ylethanamine for piperidine. 'H NMR (300
MHz,
DMSO-d6) 6 ppm 13.4 (br s, 1 H), 9.12 (d, 1 H), 8.4 (s, 1 H), 8.22 (s, 1 H),
7.9 (d, 1 H), 7.7
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(d, 1 H), 7.2-7.4 (m, 6 H), 5.2 (m, 1 H), 3.2 (m, 2 H), 2.3 (m, 4 H), 1.2-1.4
(m, 6 H). MS
(ESI+) m/z 416 (M+H)+.
Example 338
N-[2-(1H-imidazol-l-yl)-1-phenylethyl]-5-(1H-indazol-5-yl)isoxazole-3-
carboxamide
The title compound was prepared according to the procedure outlined in Example
81B
substituting 2-(1H-imidazol-l-yl)-1-phenylethanamine for piperidine. iH NMR
(300 MHz,
DMSO-d6) 6 ppm 13.4 (br s, 1 H), 9.5 (d, 1 H), 8.4 (s, 1 H), 8.22 (s, 1 H),
7.78 (m, 1 H), 7.52
(d, 2 H), 7.72 (d, 2 H), 7.2-7.4 (m, 5 H), 6.85 (s, 1 H), 5.44 (m, 1 H), 4.44
(m, 2 H). MS
(ESI+) m/z 399 (M+H)+.
Example 339
5-(1 H-indazol-5-yl)-N-(2-morpholin-4-yl-l-phenylethyl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81B
substituting 2-morpholin-4-yl-l-phenylethanamine for piperidine. iH NMR (300
MHz,
DMSO-d6) 6 ppm 13.4 (br s, 1 H), 9.2 (d, 1 H), 8.4 (s, 1 H), 8.22 (s, 1 H),
7.9 (d, 1 H), 7.7 (d,
1 H), 7.2-7.4 (m, 6 H), 5.2 (m, 1 H), 3.6 (m, 4 H), 3.4 (m, 2 H), 2.4 (m, 4
H). MS (ESI+) m/z
418 (M+H)+.
Example 340
5-(1 H-indazol-5-yl)-N-[2-(4-methylpiperazin-l-yl)-l -phenylethyl]isoxazole-3-
carboxamide
The title compound was prepared according to the procedure outlined in Example
81B
substituting 2-(4-methylpiperazin-l-yl)-1-phenylethanamine for piperidine. iH
NMR (300
MHz, DMSO-d6) 6 ppm 13.6 (br s, 1 H), 9.14 (d, 1 H), 8.4 (s, 1 H), 8.22 (s, 1
H), 7.9 (d, 1
H), 7.7 (d, 1 H), 7.2-7.4 (m, 6 H), 5.2 (m, 1 H), 3.2 (m, 2 H), 2.4 (m, 4 H),
2.2 (m, 4 H), 2.1
(m, 3 H). MS (ESI+) m/z 432 (M+H)+.
Example 341
5-(1 H-indazol-5-yl)-N-(1-phenyl-2-pyrrolidin-1-ylethyl)isoxazole-3-
carboxamide
The title compound was prepared according to the procedure outlined in Example
81B
substituting 1-phenyl-2-pyrrolidin-1-ylethanamine for piperidine. 'H NMR (300
MHz,
DMSO-d6) 6 ppm 13.4 (br s, 1 H), 9.14 (d, 1 H), 8.4 (s, 1 H), 8.22 (s, 1 H),
7.9 (d, 1 H), 7.7
(d, 1 H), 7.2-7.4 (m, 6 H), 5.18 (m, 1 H), 3.2 (m, 2 H), 2.4 (m, 4 H), 1.8 (m,
3 H). MS (ESI+)
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m/z 402.5 (M+H)+.
Example 342
tert-butyl 2-( { [5 -(1 H-indazol-5 -yl)isoxazol-3 -yl] carbonyl} amino)-2-
phenylethylcarbamate
The title compound was prepared according to the procedure outlined in Example
81B
substituting tert-butyl 2-amino-2-phenylethylcarbamate for piperidine. 'H NMR
(300 MHz,
DMSO-d6) 8 ppm 13.4 (br s, 1 H), 9.14 (d, 1 H), 8.4 (s, 1 H), 8.22 (s, 1 H),
7.9 (d, 1 H), 7.7
(d, 1 H), 7.2-7.4 (m, 6 H), 7.00 (t, 1 H), 5.18 (m, 1 H), 3.2 (m, 2 H), 1.4
(s, 9 H). MS (ESI+)
m/z 449 (M+H)+.
Example 343
5-(1 H-indazol-5-yl)-N-(1-naphthylmethyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 1-(1-naphthyl)methanamine was substituted for 1-cyclohexylmethanamine.
'H NMR
(500 MHz, DMSO-d6/D20) 8 ppm 4.93 - 4.99 (m, 2 H), 7.28 - 7.32 (m, 1 H), 7.48 -
7.66 (m,
4H),7.70-7.76(m,IH),7.86-7.92(m,2H),7.96-8.00(m,1H),8.18-8.23(m,1H),
8.24 - 8.27 (m, 1 H), 8.38 - 8.44 (m, 1 H); ). MS (ESI-) m/z 367 (M-H)-.
Example 344
5 -(1 H-indazol-5 -yl)-N-(2-phenylethyl)isoxazole-3 -carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 2-phenylethanamine was substituted for 1-cyclohexylmethanamine. 'H NMR
(500
MHz, DMSO-d6/D20) 8 ppm 2.84 - 2.92 (t, 2 H), 3.47 - 3.57 (t, 2 H), 7.18 -
7.35 (m, 6 H),
7.69 - 7.77 (m, 1 H), 7.86 - 7.91 (m, 1 H), 8.22 - 8.29 (m, 1 H), 8.37 - 8.44
(m, 1 H). MS
(ESI+) m/z 333 (M+H)+; (ESI-) m/z 331 (M-H)-.
Example 345
5-(1 H-indazol-5-yl)-N-(2-pyridin-2-ylethyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 2-pyridin-2-ylethanamine was substituted for 1-cyclohexylmethanamine.
'H NMR
(500 MHz, DMSO-d6/D20) b ppm 3.22 - 3.29 (t, 2 H), 3.71 - 3.75 (t, 2 H), 7.14 -
7.26 (m, 1
H), 7.70 - 7.75 (m, 1 H), 7.81 - 7.94 (m, 3 H), 8.23 - 8.29 (m, 1 H), 8.35 -
8.44 (m, 2 H), 8.71
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- 8.83 (m, 1 H). MS (ESI+) m/z 334 (M+H) (ESI-) m/z 332 (M-H)-.
Example 346
5-(1 H-indazol-5-yl)-N-(2-pyridin-3-ylethyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 2-pyridin-3-ylethanamine was substituted for 1-cyclohexylmethanamine.
'H NMR
(500 MHz, DMSO-d6/D20) b ppm 3.01 - 3.13 (t, 2 H), 3.55 - 3.70 (t, 2 H), 7.14 -
7.26 (m, 1
H),7.70-7.77(m,1H),7.84-7.95(m,2H),8.25-8.29(m,1H),8.36-8.45(m,2H),8.69
- 8.75 (m, 1 H), 8.77 - 8.84 (m, 1 H). MS (ESI+) m/z 334 (M+H)+; (ESI-) m/z
332 (M-H)-.
Example 347
5-(1 H-indazol-5-yl)-N-(2-pyridin-4-ylethyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 2-pyridin-4-ylethanamine was substituted for 1-cyclohexylmethanamine.
'H NMR
(500 MHz, DMSO-d6/D20) 8 ppm 3.12 - 3.23 (t, 2 H), 3.67 - 3.71 (t, 2 H), 7.20 -
7.21 (m, 1
H), 7.69 - 7.76 (m, 1 H), 7.86 - 7.91 (m, 3 H), 8.25 - 8.27 (m, 1 H), 8.38 -
8.41 (m, 1 H), 8.70
- 8.77 (m, 2 H). MS (ESI+) m/z 334 (M+H)+; (ESI-) m/z 332 (M-H)-.
Example 348
N-[2-(2-chlorophenyl)ethyl]-5-(IH-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 2-(2-chlorophenyl)ethanamine was substituted for 1-
cyclohexylmethanamine. 'H
NMR (500 MHz, DMSO-d6/D20) 8 ppm 2.99 - 3.05 (t, 2 H), 3.54 - 3.61 (t, 2 H),
7.21 - 7.23
(m, 1 H), 7.26 - 7.33 (m, 2 H), 7.35 - 7.40 (m, 1 H), 7.41 - 7.47 (m, 1 H),
7.70 - 7.75 (m, 1
H), 7.87 - 7.93 (m, 1 H), 8.23 - 8.31 (m, 1 H), 8.37 - 8.44 (m, 1 H). MS
(ESI+) m/z 367
(M+H) (ESI-) m/z 365 (M-H)-.
Example 349
N-[2-(3-chlorophenyl)ethyl]-5-(IH-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 2-(3-chlorophenyl)ethanamine was substituted for 1-
cyclohexylmethanamine. iH
NMR (500 MHz, DMSO-d6/D20) 8 ppm 2.89 (t, 2 H), 3.54 (t, 2 H), 7.19 - 7.42 (m,
5 H),
7.69 - 7.77 (m, 1 H), 7.86 - 7.94 (m, 1 H), 8.22 - 8.29 (m, 1 H), 8.38 - 8.42
(m, 1 H). MS
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(ESI-) m/z 365 (M-H)-.
Example 350
N-[2-(4-chlorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 2-(4-chlorophenyl)ethanamine was substituted for 1-
cyclohexylmethanamine. iH
NMR (500 MHz, DMSO-d6/D20) 8 ppm 2.86 (t, 2 H), 3.50 (t, 2 H), 7.17 - 7.24 (m,
1 H),
7.27-7.41(m,4H),7.71-7.76(m,1H),7.85-7.91(m,1H),8.21-8.29(m,1H),8.34-
8.44 (m, 1 H). MS (ESI-) m/z 365 (M-H)-.
Example 351
N-benzyl-N-ethyl-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except N-benzyl-N-ethylamine was substituted for 1-cyclohexylmethanamine. iH
NMR (500
MHz, DMSO-d6/D20) 8 ppm 1.06 - 1.19 (m, 3 H), 3.37 - 3.49 (m, 2 H), 4.69 -
4.76 (m, 2 H),
7.21-7.28(m,1H),7.28-7.49(m,5H),7.69-7.78(m,1H),7.83-7.97(m,1H),8.24-
8.32 (m, 1 H), 8.36 - 8.46 (m, 1 H). MS (ESI+) m/z 347 (M+H)+; (ESI-) m/z 345
(M-H)-.
Example 352
5-(1H-indazol-5-yl)-N-methyl-N-(1-naphthylmethyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except N-methyl-N-(1-naphthylmethyl)amine was substituted for 1-
cyclohexylmethanamine.
iH NMR (500 MHz, DMSO-d6/D20) 8 ppm 3.04 - 3.11 (m, 3 H), 5.20 - 5.35 (m, 2
H), 7.20 -
7.31(m,1H),7.33-7.66(m,4H),7.66-7.77(m,1H),7.81-8.18(m,4H),8.20-8.28(m,
1 H), 8.31 - 8.45 (m, 1 H). MS (ESI+) m/z 383 (M+H)+; (ESI-) m/z 381 (M-H)-.
Example 353
5-(1H-indazol-5-yl)-N-methyl-N-(2-phenylethyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except N-methyl-N-(2-phenylethyl)amine was substituted for 1-
cyclohexylmethanamine. 'H
NMR (500 MHz, DMSO-d6/D20) 8 ppm 2.86 - 2.97 (m, 2 H), 3.06 - 3.13 (m, 3 H),
3.70 -
3.74 (m, 2 H), 6.64 - 7.39 (m, 6 H), 7.69 - 7.92 (m, 2 H), 8.24 - 8.44 (m, 2
H). MS (ESI+)
m/z 347 (M+H)+; (ESI-) m/z 345 (M-H)-.
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Example 354
5-(IH-indazol-5-yl)-N-methyl-N-(2-pyridin-2-ylethyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except N-methyl-N-(2-pyridin-2-ylethyl)amine was substituted for 1-
cyclohexylmethanamine. 'H NMR (500 MHz, DMSO-d6/D20) 8 ppm 3.07 - 3.22 (m, 3
H),
3.26-3.39(m,2H),3.92-4.04(m,2H),6.85-7.14(m,1H),7.65-8.05(m,4H),8.23-
8.56 (m, 3 H), 8.65 - 8.86 (m, 1 H). MS (ESI+) m/z 348 (M+H)+; (ESI-) m/z 346
(M-H)-.
Example 355
5-(1 H-indazol-5-yl)-N-[(1 R)-1-phenylethyl]isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except (1R)-1-phenylethanamine was substituted for 1-cyclohexylmethanamine. iH
NMR
(500 MHz, DMSO-d6/D20) 8 ppm 1.49 - 1.54 (m, 3 H), 5.12 - 5.20 (m, 1 H), 7.23 -
7.29 (m,
2H),7.33-7.46(m,4H),7.71-7.75(m,1H),7.87-7.91(m,1H),8.22-8.28(m,1H),
8.37 - 8.42 (m, 1 H). MS (ESI+) m/z 333 (M+H)+; (ESI-) m/z 331 (M-H)-.
Example 356
5-(IH-indazol-5-yl)-N-1,2,3,4-tetrahydronaphthalen-1-ylisoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326
except 1,2,3,4-tetrahydronaphthalen-l-amine was substituted for 1-
cyclohexylmethanamine.
iH NMR (500 MHz, DMSO-d6/D20) 6 ppm 1.72 - 2.09 (m, 4 H), 2.68 - 2.85 (m, 2
H), 5.19 -
5.26(m,1H),7.12-7.24(m,4H),7.29-7.35(m,1H),7.69-7.77(m,1H),7.86-7.93(m,
1 H), 8.25 - 8.30 (m, 1 H), 8.38 - 8.43 (m, 1 H). MS (ESI-) m/z 357 (M-H)-.
Example 357
5-(1H-indazol-5-yl)-N-[(1 S)-1-(1-naphthyl)ethyl]isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81B
substituting (IS)-1-(1-naphthyl)ethanamine for piperidine. 'H NMR (300 MHz,
DMSO-d6) b
ppm 13.4 (br s, 1 H), 9.4 (d, 1 H), 8.4 (s, 1 H), 8.25 (s, 1 H), 8.22 (br s, 1
H), 7.95 (d, 1 H),
7.85 (m, 2 H), 7.65 (m, 2 H), 7.5 (m, 3 H), 7.3 (s, 1 H), 5.9 (m, 1 H), 1.65
(d, 3 H). MS
(ESI+) m/z 382.9 (M+H)+.
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Example 358
5-(1 H-indazol-5-yl)-N-[(1 R)-1-(1-naphthyl)ethyl]isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81B
substituting (1R)-1-(1-naphthyl)ethanamine for piperidine. iH NMR (300 MHz,
DMSO-d6) 8
ppm 13.4 (br s, 1 H), 9.4 (d, 1 H), 8.4 (s, 1 H), 8.25 (s, 1 H), 8.22 (br s, 1
H), 7.95 (d, 1 H),
7.85 (m, 2 H), 7.65 (m, 2 H), 7.5 (m, 3 H), 7.3 (s, 1 H), 5.9 (m, 1 H), 1.65
(d, 3 H). MS
(ESI+) m/z 382.9 (M+H)+.
Example 359
N-[3-(dimethylamino)-1-phenylpropyl]-5-(1H-indazol-5-yl)isoxazole-3-
carboxamide
The title compound was prepared according to the procedure outlined in Example
81B
substituting N3,N3-dimethyl-l-phenylpropane-1,3-diamine for piperidine. iH NMR
(300
MHz, DMSO-d6) 8 ppm 13.4 (br s, 1 H), 9.4 (d, 1 H), 8.4 (s, 1 H), 8.25 (s, 1
H), 7.92 (m, 1
H), 7.7 (m, 1 H), 7.3-7.5 (m, 6 H), 5.15 (m, 1 H), 3.2 (m, 2 H), 7.75 (s, 6
H), 2.35 (m, 1 H),
2.15 (m, 1 H). MS (ESI+) m/z 390 (M+H)+.
Example 360
N-(2,3-dihydro-1,4-benzodioxin-5-ylmethyl)-5-(1 H-indazol-5-yl)isoxazole-3-
carboxamide
The title compound was prepared according to the procedure outlined in Example
81B
substituting 1-(2,3-dihydro-1,4-benzodioxin-5-yl)methanamine for piperidine.
'H NMR (300
MHz, DMSO-d6) 8 ppm 13.4 (br s, 1 H), 9.24 (t, 1 H), 8.4 (s, 1 H), 8.25 (s, 1
H), 7.92 (d, 1
H), 7.7 (d, 1 H), 7.24 (s, 1 H), 6.9 (m, 3 H), 4.4 (d, 2 H), 4.3 (d, 2 H),
4.25 (d, 2 H). MS
(ESI+) m/z 377 (M+H)+.
Example 361
N-(3,4-dihydro-2H-1,5-benzodioxepin-6-ylmethyl)-5-(1H-indazol-5-yl)isoxazole-3-
carboxamide
The title compound was prepared according to the procedure outlined in Example
81B
substituting 1-(3,4-dihydro-2H-1,5-benzodioxepin-6-yl)methanamine for
piperidine. 'H
NMR (300 MHz, DMSO-d6) 6 ppm 13.4 (br s, 1 H), 9.2 (t, 1 H), 8.4 (s, 1 H),
8.25 (s, 1 H),
7.92 (d, 1 H), 7.7 (d, 1 H), 7.24 (s, 1 H), 6.9 (m, 3 H), 4.42 (d, 2 H), 4.15
(m, 4 H), 2.2 (m, 2
H). MS (ESI+) m/z 391 (M+H)+.
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Example 362
5-(1H-indazol-5-yl)-N-[(1-methyl-lH-indol-4-yl)methyl]isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example
81B
substituting (1-methyl-lH-indol-4-yl)methylamine for piperidine. iH NMR (300
MHz,
DMSO-d6) 6 ppm 13.4 (br s, 1 H), 9.24 (t, 1 H), 8.4 (s, 1 H), 8.25 (s, 1 H),
7.92 (d, 1 H), 7.7
(d, 1 H), 7.38 (m, 3 H), 7.18 (m, 1 H), 7.0 (d, 1 H), 6.6 (s, 1 H), 4.7 (d, 2
H), 3.8 (s, 3 H). MS
(ESI+) m/z 372 (M+H)+.
Example 363
5- {3-[(3-phenylpyrrolidin-1-yl)carbonyl]isoxazol-5 -yl}-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
81B
substituting 3-phenylpyrrolidine for piperidine. 'H NMR (300 MHz, DMSO-d6) 6
ppm 13.4
(br s, 1 H), 8.4 (m, 1 H), 8.25 (s, 1 H), 7.92 (d, 1 H), 7.8 (d, 1 H), 7.24
(m, 6 H), 4.4 (m, 1 H),
3.4 (m, 2 H), 2.4 (m, 2 H), 2.0 (m, 2 H). MS (ESI+) m/z 359 (M+H)+.
Example 364
5- {3-[(2-phenylpyrrolidin-1-yl)carbonyl]isoxazol-5 -yl}-1 H-indazole
The title compound was prepared according to the procedure outlined in Example
81B
substituting 2-phenylpyrrolidine for piperidine. 'H NMR (300 MHz, DMSO-d6) 6
ppm 13.4
(br s, 1 H), 8.4 (m, 1 H), 8.25 (s, 1 H), 7.92 (d, 1 H), 7.8 (d, 1 H), 7.24
(m, 6 H), 5.6 (m, 0.3
H), 5.2 (m, 0.7 H), 4.0 (m, 2 H), 1.8-2.0 (m, 4 H). MS (ESI+) m/z 390 (M+H)+.
Example 365
5- {3-[(2-phenylpiperidin-1-yl)carbonyl]isoxazol-5-yl}-1H-indazole
The title compound was prepared according to the procedure outlined in Example
81B
substituting 2-phenylpiperidine for piperidine. 'H NMR (300 MHz, DMSO-d6) 6
ppm 13.4
(br s, 1 H), 8.4 (m, 1 H), 8.25 (s, 1 H), 7.92 (d, 1 H), 7.8 (d, 1 H), 7.24
(m, 6 H), 5.6 (m, 0.3
H), 5.2 (m, 0.7 H), 4.0 (m, 2 H), 1.8-2.0 (m, 6 H). MS (ESI+) m/z 373 (M+H)+.
Example 366
5-(1H-indazol-5-yl)-N-[(1 S)-1-phenylethyl]isoxazole-3-carboxamide
5-(1H-Indazol-5-yl)isoxazole-3-carboxylic acid (36 mg, 0.16 mmol, Example
71A),
was dissolved in N,N-dimethylformamide (1.0 mL) followed by the addition of
HATU (60
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mg, 0.16 mmol) dissolved in N,1V-dimethylformamide (0.5 mL). Then a solution
of (S)-1-
phenylethanamine (22 mg, 0.18 mmol), dissolved in N,N-dimethylformamide (0.6
mL) was
added, followed by diisopropylethylamine (56 L,0.32 mmol) dissolved in N,N-
dimethylformamide (0.2 mL). The resulting mixture was shaken for 3 hours at 40
C. The
reaction was filtered, checked by LC/MS and concentrated to dryness. The
residues were
dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase
HPLC
(Phenomenex Luna C8(2) 5 gm 100A AXIATM column (30 mm X 75 mm), 50 mL/min,
10-100% acetonitrile/0.1% trifluoroacetic acid in water) to provide the title
product. 'H
NMR (500 MHz, DMSO-d6/D20) 6 ppm 1.50 (d, 3 H), 5.06 - 5.22 (m, 1 H), 7.23 -
7.29 (m, 2
H), 7.34 - 7.38 (m, 2 H), 7.40 - 7.45 (m, 2 H), 7.70 - 7.75 (m, 1 H), 7.87 -
7.92 (m, 1 H), 8.25
- 8.27 (m, 1 H), 8.39 - 8.41 (m, 1 H), 9.28 (d, 1 H). MS (ESI+) m/z 333 (M+H)
(ESI-) m/z
331 (M-H)-.
Example 367
5-(1H-indazol-5-yl)-N-[(1R)-1-(4-methylphenyl)ethyl]isoxazole-3-carboxamide
The title compound was prepared using the procedure descriped in Example 366
except (1R)-1-(4-methylphenyl)ethanamine was substituted for (S)-1-
phenylethanamine. 'H
NMR (500 MHz, DMSO-d6/D20) 6 ppm 1.49 (d, 3 H), 2.25 - 2.31 (m, 3 H), 5.09 -
5.18 (m,
1H),7.14-7.18(m,2H),7.23-7.24(m,1H),7.28-7.32(m,2H),7.70-7.75(m,1H),
7.86 - 7.92 (m, 1 H), 8.22 - 8.29 (m, 1 H), 8.37 - 8.42 (m, 1 H), 9.19 (d, 1
H). MS (ESI+) m/z
347 (M+H)+; (ESI-) 345 (M-H)-.
Example 368
5-(1H-indazol-5-yl)-N-[(1 S)-1-(4-methylphenyl)ethyl]isoxazole-3-carboxamide
The title compound was prepared using the procedure descriped in Example 366
except (1S)-1-(4-methylphenyl)ethanamine was substituted for (S)-l-
phenylethanamine. 'H
NMR (500 MHz, DMSO-d6/D20) 6 ppm 1.48 (d, 3 H), 2.26 - 2.30 (m, 3 H), 5.05 -
5.23 (m,
1H),7.15-7.17(m,2H),7.22-7.25(m,1H),7.28-7.32(m,2H),7.67-7.79(m,1H),
7.86 - 7.93 (m, 1 H), 8.22 - 8.30 (m, 1 H), 8.38 - 8.41 (m, 1 H), 9.21 (d, 1
H). MS (ESI-) m/z
345(M-H)-.
Example 369
N-[(1 R,2S)-2-hydroxy-2,3-dihydro-1 H-inden-1-yl]-5-(1 H-indazol-5-
yl)isoxazole-3-
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carboxamide
The title compound was prepared using the procedure descriped in Example 366
except (1R,2S')-1-aminoindan-2-ol was substituted for (S)-1-phenylethanamine.
'H NMR
(500 MHz, DMSO-d6/D20) 8 ppm 2.89 - 2.96 (m, 1 H), 3.13 - 3.21 (m, 1 H), 4.55 -
4.61 (m,
1 H), 5.40 - 5.47 (m, 1 H), 7.21 - 7.34 (m, 4 H), 7.39 - 7.42 (m, 1 H), 7.72 -
7.77 (m, 1 H),
7.91 - 7.95 (m, 1 H), 8.25 - 8.29 (m, 1 H), 8.42 - 8.45 (m, 1 H). MS (ESI-)
m/z 359 (M-H)-.
Example 370
N-[(1 R,2R)-2-hydroxy-2,3-dihydro-1 H-inden-l-yl]-5-(1 H-indazol-5-
yl)isoxazole-3-
carboxamide
The title compound was prepared using the procedure descriped in Example 366
except (1R,2R)-1-aminoindan-2-ol was substituted for (S)-1-phenylethanamine.
iH NMR
(500 MHz, DMSO-d6/D20) 8 ppm 2.72 - 2.83 (m, 1 H), 3.13 - 3.30 (m, 1 H), 4.44 -
4.53 (m,
1H),5.24-5.32(m,1H),7.10-7.18(m,1H),7.20-7.27(m,3H),7.30-7.33(m,1H),
7.72 - 7.78 (m, 1 H), 7.91 - 7.93 (m, 1 H), 8.24 - 8.29 (m, 1 H), 8.41 - 8.45
(m, 1 H), 9.17 (d,
1 H). MS (ESI-) m/z 359 (M-H)-.
Example 371
N-[(1 R)-1-(4-bromophenyl)ethyl]-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared using the procedure descriped in Example 366
except (1R)-1-(4-bromophenyl)ethanamine was substituted for (S)-1-
phenylethanamine. 'H
NMR (500 MHz, DMSO-d6/D20) 6 ppm 1.50 (d, 3 H), 5.08 - 5.18 (m, 1 H), 7.21 -
7.27 (m,
1H),7.36-7.41(m,2H),7.50-7.59(m,2H),7.70-7.76(m,1H),7.86-7.93(m,1H),
8.23 - 8.29 (m, 1 H), 8.38 - 8.41 (m, 1 H), 9.32 (d, 1 H). MS (ESI+) m/z 411
(M+H)+.
Example 372
N-[(1 S)-1-(4-bromophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared using the procedure descriped in Example 366
except (1S)-1-(4-bromophenyl)ethanamine was substituted for (S)-1-
phenylethanamine. 'H
NMR (500 MHz, DMSO-d6/D20) 8 ppm 1.49 (d, 3 H), 5.09 - 5.19 (m, 1 H), 7.23 -
7.25 (m,
1H),7.37-7.40(m,2H),7.53-7.57(m,2H),7.71-7.75(m,1H),7.87-7.92(m,1H),
8.25 - 8.27 (m, 1 H), 8.38 - 8.41 (m, 1 H), 9.32 (d, 1 H). MS (ESI) negative
ion 409 (M-H)-.
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Example 373
N-[(1 R)-1-(4-chlorophenyl)ethyl]-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared using the procedure descriped in Example 366
except (1R)-1-(4-chlorophenyl)ethanamine was substituted for (S)-1-
phenylethanamine. 'H
NMR (500 MHz, DMSO-d6/D20) 6 ppm 1.50 (d, 3 H), 5.10 - 5.21 (m, 1 H), 7.22 -
7.26 (m,
1 H), 7.38 - 7.47 (m, 4 H), 7.70 - 7.75 (m, 1 H), 7.87 - 7.92 (m, 1 H), 8.20 -
8.28 (m, 1 H),
8.38 - 8.41 (m, 1 H), 9.33 (d, 1 H). MS (ESI-) m/z 365 (M-H)-.
Example 374
N-[(1S)-1-(4-chlorophenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared using the procedure descriped in Example 366
except (1S)-1-(4-chlorophenyl)ethanamine was substituted for (S)-1-
phenylethanamine. 'H
NMR (500 MHz, DMSO-d6/D20) 6 ppm 1.49 (d, 3 H), 5.12 - 5.19 (m, 1 H), 7.23 -
7.25 (m,
1 H), 7.39 - 7.47 (m, 4 H), 7.71 - 7.74 (m, 1 H), 7.87 - 7.91 (m, 1 H), 8.25 -
8.27 (m, 1 H),
8.37 - 8.43 (m, 1 H), 9.32 (d, 1 H). MS (ESI-) m/z 365 (M-H)-.
Example 375
5-(1H-indazol-5-yl)-N-[(1 S)-1-(2-naphthyl)ethyl]isoxazole-3-carboxamide
The title compound was prepared using the procedure descriped in Example 366
except (1S)-1-(2-naphthyl)ethanamine was substituted for (S)-1-
phenylethanamine. iH NMR
(500 MHz, DMSO-d6/D20) 6 ppm 1.61 (d, 3 H), 5.30 - 5.38 (m, 1 H), 7.25 - 7.26
(m, 1 H),
7.48-7.55(m,2H),7.60-7.63(m,1H),7.72-7.75(m,1H),7.88-7.95(m,5H),8.25-
8.28 (m, 1 H), 8.39 - 8.43 (m, 1 H), 9.39 (d, 1 H). MS (ESI-) m/z 381 (M-H)-.
Example 376
N-[1-(4-ethoxyphenyl)-2-hydroxyethyl]-5-(1H-indazol-5-yl)isoxazole-3-
carboxamide
The title compound was prepared using the procedure descriped in Example 366
except 2-amino-2-(4-ethoxyphenyl)ethanol was substituted for (S)-1-
phenylethanamine. iH
NMR (500 MHz, DMSO-d6/D20) 6 ppm 1.32 (t, 3 H), 3.62 - 3.67 (m, 1 H), 3.70 -
3.73 (m, 1
H),3.96-4.06(m,2H),4.98-5.06(m,1H),6.87-6.91(m,2H),7.23-7.36(m,3H),7.70
- 7.75 (m, 1 H), 7.88 - 7.91 (m, 1 H), 8.25 - 8.27 (m, 1 H), 8.39 - 8.42 (m, 1
H). MS (ESI-)
m/z 391 (M-H)-.
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Example 377
N-[2-hydroxy-l-(4-isopropylphenyl)ethyl]-5-(1 H-indazol-5-yl)isoxazole-3-
carboxamide
The title compound was prepared using the procedure descriped in Example 366
except 2-amino-2-(4-isopropylphenyl)ethanol was substituted for (S)-1-
phenylethanamine.
iH NMR (500 MHz, DMSO-d6/D20) b ppm 1.18 (d, 6 H), 2.81 - 2.91 (m, 1 H), 3.65 -
3.70
(m, 1 H), 3.72 - 3.74 (m, 1 H), 5.01 - 5.09 (m, 1 H), 7.20 - 7.28 (m, 3 H),
7.29 - 7.35 (m, 2
H), 7.72 - 7.80 (m, 1 H), 7.87 - 7.95 (m, 1 H), 8.24 - 8.29 (m, 1 H), 8.38 -
8.44 (m, 1 H). MS
(ESI-) m/z 389 (M-H)-.
Example 378
N-[ 1-(3,4-dimethylphenyl)-2-hydroxyethyl]-5-(1 H-indazol-5-yl)isoxazole-3 -
carboxamide
The title compound was prepared using the procedure descriped in Example 366
except 2-amino-2-(3,4-dimethylphenyl)ethanol was substituted for (S)-1-
phenylethanamine.
'H NMR (500 MHz, DMSO-d6/D20) 8 ppm 2.30 (d, 6 H), 3.56 - 3.63 (m, 1 H), 3.65 -
3.73
(m, 1 H), 5.32 - 5.42 (m, 1 H), 7.06 - 7.08 (m, 2 H), 7.23 - 7.28 (m, 2 H),
7.69 - 7.76 (m, 1
H), 7.87 - 7.95 (m, 1 H), 8.25 - 8.28 (m, 1 H), 8.39 - 8.43 (m, 1 H). MS (ESI-
) m/z 375 (M-
H)-.
Example 379
N-[2-hydroxy-l-(2-methoxyphenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-
carboxamide
The title compound was prepared using the procedure descriped in Example 366
except 2-amino-2-(2-methoxyphenyl)ethanol was substituted for (S)-1-
phenylethanamine. 'H
NMR (500 MHz, DMSO-d6/D20) 8 ppm 3.60 - 3.66 (m, 2 H), 3.84 - 3.88 (m, 3 H),
5.37 -
5.48 (m, 1 H), 6.95 (t, 1 H), 7.00 - 7.06 (m, 1 H), 7.24 - 7.31 (m, 2 H), 7.32
- 7.36 (m, 1 H),
7.71 - 7.77 (m, 1 H), 7.85 - 7.97 (m, 1 H), 8.24 - 8.28 (m, 1 H), 8.40 - 8.45
(m, 1 H). MS
(ESI+) m/z 379 (M+H) negative ion 377 (M-H)-.
Example 380
N-[2-hydroxy-l-(4-methylphenyl)ethyl]-5-(1H-indazol-5-yl)isoxazole-3-
carboxamide
The title compound was prepared using the procedure descriped in Example 366
except 2-amino-2-(4-methylphenyl)ethanol was substituted for (S)-1-
phenylethanamine. 1 H
NMR (500 MHz, DMSO-d6/D20) 8 ppm 2.26 - 2.32 (m, 3 H), 3.65 - 3.70 (m, 1 H),
3.72 -
3.75(m,1H),5.01-5.08(m,1H),7.10-7.21(m,2H),7.25-7.35(m,3H),7.70-7.77(m,
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1 H), 7.86 - 7.95 (m, 1 H), 8.26 - 8.28 (m, 1 H), 8.39 - 8.46 (m, 1 H). MS
(ESI+) m/z 363
(M+H)+; (ESI-) m/z 361 (M-H)-.
Example 381
5-(1H-indazol-5-yl)-N-[(1R)-1-(2-methoxyphenyl)ethyl]isoxazole-3-carboxamide
The title compound was prepared using the procedure descriped in Example 366
except (1R)-1-(2-methoxyphenyl)ethanamine was substituted for (S)-1-
phenylethanamine.
iH NMR (500 MHz, DMSO-d6/D20) 6 ppm 1.43 (d, 3 H), 3.82 - 3.86 (m, 3 H), 5.41 -
5.50
(m, 1 H), 6.95 (t, 1 H), 7.00 - 7.05 (m, 1 H), 7.23 - 7.29 (m, 2 H), 7.35 -
7.39 (m, 1 H), 7.71 -
7.76 (m, 1 H), 7.88 - 7.92 (m, 1 H), 8.25 - 8.27 (m, 1 H), 8.37 - 8.43 (m, 1
H). MS (ESI+)
m/z 363 (M+H)+; (ESI-) m/z 361 (M-H)-.
Example 382
N-[(1 S)-1-(3,4-difluorophenyl)ethyl]-5-(1 H-indazol-5-yl)isoxazole-3-
carboxamide
The title compound was prepared using the procedure descriped in Example 366
except (1S)-1-(3,4-difluorophenyl)ethanamine was substituted for (S)-1-
phenylethanamine.
iH NMR (500 MHz, DMSO-d6/D20) 6 ppm 1.50 (d, 3 H), 5.09 - 5.24 (m, 1 H), 7.21 -
7.30
(m,2H),7.35-7.44(m,1H),7.44-7.53(m,1H),7.68-7.82(m,1H),7.86-7.94(m,1
H), 8.26 - 8.27 (m, 1 H), 8.39 - 8.42 (m, 1 H). MS (ESI-) m/z 367 (M-H)-.
Example 383
5-(1H-indazol-5-yl)-N-[(1R)-1-(3-methoxyphenyl)ethyl]isoxazole-3-carboxamide
The title compound was prepared using the procedure descriped in Example 366
except (1R)-1-(3-methoxyphenyl)ethanamine was substituted for (S)-1-
phenylethanamine.
iH NMR (500 MHz, DMSO-d6/D20) 6 ppm 1.50 (d, 3 H), 3.75 - 3.77 (m, 3 H), 5.01 -
5.19
(m,1H),6.80-6.87(m,1H),6.97-7.02(m,2H),7.21-7.32(m,2H),7.70-7.75(m,1
H), 7.87 - 7.95 (m, 1 H), 8.22 - 8.31 (m, 1 H), 8.37 - 8.43 (m, 1 H). MS (ESI-
) m/z 361 (M-
H)-.
Example 384
5-(1H-indazol-5-yl)-N-{(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}isoxazole-3-
carboxamide
The title compound was prepared using the procedure descriped in Example 366
except (1R)-1-[3-(trifluoromethyl)phenyl]ethanamine was substituted for (S)-1-
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phenylethanamine. iH NMR (500 MHz, DMSO-d6/D20) 6 ppm 1.54 (d, 3 H), 5.22 -
5.29
(m, 1 H), 7.23 - 7.27 (m, 1 H), 7.58 - 7.69 (m, 2 H), 7.71 - 7.75 (m, 2 H),
7.77 - 7.83 (m, 1
H), 7.87 - 7.92 (m, 1 H), 8.24 - 8.29 (m, 1 H), 8.38 - 8.42 (m, 1 H). MS (ESI-
) m/z 399 (M-
H)-.
Example 385
N-[ 1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]-5-(1 H-indazol-5-yl)isoxazole-3-
carboxamide
The title compound was prepared using the procedure descriped in Example 366
except 1-(2,3 -dihydro- 1,4-benzodioxin-6-yl)ethanamine was substituted for
(S)-1-
phenylethanamine. iH NMR (500 MHz, DMSO-d6/D20) 6 ppm 1.46 (d, 3 H), 4.18 -
4.25
(m,4H),5.01-5.10(m,1H),6.80-6.95(m,3H),7.22-7.24(m,1H),7.70-7.74(m,1
H), 7.87 - 7.91 (m, 1 H), 8.26 - 8.27 (m, 1 H), 8.39 - 8.41 (m, 1 H). MS (ESI-
) m/z 389 (M-
H)-.
Example 386
N-[1-(3,5-dichlorophenyl)-2-hydroxyethyl]-5-(1H-indazol-5-yl)isoxazole-3-
carboxamide
The title compound was prepared using the procedure descriped in Example 366
except 2-amino-2-(3,5-dichlorophenyl)ethanol was substituted for (S)-1-
phenylethanamine.
'H NMR (500 MHz, DMSO-d6/D20) 6 ppm 3.68 - 3.72 (m, 1 H), 3.76 - 3.78 (m, 1
H), 5.02 -
5.10 (m, 1 H), 7.26 - 7.29 (m, 1 H), 7.47 - 7.52 (m, 3 H), 7.72 - 7.75 (m, 1
H), 7.89 - 7.93 (m,
1 H), 8.25 - 8.28 (m, 1 H), 8.39 - 8.44 (m, 1 H). MS (ESI-) m/z 415 (M-H)-.
Example 387
tert-butyl5-(1-benzyl-lH-1,2,3-triazol-4-yl)-3-[({[6-(trifluoromethyl)pyridin-
2-
yl] amino } carbonyl)amino]-1Fl-indazole-l-carboxylate
A solution of triphosgene in dichloromethane was cooled to 0 C under nitrogen.
Then a mixture of triethylamine (0.426 mL, 3.07 mmol) and Example 64A (150 mg,
0.384
mmol) in dichloromethane (2 mL) was slowly added dropwise. The resultant
mixture was
stirred at room temperature for 1 hour. Then 6-(trifluoromethyl)pyridin-2-
amine (62.3 mg,
0.384 mmol) was added followed by stirring overnight at room temperature. The
precipitate
was filtered off and washed with dichloromethane and water. The product was
dried under
vacuum to provide the title compound. MS m/z 579.3 (M+H)+.
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Example 388
5-(1-b enzyl-1 H-1,2, 3-triazol-4-yl)-1- [(1-methylpip eridin-2-yl)carbonyl] -
1 H-indazol-3 -amine
1-Methylpiperidine-3-carboxylic acid hydrochloride was combined with a mixture
of
dimethylformamide and dichloromethane under nitrogen and stirred for 15
minutes. Then
carbonyldiimidazole was added portionwise. The resultant solution was stirred
at room
temperature for 1 hour. Then Example 62 was added followed by stirring at 60
C for 2
hours and then at room temperature overnight. The reaction mixture was poured
into ice
water and brine was added. The cold solution was decanted, and the residue was
taken into
dichloromethane and washed with water (2X). The organic layer was dried with
magnesium
sulfate, and the volatiles were removed under reduced pressure. The decanted
solution was
extracted with ethyl acetate (3X). The combined organic layers were washed
with brine
(2X), dried with magnesium sulfate, and concentrated. The residue was taken
into a small
amount of acetone and then dropped into distilled water. A precipitate was
collected by
filtration, washed with water, and dried to provide the title compound. MS m/z
579.3
(M+H)+.
Example 389
5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1-[(dimethylamino)acetyl]-1H-indazol-3-
amine
2-(Dimethylamino)acetic acid was dissolved in dimethylformamide and pyridine
under nitrogen at room temperature over 15 minutes. Carbonyldiimidazole was
added
portionwise. The resultant mixture was stirred at room temperature for 1 hour.
Then
Example 62 was added, and the mixture was stirred overnight at room
temperature. The
volatile material was removed under reduced pressure, and the remainder was
added to ice
water. Sodium chloride was added and thick oil came out of the cool solution.
The solution
was decanted. The residue was washed with water (3X) and then dried. From the
decanted
solution, a precipitate came out overnight of the water/dimethylformamide
mixture. This
proved to be starting material which was filtered off and discarded. The
product residue was
crystallized in dichloromethane, collected by filtration, rinsed with a small
quantity of
dichloromethane and ether. The product was dried to provide the title
compound. MS m/z
376.3 (M+H)+.
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Example 390
tert-butyl3-amino-5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1H-indazole-l-carboxylate
Example 62 was suspended in dichloromethane along with a catalytic amount of
dimethylaminopyridine. A solution of di-tert-butyl dicarbonate in
dichloromethane (160 mL)
was added over 1 hour. The reaction mixture was stirred for approximately 40
hours. Silica
gel was added, and the mixture was concentrated. This silica mixture was added
to a silica
gel column and the material was eluted first with dichloromethane and then
with 1%
methanol/dichloromethane and lastly with 2% methanol/dichloromethane. The
fractions
containing the desired product were combined and concentrated to provide the
title
compound. MS m/z 391.3 (M+H)+.
Example 391
N-[5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-piperidin-1-
ylacetamide
2-(Piperidin-l-yl)acetic acid was combined with dimethylformamide and
pyridine.
The mixture was stirred for 15 minutes at room temperature, and then
carbonyldiimidazole
was added portionwise. Stirring was continued at room temperature for 1 hour,
and then
Example 64A was added followed by continued stirring for 24 hours. The
reaction mixture
was warmed to 60 C for 14 hours. A small amount of the title compound was
obtained. MS
m/z 416.3 (M+H)+.
Example 392
N-[5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-2-morpholin-4-
ylacetamide
2-Morpholinoacetic acid was combined with dimethylformamide and pyridine. The
mixture was stirred for 15 minutes at room temperature, and then
carbonyldiimidazole was
added portionwise. Stirring was continued at room temperature for 1 hour, and
then Example
64A was added followed by continued stirring for 28 hours. The reaction
mixture was
warmed to 60 C for 4 hours and then stirring was continued overnight at room
temperature.
The reaction mixture was warmed again to 60 C for 7 hours. A small amount of
the title
compound was obtained. MS m/z 418.3 (M+H)+.
Example 393
N-[5-(1-benzyl-lH-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-1-methylpiperidine-2-
carboxamide
1-Methylpiperidine-3-carboxylic acid hydrochloride was combined with
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dimethylformamide and pyridine. The mixture was stirred for 15 minutes at room
temperature, and then carbonyldiimidazole was added portionwise. Stirring was
continued at
room temperature for 1 hour, and then Example 64A was added followed by
continued
stirring for 28 hours. The reaction mixture was warmed to 60 C for 4.25 hours
and then
stirring was continued overnight at room temperature. The reaction mixture was
warmed
again to 60 C for 7 hours. A small amount of the title compound was obtained.
MS m/z
416.3 (M+H)+.
Biological Data
ROCK-2 Inhibitory AssaX
The compounds of formula (I) were tested for their ability to inhibit N-
terminal His6-
tagged recombinant human ROCK-2 residues 11-552 expressed by baculovirus in
Sf21 cells
(Upstate). In 384-well v-bottom polypropylene plates (Axygen), 1 nM (final
concentration)
in 10 ul recombinant N-terminal His6-tagged recombinant human ROCK-2 residues
11-552
expressed by baculovirus in Sf21 cells (Upstate) was mixed with 2 uM (final
concentration)
in 10 ul biotinylated peptide substrate
(biotin-Aha-KEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK (SEQ ID NO: 1))
(Genemed), and various concentration of inhibitor (2% DMSO final) in reaction
buffer (25
mM HEPES, pH 7.5, 0.5 mM DTT, 10 mM MgC1z, 100 uM Na3VO4, 0.075 mg/ml Triton X-
100), and the reaction was initiated by addition of 5 uM unlabelled ATP
containing 0.01 uCi
[33P]-ATP (Perkin Elmer). The reaction was quenched after 1 hour by the
addition of 50 ul
stop buffer (50 mM EDTA, 2M NaCI final concentration). 80 uL of the stopped
reactions
were transferred to 384-well streptavidin-coated FlashPlates (Perkin Elmer),
incubated 10
minutes at room temperature, washed 3 times with 0.05% Tween-20/PBS using an
ELX-405
automated plate washer (BioTek), and counted on a TopCount Scintillation Plate
Reader
(Packard).
ROCK-1 Inhibito ,r~y
The compounds of formula (I) were tested for their ability to inhibit N-
terminal His6-
tagged, recombinant, human ROCK-1 amino acids 17-535 expressed by baculovirus
in Sf21
cells (Upstate). In 384-well v-bottom polypropylene plates (Axygen), 2 nM
(final
concentration) in 10 ul recombinant N-terminal His6-tagged, recombinant, human
ROCK-1
amino acids 17-535 expressed by baculovirus in Sf21 cells (Upstate) in
reaction buffer was
mixed with 2 uM (final concentration) biotinylated peptide substrate
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(biotin-Aha-VRRLRRLTAREAA (SEQ ID NO: 2)) (Genemed), and various concentration
of
inhibitor (2% DMSO final) in 10 ul reaction buffer (25 mM HEPES, pH 7.5, 0.5
mM DTT,
mM MgClz, 100 uM Na3VO4, 0.075 mg/ml Triton X-100), and the reaction was
initiated
by addition of 5 uM unlabelled ATP containing 0.01 uCi [33P]-ATP (Perkin
Elmer). The
5 reaction was quenched after 1 hour by the addition of 50 ul stop buffer (50
mM EDTA, 2M
NaCI final concentration). 80 uL of the stopped reactions were transferred to
384-well
streptavidin-coated FlashPlates (Perkin Elmer), incubated 10 minutes at room
temperature,
washed 3 times with 0.05% Tween-20/PBS using an ELX-405 automated plate washer
(BioTek), and counted on a TopCount Scintillation Plate Reader (Packard).
GSK inhibito .r~y
The compounds of formula (I) were tested for their ability to inhibit N-
terminal His6-
tagged GSK-3 expressed by baculovirus in Sf2l cells (Upstate). In 384-well v-
bottom
polypropylene plates (Axygen), 10 ul recombinant N-terminal His-tagged GSK3
expressed
by baculovirus in Sf21 cells (Upstate) was mixed with 10 l biotinylated
peptide substrate
(biotin-ahx-YRRAAVPPSPSLSRHSSPHQS(p)EDEEE (SEQ ID NO: 3)), 2 gM final
concentration (Genemed), and various concentration of inhibitor (2% DMSO
final) in
reaction buffer (20 mM HEPES, pH 7.5, 1 mM DTT, 10 mM MgClz 100 uM Na3VO4,
0.075
mg/ml Triton X-100), and the reaction was initiated by addition of 20 l [33P]-
ATP, 5 gM
final concentration, 2 mCi/umol (Perkin Elmer). The reaction was quenched
after 1 hour by
the addition of 50 ul stop buffer (50 mM EDTA, 2M NaCI final concentration).
80 L of the
stopped reactions were transferred to 384-well streptavidin-coated FlashPlates
(Perkin
Elmer), incubated 10 minutes at room temperature, washed 3 times with 0.05%
Tween-
20/PBS using an ELX-405 automated plate washer (BioTek), and counted on a
TopCount
Scintillation Plate Reader (Packard).
Human GSK-3(3 Inhibitory AssaX
Compounds were tested for their ability to inhibit human Glycogen Synthase
kinase-3
beta (hGSK-3(3) to phosphorylate biotin-YRRAAVPPSPSLSRHSSPHQ(pS)EDEEE.
Compounds were incubated with 0.5 Ci 33P-ATP, 10 M ATP, 0.0125U hGSK-3(3
(Upstate
cell signaling solutions) and 1 M substrate
(biotin-YRRAAVPPSPSLSRHSSPHQ(pS)EDEEE (SEQ ID NO: 3)) in 50 mM HEPES, 10
mM MgClz, 100 uM Na3VO4, 1 mM DTT, 0.0075% Triton, 2% DMSO (total volume 50
L)
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WO 2008/154241 PCT/US2008/065727
for 30 minutes at room temperature. The incubation was stopped by addition of
an equal
volume of 100 mM EDTA, 4 M NaC12. 80 L of this mixture was added to
streptavidin-
coated Flashplates (PerkinElmer). Following a wash step, 33P incorporation was
quantified on
a MicroBeta microplate liquid scintillation counter (PerkinElmer). IC50s were
determined by
fitting a sigmoidal dose-response curve to the counts obtained at the
different concentrations
in GraphPad Prism.
Human GSK-3a Inhibitory Assay
Compounds were tested for their ability to inhibit human Glycogen Synthase
kinase-3
alpha (hGSK-3a) 0.5 nM final concentration of to phosphorylate
biotin-YRRAAVPPSPSLSRHSSPHQ(pS)EDEEE (SEQ ID NO: 3). Compounds were
incubated with 0.5 Ci 33P-ATP, 10 M ATP, 0.0125U hGSK-3 (Upstate cell
signaling
solutions) and 2 M substrate (biotin-YRRAAVPPSPSLSRHSSPHQ(pS)EDEEE) in 50 mM
HEPES, 10 mM MgC1z, 100 uM Na3VO4, 1 mM DTT, 0.0075% Triton, 2% DMSO (total
volume 50 gL) for 30 minutes at room temperature. The incubation was stopped
by addition
of an equal volume of 100 mM EDTA, 4M NaC12. 80 L of this mixture was added
to
streptavidin-coated Flashplates (PerkinElmer). Following a wash step, 33P
incorporation was
quantified on a MicroBeta microplate liquid scintillation counter
(PerkinElmer). IC50s were
determined by fitting a sigmoidal dose-response curve to the counts obtained
at the different
concentrations in GraphPad Prism.
JAK2 Inhibition Assay
Jak2 kinase activity was assayed by a homogenous time-resolved fluorescence
(HTRF) in vitro kinase assay (Mathis, G., HTRF(R) Technology. J Biomol Screen,
1999.
4(6): p. 309-314). Specifically, 10 gL C-terminal His6-tagged, recombinant,
human JAK2,
amino acids 808-end, expressed by baculovirus in Sf21 cells (Upstate) was
mixed with 10 ul
inhibitor (various concentrations, 2% final DMSO) and 10 ul of ATP (5 gM final
concentration) in reaction buffer (50 mM HEPES, pH 7.5, 10 mM MgCl2, 2 mM
MnC12,
0.1% BSA and 1 mM DTT, 40 L final volume). The reaction was initiated by
addition of
10 ul of Bio-PDK peptide
(Biotin-Ahx-KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC (SEQ ID NO: 4),
0.5 M final concentration) in a black 384-well plate (Packard). After 60
minutes incubation
at room temperature, the reaction was quenched by addition 60 L
stop/revelation buffer to
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give 30 mM EDTA, 1 g/mi streptavidin-APC (Prozyme), 50 ng/ml anti-
phosphotyrosine
mAb PT66-K Europium Cryptate, 30 mM HEPES, pH 7.5, 120 mM KF, 0.005% Tween-20,
0.05% BSA). The quenched reaction was allowed to stand at room temperature for
1 hour
and then read in a time-resolved fluorescence detector (Envision, Perkin
Elmer) at 615 nm
and 665 nm simultaneously. The ratio between the signal of 615 nm and 665 nm
was used in
the calculation of the IC50=
Methods - 0-catenin reporter-gene assay
Compounds were tested for their ability to modulate 0-catenin-modulated gene
transcription in a LEF/TCF(T-cell factor) reporter gene assay. SY-SY5Y human
neuroblastoma cells were transiently transfected with 80 ng/well TOPFLASH
plasmid
(Upstate cell signaling solutions) containing two sets of three copies of the
TCF binding site
upstream of the Thymidine kinase minimal promoter and firefly Luciferase open
reading
frame or with 80 ng/well FOPFLASH plasmid (Upstate cell signaling solutions)
containing
three copies of a mutated TCF binding site upstream of the Thymidine kinase
minimal
promoter and firefly Luciferase open reading frame. In addition, all cells
were transiently
transfected with the 20 ng/well pRL-TK plasmid (Promega) containing the herpes
simplex
virus thymidine kinase promoter to provide low to moderate levels of Renilla
Luciferase
expression. Transfection medium was exchanged for serum-free medium containing
the test
substance and incubated for 24 hours at 37 C. The incubation was stopped and
quantified
using the Dual Glo Luciferase Assay (Promega) as indicated and quantified on a
Pherastar
reader (BMG).
Firefly Luciferase activity was normalized for Renilla Luciferase activity per
well.
Subsequently, the normalised TOPFLASH response was compared to the normalised
FOPFLASH response, thus giving the LEF/TCF specific signal. The maximal
response is the
maximal ratio between the normalised TOPFLASH and FOPFLASH signals. Sigmoidal
dose-response curves were fitted using Graphpad Prism.
Murine Asthma Model of acute asthma
Female Balb/c mice were purchased from Taconic and housed at Abbott
Bioresearch
Center. Animals were utilized at 8-12 weeks of age. All protocols were
approved by the
Institutional Animal Care and Use Committee (IACUC). Dexamethasone (Dex), and
ovalbumin (OVA) were purchased from Sigma. Endotoxin was removed from
ovalbumin
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using DetoxiGel (Pierce) according to manufacturer's protocol and the final
material
contained less than 0.1 EU/mg protein. Alum Imject was purchased from Pierce.
Animals were sensitized to OVA on day 0 and 7 with an i.p. injection of 8 ug
OVA in
2 mg alum. On days 14 and 16, animals received intra-nasal challenge of 0.3 g
OVA in 50
1 sterile PBS. Animals were dosed i.p. with a representative compound of
formula (I)
(dissolved with 0.5% HMPC, 0.02% Tween 80 in water) twice per day at doses of
3, 10, and
30 mg/kg/dose beginning the afternoon of day 13. The final dose of compound
was
administered 30 minutes prior to measurement of airway hyperresponsiveness
(AHR).
Dexamethasone was administered orally once a day on days 13-17 at a dose of 3
mg/kg. All
endpoints were analyzed on day 17, 24 hours after the second OVA challenge.
AHR was
assessed using unconscious restrained whole body plethysmography. Briefly, a
surgical
plane of anesthesia was induced with an i.p. injection of ketamine and
xylazine. A tracheal
canula was surgically inserted between the third and fourth tracheal rings.
Spontaneous
breathing was prevented by an intravenous (i.v.) jugular vein injection of
pancuronium
bromide. Animals were placed in a whole body plethysmograph (Buxco) and
mechanically
ventilated with 0.2 ml room air at 150 breaths per minute with a volume-
controlled ventilator
(Harvard Apparatus). Pressure in the lung and flow within the plethysmograph
were
measured using transducers, and lung resistance was calculated as
pressure/flow using
Biosystem Xa software. Baseline resistance as well as resistance following
challenge with
methacholine (3, 10 or 30 mg/ml) that was delivered with an inline ultrasonic-
nebulizer were
measured. Upon completion of pulmonary function testing, the lungs were
lavaged 4 times
with 0.5 ml sterile PBS. Lavage fluid was analyzed for IL-13, AMCase, Muc5ac
and cellular
infiltrates. The efficacy of the test compound was tested at doses of 3, 10
and 30 mg/kg b.i.d
(6, 20, 60 mg/kg/day). Challenge with OVA caused an increase in lung
resistance to 6.90 cm
HzO/ml/sec vs. 4.65 em HzO/ml/sec in animals challenged with PBS. Treatment of
mice
with the test compound significantly inhibited (p<0.001) methacholine-induced
airways
resistance down to 4.55 cm Hz0/mUsec and 4.77 cm H20/ml/sec at doses ranging
between 1
and 100 mg/kg. The preferred compounds require a dose of less than 50 mg/kg to
exhibit
said response. The most preferred compounds require a dose of less than 30
mg/kg to exhibit
said response. This inhibition was equivalent to measurements taken in the PBS
challenged
group (4.65 cm H20/ml/sec) and to treatment of 3 mg/kg dexamethasone (4.76 cm
HzO/mUsec).
IL- 13 measurement: IL- 13 concentrations in the bronchoalveolar lavage fluid
(BAL)
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were measured by ELISA (R & D Systems) according to manufacturer's
instructions. IL-13
concentrations in the BAL fluid were significantly induced to 102.5 pg/ml in
OVA
challenged mice as compared to levels below detection in the PBS challenged
group. This
induction was significantly inhibited (p<0.05) by 60% after administration of
the test
compounds administration at the 30 mg/kg dose. There was no significant
inhibition at the 3
mg/kg or 10 mg/kg dose groups.
AMCase measurement: Acidic mammalian chitinase (AMCase) activity was
determined in a 1:10 dilution of BAL fluid with 0.01% BSA, 30 mM sodium
citrate, 60 mM
sodium phosphate, pH 5.2 in the presence of 80 uM 4-methylumbelliferyl (3-D-
N,N'-
diacetylchitobioside. Reactions were incubated for 15 minutes at room
temperature and
quenched by addition of 100 uL of 1 M glycine/NaOH pH 10.6. Product formation
was
determined by fluorescence emission at 460 nm using excitation at 385 nm on a
Fluoroskan
Ascent fluorometer. AMCase activity was induced to 28.5U in OVA challenged
animals
compared to 2.17U in the PBS challenged animals. This induction was
significantly inhibited
(p<0.01) in the 30 mg/kg group by 35% after test compounds were administered.
MUC5AC measurement: Concentrations of the mucin gene MUC5AC were
quantitated by ELISA format. Briefly, BAL samples are diluted 1:2 in buffer
(2% BSA in
PBS) and plated onto high protein binding 96-well plates (Costar) and dried.
After a series of
washes, a 1:100 dilution of biotinylated MUC5AC antibody (Clone 45M,
LabVision) was
added for 1 hour. Plates are washed and a 1:3000 dilution of streptavidin-HRP
(Southern
Biotech) was added to the plate for 15 minutes. Plates were then developed
using a TMB
substrate (Sigma) for 30 minutes. The reaction was stopped using 1M H2SO4 and
then read
in a spectrophotometer at OD 450nm. Levels of MUC5AC were reduced by greater
than
50% after administration of test compounds.
Determination of Antinociceptive Effect: Models for Neuropathic Pain
Spinal Nerve (L5/L6) Ligation Model of Neuropathic Pain. As previously
described
in detail by Kim and Chung (Kim S. H.; Chung J.M. An experimental model for
peripheral
neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992,
50, 355-363),
a 1.5 cm incision was made dorsal to the lumbosacral plexus. In anesthetized
rats, the
paraspinal muscles (left side) were separated from the spinous processes, the
L5 and L6
spinal nerves isolated, and tightly ligated with 3-0 silk threads. Following
hemostasis, the
wound was sutured and coated with antibiotic ointment. The rats were allowed
to recover
and then placed in a cage with soft bedding for 14 days before behavioral
testing for
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mechanical allodynia.
Sciatic Nerve Ligation Model of Neuropathic Pain. As previously described in
detail
by Bennett and Xie (Bennett G. J.; Xie Y-K. A peripheral mononeuropathy in rat
that
produces disorders of pain sensation like those seen in man. Pain 1988, 33, 87-
107), in
anesthetized rats, a 1.5 cm incision was made 0.5cm below the pelvis and the
biceps femoris
and the gluteous superficialis (right side) were separated. The sciatic nerve
was exposed,
isolated, and four loose ligatures (5-0 chromic catgut) with 1 mm spacing were
placed around
it. The rats were allowed to recover and then placed in a cage with soft
bedding for 14 days
before behavioral testing for mechanical allodynia as described above. In
addition, animals
were also tested for cold allodynia by dipping their hind paw in a cold-water
bath (4.5 C) and
determining the paw withdrawal latency.
Selected analogs of compounds of formula (I), dosed either i.p. or p.o.
demonstrated
greater than 30% inhibition of tactile allodynia in the Chung and Bennett
models of
neuropathic pain described herein at doses ranging from 1-150 mg/kg.
In summary, a representative compound of formula (I) in a mouse model of acute
asthma was effective in inhibiting airway resistance in a dose range between 1
and 100
mg/kg. High dose (30 mg/kg) treatment also inhibited IL-13 induction as well
as AMCase
activity and MUC5AC levels in the BAL fluid.
Representative compounds of formula (I) in rat models of neuopathic pain were
effective as demonstrated by a greater than 30% inhibition of tactile
allodynia at doses
ranging from 1-150 mg/kg.
The compounds of formula (I) were found to inhibit human ROCK-2, N-terminal
His-
tagged GSK-3(3, human GSK-3(3, His6-tagged, recombinant, human JAK2 and
Firefly
Luciferase exhibiting an IC50 of about 1.0 gM to about 10 M, preferably about
100 nM to
about 1.0 M. More preferably, compounds of formula (I) were found to inhibit
human
ROCK-2, N-terminal His-tagged GSK-30, human GSK-3(3, His6-tagged, recombinant,
human JAK2 and Firefly Luciferase exhibiting an IC50 of about 10 nM to about
100 nM, and
most preferably less than 10 nM.
In addition, certain compounds of formula (I) exhibited inhibition of human
ROCK-2
with a selectivity of greater than 10 fold against a panel of 50 kinase
targets. Certain
compounds of formula (I) exhibited inhibition of human GSK-30 with a
selectivity of greater
than 10 fold against a panel of 50 kinase targets. Certain compounds of
formula (I) exhibited
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inhibition of His6-tagged, recombinant, human JAK2 with a selectivity of
greater than 10
fold against a panel of 50 kinase targets.
Methods of Administration
The present invention also provides pharmaceutical compositions that comprise
compounds of the present invention. The pharmaceutical compositions comprise
compounds
of the present invention formulated together with one or more non-toxic
pharmaceutically
acceptable carriers.
The pharmaceutical compositions of this invention can be administered to
humans
and other mammals orally, rectally, parenterally, intracisternally,
intravaginally, topically (as
by powders, ointments or drops), bucally or as an oral or nasal spray. The
term
"parenterally," as used herein, refers to modes of administration that include
intravenous,
intramuscular, intraperitoneal, intrastemal, subcutaneous and intraarticular
injection and
infusion.
The term "pharmaceutically acceptable carrier," as used herein, means a non-
toxic,
inert solid, semi-solid or liquid filler, diluent, encapsulating material or
formulation auxiliary
of any type. Some examples of materials which can serve as pharmaceutically
acceptable
carriers are sugars such as, but not limited to, lactose, glucose and sucrose;
starches such as,
but not limited to, corn starch and potato starch; cellulose and its
derivatives such as, but not
limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose
acetate; powdered
tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa
butter and
suppository waxes; oils such as, but not limited to, peanut oil, cottonseed
oil, safflower oil,
sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene
glycol; esters such
as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents
such as, but not
limited to, 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, but not limited to, 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.
Pharmaceutical compositions of this invention for parenteral injection
comprise
pharmaceutically acceptable sterile aqueous or nonaqueous solutions,
dispersions,
suspensions or emulsions as well as sterile powders for reconstitution into
sterile injectable
solutions or dispersions just prior to use. Examples of suitable aqueous and
nonaqueous
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carriers, diluents, solvents or vehicles include water, ethanol, polyols (such
as glycerol,
propylene glycol, polyethylene glycol and the like), vegetable oils (such as
olive oil),
injectable organic esters (such as ethyl oleate) and suitable mixtures
thereof. Proper fluidity
can be maintained, for example, by the use of coating materials such as
lecithin, by the
maintenance of the required particle size in the case of dispersions and by
the use of
surfactants.
These compositions may also contain adjuvants such as preservatives, wetting
agents,
emulsifying agents and dispersing agents. Prevention of the action of
microorganisms can be
ensured by the inclusion of various antibacterial and antifungal agents, for
example, paraben,
chlorobutanol, phenol sorbic acid and the like. It may also be desirable to
include isotonic
agents such as sugars, sodium chloride and the like. Prolonged absorption of
the injectable
pharmaceutical form can be brought about by the inclusion of agents, which
delay absorption
such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is desirable to
slow the
absorption of the drug from subcutaneous or intramuscular injection. This can
be
accomplished by the use of a liquid suspension of crystalline or amorphous
material with
poor water solubility. The rate of absorption of the drug 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 drug form is accomplished by
dissolving or
suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug
in
biodegradable polymers such as polylactide-polyglycolide. Depending upon the
ratio of drug
to polymer and the nature of the particular polymer employed, the rate of drug
release can be
controlled. Examples of other biodegradable polymers include poly(orthoesters)
and
poly(anhydrides). Depot injectable formulations are also prepared by
entrapping the drug in
liposomes or microemulsions, which are compatible with body tissues.
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 just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills,
powders
and granules. In such solid dosage forms, the active compound may be mixed
with at least
one inert, pharmaceutically acceptable carrier or excipient, such as sodium
citrate or
dicalcium phosphate and/or a) fillers or extenders such as starches, lactose,
sucrose, glucose,
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mannitol and silicic acid; b) binders such as carboxymethylcellulose,
alginates, gelatin,
polyvinylpyrrolidone, 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 qu.a.ternary ammonium compounds; g) wetting agents such
as 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 thereo In the case of capsules, tablets
and pills, the
dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft
and hard-
filled gelatin capsules using such carriers 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 may
also be of a composition such 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.
The active compounds can also be in micro-encapsulated form, if appropriate,
with
one or more of the above-mentioned carriers.
Liquid dosage forms for oral administration include pharmaceutically
acceptable
emulsions, 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, dimethyl formamide, 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 may also include adjuvants such
as
wetting agents, emulsifying and suspending agents, sweetening, flavoring and
perfuming
agents.
Suspensions, in addition to the active compounds, may contain suspending
agents as,
for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and
sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar,
tragacanth and
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mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories
which
can be prepared by mixing the compounds of this invention with suitable non-
irritating
carriers or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are
solid at room temperature but liquid at body temperature and therefore melt in
the rectum or
vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of
liposomes. As is known in the art, liposomes are generally derived from
phospholipids or
other lipid substances. Liposomes are formed by mono- or multi-lamellar
hydrated liquid
crystals that are dispersed in an aqueous medium. Any non-toxic,
physiologically acceptable
and metabolizable lipid capable of forming liposomes can be used. The present
compositions
in liposome form can contain, in addition to a compound of the present
invention, stabilizers,
preservatives, excipients and the like. The preferred lipids are natural and
synthetic
phospholipids and phosphatidyl cholines (lecithins) used separately or
together.
Methods to form liposomes are known in the art. See, for example, Prescott,
Ed.,
Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p.
33 et
seq.
Dosage forms for topical administration of a compound of this invention
include
powders, sprays, ointments and inhalants. The active compound may be mixed
under sterile
conditions with a pharmaceutically acceptable carrier and any needed
preservatives, buffers
or propellants, which may be required. Ophthalmic formulations, eye ointments,
powders
and solutions are also contemplated as being within the scope of this
invention.
Actual dosage levels of active ingredients in the pharmaceutical compositions
of this
invention can be varied so as to obtain an amount of the active compound(s)
that is effective
to achieve the desired therapeutic response for a particular patient,
compositions and mode of
administration. The selected dosage level will depend upon the activity of the
particular
compound, the route of administration, the severity of the condition being
treated and the
condition and prior medical history of the patient being treated.
When used in the above or other treatments, a therapeutically effective amount
of one
of the compounds of the present invention can be employed in pure form or,
where such
forms exist, in pharmaceutically acceptable salt, ester or prodrug form. The
phrase
"therapeutically effective amount" of the compound of the invention means a
sufficient
amount of the compound to treat disorders, at a reasonable benefit/risk ratio
applicable to any
medical treatment. It will be understood, however, that the total daily usage
of the
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compounds and compositions of the present invention will be decided by the
attending
physician within the scope of sound medical judgment. The specific
therapeutically effective
dose level for any particular patient will depend upon a variety of factors
including the
disorder being treated and the severity of the disorder; 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 "pharmaceutically acceptable salt," as used herein, means salts
derived from
inorganic or organic acids. The salts can be prepared in situ during the final
isolation and
purification of compounds of Formula (I) or separately by reacting the free
base of a
compound of Formula (I) with an inorganic or organic acid. Representative acid
addition
salts include, but are not limited to, acetate, adipate, alginate, citrate,
aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,
digluconate,
glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,
hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate,
maleate,
fumarate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,
pamoate, pectinate,
persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate,
sulfate, (L) tartrate,
(D) tartrate, (DL) tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-
toluenesulfonate,
and undecanoate.
The term "pharmaceutically acceptable prodrug" or "prodrug,"as used herein,
represents those prodrugs of the compounds of the present invention which are,
within the
scope of sound medical judgment, suitable for use in contact with the tissues
of humans and
lower animals without undue toxicity, irritation, allergic response, and the
like. Prodrugs of
the present invention may be rapidly transformed in vivo to compounds of
Formula (I), for
example, by hydrolysis in blood.
The present invention contemplates compounds of Formula (I) formed by
synthetic
means or formed by in vivo biotransformation.
The compounds of the invention can exist in unsolvated as well as solvated
forms,
including hydrated forms, such as hemi-hydrates. In general, the solvated
forms, with
pharmaceutically acceptable solvents such as water and ethanol among others,
are equivalent
to the unsolvated forms for the purposes of the invention.
The total daily dose of the compounds of this invention administered to a
human or
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lower animal may range from about 0.003 to about 30 mg/kg/day. For purposes of
oral
administration, more preferable doses can be in the range of from about 0.01
to about 10
mg/kg/day. If desired, the effective daily dose can be divided into multiple
doses for
purposes of administration; consequently, single dose compositions may contain
such
amounts or submultiples thereof to make up the daily dose.
Protein kinases can be classified into broad groups based upon the identity of
the
amino acid(s) that they target (serine/threonine, tyrosine, lysine, and
histidine). For example,
tyrosine kinases include receptor tyrosine kinases (RTKs), such as growth
factors and non-
receptor tyrosine kinases, such as the src kinase family. There are also dual-
specific protein
kinases that target both tyrosine and serine/threonine, such as cyclin
dependent kinases
(CDKs) and mitogen-activated protein kinases (MAPKs).
The protein tyrosine kinases (PTKs) compose a large family of kinases that
regulate
cell to cell signals involved in growth, differentiation, adhesion, motility,
and death (Pearson,
M. et al., In Protein Tyrosine Kinases; Fabbro, D., McCormick, F., Eds.;
Humana Press Inc.,
2006; pp 1-29.). Members of the tyrosine kinase include, but are not limited
to, Yes, BMX,
Syk, EphAl, FGFR3, RYK, MUSK, JAKl and EGFR. Tyrosine kinases are
distinguished
into two classes, i.e., the receptor type and non-receptor type tyrosine
kinases. Interestingly,
the entire family of tyrosine kinases consists of at least 90 characterized
kinases with at least
58 receptor type and at least 32 nonreceptor type kinases comprising at least
30 total
subfamilies. Tyrosine kinases have been implicated in a number of diseases in
humans,
including diabetes and cancer (Pearson, M. et al., In Protein Tyrosine
Kinases; Fabbro, D.,
McCormick, F., Eds.; Humana Press Inc., 2006; pp 1-29.). Tyrosine kinases are
often
involved in most forms of human malignancies and have been linked to a wide
variety of
congenital syndromes (Robertson et al., Trends Genet. 16:265-271, 2000).
The non-receptor tyrosine kinases represent a group of intracellular enzymes
that lack
extracellular and transmembrane sequences. Currently, over 32 families of non-
receptor
tyrosine kinases have been identified (Robinson et al., Oncogene 19, 5548-
5557, 2000).
Representative examples include Src, Btk, Csk, ZAP70 and Kak families. In
particular, the
Src family of non-receptor tyrosine kinase family is the largest, consisting
of Src, Yes, Fyn,
Lyn, Lck, Blk, Hck, Fgr and Yrk protein tyrosine kinases. The Src family of
kinases have
been linked to oncogenesis, cell proliferation and tumor progression. Many of
the protein
tyrosine kinases have been found to be involved in cellular signaling pathways
involved in
various pathological conditions including but not limited to cancer and
hyperproliferative
disorders and immune disorders.
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The cyclin dependent kinases CDKs represent a group of intracellular enzymes
that
control progression through the cell cycle and have essential roles in cell
proliferation
(Cohen, P. Nature Reviews Drug Discovery 1, 309-315, 2002). Representative
examples of
CDKs include, but are not limited to, cyclin dependent kinase 2 (CDK2), cyclin
dependent
kinase 7 (CDK7), cyclin dependent kinase 6 (CDK6) and cell division control 2
protein
(CDC2). CDKs have been implicated in the regulation of transitions between
different
phases of the cell cycle, such as the progression from a quiescent stage in Gl
(the gap
between mitosis and the onset of DNA replication for a new round of cell
division) to S (the
period of active DNA synthesis), or the progression from G2 to M phase, in
which active
mitosis and cell division occur (Rowell et al. Critical Reviews in Immunology
26(3), 189-
212, 2006). CDK complexes are formed through association of a regulatory
cyclin subunit
(e.g., cyclin A, B1,B2, Dl, D2, D3, and E) and a catalytic kinase subunit
(e.g., cdc2 (CDKl),
CDK2, CDK4, CDK5, and CDK6). CDKs display an absolute dependence on the cyclin
subunit in order to phosphorylate their target substrates, and different
kinase/cyclin pairs
function to regulate progression through specific portions of the cell cycle.
Furthermore,
CDKs have been implicated in various disease states, including but not limited
to, those
displaying the cancer phenotype, various neoplastic disorders and in
neurological disorders
(Pallas et al. CuYYentMedicinal Chemistry: Central Nervous System Agents 5(2),
101-109,
2005).
The mitogen activated protein (MAP) kinases participate in the transduction of
signals
to the nucleus of the cell in response to extracellular stimuli.
Representative examples of
MAP kinases include, but are not limited to, mitogen activated protein kinase
3 (MAPK3),
mitogen-activated protein kinase 1(ERK2), mitogen-activated protein kinase 7
(MAPK7),
mitogen-activated protein kinase 8(JNKl), mitogen-activated protein kinase 14
(p38 alpha),
mitogen-activated protein kinase 10 (MAPK 10), JNK3 alpha protein kinase,
stress-activated
protein kinase JNK2 and mitogen-activated protein kinase 14 (MAPK14). MAP
kinases are a
family of proline-directed serine/threonine kinases that mediate signal
transduction from
extracellular receptors or heath shock, or UV radiation (Barr et al., Trends
in
Pharmacological Sciences 27(10), 525-530, 2006). MAP kinases activate through
the
phosphorylation of threonine and tyrosine by dual-specificity protein kinases,
including
tyrosine kinases such as growth factors. Cell proliferation and
differentiation have been
shown to be under the regulatory control of multiple MAP kinase cascades
(Sridhar et al.,
Pharmaceutical Research, 17:11 1345-1353, 2000). As such, the MAP kinase
pathway plays
critical roles in a number of disease states, for example, defects in
activities of MAP kinases
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have been shown to lead to aberrant cell proliferation and carcinogenesis (Qi
et al., Journal of
Cell Science 118(16), 3569-3572, 2005). Moreover, MAP kinase activity has also
been
implicated in insulin resistance associated with type-2 diabetes (Fujishiro et
al. Recent
Research Developments in Physiology 1(Pt. 2), 801-812, 2003).
The p90 ribosomal S6 kinases (Rsk) are serine/threonine kinases which function
in
mitogen-activated cell growth and proliferation, differentiation, and cell
survival. Examples
of members of the Rsk family of kinases include, but are not limited to,
ribosomal protein S6
kinase, 90 kDa, polypeptide 2 (Rsk3), ribosomal protein S6 kinase, 90 kDa,
polypeptide 6
(Rsk4), ribosomal protein S6 kinase, 90 kDa, polypeptide 3 (Rsk2) and
ribosomal protein S6
kinase, 90 kDa, polypeptide 1(Rskl/p90Rsk). The Rsk family members are
activated by
extracellular signal-related kinases and phosphoinositide-dependent protein
kinase 1(Frodin
and Gammeltoft, Mol. Cell. Endocrinol. 151, 65-77, 1999). Under basal
conditions, RSK
kinases are localized in the cytoplasm of cells and upon stimulation by
mitogens, the
activated (phosphorylated by extracellular-related kinase) RSK transiently
translocates to the
plasma membrane where they become fully activated. The fully activated RSK
phosphorylates substrates that are involved in cell growth, proliferation,
differentiation, and
cell survival (Clark et al. Cancer Research 65, 3108-3116, 2005). RSK
signaling pathways
have also been associated with the modulation of the cell cycle (Gross et al.,
J. Biol. Chem.
276, 46099-46103, 2001). Current data suggests that small molecules that
inhibit Rsk may be
useful therapeutic agents for the prevention and treatment of cancer and
inflammatory
diseases.
Members of the checkpoint protein kinase family (CHK) are serine/threonine
kinases
that play an important role in cell cycle progression. Examples of members of
the checkpoint
family include, but are not limited to, CHKI and CHK2. Checkpoints kinases are
control
systems that coordinate cell cycle progression by influencing the formation,
activation and
subsequent inactivation of the cyclin-dependent kinases. Checkpoints kinases
prevent cell
cycle progression at inappropriate times, maintain the metabolic balance of
cells while the
cell is arrested, and in some instances can induce apoptosis (programmed cell
death) when
the requirements of the checkpoint have not been met (Nurse, Cell, 91, 865-
867, 1997;
Hartwell et al., Science, 266, 1821-1828, 1994). Members of the checkpoint
family of
kinases have been implicated in cell proliferative disorders, cancer
phenotypes and other
diseases related to DNA damage and repair (Kumagai and Dunphy Cell Cycle, 5,
1265-1268
(2006); Xiao et al., Molecular Cancer Therapeutics 5, 1935-1943, 2006).
Aurora kinases are a family of multigene mitotic serine-threonine kinases that
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functions as a class of novel oncogenes. These kinases comprise aurora-A and
aurora-B
members. Aurora kinases are hyperactivated and/or over-expressed in several
solid tumors
including but not limited to, breast, ovary, prostate, pancreas, and
colorectal cancers. In
particular aurora-A is a centrosome kinase that plays an important role cell
cycle progression
and cell proliferation. Aurora-A is located in the 20q13 chromosome region
that is frequently
amplified in several different types of malignant tumors such as colorectal,
breast and bladder
cancers. There is also a high correlation between aurora-A and high histo-
prognostic grade
aneuploidy, making the kinase a potential prognostic vehicle. Inhibition of
aurora kinase
activity may reduce cell proliferation, tumor growth and potentially
tumorigenesis. A
detailed description of aurora kinase function is reviewed in Journal of Cell
Science, 119,
3664-3675, 2006.
The Rho-associated coiled-coil-containing protein serine/threonine kinases
ROCK-1
and ROCK-2 are thought to play a major role in cytoskeletal dynamics by
serving as
downstream effectors of the Rho/Rac family of cytokine-and growth factor-
activated small
GTPases. ROCKs phosphorylate various substrates, including, but not limited
to, myosin
light chain phosphatase, myosin light chain, ezrin-radixin-moesin proteins and
LIM (for
Linl 1, Isll and Mec3) kinases. ROCKs also mediate the formation of actin
stress fibers and
focal adhesions in various cell types. ROCKs have an important role in cell
migration by
enhancing cell contractility and are required for tail retraction of monocytes
and cancer cells.
ROCK inhibitors have also been shown to reduce tumor-cell dissemination in
vivo. Recent
experiments have defined new functions of ROCKs in cells, including centrosome
positioning and cell-size regulation, which might contribute to various
physiological and
pathological states (Mueller et al, Nature Reviews Drug Discovery 4, 387-398,
2005). The
ROCK family members are attractive intervention targets for a variety of
pathologies
including cancer and cardiovascular disease. ROCK inhibitors can be useful
therapeutic
agents for hypertension, angina pectoris, and asthma. Furthermore, Rho is
expected to play a
role in peripheral circulation disorders, arteriosclerosis, inflammation, and
autoimmune
disease and as such, is a useful target for therapy (Shimokawa et al,
Arteriosclerosis,
Thrombosis, and Vascular Biology, 25, 1767-1775, 2005).
The limited success of pharmacotherapeutic approaches in spinal-cord injury is
based
to a large extent on the inability of injured nerve fibers in the white matter
of the human
spinal cord to regrow and re-establish synaptic contacts with their
disconnected partner
neurons. A hostile micro-environment, characterized by the presence of a large
variety of
molecular neurite-growth inhibitors at the lesion site, in the scar tissue and
on CNS myelin,
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accounts for this irreversible arrest of neurite-growth. In tissue culture,
these inhibitors of
neurite growth often induce very dramatic responses, including the collapse of
the formation
and withdrawal of the neurite. Scar tissue in the human brain and spinal cord
is a strong and
persistent barrier for any regenerative neurite growth and ROCK inhibitors
might help injured
fibers to grow or sprout beyond this regeneration-inhibiting tissue. A variety
of evidence
indicates that injury to brain and spinal cord results in a strongly activated
RhoA-ROCK
pathway. Due to the persistent presence of the neurite growth inhibitors at or
around the
lesion site and in CNS myelin, such activation could potentially persist for a
long time,
making ROCK inhibition an attractive goal not only for acute and sub-acute
treatment, but
also for chronic treatment of spinal-cord injury. Inhibition of ROCK by two
different small-
molecule ROCK inhibitors (Y-27632 and fasudil) stimulated or accelerated
functional
recovery in different mouse and rat spinal-cord-injury models when given
locally or
systemically immediately after injury as a single dose or over several weeks
(Dergham, P. et
al. Rho signaling pathway targeted to promote spinal cord repair. J. Neurosci.
22, 6570-6577,
2002; Hara, M. et al. Protein kinase inhibition by fasudil hydrochloride
promotes
neurological recovery after spinal cord injury in rats. J. Neurosurg. Spine
93, 94-101, 2000.;
Fournier, A. E. et al. ROCK inhibition enhances axonal regeneration in the
injured CNS. J.
Neurosci. 23, 1416-1423, 2003; Sung, J. K. et al. A possible role of RhoA/Rho-
kinase in
experimental spinal cord injury in rat. Brain Res. 959, 29-38, 2003; Tanaka,
H. et al.
Cytoplasmic p21(Cipl/WAF1) enhances axonal regeneration and functional
recovery after
spinal cord injury in rats. Neuroscience 127, 155-164, 2004). In these
studies, ROCK
inhibition not only enhanced nerve-fiber growth beyond the lesion site, but
was also
neuroprotective and decreased tissue damage and cavity formation. On the basis
of these
rodent studies, ROCK inhibitors, which possess neuroprotective and
neuroregeneration-
stimulating activities, could offer significant benefit for spinally injured
patients. In addition,
they could normalize spinal blood flow due to their vasodilatory effects,
thereby further
enhancing tissue preservation.
Pathologically, Alzheimer's disease is characterized at the microscopic level
by
intracellular neurofibrillary tangles and extracellular amyloid aggregates.
Neurofibrillary
tangles contain aberrantly phosphorylated tau protein, a microtubule-
associated protein and
substrate for ROCK, whereas the amyloid aggregates are formed primarily by
toxic 42-
amino-acid long amyloid-(3 (A(3) peptides. It was recently shown (Zhou, Y. et
al.
Nonsteroidal anti-inflammatory drugs can lower amyloidogenic A042 by
inhibiting Rho.
Science 302, 1215-1217, 2003) that in cells secreting A(342 and in transgenic
PDAPP MICE
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producing large amounts of A(342, some NSAIDs lowered A(342 by inhibiting the
RhoA-
ROCK pathway. The ROCK inhibitor Y-27632 was effective in lowering A0421evels
both
in cell culture and in PDAPP transgenic mice after intra-cerebroventricular
injection.
Activation of Rho by geranylgeranylpyrophosphate, a lipid required for the
membrane
attachment of Rho, increased A(3421evels; this increase was completely
prevented by Y-
27632. The ROCK inhibitor Y-27632 used in animal Alzheimer's disease models
was
efficient in lowering the amount of the toxic A(3421evels, but had no effect
on total A(3levels
and this effect of Rho or ROCK inhibitors is at least one mechanism by which
NSAIDs
reduce A0421evels. In addition to many other therapeutic interventions, these
inhibitors have
the well-documented advantage of stimulating regenerative growth of neuritis
and it is
therefore possible that the inhibition of this pathway could result in repair
of the amyloid-
damaged neural circuitry.
Most important in disease pathogenesis is the migration of leukocytes beyond
the
brain endothelium into the CNS and the inflammatory cascade stimulated by
these cells,
which finally results in demyelination of CNS fiber tracts and in neurite
damage and loss.
Leukocytes require active RhoA and ROCK for their journey beyond brain
endothelium,
because their trans-endothelial migration was prevented by the ROCK inhibitor
Y-2763294.
Neuroprotective activities of the ROCK inhibitors fasudil and hydroxy-fasudil
are not
restricted to spinal-cord injury models, but have also been reported in
cerebral multi-infarct
models in gerbils and rats (Toshima Y, Satoh S, Ikegaki I, Asano T. A new
model of
cerebral microthrombosis in rats and the neuroprotective effect of a Rho-
kinase inhibitor.
Stroke 31, 2245-2250, 2000; Satoh, S. et al. Pharmacological profile of
hydroxy fasudil as a
selective ROCK inhibitor on ischemic brain damage. Life Sci. 69, 1441-1453,
2001;
Kitaoka, Y. et al. Involvement of RhoA and possible neuroprotective effect of
fasudil, a
ROCK inhibitor, in NMDA-induced neurotoxicity in the rat retina. Brain
Res.1018, 111-118,
2004). In rodent stroke models, several regeneration inhibitors, such as the
ROCK-activating
NgRl complex and one of its ligands, NOGO-A, have been neutralized 24 hours or
even 1
week after induction of a cerebral stroke and improved functional recovery has
been observed
(Lee, J. K., Kim, J. E., Sivula, M. & Strittmatter, S. M. Nogo receptor
antagonism promotes
stroke recovery by enhancing axonal plasticity. J. Neurosci. 24, 6209-6217,
2004; Wiessner,
C. et al. Anti-Nogo-A antibody infusion 24 hours after experimental stroke
improved
behavioral outcome and corticospinal plasticity in normotensive and
spontaneously
hypertensive rats. J. Cereb. Blood FlowMetab. 23, 154-165, 2003). Blocking
ROCK is
therefore a feasible neuroregenerative strategy; furthermore, such a strategy
has the
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advantage that the therapeutic treatment window for the use of these
inhibitors might be
larger than for thrombolytic or neuroprotective stroke treatment options.
Neuronal injuries in the peripheral nervous system or in the CNS of humans can
lead
to a chronic pain state known as neuropathic pain. Inflammatory mediators such
as
lysophosphatidic acid (LPA) which is produced in response to injury has
recently been shown
to be involved in initiation of neuropathic pain in a mouse model of
peripheral nerve injury
(Inoue, M. et al. Initiation of neuropathic pain requires lysophosphatidic
acid receptor
signaling. Nature Med. 10, 712-718, 2004). LPA is present at lesion sites in
the PNS and
CNS, and exerts its function by binding to G-protein-coupled LPA receptors
which results in
activation of the RhoA-ROCK pathway. The ROCK inhibitor Y-27632 prevented the
initiation of neuropathic pain after nerve injury or LPA injection, whereas
another ROCK
inhibitor, H- 1152, relieved neuropathic pain in an L5 spinal-nerve-
transection model
(Tatsumi, S. et al. Involvement of Rho-kinase in inflammatory and neuropathic
pain through
phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS).
Neuroscience
131, 491-498, 2005). The results of these studies indicate that ROCK is a
potential drug
target responsible for the induction and also maintenance of persistent pain
states.
Moreover, Schueller et al. (Abstract 1216, 8th World Congress on Inflammation,
Copenhagen, Denmark, June 16-20, 2007) have demonstrated that SLx-2119, an
orally
bioavailable, potent and highly selective inhibitor of ROCK 2 reduces
atherogenesis in the
presence of dramatically elevated lipid levels in groups of 8 ApoE knockout
mice,
indicaticating that selective inhibition of ROCK 2 has the potential to limit
atherosclerosis.
The 70 kDa ribosomal S6 kinase (p70S6K) is activated by numerous mitogens,
growth factors and hormones. Activation of p70S6K occurs through
phosphorylation at a
number of sites and the primary target of the activated kinase is the 40S
ribosomal protein S6,
a major component of the machinery involved in protein synthesis in mammalian
cells. In
addition, p70S6K activation has been implicated in cell cycle control,
neuronal cell
differentiation, regulation of cell motility and a cellular response that is
important in tumor
metastases, immunity and tissue repair. Modulation of p70S6 kinase activity
may also have
therapeutic implications in disorders such as cancer, inflammation, and
various neuropathies.
A detailed discussion of p70S6K kinases can be found in Prog. Cell Cycle Res.,
1, 21-32,
1995, and Immunol. Cell Biol. 78, 447-5 1, 2000.
Glycogen synthase kinase 3 (GSK-3) is a ubiquitously expressed constitutively
active
serine/threonine kinase that phosphorylates cellular substrates and thereby
regulates a wide
variety of cellular functions, including development, metabolism, gene
transcription, protein
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translation, cytoskeletal organization, cell cycle regulation, and apoptosis.
GSK-3 was
initially described as a key enzyme involved in glycogen metabolism, but is
now known to
regulate a diverse array of cell functions. Two forms of the enzyme, GSK-3+f
and GSK-
3+f, have been previously identified. The activity of GSK-3+f is negatively
regulated by
protein kinase B/Akt and by the Wnt signaling pathway. Small molecules
inhibitors of GSK-
3 may, therefore, have several therapeutic uses, including the treatment and
prevention of
neurodegenerative diseases and stimulation of neurogeneration in various
neurological
disorders (Gartner et al. J. Cell Science, 2006, 119, 3927-3934. Zhou et al.
Neuron, 2004,
42, 897-912), type II diabetes, bipolar disorders, stroke, cancer,
osteoarthritis, osteoporosis,
rheumatoid arthritis (Cuzzocrea et al. Clinical Immunology, 2006, 120, 57-67)
and chronic
inflammatory disease. General review: Kockeritz et al., Current Drug Targets,
7, 1377-
1388, 2006. Review of neurological applications: CurrentDNug Targets, 7(11),
1389-1397
and 1399-1409, 2006.
Protein kinases have become attractive targets for the treatment of cancers
(Fabbro et
al., Pharmacology & Therapeutics 93:79-98, 2002). It has been proposed that
the
involvement of protein kinases in the development of human malignancies may
occur by: (1)
genomic rearrangements (e.g., BCR-ABL in chronic myelogenous leukemia), (2)
mutations
leading to constitutively active kinase activity, such as acute myelogenous
leukemia and
gastrointestinal tumors, (3) deregulation of kinase activity by activation of
oncogenes or loss
of tumor suppressor functions, such as in cancers with oncogenic RAS, (4)
deregulation of
kinase activity by over-expression, as in the case of EGFR and (5) ectopic
expression of
growth factors that can contribute to the development and maintenance of the
neoplastic
phenotype (Fabbro et al., Pharmacology & Therapeutics 93:79-98, 2002).
Certain cancers are associated with angiogenesis. Angiogenesis is the growth
of new
capillary blood vessels from pre-existing vasculature (Risau, W., Nature
386:671-674, 1997).
It has been shown that protein kinases can contribute to the development and
maintenance of
the neoplastic phenotype (Fabbro et al., Pharmacology & Therapeutics 93:79-98,
2002). For
example, VEGF A-D and their four receptors have been implicated in phenotypes
that
involve neovascualrization and enhanced vascular permeability, such as tumor
angiogenesis
and lymphangiogenesis (Matter, A., Drug Discov. Today 6:1005-1023, 2001).
It has been recognized that a single agent approach that specifically targets
one kinase
or one kinase pathway may be inadequate to treat diseases and disorders, in
particular cancer,
for several reasons. Models have suggested that 5 to 7 mutations are necessary
for the
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progression of a normal cell to a malignant one. Furthermore, it is widely
recognized that
cancer is the result of alterations in multiple pathways, in particular
protein kinase pathways
that are associated with processes such as cell growth, proliferation,
apoptosis, motility, or
invasion. In a majority of cancers, a common feature is the simultaneous
overexpression
and/or hyper-activation of a variety of protein kinases, such as receptor and
non-receptor
kinases, serine/threonine kinases, P13 kinases and cell cycle associated
kinases. In fact,
several of these kinases, either alone or in conjunction with other kinases,
have been
implicated in a number of processes important for cell survival,
proliferation, growth and
malignant transformation, motility and invasion leading to metastasis and
angiogenesis or
inflammation, and diseases, disorders, and conditions associated therewith.
Accordingly, blocking one target kinase may not be clinically sufficient
because there
are multiple target kinases that affect the progression of a condition,
disease, or disorder. In
addition, blocking one target kinase may not be clinically sufficient because
redundant
kinase-mediated pathways and alternative oncogenic or inflammatory mechanisms
may
compensate for the blocked target kinase. Moreover, the use of a single agent
can also
increase the chances that resistance to that agent will develop.
Cardiovascular disease accounts for nearly one quarter of total annual deaths
worldwide. Vascular disorders such as atherosclerosis and restenosis result
from
dysregulated growth of the vessel walls and the restriction of blood flow to
vital organs.
Various kinase pathways, e.g. JNK, are activated by atherogenic stimuli and
regulated
through local cytokine and growth factor production in vascular cells (Yang et
al., Immunity
9:575, 1998). Ischemia and ischemia coupled with reperfusion in the heart,
kidney or brain
result in cell death and scar formation, which can ultimately lead to
congestive heart failure,
renal failure or cerebral dysfumction. In organ transplantation, reperfusion
of previously
ischemic donor organs results in acute leukocyte-mediated tissue injury and
delay of graft
function. Ischemia and reperfusion pathways are mediated by various kinases.
For example,
the JNK pathway has been linked to leukocyte-mediated tissue damage (Li et
al., Mol. Cell.
Biol. 16:5947-5954, 1996). Finally, enhanced apoptosis in cardiac tissues has
also been
linked to kinase activity (Pombo et al., J. Biol. Chem. 269:26546-26551,
1994).
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