U.S. patent application number 11/329303 was filed with the patent office on 2006-05-25 for indazole compounds, pharmaceutical compositions, and methods for mediating or inhibiting cell proliferation.
This patent application is currently assigned to AGOURON PHARMACEUTICALS, INC.. Invention is credited to Ted Michael Bleckman, Susan Elizabeth Kephart, Siegfried Heinz Reich, William Henry Romines, Michael B. Wallace.
Application Number | 20060111322 11/329303 |
Document ID | / |
Family ID | 22644536 |
Filed Date | 2006-05-25 |
United States Patent
Application |
20060111322 |
Kind Code |
A1 |
Reich; Siegfried Heinz ; et
al. |
May 25, 2006 |
Indazole compounds, pharmaceutical compositions, and methods for
mediating or inhibiting cell proliferation
Abstract
The invention is directed to intermediates useful for making
indazole compounds that modulate and/or inhibit cell
proliferation.
Inventors: |
Reich; Siegfried Heinz;
(Solana Beach, CA) ; Bleckman; Ted Michael; (La
Jolla, CA) ; Kephart; Susan Elizabeth; (San Diego,
CA) ; Romines; William Henry; (San Diego, CA)
; Wallace; Michael B.; (San Diego, CA) |
Correspondence
Address: |
AGOURON PHARMACEUTICALS, INC.
10777 SCIENCE CENTER DRIVE
SAN DIEGO
CA
92121
US
|
Assignee: |
AGOURON PHARMACEUTICALS,
INC.
|
Family ID: |
22644536 |
Appl. No.: |
11/329303 |
Filed: |
January 10, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11112423 |
Apr 22, 2005 |
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11329303 |
Jan 10, 2006 |
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10291158 |
Nov 8, 2002 |
6919461 |
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11112423 |
Apr 22, 2005 |
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09761656 |
Jan 18, 2001 |
6555539 |
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10291158 |
Nov 8, 2002 |
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60176484 |
Jan 18, 2000 |
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Current U.S.
Class: |
514/63 ; 514/64;
548/110 |
Current CPC
Class: |
C07D 403/04 20130101;
C07D 471/04 20130101; A61P 43/00 20180101; C07F 7/1804 20130101;
C07D 401/04 20130101; A61P 9/00 20180101; C07D 401/14 20130101;
C07D 233/56 20130101; A61P 35/00 20180101; C07D 249/08 20130101;
C07D 231/12 20130101; C07D 231/56 20130101; B22D 41/56
20130101 |
Class at
Publication: |
514/063 ;
514/064; 548/110 |
International
Class: |
A61K 31/695 20060101
A61K031/695; A61K 31/69 20060101 A61K031/69; C07F 5/02 20060101
C07F005/02 |
Claims
1. A compound having the formula ##STR146## wherein PG is
(trimethyl silyl) ethoxy methyl (SEM), p-methoxybenzyl (PMB),
benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (BOC), tetra
hydropyranyl (THP), or fluorene-9-methyloxycarbonyl; T is
substituted or unsubstituted boron, halo, NO.sub.2, or NH.sub.2
group; and T' is CO.sub.2H.
2. The compound according to claim 1 wherein PG is SEM.
3. A compound selected from the group consisting of: ##STR147##
Description
[0001] This is a Divisional of U.S. application Ser. No.
11/112,423, filed Apr. 22, 2005, which is a Divisional of U.S.
application Ser. No. 10/291,158, filed Nov. 8, 2002, which is a
Divisional of U.S. application Ser. No. 09/761,656, filed Jan. 18,
2001, now U.S. Pat. No. 6,555,539, which claims the benefit of U.S.
Provisional Application No. 60/176,484, filed Jan. 18, 2000, the
disclosures of which are incorporated by reference herein in their
entireties.
FIELD OF THE INVENTION
[0002] This invention is directed to indazole compounds that
mediate and/or inhibit cell proliferation, for example, through the
inhibition of the activity of protein kinases, such as VEGF, CHK-1,
and cyclin-dependent kinases (CDKs), such as CDK1, CDK2, CDK4, and
CDK6. The invention is further related to pharmaceutical
compositions containing such compounds and compositions, and to
methods of treating cancer as well as other disease states
associated with unwanted angiogenesis and/or cellular
proliferation, by administering effective amounts of such
compounds.
BACKGROUND OF THE INVENTION
[0003] Uncontrolled cell proliferation is the insignia of cancer.
Cell proliferation in response to various stimuli is manifested by
a deregulation of the cell division cycle, the process by which
cells multiply and divide. Tumor cells typically have damage to the
genes that directly or indirectly regulate progression through the
cell division cycle.
[0004] Hyperproliferative disease states, including cancer, are
characterized by cells rampantly winding through the cell cycle
with uncontrolled vigor due to, for example, damage to the genes
that directly or indirectly regulate progression through the cycle.
Thus, agents that modulate the cell cycle, and thus
hyperproliferation, could be used to treat various disease states
associated with uncontrolled or unwanted cell proliferation. In
addition to cancer chemotherapeutic agents, cell cycle inhibitors
are also proposed as antiparasitics (See, Gray et al., Curr. Med.
Chem. 6, 859-875 (1999)) and recently demonstrated as potential
antivirals (See, Schang et al., J. Virol. 74, 2107-2120 (2000)).
Moreover, the applicability of antiproliferative agents may be
expanded to treating cardiovascular maladies such as
artherosclerosis or restenosis (See Braun-Dullaeus et al.,
Circulation, 98, 82-89 (1998)), and states of inflammation, such as
arthritis (See, Taniguchi et al., Nature Med., 5, 760-767(1999)) or
psoriasis.
[0005] Mechanisms of cell proliferation are under active
investigation at cellular and molecular levels. At the cellular
level, de-regulation of signaling pathways, loss of cell cycle
controls, unbridled angiogenesis or stimulation of inflammatory
pathways are under scrutiny, while at the molecular level, these
processes are modulated by various proteins, among which protein
kinases are prominent suspects. Overall abatement of proliferation
may also result from programmed cell death, or apoptosis, which is
also regulated via multiple pathways, some involving proteolytic
enzyme proteins.
[0006] Among the candidate regulatory proteins, protein kinases are
a family of enzymes that catalyze phosphorylation of the hydroxyl
group of specific tyrosine, serine, or threonine residues in
proteins. Typically, such phosphorylation dramatically perturbs the
function of the protein, and thus protein kinases are pivotal in
the regulation of a wide variety of cellular processes, including
metabolisim, cell proliferation, cell differentiation, and cell
survival. Of the many different cellular functions in which the
activity of protein kinases is known to be required, some processes
represent attractive targets for therapeutic intervention for
certain disease states. Two examples are cell-cycle control and
angiogenesis, in which protein kinases play a pivotal role; these
processes are essential for the growth of solid tumors as well as
for other diseases.
[0007] CDKs constitute a class of enzymes that play critical roles
in regulating the transitions between different phases of the cell
cycle, such as the progression from a quiescent stage in G.sub.1
(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 G.sub.2 to M phase, in which active mitosis
and cell-division occur. See, e.g., the articles compiled in
Science, vol. 274 (1996), pp. 1643-1677; and Ann. Rev. Cell Dev.
Biol., vol. 13 (1997), pp. 261-291. CDK complexes are formed
through association of a regulatory cyclin subunit (e.g., cyclin A,
B1, B2, D1, D2, D3, and E) and a catalytic kinase subunit (e.g.,
cdc2 (CDK1), CDK2, CDK4, CDK5, and CDK6). As the name implies, the
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.
[0008] The D cyclins are sensitive to extracellular growth signals
and become activated in response to mitogens during the G.sub.1
phase of the cell cycle. CDK4/cyclin D plays an important role in
cell cycle progression by phosphorylating, and thereby
inactivating, the retinoblastoma protein (Rb). Hypophosphorylated
Rb binds to a family of transcriptional regulators, but upon
hyperphosphorylation of Rb by CDK4/cyclin D, these transcription
factors are released to activate genes whose products are
responsible for S phase progression. Rb phosphorylation and
inactivation by CDK4/cyclin D permit passage of the cell beyond the
restriction point of the G.sub.1 phase, whereupon sensitivity to
extracellular growth or inhibitory signals is lost and the cell is
committed to cell division. During late G.sub.1, Rb is also
phosphorylated and inactivated by CDK2/cyclin E, and recent
evidence indicates that CDK2/cyclin E can also regulate progression
into S phase through a parallel pathway that is independent of Rb
phosphorylation (see Lukas et al., "Cyclin E-induced S Phase
Without Activation of the pRb/E2F Pathway," Genes and Dev., vol. 11
(1997), pp. 1479-1492).
[0009] The progression from G.sub.1 to S phase, accomplished by the
action of CDK4/cyclin D and CDK2/cyclin E, is subject to a variety
of growth regulatory mechanisms, both negative and positive. Growth
stimuli, such as mitogens, cause increased synthesis of cyclin D1
and thus increased functional CDK4. By contrast, cell growth can be
"reined in," in response to DNA damage or negative growth stimuli,
by the induction of endogenous inhibitory proteins. These naturally
occurring protein inhibitors include p21.sup.WAF1/CIP1,
p27.sup.KIP1, and the p16.sup.INK4 family, the latter of which
inhibit CDK4 exclusively (see Harper, "Cyclin Dependent Kinase
Inhibitors," Cancer Surv., vol. 29 (1997), pp. 91-107). Aberrations
in this control system, particularly those that affect the function
of CDK4 and CDK2, are implicated in the advancement of cells to the
highly proliferative state characteristic of malignancies, such as
familial melanomas, esophageal carcinomas, and pancreatic cancers
(see, e.g., Hall and Peters, "Genetic Alterations of Cyclins,
Cyclin-Dependent Kinases, and CDK Inhibitors in Human Cancer," Adv.
Cancer Res., vol. 68 (1996), pp. 67-108; and Kamb et al., "A Cell
Cycle Regulator Potentially Involved in Genesis of Many Tumor
Types," Science, vol. 264 (1994), pp. 436-440). Over-expression of
cyclin D1 is linked to esophageal, breast, and squamous cell
carcinomas (see, e.g., DelSal et al., "Cell Cycle and Cancer:
Critical Events at the G. Restriction Point," Critical Rev.
Oncogenesis, vol. 71 (1996), pp. 127-142). Genes encoding the
CDK4-specific inhibitors of the p16 family frequently have
deletions and mutations in familial melanoma, gliomas, leukemias,
sarcomas, and pancreatic, non-small cell lung, and head and neck
carcinomas (see Nobori et al., "Deletions of the Cyclin-Dependent
Kinase-4 Inhibitor Gene in Multiple Human Cancers," Nature, vol.
368 (1994), pp. 753-756). Amplification and/or overexpression of
cyclin E has also been observed in a wide variety of solid tumors,
and elevated cyclin E levels have been correlated with poor
prognosis. In addition, the cellular levels of the CDK inhibitor
p27, which acts as both a substrate and inhibitor of CDK2/cyclin E,
are abnormally low in breast, colon, and prostate cancers, and the
expression levels of p27 are inversely correlated with the stage of
disease (see Loda et al., "Increased Proteasome-dependent
Degradation of the Cyclin-Dependent Kinase Inhibitor p27 in
Aggressive Colorectal Carcinomas," Nature Medicine, vol. 3 (1997),
pp. 231-234). Recently there is evidence that CDK4/cyclin D might
sequester p27, as reviewed in Sherr, et al., Genes Dev., Vol. 13
(1999), pp. 1501-1512. The p21 proteins also appear to transmit the
p53 tumor-suppression signal to the CDKs; thus, the mutation of p53
in approximately 50% of all human cancers may indirectly result in
deregulation of CDK activity.
[0010] The emerging data provide strong validation for the use of
compounds inhibiting CDKs, and CDK4 and CDK2 in particular, as
anti-proliferative therapeutic agents. Certain biomolecules have
been proposed for this purpose. For example, U.S. Pat. No.
5,621,082 to Xiong et al. discloses nucleic acid encoding of
inhibitors of CDK6, and WO 99/06540 for CDK's. Peptides and
peptidomimetic inhibitors are described in European Patent
Publication No. 0 666 270 A2, Bandara, et al., Nature
Biotechnology, Vol. 15 (1997), pp. 896-901 and Chen, et al.,
Proceedings of the National Academy of Science, USA, Vol. 96
(1999), pp. 4325-4329. Peptide aptamers were identified from
screening in Cohen, et al., Proc. Natl. Acad. Sci. U.S.A., Vol. 95
(1998), pp. 14272-14277. Several small molecules have been
identified as CDK inhibitors (for recent reviews, see Webster, "The
Therapeutic Potential of Targeting the Cell Cycle," Exp. Opin.
Invest. Drugs, vol. 7 (1998), pp. 865-887, and Stover, et al.,
"Recent advances in protein kinase inhibition: current molecular
scaffolds used for inhibitor synthesis," Current Opinion in Drug
Discovery and Development, Vol. 2 (1999), pp. 274-285). The flavone
flavopiridol displays modest selectivity for inhibition of CDKs
over other kinases, but inhibits CDK4, CDK2, and CDK1 equipotently,
with IC.sub.50s in the 0.1-0.3 .mu.M range. Flavopiridol is
currently in Phase II clinical trials as an oncology
chemotherapeutic (Sedlacek et al., "Flavopiridol (L86-8275; NSC
649890), A New Kinase Inhibitor for Tumor Therapy," Int. J. Oncol.,
vol. 9 (1996), pp. 1143-1168). Analogs of flavopiridol are the
subject of other publications, for example, U.S. Pat. No. 5,733,920
to Mansuri et al. (International Publication No. WO 97/16447) and
International Publication Nos. WO 97/42949, and WO 98/17662.
Results with purine-based derivatives are described in Schow et
al., Bioorg. Med. Chem. Lett., vol. 7 (1997), pp. 2697-2702; Grant
et al., Proc. Amer. Assoc. Cancer Res, vol. 39 (1998), Abst. 1207;
Legravend et al., Bioorg. Med. Chem. Lett., vol. 8 (1998), pp.
793-798; Gray et al., Science, vol. 281 (1998), pp. 533-538; Chang,
et al., Chemistry & Biology, Vol. 6 (1999), pp. 361-375, WO
99/02162, WO 99/43675, and WO 99/43676. In addition, the following
publications disclose certain pyrimidines that inhibit
cyclin-dependent kinases and growth-factor mediated kinases:
International Publication No. WO 98/33798; Ruetz et al., Proc.
Amer. Assoc. Cancer Res, vol. 39 (1998), Abst. 3796; and Meyer et
al., Proc. Amer. Assoc. Cancer Res., vol. 39 (1998), Abst.
3794.
[0011] Benzensulfonamides that block cells in G1 are in development
by Eisai, see Owa, et al., J. Med. Chem., Vol. 42 (1999), pp.
3789-3799. An oxindole CDK inhibitor is in development by
Glaxo-Wellcome, see Luzzio, et al., Proc. Amer. Assoc. Cancer Res.,
Vol. (1999), Abst. 4102 and WO99/15500. Paullones were found in
collaboration with the NCI, Schultz, et al., J. Med. Chem., Vol.
(1999), pp. 2909-2919. Indenopyrazoles are described in WO99/17769
and by Seitz, et al, 218.sup.th ACS Natl. Mtg. (Aug. 22-26, 1999,
New Orleans), Abst MEDI 316. Aminothiazoles are used in WO99/24416
and WO99/21845.
[0012] CHK1 is another protein kinase. CHK 1 plays an important
role as a checkpoint in cell cycle progression. Checkpoints are
control systems that coordinate cell cycle progression by
influencing the formation, activation and subsequent inactivation
of the cyclin-dependent kinases. Checkpoints 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. See, e.g., O'Connor, Cancer
Surveys, 29, 151-182 (1997); Nurse, Cell, 91, 865-867 (1997);
Hartwell et al., Science, 266, 1821-1828 (1994); Hartwell et al.,
Science, 246, 629-634 (1989).
[0013] One series of checkpoints monitors the integrity of the
genome and, upon sensing DNA damage, these "DNA damage checkpoints"
block cell cycle progression in G.sub.1 & G.sub.2 phases, and
slow progression through S phase. O'Connor, Cancer Surveys, 29,
151-182 (1997); Hartwell et al., Science, 266, 1821-1828 (1994).
This action enables DNA repair processes to complete their tasks
before replication of the genome and subsequent separation of this
genetic material into new daughter cells takes place. Importantly,
the most commonly mutated gene in human cancer, the p53 tumor
suppressor gene, produces a DNA damage checkpoint protein that
blocks cell cycle progression in G.sub.1 phase and/or induces
apoptosis (programmed cell death) following DNA damage. Hartwell et
al., Science, 266, 1821-1828 (1994). The p53 tumor suppressor has
also been shown to strengthen the action of a DNA damage checkpoint
in G.sub.2 phase of the cell cycle. See, e.g., Bunz et al.,
Science, 28, 1497-1501 (1998); Winters et al., Oncogene, 17,
673-684 (1998); Thompson, Oncogene, 15, 3025-3035 (1997).
[0014] Given the pivotal nature of the p53 tumor suppressor pathway
in human cancer, therapeutic interventions that exploit
vulnerabilities in p53-defective cancer have been actively sought.
One emerging vulnerability lies in the operation of the G.sub.2
checkpoint in p53 defective cancer cells. Cancer cells, because
they lack G.sub.1 checkpoint control, are particularly vulnerable
to abrogation of the last remaining barrier protecting them from
the cancer killing effects of DNA-damaging agents: the G.sub.2
checkpoint. The G.sub.2 checkpoint is regulated by a control system
that has been conserved from yeast to humans. Important in this
conserved system is a kinase, CHK1, which transduces signals from
the DNA-damage sensory complex to inhibit activation of the cyclin
B/Cdc2 kinase, which promotes mitotic entry. See, e.g., Peng et
al., Science, 277, 1501-1505 (1997); Sanchez et al., Science, 277,
1497-1501 (1997). Inactivation of CHK1 has been shown to both
abrogate G.sub.2 arrest induced by DNA damage inflicted by either
anticancer agents or endogenous DNA damage, as well as result in
preferential killing of the resulting checkpoint defective cells.
See, e.g., Nurse, Cell, 91, 865-867 (1997); Weinert, Science, 277,
1450-1451 (1997); Walworth et al., Nature, 363, 368-371 (1993); and
Al-Khodairy et al., Molec. Biol. Cell, 5, 147-160 (1994).
[0015] Selective manipulation of checkpoint control in cancer cells
could afford broad utilization in cancer chemotherapeutic and
radiotherapy regimens and may, in addition, offer a common hallmark
of human cancer "genomic instability" to be exploited as the
selective basis for the destruction of cancer cells. A number of
factors place CHK1 as a pivotal target in DNA-damage checkpoint
control. The elucidation of inhibitors of this and functionally
related kinases such as CDS1/CHK2, a kinase recently discovered to
cooperate with CHK1 in regulating S phase progression (see Zeng et
al., Nature, 395, 507-510 (1998); Matsuoka, Science, 282, 1893-1897
(1998)), could provide valuable new therapeutic entities for the
treatment of cancer.
[0016] Another group of kinases are the tyrosine kinases. Tyrosine
kinases can be of the receptor type (having extracellular,
transmembrane and intracellular domains) or the non-receptor type
(being wholly intracellular). At least one of the non-receptor
protein tyrosine kinases, namely, LCK, is believed to mediate the
transduction in T-cells of a signal from the interaction of a
cell-surface protein (Cd4) with a cross-linked anti-Cd4 antibody. A
more detailed discussion of non-receptor tyrosine kinases is
provided in Bolen, Oncogene, 8, 2025-2031 (1993), which is
incorporated herein by reference.
[0017] In addition to its role in cell-cycle control, protein
kinases also play a crucial role in angiogenesis, which is the
mechanism by which new capillaries are formed from existing
vessels. When required, the vascular system has the potential to
generate new capillary networks in order to maintain the proper
functioning of tissues and organs. In the adult, however,
angiogenesis is fairly limited, occurring only in the process of
wound healing and neovascularization of the endometrium during
menstruation. See Merenmies, J., Parada, L. F., Henkemeyer, M.,
Cell Growth & Differentiation, 8, 3-10 (1997). On the other
hand, unwanted angiogenesis is a hallmark of several diseases, such
as retinopathies, psoriasis, rheumatoid arthritis, age-related
macular degeneneration, and cancer (solid tumors). Folkman, Nature
Med., 1, 27-31 (1995). Protein kinases which have been shown to be
involved in the angiogenic process include three members of the
growth factor receptor tyrosine kinase family: VEGF-R2 (vascular
endothelial growth factor receptor 2, also know as KDR (kinase
insert domain receptor) and as FLK-1); FGF-R (fibroblast growth
factor receptor); and TEK (also known as Tie-2).
[0018] VEGF-R2, which is expressed only on endothelial cells, binds
the potent angiogenic growth factor VEGF and mediates the
subsequent signal transduction through activation of its
intracellular kinase activity. Thus, it is expected that direct
inhibition of the kinase activity of VEGF-R2 will result in the
reduction of angiogenesis even in the presence of exogenous VEGF
(see Strawn et al., Cancer Research, 56, 3540-3545 (1996)), as has
been shown with mutants of VEGF-R2 which fail to mediate signal
transduction. Millauer et al., Cancer Research, 56, 1615-1620
(1996). Furthermore, VEGF-R2 appears to have no function in the
adult beyond that of mediating the angiogenic activity of VEGF.
Therefore, a selective inhibitor of the kinase activity of VEGF-R2
would be expected to exhibit little toxicity.
[0019] Similarly, FGF-R binds the angiogenic growth factors aFGF
and bFGF and mediates subsequent intracellular signal transduction.
Recently, it has been suggested that growth factors such as bFGF
may play a critical role in inducing angiogenesis in solid tumors
that have reached a certain size. Yoshiji et al., Cancer Research,
57, 3924-3928 (1997). Unlike VEGF-R2, however, FGF-R is expressed
in a number of different cell types throughout the body and may or
may not play important roles in other normal physiological
processes in the adult. Nonetheless, systemic administration of a
small molecule inhibitor of the kinase activity of FGF-R has been
reported to block bFGF-induced angiogenesis in mice without
apparent toxicity. Mohammad et al., EMBO Journal, 17, 5996-5904
(1998).
[0020] TEK (also known as Tie-2) is another receptor tyrosine
kinase expressed only on endothelial cells which has been shown to
play a role in angiogenesis. The binding of the factor
angiopoietin-1 results in autophosphorylation of the kinase domain
of TEK and results in a signal transduction process which appears
to mediate the interaction of endothelial cells with
peri-endothelial support cells, thereby facilitating the maturation
of newly formed blood vessels. The factor angiopoietin-2, on the
other hand, appears to antagonize the action of angiopoietin-1 on
TEK and disrupts angiogenesis. Maisonpierre et al., Science, 277,
55-60 (1997).
[0021] As a result of the above-described developments, it has been
proposed to treat angiogenesis by the use of compounds inhibiting
the kinase activity of VEGF-R2, FGF-R, and/or TEK. For example,
WIPO International Publication No. WO 97/34876 discloses certain
cinnoline derivatives that are inhibitors of VEGF-R2, which may be
used for the treatment of disease states associated with abnormal
angiogenesis and/or increased vascular permeability such as cancer,
diabetes, psoriosis, rheumatoid arthritis, Kaposi's sarcoma,
haemangioma, acute and chronic nephropathies, atheroma, arterial
restinosis, autoimmune diseases, acute inflammation and ocular
diseases with retinal vessel proliferation.
[0022] In addition to the protein kinases identified above, many
other protein kinases have been considered to be therapeutic
targets, and numerous publications disclose inhibitors of kinase
activity, as reviewed in the following: McMahon et al., Current
Opinion in Drug Discovery & Development, 1, 131-146 (1998);
Strawn et al., Exp. Opin. Invest. Drugs, 7, 553-573 (1998).
[0023] There is still a need, however, for other small-molecule
compounds that may be readily synthesized and are potent inhibitors
of cell proliferation, for example, inhibitors of one or more
protein kinases, such as CHK1, VEGF, CDKs or CDK/cyclin complexes.
Because CDK4 may serve as a general activator of cell division in
most cells, and because complexes of CDK4/cyclin D and CDK2/cyclin
E govern the early G.sub.1 phase of the cell cycle, there is a need
for effective and specific inhibitors of CDK4 and/or CDK2 for
treating one or more types of tumors.
SUMMARY OF THE INVENTION
[0024] An object of the invention is to provide potent
anti-proliferative agents. Accordingly, one object of the invention
is to attain compounds and drug compositions that inhibit the
activity of one or more kinases, such as CDKs, VEGF, and CHK-1, or
cyclin complexes thereof. A further object is to provide an
effective method of treating cancer indications through kinases
inhibition, such as through inhibition of VEGF, CHK-1, CDK4 or
CDK4/D-type cyclin complexes and/or CDK2 or CDK2/E-type cyclin
complexes. Another object is to achieve pharmaceutical compositions
containing compounds effective to block the transition of cancer
cells into their proliferative phase. These and other objects and
advantages of the invention, which will become apparent in light of
the detailed description below, are achieved through use of
cell-cycle control agents of the invention described below.
[0025] According to these objectives, there is provided in
accordance with the present invention a compound represented by the
Formula I ##STR1## wherein: [0026] R.sub.1 is a substituted or
unsubstituted alkyl, aryl, heteroaryl, carbocycle, or heterocycle
group, or ##STR2## [0027] wherein R.sub.4 is H or lower alkyl, and
X is a substituted or unsubstituted alkyl, aryl, heteroaryl,
carbocycle, or heterocycle group; and [0028] R.sub.2 is a
substituted or unsubstituted alkyl, aryl, heteroaryl, carbocycle,
or heterocycle group, or ##STR3## [0029] wherein R.sub.4 is H or
lower alkyl, and X is a substituted or unsubstituted aryl,
heteroaryl, carbocycle, or heterocycle group; or [0030] a
pharmaceutically acceptable salt of a compound of the Formula I; or
a prodrug or pharmaceutically active metabolite of a compound of
the Formula I, or a pharmaceutically acceptable salt of the prodrug
or metabolite.
[0031] According to these objectives, there is also provided a
compound represented by Formula II: ##STR4##
[0032] wherein R'.sub.1 is a substituted or unsubstituted alkyl,
aryl, heteroaryl, carbocycle, heterocycle, ##STR5## or ##STR6##
group [0033] wherein each R.sub.4 is individually H or lower alkyl
and X is a substituted or unsubstituted alkyl, aryl, heteroaryl,
carbocycle, or heterocycle group; and
[0034] R'.sub.2 is a substituted or unsubstituted amino, nitro,
alkenyl, alkyl, aryl, heteroaryl, carbocycle, heterocycle, ##STR7##
or ##STR8## group, [0035] wherein R.sub.4 is independently H or
lower alkyl, and X is a substituted or unsubstituted aryl,
heteroaryl, carbocycle, or heterocycle group; or a pharmaceutically
acceptable salt of a compound of the Formula II; or a prodrug or
pharmaceutically active metabolite of a compound of the Formula II,
or a pharmaceutically acceptable salt of the prodrug or metabolite
thereof. There is also provided in accordance with the invention, a
pharmaceutical composition comprising: (a) a cell-cycle control
agent selected from: (i) a compound of the Formula I or II, [0036]
(ii) a pharmaceutically acceptable salt of a compound of the
Formula I or II; or [0037] (iii) a prodrug or pharmaceutically
active metabolite of a compound of the Formula I or II, or a
pharmaceutically acceptable salt of the prodrug or metabolite;
and
[0038] (b) a pharmaceutically acceptable carrier.
[0039] The invention also provides methods for making compounds of
Formula I and II.
[0040] There is further provided in accordance with the invention,
a method of using a compound as a cell-cycle control agent for
treating a disease or disorder mediated by inhibition of kinase
comprising administering to a patient in need thereof, a compound
of Formula I or II, or a pharmaceutically acceptable salt of a
compound of the Formula I or II; or a prodrug or pharmaceutically
active metabolite of a compound of the Formula I or II, or a
pharmaceutically acceptable salt of the metabolite or prodrug.
[0041] The invention further provides a method of treating mycotic
infection, malignancies or cancer as well as other disease states
associated with unwanted angiogenesis and/or cellular
proliferation, comprising administering effective amounts of a
compound of Formula I or II or a pharmaceutically acceptable salt
of a compound of the Formula I or II; or a prodrug or
pharmaceutically active metabolite of a compound of the Formula I
or II, or a pharmaceutically acceptable salt of the metabolite or
prodrug, to a patient in need of such treatment.
[0042] The invention also provides a method of modulating and/or
inhibiting kinase activity by administering a compound of the
Formula I or II or a pharmaceutically acceptable salt of a compound
of the Formula I or II; or a prodrug or pharmaceutically active
metabolite of a compound of the Formula I or II, or a
pharmaceutically acceptable salt of the metabolite or prodrug, to a
patient in need thereof.
[0043] There is also provided in accordance with the invention, a
pharmaceutical composition containing a compound of the Formula I
or II or a pharmaceutically acceptable salt of a compound of the
Formula I or II; or a prodrug, or pharmaceutically active
metabolite of a compound of the Formula I or II, or a
pharmaceutically acceptable salt of the metabolite or prodrug, and
the therapeutic use of the composition in treating diseases
mediated by kinase activity, such as cancer, as well as other
disease states associated with unwanted angiogenesis and/or
cellular proliferation, such as diabetic retinopathy, neovascular
glaucoma, rheumatoid arthritis, and psoriasis.
[0044] For the pharmaceutical composition and method aspects of the
invention, R.sub.1 can also be hydrogen, in Formula I or II.
[0045] The inventive agents and compositions containing such agents
may be useful in treating various disorders or disease states
associated with uncontrolled or unwanted cellular proliferation,
such as cancer, autoimmune disorders, viral diseases, fungal
diseases, neurodegenerative disorders, and cardiovascular diseases.
Thus, the invention is also directed to methods of treating such
diseases by administering an effective amount of the inventive
agent.
[0046] Other aspects, advantages, and features of the invention
will become apparent from the detailed description below.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS OF THE INVENTION
[0047] The compounds and compositions of the present invention, are
useful as anti-proliferative agents and as inhibitors of mammalian
kinase complexes, insect kinase or fungal kinase complexes. For
example, VEGF, CHK-1, and/or CDK complexes can be inhibited. Such
compounds and compositions are also useful for controlling
proliferation, differentiation, and/or apoptosis.
[0048] Examples of R.sub.1, R.sub.2, R'.sub.1, and R'.sub.2
preferred in compounds of Formula I or II groups are set forth
below: TABLE-US-00001 R.sub.1 and R'.sub.1 R.sub.2 and R'.sub.2
##STR9## ##STR10## ##STR11## ##STR12## ##STR13## ##STR14##
##STR15## ##STR16## ##STR17## ##STR18## ##STR19## ##STR20##
[0049] Preferably R.sub.1 and R'.sub.1 are: ##STR21## [0050]
wherein Y is CH or N or CR.sub.3, X is as defined above and R.sub.3
is H, or one or more substituents located on the ring, such as a
substituted or unsubstituted alkyl, alkenyl, aryl, heteroaryl,
carbocycle, heterocycle, hydroxy, halogen, alkoxy, aryloxy,
heteroaryloxy, thioalkyl, thioaryl, thioacyl, thioheteroaryl or
amino; [0051] or ##STR22## [0052] wherein the two Y's can be the
same or different.
[0053] In those embodiments, wherein R.sub.1 or R'.sub.1 is
##STR23## there can be one or more R.sub.3 substituents on the
phenyl ring.
[0054] More preferably, R.sub.1 and R'.sub.1 are substituted or
unsubstituted ##STR24## wherein the R.sub.3 groups are as defined
above. Also, two R.sub.3's together with an adjacent nitrogen can
form a heteroaryl or heterocycle ring.
[0055] Preferably, R.sub.2 and R'.sub.2 are unsubstituted or
substituted phenyl or ##STR25## [0056] wherein R.sub.4 is H or
lower alkyl, and X is a substituted or unsubstituted group selected
from alkyl, aryl, heteroaryl, carbocycle, or heterocycle.
[0057] Other preferred R.sub.2 and R'.sub.2 groups are substituted
or unsubstituted heteroaryls such as ##STR26##
[0058] Other preferred R.sub.2 and R'.sub.2 groups are
##STR27##
[0059] where R.sub.3 is as defined above.
[0060] Especially preferred substituents for the phenyl of R.sub.2
include fluorine, chlorine, hydroxyl, or an alkoxy group, such as
methoxy. Examples of preferred R groups, X, and Y groups are found
in the exemplary compounds that follow.
[0061] Y is preferably nitrogen.
[0062] X is preferably aryl, heteroaryl, carbocycle, or
heterocycle, most preferably phenyl.
[0063] R.sub.2 and R'.sub.2 can also be an amino (--NR'R''),
wherein R' and R'' are independently as defined for R.sub.3 above,
and together with an adjacent nitrogen can form a ring.
[0064] R.sub.4 is preferably hydrogen, or can be a lower alkyl
having 1-6 carbon atoms, which may be substituted or unsubstituted.
The two R.sub.4's can be the same or different.
[0065] Other preferred R.sub.1, R.sub.2, R'.sub.1, and R'.sub.2
groups are found in the exemplary compounds that follow.
[0066] Any desired alkyl group can be used, e.g., as R.sub.1 or
R.sub.2 or R'.sub.1 or R'.sub.2 or R.sub.3 or X. The alkyl group
can be a straight- or branched-chain alkyl group having one to
twelve carbon atoms. Exemplary alkyl groups include methyl, ethyl,
n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like. The
alkyl can be substituted or unsubstituted. Preferred substituted
alkyls include fluoromethyl, difluoromethyl, trifluoromethyl,
2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl,
3-hydroxypropyl, and the like.
[0067] Any desired aryl, heteroaryl, carbocycle, or heterocycle
group can be used as, e.g., R.sub.1 or R.sub.2 or R'.sub.1 or
R'.sub.2 or R.sub.3 or X. The groups can be fused or non-fused,
monocyclic or polycyclic.
[0068] Preferred aryl and heteroaryl groups include monocyclic and
polycyclic unsaturated or aromatic ring structures, with "aryl"
referring to those that are carbocycles and "heteroaryl" referring
to those that are heterocycles. Examples of ring structures include
phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, furyl, thienyl,
pyrrolyl, pyridyl, pyridinyl, pyrazolyl, imidazolyl, pyrazinyl,
pyridazinyl, 1,2,3-triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
1-H-tetrazol-5-yl, indolyl, quinolinyl, benzothiophenyl
(thianaphthenyl), furanyl, thiophenyl, imidazolyl, oxazolyl,
isoxazolyl, thiazolyl, triazolyl, tetrazolyl, isoquinolinyl,
acridinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, and the
like.
[0069] Preferred carbocyclic groups include those having from three
to twelve carbon atoms, including bicyclic and tricyclic cycloalkyl
structures. Preferred carbocyclic groups include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
[0070] Preferred heterocyclic groups include saturated rings
containing carbon atoms, for example containing 4 or 5 ring carbon
atoms, and at least one heteroatom selected from nitrogen, oxygen
and sulfur, and having no unsaturation. Preferred heterocyclic
groups include pyrrolidinyl, piperidinyl, thiazinyl, and
morpholinyl.
[0071] R.sub.1, R.sub.2, R.sub.3, Y, X, and other R groups can be
unsubstituted or substituted with any desired substituent or
substituents that do not adversely affect the desired activity of
the compound. Examples of preferred substituents are those found in
the exemplary compounds that follows, as well as halogen (chloro,
iodo, bromo, or fluoro); C.sub.1-6-alkyl; C.sub.1-6-alkenyl;
C.sub.1-6-alkynyl; hydroxyl; C.sub.1-6 alkoxyl; amino; nitro;
thiol; thioether; imine; cyano; amido; phosphonato; phosphine;
carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde;
ester; oxygen (.dbd.O); haloalkyl (e.g., trifluoromethyl);
carbocyclic cycloalkyl, which may be monocyclic or fused or
non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl,
or cyclohexyl), or a heterocycloalkyl, which may be monocyclic or
fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl,
piperazinyl, morpholinyl, or thiazinyl); carbocyclic or
heterocyclic, monocyclic or fused or non-fused polycyclic aryl
(e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl,
imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl,
pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl,
pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl,
benzothiophenyl, or benzofuranyl); amino (primary, secondary, or
tertiary); nitro; thiol; thioether, O-lower alkyl; O-aryl, aryl;
aryl-lower alkyl; CO.sub.2CH.sub.3; CONH.sub.2;
OCH.sub.2CONH.sub.2; NH.sub.2; SO.sub.2NH.sub.2; OCHF.sub.2;
CF.sub.3; OCF.sub.3; and the like. Such moieties may also be
optionally substituted by a fused-ring structure or bridge, for
example OCH.sub.2--O.
[0072] These substituents may optionally be further substituted
with a substituent selected from such groups.
[0073] Preferred compounds are shown in the examples that follow as
well as: ##STR28##
[0074] The present invention also relates to intermediates useful
in the preparation of compounds of Formula I or II. A particularly
preferred intermediate has the structure ##STR29##
[0075] Another preferred intermediate has the structure
##STR30##
[0076] Another preferred intermediate has the structure
##STR31##
[0077] In place of SEM, in the above three intermediates, other
known protecting groups, such as benzyloxycarbonyl (CBZ),
tert-butoxycarbonyl (BOC), tetra hydropyranyl (THP), and
fluorene-9-methyloxycarbonyl (FMOC), can be used.
[0078] Other preferred intermediates include ##STR32##
##STR33##
[0079] The abbreviations "SEM" and "PMB" refer to (trimethyl silyl)
ethoxy methyl and p-methoxybenzyl, respectively.
[0080] A preferred intermediate has the structure ##STR34##
[0081] wherein PG is a protecting group, T is a reactive group such
as a substituted or unsubstituted boron, halogen, NO.sub.2, or
NH.sub.2 group, and T' is a reactive group such as CHO, CO.sub.2H,
CO.sub.2R.sub.3, CONR.sub.3R.sub.3, where R.sub.3 groups are as
defined above.
[0082] Pharmaceutical compositions according to the invention may,
alternatively or in addition to a compound of the Formula I or II,
comprise as an active ingredient a pharmaceutically acceptable salt
of a compound of the Formula I or II, or a prodrug or
pharmaceutically active metabolite of such a compound or salt or a
salt of the prodrug or metabolite. Such compounds, salts, prodrugs,
and metabolites are sometimes referred to herein collectively as
"cell-cycle control agents."
[0083] The term "prodrug" refers to a metabolic precursor of a
compound of the Formula I or II (or a salt thereof) that is
pharmaceutically acceptable. A prodrug may be inactive when
administered to a subject but is converted in vivo to an active
compound of the Formula I or II. The term "active metabolite"
refers to a metabolic product of a compound of the Formula I or II
that is pharmaceutically acceptable and effective. Prodrugs and
active metabolites of compounds of the Formula I or II may be
determined using techniques known in the art.
[0084] Prodrugs and active metabolites of a compound may be
identified using routine techniques known in the art. See, e.g.,
Bertolini et al., J. Med. Chem., 40, 2011-2016 (1997); Shan, et
al., J. Pharm. Sci., 86 (7), 765-767; Bagshawe, Drug Dev. Res., 34,
220-230 (1995); Bodor, Advances in Drug Res., 13, 224-331 (1984);
Bundgaard, Design of Prodrugs (Elsevier Press 1985); and Larsen,
Design and Application of Prodrugs, Drug Design and Development
(Krogsgaard-Larsen et al., eds., Harwood Academic Publishers,
1991).
[0085] Within the invention it is understood that a compound of
Formula I or II may exhibit the phenomenon of tautomerism and that
the formula drawings within this specification represent only one
of the possible tautomeric forms. It is to be understood that the
invention encompasses any tautomeric form which modulates and/or
inhibits kinase activity and is not to be limited merely to any one
tautomeric form utilized within the formula drawings.
[0086] Some of the inventive compounds may exist as single
stereoisomers (i.e., essentially free of other stereoisomers),
racemates, and/or mixtures of enantiomers and/or diastereomers. All
such single stereoisomers, racemates and mixtures thereof are
intended to be within the scope of the present invention.
Preferably, the inventive compounds that are optically active are
used in optically pure form.
[0087] As generally understood by those skilled in the art, an
optically pure compound having one chiral center (i.e., one
asymmetric carbon atom) is one that consists essentially of one of
the two possible enantiomers (i.e., is enantiomerically pure), and
an optically pure compound having more than one chiral center is
one that is both diastereomerically pure and enantiomerically pure.
Preferably, the compounds of the present invention are used in a
form that is at least 90% optically pure, that is, a form that
contains at least 90% of a single isomer (80% enantiomeric excess
("e.e.") or diastereomeric excess ("d.e.")), more preferably at
least 95% (90% e.e. or d.e.), even more preferably at least 97.5%
(95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or
d.e.).
[0088] Additionally, Formulas I and II are intended to cover
solvated as well as unsolvated forms of the identified structures.
For example, Formulas I and II include compounds of the indicated
structure in both hydrated and non-hydrated forms. Other examples
of solvates include the structures in combination with isopropanol,
ethanol, methanol, DMSO, ethyl acetate, acetic acid, or
ethanolamine.
[0089] "A pharmaceutically acceptable salt" is intended to mean a
salt that retains the biological effectiveness of the free acids
and bases of the specified compound and that is not biologically or
otherwise undesirable. A compound of the invention may possess a
sufficiently acidic, a sufficiently basic, or both functional
groups, and accordingly react with any of a number of inorganic or
organic bases, and inorganic and organic acids, to form a
pharmaceutically acceptable salt. Exemplary pharmaceutically
acceptable salts include those salts prepared by reaction of the
compounds of the present invention with a mineral or organic acid
or an inorganic base, such as salts including sulfates,
pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,
monohydrogenphosphates, dihydrogenphosphates, metaphosphates,
pyrophosphates, chlorides, bromides, iodides, acetates,
propionates, decanoates, caprylates, acrylates, formates,
isobutyrates, caproates, heptanoates, propiolates, oxalates,
malonates, succinates, suberates, sebacates, fumarates, maleates,
butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,
methylbenzoates, dinitrobenzoates, hydroxybenzoates,
methoxybenzoates, phthalates, sulfonates, xylenesulfonates,
phenylacetates, phenylpropionates, phenylbutyrates, citrates,
lactates, .gamma.-hydroxybutyrates, glycollates, tartrates,
methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,
naphthalene-2-sulfonates, and mandelates.
[0090] If the inventive compound is a base, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method available in the art, for example, treatment of the free
base with an inorganic acid, such as hydrochloric acid, hydrobromic
acid, sulfuric acid, nitric acid, phosphoric acid and the like, or
with an organic acid, such as acetic acid, maleic acid, succinic
acid, mandelic acid, fumaric acid, malonic acid, pyrovic acid,
oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid,
such as glucuronic acid or galacturonic acid, an alpha-hydroxy
acid, such as citric acid or tartaric acid, an amino acid, such as
aspartic acid or glutamic acid, an aromatic acid, such as benzoic
acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic
acid or ethanesulfonic acid, or the like.
[0091] If the inventive compound is an acid, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method, for example, treatment of the free acid with an inorganic
or organic base, such as an amine (primary, secondary or tertiary),
an alkali metal hydroxide or alkaline earth metal hydroxide, or the
like. Illustrative examples of suitable salts include organic salts
derived from amino acids, such as glycine and arginine, ammonia,
primary, secondary, and tertiary amines, and cyclic amines, such as
piperidine, morpholine and piperazine, and inorganic salts derived
from sodium, calcium, potassium, magnesium, manganese, iron,
copper, zinc, aluminum and lithium.
[0092] In the case of agents that are solids, it is understood by
those skilled in the art that the inventive compounds and salts may
exist in different crystal or polymorphic forms, all of which are
intended to be within the scope of the present invention and
specified formulas.
[0093] Cell-cycle control agents in accordance with the invention
are useful as pharmaceuticals for treating proliferative disorders
in mammals, especially humans, marked by unwanted proliferation of
endogenous tissue. Compounds of the Formula I or II may be used for
treating subjects having a disorder associated with excessive cell
proliferation, e.g., cancers, psoriasis, immunological disorders
involving undesired proliferation of leukocytes, and restenosis and
other smooth-muscle disorders. Furthermore, such compounds may be
used to prevent de-differentiation of post-mitotic tissue and/or
cells.
[0094] Diseases or disorders associated with uncontrolled or
abnormal cellular proliferation include, but are not limited to,
the following: [0095] a variety of cancers, including, but not
limited to, carcinoma, hematopoietic tumors of lymphoid lineage,
hematopoietic tumors of myeloid lineage, tumors of mesenchymal
origin, tumors of the central and peripheral nervous system and
other tumors including melanoma, seminoma and Kaposi's sarcoma and
the like. [0096] a disease process which features abnormal cellular
proliferation, e.g., benign prostatic hyperplasia, familial
adenomatosis polyposis, neuro-fibromatosis, atherosclerosis,
pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis,
restenosis following angioplasty or vascular surgery, hypertrophic
scar formation, inflammatory bowel disease, transplantation
rejection, endotoxic shock, and fungal infections. [0097] defective
apoptosis-associated conditions, such as cancers (including but not
limited to those types mentioned hereinabove), viral infections
(including but not limited to herpesvirus, poxvirus, Epstein-Barr
virus, Sindbis virus and adenovirus), prevention of AIDS
development in HIV-infected individuals, autoimmune diseases
(including but not limited to systemic lupus erythematosus,
rheumatoid arthritis, psoriasis, autoimmune mediated
glomerulonephritis, inflammatory bowel disease and autoimmune
diabetes mellitus), neurodegenerative disorders (including but not
limited to Alzheimer's disease, amyotrophic lateral sclerosis,
retinitis pigmentosa, Parkinson's disease, AIDS-related dementia,
spinal muscular atrophy and cerebellar degeneration),
myelodysplastic syndromes, aplastic anemia, ischemic injury
associated with myocardial infarctions, stroke and reperfusion
injury, arrhythmia, atherosclerosis, toxin-induced or alcohol
related liver diseases, hematological diseases (including but not
limited to chronic anemia and aplastic anemia), degenerative
diseases of the musculoskeletal system (including but not limited
to osteroporosis and arthritis), aspirin-sensitive rhinosinusitis,
cystic fibrosis, multiple sclerosis, kidney diseases and cancer
pain.
[0098] The active agents of the invention may also be useful in the
inhibition of the development of invasive cancer, tumor
angiogenesis and metastasis.
[0099] Moreover, the active agents of the invention, for example,
as inhibitors of the CDKs, can modulate the level of cellular RNA
and DNA synthesis and therefore are expected to be useful in the
treatment of viral infections such as HIV, human papilloma virus,
herpes virus, Epstein-Barr virus, adenovirus, Sindbis virus, pox
virus and the like.
[0100] Compounds and compositions of the invention inhibit the
kinase activity of, for example, CDK/cyclin complexes, such as
those active in the G.sub.0 or G.sub.1 stage of the cell cycle,
e.g., CDK2, CDK4, and/or CDK6 complexes.
[0101] The specific dosage amount of a cell-cycle control agent
being administered to obtain therapeutic or inhibitory effects may
be determined in a manner known in the art according to the
particular circumstances surrounding the case, including, e.g., the
specific agent being administered, the route of administration, the
condition being treated, and the subject or host being treated. An
exemplary total daily dose of a cell-cycle control agent, which may
be administered in single or multiple doses, contains a dosage
level of from about 0.01 mg/kg body weight to about 50 mg/kg body
weight.
[0102] The cell-cycle control agents of the invention may be
administered by any of a variety of suitable routes, such as
orally, rectally, transdermally, subcutaneously, intravenously,
intramuscularly, or intranasally. The cell-cycle control agents are
preferably formulated into compositions suitable for the desired
routes before being administered.
[0103] A pharmaceutical composition or preparation according to the
invention comprises an effective amount of a cell-cycle control
agent, optionally one or more other active agents, and a
pharmaceutically acceptable carrier, such as a diluent or excipient
for the agent; when the carrier serves as a diluent, it may be a
solid, semi-solid, or liquid material acting as a vehicle,
excipient, or medium for the active ingredient(s). Compositions
according to the invention may be made by admixing the active
ingredient(s) with a carrier, or diluting it with a carrier, or
enclosing or encapsulating it within a carrier, which may be in the
form of a capsule, sachet, paper container, or the like. Exemplary
ingredients, in addition to one or more cell-cycle control agents
and any other active ingredients, include Avicel (microcrystalline
cellulose), starch, lactose, calcium sulfate dihydrate, terra alba,
sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,
stearic acid, peanut oil, olive oil, glyceryl monostearate, Tween
80 (polysorbate 80), 1,3-butanediol, cocoa butter, beeswax,
polyethylene glycol, propylene glycol, sorbitan monostearate,
polysorbate 60, 2-octyldodecanol, benzyl alcohol, glycine, sorbic
acid, potassium sorbate, disodium hydrogen phosphate, sodium
chloride, and water.
[0104] The compositions may be prepared in any of a variety of
forms suitable for the desired mode of administration. For example,
pharmaceutical compositions may be prepared in the form of tablets,
pills, powders, lozenges, sachets, cachets, elixirs, suspensions,
emulsions, solutions, syrups, aerosols (as solids or in liquid
media), ointments (e.g., containing up to 10% by weight of a
cell-cycle control agent), soft-gel and hard-gel capsules,
suppositories, sterile injectable solutions, sterile packaged
powders, and the like.
[0105] Similarly, the carrier or diluent may include time-delay or
time-release material known in the art, such as glyceryl
monostearate or glyceryl distearate alone or with a wax,
ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate
and the like.
[0106] A variety of pharmaceutical forms can be employed. Thus, if
a solid carrier is used, the preparation can be tableted, placed in
a hard gelatin capsule in powder or pellet form or in the form of a
troche or lozenge. The amount of solid carrier may vary, but
generally will be from about 25 mg to about 1 g. If a liquid
carrier is used, the preparation can be in the form of syrup,
emulsion, soft gelatin capsule, sterile injectable solution or
suspension in an ampoule or vial or non-aqueous liquid
suspension.
[0107] To obtain a stable water-soluble dose form, a
pharmaceutically acceptable salt of an inventive agent is dissolved
in an aqueous solution of an organic or inorganic acid, such as
0.3M solution of succinic acid or citric acid. If a soluble salt
form is not available, the agent may be dissolved in a suitable
cosolvent or combinations of cosolvents. Examples of suitable
cosolvents include, but are not limited to, alcohol, propylene
glycol, polyethylene glycol 300, polysorbate 80, gylcerin and the
like in concentrations ranging from 0-60% of the total volume. A
compound of Formula I or II may be dissolved in DMSO and diluted
with water. The composition may also be in the form of a solution
of a salt form of the active ingredient in an appropriate aqueous
vehicle such as water or isotonic saline or dextrose solution.
[0108] The compositions of the invention may be manufactured in
manners generally known for preparing pharmaceutical compositions,
e.g., using conventional techniques such as mixing, dissolving,
granulating, dragee-making, levigating, emulsifying, encapsulating,
entrapping or lyophilizing. Pharmaceutical compositions may be
formulated in a conventional manner using one or more
physiologically acceptable carriers, which may be selected from
excipients and auxiliaries that facilitate processing of the active
compounds into preparations which can be used pharmaceutically.
[0109] Proper formulation is dependent upon the route of
administration chosen. For injection, the agents of the invention
may be formulated into aqueous solutions, preferably in
physiologically compatible buffers such as Hanks's solution,
Ringers solution, or physiological saline buffer. For transmucosal
administration, penetrants appropriate to the barrier to be
permeated are used in the formulation. Such penetrants are
generally known in the art.
[0110] For oral administration, the compounds can be formulated
readily by combining the active compounds with pharmaceutically
acceptable carriers known in the art. Such carriers enable the
compounds of the invention to be formulated as tablets, pills,
dragees, capsules, liquids, gels, syrups, slurries, suspensions and
the like, for oral ingestion by a patient to be treated.
Pharmaceutical preparations for oral use can be obtained using a
solid excipient in admixture with the active ingredient (agent),
optionally grinding the resulting mixture, and processing the
mixture of granules after adding suitable auxiliaries, if desired,
to obtain tablets or dragee cores. Suitable excipients include:
fillers such as sugars, including lactose, sucrose, mannitol, or
sorbitol; and cellulose preparations, for example, maize starch,
wheat starch, rice starch, potato starch, gelatin, gum,
hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose,
methyl cellulose, or polyvinylpyrrolidone (PVP). If desired,
disintegrating agents may be added, such as crosslinked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof such as sodium
alginate.
[0111] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used, which may
optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel,
polyethylene glycol, and/or titanium dioxide, lacquer solutions,
and suitable organic solvents or solvent mixtures. Dyestuffs or
pigments may be added to the tablets or dragee coatings for
identification or to characterize different combinations of active
agents.
[0112] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with fillers such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate, and,
optionally, stabilizers. In soft capsules, the active agents may be
dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration
should be in dosages suitable for such administration. For buccal
administration, the compositions may take the form of tablets or
lozenges formulated in conventional manner.
[0113] For administration intranasally or by inhalation, the
compounds for use according to the present invention are
conveniently delivered in the form of an aerosol spray presentation
from pressurized packs or a nebulizer, with the use of a suitable
propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol the dosage unit may be determined
by providing a valve to deliver a metered amount. Capsules and
cartridges of gelatin for use in an inhaler or insulator and the
like may be formulated containing a powder mix of the compound and
a suitable powder base such as lactose or starch.
[0114] The compounds may be formulated for parenteral
administration by injection, e.g., by bolus injection or continuous
infusion. Formulations for injection may be presented in
unit-dosage form, e.g., in ampoules or in multi-dose containers,
with an added preservative. The compositions may take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilizing
and/or dispersing agents.
[0115] Pharmaceutical formulations for parenteral administration
include aqueous solutions of the active compounds in water-soluble
form. Additionally, suspensions of the active agents may be
prepared as appropriate oily injection suspensions. Suitable
lipophilic solvents or vehicles include fatty oils such as sesame
oil, or synthetic fatty acid esters, such as ethyl oleate or
triglycerides, or liposomes. Aqueous injection suspensions may
contain substances which increase the viscosity of the suspension,
such as sodium carboxymethyl cellulose, sorbitol, or dextran.
Optionally, the suspension may also contain suitable stabilizers or
agents which increase the solubility of the compounds to allow for
the preparation of highly concentrated solutions.
[0116] For administration to the eye, the active agent is delivered
in a pharmaceutically acceptable ophthalmic vehicle such that the
compound is maintained in contact with the ocular surface for a
sufficient time period to allow the compound to penetrate the
corneal and internal regions of the eye, including, for example,
the anterior chamber, posterior chamber, vitreous body, aqueous
humor, vitreous humor, cornea, iris/ciliary, lens, choroid/retina
and sclera. The pharmaceutically acceptable ophthalmic vehicle may
be an ointment, vegetable oil, or an encapsulating material. A
compound of the invention may also be injected directly into the
vitreous and aqueous humor.
[0117] Alternatively, the active ingredient may be in powder form
for constitution with a suitable vehicle, e.g., sterile
pyrogen-free water, before use. The compounds may also be
formulated in rectal compositions such as suppositories or
retention enemas, e.g., containing conventional suppository bases
such as cocoa butter or other glycerides.
[0118] The compounds may also be formulated as a depot preparation.
Such long-acting formulations may be administered by implantation
(for example, subcutaneously or intramuscularly) or by
intramuscular injection. Thus, for example, the compounds may be
formulated with suitable polymeric or hydrophobic materials (for
example, as an emulsion in an acceptable oil) or ion-exchange
resins, or as sparingly soluble derivatives, for example, as a
sparingly soluble salt.
[0119] A pharmaceutical carrier for hydrophobic compounds is a
cosolvent system comprising benzyl alcohol, a nonpolar surfactant,
a water-miscible organic polymer, and an aqueous phase. The
cosolvent system may be a VPD co-solvent system. VPD is a solution
of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant
polysorbate 80, and 65% w/v polyethylene glycol 300, made up to
volume in absolute ethanol. The VPD co-solvent system (VPD:5W)
contains VPD diluted 1:1 with a 5% dextrose in water solution. This
co-solvent system dissolves hydrophobic compounds well, and itself
produces low toxicity upon systemic administration. Naturally, the
proportions of a co-solvent system may be varied considerably
without destroying its solubility and toxicity characteristics.
Furthermore, the identity of the co-solvent components may be
varied: for example, other low-toxicity nonpolar surfactants may be
used instead of polysorbate 80; the fraction size of polyethylene
glycol may be varied; other biocompatible polymers may replace
polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars
or polysaccharides may be substituted for dextrose.
[0120] Alternatively, other delivery systems for hydrophobic
pharmaceutical compounds may be employed. Liposomes and emulsions
are known examples of delivery vehicles or carriers for hydrophobic
drugs. Certain organic solvents such as dimethylsulfoxide also may
be employed, although usually at the cost of greater toxicity.
Additionally, the compounds may be delivered using a
sustained-release system, such as semipermeable matrices of solid
hydrophobic polymers containing the therapeutic agent. Various
sustained-release materials have been established and are known by
those skilled in the art. Sustained-release capsules may, depending
on their chemical nature, release the compounds for a few weeks up
to over 100 days. Depending on the chemical nature and the
biological stability of the therapeutic reagent, additional
strategies for protein stabilization may be employed.
[0121] The pharmaceutical compositions also may comprise suitable
solid- or gel-phase carriers or excipients. Examples of such
carriers or excipients include calcium carbonate, calcium
phosphate, sugars, starches, cellulose derivatives, gelatin, and
polymers such as polyethylene glycols.
[0122] Some of the compounds of the invention may be provided as
salts with pharmaceutically compatible counter ions.
Pharmaceutically compatible salts may be formed with many acids,
including hydrochloric, sulfuric, acetic, lactic, tartaric, malic,
succinic, etc. Salts tend to be more soluble in aqueous or other
protonic solvents than are the corresponding free-base forms.
[0123] A pharmaceutical composition according to the invention
comprises a cell-cycle control agent and, optionally, one or more
other active ingredients, such as a known antiproliferative agent
that is compatible with the cell-cycle control agent and suitable
for the indication being treated.
[0124] The compounds are useful as anti-angiogenesis agents and as
agents for modulating and/or inhibiting the activity of protein
kinases, thus providing treatments for cancer or other diseases
associated with cellular proliferation mediated by protein
kinases.
[0125] Therapeutically effective amounts of the agents of the
invention may be used to treat diseases mediated by modulation or
regulation of protein kinases. An "effective amount" is intended to
mean that amount of an agent that, when administered to a mammal in
need of such treatment, is sufficient to effect treatment for a
disease mediated by the activity of one or more kinases. Thus,
e.g., a therapeutically effective amount of a compound of the
Formula I or II, salt, active metabolite or prodrug thereof is a
quantity sufficient to modulate, regulate, or inhibit the activity
of one or more kinases such that a disease condition which is
mediated by that activity is reduced or alleviated.
[0126] "Treating" is intended to mean at least the mitigation of a
disease condition in a mammal, such as a human, that is affected,
at least in part, by the activity of one or more kinases, and
includes: preventing the disease condition from occurring in a
mammal, particularly when the mammal is found to be predisposed to
having the disease condition but has not yet been diagnosed as
having it; modulating and/or inhibiting the disease condition;
and/or alleviating the disease condition.
[0127] The inventive agents may be prepared using the reaction
routes and synthesis schemes as described below, employing the
techniques available in the art using starting materials that are
readily available.
[0128] Exemplary general Schemes 1-6, shown below, can be used to
make the compounds of the invention. ##STR35##
[0129] The halogenated intermediate A can be obtained by standard
diatozation of 5-amino indazole and treatment of the resulting
diazonium salt with an appropriate halide salt, such as CuCl or KI.
Further halogenation to afford the 3-haloindazole B is achieved by
treatment with a suitable base such as sodium hydroxide or
potassium hydroxide and elemental halogen such as iodine.
Intermediate B is protected using any number of suitable protecting
groups and treated with a (preferably stoichiometric) alkyl or aryl
boronic acid or ester and a suitable Pd catalyst, for example,
Pd(PPh.sub.3).sub.4, to affect selective reaction at the C-3
position. Further reaction with a second alkyl or aryl boronic acid
or ester and a suitable Pd catalyst affords the desired
3,5-disubstituted intermediate E which is then deprotected to
afford the final compound F. Deprotection conditions are consistent
with the specific protecting group employed, for example, acidic
conditions for removal of a THP protecting group. R.sub.1 and
R.sub.2 are as defined above, and can be R'.sub.1 and R'.sub.2.
##STR36##
[0130] The above alternative synthetic variation to Route 1
involves treatment of intermediate C wherein X is Cl with an alkyl
ditin species, such as hexamethyl ditin, and an appropriate Pd
catalyst, to afford intermediate G. Reaction of intermediate G with
an alkyl or aryl halide and a suitable Pd catalyst provides the
desired intermediate D which can be further elaborated as described
above. ##STR37##
[0131] Alternatively, as shown in Route 2 above, a 5-nitro indazole
can be halogenated as described above for intermediate A, to afford
nitro compound H, by treatment with a suitable base such as sodium
hydroxide or potassium hydroxide and elemental halogen such as
iodine to yield an intermediate I after standard protection with an
appropriate protecting group.
[0132] Treatment of intermediate I with an alkyl ditin species,
such as hexamethyl ditin, and a suitable Pd catalyst, can afford
intermediate J. Further reaction of nitro compound J with an alkyl
or aryl boronic acid or ester and a suitable Pd catalyst affords
the 3-substituted indazole K. Reduction of K with a suitable
reducing agent, such as hydrogen with palladium catalyst or
SnCl.sub.2, affords the amine. Diazotization of the resulting
5-amino indazole and treatment of the resulting diazonium salt with
a suitable halide salt, such as CuCl or KI affords intermediate
halo compound L. Reaction of L with an alkyl or aryl boronic acid
or ester and a suitable Pd catalyst affords the intermediate M
which is deprotected as before to yield final compound F. R.sub.1
and R.sub.2 are as defined above, and can be R'.sub.1 and R'.sub.2.
##STR38##
[0133] In Route 3 shown above, 3-carboxyindazole is activated to
provide an active acylating species, such as with
carbonyldiimidazole, which is then treated with a suitable
alkoxy-alkyl amine, such N,N-dimethylhydroxylamine, to afford the
amide A'. Selective halogenation of intermediate A' with elemental
halogen such as bromine or iodine and preferably with a catalyst
such as bis(trifluoroacetoxy)iodosobenzene or bis(acetoxy)
iodosobenzene yields the 5-halo indazole B'. Protection of
intermediate B' under standard conditions with a suitable
protecting group such as PMB or THP affords protected amide C'.
Reduction of C' with an appropriate reductant such as lithium
aluminum hydride or an equivalent hydride reducing agent yields key
intermediate aldehyde D'. R.sub.3 is as defined above, and is
preferably substituted or unsubstituted alkyl, preferably lower
alkyl. ##STR39##
[0134] In Route 4 shown above, intermediate D' is reacted with a
substituted diamine B'' and a suitable oxidizing agent such as
sulfur to afford the benzimidazole C''. Conversion of compound C''
to the corresponding borinate ester D'' is accomplished by reacting
with a suitable diboron species, such as dipinacolatodiboron, or
other electrophilic source of boron, with an appropriate palladium
catalyst. Intermediate D'' is further reacted with a halogenated
aryl or alkyl halide under palladium catalysis to give
5-substituted indazole intermediate E'', which after appropriate
deprotection affords the final compound H''.
[0135] Alternatively, starting compound D' is reacted with a
suitable diboron species, such as bis(pinacolato)diboron, or other
suitable electrophilic source of boron, and an appropriate
palladium catalyst to give boron ester F''. Elaboration of compound
F'' into intermediate D'' is accomplished as described before for
intermediate D'.
[0136] Another alternative conversion can be accomplished by
reacting intermediate aldehyde F'' with a substituted aryl or alkyl
halide to provide R.sub.2 with a palladium catalyst to afford G''
which is further reacted with a substituted diamine B'' and a
suitable oxidizing agent such as sulfur to afford the benzimidazole
E''. Deprotection as before yields final compound H''. R.sub.2 is
as defined above and can be R'.sub.2. R.sub.3 is as defined
above.
[0137] Yet another preparation of intermediate E'' can be
accomplished by reacting compound such as C'' directly with a
suitable alkyl borinic acid or ester under suitable palladium
catalysis.
[0138] Additional electrophilic boron species that can be used have
the structure: ##STR40## where R.sub.3 is as defined above and two
R.sub.3 groups can form a ring.
[0139] Specific examples include: ##STR41## ##STR42##
[0140] In Route 5 above, alcohol intermediate X.sub.1 can be
activated for example by reaction with a sulfonyl halide such as
methanesulfonyl chloride and a suitable base such as triethylamine
and this electrophilic species reacted further with a nucleophile
such as a substituted amine to afford the intermediate X.sub.2
which is then deprotected under the appropriate conditions. R.sub.2
is as defined above, and can be R'.sub.2. R.sub.3 is as defined
above. ##STR43##
[0141] In Route 6 shown above, the core indazole structure is
formed in an annulation of a 2-halo-5-nitrophenyl aryl ketone Y1
with hydrazine to provide the requisite 3-aryl-5-nitroindazole Y2.
Subsequent protection and reduction provides the amine Y4. As
described for Route 2, diazotization, treatment of the diazonium
salt with KI, followed by Pd catalyzed coupling of the iodo
intermediate with an aryl boronic acid affords the protected
3,5-bisarylindazole intermediate Y6. Standard deprotection then
yields the final products. R.sub.1 and R.sub.2 are as defined
above, and can be R'.sub.1 and R'.sub.2.
[0142] The preparation of specific preferred compounds of the
invention is described in detail in the following examples. The
artisan will recognize that the chemical reactions described may be
readily adapted to prepare a number of other kinase inhibitors of
the invention. For example, the synthesis of non-exemplified
compounds according to the invention may be successfully performed
by modifications apparent to those skilled in the art, e.g., by
appropriately protecting interfering groups, by changing to other
suitable reagents known in the art, or by making routine
modifications of reaction conditions. Alternatively, other
reactions disclosed herein or known in the art will be recognized
as having applicability for preparing other compounds of the
invention.
[0143] In the examples described below, unless otherwise indicated
all temperatures are set forth in degrees Celsius and all parts and
percentages are by weight. Reagents were purchased from commercial
suppliers such as Aldrich Chemical Company or Lancaster Synthesis
Ltd. and were used without further purification unless otherwise
indicated. Tetrahydrofuran (THF) distilled from calcium hydride and
N,N-dimethylformamide (DMF) were purchased from Aldrich in Sure
seal bottles and used as received. All solvents were purified using
standard methods readily known to those skilled in the art, unless
otherwise indicated.
[0144] The reactions set forth below were done generally under a
positive pressure of argon or with a drying tube, at ambient
temperature (unless otherwise stated), in anhydrous solvents, and
the reaction flasks were fitted with rubber septa for the
introduction of substrates and reagents via syringe. Glassware was
oven dried and/or heat dried. Analytical thin layer chromatography
(TLC) was performed on glass-backed silica gel 60 F 254 plates
Analtech (0.25 mm) and eluted with the appropriate solvent ratios
(v/v), and are denoted where appropriate. The reactions were
assayed by TLC and terminated as judged by the consumption of
starting material.
[0145] Visualization of the TLC plates was done with a
p-anisaldehyde spray reagent or phosphomolybdic acid reagent
(Aldrich Chemical 20 wt % in ethanol) and activated with heat.
Work-ups were typically done by doubling the reaction volume with
the reaction solvent or extraction solvent and then washing with
the indicated aqueous solutions using 25% by volume of the
extraction volume unless otherwise indicated. Product solutions
were dried over anhydrous Na.sub.2SO.sub.4 or MgSO.sub.4 prior to
filtration and evaporation of the solvents under reduced pressure
on a rotary evaporator and noted as solvents removed in vacuo.
Flash column chromatography (Still et al., J. Org. Chem., 43, 2923
(1978)) was done using Baker grade flash silica gel (47-61 .mu.m)
and a silica gel: crude material ratio of about 20:1 to 50:1 unless
otherwise stated. Hydrogenation was done at the pressure indicated
in the examples or at ambient pressure.
[0146] .sup.1H-NMR spectra were recorded on a Bruker instrument
operating at 300 MHz or 500 MHz and .sup.13C-NMR spectra were
recorded operating at 75 MHz. NMR spectra were obtained as
CDCl.sub.3 solutions (reported in ppm), using chloroform as the
reference standard (7.25 ppm and 77.00 ppm) or CD.sub.3OD (3.4 ppm
and 4.8 ppm and 49.3 ppm), or internal tetramethylsilane (0.00 ppm)
when appropriate. Other NMR solvents were used as needed. When peak
multiplicities are reported, the following abbreviations are used:
s (singlet), d (doublet), t (triplet), m (multiplet), br
(broadened), dd (doublet of doublets), dt (doublet of triplets).
Coupling constants, when given, are reported in Hertz (Hz).
[0147] Infrared (IR) spectra were recorded on a Perkin-Elmer FT-IR
Spectrometer as neat oils, or as KBr pellets, and when given are
reported in wave numbers (cm.sup.-1). The mass spectra were
obtained using LSIMS or electrospray. All melting points (mp) are
uncorrected.
[0148] The starting materials used in the examples are commercially
available and/or can be prepared by techniques known in the
art.
EXAMPLE 1
5-Phenyl-3-Styryl-1H-Indazole
[0149] ##STR44##
(a) Intermediate 1a--5-Chloro-3-iodo-1H-indazole
[0150] 5-Amino-1H-indazole (15.41 g, 116 mmol) was suspended in a
mixture of water (250 mL), ice (250 mL), and concentrated HCl (100
mL). The mixture was cooled in an ice-salt bath to an internal
temperature of -5.degree. C. To this mixture, was added a solution
of sodium nitrite (8.78 g, 127 mmol) in water (75 mL), which had
been cooled to 0.degree. C. The resulting diazonium solution was
stirred for 15 minutes at -5.degree. C. A solution of copper (I)
chloride (14.9 g, 151 mmol) in concentrated HCl (150 mL) was cooled
to 0.degree. C. and then added to the diazonium solution dropwise,
causing an orange precipitate to form. The cooling bath was removed
to allow the reaction to warm to room temperature. Gas evolution
began at 10.degree. C. internal temperature. After stirring at room
temperature for 1.5 hours, the gas evolution subsided. The flask
was then heated to 60.degree. C. for 30 minutes, then cooled to
.about.15.degree. C. A brown precipitate formed. The precipitate
was collected by suction filtration and dried in a vacuum
dessicator over NaOH for 16 hours to give crude
5-chloro-1H-indazole (25.6 g) as a tan powder.
[0151] This crude intermediate was dissolved in 1,4-dioxane (400
mL). 3 M Aqueous NaOH (400 mL) and iodine flakes (35.3 g, 139 mmol)
were added to the solution. After stirring at room temperature for
2 hours, the reaction mixture was neutralized to pH=6 with 20%
aqueous citric acid, causing the dark color to change to light
green. Saturated aqueous sodium thiosulfate (.about.400 mL) was
added to the solution, causing the color to change from green to
yellow, and the solution extracted with ethyl acetate (3.times.1000
mL). The combined organic extracts were dried over sodium sulfate,
suction filtered through a coarse frit, and concentrated to a green
sludge which was then redissolved in ethyl acetate (500 mL),
filtered through a Celite pad, and concentrated to a green solid.
Purification by silica gel chromatography (25% ethyl acetate in
hexanes) yielded 5-Chloro-3-iodo-1H-indazole 1a (14.18 g, 44% from
5-amino-1H-indazole) as an off-white solid: mp=198-199.degree. C.;
R.sub.f=0.53 (50% ethyl acetate/hexanes); .sup.1H NMR
(DMSO-d.sub.6) .delta. 7.44 (m, 2H), 7.60 (d, 1H, J=8.7 Hz), 13.68
(s, 1H). Anal. (C.sub.7H.sub.4ClIN.sub.2) C, H, N.
(b) Intermediate
1b--5-Chloro-3-iodo-1-[2-(trimethylsilanyl)-ethoxymethyl]-1H-indazole
[0152] 5-Chloro-3-iodo-1H-indazole 1a (8.86 g, 31.8 mmol) was
dissolved in THF (100 mL) and cooled in an ice-salt bath to
0.degree. C. Solid sodium t-butoxide (3.67 g, 38.2 mmol) was added,
and the mixture stirred at 0.degree. C. for 1 hour.
2-(Trimethylsilyl)ethoxymethyl chloride (7.96 g, 38.2 mmol) was
then added, and stirring continued at 0.degree. C. for 1 hour more.
The solution was diluted with ethyl acetate (200 mL), washed with
water (100 mL), and brine (100 mL). The organic layer was dried
over magnesium sulfate, filtered, and concentrated. Silica gel
chromatography (5 to 20% ethyl acetate in hexanes) afforded 1b
(9.75 g, 75%) as a yellow oil: R.sub.f=0.39 (5% ethyl
acetate/hexanes); .sup.1H NMR (CDCl.sub.3) .delta. -0.06 (s, 9H),
0.87 (t, 2H, J=8.1 Hz), 3.55 (t, 2H, J=8.1 Hz), 5.70 (s, 2H), 7.43
(dd, 1H, J=8.9, 1.7 Hz), 7.49 (m, 2H). Anal.
(C.sub.13H.sub.18ClIN.sub.2OSi) C, H, N.
(c) Intermediate
1c--5-Chloro-3-styryl-1-[2-(trimethylsilanyl)-ethoxymethyl]-1H-indazole
[0153] 5-Chloro-3-iodo-2-SEM-indazole 1b (553 mg, 1.35 mmol),
styryl boronic acid (300 mg, 2.03 mmol), and
tetrakis(triphenylphosphine) palladium (78.2 mg, 0.068 mmol) were
dissolved in toluene (10 mL) and methanol (1.4 mL). Saturated
aqueous sodium bicarbonate solution (1.7 mL) was added, and the
mixture heated in a 90.degree. C. oilbath for 3 hours. Slight
refluxing was observed. After cooling to room temperature, the
solution was diluted with water (15 mL) and extracted with ethyl
acetate (4.times.50 mL). The combined organic extracts were dried
over magnesium sulfate, filtered, and concentrated. Purification by
silica gel chromatography (toluene) gave pure 1c (350.7 mg, 67%) as
a yellow oil: R.sub.f=0.20 (toluene); .sup.1H NMR (CDCl.sub.3)
.delta. -0.09 (s, 9H), 0.86 (t, 2H, J=8.1 Hz), 3.55 (t, 2H, J=8.3
Hz), 5.65 (s, 2H), 7.2-7.4 (m, 7H), 7.54 (d, 2H, J=7.6 Hz), 7.93
(d, 1H, J=1.6 Hz). .sup.13C NMR (CDCl.sub.3) .delta. -1.5, 17.7,
66.5, 77.9, 111.0, 119.2, 120.3, 123.6, 126.5, 127.3, 127.4, 128.0,
128.7, 131.6, 136.9, 139.4, 142.5. Anal.
(C.sub.21H.sub.25ClN.sub.2OSi.0.02CHCl.sub.3) C, H, N, Cl.
(d) Intermediate
1d--5-Phenyl-3-styryl-1-[2-(trimethylsilanyl)-ethoxymethyl]-1H-indazole
[0154] To a solution of 5-chloro-3-styryl-2-SEM-indazole 1c (209.4
mg, 0.544 mmol) in dry 1,4-dioxane (0.5 mL) was added phenyl
boronic acid (69.6 mg, 0.571 mmol), cesium carbonate (213 mg, 0.653
mmol), and tris(dibenzylidineacetone)dipalladium (10.0 mg, 0.0108
mmol). A solution of tri-tert-butyl phosphine in 1,4-dioxane (0.1
M, 0.217 mL) was added, and the mixture heated to 80.degree. C. for
6 hours. After cooling to room temperature, the solution was
diluted with ethyl ether (20 mL), and filtered through a Celite pad
to remove the black palladium precipitate. The filtrate was dried
over magnesium sulfate, filtered, concentrated, and purified by
silica gel chromatography (toluene) to give 1d (77.2 mg, 33%) as a
colorless oil: R.sub.f=0.09 (toluene); .sup.1H NMR (CDCl.sub.3)
.delta. -0.04 (s, 9H), 0.93 (t, 2H, J=8.1 Hz), 3.62 (t, 2H, J=8.1
Hz), 5.76 (s, 2H, J), 7.3-7.7 (m, 14H) 8.17 (s, 1H). Anal.
(C.sub.27H.sub.30N.sub.2OSi.0.2H.sub.2O) C, H, N.
(e) Example 1--5-Phenyl-3-Styryl-1H-Indazole
[0155] Intermediate 1d (68.1 mg, 0.16 mmol) was dissolved in
absolute ethanol (2.0 mL) and 3 M HCl (2.0 mL). The solution was
heated to reflux for 20 hours, cooled to room temperature, and
extracted with ethyl acetate (3.times.30 mL). The combined organic
extracts were dried over magnesium sulfate, filtered, concentrated,
and purified by silica gel chromatography (25 to 50% ethyl acetate
in hexanes), affording the title compound (19.2 mg, 40%) as a white
solid: R.sub.f=0.14 (25% ethyl acetate/hexanes); .sup.1H NMR
(CDCl.sub.3) .delta. 6.92 (d, 1H, J=6.3 Hz), 7.3-7.7 (m, 13H), 8.20
(s, 1H), 10.3 (br s, 1H). HRMS calculated for
C.sub.21H.sub.17N.sub.2 297.1392 (MH.sup.+), found 297.1398. Anal.
(C.sub.21H.sub.16N.sub.2.0.7H.sub.2O) C, H, N.
EXAMPLE 2
3,5-Distyryl-1H-Indazole
[0156] ##STR45##
(a) Intermediate 2a--5-Iodo-1H-indazole
[0157] 5-Amino-1H-indazole (10.21 g, 76.7 mmol) was suspended in a
mixture of water (100 mL), ice (100 mL), and concentrated HCl (35
mL). The mixture was cooled in an ice-salt bath to an internal
temperature of -5.degree. C. To this mixture was added a solution
of sodium nitrite (5.82 g, 84.4 mmol) in water (30 mL), which had
been cooled to 0.degree. C. The resulting diazonium solution was
stirred for 10 minutes at -5.degree. C., then a solution of
potassium iodide (15.3 g, 92 mmol) in water (50 mL) was added
slowly dropwise. Significant foaming occurred with the first few
drops of KI solution, and then a black, tarry gum formed. After the
addition was completed, the mixture was heated to 90.degree. C. for
1 hour. The tarry precipitate dissolved and purple vapor was
evolved during heating. The reaction was then cooled to room
temperature, causing a fine brown precipitate to form. This
precipitate was collected by suction filtration, and dried under
vacuum to give 5-iodoindazole 2a (14.12 g, 75%) as a brown powder:
R.sub.f=0.28 (50% ethyl acetate/hexanes); .sup.1H NMR
(DMSO-d.sub.6) .delta. 7.40 (d, 1H, J=9.0 Hz), 7.56 (dd, 1H, J=8.5,
1.5 Hz), 8.01 (s, 1H) 8.16 (s, 1H), 13.23 (s, 1H). Anal.
(C.sub.7H.sub.5IN.sub.2) C, H, I, N.
(b) Intermediate 2b--3,5-Diiodo-1H-indazole
[0158] Intermediate 2b was prepared by a synthetic method analogous
to intermediate 1a synthesis. Treatment of intermediate 2a with
iodine and sodium hydroxide yielded 3,5-diiodo-1H-indazole 2b (84%)
as a yellow solid: R.sub.f=0.39 (30% ethyl acetate/hexanes);
.sup.1H NMR (DMSO-d.sub.6) .delta. 7.41 (d, 1H, J=8.7 Hz), 7.66
(dd, 1H, J=8.7, 1.5 Hz), 7.77 (d, 1H, J=0.9 Hz) 13.65 (s, 1H).
(c) Intermediate
2c--3,5-Diiodo-1-[2-(trimethylsilanyl)-ethoxymethyl]-1H-indazole
[0159] By a synthetic method similar to intermediate 1b, treatment
of 3,5-diiodoindazole 2b with sodium t-butoxide and
2-(trimethylsilyl)ethoxymethyl chloride afforded 2c (64%) as a
yellow oil: R.sub.f=0.53 (30% ethyl acetate/hexanes); .sup.1H NMR
(CDCl.sub.3) .delta. -0.05 (s, 9H), 0.86 (t, 2H, J=8.1 Hz), 3.54
(t, 2H, J=8.1 Hz), 5.69 (s, 2H), 7.34 (d, 1H, J=8.7 Hz), 7.69 (dd,
1H, J=8.7, 1.5 Hz), 7.87 (d, 1H, J=1.5 Hz).
(d) Intermediate
2d--3,5-Distyryl-1-[2-(trimethylsilanyl)-ethoxymethyl]-1H-indazole
[0160] Styryl boronic acid (186 mg, 1.26 mmol) was added to a
solution of 2c (210.0 mg, 0.42 mmol) and
tetrakis(triphenylphosphine) palladium (48.5 mg, 0.042 mmol) in
toluene (3.5 mL) and methanol (0.5 mL). Saturated aqueous sodium
bicarbonate solution (1.05 mL) was added, and the mixture heated in
a 90.degree. C. oilbath (slight reflux) for 4 hours. After cooling
to room temperature, the reaction was poured into water (15 mL) and
extracted with ethyl acetate (4.times.50 mL). The combined organic
extracts were dried over magnesium sulfate, filtered, concentrated,
and purified by silica gel chromatography (toluene), to give 2d
(170.9 mg, 90%) as a yellow oil: R.sub.f=0.10 (toluene); .sup.1H
NMR (CDCl.sub.3) .delta. 0.01 (s, 9H), 0.98 (t, 2H, J=8.5 Hz), 3.67
(t, 2H, J=8.5 Hz), 5.73 (s, 2H), 7.17 (d, 1H, J=16 Hz), 7.3-7.7 (m,
15H), 8.05 (s, 1H). .sup.13C NMR (CDCl.sub.3) .delta. -1.5, 17.6,
66.4, 77.7, 110.1, 119.4, 119.8, 123.3, 125.1, 126.3, 126.5, 127.8,
128.6, 128.7, 128.9, 131.3, 137.1, 137.3, 140.6, 143.3. Anal.
(C.sub.29H.sub.32N.sub.2OSi.0.1CHCl.sub.3) C, H, N.
(e) Example 2--3,5-Distyryl-1H-Indazole
[0161] Example 2 was prepared analogous to example 1, by treatment
of 2d with 3M HCl which afforded 3,5-distyryl-1H-indazole (33%) as
a bright yellow solid: R.sub.f=0.11 (25% ethyl acetate/hexanes);
.sup.1H NMR (CDCl.sub.3) .delta. 7.2-7.7 (m, 16H) 8.076 (s, 1H),
10.05 (br s, 1H). HRMS calculated for C.sub.23H.sub.19N.sub.2
323.1548 (MH.sup.+), found 323.1552. Anal.
(C.sub.23H.sub.18N.sub.2.0.5H.sub.2O) C, H, N.
EXAMPLE 3
3-(1H-Benzoimidazol-2-yl)-5-Phenyl-1H-Indazole
[0162] ##STR46## ##STR47##
(a) Intermediate 3a--1-[2-(Trimethylsilanyl)-ethoxymethyl]-1H
benzoimidazole
[0163] (See Whitten et. al., J. Org. Chem. 51, 1891 (1986)
incorporated herein by reference, for a similar procedure): Solid
1H-benzoimidazole (30 g, 254 mmol) was added in small portions to a
suspension of sodium hydride (10.2 g of 60% dispersion in mineral
oil, 254 mmol) in DMF (350 mL) at room temperature. The mixture was
stirred for 3 hours, and then cooled to 0.degree. C. in an ice
bath. 2-(Trimethylsilyl)ethoxymethyl chloride (46.57 g, 279 mmol)
was added dropwise over 10 minutes. The reaction was stirred for 16
hours, warming to room temperature as the ice bath melted, then
poured into water (1 L), and extracted with ethyl acetate. The
organic layer was washed with brine, dried over sodium sulfate,
filtered, concentrated, and purified by silica gel chromatography
(50 to 85% ethyl acetate in hexanes) to give 3a (56.63 g, 90%) as
an amber oil: R.sub.f=0.40 (50% ethyl acetate/hexanes); .sup.1H NMR
(CDCl.sub.3) .delta. -0.04 (s, 9H), 0.90 (t, 2H, J=8.1 Hz), 3.50
(t, 2H, J=8.1 Hz), 5.53 (s, 2H), 7.31 (m, 2H), 7.54 (m, 1H), 7.81
(m, 1H), 7.96 (s, 1H). Anal.
(C.sub.13H.sub.20N.sub.2OSi.0.5H.sub.2O) C, H, N.
(b) Intermediate
3b--2-Iodo-1-[2-(trimethylsilanyl)-ethoxymethyl]-1H-benzoimidazole
[0164] A solution of N-SEM-benzimidazole (intermediate 3a) (19.19
g, 77.25 mmol) in dry ethyl ether (150 mL) and cooled to
-78.degree. C. in a dry ice/acetone bath, was added dropwise via
cannula to a solution of n-butyllithium (46 mL of 2.5 M in hexanes,
116 mmol) in dry ethyl ether (150 mL), also cooled to -78.degree.
C. in a dry ice/acetone bath. Addition of the benzimidazole
solution took 10 minutes. Stirring was continued 15 minutes longer,
during which time a dark red color developed. The resulting
aryllithium solution was added dropwise via cannula to a solution
of iodine flakes (49 g, 193 mmol) in dry ether (500 mL), itself
cooled to -78.degree. C. in a dry ice/acetone bath. After the
addition was complete (10 minutes), the cooling bath was removed,
and the reaction mixture was allowed to warm for 30 minutes to an
internal temperature of -10.degree. C. Water (250 mL) was added,
and the mixture was washed with saturated aqueous sodium bisulfite
solution (2.times.200 mL). The organic layer was dried over sodium
sulfate, filtered, concentrated, and purified by silica gel
chromatography to give 3-iodo-n-SEM-benzimidazole 3b (22.84 g, 80%)
as a yellow solid: mp=60-63.degree. C.; R.sub.f=0.70 (ethyl
acetate); .sup.1H NMR (CDCl.sub.3) .delta. -0.04 (s, 9H), 0.92 (t,
2H, J=8.1 Hz), 3.58 (t, 2H, J=8.1 Hz), 5.53 (s, 2H), 7.27 (m, 2H),
7.51 (m, 1H), 7.73 (m, 1H). HRMS calculated for
C.sub.13H.sub.19IN.sub.2OSiNa 397.0209 (MNa.sup.+), found 397.0204.
Anal. (C.sub.13H.sub.19IN.sub.2OSi) C, H, I, N.
(c) Intermediate
3c--5-Chloro-1-[2-(trimethylsilanyl)-ethoxymethyl]-3-(trimethylstannyl)-1-
H-indazole
[0165] A mixture of intermediate 1b (6.25 g, 15.3 mmol),
hexamethylditin (10.2 g, 30.5 mmol), and
bis(triphenylphosphine)palladium(II)dibromide (242 mg, 0.306 mmol)
in toluene (50 mL) was heated to reflux for 30 minutes, then
cooled, filtered, and concentrated. Purification by silica gel
chromatography (5 to 50% ethyl acetate in hexanes) gave 3c (6.34 g,
93%) as a slightly yellow oil: R.sub.f=0.21 (5% ethyl
acetate/hexanes), R.sub.f=0.23 (toluene); .sup.1H NMR (CDCl.sub.3)
.delta. -0.06 (s, 9H), 0.56 (s with small side bands, 9H), 0.87 (t,
2H, J=8.4 Hz), 3.54 (t, 2H, J=8.4 Hz), 5.75 (s, 2H), 7.34 (dd, 1H,
J=8.7, 1.8 Hz), 7.51 (d, 1H, J=8.7 Hz), 7.66 (d, 1H, J=1.8 Hz).
Anal. (C.sub.16H.sub.27ClN.sub.2OSiSn) C, H, Cl, N
(d) Intermediate
3d--5-Chloro-1-[2-(trimethylsilanyl)-ethoxymethyl]-3-{1-[2-(trimethylsila-
nyl)-ethoxymethyl]-1H-benzoimidazol-2-yl}-1H-indazole
[0166] A mixture of 3c (4.47 g, 10.03 mmol), 3b (4.12 g, 11.03
mmol), tetrakis(triphenylphosphine)palladium(0) (579 mg, 0.50
mmol), and copper(I) iodide (190 mg, 1.00 mmol) in THF (100 mL) was
heated to reflux for 1 hour. Additional catalyst (580 mg, 0.50
mmol) and CuI (200 mg, 1.05 mmol) were added, and refluxing
continued for 20 hours. After cooling to room temperature, the
black precipitate was filtered off, the filtrate concentrated, and
the residue purified by silica gel chromatography (toluene) to give
pure 3d (2.29 g, 43%) as a colorless oil which crystallizes on
standing: mp=80-82.degree. C.; R.sub.f=0.12 (10% ethyl
acetate/hexanes), R.sub.f=0.13 (toluene); .sup.1H NMR (CDCl.sub.3)
.delta. -0.15 (s, 9H), -0.06 (s, 9H), 0.85 (t, 2H, J=8.1 Hz), 0.91
(t, 2H, J=8.4 Hz), 3.60 (t, 2H, J=8.4 Hz), 3.61 (t, 2H, J=8.1 Hz),
5.80 (s, 2H), 6.24 (s, 2H), 7.36 (m, 2H), 7.47 (dd, 1H, J=9.0, 2.1
Hz), 7.57 (d, 1H, J=9.0 Hz), 7.62 (m, 1H), 7.91 (m, 1H), 8.73 (d,
1H, J=2.1 Hz). Anal. (C.sub.26H.sub.37ClN.sub.4O.sub.2Si.sub.2) C,
H, Cl, N.
(e) Intermediate
3e--5-Phenyl-1-[2-(trimethylsilanyl)-ethoxymethyl]-3-{1-[2-(trimethylsila-
nyl)-ethoxymethyl]-1H-benzoimidazol-2-yl}-1H-indazole
[0167] A mixture of 3d (192.0 mg, 0.363 mmol), phenylboronic acid
(66.4 mg, 0.544 mmol), palladium(II) acetate (3.3 mg, 0.0145 mmol),
CyMAP-1 (See Old et. al., J. Am. Chem. Soc., 120, 9722 (1998) for a
similar procedure) (5.7 mg, 0.0145 mmol), and cesium fluoride (165
mg, 1.09 mmol) in 1,4-dioxane (3.6 mL) was heated in a 100.degree.
C. oilbath for 1 hour. After cooling to room temperature, the
mixture was diluted with ethyl acetate (20 mL) and filtered to
remove the black precipitate. The filtrate was washed with 1 M
aqueous sodium hydroxide (20 mL), dried over magnesium sulfate,
concentrated, and purified by silica gel chromatography (0 to 4%
methanol in dichloromethane) to give 3e (107.0 mg, 52%) as a
slightly yellow oil: R.sub.f=0.26 (dichloromethane); .sup.1H NMR
(CDCl.sub.3) .delta. -0.15 (s, 9H), -0.04 (s, 9H), 0.86 (t, 2H,
J=8.1 Hz), 0.95 (t, 2H, J=8.1 Hz), 3.61 (t, 2H, J=8.1 Hz), 3.66 (t,
2H, J=8.1 Hz), 5.85 (s, 2H), 6.28 (s, 2H), 7.37 (m, 3H), 7.49 (t,
2H, J=7.5 Hz), 7.63-7.80 (m, 5H), 7.91 (m, 1H), 8.88 (s, 1H). Anal.
(C.sub.32H.sub.42N.sub.4O.sub.2Si.sub.2.0.4H.sub.2O) C, H, N.
EXAMPLE 3
3-(1H-Benzoimidazol-2-yl)-5-phenyl-1H-indazole
[0168] Tetrabutylammonium fluoride (1.0 M in THF, 3.16 mL) and
1,2-diaminoethane (95 mg, 1.58 mmol) were added to intermediate 3e
(90.2 mg, 0.158 mmol). The solution was heated in a 70.degree. C.
oilbath for 20 hours, then heated to reflux for 24 hours longer.
After cooling to room temperature, the solution was diluted with
ethyl acetate (30 mL) and washed with saturated aqueous sodium
bicarbonate solution (20 mL). The organic layer was dried over
magnesium sulfate, filtered, concentrated, and purified by silica
gel chromatography (25 to 50% ethyl acetate in hexanes) to give
3-(1H-Benzoimidazol-2-yl)-5-Phenyl-1H-Indazole 3 (33.9 mg, 69%) as
a white solid: R.sub.f=0.30 (50% ethyl acetate/hexanes); .sup.1H
NMR (CDCl.sub.3) .delta. 7.21 (quintet of d, 2H, J=5.7, 1.5 Hz),
7.39 (t, 1H, J=7.4 Hz), 7.53 (t, 3H, J=7.5 Hz), 7.76 (m, 5H), 8.71
(s, 1H), 13.01 (s, 1H), 13.70 (s, 1H). HRMS calculated for
C.sub.20H.sub.15N.sub.4 311.1297 (MH.sup.+), found 311.1283.
EXAMPLE 4
3-[3-1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-phenol
[0169] ##STR48##
(a) Intermediate
4a--5-(3-Methoxyphenyl)-1-[2-(trimethylsilanyl)-ethoxymethyl]-3-{1-[2-(tr-
imethylsilanyl)-ethoxymethyl]-1H-benzoimidazol-2-yl}-1H-indazole
[0170] A mixture of intermediate 3d (371.5 mg, 0.702 mmol),
3-methoxyphenylboronic acid (160 mg, 1.05 mmol), palladium(II)
acetate (7.9 mg, 0.0355 mmol), CyMAP-1 (See Old et. al., J. Am.
Chem. Soc., 120, 9722 (1998), incorporated herein by reference, for
a similar procedure) (14 mg, 0.0355 mmol), and cesium fluoride (320
mg, 2.11 mmol) in 1,4-dioxane (7.1 mL) was heated in a 90.degree.
C. oilbath for 22 hours. After cooling to room temperature, the
mixture was diluted with ethyl acetate (50 mL) and filtered to
remove the black precipitate. The filtrate was dried over magnesium
sulfate, concentrated, and purified by silica gel chromatography
(10% ethyl acetate in hexanes) to give 4a (178.3 mg, 42%) as a
slightly yellow oil: R.sub.f=0.20 (10% ethyl acetate/hexanes);
.sup.1H NMR (CDCl.sub.3) .delta. -0.14 (s, 9H), -0.03 (s, 9H), 0.86
(t, 2H, J=8.1 Hz), 0.95 (t, 2H, J=8.1 Hz), 3.61 (t, 2H, J=8.1 Hz),
3.66 (t, 2H, J=8.1 Hz), 3.91 (s, 3H), 5.85 (s, 2H), 6.27 (s, 2H),
6.93 (ddd, 1H, J=1.1, 2.5, 8.1 Hz), 7.27-7.40 (m, 5H), 7.63-7.70
(m, 2H), 7.77 (dd, 1H, J=1.5, 8.7 Hz), 7.93 (m, 1H) 8.87 (s, 1H).
Anal. (C.sub.33H.sub.44N.sub.4O.sub.3Si.sub.2) C, H, N.
(b) Example
4--3-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-phenol
[0171] A solution of intermediate 4a (88.3 mg, 0.147 mmol) in
1,2-dichloroethane (3.0 mL) was treated with boron
tribromide-methyl sulfide complex (1.0 M in dichloromethane, 0.588
mL) and heated to reflux for 1 hour. Stirring was continued at room
temperature for 16 hours. Water (5.0 mL) was added, and stirring
continued for 30 minutes at room temperature. The mixture was
diluted with diethyl ether (30 mL), and washed with saturated
aqueous sodium bicarbonate solution (20 mL). The organic layer was
washed with 1 M NaOH (3.times.30 mL). The combined aqueous washes
were acidified to pH=1 with 6 M HCl and extracted sequentially with
ether (30 mL), ethyl acetate (30 mL), and dichloromethane
(2.times.20 mL). These organic extracts were combined, dried over
magnesium sulfate, filtered, concentrated, and purified by silica
gel chromatography (50 to 75% ethyl acetate in hexanes) to give the
phenol 4 (11.6 mg, 24%) as a white powder: .sup.1H NMR
(DMSO-d.sub.6) .delta. 6.78 (dd, 1H, J=1.9, 7.7 Hz), 7.12-7.27 (m,
4H), 7.31 (t, 1H, J=7.7 Hz), 7.52 (dd, 1H, J=2.1, 6.6 Hz), 7.71 (d,
2H, J=1.1 Hz), 7.76 (dd, 1H, J=1.5, 6.8 Hz), 8.67 (s, 1H), 9.57 (s,
1H), 13.00 (s, 1H), 13.68 (s, 1H). HRMS calculated for
C.sub.20H.sub.15N.sub.4O 327.1246 (MH.sup.+), found 327.1231.
EXAMPLE 5
3-(1H-Benzoimidazol-2-yl)-5-(3-methoxyphenyl)-1H-indazole
[0172] ##STR49##
(a) Example
5--3-(1H-Benzoimidazol-2-yl)-5-(3-methoxyphenyl)-1H-indazole
[0173] The same crude reaction mixture from which example 4 was
obtained also yielded the methoxyphenyl analog 5 as follows:
[0174] A solution of intermediate 4a (88.3 mg, 0.147 mmol) in
1,2-dichloroethane (3.0 mL) was treated with boron
tribromide-methyl sulfide complex (1.0 M in dichloromethane, 0.588
mL) and heated to reflux for 1 hour. Stirring was then continued at
room temperature for 16 hours. Water (5.0 mL) was added, and
stirring continued for 30 minutes at room temperature. The mixture
was diluted with diethyl ether (30 mL), and washed with saturated
aqueous sodium bicarbonate solution (20 mL). The organic layer was
washed with 1 M NaOH (3.times.30 mL). The organic layer was then
dried, filtered, concentrated, and purified by silica gel
chromatography (50 to 75% ethyl acetate in hexanes) to give 5 (9.3
mg, 19%) as a white powder: .sup.1H NMR (DMSO-d.sub.6) .delta. 3.86
(s, 3H), 6.98 (dd, 1H, J=2.1, 7.8 Hz), 7.19-7.23 (m, 3H), 7.30 (d,
1H, J=7.8 Hz), 7.45 (t, 1H, J=7.8 Hz), 7.52 (dd, 1H, J=1.8, 5.7
Hz), 7.75 (m, 3H), 8.70 (s, 1H), 13.00 (s, 1H), 13.70 (s, 1H). HRMS
calculated for C.sub.21H.sub.16N.sub.4ONa 363.1222 (MNa.sup.+),
found 363.1225.
EXAMPLE 6
3-(1H-Benzoimidazol-2-yl)-5-(2-fluorophenyl)-1H-Indazole
[0175] ##STR50##
(a) Intermediate
6a--5-(2-Fluorophenyl)-1-[2-(trimethylsilanyl)-ethoxymethyl]-3-{1-[2-(tri-
methylsilanyl)-ethoxymethyl]-1H-benzoimidazol-2-yl}-1H-indazole
[0176] A mixture of intermediate 3d (419.0 mg, 0.792 mmol),
2-fluorophenylboronic acid (166 mg, 1.19 mmol), palladium(II)
acetate (9.0 mg, 0.04 mmol), CyMAP-1 (See Old et. al., J. Am. Chem.
Soc., 120, 9722 (1998) incorporated herein by reference, for a
similar procedure) (16 mg, 0.04 mmol), and cesium fluoride (361 mg,
2.38 mmol) in 1,4-dioxane (8.0 mL) was heated in a 70.degree. C.
oilbath for 1 hour. As only partial conversion was observed, more
palladium (II) acetate (12 mg, 0.05 mmol) and CyMAP-1 (14 mg, 0.035
mmol) were added, and stirring continued at 70.degree. C. for 16
hr. After cooling to room temperature, the mixture was diluted with
ethyl acetate (50 mL) and filtered to remove the black precipitate.
The filtrate was dried over magnesium sulfate, concentrated, and
purified by silica gel chromatography (10% ethyl acetate in
hexanes) to give 6a (155.6 mg, 43%) as a colorless oil: .sup.1H NMR
(CDCl.sub.3) .delta. -0.14 (s, 9H), -0.03 (s, 9H), 0.86 (t, 2H,
J=8.1 Hz), 0.95 (t, 2H, J=8.1 Hz), 3.61 (t, 2H, J=8.1 Hz), 3.66 (t,
2H, J=8.1 Hz), 5.86 (s, 2H), 6.27 (s, 2H), 7.15-7.39 (m, 5H),
7.57-7.75 (m, 4H), 7.88 (m, 1H) 8.82 (s, 1H). Anal.
(C.sub.32H.sub.41FN.sub.4O.sub.2Si.sub.2.0.4H.sub.2O) C, H, N.
(b) Example
6--3-(1H-Benzoimidazol-2-yl)-5-(2-fluorophenyl)-1H-indazole
[0177] Example 6 was prepared by a synthetic method analogous to
example 3. Treatment of intermediate 6a with tetrabutylammonium
fluoride afforded 6 (21.2 mg, 18%) as a white powder: R.sub.f=0.35
(50% ethyl acetate/hexanes); .sup.1H NMR (DMSO-d.sub.6) .delta.
7.20 (m, 2H), 7.33-7.52 (m, 4H), 7.62 (m, 2H), 7.74 (m, 2H), 8.65
(s, 1H), 13.02 (s, 1H), 13.75 (s, 1H). HRMS calculated for
C.sub.20H.sub.14FN.sub.4 329.1202 (MH.sup.+), found 329.1212. Anal.
(C.sub.20H.sub.13FN.sub.4.1.1H.sub.2O) C, H, N.
EXAMPLE 7'
3-(1H-Benzoimidazol-2-yl)-5-(4-methoxyphenyl)-1H-indazole
[0178] ##STR51##
(a) Intermediate
7a'--5-Iodo-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-
e
[0179] Intermediate 7a' was prepared from 5-nitroindazole (Acros
organics, a division of Fisher Scientific, Pittsburg, Pa.) in five
steps according to the method used to prepare
6-Iodo-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole
from 6-nitroindazole (Found in: Kania, Braganza, et al., patent
application "Compounds and Pharmaceutical Compositions for
Inhibiting Protein Kinases, and Methods for Their Use", p. 52, line
10 to p. 53, line 26; and p. 59, line 16 to p. 60, line 4, U.S.
Provisional Ser. No. 60/142,130, filed Jul. 2, 1999, incorporated
by reference herein in its entirety.): .sup.1H NMR (CDCl.sub.3)
.delta. -0.06 (s, 9H), 0.89 (t, 2H, J=8.4 Hz), 3.57 (t, 2H, J=8.4
Hz), 5.70 (s, 2H), 7.29-7.44 (m, 6H), 7.59 (d, 2H, J=7.0 Hz), 7.67
(dd, 1H, J=8.7, 1.5 Hz), 8.36 (s, 1H).
(b) Intermediate
7b'--5-Iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-carbaldehyd-
e
[0180] Ozone was bubbled into a solution of
5-iodo-3-styryl-2-SEM-indazole 7a' (4.93 g, 10.35 mmol) in
dichloromethane (500 mL) at -78.degree. C. After 20 minutes the
solution color had changed from orange to deep blue. The mixture
was purged with Argon for 30 minutes to remove excess ozone, then
dimethylsulfide (1.29 g, 20.7 mmol) was added. The cooling bath was
removed, and stirring continued until the internal temperature
reached 15.degree. C., about 2 hours. The solution was washed with
water (2.times.200 mL), dried over magnesium sulfate, filtered and
concentrated. Purification by silica gel chromatography (10% ethyl
acetate in hexanes) afforded aldehyde 7b' (2.74 g, 66%) as a yellow
oil: .sup.1H NMR (CDCl.sub.3) .delta. -0.05 (s, 9H), 0.89 (t, 2H,
J=8.4 Hz), 3.56 (t, 2H, J=8.4 Hz), 5.79 (s, 2H), 7.43 (d, 1H, J=8.7
Hz), 7.76 (dd, 1H, J=8.8, 1.5 Hz), 8.71 (s, 1H), 10.22 (s, 1H).
(c) Intermediate
7c'--3-(1H-Benzoimidazol-2-yl)-5-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-
-1H-indazole
[0181] To a solution of aldehyde 7b' (2.74 g, 6.81 mmol) in DMF
(130 mL) were added 1,2-phenylenediamine (0.74 g, 6.81 mmol) and
elemental sulfur (0.26 g, 8.2 mmol). The mixture was heated in a
95.degree. C. oilbath for 14.5 hours, cooled to room temperature,
and diluted with ethyl acetate (500 mL). The solution was washed
with a mixture of saturated aqueous sodium chloride (100 mL) and
water (100 mL). The organic layer was then washed with saturated
aqueous sodium bicarbonate (100 mL), followed by water (100 mL),
dried over magnesium sulfate, filtered, concentrated, and purified
by silica gel chromatography (20% ethyl acetate in hexanes) to give
impure 7c' as a pale yellow solid. Precipitation from
chloroform/hexanes afforded pure 7c' (2.15 g, 64%) as a white
powder: R.sub.f=0.23 (20% ethyl acetate/hexanes); .sup.1H NMR
(DMSO-d.sub.6) .delta. -0.12 (s, 9H), 0.82 (t, 2H, J=7.9 Hz), 3.59
(t, 2H, J=7.9 Hz), 5.87 (s, 2H), 7.23 (m, 2H), 7.52 (d, 1H, J=7.2
Hz), 7.73-7.84 (m, 3H), 8.94 (s, 1H), 13.13 (s, 1H). HRMS
calculated for C.sub.20H.sub.23IN.sub.4Osi 491.0759 (MH.sup.+),
found 491.0738.
(d) Intermediate
7d'--3-(1H-Benzoimidazol-2-yl)-5-(4-methoxy-phenyl)-1-(2-trimethylsilanyl-
-ethoxymethyl)-1H-indazole
[0182] 2M aqueous sodium carbonate solution (6.4 mL) was added to a
solution of 7c' (2.50 g, 5.10 mmol), 4-methoxyphenyl boronic acid
(1.01 g, 6.63 mmol), and tetrakis(triphenylphosphine)palladium
(0.59 g, 0.51 mmol) in 1,4-dioxane (35 mL) and methanol (15 mL).
The mixture was heated to reflux for 5 hours, then cooled and
partitioned between ethyl acetate (300 mL) and a mixture of
saturated aqueous sodium chloride (100 mL) and water (100 mL). The
organic layer was dried over magnesium sulfate, filtered,
concentrated, and purified by silica gel chromatography (20% ethyl
acetate in hexanes) to give a dark brown solid. Precipitation from
dichloromethane/hexanes afforded pure 7d' (948.6 mg, 40%) as a
white powder: R.sub.f=0.13 (20% ethyl acetate/hexanes); .sup.1H NMR
(DMSO-d.sub.6) .delta. -0.10 (s, 9H), 0.85 (t, 2H, J=7.9 Hz), 3.63
(t, 2H, J=7.9 Hz), 3.82 (s, 3H), 5.91 (s, 2H), 7.10 (d, 2H, J=8.7
Hz), 7.23 (m, 2H), 7.43 (m, 1H), 7.54 (d, 1H, J=6.8 Hz), 7.69 (d,
2H, J=8.7 Hz), 7.80 (m, 1H), 7.92 (d, 1H, J=8.9 Hz), 8.70 (s, 1H),
13.08 (s, 1H).
(e) Example
7'--3-(1H-Benzoimidazol-2-yl)-5-(4-methoxy-phenyl)-1H-indazole
[0183] A solution of intermediate 7d' (148.4 mg, 0.315 mmol) in
ethyl acetate (15 mL) at -78.degree. C. was treated with boron
tribromide (1.0 M in dichloromethane, 4.73 mL). The solution was
stirred for 17 hours, allowing the mixture to gradually warm to
room temperature. Water (10 mL) was added, and the mixture allowed
to stir at room temperature for 6 days. The solution was treated
with 3M sodium hydroxide solution to bring the pH to 10, then
extracted with ethyl acetate (3.times.20 mL). The combined organic
extracts were dried over magnesium sulfate, filtered, and
concentrated. Purification by silica gel chromatography (50% ethyl
acetate in hexanes) afforded 7' (60.5 mg, 56%) as a white solid:
R.sub.f=0.21 (50% ethyl acetate/hexanes); .sup.1H NMR
(DMSO-d.sub.6) .delta. 3.82 (s, 3H), 7.08 (d, 2H, J=8.9 Hz), 7.21
(m, 2H), 7.53-7.78 (m, 6H), 8.66 (s, 1H), 12.96 (s, 1H), 13.63 (s,
1H). Anal. (C.sub.21H.sub.16N.sub.4O.0.25CH.sub.2Cl.sub.2) C, H,
N.
EXAMPLE 8'
4-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-phenol
[0184] ##STR52##
[0185] A mixture of anisole 7' (44.6 mg, 0.131 mmol) and pyridine
hydrochloride (912 mg, 7.9 mmol) was heated in a 180.degree. C.
oilbath for 3 hours. The pyridine salt is liquid at this
temperature. After cooling to room temperature, the mixture was
partitioned between ethyl acetate (20 mL) and saturated aqueous
sodium bicarbonate (15 mL). The aqueous layer was further extracted
with ethyl acetate (3.times.20 mL). The combined organic extracts
were dried over magnesium sulfate, filtered, concentrated and
purified by silica gel chromatography (50% ethyl acetate/hexanes)
to give pure phenol 8' (29.4 mg, 69%) as a pale yellow solid:
R.sub.f=0.23 (60% ethyl acetate/hexanes); .sup.1H NMR
(DMSO-d.sub.6) .delta. 6.91 (d, 2H, J=8.4 Hz), 7.21 (m, 2H), 7.53
(m, 3H), 7.68 (s, 2H), 7.75 (d, 1H, J=6.9 Hz), 8.61 (s, 1H), 9.53
(s, 1H), 12.98 (s, 1H), 13.63 (s, 1H). HRMS calculated for
C.sub.20H.sub.14N.sub.4O 327.1246 (MH.sup.+), found 327.1253. Anal.
(C.sub.20H.sub.13N.sub.4O.0.8 DMSO) C, H, N.
EXAMPLE 9'
3-(1H-Benzoimidazol-2-yl)-5-(3-methoxy-2-methyl-phenyl)-1H-indazole
[0186] ##STR53## ##STR54##
(a) Intermediate 9a'--3-Methoxy-2-methyl-phenylamine
[0187] A suspension of 2-methyl-3-nitroanisole (Aldrich Chemicals)
(8.87 g, 53 mmol) and 10% palladium on carbon (800 mg) in ethanol
(400 mL) was shaken under 40 psi hydrogen for 1 hour. After
filtration through a Celite pad, the solution was concentrated and
purified by silica gel chromatography (30% ethyl acetate in
hexanes) to give aniline 9a' (6.94 g, 95%) as a slightly orange
oil: R.sub.f=0.20 (25% ethyl acetate/hexanes); .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.88 (s, 3H), 3.68 (s, 3H), 4.74 (br s, 2H),
6.17 (d, 1H, J=8.1 Hz), 6.26 (d, 1H, J=8.1 Hz), 6.81 (t, 1H, J=8.1
Hz). Anal. (C.sub.8H.sub.11NO) C, H, N.
(b) Intermediate 9b'--1-Iodo-3-methoxy-2-methyl-benzene
[0188] 3-Methoxy-2-methyl-phenylamine (5.28 g, 38.5 mmol) was
diazotized according to the method of DeGraw, et al. [DeGraw, J.
I.; Brown, V. H.; Colwell, W. T.; Morrison, N. E., J. Med. Chem.,
17, 762 (1974)], incorporated herein by reference, affording aryl
iodide 9b' (4.17 g, 44%) as a yellow oil: R.sub.f=0.53 (10% ethyl
acetate/hexanes); .sup.1H NMR (CDCl.sub.3) .delta. 2.36 (s, 3H),
3.80 (s, 3H), 6.81 (m, 2H), 7.42 (dd, 1H, J=7.5, 1.5 Hz).
(c) Intermediate
9c'--2-(3-Methoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]
dioxaborolane
[0189] 1-Iodo-3-methoxy-2-methyl-benzene (3.80 g, 15.3 mmol),
Bis(pinacolato)diboron (4.28 g, 16.8 mmol), potassium acetate (4.51
g, 46.0 mmol), and
1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (625 mg,
0.766 mmol) were dissolved in DMSO (70 mL) and heated to 80.degree.
C. internal temperature for 1 hour. After cooling, the mixture was
diluted with toluene (400 mL), washed with water (2.times.100 mL),
dried over magnesium sulfate, filtered, and concentrated.
Purification by silica gel chromatography (5 to 20% ethyl acetate
in hexanes) yielded boronic ester 9c' (19.6 g, 52%) as a white,
crystalline solid: R.sub.f=0.27 (5% ethyl acetate/hexanes); .sup.1H
NMR (CDCl.sub.3) .delta. 1.34 (s, 12H), 2.42 (s, 3H), 3.81 (s, 3H),
6.91 (d, 1H, J=8.1 Hz), 7.14 (t, 1H, J=7.8 Hz), 7.34 (d, 1H, J=7.5
Hz). Anal. (C.sub.14H.sub.21BO.sub.3) C, H.
(d) Intermediate
9d'--3-(1H-Benzoimidazol-2-yl)-5-(3-methoxy-2-methyl-phenyl)-1-(2-trimeth-
ylsilanyl-ethoxymethyl)-1H-indazole
[0190] Aqueous sodium carbonate solution (2M, 2.65 mL) was added to
a solution of 7c' (519.4 mg, 1.06 mmol), boronic ester 9c' (262.8
mg, 1.06 mmol), and
1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (43.2 mg,
0.053 mmol) in DMF (12 mL). The mixture was heated in a 75.degree.
C. oilbath for 4.5 hours, then cooled and partitioned between ethyl
acetate (100 mL) and a mixture of saturated aqueous sodium chloride
(50 mL) and water (50 mL). The organic layer was dried over
magnesium sulfate, filtered, concentrated, but .sup.1H NMR of this
crude material showed only 60% conversion. The crude mixture was
redissolved in DMF (12 mL) and additional boronic ester (253 mg,
1.01 mmol), catalyst (140 mg, 0.17 mmol), and sodium carbonate
solution (2.65 mL) were added. Stirring was continued at 80.degree.
C. for 15.5 hours. After the same workup as above, crude .sup.1H
NMR showed less than 5% 7c' remaining. Purification by silica gel
chromatography (10 to 30% ethyl acetate in hexanes) afforded 9d'
(410.7 mg, 80%) as a white foam: R.sub.f=0.37 (30% ethyl
acetate/hexanes, same as 7c'); .sup.1H NMR (DMSO-d.sub.6) .delta.
-0.10 (s, 9H), 0.85 (t, 2H, J=7.9 Hz), 2.06 (s, 3H), 3.64 (t, 2H,
J=7.9 Hz), 3.85 (s, 3H), 5.92 (s, 2H), 6.92 (d, 1H, J=7.2 Hz), 7.02
(d, 1H, J=8.3 Hz), 7.17-7.30 (m, 3H), 7.47-7.53 (m, 2H), 7.70 (d,
1H, J=7.7 Hz), 7.90 (d, 1H, J=8.7 Hz), 8.45 (s, 1H), 13.09 (s, 1H).
Anal. (C.sub.28H.sub.32N.sub.4O.sub.2Si.0.3H.sub.2O) C, H, N.
(e) Example
9'--3-(1H-Benzoimidazol-2-yl)-5-(3-methoxy-2-methyl-phenyl)-1H-indazole
[0191] In an analogous manner to example 3, treatment of
intermediate 9d' with tetrabutylammonium fluoride afforded 9' (47.2
mg, 30%) as a white powder: R.sub.f=0.23 (5%
methanol/dichloromethane); .sup.1H NMR (DMSO-d.sub.6) .delta. 2.07
(s, 3H), 3.85 (s, 3H), 6.91 (d, 1H, J=7.4 Hz), 7.01 (d, 1H, J=8.1
Hz), 7.24 (m, 3H), 7.39 (dd, 1H, J=8.7, 1.5 Hz), 7.50 (m, 1H), 7.68
(d, 2H, J=8.5 Hz), 8.40 (s, 1H), 12.96 (s, 1H), 13.66 (s, 1H).
Anal. (C.sub.22H.sub.18N.sub.4O.0.3H.sub.2O) C, H, N.
EXAMPLE 10'
3-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-2-methyl-phenol
[0192] ##STR55##
[0193] Phenol 10' was prepared by a synthetic method analogous to
phenol 8', by treatment of 9' (31.6 mg, 0.089 mmol) with pyridine
hydrochloride yielded phenol 10' (20.8 mg, 70%) as an off-white
solid: R.sub.f=0.21 (60% ethyl acetate/hexanes); .sup.1H NMR
(DMSO-d.sub.6) .delta. 2.04 (s, 3H), 6.75 (d, 1H, J=7.0 Hz), 6.85
(d, 1H, J=7.7 Hz), 7.08 (t, 1H, J=7.7 Hz), 7.19 (quint, 2H, J=7.7
Hz), 7.39 (dd, 1H, J=8.7,1.5 Hz), 7.50 (d, 1H J=7.5 Hz), 7.68 (m,
2H), 8.39 (s, 1H), 9.39 (s, 1H), 12.95 (s, 1H), 13.64 (s, 1H). HRMS
calculated for C.sub.21H.sub.16N.sub.4O 341.1402 (MH.sup.+), found
341.1410. Anal. (C.sub.21H.sub.16N.sub.4O.1.0MeOH) C, H, N.
EXAMPLE 11
5-(2-Methylphenyl)-3-phenyl-1H-indazole
[0194] ##STR56##
(a) Intermediate 11a--5-Nitro-3-phenyl-1H-indazole
[0195] To a solution of 2-chloro-5-nitrobenzophenone (15 g, 57
mmol) in ethanol (300 mL) was added hydrazine monohydrate (50 mL, 1
mol). The resultant solution was stirred overnight (16 hrs.) at
ambient temperature, then poured into water (2 L) and stirred for
an additional 2 hours. The precipitate that formed was collected by
filtration, washed with water (2.times.100 mL) and air dried to
give 5-Nitro-3-phenyl-1H-indazole 11a (13.1 g, 80%) as a yellow
solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 7.48 (tt, 1H, J=1.3, 7.4
Hz), 7.58 (dd, 2H, J=7.1, 7.4 Hz), 7.78 (d, 1H, J=9.2 Hz), 8.01
(dd, 2H, J=1.3, 7.1. Hz), 8.25 (dd, 1H, J=2.1, 9.2 Hz), 8.91 (d,
1H, J=2.1 Hz), 13.88 (s, 1H). Anal. (C.sub.13H.sub.9N.sub.3O.sub.2)
C, H, N.
(b) Intermediate 11
b--5-Nitro-3-phenyl-1-[2-trimethylsilanyl)ethoxymethyl]-1H-indazole
[0196] Diisopropylethylamine (15 mL, 86.1 mmol) was added,
dropwise, to a solution of 5-nitro-3-phenyl-1H-indazole 11a (13 g,
54.3 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (15 g, 90
mmol) in acetonitrile (400 mL). The resultant reaction mixture was
stirred at ambient temperature for 2 hours, then poured into water
(1 L) and extracted with ethyl acetate (3.times.300 mL). The
combined organic extracts were dried over sodium sulfate and
concentrated. The residue obtained was dissolved in toluene (40
mL). To this solution were added 2-(trimethylsilyl)ethoxymethyl
chloride (3 mL, 17 mmol), tetrabutylammonium bromide (500 mg) and
silica (40 g). This mixture was stirred overnight at ambient
temperature, then filtered. The filtrate was subsequently
concentrated. Silica gel chromatography (5% ethyl acetate/hexanes)
provided 11b (15 g, 75%) as a yellow solid: .sup.1H NMR
(DMSO-d.sub.6) .delta. -0.11 (s, 9H), 0.83 (t, 2H, J=7.9 Hz), 3.62
(t, 2H, J=7.9 Hz), 5.91 (s, 2H), 7.52 (tt, 1H, J=0.7, 7.4 Hz), 7.60
(dd, 2H, J=7.1, 7.4 Hz), 8.00 (d, 1H, J=9.2 Hz), 8.02 (dd, 2H,
J=0.7, 7.1 Hz), 8.35 (dd, 1H, J=2.1, 9.2 Hz), 8.91 (d 1H, J=2.1
Hz).
(c) Intermediate 11c--5-Amino-3-phenyl-1-[2-(trimethylsilanyl)
ethoxymethyl]-1H-indazole
[0197] A mixture of
5-nitro-3-phenyl-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-indazole
11 b (14 g, 37.9 mmol) and 10% palladium on carbon (1 g) in ethyl
acetate (500 mL) was stirred under an atmosphere of hydrogen
overnight. The reaction mixture was filtered through celite, then
concentrated to provide 11c (12.2 g, 95%) as a white solid: .sup.1H
NMR (DMSO-d.sub.6) .delta. -0.12 (s, 9H), 0.80 (t, 2H, J=8.0 Hz),
3.54 (t, 2H, J=8.0 Hz), 5.01 (br s, 2H), 5.67 (s, 2H), 6.89 (dd,
1H, J=1.8, 8.8 Hz), 7.12 (d, 1H, J=1.8 Hz) 7.37 (tt, 1H, J=0.5, 7.4
Hz), 7.47 (d, 1H, J=8.8 Hz), 7.50 (dd, 2H, J=7.2, 7.4 Hz), 7.87
(dd, 2H, J=0.5, 7.2 Hz).
(d) Intermediate 11d--5-Iodo-3-phenyl-1-[2-(trimethylsilanyl)
ethoxymethyl]-1H-indazole
[0198] Intermediate 11c (12 g, 35.3 mmol) was dissolved in a
mixture of acetic acid (300 mL) and water (50 mL). The mixture was
cooled in an ice-salt bath to -5.degree. C. To this mixture was
slowly added a solution of sodium nitrite (4.5 g, 65.2 mmol) in
water (10 mL) at such a rate to maintain the reaction temperature
below 3.degree. C. The resultant diazonium solution was stirred at
0.degree. C. for 20 minutes. A solution of potassium iodide (6.5 g,
39.2 mmol) in water (10 mL) was then slowly added to the reaction,
again at a rate to maintain the reaction temperature below
3.degree. C. The reaction was left stirring overnight, gradually
equilibrating to room temperature. The crude reaction mixture was
poured into water (300 mL) and extracted with ethyl acetate
(2.times.500 mL). The combined organic extracts were dried over
sodium sulfate and concentrated. Silica gel chromatography (5%
ethyl acetate/hexanes) provided 11d (4 g, 25%) as a yellow oil:
.sup.1H NMR (DMSO-d.sub.6) .delta. -0.12 (s, 9H), 0.83 (t, 2H,
J=7.9 Hz), 3.57 (t, 2H, J=7.9 Hz), 5.80 (s, 2H), 7.45 (tt, 1H,
J=1.3, 7.5 Hz), 7.54 (dd, 2H, J=7.1, 7.5 Hz), 7.67 (d, 1H, J=8.8
Hz), 7.75 (dd, 1H, J=1.5, 8.8 Hz), 7.94 (dd, 2H, J=1.3, 7.1 Hz),
8.40 (d, 1H, J=1.5 Hz).
(e) Intermediate
11e--5-(2-Methylphenyl)-3-phenyl-1-[2-(trimethylsilanyl)
ethoxymethyl]-1H-indazole
[0199] Aqueous saturated sodium bicarbonate (2 mL) was added to a
mixture of intermediate 11d (130 mg, 0.3 mmol),
2-methylphenylboronic acid (120 mg, 0.9 mmol) and
tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.02 mmol) in
1,4-dioxane (10 mL). The resultant reaction mixture was heated in a
90.degree. C. oil bath for 18 hours. After cooling to room
temperature, the crude reaction mixture was poured into water (50
mL) and extracted with ethyl acetate (2.times.25 mL). The combined
organic extracts were dried over sodium sulfate and concentrated.
Silica gel chromatography (10% ethyl acetate/hexanes) afforded 11e
(100 mg, 84%) as an off-white solid: .sup.1H NMR (DMSO-d.sub.6)
.delta. -0.10 (s, 9H), 0.85 (t, 2H, J=8.0 Hz), 2.24 (s, 3H), 3.62
(t, 2H, J=8.0 Hz), 5.85 (s, 2H), 7.29 (m, 4H), 7.42 (tt, 1H, J=1.4,
7.4 Hz), 7.47 (dd, 1H, J=1.5, 8.3 Hz), 7.52 (dd, 2H, J=7.1, 7.4
Hz), 7.84(d, 1H, J=8.3 Hz), 7.93 (d, 1H, J=1.5 Hz), 7.99 (dd, 2H,
J=1.4, 7.1 Hz).
(f) Example 11--5-(2-Methylphenyl)-3-phenyl-1H-indazole
[0200] Tetrabutylammonium fluoride (1.0 M in THF, 2 mL) was added
to a solution of intermediate 11e (100 mg, 0.24 mmol) in
tetrahydrofuran (5 mL). This solution was heated in a 60.degree. C.
oil bath for 18 hours, then poured into water (25 mL) and extracted
with ethyl acetate (2.times.25 mL). The combined organic extracts
were dried over sodium sulfate and concentrated. Silica gel
chromatography (20% ethyl acetate/hexanes) provided
5-(2-methylphenyl)-3-phenyl-1H-indazole 11 (55 mg, 80%) as an
off-white solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 2.24 (s, 3H),
7.28 (m, 4H), 7.37 (dd, 1H, J=1.5, 8.6 Hz), 7.38 (tt, 1H, J=1.4,
7.5 Hz), 7.50 (dd, 2H, J=7.1, 7.5 Hz), 7.64(d, 1H, J=8.6 Hz), 7.91
(d, 1H, J=1.5 Hz), 7.99 (dd, 2H, J=1.4, 7.1 Hz), 13.30 (s, 1H).
Anal. (C.sub.20H.sub.16N.sub.2.0.25H.sub.2O) C, H, N.
EXAMPLE 12
3-Phenyl-5-[2-(trifluormethyl)phenyl]-1H-indazole
[0201] ##STR57##
(a) Intermediate 12a--3-Phenyl
5-[2-(trifluoromethyl)phenyl]-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-ind-
azole
[0202] 12a was prepared by a synthetic method analogous to
intermediate 11e. Palladium catalyzed coupling of intermediate 11d
with 2-(trifluoromethyl)phenylboronic acid yielded 12a (48%) as a
white solid: .sup.1H NMR (DMSO-d.sub.6) .delta. -0.12 (s, 9H), 0.87
(t, 2H, J=8.1 Hz), 3.72 (t, 2H, J=8.1 Hz), 5.62 (s, 2H), 7.32 (m,
1H) 7.38 (tt, 1H, J=0.8, 7.4 Hz), 7.48 (dd, 2H, J=7.1, 7.4 Hz),
7.51 (m, 1H), 7.63 (dd, 1H, J=7.2, 7.7 Hz), 7.66 (dd, 1H, J=1.6,
8.6 Hz), 7.75(m, 1H), 7.82 (d, 1H, J=8.6 Hz), 7.91 (d, 1H, J=1.6
Hz), 7.96 (dd, 2H, J=0.8, 7.1 Hz).
(b) Example 12--3-Phenyl
5-[2-(trifluoromethyl)phenyl]-1H-indazole
[0203] 12 was prepared similar to example 11. Treatment of 12a with
tetrabutylammonium fluoride afforded 3-phenyl
5-[2-(trifluoromethyl)phenyl]-1H-indazole 12 (74%) as a white
solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 7.34 (m, 1H), 7.38 (tt,
1H, J=1.3, 7.3 Hz), 7.49 (dd, 2H, J=7.1, 7.3 Hz), 7.52 (m, 1H),
7.62 (dd, 1H, J=7.4, 7.7 Hz), 7.65 (dd, 1H, J=1.9, 8.6 Hz), 7.73
(dd, J=7.2, 7.5 Hz), 7.85 (d, 1H, J=8.6 Hz), 7.94 (d, 1H, J=1.9
Hz), 7.96 (dd, 2H, J=1.3, 7.1 Hz). Anal.
(C.sub.20H.sub.13N.sub.2F.sub.3.0.1H.sub.2O) C, H, N.
EXAMPLE 13
5-(4-Hydroxy-2-methylphenyl)-3-phenyl-1H-indazole
[0204] ##STR58##
(a) Intermediate 13a--5-(2-methyl-4-[2-(trimethylsilanyl)
ethoxymethoxy]phenyl)-3-phenyl-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-in-
dazole
[0205] 13a was prepared similar to intermediate 11e. Palladium
catalyzed coupling of intermediate 11d with
(2-methyl-4-[2-(trimethylsilanyl)ethoxymethoxy]phenyl)boronic acid
yielded 13a (59%) as a pale yellow foam: .sup.1H NMR (DMSO-d.sub.6)
.delta. -0.09 (s, 9H), 0.00 (s, 9H), 0.85 (t, 2H, J=8.0 Hz), 0.92
(t, 2H, J=8.1 Hz), 2.22 (s, 3H), 3.62 (t, 2H, J=8.0 Hz), 3.73 (t,
2H, J=8.1 Hz), 5.25 (s, 2H), 5.85 (s, 2H), 6.93 (dd, 1H, J=2.6, 8.3
Hz), 6.98 (d, 1H, J=2.6 Hz), 7.22 (d, 1H, J=8.3 Hz), 7.43 (tt, 1H,
J=0.9, 7.7 Hz), 7.45 (dd, 1H, J=1.3, 8.6 Hz), 7.52 (dd, 2H, J=7.2,
7.7 Hz), 7.82 (d, 1H, J=8.6 Hz), 7.89 (d, 1H, J=1.3 Hz), 7.99 (dd,
2H, J=0.9, 7.2 Hz).
(b) Example
13--5-(4-Hydroxy-2-methylphenyl)-3-phenyl-1H-indazole
[0206] 13 was prepared similar to example 11. Treatment of 13a with
tetrabutylammonium fluoride afforded
5-(4-hydroxy-2-methylphenyl)-3-phenyl-1H-indazole 13 (75%) as a
pale yellow solid: .sup.1H NMR (DMSO-d.sub.6) 2.17 (s, 3H), 6.66
(dd, 1H, J=2.3, 8.2 Hz), 6.70 (d, 1H, J=2.3 Hz), 7.08 (d, 1H, J=8.2
Hz), 7.32 (dd, 1H, J=1.5, 8.6 Hz), 7.39 (tt, 1H, J=1.4, 7.7 Hz),
7.50 (dd, 2H, J=7.2, 7.7 Hz), 7.59 (d, 1H, J=8.6 Hz), 7.83 (d, 1H,
J=1.5 Hz), 7.97 (dd, 2H, J=1.4, 7.2 Hz) 9.28 (s, 1H), 13.22 (s,
1H). Anal. (C.sub.20H.sub.16N.sub.2O.0.8H.sub.2O) C, H, N.
EXAMPLE 14
3-Phenyl-5-(Pyrid-4-yl)-1H-indazole
[0207] ##STR59##
(a) Intermediate
14a--3-Phenyl-5-(pyrid-4-yl)-1-[2-trimethylsilanyl)ethoxymethyl]-1H-indaz-
ole
[0208] 14a was prepared similar to example 11e. Palladium catalyzed
coupling of intermediate 11d with pyridine-4-Iboronic acid yielded
14a (76%) as a white solid: .sup.1H NMR (DMSO-d.sub.6) .delta.
-0.11 (s, 9H), 0.84 (t, 2H, J=7.9 Hz), 3.62 (t, 2H, J=7.9 Hz), 5.86
(s, 2H), 7.46 (tt, 1H, J=1.1, 7.4 Hz), 7.51 (d, 1H, J=8.3 Hz), 7.56
(dd, 2H, J=7.1, 7.4 Hz), 7.80 (dd, 1H, J=1.4, 8.3 Hz), 7.85 (dd,
2H, J=1.6, 4.5 Hz), 8.07 (dd, 2H, J=1.1, 7.1 Hz), 8.41 (d, 1H,
J=1.4 Hz), 8.64 (dd, 2H, J=1.6, 4.5 Hz).
(b) Example 14--3-Phenyl 5-(pyrid-4-yl)-1H-indazole
[0209] 14 was prepared similar to example 11. Treatment of 14a with
tetrabutylammonium fluoride afforded
3-phenyl-5-(pyrid-4-yl)-1H-indazole 14 (85%) as a white solid:
.sup.1H NMR (DMSO-d.sub.6) .delta. 7.43 (tt, 1H, J=1.2, 7.6 Hz),
7.54 (dd, 2H, J=7.1, 7.6 Hz), 7.72 (d, 1H, J=8.8 Hz), 7.83 (dd, 2H,
J=1.6, 4.5 Hz), 7.84 (dd, 1H, J=1.5, 8.8 Hz), 8.07 (dd, 2H, J=1.2,
7.1 Hz), 8.40 (d, 1H, J=1.5 Hz), 8.63 (dd, 2H, J=1.6, 4.5 Hz) 13.39
(s, 1H). Anal. (C.sub.18H.sub.13N.sub.3.0.2H.sub.2O) C, H, N.
EXAMPLE 14b
3-Phenyl-5-(pyrid-3-yl)-1H-indazole
[0210] ##STR60##
(a) Intermediate 14b'--3
phenyl-5-(pyrid-3-yl)-1-[2-trimethylsilanyl)ethoxymethyl]-1H-indazole
[0211] 14b' was prepared similar to intermediate 11e. Palladium
catalyzed coupling of intermediate 11d with pyridine-3-boronic acid
yielded 14b' (66%) as a white solid: .sup.1H NMR (DMSO-d.sub.6)
.delta. -0.10 (s, 9H), 0.83 (t, 2H, J=7.9 Hz), 3.63 (t, 2H, J=7.9
Hz), 5.86 (s, 2H), 7.43 (tt, 1H, J=1.2, 7.5 Hz), 7.51 (dd, 1H,
J=4.7, 8.0 Hz), 7.54 (dd, 2H, J=7.1, 7.5 Hz), 7.65 (d, 1H, J=8.6
Hz), 7.73 (dd, 1H, J=1.5, 8.6 Hz), 8.07 (dd, 2H, J=1.2, 7.1 Hz),
8.18 (ddd, 1H, J=1.6, 2.3, 8.0 Hz), 8.32 (d, 1H, J=1.5 Hz), 8.56
(dd, 1H, J=1.6, 4.7 Hz), 8.90 (d, 1H, J=2.3 Hz).
(b) Example 14b--3-Phenyl 5-(pyrid-3-yl)-1H-indazole
[0212] Similar to example 11, treatment of 14b' with
tetrabutylammonium fluoride afforded
3-phenyl-5-(pyrid-3-yl)-1H-indazole 14b (79%) as a white solid:
.sup.1H NMR (DMSO-d.sub.6) .delta. 7.41 (tt, 1H, J=1.3, 7.4 Hz),
7.49 (dd, 1H, J=4.7, 7.9 Hz), 7.53 (dd, 2H, J=7.1, 7.4 Hz), 7.70
(d, 1H, J=8.7 Hz), 7.76 (dd, 1H, J=1.5, 8.7 Hz), 8.08 (dd, 2H,
J=1.3, 7.1 Hz), 8.17 (ddd, 1H, J=1.7, 2.0, 7.9 Hz), 8.31 (d, 1H,
J=1.5 Hz) 8.56 (dd, 1H, J=1.7, 4.7 Hz), 8.99 (d, 1H, J=2.0 Hz),
13.35 (s, 1H). Anal. (C.sub.18H.sub.13N.sub.3) C, H, N.
EXAMPLE 15
2-Methyl-3-[3-(E)-styryl)-1H-indazol-5-yl]-phenol
[0213] ##STR61##
(a) Intermediate
15a'--5-(3-Methoxy-2-methyl-phenyl)-3-((E)-styryl)-1-(2-trimethylsilanyl--
ethoxymethyl)-1H-indazole
[0214] Intermediate 15a' was prepared from 7a' (571.8 mg, 1.42
mmol) by a synthetic method analogous to 9d', yielding styryl
analog 15a' (442.5 mmol, 66%) as a yellow oil: .sup.1H NMR
(DMSO-d.sub.6) .delta. -0.10 (s, 9H), 0.83 (t, 2H, J=8.1 Hz), 2.07
(s, 3H), 3.58 (t, 2H, J=7.9 Hz), 3.84 (s, 3H), 5.79 (s, 2H), 6.91
(d, 1H, J=7.6 Hz), 6.99 (d, 1H, J=8.3 Hz), 7.22-7.41 (m, 5H), 7.56
(d, 2H, J=5.1 Hz), 7.70-7.78 (m, 3H), 8.09 (s, 1H).
(b) Intermediate
15b'--5-(3-Methoxy-2-methyl-phenyl)-3-((E)-styryl)-1H-indazole
[0215] 15b' was prepared similar to example 3. Treatment of 15a'
(211.4 mg, 0.449 mmol) yielded 15b' (132.7 mg, 87%) as a white
foam: R.sub.f=0.38 (50% ethyl acetate/hexanes); .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.98 (s, 3H), 3.84 (s, 3H), 6.91 (d, 1H,
J=7.5 Hz), 6.98 (d, 1H, J=8.1 Hz), 7.2-7.61 (m, 8H), 7.70 (d, 2H,
J=7.4 Hz), 8.05 (s, 13H), 13.18 (s, 1H). HRMS calculated for
C.sub.23H.sub.20N.sub.2O 341.1648 (MH.sup.+), found 341.1638. Anal.
(C.sub.23H.sub.20N.sub.2O.0.2H.sub.2O) C, H, N.
(c) Example
15--2-Methyl-3-[3-((E)-styryl)-1H-indazol-6-yl]-phenol
[0216] Phenol 15' was prepared similar to phenol 8'. Treatment of
intermediate 15b' (63.1 mg, 0.185 mmol) with pyridine hydrochloride
yielded phenol 15' (39.7 mg, 66%) as an off-white solid:
R.sub.f=0.24 (50% ethyl acetate/hexanes); .sup.1H NMR
(DMSO-d.sub.6) .delta. 2.05 (s, 3H), 6.74 (d, 1H, J=7.5 Hz), 6.83
(d, 1H, J=7.9 Hz), 7.05 (t, 1H, J=7.7 Hz), 7.25-7.62 (m, 7H), 7.70
(d, 2H, J=7.2 Hz), 8.03 (s, 1H), 9.34 (s, 1H), 13.16 (s, 1H). HRMS
calculated for C.sub.22H.sub.18N.sub.2O 327.1497 (MH.sup.+), found
327.1487. Anal. (C.sub.22H.sub.18N.sub.2O.0.5H.sub.2O) C, H, N.
EXAMPLE 16
4-[3-(E)-Styryl)-1H-indazol-5-yl]-isoquinoline
[0217] ##STR62##
(a) Intermediate
16a--3-((E)-Styryl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-
-trimethylsilanyl-ethoxymethyl)-1H-indazole
[0218] A mixture of 7a' (2.0 g, 4.2 mmol), bis(pinacolato)diboron
(1.17 g, 4.6 mmol), potassium acetate (1.24 g, 12.6 mmol) and DMSO
(25 mL) was degassed under vacuum with argon replacement three
times.
1,1-Bis(Diphenylphosphino)ferrocenedichloropalladium(II)-CH.sub.2Cl.sub.2
(0.172 g, 0.21 mmol) was added and the degassing procedure was
repeated. The reaction was heated to 80.degree. C. for 1 hour and
the mixture was poured into water and extracted with ethyl
acetate-hexanes (2:1), washed with brine, dried over MgSO.sub.4,
and concentrated. Chromatography on silica 6:1 hexanes-Et.sub.2O
afforded 1.09 g 16a (55%). .sup.1H NMR (CDCl.sub.3) .delta. 8.51
(s, 1H), 7.88 (d, 1H, J=8.4 Hz), 7.64 (d, 1H, J=7.2 Hz), 7.58 (m,
2H), 7.48 (s, 1H), 7.41 (m, 3H), 7.31 (m, 1H), 3.59 (t, 2H, J=7.3
Hz), 1.41 (s, 12H), 0.91 (t, 2H, J=8.3 Hz), -0.06 (s, 9H). Anal.
(C.sub.27H.sub.37N.sub.2O.sub.3SiB) C, H, N.
(b) Intermediate
16b--4-[3-((E)-Styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-y-
l]-isoquinoline
[0219] Intermediate 16a (0.218 g, 0.47 mmol), 4-bromoisoquinoline
(0.082 g, 0.39 mmol) and Na.sub.2CO.sub.3 (0.1 g, 0.95 mol) were
combined with 3 mL DME and 0.5 mL water and the mixture was
degassed and purged with argon.
Tetrakis(triphenylphosphino)palladium(0) (0.023 g, 0.02 mmol) was
added and the mixture was again degassed and then heated to reflux
under argon for 15 hours. Aqueous work up as with 16a and
chromtagraphy on silica (4:1 hexanes-ethyl acetate) yielded 0.181 g
(96%) of 16b; .sup.1H NMR (CDCl.sub.3) .delta. 8.59 (s, 1H), 8.13
(m, 2H), 7.97 (d, 1H, J=7.6 Hz), 7.73 (m, 3H), 7.58 (m, 3H), 7.50
(d, 2H, J=9.5 Hz), 7.26 (m, 4H), 5.82 (s, 2H), 3.68 (t, 2H, J=8.1
Hz), 0.97 (t, 2H, J=8.3 Hz), -0.03 (s, 9H). Anal.
(C.sub.30H.sub.31N.sub.3OSi.0.75H.sub.2O) C, H, N.
(c) Example 16--4-[3-(E)-Styryl)-1H-indazol-5-yl]-isoquinoline
[0220] A solution of 16b (0.17 g, 0.35 mmol) in 3.6 mL of 1M
tetrabutylammonium fluoride in THF and ethylenediamine (0.475 uL,
0.427 g, 7.1 mmol) was heated to reflux for 1 hour. The reaction
was diluted with ethyl acetate and brought to pH 7 with 0.4 M HCl,
washed with brine, dried over MgSO.sub.4, and concentrated.
Chromtagraphy on silica (1:1 hexanes-ethyl acetate) yielded 0.079 g
(64%) of 16 as a white solid. .sup.1H NMR (CDCl.sub.3) .delta.
10.20 (brs, 1H), 9.31 (s, 1H), 8.59 (s, 1H), 8.16 (s, 1H), 8.09 (d,
1H, J=7.2 Hz), 7.93 (d, 1H, J=7.2 Hz), 7.20-7.75 (m, 11H). Anal.
(C.sub.24H.sub.17N.sub.3.0.4H.sub.2O) C, H, N.
EXAMPLE 17
4-[3-(E)-Styryl)-1H-indazol-5-yl]-quinoline
[0221] ##STR63##
(a) Intermediate
17a--4-[3-((E)-Styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-y-
l]-quinoline
[0222] 17a was prepared by a synthetic method analogous to
intermediate 16b. Employing 4-chloroquinoline, 17a was prepared in
79% yield. .sup.1H NMR (CDCl.sub.3) .delta. 8.99 (d, 1H, J=4.4 Hz),
8.21 (d, 1H, J=7.9 Hz), 8.15 (s, 1H,), 7.95 (d, 1H, J=8.4 Hz), 7.72
(m, 2H), 7.42-7.62 (m, 10H), 5.82 (s, 2H), 3.67 (t, 2H, J=9.3 Hz),
0.97 (t, 2H, J=8.3 Hz), -0.02 (s, 9H). Anal.
(C.sub.30H.sub.31N.sub.3OSi.0.5H.sub.2O) C, H, N.
(b) Example 17--4-[3-((E)-Styryl)-1H-indazol-5-yl]-quinoline
[0223] Example 17 was prepared similar to intermediate 16. 17a was
deprotected to afford 17 in 50% yield as a white solid. .sup.1H NMR
(CDCl.sub.3) .delta. 13.10 (brs, 1H), 8.98 (d, 1H, J=4.4 Hz), 8.37
(s, 1H), 8.15 (d, 1H, J=8.4 Hz), 8.00 (d, 1H, J=8.4 Hz), 7.54-7.79
(m, 9H), 7.37 (m, 2H), 7.26 (m, 1H). Anal.
(C.sub.24H.sub.17N.sub.3.1.0H.sub.2O) C, H, N.
EXAMPLE 18
5-(4-Pyridyl)-3-(2-Pyrrolyl)-1H-Indazole
[0224] ##STR64## ##STR65##
(a) Intermediate 18a--2-Fluoro-5-nitrobenzoyl chloride
[0225] A solution of 2-chloro-5-nitrobenzoic acid (10.3 g, 56 mmol)
in thionyl chloride (90 ml, 1.2 mol) was heated at reflux for 2
hours. Excess thionyl chloride was removed by concentration, in
vacuo. The residue obtained was dissolved in ether (150 ml), then
concentrated to provide 2-fluoro-5-nitrobenzoyl chloride 18a (11.21
g, 99%) as an off-white solid: .sup.1H NMR (DMSO-d.sub.6) .delta.
7.62 (dd, 1H, J=9.1, 9.6 Hz), 8.48 (ddd, 1H, J=3.0, 6.9, 9.1 Hz),
8.60 (dd, 1H, J=3.0, 6.3 Hz). Anal. (C.sub.7H.sub.3NO.sub.3ClF) C,
H, N. Cl.
(b) Intermediate
18b--1-(2-Fluoro-5-nitrophenyl)-1-(1H-pyrrol-2-yl)methanone
[0226] A solution of 2-chloro-5-nitrobenzoyl chloride 18a (10.04 g,
49 mmol) and pyrrole (3.4 ml, 3.29 g, 49 mmol) in
1,2-dichloroethane (110 ml) was cooled to 0.degree. C. prior to
addition of AlCl.sub.3 (6.61 g, 49.6 mmol) as the solid. The
resultant reaction mixture was stirred overnight, gradually warming
to room temperature. The crude reaction was, subsequently, poured
into a mixture of concentrated HCl (20 ml) and ice water (200 ml).
After stirring for an additional 90 minutes, the layers were
separated and the aqueous phase was extracted with CH.sub.2Cl.sub.2
(2.times.200 ml). The combined organic extracts were washed with
water (200 ml) and saturated NaHCO.sub.3 (200 ml), dried over
sodium sulfate and concentrated. Silica gel chromatography (25%
ethyl acetate/hexanes) provided 18b (7.23 g, 63%) as a pale yellow
solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 6.28 (ddd, 1H, J=2.1,
2.3, 3.6 Hz), 6.74 (ddd, 1H, J=1.3, 2.3, 2.5 Hz), 7.32 (ddd, 1H,
J=1.3, 2.4, 3.6 Hz), 7.65 (dd, 1H, J=9.0, 9.1 Hz), 8.39 (dd, 1H,
J=3.0, 5.8 Hz), 8.45 (ddd, 1H, J=3.0, 4.4, 9.1 Hz), 12.33 (broad,
1H). Anal. (C.sub.1H.sub.7N.sub.2O.sub.3F.0.1 HCl) C, H, N.
(c) Intermediate
18c--1-(2-Fluoro-5-nitrophenyl)-1-(1-[2-(trimethylsilanyl)ethoxymethyl]-1-
H-pyrrol-2-yl)methanone
[0227] A solution of
1-(2-fluoro-5-nitrophenyl)-1-(1H-pyrrol-2-yl)methanone 18b (1.72 g,
7.3 mmol) in THF (30 ml) was added dropwise, under an argon
atmosphere, to a stirred suspension of NaH (350 mg, 8.75 mmol) in
THF (15 ml) at 0.degree. C. This mixture was stirred at 0.degree.
C. for 45 minutes prior to addition of
2-(trimethylsilyl)ethoxymethyl chloride (1.70 g, 10.2 mmol) in a
single portion as the neat liquid. The resultant reaction mixture
was stirred at ambient temperature overnight, then poured into
saturated NaHCO.sub.3 (80 ml). The layers were separated and the
aqueous phase was extracted with ethyl acetate (2.times.50 ml). The
combined organic extracts were washed with brine (60 ml), dried
over sodium sulfate and concentrated. Silica gel chromatography
(10% ethyl acetate/hexanes) provided 18c (2.24 g, 84%) as a yellow
syrup: .sup.1H NMR (DMSO-d.sub.6) .delta. -0.07 (s, 9H), 0.83 (t,
2H, J=7.8 Hz), 3.53 (t, 2H, J=7.8 Hz), 5.74 (s, 2H), 6.27 (dd, 1H,
J=2.5, 4.0 Hz), 6.75 (dd, 1H, J=1.4, 4.0 Hz), 7.57 (dd, 1H, J=1.4,
2.5 Hz), 7.64 (dd, 1H, J=9.0, 9.1 Hz), 8.29 (dd, 1H, J=3.0, 5.8
Hz), 8.45 (ddd, 1H, J=3.0, 4.6, 9.1 Hz). Anal.
(C.sub.17H.sub.21N.sub.2O.sub.4FSi) C, H, N.
(d) Intermediate
18d--1-(5-Amino-2-fluorophenyl)-1-(1-[2-(trimethylsilanyl)ethoxymethyl]-1-
H-pyrrol-2-yl)methanone
[0228] A mixture of
1-(2-fluoro-5-nitrophenyl)-1-(1-[2-(trimethylsilanyl)ethoxymethyl]-1H-pyr-
rol-2-yl)methanone 18c (3.63 g, 10 mmol) and 10% palladium on
carbon (365 mg) in ethyl acetate (90 ml) was stirred under an
atmosphere of hydrogen overnight. The reaction mixture was filtered
through celite, then concentrated to provide 18d (3.30 g, 99%) as
an amber syrup: .sup.1H NMR (DMSO-d.sub.6) .delta. -0.07 (s, 9H),
0.82 (t, 2H, J=8.0 Hz), 3.50 (t, 2H, J=8.0 Hz), 5.12 (br s, 2H),
5.71 (s, 2H), 6.20 (dd, 1H, J=2.5, 3.9 Hz), 6.59 (dd, 1H, J=2.9,
5.6 Hz) 6.60 (dd, 1H, J=1.8, 3.9 Hz), 6.66 (ddd, 1H, J=2.9, 4.3,
8.8 Hz), 6.93 (dd, 1H, J=8.8, 9.7 Hz), 7.42 (dd, 1H, J=1.8, 2.5
Hz). Anal. (C.sub.17H.sub.23N.sub.2O.sub.2FSi) C, H, N.
(e) Intermediate
18e--1-(2-Fluoro-5-iodophenyl)-1-(1-[2-(trimethylsilanyl)ethoxymethyl]-1H-
-pyrrol-2-yl)methanone
[0229] Intermediate 18d (332 mg, 1.0 mmol) was dissolved in a
mixture of acetic acid (10 ml) and acetonitrile (10 ml). This
vigorously stirred solution was cooled in an ice-salt bath to
-5.degree. C., prior to addition of a solution of sodium nitrite
(83 mg, 1.2 mmol) in water (10 ml). The resultant diazonium
solution was stirred for 45 minutes, gradually warming to 5.degree.
C. The reaction was, again, cooled to -5.degree. C. preceding the
addition of a solution of potassium iodide (232 mg, 1.4 mmol) in
water (3 ml). The resultant mixture was stirred for an additional 2
hours, warming to 15.degree. C., then poured into a mixture of
K.sub.2CO.sub.3 (30 g) and ice water (100 ml). This aqueous mixture
was extracted with ethyl acetate (2.times.50 ml). The combined
organic extracts were washed with 10% aqueous
Na.sub.2S.sub.2O.sub.3 (50 ml), dried over sodium sulfate and
concentrated. Silica gel chromatography (5% ethyl acetate/hexanes)
provided 18e (160 mg, 36%) as a colorless oil: .sup.1H NMR
(DMSO-d.sub.6) .delta. -0.08 (s, 9H), 0.81 (t, 2H, J=7.9 Hz), 3.50
(t, 2H, J=7.9 Hz), 5.71 (s, 2H), 6.24 (dd, 1H, J=2.6, 4.0 Hz), 6.63
(dd, 1H, J=1.7, 4.0 Hz) 7.18 (dd, 1H, J=8.7, 9.7 Hz), 7.51(dd, 1H,
J=1.7, 2.6 Hz), 7.74 (dd, 1H, J=2.3, 6.4 Hz), 7.90 (ddd, 1H, J=2.3,
4.9, 8.7 Hz). Anal. (C.sub.17H.sub.21NO.sub.2FSiI) C, H, N, I.
(f) Intermediate
18f--1-[2-Fluoro-5-(4-pyridyl)phenyl]-1-(1-[2-(trimethylsilanyl)ethoxymet-
hyl]-1H-pyrrol-2-yl)methanone
[0230] Diisopropylethylamine (1.3 ml, 7.5 mmol) was added to a
mixture of
1-(2-fluoro-5-iodophenyl)-1-(1-[2-(trimethylsilanyl)ethoxymethyl]-1H-pyrr-
ol-2-yl)methanone 18e (798 mg, 1.8 mmol),
tetrakis(triphenylphosphine)palladium(0) (65 mg, 0.06 mmol) and
pyridine-4-boronic acid (323 mg, 2.6 mmol) in DMF (20 ml). The
resultant reaction mixture was heated in a 90.degree. C. oil bath
for 18 hours, under an argon atmosphere. After cooling to room
temperature, the crude reaction mixture was poured into water (100
ml) and extracted with ethyl acetate (2.times.75 ml). The combined
organic extracts were washed with water (6.times.75 ml), dried over
sodium sulfate and concentrated. Silica gel chromatography (20%
ethyl acetate/CH.sub.2Cl.sub.2) afforded 18f (407 mg, 57%) as a
pale yellow oil: .sup.1H NMR (DMSO-d.sub.6) .delta. -0.06 (s, 9H),
0.84 (t, 2H, J=7.9 Hz), 3.54 (t, 2H, J=7.9 Hz), 5.76 (s, 2H), 6.24
(dd, 1H, J=2.6, 4.0 Hz), 6.68 (dd, 1H, J=1.8, 4.0 Hz) 7.49 (dd, 1H,
J=8.7, 9.3 Hz), 7.51 (dd, 1H, J=1.8, 2.6 Hz), 7.72 (d, 2H, J=6.2
Hz), 7.87 (dd, 1H, J=2.4, 6.5 Hz), 8.02 (ddd, 1H, J=2.4, 4.9, 8.7
Hz), 8.63 (d, 2H, J=6.2 Hz). Anal.
(C.sub.22H.sub.25N.sub.2O.sub.2FSi) C, H, N.
(g) Intermediate
18g--5-(4-Pyridyl)-3-(1-[2-(trimethylsilanyl)ethoxymethyl]-1H-pyrrol-2-yl-
)-1H-indazole
[0231] A solution of
1-[2-fluoro-5-(4-pyridyl)phenyl]-1-(1-[2-(trimethylsilanyl)ethoxymethyl]--
1H-pyrrol-2-yl)methanone 18f (504 mg, 1.3 mmol) and hydrazine
monohydrate (1.7 ml, 35 mmol) in ethanol (35 ml) was heated at
reflux for 42 hours. The ethanol was then removed by concentration,
in vacuo. The residue obtained was partitioned between water (25
ml) and ethyl acetate (25 ml). The layers were separated and the
aqueous phase was extracted with ethyl acetate (25 ml). The
combined organic extracts were washed with saturated NaHCO.sub.3
(30 ml), dried over sodium sulfate and concentrated. Silica gel
chromatography (3% CH.sub.3OH/CH.sub.2Cl.sub.2) provided 18g (430
mg, 87%) as an off-white solid: .sup.1H NMR (DMSO-d.sub.6) .delta.
-0.28 (s, 9H), 0.63 (t, 2H, J=8.0 Hz), 3.28 (t, 2H, J=8.0 Hz), 5.72
(s, 2H), 6.26 (dd, 1H, J=2.8, 3.5 Hz), 6.79 (dd, 1H, J=1.7, 3.5 Hz)
7.10 (dd, 1H, J=1.7, 2.8 Hz), 7.67 (d, 1H, J=8.9 Hz), 7.77 (d, 2H,
J=6.2 Hz), 7.81 (dd, 1H, J=1.6, 8.9 Hz), 8.19 (d, 1H, J=1.6 Hz),
8.61 (d, 2H, J=6.2 Hz), 13.25 (s, 1H). Anal.
(C.sub.22H.sub.26N.sub.4OSi) C, H, N.
(h) Example 18--5-(4-Pyridyl)-3-(2-pyrrolyl)-1H-indazole
[0232] Tetrabutylammonium fluoride (1.0 M in THF, 5 ml) was added
to a solution of intermediate 18g (366 mg, 0.9 mmol) and
1,2-diaminoethane (150 mg, 2.5 mmol) in tetrahydrofuran (20 ml).
This solution was heated at reflux for 42 hours, then poured into
saturated NaHCO.sub.3 (30 ml) and extracted with ethyl acetate
(2.times.25 ml). The combined organic extracts were dried over
sodium sulfate and concentrated. Silica gel chromatography (3%
CH.sub.3OH/CH.sub.2Cl.sub.2) provided
5-(4-Pyridyl)-3-(2-pyrrolyl)-1H-indazole 18 (71 mg, 29%) as an
off-white solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 6.20 (dd, 1H,
J=2.6, 5.6 Hz), 6.82-6.92 (m, 2H), 7.64 (d, 1H, J=8.7 Hz), 7.81
(dd, 1H, J=1.4, 8.7 Hz), 7.83 (d, 2H, J=6.1 Hz), 8.37 (d, 1H, J=1.4
Hz), 8.62 (d, 2H, J=6.1 Hz), 11.37 (s, 1H), 13.09 (s, 1H). Anal.
(C.sub.16H.sub.12N.sub.4.0.05CH.sub.2Cl.sub.2) C, H, N.
EXAMPLE 18b'
5-Nitro-3-(2-Pyrrolyl)-1H-indazole
[0233] ##STR66##
[0234] 18b' was prepared similar to intermediate 11a. Treatment of
1-(2-fluoro-5-nitrophenyl)-1-(1H-pyrrol-2-yl)methanone 18b with
hydrazine hydrate afforded 5-nitro-3-(2-pyrrolyl)-1H-indazole 18b'
(75%) as an orange-red solid: .sup.1H NMR (DMSO-d.sub.6) .delta.
6.23 (ddd, 1H, J=2.4, 2.6, 3.6 Hz), 6.81 (ddd, 1H, J=1.5, 2.5, 3.6
Hz), 6.93 (ddd, 1H, J=1.5, 2.1, 2.6 Hz), 7.70 (d, 1H, J=9.2 Hz),
8.21 (dd, 1H, J=2.0, 9.2 Hz), 8.90 (d, 1H, J=2.0 Hz), 11.57 (broad,
1H), 13.62 (s, 1H). Anal. (C.sub.11H.sub.8N.sub.4O.sub.2) C, H,
N.
EXAMPLE 19
4-[3-(4-Chloro-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinoline
[0235] ##STR67## ##STR68##
(a) Intermediate 19a--1H-Indazole-3-carboxylic acid
methoxy-methyl-amide
[0236] 3-Carboxyindazole (100 g, 617 mmol) in 1 L DMF was treated
with carbonyldiimidazole (110 g, 678 mmol) at 25.degree. C. with
gas evolution for 15 minutes. The reaction was heated to
60-65.degree. C. for 2 hours and then allowed to cool to 25.degree.
C. N,O-Dimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a
solid and the mixture was heated to 65.degree. C. for 3 hours The
reaction was concentrated to a paste and taken up in 2 L
CH.sub.2Cl.sub.2, washed with water, and then 2N HCl. Product was
visibly coming out of solution. Solid was filtered and rinsed
separately with ethyl acetate. The ethyl acetate and
CH.sub.2Cl.sub.2 layers were separately washed with NaHCO.sub.3,
and brine, dried over MgSO4 and concentrated. The resulting solids
were combined, triturated with a 1:1 mixture of
CH.sub.2Cl.sub.2-ether, filtered, and dried to afford 106 g (84%)
of intermediate 19a as a white solid: R.sub.f=0.38 (75% ethyl
acetate in hexanes); .sup.1H NMR (DMSO-d.sub.6) .delta. 13.60 (s,
1H,), 7.80 (d, 1H, J=8.2 Hz), 7.60 (d, 1H, J=8.2 Hz), 7.41 (t, 1H,
J=8.0 Hz), 7.22 (t, 1H, J=8.0 Hz), 3.77(s, 3H), 3.44 (s, 3H). Anal.
(C.sub.10H.sub.11N.sub.3O.sub.2) C, H, N.
(b) Intermediate 19b--5-Iodo-1H-indazole-3-carboxylic acid
methoxy-methyl-amide
[0237] To the amide 19a (20 g, 97.4 mmol) in 1 L CH.sub.2Cl.sub.2
was added bis(trifluoroacetoxy)iodobenzene (46 g, 107 mmol)
followed by portionwise addition of iodine (14.84 g, 58.5 mmol) at
25.degree. C. After 1 hour, 600 mL of saturated Na.sub.2HSO.sub.3
was added and a solid began to precipitate which was filtered and
rinsed with excess CH.sub.2Cl.sub.2. The filtrate was washed with
brine, dried over MgSO.sub.4, concentrated, and the remaining solid
triturated with a minimal amount of CH.sub.2Cl.sub.2. The combined
solids were dried under vacuum over KOH to give 29.26 g (91%) of
iodide 19b as a pale white solid: R.sub.f=0.31 (50% ethyl acetate
in hexanes); .sup.1H NMR (DMSO-d.sub.6) .delta. 13.79 (s, 1H), 8.39
(s, 1H), 7.65 (d, 1H, J=8.7 Hz), 7.48 (d, 1H, J=8.7 Hz), 3.76 (s,
3H), 3.44 (s, 3H). Anal. (C.sub.10H.sub.10N.sub.3IO.sub.2) C,
H.
(c) Intermediate
19c--5-Iodo-1-(4-methoxy-benzyl)-1H-indazole-3-carboxylic acid
methoxy-methyl-amide
[0238] To the iodide 19b (15 g, 45.3 mmol) in 200 mL THF was added
NaH (1.9 g of a 60% mineral oil dispersion, 1.14 g, 47.6 mmol),
portionwise with gas evolution. After 15 minutes the reaction was
cooled to 0.degree. C. and p-methoxybenzyl chloride (8.51 g, 54.4
mmol) was added followed by NaI (679 mg, 4.5 mmol). The mixture was
heated to 45.degree. C. for 9 h and allowed to cool to 25.degree.
C. The solution was diluted with ethyl acetate, washed with
saturated aqueous NH.sub.4Cl, brine and dried over MgSO.sub.4 and
concentrated to a viscous oil. Ether was added to the oil and a
solid formed which was filtered and rinsed with ether to provide
14.18 g (70%) of 19c as a faint yellow solid: R.sub.f=0.42 (50%
ethyl acetate in hexanes); .sup.1H NMR (CDCl.sub.3) .delta. 8.60
(s, 1H), 7.56 (dd, 1H, J=8.8, 1.6 Hz), 7.11 (m, 3H), 6.80 (dd, 2H,
J=6.7, 2.1 Hz), 5.52 (s, 2H), 3.81 (s, 3H), 3.75 (s, 3H), 3.51 (s,
3H). Anal. (C.sub.18H.sub.18N.sub.3O.sub.3I) C, H, N, I.
(d) Intermediate
19d--5-Iodo-1-(4-methoxy-benzyl)-1H-indazole-3-carbaldehyde
[0239] The amide 19c (12.8 g, 28.3 mmol) in 300 mL THF was cooled
to -5.degree. C. and LiAlH.sub.4 (1.29 g, 34 mmol) was added
portionwise over 10 minutes. After 30 minutes the reaction was
quenched by the slow addition of ethyl acetate at -5.degree. C. and
the whole was poured into 0.4 N NaHSO.sub.4. The organic layer was
washed with brine, dried over MgSO.sub.4, and concentrated to
afford a slightly offwhite solid which was triturated with a
minimal amount of ether, filtered, washed with ether, and dried to
give 9.79 g (88%) of aldehyde 19d as a white solid: R.sub.f=0.57
(50% ethyl acetate in hexanes); .sup.1H NMR (CDCl.sub.3) .delta.
10.20 (s, 1H), 8.96 (s, 1H), 7.63 (dd, 1H, J=8.8, 1.6 Hz), 7.18 (m,
3H), 6.83 (d, 1H, J=8.7 Hz), 5.57 (s, 3H), 3.75 (s, 3H). Anal.
(C.sub.16H.sub.13N.sub.2O.sub.2I.0.1 ethyl acetate) C, H, N, I.
(e) Intermediate
19e--1-(4-Methoxy-benzyl)-5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-y-
l)-1H-indazole-3-carbaldehyde
[0240] Bis(pinacolato)diboron (Aldrich Chemicals) (7.05 g, 27.8
mmol), iodide 19d (9.90 g, 25.24 mmol), potassium acetate (12.4 g,
126 mmol), and
1,1'-bis(diphenyl-phosphino)ferrocenedichloropalladium(II) (515 mg,
0.631 mmol) were dissolved in dimethysulfoxide (150 mL), degassed,
and heated in an 80.degree. C. oilbath for 1 hour. After cooling to
room temperature, the mixture was partitioned between ethyl acetate
(200 mL) and water (150 mL). The organic layer was dried over
magnesium sulfate, filtered, concentrated, and purified by silica
gel chromatography (25% ethyl acetate in hexanes) to give boronic
ester 19e (9.75 g, 98%) as an off-white solid: R.sub.f=0.37 (25%
ethyl acetate in hexanes); .sup.1H NMR (DMSO-d.sub.6) .delta. 1.31
(s, 12H), 3.69 (s, 3H), 5.75 (s, 2H), 6.87 (d, 2H, J=8.7 Hz), 7.27
(d, 2H, J=8.7 Hz), 7.74 (d, 1H, J=8.4 Hz), 7.91 (d, 1H, J=8.4 Hz),
8.52 (s, 1H), 10.17 (s, 1H). Anal.
(C.sub.22H.sub.25BN.sub.2O.sub.4) C, H, N.
(f) Intermediate
19f--5-Isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazole-3-carbaldehyde
[0241] To a degassed solution of boronic ester 19e (6.00 g, 15.30
mmol) and 4-bromoisoquinoline (5.17 g, 24.8 mmol) in ethylene
glycol dimethyl ether (DME, 76 mL) was added aqueous sodium
carbonate solution (2.0 M, 38.2 mL, 76.4 mmol) followed by
tetrakis(triphenylphosphine)palladium (0) (883 mg, 0.76 mmol). The
mixture was heated in an 80.degree. C. oilbath for 5 hours,
attaining a maximum internal temperature of 78.degree. C. After
cooling to room-temperature, the mixture was diluted with ethyl
acetate (200 mL), washed with water (100 mL), and saturated aqueous
sodium chloride solution (50 mL). The organic extracts were dried
over magnesium sulfate, filtered, concentrated and columned (silica
gel, 30 to 70% ethyl acetate in hexanes), affording 19f (3.56 g,
59%) as an off-white solid: R.sub.f=0.16 (50% ethyl acetate in
hexanes); .sup.1H NMR (DMSO-d.sub.6) .delta. 3.71 (s, 3H), 5.83 (s,
2H), 6.92 (d, 2H, J=8.7 Hz), 7.38 (d, 2H, J=8.7 Hz), 7.74 (m, 4H),
8.10 (d, 1H, J=8.7 Hz), 8.22 (m, 2H), 8.48 (s, 1H), 9.37 (s, 1H),
10.21 (s, 1H).
(g) Intermediate 19g--3-Chloro-benzene-1,2-diamine
[0242] A solution of sodium borohydride (1.90 g, 50.2 mmol) in
water (40 mL) was added to a suspension of 10% palladium on carbon
(250 mg) in water (50 mL) while bubbling argon into the latter
solution via pipette. To this was added a solution of
3-chloro-2-nitroaniline (Astatech Chemicals) (4.33 g, 25.1 mmol) in
2N aqueous sodium hydroxide (125 mL) dropwise via addition funnel,
slowly enough to keep gas evolution under control. The mixture was
stirred at room temperature for 10 minutes, filtered through a
Celite pad, acidified with 3N aqueous hydrochloric acid, and
extracted with dichloromethane (3.times.200 mL). The combined
organic layers were dried over magnesium sulfate, filtered,
concentrated, and purified by silica gel chromatography (1 to 20%
ethyl acetate in dichloromethane) to give diamine 19g (2.13 g, 60%)
as yellow oil: R.sub.f=0.30 (dichloromethane); .sup.1H NMR
(DMSO-d.sub.6) .delta. 4.60 (br s, 2H), 4.80 (br s, 2H), 6.37 (t,
1H, J=7.8 Hz), 6.48 (m, 2H). Anal. (C.sub.6H.sub.7ClN) C, H, Cl,
N.
(h) Intermediate
19h--4-[3-(4-Chloro-1H-benzoimidazol-2-yl)-1-(4-methoxy-benzyl)-1H-indazo-
l-5-yl]-isoquinoline
[0243] Aldehyde 19f (405.6 mg, 1.03 mmol) and diamine 19g (147 mg,
1.03 mmol) were condensed in the presence of elemental sulfur (50
mg, 1.55 mmol) analogous to the synthesis of intermediate 7c',
affording intermediate 19h (275.5 mg, 52%) as a pale yellow solid:
R.sub.f=0.12 (50% ethyl acetate in hexanes); .sup.1H NMR
(DMSO-d.sub.6) .delta. 3.74 (s, 3H), 5.83 (s, 2H), 6.93 (d, 2H,
J=8.8 Hz), 7.22 (m, 2H), 7.38 (d, 2H, J=8.5 Hz), 7.48 (d, 1H, J=7.2
Hz), 7.67 (dd, 1H, J=8.7, 1.5 Hz), 7.76 (m, 3H), 8.04 (d, 1H, J=8.7
Hz), 8.26 (dd, 1H, J=7.4, 1.5 Hz), 8.54 (s, 1H), 8.64 (s, 1H), 9.40
(s, 1H), 13.41 (s, 1H).
(i) Example
19--4-[3-(4-Chloro-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinoline
[0244] Concentrated sulfuric acid (0.3 mL) was added to a solution
of 19h (121.6 mg, 0.236 mmol) in trifluoroacetic acid (3.0 mL), and
stirred at room temperature for 19 hours. The mixture was then
diluted with water (50 mL), treated with concentrated aqueous
ammonium hydroxide until pH=8, and extracted with ethyl acetate
(3.times.50 mL). The combined organic extracts were dried over
magnesium sulfate, filtered, concentrated, and purified by silica
gel chromatography to give 19 (41.5 mg, 44%) as a white solid:
R.sub.f=0.40 (75% ethyl acetate in hexanes); .sup.1H NMR
(DMSO-d.sub.6) [Some peaks are doubled due to tautomeric
isomerization] .delta. 7.22 (m, 2H), 7.48 (d, 1H, J=7.2 Hz), 7.64
(d, 1H, J=8.7), 7.79 (m, 4H), 8.27 (d, 1H, J=7.5), 8.55 (s, 1H),
8.63 (s, 1H), 9.40 (s, 1H), 13.39 and 13.56 (2 s, 1H together),
13.94 (s, 1H). Anal. (C.sub.23H.sub.14ClN.sub.5.1.2 CH.sub.3OH) C,
H, Cl, N.
EXAMPLE 20
4-{3-[5-(4-Methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-5-yl}--
isoquinoline
[0245] ##STR69##
(a) Intermediate
20a--4-{1-(4-Methoxy-benzyl)-3-[5-(4-methyl-piperazin-1-yl)-1H-benzoimida-
zol-2-yl]-1H-indazol-5-yl}-isoquinoline
[0246] A suspension of
5-(4-Methyl-piperazin-1-yl)-2-nitro-phenylamine (513.0 mg, 2.17
mmol) [See Kim, Jung Sun; et al.; J. Med. Chem.; 39; 992 (1996) for
the synthesis of this compound] and 10% palladium on carbon (200.8
mg) in ethyl acetate (50 mL) was shaken under 40 psi H.sub.2 for 17
hours. The catalyst was removed by filtration through a Celite pad,
and the mixture concentrated to afford crude
4-(4-Methyl-piperazin-1-yl)-benzene-1,2-diamine (522 mg) as a
yellow foam. This crude diamine was added to a solution of aldehyde
19f (853.7 mg, 2.17 mmol) and elemental sulfur (83 mg, 2.60 mmol)
in anhydrous dimethylformamide (40 mL), and the solution heated in
an 80.degree. C. oilbath for 6 hours. After cooling to room
temperature, the solution was diluted with ethyl acetate (150 mL)
and washed with water (50 mL) and saturated aqueous sodium chloride
solution (50 mL). The organic layer was dried over magnesium
sulfate, filtered, concentrated, and purified by silica gel
chromatography (1:20:400 concentrated aqueous
NH.sub.4OH:EtOH:CH.sub.2Cl.sub.2), affording 20a (623 mg, 50%) as
an orange-brown foam: R.sub.f=0.20 (10% ethanol in
dichloromethane); .sup.1H NMR (DMSO-d.sub.6) [Some peaks are
doubled due to tautomeric isomerization] .delta. 2.23 (s, 3H), 2.49
(m, 4H), 3.10 (m, 4H), 3.71 (s, 3H), 5.80 (s, 2H), 6.91 (m, 4H),
7.36 and 7.47 (2 d, 3H together, J=8.3, 8.7 Hz), 7.64 (d, 1H, J=8.9
Hz), 7.77 (m, 3H), 7.99 (m, 1H), 8.25 (d, 1H, J=7.2 Hz), 8.53 (s,
1H), 8.62 and 8.64 (2 s, 1H together), 9.39 (s, 1H), 12.78 and
12.83 (2 s, 1H together). Anal.
(C.sub.36H.sub.33N.sub.7O.0.9H.sub.2O) C, H, N.
EXAMPLE 20
4-{3-[5-(4-Methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H
indazol-5-yl}-isoquinoline
[0247] Anisole (229.4 mg, 2.12 mmol) was added to a solution of 20a
(123.0 mg, 0.212 mmol) in glacial acetic acid (2.12 mL).
Concentrated aqueous hydrobromic acid (2.12 mL) was added, and the
mixture heated to reflux for 21 hours. After cooling, the reaction
solution was added dropwise to a rapidly stirred mixture of
dichloromethane (50 mL), tetrahydrofuran (20 mL), and saturated
aqueous sodium bicarbonate (30 mL). The layers were separated, and
the organic layer was washed with saturated aqueous sodium
bicarbonate (20 mL), followed by water (20 mL). The organic layer
was dried over magnesium sulfate, filtered, concentrated, and
purified by silica gel chromatography (1:20:100 concentrated
aqueous NH.sub.4OH:EtOH:CH.sub.2Cl.sub.2), yielding slightly impure
20 (76.0 mg, 78%) as a red foam. Further purification by
precipitation from dichloromethane/hexanes afforded pure 20 (47.1
mg, 48%) as a pink solid: R.sub.f=0.20 (1:20:50 concentrated
aqueous NH.sub.4OH:EtOH:CH.sub.2Cl.sub.2); .sup.1H NMR
(DMSO-d.sub.6) [Some peaks are doubled due to tautomeric
isomerization] .delta. 2.23 (s, 3H), 2.49 (m, 4H), 3.11 (m, 4H),
6.91 (m, 2H), 7.35 and 7.47 (2 d, 1H together, J=9.0, 8.9 Hz), 7.61
(d, 1H, J=8.9 Hz), 7.80 (m, 4H), 8.26 (d, 1H, J=7.7 Hz), 8.54 (s,
1H), 8.59 and 8.62 (2 s, 1H together), 9.39 (s, 1H), 12.74 and
12.79 (2 s, 1H together), 13.73 and 13.76 (2 s, 1H together). Anal.
(C.sub.28H.sub.25N.sub.7.0.7H.sub.2O) C, H, N.
EXAMPLE 21
2-[5-(3-Hydroxy-2-methyl-phenyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ol
[0248] ##STR70##
(a) Intermediate
21a--2-[5-Iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-yl]-1H-be-
nzoimidazol-4-ol
[0249] Aldehyde 7b' (2.66 g, 6.62 mmol), and 2,3-diaminophenol
(available from Aldrich Chemicals) (822 mg, 6.62 mmol) were
condensed in the presence of elemental sulfur analogous to the
synthesis of intermediate 7c', affording 21a (2.04 g, 61%) as a
yellow solid: R.sub.f=0.15 (25% ethyl acetate in hexanes); .sup.1H
NMR (DMSO-d.sub.6) [Some peaks are doubled due to tautomeric
isomerization] .delta. -0.13 (s, 9H), 0.82 (t, 2H, J=8.1 Hz), 3.59
(t, 2H, J=7.8 Hz), 5.85 (s, 2H), 6.59 (d, 1H, J=7.5 Hz), 7.01 (m,
2H), 7.71 (d, 1H, J=8.7 Hz), 7.81 (dd, 1H, J=8.8, 1.5 Hz), 8.90 and
9.04 (2 s, 1H together), 9.49 and 9.74 (2 s, 1H together), 12.69
and 12.96 (2 s, 1H together). Anal.
(C.sub.20H.sub.23IN.sub.4O.sub.2Si) C, H, N.
(b) Intermediate
21b--2-[5-(3-Methoxy-2-methyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-
-1H-indazol-3-yl]-1H-benzoimidazol-4-ol
[0250] Boronic ester 9c' (250 mg, 1.01 mmol) and iodide 21a (510.6
mg, 1.01 mmol) were coupled by the procedure analogous to
intermediate 9d' synthesis, affording 21 b (256.7 mg, 51%) as a
yellow foam: R.sub.f=0.22 (30% ethyl acetate in hexanes, co-spots
with 21a); .sup.1H NMR (DMSO-d.sub.6) [Some peaks are doubled due
to tautomeric isomerization] .delta. -0.11 (s, 9H), 0.85 (t, 2H,
J=8.1 Hz), 2.06 (s, 3H), 3.64 (t, 2H, J=7.7 Hz), 3.85 (s, 3H), 5.90
(s, 2H), 6.55 (dd, 1H, J=7.2, 1.1 Hz), 6.96 (m, 4H), 7.26 (t, 1H,
J=7.9 Hz), 7.46 (dd, 1H, J=8.7, 1.5 Hz), 7.87 (d, 1H, J=8.7 Hz),
8.40 and 8.55 (2 s, 1H together), 9.45 and 9.61 (2 s, 1H together),
12.62 and 12.91 (2 s, 1H together). Anal.
(C.sub.28H.sub.32N.sub.4O.sub.3Si.0.4H.sub.2O) C, H, N.
(c) Intermediate
21c--2-[5-(3-Methoxy-2-methyl-phenyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-
-ol
[0251] In an analogous manner to example 3, treatment of 21b (174.5
mg, 0.349 mmol) with tetrabutylammonium fluoride afforded 21c (59.8
mg, 46%) as an off-white solid: R.sub.f=0.26 (5% methanol in
dichloromethane); .sup.1H NMR (DMSO-d.sub.6) [Some peaks are
doubled due to tautomeric isomerization] .delta. 2.07 (s, 3H), 3.85
(s, 3H), 6.53 and 6.62 (2 d, 1H together, J=7.4, 7.7 Hz), 6.96 (m,
4H), 7.26 (t, 1H, J=7.9 Hz), 7.37 (d, 1H, J=8.5 Hz), 7.66 (d, 1H,
J=8.5 Hz), 8.35 and 8.49 (2 s, 1H together), 9.45 and 9.55 (2 s, 1H
together), 12.53 and 12.78 (2 s, 1H together), 13.57 and 13.62 (2
s, 1H together). HRMS calculated for C.sub.22H.sub.19N.sub.4O.sub.2
371.1508 (MH.sup.+), found 371.1523.
(d) Example
21--2-[5-(3-Hydroxy-2-methyl-phenyl)-1H-indazol-3-yl]-1H-benzoimidazol-4--
ol
[0252] By a procedure analogous to phenol 8' synthesis, treatment
of 21c (45.9 mg, 0.124 mmol) with pyridine hydrochloride afforded
21 (29.0 mg, 66%) as a tan powder: R.sub.f=0.28 (10% methanol in
dichloromethane); .sup.1H NMR (DMSO-d.sub.6) [Some peaks are
doubled due to tautomeric isomerization] .delta. 2.04 (s, 3H), 6.54
and 6.62 (dd and d, 1H together, J=7.2, 1.3 and 7.7 Hz), 6.75 (d,
1H, J=7.4 Hz), 6.85 (d, 1H, J=7.9 Hz) 7.01 (m, 3H), 7.37 and 7.38
(dd and dd, 1H together, J=8.5, 1.5 Hz for each), 7.65 and 7.66 (2
d, 1H together, J=8.7 Hz for each), 8.35 and 8.48 (2 s, 1H
together), 9.38 and 9.39 (2 s, 1H together), 9.46 and 9.56 (2 s, 1H
together), 12.52 and 12.77 (2 s, 1H together), 13.55 and 13.60 (2
s, 1H together). HRMS calculated for C.sub.21H.sub.17N.sub.4O.sub.2
357.1351 (MH.sup.+), found 357.1360. Anal.
(C.sub.21H.sub.16N.sub.4O.sub.2.0.8 CH.sub.3OH) C, H, N.
EXAMPLE 22
6-(3-Hydroxy-propyl)-2-methyl-3-[3-((E)-styryl)-1H-indazol-5-yl]-phenol
[0253] ##STR71## ##STR72##
(a) Intermediate 22a--3-Amino-2-methyl-phenol
[0254] A suspension of 2-methyl-3-nitro-phenol (Aldrich Chemicals)
(29.8 g, 194.6 mmol) and 10% palladium on carbon (3.01 g) in
ethanol (350 mL) was shaken under 40 psi hydrogen for 3.5 hours.
After filtration through a Celite pad, the solution was
concentrated and purified by silica gel chromatography (50% ethyl
acetate in hexanes) to give aniline 22a (20.32 g, 85%) as a
colorless solid: R.sub.f=0.50 (50% ethyl acetate/hexanes); .sup.1H
NMR (DMSO-d.sub.6) .delta. 1.87 (s, 3H), 4.63 (s, 2H), 6.08 (dd,
2H, J=7.9, 10.5 Hz), 6.64 (t, 1H, J=7.9 Hz), 8.76 (s, 1H). Anal.
(C.sub.7H.sub.9NO) C, H, N.
(b) Intermediate 22b--3-Iodo-2-methyl-phenol
[0255] 3-Amino-2-methyl-phenol 22a (18.35 g, 149 mmol) was
diazotized according to the method of DeGraw, et al. [DeGraw, J.
I.; Brown, V. H.; Colwell, W. T.; Morrison, N. E., J. Med. Chem.,
17, 762 (1974)]. After column chromatography (10-50% ethyl acetate
in hexanes), aryl iodide 22b (9.06 g, 26%) was isolated as an
orange solid. Further purification by recrystallization from
hexanes afforded 5.63 g pale orange needles: R.sub.f=0.35 (20%
ethyl acetate/hexanes); .sup.1H NMR (DMSO-d.sub.6) .delta. 2.22 (s,
3H), 6.80 (m, 2H), 7.24 (dd, 1H, J=7.5, 1.5 Hz), 9.75 (s, 1H).
(c) Intermediate 22c--1-Allyloxy-3-iodo-2-methyl-benzene
[0256] Allyl bromide (1.57 g, 13.0 mmol) was added to a solution of
3-iodo-2-methyl phenol (2.026 g, 8.66 mmol) in acetone (18 mL). The
solution was heated at reflux for 2 hours, then cooled to room
temperature, diluted with ethyl acetate (50 mL), and acidified with
1N aqueous hydrochloric acid until an aqueous of pH=2 was obtained.
The layers were separated, and the aqueous layer extracted with
ethyl acetate (2.times.10 mL). The combined organic extracts were
dried over magnesium sulfate, filtered, concentrated and purified
by silica gel chromatography (5% ethyl acetate in hexanes) to give
allyl ether 22c (2.1353 g, 90%) as a yellow oil: R.sub.f=0.60 (20%
ethyl acetate/hexanes); .sup.1H NMR (CDCl.sub.3) .delta. 2.40 (s,
3H), 4.53 (d of t, 2H, J=5.1, 1.5 Hz), 5.28 (d of q, 1H, J=10.6,
1.5 Hz), 5.42 (d of q, 1H, J=17.3, 1.5 Hz), 6.05 (m, 1H), 6.82 (m,
2H), 7.43 (dd, 1H, J=7.2, 1.9 Hz).
(d) Intermediate 22d--6-Allyl-3-iodo-2-methyl-phenol
[0257] Intermediate 22c (1.0954 g, 3.996 mmol) was heated in a
sealed tube in a 200.degree. C. oilbath for 2 hours. After cooling
and column chromatography, phenol 22d (767.2 mg, 70%) was obtained
as an amber oil: R.sub.f=0.31 (10% ethyl acetate/hexanes); .sup.1H
NMR (DMSO-d.sub.6) .delta. 2.30 (s, 3H), 3.28 (d, 2H, J=6.6 Hz),
5.02 (m, 2H), 5.90 (m, 1H), 6.66 (d, 1H, J=7.9 Hz), 7.26 (d, 1H,
J=8.1 Hz), 8.63 (s, 1H).
(e) Intermediate
22e--6-(3-Hydroxy-propyl)-3-iodo-2-methyl-phenol
[0258] Borane-dimethylsulfide complex (0.159 mL, 1.68 mmol borane)
was added dropwise to a chilled solution (0.degree. C.) of
intermediate 22d (459.8 mg, 1.677 mmol) in dry ether (5.0 mL). The
cooling bath was removed, and stirring continued for 1 hour.
Absolute ethanol (2.5 mL) was added, followed by aqueous sodium
hydroxide (2.5 N, 3.35 mL). The mixture was recooled to 0.degree.
C., and hydrogen peroxide added (30 wt % in H.sub.2O, 0.27 mL).
After stirring at 0.degree. C. for 15 minutes, the cooling bath was
removed, and the mixture was allowed to warm to room temperature
over 1 hour. The solution was partitioned between ether (50 mL) and
1N aqueous hydrochloric acid (final aqueous pH .about.2-3). The
organic layer was dried over magnesium sulfate, filtered, and
concentrated to an orange oil. Purification by silica gel
chromatography yielded alcohol 22e (353.1 mg, 72%) as a yellow oil
R.sub.f=0.11 (20% ethyl acetate/hexanes); .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.64 (quint, 2H, J=7.0 Hz), 2.29 (s, 3H),
2.54 (t, 2H, J=7.5 Hz) 3.39 (t, 2H, J=6.5 Hz), 4.54, (brs, 1H),
6.68 (d, 1H, J=8.1 Hz), 7.23 (d, 1H, J=8.1 Hz), 8.58 (s, 1H).
(f) Intermediate
22f--6-(3-Hydroxy-propyl)-2-methyl-3-[3-((E)-styryl)-1-(2-trimethylsilany-
l-ethoxymethyl)-1H-indazol-5-yl]-phenol
[0259] Aqueous sodium carbonate solution (2M, 1.79 mL) was added to
a degassed solution of boronic ester 16a (534.1 mg, 1.12 mmol),
aryl iodide 22e (209.1 mg, 0.716 mmol), and
1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (29 mg,
0.036 mmol) in DMF (3.2 mL). The mixture was heated in an
80.degree. C. oilbath for 1.5 hours, then cooled and partitioned
between ethyl acetate (50 mL) and water (10 mL). The organic layer
was dried over magnesium sulfate, filtered, and concentrated.
Purification by silica gel chromatography (20 to 50% ethyl acetate
in hexanes) afforded 22f (301.9 mg, 82%) as a yellow foam:
R.sub.f=0.07 (20% ethyl acetate/hexanes); .sup.1H NMR
(DMSO-d.sub.6) .delta. -0.09 (s, 9H), 0.83 (t, 2H, J=7.9 Hz), 1.73
(quint, 2H, J=7.5 Hz), 2.09 (s, 3H), 2.65 (t, 2H, J=7.5 Hz), 3.46
(t, 2H, J=6.5 Hz), 3.58 (t, 2H, J=8.0 Hz), 5.78 (s, 2H), 6.74 (d,
1H, J=7.7 Hz), 6.98 (d, 1H, J=7.9 Hz), 7.27 (m, 1H), 7.37 (m, 3H),
7.56 (m, 2H), 7.73 (m, 3H), 8.06 (s, 1H), 8.25 (br s, 1H). Anal.
(C.sub.31H.sub.38N.sub.2O.sub.3Si.0.5 CH.sub.2Cl.sub.2) C, H,
N.
(g) Intermediate
22--6-(3-Hydroxy-propyl)-2-methyl-3-[3-((E)-styryl)-1H-indazol-5-yl]-phen-
ol
[0260] 22 was prepared similar to example example 3, treatment of
intermediate 22f (202.9 mg, 0.394 mmol) with tetrabutylammonium
fluoride afforded 22 (34.3 mg, 23%) as a white powder: R.sub.f=0.19
(50% ethyl acetate/hexanes); .sup.1H NMR (DMSO-d.sub.6) .delta.
1.72 (quint, 2H, J=7.4 Hz) 2.10 (s, 3H), 2.64 (t, 2H, J=7.4 Hz),
3.45 (t, 2H, J=6.2 Hz), 4.59 (brs, 1H), 6.74 (d, 1H, J=7.7 Hz),
6.97 (d, 1H, J=7.7 Hz), 7.33 (m, 4H), 7.45 (m, 5H), 8.02 (s, 1H),
8.26 (s, 1H), 13.18 (s, 1H). Anal.
(C.sub.25H.sub.24N.sub.2O.sub.2.0.6H.sub.2O) C, H, N.
EXAMPLE 23
3-[3-(4-Hydroxymethyl-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-2-methyl-phe-
nol
[0261] ##STR73##
(a) Intermediate 23a--(2-Amino-3-nitro-phenyl)-methanol
[0262] 3-Nitroanthranilic acid [See Chapman, E. and Stephen, H. J.
Chem. Soc., 127, 1791, (1925) for the synthesis of this reagent]
(5.00 g, 27.45 mmol) was reduced with borane-dimethylsulfide
complex according to the method of Mikelson, et al. [Mickelson,
John W.; et al. J. Med. Chem.; 39; 4654 (1996)], affording benzyl
alcohol 23a (4.27 g, 93%) as an orange crystalline solid:
R.sub.f=0.22 (75% ethyl acetate in hexanes); .sup.1H NMR
(DMSO-d.sub.6) .delta. 4.50 (d, 2H, J=5.4 Hz), 5.43 (t, 1H, J=5.4
Hz), 6.65 (dd, 1H, J=8.7, 7.2 Hz), 7.10 (brs, 2H), 7.47 (d, 1H,
J=7.0 Hz), 7.94 (dd, 1H, J=8.8, 1.5 Hz). Anal.
(C.sub.7H.sub.8N.sub.2O.sub.3) C, H, N.
(b) Intermediate 23b--(2,3-Diamino-phenyl)-methanol
[0263] In a manner analogous to the synthesis of 9a', intermediate
23a (3.16 g, 18.8 mmol) was hydrogenated in ethanol (300 mL) to
give 23b (2.23 g, 86%) as a yellow-brown solid. Further
purification by recrystalization from ethanol gave 23b (1.04 g,
40%) as yellow needles: R.sub.f=0.17 (75% ethyl acetate in
hexanes); .sup.1H NMR (DMSO-d.sub.6) .delta. 4.36 (br s, 6H), 4.90
(br s, 1H), 6.42 (m, 3H). Anal. (C.sub.7H.sub.10N.sub.2O) C, H,
N.
(c) Intermediate
23c--{2-[5-Iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-yl]-1H-b-
enzoimidazol-4-yl}-methanol
[0264] 23c was prepared similar to 7c' synthesis. Condensation of
diamine 23b (587.3 mg, 4.25 mmol) with aldehyde 7b' (1.71 g, 4.25
mmol) in the presence of elemental sulfur afforded 23c (1.57 g,
71%) as a yellow solid: .sup.1H NMR (DMSO-d.sub.6) [Some peaks are
doubled due to tautomeric isomerization] .delta. -0.13 (s, 9H),
0.82 (t, 2H, J=7.7 Hz), 3.58 (t, 2H, J=7.9 Hz), 4.87 (br s, 1H),
5.04 (br s, 1H), 5.22 (br s, 1H), 5.87 (s, 2H), 7.26 (m, 2H), 7.39
and 7.67 (m and br s, 1H together), 7.75 (d, 1H, J=8.7 Hz), 7.83
(dd, 1H, J=8.8, 1.5 Hz), 8.95 (d, 1H, J=1.1 Hz), 12.97 and 13.13 (2
s, 1H together). Anal. (C.sub.21H.sub.25IN.sub.4O.sub.2Si) C, H, I,
N.
(d) Intermediate
23d--2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol
[0265] By a synthetic method analogous to 9c' synthesis, iodide 22b
(1.21 g, 5.17 mmol) was converted to boronic ester 23d (1.159,
95%), a white, crystalline solid: R.sub.f=0.18 (10% ethyl acetate
in hexanes); .sup.1H NMR (CDCl.sub.3) .delta. 1.35 (s, 12H), 2.46
(s, 3H), 6.87 (dd, 1H, J=7.9, 1.0 Hz), 7.08 (t, 1H, J=7.5 Hz), 7.35
(dd, 1H, J=7.4, 1.1 Hz). Anal.
(C.sub.13H.sub.19BO.sub.3.0.2H.sub.2O) C, H.
(e) Intermediate
23e--3-[3-(4-Hydroxymethyl-1H-benzoimidazol-2-yl)-1H-2-trimethylsilanyl-e-
thoxymethyl)-1H-indazol-5-yl]-2-methyl-phenol
[0266] 23e was prepared similar to 9d' synthesis. Iodide 23c (276.3
mg, 0.514 mmol) and boronic ester 23d (300 mg, 1.28 mmol) were
coupled to give 23e (128.2 mg, 50%) as a yellow solid: R.sub.f=0.16
(40% ethyl acetate in hexanes); .sup.1H NMR (DMSO-d.sub.6) [Some
peaks are doubled due to tautomeric isomerization] .delta. -0.11
(s, 9H), 0.85 (t, 2H, J=7.9 Hz), 2.03 and 2.07 (2 s, 3H together),
3.63 (t, 2H, J=7.7 Hz), 4.87 and 4.97 (2 d, 2H together, J=5.8 and
5.5 Hz), 5.11 and 5.25 (2 t, 1H together, J=5.6 and 6.1 Hz), 5.92
and 5.93 (2 s, 2H together), 6.76 (dd, 1H, J=7.5, 3.4 Hz), 6.86 (d,
1H, J=7.9 Hz), 7.17 (m, 3H), 7.39 and 7.60 (dd and d, 1H together,
J=6.8, 2.1 and 7.9 Hz), 7.49 (d, 1H, J=8.7 Hz), 7.89 (d, 1H, J=8.9
Hz), 8.44 and 8.47 (2 s, 1H together), 9.46 and 9.48 (2 s, 1H
together), 12.91 and 13.09 (2 s, 1H together). Anal.
(C.sub.28H.sub.32N.sub.4O.sub.3Si.0.3H.sub.2O) C, H, N.
(f) Example
23--3-[3-(4-Hydroxymethyl-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-2-methy-
l-phenol
[0267] 23 was prepared similar to example 3. Treatment of 23e
(130.7 mg, 0.261 mmol) with tetrabutylammonium fluoride afforded 23
(61.6 mg, 64%) as a white solid: R.sub.f=0.22 (70% ethyl acetate in
hexanes); .sup.1H NMR (DMSO-d.sub.6) [Some peaks are doubled due to
tautomeric isomerization] .delta. 2.04 and 2.07 (2 s, 3H together),
4.86 and 4.97 (2 d, 2H together, J=6.0 and 5.7 Hz), 5.10 and 5.23
(2 t, 1H together, J=5.6 and 6.0 Hz), 6.76 (d, 1H, J=7.2 Hz), 6.85
(d, 1H, J=8.1 Hz), 7.14 (m, 3H), 7.37 and 7.58 (dd and d, 1H
together, J=7.2, 1.9 and 7.7 Hz), 7.40 (dd, 1H, J=8.5, 1.5 Hz),
7.67 (d, 1H, J=8.1 Hz), 8.39 and 8.42 (2 s, 1H together), 9.43 and
9.45 (2 s, 1H together), 12.81 and 12.96 (2 s, 1H together), 13.65
and 13.70 (2 s, 1H together). Anal.
(C.sub.224H.sub.18N.sub.4O.sub.2.1.0CH.sub.3OH) C, H, N.
EXAMPLE 24
7-[3-((E)-Styryl)-1H-indazol-5-yl]-isoquinoline
[0268] ##STR74##
(a) Intermediate 24a--1,1,1-Trifluoro-methanesulfonic acid
isoquinolin-7-yl ester
[0269] Trifluoromethanesulfonic anhydride (4.54 g, 16.10 mmol) was
added dropwise to a chilled (0.degree. C.) mixture of
7-hydroxyisoquinoline (1.9477 g, 13.24 mmol, Lancaster Chemicals)
in pyridine (14 mL). Stirring was continued at 0.degree. C. for 1
hour, then at room temperature for 24 hours. The solution was
partitioned between dichloromethane and saturated aqueous sodium
bicarbonate solution. The organic layer was dried over magnesium
sulfate, filtered, concentrated, and purified by silica gel
chromatography (50% ethyl acetate in hexanes) to give triflate 24a
(3.27 g, 88%) as a pale yellow oil: R.sub.f=0.23 (50% ethyl
acetate/hexanes); .sup.1H NMR (DMSO-d.sub.6) .delta. 7.72 (dd, 1H,
J=9.0, 2.5 Hz), 7.80 (d, 1H, J=5.8 Hz), 8.06 (d, 1H, J=9.0 Hz),
8.23 (d, 1H, J=2.5 Hz), 8.55 (d, 1H, J=5.7 Hz), 9.39 (s, 1H).
.sup.13C NMR (DMSO-d.sub.6) .delta. 118.33 (q, J=320 Hz), 119.35,
119.99, 124.17, 128.03, 129.9, 134.31, 144.09, 147.02, 152.46.
Anal. (C.sub.10H.sub.6F.sub.3NO.sub.3S.0.1H.sub.2O) C, H, N, S.
(b) Intermediate
24b--7-[3-((E)-Styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-y-
l]-isoquinoline
[0270] Isoquinoline triflate 24a (150 mg, 0.540 mmol) was added to
a degassed solution of boronic ester 16a (282.9 mg, 0.594 mmol),
powdered potassium phosphate (344 mg, 1.62 mmol),
1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (13 mg,
0.016 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (9 mg, 0.016
mmol) in 1,4-dioxane (10 mL). The mixture was heated in an
80.degree. C. oilbath for 6 hours, then cooled and partitioned
between ethyl acetate (50 mL) and saturated aqueous sodium chloride
solution (25 mL). The organic layer was dried over magnesium
sulfate, filtered, and concentrated. Purification by silica gel
chromatography (10 to 75% ethyl acetate in hexanes) afforded 24b
(92.7 mg, 36%) as a fluorescent pink gel: R.sub.f=0.06 (20% ethyl
acetate/hexanes); .sup.1H NMR (CDCl.sub.3) .delta. -0.04 (s, 9H),
0.94 (t, 2H, J=8.4 Hz), 3.64 (t, 2H, J=8.1 Hz), 5.79 (s, 2H),
7.30-8.09 (m, 14H), 8.26 (d, 2H, J=12.9 Hz).
(c) Example 24--7-[3-((E)-Styryl)-1H-indazol-5-yl]-isoquinoline
[0271] Similar to example 3, treatment of intermediate 24b (86 mg,
0.18 mmol) with tetrabutylammonium fluoride afforded 24 (27.2 mg,
43%) as a white solid: R.sub.f=0.11 (70% ethyl acetate in hexanes);
.sup.1H NMR (DMSO-d.sub.6) .delta. 7.29 (t, 1H, J=7.2 Hz), 7.41 (t,
2H, J=7.2 Hz), 7.66 (m, 5H), 7.88 (t, 2H, J=5.7 Hz), 8.09 (d, 1H,
J=8.7 Hz), 8.29 (dd, 1H, J=8.4, 1.8 Hz), 8.51 (m, 3H), 9.41 (s,
1H), 13.28 (s, 1H). Anal. (C.sub.24H.sub.17N.sub.3.0.6 CH.sub.2OH)
C, H, N.
EXAMPLE 25
4-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinoline
[0272] ##STR75##
(a) Intermediate
25a--3-(1H-Benzoimidazol-2-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborola-
n-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole
[0273] By a procedure analogous to boronic ester 19e synthesis,
iodide 7c' (2.36 g, 4.81 mmol) was converted to boronic ester 25a
(1.43 g, 61%), a white, crystalline solid: .sup.1H NMR
(DMSO-d.sub.6) .delta. -0.13 (s, 9H), 0.82 (t, 2H, J=7.7 Hz), 1.35
(s, 12H), 3.59 (t, 2H, J=7.9 Hz), 5.89 (s, 2H), 7.24 (m, 2H), 7.53
(m, 1H), 7.83 (m, 3H), 8.95 (s, 1H), 13.15 (s, 1H). Anal.
(C.sub.26H.sub.35BN.sub.4O.sub.3Si) C, H, N.
(b) Intermediate
25b--4-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H--
indazol-5-yl]-isoquinoline
[0274] By a procedure analogous to 19f synthesis,
4-bromoisoquinoline (238 mg, 1.14 mmol) was coupled with boronic
ester 25a (280.4 mg, 0.572 mmol) to give 25b (237.5 mg, 84%) as a
white solid: R.sub.f=0.20 (50% ethyl acetate in hexanes); .sup.1H
NMR (DMSO-d.sub.6) .delta. -0.07 (s, 9H), 0.86 (m, 2H), 3.67 (t,
2H, J=7.9 Hz), 5.98 (s, 2H), 7.20 (br m, 2H), 7.55 (br m, 1H), 7.65
(br m, 1H), 7.71 (m, 4H), 8.07 (d, 1H, J=8.7 Hz), 8.27 (dd, 1H,
J=7.2, 1.7 Hz), 8.56 (s, 1H), 8.66 (d, 1H, J=0.8 Hz), 9.41 (s, 1H),
13.17 (s, 1H).
(c) Example
25--4-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinoline
[0275] 25 was prepared similar to example 3. Intermediate 25b
(152.4 mg, 0.310 mmol) was treated with tetrabutylammonium fluoride
to give 25 (61.9 mg, 55%) as a white foam: R.sub.f=0.16 (70% ethyl
acetate in hexanes); .sup.1H NMR (DMSO-d.sub.6) .delta. 7.18 (br m,
2H), 7.56 (br m, 2H), 7.63 (dd, 1H, J=8.5, 1.7 Hz), 7.81 (m, 4H),
8.27 (dd, 1H, J=7.4, 1.2 Hz), 8.55 (s, 1H), 8.62 (s, 1H), 9.40 (s,
1H), 13.05 (brs, 1H), 13.84 (s, 1H).
EXAMPLE 26
3-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-6-(3-hydroxy-propyl)-2-methy-
l-phenol
[0276] ##STR76##
(a) Intermediate
26a--3-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H--
indazol-5-yl]-6-(3-hydroxy-propyl)-2-methyl-phenol
[0277] By a procedure analogous to the synthesis of 25b, boronic
ester 25a (303 mg, 0.618 mmol) was coupled with iodide 22e (180.5
mg, 0.618 mmol), affording 26a (124.4 mg, 38%) as a white solid:
R.sub.f=0.30 (50% ethyl acetate in hexanes); .sup.1H NMR
(DMSO-d.sub.6) .delta. -0.11 (s, 9H), 0.85 (t, 2H, J=7.9 Hz), 1.74
(quint, 2H, J=7.0 Hz), 2.08 (s, 3H), 2.66 (t, 2H, J=7.7 Hz), 3.47
(q, 2H, J=5.3 Hz), 3.63 (t, 2H, J=7.9 Hz), 4.60 (t, 1H, J=5.0 Hz),
5.91 (s, 2H), 6.75 (d, 1H, J=7.7 Hz), 7.01 (d, 1H, J=7.7 Hz), 7.20
(quint, 2H, J=8.1 Hz), 7.49 (m, 2H), 7.71 (d, 1H J=7.7 Hz), 7.88
(d, 1H, J=8.7 Hz), 8.33 (s, 1H), 8.42 (s, 1H), 13.11 (s, 1H). Anal.
(C.sub.30H.sub.36N.sub.4O.sub.3Si.0.6 ethyl acetate) C, H, N.
(b) Example
26--3-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-6-(3-hydroxy-propyl)-2--
methyl-phenol
[0278] By a procedure analogous to example 3, deprotection of 26a
(99.4 mg, 0.188 mmol) with tetrabutylammonium fluoride afforded 26
(26.9 mg, 36%) as a white solid: R.sub.f=0.19 (70% ethyl acetate in
hexanes); .sup.1H NMR (DMSO-d.sub.6) .delta. 1.74 (quint, 2H, J=7.4
Hz), 2.08 (s, 3H), 2.66 (t, 2H, J=7.4 Hz), 3.47 (q, 2H, J=5.1 Hz),
4.59 (t, 1H, J=5.1 Hz), 6.74 (d, 1H, J=7.7 Hz), 7.00 (d, 1H, J=7.7
Hz), 7.19 (quint, 2H, J=7.9 Hz), 7.38 (dd, 1H J=8.5, 1.5 Hz), 7.50
(d, 1H, J=7.4 Hz), 7.67 (m, 2H), 8.30 (s, 1H), 8.37 (s, 1H), 12.96
(s, 1H), 13.66 (s, 1H). Anal. (C.sub.24H.sub.22N.sub.4O.sub.2.0.4
ethyl acetate) C, H, N.
EXAMPLE 27
1-[3-((E)-Styryl)-1H-indazol-5-yl]-piperidin-4-ol
[0279] ##STR77##
(a) Intermediate
27a--4-(tert-Butyl-dimethyl-silanyloxy)-piperidine
[0280] Imidazole (4.18 g, 61.4 mmol), 4-hydroxypiperidine (2.07 g,
20.46 mmol), and tert-butyldimethylsilyl chloride (4.63 g, 30.7
mmol) were dissolved in dichloromethane (50 mL) and stirred at
23.degree. C. for 4 hours. The mixture was then washed with
saturated aqueous sodium bicarbonate solution (3.times.50 mL) and
water (50 mL), dried over magnesium sulfate, filtered, and
concentrated under high vacuum to give 27a (2.60 g, 59%) as a
yellow oil which crystallizes on standing.: .sup.1H NMR
(CDCl.sub.3) .delta. 0.05 (s, 6H), 0.90 (s, 9H), 1.46 (m, 2H), 1.81
(m, 2H), 2.71 (m, 2H), 3.09 (m, 3H), 3.77 (septet, 1H, J=3.9 Hz),
Anal. (C.sub.11H.sub.25NOSi.0.2CH.sub.2Cl.sub.2) C, H, N.
(b) Intermediate
27b--5-{4-[(Dimethyl-ethyl)-dimethyl-silanyloxy]-piperidin-1-yl}-3-((E)-s-
tyryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole
[0281] Sodium tert-butoxide (163 mg, 1.70 mmol),
tris(dibenzylidineacetone)-dipalladium(0) (26 mg, 0.03 mmol), and
CyMAP-1 (See Old et. al., J. Am. Chem. Soc., 120, 9722 (1998) for
the structure of this ligand) (33 mg, 0.085 mmol) were added to a
degassed solution of 27a (241.1 mg, 1.12 mmol) and iodide 7a'
(269.3 mg, 0.565 mmol), in ethylene glycol dimethyl ether (DME, 2.0
mL). The mixture was heated in an 80.degree. C. oilbath for 17
hours. After cooling to room temperature, the mixture was diluted
with ethyl acetate (50 mL) and filtered to remove the black
precipitate. The filtrate was washed with water (10 mL) and
saturated aqueous sodium chloride (10 mL), dried over magnesium
sulfate, filtered, concentrated, and purified by silica gel
chromatography (10 to 50% ethyl acetate in hexanes) to give 27b
(177.7 mg, 56%) as an orange oil: R.sub.f=0.28 (20% ethyl acetate
in hexanes); .sup.1H NMR (CDCl.sub.3) .delta. -0.06 (s, 9H), 0.09
(s, 6H), 0.90 (m, 2H), 0.92 (s, 9H), 1.80 (m, 2H), 1.97 (m, 2H),
3.07 (m, 2H), 3.44 (m, 2H), 3.58 (t, 2H, J=8.4 Hz), 3.92 (m, 1H),
5.69 (s, 2H), 7.29 (m, 2H), 7.41 (m, 6H), 7.61 (d, 2H, J=8.7
Hz).
(c) Example
27--1-[3-((E)-Styryl)-1H-indazol-5-yl]-piperidin-4-ol
[0282] By a procedure analogous to example 3, treatment of
intermediate 27b (121.4 mg, 0.22 mmol) with tetrabutylammonium
fluoride afforded 27 (33.1 mg, 47%) as a yellow foam: R.sub.f=0.15
(70% ethyl acetate/hexanes); .sup.1H NMR (DMSO-d.sub.6) .delta.
1.55 (m, 2H), 1.86 (m, 2H), 2.83 (m, 2H), 3.47 (m, 2H), 3.61 (m,
1H), 4.68 (d, 1H, J=4.2 Hz), 7.22 (m, 2H), 7.37 (m, 5H), 7.55 (d,
1H, J=16.5 Hz), 7.69 (d, 2H, J=7.2 Hz), 12.89 (s, 1H). Anal.
(C.sub.20H.sub.21N.sub.3O.0.4H.sub.2O.0.4 ethyl acetate) C, H,
N.
EXAMPLE 28
1-[3-((E)-Styryl)-1H-indazol-5-yl]-piperidin-3-ol
[0283] ##STR78##
(a) Intermediate
28a--3-(tert-Butyl-dimethyl-silanyloxy)-piperidine
[0284] By a procedure analogous to the synthesis of 27a,
3-hydroxypiperidine hydrochloride (2.76 g, 20.06 mmol) was
converted to 28a (2.92 g, 68%), a yellow oil which crystallizes on
standing.: .sup.1H NMR (CDCl.sub.3) .delta. 0.05 (s, 6H), 0.89 (s,
9H), 1.46 (m, 2H), 1.77 (m, 2H), 2.39 (br s, 1H), 2.61 (m, 2H),
2.82 (m, 1H), 2.97 (dd, 1H, J=12.3, 2.7 Hz), 3.66 (septet, 1H,
J=3.6 Hz). Anal. (C.sub.11H.sub.25NOSi.0.2 CH.sub.2Cl.sub.2) C, H,
N.
(b) Intermediate
28b--5-{3-[(Dimethyl-ethyl)-dimethyl-silanyloxy]-piperidin-1-yl}-3-((E)-s-
tyryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole
[0285] 28b was prepared by a procedure analogous to 27b synthesis.
Intermediates 7a' (269.3 mg, 0.565 mmol) and 28a (244 mg, 1.13
mmol) were used to form 28b (212.0 mg, 66%) as a brown oil:
R.sub.f=0.17 (10% ethyl acetate in hexanes); .sup.1H NMR
(CDCl.sub.3) .delta. -0.05 (s, 9H), 0.09 (s, 6H), 0.92 (m, 2H),
0.96 (s, 9H), 1.44 (m, 1H), 1.65-2.05 (m, 3H), 2.69 (m, 2H), 3.56
(m, 4H), 3.92 (m, 1H), 5.70 (s, 2H), 7.25 (m, 2H), 7.40 (m, 6H),
7.60 (d, 2H, J=8.4 Hz). Anal.
(C.sub.32H.sub.49N.sub.3O.sub.2Si.sub.2.0.6H.sub.2O) C, H, N.
(c) Example
28--1-[3-((E)-Styryl)-1H-indazol-5-yl]-piperidin-3-ol
[0286] By a procedure analogous to example 3, treatment of
intermediate 28b (181.5 mg, 0.322 mmol) with tetrabutylammonium
fluoride afforded 28 (47.6 mg, 46%) as a yellow foam: R.sub.f=0.19
(70% ethyl acetate/hexanes); .sup.1H NMR (DMSO-d.sub.6) .delta.
1.34 (m, 1H), 1.70 (m, 1H), 1.95 (m, 2H), 2.55 (m, 1H), 2.72 (m
1H), 3.46 (m, 1H), 3.63 (m, 1H), 3.74 (m, 1H), 4.88 (d, 1H, J=4.5
Hz), 7.24 (dd, 1H, J=9.0, 1.8 Hz), 7.33 (t, 1H, J=7.2 Hz), 7.42 (m,
5H), 7.63 (d, 1H, J=16.5 Hz), 7.76 (d, 2H, J=7.2 Hz), 12.97 (s,
1H). Anal. (C.sub.20H.sub.21N.sub.3O.0.3H.sub.2O) C, H, N.
EXAMPLE 29
[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-yl]-methanol
[0287] ##STR79##
(a) Intermediate
29a--{2-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethyls-
ilanyl-ethoxymethyl)-1H-indazol-3-yl]-1H-benzoimidazol-4-yl}-methanol
[0288] By a procedure-similar to the synthesis of boronic ester
19e, iodide 23c (512.8 mg, 0.985 mmol) was converted to boronic
ester 29a (312.0 mg, 61%), a white foam: R.sub.f=0.28 (5% methanol
in dichloromethane); .sup.1H NMR (DMSO-d.sub.6) [Some peaks are
doubled due to tautomeric isomerization] .delta. -0.13 (s, 9H),
0.83 (t, 2H, J=7.7 Hz), 1.35 (s, 12H), 3.60 (t, 2H, J=8.1 Hz), 4.87
(br s, 1H), 5.06 (br s, 1H), 5.24 (m, 1H), 5.90 (s, 2H), 7.26 (m,
2H), 7.40 and 7.71 (2 d, 1H together, J=7.2 and 7.9 Hz), 7.82 (m,
2H), 8.95 (s, 1H), 12.93 and 13.10 (2 s, 1H together). Anal.
(C.sub.27H.sub.37BN.sub.4O.sub.4Si.0.5H.sub.2O) C, H, N.
(b) Intermediate
29b--{2-[5-Isoquinolin-4-yl-1-(2-trimethylsilanyl-ethoxy-methyl)-1H-indaz-
ol-3-yl]-1H-benzoimidazol-4-yl}-methanol
[0289] By a procedure similar to the synthesis of 19f,
4-bromoisoquinoline (193 mg, 0.927 mmol) was coupled with boronic
ester 29a (241.2 mg, 0.463 mmol) to give 29b (171.1 mg, 71%) as a
white foam: R.sub.f=0.22 (75% ethyl acetate in hexanes); .sup.1H
NMR (DMSO-d.sub.6) [Some peaks are doubled due to tautomeric
isomerization] .delta. -0.08 (s, 9H), 0.88 (t, 2H, J=7.7 Hz), 3.68
(t, 2H, J=7.9 Hz), 4.88 (d, 2H, J=5.3 Hz), 5.05 and 5.25 (2 br s,
1H together), 5.98 (s, 2H), 7.22 (m, 2H), 7.40 and 7.57 (2m, 1H
together), 7.77 (m, 4H), 8.07 (d, 1H, J=8.5 Hz), 8.27 (dd, 1H, J
7.2, 1.5 Hz), 8.57 (s, 1H), 8.70 (br s, 1H), 9.41 (s, 1H), 12.97
and 13.14 (2 s, 1H together). Anal.
(C.sub.30H.sub.31N.sub.5O.sub.2Si.0.4H.sub.2O) C, H, N.
(c) Example
29--[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-yl]-methan-
ol
[0290] 29 was prepared similar to example 3. Treatment of
intermediate 29b (129.0 mg, 0.247 mmol) with tetrabutylammonium
fluoride afforded 29 (58.3 mg, 60%) as a white powder: .sup.1H NMR
(DMSO-d.sub.6) [Some peaks are doubled due to tautomeric
isomerization] .delta. 4.88 (t, 2H, J=6.2 Hz), 5.03 and 5.23 (2 t,
1H together, J=5.6 and 6.2 Hz), 7.20 (m, 2H), 7.38 and 7.53 (m and
d, 1H together, J=7.4 Hz for the doublet), 7.63 (dd, 1H, J=8.7, 1.3
Hz), 7.82 (m, 4H), 8.27 (d, 1H, J=7.4 Hz), 8.55 (s, 1H), 8.63 and
8.66 (2 s, 1H together), 9.40 (s, 1H), 12.87 and 13.02 (2 s, 1H
together), 13.81 and 13.86 (2 s, 1H together). Anal.
(C.sub.24H.sub.17N.sub.5O.0.4H.sub.2O.0.3CH.sub.2Cl.sub.2) C, H,
N.
EXAMPLE 30
2-[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-yl]-ethanol
[0291] ##STR80##
(a) Intermediate
30a--2-{2-[5-Isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-be-
nzoimidazol-4-yl}-ethanol
[0292] A suspension of 10% palladium on carbon (66 mg) and
2-(2-amino-3-nitrophenyl)ethanol [See Seno, Kaoru; Hagishita,
Sanji; Sato, Tomohiro; Kuriyama, Kaoru; J. Chem. Soc. Perkin Trans.
1; 2012 (1984) for the synthesis of this reagent] (531.5 mg, 2.92
mmol) in absolute ethanol (50 mL) was shaken under 40 psi hydrogen
for 3 hours. After filtration and concentration, crude
2-(2,3-diaminophenyl)ethanol (474.4 mg) was obtained as a red oil,
which crystallized on standing: R.sub.f=0.08 (75% ethyl acetate in
hexanes); .sup.1H NMR (DMSO-d.sub.6) .delta. 2.58 (t, 2H, J=6.9
Hz), 3.53 (t, 2H, J=7.2 Hz), 4.32 (br s, 5H), 6.29 (m, 2H), 6.40
(dd, 1H, J=6.9, 2.1 Hz).
[0293] Without further purification, this crude diamine was
condensed with aldehyde 19f (1.10 g, 2.81 mmol) in the presence of
sulfur, similar to the synthesis of intermediate 7c', affording 30a
(930.8 mg, 63%) as a yellow foam: R.sub.f=0.19 (ethyl acetate);
.sup.1H NMR (DMSO-d.sub.6) [Some peaks are doubled due to
tautomeric isomerization] .delta. 3.10 (m, 2H), 3.71 (s, 3H), 3.74
(m, 2H), 4.66 and 4.80 (2 br s, 1H together), 5.82 (s, 2H), 6.93
(d, 2H, J=8.7 Hz), 7.05 (m, 2H), 7.39 (m, 3H), 7.65 (d, 1H, J=9.2
Hz), 7.81 (m, 3H), 8.00 (m, 1H), 8.26 (dd, 1H, J=7.2, 2.1 Hz), 8.54
(s, 1H), 8.65 (s, 1H), 9.39 (s, 1H), 12.96 and 13.02 (2 s, 1H
together).
(b) Example
30--2-[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-yl]-etha-
nol
[0294] Intermediate 30a (169.1 mg, 0.322 mmol) was deprotected by a
synthetic method analogous to example 19, affording 30 (28.2 mg,
22%) as a white powder: R.sub.f=0.33 (ethyl acetate); .sup.1H NMR
(DMSO-d.sub.6) [Some peaks are doubled due to tautomeric
isomerization] .delta. 3.11 (m, 2H), 3.73 (m, 2H), 4.68 and 4.85 (2
t, 1H together, J=5.2 and 5.5 Hz), 7.04 (m, 2H), 7.35 and 7.47 (2
d, 1H together, J=7.9 and 7.2 Hz), 7.63 (d, 1H, J=8.7 Hz), 7.83 (m,
4H), 8.26 (d, 1H, J=7.5), 8.55 (s, 1H), 8.63 (s, 1H), 9.39 (s, 1H),
12.97 and 13.01 (2 s, 1H together), 13.86 and 13.87 (2 s, 1H
together). Anal. (C.sub.25H.sub.19N.sub.5O.0.3H.sub.2O.0.4 ethyl
acetate-0.06 S) C, H, N.
EXAMPLE 31
[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]-dimet-
hyl-amine
[0295] ##STR81##
(a) Intermediate
31a--{2-[5-Isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benz-
oimidazol-4-yl}-methanol
[0296] By a synthesis similar to the synthesis of 19h, aldehyde 19f
(3.67 g, 9.33 mmol) and diamine 23b (1.29 g, 9.33 mmol) were
condensed in the presence of sulfur to give 31a (2.60 g, 54%) as a
yellow solid: R.sub.f=0.19 (75% ethyl acetate in hexanes); .sup.1H
NMR (DMSO-d.sub.6) [Some peaks are doubled due to tautomeric
isomerization] .delta. 3.71 (s, 3H), 4.88 (d, 2H, J=5.5 Hz), 5.04
and 5.25 (2 t, 1H together, J=5.6 and 6.1 Hz), 5.81 and 5.83 (2 s,
2H together), 6.93 (d, 2H, J=8.5 Hz), 7.21 (m, 2H), 7.38 and 7.54
(2 d, 3H together, J=7.4 and 7.5 Hz), 7.66 (d, 1H, J=8.7 Hz), 7.77
(m, 3H), 8.01 (dd, 1H, J=8.7, 4.0 Hz), 8.26 (d, 1H, J=7.7 Hz), 8.54
and 8.55(2 s, 1H together), 8.65 and 8.68 (2 s, 1H together), 9.39
(s, 1H), 12.88 and 13.05 (2 s, 1H together). Anal.
(C.sub.32H.sub.25N.sub.5O.sub.2.0.3H.sub.2O) C, H, N.
(b) Intermediate 31
b--{2-[5-Isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benzoi-
midazol-4-ylmethyl}-dimethyl-amine
[0297] Methane sulfonyl chloride (119.3 mg, 1.04 mmol) was added
dropwise to a solution of 31a (527.5 mg, 1.03 mmol) and
diisopropylethyl amine (153.3 mg, 1.19 mmol) in tetrahydrofuran
(12.0 mL), cooled to 0.degree. C. in an icebath. After stirring at
0.degree. C. for 2.5 hours, the reaction flask was fitted with a
dry ice-cooled cold finger condenser, and dimethyl amine gas was
condensed into the reaction solution until the volume had increased
by about 5 mL. Stirring was continued at 0.degree. C. for 4 hours,
then at room temperature for 15 hours. The mixture was partitioned
between ethyl acetate (100 mL) and saturated aqueous sodium
bicarbonate solution (20 mL). The organic extracts were dried over
magnesium sulfate, filtered, concentrated, and columned (silica
gel, 5 to 10% methanol in dichloromethane), affording 31b (250.2
mg, 45%) as a pale yellow solid: R.sub.f=0.26 (10% methanol in
dichloromethane); .sup.1H NMR (DMSO-d.sub.6) .delta. 2.20 (s, 6H),
3.71 (s, 3H), 3.84 (s, 2H), 5.83 (s, 2H), 6.93 (d, 2H, J=8.7 Hz),
7.14 (m, 2H), 7.36 (d, 2H, J=8.5 Hz), 7.48 (m, 1H), 7.67 (d, 1H,
J=8.9 Hz), 7.77 (quintet, 2H, J=6.4 Hz), 7.89 (m, 1H), 8.00 (d, 1H,
J=8.9 Hz), 8.26 (d, 1H, J=7.5 Hz), 8.55 (s, 1H), 8.71 (s, 1H), 9.39
(s, 1H), 13.03 (br s, 1H). Anal.
(C.sub.34H.sub.30N.sub.6O.1.1H.sub.2O) C, H, N.
(c) Example
31--[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]--
dimethyl-amine
[0298] A mixture of 31b (125.7 mg, 0.233 mmol), anisole (252 mg,
2.33 mmol), trifluoroacetic acid (2.3 mL), and concentrated
sulfuric acid (0.2 mL) was stirred at room temperature for 66
hours, then added dropwise to a rapidly stirred mixture of
saturated aqueous sodium bicarbonate (75 mL) and ethyl acetate (25
mL). The layers were separated and the aqueous layer extracted with
ethyl acetate (2.times.50 mL). The combined organic layers were
dried over magnesium sulfate, filtered, concentrated, and purified
by silica gel chromatography (25 to 40% methanol in
dichloromethane) to give 31 (35.8 mg, 37%) as a white powder:
R.sub.f=0.09 (10% methanol in dichloromethane); .sup.1H NMR
(DMSO-d.sub.6) [Some peaks are doubled due to tautomeric
isomerization] .delta. 2.15 and 2.21 (2 br s, 6H together), 3.80
(s, 2H), 7.12 (br s, 2H), 7.40 and 7.54 (2 m, 1H together), 7.64
(d, 1H, J=9.0 Hz), 7.83 (m, 4H), 8.26 (d, 1H, J=7.5 Hz), 8.55 (s,
1H), 8.63 and 8.73 (2 br s, 1H together), 9.39 (s, 1H), 13.02 (br
s, 1H), 13.83 (br s, 1H). Anal.
(C.sub.26H.sub.22N.sub.6.0.7H.sub.2O.1.0CH.sub.3OH) C, H, N.
EXAMPLE 32
[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]-methy-
l-amine
[0299] ##STR82##
(a) Intermediate
32a--{2-[5-Isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benz-
oimidazol-4-ylmethyl}-methyl-amine
[0300] By a procedure similar to the synthesis of 31b, alcohol 31a
(516.6 mg, 1.01 mmol) was treated with methanesulfonyl chloride and
diisopropylethyl amine at 0.degree. C. for 1 hour. Instead of
condensed gas, however, a solution of methylamine in
tetrahydrofuran (2.0 M, 5.0 mL) was then added, and stirring
continued at room temperature for 15 hours. Extractive workup and
silica gel chromatography similar to 31 b afforded mono-methyl
analog 32a (170.5 mg, 32%) as an off-white solid: R.sub.f=0.16
(1:20:300 concentrated aqueous NH.sub.4OH:ethanol:dichloromethane);
.sup.1H NMR (DMSO-d.sub.6) .delta. 2.26 (s, 3H), 3.71 (s, 3H), 4.03
(s, 2H), 5.82 (s, 2H), 6.93 (d, 2H, J=8.7 Hz), 7.14 (d, 2H, J=4.7
Hz), 7.37 (d, 2H, J=8.7 Hz), 7.46 (m, 1H), 7.67 (dd, 1H, J=8.7, 1.3
Hz), 7.77 (m, 2H), 7.89 (d, 1H, J=7.7 Hz), 8.01 (d, 1H, J=8.5 Hz),
8.25 (dd, 1H, J=7.0, 1.8 Hz), 8.55 (s, 1H), 8.68 (s, 1H), 9.39 (s,
1H). Anal. (C.sub.33H.sub.28N.sub.6O.0.6H.sub.2O) C, H, N.
(b) Example
32--[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]--
methyl-amine
[0301] Deprotection by a procedure similar to the synthesis of 31
afforded 32 (47.5 mg, 63%) as an off-white foam: R.sub.f=0.29
(1:20:100 concentrated aqueous NH.sub.4OH:ethanol:dichloromethane);
.sup.1H NMR (DMSO-d.sub.6) .delta. 2.30 (s, 3H), 4.07 (s, 2H), 7.15
(d, 2H, J=4.5 Hz), 7.47 (m, 1H), 7.64 (dd, 1H, J=8.5, 1.5 Hz), 7.83
(m, 4H), 8.26 (d, 1H, J=7.2 Hz), 8.56 (s, 1H), 8.66 (s, 1H), 9.39
(s, 1H). Anal. (C.sub.25H.sub.20N.sub.6.1.0EtOH.0.2 hexanes) C, H,
N.
EXAMPLE 33
4-[3-(4-Pyrrolidin-1-ylmethyl-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-isoq-
uinoline
[0302] ##STR83##
(a) Intermediate
33a--4-[1-(4-Methoxy-benzyl)-3-(4-pyrrolidin-1-ylmethyl-1H-benzoimidazol--
2-yl)-1H-indazol-5-yl]-isoquinoline
[0303] By a synthetic method analogous to the synthesis of 31b,
alcohol 31a (435.0 mg, 0.850 mmol) was treated with methanesulfonyl
chloride and diisopropylethyl amine at 0.degree. C. for 2 hours.
Pyrrolidine (605 mg, 8.5 mmol) was added, and the mixture allowed
to warm to room temperature over 20 hours. Extractive workup and
silica gel chromatography similar to 31b afforded 33a (303.0 mg,
63%) as a yellow foam: R.sub.f=0.13 (1:20:400 concentrated aqueous.
NH.sub.4OH:ethanol:dichloromethane); .sup.1H NMR (DMSO-d.sub.6)
.delta. 1.61 (br s, 4H), 2.51 (br s, 4H), 3.71 (s, 3H), 3.97 (s,
2H), 5.83 (s, 2H), 6.93 (d, 2H, J=8.8 Hz), 7.14 (d, 2H, J=3.6 Hz),
7.36 (d, 2H, J=8.7 Hz), 7.45 (m, 1H), 7.67 (d, 1H, J=8.5 Hz), 7.76
(m, 2H), 7.89 (m, 1H), 8.00 (d, 1H, J=8.7 Hz), 8.25 (d, 1H, J=6.6
Hz), 8.54 (s, 1H), 8.70 (br s, 1H), 9.39 (s, 1H), 13.03 (br s, 1H).
Anal. (C.sub.36H.sub.32N.sub.6O.0.2 CH.sub.2Cl.sub.2) C, H, N.
(b) Example
33--4-[3-(4-Pyrrolidin-1-ylmethyl-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-
-isoquinoline
[0304] A solution of 33a (109.2 mg, 0.193 mmol) in 25% concentrated
sulfuric acid/trifluoroacetic acid (2.0 mL) was stirred at room
temperature for 21 hours, then added dropwise to a rapidly stirred
mixture of tetrahydrofuran (25 mL), and saturated aqueous sodium
carbonate (25 mL). Ethyl acetate (25 mL) and water (15 mL) were
added, and the layers separated. The aqueous layer was extracted
with ethyl acetate (3.times.50 mL), and the combined organic
fractions dried over magnesium sulfate, filtered and concentrated.
Purification by silica gel chromatography (1:20:100 concentrated
aqueous NH.sub.4OH:ethanol:dichloromethane) afforded 33 (25.4 mg,
30%) as a white powder: .sup.1H NMR (CD.sub.3OD) .delta. 1.77 (br
s, 4H), 2.69 (br s, 4H), 4.12 (s, 2H), 7.24 (d, 2H, J=4.0 Hz), 7.80
(m, 5H), 8.06 (d, 1H, J=7.9 Hz), 8.23 (d, 1H, J=7.5 Hz), 8.53 (s,
1H), 8.69 (s, 1H), 9.29 (s, 1H). Anal. (C.sub.28H.sub.24N.sub.6.0.9
MeOH) C, H, N.
EXAMPLE 34
4-{3-[4-(2-Pyrrolidin-1-yl-ethyl)-1H-benzoimidazol-2-yl]-1H-indazol-5-yl}--
isoquinoline
[0305] ##STR84##
(a) Intermediate
34a--4-{1-(4-Methoxy-benzyl)-3-[4-(2-pyrrolidin-1-yl-ethyl)-1H-benzoimida-
zol-2-yl]-1H-indazol-5-yl}-isoquinoline
[0306] By a procedure similar to the synthesis of 33a, alcohol 30a
(441.5 mg, 0.84 mmol) was converted into 34a (204.6 mg, 42%), an
off-white foam: R.sub.f=0.08 (1:20:400 concentrated aqueous
NH.sub.4OH:ethanol:dichloromethane); .sup.1H NMR (DMSO-d.sub.6)
.delta. 1.38 (br s, 4H), 2.31 (br s, 4H), 2.79 (m, 2H), 3.07 (m,
2H), 3.71 (s, 3H), 5.81 (s, 2H), 6.93 (d, 2H, J=8.8 Hz), 6.98 (d,
1H, J=7.2 Hz), 7.08 (t, 1H, J=7.7 Hz), 7.36 (d, 2H, J=8.7 Hz), 7.39
(m, 1H), 7.66 (dd, 1H, J=8.5, 1.5 Hz), 7.76 (m, 2H), 7.89 (d, 1H,
J=7.7 Hz), 8.01 (d, 1H, J=8.7 Hz), 8.25 (d, 1H, J=7.4 Hz), 8.53 (s,
1H), 8.75 (br s, 1H), 9.38 (s, 1H), 13.00 (br s, 1H). Anal.
(C.sub.37H.sub.34N.sub.6O.0.6H.sub.2O) C, H, N.
(b) Example
34--4-{3-[4-(2-Pyrrolidin-1-yl-ethyl)-1H-benzoimidazol-2-yl]-1H-indazol-5-
-yl}-isoquinoline
[0307] 34 was prepared similar to example 33. Treatment of 34a
(66.2 mg, 0.114 mmol) with 3:1 trifluoroacetic acid/sulfuric acid
yielded 34 (24.7 mg, 47%) as a white powder: R.sub.f=0.38 (1:20:100
concentrated aqueous NH.sub.4OH:ethanol:dichloromethane); .sup.1H
NMR (DMSO-d.sub.6) .delta. 1.37 (br m, 6H), 2.27 (br m, 2H), 2.80
(m, 2H), 3.07 (m, 2H), 6.98 (d, 1H, J=7.2 Hz), 7.09 (t, 1H, J=7.5
Hz), 7.36 (br s, 1H), 7.63 (dd, 1H, J=8.5, 1.5 Hz), 7.82 (m, 4H),
8.26 (d, 1H, J=7.4 Hz), 8.54 (s, 1H), 8.75 (br s, 1H), 9.39 (s,
1H), 12.98 (br s, 1H), 13.79 (s, 1H). Anal.
(C.sub.29H.sub.26N.sub.6.0.7 EtOH) C, H, N.
EXAMPLE 35
3-{[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]-am-
ino}-2-methyl-propan-1-ol
[0308] ##STR85##
(a) Intermediate
35a--Cyclopropylmethyl-{2-[5-isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-ind-
azol-3-yl]-1H-benzoimidazol-4-ylmethyl}-amine
[0309] By a procedure similar to 31 b synthesis, alcohol 31a (512.0
mg, 1.00 mmol) was treated with methanesulfonyl chloride and
diisopropylethyl amine at 0.degree. C. for 1 hour.
Aminomethylcyclopropane (712 mg, 10.0 mmol) was then added, and
stirring continued at room temperature for 15 hours. After
extractive workup and column chromatography similar to 31 b,
intermediate 35a (209.3 mg, 37%) was obtained as an off-white
powder: R.sub.f=0.16 (1:20:300 concentrated aqueous
NH.sub.4OH:ethanol:dichloromethane); .sup.1H NMR (DMSO-d.sub.6)
.delta. -0.24 (br s, 2H), -0.04 (br s, 2H), 0.66 (br s, 1H), 2.30
(br s, 2H), 3.71 (s, 3H), 4.04 (br s, 2H), 5.83 (s, 2H), 6.93 (d,
2H, J=8.7 Hz), 7.11 (m, 2H), 7.37 (d, 2H, J=8.7 Hz), 7.42 (m, 1H),
7.67 (dd, 1H, J=8.7, 1.5 Hz), 7.76 (m, 2H), 7.87 (d, 1H, J=8.1 Hz),
8.02 (d, 1H, J=8.7 Hz), 8.25 (dd, 1H, J=6.8, 1.9 Hz), 8.53 (s, 1H),
8.68 (br s, 1H), 9.38 (s, 1H). Anal.
(C.sub.36H.sub.32N.sub.6O.0.5H.sub.2O) C, H, N.
(b) Example
35--3-{[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethy-
l]-amino}-2-methyl-propan-1-ol
[0310] 35 was prepared similar to example 33. Treatment of 35a
(107.1 mg, 0.19 mmol) with 3:1 trifluoroacetic acid/sulfuric acid
yielded ring-opened analog 35 (25.3 mg, 29%) as a white powder:
R.sub.f=0.35 (1:20:100 concentrated aqueous
NH.sub.4OH:ethanol:dichloromethane); .sup.1H NMR (CD.sub.3OD)
.delta. 0.67 (d, 3H, J=6.8 Hz), 1.33 (m, 1H), 1.80 (m, 1H), 2.60
(m, 1H), 2.75 (m, 1H), 3.20 (m, 1H), 4.26 (s, 2H), 7.22 (m, 2H),
7.57 (d, 1H, J=7.7 Hz), 7.63 (dd, 1H, J=8.7, 1.7 Hz), 7.79 (m, 3H),
7.99 (d, 1H, J=7.5 Hz), 8.22 (d, 1H, J=7.5 Hz), 8.51 (s, 1H), 8.72
(br s, 1H), 9.29 (s, 1H). .sup.13C NMR (CD.sub.3OD, DEPT) .delta.
15.0 (CH.sub.3), 35.6 (CH), 50.9 (CH.sub.2), 54.0 (CH.sub.2), 67.4
(CH.sub.2), 111.7 (CH), 123.4 (CH), 124.0 (CH), 124.3 (CH), 125.8
(CH), 128.9 (CH), 129.3 (CH), 130.4 (CH), 132.6 (CH), 142.9 (CH),
152.6 (CH). Anal. (C.sub.28H.sub.26N.sub.6O.0.6
CH.sub.2Cl.sub.2.0.4 hexanes) C, H, N.
EXAMPLE 36
Diethyl-[2-(5-isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethy-
l]-amine
[0311] ##STR86##
(a) Intermediate
36a--Diethyl-{2-[5-isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-
-1H-benzoimidazol-4-ylmethyl}-amine
[0312] By a procedure similar to 31 b, alcohol 31a (511.4 mg, 1.00
mmol) was treated with methanesulfonyl chloride and
diisopropylethyl amine at 0.degree. C. for 2.5 hours. Diethylamine
(731.4 mg, 10.0 mmol) was then added, and stirring continued at
room temperature for 25 hours. After extractive workup and column
chromatography similar to 31 b, intermediate 36a (434.6 mg, 77%)
was obtained as a yellow foam: R.sub.f=0.22 (1:20:400 concentrated
aqueous NH.sub.4OH:ethanol:dichloromethane); .sup.1H NMR
(DMSO-d.sub.6) [Some peaks are doubled due to tautomeric
isomerization] .delta. 0.87 and 1.01 (2 br s, 6H together), 2.41
and 2.56 (2 br s, 4H together), 3.71 (s, 3H), 3.89 and 3.94 (2 br
s, 2H together), 5.82 (s, 2H), 6.92 (d, 2H, J=8.7 Hz), 7.13 (m,
2H), 7.37 (d, 2H, J=8.5 Hz), 7.50 (m, 1H), 7.67 (d, 1H, J=8.7 Hz),
7.76 (m, 2H), 7.91 (m, 1H), 8.01 (d, 1H, J=8.7 Hz), 8.25 (dd, 1H,
J=6.6, 1.9 Hz), 8.53 (s, 1H), 8.63 and 8.77 (2 br s, 1H together),
9.38 (s, 1H), 13.02 (s, 1H). Anal.
(C.sub.36H.sub.34N.sub.6O.0.4H.sub.2O) C, H, N.
(b) Example
36--Diethyl-[2-(5-isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-yl-
methyl]-amine
[0313] Similar to example 33, treatment of 36a (266.5 mg, 0.47
mmol) with 3:1 trifluoroacetic acid/sulfuric acid yielded 36 (67.5
mg, 32%) as a white powder: R.sub.f=0.30 (1:20:200 concentrated
aqueous NH.sub.4OH:ethanol:dichloromethane); .sup.1H NMR
(DMSO-d.sub.6) [Some peaks are doubled due to tautomeric
isomerization] .delta. 0.94 (br m, 6H), 2.44 and 2.55 (2 br s, 4H
together), 3.94 (br s, 2H), 7.14 (br s, 2H), 7.39 and 7.50 (2 br s,
1H together), 7.64 (dd, 1H, J=8.7, 1.5 Hz), 7.77 (m, 4H), 8.25 (d,
1H, J=7.4 Hz), 8.54 (s, 1H), 8.63 and 8.74 (2 br s, 1H together),
9.39 (s, 1H), 12.99 (s, 1H), 13.81 (s, 1H). Anal.
(C.sub.28H.sub.26N.sub.6.0.5 EtOH) C, H, N.
EXAMPLE 37
Ethyl-[2-(5-isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmethyl]-
-amine
[0314] ##STR87##
(a) Intermediate
37a--Ethyl-{2-[5-isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1-
H-benzoimidazol-4-ylmethyl}-amine
[0315] By a synthetic method similar to 31 b, alcohol 31a (371.5
mg, 0.726 mmol) was treated with methanesulfonyl chloride and
diisopropylethyl amine at 0.degree. C. for 2.5 hours. The reaction
flask was then fitted with a dry ice-cooled cold finger condenser,
and ethylamine gas was condensed into the reaction solution until
the volume had increased by about 5 mL. Stirring was continued at
room temperature for 15 hours. After extractive workup and column
chromatography similar to 31 b, intermediate 37a (260.1 mg, 67%)
was obtained as a pale yellow foam: .sup.1H NMR (DMSO-d.sub.6)
.delta. 0.84 (br s, 3H), 3.39 (br s, 2H), 3.71 (s, 3H), 4.04 (s,
2H), 5.82 (s, 2H), 6.93 (d, 2H, J=8.7 Hz), 7.12 (m, 2H), 7.37 (d,
2H, J=8.7 Hz), 7.44 (m, 1H), 7.67 (dd, 1H, J=8.7, 1.5 Hz), 7.76 (m,
2H), 7.89 (m, 1H), 8.01 (d, 1H, J=8.7 Hz), 8.25 (dd, 1H, J=6.6, 1.9
Hz), 8.54 (s, 1H), 8.67 (s, 1H), 9.39 (s, 1H). Anal.
(C.sub.34H.sub.30N.sub.6O.0.7H.sub.2O) C, H, N.
(b) Example
37--Ethyl-[2-(5-isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylme-
thyl]-amine
[0316] Similar to example 33, treatment of 37a (123.3 mg, 0.229
mmol) with 3:1 trifluoroacetic acid/sulfuric acid yielded 37 (21.8
mg, 23%) as an off-white powder: .sup.1H NMR (DMSO-d.sub.6) .delta.
0.84 (br s, 3H), 2.57 (br s, 2H), 4.10 (s, 2H), 7.13 (m, 2H), 7.46
(m, 1H), 7.64 (dd, 1H, J=8.7, 1.7 Hz), 7.80 (m, 4H), 8.26 (dd, 1H,
J=7.2, 1.7 Hz), 8.55 (s, 1H), 8.66 (s, 1H), 9.39 (s, 1H), 13.85 (br
s, 1H). Anal. (C.sub.26H.sub.22N.sub.6.0.6EtOH.1.0CH.sub.2Cl.sub.2)
C, H, N.
EXAMPLE 38
Isopropyl-[2-(5-isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylmet-
hyl]-amine
[0317] ##STR88##
(a) Intermediate
38a--Isopropyl-{2-[5-isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-y-
l]-1H-benzoimidazol-4-ylmethyl}-amine
[0318] By a procedure similar to 31b, alcohol 31a (518.0 mg, 1.01
mmol) was treated with methanesulfonyl chloride and
diisopropylethyl amine at 0.degree. C. for 2.5 hours. Isopropyl
amine (597 mg, 10.1 mmol) was then added, and stirring continued at
room temperature for 24 hours. After extractive workup and column
chromatography similar to 31 b, intermediate 38a (417.8 mg, 75%)
was obtained as a yellow foam: .sup.1H NMR (DMSO-d.sub.6) .delta.
0.77 (br s, 6H), 2.63 (br s, 1H), 3.71 (s, 3H), 4.02 (br s, 2H),
5.82 (s, 2H), 6.93 (d, 2H, J=8.7 Hz), 7.11 (m, 2H), 7.37 (d, 2H,
J=8.7 Hz), 7.42 (m, 1H), 7.67 (dd, 1H, J=8.7, 1.5 Hz), 7.76 (m,
2H), 7.88 (d, 1H, J=7.7 Hz), 8.02 (d, 1H, J=8.7 Hz), 8.25 (dd, 1H,
J=6.6, 2.1 Hz), 8.53 (s, 1H), 8.69 (br s, 1H), 9.38 (s, 1H). Anal.
(C.sub.35H.sub.32N.sub.6O.0.7H.sub.2O) C, H, N.
(b) Example
38--Isopropyl-[2-(5-isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzo-imidazol-4-
-ylmethyl]-amine
[0319] 38 was prepared similar to example 33. Treatment of 38a
(243.3 mg, 0.44 mmol) with 3:1 trifluoroacetic acid/sulfuric acid
yielded 38 (89.9 mg, 47%) as an off-white powder: .sup.1H NMR
(CD.sub.3OD) .delta. 1.03 (d, 6H, J=6.4 Hz), 2.99 (septet, 1H,
J=6.4 Hz), 4.27 (s, 2H), 7.23 (m, 2H), 7.57 (dd, 1H, J=7.7, 1.1
Hz), 7.67 (dd, 1H, J=8.7, 1.7 Hz), 7.81 (m, 3H), 8.01 (d, 1H, J=8.3
Hz), 8.23 (d, 1H, J=7.5 Hz), 8.51 (s, 1H), 8.71 (br s, 1H), 9.30
(s, 1H).
EXAMPLE 39
tert-Butyl-[2-(S-isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-ylme-
thyl]-amine
[0320] ##STR89##
(a) Intermediate
39a--tert-Butyl-{2-[5-isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3--
yl]-1H-benzoimidazol-4-ylmethyl}-amine
[0321] By an analogous method to 31b, alcohol 31a (623.2 mg, 1.22
mmol) was treated with methanesulfonyl chloride and
diisopropylethyl amine at 0.degree. C. for 1 hour. tert-Butylamine
(890 mg, 12.2 mmol) was then added, and stirring continued at room
temperature for 20 hours. After extractive workup and column
chromatography similar to 31 b, intermediate 39a (299.7 mg, 43%)
was obtained as a yellow foam: .sup.1H NMR (CD.sub.3OD) .delta.
1.01 (s, 9H), 3.76 (s, 3H), 4.11 (s, 2H), 5.78 (s, 2H), 6.91 (d,
2H, J=8.7 Hz), 7.19 (m, 2H), 7.36 (d, 2H, J=8.7 Hz), 7.50 (dd, 1H,
J=7.9, 1.1 Hz), 7.62 (dd, 1H, J=8.7, 1.7 Hz), 7.77 (m, 3H), 7.95
(d, 1H, J=7.9 Hz), 8.22 (dd, 1H, J=7.0, 1.7 Hz), 8.48 (s, 1H), 8.74
(s, 1H), 9.29 (s, 1H). Anal. (C.sub.36H.sub.34N.sub.6O.0.3H.sub.2O)
C, H, N.
(b) Example
39--tert-Butyl-[2-(5-isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzo-imidazol--
4-ylmethyl]-amine
[0322] A solution of 39b (103.7 mg, 0.183 mmol),
trifluoromethanesulfonic acid (0.48 mL), and trifluoroacetic acid
(1.6 mL) was stirred at room temperature for 17 hours, and then at
100.degree. C. for 1.5 hours. The solution was added dropwise to a
rapidly stirred mixture of concentrated aqueous NH.sub.4OH (10 mL),
water (10 mL), and ethyl acetate (10 mL). Extraction and
purification similar to example 33, afforded 39 (40.2 mg, 49%) as a
white powder: .sup.1H NMR (CD.sub.3OD) .delta. 1.30 (s, 9H), 4.56
(s, 2H), 7.33 (m, 2H), 7.68 (m, 2H), 7.81 (m, 3H), 8.01 (d, 1H,
J=8.5 Hz), 8.25 (d, 1H, J=8.5 Hz), 8.51 (s, 1H), 8.73 (s, 1H), 9.32
(s, 1H). Anal. (C.sub.28H.sub.26N.sub.6.1.6HOAc) C, H, N.
EXAMPLE 40
4-[3-(4-Imidazol-1-ylmethyl-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-isoqui-
noline
[0323] ##STR90##
(a) Intermediate
40a--4-[3-(4-Imidazol-1-ylmethyl-1H-benzoimidazol-2-yl)-1-(4-methoxy-benz-
yl)-1H-indazol-5-yl]-isoquinoline
[0324] By an analogous method to 31b, alcohol 31a (572.0 mg, 1.12
mmol) was treated with methanesulfonyl chloride and
diisopropylethyl amine at 0.degree. C. for 1 hour. Imidazole (761
mg, 11.2 mmol) was then added, and stirring was continued at room
temperature for 24 hours. After extractive workup and column
chromatography similar to 31b, intermediate 40a (269.1 mg, 43%) was
obtained as a white powder: .sup.1H NMR (CD.sub.3OD) .delta. 3.77
(s, 3H), 5.58 (s, 2H), 5.79 (s, 2H), 6.73 (br s, 1H), 6.91 (d, 2H,
J=8.8 Hz), 7.07 (d, 1H, J=7.4 Hz), 7.23 (m, 2H), 7.36 (d, 2H, J=8.8
Hz), 7.53-7.83 (m, 6H), 8.03 (d, 1H, J=7.9 Hz), 8.22 (d, 1H, J=7.9
Hz), 8.51 (s, 1H), 8.73 (br s, 1H), 9.28 (s, 1H). Anal.
(C.sub.35H.sub.27N.sub.7O) C, H, N.
(b) Example
40--4-[3-(4-Imidazol-1-ylmethyl-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-i-
soquinoline
[0325] A solution of 40a (152.0 mg, 0.271 mmol),
trifluoromethanesulfonic acid (0.271 mL), and trifluoroacetic acid
(2.71 mL) was stirred at 60.degree. C. for 1 hour. The solution was
added dropwise to a rapidly stirred mixture of concentrated aqueous
NH.sub.4OH (10 mL), water (10 mL), THF (10 mL), and ethyl acetate
(20 mL). Extraction and purification similar to example 33,
afforded crude 40 as a pink solid (24.9 mg), which still showed
impurities in the .sup.1H NMR spectrum.
[0326] Trituration from acetonitrile afforded pure 40 (11.0 mg, 9%)
as a pink powder: .sup.1H NMR (CD.sub.3OD) .delta. 5.59 (s, 2H),
6.74 (br s, 1H), 7.08 (d, 1H, J=7.4 Hz), 7.25 (m, 2H), 7.55-7.85
(m, 6H), 8.07 (d, 1H, J=7.9 Hz), 8.24 (d, 1H, J=7.5 Hz), 8.54 (s,
1H), 8.72 (brs, 1H), 9.30 (s, 1H). HRMS calculated for
C.sub.27H.sub.20N.sub.7 442.1780 (MH.sup.+), found 442.1794.
EXAMPLE 41
5-(3-Methyl-pyridin-4-yl)-3-(E)-styryl-1H-indazole
[0327] ##STR91##
(a) Intermediate
41a--5-(3-Methyl-pyridin-4-yl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethox-
ymethyl)-1H-indazole
[0328] Intermediate 16a (300 mg, 0.63 mmol),
4-bromo-3-methyl-pyridine (see Baliki et al., Gazz. Chim. Ital.
124, 9, 1994, 385-386) (112 mg, 0.65 mmol), and sodium carbonate
(140 mg, 1.3 mmol) were stirred in DME (6 mL)/H.sub.2O (1 mL) in a
flask purged with argon. Tetrakis(triphenylphosphine)palladium (0)
(60 mg, 0.05 mmol) was added, and the reaction stirred at reflux
under argon for 24 hours. The solution was diluted with ethyl
acetate, washed with H.sub.2O and brine, dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. Purification by silica
gel chromatography (20% ethyl acetate/hexanes) gave 234 mg (84%) of
intermediate 41a as a clear oil. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.56 (s, 1H), 8.52 (d, 1H, J=7.8 Hz), 7.95 (s, 1H),
7.24-7.67 (m, 10H), 5.78 (s, 2H), 3.64 (t, 2H, J=8.1 Hz), 2.33 (s,
3H), 0.94 (t, 2H, J=8.1 Hz), -0.04 (s, 9H). Anal.
(C.sub.27H.sub.31N.sub.3OSi.0.2H.sub.2O) C, H, N.
(b) Example
41--5-(3-Methyl-pyridin-4-yl)-3-(E)-styryl-1H-indazole
[0329] Intermediate 41a (218 mg, 0.49 mmol) was stirred in a
mixture of ethylenediamine (0.34 mL, 4.9 mmol) and TBAF (1 M in
THF, 2.5 mL, 2.5 mmol) at 72.degree. C. for 20 hours. The solution
was diluted with ethyl acetate, washed with sat. NaHCO.sub.3 and
brine, dried (Na.sub.2SO.sub.4), and concentrated in vacuo.
Purification by silica gel chromatography (1:1:1 ethyl
acetate/THF/hexanes) gave 122 mg (79%) of the title compound as a
white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.29 (s,
1H), 8.52 (s, 1H), 8.46 (d, 1H, J=4.8 Hz), 8.22 (s, 1H), 7.55-7.73
(m, 5H), 7.26-7.44 (m, 5H), 2.31 (s, 3H). Anal.
(C.sub.21H.sub.17N.sub.3) C, H, N. MS (ES) [m+H]/z calculated 312,
found 312; [m-H]/z calculated 310, found 310.
EXAMPLE 42
5-(4-Chloro-pyridin-3-yl)-3-(E)-styryl-1H-indazole
[0330] ##STR92##
(a) Intermediate
42a--5-(4-Chloro-pyridin-3-yl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethox-
ymethyl)-1H-indazole
[0331] The title compound was prepared in 73% yield from
intermediate 16a and 4-chloro-3-iodo-pyridine (see Cho et al.,
Heterocycles, 43, 8, 1996, 1641-1652) analogous to intermediate
41a. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.67 (s, 1H), 8.52
(d, 1H, J=7.8 Hz), 8.08 (s, 1H), 7.26-7.70 (m, 10H), 5.79 (s, 2H),
3.64 (t, 2H, J=8.1 Hz), 0.94 (t, 2H, J=8.1 Hz), -0.03 (s, 9H).
Anal. (C.sub.26H.sub.28ClN.sub.3OSi.0.3H.sub.2O) C, H, N.
(b) Example
42--5-(4-Chloro-pyridin-3-yl)-3-(E)-styryl-1H-indazole
[0332] The title compound was prepared in 66% yield by the
SEM-deprotection of intermediate 42a in a method analogous to
example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.30 (s,
1H), 8.70 (s, 1H), 8.56 (d, 1H, J=5.4 Hz), 8.31 (s, 1H), 7.63-7.73
(m, 4H), 7.57 (d, 2H, J=4.2 Hz), 7.50 (dd, 1H, J=8.4, 1.2 Hz),
7.26-7.40 (m, 3H). Anal. (C.sub.20H.sub.14ClN.sub.3.0.05H.sub.2O)
C, H, N. MS (ES) [m+H]/z calculated 332/334, found 332/334; [m-H]/z
calculated 330/332, found 330/332.
EXAMPLE 43
5-(4-Methyl-pyridin-3-yl)-3-(E)-styryl-1H-indazole
[0333] ##STR93##
(a) Intermediate
43a--5-(4-Methyl-pyridin-3-yl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethox-
ymethyl)-1H-indazole
[0334] The title compound was prepared in 90% yield from
intermediate 16a and 3-bromo-4-methyl-pyridine similar to the
procedure for intermediate 41a. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.54 (s, 1H), 8.50 (d, 1H, J=7.8 Hz), 7.95 (s, 1H),
7.23-7.67 (m, 10H), 5.78 (s, 2H), 3.64 (t, 2H, J=8.1 Hz), 2.33 (s,
3H), 0.94 (t, 2H, J=8.1 Hz), -0.04 (s, 9H). Anal.
(C.sub.27H.sub.31N.sub.3OSi) C, H, N.
(b) Example
43--5-(4-Methyl-pyridin-3-yl)-3-(E)-styryl-1H-indazole
[0335] The title compound was prepared in 48% yield by the
SEM-deprotection of intermediate 43a in a method analogous to
example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.26 (s,
1H), 8.47 (s, 1H), 8.44 (d, 1H, J=4.8 Hz), 8.20 (s, 1H), 7.71 (d,
2H, J=7.2 Hz), 7.55-7.64 (m, 3H), 7.26-7.42 (m, 5H), 2.31 (s, 3H).
Anal. (C.sub.21H.sub.17N.sub.3. 0.13H.sub.2O) C, H, N. MS (ES)
[m+H]/z calculated 312, found 312; [m-H]/z calculated 310, found
310.
EXAMPLE 44
5-Fluoro-4-[3-(E)-styryl)-1H-indazol-5-yl]-isoquinoline
[0336] ##STR94##
(a) Intermediate 44a--4-Bromo-5-fluoro-isoquinoline
[0337] 5-Amino-4-bromo-isoquinoline (see Gordon et al., J.
Heterocycl. Chem., 4, 1967, 410-411) (1.86 g, 8.34 mmol) was
stirred in 48% fluoroboric acid (15 mL)/EtOH (15 mL) until
completely dissolved. The solution was cooled to 0.degree. C., and
sodium nitrite (660 mg, 9.59 mmol) in H.sub.2O (1 mL) was added
dropwise. The solution was diluted with Et.sub.2O (30 mL), and the
tan diazonium fluoroborate salt was collected by filtration and
dried under vacuum. The solid was placed in a flask and carefully
heated over a flame to expel nitrogen. The dark brown residue was
diluted with 10% NaOH and extracted with chloroform. Organics were
washed with brine, dried over MgSO.sub.4, and concentrated in
vacuo. Purification by silica gel chromatography (40% to 50% ethyl
acetate/hexanes) gave 798 mg (42%) of 4-bromo-5-fluoro-isoquinoline
as a white solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.36
(d, 1H, J=2.4 Hz), 8.74 (s, 1H), 8.07-8.11 (m, 1H), 7.70-7.80 (m,
2H). Anal. (C.sub.9H.sub.5BrFN) C, H, N.
(b) Intermediate
44b--5-Fluoro-4-[3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-in-
dazol-5-yl]-isoquinoline
[0338] The title compound was prepared in 83% yield from
intermediate 16a and 4-bromo-5-fluoro-isoquinoline similar to
intermediate 41a. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.32
(d, 1H, J=1.8 Hz), 8.52 (s, 1H), 8.07 (s, 1H), 7.91 (dd, 1H, J=8.1,
0.9 Hz), 7.26-7.66 (m, 11H), 5.80 (s, 2H), 3.67 (t, 2H, J=8.1 Hz),
0.95 (t, 2H, J=8.1 Hz), -0.03 (s, 9H). Anal.
(C.sub.30H.sub.30FN.sub.3OSi.0.2H.sub.2O) C, H, N.
(c) Example
44--5-Fluoro-4-[3-((E)-styryl)-1H-indazol-5-yl]-isoquinoline
[0339] The title compound was prepared in 83% yield by the
SEM-deprotection of intermediate 44b in a manner analogous to
example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.26 (s,
1H), 9.44 (d, 1H, J=1.8 Hz), 8.47 (s, 1H), 8.29 (s, 1H), 8.12 (d,
1H, J=7.2 Hz), 7.44-7.78 (m, 8H), 7.35 (t, 2H, J=7.2 Hz), 7.24 (t,
1H, J=7.2 Hz). Anal. (C.sub.24H.sub.16FN.sub.3.0.6H.sub.2O) C, H,
N. MS (ES) [m+H]/z calculated 366, found 366; [m-H]/z calculated
364, found 364.
EXAMPLE 45
4-[3-(E)-Styryl)-1H-indazol-5-yl]-isoquinolin-8-ylamine
[0340] ##STR95##
(a) Intermediate
45a--4-[3-((E)-Styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-y-
l]-isoquinolin-8-ylamine
[0341] The title compound was prepared in 82% yield from
intermediate 16a and 8-amino-4-bromo-isoquinoline (see Elpern et
al., J. Amer. Chem. Soc., 68, 1946, 1436) similar to the procedure
for intermediate 41a. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
9.36 (d, 1H, J=0.6 Hz), 8.53 (s, 1H), 8.13 (s, 1H) 7.26-7.72 (m,
11H), 6.86 (dd, 1H, J=7.5, 0.6 Hz), 5.81 (s, 2H), 4.51 (s, 2H),
3.66 (t, 2H, J=8.1 Hz), 0.96 (t, 2H, J=8.1 Hz), -0.03 (s, 9H).
Anal. (C.sub.30H.sub.32N.sub.4OSi) C, H, N.
(b) Example
45--4-[3-(E)-Styryl)-1H-indazol-5-yl]-isoquinolin-8-ylamine
[0342] The title compound was prepared in 70% yield by the
SEM-deprotection of intermediate 45a in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.30 (s, 1H), 9.50 (s, 1H), 8.36 (s, 1H), 8.26 (s, 1H),
7.24-7.71 (m, 10H), 6.91 (d, 1H, J=207.8 Hz), 6.77 (t, 1H, J=7.8
Hz), 6.33 (s, 2H). Anal. (C.sub.24H.sub.18N.sub.4.0.45H.sub.2O) C,
H, N. MS (ES) [m+H]/z calculated 363, found 363.
EXAMPLE 46
5-(4-Chloro-5-ethyl-pyridin-3-yl)-3-(E)-styryl-1H-indazole
[0343] ##STR96##
(a) Intermediate 46a--4-Chloro-3-ethyl-5-iodo-pyridine
[0344] LDA was prepared by the addition of n-butyllithium (2.5 M in
hexanes, 0.95 mL, 2.38 mmol) to a solution of diisopropylamine
(0.345 mL, 2.42 mmol) in THF (5 mL) at -20.degree. C. After 10
minutes, the solution was cooled to -78.degree. C.
4-Chloro-3-iodo-pyridine (500 mg, 2.09 mmol) in THF (3 mL) was
added dropwise, and the reaction stirred for 30 minutes Iodoethane
(0.2 mL, 2.5 mmol) was added, and the reaction was stirred for 1
hour at -78.degree. C., then 1 hour while warming to 0.degree. C.
The reaction was quenched with sat. NH.sub.4Cl, made basic with
saturated NaHCO.sub.3, and extracted with ethyl acetate. Organics
were washed with brine, dried over Na.sub.2SO.sub.4, and
concentrated in vacuo. Purification by silica gel chromatography
(20% ethyl acetate/hexanes) gave 429 mg (77%) of
4-chloro-3-ethyl-5-iodo-pyridine as a waxy white solid. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 8.78 (s, 1H), 8.33 (s, 1H), 2.83 (q,
2H, J=7.5 Hz), 1.26 (t, 3H, J=7.5 Hz). Anal. (C.sub.7H.sub.7ClIN)
C, H, N.
(b) Intermediate
46b--544-Chloro-5-ethyl-pyridin-3-yl)-3-((E)-styryl)-1-(2-trimethylsilany-
l-ethoxymethyl)-1H-indazole
[0345] The title compound was prepared in 69% yield from
intermediate 16a and 4-chloro-3-ethyl-5-iodo-pyridine similar to
the procedure for intermediate 41a. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.49 (d, 2H, J=3.3 Hz), 8.06 (s, 1H) 7.26-7.69
(m, 9H), 5.79 (s, 2H), 3.65 (t, 2H, J=8.1 Hz), 2.88 (q, 2H, J=7.5
Hz), 1.35 (t, 3H, J=7.5 Hz), 0.95 (t, 2H, J=8.1 Hz), -0.03 (s, 9H).
Anal. (C.sub.28H.sub.32ClN.sub.3OSi) C, H, N.
(c) Example
46--5-(4-Chloro-5-ethyl-pyridin-3-yl)-3-(E)-styryl-1H-indazole
[0346] The title compound was prepared in 80% yield by the
SEM-deprotection of intermediate 46b in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.25 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.27 (s, 1H),
7.55-7.72 (m, 5H), 7.26-7.48 (m, 4H), 2.83 (q, 2H, J=7.5 Hz), 1.26
(t, 2H, J=7.5 Hz). Anal. (C.sub.22H.sub.18N.sub.3Cl.0.3H.sub.2O) C,
H, N. MS (ES) [m+H]/z calculated 360, found 360.
EXAMPLE 47
3-[3-(1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-2-methoxy-phenol
[0347] ##STR97##
(a) Intermediate
47a--3-(1H-Benzoimidazol-2-yl)-5-{2-methoxy-3-[2-(2-trimethylsilanyl-etho-
xymethyl)-ethoxy]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole
[0348] The title compound was prepared in 92% yield from
intermediate 7c' and
2-methoxy-3-[2-(2-trimethylsilanyl-ethoxy)-ethoxy]-boronic acid
(Found in: Kania, Braganza, et al., patent application "Compounds
and Pharmaceutical Compositions for Inhibiting Protein Kinases, and
Methods for Their Use", p. 52, line 10 to p. 53, line 26; and p.
59, line 16 to p. 60, line 4, U.S. Provisional Ser. No. 60/142,130,
filed Jul. 2, 1999, incorporated by reference herein in its
entirety.), similar to the procedure for intermediate 7d'. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 9.92 (s, 1H), 8.79 (s, 1H),
7.86-7.89 (m, 1H), 7.79 (dd, 1H, J=8.7, 1.5 Hz), 7.63 (d, 1H, J=8.7
Hz), 7.49-7.52 (m, 1H), 7.28-7.31 (m, 3H), 7.19 (dd, 1H, J=8.4, 1.8
Hz), 7.15 (d, 1H, J=7.8 Hz), 5.82 (s, 2H), 5.34 (s, 2H), 3.86 (t,
2H, J=8.4 Hz), 3.65 (t, 2H, J=8.1 Hz), 3.59 (s, 3H), 0.92-1.02 (m,
4H), 0.02 (s, 9H), -0.03 (s, 9H).
(b) Example
47--3-[3-(1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-2-methoxy-phenol
[0349] The title compound was prepared in 61% yield by the
SEM-deprotection of intermediate 47a in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.64 (s, 1H), 12.98 (s, 1H), 9.36 (s, 1H), 8.59 (s, 1H),
7.68 (dd, 1H, J=8.4, 0.6 Hz), 7.60 (br s, 2H), 7.59 (dd, 1H, J=8.4,
1.5 Hz), 7.18-7.22 (m, 2H), 7.03 (t, 1H, J=7.8 Hz), 6.83-6.92 (m,
2H), 3.46 (s, 3H). Anal.
(C.sub.21H.sub.16N.sub.4O.sub.2.1.0H.sub.2O) C, H, N. MS (ES)
[m+H]/z calculated 357, found 357; [m-H]/z calculated 355, found
355.
EXAMPLE 48
3-(1H-Benzoimidazol-2-yl)-5-(1H-indol-4-yl)-1H-indazole
[0350] ##STR98##
(a) Intermediate
48a--4-Bromo-tert-butyl-dimethyl-silanyl)-1H-indole
[0351] Sodium hydride (60% dispersion in mineral oil, 1.84 g, 46
mmol) was washed with hexanes and then stirred in THF (30 mL) under
argon at 0.degree. C. 4-Bromoindole (3.0 g, 15.3 mmol) in THF (10
mL) was added slowly, and the reaction stirred 1 hour while warming
to room temperature. tert-Butyl-dimethylsilyl chloride (3.5 g, 23
mmol) was added, and the reaction stirred 16 hours before it was
diluted with ether (100 mL) and slowly quenched with H.sub.2O.
Organics were separated and washed with brine, dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. Purification by silica
gel chromatography (5% ether/hexanes) gave 4.28 g (90%)
intermediate 48a as a white solid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.44 (d, 1H, J=8.4 Hz), 7.27 (d, 1H, J=8.4 Hz),
7.22 (d, 1H, J=3.3 Hz), 7.00 (t, 1H, J=8.1 Hz), 6.67 (dd, 1H,
J=3.3, 0.9 Hz), 0.92 (s, 9H), 0.60 (s, 6H). Anal.
(C.sub.14H.sub.20BrNSi) C, H, N.
(b) Intermediate
48b--1-(tert-Butyl-dimethyl-silanyl)-1H-indole-4-boronic acid
[0352] Intermediate 48a (2.22 g, 7.16 mmol) was stirred in dry THF
(15 mL) at -78.degree. C. n-Butyllithium (2.5 M in hexanes, 3.45
mL, 8.6 mmol) was added slowly. The reaction stirred for 20 minutes
before it was transferred via cannula to a flask of trimethyl
borate (8.0 mL, 72 mmol) in dry THF (10 mL) at -78.degree. C. The
reaction stirred for 30 minutes at -78.degree. C. and then 3 hours
while warming to room temperature. It was quenched with H.sub.2O
and extracted with ether. Organics were washed with brine, dried
over Na.sub.2SO.sub.4, and concentrated in vacuo. Purification by
silica gel chromatography (33% ethyl acetate/hexanes) gave 1.28 g
(65%) of intermediate 48b as a white foam. .sup.1H NMR (300 MHz,
DMSO-d.sub.6w/D.sub.2O) .delta. 7.55 (d, 1H, J=8.4 Hz), 7.45 (d,
1H, J=8.4 Hz), 7.28 (s, 1H), 7.03-7.09 (m, 1H), 6.96 (s, 1H), 0.84
(s, 9H), 0.57 (s, 6H). Anal.
(C.sub.14H.sub.22BNO.sub.2Si-0.9H.sub.2O) C, H, N.
(c) Intermediate
48c--3-(1H-Benzoimidazol-2-yl)-5-[1-(tert-butyl-dimethyl-silanyl)-1H-indo-
l-4-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole
[0353] The title compound was prepared in 95% yield from
intermediate 7c' and intermediate 48b similar to the procedure for
intermediate 7d'. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.90
(s, 1H), 8.96 (d, 1H, J=0.9 Hz), 7.84-7.90 (m, 2H), 7.69 (d, 1H,
J=8.7 Hz), 7.48-7.53 (m, 2H), 7.23-7.33 (m, 5H), 6.82 (d, 1H, J=3.3
Hz), 5.84 (s, 2H), 3.67 (t, 2H, J=8.1 Hz), 0.96 (s, 9H), 0.94 (t,
2H, J=8.1 Hz), 0.65 (s, 6H), -0.03 (s, 9H). Anal.
(C.sub.34H.sub.43N.sub.5OSi.sub.2) C, H, N.
(d) Example
48--3-(1H-Benzoimidazol-2-yl)-5-(1H-indol-4-yl)-1H-indazole
[0354] The title compound was prepared in 79% yield by the SEM,
TBDMS-deprotection of intermediate 48c in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.66 (s, 1H), 12.97 (s, 1H), 11.25 (s, 1H), 8.78 (s, 1H),
7.68-7.81 (m, 3H), 7.51 (d, 1H, J=7.2 Hz), 7.42-7.46 (m, 2H),
7.14-7.26 (m, 4H), 6.59 (t, 1H, J=2.1 Hz). Anal.
(C.sub.22H.sub.15N.sub.5.0.3H.sub.2O) C, H, N. MS (ES) [m+H]/z
calculated 350, found 350; [m-H]/z calculated 348, found 348.
EXAMPLE 49
3-[-3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-2,4-difluoro-phenol
[0355] ##STR99##
(a) Intermediate
49a--[2-(2,4-Difluoro-phenoxymethoxy)-ethyl]-trimethyl-silane
[0356] 2,4-Difluoro-phenol (6.0 g, 46.1 mmol) and DIEA (9.64 mL,
55.3 mmol) were stirred in dry CH.sub.2Cl.sub.2 (100 mL) at room
temperature. 2-(Trimethylsilyl)ethoxymethyl chloride (9.0 mL, 50.8
mmol) was added, and the reaction stirred 1 for hour The solution
was washed with H.sub.2O and brine, dried over Na.sub.2SO.sub.4,
and concentrated in vacuo. Purification by silica gel
chromatography gave 10.88 g (91%) of the title compound as a clear
oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.11-7.20 (m, 1H),
6.74-6.89 (m, 2H), 5.20 (s, 2H), 3.77-3.83 (m, 2H), 0.93-0.99 (m,
2H), 0.01 (s, 9H).
(b) Intermediate
49b--3-(1H-Benzoimidazol-2-yl)-5{2,6-difluoro-3-[2-(2-trimethylsilanyl-et-
hoxy-ethoxy]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole
[0357] Intermediate 49a (1.4 g, 5.38 mmol) was stirred in dry THF
(16 mL) under argon at -78.degree. C. n-Butyllithium (2.5 M in
hexanes, 2.32 mL, 5.8 mmol) was added dropwise, and the reaction
stirred for 20 minutes. The solution was then transferred via
cannula to a flask of dry zinc chloride under argon at room
temperature. After 30 minutes intermediate 7c' (320 mg, 0.65 mmol)
and tetrakis(triphenylphosphine)palladium (0) (60 mg, 0.05 mmol)
were added, and the reaction stirred at room temperature for 2
hours The solution was diluted with ether and washed with H.sub.2O,
saturated NaHCO.sub.3, and brine. Organics were dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. Purification by silica
gel chromatography (20% to 30% Et.sub.2O/hexanes) gave 372 mg (92%)
of the title compound as a white solid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 9.89 (s, 1H), 8.80 (s, 1H), 7.86-7.89 (m, 1H),
7.70 (dd, 1H, J=8.7, 0.9 Hz), 7.58 (dd, 1H, J=8.7, 1.2 Hz),
7.49-7.53 (m, 1H), 7.17-7.31 (m, 3H), 6.90-6.97 (m, 1H), 5.82 (s,
2H), 5.28 (s, 2H), 3.86 (t, 2H, J=8.4 Hz), 3.67 (t, 2H, J=8.1 Hz),
0.92-1.04 (m, 4H), 0.02 (s, 9H), -0.02 (s, 9H). Anal.
(C.sub.32H.sub.40F.sub.2N.sub.4O.sub.3Si.sub.2.0.25H.sub.2O) C, H,
N.
(c) Example
49--3-[-3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-2,4-difluoro-phenol
[0358] The title compound was prepared in 70% yield by the
SEM-deprotection of intermediate 49b in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.75 (s, 1H), 13.00 (s, 1H), 9.88 (s, 1H), 8.56 (s, 1H),
7.70-7.78 (m, 2H), 7.48-7.53 (m, 2H), 7.17-7.25 (m, 2H), 6.99-7.05
(m, 2H). Anal. (C.sub.20H.sub.12FN.sub.4O.0.33H.sub.2O) C, H, N. MS
(ES) [m+H]/z calculated 363, found 363; [m-H]/z calculated 361,
found 361.
EXAMPLE 50
4-[-3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-3,5-difluoro-phenol
and
EXAMPLE 51
2-[-3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-3,5-difluoro-phenol
[0359] ##STR100##
(a) Intermediate
50a--[2-(3,5-Difluoro-phenoxymethoxy)-ethyl]-trimethyl-silane
[0360] The title compound was prepared in 94% yield from
3,5-difluorophenol analogous to the procedure to intermediate 49a.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.55-6.60 (m, 2H),
6.40-6.48 (m, 1H), 5.18 (s, 2H), 3.70-3.76 (m, 2H), 0.92-0.98 (m,
2H), 0.01 (s, 9H).
(b) Intermediate mixture 50b and
50c--3-(1H-Benzoimidazol-2-yl)-5{2,6-difluoro-4-[2-(2-trimethylsilanyl-et-
hoxy-ethoxy]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole
and
3-(1H-Benzolmidazol-2-yl)-5{2,4-difluoro-6-[2-(2-trimethylsilanyl-ethoxy--
ethoxy]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole
[0361] The title compounds were prepared in 52% yield as an
inseparable mixture from intermediate 50a similar to the procedure
for intermediate 49b. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
9.89 (s, 1H), 8.44-8.75 (m, 1H), 7.83-7.93 (m, 1H), 7.45-7.69 (m,
3H), 7.26-7.39 (m, 2.5H), 6.58-6.88 (m, 1.5H), 5.81 (s, 1H), 5.80
(s, 1H), 5.26 (s, 1H), 5.13 (s, 1H), 3.57-3.82 (m, 4H), 0.86-1.04
(m, 4H), -0.06-0.02 (m, 18H).
(c) Example
50--4-[-3-1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-3,5-difluoro-phenol
[0362] The title compound was prepared in 36% yield by the
SEM-deprotection of intermediate mixture 50b and 50c in a manner
analogous to the procedure for example 41. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 13.73 (s, 1H), 13.01 (s, 1H), 10.50 (s, 1H),
8.50 (s, 1H), 7.70-7.74 (m, 2H), 7.43-7.52 (m, 2H), 7.15-7.25 (m,
2H), 6.62 (dd, 2H, J=13.8, 1.5 Hz). Anal.
(C.sub.20H.sub.12FN.sub.4O.0.7H.sub.2O) C, H, N. MS (ES) [m+H]/z
calculated 363, found 363; [m-H]/z calculated 361, found 361.
(d) Example
51--2-[-3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-3,5-difluoro-phenol
[0363] The title compound was prepared in 40% yield by the
SEM-deprotection of intermediate mixture 50b and 50c in a manner
analogous to the procedure for example 41. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 13.65 (s, 1H), 12.98 (s, 1H), 10.39 (s, 1H),
8.47 (s, 1H), 7.66-7.72 (m, 2H), 7.50 (d, 1H, J=7.2 Hz), 7.40 (d,
1H, J=8.4 Hz), 7.14-7.24 (m, 2H), 6.73-6.80 (m, 1H), 6.64 (d, 1H,
J=10.5 Hz). Anal. (C.sub.20H.sub.12FN.sub.4O.0.9H.sub.2O) C, H, N.
MS (ES) [m+H]/z calculated 363, found 363; [m-H]/z calculated 361,
found 361.
EXAMPLE 52
3-(1H-Benzoimidazol-2-yl)-5-(4-chloro-pyridin-3-yl)-1H-indazole
[0364] ##STR101##
(a) Intermediate
52a--3-(1H-Benzoimidazol-2-yl)-5-(4-chloro-pyridin-3-yl)-1-(2-trimethylsi-
lanyl-ethoxymethyl)-1H-indazole
[0365] The title compound was prepared in 88% yield from
intermediate 25a and 4-chloro-3-iodo-pyridine similar to the
procedure for intermediate 41a. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 9.96 (s, 1H), 8.77 (s, 1H), 8.72 (s, 1H), 8.53 (d, 1H,
J=5.4 Hz), 7.85-7.89 (m, 1H), 7.72 (dd, 1H, J=8.7, 0.9 Hz), 7.61
(dd, 1H, J=8.7, 1.5 Hz), 7.50-7.53 (m, 1H), 7.47 (d, 1H, J=5.4 Hz),
7.28-7.35 (m, 2H), 5.84 (s, 2H), 3.65 (t, 2H, J=8.1 Hz), 0.95 (t,
2H, J=8.1 Hz), -0.03 (s, 9H).
(b) Example
52--3-(1H-Benzoimidazol-2-yl)-5-(4-chloro-pyridin-3-yl)-1H-indazole
[0366] The title compound was prepared in 54% yield by the
SEM-deprotection of intermediate 52a in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.81 (s, 1H), 13.02 (s, 1H), 8.70 (s, 1H), 8.56-8.60 (m,
2H), 8.22 (s, 1H), 7.55-7.80 (m, 5H), 7.20 (d, 5H, J=3.6 Hz). Anal.
(C.sub.22H.sub.18ClN.sub.3.0.5H.sub.2O) C, H, N. MS (ES) [m+H]/z
calculated 346, found 346.
EXAMPLE 53
5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-[3,4']bipyridinyl
[0367] ##STR102##
(a) Intermediate 53a--5-(Bromo-4-methyl-[3,4']bipyridinyl
[0368] 3,5-Dibromo-4-methyl-pyridine (2.21 g, 8.8 mmol),
4-pyridylboronic acid (1.08 g, 8.8 mmol) and potassium phosphate
(2.8 g, 13.2 mmol) were stirred in DMA (50 mL)/H.sub.2O (6 mL) in a
flask purged with argon. Tetrakis(triphenylphosphine)palladium (0)
(812 mg, 0.7 mmol) was added, and the reaction stirred at
92.degree. C. under argon for 16 hours. The solution was
concentrated in vacuo, and the residue was dissolved in ethyl
acetate. Organics were washed with H.sub.2O and brine, dried
(Na.sub.2SO.sub.4), and concentrated in vacuo. Purification by
silica gel chromatography (40% to 50% ethyl acetate/hexanes) gave
1.14 g (60%) of intermediate 53a as a white solid. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.73 (dd, 2H, J=4.5, 1.5 Hz), 8.72 (s,
1H), 8.32 (s, 1H), 7.25 (dd, 2H, J=4.5, 1.5 Hz), 2.35 (s, 3H).
Anal. (C.sub.11H.sub.9BrN.sub.2) C, H, N.
(b) Intermediate
53b--5-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H--
indazol-5-yl]-4-methyl-[3,4']bipyridinyl
[0369] The title compound was prepared in 64% yield from
intermediate 25a and intermediate 53a similar to the procedure for
intermediate 41a. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.21
(s, 1H), 8.70-8.76 (m, 3H), 8.61 (s, 1H), 8.46 (s, 1H), 7.85-7.88
(m, 1H), 7.72 (dd, 1H, J=8.7, 0.9 Hz), 7.47-7.53 (m, 2H), 7.24-7.37
(m, 4H), 5.84 (s, 2H), 3.64 (t, 2H, J=8.1 Hz), 2.19 (s, 3H), 0.94
(t, 2H, J=8.1 Hz), -0.04 (s, 9H).
(c) Example
53--5-[3-1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-[3,4']bipyridin-
yl
[0370] The title compound was prepared in 71% yield by the
SEM-deprotection of intermediate 53b in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.79 (s, 1H), 13.02 (s, 1H), 8.71 (d, 2H, J=4.8 Hz), 8.55
(s, 1H), 8.51 (s, 1H), 8.47 (s, 1H), 7.78 (d, 1H, J=8.7 Hz),
7.52-7.58 (m, 5H), 7.18-7.21 (m, 2H), 2.17 (s, 3H). Anal.
(C.sub.25H.sub.18N.sub.6.0.75H.sub.2O) C, H, N. MS (ES) [m+H]/z
calculated 403, found 403; [m-H]/z calculated 401, found 401.
EXAMPLE 54
5-[3-(1H-Benzolimidazol-2-yl)-1H-indazol-5-yl]-1,2,3,4,4a,8a-hexahydro-[1,-
7]naphthyridine
[0371] ##STR103## ##STR104##
(a) Intermediate 54a--3-(3,5-Dibromo-pyridin-4-yl)-propylamine
[0372] LDA was prepared by the addition of n-butyllithium (2.5 M in
hexanes, 6.8 mL, 17.0 mmol) to a solution of diisopropylamine (2.5
mL, 17.8 mmol) in THF (40 mL) at -20.degree. C. After 10 minutes,
the solution was cooled to -78.degree. C. 3,5-Dibromopyridine (3.84
g, 16.2 mmol) in THF (25 mL) was added dropwise, and the reaction
stirred for 30 minutes
1-(3-Bromopropyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentat-
e (5 g, 17.8 mmol) was added, and the reaction stirred for 1 hour
at -78.degree. C. and then for 1 hour while warming to 0.degree. C.
The reaction was quenched with sat. NH.sub.4Cl, made basic with
saturated NaHCO.sub.3, and extracted with ethyl acetate. Organics
were washed with brine, dried over Na.sub.2SO.sub.4, and
concentrated in vacuo. Purification by silica gel chromatography
(15% MeOH/CHCl.sub.3) gave 2.72 g (54%) of intermediate 54a as a
light brown oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.55 (d,
2H), 2.72-3.05 (m, 6H), 1.70-1.77 (m, 2H).
(b) Intermediate 54b--2-Trimethylsilanyl-ethanesulfonic acid
[3-(3,5-dibromo-pyridin-4-yl)-propyl]-amide
[0373] Intermediate 54a (2.7 g, 9.2 mmol) was stirred with
triethylamine (1.92 mL, 13.8 mmol) in dry DMF (20 mL) at 0.degree.
C. 2-Trimethylsilyanyl-ethanesulfonyl chloride, SES-Cl, (see
Weinreb et al., Tet. Lett. 27, 19, 1986, 2099-2102) (1.9 g, 9.5
mmol) was added slowly, and the reaction stirred for 1.5 hours at
0.degree. C. The reaction was diluted with H.sub.2O and extracted
with ether. Organics were washed with brine, dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. Purification by silica
gel chromatography (33% ethyl acetate/hexanes) gave 2.37 g (56%) of
intermediate 54b as a white solid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.58 (s, 2H), 4.36 (t, 1H, J=6.3 Hz), 3.26 (q,
2H, J=6.3 Hz), 2.93-3.06 (m, 4H), 1.81-1.89 (m, 2H), 1.00-1.07 (m,
2H), 0.07 (s, 9H). Anal.
(C.sub.13H.sub.22Br.sub.2N.sub.2O.sub.2SSi) C, H, N, S.
(c) Intermediate
54c--5-Bromo-1-(2-trimethylsilanyl-ethanesulfonyl)-1,2,3,4-tetrahydro-[1,-
7]naphthyridine
[0374] Intermediate 54b (860 mg, 1.88 mmol) and potassium carbonate
(390 mg, 2.82 mmol) were stirred in dry toluene (15 mL) in a flask
purged with argon. Tetrakis(triphenylphosphine)palladium (0) (218
mg, 0.19 mmol) was added, and the reaction stirred under argon at
102.degree. C. for 48 hours. The reaction was diluted with ethyl
acetate and washed with brine, dried (Na.sub.2SO.sub.4), and
concentrated in vacuo. Purification by silica gel chromatography
(25% ethyl acetate/hexanes) gave 372 mg (52%) of intermediate 54c
as a waxy white solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.70 (s, 1H), 8.42 (s, 1H), 3.72-3.76 (m, 2H), 3.07-3.14 (m, 2H),
2.83 (t, 2H, J=6.9 Hz), 2.07-2.12 (m, 2H), 1.04-1.11 (m, 2H), 0.05
(s, 9H). Anal. (C.sub.13H.sub.21BrN.sub.2O.sub.2SSi) C, H, N,
S.
(d) Intermediate
54d--5-[3-(1H-Benzolimidazol-2-yl)-1-(2-trimethylsilanl-ethoxymethyl)-1H--
indazol-5-yl]-1-(2-trimethylsilanyl-ethanesulfonyl)-1,2,3,4,4a,8a-hexahydr-
o-[1,7]naphthyridine
[0375] The title compound was prepared in 51% yield from
intermediate 25a and intermediate 54c similar to the procedure for
intermediate 41a. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.36
(s, 1H), 8.88 (s, 1H), 8.64 (t, 1H, J=0.9 Hz), 8.29 (s, 1H),
3.82-3.86 (m, 1H), 7.69 (dd, 1H, J=8.7, 0.9 Hz), 7.50-7.52 (m, 1H),
7.41 (dd, 1H, J=8.7, 1.5 Hz), 7.26-7.33 (m, 2H), 5.83 (s, 2H), 3.80
(t, 2H, J=5.7 Hz), 3.63 (t, 2H, J=8.1 Hz), 3.13-3.20 (m, 2H), 2.72
(t, 2H, J=6.6 Hz), 1.93-1.99 (m, 2H), 1.10-1.16 (m, 2H), 0.94 (t,
2H, J=8.1 Hz), 0.09 (s, 9H), -0.05 (s, 9H).
(e) Example
54--5-[3-(1H-Benzolimidazol-2-yl)-1H-indazol-5-yl]-1,2,3,4,4a,8a-hexahydr-
o-[1,7]naphthyridine
[0376] The title compound was prepared in 64% yield by the SEM,
SES-deprotection of intermediate 54d in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.71 (s, 1H), 13.00 (s, 1H), 8.41 (s, 1H), 7.82 (s, 1H),
7.69 (d, 2H, J=8.7 Hz), 7.63 (s, 1H), 7.50 (d, 1H, J=7.2 Hz), 7.44
(dd, 1H, J=8.7, 1.5 Hz), 7.16-7.22 (m, 2H), 6.11 (s, 1H), 3.23 (br
s, 2H), 2.55 (t, 2H, J=6.0 Hz), 1.68-1.73 (m, 2H). Anal.
(C.sub.22H.sub.18N.sub.6.0.45H.sub.2O) C, H, N. MS (ES) [m+H]/z
calculated 366, found 366.
EXAMPLE 55
N-{4-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinolin-8-yl}-5
nicotinamide
[0377] ##STR105##
(a) Intermediate 55a--N-(4-Bromo-isoquinolin-8-yl)-nicotinamide
[0378] 8-Amino-4-bromo-isoquinoline (328 mg, 1.47 mmol),
triethylamine (820 .mu.L, 5.9 mmol), and DMAP (10 mg) were stirred
in CH.sub.2Cl.sub.2 (50 mL). Nicotinoyl chloride, hydrochloride
(395 mg, 2.2 mmol) was added, and the reaction stirred at reflux
for 18 hours. The reaction was concentrated in vacuo and purified
by silica gel chromatography (3% MeOH/ethyl acetate) to give 272 mg
(56%) of intermediate 55a as a white solid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 10.95 (s, 1H), 9.46 (s, 1H), 9.25 (d, 1H, J=1.5
Hz), 8.81 (dd, 2H, J=4.8, 1.5 Hz), 8.40-8.45 (m, 1H), 7.92-8.06 (m,
3H), 7.59-7.64 (m, 1H). Anal. (C.sub.15H.sub.10BrN.sub.3O) C, H,
N.
(b) Intermediate
55b--N-{4-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethyoxymethyl)-
-1H-indazol-5-yl]-isoquinolin-8-yl}-nicotinamide
[0379] The title compound was prepared in 76% yield from
intermediate 25a and intermediate 55a similar to the procedure for
intermediate 41a. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.27
(s, 1H), 9.48 (s, 1H), 9.29 (d, 1H, J=1.8 Hz), 8.83-8.88 (m, 2H),
8.79 (s, 1H), 8.58 (s, 1H), 8.36 (d, 1H, J=7.8 Hz), 8.02 (d, 1H,
J=6.9 Hz), 7.73-7.81 (m, 3H), 7.58-7.65 (m, 2H), 7.47-7.53 (m, 2H),
7.24-7.29 (m, 2H), 5.86 (s, 2H), 3.67 (t, 2H, J=8.1 Hz), 0.96 (t,
2H, J=8.1 Hz), -0.04 (s, 9H).
(c) Example
55--N-{4-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinolin-8-yl}-ni-
cotinamide
[0380] The title compound was prepared in 78% yield by the
SEM-deprotection of intermediate 55b in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.85 (s, 1H), 13.04 (s, 1H), 10.98 (s, 1H), 9.54 (s, 1H),
9.30 (d, 2H, J=1.8 Hz), 8.83 (dd, 1H, J=4.8, 1.8 Hz), 8.65 (s, 1H),
8.59 (s, 1H), 8.45-8.50 (m, 4H), 7.52-7.66 (m, 4H), 7.18 (br s,
2H). Anal. (C.sub.29H.sub.19N.sub.7O.0.5H.sub.2O) C, H, N. MS (ES)
[m+H]/z calculated 482, found 482.
EXAMPLE 56
N-{4-[3-(1H-Benzoimidazol-2-yl)1H-indazol-5-yl]-isoquinolin-8-yl}-acetamid-
e
[0381] ##STR106##
(a) Intermediate 56a--N-(4-Bromo-isoquinolin-8-yl)-acetamide
[0382] 8-Amino-4-bromo-isoquinoline (300 mg, 1.35 mmol), DIEA (0.94
mL, 5.38 mmol), and acetic anhydride (255 .mu.L, 2.7 mmol) were
stirred in chloroform (20 mL) at reflux for 16 hours. The solution
was washed with H.sub.2O and brine, dried (Na.sub.2SO.sub.4), and
concentrated in vacuo. The residue was stirred in ethanol (6 mL)
with HOAc (2 mL) at 72.degree. C. for 20 hours. The solution was
allowed to cool and was diluted with ethyl acetate. Organics were
washed with 1 N NaOH and brine, dried (MgSO.sub.4), and
concentrated in vacuo. Purification by silica gel chromatography
(ethyl acetate) gave 232 mg (65%) of intermediate 56a as a white
solid. .sup.1H NMR (300 MHz, CDCl.sub.3) 810.31 (s, 1H), 9.47 (s,
1H), 8.77 (s, 1H), 7.90-7.97 (m, 3H), 2.21 (s, 3H). Anal.
(C.sub.11H.sub.9BrN.sub.2O) C, H, N.
(b) Intermediate
56b--N-{4-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethyoxymethyl)-
-1H-indazol-5-yl]-isoquinolin-8-yl}-acetamide
[0383] The title compound was prepared in 80% yield from
intermediate 25a and intermediate 56a similar to the procedure for
intermediate 41a. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.39
(s, 1H), 9.46 (s, 1H), 8.76 (s, 1H), 8.53 (s, 1H), 8.42 (s, 1H),
7.91 (d, 1H, J=7.2 Hz), 7.89 (d, 1H, J=7.2 Hz), 7.62-7.72 (m, 3H),
7.48-7.57 (m, 3H), 7.24-7.28 (m, 1H), 5.83 (s, 2H), 3.65 (t, 2H,
J=8.1 Hz), 2.35 (s, 3H), 0.95 (t, 2H, J=8.1 Hz), -0.04 (s, 9H).
(c) Example
56--N-{4-[3-(1H-Benzoimidazol-2-yl)1H-indazol-5-yl]-isoquinolin-8-yl}-ace-
tamide
[0384] The title compound was prepared in 68% yield by the
SEM-deprotection of intermediate 56b in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.84 (s, 1H), 13.03 (s, 1H), 10.34 (s, 1H), 9.56 (s, 1H),
8.61 (s, 1H), 8.55 (s, 1H), 7.82-7.89 (m, 2H), 7.74 (t, 1H, J=7.2
Hz), 7.59-7.66 (m, 3H), 7.51 (d, 1H, J=7.2 Hz), 7.13-7.21 (m, 2H),
2.25 (s, 3H). Anal. (C.sub.25H.sub.18N.sub.6O.0.4H.sub.2O) C, H, N.
MS (ES) [m+H]/z calculated 419, found 419.
EXAMPLE 57
N-{4-[3-(1H-Benzoimidazol-2-yl)1H-indazol-5-yl]-isoquinolin-8-yl}-benzyl-a-
mine
[0385] ##STR107##
(a) Intermediate 57a--Benzyl-(4-bromo-isoquinoline-8-yl)-amine
[0386] 8-Amino-4-bromo-isoquinoline (220 mg, 0.99 mmol) and
benzaldehyde (110 .mu.L, 1.1 mmol) were stirred in ethanol (15
mL)/HOAc (0.2 mL) at reflux for 24 hours. The reaction was cooled
to 0.degree. C., and sodium cyanoborohydride (622 mg, 9.9 mmol) was
added in portions. After stirring for 1 hour, the reaction was
diluted with H.sub.2O and extracted with ethyl acetate. Organics
were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated
in vacuo. Purification by silica gel chromatography (33% ethyl
acetate/hexanes) gave 136 mg (44%) of intermediate 57a as a light
yellow solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.61 (s,
1H), 8.64 (s, 1H), 7.79 (t, 1H, J=5.7 Hz), 7.55 (t, 1H, J=8.1 Hz),
7.28-7.42 (m, 4H), 7.15-7.24 (m, 2H), 6.58 (d, 1H, J=8.4 Hz), 4.53
(d, 2H, J=5.7 Hz). Anal. (C.sub.16H.sub.13BrN.sub.3) C, H, N.
(b) Intermediate
57b--N-{4-[3-1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethyoxymethyl)--
1H-indazol-5-yl]-isoquinolin-8-yl}-benzyl-amine
[0387] The title compound was prepared in 72% yield from
intermediate 25a and intermediate 57a similar to the procedure for
intermediate 41a. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.02
(s, 1H), 9.38 (s, 1H), 8.82 (s, 1H), 8.56 (s, 1H), 7.82 (d, 1H,
J=8.7 Hz), 7.73 (d, 1H, J=8.7 Hz), 7.63 (dd, 1H, J=8.4, 1.5 Hz),
7.24-7.52 (m, 9H), 7.17 (d, 1H, J=8.4 Hz), 6.69 (d, 1H, J=7.5 Hz),
5.86 (s, 2H), 5.23 (s, 1H), 4.58 (d, 2H, J=4.5 Hz), 3.67 (t, 2H,
J=8.1 Hz), 0.97 (t, 2H, J=8.1 Hz), -0.03 (s, 9H).
(c) Example
57--N-{4-[3-(1H-Benzoimidazol-2-yl)1H-indazol-5-yl]-isoquinolin-8-yl}-ben-
zyl-amine
[0388] The title compound was prepared in 72% yield by the
SEM-deprotection of intermediate 57b in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.80 (s, 1H), 13.01 (s, 1H), 9.71 (s, 1H), 8.56 (s, 1H),
8.42 (s, 1H), 7.71-7.81 (m, 2H), 7.30-7.63 (m, 8H), 7.17-7.25 (m,
3H), 6.90 (d, 1H, J=7.2 Hz), 6.52 (d, 1H, J=7.2 Hz), 4.57 (d, 2H,
J=5.4 Hz). Anal. (C.sub.30H.sub.22N.sub.6.0.5H.sub.2O) C, H, N. MS
(ES) [m+H]/z calculated 467, found 467.
EXAMPLE 58
3-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-[3,3']bipyridinyl
[0389] ##STR108##
(a) Intermediate 58a--5-Bromo-4-methyl-[3,3']bipyridinyl
[0390] The title compound was prepared in 54% yield from
3,5-dibromo-4-methyl-pyridine and 3-pyridyl boronic acid analogous
to the procedure for intermediate 53a. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.67-8.71 (m, 2H), 8.59 (dd, 1H, J=2.4, 0.6
Hz), 8.33 (s, 1H), 7.62-7.66 (m, 1H), 7.39-7.44 (m, 1H), 2.35 (m,
3H). Anal. (C.sub.11H.sub.9BrN.sub.2.0.1H.sub.2O) C, H, N.
(b) Intermediate
58b--3-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H--
indazol-5-yl]-4-methyl-[3,3']bipyridinyl
[0391] The title compound was prepared in 37% yield from
intermediate 25a and intermediate 58a analogous to the procedure
for intermediate 41a. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
10.24 (s, 1H), 8.68-8.71 (m, 3H), 8.61 (s, 1H), 8.47 (s, 1H),
7.85-7.88 (m, 1H), 7.70-7.78 (m, 2H), 7.42-7.53 (m, 3H), 7.26-7.33
(m, 2H), 5.83 (s, 2H), 3.64 (t, 2H, J=8.1 Hz), 2.19 (s, 3H), 0.95
(t, 2H, J=8.1 Hz), -0.05 (s, 9H).
(c) Example
58--3-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-[3,3']bipyridi-
nyl
[0392] The title compound was prepared in 74% yield by the
SEM-deprotection of intermediate 58b in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.79 (s, 1H), 13.02 (s, 1H), 8.72 (d, 1H, J=1.5 Hz), 8.65
(dd, 1H, J=4.8, 1.5 Hz), 8.54 (s, 1H), 8.52 (s, 1H), 8.48 (s, 1H),
7.96-8.00 (m, 1H), 7.78 (d, 1H, J=8.7 Hz), 7.69 (d, 1H, J=7.5 Hz),
7.49-7.57 (m, 3H), 7.17-7.23 (m, 2H), 2.16 (s, 3H). Anal.
(C.sub.25H.sub.18N.sub.6.0.6H.sub.2O) C, H, N. MS (ES) [m+H]/z
calculated 403, found 403.
EXAMPLE 59
(E)-3-{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-yl-
}-prop-2-en-1-ol and
EXAMPLE 60
(E)-3-{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-yl-
}-propan-1-ol
[0393] ##STR109##
(a) Intermediate 59a--5-Bromo-4-methyl-pyridine-3-carbaldehyde
[0394] 3,5-Dibromo-4-methyl-pyridine (3.8 g, 15.1 mmol) was stirred
in dry THF (150 mL) at -100.degree. C. (N.sub.2/ether) under argon.
n-Butyllithium (2.5 M in hexanes, 6.2 mL, 15.4 mmol) was added
dropwise, and the reaction stirred for 5 minutes DMF (1.8 mL, 23.2
mmol) was added, and the reaction was stirred for 20 minutes at
-100.degree. C. and then for 1 hour at -78.degree. C. The reaction
was quenched with sat. NH.sub.4Cl and extracted with ether.
Organics were washed with brine, dried over Na.sub.2SO.sub.4, and
concentrated in vacuo. Purification by silica gel chromatography
(20% ethyl acetate/hexanes) gave 2.18 g (72%) of intermediate 59a
as a clear oil which slowly solidified. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 10.25 (s, 1H), 8.84 (s, 1H), 8.83 (s, 1H), 2.76
(s, 3H). Anal. (C.sub.7H.sub.6BrNO) C, H, N.
(b) Intermediate 59b--(E)-3-(5-Bromo-4-methyl-pyridin-3-yl)-acrylic
acid ethyl ester
[0395] Intermediate 59a (690 mg, 3.45 mmol), ethyl hydrogen
malonate (600 mg, 4.5 mmol), and piperidine (170 .mu.L, 1.73 mmol)
were refluxed in pyridine (5 mL) for 7 hours The reaction was
concentrated in vacuo and purified by silica gel chromatography
(20% ethyl acetate/hexanes) to give 560 mg (60%) of intermediate
59b as a waxy white solid. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.65 (s, 1H), 8.57 (s, 1H), 7.87 (d, 1H, J=15.9 Hz), 6.39
(d, 1H, J=15.9 Hz), 4.29 (q, 2H, J=7.2 Hz), 2.50 (s, 3H), 1.35 (t,
3H, J=7.2 Hz). Anal. (C.sub.11H.sub.12BrNO.sub.2) C, H, N.
(c) Intermediate
59c--(E)-3-{5-[3-1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethy-
l)-1H-indazol-5-yl]-4-methyl-pyridin-3-yl}-acrylic acid ethyl
ester
[0396] The title compound was prepared in 83% yield from
intermediate 25a and intermediate 59b similar to the procedure for
intermediate 41a. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.00
(s, 1H), 8.74 (s, 1H), 8.65 (s, 1H), 8.55 (s, 1H), 7.99 (d, 1H,
J=15.9 Hz), 7.83-7.87 (m, 1H), 7.71 (d, 1H, J=8.7 Hz), 7.50-7.53
(m, 1H), 7.43 (dd, 1H, J=8.7, 1.5 Hz), 7.27-7.32 (m, 2H), 6.50 (d,
1H, J=15.9 Hz), 5.84 (s, 2H), 4.31 (q, 2H, J=7.2 Hz), 3.65 (t, 2H,
J=8.1 Hz), 2.36 (s, 3H), 1.37 (t, 3H, J=7.2 Hz), 0.95 (t, 2H, J=8.1
Hz), -0.04 (s, 9H).
(d) Intermediate
59d--(E)-3-{5-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymeth-
yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-yl}-prop-2-en-1-ol
[0397] A solution of intermediate 59c (402 mg, 0.73 mmol) in ether
(10 mL) was added dropwise to a stirred suspension of LAH (180 mg,
4.74 mmol) in ether (10 mL) at 0.degree. C. The reaction was
allowed to stir for 3 hours while warming to room temperature. The
reaction was quenched with water and extracted with ethyl acetate.
Organics were washed with brine, dried over Na.sub.2SO.sub.4, and
concentrated in vacuo. Purification by silica gel chromatography
(50% to 100% ethyl acetate/hexanes) gave 72 mg (19%) of
intermediate 59d as a white foam (followed by 186 mg (50%) of
intermediate 59e). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.99
(s, 1H), 8.64 (s, 1H), 8.63 (s, 1H), 8.45 (s, 1H), 7.83-7.87 (m,
1H), 7.69 (d, 1H, J=8.7 Hz), 7.50-7.53 (m, 1H), 7.43 (dd, 1H,
J=8.7, 1.5 Hz), 7.26-7.32 (m, 2H), 6.86 (d, 1H, J=15.9 Hz),
6.33-6.41 (m, 1H), 5.84 (s, 2H), 4.42 (br s, 2H), 3.65 (t, 2H,
J=8.1 Hz), 2.28 (s, 3H), 1.73 (br s, 1H), 0.95 (t, 2H, J=8.1 Hz),
-0.04 (s, 9H).
(e) Intermediate
59e--(E)-3-{5-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymeth-
yl)-1H-indazol-5-yl]4-methyl-pyridin-3-yl}-propan-1-ol
[0398] See the procedure for intermediate 59d above. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 10.17 (s, 1H), 8.63 (s, 1H), 8.40 (s,
2H), 7.83-7.87 (m, 1H), 7.68 (d, 1H, J=8.7 Hz), 7.49-7.52 (m, 1H),
7.43 (dd, 1H, J=8.7, 1.5 Hz), 7.26-7.31 (m, 2H), 5.83 (s, 2H), 3.77
(t, 2H, J=6.3 Hz), 3.65 (t, 2H, J=8.1 Hz), 2.82 (t, 2H, J=7.5 Hz),
2.24 (s, 3H), 1.88-1.95 (m, 2H), 1.74 (br s, 1H), 0.94 (t, 2H,
J=8.1 Hz), -0.05 (s, 9H).
(f) Example
59--(E)-3-{5-[3-1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin--
3-yl}-prop-2-en-1-ol
[0399] The title compound was prepared in 50% yield by the
SEM-deprotection of intermediate 59d in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.78 (s, 1H), 13.02 (s, 1H), 8.63 (s, 1H), 8.43 (s, 1H),
8.35 (s, 1H), 7.75 (d, 1H, J=8.7 Hz), 7.63 (br.s, 1H), 7.55 (br s,
1H), 7.46 (dd, 1H, J=8.7, 1.5 Hz), 7.20 (br s, 2H), 6.83 (d, 1H,
J=15.9 Hz), 6.37-6.46 (m, 1H), 4.99 (t, 1H, J=5.4 Hz), 4.19 (s,
2H), 2.23 (s, 3H). Anal. (C.sub.23H.sub.19N.sub.5O.0.6H.sub.2O) C,
H, N. MS (ES) [m+H]/z calculated 382, found 382.
(g) Example
60--(E)-3-{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-
-3-yl}-propan-1-ol
[0400] The title compound was prepared in 62% yield by the
SEM-deprotection of intermediate 59e in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0
13.77 (s, 1H), 13.02 (s, 1H), 8.41 (s, 1H), 8.37 (s, 1H), 8.30 (s,
1H), 7.73 (d, 1H, J=8.7 Hz), 7.67 (br.s, 1H), 7.52 (br s, 1H), 7.44
(dd, 1H, J=8.7, 1.5 Hz), 7.19 (br s, 2H), 4.57 (t, 1H, J=5.1 Hz),
3.49 (q, 2H, J=6.0 Hz), 2.74 (t, 2H, J=7.8 Hz), 2.21 (s, 3H),
1.69-1.79 (m, 2H). Anal. (C.sub.23H.sub.21N.sub.5O.0.5H.sub.2O) C,
H, N. MS (ES) [m+H]/z calculated 384, found 384.
EXAMPLE 61
5-[3-1H-Benzoimidazol-2yl)-1H-indazol-5-yl]-4-ethyl-[3,4']bipyridinyl
[0401] ##STR110##
(a) Intermediate 61a--3,5-Dibromo-4-ethyl-pyridine
[0402] The title compound was prepared in 74% yield by the
substitution of iodoethane for iodomethane in the procedure for the
preparation of 3,5-dibromo-4-methyl-pyridine (see Gu, et al., Tet.
Lett., 37, 15, 1996, 2565-2568). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.49 (s, 2H), 2.92 (q, 2H, J=7.5 Hz), 1.12 (t, 3H, J=7.5
Hz).
(b) Intermediate 61b--5-Bromo-4-ethyl-[3,4']bipyridinyl
[0403] The title compound was prepared in 51% yield from
intermediate 61a and 4-pyridyl boronic acid similar to the
procedure for intermediate 53a. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.71-8.74 (m, 3H), 8.28 (s, 1H), 7.24 (dd, 2H, J=4.5, 1.5
Hz), 2.70 (q, 2H, J=7.5 Hz), 1.10 (t, 3H, J=7.5 Hz). Anal.
(C.sub.12H.sub.11BrN.sub.2) C, H, N. MS (ES) [m+H]/z calculated
263/265, found 263/265.
(c) Intermediate
61c--5-[3-(1H-Benzoimidazol-2yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-i-
ndazol-5-yl]-4-ethyl-[3,4']bipyridinyl
[0404] Intermediate 61b (188 mg, 0.71 mmol), intermediate 25a (385
mg, 0.79 mmol) and potassium phosphate (226 mg, 1.06 mmol) were
stirred in DMA (6 mL)/H.sub.2O (0.8 mL) in a flask purged with
argon. Tetrakis(triphenylphosphine)palladium (0) (82 mg, 0.07 mmol)
was added, and the reaction stirred at 92.degree. C. under argon
for 16 hours The solution was diluted with ethyl acetate, washed
with H.sub.2O and brine, dried over Na.sub.2SO.sub.4, and
concentrated in vacuo. Purification by silica gel chromatography
(75% to 100% ethyl acetate/hexanes) gave 232 mg (60%) of
intermediate 61c as a clear oil. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 10.18 (s, 1H), 8.71-8.75 (m, 3H), 8.57 (s, 1H), 8.41 (s,
1H), 7.84-7.87 (m, 1H), 7.71 (d, 1H, J=8. Hz), 7.48-7.53 (m, 2H),
7.36 (dd, 2H, J=4.5, 1.5 Hz), 7.26-7.32 (m, 2H), 5.84 (s, 2H), 3.65
(t, 2H, J=8.1 Hz), 2.64 (q, 2H, J=7.5 Hz), 0.94 (t, 2H, J=8.1 Hz),
0.77 (t, 3H, J=7.5 Hz), -0.04 (s, 9H).
(d) Example
61--5-[3-(1H-benzoimidazol-2yl)-1H-indazol-5-yl]-4-ethyl-[3,4']bipyridiny-
l
[0405] The title compound was prepared in 61% yield by the
SEM-deprotection of intermediate 61c in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.79 (s, 1H), 13.02 (s, 1H), 8.71 (dd, 2H, J=4.5, 1.5 Hz),
8.51 (s, 2H), 8.40 (s, 1H), 7.78 (d, 1H, J=8.7 Hz), 7.68 (d, 1H,
J=7.5 Hz), 7.49-7.56 (m, 4H), 7.14-7.25 (m, 2H), 2.59 (q, 2H, J=7.5
Hz), 0.69 (t, 3H, J=7.5 Hz). Anal.
(C.sub.26H.sub.20N.sub.6.0.3H.sub.2O) C, H, N. MS (ES) [m+H]/z
calculated 417, found 417.
EXAMPLE 62
3-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-[2,3']bipyridinyl
[0406] ##STR111## ##STR112##
(a) Intermediate
62a--3-(1H-Benzoimidazol-2-yl)-5-iodo-1-(4-methoxy-benzyl)-1H-indazole
[0407] The title compound was prepared in 59% yield from
intermediate 19d and phenylenediamine similar to the procedure for
intermediate 7c'. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.06
(s, 1H), 8.91 (s, 1H), 7.70-7.78 (m, 3H), 7.51 (dd, 1H, J=6.3, 2.1
Hz), 7.19-7.28 (m, 4H), 6.88 (dd, 2H, J=6.6, 2.1 Hz), 5.72 (s, 2H),
3.69 (s, 3H). Anal. (C.sub.22H.sub.17IN.sub.4O) C, H, N.
(b) Intermediate
62b--3-(1H-Benzoimidazol-2-yl)-1-(4-methoxy-benzyl)-5-(4,4,5,5-tetramethy-
l[1,3,2]dioxaborolan-2-yl)-1H-indazole
[0408] The title compound was prepared in 73% yield from
intermediate 62a in a manner analogous to the preparation of
intermediate 19e. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.03
(s, 1H), 8.93 (d, 1H, J=4.2 Hz), 7.78-7.84 (m, 2H), 7.73 (dd, 1H,
J=8.7, 0.9 Hz), 7.51 (d, 1H, J=7.2 Hz), 7.20-7.27 (m, 4H), 6.87 (d,
2H, J=8.7 Hz), 5.74 (s, 2H), 3.68 (s, 3H), 1.34 (s, 12H). Anal.
(C.sub.28H.sub.29BN.sub.4O.sub.3) C, H, N.
(c) Intermediate 62c--5'-Bromo-4'-methyl-[2,3']bipyridinyl
[0409] 3,5-Dibromo-4-methyl-pyridine (2.0 g, 7.8 mmol) and
2-tributylstannanyl-pyridine (2.4 g, 6.5 mmol) were stirred in
dioxane (20 mL) in a flask purged with argon.
Tetrakis(triphenylphosphine)-palladium(0) (600 mg, 0.5 mmol) was
added, and the reaction stirred at 100.degree. C. for 80 hours. The
solution was concentrated in vacuo and purified by silica gel
chromatography (30% to 50% ethyl acetate/hexanes, two
purifications) to give 788 mg (49%) of intermediate 62c as a white
solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.72-8.75 (m, 1H),
8.70 (s, 1H), 8.46 (s, 1H), 7.78-7.84 (m, 1H), 7.31-7.42 (m, 2H),
2.42 (s, 3H). Anal. (C.sub.1HaBrN.sub.2) C, H, N.
(d) Intermediate
62d--3-[3-(1H-Benzoimidazol-2-yl)-1-(4-methoxy-benzyl)-1H-indazol-5-yl]-4-
-methyl-[2,3']bipyridinyl
[0410] The title compound was prepared in 76% yield from
intermediate 62b and intermediate 62c similar to the procedure for
intermediate 61c. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.08
(s, 1H), 8.73 (d, 1H, J=4.2 Hz), 8.52-8.57 (m, 3H), 7.92-7.98 (m,
2H), 7.68-7.72 (m, 2H), 7.58 (dd, 1H, J=8.7, 1.5 Hz), 7.51 (d, 1H,
J=7.2 Hz), 7.43-7.47 (m, 1H), 7.36 (d, 2H, J=8.7 Hz), 7.17-7.23 (m,
2H), 6.91 (d, 2H, J=8.7 Hz), 5.79 (s, 2H), 3.70 (s, 3H), 2.21 (s,
3H). Anal. (C.sub.33H.sub.26N.sub.6O) C, H, N.
(e) Example
62--3-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-[2,3']bipyridi-
nyl
[0411] Intermediate 62d (400 mg, 9.77 mmol) was stirred in a
solution of concentrated H.sub.2SO.sub.4 (1 mL) and anisole (1 mL)
in TFA (8 mL) for 48 hours. The solution was concentrated to
.about.3 mL in vacuo, and was then quenched with sat. NaHCO.sub.3
and extracted with 4:1 ethyl acetate/THF. Organics were washed with
brine, dried (MgSO.sub.4), and concentrated in vacuo. Purification
by silica gel chromatography (0.2% NH.sub.4OH/6% to 10% MeOH/ethyl
acetate) gave 102 mg (33%) of example 62 as a white solid. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 13.78 (s, 1H), 13.02 (s, 1H),
8.74 (d, 1H, J=4.2 Hz), 8.57 (s, 1H), 8.53 (s, 1H), 7.51 (s, 1H),
7.93-7.99 (m, 1H), 7.77 (d, 1H, J=8.7 Hz), 7.70 (d, 2H, J=7.8 Hz),
7.43-7.56 (m, 3H), 7.20 (br s, 2H), 2.23 (s, 3H). Anal.
(C.sub.25H.sub.18N.sub.6.0.5H.sub.2O) C, H, N. MS (ES) [m+H]/z
calculated 403, found 403.
EXAMPLE 63
1-{5-[3-(1H-Benzoimidazol-2yl)-1H-indazol-5-yl]-3,4-dihydro-2H-[1,7]naphth-
yridin-1-yl}-ethanone
[0412] ##STR113## ##STR114##
(a) Intermediate
63a--5-Bromo-1,2,3,4-tetrahydro-[1,7]naphthyridine
[0413] Intermediate 54c (1.16 g, 3.08 mmol) was stirred with
tetrabutylammonium fluoride hydrate (2.0 g, 7.65 mmol) in
acetonitrile (16 mL) at 72.degree. C. for 18 hours. The solution
was allowed to cool and was diluted with ethyl acetate. Organics
were washed with sat. NaHCO.sub.3 and brine, dried
(Na.sub.2SO.sub.4), and concentrated in vacuo. Purification by
silica gel chromatography gave 524 mg (80%) of intermediate 63a as
a white solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.96 (s,
1H), 7.74 (s, 1H), 4.00 (br s, 1H), 3.28-3.33 (m, 2H), 2.74 (q, 2H,
J=6.6 Hz), 1.92-2.01 (m, 2H). Anal. (C.sub.8H.sub.9BrN.sub.2) C, H,
N.
(b) Intermediate
63b--1-(5-Bromo-3,4-dihydro-2H-[1,7]naphthyridin-1-yl)-ethanone
[0414] Intermediate 63a (212 mg, 1.0 mmol), DIEA (1.4 mL, 8.0
mmol), and acetic anhydride (4.0 mmol) were stirred in dry
chloroform (10 mL) at 68.degree. C. for 40 hours. The solution was
washed with saturated NaHCO.sub.3 and brine, dried
(Na.sub.2SO.sub.4), and concentrated in vacuo. Purification by
silica gel chromatography (70% ethyl acetate/hexanes) gave 242 mg
(95%) of intermediate 63b as a white solid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.61 (br s, 1H), 8.46 (s, 1H), 3.79 (q, 2H,
J=6.0 Hz), 2.83 (t, 2H, J=6.9 Hz), 2.93 (s, 3H), 2.01-2.08 (m, 2H).
Anal. (C.sub.10H.sub.11BrN.sub.2O) C, H, N.
(c) Intermediate
63c--1-{5-[3-(1H-Benzoimidazol-2yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1-
H-indazol-5-yl]-3,4-dihydro-2H-[1,7]naphthyridin-1-yl}-ethanone
[0415] The title compound was prepared in 83% yield from
intermediate 25a and intermediate 63c similar to the procedure for
intermediate 61c. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.06
(s, 1H), 8.68 (s, 1H), 8.55 (br s, 1H), 8.42 (s, 1H), 7.84-7.87 (m,
1H), 7.71 (d, 1H, J=8.7 Hz), 7.50-7.53 (m, 1H), 7.46 (dd, 1H,
J=8.7, 1.5 Hz), 7.27-7.32 (m, 2H), 5.84 (s, 2H), 3.84 (t, 2H, J=6.6
Hz), 3.64 (t, 2H, J=8.1 Hz), 2.70 (t, 2H, J=6.6 Hz), 2.36 (s, 3H),
1.87-1.93 (m, 2H), 0.94 (t, 2H, J=8.1 Hz), -0.04 (s, 9H). Anal.
(C.sub.30H.sub.34N.sub.6O.sub.2Si.0.5H.sub.2O) C, H, N.
(d) Example
63--1-{5-[3-(1H-Benzoimidazol-2yl)-1H-indazol-5-yl]-3,4-dihydro-2H-[1,7]n-
aphthyridin-1-yl}-ethanone
[0416] The title compound was prepared in 65% yield by the
SEM-deprotection of intermediate 63c in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.77 (s, 1H), 13.02 (s, 1H), 8.78 (s, 1H), 8.46 (br s,
1H), 8.27 (s, 1H), 7.75 (d, 1H, J=8.7 Hz), 7.67 (br.s, 1H), 7.49
(dd, 2H, J=5.7, 1.5 Hz), 7.20 (br s, 2H), 3.74 (t, 2H, J=6.3 Hz),
2.63 (t, 2H, J=6.3 Hz), 2.27 (s, 3H), 1.79-1.85 (m, 2H). Anal.
(C.sub.24H.sub.20N.sub.6O) C, H, N. MS (ES) [m+H]/z calculated 409,
found 409.
EXAMPLE 64
5-[3-1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-nicotinamide
[0417] ##STR115##
(a) Intermediate 64a--3-Bromo-4-methyl-5-carboxamoyl-pyridine
[0418] A solution of 3,5-dibromopyridine (3 g, 11.9 mmol) in 150 mL
dry THF was cooled to -100.degree. C. (ether-N.sub.2 bath) and BuLi
(5 mL of a 2.5 M solution in hexanes, 12.5 mmol) was added dropwise
over 3 minutes. After 2 additional minutes trimethylsilylisocyanate
(3.8 mL of 85% solution, 3.24 g, 24 mmol) was added to the yellow
anion and the whole was stirred for 30 minutes at -100.degree. C.,
30 minutes at -60.degree. C. and then it was allowed to reach
25.degree. C. and stirred for 12 hours. The reaction was poured
into saturated aqueous NH.sub.4Cl, extracted with ethyl acetate,
the organic layers were washed with brine, dried
(Na.sub.2SO.sub.4), and concentrated. Purification of the residue
by chromatography on silica (5:1 to 10:1 hexanes-ethyl acetate then
100% ethyl acetate) afforded 236 mg (9%) of amide 64a. R.sub.f=0.09
(50% ethyl acetate in hexanes); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.70 (bs, 1H), 8.54 (bs, 1H), 5.98 (bs, 1H), 5.93 (bs, 1H).
(LCMS: M+215).
(b) Intermediate
64b--5-[3-(1H-Benzoimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H--
indazol-5-yl]-4-methyl-nicotinamide
[0419] The title compound was prepared in 75% yield from
intermediate 25a and intermediate 64a similar to the procedure for
intermediate 61c. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.18
(s, 1H), 8.66 (s, 1H), 8.64 (s, 1H), 8.59 (s, 1H), 7.82-7.86 (m,
1H), 7.70 (d, 1H, J=8.4 Hz), 7.48-7.52 (m, 1H), 7.42 (dd, 1H,
J=8.4, 1.5 Hz), 7.26-7.31 (m, 2H), 6.13 (br s, 1H), 5.91 (br s,
1H), 5.83 (s, 2H), 3.64 (t, 2H, J=8.1 Hz), 2.40 (s, 3H), 0.94 (t,
2H, J=8.1 Hz), -0.04 (s, 9H).
(c) Example
64--5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-nicotinamide
[0420] The title compound was prepared in 77% yield by the
SEM-deprotection of intermediate 64b in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.80 (s, 1H), 13.03 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H),
8.45 (s, 1H), 8.05 (s, 1H), 7.76 (d, 1H, J=8.7 Hz), 7.68 (br.s,
2H), 7.44-7.52 (m, 2H), 7.16-7.22 (m, 2H), 2.29 (s, 3H). Anal.
(C.sub.21H.sub.16N.sub.6O.0.55H.sub.2O) C, H, N. MS (ES) [m+H]/z
calculated 369, found 369.
EXAMPLE 65
3-(1H-Benzoimidazol-2-yl)-5-[5-(H-imidazol-4-yl)-4-methyl-pyridin-3-yl]-1H-
-indazole
[0421] ##STR116##
(a) Intermediate
65a--3-Bromo-4-methyl-5-1H-imidazol-4-yl-pyridine
[0422] To a stirred suspension of tosylmethyl isocyanide (1.02 g,
5.25 mmol) and 3-bromo-4-methyl-5-formyl pyridine (1.0 g, 5 mmol)
in 5 mL of dry ethanol was added finely powdered NaCN (25 mg, 0.5
mmol) at 25.degree. C. After 30 minutes the reaction was
concentrated to an oil. The resulting oil was added to a saturated
solution of ammonia in dry methanol in a sealed tube and heated to
100.degree. C. for 24 hours. Cooling and concentration followed by
chromatography on silica (10:1 ethyl acetate-hexanes) afforded 167
mg (14%) of 65a as a white solid. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 12.45 (bs, 1H), 8.71 (s, 1H), 8.55 (s, 1H),
7.83 (s, 1H), 7.52 (s, 1H), 2.56 (s, 3H).
(b) Intermediate
65b--3-Bromo-4-methyl-5-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol--
4-yl]-pyridine
[0423] Intermediate 65a was SEM-protected in 45% yield in a manner
analogous to the procedure for intermediate 49a. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.67 (s, 1H), 8.60 (s, 1H), 7.70 (s, 1H),
7.21 (d, 1H, J=1.2 Hz), 5.33 (s, 2H), 3.56 (t, 2H, J=8.1 Hz), 2.58
(s, 3H), 0.94 (t, 2H, J=8.1 Hz), 0.00 (s, 9H). Anal.
(C.sub.15H.sub.22BrN.sub.3OSi) C, H, N.
(c) Intermediate
65c--3-(1H-Benzoimidazol-2-yl)-5-{5-[1-(2-trimethylsilanyl-ethoxymethyl)--
1H-imidazol-4-yl]-4-methyl-pyridin-3-yl}-1-(2-trimethylsilanyl-ethoxymethy-
l)-1H-indazole
[0424] The title compound was prepared in 83% yield from
intermediate 25a and intermediate 65b similar to the procedure for
intermediate 61c. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.09
(s, 1H), 8.85 (s, 1H), 7.70 (s, 1H), 8.50 (s, 1H), 7.84-7.88 (m,
1H), 7.68-7.74 (m, 2H), 7.47-7.52 (m, 2H), 7.26-7.31 (m, 3H), 5.84
(s, 2H), 5.36 (s, 2H), 3.55-3.68 (m, 4H), 2.41 (s, 3H), 0.92-0.98
(m, 4H), -0.01 (s, 9H), -0.05 (s, 9H).
(d) Example
65--3-(1H-Benzoimidazol-2-yl)-5-[5-(1H-imidazol-4-yl)-4-methyl-pyridin-3--
yl]-1H-indazole
[0425] The title compound was prepared in 43% yield by the
SEM-deprotection of intermediate 65c in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.78 (s, 1H), 13.02 (s, 1H), 12.38 (s, 1H), 8.83 (s, 1H),
8.47 (s, 1H), 8.35 (s, 1H), 7.83 (d, 1H, J=0.9 Hz), 7.76 (d, 1H,
J=8.4 Hz), 8.69 (d, 1-H, J=7.5 Hz), 7.47-7.51 (m, 3H), 7.16-7.22
(m, 2H), 2.37 (s, 3H). Anal. (C.sub.23H.sub.17N.sub.7.2.5H.sub.2O)
C, H, N. MS (ES) [m+H]/z calculated 392, found 392.
EXAMPLE 66
4-[3-4,5,6,7-Tetrahydro-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinoli-
ne
[0426] ##STR117##
(a) Intermediate
66a--5-Iodo-3-(4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl)-1H-indazole
[0427] A solution of intermediate 7b' (500 mg, 1.24 mmol),
1,2-cyclohexanedione (146 mg, 1.3 mmol), and ammonium acetate (575
mg, 7.44 mmol) in ethanol (12 mL) was stirred at reflux for 4
hours. The reaction was diluted with ethyl acetate and washed with
brine, dried (Na.sub.2SO.sub.4), and concentrated in vacuo.
Purification by silica gel chromatography (20% ethyl
acetate/hexanes) gave 366 mg (60%) of the title compound as a light
yellow foam. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.47 (br s,
1H), 8.88 (d, 1H, J=0.9 Hz), 7.69 (dd, 1H, J=8.7,1.5 Hz), 7.31 (d,
1H, J=8.7 Hz), 5.67 (s, 2H), 3.52 (t, 2H, J=8.1 Hz), 2.70 (br s,
4H), 1.89 (br s, 4H), 0.88 (t, 2H, J=8.1 Hz), -0.06 (s, 9H). Anal.
(C.sub.20H.sub.271N.sub.4OSi) C, H, N.
(b) Intermediate
66b--4-[3-(4,5,6,7-Tetrahydro-1H-benzoimidazol-2-yl)-1-(2-trimethylsilany-
l-ethoxymethyl)-1H-indazol-5-yl]-isoquinoline
[0428] The title compound was prepared in 75% yield from
intermediate 66a and isoquinoline-4-boronic acid (EP 976747)
similar to the procedure for intermediate 7d'. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 9.57 (br s, 1H), 9.28 (s, 1H), 8.67 (s,
1H), 8.58 (s, 1H), 8.04-8.08 (m, 1H), 7.85-7.89 (s, 1H), 7.57-7.70
(m, 4H), 5.80 (s, 2H), 3.63 (t, 2H, J=8.1 Hz), 2.7 (br s, 4H), 1.86
(br s, 4H), 0.96 (t, 2H, J=8.1 Hz), -0.03 (s, 9H).
(c) Example
66--4-[3-(4,5,6,7-Tetrahydro-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-isoq-
uinoline
[0429] The title compound was prepared in 64% yield by the
SEM-deprotection of intermediate 66b in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.31 (s, 1H), 12.25 (s, 1H), 9.36 (s, 1H), 8.49 (s, 1H),
8.43 (s, 1H), 8.24 (d, 1H, J=7.8 Hz), 7.69-7.85 (m, 4H), 7.53 (dd,
1H, J=8.7, 1.8 Hz), 2.50 (br s, 4H), 1.73 (br s, 4H). Anal.
(C.sub.23H.sub.19N.sub.5.0.2H.sub.2O) C, H, N. MS (ES) [m+H]/z
calculated 366, found 366.
EXAMPLE 67
4-[3-(4-Methyl-5-phenyl-1H-imidazol-2-yl)-1H-indazol-5-yl]-isoquinoline
[0430] ##STR118##
(a) Intermediate
67a--5-Iodo-1-(4-methoxy-benzyl)-3-(4-methyl-5-phenyl-1H-imidazol-2-yl)-1-
H-indazole
[0431] The title compound was prepared from intermediate 19d and
1-phenyl-1,2-propanedione similar to the procedure for intermediate
66a. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.87 (br s, 0.5H),
9.71 (br s, 0.5H), 8.98 (br s, 0.5H), 8.92 (br s, 0.5H), 7.84 (d,
1H, J=7.2 Hz), 7.61 (dd, 1H, J=8.7, 1.5 Hz), 7.44-7.53 (m, 3H),
7.31 (d, 1H, J=7.5 Hz), 7.11 (app d, 3H, J=8.7 Hz), 6.81 (dd, 2H,
J=6.6, 1.8 Hz), 5.49 (s, 2H), 3.77 (s, 3H), 2.55 (s, 3H). Anal.
(C.sub.25H.sub.21IN.sub.4O) C, H, N.
(b) Intermediate
67b--4-[1-(4-Methoxy-benzyl)-3-(4-methyl-5-phenyl-1H-imidazol-2-yl)-1H-in-
dazol-5-yl]-isoquinoline
[0432] The title compound was prepared in 75% yield from
intermediate 67a and isoquinoline-4-boronic acid (EP 976747) in a
manner analogous to the procedure for intermediate 7d' .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 9.97 (br s, 0.5H), 9.85 (br s, 0.5H),
9.28 (s, 1H), 8.76 (br s, 0.5H), 8.70 (br s, 0.5H), 8.59 (s, 1H),
8.03-8.10 (m, 1H), 7.90 (br s, 1H), 7.75 (br s, 1H), 7.37-7.68 (m,
8H), 7.20-7.26 (m, 2H), 6.86 (dd, 2H, J=6.6, 1.5 Hz), 5.60 (s, 2H),
3.78 (s, 3H), 2.54 (br s, 1.5H), 2.49 (br s, 1.5H).
(c) Example
67--4-[3-(4-Methyl-5-phenyl-1H-imidazol-2-yl)-1H-indazol-5-yl]-isoquinoli-
ne
[0433] The title compound was prepared in 15% yield by the
PMB-deprotection of intermediate 67b in a manner analogous to the
procedure for example 62. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 12.67 (s, 1H), 13.02 (s, 1H), 9.38 (s, 1H), 8.57 (s, 1H),
8.53 (s, 1H), 8.25 (d, 1H, J=7.5 Hz), 7.66-7.91 (m, 6H), 7.57 (dd,
1H, J=8.7, 1.5 Hz), 7.30-7.33 (m, 2H), 7.15-7.18 (m, 1H), 2.50 (s,
3H). Anal. (C.sub.26H.sub.19N.sub.5.0.5H.sub.2O) C, H, N. MS (ES)
[m+H]/z calculated 402, found 402.
EXAMPLE 68
Dimethyl-{2-[5-(4-methyl-[3,4']bipyridinyl-5-yl)-1H-indazol-3-yl]-1H-benzo-
imidazol-4-ylmethyl}-amine
[0434] ##STR119## ##STR120##
(a) Intermediate
68a--{2-[5-Iodo-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benzoimidazol-4--
ylmethyl}-methanol
[0435] The title compound was prepared in 40% yield from
intermediate 19d and intermediate 23b similar to the procedure for
intermediate 7c'. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.02
(s, 0.5H), 12.87 (s, 0.5H), 8.91 (s, 1H), 7.64-7.77 (m, 2.5H), 7.37
(dd, 0.5H, J=7.5, 1.5 Hz), 7.18-7.27 (m, 4H), 6.88 (d, 2H, J=8.4
Hz), 5.73 (s, 1H), 5.71 (s, 1H), 5.14-5.24 (m, 1H), 5.03 (d, 1H,
J=5.7 Hz), 4.86 (d, 1H, J=5.7 Hz), 3.69 (s, 3H).
(b) Intermediate
68b--{2-[5-Iodo-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-benzoimidazol-4--
ylmethyl}-dimethyl-amine
[0436] Intermediate 68a (2.5 g, 4.9 mmol) and DIEA (1.38 mL, 10
mmol) were stirred in THF (90 mL) at 0.degree. C. Methanesulfonyl
chloride (0.76 mL, 9.8 mmol) was added, and the reaction stirred
for 2.5 hours at 0.degree. C. Dimethylamine was bubbled through the
solution for 1 minute, and the reaction was allowed to stir for 2
hours while warming to room temperature. The solution was quenched
with H.sub.2O and extracted with ethyl acetate. Organics were
washed with sat. NaHCO.sub.3 and brine, dried (Na.sub.2SO.sub.4),
and concentrated in vacuo. Purification by silica gel
chromatography (0.2% NH.sub.4OH/3% MeOH/ethyl acetate) gave 2.56 g
(97%) of intermediate 68b as a white foam. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 9.07 (d, 1H, J=0.9 Hz), 7.80 (d, 1H, J=7.8 Hz),
7.63 (dd, 1H, J=8.7, 1.5 Hz), 7.07-7.25 (m, 5H), 6.85 (dd, 2H,
J=6.6, 1.8 Hz), 5.61 (s, 2H), 3.77 (app s, 5H), 2.33 (s, 6H).
(c) Intermediate
68c--{2-[1-(4-Methoxy-benzyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan--
2-yl)-1H-indazol-3-yl]-1H-benzoimidazol-4-ylmethyl}-dimethyl-amine
[0437] The title compound was prepared in 62% yield from
intermediate 68b similar to the method for the preparation of
intermediate 19e. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.11
(s, 1H), 7.82 (dd, 2H, J=8.4, 0.9 Hz), 7.35 (dd, 1H, J=8.4, 0.9
Hz), 7.16-7.21 (m, 4H), 6.85 (dd, 2H, J=6.9, 1.8 Hz), 5.64 (s, 2H),
3.80 (br s, 2H), 3.76 (s, 3H), 2.35 (s, 6H), 1.37 (s, 12H).
(d) Intermediate
68d--Dimethyl-{2-[5-(4-methyl-[3,4']bipyridinyl-5-yl)-1-(4-methoxy-benzyl-
)-1H-indazol-3-yl]-1H-benzoimidazol-4-ylmethyl}-amine
[0438] The title compound was prepared in 85% yield from
intermediate 68c and intermediate 53a similar to the procedure for
intermediate 61c. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.69-8.75 (m, 4H), 8.57 (s, 1H), 8.43 (s, 1H), 7.75 (d, 1H, J=8.1
Hz), 7.46 (d, 1H, J=8.7 Hz), 7.34-7.40 (m, 3H), 7.25-7.28 (m, 1H),
7.19 (t, 1H, J=7.6 Hz), 7.08 (d, 1H, J=7.2 Hz), 6.89 (d, 2H, J=8.7
Hz), 5.70 (s, 2H), 3.79 (app s, 5H), 2.34 (s, 6H), 2.19 (s,
3H).
(e) Example
68--Dimethyl-{2-[5-(4-methyl-[3,4']bipyridinyl-5-yl)-1H-indazol-3-yl]-1H--
benzoimidazol-4-ylmethyl}-amine
[0439] The title compound was prepared in 20% yield by the
PMB-deprotection of intermediate 68d in a manner analogous to the
procedure for example 62. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.80 (s, 1H), 13.01 (s, 1H), 8.71 (dd, 2H, J=4.5, 1.5 Hz),
8.56 (br s, 2H), 8.47 (s, 1H), 7.78 (d, 1H, J=8.7 Hz), 7.39-7.58
(m, 4H), 7.17 (br s, 2H), 3.76-3.99 (m, 2H), 2.14-7.29 (m, 9H).
Anal. (C.sub.28H.sub.25N.sub.7.1.5H.sub.2O) C, H, N. MS (ES)
[m+H]/z calculated 460, found 460.
EXAMPLE 69
(3-{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl)]-4-methyl-pyridin-3-yl}--
phenyl)-methanol
[0440] ##STR121##
(a) Intermediate
69a--[3-(5-Bromo-4-methyl-pyridin-3-yl)-phenyl]-methanol
[0441] The title compound was prepared in 79% yield from
3,5-dibromo-4-methyl-pyridine and 3-(hydroxymethyl)-phenyl-boronic
acid similar to the procedure for intermediate 53a. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 8.62 (s, 1H), 8.22 (s, 1H), 7.42-7.46
(m, 2H), 7.29 (s, 1H), 7.16-7.20 (m, 1H), 4.76 (d, 2H, J=5.7 Hz),
2.48 (t, 1H, J=5.7 Hz), 2.32 (s, 3H). Anal.
(C.sub.13H.sub.12BrNO.0.2H.sub.2O) C, H, N.
(b) Intermediate
69b--(3-{5-[3-(1H-Benzoimidazol-2-yl)-1-(4-methoxy-benzyl)-1H-indazol-5-y-
l]4-methyl-pyridin-3-yl}-phenyl)-methanol
[0442] The title compound was prepared in 83% yield from
intermediate 62b and intermediate 69a similar to the procedure for
intermediate 61c. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.39
(s, 1H), 8.69 (s, 1H), 8.45 (s, 1H), 8.36 (s, 1H), 7.83-7.87 (m,
1H), 7.36-7.49 (m, 7H), 7.22-7.31 (m, 4H), 6.84 (d, 2H, J=8.7 Hz),
5.60 (s, 2H), 4.79 (s, 2H), 3.76 (s, 3H), 2.51 (br s, 1H), 2.11 (s,
3H).
(c) Example
69--(3-{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3--
yl}-phenyl)-methanol
[0443] The title compound was prepared in 41% yield by the
PMB-deprotection of intermediate 69b in a manner analogous to the
procedure for example 62. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.79 (s, 1H), 13.02 (s, 1H), 849 (d, 2H, J=6.3 Hz), 8.41
(s, 1H), 7.76 (d, 1H, J=8.7 Hz), 7.34-7.69 (m, 7H), 7.19-7.22 (m,
2H), 5.25 (br s, 1H), 4.58 (s, 2H), 2.15 (s, 3H). Anal.
(C.sub.27H.sub.21N.sub.5O.sub.2.1.2H.sub.2O) C, H, N. MS (ES)
[m+H]/z calculated 432, found 432.
EXAMPLE 70
N-[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-methanesu-
lfonamide
[0444] ##STR122##
(a) Intermediate
70a--N-{2-[5-Isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-3H-be-
nzoimidazol-5-yl}-methanesulfonamide
[0445] The title compound was prepared in 89% yield from
intermediate 19f and N-(3,4-diaminophenyl)methanesulfonamide (see
Rajappa et al., Indian J. Chem. Sect. B, 19, 7, 1980, 533-535)
similar to the procedure for intermediate 7c'. .sup.1H NMR (300
MHz, MeOD-d.sub.4) .delta. 9.26 (s, 1H), 8.63 (s, 1H), 8.49 (s,
1H), 8.20 (d, 1H, J=7.8 Hz), 7.96 (d, 1H, J=7.8 Hz), 7.72-7.81 (m,
3H), 7.58-7.63 (m, 3H), 7.35 (d, 2H, J=8.7 Hz), 7.16 (brs, 1H),
6.89 (d, 2H, J=8.7 Hz), 5.76 (s, 2H), 3.75 (s, 3H), 2.93 (s,
3H).
(b) Example
70--N-[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-meth-
anesulfonamide
[0446] The title compound was prepared in 48% yield by the
PMB-deprotection of intermediate 70a in a manner analogous to the
procedure for example 62. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.83 (s, 1H), 13.04 (s, 1H), 9.54 (br s, 1H), 9.40 (s,
1H), 8.60 (s, 1H), 8.55 (s, 1H), 8.27 (d, 1H, J=8.7 Hz), 7.72-7.88
(m, 4H), 7.63 (dd, 1H, J=8.7, 1.5 Hz), 7.54 (br s, 1H), 7.46 (s,
1H), 7.07 (d, 1H, J=7.8 Hz), 2.91 (s, 3H). Anal.
(C.sub.24H.sub.18N.sub.6O.sub.2S.1.05H.sub.2O) C, H, N, S. MS (ES)
[m+H]/z calculated 455, found 455.
EXAMPLE 71
N-{2-[5-(4-methyl-[3,4']bipyridinyl-5-yl)-1H-indazol-3-yl}-3H-benzoimidazo-
l-5-yl]-methanesulfonamide
[0447] ##STR123##
(a) Intermediate
71a--1-(4-Methoxy-benzyl)-6-(4-methyl-[3,4']bipyridinyl-5-yl)-1H-indazole-
-3-carbaldehyde
[0448] The title compound was prepared in 76% yield from
intermediate 19e and intermediate 53a similar to the procedure for
intermediate 61c. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.28
(s, 1H), 8.73 (dd, 2H, J=4.5, 1.5 Hz), 8.49 (s, 1H), 8.43 (s, 1H),
8.31 (s, 1H), 7.53 (d, 1H, J=8.7 Hz), 7.40 (dd, 1H, J=8.7, 1.5 Hz),
7.26-7.34 (m, 4H), 6.89 (d, 2H, J=8.7 Hz), 5.67 (s, 2H), 3.79 (s,
3H), 2.15 (s, 3H). Anal.
(C.sub.27H.sub.22N.sub.4O.sub.2.0.25H.sub.2O) C, H, N.
(b) Intermediate
71b--N-{2-[5-(4-methyl-[3,4']bipyridinyl-5-yl)-1-(4-methoxy-benzyl)-1H-in-
dazol-3-yl)-3H-benzoimidazol-5-yl]-methanesulfonamide
[0449] The title compound was prepared in 96% yield from
intermediate 71a and N-(3,4-diaminophenyl)methanesulfonamide
similar to the procedure for intermediate 7c'. .sup.1H NMR (300
MHz, MeOD-d.sub.4) .delta. 8.66 (dd, 2H, J=4.5, 1.5 Hz), 8.52 (s,
2H), 8.39 (s, 1H), 7.73 (d, 1H, J=8.7 Hz), 7.47-7.65 (m, 5 Hz),
7.35 (d, 2H, J=8.7 Hz), 7.17 (br s, 1H), 6.86 (d, 2H, J=8.7 Hz),
5.72 (s, 2H), 3.73 (s, 3H), 2.94 (s, 3H), 2.24 (s, 3H).
(c) Example
71--N-{2-[5-(4-methyl-[3,4']bipyridinyl-5-yl)-(1H-indazol-3-yl]-3H-benzoi-
midazol-5-yl-methanesulfonamide
[0450] The title compound was prepared in 35% yield by the
PMB-deprotection of intermediate 71 b in a manner analogous to the
procedure for example 62. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.79 (s, 1H), 13.02 (s, 1H), 9.56 (s, 1H), 8.70 (d, 2H,
J=5.7 Hz) 8.54 (s, 1H), 8.47 (d, 2H, J=7.8 Hz), 7.78 (d, 1H, J=8.7
Hz), 7.49-7.58 (m, 5H), 7.10 (d, 1H, J=8.7 Hz), 2.93 (s, 3H), 2.17
(s, 3H). Anal. (C.sub.26H.sub.21N.sub.7O.sub.2S.1.45H.sub.2O) C, H,
N, S. MS (ES) [m+H]/z calculated 496, found 496.
EXAMPLE 72
{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-yl}-meth-
anol
[0451] ##STR124##
(a) Intermediate 72a--(5-Bromo-4-methyl-pyridin-3-yl)-methanol
[0452] Intermediate 59a (1.5 g, 7.5 mmol) was stirred in MeOH at
0.degree. C. Sodium borohydride (850 mg, 22.5 mmol) was added in
portions, and the reaction was stirred for 1 hour. The solution was
diluted with ethyl acetate, and organics were washed with H.sub.2O
and brine, dried (MgSO.sub.4), and concentrated in vacuo.
Purification by silica gel chromatography (80% to 100% ethyl
acetate/hexanes) gave 1.39 g (92%) of intermediate 72a as a white
solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.59 (s, 1H), 8.38
(s, 1H), 8.43 (s, 1H), 4.75 (d, 1H, J=5.4 Hz), 2.45 (s, 3H), 2.37
(t, 1H, J=5.4 Hz).
(b) Intermediate
72b--{5-[3-(1H-Benzoimidazol-2-yl)-1-(4-methoxy-benzyl)-1H-indazol-5-yl]4-
-methyl-pyridin-3-yl}-methanol
[0453] The title compound was prepared in 92% yield from
intermediate 62b and intermediate 72a similar to the procedure for
intermediate 61c. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.48
(s, 1H), 8.62 (s, 1H), 8.48 (s, 1H), 8.42 (s, 1H), 7.83 (br s, 1H),
7.45 (d, 2H, J=8.7 Hz), 7.21-7.32 (m, 5H), 6.83 (d, 2H, J=8.7 Hz),
5.60 (d, 2H, J=4.5 Hz), 4.80 (s, 2H), 3.76 (s, 3H), 2.25 (s, 3H),
1.94 (br s, 1H).
(c) Example
72--{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]4-methyl-pyridin-3-yl}--
methanol
[0454] The title compound was prepared in 59% yield by the
PMB-deprotection of intermediate 72b in a manner analogous to the
procedure for example 62. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.78 (s, 1H), 13.01 (s, 1H), 8.52 (s, 1H), 8.43 (s, 1H),
8.39 (s, 1H), 7.75 (dd, 1H, J=8.4, 0.6 Hz), 7.68 (d, 1H, J=7.2 Hz),
7.50 (d, 1H, J=7.2 Hz), 7.44 (dd, 1H, J=8.4, 1.5 Hz), 7.15-7.23 (m,
2H), 5.29 (t, 1H, J=5.4 Hz), 4.64 (d, 2H, J=5.4 Hz), 2.22 (s, 3H).
Anal. (C.sub.21H.sub.17N.sub.5O.1.25H.sub.2O) C, H, N. MS (ES)
[m+H]/z calculated 356, found 356.
EXAMPLE 73
{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl-
}-dimethyl-amine
[0455] ##STR125##
(a) Example
73--{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylm-
ethyl}-dimethyl-amine
[0456] The title compound was prepared in 36% yield from example 72
and dimethylamine by a synthetic method analogous to intermediate
68b. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.77 (s, 1H),
13.02 (s, 1H), 8.38-8.42 (m, 3H), 7.67-7.76 (m, 2H), 7.50 (d, 1H,
J=7.8 Hz), 7.44 (dd, 1H, J=8.7,1.5 Hz), 7.14-7.24 (m, 2H), 3.48 (br
s, 2H), 2.28 (s, 3H), 2.21 (s, 6H). Anal.
(C.sub.23H.sub.22N.sub.6.0.8H.sub.2O) C, H, N. MS (ES) [m+H]/z
calculated 383, found 383.
EXAMPLE 74
{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl-
}-ethyl-amine
[0457] ##STR126##
(a) Example
74--{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylm-
ethyl}-ethyl-amine
[0458] The title compound was prepared in 23% yield from example 72
and ethylamine by a synthetic method analogous to intermediate 68b.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) 613.76 (s, 1H), 13.01 (s, 1H),
8.48 (s, 1H), 8.42 (s, 1H), 8.36 (s, 1H), 7.74 (d, 1H, J=8.7 Hz),
7.68 (d, 1H, J=7.5 Hz), 7.50 (d, 1H, J=7.5 Hz), 7.43 (dd, 1H,
J=8.7,1.5 Hz), 7.14-7.23 (m, 2H), 3.81 (s, 2H), 2.65 (q, 2H, J=7.2
Hz), 2.26 (s, 3H), 1.08 (t, 3H, J=7.2 Hz). Anal.
(C.sub.23H.sub.22N.sub.6.0.5H.sub.2O) C, H, N. MS (ES) [m+H]/z
calculated 383, found 383.
EXAMPLE 75
(3-(1H-Benzoimidazol-2-yl)-5-(4,5-dimethyl-pyridin-3-yl)-1H-indazole
[0459] ##STR127##
(a) Intermediate 75a--5-Bromo-3,4-dimethyl-pyridine
[0460] The title compound was prepared from
3,5-dibromo-4-methyl-pyridine and iodomethane similar to the
procedure for intermediate 59a. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.50 (s, 1H), 8.22 (s, 1H), 2.36 (s, 3H), 2.30 (s, 3H).
(b) Intermediate
75b--3-(1H-Benzoimidazol-2-yl)-5-(4,5-dimethyl-pyridin-3-yl)-1-(4-methoxy-
-benzyl)-1H-indazole
[0461] The title compound was prepared in 79% yield from
intermediate 62b and intermediate 75a similar to the procedure for
intermediate 61c. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.66
(s, 1H), 8.64 (s, 1H), 8.40 (s, 1H), 8.36 (s, 1H), 7.81-7.85 (m,
1H), 7.41-7.49 (m, 2H), 7.18-7.27 (m, 5H), 6.81 (d, 2H, J=4.5 Hz),
5.57 (s, 2H), 3.74 (s, 3H), 2.31 (s, 3H), 2.16 (s, 3H).
(c) Example
75--3-(1H-Benzoimidazol-2-yl)-5-(4,5-dimethyl-pyridin-3-yl)-1H-indazole
[0462] The title compound was prepared in 37% yield by the
PMB-deprotection of intermediate 75b in a manner analogous to
example 62. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.76 (s,
1H), 13.02 (s, 1H), 842 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 7.74
(dd, 1H, J=8.4, 0.6 Hz), 7.51-7.69 (m, 2H), 7.44 (dd, 1H, J=8.7,
1.8 Hz), 7.17-7.22 (m, 2H) 2.33 (s, 3H), 2.18 (s, 3H). Anal.
(C.sub.21H.sub.17N.sub.5.1.0H.sub.2O) C, H, N. MS (ES) [m+H]/z
calculated 340, found 340.
EXAMPLE 76
3-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-quinoline
[0463] ##STR128##
(a) Intermediate
76a--3-[3-(1H-Benzoimidazol-2-yl)-1-(4-methoxy-benzyl)-1H-indazol-5-yl]-4-
-methyl-quinoline
[0464] The title compound was prepared in 86% yield from
intermediate 62b and 3-bromo-4-methylquinoline (see Kwon et al.,
Synthesis, 1976, 249) similar to the procedure for intermediate
61c. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.24 (s, 1H), 8.94
(s, 1H), 8.78 (s, 1H), 8.25 (dd, 1H, J=7.8, 0.3 Hz), 8.14 (dd, 1H,
J=7.8, 0.3 Hz), 7.75-7.88 (m, 2H), 7.64-7.70 (m, 1H), 7.45-7.57 (m,
3H), 7.27-7.35 (m, 4H), 6.91 (d, 2H, J=6.9 Hz), 5.68 (s, 2H), 3.82
(s, 3H), 2.70 (s, 3H). Anal.
(C.sub.32H.sub.25N.sub.5O.0.15H.sub.2O) C, H, N.
(b) Example
76--3-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]4-methyl-quinoline
[0465] The title compound was prepared in 72% yield by the
PMB-deprotection of intermediate 76a in a manner analogous to the
procedure for example 62. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.81 (s, 1H), 13.06 (s, 1H), 8.86 (s, 1H), 8.55 (s, 1H),
8.23 (d, 1H, J=7.8 Hz), 8.09 (d, 1H, J=7.2 Hz), 7.68-7.84 (m, 3H),
7.55-7.59 (m, 3H), 7.17-7.23 (m, 2H), 2.66 (s, 3H). Anal.
(C.sub.24H.sub.17N.sub.5.0.8H.sub.2O) C, H, N. MS (ES) [m+H]/z
calculated 376, found 376.
EXAMPLE 77
5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ol
[0466] ##STR129##
(a) Intermediate 77a--5-Bromo-4-methyl-pyridin-3-ol
[0467] 3,5-Dibromo-4-methyl-pyridine (2.42 g, 9.64 mmol) and sodium
methoxide (3.12 g, 57.8 mmol) were stirred in a mixture of DMF (8
mL) and MeOH (2 mL) in a sealed tube at 180.degree. C. for 24
hours. The reaction was allowed to cool and was concentrated in
vacuo. Purification by silica gel chromatography (100% ethyl
acetate) gave 1.10 g (61%) of intermediate 77a as a white solid.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.31 (s, 1H), 8.12 (s,
1H), 8.04 (s, 1H), 2.21 (s, 3H). Anal. (C.sub.6H.sub.6BrNO) C, H,
N.
(b) Intermediate
77b--3-Bromo-5-(4-methoxy-benzyloxy)-4-methyl-pyridine
[0468] Intermediate 77a (1.0 g, 5.3 mmol), tetramethylammonium
iodide (107 mg, 0.53 mmol), and potassium carbonate (1.47 g, 10.6
mmol) were stirred in acetone (30 mL). p-Methoxybenzyl chloride
(1.08 mL, 7.98 mmol) was added, and the reaction stirred at
55.degree. C. for 8 hours. The solution was diluted with ethyl
acetate. Organics were washed with H.sub.2O and brine, dried
(MgSO.sub.4), and concentrated in vacuo. Purification by silica gel
chromatography (25% ethyl acetate/hexanes) gave 648 mg (40%) of
intermediate 77b as a white solid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.33 (s, 1H), 8.16 (s, 1H), 7.34 (d, 2H, J=8.7
Hz), 7.93 (d, 2H, J=8.7 Hz), 5.08 (s, 2H), 3.83 (s, 3H), 2.34 (s,
3H). Anal. (C.sub.14H.sub.14BrNO.sub.2) C, H, N.
(c) Intermediate
77c--5-[3-(1H-Benzoimidazol-2-yl)-1-(4-methoxy-benzyl)-1H-indazol-5-yl]-4-
-methyl-pyridin-3-ol
[0469] The title compound was prepared in 89% yield from
intermediate 62b and intermediate 77b similar to the procedure for
intermediate 61c. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.17
(s, 1H), 8.64 (s, 1H), 8.29 (s, 1H), 8.25 (s, 1H), 7.81-7.86 (m,
1H), 7.34-7.49 (m, 5H), 7.21-7.29 (m, 4H), 6.95 (d, 2H, J=8.7 Hz),
6.85 (d, 2H, J=8.7 Hz), 5.61 (s, 2H), 5.16 (s, 2H), 3.83 (s, 3H),
3.76 (s, 3H), 2.20 (s, 3H).
(d) Example
77--5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ol
[0470] The title compound was prepared in 47% yield by the
PMB-deprotection of intermediate 77c in a manner analogous to the
procedure for example 62. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.74 (s, 1H), 13.01 (s, 1H), 9.91 (s, 1H), 8.43 (s, 1H),
8.14 (s, 1H), 7.98 (s, 1H), 7.72 (dd, 1H, J=8.4, 0.6 Hz), 7.69 (bs,
1H), 7.51 (bs, 1H), 7.45 (dd, 1H, J=8.7, 1.5 Hz), 7.17-7.22 (m, 2H)
2.09 (s, 3H). Anal. (C.sub.20H.sub.15N.sub.5O.0.3H.sub.2O) C, H, N.
MS (ES) [m+H]/z calculated 340, found 340.
EXAMPLE 78
{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl-
}-isopropyl-amine
[0471] ##STR130##
(a) Example
78--{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylm-
ethyl}-iospropyl-amine
[0472] The title compound was prepared in 28% yield from example 72
and isopropylamine using an analogous procedure to the preparation
of intermediate 68b. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
13.76 (s, 1H), 13.01 (s, 1H), 8.48 (s, 1H), 8.42 (s, 1H), 8.35 (s,
1H), 7.74 (d, 1H, J=8.7 Hz), 7.68 (d, 1H, J=7.8 Hz), 7.50 (d, 1H,
J=7.2 Hz), 7.43 (dd, 1H, J=8.7, 1.5 Hz), 7.15-7.25 (m, 2H), 3.79
(s, 2H), 2.80-2.86 (m, 1H), 2.27 (s, 3H), 1.07 (d, 6H, J=6.6 Hz).
Anal. (C.sub.24H.sub.24N.sub.6.0.7H.sub.2O) C, H, N. MS (ES)
[m+H]/z calculated 397, found 397.
EXAMPLE 79
(5-Isoquinolin-4-yl-1H-indazol-3-ylmethylene)-pyrrol-1-yl-amine
[0473] ##STR131##
(a) Intermediate
79a--5-Isoquinolin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-
-carbaldehyde
[0474] The title compound was prepared in a manner analogous to the
preparation of intermediate 19f, substituting a SEM-protection (see
intermediate 3a) for the PMB-protection of intermediate 19c.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.30 (s, 1H), 9.30 (s,
1H), 8.54 (s, 1H), 8.48 (s, 1H), 8.08 (dd, 1H, J=6.6, 2.4 Hz), 7.86
(dd, 1H, J=6.6, 0.6 Hz), 7.81 (dd, 1H, J=8.7, 0.9 Hz), 7.64-7.70
(m, 3H), 5.91 (s, 2H), 3.66 (t, 2H, J=8.4 Hz), 0.97 (t, 2H, J=8.4
Hz), -0.02 (s, 9H).
(b) Intermediate
79b--[5-Isoquinolin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-
-ylmethylene]-pyrrol-1-yl-amine
[0475] Intermediate 79a (400 mg, 0.99 mmol) and 1-aminopyrrole (98
mg, 1.2 mmol) were stirred with p-tolunesulfonic acid (10 mg) in
toluene (6 mL) at 80.degree. C. for 2 hours. The solution was
concentrated in vacuo and purified by silica gel chromatography
(50% ethyl acetate/hexanes) to give 410 mg (89%) of intermediate
79b as a yellow oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.31
(s, 1H), 8.77 (s, 1H), 8.58-8.60 (m, 2H), 8.09 (dd, 1H, J=7.2, 0.9
Hz), 7.92 (d, 1H, J=7.8 Hz), 7.76 (dd, 1H, J=8.7, 0.9 Hz),
7.63-7.70 (m, 3H), 7.19 (t, 2H, J=2.4 Hz), 6.26 (t, 2H, J=2.4 Hz),
5.85 (s, 2H), 3.66 (t, 2H, J=8.4 Hz), 0.97 (t, 2H, J=8.4 Hz), -0.02
(s, 9H).
(c) Example
79--(5-Isoquinolin-4-yl-1H-indazol-3-ylmethylene)-pyrrol-1-yl-amine
[0476] The title compound was prepared in 68% yield by the
SEM-deprotection of intermediate 79b in a manner analogous to the
procedure for example 41. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.82 (s, 1H), 9.38 (s, 1H), 9.09 (s, 1H), 8.52 (s, 1H),
8.41 (s, 1H), 8.24 (dd, 1H, J=7.2, 1.5 Hz), 7.71-7.85 (m, 4H), 7.61
(dd, 1H, J=8.4, 1.5 Hz), 7.46 (t, 2H, J=2.4 Hz), 6.15 (t, 2H, J=2.4
Hz). Anal. (C.sub.21H.sub.15N.sub.5) C, H, N. MS (ES) [m+H]/z
calculated 338, found 338.
EXAMPLE 80
2-[5-(5-Ethylaminomethyl-4-methyl-pyridin-3-yl)-1H-indazol-3-yl]-1H-benzoi-
midazole-4-carboxylic acid methylamide
[0477] ##STR132##
(a) Intermediate
80a--(5-Bromo-4-methyl-pyridin-3-ylmethyl)-ethyl-amine
[0478] The title compound was prepared in 95% yield from
intermediate 72a and ethylamine using an analogous procedure to the
method outlined for the preparation of intermediate 68b. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.59 (s, 1H), 8.37 (s, 1H), 3.83
(s, 2H), 2.73 (q, 2H, J=7.2 Hz), 2.48 (s, 3H), 1.16 (t, 3H, J=7.2
Hz).
(b) Intermediate
80b--5-Bromo-4-methyl-pyridin-3-ylmethyl)-ethyl-carbamic acid
dimethyl-ethyl ester
[0479] Intermediate 80a (850 mg, 3.7 mmol) was stirred in a
solution of THF (80 mL) and 1 N NaOH (10 mL). Di-tert-butyl
dicarbonate (1.09 g, 5 mmol) was added, and the reaction stirred
for 2 hours at room temperature. The solution was diluted with
ethyl acetate. Organics were washed with H.sub.2O and brine, dried
(MgSO.sub.4), and concentrated in vacuo. Purification by silica gel
chromatography (33% ethyl acetate/hexanes) gave 760 mg (62%) of
intermediate 80b as a clear oil. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.8.60 (s, 1H), 8.24 (s, 1H), 4.49 (s, 2H), 3.18 (bs, 2H),
2.39 (s, 3H), 1.47 (s, 9H), 1.05 (t, 3H, J=7.2 Hz).
(c) Intermediate
80c--Ethyl-[5-(3-formyl-1H-indazol-5-yl)-4-methyl-pyridin-3-ylmethyl]
carbamic acid dimethyl-ethyl ester
[0480] The title compound was prepared in 85% yield from
intermediate 19e and intermediate 80b similar to the procedure for
intermediate 61c. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.27
(s, 1H), 8.38 (s, 1H), 8.35 (s, 1H), 8.23 (s, 1H), 7.49 (dd, 1H,
J=8.7, 0.6 Hz), 7.26-7.51 (m, 3H), 6.89 (dd, 2H, J=6.6, 2.1 Hz),
5.66 (s, 2H), 4.53 (s, 2H), 3.79 (s, 3H), 3.24 (bs, 2H), 2.18 (s,
3H), 1.48 (s, 9H), 1.10 (t, 3H, J=7.2 Hz).
(d) Intermediate
80d--Ethyl-{5-[1-(4-methoxy-benzyl)-3-(4-methylcarbamoyl-1H-benzoimidazol-
-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-carbamic acid
dimethyl-ethyl ester
[0481] The title compound was prepared in 78% yield from
intermediate 80c and 2-amino-N-methyl-3-nitro-benzamide (Found in:
Kania, Braganza, et al., patent application "Compounds and
Pharmaceutical Compositions for Inhibiting Protein Kinases, and
Methods for Their Use", p. 52, line 10 to p. 53, line 26; and p.
59, line 16 to p. 60, line 4, U.S. Provisional Ser. No. 60/142,130,
filed Jul. 2, 1999, incorporated by reference herein in its
entirety.), similar to the procedure for intermediate 7c'. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 11.50 (s, 0.3H), 10.21 (s, 0.7H),
9.86 (bs, 1H), 8.36-8.57 (m, 3H), 8.18 (dd, 0.7H, J=7.8, 1.2 Hz),
7.97 (dd, 0.3H, J=7.8, 1.2 Hz), 7.63 (dd, 0.7H, J=7.8, 1.2 Hz),
7.24 (m, 5.3H), 6.88 (d, 2H, J=6.3 Hz), 5.65 (s, 1.4H), 5.63 (s,
0.6H), 4.57 (bs, 2H), 3.79 (s, 3H), 3.27 (bs, 2H), 3.12 (d, 0.9H,
J=4.8 Hz), 3.06 (d, 2.1H, J=4.8 Hz), 2.29 (s, 2.1H), 2.21 (s,
0.9H), 1.48 (s, 9H), 1.11 (t, 3H, J=6.9 Hz).
(e) Example
80--2-[5-(5-Ethylaminomethyl-4-methyl-pyridin-3-yl)-1H-indazol-3-yl]-1H-b-
enzoimidazole-4-carboxylic acid methylamide
[0482] The title compound was prepared in 36% yield by the
PMB-deprotection of intermediate 80d in a manner analogous to the
procedure for example 62, with a final purification by preparatory
HPLC (0.1% TFA-ACN/0.1% TFA-H.sub.2O). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 14.02 (s, 1H), 13.62 (bs, 1H), 9.72 (bs, 1H),
8.88 (bs, 2H), 8.63 (s, 2H), 8.44 (s, 1H), 7.83-7.88 (m, 2H), 7.72
(d, 1H, J=7.2 Hz), 7.52 (dd, 1H, J=8.4,1.5 Hz), 7.36 (t, 1H, J=7.8
Hz), 4.33 (bs, 2H), 3.15 (q, 2H, J=7.2 Hz), 2.90 (d, 3H, J=4.5 Hz),
2.43 (s, 3H), 1.27 (t, 3H, J=7.2 Hz). Anal.
(C.sub.25H.sub.25N.sub.7O.3 TFA) C, H, N. MS (ES) [m+H]/z
calculated 440, found 440.
EXAMPLE 81
Ethyl-4-{methyl-5-[3-(4-methylsulfanyl-1H-benzoimidazol-2-yl)-1H-indazol-5-
-yl]-pyridin-3-ylmethyl}-amine
[0483] ##STR133##
(a) Intermediate 81a--3-Methylsulfanyl-2-nitro-phenylamine
[0484] 3-Chloro-2-nitro-aniline (1.0 g, 5.8 mmol) and potassium
carbonate (880 mg, 6.4 mmol) were stirred in dry DMF (15 mL) in a
sealable tube at 0.degree. C. Methanethiol was bubbled through the
solution for 4 minutes. The tube was sealed and the reaction
stirred at 122.degree. C. for 16 hours. The cooled reaction was
diluted with H.sub.2O and extracted with ethyl acetate. Organics
were washed with brine, dried (Na.sub.2SO.sub.4), and concentrated
in vacuo. Purification by silica gel chromatography (33% ethyl
acetate/hexanes) gave 950 mg (89%) of intermediate 81a as a bright
red-orange solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.21
(t, 1H, J=8.1 Hz), 6.55 (d, 2H, J=8.1 Hz), 5.93 (bs, 2H), 2.42 (s,
3H). Anal. (C.sub.7H.sub.8N.sub.2O.sub.2S) C, H, N, S.
(b) Intermediate 81b--3-Methylsulfanyl-benzene-1,2-diamine
[0485] The title compound was prepared in 96% yield from
intermediate 81a similar to the hydrogenation procedure outlined
for intermediate 9a'. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
6.93-6.97 (m, 1H), 6.63-6.70 (m, 2H), 3.71 (bs, 4H), 2.36 (s, 3H).
Anal. (C.sub.7H.sub.10N.sub.2S) C, H, N, S.
(c) Intermediate
81c--Ethyl-{5-[1-(4-methoxy-benzyl)-3-(4-methylsulfanyl-1H-benzoimidazol--
2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl}-carbamic acid
dimethyl-ethyl ester
[0486] The title compound was prepared in 80% yield from
intermediate 81 b and intermediate 80c similar to the procedure for
intermediate 7c'. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.15
(s, 0.6H), 10.12 (s, 0.4H), 8.64 (s, 0.4H), 8.59 (s, 0.6H), 8.47
(s, 1H), 8.37 (s, 1H), 7.72 (d, 0.6H, J=7.5 Hz), 7.45 (t, 1H, J=7.2
Hz), 7.19-7.34 (m, 5H), 7.10 (d, 0.4H, J=7.5 Hz), 6.83-6.89 (m,
2H), 5.65 (s, 1.2H), 5.61 (s, 0.8H), 4.55 (bs, 2H), 3.78 (s, 1.8H),
3.77 (s, 1.2H), 3.26 (bs, 2H), 2.67 (s, 1.2H), 2.57 (s, 1.8H), 2.24
(s, 1.2H), 2.22 (s, 1.8H), 1.49 (s, 9H), 1.12 (t, 3H, J=6.9
Hz).
(d) Example
81--Ethyl-4-{methyl-5-[3-(4-methylsulfanyl-1H-benzoimidazol-2-yl)-1H-inda-
zol-5-yl]-pyridin-3-ylmethyl}-amine
[0487] The title compound was prepared in 25% yield by the
PMB-deprotection of intermediate 81c in a manner analogous to the
procedure for example 62. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.78 (s, 1H), 13.10 (s, 1H), 8.48 (s, 1H), 8.44 (s, 1H),
8.39 (s, 1H), 7.75 (d, 1H, J=8.7 Hz), 7.44 (d, 1H, J=8.7, 1.8 Hz),
7.30 (d, 1H, J=7.8 Hz), 7.19 (t, 1H, J=7.8 Hz), 6.99 (d, 1H, J=7.2
Hz), 3.82 (s, 2H), 2.66 (q, 2H, J=7.2 Hz), 2.56 (s, 3H), 2.28 (s,
3H), 1.08 (t, 3H, J=7.2 Hz). Anal.
(C.sub.24H.sub.24N.sub.6S.1.5H.sub.2O) C, H, N, S. MS (ES) [m+H]/z
calculated 429, found 429.
EXAMPLE 82
N-{2-[5-(5-Ethylaminomethyl-4-methyl-pyridin-3-yl)-1H-indazol-3-yl]-1H-ben-
zoimidazol-4-yl}-acetamide
[0488] ##STR134##
(a) Intermediate 82a--N-2,3-diamino-phenyl)-acetamide
[0489] The title compound was prepared in 98% yield from
N-(2-amino-3-nitro-phenyl)-acetamide (see Harvey et al., J. Chem.
Soc. Perk. Trans. 1, 1988, 1939-1944) in a manner analogous to the
hydrogenation of intermediate 9a'. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 9.04 (s, 1H), 6.35-6.49 (m, 3H), 4.38 (bs, 4H),
2.00 (s, 3H).
(b) Intermediate
82b--{5-[3-(4-Acetylamino-1H-benzoimidazol-2-yl)-1-(4-methoxy-benzyl)-1H--
indazol-5-yl]4-methyl-pyridin-3-ylmethyl}-ethyl-carbamic acid
dimethyl-ethyl ester
[0490] The title compound was prepared in 65% yield from
intermediate 82a and intermediate 80c similar to the procedure for
intermediate 7c'. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 12.35
(bs, 1H), 10.80 (bs, 1H), 7.90-8.85 (m, 4H), 6.76-7.46 (m, 8H),
5.60 (bs, 2H), 4.51 (bs, 2H), 3.78 (s, 3H), 3.61 (bs, 2H), 3.19
(bs, 3H), 1.74 (bs, 12H), 1.18 (bs, 3H). MS (ES) [m+H]/z calculated
660, found 660.
(c) Example
82--N-{2-[5-(5-Ethylaminomethyl-4-methyl-pyridin-3-yl)-1H-indazol-3-yl]-1-
H-benzoimidazol-4-yl}-acetamide
[0491] The title compound was prepared in 6% yield by the
PMB-deprotection of intermediate 82b in a manner analogous to the
procedure for example 62. .sup.1H NMR (300 MHz, MeOD-d.sub.4)
.delta. 8.64 (s, 1H), 8.58 (s, 1H), 8.45 (s, 1H), 7.82 (d, 1H,
J=8.4 Hz), 7.57 (d, 1H, J=7.2 Hz), 7.50 (d, 2H, J=7.2 Hz), 7.34 (t,
1H, J=8.4 Hz), 4.44 (s, 2H), 3.27 (q, 2H, J=7.5 Hz), 2.43 (s, 3H),
2.22 (s, 3H), 1.41 (t, 3H, J=7.5 Hz). MS (ES) [m+H]/z calculated
440, found 440.
EXAMPLE 83
5-(2,6-Difluorophenyl)-3-Phenyl-1H-indazole
[0492] ##STR135##
(a) Intermediate
83a--5-(2,6-Difluorophenyl)-3-phenyl-1-[2-(trimethylsilanyl)ethoxymethyl]-
-1H-indazole
[0493] By a synthetic method analogous to intermediate 11e,
palladium catalyzed coupling of intermediate 11d with
2,6-difluorophenylboronic acid yielded 83a (65%) as a pale yellow
foam: .sup.1H NMR (DMSO-d.sub.6) .delta. -0.09 (s, 9H), 0.84 (t,
2H, J=8.0 Hz), 3.62 (t, 2H, J=8.0 Hz), 5.86 (s, 2H),7.24 (dd, 2H,
J=8.1, 8.3 Hz), 7.44 (tt, 1H, J=1.3, 7.2 Hz), 7.47-7.58 (m, 4H),
7.92 (dd, 1H, J=0.5, 8.8 Hz), 7.98 (dd, 2H, J=1.3, 8.2 Hz), 8.14
(d, 1H, J=0.5 Hz).
(a) Example 83--5-(2,6-Difluorophenyl)-3-phenyl-1H-indazole
[0494] Similar to example 7', treatment of 83a with
tetrabutylammonium fluoride afforded
5-(2,6-difluorophenyl)-3-phenyl-1H-indazole 83 (95%) as a yellow
solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 7.23 (dd, 2H, J=8.1, 8.3
Hz), 7.40 (tt, 1H, J=1.3, 7.2 Hz), 7.43-7.56 (m, 4H), 7.70 (dd, 1H,
J=0.6, 8.7 Hz), 7.98 (dd, 2H, J=1.3, 8.4 Hz), 8.11 (d, 1H, J=0.6
Hz), 13.38 (s, 1H). Anal. (C.sub.19H.sub.12N.sub.2F.sub.2) C, H,
N.
EXAMPLE 84
5-Amino-3-(2-Pyrrolyl)-1H-indazole
[0495] ##STR136##
[0496] By a synthetic method analogous to intermediate 18c,
hydrogenation of 5-nitro-3-(2-pyrrolyl)-1H-indazole 18b' over 10%
palladium on carbon afforded 5-amino-3-(2-pyrrolyl)-1H-indazole 84
(99%) as a beige solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 6.13
(dd, 1H, J=2.4, 2.6 Hz), 6.49 (dd, 1H, J=1.5, 2.4 Hz), 6.76 (dd,
1H, J=1.5, 2.6 Hz), 6.79 (dd, 1H, J=2.1, 8.9 Hz), 7.03 (d, 1H,
J=2.1 Hz), 7.22 (d, 1H, J=8.9 Hz), 11.16 (s, 1H), 12.45 (s, 1H).
Anal. (C.sub.11H.sub.10N.sub.4.0.2 ethyl acetate) C, H, N.
EXAMPLE 85
5-(Benzylamino)-3-(2-Pyrrolyl)-1H-indazole
[0497] Benzaldehyde (100 mg, 1 mmol) was added to a solution of
5-amino-3-(2-pyrrolyl)-1H-indazole 84 (100 mg, 0.5 mmol) in EtOH
(100 ml). The resultant solution was stirred for 2 hours at ambient
temperature prior to addition of NaBH.sub.3CN (50 mg, 0.8 mmol) in
a single portion as the solid. After stirring for an additional 2
hours, the crude reaction mixture was poured into H.sub.2O (200 ml)
and extracted with ethyl acetate (2.times.100 ml). The combined
organic extracts were dried over sodium sulfate and concentrated.
Silica gel chromatography (60% ethyl acetate/hexanes) provided 85
(21%) as a beige solid: .sup.1H NMR (DMSO-d.sub.6) .delta. 4.33 (s,
2H), 6.11 (dd, 1H, J=2.5, 2.6 Hz), 6.38 (dd, 1H, J=1.5, 2.5 Hz),
6.74 (dd, 1H, J=1.5, 2.6 Hz), 6.81 (s, 1H), 6.91 (dd, 1H, J=1.9,
8.9 Hz), 7.17-7.36 (m, 5H), 7.43 (d, 1H, J=8.9 Hz), 7.45 (d, 1H,
J=1.9 Hz), 11.13 (s, 1H), 12.48 (s, 1H). Anal.
(C.sub.18H.sub.16N.sub.4.0.33H.sub.2O) C, H, N.
EXAMPLE 86
5-(3-Methoxyphenyl)-3-(phenyl)-1H-indazole
[0498] ##STR137##
(a) Intermediate
86a--5-(3-Methoxyphenyl)-3-phenyl-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-
-indazole
[0499] By a synthetic method to intermediate 11e, palladium
catalyzed coupling of intermediate 11d with 3-methoxyphenylboronic
acid yielded 86a (46%) as a pale yellow solid: .sup.1H NMR
(DMSO-d.sub.6) .delta. -0.10 (s, 9H), 0.84 (t, 2H, J=8.0 Hz), 3.62
(t, 2H, J=8.0 Hz), 5.86 (s, 2H), 7.24-7.34 (m, 4H), 7.38-7.56 (m,
4H), 7.84(d, 1H, J=8.3 Hz), 7.91-8.03 (m, 3H).
(b) Example 86--5-(3-Methoxyphenyl)-3-phenyl-1H-indazole
[0500] Similar to example 11, treatment of 86a with
tetrabutylammonium fluoride afforded
5-(3-methoxyphenyl)-3-phenyl-1H-indazole 86 (71%) as a white solid:
.sup.1H NMR (DMSO-d.sub.6) .delta. 3.83 (s, 3H), 6.93 (dd, 1H,
J=1.9, 8.0 Hz), 7.22-7.75 (m, 8H), 8.04 (dd, 2H, J=1.3, 7.2 Hz),
8.20 (d, 1H, J=0.3 Hz), 13.27(s, 1H). Anal.
(C.sub.20H.sub.16N.sub.2O.0.2H.sub.2O) C, H, N.
EXAMPLE 87
{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-6-yl]-4-methyl-pyridin-3-ylmethyl-
}-isobutyl-amine
[0501] ##STR138##
(a) Example
87--{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylm-
ethyl}-isobutyl-amine
[0502] The title compound was prepared in 81% yield from example 72
and isobutylamine using an analogous procedure to the preparation
of intermediate 68b. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
13.77 (s, 1H), 13.02 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 8.37 (s,
1H), 7.74 (d, 1H, J=8.7 Hz), 7.68 (d, 1H, J=7.5 Hz), 7.50 (d, 1H,
J=7.5 Hz), 7.43 (dd, 1H, J=8.7,1.5 Hz), 7.14-7.24 (m, 2H), 3.85 (s,
2H), 2.49 (bs, 2H), 2.27 (s, 3H), 1.73-1.79 (m, 1H), 0.90 (d, 6H,
J=6.6 Hz). Anal. (G.sub.25H.sub.26N.sub.6.0.3H.sub.2O) C, H, N. MS
(ES) [m+H]/z calculated 411, found 411.
EXAMPLE 88
{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl-
}-benzyl-amine
[0503] ##STR139##
(a) Example
88--{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylm-
ethyl}-benzyl-amine
[0504] The title compound was prepared in 73% yield from example 72
and benzylamine similar to intermediate 68b. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) 613.77 (s, 1H), 13.02 (s, 1H), 8.51 (s, 1H), 8.42 (s,
1H), 8.38 (s, 1H), 7.74 (d, 1H, J=8.7 Hz), 7.68 (d, 1H, J=7.5 Hz),
7.50 (d, 1H, J=7.5 Hz), 7.16-7.44 (m, 8H), 3.90 (bs, 4H), 2.23 (s,
3H). Anal. (C.sub.28H.sub.24N.sub.6.1.2H.sub.2O) C, H, N. MS (ES)
[m+H]/z calculated 445, found 445.
EXAMPLE 89
2-({5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmet-
hyl}-amino)-ethanol
[0505] ##STR140##
(a) Example
89--2-({5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3--
ylmethyl}-amino)-ethanol
[0506] The title compound was prepared in 54% yield from example 72
and ethanolamine similar to intermediate 68b. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 13.78 (s, 1H), 13.01 (s, 1H), 8.54 (s, 1H),
8.43 (s, 1H), 8.42 (s, 1H), 7.75 (d, 1H, J=8.7 Hz), 7.67 (d, 1H,
J=7.5 Hz), 7.51 (d, 1H, J=7.5 Hz), 7.43 (dd, 1H, J=8.7, 1.5 Hz),
7.15-7.23 (m, 2H), 4.82 (bs, 1H), 4.03 (s, 2H), 3.60 (d, 2H, J=2.7
Hz), 2.87 (t, 2H, J=2.7 Hz), 2.29 (s, 3H). Anal.
(C.sub.23H.sub.22N.sub.6O.0.1H.sub.2O) C, H, N. MS (ES) [m+H]/z
calculated 399, found 399.
EXAMPLE 90
{1-[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-yl]-ethyl}-m-
ethyl-amine
[0507] ##STR141## ##STR142##
(a) Intermediate 90a--N-(2-Acetyl-6-nitro-phenyl)-acetamide
[0508] A solution of 2,3-dimethyl-7-nitroindole (Acros Organics,
13.55 g, 71.24 mmol) in dichloromethane (1.0 L) was cooled to
-60.degree. C. internal temperature and treated with ozone gas for
1.5 hours. A color change from orange to yellow-green was observed
in this time. Argon was bubbled through the solution for one hour,
causing the color to change to yellow. Dimethylsulfide (10.5 mL,
142.5 mmol) was added, and stirring continued at -60.degree. C. for
1.5 hours. After warming to room temperature, the solution was
concentrated in vacuo to -200 mL, washed with water (2.times.50
mL), dried over magnesium sulfate, filtered, concentrated, and
purified by silica gel chromatography (50 to 100% ethyl acetate in
hexanes), affording 90a (11.85 g, 75%) as an orange solid.
R.sub.f=0.36 (75% ethyl acetate/hexanes); .sup.1H NMR
(DMSO-d.sub.6) .delta. 2.02 (s, 3H), 2.52 (s, 3H), 7.52 (t, 1H,
J=7.9 Hz), 8.00 (dd 1H, J=7.9, 1.5 Hz), 8.05 (dd, 1H, J=8.1, 1.5
Hz),10.32 (s, 1H). Anal.
(C.sub.10H.sub.10N.sub.2O.sub.4.0.4H.sub.2O) C, H, N.
(b) Intermediate 90b--1-(2-Amino-3-nitro-phenyl)-ethanone
[0509] Concentrated hydrochloric acid (40 mL) was added to a
solution of 90a (4.00 g, 18.0 mmol) in absolute ethanol (80 mL) and
water (40 mL). The mixture was heated to reflux (87.degree. C.
internal temperature) for 1 hour. After cooling to room
temperature, saturated aqueous sodium bicarbonate solution was
added to bring the pH to 8. The solution was extracted with ethyl
acetate (2.times.200 mL). The combined organic extracts were dried
over magnesium sulfate, filtered, concentrated and purified by
silica gel chromatography (20 to 70% ethyl acetate in hexanes) to
give 90b (2.67 g, 82%) as a yellow solid. R.sub.f=0.45 (50% ethyl
acetate/hexanes); .sup.1H NMR (DMSO-d.sub.6) .delta. 2.62 (s, 3H),
6.74 (t, 1H, J=8.1 Hz), 8.31 (m. 2H), 8.85 (br s, 2H). Anal.
(C.sub.8H.sub.8N.sub.2O.sub.3) C, H, N.
(c) Intermediate 90c--1-(2,3-Diamino-phenyl)-ethanone
[0510] By a synthetic method analogous to the synthesis of 9a,
hydrogenation of 90b (2.00 g, 11.1 mmol) in ethanol afforded 90c
(1.54 g, 92%) as bright yellow crystals. R.sub.f=0.34 (50% ethyl
acetate/hexanes); .sup.1H NMR (DMSO-d.sub.6) .delta. 2.47 (s, 3H),
4.75 (br s, 2H), 6.40 (dd, 1H, J=7.5, 8.1 Hz), 6.69 (dd, 1H, J=7.5,
1.3 Hz), 6.79 (br s, 2H), 7.10 (dd, 1H, J=8.1, 1.3 Hz). Anal.
(C.sub.8H.sub.10N.sub.2O) C, H, N.
(d) Intermediate
90d--1-{2-[5-Isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-be-
nzoimidazol-4-yl}-ethanone
[0511] Similar to the synthesis of 19h, aldehyde 19f (2.02 g, 5.13
mmol) and diamine 90c (771 mg, 5.13 mmol) were condensed in the
presence of sulfur to give 90d (1.83 g, 68%) as a bright yellow
solid. R.sub.f=0.19 (75% ethyl acetate/hexanes); .sup.1H NMR
(DMSO-d.sub.6) [Some peaks are doubled due to tautomeric
isomerization] .delta. 2.72 and 2.87 (2 br s, 3H together), 3.71
(s, 3H), 5.85 (s, 2H), 6.93 (d, 2H, J=8.7 Hz), 7.34 (m, 3H), 7.75
(m, 5H), 8.07 (m, 2H), 8.25 (d, 1H, J=7.5 Hz), 8.56 and 8.80 (2 br
s, 2H together), 9.38 (s, 1H), 11.83 (s, 1H), 13.53 (s, 1H).
(e) Intermediate
90e--(1-{2-[5-Isoquinolin-4-yl-1-(4-methoxy-benzyl)-1H-indazol-3-yl]-1H-b-
enzoimidazol-4-yl}-ethyl)-methyl-amine
[0512] A solution of methylamine in methanol (2.0 M, 3.02 mL, 6.04
mmol) was added to ketone 90d (527.8 mg, 1.01 mmol) at room
temperature, followed by hydrochloric acid (4.0 mL in dioxane,
0.504 mL, 2.02 mmol), methanol (6.0 mL), and sodium
cyanoborohydride (38.0 mg, 0.605 mmol). The suspension was stirred
at room temperature for 23 hours, but no reaction was observed by
TLC analysis. Anhydrous THF (10 mL) was added to increase
solubility, and stirring continued for 70 hours. The mixture was
partitioned between ethyl acetate and saturated aqueous sodium
bicarbonate solution. The organic phase was dried over magnesium
sulfate, filtered, concentrated and purified by silica gel
chromatography (1:20:200 aq. NH.sub.4OH:ethanol:dichloromethane),
yielding 90e (275.0 mg, 51%) as a yellow foam. R.sub.f=0.09
(1:20:400 aqueous NH.sub.4OH: ethanol: dichloromethane); .sup.1H
NMR (CD.sub.3OD) .delta. 1.53 (d, 3H, J=6.8 Hz), 2.24 (s, 3H), 3.75
(s, 3H), 4.28 (q, 1H, J=6.8 Hz), 5.45 (s, 1H), 5.77 (s, 2H), 6.89
(d, 2H, J=8.7 Hz), 7.22 (m, 2H), 7.34 (d, 2H, J=8.7 Hz), 7.52 (d,
1H, J=7.9 Hz),7.61 (dd, 1H, J=8.7, 1.5 Hz), 7.76 (m, 3H), 7.99 (d,
1H, J=8.3 Hz), 8.20 (dd, 1H, J=7.2, 1.7 Hz), 8.48 (s, 1H), 8.70 (s,
1H), 9.27 (s, 1H). Anal. (C.sub.34H.sub.30N.sub.6O.1.0H.sub.2O) C,
H, N.
(f) Example
90--{1-[2-(5-Isoquinolin-4-yl-1H-indazol-3-yl)-1H-benzoimidazol-4-yl]-eth-
yl}-methyl-amine
[0513] A solution of 90e (179.7 mg, 0.334 mmol),
trifluoromethanesulfonic acid (0.84 mL), and trifluoroacetic acid
(3.34 mL) was stirred at 50.degree. C. for 2 hours. The solution
was then added dropwise to a rapidly stirred mixture of
concentrated aqueous NH.sub.4OH (10 mL) and ethyl acetate (30 mL).
Extraction and purification similar to example 33, afforded 90 as
an off-white solid (140.9 mg). Although this material appeared pure
by HPLC and .sup.1H NMR analysis, the elemental analysis showed
significant impurities. The impure material was dissolved in ethyl
acetate (50 mL) and washed with water (10 mL), saturated aqueous
sodium bicarbonate solution (10 mL), and saturated aqueous sodium
chloride solution (10 mL). The organic layer was dried over
magnesium sulfate, filtered and concentrated to give 90 (49.4 mg,
35%) as a white solid: .sup.1H NMR (CD.sub.3OD) .delta. 1.71 (d,
3H, J=6.8 Hz), 2.45 (s, 3H), 4.66 (q, 1H, J=7.0 Hz), 7.24 (d, 1H,
J=7.5 Hz), 7.32 (t, 1H, J=7.7 Hz), 7.61 (dd, 1H, J=7.9, 1.0
Hz),7.67 (dd, 1H, J=8.5, 1.5 Hz), 7.82 (m, 3H), 8.03 (d, 1H, J=8.3
Hz), 8.24 (d, 1H, J=7.5 Hz), 8.53 (s, 1H), 8.71 (s, 1H), 9.30 (s,
1H). Anal. (C.sub.26H.sub.22N.sub.6.0.4 CH.sub.2Cl.sub.2) C, H,
N.
EXAMPLE 91
3-(1H-Benzolmidazol-2-yl)-5-(4-methyl-5-morpholin-4-ylmethyl-pyridin-3-yl)-
-1H-indazole
[0514] ##STR143##
(a) Example
91--3-(1H-Benzoimidazol-2-yl)-5-(4-methyl-5-morpholin-4-ylmethyl-pyridin--
3-yl)-1H-indazole
[0515] The title compound was prepared in 68% yield from example 72
and morpholine using an analogous procedure to the preparation of
intermediate 68b. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.78
(s, 1H), 13.02 (s, 1H), 8.42 (s, 2H), 8.40 (s, 1H), 7.75 (d, 1H,
J=8.7 Hz), 7.59 (br s, 2H), 7.44 (dd, 1H, J=8.7,1.5 Hz), 7.17-7.22
(m, 2H), 3.58-3.67 (m, 6H), 2.48 (br s, 4H), 2.30 (s, 3H). Anal.
(C.sub.25H.sub.24N.sub.6O.0.7H.sub.2O) C, H, N. MS (ES) [m+H]/z
calculated 425, found 425.
EXAMPLE 92
{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl-
}-cyclopentyl-amine
[0516] ##STR144##
(a) Example
92--{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylm-
ethyl}-cyclopentyl-amine
[0517] The title compound was prepared in 49% yield from example 72
and cyclopentylamine using an analogous procedure to the
preparation of intermediate 68b. .sup.1H NMR (300 MHz,
MeOD-d.sub.4) .delta. 8.49 (s, 1H), 8.46 (s, 1H), 8.42 (s, 1H),
7.73 (d, 1H, J=8.7 Hz), 7.64 (br s, 2H), 7.45 (d, 1H, J=8.7 Hz),
7.24-7.28 (m, 2H), 3.95 (s, 2H), 3.25 (br s, 1H), 2.39 (s, 3H)
1.96-2.02 (m, 2H), 1.71-1.78 (m, 2H), 1.46-1.67 (m, 4H). Anal.
(C.sub.26H.sub.26N.sub.6.0.25H.sub.2O) C, H, N. MS (ES) [m+H]/z
calc'd 423, found 423.
EXAMPLE 93
{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylmethyl-
}-pyridin-3-yl-amine
[0518] ##STR145##
(a) Example
93--{5-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-4-methyl-pyridin-3-ylm-
ethyl}-pyridin-3-yl-amine
[0519] The title compound was prepared in 10% yield from example 72
and 3-amino-pyridine using an analogous procedure to the
preparation of intermediate 68b. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 13.79 (s, 1H), 13.03 (s, 1H), 8.49 (s, 1H),
8.45 (s, 1H), 8.42 (s, 1H), 8.09 (s, 1H), 7.83 (s, 1H), 7.75 (d,
1H, J=8.7 Hz), 7.59 (br s, 2H), 7.45 (d, 1H, J=8.7 Hz), 7.09-7.22
(m, 4H), 6.55 (br s, 1H), 4.40 (d, 1H, J=6.0 Hz), 2.28 (s, 3H).
Anal. (C.sub.26H.sub.21N.sub.7.0.5H.sub.2O) C, H, N. MS (ES)
[m+H]/z calc'd 432, found 432.
Biochemical and Biological Evaluation
[0520] Cyclin-dependent kinase activity was measured by quantifying
the enzyme-catalyzed, time-dependent incorporation of radioactive
phosphate from [.sup.32P]ATP or [.sup.33P]ATP into a protein
substrate. Unless noted otherwise, assays were performed in 96-well
plates in a total volume of 50 .mu.L, in the presence of 10 mM
HEPES (N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid]) (pH
7.4), 10 mM MgCl.sub.2, 25 .mu.M adenosine triphosphate (ATP), 1
mg/mL ovalbumin, 5 .mu.g/mL leupeptin, 1 mM dithiothreitol, 10 mM
beta-glycerophosphate, 0.1 mM sodium vanadate, 1 mM sodium
fluoride, 2.5 mM ethylene glycol-bis(.beta.-aminoethyl
ethKer)-N,N,N'N'-tetraacetic acid (EGTA), 2% (v/v)
dimethylsulfoxide, and 0.03-0.4 .mu.Ci [.sup.32/33P]ATP per
reaction. Reactions were initiated with appropriate enzyme,
incubated at 30.degree. C., and terminated after 20 minutes by the
addition of ethylenediaminetetraacetic acid (EDTA) to 250 mM. The
phosphorylated substrate was then captured on a nitrocellulose or
phosphocellulose membrane using a 96-well filtration manifold, and
unincorporated radioactivity was removed by repeated washing with
0.85% phosphoric acid. Radioactivity was quantified by exposing the
dried membranes to a phosphorimager.
[0521] Apparent K.sub.i values were measured by assaying enzyme
activity in the presence of different inhibitor compound
concentrations and subtracting the background radioactivity
measured in the absence of enzyme. Inhibition data were fit to an
equation for competitive inhibition using Kaleidagraph (Synergy
Software), or were fit to an equation for competitive tight-binding
inhibition using the software KineTic (BioKin, Ltd.).
Inhibition of CDK4/Cyclin D Retinoblastoma Kinase Activity
[0522] A complex of human CDK4 and cyclin D3, or a complex of human
CDK4 and genetically truncated (1-264) cyclin D3, was purified
using traditional biochemical chromatographic techniques from
insect cells that had been co-infected with the corresponding
baculovirus expression vectors (see e.g., Meijer and Kim, "Chemical
Inhibitors of Cyclin-Dependent Kinases," Methods in Enzymol, vol.
283 (1997), pp. 113-128.). The enzyme complex (5 or 50 nM) was
assayed with 0.3-0.5 .mu.g of purified recombinant retinoblastoma
protein fragment (Rb) as a substrate. The engineered Rb fragment
(residues 386-928 of the native retinoblastoma protein; 62.3 kDa)
contains the majority of the phosphorylation sites found in the
native 106-kDa protein, as well as a tag of six histidine residues
for ease of purification. Phosphorylated Rb substrate was captured
by microfiltration on a nitrocellulose membrane and quantified
using a phosphorimager as described above. For measurement of
tight-binding inhibitors, the enzyme complex concentration was
lowered to 5 nM, and the assay duration was extended to 60 minutes,
during which the time-dependence of product formation was
linear.
Inhibition of CDK2/Cyclin A Retinoblastoma Kinase Activity
[0523] CDK2 was purified using published methodology (Rosenblatt et
al., "Purification and Crystallization of Human Cyclin-dependent
Kinase 2," J. Mol. Biol., vol. 230, 1993, pp. 1317-1319) from
insect cells that had been infected with a baculovirus expression
vector. Cyclin A was purified from E. coli cells expressing
full-length recombinant cyclin A, and a truncated cyclin A
construct was generated by limited proteolysis and purified as
described previously (Jeffrey et al., "Mechanism of CDK activation
revealed by the structure of a cyclin A-CDK2 complex," Nature, vol.
376 (27 Jul. 1995), pp. 313-320). A complex of CDK2 and proteolyzed
cyclin A was prepared and purified by gel filtration. The substrate
for this assay was the same Rb substrate fragment used for the CDK4
assays, and the methodology of the CDK2/cyclin A and the
CDK4/cyclin D3 assays was essentially the same, except that CDK2
was present at 150 nM or 5 nM. K.sub.i values were measured as
described above.
[0524] The stimulation of cell proliferation by growth factors such
as VEGF and others is dependent upon their induction of
autophosphorylation of each of their respective receptor's tyrosine
kinases. Therefore, the ability of a protein kinase inhibitor to
block cellular proliferation induced by these growth factors is
directly correlated with its ability to block receptor
autophosphorylation. To measure the protein kinase inhibition
activity of the compounds, the following constructs were used.
VEGF-R2 Construct for Assay
[0525] This construct determines the ability of a test compound to
inhibit tyrosine kinase activity. A construct (VEGF-R2.DELTA.50) of
the cytosolic domain of human vascular endothelial growth factor
receptor 2 (VEGF-R2) lacking the 50 central residues of the 68
residues of the kinase insert domain was expressed in a
baculovirus/insect cell system. Of the 1356 residues of full-length
VEGF-R2, VEGF-R2.DELTA.50 contains residues 806-939 and 990-1171,
and also one point mutation (E990V) within the kinase insert domain
relative to wild-type VEGF-R2. Autophosphorylation of the purified
construct was performed by incubation of the enzyme at a
concentration of 4 .mu.M in the presence of 3 mM ATP and 40 mM
MgCl.sub.2 in 100 mM Hepes, pH 7.5, containing 5% glycerol and 5 mM
DTT, at 4.degree. C. for 2 hours After autophosphorylation, this
construct has been shown to possess catalytic activity essentially
equivalent to the wild-type autophosphorylated kinase domain
construct. See Parast et al., Biochemistry, 37, 16788-16801
(1998).
CHK1 Construct for Assay
[0526] C-terminally His-tagged full-length human CHK1 (FL-CHK1) was
expressed using the baculovirus/insect cell system. It contains 6
histidine residues (6.times.His-tag) at the C-terminus of the 476
amino acid human CHK1. The protein was purified by conventional
chromatographic techniques.
VEGF-R2 Assay
Coupled Spectrophotometric (FLVK-P) Assay
[0527] The production of ADP from ATP that accompanies phosphoryl
transfer was coupled to oxidation of NADH using phosphoenolpyruvate
(PEP) and a system having pyruvate kinase (PK) and lactic
dehydrogenase (LDH). The oxidation of NADH was monitored by
following the decrease of absorbance at 340 nm (e.sub.340=6.22
cm.sup.-1 mM.sup.-1) using a Beckman DU 650 spectrophotometer.
Assay conditions for phosphorylated VEGF-R2A50 (indicated as FLVK-P
in the tables below) were the following: 1 mM PEP; 250 .mu.M NADH;
50 units of LDH/mL; 20 units of PK/mL; 5 mM DTT; 5.1 mM
poly(E.sub.4Y.sub.1); 1 mM ATP; and 25 mM MgCl.sub.2 in 200 mM
Hepes, pH 7.5. Assay conditions for unphosphorylated
VEGF-R2.DELTA.50 (indicated as FLVK in the tables) were the
following: 1 mM PEP; 250 .mu.M NADH; 50 units of LDH/mL; 20 units
of PK/mL; 5 mM DTT; 20 mM poly(E.sub.4Y.sub.1); 3 mM ATP; and 60 mM
MgCl.sub.2 and 2 mM MnCl.sub.2 in 200 mM Hepes, pH 7.5. Assays were
initiated with 5 to 40 nM of enzyme. K.sub.i values were determined
by measuring enzyme activity in the presence of varying
concentrations of test compounds. The data were analyzed using
Enzyme Kinetic and Kaleidagraph software.
ELISA Assay
[0528] Formation of phosphogastrin was monitored using biotinylated
gastrin peptide (1-17) as substrate. Biotinylated phosphogastrin
was immobilized using streptavidin coated 96-well microtiter plates
followed by detection using anti-phosphotyrosine-antibody
conjugated to horseradish peroxidase. The activity of horseradish
peroxidase was monitored using
2,2'-azino-di-[3-ethylbenzathiazoline sulfonate(6)] diammonium salt
(ABTS). Typical assay solutions contained: 2 .mu.M biotinylated
gastrin peptide; 5 mM DTT; 20 .mu.M ATP; 26 mM MgCl.sub.2; and 2 mM
MnCl.sub.2 in 200 mM Hepes, pH 7.5. The assay was initiated with
0.8 nM of phosphorylated VEGF-R2A50. Horseradish peroxidase
activity was assayed using ABTS, 10 mM. The horseradish peroxidase
reaction was quenched by addition of acid (H.sub.2SO.sub.4),
followed by absorbance reading at 405 nm. K.sub.i values were
determined by measuring enzyme activity in the presence of varying
concentrations of test compounds. The data were analyzed using
Enzyme Kinetic and Kaleidagraph software.
CHK1 Assay
[0529] The production of ADP from ATP that accompanies phosphoryl
transfer to the synthetic substrate peptide Syntide-2
(PLARTLSVAGLPGKK) was coupled to oxidation of NADH using
phosphoenolpyruvate (PEP) through the actions of pyruvate kinase
(PK) and lactic dehydrogenase (LDH). The oxidation of NADH was
monitored by following the decrease of absorbance at 340 nm
(.epsilon.340=6.22 cm.sup.-1 mM.sup.-1) using a HP8452
spectrophotometer. Typical reaction solutions contained: 4 mN PEP;
0.15 mM NADH; 28 units of LDH/ml; 16 units of PK/ml; 3 mM DTT;
0.125 mM Syntide-2; 0.15 mM ATP; 25 mM MgCl.sub.2 in 50 mM TRIS, pH
7.5; and 400 mM NaCl. Assays were initiated with 10 nM of FL-CHK1.
K.sub.i values were determined by measuring initial enzyme activity
in the presence of varying concentrations of test compounds. The
data were analyzed using Enzyme Kinetic and Kaleidagraph
software.
Inhibition of Phosphorylated FGF Receptor and LCK Tyrosine Kinase
Activity
[0530] Cloning, expression and purification of the cytosolic domain
of FGFR1 tyrosine kinase (amino acids 456-766) containing three
amino acid substitutions (L457V, C488A, and C584S) were conducted
as previously described (Mohammadi, M., Schlessinger, J., &
Hubbard, S. R. (1996) Cell 86, 577-587). This domain was expressed
in Sf9 insect cells using a baculovirus expression vector, and
protein was purified using conventional techniques. The LCK
tyrosine kinase was expressed in insect cells as an N-terminal
deletion starting from amino acid 223 to the end of the protein at
amino acid 509. The N-terminus of the protein also had two amino
acid substitutions, P223M and C 224D. Kinases were purified using
conventional chromatographic methods.
[0531] Tyrosine kinase activity was measured using a coupled,
continuous spectrophotometric assay, in which production of
phosphorylated poly(Glu,Tyr; 4:1) substrate and ADP is coupled to
the pyruvate kinase-catalyzed transfer of a phosphate from
phosphoenolpyruvate to ADP, with generation of pyruvate and
regeneration of ATP. Pyruvate production is in turn coupled to the
lactate dehydrogenase-catalyzed reduction of pyruvate to form
lactate, with concomitant conversion of NADH to NAD.sup.+. Loss of
NADH is monitored by measuring absorbance at 340 nm (see e.g.,
Technikova-Dobrova et al., "Spectrophotometric determination of
functional characteristics of protein kinases with coupled
enzymatic assay," FEBS Letters, vol. 292 (1991), pp. 69-72). Enzyme
activity was measured in the presence of 200 mM HEPES (pH 7.5), 2
mM phosphoenolpyruvate, 0.3 mM NADH, 20 mM MgCl.sub.2, 100 .mu.M
ATP, 5 mM DTT, 5.1 or 25 mM poly (Glu,Tyr) 4:1 for P-FGF or P-LCK
assays, respectively, and 15 units/mL each of pyruvate kinase and
lactate dehydrogenase. Phosphorylated FGF receptor kinase was
present at 100 nM and phosphorylated LCK kinase was present at 50
nM. Assays were performed under initial rate conditions at
37.degree. C., and rates were corrected for any background rate
measured in the absence of enzyme. Percent inhibition was
calculated relative to control enzyme assayed in the presence of 2%
(v/v) DMSO. The results are shown in Table 1.
Coupled Spectrophotometric (FAK) Assay
[0532] Tyrosine kinase assays were monitored using a Beckman DU 650
Spectrophotometer. Production of ADP was coupled to oxidation of
NADH using phosphoenolpyruvate (PEP) through the actions of
pyruvate kinase (PK) and lactic dehydrogenase (LDH). The oxidation
of NADH was monitored by following the decrease in absorbance at
340 nm (-340=6.22 cm.sup.-1 mM.sup.-1). Typical reaction solutions
contained: 1 mM PEP, 250 .mu.M NADH, 50 units of LDH/mL, 20 units
of PK/mL, 5 mM DTT, in 200 mM Hepes, pH 7.5 and varying
concentrations of poly(E.sub.4Y.sub.1), ATP and MgCl.sub.2. Assays
were initiated with 40 nM of cdFGFR1.
[0533] Results of assays performed on compounds, which include the
specific examples described above are provided below in Table I.
Unless indicated otherwise in a particular entry, the units and
assays used are as indicated in the applicable column of the table.
TABLE-US-00002 TABLE I K.sub.i with Kinases K.sub.i K.sub.i K.sub.i
K.sub.i K.sub.i K.sub.i VEGF (.mu.M) LCK (.mu.M) FGF (.mu.M) FAK %
Ex. CDK4/D CDK2/A CHK1 (.mu.M) or % Inhib. or % Inhib. or % Inhib.
Inhibition No. (.mu.M) (.mu.M) or % Inhib. at 1 .mu.M at 1 .mu.M at
1 .mu.M at 1 .mu.M 1 1.7 +/- 0.6 11 +/- 2 6.7 +/- 0.09 NT NT NT 32
2 7.9 +/- 3.0 NT NT NT NT NT NT 3 0.37 +/- 0.05 0.24 +/- 0.01 75%
NT NT NT NT inhibition at 20 .mu.M 4 0.11 +/- 0.02 0.14 +/- 0.01
1.09 +/- 0.12 0.0264 +/- 0.002 NT NT NT 5 0.48 +/- 0.04 0.69 +/-
0.03 56% NT NT NT NT inhibition at 20 .mu.M 6 0.2 +/- 0.03 0.16 +/-
0.02 80% 64% 11% 53% NT inhibition at 20 .mu.M 7' 1.2 +/- 0.3 0.79
+/- 0.12 NT NT NT NT NT 8' 0.59 +/- 0.10 0.37 +/- 0.04 NT NT NT NT
NT 9' 2.2 +/- 0.3 0.67 +/- 0.07 NT NT NT NT NT 10' 0.074 +/- 0.009
0.033 +/- 0.003 5% inhibition NT 21% 61% NT @ 10 .mu.M 11 39% 2.6
+/- 0.3 NT NT NT NT NT inhibition at 10 .mu.M 11a 48% 13 NT NT NT
NT NT inhibition at 100 .mu.M 12 19% 6.3 +/- 1.1 NT NT NT NT NT
inhibition at 5 .mu.M 13 3.4 +/- 0.7 2.7 +/- 0.7 NT NT NT NT NT 14
2.4 +/- 0.5 2.5 +/- 0.4 NT NT NT NT NT 14b 20% NT NT NT NT NT NT
inhibition at 1 .mu.M 15' 0.018 0.062 +/- 0.007 16% NT 17% 87% NT
inhibition at 1 .mu.M 16 0.035 0.015 81 36% NT 1 47% 17 NT 1.4 NT
NT NT 42.6% NT 18 0.96 NT NT NT NT NT NT 18b' 6.6 3.3 NT NT NT NT
NT 19 0.054 0.001 NT NT NT 31.3% NT inhibition 20 0.0021 0.00093 NT
NT NT 96.9% NT 21 0.237 0.049 8.55 NT 23% 54% NT 22 0.015 0.094 NT
NT NT 93.5% NT 23 0.065 0.041 NT NT NT 0.8 NT 24 0.69 1.1 NT NT NT
45.4% NT 25 0.01 0.001 NT NT NT 0.44 NT 26 0.083 0.072 NT NT NT NT
NT 27 1.5 1.6 NT NT NT NT 44% 28 0.68 0.72 NT NT NT NT 61% 29
0.0077 0.00047 NT 6% NT 2.2 NT 30 0.011 0.001 NT NT NT 52.4% NT 31
0.00037 0.00021 NT 2.9; 17% NT 55.5% NT 32 0.00041 0.00025 NT NT NT
29.7% NT 33 0.0011 0.001 NT NT NT 51.6% NT 34 0.019 0.001 NT NT NT
26.9% NT 35 0.0032 0.001 NT NT NT 40.5% NT 36 0.0023 0.001 NT 15%
NT 55.8% NT 37 0.00076 0.00022 NT 17% NT 34.4% NT 38 0.000798 0.001
NT 9% NT 42.4% NT 39 0.009 0.0011 NT NT NT NT NT 40 0.0022 0.00038
NT NT NT NT NT 41 0.078 0.25 NT NT NT NT NT 42 0.0082 0.0172 NT NT
NT 70.3% 78% 43 0.015 0.029 NT NT NT 59.6% NT 44 0.019 0.029 NT NT
NT 56.2% NT 45 0.012 0.017 NT NT NT 58.7% 63% 46 0.03 0.028 NT 51%
NT 50.5% NT 47 0.094 0.1 NT NT NT 81.1% NT 48 0.021 0.055 7.82 NT
NT 68.5% NT 49 0.095 0.049 NT NT NT 86.7% NT 50 0.253 0.073 NT NT
NT 89.6% NT 51 1.1 0.4 NT NT NT NT NT 52 0.0035 0.0026 NT 38% NT
55% NT 53 0.0026 0.00029 NT 32% NT 32% NT 54 0.026 0.00027 NT 46%
NT 81.5% NT 55 0.041 0.0011 NT 32% NT 83.6% NT 56 0.036 0.001 NT NT
NT NT NT 57 0.65 0.037 NT NT NT NT NT 58 0.0067 0.001 NT 17% NT 3;
20.3% NT 59 0.0016 0.00058 NT 31% NT 47.6% NT 60 0.0016 0.0006 NT
26% NT 40.8% NT 61 0.017 0.0012 NT 18% NT 0.48; 60.7% NT 62 0.05
0.0037 NT NT NT NT NT 63 0.22 0.0012 NT NT NT NT NT 64 0.19 0.014
NT NT NT NT NT 65 0.0028 0.001 NT NT NT 44.1% NT 66 0.055 0.001 NT
NT NT NT NT 67 0.22 0.016 NT NT NT NT NT 68 0.0047 0.0011 NT NT NT
12.6% NT 69 0.015 0.0041 NT 38% NT 25.6% NT 70 0.0018 0.00023 NT
45% NT 63% NT 71 0.00085 0.001 NT 42% NT 28.8% NT 72 0.012 0.0076
NT 24% NT 48.6% NT 73 0.0069 0.0027 NT 15% NT 42.9 NT 74 0.00052
0.0016 NT 14% NT 82.6 NT 75 0.0098 0.0014 NT NT NT NT NT 76 0.15
0.027 NT NT NT NT NT 77 0.0058 0.00038 NT NT NT NT NT 78 0.0055
0.0007 NT NT NT NT NT 79 0.0022 0.00042 NT NT NT NT NT 80 0.014
0.00025 NT NT NT NT NT 81 0.0008 0.0049 NT NT NT NT NT 82 0.11
0.0024 NT NT NT NT NT 83 30% at 30% at NT NT NT NT NT 10 .mu.M 10
.mu.M 84 34 28 22.5 NT NT NT NT 85 16 6.6 NT NT NT NT NT 86 18% at
45% at NT NT NT NT NT 10 .mu.M 10 .mu.M 87 0.0042 0.0019 NT NT NT
NT NT 88 0.0035 0.0014 NT NT NT NT NT 89 0.001 0.00094 NT NT NT NT
NT 90 0.00009 0.0003 NT NT NT NT NT 91 0.0075 0.0028 NT NT NT NT NT
92 0.0078 0.0027 NT NT NT NT NT 93 0.0019 0.00061 NT NT NT NT NT
Note: NT = not tested.
Inhibition of Cell Growth: Assessment of Cytotoxicity
[0534] Inhibition of cell growth was measured using the tetrazolium
salt assay, which is based on the ability of viable cells to reduce
3-(4,5-dimethylthiazol-2-yl)-2,5-[2H]-diphenyltetrazolium bromide
(MTT) to formazan (Mossman, Journal of Immunological Methods, vol.
65 (1983), pp. 55-58). The water-insoluble purple formazan product
was then detected spectrophotometrically. The HCT 116 cell line was
grown in 96-well plates. Cells were plated in the appropriate
medium at a volume of 135 .mu.l/well in McCoy's 5A Medium. Plates
were incubated for four hours before addition of inhibitor
compounds. Different concentrations of inhibitor compounds were
added in 0.5% (v/v) dimethylsulfoxide (15 .mu.L/well), and cells
were incubated at 37.degree. C. (5% CO.sub.2) for four to six days
(depending on cell type). At the end of the incubation, MTT was
added to a final concentration of 0.2 mg/mL, and cells were
incubated for 4 hours more at 37.degree. C. After centrifugation of
the plates and removal of medium, the absorbance of the formazan
(solubilized in dimethylsulfoxide) was measured at 540 nm. The
concentration of inhibitor compound causing 50% inhibition of
growth was determined from the linear portion of a semi-log plot of
inhibitor concentration versus percentage inhibition. All results
were compared to control cells treated only with 0.5% (v/v)
dimethylsulfoxide. TABLE-US-00003 TABLE II HCT 116 HCT 116 Example
No. IC50 (uM) IC90 (uM) 4 2.7 6.2 6 6 21 10 1.5 3.8 15 1.2 2.5 16 3
5 17 3.2 5 19 0.78 1.6 20 0.07 0.4 22 5 5 23 4 5 25 0.33 1.1 26 2.8
5 29 0.18 0.8 30 0.18 0.62 31 0.22 0.058 32 0.086 0.23 33 0.055
0.16 34 0.2 0.58 35 0.13 0.37 36 0.024 0.06 37 0.041 0.12 38 0.029
0.06 39 0.018 0.06 42 3 5 43 1.9 5 44 5 5 45 2.1 5 47 2.1 5 48 3.9
5 49 2.3 4.8 50 1.8 5 52 0.5 2.2 53 0.2 0.75 54 0.079 0.23 55 1.5 5
56 0.48 1.3 57 2 5 58 0.46 1.3 59 0.2 0.48 60 0.2 0.5 61 0.22 0.5
62 1 2.4 63 0.43 1.3 64 1.3 5 65 0.39 1.3 66 0.49 1.6 67 2 4.7 68
0.16 0.6 69 0.69 2.1 70 0.18 0.44 71 0.7 2 72 0.15 0.53 73 0.2 0.6
75 0.4 1.3 76 0.5 0.5 77 0.31 0.5 78 0.085 0.22 79 0.5 0.5 80 0.09
0.22 81 0.086 0.21 82 >0.5 >0.5 87 0.16 0.42 88 >0.5
>0.5 89 0.15 0.25 90 0.03 0.12 91 0.34 >0.5 92 0.18 0.5 93
0.32 >0.5
[0535] The examples above illustrate compounds according to Formula
I or II and assays that may readily be performed to determine their
activity levels against the various kinase complexes. It will be
apparent that such assays or other suitable assays known in the art
may be used to select an inhibitor having a desired level of
activity against a selected target.
[0536] The exemplary compounds described above may be formulated
into pharmaceutical compositions according to the following general
examples.
Parenteral Composition
[0537] To prepare a parenteral pharmaceutical composition suitable
for administration by injection, 100 mg of a water-soluble salt of
a compound of Formula I or II is dissolved in DMSO and then mixed
with 10 mL of 0.9% sterile saline. The mixture is incorporated into
a dosage unit injection.
Oral Composition
[0538] To prepare a pharmaceutical composition for oral delivery,
100 mg of a compound of Formula I or II is mixed with 750 mg of
lactose. The mixture is incorporated into an oral dosage unit for,
such as a hard gelatin capsule, which is suitable for oral
administration.
[0539] It is to be understood that the foregoing description is
exemplary and explanatory in nature, and is intended to illustrate
the invention and its preferred embodiments. Thus, the scope of the
invention should be understood to be defined not by the foregoing
description, but by the following claims and their equivalents.
* * * * *