Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use

INDAZOLE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS FOR INHIBITING PROTEIN KINASES, AND METHODS FOR THEIR USE

FIELD OF THE INVENTION

This invention is directed to indazole compounds that mediate and/or inhibit the activity of certain protein kinases, and to pharmaceutical compositions containing such compounds. The invention is

<td> also</td><td> directed</td><td> to</td><td> the therapeutic</td><td> or</td>

<td> such</td><td> compounds</td><td> and</td><td> compositions, and</td><td> to</td>

<td colspan="2"> cancer as well</td><td> as</td><td> other disease stat</td><td> es</td>

associated with unwanted angiogenesis and/or cellular proliferation, by administering effective amounts of such compounds .

BACKGROUND OF THE INVENTION

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 angiogenesis and cellcycle control, in which protein kinases play a pivotal role;

<img file="MY139999A_D0001.tif" />

-2these processes are essential for the growth of solid tumors as well as for other diseases.

Angiogenesis 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 et al., Cell Growth &amp; 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 degeneration (AMD), 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 known as

KDR (kinase insert domain receptor) and as FLK-1); FGF-R (fibroblast growth factor receptor); and TEK (also known as Tie-2).

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,

-31615-1620 (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.

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).

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

-4angiopoietin-1 on TEK and disrupts angiogenesis. Maisonpierre et al., Science,

277,55-60 (1997).

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, psoriasis, rheumatoid arthritis, Kaposi’s sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restinosis, autoimmune diseases, acute inflammation, and ocular diseases with retinal vessel proliferation.

Phosphorylase kinase activates glycogen phosphorylase, thus increasing glycogen breakdown and hepatic glucose release. Hepatic glucose production is disregulated in type 2 diabetes, and is the primary cause of fasting hyperglycemia, which results in many of the secondary complications afflicting these patients.

Thus, reduction in glucose release from the liver would lower elevated plasma glucose levels. Inhibitors of phosphorylase kinase should therefore decrease phosphorylase activity and glycogenolysis, thus reducing hyperglycemia in patients.

Another physiological response to VEGF is vascular hyperpermeability, which has been proposed to play a role in the early stages of angiogenesis. In ischemic tissues, such as those occurring in the brain of stroke victims, hypoxia trigger VEGF expression, leading to increased vascular permeability and

-5ultimately edema in the surrounding tissues. In a rat model for stroke, it has been shown by van Bruggen et al., J. Clinical Invest., 104, 1613-20 (1999) that administration of a monoclonal antibody to VEGF reduces the infarct volume.

Thus, inhibitors of VEGFR are anticipated to be useful for the treatment of stroke.

In addition to its role in angiogenesis, protein kinases also play a crucial role in cell-cycle control. Uncontrolled cell proliferation is the insignia of cancer.

Cell proliferation in response to various stimuli is manifested by a de-regulation 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.

Cyclin-dependent kinases (CDKs) are serine-tlireonine protein kinases that play critical roles in regulating the transitions between different phases of the cell cycle. See, e.g., the articles compiled in Science, 274, 1643-1677 (1996). CDK complexes are formed through association of a regulatory cyclin subunit (e.g., cyclin A, BI, B2, Dl, 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 phases of the cell cycle.

It is CDK4 complexed to the D cyclins that plays a critical part in initiating the cell-division cycle from a resting or quiescent stage to one in which cells become committed to cell division. This progression is subject to a variety of growth regulatory mechanisms, both negative and positive. Aberrations in this

-6control system, particularly those that affect the function of CDK4, have been implicated in the advancement of cells to the highly proliferative state characteristic of malignancies, particularly familial melanomas, esophageal carcinomas, and pancreatic cancers. See, e.g., Kamb, Trends in Genetics, 11,

136-140 (1995); Kamb et al., Science, 264, 436-440 (1994).

Myriad publications describe a variety of chemical compounds useful against a variety of therapeutic targets. For example, WLPO International

Publication Nos. WO 99/23077 and WO 99/23076 describe indazole-containing compounds having phosphodiesterase type IV inhibitory activity produced by an indazole-for-catechol bioisostere replacement. U.S. Patent No. 5,760,028 discloses heterocycles including 3-[l-[3-(imidazolin-2-ylamino)propyl]indazol-5 ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid, which are useful as antagonists of the α_νβ₃ integrin and related cell surface adhesive protein receptors. WIPO International Publication No. WO 98/09961 discloses certain indazole derivatives and their use as inhibitors of phosphodiesterase (PDE) type

IV or the production of tumor necrosis factor (TNF) :in a mammal. Recent additions to the virtual library of known compounds include those described as being anti-proliferative therapeutic agents that inhibit CDKs. For example, U.S.

Patent No. 5,621,082 to Xiong et al. discloses nucleic acid encoding an inhibitor of CDK6, and European Patent Publication No. 0 666 270 A2 describes peptides and peptide mimetics that act as inhibitors of CDK1 and CDK2. WIPO

International Publication No. WO 97/16447 discloses certain analogs of chromones that are inhibitors of cyclin-dependeni kinases, in particular of

-ΊCDK/cyclin complexes such as CDK4/cyclin Dl, which may be used for inhibiting excessive or abnormal cell proliferation, and therefore for treating cancer. WIPO International Publication No. WO 99/21845 describes 4aminothiazole derivatives that are useful as CDK inhibitors.

There is still a need, however, for small-molecule compounds that may be readily synthesized and are effective in inhibiting one or more CDKs or

CDK/cyclin complexes. Because CDK4 may serve as a general activator of cell division in most cells, and complexes of CDK4 and D-type cyclins govern the early Gi phase of the cell cycle, there is a need for effective inhibitors of CDK4, and D-type cyclin complexes thereof, for treating one or more types of tumors.

Also, the pivotal roles of cyclin E/CDK2 and cyclin B/CDK1 kinases in the G,/S phase and G₂/M transitions, respectively, offer additional targets for therapeutic intervention in suppressing deregulated cell-cycle progression in cancer.

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).

-8One series of checkpoints monitors the integrity of the genome and, upon sensing DNA damage, these “DNA damage checkpoints” block cell-cycle progression in Gj and G₂ 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 Gj 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 G₂ phase of the cell cycle. See, e.g., Bunz et al., Science, 28, 1497-1501 (1998); Winters et al., Oncogene, Yl, 673-684 (1998); Thompson, Oncogene, 15, 3025-3035 (1997).

Given the pivotal nature of the p5 3 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 G₂ checkpoint in p53 defective cancer cells. Cancer cells, because they lack G_; checkpoint control, are particularly vulnerable to abrogation of the last remaining barrier protecting them from the cancer-killing effects of DNA-damaging agents: the G₂ checkpoint. The G₂ 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-9damage 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 G₂ 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, 865867 (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).

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

Cdsl/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.

Integrin receptor binding to ECM initiates intracellular signals mediated by FAK (Focal Adhesion Kinase) that are involved in cell motility, cellular proliferation, and survival. In human cancers, FAK overexpression is implicated

-10in. tumorigenesis and metastatic potential through its role in integrin mediated signaling pathways.

Tyrosine kinases can be of the receptor type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly 5 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.

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, Oncologist, 5, 3-10 (2000); Holash et al., Oncogene, 18, 5356-62 (1999); Thomas et al., J. Biol. Chem., 274, 36684-92 (1999); Cohen, Curr. Op.

Chem. Biol., 3, 459-65 (1999); Klohs et al., Curr. Op. Chem. Biol., 10, 544-49 (1999); McMahon et al., Current Opinion in Drug Discovery &amp; Development, 1, 131-146 (1998); Strawn et al., Exp. Opin. Invest. Drugs, 7, 553-573 (1998).

WEPO International Publication WO 00/18761 discloses certain substituted 3cyanoquinolines as protein kinase inhibitors.

There is still a need, however, for effective inhibitors of protein kinases.

Moreover, as is understood by those skilled in the art, it is desirable for kinase inhibitors to possess both high affinity for the target kinase or kinases as well as high selectivity versus other protein kinases.

-11SUMMARY OF THE INVENTION

Thus, an objective of the invention is to discover potent inhibitors of protein kinases. Another objective of the invention is to discover effective kinase inhibitors having a strong and selective affinity for one or more particular kinases.

These and other objectives of the invention, which will become apparent from the following description, have been achieved by the discovery of the indazole compounds, pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts thereof (such compounds, prodrugs, metabolites and salts are collectively referred to as “agents”) described below, which modulate and/or inhibit the activity of protein kinases. Pharmaceutical compositions containing such agents are useful 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. Further, the agents have advantageous properties relating to the modulation and/or inhibition of the kinase activity associated with VEGF-R, FGF-R, CDK complexes, CHK1, LCK, TEK, FAK, and/or phosphorylase kinase.

In a general aspect, the invention relates to compounds of the Formula I:

<img file="MY139999A_D0002.tif" />

wherein:

-12R¹ is a substituted or unsubstituted aryl or heteroaryl, or a group of the formula CH=CH—R³ or CH=N—R³ where R³ is a substituted or unsubstituted alkyl, alkenyl, cycioalkyl, heterocycloalkyl, aryl, or heteroaryl; and

R² is a substituted or unsubstituted aryl, heteroaryl, or Y-X, where Y is O,

S, C=CH₂, C=0, S=0, S0₂, alkylidene, NH, or N-(Cj -C₈ alkyl), and X is substituted or unsubstituted Ar, heteroaryl, NH-(alkyl), NH-(cycloalkyl), NH(heterocycloalkyl), NH(aryl), NH(heteroaryl), NH-(alkoxyl), or NH(dialkylamide), where Ar is aryl;

The invention is also directed to pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of the compounds of Formula I. Advantageous methods of making the compounds of the Formula I are also described.

In another general aspect, the invention relates to compounds of the

Formula 1(a):

<img file="MY139999A_D0003.tif" />

wherein:

R¹ is a substituted or unsubstituted aryl or heteroaryl, or a group of the formula CH=CH—R³ or CH=N—R³ where R³ is a substituted or unsubstituted alkyl, alkenyl, cycioalkyl, heterocycloalkyl, aryl, or heteroaryl; and

-13R² is a substituted or unsubstituted aryl or Y-Ar, where Y is O, S, C=CH₂, C=0, S=0, S0₂, CH₂, CHCHj, NH, or N-(Ci-C₈ alkyl), and Ar is a substituted or unsubstituted aryl.

The invention is also directed to pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of the compounds of Formula 1(a). Advantageous methods of making the compounds of the Formula 1(a) are also described.

In one preferred general embodiment, the invention relates to compounds having the Formula II:

<img file="MY139999A_D0004.tif" />

wherein:

R¹ is a substituted or unsubstituted aryl or heteroaryl, or a group of the formula CH=CH—R³ or CH=N—R³, where R³ is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R⁴ and R⁷ are each independently hydrogen, OH, halo, C,-C₈ alkyl, Cj-Cg alkoxy, C,-C_g alkenyl, aryloxy, thioaryl, CH₂-0H, CH₂-O- (C,-C₈ alkyl), CH₂-Oaryl, CH₂-S-(C]-C₈ alkyl), or CH₂-S-aryl;

-14R⁵ and R⁶ are each independently hydrogen, OH, halo, Z-alkyl, Z-aryl, or Z-CH,CH=CH₂, where Z is O, S, NH, or CH₂, and the alkyl and aryl moieties of

Z-alkyl and Z-aryl are each optionally substituted;

and pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts thereof.

In a preferred embodiment of Formula II: R¹ is a substituted or unsubstituted bicyclic heteroaryl, or a group of the formula CH=CH—R³ where R³ is a substituted or unsubstituted aryl or heteroaryl; R⁴ and R⁷ are each independently hydrogen or Cj-C8 alkyl; and R⁵ and R⁶ are each independently halo, Z-alkyl, or Z-CH2CH=CH₂, where Z is O or S.

In another preferred general embodiment, compounds of the invention are of Formula III:

<img file="MY139999A_D0005.tif" />

wherein:

R¹ is a substituted or unsubstituted aryl or heteroaryl, or a group of the formula CH=CH—R³ or CH=N—R³, where R³ is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Y is O, S, C=CH₂, C=O, S=O, SO₂, CH₂, CHCH₃, NH, or N-(C_rC₈ alkyl); R⁸ is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, or aryloxyl;

-15R¹⁰ is independently selected from hydrogen, halogen, and lower-alkyl; and pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and pharmaceutically acceptable salts thereof.

More preferably, in Formula III: R¹ is a substituted or unsubstituted 5 bicyclic heteroaryl, or a group of the formula CH=CH—R³ where R³ is a substituted or unsubstituted aryl or heteroaryl; Y is O, S, C=CH₂, C=0, NH, or N(C]-C_g alkyl); R⁸ is a substituted or unsubstituted aryl, heteroaryl, alkyl, and alkenyl, and R¹⁰ is hydrogen or halogen.

In another preferred general embodiment, compounds of the invention are of Formula 111(a):

<img file="MY139999A_D0006.tif" />

<img file="MY139999A_D0007.tif" />

wherein:

R¹ is a substituted or unsubstituted aryl or heteroaryl, or a group of the formula CH=CH—R³ or CH=N—R³, where R³ is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Y is 0, S, C=CH₂, C=0, S=0, S0₂, CH₂, CHCH₃, NH, or N-(C,-C₈ alkyl); R⁸ is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, or aiyloxyl;

and pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and pharmaceutically acceptable salts thereof.

-16More preferably, in Formula 111(a): R¹ is a substituted or unsubstituted bicyclic heteroaryl, or a group of the formula CH=CH—R³ where R³ is a substituted or unsubstituted aryl or heteroaryl; Y is O. S, C=CH₂, OO, NH, or N(Ci-C₈ alkyl); and R⁸ is a substituted or unsubstituted aryl or heteroaryl.

In another preferred general embodiment, compounds of the invention are of Formula IV:

<img file="MY139999A_D0008.tif" />

wherein:

R¹ is a substituted or unsubstituted aryl or heteroaryl, or a group of the 10 formula CH=CH—R³ or CH=N—R³, where R³ is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Y is O, S, C=CH₂, C=0, S=0, S0₂, CH₂, CHCH₃, NH, or N-(C,-C₈ alkyl); R⁹ is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, aryloxyl, cycloalkoxyl, NHrfCj-Cg alkyl), NH-(aryl),

NH-(heteroaryl), N=CH-(alkyl), NH(C=O)R^1!, or NH₂, where R is independently selected from hydrogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and

R¹⁰ is independently selected from hydrogen, halogen, and lower-alkyl;

and pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and pharmaceutically acceptable salts thereof.

-17More preferably, in Formula IV: R¹ is a group of the formula CH=CH— R³ where R³ is a substituted or unsubstituted aryl or heteroaryl; Y is S or NH, and R⁹ is a substituted or unsubstituted alkyl, alkoxyl, or NH-(heteroaryl).

Most preferred are compounds of the invention selected from:

<img file="MY139999A_D0009.tif" />

I

<img file="MY139999A_D0010.tif" />

<img file="MY139999A_D0011.tif" />

<img file="MY139999A_D0012.tif" />

<img file="MY139999A_D0013.tif" />

<img file="MY139999A_D0014.tif" />

N

-20H

<img file="MY139999A_D0015.tif" />

-21The invention also relates to a method of modulating and/or inhibiting the kinase activity of VEGF-R, FGF-R, a CDK complex, CHK1, LCK, TEK, FAK, and/or phosphorylase kinase by administering a compound of the Formula I, II,

III, or IV, or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof. Preferred compounds of the present invention that have selective kinase activity—i.e., they possess significant activity against one or more specific kinases while possessing less or minimal activity against one or more different kinases. In one preferred embodiment of the invention, compounds of the present invention are those of 10 Formula I possessing substantially higher potency against VEGF receptor tyrosine kinase than against FGF-R1 receptor tyrosine kinase. The invention is also directed to methods of modulating VEGF receptor tyrosine kinase activity without significantly modulating FGF receptor tyrosine kinase activity.

The inventive compounds may be used advantageously in combination 15 with other known therapeutic agents. For example, compounds of Formula I, II,

III, or IV which possess antiangiogenic activity may be co-administered with cytotoxic chemotherapeutic agents, such as taxol, taxotere, vinblastine, cis-platin, doxorubicin, adriamycin, and the like, to produce an enhanced antitumor effect. Additive or synergistic enhancement of therapeutic effect may also be obtained by co-administration of compounds of Formula I, II, III, or IV which possess antiangiogenic activity with other antiangiogenic agents, such as combretastatin A-4, endostatin, prinomastat, celecoxib, rofocoxib, EMD121974, IM862, antiVEGF monoclonal antibodies, and anti-KDR monoclonal antibodies.

-22The invention also relates pharmaceutical compositions, each comprising an effective amount of an agent selected from compounds of Formula I and pharmaceutically acceptable salts, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs thereof; and a pharmaceutically acceptable carrier or vehicle for such agent. The invention further provides methods of treating cancer as well as other disease states associated with unwanted angiogenesis and/or cellular proliferation, comprising administering effective amounts of such an agent to a patient in need of such treatment.

DETAILED DESCRIPTION OF ΓΝΛΈΝΤΙΟΝ AND PREFERRED EMBODIMENTS

The inventive compounds of the Formula I, II , III, and IV are useful for mediating the activity of protein kinases. More particularly, 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.

The term “alkyl” as used herein refers to straight- and branched-chain alkyl groups having one to twelve carbon atoms. Exemplary alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (t-Bu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like. The term “lower alkyl” designates an alkyl having from 1 to 8 carbon atoms (a C^-alkyl). Suitable substituted alkyls include fluoromethyl, difluoromethyl, trifluoromethyl, 2fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like.

-23The term “alkylidene” refers to a divalent radical having one to twelve carbon atoms. Illustrative alkylidene groups include CH₂, CHCH₃, (CH₃)₂, and the like.

The term “alkenyl” refers to straight- and brar ched-chain alkenyl groups having from two to twelve carbon atoms. Illustrative alkenyl groups include prop-25 enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, and the like.

The term “alkynyl” refers to straight- and branched-chain alkynyl groups having from two to twelve carbon atoms.

The term “cycloalkyl” refers to saturated or partially unsaturated carbocycles having from three to twelve carbon atoms, including bicyclic and tricyclic cycloalkyl structures. Suitable cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

A “heterocycloalkyl” group is intended to mean a saturated or partially unsaturated monocyclic radical containing carbon atoms, preferably 4 or 5 ring carbon atoms, and at least one heteroatom selected from nitrogen, oxygen and sulfur.

The terms “aryl” and “heteroaryl” refer to 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 aromatic ring structures include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, furyl, thienyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,320 triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, l-H-tetrazol-5-yl, indolyl, quinolinyl, benzofuranyl, benzothiophenyl (thianaphthenyl), and. the like. Such moieties may be optionally substituted by a fused-ring structure or bridge, for example OCH₂-O.

-24The term “alkoxy” is intended to mean the radical -O-alkyl. Illustrative examples include methoxy, ethoxy, propoxy, and the like.

The term “aryloxy” respresents -0—aryl, wherein aryl is defined above.

The term “cycloalkoxyl” represents -0—cycloalkyl, wherein cycloalkyl is defined above.

The term “halogen” represents chlorine, fluorine, bromine or iodine. The term “halo” represents chloro, fluoro, bromo or iodo.

In general, the various moieties or functional groups for variables in the formulae may be optionally substituted by one or more suitable substituents.

Exemplary substituents include a halogen (F, Cl, Br, or I), lower alkyl, -OH, -NO,, CN, -CO,H, -O-lower alkyl, -aryl, -aryl-lower alkyl, -CO₂CH₃, -CONH₂, OCH₂CONH₂, -NH₂, -SO₂NH₂, haloalkyl (e.g., -CF₃, -CH₂CF₃), -O-haloalkyl (e.g., OCF₃, -OCHF₂), and the like.

The terms “comprising” and “including” are used in an open, non-limiting sense.

It is understood that while a compound of Formula I may exhibit the phenomenon of tautomerism, the formula drawings within this specification expressly depict only one of the possible tautomeric forms. It is therefore to be understood that within the invention the formulae are intended to represent any tautomeric form of the depicted compound and is not to be limited merely to a specific tautomeric form depicted by the formula drawings.

Some of the inventive compounds may exist as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, ard/or mixtures of enantiomers

-25and/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.

As generally understood by those skilled in the art, an optically pure compound having one chiral center 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, ε. 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.).

Additionally, the formulas are intended to cover solvated as well as unsolvated forms of the identified structures. For example, Formula I includes 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.

In addition to compounds of the Formula I, II, III, and IV, the invention includes pharmaceutically acceptable prodrues, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds.

“A pharmaceutically acceptable prodrug” is a. compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.

-26“A pharmaceutically active metabolite” is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein.

Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art. See, e.g., Bertolini, G. et al., J. Med. Chem., 40,

2011-2016 (1997); Shan, D. et al.,7. Pharm. Sci., 86 (7), 765-767; Bagshawe K.,

Drug Dev. Res., 34, 220-230 (1995); Bodor, N., Advances in Drug Res., 13, 224-331 (1984); Bundgaard, H., Design of Prodrugs (Elsevier Press 1985); and Larsen, I. K.,

Design and Application of Prodrugs, Drug Design and Development (KrogsgaardLarsen et al., eds., Harwood Academic Publishers, 1991).

“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 cr 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,

-27caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne1,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates, methane-sulfonates, propan esulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

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, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alphahydroxy 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.

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

-28derived 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.

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.

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 protein kinases, such as tryosine kinases. Thus, e.g., a therapeutically effective amount of a compound of the Formula I, salt, active metabolite or prodrug thereof is a quantity sufficient to modulate, regulate, or inhibit the activity of one or more protein kinases such that a disease condition which is mediated by that activity is reduced or alleviated.

The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art. “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 protein kinases, such as

-29tyrosine 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.

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.

In one general synthetic process, compounds of Formula I are prepared according to the following reaction scheme:

-30N

IL no₂

1) NaOH, l₂

2) Pg-X

Pg

<img file="MY139999A_D0016.tif" />

R¹-M

<img file="MY139999A_D0017.tif" />

SnO₂

Pg ,N

NO,

R¹'

Ϊ I)

VII

NaNO,

KI

1) I to M exchange

2) R² +

<img file="MY139999A_D0018.tif" />

R¹ IX

<img file="MY139999A_D0019.tif" />

6-Nitroindazole (compound V) is treated with iodine and base, e.g.,

NaOH, in an aqueous/organic mixture, preferably wiih dioxane. The mixture is acidified and the product isolated by filtration. To the resulting 3-iodo-6-31nitroindazole in dichloromethane-50% aqueous KOH at 0 °C is added a protecting group (“Pg”) reagent (wherein X = halo), preferably trimethylsilylethoxymethyl chloride (SEM-C1), and a phase transfer catalyst, e.g., tetrabutylammonium bromide (TBABr). After 1-4 hours, the two phases are diluted, the organics are separated, dried with sodium sulfate, filtered and concentrated. The crude product is purified by silica gel chromatography to give compounds of formula VI. Treatment of compounds of formula VI in a suitable organic solvent with a suitable R¹ -organometallic reagent, preferably an R¹boronic acid, in the presence of aqueous base, e.g., sodium carbonate, and a suitable catalyst, preferably Pd(PPh₃)₄ gives, after extractive work-up and silica gel chromatography, compounds of formula VII. The R¹ substituent may be exchanged within compounds of formula VII or later intermediates throughout this scheme by oxidative cleavage (e.g., ozonolysis) followed by additions to the resulting aldehyde functionality with Wittig or condensation transformations (typified in Example 42(a-e)). Treatment of compounds of formula VII with a reducing agent, preferably SnCl₂, provides, after conventional aqueous work up and purification, compounds of formula VIII. For the series of derivatives where Y = NH or N-lower alkyl, compounds of formula VIII may be treated with aryl or heteroaryl chlorides, bromides, iodides or tritiates in the presence of a base, preferably Cs₂CO₃, and catalyst, preferably Pd-BINAP, (and where Y = N-lower alkyl, with a subsequent alkylation step) to provide compounds of formula X. To produce other Y linkages, sodium nitrite is added to compounds of formula VIII under chilled standard aqueous acidic conditions followed by the addition of

-32potassium iodide and gentle warming. Standard work-up and purification produces iodide compounds of formula IX.

Treatment of compounds of formula IX with an organometallic reagent, e.g., butyllithium, promotes lithium halogen exchange. This intermediate is then reacted with an R² electrophile, e.g., a carbonyl or triflate, through the possible mediation of additional metals and catalysts, preferably zinc chloride and Pd(PPh₃)₄ to provide compounds of formula X. Alternatively, compounds of formula IX may be treated with an organometallic reagent such as an organoboronic acid in the presence of a catalyst, e.g., Pd(PPh₃)₄, under a carbon monoxide atmosphere to give compounds of formula X. Alternatively, for derivatives where Y = NH or S, compounds of formula IX may be treated with appropriate amines or thiols in the presence of base, preferably Cs₂CO₃ or K₃PO₄ and a catalyst, preferably Pd-BINAP or Pd-(biscyclohexyl)biphenylphosphine to provide compounds of formula X. Conventional functional group interchanges, such as oxidations, reductions, alkylations, acylations, condensations, and deprotections may then be employed to further derivatize this series giving final compounds of Formula I.

The inventive compounds of Formula I may also be prepared according general procedure shown in the following scheme:

<img file="MY139999A_D0020.tif" />

R¹-M catalyst

<img file="MY139999A_D0021.tif" />

6-Iodoindazole (XI) is treated with iodine and base, e.g., NaOH, in an aqueous/organic mixture, preferably with dioxane. The mixture is acidified and the product XII is isolated by filtration. To the resulting 3,6 di-iodoindazole in dichloromethane-50% aqueous KOH at 0 °C is added a protecting group reagent, preferably SEM-C1, and a phase transfer catalyst, e.g , TBABr. The two phases are diluted, the organics separated, dried with sodium su'.fate, filtered and concentrated.

The crude product is purified by silica gel chromatography to give compounds of the

-34formula XIII. Treatment of compounds of formula XIII in a suitable organic solvent with a suitable R²-organometallic reagent, e.g., R²-ZnCl or boron R²-boron reagent and a suitable catalyst, preferably Pd(PPh₃)₄ gives, after extractive work-up and silica gel chromatography, compounds of formula XIV. Treatment of compounds of 5 formula XIV in a suitable organic solvent with a suitable R¹ -organometallic reagent (e.g., boron R¹ -boron reagent or R’-ZnCl), in the presence of aqueous base, sodium carbonate, and a suitable catalyst, preferably Pd(PPh-₍)₄ gives, after extractive work-up and silica gel chromatography, compounds of formula XV. Conventional functional group interchanges, such as oxidations, reductions, alkylations, acylations, condensations and deprotections may then be employed to further derivatize this series giving final compounds of Formula I.

Alternatively, compounds of Formula I where R² is a substituted or unsubstituted Y-Ar, where Y is O or S may be prepared according to the following general scheme:

<img file="MY139999A_D0022.tif" />

XVI catalyst, heat or

DDQ modifications

<img file="MY139999A_D0023.tif" />

A stirred acetone solution of 3-chloro-cyclohex-2-enone (XV), H-R², and anhydrous potassium carbonate is refluxed for 15-24 hours, cooled, and filtered. Concentrating and chromatographing the filtrate on silica gel gives 3-R²5 cyclohex-2-enone (XVI).

The ketones of formula XVI may be reacted with a suitable base (M-B), preferably lithium bis (trimethyls ily)amide, and reacted with R'-CO-X (where X = halogen), which after standard acid work up and purification provides compounds of the formula XVII. This product, in HOAc/EtOH, combined with hydrazine monohydrate, is heated at a suitable temperature for an appropriate time period,

-36preferably at 60-80 °C for 2-4 hours. After cooling, the mixture is poured into saturated sodium bicarbonate solution, extracted with an organic solvent, concentrated, and purified on silica gel to give compounds of formula XVIII.

Compounds of formula XVIII may be oxidized using' a variety of known methods to give compounds of the Formula I.

Other compounds of Formula I may be prepared in manners analogous to the general procedures described above or the detailed procedures described in the examples herein. The affinity of the compounds of the invention for a receptor may be enhanced by providing multiple copies of the ligand in close 10 proximity, preferably using a scaffolding provided by a carrier moiety. It has been shown that provision of such multiple valence compounds with optimal spacing between the moieties dramatically improves binding to a receptor. See, e.g., Lee et al., Biochem, 23, 4255 (1984). The multivalency and spacing can be controlled by selection of a suitable carrier moiety or linker units. Such moieties 15 include molecular supports which contain a multiplic ity of functional groups that can be reacted with functional groups associated with the compounds of the invention. Of course, a variety of carriers can be used, including proteins such as

BSA or HAS, a multiplicity of peptides including, for example, pentapeptides, decapeptides, pentadecapeptides, and the like. The peptides or proteins can contain the desired number of amino acid residues having free amino groups in their side chains; however, other functional groups, such as sulfhydryl groups or hydroxyl groups, can also be used to obtain stable linkages.

-37Compounds that potently regulate, modulate, or inhibit the protein kinase activity associated with receptors VEGF, FGF, CDK complexes, TEK, CHK1,

LCK, FAK, and phosphorylase kinase among others, and which inhibit angiogenesis and/or cellular profileration is desirable and is one preferred embodiment of the present invention. The present invention is further directed to methods of modulating or inhibiting protein kinase activity, for example in mammalian tissue, by administering an inventive agent. The activity of the inventive compounds as modulators of protein kinase activity, such as the activity of kinases, may be measured by any of the methods available to those skilled in the art, including in vivo and/or in vitro assays. Examples of suitable assays for activity measurements include those described in Parast C. et al., Biochemistry,

37, 16788-16801 (1998); Jeffrey et al., Nature, 376, 313-320 (1995); WIPO

International Publication No. WO 97/34876; and WIPO International Publication No. WO 96/14843. These properties may be assessed, for example, by using one or more of the biological testing procedures set out in the examples below.

The active agents of the invention may be formulated into pharmaceutical compositions as described below. Pharmaceutical compositions of this invention comprise an effective modulating, regulating, or inhibiting amount of a compound of Formula I, II, III, or IV and an inert, pharmaceutically acceptable carrier or diluent. In one embodiment of the pharmaceutical compositions, efficacious levels of the inventive agents are provided so as to provide therapeutic benefits involving modulation of protein kinases. By “efficacious levels” is meant levels in which the effects of protein kinases are, at a minimum, regulated.

-38These compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g., parenteral or oral administration.

. An inventive agent is administered in conventional dosage form prepared by combining a therapeutically effective amount of an agent (e.g., a compound of Formula I) as an active ingredient with appropriate pharmaceutical carriers or diluents according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

The pharmaceutical carrier employed may be either a solid or liquid. Exemplary of solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. 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 :md the like.

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 will 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.

-39To 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. In an exemplary embodiment, a compound of Formula I is 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.

It will be appreciated that the actual dosages of the agents used in the compositions of this invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, host and disease being treated. Optimal dosages for a given set of conditions can be ascertained by those skilled in the art using conventional dosagedetermination tests in view of the experimental data for an agent. For oral administration, an exemplary daily dose generally employed is from about 0.001 to about 1000 mg/kg of body weight, more preferably from about 0.001 to about 50 20 mg/kg body weight, with courses of treatment repeated at appropriate intervals.

Administration of prodrugs are typically dosed at weight levels which are chemically equivalent to the weight levels of the fully active form.

-40The 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.

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, Ringer's 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.

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, 1o obtain tablets or dragee cores. Suitable excipients include: fillers such as sugars, including lactose, sucrose,

-41mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, 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.

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 coatirgs for identification or to characterize different combinations of active agents.

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.

-42For 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 nebuliser, 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 insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

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.

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

-43increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

For administration to the eye, a compound of the Formula I, II, III, or IV 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/cilary, lens, choroid/retina and selera.

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.

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.

In addition to the formulations described above, 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.

-44A 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 3C0, 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.

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

-45their 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.

The pharmaceutical compositions also may comprise suitable solid- or gelphase 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.

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.

The preparation of preferred compounds of th e present invention is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other protein kinase inhibitors of the invention. For example, the synthesis of non-ex emplified 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.

EXAMPLES

-46In 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), Ν,Ν-dimethylformamide (DMF), dichloromethane, toluene, and dioxane 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.

The reactions set forth below were done generally under a positive pressure of 10 argon or nitrogen 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.

Visualization of the TLC plates was done with a/?-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 Na₂SO₄ prior to filtration and

-47evaporation 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 pm) and a silica gel: crude material ratio of about 20:1 to 50:1 unless otherwise stated.

Hydrogenolysis was done at the pressure indicated in the examples or at ambient pressure.

’H-NMR spectra were recorded on a Bruker instrument operating at 300 MHz and ¹³C-NMR spectra were recorded operating at 75 MHz. NMR spectra were obtained as CDC1₃ solutions (reported in ppm), using chloroform as the reference standard (7.25 ppm and 77.00 ppm) or CD₃OD (3.4 and 4.8 ppm and 49.3 ppm), or internally 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).

Infrared (IR) spectra were recorded on a Perkin-Elmer FT-IR Spectrometer as neat oils, as KBr pellets, or as CDC1₃ solutions, and when given are reported in wave numbers (cm'¹). The mass spectra were obtained using LSIMS or electrospray. All melting points (mp) are uncorrected.

Example 1 (a): 3-[E-2-(3,4-Dimethoxy-phenyl)vinyl]-6-(3-methoxy-4-hydroxyphenyl)-l/i-indazole

<img file="MY139999A_D0024.tif" />

C\ TFA/hJO/THF

2:1:1,23 C, 30 min

O' lj (cat.), CfeCt 23 °C, 16 h

CH

<img file="MY139999A_D0025.tif" />

0'

The 3-[E/Z-2-(3,4-dimethoxy-phenyl)vinyl]-6-[3-methoxy-4(methoxymethoxy)phenyl]-l/7-indazole (-205 mg, 0 461 mmol (theoretical)) was dissolved in tetrahydrofuran (THF, 10 mL) and was treated with water (10 mL) and trifluoroacetic acid (TFA, 20 mL). The reaction mixmre was allowed to stir at 23 °C for 30 minutes (min.). The mixture was diluted with toluene (100 mL) and the volatile materials were removed under reduced pressure (30 mm Hg, 35 °C) to give a concentrated volume of - 5 mL. Again, toluene (10C&gt; mL) was added and the mixture was concentrated under reduced pressure to give crude material which still contained some acid. The material was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic material was separated, dried over sodium sulfate, decanted, and concentrated under reduced pressure. The residue, a mixture of olefin isomers, (-185 mg, 0.461 mmol (theoretical)) was taken up in dichloromethane (50 mL) at 23 °C and was treated with iodine (80 mg). The mixture was allowed to stir at 23 °C for 12 hours (h). The mixture was treated with saturated sodium bicarbonate (10 mL) and 5% aqueous sodium bisulfite (10 mL). The mixture was diluted with ethyl acetate (200 mL) and the organic material was washed with saturated sodium bicarbonate (100 mL), dried over sodium sulfate, decanted, and concentrated under reduced pressure to give crude product. The crude was purified on silica (40 mL, 6:4 -&gt; 7:3 ethyl acetate/hexane) and all fractions containing desired were combined, concentrated and precipitated from a dichloromethane/hexane bilayer (1:3) to give 3-49[E-2-(3,4-Dimethoxy-phenyl)vinyl]-6-(3-methoxy-4-hydroxy-phenyl)-l//-indazole as a white solid (93 mg combined crops): Ry sm 0.42, p 0.35 (ethyl acetate-hexane 7:3); FTIR (thin film) 3324, 1600, 1514, 1463, 1422, 1264, 1137, 1024, 959, 852 cnr¹; lH

NMR (CDCI3) δ 10.0 (bs, IH), 8.08 (d, IH, J = 8.4 Hz), 7.59 (s, IH), 7.49 (d, IH, J =

16.6 Hz), 7.45 (dd, IH, J = 1.4, 8.4 Hz), 7.34 (d, IH, J = 16.6 Hz), 7.20-7.12 ( m,

4H), 7.03 (d, IH, J = 8.0 Hz), 6.91 (d, IH, J = 8.2 Hz), 5.68 (bs, IH), 3.99 (s, 3H),

3.97 (s, 3H), 3.93 (s, 3H); ¹³C NMR (CDCI3) δ 149.6, 149.5, 146.0, 144.0, 142.6,

140.8, 133.9, 131.4, 130.7, 121.7, 121.4, 120.9, 120.4, 120.2, 118.6, 115.4, 111.7,

110.8, 109.1, 108.2, 56.4, 56.3, 56.2. HRMS (ES) [m+H]/z Calc’d 403.1658, found

403.1658. [m-H]/z Calc’d 401. Found 401.

The starting material was prepared as follows (i)

N nh₂

NaNOj, HCI KI, H₂O 0 to 50 ’C

To 6-aminoindazole (40.8 g, 0.3065 mol, 1 equiv) in a 2-liter (2-L) round15 bottom flask containing a large magnetic stir bar was added ice (256 g), followed by water (128 mL) and the reaction vessel was lowered into an ice bath. To this stirring slurry at 0 °C was added concentrated aqueous HCI (128 mL, 1.53 mol, 5 equiv). Immediately after, a solution of NaNC&gt;2 (23.3 g, 0.338 mol, 1.1 equiv) in water (96 mL) was added. After 10 min of stirring at 0 °C, KI (61 g, 0.368 mol, 1.2 equiv) was 20 added very slowly at first (-100 mg at a time because the first small bits of KI cause an abrupt evolution of gas) then more rapidly (5 min total time). The cold bath was removed and the reaction mixture was warmed to 40 °C (gas evolved). When the rate

-50of gas evolution decreased (-30 min) the reaction mixture was warmed to 50 °C for min. The mix was then cooled to 23 °C, and 3N NaOH (320 mL) was added to neutralize followed by 50% saturated NaHCOj (320 mL). The slurry was then .

filtered through a Buchner funnel to give a dark reddish-brown solid. The solid was taken up in warm THF (800 mL) and silica (600 mL dry) was added with stirring. To this slurry was added hexane (1.2 L) and the mix was vacuum filtered through a pad of silica (300 mL) in a large fritted filter. The silica was further washed with 2 L of

40% THF in hexane. The filtrates were combined and concentrated under reduced pressure to give a solid. The solid was further triturated with ethyl acetate (-100 10 mL), filtered and dried under reduced pressure to give 6-iodo-lH-indazole as a light brown solid (36.1 g, 48% yield): Ry sm 0.12, p 0.48 (Hex-EtOAc 1:1); NMR (300 MHz, CDC1₃) 7.9 (s, IH), 7.8 (s, IH), 7.42 (d, IH), 7.33 (d, IH); MS (ES) [m+H]/z Calc’d 245, Found 245, [m-H]/z Calc’d 243, Found 243.

(ii)

<img file="MY139999A_D0026.tif" />

NaO-t-Bu, MtsCI, THF, 0 *C, 40 min -&gt;Mts.

<img file="MY139999A_D0027.tif" />

To a solution of 6-iodo-lH-indazole (7.35 g, 30.1 mmol, 1 equiv) in THF (100 mL) cooled to 0 °C under argon, was added sodium Z-butoxide (2.89 g, 30.1 mmol, 1 equiv). A color change from orange to red was observed.

Mesitylenesulfonyl chloride (6.60 g, 30.1 mmol, 1 equiv) was added in one portion 20 and the ice bath was removed allowing the reaction mixture to warm to 23 °C. After min the mixture was quenched with saturated ammonium chloride and partitioned between water and ethyl acetate. The aqueous was extracted a total of 3 times with

-51ethyl acetate. The combined organic material was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 6-iodo-l-(2,4,6trimethyl-benzenesulfonyl)-lH-indazole as an orange solid (12.8 g, 100% yield, 2:1 mixture). ^NMRACDCri) 8.51 (s, 1H), 7.95 (s, 0.66H, major isomer), 7.91 (s,

0.33H, minor isomer), 7.47 (d, 0.33H, J = 8.4 Hz), 7.29 (d, 0.33H, J = 8.4 Hz), 7.26 (d, 0.66H, J = 8.9 Hz), 7.18 (d, 0.66H, 8.9 Hz), 6.84 (s, 2H), 2.51 (s, 6H), 2.15 (s, 3H).

(iii)

HQ.

OH

I

PdCUPPhk, EtN, K£O, dioxane/yO, 90°C, 2 h -&gt;-

<img file="MY139999A_D0028.tif" />

A mixture of 6-iodo-l-(2,4,6-trimethyl-benzenesulfonyl)-lH-indazole (5.78 g,

13.56 mmol, 1.00 equiv) and 3-methoxy-4-(methoxymethoxy)benzene-boronic acid (3.45 g, 16.27 mmol, 1.20 equiv) under argon was dissolved in dioxane (15 mL) and water (2.0 mL). To this solution was added triethylamine (2.83 mL, 20.3 mmol, 1.5 equiv), potassium carbonate (2.8 g, 20.3 mmol, 1.5 equiv) and dichlorobis(triphenylphosphine)palladium (476 mg, 0.678 mmol, 0.05 equiv). The reaction mixture was heated to 90 °C for 2 h and then was cooled to 23 °C. The mixture was separated between ethyl acetate (250 ml-) and saturated sodium bicarbonate (150 mL). The organic material was dried over sodium sulfate, decanted and concentrated under reduced pressure to give crude 6-(3-methoxy-420 methoxymethoxy-phenyl)-l-(2,4,6-trimethyI-benzenesulfonyl)-lH-indazole that was dried under high vacuum for 15 h and was used without further purification.

-523-Methoxy-4-(methoxymethoxy)benzeneboronic acid was prepared as follows: In a 100 mL flask a mixture of 50% KOH in water (20 g KOH, 7 equiv, 20 g ice) was prepared under argon. To this rapidly stirring mixture at 0 °C (maintained with an ice bath) was added di chloromethane (50 mL) followed by 4-bromo-25 methoxyphenol (10.lg, 50 mmol, 1.00 equiv), methoxymethylchloride (MOMC1) (4.00 mL, 42.5 mmol, 1.05 equiv) and tetrabutylammonium bromide (322 mg, 1 mmol, 0.02 equiv). The bath was removed and the mixture was slowly allowed to warm to 23 °C with rapid stirring for 2 h. The mixture is transferred to a separatory funnel and diluted with dichloromethane (350 mL) and water (300 mL) which are used to aid the transfer. The organic material (now the bottom layer) are separated, dried over sodium sulfate, decanted and concentrated under reduced pressure to give

4-bromo-2-methoxy-l-(methoxymethoxy)benzene as a yellow liquid which is pure by ^]H NMR (11.9 g, 97%): ^NMR (CDC1₃) δ 7.0 (s, 3H), 5.13 (s, 2H), 3.84 (s, 3H),

3.47 (s,3H). MS (El) [m+H]/z Calc’d 235, found 235. In a 50 mL round-bottom flask, 4-bromo-2-methoxy-l-(methoxymethoxy)benzene (4.80 g, 19.4 mmol, 1.00 equiv) was taken up in THF (35 mL) and was cooled to -78 °C (20 min for this volume). To this was added «-BuLi (12.75 mL, 1.6 M in hexane, 20.4 mmol, 1.05 equiv) and the mixture was allowed to stir at -78 °C for 40 min. This was then added via cannula to a second flask containing B(OMe)₃ (22 mL, 194 mmol, 10 equiv) in

THF (50 mL) at -78 °C. After 20 min, the cold bath was removed. After 15 min of warming (~0 °C, ice on the side of the flask begins to melt) water (50 mL) was added to the reaction mixture which was stirred for 45 min. The mixture was concentrated under reduced pressure to remove most THE and was then partitioned between ethyl

-53acetate (300 mL) and water (150 mL) which was made acidic by addition of a small amount of 20% citric acid (~10 mL.). The organic material was dried over sodium sulfate and concentrated under reduced pressure to give a solid. Trituration with ethyl acetate (10 mL) and hexane (5 mL) followed by filtering gave 3-methoxy-45 (methoxymethoxy)benzene-boronic acid as a white solid (3.15 g, 77%): Ry sm 0.59, p 0.18 (ethyl acetate-hexane 1:1); 1HNMR (CDC1₃) δ 7.85 (d, 1H, J = 8 Hz), 7.72 (s,

1H), 7.22 (d, 1H, J = 8 Hz), 5.30 (s, 2H), 4.00 (s, 3H), 3.55 (s, 3H).

(iv)

<img file="MY139999A_D0029.tif" />

Unpurified 6-(3-methoxy-4-methoxymethoxy-phenyl)-l-(2,4,6trimethyl-benzenesulfonyl)-lH-indazole (under argon) was dissolved in THF (20 mL) and was treated with IN NaOH in MeOH (70 mL degassed by bubbling through argon for 3 to 5 min). The mixture was heated to 45 °C for 1 h and allowed to cool. The mixture was neutralized by addition of IN HCI (50 mL) followed by saturated sodium bicarbonate (200 mL). The product was extracted into ethyl acetate (350 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude 6-(3-methoxy-4-methoxymethoxy-phenyl)-lfi-indazole. Purification by silica gel chromatography (500 mL silica, 20% ethyl acetate in benzene (1.8 L), 30% ethyl acetate in benzene (1.8 L)) gave 6-(3-methoxy-4-methoxymethoxy-phenyl)-lL720 indazole (1.19 g, 31%): ^NMRiCDCb) δ 7.80 (s, 1H), 7.69 (d, 1H, J = 8.5 Hz),

-547.52 (s, 1H), 7.29 (d, 1H, J = 8.5 Hz), 7.16 (s, 1H), 7.13 (s, 1H), 7.08 (s, 1H). MS (ES) [m+Na]/z Calc’d 337, found 337; [m+CL]/z Cak’d 349, found 349.

(v)

<img file="MY139999A_D0030.tif" />

In a 100-mL round-bottom flask under argon, 6-(3-methoxy-4methoxymethoxy-phenyl)-17f-indazole (1.19 g, 4.18 mmofrl equiv) was dissolved in dioxane (25 mL) and 3N NaOH (14 mL). This mixture was treated with iodine (1.17 g, 14.60 mmol, 1.10 equiv) added in ~5 portions (~10 min). Several (~4) additional portions of iodine (50 mg each) were added until the reaction was complete as visualized by TLC (3:7 ethyl acetate/hexane). The mixture was acidified with 20% citric acid (25 mL) and 5% NaHSO3 (20 mL) was added. The mixture was partitioned between ethyl acetate (150 mL) and water (100 mL). The organic material was washed with saturated sodium bicarbonate (80 mL) and brine (50 mL) and were dried over sodium sulfate and concentrated under reduced pressure.

Purification by crystallization from ethyl acetate (3 mL) then hexane (7 mL) gave pure 3-iodo-6-(3-methoxy-4-methoxymethoxy-phenyl)-l/7-indazole as a solid (1.33 g, 78 %): !H NMR (CDC1₃) δ 10.48 (bs, 1H), 7.62 (s, 1H), 7.57 (d, 1H, J = 8.5 Hz),

7.47 (dd, 1H, J = 1.3, 8.5 Hz), 7.18 (m, 3H), 5.29 (s, 2H), 3.99 (s, 3H), 3.55 (s, 3H).

(vi)

<img file="MY139999A_D0031.tif" />

-55In a 100-mL round-bottom flask, 3-iodo-6-(3-xnethoxy-4-methoxymethoxyphenyl)-l/7-indazole (921 mg, 2.245 mmol, 1.00 equiv) was dissolved in THF (36 mL) and cooled to. -78 °C (allow 8 min at this scale). A solution of PhLi (2.5 mL, 1.8

M, 4.49 mmol, 2.00 equiv) was added and the mixture was allowed to stir for 30 min.

A solution ofs-BuLi (3.63 mL, 4.71 mmol, 2.1 equiv) was added and the reaction mixture was allowed to stir for 1 h at -78 °C. Neat DMF (1.4 mL, 18 mmol, 8.0 equiv) was added. The cold bath was removed and the reaction was allowed to slowly warm to 0 °C in the air. As the ice melted saturated sodium bicarbonate (20 mL) was added. The product was extracted into ethyl acetate (200 mL) from saturated sodium bicarbonate (75 mL more), dried over sodium sulfate, decanted and concentrated under reduced pressure. Purification by silica gel chromatography (450 mL silica, 4:6 ethyl acetate/hexane) gave 6-(3-methoxy-4-methoxymethoxy-phenyl)l/7-indazole-3-carbaldehyde (498 mg, 71%)): Ry sm 0.30, p 0.14 (ethyl acetatehexane 4:6); ^]H NMR (CDC1₃) δ 10.85 (bs, 1H), 10.25 (s, 1H), 8.37 (d, 1H, J = 8.4

Hz), 7.67 (s, 1H), 7.60 (d, 1H, J = 8.4 Hz), 6.26 (d, 1H, J = 8.7 Hz), 7.19 (m, 2H),

5.30 (s, 2H), 3.99 (s, 3H), 3.55 (s, 3H).

(νϋ)

<img file="MY139999A_D0032.tif" />

6-(3-methoxy-4-methoxymethoxy-phenyl)-l//-indazole-3-carbaldehyde (441 20 mg, 1.41 mmol, 1.0 equiv) was taken up as a suspension in dichloromethane (15 mL) and was cooled to 0 °C. This mixture was treated with mesitylene sulfonyl chloride

-56(324 mg, 1.48 mmol, 1.05 equiv) and dimethylamino pyridine (DMAP) (181 mg,

1.48 mmol, 1.05 equiv). The mixture was allowed to stir for 1 h at 0 °C and was quenched with the addition of water. The mixture was partitioned between water and a 1:1 ethyl acetate/hexane organic layer. The organic material was dried over sodium sulfate, decanted and concentrated under reduced pressure to give crude material which was purified by silica gel chromatography (50 mL silica, 3:7 ethyl acetate/hexane) to give 6-(3-methoxy-4-methoxymethoxy-phenyl)-l-(2,4,6-trimethylbenzenesulfonyl)-177-indazole-3-carbaldehyde (374 mg, 54%): Ry sm 0.17, p 0.53 (ethyl acetate-hexane 4:6); ^!H NMR (CDC1₃) δ 10.20 (s, IH), 8.41 (s, IH), 8.37 (d,

IH, J = 8.5 Hz), 7.73 (dd, IH, J = 1.4, 8.4 Hz), 7.3 (m, 3H), 7.08 (s, 2H), 5.36 (s, 2H),

4.08 (s, 3H), 3.71 (s, 3H), 2.74 (s, 6H), 2.40 (s, 3H).

(viii)

<img file="MY139999A_D0033.tif" />

Finely ground triphenyl(3,4-dimthoxybenzyl)phosphonium bromide (1.09 g, 2.22 mmol, 4.0 equiv) was taken up as a slurry in THF (15 mL) and was cooled to 78 °C. To this mixture was added n-BuLi (1.04 mL, 1.6 M, 1.66 mmol, 3.0 equiv) which gave a red/orange solution. The mixture was allowed to warm to 23 °C for 1

h. This mixture was then added to a 0 °C solution of 6-(3-methoxy-4methoxymethoxy-phenyl)-l-(2,4,6-trimethyl-benzenesulfonyl)-l/7-indazole-3carbaldehyde (274 mg, 0.554 mmol, 1.0 equiv) in THF (5 mL) via cannula. The resulting mixture was allowed to stir at 0 °C for 10 min and was quenched with

-57saturated sodium bicarbonate. The resulting mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The organic material was concentrated under reduced pressure and the residue was purified by silica gel.

chromatography (50 mL silica, 3:7 -&gt; 4:6 ethyl acetate/hexane) to give a 2.5:1 5 mixture of cis/trans 3-[2-(3,4-dimethoxy-phenyl)-vinyl]-6-(3-methoxy-4methoxymethoxy-phenyl)-l-(2,4,6-trimethyl-benzenesulfonyl)-lH-indazole (289 mg, 83%): Ry sm 0.53, p 0.32 (ethyl acetate-hexane 4:6); ^JH NMR (CDCI3) δ 8.35 (s,

0.3H), 8.32 (s, 0.7H), 8.03 (d, 0.3H, J = 8.4 Hz), 7.60-6.85 (m, H), 6.65 (d, 0.7H, J =

8.4 Hz), 6.60 (d, 0.7H, J = 12.5 Hz), 5.30 (s, 0.6H), 5.29 (s, 1.4H), 4.00-3.50 (8 singlets, 12H), 2.72 (s, 1.8H), 2.67 (s, 4.2H), 2.34 (s, 3H); MS (ES) [m+H]/z Calc’d

629, found 629, [m-H]/z Calc’d 627, found 627.

(ix)

<img file="MY139999A_D0034.tif" />

A 1M solution of KOH (1.0 g, 17.8 mmol) in 1:1 water/MeOH (18 mL total) was prepared under argon and was degassed by vacuum/purge cycles with argon (5 times). In a separate flask, 3-[2-(3,4-dimethoxy-phenyl)-vinyl]-6-(3-methoxy-4methoxymethoxy-phenyl)-l-(2,4,6-trimethyl-benzenesulfonyl)-l/y-indazole (289 mg,

0.461 mmol, 1.0 equiv) was dissolved in THF (8 mL) under argon. To this solution was added the above 1M KOH solution (10 mL, 1:1 water/MeOH). The reaction was warmed to 30 °C and was allowed to stir for 7 h. The reaction mix was neutralized by the addition of 20% citric acid (7 mL). The resulting mix was partitioned between

-58ethyl acetate (150 mL) and water (100 mL). The organic material was separated, dried over sodium sulfate, decanted, and concentrated under reduced pressure to give cis and trans 3-[2-(3,4-dimethoxy-phenyl)-vinyl]-6-(3-methoxy-4-methoxymethoxyphenyl)-1/7-indazole (used crude): Ry sm 0.46, pi 0.17, p2 0.23 (ethyl acetate5 hexane 1:1); NMR cis isomer (CDCI3) δ 7.55 (s, 1H), 7.3-7.1 (m, 6H), 7.02 (dd,

1H, J = 1.9, 8.3 Hz), 6.85 (d, 1H, J = 12.5 Hz), 6.78 (d, 1H, J = 12.5 Hz), 6.74 (d, 1H, J = 8.3 Hz), 5.21 (s, 2H), 3.88_(s, 3H), 3.70 (s, 3H), 3 43 (s, 3H), 3.42 (s, 3H). MS (ES) [m+H]/z Calc’d 447, found 447, [m-H]/z Calc’d 445, found 445.

Example 1(b): 3-(E-styryl)-6-(3-benzyloxy-4-hydroxy-phenyl)-l/7-indazole

<img file="MY139999A_D0035.tif" />

Example 1(b) was prepared in a similar manner to that described for Example 1(a), except that 4-bromo-2-benzyloxy-phenol was used in step(iii) in place of 4bromo-2-methoxy-phenol. Ry sm 0.35, p 0.30 (ethyl acetate-hexane 4:6); ^!H NMR (CDCI3) δ 8.06 (d, 1H, J = 8.6 Hz), 7.63- 7.18 (m, 17H), 7.05 (d, 1H, J = 8.2 Hz),

5.19 (s,2H). MS (CI) [m+H]/z Calc’d 419, found 419, [m-H]/z Calc’d 417, found

417.

E x ample 1 (c): 3- [E-2-(3,4-Dim etho xy-ph enyl)vinyl] -6-(3-ally lo xy-4-hy droxyphenyl)-Lff-indazole

<img file="MY139999A_D0036.tif" />

Example 1(c) was prepared in a similar manner to that described for Example 1(a), except that 3-allyloxy-4-(methoxymethoxy)benzene-boronic acid was used instead of 3-methoxy-4-(methoxymethoxy)benzene-boronic acid in step (iii). MS (ESI) [M+H]/z Calc’d 429, found 429; MS (ESI) [M-H]/z Calc’d 427, found 427. Example 2(a): 3-(Naphthalen-2-yI)-6-(3-methoxy-4-hydroxy-phenyI)-l/7indazole

<img file="MY139999A_D0037.tif" />

6-(4-Benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-17f-indazole (25 mg,

0.055 mmol) was dissolved in a mixture of ethyl acetate (2 mL), benzene (2 mL) and methanol (2 mL). To this solution was added palladium on carbon (25 mg, 10% wt) and the reaction vessel was vacuum/purged with hydrogen gas for five cycles. The reaction mixture was allowed to stir for 3 days (d) at 23 °C and was filtered through a plug of Celite. Concentration and purification by silica gel chromatography afforded

3-(Naphthalen-2-yl)-6-(3-methoxy-4-hydroxy-phenyl)-17f-indazole (8 mg, 40%):

NMR (CDC1₃) 5 10.3 (bs, 1H), 8.50 (s, 1H), 8.20 (d, 1H, J - 8 Hz), 7.98 (d, 1H, J =

8Hz), 7.90 (m, 1H), 7.7-6.8 (m, 9H), 3.98 (s, 3H). MS (ES) [m+H]/z Calc’d 367, found 367, [m-H]/z Calc’d 365, found 365.

-60The starting material was prepared as follows:

(i)

<img file="MY139999A_D0038.tif" />

<img file="MY139999A_D0039.tif" />

2-Bromonaphthalene (117 mg, 0.564 mmol, 6.0 equiv) was dissolved in THF (0.75 mL) and cooled to -78 °C. The mixture was treated with H-BuLi (226 pL, 2.5

M, 6.0 equiv) and was allowed to stir at -78 °C for 30 min. The mixture was then added to freshly dried ZnCh solid (139 mg, 0.80 mmol, 8.5 equiv) via cannula and the resulting mix was allowed to warm to 23 °C (during the addition the yellow color disappears). After 30 min at 23 °C the mixture is added to a mixture of 6-(4benzyloxy-3 -methoxy-phenyl)-3-iodo-1 -(2,4,6-trimethyl-benzenesulfonvl)-177indazole (60 mg, 0.094 mmol, 1 equiv) and Pd(PPh3)4 (6 mg, 0.005 mmol, 0.05 equiv) via cannula. The resulting solution was allowed to stir for 16 h. Saturated sodium bicarbonate was added and the mixture was partitioned between saturated sodium bicarbonate (15 mL) and ethyl acetate (15 mL). The organic material was dried over sodium sulfate, decanted and concentrated. Purification by silica gel chromatography (1:9 -2:8 ethyl acetate-hexane) gave 6-(4-benzyloxy-3-methoxyphenyl)-3-naphthalen-2-yl-l-(2,4,6-trimethyl-benzenesulfonyl)-177-indazole as a solid (42 mg, 70%): Ry sm 0.4, p 0.4 (ethyl acetate-hexane 3:7); 'HNMR (CDCI3) δ 8.44 (s, 1H), 8.41 (s, 1H), 8.12 (d, 1H, J = 8 Hz), 8.05-7.00 (m, 17H), 5.30 (s, 2H),

4.02 (s, 3H), 2.80 (s, 3H), 2.34 (s, 3H).

-616-(4-benzyloxy-3-methoxy-phenyl)-3-iodo-l-(2,4,6-trimethylbenzenesulfonyl)-177-indazole was prepared in a similar manner as described in

Example 1(a), steps (i) to (v).

(ii)

<img file="MY139999A_D0040.tif" />

6-(4-Benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-l-(2,4,6-trimethylbenzenesulfonyl)-l/Z-indazole was converted to 6-(4-benzyloxy-3-methoxy-phenyl)3-naphthalen-2-yl-l//-indazole as described in Example 1(a), step (ix). Ry sm 0.40, p

0.17 (ethyl acetate-hexane 3:7); ’HNMR (CDCI3) δ 3.40 (s, 1H), 8.12 (d, 1H,J = 8.5

Hz), 8.10 (dd, 1H, J = 1.6, 8.4 Hz), 7.93 (d, 1H, J = 8.3 Hz), 7.88 (m, 2H), 7.61 (m,

1H) 7.56 (s, 1H), 7.43 (m, 5H), 7.30 (m 3H), 7.15 (d, 1H, J = 2.0 Hz), 7.08 (dd, 1H, J = 2.1, 8.3 Hz), 6.91 (d, 1H, J = 8.3 Hz), 5.16 (s, 2H), 3.91 (s, 3H).

Example 2(b): 3-phenyl-6-(3-methoxy-4-hydroxy-phenyl)-l/7-indazole

<img file="MY139999A_D0041.tif" />

Example 2(b) was prepared in a similar maimer to that described for Example 2(a), except that phenyllithium was used in place of 2-napthyllitium generated from 2-bromonaphthylene in step (i). ’H NMR (300 MHz, CDCI3) δ 7.87 (d, 1H), 7.83 (d,

-622H), 7.55-7.27 (m, 5H), 7.01 (m, 2H), 6.80 (d, 1H), 3.83 (s, 3H). MS (ES) [m+H]/z

Calc’d 317, Found 317, [m-H]/z Calc’d 315, found 315.

Example 2(c); 3-(3,4,5-trimethoxyphenyl)-6-(3-methoxy-4-hydroxy-phenyl)-l/7indazole

<img file="MY139999A_D0042.tif" />

Exaniple 2(c) was prepared in a similar manner to that described for Example 2(a), except that 3,4,5-trimethoxyphenyl bromide was used in step (i) in place of 2bromonaphthylene. Ry sm 0.67, p 0.38 (ethyl acetate-hexane 8:2); NMR (CDCI3) δ 7.93 (d, 1H, J = 8 Hz), 7.58 (s, 1H), 7.39 (d, 1H, J == 8 Hz), 7.10 (m, 4H), 6.92 (d,

1H, J = 8 Hz), 3.90 (s, 9H), 3.85 (s, 3H); MS (ES) [m+H]/z Calc’d 407, Found 407, [m-H]/z Calc’d 405, Found 405.

Example 2(d): 3-(l/F-Indol-2-yl) -6-(3-methoxy-4-hydroxy-phenyl)-l/7-indazole

<img file="MY139999A_D0043.tif" />

Example 2(d) was prepared in a similar manner to that described for Example 15 2(a) above, except that 1-phenylsulfonyl-indazole was used in place of 2bromonaphthylene in step (i). Ry sm 0.20, p 0.15 (ethyl acetate-hexane 4:6); ^}H NMR (CDCI3) δ 10.0 (bs, 1H), 9.05 (bs, 1H), 8.01 (d, 1H, J = 8.0 Hz), 7.55 (d, 1H, J = 8.0 Hz), 7.49 (s, 1H), 7.37 (d, 1H, J = 8 Hz), 7.29 (d, 1H, J = 8 Hz), 7.2-7.1 (m,

-635H), 6.92 (d, IH, J = 8 Hz), 5.63 (bs, 1H); MS (ES) [m+H]/z Calc’d 356, Found 356;

[m-H]/z Calc’d 354, found 354.

Example 2(e): 3-(Benzofuran-2-yl)-6-(3-benzyloxy-4-hydroxy-phenyI)1/7-indazole

<img file="MY139999A_D0044.tif" />

Example 2(e) was prepared in a similar manner to that described for Example

2(a) above, except that benzofuran was used in place of 2-bromonaphthylene in step (i). ^!H NMR (CDC1₃) δ 8.21 (d, IH, J = 8.0 Hz), 7.60 (m, 3H), 7.30-7.10 (m, 12H),

7,01 (d, IH, J = 8 Hz), 5.82 (bs, IH), 5.15 (s, 3H).

Example 3: 3-(l/7-IndoI-2-yI) -6-(3-methoxy-4-hydroxy-phenyl)-l/7-indazoIe

<img file="MY139999A_D0045.tif" />

3-(l//-Benzoimidazol-2-yl)-6-(3-methoxy-4-methoxymethoxy-phenyl)-l/7indazole was converted to 4-[3-(137-benzoimidazol-2-yl)-lF/’-indazol-6-yl]-2methoxy-phenol according to the procedure described in Example 1(a) (3.5 mg,

28%). HRMS (FAB) [m+H]/z Calc’d 357.1351, Found 357.1349.

The starting material was prepared as follows:

-64OHC

<img file="MY139999A_D0046.tif" />

6-(3-Methoxy-4-methoxymethoxy-phenyl)-lH-indazole-3-carbaldehyde (from Example 1(a), step (vi)) (20 mg, 0.064 mmol, 1 equiv) was dissolved in degassed 1:1

MeOH-water (0.7 mL) and was treated with acetic ac:id (19 pL, 5 equiv), 1,25 diaminobenzene (8.3 mg, 1.2 equiv) and copper(II) acetate (18 mg, 1.4 equiv) at 23 °C. The mixture stirred for 30 min, was diluted with ethanol (3 mL) and water (2 mL) and was treated with a bubbling stream of SH2 for 3 min which gave a black precipitate. The mixture was allowed to stir for 12 h. The mixture was filtered and concentrated. Purification by silica gel chromatography (6:4 ethyl acetate-hexane) gave 3-(l/i-benzoimidazol-2-y 1)-6-(3-methoxy-4-meilioxymethoxy-phenyl)- 1Hindazole as a solid (14 mg, 54%); R/· sm 0.39, p 0.24 (ethyl acetate-hexane 6:4);

NMR (CDCI3) δ 8.69 (d, 1H, J = 8Hz), 7.70 (bs, 2H)_: 7.58 (s, 1H), 7.53 (d, 1H, J = 8

Hz), 7.30-7.15 (m, 7H), 5.30 (s, 2H), 3.97 (s, 3H), 3.58 (s, 3H); MS (ES) [m+H]/z

Calc’d 401, found 401, [m-H]/z Calc’d 399, Found 399.

Example 4(a): 7V-[3-(3-Styryl-lH-indazol-6-yloxy)-phenyl]-benzamide

A solution of N-[3-(2-benzoyl-3-styrl-lH-indazol-6-yloxy)-phenyl]benzamide (0.09 g, 0.17 mmol) in 2 mL of 6N HCI (aqueous) and 3 mL of MeOH

-65was heated at 65 °C for about 4 h. The cooled solution was poured cautiously into saturated sodium bicarbonate solution. The precipitate was filtered, collected and chromatographed on silica gel eluting hexanes/EtOAc (1:1). N-[3-(3-Styryl-lHindazol-6-yloxy)-phenyl]-benzamide was obtained as a beige solid (32 mg, 50%): ’H

NMR (DMSO-d₆) δ 13.50 (s, IH), 10.32 (s, IH), 8.23 (d, IH, J = 8.7 Hz), 7.92 (d,

2H, J = 6.8 Hz), 7.72 (d, 2H, J = 7.3 Hz), 7.71-7.51 (m, 7H), 7.51 - 7.47 (m, 3H),

7.30 (t, IH, J = 7.2 Hz), 7.05 (s, IH), 7.01 (d, IH, J = 8.7 Hz), 6.86 (dd, IH, J = 8.2,

2.3 Hz). Anal. Calc, for C₂₈H₂₁N₃O₂· 0.3H₂O: C, 76.9'/; H, 4.98: N, 9.62. Found: C,

76.94; H, 5.13; N, 9.40.

<img file="MY139999A_D0047.tif" />

A suspension ofthe 3-(benzhydrylidene-amino)-phenol (10.47 g, 38.3 mmol),

3-chloro-cyclohex-2-enone (5.00 g, 38.3 mmol) and potassium carbonate (5.82, 42.1 mmol) in 150 mL of acetone was heated at reflux overnight. The cooled reaction mixture was filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting hexanes/EtOAc (2:1). In this manner, 3-[3(benzhydrylidene-amino)-phenoxy]-cyclohex-2-enone was obtained as a yellow solid, (8.82 g, 63%): Ή NMR (CDC1₃) δ 7.78 (d, 2H, J = 7.0 Hz), 7.50 (d, IH, J =

7.1 Hz), 7.45 (d, 2H, J = 7.7 Hz), 7.34-7.10 (m, 6H), 6.69 (d, IH, J = 8.0 Hz), 6.61 (d

-661H, J = 8.0 Hz), 6.38 (s, 1H), 4.89 (s, 1H), 2.55 (t, 2H, J = 6.2 Hz), 2.34 (t, 2H, J =

6.2 Hz), 2.06 (m, 2H). Anal. Calc, for C₂₅H₂₁NO₂ 0.2H₂O: C, 80.92; H, 5.81; N,

3.78. Found: C, 81.12; H, 5.81; N, 3.72.

3-(Benzhydrylidene-amino)-phenol was prepared as follows: A stirred solution of benzophenone imine (15.0 g, 82.8 mmol) and 3-aminophenol (9.03 g,

82.8 mmol) in 25 mL toluene was heated at reflux with removal of H₂O with a DeanStark trap for 3.5 h. The crystals that formed from the cooled reaction mixture were collected by vacuum filtration, washed with hexanes and air dried. In this manner, 3(benzhydrylidene-amino)-phenol was obtained as a light yellow solid (17.3 g, 76%):

Ή NMR (CDC1₃) δ 7.64 (d, 2H,J = 7.1 Hz), 7.38 (d, 1H,J = 7.1 Hz), 7.34 - 7.15 (m, 7H), 7.04 (d, 2H, J = 7.2 Hz), 6.88 (t, 1H, J = 8.1 Hz), 6.82 (d, 1H, J = 8.2 Hz), 6.23 (s, 1H), 6.21 (d, 1H, J = 7.8 Hz). Anal. Calc, for C₁₉H₁₅NO: C, 83.49; H, 5.53; N,

5.12. Found: C, 83.51; H, 5.65; N, 5.03.

(ii) o

<img file="MY139999A_D0048.tif" />

<img file="MY139999A_D0049.tif" />

A solution of 3-[3-(benzhydrylidene-amino)-phenoxy]-cyclohex-2-enone (4.37g, 11.89 mmol) in 20 mL of THF was added slowly to a solution of LiHMDS (25.0 mL of 1.0 M solution in THF) in 10 mL of THF at-78 °C. Five minutes after the addition was complete trans-cinnamoyl chloride (1.98 g, 11.89 mmol) was added all at once, and stirring was continued at -78 °C for 30 min. The reaction was

-67quenched with saturated NH₄C1 solution. And extracted with EtOAc (2x). The combined organic layers were washed with saturated NaCl solution, dried (MgSO₄) and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting hexanes/EtOAc (5:1). In this manner, 3-[3-(benzhydrylidene-amino)5 phenol]-6-(3-phenyl-acryloyl)-cyclohex-2-enone was obtained as a yellow-orange solid (3.34 g, 56%): ’HNMR(CDC1₃) δ: 15.69 (s, 1H), 7.80 (d, 2H, J = 7.1 Hz), 7.637.01 (m, 15H), 6.93 (d, 1H, J = 15.6 Hz), 6.75 (d, 1H, J = 7.6 Hz), 6.66 (d, 1H, J = 8.0

Hz), 6.46 (s, 1H), 4.92 (s, 1H), 2.85 (t, 2H, J = 7.2 Hz), 2.62 (t, 2H, J = 7.2 Hz).

Anal. Calc, for C₃₄H₂₇NO₃: C, 82.07; H, 5.47; N, 2.82. Found: C, 81.88; H, 5.53; N,

2.81.

<img file="MY139999A_D0050.tif" />

To a stirred solution of 3-[3-(benzhydrylidene-amino)-phenol]-6-(3-phenylacryloyl)-cyclohex-2-enone (1.81 g, 3.64 mmol) dissolved in 10 mL of

HOAc/EtOH(l: 1) was added hydrazine hydrate (2.0 mL, 41.23 mmol). The solution was heated at 75 °C for 25 min. After cooling, the reaction mixture was cautiously poured into saturated sodium bicarbonate solution and extracted with EtOAc (2x).

The combined organic layer was washed with saturated NaCl solution, dried (MgSO₄) and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting hexanes/EtOAc (1:1). 3-(3-Styryl-4, 5-dihydro-1 H-indazol-6-yloxy)phenylamine was obtained as a yellow solid (539 mg, 45%). 'H NMR (DMSO-d₆) δ

-687.55 (d, 2H, J = 7.2Hz), 7.38 (t, 2 H, J = 7.2 Hz), 7.27 (t, IH, J = 7.2 Hz), 7.05 (m,

3H), 6.38 (d, IH, J = 8.0 Hz), 6.31 (s, IH), 6.23 (d, IH, J = 7.9 Hz), 5.52 (s, IH), 5.26 (s, 2H), 2.92 (t, 2H, J = 8.0 Hz), 2.58 (t, 2H, J = 8.1 Hz). Anal. Calc, for C₂₁H₁₉N₃O ·

0.3H₂O: C, 75.33; H, 5.90; N, 12.55. Found: C, 75.46; H, 5.96; N, 12.35.

<img file="MY139999A_D0051.tif" />

<img file="MY139999A_D0052.tif" />

To a stirred solution of 3-(3-styryl-4, 5-dihydro-lH-indazol-6-yloxy)phenylamine (50 mg, 0.15 mmol) and AhV-diisopropylethylamine (54 μΐ, 0.31 mmol) in 5 mL of CH₂C1₂, was added benzoyl chloride (36 μΐ, 0.31 mmol). After 15 min, the reaction mixture was diluted with CH₂C1₂ and washed sequentially with 0.5N HCI, saturated sodium bicarbonate solution and brine, dried (MgSO₄) and concentrated under reduced pressure. To a stirred solution of the residue in 1,4dioxane was added 2,3-dichloro-5,6-dicyano-l,4-berzoquinone (DDQ) (35 mg, 0.15 mmol). After 1 h, the reaction mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel eluting hexanes/EtOAc (2:1). In this manner, N-[3-(2-benzoyl-3-styrl-lH-indazol-6-yloxy)-phenyl]-benzamide was prepared as a rust colored solid (90 mg, -quantitative): ’H NMR (CDC1₃) 5 8.13 (s, IH), 8.02 (d, 2H, J = 7.0 Hz), 7.94 (d, IH, J = 8.7 HL:), 7.74 (d, 2H, J = 6.8 Hz), 7.577.19 (m, 17H), 6.84 (d, IH, J = 8.3 Hz).

Example 4(b): N-[3-(3-Styryl-lH-indazol-6-yloxy)-phenyl]-acetamide

<img file="MY139999A_D0053.tif" />

<img file="MY139999A_D0054.tif" />

6N KCI, MeOH

Example 4(b) was prepared in a similar manner to that described for Example

4(a) above, except that acetic anhydride was used instead of benzoyl chloride in step (iv). Ή NMR(DMSO-d₆) δ 13.08 (bs, 1H), 10.03 (s, 1H), 8.22 (d, 1H, J = 8.7 Hz),

7.72(d, 2H, J ^7.3 Hz), 7.52 (s, 2H), 7.44-7.27 (m, 6H), 7.01 (s, 1H), 6.96 (dd, 1H, J = 8.7, 2.1 Hz), 6.78 (d, 1H, J = 6.9 Hz), 2.01 (s, 3H). Anal. Calc, for C₂₃H₁₉N₃O₂ ’

0.25 H₂O: C, 73.88; H, 5.26; N, 11.24. Found: C, 74.20; H, 5.57; N, 10.82.

Example 5(a): 5-Methvl-thiazole-2-carboxylic acid {3-(3- styryl -lH-indazol-6ylo xy)-phenyl] -amide

<img file="MY139999A_D0055.tif" />

A suspension of 5-methyl-thiazole-2-carboxylic acid {3-[l-(5-methylthiazole-2-carbonyl)-3-styryl-177-indazol-6-yloxyl-phenyl}amide (57 mg, 0.10 mmol) and potassium carbonate (50 mg, 0.36 mmol) in MeOH was stirred at 23 °C for 20 min. The solution was filtered, diluted with EtOAc and washed with brine (2x). The organic layer was dried (MgSO₄) and concentrated under reduced pressure. In this manner, 5-methyl-thiazole-2-carboxylic acid {3-(3- styryl -lH-indazol-6-yloxy)phenyl]-amide was prepared as a tan solid in 47% yield.: Ή NMR (DMSO-d₆) δ

13.00 (s, 1H), 10.80 (s, 1H), 8.23 (d, 1H, J = 8.8 Hz), 7.79 (s, 2H), 7.71 (t, 2H, J = 8.6

-70Hz), 7.53 (s, 2H), 7.41-7.27 (m, 5H), 7.04 (s, IH), 7.00 (d, IH, J = 8.7 Hz), 6.89 (d,

IH, J = 8.5 Hz), 2.54 (s, 3H). Anal. Calc, for C₂₆H₂₀N&lt;O₂S · 1.15H₂O: C, 65.98; H,

4.75; N, 11.84; S, 6.78. Found: C, 65.99; H, 4.71; N, 11.58; S, 6.76.

The starting material was prepared as follows:

(i)

<img file="MY139999A_D0056.tif" />

<img file="MY139999A_D0057.tif" />

3-(3-Styryl-4, 5-dihydro-lH-mdazol-6-yloxy)-phenylamine was converted to 5-methyl-thiazole-2-carboxylic acid {3-[l-(5-methyl-thiazole-2-carbonyl)-3-styryl177-indazol-6-yloxyl-phenyl}amide by treatment with 5-methyl-thiazole-210 carboxylic acid and HATU (o-(2-azabenzotriazol-l-yl)-N,N,N’,N’tetramethyluronium hexafluorophosphate) in DMF arid analogous work-up, DDQ treatment and isolation to Example 4(a), step (iv) (50% yield): ’H NMR(DMSO-d₆) 5 10.85 (s, IH), 8.45 (d, IH, J = 9.8 Hz), 8.24 (m, 3H), 7.99-7.62 (m, 6H), 7.54-7.34 (m, 5H), 6.96 (d, IH, J = 8.5 Hz), 2.64 (s, 3H), 2.54 (s, 3H).

Example 5(b): 3-Methyl-N-[3-(3-styryl-lh-indazol-6-yloxy)-phenvl]-benzamide

<img file="MY139999A_D0058.tif" />

KzCOj, MeOH

-►

<img file="MY139999A_D0059.tif" />

Example 5(b) was prepared in a similar manner to that described for Example

5(a) above, except that zw-tolylchloride was used in place of 5-methyl-thiazole-2-71carboxylic acid and HATU in step (i). 'HNMR (DMSO-d₆) δ 13.04 (s, IH), 10.28 (s, 1H), 8.23 (d, IH, J = 8.8 Hz), 7.73-7.30 (m, 14 H), 7.05 (s, IH), 6.99 (d, IH, J = 8.5

Hz), 6.87 (d, IH, J = 7.7 Hz), 2.38 (s, 3H). Anal. Calc, for C₂₉H₂₃N₃O2 0.2H₂O · 0.2 hexanes: C, 77.78; H, 5.66; N, 9.01. Found: C, 77.80; H, 5.84; N, 8.93.

Example 6(a): N-(3-{3-[2-(4-Chloro-phenyl)-vinyl|-lH-indazol-6-yloxy}-phenyl)benzamide

<img file="MY139999A_D0060.tif" />

<img file="MY139999A_D0061.tif" />

Starting from N-(3-{l-benzoyl-3-[2-(4-chlorc-phenyl)-vinyl]-lH-indazol-6yloxyl}-phenyl)-benzamide, the general procedure for example 5(a) was used to prepare the title compound as an off-white solid in 72% yield: Ή NMR (DMSO-d₆) δ 13.07 (s, IH), 10.32 (s, IH), 8.24 (d, IH, J = 8.8 Hz), 7.92 (d, 2H, J = 7.1 Hz), 7.76 (d, 2H, J = 8.5 Hz), 7.59-740 (m, 10H), 7.05 (s, IH), 7.00 (d, IH, J = 8.7 Hz), 6.87 (d, IH, J = 7.9 Hz). Anal. Calc, for C₂₈H₂₀ClN₃O₂ 0.4H₂O Ό.15 hexanes; C, 71.41; H,

4.75; N, 8.65. Found: C, 71.62; H, 14.83; N, 8.45.

The starting material was prepared as follows:

<img file="MY139999A_D0062.tif" />

-72Starting with 3-[3-(benzhydrylidene-amino)-phenoxy]-cyclohex-2-enone and

3-(4-chloro-phenyl)-acryloyl chloride (prepared as described below), the general procedure for Example 4(a), step (ii) was employed. The product was used without purification in the hydrazine cyclization procedure, Example 4(a) step (iii), to give 35 {3-[2-(4-chloro-phenyl)-vinyl]-4,5-dihydro-lH -indazol-6-yloxyl}-phenylamine as a yellow solid in 30% yield. Ή NMR (DMSO-d₆) δ 12.45 (s, 1H), 7.58 (d, 2H, J = 8.5 Hz), 7.43 (d, 2H, J = 8.5 Hz), 5.52 (s, 1H), 5.26 (s, 2H), 2.92 (t, 2H, J = 8.0 Hz), 2.58 (t, 2H, J = 8.0 Hz). Anal. Calc, for C₂₁H₁₈CIN₃O 0.75H₂O: C, 66.84; H, 5.21; N,

11.14. Found: C, 66.73; H, 4.89; Ν, 11.01.

3-(4-chloro-phenyl)-acryloyl chloride was prepared as follows: To a stirred suspension of 4-chloro-trans-cinnamic acid (2.51 g, 13.77 mmol) in benzene was added thionyl chloride (1.1 mL, 15.14 mmol) and a catalytic amount of DMAP. The reaction mixture was heated at reflux for 1.5 h. The volatile materials were removed under reduced pressure. The white residue was dissolved in Et₂O and concentrated again under reduced pressure, to give 3-(4-chloro-phenyl)-acryloyl chloride (2.78 g, quantitative) as a white solid: 'HNMR (CDC1₃) δ 7.81 (d, 1H, J = 15.6 Hz), 7.54 (d, 2H, J = 8.6 Hz), 7.44 (d, 2H, J = 8.6 Hz), 6.65 (d, 1H, J = 15.6 Hz).

(ii)

<img file="MY139999A_D0063.tif" />

<img file="MY139999A_D0064.tif" />

-733-{3-[2-(4-Chloro-phenyl)-vinyl]-4,5-dihydro-lH -indazol-6-yloxyl}phenylamine was converted into N-(3-{l-benzoyl-3-[2-(4-chloro-phenyl)-vinyl]-lHindazol-6-yloxyl}-phenyl)-benzamide by the procedure described in Example 4(a), step (iv) (85% yield). 'HNMR (DMSO-d₆) δ 10.37 (s, 1H), 8.43 (d, 1H, J = 8.8 Hz),

8.00-7.39 (m, 21H), 7.34 (d, 1H, J = 8.8 Hz), 6.93 (d, 1H, J = 8.8 Hz).

Example 6(b): N-{3-[3-(2-Indolyl)-lH-indazol-6-yloxy]-phenyl}-3-methylbenzamide

<img file="MY139999A_D0065.tif" />

Example 6(b) was prepared in a similar manner to that described for Example

6(a) above, except that l-SEM-indazole-2-carboxylic acid was used in step (i) in place of 4-chlor-ira«5-cmnamic acid. ’H NMR (DMSO-d₆) δ 13.19 (s, 1H), 11.59 (s,

1H), 10.29 (s,lH), 8.23 (d, 1H, J = 8.7 Hz), 7.73-7.38 (m, 9H), 7.12 (s,lH), 7.03 (d,

2H, J = 7.3 Hz), 6.88 (d, 1H, J = 7.8 Hz), 2.38 (s, 1H). HRMS [m+H]/z Calc’d:

459.1821, found 459.1836.

Example 7: 3-(Styryl-lH-indazol-6-yloxy)-phenylamine

<img file="MY139999A_D0066.tif" />

<img file="MY139999A_D0067.tif" />

A suspension of 3-(3-styryl-4, 5-dihydro-lH-indazol-6-yloxy)-phenylamine (75 mg, 0.23 mmol) and 90 mg of 5% palladium on carbon (Pd/C) was heated at 155 °C. After 4 h, more 5% Pd/C (39 mg) was added. After 22 h, more 5%Pd/C (30 mg)

-Ί4was added. The reaction mixture was filtered while hot after 26 h. The catalyst was washed and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica eluting hexanes/EtOAc (1:1). The appropriate fractions were concentrated and triturated with CH₂Cl₂/hexanes to give the title compound as an off-white solid (20 mg, 27%); ’HNMR (DMSO-d₆) δ 8.16 (d, 1H, J = 8.5 Hz), 7.71 (d, 2H, J = 6.7 Hz), 7.50 (s, 2H), 7.40 (t, 2H, J = 7.0 Hz), 7.30 (d, 1H, J = 6.5

Hz), 7.06-6.92 (m, 3H), 6.35 (d, 1H, J = 8.3 Hz), 6.23 (s, 2H), 5.26 (s, 2H). Anal. Calc, for C₂₁H_]7N₃O ’ O.15CH₂C1₂: C, 74.69; H, 5.13; N, 12.36. Found: C, 74.64; H,

5.23; N, 12.25.

Example 8(a): 3-(E-styryl)-6-phenoxy-l/7-indazole

<img file="MY139999A_D0068.tif" />

A suspension of 3-(E-styryl)-6-phenoxy-4,5-dihydro-l/7-indazole (200 mg. 0.64 mmol) and 5% Pd/C (200 mg) in 10 mL of tetralin was heated at 155 °C for 18 h. The catalyst was removed by filtering the hot solution and washed with THF,

EtOAc and MeOH. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel eluting hexanes/EtOAc (2:1) to provide 3 (E-styryl)-6-phenoxy-l/Y-inda7ole as an off-white solid (110 mg, 55%). ^]H NMR (DMSO-d₆) δ 6.96 (s, 2H), 7.10 (d, 2H, J = 7.7 Hz), 7.20 (t, IH, J = 7.1 Hz), 7.30 (t,

1H, J = 7.1 Hz), 7.44 (m, 6H), 7.71 (d, 2H, J = 7.5 Hi:), 8.20 (d, 1H, J = 9.2 Hz),

12.90 (s, 1H). Anal. Calc, for C₂₁H₁₆N₂O -0.1H₂O: C, 80.28; H, 5.20; N, 8.92.

Found: C, 80.20; H, 5.21; N, 8.93.

-75The starting material was prepared as follows (i) To a stirred solution of 3-chloro-cyclohex-2-enone (3.00g, 23.0 mmol) and phenol (2.16 g, 23.0 mmol) in 25 mL of acetone was added powdered, anhydrous

K₂CO₃ (3.81 g, 27.6 mmol). After refluxing for 18 h, the mixture was cooled and filtered. The filtrate was concentrated under reduced pressure and chromatographed on silica gel eluting with hexanes/EtOAc (4:1) to give 3-phenoxy-cyclohex-2-enone as a white solid: NMR (CDC1₃) δ 2.10 (quint, 2H, J = 6.3 Hz), 2.40 (t, 2H, J = 6.2

Hz), 2.68 (t, 2H, J = 6.3 Hz), 5.14 (s,lH), 7.05 (d, 2H, J = 7.5 Hz), 7.26 (t, 1H, J =

7.3 Hz), 7.41 (t, 2H, J = 7.6 Hz).

(ii) A solution of 3-phenoxy-cyclohex-2-eno:ae (301 mg, 1.6 mmol) in 1 mL of THF was added to a stirred solution of 1.0 M solu tion of lithium bis(trimethylsilyl)amide in THF (3.2 mL) at -78°C. After 15 min, cinnamoyl chloride (266 mg, 1.6 mmol) was added all at once. After 15 min, the reaction mixture was poured into 0.5 N HCI and extracted with EtOAc (2x). The combined organic layers were washed with saturated NaCl solution, dried (MgSO₄), filtered, and concentrated under reduced pressure. Chromatography of the residue with 4:1 hexanes/ethyl acetate as eluant provided 220 mg (43%) of 3-phenoxy-6-(3-phenylacryloyl)-cyclohex-2-enone as a yellow solid (220 mg, 43%): *H NMR (CDC1₃) (enol form) δ 2.66 (t, 2H, J = 7.2 Hz), 2.84 (t, 2H, J = 7.1 Hz), 5.11 (s, 1H), 6.86 (d,

1H, J = 15.6 Hz), 7.02 (d, 2H, J = 8.1 Hz), 7.20 (m,2H), 7.28-7.38 (m, 3H). HRMS

M+H⁺calc: 319.1334, found 319.1340.

(iii) To a stirred solution of 3-phenoxy-6-(3-phenyl-acryloyl)-cyclohex-2enone (1.13 g, 3.55 mmol) in 20 mL of HOAc/EtOH(l:l) was added hydrazine

-76monohydrate (.21 mL, 4.3 mmol). The reaction was heated at 70 °C for 3 h, cooled and poured cautiously into saturated Na HCO₃ solution and extracted with EtOAc (2x). The combined organic layers were washed with saturated NaCl solution, dried (MgSOJ and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting hexanes/EtOAc (2:1) to give 6-phenoxy-3styryl-4,5-dihydro-lH-indazole (3) as an off-white solid (406 mg, 36%): ’H NMR (DMSO-d₆) δ 2.64 (t, 2H, J = 8.0 Hz), 2.95 (t, 2H, J == 8.0 Hz), 5.46 (s,lH), 7.04 (AB,

2H, J = 16.8 Hz), 7.15 (d, 2H, J = 8.1 Hz), 7.25 (m, 2Ή), 7.42 (m, 4H), 7.55 (d, 2H, J = 7.7 Hz), 12.44 (s, IH). Anal. Calc, for C₂H₁₈N₂OO.2H₂O: C, 79.32; H, 5.83, N,

8.81. Found: C, 79.36; H, 5.85; N, 8.84.

Example 8(b): 3-(E-styryI)-6-[4-(methoxymethoxy)phenoxy]-lZF-indazole

<img file="MY139999A_D0069.tif" />

Example 8(b) was prepared in a similar manner to that described for Example 8(a) above, except that 4-(methoxymethoxy)phenol was used in place of phenol in step(i). Ή NMR (DMSO-d₆) δ 12.90 (s, IH), 8.17 (d, IH, J = 8.8 Hz), 7.71 (d, 2H, J = 7.6 Hz), 7.50 (s, 3H), 7.41 (t, 2H, J = 7.6 Hz), 7.31 (d, IH, J = 7.4 Hz), 7.10 (s, 3H),

6.95 (dd, IH, J = 8.8, 1.9 Hz), 6.84 (s, IH), 5.20 (s, 2H), 3.42 (s, 3H). Anal. Calc, for

C₂₃H₂₀N₂O₃: C, 74.17; H, 5.41, N, 7.52. Found: C, 74.21; H, 5.59; N, 7.46.

Example 8(c): 3-(E-styryI)-6-phenylsuIfanyI-177-indazole

<img file="MY139999A_D0070.tif" />

-ΊΊExample 8(c) was prepared in a similar manner to that described for Example 8(a) above, except that thiophenol was used in step (i) in place of phenol. ^JH NMR (DMSO-d₆) δ 7.29 (d, 1H, J = 8.5 Hz), 7.45-7.59 (m, 9H), 7.67 .(s, 2H), 7.86 (d, 2H, J = 7.2 Hz), 8.35 (d, 1H, J = 8.5 Hz), 13.30 (s, 1H). Anal. Calc. For C₂iH₁₆N₂S'

0.25H20: C, 75.76; H, 5.00; N, 8.41; S, 9.63. Found: C, 75.79; H, 4.99; N, 8.16; S,

9.63.

Example 8(d): 6-(3-Bromo-phenoxy)-3-styryl-lH-indazole

<img file="MY139999A_D0071.tif" />

Example 8(d) was prepared in an analogous manner to that described for 10 Example 8(a) above, except that 3-bromophenol was used in step (i) in place of phenol. Ή NMR (DMSO-d₆) δ 13.08 (s, 1H), 8.23 (d, 1H, J = 8.8 Hz), 7.72 (d, 2H, J = 7.3 Hz), 7.53 (s, 2H), 7.43 - 7.35 (m, 4H), 7.30 (t, 2H, J = 7.2 Hz), 7.11 (d, 1H, J =

7.2 Hz), 7.09 (s, 1H), 6.98 (d, 1H, J = 8.8 Hz). Anal. Calc, for C₂₁H₁₅BrN₂O: C,

64.46; H, 3.86; Br, 20.42; N, 7.16. Found: C, 64.31; H, 3.99; Br, 20.52; N, 7.11.

Example 9 (a): 3-(E-styryI)-6-[3-hydroxyphenoxy]-177-indazole

<img file="MY139999A_D0072.tif" />

To a stirred solution of 3-(E-styryl)-6-[3-(methoxymethoxy)phenoxy]-17Yindazole (50 mg, 0.13 mmol) in 5 mL CH₂C1₂ at -25°C was added trimethylsilylbromide (75 μΐ, 0.57 mmol). After 1.5 h, saturated NaHCO₃ solution was added and the product was extract with EtOAc (2x). The combined organic

-78layers were washed with saturated NaCl solution, dried (MgSO₄) and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting hexanes/EtOAc (1:1) to give, after trituration with CH₂Cl₂/hexanes, 3-(E-styryl)-6-[3hydroxyphenoxy]-177- as an off-white solid (22 mg, 50%): NMR (DMSO-d₆) δ

6.37 (s, 1H), 6.43 (d, 1H, J = 8.1 Hz), 6.50 (d, 1H, J == 8.1Hz), 6.88 (d, 1H, J = 8.8

Hz), 6.92 (s, 1H), 7.12 (t, 1H, J = 8.1 Hz), 7.24 (t, IE, J = 7.3 Hz), 7.31 (t, 2H, J = 7.6

Hz), 7.44 (s, 2H), 7.64 (d, 2H, J = 7.5 Hz), 8.12 (d, 1H, J = 8.7 Hz), 9.54 (s,lH),

12.92 (s, 1H). Anal. Calc. For C₂₁H₁₆N₂O₂O.3H₂O: C, 75.57; H, 5.01; N, 8.39. Found:

C, 75.74;H, 5.11;N, 8.25.

The starting material, 3-(E-styryl)-6-[3-(methoxymethoxy)phenoxy]-177indazole, was prepared as described in Example 8(b).

<img file="MY139999A_D0073.tif" />

^]H NMR (CDC1₃) δ 3.42 (s, 3H), 5.10 (s, 2H), 6.64 (d, 1H, J = 8.2 Hz), 6.72 (s, 1H), 6.80 (d, 1H, J = 8.3 Hz), 6.98 (s, 1H), 7.00 (d, 1H, J = 8.8 Hz), 7.19-7.38 (m, 5H),

7.53 (m, 3H), 7.92 (d, 1H, J = 8.9 Hz). Anal. Calc. For C₂₃H₂₀N₂O₃: M+H⁺:

373.1552, found 73.1546

Example 9(b): 3-(E-styryl)-6-[4-hydroxyphenoxy |-l/f-indazole

<img file="MY139999A_D0074.tif" />

Example 9(b) was prepared like Example 9(a) above, except that 3-(E-styryl)20 6-[4-(methoxymethoxy)phenoxy]-17/-indazole was used in place of 3-(E-styryl)-6-[3-79(methoxymethoxy)phenoxy]-177-indazole. 'H NMR (DMSO-d₆) δ 12.95 (s, IH), 9.58 (s, IH), 8.33 (d, IH, J = 9.0 Hz), 7.89 (d, 2H, J = 7.1 Hz), 7.68 (s, IH), 7.58 (t, IH, J = 7.3 Hz), 7.48 (d, IH, J = 7.3 Hz), 7.24 (s, IH), 7.13 (m,

3H), 6.99 (d, 2H, J = 8.8 Hz). HRMS [m+H]/z Calc’d: 329.1290. Found:

329.1293. Anal. Calc, for C₂₁H₁₆N₂O₂ · O.35H₂O: C, 75.36; H, 5.03; N, 8.37. Found:

C, 75.35; H, 5.22; N, 8.24.

Example 10: 6-(l-Phenyl-vinyI)-22StyryJ-177-indazole

<img file="MY139999A_D0075.tif" />

<img file="MY139999A_D0076.tif" />

6-( 1 -Phenyl-vinyl)-3-styryl-1 -[2-(trimethyl-silanyl)-ethoxymethyl]-17710 indazole (16.2 mg, 0.0358 mmol) was dissolved in THF (0.6 mL) and was treated with tetrabutylammonium fluoride (TBAF, 1M in THF, 0.6 mL). The mixture was heated to 60 °C under argon for 4 h. The mix was cooled, neutralized with excess saturated sodium bicarbonate and the organic material was extracted into ethyl acetate and concentrated. This mix of 3 compounds (by TLC visualization) was treated with THF-water-TFA (1:1:2, 4 mL) for 30 min. The mix was diluted with toluene (20 mL), concentrated, neutralized with excess saturated sodium bicarbonate, and the organic material was extracted into ethyl acetate. The organic material was dried over sodium sulfate, decanted and concentrated.. Purification by silica gel chromatography (2:8 ethyl acetate-hexane) gave 6-(l-Phenyl-vinyl)-3-styryl-17720 indazole (4.6 mg, 40%): Py sm 0.62, p 0.24 (ethyl acetate-hexame 3:7); *H NMR (300 MHz, CDC1₃) δ 7.99 (d, IH, J = 8.5 Hz), 7.60-7.25 (m, 14H), 5.58 (d, IH, J =

-801.1 Hz), 5.56 (d, 1H, J = 1.1 Hz); HRMS (FAB) [m+H]/z Calc’d 323.1548, Found

323.1545.

The starting material was prepared as follows:

(i)

I₂, NaOH, dioxane-water

Ν'

6-Iodoindazole was converted to 3,6-diiodoindazole (82%) as described in

Example 1(a), step (v): Ή NMR (300 MHz, CDCI3) δ 10.3 (bs, 1H), 7.90 (s, 1H),

7.52 (dd, 1H, J = 1.2, 8.5 Hz), 7.24 (d, 1H, J = 8.5 Hz).

(ii)

SEMBr, TBABr 50% KOH, CHjCI,

<img file="MY139999A_D0077.tif" />

SEM

Η I

3,6-Diiodoindazole (755 mg, 2.04 mmol) was added to 50% KOH (2.5 g in

2.5 mL water) at 0 °C and dichloromethane (4 mL) was added. To this mixture was added tetrabutylammonium bromide (TBABr, 6.6 me, 0.02 mmol, 0.01 equiv) and 2(trimethyl-silanyl)-ethoxymethyl chloride (SEM-Cl, 397 pL, 2.24 mmol, 1.10 equiv) 15 was added dropwise over a 3 min period. The mixture was stirred rapidly at 0 °C for

1.5 h. Water (20 mL) and dichloromethane (20 mL) were added and the organic material was separated, dried over sodium sulfate and. concentrated. Silica gel chromatography (5% ethyl acetate in hexane; 150 mL. silica) gave 2 isomeric compounds (1-SEM, 763 mg, 75%; and 2-SEM, 105 mg, 10%): Ry sm0.08, p 0.34 and 0.27 (ethyl acetate-hexane 1:9); ^JH NMR (300 MHz, CDCI3) δ 8.0 (s, 1H), 7.55

-81(d, 1H, J = 8.5 Hz), 7.24 (d, 1H, J = 8.5 Hz), 5.69 (s, 2H), 3.58 (t, 2H J = 8.2 Hz),

0.90 (t, 2H, J = 8.2 Hz), -0.1 (s, 9H).

(iii)

<img file="MY139999A_D0078.tif" />

1-Bromostyrene (26 pL, 0.20 mmol, 2.0 equiv) was dissolved in THF (0.75 mL), cooled to -78 °C and was treated with r-BuLi (235 pL, 0.40 mmol, 1.70 M, 4.0 equiv). The mixture was allowed to warm to -42 °C for 10 min and was added to freshly dried zinc chloride (34 mg, 0.25 mmol, 2.5 equiv). The resulting solution was allowed to warm to 23 °C with stirring for 25 min. TLtis mix was added to a mixture ofneat 3,6-Diiodo-l-[2-(trimethyl-silanyl)-ethoxymethyl]-l/7-indazole (50 mg, 0.10 mmol, 1 equiv) and Pd(PPh3)4 (5 mg, 0.004 mmol, 0.04 equiv). After 10 min the reaction was determined to be complete by TLC monitoring and was quenched with saturated sodium bicarbonate. Organic material was extracted into ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Silica gel chromatography (5:95 ethyl acetate-hexane) provided 3-Iodo-6-(l-phenyl-vinyl)-1[2-(trimethyl-silanyl)-ethoxymethyl]-177’-indazole (33.1 mg, 70 %): Ry sm 0.39, p

0.36 (ethyl acetate-hexane 1:9); 'HNMR (300 MHz, CDCI3) δ 7.50 (s, 1H), 7.42 (d,

1H, J = 8.4 Hz), 7.33 (m, 5H), 7.22 (dd, 1H, J = 1.2,8.4 Hz), 5.68 (s, 2H), 5.59 (d,

1H, J = 1.0 Hz), 5.57 (d, 1H, J = 1.0 Hz), 3.58 (t, 2H, J = 8.2 Hz), 0.88 (t, 2H, J = 8.2

Hz), -.09 (s, 9H); HRMS (FAB) [m+H]/z Calc’d 477.0859, Found 477.0866.

(iv)

-82Br.

<img file="MY139999A_D0079.tif" />

f-BuLI, ZnClj, THF, Pd(PPh,)₄

<img file="MY139999A_D0080.tif" />

Preparation of 6-( l-Phenyl-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-l/7-indazole: E-2-Bromostyrene (23 pL, 0.174 mmol, 2.5 equiv) was dissolved in THF (1.0 mL) and was cooled to -78 °C. z-BuLi (205 pL, 0.348 mmol,

5.00 equiv) was added and the mixture was warmed to -42 °C for 7 min to give a deep red mixture. The solution was added to freshly dried zinc chloride (29 mg, 0.209 mmol, 3.00 equiv) via cannula and the mix was allowed to warm to 23 °C with stirring for 20 min. This solution was added to a neat mixture of 3-Iodo-6-(l -phenylvinyl)-l-[2-(trimethyl-silanyl)-ethoxymethyl]-177-indazole (33.1 mg, 0.0696 mmol,

1.0 equiv) and Pd(PPh3)4 (4 mg, 0.0035 mmol, 0.05 equiv) at 23 °C via cannula.

This solution was allowed to stir for 15 min and was treated with saturated sodium bicarbonate and extracted with ethyl acetate. The organic material was dried over sodium sulfate, decanted and concentrated. Purification by silica gel chromatography using two columns (5:95 ethyl acetate-hexane; 12 mL silica: and 1:99 ethyl acetate15 benzene;12 mL silica) gave 6-(l-Phenyl-vinyl)-3-styryl-l-[2-(trimethyl-silanyl)ethoxymethyl]-l/7-indazole (16.2 mg, 51%): Ry sm 0.38, p 0.29 (ethyl acetatehexane 1:9); ’HNMR (300 MHz, CDC1₃) δ 7.98 (d, 1H, J = 8.4 Hz), 7.62-7.22 (m, 14H), 5.71 (s, 2H), 5.57 (s, 2H), 3.60 (t, 2H, J = 8.2 Hz), 0.90 (t, 2H, J = 8.2 Hz), -.08 (s, 9H); HRMS (FAB) [m+H]/z Calc’d 453.2362, Found 453.2354.

Example 11: yV-Methyl-yVrfS-styryl-l/f-indazol^-ylj-benzene-LS-diamine

<img file="MY139999A_D0081.tif" />

1MTBAF/THF, EDA 70 °C

<img file="MY139999A_D0082.tif" />

To A-methyl-A- {3 -styryl-1 -[2-(trimethyl-silanyl)-ethoxymethyl]- 1/7-indazol6-yl}-benzene-l,3-diamine (237 mg, 0.5 mmol) was added 1M TBAF in THF (10.1 mL, 10.1 mmol), followed by ethylenediamine (0.34 mL, 5.04 mmol, 10 equiv). The resulting mixture was heated to 70 °C for 5 h. The reaction was then quenched with saturated NaHCO3 (10 mL) and extracted 3x35 mL EtOAc. The pooled EtOAc phase was washed 5 x 20 mL H2O, then brine (20 ml.), dried with Na2SO4, decanted and concentrated under reduced pressure to a foam. The crude material was purified by silica gel chromatography (9:1 dichloromethane/ethyl acetate) to give Ά-methyl10 V-(3-styiyl-l/7-indazol-6-yl)-benzene-l,3-diamine as a foam (120 mg, 70% yield).

Rfsm 0.73, R/p 0.27 (dichloromethane:ethylacetate 7:3); NMR (75 MHz,

CDCI3) δ 150.3, 148.8, 147.5, 147.5, 143.9, 143.4, 137.5, 131.1, 130.3, 129.3, 128.9,

128.2, 127.9, 126.7, 121.0, 120.5, 117.0, 116.0, 112.6, 109.8, 109.0, 98.3,40.7;

LCMS (ESI) [M+H]/z Calc’d 341, Found 341. Anal. Calc’d: C, 77.62; H, 5.92; N,

16.46. Found: C, 76.16; H, 5.88; N, 15.95.

Starting material prepared as follows:

(i) l₂, 3N NaOH

NO₂ dioxane, 23“C

I

-846-nitro-l/7-indazole was converted to 3-Iodo-6-nitro- 1H-indazole as described in Example 1(a), step (v) (50.6 g, 87%): FTIR (KBr) 3376, 3076, 2964, 2120, 1739,

1626, 1526, 1439, 1294, 1128,954 cm-l;¹H NMR (300 MHz, CDCl3)5 8.28 (s, 1H),

8.05 (s, 1H), 7.66 (d, 1H, J = 8.13 Hz), 7.45 (dd, 1H, J = 8.33, 1.38 Hz), 7.17 (d, 1H,

J = 1.01 Hz), 7.14 (s, 1H), 7.03 (d, 1H, J = 8.04 Hz), 6.89 (s, 2H), 3.82 (s, 3H), 2.55 (s, 6H), 2.21 (s, 3H) 1.32 (s, 9H). MS (FAB) [M+H]/z Calc’d 311, Found 311. Anal.

Calc’d: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.41; H, 5.98; N, 8.79.

(ii)

SEMCI, TBAB ^NOj 50% KOH, CH₂CI₂0 to 23 °C

<img file="MY139999A_D0083.tif" />

SEM

<img file="MY139999A_D0084.tif" />

3-Iodo-6-nitro-l//-indazole was converted to 5-Nitro-3-iodo-[2-(trimethylsilanyl)-ethoxymethyl]-l//-indazole as described in Example 10, step (ii) (10.2 g, 81%yield): mp 58 °C. Anal. Calc’d: C, 37.24; H, 4.33;N, 10.02. Found: C,

37.21; H, 4.38; N, 10.00.

(iii)

<img file="MY139999A_D0085.tif" />

<img file="MY139999A_D0086.tif" />

To 6-nitro-3-iodo-[2-(trimethyl-silanyl)-ethoxymethyl]-l/7-indazole (11.0 g,

26.1 mmol), styryl boronic acid (4.64, 31.4 mmol), and Pd(PPh3)4 (1.25 g, 1.08 mmol) under an atmosphere of argon was added toluene (192 mL), MeOH (4 mL) and 2N NaOH (aq) (32.6 mL, 65.3 mmol). The resulting heterogeneous mixture was

-85heated to 90 °C. After 8 h the reaction was diluted with EtOAc (150 mL) and water (50 mL), the phases were separated and the organic was extracted 2x 50 mL EtOAc.

The pooled organic phase was washed with brine (50 mL), then dried with Na2SO4, filtered and concentrated under reduced pressure. The crude reaction was purified by silica gel chromatography (1:9 EtOAc:hexane) to give 6-nitro-3-styryl-l-[2(trimethyl-silanyl)-ethoxymethyl]-177-indazole as a yellow solid (7.65 g, 74%);

NMR (75 MHz, CDCl3).5 148.3, 145.0, 141.3, 138.1, 134.2, 130.5, 129.9 J29.8,

129.5, 128.1, 127.4, 123.2, 119.8, 117.8, 108.2, 79.7, 68.5, 19.2, 0.0; MS (FAB) [M+Na]/z Calc’d 418, found 418. Anal. Calc’d: C, 63.77; H, 6.37; N, 10.62. Found:

<img file="MY139999A_D0087.tif" />

6-Nitro-3-styryl-l-[2-(trimethyl-silanyl)-ethoxymethyl]-l//-indazole (8.1 g, 20.5 mmol) was dissolved in DMF (75 mL) at 23 °C under an atmosphere of argon.

SnCl2 (12.9 g, 67.7 mmol) was added followed by water (1.7 mL, 92.2 mmol) and the resulting mixture was heated to 50 °C. After 4 h, 3N NaOH (45 mL, 135 mmol) was added followed by EtOAc (100 mL). The resulting emulsion was filtered hot through Celite and the bed of Celite was washed with hot EtOAc (3 x 100 mL). The filtrate was concentrated under reduced pressure, the residue was dissolved in EtOAc, washed with brine, dried with Na2SO4, filtered and concentrated under reduced

-86pressure to give a solid. The crude material was purified by silica gel chromatography (2:8 7: 3 ethyl acetate ihexane), to give 3-styryl-l-[2-(trimethylsilanyl)-ethoxymethyl]-177-indazol-6-ylamine as a yellow solid (5.1 g, 68% yield).

MS (FAB) [M+H]/z Calc’d 366, found 366.

(v)

I

<img file="MY139999A_D0088.tif" />

To 3-styryl-l-[2-(trimethyl-silanyl)-ethoxymeiiiyl]-177-indazol-6-ylamine (1.1 g, 3 mmol, m-nitro-iodobenzene (0.9 g, 3.6 mmol), BINAP (0.07 g, 0.133 mmol),

Pd2(dba)3 (34 mg, 0.0375 mmol) and CS2CO3 (1.37 g, 4.2 mmol) under an atmosphere of argon was added toluene (6 mL). The resulting heterogeneous mixture was heated to 80 °C. After 46 h the reaction was cooled to 23 °C diluted with ethyl acetate (EtOAc) (20 mL) and filtered. Water (5 mL) was added, the phases were separated, and the organic was extracted 2x50 mL EtOAc. The pooled organic material was washed with brine, then dried with Na2SO4, filtered and concentrated under reduced pressure. The crude reaction was purified by silica gel chromatography (eluting with 9:1 hexane:EtOAc) to give (3-nitro-phenyl)-{3-styryll-[2-(trimethyl-silanyl)-ethoxymethyl]-177-indazol-6-yl}-amine as a yellow solid (7.65 g, 74%): TLC (Hexane:EtOAc 7:3) R/sm 0.16, R/p 0.30 (ethyl acetate:hexane 3:7); FTIR (KBr) 3391, 3059, 2952, 2894, 1614, 1530, 1483, 1346,

-871248, 1076, 836,734 cm-l^HNMR (300 MHz, CDCI3) δ 7.86 (s, IH), 7.83 (s, IH),

7.65 (dt, IH, J = 2.21, 5.13 Hz), 7.15-7.41 (m, 5H), 5.93 (dd, IH, J = 1.87, 8.67 Hz),

5.56 (s,2H), 3.51 (t, 2H, J = 8.17 Hz), 0.81 (t, 2H,J = 7.96 Hz), -0.15 (s, 9H); ^{10 * * 13 * 15 * * * * 20}C NMR (75 MHz, CDCI3) δ 149.6, 144.8, 143.5, 142.4, 140.9, 137.3, 131.8, 130.3,

129.0, 128.2, 126.7, 122.8, 122.6, 120.1, 119.3, 116.1, 115.6, 111.4,98.5, 77.9, 66.7,

18.0, -1.2; MS (ESI) [M+HJ/z Calc’d 487, found 487. Anal. Calc’d: C, 66.64; H,

6.21; N, 11.51. Found: C, 66.91; H, 6.21; N, 11.44.

(vi)

<img file="MY139999A_D0089.tif" />

<img file="MY139999A_D0090.tif" />

To (3-nitro-phenyl)-{3-styryl-l-[2-(trimethyl-silanyl)-ethoxymethyl]-177indazol-6-yl}-amine (434 mg, 0.89 mmol) in THF (5 mL) cooled to -5 °C under an atmosphere of argon, was added dimethylsulfate (0.42 mL, 4.5 mmol) followed by

LiHMDS (1M in THF) (1.8 mL, 1.8 mmol). After 20 min the reaction was quenched with saturated NH4Cl(aq) (2 mL), then extracted 3x20 mL EtOAc. The pooled organic material was washed with brine (10 mL), dried with Na2SO4, decanted and concentrated under reduced pressure. Purification by silica gel chromatography (eluting with hexane:EtOAc 9:1) gave methyl-(3-niUO-phenyl)-{3-styryl-l-[2(trimethyl-silanyl)-ethoxymethyl]-l/7-indazol-6-yl}-amine, as an oil (367 mg, 82%):

TLC (Hexane:EtOAc 7:3) fy^sm 0.29, R/p 0.39 (ethyl acetate: hexane 3:7); FTIR (KBr) 2951, 2894, 1611, 1528, 1485, 1348, 1248, 1077 cm'¹ ;^H NMR (300 MHz,

-88CDC13) δ 7.99 (d, 1Η, J = 8.67 Hz) 7.77 (t, 1H, J = 2.25 Hz), 7.72 (dd, 1H, J = 0.79,

2.09 Hz), 7.60, (d, 2H, J = 7.22 Hz), 7.26 - 7.54 (m, 7H), 7.19 (dd, 1H, J = 0.78, 2.41

Hz) 7.07 (dd, 1H, J = 1.85, 8.69 Hz), 5.70 (s, 2H), 3.63 (t, 2H, J = 8.10 Hz), 3.48 (s,

3H), 0.92 (t, 2H, J = 8.10 Hz), -0.04 (s, 9H); 13_C NMR (75 MHz, CDCI3) δ 150.2,

149.6, 147.1, 143.5, 142.5, 137.3, 131.9, 129.8, 129.0, 128.2, 126.8, 123.1, 122.6,

120.2, 120.0, 119.7, 114.4, 111.4, 104.5,78.0,66.8,41.1, 18.0,-1.2; LCMS (ESI) [M+H]/z Calc’d 501, Found 510.

(vii)

<img file="MY139999A_D0091.tif" />

Methyl-(3-nitro-phenyl)-{3-styryl-l-[2-(trimethyl-silanyl)-ethoxymethyl]-177indazol-6-yl}-amine was converted to A-methyl-.V-{3-styryl-l-[2-(trimethyl-silany 1)ethoxymethyl]-177-indazol-6-yl}-benzene-l,3-diamine as described in Example 11, step (iv). Rfsm 0.55, Γζ6ρ 0.31 (ethyl acetate:hexane 3:7); FTIR (thin film) 3455,

3360, 2951, 2893, 1621, 1601, 1494, 1449, 1249, 1074 cm’ijHNMR (300 MHz,

CDCI3) δ 7.81 (d, 1H, J = 8.8 Hz) 7.58 (d, 2H, J = 7.21 Hz), 7.26 - 7.50 (m 5H), 7.12 (t, 1H, J = 7.93 Hz), 7.01 (d, 1H, J = 1.73 Hz), 6.95 (dd, 1H, J = 1.99, 8.85 Hz), 5.67 (s, 2H), 3.63 (t, 2H, J = 8.12 Hz), 3.38 (s, 3H), 0.93 (t, 2H, J = 8.13 Hz), -0.04 (s,

9H); 13C NMR (75 MHz, CDCI3) δ 150.3, 149.0, 147.7, 143.4, 143.0, 137.6, 131.3,

-89130.4, 128.9, 128.0, 126.7, 121.2, 120.6, 117.3, 117.0, 113.1, 110.1, 109.3, 97.5,

77.8, 66.6, 41.0, 18.0, -1.2; LCMS (ESI) [M+H]/z Calc’d 471, Found 471. Example 12(a): 2ν-{3-|Μ6ΐ1ιγ1-(3-5ίγΓγ1-1//-ίηΰ3ζο1-6-γ1)-3ΐηίηο]-ρ1ΐ6ηγ1}acetamide

<img file="MY139999A_D0092.tif" />

V-Methyl-A^r-{3-styryl-l-[2-(trimethyl-silanyl)--ethoxymethyl]-l//-indazol-6yl}-benzene-l,3-diamine, prepared in Example 11 (34 mg, 0.041 mmol) was suspended in CH2CI2 (0.5 mL) at 23 °C under an atmosphere of argon. Pyridine (81 μΐ, 1.0 mmol), Ac2O (94 μΐ, 1.0 mmol) and DMAP (cat.) were added. The reaction became homogeneous immediately. After 1 h, TLC analysis (CH2Cl2:EtOAc 4:1) indicated no starting material. The reaction was quenched with saturated NaHCC&gt;3(aq) (2 mL) then diluted with EtOAc (15 mL) and the organic phase was washed with brine (3 mL), decanted and concentrated under reduced pressure to an oil. The oil was suspended in MeOH (2 mL) and K.2CO3 (83 mg, 0.6 mmol) was added. The resulting mixture was stirred at 23 °C under an atmosphere of argon.

After 1 h, the reaction was diluted with EtOAc (15 mL) and the organic phase was washed with brine (3 mL), decanted and concentrated under reduced pressure. The crude material was purified by semi-prep HPLC to give 7V-{3-[methyl-(3-styTyl-177indazol-6-yl)-amino]-phenyl}-acetamide (8.4 mg, 22%). ^H NMR (300 MHz,

CDCI3) δ 7.86 (d, 1H, J = 8.68 Hz), 7.58 (d, 1H, J = 7.17 Hz), 7.16 - 7.45 (m, 7H),

-907.15 (d, 1H, J = 8.29 Hz), 6.98 (m, IH), 6.95 (d, IH, J = 1.92 Hz), 6.8 (dd, IH, J =

1.16, 8.05 Hz), 3.37 (s, 3H), 2.14 (s, 3H). LCMS (ESI) [M+H]/z Calc’d 383, Found

383. Anal. Calc’d: C, 75.37; H, 5.80; N, 14.65. Found: C, 73.53; H, 6.01; N, 13.73.

Example 12(b): .Y-{3-[Methyl-(3-styryl-l/7-indazol-6-yl)-amino]-phenyl}5 benzamide

<img file="MY139999A_D0093.tif" />

NHBz

Example 12(b) was prepared in a similar manner to that described for

Example 12(a) above, except that benzoyl chloride was used instead of acetic anhydride. LCMS (ESI) [M+Hj/z Calc’d 475, Found 475; Anal. Calc’d C (78.36), H (5.44), N (12.60) Found,C (76.57), H (5.50), N (12.12).

Example 12(c): {3-[Methyl-(3-styryl-l/7-indazol-6-yl)-amino]-phenyl}-carbamic acid benzyl ester

<img file="MY139999A_D0094.tif" />

&lt; ,NHCbz

<img file="MY139999A_D0095.tif" />

that described for

Example 12(c) was prepared in a similar manner to 15 Example 12(a) above, except that carbobenzyloxy chloride was used instead of acetic anhydride. R/' sm 0.30, Rf p 0.57 (CH2Cl2:EtOAc 8:2); LCMS (ESI+) [M+H]/z

-91Calc’d 475 Found 475; Anal. Calc’d C (75.93), H (5.52), N (11.81) Found,C (75.60),

H (5.96), N (10.75).

Example 12(d): 5-Methyl-thiazoIe-2-carboxylic acid {3-[methyl-(3-styryl-l/ZindazoI-6-yl)-amino]-phenyl}-amide o

<img file="MY139999A_D0096.tif" />

To a solution of A-methyl-A-(3 -styryl- l//-indazol-6-yl)-benzene-1,3 -diamine, prepared in Example 11, (26 mg, 0.075 mmol) and 5-inethyl-thiazole-2-carboxylic acid (64 mg, 0.45 mmol) in DMF (0.375 mL) at 23 °C under an atmosphere of argon was added HATU (171 mg, 0.45 mmol). After 1 h, TLC analysis (CH2Cl2:EtOAc

8:2) indicated no starting material. The reaction was quenched with saturated

NaHCO3(aq) (2 mL) then diluted with EtOAc (15 mL) and the organic phase was washed with brine (3 mL), decanted and concentrated under reduced pressure. The oil was suspended in MeOH (2 mL) and K2CO3 (62 mg, 0.45 mmol) was added. The resulting mixture was stirred at 23 °C under an atmosphere of argon. After 1 h TLC 15 analysis (CH2Cl2:EtOAc 8:2) indicated no starting material. The reaction was diluted with EtOAc (15 mL) and the organic phase was washed with brine (3 mL), decanted and concentrated under reduced pressure to a solid. The crude material was purified by silica gel chromatography (eluting with CH2Cl2:EtOAc 85:15) to give the title compound after purification by semi-prep. HPLC (9.9 mg, 28 %). Rf sm

-920.25, R/p 0.39 (hexane:EtOAc 8:2); LCMS (ESI+) [M+H]/z Calc’d 466, Found 466.

Anal. Calc’d C (69.65), H (4.98), N (15.04) S (6.89). Found: C (69.24), H (5.35), N (13.97) S (5.95).

Example 13: 7V-[3-(3-Styryl-177-indazol-6-ylamino)-phenyl]-benzamide

<img file="MY139999A_D0097.tif" />

jV-(3-{3-Styryl-l-[2-(trimethyl-silanyl)-ethoxymethyl]-177-indazol-6ylammo}-phenyl)-benzamide was converted to ?/-[3-(3-styryl-177-indazol-6ylamino)-phenyl]-benzamide as described in Example 11. LCMS (ESI) [M+H]/z Calc’d 431, Found 431. Anal. Calc’d: C, 78.12; H, 5.15; N, 13.01. Found: C,

77.06; H, 6.91; N, 9.88.

The starting material was prepared as follows:

(i)

<img file="MY139999A_D0098.tif" />

(3-Nitro-phenyl)- {3-styryl-1 -[2-(trimethyl-silanyl)-ethoxymethyl]-l/715 indazol-6-yl}-amine, prepared in Example 11, step (vi), was converted to N~{3styryl-l-[2-(trimethyl-silanyl)-ethoxymethyl]-177-indazol-6-yl}-benzene-l,3-diamine as described in Example 11, step (iv). LCMS (ESI) [M+H]/z Calc’d 457, Found 457.

(ii)

<img file="MY139999A_D0099.tif" />

To a solution of7V-{3-styryl-l-[2-(trimethyl-silanyl)-ethoxymethyl]-l/7indazol-6-yl}-benzene-l,3-diamine (91 mg, 0.2 mmol) and pyridine (0.081 mL, 1.0 mmol) in CH2CI2 (0.5 mL) cooled to -5 °C under an atmosphere of argon was added benzoyl chloride (0.028 mL, 0.24 mmol). After 0.5 h the reaction was quenched with saturated NaHCC&gt;3(aq) then extracted 2x5 mL CH2CI2. The pooled organic material was washed with brine (5 ml.), dried with Na₂SO₄, decanted and concentrated under reduced pressure to give an oil. The crude material was purified by silica gel chromatography (eluting with hexane:EiOAc 3:2) to give A-(3-{310 Styryl-l-[2-(trimethyl-silanyl)-ethoxymethyl]-l/7-indazol-6-ylamino}-phenyl)benzamide (108 mg, 96% yield). R/sm 0.35, R/“p 0.44 (ethyl acetate:hexane 1:1);

FTIR (thin film) 3320, 2951, 2893, 1657, 1604, 1537, 1493, 1409, 1303, 1248, 1074 cm-1; LCMS (ESI) [M+H]/z Calc’d 561, Found 561. Anal. Calc’d: C, 72.82; H,

6.47; N, 9.99. Found: C, 72.33; H, 6.39; N, 9.81.

Example 14: Methyl-phenyl-(3-styryl-W-indazol-6-yl)-amine

<img file="MY139999A_D0100.tif" />

Methyl-phenyl- {3 -styryl-1 -[2-(trimethyl-silanyl)-ethoxymethyl]-1 H-indazol6-yl}-amine was converted to methyl-phenyI-(3-styryl-l/7-indazol-6-yl)-amine as described in Example 11. MS (ESI) [M+H]/z Calc’d 326, Found 326.

<img file="MY139999A_D0101.tif" />

The starting material was made as follows:

(i)

<img file="MY139999A_D0102.tif" />

1) NaNQ (aq) AcOH, cone. HCI 0 °C

2) Kl/fe (aq) 0-23 °C___t

To a solution of 3-styryl-]-[2-(trimethyl-silariyl)-ethoxymethyl]-l/7-indazol5 ' 6-ylamine (1.58 g, 4 mmol) in AcOH (14 mL), water (3 mL) and concentrated HCI — (1.67 mL) cooled to 2 °C was added a solution of NaNO2 (304 mg, 4.4 mmol) in water (0.5 mL) over 5 min. The resulting dark red solution was stirred at 2 °C for 0.5 h, then a solution of KI (797 mg, 4.8 mmol) and 12 (610 mg, 2.4 mmol) in water (1 mL) was added drop-wise so as to keep the internal temperature below 5 °C. After 2 h at 2 °C the reaction was allowed to stir at 23 °C for 17 h. The reaction was quenched with 3 N NaOH (aq), diluted with EtOAc (50 mL) and H2O (15 mL), the phases were separated and the aqueous was extracted 2x15 mL EtOAc. The pooled organic phase was washed 3 x 20 mL 5% NaHSO3, brine (15 mL), dried with Na2SO4, decanted and concentrated under reduced pressure. The crude reaction was purified 15 by silica gel chromatography (eluting with 1:1 hexane:EtOAc) to give 6-iodo-3styryl-l-[2-(trimethyl-silanyl)-ethoxymethyl]-177-indazole as a white solid (1.3 g,

68% yield). NMR (300 MHz, CDCI3) δ 8.03 (s, 1H), 7.79 (d, 1H, J = 9.0 Hz),

7.30 - 7.60 (m, 8H), 5.73 (s, 2H), 3.63 (t, 2H, J = 6.0 Hz), 0.96 (t, 2H, J = 6.0 Hz), 0.0 (s, 9); ¹³C NMR (75 MHz, CDCI3) δ 143.6, 142.4, 137.2, 132.1, 130.8, 129.0, 128.3,

-95126.8, 122.5, 122.4, 119.6, 119.5, 92.9, 78.1, 66.9,18.0, -1.2. Anal. Calc’d: C,

52.94; H, 5.29; N, 5.88. Found: C, 52.66; H, 5.29; N, 5.74.

(ii)

<img file="MY139999A_D0103.tif" />

6-Iodo-3-styryl-l-[2-(trimethyl-silanyl)-ethoxymethyl]-l/7-indazole was converted to methyl-phenyl- {3 -styryl-1 -[2-(trimethyl -silanyl)-ethoxymethyl] -1Hindazol-6-yl}-amine as described in Example 11, step (v). R/sm 0.35 Rfp 0.13 (EtOAc:hexane 1:9); IR (KBr) 3031, 2951, 1625, 1595, 1498, 1449, 1326, 1303,

1248, 1212, 1076, 835, 694 cm’i; MS (ESI) [M+H]/z Calc’d 456, Found 456.

Example 15: 7V-[3-(2-Benzo[l,3]dioxol-5-yl-vinyl)-lET-indazol-6-yl]-7V-methylbenzene-l,3-diamine

<img file="MY139999A_D0104.tif" />

[3-(2-Benzo[l,3]dioxol-5-yl-vinyl)-l//-indazol-6-yl]-methyl-(3-nitro-phenyl)amine was converted to A-[3-(2-benzo[l,3]dioxol-5-yl-vinyl)-177-indazol-6-yl]-A^r15 methyl-benzene-1,3-diamine as described in Example 11, step (iv). LCMS (ESI) [M+H]/z Calc’d 385, Found 385. Anal. Calc’d: C, 71.86; H, 5.24; N, 14.57. Found:

C, 70.99; H, 5.60; N, 13.80.

The starting material was prepared as follows::

-96(i)

<img file="MY139999A_D0105.tif" />

To a mixture of 6-nitro-3-iodo-[2-(trimethyl-silanyl)-ethoxymethyl]-l/7iudazole (4.2 g, 10 mmol), boronic acid (3.46 g, 15 mmol), and Pd(PPh3)4 (0.58 g,

0.5 mmol) at 23 °C under an atmosphere of argon was added 1,4-dioxane (38 mL) and 2N NaOH (aq) (12.5 mL, 25 mmol). The resulting mixture was heated to 90 °C.

After 2 h the reaction was diluted with EtOAc (100 rnL) and water (70 mL), the phases were separated and the organic was extracted 2 X 100 mL EtOAc. The pooled organic phase was washed with brine (20 mL) then cried with Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (eluting with 9:1 hexane:EtOAc) to give 3-(2-benzo[l,3]dioxol-5-ylvinyl)-6-nitro-l-[2-(trimethyl-silanyl)-ethoxymethyl]-177-mdazole as a yellow solid (4.15 g, 94% yield). FTIR (thin film) 2950, 2898, 1523, 1501, 1483, 1446, 1344,

1249, 1080, 1043,927 cm'¹; ^]H NMR (300 MHz, CDCI3) δ 8.56 (dd, 1H,J = O.68,

1.75 Hz), 8.14 (d, IH, J = 1.78 Hz), 8.13 (d, IH, J = 0.67 Hz), 7.50 (d, IH, 16.53 Hz),

7.25 (d, IH, 16.52 Hz), 7.18 (d, IH, J = 1.67 Hz), 7.07 (dd, IH, J = 1.65, 8.13 Hz), 6.88 (d, IH, J = 8.0 Hz), 6.05 (s, 2H), 5.84 (s, 2H), 3.66 (t, 2H, J = 7.33 Hz), 0.97 (t,

2H, J = 7.24 Hz), 0.0 (s, 9H); ¹³C NMR (75 MHz, CDCI3) δ 148.5, 148.2, 147.0,

143.9, 140.1, 132.7, 131.3, 126.1, 122.3, 121.9, 116.7, 116.5, 108.7, 106.9, 105.7,

101.5, 78.4, 67.2, 17.9, -1.3; LCMS (ESI) [M+H]/z Calc’d 531, Found 531.

-9Ί-

<img file="MY139999A_D0106.tif" />

3-(2-Benzo[l,3]dioxol-5-yl-vinyl)-6-nitro-l-[2-(trimethyl-silanyl)ethoxymethyl]-177-indazole was converted to 3-(2-Benzo[l,3]dioxol-5-yl-vinyl)-l-[2· (trimethyl-silanyl)-Wioxymethyl]-l/7-indazol-6-ylairine as described in Example 11, step (iv). ^H NMR (300 MHz, CDCI3) δ 7.73 (d, 1H, J = 8.56 Hz), 7.52 (d, 1H, J =

16.57 Hz), 7.18 (d, 1H,J= 16.56 Hz), 7.10 (d, 1H, J == 1.49 Hz), 6.98 (dd, 1H, J =

1.52, 8.06 Hz), 6.80 (d, 1H, J = 8.01 Hz), 6.68 (d, 1H, J = 1.44 Hz), 6.63 (dd, 1H, J =

1.86, 8.57 Hz), 5.95 (s, 2H), 5.59 (s, 2H), 3.59 (t, 2H. J = 8.17 Hz), 0.91 (t, 2H, J =

8.33 Hz), 0.04 (s, 9H);¹³C NMR (75 MHz, CDCI3) δ 148.3, 147.6, 146.4, 143.4,

143.0, 132.0, 130.8, 122.0, 121.7, 118.8, 116.5,113.1, 108.5, 105.5, 101.3, 92.9,

77.6, 66.3, 17.9, -1.3; LCMS (ESI) [M+H]/z Calc’d 410, Found 410.

(iii)

<img file="MY139999A_D0107.tif" />

3-(2-Benzo[l,3]dioxol-5-yl-vinyl)-l-[2-(trimethyl-silanyl)-ethoxymethyl]-177 indazol-6-ylamine was converted to {3-(2-Benzo[l,3]dioxol-5-yl-vinyl)-l-[2-98(trimethyl-silanyl)-ethoxymethyl]-lH-indazol-6-yl}-(3-nitro-phenyl)-amine as described in Example 11, step (v). 1³C NMR (75 MHz, CDCI3) δ 150.8, 149.7,

149.1, 146.0, 144.8, 143.6, 142.1, 133.1, 132.7, 131.5, 124.0, 123.8, 123.1, 120.4,

119.5, 117.2, 116.8, 112.6, 109.9, 106.9, 102.6,99.7,79.1,67.9, 19.2, 0.0; MS (FAB) [M+H]/z Calc’d 531, Found 531. Anal. Calc’d: C, 63.38; H, 5.70; N, 10.56.

Found: C, 63.49; H, 5.76; N, 10.42.

(iv)

<img file="MY139999A_D0108.tif" />

{3-(2-Benzo[l,3]dioxol-5-yl-vinyl)-l-[2-(triraethyl-silanyl)-ethoxym ethyl]10 l/7-indazol-6-yl}-(3-nitro-phenyl)-amine was converted to {3-(2-Benzo[l,3]dioxol-5 yl-vinyl)-l-[2-(trimethyl-silanyl)-ethoxymethyl]-l//-indazol-6-yl}-methyl-(3-nitrophenyl)-amine as described in Example 11, step (vi). FTIR (KBr) 2952, 2894, 1612, 1529, 1503, 1489, 1446, 1407, 1348, 1306, 1251, 1077, 1039 cm-1; ¹³C NMR (75

MHz, CDCI3) δ 150.1, 149.5, 148.4, 147.8, 147.0, 143.5, 142.4, 131.8, 131.5, 129.8,

123.0, 122.49, 121.9, 120.1, 119.5, 118.2, 114.3, 11.3, 108.7, 105.7, 104.5, 101.4,

78.0, 66.8, 41.0, 17.9, -1.2; MS (FAB) [M+H]/z Calc’d 545, Found 545. Anal.

Calc’d: C, 63.95; H, 5.92; N, 10.29. Found: C, 62.63; H, 5.72; N, 9.62.

(v)

<img file="MY139999A_D0109.tif" />

{3-(2-Benzo[l,3]dioxol-5-yl-vinyl)-l-[2-(trimethyl-silanyl)-ethoxymethyl]177-indazol-6-yl}-methyl-(3-nitro-phenyl)-amine was converted to [3-(2Benzo [1,3] dioxol-5 -yl-vinyl)- 177-indazol-6-yl]-methyl-(3-nitro-phenyl)-amine as described in Example 11. LCMS (ESI) [M+H]/z Calc’d 415, Found 415. Anal.

Calc’d: C, 66.66; H, 4.38; N, 13.52. Found: C, 66.56; H, 4.48; N, 13.35.

Example 16(a): 7V-(3-{[3-(2-Benzo[l,3]dioxoI-5-yl-vinyI)-Lff-indazoI-6-yl]methyl-amino}-phenyl)-benzamide

<img file="MY139999A_D0110.tif" />

<img file="MY139999A_D0111.tif" />

A-[3-(2-Benzo[l,3]dioxol-5-yl-vinyl)-l//-indazol-6-yl]-A-methyl-benzene1,3-diamine (prepared as described in Example 15) was converted to A-(3-{[3-(2benzo[ 1,3]dioxol-5-yl-vinyl)- 177-indazol-6-yl]-methyl-amino} -phenyl)-benzamide in the manner described in Example 12(a). LCMS (ES 1) [M+H]/z Calc’d 489, Found

489. Anal. Calc’d: C, 73.76; H, 4.95; N, 11.47. Found: C, 73.19; H, 5.09; N, 11.20.

Example 16(b): 7V-(3-{[3-(2-Benzo[l,3]dioxol-5-yl-vinyl)-lFf-indazol-6-yl]methyl-amino}-phenyI)-3-methvl-benzamide

-100-

<img file="MY139999A_D0112.tif" />

o

Example 16(b) was prepared in a similar manner to that described for Example 16(a) above, except that m-toluyl chloride was used instead of benzoyl chloride. LCMS (ESI) [M+H]/z Calc’d'504, Found 504. Anal. Calc’d: C, 74.09; H,

5.21; N, 11.15. Found: C, 73.04; H, 5.84; N, 10.29.

Example 16(c): 7V-(3-{[3-(2-Benzo[l,3]dioxol-5-yl-vinyl)-l/7-indazol-6-yl]methyl-amino}-phenyl)-3-dimethylamino-benzamide

<img file="MY139999A_D0113.tif" />

Example 16(c) was prepared in a similar manner to that described for

Example 16(a), except that m-dimethylaminobenzoyl chloride was used instead of benzoyl chloride. LCMS (ESI) [M+H]/z Calc’d 532., Found 532. Anal. Calc’d: C,

72.30; H, 5.50; N, 13.17. Found: C, 71.61; H, 5.80; N, 12.75.

Example 16(d): 7V-(3-{ [3-(2-Benzo [1,3] dioxol-5-yI -vinyl)-l//-indazoI-6-yl]methyI-amino}-phenyI)-3-trifluoromethyl-benzamide

-101-

<img file="MY139999A_D0114.tif" />

Example 16(d) was prepared in a similar manner to that described for

Example 16(a), except that m-trifluoromethylbenzoyl chloride was used instead of benzoyl chloride. LCMS (ESI) [M+H]/z Calc’d 557, found 557. Anal. Calc’d: C,

66.90; H, 4.17; N, 10.07. Found: C, 66.64; H, 4.34; N, 9.82.

Example 16(e): 3-Acetyl-A-(3-{[3-(2-benzo[l,3]dio\oI-5-yI-vinyl)-l//-indazol6-yl]-methyl-amino}-phenyl)-benzamide

<img file="MY139999A_D0115.tif" />

Example 16(e) was prepared in a similar manner to that described for 10 Example 16(a), except that m-acetylbenzoyl chloride was used instead of benzoyl chloride. LCMS (ESI) [M+H]/z Calc’d 531, Found 531. Anal. Calc’d: C, 72.44; H,

4.94; N, 10.56. Found: C, 55.51; H, 4.21; N, 7.58.

Example 16(f): 6-[N-(3-(4-Zeri-butyl-3-hydroxybenzamido)phenyl)-Nmethylamino]-3-E-[(3,4-methy]enedioxyphenyl)ethenyl]-17/-indazole

-102-

<img file="MY139999A_D0116.tif" />

Example 16(f) was prepared in a similar manner to that described for Example 16(a), except that 3-rerz-butyl-4-hydroxy-benzoic acid, HATU, and TEA were used instead of benzoyl chloride. Ή NMR (300 MHz, CD₃OD) δ: 7.90 (d, 1H, J = 8.91 Hz), 7.83 (d, 1H, J = 2.29 Hz), 7.63 (dd, 1H, J = 8.36 Hz, J = 2.31 Hz), 7.54 (t, 1H, J = 1.97

Hz), 7.25-7.43 (m, 4H), 7.14-7.20 (m,2H), 7.06 (dd, 1H, J = 8.11 Hz, J = 1.55 Hz), 6.96 (dd, 1H, J = 8.93 Hz, J = 1.97 Hz), 6.90 (m, 1H). 6.82 (t, 2H, J = 8.18 Hz), 6.0 (s,2H), 3.41 (s, 3H), 1.42 (s,9H).

Example 17: Phenyl-(3-styryl-lH-indazol-6-yI)-methanone

<img file="MY139999A_D0117.tif" />

<img file="MY139999A_D0118.tif" />

Phenyl-{3-styryl-l-[2-(trimethyI-silanyl)-ethcxymethyl]-17Y-indazol-6-yl}methanone was converted to phenyl-(3-styryl-l//-indazol-6-yl)-methanone as described in Example 11 (30 mg, 78%). ; MS (ESI) [M+H]/z Calc’d 325, Found 325

Anal. Calc’d: C, 81.46; H, 4.97; N, 8.46. Found: C, 80.36; H, 5.16; N, 8.51.

The starting material was prepared as follows:

(i)

-103-

<img file="MY139999A_D0119.tif" />

<img file="MY139999A_D0120.tif" />

To a solution of 6-iodo-3-styryl-l-[2-(trimethyl-silanyl)-ethoxymethyl]-lF7indazole, prepared in Example 14, step (i), (143 mg, 0.3 mmol) in THF (1 mL) cooled to -78 °C under an atmosphere of argon was added zz-BuLi (0.2 mL, 0.315 mmol) dropwise. The resulting mixture was stirred at -78 °C-for 30'min, then a solution of benzaldehyde (0.035 mL, 0.33 mmol) in THF (0.5 mL) was added rapidly via a cannula. After 0.5 h the reaction was quenched with saturated NH4CI (aq) and diluted with EtOAc (10 mL) and H2O (3 mL). The phases were separated and the aqueous was extracted 2x10 mL. EtOAc. The pooled EtOAc was washed with brine (5 mL.), dried with Na2SO4, decanted and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (eluting with hexane:EtOAc 4:1) to give phenyI-{3-styryl-l-[2-(trimethyI-silanyl)-ethoxymethyl]-177-indazol-6yl}-methanol (68 mg, 50% yield). Rfsm = 0.72; R/'p = 0.39 (7:3 hexane:EtOAc);

FTIR (thin film) 3368, 2952, 2893, 1621, 1478, 1449, 1374, 1307, 1249, 1216, 1078,

960,859,835 cm-¹. MS (ESI) [M+H]/z Calc’d 457, found 457.

(ii)

<img file="MY139999A_D0121.tif" />

Dess-Martin CH₂CI₂, 23 °C

<img file="MY139999A_D0122.tif" />

-104To a solution of phenyl-{3-styryl-l-[2-(trimetliyl-silanyl)-ethoxymethyl]-177indazol-6-yl}-methanol (68 mg, 0.15 mmol) in dichlcromethane (3 mL) at 23 °C under an atmosphere of .argon was added periodinane (Dess-Martin reagent) (190 mg,

0.45 mmol). The resulting mixture was stirred at 23 °C for 1 hour. The solution was then diluted with hexane (3 mL) then filtered through Celite and concentrated under reduced pressure to a solid. The crude mixture was purified by silica gel chromatography (eluting with hexane:EtOAc 9:1) to give phenyl-{3-styryl-1-[2(trimethyl-silanyl)-ethoxymethyl]-177-indazol-6-yl}-inethanone (54 mg, 79% yield). R/sm = 0.41, R/p = 0.63 (7:3 hexane:EtOAc); FTIR (thin film) 3059, 2952, 2894,

1659, 1474, 1448, 1307, 1249, 1078, 836, 649 cm’¹. MS (ESI) [M+H]/z Calc’d 455, found 455.

Example 18: (3-Amino-phenyl)-(3-styryl-l/7-inda:zol-6-yl)-methanone

<img file="MY139999A_D0123.tif" />

(3-Amino-phenyl)-{3-styryl-l-[2-(trimethyl-silanyl)-ethoxymethyl]-17715 indazol-6-yl} -methanone was converted to (3-amino -phenyl)-(3-styryl-177-indazol-6yl)-methanone as described in Example 11. iH NMR (300 MHz, CDCI3) δ 8.07 (dd,

1H, J = 0.71, 8.50 Hz), 7.91 (s, 1H), 7.64 (dd, 1H, J == 1.35, 8.48 Hz), 7.54 - 7.60 (m, 2H), 7.46 (d, 2H, J = 12.84 Hz), 7.35 - 7.40 (m, 2H), 7.22 - 7.31 (m, 2H), 7.16 - 7.13 (m, 2H), 6.91 (ddd, 1H, J = 1.08, 7.89 Hz). LCMS (ESI) [M+H]/z Calc’d 340, found

340.

-105The starting material was prepared as follows:

(i)

<img file="MY139999A_D0124.tif" />

<img file="MY139999A_D0125.tif" />

6-Iodo-3-styryl-1 -[2-(trimethyl-silanyl)-ethoxymethyl]-l/7-indazole was 5 converted to (3-nitro-phenvl)-{3-styryl-l-[2-(trimethyl-silanyl)-ethoxymethyl]-lHindazol-6-yl}-methanol as described in Example 17, step (i). R/sm = 0.71, R/~P ~ 0.25 (7:3 hexane:EtOAc); FTIR (thin film) 3369, 3061, 2952, 2894, 2361, 1620,

1578, 1530, 1478, 1449, 1350, 1308, 1249, 1215, 1080, 961, 859 cm¹; ^NMR (300 MHz, CDCI3) δ 8.35 (s, 1H), 8.14 (dd, 1H, J = 1.34, 8.14 Hz), 7.99 (d, 1H, J =

8.38 Hz), 7.76 (d, 1H, J = 7.72 Hz), 7.68 (s, 1H), 7.59 - 7.30 (m, 8H), 7.21 (d, 1H, J

8.33 Hz), 6.09 (s, 1H), 5.73 (s, 2H), 3.61 (t, 2H, J = 8.30 Hz), 090 (t, 2H, J - 8.30

Hz), -0.06 (s, 9H). 13c NMR (75 MHz, CDCI3) δ 148.5, 145.9, 143.4, 142.4, 141.3,

137.1, 132.7, 132.0, 129.5, 128.9, 128.2, 126.7, 122.6, 122.6, 121.8, 121.5, 120.8,

119.6, 107.8, 77.7, 75.4, 66.8, 17.8, -1.3. Anal. Calc’d: C, 67.04; H, 6.23; N, 8.38.

Found: C, 66.93; H, 6.20; N, 8.41.

(ii)

SBVI

<img file="MY139999A_D0126.tif" />

Dess-Martin CH₂CI₂, 23 °C

SHYI

O

<img file="MY139999A_D0127.tif" />

NOj — 106— (3-Nitro-phenyl)-{3-styryl-l-[2-(trimethyl-sil&lt;myl)-ethoxymethyl]-17/·indazol-6-yl}-methanol was converted to (3-nitro-pbenyl)-{3-styryl-l-[2-(trimethylsilanyl)-ethoxymethyl]-l//-indazol-6-yl}-methanone as described in Example 17, step (ii) (129 mg, 91%). IVsm = 0.46, IV P = 0.23 (7:3 hexane:EtOAc); FTIR (thin film) 3082, 2952, 2894, 1665, 1613, 1532, 1476, 1349, 1298, 1250, 1080, 836, 718 cm'¹; LCMS (ESI) [M+H]/z Calc’d. 500, found 500.

(iii)

<img file="MY139999A_D0128.tif" />

<img file="MY139999A_D0129.tif" />

(3-Nitro-phenyl)-{3-styryl-l-[2-(trimethyl-silanyl)-ethoxymethyl]-17710 indazol-6-yl}-methanone was converted to (3-amino-phenyl)-{3-styryl-1-[2(trimethyl-silanyl)-ethoxymethyl]-177-indazol-6-yl}-inethanone as described in

Example 11, step (iv) (102 mg, 84%). LCMS (ESI) [M+H]/z Calc'd 340, found 340.

Example 19(a): 7V-[3-(3-Styryl-177-indazoIe-6-carbonyI)-phenyI]-acetamide

<img file="MY139999A_D0130.tif" />

(3-Amino-phenyl)-(3-styryl-177-indazol-6-yl)-methanone, prepared in

Example 18, was converted to jV-[3-(3-styryl-177-indazole-6-carbonyl)-phenyl]acetamide as described in Example 12(a) (12.2 mg, 78%). R/sm= 0.16, IVp = 0.35

-107(8:2 CH2Cl2:EtOAc); LCMS (ESI) [M+H]/z Calc’d 382, Found 382. Anal. Calc’d:

C, 75.57; H, 5.02; N, 11.02. Found: C, 74.32; H, 5.41; N, 10.54.

Example 19(b): /V-[3-(3-StyryI-177-indazoIe-6-carbonyI)-phenyI]-benzamide

<img file="MY139999A_D0131.tif" />

<img file="MY139999A_D0132.tif" />

Example 19(b) was prepared in a similar manner to that described for

Example 19(a), except that benzoyl chloride was used instead of acetic anhydride.

IH NMR (300 MHz, CDCI3) δ 8.40 (s, IH), 8.02 (d, IH, J = 8.49 Hz), 7.98 (d, IH, J = 1.01 Hz), 7.95 (s, IH), 7.95 (s, IH), 7.83 - 7.88 (m, 3H), 7.65 (dd, IH, J = 1.04, 8.48 Hz), 7.29 - 7.56 (m, 1 IH). MS (ESI) [M+H]/z Calc’d 444, found 444. Anal.

Calc’d: C, 78.54; H, 4.77; N, 9.47. Found: C, 78.01; H, 4.87; N, 9.32.

Example 19(c): [3-(3-Styryl-177-indazole-6-carbonyl)-phenyI]-carbamic acid benzyl ester

<img file="MY139999A_D0133.tif" />

<img file="MY139999A_D0134.tif" />

The title compound was prepared in a similar manner to that described for

Example 19(a), except that carboxybenzyloxy chloride was used instead of acetic anhydride. Ή NMR (300 MHz, DMSO-d6) δ 8.37 (d, IH, J = 8.48 Hz), 7.98 (s, 1H),

7.88 (s, 1H), 7.79 (s, 1H), 7.75 (d, 2H, J = 7.44 Hz), 7.61 (d, 2H, J = 1.81 Hz), 7.58

-108(s, IH), 7.51 (t, 1H, J = 7.79 Hz), 7.42 (t, 5H, J = 6.56 Hz), 7.31 - 7.37 (m, 4H), 5.16 (s, 2H); LCMS (ESI) [M+H]/z Calc’d 474, Found 474. Anal. Calc’d: C, 76.09; H,

4.90; N, 8.87. Found: C, 73.82; H, 4.93; N, 8.27.

Example 19(d): 5-MethyI-thiazoIe-2-carboxvlic acid [3-(3-styryl-17/-indazoIe-65 carbonyl)-phenyl]-amide

<img file="MY139999A_D0135.tif" />

(3-Amino-phenyl)-(3-styryl-lTF-indazol-6-yl)-methanone was converted to 5methyl-thiazole-2-carboxylic acid [3-(3-styryl-l/7-indazole-6-carbonyl)-phenyl]amide as described in Example 12(d) (9.9 mg, 28 %). 'h NMR (300 MHz, CDCI3) δ

8.15 (d, IH, J = 8.49 Hz), 8.09 (t, IH, J = 1.86 Hz), 8.04 (dd, IH, J = 1.0, 7.98 Hz),

7.99 (s, IH), 7.75 (dd, IH, J = 1.31, 8.47 Hz), 7.67 (s, IH), 7.63 (d, 2H, J = 7.30 Hz),

7.54 - 7.58 (m, 3H), 7.50 (s, 1H), 7.42 (t, 3H, J = 8.09 Hz); LCMS (ESI) [M+H]/z

Calc’d 465, found 465.

Example 19(e): 6-[3-(5-methylpyridin-3-ylcarboxa.mido)benzoyI]-3-E-styryl-17715 indazole

<img file="MY139999A_D0136.tif" />

O

-109Example 19(e) was prepared in a similar manner to Example 19(d) except that 5-methyl-nicotinic acid was used instead of 5-methyl-thiazole-2-carboxylic acid. ’H

NMR (300 MHz, CDC1₃) δ 9.22 (s, 1H), 8.99 (d, 1H, J = 0.59 Hz), 8.67 (s, 1H), 8.24 (s, 1H), 8.16 (d, 1H, J = 8.32 Hz), 2.97 (dd, 1H, J = 8.3 Hz, J = 0.94 Hz), 7.72 (d, 1H,

J = 16.65 Hz), 7.64 (d, 2H, J = 7.21 Hz), 7.19-7.47 (m, 8H), 6.95 (d, 1H, J = 6.43 Hz),

2.49 (s, 3H). MS (ESI+) [M+H]/z Calc’d 459, found 459. Anal. Calc’d: C, 75.97. H,

4.84. N, 12.22. Found: C, 75.86. H, 4.94. N, 12.10.

Example 19(f): 6-[3-(indol-4-ylcarboxamido)benzoyI]-3-E-styryl-l/F-indazole

<img file="MY139999A_D0137.tif" />

<img file="MY139999A_D0138.tif" />

Example 19 (f) was prepared in a similar manner to Example 19 (d) except lH-Indole-4-carboxylic acid was used instead of 5-methyl-thiazole-2-carboxylic acid.

LCMS (ESI+) [M+H]/z Calc’d 483, Found 483. Anal. Calc’d: C, 77.16; H, 4.60; N,

11.61. Found: C, 76.15; H, 4.49; N, 11.31.

Example 19(g): 6-[3-(pyridin-2-ylacetamido)benzoyl]-3-E-styryl-l/7-indazoIe

<img file="MY139999A_D0139.tif" />

Example 19(g) was prepared in a similar manner to Example 19(d), except that pyridin-2-yl-acetic acid was used instead. ^]H NMR (300 MHz, CDC1₃) δ 8.50 (dd, 1H, J = 4.86 Hz, J = 0.91 Hz), 8.37 (d, 1H, J = 8.51 Hz), 8.09 (s, 1H), 7.94 (d,

-1101H, J = 7.89 Hz), 7.87 (s, 1H), 7.73-7.79 (m, 3H), 7.25-7.60 (m, 10H) 3.86 (s, 2H).

MS (ESI) [M+H]/z Calc’d 459, found 459. Anal. Calc’d: C, 75.97. H, 4.84. N, 12.22.

Found: C, 74.70. H, 4.83. N, 11.99.

Example 19(h): 6-[3-(2-methylpropionamido)benz{)yl]-3-E-styryl-lEf-indazole

<img file="MY139999A_D0140.tif" />

Example 19(h) was prepared in a similar manner to Example 19(a).

Isobutyryl chloride was used instead of acetyl chloride. Ή NMR (300 MHz, DMSOd6) δ 8.38 (d, 1H, J = 8.13 Hz), 8.08 (t, 1H), 7.96 (s, 1H, J = 7.8 Hz, J = 1.91 Hz),

7.88 (s, 1H), 7.75 (d, 2H, J = 7.25 Hz), 7.61 (d, 2H, 2.05 Hz), 7.40-7.58 (m, 5H), 7.31 (m, 1H), 2.60 (m, 1H, J = 6.82 Hz), 1.1 (d, 6H, J = 6.82 Hz). (MS (ESI+) [M+Na]/z

Calc’d 432, found 432. Anal. Calc’d: C, 76.26. H, 5.66. N, 10.26. Found: C, 75.14.

H, 5.62. N, 10.08.

Example 19(1): 6-[3-(2-acetamido-2-phenylacetamido)benzoyl]-3-E-styryl-l/7indazole

<img file="MY139999A_D0141.tif" />

Example 19(i) was prepared in a similar manner to Example 19(d) except that acetylamino-2-phenyl-acetic acid was used instead of 5-methyl-thiazole-2-carboxylic acid. Ή NMR (300 MHz, DMSO-d₆) δ 13.5 (s, 1H), 10.6 (s, 1H), 8.66 (d, 1H, J = 7.66 Hz), 8.36 (d, 1H, J = 8.47 Hz), 8.07 (s, 1H), 7.92 (d, 1H, J = 7.63 Hz), 7.86 (s,

-1111H), 7.75 (d, 2H, J = 7.33 Hz), 7.29-7.60 (m, 13H), 5.61 (d, IH, J = 7.6 Hz), 1.92 (s, 3H). LCMS (ESI+) [M+H]/z Calc’d 515, Found 515. Anal. Calc’d: C, 74.69. H,

5.09. N, 10.89. Found: C, 73.01. Η, 5.01.N, 10.60.

Example 19(j): 6-[3-(pyridin-4-ylcarboxamido)benzovl]-3-E-styryl-l/f-indazole

<img file="MY139999A_D0142.tif" />

Example 19(j) was prepared in a similar manner to Example 19(d) except that isonicotinic acid was used instead of 5-methyl-thiazo]e-2-carboxylic acid. MS (ESI+) [M+Na]/z Calc’d 467, Found 467. Anal. Calc’d: C, 75.66; H, 4.54; N, 12.60. Found:

C, 74.17; H, 4.62; N, 12.31.

Example 19(k): 6-[3-(pyridin-2-ylcarboxamido)benzoyl]-3-E-styryl-l/i-indazoIe

<img file="MY139999A_D0143.tif" />

Example 19(k) was prepared in a similar manner to Example 19(d) except that pyridine-2-carboxylic acid was used instead of 5-methyl-thiazole-2-carboxylic acid.

MS (ESI+) [M+Na]/z Calc’d 467, Found 467. Anal. Calc’d: C, 75.66; H, 4.54; N,

12.60. Found: C, 74.17; H, 4.61; N, 12.44.

Example 19(1): 6-[3-(isoxazol-4-ylcarboxamido)benzoyl]-3-E-styryl-l/i-indazole

-112-

<img file="MY139999A_D0144.tif" />

Example 19(1) was prepared in a similar manner to Example 19(d) except that isoxazole-5-carboxylic acid was used instead of 5-methyl-thiazole-2-carboxylic acid. MS (ESI+) [M+H]/z Calc’d 435, Found 435. Anal. Calc’d: C, 71.88; H, 4.18; N,

12.90. Found: C, 71.36; H, 4.33; N, 12.47.

Example 19(m): 6-[3-(6-chloropyridin-2-yIcarboxamido)benzoyl]-3-E-styrvI-177indazole

<img file="MY139999A_D0145.tif" />

<img file="MY139999A_D0146.tif" />

Example 19(m) was prepared in a similar manner to Example 19(d) except that 6-chloro-pyridine-2-carboxylic acid was used instead of 5-methyl-thiazole-2carboxylic acid. MS (ESI+) [M+Na]/z Calc’d 501, Found 501.

Example 19(n): 6-[3-(4-chIoropyridin-2-yIcarboxamido)benzoyl]-3-E-styryl-177indazole

<img file="MY139999A_D0147.tif" />

Example 19(n) was prepared in a similar manner to Example 19(d) except 4chloro-pyridine-2-carboxylic acid was used instead of 5-methyl-thiazole-2-carboxylic

-113acid. MS (ESI+) [M+H]/z Calc’d 479, Found 479. Anal. Calc’d: C, 70.22; H, 4.00;

N, 11.70. Found: C, 70.07; H, 4.09; N, 11.64.

Example 19(o): 6-[3-(2-chloropyridin-4-ylcarboxamido)benzoyl]-3-E-styryl-l/Zindazole

<img file="MY139999A_D0148.tif" />

Example 19(o) was prepared in a similar manner to Example 19(d) except 2chloro-isonicotinic acid was used instead of 5-methyl-thiazole-2-carboxylic acid. MS (ESI+) [M+H]/z Calc’d 479, Found 479.

Example 19(p): 6-(3-(2-methylamino-2-phenylaceramido)benzoyl]-3-E-styryl-l/Z10 indazole

<img file="MY139999A_D0149.tif" />

To a solution of 6-[3-(2-(N-z-butoxycarbonyl-N-methylamino)-2-phenylacetamido)benzoyl]-3-E-styryl-177-indazole (115 mg, 0.2 mmol) in CH₂C1₂ (2 ml) cooled to 0 °C was added TFA (2 ml). After 40 min. the reaction mixture was quenched with saturated NaHCO₃ (aq), then extracted with CH₂C1₂ (2x10 ml). The Organics were washed with brine, dried with Na₂SO_il5 decanted and concentrated. Purification by silica gel chromatography (1:10 methanol-dichloromethane) gave 6[3-(2-methylamino-2-phenylacetamido)benzoyl]-3-E-styryl-17Y-indazole (38 mg,

-11439%). MS (ESI+) [M+H]/z Calc’d 487, Found 487. Anal. Calc’d: C, 76.52; H, 5.39;

N, 11.51. Found: C, 74.99; H, 5.76; N, 10.89.

The starting material was prepared as described below:

(i) 6-[3-(2-(N-r-butoxycarbonyl-N-methylamino)-2-phenyl5 acetamido)benzoyl]-3-E-styryl-177-indazole

<img file="MY139999A_D0150.tif" />

<img file="MY139999A_D0151.tif" />

6-[3-(2-(N-/-butoxycarbony]-N-methylamino)-2-phenyl-acetamido)benzoyl]-3-Estyryl-177-indazole was prepared in a similar manner to Example 19(d) except that (tbutoxycarbonyl-methyl-amino)-phenyl-acetic acid was used instead of 5-methyl10 thiazole-2-carboxylic acid. MS (ESI+) [M+H]/z Calc’d 587, Found 587.

Example 20(a): 6-(3-Acetamido-phenylsulfanyl)-3-styryl-177-indazole

<img file="MY139999A_D0152.tif" />

6-(3-Acetamido-phenylsulfanyl)-3 -styryl-1 -[2-(trimethyl-silanyl)ethoxymethyl]-177-indazole was converted to 6-(3-acetamido-phenylsulfanyl)-315 styiyl-177-indazole as described in Example 11 (30 mg, 81%): Ry sm 0.65, p 0.35 (10% methanol in dichloromethane); ^]HNMR (300 MHz, CDCI3) δ 7.81 (d, 1H, J =

8.5 Hz), 7.59 (bs, 1H), 7.48-7.0 (m, 13H), 1.98 (s, 3H); HRMS (FAB) [M+Na]/z

Calc’d 408.1147, Found 408.1156.

The starting material was prepared as follows:

-115(i) ο

<img file="MY139999A_D0153.tif" />

To the 9-BBN adduct of 3-phthalamido-thiophenol (1.4 equiv), which was prepared in situ as described below, was added 3,6-Diiodo-l-[2-(trimethyl-silanyl)ethoxymethyl]-l/7-indazole (250 mg, 0.5 mmol), Pd(dppf)Cl₂ (87 mg, 0.2 equiv) and potassium phosphate (339 mg, 1.6 mmol, 3.00 equiv) in DMF (3.0 mL). The reaction mixture was heated to 90 °C for 9 h. The mixture was cooled and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic material was dried over sodium sulfate, decanted and concentrated. Purification by silica gel chromatography (2:8 ethyl acetate-hexane) gave 6-(3-phthalamido-phenylsulfanyl)-3iodo-177-indazole as an oil (159 mg, 50%): ^JH NMR (300 MHz, CDCI3) δ 7.93 (m,

2H), 7.79 (m, 2H), 7.62 (s, 1H), 7.5-7.3 (m, 5H), 7.22 (d, 1H), 5.68 (s, 2H), 3.55 (t,

2H, J = 8.2 Hz), 0.87 (t, 2H, J = 8.2 Hz), -.06 (s, 9H); HRMS (FAB) [M+Cs]/z Calc’d

759.9563, found 759.9571.

The boron reagent was prepared as follows: In a 10 mL Schlenk flask 3phthalamido-thiophenol was dried under high vacuum. To this was added a solution of 9-BBN (0.5 M in THF, 1.6 mL, 1.0 equiv). The mixture was heated to 55 °C for 2

h. The volatile material was removed under a stream of argon at 70 °C for 1.5 h. The residue was used without further manipulation.

(ii)

-116-

<img file="MY139999A_D0154.tif" />

<img file="MY139999A_D0155.tif" />

6-(3-Phthalamido-phenylsulfanyl)-3-iodo-17T-indazole was converted to 6-(3phthalamido-phenylsulfanyl)-3-styryl-l/Y-indazole as described in Example 11, step (iii). ^JH NMR (300 MHz, CDC1₃) δ 7.93 (m, 3H), 7.78 (m 2H), 7.7 (s, IH), 7.58 (m,

2H), 7.47-7.26 (m, 10H), 5.71 (s, 2H), 3.59 (t, 2H, J = 8.2 Hz), 0.89 (t, 2H, J = 8.2

Hz), -0.06 (s, 9H); HRMS (FAB) [M+Cs]/z Calc’d 735.1066, found 736.1058.

(iii)

<img file="MY139999A_D0156.tif" />

To a solution of 6-(3-phthalamidophenylsulfanyl)-3-styryl-177-mdazole (121 10 mg, 0.2 mmol) in ethanol (3.5 mL) was added hydrazine (63 pL, 2.0 mmol, 10 equiv). The reaction mixture was allowed to stir at 23 °C for 45 min and was diluted with saturated sodium bicarbonate and ethyl acetate. The organic material was dried over sodium sulfate, decanted and concentrated. Purification by silica gel chromatography (3:7 ethyl acetate-hexane) gave 6-(3-aminophenylsulfanyl)-3-styryl15 17T-indazole as an oil (79 mg, 90%); ^jH NMR (300 MHz, CDCI3) δ 7.92 (d, IH, J =

8.5 Hz), 7.57 (m, 3H), 7.49 (d, IH, J = 16.8 Hz), 7.4-7.25 (m, 4H), 7.23 (dd, IH, J =

1.5, 8.5 Hz), 7.11 (t, IH, J = 7.9 Hz), 6.79 (m, IH), 6.70 (t, IH, J = 1.9 Hz), 6.59 (m,

IH), 5.66 (s, 2H), 3.60 (bs, 2H), 3.59 (t, 2H, J = 8.2 Hz), 0.90 (t, 2H, J = 8.2 Hz), 0.05 (s, 9H); HRMS (FAB) [M+H]/z Calc’d 474.2035, found 474.2019.

-117(iv)

<img file="MY139999A_D0157.tif" />

<img file="MY139999A_D0158.tif" />

To a solution of 6-(3-aminophenylsulfanyl)-3-styryl-lE7-indazole (43.7 mg,

0.10 mmol) in diehloromethane (0.5 mL) was added pyridine (81 pL, 1.0 mmol, 10 equiv), and acetic anhydride (47 pL, 0.5 mmol, 5 equiv). The mixture was allowed to stir for 10 min at 23 °C. The mixture was diluted with water”md the product was extracted with 30% hexane in ethyl acetate. The organic material was washed with

5% citric acid and saturated sodium bicarbonate. The organic material was dried over sodium sulfate, decanted and concentrated. Purification by silica gel chromatography (3:7 ethyl acetate-hexane) gave 6-(3-acetamido-phenylsulfany 1)-3styryl-177-indazole as an oil (50 mg, 97%): R/' sm 0.33, R/p 0.18 (ethyl acetatehexane 3:7); ^JH NMR (300 MHz, CDC1₃) δ 7.94 (d, 1H), 7.65-7.1 (m, 13H), 5.70 (s,

2H), 3.62 (t, 2H, J = 8.2 Hz), 2.18 (s, 3H), 0.93 (t, 2H, J = 8.2 Hz), -0.05 (s, 9H).

HRMS (FAB) [M+Cs]/z Calc’d 648.1117, found 648.1098.

Example 20(b): 6-(3-(Benzoylamido)-phenylsulfanyl)-3-styryI-l/f-indazoIe

<img file="MY139999A_D0159.tif" />

The title compound was prepared like Example 20(a),, except that benzoyl chloride was used instead of acetic anhydride in step (iv). *H NMR (300 MHz,

CDCI3) δ 8.03 (s, IH), 7.73 (d, 1H, J = 8.5 Hz), 7.63 (m, 2H). 7.47 (m, 1H), 7.42 (t,

-1181H, J = 1.9 Hz), 7.37 (m, 3H), 7.31 (m, 1H), 7.28-6.98 (m, 9H); HRMS (FAB) [M+H]/z Calc’d 448.1484, found 448.1490.

Example 21: 6-(l-(3-Aminophenyl)-vinyl)-3-styryl-l/7-indazole

<img file="MY139999A_D0160.tif" />

TBAF, h₂N nh₂

<img file="MY139999A_D0161.tif" />

6-(l-(3-Aminophenyl)-vinyl)-3-styryl-l-[2-(trimethyl-silanyl)-ethoxymethyl]177-indazole was converted to the title compound as described for Example 11 (85 mg, 85%): Ry sm 0.72, p 0.37 (ethyl acetate-hexane 1:1); FTIR (thin film) 3385,

3169, 2953, 1621, 1581, 1489, 1447, 1349, 1251, 1165, 1071, 959, 906, 870, 817 cm

1; ^JH NMR (300 MHz, CDC1₃) δ 7.98 (d, 1H,J = 8.5 Hz), 7.60 (m, 2H), 7.51 (s, 1H),

7.48 (s, 1H), 7.40 (m, 3H), 7.29 (m, 2H), 7.15 (m, 1H), 6.78 (m, 1H), 6.68 (m, 2H),

5.50 (s, 2H), 3.65 (bs, 2H); MS (ES) [M+H]/z Calc’d 338, found 338; MS (ES) [MH]/z Calc’d 336, found 336.

The starting material was prepared as follows:

(i)

SEM

<img file="MY139999A_D0162.tif" />

n-BuLi, ZnQJ Pd(PPIg)₄

SEM

<img file="MY139999A_D0163.tif" />

To a solution of 6-iodo-3-styryl-l-[2-(trimethyl-silanyl)-ethoxymethyl]-177indazole, prepared in Example 14, step (i), (330 mg, 0.693 mmol) in THF (3.0 mL) at -78 °C was added n-butyllithium (0.56 mL, 1.5 M, 1.2 equiv). After 20 min, this solution was then added to anhydrous zinc chloride (170 mg) and the mixture was

-119warmed to 23 °C and stirred for 15 min. To this mixture was added l-(3-nitrophenyl)vinyltriflate (146 pL, 1.05 equiv) and Pd(PPh₃)₄ (40 mg, 0.05 equiv). This mixture was stirred for 30 min, was partitioned between ethyl acetate and saturated sodium bicarbonate and the organic layer was separated. The organic material was dried over sodium sulfate, decanted and concentrated under reduced pressure.

Purification by silica gel chromatography (1:9 ethyl acetate-hexane) then a second column (1% ethyl acetate/benzene) gave 6-(l-(3-nitrophenyl)-vinyl)-3-styryl-l-[2(trimethyl-silanyl)-ethoxymethyl]-177'-indazole as an oil (180 mg, 52%): FTIR (thin film) 2951, 1616, 1530, 1477, 1448, 1348, 1305, 1248, 1217, 1077, 961, 913, 859 cm-¹; ^]Η NMR (300 MHz, CDCI3) δ 8.26 (t, IH, J= 1.9 Hz), 8.21 (m, IH), 8.00 (d,

IH, J = 8.5 Hz), 7.69 (dt, IH, J = 1.4, 7.8), 7.62-7.28 (m, 9H), 7.19 (dd, IH, J = 1.4, 8.4 Hz), 5.72 (s, 3H), 5.69 (s, IH), 3.60 (t, 2H, J = 8.2 Hz), 0.89 (t, 2H, J = 8.2 Hz), 0.05 (s, 9H); ¹³C NMR (75 MHz, CDCI3) δ 149.9, 149.6, 144.7, 144.5, 142.8, 140.7,

138.6, 135.6, 133.1, 130.7, 130.2, 129.4, 128.0, 124.4, 124.2, 124.1, 123.8, 122.6,

121.2, 118.9, 111.0,79.2,68.0, 19.2, 0.0; HRMS (FAB) [M+Na]/z Calc’d 520.2031, found 520.2046.

(ii)

<img file="MY139999A_D0164.tif" />

6-(l-(3-Nitrophenyl)-vinyl)-3-styryl-l-[2-(tnmethyl-silanyl)-ethoxymethyl]20 1/7-indazole was converted to 6-(l-(3-aminophenyl)-vinyl)-3-styryl-l-[2-(trimethylsilanyl)-ethoxymethyl]-lF/'-indazole as described in Example 11, step (iv) (140 mg,

-12095%): Ry sm 0.59, p 0.46 (ethyl acetate-hexane 4:6); FTIR (thin film) 3460, 3366,

3223, 3084, 3028, 2952, 2894, 2246, 1616, 1601, 1581, 1489, 1474, 1448, 1359,

1303, 1249, 1217, 1076, 961, 909, 860, 836, 733, 692 cm'¹; ’HNMR (300 MHz,

CDC1₃) δ 7.96 (d, 1H, J = 8.5 Hz), 7.59 (m, 3H), 7.50 (s, 1H), 7.46 (s, 1H), 7.40 (m,

2H), 7.30 (m, 1H), 7.25 (m, 1H), 7.14 (m, 1H), 6.77 (m, 1H), 6.68 (m, 2H); ’³C NMR (75 MHz, CDCI3) δ 151.6, 147.7, 144.6, 143.9, 142.8, 142.4, 138.6, 132.8, 130.6,

130.2, 129.3, 128.0, 124.4^ 123.6,121.9, 121.5, 120.2,116.4, 116.1, 110.8, 79.0,67.9, 19.2,0.0; HRMS (FAB) [M+Na]/z Calc'd 490.2291, found 490.2302.

Example 22(a): 6-(l-(3-(5-Methvl-thiaxole-2-carboxoylamido)phenyl)-vinyl)-310 styryl-l/7-indazole

<img file="MY139999A_D0165.tif" />

<img file="MY139999A_D0166.tif" />

<img file="MY139999A_D0167.tif" />

6-(l-(3-Aminophenyl)-vinyl)-3-styryl-l/7-indazole was converted to the title compound as described in Example 12(d) (20 mg, 72%): FTIR (thin film) 3271,

1673, 1605, 1585, 1538, 1486, 1428, 1349, 1304, 1090, 960, 907, 871 cm-’; Ή

NMR (300 MHz, CDCI3) δ 10.7 (bs, 1H), 9.09 (s, 1H), 8.0 (d, 1H), 7.79 (m, 1H),

7.60 (m, 3H), 7.51 (m, 3H), 7.44-7.15 (m, 7H), 5.59 (s, 2H), 2.54 (s, 3H); ’³C NMR (75 MHz, CDCI3) δ 162.2, 157.9, 149.8, 144.4, 142.8, 142.2, 141.9, 141.5, 140.6,

137.63, 137.56, 131.6, 129.5, 129.1, 128.3, 126.9, 125.1, 122.6, 121.2, 120.9, 120.5,

120.2, 119.8, 116.1, 110.2, 12.8; HRMS (FAB) [M+H]/z Calc'd 463.1593, found

463,1582.

-121Example 22(b): 6-(l-(3-(Benzoylamido)phenyl)-vinyl)-3-styryl-l//-indazole

<img file="MY139999A_D0168.tif" />

<img file="MY139999A_D0169.tif" />

Example 22(b) was prepared in a similar manner to that described for

Example 22(a), except that benzoyl chloride was used instead of 5-methyl-thiazole-2 carboxylic acid and HATU. FTIR (thin film) 3243, 1651, 1606, 1580, 1538, 1485,

1447, 1428, 1349, 1307, 1258, 1073, 959, 907 cm’¹; ^]HNMR (300 MHz, CDC1₃) δ

9.09 (s, 1H), 7.99 (d, 1H, J = 8.5 Hz), 7.78 (m, 1H), 7.60 (m, 3H), 7.51 (m, 3H), 7.43

7.15 (m, 10H), 5.56 (d, 2H, J = 3.2 Hz); ¹³C NMR (75 MHz, CDCI3) δ 166.5, 149.7,

144.3, 142.7, 142.1, 140.6, 138.1, 137.6, 135.0, 132.3, 131.6, 129.4, 129.1, 128.3,

127.4, 126.9, 125.0, 122.5, 120.9, 120.8, 120.6, 120 5, 115.9, 110.2; HRMS (FAB) [M+H]/z Calc’d 442.1919, found 442.1919.

Example 22(c): e-U-iS-fBenzoylamidolphenyD-vinyO-S-styryl-l/f-indazoIe

<img file="MY139999A_D0170.tif" />

<img file="MY139999A_D0171.tif" />

The title compound was prepared in a similar manner to that described for

Example 22(a), except that carbobenzyloxy chloride was used instead of 5-methylthiazole-2-carboxylic acid and HATU. FTIR (thin film) 3305, 1712, 1606, 1586,

1537, 1487, 1445, 1348, 1216, 1059, 959, 908 cm’¹, ’HNMR (300 MHz, CDCI3) δ

7.99 (d, 1H, J = 8.5 Hz), 7.6-7.0 (m, 18H), 5.55 (s, 2H), 5.19 (s, 2H); ¹³C NMR (75

MHz, CDCI3) δ 153.9, 149.8, 144.3, 142.7, 142.1, 140.7, 138.2, 137.6, 136.3, 131.7,

-122129.4, 129.1, 129.0, 128.7, 128.7, 128.3, 126.9, 124.0, 122.6, 121.1,120.8, 120.4,

115.9, 110.1, 67.4; HRMS (FAB) [M+H]/z Calc’d 472.025, found 472.2026. Example 23: 6-(l-(3-Acetamido-phenyl)-vinyl)-3-:;tyryl-l/f-indazole

<img file="MY139999A_D0172.tif" />

6-(l-(3-Acetamido-phenyl)-vinyl)-3-styryl-l-[2-trimethylsilanyl- ethoxymethyl]-177-indazole was converted to 6-(l-(3-acetamido-phenyl)-vinyl)-3styryl-177-indazole as described for Example 11: FTIR (thin film) 3252, 1667, 1606,

1557, 1486 cm-¹; ^JH NMR (300 MHz, CDC1₃) δ 10.4 (bs, 1H), 7.91 (d, 1H, J= 8.5

Hz), 7.5-7.0 (m, 13H), 5.47 (s, 2H), 2.10 (s, 3H); MS (ES) [M+H]/z Calc’d 380, found

380; [M-H]/z Calc’d 378, found 378.

The starting material was prepared as follows:

<img file="MY139999A_D0173.tif" />

<img file="MY139999A_D0174.tif" />

6-(l-(3-Aminophenyl)-vinyl)-3-styryl-l-[2-trimethylsilanyl-ethoxymethyl]1/7-indazole was converted to 6-(l-(3-acetamido-phenyl)-vinyl)-3-styryl-l-[215 trimethylsilanyl-ethoxymethyl]-l A-indazole as described for Example 12(a): Ry sm

0.42, p 0.26 (ethyl acetate-hexane 4:6); FTIR (thin film) 3305, 3059, 2952, 1667,

1608, 1585, 1555, 1486, 1448, 1433, 1369, 1306, 1249, 1076, 912, 859, 836, 748,

693 cm-¹; ^JH NMR (300 MHz, CDCI3) δ 7.98 (d, 1H, J = 8.5 Hz), 7.7-7.4 (m, 9H),

7.35 (m, 2H), 7.26 (dd, 1H, J = 1.3, 8.4 Hz), 7.16 (bd, 1H, J = 7.8 Hz), 5.75 (s, 2H),

-1235.62 (s, 1H), 5.61 (s, 1H), 3.66 (t, 2H, J = 8.2 Hz), 2.16 (s, 3H), 0.98 (t, 2H, J= 8.2 Hz), -0.02 (s, 9H); ¹³C NMR (75 MHz, CDC1₃) δ 169.8, 150.9, 144.6, 143.5, 142.8,

142.0, 139.4, 138.6, 132.9, 130.3, 129.3, 127.9, 125.6, 124.2, 123.7, 122.0, 121.3,

121.0, 117.1, 110.8,68.0,25.8, 19.1, 0.0; HRMS (FAB) [M+Na]/z Calc’d 532.2396, found 532.2410.

Example 24(a): 4-[3-(l-J7-Benzoimidazol-2-yl)-l-.H^r-indazol-6-yl]-2-methoxy5-methyl-phenol

<img file="MY139999A_D0175.tif" />

<img file="MY139999A_D0176.tif" />

6-{5-Methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]10 phenyl}-1 -[2-(trimethyl-silanyl)-ethoxymethyl]-3-{ 1 -[2-(trimethyl-silanyl)ethoxymethyl]-l-Z/-benzamidazol-2-yl}-l-//'-indazole (326 mg, 0.43 mmol) was stirred in a solution of TBAF (4.5 mL of 1 M in THF, which was concentrated in vacuo to 2.5 mL) and ethylenediamine (0.6 mL, 8.9 mmol) at reflux for 40 h. The reaction was diluted with ethyl acetate/THF (40 mL/5 mL) and washed with H₂O (20 mL) and brine (20 mL). Organics were dried (MgSO₄) and concentrated in vacuo. Purification by silica gel chromatography (60% THF/hexanes) and then precipitation from chloroform gave 108 mg (68%) cf 4-[3-(l-/7-benzoimidazol-2yl)-l-77-indazol-6-yl]-2-methoxy-5-methyl-phenol as a white solid. 'HNMR

-124(300 MHz, DMSO-J5) δ 13.62 (s, 1 Η), 13.05 (br s, 1 H), 9.01 (s, 1 H), 8.50 (d, 1

H, J = 8.4 Hz), 7.62 (br s, 2 H), 7.49 (s, 1 H), 7.28-7.20 (m, 3 H), 6.85 (s, 1 H),

6.74 (s, 1 H), 3.77 (s, 3 H), 2.15 (s, 3 H). Anal. (C₂₂H₁₈N₄O₂ 1.3 H₂O) C, Η, N.

Calculated: C, 67.10; H, 5.27; N, 14.23. Found: C, 67.30; H, 5.27; N, 14.11.

The starting materials were prepared as follows:

(i)

<img file="MY139999A_D0177.tif" />

1) n-BuLi, THF

2) l_; ·&gt;

SEM

<img file="MY139999A_D0178.tif" />

Preparation of 2-iodo-l-[2-(trimethyl-silanyl)-ethoxymethyl]-l/7benzoimidazole. A solution of l-[2-(trimethyl-silanyl)-ethoxymethyl]-l/710 benzoimidazole (5.029 g, 20.25 mmol) (see Witten et al., J. Org. Chem., 51,

1891-1894 (1986)) in THF (50 mL) was cooled to -78 C and added dropwise over 12 min via cannula to a flask containing n-butyllithium (2.5 M in hexanes, 12.2 mL) in THF (30 mL) at -78 C under argon. After stirring for 25 min at -78 C, the flask was warmed to 0 C for 10 min, then cooled again to-78 C. This solution was then added via cannula to a second flask containing iodine (25.7 g,

101 mmol) in THF (50 mL) at -78 C. Once the addition was complete (-5 min), the cooling bath was removed, and stirring was contmued for 30 min. The reaction mixture was partitioned between ethyl acetate (500 mL) and water (100 mL). The organic layer was washed with saturated aqueous sodium metabisulfite (2 x 100 mL) to remove the dark iodine color, dried (MgSO₄), and concentrated in vacuo. Purification by flash chromatography (10% to 50% ethyl acetate/hexanes) yielded 4.79 g (63%) of pure 2-iodo-l-[2-(trimethyl-silanyl)-ethoxymethyl]-177-125benzoimidazole as a yellow solid. 'H NMR (300 MHz, CDC1₃) δ 7.76-7.72 (m, 1 H), 7.54-7.51 (m, 1 H), 7.29-7.25 (m, 2 H), 5.54 (s, 2 H), 3.59 (t, 2 H, J = 8.1 Hz), 0.92 (t, 2 H, J= 8.1 Hz), -0.03 (s, 9 H). Anal. (C₁₃H₁₉IN₂OS) C, H. Calculated:

C, 41.71; H, 5.12; I, 33.90; N, 7.48. Found: C, 41.90; H, 5.09; I, 34.00; N, 7.37.

(ii)

<img file="MY139999A_D0179.tif" />

NO]

Preparation of 6-nitro-l-[2-(trimethyl-silanyl)-ethoxymethyF|-3-(trimethylstannanyl)-l -//-indazole: 3-Iodo-6-mtro-l-[2-(trimethyl-silanyl)-ethoxymethyl]1-//-indazole (10.0 g, 23.9 mmol) and hexamethylditin (10.0 g, 30.5 mmol) were 10 combined with dry toluene (45 mL) in a flask purged with argon.

Tetrakis(triphenylphosphine)-palladium(0) (300 mg, 0.26 mmol) was added, and the reaction stirred at reflux under argon for 2.5 h. The reaction was cooled to 23

C and diluted with ether (60 mL). Organics were washed with 0.1 N HCI (20 mL) and brine (20 mL), dried (MgSO₄), and concentrated. Purification by silica gel chromatography (3% to 8% ether/hexanes) gave 7.70 g (71%) of 6-nitro-l-[2(trimethyl-silanyl)-ethoxymethyl]-3-(trimethyl-stannanyl)-l-//-indazole as a faintly yellow solid. Ή NMR (300 MHz, CDC1₃) δ 8.53 (d, 1 H, J = 1.8 Hz),

8.03 (dd, 1 H, J = 8.7, 1.8 Hz), 7.81 (d, 1 H, J = 8.7 Hz), 5.84 (s, 2 H), 3.58 (t, 2

H, J = 8.1 Hz), 0.90 (t, 2H,J = 8.1 Hz), 0.50 (t, 9 H, J = 28.2 Hz), -0.05 (s, 9 H).

Anal. (C₁₆H₂₇N₃O₃SiSn) C, Η, N. Calculated: C, 42.13; H, 5.97; N, 9.21. Found:

C, 42.39; H, 6.01; N, 9.26.

-126(iii)

Cul (Ph^Pd*

<img file="MY139999A_D0180.tif" />

<img file="MY139999A_D0181.tif" />

SEM

<img file="MY139999A_D0182.tif" />

THF

T= N / \ &lt;^ⁿ'SEM

Preparation of 6-nitro-l-[2-(trimethyl-silanyli-ethoxymethyl]-3-{l-[2(trimethyl-silanyl)-ethoxymethyl]-l-/7-benzoimidazol-2-yl}-l-/7-indazole: 6Nitro-1 -[2-(trimethyl-silanyl)-ethoxymethyl]-3 -(trimethyl-stannanyl)-1 -Hindazole (7.50 g, 16.4 mmol), 3-iodo-l-[2-(trimethyl-silanyl)-ethoxymethyl]-l-77benzimidazole (6.50 g, 17.4 mmol), and copper® iodide (313 mg, 1.64 mmol) were combined with dry THF (150 mL) in a flask purged with argon. Tetrakis(triphenylphosphine)palladium(0) was added, and the reaction stirred at reflux under argon for 23 h. The reaction was cooled and adsorbed directly onto silica gel (~ 16 g). Purification by silica gel chromatography (4% to 15% ethyl acetate/hexanes) gave 7.28 g (82%) of 6-nitro-l-[2-(trimethyl-silanyl)ethoxymethyl] -3 - {1 -[2-(trimethyl-silanyl)-ethoxymethyl]-1 -77-benzoimidazol-2yl}-l-/7-indazole as a light yellow solid. 'H NMR (300 MHz, CDC1₃) δ 8.91 (d,

H, J = 9.0 Hz), 8.59 (d, 1 H, J = 1.8 Hz), 8.22 (dd, 1 H, J = 8.7, 1.8 Hz), 7.927.89 (m, 1 H), 7.66-7.62 (m, 1 H), 7.40-7.36 (m, 2 H), 6.24 (s, 2 H), 5.90 (s, 2 H),

3.68-3.59 (m, 4 H), 0.94 (t, 2 H, J = 8.1 Hz), 0.86 (t. 2 H, J = 8.1 Hz), -0.04 (s, 9

H), -0.15 (s, 9 H). Anal. (C₂₆H₃₇N₅O₄Si₂) C, Η, N. Calculated: C, 57.85; H, 6.91;

N, 12.97. Found: C, 57.60; H, 6.81; N, 12.82.

(iv)

-127-

<img file="MY139999A_D0183.tif" />

<img file="MY139999A_D0184.tif" />

Preparation of 6-Amino-l-[2-(trimethyl-siianyl)-ethoxymethyl]-3-{l-[2(trimethyl-silanyl)-ethoxymethyl]-1 -77-benzoimidazol-2-yl} -1 -77-indazole:

Tin(II) chloride (12.0 g, 63.3 mmol) was added to a solution of 6-nitro-l-[25 (trimethyl-silanyl)-ethoxymethyl]-3-{l-[2-(trimethyl-silanyl)-ethoxymethyl]-l-L7benzoimidazol-2-yl}-l-77-indazole (7.18 g, 13.3 mmol) in DMF/H₂O (160 mL/10 mL), and the reaction stirred at 50 C for 2.5 h. The reaction was cooled to 0 C, and saturated sodium bicarbonate was added slowly, with mixing, until all frothing from quenching had subsided. The material was concentrated in vacuo and taken up in ether (100 mL). Insoluble material was removed by filtration and rinsed with ether (50 mL). The filtrate was washed with brine (50 mL), dried (Na₂SO₄), and concentrated in vacuo. Purification by silica gel chromatography (25% ethyl acetate/hexane) gave 6.05 g (89%) of 6-amino-l-[2-(trimethylsilanyl)-ethoxymethyl]-3 - {1 -[2-(trimethyl-silanyl)-ethoxymethyl]-1 -H15 benzoimidazol-2-yl}-l-77-indazole as a faintly yellow waxy solid. ’H NMR (300

MHz, CDC1₃) δ 8.40 (d, 1 H, J = 9.0 Hz), 7.89-7.86 (m, 1 H), 7.63-7.60 (m, 1 H),

7.35-7.31 (m, 2 H), 6.78 (dd, 1 H, J = 8.7, 1.8 Hz), 6.75 (s, 1 H), 6.25 (s, 2 H),

5.69 (s, 2 H), 3.93 (br s, 2 H), 3.65-3.55 (m, 4 H), 0.93 (t, 2 H, J = 8.1 Hz), 0.85 (t, 2 H, J = 8.1 Hz), -0.04 (s, 9 H), -0.15 (s, 9 H). Anal. (C₂₆H₃₉N₅O₂Si₂) C, Η, N.

Calculated: C, 61.26; H, 7.71; N, 13.74. Found: C, 61.18; H, 7.65; N, 13.82.

-128(v)

<img file="MY139999A_D0185.tif" />

2) KI, l₂

1) HCI, NaNOj H₂O , HOAc

<img file="MY139999A_D0186.tif" />

Preparation of 6-iodo-l-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{l-[2(trimethyl-silanyl)-ethoxymethyl]-l-7y-benzoimidazol-2-yl}-l-/y-indazole: A solution of 6-amino-l-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{l-[2-(trimethylsilanyl)-ethoxymethyl]-l-77'-benzoimidazol-2-yl}-l-rf-indazole (500 mg, 0.98 mmol) in acetic acid (1.5 mL) was diluted with H₂O (1.0 mL) and stirred at 0 C.

Concentrated HCI (250 pL, ~ 3 mmol) in H₂O (250 pL) was added. Sodium nitrate (90 mg, 1.3 mmol) in H₂O (300 pL) was added, and the reaction stirred for

8 min. Iodine (10 mg) and a solution of potassium iodide (250 mg, 1.3 mmol) in

H₂O (250 pL) were added, and the frothing reaction stirred for 30 min at 23 C.

The reaction was diluted with H₂O (25 mL) and extracted with ethyl acetate (2 x mL). Organics were washed with saturated sodium metabisulfite solution (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated in vacuo. Purification by silica gel chromatography (8% ethyl acetate/hexanes) gave 316 mg (52%) of 6-iodo-1 -[2-(trimethyl-silanyl)-ethoxymethyl]-3 - {1 - [2-(trimethyl-silanyl)ethoxymethyl]-l-77-benzoimidazol-2-yl}-l-7y-indazole as a faintly yellow oil, which slowly crystallized to a white solid. ’H NMR (300 MHz, CDC1₃) 5 8.45 (d, 1 H, J = 9.0 Hz), 8.05 (s, 1 H), 7.91-7.88 (m, 1 E), 7.67-7.62 (m, 2 H), 7.3820

7.34 (m, 2 H), 6.24 (s, 2 H), 5.77 (s, 2 H), 3.65-3.57 (m, 4 H), 0.93 (t, 2 H, J = 8.1

-129Hz), 0.85 (t, 2 H, J = 8.1 Hz), -0.04 (s, 9 H), -0.15 (s, 9 H). Anal.

(C₂₆H₃₇IN₄O₂Si₂) C, Η, N. Calculated: C, 50.31; H, 6.01; N, 9.03. Found: C,

50.55; H, 6.08; N, 9.00.

(vi)

Br

<img file="MY139999A_D0187.tif" />

OH

Br

SEM-CI , DIEA -&gt;CH₂CI₂ σ

<img file="MY139999A_D0188.tif" />

SEM

Preparation of [2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)ethylj-trimethyl-silane: 4-Bromo-2-methoxy-5-methyl-phenol (see Chien-Hsun et al., Syn. Lett., 12, 1351-1352 (1997)) was stirred in dry CH₂C1₂ (100 mL) at 23

C. DIEA (6.05 mL, 34.6 mmol), and then 2-(trimethylsilyl)ethoxymethyl chloride (5.6 mL, 31.7 mmol) were added. After stirring for 1 h, the solution was washed with H₂O, 0.1 N HCI, H₂O, saturated NaHCO₃, and brine (25 mL each). Organics were dried (Na₂SO₄) and concentrated in vacuo. Purification by silica gel chromatography (6% ethyl acetate/hexanes) gave 9.06 g (91%) of [2-(4bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane as a clear oil. ’HNMR (300 MHz, CDC1₃) δ 7.06 (s, 1 H), 7.02 (s, 1 H), 5.24 (s, 2 H), 3.84 (s, 3 H), 3.79 (t, 2 H, J = 8.4 Hz), 2.31 (s, 3 H), 0.96 (t, 2 H, J = 8.4 Hz), 0.01 (s, 9

H).

<img file="MY139999A_D0189.tif" />

2) B(OMe)₃

3) H₂O (vii)

SEM

-130Preparation of 5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)ethoxymethoxy]-phenyl-boronic acid: [2-(4-Bromo-2-methoxy-5-methylphenoxymethoxy)-ethyl]-trimethyl-silane (2.6 g, 7.5 mmol) was stirred in dry THF (10 mL) at-78 C under argon. n-Butyllithium (3.75 mL, 2.5 M in hexanes,

9.36 mmol) was added dropwise, and the reaction stiiTed for 30 min before it was transferred via cannula to a flask of trimethyl borate (8.4 mL, 75 mmol) in THF (15 mL), which was also stirring at-78 C under argon. After addition was complete, the reaction stirred 30 min at -78 C and then 30 min while warming to 0 C. It was then quenched with H₂O (20 mL), acidified with 0.1 N HCI, and extracted with ethyl acetate (2 x 25 mL). Organics were washed with brine (20 mL), dried (Na₂SO₄), and concentrated in vacuo. Purification by silica gel chromatography (20% to 50% ethyl acetate/hexanes) gave 1.11 g (47%) of 5methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid as a white solid. Ή NMR (300 MHz, CDC1₃) δ 7.78 (s, 1 H), 7.10 (s, 1 H), 5.36 (s, 2 H), 3.93 (s, 3 H), 3.83 (t, 2 H, J = 8.4 Hz), 2.79 (s, 3 H), 0.98 (t, 2 H, J = 8.4

Hz), 0.01 (s, 9 H). Anal. (C₁₄H₂₅BO₅Si - H₂O) C, H. Calculated: C, 57.15; H,

7.88. Found: C, 56.89; H, 7.87.

(viii)

-13110

<img file="MY139999A_D0190.tif" />

Preparation of 6-{5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)ethoxymethoxy]-phenyl} -1 -[2-(trimethyl-silanyl)-ethoxymethyI]-3 - {T -[2(trimethyl-silanyl)-ethoxymethyl]-1 -//-benzamidazol-2-yl} -1 -//’-indazole. 6Iodo-l-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{l-[2-(trimethyl-silanyl)ethoxymethyl]-l-//-benzoimidazol-2-yl}-l-//-indazole (350 mg, 0.56 mmol), 5methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid (211 mg, 0.68 mmol), and sodium carbonate (72 mg, 0.68 mmol) were stirred in a mixture of benzene (5 mL), H₂O (330 pL), and methanol (1 mL) in a flask purged with argon. Tetrakis(triphenylphosphine)palladium(0) was added, and the reaction stirred at reflux under argon for 16 h. After cooling to 23 C, the reaction was diluted with ether (20 mL), washed with H₂O (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated in vacuo. Purification by silica gel chromatography (15% ethyl acetate/hexanes) gave 382 mg (89%) of 6-{5methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl}-l-[2(trimethyl-silanyl)-ethoxymethyl]-3- {1 -[2-(trimethyl-silanyl)-ethoxymethyl]-l -Hbenzamidazol-2-yl}-l-//-indazole as a white solid. 'H NMR (300 MHz, CDC1₃) δ

8.68 (d, 1 H, J = 8.4 Hz), 7.93-7.90 (m, 1 H), 7.67-7.63 (m, 1 H), 7.54 (s, 1 H),

-1327.38-7.32 (m, 3 Η), 7.13 (s, 1 Η), 6.86 (s, 1 Η), 6.29 (s, 2 Η), 5.83 (s, 2 Η), 5.34 (s, 2 Η), 3.89 (s, 3 Η), 3.86 (t, 2 H, J = 8.4 Hz), 3.69-3.58 (m, 4 H), 2.22 (s, 3 H),

1.01 (t, 2 H, J = 8.4 Hz), 0.95-0.83 (m, 4 H), 0.03 (s, 9 H), -0.05 (s, 9 H), -0.15 (s,

H). Anal. (C^^N.OjSij) C, Η, N. Calculated: C, 63.12; H, 7.95; N, 7.36.

Found: C, 63.22; H, 7.93; N, 7.46.

Example 24(b): 4-[3-(l-F7-BenzoimidazoI-2-yl)-l-/7-indazoI-6-yI]-3-methylphenol

<img file="MY139999A_D0191.tif" />

To prepare the title compound, the procedure described for Example 24(a) was followed, with 2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenylboronic acid (prepared as described below) substituted for 5-methoxy-2-methyl-4-[2(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid in step (viii). ’HNMR (300

MHz, DMSO-4y) δ 13.60 (s, 1 H), 12.99 (brs, 1 H), 9.41 (s, 1 H), 8.49 (d, 1 H, J = 8.4 Hz), 7.72 (br s, 1 H), 7.52 (br s, 1 H), 7.45 (s, 1 H), 7.25-7.21 (m, 3 H), 7.12 (d, 1

H, J = 8.1 Hz), 6.73-6.67 (m, 2 H), 2.20 (s, 3 H). Anal. (C₂₁H₁₆N₄O 0.7 H₂O) C, H,

N. Calculated: C, 71.45; H, 4.97; N, 15.87. Found: C, 71.44; H, 4.96; N, 15.77. 2-Methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid was prepared as follows:

(i)

-133-

<img file="MY139999A_D0192.tif" />

<img file="MY139999A_D0193.tif" />

<img file="MY139999A_D0194.tif" />

[2-(4-Bromo-3-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane was prepared in 86% yield from 4-bromo-3-methyl-phenol according to the procedure for [2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane.

Ή NMR (300 MHz, CDC1₃) δ 7.39 (d, 1 H, J = 8.7 Hz), 6.93 (d, 1 H, J = 2.7 Hz), 6.75 (dd, 1 H, J = 8.7, 2.7 Hz), 5.16 (s, 2 H), 3.74 (t, 2 H, J = 8.4 Hz), 2?36 (s, 3 H), 0.95 (t, 2 H, J = 8.4 Hz), 0.01 (s, 9 H). Anal. (C_nH₂₁BrO₂Si) C, H.

Calculated: C, 49.21; H, 6.67. Found: C, 49.33; H, 6.67.

(H)

1) π-BuLi, THF -&gt;

2) B(OMe)₃

3) HjO

2-Methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid was prepared in 52% yield from [2-(4-bromo-3-methyl-phenoxymethoxy)-ethyl]trimethyl-silane according to the procedure for 5-methoxy-2-methyl-4-[215 (trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid above. 'HNMR (300

MHz, CDC1₃) δ 8.15 (d, 1 H, J = 8.1 Hz), 6.98-6.92 (m, 2 H), 5.29 (s, 2 H), 3.78 (t, 2 H, J = 8.4 Hz), 2.78 (s, 3 H), 0.98 (t, 2 H, J = 8.4 Hz), 0.01 (s, 9 H). Anal. (C₁₃H₂₃BO₄Si - H₂O) C, H. Calculated: C, 59.10; H, 8.01. Found: C, 59.07; H,

8.08.

-134Example 24(c): 4-[3-(l-H-Benzoimidazol-2-yl)-l-.fl'-indazol-6-yl]-2-chIoro-5methvl-phenol

<img file="MY139999A_D0195.tif" />

To prepare the title compound, 5-chloro-2-methyl-4-[2-(trimethyl-silanyl) 5 ethoxymethoxy]-phenyl-boronic acid, prepared as described below, was substituted for 5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]phenyl-boronic acid in the procedure described in Example 24(a), step (viii). ’H

NMR (300 MHz, DMSO-rftf) δ 13.61 (s, 1 H), 13.00 (br s, 1 H), 10.22 (s, 1 H),

8.51 (d, 1 H, J = 8.4 Hz), 7.64 (br s, 2 H), 7.50 (s, 1 H), 7.26-7.21 (m, 4 H), 6.95 (s, 1 H),2.19(s, 3H).

5-Chloro-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenylboronic acid was prepared as follows:

(i)

Br

<img file="MY139999A_D0196.tif" />

2-Chloro-5-methyl-phenol (6.68 g, 46.9 mmol) was stirred in acetonitrile (200 mL). ;V-Bromosuccinimide (8.5 g, 47.8 mmol) was added, and the reaction stirred for 45 min. The solution was concentrated in vacuo and re-dissolved in

-135chloroform (100 mL). Organics were washed with saturated NaHCO₃ (50 mL) and brine (50 mL), dried (MgSO₄), and concentrated in vacuo. Purification by silica gel chromatography (8% ethyl acetate/hexanes) gave 7.98 g (77%) of 4bromo-3-chloro-5-methyl-phenol as a clear oil. ’H NMR (300 MHz, CDC1₃) δ 5 7.47 (s, 1 H), 6.91 (s, 1 H), 5.52 (brs, 1 H), 2.32 (s, 3 H). Anal. (C₇H₆ClBrO 0.1

H_;O)C,H. Calculated: C, 37.66; H, 2.80. Found: C, 37.57; H, 2.82.

(ii)

<img file="MY139999A_D0197.tif" />

[2-(4-Bromo-2-chloro-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane 10 was prepared in 83% yield from 4-bromo-3-chloro-5-methyl-phenol according to the procedure for [2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]trimethyl-silane. Ή NMR (300 MHz, CDC1₃) δ 7.51 (s, 1 H), 7.09 (s, 1 H), 5.26 (s, 2 H), 3.79 (t, 2 H, J = 8.4 Hz), 2.35 (s, 3 H), 0.95 (t, 2 H, J = 8.4 Hz), 0.02 (s, 9 H). Anal. (C_]3H₂₀ClBrO₂Si) C, H. Calculated: C, 44.39; H, 5.73. Found: C,

45.08; H, 5.91.

(iii)

Br

Cl

<img file="MY139999A_D0198.tif" />

1) n-BuLi, THF -&gt;

2) B(OMe)₃

HO , OH

SEM ° SEM 3) H₂O

5-Chloro-2-methyl-4-[2'(trimethyl-silanyl)-ethoxymethoxy]-phenylboronic acid was prepared in 54% yield from [2-(4-bromo-2-chloro-5-methyl20 pbenoxymethoxy)-ethyl]-trimethyl-silane according to the procedure for 5-136methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid.

Ή NMR (300 MHz, CDC1₃) δ 8.11 (s, 1 H), 7.09 (s, 1 H), 5.37 (s, 2 H), 3.84 (t, 2 H, J.= 8.4 Hz), 2.76 (s, 3 H), 0.98 (t, 2 H, J = 8.4 Hz), 0.01 (s, 9 H). Anal.

(C₁₃H₂₂BC10₄Si - H_:O) C, H. Calculated: C, 52.28; H, 6.75. Found: C, 51.98;

H, 6.84.

Example 24(d): 3-l//-Benzoimidazol-2-yl-6-(4-hydroxy-2-methoxyphenyl)-l/7 indazole

<img file="MY139999A_D0199.tif" />

Example 24 (d) was prepared in a similar mariner to that described for

Example 24(a), except that 4-bromo-3-methoxy-phenol, prepared as described by

Carreno et. al., Syn. Lett., 11, 1241-42 (1997), was used instead of 4-bromo-2methoxy-5-methyl-phenol in step (vi). ’H NMR (300 MHz, DMSO-i/tf) δ 13.52 (s IH), 12.98 (s, IH), 9.63 (s, IH), 8.44 (d, IH, J= 8.41Hz), 7.72 (d, 1H,7= 6.9Hz),

7.61 (s, IH), 7.50 (d, IH, J= 6.9Hz), 7.36 (dd, IH, 7=8.4, 1.5Hz), 7.18-7.22 (m,

3H), 6.55 (d, IH, J= 2.1Hz), 6.48 (dd, IH,/= 8.1, 2.1Hz), 3.74 (s, 3H). MS (ES) [m+H]/z calc’d 357, found 357; [m-H]/z calc’d 355, found 355.

Example 24(e): 3-l//-Benzoimidazol-2-yl-6-(2-ethyl-4-hydroxvphenyl)- ΪΗindazole

-137-

<img file="MY139999A_D0200.tif" />

Example 24 (e) was prepared in a similar manner to that described for Example 24(a), except that 4-bromo-3-ethyl-phenol, prepared in 80% yield according to the procedure described by Carreno et. al., Syn. Lett., 11, 1241-42 (1997) for the synthesis of 4-bromo-3-methyl-phenol, was used instead of 4-bromo-2-methoxy-5methyl-phenol in step (vi). ‘HNMR (300 MHz, DMSO-rftf) δ 13.66 (s, 1H), 13.02 (s, 1H), 9.43 (s, 1H), 8.49 (d, 1H, 7- 8.4Hz), 7.72 (d, 1H, J= 6.9Hz), 7.53 (d, 1H, J =

6.9Ήζ),ΊΑ4 (s, 1H), 7.18-7.25 (m, 3H), 7.06 (d, 1H, 7= 8.1Hz), 6.75 (d, 1H,7 = 2.1Hz), 6.66 (dd, 1H, 7= 8.1, 2.1Hz), 2.50 (q, 2H,7= 7.5Hz), 1.04 (t, 3H, J = 7.5Hz).

MS (ES) [m+H]/z calc’d 355, found 355; [m-H]/z calc’d 353, found 353.

Example 24(f): 3-127-BenzoimidazoI-2-yI-6-(2, 4-di hydroxyphenyl)- 177-indazole

<img file="MY139999A_D0201.tif" />

6-(2-methoxy-4-hydroxyphenyl)-3-l//'-benzoimidazol-2-yl-l/7-indazole, prepared in example 24(d), (46 mg, 0.13 mmol) was heated in pyridinium chloride (0.5 g) at 180 °C for 2 h. The reaction was allowed to cool, and was quenched with sat. NaHCO₃ (15 mL) and extracted with EtOAc (2 x 20 mL). Organics were dried

-138(Na₂SO₄) and concentrated in vacuo. Purification by silica gel chromatography (60% THF/hexanes) gave 26 mg (59%) of the title compound as a white solid. ’H NMR (300 MHz, DMSO-rftf) δ 13.49 (s, 1H), 12.94 (s, 1H), 9.49 (s, 1H), 9.39 (s, 1H), 8.43 (d, 1H, J= 8.4Hz), 7.71-7.74 (m, 2H), 7.50 (d, lH,7=6.9Hz), 7.43 (dd, 1H,7= 8.4,

1.2Hz), 7.16-7.23 (m,3H), 6.45 (d, 1H, J= 2.1Hz), 6.35 (dd, 1H, 7= 8.4, 2.1Hz).

MS (ES) [m+HQ/z calc’d 343, found 343; [m-H]/z calc’d 341, found 341.

Example 24(g): 3-l/7-Benzoimidazol-2-yl-6-(2-phenoxy-4-hydroxyphenyl)- 1/7indazole

<img file="MY139999A_D0202.tif" />

Example 24 (g) was prepared in a similar manner to that described for

Example 24(c), except that 3-phenoxy-phenol was used instead of 2-chloro-5-methylphenol in step (i). ’HNMR (300 MHz, DMSO-cfc) δ 13.54 (s, IH), 12.95 (s, 1H), 9.78 (s, IH), 8.43 (d, IH, J= 8.4Hz), 7.67-7.72 (m, 2H), 7.49 (dd, IH, J= 6.3,

2.1Hz), 7.43 (d, 2H,7= 8.4Hz) ,7.33 (t, 2H, J= 7.5Hz), 7.17-7.22 (m, 2H), 6.96-7.07 (m, 3H), 6.72 (dd, IH, 7= 8.4, 2.1Hz), 6.40 (d, IH, 7= 2.1Hz). MS (ES) [m+H]/z calc’d 419, found 419; [m-H]/z calc’d 417, found 417.

Example 24(h): 3-l/7-Benzoimidazol-2-vl-6-(2-(2-methoxyethyl)-4hydroxyphenyl)- 1/7-indazole

-139-

<img file="MY139999A_D0203.tif" />

Example 24 (h) was prepared in a similar manner to that described for

Example 24(a), except that {2-[4-bromo-3-(2-methoxy-ethyl)-phenoxymethoxy]ethyl}-trimethyl-silane, prepared as described below, was used instead of [2-(45 bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethylsilane in step (vii). ’H

NMR (300 MHz, DMSO-&lt;/&lt;$) δ 13.60 (s, 1H), 13.01 (s, 1H), 9.44 (s, 1H), 8.49 (d, 1H,

J=8.4Hz), 7.73 (brs, 1H), 7.51 (brs, 1H),7.46 (s, 1H), 7.21 (app d, 3H,J= 8.1Hz), 7.09 (d, 1H, J= 8.1Hz), 6.78 (d, 1H, J= 2.4Hz), 6.70 (dd, 1H, J= 8.1,2.4Hz), 3.40 (t, 2H, J= 7.2Hz), 3.12 (s, 3H), 2.75 (t, 2H, J= 7.2Hz). MS (ES) [m+H]/z calc’d

385, found 385; [m-H]/z calc’d 383, found 383.

The starting material was prepared as follows:

(i)

Br

<img file="MY139999A_D0204.tif" />

4-Bromo-3-(2-hydroxy-ethyl)-phenol was prepared in 88% yield by the 15 substitution of 3-(2-hydroxy-ethyl)-phenol in the procedure described in Example

24(c), step (i). Ή NMR (300 MHz, CDC1₃) δ 9.56 (s, 1H), 7.29 (d, 1H, J= 8.7Hz),

-14 06.74 (d, IH, J= 3.0 Hz), 6.55 (dd, IH, J= 8.7, 3.0 Hz), 4.71 (t, IH, J= 5.4Hz), 3.523.59 (m, 2H), 2.73 (t, 2H, J= 7.2Hz).

(ii)

<img file="MY139999A_D0205.tif" />

Preparation of 2-[2-Bromo-5-(2-trimethylsilanyl-ethoxymethoxy)-phenyl] was prepared in 65% yield by the substitution of 4-bromo-3-(2-hydroxy-ethyl)-phenol in the procedure described in Example 24(a), step (vi). 'H NMR (300 MHz, CDC1₃) δ 7.43 (d, IH, J= 8.7Hz), 6.97 (d, IH, J= 3.0 Hz), 6.82 (dd, IH, J= 8.7, 3.0 Hz), 5.19 (s, 2H), 3.88 (q, 2H, J= 6.6Hz), 3.74 (t, 2H, J= 8.4Hz), 2.99 (t, 2H, J= 6.6Hz), 1.42 (t, lH,J=6.6Hz). 0.94 (t,2H,J=8.4Hz),-0.01 (s, 9H).

(hi)

<img file="MY139999A_D0206.tif" />

OH

SEM

Mel, KOH, DMSO

<img file="MY139999A_D0207.tif" />

'SEM {2-[4-Bromo-3-(2-methoxy-ethyl)-phenoxymethoxy'|-ethyl}-trimethyl-silane: 2-[2Bromo-5-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-ethanol (1.9 g, 6.0 mmol) was added to a solution of potassium hydroxide (1.35 g, 24 mmol) in DMSO (16 rnL).

Iodomethane (1.12 mL, 18 mmol) was added, and the solution stirred for 16 h. The reaction was diluted with water (50 mL) and extracted with ether (2 x 40 mL).

Organics were washed with brine (40 mL), dried (Na_;SO₄) and concentrated in vacuo Purification by silica gel chromatography (10% ether/hexanes) gave 1.28 g of {2-[4-141bromo-3-(2-methoxy-ethyl)-phenoxymethoxy]-ethyl}-trimethyl-silane as a clear oil.

’HNMR (300 MHz, CDC1₃) δ 7.40 (d, 1H, J= 8.7Hz), 6.96 (d, 1H, J= 3.0 Hz), 6.80 (dd, 1H, J= 8.7, 3.0 Hz), 5.18 (s, 2H), 3.74 (t, 2H, 7- 8.4Hz), 3.60 (t, 2H, 7 = 7.2Hz), 3.37 (s, 3H), 2.98 (t, 2H, 7= 7.2Hz), 0.95 (t, 2H, 7= 8.4Hz), -0.01 (s, 9H).

Example 24(i): 3-l//-Benzoimidazol-2-yI-6-(2-(2-hydroxyethyI)-4hydroxvphenyl)- 1/7-indazole

<img file="MY139999A_D0208.tif" />

BBr-,

EtOAc

<img file="MY139999A_D0209.tif" />

OH

3-l/Z-Benzoimidazol-2-yl-6-(2-(2-methoxyetliyl)-4-hydroxyphenyl)-l/7indazole, from Example 24(i), (99 mg, 0.26 mmol) was dissolved in EtOAc (20 mL) and cooled to -78 °C under argon. Boron tribromide was added dropwise, and the reaction was allowed to stir while warming to r.t over 3 h. The solution was diluted with EtOAc (60 mL) and washed with sat NaHCO₃ and brine (20 mL each). Organics were dried (Na₂SO₄) and concentrated in vacuo. Purification by silica gel chromatography (THF) gave 56 mg (59%) of the title compound as a white solid. ’H

NMR (300 MHz, DMSO-7tf) δ 13.60 (s, 1H), 13.01 (s, 1H), 9.41 (s, 1H), 8.49 (d, 1H,

7= 8.4Hz), 7.71 (brs, 1H), 7.51 (brs, 1H), 7.46 (s, 1H), 7.21 (app d, 3H, 7= 8.1Hz),

7.08 (d, lH,7=8.4Hz), 6.77 (d, 1H, 7= 2.1Hz), 6.69 (dd, 1H, 7= 8.1, 2.1Hz), 4.57

-142(br s, IH), 3.46 (t, 2H, J= 7.2Hz), 2.68 (t, 2H, J= 7.2Hz). MS (ES) [m+H]/z calc’d

371, found 371; [m-H]/z calc’d 369, found 369.

Example 24(j): 3-l/7-BenzoimidazoI-2-yl-6-(2,6-dimethyl-4-hydroxyphenyI)- 1Hindazole

<img file="MY139999A_D0210.tif" />

Example 24 (j) was prepared in a similar manner to that described for Example 24(a), except that 4-bromo-3,5-dimethyl -phenol was used instead of 4bromo-2-methoxy-5-methyl-phenol in step (vi). ’H NMR (300 MHz, DMSO-6/5) δ 13.57 (s, IH), 12.99 (s, IH), 9.22 (s, IH), 8.52 (d, IH, J= 8.4Hz), 7.72 (d, 1H,J =

6.6Hz), 7.51 (d, 1H,7= 6.6Hz), 7.31 (s, IH), 7.16-7.25 (m, 2H), 7.02 (d, 1H,7 =

8.4Hz), 6.55 (s, 2H), 1.93 (s, 6H). MS (ES) [m+H]/z calc’d 355, found 355; [m-H]/z calc’d 353, found 353.

Example 24(k): 3-l/7-Benzoimidazol-2-yl-6-(2-methylsulfanyl-4-hydroxyphenyl) l//-indazole

<img file="MY139999A_D0211.tif" />

Example 24 (k) was prepared in a similar manner to that described for Example 24(c), except that 3-methylsulfanyl-phenol, prepared as described below,

-143was used instead of 2-chloro-5-methyl-phenol in step (i). ’H NMR (300 MHz,

DMSO-cfc) δ 13.59 (s, 1H), 12.98 (s, 1H), 9.64 (s, 1H), 8.48 (d, 1H, J= 8.4Hz), 7.71 (br.s, 1H), 7.52 (app s, 2H), 7.20-7.27 (m, 3H), 7.12 (d, 1H, J= 8.4Hz), 6.76 (d, 1H, J = 2.1Hz), 6.65 (dd, 1H, J= 8.4, 2.1Hz), 2.34 (s, 3H). MS (ES) [m+H]/z calc’d 373, found 373; [m-H]/z calc’d 371, found 371.

The starting material was prepared as follows:

(i)

<img file="MY139999A_D0212.tif" />

<img file="MY139999A_D0213.tif" />

Preparation of 3-methylsulfanyl-phenol. 3-Hydroxythiophenol (5.0 g, 39.7 mmol) and potassium carbonate (6.03 g, 43.6 mmol) were stirred in acetone (80 mL) at 0 °C.

Iodomethane (2.5 mL, 40 mmol) was added dropwise, and the reaction stirred for 45 min. The solution was diluted with H,0 (150 mL) and extracted with EtOAc (2 x

100 mL). Organics were washed with brine (100 ml,), dried (Na₂SO₄) and concentrated in vacuo. Purification by silica gel chromatography (25%

EtOAc/hexanes) 5.08 g (91%) of 3-methylsulfanyl-phenol as a clear oil. ’H NMR (300 MHz, CDC1₃)6 7.15 (t, 1H, 7= 8.1Hz), 6.82 (d, 1H, J= 8.1Hz), 6.74 (t, 1H, 7 =

1.8Hz), 6.60 (dd, 1H,7=8.1, 1.8Hz), 4.86 (s, 1H), 2.47 (s, 3H).

Example 24(1): 3-177-Benzoimidazol-2-yl-6-(2-(ethoxymethyl)-5-methoxy-4hydroxy-phenyl)-l/7-indazole

-144-

<img file="MY139999A_D0214.tif" />

Example 24 (1) was prepared in a similar manner to that described for

Example 24(a), except that [2-(4-bromo-5-ethoxymefhyl-2-methoxyphenoxymethoxy)-ethyl]-trimethyl-silane, prepared as described below, was used 5 instead of [2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethylsilane in step (vii). ’HNMR (300 MHz, DMSO-dtf) δ 13.63 (s, 1H), 12.99 (s, 1H), 9.15 (s, 1H), 8.50 (d, lH,7=8.4Hz), 7.73 (dd, 1H,7=6.6, 2.1Hz), 7.59 (s, 1H), 7.51 (dd,

1H, J= 6.6, 2.1Hz), 7.32 (d, 1H, J= 8.4Hz), 7.19-7.24 (m, 2H), 6.94 (s, 1H), 6.91 (s,

1H), 4.22 (s,2H), 3.81 (s, 3H), 3.39 (q, 2H, 7 = 6.9Hz), 1.13 (t, 3H, 7= 6.9Hz). MS (ES) [m+H]/z calc’d 415, found 415.

The starting material was prepared as follows:

(i)

<img file="MY139999A_D0215.tif" />

SEM-Cl DIEA, CH₂CI₂

<img file="MY139999A_D0216.tif" />

2-Bromo-4-methoxy-5 -(2-trimethylsilanyl-ethoxymethoxy)-benzaldehyde was prepared in 79% yield by the substitution of 4-bromo-3-formyl-2-methoxy-phenol (Hazlet et. al., 7. Org. Chem., 27, 3253-55 (1962)) in the procedure described in

-145Example 24(a), step (vi). ’HNMR (300 MHz, CDC1₃) δ 10.16 (s, IH), 7.68 (s, IH), 7.07 (s, IH), 5.28 (s, 2H), 3.94 (s, 3H), 3.77 (t, 2H, J = 8.4Hz), 0.94 (t, 2H, 7 = 8.4Hz),-0.03 (s, 9H).

(ii)

<img file="MY139999A_D0217.tif" />

Preparation of [2-(4-Bromo-5-ethoxymethyl-2-methcxy-phenoxymethoxy)-ethyl]trimethyl-silane: Sodium borohydride (275 mg, 7.2 mmol) was added in portions over 10 min to a solution of 2-bromo-4-methoxy-5-(2-trimethylsilanylethoxymethoxy)-benzaldehyde (1.3 g, 3.6 mmol) in MeOH (20 mL) at 0 °C. After 30 min, the reaction was diluted with H₂O (40 mL) and extracted with EtOAc (2 x 30 mL). Organics were washed with brine (30 mL), dried (Na₂SO₄) and concentrated in vacuo to give 1.3 lg of [2-bromo-4-methoxy-5-(2-trimethylsilanyl-ethoxmethoxy)phenyl]-methanol as a clear oil. ’H NMR (300 MHz, CDC1₃) δ 7.29 (s, IH), 7.05 (s, IH), 5.27 (s, 2H), 4.66 (d, 2H, 7= 6.6Hz), 3.87 (s, 3H), 3.79 (t, 2H, 7= 8.4Hz), 1.92 (t, IH, J = 6.6Hz), 0.96 (t, 2H, 7= 8.4Hz), 0.01 (s, 9ΡΓ).

The crude benzyl alcohol was stirred with a solution of potassium hydroxide (800 mg, 14.4 mmol) in DMSO (8 mL). Iodoethane (580 mL, 7.2 mmol) was added, and the reaction stirred for 16 h before it was diluted with H₂O (30 mL) and extracted with ether (2 x 30 mL). Organics were washed with brine (20 mL), dried (Na₂SO₄) and concentrated in vacuo. Purification by silica gel chromatography (15%

EtOAc/hexanes) gave 1.30 g (92%) of the title compound as a clear oil. ’HNMR

-14 6(300 MHz, CDC1₃) δ 7.29 (s, 1H), 7.03 (s, 1H), 5.26 (s, 2H), 4.48 (s, 2H), 3.85 (s, 3H), 3.79 (t, 2H,/= 8.4Hz), 3.58 (q, 2H,/=6.9Hz), 1.26 (t, 3H, J= 6.9Hz), 0.95 (t,

2H,/=8.4Hz),-0.01 (s, 9H).

Example 24(m): 3-l/7-Benzoimidazol-2-yl-6-(2-(hydroxymethyl)-4-ethoxy-55 methoxy-phenyl)- 177-indazole

<img file="MY139999A_D0218.tif" />

Example 24 (m) was prepared in a similar manner to that described for

Example 24(a), except that [2-(2-bromo-5-ethoxy-4-methoxy-benzyloxymethoxy)ethylj-trimethyl-silane, prepared as described below, was used instead of [2-(410 bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethylsilane in step (vii). 'H

NMR (300 MHz, DMSO-^) δ 13.64 (s, 1H), 13.00 (s, 1H), 8.50 (d, lH,/=8.4Hz),

7.73 (d, lH,/=8.4Hz), 7.62 (s, 1H), 7.52 (dd, 1H,/=6.O, 1.8Hz), 7.32 (dd, lH,/ =

8.4, 1.2Hz), 7.19-7.24 (m, 2H), 7.15 (s, 1H), 6.91 (s, 1H), 5.11 (t, 1H,/= 5.1Hz),

4.37 (d, 2H, /= 5.1Hz), 4.08 (q, 2H, /= 6.9Hz), 3.80 (s, 3H), 1.37 (t, 3H, /= 6.9Hz).

MS (ES) [m+H]/z calc’d 415, found 415.

The starting material was prepared as follows:

(i)

<img file="MY139999A_D0219.tif" />

-147Preparation of 4-bromo-2-methoxy-5-(2-trimethylsilanyl-ethoxymethyl)phenol: [2-Bromo-4-methoxy-5-(2-trimethylsilanyl-ethoxmethoxy)-phenyl]methanoL upon sitting for periods of over a week, underwent SEM-migration from the phenolic to the benzylic alcohol to yield the title compound. ’HNMR (300 MHz,

CDC1₃) δ 7.04 (s, 1H), 7.01 (s, 1H), 5.54 (s, 1H), 4.77 (s, 2H), 4.57 (s, 2H), 3.88 (s, 3H), 3.68 (t, 2H, 7= 8.4Hz), 0.97 (t, 2H, 7= 8.4Hz), 0.02 (s, 9H).

(ii)

<img file="MY139999A_D0220.tif" />

Preparation of [2-(2-bromo-5-ethoxy-4-methoxy-benzyloxymethoxy)-ethyl]10 trimethyl-silane: 4-Bromo-2-methoxy-5-(2-trimethylsilanyl-ethoxymethyl)-phenol (1.28 g, 3.53 mmol) was stirred with a solution of potassium hydroxide (790 mg, 14.1 mmol) in DMSO (8 mL). Iodoethane (565 mL, 7.1 mmol) was added, and the reaction stirred for 16 h before it was diluted with H₂O (30 mL) and extracted with e±er (2 x 30 mL). Organics were washed with brine (20 mL), dried (Na₂SO₄) and concentrated in vacuo. Purification by silica gel chromatography (15%

EtOAc/hexanes) gave 1.26 g (91%) of the title compound as a clear oil. ’HNMR (300 MHz, CDC1₃) δ 7.02 (s, 1H), 6.98 (s, 1H), 4.78 (s, 2H), 4.60 (s, 2H), 4.09 (q, 2H,

7= 6.6Hz), 3.86 (s, 3H), 3.69 (t, 2H, 7= 8.4Hz), 1.46 (t, 3H, 7= 6.6Hz), 0.97 (t, 2H,

7= 8.4Hz), 0.04 (s, 9H).

Example 24(n): 3-l/7-Benzoimidazol-2-yl-6-(2-(hydroxymethyI)-5-methoxy-4hydroxy-phenyl)-l/7-indazole

-148-

<img file="MY139999A_D0221.tif" />

Example 24 (n) was prepared in a similar manner to that described for

Example 24(a), except that 6-[5-methoxy-2-hydroxymethyl-4-(2-trimethylsilanylethoxymethoxy)-phenyl]-l-(2-trimethylsilanyl-ethoxymethyl)-3-[ 1-(2- — trimethylsilanyl-ethoxymethyl)-l/7-benzoimidazol-2-yl]-l/7-mdazole, prepared as described below, was used instead of 6-[5-methoxy-2-methyl-4-(2-trimethylsilanylethoxymethoxy)-phenyl]-l-(2-trimethylsilanyl-ethoxymethyl)-3-[l-(2trimethylsilanyl-ethoxymethyl)-l//-benzoimidazol-2-yl]-l//-indazole. ’H NMR (300 MHz, DMSO-cfc) δ 13.59 (s, IH), 12.95 (s, 1H), 9.05 (s, IH), 8.49 (d, IH, J= 8.4Hz),

7.72 (dd, IH, 7= 6.3, 2.1Hz), 7.60 (s, IH), 7.51 (dd, IH, 7= 6.3, 2.1Hz), 7.31 (d, IH,

7= 8.4Hz), 7.20-7.24 (m, 2H), 7.02 (s, IH), 6.87 (s, IH), 5.02 (t, 1H,7= 5.4Hz), 4.32 (d, 2H, 7= 5.4Hz), 3.80 (s, 3H). MS (ES) [m+H]/z calc’d 387, found 387; [m-H]/z calc’d 385, found 385.

The starting material was prepared as follows:

(i)

<img file="MY139999A_D0222.tif" />

-14 9Preparation of 4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2trimethylstannanyl-benzaldehyde: 2-Bromo-4-methoxy-5-(2-trimethylsilanylethoxymethoxy)-benzaldehyde (3.36 g, 9.3 mmol) and hexamethylditin (5.0 g, 15.3 mmol) were stirred in dry toluene (60 mL) in a flask purged with argon.

Tetrakis(triphenylphosphine)palladium(0) (500 mg, 0.45 mmol) was added, and the reaction stirred at 100 °C for 23 h. The reaction was cooled and concentrated in vacuo. Purification by silica gel chromatography (5% EtOAc/hexanes) gave 2.77 g (67%) of 4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanylbenzaldehyde as a clear oil. ’HNMR (300 MHz, CI)C1₃) δ 9.81 (dd, 1H, J= 3.0,

0.9Hz), 7.66 (t, 1H, J= 6.6Hz), 7.21 (t, 1H, 7= 9.0 Hz), 5.35 (s, 2H), 3.99 (s, 3H),

3.82 (t, 2H, 7= 8.4Hz), 0.25 (t, 9H, 7= 26.7Hz), 0.98 (t, 2H, J= 8.4Hz), -0.01 (s,

9H).

(ii)

<img file="MY139999A_D0223.tif" />

Preparation of[4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2trimethylstannanyl-phenyl]-methanol: 4-Methoxy-5-(2-trimethylsilanylethoxymethoxy)-2-trimethylstannanyl-benzaldehyde (2.36 g, 5.3 mmol) was stirred in MeOH (30 mL) at 0 °C. Sodium borohydride (400 mg, 10.6 mmol) was added, and the reaction stirred for 1 h. The solution was diluted with H₂O (60 mL), and extracted with EtOAc (2 x 50 mL). Organics were washed with brine (50 mL), dried

-150(Na₂SO₄), and concentrated in vacuo to give 2.16 g (91%) of [4-methoxy-5-(2trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-phenyl]-methanol as a clear oil.· Ή NMR (300 MHz, CDC1₃)8 7.18 (t, IH, J= 6.9Hz), 7.03 (t, IH, J=9.3Hz), 5.27 (s, 2H), 4.58-4.63 (m, 2H), 3.89 (s, 3H), 3.80 (t, 2H, J= 8.4Hz), 1.53 (t, IH, J =

6.0 Hz), 0.96 (t, 2H, J= 8.4Hz), 0.31 (t, 9H, J= 27.3Hz), 0.01 (s, 9H).

(iii)

<img file="MY139999A_D0224.tif" />

Preparation of 6-[5-methoxy-2-hydroxymethyl-4-(2-trimethylsilanylethoxymethoxy)-phenyl]-l-(2-trimethylsilanyl-ethoxymethyl)-3-[ 1-(210 trimethylsilanyl-ethoxymethyl)-l/7-benzoimidazol-2-yl]-l/7-indazole: 6-Iodo-l-[2(trimethyl-silanyl)-ethoxymethyl]-3-{l-[2-(trimethyl-silanyl)-ethoxymethyl]-l//benzoimidazol-2-yl}-l/7-indazole [Example 24(a), step (v)] (300 mg, 0.48 mmol) and [4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-2-trimethylstannanyl-phenyl]methanol (282 mg, 0.63 mmol) were stirred in dioxane (8 mL) under argon at 98 °C for 16 h. The reaction was allowed to cool and was diluted with EtOAc. Organics were washed with sat NaHCO₃ and brine, dried (Na₂SO₄), and concentrated in vacuo. Purification by silica gel chromatography (20% EtOAc/hexanes) gave 224 mg (60%) of 6 -[5 -methoxy-2 -hydroxymethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-pheny 1] -1 -151 (2-trimethylsilanyl-ethoxymethyl)-3-[l-(2-trimethylsilanyl-ethoxymethyl)-l/7benzoimidazol-2-yl]-l/7-indazol as a faint yellow oil. 'HNMR (300 MHz, CDC1₃) δ 8.70 (d, IH, J= 8.4Hz), 7.89-7.92 (m, IH), 7.63-7.66 (m, 2H), 7.34-7.41 (m, 4H),

6.91 (s, IH), 6.29 (s, 2H), 5.83 (s, 2H), 5.36 (s, 2H), 4.55 (s, 2H), 3.78-3.92 (m, 5H),

3.59-3.70 (m, 4H), 0.83-1.04 (m, 6H), 0.03 (s, 9H), -0.04 (s, 9H), -0.13 (s, 9Hz).

Example 24(o): 3-l/7-Benzoimidazol-2-yl-6-(3-hycLroxyphenyl)- 1/7-indazole

<img file="MY139999A_D0225.tif" />

Example 24 (o) was prepared in a similar maimer to that described for

Example 24(f), except that 6-(3-methoxy-phenyl)-3-l//-benzoimidazol-2-yl-1/710 indazole, prepared in a similar manner to that described for example 24(a) except that

3-methoxy-phenylboronic acid was used instead of 5-methoxy-2-methyl-4-[2(trimethylsilanyl)-ethoxymethoxy]-phenylboronic acid in step (viii), was used instead of 6-(2-methoxy-4-hydroxypbenyl)-3-l//-benzoimidazol-2-yl- 1/7-indazole. 'H NMR (300 MHz, DMSO-75) δ 13.67 (s, IH), 13.00 (s, IH), 9.58 (s, IH), 8.55 (d, IH, J =

8.4Hz), 7.71-7.75 (m, 2H), 7.49-7.57 (m, 2H), 7.30 ¢:, 1H,7= 7.8Hz), 7.12-7.24 (m,

4H), 6.80 (dd, 1H,7= 8.1, 1.5Hz). MS (ES) [m+H]/z calc’d 327, found 327; [m-H]/z calc’d 325, found 325.

Example 24(p): 3-l/7-Benzoimidazol-2-yl-6-(2-mel:hoxy-3-hydroxyphenyl)- 1/7indazole

-152-

<img file="MY139999A_D0226.tif" />

Example 24 (p) was prepared in a similar manner to that described for Example 24(a), except that 3-bromo-2-methoxy-phenol, prepared as described by Aristoff et.al., Tet. Lett., 25, 3955-58 (1984) was used instead of 4-bromo-2-methoxy·

5-methyl-phenol in step (vi). ’HNMR (300 MHz, DMSO-Ztf) δ 13.60 (s, 1H), 12.97 (s, lH),9.37(s, 1H), 8.52 (d, 1H, J= 8.4Hz), 7.69-7.74 (m, 2H), 7.51 (dd, 1H,J =

7.8, 1.8Hz), 7.43 (dd, 1H,7=8.4, 1.2Hz), 7.19-7.24 (m, 2H), 7.02 (t, 1H,7= 7.8Hz), 6.85-6.93 (m, 2H), 3.50 (s, 3H). MS (ES) [m+H]/z calc’d 357, found 355, [m-H]/z calc’d 357, found 355.

Example 25(a): 3-(3H-Imidazo[4,5-c]pyridln-2-yl)-6-(4-hydroxy-2methoxyphenyl)-l/7-indazole

<img file="MY139999A_D0227.tif" />

A solution of of 6-[5-methoxy~2-methyl-4-(2-trimethylsilanylethoxymethoxy)-phenyl]-l-(2-trimethylsilanyl-ethoxymethyl)-3-[3-(215 trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-c]pyridin-2-yl]- 177-indazole (68 mg, 0.11 mmol) in TBAF (1 M in THF, 1.2 mL, 1.2 mmol) with ethylenediamine (150 mL, 2.2 mmol) was stirred at 68 °C for 48 h. The solution was concentrated in vacuo and purified by silica gel chromatography (2:1 EtOH/EtOAc). Precipitation from

-153acetonitrile gave 21 mg (53%) of 3-(3H-imidazo[4,5-c]pyridin-2-yl)-6-(4-hydroxy-2methoxyphenyl)-177-inda2ole as a white solid. 'H NMR (300 MHz, DMSO-d^)

13.70 (s, 1H), 13.49 (br s, 1H), 9.62 (s, 1H), 9.01 (brs, 1H), 8.43 (d, 1H, J= 8.7Hz),

8.34 (d, 1H, 7= 5.7Hz), 7.64 (s, IH), 7.57 (br s, IH), 7.39 (dd, 1H,7=8.7, 1.5Hz),

7.21 (d, IH, 7 = 8.1Hz), 6.55 (d, IH, 7= 2.1Hz), 6.49 (dd, 1H,7= 8.1,2.1Hz), 3.74 (s, 3H). MS (ES) [m+H]/z calc’d 358, found 358; [ra-H]/z calc’d 356, found 356. The intermediates were prepared as follows:

(i)

<img file="MY139999A_D0228.tif" />

3-(1,l-Dimethoxy-methyl)-6-iodo-l-(2-trimethylsUanyl-ethoxymethyl)-l//indazole. A solution of 6-iodo-3-styryl-l-[2-(trimethyl-silanyl)-ethoxymethylJ-17/indazole [Example 14, step (i)] (1.28 g, 2.69 mmol) in CH₂C1₂ (40mL)/MeOH (40 mL) was stirred at -78 °C. The reaction was treated with ozone until a blue color persisted, and then was purged with argon. Methyl sulfide (4 mL) was added, and foe reaction stirred 4 h while warming to r.t. Concentration in vacuo gave a crude mixture of acetal and aldehyde, which was converted completely to the acetal by stirring in trimethyl orthoformate (10 mL) with Amberlyst 15(wet) acidic ionexchange resin (0.8 g) for 1 h. The resin was removed by filtration, and the solution was concentrated in vacuo. Purification by silica gel chromatography gave 1.11 g (92%) of 3-(1 ,l-dimethoxy-methyl)-6-iodo-l-(2-trimethylsilanyl-efooxymefoyl)-l7Z-154 indazole as a clear oil. ’HNMR (300 MHz, CDC1₃) 7.98 (s, 1H), 7.68 (d, 1H, J = 8.4Hz), 7.48 (dd, 1H, 7 = 8.4, 1.2Hz), 5.77 (s, 1H), 5 69 (s, 2H), 3.53 (t, 2H, 7= 8.4Hz), 3.43 (s, 6H), 0.88 (t, 2H, 7= 8.4Hz), -0.06 (s, 9H).

(ii)

<img file="MY139999A_D0229.tif" />

3-(1, l-Dimethoxy-methyl)-6-[2-methoxy-4-(2-trimi;thylsilanyl-ethoxymethoxy )phenyl]-l-(2-trimethylsilanyl-ethoxymethyl)-l/7-imdazole. 3-(1,1 -Dimethoxymethyl)-6-iodo-l-(2-trimethylsilanyl-ethoxymethyl)-l//-indazole (1.06 g, 2.37 mmol), 2-methoxy-4-(trimethylsilanyl-ethoxymethoxy)-phenylboronic acid (0.99 g,

3.32 mmol), and sodium carbonate (352 mg, 1.4 mmol) were stirred in a mixture of benzene (15 mL), MeOH (3 mL), and water (1 ml.) in a flask purged with argon. Tetrakis(triphenylphosphine)palladium(0) (220 mg, 0.19 mmol) was added, and the reaction stirred at reflux for 16 h. The reaction was allowed to cool and was diluted with ether (70 mL). Organics were washed with H₂O and brine (30 mL each), dried (Na₂SO₄), and concentrated in vacuo. Purification by silica gel chromatography (15% EtOAc/hexanes) gave 1.12 g (82%) of 3-(1, l-djmethoxy-methyl)-6-[2methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-l-(2-trimethylsilanylethoxymethyl)-l//-indazole as a faintly yellow oil. Ή NMR (300 MHz, CDC1₃)

7.91 (d, 1H, 7 = 8.4Hz),7.64 (s, 1H),7.37 (dd, 1H,7=8.4, 1.2Hz),7.29 (d, 1H,7 =

-1558.4Hz), 6.71-6.77 (m, 2H), 5.82 (s, 1H), 5.75 (s, 2H), 5.28 (s, 2H), 3.77-3.83 (m, 5H) 3.57 (t, 2H, 7= 8.4Hz), 3.46 (s, 6H), 1.00 (t, 2H, 7= 8.4Hz), 0.88 (t, 2H,7=8.4Hz),

0.03 (s, 9H), -0.05 (s, 9H).

(Hi)

<img file="MY139999A_D0230.tif" />

6-[2-Methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-l-(2trimethylsilanyl-ethoxymethyl)-l/7-indazole-3-carbaldehyde. 3-(l,l-Dimethoxymethyl)-6-[2-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-l-(2trimethylsilanyl-ethoxymethyl)-177-indazole (1.1 g, 1.92 mmol) was stirred in 1%

TFA/CH₂C1₂ (20 mL) for 1 h at rt. Concentration in vacuo yielded 1.01 g (100%) of 6-[2-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-l-(2-trimethylsilanylethoxymethyl)-177-indazole-3-carbaldehyde as a clear oil. ’H NMR (300 MHz, CDClj) 10.27 (s, 1H), 8.28 (d, lH,7=8.4Hz), 7.73 (s, 1H), 7.55 (dd, 1H,7= 8.4, 1.2Hz), 7.29 (d, 1H,7= 8.4Hz), 6.72-6.79 (m, 2H), 5.82 (s, 2H), 5.28 (s, 2H), 3.7815 3.84 (m, 5H), 3.61 (t, 2H, 7= 8.1Hz), 0.89-1.03 (m, 4H), 0.03 (s, 9H), -0.05 (s, 9H).

(iv)

<img file="MY139999A_D0231.tif" />

SEM /

o nh₂ nh₂ u

S, DMF

<img file="MY139999A_D0232.tif" />

OSEM

-1566-[5-methoxy-2-methyI-4-(2-trimethylsilanyI-ethoxymethoxy)-phenyl]-l-(2trimethylsilanyI-ethoxymethyI)-3-[3-(2-trimethylsilanyl-ethoxymethyl)-3Himidazo[4,5-c]pyridin-2-yl]-l/f-indazole. 6-[2.-Meihoxy-4-(2-trimethyl-silanylethoxymethoxy)-phenyl]-l-(2-trimethylsilanyl-ethoxymethyl)-l/7-indazole-35 carbaldehyde (320 mg, 0.61 mmol), 3,4-diamino-pyridine (68 mg, 0.62 mmol), and sulfur (23 mg, 0.73 mmol) were combined in dry DMF (2 mL) and stirred at 90 °C for 16 h under argon. The reaction was allowed to cool and was diluted with EtOAc (20 mL). Organics were washed with sat. NaHCO₃ and brine (15 mL each), dried (Na₂SO₄), and concentrated in vacuo. Purification by silica gel chromatography (75% to 100% EtOAc/hexanes) gave 78 mg (21%) of 6-[5-methoxy—2-methyl-4-(2trimethylsilanyl-ethoxymethoxy)-phenyl]-l-(2-trimethylsilanyl-ethoxymethyl)-3-[3(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-c]pyridin-2-yl]-l//-mdazole as a white solid. Ή NMR (300 MHz, CDC1₃) 10.69 (br s, IH), 9.21 (s, IH), 8.63 (dd, IH J= 8.4, 0.3Hz), 8.50 (d, IH, J= 5.4Hz), 7.73 (s, IH), 7.47 (br s, IH), 7.57 (dd,

IH, 7 = 8.7, 1.2Hz), 7.33 (d, IH, 7= 8.4Hz), 6.74-6.80 (m, 2H), 5.80 (s, 2H), 5.29 (s,

2H), 3.78-3.85 (m, 5H), 3.63 (t, 2H,7 = 8.1Hz), 0.89-1.04 (m, 4H), 0.04 (s, 9H), 0.06 (s, 9H).

Example 25(b): 3-[6-(2-morpholin-4-yl-ethylcarbamoyl)-l/7-benzoimidazol-2-yl]

6-(2-methoxy-4-hydroxyphenyl)-l/7-indazole

H .N /

o

HN

<img file="MY139999A_D0233.tif" />

OH

N

-157Example 25 (b) was prepared in a similar manner to that described for Example 25(a), except that 3,4-diamino-A-(2-morpholin-4-yl-ethyl)-benzamide, prepared as described below, was used instead of 3,4-diaminopyndine in step (iv). ‘H NMR (300 MHz, DMSO-rftf) 13.61 (s, 0.5H), 13.59 (s, 0.5H), 13.22 (s, 0.5H), 13.18 (s, 0.5H),

9.59 (s, IH), 8.35-8.46 (m, 2H), 8.27 (s, 0.5H), 8.02 (s, 0.5H), 7.71-7.79 (m, 1.5H),

7.63 (s, IH), 7.53 (d, 0.5H, J= 8.7Hz), 7.38 (d, IH, J = 8.7Hz), 7.21 (d, IH, J=

8.7Hz), 6.55 (d, IH, J= 2.1Hz), 6.49 (dd, IH, 7= 8.4, 2.1Hz), 3.75 (s, 3H), 3.58 (t, 4H, J= 4.5Hz), 3.42 (q, 2H, J= 6.0 Hz), 2.43-2.51 (m, 6H). MS (ES) [m+H]/z calc’d

513, found 513; [m-H]/z calc’d 511, found 511.

3,4-Diamino-A-(2-morpholin-4-yl-ethyl)-benzamide was prepared as follows:

<img file="MY139999A_D0234.tif" />

3,4-Diamino-7V-(2-morpholin-4-yI-ethyl)-benzamide. 3,4-Diaminobenzoic acid (5 g, 32.9 mmol), 4-(2-aminoethyl)morpholine (5.2 ml-, 39.4 mmol), triethylamine (9.2 mL, 66 mmol), and DMAP (0.40 g, 3.3 mmol) were combined in dry DMF (80 mL) at 0 °C. EDC (9.45 g, 49.3 mmol) was added, and the reaction stirred for 24 h at r.t.

Concentration in vacuo and purification by silica gel chromatography (10% MeOH/CH₂Cl₂ with 0.2% NH₄OH) gave 2.6 g (31%) of 3,4-diamino-A-(2-morpholin4-yl-ethyl)-benzamide as a light brown solid. ’H NMR (300 MHz, DMSO-i/5) 7.72 (t, 1H, 7= 5.4Hz), 7.02 (d, 1H,7 = 1.8Hz), 6.92 (dd, 1H,7=8.1, 1.8Hz), 6.46 (d, IH,

J= 8.1Hz), 4.89 (br s, 2H), 4.51 (br s, 2H), 3.55 (t, 4H, J= 4.8Hz), 3.29 (q, 2H, J=

Ί.2Ηζ), 2.36-2.43 (m, 6H).

-158Example 25(c): 3-[6-(4-methylpiperazin-l-yl)-177-benzoimidazol-2-yl]-6-(2methoxy-4-hydroxyphenyI)- 177-indazole

<img file="MY139999A_D0235.tif" />

Example 25 (c) was prepared in a similar manner to that described for Example 25(a), except 4-(4-methyl-piperazin-l-yl)-benzene-l ,2-diamine (Harapanhalli et al., J. Med. Chem., 39, 4804-09 (1996)) was used instead of 3,4-diaminopyridine in step (iv). ’H NMR (300 MHz, DMSO-/y) 13.51 (s, 0.33H), 13.38 (s, 0.67H), 12.66 (s, 0.33H),

12.59 (s, 0.67H), 9.58 (s, 1H), 8.42 (d, 0.33H, /= 8.4Hz), 8,41 (d, 0.67H, /= 8.4Hz),

7.59 (s, 1H), 7.55 (d, 0.67H, /= 8.7Hz), 7.31-7.37 (m, 1.33H), 7.20 (app d, 1,33H, / =8.4Hz), 6.92-7.01 (m, 1.67H), 6.55 (d, lH,/= 1.5Hz), 6.48 (dd, lH,/= 8.4,

2.1Hz), 3.74 (s, 3H), 3.12 (br s, 4H), 2.50 (brs, 4H), 2.22 (s, 3H). MS (ES) [m+H]/z calc’d 455, found 455; [m-H]/z calc’d 453, found 453.

Example 25(d): 3-[4-(4-methylpiperazin-l-yl)-l//-benzoimidazol-2-yl]-6-(2methoxy-4-hvdroxyphenyl)-177-indazole

<img file="MY139999A_D0236.tif" />

-159Example 25 (d) was prepared in a similar manner to tliat described for Example 25(a), except 3-(4-methyl-piperazin-l-yl)-benzene-l,2-diamine (Harapanhalli et al., J. Med. Chem., 39, 4804-09 (1996)), analogous to the 4-isomer preparation) was used instead of 3,4-diaminopyridine in step (iv). ^]H NMR (300 MHz, DMSO-ri^) 13.41 (br s,

IH), 12.79 (br s, IH), 9.60 (br s, IH), 8.37 (d, IH, J =- 8.4Hz), 7.60 (s, IH), 7.36 (dd, IH, J= 8.4, 1.2Hz), 7.22 (d, IH, J= 8.4Hz), 7.03-7.07 (m, 2H), 6.46-6.56 (m, 3H),

3.75 (s, 3H), 3.62 (br s, 4H), 2.62 (br s, 4H), 2.28 (s, 3H). MS (ES) [m+H]/z calc’d 455, found 455; [m-H]/z calc’d 453, found 453.

Example 25(e): 3-imidazoI-2-yI-6-(2-methoxy-4-hydroxyphenyI)-l/7-indazole

<img file="MY139999A_D0237.tif" />

Example 25 (d) was prepared in a similar maimer to that described for Example 25(a), except 6-[5-methoxy-2-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(2trimethylsilanyl-ethoxymethyI)-3-imidazol-2-yl-l/7-indazole was used instead of 6[5-methoxy-2-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-l-(215 trimethyIsilanyl-ethoxymethyl)-3-[3-(2-trimethylsilanyl-ethoxymethyl)-3Himidazo[4,5-c]pyridin-2-yl]-l/7-indazole. Ή NMR (300 MHz, DMSO-c/5) 13.10 (s, IH), 12.59 (s, IH), 9.56 (s, IH), 8.27 (d, IH, J= 8.4Hz), 7.53 (s, IH), 7.25 (dd,

IH,/=8.4, 1.2Hz), 7.13-7.20 (m, 3H), 6.54 (d, IH, J= 2.1Hz), 6.47 (dd, lH,/= 8.4,

2.1Hz), 3.73 (s, 3H). MS (ES) [m+H]/z calc’d 307, found 307.

The starting material was prepared as follows:

-160-

<img file="MY139999A_D0238.tif" />

<img file="MY139999A_D0239.tif" />

OSEM

Glyoxal (40 wt% in H₂O, 0.4 mL, 3.5 mmol) was added dropwise to a solution of 420 mg (0.8 mmol) 6-[2-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenylj-1-(2trimethylsilanyl-ethoxymethyl)-l/7-indazole-3-carbaldehyde, from Example 25(a) step (iii), and 28% aqueous ammonia (0.6 mL) in THF (8 mL)/MeOH (8 mL), and the solution was stirred at r.t. for 16 h. The reaction was concentrated in vacuo and dissolved in CHC1₃ (50 mL). Organics were washed with H₂O and brine (25 mL each), dried (Na₂SO₄) and concentrated in vacuo. Purification by silica gel chromatography (40% EtOAc/hexanes) gave 120 mg (27%) of 6-[5-methoxy-210 methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-l -(2-trimethylsilanylethoxymethyl)-3-imidazoI-2-yl-l/7-indazole as a clear oil. Ή NMR (300 MHz, CDC1₃) 10.03 (s, IH), 8.48 (d, IH, J= 8.4Hz), 7.65 (s, IH), 7.46 (dd, IH, 7= 8.4,

1.5Hz), 7.29-7.48 (m, 2H), 7.13 (d, IH, 7= 1.5Hz), 6.73-6.78 (m, 2H), 5.73 (s, 2H),

5.28 (s, 2H), 3.78-3.86 (m, 5H), 3.60 (t, 2H,7= 8.4Hz), 0.88-1.03 (m, 4H), 0.03 (s,

9H), -0.05 (s, 9H).

Example 25(f): 3-[4-(2-hydroxyethylsulfanyl)-17f-benzoimidazol-2-yl]-6-(2methoxv-4-hydroxyphenyl)-l/7-indazole

<img file="MY139999A_D0240.tif" />

-161-

<img file="MY139999A_D0241.tif" />

<img file="MY139999A_D0242.tif" />

Example 25 (f) was prepared in a similar manner to that described for Example 25(a), except that 2-(2,3-diamino-phenylsulfanyl)-ethanol) was used instead of 3,4diaminopyridine in step (iv). 'H NMR (300 MHz, DMSO-7(j) 13.51 (s, IH), 13.02 (s, IH), 9.59 (s, IH), 8.45 (d, IH, J= 8ABz), 7.61 (s, IH), 7.32-7.40 (m, 2H), 7.115 7.23 (m, 3H), 6.55 (d, IH, 7= 2.4Hz), 6.48 (dd, IH, 7= 8.1, 2.4Hz), 4.96 (br s, IH),

3.75 (s, 3H), 3.65 (br s, 2H), 3.33 (t, 2H, 7= 6.9Hz). MS (ES) [m+Na]/z calc’d 455, found 455, [m-H]/z calc’d 431, found 431.

The starting material was prepared as follows:

s^^0H s^^0H^HS-^OH Hs, 10% Pd/c

KjCOj, DMF EtOA:

2-(3-Amino-2-nitro-phenylsulfanyl)-ethanol. 3-Chjioro-2-nitro-aniline (1.12 g, 6.5 mmol), 2-mercaptoethanol (0.60 ml, 8.6 mmol), and potassium carbonate (0.99 g, 7.1 mmol) were combined in dry DMF (15 ml) and stirred at 130 °C for 4 h. The solution was allowed to cool and was concentrated in vacuo. Purification by silica gel chromatography (70% EtOAc/hexanes) gave 1.29 g (93%) of 2-(3-amino-2-nitro15 phenylsulfanyl)-ethanol as a bright red solid. ’HNMR (300 MHz, DMSO-7,5) 7.20 (t, IH, J= 8.1Hz), 6.80 (s, 2H), 6.73 (dd, 1H,7= 8.4, 0.9Hz), 6.63 (dd, 1H,7= 7.8,

1,2Hz), 4.92 (t, IH, 7= 6.0 Hz), 3.58 (q, 2H, 7= 6.0 Hz), 2.98 (t, 2H, 7= 6.0 Hz). 2-(2,3-Diamino-phenylsuIfanyl)-ethanoL 2-(3-Amino-2-nitro-phenylsulfanyl)ethanol (1.02 g, 4.8 mmol) was reduced by hydrogenation using 45 psi of H₂ with

10% Pd-C (180 mg) in EtOAc (25 mL) for 6 h. After filtering through Celite, solvent was removed in vacuo. Purification by silica gel chromatography (EtOAc) gave 762

-162mg (87%) of 2-(2,3-diamino-phenylsulfanyl)-ethanol as a faintly yellow solid. 'H NMR (300 MHz, CDC1₃) 6.98 (dd, lH,/= 7.5, 1,5Hz), 6.60-6.72 (m, 2H), 3.65 (t,

2H, J= 5.7Hz), 3.55 (br s, 5H), 2.91 (t, 2H, J= 5.7Hz).

Example 25(g): 3-(5-methylcarbamoyl-177-benzoimidazol-2-yI)-6-(2-methoxy-45 hydroxyphenyl)-177-indazole

<img file="MY139999A_D0243.tif" />

Example 25 (g) was prepared in a similar manner to that described for Example 25(a), except 3,4-diamino-7V-methyl-benzamide (Kumar, et. al. J. Med. Chem., 27,1083-89 (1984)) was used instead of 3,4-diaminopyridine in step (iv). Ή NMR (300 MHz,

DMSO-/tf) 13.59 (s, 0.5H), 13.55 (s, 0.5H), 13.21 (s, 0.5H), 13.14 (s, 0.5H), 9.60 (s, 1H), 8.38-9.46 (m, 2H), 8.26 (s, 0.5H), 8.03 (s, 0.5H), 7.71-7.79 (m, 1.5H), 7.63 (s, 1H), 7.52 (d, 0.5H,/= 8.4Hz), 7.35-7.40 (m, 1H), 7.21 (d, 1H,/= 2.1Hz), 6.55 (d, lH,/=2.4Hz), 6.49 (dd, lH,/= 8.4, 2.4Hz), 3.75 (s, 3H), 2.82 (d, 1.5H,/ = 1.5Hz), 2.81 (d, 1.5H,/ = 1.5Hz). MS (ES) [m+H]/z calc’d 414, found 414, [m-H]/z calc’d 412, found 412.

Example 25(h): 3-(5-Dimethylamino-177-benzoimidazol-2-yl)-6-(2-methoxy-4hydroxy-phenyl)-177-indazole

-163-

<img file="MY139999A_D0244.tif" />

Example 25 (h) was prepared in a similar manner to that described for Example 25(a), except 3,4-diamino-jV,jV-dimethyl-aniline (Cazaux, e:;. al., Can. J. Chem., 71, 1236-46 (1993)) was used instead of 3,4-diaminopyridine in step (iv). ’HNMR (300 MHz,

DMSO-75) 13.36 (s, 1H), 12.51 (b7s, 1H), 9.58 (s, 1H), 8.42 (d, 1H, 7= 8.4Hz), 7.59 (s, 1H), 7.49 (brs, 1H), 7.33 (dd, 1H,7= 8.4, 1.2Hz), 7.20 (d, 1H,7= 8.1Hz),

6.87 (br d, 2H, 7= 8.1Hz), 6.55 (d, 1H, 7= 2.1Hz), 6.48 (dd, 1H, 7= 8.1, 2.1Hz),

3.73 (s, 3H), 2.92 (s, 6H). MS (ES) [m+H]/z calc’d 400, found 400, [m-H]/z calc’d

398, found 398.

Example 25(i): 3-(5-Aminosulfonyl-177-benzoimidazoI-2-yl)-6-(2-methoxy-4hydroxy-phenyl)-l£7-indazole

<img file="MY139999A_D0245.tif" />

Example 25 (i) was prepared in a similar manner to that described for Example 25(a), except 3,4-diarnino-benzenesulfonamide was used instead of 3,4-diaminopyridine in 15 step(iv). Ή NMR (300 MHz, DMSO-75) 13.67 (s, 0.5H), 13.64 (s, 0.5H), 13.39 (s, 0.5H), 13.35 (s, 0.5H), 9.60 (s, 1H), 8.43 (d, 1H, 7= 8.1Hz), 8.18 (d, 0.5H, J =

1,5Hz), 7.99 (d, 0.5H, 7= 1.5Hz), 7.86 (d, 0.5H, 7= 8.4Hz), 7.62-7.72 (m, 2.5H),

-1647.29 (d, 1H, 7= 8.4Hz), 7.20-7.28 (m, 3H), 6.55 (d, 1H, J= 2.1Hz), 6.49 (dd, 1H,7 = 8.4, 2.1Hz), 3.75 (s, 3H). MS (ES) [m+H]/z calc’d 436, found 436, [m-H]/z calc’d . 434, found 434.

Example 25(j): 3-(4-methylcarbamoyl-l/7-benzoimidazol-2-yl)-6-(2-methoxy-45 hydro xy-phenyl)-l/7-indazole

<img file="MY139999A_D0246.tif" />

Example 25 (i) was prepared in a similar manner to that described for Example 25(a),

2,3-diamino-jV-methyl-benzamide was used instead of 3,4-diaminopyridine in step (iv). Ή NMR (300 MHz, DMSO-7«y) 13.71 (s, 1H), 13.46 (s, 1H), 9.85 (br d, 1H, J =4.8Hz), 9.61 (s, 1H), 8.38 (d, 1H, J= 8.4Hz), 7.89 (dd, 1H,7=7.5, 1.2Hz), 7.667.72 (m, 2H), 7.47 (dd, 1H, J= 8.4, 1.2Hz), 7.36 (t, 1H, J= 7.8Hz), 7.23 (d, 1H, J =

8.1Hz), 6.56 (d, 1H, J= 2.4Hz), 6.50 (dd, 1H, J= 8.4, 2.4Hz), 3.76 (s, 3H), 3.10 (d,

3H, J = 1.8Hz). MS (ES) [m+H]/z calc’d 414, found 414, [m-H]/z calc’d 412, found

412.

2,3-Diamino-M-methyl-benzamide was prepared as follows:

0^ OH

MeNH₂HCl . EDO . DIEA

NO,

CH₂Cl₂, DMF a:

NH

H_a. 10%Pd/C

E,OA=

EtOAc

-1652-Amino-7V-methyl-3-nitro-benzamide. 2-Amino-3-.uitro-benzoic acid (1.8 g, 9.9 mmol) and methylamine hydrochloride (1.33 g, 19.8 mmol), were stirred in dry

CH₂C1₂ (30 ml)/DMF (5 mL) at 0 °C. EDC (2.83 g, 14.8 mmol) and DIEA (4.92 mL,

27.7 mmol) were added, and the solution stirred 3 h while warming to r.t. The reaction was concentrated in vacuo and purified by silica gel chromatography (8% MeOH/CHCl₃) to give 1.42 g (74%) of 2-amino-jV-methyl-3-nitro-benzamide as a yellow solid. Ή NMR (300 MHz, DMSO-dtf) 8.58 (br s, IH), 8.23 (br s, 2H), 8.15 (dd, IH, J= 8.1, 1.8Hz), 7.82 (dd, IH, J= 8.1, 1.8Hz), 6.68 (t, IH, J= 8.1Hz), 2.76 (d, 3H, 7= 4.5Hz).

2,3-Diamino-7V-methvl-benzamide. 2-Amino-jV-methyl-3-nitro-benzamide (1.4 g, 7.2 mmol) was reduced by hydrogenation using 50 psi of H₂ with 10% Pd-C (250 mg) in EtOAc (25 mL) for 5 h. After filtering throuiih Celite, solvent was removed in vacuo. Purification by silica gel chromatography (10% MeOH/CHCl₃) gave 1.08 mg (91%) of 2,3-diammo-jV-methyl-benzamide as a faintly yellow solid. 'H NMR (300

MHz,CDCI₃) 6.87 (dd, IH, 7=7.8, 1.5Hz), 6.76 (dd, 1H,7 = 7.8, 1.5Hz), 6.59 (t,

IH, J= 7.8Hz), 6.14 (br s, IH), 4.28 (br s, 4H), 2.95 (d, 3H, J= 5.1Hz).

Example 26: 6-(4-Hydroxy-3methoxyphenyl)-3-[E-2-(4-glycylamino-phenyI)ethenyl] -1 H-indazole

OH

H ,N

-166Example 26 was prepared from the starting material described below in a similar manner to that described for Example 1(a): ’H NMR (300 MHz, CDC1₃)

8.29 (d, IH), 7.80 (m, 5H), 7.58 (m, 3H), 7.38 (s, H), 7.27 (d, IH), 7.01 (d, IH), 4.00 (s, 3H), 3.42 (s, 2H); LCMS (100% area) Rt = 3.44 min, (pos) [M+H]/z Calc'd 415.1, found 415.2.

The starting materia] was prepared as follows:

(i)

<img file="MY139999A_D0247.tif" />

3-Iodo-6-(3-methoxy-4-methoxymethoxy-phenyl)-l-[2-(trimethyl-silanyl)10 ethoxymethyl]-l//-indazole was prepared from the compound prepared in Example

1(a), step (v) in a similar manner to that described for Example 10, step (ii): Ry sm 0.11, p 0.43 (ethyl acetate-hexane 3:7); 'H NMR (300 MHz, CDC1₃) 7.71 (s, IH), 7.55 (m, 2H), 7.33 (m, IH), 7.20 (m, 2H), 5.82 (s, 2H), 5.33 (s, 2H), 4.02 (s, 3H),

3.64 (t, 2H), 3.59 (s, 3H), 0.95 (t, 2H), -.03 (s, 9H).

(ii)

<img file="MY139999A_D0248.tif" />

3-Styryl-6-(3-methoxy-4-methoxymethoxy-phenyl)-l-[2-(trimethyl-silanyl)ethoxymethyl]-1//-indazole was prepared in a similar manner to that described for Example 11, step (iii): Ry sm 0.41, p 0.35 (ethyl acetate-hexane 2:8); 'H NMR (300

-167MHz, CDC1₃) 8.12 (d, 1H), 7.73 (s, 1H), 7.62 (m, 2H), 7.51 (m, 2h), 7.46 (m, 2H),

7.38 (m, 1H), 7.30 (m, 4H), 5.85 (s, 2H), 5.38 (s, 2H), 4.03 (s, 3H), 3.70 (t, 2H), 3.62 (s, 3H), 0.98 (t, 2H),.-0.02 (s, 9H).

(in)

OHC

<img file="MY139999A_D0249.tif" />

3-Carboxaldehyde-6-(3-methoxy-4-methoxymethoxy-phenyl)-l-[2-(trimethylsilanyl)-ethoxymethyl]-l/7-indazole was prepared in a similar manner to that described for Example 33(a), step (i): ’HNMR (300 MHz, CDC1₃) 10.33 (s, 1H),

8.34 (d, 1H), 7.82 (s, 1H), 7.65 (d, 1H), 7.25 (m, 3H), 5.90 (s, 2H), 5.36 (s, 2H), 4.02 (s, 3H), 3.67 (t, 2H), 3.51 (s, 3H), 0.98 (t, 2H), -0.02 (s, 9H).

(iv)

3-(4-Nitrostyryl)-6-(3-methoxy-4-methoxymethoxy-phenyl)-l-[2-(trimethyl-silanyl)ethoxymethyl]-177-indazole was prepared in a similar manner to that described for 15 Example 33(a), step (ii) except that 4-nitrobenzyltriphenylphosphonium bromide and lithium hexamethyldisilazide were used instead of 2-picolyltriphenylphosphonium chloride-potassium hydride: LCMS (100% area) Rt = 6.89 min, (pos) [M+H]/z

Calc’d 562.4, found 562.4.

(v) — 168 —

<img file="MY139999A_D0250.tif" />

3-(4-Nitrostyryl)-6-(3-methoxy-4-methoxymethoxy-phenyl)- 177-indazole was prepared in a similar manner to that described for Exiimple 11: FTIR (thin film)

3335, 3178,2954, 1592, 1512, 1338, 1257, 1136, 1257, 1136, 987 cm’¹; 'HNMR (300 MHz, CDC1₃) 8.22 (d, 2H, J = 8.8 Hz), 8.02 (d, 1H, J = 8.5 Hz), 7.70 (d, 2H, -J= 8.8 Hz), 7.58 (m, 3H), 7.45 (dd, 1H, J = 1.3, 8.5 Hz), 7.20 (m, 4H), 7.26 (s, 2H),

3.95 (s, 3H), 3.53 (s, 3H); LCMS (100% area) Rt = 5.13 min, (pos) [M+H]/z Calc’d

432.1, found 432.1.

(vi)

<img file="MY139999A_D0251.tif" />

3-(4-aminostyryl)-6-(3-methoxy-4-methoxymethoxy-phenyl)- 177-indazole was prepared in a similar manner to that described for Example 11, step (iv): Ry sm 0.39, p 0.26 (ethyl acetate-hexane 6:4); FTIR (thin film) 3366, 3210, 2954, 1608, 1517, 1465, 1412, 1259, 1157, 1077, 989, 912 cm'¹;'H NMR (300 MHz, CDC1₃) 8.11 (d,

1H), 7.63 (s, 1H), 7.50-7.15 (m, 8H), 6.71 (d, 2H), 5.36 (s, 2H), 3.97 (s, 3H), 3.61 (s,

3H); LCMS (100% area) Rt = 4.40 min, (pos) [M+Hj/z Calc’d 402.2, found 402.2.

(vii)

-169-

<img file="MY139999A_D0252.tif" />

3-(4-aminostyTyl)-6-(3-methoxy-4-methoxymethoxy-phenyI)- IH-indazole (90 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL) and was treated with Bocglycine (196 mg, 1.12 mmol, 5 equiv), DMAP (82 mg, 3 equiv) and HATU (426 mg,

5 equiv). The mixture was allowed to stir for 30 min. The mixture was partitioned between ethyl acetate and water. The organic material was concentrated, taken up in methanol (5 mL) and was treated with potassium carbonate (100 mg). The mixture was heated to 50 °C for 3 d. The resulting mix was again partitioned between ethyl acetate and water. The organic material was concentrated, and purified by silica (109 10 mg, 66%): Ry sm 0.32, p 0.46 (ethyl acetate-hexane 6:4); 'H NMR (300 MHz,

CDC1₃) 8.18 (bs, IH), 8.03 (d, IH, J - 8.1 Hz), 7.56 (m, 5H), 7.40 (m, 3H), 7.20 (m,

3H), 5.29 (s, 2H), 5.20 (bs, IH), 3.98 (s, 3H), 3.96 (d, 2H), 3.54 (s, 3H), 1.48 (s, 9H).

Example 27(a): 6-phenyl-3-E-styryl-lH-indazole

N

H ,N

<img file="MY139999A_D0253.tif" />

6-phenyl-3-styryl-l-[2-(trimethyl-silanyl)ethoxymethyl]-177- indazole (345 mg, 0.81 mmol) was treated with a solution of TBAF (16 ml of a 1 M solution in

THF, 16 mmol), and ethylene diamine (0.53 ml, 8.1 mmol), and heated at 70 °C for 2

h. The solution was then poured into brine (200 ml), and extracted with ethyl acetate

-17 0(3x30 ml). The organic layer was dried over MgSO₄, and concentrated under reduced pressure. Purification by silica gel chromatography gave 6-phenyl-3-E-styryl-lHindazole as a white solid (80 mg, 34%): ’HNMR (300 MHz, CDC1₃) 8.10 (d, IH, J = 8.5 Hz); HRMS (FAB) [M+H]/z Calc’d 297.1392, found 297.1393. Anal. Calc’d, C (85.10), H (5.44), N (9.45). Found: C (85.10), H (5.46), N (9.43).

The starting material was prepared as follows:

(i)

<img file="MY139999A_D0254.tif" />

<img file="MY139999A_D0255.tif" />

A solution of 476 mg (1.0 mmol) of 6-iodo-3-styryl-l-[2-(trimethyl10 silanyl)ethoxymethyl]-l/7- indazole, from Example 14 step (i), in dioxane (3 ml, degassed by sonication and bubbling argon), Pd(PPh₃)₄ (23 mg, 0.05 mmol), phenylboronic acid (302 mg, 2.5 mmol), and Na_;CO₃ (1.25 ml of a 2M aqueous solution, degassed as above) was heated at 90 °C for 2 h. The solution was then diluted with ethyl acetate (100 ml) and washed with brine (2x20 ml). The organic layer was dried over MgSO₄, and concentrated under reduced pressure. Purification by silica gel chromatography gave of 6-pheny 1-3-styryl-l-[2-(trimethylsilanyl)ethoxymethyl]-lH- indazole as a brown oil (345 mg, 81%). ’H NMR (300 MHz, CDC1₃) 8.09 (dd, IH, J=8.5, 0.7 Hz), 7.75 (s, 1H), 7.70 (d, IH, J=7.0 Hz), 7.64-7.58 (m, 2H), 7.56-7.51 (m, 2H), 7.50-7.45 (m, 2H), 7.45-7.36 (m, 4H), 7.3420 7.27 (m, IH), 5.80 (s, 2H), 3.73 (t, 2H, J=8.3Hz), 1.12 (t, 2H, J=8.3Hz).

Example 27(b): 6-(3-methoxyphenyI)-3-E-styryl-lH-indazole — 171 —

<img file="MY139999A_D0256.tif" />

Example 27 (b) was prepared in a similar manner to that described for Example 27(a), except that 3-methoxyphenylboronic acid was used instead of phenylboronic acid in step (i). 'H NMR (300 MHz, MeOH-d₄) 8.16 (d, IH, J=8.4

Hz), 7.70 (s, IH), 7.67-7.61 (m, 2H), 7.60-7.43 (m, 3H), 7.43-7.33 (m, 3H), 7.32-7.21 (m, 3H), 6.99-6.92 (m, IH), 3.88 (s, 3H). HRMS (FAB) [M+Na]/z Calc'd 349.1317, found 349.1342. Analyzed with 0.1 H,0 Calc’d, C (80.50), H (5.59), N (8.55).

Found: C (80.44), H (5.49), N (8.55).

Example 27(c): 6-(4-methoxyphenyI)-3-E-styryl-lH-indazoIe

<img file="MY139999A_D0257.tif" />

Example 27 (b) was prepared in a similar manner to that described for Example 27(a), except that 4-methoxyphenylboronic acid was used instead of phenylboronic acid in step (i). ’H NMR (300 MHz, DMSO-d₆) 13.20 (s, IH), 8.23 (d, IH, J=8.4 Hz), 7.76-7.64 (m, 5H), 7.54 (s, IH), 7.50-7.37 (m, 3H), 7.33-7.25 (m,

IH), 7.07 (d, 2H, J=8.8 Hz), 3.82 (s, 3H) HRMS (FAB) [M+H]/z Calc'd 327.1497, found 327.1502. Anal. Calc’d, C (80.96), H (5.56), N (8.58). Found: C (80.71), H (5.42), N (8.47).

Example 27(d): 6-naphth-l-yl-3-E-styryl-lH-indazole

-172-

<img file="MY139999A_D0258.tif" />

Example 27 (d) was prepared in a similar manner to that described for Example 27(a), except that 1-naphthaleneboronic acid was used instead of phenylboronic acid in step (i) 'H NMR (300 MHz, DMSO-d₆) 10.11 (s, 1H), 8.45 (d, 1H. J=8.41), 7.97-7.87 (m, 3H), 7.66-7.37 (m, 13H), 7.35-7.28 (m, 1H). HRMS (FAB) [M+Na]/z Calc’d 369.1368, found 369.1359. Anal. Calc’d C (86.68), H (5.32), N (8.19). Found: C (86.52), H (5.32), N (8.19).

Example 27(e) 6-pyridin-3-yl-3-E-styryI-177-indazole

<img file="MY139999A_D0259.tif" />

Example 27 (e) was prepared in a similar manner to that described for

Example 27(a), except that 3-pyridineboronic acid was used instead of phenylboronic acid in step (i). 'HNMR (300 MHz, MeOH-d₄) 8 97 (s, 1H), 8.63 (d, 1H, J=4.8 Hz), 8.30 (d, 1H, H=8.5 Hz), 8.27 (d, 1H, J=8.1 Hz), 7.86 (s, 1H), 7.72 (d, 2H, J=7.5 Hz), 7.69-7.56 (m, 4H), 7.54-7.42 (m, 2H), 7.40-7.32 (m, 1H). HRMS (FAB) [M+H]/z Calc’d 298.1344, found 298.1356. Analyzed with 0.25 H₂O Calc’d, C (79.58), H (5.18), N (13.92). Found: C (79.53), H (5.16), N (13.80).

Example 27(f) 6-pyridin-4-yl-3-E-stvryl-l//-indazoIe

-173-

<img file="MY139999A_D0260.tif" />

Example 27(f) was prepared in a similar manner to that described for Example

27(a), except that 4-pyridineboronic acid was used instead of phenylboronic acid in step (i). Ή NMR (300 MHz, MeOH-d₄) 8.69 (bs, 2H), 8.30 (d, IH, J=8.5 Hz), 7.96 (s, IH), 7.87 (d, 2H, H=5.6 Hz), 7.75-7.68 (m, 3H), 7.68-7.50 (m, 2H), 7.50-7.42 (m,

2H), 7.40-7.31 (m, IH). HRMS (FAB) [M+H]/z Calc'd 298.1344, found 298.1357.

Analyzed with 0.3 H₂O Calc’d, C (79.34), H (5.19), N (13.88). Found: C (79.14), H (5.08), N (13.84).

Example 27(g): 6-indol-4-yl-3-E-styryl-l//-indazo le

<img file="MY139999A_D0261.tif" />

Example 27(g) was prepared in a similar manner to that described for

Example 27(a), except that 4-indoleboronic acid was used instead of phenylboronic acid in step (i). ’HNMR (300 MHz, MeOH-d₄) 8.25 (d, IH, J=8.5 Hz), 7.85 (s, IH), 7.75-7.67 (m, 3H), 7.67-7.52 (m, 2H), 7.52-7.42 (m, 3H), 7.39-7.22 (m, 4H),

6.72 (d, IH, J=3.2 Hz). HRMS (FAB) [M+H]/z Calc'd 336.1501, found 336.1506.

Analyzed with 0.3 H₂O Calc’d, C (78.97), H (5.36), N (12.01). Found: C (78.95), H (5.20), N (12.03).

Example 27(h): 6-[3-ethoxy-4-hydroxyphenyl]-3-E-styryl-lH-indazole

-174-

<img file="MY139999A_D0262.tif" />

Example 27(h) was prepared in a similar manner to that described for Example 27(a), except that 3-ethoxy-4-(2-trimethylsilanyl-ethoxymethoxy)benzene boronic acid was used instead of phenylboronic acid in step (i). Ή NMR (300 MHz,

CDC1₃) S.lOJd, 1H, J=8.7 Hz), 7.74 (s, 1H), 7.74-7.16 (m, 10H), 7.07 (d, 1H,

J=8.15 Hz), 4.27 (q, 2H, J=14.0 Hz), 1.54 (t, 3H, J= 14.0 Hz). HRMS (FAB) [M+H]/z

Calc’d 357.1603, found 357.1611. Analyzed with 0.2 H₂O, Calc’d, C (76.73), H (5.71), N (7.78). Found: C (76.72), H (5.91), N (7.63).

Starting material was prepared as follows:

(i)

<img file="MY139999A_D0263.tif" />

4-Bromo-2-ethoxy-phenol (Smith et al., Soc. Pl., 1377-78 (1992)) was converted to

3-ethoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-benzene boronic acid in a manner similar to that described for Example 24(a) steps (vi)-(vii). ’H NMR (300 MHz,

CDC1₃) 7.82 (d, 1H, J= 8.0 Hz), 7.72 (s, 1H), 7.31 (d, 1H, J= 8.1 Hz), 5.37 (s, 2H),

4.29 (q, 2H, &gt; 14.0 Hz), 3.87 (t, 2H, J= 16.8 Hz), 1.54 (t, 2H, J= 14.0 Hz), 0.99 (t,

2H, J=16.8 Hz), 0.03 (s, 9H).

Example 27(i): 6-[3-(2-hydroxyethoxy)-4-hydroxyphenyl]-3-E-styryl-1 H-indazole

-175N

Η ,Ν

<img file="MY139999A_D0264.tif" />

OH

<img file="MY139999A_D0265.tif" />

Example 27(i) was prepared in a similar manner to that described for Example 27(a), except that 3-[2-(trimethylsilanyl-ethoxymethcxy)-ethoxy]-4-(2trimethylsilanyl-ethoxymethoxy)-benzene boronic acid, prepared from 2-(2-hydroxy5 ethoxy)-phenol (Yamaguchi et al., Bull. Chem. Soc. Jpn., 61, 2047-54 (1988)) in a similar manner to that described in Example 24(c) steps (i)-(iii) and was used instead of phenylboronic acid in step (i). 'H NMR (300 MHz, DMSO-d₆) 8.17 (d, IH,

J=8.7 Hz), 7.73- 7.17 (m, 11 H), 6.92 (d, IH, J=8.2 Hz), 4.13 (t, 2H, J=9.7 Hz), 3.8 (t,

2H, J=9.7 Hz). HRMS (FAB) [M+H]/z Calc’d 373.1552, found 373.1563. Analyzed with 0.05 trifluoroacetic acid, Calc’d, C (73.37), H (5.35), N (7.41). Found: C (73.11), H (5.33), N (7.39).

Example 27(j): 6-(3,4-dimethoxyphenyl)-3-E-styryl-lH-indazole

Example 27 (j) was prepared in a similar manner to that described for

Example 27(a), except that 3,4-dimethoxyphenylboronic acid was used instead of phenylboronic acid in step (i). Ή NMR (300 MHz, DMSO-d₆) 8.01 (d, IH, J=8.1 Hz), 7.51-7.05 (m, 1 IH), 6.86 (d, IH, J=8.0 Hz) 3.58 (s, 3H), 3.65 (s, 3H). HRMS

-176(FAB) [M+H]/z Calc’d 357.1598, found 357.1508. Analyzed with 0.2 H₂O, Calc’d, C (76.73), H (5.71), N (7.78). Found: C (76.45), H (5.70), N (7.68).

Example 27(k): 6-(2-methoxypyridin-5-yI)-3-E-styiryl-lH-indazole

<img file="MY139999A_D0266.tif" />

6-(2-methoxypyridin-5-yl)-3-((E)-styryl)-l-.(2-trimethylsilanyl-ethoxymethyl)ΙΗ-indazole was converted to 6-(2-methoxypyridin-5-yl)-3-E-styryl-lH-indazole in a similar maimer to that described for Example 27(a). ‘H NMR (300 MHz, CDC1₃)

8.53 (d, IH, J=2.1 Hz), 8.15 (d, IH, J=9.2 Hz), 7.97 (dd, IH, J=2.6, 8.6 Hz), 7.79 (s, IH), 7.74-7.34 (m, 8H), 6.94 (d, IH, J=8.6 Hz). HRMS (FAB) [M+H]/z Calc'd

328.1450, found 328.1462. Anal. Calc’d, C (77.04)., H (5.23), N (12.83). Found: C (77.00), H (5.28), N (12.65).

The starting material was prepared as follows:

(i)

<img file="MY139999A_D0267.tif" />

A solution of 5-bromo-2-methoxypyridine (2.00 g, 6.10 mmol), hexamethylditin (1.15 g, 6.10 mmol), and Pd( PPh₃)₄ (0.28 g, 0.24 mmol) in degassed dioxane (10 ml) was refluxed under for 16 h. 6-Iodo-3-((E)-styryl)-l-(2-trimethylsilanylethoxymethyl)-lH-indazole (2.90 g, 6.10 mmol) was added to above mixture,

-177followed by Pd( PPh₃)₄ (0.35 g 0.31 mmol). The reaction mixture was refluxed for 16 h. The mixture was then diluted with ethyl acetate (150ml), and washed with brine (30 ml). The organics were dried over MgSO₄, then concentrated under reduced pressure. Purification by silica gel chromatography gave 6-(25 methoxypyridin-5-yl)-3-((E)-styryl)-l-(2-trimethylsilanyl-ethoxymethyl)-lH-indazGle as a yellow solid (1.12 g, 40%). 'HNMR (300 MHz, CDC1₃) 8.51 (d, IH, J= 2.5 Hz), 8.50 (d, IH, J= 9.1 Hz), 7.93 (dd, IH, J=2.5, 8.6 Hz), 7.69 (s,lH), 7.69-7.28 (m,

8H), 6.89 (d, IH, J=8.6 Hz), 5.83 (s, 2H), 4.03 (s, 3H), 3.64 (t, 2H, J= 8.3 Hz), 0.93 (t, 2H, J= 8.3 Hz), -0.03 (s, 9H).

Example 28(a) 6-(3-hydroxyphenyl)-3-E-styryI-lH-indazole

<img file="MY139999A_D0268.tif" />

A solution of 100 mg (.3 mmol) 6-(3-methoxyphenyl)-3-E-styryl-lH-indazole, from Example 27(b), was cooled to -78 °C and treated with BBr₃ (1.8 ml of a 1M solution in CH₂C1₂, 1.8 mmol). The resulting solution was held at-78 °C for 15 min, then warmed to 0 °C, and held 3 h. A solution of saturated aqueous sodium bicarbonate was then added (10 ml), followed by ethyl acetate (50 ml). The organic layer was washed with brine (20 ml), then concentrated under reduced pressure. Purification by silica gel chromatography gave 6-(3-hydroxyphenyl)-3-E-styryl- 1Hindazole as a white solid (55 mg, 59%). ’H NMR (300 MHz, MeOH-d₄) 8.16 (d,

IH, J=8.5 Hz), 7.71-7.62 (m, 3H), 7.61-7.44 (m, 3H), 7.43-7.35 (m, 2H), 7.33-7.25

-178(m, 2H), 7.20-7.10 (m, 2H), 6.85-6.79 (m, IH); 13.14 (s, IH), 9.60 (s, 1H), 8.20 (d, IH, J=8.4Hz), 7.73 (d, 2H, J=7.3), 7.64-7.52 (m, 5H), 7.47-7.37 (m, 3H), 7.33-7.25 (m, IH), 6.89 (d, 2H, J=8.6Hz).

Example 28(b): 6-(4-hydroxyphenyl)-3-E-styryl-lH-indazole

<img file="MY139999A_D0269.tif" />

6-(4-methoxyphenyl)-3-E-styryl-ΙΗ-indazole, from Example 27(c), was converted to 6-(4-hy droxypheny 1)-3-E-styryl-IH-indazole in a similar manner to that described for Example 28(a). 'HNMR (300 MHz, DMSO-d₆) 13.14 (s, IH), 9.60 (s, 1H), 8.20 (d, IH, J=8.4 Hz), 7.73 (d, 2H, J=7.3 Hz), 7.64-7.52 (m, 5H), 7.47-7.37 (m, 3H), 7.33-7.25 (m, IH), 6.89 (d, 2H, J=8.6 Hz). HRMS (FAB) [M+Na]/z Calc’d

313.1341, found 313.1347. Analyzed with 0.5 H₂O Calc’d, C (78.48), H (5.33), N (8.72). Found: C (78.35), H (5.26), N (8.49).

Example 28(c): 6-(2-hydroxypyridin-5-yl)-3-E-styryl-lH-indazole

<img file="MY139999A_D0270.tif" />

6-(2-Methoxypyridin-5-yl)-3-E-styryl-lH-indazole indazole, from Example

27(k), was converted to 6-(2-hydroxypyridin-5-yl)-3-E-styryl-lH-indazole in a similar manner to that described for Example 28(a). Ή NMR (300 MHz, DMSO-d₆)

8.22 (d, IH, J= 8.4 Hz), 7.96 (dd, IH, J=2.6, 9.65 Hz), 7.81 (d, IH, J=2.0 Hz) ,

-1797.74-7.30 (m, 9H), 6.50 (d, 1H, J=9.4 Hz). HRMS (FAB) [M+H]/z Calc’d 314.1293, found 314.1280. Analyzed with 0.1 trifluoroacetic acid, Calc’d, C (72.69), H (4.86),

N (12.59). Found: C (72.77), H (4.81), N (12.65).

Example 28(d): 6-(3,4-dihydroxyphenyl)-3-E-styryl-lH-indazole

<img file="MY139999A_D0271.tif" />

6-(3,4-Dimethoxyphenyl)-3-E-styryl-lH-indazole, from Example 27()), was converted 6-(3,4-dihydroxyphenyl)-3-E-styryl-ΙΗ-indazole in a similar manner to that described for Example 28(a). Ή NMR (300 MHz, DMSO-d₆) 9.09 (br s, 1H), 9.07 (br s, 1H), 8.20 (d, 1H, J= 8.5), 7.73 (d, 2H, J=7.5 Hz), 7.56 (d, 2H, J=10.1 Hz),

7.53 (s, 1H), 7.43-7.29 (m, 4H), 7.11 (s, 1H), 7.04 (d, 1H, J=8.2 Hz), 6.86 (d, 1H,

J=8.2 Hz). HRMS (FAB) [M+H]/z Calc’d 329.1290, found 329.1274. Analyzed with 1.0 H₂O, Calc’d, C (66.79), H (4.73), N (7.15). Found: C (66.54), H (4.56), N (7.36).

Example 29(a): 6-pyrid-4-yl-3-E-[2-(2,6-dichlorophenyl)ethenyl]-lH-indazole

<img file="MY139999A_D0272.tif" />

6-Pyrid-4-yl-3-E-[2-(2,6-dichlorophenyl)ethenylJ-l-(2-trimethylsilanylethoxymethyl)-lH-indazole was converted to 6-pyrid-4-yl-3-E-[2-(2,6dichlorophenyl)ethenyl]-lH-indazole in a similar manner to that described for Example 27(a). ‘HNMR (300 MHz, CDC1₃) 13.55 (s, 1H), 8.68 (dd, 2H, J=4.6, 1.6 — 180 —

Hz), 8.21 (d, 1H, J=8.5 Hz), 7.96 (s, 1H), 7.81 (dd, 2H, J=4.5, 1.6 Hz), 7.66 (dd, 1H,

J 1=8.5,1.4 Hz), 7.58 (d, 2H, J=8.0 Hz), 7.51 (s, 2H), 7.39-7.32 (m, 1H). MS (FAB) [M+H]/z Calc’d 366, found 366. Analyzed with 0.7 H₂O Calc’d, C (63.40), H (3.83),

N (11.09). Found: C (63.63), H (3.75), N (10.83).

The starting material was prepared as follows:

(i)

Cl

<img file="MY139999A_D0273.tif" />

2, 6-Dichlorobenzyl bromide (1.20 g, 5 mmol) was mixed with triethyl phosphite (1.66 g, 10 mmol) and heated at 150 °C for 2 h. The resulting mixture was then distilled at 160 ⁰ C under reduced pressure (10 mm Hg) to remove the excess triethyl phosphite. (2,6-Dichloro-benzyl)-phosphonic acid diethyl ester was obtained as a colorless liquid (1.46g, 100%). Ή NMR (300 MHz, CDC1₃) 7.33-7.28 (m, 2H), 7.15-7.07 (m, 1H), 4.14-4.02 (m, 4H), 3.60 (d, 2H, J=22.4Hz), 1.27 (t, 6H, J=7.0Hz).

(ϋ)

<img file="MY139999A_D0274.tif" />

Ozone gas was bubbled through a solution of 6-pyrid-4-yl-3-E-styryl-1-(2trimethylsilanyl-ethoxymethyl)-lH-indazole (2.13 g, 5.0 mmol) in THF (25 ml) and

MeOH (25 ml) at -78 °C for 15 min. Argon was then bubbled through the solution for 10 min at-78 °C for 10 min, then dimethyl sulfide (1.46 ml, 20 mmol) was added.

The solution was allowed to warm to rt, and held for 2 h. The solution was poured

-181into brine (300 ml), then extracted with ethyl acetate (3x100 ml). The organics were dried over MgSO₄, then evaporated under reduced pressure. Purification by silica gel chromatography gave 6-pyridin-4-yl-1 -(2-trimethylsilanyl-ethoxymethyl)-1Hindazole-3-carbaldehyde as a white solid (2.2 g, 75%). ’H NMR (300 MHz, CDC1₃)

10.39 (s, 1H), 8.75 (d, 2H, J = 1.6 Hz), 8.45 (d, 1H, J = 2.8 Hz), 7.91 (s, 1H), 7.757.66 (m, 3H), 5.90 (s, 2H), 3.63 (t, 2H, J = 2.7 Hz), 0.93 (t, 2H, J = 2.8 Hz), 0.00 (s,

9H).

(iii)

<img file="MY139999A_D0275.tif" />

A solution of (2,6-dichlorobenzyl)phosphinic acid ciethyl ester (582 mg, 2.0 mmol) in DMF (15 ml) was cooled to 0 °C and treated with NaH (160 mg of 60% in mineral oil, 4.0 mmol). The resulting solution was held at 0 °C for 30 min, then treated with

6-pyridin-4-yl-1 -(2-trimethylsilanyl-ethoxymethyl)-1 H-indazole-3-carbaldehyde (353 mg, 1.0 mmol). The resulting solution was allowed to warm to rt over lh, then held 15 at rt 2h. The solution was poured into brine (250 ml), then extracted with ethyl acetate (3x80 ml). The organics were dried over MgSO₄, then concentrated under reduced pressure. Purification by silica gel chromatography gave 6-pyrid-4-yl-3-E[2-(2,6-dichlorophenyl)ethenyl]-l-(2-trimethylsilanyl-ethoxymethyl)-lH-indazole as a yellow oil (330 mg, 67 %). Ή NMR (300 MHz, CDC1₃) 7.72 (dd, 2H, J=4.6, 1.5

Hz), 8.16 (d, 1H, J=8.5 Hz), 7.84 (s, 1H), 7.62 (ss, 2H, J=4.5, 1.6 Hz), 7.60 (s, 2H),

-1827.56 (dd, IH, J=8.5, 1.5 Hz), 7.39 (d, IH, J=8.1 Hz), 7.18-7.12 (m, IH), 3.64 (t, 2H,

J=8.3 Hz), 0.92 (t, 2H, &gt;8.3 Hz), 0.00 (s, 9H).

Example 29(b): 6-pyrid-4-yl-3-E-[2-(3-methylphenyl)ethenyl]-lH-indazole

<img file="MY139999A_D0276.tif" />

6-Pyridin-4-yl-1 -(2-trimethylsilanyl-ethoxymethy 1)-1 //-mdazole-3 carbaldehyde was converted to the desired product in a similar manner to that described for Example 29(a). ’H NMR (300 MHz, MeOH-d₄) 8.88 (d, IH, J=6.7 Hz), 8.41-8.35 (m, 3H), 8.16 (s, IH), 7.80 (dd, IH, &gt;8.6, 1.6 Hz), 7.67-7.48 (m, 4H), 7.35 (t, IH, &gt;7.6 Hz), 7.22-7.17 (m, IH), 4.88 (s, 3H). MS (FAB) [M+H]/z Calc’d 312, found 312. Analyzed with 0.2 H₂O, 1.1 trifluoroacetic acid Calc’d, C (63.27), H (4.23), N (9.54). Found: C (63.08), H (4.18), N (9.80).

Example 29(c): 6-pyrid-4-yl-3-E-[2-(4-chlorophenvl)ethenyl]-lH-indazole

<img file="MY139999A_D0277.tif" />

6-Pyridin-4-y]-l-(2-trimethylsilanyl-ethoxymethyl)-177-indazole-315 carbaldehyde was converted to the desred product ir a similar manner to that described for Example 29(a). 'H NMR (300 MHz, I)MSO-d₆) 13.40 (s, IH), 8.67 (dd, 2H, &gt;4.6, 1.6 Hz), 8.33 (d, IH, &gt;8.5 Hz), 7.92 (s, IH), 7.81 (dd, 2H, J=4.6, 1.6 Hz), 7.78 (d, 2H, &gt;8.5 Hz), 7.67-7.56 (m, 3H), 7.46 (d, 2H, J=8.5Hz). Analyzed

-183with 0.15 H₂O, Calc’d, C (71.81), H (4.31), N (12.56). Found: C (71.85), H (4.26),

N (12.48).

Example 29(d): 6-pyrid-4-yl-3-E-[2-(biphenyl-4-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0278.tif" />

6-Pyridin-4-yl-l-(2-trimethylsilanyl-ethoxymethyl)-l/7-indazole-3carbaldehyde was converted to Example 29(d) in a similar manner to that described for Example 29(a). Ή NMR (300 MHz, DMSO-d₆) 13.40 (s, IH), 8.68 (d, 2H, J=4.6, 1.5 Hz), 8.35 (d, IH, J=8.5Hz), 7.93 (s, IH), 7.87-7.79 (m, 4H), 7.73 (d, 4H,

J=8.1 Hz), 7.66-7.60 (m, 3H), 7.45 (m, 2H), 7.41-7.34 (m, IH). MS (FAB) [M+H]/z

Calc’d 374, found 374. Analyzed with 0.20 H₂O Calc’d, C (82.82), H (5.19), N (11.15). Found: C (82.82), H (5.19), N (11.16).

Example 29(e): 6-pyrid-4-yl-3-E-[2-(3-methoxyphenyI)ethenyI]-lH-indazole

<img file="MY139999A_D0279.tif" />

6-Pyridin-4-yl-l-(2-trimethylsilanyl-ethoxymethy])-l//-indazole-315 carbaldehyde was converted to Example 29(e) in a similar manner to that described for Example 29(a). Ή NMR (300 MHz, DMSO-d₆) 13.39 (s, IH), 8.67 (d, 2H, J=5.3 Hz), 8.33 (d, 2H, J=8.5 Hz), 7.92 (s, IH), 7.81 (dd, 2H, J=4.6, 1.5 Hz), 7.657.54 (m, 3H), 7.35-7.28 (m, 3H), 3.83 (s, 3H). MS (FAB) [M+H]/z Calc’d 328, found

-184328. Analyzed with 0.20 H₂O Calc’d, C (76.20), H (5.30), N (12.70). Found: C (76.17), H (5.34), N (12.65).

Example 29(f): 6-pyrid-4-yl-3-E-[2-(pyrid-2-vI)ethenyl]-lH-indazole

H

<img file="MY139999A_D0280.tif" />

<img file="MY139999A_D0281.tif" />

6-Pyridin-4-yl-l-(2-trimethylsilanyl-ethoxymethyl)-l//-indazole-3-carbaldehyde was converted to Example 29(f) in a similar manner to that described for Example 29(a). Ή NMR (300 MHz, DMSO-d₆) 8.68 (dd, 2H, &gt;4.5, 1.6 Hz), 8.62 (d, 1H,&gt;3.8 Hz), 8.33 (d, 1H, &gt;8.5 Hz), 7.99 (d, 1H, &gt;16.4 Hz). 7.94 (s, 1H), 7.86-7.78 (m, 3H),

7.73-7.57 (m, 3H), 7.32-7.26 (m, 1H). Analyzed with 0.05 H₂O Calc’d, C (76.26), H (4.75), N (18.72). Found: C (76.22), H (4.79), N (18.76).

Example 29(g): 6-pyrid-4-yl-3-E-[2-(3-fluorophenyl)ethenyl]-lH-indazole

<img file="MY139999A_D0282.tif" />

6-Pyridin-4-yl-l-(2-trimethylsilanyl-ethoxymethyl)-177-indazole-3carbaldehyde was converted to Example 29(g) in a similar manner to that described 15 for Example 29(a). Ή NMR (300 MHz, DMSO-d₆) 13.40 (s, 1H), 8.68 (dd, 2H, &gt;4.5, 1.6 Hz), 8.34 (d, 1H, &gt;8.4 Hz), 7.92 (s, 1H), 7.81 (dd, 2H, Jl=4.5, 1.6 Hz),

7.74-7.52 (m, 5H), 7.49-7.40 (m, 1H), 7.16-7.07 (m, 1H). MS (FAB) [M+H]/z Calc’d 316, found 316. Anal. Calc’d, C (76.17), H (4.48), N (13.33). Found: C (76.07), H (4.53), N (13.36).

-185Example 29(h): 6-pyrid-4-yl-3-E-[2-(2-fluorophenyl)ethenyl]-lH-indazole

<img file="MY139999A_D0283.tif" />

6-Pyridin-4-yl-l-(2-trimethylsilanyl-ethoxymethyl)-177-indazole-3carbaldehyde was converted to Example 29(h) in a similar manner to that described 5 . for Example 29(a). Ή NMR (300 MHz, DMSO-d₆) 13.43 (s, IH), 8.66 (dd, 2H,

J=4.5, 1.6 Hz), 8.23 (d, IH, J=8.2 Hz), 7.98-7.90 (m, 2H), 7.80 (dd, 2H, J=4.5, 1.7

Hz), 7.73-7.54 (m, 3H), 7.40-7.31 (m, IH), 7.30-7.2] (m, 2H). MS (FAB) [M+H]/z Calc'd 316, found 316. Anal. Calc’d, C (76.17), H (4.48), N (13.33). Found: C (76.12), H (4.51), N (13.29).

Example 29(i): 6-pyrid-4-yl-3-E-[2-(3-chlorophenyl)ethenyl]-lH-indazole

<img file="MY139999A_D0284.tif" />

6-Pyridin-4-yl-l-(2-trimethylsilanyl-ethoxymethyl)-177-indazole-3carbaldehyde was converted to Example 29(i) in a similar manner to that described for Example 29(a). Ή NMR (300 MHz, DMSO-d₆) 13.42 (s, IH), 8.68 (dd, 2H,

J=4.5, 1.6 Hz), 8.35 (d, IH, J=8.1 Hz), 7.92 (s, IH), 7.86 (s, IH), 7.82 (dd, 2H, J=4.5,

1.7 Hz), 7.74-7.51 (m, 4H), 7.43 (t, IH, J=7.8 Hz), 7.37-7.21 (m, IH). MS (FAB) [M+H]/z Calc'd 332, found 332. Anal. Calc’d, C (72.40), H (4.25), N (12.67).

Found: C (72.52), H (4.28), N (12.57).

Example 29(j): 6-pyrid-4-yl-3-E-[2-(2-methylthiazol-4-yl)ethenyl]-lH-indazole

-186-

<img file="MY139999A_D0285.tif" />

6-Pyridin-4-yl-l-(2-trimethylsilanyl-ethoxymethyl)-1//-indazole-3-carbaldehyde was converted to Example 29(j) in a similar manner to that described for Example 29(a). Ή NMR (300 MHz, DMSO-d₆) 13.38 (s, IH), 8.67 (dd, 2H, J=4.5, 1.6 Hz), 8.25 (d,

IH, J=8.5 Hz), 7.92 (s, IH), 7.81 (dd, 2H, J=4.5, 1.6 Hz), 7.70-7.50 (m,.4H), 2.72 (s,

3H). MS (FAB) [M+H]/z Calc'd 319, found 319. Analyzed with 0.15 trifluoroacetic acid, Calc’d, C (65.51), H (4.25), N (16.70). Found: C (65.56), H (4.37), N 16.53).

Example 29(k): 6-pyrid-4-yl-3-E-[2-(naphthalen-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0286.tif" />

6-Pyridin-4-yl-l-(2-trimethylsilanyl-ethoxymethyl)-l//-mdazole-3carbaldehyde was converted to Example 29(k) in a similar manner to that described for Example 29(a). Ή NMR (300 MHz, DMSO-d₆) 13.40 (s, IH), 8.68 (dd, 2H, J=4.6, 1.4 Hz), 8.39 (d, IH, J=8.5 Hz), 8.17 (s, IH), 8.09-7.89 (m, 8H), 7.83 (dd, 2H, J=4.6, 1.6 Hz), 7.74 (s, 2H), 7.65 (dd, IH, J=8.5, 1.4 Hz), 7.60-7.46 (m, 4H). MS (FAB) [M+H]/z Calc'd 348, found 348. .Analyzed with 1.05 trifluoroacetic acid,

Calc’d, C (67.10), H (3.89), N (9.00). Found: C (67.20), H (3.93), N (9.05).

Example 29(1): 6-pyrid-4-yl-3-E-[2-(2,3-difluorophenyl)ethenyl]-lH-indazole

-187-

<img file="MY139999A_D0287.tif" />

6-Pyridin-4-yl-l-(2-trimethylsilanyl-ethoxymethyl)-l//-indazole-3carbaldehyde was converted to Example 29(1) in a similar manner to that described for Example 29(a). Ή NMR (300 MHz, CDC1₃ + MeOH-d₄) 8.68 (d, 2H, J=5.6

Hz,), 8.02 (d, 1H, J=8.5 Hz), 7/70 (s, lH), 7.58 (dd, 2H,2=4.8,1.5 Hz), 7.57-7.39 (m

3H), 7.38-7.31 (m, 1H), 7.06-6.96 (m, 2H). MS (FAB) [M+H]/z Calc’d 334, found

334. Analyzed with 0.80 H₂O, Calc’d, C (69.08), H (4.23), N (12.08). Found: C (68.77), H (3.93), N (11.85).

Example 29(m): 6-pyrid-4-yI-3-E-[2-(3,5-difluorophenyl)ethenyl]-lH-indazole

<img file="MY139999A_D0288.tif" />

6-Pyridin-4-yl-1 -(2-trimethylsilanyl-ethoxymethyl)-1 //-indazole-3 carbaldehyde was converted to Example 29(m) in a similar manner to that described for Example 29(a). Ή NMR (300 MHz, MeOH-d₄) 8.69 (d, 2H, J= 6.3 Hz), 8.34 (d, 1H, J= 8.5 Hz), 7.97 (s, 1H), 7.97 (d, 2H, J= 6.3 Hz), 7.71 (d, 1H, J= 10.0 Hz),

7.62 (s 1H), 7.60 (s, 1H), 7.36 (d, 1H,J= 11.11), 6.95- 6.89 (m, 1H). MS (ES) [M+H]/z Calc’d 334, found 334. Anal. Calc’d, C (72.06), H (3.93), N (12.61).

Found: C (72.20), H (4.01), N (12.58).

Example 29(n): 6-pyrid-4-vl-3-E-[2-(biphenyl-3-yl)ethenyl]-lH-indazole

-188-

<img file="MY139999A_D0289.tif" />

6-Pyridin-4-yl-l-(2-trimethylsilanyl-ethoxymethyl)-17/-mdazole-3carbaldehyde was converted to Example 29(n) in a similar manner to that described for Example 29(a). ’HNMR (300 MHz, DMSO-d₆) 8.68 (d, 2H, J= 6.1 Hz ), 8.39 .5 (d, 1H,J=8.5_), 8.04(s, IH), 7.92 (s, IH), 7.82 (d, 2H, J= 6.2 Hz), 7.79-7.37 (m, 11

H). MS (ES) [M+H]/z Calc’d 374, found 374. Anal. Calc’d, C (83.62), H (5.13), N (11.25). Found: C (83.47), H (5.08), N (11.32).

Example 29(o): 6-pyrid-4-yl-3-E-[2-(2,6-difluorophenyl)ethenyl]-lH-indazole

<img file="MY139999A_D0290.tif" />

6-Pyridin-4-yl-l-(2-trimethylsilanyl-ethoxyme±yl)-17/-indazole-3carbaldehyde was converted to Example 29(o) in a similar manner to that described for Example 29(a). Ή NMR (300 MHz, MeOH-d₄) 8.69 (d, 2H, J= 6.3 Hz), 8.21 (d, IH, J= 8.6 Hz), 7.97 (s, IH), 7.88 (d, 2H, J= 6.3 Hz), 7.83 (d, IH, J= 17.1 Hz),

7.71 (IH, J=8.6 Hz), 7.65 ( d, IH, J= 17.1 Hz ), 7.40- 7.35 (m, IH), 7.13-7.08 (m,

2H). MS (ES) [M+H]/z Calc’d 334, found 334. Analyzed with 0.1 H,O, Calc’d, C (71.67), H (3.97), N (12.54). Found: C (71.37), H (3.90), N (12.31).

Example 29(p): 6-pyrid-4-yl-3-E-[2-(3-trfluoromethoxyphenyl)ethenyl]-lHindazole

-189-

<img file="MY139999A_D0291.tif" />

6-Pyridin-4-yl-l-(2-trimethylsilanyl-ethoxymethyl)-177-indazole-3carbaldehyde was converted to Exaniple 29(p) in a similar manner to that described for Example 29(a). Ή NMR (300 MHz, DMSO-d₆) 8.84 (d, 2H, J= 6.4 Hz), 8.43 (d, 1H, J= 8.5 Hz), 8.19 (d, 2H, J= 6.4 Hz), 8.07 (s, 1H), 7.81-7.27 (m, 5H), 7.78 (s,

1H). MS (ES) [M+H]/z Calc’d 382, found 382. Analyzed with 1.0 trifluoroacetic acid, Calc’d, C (55.76), H (3.05), N (8.48). Found: C (55.84), H (3.09), N (8.45).

Example 29(q): 6-pyrid-4-yl-3-E-[2-(benzimidazol-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0292.tif" />

6-Pyridin-4-yl-l-(2-trimethylsilanyl-ethoxymethyl)-l/7-indazole-3carbaldehyde was converted to Example 29(q) in a similar manner to that described for Example 29(a). Ή NMR (300 MHz, DMSO-d₆) 8.69 (d, 2H, J= 6.1 Hz), 8.25 (d, 1H, J= 8.5 Hz), 8.03 (d, 1H, J= 16.7 Hz), 7.97 (s, 1H ), 7.84 (d, 2H, J= 6.2), 7.72 (d, 1H, J= 8.5 Hz), 7.60 - 7.57 (m, 2H), 7.53 (d, 1H, J= 16.7 Hz), 7.22-7.19 (m, 2H).

MS (ES) [M+H]/'z Calc’d 338, £538. Analyzed with 2.0 trifluoroacetic acid, 0.2 H₂O, Calc’d, C (52.77), H (3.08), N (12.31). Found: C (52.59), H (3.17), N (12.18).

Example 29(r): 6-pyrid-4-yl-3-E-[2-(3,4-methylenedioxyphenyl)ethenyl]-lHindazole

-190-

<img file="MY139999A_D0293.tif" />

6-Pyridin-4-yl-1 -(2-trimethylsilanyl-ethoxymethyl)- l/7-indazole-3 carbaldehyde was converted to Example 29r in a similar manner to that described for Example 29(a). 'HNMR (300 MHz, DMSO-d₆) 8.67 (d, 2H, J= 6.1 Hz), 8.30 (d,

IH, J= 8.5 Hz), 7.89 (s,lH), 7.81 (d, 2H, J= 6.1Jiz), 7..61 (d, IH, J= 9.9 Hz), 7.467.42 (m, 3H), 7.18 (d, IH, J= 9.6 Hz), 6.95 (d, IH, 8.0 Hz), 6.05 (s, 2H). MS (ES) [M+H]/z Calc'd 342, found 342. Anal. Calc’d, C (73.89), H (4.43), N (12.31).

Found: C (73.74), H (4.52), N (12.40).

Example 29(s): 6-pyrid-4-yl-3-E-[2-(2,5-difluorophenyI)ethenyl]-lH-indazoIe

<img file="MY139999A_D0294.tif" />

6-Pyridin-4-yl-l-(2-trimethylsilanyl-ethoxymethyl)-lH-indazole-3carbaldehyde was converted to Example 29(s) in a similar manner to that described for Example 29(a). Ή NMR (300 MHz, MeOH-d₄) 8.53 (d, 2H, J=6.0Hz), 8.03 (d, IH, J=8.5Hz), 7.60 (d, 2H, J=6.2Hz), 7.56-7.35 (m, 3H), 7.34-7.26 (m, IH), 7.0315 6.93 (m, IH), 6.90-6.81 (m, IH). MS (ES) [M+Hj/z Calc’d 334, found 334.

Analyzed with 0.30 H_:O, Calc’d, C (70.91), H (4.05), N (12.37). Found: C (70.97),

H (4.17), N (12.37).

Example 29(t): 6-pyrid-4-yl-3-E-[2-(lH-pyrrol-2-yl)ethenyl]-l H-indazole

-191-

<img file="MY139999A_D0295.tif" />

6-Pyridin-4-yl-l-(2-trimethylsilanyl-ethoxymethyl)-lH-indazole-3carbaldehyde was converted to Example 29(t) in a similar manner to that described for Example 29(a). Ή NMR (300 MHz, MeOH-d₄) 8.60 (d, 2H, J=6.3Hz), 8.13 (d,

1H, J=8.5Hz), 7.86 (s&lt;, 1H), 7.79 (d, 2H, J=6.2Hz), 7.57 (dd, 1H, Jl=8.5Hz,

J2=1.5Hz), 7.40 (d, 1H, J=16.8Hz), 7.09 (d, 1H, J=16.7Hz), 6.87-6.82 (m, 1H), 6.406.35 (m, 1H), 6.16 (t, 1H, J=2.9Hz). MS (ES) [M+H]/z Calc’d 287, found 287. Analyzed with 0.5 ethyl acetate, 0.3 tetrahydrofuran, 0.1 hexanes, 0.1 ethylene diamine, Calc’d, C (72.07), H (6.21), N (16.05). Found: C (71.95), H (6.20), N (15.76).

The starting material was prepared as follows:

<img file="MY139999A_D0296.tif" />

(i) A solution of l/7-pyrrole-2-carbaldehyde (9.5 g, 100 mmol) and THF (500 ml) was cooled with an ice bath. Bu'ONa (19.2 g, 200 mmol) was added and reaction mixture was stirred at 0 °C for 1 h. MtsCl (32.7 g, 150 mmol) was then added. The reaction mixture was allowed to warm to rt and held for 2 h at rt. The solution was then treated with saturated aqueous NH₄C1 (100 ml) and the mixture was poured into brine (2 L). The mixture was extraced with EtOAc (3x300 ml). The combined organic layer was dried over MgSO4 and concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography to yield 1 -(2,4,6-trimethyl-192benzenesulfonyl)-l/7-pyrrole-2-carbaldehyde as a light yellow oil (15.7 g, 57%). ’H NMR (CDC1₃) 9.50 (s, IH), 7.79-7.74 (m, IH), 7.12 (dd, IH, J=3.7, 1.8 Hz), 6.95 (s, 2H), 6.38 (t, IH, J=3.4 Hz), 2.50 (s, 6H), 2.30 (s, 3H).

// V 'N MTs

OH (ii) l-(2,4,6-Trimethyl-benzenesulfonyl)-l/7-pyrrole-2-carbaldehyde (2.77 g, 10 mmol) in THF (100 ml) was treated with LiBH₄ (0.44 g, 20 mmol) at rt. The resulting solution was held at rt for 1 h. MeOH (10 ml) was then added, and the resulting mixture mixture was poured into brine (600 ml), and extracted with EtOAc (3x200 ml). The combined organic layer was dried over MgSO4 and concentrated under reduced pressure. The resulting oil was then purified on silica gel column to yield [l-(2,4,6-Trimethyl-benzenesulfonyl)-l/7-pyrrol-2-yl]-methanol as a light brown oil (2.43 g, 87%). 'HNMR(CDC1₃) 7.17 (dd, IH, J=3.3, 1.8 Hz), 6.99 (s, 2H), 6.28-6.23 (m, IH), 6.18 (t, IH, J=3.3 Hz), 4.42 (s, 2H), 2.50 (s, 6H), 2.30 (s,

3H).

N

MTs (iii) A solution of [l-(2,4,6-Trimethyl-benzenesulfonyl)-l//-pyrrol-2-yl]-methanol (1.4 g, 5.0 mmol) in CHC13 (25 ml) was cooled with an ice bath. SOC1₂ (1.1 ml, 15 mmol) was added slowly. The solution was allowed to warm to rt, and held an additional 45 min. The solution was then concentrated under reduced pressure. 2Chloromethyl-l-(2,4,6-trimethyl-benzenesulfonyl)-T/7-pyrrole was obtained as a brown solid (1.5 g, 100%). ’HNMR(CDC1₃) 7.23 (dd, IH, J=3.3, 1.7 Hz), 6.98 (s,

-1932H), 6.38-6.34 (m, IH), 6.19 (t, 1H, &gt;3.4 Hz), 4.58 (s, 2H), 2.50 (s, 6H), 2.30 (s,

3H).

Example 29(u): 6-pyrid-4-yI-3-E-[2-(3methylcarbamoylmethoxyphenyl)ethenyl]-lH-indazole

<img file="MY139999A_D0297.tif" />

6-Pyridin-4-yl-l-(2-trimethylsilanyl-ethoxymethyl)-l//-indazole-3carbaldehyde was converted to Example 29(u) in a similar manner to that described for Example 29(a). Ή NMR (300 MHz, MeOH-d₄) 8.68 (d, 2H, &gt;5.9 Hz), 8.51 (br s, IH), 8.37 (d, IH, J=8.5 Hz), 8.19 (s, 1H), 7.93 (s.lH), 7.87 (d, IH, &gt;7.7 Hz), 7.85 (d, 2H, &gt;6.1 Hz), 7.62 (d, IH, &gt; 8.1 Hz), 7.65 - 7.63(m, 3H), 7.51 (t, IH, &gt;7.6Hz).

MS (ES) [M+H]/z Calc'd 355, found 355. Analyzed with 0.4 trifluoroacetic acid,

0.50 H,O, Calc’d, C (69.67), H (4.98), N (14.26). Found: C (69.78), H (5.18), N (14.08).

Example 30(a): 6-[3-benzamidophenoxy]-3-E-[2-(thien-2-yI)ethenyl]-lH-indazoIe

<img file="MY139999A_D0298.tif" />

Example 30(a) was prepared in a manner similar to example 6(a) except that (E)-3-thiophen-2-yl-acryloyl chloride was used in place of 3-(4chlorophenyl)acryloyl chloride in step (i). ’H NMR (DMSO-d₆) 13.05 (s, IH),

-19410.33 (s, IH), 8.19 (d, IH, J = 8.8 Hz), 7.92 (d, 2H, J = 6.9 Hz), 7.70 (d, IH, J = 16.5 Hz), 7.65-7.49 (m, 6H), 7.40 (t, IH, J = 8.1 Hz), 7.35 (s, IH, with fine splitting), 7.20 (d, IH, J = 16.5 Hz),7.10 (m, IH), 7.04 (s, IH), 6.98 (d, IH, J = 8.8 Hz), 6.86 (s, IH,

J = 9.8 Hz). Anal. Calc for C₂₆H₁₉N₃O₂S 0.6 H₂O: C, 69.65; H, 4.54; N, 9.37; S,

7.15. Found: C, 69.77; H, 4.45; N, 9.52; S, 7.02.

Example 30(b) 6-(3-(1-acetylpiperidin-4-ylcarboxamido)phenoxy]-3-E-[2-(4chlo ro phenyl)ethenyl] -1 H-indazo Ie

<img file="MY139999A_D0299.tif" />

H

Example 30(b) was prepared in a similar manner to that described for 6(a) except that 1 -acetyl-piperidine-4-carboxylic acid and HATU was used in place of benzoyl chloride in step(ii). 'H NMR (DMSO-d₆) (J = 8.6 Hz) 7.76, (d, J = 8.6 Hz), 7.53 (d, J = 6.2 Hz), 7.46 (d, J = 8.4 Hz), 7.37 (m, 3H), 7.01 (s, IH, with fine splitting), 6.97 (d, J = 8.8 Hz), 6.78 (d, J = 7.7 Hz), 4.38 (m, IH), 3.85 (m, IH), 3.092.96 (m, IH), 2.58 (m, 2H), 1.99 (s, 3H), 1.77 (m, 2H), 1.55 (m, IH), 1.37 (m, IH).

Anal. Calc for C₂₉H₂₇C1N₄O₃' 1.3 H₂O: C, 64.69; H, 5.54; N, 10.41. Found: C,

64.64; H, 5.51; N, 10.23.

Example 30(c): 6-[3-benzamidophenoxy]-3-E-[2-(fur-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0300.tif" />

-195Example 30(c) was prepared in a manner similar to example 6(a) except that (E)-3-furan-2-yl-acryloyl chloride, prepared according to Collect, Czech. Chem.

Comm., 52, 409-24 (1987), was used in place of 3-(4-chlorophenyl)-acryloyl chloride in step (i). Ή NMR (DMSO-d₆) 13.00 (s, 1H), 10.32 (s, 1H), 8.14 (d, 1H, J = 8.8

Hz), 7.91 (d, 2H, J = 7.0 Hz), 7.73 (s, 1H), 7.70-7.51 (m, 5H), 7.40 (t, 1H, J = 8.4

Hz), 7.30 (AB, 2H, J = 16.7 Hz), 7.04 (s, 1H), 6.98 (d, 1H, J = 8.7 Hz), 6.86 (d, 1H, J = 8.0 Hz), 6.65 (s, lH,with fine splitting), 6.60 (s, 1 H,with fine splitting). Anal. Calc for C₂₆H₁₉N₃O₂ 0.7 H₂O: C, 71.94; H, 4.74; N, 9.68. Found: C, 72.17; H, 4.83; N,

9.44.

Example 30(d): 6-[3-(indol-4-ylcarboxamido)pheuoxy]-3-E-stryryIindazoIe

<img file="MY139999A_D0301.tif" />

<img file="MY139999A_D0302.tif" />

Example 30(d) was prepared in a similar manner to that described for Example 30(a) using 3-(styryl-lH-indazol-6-yloxy)-phenylamine in place of 3-(3styryl-4,5-dihydro-lH-indazol-6-yloxy)phenylamine and lH-indole-4-carboxylic acid in place of benzoic acid in step (ii). ’HNMR (DMSO-d₆) 12.99 (s, 1H), 11.33 (s, 1H), 10.24 (s, 1H), 8.22 (d, 1H, J = 8.7 Hz), 7.72-7.38 (m, 10H), 7.30 (d, 1H, J = 7.1

Hz), 7.19 (m, 2H), 7.04 (m, 3H), 6.82 (m, 2H). Anal. Calc for C₃₀H₂₂N₄O₂ 0.6 H₂O:

C, 74.86; H, 4.86; N, 11.64. Found: C, 74.90; H, 5.01; N, 11.33.

Example 30(e): 6-[3-((l-Ethyl-3-methyl-lH-pyrazoI-5-yl)carboxamido)phenoxy]20 3-E-stryryIindazoIe

-196-

<img file="MY139999A_D0303.tif" />

Example 30(e) was prepared in a similar manner to that described for

Example 30(a) using 3-(styryl-lH-indazol-6-yloxy)-phenylamine in place of 3-(3styryl-4,5-dihydro-lH-indazol-6-yloxy)phenylamine and 1-ethyl-3-methyl-1H5 pvrazole-5-carboxylic acid in place of benzoic acid :in step (ii).

Example 31(a): 6-[3-benzamidophenoxy]-3-E-[2-(pyridin-2-yl)ethenyl]-lHindazole

<img file="MY139999A_D0304.tif" />

<img file="MY139999A_D0305.tif" />

To a stirred solution of 6-[3-benzamidophenoxy]-3-E-[2-(pyridin-210 yl)ethenyl]-4,5-dihydro-lH-indazole (492 mg, 1.13 mmol) in 15 mL of 1,4-dioxane was added 386 mg (1.7 mmol) 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ).

The reaction mixture was stirred for 30 min at room temperature, then poured into sat

NaHCO₃ solution and EtOAc. Layers were separated and the aqueous layer was reextracted with EtOAc. The combined organic layers were washed sequentially with sat NaHCO₃ solution and sat NaCl solution, dried over MgSO₄ and cone, under reduced pressure. The residue was flash chromatographed on silica gel eluting

CH₂Cl₂/EtOAc: MeOH (1:1:0.1). The oil obtained was triturated from EtOAc/hexanes to give the title compound as a tan solid (420mg, 86%). ’H NMR

-197(DMSO-d₆) 13.12 (s, 1H), 10.30 (s, 1H), 8.60 (d, 1H, J = 3.8 Hz), 8.22 (d, 1H, J = 8.8 Hz), 7.93 (m, 3H), 7.82 (t, 1H, J = 7.7 Hz), 7.68 -7.49 (m, 7H), 7.40 (t, 1H, J = 8.1 Hz), 7.27 (m, 1H), 7.08 (s, 1H), 7.03 (s,lH), 7.03 (d, 1H, J = 8.7 Hz), 6.87 (d, 1H, J = 8.1 Hz, wi± fine splitting). Anal. Calc for C₂₇H_2[N₄O₂ 0.65 EtOAc : C, 72.59;

H, 5.19; N, 11.44. Found: C, 72.34; H, 5.11; N, 11.82.

The starting material was prepared as follows:

step (i)

<img file="MY139999A_D0306.tif" />

3) n&gt;H₄ β,ο

A solution of 3-[3-(benzhydrylidene-amino)-phenoxy]-cyclohex-2-enone (4.00g, 10.9 mmol) in 20 mL of THF was added slowly to a-78 °C solution of LiHMDS (36 mL of 1.0M solution in THF). Fifteen minutes after addition was complete, (E)-3pyridin-2-yl-acryloyl chloride hydrochloride was added and stirring was continued at

-78 °C for 30 min. The reaction was quenched with sat. NH₄C1 solution and extracted with EtOAc (3x). The combined organic layers were washed with sat NaCl solution, dried over MgSO₄ and cone, under reduced pressure. The residue was flash chromatographed on silica gel eluting Hexanes/EtOAc (2:1). The appropriate fractions were concentrated under reduced pressure and dissolved in EtOH/HOAc (1:1, 8ml). To this solution at 80 °C was added hydrazine hydrate (3.4ml, 70.0 mmol). After 15 min, all starting material was gone and the reaction mixture was cautiously poured into sat. NaHCO₃ and extracted with EtOAc (2x). The combined

-198organic layers were washed with sat NaCI solution, dried over MgSO₄ and cone.

under reduced pressure. The residue was flash chromatographed on silica gel eluting

CH₂Cl₂/MeOH (9:1) to give 6-(3-aminophenoxy)-3-E-[2-(pyridin-2-yl)ethenyl]-4,5dihydro-lH-indazole (676mg, 19%). Ή NMR (DMSO-d₆) 12.51 (s, IH), 8.57 (d, IH, J = 3.8 Hz), 7.78 (t, IH, J = 7.8 Hz), 7.51 (m, 2H), 7.25 (m, IH), 7.05 (m, 2H),

6.35 (d, IH, J = 7.9 Hz, with fine splitting), 6.32 (t, IH, J = 2.1 Hz), 6.23 (d, IH, J =

7.9 Hz), 5.54 (s, 1H), 5.23 (s, 2H), 2.95 (t, 2H, J = 8.2 Hz), 2.60 (t, 2H, J = 8.2 Hz); MS [m+H]/z Calc’d 331. Found 331. Anal. Calc for C₂₀H₁₈N₄O'0.15 H₂O: C, 72.12;

H, 5.54; N, 16.82. Found: C, 72.11; H, 5.55; N, 16.61.

step (ii)

<img file="MY139999A_D0307.tif" />

To a stirred solution ofthe dihydro aniline (350mg, 1.06 mmol) and benzoic acid (776mg, 6.36mmol) in 15 mL of DMF, was added FIATU (2.42g, 6.36mmol) and

NEt₃ (1.8ml, 12.71 mmol). The reaction mixture was heated at 50°C for 1.5 hr, cooled and poured into ice/sat NaCI solution. The ppt was collected by vacuum filtration, washed with H₂O and air dried. To this filter cake dissolved in 10 mL of MeOH/THF (1:1), was added K₂CO₃ (650mg) and 1 mL of H,O. After lhr, the reaction mixture was poured into sat NaCI solution and extracted with EtOAc (2x).

The combined organic layers were washed with sat NaCI solution, dried over MgSO₄ and cone, under reduced pressure. The residue was flash chromatographed on silica gel eluting CH₂Cl₂/EtOAc/MeOH (1:1:0.1) to give 6-[3-benzamidophenoxy]-3-E-[2-199(pyridin-2-yl)ethenyl]-4,5-dihydro-lH-indazole (333mg, 72%). 'HNMR (DMSO-d₆) 12.58 (bs, IH), 10.34 (s, IH), 8.57 (d, IH, J = 3.8 Hz), 7.95 (d, 2H, J = 6.8 Hz),

7.81 -7.70 (m, 2H), 7.63-7.50 (m, 6H), 7.40 (t, IH, J = 8.1 Hz), 7.25 (m, IH), 7.09 (d,lH, J = 16.3 Hz), 6.89 (d, IH, J = 8.0 Hz ), 5.64 (s, IH), 2.99 (t, 2H, J = 8.1 Hz),

2.66 (t, 2H, J = 8.1 Hz). Anal. Calc for C₂₇H₂₂N₄O₂ 0.1 CH₂C1₂: C, 73.48; H, 5.05;

N, 12.65. Found: C, 73.48; H, 5.05; N, 12.48.

Example 31 (b): 6-(3-((1,5-DimethyI-lH-pyrazol-3-yl)carboxamido)phenoxy]-3-E [2-(pyridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0308.tif" />

Example 31 (b) was prepared in a similar manner to that described for

Example 31(a) except that l,5-dimethyl-lH-pyrazole-3 carboxylic acid was used in place of benzoic acid in step (ii). 'H NMR (DMSO-d₆) 13.13 (s, IH), 10.07 (s, IH), 8.60 (d, IH, J = 4.3 Hz), 8.21 (d, IH, J = 8.7 Hz), 7.93 (d, IH, J = 16.3 Hz), 7.82 (t, IH, J = 7.4 Hz), 7.69 (m, 3H), 7.56 ( d, IH, J = 16.3 Hz), 7.32 (m,

2H), 7.05 (s, IH), 7.01 (d, IH, J = 8.7 Hz), 6.80 (m, IH), 6.52 (s,lH), 3.81 (s, 3H)

2.29 (s, 3H). Anal. Calc for C₂₆H₂₂N₆O₂ 0.1 CH₂C1₂70.1 hexanes : C, 68.58; H,

5.09; N, 17.97. Found: C, 68.26; H, 5.25; N, 17.61

Example 31(c): 6-[3-((5-methylsulfonylthien-2-yl)carboxamido)phenoxy]-3-E-[2 (pyridin-2-yI)ethenyI]-lH-indazo!e

-200-

<img file="MY139999A_D0309.tif" />

Example 31 (c) was prepared in a similar manner to that described for Example 31(a) except that 5-methanesulfonyl-thiophene-2-carboxylic acid was used in place of benzoic acid in step (ii). 'H NMR (DMSO-d₆) 13.17 (s, IH),

10.58 (s, IH), 8.61 (d, IH, J = 4.0 Hz), 8.24 (d, IH, J = 8.8 Hz), 8.05_(d, IH, J =.

4.1 Hz), 7.97 -7.79 (m, 3H), 7.68 (d, IH, J = 7.8 Hz), 7.60-7.48 (m, 3H), 7.43 (t,

IH, J = 8.2 Hz), 7.28 (m, IH), 7.10 (s,lH, with fine splitting), 7.00 (d, IH, J = 8.7 Hz), 6.92 (d, IH, J = 8.1 Hz, with fine splitting), 3.41 (s, 3H). Anal. Calc for C₂₆H₂₀N₄O₄S₂'0.4 EtOAc : C, 60.07; H, 4.24; N, 10.15; S, 11.62. Found: C,

60.22; H, 4.48; N, 10.05; S, 11.49.

Example 31(d): 6-[3-((l-Ethyl-3-methyl-lH-pvrazol-5yl)carboxamido)phenoxy]-3-E-[2-(pyridin-2-yI)ethenyl]-lH-indazole

<img file="MY139999A_D0310.tif" />

Example 31 (d) was prepared in a similar manner to that described for 15 Example 31 (a) except that 1 -ethyl-3-methyl-1 H-pyrazole-5-carboxylic acid was used in place of benzoic acid in step (ii). *H NMR (DMSO-d₆) 13.15 (s, IH), 10.18 (s, IH), 8.61 (d, IH, J = 3.7 Hz), 8.22 (d, IH, J = 8.8 Hz), 7.94 (d, IH, J = 16.3 Hz), 7.82 (t, IH, J = 7.5 Hz), 7.67 (d, IH, J = 7.7 Hz), 7.55 (m, 3H), 7.40 (t, IH, J = 8.1 Hz),

-2017.28 (m, 1H), 7.06 (s, 1H), 7.01 (d, 1H, J = 8.8 Hz), 6.89 (d, 1H, J = 7.9 Hz), 6.78 (s,

1H), 4.38 (q, 2H, J = 7.1 Hz), 2.19 (s, 3H), 1.29 (t, 3H, J = 7.1 Hz). Anal. Calc for

C₂₇H₂₄N₆O₂ 0.6 EtOAc : C, 68.25; H, 5.61; N, 16.24. Found: C, 68.28; H, 5.88; N,

16.01.

Example 31(e): 6-[3-((l-Methylimidazol-2-yl)carboxamido)phenoxy]-3-E-[2(pyridin-2-vl)ethenyl]-lH-indazole

<img file="MY139999A_D0311.tif" />

H /

Example 31(e) was prepared in a similar manner to that described for

Example 31(a) except that l-methyl-lH-imidazole-2-carboxylic acid was used in 10 place of benzoic acid in step (ii). 'HNMR (DMSO-d₆) 13.13 (s, 1H), 10.47 (s,

1H), 8.60 (d, 1H, J = 3.9 Hz), 8.21 (d, 1H, J = 8.7 Hz), 7.93 (d, 1H, J = 16.3 Hz),

7.82 (t, 1H, J = 7.6 Hz), 7.65 (m, 3H), 7.56 ( d, 1H, .1 = 16.3 Hz), 7.43 (s, 1H), 7.37 (t,

1H, J = 8.1 Hz), 7.28 (m,lH), 7.04 (m, 3H), 6.84 (d, 1H, J = 7.7 Hz), 3.95 (s, 3H). Anal. Calc for C₂₅H₂₀N₆O₂ 0.4 H,O: C, 67.49; H, 4.80; N, 18.65. Found: C, 67.68;

H, 4.73; N, 18.94.

Example 31(f): 6-[3-((l-Ethvl-3-methyl-lH-pyrazol-5-yl)carboxamido)phenoxy]3-E-[2-(l,2-dimethyl-lH-imidazol-4-yI)ethenyl]-lH-indazoIe

-202-

<img file="MY139999A_D0312.tif" />

Example 31 (f) was prepared in a similar manner to that described for Example

31(a) except that (E)-3-(l,2-dimethyl-lH-imidazol-4-yl)acryloyI chloride hydrochloride was used in place of (E)-3-pyridin-2-vl-acryloyl chloride hydrochloride in step (i) and 1-ethyl-3-methyl-lH-pyrazole-5-carboxylic acid was used in place of benzoic acid in step (ii). ’HNMR (DMSO-d₆) 12.82 (s, 1H), 10.17 (s, 1H), 8.05 (d, 1H, J = 8.8 Hz), 7.58 (d, 1H, J = 8.4 Hz), 7.48 (s, 1H), 7.38 (t, 1H, J = 8.1 Hz), 7.25 (s, 2H), 7.20 (s, 1H), 7.01 (s, 1H), 6.92 (d, 1H, J = 8.7 Hz), 6.85 (d,

1H, J = 8.7 Hz), 6.78 (s, 1H), 4.37 (q, 2H, J = 7.0 Hz), 3.56 (s, 3H), 2.31 (s, 3H),

2.19 (s, 3H), 1.29 (t, 3H, J = 7.0 Hz). Anal. Calc for C₂₇H₂₇N₇O₂ 1.0 H₂O · 0.3

EtOAc: C, 64.39; H, 6.02; N, 18.64. Found: C, 64.52; H, 5.98; N, 18.52.

Example 32(a): 6-[3-benzamidophenoxy]-3-E-[2-(lH-imidazol-4-yl)ethenyI]-lHindazole

<img file="MY139999A_D0313.tif" />

<img file="MY139999A_D0314.tif" />

To a stirred solution of the 6-(3-benzamidophenoxy)-3-E-[2-( 1-(2trimethylsilanyl-ethoxy)-methyl-imidazol-4-yl)ethenyl]-1 H-indazole compound (213mg, 0.39mmol) in 5 mL of THF was added 1.0 M TBAF in THF (6.0ml,

6.0mmol) and ethylenediamine (0.26ml, 3.86mmol). After heating at 70 °C for 18 h,

-203the reaction mixture was cooled, diluted with EtOAc, and washed repeatedly with sat

NaHCO₃ solution. The organic layer was dried over MgSO₄ and cone, under reduced pressure. The residue was flash chromatographed on silica gel eluting CH₂Cl₂:EtOAc: MeOH (1:1:0.2). The oil obtained was triturated from

EtOAc/hexanes to give AG13853 (65mg, 40%). Ή NMR (DMSO-d₆) 12.90 (s,

IH), 12.35 (s, IH), 10.32 (s, 1H), 8.08 (d, IH, J = 8.7 Hz), 7.91 (d, 2H, J = 6.8 Hz), 7.81 (s, IH), 7.64-7.49 (m, 5H), 7.42-7.31 (m, 4H), 7.03 (s, IH), 6.96 (d, IH, J = 8.7 Hz), 6.85 (d, IH, J = 8.1 Hz). Anal. Calc for C₂₅H₁₉N₅O₂ 0.7 H₂O' 0.4 EtOAc: C,

68.07; H, 5.07; N, 14.92. Found: C, 67.93; H, 4.89; N, 15.06.

The starting material was prepared in a similar manner to that desribed for Example 31(a) except that (E)-3-{l-(2-trimethylsilanyl)-ethoxymethyl)-lH-imidazol-4-yl]acryloyl chloride hydrochloride was used in place of (E)-3-pyridin-2-yl-acryloyl chloride hydrochloride in step (i).

Example 32(b): 6-[3-((l-Ethyl-3-methyl-lH-pyrazol-5-yI)carboxamido)phenoxy]15 3-E-[2-(lH-imidazoI-4-yl)ethenyI]-lH-indazoIe

<img file="MY139999A_D0315.tif" />

Example 32(b) was prepared in a similar manner to that described for Example 32(a) except that 1 -ethyl-3-methyl-lH-pyrazole-5-carboxylic acid was used in place of benzoic acid in step (ii). ’H NMR (DMSO-d₆) 12.89 (s, IH), 12.37 (s,

IH), 10.18 (s, 1H), 8.07 (d, IH, J = 8.9 Hz), 7.74 (s, 1H), 7.58 (d, 1H,J = 8.3 Hz),

-2 047.49 (s, IH), 7.44-7.32 (m, 3H), 7.28 (s, IH), 7.01 (s,lH), 6.95 (d, IH, J = 8.9 Hz),

6.86 (d, IH, J = 8.6 Hz), 6.78 (s, IH), 4.38 (q, 2H, J = 7.1 Hz), 2.19 (s, 3H), 1.29 (t, 3H, J = 7.1 Hz). Anal. Calc for C₂₅H₂₃N₇O₂ 0.8 H₂Q 0.1 EtOAc: C, 63.99; H, 5.37;

N, 20.57. Found: C, 63.72; H, 5.12; N, 20.25.

Example 32(c): 6-[3-((l-Ethyl-3-methyl-lH-pyrazol-5-yl)carboxamido)phenoxy]3-E-[2-(2-methylimidazol-4-yl)ethenyl]-lH-indazoIe

<img file="MY139999A_D0316.tif" />

Example 32(c) was prepared in a simialr manner to that described for 32(b) except that ( E)-3-[2-methyl-l-(2-trimethylsilanyl)-e'thoxymethyl)-lH-imidazol-410 yl]-acryloyl chloride hydrochloride was used in place of (E)-3-[ 1-(2trimethylsilanyl)-ethoxymethyl)-1 H-imidazol-4-yl] -acryloyl chloride hydrochloride in step (i). Ή NMR (DMSO-d₆) 12.85 (bs, IH), 11.80 (bs, IH), 10.18 (s, IH), 8.05 (d, IH, J = 8.7 Hz), 7.58 (d, IH, J = 8.4 Hz), 7.48 (s, IH), 7.39 (t, IH, J = 8.2 Hz),

7.33-7.05 (m, 3H), 7.00 (s,lH), 6.93 (d, IH, J = 8.7 ELz), 6.86 (d, IH, J = 8.2 Hz),

6.78 (s, IH), 4.38 (q, 2H, J = 7.1 Hz), 2.31 (s, 3H), 2.19 (s, 3H), 1.29 (t, 3H, J = 7.1

Hz). Anal. Calc for C₂₆H₂₅N₇O₂ 0.9 H₂O 0.4 EtOAc: C, 63.87; H, 5.83; N, 18.89.

Found: C, 63.64; H, 5.76; N, 18.85.

Example 33(a): 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2yl)ethenyl] indazole

-205-

<img file="MY139999A_D0317.tif" />

Example 33(a) was prepared from 6-[2-(methylcarbamoyl)phenylsulfanyl]-3E-[2-(pyridin-2-yl)ethenyl]-l-[2-(trimethyl-silanyl)ethoxymethyl]-lH-indazole in a similar manner to that described for Example 11. Rf sm 0.8, p 0.15 (ethyl acetate);

Ή NMR (300 MHz, dmso-d6) 13.45 (s, IH), 8.72 (d, IH, J = 3.9 Hz), 8.47 (m, IH), 8.31 (d, IH, J = 8.5 Hz), 8.06 (d, IH, J = 16.4 Hz), 7.92 (dt, IH, J = 1.7, 7.6 Hz), 7.78 (d, IH, J = 7.8 Hz), 7.71 (s, IH), 7.68 (d, IH, J = 16.5 Hz), 7.61 (dd, IH, J = 1.7, 7.2

Hz), 7.45-7.36 (m, 3H), 7.31 (d, IH, J = 8.5 Hz), 7.17 (m, IH), 2.89 (d, 3H, J = 4.6 Hz); ¹³C NMR (75 MHz, dmso-d6) 167.8, 154.8, 149.5, 141.9, 141.8, 137.0, 136.8,

135.4, 132.5, 130.2, 130.0, 129.2, 127.7, 126.1, 125.4, 123.5, 122.5, 122.4, 121.6,

120.2, 114.5; LCMS (100% area) Rt = 3.5 min (pos) [M+H]/z Calc'd 387, found 387. Analyzed with 0.1 H₂O, 0.1 EtOAc Calc’d, C (67.78), H (4.82), N (14.11), S (8.08).

Found: C (67.78), H (4.77), N (14.06), S (8.08).

The starting material was prepared as follows:

(i)

<img file="MY139999A_D0318.tif" />

Under argon, 6-iodo-3-styryl- l-[2-(trimethyl-silanyl)-ethoxymethyl]-lH-indazole (30.0 g, 62.9 mmol) prepared in Example 14, step (i), was dissolved in dichloromethane (375 mL) and was cooled to -42 °C in an acetonitile-dry ice bath.

-206Ozone was then bubbled through the mix (1 L/min, 60 V, 1.8 Amps) for 45 min. Standard indicators did not give a clear color change due to the solutions background color. To avoid over-oxidation, the reactions progress was monitored by TLC (1:9 EtOAc-Hex). The ozone addition was stopped and the flask was flushed with argon.

Dimethyl sulfide (30 mL) was then added and the mixture was allowed to warm to 23 °C. This mixture was stirred for 4h and was concentrated under reduced pressure.

The oil was placed under high vacuum for 16 h. The residue was dissolved in dichloromethane (15 mL) and was diluted with hexane (100 mL) to give some crystals (not desired product). The mixture was filtered and the filtrate was concentrated. The residue was dissolved in 8:2 Hex-EtOAc (250 mL), treated with mL silica., filtered, and concentrated. 6-lodo-3-carboxaldehyde-l-[2-(trimethylsilanyl)-ethoxymethyl]-lH-indazole formed as a yellow solid after 72 h under high vacuum (24.17 g, -95% pure by NMR, 91 % yield): Ry sm 0.34, p 0.29 (ethyl acetate-hexane 1:9); ’HNMR (300 MHz, CDC1₃) 10.25 (s, 1H), 8.09 (s, 1H), 8.05 (d, 1H), 7.80 (d, 1H), 5.88 (s, 2H), 3.71 (t, 2H), 0.93 (t, 2H), 0.0 (s, 9H).

(ii)

<img file="MY139999A_D0319.tif" />

6-Iodo-3-carboxaldehyde-l-[2-(trimethyl-silanly)-ethoxymethyl]-lH-indazole (24.0 g, 59.7 mmol) was dissolved in THF (350 mL) and was cooled to -5 °C. To this was added solid 2-picolyltriphenylphosphonium chloride-potassium hydride (45.7 g, 100

-207mmol, 1.68 equiv). The reaction mixture was allowed to stir for 45 min. To the mixture, was added 3N HCI (20 mL) followed by saturated aqueous sodium bicarbonate (50 mL) to give a pH of 6. Excess THF was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The 5 organics were washed with saturated aqueous sodium bicarbonate, water and the organic layer was separated, dried over sodium sulfate, decanted and concentrated under reduced pressure. The residue was taken up in 1:9 ethyl acetate-hexane and was filtered. The filtrate was purified by silica gel chromatography (2L silica, 20 to to 50 % ethyl acetate-hexane) to give 6-Iodo-3-E-[2-(pyridin-2-yl)ethenyl-l-[210 (trimethyl-silanly)-ethoxymethylJ-lH-indazole (18.9 g, 66% yield): Rf sm 0.52, p

0.25 (ethyl acetate-hexane 2:8); ’HNMR (300 MHz, CDC1₃) 8.64 (m, IH), 8.00 (d, IH, J = 0.7 Hz), 7.87 (d, IH, J = 16.4 Hz), 7.80 (d, IH, J = 8.5 Hz), 7.69 (td, IH, J =

Ί.Ί, 1.8 Hz), 7.55 (d, IH, J = 16.4 Hz), 7.55 (dd, IH, J = 8.5, 1.3 Hz), 7.47 (d, IH, J = 7.9 Hz), 7.18 (dd, IH, J = 1.1,4.8 Hz), 5.70 (s, 2H), 3.59 (t, 2H, J = 8.2 Hz), 0.90 (t,

2H, J = 8.2 Hz),-0.04 (s, 9H); ¹³C NMR (75 MHz, CDC1₃) 156.8,151.2,144.2,

143.6, 138.0, 132.3, 132.2, 124.4, 124.0, 123.8, 123.7, 123.5, 120.7, 94.1, 79.4, 68.1,

19.17,0.0.

(iii)

<img file="MY139999A_D0320.tif" />

In a 200 mL round bottom flask was weighed cesium carbonate (13.7 g, 41.9 mmol,

2.5 equiv) and this salt was dried under high vacuum with a heat gun. The catalyst

-208[Pd(dppf)Cl₂-CH₂Cl₂] (1.37g, 1.68 mmol, 0.1 equiv) and 6-Iodo-3-E-[2-(pyridin-2yl)ethenyl-l-[2-(trimethyl-silanly)-ethoxymethyl]-l H-indazole (8.0 g, 16.76 mmol) were then added and the mix was taken up in DMF (71 mL). To this mixture was added methyl thiosalicylate (4.62 mL, 33.5 mmol, 2.0 equiv) and the vessel was warmed to 85 °C for 4.5 h. This mixture was cooled to 23 °C, was partitioned between ethyl acetate (350 mL) and 50%-saturated aqueous sodium bicarbonate (300 mL). The organics were washed with 10% sodium bisulfite (200 mL), brine and the organic layer was separated. The organic material was dried over sodium sulfate, decanted and concentrated under reduced pressure. Purification by silica gel chromatography (500 mL silica; 30 to 40 to 50% ethyl acetate-hexane) gave 6-[(2methoxycarbonylphenyl)sulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-l-[2-(trimethylsilanyl)ethoxymethyl]-lH-indazole (6.44 g, 74%); Rf sm 0.52, p 0.19 (ethyl acetatehexane 3:7); FTIR (thin film) 2950, 2887, 2356, 1713, 1585, 1464, 1433, 1250,

1076, 837 cm·'; ’HNMR (300 MHz, CDC1₃) 8.70 (d, 1H), 8.12 (d, 1H), 8.04 (d,

1H), 7.99 (d, 1H, J = 16.4 Hz), 7.90 (s, 1H), 7.88 (t. 1H), 7.76 (d, 1H, jJ = 16.4 Hz),

7.62 (d, 1H), 7.55 (d, 1H), 7.30-7.15 (m, 3H), 6.92 (d, 1H), 5.80 (s, 2H), 4.01 (s, 3H), 3.78 (t, 2H), 0.96 (t, 2H),-0.03 (s, 9H); ¹³CNMR(75 MHz, CDC1₃) 168.3, 156.8,

151.2, 144.3, 144.2, 143.2, 138.0, 133.8, 133.6, 132.5, 132.4, 129.9, 129.3, 128.5,

126.0, 124.7, 124.6, 123.8, 123.5, 118.3, 79.4, 68.2, 53.7, 19.2, 0.0; LCMS (100% area) Rt = 4.4 min, (pos) [M+H]/z Calc’d 518.2, found 518.2.

(iv)

-209-

<img file="MY139999A_D0321.tif" />

To 6-[(2-methoxycarbonylphenyl)sulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-l-[2(trimethyl-silanyl)ethoxymethyl]-lH-indazole (8.50 g, 16.4 mmol) was added THF (120 mL), methanol (120 mL), water (120 mL) and potassium carbonate (15.9 g, 115

5- mmol, 7.0 equiv). This mixture was heated to 67 °C and was stirred for 22 h. The mixture was cooled and the excess solvents were removed. The residue was partitioned between ethyl acetate (300 mL) and water (250 mL). The aqueous was acidified with 20% citric acid to pH 5 (~70 mL) and the aqueous was drained. The organic layer was washed with water (50 mL) and hexane (100 mL) was added to help precipitate the crystals that were forming in the ethyl acetate layer. The solid was filtered and dried to give 6-[(2-carboxyphenyl);ulfanyl]-3-E-[2-(pyridin-2yl)ethenyl]-l-[2-(trimethyl-silanyl)ethoxy-methyl]-lH-indazole (7.56 g, 91 %): Ry sm 0.67, p 0.41 (ethyl acetate-hexane 8:2); ’HNMR (300 MHz, CDC1₃) 8.60 (m, lH),8.10(d, 1H, J = 8.4 Hz), 8.04 (dd, 1H,J= 1.7, 7.7 Hz), 7.85 (d, 1H, J =16.5

Hz), 7.83 (s, 1H), 7.70 (dt, 1H, J = 1.7, 7.7 Hz), 7.59 (d, 1H, J = 16.5 Hz), 7.52 (d,

1H, J = 7.9 Hz), 7.38 (dd, 1H, J = 1.3, 8.4 Hz), 7.22- 7.10 (m, 3H), 6.80 (dd, 1H, J =

1.0, 8.0 Hz), 3.59 (t, 2H, J = 8.1 Hz), 0.85 (t, 2H, J = 8.8.1 Hz), -0.1 (s, 9H).

(v)

-210-

<img file="MY139999A_D0322.tif" />

6-[(2-Carboxyphenyl)sulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-l-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazole (820 mg, 1.63 mmol) was dissolved in DMF (5 mL.) and was treated with methyl amine (2M in THF, 4.1 mL. 8.13 mmol, 50 equiv) and with

HATU (929 mg, 2.44 mmol, 1.5 equiv). This mixture was stirred for 30 min, was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate and the organic layer was separated. The organic material was dried over sodium sulfate, decanted and concentrated under reduced pressure. Purification by silica gel chromatography (50 mL silica; 60 to 70% ethyl acetate-hexane) gave 6-[210 (methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-l-[2-(trimethylsilanyl)ethoxymethyl]-lH-indazole as a solid (795 mg, 94%): Ry sm 0.35, p 0.23 (ethyl acetate-hexane 6:4); FTIR (thin film) 3306, 2951, 1643, 1606, 1587, 1563, 1469, 1433, 1410, 1303, 1249, 1217, 1075, 836 cm¹; ’HNMR (300 MHz, CDC1₃) 8.70 (m, IH), 8.06 (d, IH, J = 8.4 Hz), 7.94 (d, IH, J = 16.3 Hz), 7.74 (dt, IH, J =

1.8, 7.7 Hz), 7.70-7.60 (m, 3H), 7.52 (d, IH, J = 7.9 Hz), 7.35-7.20 (m, 5H), 6.45 (bs,

IH), 5.80 (s, 2H), 3.62 (t, 2H), 3.00 (d, 3H), 0.93 (t, 2H), -0.05 (s, 9H); ^I3C NMR (75 MHz, CDC1₃) 179.7, 169.9, 156.8, 151.1, 144.2, 143.0, 138.1, 136.1, 135.4, 133.2,

132.2, 132.1, 130.2, 128.5, 127.2, 124.7, 124.1, 123.8, 123.5, 123.3, 114.9, 68.1,

28.2, 19.2,0.00; LCMS (100% area) Rt = 4.15 min, (pos) [M+H]/z Calc'd 517.2, found 517.2

-211Example 33(b): 6-[2-(2-methylquinol-6-ylcarbamoyl)phenylsulfanyl]-3-E-[2(pyridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0323.tif" />

Example 33(b) was prepared in a similar manner to that described for 5 Example 33(a) except that, in step (v), 6-amino-‘2-methylquinolme was used instead of methylamine: Ή NMR (300 MHz, CDC1₃) 10.2 (bs, IH), 8.64 (m, IH), 8.40 (s, IH), 8.23 (s, IH), 7.98-7.80 (m, 4H), 7.69 (dt, IH, J = 1.7, 7.7 Hz), 7.55-7.40 (m,

7H), 7.25-7.16 (m, 3H), 2.71 (s, 3H).

Example 33(c): 6-[2-(phenylcarbamoyl)phenvlsulfanyl]-3-E-[2-(pyridin-210 yl)ethenyl]-l H-indazole

<img file="MY139999A_D0324.tif" />

Example 33(c) was prepared in a similar manner to that described for Example 33(a) except that, in step (v), aniline was used instead of methyl amine: 'H NMR (300 MHz, dmso-d6) 13.35 (s, IH), 10.53 (s, IH), 8.67 (m, IH), 8.22 (d, IH,

J = 7.5 Hz), 7.99 (d, IH, J = 16.4 Hz), 7.85 (dt, IH, J = 1.8, 7.6 Hz), 7.80-7.55 (m, 5H), 7.45-7.10 (m, 9H); LCMS (100% area) Rt= 3.86, (pos) [M+H]/z Calc'd 449.1, found 449.1. Analyzed with 0.41 H₂O Calc'd, C (71.13), H (4.60), N (12.29), S (7.03). Found: C (71.04), H (4.62), N (12.31), S (7.01).

-212Example 33(d): 6-[2-(3-chlorophenylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0325.tif" />

<img file="MY139999A_D0326.tif" />

Example 33(d) was prepared in a similar manner to that described for 5 Example 33(a) except that, in step (v), 3-chloroaniline was used instead of methyl amine: Ή NMR (300 MHz, CDC1₃) 8.53 (m, 1H), 7.92 (d, 1H, J = 8.4 Hz), 7.77 (d, 1H, J = 16.4 Hz), 7.68 (dt, 1H, J = 1.7, 7.7 Hz), 7.64-7.56 (m, 2H), 7.51-7.43 (m, 3H), 7.35-7.28 (m, 4H), 7.19-7.12 (m, 3H), 7.02 (m, 1H); LCMS (100% area) Rt 3.98 min, (pos) [M+H]/z Calc’d 483.1, found 483.1. Analyzed with 0.3 H2O Calc’d, C (66.40),

H (4.05), N (11.47), S (6.57). Found: C (66.36), H (4.08), N (11.49), S (6.55).

Example 33(e): 6-[2-(cyclopropylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2yl)ethenyl]-lH—lH-indazole

<img file="MY139999A_D0327.tif" />

Example 33(e) was prepared in a similar manner to that described for 15 Example 33(a) except that, in step (v), cyclopropylamine was used instead of methylamine: ^!H NMR (300 MHz, dmso-d6) 13.45 (s, 1H), 8.73 (d, 1H, J = 3.9 Hz), 8.56 (d, 1H,J = 4.3 Hz), 8.31 (d, 1H,J=8.5 Hz), 8.08 (d, 1H,J= 16.4 Hz), 7.91 (dt, 1H, J = 1.7, 7.7 Hz), 7.78 (d, 1H, J = 7.8 Hz), 7.70 (m, 2H), 7.57 (m, 1H,), 7.40

-213(m, 3H), 7.30 (d, IH, J = 8.4 Hz), 7.20 (d, IH, J = 7.8 Hz), 2.94 (m, IH), 0.80 (m,

2H), 0.65 (m, 2H); LCMS (100% area) Rt 3.51 min, (pos) [M+H]/z Calc’d 413.1, found 413.1.

Example 33(f): 6-(2-(2,2,2-trifluoroethylcarbamoyl)phenylsulfanyl]-3-E-[25 (pyridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0328.tif" />

Example 33(f) was prepared in a similar manner to that described for Example 33(a) except that, in step (v), 2,2,2-trifluoroethylamme was used instead of methylamine: Ή NMR (300 MHz, dmso-d6) 13.5 (s, IH), 9.29 (t, IH, J = 6.3 Hz),

8.74 (m, IH), 8.37 (d, IH, J = 8.3 Hz), 8.10 (d, IH, J = 16.4 Hz), 7.94 (dt, IH, J =

1.8, 7.6 Hz), 7.80 (d, IH, J = 7.9 Hz), 7.75-7.65 (m, 3H), 7.55-7.40 (m, 3H), 7.33 (d,

IH), 7.22 (d, 1H), 4.22 (m, 2H); LCMS (100% area) Rt = 3.70 min, (pos) [M+H]/z

Calc’d 455.1, found 455.1.

Example 33(g): 6-[2-(carboxy)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-l H—

ΙΗ-indazole, tetrabutylammonium salt

<img file="MY139999A_D0329.tif" />

Example 33(g) was prepared in a similar manner to that described for Example 33(a) except that step (v) was omitted: Rr sm 0.41, p 0.0 (ethyl acetate-214hexane 8:2); 'H NMR (300 MHz, dmso-d6) 8.75 (m, 1H), 8.25 (d, 1H, J = 8.6 Hz), 8.05 (d, 1H, 16.4 Hz), 7.88 (dt, 1H, J = 1.8, 7.8 Hz), 7.83-7.60 (m, 4H), 7.33 (m, 2H),

7.16 (m, 2H),6.70 (m, 1H), 3.30 (m, 8H), 1.70 (m, 8H), 1.42 (m, 8H), 1.05 (t, 12H); LCMS (100% area) Rt 3.24 (pos) [M+H (acid component only)]/z Calc’d 374,1, found 374.1. Analyzed with 0.1 H₂O Calc’d, C (72.07), H (8.21), N (9.09), S (5.20). Found: C (72.04), H (8.29), N (9.06), S (5.12).

Example 33(h): 6-[2-(3-chlorophenylcarbamoyl)phenvlsulfanyl]-3-Z-[2-(pyridin2-yl)ethenyI]-l H-indazole

<img file="MY139999A_D0330.tif" />

Example 33(h) was prepared in the same reaction as Example 33(d). It should be noted that, although this compound was isolated and characterized pure, it was found to isomerize to Example 33(d) under assay conditions. Ή NMR (300 MHz, CDC1₃) 8.82 (m, 1H), 8.31 (s, 1H), 7.86 (m, 2H), 7.77 (m, 2H), 7.61 (t, 1H, J = 2.0 Hz), 7.46 (d, 1H, J = 8.0 Hz), 7.33 (m, 5H), 7.21 (t, 1H, J = 8.0 Hz), 7.13 (dd, 1H, J =

1.5, 8.1 Hz), 7.08 (m, 1H), 6.98 (d, 1H, J = 13.0 Hz), 6.66 (d, 1H, J = 13.1 Hz);

LCMS (100% area) Rt 4.40 min, (pos) [M+H]/z Calc’d 483.1, found 483.1. Analyzed with 0.3 H₂O Calc’d, C (66.40), H (4.05), N (11.47), S (6.57). Found: C (66.36), H (4.08), N (11.49), S (6.55).

Example 34: 6-[2-((RS-(ira«s-2-phenylcyclopropyl)carbamoyl)phenylsulfanyl]-320 E-[2-(pyridin-2-yl)ethenyI]-lH-indazole

-215-

<img file="MY139999A_D0331.tif" />

H

<img file="MY139999A_D0332.tif" />

Example 33(g) was converted to Example 34 in a similar manner to that described for Example 33(a), step (v) except that trans-2-phenylcyclopropylamine was used instead of methylamine: FTIR (thin film) 1704, 1638, 1584, 1559, 1530,

1497, 1460, 1430, 133971306, 1269, 1223, 1152, 1086, 1061, 966, 844 cm'¹; Ή

NMR (300 MHz, CDC1₃) 13.3 (s, IH), 8.71 (d, IH, J = 4.4 Hz), 8.61 (d, IH, J = 3.9

Hz), 8.20 (d, IH, J = 8.5 Hz), 7.96 (d, IH, J = 16.4 Hz), 7.81 (dt, IH, J = 1.7, 7.6 Hz) 7.66 (d, IH, J = 7.8 Hz), 7.59-7.50 (m, 3H), 7.37-7.25 (m, 5H), 7.21-7.08 (m, 5H), 3.01 (m, IH), 2.03 (m, IH), 1.25 (m, 2H); LCMS (100% area) Rt = 3.72 min, (pos) [M+H]/z Calc'd 489.2, found 489.2. Analyzed with 0.6 MeOH, 0.16 CH₂C1₂ Calc’d,

C (70.86), H (5.17), N (10.75), S (6.15). Found: C (70.87), H (5.18), N (10.75), S (5.96).

Example 35(a): 6-[2-(n-Propylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2yI)ethenyI]-lH-indazo!e

H

<img file="MY139999A_D0333.tif" />

6-[2-(Pentafluorophenoxycarbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2yl)ethenyl]-lH—indazole (60 mg, 0.1112 mmol) was dissolved in DMF (0.8 mL), treated with n-propylamine (11 L, 0.1335 mmol) and stirred at room temperature.

-216HPLC analysis after 15 minutes indicated that all staring material had been consumed. The reaction mixture was concentrated by high vacuum rotary evaporation, giving a solid. The solid was sonicated with CH₂C1₂ giving a fine suspension, which was filtered, and rinsed with CH₂Cl₂to provide 40 mg (87% yield) 5 ofthe title compound. 'HNMR (DMSO-d₆) 13.31 (s, IH), 8.60 (d,/= 4.0 Hz, IH),

8.41 (t,/= 6.2 Hz, IH), 8.19 (d,/ = 8.5 Hz, IH), 7.94 (m, 3H), 7.81 (dt, / = 1.7, 7.5

Hz, IH), 7.66 (t,/= 8.7 Hz, IH), 7.56 (m, 2H), 7.47 (m, IH), 7.30 (m, 3H), 7.18 (d,/ = 8.3 Hz, IH), 3.20 (q,/= 6.0 Hz, 2H), 1.55 (septet./= 5.9 Hz, 2H), 0.92 (t,/= 6.0 Hz, 3H). Anal. Calcd. for C₂₄H₂₂N₄OS-(1.5 H₂O, 0.8 DMF): C, 63.41; H, 6.17; N,

13.45; S, 6.41. Found: C, 63.37; H, 5.68; N, 13.44; S, 6.32.

The starting material was prepared as follows:

<img file="MY139999A_D0334.tif" />

A solution of the tetrabutyl ammonium salt of 6-(2-carboxyphenylsulfanyl)-3-E-[2(pyridin-2-yl)ethenyl]-lH—indazole) (615 mg, 1.0 mmol) dissolved in dry DMF (10.0 ml) was treated with pyridine (89 L, 1.1 mmol), and pentafluorophenyl trifluoroacetate (206 L, 1.2 eq), at room temperature, under an argon atmosphere. HPLC analysis after 45 minutes showed mostly unreacted carboxylic acid, so additional pyridine (89 L, 1.1 mmol), and pentafluorophenyl trifluoroacetate (206

L, 1.2 eq) were added. HPLC analysis 15 minutes later indicated that starting acid

-217had been completely consumed. The reaction mixture was concentrated under high vacuum rotary evaporation, then triturated with CH₂C1₂ (~lmL) causing the formation of crystals, which were collected by filtration, rinsed with additional CH₂C1₂, and dried. The mass of the bright yellow crystals was 336 mg. The remaining filtrate 5 was concentrated and purified by flash chromatography (10% acetontrile/CH₂Cl₂ to

80% acetonitrile/CH₂Cl₂), yielding an additional 70 mg of solid. The total yield of 6[2-(Pentafluorophenoxycarbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]-lH~ indazole was 406 mg, or 89%. ’HNMR(CDC1₃) 10.22 (1H, bs), 8.66 (1H, d, J =

4.5 Hz), 8.28 (2H, dd,7= 7.7. 1.5 Hz), 8.15 (1H, d,7= 8.5 Hz), 7.97 (1H, d,7 = 16.2

Hz), 7.79 (1H, s), 7.15-7.75 (7H, m), 6.92 (1H, d, J= 8.1 Hz).

Example 35(b): 6-[2-(/-Propylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2yl)ethenyl]-l H-indazole

<img file="MY139999A_D0335.tif" />

Example 35(b) was prepared in a similar manner to that described for 15 Example 35(a) except that isopropylamine was used instead of «-propylamine. Ή

NMR (DMSO-d₆) 13.30 (s, 1H), 8.60 (d, 7 = 4.5 Hz, 1H), 8.26 (d, J= 7.34 Hz, 1H),

8.19 (d, 7=8.3 Hz, 1H), 7.94 (d, J= 16.4 Hz, 1H), 7.80 (dt, J= 1.7, 7.5 Hz, 1H),

7.66 (d, J= 7.7 Hz, 1H), 7.56 (m, 2H), 7.45 (m, 1H), 7.30 (m, 3H), 7.18 (d,7= 8.5 Hz, 1H), 7.08 (m, 1H), 4.04 (septet, 7= 7.4 Hz, 1H), 1.15 (d, 7= 6.6 Hz, 6H). Anal.

-218Calcd. for C₂₄H₂₂N₄OS-1.7 H₂O: C, 64.75; H, 5.75; N, 12.59; S, 7.20. Found: C,

64.79; H, 5.36; N, 12.74; S, 7.08.

Example 35(c): 6-[2-(Cyclobutylcarbamoyl)phenylsulfanyl]-3-E-[2-(pvridin-2yI)ethenyI]-lH-indazo!e

<img file="MY139999A_D0336.tif" />

Example 35(c) was prepared in a similar manner to that described for Example 35(a) except that cyclobutylamine was used instead of n-propylamine. 'H NMR (DMSO-d₆) 13.31 (s, IH), 8.62 (m, 2H), 8.19 (d, J= 8.5 Hz, IH), 7.94 (m,

2H), 7.80 (dt,7= 1.7, 7.5 Hz, IH), 7.65 (t, J= 8.1 Hz, IH), 7.56 (s, IH), 7.47 (m,

IH), 7.30 (m, 3H), 7.17 (d, 7= 8.3 Hz, IH), 4.36 (septet, J= 8.1 Hz, IH), 2.22 (m,

2H), 2.03 (m, 2H), 1.67 (m, 2H). Anal. Calcd. for C_2JH₂₂N₄OS-(0.5 H₂O, 0.9 DMF)

C, 66.36; H, 5.89; N, 13.69; S, 6.40. Found: C, 66.21; H, 5.78; N, 13.82; S, 6.36.

Example 35(d): 6-(2-CarbamoylphenyIsulfanyl)-3-E-[2-(pyridin-2-yI)ethenyl]lH-indazole

<img file="MY139999A_D0337.tif" />

Example 35(d) was prepared in a similar manner to that described for Example 35(a) except that ammonia was used instead of «-propylamine. *H NMR (DMSO-d₆) 8.60 (d, 7= 4.9 Hz, IH), 8.21 (d, 7= 8.3 Hz, IH), 7.94 (m, 3H), 7.81

-219(dt, J= 1.1, 7.5 Hz, IH), 7.60 (m, 4H), 7.48 (bs, IH), 7.25 (m, 4H), 7.0 (m, IH). Anal. Calcd. for C₂₁H₁₆N₄OS-0.25 H₂O: C, 66.91; H, 4.41; N, 14.86; S, 8.51. Found:

C, 66.99; H, 4.40; N, 15.10; S, 8.49.

Example 35(e): 6-[2-((l-methylpyrrol-2-ylhydrazido)carbonyl)phenylsulfanyl]-35 E-[2-(pyridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0338.tif" />

Example 35(e) was prepared in a similar manner to that described for Example 35(a) except that l-methylpyrrol-2-ylhydrazide was used instead ofnpropylamine. Ή NMR (DMSO-d₆) 13.34 (s, IH), 10.25 (s, IH), 10.05 (s, IH), 8.60 (d, J= 4.5 Hz, IH), 8.22 (d,7 = 8.7 Hz, 1H), 7.95 (d, J= 16.2 Hz, IH), 7.81 (dt, 7=

1.7,7.5 Hz, IH), 7.66 (m, 3H), 7.57 (d, 7 = 16.0 Hz, IH), 7.43-7.18 (m, 4H), 7.07 (d, 7= 7.9 Hz, IH), 7.00 (d, 7= 3.4 Hz, 2H), 6.07 (t, 7 = 3.2 Hz, IH), 3.88 (s, 3H). Anal. Calcd. for C₂₇H₂₂N₆O₂S-0.6 H₂O: C, 64.17; H, 4.63; N, 16.63; S, 6.34. Found: C,

64.24; H, 4.48; N, 16.56; S, 6.28.

Example 35(f): 6-(2-((2-fluorobenzyI)methylcarbamoyl)phenylsulfanyl]-3-E-[2(pyridin-2-yI)ethenyl]-lH-indazole

<img file="MY139999A_D0339.tif" />

CN.

<img file="MY139999A_D0340.tif" />

F

Ά'

-220Example 35(f) was prepared in a similar manner to that described for Example 35(a) except that 2-fluorobenzy] amine was used instead of n-propylamine. ’HNMR (DMSO-d₆) 13.31 (s, 1H), 8.99(t,/=5.8 Hz, IH), 8.61 (d,/= 4.5 Hz, IH), 8.19 (d, /=8.5 Hz, IH), 7.94 (d,/= 16.2 Hz, IH), 7.81 (dt,/= 1.7,7.5 Hz, IH), 7.66 (d,/ =

8.1 Hz, IH), 7.56 (m, 3H), 7.47 (t,/= 7.9 Hz, 1H), 7.31 (m, 4H), 7.15 (m, 4H), 4.51 (d, /= 5.7 Hz, 2H). Anal. Calcd. for C₂₈H₂₁FN₄OS-0.25 H₂O: C, 69.33; H, 4.47; N,

11.55; S, 6.61. Found: C, 69.32; H, 4.41; N, 11.58; S, 6.59.

Example 35(g): 6-[2-((4-MethoxybenzyI)methylcarbamoyl)phenylsulfanyl]-3-E[2-(pyridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0341.tif" />

Example 35(g) was prepared in a similar manner to that described for

Example 35(a) except that 4-methoxybenzyl amine was used instead of npropylamine. Ή NMR (DMSO-d₆) 13.31 (s, IH), 8.90 (t,/= 5.5 Hz, IH), 8.60 (d, /=4.2 Hz, IH), 8.19 (d,/= 8.3 Hz, IH), 7.95 (d,/= 16.3 Hz, IH), 7.81 (dt,/= 1.7,

7.5 Hz, IH), 7.66 (d,/= 7.9 Hz, IH), 7.55 (m, 3H), 7.30 (m, 5H), 7.18 (d, /= 8.5 Hz,

IH), 7.10 (d, /= 8.3 Hz, IH), 4.39 (d, /= 6.0 Hz, 2®, 3.72 (s, 3H). Anal. Calcd. for

C₂₉H₂₄N₄O₂S-0.6 H₂O: C, 69.19; H, 5.05; N, 11.13; S, 6.37. Found: C, 69.12; H,

4.85; N, 11.24; S, 6.35.

Example 35(h): 6-[2-((5-MethyIfur-2-yl)methyIcarbamoyl)phenylsuIfanyl]-3-E20 [2-(pyridin-2-yl)ethenyI]-lH-indazole

-221N

Η ,Ν

<img file="MY139999A_D0342.tif" />

□

<img file="MY139999A_D0343.tif" />

ch₃

Example 35(h) was prepared in a similar manner to that described for Example 35(a) except that 5-methylfur-2-yl amine was used instead of npropylamine. ’HNMR(DMSO-d₆) 13.31 (s, 1H), 8.88 (t,/= 5.3 Hz, 1H), 8.60 (d, /=4.3 Hz, 1H), 8.19 (d,/= 8.3 Hz, 1H), 7.95 (d,/= 16.3 Hz, 1H),T.81 (dt,/= 1.7,

7.5 Hz, 1H), 7.66 (d,/= 8.1 Hz, 1H), 7.54 (m, 3H), 7.30 (m, 4H), 7.18 (d, /= 8.3 Hz, 1H), 7.06 (d,/= 8.1 Hz, 3H). Anal. Calcd. for C₂₇H₂₂N₄O₂S-0.4 H₂O: C, 68.45; H,

4.85; N, 11.83; S, 6.77. Found: C, 68.35; H, 4.80; N, 11.85; S, 6.68.

Example 35(i): 6-[2-(Benzyloxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-210 yl)ethenyl]-lH-indazole

<img file="MY139999A_D0344.tif" />

Example 3 5(i) was prepared in a similar manner to that described for Example 35(a) except that O-benzyl hydroxylamine was used instead of n-propylamine. ’H NMR (DMSO-d₆) 13.31 (s, 1H), 11.64 (s, 1H), 8.90 (t,/ = 5.5 Hz, 1H), 8.60 (d,/ =

4.1 Hz, 1H), 8.19 (d,/= 8.3 Hz, 1H), 7.95 (d,/= 16.3 Hz, 1H),7.81 (dt,/= 1.7, 7.5

Hz, 1H), 7.66 (d, /= 7.9 Hz, 1H), 7.56 (m, 2H), 7.50-7.24 (m, 9H), 7.17 (t,/= 8.5 Hz, 2H), 4.94 (s, 2H). Anal. Calcd. for C₂₈H₂₂N₄O₂S-0.8 H₂O: C, 68.22; H, 4.83; N,

11.37; S, 6.50. Found: C, 68.08; H, 4.65; N, 11.41; S, 6.47.

-222Example 35(j): 6-[2-(Allyloxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2yl)ethenyl]-lH-indazole

<img file="MY139999A_D0345.tif" />

Example 3 5(j) was prepared in a similar manner to that described for Exaniple 5 35(a) except that O-allyThydroxylarnine was used instead of τζ-propylarnine. Ή

NMR (DMSO-d₆) 13.32 (s, 1H), 11.56 (s, 1H), 8.60 (d, J= 4.1 Hz, 1H), 8.19 (d, J=

8.3 Hz, 1H), 7.95 (d, J= 16.5 Hz, 1H), 7.81 (dt, 7= 1.7,7.5 Hz, 1H),7.66 (d,7 = 7.9

Hz, 1H), 7.56 (m, 2H), 7.48-7.24 (m, 5H), 7.16 (m, ,2H), 6.00 (m, 1H), 5.37 (d, J=

18.3 Hz, 1H), 5.27 (d,7 = 11.3 Hz, 1H),4.42 (d, 7-6.0 Hz, 1H). Anal. Calcd. for

C₂₄H₂₀N₄O₂S-(0.2 H₂O, O.2CH₂C1₂): C, 65.35; H, 4.96; N, 12.10; S, 6.92. Found: C,

65.24; H, 4.50; N, 12.56; S, 7.17.

Example 35(k): 6-[2-(Isopropoxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2yl)eth enyl] -1 H-in dazol e

<img file="MY139999A_D0346.tif" />

Example 35(k) was prepared in a similar manner to that described for

Example 35(a) except that O-isopropyl hydroxylamine was used instead of npropylamine. ’HNMR (DMSO-d₆) 13.30 (s, 1H), 11.33 (s, 1H), 8.60 (d, 7= 4.1 Hz, 1H), 8.19 (d,7= 8.3 Hz, 1H), 7.95 (d,7= 16.5 Hz, 1H), 7.81 (dt,7= 1.7, 7.5 Hz,

-2231H), 7.66 (d, J= 7.9 Hz, IH), 7.55 (m, 2H), 7.48-7.24 (m, 4H), 7.17 (d, /= 8.3 Hz, 2H), 4.12 (septet,/= 5.7 Hz, IH), 1.21 (d,/= 6.2 Hz, 6H. Anal. Calcd. for

C₂₄H₂₂N₄O₂S-(0.4 H₂O, 0.7 CH₂C1₂): C, 59.67; H, 4.91;N, 11.27; S, 6.45. Found: C,

59.61; H, 4.81; N, 11.42; S, 6.45.

Example 35(1): 6-[2-((4-Aminobenzyi)methylcarbamoyI)phenylsulfanyI]-3-E-[2(pyridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0347.tif" />

Example 35(1) was prepared in a similar mariner to that described for Example 35(a) except that 4-aminobenzyl amine was used instead of n-propylamine. 'H NMR (DMSO-d₆) 13.31 (s, IH), 8.78 (t,/= 6.0 Hz, IH), 8.60 (d,/= 4.3 Hz, lH),8.19(d, /= 8.1 Hz, IH), 7.95 (d,/= 16.3 Hz, IH), 7.85 (bs, IH), 7.81 (dt,/= 1.7, 7.5 Hz,

IH), 7.66 (d, /= 7.9 Hz, IH), 7.59 (s, IH), 7.51 (m, 2H), 7.30 (m, 3H), 7.19 (d, /=

8.7 Hz, IH), 7.05 (m, 3H), 6.56 (d,/= 8.7 Hz, IH), 6.51 (d,/= 8.5 Hz, 2H),4.29 (d, /= 6.0 Hz, 2H). Anal. Calcd. for C₂₈H₂₃N₅OS-0.6 H_;O: C, 68.86; H, 4.99; N, 14.34;

S, 6.57. Found: C, 68.83; H, 4.80; N, 14.16; S, 6.52.

Example 35(m): 6-[2-((Thien-2-ylhydrazido)carbonyl)phenylsulfanyI]-3-E-[2(pyridin-2-yl)ethenyl]-lH-indazole

-224-

<img file="MY139999A_D0348.tif" />

Example 35(m) was prepared in a similar manner to that described for Example 35(a) except that thien-2-ylhydrazide was used instead of «-propylamine. ’HNMR (DMSO-d₆) 13.49 (bs, 1H), 10.64 (s, 1H), 10.47 (s, 1H), 8.66 (d,7 = 4.0

Hz, 1H), 8.22 (d, 7= 8.5 Hz, 1H), 8.08-7.82 (m, 5H), 7.66 (m, 3H), 7.39 (m, 3H),

7.24 (m, 2H), 7.09 (d, 7= 8.1 Hz, 1H), 7.00 (d, 7= 3.4 Hz, 2H), 6.07 (t, 7= 3.2 Hz, 1H), 3.88 (s, 3H). Anal. Calcd. for C₂₆H₁₉N₅O₂S₂· 1..5 H₂O: C, 59.52; H, 4.23; N,

13.35; S, 12.22. Found: C, 59.56; H, 4.42; N, 13.33; S, 11.75.

Example 35(n): 6-[2-(N²-(pyrid-2-ylhydrazino)carbonyl)phenylsulfanyl]-3-E-[210 (pyridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0349.tif" />

Example 35(n) was prepared in a similar manner to that described for Example 35(a) except that 2-hydrazinopyridine was used instead of «-propylamine. ’HNMR(DMSO-d₆) 13.31 (s, 1H), 10.30 (s, 1H), 8.60 (d, 7= 4.4 Hz, 1H), 8.48 (s,

1H), 8.21 (d, 7= 8.5 Hz, 1H), 8.09 (d, 7= 4.9 Hz, J.H), 7.94 (d, 7= 16.4 Hz, 1H),

7.81 (dt,7= 1.7, 7.5 Hz, 1H), 7.67 (m, 1H), 7.62-7.47 (m, 3H), 7.40 (m, 2H), 7.31-2257.12 (m, 3H), 6.73 (m, 2H). Anal. Calcd. for C₂₆H₂₀N₆OS-0.3 H₂O: C, 66.45; H, 4.42;

N, 17.88; S, 6.82. Found: C, 66.33; H, 4.50; N, 17.78; S, 6.60.

Example 35(o): 6-(2-( N-Hydroxy-N-methylcarbamoyl)phenylsulfanyl]-3-E-[2(pyridin-2-yl)ethenyl]-l H-indazole

OH

I

<img file="MY139999A_D0350.tif" />

<img file="MY139999A_D0351.tif" />

Example 35(o) was prepared in a similar manner to that described for

Example 35(a) except that N-methyl hydroxylamine was used instead of npropylamine. Ή NMR (DMSO-d₆) 13.24 (s, IH), 9.94 (s, IH), 8.60 (d, 7 = 4.0 Hz, IH), 8.14 (d, 7= 8.3 Hz, IH), 7.92 (d,7= 16.2 Hz, 1H),7.8O (dt,7= 1.7,7.5 Hz,

IH), 7.65 (t, 7= 8.5 Hz, IH), 7.54 (d, 7= 16.5 Hz, IH), 7.47-7.24 (m, 6H), 7.16 (d, J = 8.5 Hz, IH) 3.24 (bs, IH). Anal. Calcd. for C₂₂H₁₈N₄O₂S-(0.5 H₂O, 0.3 CH₂C1₂): C,

61.29; H, 4.52; N, 12.82; S, 7.34. Found: C, 61.24; H, 4.33; N, 12.67; S, 7.34.

Example 35(p): 6-[2-((Pyrid-4-yl)methvlcarbamoyl)phenylsulfanyl]-3-E-[2(pyridin-2-yl)ethenvl]-lH-indazole

<img file="MY139999A_D0352.tif" />

Example 35(p) was prepared in a similar manner to that described for

Example 35(a) except that 4-aminomethyl pyridine was used instead of n-226propylamine. ’HNMR (DMSO-d₆) 13.31 (bs, 1H), 9.07 (t,7= 6.8 Hz, 1H), 8.60 (d, 7=4.2 Hz, 1H), 8.48 (d,7= 5.0 Hz, 1H), 8.19 (d,7= 8.7 Hz, 1H),7.95 (d,7= 16.4

Hz, 1H), 7.80 (dt,/= 1.7, 7.5 Hz, 1H), 7.68-7.52 (m, 3H), 7.42 (m, 2H), 7.39-7.31 (m, 3H), 7.27 (m, 1H), 7.20-7.10 (m, 2H), 4.48 (d, 7= 6.2 Hz, 2H).

Example 35(q): 6-[2-((2-Methylphenylhydrazido)carbonvI)phenylsuIfanyI]-3-E[2-(pyridin-2-vI)ethenyl]-lH-indazole

<img file="MY139999A_D0353.tif" />

Example 35(q) was prepared in a similar manner to that described for Example 35(a) except that 2-methylphenyl hydrazide was used instead of n10 propylamine. ’HNMR (DMSO-d₆) 13.43 (bs, 1H), 10.45 (s, 1H), 10.28 (s, 1H), 8.64 (d,7=4.0 Hz, 1H), 8.22 (d,7= 8.2 Hz, 1H), 8.01 (d,7= 16.6 Hz, 1H),7.92 (m,

1H), 7.81 (m, 1H), 7.69 (m, 1H), 7.60 (d,7= 16.4 Hz, 1H), 7.50-7.22 (m, 8H), 7.07 (d, 7= 7.7 Hz, 1H), 2.45 (s, 3H).

Example 35(r): 6-[2-(methoxycarbamoyl)phenyIsulfanyI]-3-E-[2-(pyridin-215 yI)ethenyl]-lH-indazole

<img file="MY139999A_D0354.tif" />

Example 35(r) was prepared in a similar manner to that described for Example 35(a) except O-methyl hydroxylamine was used instead of «-propylamine. Ή NMR

-227(DMSO-d₆) 13.32 (s, 1H), 11.60 (s, 1H), 8.60 (d, 7= 3.8 Hz, 1H), 8.19 (d, 7= 8.4 Hz, 1H), 7.95 (d, 7= 16.2 Hz, 1H), 7.81 (dt, 7= 1.7, 7.5 Hz, 1H), 7.66 (d, 7= 7.9 Hz, 1H), 7.56 (m, 2H), 7.47 (dd,7= 7.4, 1.7 Hz, 1H), 7.43-7.24 (m, 3H), 7.17 (m, 2H),

3.72 (s, 3H). Anal. Calcd. for C₂₂H₁₈N₄O₂S-0.6 CH₂C1₂: C, 59.86; H, 4.27; N, 12.36;

S, 7.07. Found: C, 59.94; H, 4.40; N, 12.00; S, 6.80.

Example 35(s): 6-[2-((CyclopropyI)methoxycarbamoyI)phenylsulfanyl]-3-E-[2(pvridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0355.tif" />

Example 35(s) was prepared in a similar mariner to that described for Example 10 35(a) except that O-cyclopropyl hydroxylamine was used instead of «-propylamine.

Ή NMR (DMSO-d₆) 13.38 (s, 1H), 11.51 (s, 1H), 8.64 (d, 7= 3.8 Hz, 1H), 8.18 (d, 7= 8.4 Hz, 1H), 8.00 (d, 7= 16.4 Hz, 1H), 7.86 (m, 2H), 7.63-7.52 (m, 2H), 7.497.29 (m, 4H), 7.17 (m, 2H), 3.70 (d, 7= 7.2 Hz, 1H), 1.10 (m, 1H), 0.53 (m, 2H), 0.27 (m, 2H). Anal. Calcd. for C₂₅H₂₂N₄O₂S-1.6 H₂O: C, 63.70; H, 5.39; N, 11.89; S, 6.80.

Found: C, 63.58; H, 4.95; N, 11.71; S, 6.66.

Example 35(t): 6-[2-(«-Propoxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2yl)ethenvl]-1 H-indazole

<img file="MY139999A_D0356.tif" />

-228Example 35(t) was prepared in a similar manner to that described for Example 35(a) except that O-n-propyl hydroxylamine was used instead of n-propylamine. 'H NMR (DMSO-d₆) 13.31 (s, 1H), 11.48 (s, 1H), 8.60 (d,/= 3.8 Hz, IH), 8.19 (d,/ =

8.4 Hz, IH), 7.95 (d,/= 16.2 Hz, IH), 7.81 (dt,/= 1.7,7.5 Hz, IH), 7.66 (d,/= 7.9

Hz, IH), 7.60-7.52 (m, 2H), 7.49-7.24 (m, 4H), 7.17 (m, 2H), 3.84 (t, /= 6.6 Hz, 2H),

1.62 (septet, /= 6.4 Hz, 2H), 0.92 (t, /= 6.1 Hz, 3H). Anal. Calcd. for C₂₄H₂₂N₄O₂S-(0.5 H₂O, 0.25 CH₂C1₂): C, 63.21; H, 5.14; N, 12.16; S, 6.96. Found: C,

63.15; H, 5.13; N, 12.17; S, 6.99.

Example 35(u): 6-[2-(AlIylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-210 yl)ethenyI]-lH-indazo!e

<img file="MY139999A_D0357.tif" />

Example 35(u) was prepared in a similar manner to that described for Example 35(a) except that allylamine was used instead of n-propylamine. ’H NMR (DMSO-d₆) 13.31 (s, IH), 8.60 (m, 2H), 8.19 (d,/= 8.5 Hz, IH), 7.93 (d,/= 16.3

Hz, 3H), 7.79 (dt,/= 1.7, 7.5 Hz, IH), 7.64 (m, 1EJ, 7.60-7.48 (m, 3H), 7.37-7.23 j (m,3H), 7.17 (d,/= 8.5 Hz, IH), 7.07 (m, lH),5.87(m, IH), 5.25 (dq,/ = 17.33, 1.9

I ' Hz, 1H), 5.09 (dq,/= 10.2, 1.9 Hz, IH), 3.87 (m, 2H). Anal. Calcd. for

C₂₄H₂₀N₄OS-0.8 CH₂C1₂: C, 62.00; H, 4.53; N, 11.66; S, 6.67. Found: C, 62.08; H, j 4.73; N, 11.99; S, 6.66. MALDI FTMS (ΜΗ*) Calc’d, 413.1431, found 413.1449.

I

I

-229Example 35(v): 6-[2-(Cyclopropylmethyl-carbamoyl)phenylsulfanyl]-3-E-[2(pyridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0358.tif" />

Example 35(v) was prepared in a similar manner to that described for

Example 35(a) except that cyclopropylmethyl amine was used instead of npropylamine. ’HNMR (DMSO-d₆) 13.30 (s, 1H), 8.60 (d, 7=4.0 Hz, 1H), 8.48 (t, 7=5.3 Hz, 1H), 8.17 (d,7= 8.7 Hz, 1H), 7.90 (d,7= 16.4 Hz, 1H), 7.80 (dt,7= 1.7,

7.5 Hz, 1H), 7.67-7.45 (m, 4H), 7.33-7.23 (m, 3H), 7.18 (d, 7= 8.3 Hz, 1H), 7.06 (m, 1H), 3.13 (t,7= 6.2 Hz, 2H), 1.00 (m, 1H), 0.41 (m, 1H), 0.24 (m, 1H). Anal. Calcd.

for C₂₅H₂₂N₄OSO.5 CH₂C1₂: C, 65.30; H, 4.94; N, 11.95; S, 6.84. Found: C, 65.10;

H, 4.93; N, 12.04; S, 6.82. MALDIFTMS (MFT) Calc’d 427.1587, found 427.1605.

Example 35(w): 6-[2-(Cyanomethylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2 yl)ethenyl] -1 H-indazole

<img file="MY139999A_D0359.tif" />

Example 35(w) was prepared in a similar manner to that described for

Example 35(a) except that aminoacetonitrile was us ed instead of «-propylamine. 'H NMR (DMSO-d₆) 13.35 (s, 1H), 9.19 (t, 7= 5.3 Hz, 1H), 8.60 (d,7= 4.8 Hz, 1H), 8.20 (d,7= 8.7 Hz, 1H), 7.94 (d,7= 16.4 Hz, 3H), 7.79 (dt,7= 1.7, 7.5 Hz, 1H),

-2307.70-7.50 (m, 4H), 7.41-7.23 (m, 3H), 7.18 (d, J= 8.5 Hz, IH), 7.06 (d, J= 6.6 Hz, IH), 4.32 (d, J= 5.5 Hz, 2H). MALDIFTMS (MIT) Calc’d 412.1227, found

412.1215.

Example 35(x): 6-[2-(EthylcarbamoyI)phenylsulfanyl]-3-E-[2-(pyridin-25 yI)ethenyI]-lH-indazole

<img file="MY139999A_D0360.tif" />

Example 35(x) was prepared in a similar manner to that described for Example 35(a) except that ethylamine was used instead of n-propylamine. ’H NMR (DMSO-d₆) 8.60 (d, J= 4.0 Hz, IH), 8.40 (t, 7= 6.2 Hz, IH), 8.18 (d,7= 8.5 Hz,

IH), 7.94 (m, 3H), 7.81 (dt,7= 1.7, 7.5 Hz, IH), 7.68-7.44 (m, 3H), 7.56 (m, 2H),

7.30 (m, 3H), 7.17 (dd, 7= 8.1, 1.8 Hz, IH), 7.06 (m, IH), 3.24 (m, 2H), 1.11 (t,7 = 7.0 Hz, 3H). Anal. Calcd. for C₂₃H₂₀N₄OS-(1.75 H₂0,1.0 DMF): C, 61.82; H, 6.09;

N, 13.87; S, 6.35. Found: C, 61.58; H, 5.66; N, 13.96; S, 5.93. MALDI FTMS (MIT) Calc’d 401.1431, found 401.1417.

Example 35(y): 6-[2-(Thiazol-2-yIcarbamoyI)phenylsulfanyI]-3-E-[2-(pyridin-2yl)ethenyl]-1 H-indazole

H

<img file="MY139999A_D0361.tif" />

-231Example 35(y) was prepared in a similar manner to that described for Example 35(a) except that 2-aminothiazole was used instead of «-propylamine. ’H NMR (DMSO-d₆) 13.32 (s, 1H), 12.67 (s, 1H), 8.60 (d, J= 4.1 Hz, IH), 8.18 (d, J=

8.5 Hz, IH), 7.93 (d, 7= 16.3 Hz, IH), 7.80 (dt, 7= 1.7, 7.5 Hz, IH), 7.65 (d, 7= 7.9

Hz, IH), 7.65 (d,7=8.3 Hz, IH), 7.60-7.51 (m, 3H), 7.49-7.34 (m, 2H), 7.26 (m,

2H), 7.18 (m, 2H). Anal. Calcd. for C₂₄H₁₇N₅OS₂-0.75 H₂O: C, 61.45; H, 3.98; N,

14.93; S, 13.67. Found: C, 61.35; H, 4.10; N, 14.96; S, 13.68.

Example 35(z): 6-[2-(2-(Ethoxy)ethylcarbamoyl)phenylsulfanyl]-3-E-(2-(pyridin2-vl)ethenyl]-lH-indazole

<img file="MY139999A_D0362.tif" />

Example 35(z) was prepared in a similar manner to that described for

Example 35(a) except that 2-ethoxyethyl amine was used instead of «-propylamine. 'HNMR (DMSO-d₆) 13.30 (s, IH), 8.60 (d, 7= 4.0 Hz, IH), 8.45 (t, 7= 6.2 Hz, IH), 8.18 (d,7= 8.5 Hz, IH), 7.93 (m, 2H), 7.80 (dt, 7= 1.7, 7.5 Hz, IH), 7.65 (d, 7 = 7.7 Hz, IH), 7.60-7.45 (m, 3H), 7.36-7.23 (m, 3H), 7.17 (d, 7= 8.3 Hz, IH), 7.07 (m, IH), 3.50 (m, 6H), 1.10 (d, 7= 7.0 Hz, 3H). Anal. Calcd. for C_2jH₂₄N₄O₂S-0.5

CH₂C1₂: C, 62.89; H, 5.17; N, 11.50; S, 6.58. Found: C, 62.45; H, 5.33; N, 11.25; S,

6.55.

Example 35(aa): 6-[2-((3-methoxybenzyl)methylcarbamoyl)phenylsulfanyl]-3-E20 [2-(pyridin-2-yl)ethenyl]-lH-indazole

-232-

<img file="MY139999A_D0363.tif" />

Example 35(aa) was prepared in a similar manner to that described for Example 35(a) except that 3-methoxybenzyl amine was used instead of npropylamine. 'HNMR (DMSO-d₆) 13.30 (s, IH), 8.97 (t,/= 5.5 Hz, IH), 8.60 (d, /= 4.2 Hz, IH), 8.18 (d,/= 8.7 Hz, IH), 7.93 (d,/= 16.3 Hz, IH), 7.80 (dt,/= 1.7,

7.5 Hz, IH), 7.65 (d, /= 7.9 Hz, IH), 7.60-7.51 (m, 3H), 7.38-7.15 (m, 5H), 7.08 (m,

IH), 6.94 (m, 2H), 6.80 (dd,/=8.1, 1.5 Hz, IH), 4.44 (d,/= 6.6 Hz, 2H), 3.71 (s, 3H). Anal. Calcd. for C₂₉H₂₄N₄O₂S-0.4 H₂O: C, 60.25; H, 4.50; N, 17.57; S, 8.04.

Found: C, 60.14; H, 4.47; N, 17.42; S, 8.00.

Example 35(bb): 6-[2-((fur-2-yl)methylcarbamoyl)phenylsulfanyl]-3-E-[2(pvridin-2-yl)ethenyI]-lH-indazole

<img file="MY139999A_D0364.tif" />

Example 35(bb) was prepared in a similar manner to that described for Example 35(a) except that 2-aminomethyl furan was used instead of n-propylamine.

'HNMR (DMSO-d₆) 13.31 (s, IH), 8.93 (t,/= 5.7 Hz, IH), 8.60 (d,/= 4.3 Hz, IH), 8.19 (d,/= 8.0 Hz, IH), 7.93 (d,/= 16.5 Hz, IH), 7.80 (dt,/= 1.9, 7.4 Hz, IH), 7.66 (d, /= 7.7 Hz, IH), 7.59-7.48 (m, 4H), 7.30 (m, 4H), 7.37-7.24 (m, 3H),

-2337.18 (d, 7=9.2 Hz, 1H),7.O6 (d,7= 8.1 Hz, 1H), 6.40 (m, 1H), 6.31 (m, 1H),4.44 (d, 7 = 5.3 Hz, 2H). Anal. Calcd. or C₂₆H₂₀N₄O₂S-(0..1 H₂O, 0.75 CH₂C1₂): C, 62.02;

H, 4.22; N, 10.82; S, 6.19. Found: C, 61.58; H, 4.30; N, 10.55; S, 6.12.

Example 35(cc): 6-[2-(2-Propynylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-25 yI)ethenylJ-lH-indazole

<img file="MY139999A_D0365.tif" />

Example 35(cc) was prepared in a similar manner to that described for

Example 35(a) except that propargylamine was used instead of propylamine (76%): Ή NMR (300 MHz, CDC1₃) 8.56 (m, 1H), 7.96 (d, 1H, J = 8.6 Hz), 7.81 (d, 1H,

16.4 Hz), 7.68 (dt, 1H, J = 1.8, 7.8 Hz), 7.6 (m, 1H), 7.52-7.45 (m, 3H), 7.3-7.23 (m,

3H), 7.16 (m, 2H), 4.10 (m, 2), 2.20 (t, 1H. J = 2.6 Hz). LCMS (100% area) Rt =

3.36 min, (pos) [M+H]/z Calc’d 411.1, ound411.1. Analyzed with0.2 H₂O, 0.17 DMF, 1.2 dichloromethane, Calc’d, C (58.44), H (4.19), N (11.05), S (6.07). Found:

C (58.18), H (4.11), N (10.98), S (6.05).

Example 35(dd): 6-[2-(ethoxycarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2yl)ethenyl]-l H-indazole

O.

<img file="MY139999A_D0366.tif" />

<img file="MY139999A_D0367.tif" />

o

-234Example 35(dd) was prepared in a similar manner to that described for Example 35(a) except that ethoxyamine was used instead of propylamine: ’H NMR (300 MHz, CDC1₃) 11.60 (s, 1H), 8.71 (d, 1H, J = 7.9 Hz), 8.30 (d, 1H, J = 8.5 Hz), 8.05 (d, 1H, J = 16.4 Hz), 7.91 (dt, 1H, J = 1.7, 7.7 Hz), 7.76 (d, 1H, J = 7.8 Hz), 7.67 (m, 2H), 7.56 (dd, 1H, J = 1.8, 7.3 Hz), 7.52-7.36 (m, 3H), 7.28 (m, 2H)4.06 (q, 2H, j = 7.0 Hz), 1.31 (t, 2H, J = 7.0 Hz); LCMS (100% area) Rt = 3.28 min, (pos) [M+H]/z Calc’d 417.1, found 417.1. Analyzed with 0.2 H₂O Calc’d, C (65.53), H (4.98), N (13.05), S (7.48). Found: C (65.66), H (4.91), N (12.75), S (7.44).

Example 35(ee): 6-[2-(2-Methyl-2-propenylcarbamoyl)phenylsulfanyl]-3-E-[210 (pyridin-2-yl)ethenyl]-l H-indazole

<img file="MY139999A_D0368.tif" />

Example 35(ee) was prepared in a similar maimer to that described for Example 35(a) except that 2-methylallylamine was used instead propylamine: 'H NMR (300 MHz, CDC1₃) 8.56 (m, 1H), 7.98 (d, 1H, J = 8.5 Hz), 7.81 (d, 1H, J =

16.4 Hz), 7.69 (dt, 1H, J = 1.7, 7.7 Hz), 7.60 (m, 1H), 7.53-7.42 (m, 3H), 7.32-7.24 (m, 3H), 7.16 (m, 2H), 6.72 (m, 1H), 4.89 (s, 1H), 4.81 (s, 1H), 3.90 (d, 2H, J = 5.5

Hz), 1.71 (s, 3H). LCMS (100% area) Rt = 3.37 min, (pos) [M+H]/z Calc’d 427.1, found 427.1. Analyzed with 0.7 H₂O, 0.1 dichloromethane Calc’d, C (67.35), H (5.31), N (12.52), S (7.16). Found: C (67.55), H (5.39), N (12.35), S (7.15).

-235Example 35(ff): 6-[2-((3-Fluorobenzyl)methylcarbamoyl)phenylsulfanyl]-3-E-[2(pyridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0369.tif" />

Example 35(ff) was prepared in a similar manner to that described for 5 Example 35(a) except that 3-fluorobenzylamine was used instead propylamine: ’H

NMR (300 MHz, CDC1₃) 8.60 (m, IH), 7.97 (d, IH, J = 8.5 Hz), 7.86 (d, IH, J =

16.4 Hz), 7.70 (m, 2H), 7.51 (m, 2H), 7.33 (m, 4H), 7.18 (m, 2H), 7.11 (dd, IH, J =

1.6, 8.5 Hz), 6.95 (m, 3H), 4.51 (d, 2H, J = 5.7 Hz); LCMS (100% area) Rt = 3.55 min, (pos) [M+H]/z Calc'd 481.1, found 481.1. Analyzed with 0.7 H₂O, 0.5 dichloromethane, Calc’d, C (63,91), H (4.40), N (10.46), S (5.99). Found: C (63.80),

H (4.34), N (10.34), S (5.98).

Example 35(gg): 6-[2-(2-(methylamino)ethylcarbamoyl)phenylsulfanyl]-3-E-[2(pyridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0370.tif" />

Example 35(gg) was prepared in a similar manner to that described for

Example 35(a) except that N-methylethylenediamine was used instead of propylamine: Ή NMR (300 MHz, CDC1₃) 8.60 (rn, IH), 7.98 (d, IH, J = 8.5 Hz),

-2367.81 (d, IH, J = 16.4 Hz), 7.69 (dt, IH, J = 1.7, 7.7 Hz), 7.52 (m, IH), 7.50-7.40 (m, 3H), 7.30-7.20 (m, 3H), 7.16 (m, 2H), 3.45 (t, 2H), 2.69 (t, 2H), 2.15 (bs, 3H); LCMS (100% area) Rt = 3.16 min, (pos) [M+H]/z Calc'd 430.1, found 430.1. Analyzed with 0.2 H₂O, 0.6 diehloromethane, 0.06 hex, Calc’d, C (61.28), H (5.24), N (14.31), S (6.55). Found: C (61.26), H (5.14), N (14.22), S (6 56).

Example 35(hh): 6-[2-(2-(Thien-2-yl)ethylcarbamoyl)phenylsulfanyl]-3-E-[2(pyridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0371.tif" />

<img file="MY139999A_D0372.tif" />

Example 35(hh) was prepared in a similar manner to that described for 10 Example 35(a) except that 2-(2-aminoethyl)thiophene was used instead propylamine:

'HNMR (300 MHz, CDC1₃) 8.56 (m, IH), 7.98 (d, IH, J - 8.5 Hz), 7.81 (d, IH, J = 16.4 Hz), 7.69 (dt, IH, J = 1.7, Ί.Ί Hz), 7.60 (m, IH), 7.53-7.42 (m, 3H), 7.32-7.24 (m, 3H), 7.16 (m, 2H), 6.72 (m, IH), 6.63 (m, IH), 6.52 (m IH), 3.45 (q, 2H), 3.00 (t,

2H). Analyzed with 0.5 H₂O, 0.07 diehloromethane Calc’d, C (65.35), H (4.69), N (11.26), S (12.82). Found: C (65.49), H (4.80), N (11.21), S (12.77).

Example 35(ii): 6-[2-(aminocarbamoyI)phenyIsulfanyl]-3-E-[2-(pyridin-2yl)ethenyl]-1 H-indazole

<img file="MY139999A_D0373.tif" />

<img file="MY139999A_D0374.tif" />

NH₂

-237Example 35(ii) was prepared in a similar manner to that described for Example 35(a) except that hydrazine was used instead propylamine: 'H NMR (300 MHz, dmso-d6) 13.3 (s, 1H), 9.57 (s, 1H), 8.54 (d, 1H, J = 3.9 z), 8.14 (d, 1H, J =

8.5 Hz), 7.89 (d, 1H, J = 16.4 Hz), 7.73 (dt, 1H, J = 1.7, 7.6 Hz), 7.60 (d, 1H, J = 7.9

Hz), 7.50 (m, 2H), 7.40 (dd, 1H, J = 1.8, 7.1 Hz), 7.3-7.1 (m, 4H), 7.0 (m, 1H). LCMS (100% area) Rt = 0.55 min, (pos) [M+H]/z Calc’d 388.1, found 388.1. Analyzed with 0.1 DMF, 0.55 EtOAc, 0.12 Tol (NMR) and 0.15 H₂O Calc’d, C (63.98), H (5.15), N (15.63), S (7.02). Found: C (63.99), H (5.07), N (15.75), S (6.89).

Examples 35(jj-35(nn) can be prepared in a similar manner to that described for Example 35(a).

Example 35(j j)

Example 35(kk)

<img file="MY139999A_D0375.tif" />

Example 35(11)

-238-

<img file="MY139999A_D0376.tif" />

<img file="MY139999A_D0377.tif" />

<img file="MY139999A_D0378.tif" />

Example 36(a): 6-[2-(N^:-(l-Methylimidazol-2ylmethylidene)hydrazino)carbonyl)henylsulfanyl]-3-E-[2-(pyridin-2-yI)ethenyl]10 lH-indazole

<img file="MY139999A_D0379.tif" />

The compound prepared in Example 35(ii) (40 mg, 0.103 mmol) was treated with l-methyl-2-imidazolecarboxaldehyde (29 mg, 0.258 mmol, 2.5 equiv) in ethanol to give Example 36(a): 'HNMR (300 MHz, dmso--d6) 8.60 (m, 2H), 8.31 (s, IH),

8.18 (d, IH), 8.02 (d, IH), 7.98 (d, IH), 7.80 (m, 2H), 7.63 (m, 2H), 7.40 (m, 3H),

7.30 (m, IH), 7.20 (m, IH), 7.02 (m, 2H), 6.93 (s, IH), 4.00 (s, 3H); LCMS (100%

-239area) Rt = 4.0 min, (pos) [M+H]/z Calc'd 480.2, found 480.2. Analyzed with 1.45

H_;O Calc’d, C (61.76), H (4.76), N (19.39), S (6.34). Found: C (61.78), H (4.67), N (19.34), S (6.39).

Example 36(b): 6-[2-(N²-(pyrid-2-ylmethylidene)hydrazino)carbonvl)5 phenylsulfanyl]-3-E-[2-(pyridin-2-vl)ethenyl]-lH-indazole

<img file="MY139999A_D0380.tif" />

Example 36(b) prepared in a similar manner to that described for Example

36(a) except that 2-pyridylcarboxaldehyde was used instead of 1-methyl-2imidazolecarboxaldehyde: ’H NMR (300 MHz, CDC1₃) 8.57 (m, 2H), 8.45 (m,

2H), 8.22 (d, 1H), 8.10 (s, IH), 7.93 (d, IH), 7.83 (d, 1H), 7.8-7.1 (m, 11H); LCMS (100% area) Rt = 4.0 min, (pos) [M+H]/z Calc'd 477.1, found 477.1. Analyzed with 0.85 H₂O Calc’d, C (65.93), H (4.45), N (17.09), S (6.52). Found: C (66.02), H (4.42), N (16.95), 5 (6.38).

Example 36(c): 6-[2-(N²-(2,2,215 trifluroethylidene)hydrazino)carbonyl)phenylsulfanyl]-3-E-[2-(pyridin-2yl)ethenyl] -1 H-in dazole

<img file="MY139999A_D0381.tif" />

-240Example 36(c) was prepared in a similar manner to that described for

Example 36(a) except that trifluoroacetaldehyde was used instead of l-methyl-2imidazolecarboxaldehyde: Ή NMR (300 MHz, dmso-d6) 8.70 (m, 1H), 8.25 (m, 1H), 8.02 (d, 1H), 7.90 (dt, 1H), 7.80-7.20 (m, 10H). LCMS (100% area) Rt= 5.64 min, (pos) [M+H]/z Calc’d 468.1, found 468.0. Analyzed with 0.75 H₂O Calc’d, C (57.39), H (3.67), N (14.56), S (6.67). Found: C (57.44), H (3.67), N (14.56), S (6.67).

Example 37(a): 6-[6-Fluoro-2-(ethoxycarbamoyI)phenylsulfanyl]-3-E-[2(pyridin-2-yl)ethenyl]-lH-indazoIe

<img file="MY139999A_D0382.tif" />

Example 37(a) was prepared in a similar manner to that described for

Example 35(a) except that the starting material described below was employed and that ethoxyamine was used instead of propylamine: 'H NMR (300 MHz, CDC1₃)

8.59 (m, 1H), 8.08 (d, 1H), 7.88 (d, 1H, J = 16.4 Hz), 7.79 (t, 1H), 7.65 (d, 1H), 7.60 (m, 1H), 7.50 (d, 1H, J = 16.4 Hz), 7.40 (t, 1H), 7.36 (d, 1H), 7.28 (s, 1H), 7.23 (m,

1H), 7.10 (d, 1H), 3.90 (q, 2H), 1.19 (t,3H). LCMS (100% area) Rt = 4.85 min, (pos) [M+H]/z Calc’d 435.1, found 435.1, (neg) [Μ-Η]/ζ Calc’d 433.1, found 433.1. Analyzed with 0.35 H₂O, 0.07 EtOAc Calc’d, C (62.56), H (4.57), N (12.54), S (7.17). Found: C (62.61), H (4.55), N (12.49), S (7.11).

Starting material was prepared as follows:

-241(i)

CK.O

<img file="MY139999A_D0383.tif" />

A solution of ethyl-2,3 difluorobenzoate (1.07 g, 5.75 mmol) in DMF (10 mL) was treated with sodium sulfide (896 mg, 11.5 mmol, 2.0 equiv) at 23 °C. The mixture was stirred under argon for 10 h. The solution was diluted with ethyl acetate (50 mL) and water (50 mL) and 10% citric acid (5 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, decanted and concentrated under reduced pressure to give 3-Fluoro-2-mercapto-benzoic acid ethyl ester: ’HNMR (300 MHz, CDC1₃) 7.71 (t, 1H), 7.38 (m, H), 7.12 (m, 1H), 4.41 (q,

2H), 1.40 (t, 3H); LCMS (100% area) Rt = 4.53 min, (pos) [M+H]/z Calc’d 201.0, found 200.9.

(Π)

<img file="MY139999A_D0384.tif" />

The above thioether was prepared in a similar manner to that described for Example 15 33(a), step (iii) except that 3-Fluoro-2-mercapto-benzoic acid ethyl ester was used instead of thiosalicylate (320 mg, 39%); FTIR (thin film) 2952, 1727, 1607, 1586, 1564, 1469, 1433, 1366, 1292, 1249, 182, 1141, 1074, 836 cm·’; ‘HNMR (300 MHz, CDC1₃) 8.62 (m, 1H), 7.90 (d, 1H, J = 8.6 Hz), 7.85 (d, 1H, J = 16.4 Hz), 7.67 (dt, 1H, J = 1.8, 7.7 Hz), 7.57-7.38 (m, 5H), 7.23-7.10 (m, 3H), 5.65 (s, 2H), 4.34 (q, 2H,

-242J = 7.1 Hz), 3.56 (t, 2H, J = 8.2 Hz), 1.30 (t, 3H, J = 7.1 Hz), 0.88 (t, 2H,J = 8.2 Hz), -0.06 (s, 9H); LCMS (100% area) Rt = 4.44 min, (pcs) [M+H]/z Calc'd 549.2, found

549.2.

(iii)

<img file="MY139999A_D0385.tif" />

The carboxylic acid above was prepared in a similar manner to that described for Example 33(a), step (iv) (303 mg, 99%): FTIR (thin film) 2953, 2496, 1715, 1643, 1607, 1567, 1470, 1434, 1300, 1250, 1221, 1075,967,932,836 cm·¹; Ή NMR (300 MHz, CDC1₃) 8.81 (m, IH), 7.87 (m, 2H), 7.79 (m, 3H), 7.65 (m, 2H), 7.56 (m,

IH), 4.40 (m, IH), 7.30 (m, IH), 7.00 (dd, IH, J = 1.4, 8.5 Hz), 5.58 (s, 2H), 3.59 (t,

2H, J = 8.2 Hz), 0.93 (t, 2H, J = 8.2 Hz), -0.01 (s, 9H). LCMS (100% area) Rt =

10.47 min, (pos) [M+H]/z Calc'd 522.2, found 522.2.

(iv)

<img file="MY139999A_D0386.tif" />

O^O Bu₄N

<img file="MY139999A_D0387.tif" />

The above salt was prepared in a similar manner to that described for Example 33(g): Ή NMR (300 MHz, dmso-d6) 13.2 (s, IH), 8.68 (m, IH), 8.12 (d, IH, J = 8.5 Hz), 7.98 (d, IH, J J = 16.4 Hz), 7.88 (dt, IH, J = 1.8, 7.6 Hz), 7.73 (d, IH, J = 7.9 Hz),

-2437.61 (d, 1H, J = 16.4 Hz), 7.43-7.32 (m, 3H), 7.20 (m, 2H), 7.07 (t, 1H), 3.23 (m,

8H), 1.68 (m, 8H), 1.41 (m, 8H), 1.04 (t, 12H).

(v)

<img file="MY139999A_D0388.tif" />

The above pentafluorophenyl ester was prepared in a similar manner to that described for Example 35(a), step (i): LCMS (100% area) Rt = 10.53 min, (pos) [M+H]/z

Calc'd 558.1, found 558.1.

Example 37(b): 6-[6-Fluoro-2-(cyclopropyIcarbamoyl)phenylsulfanyl]-3-E-[2(pyri din-2-yl)ethenyl] -1 H-indazole

<img file="MY139999A_D0389.tif" />

Example 37(b) was prepared in a similar manner to that described for Example 37(a) except that cyclopropylamine was used instead of ethoxyamine: ’H NMR (300 MHz, dmso-d6) 8.42 (m, 1H), 8.28 (d, 1H), 7.83 (d, 1H), 7.75 (m, 2H), 7.60 (m, 1H), 7.31 (m, 2H), 7.15 (m, 4H), 6.86 (d, 1H), 2.58 (m, 1H), 0.42 (m, 2H),

0.23 (m, 2H). LCMS (100% area) Rt = 4.91 min, (pos) [M+H]/z Calc'd 431.1, found

431.1, (neg) [M-H]/z Calc'd 429.1, found 429.2. Analyzed with 0.55 H₂O Calc’d, C (65.46), H (4.60), N (12.72), S (7.28). Found: C (65.52), H (4.58), N (12.64), S (7.06).

-244Example 37(c): 6-[6-fluoro-2-(isopropoxycarbamoyl)phenylsulfanyI]-3-E-[2(pyridin-2-yl)ethenvl]-l H-indazole

<img file="MY139999A_D0390.tif" />

Example 37(c) was prepared in a similar manner to that described for 5 Example 37(a)”except that isopropoxyamine was used instead of ethoxyamine: 'H

NMR (300 MHz, CDC1₃) 9.50 (bs, IH), 8.47 (m, IH), 7.72 (d, IH), 7.68 (d, IH, J = 16.4 Hz), 7.54 (dt, IH), 7.35 (m, 4H), 7.20 (m, 4H), 4.03 (m, IH), 1.07 (d, 6H); LCMS (100% area) Rt = 4.90 min, (pos) [M+H]/z Calc'd 449.1, found 449.1. Analyzed with 0.1 DMF, 0.3 H_:O Calc’d, C (63.28), H (4.87), N (12.45), S (6.95).

Found: C (63.22), H (4.84), N (12.37), S (6.91).

Example 37(d): 6-[6-Fluoro-2-(methylcarbamoyl)phenvIsulfanyl]-3-E-[2(pvri din-2-yl)ethenyl] -1 H-indazole

<img file="MY139999A_D0391.tif" />

Example 37(d) was prepared in a similar manner to that described for 15 Example 37(a) except that methylamine was used instead of ethoxyamine: ‘H NMR (300 MHz, dmso-d6) 8.37 (m, IH), 8.18 (m, IH), 7.87 (d, IH), 7.67 (d, IH, J = 16.4 Hz), 7.59 (dt, IH), 7.40 (d, IH), 7.30 (m, 2H), 7.20 (m, 4H), 6.85 (d, IH), 2.49 (d, 3H); LCMS (100% area) Rt = 4.63 min, (pos) [M+H]/z Calc’d 405.1, found 405.2,

-245(neg) [M-H]/z Calc’d 403.1, found 403.1. Analyzed with 0.2 DMF, 0.3 CH₂C1₂(nmr), 0.3 H₂O Calc’d, C (61.13), H (4.39), N (13.07), S (7.13). Found: C (61.08), H (4.35), N (13.14), S (7.22).

Example 38(a): 6-[2-(2-Methylquinol-6-ylcarbamoyl)phenylsulfanvl]-3-E-(25 styry!)-lH-indazole

<img file="MY139999A_D0392.tif" />

<img file="MY139999A_D0393.tif" />

Example 38(a) was prepared in a similar manner to that described for Example 33(b) except that steps (i) and (ii) were omitted: 'H NMR (300 MHz, CDC1₃) 8.58 (s, IH), 8.13 (s, IH), 7.80 (m, 3H), 7.67 (t, IH), 7.43 (m, 2H), 7.3410 7.16 (m, 9H), 7.13 (d, IH), 7.07 (d, 1H),2.6O (s, 3H). LCMS (100% area) Rt = 3.87 min, (pos) [M+H]/z Calc’d 513.1, found 513.2.

Example 38(b): 6-[2-((4-piperizin-l-yl-3trifluoromethylphenyl)carbamoyl)phenylsulfanyl]-3-E-(2-styryl)-lH-indazole

<img file="MY139999A_D0394.tif" />

<img file="MY139999A_D0395.tif" />

Example 38(b) was prepared in a similar manner to that described for

Example 38(a) except that 3-trifluoromethyl-4-piperazin-l-yl-phenylamine was used instead of 6-amino-2-methylquinoline: 'H NMR (300 MHz, CDC1₃) 8.75 (s, IH), 7.95 (d, IH), 7.77 (m, 2H), 7.69 (s, IH), 7.55 (m, 31-1), 7.40-7.25 (m, 9H), 7.20 (d,

-2461H), 3.00 (m, 4H), 2.83 (m, 4H). LCMS (100% area) Rt = 3.94 min, (pos) [M+H]/z

Calc'd 600.2, found 600.2. Analyzed with 0.1 hex (nmr), 1.4 H₂O Calc’d, C (63.71),

H (5.12), N (11.06), S (5.06). Found: C (63.67), H(5.06), N (10.98), S (5.00).

Example 39(a): 6-[2-(MethylcarbamoyI)phenyIamino]-3-E-[2-(pyridin-25 yl)ethenyl]-lH-indazole

<img file="MY139999A_D0396.tif" />

A solution of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-l -(2-trimethylsilanylethoxymethy 1)-1 H-indazol-6-ylamino]-benzamide (39 mg, 0.07820 mmol) (synthesis described below), ethylene diamine (21 L, 0.3128 mmol), and 1M TBAF in THF (0.63 ml, 0.6256 mmol), was stirred in a 90 °C oil bath for 2 hr. The crude reaction mixture was diluted with ethyl acetate (50 mL), extracted 1M sodium bicarbonate solution (2 x 20 ml), brine (5 x 20 ml), dried magnesium sulfate, filtered, and concentrated to a solid. The solid was dissolved in THF, concentrated to an oil, then triturated with CH₂Cl₂/Et₂O, causing precipitation of a powder. The powder was 15 collected by filtration, rinsed with Et₂O, and dried under high vacuum. Mass of collected solid was 20 mg (70 % yield). 'H NMR (DMSO-d₆) 12.91 (bs, IH), 9.86 (s, IH), 8.60 (d, J= 4.0 Hz, IH), 8.52 (m, IH), 8.08 (d, J= 8.5 Hz, IH), 7.90 (d, J= 16.4 Hz, IH), 7.80 (dt,/= 1.7, 7.5 Hz, IH), 7.65 (d,/= 7.9 Hz, IH), 7.51 (d,/ = 16.1 Hz, IH), 7.47-7.34 (m, 2H), 7.25 (m, 2H), 7.00 (d,/= 9.6 Hz, IH), 6.89 (t,/ =

-2477.0 Hz, 1H), 2.79 (d, J= 4.7 Hz, 3H). Anal. Calcd. for C₂₂H₁₉N₅O-0.5 CH₂C1₂: C,

65.61; H, 4.89; N, 17.00. Found: C, 65.52; H, 5.08; N, 16.78.

The starting material was prepared as follows:

H

CK/N.

<img file="MY139999A_D0397.tif" />

CH₃ .A solution of 191 mg (0.4 mmol) of 6-iodo-3-carboxaldehyde-l-[2-(trimethylsilanly)-ethoxymethyl]-l H-indazole (from Example 33(a), step(ii)), methyl anthranilate (120.1 mg, 0.8 mmol), 2-(dicyclohexylphosphino) biphenyl (28 mg,0.08 mmol), Pd,(dba)₃ (18.4 mg, 0.02 mmol), K₃PO„ (212.3 mg, 1.0 mmol), dissolved in dry DME (1.0 mL), was vacuum flushed with argon (3X), then stirred under an argon atmosphere for 3d in an oil bath at 80 °C. The crude mixture was filtered through a plug of SiO₂ eluted with ethyl acetate, then purified by chromatotron radial chromatography eluted with 25% CH₃CN/CH₂C1₂. The mass of the fractions that were pure was 42 mg. An addition 120 mg of product that was -90% pure was also collected. The total yield of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-l-(2trimethylsilanyl-ethoxymethyl)-lH-indazol-6-ylamino]-benzamide was 162 mg or

-81%.

Example 39(b): 6-[2-(Prop-2-ynylcarbamoyl)phenylamino]-3-E-[2-(pyridin-2vl)ethenyl]-lH-indazole

-248-

<img file="MY139999A_D0398.tif" />

Example 39(b) was prepared in a similar manner to that described for Example 39(a) except that the propargylamine was used instead of methylamine. 'H NMR (CDC1₃) 9.50 (s, 1H), 8.64 (d, J= 4.5 Hz, 1H), 7.98 (d, J= 8.9 Hz, 1H), 7.90

5- (d,'J= 16.4 Hz, 1H), 7.70 (dt,7= 1.7, 7.5 Hz, 1H), 7.57 (d,7= 16.3 Hz, 1H), 7.527.43 (m,3H), 7.34 (dt,7= 1.5,7.2 Hz, 1H), 7.26 (m, 3H), 7.34 (ddd, 7= 1.0,4.9,7.5 Hz, 1H), 7.09 (dd,7= 1.7,9.0 Hz, 1H), 6.85 (dt,7= 1.0,7.0 Hz, 1H), 6.33 (bs, 1H), 4.24 (dd, J= 2.6, 5.3 Hz, 2H), 2.30 (t, J= 5.5 Hz, 1H). Anal. Calcd. for C₂₄H₁₉N₅OO.25 CH₂C1₂: C, 70.24; H, 4.74; N, 16.89. Found: C, 70.72; H, 4.96; N,

16.55.

Example 40(a): 6-(3-Amino-benzoyI)-3-E-[2-(pyridin-2-yI)ethenyl]-lH-indazole

<img file="MY139999A_D0399.tif" />

Example 40(a) was prepared in a similar manner to that described for Example 11. 'HNMR (300 MHz, DMSO-d₆) 13.5 (s, 1H), 8.62 (d, 1H, J = 3.86 Hz), 8.34 (d, 1H, J = 8.5 Hz), 8.01 (d, 1H, J = 16.36 Hz), 7.87 (s, 1H), 7.83 (td, 1H, J = 7.69 Hz, J = 1.81 Hz), 7.58-7.71 (m, 3H), 7.29 (cd, 1H, J = 7.39 Hz, J = 0.98 Hz), 7.21 (t, 1H, J = 7.77), 7.00 (t, 1H, J = 1.86 Hz), 6.90 (dt, 1H, J = 6.15 Hz, J = 1.40

-249Hz), 6.86 (m, IH), 5.40 (bs, 2H). MS (ESI+) [M+H]/z Calc’d 446, found 446.

Calc’d: C, 74.10; H, 4.74; N, 16.46. Found: C, 72.72; H, 4.87; N, 16.02.

The starting material was prepared as follows:

(i)

B(OH)₂

<img file="MY139999A_D0400.tif" />

\

To m-amino-phenyl boronic acid (8.22g, 60 mmol) in dimethyformamide (60 ml) at 23 °C under an atmosphere of argon was added triethylamine (10 ml, 72 mmol) and

4-(dimethylamino)pyridine (0.366 g, 3 mmol). The resulting solution was heated to 50 °C. Carbonic acid 4-nitro-phenyl ester 2-trimethylsilanyl-ethyl ester (20.4 g, 72 mmol) was added in 5 by 4g portions over 18 hours. After 44 h carbonic acid 4-nitro· phenyl ester 2-trimethylsilanyl-ethyl ester (3.4 g, 12 mmol) was added followed by triethylamine (1.7 ml, 12 mmol). After 63 h the reaction mixture was concentrated to an oil. Purification by silica gel chromatography eluting with 3-7 to 7-3 ethyl acetate hexane gave (3-boronic acid-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (8.12 g, 48%): Rf sm 0.067, p 0.33 (ethyl acetate-hexane 1:1); ’H NMR (300 MHz,

CD₃OD) 7.64 (s, IH), 7.49 (d, IH, J = 8.94 Hz), 7.26 (m, 2H), 4.23 (t, 2H, J = 8.28

Hz), 1.06 (t, 2H, J = 8.21 Hz) 0.72 (s, 9H). MS (ESI) [M+Na]/z Calc’d 304, found

304.

(ii)

-250-

<img file="MY139999A_D0401.tif" />

A mixture of 6-iodo-3-((E)-2-pyridin-2-yl-vinyl)-l-(2-trimethylsilanylethoxymethyl)-lH-indazole (7.1 g, 14.8 mmol), (3-boronic acid-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (8.32 g, 29.6 mmol), dichlorobis(triphenylphosphine)-palladium(ll) (312 mg, 0.44 mmol), potassium carbonate (6.13 g, 44.4 mmol) and triethylamine (2.1 ml, 14.8) in anisole (60 ml) was heated to 80 °C under an atmosphere of carbon monoxide. After 24 h more triethylamine (2.1 ml, 14.8 mmol) was added. After 33 hrs the reaction was determined to be complete by TLC analysis (ethyl acetate-hexane 7-3). The reaction mixture was cooled to 23 °C, then diluted with saturated NaHCO₃ (aq) (40 ml) and ethyl acetate (300 ml). The phases were separated and the aqueous was extracted with ethyl acetate (2 x 100 mis). The pooled ethyl acetate was washed with brine (100 ml) and dried over Na,SO₄, filtered and concentrated. Purification by silica gel chromatography gave (3-{l-[3-(2-Pyridin-2-yl-ethyl)-l-(2-trimethylsilanyl15 ethoxymethyl)-lH-indazol-6-yl]-methanoyl}-phenyl)-carbamic acid 2trimethylsilanyl-ethyl ester as a yellow glass (7.22 g, 79%). Ή NMR (300 MHz, CDC1₃) 8.65 (d, 1H, J = 3.93 Hz)_: 8.10 (d, 1H, J = 8.54 Hz), 8.04 (s, 1H), 7.94 (d, 1H, J = 16.33 Hz), 7.82 (s, 1H), 7.66-7.77 (m, 3H), 7.61 (d, 1H, J = 16.35 Hz), 7.407.51 (m, 3H), 7.19 (m, 1H), 7.00 (s, 1H), 5.77 (s, 2H), 4.25 (t, 2H, J = 6.93 Hz), 3.60 (t, 2H, J = 8.10 Hz), 1.04 (t, 2H, J = 6.79 Hz), 1.00 (t, 2H, J = 8.13 Hz), 0.04 (s, 9H),

0.0 (s, 9H). MS (ESI+) [M+H]/z Calc’d 615, found 615.

-251Example 40(b): 6-(3-Amino-4-methyl-benzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-lHindazole

<img file="MY139999A_D0402.tif" />

Example 40(b) was prepared in a similar manner to that of Example 40(a) except that in step (i) 4-methyl-3-amino-phenyl boronic acid, prepared as described below, was used in place of m-amino-phenyl boronic acid. *H NMR (DMSO-d₆)

13.6 (s, IH), 8.62 (d, IH, J = 3.81 Hz), 8.33 (d, IH J = 8.47 Hz), 8.01 (d, IH, J =

16.36 Hz), 7.85 (s, IH), 7.82 (dd, IH, J = 7.60 Hz, J = 1.80 Hz), 7.70 (d, IH, J = 7.81

Hz), 7.63 (d, IH, J = 16.36 Hz), 7.57 (dd, IH, J = 8.47 Hz, J = 1.2 Hz), 7.29 (m, IH),

7.12 (d, IH, J = 7.82 Hz), 7.09 (d, IH, J = 1.64 Hz), 6.90 (dd, IH, J= 7.59 Hz, J =

1.65 Hz), 5.16 (bs, IH), 2.16 (s, IH). MS (ESI+) [M+H]/z Calc’d 355, Anal. Calc’d:

C, 74.56; H, 5.12; N, 15.81. Found: C, 73.86; H, 5.25; N, 15.34.

The starting material was prepared as follows:

(i)

B(OH),

<img file="MY139999A_D0403.tif" />

A mixture of 4-methyl-3-nitro-phenyl boronic acid (3.34 g, 18.45 mmol) and 10% Pd/C (334 mg) in MeOH (30 ml) was hydrogenated (1 atm.) at 23 °C. After 22 h the reaction mixture was filtered through celite and concentrated to give 3-amino-4methyl phenyl boronic acid (2.53 g, 91%). 'H NMR (300 MHz, DMSO-d₆) 7.21 (s,

-2521H), 7.08 (d, 1H, J = 7.5 Hz), 6.92 (d, IH, J = 7.46 (Hz), 4.81 (bs, 2H), 2.09 (s, 3H).

MS (ESI) [M+H]/z Calc’d 152, found 152.

Example 40(c): 6-(5-Amino-2,4-dimethyl-benzoy]l)-3-E-[2-(pyridin-2-yl)ethenyl]lH-indazole

<img file="MY139999A_D0404.tif" />

Example 40(c) was prepared in a similar manner to that of Example 40(a) except that in step (i) 2,4-dimethyl-3-amino-phenyl boronic acid (prepared as described below) was used in place of m-amino-phenyl boronic acid: ’H NMR (DMSO-d₆) 8.62 (d, IH, J = 3.78 Hz), 8.32 (d, IH, J = 8.48 Hz), 7.99 (d, IH, J = 16.35 Hz), 7.83 (td, IH, J = 7.68 Hz, J = 1.8 Hz), 7.80 (s, IH), 7.69 (d, IH, J = 7.80 Hz), 7.64 (dd, IH, J = 8.47

Hz, J = 1.27 Hz), 7.62 (d, IH, J = 16.36 Hz), 7.29 (m, 1H), 6.94 (s, IH), 6.64 (s, IH),

4.87 (bs, 2H), 2.12 (s, 3H), 2.10 (s, 3H). LCMS (ESI+) [M+H]/z Calc’d 369, found

369. Anal. Calc’d: C, 74.98; H, 5.47; N, 15.21. Found: C, 73.85; H, 5.56; N, 14.49.

The starting material was prepared as follows:

(i)

<img file="MY139999A_D0405.tif" />

2,4-Diemthylphenyl boronic acid was made in a similar manner as that of Example 24(a), step (vii), except 2,4-dimethyl bromobenzene was used as starting material. ’H

-253NMR (CD₃OD) 7.13 (d, 1H, J = 7.43 Hz), 7.00 (s, IH), 6.97 (d, IH, J = 7.49 Hz),

2.28 (s, 3H), 2.28 (s, 3H). LCMS (ESI+) [M+H]/z Calc’d 151, found 151.

B(OH)₂

<img file="MY139999A_D0406.tif" />

NO

To fuming nitric acid (1 ml) cooled to -40 °C was added TFA (1 ml). The resulting mixture was allowed to warm slightly to -35 °C and 2,4-dimethyl phenyl boronic acid (150 mg, 1 mmol) was added in one portion. After 1 h, ice was added and the heterogenous mixture was filtered. The resulting solid was suspended in Et₂O and extracted with 3N NaOH (aq) (1 ml) then water (2 ml). The aqueous phase was acidified with 3N HCI (aq) (1 ml) and back extracted with EtOAc (3x5 ml). The pooled organics were washed with brine, dried with Na₂SO₄ decanted and concentrated to give 2,4-dimethyl-5-nitro-phenyl boronic acid (93 mg, 47%). LCMS (ESI+) [M+H]/z Calc’d 196, found 196.

(iii)

B(OH)₂

NH

3-Amino-4,6-dimethylphenyl boronic acid was prepared in a similar as that described for Example 40(b), step (i). Ή NMR (CD₃OD) 6.83 (s, 2H), 6.64 (s, IH), 2.17 (s, 3H), 2.13 (s, 3H).

-254Example 41(a): 6-[3-((l-Ethyl-3-methyl-lH-pyrazol-5-yl)carboxamido)benzoyl]3-E-[2-(pyridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0407.tif" />

To a solution of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (323 mg, 2.1 5 mmol, 2.1 equiv.) in DMF (5 ml) at 23 °C under argon was added diisopropylethylamine (365 1, 2.1 mmol, 2.1 equiv.), HATU (798 mg, 2.1 mmol, 2.1 equiv.) and DMAP (cat.). To the resulting solution was added 6-(3-Amino-benzoyl)3-E-(2-pyridin-2-yl)ethenyl)-lH-indazol (Example 40(a), 340 mg, 1 mmol, 1 equiv.).

The reaction was followed by HPLC until all the starting analine was consumed ~2 h (this gave a mixture of mono and bis acylated compounds). The reaction mixture was quenched with saturated NaHCO₃, then diluted with water and extracted with ethylacetate. The pooled EtOAc was washed with water, brine, dried with Na₂SO₄, filtered and concentrated to an oil. The oil was dissolved in methanol (10 ml), K₂CO₃ (290 mg, 2.1 mmol, 2.1 equiv.) was added and the resulting mixture was stirred at 23 °C until the bis-acylated compound was consumed (~30 min.). The reaction mixture was concentrated to an oil, then partitioned between water and EtOAc. The organic phase was washed with brine, dried with Na₂SO₄, filtered and concentrated. Purification by silica gel chromatography (1:1-8:2 ethylacetate-dichloromethane) gave Example 41(a). Ή NMR (300 MHz, DMSO-d₆) 13.6 (s, 1H), 10.3 (s, 1H),

8.62 (d, 1H, J = 3.88 Hz), 8.38 (d, 1H, J = 8.51 Hz), 8.20 (s, 1H), 8.12 (td, 1H, J =

-2557.58 Hz, J = 1.78 Hz), 8.02 (d, 1H, J = 16.36 Hz), 7.93 (s, 1H), 7.83 (td, 1H, J = 7.61 Hz, J = 1.7 Hz), 7.70 (d, 1H, J = 7.78 Hz), 7.65 (d, 1H, J = 16.23 Hz), 7.65 - 7.53 (m 3H), 7.30 (m, 1H),4.43 (q, 2H, J = 7.07 Hz), 2.21 (s, 3H), 1.31 (t, 3H,J = 7.07 Hz).

MS (ESI+) [M+H]/z Calc’d 477, found 477. Anal. Calc’d: C, 70.57; H, 5.08; N,

7.64. Found: C, 70.46; H, 5.11; N, 17.61.

Example 41(b): 6-[3-(pyridin-4-ylcarboxamido)benzoyl]-3-E-[2-(pyridin-2yl)ethenyl]-l H-indazole

<img file="MY139999A_D0408.tif" />

Example 41(b) was prepared in a similar manner to that described for 10 Example 41(a), except that isonicotinic acid was used instead of 2-ethyl-5methyl-2H-pyrazole-3-carboxylic acid. ’H NMR (300 MHz, CD₃OD) 8.74 (d, 2H, J = 6.04 Hz), 8.56 (d, 1H, J = 4.14 Hz), 8.27 (m, 2H), 8.05 (dt, 1H, J = 7.97

Hz, J = 1.64 Hz), 8.02 (s, 1H), 7.95 (d, 1H, J= 16.55 Hz), 7.83-7.91 (m, 3H), 7.73 (m, 2H), 7.56-7.67 (m, 3H), 7.32 (m, 1H). MS (ESI+) [M+H]/z Calc’d 446, found

446. Anal. Calc’d: C, 72.80; H, 4.30; N, 15.72. Found: C, 71.59; H, 4.43; N,

15.33.

Example 41(c): 6-(3-crotonylamidobenzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]-lHindazole

<img file="MY139999A_D0409.tif" />

-256Example 41(c) was prepared in a similar manner to that described for Example 41(a), except that crotonic acid was used instead of 2-ethyl-5-methyl2H-pyrazole-3-carboxylic acid. ’HNMR (300 MHz, DMSO-d₆) 13.6 (s,lH), 10.2 (s, IH), 8.63 (d, IH, J = 3.81 Hz), 8.37 (d, IH, J = 8.49 Hz), 8.12 (s, IH),

8.02 (a, IH, J = 16.34 Hz), 7.99 (d, IH, J = 7.88 Hz), 7.83 (td, IH, J = 7.67 Hz, J = 1.78 Hz), 7.70 (d, IH, J = 7.85 Hz), 7.65 (d, IH, J = 16.40 Hz), 7.63 (dd, IH, J = 8.43 Hz, J = 1.23 Hz), 7.47 - 7.56 (m, 2H), 7.29 (qd, IH, J = 7.39 Hz, J = 0.99

Hz), 6.82 (m, IH, J = 6.9 Hz), 6.11 (dd, J= 15.21 Hz, J = 1.68 Hz), 1.87 (d, 3H, J = 6.89 Hz). MS (ESI+) [M+H]/z Calc’d 409, found 409. Anal. Calc’d: C, 73.51;

H, 4.94; N, 13.72. Found: C, 72.15; H, 4.97; N, 13.39.

Example 41(d): 6-[3-(indol-4-ylcarboxamido)benzoyl]-3-E-[2-(pyridin-2yI)ethenyl]-lH-indazo!e

<img file="MY139999A_D0410.tif" />

Example 41(d) was prepared in a similar manner to that described for 15 Example 41(a), except that l/f-Indole-4-carboxylic acid was used instead of2ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. LCMS (ESI+) [M+H]/z Calc’d

484, found 484.

Example 41(e): 6-[3-((5-acetyIthien-2-yI)carboxamido)benzoyI]-3-E-[2-(pyridin

2-yl)ethenyl]-lH-indazole

-257-

<img file="MY139999A_D0411.tif" />

H

N

<img file="MY139999A_D0412.tif" />

Example 41(e) was prepared in a similar manner to that described for Example 41(a), except that 5-acetyl-thiophene-2-ca'boxylic acid was used instead of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ’H NMR (300 MHz, DMSO-d₆)

13.6 (s, IH), 10.6 (s, IH), 8.63 (d, IH, J = 3.83 Hz), 8.39 (d, IH, J = 8.51 Hz), 8.20 (s, IH), 8.14 (dt, IH, J = 7.25 Hz, J = 2.05 Hz), 8.07 (d, IH, J = 4.09 Hz), 8.02 (d,

IH, J = 16.42 Hz), 8.00 (d, IH, J = 4.01 Hz), 7.94 (s, IH), 7.83 (td, IH, J = 7.69 Hz, J = 1.78 Hz), 7.59-7.65 (m, 5H), 7.30 (qd, IH, J = 7.40 Hz, J = 0.96 Hz), 2.58 (s, 3H). MS (ESI+) [M+H]/z Calc’d 493, found 493. Anal. Calc’d: C, 68.28; H, 4.09; N,

11.37; S, 6.51. Found: C, 66.07; H, 4.34; N, 10.91; S, 6.14.

Example 41(f): 6-[3-(3,5-difluorophenylacetamido)benzovl]-3-E-[2-(pyridin-2yl)ethenyl]-lH-indazole

<img file="MY139999A_D0413.tif" />

Example 41(f) was prepared in a similar maimer to that described for Example 15 41(a), except that (3,5-difluoro-phenyl)-acetic acid was used instead of 2-ethyl-5methyl-2H-pyrazole-3-carboxylic acid. ’HNMR (300 MHz, DMSO-d₆) 13.6 (bs, IH), 10.5 (s, IH), 8.62 (d, IH, J = 4.02 Hz), 8.36 (d, IH, J = 8.51 Hz), 8.05 (s, IH),

8.01 (d, IH, J = 16.38 Hz), 7.93 (d, IH, J = 7.88 Hz), 7.90 (s, IH), 7.83 (td, IH, J =

-2587.61 Hz, J = 1.77 Hz), 7.70 (d, IH, J = 7.85 Hz), 7.64 (d, IH, J = 16.33 Hz), 7.61 (dd IH, J = 8.45 Hz, J = 1.15 Hz), 7.48-7.57 (m, 2H), 7.15-7.31 (m, 5H), 3.77 (s, 2H).

MS (ESI+) [M+H]/z Calc’d 495, found 495.

Example 41(g): 6-[3-((5-methyl-lH-pyrazol-3-yl)carboxamido)benzoyl]-3-E-[25 (pyridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0414.tif" />

<img file="MY139999A_D0415.tif" />

Example 41 (g) was prepared in a similar mcinner to that described for Example 41(a), except that 5-methyl-2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ’H NMR (300 MHz,

DMSO-d₆) 13.6 (bs, IH), 13.0 (bs, IH), 10.3 (bs, IH), 8.63 (d, IH, J = 3.95 Hz),

8.37 (d, IH, J = 8.66 Hz), 8.36 (s, IH), 8.16 (d, IH, J = 7.55 Hz), 8.02 (d, IH, J =

16.37 Hz), 7.93 (s, IH), 7.83 (dt, IH, J = 7.61 Hz, J = 1.73 Hz), 7.70 (d, IH, J =

7.82 Hz), 7.65 (d, IH, J = 16.36 Hz), 7.65 (dd, IH, J = 8.55 Hz, J = 1.12 Hz), 7.52 (m, 2H), 7.29 (m, IH), 6.50 (s, IH), 2.29 (s, 3H). MS (ESI+) [M+H]/z Calc’d 15 449, found 449. Anal. Calc’d: C, 69.63; H, 4.49; N, 18.74. Found: C, 68.53; H,

4.95; N, 17.47.

Example 41(h): 6-[3-((2-RS-/rarts-niethylcyclopropyl)carboxamido)benzoyI]-3-E [2-(pvridin-2-yI)ethenyl]-lH-indazole

-259-

<img file="MY139999A_D0416.tif" />

Example 41(h) was prepared in a similar manner to that described for

Example 41(a), except that 2-Methyl-cyclopropanecarboxylic acid was used in place of 2-ethyl-5-meth yl-2H-pyrazole-3-carboxylic acid. Rysm 0.32, Ryp 0.42 (ethyl acetate-dichloromethane 8:2). ’H NMR (300 MHz, DMSO-d₆) 13.6 (s, 1H), 10.4 (s, 1H), 8.62 (dd, 1H, J = 4.75 Hz, J = 0.96 Hz), 8.36 (d, 1H, J = 8.47 Hz), 8.06 (t, 1H, J = 1.67 Hz), 8.01 (d, 1H, J = 16.37 Hz), 7.90 (m, 2H), 7.83 (td, 1H, J = 7.68 Hz, J =

1.79 Hz), 7.70 (d, 1H, J = 7.84 Hz), 7.64 (d, 1H, J = 16.35 Hz), 7.61 (dd, 1H, J = 8.47

Hz, J = 1.32 Hz), 7.51 (t, 1H,J = 7.69 Hz), 7.45 (dt, 1H,J = 7.68 Hz, J = 1.50 Hz),

7.29 (dq, 1H, J = 7.41 Hz, J = 1.04 Hz), 1.51 (m, 1H), 1.23 (m, 1H), 1.09 (d, 3H, J =

5.93), 1.01 (m, 1H), 0.65 (m, 1H). MS (ESI+) [M+H]/z Calc’d 423, found 423.

Anal. Calc’d: C, 73.92; H, 5.25; N, 13.26. Found: C, 71.41; H, 5.56; N, 13.27.

Example 41(i): 6-(3-((1,5-dimethyl-lH-pyrazol-3-yl)carboxamido)benzoyl]-3-E[2-(pyridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0417.tif" />

<img file="MY139999A_D0418.tif" />

Example 41 (i) was prepared in a similar mariner to that described for Example

41(a), except that l,5-dimethyl-lH-pyrazole-3-carboxylic acid was used in place of2ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. 'H NMR (300 MHz, DMSO-d₆)

-26013.6 (s, 1H), 10.2 (s, IH), 8.63 (d, IH, J = 3.87 Hz)., 8.37 (d, IH, J = 8.49 Hz), 8.34 (d, IH, J = 1.63 Hz), 8.16 (td, IH, J = 7.43 Hz, J = 1.96 Hz), 8.02 (d, IH, J = 16.35

Hz), 7.92 (s, IH), 7.83 (dt, IH, J = 7.68 Hz, J = 1.79 Hz), 7.70 (d, IH, J = 7.84 Hz),

7.65 (d, IH, J = 16.35 Hz), 7.65 (dd, IH, J = 8.52 Hz, J = 1.2 Hz), 7.52 (m, 2H), 7.29 (m, IH), 6.55 (s, IH), 3.83 (s, 3H), 2.30 (s, 3H). MS (ESI+) [M+H]/z Calc’d 463, found 463. Anal. Calc’d: C, 70.12; H, 4.79; N, 18.17. Found: C, 69.59; H, 4.88; N,

17.86.

Example 41 (j): 6-[3-((3-methylpyridin-4-yl)carboxamldo)benzoyl]-3-E-[2(py ridin-2-yl)eth enyl] -1 H-indazole

<img file="MY139999A_D0419.tif" />

j Example 41 (j) was prepared in a similar manner to that described for

Example 41(a), except that 3-methyl-isonicotinic acid was used in place of 2i ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. 'HNMR (300 MHz, DMSO-d₆)

13.6 (s, IH), 10.7 (s, IH), 8.62 (dd, IH, J = 4.72 Hz, J = 0.86 Hz), 8.57 (s, IH),

8.55 (d, IH, J = 4.91 Hz), 8.37 (d, IH, J = 8.46 Hz), 8.20 (s, 1Ή), 8.07 (dt, IH, J =

7.27 Hz, J = 1.99 Hz), 8.02 (d, IH, J = 16.37 Hz), 7.93 (s, IH), 7.83 (td, IH, J =

7.69 Hz, J = 1.79 Hz), 7.70 (d, IH, J = 7.84 Hz), 7.64 (d, IH, J = 16.27 Hz), 7.55j

7.65 (m, 3H), 7.48 (d, IH, J = 4.89 Hz), 7.30 (qd, IH, J = 7.39 Hz, J = 1.02 Hz),

2.38 (s, 3H). MS (ESI+) [M+H]/z Calc’d 460, found 460.

Example 41 (k): 6-(3-(cycIopropylcarboxamido)benzoyl]-3-E-[2-(pyridin-2yl)ethenyl]-l H-indazole

-261-

<img file="MY139999A_D0420.tif" />

Example 41(k) was prepared in similar manner as Example 41(a) except that cyclopropane carboxylic acid used in place of 2-ethyl-5-methyl-2H-pyrazole-3carboxylic acid. Ή NMR (CDCl₃/MeOD) 8.52 (d, 1H, J = 3.9Hz), 8.09 (d, 1H, J =

8.5Hz), 7.93 (s, 1H), 7.85-7.80 (m, 3H), 7.71-7.63 (m, 2H), 7.55-7.48 (m, 3H), 7.39 (1H, t, J = 7.8Hz), 7.16 (1H, qd, J = 6.3, 1.5Hz), 1.62-1.57 (m, 1H), 1.25-1.84 (m, 2H), 0.87-0.81 (m, 2H). HRMS (MALDI) C₂₅H₂₀N_tO₂ [M + H*]/z Calc’d 409.1659, found 409.1660.

Example 41(1): 6-[3-((2-RS-irans-phenyIcyclopropyI)carboxamido)benzoyl]-3-E [2-(pyridin-2-yl)ethenyI]-l H-indazole

<img file="MY139999A_D0421.tif" />

Example 41(1) was prepared in similar manner as Example 41(a) except that (lS,2S)-2-phenyl-cyclopropanecarboxylic acid used in place of 2-ethyl-5methyl-2H-pyrazole-3-carboxylic acid. 'HNMR (CDCl₃/MeOD) 8.60 (d, 1H, J =4.2Hz), 8.17 (d, 1H, J = 8.4Hz), 8.02 (s, 1H),7.91 (t, 3H, J = 8.1Hz), 7.78-7.71 (m, 2H), 7.63-7.56 (m, 3H), 7.47 (t, 1H), 7.32-7.12 (m, 5H), 2.60-2.54 (m, 1H),

1.94-1.90 (m, 1H), 1.69 (q, 1H, J = 4.8Hz), 1.37-1.32 (m, 1H). HRMS

C₃₁H₂₄N₄O₂ Calc’d (M + H*)/z 485.1993, found 485.1995.

-262Example 41(m): 6-[3-((3-methylisoxazol-5-yl)carboxamido)benzoyl]-3-E-[2(pyridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0422.tif" />

Example 41(m) was prepared in similar manner as Example 41(a) except that 3-methyl-isoxazole-5-carboxylic acid used in place of 2-ethyl-5-methyl-2Hpyrazole-3-carboxylic acid. ’HNMR (DMSO-d₆) 10.95 (1H, s), 8.68 (1H, d, J = 4.2Hz), 8.44 (d, 1H, J = 8.7Hz), 8.35 (s, 1H), 8.21-8.18 (m, 1H,), 8.08 (d, 1H, J =

16.2Hz), 7.98 (s, 1H), 7.87 (td, 1H, J = 7.5, 1.8Hz), 7.76-7.64 (m, 6H), 7.37-7.33 (m, 1H), 6.72 (s, 1H) 3.36 (s, 3H). HRMS (MALDI) C₂₆H₁₉N₅O₃ [M + H*]/z:

Calc’d 450.1561, found 450.1570.

Example 41(n): 6-[3-((3-/-butyl-l-methyI-lH-pyrazol-5-yI)carboxamido)benzoyI]

3-E-[2-(pyridin-2-yI)ethenyI]-lH-indazoIe

<img file="MY139999A_D0423.tif" />

Example 41(n) was prepared in similar manner as Example 41(a) except that 5-zert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid used in place of 2-ethyl5-methyl-2H-pyrazole-3-carboxylic acid. ’HNMR (CDCl₃/MeOD) 8.59 (d, 1H, J = 4.8Hz), 8.14 (d, 1H, J = 8.4Hz), 8.08-8.04 (m, 1H,), 7.98-7.92 (m, 3H), 7.75 (td, 1H, J = 7.8, 1.8Hz), 7.68 (dd, 1H, J = 8.4Hz), 7.61-7.56 (m, 3H), 7.52 (t, 1H,

-263J = 8.70 Hz), 7.25-7.21 (m, IH,), 6.75 (s, IH,), 4.12 (s, 3H), 1.30 (s, 9H). HRMS (MALDI) C₃₀H₂₈N₆O₂(M + H*]/z: Calc. 505.2347, found 505.2353.

Example 41(o): 6-(3-((5-chlorothien-2-yl)carboxamido)benzoyl]-3-E-[2-(pyridin

2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0424.tif" />

Example 41(o) was prepared in similar manner as Example 41(a) except that 5-chloro-thiophene-2-carboxylic acid used in place of 2-ethyl-5-methyl-2Hpyrazole-3-carboxylic acid. ’H NMR (DMSO-d₆) 10.58 (s, IH,), 8.68 (d, IH, J = 4.2Hz), 8.43 (d, IH, J = 8.5Hz), 8.22 (s, IH,), 8.15 (dt, IH, J = 7.5, 2.0 Hz),

8.08 (d, IH, J = 16.4Hz), 8.00-7.98 (m, 3H), 7.88 (td, IH, J = 7.7, 1.9Hz), 7.787.62 (m,4H,), 7.33 (d, 2H, J = 4.1Hz). HRMS (MALDI) C₂₆H,₃N₄O₂C1S (M +

H*]/z: Calc. 485.0843, found 485.0853.

Example 41(p): 6-(3-((1,3-Dimethvl-lH-pyrazoI-5-yl)carboxamido)benzoyI]-3-E [2-(pyridin-2-yI)ethenyl]-1 H-indazole

<img file="MY139999A_D0425.tif" />

Example 41(p) was prepared in similar manner as Example 41(a) except that 2,5-dimethyl-2H-pyrazole-3-carboxylic acid used in place of 2-ethyl-5methyl-2H-pyrazole-3-carboxylic acid. HPLC: R, 3.90 min (100% area). ’H NMR(CDCL₃) 8.52 (d, IH, J = 4.8Hz), 8.10 (d, IH, J = 8.4Hz), 7.98 (d, IH, J =

-2648.1Hz), 7.93 (s, IH,), 7.88-7.80 (m, 3H), 7.71-7.62 (m, 2H), 7.56-7.49 (m, 4H),

7.44 (t, IH, J = 7.8Hz), 7.16 (dd, IH, J = 7.1, 4.8Hz). HRMS (MALDI)

C₂₇H₂₂N₆O₂. [M + H*]/z: Calc, 463.1877, found 465.1889.

Example 41 (q): 6-|3-((2-chloro-6-methylpyridin-4-y])carboxamido)benzoyl]-3-E 5 [2-(pyridin-2-yI)ethenyl)-lH-indazole

<img file="MY139999A_D0426.tif" />

Example 41(q) was prepared in similar manner as Example 41(a) except that 2-chloro-6-methyl-isonicotinic acid used in place of 2-ethyl-5-methyl-2Hpyrazole-3-carboxylic acid. HPLC: R₁ 4.11 min. (100% area). ’H NMR (DMSO10 d₆) 10.77 (s, IH), 8.68 (d, IH, J = 3.9Hz), 8.44 (d, IH, J = 8.4Hz), 8.28 (s, IH),

8.21 (dt, IH, J = 6.9, 2.1 Hz), 8.08 (d, IH, J = 16.2Hz), 7.98 (s, IH), 7.92-7.64 (m, 9H), 7.35 (dd, IH, J = 6.6, 4.8Hz), 2.61 (s, 3H).

Example 41(r): 6-[3-((l-«-propyI-3-methyI-lH-pyrazoI-5yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenvl]-lH-indazole

<img file="MY139999A_D0427.tif" />

<img file="MY139999A_D0428.tif" />

Example 41(r) was prepared in similar manner as Example 41(a) except that 5-methyl-2-propyl-2H-pyrazole-3-carboxylic acid used in place of 2-ethyl-5-265methyl-2H-pyrazole-3-carboxylic acid. Ή NMR (DMSO-d₆) 10.29 (s,lH),

8.58 (d, IH, J = 3.9Hz), 8.33 (d, 1H, J = 8.4 Hz), 8.13 (s, 1H), 8.10 (dt, IH, J =

5.4, 2.1Hz), 7.96 (d, IH, J = 16.5Hz), 7.87 (s, IH), 7.78 (td, IH, J = 7.5, 1.5Hz),

7.61-7.49 (m, 6H), 7.24 (dd, IH, J = 6.9, 1.8Hz), 4.32 (t, 2H, J = 6.90Hz), 1.69 (q,

2H, J = 7.2Hz), 0.77 (t, 3H, 7.5Hz). HRMS (MALDI) C₂₈H₂₀ClN₅O₂. [M + ET]/z:

Calc. 491.2190, found 491.2203.

Example 41(s): 6-[3-(4-/-butylbenzamido)benzoyI]-3-E-[2-(pyridin-2-yl)ethenyI] lH-indazole

<img file="MY139999A_D0429.tif" />

<img file="MY139999A_D0430.tif" />

Example 41 (s) was prepared in similar manner as Example 41 (a) except that 4-rert-butyl-benzoic acid used in place of 2-ethyl-5-methyl-2H-pyrazole-3carboxylic acid. HPLC: R, 4.67 min. (100% area). Ή NMR (DMSO) 10.45 (s, IH), 8.44 (d, IH, J = 8.4Hz), 8.32 (s, IH), 8.22 (d, IH, J = 7.5Hz), 8.07 (d, IH, J = 16.5Hz), 7.99-7.95 (m , 3H), 7.88 (td, IH, J = 7.7, 1.5Hz), 7.69-7.59 (m, 7H),

7.38 (dd, IH, 13.5, 5.1Hz), 1.36 (s, 9H).

Example 41(t): 6-[3-((l-Allyl-3-methyl-lH-pyrazol-5-yl)carboxamido)benzoyl]-3

E-[2-(pyridin-2-yl)ethenyl]-lH-indazole

-266-

<img file="MY139999A_D0431.tif" />

Example 41(t) was prepared in similar manner as Example 41(a) except that 2-allyl-5-methyl-2H-pyrazole-3-carboxylic acid used in place of 2-ethyl-5methyl-2H-pvrazole-3-carboxylic acid. HPLC: R_t 4.11 min. (100% area). 'H

NMR (DMSO) 10.46 (s, 1H), 8.74 (t, 1H, J = 5.1Hz), 8.48 (d, 1H, J = 8.4Hz),

8.28 (s, 1H), 8.22 (t, 1H, J = 5.4, 2.1Hz), 8.15-8.01 (m, 3H), 7.39 (td, 1H, J = 7.8, 1.8Hz), 7.82-7.63 (m, 6H) 7.39 (td, 1H, J = 7.7, 1.5Hz), 6.14-6.02 (m, 1H), 5.225.03 (m, 4H), 2.38 (s, 3H). HRMS (MALDI) C₂₉H₂₄N₆O,(M + H*)/z: Calc.

489.2034, found 489.2035.

Example 41(u): 6-[3-((2-chloro-6-methoxypyridin-4-yI)carboxamido)benzoyl]-3

E-[2-(pyridin-2-vl)ethenyl]-lH-indazole

<img file="MY139999A_D0432.tif" />

Example 41(u) was prepared in similar manner as Example 41(a) except that 2-chloro-6-methoxy-isonicotinic acid used in place of 2-ethyl-5-methyl-2H15 pyrazole-3-carboxylic acid. HPLC R_r 4.37 min. (100% area). ^]H NMR (DMSOd₆) 10.74 (s, 1H), 8.68 (d, 1H, J = 3.6Hz), 8.44 (d, 1H, J = 8.4Hz), 8.28 (s, 1H),

8.20 (td, 1H, J = 6.6, 2.4Hz), 8.07 (d, 1H, J = 16.2Hz), 7.98 (s, 1H), 7.89 (td, 1H,

-267J = 7.7, 1.8Hz), 7.77-7.62 (m, 6H), 7.38 (s, 1H),7.35 (dd, 1H, J = 6.9, 1.8Hz),

3.98 (s,3H).

Example 41(v): 6-[3-((3-Ethyl-l-methvl-lH-pyrazol-5-yl)carboxamido)benzoyl]

3-E-[2-(pyridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0433.tif" />

Example 41(v) was prepared in similar manner as Example 41(a) except that 5-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid used in place of2-ethyl-5methyl-2H-pyrazole-3-carboxylic acid. 4.16 min. (100% area). 'H NMR (DMSO-d₆) 10.44 (s, 1H), 8.73 (d, 1H, J = 3.0Hz), 8.78 (d, 1H, 8.7Hz), 8.30 (s,

1H), 8.23 (d, 1H, J = 6.9Hz), 8.14-8.03 (m, 2H), 7.93 (t, 1H, 6.9Hz), 7.82-7.63 (m, 6H), 7.40 (t, 1H, J = 6.3Hz), 7.01 (s, 1H), 4.12 (s, 1H), 2.68 (q, 2H, 7.8Hz), 1.30 (t, 3H, J = 7.5Hz). HRMS (MALDI) C₂₈H₂₄N₆O₂ [M + H⁺]/z: Calc. 477.2034, found 477.2054.

Example 41 (w): 6-[3-((2-chloropyridin-4-yl)carboxamido)benzoyl]-3-E-[215 (pyridin-2-yl)ethenvl]-l H-indazole

<img file="MY139999A_D0434.tif" />

Example 41(w) was prepared in similar manner as Example 41(a) except that 2-chloro-isonicotinic acid used in place of 2-ethyl-5-methyl-2H-pyrazole-3-268carboxylic acid. HPLC R,: 3.99 min. (100% area). ’HNMR (DMSO-d₆) 10.88 (s, IH), 7.33 (d, 2H, J = 4.8Hz), 8.49 (d, IH, J = 8.4Hz), 8.33 (s, IH), 8.26 (td,

IH, J = 6.9, 3.0Hz), 8.12-7.91 (m, 5H), 7.82-7.63 (m, 5H), 7.40 (t, IH, J = 4.8Hz).

Example 41 (x): 6-(3-((1-Isopropyl-3-methyl-lH-pvrazol-55 yI)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-l H-indazole

<img file="MY139999A_D0435.tif" />

Example 41 (x) was prepared in similar manner as Example 41(a) except that 2-isopropyl-5-methyl-2H-pyrazole-3-carboxylic acid used in place of 2-ethyl 5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R^ 4.19 min. (100% area). ’H

NMR(DMSO) 10.46 (s, IH), 8.72 (t, IH, J = 4.80Hz), 8.48 (d, IH, J = 9.0Hz),

8.31 (s. IH), 8.21 (td, IH, J = 9.6, 2.1Hz), 8.15-7.98 (m, 2H), 7.96-7.84 (m, IH),

7.82-7.65 (m, 5H), 7.42-7.38 (m, IH), 6.88 (s, IH), 5.64-5.38 (m, IH), 2.32 (s, 3H), 1.48 (d, IH, J = 6.6Hz). HRMS (MALDI) C₂₉H₂₆N₆O₂ [M + H*]/z; Calc. 491.2190, found 491.2194.

Example 41 (y): 6-[3-(isopropoxycarbonylamino)benzoyl]-3-E-[2-(pyridin-2yl)ethenyl]-l H-indazole

<img file="MY139999A_D0436.tif" />

H .N

<img file="MY139999A_D0437.tif" />

<img file="MY139999A_D0438.tif" />

-269Example 41(y) was prepared in similar manner as Example 41(a) except that isopropyl chloroformate was used in place of 2-ethyl-5-methyl-2H-pyrazole3-carboxylic acid. Ή NMR (DMSO-d₆) 9.97 (s, IH), 8.72 (t, 2H, J = 4.8Hz), 8.47 (d, IH, J = 8.7Hz), 8.34-7.96 (m, 3H), 8.01-7.87 (m, 2H), 7.82-7.69 (m, 2H),

7.52 (dt, IH, J = 7.5, 1,2Hz), 7.42-7.36 (m, 2H), 3.68 (d, 2H, J = 6.6Hz), 2.02 (m,

IH), 1.02 (d, 6H, J = 6.6Hz). HRMS (MALDI) C₂₆H₂₄N₄O₃ [M + Ηψζ: Calc’

441.1921, found 441.1937.

Example 41(z): 6-[3-((4-chloropyridin-2-yI)carboxamido)benzoyl]-3-E-[2(pyridin-2-vl)ethenyl]-lH-indazole

<img file="MY139999A_D0439.tif" />

Example 41(z) was prepared in similar manner as Example 41(a) except that used 4-chloro-pyridine-2-carboxylic acid was used in place of 2-ethyl-5methyl-2H-pyrazole-3-carboxylic acid. HPLC R,: 4.40 min. (100% area). ‘H NMR (DMSO-d₆) 10.99 (s, IH), 8.72 (d, IH, J = 5.4 Hz), 8.63 (d, IH, J = 3.9

Hz), 8.44 (s, IH), 8.38 (d, IH, J = 8.4 Hz), 8.25 (dt, IH, J = 6.6, 2.4 Hz), 8.16 (d,

IH, J = 1.8 Hz), 8.02 (d, IH, J = 16.2 Hz), 7.94 (s, IH), 7.86-7.80 (m, 2H), 7.727.58 (m, 5H), 7.29 (dd, IH, J = 6.9, 6.0Hz).

Example 41 (aa): 6-[3-(pyridin-2-ylcarboxamido)benzoyl]-3-E-[2-(pyridin-2vl)ethenyl]-l H-indazole

-270-

<img file="MY139999A_D0440.tif" />

Example 41(aa) was prepared in a similar manner to that described for

Example 41(a), except that pyridine-2-carboxylic acid was used instead of 2ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ’HNMR (300 MHz, DMF-d₅)

10.9 (s, 1H), 8.74 (m, 1H), 8.63 (dd, 1H, J = 4.78 Hz, 0.94 Hz), 8.46 (s, 1H), 8,38 (d, 1H, J = 8.48 Hz), 8.25 (dt, 1H, J = 7.17 Hz, J = 2.05 Hz), 8.16 (dt, 1H, J = 7.73

Hz, J = 1.04 Hz), 8.07 (td, 1H, J = 7.56 Hz, J = 1.67 Hz), 8.02 (d, 1H, J = 16.28

Hz), 7.95 (s, 1H), 7.83 (td, 1H, J = 7.65 Hz, J = 1.81 Hz), 7.22-7.66 (m, 4H), 7.30 (qd, 1H, J = 7.40 Hz, J = 1.02 Hz). MS (ESI+) [M--H]/z Calc’d 446, found 446.

Example 41 (bb): 6-[3-(3-methoxybenzamido)benzoyI]-3-E-[2-(pyridin-2yl)ethenyl]-lH-indazole

<img file="MY139999A_D0441.tif" />

Example 41 (bb) was prepared in similar manner as Example 41(a) except that 3-methoxy-benzoic acid used in place of 2-ethyl-5-methyl-2H-pyrazole-315 carboxylic acid. Ή NMR (DMSO-d₆) 10.50 (s, 1H,), 8.67 (d, 1H, J = 3.9Hz),

8.46 (d, 1H, J = 8.7Hz), 8.33 (s, 1H), 8.22 (dt, 1H, J = 7.8, 1.8), 8.08 (d, 1H, J =

15.0Hz), 8.00 (s, 1H,), 7.78-7.54 (m, 8H), 7.51 (t, 1H, 7.8Hz), 7.38-7.33 (m, 1H),

7.23 (dd, 1H, J = 7.5, 1.5Hz), 3.90 (s, 3H). HRMS (MALDI) C₂₉H₂₂N₄O₃. [M + Ηψζ: Calc. 475.1765, found 475.1763.

-271Example 41(cc): 6-[3-(phenoxyamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-lHindazole

<img file="MY139999A_D0442.tif" />

Example 41(cc) was prepared in a similar manner to that described for

Example 41 (a), except that phenyl chloroformate was used instead of 2-ethyl-5methyl-2H-pyrazole-3-carboxylic acid, mp 212-217 °C, *H NMR (300 MHz, DMSO d_b) 13.63 (s, IH), 10.51 (s, IH), 8.62 (d, IH, J= 4.3 Hz), 8.36 (d, IH, J= 8.6 Hz),

8.04-7.81 (m,5H), 7.71-7.40 (m,7H), 7.31-7.22 (m,4H). ESIMS m/z 461 [M + Hf.

Anal, calc’d for C₂₈H₂₀N₄O₃ x 0.3 H₂O (465.9 g mol'¹): C, 72.18; H, 4.46; N, 11.33.

Found: C, 72.41 ;H, 4.63; N, 11.57.

Example 41(dd): 6-[3-(3,3-dimethylacrylamido)benzoyl]-3-E-[2-(pvridin-2yl)ethenyl]-lH-indazole

<img file="MY139999A_D0443.tif" />

Example 41(dd) was prepared in a similar manner to that described for 15 Example 41(a), except that 3,3-dimethylacrylic acid was used instead of 2-ethyl-5methyl-2H-pyrazole-3-carboxylic acid. Ή NMR (300 MHz, DMSO-d₆) (s, IH), 10.2 (s, IH), 8.63 (d, IH, J = 3.81 Hz), 8.37 (d, IH, J = 8.49

Hz), 8.12 (s, IH), 8.02 (d, IH, J = 16.34 Hz), 7.99 (d, IH, J = 7.88 Hz), 7.83 (td, IH,

J = 7.67 Hz, J = 1.78 Hz), 7.70 (d, IH, J = 7.85 Hz), 7.63 (dd, IH, J = 8.43 Hz, J =

-2721.23 Hz), 7.47 - 7.56 (m, 2H), 7.29 (qd, 1H, J = 7.39 Hz, J = 0.99 Hz), 6.82 (m, 1H, J = 6.9 Hz), 5.85 (s, 1H), 2.12 (s, 3H), 1.85 (s, 3H). MS (ESI+) [M+H]/z Calc’d 409, found 409. Anal. Calc’d for C26H22N4O2 x 0.33 TBME: C, 73.54; H, 5.80; N,

12.41. Found: C, 73.26; H, 5.76; N, 12.36.

Example 41(ee): 6-[3-((l-Ethyl-3-methyl-lH-pyrazol-5-yi)carboxamido)-4methylbenzoyl]-3-E-[2-(pvridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0444.tif" />

Example 41(ee) was prepared in similar manner as Example 41(a) except that Example 40(b) was used in place of Example 40(a). 'H NMR (DMSO-d₆) 13.6 (s,

1H), 9.94 (s, 1H), 8.62 (d, 1H, J = 3.8 Hz), 8.36 (d, 1H, J = 8.51 Hz), 8.01 (d, 1H, J =

16.36 Hz), 7.91 (s, 1H), 7.84 (dd, 1H, J = 7.66 Hz, J = 1.74 Hz), 7.81 (s, 1H), 7.70 (d,

1H, J = 7.9 Hz), 7.64 (d, 1H, J = 16.45 Hz), 7.62 (rn, 2H), 7.50 (d, 1H, J = 7.83 Hz), 7.29 (m, 1H), 6.82 (s, 1H), 4.42 (q, 2H, J = 7.06 Hz), 2.36 (s, 3H), 2.21 (s, 3H), 1.30 (t, 3H, J = 7.09 Hz). MS (ESI+) [M+H]/z Calc’d 491, found 491. Anal. Calc’d: C,

71.00; H, 5.34; N, 17.13. Found: C, 70.80; H, 5.38; N, 17.00.

Example 41(ff): 6-[3-((l-AlIyI-3-methyI-lH-pyrazoI-5-yI)carboxamido)-4methylbenzoyl] -3-E-[2-(pyridin-2-yl)ethenyl] -1 H-indazole

-273-

<img file="MY139999A_D0445.tif" />

Example 41 (ff) was prepared in a similar manner to that described for Example 41 (ee), except that 2-allyl-5-methyl-2/7-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. Ή NMR (DMSO5 d₆) 13.6 (s, IH), 9.98 (s, IH), 8.62 (d, IH, J = 4.60 Hz), 8.36 (d, IH, J = 8.46 Hz),

8.01 (d, IH, J = 16.37 Hz), 7.91 (s, IH), 7.83 (td, IH, J = 7.69 Hz, J = 1.77 Hz), 7.78 (d, IH, J = 1.73), 7.70 (d, IH, J = 7.78 Hz), 7.59-7.70 (m, 3H), 7.50 (d, IH, J = 8.01 Hz), 7.29 (qd, IH, J = 7.46 Hz, J = 1.02 Hz), 6.86 (s, IH), 5.95 (m, IH), 4.93-5.10 (m, 4H), 2.34 (s, 3H), 2.22 (s, 3H). LCMS (ESI+) [M+H]/z Calc’d 503, found 503.

Anal. Calc’d: C, 71.70; H, 5.21; N, 16.72. Found: C, 70.98; H, 5.42; N, 15.94.

Example 41 (gg): 6-(3-acetamido-4-methylbenzoyl)-3-E-[2-(pyridin-2-yl)ethenyl]· lH-indazole

<img file="MY139999A_D0446.tif" />

Example 41(gg) was prepared in a similar manner to that described for 15 Example 41 (ee), except that acetyl chloride was used in place of 2-ethyl-5-methyl2H-pyrazole-3-carboxylic acid. ’HNMR (CD₃OD) 8.57 (d, IH, J = 4.90 Hz), 8.13 (d, IH, J = 8.49 Hz), 7.99 (s, IH), 7.95 (d, IH, J = 16.53 Hz), 7.89 (d, IH, J = 1.46 Hz), 7.86 (td, IH, J = 7.64 Hz, J = 1.73 Hz), 7.73 (d, IH, J = 7.05 Hz), 7.62-7.69 (m,

-2742H), 7.65 (d, 1H, J = 16.48 Hz), 7.44 (d, 1H, J = 7.97 Hz), 7.32 (qd, 1H, J = 7.44 Hz_;

J = 1.03 Hz), 2.38 (s, 3H), 2.18 (s, 3H). LCMS (ESI+) [M+H]/z Calc’d 397, found

397. Anal. Calc’d: C, 72.71; H, 5.08; N, 14.13. Found: C, 72.29; H, 5.09; N, 13.98

Example 41(hh): 6-[3-((l,3-Dimethvl-lH-pyrazol-5-yl)carboxamido)-45 methvlbenzoyl]-3-E-[2-(pyridin-2-yI)ethenyl]-lH-indazoIe

<img file="MY139999A_D0447.tif" />

Example 41 (hh) was prepared in a similar manner to that described for Example 41(ee), except that 2,5-dimethyl-2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC R^: 3.92 min. (100% area). Ή NMR (DMSO) 10.02 (s, 1H), 8.74 (d, 1H, J = 3.6Hz), 8.49 (d, 1H, J = 8.4 Hz), 8.13 (d, 1H, J = 16.3Hz), 8.03 (s, 1H), 7.96-7.93 (m,

2H), 7.84-7.72 (m, 4H), 7.63 (d, 1H , 8.1Hz), 7.42 (dd, 1H, J = 6.8, 1.5Hz), 6.95 (s, 1H), 4.11 (s, 1H), 2.48 (s, 1H), 2.32 (s, 1H).

Example 41 (ii): 6-[3-((l-«-propyl-3-methyl-lH-pyrazol-5-yl)carboxamido)-415 methyIbenzoyl]-3-E-[2-(pyridin-2-yl)ethenvl]-lH-indazole

<img file="MY139999A_D0448.tif" />

Example 41 (ii) was prepared in a similar manner to that described for Example 41(ee), except that 5-methyl-2-propyl-2H-pyrazole-3-carboxylic acid

-275was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R^ 4.16 min. (100% area). Ή NMR (DMSO-d₆) 10.29 (s, 1H), 8.58 (d, 1H, 3.9Hz), 8.33 (d, IH, J = 8.4 Hz), 8.13 (s, 1H), 8.10 (dt, IH, J = 5.4, 2.1Hz), 7.96 (d, IH, J = 16.5Hz), 7.87 (s, 1H), 7.78 (td, IH, J = 7.5, 1.5Hz), 7.61-7.49 (m, 6H), 7.24 (dd,

IH, J = 6.9, 1.8Hz), 4.32 (t, 2H, J = 6.90Hz), 2.58 (s, 3H), 2.22 (s, 3H) 1.69 (q,

2H, J = 7.2Hz), 0.77 (t, 3H, 7.5Hz). HRMS (MALDI) C₃₀H₂₆N₆O₂ [M + tT]/z:

Calc. 505.2347, found 505.2343.

Example 41 (jj): 6-{3-((3-Ethyl-l -methyl-lH-pyrazol-5-yl)carboxamido)-4methyIbenzoyI]-3-E-(2-(pyridin-2-yI)ethenyI]-lH-indazole

<img file="MY139999A_D0449.tif" />

Example 41 (jj) was prepared in a similar manner to that described for

Example 41 (ee), except that 5-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. 'H NMR (DMSO-d₆) 10.78 (s, IH), 9.43 (d, IH, J = 3.0Hz), 9.15 (t, IH, J = 9.6Hz), 8.82 (dd, IH, J = 16.4, 1.5Hz), 8.72-8.61 (m, 2H), 8.52-8.30 (m, 4H), 8.10 (dd, IH, J = 6.9, 5.7), 7.93-7.89 (m, IH), 7.72-7.69 (m, IH), 4.85 (s, 3H), 3.39 (q, 2H, J =

7.8Hz), 3.17 (s, 3H), 2.10 (t, 3H, J = 7.5Hz). HRMS (MALDI) C₂₉H₂₆N₆O₂ (M +

H⁺) m/r. Calc. 491.2190, found 491.2211.

Example 41(kk): 6-(3-((1-IsopropyI-3-methyI-lH-pyrazoI-5-yl)carboxamido)-420 methyIbenzoyI]-3-E-[2-(pyridin-2-yI)ethenyI]-lH-indazole

-276-

<img file="MY139999A_D0450.tif" />

Example 41(kk) was prepared in a similar manner to that described for Example 41(ee), except that 2-isopropyl-5-methyl-2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R^

4.11 min7(100% area). ’HNMR (DMSO-d₆) 9.99 (s, IH), 8.68 (d, IH, J = 3.6

Hz), 8.42 (d, IH, J = 8.7 Hz), 8.07 (d, IH, J = 16.4 Hz), 7.98 (s, IH), 7.67-7.86 (m, 2H), 7.77-7.65 (m, 4H), 7.56 (d, IH, J = 7.8 Hi), 7.37-7.33 (m, IH), 6.82 (s, IH), 5.44-5.36 (m, IH), 2.42 (s, 3H), 2.28 (s, 3H), 1.42 (d, 6H, J = 6.6 Hz). Anal.

(C₃₀H₂₈N₆O₂*0.2H₂O) Calc’d: C, 5.63; N, 16.54. Found C, 70.57; H, 5.70; N,

16.35.

Example 41(11): 6-[2,4-dimethyl-5-((l-Ethyl-3-methyl-lH-pyrazol-5yl)carboxamido)benzoyl]-3-E-[2-(pyridin-2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0451.tif" />

Example 41(11) was prepared in similar manner as Example 41(a) except that 15 Example 40(c) was used in place of Example 40(a). ’HNMR (DMSO-d₆) 13.6 (s, IH), 9.82 (s, IH), 8.63 (d, IH, J = 3.84 Hz), 8.35 (d, IH, J = 8.54 Hz), 8.00 (d, IH, J = 16.37 Hz), 7.83 (s, IH), 7.83 (td, IH, J = 7.65 Hz, J = 1.82 Hz), 7.69 (d, IH, J =

-2777.89 Hz), 7.65 (dd, IH, J = 8.52 Hz, J = 1.36 Hz), 7.62 (d, IH, J = 16.34 Hz), 7.35 (s,

1H), 7.32 (s, IH), 7.29 (qd, IH, J = 7.42 Hz, J = 1.09 Hz), 6.78 (s, IH), 4.39 (q, 2H, J = 7.15 Hz), 2.30 (s, 3H), 2.25 (s, 3H), 2.19 (s, 3H), 1.27 (t, 3H, J = 7.15 Hz). LCMS (ESI+) [M+H]/z Calc’d 505, found 505.

Example 41(mm): 6-[2,4-dimethyl-5-((l,3-dimethyl-lH-pyrazol-5yl)carboxamido)benzoyl]-3-E-[2-(pyridin&gt;2-yl)ethenyl]-lH-indazole

<img file="MY139999A_D0452.tif" />

Example 41 (mm) was prepared in a similar manner to that described for Example 41(11), except that 2,5-dimethyl-2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ’H NMR (DMSO-d₆)

13.6 (s, IH), 9.81 (s, IH), 8.62 (d, IH, J = 3.81 Hz), 8.35 (d, IH, J = 8.6 Hz), 8.00 (d,

IH, J = 16.36 Hz), 7.83 (dt, IH, J = 7.65 Hz, J = 1.8 Hz), 7.8 (s, IH), 7.69 (d, IH, J =

7.88 Hz), 7.65 (dd, IH, J = 8.53 Hz, J = 1.36 Hz), 7.62 (d, IH, J = 16.35 Hz), 7.36 (s,