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

Indazole compounds and compositions pharmaceuticals to inhibit protein kinases and methods for their use.

Field of the Invention

This invention relates to compounds of indazole that mediate and / or inhibit the activity of certain proteins kinases and pharmaceutical compositions containing said compounds. The invention also relates to therapeutic use or prophylactic of said compounds and compositions and methods for treat cancer, as well as other morbid states associated with unwanted angiogenesis and / or cell proliferation, administering effective amounts of said compounds.

Foundation of the invention

Protein kinases are a family of enzymes that catalyze the phosphorylation of the hydroxyl group of specific tyrosine, serine or threonine residues of proteins. Typically, such phosphorylation drastically disrupts the function. of protein and therefore protein kinases are crucial in the regulation of a wide variety of cellular processes, which include metabolism, cell proliferation, cell differentiation and cell survival. Of the many cellular functions different from those known to require the activity of protein kinases, some processes represent objectives attractive for therapeutic intervention in certain states morbid Two examples are angiogenesis and cycle control cellular, in which protein kinases play a role crucial; these processes are essential for the growth of solid tumors as for other diseases.

Angiogenesis is the mechanism by which They form new capillaries from existing vessels. When requires, the vascular system has the ability to generate new capillary networks to maintain the proper functioning of tissues and organs In the adult, however, angiogenesis is quite limited, taking place only in the curing process of wounds and neovascularization of the endometrium during menstruation. See Merenmies <i>et al., Cell Growth &amp; Differentiation</i>, 8, 3-10 (1997). On the other hand, angiogenesis does not Desired is a characteristic of various diseases, such as retinopathies, psoriasis, rheumatoid arthritis, macular degeneration senile (DMS) and cancer (solid tumors). Folkman,<i>Nature Med</i>., 1, 27-31 (1995). Protein kinases that have proven to be involved in the angiogenic process include three family members of the receptor tyrosine kinases of the growth factor: the growth factor receptor vascular endothelial 2 [(abbreviated VEGF-R2, for english expression <i>vascular endothelial growth receptor factor two</i>), also known as the insertion domain receptor of kinase (abbreviated KDR, for the English expression <i>kinase insert domain receiver</i>) and as FLK-1]; he fibroblast growth factor receptor (abbreviated FGF-R, for the English expression <i>fibroblast growth receiving factor</i>); and TEK (also known as Tie-2).

VEGF-R2, which is expressed only in endothelial cells, binds to the potent growth factor VEGF angiogenic and mediates subsequent signal transduction by the activation of its intracellular kinase activity. Thus expected direct inhibition of kinase activity of VEGF-R2 will result in the reduction of angiogenesis even in the presence of exogenous VEGF (see, Strawn<i>et al., Cancer Research</i>, 56, 3540-3545 (1996)), as demonstrated with mutants of VEGF-R2 that are not able to mediate transduction Of the signal. Millauer<i>et al., Cancer Research</i>, 56, 1615-1620 (1996). In addition, it seems that VEGF-R2 does not have a role in the adult beyond of mediation in the angiogenic activity of VEGF. By consequently, a selective inhibitor of the VEGF-R2 kinase activity little present toxicity.

Similarly, FGF-R binds to the angiogenic growth factors aFGF and bFGF and mediates the subsequent intracellular signal transduction. Recently, It has been suggested that growth factors, such as bFGF, may have a critical role in inducing angiogenesis in solid tumors that have reached a certain size. Yoshiji<i>et al., Cancer research</i>, 57, 3924-3928 (1997). Without However, unlike VEGF-R2, the FGF-R is expressed in several different types of cells throughout the body and may or may not have important roles in other normal physiological processes in adults. However, it has shown that systemic administration of an inhibitor of small molecular size kinase activity of FGF-R blocks bFGF-induced angiogenesis in mice without obvious toxicity. Mohammad<i>et al., EMBO Journal</i>, 17, 5996-5904 (1998).

TEK (also called Tie-2) it is another receptor tyrosine kinase that is expressed only in cells endothelial that has been shown to have a role in the angiogenesis Angiopoietin-1 factor binding gives as a result the autophosphorylation of the kinase domain of TEK and results in a signal transduction process that seems mediate the interaction of endothelial cells with support cells peri-endothelial, thereby facilitating the maturation of newly formed blood vessels. On the other hand, it seems that the angiopoietin-2 factor antagonizes the action of angiopoietin-1 on TEK and interrupts Angiogenesis Maisonpierre<i>et al., Science</i>, 277, 55-60 (1997).

As a result of the studies described above, it has been proposed to treat angiogenesis using compounds that inhibit the kinase activity of VEGF-R2, FGF-R and / or TEK. For example, the publication of WIPO International Patent Application No. WO 97/34876 describes certain cinoline derivatives that are inhibitors of VEGF-R2, which can be used for the treatment of morbid states associated with abnormal angiogenesis and / or permeability increased vascular, such as cancer, diabetes, psoriasis, arthritis rheumatoid, Kaposi's sarcoma, hemangioma, acute kidney disease and chronic, atheroma, arterial restenosis, autoimmune diseases, acute inflammation and eye diseases with proliferation of vessels retinals

Phosphorylase Kinase Activates Glycogen phosphorylase, thereby increasing glycogen breakage and release of hepatic glucose. Hepatic glucose production is de-regulates in type 2 diabetes and is the cause major of fasting hyperglycemia, which produces many of the secondary complications that affect these patients. So, the reduction in the release of glucose from the liver would decrease high levels of plasma glucose. Therefore the phosphorylase kinase inhibitors should decrease the phosphorylase activity and glycogenolysis, thus reducing the hyperglycemia in patients.

Another physiological response to VEGF is the vascular hyperpermeability, which has been proposed to play a role in the early stages of angiogenesis. In tissues ischemic, such as those that exist in the brains of stroke victims, the expression of hypoxia trigger VEGF, leads to increased vascular permeability and ultimately to edema in the surrounding tissues. In a rat model for the stroke study, van Bruggen <i>et al., J. Clinical Invest</i>., 104, 1613-20 (1999) have shown that the administration of a monoclonal antibody to VEGF reduces the heart attack volume Thus, it is anticipated that VEGFR inhibitors They are useful in the treatment of stroke.

In addition to their role in angiogenesis, the protein kinases also have a crucial role in the control of the cell cycle. Uncontrolled cell proliferation is the cancer characteristic. Cell proliferation in response to various stimuli manifested by a de-regulation of the cell division cycle, the process by which cells multiply and divide. The cells of tumors typically have lesions in the genes that regulate directly or indirectly the progression through the division cycle mobile.

Cyclin Dependent Kinases (CDK) they are the serine-threonine protein kinases that they have critical roles in regulating transitions between Different phases of the cell cycle. See, for example, the items compiled in <i>Science</i>, 274, 1643-1677 (1996). CDK complexes are formed by association of a regulatory cyclin subunit (for example, cyclin A, B1, B2, D1, D2, D3 and E) and a kinase subunit catalytic (for example, cdc2 (CDK1), CDK2, CDK4, CDK5 and CDK6). As the name indicates, the CDKs have an absolute dependence on the cyclin subunit to phosphorylate its target substrates and different pairs of kinase / cyclin act to regulate the progression through specific phases of the cell cycle.

The CDK4 that forms complex with cyclines D is which has a critical role in the initiation of the cycle of cell division from a resting or quiescent stage until another in which cells get involved in the division mobile. This progression is subject to a variety of mechanisms growth regulators, both negative and positive. Abnormalities in this control system, particularly those that affect the function of CDK4, have been involved in the progress of cells to the characteristic highly proliferating state of cancers, particularly familial melanomas, carcinomas esophageal and pancreatic cancers. See, for example, Kamb,<i>Trends in Genetics</i>, 11, 136-140 (1995); Kamb<i>et al., Science</i>, 264, 436-440 (1994).

Large number of publications describe a variety of chemical compounds useful against a variety of therapeutic goals For example, the publications of WIPO international patent applications No. WO 99/23077 and WO 99/23076 describe compounds containing indazole that have phosphodiesterase type IV inhibitory activity produced by a Bioisostic substitution of indazole by catechol. U.S. Pat. No. 5,760,028 describes heterocycles that include acid 3- [1- [3- (imidazolin-2-ylamino) propyl] indazol-5-ylcarbonylamino] -2- (benzyloxycarbonyl-amino) -propionic, which are useful as integrin antagonists α_ {v} \ beta_ {3} and are related to the receptors of adherent proteins to the cell surface. The publication WIPO International Patent Application No. WO 98/09961 describes certain derivatives of indazole and its use as inhibitors of phosphodiesterase (PDE) type IV or factor production tumor necrosis (TNF) in a mammal. Recent additions to the virtual collection of known compounds include those described as anti-proliferating therapeutic agents that inhibit CDK. For example, US Pat. No. 5,621,082 of Xiong <i>et al</i>. describes a nucleic acid encoding a CDK6 inhibitor, and European Patent Publication No. 0 666 270 A2 describes peptides and peptide mimics that act as CDK1 and CDK2 inhibitors. The patent application publication International WIPO No. WO 97/16447 describes certain analogues of chromones that are inhibitors of kinase dependent on cyclines, in particular CDK / cyclin complexes, such as CDK4 / cyclin D1, which can be used to inhibit proliferation excessive or abnormal cells and therefore to treat the Cancer. WIPO International Patent Application Publication No. WO 99/21845 describes 4-aminothiazole derivatives which are useful as CDK inhibitors.

However, compounds of small molecules that can be easily synthesized and are effective in inhibiting one or more CDKs or complexes CDK / Cyclin. Because CDK4 can serve as a general activator of cell division in most cells and that CDK4 complexes and type D cyclines regulate the early phase G1 of the cell cycle, effective inhibitors of the CDK4 and its complexes with cyclin type D, to treat one or more type of tumors Also, the crucial roles of kinases cyclin E / CDK2 and cyclin B / CDK1 in phase transitions G_ {1} / S and G_ {{}} / M, respectively, offer more objectives for therapeutic intervention in the suppression of progression unregulated cell cycle in cancer.

Another protein kinase, CHK1, has a role important as a control point in the progression of the cell cycle. Control points are control systems that coordinate the cell cycle progression influencing formation, activation and subsequent inactivation of the kinases dependent on the cyclin Control points prevent the progression of the cycle cell in inappropriate times, maintain metabolic balance of the cells while the cell is stopped and in some cases they can induce apoptosis (programmed cell death) when not the requirements of the checkpoint have been met. See for example, O'Connor, <i>Cancer Surveys</i>, 29, 151-182 (1997); Nurse,<i>Cell</i>, 91, 865-867 (1997); Hartwell<i>et al., Science</i>, 266, 1821-1828 (1994); Hartwell<i>et al., Science</i>, 246, 629-634 (1989).

A series of control points regulates the integrity of the genome and, perceiving DNA damage, these "DNA damage control points" block the progression of cell cycle in phases G1 and G2, and delay the progression through the S. O'Connor phase, <i>Cancer Surveys</i>, 29, 151-182 (1997); Hartwell<i>et al., Science</i>, 266, 1821-1828 (1994). This action allows you to complete DNA repair processes before genome replication and subsequent separation take place of this genetic material in new daughter cells. To a large degree, most of the genes generally mutated in human cancer, the p53 tumor suppressor gene, produces a knitting protein DNA damage control that blocks the progression of the cycle cell in the G1 phase and / or induces apoptosis (cell death programmed) after DNA damage. Hartwell<i>et al., Science</i>, 266, 1821-1828 (1994). It has also demonstrated that the p53 tumor suppressor reinforces the action of a DNA damage control point in the G2 phase of the cycle mobile. See, for example, Bunz<i>et al., Science</i>, 28, 1497-1501 (1998); Winters<i>et al., Oncogene</i>, 17, 673-684 (1998); Thompson,<i>Oncogene</i>, 15, 3025-3035 (1997).

Given the crucial nature of the path of P53 tumor suppressor in human cancer, have been sought actively therapeutic interventions that take advantage of V53 defective cancer vulnerabilities. A vulnerability pop-up resides in the operation of control point G_ {2} in the defective cancer cells in p53. Cancer cells, due to the lack of control point control G_ {1}, they are particularly vulnerable to the cancellation of the last barrier remnant that protects them from the harmful effects of cancer DNA damaging agents: the G2 control point. The point of control G_ {2} is regulated by a control system that has been kept from yeast to humans. Important in this maintained system is a kinase, CHK1, which transduces signals from the sensory complex that damages DNA to inhibit the activation of cyclin kinase B / Cdc2, which promotes the entry into the phase mitotic See, for example, Peng<i>et al., Science</i>, 277, 1501-1505 (1997): Sanchez <i>et al., Science</i>, 277, 1497-1501 (1997). It has been shown that CHK1 inactivation cancels both induced G2 arrest for damage to DNA inflicted by anticancer agents such as endogenous DNA damage, resulting in elimination preferential control point defective cells resulting. See, for example, Nurse,<i>Cell</i>, 91, 865-867 (1997); Weinert,<i>Science</i>, 277, 1450-1451 (1997); Walworth<i>et al., Nature</i>, 363, 368-371 (1993); and Al-Khodairy<i>et al., Molec. Biol. Cell</i>, 5, 147-160 (1994).

Selective manipulation of point control of control in cancer cells could provide ample use in chemotherapeutic and radiotherapy regimens of cancer and may also offer a usual contrast of "genomic instability" of human cancer that is exploited as the selective basis for the destruction of cells carcinogenic Several factors make CHK1 a crucial objective in control of the DNA damage control point. The elucidation of inhibitors of this kinase and functionally kinases related, such as Cds1 / CHK2, a kinase recently discovered that cooperates with CHK1 to regulate the progression of S phase (see, Zeng <i>et al., Nature</i>, 395, 507-510 (1998); Matsuoka,<i>Science</i>, 282, 1893-1897 (1998)), could provide new valuable therapeutic products for the treatment of cancer.

The integrin receptor that binds to ECM initiates intracellular signals mediated by the kinase of focal adhesion (abbreviated FAK) <i>Focal Adhesion Kinase</i>) that are involved in cell motility, cell proliferation and survival. In human cancers, the overexpression of FAK is involved in tumorigenesis and the metastatic potential through its role in the pathways of integrin mediated signaling.

Tyrosine kinases can be of the type receptor (which have extracellular, transmembrane domains and intracellular) or non-receptor type (which is totally intracellular). At least one of the tyrosine kinase proteins does not recipients, mainly LCK, are believed to mediate transduction in T lymphocytes a signal from the interaction of a cell surface protein (Cd4) with an antibody cross-linked anti-Cd4. Bolen, <i>Oncogene</i>8 2025-2031 (1993), provides one more study Detailed of non-receptor tyrosine kinases that are incorporated Here for reference.

In addition to protein kinases before identified, many other protein kinases have been considered as therapeutic goals and numerous publications describe kinase activity inhibitors, as reviewed in the following articles: Mc-Mahon <i>et al, Oncologist</i>, 5, 3-10 (2000); Holash<i>et al., Oncogene</i>, 18, 5356-62 (1999); Thomas<i>et al., J. Biol. Chem.</i>, 274, 36684-92 (1999); Cohen<i>Curr. Op. Chem. Biol</i>., 3, 459-65 (1999); Klohs <i>et al., Curr. Op. Chem. Biol.</i>, 10, 544-49 (1999); McMahon<i>et al., Current Opinion in Drug Discovery &amp; Development</i>, 1, 131-146 (1998); Strawn<i>et al., Exp. Opin. Invest. Drugs</i>, 7, 553-573 (1998). The solitude publication of WIPO International Patent WO 00/18761 describes certain 3-substituted cyanoquinolines as inhibitors of protein kinases

However, inhibitors are still needed Effective protein kinases. On the other hand, how will the skilled in the art, it is desirable that inhibitors of kinases possess both a high affinity for kinase or kinases objective as well as a high selectivity against other proteins kinases

Summary of the invention

Therefore, an object of the invention is discover potent protein kinase inhibitors. Other objective of the invention is to discover effective kinase inhibitors that have a strong and selective affinity for one or more kinases private individuals

These and other objects of the invention, which they will be evident from the following description, they have been reached by the discovery of indazole compounds and their salts pharmaceutically acceptable (said compounds and salts are collectively referred to as "agents") described below, that modulate and / or inhibit the activity of protein kinases. The Pharmaceutical compositions containing such agents are useful. in the treatment of diseases mediated by the activity of the kinase, such as cancer, as well as other morbid states associated with unwanted angiogenesis and / or cell proliferation, such such as diabetic retinopathy, neovascular glaucoma, arthritis rheumatoid and psoriasis. In addition, agents have properties advantageous related to modulation and / or inhibition of kinase activity associated with VEGFR, FGF-R, CDK, CHK1, LCK, TEK, FAK, and / or phosphorylase kinase complexes.

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

<figref>1</figref>

in where:

<dl><dt>quad</dt><dd>R1 is an aryl or heteroaryl substituted or not substituted or a group of the formula CH = CH-R3 or CH = NR 3, where R 3 is an alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl substituted or unsubstituted; and</dd></dl>

<dl><dt>quad</dt><dd>R2 is Y-Ar, where Y is NH and Ar is a substituted or unsubstituted aryl.</dd></dl>

The invention also relates to salts Pharmaceutically acceptable compounds of Formula I (a). Advantageous methods for the Preparation of the compounds of Formula I (a).

In a general preferred embodiment, the Compounds of the invention have Formula III:

<figref>2</figref>

in where:

<dl><dt>quad</dt><dd>R1 is an aryl or heteroaryl substituted or not substituted, or a group of the formula CH = CH-R3 or CH = NR 3, where R 3 is an alkyl, cycloalkyl, heterocycloalkyl, aryl or substituted heteroaryl or not substituted;</dd></dl>

<dl><dt>quad</dt><dd>Y is NH;</dd></dl>

<dl><dt>quad</dt><dd>R 8 is an alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy or aryloxy substituted or unsubstituted;</dd></dl>

<dl><dt>quad</dt><dd>R 10 is independently selected from hydrogen, halogen and lower alkyl;</dd></dl>

and its pharmaceutically acceptable salts.

More preferably, in Formula III: R1 it is a substituted or unsubstituted bicyclic heteroaryl or a group of the formula CH = CH-R 3, wherein R 3 is a substituted or unsubstituted aryl or heteroaryl; Y is NH; R 8 is an aryl, heteroaryl, alkyl and substituted or non-substituted alkenyl substituted, and R 10 is hydrogen or halogen.

In another preferred general embodiment, the Compounds of the invention have Formula III (a):

<figref>3</figref>

in where:

<dl><dt>quad</dt><dd>R1 is an aryl or heteroaryl substituted or not substituted or a group of the formula CH = CH-R3 or CH = NR 3, where R 3 is an alkyl, cycloalkyl, heterocycloalkyl, aryl or substituted heteroaryl or not substituted;</dd></dl>

<dl><dt>quad</dt><dd>Y is NH;</dd></dl>

<dl><dt>quad</dt><dd>R 8 is an alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy or aryloxy substituted or unsubstituted;</dd></dl>

and its pharmaceutically acceptable salts.

<pre listing-type="other">\ vskip1.000000 \ baselineskip</pre>

More preferably, in the Formula III (a): R1 is a bicyclic heteroaryl substituted or not substituted or a group of the Formula CH = CH-R3, wherein R 3 is an aryl or heteroaryl substituted or not replaced; Y is NH; and R 8 is a substituted aryl or heteroaryl or not substituted.

In another preferred general embodiment, the Compounds of the invention have Formula IV:

<pre listing-type="other">\ vskip1.000000 \ baselineskip</pre>

<figref>4</figref>

<pre listing-type="other">\ vskip1.000000 \ baselineskip</pre>

in where:

<dl><dt>quad</dt><dd>R1 is an aryl or heteroaryl substituted or not substituted or a group of the formula CH = CH-R3 or CH = NR 3, where R 3 is an alkyl, cycloalkyl, heterocycloalkyl, aryl or substituted heteroaryl or not substituted;</dd></dl>

<dl><dt>quad</dt><dd>Y is NH;</dd></dl>

<dl><dt>quad</dt><dd>R 9 is an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, substituted or unsubstituted cycloalkoxy, NH- (alkyl C 1 -C 8), NH- (aryl), NH- (heteroaryl), N = CH- (alkyl), NH (C = O) R 11 or NH 2, where R 11 is independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and substituted heteroaryl or not substituted; and</dd></dl>

<dl><dt>quad</dt><dd>R 10 is independently selected from hydrogen, halogen and lower alkyl;</dd></dl>

and its pharmaceutically acceptable salts.

<pre listing-type="other">\ vskip1.000000 \ baselineskip</pre>

More preferably, in Formula IV: R1 is a group of the formula CH = CH-R3, where R 3 is a substituted or unsubstituted aryl or heteroaryl; And it is NH and R 9 is an alkyl, substituted or unsubstituted alkoxy or NH- (heteroaryl).

<pre listing-type="other">\ newpage</pre>

More preferred are the compounds of the invention selected from:

<figref>5</figref>

<pre listing-type="other">\ vskip1.000000 \ baselineskip</pre>

<figref>6</figref>

The compounds of the invention can be used in a method to modulate and / or inhibit the kinase activity of VEGF-R, FGF-R, a CDK complex, CHK1, LCK, TEK, FAK and / or phosphorylase kinase by administering a compound of Formula I (a), III, III (a) or IV, or a of its pharmaceutically acceptable salts. Preferred compounds of the present invention exhibiting selective activity of kinase, that is, possess significant activity against one or more specific kinases possessing an activity at the same time lower or lower against one or more different kinases. In a preferred embodiment of the invention, the compounds of the present invention are those of Formula I (a) that possess an activity substantially higher against VEGF receptor tyrosine kinase than against the tyrosine kinase receptor of FGF-R1. The compounds of the invention can be used in methods for modulate the activity of VEGF receptor tyrosine kinase without significantly modulate tyrosine kinase activity FGF recipient.

The compounds of the invention can be used advantageously in combination with other therapeutic agents known. For example, the compounds of Formula I (a), III, III (a) or IV, who have activity anti-angiogenic, can be administered in conjunction with cytotoxic chemotherapeutic agents, such as taxol, taxotero, vinblastine, cis-platinum, doxorubicin, adriamycin and the like, producing an effect Enhanced antitumor. An additive improvement can also be obtained or synergistic of the therapeutic effect by joint administration of compounds of Formula I (a), III, III (a) or IV, which possess anti-angiogenic activity, with other agents anti-angiogenic, such as combretastatin A-4, endostatin, prinomastat, celecoxib, rofocoxib, EMD121974, IM862, anti-VEGF monoclonal antibodies and anti-KDR monoclonal antibodies.

The invention also relates to compositions pharmaceuticals that each contain an effective amount of an agent selected from compounds of Formula I (a) and their salts pharmaceutically acceptable; and an excipient or vehicle pharmaceutically acceptable for said agent. The invention also provides methods to treat cancer, as well as others morbid states associated with angiogenesis and / or proliferation unwanted cell phone, comprising administering effective amounts of said agent to a patient in need of said treatment.

Detailed description of the invention and embodiments preferred

The compounds of the invention of the Formulas I (a), III, III (a) and IV are useful to mediate the protein kinase activity. More particularly, the Compounds are useful as anti-angiogenesis agents and as agents to modulate and / or inhibit the activity of protein kinases, thus providing treatments for cancer or other diseases associated with cell proliferation mediated by protein kinases

The term "alkyl" as used in the This specification refers to straight chain alkyl groups and branched that have one to twelve carbon atoms. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, <i>tert</i>.butyl (t-Bu), pentyl, isopentyl, <i>tert</i>.pril, hexyl, isohexyl and the like. The expression "lower alkyl" designates an alkyl having 1 to 8 carbon atoms (an alkyl C_ {1-8}). Suitable substituted alkyls include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like.

The term "alkylidene" refers to a divalent radical having one to twelve carbon atoms. The Illustrative alkylidene groups include CH2, CHCH3, (CH 3) 2 and the like.

The term "alkenyl" refers to groups linear and branched chain alkenyl of two to twelve atoms of carbon. Illustrative alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl and the like.

The term "alkynyl" refers to groups linear and branched chain alkynyl having two to twelve carbon atoms

The term "cycloalkyl" refers to saturated or partially unsaturated carbocycles that have three at twelve carbon atoms, including cycloalkyl structures bicyclic and tricyclic. Suitable cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and Similar.

A "heterocycloalkyl" group is understood as which means a partially or saturated monocyclic radical unsaturated containing carbon atoms, preferably 4 or 5 carbon atoms in the ring, and at least one heteroatom selected from nitrogen, oxygen and sulfur.

The terms "aryl" and "heteroaryl" they refer to monocyclic aromatic ring structures and polycyclic, referring to "aryl" to those who are carbocycles and "heteroaryl" 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, 1,2,3-triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1-H-tetrazol-5-yl, indolyl, quinolinyl, benzofuranyl, benzothiophenyl (thianaphtenyl) and the like Said residues may be optionally substituted. with a structure or bridge of condensed rings, for example OCH_ {2} -O.

The term "alkoxy" means that means the radical -O-alkyl. Examples Illustrative include methoxy, ethoxy, propoxy and the like.

The term "aryloxy" represents -O-aryl, where aryl is as defined before.

The term "cycloalkoxyl" represents -O-cycloalkyl, where cycloalkyl is as it has been defined before.

The term "halogen" represents chlorine, fluorine, bromine or iodine. The term "halo" represents chlorine, Fluoro, bromine or iodine.

In general, the various remains or groups functional variables for the formulas may be optionally substituted with one or more suitable substituents. Examples of such substituents include halogen (F, Cl, Br or I), lower alkyl, -OH, -NO2, -CN, -CO2H, -O-lower alkyl, -aryl, -aryl-lower alkyl, -CO2CH3, -CONH 2, -OCH 2 CONH 2, -NH 2, -SO 2 NH 2, haloalkyl (for example, -CF 3, -CH 2 CF 3), -O-haloalkyl (for example, -OCF 3, -OCHF_2) and the like.

The expressions "that understand" and "that include "are used in a broad non-limiting sense.

It is to be understood that when a compound of Formula I (a) present the phenomenon of tautomería, the formula included herein only expressly represents one of the possible tautomeric forms. Therefore it should be understood that in the invention the formulas are intended to represent any form tautomer of the compound represented and are not limited only to a specific tautomeric form represented by the formula included

Some of the compounds of the invention may exist as a single stereoisomer (i.e. essentially free of other stereoisomers), racemate and / or mixture of enantiomers and / or diastereomers. It is intended that such unique stereoisomer, Racemate and its mixtures are encompassed by the scope of the present invention. Preferably, the compounds of the invention that are optically active are used in optically pure form.

How experts in general will understand technique, an optically pure compound that has a chiral center it is the one that essentially consists of one of the two enantiomers possible (that is, it is enantiomerically pure) and a compound optically pure that has more than one chiral center is one that is both diastereoisomerically pure and enantiomerically pure. Preferably, the compounds of the present invention are used in form that is optically pure by at least 90%, that is, a form containing at least 90% of a single isomer (excess enantiomer ("ee") or 80% diastereoisomeric excess ("de"), plus preferably at least 95% (ee or 90%), even more preferably at least 97.5% (ee or 95%) and more preferably at least 99% (ee or 98%).

Additionally, it is intended that the formulas encompass solvated forms, as well as non-solvated forms of Identified structures For example, Formula I (a) includes compounds of the indicated structure in both forms hydrated as not hydrated. Other examples of solvates include the structures in combination with isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine.

In addition to the compounds of the Formulas I (a), III, III (a) and IV, the invention includes salts pharmaceutically acceptable of said compounds.

<pre listing-type="other">\ newpage</pre>

"A pharmaceutically acceptable salt" is understand that it means a salt that retains the biological efficacy of the free acids and bases of the specified compound and is not biological or in any other undesirable way. A compound of the invention may possess sufficiently acid functional groups, sufficiently basic, or both, and react accordingly with any of the inorganic or organic bases and acids inorganic or organic, forming a pharmaceutically salt acceptable. Examples of pharmaceutically acceptable salts include salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or a base inorganic, such as salts that include sulfates, pyro sulfates, bisulfates, sulphites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propriolates, oxalates, malonates, succinates, suberates, sebacatos, fumarates, maleates, butino-1,4-dioates, hexino-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolate, tartrates, methane sulphonates, propanesulfonates, naphthalene-1-sulphonates, naphthalene-2-sulfonates and Mandelatos

If the compound of the invention is a base, the desired pharmaceutically acceptable salt can 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, acid nitric, phosphoric acid and the like, or with an organic acid, such like 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 acid alpha-hydroxy, such as citric acid or acid tartaric acid, an amino acid, such as aspartic acid or acid glutamic acid, an aromatic acid, such as benzoic acid or acid cinnamic, a sulfonic acid, such as acid p-toluenesulfonic acid or ethanesulfonic acid or Similar.

If the compound of the invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, by acid treatment free 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 organic salts include salts organic derivatives of amino acids, such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and amines cyclics, such as piperidine, morpholine and piperazine, and salts inorganic derivatives of sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

In the case of agents that are solid, the Those skilled in the art will understand that the compounds and salts of the invention may exist in different crystalline forms or polymorphic, pretending that all are included in the scope of the present invention and the specified formulas.

Therapeutically amounts can be used. Effective of the invention for treating diseases mediated by Modulation or regulation of protein kinases. An amount effective "is understood to mean the amount of an agent that, when administered to a mammal that needs such treatment, it is enough to treat a disease mediated by the activity of one or more protein kinases, such as tyrosine kinases Thus, for example, a therapeutically amount Effective of a compound of Formula I (a), or its salt, is a sufficient quantity to modulate, regulate or inhibit the activity of one or more protein kinases, such that a state is reduced or relieved morbid that is mediated by such activity.

The amount of a given agent that will correspond at that amount it will vary depending on factors such as the particular compound, the morbid state and its severity, the identity (for example, the weight) of the mammal that needs such treatment, but nevertheless it can usually be determined by the expert in the technique "Treat" is understood to mean at least the mitigation of a morbid state of a mammal, such as a being human, which is affected, at least in part, by the activity of one or more protein kinases, such as tyrosine kinases, and includes: avoid the appearance of the morbid state in a mammal, particularly when the mammal is predisposed to suffer said morbid state but to which it has not been diagnosed; modulate and / or inhibit the morbid state; and / or relieve the state morbid.

The agents of the invention can be prepared by the reaction pathways and the synthesis schemes described to then using the methods available in the art that They use readily available starting materials.

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In a general synthesis process, the compounds of Formula I (a) are prepared in accordance with the following reaction scheme:

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<figref>7</figref>

6-nitroindazole is treated (compound V) with iodine and a base, for example, NaOH, in a mixture aqueous / organic, preferably with dioxane. The mixture is acidify and the product is isolated by filtration. To the 3-iodo-6-nitroindazole resulting in 50% aqueous dichloromethane-KOH at 0 ° C a reagent with a protective group ("Pg") is added (where X = halo), preferably trimethylsilylethoxymethyl chloride (SEM-Cl) and a catalyst for transfer of phases, for example, tetrabutylammonium bromide (TBABr). After 1-4 hours, the two phases are diluted, the phase Organic is separated, dried with sodium sulfate, filtered and dried. concentrate. The crude product is purified by chromatography on silica gel column obtaining the compounds of formula VI. The treatment of the compounds of formula VI in a solvent suitable organic with a reagent R1 -organometallic suitable, preferably a R 1 -boronic acid, in the presence of a base aqueous, for example, sodium carbonate, and a suitable catalyst, preferably Pd (PPh3) 4 gives, after extractor treatment and silica gel column chromatography, the compounds of formula VII. The substituent R 1 can exchanged in the compounds of formula VII or in the compounds subsequent intermediates of this scheme by oxidative cleavage (by example, ozonolysis) followed by additions to the aldehyde function resulting with Wittig transformations or by condensation (illustrated in Example 42 (ae)). He treatment of the compounds of formula VII with an agent reducer, preferably SnCl2, provides, after Conventional aqueous treatment and purification, the compounds of formula VIII. The compounds of formula VIII can be treated with chlorides, bromides, iodides or triflates of aryl or heteroaryl in presence of a base, preferably Cs2CO3, and a catalyst, preferably Pd-BINAP, obtaining the compounds of formula X. To produce other Y links, it add sodium nitrite to the compounds of formula VIII in typical cold aqueous acidic conditions followed by the addition of potassium iodide and gentle heating. The treatment and the Typical purification produce iodide compounds of formula IX.

The treatment of the compounds of formula IX with an organometallic reagent, for example, butyl lithium, promotes exchange halogen-lithium. This intermediate compound is made then react with an electrophilic agent R2, by an example, a carbonyl or triflate, with the possible mediation of additional metals and catalysts, preferably chloride zinc and Pd (PPh3) 4 providing the compounds of Formula X. Alternatively, the compounds of Formula IX can be treated with an organometallic reagent, such as an organ-boronic acid in the presence of a catalyst, for example, Pd (PPh3) 4, under atmosphere of carbon monoxide obtaining the compounds of formula X. Alternatively, the compounds of formula IX may be treated with appropriate amines in the presence of a base, preferably Cs2CO3 or K3PO4 and a catalyst, preferably Pd-BINAP or Pd- (bis-cyclohexyl) biphenylphosphine obtaining the compounds of formula X. Can be used conventional exchanges of functional groups, such as oxidations, reductions, alkylations, acylations, condensations and unprotections to obtain more derivatives of this series giving the final compounds of Formula I (a).

The compounds of the invention of Formula I (a) can also be prepared according to the General procedure shown in the following scheme:

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<figref>8</figref>

6-Iodoindazole (XI) is treated with iodine and a base, for example, NaOH, in an aqueous / organic mixture, preferably with dioxane. The mixture is acidified and the product XII is isolated by filtration. At 3,6-di-iodoindazole resulting in 50% aqueous dichloromethane-KOH at 0 ° C a reagent with a protective group is added, preferably SEM-Cl, and a catalyst for transfer of phases, for example, TBABr. The two phases are diluted, the phase Organic is separated, dried over sodium sulfate, filtered and dried. concentrate. The crude product is purified by chromatography on silica gel column obtaining the compounds of the formula XIII The treatment of the compounds of formula XIII in a suitable organic solvent with a reagent R1 -organometallic suitable, for example, R2-ZnCl or boron reagent R2 -boro and a suitable catalyst, preferably Pd (PPh3) 4 provides, after extraction treatment and column chromatography of silica gel, the compounds of formula XIV. The treatment of compounds of formula XIV in a suitable organic solvent with a R1 -organometallic reagent suitable (for example, boron reagent R 1 -boro or R 1 -ZnCl), in the presence of an aqueous base, sodium carbonate, and a suitable catalyst, preferably Pd (PPh3) 4 gives, after treatment of extraction and column chromatography on silica gel, the compounds of formula XV. Exchanges may be used conventional functional groups, such as oxidations, reductions, alkylations, acylations, condensations and checkouts to obtain more derivatives of this series giving the final compounds of Formula I (a).

Other compounds of Formula I (a) may prepare analogously to the general procedures before described or the detailed procedures described in the examples of this report. The affinity of the compounds of the invention for a receiver can be improved by providing multiple very close ligand copies, preferably using a fabric provided by a rest of vehicle. Has been shown to provide said multiple valence compounds with a optimal spacing between the remains dramatically improves the bond to a receiver See, for example, Lee<i>et al., Biochem</i>, 2. 3, 4255 (1984). Multivalence and spacing can be controlled by the selection of a suitable vehicle rest or linking units. Such remains include molecular supports that contain a multiplicity of functional groups that can get reacted with functional groups associated with compounds of the invention. Naturally, a variety can be used. of vehicles, including proteins, such as BSA or HAS, a multiplicity of peptides including, for example, pentapeptides, Decapeptides, pentadecaptides and the like. Peptides or proteins can contain the desired number of amino acid residues which have free amino groups in their side chains; without However, other functional groups, such as sulfhydryl groups or hydroxyl groups, can also be used to obtain bonds stable.

Compounds that regulate, modulate or potentially inhibit the associated protein kinase activity with VEGF, FGF, CDK, TEK, CHK1, LCK, FAK receivers and phosphorylase kinase among others, and that inhibit angiogenesis and / or cell proliferation and is a preferred embodiment of the present invention The present invention further relates to methods to modulate or inhibit protein kinase activity, for example in mammalian tissue, administering an agent of the invention. The activity of the compounds of the invention as protein kinase activity modulators, such as the kinase activity, can be measured by any of the methods available to those skilled in the art, including ratings <i>in vivo</i> me <i>in vitro</i>. Examples of Appropriate assessments for activity measures include those described by Parast C. <i>et al</i>., in <i>Biochemistry</i>, 37, 16788-16801 (1998); Jeffrey<i>et al., Nature</i>, 376, 313-320 (1995); Publication of WIPO International Patent Application No. WO 97/34876; and WIPO International Patent Application Publication No. WO 96/14843. These properties can be determined, for example, by one or more of the biological test procedures collected in The following examples.

The active agents of the invention can formulated in the form of pharmaceutical compositions as described then. The pharmaceutical compositions of this invention they comprise an effective modulating, regulatory or inhibitory amount of a compound of Formula I (a), III, III (a) or IV and a pharmaceutically acceptable inert carrier or diluent. In a embodiment of the pharmaceutical compositions, are provided effective levels of the agents of the invention to obtain therapeutic benefits that involve protein modulation kinases "Effective levels" means levels at which the effects of proteins are regulated at a minimum kinases These compositions are prepared in unit dose form. appropriate for the mode of administration, for example, parenteral or oral administration.

An agent of the invention is administered in the form conventional pharmaceutical prepared by combining an amount therapeutically effective agent (for example, a compound of Formula I (a)) as active ingredient with vehicles or Appropriate pharmaceutical diluents according to procedures conventional. These procedures may involve mixing, granulation and compression or dissolution of the principles as Appropriate for the desired preparation.

The pharmaceutical vehicle used can be solid or liquid Examples of solid vehicles are lactose, sucrose, talc, gelatin, agar-agar, pectin, gum Arabic, magnesium stearate, stearic acid and the like. Examples of liquid vehicles are syrup, peanut oil, Olive oil, water and the like. Likewise, the vehicle or diluent may include delayed or slow release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with wax, ethyl cellulose, hydroxypropyl methylcellulose, methyl methacrylate and Similar.

A variety of ways can be used. Pharmaceutical Thus, if a solid vehicle is used, the preparation it can be compressed, placed in a hard gelatin capsule in powder form or pellet or in the form of a trocisco or tablet for suck. The amount of solid vehicle may vary, but It will generally be from about 25 mg to about 1 g. If a liquid vehicle is used, the preparation will be in the form of syrup, emulsion, soft gelatin capsule, solution or suspension Sterile injection in a vial or vial or liquid suspension not watery

To obtain a soluble pharmaceutical form in stable water, a pharmaceutically acceptable salt of a agent of the invention in an aqueous solution of an organic acid or inorganic, such as 0.3M solution of succinic acid or acid citric. If a soluble salt form is not available, the agent it can be dissolved in a suitable co-solvent or combinations of co-solvents. Examples of Suitable co-solvents include, but are not limited to them, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in varying concentrations between 0-60% of the total volume. In one embodiment illustrative, a compound of Formula I (a) is dissolved in DMSO and diluted with water. The composition can also be in form of a solution of a salt form of the active substance in a appropriate aqueous vehicle, such as water or isotonic saline or solution in dextrose.

It will be appreciated that the actual doses of the agents used in the compositions of this invention will vary according to with the particular complex that is used, the particular composition formulated, the mode of administration and the particular site, host and disease to be treated. Dosages optimal for a set of given conditions can be established by those skilled in the art using tests of determination of conventional dosing in light of experimental data for an agent. For oral administration, a Illustrative daily dose used in general is approximately 0.001 to about 1000 mg / kg of weight, more preferably of about 0.001 to about 50 mg / kg of weight, repeating the treatment at appropriate intervals.

The compositions of the invention may be manufactured in a generally known way to prepare pharmaceutical compositions, for example, using techniques conventional, such as mixing, dissolution, granulation, dragee formation, levigation, emulsification, encapsulation, entrapment or lyophilization. Pharmaceutical compositions can be formulated in a conventional manner using one or more vehicles physiologically acceptable, which can be selected from excipients and auxiliaries that facilitate the treatment of active compounds in preparations that can be used pharmaceutically

The appropriate formulation depends on the route of elected administration. For injections, the agents of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers, such as Hanks solution, Ringer's solution or saline buffer physiological. For transmucosal administration, they are used in the formulation penetrating agents appropriate to the barrier to be cross. Such penetrating agents are generally known in The technique.

For oral administration, the compounds may easily formulated by combining the active compounds with Pharmaceutically acceptable carriers known in the art. Such vehicles facilitate that the compounds of the invention are formulated in the form of tablets, pills, dragees, capsules, liquids, gels, syrups, porridge, suspensions and the like, for Oral digestion by a patient to be treated. The Pharmaceutical preparations for oral use can be obtained using a solid excipient mixed with the active ingredient (agent), optionally crushing the resulting mixture and treating the mixture of granules after adding the appropriate auxiliary agents, if desired, to obtain tablets or dragee cores. The Suitable excipients include: fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; and preparations cellulose, for example, corn starch, wheat starch, starch of rice, potato starch, gelatin, gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose or polyvinylpyrrolidone (PVP). If desired, agents can be added disintegrants, such as cross-linked polyvinylpyrrolidone, agar-agar or alginic acid or one of its salts, such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, solutions can be used sugar concentrates, which may optionally contain gum Arabic, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and organic solvents suitable or mixtures of said solvents. Can be added dyes or pigments to the coatings of tablets or dragees for identification or to characterize the different combinations of active agents.

The pharmaceutical preparations that can used orally include soft-adjustment capsules made of jelly, as well as soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Adjustment capsules soft can contain the active ingredients mixed with loads, such as lactose, binders, such as starches, and / or lubricates , such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the agents assets can be dissolved or suspended in liquids suitable, such as fatty oils, liquid paraffin or liquid polyethylene glycols. In addition, they can be added stabilizers All formulations for administration via route oral should be in appropriate dosages for said administration. For oral administration, the compositions may take the form of tablets or lozenges formulated from conventional way.

For intranasal or inhalation administration, The compounds for use according to the present invention are conveniently supplied in the form of a presentation to spray spray from pressurized containers or a nebulizer, using a suitable propellant gas, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In In the case of a pressurized spray the dosing unit can be determined by providing a valve to supply a dosed quantity. Gelatin capsules and cartridges for use in an inhaler or insufflator and the like can be formulated so containing a powder mixture of the compound and a powder base suitable, such as lactose or starch.

The compounds can be formulated to parenteral administration by injection, for example, by injection of a bolus or continuous infusion. Formulations for preparations injectables may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with the addition of a preservative The compositions can take forms such as suspensions, solutions or emulsions in oily vehicles or aqueous, and may contain formulation agents, such as suspending agents, stabilizers and / or dispersants

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. Additionally, the suspensions of active agents can be prepared as appropriate oily injectable suspensions. The solvents or Suitable lipophilic vehicles include fatty oils, such as sesame oil, or esters of synthetic fatty acids, such as ethyl oleate or triglycerides or liposomes. Suspensions Aqueous injectables may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may contain also stabilizers or suitable agents that increase the solubility of the compounds to obtain from the preparation very concentrated solutions.

For ophthalmic administration, a compound of Formula I (a), III, III (a) or IV is supplied in a pharmaceutically acceptable ophthalmic vehicle, such that the compound stays in contact with the eye surface for a sufficient period of time to allow the compound penetrate the corneal and internal regions of the eye, including, by example, the anterior chamber, the posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris / ciliary body, crystalline, Choroid / retina and sclera. Ophthalmic vehicle Pharmaceutically acceptable can be ointment, vegetable oil or a encapsulating material. A compound of the invention can be injected. also directly in the vitreous and aqueous humor.

Alternatively, the active substance can be in powder form for reconstitution with a vehicle suitable, for example, sterile pyrogen-free water, before use. The compounds can also be formulated in compositions rectals, such as suppositories or retention enemas, by example, containing conventional suppository bases, such as cocoa butter or other glycerides.

In addition to the formulations described above, compounds can also be formulated as a preparation of slow release. Such formulations that act in the long term can be administered by implantation (for example, subcutaneously or intramuscular) or by intramuscular injection. So, for example, the compounds can be formulated with polymeric or hydrophobic materials suitable (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparsely derived soluble, for example, as a sparingly soluble salt.

A pharmaceutical vehicle for compounds hydrophobic is a co-solvent system that comprises benzyl alcohol, a non-polar surfactant, an organic polymer Miscible in water and an aqueous phase. The system co-solvent can be a system VPD co-solvent. VPD is an alcohol solution 3% w / v benzyl, 8% w / v non-polar polysorbate surfactant 80 al and polyethylene glycol 300 at 65% w / v, completed to volume with absolute ethanol. The VPD co-solvent system (VPD: 5W) contains VPD diluted 1: 1 with a 5% dextrose solution in water This co-solvent system dissolves well hydrophobic compounds, and he himself produces low toxicity by systemic administration Naturally, the proportions of a co-solvent system may vary considerably without destroying its solubility characteristics and toxicity. In addition, the identity of the components may vary. co-solvents: for example, others can be used non-polar surfactants of low toxicity instead of polysorbate 80; the fraction size of the polyethylene glycol may vary; others Biocompatible polymers can replace polyethylene glycol, by example, polyvinylpyrrolidone; and other sugars or polysaccharides They can replace dextrose.

Alternatively, others may be used. delivery systems for hydrophobic pharmaceutical compounds. Liposomes and emulsions are known examples of vehicles or delivery excipients for hydrophobic drugs. As well certain organic solvents, such as dimethylsulfoxide, although generally at the expense of increased toxicity. Additionally, the compounds can be supplied using a extended release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various extended release materials have been established which are known to those skilled in the art. The capsules of prolonged release may release, depending on its nature Chemistry, the compounds for a few weeks up to more than 100 days. Depending on the chemical nature and stability biological of the therapeutic reagent, other may be applied strategies for protein stabilization.

The pharmaceutical compositions may contain also vehicles or excipients in solid or gel phase. Examples of said vehicles 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 counterions compatible. Pharmaceutically compatible salts can be formed. with many acids, which include hydrochloric acid, sulfuric acid, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other solvents proton solvents that forms in free base corresponding.

The preparation of the preferred compounds of The present invention is described in detail in the following examples, but the technician will recognize that chemical reactions described can be easily adapted to prepare others protein kinase inhibitors of the invention. For example, the synthesis of compounds not illustrated according to the invention can be done successfully by obvious modifications to the experts in the art, for example, by appropriately protecting interfering groups, changing to other reagents known in the technique or making usual modifications of the conditions of reaction. Alternatively, it will be recognized that other reactions described in the present invention or known in the art can applied to prepare other compounds of the invention.

Examples

In the examples described below, except opposite indication, all temperatures are in degrees Celsius and all parts and percentages by weight. Reagents were acquired from commercial firms, such as Aldrich Chemical Company or Lancaster Synthesis Ltd. and were used without further ado purification unless otherwise indicated. Tetrahydrofuran (THF), N, N-dimethylformamide (DMF), dichloromethane, toluene and dioxane were purchased from Aldrich in secure sealed jars and used, as received. All solvents were purified using usual methods easily known to experts in the technique, unless otherwise indicated.

The reactions indicated below are generally performed under positive pressure of argon or nitrogen or with a drying tube, at room temperature (unless indicated opposite), in anhydrous solvents, and reaction flasks they were provided with rubber partitions for the introduction of substrates and reagents by means of a syringe. The appliances of Glass was dried in an oven and / or heat. Layer Chromatography fine (abbreviated in the following TLC, from English <i>Thin layer Chromatography</i>) Analytical was performed on 60 F 254 gel plates of silica coated with Analtech glass (0.25 mm) and the elution is performed with the appropriate solvent ratios (v / v) that are Quote when appropriate. The reactions were assessed by TLC and were ended when it was deemed convenient by consumption of the material of departure.

The visualization of the TLC plates was performed with a spray reagent of <i>p</i>-anisaldehyde or a phosphomolibic acid reagent (Aldrich Chemical, 20% by weight in ethanol) and was activated with heat. The treatments were performed typically doubling the reaction volume with the solvent of reaction or extraction solvent and then washing with the aqueous solutions indicated using 25% by volume of the volume of extraction unless otherwise indicated. Product solutions dried over anhydrous Na2SO4 before filtration and evaporation of solvents under reduced pressure in a rotary evaporator and are called solvent removed in vacuo. Column chromatography of rapid development (Still <i>et al., J. Org. Chem</i>., 43, 2923 (1978)) was performed using silica gel Baker type (47-61 µm) and a gel ratio of silica: rough material of approximately 20: 1 to 50: 1 except opposite indication. Hydrogenolysis was performed under pressure indicated in the examples or at ambient pressure.

1 H NMR spectra (proton nuclear magnetic resonance) were recorded with a Bruker instrument that worked at 300 MHz and the spectra of 13 C-NMR were recorded working at 75 MHz. NMR spectra were obtained as solutions in CDCl3 (expressed in ppm), using chloroform as a reference standard (7.25 ppm and 77.00 ppm) or CD 3 OD (3.4 and 4.8 ppm and 49.3 ppm) or internally tetramethylsilane (0.00 ppm) when appropriate. When necessary, other NMR solvents were used. When record multiplicity of peaks, the following are used Abbreviations: s (singlet), d (doublet), t (triplet), m (multiplet), br (width), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are Express in hertz (Hz).

Infrared (IR) spectra were recorded. in an infrared Perkin-Elmer spectrometer with Fourier transform (abbreviated FTIR, from English <i>Fourier Transform Infrared</i>) as net oils, such as KBr pellets or as solutions in CDCl3, and when given they are expressed in number of waves (cm -1). The mass spectra (briefly MS, of English <i>Mass Sprectrum</i>) were obtained using Spectra of liquid secondary ion masses (abbreviated LSIMS)<i>Liquid Secondary Ion Mass Spectrum</i>) or with ionization by electrospray (abbreviated ESI, from English <i>ElectroSpray Ionization</i>). Melting points (mp) are not corrected

Reference Example 1 (a)

3- [E-2- (3,4-dimethoxy-phenyl) vinyl] -6- (3-methoxy-4-hydroxyphenyl) -1

H

-indazol

<figref>9</figref>

He 3- [E / Z-2- (3,4-dimethoxy-phenyl) vinyl] -6- [3-methoxy-4- (methoxymethoxy) phenyl] -1<i>H</i>-indazol (20205 mg, 0.461 mmol (theoretical)) was dissolved in tetrahydrofuran (THF, 10 mL) and treated with water (10 mL) and acid trifluoroacetic acid (TFA, 20 mL). The reaction mixture was left in stirring at 23 ° C for 30 minutes (min). The mixture was diluted with toluene (100 mL) and volatile materials separated under reduced pressure (30 mm Hg, 35 ° C) obtaining a volume mL5 mL concentrate. Again, toluene (100 mL) was added and the mixture was concentrated under reduced pressure to obtain the material raw that still contained some acid. The material was distributed between ethyl acetate and saturated sodium hydrogen carbonate, it separated the organic material, dried over sodium sulfate, decanted and concentrated under reduced pressure. The residue, a mixture of olefin isomers, (~ 185 mg, 0.461 mmol (theoretical)) is extracted with dichloromethane (50 mL) at 23 ° C and 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 hydrogen carbonate (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 hydrogen carbonate (100 mL), dried over sulfate sodium, decanted and concentrated under reduced pressure obtaining the raw product. Said raw product is purified on silica (40 mL, ethyl acetate / hexane 6: 4 -&gt; 7: 3) and all the desired fractions were gathered, concentrated and precipitated in a dichloromethane / hexane bilayer (1: 3) getting 3- [E-2- (3,4-dimethoxy-phenyl) vinyl] -6- (3-methoxy-4-hydroxy-phenyl) -1<i>H</i>-indazol in the form of a white solid (the collected crops were 93 mg): R<i>F</i> sm = 0.42, p = 0.35 (acetate ethyl hexane 7: 3); FTIR (thin film) 3324,1600, 1514, 1463, 1422, 1264, 1137, 1024, 959, 852 cm -1; 1 HRMN (CDCl 3) δ: 10.0 (broad s, 1H), 8.08 (d, 1H, <i>J</i> = 8.4 Hz), 7.59 (s, 1H), 7.49 (d, 1H, <i>J</i> = 16.6 Hz), 7.45 (dd, 1 HOUR, <i>J</i> = 1.4, 8.4 Hz), 7.34 (d, 1H, <i>J</i> = 16.6 Hz), 7.20-7.12 (m, 4H), 7.03 (d, 1H, <i>J</i> = 8.0 Hz), 6.91 (d, 1 H, <i>J</i> = 8.2 Hz), 5.68 (wide s, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.93 (s, 3H); 13 CRMN (CDCl 3) 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. High mass spectrum resolution (abbreviated HRMS) <i>High Resolution Mass Spectrum</i>) (ES) [M + H] / z Calculated 403,1658, found 403,1658. [MH] / z Calculated 401, found 401.

The starting material was prepared as follow:

<figref>10</figref>

A 6-aminoindazole (40.8 g, 0.3065 mol, 1 equivalent) in a 2-liter round bottom flask (2 L) containing a magnetic stir bar ice was added (256 g), followed by water (128 mL) and the reaction vessel is Introduced in an ice bath. At this suspension stirred at 0 ° C added concentrated aqueous HCl (128 mL, 1.53 moles, 5 equivalents). Immediately afterwards, a solution of NaNO2 (23.3 g, 0.338 mol, 1.1 equivalents) in water (96 mL). After 10 stirring at 0 ° C, KI (61 g, 0.368 mol, 1.2 was added equivalent) very slowly at first (? 100 mg at once because the first small pieces of KI cause an abrupt gas evolution) and then more quickly (total time 5 min) The cold bath was separated and the reaction mixture was heated up to 40 ° C (gas evolution). When the speed decreased gas evolution (~ 30 min) the reaction mixture is heated to 50 ° C for 30 min. Then the mix to 23 ° C and 3N NaOH (320 mL) was added for neutralization followed by 50% saturated NaHCO 3 (320 mL). TO The suspension was then filtered by a Buchner funnel obtaining a dark reddish-brown solid. He collected the solid in warm THF (800 mL) and silica (600 mL dry) with stirring. To this suspension hexane (1.2 L) was added and the mixture was filtered under vacuum by a silica pad (300 mL) in a wide sintered filter. The silica was also washed with 2 L THF 40% in hexane. The leaks met and concentrated under reduced pressure to obtain a solid. Solid triturated with ethyl acetate (~ 100 mL), filtered and dried under reduced pressure obtaining 6-iodine-1<i>H</i>-indazol in form of a light brown solid (36.1 g, yield 48%): R f = sm 0.12, p = 0.48 (Hex-EtOAc 1: 1); 1 HRMN (300 MHz, CDCl 3) δ: 7.9 (s, 1H), 7.8 (s, 1H), 7.42 (d, 1H), 7.33 (d, 1 H); MS (ES) [M + H] / z Calculated 245, found 245, [MH] / z Calculated 243, found 243.

<figref>11</figref>

To a solution of 6-iodine-1<i>H</i>-indazol (7.35 g, 30.1 mmol, 1 equivalent) in THF (100 mL) cooled to 0 ° C under argon was added <i>t</i>-sodium peroxide (2.89 g, 30.1 mmol, 1 equivalent). A color change from orange to red was observed. Mesitylenesulfonyl chloride (6.60 g, was added in one portion) 30.1 mmol, 1 equivalent) and the ice bath was removed leaving The reaction mixture will be heated to 23 ° C. After 40 min the reaction stopped abruptly adding to the mixture chloride saturated ammonium and partitioned between water and ethyl acetate. The aqueous phase was extracted a total of 3 times with ethyl acetate. He The combined organic material was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to obtain 6-iodo-1- (2,4,6-trimethyl-benzenesulfonyl) -1<i>H</i>-indazol in the form of an orange solid (12.8 g, 100% yield, mixture 2: 1). 1 HRMN (CDCl3) δ: 8.51 (s, 1H), 7.95 (s, 0.66H, majority isomer), 7.91 (s, 0.33H, minor isomer), 7.47 (d, 0.33H, <i>J</i> = 8.4 Hz), 7.29 (d, 0.33H, <i>J</i> = 8.4 Hz), 7.26 (d, 0.66H, <i>J</i> = 8.9 Hz), 7.18 (d, 0.66H, 8.9 Hz), 6.84 (s, 2H), 2.51 (s, 6H), 2.15 (s, 3H).

<figref>12</figref>

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A mix of 6-iodo-1- (2,4,6-trimethyl-benzenesulfonyl) -1<i>H</i>-indazol (5.78 g, 13.56 mmol, 1.00 equivalent) and acid 3-methoxy-4- (methoxymethoxy) benzene-boronic (3.45 g, 16.27 mmol, 1.20 equivalents) under argon dissolved in dioxane (15 mL) and water (2.0 mL). To this solution was added triethylamine (2.83 mL, 20.3 mmol, 1.5 equivalents), carbonate potassium (2.8 g, 20.3 mmol, 1.5 equivalents) and dichlorobis (triphenylphosphine) palladium (476 mg, 0.678 mmol, 0.05 equivalents). The reaction mixture was heated until 90 ° C for 2 h and then cooled to 23 ° C. Mix it was partitioned between ethyl acetate (250 mL) and hydrogen carbonate saturated sodium (150 mL). The organic material was dried over sulfate sodium, decanted and concentrated under reduced pressure getting 6- (3-Methoxy-4-methoxymethoxy-phenyl) -1- (2,4,6-trimethyl-benzenesulfonyl) -1<i>H</i>-indazol which was dried under high vacuum for 15 h and was used without further purification.

Acid was prepared 3-methoxy-4- (methoxymethoxy) benzeneboronic as follows: in a 100 mL flask a mixture was prepared under argon of 50% KOH in water (20 g of KOH, 7 equivalents, 20 g of ice). To this mixture rapidly stirred at 0 ° C (kept in a bath of ice) dichloromethane (50 mL) was added followed by 4-bromo-2-methoxyphenol (10.1 g, 50 mmol, 1.00 equivalent), methoxymethyl chloride (MOMCl) (4.00 mL, 42.5 mmol, 1.05 equivalents) and bromide of tetrabutylammonium (322 mg, 1 mmol, 0.02 equivalents). He withdrew bath and the mixture was allowed to slowly warm to 23 ° C with rapid agitation for 2 h. The mixture was transferred to a funnel. separator and diluted with dichloromethane (350 mL) and water (300 mL) which was used to improve the transfer. Organic material (now the bottom layer) was separated, dried over sodium sulfate, was decanted and concentrated under reduced pressure to obtain 4-Bromo-2-methoxy-1- (methoxymethoxy) benzene in the form of a yellow liquid, which was found to be pure by 1 HRMN (11.9 g, 97%): 1 HRMN (CDCl3) δ: 7.0 (s, 3H), 5.13 (s, 2H), 3.84 (s, 3H), 3.47 (s, 3H). MS (EI)<i>Electron Ionization</i>) [M + H] / z Calculated 235, found 235. In a 50 mL round bottom flask, it was collected 4-Bromo-2-methoxy-1- (methoxymethoxy) benzene (4.80 g, 19.4 mmol, 1.00 equivalent) with THF (35 mL) and cooled to -78 ° C (20 min for this volume). To this was added<i>n</i>-BuLi (12.75 mL, 1.6M in hexane, 20.4 mmol, 1.05 equivalent) and the mixture was allowed to stir at -78 ° C for 40 min. It was added by means of a cannula to a second flask that contained B (OMe) 3 (22 mL, 194 mmol, 10 equivalent) in THF (50 mL) at -78 ° C. After 20 min, he retired The cold bath After 15 min of heating (~ 0 ° C, the ice in contact with the flask begins to melt) water (50 mL) to the reaction mixture that was stirred for 45 min. Mix it was concentrated under reduced pressure eliminating most of THF and then partitioned between ethyl acetate (300 mL) and water (150 mL) that became acidic by adding a small amount of 20% citric acid (~ 10 mL). The organic material dried over sodium sulfate and concentrated under reduced pressure obtaining a solid. Trituration with ethyl acetate (10 mL) and hexane (5 mL) followed by filtration gave acid 3-methoxy-4- (methoxymethoxy) benzene-boronic in the form of a white solid (3.15 g, 77%): R f sm = 0.59, p = 0.18 (ethyl acetate-hexane 1: 1); 1 HRMN (CDCl 3) δ: 7.85 (d, 1H, <i>J</i> = 8 Hz), 7.72 (s, 1H), 7.22 (d, 1H, <i>J</i> = 8 Hz), 5.30 (s, 2H), 4.00 (s, 3H), 3.55 (s, 3H).

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<figref>13</figref>

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6- (3-Methoxy-4-methoxymethoxy-phenyl) -1- (2,4,6-trimethyl-benzenesulfonyl) -1<i>H</i>-indazol unpurified (under argon) was dissolved in THF (20 mL) and treated with 1N NaOH in MeOH (70 mL degassed by bubbling argon to its through for 3 to 5 min). The mixture was heated to 45 ° C for 1 h and allowed to cool. The mixture was neutralized by the addition of HCl. 1N (50 mL) followed by saturated sodium hydrogen carbonate (200 mL). The product was extracted with ethyl acetate (350 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain 6- (3-methoxy-4-methoxymethoxy-phenyl) -1<i>H</i>-indazol raw. Purification by gel column chromatography of silica (500 mL of silica, 20% ethyl acetate in benzene (1.8 L), 30% ethyl acetate in benzene (1.8 L)) gave 6- (3-methoxy-4-methoxymethoxyphenyl) -1<i>H</i>-indazol (1.19 g, 31%): 1 HRMN (CDCl 3) δ: 7.80 (s, 1H), 7.69 (d, 1H, <i>J</i> = 8.5 Hz), 7.52 (s, 1H), 7.29 (d, 1H, <i>J</i> = 8.5 Hz), 7.16 (s, 1H), 7.13 (s, 1H), 7.08 (s, 1H). MS (ES) [M + Na] / z Calculated 337, found 337; [M + Cl -] / z Calculated 349, found 349.

<figref>14</figref>

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In a 100 mL round bottom flask argon, dissolved 6- (3-methoxy-4-methoxymethoxy-phenyl) -1<i>H</i>-indazol (1.19 g, 4.18 mmol, 1 equivalent) in dioxane (25 mL) and 3N NaOH (14 mL) This mixture was treated with iodine (1.17 g, 14.60 mmol, 1.10 equivalent) added in \ sim5 portions (\ sim10 min). He they added several more (sim4) portions of iodine (50 mg each) until the reaction was completed by visualizing by TLC (acetate ethyl / hexane 3: 7). The mixture was acidified with 20% citric acid (25 mL) and 5% NaHSO3 (20 mL) was added. The mixture is partitioned between ethyl acetate (150 mL) and water (100 mL). He Organic material was washed with saturated sodium hydrogen carbonate (80 mL) and brine (50 mL) and dried over sodium sulfate and dried. concentrated under reduced pressure. Purification by crystallization in ethyl acetate (3 mL) and then in hexane (7 mL) gave 3-iodo-6- (3-methoxy-4-methoxymethoxyphenyl) -1<i>H</i>-indazol pure in the form of a solid (1.33 g, 78%): 1 H NMR (CDCl 3) δ: 10.48 (broad s, 1H), 7.62 (s, 1H), 7.57 (d, 1H, <i>J</i>= 8.5 Hz), 7.47 (dd, 1H, <i>J</i> = 1.3, 8.5 Hz), 7.18 (m, 3H), 5.29 (s, 2H), 3.99 (s, 3H), 3.55 (s, 3H).

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<figref>15</figref>

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In a 100 mL round bottom flask, dissolved 3-iodo-6- (3-methoxy-4-methoxymethoxyphenyl) -1<i>H</i>-indazol (921 mg, 2,245 mmol, 1.00 equivalent) in THF (36 mL) and cooled to -78 ° C (leaving 8 min at this temperature). Added one PhLi solution (2.5 mL, 1.8 M, 4.49 mmol, 2.00 equivalents) and the mixture was allowed to stir 30 min. A solution of<i>s</i>-BuLi (3.63 mL, 4.71 mmol, 2.1 equivalents) and the mixture of reaction was allowed to stir for 1 h at -78 ° C. DMF was added pure (1.4 mL, 18 mmol, 8.0 equivalents). The cold bath was removed and The reaction mixture was allowed to slowly warm to 0 ° C in air. As the ice melted, sodium hydrogen carbonate was added saturated (20 mL). The product was extracted with ethyl acetate (200 mL) of saturated sodium hydrogen carbonate (75 mL more), dried over sodium sulfate, it was decanted and concentrated under pressure reduced Purification by gel column chromatography of silica (450 mL silica, ethyl acetate / hexane 4: 6) gave 6- (3-methoxy-4-methoxymethoxy-phenyl) -1<i>H</i>-indazol-3-carbaldehyde (498 mg, 71%)): R f sm = 0.30, p = 0.14 (acetate ethyl hexane 4: 6); 1 HRMN (CDCl 3) δ: 10.85 (wide s, 1H), 10.25 (s, 1H), 8.37 (d, 1H, <i>J</i> = 8.4 Hz), 7.67 (s, 1H), 7.60 (d, 1H, <i>J</i> = 8.4 Hz), 6.26 (d, 1H,<i>J</i> = 8.7 Hz), 7.19 (m, 2H), 5.30 (s, 2H), 3.99 (s, 3H), 3.55 (s, 3H).

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<figref>16</figref>

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Was collected 6- (3-methoxy-4-methoxymethoxy-phenyl) -1<i>H</i>-indazol-3-carbaldehyde (441 mg, 1.41 mmol, 1.0 equivalent) as a suspension in dichloromethane (15 mL) and cooled to 0 ° C. This mixture was treated. with mesitylenesulfonyl chloride (324 mg, 1.48 mmol, 1.05 equivalents) and dimethylaminopyridine (DMAP) (181 mg, 1.48 mmol, 1.05 equivalents). The mixture was allowed to stir for 1 h at 0 ° C. and the reaction stopped abruptly with the addition of water. Mix it was partitioned between water and an organic layer of acetate 1: 1 ethyl / hexane. The organic material was dried over sulfate of sodium, decanted and concentrated under reduced pressure to obtain raw material that was purified by column chromatography of silica gel (50 mL silica, ethyl acetate / hexane 3: 7) getting 6- (3-Methoxy-4-methoxymethoxy-phenyl) -1- (2,4,6-trimethylbenzenesulfonyl) -1<i>H</i>-indazol-3-carbaldehyde (374 mg, 54%): R f sm = 0.17, p = 0.53 (acetate ethyl hexane 4: 6); 1 HRMN (CDCl 3) δ: 10.20 (s, 1H), 8.41 (s, 1H), 8.37 (d, 1H, <i>J</i> = 8.5 Hz), 7.73 (dd, 1H, <i>J</i> = 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).

<figref>17</figref>

Bromide was collected from triphenyl (3,4-dimethoxybenzyl) phosphonium (1.09 g, 2.22 mmol, 4.0 equivalents) finely ground into shape of a suspension in THF (15 mL) and cooled to -78 ° C. This mix was added <i>n</i>-BuLi (1.04 mL, 1.6 M, 1.66 mmol, 3.0 equivalent) that gave a red / orange solution. The mixture is allowed to warm to 23 ° C for 1 h. This mixture was added to then to a solution at 0 ° C of 6- (3-Methoxy-4-methoxymethoxy-phenyl) -1- (2,4,6-trimethyl-benzenesulfonyl) -1<i>H</i>-indazol-3-carbaldehyde (274 mg, 0.554 mmol, 1.0 equivalent) in THF (5 mL) by means of a cannula The resulting mixture was allowed to stir at 0 ° C for 10 min and the reaction stopped abruptly adding to the mixture saturated sodium hydrogen carbonate. The resulting mixture is partitioned between saturated sodium hydrogen carbonate and acetate ethyl. The organic material was concentrated under reduced pressure and the residue purified by silica gel column chromatography (50 mL of silica, ethyl acetate / hexane 3: 7 -&gt; 4: 6) obtaining a 2.5: 1 mixture of cis / trans 3- [2- (3,4-Dimethoxy-phenyl) -vinyl] -6- (3-methoxy-4-methoxymethoxyphenyl) -1- (2,4,6-trimethyl-benzenesulfonyl) -1<i>H</i>-indazol (289 mg, 83%): R f sm = 0.53, p = 0.32 (acetate ethyl hexane 4: 6); 1 HRMN (CDCl 3) δ: 8.35 (s, 0.3H), 8.32 (s, 0.7H), 8.03 (d, 0.3H, <i>J</i> = 8.4 Hz), 7.60-6.85 (m, H), 6.65 (d, 0.7H, <i>J</i> = 8.4 Hz), 6.60 (d, 0.7H, <i>J</i> = 12.5 Hz), 5.30 (s, 0.6H), 5.29 (s, 1.4H), 4.00-3.50 (8 singlets, 12H), 2.72 (s, 1.88), 2.67 (s, 4.2H), 2.34 (s, 3H); MS (ES) [M + H] / z Calculated 629, found 629, [MH] / z Calculated 627, found 627

<figref>18</figref>

A 1M solution of KOH was prepared under argon (1.0 g, 17.8 mmol) in water / MeOH 1: 1 (18 mL total) and was degassed by vacuum / purge cycles with argon (5 times). In a flask separated, dissolved 3- [2- (3,4-Dimethoxy-phenyl) -vinyl] -6- (3-methoxy-4-methoxymethoxy-phenyl) -1- (2,4,6-trimethyl-benzenesulfonyl) -1<i>H</i>-indazol (289 mg, 0.461 mmol, 1.0 equivalent) in THF (8 mL) under argon. TO this solution was added the 1M solution of previous KOH (10 mL, water / MeOH 1: 1). The reaction mixture was heated to 30 ° C and was left under stirring for 7 h. The reaction mixture was neutralized. by adding 20% ​​citric acid (7 mL). The resulting mixture is partitioned between ethyl acetate (150 mL) and water (100 mL). He organic material was separated, dried over sodium sulfate, decanted and concentrated under reduced pressure to obtain cis and trans 3- [2- (3,4-Dimethoxy-phenyl) -vinyl] -6- (3-methoxy-4-methoxymethoxyphenyl) -1<i>H</i>-indazol (used raw): R<i>F</i> sm = 0.46, p1 = 0.17, p2 = 0.23 (ethyl acetate-hexane 1: 1); 1 HRMN isomer<i>cis</i> (CDCl 3) δ: 7.55 (s, 1H), 7.3-7.1 (m, 6H), 7.02 (dd, 1H, <i>J</i> = 1.9, 8.3 Hz), 6.85 (d, 1H, <i>J</i> = 12.5 Hz), 6.78 (d, 1H, <i>J</i> = 12.5 Hz), 6.74 (d, 1H, <i>J</i> = 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 Calculated 447, found 447, [MH] / z Calculated 445, found 445.

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Reference Example 1 B)

3- (E-styryl) -6- (3-benzyloxy-4-hydroxy-phenyl) -1

H

-indazol

<figref>19</figref>

The compound of the Reference Example 1 (b) was prepared in a manner similar to that described in the Example of reference 1 (a), except that, in step (iii), was used 4-bromo-2-benzyloxy-phenol instead of 4-bromo-2-methoxy-phenol. R<i>F</i> sm = 0.35, p = 0.30 (acetate ethyl hexane 4: 6); 1 HRMN (CDCl 3) δ: 8.06 (d, 1H, <i>J</i> = 8.6 Hz), 7.63-7.18 (m, 17H), 7.05 (d, 1H, <i>J</i> = 8.2 Hz), 5.19 (s, 2H). MS (CI, of English <i>Chemical ionization</i>) [M + H] / z Calculated 419, found 419, [MH] / z Calculated 417, found 417

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Reference Example 1 C)

3- [E-2- (3,4-dimethoxy-phenyl) vinyl] -6- (3-allyloxy-4-hydroxyphenyl) -1

H

-indazol

<figref>20</figref>

The compound of Reference Example 1 (c) is prepared similarly to that described in the reference example 1 (a), except that, in step (iii), acid was used 3-allyloxy-4- (methoxymethoxy) benzene-boronic instead of acid 3-methoxy-4- (methoxymethoxy) benzene-boronic. MS (ESI) <i>Electrospray Ionization</i>) [M + H] / z Calculated 429, found 429; MS (ESI) [MH] / z Calculated 427, found 427.

Reference Example 2 (a)

3- (naphthalen-2-yl) -6- (3-methoxy-4-hydroxy-phenyl) -1

H

-indazol

<figref>21</figref>

It dissolved 6- (4-benzyloxy-3-methoxy-phenyl) -3-naphthalen-2-yl-1<i>H</i>-indazol (25 mg, 0.055 mmol) 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% by weight) and the reaction vessel is Vacuumed / purged with hydrogen gas for five cycles The reaction mixture was allowed to stir for 3 days. (d) at 23 ° C and filtered through a Celite pad. The concentration and purification by gel column chromatography of silica provided 3- (naphthalen-2-yl) -6- (3-methoxy-4-hydroxy-phenyl) -1<i>H</i>-indazol (8 mg, 40%): 1 H NMR (CDCl 3) δ: 10.3 (broad s, 1H), 8.50 (s, 1H), 8.20 (d, 1H, <i>J</i> = 8 Hz), 7.98 (d, 1H, <i>J</i> = 8Hz), 7.90 (m, 1H), 7.7-6.8 (m, 9H), 3.98 (s, 3H). MS (ES) <i>Emission Spectroscopy</i>) [M + H] / z Calculated 367, found 367, [MH] / z Calculated 365, found 365.

The starting material was prepared as follow:

<figref>22</figref>

2-Bromonaphthalene was dissolved (117 mg, 0.564 mmol, 6.0 equivalents) in THF (0.75 mL) and cooled to -78 ° C. The mixture was treated with<i>n</i>-BuLi (226 µL, 2.5 M, 6.0 equivalents) and allowed to stir at -78 ° C for 30 min. The mixture was then added to freshly dried ZnCl2 solid preparation (139 mg, 0.80 mmol, 8.5 equivalents) by means of a cannula and the resulting mixture was allowed to warm to 23 ° C (during the addition the yellow color disappears). After 30 min at 23 ° C the mixture was added to a mixture of 6- (4-Benzyloxy-3-methoxy-phenyl) -3-iodo-1- (2,4,6-trimethyl-benzenesulfonyl) -1<i>H</i>-indazol (60 mg, 0.094 mmol, 1 equivalent) and Pd (PPh3) 4 (6 mg, 0.005 mmol, 0.05 equivalent) by means of a cannula. The resulting solution is left under stirring for 16 h. Hydrogen carbonate of saturated sodium and the mixture was partitioned between hydrogen carbonate of saturated sodium (15 mL) and ethyl acetate (15 mL). The material The organic was dried over sodium sulfate, decanted and concentrated. Purification by silica gel column chromatography (ethyl acetate-hexane 1: 9-2: 8) it gave 6- (4-Benzyloxy-3-methoxyphenyl) -3-naphthalen-2-yl-1- (2,4,6-trimethyl-benzenesulfonyl) -1<i>H</i>-indazol in the form of a solid (42 mg, 70%): R f sm = 0.4, p = 0.4 (ethyl acetate-hexane 3: 7); 1 HRMN (CDCl3) δ: 8.44 (s, 1H), 8.41 (s, 1H), 8.12 (d, 1H,<i>J</i> = 8 Hz), 8.05-7.00 (m, 17H), 5.30 (s, 2H), 4.02 (s, 3H), 2.80 (s, 3H), 2.34 (s, 3H).

6- (4-Benzyloxy-3-methoxy-phenyl) -3-iodo-1- (2,4,6-trimethylbenzenesulfonyl) -1<i>H</i>-indazol it was prepared in a manner similar to that described in the Example of reference 1 (a), steps (i) to (v).

<figref>23</figref>

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6- (4-Benzyloxy-3-methoxy-phenyl) -3-naphthalen-2-yl-1- (2,4,6-trimethylbenzenesulfonyl) -1<i>H</i>-indazol became 6- (4-benzyloxy-3-methoxy-phenyl) -3-naphthalen-2-yl-1<i>H</i>-indazol as described in Reference Example 1 (a), step (ix). R<i>F</i> sm = 0.40, p = 0.17 (acetate ethyl hexane 3: 7); 1 HRMN (CDCl 3) δ: 8.40 (s, 1H), 8.12 (d, 1H, <i>J</i> = 8.5 Hz), 8.10 (dd, 1H,<i>J</i> = 1.6, 8.4 Hz), 7.93 (d, 1H, <i>J</i> = 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, 1 HOUR, <i>J</i> = 2.0 Hz), 7.08 (dd, 1H, <i>J</i> = 2.1, 8.3 Hz), 6.91 (d, 1H, <i>J</i> = 8.3 Hz), 5.16 (s, 2H), 3.91 (s, 3H).

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Reference Example 2 (b)

3-phenyl-6- (3-methoxy-4-hydroxy-phenyl) -1

H

-indazol

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<figref>24</figref>

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The compound of the Reference Example 2 (b) was prepared in a manner similar to that described in the Example of reference 2 (a), except that, in step (i), was used phenyl lithium instead of 2-Naphthyl-lithium obtained from 2-bromonaphthylene. 1 HRMN (300 MHz, CDCl 3) δ: 7.87 (d, 1H), 7.83 (d, 2H), 7.55-7.27 (m, 5H), 7.01 (m, 2H), 6.80 (d, 1H), 3.83 (s, 3H). MS (ES) [M + H] / z Calculated 317, found 317, [MH] / z Calculated 315, found 315.

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Reference Example 2 C)

3- (3,4,5-trimethoxyphenyl) -6- (3-methoxy-4-hydroxy-phenyl) -1

H

-indazol

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<figref>25</figref>

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The compound of the Reference Example 2 (c) was prepared in a manner similar to that described in the Example of reference 2 (a), except that, in step (i), was used 3,4,5-trimethoxyphenyl bromide instead of 2-bromonaphthylene. R f sm = 0.67, p = 0.38 (ethyl acetate-hexane 8: 2); 1 H NMR (CDCl3) δ: 7.93 (d, 1H, <i>J</i> = 8 Hz), 7.58 (s, 1 H), 7.39 (d, 1 H, <i>J</i> = 8 Hz), 7.10 (m, 4H), 6.92 (d, 1H, <i>J</i> = 8 Hz), 3.90 (s, 9H), 3.85 (s, 3H); MS (ES) [M + H] / z Calculated 407, found 407, [MH] / z Calculated 405, found 405

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Reference Example 2 (d)

3-(1

H

-indole-2-yl) -6- (3-methoxy-4-hydroxy-phenyl) -1

H

-indazol

<figref>26</figref>

The compound of the Reference Example 2 (d) was prepared in a manner similar to that described in the Example of reference 2 (a) above, except that, in step (i), 1-phenylsulfonyl-indazole was used in place of 2-bromonaphthylene. R_ {sm} = 0.20, p = 0.15 (ethyl acetate-hexane 4: 6); 1 HRMN (CDCl 3) δ: 10.0 (wide s, 1H), 9.05 (wide s, 1H), 8.01 (d, 1H, <i>J</i> = 8.0 Hz), 7.55 (d, 1H, <i>J</i> = 8.0 Hz), 7.49 (s, 1H), 7.37 (d, 1H, <i>J</i> = 8 Hz), 7.29 (d, 1H, <i>J</i> = 8 Hz), 7.2-7.1 (m, 5H), 6.92 (d, 1H, <i>J</i> = 8 Hz), 5.63 (broad s, 1H); MS (ES) [M + H] / z Calculated 356, found 356; [MH] / z Calculated 354, found 354.

Reference Example 2 (e)

3- (benzofuran-2-yl) -6- (3-benzyloxy-4-hydroxy-phenyl) -1

H

-indazol

<figref>27</figref>

The compound of the Reference Example 2 (e) was prepared in a manner similar to that described in the Example of reference 2 (a) above, except that, in step (i), Benzofuran was used instead of 2-bromonaphthylene. 1 HRMN (CDCl3) δ: 8.21 (d, 1H, <i>J</i> = 8.0 Hz), 7.60 (m, 3H), 7.30-7.10 (m, 12H), 7.01 (d, 1H,<i>J</i> = 8 Hz), 5.82 (wide s, 1H), 5.15 (s, 3H).

Reference Example 3

3-(1

H

-indole-2-yl) -6- (3-methoxy-4-hydroxy-phenyl) -1

H

-indazol

<figref>28</figref>

3-(1<i>H</i>-Benzoimidazol-2-yl) -6- (3-methoxy-4-methoxymethoxy-phenyl) -1<i>H</i>-indazol became 4- [3- (1<i>H</i>-benzoimide- zol-2-il) -1<i>H</i>-indazol-6-yl] -2-methoxy-phenol according to the procedure described in the Example of reference 1 (a) (3.5 mg, 28%). HRMS [bombardment with atoms fast (abbreviated FAB, from English <i>Fast atom Bombardment</i>) [M + H] / z Calculated 357.1351, found 357,1349.

The starting material was prepared as follow:

<figref>29</figref>

6- (3-Methoxy-4-methoxymethoxy-phenyl) -1<i>H</i>-indazol-3-carbaldehyde (from Reference Example 1 (a), step (vi)) (20 mg, 0.064 mmol, 1 equivalent) was dissolved in 1: 1 MeOH-water degassed (0.7 mL) and treated with acetic acid (19 µL, 5 equivalent), 1,2-diaminobenzene (8.3 mg, 1.2 equivalent) and copper (II) acetate (18 mg, 1.4 equivalent) at 23 ° C. The stirred mixture for 30 min, was diluted with ethanol (3 mL) and water (2 mL) and treated with a stream bubbling of SH2 for 3 min, which provided a black precipitate The mixture was allowed to stir for 12 h. The mixture was filtered and concentrated. Purification by chromatography silica gel column (ethyl acetate-hexane 6: 4) gave 3- (1<i>H</i>-benzoimidazol-2-yl) -6- (3-methoxy-4-methoxymethoxy-phenyl) -1<i>H</i>-indazol in the form of a solid (14 mg, 54%); R<i>F</i> sm = 0.39, p = 0.24 (ethyl acetate-hexane 6: 4); 1 HRMN (CDCl 3) δ: 8.69 (d, 1H, <i>J</i> = 8Hz), 7.70 (s wide, 2H), 7.58 (s, 1H), 7.53 (d, 1H, <i>J</i> = 8 Hz), 7.30-7.15 (m, 7H), 5.30 (s, 2H), 3.97 (s, 3H), 358 (s, 3H); MS (ES) [M + H] / z Calculated 401, found 401, [MH] / z Calculated 399, found 399.

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Reference Example 4 (a)

N

- [3- (3-styryl-1

H

-indazol-6-yloxy) -phenyl] -benzamide

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<figref>30</figref>

A solution of<i>N</i>- [3- (2-Benzoyl-3-styryl-1<i>H</i>-indazol-6-yloxy) -phenyl] -benzamide (0.09 g, 0.17 mmol) in 2 mL of 6N HCl (aqueous) and 3 mL of MeOH were heated at 65 ° C for approximately 4 h. The cooled solution is Poured cautiously over saturated hydrogen carbonate solution of sodium. The precipitate was filtered, collected and chromatographed. on silica gel eluting with hexanes / EtOAc (1: 1). It was obtained<i>N</i>- [3- (3-styryl-1<i>H</i>-indazol-6-yloxy) -phenyl] -benzamide in the form of a beige solid (32 mg, 50%): 1 HRMN (DMSO-d_ {6}) δ: 13.50 (s, 1H), 10.32 (s, 1H), 8.23 ​​(d, 1H, <i>J</i> = 8.7 Hz), 7.92 (d, 2H, <i>J</i> = 6.8 Hz), 7.72 (d, 2H, <i>J</i> = 7.3 Hz), 7.71-7.51 (m, 7H), 7.51-7.47 (m, 3H), 7.30 (t, 1H, <i>J</i> = 7.2 Hz), 7.05 (s, 1H), 7.01 (d, 1H, <i>J</i> = 8.7 Hz), 6.86 (dd, 1H, <i>J</i> = 8.2, 2.3 Hz). Anal. Calc. For C 28 H 21 N 3 O 2 • 0.3 H 2 O: C, 76.97; H 4.98; N, 9.62. Found: C, 76.94; H, 5.13; N, 9.40.

The starting material was prepared as follow:

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<figref>31</figref>

A suspension of 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 mixture of cooled reaction was filtered and concentrated under reduced pressure. He residue was chromatographed on silica gel eluting with hexanes / EtOAc (2: 1). In this way, it was obtained 3- [3- (benzhydrylidene-amino) -phenoxy] -cyclohex-2-enone in the form of a yellow solid, (8.82 g, 63%): 1 HRMN (CDCl 3) δ: 7.78 (d, 2H, <i>J</i> = 7.0 Hz), 7.50 (d, 1 HOUR, <i>J</i> = 7.1 Hz), 7.45 (d, 2H, <i>J</i> = 7.7 Hz), 7.34-7.10 (m, 6H), 6.69 (d, 1H, <i>J</i> = 8.0 Hz), 6.61 (d, 1H, <i>J</i> = 8.0 Hz), 6.38 (s, 1H), 4.89 (s, 1H), 2.55 (t, 2H, <i>J</i> = 6.2 Hz), 2.34 (t, 2H, <i>J</i> = 6.2 Hz), 2.06 (m, 2H). Anal. Calc. For C 25 H 21 NO 2 • 0.2H 2 O: C, 80.92; H, 5.81; N, 3.78. Found: C, 81.12; H, 5.81; N, 3.72.

Was prepared 3- (benzhydrylidene-amino) -phenol as continue: a stirred solution of benzophenone-imine (15.0 g, 82.8 mmol) and 3-aminophenol (9.03 g, 82.8 mmol) in 25 mL of toluene was heated to reflux with removal of H_ {2} Or with a Dean-Stark trap for 3.5 h. The crystals that formed in the cooled reaction mixture were collected by vacuum filtration, washed with hexanes and air dried. In this way, it was obtained 3- (benzhydrylidene-amino) -phenol in form of a light yellow solid (17.3 g, 76%): 1 HRMN (CDCl 3) δ: 7.64 (d, 2H, <i>J</i> = 7.1 Hz), 7.38 (d. 1 HOUR, <i>J</i> = 7.1 Hz), 7.34-7.15 (m, 7H), 7.04 (d, 2H, <i>J</i> = 7.2 Hz), 6.88 (t, 1H, <i>J</i> = 8.1 Hz), 6.82 (d, 1 HOUR, <i>J</i> = 8.2 Hz), 6.23 (s, 1H), 6.21 (d, 1H, <i>J</i> = 7.8 Hz) Anal. Calc. For C 19 H 15 NO: C, 83.49; H, 5.53; N, 5.12. Found: C, 83.51; H, 5.65; N, 5.03.

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<figref>1032</figref>

<figref>32</figref>

A solution of 3- [3- (benzhydrylidene-amino) -phenoxy] -cyclohex-2-enone (4.37 g, 11.89 mmol) in 20 mL of THF was added slowly to a LiHMDS solution (25.0 mL of 1.0M solution in THF) in 10 mL of THF at -78 ° C. Five minutes after the addition is complete, added trans-cinnamoyl chloride at one time (1.98 g, 11.89 mmol) and stirring was continued at -78 ° C for 30 min. The reaction stopped abruptly adding to the mixture a saturated NH4Cl solution and extracted with EtOAc (2x). The The combined organic layers were washed with saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. He residue was chromatographed on silica gel eluting with hexanes / EtOAc (5: 1). In this way, it was obtained 3- [3- (benzhydrylidene-amino) -phenol] -6- (3-phenyl-acryloyl) -cyclohex-2-enone in the form of a yellow-orange solid (3.34 g, 56%): 1 HRMN (CDCl 3) δ: 15.69 (s, 1H), 7.80 (d, 2H, <i>J</i> = 7.1 Hz), 7.63-7.01 (m, 15H), 6.93 (d, 1 H, <i>J</i> = 15.6 Hz), 6.75 (d, 1H, <i>J</i> = 7.6 Hz), 6.66 (d, 1 H, <i>J</i> = 8.0 Hz), 6.46 (s, 1H), 4.92 (s, 1H), 2.85 (t, 2H, <i>J</i> = 7.2 Hz), 2.62 (t, 2H, <i>J</i> = 7.2 Hz). Anal. Calcd. For C 34 H 27 NO 3: C, 82.07; H, 5.47; N, 2.82. Found: C, 81.88; H, 5.53; N, 2.81.

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<figref>33</figref>

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 (1: 1) was added hydrazine hydrate (2.0 mL, 41.23 mmol). The solution was heated to 75 ° C for 25 min. After cooling, the reaction mixture was poured cautiously over a saturated solution of sodium hydrogen carbonate and extracted with EtOAc (2x). Layers The combined organics were washed with saturated NaCl solution, dried (MgSO 4) and concentrated under reduced pressure. The residue chromatographed on silica gel eluting with hexanes / EtOAc (1: 1). It was obtained 3- (3-Styryl-4,5-dihydro-1<i>H</i>-indazol-6-yloxy) -phenylamine in the form of a yellow solid (539 mg, 45%). 1 H NMR (DMSO-d_ {6}) δ: 7.55 (d, 2H, <i>J</i> = 7.2Hz), 7.38 (t, 2H, <i>J</i> = 7.2 Hz), 7.27 (t, 1H, <i>J</i> = 7.2 Hz), 7.05 (m, 3H), 6.38 (d, 1H, <i>J</i> = 8.0 Hz), 6.31 (s, 1H), 6.23 (d, 1H, <i>J</i> = 7.9 Hz), 5.52 (s, 1H), 5.26 (s, 2H), 2.92 (t, 2H, <i>J</i> = 8.0 Hz), 2.58 (t, 2H, <i>J</i> = 8.1 Hz). Anal. Calcd. For C 21 H 19 N 3 O 3 0.3 H 2 O: C, 75.33; H, 5.90; N, 12.55. Found: C, 75.46; H, 5.96; N, 12.35.

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<figref>34</figref>

To a stirred solution of 3- (3-Styryl-4,5-dihydro-1<i>H</i>-indazol-6-yloxy) -phenylamine (50 mg, 0.15 mmol) and <i>N, N</i>-diisopropylethylamine (54 µL, 0.31 mmol) in 5 mL of CH2Cl2, benzoyl (36 µL, 0.31 mmol). After 15 min, the mixture of reaction was diluted with CH2Cl2 and washed sequentially with 0.5N HCl, saturated sodium hydrogen carbonate solution and brine, dried (MgSO4) and concentrated under pressure reduced To a stirred solution of the residue in 1,4-dioxane was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (35 mg, 0.15 mmol). After 1 h, the reaction mixture is concentrated under reduced pressure and the residue was chromatographed on silica gel eluting with hexanes / EtOAc (2: 1). In this way, it prepared<i>N</i>- [3- (2-Benzoyl-3-styryl-1<i>H</i>-indazol-6-yloxy) -phenyl] -benzamide in the form of a solid colored tile (90 mg, yield almost quantitative): 1 HRMN (CDCl 3) δ: 8.13 (s, 1H), 8.02 (d, 2H, <i>J</i> = 7.0 Hz), 7.94 (d, 1H, <i>J</i> = 8.7 Hz), 7.74 (d, 2H, <i>J</i> = 6.8 Hz), 7.57-7.19 (m, 17H), 6.84 (d, 1H, <i>J</i> = 8.3 Hz).

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Reference Example 4 (b)

N

- [3- (3-styryl-1

H

-indazol-6-yloxy) -phenyl] -acetamide

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<figref>35</figref>

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The compound of the Reference Example 4 (b) was prepared in a manner similar to that described in the Example of reference 4 (a) above, except that, in step (iv), acetic anhydride was used instead of benzoyl chloride. 1 HRMN (DMSO-d 6) δ: 13.08 (s width, 1H), 10.03 (s, 1H), 8.22 (d, 1H, <i>J</i> = 8.7 Hz), 7.72 (d, 2H, <i>J</i> = 7.3 Hz), 7.52 (s, 2H), 7.44-7.27 (m, 6H), 7.01 (s, 1H), 6.96 (dd, 1H, <i>J</i> = 8.7, 2.1 Hz), 6.78 (d, 1 HOUR, <i>J</i> = 6.9 Hz), 2.01 (s, 3H). Anal. Calc. For C 23 H 19 N 3 O 2 • 0.25 H 2 O: C, 73.88; H 5.26; N, 11.24. Found: C, 74.20; H, 5.57; N, 10.82.

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Reference Example 5 (a)

{3- (3-styryl-1

H

-indazol-6-yloxy) -phenyl] -amide of the acid 5-methyl-thiazol-2-carboxylic

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<figref>36</figref>

A suspension of {3- [1- (5-methylthiazol-2-carbonyl) -3-styryl-1<i>H</i>-indazol-6-yloxy-phenyl} amide of the acid 5-methyl-thiazol-2-carboxylic (57 mg, 0.10 mmol) and potassium carbonate (50 mg, 0.36 mmol) in MeOH stirred at 23 ° C for 20 min. The solution was filtered, diluted with EtOAc and washed with brine (2x). The organic layer was dried (MgSO 4) and concentrated under reduced pressure. In this way, he prepared {3- (3-styryl-1<i>H</i>-indazol-6-yloxy) -phenyl] -amide of the acid 5-methyl-thiazol-2-carboxylic in the form of a solid tan color with a yield of 47% .: 1 HRMN (DMSO-d 6) δ: 13.00 (s, 1H), 10.80 (s, 1H), 8.23 ​​(d, 1H, <i>J</i> = 8.8 Hz), 7.79 (s, 2H), 7.71 (t, 2H, <i>J</i> = 8.6 Hz), 7.53 (s, 2H), 7.41-7.27 (m, 5H), 7.04 (s, 1H), 7.00 (d, 1H, <i>J</i> = 8.7 Hz), 6.89 (d, 1 HOUR, <i>J</i> = 8.5 Hz), 2.54 (s, 3H). Anal. Calc. For C 26 H 20 N 4 O 2 S • 1.15 H 2 O: 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 follow:

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<figref>37</figref>

3- (3-Styryl-4,5-dihydro-1H-indazol-6-yloxy) -phenylamine became {3- [1- (5-methyl-thiazol-2-carbonyl) -3-styryl-1<i>H</i>-indazol-6-yloxy-phenyl} amide of the acid 5-methyl-thiazol-2-carboxylic by acid treatment 5-methyl-thiazol-2-carboxylic and HATU (hexafluorophosphate from o- (2-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium) in DMF and treatment with DDQ and isolation analogous to the Example 4 (a), step (iv) (50% yield): 1 HRMN (DMSO-d 6) δ: 10.85 (s, 1H), 8.45 (d, 1H, <i>J</i> = 9.8 Hz), 8.24 (m, 3H), 7.99-7.62 (m, 6H), 7.54-7.34 (m, 5H), 6.96 (d, 1H, <i>J</i> = 8.5 Hz), 2.64 (s, 3H), 2.54 (s, 3H).

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Reference Example 5 (b)

3-methyl-

N

- [3- (3-styryl-1

H

-indazol-6-yloxy) -phenyl] -benzamide

<figref>38</figref>

The compound of the Reference Example 5 (b) was prepared in a manner similar to that described in the Example of reference 5 (a) above, except that, in step (i), Chloride was used <i>m</i>-tolyl instead of acid 5-methyl-thiazol-2-carboxylic and HATU. 1 HRMN (DMSO-d 6) δ: 13.04 (s, 1H), 10.28 (s, 1H), 8.23 ​​(d, 1H, <i>J</i> = 8.8 Hz), 7.73-7.30 (m, 14 H), 7.05 (s, 1H), 6.99 (d, 1H,<i>J</i> = 8.5 Hz), 6.87 (d, 1H, <i>J</i> = 7.7 Hz), 2.38 (s, 3H). Anal. Calc. For C_ {29} H_ {23} N_ {3} O2 {\ cdot0,2 H 2 O • 0.2 hexanes: C, 77.78; H, 5.66; N, 9.01. Found: C, 77.80; H, 5.84; N, 8.93.

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Reference Example 6 (a)

N

- (3- {3- [2- (4-chloro-phenyl) -vinyl] -1

H

-indazol-6-yloxy] -phenyl) -benzamide

<figref>39</figref>

From<i>N</i>- (3- {1-benzoyl-3- [2- (4-chloro-phenyl) -vinyl] -1<i>H</i>-indazol-6-yloxy} -phenyl) -benzamide, the general procedure of the Reference Example was used 5 (a) to prepare the title compound in the form of a off-white solid with a yield of 72%: 1 HRMN (DMSO-d_ {6}) δ: 13.07 (s, 1H), 10.32 (s, 1H), 8.24 (d, 1H, <i>J</i> = 8.8 Hz), 7.92 (d, 2H, <i>J</i> = 7.1 Hz), 7.76 (d, 2H, <i>J</i> = 8.5 Hz), 7.59-7.40 (m, 10H), 7.05 (s, 1H), 7.00 (d, 1H, <i>J</i> = 8.7 Hz), 6.87 (d, 1H,<i>J</i> = 7.9 Hz). Anal. Calc. For C 28 H 20 ClN 3 O 2 \ 0.4 H 2 O \ 0.15 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 follow:

<figref>1040</figref>

<figref>40</figref>

From 3- [3- (benzhydrylidene-amino) -phenoxy] -cyclohex-2-enone and chloride of 3- (4-Chloro-phenyl) -acryloyl (prepared as described below), the general procedure of Reference Example 4 (a), step (ii). The product was used without purification in the process of hydrazine cyclization, Reference Example 4 (a) step (iii), obtaining 3- {3- [2- (4-chlorophenyl) -vinyl] -4,5-dihydro-1<i>H</i>-indazol-6-yloxy} -phenylamine in the form of a yellow solid with a yield of 30%. 1 HRMN (DMSO-d 6) δ: 12.45 (s, 1H), 7.58 (d, 2H, <i>J</i> = 8.5 Hz), 7.43 (d, 2H, <i>J</i> = 8.5 Hz), 5.52 (s, 1H), 5.26 (s, 2H), 2.92 (t, 2H, <i>J</i> = 8.0 Hz), 2.58 (t, 2H, <i>J</i> = 8.0 Hz). Anal. Calc. For C 21 H 18 CIN 3 O • 0.75 H 2 O: C, 66.84; H, 5.21; N, 11.14. Found: C, 66.73; H, 4.89; N, 11.01.

Chloride 3- (4-Chloro-phenyl) -acryloyl It was prepared as follows: to a stirred suspension of acid 4-chloro-<i>trans</i>-cinamic (2.51 g, 13.77 mmol) in benzene thionyl chloride (1.1 mL, 15.14 mmol) was added and a catalytic amount of DMAP. The reaction mixture was heated to reflux for 1.5 h. Volatile materials separated under reduced pressure The white residue was dissolved in Et2O and was concentrated again under reduced pressure, obtaining 3- (4-Chloro-phenyl) -acryloyl (2.78 g, quantitative yield) in the form of a white solid: 1 HRMN (CDCl3) δ: 7.81 (d, 1H, <i>J</i> = 15.6 Hz), 7.54 (d, 2H, <i>J</i> = 8.6 Hz), 7.44 (d, 2H, <i>J</i> = 8.6 Hz), 6.65 (d, 1H, <i>J</i> = 15.6 Hz).

<figref>41</figref>

3- {3- [2- (4-Chloro-phenyl) -vinyl] -4,5-dihydro-1<i>H</i>-indazol-6-yloxy} -phenylamine became<i>N</i>- (3- {1-benzoyl-3- [2- (4-chloro-phenyl) -vinyl] -1<i>H</i>-indazol-6-yloxy} -phenyl) -benzamide by the procedure described in the Reference Example 4 (a), step (iv) (85% yield). 1 HRMN (DMSO-d_6) δ: 10.37 (s, 1H), 8.43 (d, 1 HOUR, <i>J</i> = 8.8 Hz), 8.00-7.39 (m, 21H), 7.34 (d, 1 HOUR, <i>J</i> = 8.8 Hz), 6.93 (d, 1H, <i>J</i> = 8.8 Hz).

Reference Example 6 (b)

N

- {3- [3- (2-indolil) -1

H

-indazol-6-yloxy] -phenyl} -3-methyl-benzamide

<figref>42</figref>

The compound of the Reference Example 6 (b) was prepared in a manner similar to that described in the Example of reference 6 (a) above, except that, in step (i), acid was used 1-SEM-indazol-2-carboxylic instead of 4-chloro acid<i>trans</i>-Cramic 1 HRMN (DMSO-d 6) δ: 13.19 (s, 1H), 11.59 (s, 1H), 10.29 (s, 1H), 8.23 ​​(d, 1H, <i>J</i> = 8.7 Hz), 7.73-7.38 (m, 9H), 7.12 (s, 1H), 7.03 (d, 2H,<i>J</i> = 7.3 Hz), 6.88 (d, 1H, <i>J</i> = 7.8 Hz), 2.38 (s, 1 H). HRMS [M + H] / z Calculated: 459.1821, found: 459.1836.

Reference Example 7

3- (sterile-

1 HOUR

-indazol-6-yloxy) -phenylamine

<figref>43</figref>

A suspension of 3- (3-Styryl-4,5-dihydro-1<i>H</i>-indazol-6-yloxy) -phenylamine (75 mg, 0.23 mmol) and 90 mg of 5% palladium on carbon (Pd / C) is heated to 155 ° C. After 4 h, more 5% Pd / C (39 mg) was added. After 22 h, more 5% Pd / C (30 mg) was added. The mixture of reaction was filtered hot after 26 h. The catalyst is washed and the filtrate was concentrated under reduced pressure. The residue is chromatographed on silica gel eluting with hexanes / EtOAc (1: 1). The appropriate fractions were concentrated and crushed with CH 2 Cl 2 / hexanes obtaining the title compound in Form of an off-white solid (20 mg, 27%): 1 HRMN (DMSO-d_ {6}) δ: 8.16 (d, 1H, <i>J</i> = 8.5 Hz), 7.71 (d, 2H, <i>J</i> = 6.7 Hz), 7.50 (s, 2H), 7.40 (t, 2H,<i>J</i> = 7.0 Hz), 7.30 (d, 1H, <i>J</i> = 6.5 Hz), 7.06-6.92 (m, 3H), 6.35 (d, 1H, <i>J</i> = 8.3 Hz), 6.23 (s, 2H), 5.26 (s, 2H). Anal. Calc. For C 21 H 17 N 3 O • 0.15 CH 2 Cl 2: C, 74.69; H 5.13; N, 12.36. Found: C, 74.64; H, 5.23; N, 12.25.

Reference Example 8 (a)

3- (E-styryl) -6-phenoxy-

1 HOUR

-indazol

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<figref>44</figref>

A suspension of 3- (E-styryl) -6-phenoxy-4,5-dihydro-1<i>H</i>-indazol (200 mg, 0.64 mmol) and 5% Pd / C (200 mg) in 10 mL of tetralin heated at 155 ° C for 18 h. The catalyst was separated by filtering the hot solution and washed with THF. EtOAc and MeOH. The filtrate is concentrated under reduced pressure and the residue was chromatographed on silica gel eluting with hexanes / EtOAc (2: 1) obtaining 3- (E-styryl) -6-phenoxy-1<i>H</i>-indazol in the form of an off-white solid (110 mg, 55%). 1 HRMN (DMSO-d6) δ: 6.96 (s, 2H), 7.10 (d, 2H, <i>J</i> = 7.7 Hz), 7.20 (t, 1H, <i>J</i> = 7.1 Hz), 7.30 (t, 1H,<i>J</i> = 7.1 Hz), 7.44 (m, 6H), 7.71 (d, 2H, <i>J</i> = 7.5 Hz), 8.20 (d, 1 H, <i>J</i> = 9.2 Hz), 12.90 (s, 1H). Anal. Calc. For C 21 H 16 N 2 O • 0.1 H 2 O: C, 80.28; H, 5.20; N, 8.92. Found: C, 80.20; H, 5.21; N, 8.93.

The starting material was prepared as follow:

(i) To a stirred solution of 3-chloro-cyclohex-2-enone (3.00 g, 23.0 mmol) and phenol (2.16 g, 23.0 mmol) in 25 mL of acetone Anhydrous powdered K2CO3 (3.81 g, 27.6 mmol) was added. After refluxing for 18 h, the mixture was cooled and filter. The filtrate was concentrated under reduced pressure and was chromatographed on silica gel eluting with hexanes / EtOAc (4: 1) getting 3-phenoxy-cyclohex-2-enone in the form of a white solid: 1 HRMN (CDCl 3) δ: 2.10 (quintete, 2H, <i>J</i> = 6.3 Hz), 2.40 (t, 2H, <i>J</i> = 6.2 Hz), 2.68 (t, 2H, <i>J</i> = 6.3 Hz), 5.14 (s, 1H), 7.05 (d, 2H,<i>J</i> = 7.5 Hz), 7.26 (t, 1H, <i>J</i> = 7.3 Hz), 7.41 (t, 2H,<i>J</i> = 7.6 Hz).

(ii) A solution of 3-phenoxy-cyclohex-2-enone (301 mg, 1.6 mmol) in 1 mL of THF was added to a stirred solution of 1.0M solution of lithium bis (trimethylsilyl) amide in THF (3.2 mL) at -78 ° C. After 15 min, it was added at once cinnamoyl chloride (266 mg, 1.6 mmol). After 15 min, the reaction mixture was poured onto 0.5N HCl and extracted with EtOAc (2x). The combined organic layers were washed with saturated solution NaCl, dried (MgSO4), filtered and concentrated under pressure reduced Chromatography of the residue with hexanes / ethyl acetate 4: 1 as eluent provided 220 mg (43%) of 3-phenoxy-6- (3-phenyl-acryloyl) -cyclohex-2-enone in the form of a yellow solid (220 mg, (43%): 1 H NMR (CDCl 3) (enol form) δ: 2.66 (t, 2H, <i>J</i> = 7.2 Hz), 2.84 (t, 2H, <i>J</i> = 7.1 Hz), 5.11 (s, 1H), 6.86 (d, 1H,<i>J</i> = 15.6 Hz), 7.02 (d, 2H, <i>J</i> = 8.1 Hz), 7.20 (m, 2H), 7.28-7.38 (m, 3H). HRMS M + H + calculated: 319.1334, found: 319.1340.

(iii) To a stirred solution of 3-phenoxy-6- (3-phenyl-acryloyl) -cyclohex-2-enone (1.13 g, 3.55 mmol) in 20 ml HOAc / EtOH (1: 1) was added Hydrazine monohydrate (0.21 mL, 4.3 mmol). The reaction mixture is heated at 70 ° C for 3 h, cooled and poured with caution over saturated NaHCO3 solution and extracted with EtOAc (2x). The combined organic layers were washed with saturated solution of NaCl, dried (MgSO 4) and concentrated under reduced pressure. He residue was chromatographed on silica gel eluting with hexanes / EtOAc (2: 1) obtaining 6-phenoxy-3-styryl-4,5-dihydro-1<i>H</i>-indazol (3) in the form of an off-white solid (406 mg, 36%): 1 HRMN (DMSO-d6) δ: 2.64 (t, 2H, <i>J</i> = 8.0 Hz), 2.95 (t, 2H, <i>J</i> = 8.0 Hz), 5.46 (s, 1H), 7.04 (AB, 2H,<i>J</i> = 16.8 Hz), 7.15 (d, 2H, <i>J</i> = 8.1 Hz), 7.25 (m, 2H), 7.42 (m, 4H), 7.55 (d, 2H, <i>J</i> = 7.7 Hz), 12.44 (s, 1 H). Anal. Calc. Pa C 2 H 18 N 2 O • 0.2 H 2 O: C, 79.32; H 5.83, N, 8.81. Found: C, 79.36; H, 5.85; N, 8.84.

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Reference Example 8 (b)

3- (E-styryl) -6- [4- (methoxymethoxy) phenoxy] -1

H

-indazol

<figref>45</figref>

The compound of the Reference Example 8 (b) was prepared in a manner similar to that described in the Example of reference 8 (a) above, except that, in step (i), 4- (methoxymethoxy) phenol was used instead of phenol. 1 HRMN (DMSO-d_ {6}) δ: 12.90 (s, 1H), 8.17 (d, 1 HOUR, <i>J</i> = 8.8 Hz), 7.71 (d, 2H, <i>J</i> = 7.6 Hz), 7.50 (s, 3H), 7.41 (t, 2H, <i>J</i> = 7.6 Hz), 7.31 (d, 1H, <i>J</i> = 7.4 Hz), 7.10 (s, 3H), 6.95 (dd, 1H, <i>J</i> = 8.8, 1.9 Hz), 6.84 (s, 1H), 5.20 (s, 2H), 3.42 (s, 3H). Anal. Calc. For C 23 H 20 N 2 O 3: C, 74.17; H, 5.41, N, 7.52. Found: C, 74.21; H, 5.59; N, 7.46.

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Reference Example 8 (c)

3- (E-styryl) -6-phenylsulfanyl-1

H

-indazol

<figref>46</figref>

The compound of the Reference Example 8 (c) was prepared in a manner similar to that described in the Example of reference 8 (a) above, except that, in step (i), Thiophenol was used instead of phenol. 1 H NMR (DMSO-d_ {6}) δ: 7.29 (d, 1H, <i>J</i> = 8.5 Hz), 7.45-7.59 (m, 9H), 7.67 (s, 2H), 7.86 (d, 2H, <i>J</i> = 7.2 Hz). 8.35 (d, 1H,<i>J</i> = 8.5 Hz), 13.30 (s, 1 HOUR). Anal. Calcd. For C 21 H 16 N 2 S \ 0.25 H 2 O: 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.

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Reference Example 8 (d)

6- (3-Bromo-phenoxy) -3-styryl-1

H

-indazol

<figref>47</figref>

The compound of the Reference Example 8 (d) was prepared analogously to that described in the Example of reference 8 (a) above, except that, in step (i), 3-bromophenol was used instead of phenol. 1 HRMN (DMSO-d_ {6}) δ: 13.08 (s, 1H), 8.23 ​​(d, 1 HOUR, <i>J</i> = 8.8 Hz), 7.72 (d, 2H, <i>J</i> = 7.3 Hz), 7.53 (s, 2H), 7.43-7.35 (m, 4H), 7.30 (t, 2H, <i>J</i> = 7.2 Hz), 7.11 (d, 1H, <i>J</i> = 7.2 Hz), 7.09 (s, 1H), 6.98 (d, 1H,<i>J</i> = 8.8 Hz). Anal. Calcd. For C 21 H 15 BrN 2 O: 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.

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Reference Example 9 (to)

3- (E-styryl) -6- [3-hydroxyphenoxy] -1

H

-indazol

<figref>48</figref>

To a stirred solution of 3- (E-styryl) -6- [3- (methoxymethoxy) phenoxy] -1<i>H</i>-indazol (50 mg, 0.13 mmol) in 5 mL of CH2Cl2 at -25 ° C was added trimethylsilyl bromide (75 µL, 0.57 mmol). After 1.5 h, a saturated solution of NaHCO3 was added and the product was 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 gel silica eluting with hexanes / EtOAc (1: 1) obtaining, after crushing with CH2Cl2 / hexanes, 3- (E-styryl) -6- [3-hydroxyphenoxy] -1<i>H</i>-indazol in the form of an off-white solid (22 mg, 50%): 1 HRMN (DMSO-d6) δ: 6.37 (s, 1H), 6.43 (d, 1H,<i>J</i> = 8.1 Hz), 6.50 (d, 1H, <i>J</i> = 8.1Hz), 6.88 (d, 1H,<i>J</i> = 8.8 Hz), 6.92 (s, 1H), 7.12 (t, 1H, <i>J</i> = 8.1 Hz), 7.24 (t, 1H, <i>J</i> = 7.3 Hz), 7.31 (t, 2H, <i>J</i> = 7.6 Hz), 7.44 (s, 2H), 7.64 (d, 2H, <i>J</i> = 7.5 Hz), 8.12 (d, 1H,<i>J</i> = 8.7 Hz), 9.54 (s, 1H), 12.92 (s, 1H). Anal. Calc. For C 21 H 16 N 2 O 2 • 0.3 H 2 O: 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] -1<i>H</i>-indazol, It was prepared as described in the Reference Example 8 (b).

<figref>49</figref>

1 H NMR (CDCl 3) δ: 3.42 (s, 3H), 5.10 (s, 2H), 6.64 (d, 1H, <i>J</i> = 8.2 Hz), 6.72 (s, 1H), 6.80 (d, 1H, <i>J</i> = 8.3 Hz), 6.98 (s, 1H), 7.00 (d, 1H, <i>J</i> = 8.8 Hz), 7.19-7.38 (m, 5H), 7.53 (m, 3H), 7.92 (d, 1 HOUR, <i>J</i> = 8.9 Hz). Anal. Calc. For C 23 H 20 N 2 O 3: M + H +: 373.1552, found 373.1546.

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Reference Example 9 (b)

3- (E-styryl) -6- [4-hydroxyphenoxy] -1

H

-indazol

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<figref>50</figref>

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The compound of the Reference Example 9 (b) was prepared as Reference Example 9 (a) previous, except that it was used 3- (E-styryl) -6- [4- (methoxymethoxy) phenoxy] -1<i>H</i>-indazol instead of 3- (E-styryl) -6- [3- (methoxymethoxy) phenoxy] -1<i>H</i>-indazol. 1 HRMN (DMSO-d 6) δ: 12.95 (s, 1H), 9.58 (s, 1H), 8.33 (d, 1H, <i>J</i> = 9.0 Hz), 7.89 (d, 2H, <i>J</i> = 7.1 Hz), 7.68 (s, 1H), 7.58 (t, 1H, <i>J</i> = 7.3 Hz), 7.48 (d, 1 H, <i>J</i> = 7.3 Hz), 7.24 (s, 1H), 7.13 (m, 3H), 6.99 (d, 2H, <i>J</i> = 8.8 Hz). HRMS [M + H] / z Calculated: 329.1290. Found: 329.1293. Anal. Calc. For C 21 H 16 N 2 O 2 • 0.35 H 2 O: C, 75.36; H 5.03; N, 8.37. Found: C, 75.35; H, 5.22; N, 8.24.

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Reference Example 10

6- (1-phenyl-vinyl) -3-styryl-1

H

-indazol

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<figref>51</figref>

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It dissolved 6- (1-Phenyl-vinyl) -3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol (16.2 mg, 0.0358 mmol) in THF (0.6 mL) and treated with fluoride tetrabutylammonium (TBAF, 1M in THF, 0.6 mL). The mixture was heated up to 60 ° C under argon for 4 h. The mixture cooled, it neutralized with excess saturated sodium hydrogen carbonate and the Organic material was extracted with ethyl acetate and concentrated. This mixture of 3 compounds (visualized by TLC) was treated with THF-water-TFA (1: 1: 2.4 mL) for 30 min. The mixture was diluted with toluene (20 mL), concentrated, neutralized with excess saturated sodium hydrogen carbonate and the Organic material was extracted with ethyl acetate. The material The organic was dried over sodium sulfate, decanted and concentrated. Purification by silica gel column chromatography (ethyl acetate-hexane 2: 8) gave 6- (1-phenyl-vinyl) -3-styryl-1<i>H</i>-indazol (4.6 mg, 40%): R f sm = 0.62, p = 0.24 (acetate ethyl hexane 3: 7); 1 HRMN (300 MHz, CDCl 3) δ: 7.99 (d, 1H, <i>J</i> = 8.5 Hz), 7.60-7.25 (m, 14H), 5.58 (d, 1H, <i>J</i> = 1.1 Hz), 5.56 (d, 1H, <i>J</i> = 1.1 Hz); HRMS (FAB) [M + H] / z Calculated 323.1548, found 323.1545.

The starting material was prepared as follow:

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<figref>52</figref>

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6-Yodoindazol became 3,6-diiodoindazole (82%) as described in the Reference example 1 (a), step (v): 1 HRMN (300 MHz, CDCl 3) δ: 10.3 (broad s, 1H), 7.90 (s, 1H), 7.52 (dd, 1 HOUR, <i>J</i> = 1.2, 8.5 Hz), 7.24 (d, 1H, <i>J</i> = 8.5 Hz).

<figref>53</figref>

3,6-diiodoindazole (755 was added mg, 2.04 mmol) at 50% KOH (2.5 g in 2.5 mL of water) at 0 ° C and dichloromethane (4 mL) was added. To this mixture was added bromide of tetrabutylammonium (TBABr, 6.6 mg, 0.02 mmol, 0.01 equivalent) and be added dropwise chloride of 2- (trimethyl-silanyl) -ethoxymethyl (SEM-Cl, 397 µL, 2.24 mmol, 1.10 equivalents) over a period of 3 min. The mixture was rapidly stirred 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. Column chromatography on silica gel (acetate 5% ethyl in hexane; 150 mL of silica) gave 2 isomeric compounds (1-SEM, 763 mg, 75%; and 2-SEM, 105 mg, 10%): R<i>F</i> sm = 0.08, p = 0.34 and 0.27 (acetate ethyl hexane 1: 9); 1 HRMN (300 MHz, CDCl 3) δ: 8.0 (s, 1H), 7.55 (d, 1H, <i>J</i> = 8.5 Hz), 7.24 (d, 1 HOUR, <i>J</i> = 8.5 Hz), 5.69 (s, 2H), 3.58 (t, 2H <i>J</i> = 8.2 Hz), 0.90 (t, 2H, <i>J</i> = 8.2 Hz), -0.1 (s, 9H).

<figref>54</figref>

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1-Bromo-styrene was dissolved (26 µL, 0.20 mmol, 2.0 equivalents) in THF (0.75 mL), cooled up to -78 ° C and treated with <i>t</i>-BuLi (235 µL, 0.40 mmol, 1.70M, 4.0 equivalents). 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 equivalents). The resulting solution was left heat to 23 ° C with stirring for 25 min. This mixture is added to a mixture of 3,6-diiodo-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol pure (50 mg, 0.10 mmol, 1 equivalent) and Pd (PPh3) 4 (5 mg, 0.004 mmol, 0.04 equivalent). After 10 min the completion of the TLC reaction and the reaction stopped abruptly adding to the saturated sodium hydrogen carbonate mixture. Organic material it was extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Gel column chromatography of silica (ethyl acetate-hexane 5:95) provided 3-iodo-6- (1-phenyl-vinyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol (33.1 mg, 70%): R f sm = 0.39, p = 0.36 (acetate ethyl hexane 1: 9); 1 HRMN (300 MHz, CDCl 3) δ: 7.50 (s, 1H), 7.42 (d, 1H, <i>J</i> = 8.4 Hz), 7.33 (m, 5H), 7.22 (dd, 1H, <i>J</i> = 1.2, 8.4 Hz), 5.68 (s, 2H), 5.59 (d, 1 HOUR, <i>J</i> = 1.0 Hz), 5.57 (d, 1H, <i>J</i> = 1.0 Hz), 3.58 (t, 2H, <i>J</i> = 8.2 Hz), 0.88 (t, 2H, <i>J</i> = 8.2 Hz), -0.09 (s, 9H); HRMS (FAB) [M + H] / z Calculated 477.0859, found 477.0866.

<figref>55</figref>

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Preparation of 6- (1-Phenyl-vinyl) -3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol: E-2-bromo-styrene was dissolved (23 µL, 0.174 mmol, 2.5 equivalents) in THF (1.0 mL) and cooled to -78 ° C. Was added <i>t</i>-BuLi (205 µL, 0.348 mmol, 5.00 equivalent) and the mixture was heated to -42 ° C for 7 min obtaining a dark red mixture. The solution was added to chloride of freshly dried zinc (29 mg, 0.209 mmol, 3.00 equivalents) per medium of a cannula and the mixture was allowed to warm to 23 ° C with stirring for 20 min. This solution was added to a pure mixture. from 3-iodo-6- (1-phenyl-vinyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol (33.1 mg, 0.0696 mmol, 1.0 equivalent) and Pd (PPh3) 4 (4 mg, 0.0035 mmol, 0.05 equivalent) at 23 ° C by means of a cannula. This solution was left under stirring for 15 min and treated with hydrogen carbonate saturated sodium and extracted with ethyl acetate. The material The organic was dried over sodium sulfate, decanted and concentrated. Purification by silica gel column chromatography using two columns (ethyl acetate-hexane 5:95; 12 mL silica: and ethyl acetate-benzene 1:99; 12 mL of silica) gave 6- (1-Phenyl-vinyl) -3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol (16.2 mg, 51%): R f sm = 0.38, p = 0.29 (acetate ethyl hexane 1: 9); 1 HRMN (300 MHz, CDCl 3) δ: 7.98 (d, 1H, <i>J</i> = 8.4 Hz), 7.62-7.22 (m, 14H), 5.71 (s, 2H), 5.57 (s, 2H), 3.60 (t, 2H, <i>J</i> = 8.2 Hz), 0.90 (t, 2H, <i>J</i> = 8.2 Hz), -0.08 (s, 9H); HRMS (FAB) [M + H] / z Calculated 453.2362, found 453.2354.

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Reference Example eleven

N

-methyl-

N

- (3-styryl-1

H

-indazol-6-yl) -benzene-1,3-diamine

<figref>56</figref>

TO<i>N</i>-methyl-<i>N</i>- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -benzene-1,3-diamine (237 mg, 0.5 mmol) 1M TBAF in THF (10.1 mL, 10.1 was added mmol), followed by ethylenediamine (0.34 mL, 5.04 mmol, 10 equivalent). The resulting mixture was heated to 70 ° C for 5 h. The reaction stopped abruptly adding to the mixture Saturated NaHCO3 (10 mL) and 3x35 mL of EtOAc was extracted. The The combined EtOAc phases were washed 5 x 20 mL of H2O, at then with brine (20 mL), dried with Na2SO4, they were decanted and concentrated under reduced pressure until obtaining a foam The crude material was purified by chromatography on silica gel column (dichloromethane / ethyl acetate 9: 1) getting<i>N</i>-methyl- (3-styryl-1<i>H</i>-indazol-6-yl) -benzene-1,3-diamine in the form of a foam (120 mg, 70% yield). R_ {f} sm = 0.73, R f p = 0.27 (dichloromethane: ethyl acetate 7: 3); 13 CRMN (75 MHz, CDCl 3) 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; low energy magnetic spectrum (abbreviated LEMS, of the English <i>Low Energy Magnetic Spectrum</i>) (ESI) [M + H] / z Calculated 341, found 341. Anal. Calculated: C, 77.62; H, 5.92; N, 16.46. Found: C, 76.16; H, 5.88; N, 15.95.

The starting material was prepared as follow:

<figref>1057</figref>

<figref>57</figref>

6-Nitro-1<i>H</i>-indazol became 3-iodine-6-nitro-1<i>H</i>-indazol as described in Reference Example 1 (a), step (v) (50.6 g, 87%): FTIR (KBr) 3376, 3076, 2964, 2120, 1739, 1626, 1526, 1439, 1294, 1128, 954 cm -1; 1 H NMR (300 MHz, CDCl3) δ: 8.28 (s, 1H), 8.05 (s, 1H), 7.66 (d, 1H,<i>J</i> = 8.13 Hz), 7.45 (dd, 1H, <i>J</i> = 8.33, 1.38 Hz), 7.17 (d, 1H, <i>J</i> = 1.01 Hz), 7.14 (s, 1H), 7.03 (d, 1H, <i>J</i> = 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 Calculated 311, found 311. Anal. Calculated: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.41; H 5.98; N, 8.79.

<figref>58</figref>

3-Iodine-6-nitro-1<i>H</i>-indazol became 6-nitro-3-iodine- [2- (trimethylsilanyl) -ethoxymethyl] -1<i>H</i>-indazol as described in Reference Example 10, step (ii) (10.2 g, 81% yield): mp 58 ° C. Anal. Calculated: C, 37.24; H 4.33; N, 10.02. Found: C, 37.21; H, 4.38; N, 10.00.

<figref>59</figref>

TO 6-nitro-3-iodine- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol (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 argon atmosphere, toluene (192 mL), MeOH (4 mL) was added and 2N NaOH (aqueous) (32.6 mL, 65.3 mmol). The heterogeneous mixture The resulting was heated to 90 ° C. After 8 h the mixture of reaction was diluted with EtOAc (150 mL) and water (50 mL), the phases were separated and the organic material was extracted 2x50 mL of EtOAc. The mixture of the organic phases was washed with brine (50 mL), to It was then dried with Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified. by silica gel column chromatography (EtOAc: hexane 1: 9) getting 6-nitro-3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol in the form of a yellow solid (7.65 g, 74%): 13 CRMN (75 MHz, CDCl 3) δ: 148.3, 145.0, 141.3, 138.1, 134.2, 130.5, 129.9, 129.8, 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 Calculated 418, found 418. Anal. Calculated: C, 63.77; H, 6.37; N, 10.62. Found: C, 64.04; H, 6.29; N, 10.56.

<figref>60</figref>

6-Nitro-3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol (8.1 g, 20.5 mmol) was dissolved in DMF (75 mL) at 23 ° C under a argon atmosphere. SnCl2 (12.9 g, 67.7 mmol) was added followed by water (1.7 mL, 92.2 mmol) and the resulting mixture was heated up to 50 ° C. After 4 h, 3N NaOH (45 mL, 135 mmol) was added followed by EtOAc (100 mL). The resulting emulsion was filtered in warm through Celite and the Celite bed washed with EtOAc hot (3 x 100 mL). The filtrate was concentrated under pressure. reduced, the residue was dissolved in EtOAc, washed with brine, dried with Na2SO4, filtered and concentrated under pressure reduced obtaining a solid. The raw material was purified by silica gel column chromatography (acetate ethyl: hexane 2: 8-7: 3), obtaining 3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-ylamine in the form of a yellow solid (5.1 g, 68% yield). MS (FAB) [M + H] / z Calculated 366, found 366.

<figref>61</figref>

TO 3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-ylamine (1.1 g, 3 mmol, m-nitro-iodobenzene (0.9 g, 3.6 mmol), BINAP (0.07 g, 0.133 mmol), Pd 2 (dba) 3 (34 mg, 0.0375 mmol) and Cs 2 CO 3 (1.37 g, 4.2 mmol) under argon atmosphere is added toluene (6 mL). The resulting heterogeneous mixture was heated up to 80 ° C. After 46 h the reaction mixture was cooled to 23 ° C, diluted with ethyl acetate (EtOAc) (20 mL) and filtered. Water (5 mL) was added, the phases and the organic material were separated It was extracted with 2 x 50 mL of EtOAc. The mix of organic material washed with brine, then dried with Na2SO4, filtered and concentrated under reduced pressure. The mixture of crude reaction was purified by gel column chromatography of silica (eluting with hexane: EtOAc 9: 1) obtaining (3-nitro-phenyl) - {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -amine in the form of a yellow solid (7.65 g, 74%): TLC (Hexane: EtOAc 7: 3) R<i>F</i> sm = 0.16, R<i>F</i> p = 0.30 (acetate ethyl: hexane 3: 7); FTIR (KBr) 3391, 3059, 2952, 2894, 1614, 1530, 1483, 1346, 1248, 1076, 836, 734 cm -1; 1 H NMR (300 MHz, CDCl3) δ: 7.86 (s, 1H), 7.83 (s, 1H), 7.65 (dt, 1H,<i>J</i> = 2.21, 5.13 Hz), 7.15 - 7.41 (m, 5H), 6.93 (dd, 1H,<i>J</i> = 1.87, 8.67 Hz), 5.56 (s, 2H), 3.51 (t, 2H, <i>J</i> = 8.17 Hz), 0.81 (t, 2H, <i>J</i> = 7.96 Hz), -0.15 (s, 9H); 13 CRMN (75 MHz, CDCl 3) 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 + H] / z Calculated 487, found 487. Anal. Calculated: C, 66.64; H, 6.21; N, 11.51. Found: C, 66.91; H 6.21; N, 11.44.

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<figref>62</figref>

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TO (3-nitro-phenyl) - {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -amine (434 mg, 0.89 mmol) in THF (5 mL) cooled to -5 ° C under Argon atmosphere, dimethyl sulfate (0.42 mL, 4.5) was added mmol) followed by LiHMDS (1M in THF) (1.8 mL, 1.8 mmol). After 20 min the reaction mixture stopped abruptly adding to the saturated NH4Cl (aqueous) mixture (2 mL), then extracted 3x20 mL of EtOAc. The mixture of organic materials was washed with brine (10 mL), dried with Na2SO4, decanted and concentrated under reduced pressure. Purification by chromatography on silica gel column (eluting with hexane: EtOAc 9: 1) gave methyl- (3-nitro-phenyl) - {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -amine, in the form of an oil (367 mg, 82%): TLC (Hexane: EtOAc 7: 3) R<i>F</i> sm = 0.29, R<i>F</i> p = 0.39 (ethyl acetate: hexane 3: 7); FTIR (KBr) 2951, 2894, 1611, 1528, 1485, 1348, 1248, 1077 cm -1; 1 H NMR (300 MHz, CDCl 3) δ: 7.99 (d, 1H,<i>J</i> = 8.67 Hz), 7.77 (t, 1H, <i>J</i> = 2.25 Hz), 7.72 (dd, 1H,<i>J</i> = 0.79, 2.09 Hz), 7.60, (d, 2H, <i>J</i> = 7.22 Hz), 7.26-7.54 (m, 7H), 7.19 (dd, 1H, <i>J</i> = 0.78, 2.41 Hz) 7.07 (dd, 1H, <i>J</i> = 1.85, 8.69 Hz), 5.70 (s, 2H), 3.63 (t, 2H, <i>J</i> = 8.10 Hz), 3.48 (s, 3H), 0.92 (t, 2H,<i>J</i> = 8.10 Hz), -0.04 (s, 9H); 13 CRMN (75 MHz, CDCl 3) 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 Calculated 501, found 510.

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<figref>63</figref>

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Methyl- (3-nitro-phenyl) - {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl) -1<i>H</i>-indazol-6-yl} -amine became<i>N</i>-methyl-<i>N</i>- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -benzene-1,3-diamine as described in Reference Example 11, step (iv). R<i>F</i> sm = 0.55, R<i>F</i> p = 0.31 (ethyl acetate: hexane 3: 7); FTIR (thin film) 3455, 3360, 2951, 2893, 1621, 1601, 1494, 1449, 1249, 1074 cm -1; 1 H NMR (300 MHz, CDCl 3) δ: 7.81 (d, 1H, <i>J</i> = 8.8 Hz), 7.58 (d, 2H, <i>J</i> = 7.21 Hz), 7.26-7.50 (m 5H), 7.12 (t, 1H, <i>J</i> = 7.93 Hz), 7.01 (d, 1H, <i>J</i> = 1.73 Hz), 6.95 (dd, 1H, <i>J</i> = 1.99, 8.85 Hz), 5.67 (s, 2H), 3.63 (t, 2H, <i>J</i> = 8.12 Hz), 3.38 (s, 3H), 0.93 (t, 2H, <i>J</i> = 8.13 Hz), -0.04 (s, 9H); 13 CRMN (75 MHz, CDCl 3) δ: 150.3, 149.0, 147.7, 143.4, 143.0, 137.6, 131.3, 130.4, 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 Calculated 471, Found 471.

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Reference Example 12 (a)

N

- {3- [methyl- (3-styryl-1

H

-indazol-6-yl) -amino] -phenyl} -acetamide

<figref>64</figref>

<i>N</i>-Metil-<i>N</i>- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -benzene-1,3-diamine, prepared in Reference Example 11 (34 mg, 0.041 mmol) it was suspended in CH2Cl2 (0.5 mL) at 23 ° C under argon atmosphere. Pyridine (81 µL, 1.0 mmol) was added, Ac2O (94 µL, 1.0 mmol) and DMAP (cat.). The mixture of reaction became homogeneous immediately. After 1 h, the TLC analysis (CH 2 Cl 2: EtOAc 4: 1) did not indicate material of departure. The reaction stopped abruptly adding to the mixture Saturated NaHCO3 (aqueous) (2 mL) and then diluted with EtOAc (15 mL) and the organic phase was washed with brine (3 mL), decanted and concentrated under reduced pressure to form an oil. The oil was suspended in MeOH (2 mL) and added K 2 CO 3 (83 mg, 0.6 mmol). The resulting mixture was stirred at 23 ° C under argon atmosphere. After 1 h, the reaction mixture it was diluted with EtOAc (15 mL) and the organic phase was washed with brine (3 mL), was decanted and concentrated under reduced pressure. The material raw was purified by high liquid chromatography resolution (abbreviated HPLC) <i>High performance Liquid Chromatography)</i> semi-preparative getting<i>N</i>- {3- [methyl- (3-styryl-1<i>H</i>-indazol-6-yl) -amino] -phenyl} -acetamide (8.4 mg, 22%). 1 HRMN (300 MHz, CDCl 3) δ: 7.86 (d, 1 HOUR, <i>J</i> = 8.68 Hz), 7.58 (d, 1H, <i>J</i> = 7.17 Hz), 7.16-7.45 (m, 7H), 7.15 (d, 1H, <i>J</i> = 8.29 Hz), 6.98 (m, 1H), 6.95 (d, 1H, <i>J</i> = 1.92 Hz), 6.8 (dd, 1H,<i>J</i> = 1.16, 8.05 Hz), 3.37 (s, 3H), 2.14 (s, 3H). LCMS (ESI) [M + H] / z Calculated 383, Found 383. Anal. Calculated: C, 75.37; H, 5.80; N, 14.65. Found: C, 73.53; H, 6.01; N, 13.73.

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Reference Example 12 (b)

N

- {3- [methyl- (3-styryl-1

H

-indazol-6-yl) -amino] -phenyl} -benzamide

<figref>65</figref>

The compound of the Reference Example 12 (b) was prepared in a manner similar to that described in the Reference Example 12 (a) above, except that it was used benzoyl chloride instead of acetic anhydride. LCMS (ESI) [M + H] / z Calculated 475, found 475. Anal. Calculated: C (78.36), H (5.44), N (12.60). Found: C (76.57), H (5.50), N (12.12).

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Reference Example 12 (c)

Benzyl Acid Ester {3- [methyl- (3-styryl-1

H

-indazol-6-yl) -amino] -phenyl} -carbamic

<figref>66</figref>

The compound of the Reference Example 12 (c) was prepared in a manner similar to that described in the Reference Example 12 (a) above, except that it was used carbobenzyloxy chloride instead of acetic anhydride. R<i>F</i>sm = 0.30, R<i>F</i> p = 0.57 (CH 2 Cl 2: EtOAc 8: 2); LCMS (ESI +) [M + H] / z Calculated 475, found 475; Anal. Calculated: C (75.93), H (5.52), N (11.81). Found C (75.60), H (5.96), N (10.75).

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Reference Example 12 (d)

{3- [methyl- (3-styryl-1

H

-indazol-6-yl) -amino] -phenyl} -amide of the acid 5-methyl-thiazol-2-carboxylic

<figref>67</figref>

To a solution of<i>N</i>-methyl-<i>N</i>- (3-styryl-1<i>H</i>-indazol-6-yl) -benzene-1,3-diamine, prepared in Reference Example 11, (26 mg, 0.075 mmol) and acid 5-methyl-thiazol-2-carboxylic (64 mg, 0.45 mmol) in DMF (0.375 mL) at 23 ° C under argon HATU (171 mg, 0.45 mmol) was added. After 1 h, the analysis by TLC (CH 2 Cl 2: EtOAc 8: 2) did not indicate starting material. The reaction stopped abruptly adding to the mixture NaHCO 3 (aqueous) saturated (2 mL) and 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 The resulting mixture was stirred at 23 ° C under argon. Then of 1 h TLC analysis (CH 2 Cl 2: EtOAc 8: 2) did not indicate Starting material. The reaction mixture was diluted with EtOAc (15 mL) and the organic phase was washed with brine (3 mL), decanted and concentrated under reduced pressure to obtain a solid. The material crude was purified by silica gel column chromatography (eluting with CH 2 Cl 2: EtOAc 85:15) obtaining the title compound after HPLC purification semi-preparative (9.9 mg, 28%). R<i>F</i> sm = 0.25, R<i>F</i> p = 0.39 (hexane: EtOAc 8: 2); LCMS (ESI +) [M + H] / z Calculated 466, found 466. Anal. Calculated: 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

N

- [3- (3-styryl-1

H

-indazol-6-ylamino) -phenyl] -benzamide

<figref>68</figref>

<i>N</i>- (3- {3-Styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-ylamino} -phenyl) -benzamide became<i>N</i>- [3- (3-styryl-1<i>H</i>-indazol-6-ylamino) -phenyl] -benzamide as described in Reference Example 11. LCMS (ESI) [M + H] / z Calculated 431, found 431. Anal. Calculated: 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 follow:

<figref>69</figref>

(3-Nitro-phenyl) - {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -amine, prepared in Reference Example 11, step (vi), became in<i>N</i>- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -benzene-1,3-diamine as described in Reference Example 11, step (iv). LCMS (ESI) [M + H] / z Calculated 457, found 457.

<figref>70</figref>

To a solution of<i>N</i>- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -benzene-1,3-diamine (91 mg, 0.2 mmol) and pyridine (0.081 mL, 1.0 mmol) in CH 2 Cl 2 (0.5 mL) cooled to -5 ° C under an atmosphere of Argon benzoyl chloride (0.028 mL, 0.24 mmol) was added. Then for 0.5 h the reaction stopped abruptly adding to the mixture Saturated NaHCO3 (aqueous) and then 2 x 5 mL was extracted of CH 2 Cl 2. The mixture of organic materials was washed with brine (5 mL), dried with Na2SO4, decanted and concentrated under reduced pressure to obtain an oil. The material crude was purified by silica gel column chromatography (eluting with hexane: EtOAc 3: 2) obtaining<i>N</i>- (3- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-ylamino} -phenyl) -benzamide (108 mg, 96% yield). R<i>F</i> sm = 0.35, R<i>F</i> 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 Calculated 561, found 561. Anal. Calculated: C, 72.82; H, 6.47; N, 9.99. Found: C, 72.33; H, 6.39; N, 9.81.

Reference Example 14

Methyl-phenyl- (3-styryl-1

H

-indazol-6-yl) -amine

<figref>71</figref>

Methyl-phenyl- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazol-6-yl} -amine became methyl-phenyl- (3-styryl-1<i>H</i>-indazol-6-yl) -amine as described in Reference Example 11. MS (ESI) [M + H] / z Calculated 326, found 326.

The starting material was prepared as follow:

<figref>72</figref>

To a solution of 3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-ylamine (1.58 g, 4 mmol) in AcOH (14 mL), water (3 mL) and concentrated HCl (1.67 mL) cooled to 2 ° C, a solution of NaNO2 was added (304 mg, 4.4 mmol) in water (0.5 mL) for 5 min. The red solution The resulting dark was stirred at 2 ° C for 0.5 h, and then added a solution of KI (797 mg, 4.8 mmol) and I2 dropwise (610 mg, 2.4 mmol) in water (1 mL) so that the internal temperature below 5 ° C. After 2 h at 2 ° C the reaction mixture was allowed to stir at 23 ° C for 17 h. The reaction stopped abruptly by adding 3N NaOH to the mixture (aqueous), diluted with EtOAc (50 mL) and H2O (15 mL), The phases were separated and the aqueous phase was extracted 2 x 15 mL of EtOAc. The organic phase mixture was washed 3 x 20 mL of 5% NaHSO3 and with brine (15 mL), dried with Na2SO4, decanted and It was concentrated under reduced pressure. The raw reaction mixture was purified by silica gel column chromatography (eluting with hexane: EtOAc 1: 1) obtaining 6-iodo-3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol in the form of a white solid (1.3 g, 68% yield). 1 HRMN (300 MHz, CDCl 3) δ: 8.03 (s, 1H), 7.79 (d, 1H, <i>J</i> = 9.0 Hz), 7.30-7.60 (m, 8H), 5.73 (s, 2H), 3.63 (t, 2H, <i>J</i> = 6.0 Hz), 0.96 (t, 2H, <i>J</i> = 6.0 Hz), 0.0 (s, 9); 13 CRMN (75 MHz, CDCl 3) δ: 143.6, 142.4, 137.2, 132.1, 130.8, 129.0, 128.3, 126.8, 122.5, 122.4, 119.6, 119.5, 92.9, 78.1, 66.9, 18.0, -1.2. Anal. Calculated: C, 52.94; H, 5.29; N, 5.88. Found: C, 52.66; H, 5.29; N, 5.74.

<figref>73</figref>

6-Iodine-3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol became methyl-phenyl- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -amine as described in Reference Example 11, step (v). R<i>F</i> sm = 0.35 R<i>F</i> p = 0.13 (EtOAc: hexane 1: 9); IR (KBr) 3031, 2951, 1625, 1595, 1498, 1449, 1326, 1303, 1248, 1212, 1076, 835, 694 cm -1; MS (ESI) [M + H] / z Calculated 456, found 456

Reference Example fifteen

N

- [3- (2-benzo [1,3] dioxol-5-yl-vinyl) -1

H

-indazol-6-il] -

N

-methylbenzene-1,3-diamine

<figref>74</figref>

[3- (2-Benzo [1,3] dioxol-5-yl-vinyl) -1<i>H</i>-indazol-6-yl] -methyl- (3-nitro-phenyl) -amine became<i>N</i>- [3- (2-benzo [1,3] dioxol-5-yl-vinyl) -1<i>H</i>-indazol-6-il] -<i>N-</i>methyl benzene-1,3-diamine as described in Reference Example 11, step (iv). LCMS (ESI) [M + H] / z Calculated 385, found 385. Anal. Calculated: 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 follow:

<figref>75</figref>

To a mixture of 6-nitro-3-iodine- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol (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 Argon atmosphere 1,4-dioxane (38 mL) was added and 2N NaOH (aqueous) (12.5 mL, 25 mmol). The resulting mixture was heated up to 90 ° C. After 2 h the reaction mixture was diluted with EtOAc (100 mL) and water (70 mL), the phases and the phase were separated Organic was extracted 2 X 100 mL of EtOAc. Phase mixing Organic was washed with brine (20 mL) and then dried with Na2SO4, was filtered and concentrated under reduced pressure. The crude mixture was purified by gel column chromatography of silica (eluting with hexane: EtOAc 9: 1) obtaining 3- (2-Benzo [1,3] dioxol-5-yl-vinyl) -6-nitro-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol in the form of a yellow solid (4.15 g, 94% yield). FTIR (thin film) 2950, ​​2898, 1523, 1501, 1483, 1446, 1344, 1249, 1080, 1043, 927 cm -1; 1 HRMN (300 MHz, CDCl 3) δ: 8.56 (dd, 1H, <i>J</i> = 0.68, 1.75 Hz), 8.14 (d, 1H,<i>J</i> = 1.78 Hz), 8.13 (d, 1H, <i>J</i> = 0.67 Hz), 7.50 (d, 1H, 16.53 Hz), 7.25 (d, 1H, 16.52 Hz), 7.18 (d, 1H, <i>J</i> = 1.67 Hz), 7.07 (dd, 1H, <i>J</i> = 1.65, 8.13 Hz), 6.88 (d, 1H, <i>J</i> = 8.0 Hz), 6.05 (s, 2H), 5.84 (s, 2H), 3.66 (t, 2H, <i>J</i> = 7.33 Hz), 0.97 (t, 2H, <i>J</i> = 7.24 Hz), 0.0 (s, 9H); 13 C NMR (75 MHz, CDCl 3) 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 Calculated 531, found 531.

<figref>76</figref>

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3- (2-Benzo [1,3] dioxol-5-yl-vinyl) -6-nitro-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol became 3- (2-Benzo [1,3] dioxol-5-yl-vinyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-ylamine as described in Reference Example 11, step (iv). 1 HRMN (300 MHz, CDCl 3) δ: 7.73 (d, 1H, <i>J</i> = 8.56 Hz), 7.52 (d, 1H, <i>J</i> = 16.57 Hz), 7.18 (d, 1H, <i>J</i> = 16.56 Hz), 7.10 (d, 1H, <i>J</i> = 1.49 Hz), 6.98 (dd, 1H, <i>J</i>= 1.52, 8.06 Hz), 6.80 (d, 1H, <i>J</i> = 8.01 Hz), 6.68 (d, 1H,<i>J</i> = 1.44 Hz), 6.63 (dd, 1H, <i>J</i> = 1.86, 8.57 Hz), 5.95 (s, 2H), 5.59 (s, 2H), 3.59 (t, 2H, <i>J</i> = 8.17 Hz), 0.91 (t, 2H, <i>J</i> = 8.33 Hz), 0.04 (s, 9H); 13 CRMN (75 MHz, CDCl 3) 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 Calculated 410, found 410.

<figref>77</figref>

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3- (2-Benzo [1,3] dioxol-5-yl-vinyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-ylamine became {3- (2-Benzo [1,3] dioxol-5-yl-vinyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} - (3-nitro-phenyl) -amine as described in Reference Example 11, step (v). 13 CRMN (75 MHz, CDCl 3) δ: 150.8, 149.7, 149.1, 146.0, 144.8, 143.6, 142.1, 133.1, 132.7, 131.6, 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 Calculated 531, Found 531. Anal. Calculated: C, 63.38; H, 5.70; N, 10.56. Found: C, 63.49; H, 5.76; N, 10.42.

<figref>78</figref>

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{3- (2-Benzo [1,3] dioxol-5-yl-vinyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} - (3-nitro-phenyl) -amine became {3- (2-Benzo [1,3] dioxol-5-yl-vinyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -methyl- (3-nitro-phenyl) -amine as described in Reference Example 11, step (vi). FTIR (KBr) 2952, 2894, 1612, 1529, 1503, 1489, 1446, 1407, 1348, 1306, 1251, 1077, 1039 cm -1; 13 CRMN (75 MHz, CDCl 3) 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, 113, 108.7, 105.7, 104.5, 101.4, 78.0, 66.8, 41.0, 17.9, -1.2; MS (FAB) [M + H] / z Calculated 545, found 545. Anal. Calculated: C, 63.95; H, 5.92; N, 10.29. Found: C, 62.63; H, 5.72; N, 9.62.

<figref>79</figref>

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{3- (2-Benzo [1,3] dioxol-5-yl-vinyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -methyl- (3-nitro-phenyl) -amine became [3- (2-benzo [1,3] dioxol-5-yl-vinyl) -1<i>H</i>-indazol-6-yl] -methyl- (3-nitro-phenyl) -amine as described in Reference Example 11. LCMS (ESI) [M + H] / z Calculated 415, found 415. Anal. Calculated: C, 66.66; H 4.38; N, 13.52. Found: C, 66.56; H, 4.48; N, 13.35.

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Reference Example 16 (a)

N

- (3 - {[3- (2-benzo [1,3] dioxol-5-yl-vinyl) -1

H

-indazol-6-yl] -methyl-amino} -phenyl) -benzamide

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<figref>80</figref>

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<i>N</i>- [3- (2-Benzo [1,3] dioxol-5-yl-vinyl) -1<i>H</i>-indazol-6-il] -<i>N</i>-methyl-benzene-1,3-diamine (prepared as described in Reference Example 15) is turned into<i>N</i>- (3 - {[3- (2-benzo [1,3] dioxol-5-yl-vinyl) -1<i>H</i>-indazol-6-yl] -methyl-amino} -phenyl) -benzamide in the manner described in Reference Example 12 (a). LCMS (ESI) [M + H] / z Calculated 489, found 489. Anal. Calculated: C, 73.76; H, 4.95; N, 11.47. Found: C, 73.19; H, 5.09; N, 11.20

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Reference Example 16 (b)

N

- (3 - {[3- (2-benzo [1,3] dioxol-5-yl-vinyl) -1

H

-indazol-6-yl] -methyl-amino} -phenyl) -3-methyl-benzamide

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<figref>81</figref>

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The compound of the Reference Example 16 (b) was prepared in a manner similar to that described in the Reference example 16 (a) above, except that it was used chloride <i>m</i>-toluyl instead of benzoyl chloride. LCMS (ESI) [M + H] / z Calculated 504, found 504. Anal. Calculated: C, 74.09; H 5.21; N, 11.15. Found: C, 73.04; H, 5.84; N, 10.29.

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Reference Example 16 (c)

N

- (3 - {[3- (2-benzo [1,3] dioxol-5-yl-vinyl) -1

H

-indazol-6-yl] -methyl-amino} -phenyl) -3-dimethylamino-benzamide

<figref>82</figref>

The compound of the Reference Example 16 (c) was prepared in a manner similar to that described in the Reference Example 16 (a), except that Chloride was used<i>m</i>-dimethylaminobenzyl instead of benzoyl chloride. LCMS (ESI) [M + H] / z Calculated 532, found 532. Anal. Calculated: C, 72.30; H, 5.50; N, 13.17. Found: C, 71.61; H, 5.80; N, 12.75.

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Reference Example 16 (d)

N

- (3 - {[3- (2-benzo [1,3] dioxol-5-yl-vinyl) -1

H

-indazol-6-yl] -methyl-amino} -phenyl) -3-trifluoromethyl-benzamide

<figref>83</figref>

The compound of the Reference Example 16 (d) was prepared in a manner similar to that described in the Reference Example 16 (a), except that Chloride was used<i>m</i>-trifluoromethylbenzoyl instead of benzoyl chloride. LCMS (ESI) [M + H] / z Calculated 557, found 557. Anal. Calculated: C, 66.90; H, 4.17; N, 10.07. Found: C, 66.64; H, 4.34; N, 9.82.

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Reference Example 16 (and)

3-acetyl-

N

- (3 - {[3- (2-benzo [1,3] dioxol-5-yl-vinyl) -1

H

-indazol-6-yl] -methyl-amino} -phenyl) -benzamide

<figref>84</figref>

The compound of the Reference Example 16 (e) was prepared in a manner similar to that described in the Reference Example 16 (a), except that Chloride was used<i>m</i>-acetylbenzoyl instead of benzoyl chloride. LCMS (ESI) [M + H] / z Calculated 531, found 531. Anal. Calculated: C, 72.44; H 4.94; N, 10.56. Found: C, 55.51; H, 4.21; N, 7.58.

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Reference Example 16 (f)

6-[

N

-(3-(4-

tert

.butyl-3-hydroxybenzamido) phenyl) -

N

-methylamino] -3-E - [(3,4-methylenedioxyphenyl) ethenyl] -1

H

-indazol

<figref>85</figref>

The compound of the Reference Example 16 (f) was prepared in a manner similar to that described in the Reference Example 16 (a), except that acid was used 3-<i>tert</i>.butyl-4-hydroxybenzoic acid, HATU and TEA instead of benzoyl chloride. 1 H NMR (300 MHz, CD_ {3} OD) δ: 7.90 (d, 1H, <i>J</i> = 8.91 Hz), 7.83 (d, 1H,<i>J</i> = 2.29 Hz), 7.63 (dd, 1H, <i>J</i> = 8.36 Hz, <i>J</i> = 2.31 Hz), 7.54 (t, 1H, <i>J</i> = 1.97 Hz), 7.25-7.43 (m, 4H), 7.14-7.20 (m, 2H), 7.06 (dd, 1H, <i>J</i> = 8.11 Hz, <i>J</i> = 1.55 Hz), 6.96 (dd, 1H, <i>J</i> = 8.93 Hz, <i>J</i> = 1.97 Hz), 6.90 (m, 1H), 6.82 (t, 2H, <i>J</i> = 8.18 Hz), 6.0 (s, 2H), 3.41 (s, 3H), 1.42 (s, 9H).

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Reference Example 17

Phenyl- (3-Styryl-1

H

-indazol-6-yl) -methanone

<figref>86</figref>

Phenyl- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -methanone became phenyl- (3-styryl-1<i>H</i>- indazol-6-yl) -methanone as described in Reference Example 11 (30 mg, 78%). MS (ESI) [M + H] / z Calculated 325, found 325. Anal. Calculated: 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 follow:

<figref>87</figref>

To a solution of 6-iodo-3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol, prepared in Reference Example 14, step (i), (143 mg, 0.3 mmol) in THF (1 mL) cooled to -78 ° C under argon atmosphere added drop by drop <i>n</i>-BuLi (0.2 mL, 0.315 mmol). Mix resulting was stirred at -78 ° C for 30 min, then quickly added by means of a cannula a solution of benzaldehyde (0.035 mL, 0.33 mmol) in THF (0.5 mL). After 0.5 h the reaction was stopped abruptly by adding NH 4 Cl to the mixture (aqueous) saturated and diluted with EtOAc (10 mL) and H2O (3 mL). The phases were separated and the aqueous phase was extracted 2x10 mL of EtOAc The EtOAc mixture was washed with brine (5 mL), dried with Na2SO4, was decanted and concentrated under reduced pressure. The crude mixture was purified by gel column chromatography. of silica (eluting with hexane: EtOAc 4: 1) obtaining phenyl- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -methanol (68 mg, 50% yield). R<i>F</i> sm = 0.72; R<i>F</i> p = 0.39 (hexane: EtOAc 7: 3); FTIR (thin layer) 3368, 2952, 2893, 1621, 1478, 1449, 1374, 1307, 1249, 1216, 1078, 960, 859, 835 cm -1. MS (ESI) [M + H] / z Calculated 457, found 457.

<figref>88</figref>

To a solution of phenyl- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -methanol (68 mg, 0.15 mmol) in dichloromethane (3 mL) at 23 ° C under an atmosphere of argon was added periodinan (reagent of Dess-Martin) (190 mg, 0.45 mmol). Mix The resulting was stirred at 23 ° C for 1 hour. Then the solution was diluted with hexane (3 mL) and then filtered to through Celite and concentrated under reduced pressure until obtaining a solid. The crude mixture was purified by chromatography on silica gel column (eluting with hexane: EtOAc 9: 1) getting phenyl- {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl) -1<i>H</i>-indazol-6-yl} -methanone (54 mg, 79% yield). R<i>F</i> sm = 0.41, R<i>F</i> p = 0.63 (hexane: EtOAc 7: 3); FTIR (thin film) 3059, 2952, 2894, 1659, 1474, 1448, 1307, 1249, 1078, 836, 649 cm -1. MS (ESI) [M + H] / z Calculated 455, found 455.

Reference Example 18

(3-amino-phenyl) - (3-styryl-1

H

-indazol-6-yl) -methanone

<figref>89</figref>

(3-Amino-phenyl) - {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl) -methanone became (3-amino-phenyl) - (3-styryl-1<i>H</i>-indazol-6-yl) -methanone as described in Reference Example 11. 1 HRMN (300 MHz, CDCl 3) δ: 8.07 (dd, 1H, <i>J</i> = 0.71, 8.50 Hz), 7.91 (s, 1H), 7.64 (dd, 1H, <i>J</i> = 1.35, 8.48 Hz), 7.54-7.60 (m, 2H), 7.46 (d, 2H, <i>J</i> = 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, <i>J</i>= 1.08, 7.89 Hz). LCMS (ESI) [M + H] / z Calculated 340, found 340.

The starting material was prepared as follow:

<figref>90</figref>

6-Iodine-3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol became (3-nitro-phenyl) - {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -methanol as described in Reference Example 17, step (i). R<i>F</i> sm = 0.71, R<i>F</i> p = 0.25 (hexane: EtOAc 7: 3); FTIR (thin film) 3369, 3061, 2952, 2894, 2361, 1620, 1578, 1530, 1478, 1449, 1350, 1308, 1249, 1215, 1080, 961, 859 cm -1; 1 HRMN (300 MHz, CDCl3) δ: 8.35 (s, 1H), 8.14 (dd, 1 HOUR, <i>J</i> = 1.34, 8.14 Hz), 7.99 (d, 1H, <i>J</i> = 8.38 Hz), 7.76 (d, 1 H, <i>J</i> = 7.72 Hz), 7.68 (s, 1H), 7.59-7.30 (m, 8H), 7.21 (d, 1H, <i>J</i> = 8.33 Hz), 6.09 (s, 1H), 5.73 (s, 2H), 3.61 (t, 2H, <i>J</i> = 8.30 Hz), 0.90 (t, 2H, <i>J</i> = 8.30 Hz), -0.06 (s, 9H). 13 CRMN (75 MHz, CDCl 3) 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. Calculated: C, 67.04; H, 6.23; N, 8.38. Found: C, 66.93; H, 6.20; N, 8.41.

<figref>91</figref>

(3-Nitro-phenyl) - {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -methanol became (3-nitro-phenyl) - {3-styryl-1- [2- (trimethylsilanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -methanone as described in Reference Example 17, step (ii) (129 mg, 91%). R<i>F</i> sm = 0.46, R<i>F</i> p = 0.23 (hexane: EtOAc 7: 3); FTIR (thin film) 3082, 2952, 2894, 1665, 1613, 1532, 1476, 1349, 1298, 1250, 1080, 836, 718 cm -1; LCMS (ESI) [M + H] / z Calculated 500, found 500.

<figref>92</figref>

(3-Nitro-phenyl) - {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -methanone became (3-amino-phenyl) - {3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol-6-yl} -methanone as described in Reference Example 11, step (iv) (102 mg, 84%). LCMS (ESI) [M + H] / z Calculated 340, found 340.

Reference Example 19 (a)

N

- [3- (3-styryl-1

H

-indazol-6-carbonyl) -phenyl] -acetamide

<figref>93</figref>

(3-Amino-phenyl) - (3-styryl-1<i>H</i>-indazol-6-yl) -methanone, prepared in Reference Example 18, it became<i>N</i>- [3- (3-styryl-1<i>H</i>-indazol-6-carbonyl) -phenyl] -acetamide as described in Reference Example 12 (a) (12.2 mg, 78%). R<i>F</i> sm = 0.16, R<i>F</i> p = 0.35 (CH 2 Cl 2: EtOAc 8: 2); LCMS (ESI) [M + H] / z Calculated 382, found 382. Anal. Calculated: C, 75.57; H, 5.02; N, 11.02. Found: C, 74.32; H, 5.41; N, 10.54.

Reference Example 19 (b)

N

- [3- (3-styryl-1

H

-indazol-6-carbonyl) -phenyl) -benzamide

<figref>94</figref>

The compound of the Reference Example 19 (b) was prepared in a manner similar to that described in the Reference Example 19 (a), except that Chloride was used benzoyl instead of acetic anhydride. 1 HRMN (300 MHz, CDCl 3) δ: 8.40 (s, 1H), 8.02 (d, 1H, <i>J</i> = 8.49 Hz), 7.98 (d, 1H, <i>J</i> = 1.01 Hz), 7.95 (s, 1H), 7.95 (s, 1H), 7.83-7.88 (m, 3H), 7.65 (dd, 1H, <i>J</i> = 1.04, 8.48 Hz), 7.29-7.56 (m, 11H). MS (ESI) [M + H] / z Calculated 444, found 444. Anal. Calculated: C, 78.54; H, 4.77; N, 9.47. Found: C, 78.01; H, 4.87; N, 9.32.

Reference Example 19 (c)

Benzyl Acid Ester [3- (3-Styryl-1

H

-indazol-6-carbonyl) -phenyl] -carbamic

<figref>95</figref>

The title compound was prepared in a manner similar to that described in Reference Example 19 (a), except that carboxybenzyloxy chloride was used instead of acetic anhydride. 1 HRMN (300 MHz, DMSO-d_ {6} δ: 8.37 (d, 1H, <i>J</i> = 8.48 Hz), 7.98 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.75 (d, 2H,<i>J</i> = 7.44 Hz), 7.61 (d, 2H, <i>J</i> = 1.81 Hz), 7.58 (s, 1H), 7.51 (t, 1H, <i>J</i> = 7.79 Hz), 7.42 (t, 5H, <i>J</i> = 6.56 Hz), 7.31-7.37 (m, 4H), 5.16 (s, 2H); LCMS (ESI) [M + H] / z Calculated 474, found 474. Anal. Calculated: C, 76.09; H 4.90; N, 8.87. Found: C, 73.82; H, 4.93; N, 8.27.

Reference Example 19 (d)

[3- (3-Styryl-1

H

-indazol-6-carbonyl) -phenyl] -amide of the acid 5-methyl-thiazol-2-carboxylic

<figref>96</figref>

(3-Amino-phenyl) - (3-styryl-1<i>H</i>-indazol-6-yl) -methanone became [3- (3-Styryl-1<i>H</i>-indazol-6-carbonyl) -phenyl] -amide of the acid 5-methyl-thiazol-2-carboxylic as described in Reference Example 12 (d) (9.9 mg, 28%). 1 H NMR (300 MHz, CDCl 3) δ: 8.15 (d, 1H,<i>J</i> = 8.49 Hz), 8.09 (t, 1H, <i>J</i> = 1.86 Hz), 8.04 (dd, 1 HOUR, <i>J</i> = 1.0, 7.98 Hz), 7.99 (s, 1H), 7.75 (dd, 1H, <i>J</i> = 1.31, 8.47 Hz), 7.67 (s, 1H), 7.63 (d, 2H, <i>J</i> = 7.30 Hz), 7.54-7.58 (m, 3H), 7.50 (s, 1H), 7.42 (t, 3H,<i>J</i> = 8.09 Hz); LCMS (ESI) [M + H] / z Calculated 465, found 465

Reference Example 19 (e)

6- [3- (5-methylpyridin-3-ylcarboxamido) benzyl] -3-E-styryl-1

H

-indazol

<figref>97</figref>

The compound of the Reference Example 19 (e) was prepared in a manner similar to that described in the Reference Example 19 (d) except that acid was used 5-methyl-nicotinic instead of acid 5-methyl-thiazol-2-carboxylic. 1 HRMN (300 MHz, CDCl 3) δ: 9.22 (s, 1H), 8.99 (d, 1 HOUR, <i>J</i> = 0.59 Hz), 8.67 (s, 1H), 8.24 (s, 1H), 8.16 (d, 1H,<i>J</i> = 8.32 Hz), 2.97 (dd, 1H, <i>J</i> = 83 Hz, <i>J</i> = 0.94 Hz), 7.72 (d, 1H, <i>J</i> = 16.65 Hz), 7.64 (d, 2H, <i>J</i> = 7.21 Hz), 7.19-7.47 (m, 8H), 6.95 (d, 1H, <i>J</i> = 6.43 Hz), 2.49 (s, 3H). MS (ESI +) [M + H] / z Calculated 459, found 459. Anal. Calculated: C, 75.97, H, 4.84, N, 12.22. Found: C, 75.86, H, 4.94, N, 12.10.

Reference Example 19 (f)

6- [3- (indole-4-ylcarboxamido) benzoyl] -3-E-styryl-1

H

-indazol

<figref>98</figref>

The compound of Reference Example 19 (f) is prepared similarly to that described in the Reference Example 19 (d) except that acid was used 1<i>H</i>-indole-4-carboxylic acid in acid place 5-methyl-thiazol-2-carboxylic. LCMS (ESI +) [M + H] / z Calculated 483, found 483. Anal. Calculated: C, 77.16; H, 4.60; N, 11.61. Found: C, 76.15; H, 4.49; N, 11.31.

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Reference Example 19 (g)

6- [3- (pyridin-2-ylacetamide) benzoyl] -3-E-styryl-1

H

-indazol

<figref>99</figref>

The compound of the Reference Example 19 (g) was prepared in a manner similar to that described in the Reference Example 19 (d), except that acid was used pyridin-2-yl-acetic. 1 HRMN (300 MHz, CDCl 3) δ: 8.50 (dd, 1H, <i>J</i> = 4.86 Hz, <i>J</i> = 0.91 Hz), 8.37 (d, 1H, <i>J</i> = 8.51 Hz), 8.09 (s, 1H), 7.94 (d, 1H, <i>J</i> = 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 Calculated 459, found 459. Anal. Calculated: C, 75.97, H, 4.84, N, 12.22. Found: C, 74.70, H, 4.83, N, 11.99.

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Reference Example 19 (h)

6- [3- (2-methylpropionamido) benzoyl] -3-E-styryl-1

H

-indazol

<figref>100</figref>

The compound of the Reference Example 19 (h) was prepared in a manner similar to that described in the Reference example 19 (a). Isobutyryl Chloride was used instead of acetyl chloride. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 8.38 (d, 1H, <i>J</i> = 8.13 Hz), 8.08 (t, 1H), 7.96 (s, 1H, <i>J</i> = 7.8 Hz, <i>J</i> = 1.91 Hz), 7.88 (s, 1H), 7.75 (d, 2H, <i>J</i> = 7.25 Hz), 7.61 (d, 2H, 2.05 Hz), 7.40-7.58 (m, 5H), 7.31 (m, 1H), 2.60 (m, 1H, <i>J</i> = 6.82 Hz), 1.1 (d, 6H, <i>J</i> = 6.82 Hz). MS (ESI +) [M + Na] / z Calculated 432, found 432. Anal. Calculated: C, 76.26, H, 5.66, N, 10.26. Found: C, 75.14, H, 5.62, N, 10.08.

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Reference Example 19 (i)

6- [3- (2-Acetamido-2-phenylacetamide) benzoyl] -3-E-styryl-1

H

-indazol

<figref>101</figref>

The compound of the Reference Example 19 (i) was prepared in a manner similar to that described in the Reference Example 19 (d) except that acid was used acetylamino-2-phenyl-acetic instead of acid 5-methyl-thiazol-2-carboxylic. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.5 (s, 1H), 10.6 (s, 1H), 8.66 (d, 1H, <i>J</i> = 7.66 Hz), 8.36 (d, 1H,<i>J</i> = 8.47 Hz), 8.07 (s, 1H), 7.92 (d, 1H, <i>J</i> = 7.63 Hz), 7.86 (s, 1H), 7.75 (d, 2H, <i>J</i> = 7.33 Hz), 7.29-7.60 (m, 13H), 5.61 (d, 1H, <i>J</i> = 7.6 Hz), 1.92 (s, 3 H). LCMS (ESI +) [M + H] / z Calculated 515, found 515. Anal. Calculated: C, 74.69, H, 5.09, N, 10.89. Found: C, 73.01, H, 5.01, N, 10.60.

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Reference Example 19 (j)

6- [3- (pyridin-4-ylcarboxamido) benzoyl] -3-E-styryl-1

H

-indazol

<figref>102</figref>

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The compound of the Reference Example 19 (j) was prepared in a manner similar to that described in the Reference Example 19 (d) except that acid was used isonicotinic instead of acid 5-methyl-thiazol-2-carboxylic. MS (ESI +) [M + Na] / z Calculated 467, found 467. Anal. Calculated: C, 75.66; H, 4.54; N, 12.60. Found: C, 74.17; H, 4.62; N, 12.31.

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Reference Example 19 (k)

6- [3- (pyridin-2-ylcarboxamido) benzoyl] -3-E-styryl-1

H

-indazol

<figref>103</figref>

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The compound of the Reference Example 19 (k) was prepared in a manner similar to that described in the Reference Example 19 (d) except that acid was used pyridine-2-carboxylic instead of acid 5-methyl-thiazol-2-carboxylic. MS (ESI +) [M + Na] / z Calculated 467, found 467. Anal. Calculated: C, 75.66; H, 4.54; N, 12.60. Found: C, 74.17; H, 4.61; N, 12.44.

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Reference Example 19 (l)

6- [3- (isoxazol-4-ylcarboxamido) benzoyl) -3-E-styryl-1

H

-indazol

<figref>104</figref>

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The compound of the Reference Example 19 (l) was prepared in a manner similar to that described in the Reference Example 19 (d) except that acid was used isoxazol-5-carboxylic instead of acid 5-methyl-thiazol-2-carboxylic. MS (ESI +) [M + H] / z Calculated 435, found 435. Anal. Calculated: C, 71.88; H, 4.18; N, 12.90. Found: C, 71.36; H, 4.33; N, 12.47.

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Reference Example 19 (m)

6- [3- (6-Chloropyridin-2-ylcarboxamido) benzoyl] -3-E-styryl-1

H

-indazol

<figref>105</figref>

The compound of the Reference Example 19 (m) was prepared in a manner similar to that described in the Reference Example 19 (d) except that acid was used 6-chloro-pyridine-2-carboxylic instead of acid 5-methyl-thiazol-2-carboxylic. MS (ESI +) [M + Na] / z Calculated 501, found 501.

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Reference Example 19 (n)

6- [3- (4-Chloropyridin-2-ylcarboxamido) benzoyl] -3-E-styryl-1

H

-indazol

<figref>106</figref>

The compound of the Reference Example 19 (n) was prepared in a manner similar to that described in the Reference Example 19 (d) except that acid was used 4-chloro-pyridine-2-carboxylic instead of acid 5-methyl-thiazol-2-carboxylic. MS (ESI +) [M + H] / z Calculated 479, found 479. Anal. Calculated: C, 70.22; H, 4.00; N, 11.70. Found: C, 70.07; H, 4.09; N, 11.64.

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Reference Example 19 (or)

6- [3- (2-Chloropyridin-4-ylcarboxamido) benzoyl] -3-E-styryl-1

H

-indazol

<figref>107</figref>

The compound of the Reference Example 19 (o) was prepared in a manner similar to that described in the Reference Example 19 (d) except that acid was used 2-chloro-isonicotinic instead of acid 5-methyl-thiazol-2-carboxylic. MS (ESI +) [M + H] / z Calculated 479, found 479.

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Reference Example 19 (p)

6- [3- (2-Methylamino-2-phenylacetamide) benzoyl] -3-E-styryl-1

H

-indazol

<figref>108</figref>

To a solution of 6- [3- (2- (<i>Nt</i>-butoxycarbonyl-<i>N</i>-methylamino) -2-phenyl-acetamido) benzoyl] -3-E-styryl-1<i>H</i>-indazol (115 mg, 0.2 mmol) in CH 2 Cl 2 (2 ml), cooled to 0 ° C, TFA (2 ml) was added. After 40 min, the reaction stopped abruptly adding already saturated NaHCO 3 (aqueous) to the mixture It was then extracted with CH 2 Cl 2 (2 x 10 ml). The Organic materials were washed with brine, dried with Na 2 SO 4, decanted and concentrated. Purification by silica gel column chromatography (methanol-dichloromethane 1:10) gave 6- [3- (2-Methylamino-2-phenylacetamide) benzoyl] -3-E-styryl-1<i>H</i>-indazol (38 mg, 39%). MS (ESI +) [M + H] / z Calculated 487, found 487. Anal. Calculated: 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 describe below:

(i) 6- [3- (2- (

Nt

-butoxycarbonyl-

N

-methylamino) -2-phenyl-acetamido) benzoyl] -3-E-styryl-1

H

-indazol

<figref>109</figref>

6- [3- (2- (N-<i>t</i>-Butoxycarbonyl-N-methylamino) -2-phenyl-acetamido) benzoyl] -3-E-styryl-1<i>H</i>-indazol it was prepared in a manner similar to that described in the Example of reference 19 (d) except that acid was used (<i>t</i>-butoxycarbonyl-methyl-amino) -phenyl-acetic acid instead of acid 5-methyl-thiazol-2-carboxylic. MS (ESI +) [M + H] / z Calculated 587, found 587.

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Reference Example 20 a)

6- (3-acetamido-phenylsulfanyl) -3-styryl-1

H

-indazol

<figref>110</figref>

6- (3-Acetamido-phenylsulfanyl) -3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol became 6- (3-acetamido-phenylsulfanyl) -3-styryl-1<i>H</i>-indazol as described in Reference Example 11 (30 mg, 81%): Rf sm = 0.65, p = 0.35 (10% methanol in dichloromethane); 1 HRMN (300 MHz, CDCl 3) δ: 7.81 (d, 1H, <i>J</i> = 8.5 Hz), 7.59 (wide s, 1H), 7.48-7.0 (m, 13H), 1.98 (s, 3H); HRMS (FAB) [M + Na] / z Calculated 408.1147, found 408.1156.

The starting material was prepared as follow:

<figref>1111</figref>

<figref>111</figref>

To adduct with 9-BBN of 3-phthalamido-thiophenol (1,4 equivalent), which was prepared <i>on-site</i> as described to then it was added 3,6-diiodo-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol (250 mg, 0.5 mmol), Pd (dppf) Cl2 (87 mg, 0.2 equivalents) and potassium phosphate (339 mg, 1.6 mmol, 3.00 equivalent) in DMF (3.0 mL). The reaction mixture was heated. up to 90 ° C for 9 h. The mixture was cooled and partitioned between acetate. of ethyl and saturated sodium hydrogen carbonate. The material The organic was dried over sodium sulfate, decanted and concentrated. Purification by silica gel column síl ice (ethyl acetate-hexane 2: 8) gave 6- (3-phthalamido-phenylsulfanyl) -3-iodine-1<i>H</i>-indazol in the form of an oil (159 mg, 50%): 1 HRMN (300 MHz, CDCl 3) 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, <i>J</i> = 8.2 Hz), 0.87 (t, 2H, <i>J</i> = 8.2 Hz), -0.06 (s, 9H); HRMS (FAB) [M + Cs] / z Calculated 759,9563, found 759,9571.

The boron reagent was prepared as follows: in a 10 mL Schlenk flask dried 3-phthalamido-thiophenol low high empty. To this was added a solution of 9-BBN (0.5 M in THF, 1.6 mL, 1.0 equivalent). The mixture was heated to 55 ° C. for 2 h. The volatile material was separated under a stream of Argon at 70 ° C for 1.5 h. The residue was used without further handling.

<figref>112</figref>

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6- (3-Phthalamido-phenylsulfanyl) -3-iodine-1<i>H</i>-indazol became 6- (3-phthalamido-phenylsulfanyl) -3-styryl-1<i>H</i>-indazol as described in Reference Example 11, step (iii). 1 HRMN (300 MHz, CDCl 3) δ: 7.93 (m, 3H), 7.78 (m 2H), 7.7 (s, 1H), 7.58 (m. 2H), 7.47-7.26 (m, 10H), 5.71 (s, 2H), 3.59 (t, 2H, <i>J</i> = 8.2 Hz), 0.89 (t, 2H,<i>J</i> = 8.2 Hz), -0.06 (s, 9H); HRMS (FAB) [M + Cs] / z Calculated 736,1066, found 736,1058.

<figref>113</figref>

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To a solution of 6- (3-phthalamidophenyl sulfanyl) -3-styryl-1<i>H</i>-indazol (121 mg, 0.2 mmol) in ethanol (3.5 mL) hydrazine (63 µL, 2.0 mmol, 10 equivalents). The reaction mixture was left in stirring at 23 ° C for 45 min and diluted with hydrogen carbonate of saturated sodium and ethyl acetate. The organic material dried over sodium sulfate, it was decanted and concentrated. Purification by silica gel column chromatography (acetate ethyl-hexane 3: 7) gave 6- (3-aminophenylsulfanyl) -3-styryl-1<i>H</i>-indazol in the form of an oil (79 mg, 90%): 1 HRMN (300 MHz, CDCl 3) δ: 7.92 (d, 1H, <i>J</i> = 8.5 Hz), 7.57 (m, 3H), 7.49 (d, 1H, <i>J</i> = 16.8 Hz), 7.4-7.25 (m, 4H), 7.23 (dd, 1H, <i>J</i> = 1.5, 8.5 Hz), 7.11 (t, 1H, <i>J</i> = 7.9 Hz), 6.79 (m, 1H), 6.70 (t, 1H, <i>J</i> = 1.9 Hz), 6.59 (m, 1H), 5.66 (s, 2H), 3.60 (wide s, 2H), 3.59 (t, 2H, <i>J</i> = 8.2 Hz), 0.90 (t, 2H, <i>J</i> = 8.2 Hz). -0.05 (s, 9H); HRMS (FAB) [M + H] / z Calculated 474,2035, found 474,2019.

<figref>114</figref>

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To a solution of 6- (3-aminophenylsulfanyl) -3-styryl-1<i>H</i>-indazol (43.7 mg, 0.10 mmol) in dichloromethane (0.5 mL) pyridine was added (81 µL, 1.0 mmol, 10 equivalents) and acetic anhydride (47 µL, 0.5 mmol, 5 equivalents). The mixture was left under stirring. for 10 min at 23 ° C. The mixture was diluted with water and the product It was extracted with 30% hexane in ethyl acetate. The material organic was washed with 5% citric acid and hydrogen carbonate saturated sodium The organic material was dried over sodium sulfate, He decanted and concentrated. Purification by chromatography in silica gel column (ethyl acetate - hexane 3: 7) gave 6- (3-acetamido-phenylsulfanyl) -3-styryl-1<i>H</i>-indazol in the form of an oil (50 mg, 97%): R f sm = 0.33, R<i>F</i> p = 0.18 (ethyl acetate-hexane 3: 7); 1 HRMN (300 MHz, CDCl 3) δ: 7.94 (d, 1H), 7.65-7.1 (m, 13H), 5.70 (s, 2H), 3.62 (t, 2H,<i>J</i> = 8.2 Hz), 2.18 (s, 3H), 0.93 (t, 2H, <i>J</i> = 8.2 Hz), -0.05 (s, 9H). HRMS (FAB) [M + Cs] / z Calculated 648,1117, found 648,1098.

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Reference Example 20 (b)

6- (3- (benzylamido) -phenylsulfanyl) -3-styryl-1

H

-indazol

<figref>115</figref>

The title compound was prepared as the Reference Example 20 (a) except that, in step (iv), He used benzoyl chloride instead of acetic anhydride. 1 HRMN (300 MHz, CDCl 3) δ: 8.03 (s, 1H), 7.73 (d, 1H, <i>J</i>= 8.5 Hz), 7.63 (m, 2H). 7.47 (m, 1H), 7.42 (t, 1H,<i>J</i> = 1.9 Hz), 7.37 (m, 3H), 7.31 (m, 1H), 7.28-6.98 (m, 9H); HRMS (FAB) [M + H] / z Calculated 448.1484, found 448.1490.

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Reference Example twenty-one

6- (1- (3-aminophenyl) -vinyl) -3-styryl-1

H

-indazol

<figref>116</figref>

6- (1- (3-Aminophenyl) -vinyl) -3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol it became the title compound as described in the Reference example 11 (85 mg, 85%): R f 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; 1 HRMN (300 MHz, CDCl 3) δ: 7.98 (d, 1H, <i>J</i> = 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 (wide s, 2H); MS (ES) [M + H] / z Calculated 338, found 338; MS (ES) [MH] / z Calculated 336, found 336.

The starting material was prepared as follow:

<figref>117</figref>

To a solution of 6-iodo-3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol, prepared in Reference Example 14, step (i), (330 mg, 0.693 mmol) in THF (3.0 mL) at -78 ° C was added<i>n</i>-butyl lithium (0.56 mL, 1.5 M, 1.2 equivalent). After 20 min, this was added next solution to anhydrous zinc chloride (170 mg) and the mixture was heated until 23 ° C and stirred for 15 min. To this mixture was added triflate of 1- (3-nitro-phenyl) vinyl (146 µL, 1.05 equivalents) and Pd (PPh3) 4 (40 mg, 0.05 equivalents). This mixture was stirred for 30 min, it was partitioned between ethyl acetate and sodium hydrogen carbonate saturated and the organic layer was separated. The organic material dried over sodium sulfate, it was decanted and concentrated under pressure reduced Purification by gel column chromatography of silica (ethyl acetate-hexane 1: 9) already then in a second column (1% ethyl acetate / benzene) it gave 6- (1- (3-nitrophenyl) -vinyl) -3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol in the form of an oil (180 mg, 52%): FTIR (thin film) 2951, 1616, 1530, 1477, 1448, 1348, 1305, 1248, 1217, 1077, 961, 913, 859 cm -1; 1 HRMN (300 MHz, CDCl 3) δ: 8.26 (t, 1H,<i>J</i> = 1.9 Hz), 8.21 (m, 1H), 8.00 (d, 1H, <i>J</i> = 8.5 Hz), 7.69 (dt, 1H, <i>J</i> = 1.4, 7.8), 7.62-7.28 (m, 9H), 7.19 (dd, 1H, <i>J</i> = 1.4, 8.4 Hz), 5.72 (s, 3H), 5.69 (s, 1H), 3.60 (t, 2H, <i>J</i> = 8.2 Hz), 0.89 (t, 2H, <i>J</i> = 8.2 Hz), -0.05 (s, 9H); 13 CRMN (75 MHz, CDCl 3) 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 Calculated 520,2031, found 520,2046.

<figref>118</figref>

6- (1- (3-Nitrophenyl) -vinyl) -3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol became 6- (1- (3-aminophenyl) -vinyl) -3-styryl-1- [2- (trimethylsilanyl) -ethoxymethyl] -1<i>H</i>-indazol as described in Reference Example 11, step (iv) (140 mg, 95%): R<i>F</i> sm = 0.59, p = 0.46 (acetate ethyl 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; 1 HRMN (300 MHz, CDCl 3) δ: 7.96 (d, 1H,<i>J</i> = 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); 13 CRMN (75 MHz, CDCl 3) 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 Calculated 490.2291, found 490.2302.

Reference Example 22 (a)

6- (1- (3- (5-methyl-thiaxol-2-carboxylamido) phenyl) -vinyl) -3-styryl-1

H

-indazol

<figref>119</figref>

6- (1- (3-Aminophenyl) -vinyl) -3-styryl-1<i>H</i>-indazol it became the title compound as described in the Reference Example 12 (d) (20 mg, 72%): FTIR (film fine) 3271, 1673, 1605, 1585, 1538, 1486, 1428, 1349, 1304, 1090, 960, 907, 871 cm -1; 1 HRMN (300 MHz, CDCl 3) δ: 10.7 (wide s, 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); 13 CRMN (75 MHz, CDCl 3) 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 Calculated 463.1593, found 463.1582.

Reference Example 22 (b)

6- (1- (3- (benzoylamido) phenyl) -vinyl) -3-styryl-1

H

-indazol

<figref>120</figref>

The compound of the Reference Example 22 (b) was prepared in a manner similar to that described in the Reference example 22 (a), except that benzoyl instead of acid 5-methyl-thiazol-2-carboxylic and HATU. FTIR (thin film) 3243, 1651, 1606, 1580, 1538, 1485, 1447, 1428, 1349, 1307, 1258, 1073, 959, 907 cm -1; 1 HRMN (300 MHz, CDCl 3) δ: 9.09 (s, 1H), 7.99 (d, 1H, <i>J</i>= 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, <i>J</i> = 3.2 Hz); 13 CRMN (75 MHz, CDCl 3) 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 Calculated 442.1919, found 442.1919.

Reference Example 22 (c)

6- (1- (3- (benzoylamido) phenyl) -vinyl) -3-styryl-1

H

-indazol

<figref>121</figref>

The title compound was prepared in a manner similar to that described in Reference Example 22 (a), except that carbobenzyloxy chloride was used instead of acid 5-methylthiazol-2-carboxylic and HATU. FTIR (thin film) 3305, 1712, 1606, 1586, 1537, 1487, 1445, 1348, 1216, 1059, 959, 908 cm -1; 1 HRMN (300 MHz, CDCl_3) δ: 7.99 (d, 1H, <i>J</i> = 8.5 Hz), 7.6-7.0 (m, 18H), 5.55 (s, 2H), 5.19 (s, 2H); 13 CRMN (75 MHz, CDCl 3) δ: 153.9, 149.8, 144.3, 142.7, 142.1, 140.7, 138.2, 137.6, 136.3, 131.7, 129.4, 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 Calculated 472.025, found 472.2026.

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Reference Example 2. 3

6- (1- (3-Acetamido-phenyl) -vinyl) -3-styryl-1

H

-indazol

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<figref>122</figref>

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6- (1- (3-Acetamido-phenyl) -vinyl) -3-styryl-1- [2-trimethylsilanyl-ethoxymethyl] -1<i>H</i>-indazol became 6- (1- (3-Acetamido-phenyl) -vinyl) -3-styryl-1<i>H</i>-indazol as described in Reference Example 11: FTIR (film fine) 3252, 1667, 1606, 1557, 1486 cm -1; 1 HRMN (300 MHz, CDCl 3) δ: 10.4 (broad s, 1H), 7.91 (d, 1H, <i>J</i> = 8.5 Hz), 7.5-7.0 (m, 13H), 5.47 (s, 2H), 2.10 (s, 3H); MS (ES) [M + H] / z Calculated 380, found 380; [MH] / z Calculated 378, found 378.

The starting material was prepared as follow:

<figref>123</figref>

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6- (1- (3-Aminophenyl) -vinyl) -3-styryl-1- [2-trimethylsilanyl-ethoxymethyl] -1<i>H</i>-indazol became 6- (1- (3-Acetamido-phenyl) -vinyl) -3-styryl-1- [2-trimethylsilanyl-ethoxymethyl] -1<i>H</i>-indazol as described in Reference Example 12 (a): R f 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; 1 HRMN (300 MHz, CDCl 3) δ: 7.98 (d, 1 HOUR, <i>J</i> = 8.5 Hz), 7.7-7.4 (m, 9H), 7.35 (m, 2H), 7.26 (dd, 1H, <i>J</i> = 1.3, 8.4 Hz), 7.16 (broad d, 1H,<i>J</i> = 7.8 Hz), 5.75 (s, 2H), 5.62 (s, 1H), 5.61 (s, 1H), 3.66 (t, 2H, <i>J</i> = 8.2 Hz), 2.16 (s, 3H), 0.98 (t, 2H, <i>J</i> = 8.2 Hz), -0.02 (s, 9H); 13 CRMN (75 MHz, CDCl 3) 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 Calculated 532.2396, found 532.2410.

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Reference Example 24 (a)

4-[3-(1-

H

-benzoimidazol-2-yl) -1-

H

-indazol-6-yl] -2-methoxy-5-methyl-phenol

<figref>124</figref>

6- {5-Methoxy-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl} -1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-benzamidazol-2-yl} -1<i>H</i>-indazol (326 mg, 0.43 mmol) was stirred in a TBAF solution (4.5 mL of 1M 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 mixture is diluted with ethyl acetate / THF (40 mL / 5 mL) and washed with H2O (20 mL) and brine (20 mL). The organic materials dried (MgSO 4) and concentrated in vacuo. Purification by silica gel column chromatography (60% THF / hexanes) and the subsequent precipitation in chloroform gave 108 mg (68%) of 4- [3- (1<i>H</i>-benzoimidazol-2-yl) -1<i>H</i>-indazol-6-yl] -2-methoxy-5-methyl-phenol in the form of a white solid. 1 H NMR (300 MHz, DMSO-<i>d</i>6) δ: 13.62 (s, 1H), 13.05 (wide s, 1H), 9.01 (s, 1H), 8.50 (d, 1H, <i>J</i> = 8.4 Hz), 7.62 (wide s, 2H), 7.49 (s, 1H), 7.28-7.20 (m, 3H), 6.85 (s, 1H), 6.74 (s, 1H), 3.77 (s, 3H), 2.15 (s, 3H), Anal. (C 22 H 18 N 4 O 2 • 1.3 H 2 O) C, H, N. Calculated: C, 67.10; H, 5.27; N, 14.23. Found: C, 67.30; H 5.27; N, 14.11.

The item material was prepared as follow:

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<figref>125</figref>

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Preparation of 2-iodine-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-benzoimidazole: a solution of 1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-benzoimidazole (5,029 g, 20.25 mmol) (see Witten <i>et al., J. Org. Chem</i>., 51, 1891-1894 (1986)) in THF (50 mL) was cooled to -78 ° C and added dropwise over 12 min by means of a cannula to a flask containing <i>n</i>-butyl lithium (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 heated to 0 ° C for 10 min, and then cooled again to -78 ° C. This solution was then added by means of a cannula to a second flask containing iodine (25.7 g, 101 mmol) in THF (50 mL) at -78 ° C. Once the addition is completed (sim5 min), removed the cooling bath and stirring was continued 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 color of iodine, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (acetate 10% to 50% ethyl / hexanes) provided 4.79 g (63%) of 2-iodo-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-benzoimidazole pure in the form of a yellow solid. 1 HRMN (300 MHz, CDCl 3) δ: 7.76-7.72 (m, 1H), 7.54-7.51 (m, 1H), 7.29-7.25 (m, 2H), 5.54 (s, 2H), 3.59 (t, 2H, <i>J</i> = 8.1 Hz), 0.92 (t, 2H,<i>J</i> = 8.1 Hz), -0.03 (s, 9H). Anal. (C 13 H 18 IN 2 OS) 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.

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<figref>126</figref>

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Preparation of 6-nitro-1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- (trimethyl-stannanyl) -1<i>H</i>-indazol: 3-iodo-6-nitro-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol (10.0 g, 23.9 mmol) and hexamethyldistin (10.0 g, 30.5 mmol) were mixed with anhydrous toluene (45 mL) in a flask purged with argon.

Was added tetrakis (triphenylphosphine) -palladium (0) (300 mg, 0.26 mmol) and the reaction mixture was stirred at reflux under Argon for 2.5 h. The reaction mixture was cooled to 23 ° C and was diluted with ether (60 mL). The organic materials were washed with 0.1N HCl (20 mL) and brine (20 mL), dried (MgSO4) and dried concentrated. Purification by gel column chromatography of silica (3% to 8% ether / hexanes) gave 7.70 g (71%) of 6-nitro-1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- (trimethyl-stannanyl) -1-<i>H</i>-indazol in the form of a slightly yellow solid. 1 HRMN (300 MHz, CDCl 3) δ: 8.53 (d, 1H, <i>J</i> = 1.8 Hz), 8.03 (dd, 1H, <i>J</i> = 8.7, 1.8 Hz), 7.81 (d, 1H, <i>J</i> = 8.7 Hz), 5.84 (s, 2H), 3.58 (t, 2H, <i>J</i> = 8.1 Hz), 0.90 (t, 2H, <i>J</i> = 8.1 Hz), 0.50 (t, 9H, <i>J</i> = 28.2 Hz), -0.05 (s, 9H). Anal. (C 18 H 27 N 3 O 3 SiSn) C, H, N. Calculated: C, 42.13; H, 5.97; N, 9.21. Found: C, 42.39; H, 6.01; N, 9.26.

<figref>127</figref>

Preparation of 6-nitro-1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-benzoimidazol-2-yl} -1<i>H</i>-indazol: 6-nitro-1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- (trimethyl-stannanyl) -1<i>H</i>-indazol (7.50 g, 16.4 mmol), 3-iodo-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-benzimidazole (6.50 g, 17.4 mmol) and copper (I) iodide (313 mg, 1.64 mmol) mixed with anhydrous THF (150 mL) in a flask purged with argon. Was added tetrakis (triphenylphosphine) palladium (0) and the mixture The reaction was stirred under reflux under argon for 23 h. Mix The reaction was cooled and adsorbed directly on silica gel (\ sim16 g). Purification by gel column chromatography silica (4% to 15% ethyl acetate / hexanes) gave 7.28 g (82%) of 6-nitro-1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-benzoimidazol-2-yl) -1-<i>H</i>-indazol in the form of a light yellow solid. 1 H NMR (300 MHz, CDCl 3) δ: 8.91 (d, 1H, <i>J</i> = 9.0 Hz), 8.59 (d, 1H,<i>J</i> = 1.8 Hz), 8.22 (dd, 1H, <i>J</i> = 8.7, 1.8 Hz), 7.92-7.89 (m, 1H), 7.66-7.62 (m, 1H), 7.40-7.36 (m, 2H), 6.24 (s, 2H), 5.90 (s, 2H), 3.68-3.59 (m, 4H), 0.94 (t, 2H, <i>J</i> = 8.1 Hz), 0.86 (t, 2H, <i>J</i> = 8.1 Hz), -0.04 (s, 9H), -0.15 (s, 9H). Anal. (C 26 H 37 N 5 O 4 Si 2) C, H, N. Calculated: C, 57.85; H, 6.91; N, 12.97. Found: C, 57.60; H, 6.81; N, 12.82.

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<figref>128</figref>

Preparation of 6-amino-1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-benzoimide- zol-2-yl} -1<i>H</i>-indazol: tin (II) chloride (12.0 g, 63.3 mmol) was added to a solution of 6-nitro-1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- {1- [2 (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-benzoimidazol-2-yl} -1<i>H</i>-indazol (7.18 g, 13.3 mmol) in DMF / H2O (160 mL / 10 mL) and the mixture of The reaction was stirred at 50 ° C for 2.5 h. The reaction mixture is cooled to 0 ° C and sodium hydrogen carbonate was added slowly saturated, with mixing, until all the foam disappears produced by sudden cooling. The material was concentrated to vacuum and collected with ether (100 mL). The insoluble material is filtered off and washed with ether (50 mL). The filtrate is washed with brine (50 mL), dried (Na2SO4) and concentrated empty Purification by gel column chromatography of silica (25% ethyl acetate / hexane) gave 6.05 g (89%) of 6-amino-1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-benzoimidazol-2-yl} -1<i>H</i>-indazol in the form of a slightly yellow waxy solid. 1 HRMN (300 MHz, CDCl 3) δ: 8.40 (d, 1H, <i>J</i> = 9.0 Hz), 7.89-7.86 (m, 1H), 7.63-7.60 (m, 1H), 7.35-7.31 (m, 2H), 6.78 (dd, 1H, <i>J</i> = 8.7, 1.8 Hz), 6.75 (s, 1H), 6.25 (s, 2H), 5.69 (s, 2H), 3.93 (s width, 2H), 3.65-3.55 (m, 4H), 0.93 (t, 2H, <i>J</i>= 8.1 Hz), 0.85 (t, 2H, <i>J</i> = 8.1 Hz), -0.04 (s, 9H), -0.15 (s, 9H). Anal. (C 24 H 39 N 3 O 2 Si 2) C, H, N. Calculated: C, 61.26; H, 7.71; N, 13.74. Found: C, 61.18; H 7.65; N, 13.82.

<figref>129</figref>

Preparation of 6-iodo-1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-benzoimidazol-2-yl} -1<i>H</i>-indazol: a solution of 6-amino-1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-benzoimidazol-2-yl} -1<i>H</i>-indazol (500 mg, 0.98 mmol) in acetic acid (1.5 mL) was diluted with H2O (1.0 mL) and stirred at 0 ° C. Concentrated HCl (250 was added µL, 33 mmol) in H2O (250 µL). Nitrate was added sodium (90 mg, 1.3 mmol) in H2O (300 µL) and the mixture of reaction was stirred for 8 min. Iodine (10 mg) and a solution of potassium iodide (250 mg, 1.3 mmol) in H2O (250 µL) and the foamy reaction mixture was stirred for 30 min at 23 ° C. The reaction mixture was diluted with H2O (25 mL) and was extracted with ethyl acetate (2 x 20 mL). Organic materials they were washed with a saturated solution of sodium metabisulfite (10 mL) and brine (10 mL), dried (Na2SO4), and dried concentrated in vacuo. Purification by column chromatography silica gel (8% ethyl acetate / hexanes) gave 316 mg (52%) from 6-iodo-1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-benzoimidazol-2-yl} -1<i>H</i>-indazol in the form of a slightly yellow oil, which crystallized Slowly giving a white solid. 1 HRMN (300 MHz, CDCl 3) δ: 8.45 (d, 1H, <i>J</i> = 9.0 Hz), 8.05 (s, 1H), 7.91-7.88 (m, 1H), 7.67-7.62 (m, 2H), 7.38-7.34 (m, 2H), 6.24 (s, 2H), 5.77 (s, 2H), 3.65-3.57 (m, 4H), 0.93 (t, 2H, <i>J</i> = 8.1 Hz), 0.85 (t, 2H, <i>J</i> = 8.1 Hz), -0.04 (s, 9H), -0.15 (s, 9H). Anal. (C 26 H 37 IN 4 O 2 Si 2) C, H, N. Calculated: C, 50.31; H, 6.01; N, 9.03. Found: C, 50.55; H, 6.08; N, 9.00

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<figref>130</figref>

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Preparation of [2- (4-Bromo-2-methoxy-5-methyl-phenoxymethoxy) -ethyl] -trimethyl-silane: 4-Bromo-2-methoxy-5-methyl-phenol (see Chien-Hsun <i>et al, Syn. Lett</i>., 12, 1351-1352 (1997)) was stirred in CH2Cl2 anhydrous (100 mL) at 23 C. DIEA (diisopropylethylamine) was added (6.05 mL, 34.6 mmol) and then 2- (trimethylsilyl) ethoxymethyl (5.6 mL, 31.7 mmol). After Stir for 1 h, the solution was washed with H2O, 0.1N HCl, H2O, saturated NaHCO3, and brine (25 mL each). The Organic materials were dried (Na2SO4) and dried concentrated in vacuo. Purification by column chromatography silica gel (6% ethyl acetate / hexanes) gave 9.06 g (91%) from [2- (4-Bromo-2-methoxy-5-methyl-phenoxymethoxy) -ethyl] -trimethyl-silane in the form of a transparent oil. 1 HRMN (300 MHz, CDCl 3) δ: 7.06 (s, 1H). 7.02 (s, 1H), 5.24 (s, 2H), 3.84 (s, 3H), 3.79 (t, 2H, <i>J</i> = 8.4 Hz), 2.31 (s, 3H), 0.96 (t, 2H,<i>J</i> = 8.4 Hz), 0.01 (s, 9H).

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<figref>131</figref>

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Acid preparation 5-Methoxy-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-boronic: [2- (4-Bromo-2-methoxy-5-methyl-phenoxymethoxy) -ethyl] -trimethyl-silane (2.6 g, 7.5 mmol) was stirred in anhydrous THF (10 mL) at -78 ° C under argon. Was added dropwise n-butyllithium (3.75 mL, 2.5 M in hexanes, 9.36 mmol) and the previously stirred reaction mixture for 30 min it was transferred by means of a cannula to a flask of trimethyl borate (8.4 mL, 75 mmol) in THF (15 mL), which is also stirred at -78 ° C under argon. After the addition is complete, the reaction mixture was stirred 30 min at -78 ° C and then 30 min heating while at 0 ° C. Then the reaction stopped abruptly adding H 2 O (20 mL) to the mixture, it was acidified with 0.1N HCl and extracted with ethyl acetate (2 x 25 mL). The Organic materials were washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel column chromatography (20% ethyl acetate 50% / hexanes) gave 1.11 g (47%) of acid 5-methoxy-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-boronic in the form of a white solid. 1 HRMN (300 MHz, CDCl 3) δ: 7.78 (s, 1H), 7.10 (s, 1H), 5.36 (s, 2H), 3.93 (s, 3H), 3.83 (t, 2H, <i>J</i> = 8.4 Hz), 2.79 (s, 3H), 0.98 (t, 2H, <i>J</i>= 8.4 Hz), 0.01 (s, 9H). Anal. (C 14 H 25 BO 5 Si-H 2 O) C, H. Calculated: C, 57.15; H, 7.88. Found: C, 56.89; H, 7.87.

<figref>132</figref>

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Preparation of 6- {5-methoxy-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl} -1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-benzamidazol-2-yl} -1<i>H</i>-indazol: 6-iodo-1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-benzoimidazol-2-yl} -1<i>H</i>-indazol (350 mg, 0.56 mmol), acid 5-methoxy-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-boronic (211 mg, 0.68 mmol) and sodium carbonate (72 mg, 0.68 mmol) were stirred in a mixture of benzene (5 mL), H2O (330 µL) and methanol (1 mL) in an argon purged flask. Was added tetrakis (triphenylphosphine) palladium (0) and the mixture The reaction was stirred under reflux under argon for 16 h. After cool to 23 ° C, the reaction mixture 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 column chromatography (ethyl acetate at 15% / hexanes) gave 382 mg (89%) of 6- {5-methoxy-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl} -1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-benzamidazol-2-yl} -1<i>H</i>-indazol in the form of a white solid. 1 HRMN (300 MHz, CDCl 3) δ: 8.68 (d, 1H, <i>J</i> = 8.4 Hz), 7.93-7.90 (m, 1H), 7.67-7.63 (m, 1H), 7.54 (s, 1H), 7.38-7.32 (m, 3H), 7.13 (s, 1H), 6.86 (s, 1H), 6.29 (s, 2H), 5.83 (s, 2H), 5.34 (s, 2H), 3.89 (s, 3H), 3.86 (t, 2H,<i>J</i> = 8.4 Hz), 3.69-3.58 (m, 4H), 2.22 (s, 3H), 1.01 (t, 2H, <i>J</i> = 8.4 Hz), 0.95-0.83 (m, 4H), 0.03 (s, 9H), -0.05 (s, 9H), -0.15 (s, 9H). Anal. (C 40 H 60 N 4 O 5 Si 3) C, H, N. Calculated: C, 63.12; H, 7.95; N, 7.36. Found: C, 63.22; H, 7.93; N, 7.46.

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Reference Example 24 (b)

4-[3-(1-

H

-benzoimidazol-2-yl) -1

H

-indazol-6-yl] -3-methylphenol

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<figref>133</figref>

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To prepare the title compound, followed the procedure described in the Reference Example 24 (a), except that, in step (viii), acid was used 2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-boronic (prepared as described below) instead of acid 5-methoxy-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-boronic. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.60 (s, 1H), 12.99 (wide s, 1H), 9.41 (s, 1H), 8.49 (d, 1H, <i>J</i> = 8.4 Hz), 7.72 (wide s, 1H), 7.52 (wide s, 1H), 7.45 (s, 1H), 7.25-7.21 (m, 3H), 7.12 (d, 1H, <i>J</i> = 8.1 Hz), 6.73-6.67 (m, 2H), 2.20 (s, 3H). Anal. (C 21 H 16 N 4 O • 0.7 H 2 O) C, H, N. Calculated: C, 71.45; H, 4.97; N, 15.87. Found: C, 71.44; H, 4.96; N, 15.77.

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Acid 2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-boronic It was prepared as follows:

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<figref>134</figref>

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Was prepared [2- (4-Bromo-3-methyl-phenoxymethoxy) -ethyl] -trimethyl-silane with a yield of 86% from 4-bromo-3-methyl-phenol according to the procedure described for [2- (4-Bromo-2-methoxy-5-methyl-phenoxymethoxy) -ethyl] -trimethyl-silane. 1 HRMN (300 MHz, CDCl 3) δ: 7.39 (d, 1H, <i>J</i> = 8.7 Hz), 6.93 (d, 1H, <i>J</i> = 2.7 Hz), 6.75 (dd, 1H, <i>J</i> = 8.7, 2.7 Hz), 5.16 (s, 2H), 3.74 (t, 2H, <i>J</i> = 8.4 Hz), 2.36 (s, 3H), 0.95 (t, 2H, <i>J</i> = 8.4 Hz), 0.01 (s, 9H). Anal. (C 13 H 21 BrO 2 Si) C, H. Calculated: C, 49.21; H 6.67. Found: C, 49.33; H, 6.67.

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<figref>135</figref>

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Acid was prepared 2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-boronic with a yield of 52% from [2- (4-Bromo-3-methyl-phenoxymethoxy) -ethyl] -trimethyl-silane according to the procedure described for the acid 5-methoxy-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-boronic previous. 1 HRMN (300 MHz, CDCl 3) δ: 8.15 (d, 1H,<i>J</i> = 8.1 Hz), 6.98-6.92 (m, 2H), 5.29 (s, 2H), 3.78 (t, 2H, <i>J</i> = 8.4 Hz), 2.78 (s, 3H), 0.98 (t, 2H,<i>J</i> = 8.4 Hz), 0.01 (s, 9H). Anal. (C 13 H 23 BO 4 Si-H 2 O) C, H. Calculated: C, 59.10; H, 8.01. Found: C, 59.07; H, 8.08.

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Reference Example 24 (c)

4-[3-(1-

H

-benzoimidazol-2-yl) -1

H

-indazol-6-yl] -2-chloro-5-methyl-phenol

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<figref>136</figref>

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To prepare the title compound, was used acid 5-Chloro-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-boronic acid, prepared as described below, instead of acid 5-methoxy-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-boronic in the procedure described in the Reference Example 24 (a), stage (viii). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.61 (s, 1H), 13.00 (wide s, 1H), 10.22 (s, 1H), 8.51 (d, 1H, <i>J</i> = 8.4 Hz), 7.64 (wide s, 2H), 7.50 (s, 1H), 7.26-7.21 (m, 4H), 6.95 (s, 1H), 2.19 (s, 3H).

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Acid 5-Chloro-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-boronic It was prepared as follows:

<figref>137</figref>

It stirred 2-chloro-5-methyl-phenol (6.68 g, 46.9 mmol) in acetonitrile (200 mL). Was added<i>N</i>-bromosuccinimide (8.5 g, 47.8 mmol) and the mixture of reaction was stirred for 45 min. The solution was concentrated in vacuo and it was dissolved again in chloroform (100 mL). The materials Organic were washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried (MgSO4) and concentrated in vacuo. The purification by silica gel column chromatography (acetate 8% ethyl / hexanes) gave 7.98 g (77%) of 4-bromo-3-chloro-5-methyl-phenol in the form of a transparent oil. 1 H NMR (300 MHz, CDCl 3) δ: 7.47 (s, 1H), 6.91 (s, 1H), 5.52 (wide s, 1H), 2.32 (s, 3H). Anal. (C 7 H 6 ClBrO • 0.1 H 2 O) C, H. Calculated: C, 37.66; H, 2.80. Found: C, 37.57; H, 2.82.

<figref>1138</figref>

<figref>138</figref>

Was prepared [2- (4-Bromo-2-chloro-5-methyl-phenoxymethoxy) -ethyl] -trimethyl-silane with a yield of 83% from 4-bromo-3-chloro-5-methyl-phenol according to the procedure for [2- (4-Bromo-2-methoxy-5-methyl-phenoxymethoxy) -ethyl] -trimethyl-silane. 1 HRMN (300 MHz, CDCl 3) δ: 7.51 (s, 1H), 7.09 (s, 1H), 5.26 (s, 2H), 3.79 (t, 2H, <i>J</i> = 8.4 Hz), 2.35 (s, 3H), 0.95 (t, 2H, <i>J</i> = 8.4 Hz), 0.02 (s, 9H). Anal. (C 13 H 20 ClBrO 2 Si) C, H. Calculated: C, 44.39; H, 5.73. Found: C, 45.08; H, 5.91.

<figref>139</figref>

Acid was prepared 5-Chloro-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-boronic with a yield of 54% from [2- (4-Bromo-2-chloro-5-methyl-phenoxymethoxy) -ethyl] -trimethyl-silane according to the procedure for acid 5-methoxy-2-methyl-4- [2- (trimethyl-silanyl) -ethoxymethoxy] -phenyl-boronic. 1 HRMN (300 MHz, CDCl 3) δ: 8.11 (s, 1H), 7.09 (s, 1H), 5.37 (s, 2H), 3.84 (t, 2H, <i>J</i> = 8.4 Hz), 2.76 (s, 3H), 0.98 (t, 2H, <i>J</i> = 8.4 Hz), 0.01 (s, 9H). Anal. (C 13 H 22 BClO 4 Si-H 2 O) C, H. Calculated: C, 52.28; H, 6.75. Found: C, 51.98; H, 6.84.

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Reference Example 24 (d)

3-1

H

-benzoimidazol-2-yl-6- (4-hydroxy-2-methoxyphenyl) -1

H

-indazol

<figref>140</figref>

The compound of Reference Example 24 (d) is prepared similarly to that described in the Reference Example 24 (a), except that, in step (vi), it was used 4-bromo-3-methoxy-phenol, prepared as described by Carreno <i />et. to the<i>., Syn. Lett</i>., 11, 1241-42 (1997), instead of 4-Bromo-2-methoxy-5-methyl-phenol. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.52 (s, 1H), 12.98 (s, 1H), 9.63 (s, 1H), 8.44 (d, 1H, <i>J</i> = 8.4 Hz), 7.72 (d, 1H, <i>J</i> = 6.9 Hz), 7.61 (s, 1H), 7.50 (d, 1H, <i>J</i> = 6.9 Hz), 7.36 (dd, 1H, <i>J</i> = 8.4, 1.5 Hz), 7.18-7.22 (m, 3H), 6.55 (d, 1H, <i>J</i> = 2.1 Hz), 6.48 (dd, 1H, <i>J</i> = 8.1, 2.1 Hz), 3.74 (s, 3H). MS (ES) [M + H] / z calculated 357, found 357; [MH] / z calculated 355, found 355.

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Reference Example 24 (e)

3-1

H

-benzoimidazol-2-yl-6- (2-ethyl-4-hydroxyphenyl) -1

H

-indazol

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<figref>141</figref>

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The compound of Reference Example 24 (e) is prepared similarly to that described in the Reference Example 24 (a), except that, in step (vi), it was used 4-bromo-3-ethyl phenol, prepared with a yield of 80% according to the procedure described by Carreno <i>et. al., Syn. Lett</i>., eleven, 1241-42 (1997) for the synthesis of 4-Bromo-3-methyl phenol, instead of 4-Bromo-2-methoxy-5-methyl-phenol. 1 H NMR (300 MHz, DMSO-<i>d</i>6) δ: 13.66 (s, 1H), 13.02 (s. 1H), 9.43 (s, 1H), 8.49 (d, 1H, <i>J</i> = 8.4 Hz), 7.72 (d, 1H, <i>J</i> = 6.9 Hz), 7.53 (d, 1H, <i>J</i> = 6.9 Hz), 7.44 (s, 1H), 7.18-7.25 (m, 3H), 7.06 (d, 1H, <i>J</i> = 8.1 Hz), 6.75 (d, 1H, <i>J</i> = 2.1 Hz), 6.66 (dd, 1H, <i>J</i> = 8.1, 2.1 Hz), 2.50 (q, 2H, <i>J</i> = 7.5 Hz), 1.04 (t, 3H, <i>J</i> = 7.5 Hz). MS (ES) [M + H] / z calculated 355, found 355; [MH] / z calculated 353, found 353.

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Reference Example 24 (f)

3-1

H

-benzoimidazol-2-yl-6- (2,4-dihydroxyphenyl) -1

H

-indazol

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<figref>142</figref>

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It got hot 6- (2-Methoxy-4-hydroxyphenyl) -3-1<i>H</i>-benzoimidazol-2-yl-1<i>H</i>-indazol, prepared in Reference Example 24 (d), (46 mg, 0.13 mmol) in pyridinium chloride (0.5 g) at 180 ° C for 2 h. Mix reaction was allowed to cool and the reaction stopped abruptly adding NaHCO 3 sat. (15 mL) and extracted with EtOAc (2 x 20 mL) The organic materials were dried (Na2SO4) and dried concentrated in vacuo. Purification by column chromatography silica gel (60% THF / hexanes) gave 26 mg (59%) of the compound of the heading in the form of a white solid. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.49 (s, 1H), 12.94 (s, 1H), 9.49 (s, 1H), 9.39 (s, 1H), 8.43 (d, 1H, <i>J</i> = 8.4 Hz), 7.71-7.74 (m, 2H), 7.50 (d, 1H, <i>J</i> = 6.9 Hz), 7.43 (dd, 1H, <i>J</i> = 8.4, 1.2 Hz), 7.16-7.23 (m, 3H), 6.45 (d, 1H, <i>J</i> = 2.1 Hz), 6.35 (dd, 1H, <i>J</i> = 8.4, 2.1 Hz) MS (ES) [M + H] / z calculated 343, found 343; [MH] / z calculated 341, found 341.

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Reference Example 24 (g)

3-1

H

-benzoimidazol-2-yl-6- (2-phenoxy-4-hydroxyphenyl) -1

H

-indazol

<figref>143</figref>

The compound of Reference Example 24 (g) is prepared similarly to that described in the Reference Example 24 (c), except that, in step (i), it was used 3-phenoxyphenol instead of 2-chloro-5-methylphenol. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.54 (s, 1H), 12.95 (s, 1H), 9.78 (s, 1H), 8.43 (d, 1H, <i>J</i> = 8.4 Hz), 7.67-7.72 (m, 2H), 7.49 (dd, 1H, <i>J</i> = 6.3, 2.1 Hz), 7.43 (d, 2H, <i>J</i> = 8.4 Hz), 7.33 (t, 2H, <i>J</i> = 7.5 Hz), 7.17-7.22 (m, 2H), 6.96-7.07 (m, 3H), 6.72 (dd, 1H, <i>J</i> = 8.4, 2.1 Hz), 6.40 (d, 1H,<i>J</i> = 2.1 Hz). MS (ES) [M + H] / z calculated 419, found 419; [MH] / z calculated 417, found 417.

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Reference Example 24 (h)

3-1

H

-benzoimidazol-2-yl-6- (2- (2-methoxyethyl) -4-hydroxyphenyl) -1

H

-indazol

<figref>144</figref>

The compound of Reference Example 24 (h) is prepared similarly to that described in the Reference Example 24 (a), except that, in step (vii), was used [2- [4-Bromo-3- (2-methoxy-ethyl) -phenoxymethoxy] -ethyl} -trimethyl-silane, prepared as described below, instead of [2- (4-Bromo-2-methoxy-5-methyl-phenoxymethoxy) -ethyl] -trimethyl-silane. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.60 (s, 1H), 13.01 (s, 1H), 9.44 (s, 1H), 8.49 (d, 1H, <i>J</i> = 8.4 Hz), 7.73 (wide s, 1H), 7.51 (wide s, 1H), 7.46 (s, 1H), 7.21 (app d, 3H,<i>J</i> = 8.1 Hz), 7.09 (d, 1H, <i>J</i> = 8.1 Hz), 6.78 (d, 1H,<i>J</i> = 2.4 Hz), 6.70 (dd, 1H, <i>J</i> = 8.1, 2.4 Hz), 3.40 (t, 2H, <i>J</i> = 7.2 Hz), 3.12 (s, 3H), 2.75 (t, 2H, <i>J</i> = 7.2 Hz) MS (ES) [M + H] / z calculated 385, found 385; [MH] / z calculated 383, found 383.

The starting material was prepared as follow:

<figref>145</figref>

Was prepared 4-Bromo-3- (2-hydroxy-ethyl) -phenol with a yield of 88% by replacing 3- (2-hydroxy-ethyl) -phenol in the procedure described in the Reference Example 24 (c), step (i). 1 HRMN (300 MHz, CDCl 3) δ: 9.56 (s, 1H), 7.29 (d, 1H, <i>J</i> = 8.7 Hz), 6.74 (d, 1H, <i>J</i>= 3.0 Hz), 6.55 (dd, 1H, <i>J</i> = 8.7, 3.0 Hz), 4.71 (t, 1H,<i>J</i> = 5.4 Hz), 3.52-3.59 (m, 2H), 2.73 (t, 2H,<i>J</i> = 7.2 Hz).

<figref>146</figref>

Was prepared 2- [2-Bromo-5- (2-trimethyl-silanyl-ethoxymethoxy) -phenyl] with a yield of 65% by replacing 4-Bromo-3- (2-hydroxy-ethyl) -phenol in the procedure described in the Reference Example 24 (a), stage (vi). 1 HRMN (300 MHz, CDCl 3) δ: 7.43 (d, 1H, <i>J</i> = 8.7 Hz), 6.97 (d, 1H, <i>J</i> = 3.0 Hz), 6.82 (dd, 1H, <i>J</i> = 8.7, 3.0 Hz), 5.19 (s, 2H), 3.88 (q, 2H, <i>J</i> = 6.6 Hz), 3.74 (t, 2H, <i>J</i> = 8.4 Hz), 2.99 (t, 2H, <i>J</i> = 6.6 Hz), 1.42 (t, 1H, <i>J</i> = 6.6 Hz). 0.94 (t, 2H, <i>J</i> = 8.4 Hz), -0.01 (s, 9H).

<figref>1147</figref>

<figref>147</figref>

{2- [4-Bromo-3- (2-methoxy-ethyl) -phenoxymethoxy] -ethyl} -trimethyl-silane: was added 2- [2-Bromo-5- (2-trimethylsilanyl-ethoxymethoxy) -phenyl] -ethanol (1.9 g, 6.0 mmol) to a solution of potassium hydroxide (1.35 g, 24 mmol) in DMSO (16 mL). Iodomethane (1.12 mL, 18 mmol) was added and The solution was stirred for 16 h. The reaction mixture was diluted. with water (50 mL) and extracted with ether (2 x 40 mL). The materials organic were washed with brine (40 mL), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel column chromatography (10% ether / hexanes) gave 1.28 g of {2- [4-Bromo-3- (2-methoxy-ethyl) -phenoxymethoxy] -ethyl} -trimethyl-silane in the form of a transparent oil. 1 HRMN (300 MHz, CDCl 3) δ: 7.40 (d, 1H, <i>J</i> = 8.7 Hz), 6.96 (d, 1H,<i>J</i> = 3.0 Hz), 6.80 (dd, 1H, <i>J</i> = 8.7, 3.0 Hz), 5.18 (s, 2H), 3.74 (t, 2H, <i>J</i> = 8.4 Hz), 3.60 (t, 2H, <i>J</i> = 7.2 Hz), 3.37 (s, 3H), 2.98 (t, 2H, <i>J</i> = 7.2 Hz), 0.95 (t, 2H,<i>J</i> = 8.4 Hz), -0.01 (s, 9H).

Reference Example 24 (i)

3-1

H

-benzoimidazol-2-yl-6- (2- (2-hydroxyethyl) -4-hydroxyphenyl) -1

H

-indazol

<figref>148</figref>

It dissolved 3-1<i>H</i>-benzoimidazol-2-yl-6- (2- (2-methoxyethyl) -4-hydroxyphenyl) -1<i>H</i>-indazol, of Reference Example 24 (i), (99 mg, 0.26 mmol) in EtOAc (20 mL) and cooled to -78 ° C under argon. Was added dropwise boron tribromide and the reaction mixture was allowed to stir while heating at room temperature for 3 h. The solution was diluted with EtOAc (60 mL) and washed with sat. NaHCO3. and brine (20 mL of each). The organic materials dried (Na2SO4) and concentrated in vacuo. Purification by silica gel column chromatography (THF) gave 56 mg (59%) of title compound in the form of a white solid. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.60 (s, 1H), 13.01 (s, 1H), 9.41 (s, 1H), 8.49 (d, 1H, <i>J</i> = 8.4 Hz), 7.71 (wide s, 1H), 7.51 (wide s, 1H), 7.46 (s, 1H), 7.21 (app d, 3H, <i>J</i> = 8.1 Hz), 7.08 (d, 1H, <i>J</i> = 8.4 Hz), 6.77 (d, 1H, <i>J</i> = 2.1 Hz), 6.69 (dd, 1H, <i>J</i> = 8.1, 2.1 Hz), 4.57 (wide s, 1H), 3.46 (t, 2H, <i>J</i> = 7.2 Hz), 2.68 (t, 2H, <i>J</i> = 7.2 Hz). MS (ES) [M + H] / z calculated 371, found 371; [MH] / z calculated 369, found 369.

Reference Example 24 (j)

3-1

H

-benzoimidazol-2-yl-6- (2,6-dimethyl-4-hydroxyphenyl) -1

H

-indazol

<figref>149</figref>

The compound of Reference Example 24 (j) is prepared similarly to that described in the Reference Example 24 (a), except that, in step (vi), it was used 4-Bromo-3,5-dimethyl-phenol instead of 4-Bromo-2-methoxy-5-methyl-phenol. 1 H NMR (300 MHz, DMSO-<i>d</i>6) δ: 13.57 (s, 1H), 12.99 (s, 1H), 9.22 (s, 1H), 8.52 (d, 1H, <i>J</i> = 8.4 Hz), 7.72 (d, 1H, <i>J</i> = 6.6 Hz), 7.51 (d, 1H, <i>J</i> = 6.6 Hz), 7.31 (s, 1H), 7.16-7.25 (m, 2H), 7.02 (d, 1H, <i>J</i> = 8.4 Hz), 6.55 (s, 2H), 1.93 (s, 6H). MS (ES) [M + H] / z calculated 355, found 355; [MH] / z calculated 353, found 353

Reference Example 24 (k)

3-1

H

-benzoimidazol-2-yl-6- (2-methylsulfanyl-4-hydroxyphenyl) -1

H

-indazol

<figref>150</figref>

The compound of Reference Example 24 (k) is prepared similarly to that described in the Reference Example 24 (c), except that, in step (i), it was used 3-methylsulfanyl phenol, prepared as described below, instead of 2-chloro-5-methyl phenol. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.59 (s, 1H), 12.98 (s, 1H), 9.64 (s, 1H), 8.48 (d, 1H, <i>J</i> = 8.4 Hz), 7.71 (s wide, 1H), 7.52 (app s, 2H), 7.20-7.27 (m, 3H), 7.12 (d, 1H, <i>J</i> = 8.4 Hz), 6.76 (d, 1H, <i>J</i> = 2.1 Hz), 6.65 (dd, 1H, <i>J</i> = 8.4, 2.1 Hz), 2.34 (s, 3H). MS (ES) [M + H] / z calculated 373, found 373; [MH] / z calculated 371, found 371.

The starting material was prepared as follow:

<figref>151</figref>

Preparation of 3-methylsulfanyl phenol: 3-hydroxythiophenol (5.0 g, 39.7 mmol) and carbonate Potassium (6.03 g, 43.6 mmol) was stirred in acetone (80 mL) at 0 ° C. Iodomethane (2.5 mL, 40 mmol) was added dropwise and the mixture of reaction was stirred for 45 min. The solution was diluted with H2O (150 mL) and extracted with EtOAc (2 x 100 mL). The materials organic were washed with brine (100 mL), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel column chromatography (25% EtOAc / hexanes) gave 5.08 g (91%) of 3-methylsulfanyl-phenol in the form of a transparent oil 1 H NMR (300 MHz, CDCl 3) δ: 7.15 (t, 1H, <i>J</i> = 8.1 Hz), 6.82 (d, 1H, <i>J</i> = 8.1 Hz), 6.74 (t, 1H, <i>J</i> = 1.8 Hz), 6.60 (dd, 1H, <i>J</i> = 8.1, 1.8 Hz), 4.86 (s, 1H), 2.47 (s, 3H).

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Reference Example 24 (l)

3-1

H

-benzoimidazol-2-yl-6- (2- (ethoxymethyl) -5-methoxy-4-hydroxy-phenyl) -1

H

-indazol

<figref>152</figref>

The compound of Reference Example 24 (1) is prepared similarly to that described in the Reference Example 24 (a), except that, in step (vii), was used [2- (4-Bromo-5-ethoxymethyl-2-methoxy-phenoxymethoxy) -ethyl] -trimethyl-silane, prepared as described below, instead of [2- (4-Bromo-2-methoxy-5-methyl-phenoxymethoxy) -ethyl] -trimethylsilane. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.63 (s, 1H), 12.99 (s, 1H), 9.15 (s, 1H), 8.50 (d, 1H, <i>J</i> = 8.4 Hz), 7.73 (dd, 1H, <i>J</i> = 6.6, 2.1 Hz), 7.59 (s, 1H), 7.51 (dd, 1H,<i>J</i> = 6.6, 2.1 Hz), 7.32 (d, 1H, <i>J</i> = 8.4 Hz), 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, <i>J</i> = 6.9 Hz), 1.13 (t, 3H, <i>J</i> = 6.9 Hz). MS (ES) [M + H] / z calculated 415, found 415

The starting material was prepared as follow:

<figref>153</figref>

Was prepared 2-Bromo-4-methoxy-5- (2-trimethyl-silanyl-ethoxymethoxy) -benzaldehyde with a yield of 79% replacing 4-Bromo-3-formyl-2-methoxy-phenol (Hazlet <i>et. al., J. Org. Chem</i>., 27, 3253-55 (1962)) in the procedure described in the Reference Example 24 (a), stage (vi). 1 HRMN (300 MHz, CDCl 3) δ: 10.16 (s, 1H), 7.68 (s, 1H), 7.07 (s, 1H), 5.28 (s, 2H), 3.94 (s, 3H), 3.77 (t, 2H, <i>J</i> = 8.4 Hz), 0.94 (t, 2H, <i>J</i> = 8.4 Hz), -0.03 (s, 9H).

<figref>154</figref>

Preparation of [2- (4-Bromo-5-ethoxymethyl-2-methoxy-phenoxymethoxy) -ethyl] -trimethyl-silane: sodium borohydride (275 mg, 7.2 mmol) was added portionwise for 10 min at a solution of 2-Bromo-4-methoxy-5- (2-trimethylsilanyl-ethoxymethoxy) -benzaldehyde (1.3 g, 3.6 mmol) in MeOH (20 mL) at 0 ° C. After 30 min, the reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (2 x 30 mL). The organic materials were washed with brine (30 mL), dried (Na2SO4) and concentrated in vacuo obtaining 1.31 g of [2-Bromo-4-methoxy-5- (2-trimethylsilanyl-ethoxymethoxy) -phenyl] -methanol in the form of a transparent oil. 1 HRMN (300 MHz, CDCl 3) δ: 7.29 (s, 1H), 7.05 (s, 1H), 5.27 (s, 2H), 4.66 (d, 2H, <i>J</i> = 6.6 Hz), 3.87 (s, 3H), 3.79 (t, 2H, <i>J</i>= 8.4 Hz), 1.92 (t, 1H, <i>J</i> = 6.6 Hz), 0.96 (t, 2H, <i>J</i> = 8.4 Hz), 0.01 (s, 9H).

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) and the reaction mixture were added previously stirred for 16 h, diluted with H2O (30 mL) and It was extracted with ether (2 x 30 mL). The organic materials were washed with brine (20 mL), dried (Na2SO4) and dried concentrated in vacuo. Purification by column chromatography silica gel (15% EtOAc / hexanes) gave 1.30 g (92%) of the title compound in the form of a transparent oil. 1 HRMN (300 MHz, CDCl 3) 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,<i>J</i> = 8.4 Hz), 3.58 (q, 2H, <i>J</i> = 6.9 Hz), 1.26 (t, 3H,<i>J</i> = 6.9 Hz), 0.95 (t, 2H, <i>J</i> = 8.4 Hz), -0.01 (s, 9H).

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Reference Example 24 (m)

3-1

H

-benzoimidazol-2-yl-6- (2- (hydroxymethyl) -4-ethoxy-5-methoxy-phenyl) -1

H

-indazol

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<figref>155</figref>

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The compound of Reference Example 24 (m) is prepared similarly to that described in the Reference Example 24 (a), except that, in step (vii), was used [2- (2-Bromo-5-ethoxy-4-methoxy-benzyloxymethoxy) -ethyl] -trimethyl-silane, prepared as described below, instead of [2- (4-Bromo-2-methoxy-5-methyl-phenoxymethoxy) -ethyl] -trimethylsilane. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.64 (s, 1H), 13.00 (s, 1H), 8.50 (d, 1H, <i>J</i> = 8.4 Hz), 7.73 (d, 1H,<i>J</i> = 8.4 Hz), 7.62 (s, 1H), 7.52 (dd, 1H, <i>J</i> = 6.0, 1.8 Hz), 7.32 (dd, 1H, <i>J</i> = 8.4, 1.2 Hz), 7.19-7.24 (m, 2H), 7.15 (s, 1H), 6.91 (s, 1H), 5.11 (t, 1H, <i>J</i> = 5.1 Hz), 4.37 (d, 2H, <i>J</i> = 5.1 Hz), 4.08 (q, 2H, <i>J</i> = 6.9 Hz), 3.80 (s, 3H), 1.37 (t, 3H, <i>J</i> = 6.9 Hz). MS (ES) [M + H] / z calculated 415, found 415.

The starting material was prepared as follow:

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<figref>156</figref>

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Preparation of 4-Bromo-2-methoxy-5- (2-trimethylsilanyl-ethoxymethyl) -phenol: [2-Bromo-4-methoxy-5- (2-trimethylsilanyl-ethoxymethoxy) -phenyl] -methanol, per rest for periods of up to a week, he experienced a SEM migration from phenolic alcohol to benzyl obtaining the title compound. 1 HRMN (300 MHz, CDCl 3) 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, <i>J</i> = 8.4 Hz), 0.97 (t, 2H, <i>J</i> = 8.4 Hz), 0.02 (s, 9H).

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<figref>157</figref>

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Preparation of [2- (2-Bromo-5-ethoxy-4-methoxy-benzyloxymethoxy) -ethyl] -trimethyl-silane: it stirred 4-Bromo-2-methoxy-5- (2-trimethylsilanyl-ethoxymethyl) -phenol (1.28 g, 3.53 mmol) with a solution of potassium hydroxide (790 mg, 14.1 mmol) in DMSO (8 mL). Iodoethane (565 mL, 7.1 was added mmol) and the reaction mixture previously stirred for 16 h is diluted with H2O (30 mL) and extracted with ether (2 x 30 mL). The Organic materials were washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel column chromatography (15% EtOAc / hexanes) gave 1.26 g (91%) of the title compound as an oil transparent. 1 HRMN (300 MHz, CDCl 3) δ: 7.02 (s, 1H), 6.98 (s, 1H), 4.78 (s, 2H), 4.60 (s, 2H), 4.09 (q, 2H, <i>J</i> = 6.6 Hz), 3.86 (s, 3H), 3.69 (t, 2H, <i>J</i> = 8.4 Hz), 1.46 (t, 3H, <i>J</i> = 6.6 Hz), 0.97 (t, 2H, <i>J</i> = 8.4 Hz), 0.04 (s, 9H).

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Reference Example 24 (n)

3-1

H

-benzoimidazol-2-yl-6- (2- (hydroxymethyl) -5-methoxy-4-hydroxy-phenyl) -1

H

-indazol

<figref>158</figref>

The compound of the Reference Example 24 (n) was prepared in a manner similar to that described in the Reference Example 24 (a), except that it was used 6- [5-Methoxy-2-hydroxymethyl-4- (2-trimethylsilanyl-ethoxymethoxy) -phenyl] -1- (2-trimethylsilanyl-ethoxymethyl) -3- [1- (2-trimethylsilanyl-ethoxymethyl) -1<i>H</i>-benzoimidazol-2-yl] -1<i>H</i>-indazol, prepared as described below, instead of 6- [5-Methoxy-2-methyl-4- (2-trimethylsilanyl-ethoxymethoxy) -phenyl] -1- (2-trimethylsilanyl-ethoxymethyl) -3- [1- (2-trimethylsilanyl-ethoxymethyl) -1<i>H</i>-benzoimidazol-2-yl] -1<i>H</i>-indazol. 1 H NMR (300 MHz, DMSO-<i>d</i>6) δ: 13.59 (s, 1H), 12.95 (s, 1H), 9.05 (s, 1H), 8.49 (d, 1H, <i>J</i> = 8.4 Hz), 7.72 (dd, 1H, <i>J</i> = 6.3, 2.1 Hz), 7.60 (s, 1H), 7.51 (dd, 1H,<i>J</i> = 6.3, 2.1 Hz), 7.31 (d, 1H, <i>J</i> = 8.4 Hz), 7.20-7.24 (m, 2H), 7.02 (s, 1H), 6.87 (s, 1H), 5.02 (t, 1H, <i>J</i> = 5.4 Hz), 4.32 (d, 2H, <i>J</i> = 5.4 Hz), 3.80 (s, 3H). MS (ES) [M + H] / z calculated 387, found 387; [MH] / z calculated 385, found 385.

The starting material was prepared as follow:

<figref>159</figref>

Preparation of 4-methoxy-5- (2-trimethylsilanyl-ethoxymethoxy) -2-trimethylstannanyl-benzaldehyde: 2-Bromo-4-methoxy-5- (2-trimethylsilanyl-ethoxymethoxy) -benzaldehyde (3.36 g, 9.3 mmol) and hexamethyldisin (5.0 g, 15.3 mmol) were stirred in anhydrous toluene (60 mL) in an argon purged flask. Tetrakis (triphenylphosphine) palladium (0) was added (500 mg, 0.45 mmol) and the reaction mixture was stirred at 100 ° C for 23 h. The reaction mixture was cooled and concentrated to empty. Purification by gel column chromatography of silica (5% EtOAc / hexanes) gave 2.77 g (67%) of 4-methoxy-5- (2-trimethylsilanyl-ethoxymethoxy) -2-trimethylstannanyl-benzaldehyde in the form of a transparent oil. 1 HRMN (300 MHz, CDCl 3) δ: 9.81 (dd, 1H, <i>J</i> = 3.0, 0.9 Hz), 7.66 (t, 1H, <i>J</i> = 6.6 Hz), 7.21 (t, 1H, <i>J</i> = 9.0 Hz), 5.35 (s, 2H), 3.99 (s, 3H), 3.82 (t, 2H, <i>J</i> = 8.4 Hz), 0.25 (t, 9H, <i>J</i> = 26.7 Hz), 0.98 (t, 2H, <i>J</i> = 8.4 Hz), -0.01 (s, 9H).

<figref>160</figref>

Preparation of [4-Methoxy-5- (2-trimethylsilanyl-ethoxymethoxy) -2-trimethyl-stannanyl-phenyl] -methanol: 4-methoxy-5- (2-trimethylsilanyl-ethoxymethoxy) -2-trimethyl-stannanyl-benzaldehyde (2.36 g, 5.3 mmol) was stirred in MeOH (30 mL) at 0 ° C. Was added sodium borohydride (400 mg, 10.6 mmol) and the reaction mixture is stirred for 1 h. The solution was diluted with H2O (60 mL) and was extracted with EtOAc (2 x 50 mL). The organic materials were washed with brine (50 mL), dried (Na2SO4) and dried concentrated in vacuo to obtain 2.16 g (91%) of [4-methoxy-5- (2-trimethylsilanyl-ethoxymethoxy) -2-trimethylstannanyl-phenyl] -methanol in the form of a transparent oil. 1 HRMN (300 MHz, CDCl 3) δ: 7.18 (t, 1H, <i>J</i> = 6.9 Hz), 7.03 (t, 1H,<i>J</i> = 9.3 Hz). 5.27 (s, 2H), 4.58-4.63 (m, 2H), 3.89 (s, 3H), 3.80 (t, 2H, <i>J</i> = 8.4 Hz), 1.53 (t, 1H, <i>J</i>= 6.0 Hz), 0.96 (t, 2H, <i>J</i> = 8.4 Hz), 0.31 (t, 9H, <i>J</i> = 27.3 Hz), 0.01 (s, 9H).

<figref>161</figref>

Preparation of 6- [5-Methoxy-2-hydroxymethyl-4- (2-trimethylsilanyl-ethoxymethoxy) -phenyl] -1- (2-trimethylsilanyl-ethoxymethyl) -3- [1- (2-trimethylsilanyl-ethoxymethyl) -1<i>H</i>-benzoimidazol-2-yl] -1<i>H</i>-indazol: 6-iodo-1- [2- (trimethyl-silanyl) -ethoxymethyl] -3- {1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-benzoimidazol-2-yl} -1<i>H</i>-indazol [Reference 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 mixture was allowed to cool and diluted with EtOAc The organic materials were washed with NaHCO 3 sat. and brine, dried (Na2SO4) and concentrated in vacuo. Purification by silica gel column chromatography (20% EtOAc / hexanes) gave 224 mg (60%) of 6- [5-Methoxy-2-hydroxymethyl-4- (2-trimethylsilanyl-ethoxymethoxy) -phenyl] -1- (2-trimethylsilanyl-ethoxymethyl) -3- [1- (2-trimethylsilanyl-ethoxymethyl) -1<i>H</i>-benzoimidazol-2-yl] -1<i>H</i>-indazol in the form of a light yellow oil. 1 HRMN (300 MHz, CDCl 3) δ: 8.70 (d, 1H, <i>J</i> = 8.4 Hz), 7.89-7.92 (m, 1H), 7.63-7.66 (m, 2H), 7.34-7.41 (m, 4H), 6.91 (s, 1H), 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, 9H).

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Reference Example 24 (o)

3-1

H

-benzoimidazol-2-yl-6- (3-hydroxyphenyl) -1

H

-indazol

<figref>162</figref>

The compound of the Reference Example 24 (o) was prepared in a manner similar to that described in the Reference Example 24 (f), except that it was used 6- (3-methoxyphenyl) -3-1<i>H</i>-benzoimidazol-2-yl-1<i>H</i>-indazol, prepared in a manner similar to that described in the Example of reference 24 (a) except that in step (viii), acid was used 3-methoxy-phenylboronic instead of acid 5-methoxy-2-methyl-4- [2- (trimethylsilanyl) -ethoxymethoxy] -phenylboronic acid, instead of 6- (2-Methoxy-4-hydroxyphenyl) -3-1<i>H</i>-benzoimidazol-2-yl-1<i>H</i>-indazol. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.67 (s, 1H), 13.00 (s, 1H), 9.58 (s, 1H), 8.55 (d, 1H, <i>J</i> = 8.4 Hz), 7.71-7.75 (m, 2H), 7.49-7.57 (m, 2H), 7.30 (t, 1H, <i>J</i> = 7.8 Hz), 7.12-7.24 (m, 4H), 6.80 (dd, 1H, <i>J</i> = 8.1, 1.5 Hz). MS (ES) [M + H] / z calculated 327, found 327; [MH] / z calculated 325, found 325.

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Reference Example 24 (p)

3-1

H

-benzoimidazol-2-yl-6- (2-methoxy-3-hydroxyphenyl) -1

H

-indazol

<figref>163</figref>

The compound of the Reference Example 24 (p) was prepared in a manner similar to that described in the Reference example 24 (a), except that, in step (vi), it was used 3-bromo-2-methoxy-phenol, prepared as described by Aristoff <i>et al., Tet. Lett</i>., 25, 3955-58 (1984) instead of 4-Bromo-2-methoxy-5-methyl-phenol. 1 H NMR (300 MHz, DMSO-<i>d</i>6) δ: 13.60 (s, 1H), 12.97 (s, 1H), 9.37 (s, 1H), 8.52 (d, 1H, <i>J</i> = 8.4 Hz), 7.69-7.74 (m, 2H), 7.51 (dd, 1H, <i>J</i> = 7.8, 1.8 Hz), 7.43 (dd, 1H, <i>J</i> = 8.4, 1.2 Hz), 7.19-7.24 (m, 2H), 7.02 (t, 1H, <i>J</i> = 7.8 Hz), 6.85-6.93 (m, 2H), 3.50 (s, 3H). MS (ES) [M + H] / z calculated 357, found 355. [MH] / z Calculated 357, found 355.

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Reference Example 25 (a)

3-(3

H

-imidazo [4,5-c] pyridin-2-yl) -6- (4-hydroxy-2-methoxyphenyl) -1

H

-indazol

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<figref>164</figref>

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A solution of 6- [5-Methoxy-2-methyl-4- (2-trimethyl-silanyl-ethoxymethoxy) -phenyl] -1- (2-trimethyl-silanylethoxymethyl) -3- [3- (2-trimethyl-silanyl-ethoxymethyl) -3<i>H</i>-imidazo [4,5-c] pyridin-2-yl] -1<i>H</i>-indazol (68 mg, 0.11 mmol) in TBAF (1M 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 chromatography on silica gel column (EtOH / EtOAc 2: 1). Precipitation in acetonitrile gave 21 mg (53%) of 3- (3H-imidazo [4,5-c] pyridin-2-yl) -6- (4-hydroxy-2-methoxyphenyl) -1<i>H</i>-indazol in the form of a white solid. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.70 (s, 1H), 13.49 (wide s, 1H), 9.62 (s, 1H), 9.01 (wide s, 1H), 8.43 (d, 1H, <i>J</i> = 8.7Hz), 8.34 (d, 1 H, <i>J</i> = 5.7Hz), 7.64 (s, 1H), 7.57 (wide s, 1H), 7.39 (dd, 1H, <i>J</i> = 8.7, 1.5Hz), 7.21 (d, 1H, <i>J</i> = 8.1Hz), 6.55 (d, 1H, <i>J</i> = 2.1Hz), 6.49 (dd, 1H, <i>J</i> = 8.1, 2.1Hz), 3.74 (s, 3H). MS (ES) [M + H] / z, calculated 358, found 358; [mH] / z, calculated 356, found 356

Intermediates were prepared as follow:

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<figref>165</figref>

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<i>3- (1,1-Dimethoxy-methyl) -6-iodo-1- (2-trimethyl-silanyl-ethoxymethyl) -1<u>H</u>-indazol</i>. A solution of 6-iodo-3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol [Reference example 14, step (i)] (1.28 g, 2.69 mmol) in CH 2 Cl 2 (40 mL) / MeOH (40 mL) was stirred at -78 ° C. Mix reaction was treated with ozone until a blue color persisted already It was then purged with argon. Methyl sulfide (4 mL) was added and the reaction mixture was stirred 4 h while heating until room temperature. Concentration under vacuum gave a mixture in crude acetal and aldehyde, which became completely the acetal by stirring in trimethyl orthoformate (10 mL) with resin Amberlyst 15 ion exchanger acid (wet) (0.8 g) for 1 h. The resin was filtered off and the solution was concentrated in vacuo. Purification by column chromatography of silica gel gave 1.11 g (92%) of 3- (1,1-dimethoxy-m ethyl) -6-iodo-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol in the form of a transparent oil. 1 H NMR (300 MHz, CDCl 3) δ: 7.98 (s, 1H), 7.68 (d, 1H, <i>J</i> = 8.4Hz), 7.48 (dd, 1H, <i>J</i> = 8.4, 1.2Hz), 5.77 (s, 1H), 5.69 (s, 2H), 3.53 (t, 2H, <i>J</i> = 8.4Hz), 3.43 (s, 6H), 0.88 (t, 2H, <i>J</i>= 8.4Hz), -0.06 (s, 9H).

<figref>166</figref>

<i>3- (1,1-Dimethoxy-methyl) -6- [2-methoxy-4- (2-trimethyl-silanyl-ethoxymethoxy) -phenyl] -1- (2-trimethyl-silanyl-ethoxymethyl) -1<u>H</u>-indazol</i>. 3- (1,1-Dimethoxymethyl) -6-iodo-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol (1.06 g, 2.37 mmol), acid 2-methoxy-4- (trimethyl-silanyl-ethoxymethoxy) -phenyl-boronic (0.99 g, 3.32 mmol) and sodium carbonate (352 mg, 1.4 mmol) are stirred in a mixture of benzene (15 mL), MeOH (3 mL) and water (1 mL) in an argon purged flask. Was added tetrakis (triphenylphosphine) palladium (0) (220 mg, 0.19 mmol) and the reaction mixture was stirred at reflux for 16 h. The reaction mixture was allowed to cool and diluted with ether (70 mL). The organic materials were washed with H2O and brine (30 mL each time), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel column chromatography (15% EtOAc / hexanes) gave 1.12 g (82%) of 3- (1,1-dimethoxy-methyl) -6- [2-methoxy-4- (2-trimethyl-silanyl-ethoxymethoxy) -phenyl] -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol in the form of a slightly yellow oil. 1 H NMR (300 MHz, CDCl 3) δ: 7.91 (d, 1H, <i>J</i> = 8.4Hz), 7.64 (s, 1H), 7.37 (dd, 1H, <i>J</i> = 8.4, 1.2Hz), 7.29 (d, 1H, <i>J</i> = 8.4Hz), 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,<i>J</i> = 8.4Hz), 3.46 (s, 6H), 1.00 (t, 2H, <i>J</i> = 8.4Hz), 0.88 (t, 2H, <i>J</i> = 8.4Hz), 0.03 (s, 9H), -0.05 (s, 9H).

<figref>1167</figref>

<figref>167</figref>

<i>6- [2-Methoxy-4- (2-trimethyl-silanyl-ethoxymethoxy) -phenyl] -1- (2-trimethyl-silanyl-ethoxymethyl) -1<u>H</u>-indazol-3-carbaldehyde</i>. 3- (1,1-Dimethoxymethyl) -6- [2-methoxy-4- (2-trimethyl-silanyl-ethoxymethoxy) -phenyl] -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-inda- zol (1.1 g, 1.92 mmol) was stirred in 1% TFA / CH 2 Cl 2 (20 mL) for 1 h at room temperature. Vacuum concentration provided 1.01 g (100%) of 6- [2-Methoxy-4- (2-trimethyl-silanyl-ethoxymethoxy) -phenyl] -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde in the form of a transparent oil. 1 H NMR (300 MHz, CDCl 3) δ: 10.27 (s, 1H), 8.28 (d, 1H, <i>J</i> = 8.4Hz), 7.73 (s, 1H), 7.55 (dd, 1H, <i>J</i> = 8.4, 1.2Hz), 7.29 (d, 1 HOUR, <i>J</i> = 8.4Hz), 6.72-6.79 (m, 2H), 5.82 (s, 2H), 5.28 (s, 2H), 3.78-3.84 (m, 5H), 3.61 (t, 2H,<i>J</i> = 8.1 Hz), 0.89-1.03 (m, 4H), 0.03 (s, 9H), -0.05 (s, 9H).

<figref>168</figref>

<i>6- [5-Methoxy-2-methyl-4- (2-trimethyl-silanyl-ethoxymethoxy) -phenyl] -1- (2-trimethyl-silanyl-ethoxymethyl) -3- [3- (2-trimethyl-sila- nil-ethoxymethyl) -3<u>H</u>-imidazo [4,5-c] pyridin-2-yl] -1<u>H</u>-indazol</i>. 6- [2-Methoxy-4- (2-trimethyl-silanyl-ethoxymethoxy) -phenyl] -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde (320 mg, 0.61 mmol), 3,4-diamino-pyridine (68 mg, 0.62 mmol) and sulfur (23 mg, 0.73 mmol) were mixed in anhydrous DMF (2 mL) and stirred at 90 ° C for 16 h under argon. The mixture of The reaction was allowed to cool and diluted with EtOAc (20 mL). The Organic materials were washed with NaHCO3 sat. and brine (15 mL each time), dried (Na2SO4) and concentrated to empty. Purification by gel column chromatography of silica (75% to 100% EtOAc / hexanes) gave 78 mg (21%) of 6- [5-Methoxy-2-methyl-4- (2-trimethyl-silanyl-ethoxymethoxy) -phenyl] -1- (2-trimethyl-silanyl-ethoxymethyl) -3- [3- (2-trimethyl-silanyl- ethoxymethyl) -3<i>H</i>-imidazo [4,5-c] pyridin-2-yl] -1<i>H</i>-indazol in the form of a white solid. 1 HRMN (300 MHz, CDCl 3) δ: 10.69 (broad s, 1H), 9.21 (s, 1H), 8.63 (dd, 1H <i>J</i>= 8.4, 0.3Hz), 8.50 (d, 1H, <i>J</i> = 5.4Hz), 7.73 (s, 1H), 7.47 (s width, 1H), 7.57 (dd, 1H, <i>J</i> = 8.7, 1.2Hz), 7.33 (d, 1H,<i>J</i> = 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,<i>J</i> = 8.1 Hz), 0.89-1.04 (m, 4H), 0.04 (s, 9H), -0.06 (s, 9H).

Reference Example 25 (b)

3- [6- (2-morpholin-4-yl-ethylcarbamoyl) -1

H

-benzoimidazol-2-yl] -6- (2-methoxy-4-hydroxyphenyl) -1

H

-indazol

<figref>169</figref>

The compound of the Reference Example 25 (b) was prepared in a manner similar to that described in the Reference example 25 (a), except that the 3,4-diamino-<i>N</i>- (2-morpholin-4-yl-ethyl) -benzamide, It was prepared as described below. 1 HRMN (DMSO-<i>d</i>6) δ: 13.61 (s, 0.5H), 13.59 (s, 0.5H), 13.22 (s, 0.5H), 13.18 (s, 0.5H), 9.59 (s, 1H), 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, 1H), 7.53 (d, 0.5H,<i>J</i> = 8.7Hz), 7.38 (d, 1H, <i>J</i> = 8.7Hz), 7.21 (d, 1H,<i>J</i> = 8.7Hz), 6.55 (d, 1H, <i>J</i> = 2.1Hz), 6.49 (dd, 1H,<i>J</i> = 8.4, 2.1Hz), 3.75 (s, 3H), 3.58 (t, 4H, <i>J</i> = 4.5Hz), 3.42 (q, 2H, <i>J</i> = 6.0 Hz), 2.43-2.51 (m, 6H). MS (ES) [M + H] / z, calculated 513, found 513; [mH] / z, calculated 511, found 511.

3,4-Diamino-<i>N</i>- (2-morpholin-4-yl-ethyl) -benzamide It was prepared as follows:

<figref>170</figref>

<i>3,4-Diamino-<u>N</u>- (2-morpholin-4-yl-ethyl) -benzamide</i>. 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 mixed in anhydrous DMF (80 mL) at 0 ° C. EDC (9.45 g, 49.3 was added mmol) and the reaction mixture was stirred for 24 h at the temperature ambient. Concentration under vacuum and purification by silica gel column chromatography (MeOH al 10% / CH 2 Cl 2 with 0.2% NH 4 OH) gave 2.6 g (31%) of 3,4-diamino-<i>N</i>- (2-morpholin-4-yl-ethyl) -benzamide in the form of a light brown solid. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 7.72 (t, 1H, <i>J</i> = 5.4Hz), 7.02 (d, 1H, <i>J</i> = 1.8Hz), 6.92 (dd, 1H, <i>J</i> = 8.1, 1.8Hz), 6.46 (d, 1 H, <i>J</i> = 8.1Hz), 4.89 (wide s, 2H), 4.51 (wide s, 2H), 3.55 (t, 4H, <i>J</i> = 4.8Hz), 3.29 (q, 2H, <i>J</i> = 7.2Hz), 2.36-2.43 (m, 6H).

Reference Example 25 (c)

3- [6- (4-methylpiperazin-1-il) -1

H

-benzoimidazol-2-yl] -6- (2-methoxy-4-hydroxyphenyl) -1

H

-indazol

<figref>171</figref>

The compound of the Reference Example 25 (c) was prepared in a manner similar to that described in the Reference example 25 (a), except that, in step (iv), it was used 4- (4-methyl-piperazin-1-yl) -benzene-1,2-diamine (Harapanhalli <i>et al., J. Med. Chem</i>., 39, 4804-09 (1996)) instead of 3,4-diaminopyridine. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 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, <i>J</i> = 8.4Hz), 8.41 (d, 0.67H, <i>J</i> = 8.4Hz), 7.59 (s, 1H), 7.55 (d, 0.67H, <i>J</i> = 8.7Hz), 7.31-7.37 (m, 1.33H), 7.20 (app d, 1.33H, <i>J</i> = 8.4Hz), 6.92-7.01 (m, 1.67H), 6.55 (d, 1H, <i>J</i> = 1.5Hz), 6.48 (dd, 1H, <i>J</i> = 8.4, 2.1Hz), 3.74 (s, 3H), 3.12 (s width, 4H), 2.50 (s width, 4H), 2.22 (s, 3H). MS (ES) [M + H] / z, calculated 455, found 455; [mH] / z, calculated 453, found 453.

Reference Example 25 (d)

3- [4- (4-methylpiperazin-1-il) -1

H

-benzoimidazol-2-yl] -6- (2-methoxy-4-hydroxyphenyl) -1

H

-indazol

<figref>172</figref>

The compound of the Reference Example 25 (d) was prepared in a manner similar to that described in the Reference example 25 (a), except that, in step (iv), it was used 3- (4-methyl-piperazin-1-yl) -benzene-1,2-diamine (Harapanhalli <i>et al., J. Med. Chem</i>., 39, 4804-09 (1996)), analogous to the preparation of isomer 4) instead of 3,4-diaminopyridine. 1 H NMR (300 MHz, DMSO-<i>d</i>6) δ: 13.41 (broad s, 1H), 12.79 (wide s, 1H), 9.60 (wide s, 1H), 8.37 (d, 1H, <i>J</i> = 8.4Hz), 7.60 (s, 1H), 7.36 (dd, 1H, <i>J</i> = 8.4, 1.2Hz), 7.22 (d, 1 HOUR, <i>J</i> = 8.4Hz), 7.03-7.07 (m, 2H), 6.46-6.56 (m, 3H), 3.75 (s, 3H), 3.62 (wide s, 4H), 2.62 (broad s, 4H), 2.28 (s, 3H). MS (ES) [M + H] / z, calculated 455, found 455; [mH] / z, calculated 453, found 453

Reference Example 25 (e)

3-imidazol-2-yl-6- (2-methoxy-4-hydroxyphenyl) -1

H

-indazol

<figref>173</figref>

The compound of the Reference Example 25 (e) was prepared in a manner similar to that described in the Reference example 25 (a), except that it was used 6- [5-Methoxy-2-methyl-4- (2-trimethyl-silanyl-ethoxymethoxy) -phenyl] -1- (2-trimethyl-silanyl-ethoxymethyl) -3-imidazol-2-yl-1<i>H</i>-indazol instead of 6- [5-Methoxy-2-methyl-4- (2-trimethyl-silanyl-ethoxymethoxy) -phenyl] -1- (2-trimethyl-silanyl-ethoxymethyl) -3- [3- (2-trimethyl-silanyl- ethoxymethyl) -3<i>H</i>-imidazo [4,5-c] pyridin-2-yl] -1<i>H</i>-indazol. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.10 (s, 1H), 12.59 (s, 1H), 9.56 (s, 1H), 8.27 (d, 1H, <i>J</i> = 8.4Hz), 7.53 (s, 1H), 7.25 (dd, 1H, <i>J</i> = 8.4, 1.2Hz), 7.13-7.20 (m, 3H), 6.54 (d, 1H, <i>J</i> = 2.1Hz), 6.47 (dd, 1H, <i>J</i> = 8.4, 2.1Hz), 3.73 (s, 3H). MS (ES) [M + H] / z, calculated 307, found 307.

The starting material was prepared as follow:

<figref>174</figref>

Glioxal was added dropwise (40% by weight in H2O, 0.4 mL, 3.5 mmol) to a solution of 420 mg (0.8 mmol) of 6- [2-Methoxy-4- (2-trimethyl-silanyl-ethoxymethoxy) -phenyl] -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde, of Reference Example 25 (a) step (iii), and ammonia 28% aqueous (0.6 mL) in THF (8 mL) / MeOH (8 mL) and the solution is stirred at room temperature for 16 h. Reaction mixture it was concentrated in vacuo and dissolved in CHCl3 (50 mL). The Organic materials were washed with H2O and brine (25 mL each once), dried (Na2SO4) and concentrated in vacuo. The purification by silica gel column chromatography (EtOAc 40% / hexanes) gave 120 mg (27%) of 6- [5-Methoxy-2-methyl-4- (2-trimethyl-silanyl-ethoxymethoxy) -phenyl] -1- (2-trimethyl-silanyl-ethoxymethyl) -3-imidazol-2-yl-1<i>H</i>-indazol in the form of a transparent oil. 1 H NMR (300 MHz, CDCl 3) δ: 10.03 (s, 1H), 8.48 (d, 1H, <i>J</i> = 8.4Hz), 7.65 (s, 1H), 7.46 (dd, 1H, <i>J</i> = 8.4, 1.5Hz), 7.29-7.48 (m, 2H), 7.13 (d, 1H, <i>J</i> = 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, <i>J</i> = 8.4Hz), 0.88-1.03 (m, 4H), 0.03 (s, 9H), -0.05 (s, 9H).

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Reference Example 25 (f)

3- [4- (2-hydroxyethylsulfanyl) -1

H

-benzoimidazol-2-yl] -6- (2-methoxy-4-hydroxyphenyl) -1

H

-indazol

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<figref>175</figref>

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The compound of Reference Example 25 (f) is prepared similarly to that described in the Reference Example 25 (a), except that, in step (iv), it was used 2- (2,3-diaminophenylsulfanyl) -ethanol) instead of 3,4-diaminopyridine. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.51 (s, 1H), 13.02 (s, 1H), 9.59 (s, 1H), 8.45 (d, 1H, <i>J</i> = 8.4Hz), 7.61 (s, 1H), 7.32-7.40 (m, 2H), 7.11-7.23 (m, 3H), 6.55 (d, 1H, <i>J</i> = 2.4Hz), 6.48 (dd, 1H, <i>J</i> = 8.1, 2.4Hz), 4.96 (wide s, 1H), 3.75 (s, 3H), 3.65 (wide s, 2H), 3.33 (t, 2H, <i>J</i> = 6.9Hz). MS (ES) [M + Na] / z, calculated 455, found 455, [mH] / z, calculated 431, found 431

The starting material was prepared as follow:

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<figref>176</figref>

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<i>2- (3-Amino-2-nitro-phenylsulfanyl) -ethanol</i>. 3-Chloro-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 mixed in DMF anhydrous (15 ml) and stirred at 130 ° C for 4 h. The solution is allowed to cool and concentrated in vacuo. Purification by silica gel column chromatography (70% EtOAc / hexanes) gave 1.29 g (93%) of 2- (3-amino-2-nitro-phenylsulfanyl) -ethanol in the form of a bright red solid. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 7.20 (t, 1H, <i>J</i> = 8.1Hz), 6.80 (s, 2H), 6.73 (dd, 1H, <i>J</i> = 8.4, 0.9Hz), 6.63 (dd, 1H,<i>J</i> = 7.8, 1.2Hz), 4.92 (t, 1H, <i>J</i> = 6.0 Hz), 3.58 (q, 2H, <i>J</i> = 6.0 Hz), 2.98 (t, 2H, <i>J</i> = 6.0 Hz).

<i>2- (2,3-Diamino-phenylsulfanyl) -ethanol</i>. 2- (3-Amino-2-nitro-phenylsulfanyl) -ethanol (1.02 g, 4.8 mmol) was reduced by hydrogenation using 0.31 MPa of H2 with 10% Pd / C (180 mg) in EtOAc (25 mL) for 6 h. After filtering through Celite, the solvent was removed at empty. Purification by gel column chromatography of silica (EtOAc) gave 762 mg (87%) of 2- (2,3-diamino-phenylsulfanyl) -ethanol in the form of a slightly yellow solid. 1 HRMN (300 MHz, CDCl 3) δ: 6.98 (dd, 1H, <i>J</i> = 7.5, 1.5Hz), 6.60-6.72 (m, 2H), 3.65 (t, 2H, <i>J</i> = 5.7Hz), 3.55 (wide s, 5H), 2.91 (t, 2H, <i>J</i> = 5.7Hz)

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Reference Example 25 (g)

3- (5-methylcarbamoyl-1

H

-benzoimidazol-2-yl) -6- (2-methoxy-4-hydroxyphenyl) -1

H

-indazol

<figref>177</figref>

The compound of Reference Example 25 (g) is prepared similarly to that described in the Reference Example 25 (a), except that, in step (iv), it was used 3,4-diamino-<i>N</i>-methylbenzamide (Kumar, <i>et al., J. Med. Chem</i>., 27, 1083-89 (1984)) in 3,4-diaminopyridine site. 1 H NMR (300 MHz, DMSO-<i>d</i>6) δ: 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,<i>J</i> = 8.4Hz), 7.35-7.40 (m, 1H), 7.21 (d, 1H,<i>J</i> = 2.1Hz), 6.55 (d, 1H, <i>J</i> = 2.4Hz), 6.49 (dd, 1H,<i>J</i> = 8.4, 2.4Hz), 3.75 (s, 3H), 2.82 (d, 1.5H, <i>J</i> = 1.5Hz), 2.81 (d, 1.5H, <i>J</i> = 1.5Hz) MS (ES) [M + H] / z, calculated 414, found 414, [mH] / z, calculated 412, Found 412.

Reference Example 25 (h)

3- (5-dimethylamino-1

H

-benzoimidazol-2-yl) -6- (2-methoxy-4-hydroxy-phenyl) -1

H

-indazol

<figref>178</figref>

The compound of the Reference Example 25 (h) was prepared in a manner similar to that described in the Reference example 25 (a), except that, in step (iv), it was used 3,4-diamino-<i>N, N</i>-dimethyl-aniline (Cazaux, <i>et. al., can. J. Chem</i>., 71, 1236-46 (1993)) instead of 3,4-diaminopyridine. 1 H NMR (300 MHz, DMSO-<i>d</i>6) δ: 13.36 (s, 1H), 12.51 (s width, 1H), 9.58 (s, 1H), 8.42 (d, 1H, <i>J</i> = 8.4Hz), 7.59 (s, 1H), 7.49 (broad s, 1H), 7.33 (dd, 1H, <i>J</i> = 8.4, 1.2Hz), 7.20 (d, 1H, <i>J</i> = 8.1Hz), 6.87 (broad d, 2H, <i>J</i> = 8.1Hz), 6.55 (d, 1 H, <i>J</i> = 2.1Hz), 6.48 (dd, 1H, <i>J</i> = 8.1, 2.1Hz), 3.73 (s, 3H), 2.92 (s, 6H). MS (ES) [M + H] / z, calculated 400, found 400, [mH] / z, calculated 398, found 398.

Reference Example 25 (i)

3- (5-aminosulfonyl-1

H

-benzoimidazol-2-yl) -6- (2-methoxy-4-hydroxy-phenyl) -1

H

-indazol

<figref>179</figref>

The compound of the Reference Example 25 (i) was prepared in a manner similar to that described in the Reference example 25 (a), except that, in step (iv), it was used 3,4-diaminobenzenesulfonamide in 3,4-diaminopyridine site. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 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,<i>J</i> = 8.1Hz), 8.18 (d, 0.5H, <i>J</i> = 1.5Hz), 7.99 (d, 0.5H,<i>J</i> = 1.5Hz), 7.86 (d, 0.5H, <i>J</i> = 8.4Hz), 7.62-7.72 (m, 2.5H), 7.29 (d, 1H, <i>J</i> = 8.4Hz), 7.20-7.28 (m, 3H), 6.55 (d, 1H, <i>J</i> = 2.1Hz), 6.49 (dd, 1H, <i>J</i> = 8.4, 2.1Hz), 3.75 (s, 3H). MS (ES) [M + H] / z, calculated 436, found 436, [mH] / z, calculated 434, found 434.

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Reference Example 25 (j)

3- (4-methylcarbamoyl-1

H

-benzoimidazol-2-yl) -6- (2-methoxy-4-hydroxy-phenyl) -1

H

-indazol

<figref>180</figref>

The compound of the Reference Example 25 (i) was prepared in a manner similar to that described in the Reference example 25 (a), except that, in step (iv), it was used 2,3-diamino-<i>N</i>-methyl-benzamide instead of 3,4-diaminopyridine. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.71 (s, 1H), 13.46 (s, 1H), 9.85 (broad d, 1H, <i>J</i> = 4.8Hz), 9.61 (s, 1H), 8.38 (d, 1H,<i>J</i> = 8.4Hz), 7.89 (dd, 1H, <i>J</i> = 7.5, 1.2Hz), 7.66-7.72 (m, 2H), 7.47 (dd, 1H, <i>J</i> = 8.4, 1.2Hz), 7.36 (t, 1H, <i>J</i> = 7.8Hz), 7.23 (d, 1H, <i>J</i> = 8.1Hz), 6.56 (d, 1H, <i>J</i> = 2.4Hz), 6.50 (dd, 1H, <i>J</i> = 8.4, 2.4Hz), 3.76 (s, 3H), 3.10 (d, 3H, <i>J</i> = 1.8H). MS (ES) [M + H] / z, calculated 414, found 414, [mH] / z, calculated 412, found 412.

The 2,3-diamino-<i>N</i>-methyl-benzamide It was prepared as follows:

<figref>181</figref>

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<i>2-Amino-<u>N</u>-methyl-3-nitro-benzamide</i>. Acid 2-amino-3-nitro-benzoic (1.8 g, 9.9 mmol) and methylamine hydrochloride (1.33 g, 19.8 mmol) stirred in anhydrous CH 2 Cl 2 (30 ml) / DMF (5 mL) at 0 ° C. He added EDC (2.83 g, 14.8 mmol) and DIEA (4.92 mL, 27.7 mmol) and the solution was stirred 3 h while heating to temperature ambient. The reaction mixture was concentrated in vacuo and purified. by silica gel column chromatography (MeOH al 8% / CHCl 3) obtaining 1.42 g (74%) of 2-amino-<i>N</i>-methyl-3-nitrobenzamide in the form of a yellow solid. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 8.58 (wide s, 1H), 8.23 ​​(wide s, 2H), 8.15 (dd, 1H, <i>J</i> = 8.1, 1.8Hz), 7.82 (dd, 1H, <i>J</i> = 8.1, 1.8Hz), 6.68 (t, 1H, <i>J</i> = 8.1Hz), 2.76 (d, 3H, <i>J</i> = 4.5Hz)

<i>2,3-Diamino-<u>N</u>-methyl-benzamide</i>. 2-Amino-<i>N</i>-methyl-3-nitro-benzamide (1.4 g, 7.2 mmol) was reduced by hydrogenation using 0.345 MPa of H2 with 10% Pd / C (250 mg) in EtOAc (25 mL) for 5 h. After filtration through Celite, the solvent was removed at empty. Purification by gel column chromatography of silica (10% MeOH / CHCl3) gave 1.08 mg (91%) of 2,3-diamino-<i>N</i>-methyl-benzamide in the form of a slightly yellow solid. 1 HRMN (300 MHz, CDCl 3) δ: 6.87 (dd, 1H, <i>J</i> = 7.8, 1.5Hz), 6.76 (dd, 1H, <i>J</i> = 7.8, 1.5Hz), 6.59 (t, 1H, <i>J</i> = 7.8Hz), 6.14 (wide s, 1H), 4.28 (wide s, 4H), 2.95 (d, 3H, <i>J</i> = 5.1Hz)

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Reference Example 26

6- (4-hydroxy-3-methoxyphenyl) -3- [E-2- (4-glycylamino-phenyl) -etenyl] -1

H

-indazol

<figref>182</figref>

The compound of Reference Example 26 is prepared from the starting material described below of similar to that described in the Reference Example 1 (a): 1 HRMN (300 MHz, CDCl 3) δ: 8.29 (d, 1H), 7.80 (m, 5H), 7.58 (m, 3H), 7.38 (s, H), 7.27 (d, 1H), 7.01 (d, 1H), 4.00 (s, 3H), 3.42 (s, 2H); LCMS (100% area) Rt = 3.44 min, (pos) [M + H] / z, calculated 415.1, found 415.2.

The starting material was prepared as follow:

<figref>183</figref>

Was prepared 3-iodo-6- (3-methoxy-4-methoxymethoxy-phenyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol from the compound prepared in the Reference Example 1 (a), step (v) in a manner similar to that described in the Reference example 10, step (ii): R<i>F</i> sm = 0.11, p = 0.43 (ethyl acetate-hexane 3: 7); 1 HRMN (300 MHz, CDCl 3) δ: 7.71 (s, 1H), 7.55 (m, 2H), 7.33 (m, 1H), 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), -0.03 (s, 9H).

<figref>184</figref>

Was prepared 3-Styryl-6- (3-methoxy-4-methoxymethoxy-phenyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol similar to that described in Reference Example 11, step (iii): R f sm = 0.41, p = 0.35 (acetate ethyl hexane 2: 8); 1 HRMN (300 MHz, CDCl 3) δ: 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).

<figref>185</figref>

Was prepared 3-Carboxaldehyde-6- (3-methoxy-4-methoxymethoxy-phenyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol similar to that described in the Reference Example 33 (a), step (i): 1 HRMN (300 MHz, CDCl 3) δ: 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).

<figref>186</figref>

Was prepared 3- (4-nitrostyryl) -6- (3-methoxy-4-methoxymethoxy-phenyl) -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol similar to that described in the Reference Example 33 (a), step (ii) except that bromide of 4-nitrobenzyltriphenylphosphonium and hexamethyldisilazide of lithium instead of chloride 2-picolyltriphenylphosphonium hydride Potassium: LCMS (100% area) Rt = 6.89 min, (pos) [M + H] / z, calculated 562.4, found 562.4.

<figref>187</figref>

Was prepared 3- (4-nitrostyril) -6- (3-methoxy-4-methoxymethoxy-phenyl) -1<i>H</i>-indazol similar to that described in Reference Example 11: FTIR (thin film) 3335, 3178, 2954, 1592, 1512, 1338, 1257, 1136, 1257, 1136, 987 cm -1; 1 HRMN (300 MHz, CDCl 3) δ: 8.22 (d, 2H, <i>J</i> = 8.8 Hz), 8.02 (d, 1H, <i>J</i> = 8.5 Hz), 7.70 (d, 2H, <i>J</i> = 8.8 Hz), 7.58 (m, 3H), 7.45 (dd, 1 HOUR, <i>J</i> = 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, calculated 432.1, found 432.1.

<figref>188</figref>

Was prepared 3- (4-aminoestyryl) -6- (3-methoxy-4-methoxymethoxy-phenyl) -1<i>H</i>-indazol similar to that described in Reference Example 11, stage (iv): R<i>F</i> sm = 0.39, p = 0.26 (acetate ethyl hexane 6: 4); FTIR (thin film) 3366, 3210, 2954, 1608, 1517, 1465, 1412, 1259, 1157, 1077, 989, 912 cm -1; 1 HRMN (300 MHz, CDCl 3) δ: 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 + H] / z, calculated 402.2, found 402.2.

<figref>189</figref>

It dissolved 3- (4-aminoestyryl) -6- (3-methoxy-4-methoxymethoxy-phenyl) -1<i>H</i>-indazol (90 mg, 0.224 mmol) in dichloromethane (2 mL) and treated with Boc-glycine (196 mg, 1.12 mmol, 5 equivalents), DMAP (82 mg, 3 equivalents) and HATU (426 mg, 5 equivalents). The mixture was allowed to stir for 30 min. The mixture was distributed between ethyl acetate and water. The organic material was concentrated, was collected with methanol (5 mL) and treated with potassium carbonate (100 mg) The mixture was heated to 50 ° C for 3 days. Mix resulting was partitioned again between ethyl acetate and water. He Organic material was concentrated and purified by silica (109 mg, 66%): R f sm = 0.32, p = 0.46 (acetate ethyl hexane 6: 4); 1 HRMN (300 MHz, CDCl 3) δ: 8.18 (broad s, 1H), 8.03 (d, 1H, <i>J</i> = 8.1 Hz), 7.56 (m, 5H), 7.40 (m, 3H), 7.20 (m, 3H), 5.29 (s, 2H), 5.20 (wide s, 1H), 3.98 (s, 3H), 3.96 (d, 2H), 3.54 (s, 3H), 1.48 (s, 9H).

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Reference Example 27 (a)

6-phenyl-3-E-styryl-1

H

-indazol

<figref>190</figref>

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It was treated 6-phenyl-3-styryl-1- [2- (trimethyl-silanyl) ethoxymethyl] -1<i>H</i>-indazol (345 mg, 0.81 mmol) with a solution of TBAF (16 ml of a solution 1M in THF, 16 mmol) and ethylenediamine (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 (3x30 ml). The Organic layer was dried over MgSO4 and concentrated under pressure reduced Purification by gel column chromatography of silica gave 6-phenyl-3-E-styryl-1<i>H</i>-indazol in the form of a white solid (80 mg, 34%): 1 H NMR (300 MHz, CDCl 3) δ: 8.10 (d, 1H, <i>J</i> = 8.5 Hz); HRMS (FAB) [M + H] / z, calculated 297.1392, found 297.1393. Anal. Calculated, 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 follow:

<figref>191</figref>

A solution of 476 mg (1.0 mmol) of 6-iodo-3-styryl-1- [2- (trimethyl-silanyl) ethoxymethyl] -1<i>H</i>-indazol, of Reference Example 14 step (i), in dioxane (3 ml, degassed by ultrasonic treatment and bubbling of argon), Pd (PPh3) 4 (23 mg, 0.05 mmol), acid phenyl boronic (302 mg, 2.5 mmol) and Na2CO3 (1.25 ml of a 2M aqueous solution, degassed as has been indicated above) was heated at 90 ° C for 2 h. The solution it was then diluted with ethyl acetate (100 ml) and washed with brine (2x20 ml). The organic layer was dried over MgSO4 and was concentrated under reduced pressure. Purification by chromatography on silica gel column gave 6-phenyl-3-styryl-1- [2- (trimethyl-silanyl) ethoxymethyl] -1<i>H</i>-indazol in the form of a brown oil (345 mg, 81%). 1 HRMN (300 MHz, CDCl 3) δ: 8.09 (dd, 1H, <i>J</i> = 8.5, 0.7 Hz), 7.75 (s, 1H), 7.70 (d, 1H, <i>J</i> = 7.0 Hz), 7.64-7.58 (m, 2H), 7.56-7.51 (m, 2H), 7.50-7.45 (m, 2H), 7.45-736 (m, 4H), 7.34-7.27 (m, 1H), 5.80 (s, 2H), 3.73 (t, 2H,<i>J</i> = 8.3Hz), 1.12 (t, 2H, <i>J</i> = 8.3Hz).

Reference Example 27 (b)

6- (3-methoxyphenyl) -3-E-styryl-1

H

-indazol

<figref>192</figref>

The compound of the Reference Example 27 (b) was prepared in a manner similar to that described in the Reference example 27 (a), except that, in step (i), 3-methoxyphenyl boronic acid was used instead of phenyl boronic acid. 1 H NMR (300 MHz, MeOH-<i>d</i>4) δ: 8.16 (d, 1H, <i>J</i> = 8.4 Hz), 7.70 (s, 1H), 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, 1H), 3.88 (s, 3H). HRMS (FAB) [M + Na] / z, calculated 349.1317, found 349.1342. Analyzed with 0.1 H 2 O: Calculated, C (80.50), H (5.59), N (8.55). Found: C (80.44), H (5.49), N (8.55).

Reference Example 27 (c)

6- (4-methoxyphenyl) -3-E-styryl-1

H

-indazol

<figref>193</figref>

The compound of the Reference Example 27 (b) was prepared in a manner similar to that described in the Reference example 27 (a), except that, in step (i), 4-methoxyphenyl boronic acid was used instead of phenyl boronic acid. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.20 (s, 1H), 8.23 ​​(d, 1H,<i>J</i> = 8.4 Hz), 7.76-7.64 (m, 5H), 7.54 (s, 1H), 7.50-7.37 (m, 3H), 7.33-7.25 (m, 1H), 7.07 (d, 2H, <i>J</i> = 8.8 Hz), 3.82 (s, 3H). HRMS (FAB) [M + H] / z, calculated 327.1497, found 327.1502. Anal. Calculated, C (80.96), H (5.56), N (8.58). Found: C (80.71), H (5.42), N (8.47).

Reference Example 27 (d)

6-naft-1-il-3-E-styryl-1

H

-indazol

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<figref>194</figref>

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The compound of the Reference Example 27 (d) was prepared in a manner similar to that described in the Reference example 27 (a), except that, in step (i), 1-naphthalene boronic acid was used instead of acid phenyl-boronic. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 10.11 (s, 1H), 8.45 (d, 1H. <i>J</i>= 8.41), 7.97-7.87 (m, 3H), 7.66-7.37 (m, 13H), 7.35-7.28 (m, 1 HOUR). HRMS (FAB) [M + Na] / z, calculated 369.1368, found 369.1359. Anal. Calculated C (86.68), H (5.32), N (8.19). Found: C (86.52), H (5.32), N (8.19).

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Reference Example 27 (e)

6-pyridin-3-yl-3-E-styryl-1

H

-indazol

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<figref>195</figref>

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The compound of the Reference Example 27 (e) was prepared in a manner similar to that described in the Reference example 27 (a), except that, in step (i), 3-pyridinboronic acid was used instead of acid phenyl-boronic. 1 HRMN (300 MHz, MeOH-<i>d</i>4) δ: 8.97 (s, 1H), 8.63 (d, 1H, <i>J</i> = 4.8 Hz), 8.30 (d, 1H, H = 8.5 Hz), 8.27 (d, 1H, <i>J</i> = 8.1 Hz), 7.86 (s, 1H), 7.72 (d. 2H, <i>J</i> = 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, calculated 298.1344, found 298.1356. Analyzed with 0.25 H2O: Calculated, C (79.58), H (5.18), N (13.92). Found: C (79.53), H (5.16), N (13.80).

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Reference Example 27 (f)

6-pyridin-4-yl-3-E-styryl-1

H

-indazol

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<figref>196</figref>

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The compound of the Reference Example 27 (f) was prepared in a manner similar to that described in the Reference example 27 (a), except that, in step (i), 4-pyridinboronic acid was used instead of acid phenyl-boronic. 1 HRMN (300 MHz, McOH-<i>d</i>4) δ: 8.69 (broad s, 2H), 8.30 (d, 1H,<i>J</i> = 8.5 Hz), 7.96 (s, 1H), 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, 1H). HRMS (FAB) [M + H] / z, calculated 298.1344, found 298,1357. Analyzed with 0.3 H 2 O: Calculated, C (79.34), H (5.19), N (13.88). Found: C (79.14), H (5.08), N (13.84).

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Reference Example 27 (g)

6-indol-4-il-3-E-styryl-1

H

-indazol

<figref>197</figref>

The compound of the Reference Example 27 (g) was prepared in a manner similar to that described in the Reference example 27 (a), except that, in step (i), 4-indolboronic acid was used instead of acid phenyl-boronic. 1 H NMR (300 MHz, MeOH-<i>d</i>4) δ: 8.25 (d, 1H, <i>J</i> = 8.5 Hz), 7.85 (s, 1H), 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, 1H, <i>J</i> = 3.2 Hz) HRMS (FAB) [M + H] / z, calculated 336,1501, found 336,1506. Analyzed with 0.3 H 2 O: Calculated, C (78.97), H (5.36), N (12.01). Found: C (78.95), H (5.20), N (12.03).

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Reference Example 27 (h)

6- [3-ethoxy-4-hydroxyphenyl] -3-E-styryl-1

H

-indazol

<figref>198</figref>

The compound of the Reference Example 27 (h) was prepared in a manner similar to that described in the Reference example 27 (a), except that, in step (i), acid was used 3-ethoxy-4- (2-trimethyl-silanyl-ethoxymethoxy) benzene-boronic instead of phenyl boronic acid. 1 HRMN (300 MHz, CDCl 3) δ: 8.10 (d, 1H, <i>J</i> = 8.7 Hz). 7.74 (s, 1H), 7.74-7.16 (m, 10H), 7.07 (d, 1H, <i>J</i> = 8.15 Hz). 4.27 (q, 2H,<i>J</i> = 14.0 Hz), 1.54 (t, 3H, <i>J</i> = 14.0 Hz). HRMS (FAB) [M + H] / z, calculated 357,1603, found 357.1611. Analyzed with 0.2 H 2 O: Calculated, C (76.73), H (5.71), N (7.78). Found: C (76.72), H (5.91), N (7.63).

The starting material was prepared as follow:

<figref>199</figref>

4-Bromo-2-ethoxy-phenol (Smith <i>et al., Soc. Pl.,</i> 1877-78 (1992)) is became acidic 3-ethoxy-4- (2-trimethyl-silanylethoxymethoxy) -benzene-boronic similar to that described in the Reference Example 24 (a) stages (vi) - (vii). 1 H NMR (300 MHz, CDCl 3) δ: 7.82 (d, 1H, <i>J</i> = 8.0 Hz), 7.72 (s, 1H), 7.31 (d, 1 HOUR, <i>J</i> = 8.1 Hz), 5.37 (s, 2H), 4.29 (q, 2H, <i>J</i> = 14.0 Hz), 3.87 (t, 2H, <i>J</i> = 16.8 Hz), 1.54 (t, 2H, <i>J</i> = 14.0 Hz), 0.99 (t, 2H, <i>J</i> = 16.8 Hz), 0.03 (s, 9H).

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Reference Example 27 (i)

6- [3- (2-hydroxyethoxy) -4-hydroxyphenyl] -3-E-styryl-1

H

-indazol

<figref>200</figref>

The compound of the Reference Example 27 (i) was prepared in a manner similar to that described in the Reference example 27 (a), except that, in step (i), acid was used 3- [2- (trimethyl-silanyl-ethoxymethoxy) -ethoxy] -4- (2-trimethyl-silanyl-ethoxymethoxy) -benzene-boronic, prepared from 2- (2-hydroxy-ethoxy) -phenol (Yamaguchi <i>et al., Bull. Chem. Soc. Jpn</i>., 61, 2047-54 (1988)) in a manner similar to that described in Reference Example 24 (c) steps (i) - (iii), instead of phenyl boronic acid. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 8.17 (d, 1H, <i>J</i> = 8.7 Hz), 7.73-7.17 (m, 11 H), 6.92 (d, 1H, <i>J</i> = 8.2 Hz), 4.13 (t, 2H,<i>J</i> = 9.7 Hz), 3.8 (t, 2H, <i>J</i> = 9.7 Hz). HRMS (FAB) [M + H] / z, calculated 373,1552, found 373,1563. Analyzed with 0.05 trifluoroacetic acid: Calculated, C (73.37), H (5.35), N (7.41). Found: C (73.11), H (5.33), N (7.39).

Reference Example 27 (j)

6- (3,4-dimethoxyphenyl) -3-E-styryl-1

H

-indazol

<figref>201</figref>

The compound of the Reference Example 27 (j) was prepared in a manner similar to that described in the Reference example 27 (a), except that, in step (i), acid was used 3,4-dimethoxyphenyl boronic instead of phenyl boronic acid. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 8.01 (d, 1H, <i>J</i> = 8.1 Hz), 7.51-7.05 (m, 11H), 6.86 (d, 1H, <i>J</i> = 8.0 Hz) 3.58 (s, 3H), 3.65 (s, 3H). HRMS (FAB) [M + H] / z, calculated 357.1598, found 357.1508. Analyzed with 0.2 H 2 O: Calculated, 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-yl) -3-E-styryl-1

H

-indazol

<figref>202</figref>

6- (2-Methoxypyridin-5-yl) -3 - ((<i>AND</i>) -styryl) -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol became 6- (2-methoxypyridin-5-yl) -3-E-styryl-1<i>H</i>-indazol similar to that described in the Reference Example 27 (a). 1 HRMN (300 MHz, CDCl 3) δ: 8.53 (d, 1 HOUR, <i>J</i> = 2.1 Hz), 8.15 (d, 1H, <i>J</i> = 9.2 Hz), 7.97 (dd, 1 HOUR, <i>J</i> = 2.6, 8.6 Hz), 7.79 (s, 1H), 7.74-7.34 (m, 8H), 6.94 (d, 1H, <i>J</i> = 8.6 Hz). HRMS (FAB) [M + H] / z, calculated 328.1450, found 328.1462. Anal. Calculated, 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 follow:

<figref>203</figref>

A solution of 5-bromo-2-methoxypyridine (2.00 g, 6.10 mmol), hexamethyldisin (1.15 g, 6.10 mmol) and Pd (PPh3) 4 (0.28 g, 0.24 mmol) in degassed dioxane (10 ml) was refluxed for 16 h. He added 6-iodine-3 - ((<i>AND</i>) -styryl) -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol (2.90 g, 6.10 mmol) to the above mixture, followed by Pd (PPh3) 4 (0.35 g 0.31 mmol). The mixture of reaction was refluxed for 16 h. The mixture was diluted to then with ethyl acetate (150 ml) and washed with brine (30 ml). The organic materials were dried over MgSO4, and They were then concentrated under reduced pressure. Purification by silica gel column chromatography gave 6- (2-Methoxypyridin-5-yl) -3 - ((<i>AND</i>) -styryl) -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol in the form of a yellow solid (1.12 g, 40%). 1 HRMN (300 MHz, CDCl 3) δ: 8.51 (d, 1H, <i>J</i> = 2.5 Hz), 8.50 (d, 1H,<i>J</i> = 9.1 Hz), 7.93 (dd, 1H, <i>J</i> = 2.5, 8.6 Hz), 7.69 (s, 1H), 7.69-7.28 (m, 8H), 6.89 (d, 1H, <i>J</i> = 8.6 Hz), 5.83 (s, 2H), 4.03 (s, 3H), 3.64 (t, 2H, <i>J</i> = 8.3 Hz), 0.93 (t, 2H, <i>J</i> = 8.3 Hz), -0.03 (s, 9H).

Reference Example 28 (a)

6- (3-hydroxyphenyl) -3-E-styryl-1

H

-indazol

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<figref>204</figref>

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A solution of 100 mg (0.3 mmol) 6- (3-methoxyphenyl) -3-E-styryl-1<i>H</i>-indazol, of Reference Example 27 (b), cooled to -78 ° C and treated with BBr 3 (1.8 ml of a 1M solution in CH 2 Cl 2, 1.8 mmol). The resulting solution was maintained at -78 ° C for 15 min, and then heated to 0 ° C and held 3 h. TO then a solution of sodium hydrogen carbonate was added saturated aqueous (10 ml), followed by ethyl acetate (50 ml). The Organic layer was washed with brine (20 ml), and then concentrated under reduced pressure. Purification by chromatography on silica gel column gave 6- (3-hydroxyphenyl) -3-E-styryl-1<i>H</i>-indazol in the form of a white solid (55 mg, 59%). 1 HRMN (300 MHz, MeOH-<i>d</i>4) δ: 8.16 (d, 1H, <i>J</i> = 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 (m, 2H), 7.20-7.10 (m, 2H), 6.85-6.79 (m, 1 H); 313.14 (s, 1H), 9.60 (s, 1H), 8.20 (d, 1 H, <i>J</i> = 8.4Hz), 7.73 (d, 2H, <i>J</i> = 7.3), 7.64-7.52 (m, 5H), 7.47-7.37 (m, 3H), 7.33-7.25 (m, 1H), 6.89 (d. 2H, <i>J</i> = 8.6Hz)

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Reference Example 28 (b)

6- (4-hydroxyphenyl) -3-E-styryl-1

H

-indazol

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<figref>205</figref>

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6- (4-methoxyphenyl) -3-E-styryl-1<i>H</i>-indazol, from Reference Example 27 (c), it became 6- (4-hydroxyphenyl) -3-E-styryl-1<i>H</i>-indazol similar to the one described in the Reference Example 28 (a). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.14 (s, 1H), 9.60 (s, 1H), 8.20 (d, 1H, <i>J</i> = 8.4 Hz), 7.73 (d, 2H, <i>J</i> = 7.3 Hz), 7.64-7.52 (m, 5H), 7.47-7.37 (m, 3H), 7.33-7.25 (m, 1H), 6.89 (d, 2H, <i>J</i> = 8.6 Hz). HRMS (FAB) [M + Na] / z, calculated 313.1341, found 313.1347. Analyzed with 0.5 H2O: Calculated, C (78.48), H (5.33), N (8.72). Found: C (78.35), H (5.26), N (8.49).

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Reference Example 28 (c)

6- (2-hydroxypyridin-5-yl) -3-E-styryl-1

H

-indazol

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<figref>206</figref>

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6- (2-Methoxypyridin-5-yl) -3-E-styryl-1<i>H</i>-indazol, from Reference Example 27 (k), it became 6- (2-hydroxypyridin-5-yl) -3-E-styryl-1<i>H</i>-indazol similar to that described in the Reference Example 28 (a). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 8.22 (d, 1H, <i>J</i> = 8.4 Hz), 7.96 (dd, 1H, <i>J</i> = 2.6, 9.65 Hz), 7.81 (d, 1H, <i>J</i> = 2.0 Hz), 7.74-7.30 (m, 9H), 6.50 (d, 1H, <i>J</i> = 9.4 Hz). HRMS (FAB) [M + H] / z, calculated 314,1293, found 314.1280. Analyzed with 0.1 acid Trifluoroacetic: Calculated, C (72.69), H (4.86), N (12.59). Found: C (72.77), H (4.81), N (12.65).

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Reference Example 28 (d)

6- (3,4-dihydroxyphenyl) -3-E-styryl-1

H

-indazol

<figref>207</figref>

6- (3,4-Dimethoxyphenyl) -3-E-styryl-1<i>H</i>-indazol, from Reference Example 27 (j), it became 6- (3,4-dihydroxyphenyl) -3-E-styryl-1<i>H</i>-indazol similar to that described in the Reference Example 28 (a). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 9.09 (wide s, 1H), 9.07 (wide s, 1H), 8.20 (d, 1H, <i>J</i> = 8.5), 7.73 (d, 2H, <i>J</i> = 7.5 Hz), 7.56 (d, 2H, <i>J</i> = 10.1 Hz), 7.53 (s, 1H), 7.43-7.29 (m, 4H), 7.11 (s, 1H), 7.04 (d, 1 H, <i>J</i> = 8.2 Hz), 6.86 (d, 1H, <i>J</i> = 8.2 Hz). HRMS (FAB) [M + H] / z, calculated 329.1290, found 329.1274. Analyzed with 1.0 H 2 O: Calculated, C (66.79), H (4.73), N (7.15). Found: C (66.54), H (4.56), N (7.36).

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Reference Example 29 (a)

6-pyrid-4-yl-3-E- [2- (2,6-dichlorophenyl) ethenyl] -1

H

-indazol

<figref>208</figref>

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6-Pyrid-4-yl-3-E- [2- (2,6-dichlorophenyl) ethenyl] -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol became 6-pyrid-4-yl-3-E- [2- (2,6-dichlorophenyl) ethenyl] -1<i>H</i>-indazol similar to that described in the Reference Example 27 (a). 1 HRMN (300 MHz, CDCl 3) δ: 13.55 (s, 1H), 8.68 (dd, 2H, <i>J</i> = 4.6, 1.6 Hz), 8.21 (d, 1H,<i>J</i> = 8.5 Hz), 7.96 (s, 1H), 7.81 (dd, 2H, <i>J</i> = 4,5, 1,6 Hz), 7.66 (dd, 1H, J1 = 8.5, 1.4 Hz), 7.58 (d, 2H, <i>J</i> = 8.0 Hz), 7.51 (s, 2H), 7.39-7.32 (m, 1H). MS (FAB) [M + H] / z, calculated 366, found 366. Analyzed with 0.7 H2O: Calculated, 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 follow:

<figref>209</figref>

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 distilled at then at 160 ° C under reduced pressure (10 mm Hg) to remove excess triethyl phosphite. The ester was obtained acid diethyl (2,6-Dichloro-benzyl) -phosphonic in the form of a colorless liquid (1.46 g, 100%). 1 HRMN (300 MHz, CDCl 3) δ: 7.33-7.28 (m, 2H), 7.15-7.07 (m, 1H), 4.14-4.02 (m, 4H), 3.60 (d, 2H, <i>J</i> = 22.4Hz), 1.27 (t, 6H, <i>J</i> = 7.0Hz)

<figref>210</figref>

Gaseous ozone was bubbled through a solution of 6-pyrid-4-yl-3-E-styryl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol (2.13 g, 5.0 mmol) in THF (25 ml) and MeOH (25 ml) at -78 ° C for 15 min. Then argon is bubbled through the solution for 10 min at -78 ° C for 10 min, and then added dimethyl sulfide (1.46 ml, 20 mmol). The solution was left heat to room temperature and kept for 2 h. The solution was poured into brine (300 ml), and then extracted with ethyl acetate (3x100 ml). Organic materials are dried over MgO 4, and then evaporated under pressure reduced Purification by gel column chromatography of silica gave 6-pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde in the form of a white solid (2.2 g, 75%). 1 HRMN (300 MHz, CDCl 3) δ: 10.39 (s, 1H), 8.75 (d, 2H, <i>J</i> = 1.6 Hz), 8.45 (d, 1H, <i>J</i> = 2.8 Hz), 7.91 (s, 1H), 7.75-7.66 (m, 3H), 5.90 (s, 2H), 3.63 (t, 2H,<i>J</i> = 2.7 Hz), 0.93 (t, 2H, <i>J</i> = 2.8 Hz), 0.00 (s, 9H).

<figref>211</figref>

A solution of diethyl acid ester (2,6-dichlorobenzyl) phosphine (582 mg, 2.0 mmol) in DMF (15 ml) was cooled to 0 ° C and treated with NaH (160 mg 60% in mineral oil, 4.0 mmol). The resulting solution is held at 0 ° C for 30 min, and then treated with 6-pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde (353 mg, 1.0 mmol). The resulting solution was allowed to warm to the room temperature for 1 h and then kept at this temperature 2 h. The solution was poured into brine (250 ml) and It was then extracted with ethyl acetate (3x80 ml). The Organic materials were dried over MgSO4 and then they were concentrated under reduced pressure. Purification by silica gel column chromatography gave 6-pyrid-4-yl-3-E- [2- (2,6-dichlorophenyl) ethenyl] -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol in the form of a yellow oil (330 mg, 67%). 1 H NMR (300 MHz, CDCl 3) δ: 7.72 (dd, 2H, <i>J</i> = 4.6, 1.5 Hz), 8.16 (d, 1H, <i>J</i> = 8.5 Hz), 7.84 (s, 1H), 7.62 (ss, 2H, <i>J</i> = 4.5, 1.6 Hz), 7.60 (s, 2H), 7.56 (dd, 1H, <i>J</i> = 8.5, 1.5 Hz), 7.39 (d, 1 H, <i>J</i> = 8.1 Hz), 7.18-7.12 (m, 1H), 3.64 (t, 2H, <i>J</i> = 8.3 Hz), 0.92 (t, 2H, <i>J</i> = 8.3 Hz), 0.00 (s, 9H).

Reference Example 29 (b)

6-pyrid-4-yl-3-E- [2- (3-methylphenyl) ethenyl] -1

H

-indazol

<figref>212</figref>

6-Pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde it became the desired product so similar to that described in Reference Example 29 (a). 1 HRMN (300 MHz, MeOH-<i>d</i>4) δ: 8.88 (d, 1H,<i>J</i> = 6.7 Hz), 8.41-8.35 (m, 3H), 8.16 (s, 1H), 7.80 (dd, 1H, <i>J</i> = 8.6.1.6 Hz), 7.67-7.48 (m, 4H), 7.35 (t, 1H, <i>J</i> = 7.6 Hz), 7.22-7.17 (m, 1H), 4.88 (s, 3H). MS (FAB) [M + H] / z, calculated 312, found 312. Analyzed with 0.2 H 2 O, 1.1 trifluoroacetic acid: Calculated, C (63.27), H (4.23), N (9.54). Found: C (63.08), H (4.18), N (9.80).

Reference Example 29 (c)

6-pyrid-4-yl-3-E- [2- (4-chlorophenyl) ethenyl] -1

H

-indazol

<figref>213</figref>

6-Pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde became the desired product in a manner similar to that described in Reference Example 29 (a). 1 H NMR (300 MHz, DMSO-<i>d</i>6) δ: 13.40 (s, 1H), 8.67 (dd, 2H,<i>J</i> = 4.6, 1.6 Hz), 8.33 (d, 1H, <i>J</i> = 8.5 Hz), 7.92 (s, 1H), 7.81 (dd, 2H, <i>J</i> = 4.6, 1.6 Hz), 7.78 (d, 2H, <i>J</i> = 8.5 Hz), 7.67-7.56 (m, 3H), 7.46 (d, 2H, <i>J</i> = 8.5Hz) Analyzed with 0.15 H 2 O: Calculated, C (71.81), H (4.31), N (12.56). Found: C (71.85), H (4.26), N (12.48).

Reference Example 29 (d)

6-pyrid-4-yl-3-E- [2- (biphenyl-4-yl) ethenyl] -1

H

-indazol

<figref>214</figref>

6-Pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde became the compound of Reference Example 29 (d) similar to that described in the Reference Example 29 (a). 1 H NMR (300 MHz. DMSO-<i>d</i>6) δ: 13.40 (s, 1H), 8.68 (d, 2H, <i>J</i> = 4.6, 1.5 Hz), 8.35 (d, 1H,<i>J</i> = 8.5Hz), 7.93 (s, 1H), 7.87-7.79 (m, 4H), 7.73 (d, 4H, <i>J</i> = 8.1 Hz), 7.66-7.60 (m, 3H), 7.45 (m, 2H), 7.41-7.34 (m, 1H). MS (FAB) [M + H] / z, calculated 374, found 374. Analyzed with 0.20 H 2 O: Calculated, C (82.82), H (5.19), N (11.15). Found: C (82.82), H (5.19), N (11.16).

Reference Example 29 (e)

6-pyrid-4-yl-3-E- [2- (3-methoxyphenyl) ethenyl] -1

H

-indazol

<figref>215</figref>

6-Pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde became the compound of Reference Example 29 (e) similar to that described in the Reference Example 29 (a). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.39 (s, 1H), 8.67 (d, 2H, <i>J</i> = 5.3 Hz), 833 (d, 2H, <i>J</i>= 8.5 Hz), 7.92 (s, 1H), 7.81 (dd, 2H, <i>J</i> = 4.6, 1.5 Hz), 7.65-7.54 (m, 3H), 7.35-7.28 (m, 3H). 3.83 (s, 3 H). MS (FAB) [M + H] / z, calculated 328, found 328. Analyzed with 0.20 H 2 O: Calculated, C (76.20), H (5.30), N (12.70). Found: C (76.17), H (5.34), N (12.65).

Reference Example 29 (f)

6-pyrid-4-yl-3-E- [2- (pyrid-2-yl) ethenyl] -1

H

-indazol

<figref>216</figref>

6-Pyridin-4-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde became the compound of Reference Example 29 (f) similar to that described in the Reference Example 29 (a). 1 H NMR (300 MHz, DMSO-<i>d</i>6) δ: 8.68 (dd, 2H, <i>J</i> = 4.5, 1.6 Hz), 8.62 (d, 1H, <i>J</i> = 3.8 Hz), 833 (d, 1H, <i>J</i> = 8.5 Hz), 7.99 (d, 1H, <i>J</i> = 16.4 Hz), 7.94 (s, 1H), 7.86-7.78 (m, 3H), 7.73-7.57 (m. 3H), 7.32-7.26 (m, 1 HOUR). Analyzed with 0.05 H2O. Calculated, C (76.26), H (4.75), N (18.72). Found: C (76.22). H (4.79). N (18.76).

Reference Example 29 (g)

6-pyrid-4-yl-3-E- [2- (3-fluorophenyl) ethenyl] -1

H

-indazol

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<figref>217</figref>

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6-Pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde became the compound of Reference Example 29 (g) similar to that described in the Reference Example 29 (a). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.40 (s, 1H), 8.68 (dd, 2H, <i>J</i> = 4.5, 1.6 Hz), 8.34 (d, 1H,<i>J</i> = 8.4 Hz), 7.92 (s, 1H), 7.81 (dd, 2H, J1 = 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, calculated 316, found 316. Anal. Calculated, C (76.17), H (4.48), N (13.33). Found: C (76.07), H (4.53). N (13.36).

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Reference Example 29 (h)

6-pyrid-4-yl-3-E- [2- (2-fluorophenyl) ethenyl] -1

H

-indazol

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<figref>218</figref>

6-Pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde became the compound of Reference Example 29 (h) similar to that described in the Reference Example 29 (a). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.43 (s, 1H), 8.66 (dd, 2H, <i>J</i> = 4.5, 1.6 Hz), 8.23 ​​(d, 1H,<i>J</i> = 8.2 Hz), 7.98-7.90 (m, 2H), 7.80 (dd, 2H, <i>J</i> = 4.5, 1.7 Hz), 7.73-7.54 (m, 3H), 7.40-7.31 (m, 1H), 7.30-7.21 (m, 2H). MS (FAB) [M + H] / z, calculated 316, found 316. Anal. Calculated, C (76.17), H (4.48), N (13.33). Found: C (76.12), H (4.51), N (13.29).

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Reference Example 29 (i)

6-pyrid-4-yl-3-E- [2- (3-chlorophenyl) ethenyl] -1

H

-indazol

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<figref>219</figref>

6-Pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde became the compound of Reference Example 29 (i) similar to that described in the Reference Example 29 (a). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.42 (s, 1H), 8.68 (dd, 2H, <i>J</i> = 4.5, 1.6 Hz), 8.35 (d, 1H,<i>J</i> = 8.1 Hz), 7.92 (s, 1H), 7.86 (s, 1H), 7.82 (dd, 2H,<i>J</i> = 4.5, 1.7 Hz). 7.74-7.51 (m, 4H), 7.43 (t, 1 HOUR, <i>J</i> = 7.8 Hz), 7.37-7.21 (m, 1H). MS (FAB) [M + H] / z, calculated 332, found 332. Anal. Calculated, C (72.40), H (4.25), N (12.67). Found: C (72.52), H (4.28), N (12.57).

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Reference Example 29 (j)

6-pyrid-4-yl-3-E- [2- (2-methylthiazol-4-yl) ethenyl] -1

H

-indazol

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<figref>220</figref>

6-Pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde became the compound of Reference Example 29 (j) similar to that described in the Reference Example 29 (a). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.38 (s, 1H), 8.67 (dd, 2H, <i>J</i> = 4.5, 1.6 Hz), 8.25 (d, 1H,<i>J</i> = 8.5 Hz), 7.92 (s, 1H), 7.81 (dd, 2H, <i>J</i> = 4,5, 1,6 Hz), 7.70-7.50 (m, 4H), 2.72 (s, 3H). MS (FAB) [M + H] / z, calculated 319, found 319. Analyzed with 0.15 acid trifluoroacetic: Calculated, C (65.51), H (4.25), N (16.70). Found: C (65.56), H (4.37), N 16.53).

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Reference Example 29 (k)

6-pyrid-4-yl-3-E- [2- (naphthalen-2-yl) ethenyl] -1

H

-indazol

<figref>221</figref>

He 6-pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde became the compound of Reference Example 29 (k) similar to that described in the Reference Example 29 (a). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.40 (s, 1H), 8.68 (dd, 2H, <i>J</i> = 4.6, 1.4 Hz), 8.39 (d, 1H,<i>J</i> = 8.5 Hz), 8.17 (s, 1H), 8.09-7.89 (m, 8H), 7.83 (dd, 2H, <i>J</i> = 4.6, 1.6 Hz), 7.74 (s, 2H), 7.65 (dd, 1 HOUR, <i>J</i> = 8.5, 1.4 Hz), 7.60-7.46 (m, 4H). MS (FAB) [M + H] / z, calculated 348, found 348. Analyzed with 1.05 trifluoroacetic acid: Calculated, C (67.10), H (3.89), N (9.00). Found: C (67.20), H (3.93), N (9.05).

Reference Example 29 (l)

6-pyrid-4-yl-3-E- [2- (2,3-difluorophenyl) ethenyl] -1

H

-indazol

<figref>1000</figref>

He 6-pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde became the compound of Reference Example 29 (l) similar to that described in the Reference Example 29 (a). 1 HRMN (300 MHz, CDCl 3 + MeOH-<i>d</i>4) δ: 8.68 (d, 2H, <i>J</i> = 5.6 Hz,), 8.02 (d, 1H, <i>J</i> = 8.5 Hz), 7.70 (s, 1H), 7.58 (dd, 2H,<i>J</i> = 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, calculated 334, found 334. Analyzed with 0.80 H 2 O: Calculated, C (69.08), H (4.23). N (12.08). Found: C (68.77), H (3.93), N (11.85).

Reference Example 29 (m)

6-pyrid-4-yl-3-E- [2- (3,5-difluorophenyl) ethenyl] -1

H

-indazol

<figref>222</figref>

He 6-pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde became the compound of Reference Example 29 (m) similar to that described in the Reference Example 29 (a). 1 HRMN (300 MHz, MeOH-<i>d</i>4) δ: 8.69 (d, 2H, <i>J</i> = 6.3 Hz), 8.34 (d, 1H, <i>J</i> = 8.5 Hz), 7.97 (s, 1H), 7.97 (d, 2H, <i>J</i> = 6.3 Hz), 7.71 (d, 1H,<i>J</i> = 10.0 Hz), 7.62 (s 1H), 7.60 (s, 1H), 7.36 (d, 1H, <i>J</i> = 11.11), 6.95-6.89 (m, 1H). MS (ES) [M + H] / z, calculated 334, found 334. Anal. Calculated, C (72.06), H (3.93), N (12.61). Found: C (72.20), H (4.01), N (12.58).

Reference Example 29 (n)

6-pyrid-4-yl-3-E- [2- (biphenyl-3-yl) ethenyl] -1

H

-indazol

<figref>223</figref>

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6-Pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde became the compound of Reference Example 29 (n) similar to that described in the Reference Example 29 (a). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 8.68 (d, 2H, <i>J</i> = 6.1 Hz), 8.39 (d, 1H, <i>J</i> = 8.5), 8.04 (s, 1H), 7.92 (s, 1H), 7.82 (d, 2H, <i>J</i> = 6.2 Hz), 7.79-7.37 (m, 11 H). MS (ES) [M + H] / z, calculated 374, found 374. Anal. Calculated, C (83.62), H (5.13), N (11.25). Found: C (83.47), H (5.08), N (11.32).

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Reference Example 29 (o)

6-pyrid-4-yl-3-E- [2- (2,6-difluorophenyl) ethenyl] -1

H

-indazol

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<figref>224</figref>

6-Pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde became the compound of Reference Example 29 (or) similar to that described in the Reference Example 29 (a). 1 HRMN (300 MHz, MeOH-<i>d</i>4) δ: 8.69 (d, 2H, <i>J</i> = 6.3 Hz), 8.21 (d, 1H, <i>J</i> = 8.6 Hz), 7.97 (s, 1 H), 7.88 (d, 2 H. <i>J</i> = 6.3 Hz), 7.83 (d, 1H,<i>J</i> = 17.1 Hz), 7.71 (1H, <i>J</i> = 8.6 Hz), 7.65 (d, 1H, <i>J</i> = 17.1 Hz), 7.40-7.35 (m, 1H), 7.13-7.08 (m, 2H). MS (ES) [M + H] / z, calculated 334, found 334. Analyzed with 0.1 H 2 O: Calculated, C (71.67), H (3.97). N (12.54). Found: C (71.37), H (3.90), N (12.31).

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Reference Example 29 (p)

6-pyrid-4-yl-3-E- [2- (3-trfluoromethoxyphenyl) ethenyl] -1

H

-indazol

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<figref>225</figref>

He 6-pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde became the compound of Reference Example 29 (p) similar to that described in the Reference Example 29 (a). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 8.84 (d, 2H, <i>J</i> = 6.4 Hz), 8.43 (d, 1H, <i>J</i> = 8.5 Hz), 8.19 (d, 2H, <i>J</i> = 6.4 Hz), 8.07 (s, 1H), 7.81-7.27 (m, 5H), 7.78 (s, 1H). MS (ES) [M + H] / z, calculated 382, ​​found 382. Analyzed with 1.0 acid trifluoroacetic: Calculated, C (55.76), H (3.05), N (8.48). Found: C (55.84), H (3.09), N (8.45).

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Reference Example 29 (q)

6-pyrid-4-yl-3-E- [2- (benzimidazol-2-yl) ethenyl] -1

H

-indazol

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<figref>226</figref>

He 6-pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde became the compound of Reference Example 29 (q) similar to that described in the Reference Example 29 (a). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 8.69 (d, 2H, <i>J</i> = 6.1 Hz), 8.25 (d, 1H, <i>J</i> = 8.5 Hz), 8.03 (d, 1H, <i>J</i> = 16.7 Hz), 7.97 (s, 1H), 7.84 (d, 2H,<i>J</i> = 6.2), 7.72 (d, 1H, <i>J</i> = 8.5 Hz), 7.60-7.57 (m, 2H), 7.53 (d, 1H, <i>J</i> = 16.7 Hz), 7.22-7.19 (m, 2H). MS (ES) [M + H] / z, calculated 338, found 338. Analyzed with 2.0 trifluoroacetic acid, 0.2 H2O: Calculated, C (52.77), H (3.08), N (12.31). Found: C (52.59), H (3.17), N (12.18).

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Reference Example 29 (r)

6-pyrid-4-yl-3-E- [2- (3,4-methylenedioxy-phenyl) ethenyl] -1

H

-indazol

<figref>227</figref>

He 6-pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde became the compound of Reference Example 29 (r) similar to that described in the Reference Example 29 (a). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 8.67 (d, 2H, <i>J</i> = 6.1 Hz), 8.30 (d, 1H, <i>J</i> = 8.5 Hz), 7.89 (s, 1H), 7.81 (d, 2H, <i>J</i> = 6.1 Hz), 7.61 (d, 1H, <i>J</i>= 9.9 Hz), 7.46-7.42 (m, 3H), 7.18 (d, 1H, <i>J</i>= 9.6 Hz), 6.95 (d, 1H, 8.0 Hz), 6.05 (s, 2H). MS (ES) [M + H] / z, calculated 342, found 342. Anal. Calculated, C (73.89), H (4.43), N (12.31). Found: C (73.74), H (4.52), N (12.40).

Reference Example 29 (s)

6-pyrid-4-yl-3-E- [2- (2,5-difluorophenyl) ethenyl] -1

H

-indazol

<figref>228</figref>

He 6-pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1H-indazol-3-carbald ehyde became the compound of Reference Example 29 (s) similar to that described in the Reference Example 29 (a). 1 HRMN (300 MHz, MeOH-<i>d</i>4) δ: 8.53 (d, 2H, <i>J</i> = 6.0 Hz), 8.03 (d, 1H, <i>J</i> = 8.5 Hz), 7.60 (d, 2H, <i>J</i> = 6.2 Hz), 7.56-7.35 (m, 3H), 7.34-7.26 (m, 1H), 7.03-6.93 (m, 1H), 6.90-6.81 (m, 1H). MS (ES) [M + H] / z, calculated 334, found 334. Analyzed with 0.30 H 2 O: Calculated, C (70.91), H (4.05), N (12.37). Found: C (70.97), H (4.17), N (12.37).

Reference Example 29 (t)

6-pyrid-4-yl-3-E- [2- (1

H

-pyrrol-2-yl) ethenyl] -1

H

-indazol

<figref>229</figref>

He 6-pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1H-indazol-3-carbaldehyde became the compound of Reference Example 29 (t) similar to that described in the Reference Example 29 (a). 1 HRMN (300 MHz, MeOH-<i>d</i>4) δ: 8.60 (d, 2H, <i>J</i> = 6.3 Hz), 8.13 (d, 1H, <i>J</i> = 8.5 Hz), 7.86 (s, 1H), 7.79 (d, 2H, <i>J</i> = 6.2 Hz), 7.57 (dd, 1H, J1 = 8.5 Hz, J2 = 1.5 Hz), 7.40 (d, 1H, <i>J</i> = 16.8 Hz), 7.09 (d, 1H,<i>J</i> = 16.7 Hz), 6.87-6.82 (m, 1H), 6.40-6.35 (m, 1H), 6.16 (t, 1H, <i>J</i> = 2.9 Hz). MS (ES) [M + H] / z, calculated 287, found 287. Analyzed with 0.5 ethyl acetate, 0.3 tetrahydrofuran, 0.1 hexanes, 0.1 ethylenediamine: Calculated, 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 follow:

<figref>230</figref>

(i) A solution of 1<i>H</i>-pyrrol-2-carbaldehyde (9.5 g, 100 mmol) and THF (500 ml) was cooled with an ice bath. He Bu t ONa (19.2 g, 200 mmol) was added and the reaction mixture was stirred at 0 ° C for 1 h. Then MtsCl (32.7 g, 150 mmol). The reaction mixture was allowed to warm to room temperature and kept for 2 h temperature ambient. The solution was then treated with aqueous NH4Cl saturated (100 ml) and the mixture was poured into brine (2 L). Mix It was extracted with EtOAc (3x300 ml). The combined organic layers are dried over MgSO4 and concentrated under reduced pressure. He resulting oil was purified by gel column chromatography of silica getting 1- (2,4,6-Trimethyl-benzenesulfonyl) -1<i>H</i>-pyrrol-2-carbaldehyde in the form of a light yellow oil (15.7 g, 57%). 1 HRMN (CDCl 3) δ: 9.50 (s, 1H), 7.79-7.74 (m, 1H), 7.12 (dd, 1H, <i>J</i> = 3.7, 1.8 Hz), 6.95 (s, 2H), 6.38 (t, 1 HOUR, <i>J</i> = 3.4 Hz), 2.50 (s, 6H), 2.30 (s, 3H).

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<figref>231</figref>

(ii) 1- (2,4,6-Trimethyl-benzenesulfonyl) -1<i>H</i>-pyrrol-2-carbaldehyde (2.77 g, 10 mmol) in THF (100 ml) was treated with LiBH 4 (0.44 g, 20 mmol) at room temperature. The resulting solution is kept at room temperature for 1 h. Then you MeOH (10 ml) was added and the resulting mixture was poured into brine (600 ml) and extracted with EtOAc (3x200 ml). Organic layers The combined were dried over MgSO4 and concentrated under pressure reduced The resulting oil was then purified on a silica gel column getting [1- (2,4,6-Trimethyl-benzenesulfonyl) -1<i>H</i>-pyrrol-2-yl] -methanol in the form of a light brown oil (2.43 g, 87%). 1 HRMN (CDCl 3) δ: 7.17 (dd, 1H, <i>J</i> = 3.3, 1.8 Hz), 6.99 (s, 2H), 6.28-6.23 (m, 1H), 6.18 (t, 1H, <i>J</i> = 33 Hz), 4.42 (s, 2H), 2.50 (s, 6H), 2.30 (s, 3H).

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<figref>232</figref>

(iii) A solution of [1- (2,4,6-Trimethyl-benzenesulfonyl) -1<i>H</i>-pyrrol-2-yl] -methanol (1.4 g, 5.0 mmol) in CHCl3 (25 ml) was cooled in a bath of oil. SOCl2 (1.1 ml, 15 mmol) was added slowly. The solution was allowed to warm to room temperature and was He kept 45 min more. The solution was then concentrated under reduced pressure It was obtained 2-chloromethyl-1- (2,4,6, trimethyl-benzenesulfonyl) -1<i>H</i>-pyrrol in the form of a brown solid (1.5 g, 100%). 1 HRMN (CDCl 3) δ: 7.28 (dd, 1H, <i>J</i> = 3.3, 1.7 Hz), 6.98 (s, 2H), 6.38-6.34 (m, 1H), 6.19 (t, 1H, <i>J</i> = 3.4 Hz), 4.58 (s, 2H), 2.50 (s, 6H), 2.30 (s, 3H).

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Reference Example 29 (u)

6-pyrid-4-yl-3-E- [2- (3-methylcarbamoylmethoxy-phenyl) ethenyl] -1

H

-indazol

<figref>233</figref>

He 6-pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde became the compound of Reference Example 29 (u) similar to that described in the Reference Example 29 (a). 1 HRMN (300 MHz, MeOH-<i>d</i>4) δ: 8.68 (d, 2H, <i>J</i> = 5.9 Hz), 8.51 (wide s, 1H), 8.37 (d, 1H,<i>J</i> = 8.5 Hz), 8.19 (s, 1H), 7.93 (s, 1H), 7.87 (d, 1H,<i>J</i> = 7.7 Hz), 7.85 (d, 2H, <i>J</i> = 6.1 Hz), 7.62 (d, 1H,<i>J</i> = 8.1 Hz), 7.65-7.63 (m, 3H), 7.51 (t, 1H, <i>J</i> = 7.6Hz). MS (ES) [M + H] / z, calculated 355, found 355. Analyzed with 0.4 trifluoroacetic acid, 0.50 H2O: Calculated, C (69.67), H (4.98), N (14.26). Found: C (69.78), H (5.18), N (14.08).

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Reference Example 30 (a)

6- [3-benzamidophenoxy] -3-E- [2- (tien-2-yl) ethenyl] -1

H

-indazol

<figref>234</figref>

The compound of the Reference Example 30 (a) was prepared in a manner similar to that described in the Reference example 6 (a) except that, in step (i), used chloride (<i>AND</i>) -3-thiophene-2-yl-acryloyl instead of chloride 3- (4-chlorophenyl) acryloyl. 1 HRMN (DMSO-<i>d</i>6) δ: 13.05 (s, 1H), 10.33 (s, 1H), 8.19 (d, 1H, <i>J</i> = 8.8 Hz), 7.92 (d, 2H, <i>J</i> = 6.9 Hz), 7.70 (d, 1H, <i>J</i> = 16.5 Hz), 7.65-7.49 (m, 6H), 7.40 (t, 1H, <i>J</i> = 8.1 Hz), 7.35 (s, 1H, with fine division), 7.20 (d, 1H, <i>J</i> = 16.5 Hz), 7.10 (m, 1H), 7.04 (s, 1H), 6.98 (d, 1 HOUR, <i>J</i> = 8.8 Hz), 6.86 (s, 1H, <i>J</i> = 9.8 Hz). Anal. Calc. for C 26 H 19 N 3 O 2 S • 0.6 H 2 O: 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.

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Reference Example 30 (b)

6- [3- (1-Acetylpiperidin-4-ylcarboxamido) phenoxy] -3-E- [2- (4-chlorophenyl) ethenyl] -1

H

-indazol

<figref>235</figref>

The compound of the Reference Example 30 (b) was prepared in a manner similar to that described in the Reference example 6 (a) except that, in the step (ii), acid was used 1-acetyl-piperidine-4-carboxylic and HATU instead of benzoyl chloride. 1 HRMN (DMSO-<i>d</i>_{6}) (<i>J</i> = 8.6 Hz) δ: 7.76, (d,<i>J</i> = 8.6 Hz), 7.53 (d, <i>J</i> = 6.2 Hz), 7.46 (d, <i>J</i>= 8.4 Hz), 737 (m, 3H), 7.01 (s, 1H, with fine division), 6.97 (d,<i>J</i> = 8.8 Hz), 6.78 (d, <i>J</i> = 7.7 Hz), 4.38 (m, 1H), 3.85 (m, 1H), 3.09-2.96 (m, 1H), 2.58 (m, 2H), 1.99 (s, 3H), 1.77 (m, 2H), 1.55 (m, 1H), 1.37 (m, 1H). Anal. Calc. For C 29 H 27 ClN 4 O 3, 13 H 2 O: C, 64.69; H 5.54; N, 10.41. Found: C, 64.64; H, 5.51; N, 10.23.

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Reference Example 30 (c)

6- [3-benzamidophenoxy] -3-E- [2- (fur-2-yl) ethenyl] -1

H

-indazol

<figref>236</figref>

The compound of the Reference Example 30 (c) was prepared in a manner similar to that described in the Reference example 6 (a) except that, in step (i), used chloride (<i>AND</i>) -3-furan-2-yl-acryloyl, prepared according to Collect, <i>Czech Chem. Comm</i>., 52, 409-24 (1987), instead of chloride 3- (4-chlorophenyl) -acryloyl. 1 HRMN (DMSO-<i>d</i>6) δ: 13.00 (s, 1H), 10.32 (s, 1H), 8.14 (d, 1H, <i>J</i> = 8.8 Hz), 7.91 (d, 2H, <i>J</i> = 7.0 Hz), 7.73 (s, 1H), 7.70-7.51 (m, 5H), 7.40 (t, 1H,<i>J</i> = 8.4 Hz), 7.30 (AB, 2H, <i>J</i> = 16.7 Hz), 7.04 (s, 1H), 6.98 (d, 1H, <i>J</i> = 8.7 Hz), 6.86 (d, 1H, <i>J</i> = 8.0 Hz), 6.65 (s, 1H, with fine division), 6.60 (s, 1H, with division fine). Anal. Calc. For C_ {26} H_ {19} N_ {3} O2 {\ cdot0.7 H2O: C, 71.94; H, 4.74; N, 9.68. Found: C, 72.17; H, 4.83; N, 9.44.

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Reference Example 30 (d)

6- [3- (indole-4-ylcarboxamido) phenoxy] -3-E-styrylindazole

<figref>237</figref>

The compound of the Reference Example 30 (d) was prepared in a manner similar to that described in the Reference example 30 (a) except that, in step (ii), They were used 3- (sterile-1<i>H</i>-indazol-6-yloxy) -phenylamine instead of 3- (3-Styryl-4,5-dihydro-1<i>H</i>-indazol-6-yloxy) phenylamine and acid 1<i>H</i>-indole-4-carboxylic acid in instead of benzoic acid. 1 HRMN (DMSO-<i>d</i>6) δ: 12.99 (s, 1H), 11.33 (s, 1H), 10.24 (s, 1H), 8.22 (d, 1H, <i>J</i>= 8.7 Hz), 7.72-7.38 (m, 10H), 7.30 (d, 1H, <i>J</i> = 7.1 Hz), 7.19 (m, 2H), 7.04 (m, 3H), 6.82 (m, 2H). Anal. Calc. for C 30 H 22 N 4 O 2 • 0.6 H 2 O: C, 74.86; H 4.86; N, 11.64. Found: C, 74.90; H, 5.01; N, 11.33.

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Reference Example 30 (e)

6- [3 - ((1-ethyl-3-methyl-1

H

-pyrazol-5-yl) carboxamido) phenoxy] -3-E-styrylindazole

<figref>238</figref>

The compound of the Reference Example 30 (e) was prepared in a manner similar to that described in the Reference example 30 (a) except that, in step (ii), They were used 3- (sterile-1<i>H</i>-indazol-6-yloxy) -phenylamine instead of 3- (3-Styryl-4,5-dihydro-1<i>H</i>-indazol-6-yloxy) phenylamine and acid 1-ethyl-3-methyl-1<i>H</i>-pyrazol-5-carboxylic instead of benzoic acid.

Reference Example 31 (a)

6- [3-benzamidophenoxy] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>239</figref>

To a stirred solution of 6- [3-benzamidophenoxy] -3-E- [2- (pyridin-2-yl) ethenyl] -4,5-dihydro-1<i>H</i>-indazol (492 mg, 1.13 mmol) in 15 mL of 1,4-dioxane was added 386 mg (1.7 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The reaction mixture was stirred for 30 min at room temperature and then poured into solution saturated NaHCO3 and EtOAc. The layers and the layer were separated aqueous was reextracted with EtOAc. The combined organic layers washed sequentially with saturated NaHCO3 solution and saturated NaCl solution, dried over MgSO4 and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel eluting with CH 2 Cl 2 / EtOAc / MeOH (1: 1: 0.1). The oil obtained is triturated in EtOAc / hexanes to obtain the title compound in form of a tan solid (420 mg, 86%). 1 HRMN (DMSO-<i>d</i>6) δ: 13.12 (s, 1H), 10.30 (s, 1H), 8.60 (d, 1H, <i>J</i> = 3.8 Hz), 8.22 (d, 1H, <i>J</i> = 8.8 Hz), 7.93 (m, 3H), 7.82 (t, 1H, <i>J</i> = 7.7 Hz), 7.68-7.49 (m, 7H), 7.40 (t, 1H, <i>J</i> = 8.1 Hz), 7.27 (m, 1H), 7.08 (s, 1H), 7.03 (s, 1H), 7.03 (d, 1H, <i>J</i> = 8.7 Hz), 6.87 (d, 1H, <i>J</i> = 8.1 Hz, with fine division). Anal. Calc. For C 27 H 20 N 4 O 2 • 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 follow:

Stage (i)

<figref>240</figref>

A solution of 3- [3- (benzhydrylidene-amino) -phenoxy] -cyclohex-2-enone (4.00 g, 10.9 mmol) in 20 mL of THF was slowly added to a -78 ° C solution of LiHMDS (36 mL of 1.0M solution in THF). Fifteen minutes after the addition was completed, hydrochloride was added of chloride (<i>AND</i>) -3-pyridin-2-yl-acryloyl and stirring was continued at -78 ° C for 30 min. The reaction is stopped abruptly by adding a saturated solution of NH4Cl and extracted with EtOAc (3x). The combined organic layers washed with saturated NaCl solution, dried over MgSO4 and concentrated under reduced pressure. The residue is subjected to flash chromatography on silica gel eluting with hexanes / EtOAc (2: 1). The appropriate fractions are concentrated under reduced pressure and dissolved in EtOH / HOAc (1: 1, 8ml). To this solution at 80 ° C hydrazine hydrate was added (3.4 ml, 70.0 mmol). After 15 min, all the disappeared starting material and the reaction mixture was poured carefully over saturated NaHCO3 and extracted with EtOAc (2x). The combined organic layers were washed with saturated solution NaCl, dried over MgSO4 and concentrated under pressure reduced The residue was subjected to flash chromatography. on silica gel eluting with CH2Cl2 / MeOH (9: 1) getting 6- (3-aminophenoxy) -3-E- [2- (pyridin-2-yl) ethenyl] -4,5-dihydro-1<i>H</i>-indazol (676 mg, 19%). 1 HRMN (DMSO-<i>d</i>6) δ: 12.51 (s, 1H), 8.57 (d, 1H, <i>J</i> = 3.8 Hz), 7.78 (t, 1H, <i>J</i> = 7.8 Hz), 7.51 (m, 2H), 7.25 (m, 1H), 7.05 (m, 2H), 6.35 (d, 1H, <i>J</i>= 7.9 Hz, with fine division), 6.32 (t, 1H, <i>J</i> = 2.1 Hz), 6.23 (d, 1H, <i>J</i> = 7.9 Hz), 5.54 (s, 1H), 5.23 (s, 2H), 2.95 (t, 2H,<i>J</i> = 8.2 Hz), 2.60 (s, 2H, <i>J</i> = 8.2 Hz); MS [M + H] / z, Calculated 331, Found: 331. Anal. Calc. For C 20 H 18 N 4 O • 0.15 H 2 O: C, 72.12; H, 5.54; N, 16.82. Found: C, 72.11; H, 5.55; N, 16.61.

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Stage (ii)

<figref>241</figref>

To a stirred solution of dihydroaniline (350 mg, 1.06 mmol) and benzoic acid (776 mg, 6.36 mmol) in 15 mL of DMF, HATU (2.42 g, 6.36 mmol) and NEt 3 (1.8 ml, 12.71 was added mmol). The reaction mixture was heated at 50 ° C for 1.5 h, cooled and poured onto ice / saturated NaCl solution. He precipitate was collected by vacuum filtration, washed with H2O and dried in the air. To this filter cake dissolved in 10 mL of MeOH / THF (1: 1), K 2 CO 3 (650 mg) and 1 mL of H2O. After 1 h, the reaction mixture was poured onto a Saturated NaCl solution and extracted with EtOAc (2x). Layers The combined organics were washed with saturated NaCl solution, dried over MgSO4 and concentrated under reduced pressure. The residue was subjected to flash chromatography on gel. of silica eluting with CH2Cl2 / EtOAc / MeOH (1: 1: 0.1) getting 6- [3-benzamidophenoxy] -3-E- [2- (pyridin-2-yl) ethenyl] -4,5-dihydro-1<i>H</i>-indazol (333 mg, 72%). 1 HRMN (DMSO-<i>d</i>6) δ: 12.58 (s width, 1H), 10.34 (s, 1H), 8.57 (d, 1H, <i>J</i> = 3.8 Hz), 7.95 (d, 2H, <i>J</i> = 6.8 Hz), 7.81-7.70 (m, 2H), 7.63-7.50 (m, 6H), 7.40 (t, 1H, <i>J</i> = 8.1 Hz), 7.25 (m, 1H), 7.09 (d, 1H, <i>J</i> = 16.3 Hz), 6.89 (d, 1H, <i>J</i>= 8.0 Hz), 5.64 (s, 1H), 2.99 (t, 2H, <i>J</i> = 8.1 Hz), 2.66 (t, 2H, <i>J</i> = 8.1 Hz). Anal. Calc. For C 27 H 22 N 4 O 2 • 0.1 CH 2 Cl 2: C, 73.48; H, 5.05; N, 12.65. Found: C, 73.48; H, 5.05; N, 12.48.

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Reference Example 31 (b)

6- [3 - ((1,5-dimethyl-1

H

-pyrazol-3-yl) carboxamido) phenoxy] -3-E- [2- (pyridin-2-) ethenyl] -1

H

-indazol

<figref>242</figref>

The compound of the Reference Example 31 (b) was prepared in a manner similar to that described in the Reference example 31 (a) except that, in step (ii), acid was used 1,5-dimethyl-1<i>H</i>-pyrazol-3 carboxylic instead of benzoic acid. 1 HRMN (DMSO-<i>d</i>6) δ: 13.13 (s, 1H), 10.07 (s, 1H), 8.60 (d, 1H, <i>J</i> = 4.3 Hz), 8.21 (d, 1H, <i>J</i> = 8.7 Hz), 7.93 (d, 1H, <i>J</i> = 16.3 Hz), 7.82 (t, 1H, <i>J</i> = 7.4 Hz), 7.69 (m, 3H), 7.56 (d, 1H, <i>J</i> = 16.3 Hz), 7.32 (m, 2H), 7.05 (s, 1H), 7.01 (d, 1H, <i>J</i> = 8.7 Hz), 6.80 (m, 1H), 6.52 (s, 1H), 3.81 (s, 3H) 2.29 (s, 3H). Anal. Calc. For C_26 H_ {22} N6 {O2} \ cdot0.1 CH2Cl2 \ cdot / 0.1 hexanes: C, 68.58; H, 5.09; N, 17.97. Found: C, 68.26; H, 5.25; N, 17.61.

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Reference Example 31 (c)

6- [3 - ((5-Methylsulfonylthien-2-yl) carboxamido) phenoxy] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>243</figref>

The compound of the Reference Example 31 (c) was prepared in a manner similar to that described in the Reference example 31 (a) except that, in step (ii), acid was used 5-methanesulfonyl-thiophene-2-carboxylic instead of benzoic acid. 1 HRMN (DMSO-<i>d</i>6) δ: 13.17 (s, 1H), 10.58 (s, 1H), 8.61 (d, 1H, <i>J</i> = 4.0 Hz), 8.24 (d, 1H, <i>J</i> = 8.8 Hz), 8.05 (d, 1H, <i>J</i> = 4.1 Hz), 7.97 -7.79 (m, 3H), 7.68 (d, 1H, <i>J</i> = 7.8 Hz), 7.60-7.48 (m, 3H), 7.43 (t, 1H, <i>J</i> = 8.2 Hz), 7.28 (m, 1H), 7.10 (s, 1H, with fine division), 7.00 (d, 1H, <i>J</i>= 8.7 Hz), 6.92 (d, 1H, <i>J</i> = 8.1 Hz, with fine division), 3.41 (s, 3H). Anal. Calc. For C 28 H 20 N 4 O 4 S 2 • 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.

Reference Example 31 (d)

6- [3 - ((1-ethyl-3-methyl-1H-pyrazol-5-yl) carboxamido) phenoxy] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>244</figref>

The compound of Reference Example 31 (d) is prepared similarly to that described in the Reference Example 31 (a) except that, in step (ii), acid was used 1-ethyl-3-methyl-1<i>H</i>-pyrazol-5-carboxylic instead of benzoic acid. 1 HRMN (DMSO-<i>d</i>6) δ: 13.15 (s, 1H). 10.18 (s, 1H), 8.61 (d, 1H, <i>J</i> = 3.7 Hz), 8.22 (d, 1H, <i>J</i> = 8.8 Hz), 7.94 (d, 1H, <i>J</i> = 16.3 Hz), 7.82 (t, 1H, <i>J</i> = 7.5 Hz), 7.67 (d, 1H, <i>J</i> = 7.7 Hz), 7.55 (m, 3H), 7.40 (t, 1H, <i>J</i> = 8.1 Hz), 7.28 (m, 1H), 7.06 (s, 1H), 7.01 (d, 1H, <i>J</i> = 8.8 Hz), 6.89 (d, 1H,<i>J</i> = 7.9 Hz), 6.78 (s, 1H), 4.38 (q, 2H, <i>J</i> = 7.1 Hz), 2.19 (s, 3H), 1.29 (t, 3H, <i>J</i> = 7.1 Hz). Anal. Calc. For C 27 H 24 N 6 O 2 • 0.6 EtOAc: C, 68.25; H, 5.61; N. 16.24. Found: C, 68.28; H, 5.88; N, 16.01.

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Reference Example 31 (e)

6- [3 - ((1-methylimidazol-2-yl) carboxamido) phenoxy] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>245</figref>

The compound of the Reference Example 31 (e) was prepared in a manner similar to that described in the Reference example 31 (a) except that, in step (ii), acid was used 1-methyl-1<i>H</i>-imidazol-2-carboxylic instead of benzoic acid. 1 H NMR (DMSO-<i>d</i>6) δ: 13.13 (s, 1H), 10.47 (s, 1H), 8.60 (d, 1H, <i>J</i> = 3.9 Hz), 8.21 (d, 1H, <i>J</i> = 8.7 Hz), 7.93 (d, 1H, <i>J</i> = 16.3 Hz), 7.82 (t, 1H, <i>J</i> = 7.6 Hz), 7.65 (m, 3H), 7.56 (d, 1H,<i>J</i> = 16.3 Hz), 7.43 (s, 1H), 7.37 (t, 1H, <i>J</i> = 8.1 Hz), 7.28 (m, 1H), 7.04 (m, 3H), 6.84 (d, 1H, <i>J</i> = 7.7 Hz), 3.95 (s, 3H). Anal. Calcd. For C 25 H 20 N 6 O 2 \ 0.4 H2O: C, 67.49; H, 4.80; N, 18.65. Found: C, 67.68; H 4.73; N, 18.94.

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Reference Example 31 (f)

6- [3 - ((1-ethyl-3-methyl-1

H

-pyrazol-5-yl) carboxamido) phenoxy] -3-E- [2- (1,2-dimethyl-1

H

-imidazol-4-yl) ethenyl] -1

H

-indazol

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<figref>246</figref>

The compound of the Reference Example 31 (f) was prepared in a manner similar to that described in the Reference example 31 (a) except that, in step (i), used chloride hydrochloride (E) -3- (1,2-dimethyl-1<i>H</i>-imidazol-4-yl) acryloyl instead of chloride hydrochloride (E) -3-pyridin-2-yl-acryloyl and, in step (ii), acid was used 1-ethyl-3-methyl-1<i>H</i>-pyrazol-5-carboxylic instead of benzoic acid. 1 HRMN (DMSO-<i>d</i>6) δ: 12.82 (s, 1H), 10.17 (s, 1H), 8.05 (d, 1H, <i>J</i> = 8.8 Hz), 7.58 (d, 1H, <i>J</i> = 8.4 Hz), 7.48 (s, 1H), 7.38 (t, 1H,<i>J</i> = 8.1 Hz), 7.25 (s, 2H), 7.20 (s, 1H), 7.01 (s, 1H), 6.92 (d, 1H, <i>J</i> = 8.7 Hz), 6.85 (d, 1H, <i>J</i> = 8.7 Hz), 6.78 (s, 1H), 437 (q, 2H, <i>J</i> = 7.0 Hz), 3.56 (s, 3H), 2.31 (s, 3H), 2.19 (s, 3H), 1.29 (t, 3H, <i>J</i> = 7.0 Hz). Anal. Calc. for C_27 H_ {27} N_ {O} {2} \ cdot1.0 H2_O \ cdot0.3 EtOAc: C, 64.39; H, 6.02; N, 18.64. Found: C, 64.52; H, 5.98; N, 18.52.

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Reference Example 32 (a)

6- [3-benzamidophenoxy] -3-E- [2- (1

H

-imidazol-4-yl) ethenyl] -1

H

-indazol

<figref>247</figref>

To a stirred solution of the compound 6- (3-Benzamidophenoxy) -3-E- [2- (1- (2-Trimethyl-silanyl-ethoxy) -methyl-imidazol-4-yl) ethenyl] -1<i>H</i>-indazol (213 mg, 0.39 mmol) in 5 mL of THF 1.0M TBAF in THF (6.0 ml, 6.0 mmol) and ethylenediamine (0.26 ml, 3.86 mmol). After heating at 70 ° C for 18 h, the reaction mixture was cooled, diluted with EtOAc and washed repeatedly with saturated solution of NaHCO 3. The organic layer was dried over MgSO4 and was concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel eluting with CH 2 Cl 2: EtOAc: MeOH (1: 1: 0.2). The oil obtained was crushed in EtOAc / hexanes obtaining AG13853 (65 mg, 40%). 1 H NMR (DMSO-<i>d</i>6) δ: 12.90 (s, 1H), 12.35 (s, 1H), 10.32 (s, 1H), 8.08 (d, 1H, <i>J</i> = 8.7 Hz), 7.91 (d, 2H, <i>J</i> = 6.8 Hz), 7.81 (s, 1H), 7.64-7.49 (m, 5H), 7.42-7.31 (m, 4H), 7.03 (s, 1H), 6.96 (d, 1H,<i>J</i> = 8.7 Hz), 6.85 (d, 1H, <i>J</i> = 8.1 Hz). Anal. Calc. for C 25 H 19 N 5 {O} {2} \ cdot0.7 H2 O \ cdot0.4 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 so similar to that described in Reference Example 31 (a) except that, in step (i), chloride chloride hydrochloride was used (<i>AND</i>) -3- [1- (2-Trimethyl-silanyl) -ethoxymethyl) -1<i>H</i>-imidazol-4-yl] -acryloyl instead of chloride hydrochloride (<i>AND</i>) -3-pyridin-2-yl-acryloyl.

Reference Example 32 (b)

6- [3 - ((1-ethyl-3-methyl-1

H

-pyrazol-5-yl) carboxamido) phenoxy] -3-E- [2- (1

H

-imidazol-4-yl) ethenyl] -1

H

-indazol

<figref>248</figref>

The compound of the Reference Example 32 (b) was prepared in a manner similar to that described in the Reference example 32 (a) except that, in step (ii), acid was used 1-ethyl-3-methyl-1H-pyrazol-5-carboxylic instead of benzoic acid. 1 HRMN (DMSO-<i>d</i>6) δ: 12.89 (s, 1H), 12.37 (s, 1H), 10.18 (s, 1H), 8.07 (d, 1H, <i>J</i> = 8.9 Hz), 7.74 (s, 1H), 7.58 (d, 1H, <i>J</i> = 8.3 Hz), 7.49 (s, 1H), 7.44-7.32 (m, 3H), 7.28 (s, 1H), 7.01 (s, 1H), 6.95 (d, 1H, <i>J</i> = 8.9 Hz), 6.86 (d, 1H, <i>J</i> = 8.6 Hz), 6.78 (s, 1H), 438 (q, 2H, <i>J</i> = 7.1 Hz), 2.19 (s, 3H), 1.29 (t, 3H, <i>J</i> = 7.1 Hz). Anal. Calc. For C 25 H 23 N 7 O 2, 0.8 H 2 O 0.1 EtOAc: C, 63.99; H, 5.37; N, 20.57. Found: C, 63.72; H, 5.12; N, 20.25.

Reference Example 32 (c)

6- [3 - ((1-ethyl-3-methyl-1

H

-pyrazol-5-yl) carboxamido) phenoxy] -3-E- [2- (2-methylimidazol-4-yl) ethenyl] -1

H

-indazol

<figref>249</figref>

The compound of the Reference Example 32 (c) was prepared in a manner similar to that described in the Reference example 32 (b) except that, in step (i), used chloride hydrochloride (E) -3- [2-methyl-1- (2-trimethyl-silanyl) -ethoxymethyl-1H-imidazol-4-yl] -acryloyl instead of chloride hydrochloride (E) -3- [1- (2-Trimethyl-silanyl) ethoxymethyl) -1<i>H</i>-imidazol-4-yl] -acryloyl. 1 HRMN (DMSO-<i>d</i>6) δ: 12.85 (broad s, 1H), 11.80 (broad s, 1H), 10.18 (s, 1H), 8.05 (d, 1H, <i>J</i> = 8.7 Hz), 7.58 (d, 1H, <i>J</i> = 8.4 Hz), 7.48 (s, 1H), 7.39 (t, 1H,<i>J</i> = 8.2 Hz), 7.33-7.05 (m, 3H), 7.00 (s, 1H), 6.93 (d, 1 H, <i>J</i> = 8.7 Hz), 6.86 (d, 1H, <i>J</i> = 8.2 Hz), 6.78 (s, 1H), 4.38 (q, 2H, <i>J</i> = 7.1 Hz), 2.31 (s, 3H), 2.19 (s, 3H), 1.29 (t, 3H, <i>J</i> = 7.1 Hz). Anal. Calc. For C 26 H 25 N 7 O 2 {0.9 H 2 O • 0.4 EtOAc: C, 63.87; H, 5.83; N, 18.89. Found: C, 63.64; H, 5.76; N, 18.85.

Reference Example 33 (a)

6- [2- (methylcarbamoyl) phenylsufanyl] -3-E- [2- (pyridin-2-yl) ethenyl] indazole

<figref>250</figref>

The compound of the Reference Example 33 (a) was prepared from 6- [2- (methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1- [2- (trimethyl-silanyl) ethoxymethyl) -1<i>H</i>-indazol similar to that described in Reference Example 11. R f sm = 0.8, p = 0.15 (ethyl acetate); 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.45 (s, 1H), 8.72 (d, 1H, <i>J</i>= 3.9 Hz), 8.47 (m, 1H), 8.31 (d, 1H, <i>J</i> = 8.5 Hz), 8.06 (d, 1 HOUR, <i>J</i> = 16.4 Hz), 7.92 (dt, 1H, <i>J</i> = 1,7,7,6 Hz), 7,78 (d, 1H, <i>J</i> = 7.8 Hz), 7.71 (s, 1H), 7.68 (d, JH, <i>J</i> = 16.5 Hz), 7.61 (dd, 1H, <i>J</i> = 1.7, 7.2 Hz), 7.45-7.36 (m, 3H), 731 (d, 1H, <i>J</i> = 8.5 Hz), 7.17 (m, 1H), 2.89 (d, 3H, <i>J</i> = 4.6 Hz); 13 C NMR (75 MHz, DMSO-<i>d</i>6) δ: 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 (area 100%) Rt = 3.5 min (pos) [M + H] / z, calculated 387, found 387. Analyzed with 0.1 H 2 O, 0.1 EtOAc: Calculated, 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 follow:

<figref>251</figref>

Under argon, it dissolved 6-iodo-3-styryl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol (30.0 g, 62.9 mmol) prepared in Reference Example 14, step (i), in dichloromethane (375 mL) and cooled to -42 ° C in a bath of acetonitrile-carbonic snow. Then you bubbled ozone through the mixture (1 L / min, 60 V, 1.8 Amps) for 45 min. The standard indicators did not show a net change due to the background color of the solutions. To avoid the over-oxidation, the progress of the reactions is monitored by TLC (EtOAc-Hex 1: 9). He stopped the Ozone addition and the flask was swept with argon. Then you dimethyl sulfide (30 mL) was added and the mixture was allowed to warm up to 23 ° C. This mixture was stirred for 4 h and concentrated under reduced pressure The oil was placed under high vacuum for 16 h. He residue was dissolved in dichloromethane (15 mL) and diluted with hexane (100 mL) obtaining some crystals (unwanted product). The mixture was filtered and the filtrate was concentrated. The residue dissolved in Hex-EtOAc 8: 2 (250 mL), it was treated with 50 mL of silica, filtered and concentrated. It was obtained 6-iodo-3-carboxaldehyde-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol in the form of a yellow solid after 72 h high vacuum (24.17 g, sim95% purity by NMR, yield 91%): R<i>F</i> sm = 0.34, p = 0.29 (1: 9 ethyl acetate-hexane); 1 HRMN (300 MHz, CDCl 3) δ: 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).

<figref>252</figref>

6-Iodine-3-carboxaldehyde-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol (24.0 g, 59.7 mmol) was dissolved in THF (350 mL) and cooled to -5 ° C. To this was added chloride of 2-picolyltriphenylphosphonium hydride solid potassium (45.7 g, 100 mmol, 1.68 equivalents). The mixture of reaction was allowed to stir for 45 min. To the mix, it added 3N HCl (20 mL) followed by aqueous sodium hydrogen carbonate saturated (50 mL) obtaining a pH of 6. The excess of THF under reduced pressure and the residue was partitioned between acetate ethyl and water. The organic materials were washed with saturated aqueous sodium hydrogen carbonate, water and layer Organic was separated, dried over sodium sulfate, decanted and concentrated under reduced pressure. The residue was extracted with acetate of ethyl hexane 1: 9 and filtered. The filtrate is purified by silica gel column chromatography (2L silica, ethyl acetate of 20 to 30 to 50% -hexane) obtaining 6-iodo-3-E- [2- (pyridin-2-yl) ethenyl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol (18.9 g, 66% yield): R f sm = 0.52, p = 0.25 (acetate ethyl hexane 2: 8); 1 HRMN (300 MHz, CDCl 3) δ: 8.64 (m, 1H), 8.00 (d, 1H, <i>J</i> = 0.7 Hz), 7.87 (d, 1 HOUR, <i>J</i> = 16.4 Hz), 7.80 (d, 1H, <i>J</i> = 8.5 Hz), 7.69 (td, 1 HOUR, <i>J</i> = 7.7, 1.8 Hz), 7.55 (d, 1H, <i>J</i> = 16.4 Hz). 7.55 (dd, 1H, <i>J</i> = 8.5, 1.3 Hz), 7.47 (d, 1H, <i>J</i> = 7.9 Hz), 7.18 (dd, 1H, <i>J</i> = 1.1, 4.8 Hz), 5.70 (s, 2H), 3.59 (s, 2H,<i>J</i> = 8.2 Hz), 0.90 (t, 2H, <i>J</i> = 8.2 Hz), -0.04 (s, 9H); 13 CRMN (75 MHz. CDCl 3) δ: 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.

<figref>253</figref>

In a 200 mL round bottom flask it was weighed cesium carbonate (13.7 g, 41.9 mmol, 2.5 equivalents) and this salt It was dried under high vacuum with a hot air gun. TO then the catalyst was added [Pd (dppf) Cl_ {2} -CH_ {2} Cl_ {2}] (1.37 g, 1.68 mmol, 0.1 equivalent) and 6-iodo-3-E- [2- (pyridin-2-yl) ethenyl-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol (8.0 g, 16.76 mmol) and the mixture was collected with DMF (71 mL). This mixture was added methyl thiosalicylate (4.62 mL, 33.5 mmol, 2.0 equivalent) and the vessel was heated to 85 ° C for 4.5 h. This mixture was cooled to 23 ° C, partitioned between acetate ethyl (350 mL) and 50% saturated aqueous sodium hydrogen carbonate (300 mL). The organic materials were washed with sodium bisulfite 10% (200 mL), brine and the organic layer was separated. The material Organic was dried over sodium sulfate, decanted and concentrated under reduced pressure. Purification by column chromatography silica gel (500 mL silica; ethyl acetate 30 to 40 50% -hexane) gave 6 - [(2-methoxycarbonylphenyl) sulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol (6.44 g, 74%): R<i>F</i> sm = 0.52, p = 0.19 (acetate ethyl hexane 3: 7); FTIR (thin film) 2950, ​​2887, 2356, 1713, 1585, 1464, 1433, 1250, 1076, 837 cm -1; 1 HRMN (300 MHz, CDCl3) δ: 8.70 (d, 1H), 8.12 (d, 1H), 8.04 (d, 1H), 7.99 (d, 1H, <i>J</i> = 16.4 Hz), 7.90 (s, 1H), 7.88 (t, 1H), 7.76 (d, 1H, <i>J</i> = 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); 13 CRMN (75 MHz, CDCl 3) δ: 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, calculated 518.2, found 518.2.

<figref>254</figref>

TO 6 - [(2-methoxycarbonylphenyl) sulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol (8.50 g, 16.4 mmol) THF (120 mL), methanol (120 mL), water was added (120 mL) and potassium carbonate (15.9 g, 115 mmol, 7.0 equivalent). This mixture was heated to 67 ° C and stirred for 22 h. The mixture was cooled and excess solvents removed. He residue was partitioned between ethyl acetate (300 mL) and water (250 mL) The aqueous layer was acidified with 20% citric acid until pH 5 (? 70 mL) and drained. The organic layer was washed with water (50 mL) and hexane (100 mL) was added to keep the precipitates precipitated crystals that formed in the ethyl acetate layer. Solid it was filtered and dried obtaining 6 - [(2-carboxyphenyl) sulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1- [2- (trimethyl-silanyl) ethoxy-methyl] -1<i>H</i>-indazol (7.56 g, 91%): R f sm = 0.67, p = 0.41 (acetate ethyl hexane 8: 2); 1 HRMN (300 MHz, CDCl 3) δ: 8.60 (m, 1H), 8.10 (d, 1H, <i>J</i> = 8.4 Hz). 8.04 (dd, 1 HOUR, <i>J</i> = 1.7, 7.7 Hz), 7.85 (d, 1H, <i>J</i> = 16.5 Hz), 7.83 (s, 1H), 7.70 (dt, 1H, <i>J</i> = 1.7, 7.7 Hz), 7.59 (d, 1H,<i>J</i> = 16.5 Hz), 7.52 (d, 1H, <i>J</i> = 7.9 Hz), 7.38 (dd, 1H,<i>J</i> = 1.3, 8.4 Hz), 7.22-7.10 (m, 3H), 6.80 (dd, 1H, <i>J</i> = 1.0, 8.0 Hz), 3.59 (t, 2H, <i>J</i> = 8.1 Hz), 0.85 (t, 2H, <i>J</i> = 8.8.1 Hz), -0.1 (s, 9H).

<figref>1255</figref>

<figref>255</figref>

6 - [(2-Carboxyphenyl) sulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1- [2- (trimethyl-silanyl) -ethoxy-methyl] -1<i>H</i>-indazol (820 mg, 1.63 mmol) was dissolved in DMF (5 mL) and treated with methylamine (2M in THF, 4.1 mL, 8.13 mmol, 50 equivalents) and with HATU (929 mg, 2.44 mmol, 1.5 equivalents). This mixture was stirred. for 30 min, it was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate and the layer was separated organic The organic material was dried over sodium sulfate, decanted and concentrated under reduced pressure. Purification by silica gel column chromatography (50 mL of silica; acetate from 60 to 70% ethyl -hexane) gave 6- [2- (methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1- [2- (trimethyl-silanyl) -ethoxymethyl] -1H-indazole in the form of a solid (795 mg, 94%): R f 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 cm -1; 1 HRMN (300 MHz, CDCl 3) δ: 8.70 (m, 1H), 8.06 (d, 1H, <i>J</i> = 8.4 Hz), 7.94 (d, 1 HOUR, <i>J</i> = 16.3 Hz), 7.74 (dt, 1H, <i>J</i> = 1.8, 7.7 Hz), 7.70-7.60 (m, 3H), 7.52 (d, 1H, <i>J</i> = 7.9 Hz), 7.35-7.20 (m, 5H), 6.45 (wide s, 1H), 5.80 (s, 2H), 3.62 (t, 2H), 3.00 (d, 3H), 0.93 (t, 2H), -0.05 (s, 9H); 13 CRMN (75 MHz, CDCl 3) δ: 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, calculated 517.2, found 517.2.

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Reference Example 33 (b)

6- [2- (2-Methylquinol-6-ylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>256</figref>

The compound of the Reference Example 33 (b) was prepared in a manner similar to that described in the Reference example 33 (a) except that, in step (v), use 6-amino-2-methylquinoline instead of methylamine: 1 HRMN (300 MHz, CDCl 3) δ: 10.2 (wide s, 1H), 8.64 (m, 1H), 8.40 (s, 1H), 8.23 ​​(s, 1H), 7.98-7.80 (m, 4H), 7.69 (dt, 1H, <i>J</i> = 1.7, 7.7 Hz), 7.55-7.40 (m, 7H), 7.25-7.16 (m, 3H), 2.71 (s, 3H).

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Reference Example 33 (c)

6- [2- (phenylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>257</figref>

The compound of the Reference Example 33 (c) was prepared in a manner similar to that described in the Reference example 33 (a) except that, in step (v), used aniline instead of methylamine: 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.35 (s, 1H), 10.53 (s, 1H), 8.67 (m, 1H), 8.22 (d, 1H, <i>J</i> = 7.5 Hz), 7.99 (d, 1H, <i>J</i> = 16.4 Hz), 7.85 (dt, 1H, <i>J</i> = 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, calculated 449.1, found 449.1. Analyzed with 0.41 H 2 O: Calculated, 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).

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Reference Example 33 (d)

6- [2- (3-Chlorophenylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>258</figref>

The compound of the Reference Example 33 (d) was prepared in a manner similar to that described in the Reference example 33 (a) except that, in step (v), used 3-chloroaniline instead of methylamine: 1 HRMN (300 MHz, CDCl 3) δ: 8.53 (m, 1H), 7.92 (d, 1 HOUR, <i>J</i> = 8.4 Hz), 7.77 (d, 1H, <i>J</i> = 16.4 Hz), 7.68 (dt, 1 HOUR, <i>J</i> = 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 (area 100%) Rt 3.98 min, (pos) [M + H] / z, calculated 483.1, found 483.1. Analyzed with 0.3 H 2 O: Calculated, 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).

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Reference Example 33 (e)

6- [2- (cyclopropylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-1

H

-indazol

<figref>259</figref>

The compound of the Reference Example 33 (e) was prepared in a manner similar to that described in the Reference example 33 (a) except that, in step (v), used cyclopropylamine instead of methylamine: 1 H NMR (300 MHz, DMSO-<i>d</i>6) δ: 13.45 (s, 1H), 8.73 (d, 1H, <i>J</i>= 3.9 Hz), 8.56 (d, 1H, <i>J</i> = 4.3 Hz), 8.31 (d, 1H, <i>J</i> = 8.5 Hz), 8.08 (d, 1H, <i>J</i> = 16.4 Hz), 7.91 (dt, 1H, <i>J</i> = 1.7, 7.7 Hz), 7.78 (d, 1H, <i>J</i> = 7.8 Hz), 7.70 (m, 2H), 7.57 (m, 1H,), 7.40 (m, 3H), 7.30 (d, 1H, <i>J</i> = 8.4 Hz), 7.20 (d, 1 HOUR, <i>J</i> = 7.8 Hz), 2.94 (m, 1H), 0.80 (m, 2H), 0.65 (m, 2H); LCMS (100% area) Rt 3.51 min, (pos) [M + H] / z, calculated 413.1, found 413.1.

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Reference Example 33 (f)

6- [2- (2,2,2-Trifluoroethylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>260</figref>

The compound of the Reference Example 33 (f) was prepared in a manner similar to that described in the Reference example 33 (a) except that, in step (v), used 2,2,2-trifluoroethylamine instead of methylamine: 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.5 (s, 1H), 9.29 (t, 1H, <i>J</i> = 6.3 Hz), 8.74 (m, 1H), 837 (d, 1H, <i>J</i> = 8.3 Hz), 8.10 (d, 1H, <i>J</i> = 16.4 Hz), 7.94 (dt, 1H, <i>J</i>= 1.8, 7.6 Hz), 7.80 (d, 1H, <i>J</i> = 7.9 Hz), 7.75-7.65 (m, 3H), 7.55-7.40 (m, 3H), 7.33 (d, 1H), 7.22 (d, 1H), 4.22 (m, 2H); LCMS (100% area) Rt = 3.70 min, (pos) [M + H] / z, calculated 455.1, found 455.1.

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Reference Example 33 (g)

Tetrabutylammonium salt 6- [2- (carboxy) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-1

H

-indazol

<figref>261</figref>

The compound of the Reference Example 33 (g) was prepared in a manner similar to that described in the Reference Example 33 (a) except that the step was omitted (v): R f sm = 0.41, p = 0.0 (acetate ethyl hexane 8: 2); 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 8.75 (m, 1H), 8.25 (d, 1H, <i>J</i> = 8.6 Hz), 8.05 (d, 1H, 16.4 Hz), 7.88 (dt, 1H, <i>J</i> = 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 (area 100%) Rt = 3.24 (pos) [M + H (component only) acid)] / z, calculated 374.1, found 374.1. Analyzed with 0.1 H2O: Calculated, 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).

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Reference Example 33 (h)

6- [2- (3-Chlorophenylcarbamoyl) phenylsulfanyl] -3

Z

- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>262</figref>

The compound of the Reference Example 33 (h) was prepared in the same reaction as the compound of Reference example 33 (d). It should be noted that, although this compound was isolated and characterized pure, it was found that it isomerizes the compound of Reference Example 33 (d) in the valuation conditions. 1 H NMR (300 MHz, CDCl 3) δ: 8.82 (m, 1H), 8.31 (s, 1H), 7.86 (m, 2H), 7.77 (m, 2H), 7.61 (t, 1H, <i>J</i> = 2.0 Hz), 7.46 (d, 1H, <i>J</i> = 8.0 Hz), 7.33 (m, 5H), 7.21 (t, 1H, <i>J</i> = 8.0 Hz), 7.13 (dd, 1H,<i>J</i> = 1.5, 8.1 Hz), 7.08 (m, 1H), 6.98 (d, 1H, <i>J</i> = 13.0 Hz), 6.66 (d, 1H, <i>J</i> = 13.1 Hz); LCMS (100% area) Rt = 4.40 min, (pos) [M + H] / z, calculated 483.1, found 483.1. Analyzed with 0.3 H 2 O: Calculated, 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).

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Reference Example 3. 4

6-[2-((

RS

-(

trans

-2-phenylcyclopropyl) carbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>263</figref>

The compound of the Reference Example 33 (g) became the compound of the Reference Example 34 in a manner similar to that described in the Reference Example 33 (a), step (v) except that it was used trans-2-phenylcyclopropylamine in Methylamine site: FTIR (thin film) 1704, 1638, 1584, 1559, 1530, 1497, 1460, 1430, 1339, 1306, 1269, 1223, 1152, 1086, 1061, 966, 844 cm -1; 1 HRMN (300 MHz, CDCl 3) δ: 13.3 (s, 1H), 8.71 (d, 1H, <i>J</i> = 4.4 Hz), 8.61 (d, 1H, <i>J</i> = 3.9 Hz), 8.20 (d, 1H, <i>J</i> = 8.5 Hz), 7.96 (d, 1H, <i>J</i> = 16.4 Hz), 7.81 (dt, 1H, <i>J</i> = 1.7, 7.6 Hz), 7.66 (d, 1H,<i>J</i> = 7.8 Hz), 7.59-7.50 (m, 3H), 7.37-7.25 (m, 5H), 7.21-7.08 (m, 5H), 3.01 (m, 1H), 2.03 (m, 1H), 1.25 (m, 2H); LCMS (100% area) Rt = 3.72 min, (pos) [M + H] / z, calculated 489.2, found 489.2. Analyzed with 0.6 MeOH, 0.16 CH 2 Cl 2: Calculated, 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).

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Reference Example 35 (a)

6-[2-(

n

-propylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>264</figref>

It dissolved 6- [2- (pentafluorophenoxycarbonyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1<i>H</i>-indazol (60 mg, 0.1112 mmol) in DMF (0.8 mL), treated with<i>n</i>-propylamine (11 µL, 0.1335 mmol) and stirred at room temperature. HPLC analysis after 15 minutes He indicated that all the starting material had been consumed. The reaction mixture was concentrated by rotary evaporation at high empty giving a solid. The solid was treated with ultrasound with CH 2 Cl 2 giving a fine suspension, which was filtered and washed with CH 2 Cl 2 providing 40 mg (87% yield) of title compound. 1 HRMN (DMSO-<i>d</i>6) δ: 13.31 (s, 1 H), 8.60 (d, <i>J</i> = 4.0 Hz, 1H), 8.41 (t, <i>J</i> = 6.2 Hz, 1H), 8.19 (d, <i>J</i> = 8.5 Hz, 1H), 7.94 (m, 3H), 7.81 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.66 (t, <i>J</i> = 8.7 Hz, 1H), 7.56 (m, 2H), 7.47 (m, 1H), 7.30 (m, 3H), 7.18 (d, <i>J</i> = 8.3 Hz, 1H), 3.20 (q, <i>J</i> = 6.0 Hz, 2H), 1.55 (septet, <i>J</i> = 5.9 Hz, 2H), 0.92 (t, <i>J</i> = 6.0 Hz, 3H). Anal. Calc. For C 24 H 22 N 4 OS • (1.5 H 2 O, 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.

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The starting material was prepared as follow:

<figref>265</figref>

A solution of the tetrabutylammonium salt of 6- (2-carboxyphenylsulfanyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1<i>H</i>-indazol) (615 mg, 1.0 mmol) dissolved in anhydrous DMF (10.0 ml) was treated with pyridine (89 µL, 1.1 mmol) and trifluoroacetate pentafluorophenyl (206 µL, 1.2 equivalents), at temperature atmosphere, under argon atmosphere. HPLC analysis after 45 minutes showed most of the carboxylic acid without react, so more pyridine (89 µL, 1.1 mmol) was added and pentafluorophenyl trifluoroacetate (206 mL, 1.2 equivalents). HPLC analysis 15 minutes later indicated that it had completely consumed the starting acid. Reaction mixture It was concentrated by rotary evaporation under high vacuum, then triturated with CH 2 Cl 2 (sim1 mL) causing the crystal formation, which was collected by filtration, washed with more CH 2 Cl 2 and dried. The mass of the crystals of Vivid yellow color was 336 mg. The remaining filtrate was concentrated and purified by flash chromatography (acetonitrile al 10% / CH 2 Cl 2 to 80% acetonitrile / CH 2 Cl 2), obtaining 70 mg more solid. The total yield of 6- [2- (pentafluorophenoxycarbonyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1<i>H</i>-indazol it was 406 mg or 89%. 1 HRMN (CDCl3) δ: 10.22 (1H, s width), 8.66 (1H, d, <i>J</i> = 4.5 Hz), 8.28 (2H, dd, <i>J</i> = 7.7, 1.5 Hz), 8.15 (1H, d, <i>J</i> = 8.5 Hz), 7.97 (1H, d, <i>J</i>= 16.2 Hz), 7.79 (1H, s), 7.15-7.75 (7H, m), 6.92 (1H, d, <i>J</i> = 8.1 Hz).

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Reference Example 35 (b)

6-[2-(

i

-propylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>266</figref>

The compound of the Reference Example 35 (b) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used isopropylamine instead of <i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.30 (s, 1H), 8.60 (d, <i>J</i> = 4.5 Hz, 1H), 8.26 (d, <i>J</i> = 7.34 Hz, 1H), 8.19 (d, <i>J</i> = 8.3 Hz, 1H), 7.94 (d, <i>J</i> = 16.4 Hz, 1H), 7.80 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.66 (d, <i>J</i> = 7.7 Hz, 1H), 7.56 (m, 2H), 7.45 (m, 1H), 7.30 (m, 3H), 7.18 (d, <i>J</i> = 8.5 Hz, 1H), 7.08 (m, 1H), 4.04 (septet, <i>J</i> = 7.4 Hz, 1H), 1.15 (d, <i>J</i> = 6.6 Hz, 6H). Anal. Calc. For C_ {24} H_ {22} N_ {4} OS \ cdot1,7 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.

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Reference Example 35 (c)

6- [2- (cyclobutylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>267</figref>

The compound of the Reference Example 35 (c) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used cyclobutylamine instead of <i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.31 (s, 1H), 8.62 (m, 2H), 8.19 (d, <i>J</i> = 8.5 Hz, 1H), 7.94 (m, 2H), 7.80 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.65 (t, <i>J</i> = 8.1 Hz, 1H), 7.56 (s, 1H), 7.47 (m, 1H), 7.30 (m, 3H), 7.17 (d, <i>J</i> = 8.3 Hz, 1H), 4.36 (septete, <i>J</i> = 8.1 Hz, 1H), 2.22 (m, 2H), 2.03 (m, 2H), 1.67 (m, 2H). Anal. Calc. For C 25 H 22 N 4 OS • (0.5 H 2 O, 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.

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Reference Example 35 (d)

6- (2-carbamoylphenylsulfanyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>268</figref>

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The compound of the Reference Example 35 (d) was prepared in a manner similar to that described in the Reference Example 35 (a) except that ammonia was used in instead of <i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 8.60 (d, <i>J</i> = 4.9 Hz, 1H), 8.21 (d, <i>J</i> = 8.3 Hz, 1H), 7.94 (m, 3H), 7.81 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.60 (m, 4H), 7.48 (broad s, 1H), 7.25 (m, 4H), 7.0 (m, 1H). Anal. Calc. for C 21 H 16 N 4 OS • 0.25H 2 O: 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.

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Reference Example 35 (e)

6- [2 - ((1-methylpyrrol-2-ylhydrazido) carbonyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>269</figref>

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The compound of the Reference Example 35 (e) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used 1-methylpyrrol-2-ylhydrazide instead of <i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.34 (s, 1H), 10.25 (s, 1H), 10.05 (s, 1H), 8.60 (d,<i>J</i> = 4.5 Hz, 1H), 8.22 (d, <i>J</i> = 8.7 Hz, 1H), 7.95 (d,<i>J</i> = 16.2 Hz, 1H), 7.81 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.66 (m, 3H), 7.57 (d, <i>J</i> = 16.0 Hz, 1H), 7.43-7.18 (m, 4H), 7.07 (d, <i>J</i> = 7.9 Hz, 1H), 7.00 (d, <i>J</i> = 3.4 Hz, 2H), 6.07 (t, <i>J</i> = 3.2 Hz, 1H), 3.88 (s, 3 H). Anal. Calc. For C 27 H 22 N 6 O 2 S • 0.6 H 2 O: 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.

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Reference Example 35 (f)

6- [2 - ((2-Fluorobenzyl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>270</figref>

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The compound of the Reference Example 35 (f) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used 2-fluorobenzylamine instead of<i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.31 (s, 1H), 8.99 (t, <i>J</i> = 5.8 Hz, 1H), 8.61 (d, <i>J</i> = 4.5 Hz, 1H), 8.19 (d, <i>J</i> = 8.5 Hz, 1H), 7.94 (d, <i>J</i> = 16.2 Hz, 1H), 7.81 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.66 (d,<i>J</i> = 8.1 Hz, 1H), 7.56 (m, 3H), 7.47 (t, <i>J</i> = 7.9 Hz, 1H), 7.31 (m, 4H), 7.15 (m, 4H), 4.51 (d, <i>J</i> = 5.7 Hz, 2H). Anal. Calcd. For C 28 H 21 FN 4 OS \ 0.25 H 2 O: 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.

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Reference Example 35 (g)

6- [2 - ((4-methoxybenzyl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>271</figref>

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The compound of the Reference Example 35 (g) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used 4-methoxybenzylamine instead of<i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.31 (s, 1 H), 8.90 (t, <i>J</i> = 5.5 Hz, 1H), 8.60 (d, <i>J</i> = 4.2 Hz, 1H), 8.19 (d, <i>J</i> = 8.3 Hz, 1H), 7.95 (d, <i>J</i> = 16.3 Hz, 1H), 7.81 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.66 (d,<i>J</i> = 7.9 Hz, 1H), 7.55 (m, 3H), 7.30 (m, 5H), 7.18 (d,<i>J</i> = 8.5 Hz, 1H), 7.10 (d, <i>J</i> = 8.3 Hz, 1H), 4.39 (d,<i>J</i> = 6.0 Hz, 2H), 3.72 (s, 3H). Anal. Calc. For C 29 H 24 N 4 O 2 S • 0.6 H 2 O: 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.

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Reference Example 35 (h)

6- [2 - ((5-methylfur-2-yl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>272</figref>

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The compound of the Reference Example 35 (h) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used 5-methylfur-2-ylamine instead of <i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.31 (s, 1H), 8.88 (t, <i>J</i> = 5.3 Hz, 1H), 8.60 (d,<i>J</i> = 4.3 Hz, 1H), 8.19 (d, <i>J</i> = 8.3 Hz, 1H), 7.95 (d,<i>J</i> = 16.3 Hz, 1H), 7.81 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.66 (d, <i>J</i> = 8.1 Hz, 1H), 7.54 (m, 3H), 7.30 (m, 4H), 7.18 (d,<i>J</i> = 8.3 Hz, 1H), 7.06 (d, <i>J</i> = 8.1 Hz, 3H). Anal. Calc. for C 27 H 22 N 4 O 2 S • 0.4 H 2 O: 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.

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Reference Example 35 (i)

6- [2- (benzyloxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>273</figref>

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The compound of the Reference Example 35 (i) was prepared in a manner similar to that described in the Reference Example 5 (a) except that it was used O-benzyl hydroxylamine instead of<i>n</i>-propylamine. 1 H NMR (DMSO-<i>d</i>6) δ: 13.31 (s, 1H), 11.64 (s, 1H), 8.90 (t, <i>J</i> = 5.5 Hz, 1H), 8.60 (d, <i>J</i> = 4.1 Hz, 1H), 8.19 (d, <i>J</i> = 8.3 Hz, 1H), 7.95 (d, <i>J</i> = 16.3 Hz, 1H), 7.81 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.66 (d, <i>J</i> = 7.9 Hz, 1H), 7.56 (m, 2H), 7.50-7.24 (m, 9H), 7.17 (t, <i>J</i> = 8.5 Hz, 2H), 4.94 (s, 2H). Anal. Calc. For C 28 H 22 N 4 O 2 S • 0.8H 2 O: 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.

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Reference Example 35 (j)

6- [2- (allyloxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>274</figref>

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The compound of the Reference Example 35 (j) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used O-allylhydroxylamine instead of<i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.32 (s, 1H), 11.56 (s, 1H), 8.60 (d, <i>J</i> = 4.1 Hz, 1H), 8.19 (d, <i>J</i> = 8.3 Hz, 1H), 7.95 (d, <i>J</i> = 16.5 Hz, 1H), 7.81 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.66 (d, <i>J</i> = 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, <i>J</i> = 18.3 Hz, 1H), 5.27 (d, <i>J</i> = 11.3 Hz, 1H), 4.42 (d, <i>J</i> = 6.0 Hz, 1H). Anal. Calc. For C 24 H 20 N 4 O 2 S (0.2 H 2 O, 0.2CH 2 Cl 2): 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.

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Reference Example 35 (k)

6- [2- (isopropoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>275</figref>

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The compound of the Reference Example 35 (k) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used O-isopropyl hydroxylamine instead from <i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.30 (s, 1H), 11.33 (s, 1H), 8.60 (d, <i>J</i> = 4.1 Hz, 1H), 8.19 (d, <i>J</i> = 8.3 Hz, 1H), 7.95 (d, <i>J</i> = 16.5 Hz, 1H), 7.81 (dt, <i>J</i> = 1.7, 1.5 Hz, 1H), 7.66 (d, <i>J</i> = 7.9 Hz, 1H), 7.55 (m, 2H), 7.48-7.24 (m, 4H), 7.17 (d, <i>J</i>= 8.3 Hz, 2H), 4.12 (septet, <i>J</i> = 5.7 Hz, 1H), 1.21 (d,<i>J</i> = 6.2 Hz, 6H. Anal. Calc. For C 24 H 22 N 4 O 2 S \ (0.4 H 2 O, 0.7 CH 2 Cl 2): ​​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.

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Reference Example 35 (l)

6- [2 - ((4-aminobenzyl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>276</figref>

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The compound of the Reference Example 35 (l) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used 4-amino-benzylamine instead of<i>n</i>-propylamine. 1 H NMR (DMSO-<i>d</i>6) δ: 13.31 (s, 1 H), 8.78 (t, <i>J</i> = 6.0 Hz, 1H), 8.60 (d, <i>J</i> = 4.3 Hz, 1H), 8.19 (d, <i>J</i> = 8.1 Hz, 1H), 7.95 (d, <i>J</i> = 16.3 Hz, 1H), 7.85 (broad s, 1H), 7.81 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.66 (d, <i>J</i> = 7.9 Hz, 1H), 7.59 (s, 1H), 7.51 (m, 2H), 7.30 (m, 3H), 7.19 (d, <i>J</i> = 8.7 Hz, 1H), 7.05 (m, 3H), 6.56 (d, <i>J</i> = 8.7 Hz, 1H), 6.51 (d, <i>J</i> = 8.5 Hz, 2H), 4.29 (d, <i>J</i> = 6.0 Hz, 2H). Anal. Calc. For C 28 H 23 N 5 OS • 0.6 H 2 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.

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Reference Example 35 (m)

6- [2 - ((tien-2-ylhydrazide) carbonyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>277</figref>

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The compound of the Reference Example 35 (m) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used tien-2-ilhydrazide instead of<i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.49 (wide s, 1H), 10.64 (s, 1H), 10.47 (s, 1H), 8.66 (d, <i>J</i>= 4.0 Hz, 1H), 8.22 (d, <i>J</i> = 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, <i>J</i> = 8.1 Hz, 1H), 7.00 (d, <i>J</i> = 3.4 Hz, 2H), 6.07 (t, <i>J</i> = 3.2 Hz, 1H), 3.88 (s, 3H). Anal. Calc. for C 26 H 19 N 5 O 2 S 2 {2} \ H 2 O: 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.

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Reference Example 35 (n)

6-[2-(

N

2 - (pyrid-2-ylhydrazino) carbonyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>278</figref>

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The compound of the Reference Example 35 (n) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used 2-hydrazinopyridine instead of<i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.31 (s, 1H), 10.30 (s, 1H), 8.60 (d, <i>J</i> = 4.4 Hz, 1H), 8.48 (s, 1H), 8.21 (d, <i>J</i> = 8.5 Hz, 1H), 8.09 (d, <i>J</i> = 4.9 Hz, 1H), 7.94 (d, <i>J</i> = 16.4 Hz, 1H), 7.81 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.67 (m, 1H), 7.62-7.47 (m, 3H), 7.40 (m, 2H), 7.31-7.12 (m, 3H), 6.73 (m, 2H). Anal. Calcd. For C 26 H 20 N 6 OS • 0.3H 2 O: 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.

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Reference Example 35 (o)

6-[2-(

N

-hydroxy

N

-methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>279</figref>

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The compound of the Reference Example 35 (o) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used N-methyl hydroxylamine instead of<i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.24 (s, 1H), 9.94 (s, 1H), 8.60 (d, <i>J</i> = 4.0 Hz, 1H), 8.14 (d, <i>J</i> = 83 Hz, 1H), 7.92 (d, <i>J</i> = 16.2 Hz, 1H), 7.80 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.65 (t, <i>J</i> = 8.5 Hz, 1H), 7.54 (d, <i>J</i> = 16.5 Hz, 1H), 7.47-7.24 (m, 6H), 7.16 (d, <i>J</i> = 8.5 Hz, 1H) 3.24 (wide s, 1H). Anal. Calc. for C 22 H 18 N 4 O 2 S · (0.5H 2 O, 0.3 CH 2 Cl 2): ​​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.

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Reference Example 35 (p)

6- [2 - ((pyrid-4-yl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>280</figref>

The compound of the Reference Example 35 (p) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used 4-aminomethylpyridine instead of<i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.31 (broad s, 1H), 9.07 (t, <i>J</i> = 6.8 Hz, 1H), 8.60 (d,<i>J</i> = 4.2 Hz, 1H), 8.48 (d, <i>J</i> = 5.0 Hz, 1H), 8.19 (d,<i>J</i> = 8.7 Hz, 1H), 7.95 (d, <i>J</i> = 16.4 Hz, 1H), 7.80 (dt,<i>J</i> = 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, <i>J</i> = 6.2 Hz, 2H).

Reference Example 35 (q)

6- [2 - ((2-methylphenylhydrazido) carbonyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>281</figref>

The compound of the Reference Example 35 (q) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used 2-methyl-phenylhydrazide instead of<i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.43 (broad s, 1H), 10.45 (s, 1H), 10.28 (s, 1H), 8.64 (d, <i>J</i>= 4.0 Hz, 1H), 8.22 (d, <i>J</i> = 8.2 Hz, 1N), 8.01 (d, <i>J</i> = 16.6 Hz, 1H), 7.92 (m, 1H), 7.81 (m, 1H), 7.69 (m, 1H), 7.60 (d,<i>J</i> = 16.4 Hz, 1H), 7.50-7.22 (m, 8H), 7.07 (d,<i>J</i> = 7.7 Hz, 1H), 2.45 (s, 3H).

Reference Example 35 (r)

6- [2- (methoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>282</figref>

The compound of the Reference Example 35 (r) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used O-methyl hydroxylamine instead of<i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.32 (s, 1H), 11.60 (s, 1H), 8.60 (d, <i>J</i> = 3.8 Hz, 1H), 8.19 (d, <i>J</i> = 8.4 Hz, 1H), 7.95 (d, <i>J</i> = 16.2 Hz, 1H), 7.81 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.66 (d, <i>J</i> = 7.9 Hz, 1H), 7.56 (m, 2H), 7.47 (dd, <i>J</i> = 7.4, 1.7 Hz, 1H), 7.43-7.24 (m, 3H), 7.17 (m, 2H), 3.72 (s, 3H). Anal. Calc. For C 22 H 18 N 4 O 2 S 2 0.6CH 2 Cl 2: 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.

Reference Example 35 (s)

6- [2 - ((cyclopropyl) methoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>283</figref>

The compound of the Reference Example 35 (s) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used O-cyclopropyl-hydroxylamine instead from <i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.38 (s, 1H), 11.51 (s, 1H), 8.64 (d, <i>J</i> = 3.8 Hz, 1H), 8.18 (d, <i>J</i> = 8.4 Hz, 1H), 8.00 (d, <i>J</i> = 16.4 Hz, 1H), 7.86 (m, 2H), 7.63-7.52 (m, 2H), 7.49-7.29 (m, 4H), 7.17 (m, 2H), 3.70 (d, <i>J</i> = 7.2 Hz, 1H), 1.10 (m, 1H), 0.53 (m, 2H), 0.27 (m, 2H). Anal. Calc. for C 25 H 22 N 4 O 2 S • 1.6H 2 O: 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.

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Reference Example 35 (t)

6-[2-(

n

-propoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>284</figref>

The compound of the Reference Example 35 (t) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used OR-<i>n</i>-propyl-hydroxylamine instead of<i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.31 (s, 1H), 11.48 (s, 1H), 8.60 (d, <i>J</i> = 3.8 Hz, 1H), 8.19 (d, <i>J</i> = 8.4 Hz, 1H), 7.95 (d, <i>J</i> = 16.2 Hz, 1H), 7.81 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.66 (d, <i>J</i> = 7.9 Hz, 1H), 7.60-7.52 (m, 2H), 7.49-7.24 (m, 4H), 7.17 (m, 2H), 3.84 (t, <i>J</i> = 6.6 Hz, 2H), 1.62 (septet,<i>J</i> = 6.4 Hz, 2H), 0.92 (t, <i>J</i> = 6.1 Hz, 3H). Anal. Calcd. For C_ {24} H_ {22} N_ {O} {2} S \ cdot (0.5 H2O, 0.25 CH2Cl2): 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.

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Reference Example 35 (u)

6- [2- (allylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>285</figref>

The compound of the Reference Example 35 (u) was prepared in a manner similar to that described in the Reference Example 35 (a) except that allylamine was used in instead of <i>n</i>-propylamine. 1 H NMR (DMSO-<i>d</i>6) δ: 13.31 (s, 1H), 8.60 (m, 2H), 8.19 (d, <i>J</i> = 8.5 Hz, 1H), 7.93 (d, <i>J</i> = 16.3 Hz, 3H), 7.79 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.64 (m, 1H), 7.60-7.48 (m, 3H), 7.37-7.23 (m, 3H), 7.17 (d, <i>J</i> = 8.5 Hz, 1H), 7.07 (m, 1H), 5.87 (m, 1H), 5.25 (dq, <i>J</i> = 17.33, 1.9 Hz, 1H), 5.09 (dq, <i>J</i> = 10.2, 1.9 Hz, 1H), 3.87 (m, 2H). Anal. Calcd. For C 24 H 20 N 4 {OS} 0.8 CH 2 Cl 2: C, 62.00; H, 4.53; N, 11.66; S, 6.67. Found: C, 62.08; H, 4.73; N, 11.99; S, 6.66. Mass spectrometry with transform of Fourier and laser desorption / ionization (abbreviated MALDI FTMS, from English <i>Matrix-Assisted Laser Desorption / Ionization Fourier Transform Mass Spectrum</i>) (MH +) Calculated, 413.1431, found 413.1449.

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Reference Example 35 (v)

6- [2- (cyclopropylmethyl-carbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>286</figref>

The compound of the Reference Example 35 (v) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used cyclopropyl-methylamine instead of<i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.30 (s, 1 H), 8.60 (d, <i>J</i> = 4.0 Hz, 1H), 8.48 (t, <i>J</i> = 5.3 Hz, 1H), 8.17 (d, <i>J</i> = 8.7 Hz, 1H), 7.90 (d, <i>J</i> = 16.4 Hz, 1H), 7.80 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.67-7.45 (m, 4H), 7.33-7.23 (m, 3H), 7.18 (d, <i>J</i> = 8.3 Hz, 1H), 7.06 (m, 1H), 3.13 (t,<i>J</i> = 6.2 Hz, 2H), 1.00 (m, 1H), 0.41 (m, 1H), 0.24 (m, 1H). Anal. Calc. For C_ {25} H_ {22} N_ {4} OS \ cdot0,5 CH 2 Cl 2: 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. MALDI FTMS (MH +) Calculated 427,1587, found 427,1605.

Reference Example 35 (w)

6- [2- (cyanomethylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>287</figref>

The compound of the Reference Example 35 (w) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used aminoacetonitrile instead of <i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.35 (s, 1H), 9.19 (t, <i>J</i> = 5.3 Hz, 1H), 8.60 (d, <i>J</i> = 4.8 Hz, 1H), 8.20 (d, <i>J</i> = 8.7 Hz, 1H), 7.94 (d, <i>J</i> = 16.4 Hz, 3H), 7.79 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.70-7.50 (m, 4H), 7.41-7.23 (m, 3H), 7.18 (d, <i>J</i> = 8.5 Hz, 1H), 7.06 (d, <i>J</i> = 6.6 Hz, 1H), 4.32 (d, <i>J</i> = 5.5 Hz, 2H). MALDI FTMS (MH +) Calculated 412.1227, found 412.1215.

Reference Example 35 (x)

6- [2- (ethylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>288</figref>

The compound of the Reference Example 35 (x) was prepared in a manner similar to that described in the Reference Example 35 (a) except that ethylamine was used in instead of <i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 8.60 (d, <i>J</i> = 4.0 Hz, 1H), 8.40 (t, <i>J</i> = 6.2 Hz, 1H), 8.18 (d, <i>J</i> = 8.5 Hz, 1H), 7.94 (m, 3H), 7.81 (dt,<i>J</i> = 1.7, 7.5 Hz, 1H), 7.68-7.44 (m, 3H), 7.56 (m, 2H), 7.30 (m, 3H), 7.17 (dd, <i>J</i> = 8.1, 1.8 Hz, 1H), 7.06 (m, 1H), 3.24 (m, 2H), 1.11 (t, <i>J</i> = 7.0 Hz, 3H). Anal. Calc. For C 23 H 20 N 4 OS • (1.75H 2 O, 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 (MH +) Calculated 401.1431, found 401.1417.

Reference Example 35 (y)

6- [2- (thiazol-2-ylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>289</figref>

The compound of the Reference Example 35 (y) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used 2-aminothiazole instead of <i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.32 (s, 1H), 12.67 (s, 1H), 8.60 (d, <i>J</i> = 4.1 Hz, 1H), 8.18 (d, <i>J</i> = 8.5 Hz, 1H), 7.93 (d, <i>J</i> = 16.3 Hz, 1H), 7.80 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.65 (d, <i>J</i> = 7.9 Hz, 1H), 7.65 (d, <i>J</i> = 8.3 Hz, 1H), 7.60-7.51 (m, 3H), 7.49-7.34 (m, 2H), 7.26 (m, 2H), 7.18 (m, 2H). Anal. Calcd. For C_ {24} H_ {17} N_ {5} OS_ {2} \ cdot0.75H2 {O}, 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.

Reference Example 35 (z)

6- [2- (2- (ethoxy) ethylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>290</figref>

The compound of the Reference Example 35 (z) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used 2-ethoxyethylamine instead of <i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.30 (s, 1H), 8.60 (d,<i>J</i> = 4.0 Hz, 1H), 8.45 (t, <i>J</i> = 6.2 Hz, 1H), 8.18 (d,<i>J</i> = 8.5 Hz, 1H), 7.93 (m, 2H), 7.80 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.65 (d, <i>J</i> = 7.7 Hz, 1H), 7.60-7.45 (m, 3H), 7.36-7.23 (m, 3H), 7.17 (d, <i>J</i> = 8.3 Hz, 1H), 7.07 (m, 1H), 3.50 (m, 6H), 1.10 (d, <i>J</i> = 7.0 Hz, 3H). Anal. Calc. For C 25 H 24 N 24 O 2 S \ 0.5 CH 2 Cl 2: 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.

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Reference Examples 35 (aa)

6- [2 - ((3-Methoxybenzyl) methylcarbamoyl) -phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>291</figref>

The compound of the Reference Example 35 (aa) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used 3-methoxybenzylamine instead of n-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.30 (s, 1H), 8.97 (t, <i>J</i> = 5.5 Hz, 1H), 8.60 (d,<i>J</i> = 4.2 Hz, 1H), 8.18 (d, <i>J</i> = 8.7 Hz, 1H), 7.93 (d,<i>J</i> = 16.3 Hz, 1H), 7.80 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.65 (d, <i>J</i> = 7.9 Hz, 1H), 7.60-7.51 (m, 3H), 7.38-7.15 (m, 5H), 7.08 (m, 1H), 6.94 (m, 2H), 6.80 (dd, <i>J</i> = 8.1, 1.5 Hz, 1H), 4.44 (d, <i>J</i> = 6.6 Hz, 2H), 3.71 (s. 3H). Anal. Calc. For C 29 H 24 N 4 O 2 S • 0.4 H 2 O: 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.

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Reference Example 35 (bb)

6- [2 - ((fur-2-yl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>292</figref>

The compound of the Reference Example 35 (bb) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used 2-aminomethylfuran instead of <i>n</i>-propylamine. 1 HRMN (DMSO-<i>d</i>6) δ: 13.31 (s, 1H), 8.93 (t,<i>J</i> = 5.7 Hz, 1H), 8.60 (d, <i>J</i> = 4.3 Hz, 1H), 8.19 (d,<i>J</i> = 8.0 Hz, 1H), 7.93 (d, <i>J</i> = 16.5 Hz, 1H), 7.80 (dt,<i>J</i> = 1.9, 7.4 Hz, 1H), 7.66 (d, <i>J</i> = 7.7 Hz, 1H), 7.59-7.48 (m, 4H), 7.30 (m, 4H), 7.37-7.24 (m, 3H), 7.18 (d, <i>J</i> = 9.2 Hz, 1H), 7.06 (d, <i>J</i> = 8.1 Hz, 1H), 6.40 (m, 1H), 6.31 (m, 1H), 4.44 (d, <i>J</i> = 53 Hz, 2H). Anal. Calc. For C 26 H 20 N 4 O 2 S · (0.1H 2 O, 0.75 CH 2 Cl 2): ​​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.

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Reference Example 35 (cc)

6- [2- (2-propynylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>293</figref>

The compound of the Reference Example 35 (cc) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used propargilamine instead of propylamine (76%): 1 HRMN (300 MHz, CDCl 3) δ: 8.56 (m, 1H), 7.96 (d, 1H, <i>J</i> = 8.6 Hz), 7.81 (d, 1H, 16.4 Hz), 7.68 (dt, 1H, <i>J</i> = 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, <i>J</i> = 2.6 Hz). LCMS (100% area) Rt = 3.36 min, (pos) [M + H] / z, calculated 411.1, found 411.1. Analyzed with 0.2 H2O, 0.17 DMF, 1,2-dichloromethane: Calculated, 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).

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Reference Example 35 (dd)

6- [2- (ethoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>294</figref>

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The compound of the Reference Example 35 (dd) was prepared in a manner similar to that described in the Reference Example 35 (a) except that ethoxyamine was used in Propylamine site: 1 HRMN (300 MHz, CDCl 3) δ: 11.60 (s, 1H), 8.71 (d, 1H, <i>J</i> = 7.9 Hz), 8.30 (d, 1H,<i>J</i> = 8.5 Hz), 8.05 (d, 1H, <i>J</i> = 16.4 Hz), 7.91 (dt, 1H,<i>J</i> = 1.7, 7.7 Hz), 7.76 (d, 1H, <i>J</i> = 7.8 Hz), 7.67 (m, 2H), 7.56 (dd, 1H, <i>J</i> = 1.8, 7.3 Hz), 7.52-7.36 (m, 3H), 7.28 (m, 2H) 4.06 (q, 2H,<i>J</i> = 7.0 Hz), 1.31 (t, 2H, <i>J</i> = 7.0 Hz); LCMS (area 100%) Rt = 3.28 min, (pos) [M + H] / z, calculated 417.1, found 417.1. Analyzed with 0.2 H 2 O: Calculated, 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).

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Reference Example 35 (ee)

6- [2- (2-methyl-2-propenylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>295</figref>

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The compound of the Reference Example 35 (ee) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used 2-Methylamine instead of propylamine: 1 HRMN (300 MHz, CDCl 3) δ: 8.56 (m, 1H), 7.98 (d, 1H, <i>J</i>= 8.5 Hz), 7.81 (d, 1H, <i>J</i> = 16.4 Hz), 7.69 (dt, 1H, <i>J</i>= 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, <i>J</i> = 5.5 Hz), 1.71 (s, 3H). LCMS (100% area) Rt = 3.37 min, (pos) [M + H] / z, calculated 427.1, found 427.1. Analyzed with 0.7 H2O, 0.1 dichloromethane: Calculated, 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).

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Reference Example 35 (ff)

6- [2 - ((3-fluorobenzyl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>296</figref>

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The compound of the Reference Example 35 (ff) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used 3-fluorobenzylamine instead of propylamine: 1 HRMN (300 MHz, CDCl 3) δ: 8.60 (m, 1H), 7.97 (d, 1 HOUR, <i>J</i> = 8.5 Hz), 7.86 (d, 1H, <i>J</i> = 16.4 Hz), 7.70 (m, 2H), 7.51 (m, 2H), 7.33 (m, 4H), 7.18 (m, 2H), 7.11 (dd, 1H,<i>J</i> = 1.6, 8.5 Hz), 6.95 (m, 3H), 4.51 (d, 2H, <i>J</i> = 5.7 Hz); LCMS (100% area) Rt = 3.55 min, (pos) [M + H] / z, calculated 481.1, found 481.1. Analyzed with 0.7 H2O, 0.5 dichloromethane: Calculated, 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).

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Reference Example 35 (gg)

6- [2- (2- (methylamino) ethylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>297</figref>

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The compound of the Reference Example 35 (gg) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used<i>N</i>-methylethylenediamine instead of propylamine: 1 HRMN (300 MHz, CDCl 3) δ: 8.60 (m, 1H), 7.98 (d, 1H, <i>J</i> = 8.5 Hz), 7.81 (d, 1H, <i>J</i> = 16.4 Hz), 7.69 (dt, 1H, <i>J</i> = 1.7, 7.7 Hz), 7.52 (m, 1H), 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 (broad s, 3H); LCMS (100% area) Rt = 3.16 min, (pos) [M + H] / z, calculated 430.1, found 430.1. Analyzed with 0.2 H2O, 0.6 dichloromethane, 0.06 hexane: Calculated, 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).

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Reference Example 35 (hh)

6- [2- (2- (tien-2-yl) ethylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>298</figref>

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The compound of the Reference Example 35 (hh) was prepared in a manner similar to that described in the Reference Example 35 (a) except that it was used 2- (2-aminoethyl) thiophene instead of propylamine: 1 HRMN (300 MHz, CDCl 3) δ: 8.56 (m, 1H), 7.98 (d, 1H, <i>J</i> = 8.5 Hz), 7.81 (d, 1H, <i>J</i> = 16.4 Hz), 7.69 (dt, 1H, <i>J</i> = 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), 6.63 (m, 1H), 6.52 (m 1H). 3.45 (q, 2H), 3.00 (t, 2H). Analyzed with 0.5 H 2 O, 0.07 dichloromethane: Calculated, 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).

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Reference Example 35 (ii)

6- [2- (aminocarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>299</figref>

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The compound of the Reference Example 35 (ii) was prepared in a manner similar to that described in the Reference Example 35 (a) except that hydrazine was used in Propylamine site: 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.3 (s, 1H), 9.57 (s, 1H), 8.54 (d, 1H, <i>J</i> = 3.9 z), 8.14 (d, 1H, <i>J</i> = 8.5 Hz), 7.89 (d, 1H, <i>J</i> = 16.4 Hz), 7.73 (dt, 1H, <i>J</i> = 1.7, 7.6 Hz), 7.60 (d, 1H, <i>J</i> = 7.9 Hz), 7.50 (m, 2H), 7.40 (dd, 1H, <i>J</i> = 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, calculated 388.1, found 388.1. Analyzed with 0.1 DMF, 0.55 EtOAc, 0.12 Tol (NMR) and 0.15 H 2 O: Calculated, 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).

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The compounds of the Reference Examples 35 (jj) -35 (nn) can be prepared from similar to that described in Example 35 (a).

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Reference Example 35 (jj)

<figref>300</figref>

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Reference Example 35 (kk)

<figref>301</figref>

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Reference Example 35 (ll)

<figref>302</figref>

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Reference Example 35 (mm)

<figref>303</figref>

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Reference Example 35 (nn)

<figref>304</figref>

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Reference Example 36 (a)

6-[2-(

N

2 - (1-methylimidazol-2-ylmethyliden) hydrazino) carbonyl) -phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>305</figref>

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The compound prepared in the Example of reference 35 (ii) (40 mg, 0.103 mmol) was treated with 1-methyl-2-imidazolecarboxaldehyde (29 mg, 0.258 mmol, 2.5 equivalents) in ethanol obtaining the Compound of Reference Example 36 (a): 1 H NMR (300 MHz, DMSO-<i>d</i>6) δ: 8.60 (m, 2H), 8.31 (s, 1H), 8.18 (d, 1H), 8.02 (d, 1H), 7.98 (d, 1H), 7.80 (m, 2H), 7.63 (m, 2H), 7.40 (m, 3H), 7.30 (m, 1H), 7.20 (m, 1H), 7.02 (m, 2H), 6.93 (s, 1H), 4.00 (s, 3H); LCMS (100% area) Rt = 4.0 min, (pos) [M + H] / z, calculated 480.2, found 480.2. Analyzed with 1.45 H 2 O: Calculated, 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).

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Reference Example 36 (b)

6-[2-(

N

2 - (pyrid-2-ylmethyliden) hydrazino) carbonyl) -phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>306</figref>

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The compound of the Reference Example 36 (b) was prepared in a manner similar to that described in the Reference Example 36 (a) except that it was used 2-pyridylcarboxaldehyde instead of 1-methyl-2-imidazolecarboxaldehyde: 1 HRMN (300 MHz, CDCl 3) δ: 8.57 (m, 2H), 8.45 (m, 2H), 8.22 (d, 1H), 8.10 (s, 1H), 7.93 (d, 1H), 7.83 (d, 1H), 7.8-7.1 (m, 11H); LCMS (100% area) Rt = 4.0 min, (pos) [M + H] / z, calculated 477.1, found 477.1. Analyzed with 0.85 H2O: Calculated, C (65.93), H (4.45), N (17.09), S (6.52). Found: C (66.02), H (4.42), N (16.95), S (6.38).

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Reference Example 36 (c)

6-[2-(

N

2 - (2,2,2-trifluroethylidene) hydrazino) carbonyl) -phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>307</figref>

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The compound of the Reference Example 36 (c) was prepared in a manner similar to that described in the Reference Example 36 (a) except that it was used trifluoroacetaldehyde instead of 1-methyl-2-imidazolecarboxaldehyde: 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 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, calculated 468.1, found 468.0. Analyzed with 0.75 H 2 O: Calculated, 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).

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Reference Example 37 (a)

6- [6-fluoro-2- (ethoxycarbamoyl) phenylsulfanyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>308</figref>

The compound of the Reference Example 37 (a) was prepared in a manner similar to that described in the Reference Example 35 (a) except that the material was used starting point described below and that ethoxyamine was used instead propylamine: 1 H NMR (300 MHz, CDCl 3) δ: 8.59 (m, 1H), 8.08 (d, 1H), 7.88 (d, 1H, <i>J</i> = 16.4 Hz), 7.79 (t, 1H), 7.65 (d, 1H), 7.60 (m, 1H), 7.50 (d, 1H, <i>J</i> = 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, calculated 435.1, found 435.1, (neg) [MH] / z, calculated 433.1, found 433.1. Analyzed with 0.35 H 2 O, 0.07 EtOAc: Calculated, 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).

The starting material was prepared as follow:

<figref>309</figref>

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 equivalent) 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 hydrogen carbonate, dried over sulfate sodium, decanted and concentrated under reduced pressure obtaining ethyl ester of acid 3-fluoro-2-mercapto-benzoic: 1 HRMN (300 MHz, CDCl3) δ: 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, calculated 201.0, found 200.9.

<figref>310</figref>

The anterior thioether was prepared similarly to that described in Reference Example 33 (a), step (iii) except that ethyl acid ester was used 3-fluoro-2-mercapto-benzoic instead of thiosalicylate (320 mg, 39%): FTIR (thin film) 2952, 1727, 1607, 1586, 1564, 1469, 1433, 1366, 1292, 1249, 182, 1141, 1074, 836 cm -1; 1 HRMN (300 MHz, CDCl 3) δ: 8.62 (m, 1H), 7.90 (d, 1H, <i>J</i> = 8.6 Hz), 7.85 (d, 1H,<i>J</i> = 16.4 Hz), 7.67 (dt, 1H, <i>J</i> = 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, <i>J</i> = 7.1 Hz), 3.56 (t, 2H,<i>J</i> = 8.2 Hz), 1.30 (t, 3H, <i>J</i> = 7.1 Hz), 0.88 (t, 2H, <i>J</i> = 8.2 Hz), -0.06 (s, 9H); LCMS (100% area) Rt = 4.44 min, (pos) [M + H] / z, calculated 549.2, found 549.2.

<figref>311</figref>

The above carboxylic acid was prepared from similar to that described in the Reference 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; 1 HRMN (300 MHz, CDCl 3) δ: 8.81 (m, 1H), 7.87 (m, 2H), 7.79 (m, 3H), 7.65 (m, 2H), 7.56 (m, 1H), 4.40 (m, 1H), 7.30 (m, 1H), 7.00 (dd, 1H, <i>J</i> = 1.4, 8.5 Hz), 5.58 (s, 2H), 3.59 (t, 2H, <i>J</i> = 8.2 Hz), 0.93 (t, 2H,<i>J</i> = 8.2 Hz), -0.01 (s, 9H). LCMS (100% area) Rt = 10.47 min, (pos) [M + H] / z, calculated 522.2, found 522.2.

<figref>312</figref>

The above salt was prepared similarly to that described in Example 33 (g): 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.2 (s, 1H), 8.68 (m, 1H), 8.12 (d, 1 HOUR, <i>J</i> = 8.5 Hz), 7.98 (d, 1H, <i>JJ</i> = 16.4 Hz), 7.88 (dt, 1H, <i>J</i> = 1.8, 7.6 Hz), 7.73 (d, 1H, <i>J</i> = 7.9 Hz), 7.61 (d, 1H, <i>J</i> = 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).

<figref>313</figref>

The above pentafluorophenyl ester was prepared similar to that described in the Reference Example 35 (a), stage (i): LCMS (100% area) Rt = 10.53 min, (pos) [M + H] / z, calculated 558.1, found 558.1.

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Reference Example 37 (b)

6- [6-fluoro-2- (cyclopropylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>314</figref>

The compound of the Reference Example 37 (b) was prepared in a manner similar to that described in the Reference Example 37 (a) except that it was used cyclopropylamine instead of ethoxyamine: 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 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, calculated 431.1, found 431.1, (neg) [MH] / z, calculated 429.1, found 429.2. Analyzed with 0.55 H 2 O: Calculated, 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).

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Reference Example 37 (c)

6- [6-fluoro-2- (isopropoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>315</figref>

The compound of the Reference Example 37 (c) was prepared in a manner similar to that described in the Reference Example 37 (a) except that it was used isopropoxyamine instead of ethoxyamine: 1 HRMN (300 MHz, CDCl 3) δ: 9.50 (broad s, 1H), 8.47 (m, 1H), 7.72 (d, 1H), 7.68 (d, 1H, <i>J</i> = 16.4 Hz), 7.54 (dt, 1H), 7.35 (m, 4H), 7.20 (m, 4H), 4.03 (m, 1H), 1.07 (d, 6H); LCMS (100% area) Rt = 4.90 min, (pos) [M + H] / z, calculated 449.1, found 449.1. Analyzed with 0.1 DMF, 0.3 H 2 O: Calculated, 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).

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Reference Example 37 (d)

6- [6-fluoro-2- (methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>316</figref>

The compound of the Reference Example 37 (d) was prepared in a manner similar to that described in the Reference example 37 (a) except that methylamine was used in Ethoxyamine site: 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 8.37 (m, 1H), 8.18 (m, 1H), 7.87 (d, 1H), 7.67 (d, 1H,<i>J</i> = 16.4 Hz), 7.59 (dt, 1H), 7.40 (d, 1H), 7.30 (m, 2H), 7.20 (m, 4H), 6.85 (d, 1H), 2.49 (d, 3H); LCMS (100% area) Rt = 4.63 min, (pos) [M + H] / z, calculated 405.1, found 405.2, (neg) [M + H] / z, calculated 403.1, found 403.1. Analyzed with 0.2 DMF, 0.3 CH 2 Cl 2 (NMR), 0.3 H 2 O: Calculated, 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).

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Reference Example 38 (a)

6- [2- (2-Methylquinol-6-ylcarbamoyl) phenylsulfanyl] -3-E- (2-styryl) -1

H

-indazol

<figref>317</figref>

The compound of the Reference Example 38 (a) was prepared in a manner similar to that described in the Reference Example 33 (b) except that the stages (i) and (ii): 1 HRMN (300 MHz, CDCl 3) δ: 8.58 (s, 1H), 8.13 (s, 1H), 7.80 (m, 3H), 7.67 (t, 1H), 7.43 (m, 2H), 7.34-7.16 (m, 9H), 7.13 (d, 1H), 7.07 (d, 1H), 2.60 (s, 3H). LCMS (100% area) Rt = 3.87 min, (pos) [M + H] / z, calculated 513.1, found 513.2.

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Reference Example 38 (b)

6- [2 - ((4-piperizin-1-yl-3-trifluoromethylphenyl) -carbamoyl) phenylsulfanyl] -3-E- (2-styryl) -1

H

-indazol

<figref>318</figref>

The compound of the Reference Example 38 (b) was prepared in a manner similar to that described in the Reference Example 38 (a) except that it was used 3-trifluoromethyl-4-piperazin-1-yl-phenylamine instead of 6-amino-2-methylquinoline: 1 HRMN (300 MHz, CDCl 3) δ: 8.75 (s, 1H), 7.95 (d, 1H), 7.77 (m, 2H), 7.69 (s, 1H), 7.55 (m, 3H), 7.40-7.25 (m, 9H), 7.20 (d, 1H), 3.00 (m, 4H), 2.83 (m, 4H). LCMS (100% area) Rt = 3.94 min, (pos) [M + H] / z, calculated 6002, found 600.2. Analyzed with 0.1 hex (NMR), 1.4 H2O. Calculated, 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).

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Example 39 (a)

6- [2- (methylcarbamoyl) phenylamino] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>319</figref>

A solution of<i>N</i>-methyl-2- [3 - ((<i>AND</i>) -2-pyridin-2-yl-vinyl) -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-6-ylamino] - benzamide (39 mg, 0.07820 mmol) (synthesis described below), ethylenediamine (21 µL, 0.3128 mmol) and 1M TBAF in THF (0.63 ml, 0.6256 mmol), stirred in an oil bath at 90 ° C for 2 h. The crude reaction mixture was diluted with ethyl acetate (50 mL), extracted with 1M solution of sodium hydrogen carbonate (2 x 20 ml), brine (5 x 20 ml), dried over magnesium sulfate, filtered and concentrated to a solid. The solid is dissolved in THF, concentrated until an oil was obtained then it was triturated with CH 2 Cl 2 / Et 2 O, causing The precipitation of a dust. The powder was collected by filtration, washed with Et2O and dried under high vacuum. Solid mass Collection was 20 mg (70% yield). 1 HRMN (DMSO-<i>d</i>6) δ: 12.91 (broad s, 1H), 9.86 (s, 1H), 8.60 (d, <i>J</i> = 4.0 Hz, 1H), 8.52 (m, 1H), 8.08 (d, <i>J</i> = 8.5 Hz, 1H), 7.90 (d, <i>J</i> = 16.4 Hz, 1H), 7.80 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.65 (d, <i>J</i> = 7.9 Hz, 1H), 7.51 (d,<i>J</i> = 16.1 Hz, 1H), 7.47-7.34 (m, 2H), 7.25 (m, 2H), 7.00 (d, <i>J</i> = 9.6 Hz, 1H), 6.89 (t, <i>J</i> = 7.0 Hz, 1H), 2.79 (d, <i>J</i> = 4.7 Hz, 3H). Anal. Calc. For C 22 H 19 N 5 O • 0.5CH 2 Cl 2: 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 follow:

<figref>320</figref>

A solution of 191 mg (0.4 mmol) of 6-iodo-3-carboxaldehyde-1- [2- (trimethyl-silanyl) -ethoxymethyl] -1<i>H</i>-indazol (from Example 33 (a), step (ii)), methyl anthranilate (120.1 mg, 0.8 mmol), 2- (dicyclohexylphosphino) biphenyl (28 mg, 0.08 mmol), Pd 2 (dba) 3 (18.4 mg, 0.02 mmol), K 3 PO 4 (212.3 mg, 1.0 mmol), dissolved in anhydrous DME (1.0 mL), was flooded under vacuum with argon (3X), then stirred under an argon atmosphere for 3 days in an oil bath at 80 ° C. The crude mixture was filtered through a bed of SiO2, eluted with ethyl acetate and then purified by "chromatotron" radial chromatography eluting with CH 3 CN at 25% / CH 2 Cl 2. The mass of the pure fractions was 42 mg. An additional 120 mg of the product having a purity was also collected of \ sim90%. The total yield of<i>N</i>-methyl-2- [3 - ((<i>AND</i>) -2-pyridin-2-yl-vinyl) -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-6-ylamino] -benzamide it was 162 mg or? 81%.

Example 39 (b)

6- [2- (prop-2-inylcarbamoyl) phenylamino] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>321</figref>

The compound of Examples 39 (b) is prepared in a manner similar to that described in Example 39 (a) except that propargilamine was used instead of methylamine. 1 HRMN (CDCl 3) δ: 9.50 (s, 1H), 8.64 (d, <i>J</i> = 4.5 Hz, 1H), 7.98 (d, <i>J</i> = 8.9 Hz, 1H), 7.90 (d, <i>J</i> = 16.4 Hz, 1H), 7.70 (dt, <i>J</i> = 1.7, 7.5 Hz, 1H), 7.57 (d, <i>J</i> = 16.3 Hz, 1H), 7.52-7.43 (m, 3H), 7.34 (dt, <i>J</i> = 1.5, 7.2 Hz, 1H), 7.26 (m, 3H), 7.34 (ddd, <i>J</i> = 1.0, 4.9, 7.5 Hz, 1H), 7.09 (dd, <i>J</i> = 1.7, 9.0 Hz, 1H), 6.85 (dt, <i>J</i> = 1.0, 7.0 Hz, 1H), 6.33 (wide s, 1H), 4.24 (dd, <i>J</i> = 2.6, 53 Hz, 2H), 2.30 (t, <i>J</i> = 5.5 Hz, 1H). Anal. Calc. For C 24 H 19 N 5 O • 0.25CH 2 Cl 2: C, 70.24; H 4.74; N, 16.89. Found: C, 70.72; H, 4.96; N, 16.55.

Reference Example 40 (a)

6- (3-amino-benzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>322</figref>

The compound of the Reference Example 40 (a) was prepared in a manner similar to that described in the Reference Example 11. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.5 (s, 1H), 8.62 (d, 1H, <i>J</i> = 3.86 Hz), 8.34 (d, 1 HOUR, <i>J</i> = 8.5 Hz), 8.01 (d, 1H, <i>J</i> = 16.36 Hz), 7.87 (s, 1H), 7.83 (td, 1H, <i>J</i> = 7.69 Hz, <i>J</i> = 1.81 Hz), 7.58-7.71 (m, 3H), 7.29 (qd, 1H, <i>J</i> = 739 Hz,<i>J</i> = 0.98 Hz), 7.21 (t, 1H, <i>J</i> = 7.77), 7.00 (t, 1H,<i>J</i> = 1.86 Hz), 6.90 (dt, 1H, <i>J</i> = 6.15 Hz, <i>J</i> = 1.40 Hz), 6.86 (m, 1H), 5.40 (wide s, 2H). MS (ESI +) [M + H] / z, calculated 446, found 446. Calculated: 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 follow:

<figref>323</figref>

Acid<i>m</i>-amino-phenyl-boronic (8.22 g, 60 mmol) in dimethylformamide (60 ml) at 23 ° C under an atmosphere of argon triethylamine (10 ml, 72 mmol) was added and 4- (dimethylamino) pyridine (0.366 g, 3 mmol). The solution The resulting was heated to 50 ° C. Ester was added 2-trimethyl-silanyl-ethyl of 4-nitro-phenyl acid ester carbonic (20.4 g, 72 mmol) in 5 portions of 4 g for 18 hours. After 44 h ester was added 2-trimethyl-silanyl-ethyl of the 4-nitro-phenyl ester of carbonic acid (3.4 g, 12 mmol) followed by triethylamine (1.7 ml, 12 mmol). After 63 h the reaction mixture was concentrated until Get an oil. Purification by column chromatography of silica gel eluting with ethyl acetate-hexane from 3-7 to 7-3 gave ester 2-trimethyl-silanyl-ethyl of acid (acid 3-boronic-phenyl) -carbamic (8.12 g, 48%): R f sm = 0.067, p = 0.33 (acetate ethyl hexane 1: 1); 1 HRMN (300 MHz, CD 3 OD) δ: 7.64 (s, 1H), 7.49 (d, 1H, <i>J</i> = 8.94 Hz), 7.26 (m, 2H), 4.23 (t, 2H, <i>J</i> = 8.28 Hz), 1.06 (t, 2H, <i>J</i> = 8.21 Hz) 0.72 (s, 9H). MS (ESI) [M + Na] / z, calculated 304, found 304.

<figref>324</figref>

A mix of 6-iodine-3 - ((<i>AND</i>) -2-pyridin-2-yl-vinyl) -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol (7.1 g, 14.8 mmol), ester 2-trimethyl-silanyl-ethyl of acid (acid 3-boronic-phenyl) -carbamic (8.32 g, 29.6 mmol), dichlorobis (triphenylphosphine) -palladium (II) (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 carbon monoxide atmosphere. After 24 h it was added plus triethylamine (2.1 ml, 14.8 mmol). After 33 h the Reaction termination was determined 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 phase was extracted with acetate ethyl (2 x 100 ml). The ethyl acetate mixture was washed with brine (100 ml), dried over Na2SO4, filtered and concentrated. Purification by gel column chromatography of silica gave ester 2-trimethyl-silanyl-ethyl of the acid (3- {1- [3- (2-Pyridin-2-yl-ethyl) -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-6-yl] -metanoyl} -phenyl) -carbamic in the form of a yellow crystal (7.22 g, 79%). 1 HRMN (300 MHz, CDCl 3) δ: 8.65 (d, 1H, <i>J</i> = 3.93 Hz), 8.10 (d, 1 HOUR, <i>J</i> = 8.54 Hz), 8.04 (s, 1H), 7.94 (d, 1H, <i>J</i> = 16.33 Hz), 7.82 (s, 1H), 7.66-7.77 (m, 3H), 7.61 (d, 1H,<i>J</i> = 16.35 Hz), 7.40-7.51 (m, 3H), 7.19 (m, 1H), 7.00 (s, 1H), 5.77 (s, 2H), 4.25 (t, 2H, <i>J</i> = 6.93 Hz), 3.60 (t, 2H, <i>J</i> = 8.10 Hz), 1.04 (t, 2H, <i>J</i> = 6.79 Hz), 1.00 (t, 2H, <i>J</i> = 8.13 Hz), 0.04 (s, 9H), 0.0 (s, 9H). MS (ESI +) [M + H] / z, calculated 615, found 615.

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Reference Example 40 (b)

6- (3-amino-4-methyl-benzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>325</figref>

The compound of the Reference Example 40 (b) was prepared in a manner similar to that described in the Reference example 40 (a) except that, in step (i), used acid 4-methyl-3-amino-phenyl-boronic, prepared as described below, instead of acid<i>m</i>-amino-phenyl-boronic. 1 HRMN (DMSO-<i>d</i>6) δ: 13.6 (s, 1H), 8.62 (d, 1 HOUR, <i>J</i> = 3.81 Hz), 8.33 (d, 1H, <i>J</i> = 8.47 Hz), 8.01 (d, 1 HOUR, <i>J</i> = 16.36 Hz), 7.85 (s, 1H), 7.82 (dd, 1H, <i>J</i> = 7.60 Hz, <i>J</i> = 1.80 Hz), 7.70 (d, 1H, <i>J</i> = 7.81 Hz), 7.63 (d, 1H, <i>J</i> = 16.36 Hz), 7.57 (dd, 1H, <i>J</i> = 8.47 Hz,<i>J</i> = 1.2 Hz), 7.29 (m, 1H), 7.12 (d, 1H, <i>J</i> = 7.82 Hz), 7.09 (d, 1H, <i>J</i> = 1.64 Hz), 6.90 (dd, 1H, <i>J</i> = 7.59 Hz,<i>J</i> = 1.65 Hz), 5.16 (wide s, 1H), 2.16 (s, 1H). MS (ESI +) [M + H] / z, calculated 355. Anal. Calculated: 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 follow:

<figref>326</figref>

A mixture of acid 4-methyl-3-nitro-phenyl-boronic (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 is filtered through celite and concentrated to obtain acid 3-amino-4-methylphenyl boronic (2.53 g, 91%). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 7.21 (s, 1H), 7.08 (d, 1H, <i>J</i> = 7.5 Hz), 6.92 (d, 1H, <i>J</i>= 7.46 Hz), 4.81 (wide s, 2H), 2.09 (s, 3H). MS (ESI) [M + H] / z, calculated 152, found 152.

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Reference Example 40 (c)

6- (5-amino-2,4-dimethyl-benzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>327</figref>

The compound of the Reference Example 40 (c) was prepared in a manner similar to that described in the Reference example 40 (a) except that, in step (i), used acid 2,4-dimethyl-3-aminophenyl boronic (prepared as described below) instead of acid<i>m</i>-amino-phenyl-boronic: 1 HRMN (DMSO-<i>d</i>6) δ: 8.62 (d, 1H, <i>J</i> = 3.78 Hz), 8.32 (d, 1H, <i>J</i> = 8.48 Hz), 7.99 (d, 1H, <i>J</i> = 16.35 Hz), 7.83 (td, 1H, <i>J</i> = 7.68 Hz, <i>J</i> = 1.8 Hz), 7.80 (s, 1H), 7.69 (d, 1H, <i>J</i> = 7.80 Hz), 7.64 (dd, 1H,<i>J</i> = 8.47 Hz, <i>J</i> = 1.27 Hz), 7.62 (d, 1H, <i>J</i> = 16.36 Hz), 7.29 (m, 1H), 6.94 (s, 1H), 6.64 (s, 1H), 4.87 (wide s, 2H), 2.12 (s, 3H), 2.10 (s, 3H). LCMS (ESI +) [M + H] / z, calculated 369, found 369. Anal. Caculate: 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 follow:

<figref>328</figref>

Acid 2,4-dimethylphenyl boronic was prepared similar to that described in the Reference Example 24 (a), step (vii), except that it was used 2,4-dimethylbromo-benzene as Starting material. 1 HRMN (CD 3 OD) δ: 7.13 (d, 1H,<i>J</i> = 7.43 Hz), 7.00 (s, 1H), 6.97 (d, 1H, <i>J</i> = 7.49 Hz), 2.28 (s, 3H), 2.28 (s, 3H). LCMS (ESI +) [M + H] / z, calculated 151, found 151.

<figref>1329</figref>

<figref>329</figref>

A smoking nitric acid (1 ml) cooled to -40 ° C TFA (1 ml) was added. The resulting mixture was allowed to warm slightly to -35 ° C and added in an acidic portion 2,4-dimethylphenyl boronic (150 mg, 1 mmol). After 1 h, ice was added and the mixture was filtered heterogeneous The resulting solid was suspended in Et2O and extracted with 3N NaOH (aq) (1 ml) and then water (2 ml). The aqueous phase was acidified with 3N HCl (aq) (1 ml) and returned to extract with EtOAc (3 x 5 ml). The mixture of organic materials is washed with brine, dried with Na2SO4, decanted and concentrated obtaining acid 2,4-dimethyl-5-nitro-phenyl-boronic (93 mg, 47%). LCMS (ESI +) [M + H] / z, calculated 196, found 196

<figref>330</figref>

Acid 3-amino-4,6-dimethylphenyl boronic It was prepared in a manner similar to that described in the Example 40 (b), step (i). 1 H NMR (CD 3 OD) δ: 6.83 (s, 2H), 6.64 (s, 1H), 2.17 (s, 3H), 2.13 (s, 3H).

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Reference Example 41 (a)

6- [3 - ((1-ethyl-3-methyl-1

H

-pyrazol-5-yl) carboxamido) -benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>331</figref>

To an acid solution 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic (323 mg, 2.1 mmol, 2.1 equivalents) in DMF (5 ml) at 23 ° C under argon diisopropylethylamine (365 µL, 2.1 mmol, 2.1 was added equivalent), HATU (798 mg, 2.1 mmol, 2.1 equivalent) and DMAP (cat.). To the resulting solution was added 6- (3-amino-benzoyl) -3-E- (2-pyridin-2-yl) ethenyl) -1<i>H</i>-indazol (Reference example 40 (a), 340 mg, 1 mmol, 1 equivalent). The reaction was followed by HPLC until it had consumed all the starting aniline \ sim2 h (this gave a mixture of mono- and bis-acylated compounds). The reaction is stopped abruptly adding to the saturated NaHCO 3 mixture, to It was then diluted with water and extracted with ethyl acetate. The EtOAc mixture was washed with water, with brine, dried with Na2SO4, was filtered and concentrated to an oil. The oil was dissolved in methanol (10 ml), K2CO3 was added (290 mg, 2.1 mmol, 2.1 equivalents) and the resulting mixture was stirred at 23 ° C until the compound was consumed bis-acylated (? 30 min.). Reaction mixture concentrated to obtain an oil that was then distributed between water and EtOAc. The organic phase was washed with brine, dried with Na 2 SO 4, it was filtered and concentrated.

Purification by column chromatography of silica gel (ethyl acetate-dichloromethane 1: 1-8: 2) gave the compound of Example 41 (a). 1 H NMR (300 MHz, DMSO-<i>d</i>6) δ: 13.6 (s, 1H), 10.3 (s, 1H), 8.62 (d, 1H, <i>J</i> = 3.88 Hz), 8.38 (d, 1H,<i>J</i> = 8.51 Hz), 8.20 (s, 1H), 8.12 (td, 1H, <i>J</i> = 7.58 Hz, <i>J</i> = 1.78 Hz), 8.02 (d, 1H, <i>J</i> = 16.36 Hz), 7.93 (s, 1H), 7.83 (td, 1H, <i>J</i> = 7.61 Hz, <i>J</i> = 1.7 Hz), 7.70 (d, 1 HOUR, <i>J</i> = 7.78 Hz), 7.65 (d, 1H, <i>J</i> = 16.23 Hz), 7.65-7.53 (m, 3H), 7.30 (m, 1H), 4.43 (q, 2H,<i>J</i> = 7.07 Hz), 2.21 (s, 3H), 1.31 (t, 3H, <i>J</i> = 7.07 Hz). MS (ESI +) [M + H] / z, calculated 477, found 477. Anal. Calculated: C, 70.57; H, 5.08; N, 7.64. Found: C, 70.46; H, 5.11; N, 17.61.

Reference Example 41 (b)

6- [3- (pyridin-4-ylcarboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>332</figref>

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The compound of the Reference Example 41 (b) was prepared in a manner similar to that described in the Reference Example 41 (a), except that acid was used isonicotinic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (300 MHz, CD 3 OD) δ: 8.74 (d, 2H, <i>J</i> = 6.04 Hz), 8.56 (d, 1H, <i>J</i> = 4.14 Hz), 8.27 (m, 2H), 8.05 (dt, 1 HOUR, <i>J</i> = 7.97 Hz, <i>J</i> = 1.64 Hz), 8.02 (s, 1H), 7.95 (d, 1 HOUR, <i>J</i> = 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, calculated 446, found 446. Anal. Calculated: C, 72.80; H, 4.30; N, 15.72. Found: C, 71.59; H, 4.43; N, 15.33.

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Reference Example 41 (c)

6- (3-Crotonylamidobenzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>333</figref>

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The compound of the Reference Example 41 (c) was prepared in a manner similar to that described in the Reference Example 41 (a), except that acid was used crotonic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.6 (s, 1H), 10.2 (s, 1H), 8.63 (d, 1H, <i>J</i> = 3.81 Hz), 8.37 (d, 1H,<i>J</i> = 8.49 Hz), 8.12 (s, 1H), 8.02 (d, 1H, <i>J</i> = 16.34 Hz), 7.99 (d, 1H, <i>J</i> = 7.88 Hz), 7.83 (td, 1H, <i>J</i> = 7.67 Hz, <i>J</i> = 1.78 Hz), 7.70 (d, 1H, <i>J</i> = 7.85 Hz), 7.65 (d, 1H, <i>J</i> = 16.40 Hz), 7.63 (dd, 1H, <i>J</i> = 8.43 Hz,<i>J</i> = 1.23 Hz), 7.47-7.56 (m, 2H), 7.29 (qd, 1 HOUR, <i>J</i> = 7.39 Hz, <i>J</i> = 0.99 Hz), 6.82 (m, 1H, <i>J</i>= 6.9 Hz), 6.11 (dd, <i>J</i> = 15.21 Hz, <i>J</i> = 1.68 Hz), 1.87 (d, 3H, <i>J</i> = 6.89 Hz). MS (ESI +) [M + H] / z, calculated 409, found 409. Anal. Calculated: C, 73.51; H, 4.94; N, 13.72. Found: C, 72.15; H, 4.97; N, 13.39.

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Reference Example 41 (d)

6- [3- (indole-4-ylcarboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>334</figref>

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The compound of the Reference Example 41 (d) was prepared in a manner similar to that described in the Reference Example 41 (a), except that acid was used 1<i>H</i>-indole-4-carboxylic acid in acid place 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. LCMS (ESI +) [M + H] / z, calculated 484, found 484.

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Reference Example 41 (e)

6- [3 - ((5-acetylthien-2-yl) carboxamido) benzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>335</figref>

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The compound of the Reference Example 41 (e) was prepared in a manner similar to that described in the Reference Example 41 (a), except that acid was used 5-acetylthiophene-2-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.6 (s, 1H), 10.6 (s, 1H), 8.63 (d, 1H, <i>J</i> = 3.83 Hz), 8.39 (d, 1H,<i>J</i> = 8.51 Hz), 8.20 (s, 1H), 8.14 (dt, 1H, <i>J</i> = 7.25 Hz,<i>J</i> = 2.05 Hz). 8.07 (d, 1 H, <i>J</i> = 4.09 Hz), 8.02 (d, 1H,<i>J</i> = 16.42 Hz), 8.00 (d, 1H, <i>J</i> = 4.01 Hz), 7.94 (s, 1H), 7.83 (td, 1H, <i>J</i> = 7.69 Hz, <i>J</i> = 1.78 Hz), 7.59-7.65 (m, 5H). 7.30 (qd, 1H,<i>J</i> = 7.40 Hz,<i>J</i> = 0.96 Hz), 2.58 (s, 3H). MS (ESI +) [M + H] / z, calculated 493, found 493. Anal. Calculated: 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.

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Reference Example 41 (f)

6- [3- (3,5-Difluorophenylacetamide) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>336</figref>

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The compound of the Reference Example 41 (f) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used (3,5-Difluoro-phenyl) -acetic acid instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.6 (wide s, 1H), 10.5 (s, 1H). 8.62 (d, 1 H,<i>J</i> = 4.02 Hz), 8.36 (d, 1H,<i>J</i> = 8.51 Hz), 8.05 (s, 1H), 8.01 (d, 1H, <i>J</i> = 16.38 Hz), 7.93 (d, 1H, <i>J</i> = 7.88 Hz), 7.90 (s, 1H), 7.83 (td, 1H,<i>J</i> = 7.61 Hz, <i>J</i> = 1.77 Hz), 7.70 (d, 1H, <i>J</i> = 7.85 Hz), 7.64 (d, 1H, <i>J</i> = 16.33 Hz), 7.61 (dd, 1H, <i>J</i>= 8.45 Hz, <i>J</i> = 1.15 Hz), 7.48-7.57 (m, 2H), 7.15-7.31 (m, 5H), 3.77 (s, 2H). MS (ESI +) [M + H] / z, calculated 495, found 495.

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Reference Example 41 (g)

6- [3 - ((5-methyl-1

H

-pyrazol-3-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>337</figref>

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The compound of Reference Example 41 (g) is prepared similarly to that described in the Reference Example 41 (a) except that acid was used 5-methyl-2<i>H</i>-pyrazol-3-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.6 (wide s, 1H), 13.0 (wide s, 1H), 10.3 (wide s, 1H), 8.63 (d, 1H, <i>J</i>= 3.95 Hz), 8.37 (d, 1H, <i>J</i> = 8.66 Hz), 8.36 (s, 1H), 8.16 (d, 1 HOUR, <i>J</i> = 7.55 Hz), 8.02 (d, 1H, <i>J</i> = 16.37 Hz), 7.93 (s, 1H), 7.83 (dt, 1H, <i>J</i> = 7.61 Hz, <i>J</i> = 1.73 Hz), 7.70 (d, 1H, <i>J</i> = 7.82 Hz), 7.65 (d, 1H, <i>J</i> = 16.36 Hz), 7.65 (dd, 1H, <i>J</i> = 8.55 Hz, <i>J</i> = 1.12 Hz), 7.52 (m, 2H), 7.29 (m, 1H), 6.50 (s, 1H), 2.29 (s, 3H). MS (ESI +) [M + H] / z, calculated 449, found 449. Anal. Calculated: C, 69.63; H, 4.49; N, 18.74. Found: C, 68.53; H, 4.95; N, 17.47.

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Reference Example 41 (h)

6-[3-((2-

RS-trans

-methylcyclopropyl) carboxamido) -benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>338</figref>

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The compound of Reference Example 41 (h) is prepared similarly to that described in the Reference Example 41 (a) except that acid was used 2-methylcyclopropanecarboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. R f sm = 0.32, R f p = 0.42 (acetate ethyl dichloromethane 8: 2). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.6 (s, 1H), 10.4 (s, 1H), 8.62 (dd, 1H, <i>J</i> = 4.75 Hz, <i>J</i> = 0.96 Hz), 8.36 (d, 1H,<i>J</i> = 8.47 Hz), 8.06 (t, 1H, <i>J</i> = 1.67 Hz), 8.01 (d, 1H,<i>J</i> = 16.37 Hz), 7.90 (m, 2H), 7.83 (td, 1H, <i>J</i> = 7.68 Hz, <i>J</i> = 1.79 Hz), 7.70 (d, 1H, <i>J</i> = 7.84 Hz), 7.64 (d, 1 HOUR, <i>J</i> = 16.35 Hz), 7.61 (dd, 1H, <i>J</i> = 8.47 Hz,<i>J</i> = 1.32 Hz), 7.51 (t, 1H, <i>J</i> = 7.69 Hz), 7.45 (dt, 1H,<i>J</i> = 7.68 Hz, <i>J</i> = 1.50 Hz), 7.29 (dq, 1H, <i>J</i> = 7.41 Hz, <i>J</i> = 1.04 Hz), 1.51 (m, 1H), 1.23 (m, 1H), 1.09 (d, 3H, <i>J</i> = 5.93). 1.01 (m, 1H), 0.65 (m, 1H). MS (ESI +) [M + H] / z, calculated 423, found 423. Anal. Calculated: C, 73.92; H, 5.25; N, 13.26. Found: C, 71.41; H, 5.56; N. 13.27.

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Reference Example 41 (i)

6- [3 - ((1,5-dimethyl-1

H

-pyrazol-3-yl) carboxamido) -benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>339</figref>

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The compound of Reference Example 41 (i) is prepared similarly to that described in the Reference Example 41 (a) except that acid was used 1,5-dimethyl-1<i>H</i>-pyrazol-3-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.6 (s, 1H), 10.2 (s, 1H), 8.63 (d, 1H, <i>J</i> = 3.87 Hz), 8.37 (d, 1H,<i>J</i> = 8.49 Hz), 8.34 (d, 1H, <i>J</i> = 1.63 Hz), 8.16 (td, 1H,<i>J</i> = 7.43 Hz, <i>J</i> = 1.96 Hz), 8.02 (d, 1H, <i>J</i> = 16.35 Hz), 7.92 (s, 1H), 7.83 (dt, 1H, <i>J</i> = 7.68 Hz, <i>J</i>= 1.79 Hz), 7.70 (d, 1H, <i>J</i> = 7.84 Hz), 7.65 (d, 1H, <i>J</i>= 16.35 Hz), 7.65 (dd, 1H, <i>J</i> = 8.52 Hz, <i>J</i> = 1.2 Hz), 7.52 (m, 2H), 7.29 (m, 1H), 6.55 (s, 1H), 3.83 (s, 3H), 2.30 (s, 3H). MS (ESI +) [M + H] / z, calculated 463, found 463. Anal. Calculated: C, 70.12; H, 4.79; N, 18.17. Found: C, 69.59; H 4.88; N, 17.86.

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Reference Example 41 (j)

6- [3 - ((3-methylpyridin-4-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>340</figref>

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The compound of the Reference Example 41 (j) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used 3-methylisonicotinic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.6 (s, 1H), 10.7 (s, 1H), 8.62 (dd, 1H, <i>J</i> = 4.72 Hz, <i>J</i> = 0.86 Hz), 8.57 (s, 1H), 8.55 (d, 1H, <i>J</i> = 4.91 Hz), 8.37 (d, 1H,<i>J</i> = 8.46 Hz), 8.20 (s, 1H), 8.07 (dt, 1H, <i>J</i> = 7.27 Hz, <i>J</i> = 1.99 Hz), 8.02 (d, 1H, <i>J</i> = 16.37 Hz), 7.93 (s, 1H), 7.83 (td, 1H, <i>J</i> = 7.69 Hz, <i>J</i> = 1.79 Hz), 7.70 (d, 1H, <i>J</i> = 7.84 Hz), 7.64 (d, 1H, <i>J</i> = 16.27 Hz), 7.55-7.65 (m, 3H), 7.48 (d, 1H, <i>J</i> = 4.89 Hz), 7.30 (qd, 1H, <i>J</i> = 7.39 Hz, <i>J</i> = 1.02 Hz), 2.38 (s, 3H). MS (ESI +) [M + H] / z, calculated 460, found 460.

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Reference Example 41 (k)

6- [3- (cyclopropylcarboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>341</figref>

The compound of the Reference Example 41 (k) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used cyclopropanecarboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (CDCl3 / MeOD) δ: 8.52 (d, 1H, <i>J</i> = 3.9 Hz), 8.09 (d, 1H, <i>J</i> = 8.5 Hz), 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, <i>J</i> = 7.8 Hz), 7.16 (1H, qd, <i>J</i> = 6.3, 1.5 Hz), 1.62-1.57 (m, 1H), 1.25-1.84 (m, 2H), 0.87-0.81 (m, 2H). HRMS (MALDI) C 25 H 20 N 4 O 2 [M + H +] / z, calculated 409.1659, found 409.1660.

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Reference Example 41 (l)

6-[3-((2-

RS-trans

-phenylcyclopropyl) carboxamido) -benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>342</figref>

The compound of the Reference Example 41 (l) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used (1<i>S</i>,2<i>S</i>) -2-phenyl-cyclopropanecarboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (CDCl3 / MeOD) δ: 8.60 (d, 1H, <i>J</i> = 4.2 Hz), 8.17 (d, 1H, <i>J</i> = 8.4 Hz), 8.02 (s, 1H), 7.91 (t, 3H,<i>J</i> = 8.1 Hz), 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, <i>J</i> = 4.8 Hz), 1.37-1.32 (m, 1H). HRMS C_ {31} H_ {24} N_ {O} {2}. Calculated [M + H +] / z 485.1993, found 485.1995.

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Reference Example 41 (m)

6- [3 - ((3-methylisoxazol-5-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>343</figref>

The compound of the Reference Example 41 (m) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used 3-methyl-isoxazol-5-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (DMSO-<i>d</i>6) δ: 10.95 (1H, s), 8.68 (1H, d, <i>J</i> = 4.2 Hz), 8.44 (d, 1H, <i>J</i> = 8.7 Hz), 8.35 (s, 1H), 8.21-8.18 (m, 1H,), 8.08 (d, 1H, <i>J</i> = 16.2 Hz), 7.98 (s, 1H), 7.87 (td, 1H, <i>J</i> = 7.5, 1.8 Hz), 7.76-7.64 (m, 6H), 7.37-7.33 (m, 1H), 6.72 (s, 1H) 3.36 (s, 3H). HRMS (MALDI) C 26 H 19 N 5 O 3 [M + H +] / z: Calculated 450,1561, found 450.1570.

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Reference Example 41 (n)

6-[3-((3-

t

-butyl-1-methyl-1

H

-pyrazol-5-yl) carboxamido) benzoyl] -3-E- [2-pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>344</figref>

The compound of the Reference Example 41 (n) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used 5-<i>tert</i>.butyl-2-methyl-2<i>H</i>-pyrazol-3-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 H NMR (CDCl 3 / MeOD) δ: 8.59 (d, 1H, <i>J</i> = 4.8 Hz), 8.14 (d, 1H, <i>J</i> = 8.4 Hz), 8.08-8.04 (m, 1H,), 7.98-7.92 (m, 3H), 7.75 (td, 1H, <i>J</i> = 7.8, 1.8 Hz), 7.68 (dd, 1H, <i>J</i> = 8.4 Hz), 7.61-7.56 (m, 3H), 7.52 (t, 1H, <i>J</i> = 8.70 Hz), 7.25-7.21 (m, 1H,), 6.75 (s, 1H,), 4.12 (s, 3H), 1.30 (s, 9H). HRMS (MALDI) C 30 H 28 N 6 O 2 [M + H +] / z: Calculated 505.2347, found 505.2353.

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Reference Example 41 (o)

6- [3 - ((5-chlorothien-2-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>345</figref>

The compound of the Reference Example 41 (o) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used 5-chloro-thiophene-2-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (DMSO-<i>d</i>6) δ: 10.58 (s, 1H,), 8.68 (d, 1 HOUR, <i>J</i> = 4.2 Hz), 8.43 (d, 1H, <i>J</i> = 8.5 Hz), 8.22 (s, 1H,), 8.15 (dt, 1H, <i>J</i> = 7.5, 2.0 Hz), 8.08 (d, 1H, <i>J</i> = 16.4 Hz), 8.00-7.98 (m, 3H), 7.88 (td, 1H, <i>J</i>= 7.7, 1.9 Hz), 7.78-7.62 (m, 4H,), 7.33 (d, 2H,<i>J</i> = 4.1 Hz). HRMS (MALDI) C 26 H 17 N 4 O 2 ClS [M + H +] / z: Calculated 485.0843, found 485.0853.

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Reference Example 41 (p)

6- [3 - ((1,3-dimethyl-1

H

-pyrazol-5-yl) carboxamido) -benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>346</figref>

The compound of the Reference Example 41 (p) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used 2,5-dimethyl-2<i>H</i>-pyrazol-3-carboxylic instead of acid 2-ethyl-5-methyl-2H-pyrazol-3-carboxylic. HPLC: R t = 3.90 min (100% area). 1 H NMR (CDCl 3) δ: 8.52 (d, 1H, <i>J</i> = 4.8 Hz), 8.10 (d, 1H, <i>J</i> = 8.4 Hz), 7.98 (d, 1H, <i>J</i> = 8.1 Hz), 7.93 (s, 1H,), 7.88-7.80 (m, 3H), 7.71-7.62 (m, 2H), 7.56-7.49 (m, 4H), 7.44 (t, 1H, <i>J</i> = 7.8 Hz), 7.16 (dd, 1H, <i>J</i> = 7.1, 4.8 Hz). HRMS (MALDI) C 27 H 22 N 6 O 2, [M + H +] / z: Calculated 463.1877, found 465.1889.

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Reference Example 41 (q)

6- [3 - ((2-Chloro-6-methylpyridin-4-yl) carboxamido) -benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>347</figref>

The compound of the Reference Example 41 (q) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used 2-Chloro-6-methyl-isonicotinic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. HPLC: R f = 4.11 min. (100% area). 1 HRMN (DMSO-<i>d</i>6) δ: 10.77 (s, 1H), 8.68 (d, 1H, <i>J</i> = 3.9 Hz), 8.44 (d, 1H, <i>J</i> = 8.4 Hz), 8.28 (s, 1H), 8.21 (dt, 1H, <i>J</i> = 6.9, 2.1 Hz), 8.08 (d, 1H, <i>J</i> = 16.2 Hz), 7.98 (s, 1H), 7.92-7.64 (m, 9H), 7.35 (dd, 1H,<i>J</i> = 6.6, 4.8 Hz), 2.61 (s, 3H).

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Reference Example 41 (r)

6-[3-((1-

n

-propyl-3-methyl-1H-pyrazol-5-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>348</figref>

The compound of the Reference Example 41 (r) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used 5-methyl-2-propyl-2<i>H</i>-pyrazol-3-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 H NMR (DMSO-<i>d</i>6) δ: 10.29 (s, 1H), 8.58 (d, 1 HOUR, <i>J</i> = 3.9 Hz), 8.33 (d, 1H, <i>J</i> = 8.4 Hz), 8.13 (s, 1H), 8.10 (dt, 1H, <i>J</i> = 5.4, 2.1 Hz), 7.96 (d, 1H, <i>J</i> = 16.5 Hz), 7.87 (s, 1H), 7.78 (td, 1H, <i>J</i> = 7.5, 1.5 Hz), 7.61-7.49 (m, 6H), 7.24 (dd, 1H, <i>J</i> = 6.9, 1.8 Hz), 4.32 (t, 2H, <i>J</i> = 6.90 Hz), 1.69 (q, 2H, <i>J</i> = 7.2 Hz), 0.77 (t, 3H, 7.5 Hz). HRMS (MALDI) C 28 H 20 ClN 5 O 2, [M + H +] / z: Calculated 491.2190, found 491,2203.

Reference Example 41 (s)

6-[3-(4-

t

-butylbenzamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>349</figref>

The compound of the Reference Example 41 (s) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used 4-<i>tert</i>.butyl-benzoic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. HPLC: R t = 4.67 min. (100% area). 1 HRMN (DMSO) δ: 10.45 (s, 1H), 8.44 (d, 1H, <i>J</i> = 8.4 Hz), 8.32 (s, 1H), 8.22 (d, 1H, <i>J</i> = 7.5 Hz), 8.07 (d, 1H, <i>J</i> = 16.5 Hz), 7.99-7.95 (m, 3H), 7.88 (td, 1H, <i>J</i> = 7.7, 1.5 Hz), 7.69-7.59 (m, 7H), 7.38 (dd, 1H, 13.5, 5.1 Hz), 1.36 (s, 9H).

Reference Example 41 (t)

6- [3 - ((1-allyl-3-methyl-1

H

-pyrazol-5-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>350</figref>

The compound of the Reference Example 41 (t) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used 2-allyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. HPLC: R t = 4.11 min (100% area). 1 H NMR (DMSO) δ: 10.46 (s, 1H), 8.74 (t, 1H, <i>J</i> = 5.1 Hz), 8.48 (d, 1H,<i>J</i> = 8.4 Hz), 8.28 (s, 1H), 8.22 (t, 1H, <i>J</i> = 5.4, 2.1 Hz), 8.15-8.01 (m, 3H), 7.39 (td, 1H, <i>J</i> = 7.8, 1.8 Hz), 7.82-7.63 (m, 6H) 7.39 (td, 1H,<i>J</i> = 7.7, 1.5 Hz), 6.14-6.02 (m, 1H), 5.22-5.03 (m, 4H), 2.38 (s, 3H). HRMS (MALDI) C 29 H 24 N 6 O 2 [M + H +] /<i>z</i>, calculated 489,2034, found 489,2035.

Reference Example 41 (u)

6- [3 - ((2-Chloro-6-methoxypyridin-4-yl) carboxamido) -benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>351</figref>

The compound of the Reference Example 41 (u) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used 2-Chloro-6-methoxy-isonicotinic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. HPLC R t = 4.37 min. (100% area). 1 HRMN (DMSO-<i>d</i>6) δ: 10.74 (s, 1H), 8.68 (d, 1H, <i>J</i> = 3.6 Hz), 8.44 (d, 1H, <i>J</i> = 8.4 Hz), 8.28 (s, 1H), 8.20 (td, 1H, <i>J</i> = 6.6, 2.4 Hz), 8.07 (d, 1H, <i>J</i> = 16.2 Hz), 7.98 (s, 1H), 7.89 (td, 1H, <i>J</i> = 7.7, 1.8 Hz), 7.77-7.62 (m, 6H), 7.38 (s, 1H), 7.35 (dd, 1H,<i>J</i> = 6.9, 1.8 Hz), 3.98 (s, 3H).

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Reference Example 41 (v)

6- [3 - ((3-ethyl-1-methyl-1

H

-pyrazol-5-yl) carboxamido) -benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>352</figref>

The compound of the Reference Example 41 (v) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used 5-ethyl-2-methyl-2<i>H</i>-pyrazol-3-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. R_t = 4.16 min (100% area). 1 HRMN (DMSO-<i>d</i>6) δ: 10.44 (s, 1H), 8.73 (d, 1H, <i>J</i> = 3.0 Hz), 8.78 (d, 1H, 8.7 Hz), 8.30 (s, 1H), 8.23 ​​(d, 1H, <i>J</i> = 6.9 Hz), 8.14-8.03 (m, 2H), 7.93 (t, 1H, 6.9 Hz), 7.82-7.63 (m, 6H), 7.40 (t, 1H, <i>J</i> = 6.3 Hz), 7.01 (s, 1H), 4.12 (s, 1H), 2.68 (q, 2H, 7.8 Hz), 1.30 (t, 3H,<i>J</i> = 7.5 Hz). HRMS (MALDI) C 28 H 24 N 6 O 2 [M + H +] / z, calculated 477.2034, found 477.2054.

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Reference Example 41 (w)

6- [3 - ((2-Chloropyridin-4-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>353</figref>

The compound of the Reference Example 41 (w) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used 2-chloro-isonicotinic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. HPLC R t = 3.99 min (100% area). 1 HRMN (DMSO-<i>d</i>6) δ: 10.88 (s, 1H), 7.33 (d, 2H, <i>J</i> = 4.8 Hz ), 8.49 (d, 1H,<i>J</i> = 8.4 Hz), 8.33 (s, 1H), 8.26 (td, 1 HOUR, <i>J</i> = 6.9, 3.0 Hz), 8.12-7.91 (m, 5H), 7.82-7.63 (m, 5H), 7.40 (t, 1H, <i>J</i> = 4.8 Hz)

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Reference Example 41 (x)

6- [3 - ((1-isopropyl-3-methyl-1

H

-pyrazol-5-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>354</figref>

The compound of the Reference Example 41 (x) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used 2-isopropyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. HPLC: R t = 4.19 min (100% area). 1 H NMR (DMSO) δ: 10.46 (s, 1H), 8.72 (t, 1H, <i>J</i> = 4.80 Hz), 8.48 (d, 1H,<i>J</i> = 9.0 Hz), 8.31 (s. 1H), 8.21 (td, 1H, <i>J</i> = 9.6, 2.1 Hz), 8.15-7.98 (m, 2H), 7.96-7.84 (m, 1H), 7.82-7.65 (m, 5H), 7.42-7.38 (m, 1H), 6.88 (s, 1H), 5.64-5.38 (m, 1H), 2.32 (s, 3H), 1.48 (d, 1H, <i>J</i> = 6.6 Hz). HRMS (MALDI) C 29 H 26 N 6 O 2 [M + H +] / z, calculated 491.2190, found 491.2194.

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Reference Example 41 (y)

6- [3- (isopropoxycarbonylamino) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>355</figref>

The compound of the Reference Example 41 (y) was prepared in a manner similar to that described in the Reference Example 41 (a) except that chloroformate of isopropyl instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 H NMR (DMSO-<i>d</i>6) δ: 9.97 (s, 1H), 8.72 (t, 2H, <i>J</i> = 4.8 Hz), 8.47 (d, 1H, <i>J</i> = 8.7 Hz), 8.34-7.96 (m, 3H), 8.01-7.87 (m, 2H), 7.82-7.69 (m, 2H), 7.52 (dt, 1H, <i>J</i> = 7.5, 1.2 Hz), 7.42-7.36 (m, 2H), 3.68 (d, 2H,<i>J</i> = 6.6 Hz), 2.02 (m, 1H), 1.02 (d, 6H, <i>J</i> = 6.6 Hz). HRMS (MALDI) C 26 H 24 N 4 O 3 [M + H +] / z, calculated 441.1921, found 441.1937

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Reference Example 41 (z)

6- [3 - ((4-chloropyridin-2-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>356</figref>

The compound of the Reference Example 41 (z) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used 4-chloro-pyridine-2-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. HPLC R t = 4.40 min (100% area). 1 HRMN (DMSO-<i>d</i>6) δ: 10.99 (s, 1H), 8.72 (d, 1H, <i>J</i> = 5.4 Hz), 8.63 (d, 1H, <i>J</i> = 3.9 Hz), 8.44 (s, 1H), 8.38 (d, 1 HOUR, <i>J</i> = 8.4 Hz), 8.25 (dt, 1H, <i>J</i> = 6.6, 2.4 Hz), 8.16 (d, 1H, <i>J</i> = 1.8 Hz), 8.02 (d, 1H, <i>J</i> = 16.2 Hz), 7.94 (s, 1H), 7.86-7.80 (m, 2H), 7.72-7.58 (m, 5H), 7.29 (dd, 1H, <i>J</i> = 6.9, 6.0Hz)

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Reference Example 41 (aa)

6- [3- (pyridin-2-ylcarboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>357</figref>

The compound of the Reference Example 41 (aa) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used pyridine-2-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (300 MHz, DMF-<i>d</i>6) δ: 10.9 (s, 1H), 8.74 (m, 1H), 8.63 (dd, 1H, <i>J</i> = 4.78 Hz, 0.94 Hz), 8.46 (s, 1H), 8.38 (d, 1H, <i>J</i> = 8.48 Hz), 8.25 (dt, 1H, <i>J</i> = 7.17 Hz, <i>J</i> = 2.05 Hz), 8.16 (dt, 1H, <i>J</i> = 7.73 Hz, <i>J</i>= 1.04 Hz), 8.07 (td, 1H, <i>J</i> = 7.56 Hz, <i>J</i> = 1.67 Hz), 8.02 (d, 1H, <i>J</i> = 16.28 Hz), 7.95 (s, 1H), 7.83 (td, 1H,<i>J</i> = 7.65 Hz, <i>J</i> = 1.81 Hz), 7.22-7.66 (m, 4H), 7.30 (qd, 1H, <i>J</i> = 7.40 Hz, <i>J</i> = 1.02 Hz). MS (ESI +) [M + H] / z, calculated 446, found 446.

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Reference Example 41 (bb)

6- [3- (3-Methoxybenzamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>358</figref>

The compound of the Reference Example 41 (bb) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used 3-methoxy-benzoic instead of acid 2-ethyl-5-methyl-<i>2H</i>-pyrazol-3-carboxylic. 1 HRMN (DMSO-<i>d</i>6) δ: 10.50 (s, 1H,), 8.67 (d, 1 HOUR, <i>J</i> = 3.9 Hz), 8.46 (d, 1H, <i>J</i> = 8.7 Hz), 8.33 (s, 1H), 8.22 (dt, 1H, <i>J</i> = 7.8, 1.8 Hz), 8.08 (d, 1H, <i>J</i> = 15.0 Hz), 8.00 (s, 1H,), 7.78-7.54 (m, 8H), 7.51 (t, 1H, 7.8 Hz), 7.38-7.33 (m, 1H), 7.23 (dd, 1H,<i>J</i> = 7.5, 1.5 Hz), 3.90 (s, 3H). HRMS (MALDI) C 29 H 22 N 4 O 3, [M + H +] / z, calculated 475.1765, found 475.1763.

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Reference Example 41 (cc)

6- [3- (phenoxyamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>359</figref>

The compound of the Reference Example 41 (cc) was prepared in a manner similar to that described in the Reference Example 41 (a) except that chloroformate was used phenyl instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. Mp 212-217 ° C. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.63 (s, 1H), 10.51 (s, 1H), 8.62 (d, 1H, <i>J</i> = 4.3 Hz), 8.36 (d, 1H, <i>J</i> = 8.6 Hz), 8.04-7.81 (m, 5H), 7.71-7.40 (m, 7H), 7.31-7.22 (m, 4H). ESI-MS<i>m</i>/<i>z</i> 461 [M + H +]. Anal. Calculated for C 28 H 20 N 4 O 3 x 0.3 H 2 O (465.9 g mol -1): C, 72.18; H, 4.46; N, 11.33. Found: C, 72.41; H, 4.63; N, 11.57.

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Reference Example 41 (dd)

6- [3- (3,3-Dimethylacrylamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>360</figref>

The compound of the Reference Example 41 (dd) was prepared in a manner similar to that described in the Reference Example 41 (a) except that acid was used 3,3-dimethylacrylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 13.6 (s, 1H), 10.2 (s, 1H), 8.63 (d, 1H, <i>J</i> = 3.81 Hz), 8.37 (d, 1H,<i>J</i> = 8.49 Hz), 8.12 (s, 1H), 8.02 (d, 1H, <i>J</i> = 16.34 Hz), 7.99 (d, 1H, <i>J</i> = 7.88 Hz), 7.83 (td, 1H, <i>J</i> = 7.67 Hz, <i>J</i> = 1.78 Hz), 7.70 (d, 1H, <i>J</i> = 7.85 Hz), 7.63 (dd, 1H, <i>J</i> = 8.43 Hz, <i>J</i> = 1.23 Hz), 7.47-7.56 (m, 2H), 7.29 (qd, 1H, <i>J</i> = 7.39 Hz,<i>J</i> = 0.99 Hz), 6.82 (m, 1H, <i>J</i> = 6.9 Hz), 5.85 (s, 1H), 2.12 (s, 3H), 1.85 (s, 3H). MS (ESI +) [M + H] / z, calculated 409, found 409. Anal. Calculated for C 26 H 22 N 4 O 2 x 0.33 <i>tert</i>.butyl methyl ether (TBME): C, 73.54; H, 5.80; N, 12.41. Found: C, 73.26; H, 5.76; N, 12.36.

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Reference Example 41 (ee)

6- [3 - ((1-ethyl-3-methyl-1

H

-pyrazol-5-yl) carboxamido) -4-methylbenzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>361</figref>

The compound of the Reference Example 41 (ee) was prepared in a manner similar to that described in the Reference Example 41 (a) except that the compound was used of Reference Example 40 (b) instead of the compound of Reference example 40 (a). 1 HRMN (DMSO-<i>d</i>6) δ: 13.6 (s, 1H), 9.94 (s, 1H), 8.62 (d, 1H, <i>J</i> = 3.8 Hz), 8.36 (d, 1H, <i>J</i> = 8.51 Hz), 8.01 (d, 1H, <i>J</i> = 16.36 Hz), 7.91 (s, 1H), 7.84 (dd, 1H, <i>J</i> = 7.66 Hz, <i>J</i> = 1.74 Hz), 7.81 (s, 1H), 7.70 (d, 1H, <i>J</i> = 7.9 Hz), 7.64 (d, 1 HOUR, <i>J</i> = 16.45 Hz), 7.62 (m, 2H), 7.50 (d, 1H, <i>J</i> = 7.83 Hz), 7.29 (m, 1H), 6.82 (s, 1H), 4.42 (q, 2H, <i>J</i> = 7.06 Hz), 2.36 (s, 3H), 2.21 (s, 3H), 1.30 (t, 3H, <i>J</i> = 7.09 Hz). MS (ESI +) [M + H] / z, calculated 491, found 491. Anal. Calculated: C, 71.00; H, 5.34; N, 17.13. Found: C, 70.80; H, 5.38; N, 17.00

Reference Example 41 (ff)

6- [3 - ((1-allyl-3-methyl-1H-pyrazol-5-yl) carboxamido) -4-methylbenzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>362</figref>

The compound of the Reference Example 41 (ff) was prepared in a manner similar to that described in the Reference Example 41 (ee) except that acid was used 2-allyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (DMSO-<i>d</i>6) δ: 13.6 (s, 1H), 9.98 (s, 1H), 8.62 (d, 1H, <i>J</i> = 4.60 Hz), 8.36 (d, 1H, <i>J</i> = 8.46 Hz), 8.01 (d, 1H, <i>J</i> = 16.37 Hz), 7.91 (s, 1H), 7.83 (td, 1H,<i>J</i> = 7.69 Hz, <i>J</i> = 1.77 Hz), 7.78 (d, 1H, <i>J</i> = 1.73), 7.70 (d, 1H, <i>J</i> = 7.78 Hz), 7.59-7.70 (m, 3H), 7.50 (d, 1H, <i>J</i> = 8.01 Hz), 7.29 (qd, 1H, <i>J</i> = 7.46 Hz, <i>J</i> = 1.02 Hz), 6.86 (s, 1H), 5.95 (m, 1H), 4.93-5.10 (m, 4H), 2.34 (s, 3H), 2.22 (s, 3H). LCMS (ESI +) [M + H] / z, calculated 503, found 503. Anal. Calculated: C, 71.70; H, 5.21; N, 16.72. Found: C, 70.98; H, 5.42; N, 15.94.

Reference Example 41 (gg)

6- (3-Acetamido-4-methylbenzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>363</figref>

The compound of the Reference Example 41 (gg) was prepared in a manner similar to that described in the Reference Example 41 (ee) except that chloride was used acetyl instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (CD 3 OD) δ: 8.57 (d, 1H, <i>J</i> = 4.90 Hz), 8.13 (d, 1H, <i>J</i> = 8.49 Hz), 7.99 (s, 1H), 7.95 (d, 1H,<i>J</i> = 16.53 Hz), 7.89 (d, 1H, <i>J</i> = 1.46 Hz), 7.86 (td, 1 HOUR, <i>J</i> = 7.64 Hz, <i>J</i> = 1.73 Hz), 7.73 (d, 1H, <i>J</i>= 7.05 Hz), 7.62-7.69 (m, 2H), 7.65 (d, 1H, <i>J</i>= 16.48 Hz), 7.44 (d, 1H, <i>J</i> = 7.97 Hz), 7.32 (qd, 1H,<i>J</i> = 7.44 Hz, <i>J</i> = 1.03 Hz), 2.38 (s, 3H), 2.18 (s, 3H). LCMS (ESI +) [M + H] / z, calculated 397, found 397. Anal. Calculated: C, 72.71; H, 5.08; N, 14.13. Found: C, 72.29; H 5.09; N, 13.98.

Reference Example 41 (hh)

6- [3 - ((1,3-dimethyl-1

H

-pyrazol-5-yl) carboxamido) -4-methylbenzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>364</figref>

The compound of Reference Examples 41 (hh) it was prepared in a manner similar to that described in the Example of reference 41 (ee) except that acid was used 2,5-dimethyl-2<i>H</i>-pyrazol-3-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. HPLC R t = 3.92 min (100% area). 1 HRMN (DMSO) δ: 10.02 (s, 1H), 8.74 (d, 1H, <i>J</i> = 3.6 Hz), 8.49 (d, 1H,<i>J</i> = 8.4 Hz), 8.13 (d, 1H, <i>J</i> = 16.3 Hz), 8.03 (s, 1H), 7.96-7.93 (m, 2H), 7.84-7.72 (m, 4H), 7.63 (d, 1H, 8.1 Hz), 7.42 (dd, 1H, <i>J</i> = 6.8, 1.5 Hz), 6.95 (s, 1H), 4.11 (s, 1H), 2.48 (s, 1H), 2.32 (s, 1H).

Reference Example 41 (ii)

6-[3-((1-

n

-propyl-3-methyl-1

H

-pyrazol-5-yl) carboxamido) -4-methylbenzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>365</figref>

The compound of the Reference Example 41 (ii) was prepared in a manner similar to that described in the Reference Example 41 (ee) except that acid was used 5-methyl-2-propyl-2<i>H</i>-pyrazol-3-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. HPLC: R t = 4.16 min (100% area). 1 HRMN (DMSO-<i>d</i>6) δ: 10.29 (s, 1H), 8.58 (d, 1H, 3.9 Hz), 8.33 (d, 1H, <i>J</i> = 8.4 Hz), 8.13 (s, 1H), 8.10 (dt, 1H, <i>J</i> = 5.4, 2.1 Hz), 7.96 (d, 1H, <i>J</i> = 16.5 Hz), 7.87 (s, 1H), 7.78 (td, 1H, <i>J</i> = 7.5, 1.5 Hz), 7.61-7.49 (m, 6H), 7.24 (dd, 1H, <i>J</i> = 6.9, 1.8 Hz), 4.32 (t, 2H, <i>J</i> = 6.90 Hz), 2.58 (s, 3H), 2.22 (s, 3H) 1.69 (q, 2H, <i>J</i> = 7.2 Hz), 0.77 (t, 3H, 7.5 Hz). HRMS (MALDI) C 30 H 26 N 6 O 2 [M + H +] / z, calculated 505.2347, found 505.2343.

Reference Example 41 (jj)

6- [3 - ((3-ethyl-1-methyl-1

H

-pyrazol-5-yl) carboxamido) -4-methylbenzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>366</figref>

The compound of the Reference Example 41 (jj) was prepared in a manner similar to that described in the Reference Example 41 (ee) except that acid was used 5-ethyl-2-methyl-2<i>H</i>-pyrazol-3-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (DMSO-<i>d</i>6) δ: 10.78 (s, 1H), 9.43 (d, 1 HOUR, <i>J</i> = 3.0 Hz), 9.15 (t, 1H, <i>J</i> = 9.6 Hz), 8.82 (dd, 1 HOUR, <i>J</i> = 16.4, 1.5 Hz), 8.72-8.61 (m, 2H), 8.52-8.30 (m, 4H), 8.10 (dd, 1H, <i>J</i> = 6.9, 5.7 Hz), 7.93-7.89 (m, 1H), 7.72-7.69 (m, 1H), 4.85 (s, 3H), 3.39 (q, 2H,<i>J</i> = 7.8 Hz), 3.17 (s, 3H), 2.10 (t, 3H, <i>J</i> = 7.5 Hz). HRMS (MALDI) C 29 H 26 N 6 O 2 [M + H +]<i>m</i>/<i>z:</i> calculated 491,2190, found 491,2211.

Reference Example 41 (kk)

6- [3 - ((1-isopropyl-3-methyl-1

H

-pyrazol-5-yl) carboxamido) -4-methylbenzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>367</figref>

The compound of the Reference Example 41 (kk) was prepared in a manner similar to that described in the Reference Example 41 (ee) except that acid was used 2-isopropyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. HPLC: R t = 4.11 min. (100% area). 1 HRMN (DMSO-<i>d</i>6) δ: 9.99 (s, 1H), 8.68 (d, 1H, <i>J</i>= 3.6 Hz), 8.42 (d, 1H, <i>J</i> = 8.7 Hz), 8.07 (d, 1H, <i>J</i> = 16.4 Hz), 7.98 (s, 1H), 7.67-7.86 (m, 2H), 7.77-7.65 (m, 4H), 7.56 (d, 1H, <i>J</i> = 7.8 Hz), 7.37-7.33 (m, 1H), 6.82 (s, 1H), 5.44-5.36 (m, 1H), 2.42 (s, 3H), 2.28 (s, 3H), 1.42 (d, 6H, <i>J</i> = 6.6 Hz). Anal. (C_30 H_ {28} N_ {2} {2} \ cdot0.2H_2 O) Calculated: C, 5.63; N, 16.54. Found C, 70.57; H, 5.70; N, 16.35.

Reference Example 41 (ll)

6- [2,4-dimethyl-5 - ((1-ethyl-3-methyl-1

H

-pyrazol-5-yl) carboxamido) -benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>368</figref>

The compound of the Reference Example 41 (ll) was prepared in a manner similar to that described in the Reference Example 41 (a) except that the compound was used of Reference Example 40 (c) instead of the compound of Reference example 40 (a). 1 HRMN (DMSO-<i>d</i>6) δ: 13.6 (s, 1H), 9.82 (s, 1H), 8.63 (d, 1H, <i>J</i> = 3.84 Hz), 8.35 (d, 1H, <i>J</i> = 8.54 Hz), 8.00 (d, 1H, <i>J</i> = 16.37 Hz), 7.83 (s, 1H), 7.83 (td, 1H, <i>J</i> = 7.65 Hz, <i>J</i> = 1.82 Hz), 7.69 (d, 1H, <i>J</i> = 7.89 Hz), 7.65 (dd, 1H, <i>J</i> = 8.52 Hz, <i>J</i> = 1.36 Hz), 7.62 (d, 1H, <i>J</i> = 16.34 Hz), 7.35 (s, 1H), 7.32 (s, 1H), 7.29 (qd, 1H, <i>J</i> = 7.42 Hz,<i>J</i> = 1.09 Hz), 6.78 (s, 1H), 4.39 (q, 2H, <i>J</i> = 7.15 Hz), 2.30 (s, 3H), 2.25 (s, 3H), 2.19 (s, 3H), 1.27 (t, 3H, <i>J</i>= 7.15 Hz). LCMS (ESI +) [M + H] / z, calculated 505, found 505.

Reference Example 41 (mm)

6- [2,4-dimethyl-5 - ((1,3-dimethyl-1

H

-pyrazol-5-yl) carboxamido) -benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>369</figref>

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The compound of the Reference Example 41 (mm) was prepared in a manner similar to that described in the Reference Example 41 (ll) except that acid was used 2,5-dimethyl-2<i>H</i>-pyrazol-3-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (DMSO-<i>d</i>6) δ: 13.6 (s, 1H), 9.81 (s, 1H), 8.62 (d, 1H, <i>J</i> = 3.81 Hz), 8.35 (d, 1H, <i>J</i> = 8.6 Hz), 8.00 (d, 1H, <i>J</i> = 16.36 Hz), 7.83 (dt, 1H, <i>J</i> = 7.65 Hz, <i>J</i> = 1.8 Hz), 7.8 (s, 1H), 7.69 (d, 1H, <i>J</i> = 7.88 Hz), 7.65 (dd, 1H, <i>J</i> = 8.53 Hz, <i>J</i> = 1.36 Hz), 7.62 (d, 1 H, <i>J</i> = 16.35 Hz), 7.36 (s, 1H), 7.32 (s, 1H), 7.29 (qd, 1H, <i>J</i> = 7.41 Hz, <i>J</i> = 1.03 Hz), 6.79 (s, 1H), 3.96 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H), 2.18 (s, 3H). LCMS (ESI +) [M + H] / z, calculated 491, found 491. Anal. Calculated: C, 71.00; H, 5.34; N, 17.13. Found: C, 70.69; H, 5.57; N, 16.26.

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Reference Example 41 (nn)

6- (5-acetamido-2,4-dimethylbenzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>370</figref>

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The compound of the Reference Example 41 (nn) was prepared in a manner similar to that described in the Reference Example 41 (ll) except that Chloride was used acetyl instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (DMSO-<i>d</i>6) δ: 13.6 (broad s, 1H), 9.34 (s, 1H), 8.62 (d, 1H, <i>J</i> = 4.15 Hz), 8.33 (d, 1H, <i>J</i> = 8.6 Hz), 7.86 (d, 1H, <i>J</i> = 16.36 Hz), 7.83 (td, 1H, <i>J</i> = 7.71 Hz, <i>J</i> = 1.82 Hz), 7.81 (s, 1H), 7.69 (d, 1H, <i>J</i> = 7.84 Hz), 7.64 (dd, 1H, <i>J</i> = 1.38 Hz), 7.62 (d, 1H, <i>J</i> = 16.46 Hz), 7.48 (s, H), 7.29 (qd, 1H, <i>J</i> = 7.44 Hz, <i>J</i>= 1.02 Hz), 7.24 (s, 1H), 2.27 (s, 3H), 2.23 (s, 3H), 2.02 (s, 3H). LCMS (ESI +) [M + H] / z, calculated 411, found 411.

Reference Examples 41 (oo) -41 (lll) can be prepared so similar to that described in Example 41 (a).

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Reference Example 41 (oo)

<figref>371</figref>

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Reference Example 41 (pp)

<figref>372</figref>

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Reference Example 41 (qq)

<figref>373</figref>

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Reference Example 41 (rr)

<figref>374</figref>

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Reference Example 41 (ss)

<figref>375</figref>

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Reference Example 41 (tt)

<figref>376</figref>

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Reference Example 41 (uu)

<figref>377</figref>

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Reference Example 41 (vv)

<figref>378</figref>

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Reference Example 41 (ww)

<figref>379</figref>

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Reference Example 41 (xx)

<figref>380</figref>

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Reference Example 41 (yy)

<figref>381</figref>

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Reference Example 41 (zz)

<figref>382</figref>

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Reference Example 41 (yyyy)

<figref>383</figref>

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Reference Example 41 (bbb)

<figref>384</figref>

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Reference Example 41 (ccc)

<figref>385</figref>

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Reference Example 41 (ddd)

<figref>386</figref>

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Reference Example 41 (eee)

<figref>387</figref>

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Reference Example 41 (fff)

<figref>388</figref>

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Reference Example 41 (ggg)

<figref>389</figref>

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Reference Example 41 (hhh)

<figref>390</figref>

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Reference Example 41 (iii)

<figref>391</figref>

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Reference Example 41 (jjj)

<figref>392</figref>

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Reference Example 41 (kkk)

<figref>393</figref>

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Reference Example 41 (lll)

<figref>394</figref>

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Reference Example 42 (a)

6- (3-benzamidobenzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>395</figref>

The compound of the Reference Example 42 (a) was prepared from 6- (3-benzamidobenzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1- (2-trimethyl-silanylethoxymethyl) -1<i>H</i>-indazol similar to that described in Reference Example 12 (0.58 g, 80.6%). HPLC 4.13 min (area 98%). 1 H NMR (CDCl 3) δ: 8.66 (d, 1H, <i>J</i> = 4.1 Hz), 8.24 (d, 1H, <i>J</i> = 8.5 Hz), 8.11-8.10 (m, 3H), 8.01-7.98 (m, 4H), 7.83 (t, 2H, <i>J</i> = 7.1 Hz), 7.72-7.53 (m, 7H), 7.30 (qd, 1H, <i>J</i> = 5.2, 1.1 Hz) HRMS (MALDI) C 28 H 20 N 4 O 2, [M + H +] / z, calculated 445.1664, found 445.1659. Anal. (C 26 H 19 N 5 O 2 • 0.2 EtOAc): C, 75.87; H, 4.78; N, 12.39.

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The starting material was prepared as follow:

<figref>396</figref>

To a stirred solution of 6-iodo-3 - ((E) -styryl) -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol (4.00 g, 8.40 mmol), from Reference Example 14 step (i), in anisole (48 mL) under argon atmosphere dichloride of bis (triphenylphosphine) palladium (176 mg, 0.25 mmol), TBACl (288 mg, 1.0 mmol), 2-butanol (1.54 mL, 16.8 mmol) and potassium carbonate (3.48 g, 25.2 mmol). The resulting mixture is stirred under an atmosphere of carbon monoxide at 80 ° C for 100 h. After removal of the solvent by concentration in vacuo, the obtained residue was diluted with EtOAc (400 mL) and extracted with NaCl saturated (2 x 150 mL), saturated NaHCO3 (2 x 50 mL) and water (2 x 50 mL) and then the organic layer was filtered through 20 mL of silica The organic filtrate was then concentrated to empty, obtaining an amber oil: purification by rapid development chromatography with hexane: EtOAc (7: 3) provided 6- (3-aminobenzoyl) -3 - ((E) -styryl) -1- (2-trimethyl-silanylethoxymethyl) -1<i>H</i>-indazol which by concentration took the form of an amber oil (2.38 g, 61% yield). 1 HRMN (CDCl3) δ: 8.84 (dd, 1H,<i>J</i> = 8.70, 0.90 Hz), 8.02 (s, 1H), 7.77 (dd, 1H, <i>J</i> = 8.40, 1.50 Hz), 7.62-7.59 (m, 2H), 7.40 (t, 2H,<i>J</i> = 7.20 Hz), 7.38-7.24 (m, 4H), 7.22-7.19 (m, 3H), 6.98 (dq, 1H, <i>J</i> = 8.30, 0.90 Hz), 3.83 (broad s, 2H,), 3.61 (t, 2H. <i>J</i> = 8.10 Hz), 0.91 (t, 2H, <i>J</i> = 7.20 Hz), -0.17 (s, 9H).

<figref>397</figref>

To a stirred solution of 6- (3-aminobenzoyl) -3 - ((E) -styryl) -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol (3.22 g, 6.87 mmol) in methylene chloride (10 mL) under atmosphere of argon benzoyl chloride (0.95 mL, 8.37 mmol) was added and pyridine (0.67 mL, 3.22 mmol). After 2 h the solution was diluted with 100 mL of EtOAc and washed with saturated NaCl (1 x 50 mL), acidic citric (1M, pH 2.5, 2 x 50 mL) and NaHCO3 / water (50:50) (2 x 50 mL) The organic layer was dried over Na2SO4 and filtered to through 20 mL of silica. The organic layer was concentrated in vacuo, obtaining the product in the form of a yellow solid. The purification by flash chromatography through of silica eluting with hexane: EtOAc (7: 3) provided 6- (3-benzamidobenzoyl) -3 - ((E) -styryl) -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol in the form of a yellow foam (3.22 g, 85.1% yield). 1 H NMR (CDCl 3) δ: 8.19 (d, 1H, <i>J</i> = 8.7 Hz), 8.16 (s, 1H,), 8.11-8.10 (m, 2H), 8.03-7.93 (m, 3H), 7.82 (dd, 1H, <i>J</i> = 8.4, 1.2 Hz), 7.70-7.67 (m, 3H), 7.64-7.54 (m, 5H), 7.48 (t, 2H, <i>J</i> = 14.1 Hz) 7.39 (1H, d, <i>J</i> = 7.2 Hz).

<figref>398</figref>

A stirred solution of 6- (3-benzamidobenzoyl) -3 - ((E) -styryl) -1- (2-trimethyl-silanyl-ethoxy-methyl) -1<i>H</i>-indazol (2.35 g, 4.07 mmol) in methylene chloride (45.6 mL) was cooled up to -45 ° C using an acetonitrile / carbon dioxide bath solid. Then ozone was bubbled through the solution at a flow rate of 1.5 liters per minute (bpm), 60 amps during 15 minutes. The reaction stopped abruptly adding to the Hydrogen sulfide mixture (2.5 mL) and heated to 25 ° C. The Methylene chloride removal was performed by concentration at empty. The residue was purified through silica eluting with hexane: EtOAc (7: 3) providing 6- (3-benzamidobenzoyl) -1- (2-trimethyl-silanyl-ethoxy-methyl) -1<i>H</i>-indazol-3-carboxaldehyde in the form of a whitish foam (1.74 g, 85% yield). HPLC 3.78 min (100% area); 1 HRMN (DMSO-<i>d</i>6) δ: 10.77 (s, 1H), 10.42 (s, 1H), 8.46-8.39 (m, 2H), 8.31 (dt, 1H, <i>J</i> = 6.0, 1.8 Hz), 8.19 (s, 1H,), 8.11-8.07 (m, 2H,), 7.91 (dd, 1H, <i>J</i> = 6.0, 1.2 Hz), 7.70-7.64 (m, 5H), 5.81 (s, 2H) 3.68 (t, 2H, <i>J</i> = 6.9 Hz), 0.98 (t, 2H, <i>J</i> = 6.7 Hz), 0.02 (s, 9H).

<figref>399</figref>

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To a stirred solution of chloride 2-picolyltriphenylphosphonium and sodium hydride (2.23 g, 4.91 mmol) cooled to -78 ° C was added 6- (3-benzamidobenzoyl) -1- (2-trimethyl-silanyl-ethoxy-methyl) -1<i>H</i>-indazol-3-carboxaldehyde (1.26 g, 2.46 mmol) in 5 mL of anhydrous THF under an argon purge, stirred for 1 h at 0 ° C and the reaction stopped abruptly adding CH 3 COOH / MeOH (1: 1, 1 mL). The reaction mixture is diluted with 100 mL of EtOAc and partitioned between saturated NaCl (1 x 50 mL) and saturated NaHCO 3 (2 x 50 mL) and then the layer The organic was dried over Na2O4 and filtered through 20 mL of a silica plug (trans / cis mixture 3: 1). Purification with a 4 mm silica bed eluting with hexane / EtOAc (1: 1) provided 6- (3-Benzamidobenzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol after concentration in the form of a yellow solid (1.05 g, 62%) 1 HRMN (CDCl3) δ: 8.62 (d, 1H,<i>J</i> = 4.1 Hz), 8.22 (d, 1H, <i>J</i> = 8.5 Hz), 8.11-8.10 (m, 3H), 8.01-7.98 (m, 4H), 7.83 (t, 2H, <i>J</i> = 7.1 Hz), 7.72-7.53 (m 7H), 7.30 (qd, 1H, <i>J</i> = 5.2, 1.1 Hz), 5.81 (s, 2H) 3.68 (t, 2H, <i>J</i> = 6.9 Hz), 0.98 (t, 2H,<i>J</i> = 6.7 Hz), 0.02 (s, 9H).

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Reference Example 42 (b)

6- (3-benzamidobenzoyl) -3- (1

H

-benzoimidazol-2-yl) -1

H

-indazol

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<figref>400</figref>

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The compound of the Reference Example 42 (b) was prepared in a manner similar to that described in the Reference Example 42 (a) except that the step (iv) by the following: The aldehyde prepared in the Example of reference 42 (a); step (iii) was added 1,2-diaminobenzene (0.011 g, 011 mmol), sulfur elemental (USP quality, 0.4 g, 0.1201 mmol), 2 mL of anhydrous DMF and The mixture was heated to 90 ° C for 18 h and cooled to 25 ° C. The reaction mixture was diluted with 10 mL of ethyl acetate and was washed with saturated NaCl (1 X 10 mL), NaHCO 3 (1 X 10 mL) and 10 mL of water, dried over NaSO4, filtered through a filter of 0.22 mM Teflon and concentrated to a colored oil amber. Purification by radial chromatography followed by 2 mL precipitation of methylene chloride and hexane (2 mL) provided an intermediate compound as a precipitate White. 1 HRMN (Acetone-<i>d</i>6) δ: 8.81 (d, 1H,<i>J</i> = 8.6), 8.30-8.25 (m, 2H), 8.11 (s, 1H), 8.02-7.99 (m, 2H), 7.79 (td, 2H, <i>J</i> = 12.2, 1.2 Hz), 7.63-7.47 (m, 7H), 7.28-7.40 (m, 2H). HRMS (MALDI) <i>m</i>/<i>z, c</i>28 H 19 N 3 O 2 Calculated [M + H +]: 458.1617, found 458.1632.

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Reference Example 42 (c)

6- (3-benzamidobenzoyl) -3-E- [2- (2-methylthiazol-4-yl) ethenyl] -1

H

-indazol

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<figref>401</figref>

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The compound of the Reference Example 42 (c) was prepared in a manner similar to that described in the Reference example 42 (a) except that, in step (iv), Chloride was used 4- (2-methylthiazyl) -methyltriphenylphosphonium instead of 2-picolyltriphenylphosphonium chloride. 1 H NMR (DMSO) δ: 8.11-8.01 (m, 4H), 7.92 (d, 2H, <i>J</i> = 6.9 Hz), 7.76-7.71 (m, 2H), 7.65-7.62 (m, 1H), 7.56-7.48 (m, 5H,), 7.15 (s, 1H,). 2.81 (s, 3 H). HRMS (MALDI) C 27 H 20 N 4 O 2 S [M + H +] / z: Calculated 465.1380, found 465.1373.

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Reference Example 42 (d)

6- (3-benzamidobenzoyl) -3- (3H-imidazo [4,5-b] pyridin-2-yl) -1

H

-indazol

<figref>402</figref>

The compound of the Reference Example 42 (d) was prepared in a manner similar to that described in the Reference Example 42 (b) except that it was used 1,2-diamine-2-pyridine instead of 1,2-diaminobenzene. HPLC: 3.88 min (area 95%); 1 HRMN (DMSO-<i>d</i>6) δ: 10.62 (s, 1H), 8.83 (d, 1 H, <i>J</i> = 8.4 Hz), 8.53 (s, 1H), 8.43 (s, 1H), 8.32 (dt, 1H, <i>J</i> = 6.9, 1.8 Hz), 8.15 (d, 1H, <i>J</i> = 12.9 Hz), 8.11-8.10 (m, 2H), 7.91 (d, 1H, <i>J</i> = 9.0 Hz), 7.72-7.65 (m, 6H), 7.43 (dd, 1H, <i>J</i> = 6.3, 4.8 Hz) HRMS (MALDI)<i>m</i>/<i>z, c</i>27 H 18 N 6 O 2. Calculated [M + H +]: 459.1564, found 459.1555. Anal. (C 27 H 18 N 6 O 2 \ 0.4 CH 2 Cl 2): Calculated C, 66.83; H, 3.85; N, 17.07. Found: C, 66.93; H 4.04, N, 16.68.

Example 42 (e)

6- (3-benzamidobenzoyl) -3-E- [

N

-(4

H

-1,2,4-triazol-4-yl) iminomethyl] -1

H

-indazol

<figref>403</figref>

The compound of Example 42 (e) was prepared similar to that described in the Reference Example 42 (a) except that they were used 4-amino-1,2,4-triazole and PPTS at 80 ° C instead of 2-picolyltriphenylphosphonium and potassium hydride a 23 ° C. HPLC R t = 4.05 min (96% area); 1 HRMN (DMSO-<i>d</i>6) δ: 10.58 (s, 1H), 9.53 (s, 1H), 9.40 (s, 2H), 8.56 (d, 1H, <i>J</i> = 8.4 Hz), 8.38 (s, 1H), 8.26 (dt, 1 HOUR, <i>J</i> = 7.2, 2.1 Hz), 8.13 (s, 1H), 8.08-8.05 (m, 2H), 7.73-7.67 (m, 5H). HRMS (MALDI) C 24 H 17 N 7 O 2 [M + H +] / z, calculated 436.1516, found 436.1510. Anal. (C 24 H 17 N 7 O 2 \ 0.4 hexane) Calculated C, 66.18; H, 4.67; N, 20.47. Found: C, 65.78; H, 4.87, N, 20.47.

Reference Example 43

6- (3-benzamidobenzoyl -) - 3-E- [2- (2-formamidophenyl) ethenyl] -1

H

-indazol

<figref>404</figref>

The compound of Reference Example 43 is prepared from 6- (3-Benzamidobenzoyl) -3-E- (2-formamidophenyl) ethenyl-1- (g2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol in a manner similar to that described in Reference Example 11. 18 mg (36%). HPLC R t = 4.19 min. 1 H NMR (CDCl 3) δ: 8.43-7.92 (m, 6H), 7.68-7.49 (m, 4H) 7.39-7.36 (m, 3H), 7.32-7.21 (m, 2H), 7.09-7.00 (m, 2H), 6.91-6.84 (m, 1H). HRMS (MALDI) C 30 H 22 N 4 O 3 [M + H] / z, calculated 509.1590, found 509.1580. Anal. (C 30 H 22 N 4 O 3 {c0.3H 2 O) Calculated: C, 73.25; H, 4.63; N, 11.39. Found: C, 73.10; H, 4.58; N, 11.28.

The starting material was prepared as follow:

<figref>405</figref>

6- (3-Benzamidobenzoyl) -1- (2-trimethyl-silanyl-ethoxy-methyl) -1<i>H</i>-indazol-3-carboxaldehyde (prepared in Reference Example 42 (a), step (iii)) became 6- (3-Benzamidobenzoyl) -3-E- (2-nitrophenyl) ethenyl-1- (2-trimethyl-silanylethoxymethyl) -1<i>H</i>-indazol similar to that described in the Reference Example 42 (a), step (iv) except that bromide was used (2-nitrobenzyl) triphenylphosphonium monohydrate instead of 2-picolyltriphenylphosphonium chloride (0.19 g, 79%). 1 H NMR (CDCl 3) δ: 8.15-7.93 (m, 5H), 7.89-7.86 (m, 3H), 7.54-7.41 (m, 6H), 7.36-7.35 (m, 2H), 7.21-7.18 (m, 2H), 7.03-6.91 (m, 1H), 3.64-3.46 (m, 2H), 0.96-0.79 (m, 2H), -0.06 (s, 9H).

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<figref>406</figref>

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6- (3-Benzamidobenzoyl) -3-E- (2-nitrophenyl) ethenyl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol (0.19 g, 0.32 mmol) was dissolved in 3 mL of DMF, treated with SnCl2 (0.26 g, 1.40 mmol) and water (0.037 mL, 1.87 mmol) and be stirred for 3 h at 50 ° C. The reaction stopped abruptly adding 0.5 mL of 3N NaOH to the mixture at 25 ° C and the precipitate is filtered off through Celite. The solution was distributed to continuation between saturated NaHCO3 / water 50/50 (2 x 30 mL) and the Organic layer was filtered through a silica plug to obtain 6- (3-Benzamidobenzoyl) -3-E- (2-aminophenyl) ethenyl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol in the form of an amber oil (0.17 g, 92%). The product is used without further purification.

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<figref>407</figref>

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6- (3-Benzamidobenzoyl) -3-E- (2-aminophenyl) ethenyl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol (0.17 g, 0.28 mmol) was dissolved in 3 mL of methylene chloride. TO this was added dropwise pentafluorophenyl acid ester formic (0.12 g, 0.56 mmol). After 3 h, the reaction mixture diluted with 40 mL of EtOAc and washed with 50/50 NaHCO3 (2 x 30 mL) and the organic layer was filtered through a silica plug. The residue was purified by radial chromatography through silica eluting with hexane: EtOAc / CH 2 Cl 2 (1: 1: 1) obtaining 6- (3-Benzamidobenzoyl) -3-E- (2-formamidophenyl) ethenyl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol in the form of a transparent oil (63 mg, 40%). 1 H NMR (CDCl3) δ: 8.48-8.36 (m, 1H), 8.20-7.84 (m, 4H), 7.61-7.52 (m, 5H), 7.41-7.32 (m, 4H), 7.26-7.01 (m, 4H), 6.82 (t, 1H, <i>J</i> = 14.2 Hz), 3.48-3.23 (m, 2H), 0.95-0.87 (m, 2H), -0.05 (s, 9H).

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Reference Example 44

6- (3-aminobenzyl) -3-E- [

N

- (pyrrole-1-yl) iminomethyl] -1

H

-indazol

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<figref>408</figref>

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The compound of Reference Example 44 is prepared from the starting material described below of similar to that described in Reference Example 12, R_ {f} sm = 0.6, p = 0.5 (ethyl acetate): 1 HRMN (300 MHz, CDCl3) δ: 8.8 (s, 1H), 8.5 (d, 1H), 7.95 (s, 1H), 7.75 (d, 1H), 7.45-7.3 (m, 7H), 7.2 (m, 1H), 6.40 (s, 2H).

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The starting material was prepared as follow:

<figref>1409</figref>

<figref>409</figref>

The aldehyde prepared in the Example of reference 33 (a), step (i) (204 mg, 0.507 mmol) and 1-aminopyrrole (67 µL, 0.66 mmol, 1.3 equivalent) were stirred together in toluene (2 mL). This mixture is PPTS (1 mg) was added and the solution was heated to 80 ° C for 1 h. The mixture was cooled and partitioned between acetate ethyl hexane 2: 8 and water. The organic material is dried over sodium sulfate, decanted and concentrated under pressure reduced The product was crystallized from dichloromethane (0.5 mL) and methanol (2 mL) (215.7 mg, 91%): 1 HRMN (300 MHz, C 6 D 6, δ: 8.71 (s, 1H), 8.25 (d, 1H, <i>J</i> = 8.5 Hz), 8.08 (s, 1H), 7.75 (d, 1H, <i>J</i> = 8.5 Hz), 6.35 (s, 2H), 5.85 (s, 2H).

<figref>410</figref>

A mixture of the previous iodide (535 mg, 1.15 mmol, 1 equivalent), acid 3-aminophenyl boronic (236 mg, 1.72 mmol, 1.5 equivalents), PdCl 2 (PPh 3) 2 (24 mg, 0.034 mg, 0.03 equivalents) and potassium carbonate se collected with anisole (6.7 mL) under carbon monoxide (1 atm). The mixture was heated to 80 ° C for 14 h. The mixture cooled, it partitioned between ethyl acetate and water. Organic materials are washed with saturated aqueous sodium hydrogen carbonate, water and brine and the organic layer was separated. The organic material dried over sodium sulfate, it was decanted and concentrated under pressure reduced Purification by gel column chromatography of silica (50 mL of silica: ethyl acetate-hexane 2: 8 to 3: 7) gave the aniline derivative as a solid (331 mg, 63%): R f sm = 0.60, p = 0.21 (acetate ethyl hexane 3: 7); 1 HRMN (300 MHz, CDCl 3) δ: 8.75 (s, 1H), 8.51 (d, 1H, <i>J</i> = 8.4 Hz), 8.06 (s, 1H), 7.76 (dd, 1H, <i>J</i> = 1.3, 8.4 Hz), 7.26 (m, 3H), 7.17 (m, 2H), 6.92 (m, 1H), 6.31 (t, 1H, <i>J</i> = 2.3 Hz), 5.79 (s, 2H), 3.84 (broad s, 2H), 3.60 (t, 2H, <i>J</i> = 8.2 Hz), 0.91 (t, 2H,<i>J</i> = 8.2 Hz), -0.08 (s, 9H). LCMS 4.98 min (pos) [M + H] / z, calculated 460, found 460.

Reference Example 45 (a)

6- [3- (indole-4-ylcarboxamido) benzoyl] -3-E- [

N

- (pyrrole-1-yl) iminomethyl] -1

H

-indazol

<figref>411</figref>

The compound of the Reference Example 45 (a) was prepared from the compound of the Example of reference 44 in a manner similar to that described in the Example of reference 12 (d), except that acid was used indole-4-carboxylic instead of acid 5-methyl-thiazol-2-carboxylic: R<i>F</i> sm = 0.0, p = 0.2 (acetate ethyl benzene 1: 3); 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 9.84 (s, 1H), 8.92 (s, 1H), 8.66 (s, 1H), 8.39 (d, 1H, <i>J</i> = 8.5 Hz), 8.02 (s, 1H), 7.86 (m, 2H), 7.66 (d, 1 H, <i>J</i> = 8.5 Hz), 7.52-7.40 (m, 4H), 7.27-7.07 (m, 5H), 6.83 (s, 1 H), 6.21 (s, 2H).

Reference Example 45 (b)

6- (3-benzamidobenzoyl) -3-E- [

N

- (pyrrole-1-yl) iminomethyl] -1

H

-indazol

<figref>412</figref>

The compound of the Reference Example 45 (b) was prepared from Reference Example 44 of similar to that described in the Reference Example 12 (d), except that benzoyl chloride was used instead of acid 5-methyl-thiazol-2-carboxylic and HATU: 1 HRMN (300 MHz, CDCl 3) δ: 11.9 (wide s, 1H), 8.70 (s, 1H), 8.43 (s, 1H), 8.39 (d, 1H, <i>J</i> = 8.4 Hz), 7.99 (s, 1H), 7.9-7.8 (m, 4H), 7.65 (d, 1H, <i>J</i>= 8.4 Hz), 7.48 (t, 2H, <i>J</i> = 7.8 Hz), 7.42-7.35 (m, 3H), 7.20 (t, 2H, 2.2 Hz), 6.28 (t, 2H, <i>J</i> = 2.2 Hz).

Example 46

6-[

N

- (3-aminophenyl) amino] -3-E-styryl-1

H

-indazol

<figref>413</figref>

The compound of Example 46 was prepared from of the starting material described below in a manner similar to the one described in Example 13 (i). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 12.6 (s, 1H), 8.07 (s, 1H), 7.97 (d, 1 HOUR, <i>J</i> = 8.73 Hz), 7.69 (d, 1H, <i>J</i> = 8.49 Hz), 7.40 (m, 4H), 7.28 (m, 1H), 7.06 (d, 1H, <i>J</i> = 1.49 Hz), 6.44 (t, 1H,<i>J</i> = 1.98 Hz), 6.34 (m, 1H), 6.14 (dd, 1H, <i>J</i> = 7.88 Hz,<i>J</i> = 1.26 Hz), 5.01 (wide s, 2H).

<figref>1414</figref>

<figref>414</figref>

The compound prepared in the Example of reference 11, step (v), became 6- [<i>N</i>- (3-nitrophenyl) amino] -3-E-styryl-1<i>H</i>-indazol in a manner similar to that described in Reference Example 12. 1 HRMN (300 MHz, CDCl 3) δ: 8.0 (m, 2H), 7.77 (m, 1H), 7.64 (d, 2H, <i>J</i> = 7.86 Hz), 7.41-7.56 (m, 6H), 7.33 (m, 2H), 7.08 (d, 1H, <i>J</i> = 8.67 Hz). MS (ESI +) [M + H] / z, calculated 357, found 357. Calculated: C, 70.77; H 4.53; N, 15.72. Found: C, 69.18; H, 4.51; N, 15.30.

Example 47

6-[

N

- (3-benzamido-4-fluorophenyl) amino] -3-E-styryl-1

H

-indazol

<figref>415</figref>

6-[<i>N</i>- (3-Benzamido-4-fluorophenyl) amino] -1- (2-trimethyl-silanyl-ethoxymethyl-3-E-styryl-1<i>H</i>-indazol it became the compound of Example 47 in a manner similar to the described in Reference Example 11. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 12.6 (s, 1H), 10.0 (s, 1H)), 8.38 (s width, 1H), 8.02 (d, 1H, <i>J</i> = 8.78), 7.98 (d, 2H, <i>J</i> = 6.87 Hz), 7.69 (d, 2H, <i>J</i> = 7.27 Hz), 7.48-7.61 (m, 4H), 7.45 (s, 2H), 7.40 (t, 2H,<i>J</i> = 7.28 Hz), 7.53-7.30 (t, 2H. <i>J</i> = 7.28 Hz), 7.53-7.30 m, 2H), 7.07 (d, 1H, <i>J</i> = 1.55 Hz), 7.03 (m, 1H), 6.95 (dd, 1H, <i>J</i> = 8.79 Hz, <i>J</i>= 1.85 Hz). MS (ESI +) [M + H] / z, calculated 449, found 449. Anal. Calculated: C, 74.98, H, 4.72, N, 12.49. Found: C, 74.29, H, 4.76, N, 12.12.

The starting material was prepared as follow:

<figref>416</figref>

To a solution of 2-fluoro-5-nitro-phenylamine (3.12 g, 20 mmol) in dichloromethane (20 ml) at 23 ° C under argon added pyridine (1.94 ml, 24 mmol) and benzoyl chloride (2.8 ml, 24 mmol). After 45 minutes a white precipitate formed. The reaction mixture was concentrated in vacuo and then diluted with water and filtered to obtain a white solid that was returned to put in suspension in MeOH and filtered again giving <i>N</i>- (2-Fluoro-5-nitro-phenyl) -benzamide (4.86 g, 93%). 1 H NMR (300 MHz, CDCl 3) δ: 9.48 (dd, 1 HOUR, <i>J</i> = 6.8 Hz, <i>J</i> = 2.81 Hz), 8.17 (wide s, 1H), 8.03 (m, 1H), 7.92 (m, 2H), 7.52-7.65 (m, 3H), 7.31 (d, 1H, <i>J</i> = 9.2 Hz).

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<figref>417</figref>

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A mix of<i>N</i>- (2-Fluoro-5-nitro-phenyl) -benzamide (4.86 g, 18.7 mmol) and 10% Pd / C (486 mg) in a 1: 1 mixture of THF-MeOH (80 ml) was hydrogenated at 23 ° C. After 2.5 h the reaction mixture was filtered through celite and concentrated getting<i>N-</i>(5-amino-2-fluoro-phenyl) -benzamide (3.92 g, 91%). MS (ESI +) [M + H] / z, calculated 231, found 231.

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<figref>418</figref>

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6- [N- (3-Benzamido-4-fluorophenyl) amino] -1- (2-trimethyl-silanyl-ethoxymethyl-3-E-styryl-1<i>H</i>-indazol it was prepared in a manner similar to that described in the Example of reference 48 (a), step (iii) except that they were used as starting materials<i>N</i>- (5-amino-2-fluoro-phenyl) -benzamide and the compound prepared in Example 14, step (i). 1 HRMN (300 MHz, CDCl 3) δ: 8.38 (dd, 1H, <i>J</i> = 6.84 Hz,<i>J</i> = 2.73 Hz), 8.09 (d, 1H, <i>J</i> = 3.08 Hz), 7.86-7.91 (m, 3H), 7.48-7.61 (m, 5H), 7.28-7.45 (m, 4H), 7.19 (d, 1H, <i>J</i> = 1.7 Hz), 7.08 (dd, 1H, <i>J</i> = 10.48 Hz), 6.90-6.96 (m, 2H), 6.03 (broad s, 1H), 5.66 (s, 2H), 3.62 (t, 2H, <i>J</i> = 8.14 Hz), 0.91 (t, 2H, <i>J</i> = 8.32 Hz), 0.0 (s, 9H). MS (ESI +) [M + H] / z, calculated 579, found 579. Anal. Calculated: C, 70.56, H, 6.10, N, 9.68. Found: C, 20.26, H, 6.08, N, 9.16.

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Example 48 (a)

6-[

N

- (5 - ((1-ethyl-3-methyl-1

H

-pyrazol-5-yl) carboxamido) -2-fluoro-4-methylphenyl) amino] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>419</figref>

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The compound of Example 48 (a) was prepared similar to that described in the Reference Example 41 (a) from the starting material described to continuation. 1 H NMR (300 MHz, CD 3 OD) δ: 8.54 (d, 1 HOUR, <i>J</i> = 4.8 Hz), 7.95 (d, 1H, <i>J</i> = 9.49 Hz), 7.84 (td, 1 HOUR, <i>J</i> = 7.71 Hz, <i>J</i> = 1.78 Hz), 7.70 (d, 1H, <i>J</i>= 7.95 Hz), 7.53 (d, 1H, <i>J</i> = 16.59 Hz), 7.40 (d, 1H, <i>J</i>= 7.92 Hz), 7.29 (qd, 1H, <i>J</i> = 7.45 Hz, <i>J</i> = 1.07 Hz), 7.11 (d, 1H, <i>J</i> = 11.8), 7.03-7.06 (m, 2H), 6.71 (s, 1H), 4.50 (q, 2H, <i>J</i> = 7.16 Hz), 2.27 (s, 3H), 2.26 (s, 3H), 1.38 (t, 3H, <i>J</i> = 7.11 Hz). MS (ESI +) [M + H] / z, calculated 496, found 496. Anal. Calculated: C, 67.86; H, 5.29; N, 19.79. Found: C, 66.24; H, 5.50; N, 18.61.

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The starting material was prepared as follow:

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<figref>420</figref>

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A mix of 1-fluoro-5-methyl-2,4-dinitro-benzene (1.0 g, 5 mmol) and 10% Pd / C (200 mg) in MeOH (20 ml) was hydrogenated at 23 ° C for 24 h. The reaction mixture was filtered through Celite and concentrated. Purification by column chromatography silica gel (ethyl acetate-hexane 1: 1) gave 4-fluoro-6-methyl-benzene-1,3-diamine (613 mg, 87%).

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<figref>421</figref>

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To an ester solution 2-trimethyl-silanyl-ethyl of 4-nitro-phenyl acid ester carbonic acid (566 mg, 2 mmol) in DMF (4 ml) at 23 ° C under an atmosphere of argon DMAP (12 mg, 0.1 mmol), DIEA (0.35 ml, 2 mmol) was added and 4-fluoro-6-methyl-benzene-1,3-diamine. The resulting solution was heated to 50 ° C for 48 h. The reaction stopped abruptly adding to the mixture NaHCO 3 saturated (aqueous) and extracted with EtOAc (3x 20 ml). The EtOAc is removed in vacuo and the residue was re-dissolved in Et2O already then washed with 3N NaOH (aqueous), water, brine, dried with Na 2 SO 4, it was filtered and concentrated. Purification by silica gel column chromatography (acetate ethyl hexane 2: 8-7: 3) gave ester 2-trimethyl-silanyl-ethyl of the acid (5-amino-4-fluoro-2-methyl-phenyl) -carbamic (160 mg, 28%). MS (ESI +) [M + H] / z, calculated 634, found 634.

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<figref>1422</figref>

<figref>422</figref>

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To a mixture of 6-iodo-3 - ((E) -2-pyridin-2-yl-vinyl) -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol (224 mg, 0.47 mmol), ester 2-trimethyl-silanyl-ethyl of the acid 5-amino-4-fluoro-2-methylphenyl) -carbamic (160 mg, 0.56 mmol), Cs2CO3 (214 mg, 0.66 mmol), PdCl 2 (PPh 3) 2 (5.4 mg, 0.0059 mmol) and BINAP (10 mg, 0.0176 mmol) under argon at 23 ° C was added toluene (0.5 ml) The resulting mixture was heated to 80 ° C for 16 h. The reaction mixture was cooled to 23 ° C and then diluted with water (20 ml) and extracted with EtOAc (3 x 50 ml). The materials organic washed with water (30 ml), brine (30 ml), dried with Na 2 SO 4, they were filtered and concentrated to obtain a foam Column chromatography on silica gel (acetate ethyl-hexane 3: 7) provided ester 2-trimethyl-silanyl-ethyl of the acid {4-fluoro-2-methyl-5- [3 - ((E) -2-pyridin-2-yl-vinyl) -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-6-ylamino] -phenyl} -carbamic (98 mg, 33%). TLC (hexane-acetate ethyl 7-3) R f sm = 0.42, R f p = 0.23. 1 HRMN (CDCl3) δ: 8.64 (dd, 1H, <i>J</i> = 4.79Hz,<i>J</i> = 0.86 Hz), 7.94 (d, 1H, <i>J</i> = 8.71 Hz), 7.91 (s width, 1H), 7.86 (d, 1H, <i>J</i> = 16.41 Hz), 7.69 (td, 1H,<i>J</i> = 7.72 Hz, <i>J</i> = 1.8 Hz), 7.55 (d, 1H, <i>J</i> = 16.44 Hz), 7.49 (d, 1H, <i>J</i> = 7.91 Hz), 7.17 (qd, 1H, <i>J</i>= 7.44 Hz, <i>J</i> = 0.98 Hz), 6.99 (dd, 1H, <i>J</i> = 8.67 Hz,<i>J</i> = 1.89 Hz), 6.93 (d, 1H, <i>J</i> = 11.2 Hz), 6.25 (s width, 1H), 5.95 (d, 1H, <i>J</i> = 1.97 Hz), 5.70 (s, 2H), 4.25 (t, 2H, <i>J</i> = 8.53 Hz), 3.60 (t, 2H, <i>J</i> = 8.24 Hz), 2.22 (s, 3H) 1.04 (t, 2H, <i>J</i> = 8.54 Hz), 0.9 (t, 2H, <i>J</i> = 8.25 Hz), 0.05 (s, 9H), 0.0 (s, 9H). 13 C NMR (CDCl 3, 75 MHz) δ: 156.0, 154.4, 149.8, 142.9, 142.8, 142.5, 136.6, 132.1, 130.1, 130.5, 128.7, 128.5, 124.3, 122.2, 122.0, 121.8, 118.2, 117.3, 117.0, 115.1, 95.2, 77.6, 77.4, 66.5, 63.7, 17.9, 17.2, -1.3. FTIR cm -1: 3326, 2947, 1716, 1617, 1534, 1514, 1244, 1057. MS (ESI +) [M + H] / z, calculated 634, found 634.

<figref>423</figref>

The anterior aniline was prepared similarly to that described in Reference Example 11. 1 HRMN (300 MHz, CD 3 OD) δ: 8.54 (m, 1H), 7.91 (dd, 1H, <i>J</i> = 8.74 Hz, <i>J</i> = 0.58 Hz), 7.83 (td, 1H, <i>J</i> = 7.72 Hz, <i>J</i>= 1.79 Hz), 7.80 (d, 1H, <i>J</i> = 16.52 Hz), 7.69 (d, 1H, <i>J</i>= 7.98 Hz), 7.52 (d, 1H, <i>J</i> = 16.58 Hz), 7.29 (qd, 1H,<i>J</i> = 7.43 Hz, <i>J</i> = 1.07 Hz), 6.94-6.99 (m, 2H), 6.83 (d, 1H, <i>J</i> = 11.98 Hz), 6.82 (d, 1H, <i>J</i> = 7.49 Hz), 2.15 (s, 3H). MS (ESI +) [M + H] / z, calculated 360, found 360

Example 48 (b)

6-[

N

- (5 - ((1,3-dimethyl-1

H

-pyrazol-5-yl) carboxamido) -2-fluoro-4-methylphenyl) amino] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>424</figref>

The compound of Example 48 (b) was prepared similar to that described in Example 48 (a) except that acid was used 2,5-dimethyl-2<i>H</i>-pyrazol-3-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic. 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 12.8 (s, 1H), 9.71 (s, 1H), 8.59 (m, 1H), 8.11 (s, 1H), 8.00 (d, 1H, <i>J</i> = 8.75 Hz), 7.87 (d, 1H, <i>J</i> = 16.37 Hz), 7.80 (td, 1H, <i>J</i>= 7.66 Hz, <i>J</i> = 1.81 Hz), 7.64 (d, 1H, <i>J</i> = 7.88 Hz), 7.49 (d, 1 H, <i>J</i> = 16.38 Hz), 7.34 (d, 1H, <i>J</i> = 8.16 Hz), 7.26 (m, 1H), 7.21 (d, 1H, <i>J</i> = 12.14 Hz), 6.97 (dd, 1H,<i>J</i> = 8.76 Hz), 6.88 (s, 1H), 6.79 (s, 1H), 3.98 (s, 3H), 2.20 (s, 3H), 2.19 (s, 3H). MS (ESI +) [M + H] / z, calculated 482, found 482. Anal. Calculated: C, 67.35; H, 5.02; N, 20.36. Found: C, 66.83; H, 5.25; N, 19.68.

Example 49 (a)

6-[

N

- (3 - ((1,3-dimethyl-1

H

-pyrazol-5-yl) carboxamido) -4-fluorophenyl) amino] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>425</figref>

The compound of Example 49 (a) was prepared similar to that described in Example 48 (a) except for the following: acid was used 2,5-dimethyl-2<i>H</i>-pyrazol-3-carboxylic instead of acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic; in step (iii), ester was used 2-trimethyl-silanyl-ethyl of the acid (5-amino-2-fluorophenyl) -carbamic, prepared as described below, instead of ester 2-trimethyl-silanyl-ethyl of the acid (5-amino-4-fluoro-2-methyl-phenyl) -carbamic, DME was used as solvent and as ligand biphenyl-2-yl-dicyclohexyl phosphane. 1 HRMN (300 MHz, CD 3 OD) δ: 12.7 (s, 1H), 9.94 (s, 1H), 8.48 (m, 1H), 8.40 (s, 1H), 8.02 (d, 1H, <i>J</i> = 6.77 Hz), 7.87 (d, 1 H, <i>J</i> = 16.37 Hz), 7.80 (d, 1H, <i>J</i> = 7.63 Hz,<i>J</i> = 1.81 Hz), 7.64 (d, 1H, <i>J</i> = 7.88 Hz), 7.49 (d, 1H,<i>J</i> = 16.39 Hz), 7.42 (dd, 1H, <i>J</i> = 6.65 Hz, <i>J</i> = 2.68 Hz), 7.24 (m, 2H), 7.06 (m, 2H), 6.96 (dd, 1H, <i>J</i> = 8.81 Hz, <i>J</i> = 1.82 Hz), 6.85 (s, 1H), 4.0 (s, 3H), 2.20 (s, 3H). MS (ESI +) [M + H] / z, calculated 468, found 468. Anal. Calculated: C, 66.80; H, 4.74; N, 20.97. Found: C, 66.01; H, 4.72; N, 20.81.

<figref>426</figref>

To a solution of 1-fluoro-2-isocyanate-4-nitro-benzene (9.82 g, 54 mmol) in THF (40 ml) at 23 ° C under argon atmosphere added 2-trimethyl-silanyl-ethanol (7.72 ml, 54 mmol). The resulting mixture was stirred for 11 hours. and then heated to 50 ° C for 2 hours. The mixture of reaction was allowed to cool to 23 ° C, and the reaction stopped abruptly adding to the mixture saturated NaHCO3 (aqueous) and extracted with EtOAc (3 x 100 ml). The mixture of the fractions of ethyl acetate was washed with 1N HCl (aqueous) (2 x 90 ml), water (90 ml) and brine (90 ml), dried with Na2SO4, filtered and concentrated to obtain yellow solid. Chromatography on silica gel column (ethyl acetate-hexane 2: 8) provided ester 2-trimethyl-silanyl-ethyl of the acid (2-fluoro-5-nitro-phenyl) -carbamic (12.3 g, 77%). 1 HRMN (300 MHz, CDCl 3) δ: 9.06 (dd, 1 HOUR, <i>J</i> = 6.89 Hz, <i>J</i> = 2.63 Hz), 7.89 (m, 1H), 7.20 (m, 1H), 6.91 (broad s, 1H), 4.31 (t, 2H, <i>J</i> = 8.67 Hz), 1.06 (t, 2H, <i>J</i> = 8.67 Hz), 0.05 (s, 9H). LCMS (ESI-) [M + H] / z, calculated 299, found 299.

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<figref>427</figref>

An ester mixture 2-trimethyl-silanyl-ethyl of the acid (2-fluoro-5-nitro-phenyl) -carbamic (3.00 g, 10 mmol) and 10% Pd / C (300 mg) in methanol (30 ml) is hydrogenated at 23 ° C. The resulting mixture was stirred for 24 h. The reaction mixture was filtered through celite and concentrated getting ester 2-trimethyl-silanyl-ethyl of the acid (5-amino-2-fluorophenyl) -carbamic (2.62 g, 97%). 1 HRMN (300 MHz, CDCl 3) δ: 7.52 (m, 1H), 6.85 (dd, 1H, <i>J</i> = 10.8 Hz, <i>J</i> = 8.69 Hz), 6.73 (s width, 1H), 6.28 (m, 1H), 4.27 (t, 2H, <i>J</i> = 8.57 Hz), 3.0-4.4 (wide s, 2H), 1.06 (t, 2H, <i>J</i> = 8.58 Hz), 0.07 (s, 9H).

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Example 49 (b)

6-[

N

- (3 - ((1,3-dimethyl-1

H

-pyrazol-5-yl) -carboxamido) -4-methylphenyl) amino] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>428</figref>

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The compound of Example 49 (b) was prepared similar to Example 49 (a) except that it was used, in the stage (i), 1-methyl-2-isocyanate-4-nitrobenzene instead of 1-fluoro-2-isocyanate-4-nitrobenzene. 1 HRMN (300 MHz, CDCl 3) δ: 8.59 (m, 1H), 8.35 (s, 1H), 8.00 (d, 1H, <i>J</i> = 8.73 Hz), 7.87 (d, 1H, <i>J</i> = 16.38 Hz), 7.80 (td, 1H, <i>J</i> = 7.66 Hz, <i>J</i> = 1.85 Hz), 7.64 (d, 1 H, <i>J</i> = 7.85 Hz), 7.49 (d, 1H, <i>J</i> = 16.35 Hz), 7.26 (m, 1H), 7.19 (m, 2H), 7.09 (d, 1H, <i>J</i> = 1.48 Hz), 7.02 (dd, 1H, <i>J</i> = 8.17 Hz, <i>J</i> = 2.24 Hz), 6.97 (dd, 1 HOUR, <i>J</i> = 8.79 Hz, <i>J</i> = 1.80 Hz), 6.81 (wide s, 1H), 4.00 (s, 3H), 2.20 (s, 3H), 2.18 (s, 3H). LCMS (ESI +) [M + H] / z, calculated 464, found 464.

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Example 49 (c)

6-[

N

- (3-acetamido-4-fluorophenyl) amino] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

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<figref>429</figref>

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The compound of Example 49 (c) was prepared similar to Example 49 (a) except that it was used acetic anhydride instead of acid 2,5-dimethyl-2<i>H</i>-pyrazol-3-carboxylic: 1 HRMN (300 MHz, CD 3 OD) δ: 8.44 (m, 1H), 7.82 (d, 1H), 7.70 (m, 3H), 7.55 (d, 1H), 7.41 (d, 1H, <i>J</i> = 16.4 Hz), 7.19 (m, 1H), 7.03 (s, 1H), 6.94 (m, 1H), 6.87 (m, 2H), 2.11 (s, 3H). LCMS (100% area) Rt = 4.53 min, (pos) [M + H] / z, calculated 388.4, found 388.4.

The compounds of the Examples 49 (d) -49 (x) can be prepared from similar to that described in Example 49 (a).

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Example 49 (d)

<figref>430</figref>

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Example 49 (e)

<figref>431</figref>

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Example 49 (f)

<figref>432</figref>

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Example 49 (g)

<figref>433</figref>

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Example 49 (h)

<figref>434</figref>

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Example 49 (i)

<figref>435</figref>

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Example 49 (j)

<figref>436</figref>

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Example 49 (k)

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<figref>437</figref>

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Example 49 (l)

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<figref>438</figref>

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Example 49 (m)

<figref>439</figref>

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Example 49 (n)

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<figref>440</figref>

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Example 49 (o)

<figref>441</figref>

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Example 49 (p)

<figref>442</figref>

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Example 49 (q)

<figref>443</figref>

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Example 49 (r)

<figref>444</figref>

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Example 49 (s)

<figref>445</figref>

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Example 49 (t)

<figref>446</figref>

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Example 49 (u)

<figref>447</figref>

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Example 49 (v)

<figref>448</figref>

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Example 49 (w)

<figref>449</figref>

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Example 49 (x)

<figref>450</figref>

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Reference Example fifty

6- [3- (5-amino-2-fluorophenyl) carbamoyl-5-methyl-2-ethyl-2

H

-pyrazol-4-yl] -3-E- [2- (pyridin-2-yl) ethenyl] -1

H

-indazol

<figref>451</figref>

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The compound of Reference Example 50 is prepared from the starting material described below of similar to that described in Reference Example 11. MS (ESI +) [M + H] / z, calculated 482, found 482. Calculated: C, 67.35; H, 5.02; N, 20.36. Found: C, 66.70; H, 5.09; N, 19.95.

<figref>452</figref>

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The (2-fluoro-5-nitro-phenyl) -amide of the acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic it was prepared in a manner similar to that described in Example 47, step (i) except that acid was used 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic and HATU instead of benzoyl chloride. MS (ESI +) [M + H] / z, calculated 293, found 293.

<figref>453</figref>

The (2-fluoro-5-nitro-phenyl) -amide of the acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic it was prepared in a manner similar to that described in the Example of reference 40 (b), step (i). MS (ESI +) [M + H] / z, calculated 263, found 263.

<figref>454</figref>

6- [3- (5-Amino-2-fluorophenyl) carbamoyl-5-methyl-2-ethyl-2<i>H</i>-pyrazol-4-yl] -3-E- [2- (pyridin-2-yl) ethenyl] -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol It was prepared in a manner similar to that described in the Example 48 (a), step (iii) except that it was used (5-amino-2-fluoro-phenyl) -amide of the acid 2-ethyl-5-methyl-2<i>H</i>-pyrazol-3-carboxylic as starting material. MS (ESI +) [M + H] / z, calculated 612, Found 612.

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Reference Example 51

6-pyrid-4-yl-3-E- (

N

- (pyrrole-1-yl) iminomethyl) -1

H

-indazol

<figref>455</figref>

He 6-pyrid-4-yl-3-E- (<i>N</i>- (pyrrole-1-yl) iminomethyl) -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol became 6-pyrid-4-yl-3-E- (<i>N</i>- (pyrrole-1-yl) iminomethyl) -1<i>H</i>-indazol similar to that described in the Reference Example 29 (a). 1 H NMR (300 MHz, CDCl 3) δ: 8.76 (s, 1H), 8.67 (d, 2H, <i>J</i> = 6.1 Hz), 8.53 (d, 1H, <i>J</i> = 8.4 Hz), 7.74 (s, 1H), 7.61 (d, 2H, <i>J</i> = 6.2 Hz), 7.54 (d, 1H,<i>J</i> = 8.5 Hz), 7.27-7.25 (m, 2H), 6.31- 6.29 (m, 2H). MS (ES) [M + H] / z, calculated 288, found 288. Anal. Calculated, C (71.07), H (4.56), N (24.37). Found: C (70.81), H (4.57), N (24.14).

The starting material was prepared as follow:

<figref>456</figref>

A solution of 6-pyridin-4-yl-1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol-3-carbaldehyde (208 mg, 0.59 mmol), <i>N</i>-aminopyrrole (145 mg, 1.76 mmol) and acetic acid (5.8 ml) in ethanol (1 ml) was heated at 95 ° C for 16 h. The solution was then evaporated under reduced pressure and It was purified by silica gel column chromatography getting 6-pyrid-4-yl-3-E- (<i>N</i>- (pyrrole-1-yl) iminomethyl) -1- (2-trimethyl-silanyl-ethoxymethyl) -1<i>H</i>-indazol in the form of an oil (140 mg, 57%). 1 HRMN (300 MHz, CDCl 3) δ: 9.08 (s, 1H), 8.71 (d, 2H, <i>J</i> = 6.1 Hz), 8.46 (d, 1H, <i>J</i> = 8.5 Hz), 8.34 (s, 1H), 7.85 (d, 2H,<i>J</i> = 6.2 Hz), 7.80 (d, 1H, <i>J</i> = 8.5 Hz), 7.56 (t, 2H,<i>J</i> = 2.3 Hz), 6.25 (t, 2H, <i>J</i> = 2.3 Hz), 5.93 (s, 1 H), 5.74 (s, 2H), 3.64 (t, 2H, <i>J</i> = 7.9 Hz), 0.86 (t, 2H, <i>J</i>= 7.9 Hz), 0.00 (s, 9H).

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Reference Example 52 (a)

6- (7-azaindazol-4-yl) -3-E-styryl-1

H

-indazol

<figref>457</figref>

The sem compound of the Reference Example 52 (a) became the compound of Example 52 (a) in a manner similar to that described in Reference Example 27 (a). 1 HRMN (300 MHz, DMSO-<i>d</i>6) δ: 8.63 (d, 1H,<i>J</i> = 4.8 Hz), 8.41 (d, 1H, <i>J</i> = 8.5 Hz), 8.37 (s, 1H), 7.99 (s, 1H), 7.76 (d, 2H, <i>J</i> = 7.3 Hz), 7.70 (d, 1H,<i>J</i> = 8.5 Hz), 7.60-7.85 (m, 6H). HRMS (FAB) [M + H] / z, calculated 338.1400, found 338.1389. Analyzed with 1.1 trifluoroacetic acid: Calculated, C (60.21), H (3.51), N (15.13). Found: C (59.93), H (3.59), N (14.86).

The starting material was prepared as follow:

<figref>458</figref>

A solution of 3-styryl-1- (2-trimethyl-silanyl-ethoxymethyl) -6-trimethyltannil-1<i>H</i>-indazol (1.0 g, 1.90 mmol), 1- (4-iodo-pyrazolo [3,4-b] pyridin-1-yl) -ethanone (0.56 g, 1.90 mmol), AsPh 3 (116 mg, 0.38 mmol) and Pd 2 dba 3 (87 mg, 0.09 mmol) in degassed dioxane (10 ml) was heated at 110 ° C for 3 h. The solution was diluted to then with ethyl acetate (50 ml), washed with brine (2x10 ml), dried over MgSO4 and concentrated under pressure reduced Purification by gel column chromatography of silica gave Reference Example 52 (a) in the form of a white solid (412 mg, 46%). 1 HRMN (300 MHz, CDCl 3) δ: 8.82 (d, 1H, <i>J</i> = 5.8 Hz), 8.52 (s, 1H), 8.29 (d, 1 HOUR, <i>J</i> = 8.2 Hz), 8.05 (s, 1H), 7.73-7.32 (m, 10H), 5.86 (s, 2H), 3.69 (t, 2H, <i>J</i> = 8.2 Hz), 0.97 (t, 2H, <i>J</i> = 8.2 Hz), -0.03 (s, 9H).

<figref>459</figref>