WO2007099166A1 - Pyrazolo-pyridine derivatives active as kinase inhibitors - Google Patents

Abstract

A compound represented by Formula (I): wherein R and R1 are as defined in the specification, pharmaceutical formulas thereof, and methods of use thereof.

Description

PYRAZOLO-PYR1DINE DERIVATIVES ACTIVE AS KINASE INHIBITORS

BACKGROUMD OF THE INVENTION

Field of the Invention

The present invention relates to certain pyrazolo[4,3-c]pyridine compounds, to pharmaceutical compositions thereof, and to the use of these pyrazo!o[4,3-c] pyridine compounds in the treatment of certain diseases.

Discussion of the Background

The insulin-like growth factor 1 receptor (IGF-1 R, IGF1 R) is a member of the insulin receptor subfamily of RTKs. IGF-1R has a relatively ubiquitous pattern of tissue expression, and consists of two alpha chains, which are extracellular and contain ligand binding function, and two beta chains, which span the cell membrane and contain the intracellular kinase domains. The mature receptor consists of a disulphide-linked heterodimer of two pairs of alpha/beta subunits, resulting in an (alpha/beta)2 complex. IGF-1R is able to bind and be activated by the ligands insuirπ-like growth factor- f and -2 (IGF-1 and IGF-2). Insulin will also activate IGF- 1 R, but only at supraphysioiogical concentrations (i.e. in the range of circa 100 nanoM-1 microM),

IGF-I and JGF-2 are circulating growth factors which mediate many of the effects of Growth Hormone (GH)₁ and which therefore have important roles in foetat and post-natal growth and metabolism. IGF-1 R, like several other RTKs such as the EGF and PDGF receptor families, has potent mitogenic, anti-apoptotic and transforming activity in a wide range of cell types, Notably, it directly activates at least two major cell signaling pathways, the ras/MAPK pathway, through recruitment of SHC, and the PI-3 kinase/AKT (PKB) pathway, through recruitment and phosphorylation of the IRS adapter proteins

There exist several lines of evidence suggesting that IGF-1 R signaling can contribute to tumorigenesis, and that interfering with IGF-1 R function represents a valid therapeutic option in cancer. !GF-1 R signaling can promote tumorigenesis through multiple mechanisms. Aside from being mitogenic for most, if not all cells which express IGF-1 R it promotes cell survival and inhibits apoptosiε through activation of the PI-3K/AKT and ras/MAPK, as well as other signaling pathways, depending on cellular context.

Various experimental strategies have demonstrated that interference wfth IGF-I R function can result in anti-tumor effects in a wide range of tumor cell types Low moiecular weight, selective inhibitors of IGF-IR kinase activity have also been described and these agents inhibit the in vitro and in vivo growth of a wide range of human tumor cells Since 1GF-1R promotes cell proliferation, transformation, and protection from apoptosis in a wide range of cell types and in response to cooperation with diverse stimuli, it follows that inhibition of IGF-1 R function might potentiate the effects of chemotherapeutic agents having diverse mechanisms of action. A blockade of IGF-1 R function using the strategies described above, including selective K3F-1R kinase inhibitors, has been found to augment the in vitro, and/or in vivo activity of a wide range of agents including signal transduction inhibitors such as Gleevec, anti-EGFR and anti~HER2 blocking antibodies, cytotoxic agents such as adriamycin, doxorubicin, 5-FU, vinorelbine, and antihormonal therapy

Aside from cancer, IGF-1 R activity is also implicated in a wide range of pathophysiological processes in which inhibition of receptor activity could be expected to yield clinical benefit These include, but are not limited to, acromegaly, conditions involving persistent inflammation and/or cell proliferation such as psoriasis and fibrotic lung disease, and benign prostatic hyperplasia. Reduction of IGF-IR signaling has also been associated with increased longevity in several animal models, potentially due to increased tolerance of oxidative stress, such as that which occurs during hyperoxia, and related settings could also be therapeutically targeted by Inhibiting the receptor

IGF-1 R signaling provides angiogenic stimulus in many tissues, at least in part through stimulation of hypoxic responses, including upregulation of VEGF expression Accordingly, systemic blockade of IGF-1R using a monoclonal antibody has been found to be an effective treatment in an animal model of diabetic retinopathy, a condition involving inappropriate VEGF expression. Similarly, IGF-1 R function has aiso been strongly implicated in contributing to development of retinopathy of prematurity as well as in age-related macular degeneration. There is also evidence that IGF-1 contributes to vascular neσintimal formation, and to atherosclerotic processes

Thus, IGFs/!GF-1R play a significant role in tumorigenic processes in a wide range of human tumors, and inhibition of IGF-1 R function through approaches that include inhibitors of IGF-1 R kinase activity could be expected to yield therapeutic benefit, either alone or in combination with many agents. Such therapy could be extended to several other pathologies which involve inappropriate IGF-1 R activity. Accordingly, there is a need for new compounds that can inhibit IGF-1 R kinase activity. SUMMARY OF THE INVENTION

it has been found that the compounds of Formula (I)₁ described below, are inhibitors of the tyrosine kinase activity of the IGF-I R. The presence of a sulfonyl group linked to the nitrogen of the six-membered ring of the bicyclic pvrazoio[4,3-c]pyridine system is crucial for the activity of the compounds of the present invention as IGF-1 R tyrosine kinase inhibitors.

Accordingly, the present Invention provides a method for treating diseases caused by and/or associated with dysregufated activity of IGF-1R tyrosine kinase and/or other protein kinases, which comprises administering to a mammal in need thereof an effective amount of a pyrazolo[4,3-c]pyridine compound represented by Formula (I):

wherein:

R is an aryl or hetβroaryi, wherein the aryi or heteroary! groups can be unsubstituted or substituted by one to three substituents selected from the group consisting of aikyl, halogen, trifluoromethyi, hydroxy, hydroxyalkyl, alkoxy, alkylthio, cyano, formyf, alkylcarbonyl, alkyfsulphonyi, amino, monoaikylamino, dialkyiamlno, arylalkylamino, carboxy, carboxamido, monoalkylcarboxamido and diaSkyicarboxamido; and

R¹ is a heterocycloaikyf, wherein said herocycloalkyl can be substituted or unsubstituted by one or two substituents independently selected from the group consisting of alkyl, aryl, halogen, triffuoromethy!, hydroxy, hydroxyalkyl, alkoxy, aSkylthio, cyano, formyl, alkylcarbonyl, alkylsulfonyl, amino, monoalkyiamino, dialkylamino, arylalkylamino, carboxy, carboxamido, monoalkylcarboxamido, and diaikylcarboxamido; or a pharmaceutically acceptable salt or solvate thereof. Another aspect of the invention relates to a method of treating a disorder or condition in a mammal, wherein said disorder or condition is caused by or associated with dysregulated protein kinase activity, particularly IGF-1 R or Aurora kinase activity, and more particularly IGF- 1 R kinase activity , comprising administering to said mammal in need of said treatment the compound of Formula (I). Another aspect of the invention relates to a method of inhibiting tyrosine kinase activity of IGF-1 R₁ comprising administering to the IGF-1R an amount of the compound of Formula (I) that is effective in inhibiting tyrosine kinase activity of the IGF-1 R,

Another aspect of the invention relates to a method of treating a disorder or condition in a mammal, wherein inhibition of tyrosine kinase activity of the IGF-1 R is needed in said mammal, comprising administering to said mammal an amount of a compound of Formula 1 that is effective in inhibiting tyrosine kinase activity of the IGF-1 R ,

Another aspect of the invention relates to a method of treating a disorder or condition in a mammal for which inhibition of tyrosine kinase activity of the IGF-1 R is needed in said mammal, comprising administering to said mammal an amount of the compound of Formula (I) that Is effective in treating said disorder or condition

Another aspect of the invention relates to a method of treating a disorder or condition selected from the group consisting of cancer, cell proliferative disorders, virai infections, retinopathies, age related macular degeneration, atherosclerosis, conditions involving vascular smooth muscle proliferation or neointimal formation, restenosis following angioplasty or surgery, graft vessel disease, acromegaly, disorders secondary to acromegaly, hypertrophic conditions in which 1GF/IGF-1 R signaling is implicated, benign prostatic hyperplasia, psoriasis, pulmonary fibrosis, pathologies related to chronic or acute oxidative stress or hyperoxia-induced tissue damage, metabolic disorders in which elevated IGF levels or IGF-1 R activity are implicated, and obesity, in a mammal, comprising administering to said mammal in need of said treatment an amount of a compound of Formula (I) that is effective in treating said disorder or condition,

Another aspect of the invention relates to a method of treating a disorder or condition selected from the group consisting of cancer, celi proliferative disorders, viral infections, retinopathies, age related macular degeneration, atherosclerosis, conditions involving vascular smooth muscle proliferation or neointimal formation, restenosis following angioplasty or surgery, graft vessel disease, acromegaly, disorders secondary to acromegaly, hypertrophic conditions in which IGF/IGF-1 R signaling is implicated, benign prostatic hyperplasia, psoriasis, pulmonary fibrosis, pathologies related to chronic or acute oxidative stress or hyperoxia-induced tissue damage, metabolic disorders in which elevated IGF levels or IGF-1 R activity are implicated, and obesity, in a mammal, comprising administering to said mammal in need of said treatment an amount of a compound of Formula (I) that is effective in inhibiting tyrosine kinase activity of IGF- 1 R.

In another embodiment, the cancer in the above methods is selected from the group consisting of carcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer, and Kaposi's sarcoma.

In another embodiment, the proliferative disorder in the above methods is selected from the group consisting of familial adenomatosis polyposis, neuro-fϊbromatosis, arthritis and glomerulonephritis

Another aspect of the invention relates to a pharmaceutical composition comprising an amount of the compound according to Formula (1), or a pharmaceutically acceptable salt or solvate threreof, and a pharmaceutically acceptable carrier.

Another aspect of the invention relates to a method of treating diseases mediated by dysregulated protein kinase activity, which includes receptor tyrosine kinases (rtks), nonreceptor protein tyrosine kinases (ctks) and serine/threonine protein kinases (stks), in a mammal, which method comprises administering to said mammal in need of said treatment a pharmaceutical composition comprising a compound of formula (i) in combination with one or more chemotherapeutic agents or radiotherapy. Such chemotherapeutic agents can include, but are not limited to, antihormoπa! agents such as antiestrogens, antiandrogens and aromatase inhibitors, topoisomerase i inhibitors, topoisomerase H inhibitors, agents that target microtubules, platin-based agents, alkylating agents, dπa damaging or intercalating agents, antineoplastic antimetabolites, other kinase inhibitors, other anti-angiogenic agents, inhibitors of kinesins, therapeutic monoclonal antibodies, inhibitors of mtor, histone deacetylase inhibitors, farnesyl transferase inhibitors, and inhibitors of hypoxic response

BRIEF DESCRIPTION OF THE FIGURES

FIGURE 1 : Figure 1 represents SEQ ID NO: 3, which is a fusion protein which consists essentially of an N-termiπa! GST/linker peptide moiety (amino acids 1-231 of SEQ ID NO: 3) and a C-termlnaS moiety representing the human IGF-1R Intracellular domain (amino acids 232-639 Of SEQ ID NO: 3).

FIGURE 2: Figure 2 shows the inhibition of IGF1 R auto-phosphoryfation in MCF-7 starved cells stimulated with 10 nM IGF1 by compounds of formula (I), exemplified by compound of example 24. Treatment of starved MCF-7 cells with 10 nM IGF1 induced receptor auto-phosphorylatioπ as shown by the appearance of a more intense band of phosphorylated IGF1R (plGFI R), Incubation of cells with increasing concentrations of compounds described in examples 24 prior to treatment with IGF1 resulted in inhibition of IGF1-induced IGF1 R auto- phosphorylation as shown by the decrease in intensity of the band of phosphorylated IGF1 R (pIGFI R). DETAILED DESCRIPTION OF THE INVENTION

The present invention also provides pyrazolo[4,3-c]pyrldlne derivatives of Formula (I):

wherein:

R is an aryl or heteroaryl, wherein the aryl or heteroary! groups can be unsubstituted or substituted by one to three substituents selected from the group consisting of alky!, halogen, triftuorom ethyl, hydroxy, hydroxyalkyl, alkoxy, alkyUhio, cyano, formyi, alkylcarbonyS, alkylsulphonyl, amino, monoalkyiamino, dialkylamino, arylalkytamino, carboxy, carboxamido, monoalkylcarboxamido and dialkylcarboxamido; and

R¹ is a heterocycloalkyl, wherein said herocycloaikyi can be substituted or unsubstituted by one or two substituents independently selected from the group consisting of alkyl, aryl, halogen, trifTuorαmethyl, hydroxy, hydroxyalkyl, alkoxy, alkylthio, cyano, formyi, alkylcarbonyl, alkyisutfonyi, amino, monoaikylamino, dialkylamino, arylalkylamino, carboxy, carboxamido, monoalkyicarboxamido, and dialkylcarboxamido; or a pharmaceutically acceptable salt or solvate thereof.

The pyrazolo[4,3-c]pyridine derivatives of Formula (I) can be prepared through a synthetic process consisting of standard synthetic transformations, which are comprised within the scope of the invention, and reported for instance in Smith, Michael - March's Advanced Organic Chemistry: reactions mechanisms and structure - δ"" Edition, Michael B Smith and Jerry March, John Wiley & Sons Inc., New York (NY)₁ 2001), which is incorporated herein as reference, It is known to the skilled person that transformation of a chemical function into another can require that one or more reactive centers in the compound containing this function be protected in order to avoid undesired side reactions . Protection of such reactive centers, and subsequent deprotection at the end of the synthetic transformations, can be accomplished following standard procedures described in: Green, Theodora W and Wuts, Peter GM- - Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons Inc., New York (NY), 1999, which is incorporated herein as reference. Analogues of compounds of Formula (I) have been described in the PCT International application WO 2002/012242 which is incorporated herein by reference

The present invention also provides a pharmaceutical composition comprising one or more compounds of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, carrier or diluent.

The compounds of Formula (I) can have one or more asymmetric centres, and can therefore exist as individual optica! isomers or racemic mixtures. Accordingly, all the possible isomers and their mixtures of the compounds of Formula (I) are within the scope of the present invention.

Derivatives of compounds of Formula (I) originating from metabolism In a mammal, and the pharmaceutically acceptable bio-precursors (otherwise referred to as pro-drugs) of the compounds of Formula (I) are also within the scope of the present Invention.

In addition to the above, as known to those skilled in the art, the unsubstltuted pyrazole ring of the compounds of Formula (I) rapidly equilibrates in solution to form mixtures of tautomers, as depicted below:

Accordingly, in the present invention, where only one tautomer is indicated for the compounds of Formula (I), the other tautomer (Ia) is also within the scope of the present invention, unless otherwise indicated.

Except where stated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms Hence the definition of "alkyl" applies to "alkyT as well as to the "alky!" portions of "aikylamiπo", "dialkylamino" etc, "Mammal" means humans and other animals.

"Treating" refers to, and Includes, reversing, alleviating, inhibiting the progress of, or preventing, a disease, disorder or condition, or one or more symptoms thereof; and, "treatment" and "therapeutically" refer to the act of treating, as defined above The term "effective amount" means an amount of compound of the present invention that is capabie of treating a specific disease or antagonizing a specific enzyme, such as a specific protein kinase. The particular dose of compound administered according to the invention will be determined by the particular circumstances surrounding the case including, for example, the compound administered, the route of administration, the state of being of the subject, and the severity of the pathological condition being treated

The term "aryi" refers to a mono-, bi- or poly-carbocylic hydrocarbon with from 1 to 4 ring systems, either fused or linked to each other by single bonds, wherein at least one of the carbocylic rings is aromatic. Not iϊmiting examples of ary! groups include phenyl, indanyl, biphenyl, α- or β-naphthyi, fluoreπyl, 9, 1 O-dihydroanthracenyi, and the like.

The term "heteroaryl" refers to a mono-, bi- or poiy-heterocyclic hydrocarbon with from 1 to 4 ring systems, either fused or linked to each other by single bonds, wherein at least one of the heterocyclic rings is aromatic Not limiting examples of heteroaryl groups include pyrroly!, furoyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazoiyf, thiazolyl, isolhiazolyl, indoiyl, benzofuranyl, benzothiophenyf, benzimldazolyl, benzopyrazoiyl, benzoxazolyl, benzoisoxazoly!, benzothiazolyi, benzoisothiazoiyi, triazoSyl, oxadiazolyl, tetrazoiyl, pyridyl, pyrazinyi, pyrimidinyl, pyridazinyl, quinolinyi, isoquinoliny!, quinazolinyi, quinoxaϋnyi, and the llke.The terms "ary!" and "heteroaryl" can aiso refer to aromatic carbocyclic or heterocyclic rings, respectively, further fused or linked to non-aromatic heterocyclic rings, typically 5- to 7-membered heterocycles. Not limiting examples of such aryl and heteroaryl groups are, for instance, 2,3-dihydrαindolyl, 2,3- dihydrobenzofuranyl, 2,3-dihydrobenzothiophenyJ; benzopyranyl, 2,3-dihydrobθnzoxazinyl, 2,3- dihydroquinoxalinyl, and the like. The aryl or heteroaryl groups can be unsubstituted or substituted by one to three, preferably one or two, substttuents selected from the group consisting of (Cr-C^alkyi, halogen, trifiuoromethyl, hydroxy, hydroxyalkyl, alkoxy, alkylthio, cyano, formyt, alkyfcarbonyf, alkytsuiphonyl, amino, monoaJkyfamino, dialkyiamino, aryjaikylamino, carboxy, carboxamido, monoalkylcarboxamtdo and dialkylcarboxamido.

The term "heterocycloalkyi" refers to a 3- to 7-membered, saturated or partially unsaturated carbocyclic ring where one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur Not limiting examples of heterocycloalkyi groups are, for instance, oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyi, dihydrofuranyi, tetrahydrothiophenyi, dihydrothiophenyl, pyrrolidtnyl, dihydropyrrolyl, pyranyl, dihydropyranyl, telrahydropyranyl, tetrahydrothtopyranyl, plperidlnyi, pyrazolinyl, isoxazolidiπyS, isoxazolinyl, thiazolidinyl, thiazoϋnyl, isothiazolinyl, dioxanyt, piperazinyl, morpholiny!, thiomorpholinyl, examethyleneiminyl, homopjperazinyl and the like, A heterocycloalkyi group can be substituted or unsubstituted. When substituted, the substituent groups are preferably one or two substituents, independently selected from the group consisting of (CpC^alkyl, aryl, halogen, trifluoromethyl, hydroxy, hydroxyalkyi, alkoxy, alkylthio, cyano, formyl, alkylcarbonyl, alkylsulfonyl, amino, monoalkylamino, dialkyiamino, arylalkyiamino, carboxy, carboxamido, monoalkylcarboxamido and dialkylcarboxamido. The term "(C-rCjJalkyi" indicates a saturated aliphatic hydrocarbon radical, Including straight chain and branched chain groups of from 1 to 4 carbon atoms, e g methyl, ethyl, propyl, 2-propyi, n-butyl, iso-butyl, and tert-butyl The (CrCjJalkyi group can be substituted or unsubstituted When substituted, the substituent group is selected from the group consisting of halogen, trifluoromethyi, hydroxy, alkoxy, alkylthio, cyano, formyi, alkylcarbonyl, alkylsuifonyl, amino, monoalkylamino, dialkyiamino, carboxy, carboxamido, monoalkylcarboxamido and diatkylcarboxamido

The term "halogen" indicates fluorine, chlorine, bromine or iodine

The term "trifluoromethyl" indicates a -CF₃ group

The term "hydroxy" indicates an -OH group. The term "hydroxyaikyl" indicates a hydroxy group linked to an alkyl group. Examples of hydroxyalkyl groups are hydroxymethyi (-CH₂OH), hydroxyethyl (-CH₂CH₂OH) and the like

The term "alkoxy" indicates a residue where an alkyl group substitutes the hydrogen of the hydroxy Examples of alkoxy groups are methoxy (-OCH₃), ethoxy (-OCH₂CH₃), isopropyloxy [-OCH(CH₃)J₁ and the like The term "alkylthio" indicates an alky! group linked to a sulphur atom (-S-alkyl)

Examples of alkythio groups are methylthto (-SCH₃), ethylthio (-SCH₂CH₃), isopropylthio [-SCH(CH₃)J, and the like

The term "cyano" indicates a -CN residue

The term "formyl" indicates a -CHO residue The term "alkyicarbonyT indicates an alkyl residue linked to a CO group [-C(=O)aikyI],

Examples of alkylcarbonyl are methylcarbonyl [-C(=0)CH₃], ethylcarbonyl [-Cf=O)CH₂CH₃], and the like.

The term "alkylsulfonyl" indicates a -S0₂alkyl group Examples of alkylsulfonyl groups are methylsulfonyl (-SO₂CH₃), ethylsuifonyl (-SO₂CH₂CH₃), and the like The term "amino" indicates an -NH₂ group

The terms "monoalkylamino" or "dialkyiamino" indicate an amino group where one or both hydrogens are substituted by an alkyl group. Examples of monoaSkylamino are methylamino (-NHCH₃), ethylamino (-NHCH₂CH₃) and the like Examples of dialkyiamino are dimethylamino [-N(CH₃J₂], diethylamino [-N(CH₂CH₃J₂], and the like. The term "arylaikylamiπo" indicates an aryl group linked to an amino function through an alky] group. Examples or arylalkylamino are benzyiamino (-NHCHjjPhenyi), phenethylamino (-NHCHaCHaPhenyi), and the like

The term "carboxy" indicates a -COOH group. The term "carboxamido" indicates a -CONH₂ group.

The terms "monoalkylcarboxamldo" or "dialkylcarboxamido" indicate a carboxamido group where one or both hydrogens are substituted by an alkyi group. Examples of monoalkylcarboxamido are methyicarboxamido (-COHHCH₃), ethylcarboxamido (-CONHCH₂CH₃), and the like. Examples of dialkylcarboxamido are dtmethylcarboxamido [-CON(CH₃)z], diethylcarboxamido [-CON(CH₂CHa)₂], and the like,

The term "pharmaceutically acceptable salt" of compounds of Formula (!) refers to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include: acid addition salt with inorganic acids such as hydrochloric, hydrobromic, nitric, phosphoric, sulfuric, and perchloric acid and the like, or with organic acids such as acetic, trifluoroacetic, propionic, giycolic, lactic, (D) or (L) malic, maleic, methanesulfonic, ethanesulfonic, benzoic, p-toluenesulfonic, salicylic, cinnamtc, maπdeiic, tartaric, citric, succinic or malonic acid and the like; salts formed when an acidic proton present in a compound of Formula (I) is either replaced by a meta! ion, e.g., an alkali metal ion such as sodium or potassium, or an alkaline earth ion such as calcium or magnesium, or coordinates with an organic base such as ethanoiamiπe, diethanolamine, triethanolamine, tromethamine, N-melhylglucamine, and the like

Prodrugs and solvates of the compounds of the invention are also contemplated herein.

The term "prodrug", as employed herein, denotes a compound that is a drug precursor, which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula (1) or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V, Stella, Pro-drugs as Novel Delivery Systems (1987)

Volume 14 of the A-CS, Symposium Series, and in Bioreversible Carriers in Drug Design,

(1987) Edward B Roche, ed,., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.

"Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates, Noπ- limiting examples of suitable solvates include ethanolates, melhanolates, and the like, "Hydrate" is a solvate wherein the solvent molecule is H₂O.

Preferred compounds of the invention are the compounds of Formula (I) wherein R is aryl and R¹ is six-membered heterocycloalky!. Further preferred compounds of the invention are the compounds of Formula (I) wherein:

R is selected from phenyl, a 2-substituted-phenyl, a 3-substituted-phβnyi, a 2,6- disubstituted-phenyl and a 3,5-disubstituted-pheny! and

R¹ is selected from morphoiine and a substituted-piperazine. Most preferred compounds of the invention are the compounds of Formula (I) wherein:

R is selected from the group consisting of a 3-substituted-phenyl and a 3,5- disubstituted-phenyl; and

R¹ is a substituted-piperazine.

Specific, not limiting, examples of compounds of the invention, whenever appropriate in the form of pharmaceutically acceptable salts, are the following:

N-tS-benzenesulfonyl^.S.βJ-tetrahydro-I H-pyrazolo^.S-cJpyridin-S-yO^-fA-methyl-piperazJn-i- yl)-benzamide;

N-(5-benzenesulfonyl-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridin-3-yt)-4-morpholin-4-yl- beπzamide;

N-[5-{3"fiuoro-benzenesuifonyl)-4,5,6,7-tetrahydro-1H-pyrazo!o[4,3-c]pyrldin~3-yl3-4-(4-methyi- piperazi n-1 -yl )-benzam id e;

N-[5-(3-ch!oro-ben.:enesulfonyS)-4,5,6_p7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]~4-(4"methyl- piperazin-1 -yl)-benzam ide;

4-{3,4-dimethy!-piperazin-1-yl)-N-[5-{3-fluoro-benzenesu!fonyi)-4,5,6,7-tetrahydro-1 H- pyrazolo[4₍3-c]pyridin-3-yl]-benzamide;

N-t5-(3-hydroxy-benzenesulfonyl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3'C]ρyridin-3-yl]-4-(4-methyl« piperazin-1 -yi)-benzamide; N-IS-Ca.S-difiuoro-benzenesiJifonyO^.S.e.T-tetrahydro-I H-pyrazoio^.S-clpyridin-S-yll-^f^ methyt-piperaan-1-yl)-benzamide;

N-[5-(2,5-dif]uoro-benzenesiJlfonyI)-4_p5,6,74etrahydro-1 H-pyrazolo[4,3-c]pyridin-3-yl]-4-(4- methyl-piperazin-1 -yl}-benzamlde;

N-[5-{2-fluoro-benzenesiJlfony])-4_>5,6,7_"tetrahydro-1 H-pyrazo!o[4,3-c]pyridiπ~3-yl]-4-(4-methyi- piperazin-1 -yl )-benzam ide;

N-[5-(4-fluorobenzenesϋlfonyl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridln-3-yi]-4-(4-methy]- piperazin-1-yl)-benzaroide;

N-[5-(4-ch!oro-benzenesulfonylH_» ⁵.6.7^r-tetrahydro-1 H-pyrazoio[4,3-c]pyridin-3-yl]-4-{4-methyl- pipβrazin-1-yl)-benzamide;

N-[5»{3'methoxy-benzenesulfonyl}-4,5,6,7-tetrahydro-1H-pyraEolo[4,3-c]pyridin-3-yl]~4-(4-methyl- piperazin-1 -yi)-benzamtde;

N.[5-(4_rneUioxy-benzenesuifonyl)-4,5,6,7-tetrahydro-1H-pyrazo!o[4_I3-c]pyridin-3-yl]-4-(4'methyl- piperazin-1 -yl)-benzamide;

4-{4-methyl-piperazin-1-yl)-N-[5-(2-trifluoromethy!-beπzenesulfony))-4,5_l6,7-tetrahydr{>'1 H- pyrazoto[4,3-c]pyridin-3-yf]-benzamide;

4-(4-methyl-piperazin-1-yl)-N-[5-(3-trffluoromethyl-benzenesulfonyl)-4_l5,6,7"tetrahydro-1 H- pyrazol o[4 , 3-c]pyridin-3-yl]-benzam ide;

4-{4-methy!-piperazin-1-yi}-N-[5-{4-trifluoromethyi-benzenesuifonyl)~4,5,6,7-tetrahydro-1 H- pyrazo!o[4,3-c]pyridin-3-yI]-benzamide;

4-(4-rnethyl-piperaziπ-1 -yl)-N-[5-(toluenfr-3-su!fony!)-4,5,6,7-tetrahydro-1 H-pyrazoloE4,3-c]pyridin-

3-yl]-benzamlde;

4-(4-mβthyl_"piperazin-1-yl)-N-[5-(toluerie-4-sulfonyi)-4,5,6,7-tetrahydro-1 H-pyrazolo[4_l3-c]pyridiπ- 3-yi]-benzamide; N-[5-(2»cyanobenzenesulfoπyl}-4₍5,6,7-tetrahydro-1H-pyrazoloi;4,3-c]pyridin-3-ylH-{4-methyl- ρiρeraziπ-1 -yl )-benzam ide;

N-[5-(2,5--dif!uoro-bβnzβnθsulfonyl)-4_>5_l6_l7-tebⁱahyc!ro-1H-pyrazolo[4_l3-c]pyrldlπ-3-yl]~4-(4- methyl-piperazin-1 -y!)-benzamide;

N-[5-(2,6'difluoro-benzenesulfony))-4,5,6,7-tetrahydro-1 H-pyrazoloE4,3-c]pyridin-3-yl3-4-(4- methyl-piperazin-1 -yl)-bβπzamidθ;

N-[5-(3,4-dif!uoro-benzeπesulfony!)-4,5,6,7-tetrahydro-1 H-ρyrazolot4,3-c]pyridin-3-yl]-4-(4" methyl-piperazin-1 -yl)-benzamide;

4-(4-methyl-piperazin-1~yS)-N-t5-(thlophene-2-sulfonyi)-4_I5,6,7-tetrahydro-1H-pyrazoIo[4_>3- c]pyridin-3-yl]-benzamide;

N-[5-(1 ,2-dimethyM H-imidazole-4-sulfonyf)-4,5,6,7~tθtrahydro-1 H-pyrazo!o[4,3-c]pyridin-3-yt]-4- (4-mβthyl-piperazin-1-yl)-beπzamide; and

4-(4-methyl-piperaziπ-1-y!}-N-[5-(quinoline-8-suifonyl)-4,5,6,7-tetrahydro-1 H-pyrazolof4,3- cJpyrid!n-3-yt]»bBπzamide,

The process for preparing the compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof, comprises: a) reacting a compound of Formula (II) with a compound of Formula (III)

wherein R¹ is as defined above, Q is a lower alkyl group, for instance a (Ci-C₄)alkyl group, more preferably methyl or ethyl, tbu represents tert-buiyl and Z Is hydroxy, halogen or a suitable leaving group, so as to obtain a compound of Formula (IV)

b) reacting the compound of Formula (IV)₁ wherein R¹ and Q are as defined above, under acidic conditions so as to obtain a compound of Formula (V)

c) reacting the compound of Formula (V), wherein R¹ and Q are as defined above, with a compound of Formula (Vl)

wherein R and Z are as defined above, so as to obtain a compound of Formula (VII)

d) reacting a compound of Formula (VII), wherein R¹, R and Q are as defined above, under basic conditions so as to obtain the corresponding compound of Formula (I), which can be further separated Into the single isomers when It contains one or more asymmetric centers, or can be converted into a pharmaceutically acceptable salt or solvate. it is to be noted that a compound of formula (II), (!V), (V) and (VII) as above defined can be in any one of its isomeric forms a or b:

The following procedures provide examples, without limiting them, of preparations of the compounds of the present invention

According to step a) of the process, the reaction between a compound of Formula (II) and a compound of Formula (III) can be carried out in a variety of ways according to conventional methods for acyiating amino derivatives. As an example, a compound of Formula (II) can be reacted with an acyl chloride of Formula (ItI), in which case Z represents a chlorine atom

Preferably, this reaction is carried out at a temperature ranging from about room temperature to about reflux temperature, in a suitable solvent such as, for instance, tetrahydrofuran, dichlorom ethane, toluene, 1,4-dioxane, or acetonitrile and in the presence of a proton scavenger such as, for example, frlethylamine, pyridine, N,N-dissopropylethylamine, for a period of time ranging from about 30 min. to about 96 hours.

According to step b) of the process, a compound of Formula (IV) is easily deprotected at the tetrahydropyridine nitrogen atom by acidic treatment. This reaction can be conveniently carried out in the presence of an inorganic or organic acid such as, for instance, hydrochloric, trifluoroacetic or methanesuSfonic acid, in a suitable solvent such as dichloromethane, 1 ,4- dioxane, or a lower alcohol (e.g. methanol or ethanol), The reaction can be carried out at a temperature ranging from about room temperature to about 40°C, and for a period of time ranging from about 1 hour to about 48 hours, The compound of Formula (V) thus obtained is further reacted, according to slep c) of the process, with a compound of Formula (Vl), From the above it is clear to the skilled artisan that this sulfonylation reaction can be accomplished in a variety of ways and experimental conditions which are known in the art for the preparation of sulfonamides. As an example, the reaction between a compound of Formula (V) and a sulfonyl chloride of Formula (Vl), in which case Z is a chlorine atom, can be carried out in a suitable solvent such as, for instance, diethyl ether, tetrahydrofuran, dichloromethane, chloroform, toluene, 1 ,4-dioxane, or acetonitrile, in the presence of a proton scavenger such as triethylamine, pyridine, or N,N-dilsopropyIethylamine. The reacton can be carried out at a temperature ranging from about -10°C to about reflux temperature, and for a period of time ranging, for instance, from about 30 min, to about 96 hours.

Finally, according to step d) of the process, a compound of Formula (VII) is transformed into a compound of Formula (i) by deprotection of the pyrazoie nitrogen atom by conventional methods known to one skilled In the art, for instance, the selective hydrolysis of a carbamate group. As an example, this reaction can be carried out under basic conditions, for instance in the presence of sodium hydroxide or potassium hydroxide or lithium hydroxide, or of a tertiary amine such as triethylamine, and in a suitable solvent such as N,N-dimethylformarnide, methanol, ethanol, tetrahydrofuran, water and mixtures thereof Typically, the reaction is carried out at a temperature ranging from room temperature to about 60⁰C and for a period of time varying from about 30 minutes to about 96 hours. In cases where a compound of Formula (!) contains one or more asymmetric centers, this compound can be separated into the single isomers by procedures known to those skilled in the art, Such procedures comprise standard chromatographic techniques, including chromatography using a chiral stationary phase, or crystallization. General methods for separation of compounds containing one or more asymmetric centers are reported, for instance, in Jacques, Jean; Collet, Andre; Wilen, Samuel H,, - Enantiorners, Racemates, and Resolutions, John Wiley & Sons Inc., New York (NY), 1981, which is incorporated herein as reference,

A compound of Formula (I) can also be transformed into a pharmaceutically acceptable sail according to standard procedures that are known to those skilled in the art. Alternatively, a compound of Formula (I) that is obtained as a salt can be transformed Into the free base or the free acid according to standard procedures that are known to the skilled artisan.

The starting materials of the process of the present invention are either known or easily prepared according to known methods

As an example, the preparation of a compound of Formula (Ii), wherein Q represents ethyj, is disclosed In the aforementioned International applications WO 2002/12242 and WO

2004/080457 which are both incorporated by reference in its entirety (see, in particular, example

18 at page 48; this same compound is therein named as 3-aminα-5-tert-butyioxycarbonyl-1- ethoxycarbonyl-pyrazolo[4,3-e]4,5,6,7-tetrahydropyridine), Additional compounds of Formula (II), wherein Q represents a lower alkyl group other than ethyl, can be prepared by applying procedures similar to those disclosed in the above mentioned patent applications.

The compounds of Formula (ill), wherein Z represents a halogen atom, e g. a chlorine atom, are either known or can be obtained from the corresponding carboxylic acids, that are either known or can be prepared by working according to conventional methods The compounds of Formula (Vl)₁ for instance those wherein Z represents a halogen atom, e.g a chlorine atom, are either known or can be prepared from sulfonic acids according to conventional methods.

Assays

Compounds of the present invention were tested in biochemical as weSI as in cell-based assays, as described below.

The short forms and abbreviations used have the following mening:

Ci Curie

DMSO dirnethylsuifoxlde

ID identity

KDa kiloDaltoπ microCi microCurie mg milligram microg microgram mL milliliter microL microliter M molar mM millimolar microM micromoSar nM nanomolar

Preparation of IGF-1R for use in biochemical assay

Cloning and expression

Human cDNA was used as template for amplification by polymerase chain reaction (PCR) of the whole cytoplasmic portion of IGF-1R (amino acid residues 960-1367), which includes the entire kinase domain. PCR was conducted using the forward primer sequence 5'- CTCGGATCCAGAMGAGAAATAACAGCAGGCTG-3' (SEQ ID NO; 1) and the reverse primer sequence 5'-CTCGGATCCTCAGCAGGTCGAAGACTGGGGCAGCGG-3' (SEQ ID NO: 2). In order to facilitate subsequent cloning steps, both primers comprise a BamHI restriction endonuclease site sequence. The PCR product was cloned into a transfer vector for the baculovirus expression system, pVL1393 (Pharmingen), modified to include the sequence encoding the Glutathione S-transferase (GST) fusion protein and a PreScission cleavage site upstream of the inserted gene of interest The GST-1GF-1 R coding region corresponds to nucleic acid residues of 4168-6084. The final protein encoded by the open reading frame corresponds to a fusion protein of 639 amino acids, shown in Sequence ID 3 (Figure 1 ). This fusion protein consists essentially of an N-terminal GST/linker peptide moiety (amino acids 1- 231 of SEQ ID NO: 3) and a C-termina! moiety representing the human IGF-1 R intracellular domain (amino acids 232-639 of SEQ ID NO: 3) The fusion protein has a predicted molecular weight of 72 8 kDa, In order to obtain fusion protein, Sf21 insect cells (Invitrogen) were cotransfected with 2 micrag of purified piasmid and 1 microg of virus DNA (BacufoGoldTM Transfection Kit, Pharmingen), as described in the Baculovirus instruction manual (Pharmingen) A first amplification of the virus was performed using 600 microL of cotransfected virus on 6 x 10⁶ Sf21 in a monolayer culture, in 12 mL of medium (TNM-FH Grace's medium - Pharmingen), After 3 days the medium was collected, centrifuged and transferred to a sterile tube A second amplification was prepared with the same method using 2 mL on 3 x 10⁷ cells, diluted in 40 mL of medium For the third amplification of virus, 1 mL of supernatant from the second round were used per 3 x 10⁷ cells diluted in 40 mL of medium.

Protein expression was performed in H5 insect cells Infected with 14 mL virus / 1 x 10^β insect cells (MOI = 1 5) for 65 h with shaking at 27⁰C Cells were harvested by centrifugation at 1200xg for 10 minutes.

Protein purification

Cells were resuspended in phosphate buffered saline solution (PBS), 20 mM dithiothrβitol (DTT), CHAPS 0.2%, 20% glycerol, 1 mM OVA, "Complete" protease inhibitor cocktail (1 tablet/ 50 mL buffer; Roche Diagnostics, Milan, Italy) and lysed by liquid extrusion with a Gaullπ homogeπizer (Niro Soavi, Italy), The lysate was centrifuged at 14000xg for 45 minutes and the supernatant was loaded onto a column containing 10 mL Glutathione Sepharosβ (Amersham Biosciences). The column was first washed with PBS buffer for 5 cotumn volumes, then with 100 mM Tris pH 8,0, 20% glycerol for 5 coSumn volumes, and lastly eluted with 10 mM glutathione in 100 mM Tris pH 8.0, 20% glycerol. Fractions of 10 mL were collected, and protein-rich fractions were pooled- Typically, 20 mg of fusion protein were recovered from 1 x 10⁹ cells, and this was typically >85% pure as judged by SDS-PAGE followed by Coomassie staining. Purified protein was stored at -80⁰C prior to its use In biochemical assays

inhibition assay for IGF-1 R kinase activity

The inhibitory activity of putative kinase inhibitors and the potency of selected compounds was determined using a Scintillation Proximity Assay (SPA) in 96 well microtiter plate format The assay is based on the ability of strepiavidin-coated SPA beads to capture a biotinySated peptide containing a site that can be phosphorylated by IGF-1 R kinase. When a radioactively labeled phosphate moiety is transferred by the kinase to the biotiπylated peptide, this stimulates light emission by the bead, which is measured in a scintillation counter.

The buffers/components used in the assay were as follows. Kinase Buffer (buffer KB) was composed of 50 mM HEPES, 3 mM MnCI₂, 1 mM DTT, 3 microM Na₃VO₄, pH 7.9. Enzyme Buffer (buffer EB) was composed of buffer KB containing 0.6 mg/mL BSA (bovine serum albumin). SPA scintillation beads (Product Code Number RPNQ0007, Amersham Biosciences, Piscataway, NJ USA) were prepared as a 10 mg/mL suspension in PBS containing 32 mM EDTA, 500 microM unlabeled ATP₁ and 0.1% Triton X-100 This preparation is referred to below as "SPA bead suspension". On the day of assay, IGF-1 R was pre-phosphorylated in order to linearize reaction kinetics. To achieve this, the desired quantity of enzyme was incubated for 30 min at 28⁰C at a concentration of 1050 nM enzyme in buffer EB containing 100 microM unlabeled ATP, After preincubation, and immediately before assay, this pre-phosphorylated IGF- 1 R kinase preparation was diluted to an enzyme concentration of 60 nM by addition of 16.5 volumes of buffer KB. This diluted prephosphorytated enzyme is referred to below as "enzyme mix".

The substrate used in the assay was a carboxy-terminally biotinylated peptide of the following sequence: KKKSPGEYVNiEFGGGGGK-biotin (SEQ ID NO: 4). The peptide was obtained in batches of >95% peptide purity from American Peptide Company, lnc (Sunnyvale, CA, USA). "ATP Mix", referred to below, consisted of buffer KB containing 6 nM ³³Py-ATP (gamma phosphate-labeled, Redivue™ Code Number AH9968, 1000-3000Ci/mmole, Amβrsham Biosciences Piscataway, NJ USA), 18 microM unlabeled ATP, and 30 microM biαtiπylated substrate peptide. This solution contained these components at 3X their final reaction concentration. Compounds to be tested were prepared in 100% DMSO at appropriate concentrations. These preparations were then diluted 33-fo!d using buffer KB, so as to obtain compound at 3X the desired final assay concentration in buffer KB containing 3% DMSO. This 3X preparation is referred to below as "compound working solution"

Kinase reaction: Reactions were performed in 96-well U-bottom microliter plates {such as Product #650101, Greiner Bio-One, Kremsmuenster Austria) in a final reaction volume of 30 microL. To each test well were added 10 microL of "compound working solution" containing appropriate dilution of compound, followed by 10 microL "ATP Mix" and 10 microL "Enzyme Mix", thus starting the reaction. Well contents were immediately mixed by pipetting, and reactions were incubated for 60 minutes at room temperature. After incubation, reactions were stopped by adding 100 microL/well "SPA bead suspension". Wells were incubated a further 15 minutes at room temperature, then 110 microL were withdrawn from each well and transferred to separate wells of 96-well opaque scintillation counting plates (such as OptiPlate™-96, PerkinElmer LAS, Inc. Boston, MA, USA), each containing 100 microL/well 5M CsCI. After 4 hours resting at room temperature to allow SPA bead floatation, these plates were read using a scintillation counter (Packard TopCount NXT, PerkinEimer LAS, !nc Boston, MA, USA) in order to quantitate the light emitted from each well (proportional to the amount of phosphate incorporated into the substrate peptide during kinase reaction).

Many of the steps described above, such as those involving compound dilution, addition of mixes to the reaction, and transfer of completed reaction to counting plates can be automated using robotized pipetting stations (such as Multimek and Biomek Efquid handlers, Beckman Coulter Inα, Fuilerton CA USA), and a dilution curve of a known kinase inhibitor such as staurosporine can be routinely included as a positive control for IGF-1 R inhibition.

Results: data were analyzed using the "Assay Explorer" software package (Elsevier MDL, San Leaπdro, CA 94577) . For single compound concentrations, inhibitory activity wss typically expressed as % inhibition obtained in presence of compound, compared to total activity of enzyme obtained when inhibitor is omitted . Compounds showing desired inhibition can be further analyzed in order to study the potency of the inhibitor through IC₅₀ calculation. In this case, inhibition data obtained using serial dilutions of the inhibitor can be fitted by nonlinear regression using the following equation:

1 + 10 _Λ(log/C_J()-logl/J) where V_b is the baseline velocity, v is the observed reaction velocity, V₀ is the velocity in the absence of inhibitors, and [i] is the inhibitor concentration

Inhibition assay for aurora-2 kinase activity The inhibiting activity and the potency of selected compounds was determined through a method of assay based on the use of the streptavidin scintillation proximity assay beads (Amersham -Pharmacia biotech) run in a 96 wefl plates. At the end of the reaction, the biotinyiated peptide substrate was captured with the beads and subsequently allowed to stratify using CsCI, When a radioactivity labeled phosphate moiety was transferred by the kinase to the beads-bound peptide, light emitted was measured in a scintillation counter. The inhibition assay of Aurora-2 activity was performed in 96 welts plate according to the following protocol Kinase reaction: 8 micro biofinylated peptide (4 repeats of LRRWSLG), 10 microM ATP (0 5 microCi ³³Pγ-ATP), 10 nM Aurora2, 10 microM inhibitor in a final volume of 60 mlcroL buffer (50 mM HEPES pH 7.0, 10 mM MgCI₂, 1 mM DTT, 0 125 mg/mL BSA, 3 rnicroM orthovanadate) were added to each well of a 96 U bottom well plate. After 30-minute incubation at room temperature, reaction was stopped and biotinyiated peptide captured by adding 100 microL of bead suspension Stratification: 100 microL of 75M CsCI were added to each well and let stand one hour before radioactivity was counted in the Top-Count instrument

Results: data were analyzed and expressed as % inhibition referred to total activity of enzyme (=100%)

All compounds showing inhibition >60% were further analyzed in order to study the potency of the inhibitor through IC₅₀ calculation.

The protocol used was the same described above, except that serlaS dilution of the inhibitor was used Experimental data were fitted by nonlinear regression using the following equation:

O J _{+ 1}QIt(IOgZr₁₀-IOg[Jj)

where v_b is the baseline velocity, v is the observed reaction velocity, v₀ is the velocity in the absence of inhibitors, and [I] is the inhibitor concentration Western blot analysis of receptor phosphorylation following stimulation with IGF-1 in IVtCF-7 human breast cancer cells

MCF-7 cells (ATCC# HTB-22) were seeded in 12-wel! tissue culture plates at 2x10⁵ cells/well in E-MEM medium (MEM+ Earle's BSS+ 2 mM glulamiπe + QA mM πσn-esseπtial amino acids) + 10% FCS, and Incubated overnight at 37°C, 5% CO2, 100% relative humidity Ceils were then starved by replacing E-MEM + 10% FCS with E-MEM + 0 1% BSA, and incubating overnight After this incubation, wells were treated with desired concentrations of compound for 1 hour at 37°C, and were then stimulated with 10 nM recombinant human IGF-1 {invitrogen, Carlsbad, CA, USA) for 10 minutes at 37⁰C. Cells were then washed with PBS and tysed in 100 mlcroL/weil cell iysis buffer (M-PER Mammalian Protein Extraction Reagent [Product #78501, Pierce, Rockford, IL, USA] + 10 mM EDTA + Protease inhibitor cocktail [Sigma-Aldrich product #P8340] + phosphatase inhibitor cocktail [Sigma-Aldrich products #P2850 + #P5726]). Cell iysates were cleared by centrifugatlon at 10,000xg for 5 minutes, and 10 microg/laπe of cleared Jysate protein were run on NuPAGE geis (NuPAGE 4-12% 10-lane Bis-Tris gels, Invitrogen) with MOPS running buffer, then transferred onto Hybond-ECL nitrocellulose filters (Amersham Biosciences, Little Chaifont, Buckinghamshire, UK) using Mini PROTEAN It chambers (Bio-Rad Laboratories, Hercules, CA, USA). Filters bearing transferred protein were incubated for 1 hour in blocking buffer {TBS + 5% BSA + 0.15% Tween 20), and probed for 2 hours in the same buffer containing 1/1000 rabbit anti-phospho IGF-1 R Tyr1131/lnsR Tyr 1146 antibody (product #3021 , Cell Signaling Technology, Beverly, MA, USA) for the detection of phosphoryiated IGF-1 R, or 1/1000 dilution of rabbit IGF-!rβ(H-60) antibody (product #sc-9038, Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA) for detecting total IGF-1 R β chain. In either case, filters were then washed for 30 minutes with several changes of TBS + 0.15% Twβeπ 20, and incubated for 1 hour in washing buffer containing 1/5000 dilution of horseradish peroxidase conjugated anti-rabbit IgG (Amersham, product #NA934), then were washed again and developed using the ECL chemϋurninesceπce system (Amersham) according to manufacturer's recommendations. Unless otherwise stated, reagents used were from Sigma- Aldrich, St Louis, MO, USA.

Growth factor induced 56 rtbosomat protein phosphorylation in primary, human fibroblasts.

Phosphorylation of S6 ribosomal protein In response to growth factor stimulation of norma! human derma! fibroblasts (NHDF) was used to assess compound potency in inhibiting IGF-1 induced signal transduction in cells, and selectivity towards EGF and PDGF stimulus NHDF cells obtained from PromoCel! (Heidelberg, Germany), were maintained at 37⁰C in a humidified atmosphere with 5% CO₂ in complete Fibroblast Growth Medium (PromoCell). For assay, NHDF were seeded in 384-weil tissue culture plates (clear- and fiat-bottomed black plates; Matrix Technologies lnc , Hudson, NH, USA) at a density of 5000 cells/well in serum-free medium containing 0,1 % bovine serum albumin (BSA) and incubated for 5 days Starved cells were treated for 1 hour with desired doses of compounds and then stimulated for a further 2 hours with either 10 nM IGF-1 (Invltrogen Corp , CA, USA), 10 nM EGF (Gibco BRL, USA) or 1 nM PDGF-B/B (Roche Diagnostics GmbH, Germany). Cells were then fixed in PBS/3.7% paraformaldehyde for 20 minutes at room temperature, washed twice with PBS, and permeabilized with PBS/0 3% Triton X-100 for 15 minutes, Wells were then saturated with PBS/1 % non-fat dry milk (Bio-Rad Laboratories, Hercules, CA, USA) for 1 hour, and then probed for 1 hour at 37°C with ant!~phospho-S6 (Ser 235/236) antibody (Ceil Signaling Technology, Beverly, MA, USA, cat, #2211 ) at 1/200 dilution in PBS/1 % miik/0 3% Tween 20, Wells were then washed twice with PBS, and incubated for 1 hour at 37°C with PBS/1% milk/0,3% Tween 20 + 1 microg/mL DAPI (4,6-diamidi^'nα-2-pheπylindαie) + 1/500 Goat anti-rabbit Cy5™- conjugated secondary antibody (Amersham Biosciences, Little Chalfont, Buckinghamshire, UK) Wells were then washed twice with PBS, and 40 microL PBS were left in each well for immunofluorescence analysis, Fluorescence images in the DAPI and Cy5™ channels were automatically acquired, stored and analysed using a Cellomlcs ArrayScan™ IV instrument (Cellomics, Pittsburgh, USA); the Cellomics Cytotoxicity Algorithm was used to quantify cytoplasmic fluorescence associated with phospho-S6 (Cy5™ signal parameter: "Mean Lyso Mass-pH") for each cell in 10 fields/well, and eventually expressed as a mean population value. Unless otherwise stated, reagents were obtained from Sigma-A!drich, St Louis, MO, USA

Biochemical and cell-based assay dala for representative compounds are reported in

Table 1.

The same compound was tested for inhibition of IGF1-lnduced IGF1 R phosphorylation in MCF-7 cells and results are shown m figure 2.

The compounds of the present invention can be administered either as single agents or, alternatively, in combination with known anticancer treatments such as radiation therapy or chemotherapy regimen in combination with, for example, antihormonal agents such as antiestrogens, antiandrogens and aromatase inhibitors, topoisom erase I inhibitors, topoisomerase Il inhibitors, agents that target microtubules, platin-baεed agents, alkylating agents, DNA damaging or intercalating agents, antineoplastic antimetabolites, other kinase inhibitors, other anti-angiogenic agents, inhibitors of kinesins, therapeutic monoclonal antibodies, inhibitors of mTOR, histone deacetylase inhibitors, farnesyl transferase inhibitors, and inhibitors of hypoxic response,

!f formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within the approved dosage range Compounds of formula (I) may be used sequentially with known anticancer agents when a combination formulation is inappropriate.

The compounds of formula (I) of the present invention, suitable for administration to a mammal, e.g., to humans, can be administered by the usual routes and the dosage level depends upon the age, weight, and conditions of the patient and administration route.

For example, a suitable dosage adopted for oral administration of a compound of formula (I) may range from about 10 to about 500 mg per dose, from 1 to 5 times daily. The compounds of the invention can be administered in a variety of dosage forms, e g , orally, in the tablet form, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form suppositories; parenterally, e.g., intramuscularly, or through intravenous and/or intrathecal and/or intraspinal injection or infusion. The present invention also includes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient, which may be a carrier or a diluent.

The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a suitable pharmaceutical form. For example, the solid oral forms may contain, together with the active compound, diluents, e.g., tactose, dextrose saccharose, sucrose, cellutøse, corn starch or potato starch; lubricants, e.g,, silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g., starches, arabic gum, gelatine methylceilulose, carboxymethylceliuiose or polyvinyl pyrrolidone; disintegrating agents, e.g,, starch, alginic acid, alginates or sodium starch glycoiate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. These pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes, The liquid dispersions for oral administration may be, e g , syrups, emulsions and suspensions. As an example the syrups may contain, as a carrier, saccharose or saccharose with glycerine and/or mannitoS and sorbitol.

The suspensions and the emulsions may contain, as examples of carriers, natural gum, agar, sodium alginate, pectin, methyfcelfutose, carboxymethyJcelfulose or polyvinyl alcohol

The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e,g., sterile water, olive oil, ethyl oleate, glycols, e.g., propylene glycol and, if desired, a suitable amount of lldocaine hydrochloride.

The solutions for intravenous injections or infusions may contain, as a carrier, sterile water or preferably they may be in the form of sterile, aqueous, isotonic, saline solutions or they may contain propylene glycol as a carrier.

The suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g , cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin With the aim to better illustrate the present invention, without posing any limitation to it, the following examples are now given.

Examples

General methods

Flash Chromatography was performed on silica gel (Merck grade 9395, 60A) HPLC was performed on Waters X Terra RP 18 (4,6 x 50 mm, 3,5 μm) column using a Waters 2790 HPLC system equipped with a 996 Waters PDA detector and Mioromass mod ZQ single quadrupole mass spectrometer, equipped with an electrospray (ESI) ion source Mobile phase A was ammonium acetate 5 mM buffer (pH 5 5 with acetic acid/acetonitrile 95:5), and Mobile phase B was water/acetonitrile (5:95) Gradient from 10 to 90% B in 8 minutes, hold 90% B 2 minutes. UV detection was at 220 nm and 254 nm. Flow rate was 1 mL/min. Injection volume was 10 microL. Full scan, mass ranged from 100 to 800 arnu Capillary voitage was 2 5 KV; source temperature was 12O⁰C; and cone was 10 V Retention times (HPLC r,t) are given in minutes at 220 nm or at 254 nm. Mass are given as m/z ratio.

When necessary, compounds were purified by preparative HPLC on a Waters Symmetry C18 (19 x 50 mm, 5 um) column or on a Waters X Terra RP 18 (30 x 150 mm, 5 μm} column using a Waters preparative HPLC 600 equipped with a 996 Waters PDA detector and a Mlcromass mod ZMD single quadrupole mass spectrometer, electron spray ionization, positive mode Mobile phase A was water 0,01 %/trifluoroacetic acid, and mobile phase B was acetonitrlle. Gradient was from 10 to 90% B in 8 min, hold was 90% B 2 min. Flow rate was 20 mL/min. In the alternative, mobile phase A was water/0 1 % NH₃, and mobile phase B was acetonitriie. Gradient was from 10 to 100% B tπ 8 min, hold was 100% B 2 min Flow rate was 20 mL/min

1 H-NMR spectrometry was performed on a Mercury VX 400 operating at 400.45 MHz equipped with a 5 mm double resonance probe [W (15N-31P) !D_PFG Varian].

Example 1

Preparation of 3_"amino-6,7-dihydro-4H-pyrazo!o[4,3-c]pyriciine-1_T5-dicarboxylic acid 5-tert-butyl ester 1 -ethyl ester

Step 1. 5-cyano-4Φydroxy-3,6-dihydro-2H-pyridtne-1«carboxylic acid tert-butyl ester

To a refSuxing solution of 206 g of potassium tert-butoxide in 2 L of toluene, 200 mL of a.S'-iminodipropfoπitrife was dropped in 40' under N₂ stream. The suspension was refϊuxed for

30 min. while stirring Then, 400 mL of water was added, followed by 600 rnL of 37% HCI The two-phases solution was stirred at 80 "C for 30 min,, then cooled at room temperature, 1 L of ca toluene was added to the reaction mixture. The acidic two-phase solution was cooied and treated with 1 L of 28% NaOH. The basic two-phase solution thus obtained was cooled and treated with 388 g of (BOc)₂O. The mixture was kept under stirring for 2,5 hours at room temperature The resulting suspension was cooled and brought to acidic phi by adding dropwise

660 mL of 37% HCI The two phases were separated and the aqueous Sayer was extracted with ethy! acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to dryness to obtain 330.9 g of a light yellow solid

Step 2. 3-amtno-1,4,6_p7-tetrahydro-pyra2olot4,3-c]pyridine-5-carboxyiic acid tert- butyl ester

To a solution of 141,5 g of S-cyano^-hydroxy-S.e-dihydro^H-pyridine-i-carboxylic acid tert-butyl ester in 1200 mL of ethaπol were added under stirring 57.8 mL of aqueous 35% hydrazine. The mixture was heated to 70 °C for 4 hours, The solution was evaporated under vacuum, and the residue was diluted with 1 L of water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to dryness. The crude product was taken-up with 300 mL of tert-butyl methyl ether and the crystallized compound was collected by filtration to give 1 15 6 g of the title compound

1 H-NMR (400 MHz), δ {ppm, DMSOd₆): 11.06 (bs, IH), 4.58 (bs, 2H)₁ 4 14 {s, 2H), 3.51 (bt, J=5,5 Hz, 2H), 2.47 (bt, J=5 5 Hz, 2H), 1.41 (s, 9H),

Step 3. a-amino-ej-dihydro^H-pyrazolor^S-cJpyridine-ijS-dfcarboxytic acid 5- tert-butyl ester 1 -ethyl ester and

3-amino-6,7-dihydro-4H-pyrazolo[4,3-cJpyridine-2,5-dicarboxyiic acid 5-tert-butyl ester 2-ethyi ester

To a solution of 94.1 g of 3-amino-1,4,6,7-tetrahydro-pyrazoio[4,3-c]pyrldine-5- carboxylic acid tert-butyl ester in 1.7 L of THF were added 135 ml of N.N-diisopropyiethylamiπe A solution of 37,6 mL of ethylchioroformate in 300 mL of THF was added dropwise at 0 ⁰C during 75 rnin. The mixture was stirred at 0 ⁰C for 30 min. then evaporated under vacuum. The residue was taken-up with ca. 1 L of water and extracted with ethyl acetate The combined organic extracts were washed with 500 mL of brine, dried over sodium sulfate, and evaporated to dryness. The crude mixture of isomers was purified by silica geS flash-chromatography using a starting 87: 13 mixture of dichlorom ethane-ethyl acetate as eluant, and increasing the percentage of ethyl acetate up to 50% The fractions containing the same isomers were evaporated to give 61.6 g of 3-amino-6,7-dihydro-4H-pyrazolof4,3-c]pyridine-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester. 1 H-NMR (400 MHz), δ (ppm, DMSO-Qf₆): 6,37 (bs, 2H), 4.35 (q, ^j>7.1 Hz₁ 2H), 4, 19 (bs, 2H), 355 (bt, J=S 8 Hz, 2H), 249 (bt, J=58 Hz, 2H), 1,43 (s, 9H), 1.32 (t, J=7 1 Hz, 3H)

Evaporation of the fractions containing the other isomer gave 29 g of 3-amino-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine-1,5-d!carboxylic acid 5-tert-butyi ester 1-ethyl ester, 1 H-NMR (400 MHz), δ (ppm, DMSO-Of₆): 5.52{bs, 2H), 428 (q, J=7 1 Hz, 2H), 4 16 (bs,

2H), 356 (bt, J=58 Hz, 2H), 2,84 (bt, J=S 8 Hz, 2H), 1.44 (s, 9H), 1 29 (t, J=7 1 Hz, 3H).

Example 2

Preparation of 4-(4-methyl-piperaziπ-1 yl)-bβnzoic acid

To a solution of 25 g of 4-fluoro-benzoic acid ethyl ester in 100 ml of DMSO were added 20 mL of N-methylpiperazine and 204 g of potassium carbonate The mixture was heated at 95°C during twelve hours, and then poured into 300 mL of water. The aqueous phase was extracted four times with dichloromethane. The combined organic extracts were washed several times with 1N HCi solution. The acidic extracts were combined, cooled on an ice-water bath, 20% NaOH solution added until neutral pH, and finally extracted several times with dichloromethane. The combined extracts were dried under anhydrous sodium sulphate and evaporated to dryness to give 18 g of 4-(4-methyl-piperazin-1-yl)-benzoic acid ethyl ester as a white solid

To a solution of 18 g of 4-{4-methy]-pipβrazm-1-yl)-bertzαic acid ethyl ester in 140 mL of methanol were added, under stirring, 115 mL of 2N NaOH. The reaction was left standing for 72 hours. The solvent was evaporated to small volume, 200 mL of water were added, and the solution was extracted with dichloromethane The aqueous phase was cooled on an ice-water bath, and the pH was adjusted to 7 by adding 25% v/v HCI solution. The resulting precipitate was filtered, washed with ice-water, and dried under vacuum to give 13.45 g of 4-(4~methyS- piperazin-1~yl)-benzosc acid, m.p. >230°C.

1 H-NMR (400 MHz), 5 (ppm, DMSO-Cf₆): 7.77 (m, 2H), 6 97 (m, 2H), 3,30 (m, 4H), 2.44 (m, 4H), 223 (s, 3H).

Operating as described in the previous example, the following acids were obtained: 4-morpholirv4-yl-benzoic acid

1 H-NMR (400 MHz), 5 (ppm, DMSO-d_δ): 778 (m, 2H), 6.97 (m, 2H), 3.73 (m, 4H), 3,25

(m, 4H).

4-(3,4»dfmethyl-piperazin-1-yl)»benzoic acid

1 H-NMR (400 MHz), 6 (ppm, DMSO-CZ₆): 12,37, 1148 (2bs, 2H), 7 78 <m,2H), 703 <m, 2H), 4.10-2,95 (m, 7H), 2.73 {bs, 3H), 1.34 (bs₍ 3H)

Example 3 Preparation of 4-(4-methyl-piperazin-1 -yl)*benzoy! chloride

To a suspension of 1.07 g of 4-(4-mβthyl-piperazln-1-yl)-berizoic acid in 50 ml of anhydrous dichloromethane were added 2.1 mL of oxalyl chloride and 3 drops of dimethylformamide. The suspension was heated at 50⁰C for 4 hours. After cooling, the solid was Filtrated, washed first with anhydrous dichloromethane followed by toluene, The soiid was dried at 50 "C under vacuum, and used as such.

Operating as described in Example 3, the following acid chlorides in Examples 4-5 were obtained:

Example 4

4-morphoiin-4-yl-benzoyI chloride

Example β 4-(3,4-d!methyl-ptperazln-1-yl)-benzoyl chloride Example 6

Preparation of N-(5-benzenesulfonyl-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3Hc]pyridin-3-yl)-4-

{4-methyl-piperazin-1-y!)-benzamide

Step 1. Preparation of 3-{4-(4-methyl-p)pera2Jn-1-yJ)-bβnzoylamino]-β,7-dihyciro- 4H-pyrazoio[4,3-c]pyridtne-1,5-dicarboxylic acid 5-tert-butyi ester 1 -ethyl ester

To a solution of 0,98 g of 3-amino-β,7-dihydro-4H-pyrazolo[4_P3--c3pyridine-1,5- dicarboxyiic acid 5-tert-buiy⁾ ester 1 -ethyl ester and 2.7 mL of di-isopropy!ethyiamine in 60 m L of anhydrous tetrahydrofuran were added 1 2 g of 4-{4-melhyl-ρiperazin-1-yl)-benzoyl chloride, and the reaction mixture stirred for 18 hours. The solvent was evaporated, and the residue taken up in dichlorαmethane. The organic phase was washed with sodium hydrogenocarboπate, water, and finally with brine. The solvent was evaporated, and the residue purified by silica gel column chromatography, using dichSorom ethane followed by dichloromethane-acetone 7:3 (v/v) as eluant, to furnish 133 g of the title compound.

1 H-NMR {400 MHz), δ (ppm, DMSOd₆): 10.75 (bs, 1H), 7.3 (m, 2H), 7.01 (rn, 2H), 440 (q, J=7.1 Hz, 2H), 428 (m, 2H), 364 (m, 2H), 341 (m, 4H), 2.99 (m, 2H), 2.48 <m, 4H), 2.26 {bs, 3H), 1 41 (bs, 9H), 1,35 (t, J=7 1 Hz, 3H). Step 2. Preparation of 3"[4-(4-methyf-pfperazln-1-yJ)-benzoyJamJno]-4,5₍6,7- tetrahydro-ρyrazolo[4,3-c]pyridine-1-carboxylic acid ethyl ester dthydrochlorlde

To a solution of 0,82 g of 3-{4-(4-methyf-piperazin-1-yl}-benzoyIamfπo]-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-1 ,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester In 20 mL of dichloromethane were added 2 mL of 4N HC! in dioxaπe followed by 15 mL of methanol . The reaction mixture was stirred for 18 hours The solvent was removed under reduced pressure, the residue was triturated with acetone, filtered, washed with a few millilitres of methanol, and dried under vacuum to give 0.47 g of the title compound, which was used as such for the next reaction.

IH-NMR (400 MHz), δ (ppm, DMSO-otø; 11,05 (s, 1H)₁ 10.60 {bs, 1H), 9-27 (bs, 2H), 8.00 (m, 2H), 7 10 (m, 2H)₁ 4.44 (q, J=7 1 Hz, 2H), 4.09 (m, 4H), 3.55-3.05 {m. 8H), 2.84 (bs, 3H), 1.36 {t, J=7 1 Hz₁ 3H).

Step 3. Preparation of 5_"benzenesulfonyi-3^»[4-(4-methyl-piperazin-1-yl)- benzoylamino]^,5,6,7-tetrahydro-pyrazolo[4_l3-clpyridine-1-_''carboxylic acid ethyl ester

To a suspension of 0,16 g of S-^-^-methyl-piperazin-i-yJJ-benzoylaminoH.S.βJ- tetrahydro-pyrazolo[4,3-c3pyridine-1-carboxylic acid ethyi ester dlhydrochloride in 40 mL of anhydrous dlchioromethane were added 0.2 mL of triethylamine followed by 0 06 mL of benzenesuifonyl chloride The reaction was left standing at room temperature for 18 hours, and then was diluted with dichloromethane, washed with sodium hydrogeπocarbαnate solution, water, and brine. The solvent was removed under reduced pressure and the residue was triturated with diethyl ether to furnish 0 17 g of the title compound

Step 4. N-(5-benzenesulfoπyI-4,5,6,7-tetrahydro-1H-pyrazoloI4,3-c]pyrid!n-3-yl)-4-

(4-metfiyl-piperazin-1-yl)-benzamidθ,

To a solution of 0 16 g of 5-benzenesuifonyl-3-[4-(4-methyl-piperaan-1-yi)- benzoyiamino]-4,5,6,7-tetrahydro-pyra2olo[4,3-c]pyridine-1 -carboxylic acid ethyl ester in 30 mL of methanol were added 2 mL of triethyiamine, and the reaction mixture was heated at 60 ⁰C for 2 hours. The solvent was evaporated under reduced pressure, the residue was triturated with diethyl ether, filtered, washed with diethyl ether and dried under vacuum The title compound was obtained as a white solid (0.12 g)

1 H-NMR {400 MHz), δ (ppm, DMSO-Df₆): 12,23 (bs, 1 H), 10.19 (s, 1H), 7 90 {m, 2H), 7 83-7.78 (m, 2H)₁ 7.71 (m, 1H), 7.65-7 60 {m, 2H), 7.01 (m, 2H), 4.08 (bs, 2H), 3.41 {m, 2H), 3.34 (m, 4H), 2.89 {m, 2H), 2.5 (m, 4H), 2.31 (bs, 3H).

Operating as described in Example 6 above, the following compounds in Examples 7-29 were obtained

Example 7 N-(5-Benzenesu!fonyl-4,5,6,7-tetrahydro-1H-pyrazoIo[4,3 c]pyridin-3"yl)-4-moφholin-4-y!- benzamide

IH-NMR {400 MHz), δ (ppm, DMSO~c/_e): 1220 (bs, 1H), 10.17 {s, 1H)₁ 7.88 (m, 2H), 7 77 (m, 2H), 7.67 (m, 1H), 7.59 (m, 2H),6,97 (m, 2H). 404 (s, 2H), 373 {m, 4H), 337 (m, 2H), 3.23 (m, 4H), 266 {m, 2H).

Example 8

N-[5-<2-Ffuoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-{4- methyt-plperazfn-1-yl}-benzamJde

1 H-NMR (400 MHz), δ {ppm, DMSO-d₆): 1227 (bs, 1H), 1023 (s, 1H), 7.90 {m, 2H), 7 86 (m, 1H), 7.75 (m, 1H), 746 (m, 1H), 743 (m, 1H), 7 01 (m, 2H), 4 18 (bs, 2H), 355 (m, 2H), 3.35 (m, 4H)₁ 2,85-2.60 (m, 6H), 2.43 (bs, 3H). Example 9

N-j5-(3-FiuorO"benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazoio[4,3_"Cjpyridin-3-yJ]-4-(4- methy l-piperazi n-1 -yl)-benzamide

1 H-NMR (400 MHz), δ (ppm, DMSO-ofe): 12.24 (bs, 1H), 10 22 (S₁ 1H), 792 (m, 2H),

770-753 (m, 4H), 7.02 <m, 2H), 414 <bs, 2H), 347 (m, 2H), 334 (m, 4H), 2 9-2.6 (m, 6H), 2,43 (bs, 3H)

Example 10 N-[5-(4-Fluoro-benzenesutfonyl)_"4,5,6,7-tetrahydro~1H pyrazotor4,3-c]pyridin-3-ylJ-4-(4- methyl-piperazin-1-yl)-benzamide

1H-NMR (400 MHz), 6 (ppm, DMSCWe): 1223 (bs, 1H), 10 1β (s, 1H), 793-784 (m, 4H), 745 (m, 2H), 7,00 (m, 2H)₁ 4.10 (bs, 2H), 3.43 <m, 2H), 3 31 (m, 4H), 269 (m, 2H), 2.49 (m, 4H), 2 26 {bs, 3H). Example 11

N-IS-fS-Chtoro-benzenesulfonyO^.S.ej-tetrahydro-IH-pyrazoloH^-clpyridin-a-yll-^-tA- methyl-plperazin-1-yl)-benzamide

1 H-NMR (400 MHz), 5 (ppm, DMSO-Cl₆): 12.25 (bs, 1H), 10.23 (s, 1H), 7.93 (m, 2H), 7,83 (m, 1H), 7.80-7.75 (m, 2H), 7,64 (m, 1H)₁ 7.04 (m, 2H)₁ 4.16 (bs, 2H), 3.48 (m, 2H), 3.32 (m, 4H), 2.69 (m, 2H), 30-2.7 (m, 4H), 2.50 (bs, 3H).

Example 12

N-[5-(4-Chloro-ben2enesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo{4,3-c]pyridin-3-yl]-4-(4- methyl-piperazm-1-yl}-benzamfde

1 H-NMR (400 MHz), δ {ppm, DMSO-c/₆): 12.24 (bs, 1H), 10.20 (s, 1H), 791 (m, 2H), 7.82 (m, 2H), 7.68 (m, 2H), 7.01 (m, 2H), 4.12 (bs, 2H), 3,44 (m, 2H), 332 (m, 4H)₁ 2-69 (m, 2H), 2.57 (m, 4H), 2.33 (bs, 3H). Example 13

N-ϊ5-{3-Hydroxy-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazoloϊ4,3-c]pyridin-3-y!]-4-(4- methyl -piperazin-i-ylj-benzamide

1H-NMR (400 MHz), δ (ppm, DMSO-cfe): 1226 (bs, 1H)₁ 1020 {bs, 1H), 10 17 (s, 1H), 7 91 (m. 2H), 7 43 (m, 1 H), 7.20 (m, 1H), 7 15 (m, 1 H), 7.07 (m, 1H)₁ 7 01 (m, 2H), 4.03 (bs, 2H), 3,40-3.20 {m, 6H)₁ 2 74 (m, 2H), 2 61 {m, 4H)₁ 2 34 (bs, 3H)

Example 14

N-I5-{3-Methoxy-beπzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-clpyridin-3-yl]-4-(4- methyl-piperazin-1-yl}-beπzamϊde

1 H-NMR (400 MHz), δ (ppm, DMSOd₆): 12 23 {bs, 1 H), 10,20 (s, 1 H), 7 90 (m. 2H), 7,54 (m, 1 H), 7.37 (m, 1H), 7.27-7-22 (m, 2H), 7,00 (m, 2H), 4.12 (bs, 2H), 3,81 (s, 3H), 343 (m, 2H), 3.32 <m, 4H), 2.66 (m, 2H), 2.52 (m, 4H), 2.29 (bs, 3H). Example 15

N-IS^Methoxy-faenzenesulfonyO^.S.ej-tetrahydro-IH-pyrazoIoW.S-clpyridin-S-yq-'l-t'l- methyl-piperazin~1-yl)-benzamide

1 H-NMR (400 MHz), 5 (ppm, DMSOd₆): 12,23 {bs, 1H), 10,1? (s, 1H), 7.90 (m, 2H), 7 73 (m, 2H), 7.13 (m, 2H), 7,00 (m, 2H), 4.02 (bs, 2H)₁ 3 85 (s, 3H), 3.35 (m, 2H), 3 31 (m, 4H), 2 70 {m, 2H), 2.49 (m, 4H), 2.27 {bs, 3H)

Example 16

4-(4-IVIethyl-piperazin-1-yl)-N-[5-(2-trifluoromethyl-benzenesulfoπyl}-4,S,6,7-tβtrahydro-1H- pyrazoio[4,3-c]pyridin-3-yl]-benzaniide [4,3-c]pyridine

1 H-NMR (400 MHz), δ (ppm, DMSO-c/_β): 12.32 (bs, 1H), 10 24 (s, 1 H), 8 13-8.0 (m, 2H), 7.92-785 (m, 4H), 6.99 (m. 2H), 4,31 (bs, 2H)₁ 3.66 (m, 2H), 3 35 (m, 4H), 2.76 (m, 2H), 2 55 (m, 4H)₁ 2 31 (bs, 3H). Example 17

4-(4-Mθthyl-pϊperazin-1~yl)-N-[5-(3-trifIuoromethyl-bβnzenesulfonyl)-4,5,6,7-tβtrahydro-1H- pyrazo1o[4,3-c]pyridin-3~yl]-benzarnide

1 H-NMR (400 MHz), δ {ppm, DMSO-Cf₆): 12,21 (bs, 1H)₁ 10.21 (s, 1H), 8 16-8-12 (m, 1 H), 8.10-8,05 (m, 2H), 7 91 (m, 2H), 7.89-7.82 (m, 1 H), 7,01 {m, 2H), 4,23 (bs, 2H), 3.52 (m, 2H), 3.09 (m, 4H), 2.70-2.50 (m, 6H), 2.36 (bs, 3H).

Example 18

4-(4-Wlethyl-pip6razin-1-yl)'N-[5-(4-trifluoromet{iyl_"benzenesulfonyl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c3pyr[dl n-3-y IJ-benzam ide

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.25 (bs, 1H), 10.22 (s, 1H), 8 06-7.96 (m, H), 7,91 (m, 2H), 7.01 (m, 2H), 4.17 {bs, 2H), 3.49 (m, 2H), 3.31 (8m, 4H), 2.69 (m, 2H), 2 65- 2 50 (m, 4H), 2,34 {bs, 3H) Example 19

^(^Methyl-piperazin-i-yO-N-ΪS-ftoIuene-S-sulfonylH^.ej-tetrahydro-IH-pyrazolo^^- c]pyridin-3-yl]-benzamide

1 H-NMR (400 MHz)₁6 (ppm, DMSOd₆): 1226 (bs, 1H), 10,27 (s, 1H), 7,96 (m, 2H),

7.63 (m, IH), 7.59 (m, 1H), 7.52-7.49 (m, 2H), 7,09 (m, 2H), 4.10-4.0 (m, 4H), 3.52 (m, 2H), 3.45-3.35 (m, 4H), 3,16 (m, 2H), 2,85 (s, 3H), 2.69 (m, 2H), 240 (s, 3H)

Example 20 4-(4-Methyl-plperazln-1-yl}-N-[5-(toluene-4-sutfonyl)-4,S,6,7-tetrahydro-tH-pyrazolo[4,3- c]pyrJdin-3-yl]-benzamlde

1 H-NMR (400 MHz), δ (ppm, DMSO-Of₆): 1224 (bs, 1H)₁ 10.20 (s, 1H), 791 (m, 2H), 7.69 (m, 2H), 7.43 (m, 2H), 7.02 (m, 2H), 4.03 (bs, 2H), 3.5-3.2 (m, 6H), 2.9-2.5 (m, 6H), 245 (bs, 3H), 240 (s, 3H).

Example 21

N-[5-(2-Cyaπo-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazoloϊ4,3-c]pyridin-3-yt]-4-(4- methyt-piperazin-1-ylj-benzamlde

1 H-NMR (400 MHz), 6 (ppm, DMSO-cfe): 12.27 (bs, 1H), 10 21 (s, 1 H), 8.15-8 06 (m, 2H), 7.96-7 83 (m, 4H), 6.99 (m, 2H), 4.24 (bs, 2H), 3.64 (m, 2H), 3.5-3.0 (m, 4H), 2 76 (m, 2H), 2 65-2 5 (m, 4H), 2 30 {bs, 3H).

Example 22

4-(3,4-Dimethyl-plperaztn-1-yl)-N-[5-(3-fluoro-benzenesulfonyl)-4,5,6_l7-tetrahydro-1H- pyrazata[4,3~cfoyridln-3-y1J~benzamlde

1 H-NMR (400 MHz), 6 (ppm, OMSO-(Z₆): 12 26 (bs, 1H), 10 27 (s, 1H), 7.95 (m, 2H), 7.70-7.53 (m, 4H), 7 09 (m, 2H), 4 15 (bs, 2H), 4,08 (m, 2H), 3 48 (m, 2H), 3.4-2 7 (m, 8H), 2.69 (m, 2H), 1 32 (bs, 3H) Example 23

N-fS^.S-Difluoro-benzenesulfonylJ^.S.e.T-tetrahydro-IH-pyrazolo^.S-clpyrfdin-S-ylH-t'i- methyl-piperazin-1-yl)-benzamtde

1 H-NMR (400 MHz), 6 (ppm, DMSO-d_β): 12,28 (bs, 1 H), 10.24 (s, 1 H)₁ 7.91 (m, 2H), 7.70-7.60{m, 2H), 7,55 (m, 1H), 7,01 (m, 2H), 4,24 {m, 2H), 3.59 (m, 2H), 3.2 (m, 4H), 2 73 (m, 2H)₁ 2.80-2.55 (m, 4H)₁ 2.3Θ (bs, 3H)..

Example 24

N-tδ-tS.δ-Difluoro-betizenesulfonyO^.S^J-tβtrahydro-IH-pyrazolo^S-clpyridin- S-yπ^^Φ methyl-piperazin-1-yfj-benzamfde

1H-NMR (400 MHz), δ (ppm, DMSO-Of₆): 12.25 {bs, 1H), 10.20 (ε, 1H), 7.91 (m, 2H), 7.66 (m, 1 H), 7.60-7,55 (m, 2H)₁ 7.00 (m, 2H)₁ 4.20 (bs, 2H), 3.53 (m, 2H), 3 32 (m, 4H), 2 69 (m, 2H), 2.49 (m, 4H), 2.27 (bs, 3H). Example 25

N-ΪS-fa.e-Difluoro-faenzenβsuifonylJ^.S.ej-tetrahydrO'lH-pyrazolo^.a-clpyridin-a-ylH-tΦ methyt-piperazin-1-y!)-bθnzamide

1 H-NMR (400 MHz), 6 (ppm, DMSO-c/g): 12.32 (bs, IH), 10.31 (s, 1H), 7,95 (m, 2H),

7.77 (m, 1H), 7.36-7,30 (m, 2H), 7,08 (m, 2H), 4.24 {bs, 2H), 3 60 (m, 2H), 3.5-3 0{m, 8H), 2.82 (bs, 3H), 2.77 {m, 2H),

Example 26 N-[5-{3,4-DifIuoro-bθnzenesulfonyl)-4,5,6,7-tθtrahydro-1H-pyrazoloϊ4,3_'-c]pyr1din-3-yt]-4.{4- methyl-pi perazm-1 -y l)-benzamide

1 H-NMR (400 MHz), 6 {ppm, DMSO-c/₆): 12.24 (bs, IH), 10 20 {s, 1 H), 8 0-7.88 {m, 3H), 774-764 (m, 2H), 7,00 {m, 2H), 4 16 {bs, 2H)₁ 349 (m, 2H), 3.32 (m, 4H)₁ 2.68 (m, 2H), 2.52 {m, 4H), 2.29 {bs, 3H).

Example 27

4-(4-Methyl-piperazin-1-yl)-N-t5-{thlophene-2-sulfonyI)-4,5,6,7-tetrahydro-iH-pyrazolo[4,3- cJpyridin-3-yl]-benzamlde

1 H-NMR (400 MHz), δ (ppm, DMSO-Cf₆): 12,28 (bs, 1H), 10.20 {s, 1H), 803 (m, 1H), 790 (m, 2H), 768 (s, 1H)₁ 726 (m, !H), 6.89 (m, 2H), 4.09 {bs, 2H), 3.40 (m, 2H), 3,30 (m, 4H), 2.77 {m, 2H), 2 47 (m, 4H)₁ 2.25 (bs, 3H)

Example 28

N-[5-{1 ,2-DϊmethyJ-1 H-imtdazole-4-sulfonyl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridin- 3-yI]-4~(4-methyf-piperazin-1-yi)-benzamido

1 H-NMR (400 MHz), δ (pprn, DMSOd₆): 12 26 (bs, 1 H)₁ 10.15 (s, 1 H), 7 89 (m, 2H), 7 75 (s, 1H), 6 99 (m, 2H), 4.03 (bs, 2H), 3,60 (s, 3H), 3 39 <m, 2H), 3.30 (m, 4H), 2.78 (m, 2H), 2.50 (m, 4H), 2.30 (s, 3H)₁ 2.28 (bs, 3H).

Example 29

4-{4-W!ethyl-piperazin«1 -y l)-N-f5-(qui n ol !ne-8-su lfonyl)-4,5,6,7-tetrahyd ro»1 H-py razolo [4,3- c]pyridin-3-yI]-bena:amide

1 H-NMR (400 MHz), δ ppm, DMSO-d₆): 12.14 (bs, 1 H), 10,16 (bs, 1 H), 9.01 (m, 1 H), 8.52 (m, 1 H), 8.41 {m, 1H)₁ 8.30 (m, 1 H), 7,88 (m, 2H)₁ 7,76 (m, 1 H), 7,68 (m, 1 H)₁ 6 98 {m, 2H), 4 31 (bs, 2H), 3 77 (m, 2H), 3 29 (m. 4H)₁ 2.62 (m, 2H), 2 45 (m, 4H), 2 24 (s, 3H)

It is to be understood that many modifications and variations may be devised given the above description of the principles of the invention. It is intended that all such modifications and variations can be considered as within the spirit and scope of this invention, as it is defined in the following ciaims.

Claims

What is claimed is:

1. A compound represented by Formula (I);

wherein:

R is an aryl or heteroaryl, wherein the aryl or heteroaryf groups can be unsubstituted or substituted by one to three substiiuents selected from the group consisting of alkyl, halogen, trlfluoromethyi, hydroxy, hydroxyalkyl, aikoxy, alkylthio, cyano, formyl, alkylcarbonyl, alkylsuiphonyl, amino, monoalkytamino, dialkylamiπo, arylaikyJamino, carboxy, carbσxamldo, monoalkylcarboxamido and dialkylcarboxamido; and

R¹ is a heterocycloalkyl, wherein said herocycloalkyl can be substituted or unsubstituted by one or two substituents independently selected from the group consisting of alkyl, aryl, halogen, trifluoromethyl, hydroxy, hydroxyalkyl, aikoxy, alkyithlo, cyano, formyt, aikytcarboπyi, alkylsulfonyl, amino, monoalkylamino, dialkylamino, aryialkyiamino, carboxy, carboxamido, monoalkyicarboxamido and diaikylcarboxamido; or a pharmaceutically acceptable salt or solvate thereof,

2. The compound according to claim 1, wherein R is aryl and R¹ is a six-membered heterocycloaikyl

3 The compound according to claim 1 , wherein

R is selected from the group consisting of from phenyl, a 2-substituted-phenyi, a 3- substituted-phenyl, a 2,6-disubslituled-phenyi and a 3,5-disubstituted-pheny!; and

R¹ is selected from the group consisting of morphollne and a substituted-piperazine.

4. The compound according to claim 1, wherein:

R is selected from the group consisting of a 3-substituted-phenyl and a 3,5- disubstituted-pheny! and

R¹ is a substituted-piperazine.

5 A pharmaceutical composition comprising an amount of the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier,

6. A compound according to claim 1 selected from the group consisting of:

N-(5-benzenesuIfonyt-4₁5,6,7-tetrahydro-iH-pyrazolo[4,3-c]pyridln-3-yi)-4-(4-methyi- piperazfπ-1 -yl)-benzamide;

N-(5-benzenesulfonyf~4,5,e,7-tetrahydro-1 H"pyrazolo[4,3-c]pyridin-3-y!)-4-morpholtn-4- yi-benzamtde;

N-[5-(3-fiuoro-benzenesulfonyl)-4,5,6,74etrahydrθ"1H-pyrazo!o[4,3-c]pyridin-3-yi]-4-{4- methyl-piperazin~1~yf)-benzamide;

N-E5-(3"Chloro-benzenesulfonyl)-4,5,6,7-tetrahydro-1 H-pyrazolQ[4,3-c]pyridtn-3-yl]-4-(4- methyl-piperazin-1 ~yf)-benzamide;

4-{3_J4-dimethyl-piperazin-1-yl)-N-[5"(3-fluoro-benzenesulfonyl)-4,5,6,74etrahydro-1 H- pyrazolo[4,3-c]pyridin-3-yϊJ-benzamide;

N-[5-(3-hydroxy-benzenesulfonyl)-4,5,6,7*tetrahydro-1H-pirazolo[4,3-c]pyridin-3-y]]-4-(4" metrιyl'piperaz;tn~1-yi)-benzamide;

N-[5-(3,S-dif!uoro-benzenesulfony!)-4,5,6,7-tefa-ahydro-1 H-pyrazolo[4,3~c]pyridin-3-yS]-4-

(4-methy!-piperazin-1-yi)-benzamide;

N-t5-(2,5-difluoro-benzenesutfonyl)-4₎5,6,7-tetrahydro-1 H-pyrazoiof4,3-c]pyr!din-3-yl3-4- (4-methyl-piperazin-1-yl)-benzamide;

N-t5-(2-fiυoro-benzenesuifonyi}-4,5,6,7-tθtrahydro-1H-pyrazo!o[4,3-c]pyridin-3-yl]-4-(4- methyl-piperazin«1-yl)-benzamide;

N-[5-(4-f1uoro-benzenesulfonyl}-4,5,6,7-tetrahydro-1 H-pyrazo!o[4,3-c]pyridln-3-y!H-(4- methyi-piperazin-1 -yi)-benzamide; N-[5-{4^h!oro-benzenesulfoπyl)-4,5,6,74θϋ-ahydr&~1H-pyra2:olo[4,3-c]pyridlri-3-yl]-4-(4- methyS"piperazin-1-yl)-benzamide;

N-t5-(3-m8thoxy-benzenesulfonyl)-4,5,6,7~telrahydro-1H-pyrazoloE4,3-c]pyridin-3-y)]-4- {4~methyi-piperazin-1 ~yi)-benzamide,'

N-E5-(4-methoxy-benHenesulfonyl)-4_>5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyrtdln-3-yi]-4- (4-methyl-piperazin-1-yl)-benzamide,'

4-(4-methyl-piperazin-1-yl}-N-[5-(2->trifluoromβthyl-benzenesulfonyl)-4_l5,6,7-tetrahydro-

1 H-ρyrazolo[4, 3-c]pyridin-3~ylJ-beπzam ide;

4-(4-methyl-plperaziπ-1-yl)-N-f5-{3-trifluoromethyi-benzenesulfoπyi)-4,5_t6₍7-tetrahydro- 1H-pyrazo!of4,3-c]pyridin-3-yi]-benzamide;

4-{4-methyl-piperazin-1-yl)-N-[5-(4-frifluoromethyI~benzeπesuIfony!)-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-c]pyridin-3-yl]-benzamide;

4-(4-methyl-piperazln-1-yl)-N-[5-(loluene"3-sυlfonyl)-4,5_l6,7-tetrahydro-1H-pyrazolo[4,3- c] pyrid in-3-y]]-benzam ide;

4-(4-methyf-piperazin-1-y!)-N-[5-{toluene-4-sulfony))-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridln-3-yl]-benza m ide;

N-[5-(2-cyaπo-benzeπesulfonyl)-4_I5_>6₁7^etrahydro-lH-pyrazo]o{4₍3-c]pyridiπ-3-yl]-4-(4- methy!-piperaziπ-1 -yl)-benzamide;

N'[5-(2,5-difluoro-benzenesu!fonyl)-4,5,6,7-tetrahydro-1H-pyrazoloE4,3-c]pyridin-3-ylJ-4- (4-methyl-piperazin-1-yl)-beπzamide;

N-[5-{2,6-dif}uoro-benzenesulfoπyl)-4,5,6,7"tetrahydro-1 H-pyrazolo[4,3-c3pyridln-3-yl]-4-

(4-methyt-piperaziπ-1-yl)-benzamide;

N-[5-(3,4-difJuoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1 H-pyrazoio[4,3-c]pyridin-3-yl3-4- (4-methyl-piperaziπ-1-y!)-benzamide; 4^4-methyl-piperazin-1-yl)-N-[5-(thiophene"2-sulfonyl)-4,5,6,7-tetrahydro-1H- ρyrazolo[4,3-c]pyridin-3-y]]-benzamide;

N-tS-fi^-dimθthyi-IH-imidazole^-sulfonyO^.S.βJ-tetrahydro-IH-pyrazoIo^^-clpyrfciiπ- 3-yi]-4-(4-methy!-piperazin-1-yl)-benzamfde; and

4-(4-methy)'piperazin-1-y))-N-[5-{quinoline-8-suifonyl)-4_P5,6,7-teirahydro-1H- pyrazo!o£4,3-c]ρyridin-3-y!J-benzamide.

7 A method of treating a disorder or condition in a mammal, wherein said disorder or condition is caused by or associated with dysregutated protein kinase activity comprising administering to said mamma! in need of said treatment a compound according to claim 1 ,

8. A method of treating a disorder or condition in a mammal, wherein said disorder or condition is caused by or associated with IGF-1R or Aurora kinase activity comprising administering to said mammal in need of said treatment a compound according to claim 1

9. A method of treating a disorder or condition in a mammal, wherein said disorder or condition is caused by or associated with IGF-IR kinase activity comprising administering to said mammal in need of said treatment a compound according to claim 1

10. A method of inhibiting tyrosine kinase activity of IGF-1R receptors, comprising administering to the IGF-1R receptors an amount of a compound of claim 1 that is effective in inhibiting tyrosine kinase activity of the 1GF-1R receptors.

11. A method of treating a disorder or condition in a mammal, wherein inhibition of tyrosine kinase activity of the IGF-1 R receptor is needed in said mammal, comprising administering to said mammal an amount of a compound of claim 1 that is effective in inhibiting tyrosine kinase activity of the IGF-1R receptor,

12. A method of treating a disorder or condition in a mammal for which inhibition of tyrosine kinase activity of the IGF-1 R receptor is needed in said mammal, comprising administering to said mammal an amount of a compound of claim 1 that is effective in treating said disorder or condition.

13. A method of treating a disorder or condition selected from the group consisting of cancer, cell proliferative disorders, viral infections, retinopathies, age related macular degeneration, atherosclerosis, conditions involving vascular smooth muscle proliferation or neointimai formation, restenosis following angioplasty or surgery, graft vessel disease, acromegaly, disorders secondary to acromegaly, hypertrophic conditions In which IGF/IGF-1 R signaling is implicated, benign prostatic hyperplasia, psoriasis, pulmonary fibrosis, pathologies related to chronic or acute oxidative stress or hyperoxia-induced tissue damage, metabolic disorders in which elevated IGF levels or IGF-1R activity are implicated, and obesity, in a mammal, comprising administering to said mammal in need of said treatment an amount of a compound of according of claim 1 that is effective in treating said disorder or condition.

14 A method of treating a disorder or condition selected from the group consisting of cancer, cell proliferative disorders, viral infections, retinopathies, age related macular degeneration, atherosclerosis, conditions involving vascular smooth muscle proliferation or neointimai formation, restenosis following angioplasty or surgery, graft vessel disease, acromegaly, disorders secondary to acromegaly, hypertrophic conditions in which IGF/IGF-1 R signaling is implicated, benign prostatic hyperplasia, psoriasis, pulmonary fibrosis, pathologies related to chronic or acute oxidative stress or hyperoxia-induced tissue damage, metabolic disorders in which elevated IGF levels or IGF-1 R activity are implicated, and obesity, in a mammal, comprising administering to said mammal in need of said treatment an amount of a compound according to claim 1 that is effective in inhibiting tyrosine kinase activity of IGF-1 R receptors.

15 The method according to claim 14, wherein said cancer is selected from the group consisting of carcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer, and Kaposi's sarcoma

16 A method of treating a disorder or condition according to claim 13, wherein said cell proliferative disorder is selected from the group consisting of familial adenomatosis polyposis, neurα-fibromatosis, arthritis and glomerulonephritis

17. A method of treating a disorder or condition according to ciaim 14, wherein said cell proliferative disorder is selected from the group consisting of familial adenomatosis polyposis, neuro-fibromatosis, arthritis and glomerulonephritis

18 A method of treating diseases mediated by dysregulated protein kinase activity in an mammal, which method comprises administering to said mamma! in need of said treatment a pharmaceutical composition comprising a compound according to claim 1 in combination with one or more chemotherapeutic agents or radiotherapy

19 The method according to claim 18, wherein said chemotherapeutfc agents are selected from the group consisting of antihormonai agents, aromatase inhibitors, topoisomerase I inhibitors, topoisomerase Il inhibitors, agents that target microtubules, platin-based agents, alkylating agents, DNA damaging or intercalating agents, antineoplastic antimetabolites, kinase inhibitors, anti-angiogenlc agents, inhibitors of kiπesins, therapeutic monoclonal antibodies, inhibitors of nriTOR, histone deacetylase inhibitors, famesyj transferase Inhibitors, and Inhibitors of hypoxic response.