WO2008060866A1 - Novel compounds - Google Patents

Abstract

The present invention relates to pyrimidine derivatives, compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions and medicaments. Such pyrimidine derivatives are potentially useful in the treatment of diseases associated with inappropriate c-Met activity. A compound of Formula (I):

Description

NOVEL COMPOUNDS

FIELD OF THE INVENTION The present invention relates to pyrimidine derivatives, compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions and medicaments. Such pyrimidine derivatives are potentially useful in the treatment of diseases associated with inappropriate c- Met activity.

BACKGROUND OF THE INVENTION

Protein kinases represent a large family of enzymes that catalyse the phosphorylation of proteins, and play a central role in the regulation of a wide variety of cellular processes. Abnormal protein kinase activity has been related to a plethora of disorders ranging from diseases such as psoriasis to virulent diseases such as glioblastoma (brain cancer).

Kinases and their ligands play critical roles in various cellular activities. Thus deregulation of kinase enzymatic activity can lead to altered cellular properties such as uncontrolled cell growth that is associated with cancers. A number of pathological diseases have been linked to altered kinase signalling, including immunological disorders and degenerative, inflammatory and cardiovascular diseases. Therefore the kinase enzyme family has become an important and interesting therapeutic target.

The hepatocyte growth factor receptor ("HGFR" or "c-Met") is a receptor tyrosine kinase (RTK) which is an attractive target for oncological, antiangiogenic and antiproliferative activity [Birchmeier et al, Nature Reviews, 4:915-925 (2003)]. c-Met RTK is encoded by the Met proto-oncogene. It is a member of a subfamily of heterodimeric RTKs which include Met, Ron and Sea. c-Met is expressed in numerous tissues such as epithelial, endothelial and mesenchymal cells, although primarily cells of epithelial origin [Maulik et al., Cytokine and Growth Factor Rev., 13:41-59, (2002)]. Activation of the c-Met enzyme induces proliferation, motility, invasion and angiogenesis. It has also been shown to be important in morphogenic differentiation and organisation of three-dimensional tubular structures, for example gland formation and renal tubular cells [Ma et al., Cancer and Metastasis Rev., 22:309-325, (2003)].

The endogenous ligand for c-Met is hepatocyte growth factor (HGF), also known as "scatter factor" (SF). HGF is a heterodimeric protein which is secreted by mescenchymal or stromal cells and is a potent inducer of angiogenesis and survival factor for endothelial cells [Bussolino et al., J. Cell Biol., 119(3):629-642, (1992), Birchmeier et al. Trends Cell Biol, 8:404-410 (1998)]. For an in-depth review and discussions on HGF and c-Met interactions see Goldberg and Rosen, "Hepatocyte Growth Factor-Scatter Factor and the c-Met Receptor", Birkhauser Verlag-Basel, (1993).

Various biological activities have been reported for HGF through its interactions with c-Met. Binding of HGF induces activation of c-Met via autophosphorylation which results in an increase of receptor-dependent signalling which consequently promotes cell growth and invasion. Thus, signal transduction through the activation of the c- Met receptor is responsible for many of the characteristics of tumour cells.

Both HGF and c-Met are expressed at abnormally high levels in a number of human cancers (particularly sarcomas). For tumour growth to occur, new blood vessels must be recruited into the tumour from pre-existing vessels in conjunction with invasion, adhesion and proliferation of malignant cells. c-Met gene amplification, mutation and rearrangement have also been observed in a subset of human cancers. Activating mutations in the kinase domain of the c-Met gene have been implicated as the cause of hereditary papillary renal carcinoma and have been observed in sporatic papillary renal carcinoma, ovarian cancer, childhood hepatocellular carcinoma, gastric cancer, lung cancer and squamous cell carcinoma [Langati et al., Curr. Drug Targets, 2:41-55, (2001 ), Danilkovitch-Miagkova et al., J. Clin. Invest. 109:863-867 (2002)]. Numerous studies have correlated the expression of c-Met and/or HGF with disease progression in a variety of tumour types including breast, colon, renal, lung, prostate, pancreas, brain, liver, ovaries, bone, stomach, skin bladder and gall bladder cancers in addition to squamous cell myeloid leukaemia, hemangiomas, melanomas, astrocytomas and glioblastomas. Furthermore, over expression of the c-Met oncogene has also been suggested to play a role in the progression and pathogenesis of in a number of human cancers, such as thyroid tumours [Oncogene, 7:2549-2553, (1992)].

Inhibition of angiogenesis has been shown to be linked to the suppression or reversion of tumour progression [Boehm et al., Nature, 390:404-407, (1997)], especially if multiple inhibitors are employed compared to just one. Angiogenesis can be stimulated by HGF as well as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Thus, modulation of c-Met is desirable as a means to treat cancer and cancer-related diseases.

Angiogenesis is the development of new blood vessels, generally capilliaries from pre-existing vasculature. Arteriogenesis is the process of remodelling small vessels into larger conduit vessels. These processes of vascular growth are required during beneficial processes such as tissue repair, wound healing and at certain stages of the female reproductive cycle. Inappropriate angiogenesis has been associated with several disease states including retionopathies, ischemic disease, neoplasias, rheumatoid arthritis, psoriasis, artherosolerosis, certain forms of chronic inflammatory disorders and certain forms of mascular degeneration [Middleton et al., Arthritis Res. Ther., 6(2):60-72, (2004)]. The inhibition of angiogenesis may result in blocking the development of pathological pannus tissue in rheumatoid arthritis.

Stimulation of vascular growth has potential utility for treatment of ischemia-induced pathologies such as myocardial infarction, coronary artery disease, stroke and peripheral vascular disease [Ono et al., Circulation, 95:2552-2558, (1997)]. The sprouting of new vessels and/or the expansion of smaller vessels in ischemic tissues prevents the death of ischemic tissue and encourages tissue repair. Certain diseases are well-known to be associated with deregulated angiogenesis such as retinopathies (including diabetic retinopathy) ocular neovascularisation, psoriasis, hemangioma, hermangioblastoma, age-related macular degeneration, arteriosclerosis, inflammatory disease for example rheumatoid or rheumatic inflammatory disease especially arthritis (including rheumatoid arthritis) or other chronic inflammatory disorders such as chronic asthma, arterial or post- transplantational atherosclerosis, endometriosis and neoplastic diseases such as so- called solid tumours and liquid tumours (e.g. leukemias). For a discussion on the role of angiogenesis in a various disease states see, for example. Fan et. al. Trends in Pharm. ScL, 16:54-66; Shawver et. al., DDT Vol. 2(2), (1997); Folkman, Nature Medicine, 1 :27:31 , (1995). Felmeden et al., European Heart Journal, 24:586-603 (2002).

Other non-oncological diseases and disorders that have been linked to elevated levels of c-Met and HGF include hypertension, rheumatoid arthritis and myocardial infarction. Increased levels of HGF have been observed in patients with hepatic failure [Gohda et al., Exp. Cell Res., 166:139-150 (1986)] and it has been shown to be a mitogen for certain cell types such as melanocytes, keratinocytes, renal tubular cells, cells of epithelial origin and certain endothelial cells [Igawa et al., Biochem. Biophys. Res. Comm., 174(2):831-838 (1991 )]. The c-Met oncogene has postulated to play a role in microglial reactions to CNS injuries [Oncogene, 8:219-222, (1993)].

Plasmodium, the causative agent of malaria causes an increase in HGF secretion. Inhibition of the c-Met kinase has also been shown to induce a specific increase in apoptosis of infected cells and thus a significant decrease in infection [Leirinao et. al., Cell. Microbiol., 7(4):603-609, (2005)] Infection with Helicobacter pylori is assumed to lead to invasive gastric cancer, and has also been shown to activate c-Met [Churin et al., J. Cell Bio., 161 (2):249-255, (2003)].

Therefore c-Met inhibitors may be useful in treating diseases such as cancer and other diseases related to abnormal cell growth and c-Met activation.

The present invention relates to pyrimidine derivatives or salts or solvates thereof that are histamine c-Met kinase inhibitors. Such compounds or salts or solvates thereof may be useful in the treatment of cancer, certain viral diseases, cardiovascular disorders, rheumatoid arthritis, malaria and other diseases and conditional disorders described herein that are associated with inappropriate c-Met or HGF activity.

BRIEF SUMMARY OF THE INVENTION

In one aspect of the present invention, there is provided a compound of Formula (I):

R¹ is -Ci-salkylene-morpholino (the alkylene bonded to the nitrogen of the morpholino group), -Ci-₃alkylene-piperazine [wherein the alkylene is bonded to a nitrogen in the piperizine and piperazine is substituted on the other nitrogen by SO₂Ci_-3alkyl];

R² is

-(X)_n-phenyl (wherein the phenyl is optionally fused to a cyclopentyl ring or optionally substituted one or two times with substituents independently selected from

-C_1-6alkyl, -C_1-6haloalkyl, -Ci-₆alkoxy, -Ci-₆haloalkoxy, -halogen, -COC_1-6alkyl,

-CN, -O-phenyl, -OCi_-3alkylenephenyl, -CONR^aR^b);

X is Ci-3 alkylene, -CO-, -SO₂-; n is O or 1

R^a and R^b independently represent H, -Ci_-3alkyl or together with the nitrogen to which they are joined form a morpholino or piperazine ring [wherein the piperazine is substituted on the other nitrogen atom by Ci_-3 alkyl];

-H;

-Ci-6 alkyl;

-C₃-6 cycloalkyl;

-Ci-6 hydroxyalkyl;

-C_1-3 alkylene NR^cR^α wherein R^c and R^d are independently H, Ci_-3 alkyl or together with the nitrogen to which they are joined form a piperazine or morpholino ring [and the piperazine ring is substituted on the other nitrogen by Ci_-3 alkyl]; or a salt or solvate thereof.

In a further aspect of the present invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof for use in therapy, and particularly in the treatment of diseases and conditions mediated by inappropriate c- Met activity, such as cancer, certain viral diseases and cardiovascular disorders.

In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutically acceptable carriers, diluents and excipients.

In a further aspect of the present invention, there is provided a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and one or more therapeutic agents, such as one or more anti-cancer agents, e.g. one or more antineoplastic agents.

In a further aspect of the present invention there is provided a combination comprising a compound of formula (I) and one or more therapeutic agents such as one or more anticancer agents for use in therapy, in particular the treatment of diseases and conditions mediated by inappropriate c-Met activity such as cancer, certain viral diseases and cardiovascular disorders.

In a further aspect of the present invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for use in the treatment of diseases and conditions mediated by inappropriate c-Met activity such as cancer, certain viral diseases and cardiovascular disorders.

In a further aspect there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for the treatment of cancer. In a further aspect of the present invention, there is provided a method of treating diseases and conditions mediated by inappropriate c-Met activity, such as cancer, certain viral diseases and cardiovascular disorders comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

In a further aspect of the present invention, there is provided a method of treating cancer comprising administering a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

In a further aspect of the present invention, there is provided a method of treating cancer comprising administering a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof and (ii) at least one additional anti-cancer therapy.

In a further aspect of the present invention there is provided the use of a (i) compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and (ii) at least one additional cancer therapy for the manufacture of a medicament for the treatment of cancer.

In a further aspect of the present invention, there is provided processes for the synthesis of compounds of formula (I) and salts or solvates thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

The inappropriate c-Met activity referred to herein is any c-Met activity that deviates from the normal c-Met activity expected in a particular mammalian subject. Inappropriate c-Met activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of c-Met activity. Such inappropriate activity may result then, for example, from overexpression or mutation of the protein kinase or ligand leading to inappropriate or uncontrolled activation of the receptor. Furthermore, it is also understood that unwanted c-Met activity may reside in an abnormal source, such as a malignancy. That is, the level of c-Met activity does not have to be abnormal to be considered inappropriate, rather the activity derives from an abnormal source. In a like manner, the inappropriate angiogenesis referred to herein is any angiogenic activity that deviates from the normal angiogenic activity expected in a particular mammalian subject. Inappropriate angiogenesis may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of angiogenic activity. Such inappropriate activity may result then, for example, from overexpression or mutation of a protein kinase or ligand leading to inappropriate or uncontrolled activation of angiogenesis. Furthermore, it is also understood that unwanted angiogenic activity may reside in an abnormal source, such as a malignancy. That is, the level of angiogenic activity does not have to be abnormal to be considered inappropriate, rather the activity derives from an abnormal source.

As used herein the term "alkyl" refers to a straight- or branched-chain hydrocarbon radical having the specified number of carbon atoms. As used herein, the terms "Ci- C₃ alkyl" refer to an alkyl group, as defined above, containing at least 1 , and at most 3 carbon atoms respectively. Examples of "alkyl" as used herein include methyl, ethyl, n-propyl, isopropyl.

As used herein, the term "alkylene" refers to a straight or branched chain divalent hydrocarbon radical having the specified number of carbon atoms. As used herein, the terms "Ci_C3 alkylene" refer to an alkylene group, as defined above, which contains at least 1 and at most 3 carbon atoms respectively. Examples of "alkylene" as used herein include, but are not limited to methylene, ethylene, n-propylene.

As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) and the term "halo" refers to the halogen radicals: fluoro (-F), chloro (-Cl), bromo(-Br), and iodo(-l). As used herein, the term "haloalkyl" refers to an alkyl group as defined above, substituted with at least one halo group, halo being as defined herein. Examples of such branched or straight chained haloalkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl and n-butyl substituted independently with one or more halos, e.g., fluoro, chloro, bromo and iodo.

As used herein, the term "alkoxy" refers to the group R_aO-, where R_a is alkyl as defined above and the terms "C₁-C3 alkoxy" refer to an alkoxy group as defined herein wherein the alkyl moiety contains at least 1 , and at most 3, carbon atoms. Exemplary "Ci-C₃ alkoxy" groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.

As used herein the term "haloalkoxy" refers to a group OR^a wherein R^a is haloalkyl as defined above and the terms C_1-3 and C_1-6 haloalkoxy refer to a haloalkoxy group as defined herein wherein the alkyl moiety contains at least 1 and at most 3 or 6 carbon atoms. Exemplary C_1-3 haloakloxy groups useful in the present invention include but are not limited to -OCF₃.

As used herein, the term "hydroxyl" refers to the group -OH.

As used herein, the term "C₁-C₆ hydroxyalkyl" refers to a straight or branched chain hydrocarbon containing at least 1 , and at most 6 carbon atoms substituted with at least one hydroxy, hydroxy being as defined herein. Examples of branched or straight chained "C₁-C₆ hydroxyalkyl" groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted independently with one or more hydroxy groups.

As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur, and includes both event(s), which occur, and events that do not occur.

The term "c-Met inhibitor" is used to mean a compound which inhibits c-Met. The term "c-Met mediated disease" is used to mean any disease state mediated or modulated by c-Met kinase mechanisms, in particular cancer, certain viral diseases and cardiovascular disorders.

When used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "a compound of the invention" means a compound of formula (I) or a salt, or solvate thereof.

It is to be understood that the present invention covers the compounds of formula (I) as the free base and as salts and solvates thereof, for example a pharmaceutically acceptable salt or solvate.

It is to be further understood that references hereinafter to compounds of the invention or to compounds of formula (I) means a compound of formula (I) as the free base, or as a salt, or as a solvate.

In one aspect R¹ is in the meta or para position on the phenyl ring relative to the nitrogen.

In a further aspect R¹ is in the meta position.

In one aspect, R¹,

-(CH₂J₂ , or -CH₂- -SO₂CH₃

In one aspect, R² is -CH₂CH_3, -tertiarybutyl, -phenyl (optionally substituted by one or two substituents selected from -CF₃, -F, -Cl, -CH₃, -OCF₃, -CH₂CH₃, -Ophenyl). In one aspect, R² is

While the embodiments for each variable have generally been listed above separately for each variable this invention includes those compounds in which several or each embodiment in formula (I) is selected from each of the embodiments listed above. Therefore, this invention is intended to include all combinations of embodiments for each variable.

Specific examples of compounds of the present invention include

A. N-ethyl-N'-(4-fmethvir2-α3-r2-(4-morDholinvnethyllDhenyl>aminoV4- pyrimidinyllamino}phenyl)urea

B. N-(4-fmethvir2-α3-r2-(4-morpholinvnethyllphenyl>aminoV4- Pyrimidinyllamino}phenyl)-N'-r3-(trifluoromethyl)phenvllurea

C. N-eihyl-N'-r4-(meihylf2-r(3-f r4-(meihylsulfonyl)-l- piperazinyll methyl ) phenvDaminol -4-pyrimidinyl ) amino)phenyllurea

The compound of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include acid and base addition salts. For a review on suitable salts see Berge et al., J. Pharm. ScL, 66:1-19, (1977).

As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid respectively. Indeed, in certain embodiments of the invention, pharmaceutically acceptable salts may be preferred over the respective free base or free acid because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage.

Suitable pharmaceutically acceptable salts can include acid or base additions salts.

A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, formic, sulfuric, nitric, phosphoric, succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid), optionally in a suitable solvent such as an organic solvent, to give the salt. Thus, a pharmaceutically acceptable acid addition salt of a compound of formula (I) can be for example a hydrobromide, hydrochloride, formate, sulfate, nitrate, phosphate, succinate, maleate, acetate, fumarate, citrate, tartrate, benzoate, p-toluenesulfonate, methanesulfonate or naphthalenesulfonate salt. Other representative salts include the following salts: benzenesulfonate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, Λ/-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, tannate, teoclate, tosylate, triethiodide, trimethylammonium and valerate.

Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium, and salts with organic bases, including salts of primary, secondary and tertiary amines such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine and Λ/-methyl-D-glucamine.

Other non-pharmaceutically acceptable salts, e.g. oxalates or trifluoroacetates, may be used, for example in the isolation of the compound of the invention, and are included within the scope of this invention. The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).

It will be appreciated that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvents with high boiling points and/or solvents with a high propensity to form hydrogen bonds such as water, xylene, Λ/-methyl pyrrolidinone methanol may be used to form solvates. Methods for identification of solvates include, but are not limited to, NMR and microanalysis. Solvates of the compound of the invention are within the scope of the invention. The compounds of the invention may have the ability to crystallize in more than one form, a characteristic, which is known as polymorphism, and it is understood that such polymorphic forms ("polymorphs") are within the scope of formula (I). Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallization process.

Polymorphic forms of compounds of formula (I) may be characterized and differentiated using a number of conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD) patterns, infrared (IR) spectra, Raman spectra, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (NMR).

It will be appreciated that compounds of formula (I) may possess one or more asymmetric carbon atoms so that optical isomers e.g. enantiomers or diastereoisomers may be formed. The present invention encompasses all optical isomers of the compounds of formula (I) whether as individual isomers isolated such as to be substantially free of the other isomer (i.e. pure) or as mixtures thereof (i.e. racemates and racemic mixtures). An individual isomer isolated such as to be substantially free of the other isomer (i.e. pure) may be isolated such that less than about 10%, particularly less than about 1%, for example less than about 0.1% of the other isomer is present.

Further, it will be appreciated that the R and S enantiomers may be isolated from the racemate by conventional resolution methods such as preparative HPLC involving a chiral stationary phase, by resolution using fractional crystallisation of a salt of the free base with a chiral acid, by chemical conversion to a diastereoisomer using a chiral auxiliary followed by chromatographic separation of the isomers and then removal of the chiral auxiliary and regeneration of the pure enantiomer, or by total asymmetric synthesis.

Certain compounds of formula (I) may exist in one of several tautomeric forms. It will be understood that the present invention encompasses all tautomers of the compounds of formula (I) whether as individual tautomers or as mixtures thereof. It will be appreciated from the foregoing that included within the scope of the invention are all solvates, hydrates, complexes, isomers and polymorphic forms of the compound of the invention and salts thereof.

The compounds of formula (I) and salts and solvates thereof, are believed to have therapeutic potential as a result of inhibition of the protein kinase c-Met.

The invention thus provides compounds of formula (I) and salts and solvates derivatives thereof for use in therapy, particularly in the treatment of diseases and conditions mediated by inappropriate C-Met kinase activity.

The invention also provides compounds of formula (1 ) for use in the treatment of diseases and conditions mediated by inappropriate C-Met kinase activity.

In a further aspect of the present invention, there is provided a method of treating diseases and conditions associated with inappropriate c-Met kinase activity comprising administering a compound of formula (1 ) or a salt or solvate thereof.

In a further aspect of the present invention there is provided the use of a compound of formula (1 ) or a salt or solvate thereof in the manufacture of a medicament for use in the treatment of diseases and conditions associated with inappropriate c-Met kinase activity.

Examples of diseases and conditions in which compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof may have potentially beneficial antitumour effects include, but are not limited to, cancers of the lung, bone, pancreas, skin, head, neck, uterus, ovaries, stomach, colon, breast, esophagus, small intestine, bowel, endocrine system, thyroid glad, parathyroid gland, adrenal gland, urethra, prostate, penis, testes, ureter, bladder, kidney or liver; rectal cancer; cancer of the anal region; carcinomas of the fallopian tubes, endometrium, cervix, vagina, vulva, renal pelvis, renal cell; sarcoma of soft tissue; myxoma; rhabdomyoma; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemagioma; hepatoma; fibrosarcoma; chondrosarcoma; myeloma; chronic or acute leukemia; lymphocytic lymphomas; primary CNS lymphoma; neoplasms of the CNS; spinal axis tumours; squamous cell carcinomas; synovial sarcoma; malignant pleural mesotheliomas; brain stem glioma; pituitary adenoma; bronchial adenoma; chondromatous hanlartoma; inesothelioma; Hodgkin's Disease or a combination of one or more of the foregoing cancers.

The compounds of the present invention may also be useful in the treatment of one or more diseases afflicting mammals which are characterized by cellular proliferation in the area of disorders associated with neo-vascularization and/or vascular permeability including blood vessel proliferative disorders including arthritis (rheumatoid arthritis) and restenosis; fibrotic disorders including hepatic cirrhosis and atherosclerosis; mesangial cell proliferative disorders include glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, proliferative retinopathies, organ transplant rejection and glomerulopathies; and metabolic disorders include psoriasis, diabetes mellitus, chronic wound healing, inflammation and neurodegenerative diseases.

Furthermore, the compounds of the invention may be of use in the treatment of viral diseases related to activation of c-Met kinase, including, but not limited to malaria and Helicobacter pylori infection.

Further conditions include cardiovascular disorders, such as myocardial infarction, coronary artery disease, stroke and peripheral vascular disease.

While it is possible that, for use in therapy, therapeutically effective amounts of a compound of formula (I), as well as pharmaceutically acceptable salts or solvates thereof, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. The compounds of the formula (I) and pharmaceutically acceptable salts or solvates thereof are as described above. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical composition including admixing a compound of the formula (I), or pharmaceutically acceptable salts or solvates thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, of a compound of the formula (I) depending on the condition being treated, the route of administration and the age, weight and condition of the patient. Preferred unit dosage compositions are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).

Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in- water liquid emulsions or water-in-oil liquid emulsions.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.

Capsules are made by preparing a powder mixture as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.

Where appropriate, dosage unit compositions for oral administration can be microencapsulated. The composition can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.

The compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide- phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

Pharmaceutical compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharm. Res., 3(6):318 (1986). Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouth and skin, the compositions are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.

Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or as enemas.

Pharmaceutical compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable compositions wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.

Pharmaceutical compositions adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurised aerosols, nebulizers or insufflators.

Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray compositions. Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

It should be understood that in addition to the ingredients particularly mentioned above, the compositions may include other agents conventional in the art having regard to the type of composition in question, for example those suitable for oral administration may include flavouring agents.

Therefore, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutically acceptable carriers, diluents and excipients.

A therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the composition, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. However, an effective amount of a compound of formula (I) for the treatment of disorders or diseases associated with inappropriate c-Met activity, will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day. Thus, for a 70 kg adult mammal, the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub- doses per day such that the total daily dose is the same. An effective amount of a pharmaceutically acceptable salt thereof may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above. The compounds of the present invention and their pharmaceutically acceptable salts or solvates may be employed alone or in combination with other therapeutic agents. Thus the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and one or more therapeutic agents. Particularly, combination with at least one anti-cancer therapy is envisaged. In particular, in anti-cancer therapy, combination with other chemotherapeutic, hormonal or antibody agents is envisaged, as well as combination with surgical therapy and radiotherapy. Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and the use of at least one other therapeutic agent. For example, combination therapies according to the present invention comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other pharmaceutically active agent, such as an anti-cancer therapeutic agent. The compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order. The amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.

The compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof and at least one additional cancer treatment therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination with such other anti-cancer therapies. In one embodiment, the other anti-cancer therapy is at least one additional chemotherapeutic therapy including administration of at least one anti-neoplastic agent. The administration in combination of a compound of formula (I) or pharmaceutically acceptable salts or solvates thereof with other anti-neoplastic agents may be in combination in accordance with the invention by administration concomitantly in (1 ) a unitary pharmaceutical composition including both compounds, or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one anti-neoplastic agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time. Anti-neoplastic agents may induce anti-neoplastic effects in a cell-cycle specific manner, i.e., are phase specific and act at a specific phase of the cell cycle, or bind DNA and act in a non cell-cycle specific manner, i.e., are non-cell cycle specific and operate by other mechanisms.

Anti-neoplastic agents useful in combination with the compounds and pharmaceutically acceptable salt of formula I include, but are not limited to the following classes, modes of action and substances:

(1 ) Antimetabolite-type/thymidilate synthase inhibitor antineoplastic agents, which are exemplified by, but are not limited to: allopurinol, carmofur, cladrabine, cytarabine, cytosine arabinoside, dezaguanine, fludurabine, fluorodeoxyuridine, 5- fluorouracil, hydroxyurea, isopropyl pyrrolizine, methotrexate, mercaptopurine, plicamycin, raltitrexed, tegafur, thioguanine and trimetrexate.

(2) Alkylating-type antineoplastic agents, which are exemplified by, but are not limited to: anaxirone, busulfan, carmustine, carboplatin, cisplatin, chlorambucil, cyclophosphamide, dacarbazine, elmustine, hexamethylmelamine, iproplatin, lomustine, mechlorethamine, melphalan, nitrogen mustards, nitrosoureas, oxaliplatin, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol;

(3) Antibiotic-type antineoplastic agents, which are exemplified by, but not limited to: aclarubicin, adriamycin, azino-mycin-A, bleomycin, calichemycin, chromoximycin, dactinomycin, doxorubicin, daunomycin, epirubicin, idarubicin, fostriecin, glidobactin, grincamycin, herbimycin, idarubicin, mitomycin-C, mithramycin, neoenactin, oxaunomycin, peplomycin, pilatin, rodorubicin, sibanomicin, steffimycin B, talisomycin, terpentecin, and zorubicin;

(4) Hormonal anti-neoplastic agents, such as antiprogestogens, topoisomerase I and Il inbiting agents and tubulin-interacting agents, which are exemplified by, but not limited to: α-carotene, acitretin, alstonine, amsacrine, anastrozole, ankinomycin, aphidicolin glycinate, asparaginase, baccharin, batracylin, benfiuron, benzotript,9- aminocamptothecin, camptothecin, caracemide, carmethizole hydrochloride, clan- fenur, claviridenone, CPT-11 , crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, dacarbazine, datelliptinium, didemnin-B, dmaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, docetaxel, droloxifene, elliprabin, elliptinium acetate, ergotamine, etoposide, etretinate, exemestane, fenretinide, gallium nitrate, hexadecylphosphocholine, iodoxyfene, ilmofosine, irinotecan, isoglutamine, isotretinoin, letrozole, leukoregulin, Ionidamine, megestrol acetate, merbarone, (optical forms of) 7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20- camptothecin, methylaoilinoacridine, minactivin, mitonafide, mitoquidone mopidamol, motretinide, nafazatrom, nocodazole derivative, ocreotide, oquizanocine, paclitaxel, pancratistatin, pazelliptine, piroxaotrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probimane, procarbazine, proglumide, raloxifene, razoxane, retelliptine, retinoic acid, spatol, spirogermarnum, superoxide dismutase, tamoxifen, taxol, taxotere, teniposide, thaliblastine, tocotrienol, topotecan, Topostin, toremifene, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, vorazole, and withanolides;

(5) Cytostatic agents, for example aromatase inhibitors such as antiandrogens such as bicalutamide, cyproterone acetate, flutamide, and nilutamide; LHRH agonists and antagagonists such as buserelin, goserelin acetate leuprorelin and luprolide; and testosterone 5α-dihydroreductase inhibitors such as finasteride;

(6) Agents that inhibit cancer cell invasion which are exemplified by but not limited to, for example, metalloproteinase inhibitors such as marimastat; and inhibitors of urokinase plasminogen activator receptor function;

(7) Inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies, such as anti-erb-B2 antibody trastuzumab [Herceptin™] and the anti-erb-B1 antibody cetuximab [C225], farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine-threonine kinase inhibitors such as inhibitors of the epidermal growth factor receptor (EGFr) family e.g. Λ/-(3- chloro-4-fluorophenyl-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine

[gefitinib, AZD1839], Λ/-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4- amine [erlotinib, OSI-774] and 6-acrylamido-Λ/-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)quinazolin-4-amine [CI-1033], cyclin dependent inhibitors such as CDK2 and CDK4 inhibitors, platelet derived growth factor receptor (PDGFr) inhibitors and other protein kinase inhibitors such as c-Raf and b-Raf;

(8) Antiangiogenic agents for example those which inhibit the effects of vascular endothelial growth factor receptor (VEGFR) inhibitors such as the anti-VEGFR antibody bevacizumab [Avastin™]; TIE-2 inhibitors and compounds that work by other mechanisms, such as linomide, inhibitors of integrin αvβ3 function and angiostatin;

(9) Vascular damaging agents, such as Combretastin A4;

(10) Antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503;

(1 1 ) Gene therapy approaches, for example, approaches to replace aberrant genes, such as aberrant p53, abberant BRCA1 or BRCA2; gene-directed enzyme pro-drug therapy (GDEPT); virus-directed enzyme pro-drug therapy (VDEPT); approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy;

(12) Immunotherapy approaches including, for example ex-vivo and in-vivo approaches in increase the immunogenecity of patient tumour cells, for example transfection with cyctokines such as interleukin 2, interleukin 4 or granulocyte- macrophage stimulating factor, approaches to decreased T-cell anergy, approaches using transfected immune cells, such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti- idiotypic antibodies;

(13) Cyclooxygenase Types 2 (COX-2) inhibitors, such as celecoxib and etoricoxib.

When a compound of the invention is used in combination with a second therapeutic agent active against the same disease, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.

Therefore, there is provided a combination comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents, such as one or more anti-cancer agents, e.g. one or more antineoplastic agents.

GENERAL PROCESSES The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples. Compounds of formula (I) may be prepared according to the following synthetic schemes and further detailed in the examples section following:

Scheme I

Compounds of formula I can be prepared according to the synthetic sequences illustrated in Schemes I and further detailed in the examples section following.

Typically 2,4-dichloropyrimidine undergoes a displacement reaction at C4 with an appropriate mono-protected dianiline (Ac or Boc for example) to provide the 2-chloro- 4-arylaminopyrimidine derivative (A). Subsequent N-alkylation of 2-chloro-4-arylaminopyrimidine derivative (A) under standard conditions affords the N⁴-alkyl-2-chloro-4-arylaminopyrimidine derivative (B).

Deprotection of the amino protecting group (Ac or Boc group, for example) under standard conditions) provides aniline (C), which is then converted to urea (D) derivative using conventional methods (for example isocyanate or CDI/amine).

Chloride (D) can then couple with an arylamine to provide 2,4-diarylaminopyrimidine of formula I.

Certain embodiments of the present invention will now be illustrated by way of example only. The physical data given for the compounds exemplified is consistent with the assigned structure of those compounds.

GENERAL EXPERIMENTAL

DEFINITIONS As used herein, the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); M (molar); mmol (millimoles); rt (room temperature); min (minutes); h (hour); mp (melting point); Rt (retention time); TFA (trifluoroacetic anhydride); AcOEt (EtOAc);

DCM (CH₂CI₂); DMF (Λ/,Λ/-dimethylformamide);

¹H NMR spectra were recorded on Bruker AVANCE-400. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad).

Low-resolution mass spectra (MS) were recorded on a Waters micromass ZQ2000; 2695 Alliance; 2996 Photodiode Array Detector. Preparative MS(ESI) purification uses the following condition:

Waters FractionLynx MS(ESI) condition

• Autosampler/Fractioncollector: 2767 inject collector • Waste collector: waters fraction collector 2

• HPLC: 2525 pump

• Detector: 2996 Photodiode Array Detector

• MS: ZQ2000

• Make up pump: waters reagent manager Agilent 1100 Preparative HPLC

Purification protocol

• Loading: 5-100 mg,

• 5 % (B) to 95 % (B)

• A - (Pure H2O:3 L+ 100% Formic acid 3 mL) • B - (Acetonitrile: 3 L + 100% Formic acid 3 mL)

• Flow rate: 50 mL/min

• Column: Phenomenex Geminy C-18, 30 X 100 mm (5 μm)

• Injection Volume: 1800 μL

• Collecetion done at 254 nm and 214 nm • Temperature: rt

All MPLC purification was done using Analogix IntelliFlash 280 using their Super Flash Sepra Si 50 columns. As a mobile phase can be used MeOH, dichloromethane, hexane, ethyl acetate, for example. All mass spectra were taken under electrospray ionization (ESI), chemical ionization (Cl), and electron impact (El) or by fast atom bombardment (FAB) methods. All reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid or p-anisaldehyde solution or mass spectrometry (electrospray or AP). Flash column chromatography was performed on silica gel (230-400 mesh, Merck) or using automated silica gel chromatography (Analogix IntelliFlash 280, UV detection triggering sample collection).

Example 1

N-ethyl-N'-(4-{methvir2-({3-r2-(4-morpholinyl)ethvnphenyl}amino)-4- pyrimidinyllaminolphenvDurea

To the solution of 2,4-dichloropyrimidine (3 g, 20 mmol 1.3 eq) in 2-propanol (50 ml.) was added mono-Boc-1 ,4-bisaniline (3 g, 15 mmol) followed by NaHCOs (5 g, 60 mmol, 3 eq) and the reaction mixture was refluxed over night. The suspension was the filtered hot, solution was evaporated. Oil was suspended in dichloromethane (30 ml.) and stirred for 30 min, while solid was crystallizing. Pure 1 ,1-dimethylethyl {4-[(2- chloro-4-pyrimidinyl)amino]phenyl}carbamate was then filtered, washed with cold dichloromethane and dried. 2.6 g was isolated (40 % yield). 1 H NMR (400 MHz, DMSO-de) δ ppm 1.45 (9 H, 2) 6.67 (1 H, d, J=5.81 Hz) 7.43 (4 H, br s) 8.09 (1 H, d, J=5.81 Hz) 9.35 (1 H, s) 9.95 (1 H, s)

Step 2 To the solution of 1.2 g of 1 ,1-dimethylethyl {4-[(2-chloro-4- pyrimidinyl)amino]phenyl}carbamate (3.75 mmol) in DMF ( 20 ml.) was added NaH (150 mg of 60 % suspension on mineral oil, 3.75 mmol, 1 eq). After 20 min, MeI (530mg, 3.75 mmol, 1 eq) was added and the reaction mixture was stirred for another 1 hour at the room temperature. Water (60 ml.) followed by ethyl acetate (60 ml.) was added and the layers were separated. Organic was washed with water, brine, dried over MgSO₄, filtered and evaporated to give 1.23 g (98 % yield) of pure 1 , 1 -dimethylethyl {4-[(2-chloro-4-pyrimidinyl)(methyl)amino]phenyl}carbamate. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.55 (9 H, s) 3.46 - 3.51 (3 H, m) 6.14 (1 H, d, J=6.06 Hz) 6.66 (1 H, s) 7.17 (2 H, t, J=7.83 Hz) 7.49 (2 H, d, J=8.59 Hz) 7.87 (1 H, d, J=6.06 Hz)

Step 3

1.23 g (3.7 mmol) of 1 ,1-dimethylethyl {4-[(2-chloro-4- pyrimidinyl)(methyl)amino]phenyl}carbamate was dissolved in 10 mL of TFA and the solution was stirred for 30 min, TFA was then evaporated, oil dissolved in 30 mL of ethyl acetate, and washed 2 x 20 mL of 1 M Na₂CO₃. Organic was then washed with brine, dried over MgSO₄, filtered and evaporated to give 600 mg ( 70 % yield) of pure N-(2-chloro-4-pyrimidinyl)-N-methyl-1 ,4-benzenediamine. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.44 (3 H, s) 6.12 (1 H, d, J=6.06 Hz) 6.76 (2 H, ddd, J=9.22, 3.03, 2.65 Hz) 6.97 - 7.02 (2 H, m) 7.84 (1 H, d, J=6.06 Hz)

Step 4

To the solution of N-(2-chloro-4-pyrimidinyl)-N-methyl-1 ,4-benzenediamine (100 mg, 0.43 mmol) in pyridine (2 mL) was added ethyl isocyanate 6 (200 mg, 2.8 mmol, 6.5 eq). The reaction mixture was stirred for 2 hours at the room temperature, evaporated, concentrated to 3 mL and injected to prep. MPLC system (Dichloromethane → EtOAc) to give 86 mg (65 % yield) of pure N-{4-[(2-chloro-4- pyrimidinyl)(methyl)amino]phenyl}-N'-ethylurea (65 % yield). 1 H NMR (400 MHz, MeOD) δ ppm 1.18 (3 H, t, J=7.20 Hz) 3.26 (2 H, d, J=7.33 Hz) 3.45 (3 H, s) 6.24 (1 H, d, J=6.32 Hz) 7.21 (2 H, d, J=8.84 Hz) 7.53 (2 H, d, J=8.84 Hz) 7.86 (1 H, d, J=6.32 Hz)

Step 5 To the solution of N-{4-[(2-chloro-4-pyrimidinyl)(methyl)amino]phenyl}-N'-ethylurea (43 mg, 0.14 mmol) in 2-propanol (2 mL) was added 3-[2-(4-morpholinyl) ethyl]aniline (20 mg, 0.1 mmol) followed by 6 N HCI solution (1 drop, catalytic). The reaction mixture was heated in the seal tube to 90 ⁰C, overnight, then filtered to give pure N- ethyl-N'-(4-{methyl[2-({3-[2-(4-morpholinyl)ethyl]phenyl}amino)-4-pyrimidinyl] amino}phenyl)urea as HCI salt (A) (22 mg, 46 % yield) or evaporated and purified by prep. HPLC to give pure N-ethyl-N'-(4-{methyl[2-({3-[2-(4- morpholinyl)ethyl]phenyl}amino)-4-pyrimidinyl]amino}phenyl)urea (36 mg, 76 % yield) as a free base (B).

HCI salt (A): 1 H NMR (400 MHz, DMSOd₆) δ ppm 1.03 - 1.09 (3 H, m) 3.07 - 3.14 (5 H, m) 3.31 (2 H, s) 3.49 (5 H, m) 3.62 (1 H, s) 3.76 - 3.83 (2 H, m) 3.98 (2 H, s) 6.34 (1 H, t, J=5.31 Hz) 7.09 (1 H, s) 7.25 (2 H, d, J=8.59 Hz) 7.38 (1 H, s) 7.49 (1 H, s) 7.56 (3 H, d, J=8.84 Hz) 7.87 (1 H, d, J=6.06 Hz) 8.94 (1 H, s) 10.50 (1 H, br s) 11.06 (1 H, br s) LC-MS (m/e) = 476.2 (MH+). Rt = 1.25 min

Free base (B): 1 H NMR (400 MHz, MeOD) δ ppm 1.19 (3 H, t, J=7.20 Hz) 2.97 - 3.03 (2 H, m) 3.15 - 3.22 (6 H, m) 3.27 (2 H, q, J=7.07 Hz) 3.49 - 3.54 (3 H, m) 3.87 - 3.92 (4 H, m) 5.97 (1 H, d, J=6.82 Hz) 7.04 (1 H, d, J=7.58 Hz) 7.21 - 7.26 (2 H, m) 7.32 (1 H, t, J=7.83 Hz) 7.46 (1 H, d, J=8.34 Hz) 7.50 - 7.57 (3 H, m) 7.73 (1 H, d, J=6.82 Hz) 8.18 (2 H, s) LC-MS (m/e) = 476.3 (MH+). Rt = 1.37 min

Example 2

N-ethyl-N'-r4-(methylf2-r(3-fr4-(methylsulfonyl)-1 - piperazinyllmethyl>phenyl)aminol-4-pyrimidinyl>amino)phenyllurea

To the solution of N-{4-[(2-chloro-4-pyrimidinyl)(methyl)amino]phenyl}-N'-ethylurea (43 mg, 0.14 mmol) in 2-propanol (2 ml.) was added (3-{[4-(methylsulfonyl)-1- piperazinyl]methyl}phenyl)amine (20 mg, 0.1 mmol) followed by 6 N HCI solution (1 drop, catalytic). The reaction mixture was heated in the seal tube to 90 ⁰C, overnight, then evaporated and purified by prep. HPLC to give pure N-ethyl-N'-[4-(methyl{2-[(3- {[4-(methylsulfonyl)-1-piperazinyl]methyl}phenyl)amino]-4- pyrimidinyl}amino)phenyl]urea (20 mg, 37 % yield). 1 H NMR (400 MHz, MeOD) δ ppm 1.19 (3 H, t, J=7.20 Hz) 2.63 - 2.70 (4 H, m) 2.86 (3 H, s) 3.27 (6 H, t, J=7.07 Hz) 3.53 (3 H, s) 3.63 (2 H, s) 5.98 (1 H, d, J=6.82 Hz) 7.15 (1 H, d, J=7.58 Hz) 7.22 - 7.29 (2 H, m) 7.34 (1 H, t, J=7.83 Hz) 7.48 (1 H, s) 7.52 - 7.59 (2 H, m) 7.66 (1 H, s) 7.71 (1 H, d, J=6.82 Hz) LC-MS (m/e) = 539.4 (MH+). Rt = 1.38 min

Example 3

N-(4-fmethvir2-(f3-r2-(4-morpholinyl)ethvnphenyl>amino)-4-

Pyrimidinyllamino}phenyl)-NW3-(trifluoromethyl)phenyllurea

To the solution of N-(2-chloro-4-pyrimidinyl)-N-methyl-1 ,4-benzenediamine (100 mg, 0.42 mmol) in pyridine (2 mL) was added 1-isocyanato-3-(trifluoromethyl) benzene (100 mg, 0.53 mmol, 1.2 eq). The reaction mixture was stirred for 2 hours at the room temperature, evaporated, concentrated to 3 mL and injected to prep. MPLC system (DCM → EtOAc) to give 21 mg of pure N-{4-[(2-chloro-4-pyrimidinyl)(methyl) amino]phenyl}-N'-[3-(trifluoromethyl)phenyl]urea (12 % yield). LC-MS (m/e) = 422.0 (MH+). Rt = 2.37 min

Step 2 To the solution of N-{4-[(2-chloro-4-pyrimidinyl)(methyl) amino]phenyl}-N'-[3- (trifluoromethyl)phenyl]urea (21 mg, 0.05 mmol) in 2-propanol (2 ml.) was added 3- [2-(4-morpholinyl) ethyl]aniline (10 mg, 0.05 mmol) followed by 6 N HCI solution (1 drop, catalytic). The reaction mixture was heated in the seal tube to 90 ⁰C, overnight, then evaporated and purified by prep. HPLC to give pure N-(4-{methyl[2-({3-[2-(4- morpholinyl)ethyl]phenyl}amino)-4-pyrimidinyl]amino}phenyl)-N'-[3-

(trifluoromethyl)phenyl]urea (10 mg, 34 % yield). 1 H NMR (400 MHz, MeOD) D ppm 2.96 - 3.03 (2 H, m) 3.12 - 3.18 (6 H, m) 3.54 (3 H, s) 3.85 - 3.90 (4 H, m) 5.98 (1 H, d, J=6.82 Hz) 7.02 (1 H, d, J=7.58 Hz) 7.27 - 7.34 (4 H, m) 7.48 - 7.55 (3 H, m) 7.64 (3 H, d, J=8.59 Hz) 7.74 (1 H, d, J=6.82 Hz) 7.97 (1 H, s) 8.33 (3 H, s) LC-MS (m/e) = 592.2 (MH+). Rt = 1.78 min

BIOLOGICAL DATA

CELL-BASED ASSAY FOR C-MET AUTOPHOSPHORYLATION

1. CONSTRUCTION OF THE HUMAN C-MET/CFMS CHIMERIC EXPRESSION VECTOR To generate a chimeric cDNA clone of c-Met with cFms, the extracellular domain of colony stimulating factor 1 receptor (CSF1 R encoded by cFms gene) was fused with the transmembrane and cytoplasmic domain of c-Met. Reverse-transcribed RNA from human placenta was used as template to clone c-Met. The transmembrane/ cytoplasmic domain fragment of c-Met (nucleotides 933 to 1390) containing a Notl site at both 5'- and 3'-end was generated by polymerase chain reaction (PCR) using following two oligonucleotides; 5' primer: 5'-CCCCCCGCGGCCGCCGGATTGATTGCTGGTGTTGTCTCAATATCA-S'

3' primer: 5'-CCCCCCGCGGCCGCCCTATGATGTCTCCCAGAAGGAGGCTGGTCG-S' The resulting c-Met cDNA was cloned into pCR2.1-TOPO vector (c-Met/ pCR2.1- TOPO). The extracellular domain fragment of cFms (nucleotides 1 to 512) containing BamHI site at 5'-end and Notl site at 3'-end was generated from human placenta cDNA by PCR using two oligonucleotides; 5'primer:

5'-CCCCCCGGATCCACCATGGGCCCAGGAGTTCTGCTGCTCCTGCTGGTGGCC- 3'

3'primer: 5'-AAAAAAGGCGGCCGCCTCATCCGGGGGATGCGTGTGGGCTCCTGC-S'

The resulting cFms cDNA was cloned into pcDNA3.1 vector (Invitrogen) using the BamHI and Notl sites (cFms/pcDNA3.1 ). To generate complete chimeric construct, the c-Met fragment (transmembrane and cytoplasmic domain) was digested with Notl sites (in c-Met/pCR2.1-TOPO vector) and then subcloned into cFms /pCDNA3.1 vector by Notl site (c-Met/cFms/pcDNA3.1 ).

2. ESTABLISHMENT OF C-MET/CFMS STABLE CELL LINES

NIH3T3 cells were grown in DMEM supplemented with 10% fetal bovine serum. NIH3T3 cells were transfected with c-Met/cFms/pcDNA3.1 vector alone using the calcium phosphate method according to the manufacturer's instructions. Three days after transfection, cells were selected with G418 (0.4 rrigml^"1) for 14 days and the expression of c-Met chimeric receptor in the G418-resistant colonies of NIH3T3 (c- Met/cFms/NIH3T3) cells was analyzed by immunoblot. Autophosphorylation of c-Met induced by the stimulation with M-SCF, the ligand for CSF1 R, was analyzed by immunoprecipitation and immnoblot, and prominent stable transfectant was selected for c-Met autophosphorylation assay.

3. IMMUNOPRECIPITATION AND IMMUNOBLOT ANALYSIS c-Met/cFms/NIH3T3 cells were grown to confluence in DMEM supplemented with 10% fetal bovine serum, 0.4 mgml^"1 G418 and serum starved in serum-free DMEM for 1 hour at 37 ⁰C. Cells were stimulated with M-CSF at 300 ngml^"1 for 10 min. Cells were washed once with cold PBS and lysed with TNE lysis buffer (10 mM Tris-HCI pH7.4, 150 mM NaCI, 1 mM EDTA, 1% NP-40, 10 mM NaF, 2 mM Na₃VO₄, 10 mM Na₄P₂O₇ and Protease Inhibitor Cocktail (Complete mini EDTA-free, Roche)). Debris and undissolved proteins were removed from cell lysates by centrifugation (15,000 rpm for 20 min at 4 ⁰C). Cell lysates for immunoprecipitation were cleared with Protein G-Sepharose for 1 h at 4 ⁰C and immunoprecipitated using the anti-cFms antibody overnight at 4 ⁰C. Immune complexes were then incubated with Protein G- Sepharose for 1 h at 4 ⁰C. Protein G immunoprecipitates were washed five times in TNE lysis buffer. Immunoprecipitates were resolved on 4-20% SDS-PAGE gels, and the proteins were transferred to PVDF membrane. For anti-phosphotyrosine immunoblot analysis, membranes were blocked with 3% BSA/PBS and blotted with anti-phosphotyrosine (clone 4G10, biotinylated) followed by HRP-conjugated streptavidin (PIERCE). Detection of protein was done by chemiluminescence using ECL plus reagent (Amersham) through exposing on X-ray films.

4. C-MET AUTOPHOSPHORYLATION ASSAY c-Met/cFms/NIH3T3 cells were plated at 1 x 10⁵ cells/well in collagen-coated 96-well microtitre plates and grown 24 h under standard culture conditions, followed by serum starvation for 1 h. The cells were incubated with compounds for 1 h at 37 ⁰C and followed by M-CSF (600 ngml^"1) stimulation for 10 min at 37 ⁰C. The media was removed and the cells were lysed with 120 ul/well of lysis buffer (20 mM Tris-HCI pH8.0, 137 mM NaCI, 2 mM EDTA, 10% glycerol, 1% Triton X-100, 1 mM Na₃VO₄ and Protease Inhibitor Cocktail (Complete mini EDTA-free, Roche)). Then 100 ul/well of lysate was transferred to the antibody-coated (50 ng/well goat anti-cFms antibody in PBS) ELISA plate and incubated overnight at 4 ⁰C. Plates were washed five times with PBST (PBS containing 0.05% Tween-20). Primary antibody (biotin- conjugated anti-phosphotyrosine monoclonal antibody, PIERCE) was diluted 1 :10,000 in PBST containing 1% BSA, added (100 ul/well) and incubated for 2 h at room temperature. After washing the plates five times with washing buffer, 100 ul/well of HRP-conjugated streptavidin (PIERCE) in PBST containing 1 % BSA was added and incubated for 30 min at room temperature. After washing five times with PBST, 100 ul/well of SuperSignal ELISA Femto Substrate (PIERCE) was added and incubated for almost 1 min at room temperature. Chemiluminescence was measured using Wallac 1420 multilabel counter.

5. DATA ANALYSIS

The IC50 was determined by using XLfit software (IDBS) with four-parameters, sigmoidal dose-response equation. IN VITRO SCREEN

1. SOURCE OF SUBSTRATE PEPTIDE The peptide substrate, Biotin-aminohexyl-EEEEYFELVAKKKK-amide was purchased from SynPep Solid sample is dissolved at approximately 2.5 mM in water (concentration determined by amino acid analysis) and aliquots stored at -20 ⁰C.

2. SOURCE OF ENZYME Met Kinase: A fusion protein consisting of His6-tagged Glutathione-S-Transferase (GST) and amino acid residues 956-1390 of human Met Kinase (aa 956-1390 of Entrez Protein Accession # EAL24359.1 (met proto-oncogene (hepatocyte growth factor receptor) [Homo sapiens] )) from "www.ncbi.nlm.nih.gov/entrez/") is purified from baculovirus expression system in Sf9 cells using Ni chelate column, GSH column, followed by size exclusion chromatography. Purity greater than 90%, estimated by SDS-PAGE, is achieved. Samples in 25 mM HEPES pH 7.5, 100 mM NaCI, 0.1 mM EDTA are stored at -80 ⁰C until use.

3. KINASE ASSAY OF PURIFIED MET KINASE Assays are performed in 96 well (Costar, Catalog No. 3789) or 384 well plates (Costar, Catalog No. 3705). Assay conditions for the peptide phosphorylation reaction (in 10, 20, 25, or 40 μl volume) mix are 100 mM Hepes buffer, pH 7.4; 0.1 mgml^"1 BSA; 5 mM MgCI₂; 1 mM DTT; 10 μM ATP; purified Met (1 nM final); and 1 μM peptide substrate. Compounds, titrated in DMSO, are evaluated at concentrations ranging from 50 μM to 0.2 nM. Concentrations of DMSO do not exceed 5%, resulting in less than 15% loss of Met activity relative to controls without DMSO. Reactions are incubated for 1 hour at room temperature and are stopped by addition of detection reagents containing, at final detection volume, 12.5 mM EDTA; 100 mM Hepes; 0.1 mg/ml BSA; 8 nM Streptavidin APC (Perkin Elmer catalog # CR130-150); 1 nM Europium-labelled anti-phosphotyrosine antibody (Perkin Elmer catalog #AD0067). Under the assay conditions defined above, the Km (apparent) for ATP is determined to be 40 μM.

4. DATA ANALYSIS The data for compound dose responses were plotted as % Inhibition, calculated with the data reduction formula 100^*(1-[(U1-C2)/(C1-C2)]), versus concentration of compound, where U is the unknown value, C1 is the average control value obtained for DMSO, and C2 is the average control value obtained for 0.05M EDTA. Data were fitted to the curve described by: y = ((V_max ^* x) / (K + x)) where V_max is the upper asymptote and K is the IC₅₀. The results for each compound were recorded as plC₅₀ calculated as follows: plC₅₀ = -Log10(K).

Claims

1. A compound of Formula (I):

R¹ is -d-salkylene-morpholino (the alkylene bonded to the nitrogen of the morpholino group), -Cr3alkylene-piperazine [wherein the alkylene is bonded to a nitrogen in the piperizine and piperazine is substituted on the other nitrogen by SO₂Ci_-3alkyl];

R² is

-(X)_n-phenyl (wherein the phenyl is optionally fused to a cyclopentyl ring or optionally substituted one or two times with substituents independently selected from

-C_1-6alkyl, -C_1-6haloalkyl, -d-ealkoxy, -d-₆haloalkoxy, -halogen, -COC_1-6alkyl,

-CN, -O-phenyl, -Od-salkylenephenyl, -CONR^aR^b);

X is Ci-3 alkylene, -CO-, -SO₂-; n is O or 1

R^a and R^b independently represent H, -Ci_₃alkyl or together with the nitrogen to which they are joined form a morpholino or piperazine ring [wherein the piperazine is substituted on the other nitrogen atom by Ci_3 alkyl]; -H;

-Ci_-6 alkyl; -C3-6 cycloalkyl; -C₁-6 hydroxyalkyl; -Ci-3 alkylene NR^cR^α wherein R^c and R^d are independently H, Ci_₃ alkyl or together with the nitrogen to which they are joined form a piperazine or morpholino ring [and the piperazine ring is substituted on the other nitrogen by Ci_-3 alkyl];

or a salt or solvate thereof.

2. A compound according to claim 1 which is a compound selected from

N-ethyl-N'-(4-{methyl[2-({3-[2-(4-morpholinyl)ethyl]phenyl}amino)-4- pyrimidinyl]amino}phenyl)urea

N-(4-{methyl[2-({3-[2-(4-morpholinyl)ethyl]phenyl}amino)-4- pyrimidinyl]amino}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea

N-ethyl-N'-[4-(methyl{2-[(3-{[4-(methylsulfonyl)-l- piperazinyl]methyl}phenyl)amino]-4-pyrimidinyl}amino)phenyl]urea

3. A compound according to any one of claims 1 to 2 for use in therapy.

4. A compound according to claim 1 to 2 for use in the treatment of diseases and conditions mediated by inappropriate c-Met activity.

5. A compound according to claims 1 to 2 for use in the treatment of cancer.

6. A compound according to claim 1 to 2 for use in the treatment of certain viral diseases.

7. A compound according to claim 1 to 2 for use in the treatment of cardiovascular diseases.

8. A pharmaceutical composition which comprises a compound according to claims 1 to 2 optionally with one or more pharmaceutically acceptable carriers and/or excipients.

9. A combination comprising a compound according to claims 1 to 2, and one or more other therapeutic agents.

10. The combination according to claim 9, further comprising at least one additional anti-cancer agent.

11. The use of a compound according to any of claims 1 to 2 in the manufacture of a medicament for the treatment or prophylaxis of diseases associated with inappropriate c-Met activity.

12. The use according to claim 11 , in which the disease is cancer.

13. The use according to claim 11 , in which the disease is a viral disease.

14. The use according to claim 1 1 , in which the disease is a cardiovascular disease or disorder.

15. A method for the treatment or prophylaxis of diseases associated with inappropriate c-Met activity which comprises administering to a patient in need thereof a compound of formula (I) according to claims 1 to 2.

16. A method according to claim 15, wherein the disease is cancer.

17. A method according to claim 15, wherein the disease is a cardiovascular disease.

18. A method according to claim 15, wherein the disease is a viral disease.

19. A method according to claim 16 which further comprises administration of an additional anti-cancer therapy.