Abstract

Novel pyrimidine derivatives of formula (I) Wherein R is selected from C16-10 aryl, C5-10heteroaryl, C3-12cycloalkyl and C3-10heterocycloalkyl; R<0>-R<6> as described herein; and their use for the manufacture of a medicament for the treatment or prevention of a disease wich responds to inhibition of FAK and/or ALK and/or ZAP-70 and/or IGF-IR.

Information

Application ID	553/CHENP/2006
Invention Field	CHEMICAL
Date of Application	2006-02-14
Publication Number	27/2007

Applicants

Name	Address	Country	Nationality

Specification

The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated:
Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.
Any asymmetric carbon atoms may be present in the (R)-, (S)- or (Reconfiguration, preferably in the (R)- or (S)~configuration. The compounds may thus be present as mixtures of isomers or as pure isomers, preferably as enantiomer-pure diastereomers.
The invention relates also to possible tautomers of the compounds of formula I.
C1-C8alkyl denotes a an alkyl radical having from 1 up to 8, especially up to 4 carbon atoms, the radicals in question being either linear or branched with single or multiple branching; preferably, C1-C8alkyl is butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methyl; especially methyl, propyl or tert-butyl.
C2-C8alkenyl denotes a an alkenyl radical having from 2 up to 8, especially up to 5 carbon atoms, the radicals in question being either linear or branched with single or multiple branching; preferably, C2-C8alkenyl is pentenyl, such as 3-methyl-2-buten-2-yl, butenyl, such as 1- or 2-butenyl or 2-buten-2-yl, propenyl, such as 1-propenyl orallyl, or vinyl.
C2-C8alkinyl denotes a an alkinyl radical having from 2 up to 8, especially up to 5 carbon atoms, the radicals in question being either linear or branched; preferably, C2-CBalkinyi is propinyl, such as 1-propinyl or propargyl, or acetylenyl.
C1-C8cycloalkyI denotes a cycloalkyl radical having from 3 up to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cydoheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl.
C1-C8alkoxy is especially methoxy, ethoxy, isopropyloxy, or tert-butoxy.

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Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom, especially the pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric add. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic add, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic add, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cydohexanecarboxylic acid, adamantanecarboxylic add, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic add, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1, 2-disulfonic acid, benzenesulfonic acid, 2-naphthaIenesulfonic acid, 1, 5-naphthalene-disuifonic acid, 2-, 3- or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric add, N-cyclohexylsulfamic acid, N-methyh N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.
For isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.
In view of the close relationship between the novel compounds in free form and those in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of the novel compounds, any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.
The compounds of formula I have valuable pharmacological properties, as described hereinbefore and hereinafter.
In formula I the following significances are preferred independently, collectively or in any combination or sub-combination. R is C6-10aryl, C5-10 heteroaryl, C3-12 cycloalkyl or C3. loheterocycloalkyl, preferably R is

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(f) R5 is hydrogen, halogen, e.g. chloro or bromo, haloC1-C8alkyl, e.g. trifluoromethyl, or nitro; preferably hydrogen, chloro, bromo, trifluoromethyl or nitro; in particular chloro or bromo;
(g1) R6 is hydrogen;
(h1) each of R7 and R9 independently is hydrogen, C1-C8alkyl, e.g. methyl, ethyl or isopropyl, haloC1-C8alkyl, e.g. trifluoromethyl, unsubstituted or substituted C5-C10aryI, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, C1-C8alkoxy, e.g. methoxy, ethoxy or isopropoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyIoxy, unsubstituted or substituted heterocyclylC^Csalkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, halogen, e.g. fluoro or chloro, unsubstituted or substituted carbamoyl, e.g. cyclohexylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl or morpholinocarbonyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl ordimethylsulfamoyl; preferably hydrogen, methyl, isopropyl, trifluoromethyl, phenyl, o-, m- or p-methoxyphenyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, isopropoxy, phenoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 2-(1-imidazolyl)ethoxy, dimethylamino, fluoro, morpholinocarbonyl, piperidinocarbonyl, piperazinocarbonyl or cyclohexylcarbamoyl;
(0 R8 is hydrogen, d-C8alkyI, e.g. methyl, ethyl or isopropyl, halod-Csalkyl, e.g. trifluoromethyl, C5-C10aryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, d-C8alkoxy, e.g. methoxy, ethoxy or isopropoxy, halod-Cealkoxy, e.g. trifluoromethoxy, C5-C10aryloxy, e.g. phenoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino or dimethylamino, halogen, e.g. fluoro or chloro, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl, or nitro; preferably hydrogen, methyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, trifluoromethoxy, phenoxy, 1-methyl-4-piperidyloxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-(N-methyipiperazino)-propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro;
(j1) R10 is d-C8alkyl, e.g. methyl, ethyl or butyl, halod-Csalkyl, e.g. trifluoromethyl, d-Caalkoxy, e.g. methoxy or ethoxy, unsubstituted or substituted heterocyclyld-C8alkoxy, e.g. 2-(1-

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cyclobutyloxy, 2, 2, 2-trifluoroethoxy, methoxy, isobutyloxy, t-butyloxy, isopropyloxy, methyl-amino-carbonyl, cyclopropyi-methoxy, dimethylamino-propyl-amino, methoxy-ethoxy, -X'R 4, -C(O)R 4 and -OX'R'4; wherein X1 is a bond, methylene or ethylene; R'4 is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, azepanyl and 1, 4-dioxa-8-aza~spiro[4.5]dec-8-yl; wherein Rf4 is optionally substituted by 1 to 3 radicals independently selected from methyl, isopropyi, acetyl, acetyl-methyl-amino, 3-dimethylamino-2, 2”dimethyl-propyiamino, ethyl-methyl-amino-ethoxy, diethyl-amino-ethoxy, amino-carbonyl, ethyl, 2-oxo-pyrrolidin-i-yl, pyrrolidinyl, pyrrolidinyl-methyl, piperidinyl optionally substituted with methyl or ethyl, morpholino, dimethylamino, dimethylamino-propyl-amino, methyl-amino and ethyl-amino.
Even more preferably a compound of of formula V in which R'2 is selected from hydrogen and halo; and R'3 is selected from halo, dimethyl-sulfamoyl, isobutyl-sulfamoyl, methyi-sulfamoyl, ethyl-sulfamoyl, propyl-sulfonyl, ethyl-amino-carbonyl, 1-ethyl-propyl-sulfamoyl, cyclopentyl-sulfamoyl, isopropyl-sulfamoyl, cyclohexyl-sulfonyl, cyclopropyl-methyl-sulfamoyl, cyclobutyl-sulfamoyl, isopropyl-sulfonyl,
Most preferably a compound of example 53
In a yet further embodiment of the invention the present invention also provides a process for the production of a compound of formula I, comprising reacting a compound of formula II
(II) wherein R°, R\ R2, R3, R4, R5, and R6 are as defined above, and Y is a leaving group, preferably
halogen such as bromide, iodine, or in particular chloride; with a compound of formula III

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and, if desired, converting a compound of formula I, wherein the substituents have the meaning as defined above, into another compound of formula 1 as defined;
and recovering the resulting compound of formula I in free from or as a salt, and, when required, converting the compound of formula I obtained in free form into the desired salt, or an obtained salt into the free form.
The reaction can be carried out in a manner known per se, the reaction conditions being dependent especially on the reactivity of the leaving group Y and the reactivity of the amino group in the aniline of formula 111, usually in the presence of a suitable solvent or diluent or of a mixture thereof and, if necessary, in the presence of an acid or a base, with cooling or, preferably, with heating, for example in a temperature range from approximately -30°C to approximately +150°C, especially approximately from 0°C to +100°C, preferably from room temperature (approx. +20 °C) to +80 °C, in an open or closed reaction vessel and/or in the atmosphere of an inert gas, for example nitrogen. Alternatively, the reaction can proceed in the presence of a suitable catalyst (for example, palladium di-benzyi-acetone), in the presence of a base (for example, caesium carbonate) and in the presence of a suitable reaction facilitator (for example, xanthphos).
If one or more other functional groups, for example carboxy, hydroxy or amino, are or need to be protected in a compound of formula II or 111, because they should not take part in the reaction, these are such groups as are usually used in the synthesis of peptide compounds, cephalosporins and penicillins, as well as nucleic acid derivatives and sugars.
The protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as substitution reaction or

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solvolysis. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by soivolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove.
Salts of a compound of formula I with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of formula I may thus be obtained by treatment with an acid or with a suitable anion exchange reagent.
Salts can usually be converted to compounds in free form, e.g. by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
Stereoisomeric mixtures, e.g. mixtures of diastereomers, can be separated into their corresponding isomers in a manner known per se by means of suitable separation methods. Diastereomeric mixtures for example may be separated into their individual diastereomers by means of fractionated crystallization, chromatography, solvent distribution, and similar procedures. This separation may take place either at the level of a starting compound or in a compound of formula I itself. Enantiomers may be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomer-pure chiral acid, or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands.
It should be emphasized that reactions analogous to the conversions mentioned in this chapter may also take place at the level of appropriate intermediates.
The compounds of formula I, including their salts, are also obtainable in the form of hydrates, or their crystals can include for example the solvent used for crystallization (present as solvates).
The compound of formula II used as starting materials may be obtained by reacting a compound of formula IV

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wherein R\ R2, R3, R4, R5 and R6 are as defined above, and Y1 and Y2 are identical or different leaving groups as defined above for Y. The reaction conditions are those mentioned above for the reaction of a compound of formula II with a compound of formula III.
The compounds of formula IV and V are known or may be produced in accordance with known procedures.
The compounds of formula I and their pharmaceutically acceptable salts exhibit valuable pharmacological properties when tested in vitro in cell-free kinase assays and in cellular assays, and are therefore useful as Pharmaceuticals. In particular, the compounds of the invention are inhibitors of Focal Adhesion Kinase, and are useful as Pharmaceuticals to treat conditions caused by a malfunction of signal cascades connected with Focal Adhesion Kinase, in particular tumors as described hereinbelow.
Focal Adhesion Kinase (FAK) is a key enzyme in the integrin-mediated outside-in signal cascade (D. Schlaepfer et aL, Prog Biophys Mol Biol 1999, 71, 435-478). Interaction between cells and extracellular matrix (ECM) proteins is transduced as intracellular signals important for growth, survival and migration through cell surface receptors, integrins. FAK plays an essential role in these integrin-mediated outside-in signal cascades. The trigger in the signal transduction cascade is the autophosphorylation of Y397. Phosphorylated Y397 is a SH2 docking site for Src family tyrosine kinases. The bound c-Src kinase phosphorylates other tyrosine residues in FAK. Among them, phsophorylated Y925 becomes a binding site for the SH2 site of Grb2 small adaptor protein. This direct binding of Grb2 to FAK is one of the key steps for the activation of down stream targets such as the Ras-ERK2/MAP kinase cascade.

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The inhibition of endogenous FAK signalling results in reduced motility and in some cases induces cell death. On the other hand, enhancing FAK signalling by exogenous expression increases cell motility and transmitting a cell survival signal from ECM. In addition FAK is overexpressed in invasive and metastatic epithelial, mesenchymal, thyroid and prostate cancers. Consequently, an inhibitor of FAK is likely to be a drug for anti-tumor growth and metastasis. The compounds of the invention are thus indicated, for example, to prevent and/or treat a vertebrate and more particularly a mammal, affected by a neoplastic disease, in particular breast tumor, cancer of the bowel (colon and rectum), stomach cancer and cancer of the ovary and prostate, non-small cell lung cancer, small cell lung cancer, cancer of liver, melanoma, bladder tumor and cancer of head and neck.
The relation between FAK inhibition and immuno-system is described e.g. in G.A. van Seventer et al., Eur. J. Immunol. 2001, 31, 1417-1427. Therefore, the compounds of the invention are, for example, useful to prevent and/or treat a vertebrate and more particularly a mammal, affected by immune system disorders, diseases or disorders mediated by T lymphocytes, B lymphocytes, mast cells and/or eosinophils e.g. acute or chronic rejection of organ or tissue allo- or xenografts, atherosclerosis, vascular occlusion due to vascular injury such as angioplasty, restenosis, hypertension, heart failure, chronic obstructive pulmonary disease, CNS disease such as Alzheimer disease or amyotrophic lateral sclerosis, cancer, infectious disease such as AIDS, septic shock or adult respiratory distress syndrome, ischemia/reperfusion injury e.g. myocardial infarction, stroke, gut ischemia, renal failure or hemorrhage shock, or traumatic shock. The agent of the invention are also useful in the treatment and/or prevention of acute or chronic inflammatory diseases or disorders or autoimmune diseases e.g. rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, diabetes (type I and II) and the disorders associated with therewith, respiratory diseases such as asthma or inflammatory liver injury, inflammatory glomerular injury, cutaneous manifestations of immunologically-mediated disorders or illnesses, inflammatory and hyperproliferative skin diseases (such as psoriasis, atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis), inflammatory eye diseases, e.g. Sjoegren's syndrome, keratoconjunctivitis or uveitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis.

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Compounds of the invention are active in a FAK assay system as described in the Examples, and show an inhibition IC50 in the range of 1 nM to 100 nM. Particularly active are the compounds Example No. 3-12 and No. 3-17 described hereinbelow showing IC50 vales in the range of 1 to 5 nM.
Some of the compounds of the invention exhibit also ZAP-70 (zeta chain-associated protein of 70 kD) protein tyrosine kinase inhibiting activity. ZAP-70 protein tyrosine kinase interaction of the agents of the invention may be demonstrated by their ability to prevent phosphorylation of e.g. LAT-11 (linker for activation of T cell) by human ZAP-70 protein tyrosine kinase in aqueous solution, as described in the Examples. The compounds of the invention are thus also indicated for the prevention or treatment of disorders or diseases where ZAP-70 inhibition inhibition play a role.
Compounds of the invention are active in a ZAP-70 assay system as described in the Examples, and show an inhibition IC50 in the range of 1 µMto 10µM, e.g. the compounds Example No. 2 and No. 3-2 described hereinbelow.
Compounds of the present invention are also good inhibitors of the IGF-IR (insulin like growth factor receptor 1) and are therefore useful in the treatment of IGF-1R mediated diseases for example such diseases include proliferative diseases, such as tumours, like for example breast renal, prostate, colorectal, thyroid, ovarian, pancreas, neuronal, lung, uterine and gastrointestinal tumours as well as osteosarcomas and melanomas. The efficacy of the compounds of the invention as inhibitors of IGF-IR tyrosine kinase activity can be demonstrated using a cellular “Capture ELISA”. In this assay the activity of the compounds of the invention against Insulin-like growth factor I (IGF-I) induced autophosphorylation of the IGF-IR is determined.
The compounds of formula I and their pharmaceutically acceptable salts exhibit valuable pharmacological properties when tested in vitro in cell-free kinase assays and in cellular assays, and are therefore useful as Pharmaceuticals. In particular, the compounds of the invention are inhibitors of Anaplastic Lymphoma Kinase (ALK), and are useful as Pharmaceuticals to treat conditions caused by a malfunction of signal cascades connected with Anaplastic Lymphoma Kinase, in particular tumors as described hereinbelow.
ALK-mediated signaling could play a role in the development and/or progression of a number of common solid tumors (Pulford, K., et al., J. Cell. Physioi. 2004 Jun;199(3):330-58). The

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compounds of the present invention also exhibit powerful inhibition of the tyrosine kinase activity of anaplastic lymphoma kinase (ALK) and its fusion proteins, particularly the fusion protein of NPM-ALK. This protein tyrosine kinase results from a gene fusion of nucleophosmin (NPM) and the anaplastic lymphoma kinase (ALK), rendering the protein tyrosine kinase activity of ALK ligand-independent. NPM-ALK plays a key role in signal transmission in a number of hematopoetic and other human cells leading to hematological and neoplastic diseases, for example in anaplastic large-cell lymphoma (ALCL) and non-Hodgkin's lymphomas (NHL), specifically in ALK+ NHL or Alkomas, in inflammatory myofibroblastic tumors (IMT) and neuroblastomas. (Duyster J et al. 2001 Oncogene 20, 5623-5637). NPM-ALK has been shown to be a potent oncogene in vitro, being able to transform various cell lines and primary hematopoetic cells. Furthermore, NPM-ALK transduced bone marrow cells are able to induce a lymphoma-like disease after transplantation into irradiated recipient mice. Signaling pathways activated by NPM-ALK include ras, PLC and PI3K pathways and, in addition, STAT5 has been shown to be phosphorylated by NPM-ALK. In addition to NPM-ALK, other gene fusions have been identified in human hematological and neoplastic diseases; mainly TPM3-ALK (a fusion of nonmuscle tropomyosin 3 with ALK). Further, the ALK fusion protein CLTC-ALK, is associated with diseases that include classical T cell or null ALCL, ALK* DLBCL and inflammatory myofibroblastic tumors. CLTCL-ALK is also thought to play a role in the pathogenesis of large B-cell lymphomas.
Further, the ALK fusion protein CLTC-ALK is associated with diseases that include
classical T cell or null ALCL, ALK+ DLBCL and inflammatory myofibroblastic tumors.
CLTCL-ALK is also thought to play a role in the pathogenesis of large B-cell
lymphomas.
Aberrant activity of ALK is involved in the development of brain tumors and
overexpression of ALK has been reported in neuroblastomas and several cell lines derived from neural tissue. ALK-mediated signaling could play a role in the development and/or progression of a number of common solid tumors (Pulford, K., et al., J. Cell. Physiol. 2004 Jun;199(3):330-58).
The inhibition of ALK tyrosine kinase activity can be demonstrated using known methods, for example using the recombinant kinase domain of the ALK in analogy to the VEGF-R kinase assay described in J. Wood et al. Cancer Res. 60, 2178-2189 (2000). In vitro enzyme assays using GST-ALK protein tyrosine kinase are performed in 96-well plates as

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The compounds of formula I potently inhibit the growth of human NPM-ALK overexpressing murine BaF3 cells (DSMZ Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Braunschweig, Germany). The expression of NPM-ALK is achieved by transfecting the BaF3 cell line with an expression vector pClneo™ (Promega Corp., Madison Wl, USA) coding for NPM-ALK and subsequent selection of G418 resistant cells. Non-transfected BaF3 cells depend on IL-3 for cell survival. In contrast NPM-ALK expressing BaF3 cells (named BaF3-NPM-ALK hereinafter) can proliferate in the absence of IL-3 because they obtain proliferative signal through NPM-ALK kinase. Putative inhibitors of the NPM-ALK kinase therefore abolish the growth signal and result in antiproliferative activity. The antiproliferative activity of putative inhibitors of the NPM-ALK kinase can however be overcome by addition of IL-3 which provides growth signals through an NPM-ALK independent mechanism. [For an analogous cell system using FLT3 kinase see E Weisberg et al. Cancer Cell; 1, 433-443 (2002)]. The inhibitory activity of the compounds of formula I is determined, briefly, as follows: BaF3-NPM-ALK cells (15, 000/microtitre plate well) are transferred to 96-well microtitre plates. The test compounds [dissolved in dimethyl sulfoxide (DMSO)] are added in a series of concentrations (dilution series) in such a manner that the final concentration of DMSO is not greater than 1 % (v/v). After the addition, the plates are incubated for two days during which the control cultures without test compound are able to undergo two cell-division cycles. The growth of the BaF3-NPM-ALK cells is measured by means of Yopro™ staining [T Idziorek et al. J. Immunol. Methods; 185: 249-258 (1995)]: 25 µl of lysis buffer consisting of 20 mM sodium citrate, pH 4.0, 26.8 mM sodium chloride, 0.4 % NP40, 20 mM EDTA and 20 mM is added to each well. Cell lysis is completed within 60 min at room temperature and total amount of Yopro bound to DNA is determined by

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measurement using the Cytofluor II 96-weII reader (PerSeptive Biosystems) with the following
settings: Excitation (nm) 485/20 and Emission (nm) 530/25.
IC50 values are determined by a computer-aided system using the formula:

The IC50 value in those experiments is given as that concentration of the test compound in question that results in a cell count that is 50 % lower than that obtained using the control without inhibitor. The compounds of formula I exhibit inhibitory activity with an IC50 in the range from approximately 0.01 to 1 µM.
The antiproliferative action of the compounds of formula I can also be determined in the human KARPAS-299 lymphoma cell line (DSMZ Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Braunschweig, Germany) [described in WG Dirks et al. Int. J. Cancer 100, 49-56 (2002)] using the same methodology described above for the BaF3-NPM-ALK cell line. The compounds of formula 1 exhibit inhibitory activity with an IC50 in the range from approximately 0.01 to 1 µM.
The action of the compounds of formula I on autophosphorylation of the ALK can be determined in the human KARPAS-299 lymphoma cell line by means of an immunoblot as described in WG Dirks et al. Int. J. Cancer 100, 49-56 (2002). In that test the compounds of formula I exhibit an IC50 of approximately from 0.001 to 1 µIM.
Among the compounds of formula 1, 2-[5-chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide is an especially potent ALK inhibitor, in that this compound inhibits the growth of the BaF3-NPM-ALK cells with an IC50 of 97 nM. Further specifically preferred compounds that inhibit the tyrosine kinase activity of anaplastic lymphoma kinase (ALK) are the compounds described hereinafter in the examples 7A and 7B, as well as 7-2, 7-15, 19-5, 21-1, 26-3 and 28-5, respectively, all of which are having an IC50 within the range from <0.5 to 200 nM.
For the above uses in the treatment of neoplastic diseases and immune system disorders the required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, satisfactory results are indicated to be

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obtained systemically at daily dosages of from about 0.1 to about 100 mg/kg body weight. An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 2000 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form.
The compounds of the invention may be administered by any conventional route, in particular parenterally. for example in the form of injectable solutions or suspensions, enterally, preferably orally, for example in the form of tablets or capsules, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository form. Pharmaceutical compositions comprising a compound of the invention in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent. Unit dosage forms for oral administration contain, for example, from about 0.1 mg to about 500 mg of active substance. Topical administration is e.g. to the skin. A further form of topical administration is to the eye.
The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.
Preference is given to the use of solutions of the active ingredient, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilized compositions comprising the active ingredient alone or together with a carrier, for example mannitol, can be made up before use. The pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving and lyophilizing processes. The said solutions or suspensions may comprise viscosity-increasing agents, typically sodium carboxymethylcellulose, carboxymethylcellulose. dextran, polyvinylpyrrolidone, or gelatins, or also solubilizers, e.g. Tween 80® (polyoxyethylene(20)sorbitan mono-oleate).
Suspensions in oil comprise as the oil component the vegetable, synthetic, or semi-synthetic oils customary for injection purposes. In respect of such, special mention may be made of liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to

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22, especially from 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, B-carotene or 3, 5-di-tert-butyl-4-hydroxytoluene. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a monovalent or polyvalent, for example a mono-, di- or trivalent, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or the isomers thereof, but especially glycol and glycerol. As fatty acid esters, therefore, the following are mentioned: ethyl oleate, isopropyl myristate, isopropyl paimitate, “Labrafil M 2375” (polyoxyethylene glycerol), “Labrafil M 1944 CS” (unsaturated polyglycolized glycerides prepared by alcoholysis of apricot kernel oil and consisting of glycerides and polyethylene glycol ester), “Labrasol” (saturated polyglycolized glycerides prepared by alcoholysis of TCM and consisting of glycerides and polyethylene glycol ester, all available from Gattefosse, France), and/or “Miglyol 812” (triglyceride of saturated fatty acids of chain length C8 to C12 from Huls AG., Germany), but especially vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil sesame oil, soybean oil and more especially groundnut oil.
The manufacture of injectable preparations is usually carried out under sterile conditions, as is the filling, for example, into ampoules or vials, and the sealing of the containers.
Pharmaceutical compositions for oral administration can be obtained, for example, by combining the active ingredient with one or more solid carriers, if desired granulating a resulting mixture, and processing the mixture or granules, if desired or necessary, by the inclusion of additional excipients, to form tablets or tablet cores.
Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.

WO 2005/016894 PCT/EP2004/009099
Tablet cores can be provided with suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.
Pharmaceutical compositions for oral administration also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol. The hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
Pharmaceutical compositions suitable for rectal administration are, for example, suppositories that consist of a combination of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
For parenteral administration, aqueous solutions of an active ingredient in water-soluble form, for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers, are especially suitable. The active ingredient, optionally together with excipients, can also be in the form of a lyophilizate and can be made into, a solution before parenteral administration by the addition of suitable solvents.
Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.

WO 2005/016894 PCT/EP2004/009099
Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid..
The compounds of the invention may be administered as the sole active ingredient or together with other drugs useful against neoplastic diseases or useful in immunomodulating regimens. For example, the agents of the invention may be used in accordance with the invention in combination with pharmaceutical compositions effective in various diseases as described above, e.g. with cyclophosphamide, 5-fluorouracil, fludarabine, gemcitabine, cisplatinum, carboplatin, vincristine, vinblastine, etoposide, irinotecan, paclitaxel, docetaxel, rituxan, doxorubicine, gefitinib, or imatinib; or also with cyclosporins, rapamycins, ascomycins or their immunosuppressive analogs, e.g. cyclosporin A, cyclosporin G, FK-506, sirolimus or everolimus, corticosteroids, e.g. prednisone, cyclophosphamide, azathioprene, methotrexate, gold salts, sulfasalazine, antimalarials, brequinar, leflunomide, mizoribine, mycophenolicacid, mycophenolate, mofetil, 15-deoxyspergualine, immuno-suppressive monoclonal antibodies, e.g. monoclonal antibodies to leukocyte receptors, e.g. MHC, CD2, CD3, CD4, CD7, CD25, CD28, CD40, CD45, CD58, CD80, CD86, CD152, CD137, CD154, ICOS, LFA-1, VLA-4 or their ligands, or other immunomodulatory compounds, e.g. CTLA4lg.
In accordance with the foregoing, the present invention also provides:
(1) A compound of the invention for use as a pharmaceutical;
(2) a compound of the invention for use as a 5-Chloro-N*2*-{2-methoxy-4-[4-(4-methyl-piperazin-
1 -yl)-piperidin-1 -yl]-phenyI}-N*4*-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine) for
example for use in any of the particular indications hereinbefore set forth;
(3) a pharmaceutical composition, e.g. for use in any of the indications herein before set forth,
comprising a compound of the invention as active ingredient together with one or more
pharmaceutically acceptable diluents or carriers;
(4) a method for the treatment of any particular indication set forth hereinbefore in a subject in
need thereof which comprises administering an effective amount of a compound of the invention
or a pharmaceutical composition comprising same;
(5) the use of a compound of the invention for the manufacture of a medicament for the
treatment or prevention of a disease or condition in which FAK and/or ALK and/or ZAP-70 and/or
IGF—I activation plays a role or is implicated, preferably ALK;

WO 2005/016894 PCT/EP2004/009099

WO 2005/016894 PCT/EP2004/009099
Example 4: 2-[5-Bromo-2-(subst. phenvlamino)-pvrimidin-4-vlamino1-N-propyl-benzene--sulfonamides
These compounds are prepared in analogy to Example 2 using 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-N-propyi-benzenesuIfonamide and the corresponding aniline to give compounds No. 4-1 to 4-31 having the substituent Rx as listed under Example 3 for compounds No. 3-1 to 3-31. Preparation of 2-(5-bromo-2-chlorchPvrimidin-4-vlamino)-N-propvl-ben2enesulfonamide To a solution of 5-bromo-2, 4-dichIoropyrimidine (90 µL, 0.70 mmol) and 2-amino-N-propyl-benzenesulfonamide (100 mg, 0.47 mmol), sodium hydride (54.2 mg, 0.56 mmol) in DMSO (1.0 mL) is added and the resulting solution is stirred at 80°C for 3.0 h. The mixture is poured into water and extracted with ethyl acetate three times. The organic layer is washed with water and then brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified with silica get column chromatography (n-hexane : ethyl acetate = 5 :1) to afford the title compound as a slightly yellow solid.

Example 5: 2-[5-Trifluoromethvl-2-(subst. phenvlamino-pyrimidin-4-vlaminoi-N-methvl-benzenesulfonamides
These compounds are prepared in analogy to Example 2 using 2-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide and the corresponding aniline to give compounds No. 5-1 to 5-31 having the substituent Rx as listed under Example 3 for compounds No. 3-1 to 3-31.
Preparation of 2-f2-chloro-5-trifluoromethvl-pvrimidin-4-ylamino)-N-methvl-benzenesulfonamide To a solution of 2, 4-dichloro-5-trifluoromethyl-pyrimidine (386 mg, 1.79 mmol) in acetonitrile (10 mL), 2-amino-N-methyl-benzenesulfonamide (333 mg, 1.79 mmol) and 1, 8-diaza[5.4.0]-bicyclo-7-undecene (280 µL, 1.88 mmol) are added successively at ambient temperature. After stirring for 15 h at room temperature, dichloromethane (30 mL) is added to the mixture, and the solution is washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo- The resulting solid is purified by flash chromatography.

WO 2005/016894 PCT/EP2004/009099

WO 2005/016894 PCT/EP2004/009099

To a solution of 4-Methoxy-3-nitro-phenol (1.01g, 6 mmol) in DMF (15 mL), 4-(2-Chioroethyl)morphoiine hydrochloride (1.34g, 7.2mmol), K2CO3 (2.49g, 18mmo!), Kl(2.99g, 18mmol) are added at room temperature. The mixture is heated to 80°C for 4 hours. The reaction mixture is cooled to room temperature and quenched with saturated NH4CI solution in water. The resulting mixture is extracted twice with ethyl acetate and then the organic layer is successively washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude compound in quantitative yield (1.70g). Rf = 0.14 (AcOEt only). 1H-NMR (400MHz, DMSO, 6, ppm): 2.36-2.51 (m, 4H), 2.67 (t, J=5.5, 2H), 3.52-3.60 (m, 4H), 3.86 (s, 3H), 4.11 (t, J=6.0, 2H), 7.25-7.29 (m, 2H), 7.46-7.49 (m, 1H).

To a solution of 4-(3-Methoxy-4-nitro-phenoxy)-1-methyl-piperidine (3.0g, 11.3 mmol) in ethanol (50 mL), 5% palladium on carbon(300mg) is added under a nitrogen atmosphere. The reaction vessel is fitted with a balloon adapter and charged with hydrogen and evacuated three times until the reaction is under a hydrogen atmosphere. The reaction is allowed to stir overnight. The reaction mixture is filtered through a pad of Celite and washed with methanol. The filtrate is concentrated in vacuo to afford 2-Methoxy-4-(1-methyl-piperidin-4-yloxy)-phenylamine in quantitative yield (2.7g).
Rf = 0.41 (methanol : dichloromethane = 1:1). 1H-NMR (400 MHz, CDCI3), 6 (ppm): 1.75-1.86(m, 2H), 1.92-2.05(m, 2H), 2.2-2.32 (m, 2H), 2.30 (s, 3H), 3.4-3.7(brs, 2H), 3.82(s, 3H), 4.1-4.2(m, 1H), 6.37(dd, 1H), 6.46 (d, 1H), 6.61 (d, 1H).

WO 2005/016894 PCT/EP2004/009099

Preparation of 7-Fluoro-1, 1-dioxo-1, 4-dihvdro-2H-1 X 6-benzof1, 2.41thiadiazin-3-one
To a solution of chlorosulfonylisocyanate (1.2mL, 13.5mmol) in nitroethane (10mL), 4-
fluoroaniline (1.0g, 8.97mmol) is added dropwise at 0°C and the reaction mixture is stirred for
30min. To the solution, aluminum chloride (1.3g, 9.87mmol) is added at 0°C and the mixture is
stirred at 100°C for 1 hour. After cooling to room temperature, water is added and the mixture is
extracted with ethyl acetate twice. The organic layer is washed with brine, dried over sodium
sulfate, and concentrated under reduced pressure. The resulting solids are collected by a
filtration and wahed with ether to give slightly gray solids (803.9mg, 41%).
NMR (400MHz, DMSO-d6, 5): 7.22-7.28 (m, 1H), 7.45-7.57 (m, 1H), 7.60 (m, 1H), 11.15-11.30
(m, 1H). Rf: 0.43 (MeOH:AcOEt=1:5).
Preparation of 7-Fluoro-2-methvl-1, 1-dioxo-1.4-dihvdro-2H-1 X 6-benzon.2, 41thiadiazin-3-one
To a solution of 7-Fluoro-1, 1-dioxo-1, 4-dihydro-2H-1-X6-benzo[1)2, 4]thiadiazin-3-one (5.19g, 24.0mmo!) in DMF (50mL), sodium hydride (1.04g, 26.0mmol) and iodomethane (1.5mL, 24.0mmol) are added successively and the mixture is stirred for 1 hour at 70°C. After cooling to room temperature, the mixture is poured into water and the precipitate is collected by a filtration and washed with water and hexane, successively, to give slightly gray solids (5.38g, 94%). NMR (400MHz, DMSO-d6, 5): 3.32 (s, 3H), 7.44 (dd, 1H), 7.75 (ddd, 1H), 7.94 (dd, 1H). Rf (MeOH:AcOEt = 1:5): 0.21. Rf: 0.39 (Hexane:AcOEt=1:1). Preparation of 2-Amino-5-fluoro-N-methvl-benzenesulfonamide 6.79g of 7-Fluoro-2-methyl-1, 1 -dioxo-1, 4-dihydro-2H-1 X 6-benzo[1, 2, 4]thiadiazin-3-one
(29.5mmol) is dissolved in 20% aq. sodium hydroxide and the resulting solution is stirred at
100°C for 13.5 hours. The mixture is cooled to room temperature and poured into water. 78mL
of 5M HCI aq. is added and the precipitate is collected by a filtration and washed with water to
afford slightly purple solids (3.96g, 65%).
NMR (400MHz, CDCI3, 5): 2.60 (d, 3H), 4.55-4.82 (m, 3H), 6.74 (dd, 1H), 7.05-7.12 (m, 1H),
7.45 (dd, 1H). Rf: 0.41 (Hexane:AcOEt=1:1).
2-(5-Bromo-2-chloro-pyrimidin-4-vlamino)-5-fluoro-N-methvl-benzenesulfonamide

WO 2005/016894 PCT/EP2004/009099

Example 54: Cell-free ZAP-70 Kinase assay
The ZAP-70 kinase assay is based on time-resolved fluorescence resonance energy transfer (FRET). 80 nM ZAP-70 are incubated with 80 nM Lck (lymphoid T-cell protein tyrosine kinase) and 4 ^iM ATP in ZAP-70 kinase buffer (20 mM Tris, pH 7.5,10 \M Na3VO4,1 mM DTT, 1 rnM MnCI2,0.01 % BSA, 0.05 % Tween-20) for 1 hour at room temperature in a siliconized polypropylene tube. Then, the selective Lck inhibitor PP2 (1-tert-butyl-3-(4-chloro-phenyl)-1H-pyrazoIo[3,4-d]pyrimidin-4-ylamine; Alexis Biochemicals) is added (final concentration 1.2 jaM) and incubated for further 10 min. 10 \xL of this solution is mixed with the 10 fxL biotinylated peptide LAT-11 (1 \iM) as substrate and 20 JIL of serial dilutions of inhibitors and incubated for 4 hours at room temperature. The kinase reaction is terminated with 10 ^L of a 10 mM EDTA solution in detection buffer (20 mM Tris, pH 7.5, 0.01 % BSA, 0.05 % Tween-20). 50 fxL europium-labelled anti-phosphotyrosine antibody (Eu-PT66; final concentration 0.125 nM); and 50 jiL streptavidin-allophycocyanine (SA-APC; final concentration 40 nM) in detection buffer are added. After 1 hour incubation at room temperature fluorescence is measured on the Victor2 Multilabel Counter (Wallac) at 665 nm. Background values (low control) are obtained in the absence of test samples and ATP and are subtracted from all values. Signals obtained in the absence of test samples are taken as 100% (high control). The inhibition obtained in the presence of test compounds is calculated as percent inhibition of the high control. The concentration of test compounds resulting in 50% inhibition (IC50) is determined from the dose-response curves. In this assay, the agents of the invention have IC50 values in the range of 10 nM to 2 [JM, preferably from 10 nM to 100 nM.

WO 2005/016894 PCT/EP2004/009099
Recombinant ZAP-70 kinase is obtained as follows: A nucleic acid encoding full-length human ZAP-70 (GenBank #L05148) is amplified from a Jurkat cDNA library by RT-PCR and cloned into the pBluescript KS vector (Stratagene, California, USA). The authenticity of the ZAP-70 cDNA insert is validated by complete sequence analysis. This donor plasmid is then used to construct a recombinant baculovirus transfer vector based on the plasmid pVL1392 (Pharmingen, California, USA) featuring in addition an N-terminal hexahistidine tag. Following co-transfection with AcNPV viral DNA, 10 independent viral isolates are derived via plaque-purification, amplified on small scale and subsequently analyzed for recombinant ZAP-70 expression by Western Blot using a commercially available anti-ZAP-70 antibody (Clone 2F3.1, Upstate Biotechnology, Lake Placid, NY, USA). Upon further amplification of one positive recombinant plaque, titrated virus stocks are prepared and used for infection of Sf9 cells grown in serum-free SF900 II medium (Life Technologies, Basel, Switzerland) under defined, optimized conditions. ZAP-70 protein is isolated from the lysate of infected Sf9 cells by affinity chromatography on a Ni-NTAcoIumn (Qiagen, Basel, Switzerland).
Recombtnant His-tagged ZAP-70 is also available from PanVera LLC, Madison, Wisconsin, USA.
LAT-11 (linker for activation of T cell): The biotinylated peptide LAT-11 (Biotin-EEGAPDYENLQELN) used as a substrate in the ZAP-70 kinase assay is prepared in analogy to known methods of peptide synthesis. The N-a Fmoc group of Fmoc-Asn(Trt)-oxymethyl-4-phenoxymethyl-co(polystyrene-1%-divinyl-benzene), content of Asn approx. 0.5 mmol/g, is cleaved using piperidine, 20% in DMF. Four equivalents per amino-group of Fmoc-amino add protected in their side chains [Asp(OtBu), Glu(OtBu), Asn(Trt), Gln(Trt) and Tyr(tBu)] are coupled using DIPCDI and HOBt in DMF. After complete assembly of the peptide chain the terminal Fmoc-protecting group is removed with piperidine in DMF as before. L(+)-biotinyl-aminohexanoic acid is then coupled to the terminal amino group using DIPCDI and HOBt in DMF using four equivalents of the reagents for four days at RT. The peptide is cleaved from the resin support and all side-chain protecting groups are simultaneously removed by using a reagent consisting of 5% dodecylmethylsulfide and 5% water in TFA for two hours at RT. Resin particles are filtered off, washed with TFA and the product is precipitated from the combined filtrates by the addition of 10 to 20 volumes of diethyl ether, washed with ether and dried. The product is purified by chromatography on a C-18 wide-pore silica column using a gradient of acetonitrile in 2% aqueous phosphoric acid. Fractions containing the pure compound are

WO 2005/016894 PCT/EP2004/O09099
collected, filtered through an anion-exchange resin (Biorad, AG4-X4 acetate form) and lyophilized to give the title compound. MS: 1958.0 (M-H)-1
Example 56: Anchorage-independent tumor cell growth assay
Mouse mammary carcinoma 4T1 cells (5 x 103) are plated in 96-well Ultra low Attachment plates (#3474, Corning Inc.) in 100{U}L of Dulbecco’s modified eagle medium containing 10% FBS. Cells are cultured for 2 h and inhibitors are added at various concentrations in a final concentration of 0.1% DMSO. After 48 h, cell growth is assayed with the cell counting kit-8 (Wako Pure Chemical), which uses a water soluble tetrazolium salt WST8. Twenty {U}L of the reagent is added into each well and cells are further cultured for 2 h. The optical density is measured at 450 nm. The concentration of compound causing 50 % inhibition of growth is determined.
Example 59 In vivo activity in the nude mouse xenograft model:
female or male BALB/c nude mice (5-8 weeks old, Charles River Japan, Inc., Yokohama, Japan) are kept under sterile conditions with water and feed ad libitum. Tumours are induced by subcutaneous injection of tumour cells (human epithelial cell line MIA PaCa-2; European Collection of Cell Cultures (ECACC), Salisbury, Wiltshire, UK, Catalogue Number 85062806; cell line from a 65 year old Caucasian male; undifferentiated human pancreatic carcinoma cell line) into left or right flank of mice under Forene® anaesthesia (Abbott Japan Co., Ltd., Tokyo, Japan). Treatment with the test compound is started when the mean tumor volumes reached approximately 100 mm3. Tumour growth is measured two times per week and 1 day after the last treatment by determining the length of two perpendicular axis. The tumour volumes are calculated in accordance with published methods (see Evans et ai., Brit. J. Cancer 45,466-8, 1982). The anti-tumour efficacy is determined as the mean increase in tumour volume of the treated animals divided by the mean increase in tumour volume of the untreated animals (controls) and, after multiplication by 100, is expressed as delta T/C [%]. Tumour regression is reported as the mean changes of tumor volume of the treated animals divided by the mean tumor volume at start of treatment and, after multiplication by 100, is expressed as regression [%]. The test compound is orally administered daily with or without drug holidays.

WO 2005/016894 PCT/EP2004/009099
As an alternative to cell line MIA PaCa-2, another cell line may also be used in the same manner, for example:
- the 4T1 breast carcinoma cell line (ATCC Number CRL-2539; see also Cancer. 88(12 Supple) 2979-2988, 2000) with female BALB/c mice (injection into mammary fat pad).
On the basis of these studies, a compound of formula I according to the invention shows therapeutic efficacy especially against proliferative diseases responsive to an inhibition of a tyrosine kinase.
Example 60: Tablets
Tablets comprising 50 mg of active ingredient, for example one of the compounds of formula I described in Examples 1 to 131, and having the following composition are prepared in customary manner

Preparation: The active ingredient is mixed with a portion of the wheat starch, with the lactose and the colloidal silicic acid and the mixture is forced through a sieve. A further portion of the wheat starch is made into a paste, on a water bath, with five times the amount of water and the powder mixture is kneaded with the paste until a slightly plastic mass is obtained.
The plastic mass is pressed through a sieve of about 3 mm mesh size and dried, and the resulting dry granules are again forced through a sieve. Then the remainder of the wheat starch, the talc and the magnesium stearate are mixed in and the mixture is compressed to form tablets weighing 145 mg and having a breaking notch.

WO 2005/016894 PCT/EP2004/009099
Example 61: Soft Capsules
5000 soft gelatin capsules comprising each 50 mg of active ingredient, for example one of the
compounds of formula I described in Examples 1 to 131, are prepared in customary manner:
Composition:
active ingredient 250 g
Lauroglykol 2 litres
Preparation: The pulverized active ingredient is suspended in Lauroglykol® (propylene glycol laurate, Gattefosse S.A., Saint Priest, France) and ground in a wet pulverizer to a particle size of approx. 1 to 3 {U}m. 0.419 g portions of the mixture are then dispensed into soft gelatin capsules using a capsule-filling machine.

WO 2005/016894 PCT/EP2004/009099
methylpiperazino, morpholino, 1-methyl-4-piperidinyIoxy, 3-morphoiinopropoxy or 2-morpholinoethoxy, in particular hydrogen;
R3 is hydrogen, C1-C8afkyl, e.g. methyl or ethyl, haloC1-C8alkyl, e.g. trifluoromethyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 heteroatoms selected from N, O and S, e.g. 2-pyrrolidonyl or S,S-dioxoisothiazolidinyl, C1-C8alkoxy, e.g. methoxy, substituted amino, e.g. acetylamino, acetyl-methyl-amino, benzoylamino, methylsuifonylamino or phenylsulfonylamino, C1-C8aIkylsuIfonyl, e.g. methylsulfonyl, C5-C10arylsulfonyl, e.g. phenylsulfonyl, halogen, e.g. fluoro or chloro, carboxy, substituted or unsubstituted carbamoyl, e.g. carbamoyl, methylcarbamoyl or dimethylcarbamoyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl, propylsulfamoyl, isopropylsulfamoyl, isobutylsulfamoyl, cyclopropylmethyl-sulfamoyl, 2,2,2-trifluoroethylsulfamoyl, dimethylsulfamoyl or morpholinosulfonyl; preferably sulfamoyl, methyisulfamoyl or propylsulfamoyl;
each pair of adjacent substituents R0 and R1, or R1 and R2, or R2 and R3 are -CH2-NH-CO-, -CH2-NH-SO2-, -CH2-CH2-SO2-, -O-CHrO-, or -O-CF2-O-, and such pairs wherein hydrogen in NH is replaced by Ci-C8alkyl; preferably the pair of adjacent substituents R° and R1, or R1 and R2 being -O-CH2-O-, and the pair of adjacent substituents R2 and R3 being «CH2-NH-CO- or -CH2-NH-SO2-. R4 is hydrogen;
R5 is hydrogen, halogen, e.g. chloro or bromo, haloC1-C8alkyl, e.g. trifluoromethyl, or nitro; preferably hydrogen, chloro, bromo, trifluoromethyl or nitro; in particular chloro or bromo; R6 is hydrogen;
each of R7 and R9 independently is hydrogen, C1-Csalkyl, e.g. methyl, ethyl or isopropyl, haloCrCaalkyl, e.g. trifluoromethyl, unsubstituted or substituted C5-C10aryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, C1-C8alkoxy, e.g. methoxy, ethoxy or isopropoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethyfamino or acetylamino, halogen, e.g. fluoro or chloro, unsubstituted or substituted carbamoyl, e.g. cyclohexylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbony! or morpholinocarbonyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methyisulfamoyl or dimethylsulfamoyl; preferably hydrogen, methyl, isopropyl,

WO 2005/016894 PCT/EP2004/009099
sulfamoyl, cyclopentyl-sulfamoyl, isopropyl-sulfamoyl, cyclohexyl-sulfonyl, cyclopropyl-methyl-sulfamoyl, cyclobutyl-sulfamoyl, isopropyl-sulfonyl,
10. A compound of formula I according to any one of claim 6 to 9 wherein the compound is a compound of example 53.
11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, as active ingredient together with one or more pharmaceutically acceptable diluents or earners.
12. The use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment or prevention of neoplastic diseases and immune system disorders.
13. A combination comprising a therapeutically effective amount a compound according to any one of claims 1 to 9 and one or more further drug substances, said further drug substance being useful in the treatment of neoplastic diseases or immune system disorders.
14. A method for the treatment of neoplastic diseases and immune system disorders in a subject in need thereof which comprises administering an effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutical composition comprising same.
15. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease which responds to inhibition of FAK and/or ALK and/or ZAP-70 and/or IGF-IR.
16. The use according to claim 15, wherein the disease to be treated is selected from proliferative disease.
17. The use according to claim 16, wherein the proliferative disease to be treated is selected from a tumor of, breast, renal, prostate, colorectal, thyroid, ovarian, pancreas, neuronal, lung, uterine and gastro-intestinal tumours as well as osteosarcomas and melanomas.
18. The use according to claim 15, wherein the disease to be treated is an immune disease.,

Documents

Name	Date
553-CHENP-2006 CORRESPONDENCE OTHERS.pdf	2011-12-02
553-CHENP-2006 DESCRIPTION (COMPLETE) 21-07-2009.pdf	2009-07-21
553-chenp-2006 others document 21-07-2009.pdf	2009-07-21
553-CHENP-2006 POWER OF ATTORNEY.pdf	2011-12-20
553-CHENP-2006 CORRESPONDENCE PO.pdf	2011-12-02
553-CHENP-2006 PETITIONS.pdf	2011-12-20
553-CHENP-2006 FORM-3.pdf	2011-12-20
553-CHENP-2006 FORM-18.pdf	2011-12-20
553-CHENP-2006 CLAIMS.pdf	2011-12-20
553-CHENP-2006 ABSTRACT.pdf	2011-12-20
11442-W216.pdf	2015-04-21
Form 16 [08-12-2015(online)].pdf	2015-12-08
Power of Attorney [08-12-2015(online)].pdf	2015-12-08
553-CHENP-2006 DESCRIPTION (COMPLETE).pdf	2011-12-02
553-CHENP-2006 DESCRIPTION (COMPLETE)-1.pdf	2011-12-02
IN240560.pdf	2014-05-13
Power of Attorney [11-12-2015(online)].pdf	2015-12-11
Form 16 [11-12-2015(online)].pdf	2015-12-11
Form 27 [21-03-2016(online)].pdf	2016-03-21
553-CHENP-2006 DESCRIPTION (COMPLETE)-2.pdf	2011-12-20
Assignment [08-12-2015(online)].pdf	2015-12-08
Assignment [11-12-2015(online)].pdf	2015-12-11
CERTIFIED COPIES US 72 OR FOR CERTIFICATE US-147 AND RULE 133(2) [16-01-2017(online)].pdf	2017-01-16
Form 27 [29-03-2017(online)].pdf	2017-03-29
553-CHENP-2006-RELEVANT DOCUMENTS [25-03-2019(online)].pdf	2019-03-25
553-CHENP-2006-RELEVANT DOCUMENTS [30-03-2018(online)].pdf	2018-03-30
553-CHENP-2006-RELEVANT DOCUMENTS [21-03-2020(online)].pdf	2020-03-21
553-CHENP-2006-RELEVANT DOCUMENTS [27-09-2021(online)].pdf	2021-09-27
553-CHENP-2006-FORM-26 [28-09-2018(online)].pdf	2018-09-28
CERTIFIED COPIES US 72 OR FOR CERTIFICATE US-147AND RULE 133(2) Copy-Online.pdf_1.pdf	2017-01-17
CERTIFIED COPIES US 72 OR FOR CERTIFICATE US-147AND RULE 133(2) Copy-Online.pdf	2017-01-17

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Controller

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