ZA200408314B

ZA200408314B - Diaryl urea derivatives for the treatment of protein kinase dependent diseases

Info

Publication number: ZA200408314B
Application number: ZA200408314A
Authority: ZA
Inventors: Andreas Floersheimer; Paul W Manley; Eugen Boss; Andrea Vaupel; Pascal Furet; Guido Bold; Vito Guagnano
Original assignee: Novartis Ag
Priority date: 2002-05-29
Filing date: 2004-10-14
Publication date: 2006-07-26
Also published as: GB0212413D0; ECSP045431A

Description

Diary urea derivatives useful for the treatment of protein kinase dependent diseases

Summary of the Invention

The invention relates to the use of diaryl urea derivatives in the treatment of protein kinase dependent diseases or for the manufacture of pharmaceutical compositions for use in the treatment of said diseases, methods of use of diaryl urea derivatives in the treatment of said diseases, pharmaceutical preparations comprising diary! urea derivatives for the treatment of said diseases, diaryl urea derivatives for use in the treatment of said diseases, novel diaryl urea derivatives, pharmaceutical preparations comprising these novel diaryl urea derivatives, processes for the manufacture of the novel diaryl urea derivatives, the use or methods of use of the novel diaryl urea derivatives as mentioned above, and/or these novel diary! urea derivatives for use in the treatment of the animal or human body.

Background of the Invention

Protein kinases (PKs) are enzymes which catalyze the phosphorylation of specific serine, threonine or tyrosine residues in cellular proteins. These post-translational modifications of substrate proteins act as molecular switch regulating cell proliferation, activation and/or differentiation. Aberrant or excessive PK activity has been observed in many disease states including benign and malignant oroliferative disorders. In many cases, it has been possible to treat diseases in vitro and in many cases in vivo, such as proliferative disorders, by making use of PK inhibitors.

In view of the large number of protein kinase inhibitors and the multitude of proliferative and other PK-related diseases, there is an ever-existing need to provide novel classes of com- pounds that are useful as PK inhibitors and thus in the treatment of these PTK related dis- eases. What is required are new classes of pharmaceutically advantageous PK inhibiting compounds.

General Description of the Invention

It has now been found that various compounds of the diaryl urea derivative class show inhi- bition of a number of protein tyrosine kinases. Among the advantages, a good bioavailability and, especially where substituents at the ring with A and A’ in formula | or I* given below are present, lower accessibility to metabolism are to be mentioned. The compounds of formula or I*, described below in more detail, especially show inhibition of one or more of the following protein tyrosine kinases: c-Abl, Bcr-Abl, the receptor tyrosine kinases Fit3, VEGF-R or c-Kit, as well as combinations of tow or more of these; in the case of novel diaryl urea derivatives according to the invention, the compounds are appropriate for the inhibition of these and/or other protein tyrosine kinases, especially those mentioned above and/or, in addition, the non-receptor tyrosine kinase Raf, and/or for the inhibition of mutants of these enzymes, especially of Ber-Abl, for example the Glu255 -> Lysine mutant. In view of these activities, the compounds can be used for the treatment of diseases related to especially aberrant or excessive activity of such types of kinases, especially those mentioned.

Detailed Description of the Invention

The invention especially relates to the use of diaryl urea derivatives that are compounds of the formula (CH,),

X_N. _z

NL

RIL SF . Ye .

AN 0)

Ya)n R wherein G is either not present, lower alkylene or C;-Cscycloalkylene and Z is a radical of the formula la

R,

Hn (12)

R, or Gis not present and Z is a radical of the formula Ib

P A

R,

i WO 03/099771 PCT/EP03/05634

Ais CH, Nor N—O and A’ is N or N—O, with the proviso that not more than one of A and A’ can be N-O; nis 1or2; mis 0, 10r2; pis0,2or3; ris Oto 5;

Xis NR if pis 0, wherein R is hydrogen or an organic moiety, or if p is 2 or 3, X is nitrogen which together with (CH), and the bonds represented in dotted (interrupted) lines (including the atoms to which they are bound) forms a ring, or

Xis CHK wherein K is lower alkyl or hydrogen and p is zero, with the proviso that the bonds represented in dotted lines, if p is zero, are absent;

Yiis O, S or CHy;

Y,is O, S or NH; with the proviso that (Y4),-(Y2)m does not include O-O, S-S, NH-O, NH-S or S-O groups; each of Ry, Rp, Rj and Rs, independently of the others, is hydrogen or an inorganic or organic moiety or any two of them together form a lower alkylene-dioxy bridge bound via the oxygen atoms, and the remaining one of these moieties is hydrogen or an inorganic or organic moiety; and R, (if present, that is, if r is not zero) is an inorganic or organic moiety; or a tautomer thereof; or a pharmaceutically acceptable salt thereof; in the treatment of protein kinase (especially tyrosine protein kinase) dependent diseases or for the manufacture of pharmaceutical compositions for use in the treatment of said disea- ses, methods of use of diaryl urea derivatives in the treatment of said diseases, pharmaceu- tical preparations comprising diaryl urea derivatives for the treatment of said diseases, diary! urea derivatives for use in the treatment of said diseases.

The invention further also relates to the use or diaryl urea derivatives as described above, . wherein the diaryl urea derivative is a compound of the formula I*

{CH,), : \ H 0 OY ; (Ry); \ " Y (1)

ANA NG Ry © J 2) 5

R; R, wherein A, A’, n, m, p, I, X, Y3, Y2 and Ry-Rs have the meanings as defined above for a compound of formula |; or a tautomer thereof; or pharmaceutically acceptable salts thereof.

The invention especially relates to novel diaryl urea derivatives, especially a compound se- lected from the compounds of the formula | or I* in the Examples, or a salt thereof, especially (i) the novel compounds of the formula | wherein

Ais CH, Nor N»>O and A’ is N or N—0O, with the proviso that not more than one of A and A’ can be N—O; nis 1or2; mis 0, 1o0r2; pis0,2or3; ris 1to5;

X is NR if p is 0, wherein R is hydrogen or an organic moiety, or if pis 2 or 3, X is nitrogen which together with (CH), and the bonds represented in dotted (interrupted) lines (including the atoms to which they are bound) forms a ring, with the proviso that if X is NH, each of Ry, independently of the others if r>1, is a moiety as defined above under formula | but not bound to the rest of formula | via a -C(=0)-, -C(NR)- or -S(O.)- bridge, or ’ X is CHK wherein K is lower alkyl or hydrogen and p is zero, with the proviso that the bonds represented in dotted lines, if p is zero, are absent;

Y, is O, S or CHy;

Y,is O, Sor NH; with the proviso that (Y;).-(Y2)m does not include O-O, S-S, NH-O, NH-S or S-O groups;

each of Ry, Ra, R; and Rs, independently of the others, is hydrogen or an inorganic or organic moiety or any two of Ry, R; and R; together form a lower alkylene-dioxy bridge bound via the oxygen atoms, and the remaining one of these moieties is hydrogen or an inorganic or organic moiety, with the proviso that if G is not present and Z is a radical of the formula la, Ry, R; and R3 cannot all be hydrogen and with the further proviso that if one of

Rs, R; and R; is halo or lower alkyl-sulfonyl, the other two cannot both be hydrogen;

Rs is an inorganic or organic moiety, with the proviso thatif nis 1, mis 0, pis 0, ris 1, X'is

NH, Y; is O, Gis not present and Z is a radical of the formula la, Rs, together with the benzene ring containing A and A’, does not form methylpyridinyl, 2-hydroxy-pyridin-4-yl or 1-

H-2-oxo0-1,2-dihydropyridin-4-yi; and

G and Z have the meanings given above under formula I; or a tautomer thereof; or pharmaceutically acceptable salts thereof; and (ii) the novel compounds of the formula I* wherein

Ais CH, Nor NO and A’ is N or N—O, with the proviso that not more than one of A and A’ can be N-O; nis 1; m is 0; pis0, 2or3; ris 1;

Xis NR if pis 0, wherein R is hydrogen or lower alkyl, or if p is 2 or 3, X is nitrogen which together with (CH,), and the bonds represented in dotted (interrupted) lines (including the atoms to which they are bound) forms a ring, or

X is CH, and p is zero, with the proviso that the bonds represented in dotted lines, if p is zero, are absent;

Yi is O or CH; each of Ry, Rz and Rj independently of the others, is hydrogen, lower alkyl, halo, especially } bromo or chloro, halo-lower alkyl, especially trifluoromethyl, lower alkoxy, especially metho- xy, halo-lower alkoxy, especially 2,2,2-trifluoroethoxy, phenyl, piperidyl, especially piperidin- . 1-yl, piperazinyl, especially piperazin-1-yl, morpholinyl, especially morpholine, thiomorpho- linyl, especially thiomorpholino, or any two of them together form a lower alkylene-dioxy bridge bound via the oxygen atoms, and the remaining one of these moieties is hydrogen or one of the moieties mentioned, with the proviso that Ry, R; and R; cannot all be hydrogen and with the further proviso that if one of Ry, R; and R; is halo, the other two cannot both be hydrogen;

R, is lower alkoxy, especially methoxy, lower alkanoylamino, especially acetylamino, hydroxyphenylamino, especially p-hydroxyphenylamino, amino-lower alkyl-oxyphenyl-amino, especially 4-[(2-aminoethyl)-oxyphenyl}-amino, sulfamoylphenylamino, especially 4- sulfamoylphenylamino, carbamoylphenylamino, especially 4-carbamoylphenylamino, [N- (hydroxy-lower alkyl)-carbamoyl]-phenylamino, especially [N-(2-hydroxyethyl)-carbamoyi]- phenylamino, or halo, especially chloro; and

Rs is hydrogen, lower alkyl or halo, especially hydrogen; or a tautomer thereof; or pharmaceutically acceptable salts thereof; to pharmaceutical preparations comprising these novel diaryl urea derivatives or pharma- ceutically acceptable salts thereof, processes for the manufacture of the novel diaryl urea derivatives or pharmaceutically acceptable salts thereof, the use or methods of use of the novel diaryl urea derivatives or pharmaceutically acceptable salts thereof as mentioned above, and/or these novel diaryl urea derivatives or pharmaceutically acceptable salts the- reof for use in the treatment of the animal or human body.

The general terms used hereinbefore and hereinafter preferably have, within this disclosure, the following meanings, unless otherwise indicated:

The prefix "lower" denotes a radical having 1 up to and including a maximum of 7, especially 1 up to and including a maximum of 4 carbon atoms, the radicals in question being either li- near or branched with single or multiple branching. Lower alkyl, for example, is methyl, ethyl, n-propyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl or n-heptyl.

Where the plural form is used for compounds, salts, pharmaceutical preparations, diseases - and the like, this is intended to mean also a single compound, salt, or the like.

Halo(geno) is preferably iodo, bromo, chloro or fluoro, especially fluoro, chloro or bromo.

In view of the close relationship between the diaryl urea derivatives in free form and 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, tautomers or tautomeric mixtures and their salts, any reference hereinbefore and hereinafter to these compounds, especially the compounds of the formula | or I*, is to be understood as referring also to the . corresponding tautomers of these compounds, especially of compounds of the formula I or

I*, tautomeric mixtures of these compounds, especially of compounds of the formula { or I*, or salts of any of these, as appropriate and expedient and if not mentioned otherwise. Tauto- mers can, e.g., be present in cases where amino or hydroxy, each with a least one bound hydrogen, are bound to carbon atoms that are bound to adjacent atoms by double bonds (e.g. keto-enol or imine-enamine tautoemerism). Preferred tautomers are the pyridin-on-yi or pyrimidin-on-yl forms of compounds wherein Ry is hydroxy and the other moieties are defined as for compounds of the formula | or I*, respectively.

Where “a compound ..., a tautomer thereof; or a salt thereof” or the like is mentioned, this means “a compound ..., a tautomer thereof, or a salt of the compound or the tautomer”.

Any asymmetric carbon atom may be present in the (R)-, (S)- or (R,S)-configuration, pre- ferably in the (R)- or (S)-configuration. Substituents at a ring at atoms with saturated bonds may, if possible, be present in cis- (= Z-) or trans (= E-) form. The compounds may thus be present as mixtures of isomers or preferably as pure isomers, preferably as enantiomer-pure diastereomers or pure enantiomers.

Salts are preferably the pharmaceutically acceptable salts of the diaryl urea derivatives, es- pecially of compounds of the formula | or I* if they are carrying salt-forming groups.

Salt-forming groups are groups or radicals having basic or acidic properties. Compounds ha- ving at least one basic group or at least one basic radical, for example amino, a secondary amino group not forming a peptide bond or a pyridyl radical, may form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulfuric acid or a phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example aliphatic mono- or di-carbo- xylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or amino acids such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid, 4-aminosalicylic acid, aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid, hetero-

aromatic carboxylic acids, such as nicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such as methane-, ethane- or 2-hydroxyethanesulfonic acid, or aromatic sulfonic acids, for example benzene-, p-toluene- or naphthalene-2-sulfonic acid. When several basic groups are present mono- or poly-acid addition salts may be formed.

Compounds having acidic groups, a carboxy group or a phenolic hydroxy group, may form metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example so- dium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri-(2-hydroxy- ethyl)}-amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N-dimethylpiper- azine. Mixtures of salts are possible.

Compounds having both acidic and basic groups can form internal salts.

For the purposes of isolation or purification, as well as in the case of compounds that are used further as intermediates, it is also possible to use pharmaceutically unacceptable salts, e.g. the picrates. Only pharmaceutically acceptable, non-toxic salts may be used for thera- peutic purposes, however, and those salts are therefore preferred.

An organic moiety R is preferably unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted cycloalkenyl; preferred is unsubstituted alkyl. “Substituted”, whereever used for a moiety, means that one or more hydrogen atoms in the respective moiety, especially up to 5, more especially up to three, of the hydrogen atoms are replaced independently of each other by the corresponding number of substituents which preferably are independently selected from the group consisting of lower alkyl, for example methyl, ethyl or propyl, halo-lower alkyl, for example trifluoromethyl, C¢-C,¢-aryl, especially phenyl or naphthyl (where Cs-Cyg-aryl, especially phenyl or napthyl, is unsubstituted or sub- stituted by one or more, especially up to three moieties selected from halogen, carboxy, lower alkoxycarbonyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkanoyloxy, lower alkanoyl, amino, N-lower alkylamino, N,N-di-lower alkylamino, N-phenyl-lower alkylamino,

N,N-bis(phenyl-lower alkyl)-amino, lower alkanoylamino, halo, halo-lower alkyl, e.g. trifluoro-

. a. methyl, sulfo, sulfamoyl, carbamoyl, N-lower alkyl-carbamoyl, N-(hydroxy-lower alkyl)-carb- amoyl, such as N-(2-hydroxyethyl)-carbamoyl, cyano, cyano-lower alkyl and nitro), C3-Cio- cycloalkyl, especially cyclopropyl or cyclohexyl, hydroxy-Cs;-Cg-cycloalkyl, such as hydroxy- cyclohexyl, heterocyclyl with 5 or 6 ring atoms and 1 to 3 ring heteroatoms selected from O,

N and S, especially piperidinyl, especially piperidin-1-yl, piperazinyl, especially piperazin-1-yl, morpholinyl, especially morpholin-1-yl, hydroxy, lower alkoxy, for example methoxy, halo- lower alkoxy, especially 2,2,2-trifluoroethoxy, phenyl-lower alkoxy, amino-lower alkoxy, such as 2-eminoethoxy; lower alkanoyloxy, hydroxy-lower alkyl, such as hydroxymethyl or 2-hy- droxyethyl, amino, N-lower alkylamino, N,N-di-lower alkylamino, N-phenyi-lower alkylamino,

N,N-bis(phenyl-lower alkyl)-amino, lower alkanoylamino, especially acetylamino, benzoyl- amino, carbamoyi-lower alkoxy, N-lower alkylcarbamoyi-lower alkoxy or N,N-di-lower alkyl- carbamoyl-lower alkoxy, amidino, N-hydroxy-amidino, guanidino, amino-lower alkyl, such as aminomethyl or 2-aminoethyl, amidino-lower alkyl, such as 2-amidinoethyl, N-hydroxyami- dino-lower alkyl, such as N-hydroxy-amidino-methyl or —2-ethyl, halogen, for example fluoro, chloro, bromo or iodo, carboxy, lower alkoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, lower alkanoyl, sulfo, lower alkanesulfonyl, for example methanesulfonyl (CH3-S(0)2-), phosphono (-P(=0)(OH)»), hydroxy-lower alkoxy phosphoryl or di-lower alkoxyphosphoryl, carbamoyl, mono- or di-lower alkylcarbamoyl, mono- or di-(hydroxy-lower alkyl)-carbamoyl, sulfamoyl, mono- or di-lower alkylaminosulfo- nyl, nitro, cyano-lower alkyl, such as cyanomethyl, and cyano. It goes without saying that substitutents are only at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort which substitutions are possible and which are not. For example, amino or hydroxy groups with free hydrogen may be unstable if bound to carbon atoms with unsaturated (e.g. olefinic) bonds.

Alkyl preferably has up to 20, more preferably up to 12 carbon atoms and is linear or bran- ched one or more times; preferred is lower alkyl, especially C;-C,-alkyl, in particular methyl, ethyl or n-propyl. Alkyl is unsubstituted or substituted, preferably by one or more substituents independently selected from those mentioned above under “Substituted”. Unsubstituted al- kyl, preferably lower alkyl, is especially preferred as an organic moiety R.

Among the moieties corresponding to substituted alkyl, hydroxy-lower alkyl, especially 2-hy- droxyethyl, and/or halo-lower alkyl, especially trifluoromethyl or 2,2,2-trifluoroethyl, are espe- cially preferred.

Alkenyl is preferably a moiety with one or more double bonds and preferably has 2 to 20, more preferably up to 12, carbon atoms; it is linear or branched one or more times (as far as possible in view of the number of carbon atoms). Preferred is C,-C;-alkenyl, especially Cs-

Cs-alkenyl, such as allyl or crotyl. Alkenyl can be unsubstituted or substituted, especially by one or more, more especially up to three, of the substituents mentioned above under ,substi- tuted“. Substituents such as amino or hydroxy (with free dissociable hydrogen) preferably are not bound to carbon atoms that participate at a double bond, and also other subtituents that are not sufficiently stable are preferably excluded. Unsubstituted alkenyl, in particular

C2-Cr-alkenyl, is preferred.

Alkynyl is preferably a moiety with one or more triple bonds and preferably has 2 to 20, more preferably up to 12, carbon atoms; it is linear of branched one or more times (as far as pos- sible in view of the number of carbon atoms). Preferred is C,-C7-alkynyl, especially C3-Cs- alkynyl, such as ethinyl or propin-2-yl. Alkynyl can be unsubstituted or substituted, especially by one or more, more especially up to three, of the substituents mentioned above under substituted”. Substituents such as amino or hydroxy (with free dissociable hydrogen) preferably are not bound to carbon atoms that participate at a triple bond, and also other subtituents that are not sufficiently stable are preferably excluded. Unsubstituted alkynyl, in particular C,-C;-alkynyl, is preferred.

Aryl preferably has a ring system of not more than 16 carbon atoms, is preferably mono-, bi- or tric-cyclic, and is unsubstituted or substituted preferably as defined above under “Sub- stituted”. Preferably, aryl is selected from phenyl, naphthyl, indenyl, azulenyl and anthryl, and is preferably in each case unsubstituted or lower alkyl, especially methyl, ethyl or n-propyi, halo (especially fluoro, chloro, bromo or iodo), halo-lower alkyl (especially trifluoromethyl), hydroxy, lower alkoxy (especially methoxy), halo-lower alkoxy (especially 2,2,2-trifluoroetho- xy), amino-lower alkoxy (especially 2-amino-ethoxy), lower alkyl (especially methyl or ethyl) carbamoyl, N-(hydroxy-lower alkyl)-carbamoyl! (especially N-(2-hydroxyethyl)-carbamoyl) and/or sulfamoyl-substituted aryl, especially a corresponding substituted or unsubstituted phenyl.

Heterocyclyl is preferably a heterocyclic radical that is unsaturated, saturated or partially sa- turated in the bonding ring and is preferably a monocyclic or in a broader aspect of the in- vention bicyclic or tricyclic ring; has 3 to 24, more preferably 4 to 16 ring atoms; wherein at least in the ring bonding to the radical of the molecule of formula | or I* one or more, preferably one to four, especially one or two carbon ring atoms are replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, the bonding ring preferably having 4 to 12, especially 5 to 7 ring atoms; heteroaryl being unsubstituted or substituted by one or more, especially 1 to 3, substitutents independently selected from the group consisting of the substituents defined above under “Substituted”; especially being a heteroaryl radical selected from the group consisting of oxiranyl, azirinyl, 1,2-oxathiolanyl, imidazolyl, thienyl, fury, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, pyranyol, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, especially : piperidin-1-yl, piperazinyl, especially piperazin-1-yl, pyridazinyl, morpholinyl, especially morpholino, thiomorpholinyl, especially thiomorpholino, indolizinyl, isoindolyl, 3H-indolyl, in- dolyl, benzimidazolyl, cumaryl, indazolyl, triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyil, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, B-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, furazanyi, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl and chromanyl, each of these radicals being unsubstituted or substituted by one to two radicals selected from the group consisting of lower alkyl, especially methyl! or tert-butyl, lower alkoxy, especially methoxy, and halo, especially bromo or chloro. Unsubstituted heterocyclyl, especially piperidyl, piperazinyl, thiomorpholino or morpholino, is preferred.

Cycloalkyl is preferably C;-Cqg-cycloalkyi, especially cyclopropyl, dimethylcyclopropyl, cyclo- butyl, cyclopentyl, cyclohexyl or cycloheptyl, cycloalkyl being unsubstituted or substituted by } one or more, especially 1 to 3, substitutents independently selected from the group consis- ting of the substituents defined above under “Substituted”.

Claims

What is claimed is:

1. Use of a diary! urea derivative of the formula (CH), XN 2 NL I RO— SF W Ye ? AA 0 (Yo) R wherein G is either not present, lower alkylene or C;-Cscycloalkylene and Z is a radical of the formula la R, R, or G is not present and Z is a radical of the formula Ib + 3 Ry Ais CH, N or N=O and A’ is N or N—O, with the proviso that not more than one of A and A’ can be N—O; nis 1or2, : mis 0, 1or2; pis 0, 2o0r3; ’ ris 0 to 5; Xis NR if p is 0, wherein R is hydrogen or an organic moiety, or if p is 2 or 3, X is nitrogen which together with (CH,), and the bonds represented in dotted (interrupted) lines (including the atoms to which they are bound) forms a ring,

or X is CHK wherein K is lower alkyl or hydrogen and p is zero, with the proviso that the bonds represented in dotted lines, if p is zero, are absent; Y;is O, Sor CH, Y2is O, S or NH; with the proviso that (Y1)n-(Y2)m does not include 0-0, S-S, NH-O, NH-S or S-O groups; each of Ry, Ry, R; and Rs, independently of the others, is hydrogen or an inorganic or organic moiety or any two of them together form a lower alkylene-dioxy bridge bound via the oxygen atoms, and the remaining one of these moieties is hydrogen or an inorganic or organic moiety; and R, (if present, that is, if r is not zero) is an inorganic or organic moiety; or a tautomer thereof; or a pharmaceutically acceptable salt thereof; for the manufacture of pharmaceutical compositions for use in the treatment of protein kinase dependent diseases.

2. The use according to claim 1 wherein the diaryl urea derivative is a compound of the formula | according to claim 1 wherein G is either not present, lower alkylene, especially methylene or ethylene, or Cs- Cscycloalkylene, especially cyclopropylene, and Z is a radical of the formula la according to claim 1, or G is not present and Z is a radical of the formula Ib according to claim 1; AisCHorNand A’ is N or N-»O; nis 1; mis Oor1; pis0,2o0r3; risoorf; Xis NR if p is 0, wherein R is hydrogen or lower alkyl, or if p is 2 or 3, X is nitrogen which together with (CH), and the bonds represented in dotted (interrupted) lines (including the atoms to which they are bound) forms a ring, or X is CHK wherein K is hydrogen and p is zero, with the proviso that the bonds represented in dotted lines, if p is zero, are absent; Y;is O, S or CH;

Y,is O; with the proviso that (Y1).-(Y2)m does not include O-O, or S-O groups;

‘each of Ry, Rp and Rs, independently of the others, is hydrogen, lower alkyl, especially methyl, ethyl, n-propyl, isopropyl or tert-butyl, lower alkenyl, especially isopropenyl, hydroxy-

lower alkyl, especially hydroxy-propyl, lower alkoxy, especially methoxy, halo, especially chloro or bromo, halo-lower alkyl, especially trifluoromethyl, halo-lower alkoxy, especially trifluoromethoxy or trifluoroethoxy, amino-lower alkyl, especially aminomethyl, amino-lower alkoxy, especially aminoethoxy, di-lower alkyl-amino, especially diethylamino, hydroxy-lower alkyl-amino, especially hydroxy-propylamino, bis-(lower alkoxy-lower alkyl)-amino, especially bis-(2-methoxy-ethyl)-amino, di-lower alkyl-amino-lower alkyl, especially dimethytaminomethyl, phenyl, morpholinyl, especially morpholin-4-yl, piperidyl, especially piperidin-1-yl, piperidyl-lower alkyl, especially piperidin-1-ylmethyl, lower alkyl-piperazinyl, especially 4-methyl-piperazin-1-yl or 4-ethyl-piperazin-1-yl, lower alkyl-piperazinyl-lower alkyl, especially 4-methyl-piperazin-1-ylmethyl or 4-ethyl-piperazin-1-ylmethyl, pyridyl, especially pyridin-2-yl, or lower alkyl-imidazolyl, especially 2- or 4-methyl-imidazol-1-yl; if ris 1, Ry is lower alkyl, especially methyl, ethyl or ispropyl, hydroxy, aminocarbonyi, lower alkyl-carbonyl, especially methylcarbonyl, cyclohexyl, halo, especially chloro or fluoro, halo- lower alkyl, especially trifluoromethyl, lower alkoxy, especially methoxy, amino, lower alkyl- amino, especially methylamino, ethylamino, isopropylamino or tert-butylamino, di-lower alkyl- amino, especially dimethylamino, lower alkenyl-amino, especially prop-2-enylamino or but-3- enylamino, lower alkyl-carbonyl-amino, especially methylcarbonylamino, cyano, azido, hydroxy-phenyl-amino, especially 3- or 4-hydroxy-phenyl-amino, mono or tri-lower atkoxy- phenyl-amino, especially methoxy-phenyl-amino or trimethoxy-phenyl-amino, lower alkoxy- halo-phenyl-amino, especially methoxy-fluoro-phenyl-amino, phenyl-lower alkylamino, especially benzylamino, (mono or di-lower alkoxy)-phenyl-lower alkylamino, especially methoxy-benzylamino or dimethoxy-benzylamino, aminosulfonyl-phenyl-lower alkylamino, especially aminosulfonyl-benzylamino, amino-lower alkoxy-phenyl-amino, especially aminoethoxy-phenyl-amino, lower alkyl-amino-sulfonyl-lower alkyl-phenylamino, especially methylamino-sulfonylmethyl-phenylamino, lower alkyl-piperazinyl-lower alkylamino,

especially 4-methylpiperazin-1-yl-propylamino, morpholinyl-lower alkylamino, especially morpholin-4-yl-propylamino, lower alkyl-piperidyl-amino, especially 1-methyl-piperidin-4-

ylamino, tetrazolyl, especially 1H-tetrazol-5-yl, lower alkyl-tetrazolyl, especially lower alkyi- tetrazol-5-yl such as 1-methyl-1H-tetrazol-5-yl or 2-methyl-2H-tetrazol-5-yl, or (di-lower alkyl)-amino-lower alkyl-tetrazolyl, especially (di-lower alkyl)-amino-lower alkyl-tetrazol-5-yl such as 2-(3-dimethylaminopropyl)-2H-tetrazol-5-yi; Rs is most preferably hydrogen, or lower alkyl, especially methyl, or halo, especially chloro; or a tautomer thereof; or a pharmaceutically acceptable salt thereof.

3. The use according to claim 1 wherein the diaryl urea derivative is a compound of the formula | according to claim 1 wherein A and A’ are both N, nis 1, mis 0, pisOor 2, ris 1, Xis NHif pis 0, or if p is 2, X is nitrogen which together with (CH), and the bonds represented in dotted (interrupted) lines (including the atoms to which they are bound) forms aring, Yy is O, Gis not present, Z is a radical of the formula la according to claim 1, at least one of Ry, Ry and Rj is a basic organic moiety, R, is amino or lower alkylamino and Rs is hydrogen.

4. The use according to claim 1 wherein the diaryl urea derivative is a compound of the formula 1* (CH), , vv H XX oY.) X_ N R, RI— \ ID Y () AA R 0 (ohn R Rj 2 wherein A, A’, n,m, p, 1, X, Y4, Y; and R4-Rs have the meanings as defined for a compound of formula | according to claim 1; or a tautomer thereof; or a pharmaceutically acceptable salt thereof.

:

5. The use according to claim 4 of a compound of the formula I* or a tautomer thereof, or a pharmaceutically acceptable salt thereof, where, in the compound of the formula I*, Ais CH, N or N—-O and A’ is N or N—O, with the proviso that not more than one of A and A’ can be N—O; nis 1; mis 0;

pis0,2or3; ris0,1or2 X is NR if pis 0, wherein R is hydrogen or lower alkyl, or if p is 2 or 3, X is nitrogen which together with (CH), and the bonds represented in dotted (interrupted) lines (including the atoms to which they are bound) forms a ring, or X is CH, and p is zero, with the proviso that the bonds represented in dotted lines, if p is zero, are absent; Y, is O or CHy; each of Ry, R; and R; independently of the others, is hydrogen, lower alkyl, halo, especially bromo or chloro, halo-lower alkyl, especially trifluoromethyl, lower alkoxy, especially metho- xy, halo-lower alkoxy, especially 2,2,2-trifluoroethoxy, phenyl, piperidyl, especially piperidin- 1-yl, piperazinyl, especially piperazin-1-yl, morpholinyl, especially morpholine, thiomorpho- linyl, especially thiomorpholino, or any two of them together form a lower alkylene-dioxy bridge bound via the oxygen atoms, and the remaining one of these moieties is hydrogen or one of the moieties mentioned; if r is not zero, Ry is lower alkyl, especially methyl or ethyl, lower alkoxy, especially methoxy, lower alkanoylamino, especially acetylamino, hydroxyphenylamino, especially p- hydroxyphenylamino, amino-lower alkyl-oxyphenyl-amino, especially 4-[(2-aminoethyl)- oxyphenyl]-amino, sulfamoylphenylamino, especially 4-sulfamoylphenylamino, carbamo- ylphenylamino, especially 4-carbamoyiphenylamino, [N-(hydroxy-lower alkyl)-carbamoyi}- phenylamino, especially [N-(2-hydroxyethyl)-carbamoyl]-phenylamino, halo, especially chloro, or hydroxyl; and Rs is hydrogen, lower alkyl or halo, especially hydrogen.

6. The use according to any one of claims 1 to 5 where the protein kinase dependent disease is a tyrosine protein kinase dependent disease, especially a proliferative disease depending on any one or more of of the following tyrosine protein kinases: ras, Abl, VEGF- receptor tyrosine kinase, Fit3, and/or Ber-Abt activity.

7. A compound of the formula | according to claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt thereof, where, in the compound of the formula |, Ais CH, N or NO and A’ is N or N—O, with the proviso that not more than one of A and A’ can be N—-O; nis 1or2,

mis 0, 1 or 2; pis0,2o0r3; ris1to5; Xis NR if pis 0, wherein R is hydrogen or an organic moiety, or if p is 2 or 3, X is nitrogen which together with (CH,), and the bonds represented in dotted (interrupted) lines (including the atoms to which they are bound) forms a ring, with the proviso that if X is NH, each of R,, independently of the others if r>1, is a moiety as defined in claim 1 but not bound to the rest of formula 1 via a -C(=0)-, -C(NR)- or -S(0O,)- bridge, or X is CHK wherein K is lower alkyl or hydrogen and p is zero, with the proviso that the bonds represented in dotted lines, if p is zero, are absent; Y,is O, S or CH; Y,is O, S or NH; with the proviso that (Y;),-(Y2)m does not include 0-0, S-S, NH-O, NH-S or S-O groups; each of Ry, Ry, Rj and Rs, independently of the others, is hydrogen or an inorganic or organic moiety or any two of R4, R; and Rj together form a lower alkylene-dioxy bridge bound via the oxygen atoms, and the remaining one of these moieties is hydrogen or an inorganic or organic moiety, with the proviso that if G is not present and Z is a radical of the formula la according to claim 1, Ry, R2 and R; cannot all be hydrogen and with the further proviso that if one of Ry, R; and Rj is halo or lower alkyl-sulfonyl, the other two cannot both be hydrogen; Ry is an inorganic or organic moiety, with the proviso thatifnis 1, mis 0, pis 0, ris 1, Xis NH, Y, is O, Gis not present and Z is a radical of the formula la according to claim 1, Ry, together with the benzene ring containing A and A’, does not form methylpyridinyl, 2- hydroxy-pyridin-4-yl or 1-H-2-oxo0-1,2-dihydropyridin-4-yl; and G and Z have the meanings given under formula | in claim 1.

8. A compound of the formula | according to claim 7 wherein G is either not present, lower alkylene, especially methylene or ethylene, or Cs- Cscycloalkylene, especially cyclopropylene, and Z is a radical of the formula la according to claim 1, or G is not present and Z is a radical of the formula Ib according to claim 1; Ais CHor Nand A’is N or N»O;

nis 1; mis Oor1;

pis 0,2 or 3; ris 1;

X is NR if p is 0, wherein R is hydrogen or lower alkyl, or if p is 2 or 3, X is nitrogen, which together with (CH), and the bonds represented in dotted (interrupted) lines (including the atoms to which they are bound) forms a ring, or X is CHK wherein K is hydrogen and p is zero, with the proviso that the bonds represented in dotted lines, if p is zero, are absent;

Yqis O, S or CH; Y,is O; with the proviso that (Y1).-(Y2)m does not include O-O, or S-O groups; each of Ry, R, and Rs, independently of the others, is hydrogen, lower alkyl, especially methyl, ethyl, n-propyl, isopropyl or tert-butyl, lower alkenyl, especially isopropeny}, hydroxy- lower alkyl, especially hydroxy-propyl, lower alkoxy, especially methoxy, halo, especially chloro or bromo, halo-lower alkyl, especially trifluoromethyl, halo-lower alkoxy, especially trifluoromethoxy or trifluoroethoxy, amino-lower alkyl, especially aminomethyl, amino-lower alkoxy, especially aminoethoxy, di-lower alkyl-amino, especially diethylamino, hydroxy-lower alkyl-amino, especially hydroxy-propylamino, bis-(lower alkoxy-lower alkyl)-amino, especially bis-(2-methoxy-ethyl)-amino, di-lower alkyl-amino-lower alkyl, especially dimethylaminomethyl, phenyl, morpholinyl, especially morpholin-4-yl, piperidyl, especially piperidin-1-yl, piperidyl-lower alkyl, especially piperidin-1-ylmethyl, lower alkyl-piperazinyl, especially 4-methyl-piperazin-1-yl or 4-ethyl-piperazin-1-yl, lower alkyl-piperazinyl-lower alkyl, especially 4-methyl-piperazin-1-ylmethyl or 4-ethyl-piperazin-1-ylmethyl, pyridyl, especially pyridin-2-yl, or lower alkyl-imidazolyl, especially 2- or 4-methyl-imidazol-1-yl, with the proviso that if G is not present and Z is a radical of the formula la according to claim 1, Ry, R; and R, cannot all be hydrogen and with the further proviso that if one of Ry, R; and Rs is halo, the other two cannot both be hydrogen; R, is lower alkyl, especially methyl, ethyl or ispropyl, hydroxy, aminocarbonyl, lower alkyl- carbonyl, especially methylcarbonyl, cyclohexyl, halo, especially chloro or fluoro, halo-lower alkyl, especially trifluoromethyl, lower alkoxy, especially methoxy, amino, lower alkyl-amino, especially methylamino, ethylamino, isopropylamino or tert-butylamino, di-lower alkyl-amino, especially dimethylamino, lower alkenyl-amino, especially prop-2-enylamino or but-3- enylamino, lower alkyl-carbonyl-amino, especially methylcarbonylamino, cyano, azido,

hydroxy-phenyl-amino, especially 3- or 4-hydroxy-phenyl-amino, mono or tri-lower alkoxy- phenyl-amino, especially methoxy-phenyl-amino or trimethoxy-phenyl-amino, lower alkoxy- halo-phenyl-amino, especially methoxy-fluoro-phenyl-amino, phenyl-lower alkylamino, especially benzylamino, (mono or di-lower alkoxy)-phenyl-lower alkylamino, especially methoxy-benzylamino or dimethoxy-benzylamino, aminosulfonyl-phenyl-lower alkylamino, especially aminosulfonyl-benzylamino, amino-lower alkoxy-phenyl-amino, especially aminoethoxy-phenyl-amino, lower alkyl-amino-sulfonyl-lower alkyl-phenylamino, especially methylamino-sulfonylmethyl-phenylamino, lower alkyl-piperazinyl-lower alkylamino, } especially 4-methylpiperazin-1-yl-propylamino, morpholinyl-lower alkylamino, especially morpholin-4-yl-propylamino, lower alkyl-piperidyl-amino, especially 1-methyl-piperidin-4- ylamino, tetrazolyl, especially 1H-tetrazol-5-yl, lower alkyl-tetrazolyl, especially lower alkyl- tetrazol-5-yl such as 1-methyl-1H-tetrazol-5-yl or 2-methyl-2H-tetrazol-5-yl, or (di-lower alkyl)-amino-lower alkyl-tetrazolyl, especially (di-lower alkyl)-amino-lower alkyl-tetrazol-5-yl such as 2-(3-dimethylaminopropyl)-2H-tetrazol-5-yl, with the proviso that if X is NH, Ry is not aminocarbonyl or lower alkyl-carbonyl and with the further proviso thatifnis 1, mis 0, pis 0, ris 1, Xis NH, Y; is O, G is not present and Z is a radical of the formula la according to claim 1, R4, together with the benzene ring containing A and A’, does not form methylpyridinyl, 2-hydroxy-pyridin-4-yl or 1-H-2-oxo-1,2-dihydropyridin-4-y}; Rs is most preferably hydrogen, or lower alkyl, especially methyl, or halo, especially chloro; or a tautomer thereof; or a pharmaceutically acceptable salt thereof.

9. A compound of the formula | according to claim 7 wherein A and A’ are both N, nis 1, mis 0,pisOor2 ris1, Xis NHif pis 0, orif pis 2, X is nitrogen which together with (CH), and the bonds represented in dotted (interrupted) lines (including the atoms to which they are bound) forms a ring, Y; is O, G is not present, Z is a radical of the formula la according to claim 1, at least one of Ry, R, and R; is a basic organic moiety, R4 is amino or lower alkylamino and Rs is hydrogen, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

10. A compound of the formula I* according to claim 4 or a tautomer thereof, or a pharmaceutically acceptable salt thereof, where, in the compound of the formula I*, Ais CH, N or N—»O and A’ is N or N-O, with the proviso that not more than one of Aand A’ can be N-O;

nis 1; mis 0; pis0,2or3; ris 1; X is NR if p is 0, wherein R is hydrogen or lower alkyl, or if p is 2 or 3, X is nitrogen which together with (CH), and the bonds represented in dotted (interrupted) lines (including the atoms to which they are bound) forms a ring, or X is CH, and p is zero, with the proviso that the bonds represented in dotted lines, if p is zero, are absent; Y,is O or CHy; each of Ry, R, and R; independently of the others, is hydrogen, lower alkyl, halo, especially bromo or chloro, halo-lower alkyl, especially trifluoromethyl, lower alkoxy, especially metho- xy, halo-lower alkoxy, especially 2,2,2-trifluoroethoxy, phenyl, piperidyl, especially piperidin- 1-yl, piperazinyl, especially piperazin-1-yl, morpholinyl, especially morpholine, thiomorpho- linyl, especially thiomorpholino, or any two of them together form a lower alkylene-dioxy bridge bound via the oxygen atoms, and the remaining one of these moieties is hydrogen or one of the moieties mentioned, with the proviso that Ry, R; and R; cannot all be hydrogen and with the further proviso that if one of Ry, R, and R; is halo, the other two cannot both be hydrogen; R, is lower alkoxy, especially methoxy, lower alkanoylamino, especially acetylamino, hydroxyphenylamino, especially p-hydroxyphenylamino, amino-lower alkyl-oxyphenyl-amino, especially 4-[(2-aminoethyl)-oxyphenyl]-amino, sulfamoylphenylamino, especially 4- sulfamoylphenylamino, carbamoylphenylamino, especially 4-carbamoylphenylamino, [N- (hydroxy-lower alkyl)-carbamoyl]-phenylamino, especially [N-(2-hydroxyethyl)-carbamoyl]- phenylamino, or halo, especially chloro; and Rs is hydrogen, lower alkyl or halo, especially hydrogen.

11. A compound of the formula I* according to claim 4 or a tautomer thereof, or a pharmaceutically acceptable salt thereof, where, in the compound of the formula I*, A, A, n,m, p, Yq, Ya, Ry, Ry, Ry and Ry have the meanings given under formula 1* in claim 4, andris 1to 5, Xis NR if p is 0, wherein R is hydrogen or an organic moiety, or if pis 2 or 3, X is nitrogen which together with (CH), and the bonds represented in dotted (interrupted) lines (including the atoms to which they are bound) forms a ring, or Xis CH, and p is zero,

and, if p is zero, the bonds represented in dotted lines are absent; with the proviso that if X is NH, each of Ry, independently of the others, if present, is a moi- ety as defined in claim 4 but not bound to the rest of formula 1* via a -C(=0)-, -C(NR)- or -S(0,)- bridge, and the substituents Ry, R, and R; are selected from the following moieties, whereby positions (0 = ortho, m = meta, p = para) are indicated with regard to the position where the ring is bound to the rest of the molecule in formula I* (via the NH-C(=0)-X- moiety): if only Ry is other than hydrogen: R; = p-lower alkyl, especially p-methyl, p-ethyl, p-n-propyl; m-halo-lower alkyl, especially m-trifluoromethyl; or phenyl, p-piperidin-1-yl or p-piperazin-1-yl; if both Ry and R; are other than hydrogen: R, = m-halo-lower alkyl, especially m-trifluoromethyl, and Rx = p-halo, especially p- bromo; R, = m-halo-lower alkyl, especially m-trifluoromethyl, and R; = p-halo-lower alkoxy, especially p-(2,2,2-trifluoroethoxy); R: = m-halo-lower alkyl, especially m-trifluoromethyl, and R; = m-lower alkoxy, especially m-methoxy; R= m-halo-lower alkyl, especially m-trifluoromethyl, and R, = p-phenyl; R, = m-halo-lower alkyl, especially m-trifluoromethyl, and R; = p-piperidin-1-yl or p- piperazin-1-yl; R, = m-halo-lower alkyl, especially m-trifluoromethyl, and R, = p-N-morpholino or p-N- thiomorpholino; R; = m-lower alkoxy, especially m-methoxy, and R; = p-halo, especially p-bromo (less preferred); R, = m-lower alkoxy, especially m-methoxy, and R, = p-halo-lower alkoxy, especially p-2,2,2-trifluoroethoxy; R, = m-lower alkoxy, especially m-methoxy, and R, = p-phenyl; or R, = m-lower alkoxy, especially m-methoxy, and R, = p-piperidin-1-yl or p-piperazin-1- yh; or, if Ry, R2 and Rj are other than hydrogen: R, = m-lower alkoxy, especially m-methoxy; R; = m-lower alkoxy, especially m-metho- xy; and R; = p-lower alkoxy, especially p-methoxy; or

R, = lower alkoxy, especially methoxy, and R; and R; together form a lower-alkylene- dioxy, especially —O-CH,-CH,-O-, bridge; and Rs is hydrogen, lower alkyl or halo, especially hydrogen; with the proviso that if nis 1, m is0,pis 0, ris 1, Xis NH and Y; is O, Rs, together with the benzene ring containing A and A’, does not form methylpyridinyl, 2-hydroxy-pyridin-4-yl or 1-H-2-oxo0-1,2-dihydropyridin-4-yl.

12. A compound of the formula I* according to claim 4 or a tautomer thereof, or a pharmaceutically acceptable salt thereof, where, in the compound of the formula 1*, Ais CH, Nor N—>O and A’ is N or N—O, with the proviso that not more than one of A and A’ can be N—-O; nis 1; mis 0; pis 0, 2 or 3; ris1or2; Xis NR if p is 0, wherein R is hydrogen or lower alkyl, or if p is 2 or 3, X is nitrogen which together with (CH,), and the bonds represented in dotted (interrupted) lines (including the atoms to which they are bound) forms a ring, or Xis CH; and p is zero, with the proviso that the bonds represented in dotted lines, if p is zero, are absent; Y, is O or CH; R;, R; and R; are selected from the following moieties, whereby positions (o = ortho, m = meta, p = para) are indicated with regard to the position where the ring is bound to the rest of the molecule in formula I* (via the NH-C(=0)-X-moiety): if only R, is other than hydrogen: R, = p-lower alkyl, especially p-methyl, p-ethyl, p-n-propyl; m-halo-lower alkyl, especially m-trifluoromethyi; or phenyl, p-piperidin-1-yl or p-piperazin-1-yl; if both Ry and R; are other than hydrogen: R: = m-halo-lower alkyl, especially m-trifluoromethyl, and R, = p-halo, especially p- bromo; R; = m-halo-lower alkyl, especially m-trifluoromethyl, and R, = p-halo-lower alkoxy, especially p-(2,2,2-trifluoroethoxy); R; = m-halo-lower alkyl, especially m-trifluoromethyl, and R, = m-lower alkoxy, especially m-methoxy;

R; = m-halo-lower alkyl, especially m-trifluoromethyl, and R, = p-phenyi; R; = m-halo-lower alkyl, especially m-trifluoromethyl, and R; = p-piperidin-1-yl or p- : piperazin-1-yl; R; = m-halo-lower alkyl, especially m-trifluoromethyl, and R, = p-N-morpholino or p-N- thiomorpholino; R: = m-lower alkoxy, especially m-methoxy, and R, = p-halo, especially p-bromo (less preferred); R, = m-lower alkoxy, especially m-methoxy, and R; = p-halo-lower alkoxy, especially p-2,2,2-trifluoroethoxy; R= m-lower alkoxy, especially m-methoxy, and R, = p-phenyl; or R: = m-lower alkoxy, especially m-methoxy, and R, = p-piperidin-1-yl or p-piperazin-1- yh; or, if Ry, R; and Rj; are other than hydrogen: Ry = m-lower alkoxy, especially m-methoxy; R, = m-lower alkoxy, especially m-metho- xy; and R3 = p-lower alkoxy, especially p-methoxy; or R1 = lower alkoxy, especially methoxy, and R; and Rj together form a lower-alkylene- dioxy, especially —O-CH,-CH,-O-, bridge; and, if r is not zero, Ry is lower alkoxy, especially methoxy, lower alkanoylamino, especially acetylamino, hydroxyphenylamino, especially p-hydroxyphenylamino, amino-lower alkyl- oxyphenyl-amino, especially 4-[(2-aminoethyl)-oxyphenyl}-amino, sulfamoylphenylamino, especially 4-sulfamoylphenylamino, carbamoylphenylamino, especially 4- carbamoylphenylamino, [N-(hydroxy-lower alkyl)-carbamoyl]-phenylamino, especially [N-(2- hydroxyethyl)-carbamoyl]-phenylamino, or halo, especially chloro; and Rs is halo, especially chloro, lower alkyl, especially methyl, or preferably hydrogen.

13. A compound of the formula {* selected from the group consisting of N-(4-pyridin-4-yl-oxy-phenyl)-N'-(4-ethyl-phenyl)-urea, N-(4-pyridin-4-yl-oxy-phenyl)-N'-(3-trifluoromethyl-phenyl)-urea, N-(4-pyridin-4-yl-oxy-phenyl)-N'-(4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-phenyl)-urea; N-(4-(4-(4-hydroxyphenylamino)-pyrimidin-6-yl)-oxyphenyl)-N'-(3-trifluoromethylphenyl)-urea; and N-(4-(2-methyl-pyridin-4-yl)-oxyphenyl)-N'-(3-trifluoromethyl-phenyl)-urea; or a pharmaceutically acceptable salt thereof.

14. A compound of the formula I* selected from the group consisting of

N-(4-pyridin-4-yl-oxy-phenyl)-N'-(4-n-propyl-phenyl)-urea, N-(4-pyridin-4-yl-oxy-phenyl)-N'-(4-methyl-phenyl)-urea, N-methyl-N-(4-pyridin-4-yl-oxy-phenyl)-N'-(4-ethyl-phenyl)-urea, N-methyl-N-(4-pyridin-4-yl-oxy-phenyl)-N’-(3-trifluoromethyl-phenyl)-urea,

N-methyl-N-(4-pyridin-4-yl-oxy-phenyl)-N'-(4-n-propyl-phenyl)-urea, N-methyl-N-(4-pyridin-4-yl-oxy-phenyl)-N’-(4-methyl-phenyl)-urea, N-(4-pyridin-4-yl-oxy-phenyl)-N'-(4-bromo-3-trifluoromethyl-phenyl)-urea, N-(4-pyridin-4-yl-oxy-phenyl)-N'-(3-methoxy-5-trifluoromethyl-phenyl)-urea, N-(4-pyridin-4-ylmethyl-pheny!)-N'-(4-n-propyl-phenyl)-urea, N-(4-pyridin-4-yimethyl-phenyl)-N’-(4-ethyl-phenyl)-urea, N-(4-pyridin-4-ylmethyl-phenyl)-N'-(4-methyl-phenyl)-urea, N-(4-pyridin-4-ylmethyl-phenyl)-N'-(3-trifluoromethyl-phenyl)-urea, N-(4-pyridin-4-yl-oxy-phenyl)acetyl-(4-ethyl-phenyl)-amide, N-(4-pyridin-4-yl-oxy-phenyl)acetyl-(4-methyl-phenyl)-amide, N-(4-pyridin-4-yl-oxy-phenyl)acetyl-(4-n-propyl-phenyl)-amide, 5-(4-pyridyl-oxy)-N-(3-trifluoromethyl-phenyl)amino-carbonyi-2,3-dihydroindole, 5-(4-pyridyl-oxy)-N-(3-trifluoromethyl-phenyl)amino-carbonyl-1,2,3,4-tetrahydroquinoline, N-(4-(4-Chloropyrimidin-6-yl)-oxyphenyl)-N'-(3-trifluoromethylphenyl)-urea, N-(4-pyridin-4-yl-oxyphenyl)-N'-(4-phenyl-3-trifluoromethyl-phenyl)-urea, N-(4-pyridin-4-yl-oxyphenyl)-N’-(4-(piperidin-1-yl)-3-trifluoromethyl-phenyt)-urea, N-(4-pyridin-4-yl-oxyphenyl)-N'~(4-(morpholino)-3-trifluoromethyl-phenyl)-urea, N-(4-pyridin-4-yl-oxyphenyl)-N’-(3,4,5-trimethoxy-phenyl)-urea, N-(4-pyridin-4-yl-oxyphenyl)-N'-(3-methoxy-4-phenyl-phenyl)-urea, N-(4-pyridin-4-yl-oxyphenyl)-N'-(3-methoxy-4,5-(ethylen-1,2-dioxy)-phenyl)-urea, N-(4-pyridin-4-yl-oxyphenyl)-N’-(3-methoxy-4-(2,2,2-trifluoroethoxy)-phenyl)-urea, N-(4-pyridin-4-yl-oxyphenyl)-N’-(3-methoxy-4-piperidin-1-yl-phenyl)-urea, N-(4-pyridin-4-yl-oxyphenyl)-N’-(4-piperidin-1-yl-phenyl)-urea, N-(4-[2-(4-hydroxyphenyl)-amino-pyrimidin-4-yl]-oxyphenyl-N'-(3-trifluoromethyl-phenyl)- urea, : N-(4-[4-(4-sulfamoylphenyl)-amino-pyrimidin-6-yl]-oxyphenyl-N'-(3-trifluoromethyl-phenyl)- urea, N-(4-[4-(4-carbamoylphenyl)-amino-pyrimidin-6-yl]-oxyphenyl-N'-(3-trifluoromethyl-phenyl)- urea,

Case 4-32508A a -166- N-(4-{4-(4-(N-2-hydroxyethylcarbamoyl)-phenyi)-amino-pyrimidin-6-yl]-oxyphenyl-N'-(3- trifluoromethyl-phenyl)-urea, N-{4-[4-(4-hydroxyphenyl)-amino-pyrimidin-6-yil-oxyphenyl-N'-(3-trifluoromethyl-4-(2,2,2- trifluoroethoxy)-phenyl)-urea, N-(4-(N-oxido-pyridin-4-yl}-oxyphenyl)-N"-(3-trifluoromthyl-phenyi)-urea, N-(4-(2-methoxypyridin-5-yl)-oxyphenyl)-N'-(3-trifluoromethyl-phenyl)-urea, N-(4-(2-pyridon-5-yi}-oxyphenyl)-N'-(3-trifluoromethyl-phenyi)-urea, N-{4-{(2-acetylamino)-pyridin-4-yi}-oxy}-phenyl-N'-(3-trifluoromethyi-phenyl)-urea, N-{4-(pyridin-4-yl-oxy)-2-chloro-phenyi}-N'-(3-trifluoromethyl-phenyl)-urea, N-{4-(pyridin-4-yl-oxy)-2-methyl-phenyi}-N'-(3-trifluoromethy-phenyi)-urea, and N-(4-{4-(2-aminoethoxyphenyl}-amino-pyrimidin-6-yi]-oxyphenyl-N'-(3-trifluoromethyl-phenyl)- urea, or a pharmaceutically acceptable salt thereof.

15. A compound selected from the group consisting of the compounds of Examples 1 - ’ 164c) as described in the description and pharmaceutically acceptable salts thereof.

16. A pharmaceutical preparation comprising a compound of the formula | or I* according to any one of claims 7 to 15, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable camier material.

17. A compound of the formula | or I* according to any one of claims 7 to 15, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of the animal or human body, especially in the treatment of a tyrosine kinase dependent disease.

18. Use of a compound of the formula | or I* according to any one of claims 1 to 15 for use in the treatment of a tyrosine protein kinase dependent disease.

19. Use of a compound of formula | or I* according to any one of claims 1 to 15 in the manufacture of a medicament for treating a disease that responds to inhibition of an (especially tyrosine) protein kinase. AMENDED SHEET

20. A process for the preparation of a compound of the formula | according to claim 7, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that : (a) for the synthesis of a compound of the formula | wherein X NR if pis 0, or if p is 2 or 3, X is nitrogen which together with (CH), and the bonds represented in dotted (interrupted) lines (including the atoms to which they are bound) forms a ring, and G, Z, A, A’, Ys, Ya, R, Ry, Ra, Rs, Ry, Rs, m, n, p and r have the meanings as defined for a compound of formula | according to claim 7, an amino compound of the formula II (CH), XH IAN . RIL SF \ (n) AA Vn OR wherein X is as just defined and Ry, Rs, A, A’, Y4, Y5, m, n, p, r and the bonds represented in dotted (interrupted) lines have the meanings as defined for a compound of formula | according to claim 7, is reacted with an isocyanate of the formula II O—C=N—G—Z (111) wherein G, Z, Ry, R; and Rj have the meanings as defined for a compound of formula according to claim 7, or (b) for the synthesis of a compound of the formula | wherein m is 0 (and thus Y, is missing), nis 1, Yyis Oand G, Z, X, Ry, Ry, Ry, Ry, Rs, A, A', p and r have the meanings as defined for a compound of formula | according to claim 7, a hydroxy compound of the formula IV (CH),

(XN. _z ‘ NA IES Oa Oo HO Rs wherein G, Z, X, Ry, Ry, Rs, Rs, p and the bonds represented in dotted (interrupted) lines have the meanings as defined for a compound of formula | according to claim 7, is etherified with a halo compound of the formula V Hal RIL AA wherein R, and r have the meanings as defined for a compound of formula | according to claim 7 and Hal is halo, especially chloro, or (c) for the synthesis of a compound of the formula | wherein p is zero, X is CHK, especially CH,, and G, Z, K, Y3, Y2, Ry, Ra, Rs, Ry, Rs, A, A’, m, n and r have the meanings as defined for a compound of formula | according to claim 7, a carboxyl compound of the formula VI K XX Y COOH RI— SF 2 h (VI) AA Vn OR wherein K is lower alkyl or preferably hydrogen and A, A’, Y3, Y2, Rg, Rs, m, nand r have the meanings as defined for a compound of formula | according to claim 7, or a reactive derivative thereof, is condensed with an amino compound of the formula VII HN—G—Z (VI) } wherein G, Z, R,, R; and R; have the meanings as defined for a compound of formula according to claim 7, or : (d) for the synthesis of a compound of the formula | wherein X is NH, p is zero and G, Z, A, A, Y4, Ya, Ry, Ro, Rs, Rs, Rs, m, n and r have the meanings as defined for a compound of formula | according to claim 7, an isocyanate of the formula VIl

A N AN RY Vr (vin) AN (Yo) R wherein Ry, A, A’, Y3, Y2, m, 0, r and Rs have the meanings as defined for a compound of formula | according to claim 7, is reacted with an amino compound of the formula IX HN—G—Z (1X) wherein G, Z, Ry, R; and R; have the meanings as defined for a compound of formula according to claim 7, and, if desired, after reaction (a), (b), (c) or (d) an obtainable compound of formula | is transformed into a different compound of formula |, a salt of an obtainable compound of formula | is transformed into the free compound or a different salt, or an obtainable free compound of formula | is transformed into a salt; and/or an obtainable mixture of isomers of compounds of formula | is separated into the individual isomers; where for all reactions mentioned functional groups in the starting materials that shall not take part in the reaction are, if required, present in protected form by readily removable pro- tecting groups, and any protecting groups are subsequently removed.

21. Use according to any one of claims 1, 4, 18 or 19, substantially as herein described and exemplified.

22. A compound according to any one of claims 7, 10, 11, 12, 13 or 14, substantially as herein described and exemplified.

23. A pharmaceutical preparation according to claim 16, substantially as herein described and exemplified.

24. A process according to claim 20, substantially as herein described and exemplified. AMENDED SHEET