MXPA06010186A - Novel dichloro-phenyl-pyrido [2,3-d]pyrimidine derivates, their manufacture and use as pharmaceutical agents - Google Patents

Abstract

The invention describes compounds of the general formula (I), a process for their manufacture, medicaments containing them and their manufacture as well as the use of these compounds as pharmaceutically active agents. The said compounds show activity as protein kinase inhibitors, in particular src family tyrosine kinase inhibitors, and may therefore be useful for the treatment of diseases mediated by said tyrosine kinases.

Description

NEW DERIVATIVES OF DIC ORO-FENIL-PIRIDO [2, 3-D] PYRIMIDINA, ITS MANUFACTURE AND USE AS PHARMACEUTICAL AGENTS DESCRIPTION OF THE INVENTION The present invention relates to new bicyclic pyrido [2,3-d] pyrimidines, a process for their manufacture, medicaments containing them and their manufacture as well as the use of these compounds as pharmaceutically active agents. Some substituted bicyclic nitrogen heterocycles are known in the art for their protein kinase, as well as their tyrosine kinase inhibitory activity. WO 02/090360 describes pyrido [2,3-d] pyrimidines useful as inhibitors of enzyme kinase and for the treatment of hyperproliferative diseases. WO 03/000011 describes phosphorus-containing derivatives of pyrido [2,3-d] irimidine as inhibitors of protein kinase and for the treatment of bone disorders, cancer and signaling disorders in general. WO 96/15128 describes 6-aryl-pyrido [2,3-d] pyrimidines as inhibitors of protein tyrosine kinases and for the treatment of atherosclerosis, restenosis, psoriasis, bacterial infections and cancer. Despite the progress documented in the literature mentioned above, there remains a need for new Ref. 174927 compounds with an improved therapeutic index, such as improved activity, tolerability, selectivity or stability to name but a few. The present derivatives are new compounds of the general formula (formula I), wherein R 1 is -C (O) -NH-alkyl or -C (O) -N (alkyl) 2, the alkyl groups are optionally substituted with -OH; -NH (alkyl); -N (alkyl) 2; -NH-C (O) -alkyl; -C (O) -NH-alkyl; -C (O) -N (alkyl) 2; -C (0) -NH2; -O-alkyl; -heterocyclyl; -NH-heterocyclyl; -NH-S (0) 2-alkyl ?; -S (0) 2-NH2; or -S (O) -alkyl, all alkyl groups are optionally substituted with -OH; or a -CN group; -C (0) -NH2; -C (0) -NH-heterocyclyl; -C (0) -NH-NH-C (0) -NH2; or -C (0) -NH-NH-C (0) -alkyl; the alkyl is optionally substituted with -NH (alkyl); or -N (alkyl) 2; and halogen; heterocyclyl; I rent; -NH-C (0) -alkyl; -NH-S (0) 2-alkyl; - (CH2) m-S (0) 2-NH2; - (CH2) m-S (0) 2-N (alkyl) 2; - (CH2) m-S (0) 2-NH- (alkyl); -0-alkyl; or -S (0) n-a.alkyl, all alkyl groups are optionally substituted by -OH; -O-alkyl; -NH-alkyl; or -N (alkyl) 2; X is -CH = or N =; m is 0, 1, 2, 3, 4, 5 or 6; n is 0, 1 or 2; and pharmaceutically acceptable salts thereof. The compounds according to this invention show activity as protein kinase inhibitors, in particular inhibitors of the src tyrosine kinase family, and therefore may be useful for the treatment of diseases mediated by tyrosine kinases. The family of tyrosine kinases plays an important role in the regulation of cell signaling and cell proliferation by residues by phosphorylating the tyrosine residues of peptides and proteins. It is known that inappropriate activation of tyrosine kinases is involved in a variety of disease states including inflammatory, immunological CNS disorders, or oncological disorders, or bone disorders. See for example Susva, M., et al., Trends Pharmacol. Sci (2000) 489-495; Biscardi, J. S., et al., Adv. Cancer Res. 76 (2000) 61-119. The compounds of the present invention can be used as active agents in the prevention and therapy of, for example, rejection of transplant, inflammatory bowel syndrome, rheumatoid arthritis, psoriasis, restenosis, allergic asthma, Alzheimer's disease, Parkinson's disease, stroke, osteoporosis, cancer, and benign hyperplasia. It has surprisingly been found that the compounds of the present invention show improved stability and / or metabolic selectivity, together with at least the same activity against src tyrosine kinase compared to compounds known in the art. The objects of the present invention are the compounds of formula 1 and pharmaceutically acceptable salts and their enantiomeric forms, the preparation of the compounds mentioned above, medicaments containing them and their manufacture as well as the use of the aforementioned compounds in the control or prevention of ailments, especially of ailments and disorders as mentioned above or in the manufacture of corresponding medicaments. As used herein, the term "alkyl" means a branched or straight chain, saturated hydrocarbon containing from 1 to 6, preferably from 1 to 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl, n-pentyl, n-hexyl as well as their isomers. "Optionally substituted" alkyl groups are alkyl groups as defined previously, which are either unsubstituted or one or, if possible, twice substituted. As used herein, the term "alkyl of (C? -C4) "means a branched or straight chain, saturated hydrocarbon containing from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-? butyl The term "heterocyclyl" as used herein means an aromatic or non-aromatic hydrocarbon, mono- or bicyclic, of 5 to 10 members, wherein 1 to 3, preferably 1 or 2, carbon atoms are replaced by a Nitrogen, oxygen or sulfur atom, or for a group -S (0) 2- The heterocyclyl group is optionally substituted once or several times with alkyl, oxo or -C (0) -NH2 The examples are 2-oxo -imidazolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 2-oxo-pyrrolidin-1-yl, 1-methyl-pyrrolidin-2-yl, imidazol-4-yl, pyrazol-3-yl; 2-methyl-pyrazol-3-yl; l-methyl-pyrazol-5-yl; 1,5-dimethyl-pyrazol-3-yl; 4-carbamoyl-pyrazol-3-yl; piperidin-3-yl; piperidin; 4-yl, l-methyl-piperidin-4-yl, morpholin-4-yl, pyridin-2-yl, l-aza-bicyclo [2.2.2] oct-3-yl or 4,4-dioxo-2 , 3-dihydro-benzo [1,4] oxathiain-6-yl. As used herein, the term halogen means fluoro, chloro, bromo and iodo, preferably fluoro, chloro and bromo and more preferably fluoro and chloro.

Preferably the substituent R2 in formula I is located in the para or meta position. A preferred embodiment of the present invention are the compounds of the formula I, wherein X is -CH =; R1 is -C (0) -NH-alkyl, the alkyl group is optionally substituted with -OH; -NH (alkyl); -N (alkyl) 2; -NH-C (O) -alkyl; -C (O) -NH-alkyl; -C (0) -N (alkyl) 2; -C (0) -NH2; -O-alkyl; -heterocyclyl; -NH-heterocyclyl; -NH-S (0) 2-alkyl; -S (0) 2-NH2; or -S (O) -alkyl, all alkyl groups are optionally substituted with -OH; and R2 has the meaning given above. Another embodiment of the present invention are the compounds of the formula I, wherein X is -CH =; R1 is -C (0) -NH-methyl; or -C (0) -NH-ethyl, the methyl or ethyl group is unsubstituted or once substituted with -OH; -pyrrolidinyl; or -NH-S (0) 2-CH 3; and R2 has the meaning given above. Still another embodiment of the present invention are the compounds of the formula I, wherein X is -CH =; R1 is -C (0) -NH-ethyl; or -C (0) -NH-methyl, the methyl or ethyl groups are once substituted with -OH; or -pyrrolidinyl; and R2 is morpholin-4-yl; -NH-S (0) 2-CH 3; -O-alkyl; or -S (0) n-alkyl, all alkyl groups are optionally once substituted by -OH; -0-alkyl; -NH-alkyl; or -N (alkyl) 2; n is 0, 1 or 2; and pharmaceutically acceptable salts thereof. Such compounds are, for example: 6- (2,6-dichloro-phenyl) -2- [4- (2-hydroxy-ethoxy) -phenylamino] -pyrido (2-hydroxy-ethyl) -amide [2, 3 -d] pyrimidine-7-carboxylic acid; (2- (2,6-dichloro-phenyl) -2- (4-morpholin-4-yl) -phenylamino) -pyrido [2,3-d] pyrimidin-7-hydroxy-ethyl) -amide carboxylic; ((R) -l-pyrrolidin-2-ylmethyl) -amide of 6- (2,6-dichloro-phenyl) -2- [4- (2-hydroxy-ethoxy) -phenylamino] -pyrido [2, 3] -d] pyrimidine-7-carboxylic acid; ((R) -l-pyrrolidin-2-ylmethyl) -amide of 6- (2,6-dichloro-phenyl) -2- (4-morpholin-4-yl-phenylamino) -pyrido [2, 3-d] ] pyrimidine-7-carboxylic acid. Still another embodiment of the present invention are the compounds of the formula I, wherein X is -CH =; R1 is -C (0) -NH- (CH2) 2-NH-S (0) 2-CH3; and R2 is morpholin-4-yl; 4-methyl-piperazin-1-yl; -NH-S (0) 2-CH 3; -O-alkyl; or -S (O) n-alkyl, all alkyl groups are optionally once substituted by -OH; -O-alkyl, • -NH-alkyl; or -N (alkyl) 2; n is 0, 1 or 2; and pharmaceutically acceptable salts thereof. Such compounds are, for example: 6- (2,6-dichloro-phenyl) -2- (4-morpholin-4-yl-phenylamino) -pyrido [2, 3-d] (2-methanesulfonylamino-ethyl) -amide. ] pyrimidine-7-carboxylic acid; 6- (2,6-Dichloro-phenyl) -2- [4- (2-hydroxy-ethoxy) -phenylamino] -pyrido [2,3-d] pyrimidine-7-methanesulfonylamino-ethyl) -amide -carboxylic; 6- (2,6-Dichloro-phenyl) -2- (3-methanesulfonylamino-phenylamino) -pyrido [2,3-d] pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl) -amide; 6- (2,6-Dichloro-phenyl) -2- [3- (2-hydroxy-ethylsulfanyl) -phenylamino] -pyrido [2,3-d] pyrimidine-7-methanesulfonylamino-ethyl) -amide -carboxylic; 6- (2,6-Dichloro-phenyl) -2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrido [2-methanesulfonylamino-ethyl] -amide [2,3-d] ] pyrimidine-7-carboxylic acid; 6- (2,6-Dichloro-phenyl) -2- (3-methylsulfanyl-phenylamino) -pyrido [2,3-d] pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl) -amide; Still another embodiment of the present invention are the compounds of the formula I, wherein X is -CH =; R1 is -C (0) -NH2; and R2 is morpholin-4-yl; -NH-S (0) 2-CH 3; -O-alkyl; or -S (O) n-alkyl, all alkyl groups are optionally once substituted by -OH; -O-alkyl; -NH-alkyl; or -N (alkyl) 2; n is OA or 2; and pharmaceutically acceptable salts thereof. Such compounds are, for example: 6- (2,6-dichloro-phenyl) -2- (4-morpholin-4-yl-phenylamino) -pyrido [2,3-d] pyrimidine-7-carboxylic acid amide; or 6- (2,6-dichloro-phenyl) -2- [4- (2-hydroxy-ethoxy) -phenylamino) -pyrido [2,3-d] pyrimidine-7-carboxylic acid amide. Still another embodiment of the present invention are the compounds of the formula I, wherein X is -CH =; R1 is -CN; and R2 is morpholin-4-yl; -NH-S (0) 2-CH 3; -O-alkyl; or -S (O) n-alkyl, all alkyl groups are optionally once substituted by -OH; -O-alkyl; -NH-alkyl, • or -N (alkyl) 2; n is 0, 1 or 2; and pharmaceutically acceptable salts thereof. Such compounds are for example: 6- (2,6-dichloro-phenyl) -2- [4- (2-diethylamino-ethoxy) -phenylamino] -pyrido [2,3-d] pyrimidine-7-carbonitrile; 6- (2,6-dichloro-phenyl) -2- (4-morpholin-4-yl-phenylamino) -pyrido [2,3-d] pyrimidine-7-carbonitrile; or 6- (2,6-dichloro-phenyl) -2- [4- (2-hydroxy-ethoxy) -phenylamino] -pyrido [2,3-d] pyrimidine-7-carbonitrile. Still another embodiment of the present invention are the compounds of formula I, wherein X is -N =; R1 is -C (0) -NH- (CH2) 2-NH-S (0) 2-CH3; and R2 is alkyl; -NH-S (0) 2-CH 3; -O-alkyl; or -S (O) n-alkyl, all alkyl groups are optionally once substituted by -OH; -O-alkyl; -NH-alkyl; or -N (alkyl) 2; n is 0, 1 or 2; and pharmaceutically acceptable salts thereof. Such compounds are, for example: 6- (2,6-dichloro-phenyl) -2- (6-methyl-pyridin-3-ylamino) -pyrido [2, 3-d] (2-methanesulfonylamino-ethyl) -amide. ] pyrimidine-7-carboxylic acid. Still another embodiment of the invention is a process for the manufacture of the compounds according to this invention, wherein (a) the sulfide group in the compounds of the general formula (II) formula (II), is converted to the corresponding sulfoxide group, the sulfoxide group is (b) substituted by the respective anilines of the formula (II-A) formula (II-A) wherein R2 and X have the meaning given hereinbefore, to produce the compounds of the general formula (IV) formula (IV), (c) the group -COOH in the formula (IV) is converted to an amide derivative of the formula (I); and (d) if desired a primary amide derivative obtained from (c) is further converted to its corresponding 7- carbonitrile derivative of the formula (I); and (e) if desired the compound of the general formula (I), obtained from (c) or (d), is converted to its pharmaceutically acceptable salt. In a more detailed description, the compounds of the formula (I) wherein R 1 is attached via an amide group are represented by the general formula (la). Such compounds can be prepared from the carboxylic acids of the formula (II), using standard reactions well known to a person skilled in the art. The synthesis of the compounds of the general formula (la) is shown in reaction scheme 1, wherein R 3 has the meaning given above for R 1 without the group -CN, therefore R 3 is -C (0) -NH -alkyl or -C (0) -N (alkyl) 2, the alkyl groups are optionally substituted with -OH; -NH (alkyl); -N (alkyl); -NH-C (0) -alkyl; -C (0) -NH-alkyl; -C (0) -N (alkyl) 2; -C (0) -NH2; -0-alkyl; -heterocyclyl; -NH-heterocyclyl; -NH-S (0) 2-alkyl; -S (0) 2-NH2; or -S (0) -alkyl, all alkyl groups are optionally substituted with -OH; or a group -C (0) -NH2; -C (O) -NH-heterocyclyl; -C (0) -NH-NH-C (0) -NH2; or -C (0) -NH-NH-C (0) -alkyl, the alkyl is optionally substituted with -NH (alkyl); or -N (alkyl) 2; and R2 and X have the meanings given above. The derivatives of the general formula (I), or a pharmaceutically acceptable salt thereof, can be prepared by any process known to be applicable for the preparation of chemically related compound by one skilled in the art. Such processes, when used to prepare the diazine derivatives of the formula (I), or a pharmaceutically acceptable salt thereof, are provided as a further feature of the invention and are illustrated by the following representative examples of reaction scheme 1 to reaction scheme 4, in which, unless stated otherwise, R1, R2 and X have the meaning given hereinbefore. The necessary starting materials are commercially available or can be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying examples. Alternatively, the Necessary starting materials are obtainable by procedures analogous to those illustrated which are within the ordinary experience of an organic chemist.

Reaction thread 1 (A) Stage 2 Stage 4 Alternatively, the carboxylic acids (II) can first be converted to carboxamides (V) and subsequently replaced by anilines in the 2-position according to reaction scheme 2, wherein R3, R2 and X have the meanings given above.

Reaction scheme 2 Stage 6 The primary carboxamides of the formulas (la) or (V), wherein R3 is -C (0) -NH2, can be converted to nitriles of the general formula (IB) by conventional methods, for example dehydration with SOCl2 or P0C13.

The nitriles of the formula (Ib) can also be prepared from known pyridine derivatives (VII) according to reaction scheme 3, wherein R2 and X have the meanings given in the present before and L is a leaving group suitable.

Reaction scheme 3 (VII) (VIII) Stage 11 Step 1: The 3- (2,6-dichloro-phenyl) -pyruvic acid of the formula (B), or in general arylpyrubic acids, can be condensed with a suitable pyrimidine carbaldehyde of the formula (A) to produce the compound ( II). The condensation reaction can be carried out under basic conditions, for example with sodium hydroxide (NaOH) in water or methanol (MeOH) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or tert-butoxide of potassium (KOtBu) in dimethyl formamide (DMF), 1-methyl-2-pyrrolidinone (NMP) or tetrahydrofuran (THF).

Alternatively, the condensation reaction is carried out in acetic acid in the presence of sodium acetate. The reaction temperatures vary from room temperature (RT) to 150 ° C.

Steps 2, 6 and 10: A methylthio or alternatively any other alkylthio or arylthio group in the 2-position of the pyridopyrimidines of the formulas (II), (V) or (IX) can be converted into a suitable leaving group by oxidation to the sulfone or corresponding sulfoxide of the formulas (III), (VI) or (X). Suitable reagents are for example 3-chloroperoxybenzoic acid (mCPBA) or 2-benzenesulfonyl-3-phenyl-oxaziridine in inert solvents such as dichloromethane (CH2C12), chloroform (CHC13), or methyl tert-butyl ether (MTBE) at varying temperatures -40 ° C to + 65 ° C.

Steps 3, 7 and 11: The sulfoxides or sulfones of steps 2, 6 or 10 can be reacted in purified form or as raw products with anilines to produce 2-anilino-substituted pyrimidines of the formulas (IV), (the, reaction scheme 2) or (Ib). The reaction can be carried out in excess of aniline as the solvent or in an inert solvent such as CH2C12, toluene, acetonitrile, DMF, dimethyl sulfoxide (DMSO) or NMP, and at temperatures in the range of 0 ° C to 150 ° C. Acids such as trifluoroacetic acid (ATF) or hydrochloric acid (HCl) can be added to catalyze the reaction. If the mCPBA has been used for the pre-oxidation step, the m-chlorobenzoic acid formed present in the crude reaction mixture can serve as the catalyst.

Steps 4 and 5: The appropriate carboxylic acids of the formulas (IV) or (II, reaction scheme 2) can be converted into amide derivatives of the formulas (la, reaction scheme 1) or (V) by standard procedures known in the art. For example, the acid is first activated by reaction with a carbodiimide or carbonyl diimidazole- or oxalyl chloride, and subsequently reacted without isolation with the appropriate ammonia or substituted amine. This reaction is best performed in an inert solvent such as THF, CH2Cl2 or NMP at temperatures ranging from 0 ° C to 150 ° C.

Step 8: A suitable leaving group "L" in (VIII) can be a triflate which can be prepared from (VII) by reaction with trifluoromethanesulfonic anhydride (Tf20) or N-phenyltrifluoromethanesulfonimide (PhN (Tf) 2) in a solvent inert as THF or CH2C12 or NMP, in the presence of a base such as triethyl amine (NEt3), pyridine, potassium tert-butoxide (KOtBu), lithium diisopropylamide (LDA), NaH, or C03. Another leaving group is a chlorine or bromine atom which can be introduced by halogenation of the pyridone with P0C13 or POBr3.

Step 9: The leaving group "L" in (VIII) can be replaced by an inorganic cyanide such as potassium cyanide (KCN), sodium cyanide (NaCN) or copper cyanide (CuCN) in an inert solvent such as diglyme, DMF, NMP, or sulfolane at temperatures from TA at 180 ° C, to produce (IX). Preferably, this reaction can also be catalyzed by a transition metal catalyst, for example, a Pd or Ni catalyst. In this case, also zinc cyanide (Zn (CN) 2) can be applied as the source of cyanide. Certain side chains in R3 or R2 may require protection during the reaction sequences. At this point standard protection and deprotection procedures that are well known in the art can be applied. For example, the primary and secondary amines can be applied in a protected form with t-butoxycarbonyl (Boc) or benzyloxycarbonyl and the protecting group can be removed as a last reaction step by treatment with an acid such as HCl or trifluoroacetic acid (ATF).

The compounds of the general formula I may contain one or more chiral centers and may then be present in a racemic or optically active form. The racemates can be separated according to known methods in the enantiomers. For example, diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically pure acid such as, for example, D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or acid. camphorsulfonic. Alternatively separation of the enantiomers can also be achieved using chromatography on chiral HPLC-phases which are commercially available. The compounds according to the present invention can exist in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to acid addition salts or conventional base addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from organic or inorganic bases or non-organic or inorganic acids. toxic substances. Acid addition salts include, for example, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those acid derivatives. organic compounds such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. The base addition salts include those derived from ammonium, potassium, sodium and quaternary ammonium hydroxides, such as, for example, tetramethylammonium hydroxide. The chemical modification of a pharmaceutical compound in a salt is a technique well known to pharmaceutical chemists to obtain improved chemical and physical stability, hygroscopicity, fluidity and solubility of the compounds. For example, it is described in Bastin, R. J. et al, Organic Proc. Res. Dev. 4 (2000) 427-435. The compounds according to this invention and their pharmaceutically acceptable salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration, however, can also be performed rectally, for example in the form of suppositories, or parenterally, for example in the form of solutions for injection. The pharmaceutical preparations mentioned above can be obtained by processing the compounds of according to this invention with pharmaceutically inert organic or inorganic carriers. Lactose, corn starch or derivatives thereof, talc, acids, this rich or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance none of the carriers, however, are usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. The pharmaceutical preparations may additionally contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances. A pharmaceutical preparation was obtained using the following procedure: 1. Weigh 4.0 g of glass beads into tube made in the GL 25, 4 cm fashion (the beads fill half the tube). 2. Add 50 mg of compound, disperse with spatula and vortex. 3. Add 2 ml of gelatin solution (weight of beads: gelatin solution = 2: 1) and vortex. 4. Cover and wrap in aluminum sheet for protection against light. 5. Prepare a counterweight for the mill. 6. Grind for 4 hours, 20 / s in a Retsch mill (for some substances up to 24 hours at 30 / s). 7. Remove the suspension of beads with two filter layers (100 μm) in a filter holder, coupled to a recipient vial by centrifugation at 400 g for 2 min. 8. Move the extract to measure the cylinder. 9. Repeat washing with small volumes (at this stage 1 ml steps) until the final volume is reached or the extract is clear. 10. Fill to final volume with gelatin and homogenize. The preparation described above produces micro-suspensions of the compounds of the formula I with particle sizes between 1 and 10 μm. The suspensions are suitable for oral applications and were used in the in vivo pharmacokinetic tests described below.

Inhibition of src tyrosine kinase family The activity of the compounds according to this invention as inhibitors for the src family of tyrosine kinases is shown using the following assay. As used herein this refers to the peptide: NH2-A-E-E-E-I-Y-G-E-F-E-A-K-K-K-K-CONH2; Jal33-Ro refers to the peptide: Jal33-G- aminocaprylic acid ~ A-E-E-E-I-Y-G-E-F-E-A-K-K-K-K-CONH2, wherein Jal33 is LightCycler Red 640-N-hydroxy-succinimide ester; PT66 refers to a specific antibody phosphotyrosine which can detect tyrosine tyrosine protein tyrosine kinase, and TCEP refers to Tris (2-carboxyethyl) phosphine; Lck Cisbio Mab PT66-K refers to Anti-Phosphotyrosine (PT66) -Cripatato; and Src EG &G Wallac PT66 Eu-W1024 refers to Anti-Phosphotyrosine (PT66) -Criptate labeled with Eu3A Parameters of SRC Inhibitor Assay: Reaction mixture: 5 μM ATP Peptide (Ro + Jal33-R?): 10 μM Jal3-Ro 196 nM Ro 9.8 μM PT66 230 ng / ml Test cushion: 4 mM MgCl2 TCEP 2 mM HEPES 50 mM Tween 20 at 0. 1% pH 7. 3 Enzyme: 2. 5 U / ml Inhibitor; 25 μM maximum 0. 42 nM minimum Material: Eu-labeled phosphotyrosine antibody: -for Lck Cisbio Mab PT66-K, -for Src EG &G Wallac PT66 EU-W1024 (all commercially available). Peptides: R ?: NH2-A-E-E-E-I-Y-G-E-F-E-A-K-K-K-K-K-CONH2, and Jal33-Ro: Jal33-G-aminocaprylic acid-A-E-E-E-I-Y-G-E-F-E-A-K-K-K-K-K-CONH2, wherein Jal33 is LightCycler-Red 640-N-hydroxy-succinimide ester; whereby both peptides were synthesized by an optimized solid-phase peptide synthesis protocol (Merrifield, Fed. Proc. Fed. Amer. Soc. Exp. Biol. 21 (1962) 412) in a synthesizer of peptide Zinsser SMP350. then, the peptide was assembled into 160 mg (22.8 μmol scale) of a polystyrene solid phase modified by Rink-Linker by repeatedly conjugating an excess of twenty parts of amino acids each protected by groups Fmoc labile temporary piperidine and tert-Bu labile permanent acid, BOC and tert-BuO depending on the side chain function. The substrate sequence AEEEIYGEFEAKKKK was N-terminal additionally assembled with the spacer amino acids aminocaprylic acid and glycine. After excision of the N-terminal temporary protecting group the protected and still bound peptide was labeled with an amount of 1.5 parts of LightCycler-Red 640-N-hydroxy-succinimide ester (purchased by Roche Diagnostics GmbH) and triethylamine. After 3 hrs. the resin was washed with dimethylformamide and isopropanol until the eluates of the blue resin were colorless. The fully protected and labeled peptide was removed from the solid phase and freed from the permanent protecting groups by treatment with a mixture of 80% trifluoroacetic acid, 10% ethanedithiol, 5% thioanisole and 5% water. The substrate was finally isolated by a purification with HPLC of preparative reverse phase. The purification produced 12.2 mg of pure blue single-spike material of RP-CLAR (lyophilised). The identity was verified by MALDI mass spectroscopy [2720.0].

Enzymes: Upstate Lck (p56lck, active), Upstate Src (p60c_src, partially purified) were purchased from UBI.

Temporary Resolution Fluorescence Test: Reader: Perkin Elmer, Wallac Viktor 1420-040 counted multi-labels; liquid handling system: Beckman Coulter, Biomek 2000. ATP, Tween 20, HEPES were purchased from Roche Molecular Biochemicals, MgCl2 and MnCl2 were purchased from Merck Eurolab, TCEP was purchased from Pierce, the 384 Well low volume fluorescence plates were purchased from Falcon.

Test Description: First the enzyme was preincubated for 15 min at 15 ° C in aqueous solution with corresponding amounts of inhibitors according to this invention. Then the phosphorylation reaction was initiated by adding a reaction mixture, which contains ATP, Peptide and PT66, and subsequent shaking. The procedure of this reaction was monitored immediately using fluorescence spectroscopy of Temporary resolution in a suitable cavity plate reader. The IC50 values can be obtained from the reaction rates using a non-linear curve fitting (Excelfit software (ID Business Solution Ltd., Guilford, Surrey, UK)).

In vivo assay on tumor inhibition: To generate primary tumors, HT-29 colon carcinoma cells (2.5 x 10 6 in a volume of 100 μl) were injected subcutaneously into the left flank of Severe Combined Immunodeficiency (IDCS) mice using a 1 ml syringe and a 26 gauge needle. HT-29 cells were originally obtained from NCI and deposited in a bank of working cells. The cells dissolved and expanded in vitro before using in the experiment. Mice were assigned to the treatment groups on day 9. For clustering (n = 12 mice per group), the animals were randomized to obtain a similar average primary tumor volume of almost 120 mm3 per group. The test compounds were administered orally once a day as a suspension in 7.5% gelatin, 0.22% NaCl with a volume of administration of 10 ml / kg based on the current body weights. Treatment was started on day 10, and was performed until day 30, the final day of the study. Primary subcutaneous tumors were measured twice a week, starting on day 7 after tumor cell implantation, in two dimensions (length and width) using an electronic caliper. The volume of the primary tumor was calculated using the formula: V [mm] 3 = (length [mm] x width [mm] x width [mm]) / 2. In addition, the body weight of all the animals was recorded at least twice a week. Finally, at the end of the study, the tumors were explanted and weighed. The following examples, references are provided to aid in the understanding of the present invention, the true scope of which is described in the appended claims. It is understood that modifications can be made to the described methods without departing from the spirit of the invention.

Starting Materials a) Ethyl 3- (2,6-dichlorophenyl) -2-oxopropionate 12.4 g of magnesium powder were activated by dry stirring for 1 hr under Ar atmosphere. 250 ml of dry ether were added. 25 g of 2,6-dichlorobenzyl bromide were dissolved in 150 ml of ether and 10 ml of this solution were added to the stirred magnesium suspension. A small amount of iodine was added and the mixture was heated gently for 10 min to start the reaction. Then the rest of the 2,6-dichlorobenzyl bromide solution was added at room temperature (RT) in Ihr and the mixture was subsequently refluxed for 2 hrs. The above Grignard solution was cooled to -30 ° C and added rapidly to a solution of 29.5 g of diethyl oxalate in 150 ml of ether, which was pre-cooled to -50 ° C. The mixture was allowed to reach RT and stirring at RT was continued for another 14 hrs. The mixture was washed with aqueous HCl, dried and concentrated under vacuum. The first harvest of 8.1 g of the crystalline title product was isolated by filtration. A second collection of 8.7 g was obtained after evaporation of all the volatiles at 70 ° C / 20 mbar. b > ) 3- (2,6-dichlorophenyl) -2-oxopropionic acid 8.1 g of the previous lime ester were stirred in 70 ml of ethanol with 50 ml of 1.6 M NaOH at RT for 4 hrs. The mixture was diluted with dichloromethane and acidified with aqueous HCl to a pH of 1-2, then extracted with dichloromethane. The combined dichloromethane phases were extracted with 1 M NaOH, the aqueous phase was acidified again and once more extracted with dichloromethane. Evaporation of the solvent under vacuum gave 5.0 g of the title product. c) 6- (2, β-dichloro-phenyl) -2-methylsulfanylpyrido [2, 3-d] pyrimidine-7-carboxylic acid 3.0 g of the product of example b) was dissolved in 20 ml of N, N-dimethylformamide ( DMF) dried and cooled to -20 ° C. 2.55 g of potassium tert-butylate were slowly added. 1,777 g of 4-amino-2-methylsulfanylpyrimidine-5-carbaldehyde were added at -10 ° C and the mixture was heated to 70 ° C. The resulting suspension was diluted with another 30 ml of DMF and stirring at 70 ° C was continued for 3 hrs. The mixture was cooled to RT and diluted with 300 ml of water. Up to acidification with HCl at pH 1-2 the crude product was precipitated and separated by filtration, and further purified by chromatography (silica, ethyl acetate + 5% acetic acid). 1.35 g of yield of the product of the title. d) 6- (2,6-dichloro-phenyl) -2-methylsulfanylpyrido [2,3-d] pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl) -amide 0.45 g of the product of example c) in 10 ml of dry DMF, 0.215 g of carbonyl diimidazole was added and the mixture was stirred at RT for 1 hr, 0.228 g of 2-methylsulfonylamino-ethylamine in 4 ml of DMF was added dropwise and the mixture was stirred by other DMF. hrs. The mixture was diluted with 200 ml of water. The crude title product was precipitated and collected by filtration. The filtrate was extracted with dichloromethane, and the organic phases were dried and evaporated and the residue was combined with the first precipitate of the crude product. Chromatography on silica gave 375 mg of the title product. e) 2- ( { [6- (2,6-dichloro-phenyl) -2-methylsulfonyl-pyrido [2,3-d] pyrimidine-7-carbonyl] -amino tert -butyl ester. -methyl) -pyrrolidine-1-carboxylic acid Analogous to example d) from 0.2 g of starting material c), 0.096 g of 1,1 '-carbonyldiimidazole (CDl), and 0.153 g of (R) -2- aminomethyl-1-Bo-pyrrolidine (purchased from Astatech). The reaction mixture in DMF was diluted with 100 ml of water and the crude product precipitated was isolated by filtration. The filtrate was acidified with HCl and extracted with dichloromethane. The crude precipitate from the above was dissolved in dichloromethane and washed with dilute HCl, then combined with other dichloromethane extracts. Evaporation and chromatography of the residue on silica gave 152 mg of the title product. f) 6- (2,6-dichloro-phenyl) -2-methylsulfanyl-8H-pyrido [2, 3-d] pyrimidin-7-one To a mixture of 5.0 g of 4-amino-2-methylsulfanylpyrimidin-5- carbaldehyde in 50 ml of tetralin, 10.91 g of 2,6-dichlorophenylacetic acid, 10.76 g of triethylamine and 22-45 g of pivaloyl chloride were added consecutively. The mixture was stirred at 190 ° C for 30 min, then another 2.04 ml of pivaloyl chloride was added. After 30 min, the next 2.04 ml portion of pivaloyl chloride was added and the temperature was raised to 195 ° C. After another 30 and 60 min, two more portions of pivaloyl chloride were added and finally the stirring was continued for another hour at 195 ° C. Approximately 40 ml of the solvent was removed under vacuum, 100 ml of ether were added and the crude product precipitated was isolated by filtration. The crude product was washed with ether and water to yield 4.16 g of the title product. g) 6- (2,6-dichloro-phenyl) -2-methylsulfanyl-pyrido [2, 3-d] pyrimidin-7-yl ester of trifluoro-methanesulfonic acid 4.0 g of starting material f) was suspended in 20 ml of dried N-methyl-2-pyrrolidone (NMP) and treated with 0.562 g of 60% sodium hydride. After stirring for 30 min at 40 ° C, the mixture was cooled to RT and 7.02 g of N-phenyltrifluoromethanesulfonimide were added. After 45 min at RT, another 2.01 g of N-phenyltrifluoromethanesulfonimide were added and stirring was continued for another 30 min. The solvent was removed under vacuum at 60 ° C and the residue was purified by chromatography on silica to yield 5.38 g of the title product, which contains almost 25% N-phenyltrifluoromethanesulfonamide. 2.4 g of this material was further purified by dissolution in dichloromethane and washing with aqueous sodium carbonate solution to yield 1.72 g which were used in the next step. h) 6- (2,6-dichloro-phenyl) -2-methylsulfanyl-pyrido [2, 3-d] pyrimidine-7-carbonitrile 1.72 g of starting material g) of the foregoing were treated in 17.5 ml of dry NMP with 0.423 g of tetrakis- (triphenylphosphino) palladium (0) and 0.859 g of zinc cyanide at 90 ° C for 75 min. The solvent was evaporated under vacuum and the residue was subjected to chromatography on silica to provide 0.50 g of the product of the title.

Final Products Example 1 (6- (2,6-dichloro-phenyl) -2- (4-morpholin-4-yl-phenylamino) -pyrido [2,3-d] pyrimidine) (pyrrolidin-2-ylmethyl) -amide -7- carboxylic acid 36 mg of meta-chloroperbenzoic acid were dissolved (mCPBA) at 70% in 4 ml of dichloromethane and the solution was dried by filtration over sodium sulfate. The dried mCPBA solution was added to a solution of 75 mg of starting material e) in 4 ml of dichloromethane at RT, and the oxidation reaction was monitored by CCD. After 1 hr the starting material was consumed and the excess mCPBA was cooled by the addition of a few drops of dimethylsulfide. 37 mg of 4-morpholinoaniline were added and stirring was continued at RT for 14 hrs. The mixture was diluted with dichloromethane and washed with 10% aqueous acetic acid. Evaporation of the organic phase and chromatography of the residue afforded 67 mg of the title product protected by Boc. The above material was dissolved in 2 ml of dichloromethane and stirred with 2 ml of a 2 M solution of HCl in ether at RT for 3 hrs. The precipitate was isolated by filtration, dissolved in a small amount of methanol and it was diluted with a mixture of aqueous potassium bicarbonate and dichloromethane. The dichloromethane phase was separated, dried and evaporated to give 41 mg of the title product. H NMR (CDC13): 9.15 (s, 1H); 8.47 (br s, 1H); 7.95 (s, ÍH); 7.69 (br m, 3H); 7.40 (d, 2H); 7.26 (t, ÍH); 6.98 (d, 2H); 3.89 (t, 4H); 3.48 (m, ÍH); 3.34 (m, ÍH); 3.17 (m, 5H); 2.94 (m, 2H); 1.60-2.00 (m, 3H); 1.40 (m, ÍH).

Example 2 6- (2,6-Dichloro-phenyl) -2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrido acid (2-methanesulfonylamino-ethyl) -amide [2, 3 -d] pyrimidine-7-carboxylic acid Analogous to Example 1, 50 mg of starting material d) were oxidized with 29 mg of mCPBA in dichloromethane at RT. 22 mg of 4- (4-methylpiperazino) aniline were added and the mixture was stirred 14 hrs at RT.

After dilution with another 10 ml of dichloromethane the mixture was washed with water, the organic phase was dried and evaporated and further purified by chromatography on silica (dichloromethane 19 / methanol 1 / ammonia 0.5). 44 mg yield of the title product. ^? - NMR (CD30D): 9.28 (s, ÍH); 8.18 (s, ÍH); 7.78 (br d, 2H); 7.48 (d, 2H); 7.36 (t, ÍH); 7.03 (d, 2H); 4.60 (br s, ÍH); 3.46 (t, 2H); 3.26 (t) and 3.22 (t, together 6H); 3.20 (s, 3H); 2.65 (t, 4H); 2.36 (s, 3H).

Use of 6- (2,6-dichloro-phenyl) -2- [3- (2-hydroxy-ethylsulfanyl) -phenylamino] -pyrido [2, 3-d] acid pyrimidine-7-carboxylic acid 60 mg of starting material d) were oxidized with mCPBA analogous to example 1. 27 mg of 3- (2-hydroxyethyl-sulphonyl) aniline were added and the reaction mixture was stirred for 15 hrs at RT. The mixture was diluted with 10 ml of dichloromethane, washed with 10% aqueous acetic acid and dried and evaporated. Purification first by column chromatography on silica (dichloromethane / methanol), then by preparative HPLC-MS and finally by preparative CCD on silica (dichloromethane / methanol) provided 12 mg of the title product. XH-NMR (CDC13): 9.21 (s, ÍH); 8.91 (br s, ÍH); 8.07 (Yes H); 7.83 (br s, ÍH); 7.77 (s, ÍH); 7.43 (d, 2H); 7.31 (t, ÍH); 7.25 (m, 1H); 7.05 (d, 1H); 6.85 (br s and d, 2H); 5.67 (br, ÍH); 4.13 (m, 2H); 3.58 (m, 2H); 3.35 (m, 4H); 2.93 (S, 3H).

Example 4 6- (2,6-dichloro-phenyl) -2- [4- (2-hydroxy-ethoxy) -phenylamino] -pyrido [2,3-d] pyrimidine-7-carbonitrile 100 mg of preservative material was treated. heading h) in 3.5 ml of dichloromethane with 301 mg of 2-benzenesulfonyl-3-phenyl- oxaziridine at RT. After 5.5 hrs, the excess oxidation reagent was cooled by adding 70 mg of dimethylsulfide. 265 mg of 4- (2-hydroxyethyl) aniline in 2.5 ml of NMP was added and the mixture was stirred at RT for 18.5 hrs. The solvents were removed under vacuum and the residue chromatographed on silica to provide 220 mg of crude product contaminated with excess aniline reagent. The crude product was dissolved in ethyl acetate and washed with dilute aqueous HCl. The organic phase was dried, evaporated, and the residue was finally triturated with heptane to provide 94 mg of the title product. ^ -RMN (CDC13): 9.19 (s, ÍH); 8.08 (s, 1H); 7.80 (br m, 2H); 7.63 (br s, ÍH); 7.52 (d, 2H); 7.42 (t, 1H); 7.00 (d, 2H); 4.12 (m, 2H); 3.99 (m, 2H).

Example 5 6- (2,6-Dichloro-phenyl) -2- [4- (2-hydroxy-ethoxy) -phenylamino] -pyrido [2,3-d] pyrimidine-7-carboxylic acid amide 20 mg were mixed of the product of example 3 in 1 ml of THF with 13.5 mg of potassium trimethylsilanolate under Ar atmosphere. The mixture was heated at 100 ° C for 20 min in a microwave reactor. The cooled reaction mixture was diluted with 0.1 ml of water, and a small amount of alumina chromatography. This suspension was evaporated to dryness under vacuum and the residue was packed on a column of silica chromatography. Elution with ethyl acetate 6 / heptane 1 yielded 6 mg of the title product. X H-NMR (DMS0-d 6): 10.24 (br s, ÍH); 9.41 (s, ÍH); 8.31 (s, ÍH); 8.13 (br s, ÍH); 7.92 (m, 2H); 7.56 (m, 3H), -7.42 (t, ÍH); 6.99 (d, 2H); 4.87 (t, ÍH); 4.00 (t, 2H); 3.73 (m, 2H).

Example 6 Analogous to the procedure described in example 1, but using the corresponding starting materials as described above, the following compounds can be obtained: E n g Systematic Name 1 H-NMR No. 6-3 (2-methanesulfonylamino-CDC13: 9.15 (s, ÍH); 8.52 (br ethyl) -amide of the acid t, 1H); 7.97 (s, lH); 7.80 (2,6-dichloro-phenyl) -2- (4- (br s, 1 H); 7.69 (br, 2H; morpholin-4-yl-phenylamino) -7.41 (d, 2H); 7.28 ( t, 1H) pyrido [2,3-d] pyrimidin-7- 6.98 (d, 2H); 5.23 (t, ÍH) carboxylic 3.89 (t, 4H); 3.56 (m, 2H) 3.34 (m, 2H); 3.17 (t, 4H) 2.92 (s, 3H), 6-4 (2-methanesulfonylamino-CDC13: 9.14 (s, ÍH), 8.50 (br ethyl) -amide of 6- t acid, IH), 7.96 (s, 1H); 7.91 (2,6-dichloro-phenyl) -2- [4- (br s, 1H); 7.68 (br m, 2H); (2-hydroxy-ethoxy) -7, .41 (d, 2H 7.28 (t, 1H) phenylamino] -pyrido [2, 3-6, .94 (d, 2H); 5.39 (t, 1H) d] pyrimidine-7-carboxylic acid 4.11 ( m, 2H); 3.97 (t, 2H) 3, .54 (m, 2H); 3, .33 (m, 2H) 2. .92 (s, 3H). 6-5 ((IR) -l-pyrrolidin-2-CDC13: 9.16 (s, HH), 8.50 (br-ethyl) -amide of S acid, HH), 7.95 (s, lH), 7.85 6- (2,6-dichloro-phenyl) -2- (br s, ÍH); 7.70 (brm, 2H); [4- (2-hydroxy-ethoxy) -7.40 (d, 2H); 7 26 (t, ÍH), phenylamino] -pyrido [ 2, 3-6 .97 (d, 2H); 4 11 (t, 2H), d] pyrimidine-7-carboxylic acid 3.98 (t, 2H); 3 48 (m, 1H), 3 .34 (m, 1H); 3 22 (m, ÍH), 2 .93 (m, 2H); 1 60- -1.99 (m, 3H); 1.41 (m, 1H); 6-6 (2-methanesulfonylamino-CDC13: 9.21 (s, 1H); 8.57 (t, ethyl) -amide of the acid 6H); 8.47 (br s, ÍH); 8.03 (2,6-dichloro-phenyl) -2- (3- (s, ÍH); 7.98 (br s, 2H); methanesulfonylamino- 7.42 (d, 2H); 7.35 (m, 3H) phenylamino) -pyrido [ 2.3- 7.13 (, 2H); 5.40 (t, ÍH) d] pyrimidine-7-carboxylic acid 3.54 (m, 2H); 3.37 (m, 2H) 3.06 (s) and 3.02 (s, together 6H). 6-7 (2-methanesulfonylamino-CD30D: 9.37 (s, ÍH); 8.27 (s, ethyl) -amide of 6-1H acid); 7.85 (s, ÍH); 7.80 (d, (2,6-dichloro-phenyl) -2- (3-1H), 7.50 (d, 2H), 7.39 (d) and methylsulfanyl-phenylamino) - 7.34 (t, with 2H) pyrido [2] , 3 ~ d] pyrimidin-7- 7.05 (d, ÍH); 3.48 (t, 2H) carboxylic 3.28 (t, 2H); 2.98 (s, 3H) 2.56 (s, 3H). 6-8 (2-methanesulfonylamino-CDC13: 9.23 (s, 1H); 8.84 (s, ethyl) -amide of the acid 6H); 8.63 (br t, ÍH); 8.41 (2, 6-dichloro-phenyl) -2- (6- (br s, HH); 8.05 (s, HH); methyl-pyridin-3-ylamino) -7.41 (d, 2H); 7.31 (d) and 7.26 pyrido [2,3-d] pyrimidin-7- (t, together 2H); 5.34 (br s, carboxylic H); 3.61 (m, 2H); 3.38 (m, 2H); 2.94 (s, 3H); 2.58 (s, 3H).

Example 7 Analogous to the procedure described in example 4, but using the corresponding starting materials as described above, the following compounds can be obtained: Example 8 Analogous to the procedure described in Example 5, but using the corresponding starting material as described above, the following compound can be obtained: Reference List Bastin, R. J. et al, Organic Proc. Res. Dev. 4 (2000) 427-435 Biscardi, J. S., et al. , Adv. Cancer Res. 76 (2000) 61-119 Merrifield, Fed. Proc. Fed. Amer. Soc. Exp. Biol. 21 (1962) 412 Susva, M., et al., Trends Pharmacol. Sci., 21 (2000) 489-495 WO 02/090360 WO 03/000011 WO 96/15128 It is noted that with regard to this date, the best method known to the applicant to carry out the aforementioned invention, is the which is clear from the present description of the invention.

Claims (22)

CLAIMS Having described the invention as above, the contents of the following claims are claimed as property:

1. Compounds of the formula I (formula I), characterized in that R1 is -C (O) -NH-alkyl or -C (O) -N (alkyl) 2, the alkyl groups are optionally substituted with -OH; -NH (alkyl); -N (alkyl) 2; -NH-C (O) -alkyl; -C (O) -NH-alkyl; -C (O) -N (alkyl) 2; -C (0) -NH2; -O-alkyl; -heterocyclyl;

-NH-heterocyclyl; -NH-S (0) 2-alkyl ?; -S (0) 2-NH2; or -S (0) -alkyl, all alkyl groups are optionally substituted with -OH; or a -CN group; -C (0) -NH2; -C (0) -NH-heterocyclyl; -C (0) -NH-NH-C (0) -NH2; O -C (0) -NH-NH-C (O) -alkyl; the alkyl is optionally substituted with -NH (alkyl); or -N (alkyl) 2; and halogen; heterocyclyl; I rent; -NH-C (O) -alkyl; -NH-S (0) 2-alkyl; - (CH2) Itl-S (0) 2-NH2; - (CH2) m-S (0) 2-N (alkyl) 2; - (CH2) m-S (0) 2-NH- (alkyl); -0-alkyl; or -S (0) n-alkyl, all alkyl groups are optionally substituted by

-OH; -O-alkyl; -NH-alkyl; or -N (alkyl) 2; X is -CH = or N =; m is 0, 1, 2, 3, 4, 5 or 6; n is 0, 1 or 2; and pharmaceutically acceptable salts thereof. 2. Compounds according to claim 1, characterized in that X is -CH =; R1 is -C (O) -NH-alkyl, the alkyl group is optionally substituted with -OH; -NH (alkyl); -N (alkyl) 2; -NH-C (O) -alkyl; -C (O) -NH-alkyl; -C (0) -N (alkyl) 2; -C (0) -NH2; -O-alkyl; -heterocyclyl; -NH-heterocyclyl; -NH-S (0) 2-alkyl; -S (0) 2-NH2; or

-S (O) -alkyl, all alkyl groups are optionally substituted with -OH; and R2 has the meaning in accordance with claim 1. 3. Compounds in accordance with the claim 1, characterized in that X is -CH =; R1 is -C (O) -NH-methyl; or -C (O) -NH-ethyl, the methyl or ethyl group is unsubstituted or once substituted with -OH; -pyrrolidinyl; or -NH-S (0) 2-CH 3; and R2 has the meaning in accordance with claim 1. Compounds according to claim 1, characterized by X is -CH =; R1 is -C (O) -NH-ethyl; or -C (O) -NH-methyl, the methyl or ethyl groups are once substituted with -OH; or -pyrrolidinyl; and R2 is morpholin-4-yl; -NH-S (0) 2-CH 3;

-O-alkyl; or -S (O) n-alkyl, all alkyl groups are optionally once substituted by -OH; -O-alkyl; -NH-alkyl; or -N (alkyl) 2; n is OA or 2; and pharmaceutically acceptable salts thereof. 5. Compounds in accordance with the claim 4, characterized in that they are 6- (2,6-dichloro-phenyl) -2- [4- (2-hydroxy-ethoxy) -phenylamino] -pyrido [2-hydroxy-ethyl] -amide. d] pyrimidine-7-carboxylic acid; (2- (2,6-dichloro-phenyl) -2- (4-morpholin-4-yl) -phenylamino) -pyrido [2,3-d] pyrimidin-7-hydroxy-ethyl) -amide carboxylic; ((R) -l-pyrrolidin-2-ylmethyl) -amide of 6- (2,6-dichloro-phenyl) -2- [4- (2-hydroxy-ethoxy) -phenylamino] -pyrido [2,3] -d] pyrimidine-7-carboxylic acid; and 6- (2,6-dichloro-phenyl) -2- (4-morpholin-4-yl-phenylamino) -pyrido [(3-) 2-pyrrolidin-2-ylmethyl) -amide] d] pyrimidine-7-carboxylic acid. 6. Compounds according to claim 1, characterized in that

X is -CH =; R1 is -C (0) -NH- (CH2) 2-NH-S (0) 2-CH3; and R2 is morpholin-4-yl; 4-met il-piperazin-1-yl; -NH-S (0) 2-CH 3; -O-alkyl, • or -S (O) n-alkyl, all alkyl groups are optionally once substituted by -OH; -O-alkyl; -NH-alkyl; or -N (alkyl) 2; n is 0, 1 or 2; and pharmaceutically acceptable salts thereof.

7. Compounds in accordance with the claim 6, characterized in that they are 6- (2,6-dichloro-phenyl) -2- (4-morpholin-4-yl-phenylamino) -pyrido [2, 3-d] (2-methanesulfonylamino-ethyl) -amide pyrimidine-7-carboxylic acid; 6- (2,6-Dichloro-phenyl) -2- [4- (2-hydroxy-ethoxy) -phenylamino] -pyrido [2,3-d] pyrimidine-7-methanesulfonylamino-ethyl) -amide -carboxylic; 6- (2,6-Dichloro-phenyl) -2- (3-methanesulfonylamino-phenylamino) -pyrido [2,3-d] pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl) -amide; 6- (2,6-Dichlorophenyl) -2- [3- (2-hydroxy-ethylsulfanyl) -phenylamino] -pyrido [2,3-d] pyrimidin-7-methanesulfonylamino-ethyl) -amide -carboxylic; 6- (2,6-dichloro-phenyl) -2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrido [2, 3-d] (2-methanesulfonylamino-ethyl) -amide. ] pyrimidine-7-carboxylic acid; and 6- (2,6-dichloro-phenyl) -2- (3-methylsulfanyl-phenylamino) -pyrido [2,3-d] pyrimidine-7-carboxylic acid (2-methanesulfonylamino-ethyl) -amide.

8. Compounds in accordance with the claim 1, characterized in that X is -CH =; R1 is -C (0) -NH2; and R2 is morpholin-4-yl; -NH-S (0) 2-CH 3; -O-alkyl; or -S (O) n-alkyl, all alkyl groups are optionally once substituted by -OH; -O-alkyl; -NH-alkyl; or -N (alkyl) 2; n is 0, 1 or 2; and pharmaceutically acceptable salts thereof.

9. Compounds in accordance with the claim 8, characterized in that they are 6- (2,6-dichloro-phenyl) -2- (4-morpholin-4-yl-phenylamino) -pyrido [2,3-d] pyrimidine-7-carboxylic acid amide; and 6- (2,6-dichloro-phenyl) -2- [4- (2-hydroxy-ethoxy) -phenylamino) -pyrido [2,3-d] pyrimidine-7-carboxylic acid amide.

10. Compounds according to claim 1, characterized in that X is -CH =; R1 is -CN; and R2 is morpholin-4-yl; -NH-S (0) 2-CH 3; -O-alkyl; or -S (O) n-alkyl, all alkyl groups are optionally once substituted by -OH; -O-alkyl; -NH-alkyl; or -N (alkyl) 2; n is 0, 1 or 2; and pharmaceutically acceptable salts thereof.

11. Compounds according to claim 10, characterized in that they are: 6- (2,6-dichloro-phenyl) -2- [4- (2-diethylamino-ethoxy) -phenylamino] -pyrido [2, 3-d] pyrimidin-7-carbonitrile; 6- (2,6-dichloro-phenyl) -2- (4-morpholin-4-yl-phenylamino) - pyrido [2,3-d] pyrimidine-7-carbonitrile; and 6- (2,6-dichloro-phenyl) -2- [4- (2-hydroxy-ethoxy) -phenylamino] -pyrido [2,3-d] pyrimidine-7-carbonitrile.

12. Compounds according to claim 1, characterized in that X is -N =; R1 is -C (0) -NH- (CH2) 2-NH-S (0) 2-CH3; and R2 is alkyl; -NH-S (0) 2-CH 3; -O-alkyl; or -S (O) n-alkyl, all alkyl groups are optionally substituted by -OH; -O-alkyl; -NH-alkyl; or -N (alkyl) 2; n is 0, 1 or 2; and pharmaceutically acceptable salts thereof.

13. Compound according to claim 12, characterized in that it is 6 - (2,6-dichloro-phenyl) -2- (6-methyl-pyridin-3-ylamino) (2-methanesulfonylamino-ethyl) -amide. - [2,3-d] pyrimidine-7-carboxylic acid.

14. Process for the manufacture of the compounds of the formula (I) according to claim 1, characterized in that it leads the reaction steps of (a) converting the carboxylic group to the compounds of the general formula (II) formula (II), in the corresponding amides of the formula (V) formula (V), wherein R 3 is -C (O) -NH-alkyl or -C (O) -N (alkyl) 2, the alkyl groups are optionally substituted with -OH; -NH (alkyl); -N (alkyl) 2; -NH-C (O) -alkyl; -C (O) -NH-alkyl; -C (0) -N (alkyl) 2; -C (0) -NH2; -O-alkyl; -heterocyclyl; -NH-heterocyclyl; -NH-S (0) 2 -alkyl ?; -S (0) 2-NH2; or -S (0) -alkyl, all alkyl groups are optionally substituted with -OH; or a group -C (0) -NH2; -C (0) -NH-heterocyclyl; -C (0) -NH-NH-C (0) -NH2; or -C (0) -NH-NH-C (0) -alkyl, the alkyl is optionally substituted with -NH (alkyl); or -N (alkyl) 2; (b) converting the methylthio group to the compounds of the general formula (V) into the corresponding sulfoxides of the formula (VI) formula (VI), wherein R3 has the meaning given above; (c) replacing the sulfoxide group of the formula (VI) with the respective anilines of the formula (II-A) formula (II-A) wherein R2 and X have the meanings given for formula (I) according to claim 1, to produce the corresponding compounds of formula (la); formula (la) where R3 has the meaning given above; and R2 and X have the meanings given for the formula (I) according to claim 1, (d) further converting, if desired, a primary amide derivative of the formula (la) obtained from the step (c) in its corresponding 7-carbonitrile derivative of the formula (I) according to claim 1; Y (e) converting, if desired, the compound of the formula (I), obtained from steps (c) or (d), into a pharmaceutically acceptable salt.

15. Medicament, characterized in that it contains one or more compounds according to any of claims 1 to 13 as active ingredients together with pharmaceutically acceptable adjuvants.

16. Medicament according to claim 15, characterized in that it is for the treatment of diseases mediated by an inappropriate activation of the src family of tyrosine kinases.

17. Medicament according to claim 15, characterized in that it is for the treatment of cancer.

18. Medicament according to claim 15, characterized in that it is for the treatment of inflammatory, immunological, CNS disorders or bone diseases.

19. Use of one or more compounds according to any of claims 1 to 13 for the manufacture of medicaments for the treatment of diseases mediated by an inappropriate activation of the src family of tyrosine kinases.

20. Use of one or more compounds according to any of claims 1 to 13 for the manufacture of medicaments for the treatment of cancer.

21. Use of one or more compounds according to any of claims 1 to 13 as inhibitors of the src family of tyrosine kinase.

22. Use of one or more compounds of the formula I according to any of claims 1 to 13 for the treatment of cancer.