MX2008004175A - Imidazo [1,2-a]pyridine having anti-cell-proliferation activity - Google Patents

Abstract

Compounds of formula (I):which possess cell cycle inhibitory activity are described.

Description

"IM1DAZ0 M .2-A. PYRIDINE THAT HAS ACTIVITY OF CELLULAR ANT1PRQLIFERACIÓN" FIELD OF THE INVENTION The invention relates to pyrimidine derivatives, or pharmaceutically acceptable salts or in vivo hydrolysable esters thereof, which possess cell cycle inhibitory activity and consequently, are useful for their cell antiproliferation activity (such as anticancer) and therefore are useful in methods of treating human or animal bodies. The invention also relates to processes for the manufacture of pyrimidine derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicament for use in the production of a cellular anti-proliferation effect in a warm-blooded animal such as human .

Discussion of antecedents The cell cycle is fundamental for the survival, regulation and proliferation of cells and is highly regulated to ensure that each step progresses in a timely and orderly manner. The progress of the cells through the cell cycle originates from the sequential activation and deactivation of several members of the family of cyclin-dependent kinases (CDK-cyclin-dependent kinase). The activation of CDKs is dependent on their interaction with a family of intracellular proteins called cyclins. Cyclins bind to CDKs and this association is essential for the activity of CDK within the cell. Different cyclins are expressed and degraded at different points in the cell cycle to ensure that the activation and inactivation of CDKs occurs in the correct order for progress through the cell cycle. Furthermore, it appears that the CDKs are current under a certain number of oncogene signaling trajectories. The deregulation of CDK activity by the upregulation of cyclins and / or the elimination of endogenous inhibitors seems to be an important axis between the mitogenic signaling trajectories and the proliferation of tumor cells. In accordance with the above, it has been recognized that an inhibitor of cell cycle kinases, particularly inhibitors of CDK1, CDK2, CDK4 and CDK6 (which operate in the phases G2 / M, G1 / SS-G2 / M and G1 -S, respectively) must be significant as an active inhibitor of cell proliferation, such as the growth of mammalian cancer cells. It is also believed that tumor cells are highly dependent on the continuous transcription activity of RNA polymerase I I to maintain appropriate levels of anti-apoptotic proteins and ensure the survival of tumor cells. It is known that, in particular, CDK1, CDK7, CDK8 and CDK9 regulate the activity of RNA polymerase I I through phosphorylation of the C-terminal domain of the protein. Consequently, the inhibition of RNA polymerase I I activity through inhibitors of these CDKs may contribute to a proapoptotic effect in tumor cells. The inhibition of cell cycle kinases is expected to be significant in the treatment of disease states associated with aberrant cell cycles and cell proliferation such as cancers (solid tumors and leukemias), fibroproliferative and differentiation disorders, psoriasis, rheumatoid arthritis, sarcoma of Kaposi, hemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with proliferation of the retinal vessels. WO 01/14375 describes some imidazopyridines which inhibit the effect of cell cycle kinases. WO 02/66480 describes some imidazopyridines which are useful in the treatment of disorders related to GSK-3. The present invention is based on the discovery that a novel group of imidazopyridines inhibits the effects of cell cycle kinases, particularly CDK2, and consequently possesses cell antiproliferation properties. The compounds of the present invention are not specifically described in the aforementioned applications and we have identified that these compounds may possess beneficial properties in terms of one or more of their pharmacological activities (particularly as compounds that inhibit CDK2) and / or pharmacokinetic profiles., effective, metabolic and toxicological that make them particularly suitable for in vivo administration to a warm-blooded animal, such as a human.

BRIEF DESCRIPTION OF THE INVENTION In accordance with the foregoing, the present invention provides a compound of Formula (I): (I) where: R1 is selected from halo, amino, C ^ alkyl, C3alkoxy,? / - (C1 -3alkyl) amino,? /,? / - (C1.3alkyl) 2-amino and a saturated ring composed of 4-7 members attached to a nitrogen which optionally contains an additional nitrogen, oxygen or sulfur atom; m is 0-4; where the values of R may be the same or different; R2 is selected from hydrogen, halo, amino, Ci. 3alkyl and d.3alkoxy; R3 is hydrogen or halo; R 4 is hydrogen, ethynyl, halo, cyano, hydroxy, amino, mesyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl or methoxy; Ring A is a saturated ring composed of 4-7 members attached to nitrogen which optionally contains an additional nitrogen, oxygen or sulfur atom; wherein if said ring contains an additional nitrogen atom that nitrogen can be optionally substituted by R6; R5 is a carbon substitute and is selected from halo, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, sulfamoyl, C1 -6alkyl, C2.sub.alkenyl, C2.6alkynyl, C1-6alkanoyl,? / - (C? .alkyl) carbamoyl,? /,? / - (C1.6alkyl) 2carbamoyl, C1.6alkylS (O) where a is 0 to 2, C? .6alkoxycarbonyl,? / - (C? .6alkyl) sulphamoyl and N, N- (C1. 6alkyl) 2-sulphamoyl; wherein R5 independently can optionally be substituted on carbon by one or more R7; or R5 is -NHR8, -NR9R10 or -O-R1 1; n is 0-4; where the values of R5 may be the same or different; R6 is selected from C? .6alkyl, C1 -6alkanoyl, C ,. 6alkylsulfonyl, CL-alkoxycarbonyl, carbamoyl, / V-id-ßalqui carbamoyl, and? /,? / - (C1.6alkyl) carbamoyl; where R6 can optionally be substituted on carbon with one or more R12; R8, R9, R10 and R1 1 are independently selected from C1.4alkyl, C1-4alkanoyl, C1-4alkylsulfonyl, C2. alkenylsulfonyl, C2. 4-alkynylsulphonyl, C-4-alkoxycarbonyl, carbamoyl,? / - (d. Alkyl) carbamoyl and? /,? / - (C1. Alkyl) carbamoyl, carbocyclyl and heterocyclyl; where R8, R9, R0 and R1 1 can be optionally substituted independently on carbon by a group selected from R13; and wherein if the heterocyclyl contains a residue of -NH- that nitrogen can be optionally substituted by R 14; R1 3 is selected from halo, cyano, hydroxy, amino, trifluoromethyl, trifluoromethoxy, C? -3alkyl and C? -3alkoxy; R14 is selected from d.3alkyl, d-3alkanoyl, d. 3alkylsulfonyl, d-3alkoxycarbonyl, carbamoyl,? / - (d -3alkyl) carbamoyl and? /,? / - (C 1-3alkyl) carbamoyl; and R7 and R12 are independently selected from halo, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino,? -methyl-? / - ethylamino, acetylamino,? / - methylcarbamoyl,? / - ethylcarbamoyl,? /,? / - dimethylcarbamoyl,? /,? / - diethylcarbamoyl,? / - methyl -? / - ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl,? / - methylsulfamoyl,? / - ethylsulphamoyl, N, N-dimethylsulphamoyl,? /,? / - diethylsulphamoyl and? / - methyl-? / - ethylsulphamoyl; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. In this specification, the term "alkyl" includes both straight and branched alkyl groups but references to individual alkyl groups such as "propyl" are specific only to the straight chain version. For example, "d.6alkyl" and "C? Alkyl" include methyl, ethyl, propyl, isopropyl and f-butyl. "C1 -3alkyl" includes methyl, ethyl, propyl and isopropyl. However, references to individual alkyl groups such as "propyl" are specific only to the straight chain version and references to individual branched chain alkyl groups such as "isopropyl" are specific only to the branched chain version. A similar convention applies to other radicals. The term "halo" refers to fluoro, chlorine, bromine and iodine. When optional substitutes are chosen from "one or more" groups it should be understood that this definition includes all substitutes chosen from one of the specified groups or substitutes chosen from two or more of the specified groups. A "heterocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is selected from nitrogen, sulfur or oxygen, which may be, unless otherwise specified, carbon or nitrogen linked, where a -CH2- group can optionally be replaced by a -C (O) -, an annular nitrogen atom can optionally support a d.6alkyl group and form a quaternary compound or optionally a nitrogen atom and / or annular sulfur can be oxidized in order to form the? / - oxide and / or the S-oxides. Examples and suitable values of the term "heterocyclyl" are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolyl, indolyl, quinilyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, , 5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl,? / - methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine -? / - oxide and quinoline -? / - oxide. In one aspect of the invention, a "heterocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 5 or 6 atoms of which at least one atom is selected from nitrogen, sulfur or oxygen, can be, unless otherwise specified, carbon or nitrogen linked, a -CH2- group may be optionally replaced by a -C (O) - and optionally an annular sulfur atom may be oxidized to form the S-oxides. A "carbocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring containing 3-12 atoms; where a -CH2- group can be optionally replaced by a -C (O) -. Particularly, "carbocyclyl" is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for "carbocyclyl" include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl. A "saturated ring composed of 4-7 nitrogen-bonded members optionally containing an additional nitrogen, oxygen or sulfur atom" is a saturated monocyclic ring containing 4-7 atoms bonded to formula (I) by a nitrogen atom contained in the ring, the ring optionally containing an additional heteroatom selected from nitrogen, sulfur or oxygen, where a -CH2- group can optionally be replaced by a -C (O) -, and the optional sulfur atom can optionally be oxidized to form the S-oxides. A "saturated ring composed of 5 or 6 members bonded to nitrogen optionally containing an additional nitrogen, oxygen or sulfur atom" is defined as a "saturated ring composed of 4-7 atoms bonded to nitrogen which optionally contains an additional nitrogen atom. nitrogen, oxygen or sulfur "but where the ring only has 5 or 6 atoms. Suitable values of a "saturated ring composed of 4-7 members bonded to nitrogen optionally containing an additional nitrogen, oxygen or sulfur atom" include piperidinyl, morpholinyl, pyrrolidino and piperazinyl. An additional suitable example is homopiperazinyl. Examples of "d.6alkoxycarbonyl" and "C1.4alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, n- and i-butoxycarbonyl. Examples of "d.3alkoxycarbonyl" include methoxycarbonyl and ethoxycarbonyl. Examples of "C1 -3alkoxy" include methoxy, ethoxy and propoxy. Examples of "C1.6alkyl (O) where a is 0 to 2" include methylthio, ethylthio, methylisulfinyl, ethylisulfinyl, mesyl and ethylsulphonyl. Examples of "d.6alkanoyl", "C 1-4alkanoyl" and "d.3alkanoyl" include propionyl and acetyl. Examples of "C2.6alkenyl" are vinyl, allyl and 1 -propenyl. Examples of "d-ealkynyl" are ethynyl, 1-propynyl and 2-propynyl. Examples of "? / - (d.6alkyl) sulfamoyre are N- (methyl) sulphamoyl and? / - (ethyl) sulphamoyl." Examples of "? /,? / - (C? 6alkyl) 2-sulphamoyl" are / V ,? / - (dimethyl) sulphamoyl and? / - (methyl) -? / - (ethyl) sulphamoyl The examples of "/ V-id-ßalqui carbamoyl", "N- C ^. 4alkyl) carbamoyl "and"? / - (C1 -3alkyl) carbamoyl "are methylaminocarbonyl and ethylaminocarbonyl Examples of"? /,? / - (d.6alkyl) 2carbamoyl ","? /,? / - (C1.4alkyl) ) 2carbamoyl "and"? /,? / - (C1 -3alkyl) 2carbamoyl "are dimethylaminocarbonyl and methylethylaminocarbonyl The examples of" d. 4-alkylsulfonyl "include methylsulfonyl, isopropylsulfonyl and t-butylsulfonyl Examples of" d.3alkylsulfonyl "include methylsulfonyl and isopropylsulfonyl Examples of" d. alkenylsulfonyl "include ethenylsulfonyl and alkylsulfonyl Examples of" C 4,4 alkynylsulfonyl "include ethynylsulfonyl and propynylsulfonyl Examples of"? / - (d.3alkyl) amino "include methylamino and ethylamino. Examples of"? /,? / - (C1.3alkyl) 2amino "include methylethylamino and dimethylamino A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid addition salt of a compound of the invention which is sufficiently basic, for example, a salt of acid addition with, for example, an organic or inorganic acid, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, citric or maleic acid In addition to a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is a alkali metal salt, for example, a sodium or potassium salt, an alkaline earth metal salt, for example, a calcium or magnesium salt, an ammonium salt or a salt with an organic base which delivers a physiologically acceptable cation, for example, a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine. An in vivo hydrolysable ester of a compound of the formula (I) which contains a carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the original acid or alcohol. Pharmaceutically acceptable esters for carboxy include esters of C ?. 6-alkoxymethyl, for example, methoxymethyl, Ci esters. 6-alkanoyloxymethyl, for example, pivaloyloxymethyl, phthalidyl esters, d.sub.-cycloalkoxycarbonyloxyd.-alkyl esters, for example, 1-cyclohexylcarbonyloxyethyl, 1,3-dioxolen-2-onylmethyl esters for example, 5-methyl-1,3-dioxolen- 2-onylmethyl; and d-6-alkoxycarbonyloxyethyl esters for example, 1-methoxycarbonyloxyethyl and can be formed in any carboxy group in the compounds of this invention. An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester cleavage deliver the original hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysable ester formation groups for hydroxy includes substituted alkanoyl, benzoyl, phenylacetyl and benzoyl and phenylacetyl, alkoxycarbonyl (to deliver esters of alkyl carbonate), dialkylcarbamoyl and N- (dialkylaminoethyl) -? / - alkylcarbamoyl (for deliver carbamates), dialkylaminoacetyl and carboxyacetyl. Examples of benzoyl substitutes include morpholino and piperazino linked from an annular nitrogen atom by a methylene group to the 3 or 4 position of the benzoyl ring. Some compounds of formula (I) may have chiral centers and / or geometric isomeric centers (E and Z isomers), and it should be understood that the invention encompasses all optical isomers, diastereomers and geometric isomers possessing CDK inhibitory activity.

The invention relates to each and every one of the tautomeric forms of the compounds of the formula (I) which possess CDK inhibitory activity. It should also be understood that some compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, the hydrated forms. It should be understood that the invention encompasses such solvated forms that possess CDK inhibitory activity. The particular values of variable groups are the following. Such values can be used where appropriate with any of the definitions, claims or modalities defined above or below, m is 0. R2 is selected from hydrogen or C1 -3alkyl. R2 is selected from hydrogen or methyl. R2 is methyl. R2 is hydrogen. R3 is hydrogen. R3 is halo. R3 is fluoro. R4 is hydrogen, halo or methyl. R4 is hydrogen, fluoro or methyl. Ring A is a 5-7 membered saturated ring attached to nitrogen which optionally contains an additional nitrogen or oxygen atom; where if the ring contains an additional nitrogen atom, that nitrogen can be optionally substituted by R6; where Re is d.6 alkyl. Ring A is a saturated ring composed of 5 or 6 members attached to nitrogen which optionally contains an additional nitrogen or oxygen atom; where if the ring contains an additional nitrogen atom, that nitrogen can be optionally substituted by R6; where R6 is C1 -6alkyl. Ring A is pyrrolidin-1-yl, piperazin-1-yl, homopiperazin-1-lo or morpholino; wherein the piperazin-1-yl or homopiperazin-1-yl can be optionally substituted in nitrogen by R6; where R6 is methyl or isopropyl. Ring A is pyrrolidin-1-yl, piperazin-1-yl or morpholino; wherein the piperazin-1-yl can be optionally substituted in nitrogen by R 6; where R6 is methyl. Ring A is pyrrolidin-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl or 4-isopropylhomopiperazin-1-yl or morpholino. Ring A is pyrrolidin-1-yl, 4-methylpiperazin-1-yl, or morpholino. R5 is a carbon substitute and is selected from -NR9R10; where R9 and R10 are independently selected from C? _ rent. R5 is a carbon substitute and is selected from -NR9R10; where R9 and R10 are independently selected from methyl. R5 is a carbon substitute and is dimethylamino. n is O n is 1. n is O or 1. Therefore, in a further aspect of the invention, there is provided a compound of the formula (I) (as graphically shown above), wherein: m is 0; R2 is selected from hydrogen or d-3alkyl; R3 is hydrogen; R 4 is hydrogen, halo or methyl; Ring A is a 5-7 membered saturated ring attached to nitrogen which optionally contains an additional nitrogen or oxygen atom; where if the ring contains an additional nitrogen atom, that nitrogen can be optionally substituted by R6; where R6 is C? .6alkyl. R5 is a carbon substitute and is selected from -NR9R10; wherein R9 and R10 are independently selected from d-4alkyl; n is 0 or 1; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. Therefore, in a further aspect a compound of the formula (I) is provided (as graphically represented above) where: m is 0; R2 is hydrogen; R3 is hydrogen; R 4 is hydrogen, halo or methyl; Ring A is a saturated ring composed of 5 or 6 members attached to nitrogen which optionally contains an additional nitrogen or oxygen atom; where if the ring contains an additional nitrogen atom, that nitrogen can be optionally substituted by R6; where R6 is d6alkyl; R5 is a carbon substitute and is selected from -NR9R10; wherein R9 and R10 are independently selected from C? .4alkyl; n is 0 or 1; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. Therefore, in a further aspect of the invention there is provided a compound of the formula (I) (as graphically represented above) where: m is 0; R2 is selected from hydrogen or methyl; R3 is hydrogen; R 4 is hydrogen, fluoro or methyl; Ring A is pyrrolidin-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl or 4-isopropylhomopiperazin-1-yl or morpholino; R5 is a carbon substitute and is dimethylamino; n is 0 or 1; or a pharmaccally acceptable salt or an in vivo hydrolysable ester thereof. Therefore, in a further aspect of the invention there is provided a compound of the formula (I) (as graphically shown above) where: m is 0; R2 is hydrogen; R3 is hydrogen; R 4 is hydrogen, fluoro or methyl; Ring A is pyrrolidin-1-yl, 4-methylpiperazin-1-yl, or morpholino; R5 is a carbon substitute and is dimethylamino; n is 0 or 1; or a pharmaccally acceptable salt or an in vivo hydrolysable ester thereof.

DETAILED DESCRIPTION OF THE INVENTION In another aspect of the invention, the preferred compounds of the invention are any of the examples or a pharmaccally acceptable salt or an in vivo hydrolysable ester thereof. Preferred aspects of the invention are those that relate to the compound of the formula (I) or a pharmaccally acceptable salt thereof. Another aspect of the present invention provides a process for preparing a compound of the formula (I) or a pharmaccally acceptable salt or a hydrolyzable ester in vivo from the same process as (where the variable groups are, unless otherwise specified , as defined in formula (I)) comprises: Process a) pyrimidine reaction of formula (II): (OR) where L is a displaceable group; with an aniline of the formula (III) (III) Process b) reacting a compound of the formula (IV) (IV) with a compound of the formula (V): (V) where T is O or S; Rx can be the same or different and is selected from d.6alkyl; Process c) reacting an acid of the formula (VI): (SAW) or an activated acid derivative thereof, with an amine of the formula (Vi l): (Rs) "(VIO Process d) for compounds of formula (I); reacting a pyrimidine of the formula (VI I I): with a compound of the formula (IX): (IX) where Y is a displaceable group, and, therefore, if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) eliminate any protective groups; iii) forming a pharmaccally acceptable salt or hydrolysable ester in vivo. L is a displaceable group, suitable values for L are an example, a halogen or sulfonyloxy group, for example, a chloro, bromo, methanesulfonyloxy or toluene-4-sulfonyloxy group and is a displaceable group, suitable values for Y are for example, a halogen or sulfonyloxy group, for example, a bromine, iodine or trifluoromethanesulfonyloxy group. Preferably, Y is iodine. The specific reaction conditions for the reactions above are as follows: Process a) The pyrimidines of the formula (II) and the anilines of the formula (11) can be reacted together: i) in the presence of a suitable solvent, for example , a ketone such as acetone or an alcohol such as ethanol or butanol or an aromatic hydrocarbon such as toluene or? / - methyl pyrrolidine, optionally in the presence of a suitable acid, for example, an inorganic acid such as hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid or formic acid (or a suitable Lewis acid) and at a temperature in the range of 0 ° C to reflux, preferably reflux; or ii) under conventional Buchwald conditions; (for example, see J. Am. Chem. Soc, 1 18, 721 5; J. Am. Chem. Soc, 1 19, 8451; J. Org. Chem., 62, 1 568 and 6066), for example, in the presence of palladium acetate, in a suitable solvent, for example, an aromatic solvent such as toluene, benzene or xylene, with a suitable base, for example, an inorganic base such as cesium carbonate or an organic base such as potassium butoxide, in the presence of a suitable binder such as 2,2'-bis (diphenylphosphino) -1, 1'-biphenyl and a temperature in the range of 25 to 80 ° C. The pyrimidines of the formula (I I) where L is chloro can be prepared according to Scheme 1: NaNO 2, HCl (a) Scheme 1 The anilines of the formula (11) are commercially available compounds, or are known in the literature, or are prepared by conventional processes known in the art. Process b). The compounds of the formula (IV) and the compounds of the formula (V) are reacted together in a suitable solvent such as? / -methylpyrrolidinone or butanol at a temperature in the range of 1-200-200 ° C, preferably in the range of 150-170 ° C. The reaction is preferably carried out in the presence of a suitable base such as, for example, sodium hydride, sodium methoxide or potassium carbonate. The compounds of the formula (V) can be prepared according to Scheme 2.

Scheme 2 The compounds of formula (IV) and (Va) are commercially available compounds, or are known in the literature, or are prepared by conventional processes known in the art. Process c) The acids and amines can be coupled together in the presence of a suitable coupling reagent. The conventional peptide coupling reagents known in the art can be employed as suitable coupling reagents, or for example, carbonyldiimidazole and dicyclohexylcarbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base, for example, triethylamine, and pyridine, or 2,6-di-a / gtv / 7-pyridines such as 2,6-lutidine or 2,6-di-ferf-butylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide. The coupling reaction can be conveniently carried out at a temperature in the range of -40 to 40 ° C. Suitable activated acid derivatives include acid halides, for example, acid chlorides, and active esters, for example, pentafluorophenyl esters. The reaction of these types of compounds with amines is known in the art, for example, they can be reacted in the presence of a base, such as those described above, and in a suitable solvent, such as those described above. The reaction can be conveniently carried out at a temperature in the range of -40 to 40 ° C. The compounds of the formula (VI) can be prepared by adapting Process a), b) or c). The amines of the formula (VI) are commercially available compounds, or are known in the literature, or are prepared by conventional processes known in the art. Process d) The compounds of the formula (VI II) and the amines of the formula (IX) can be reacted together under conventional Buchwald conditions as described in Process a. The synthesis of the compounds of the formula (VI I I) is described in Scheme 1. The compounds of the formula (IX) are commercially available compounds, or are known in the literature, or are prepared by conventional processes known in the art. It will be noted that some of the various ring substitutes in the compounds of the present invention may be introduced by aromatic substitution reactions or generated by conventional modifications of the functional groups either before or immediately after the above-mentioned processes, and as such are included in the aspect of the process of the invention. Such reactions and modifications include, for example, the introduction of a substitute by means of an aromatic substitution reaction, reduction of substitutes, alkylation of substitutes and oxidation of substitutes. The reactive agents and the reaction conditions for such processes are known in the field of chemistry. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an asyl group using, for example, an acyl halide and Lewis acid (such as aluminum trichloride) under Friedel Crafts conditions.; using the introduction of an alkyl group an alkyl halide and Lewis acid (such as aluminum trichloride) under Friedel Crafts conditions; and the introduction of a halogen group. Particular examples of modifications include the reduction of a nitro group to an amino group, for example, by catalytic hydrogenation with a nickel catalyst or an iron treatment in the presence of hydrochloric acid with heating; oxidation of alkylthio in alkylsulfinyl or alkylsulfonyl. It will also be noted that in some of the reactions mentioned herein it may be necessary / desirable to protect any sensitive group in the compounds. Cases where protection and appropriate methods of protection are necessary or desirable are known to those skilled in the art. Conventional protective groups can be used in accordance with conventional practice (for illustration, see T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Accordingly, if the active agents include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned above. A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example, an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example, a methoxycarbonyl group, ethoxycarbonyl or f-butoxycarbonyl, an arylmethoxycarbonyl group, for example, benzyloxycarbonyl, or an aroyl group, for example, benzoyl. The deprotection conditions for the aforementioned protective groups necessarily vary with the choice of the protecting group. Consequently, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example, lithium or sodium hydroxide. Alternatively, an acyl group such as a f-butoxycarbonyl group can be removed, for example, by treatment with a suitable acid such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group can be removed, for example, by hydrogenation on a catalyst such as palladium on carbon, or by treatment with a Lewis acid, for example, boron tris (trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which can be removed by treatment with an alkylamine, for example, dimethylaminopropylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example, an alkanoyl group such as acetyl, an aroyl group, for example, benzoyl, or an arylmethyl group, for example, benzyl. The deprotection conditions for the aforementioned protecting groups will necessarily vary with the choice of the protecting group. Consequently, for example, an acyl group such as an alkanoyl or aroyl group can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example, lithium or sodium hydroxide. Alternatively, an arylmethyl group such as a benzyl group can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon. A suitable protecting group for a carboxy group is, for example, an esterification group, for example, a methyl or ethyl group which can be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example, a f-butyl group which can be removed, for example, by treatment with an acid, for example, an organic acid such as trifluoroacetic acid, or for example, a benzyl group which can be removed, for example, by hydrogenation on a catalyst such like palladium on carbon.

The protecting groups can be removed at any convenient stage in the synthesis using conventional techniques known in the art. As set forth hereinbefore, the compounds defined in the present invention possess cellular antiproliferative activity such as anticancer activity which is considered to arise from the CDK inhibitory activity of the compound. These properties can be evaluated, for example, using the procedure set forth below.

Test The following abbreviations have been used: HEPES is? / - [2-hydroxyethyl] piperazine -? / '- [2-ethanesulfonic acid] DTT is dithiothreitol PMSF is phenylmethylsulfonyl fluoride The compounds were tested in an in vitro kinase test in a 96-cell format using the Scintillation Proximity Assay (SPA) obtained from Amersham) to measure the incorporation of [? -33-P] -denosine triphosphate into a test substrate (GST). retinoblastoma; GST-Rb). In each cell the compound to be tested was placed (diluted in DMSO and water to correct the concentrations) and in control cells either the roscovitine as an inhibitor control or DMSO as a positive control. Approximately 0.2μl of the partially purified enzyme CDK2 / Cyclin E (amount dependent on enzyme activity) diluted in 25μl of incubation buffer was added to each cell after 20μl of GST-Rb / ATP / ATP33 mixture (containing 0.5 μg of GST-Rb and 0.2μM of ATP and 0.14μCi of [? -33-P] -Adenosine Trifosphate in incubation buffer), and the resulting mixture is shaken gently, then incubated at room temperature for 60 minutes. To each cell was then added 150 μL of stop solution containing (0.8 mg / cell count of Protein A-PVT SPA (Amersham)), 20 pM / cell of Transferase of anti-glutathione, rabbit IgG (obtained from from Molecular Probes), 61 mM EDTA and 50 mM HEPES with a pH of 7.5 containing 0.05% sodium azide. The plates are sealed with Topseal-S plate sealers, allowed to spin for two hours at 2500 rpm, 1 124xg. , for 5 minutes. The plates were read in a Topcount for 30 seconds per cell. The incubation buffer used to dilute the enzyme and substrate mixtures contained 50 mM HEPES, pH 7.5, 10 mM MnCl 2, 1 mM DTT, 100 μM sodium vanadate, 100 μM NaF, 10 mM sodium glycerophosphate, BSA (1 mg / ml final).

Test substrate In this test, only part of the retinoblastoma protein was used (Science 1987, Mar 13; 235 (4794): 1394-1399; Lee WH, Bookstein R., Hong F., Young LJ, Shew JY, Lee EY), merged into a GST tag. PCR was carried out on the amino acids encoding the retinoblastoma gene 379-928 (obtained from the retinoblastoma plasmid ATCC pLRbRNL), and the sequence was cloned into a pGEx 2T fusion vector (Smith BLOCKS DIAGRAM and Johnson, KS Gene 67, 31 (1988), which contained a tac activator for inducible expression, the internal lac lq gene for use in any E. coli host, and a coding region for thrombin cleavage - obtained at from Pharmacia Biotech) that was used to amplify amino acids 792-928. This sequence was cloned again in pGEx 2T. The retinoblastoma sequence 792-928 thus obtained was expressed in E. coli (cells BL21 (DE3) pLyS) using conventional inducible expression techniques, and purified in the following manner. The E. coli paste was resuspended in 10 ml / g of NETN regulator (50mM Tris, pH 7.5, 120mM NaCl, I mM EDTA, NP-40 0.5% v / v, 1mM PMSF, 1 ug / ml of leupeptin, 1 ug / ml of aprotinin and 1 ug / ml of pepstatin) and sonified for 2 * 45 seconds per 100 ml of homogenate. After centrifugation, the supernatant was loaded onto a 10 ml Sepharose column of glutathione (Pharmacia Biotech, Herts, UK), and rinsed with NETN regulator. After rinsing with kinase regulator (50mM of HEPES, pH 7.5, 10 mM MgCl2, 1 mM DTT, 1 mM PMSF, 1 ug / ml leupeptin, 1 ug / ml aprotinin and 1 ug / ml pepstatin) the protein was eluted with 50 mM glutathione Reduced in kinase regulator. Fractions containing GST-Rb (792-927) were deposited and dialyzed overnight against the kinase regulator. The final product was analyzed by Sodium Dodecasulfate (SDS -Sodium Dodeca Sulfate) PAGE (polyacrylamide gel) using 8-16% Tris-glycine gels (Novex, San Diego, USA).

CDK2 v Cyclin E The open reading frames of CDK2 and Cyclin E were isolated by reverse transcriptase-PCR using HeLa cells and T cell-activated mRNA as template and cloned into the insect expression vector pVL1 393 (obtained from Invitrogen number of catalog 1995: V1 392-20). Then, CDK2 and cyclin E were expressed twice [using a conventional coinfection technique with Baculogold virus] in the insect cell system SF21 (Spodoptera Frugiperda cells derived from the ovarian tissue of the gardama - commercially available).

Exemplary production of cyclin E / CDK2 The following example provides details of the production of Cyclin E / CDK2 in SF21 cells (in TC100 + FBS (TCS) at 10% + 0.2% Pluronic) having double infection MOI 3 for each Cyclin E and CDK 2 virus. SF21 cells grown in a roller bottle culture at 2.33 06 cells / ml were used to inoculate 10 * 500 ml of roller bottles at 0.2 * 10E6 cells / ml. The rolling bottles were incubated in a rolling sounding at 28 ° C. After 3 days (72 hrs.) The cells were counted, and it was found that the average of the 2 bottles was 1.86 * 10E6 cells / ml. (99% viable). The cultures were then infected with the double viruses in an MOI 3 for each virus. The viruses were mixed together before the addition of the cultures, and the cultures returned to the 28 ° C rolling probe. After 2 days (48 hrs.) After infection, 5 liters of culture were harvested. The total cell count harvested was 1.58 * 10E6 cells / ml (99% viable). The cells rotated at 2500rpm, 30 minutes, 4 ° C in Heraeus Omnifuge 2.0 RS at intervals of 250 mi. The supernatant was discarded.

Partial Copurification of CDK2 and Cyclin E SF21 cells were resuspended in a lysis buffer (50 mM Tris, pH 8.2, 10 mM MgCl2, 1 mM DTT, 10 mM glycerophosphate, 0.1 mM sodium orthovanadate, 0.1 mM NaF, 1 mM PMSF, 1 ug / ml leupeptin and 1 ug / ml aprotinin) and homogenized for 2 minutes in Dounce homogenizer of 10 ml. After centrifugation, the supernatant was loaded onto a Poros HQ / M 1.4 / 100 anion exchange column (PE Biosystems, Hertford, UK). CDK2 and Cyclin E were co-eluted at the start of a gradient of 0-1 M NaCl (tested in the lysis buffer minus the protease inhibitors) on 20 column volumes. Coelution was verified by Western blot using anti-CDK2 and anti-Cyclin E antibodies (Santa Cruz Biotechnology, California, US).

By analogy, tests designed to assess the inhibition of CDK1 and CDK4 can be constructed. CDK2 (EMBL Accession No. X62071) may be used in conjunction with Cyclin A or Cyclin E (see EMBL Accession No. M73812), and additional details for such tests are included in PCT International Publication No. WO99 / 21845, relevant sections of Biochemical and Biological Evaluation which are incorporated herein by reference. Although the pharmacological properties of the compounds of the formula (I) vary with the structural change, in general, the activity possessed by the compounds of the formula (I) can be demonstrated at concentrations of I C50 or doses in the range of 250μM to 1. nM. When tested in the aforementioned in vitro test, the inhibitory activity of CDK2 of the CDK2 enzyme of Example 2 is 0.09 μM.

In vivo activity The in vivo activity of the compounds of the present invention can be evaluated by conventional techniques, for example, by measuring the inhibition of cell growth and by evaluating cytotoxicity. Inhibition of cell growth can be measured by staining cells with Sulforhodamine B (SRB), a fluorescent dye that stains proteins, and therefore, delivers a calculation of the amount of protein (i.e., cells) in a cell (see Boyd, MR ( 1989) Status of the NCI preclinical antitumour drug discovery screen (State of the discovery examination of preclinical antitumor drugs NCI), Prin. Prac Oncol 10: 1-12). Accordingly, the following details are provided to measure the inhibition of cell growth. Cells can be coated in an appropriate medium in a volume of 100ml in 96-well plates; the medium can be DMEM (Dulbecco's Modified Eagle Media) for MCF-7, SK-UT-1. The cells can bind overnight, then the inhibitor compounds added in various concentrations at a maximum concentration of 1% DMSO (v / v). A control plate can be tested to deliver a value for the cells before dosing. The cells can be incubated at 37 ° C, (5% CO2) for three days. At the end of the three days, TCA can be added to the plates at a final concentration of 16% (v / v). The plates can be incubated at 4 ° C for 1 hour, the supernatant can be removed and the plates rinsed in tap water. After drying, 100 ml of SRB dye (0.4% SRB in 1% acetic acid) can be added for 30 minutes at 37 ° C. The excess SRB can be extracted and the plates rinsed in 1% acetic acid. The SRB bound to the protein can be solubilized in 10mM Tris, pH 7.5 and stirred for 30 minutes at room temperature. The ODs can be read at 540nm, and the concentration of the inhibitor that causes a 50% inhibition of the growth determined from a semilogarithmic graphical representation of inhibitor concentration against absorbency. The concentration of compound that reduced the optical density below that obtained when the cells were coated at the beginning of the experiment should yield the value of the toxicity. Typical values of IC50 for the compounds of the invention when tested in the SRB test should be in the range of 1 mM to 1 nM. According to a further aspect of the invention, there is provided a pharmaceutical composition which comprises a pyrimidine derivative of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined above in the present in association with a pharmaceutically acceptable diluent or carrier. The composition may have a form suitable for oral administration, for example, as a tablet or capsule, for parenteral injections (including intravenous, subcutaneous, intramuscular, intravascular or infusions) as a sterile solution, suspension or emulsion, for topical administration as an ointment. or cream or for rectal administration as a suppository. In general, the aforementioned compositions can be prepared in a conventional manner using conventional excipients. The compound of the formula (I) will normally be administered to a warm-blooded animal at a unit dose in the range of 5-5000 mg per square meter of animal body area, i.e., about 0.1 -100 mg / kg, and this usually provides a therapeutically effective dose. A unit dosage form such as a tablet or capsule will generally include, for example, 1-250 mg of active ingredient. Preferably a daily dose in the range of 1-50 mg / kg is used. However, the unit dose will necessarily vary depending on the host treated, the particular route of administration, and the severity of the disease to be treated. In accordance with the above, the optimal dose can be determined by the attending physician who is treating the patient. According to a further aspect of the present invention, there is provided a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein above for use in a method of treatment of the human or animal body by therapy. We have discovered that the compounds defined in the present invention, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, are effective cell cycle inhibitors (cell antiproliferative agents), whose property is considered to derive from their CDK inhibitory properties. In accordance with the foregoing, it is expected that the compounds of the present invention will be useful in the treatment of diseases or medical conditions mediated alone or in part by CDK enzymes., ie, the compounds can be used to produce a CDK inhibitory effect in a warm-blooded animal in need of such treatment. Accordingly, the compounds of the present invention provide a method for treating the proliferation of malignant cells characterized by the inhibition of CDK enzymes, ie, the compounds can be used to produce an antiproliferative and potentially apoptotic effect mediated alone or in part by inhibition. of the CDKs. Particularly, an inhibitory effect is produced by preventing the entry into or progress through the S phase by the inhibition of CDK2, CDK4 and / or CDK6, especially CDK2 and the entry into or progress through the M phase by the inhibition of CDK1. The apoptotic effects can also be considered through the sub-regulation of RNA polymerase I I activity by the inhibition of CDK1, CDK7, CDK8 and in particular, CDK9. It is expected that such a compound of the invention possesses a wide range of anticancer properties since CDKs have been involved in very common human cancers such as leukemia and breast, lung, colon, rectal, stomach, prostate cancer, bladder, pancreas and ovaries. Consequently, it is expected that a compound of the invention possesses anti-cancer activity against these cancers. It is also expected that a compound of the present invention possesses activity against a range of leukemias, malignant lymphoid tumors and solid tumors such as carcinomas and sarcomas in tissues such as liver, kidney, prostate and pancreas. In particular, it is expected that such compounds of the invention advantageously decrease the growth of recurrent primary and solid tumors of, for example, colon, breast, prostate, lung and skin. More particularly, it is expected that such compounds of the invention, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, inhibit the growth of those recurrent primary and solid tumors which are associated with CDKs, especially those tumors that are significantly dependent on CDKs for their growth and dispersion, including, for example, some tumors of the colon, breast, prostate, lung, vulva and skin. A compound of the present invention is also expected to possess activity against other cell proliferation diseases in a wide range of other disease states including leukaemias, fibroproliferative and differentiation disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute nephropathies and chronic, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, water and chronic inflammation, bone diseases and ocular diseases with proliferation of retinal vessels. Accordingly, according to this aspect of the invention, there is provided a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinabove for use as a medicament. In a further aspect of the invention, there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as hereinafter defined in the manufacture of a medicament. for use in the production of a cell cycle inhibitory effect. In one aspect of the invention, when speaking of a cell cycle inhibitory effect it refers to the inhibition of CDK1. In a further aspect of the invention, this relates to the inhibition of CDK2. In a further aspect of the invention, this relates to the inhibition of CDK4. In a further aspect of the invention, this relates to the inhibition of CDK5. In a further aspect of the invention, this relates to the inhibition of CDK6. In a further aspect of the invention, this relates to the inhibition of CDK7. In a further aspect of the invention, this relates to the inhibition of CDK8. In a further aspect of the invention, this refers to the inhibition of CDK9. In a further aspect of the invention, there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as hereinafter defined in the manufacture of a medicament. for use in the production of a cellular antiproliferation effect. In a further aspect of the invention, there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as hereinafter defined in the manufacture of a medicament. for use in the production of a CDK2 inhibitory effect. In a further aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinabove in the manufacture of a medicament for its use in the treatment of cancer. In a further aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinabove in the manufacture of a medicament for its use in the treatment of leukemia or malignant lymphoid tumors or cancer of breast, lung, colon, rectum, stomach, liver, kidney, prostate, bladder, pancreas, vulva skin or ovaries. According to a further feature of the invention, there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as hereinafter defined in the manufacture of a medicine for use in the treatment of cancer, fibroproliferative and differentiation disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, water and chronic inflammation, bone diseases and ocular diseases with proliferation of retinal vessels. In a further aspect of the invention there is provided a method for producing a cell cycle inhibitory effect, in a warm-blooded animal in need of such treatment, which comprises administering to the animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinabove herein. In a further aspect of the invention there is provided a method for producing a cell antiproliferation effect in a warm-blooded animal in need of such treatment, which comprises administering to the animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinabove. In a further aspect of the invention, there is provided a method for producing a CDK2 inhibitory effect, in a warm-blooded animal in need of such treatment, which comprises administering to the animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein above. In a further aspect of the invention, there is provided a method of treating cancer, in a warm-blooded animal in need of such treatment, which comprises administering to the animal an effective amount of a compound of the formula (I) or a salt pharmaceutically acceptable or in vivo hydrolysable ester thereof, as defined hereinbefore. In a further aspect of the invention, there is provided a method for treating leukemia or malignant lymphoid tumors or cancers of the breast, lung, colon, rectum, stomach, liver, kidney, prostate, bladder, pancreas, vulva, skin or ovaries, in a warm-blooded animal in need of such treatment, which comprises administering to the animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein above. In a further aspect of the invention, a method is provided for treating cancer, fibroproliferative and differentiation disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, inflammation water and chronic, bone diseases and eye diseases with proliferation of the retinal vessels, in a warm-blooded animal in need of such treatment, which comprises administering to the animal an effective amount of a compound of the formula (I) or a pharmaceutically salt acceptable or in vivo hydrolysable ester thereof, as defined hereinbefore. In a further aspect of the invention, there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein above and a diluent or pharmaceutically acceptable vehicle. In a further aspect of the invention, there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein above and a diluent or pharmaceutically acceptable vehicle for use as a medicine. In a further aspect of the invention, there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein above and a diluent or pharmaceutically acceptable carrier for use in the production of a cell cycle inhibitory effect. In a further aspect of the invention, there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein above and a diluent or pharmaceutically acceptable carrier for use in the production of a cellular antiproliferative effect. In a further aspect of the invention, there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein above and a diluent or pharmaceutically acceptable carrier for use in the production of a CDK2 inhibitory effect. In a further aspect of the invention, there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein above and a diluent or pharmaceutically acceptable vehicle for use in the treatment of cancer. In a further aspect of the invention, there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein above and a diluent or pharmaceutically acceptable vehicle for use in the treatment of leukemia or malignant lymphoid tumors or cancer of the breast, lung, colon, rectum, stomach, liver, kidney, prostate, bladder, pancreas, vulva, skin or ovaries. In a further aspect of the invention, there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein above and a diluent or pharmaceutically acceptable vehicle for use in the treatment of cancer, fibroproliferative disorders fibroproliferative and differentiation disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with proliferation of retinal vessels. In a further aspect of the invention, there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinabove, in the production of a inhibiting effect of the cell cycle. In a further aspect of the invention, there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinabove, in the production of a effect of cellular antiproliferation. In a further aspect of the invention, there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinabove, in the production of a inhibitory effect of CDK2. In a further aspect of the invention, there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinabove, in the treatment of cancer . In a further aspect of the invention, there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinabove, in the treatment of the leukemia or malignant lymphoid tumors or cancer of the breast, lung, colon, rectum, stomach, liver, kidney, prostate, bladder, pancreas, vulva, skin or ovaries. According to a further feature of the invention, there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinabove in the treatment of cancer, fibroproliferative and differentiation disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with proliferation of retinal vessels . Preventing cells from entering DNA synthesis by inhibiting S phase start activities such as the initiation of CDK2 may also be useful in protecting normal cells of the body against the toxicity of cycling pharmaceutical agents specific. The inhibition of CDK2 or 4 will prevent the progress towards the cell cycle in normal cells which could limit the toxicity of the specific cycle pharmaceutical agents that act in the S, G2 phase or mitosis. Such protection can result in preventing the hair loss normally associated with these agents. Therefore, in a further aspect of the invention, there is provided a compound of the formula (I) as defined above or a pharmaceutically acceptable salt or hydrolyzable ester thereof in vivo thereof for use as a cellular protective agent. Therefore, in a further aspect of the invention, there is provided a compound of the formula (I) as defined above or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for use in combating the fall of the hair resulting from the treatment of neoplastic diseases with pharmaceutical agents. Examples of pharmaceutical agents for treating neoplastic conditions known to cause hair loss include alkylating agents such as ifosfamide and cyclophosphamide.; antimetabolites such as methotrexate, 5-fluorouracil, gemcitabine and cytarabine; vinca alkaloids and the like such as vincristine, vinblastine, vindesine, vinorelbine; taxanes such as paclitaxel and docetaxel; topoisomera I inhibitors such as irintotecan and topotecan; cytotoxic inhibitors such as doxorubicin, daunorubicin, mitoxantrone, actinomycin-D and mitomycin; and others such as etoposide and tretinoin. In another aspect of the invention, the compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, may be administered in association with one or more of the aforementioned pharmaceutical agents. In this case, the compound of the formula (I) can be administered by systemic or non-systemic means. Particularly, the compound of the formula (I) can be administered by non-systemic means, for example, by topical administration. Therefore, in a further feature of the invention, there is provided a method for preventing hair loss during treatment for one or more neoplastic conditions with pharmaceutical agents, in a warm-blooded animal, such as humans, which comprises administering to the animal an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or hydrolysable ester in vivo thereof. In a further feature, there is provided a method of preventing hair loss during treatment for one or more neoplastic conditions with pharmaceutical agents, in a warm-blooded animal, such as humans, which comprises administering to the animal an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof in simultaneous, sequential or separate administration with an effective amount of the pharmaceutical agent. According to a further aspect of the invention, there is provided a pharmaceutical composition for use in combating hair loss caused by the treatment of neoplastic conditions with pharmaceutical agents which comprises a compound of the formula (I), or a pharmaceutically acceptable salt or hydrolysable ester in vivo thereof, and the pharmaceutical agent, in association with a pharmaceutically acceptable diluent or carrier. According to a further aspect of the present invention, there is provided a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, and a pharmaceutical agent for treating known neoplastic conditions. for causing hair loss. According to a further aspect of the present invention, there is provided a kit comprising: a) a compound of the formula (I), or a pharmaceutically acceptable salt or hydrolysable ester in vivo thereof, in a first unit dose form; b) a pharmaceutical agent for treating neoplastic diseases known to cause hair loss; in a second unit dose form; and c) container means for containing said dosage unit forms is first and second. According to another feature of the invention, there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or hydrolysable ester in vivo thereof, in the manufacture of a medicament for combating hair loss during the treatment of neoplastic diseases with pharmaceutical agents. According to a further aspect of the present invention, there is provided a combination treatment for combating hair loss comprising the administration of an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or hydrolyzable ester in alive therefrom, optionally together with a pharmaceutically acceptable diluent or carrier, with simultaneous, sequential or separate administration of an effective amount of pharmaceutical agent for the treatment of neoplastic conditions in a warm-blooded animal, such as human beings. As stated previously, the size of the dose required for the therapeutic or prophylactic treatment of a particular cell proliferation disease will necessarily vary depending on the host treated, the route of administration and the severity of the disease to be treated. A unit dose is conceivable in the range, for example, of 1-100 mg / kg, preferably 1-50 mg / kg. The CDK inhibitory activity defined hereinbefore may be applied as a single therapy or may involve, in addition to a compound of the invention, one or more of the other substances and / or treatments. Such joint treatment can be achieved by the simultaneous, sequential or separate administration of the individual components of the treatment. In the field of medical oncology it is normal practice to use a combination of different forms of treatment in order to treat each patient with cancer. In medical oncology, the other components of such joint treatment in addition to the cell cycle inhibitor treatment defined hereinbefore may be: surgery, radiotherapy or chemotherapy. Such chemotherapy can cover three main categories of the therapeutic agent: (i) other cell cycle inhibitory agents that function by the same or different mechanisms from those defined above in the present; (ii) cytostatic agents such as antiestrogens (e.g., tamoxifen, toremifen, raloxifen, droloxifen, yodoxifen), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrazola, vorazole, exemestanate), antiprogestogens , antiandrogens (eg, flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH agonists and antagonists (eg, goserelin acetate, leuprorrelin), testosterone 5a-hydroreductase inhibitors (eg, finasteride), anti-invasion agents (eg, example, metalloproteinase inhibitors such as marimastat and inhibitors of the receptor function of the urokinase plasminogen activator) and inhibitors of growth factor function (such growth factors include, for example, platelet-derived growth factor and hepatocyte growth factor , such inhibitors include growth factor antibodies, cre factor receptor antibodies, foundation, tyrosine kinase inhibitors and serine / threonine kinase inhibitors); and (iii) antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as antimetabolites (for example, antifolates such as methotrexate, fluoropyrimidines such as 5-fluoroacyl, purine and adenosine analogs, cytosine arabinoside); antitumor antibodies (eg, anthracyclines such as doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, mithramycin), platinum derivatives (eg, cisplatin, carboplatin); alkylating agents (eg, nitrogen mustard, melaphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic agents (for example, vinca alkaloids such as vincristine and taxoids such as taxol or taxoter) topoisomerase inhibitors (for example, epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan). According to this aspect of the invention, there is provided a pharmaceutical product comprising a compound of the formula (I) defined hereinbefore and an additional antitumor substance as defined hereinabove for the joint treatment against cancer . In addition to their use in therapeutic medicine, the compounds of the formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardization of the in vitro and in vivo test systems for the evaluation of the effects of Inhibitors of cyclocellular activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents. In the other pharmaceutical compositions, processes, methods, uses and manufacturing features of the aforementioned medicament, the alternative and preferred embodiments of the compounds of the invention described herein also apply.

EXAMPLES The invention will now be illustrated by the following non-limiting examples in which, unless otherwise specified: (i) temperatures are determined in degrees centigrade (° C); the operations were carried out at room temperature, that is, at a temperature in the range of 18-25 ° C; (ii) the organic solutions were dried over anhydrous magnesium sulfate; the evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (600-4000 pascals, 4.5-30 mm Hg) with a bath temperature of up to 60 ° C; (iii) chromatography means flash chromatography a silica gel; Thin layer chromatography (TLC) was carried out on silica gel plates; (iv) in general, the course of the reactions was followed by the TLC and the reaction times are determined only for illustration; (v) the final products had satisfactory spectra of proton nuclear magnetic resonance (NMR) and / or mass spectral data; (vi) the returns are determined solely for purposes of illustration and are not necessarily those that can be obtained by a diligent development of the process; the preparations were repeated if more material was required; (vii) when it is, the NMR data in the form of delta values for the main diagnostic protons are determined in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using its perdeuterium dimethyl oxide (DMSO-d6) as a solvent unless otherwise indicated; (viii) chemical symbols have their usual meanings; SI units and symbols are used; (ix) the solvent ratios are determined in terms of volume: volume (v / v); and (x) mass spectra were tested with an electron energy of 70 volts electron in the mode of chemical ionization (Cl - chemical ionization) using a direct exposure probe; where the indicated ionization was effected by electronic impact (El -electronic impact), fast atomic bombardment (FAB - fast atom bombardment) or electrospray (ESP); the values for m / z are determined; generally, only the ions that indicate the original mass are reported; and unless stated otherwise, the mass ion note is (MH) +; (xi) unless otherwise indicated, the compounds containing an asymmetrically substituted carbon and / or sulfur atom have not been resolved; (xii) when a synthesis is described as analogous to that described in a previous example, the amounts used are the millimolar ratio equivalents to those used in the previous example; and (xvi) the following abbreviations have been used: MeOH methanol; DCM dichloromethane; DMSO dimethylsulfoxide; EDTA ethylenediaminetetraacetic acid; HBTU O-benzotriazole-1 -yl-? /,? /,? / ',? /' - tetramethyluronium hexafluorophosphate; DIPEA? /,? / - diisopropylethylamine; RPHPLC reverse phase high performance liquid chromatography; and Xanthphos 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene.

EXAMPLE 1 I4- (4-lmidazof 1,2-a1-pyridin-3-yl-pyrimidin-2-ylamino) -phenyl-morpholin-4-yl-methanone 4-imidazole [1, 2-a] was added pyridin-3-yl-pyrimidin-2-ylamine (Bioorganic &Medicinal Chemistry Letters 2004, 14 (9), 2245-2248) (0.20 g, 0.95 mmol), palladium acetate (9 mg, 0.038 mmol), Xanthphos ( 33 mg, 0.057 mmol), cesium carbonate (0.46 g, 1.4 mmol) and (4-iodo-phenyl) -morpholin-4-yl-methanone (Method 16a in WO 05/044814) (330 mg, 1. 05 mmol) to dioxane (7 ml) under an inert atmosphere and heated to reflux for 6 hours. Purification on silica using 0-10% MeOH in DCM as eluent delivered the main compound as a colorless foam. Further purification was achieved using RPHPLC to deliver a colorless foam (239 mg, 63%); 1 H NMR (400.1 32 MHz) 10.1 3 (d, 1 H), 9.89 (s, 1 H), 8.64 (s, 1 H), 8.48 (d, 1 H), 7.85 (d, 2 H), 7.79 ( d, 1 H), 7.52 (t, 1 H), 7.46 (d, 1 H), 7.43 (d, 2H), 7.16 (t, 1 H), 3.65-3.60 (m, 4H), 3.58-3.51 ( m, 4H); MH + 401.

Examples 2-17 The following compounds were prepared by the procedure of Example 1 using the appropriate raw materials.

Ex- NMR Compound M / z SM 17 (4-lsopropyl- (499.803 MHz, 373K) 9.65 (d, 470 4- (2-Methyl- [1,4] diazepam-1 H), 9.43 (s, 1 H) , 8.53 (d, imidazo [1, 2- 1 -yl) -. {4- [4- (2-1H), 7.79 (m, 2H), 7.59 (d, ajpyridin-3-methyl-1H ), 7.32 (d, 2H), 7.40 (m, il) -pyrimidine-imidazo [1, 2-1 H), 7.12 (d, 1 H), 6.96 (t, 1 H), 2-ylamine1; a] pipdin-3-yl) - 3.54 (m, 4H), 2.88 (m, 1 H), Method 12 pyrimidine-2- 2.62-2.70 (m, 7H), 1.73 (m, ylaminoj-phenyl). 2H), 0.98 (d, 6H) methanone Bioorganic & Medicinal Chemistry Letters 2004, 14 (9), 2245-2248.

Preparation of raw materials Method 1 (4-Bromo-2-methyl-phenyl) - (4-methyl-piperazin-1-yl) -methanone 4-Bromo-2-methylbenzoic acid (10 g, 46.5 mmol) and HBTU were dissolved (23 g, 60.5 mmol) in DMF (150 mL), then N-methyl piperazine (6.0 g, 60.5 mmol) and DI PEA (21 mL, 121 mmol) were added. The reaction was stirred overnight before the extraction of DMF in vacuo, the gum was quenched with 2.0 N NaOH (100 mL), extracted with diethyl ether (3 * 200 mL), dried (MgSO) and the solvent was extracted in vacuo to deliver a viscous gum. Purification on silica using 0-10% MeOH in DCM as eluent, delivered the main compound as a viscous oil. The oil was dissolved in the minimum amount of diethyl ether, iso-hexane was added to give a colorless solid which was filtered and dried (11.8 g, 86%); 1 H NMR (CDCl 3) 7.40 (s, 1 H), 7.36 (d, 1 H), 7.04 (d, 1 H), 3.86-3.79 (m, 2 H), 3.27-3.21 (m, 2 H), 2.51-2.45 (m, 2H), 2.32-2.29 (m, 8H); MH + 298.

Methods 2-8 Using the procedure described for Method 1, the following Methods 2-8 were prepared in a similar manner. 4-iodobenzoyl chloride (5 g, 0.019 mmol) and triethylamine (6.6 mL, 0.048 mol) were added to DCM (100 mL) and cooled to 0 ° C. To this was slowly added (S) -dimethylamino-pyrrolidine (2.2 g, 0.019 mol), the reaction was stirred for 1 hour, then the solvent was removed in vacuo at a volume of 90%. The obtained slurry was quenched with 2.0 M NaOH (50 mL), extracted with diethyl ether (3 * 200 mL), dried (MgSO4) and the solvent extracted in vacuo to yield a yellow solid. The diethyl ether was added and the system was sonicated for 10 minutes and filtered to deliver the main compound as an off-white solid (3.9 g, 60%); 1 H NMR (300.072 MHz, CDCl 3) 7.75 (d, 2 H), 7.25 (d, 2 H), 3.94-3.78 (m, 1 H), 3.66-3.25 (m, 3 H), 2.81 -2.62 (m, 1 H ), 2.30 (s, 3H), 2.21 (s, 3H), 2.16-2.02 (m, 1 H), 1 .97-1 .76 (m, 1 H); MH + 345.

Methods 10-12 Using the procedure described for Method 9, the following Methods 10-1 2 were prepared in a similar manner.

Method 1 3 1 -lsopropyl-1,4-diazepane 1,4-diazepane-1-carboxylate re-butyl ester (17 g) and acetone (10 g) were added to MeOH (150 mL) and stirred at 0 ° C. during 20 minutes. NaCNBH3 (6.4 g) was slowly added over a period of 20 minutes keeping the temperature below 0 ° C. After the complete addition, the reaction was allowed to warm to room temperature and if stirred for 56 hours. The reaction was concentrated in vacuo to yield a yellow residue. This was quenched with water (100 mL), extracted with ether (3 * 1 00 mL), dried and the solvent removed in vacuo to yield a clear viscous oil (20 g). The oil was added to TFA (50 mL) and DCM (50 mL), the reaction mixture was stirred for 16 hours before concentration in vacuo. The reaction was quenched with water (30 mL), potassium carbonate was added thereto until the aqueous was completely saturated, then it was extracted with EtOAc (3 * 200 mL), dried and the solvent was carefully extracted in vacuo. to deliver the main compound as a yellow oil (5.2 g); NMR (400.1 32 MHz, CDCl 3) 2.94-2.86 (m, 5H), 2.68-2.63 (m, 4H), 1.74-1.68 (m, 2H), 1.01 (d, 6H).

Example 18 The following representative pharmaceutical dosage forms containing the compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof (hereinafter, the X compound), for therapeutic or prophylactic use in humans humans: Note The aforementioned formulations can be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a) - (c) can be enterically coated by conventional means, for example, to provide a coating of cellulose acetate phthalate.

Claims (23)

1. CLAIMS A compound of Formula (I): (I) where: R1 is selected from halo, amino, C3-alkyl, d. 3alkoxy,? / - (C? .3alkyl) amino,? /,? / - (d.3alkyl) 2-amino and a saturated ring composed of 4-7 members attached to a nitrogen which optionally contains an additional nitrogen atom , oxygen or sulfur; m is 0-4; where the values of R1 may be the same or different; R2 is selected from hydrogen, halo, amino, d -3alkyl and C1-3alkoxy; R3 is hydrogen or halo; R 4 is hydrogen, ethynyl, halo, cyano, hydroxy, amino, mesyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl or methoxy; Ring A is a saturated ring composed of 4-7 members attached to nitrogen which optionally contains an additional nitrogen, oxygen or sulfur atom; where if said ring contains an additional nitrogen atom that nitrogen can be optionally substituted by R 6. R5 is a carbon substitute and is selected from halo, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, sulfamoyl, C1 -6alkyl, C2.6alkenyl, C2.6alkynyl, d -6alkanoyl,? / - (d- 6alkyl) carbamoyl,? /,? / - (d.6alkyl) 2carbamoyl, C? .alkylS (O) where a is 0 to 2, d.6alkoxycarbonyl,? / - (C? -6alkyl) sulphamoyl and? /, ? / - (d-6alkyl) 2-sulphamoyl; wherein R5 independently can optionally be substituted on carbon by one or more R7; or R5 is -N H R8, -NR9R1 0 or -O-R1 1; n is 0-4; where the values of R5 may be the same or different; R6 is selected from d.6alkyl, d.6alcanoyl, d. 6alkylsulfonyl, d.6alkoxycarbonyl, carbamoyl,? / - (d.6alkyl) carbamoyl and? /,? / - (C 1-6alkyl) carbamoyl; where R6 can optionally be substituted on carbon with one or more R12; R8, R9, R10 and R1 1 are independently selected from d.4alkyl, d.4alkanoyl, d. alkylsulfonyl, C2. alkenylsulfonyl, C2. 4-alkynylsulfonyl, d.4-alkoxycarbonyl, carbamoyl,? / - (C ?. 4alkyl) carbamoyl and? /,? / - (d.4alkyl) carbamoyl, carbocyclyl and heterocyclyl; where R8, R9, R10 and R1 can be optionally substituted independently on carbon by a group selected from R13; and wherein if the heterocyclyl contains a residue of -NH- that nitrogen can be optionally substituted by R 14; R13 is selected from halo, cyano, hydroxy, amino, trifluoromethyl, trifluoromethoxy, C1-3alkyl and d.3alkoxy; R14 is selected from C1 -3alkyl, d.3alkanoyl, d. 3-alkylsulfonyl, C 1-3 alkoxycarbonyl, carbamoyl, β / - (C 1-3 alkyl) carbamoyl and β /, γ / - (d.3 alkyl) carbamoyl; and R7 and R12 are independently selected from halo, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino,? -methyl-? / - ethylamino, acetylamino,? / - methylcarbamoyl,? / - ethylcarbamoyl,? /,? / - dimethylcarbamoyl,? /,? / - diethylcarbamoyl,? / - methyl -? / - ethylcarbamoyl, methylthio, ethylthio, methylisulfinyl, etiisulfinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl,? / - methylsulfamoyl,? / - ethylsulphamoyl, N, N-dimethylsulphamoyl,? /,? / - diethylsulphamoyl and? / - methyl-? / - ethylsulphamoyl; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
2. 2. A compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, according to claim 1, wherein m is 0.
3. 3. A compound of the formula (I), or a salt pharmaceutically acceptable or an in vivo hydrolysable ester thereof, according to claim 1 or claim 2, wherein R2 is selected from hydrogen or C1-3 alkyl.
4. 4. A compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, according to any of claims 1-3, wherein R3 is hydrogen.
5. 5. A compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, according to any of claims 1-4, wherein R4 is hydrogen, halo or methyl. 6. A compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, according to any of claims 1-5, wherein ring A is a saturated ring composed of 5-7 bound members to nitrogen which optionally contains an additional nitrogen or oxygen atom, where if the ring contains an additional nitrogen atom that nitrogen can be optionally substituted by R6; where R6 is d. 6alkyl A compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, according to any of claims 1-6, wherein R5 is a carbon substitute and is selected from -NR9R10; where R9 and R10 are independently selected from C1-alkyl. 8. A compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, according to any of claims 1-7, wherein n is 0 or 1. 9. A compound of the formula (I): (I) pharmaceutically acceptable or an in vivo hydrolysable ester thereof, according to any of claims 1-4, wherein R4 is hydrogen, halo or methyl.
6. 6. A compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, according to any of claims 1-5, wherein ring A is a saturated ring composed of 5-7 bound members to nitrogen which optionally contains an additional nitrogen or oxygen atom, where if the ring contains an additional nitrogen atom that nitrogen can be optionally substituted by R6; where R6 is d-6alkyl. A compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, according to any of claims 1-6, wherein R5 is a carbon substitute and is selected from -NR9R10; where R9 and R1 0 are independently selected from C ?. I rent. 8. A compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, according to any of claims 1-7, wherein n is 0 or 1. 9. A compound of the formula (I): (I) where: m is 0; R2 is selected from hydrogen or d-3alkyl; R3 is hydrogen; R 4 is hydrogen, halo or methyl; Ring A is pyrrolidin-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl or 4-isopropylhomopiperazin-1-yl or morpholino; R5 is a carbon substitute and is diethylamino; n is 0 or 1; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 10. A compound of the formula (I): (I) selected from: [4- (4-imidazo [1,2-a] pyrimidin-3-yl-pyrimidin-2-ylamino) -phenyl] -morpholin-4-yl-methanone; [4- (4-imidazo [1,2-a] pyrimidin-3-yl-pyrimidin-2-ylamino) -phenyl] - (4-methyl-piperazin-1-yl) -methanone; [4- (4-imidazo [1,2-a] pyrimidin-3-yl-pyrimidin-2-ylamino) -2-methyl-phenyl] - (4-methyl-piperazin-1-yl) -methanone; [2-fluoro-4- (4-imidazo [1,2-a] pyridin-3-yl-pyrimidin-2-ylamino) -phenyl] - (4-methyl-piperazin-1-yl) -methanone; [4- (4-imidazo [1,2-a] pyridin-3-yl-pyrimidin-2-ylamino) -2-methyl-phenyl] -morpholin-4-yl-methanone; [2-f I uoro-4- (4-imidazole [1, 2-a] pyridin-3-yl-p-r, m-di n-2-ylamin ojien il] -morpholin-4-yl -metanone; ((S) -3-dimethylamino-pyrrolidin-1-yl) - [4- (4-imidazo [1,2- a] pyridin-3-yl-pyrimidin-2-ylamino) -phenyl] -metanone; ((S) -3-dimethylamino-pyrrolidin-1-yl) - [2-fluoro-4- (4-imidazo [1, 2-a] pyridin-3-yl-pyrimidin-2-ylamino) -phenyl] -metanone; ((S) -3-dimethylamino-pyrrolidin-1-yl) -4- (4-imidazo [1,2-a] pyridin-3-yl-pyrimidin-2-ylamino) -2-methyl-phenyl ] -methanone; ((R) -3-dimethylamino-pyrrolidin-1 -yl) - [4- (4-imidazo [1,2- a] pyridin-3-yl-pyrimidin-2-ylamino) -phenyl] - methanone; ((R) -3-dimethylamino-pyrrolidin-1-yl) - [2-fluoro-4- (4-imidazo [1, 2-a] pyridin-3-yl-pyrimidin-2-ylamino) -phenyl ] -metanone; ((R) -3-d-imethylamino-non-pyrro-lidin-1-yl) - [4- (4-imidazo [1, 2-a] pyridin-3-yl-pyrimidin-2-ylamino) -2-methyl-phenyl] -methanone; [4- (4-imidazo [1,2-a] pyridin-3-yl-pyrimidin-2-ylamino) -phenyl] - (4-methyl- [1,4] diazepan-1-yl) -metanone; {. 4- [4- (2-methyl-imidazo [1,2-a] pyridin-3-yl) -pyrimidin-2-ylamino] -phenyl}. 4-methyl-piperazin-1-yl) -methanone; (4-methyl- [1,4] diazepan-1 -yl) -. { 4- [4- (2-methyl-imidazo [1,2-a] pyridin-3-yl) -pyrimidin-2-ylamino] -phenyl} -metanone; ((S) -3-dimethylamino-pyrrolidin-1-yl) -. { 4- [4- (2-methyl-imidazo [1, 2-a] pyridin-3-yl) -pyrimidin-2-ylamino] -phenyl} -metanone; and (4-isopropyl- [1,4] diazepan-1-yl) -. { 4- [4- (2-methyl-imidazo [1,2-a] pyridin-3-yl) -pyrimidin-2-ylamino] -phenyl} -metanone; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. eleven . A process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof according to claim 1, which process comprises: the reaction of Process a) of a pyrimidine of the formula (II) ): gave) where L is a displaceable group; with an aniline of the formula (l l l) (III) Process b) reacting a compound of the formula (IV) (IV) with a compound of the formula (V): (V) where T is O or S; Rx may be the same or different and is selected from C1 -6alkyl; Process c) reacting an acid of the formula (VI): (SAW) or an activated acid derivative thereof, with an amine of the formula (VII): Process d) for compounds of formula (I); reacting a pyrimidine of the formula (VI II): (VHI) with a compound of the formula (IX): (IX) where Y is a displaceable group, and therefore, if necessary, i) converting a compound of the formula (I) to another compound of the formula (I); ii) eliminate any protective groups; iii) forming a pharmaceutically acceptable salt or hydrolysable ester in vivo. 12. A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, according to any of claims 1-10, and a pharmaceutically acceptable diluent or carrier. 13. A compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any of claims 1-10, for use as a medicament. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any of claims 1-10, in the manufacture of a medicament for use in the production of a effect of cellular antiproliferation. 15. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof according to any of claims 1-10, in the manufacture of a medicament for use in the production of a inhibitory effect of CDK2. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any of claims 1-10, in the manufacture of a medicament for use in the treatment of cancer . The use of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any of claims 1-10, in the manufacture of a medicament for use in the treatment of leukemia or malignant lymphoid tumors or cancers of the breast, lung, colon, rectum, stomach, liver, kidney, prostate, bladder, pancreas, vulva skin or ovaries. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any of claims 1-10, in the manufacture of a medicament for use in the treatment of cancer , fibropoliferative and differentiation disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic neuropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with proliferation of retinal vessels. 19. A method for producing a cell antiproliferation effect in a warm-blooded animal in need of such treatment, which comprises administering to the animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or hydrolysable ester in vivo thereof, according to any of claims 1 -10. 20. A method for producing a CDK2 inhibitory effect, in a warm-blooded animal in need of such treatment, which comprises administering to the animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or hydrolysable ester in vivo thereof, according to any of claims 1 -1 0. twenty-one . A method for treating cancer, in a warm-blooded animal in need of such treatment, which comprises administering to the animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or hydrolysable ester in vivo thereof , according to any of claims 1 -10. 22. A method to treat leukemia or malignant lymphoid tumors or breast cancer, lung, colon, rectum, stomach, liver, kidney, prostate, bladder, pancreas, vulva, skin or ovaries, in a warm-blooded animal in need of such treatment, which comprises administering to the animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any of claims 1-10. 23. A method to treat cancer, fibroproliferative and differentiation disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic neuropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and eye diseases with proliferation of retinal vessels, in a warm-blooded animal in need of such treatment, which comprises administering to the animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or hydrolysable ester in vivo thereof, according to any of claims 1-10.