MXPA06008866A - Pyridinyl - or pyrimidinyl thiazoles with protein kinase inhibiting activity - Google Patents

Abstract

The present invention relates to compounds of formula (I), or a pharmaceutically acceptable salts thereof, wherein:Z1:1 is N or CH;;Z2 and Z3 are each independently N or CR7;:Rl, R2, R3, R4, R5, R6, and R7 are each independently H, R8, or R9;each R8 is independently a hydrocarbyl group;and each R9 is independently halo,NO2, alkoxy, CN, CF3, S03H, SO2NR10R11, S02R12, NR13R14 (CH2)aCOOR15, (CH2)bCONR16R17, (CH2) CCOR18 or (CH2)dOH;a, b, c and d are each independently 0, 1 2 3 or 4;R10-18 are each independently H or alkyl;provided that when Rl and R2 are both H, Zl is CH;or Z2 is N;or Zl is CH and Z2 is N;and wherein the compound is other than 4-(4, 5-dimethylthiazol- 2-yl)-N-(3, 4, 5-trimethoxyphenyl)-2-pyrimidineamine or 4-(5- (2-hydroxyethyl)-4 -methylthiazol- 2-yl)-N-(3, 4, 5-trimethoxyphenyl) -2-pyrimidineamine. Further aspects relate to the use of compounds of formula (I) in the preparation of a medicament for treating one or more disorders selected from a proliferative disorder, a viral disorder, a CNS disorder, diabetes, stroke or alopecia.

Description

COMPOUNDS The present invention relates to substituted pyrimidine derivatives. In particular, the invention relates to aryl- (4-thiazol-2-yl-pyrimidin-2-yl) -amines and aryl- (4-thiazoI-2-yl-pyridin-2-yl) -amines and their use in therapy. More specifically, but not exclusively, the invention relates to compounds that are capable of inhibiting one or more protein kinases.

BACKGROUND OF THE INVENTION In eukaryotes, all biological functions, including DNA replication, cell cycle progression, energy metabolism, and cell growth and differentiation, are regulated through reversible protein phosphorylation. The phosphorylation status of a protein determines not only its function, subcellular distribution and stability, but also that other proteins or cellular components associate with it. The balance of specific phosphorylation in the proteome as a whole, as well as individual members in a biochemical pathway, is thus used by organisms as a strategy to maintain homeostasis in response to an ever changing environment. Enzymes that carry out these stages of phosphorylation and dephosphorylation are protein kinases and phosphatases, respectively. The eukaryotic protein kinase family is one of the largest in the human genome, comprising some 500 genes [1, 2]. Most kinases contain a catalytic domain of amino acid residue 250-300 with a conserved core structure. This domain comprises a binding cavity for ATP (less frequently GTP), whose terminal phosphate group, the kinase, is covalently transferred to its macromolecular substrates. The phosphate donor always binds as a complex with a divalent ion (usually Mg2 + or Mn2 +). Another important function of the catalytic domain is the binding and orientation for phosphotransferment of the macromolecular substrate. The catalytic domains present in most kinases are more or less homologous. A wide variety of molecules capable of inhibiting protein kinase function through antagonizing ATP binding are known in the art [3-7]. By way of example, the applicant has previously described 2-anilino-4-heteroaryl-pyrimidine compounds with kinase inhibitory properties, particularly against cyclin-dependent kinases (CDKs) [8-12]. CDKs are serine / threonine protein kinases that are associated with several cyclin subunits. These complexes are important for the regulation of eukaryotic cell cycle progression, but also for the regulation of transcription [13, 14]. The present invention seeks to provide aryl- (4-thiazol-2-yl-pyrimidin-2-yl) -amines and aryl- (4-thiazoI-2-yl-pyridin-2-yl) -amines. More specifically, the invention provides aryl- (4-thiazol-2-yl-pyrimidin-2-yl) -amines and aryl- (4-thiazol-2-yl-pyridin-2-yl) -amines having broad therapeutic applications. in the treatment of a number of different diseases and / or that are capable of inhibiting one or more protein kinases.

BRIEF DESCRIPTION OF THE INVENTION A first aspect of the invention relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof, 1 where: Z1 is N or CH; Z2 and Z3 are each independently N or CR7; R \ R2, R3, R4, R5, R6, and R7 are each independently H, R8, or R9; each R8 is independently a hydrocarbyl group; and each R9 is independently halo, NO2, alkoxy, CN, CF3, SO3H, SO2NR10R11, SO2R12, NR13R14, (CH2) aCOOR15, (CH2) bCONR16R17, (CH2) cCOR18 or (CH2) dOH; a, b, c and d are each independently 0, 1 2 3 or 4; R1 0"1 8 are each independently H or alkyl; provided that when R1 and R2 are both H, Z1 is CH; or Z2 is N; or Z is CH and Z2 is N; and wherein the compound is other than 4- (4,5-dimethylthiazol-2-yl) -N- (3,4,5-trimethoxyphenyl) -2-pyrimidineamine or 4- (5- (2-hydroxyethyl) -4) -meththiazol-2-yl) -N- (3,4,5-trimethoxyphenyl) -2-pyrimidineamine. A second aspect of the invention relates to a pharmaceutical composition comprising a compound of the formula I, or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically acceptable excipient, carrier or diluent. A third aspect of the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in medicine. A fourth aspect of the invention relates to the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating one or more of the following disorders: a proliferative disorder; a viral disorder; a CNS mess; diabetes; stroke; alopecia; an inflammatory disease; or an infectious disease. A fifth aspect of the invention relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in an assay to identify candidate compounds capable of inhibiting one or more of a cyclin-dependent kinase, aurora kinase, GSK and a PLK enzyme. A sixth aspect of the invention relates to a process for preparing compounds of the formula I.

DETAILED DESCRIPTION As used herein, the term "hydrocarbyl" refers to a cyclic, branched, or straight-chain, saturated or unsaturated group comprising at least C and H which may optionally comprise one or more suitable substituents. Examples of such substituents may include halo, CF3, OH, CN, NO2, SO3H, SO2NH2, SO2Me, NH2, COOH, and CONH2. If the hydrocarbyl group comprises more than one C then those necessary carbons do not necessarily bond with each other. For example, at least two of the carbons may be linked through a suitable group or element. In this way, the hydrocarbyl group can contain heteroatoms. Suitable heteroatoms will be apparent to those skilled in the art and include, for example, sulfur, nitrogen, oxygen, phosphorus and silicone. Where the hydrocarbyl group contains one or more heteroatoms, the hydrocarbyl group can be connected to the rest of the molecule through a carbon-carbon bond or a carbon-heteroatom bond. Preferably, the hydrocarbyl group is an aryl, alkyl, cycloheteroalkyl, cycloalkyl, heteroalkyl or heteroaryl group. More preferably still, the hydrocarbyl group is an aryl, alkyl or cycloheteroalkyl group. As used herein the term "alkyl" includes both straight and branched chain alkyl groups. The alkyl group can be substituted (mono- or poly-) or unsubstituted. Suitable substituents include, for example, halo, CF3, OH, CN, NO2, SO3H, SO2NH2, SO2Me, NH2, COOH, CONH2 and alkoxy. Preferably, the alkyl group is a C1-20 alkyl group, more preferably a C1-15 alkyl group, more preferably still a C1-12 alkyl group, more preferably still a d6 alkyl group, more preferably a C1 alkyl group. 3. Particularly preferred alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl. As used herein, the term "heteroalkyl" includes an alkyl group as defined above that comprises one or more heteroatoms. As used herein, the term "cycloalkyl" refers to a cyclic alkyl group that can be substituted (mono- or poly-) not substituted. Suitable substituents include, for example, halo, CF3, OH, CN, NO2, SO3H, SO2NH2, SO2Me, NH2, COOH, CONH2 and alkoxy. In the same way, the term "cycloheteroalkyl" refers to a cyclic heteroalkyl group which can be substituted (mono- or poly-) not substituted. Suitable substituents include, for example, halo, CF3, OH, CN, NO2, SO3H, SO2NH2, SO2Me, NH2, COOH, CONH2 and alkoxy. Cycloheteroalkyl groups include morpholino, piperazinyl and piperidinyl groups. As used herein, the term "aryl" refers to a C6-10 aromatic group, substituted (mono- or poly-) or unsubstituted, and includes, for example, phenyl, naphthyl, etc. Again, suitable substituents include, for example, halo, CF3, OH, CN, NO2, SO3H, SO2NH2, SO2Me, NH2, COOH, CONH2 and alkoxy. As used herein, the term "heteroaryl" refers to an aromatic group C. 0, substituted (mono- or poly-) or unsubstituted, comprising one or more heteroatoms. Preferred heteroaryl groups include pyrrole, pyrazole, pyrimidine, pyrazine, pyridine, quinoline, thiophene and furan. Again, suitable substituents include, for example, halo, CF3, OH, CN, NO2, SO3H, SO2NH2, SO2Me, NH2, COOH, CONH2 and alkoxy. In a preferred embodiment of the invention, each R8 is independently a C1-30 hydrocarbyl group, optionally containing up to twelve heteroatoms selected from N, S, and O, and optionally carrying up to six substituents each independently selected from halo, NO2, CN, CF3, SO3H, SO2NH2, SO2Me, OH, NH2, COOH, and CONH2. More preferably, each R8 is independently an alkyl group, an aryl group or a cycloheteroalkyl group.

Preferably, the cycloheteroalkyl group is morpholinyl, pyrrolidinyl or piperidinyl. Preferably, the cycloheteroalkyl group is N-morpholinyl, N-pyrrolidinyl or N-piperidinyl. In a preferred embodiment of the invention, each R9 is independently halo, NO2, alkoxy, CN, CF3, SO3H, SO2NH2, SO2Me, OH, N H2, (CH2) aCOOR15, (CH2) dOH, CONH2 or COR18. In a more preferred embodiment of the invention, each R9 is independently halo, NO2, alkoxy, CF3, SO3H, SO2NH2, SO2Me, OH, NH2, (CH2) aCOOR15, (CH2) dOH, CONH2 or COR18. In a more preferred embodiment of the invention, each R9 is independently halo, NO2, OMe, CF3, SO3H, SO2NH2, SO2Me, OH, NH2, CH2COOMe, COOMe, COOEt, (CH2) 2OH, CONH2 or COMe. In a preferred embodiment, R5 and R6 are both H and R1 '4 and R7 are each independently H, R8 or R9. In another preferred embodiment, wherein Z2 and Z3 are both CR7, at least one of R3, R4 and R7 is different from OMe. In a particularly preferred embodiment, R1 is H, alkyl, aryl, (CH2) aCOOR15 or OH; R2 is H, (CH2) dOH, (CH2) aCOOR15, COR18 or alkyl; R3 is halo, H, alkoxy, cycloheteroalkyl, alkyl or OH; R4 is H, NH2, OH, alkyl, CF3 or NO2; and R5 and R6 are both H. In a particularly preferred embodiment, R1 is H, Me, Ph, CH2COOMe or OH; R2 is H, (CH2) 2OH, COOEt, COMe or Me; R3 is Cl, H, OMe, N-morpholinyl, N-pyrroi idinyl, Me or OH; R4 is H, NH2, OH, Me, CF3 or NO2; and R5 and R6 are both H. In another particularly preferred embodiment, R1 is H, alkyl, aryl, (CH2) aCOOR15 or OH; R2 is H, COOR15, COR18 or alkyl; R3 is halo, H, alkoxy, morpholino, alkyl or OH; R4 is H, NH2, OH, CF3 or NO2; and R5 and R6 are both H. More preferably, for this embodiment, R1 is H, Me, Ph, CH2CO2Me or OH; R2 is H, CO2Et, COMe or Me; R3 is Cl, H, OMe, morpholino, Me or OH. A preferred embodiment of the invention relates to a compound of the formula I wherein Z1 is CH and Z2 and Z3 are each independently N or CR7. In a particularly preferred embodiment, Z2 and Z3 are each independently CR7. In a particularly preferred embodiment, Z1 is CH, and Z2 and Z3 are each independently CR7. In a preferred embodiment, when Z1 is CH and Z2 and Z3 are each independently CR7, R1 is alkyl or OH; R2 is alkyl or COR18; R3 is OH or halo; and Z2 and Z3 are both CH. More preferably still, R1 is Me or OH, R2 is COMe or Me, and R3 is OH or Cl. In a preferred embodiment, when Z1 is CH and Z2 and Z3 are each independently CR7 R1 is alkyl; R2 is COR18; R3 is OH; and Z2 and Z3 are both CH. More preferably still, R1 is Me and R2 is COMe. Another preferred embodiment of the invention relates to compounds of the formula I wherein Z1 is N and Z2 and Z3 are each independently N or CR7. In a particularly preferred embodiment, Z2 and Z3 are each independently CR7. In a more preferred embodiment, Z1 is N, and Z2 and Z3 are each independently CR7. More preferably, wherein Z1 is N and Z2 and Z3 are each independently CR7, R1 is alkyl, aryl, OH or (CH2) aCOOR15; R2 is COR18, H, COOR15 or alkyl; R3 is halo, H, OH, alkyl or morpholino; R4 is H, NH2, OH, CF3 or NO2; and Z2 and Z3 are both CH.

More preferably still, R1 is Me, Ph, OH or CH2COOMe; R2 is COMe, H, COOEt or Me; and R3 is halo, H, OH, alkyl or morpholino. Still another preferred embodiment of the invention relates to compounds of the formula I wherein Z2 is N and Z3 is CR7. In another preferred embodiment, Z1 is N, Z2 is N and Z3 is CR7. For this embodiment, more preferably, R1 is H, OH or alkyl; R2 'is H, (CH2) dOH, alkyl, (CH2) aCOOR15, COR18; R3 is halo, alkoxy or heterocycloalkyl; R 4 is H or alkyl; and Z3 is CH. For this embodiment, more preferably, R1 is H, OH or Me; R2 is H, (CH2) 2OH, Me, COOEt, COMe; R3 is halo, OMe or N-pyrrolidinyl; R4 is H or Me; and Z3 is CH. In another preferred embodiment, R1 is H or alkyl; R2 is H or COR18; R3 is halo or alkoxy; and Z3 is CH. More preferably still, R1 is H or Me; R2 is H or COMe; and R3 is halo or OMe. In an especially preferred embodiment, the compound of the formula I is selected from the following: 1 -. { 2- [2- (4-Chloro-phenylamino) -pyrimidin-4-yl] -4-methyl-thiazol-5-yl} -etanone (4-Chloro-phenyl) - [4- (4-methyl-thiazol-2-yl) -pyrimidin-2-yl] -amine (4-chloro-phenyl) - [4- (4-phenyl-thiazole-2 -yl) -pyrimidin-2-yl] -amine 2- [2- (4-Chloro-phenylamino) -pyrimidin-4-yl] -4-methyl-thiazole-5-carboxylic acid ethyl ester Methyl acid ester. { 2- [2- (4-Chloro-phenylamino) -pyrimidin-4-yl] -thiazoI-4-yl} -acetic acid ethyl ester 2- [2- (4-chloro-phenylamino) -pyrimidin-4-yl] -4-hydroxy-thiazole-5-carboxylic acid? / - [4- (4,5-D-methyl- thiazol-2-yl) -pyrimidin-2-yl] -benzene-1,3-diamine 3- [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-ylamino] -phenoyl [4 - (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (3-trifluoromethyl-phenyl) -amine (4-CIOR-3-trifluoromethyl-phenyl) - [4- (4,5 -dimethyl-tlazol-2-yl) -pyrimidin-2-yl] -amine [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (3-nitro-phenyl) - amine (6-methoxy-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine (6-chloro-pyridin-3-yl) - (4-thiazol-2-yl) -pyrimidin-2-yl) -amine 1 -. { 2- [2- (6-Chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -4-methyl-tlazol-5-yl} -etanone [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (6-methoxy-pyridin-3-yl) -amine (6-chloro-pyridin-3-yl) - [4- (4,5-dimethyl-thiazol-2-yl) -pyrimidin-2-yl] -amine [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (4-morpholin-4-yl-phenyl) -amine [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (4-methyl-3-nitro-phenyl) -amine 4- [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-ylamino] -phenol 2- [2- (4-chloro-phenylamino) -pyridin-4-yl] -5-methyl -thiazole-4-ol (6-pyrrolidin-1-yl-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine Ethyl ester of 2- [2- acid (6-Chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -4-hydroxy-thiazole-5-carboxylic acid 2- [2- (6-chloro-pyridin-3-ylamino) -pyrimidin-4-yl ] -5-methyl-thiazol-4-ol 2- [2- (6-chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -5- (2-hydroxy-etiI) -thiazole-4-ol (6-Chloro-5-methyl-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine. In a particularly preferred embodiment, the compound is selected from the following: 1-. { 2- [2- (4-Chloro-phenylamino) -pyrimidin-4-yl] -4-methyl-thiazol-5-yl} -etanone (4-Chloro-phenyl) - [4- (4-methyl-thiazol-2-yl) -pyrimidin-2-yl] -amine (4-chloro-phenyl) - [4- (4-phenyl-thiazole -2-yl) -pyrimidin-2-yl] -amine 2- [2- (4-Chloro-phenylamino) -pyrimidin-4-yl] -4-methyl-thiazole-5-carboxylic acid ethyl ester acid { 2- [2- (4-Chloro-phenylamino) -pyrimidin-4-yl] -thiazol-4-yl} -acetic 2- [2- (4-Chloro-phenylamino) -pyrimidin-4-yl] -4-hydroxy-thiazole-5-carboxylic acid ethyl ester / V- [4- (4,5-Dimethyl-thiazole- 2-yl) -pyrimidin-2-yl] -benzene-1,3-diamine 3- [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-ylamino] -phenol [4- ( 4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (3-trifluoromethyl-phenyl) -amine (4-Chloro-3-trifluoromethyl-phenyl) - [4- (4,5-dimethyl-thiazol-2-yl) -pyrimidin-2-yl] -amine [4- (4,5-Dimethyl-thiazole-2 -yl) -pyrimidin-2-yl] - (3-nitro-phenyl) -amine (6-methoxy-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine ( 6-Chloro-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine 1 -. { 2- [2- (6-Chloro-pyridyl-3-ylamino) -pyrimidin-4-yl] -4-methyl-thiazol-5-yl} -etanone [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (6-methoxy-pyridin-3-yl) -amine (6-chloro-pyridin-3-yl) - [4- (4,5-dimethyl-thiazol-2-yl) -pyrimidin-2-yl] -amine [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (4-morpholin-4-yl-phenyl) -amine [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (4-methyl-3-nitro-phenyl) -amine 4- [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-ylamino] -phenol More preferably, the compound of the formula I is selected from the following: 2- [2-ethyl] ethyl ester - (4-Chloro-phenylamino) -pyrimidin-4-yl] -4-hydroxy-thiazole-5-carboxylic acid; ? / - [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] -benzene-1,3-diamine 3- [4- (4,5-Dimethyl-thiazole-2- il) -pyrimidin-2-ylamino] -phenoI [4- (4,5-Dimethyl-tlazol-2-yl) -pyrimidin-2-yl] - (3-trifluoromethyl-phenyl) -amine (4-Chloro-3-trifluoromethyl-phenyl) - [4- (4,5-dimethyl-thiazol-2-yl) -pyrimidin-2-yl] -amine (6-methoxy-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine (6-chloro-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine [4- (4,5-Dimethyl-thiazol-2-yl) -pyrmidin-2-yl] - (6-methoxy-pyridin-3-yl) -amine 2- [2- (4-chloro-phenylamino) -pyridin -4-yl] -5-methyl-thiazol-4-ol (6-pyrroidin-1-yl-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine Ethyl ester 2- [2- (6-Chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -4-hydroxy-thiazole-5-carboxylic acid 2- [2- (6-chloro-pyridin-3-ylamino] ) -pyrimidin-4-yl] -5-methyl-thiazole-4-ol 2- [2- (6-Chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -5- (2-hydroxy-ethyl) -thiazole-4-ol (6-chloro-5-methyl-pyridine- 3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine. In a particularly preferred embodiment, the compound is selected from the following: 2- [2- (4-Chloro-phenylamino) -pyrimidin-4-yl] -4-hydroxy-thiazole-5-carboxylic acid ethyl ester; ? / - [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] -benzene-1,3-diamine 3- [4- (4,5-Dimethyl-thiazole-2- il) -pyrimidin-2-ylamino] -phenol [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (3-trifluoromethyl-phenyl) -amine (4-Chloro-3-trif luoromethyl-f in yl) - [4- (4,5-dimethyl-thiazol-2-yl) -pyrimidin-2-yl-amine (6-methoxy-pyridin-3-yl) - (4-tiazol-2-yl-pyrimidin-2-yl) -amine (6-chloro-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) - amine [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (6-methoxy-pyridin-3-yl) -amine More preferably still, the compound of the Formula I is selected from the following: 2- [2- (4-Chloro-phenylamino) -pyrimidin-4-yl] -4-hydroxy-thiazole-5-carboxylic acid ethyl ester; (6-Methoxy-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine; (6-Chloro-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine 2- [2- (4-Chloro-phenylamino) -pyridin-4-yl] -5 -methyl-thiazol-4-ol (6-pyrrolidin-1-yl-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine Ethyl ester of 2- [2- (6-Chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -4-hydroxy-thiazole-5-carboxylic acid 2- [2- (6-chloro-pyridin-3-ylamino) -pyrimidin-4-yl ] -5-methyl-thiazole-4-ol 2- [2- (6-Chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -5- (2-hydroxy-ethyl) -thiazole-4-ol (6-chloro-5-methyl-pyridine- 3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine In a particularly preferred embodiment, the compound is selected from the following: 2- [2- (4-Chloro- phenylamino) -pyrimidin-4-yl] -4-hydroxy-thiazole-5-carboxylic acid; (6-Methoxy-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine; (6-Chloro-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine. More preferably still, the compound is 2- [2- (6-chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -4-hydroxy-thiazole-5-carboxylic acid ethyl ester or 2- [2- (6-Chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -5- (2-hydroxy-ethyl) -thiazole-4-ol. In a highly preferred embodiment of the invention, the compound of formula I is (6-chloro-plridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine. In a preferred embodiment, the compound of the invention is capable of inhibiting one or more kinases selected from those set forth in Tables 5 or 6.

In a particularly preferred embodiment, the compound of the invention is capable of inhibiting one or more kinases selected from a cyclin or GSK dependent kinase. More preferably, the compound is capable of inhibiting one or more of GSK3, CDK2 / E, CDK2 / A, CDK1 / B, CDK4 / D1, CDK7 / H and / or CDK9 / T1. Preferably, the compound of the invention has an IC50 value for inhibition of one of the aforementioned kinases of less than 10 μM, more preferably, less than 5 μM, more preferably still, less than 1 μM, even more preferably less than 0.1 μM , more preferably still less than 0.01 μM, as measured by appropriate kinase assay. The details of suitable trials are underlined in the accompanying examples section. In a particularly preferred embodiment, the compound of the invention is capable of selectively inhibiting GSK (preferably GSK3) on one or more cyclin-dependent kinases selected from CDK2 / E, CDK2 / A, CDK1 / B, CDK4 / D1, CDK7 / H and CDK9 / T1. Preferably, the compound shows at least a selectivity of 5 times selectively for GSK on CDK, more preferably at least a selectivity of 10 times, more preferably at least at a selectivity of 1 00 times for GSK. In an especially preferred embodiment, the compound shows at least a selectivity of 1000 times for GSK on CDK, more preferably at least selectivity of 5000 times. In a particularly preferred embodiment, the compound shows at least a 1-fold selectivity for GSK3 on a CDK selected from CDK2 / cyclin E, CDK1 / cyclin B, CDK7 / cyclin H, CDK4 / cyclin D1, CDK2 / cyclin A and CDK9 / cyclin T1. In another particularly preferred embodiment, the compound shows at least a 1 00 fold selectivity for GSK3 on a CDK selected from CDK2 / cyclin E, CDK1 / cyclin B, CDK7 / cyclin H, CDK4 / cyclin D1 and CDK2 / cyclin A. In yet another particularly preferred embodiment, the compound shows at least a 1000-fold selectivity for GSK3 on a CDK selected from CDK1 / cyclin B, CDK7 / cyclin H, CDK4 / cyclin D1 and CDK2 / cyclin A. In another preferred embodiment, the compound of the invention is capable of activating cellular glycogen synthase activity. Preferably, the compound is capable of activating cellular glycogen synthase activity as measured by monitoring the induction of GS activity in HEK293 cells, mouse myocyte or mouse adipocyte at a time. Preferably, the GS activity is activated by at least 1.5 times, more preferably at least 2 times, more preferably at least 3 times, 4 times or 5 times.

PHARMACEUTICAL COMPOSITIONS In a preferred embodiment of the invention, the compound of the formula I is administered in combination with a pharmaceutically acceptable carrier, diluent or excipient b. Even the compounds of the present invention (including their pharmaceutically acceptable salts, pharmaceutically acceptable esters and solvates) can be administered alone, generally will be administered in admixture with a pharmaceutical diluent, excipient or carrier, particularly for human therapy. The pharmaceutical compositions can be for animal or human use 5. in human and veterinary medicine. Examples of such excipients suitable for the various different forms of pharmaceutical compositions described herein can be found in "Handbook of Pharmaceutical Excipients, 2nd Edition, (1994), Edited by A Wade and PJ Weller." Diluents or carriers acceptable for therapeutic use are they are well known in the pharmaceutical field, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro, ed. 1 985) Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate , mannitol, sorbitol and the like Examples of suitable diluents include ethanol, glycerol and water The choice of pharmaceutical diluent, excipient or carrier can be selected with respect to the proposed route of administration and standard pharmaceutical practice. or in addition to the carrier, excipient or diluent any suitable binder (s) ( s), lubricant (s), suspending agent (s), coating agent (s), solubilizing agent (s). Examples of suitable binders include starch, gelatin, natural sugars, such as glucose, anhydrous lactose, free-flowing lactose, beta-lactose, corn sweeteners, synthetic and natural gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol. Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The preservatives, stabilizers, dyes and even flavoring agents can be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents can also be used. SALTS / ESTERS The compounds of the formula I can be present as salts or esters, in particular esters or pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the compounds of the invention include suitable base or acid addition salts thereof. A review of suitable pharmaceutical salts can be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). The salts are formed, for example, with strong inorganic acids such as mineral acids, for example, sulfuric acid, phosphoric acid or hydrohalic acids; with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are substituted or not substituted (for example, by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example, oxalic, masonic, succinic, maleic, fumaric, eftalic or terephthalic; with hydrocarboxylic acids, for example, ascorbic, glycolic, lactic, malic, tartaric or citric acid; with amino acids, for example, aspartic or glutamic acid; with benzoic acid; or with organic sulphonic acids, such as aryl or alkyl sulfonic acids (C! -C4) which are substituted or are not substituted (for example by a halogen) such as methane sulphonic acid or p-toluene. The esters are formed either using organic acids or alcohols / hydroxides, depending on the functional group that is esterified. Organic acids include carboxylic acids, such as alkanecarboxylic acids of 1 to 12 carbon atoms which are substituted or not substituted (for example, by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acid, for example, oxalic, masonic, succinic, maleic, fumaric, eftalic or terephthalic; with hydrocarboxylic acids, for example, ascorbic, glycolic, lactic, malic, tartaric or citric acid; with amino acids, for example, glutamic or aspartic acid; with benzoic acid; or with organic sulphonic acids, such as aryl or alkyl sulfonic acids (C? -C4) which are substituted or are not substituted (for example by a halogen) such as methane sulfonic acid or p-toluene. Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide. Alcohols include alkanoalcohols of 1-12 carbon atoms which may be substituted or unsubstituted, for example, by a halogen). ENANTIOMERS / TAUTOMERS In all aspects of the present invention previously treated, the invention includes, where appropriate, all the enantiomers and tautomers of the compounds of the formula I. The person skilled in the art will recognize compounds that possess optical properties (one or more chiral carbon atoms) or tautomeric characteristics. The corresponding enantiomers and / or tautomers can be isolated / prepared by methods known in the art. STEREOISOMERS AND GEOMETRICS Some of the specific compounds of formula I can exist as stereoisomers and / or geometric isomers, for example, they can have one or more asymmetric and / or geometric centers and thus they can exist in two or more stereoisomeric and / or geometric forms . The present invention contemplates the use of all stereoisomers and individual geometric isomers of those Inhibitory agents, and mixtures thereof. The terms used in the claims comprise these forms, stipulating that said forms retain the appropriate functional activity (although not necessarily to the same degree). The present invention also includes all suitable isotopic variations of the compound or a pharmaceutically acceptable salt thereof. An isotopic variation of an agent of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found In nature. Examples of isotopes that can be incorporated in the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31 P, 3 P, 35S, 18F and 36CI, respectively. Certain isotopic variations of the agent and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as 3H or 14C are incorporated, are useful in studies of tissue distribution of substrate and / or drug. The concentrated isotopes, ie, 3H and carbon 14 or i.e. 1 C are particularly preferred for their ease of preparation and detection. In addition, substitution with isotopes such as deuterium, i.e., 2H, may provide certain therapeutic advantages resulting in greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and therefore, may be preferred in some circumstances. The isotopic variations of the agent of the present invention and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents. SOLVATES The present invention also includes the use of solvate forms of the compounds of the present invention. The terms used in the claims comprise these forms. POLYMORPHOSES The invention also relates to the compounds of the present invention in their various crystalline forms, polymeric forms and (an) hydrous forms. It is well established within the pharmaceutical industry that chemical compounds can be isolated in any such form by slightly varying the method of purification and / or isolation of the solvents used in the synthetic preparation of such compounds. DEVICES The invention also includes the compounds of the present invention in the form of a prodrug. Such prodrugs are generally compounds of the formula I wherein one or more appropriate groups have been modified so that the modification can be reversed upon administration to a mammalian or human subject. Such reversion is usually carried out by an enzyme naturally present in such a subject, although it is possible for a second agent to be administered together with such a prodrug to perform the reversion in vivo. Examples of such modifications include ester (e.g., any of those described above), wherein the reversion may be carried out by an esterase, etc. Other such systems will be well known to those skilled in the art. THERAPEUTIC USE It has been found that the compounds of formula I possess anti-proliferative activity and therefore are believed to be of use in the treatment of proliferative disorders such as cancers, leukemia and other disorders associated with uncontrolled cell proliferation such as psoriasis and restenosis. As defined herein, an anti-proliferative effect within the scope of the present invention can be demonstrated by the ability to inhibit cell proliferation in a complete in vitro cell assay, for example, using any of the A549, HT29 cell lines. or Saos-2. Using such assays can determine whether a compound is anti-proliferative in the context of the present invention. A preferred embodiment of the present invention therefore relates to the use of one or more compounds of the formula I in the preparation of a medicament for treating a proliferative disorder. As used herein, the phrase "preparation of a medicament" includes the use of a compound of formula I directly as the medicament in addition to its use in a screening program for additional therapeutic agents or at any stage of the manufacturer of such medication. Preferably, the proliferative disorder is a cancer or leukemia. The term "proliferative disorder" is used herein in a broad sense to include any disorder that requires control of the cell cycle, for example, cardiovascular disorders such as restenosis, cardiomyopathy and myocardial infarction, autoimmune disorders such as glomerulonephritis and rheumatoid arthritis, dermatological disorders such as psoriasis, anti-inflammatory, anti-fungal, antiparasitic disorders such as malaria, episema, alopecia and chronic obstructive pulmonary disorder. In these disorders, the compounds of the present invention can induce apoptosis or maintain stasis within the desired cells as required. The compounds of the invention can inhibit any of the steps or steps in the cell cycle, for example, formation of the nuclear envelope, exit of the quiescent phase of the cell cycle (GO), G1 progression, chromosome decondensation, nuclear envelope disruption, I LESSON, start of DNA replication, DNA replication progression, termination DNA replication, centrosome duplication, G2 progression, activation of mitotic or meiotic functions, chromosome condensation, centroqma separation, microtubule nucleation, spindle and function formation, interactions with microtubule motor proteins, separation of chromate and segregation , inactivation of mitotic functions, contractile ring formation, and cytokinesis functions. In particular, the compounds of the invention can influence certain genetic functions such as chromatin binding, replication complex formation, replication authorization, phosphorylation or other secondary modification activity, proteolytic degradation, microtubule binding, actin binding, binding of septine, microtubule organizing center nucleation activity and binding to components of cell cycle signaling pathways. In one embodiment of the invention, the compound of formula I is administered in an amount sufficient to inhibit at least one CDK enzyme. Preferably, the compound of formula I is administered in an amount sufficient to inhibit at least one of CDK2 and / or CDK4. Another aspect of the invention relates to the use of a compound of the formula I in the preparation of a medicament for treating a viral disorder, such as human cytomegalovirus (HCMV), herpes simplex virus type 1 (HSV-1), human immunodeficiency (HIV-1), and varicella zoster virus (VZV). In a more preferred embodiment of the invention, the compound of formula I is administered in an amount sufficient to inhibit one or more of the CDKs host cells included in viral replication, ie. CDK2, CDK7, CDK8, and CDK9 [39]. As defined herein, an anti-viral effect within the scope of the present invention can be demonstrated by the ability to inhibit CDK2, CDK7, CDK8 or CDK9. In a particularly preferred embodiment, the invention relates to the use of one or more compounds of the formula I in the treatment of a viral disorder that is CDK-dependent or sensitive. CDK-dependent disorders are associated with an above-normal level of activity of one or more CDK enzymes. Such disorders are preferably associated with an abnormal level of activity of CDK2, CDK7, CDK8 and / or CDK9. A disorder sensitive to CDK is a disorder in which an aberration at the CDK level is not the main cause, but it is waters below the primary metabolic aberration. In such scenarios, CDK2, CDK7, CDK8 and / or CDK9 can be said to be part of the sensitive metabolic pathway and CDK inhibitors, can therefore be active to treat such disorders. Another aspect of the invention relates to the use of compounds of the formula I, or pharmaceutically acceptable salts thereof, in the preparation of a medicament for treating diabetes. In a particularly preferred embodiment, diabetes is type I diabetes. Glycogen synthase kinase 3 (GSK3) is a Ser / Thr protein kinase composed of two isoforms (a and ß), which are highly homologous with the catalytic domain. GSK3 is one of several protein kinases that phosphorylate glycogen synthase (GS). The stimulation of glycogen synthesis by insulin in skeletal muscle results from the dephosphorylation and activation of GS. The action of GSK3 in GS in this way results in the deactivation of the latter, thus suppressing the conversion of glucose into glycogen in muscles. Type II diabetes (diabetes mellitus not dependent on insulin) is a multi-factorial disease. Hyperglycemia is due to insulin resistance in the liver, muscles and other tissues, coupled with impaired insulin secretion. Skeletal muscle is the main site for insulin-stimulated glucose uptake, either removed from circulation or converted to glycogen. The deposition of muscle glycogen is the main determinant in glucose homeostasis and type I diabetics have defective muscle glycogen storage. There is evidence that an increase in GSK3 activity is important in type I diabetes [1]. In addition, it has been shown that GSK3 is overexpressed in muscle cells of type I diabetics and that an inverse correlation exists between skeletal muscle GSK3 activity and insulin action 12]. The inhibition of GSK3 may therefore be of therapeutic relevance in the treatment of diabetes, particularly type I I, and diabetic neuropathy. For a recent review in biology GSK3 refer to [3]. It should be noted that GSK3 is known to phosphorylate many substrates other than GS and thus is included in the regulation of multiple biochemical trajectories. Substrates GSK-3 include: CREB (also known as cAMP response element binding protein 1), which is included to mediate subsequent genetic transcription at increased cAMP levels and activation of cAMP-dependent protein kinase A. The response element to which CREB binds is found in a number of genes, including those that are of proposed importance to T cell function (and dysfunction, for example, leukemia and T-cell lymphoma). CREB also appears to be included in long-term potentiation in CA1 hippocampal neurons and in the regulation of neuronal function in general, as well as in cancer biology. EIF2B (eukaryotic start factor-2B), which is a GTP exchange protein, essential for protein synthesis. HSF-1 (thermal shock factor 1), which is a component of the cell voltage response. C / EBPa (also known as enhancer-binding protein A / CCAAT), which has been suggested to modulate leptin expression and has also suggested having a role in human obesity. Homozygous mice for the objective elimination of the C / E7Pa gene do not store hepatic glycogen, express low levels of GS and fail to store lipid. NF-ATc (activated T-cell nuclear factor), whose activation is controlled by calcineurin, a Ca2 + -dependent phosphatase. Originally identified in T cells as inducers of cytokine gene expression, NF-AT proteins play varied roles in non-target processes. immune, particularly those related to adaptive responses such as cardiac hypertrophy and altered metabolic balance. c-Jun, c-myc and c-myb, each of which are proto-oncogenic. β-Catenin, which is a protein found in the adherent junction and therefore is critical for the establishment and maintenance of epithelial layers. The junctions mediate adhesion between cells, facilitate cell-cell signaling, and hold the actin cytoskeleton. To serve these roles, adherent junctions regulate normal cell growth and behavior, wound healing, and tumor cell metastasis. Tau, perhaps best known for its proposed inclusion in the etiology of Alzheimer's disease. Tau is co-assembled with tubulin in microtubules, however, in Alzheimer's disease, tau forms large knots of filaments, which interrupt the microtubule structures in the nerve cell, impairing the transport of nutrients as well as the transmission of neuronal messages. The insulin-1 receptor substrate (I RS-1), which is found in a variety of tissues and cells responsive to insulin. It does not show intrinsic enzyme activity but is thought to serve as a binding protein included in the binding and activation of other signal transduction molecules after being phosphorylated by the insulin receptor kinase. I RS-1 has been proposed to play a role in the development of insulin resistance. It is notable that GSK3 is known to phosphorylate many substrates other than GS, and is thus included in the regulation of multiple biochemical trajectories. For example, GSK is highly expressed in the nervous, central and peripheral systems, and biomedical rationals for therapy through inhibition of GSK in neurodegenerative diseases have been proposed. Another aspect of the invention therefore relates to the use of compounds of the formula I, or pharmaceutically acceptable salts thereof, in the preparation of a medicament for treating CNS disorders, for example, neurodegenerative disorders. Preferably, the CNS disorder is Alzheimer's disease.

Tau is a GSK-3 substrate that has been implicated in the etiology of Alzheimer's disease. In healthy nerve cells, Tau is co-assembled with tubulin in microtubules. However, in Alzheimer's disease, tau forms large knots of filaments, which interrupt the microtubule structures in the nerve cell, thus damaging the transport of nutrients as well as the transmission of neutron messages. Without wishing to be bound by theory, it is believed that GSK3 inhibitors may be able to prevent and / or reverse the abnormal hyperphosphorylation of the mitochondrial-associated protein, tau, which is an invariant feature of Alzheimer's disease and a number of other neurodegenerative diseases. , such as progressive supranuclear palsy, corticobasal degeneration and Pick's disease. Mutations in the tau gene cause inherited forms of fronto-temporal dementia, further signaling the relevance of tau protein dysfunction to the neurodegenerative process [40]. Another aspect of the invention relates to the use of compounds of the formula I, or pharmaceutically acceptable salts thereof, in the preparation of a medicament for treating bipolar disorder. Yet another aspect of the invention relates to the use of compounds of the formula I, or pharmaceutically acceptable salts thereof, in the preparation of a medicament for treating a stroke.

The reduction of neuronal apoptosis is an important therapeutic objective in the context of head trauma, stroke, epilepsy, and neuronal motor disease [4]. Therefore GSK3 as a pro-apoptotic factor in neuronal cells makes this protein kinase an attractive therapeutic target for the design of inhibitory drugs to treat these diseases. The GSK3 inhibitors may be able to prevent and / or reverse the abnormal hyperphosphorylation of the protein associated with microtubule tau which is an invariant feature of Alzheimer's disease and a number of other neurodegenerative diseases, such as progressive supranuclear palsy, corticobasal degeneration and Pick. Mutations in the tau gene cause inherited forms of fronto-temporal dementia, further signaling the relevance of tau protein dysfunction to the neurodegenerative process [5]. Yet another aspect of the invention relates to the use of compounds of the formula I, or pharmaceutically acceptable salts thereof, in the preparation of a medicament for treating alopecia. Hair growth is controlled by Wnt signaling path, in particular Wnt-3. In skin tissue culture model systems, the expression of non-degradable ß-catenin mutants leads to a dramatic increase in the population of putative germ cells, which have a higher proliferative potential [6]. This population of germ cells expresses a higher level of β-catenin not associated with cadherin [7], which may contribute to its high proliferative potential. In addition, transgenic mice overexpressing a truncated β-catenin in the skin undergo de novo follicular pillar morphogenesis, which is normally established only during embryogenesis. This raises the possibility that the ectopic application of GSK3 inhibitors may be of use in the treatment of baldness and in restoring hair growth after alopecia induced by chemotherapy. A further aspect of the invention relates to a method for treating a GSK3-dependent disorder, said method comprising administering to a subject in need thereof, a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined above. in an amount sufficient to inhibit GSK3. Preferably, the compound of formula I, or pharmaceutically acceptable salt thereof, is administered in an amount sufficient to inhibit GSK3β. In one embodiment of the invention, the compound of formula I is administered in an amount sufficient to inhibit at least one PLK enzyme. The polo-like kinases (PLKs) constitute a family of serine / threonine protein kinases. Mutants of mitotic Drosophila melanogaster at the pole site display spindle abnormalities [41] and it was found that polo codes for a mitotic kinase [42]. In humans, there are three closely related PLKs [43]. They contain a highly homologous amino terminal catalytic kinase domain and their carboxyl terms contain two or three conserved regions, the polo boxes. The function of the polo boxes remains incompletely understood but is involved in the objective of PLKs to subcellular compartments [44,45], mediation of interactions with other proteins [46], or can be part of a self-regulating domain [47]. In addition, PLK1 activity dependent on pole box is required for appropriate metaphase / anaphase transition and cytokinesis [48, 49]. Studies have shown that human PLKs regulate some fundamental aspects of mitosis [50,51]. In particular, the activity of PLK1 is believed to be necessary for the functional maturation of centrosomes in posterior G2 / anterior prophase and subsequent establishment of a bipolar spindle. The elimination of cellular PLK1 through the small interfering RNA technique (Syria) has also confirmed that this protein is required for multiple mitotic processes and cytokinesis termination [52]. In a more preferred embodiment of the invention, the compound of formula I is administered in an amount sufficient to inhibit PLK1. One of the three human PLKs, PLK1 is the largest characterized; regulates a number of effects of the cell division cycle, including the onset of mitosis [53,54], the activation of the DNA damage checkpoint [55,56], regulation of the anaphase promoter complex [57-59], phosphorylation of the proteasome [60], and duplication of centrosome and maturation [61].

Specifically, the onset of mitosis requires activation of the M-phase promoter factor (MPF), the complex between the cyclin-dependent kinase CDK1 and type B cyclins [62]. The latter accumulate during phases S and G2 of the cell cycle and promote the inhibitory phosphorylation of the MPF complex by kinases WEE1, MIK1, and MYT1. At the end of the G2 phase, the corresponding dephosphorylation by the double specificity phosphatase CDC25C triggers the activation of MPF [63]. In metaphase, cyclin B localizes the cytoplasm [64], then phosphorylates it during prophase and this event causes nuclear translocation [65,66]. Nuclear accumulation of active MPF during profases is thought important to initiate M phase events [67]. However, nuclear MPF is kept inactive by WEE1 unless counteracted by CDC25C. CDC25C phosphatase itself, located in the cytoplasm during interphase, accumulates in the nucleus of prophase [68-71]. The nuclear entry of both cyclin B [60] and CDC25C [72] are promoted through phosphorylation by PLK1 [54]. The kinase is an important regulator of M-phase initiation. In a particularly preferred embodiment, the compounds of formula I are antagonistic ATP inhibitors of PLK1. In the present context antagonism of ATP refers to the ability of an inhibitory compound to decrease or prevent the catalytic activity of PLK, ie, phototransfer of ATP to a macromolecular PLK substrate, by virtue of binding reversibly or irreversibly in the active site. of the enzyme in such a way to deteriorate or prevent ATP binding. In another preferred embodiment, the compound of formula I is administered in an amount sufficient to inhibit PLK2 and / or PLK3. Mammalian PLK2 (also known as SNK) and PLK3 (also known as PRK and FNK) are originally shown to be immediately preceding genetic products. The activity of kinase PLK3 seems to increase during the last phases S and G2.

It is also activated during activation of the DNA damage checkpoint and severe oxidative stress. PLK3 also plays an important role in the regulation of microtubule dynamics and centrosome function in the cell and the expression of deregulated PLK3 results in cell cycle arrest and apoptosis [73].

PLK2 is the least well-understood homologue of the three PLKs. Both PLK2 and PLK3 may have additional important post-mitotic functions [46]. ADMINISTRATION The pharmaceutical compositions of the present invention can be adapted for oral, rectal, vaginal, parenteral, intramuscular, intraperitoneal, intraarterial, intrathecal, intrabronchial, subcutaneous, intradermal, intravenous, nasal, buccal or sublingual routes of administration. For oral administration, the particular use is made of compressed tablets, pills, tablets, dragees, drops and capsules. Preferably, these compositions contain from 1 to 250 mg and more preferably from 10-100 mg, of active ingredient per dose. Other forms of administration comprise solutions or emulsions that can be injected intravenously, intraarterially,. intrathecal, subcutaneous, intradermal, intraperitoneal or intramuscularly, and that are prepared from sterile or sterilizable solutions. The pharmaceutical compositions of the present invention can also be in the form of suppositories, tablets, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or powders. An alternative means of transdermal administration is by use of a skin patch. For example, the active ingredient may be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. The active ingredient may also be incorporated, in a concentration of between 1 and 10% by weight, in an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as required. Injectable forms can contain between 10-1,000 mg, preferably between 10-250 mg, of active ingredient per dose. Compositions may be formulated in unit dosage form, ie, in the form of discrete portions containing a unit dose, or a subunit or multiple of a unit dose. DOSAGE A person of skill in the art can easily determine an appropriate dose of one of the present compositions for administration to a subject without undue experimentation. Typically, a physician will determine the current dosage that will be most appropriate for an individual patient and will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and duration of action of that compound, age, body weight, general health , sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition and individual therapy. The dosages described herein are exemplary of the average case. Of course, there may be individual cases where higher or lower dosage ranges are warranted, and such are within the scope of this invention. Depending on the need, the agent can be administered in a dose of from 0.01 to 30 mg / kg body weight, such as from 0. 1 to 10 mg / kg, more preferably 0.1 to 1 mg / kg body weight. In an exemplary embodiment, one or more doses of 10 to 150 mg / day will be administered to the patient for the treatment of disease. COMBINATIONS In a particularly preferred embodiment, the one or more compounds of the formula I are administered in combination with one or more active agents, for example, existing drugs available in the market. In such cases, the compounds of the invention can be administered sequentially, simultaneously or sequentially with the one or more active agents. Anticancer drugs are generally more effective when used in combination. In particular, combination therapy is desirable to avoid a cover of major toxicities, mechanism of action and mechanism (s) of resistance. In addition, it is also desirable to administer most drugs at their maximum tolerated doses with minimum time intervals between such doses. The main advantages of combining chemotherapeutic drugs are that they can promote possible synergistic or additive effects through biochemical interactions and can also reduce the emergence of resistance in early tumor cells that would otherwise be responsive to initial chemotherapy with a single agent. An example of the use of biochemical interactions to select drug combinations is demonstrated by the administration of leucovorin to increase the binding of an active intracellular metabolite of 5-fluorouracil to its target, thymidylate synthase, thus increasing its cytotoxic effects. Numerous combinations are used in current cancer and leukemia treatments. A more extensive review of medical practices can be found in "Oncologic Therapies" edited by E. E. Vokes and H. M. Golomb, published by Springer. Beneficial combinations can be suggested by studying the growth inhibitory activity of test compounds with agents known or suspected to be valuable in the treatment of a particular cancer initially or cell lines derived from that cancer. This procedure can also be used to determine the order of administration of the agents, ie before, simultaneously, or after delivery. Such programming can be a characteristic of all the agents that act in the cycle identified in the present. TESTING Another aspect of the invention relates to the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as hereinabove defined in an assay to identify additional candidate compounds that influence the activity of a selected kinase of a cyclin-dependent kinase, aurora kinase, GSK and a polo-like kinase. Preferably, the assay is capable of identifying candidate compounds that are capable of inhibiting a kinase selected from a cyclin-dependent kinase, aurora kinase, GSK and a polo-like kinase. More preferably, the assay is a competitive binding assay. As used herein, the term "candidate compound" includes, but is not limited to, a compound that can be obtained from or produced by any suitable source, whether natural or not. The candidate compound may be designed or obtained from a library of compounds, which may comprise peptides, as well as other compounds, such as small organic molecules and particularly novel guide compounds. By way of example, the candidate compound may be a natural substance, a biological macromolecule, or an extract made from biological materials, such as bacteria, fungi or animal tissues or cells (particularly mammalian), an organic or inorganic molecule, an synthetic candidate compound, a semi-synthetic candidate compound, a structural or functional imitation, a peptide, a peptideimitation, a candidate candidate derivative, a peptide separated from a complete protein, or a synthetically synthesized peptide, for example, using either a synthesizer of peptide or by recombinant techniques or combinations thereof, a recombinant candidate compound, a natural or unnatural candidate compound, a fusion protein or equivalent thereof and mutants, derivatives or combinations thereof. The candidate compound can still be a compound that is a modulator of a cyclin-dependent kinase, aurora kinase, GSK- or polo-like kinase, such as a known inhibitor that has been modified in some way, for example, by DNA techniques. recombinant or chemical synthesis techniques. Typically, the candidate compound is prepared by recombinant DNA techniques and / or chemical synthesis techniques. Once a candidate compound capable of interacting with a cyclin-dependent kinase, aurora kinase, GSK or a polo-like kinase has been identified, additional steps can be carried out to select and / or modify candidate compounds and / or modify existing compounds, so that they are capable of modulating a cyclin-dependent kinase, aurora kinase, GSK or a polo-like kinase. Preferably, the candidate compound is generated by conventional SAR modification of a compound of the invention. As used herein, the term "conventional SAR modification" refers to standard methods known in the art for varying a given compound by chemical derivation. Thus, in one aspect, the identified compound can act as a model (eg, an annealing) for the development of other compounds. The compounds used in such a test can be free in solution, fixed to a solid support, originated on a cell surface, or located intracellularly. The abolition of activity of the formation of binding complexes between the compound and the agent being tested can be measured. The test of the present invention may be a selection, by which a number of agents are tested. In one aspect, the assay method of the present invention is a high throughput selection. This invention also contemplates the use of competitive drug screening assays in which neutralizing antibodies capable of binding a compound compete specifically with a candidate compound to bind a compound. Another screening technique provides high-throughput screening (HTS) of agents having adequate binding affinity to the substances and is based on the method described in detail in WO 84/03564. It is expected that the assay methods of the present invention will be suitable both for large scale and small scale selection of test compounds as well as in quantitative tests. One aspect of the invention relates to a process comprising the steps of: (a) performing a test method described hereinabove; (b) identifying one or more candidate compounds capable of binding to a cyclin-dependent kinase, aurora kinase, GSK or a polo-like kinase; and (c) preparing an amount of said one or more candidate compounds. Another aspect of the invention provides a process comprising the steps of: (a) performing a test method described hereinabove; (b) identifying one or more candidate compounds capable of binding to a cyclin-dependent kinase, aurora kinase, GSK or a polo-like kinase; and (c) preparing a pharmaceutical composition comprising said one or more candidate compounds. Another aspect of the invention provides a process comprising the steps of: (a) performing a test method described hereinabove; (b) identifying one or more candidate compounds capable of binding to a cyclin-dependent kinase, qulnasa aurora, GSK or a polo-like kinase; (c) modifying said one or more candidate compounds capable of binding to a cyclin-dependent kinase, aurora kinase, GSK or a polo-like kinase; (d) performing the assay method described hereinabove; (e) optionally preparing a pharmaceutical composition comprising said one or more candidate compounds. The invention also relates to candidate compounds identified by the method described hereinabove. Yet another aspect of the invention relates to a pharmaceutical composition comprising a candidate compound identified by the method described hereinabove. Another aspect of the invention relates to the use of a candidate compound identified by the method described hereinabove in the preparation of a pharmaceutical composition for use in the treatment of proliferative disorders. The above methods can be used to select a candidate compound useful as an inhibitor of a cyclin-dependent kinase, aurora kinase, GSK or a polo-like kinase. SYNTHESIS Another aspect of the invention relates to a process for preparing compounds of formula I, said process comprising reacting a compound of formula 9 with a compound of formula 10 to form a compound of formula I, wherein R " 6 are as defined above.

I Still another aspect of the invention relates to an alternative process for preparing compounds of the formula I, said process comprising reacting a compound of the formula 1 with a compound of the formula 3 to form a compound of the formula I, where R1"6 are as defined above. fS? Compounds of general structure I in which Z1 is N, ie, 2,4-disubstituted pyrimidines, can be prepared by variations of pyrimidine synthesis Traube pyrimidine [8, 9] (Scheme 1). In these processes the pyrimidine ring in I (Z1 = N) is formed by condensation of 1,3-dicarbonyl compounds 8 or the corresponding enaminones 9 (where R is for example Me) with aryloguanidines 10 [1 0]. The latter can be prepared from 1-arylamines by a variety of methods [11,12], for example, by reaction with cyanamide. Diacetones 8 can be obtained from 2-acylthiazoles 5 by acylation with acyl halides 7 (for example, X = CI) or the corresponding anhydrides. In the case where R6 = H, formylation of 5 will provide corresponding keto-aldehydes 8. Dicarbonyl compounds 8 can then be converted to enaminones 9 with appropriate bases HNR2. If both R5 and R6 are H, then enaminones 9 can be obtained from acylthiazoles directly with the aid of formamidines, acetals amide (for example, dimethylformamide dimethylacetal), or amine esters (for example, tert-butoxybis (dimethylamino) methane) [13] Scheme 1 2-Acylthiazoles 5 can be prepared by lithiation of C2 in thiazoles 6, followed by the reaction of intermediates lithiated with aldehydes R5CH2CHO and oxidation of the resulting alcohols in acylthiazoles 5. Alternatively the lithiated thiazoles can be acylated with appropriate esters R5CH2COOR, acid chlorides R5CH2COCI, or acid anhydrides (R5CH2CO) 2O to provide 2-acylthiazoles 5 [14, 15]. It is also possible to prepare 2-unsubstituted thiazole Grignard reagents 6 with the aid of magnesium ethyl bromide, followed by the reaction of these reagents with acid anhydrides.

(R 5 CH 2 CO) 2 O to provide 2-acylthiazoles 5 [16]. Another general route to 2-acylthiazoles 5 [17] initiates lactonitriles 1, which can be prepared by the addition of HCN to aldehydes R5CH2CHO. Protection of the function of alcohol, for example, as the tetrahydropyran ether (PG = tetrahydropyran-2-yl), is then carried out before the conversion of the nitrile function to thioacetamide in products 2 with for example, a saturated solution of sulfur of ethanol hydrogen containing diethylamine. The thioamides 2 can then be condensed with a-haloacetones 3 according to Hantzsch thiazole synthesis [8], followed by removal of the protecting group, to provide 1-thiazol-2-yl-ethanols 4. These are subsequently oxidized, for example , with the help of potassium dichromate in glacial acetic acid, to ketones 5: Alternative synthetic routes for compounds of general structure I are shown in Scheme 2. 1 & 17 1S 1 » Scheme 2 Here enaminones 1 3, derived from ethyl pyruvates 12 [18], are condensed with 1 0 aryloguanidines [19]. The pyrimidine esters of product 14 can be easily converted to the corresponding primary carboxamides, for example, with ethanolic ammonium solution [20, 21]. The carboxamide function is then converted to thiocarboxamide, for example, using Lawesson's reagent [22-24], phosphorous pentasulfide [18,20, 21], or ammonium sulfide [25]. The same conversion can also be achieved by activation of the amide as pyridyl triflate, followed by thiolysis with ammonium sulfide [26]. An applicable synthetic route without considering whether Z1 in general structure I is N (pyrimidines) or CH (pyridines) includes 2-halogeno-4-cyano-pyrimidines (Scheme 2; 1 8, Z1 = N) or pyridines (18, Z1 = CH) as key intermediates. These can be prepared by many methods known in the art [27-29]. In the case of pyrimidine (Z1 = N) a convenient synthesis [30] initiates 4-methyl-1 H-pyrimidin-2-ones 16, which are approximated to 17. These aldoximes can be dehydrated to the corresponding nitriles and if dehydration is carried out with, for example, phosphorous oxychloride, then chloronitriles 1 8 (X = CI) are obtained directly [31]. The halogen group (X) in 1 8 can then be substituted with 1 1 arylamines to provide intermediate compounds 19 [32]. The nitrile function at 19 is then oxidized to thiocarboxamide 1 5, for example, using a refluxing methanol solution containing ammonium sulfide. Finally, the formation of the thiazole ring is carried out, for example, by heating a metabolic solution of 15 suitable y-haloacetones in the presence of an organic base such as pyridine. These reactions proceed particularly lightly when microwave irradiation is applied. The present invention is further described by way of example and with reference to the following figures, wherein: Figure 1 shows the lack of accumulation of β-catenin in HEK293 cells in response to exposure to compound XIV (test compound) ß- catenin. Figure 2 shows the effect of compound XIV on oral glucose tolerance in ZDF fa / fa rats. Compound test is administered in 1 0-1 1 week old rats at 5 mg / kg i.v. at -270 and -30 min. A 0 min 2g / kg oral glucose load is given and blood samples are collected at 15 min intervals to determine blood glucose levels. EXAMPLES The exemplary compounds of the invention are listed in Table 1. Example 1 General NMR spectra are recorded using a Varian I NOVA-500 instrument. Chemical changes are reported in parts per million relative to the standard tetramethyl star standard. Mass spectra are obtained using a quad-mass Waters ZQ2000 mass spectrometer with electro-ionization ionization (ESI). Analytical and preparative RP-HPLC is performed using Vydac columns 218TP54 (250 x 4.6 mm) and 21 8TP1022 (250 x 22 mm), respectively. Linear gradient elution using H2O / MeCN systems (containing 0.1% CF3COOH) at flow rates of 1 mL / min (analytical) and 9 mL / min (preparative) is performed. Purity is assessed by integration of chromatograms (? = 254 nm). Silica gel (EM Kieselgel 60, 0.040-0.063 mm, Merck) or ISOLUTE pre-packed columns (Jones Chromatography Ltd. UK) are used for flash chromatography. Example 2 3-Dimethylamino-1-thiazol-2-yl-propenyone 1-thiazol-2-yl-ethanone (1.9 g, 14.9 mmol) and dimethylformamide dimethylacetal (1.98 mL, 14.9 mmol) are combined and heated to 85 ° C for 8 h. After cooling and concentration, the residue is crystallized from diethyl ether and the resulting solid title product is filtered (1.56 g, 58%). 1H-NMR (DMSO-d6) d: 2.91 &; 3.1 9 (6H, s, N (CH3) 2), 6.01 (1 H, s, CH), 7.82 (1 H, s, CH), 7.92 (1 H, d, ArH, J = 3.4 Hz), 7.95 (1 H, d, ArH, J = 3.4 Hz). ESI-MS: m / z 1 83 [M + 1] +; C18H10N2OS requires 1 82.24. Anal RP-HPLC: tR 18.4 min (0-60% MeCN gradient for 20 min); purity > 95% 3-Dimethylamino-1- (4l-5-dimethyl-thiazol-2-yl) -propenone 1- (4,5-Dimethyl-thiazol-2-yl) -ethanone (1.8 g, 1.8 mmol) and dimethylformamide dimethylacetal ( 1.7 mL, 14.2 mmol) are combined and heated to 85 ° C for 8 h. After cooling, the resulting crystalline solid is filtered and rinsed with cold diethyl ether (2.1 g, 85%). 1 H-NMR (DMSO-d 6) d: 2.25 (3 H, s, CH 3), 2.38 (3 H, s, CH 3), 2.81 & 3.1 8 (6H, s, N (CH3) 2), 5.91 (1 H, s, CH), 7.79 (1 H, s, CH). ESI-MS: m / z 210 [M + 1] +; C10H14N2OS requires 210.08. Anal. RP-HPLC: tR 14.5 min (0-60% MeCN gradient for 20 min); purity > 95% Example 3 ^ (6-Chloro-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine (XIV) 3-Dimethyl-amino-l-thiazol-2-yl-propenyone (120 mg, 0.66 mmol),? / - (6-chloro-pyridin-3-yl) -guanidine nitrate (154 mg, 0.66 mmol), prepared by guanylation of 6-chloro-pyridin-3-ylamine with Aqueous cyanamide in the presence of nitric acid, and potassium carbonate (228 mg, 1.66 mmol) are combined in 2-methoxyethane and the mixture is heated at 120 ° C for 20 h. Inorganic insolubles are removed by filtration and the filtrate is concentrated. The residue is fractionated by silica gel column chromatography. Pooling of appropriate eluent fractions and removal of the solvent afforded the title compound (69 mg, 27%). 1 H-NMR . (DMSO-d6) d: 7.48 (1 H, d, ArH, J = 8.3 Hz), 7.54 (1 H, d, ArH, J = 4.9 Hz), 8.04 (1 H, d, Ar H, J = 3.4 Hz), 8.1 1 (1 H, d, Ar H, J = 3.4 Hz), 8.25 (1 H, dd, Ar H, J = 8.3, 2.9 Hz), 8.69 (1 H, d, Ar H, J = 4.9 Hz), 8.85 (1 H, d, Ar H, J = 2.9 Hz), 10.19 (1 H , s, NH). ESI-MS: m / z 290 [M + H] +; C12H8CIN5S requires 289J02. Anal. RP-HPLC: t R 20.45 min (0-60% MeCN gradient for 20 min); purity > 95% Exemplary compounds VIII-XI II, XVI, XVII-XX, XXIII, and XXVII listed in Table 1 are prepared in a similar manner by condensation of 3-dimethyl-amino-1-thiazol-2-yl-propenyone and guanidine of phenyl or appropriate pyridyl. N- [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] -benzene-1,3-diamine (Vlll) 1 H-NMR (DMSO-d 6) d: 2.36 (3H, s, CH3), 2.43 (3H, s, CH3), 4.86 (2H, s, NH2), 6.21 (1H, d, ArH, J = 8.7 Hz), 6.93 (1H, dd, ArH, J = 8.7, 8.7 Hz), 6.98 (1H, d, ArH, J = 8.7 Hz), 7.02 (1H, s, ArH), 7. 30 (1H, d, ArH, J = 5.4 Hz), 8.52 (1H, d, ArH, J = 5.4 Hz), 9.46 (1H, s, NH). ESI-MS: m / z 298.3 [M + H] +; C15H15NSS requires 297.10. Anal.

RP-HPLC: t R 14.61 min (0-60% MeCN gradient over 20 min); purity > 95% 3- [4- (4, 5-Dimethyl-thiazol-2-yl) -pyrimidin-2-ylamino] -phenol (IX) 1 H-NMR (DMSO-d 6) d: 2.36 (3H, s, CH 3), 2.44 (3H, s, CH3), 6.39 (1H, d, ArH, J = 8.8 Hz), 7.07 (1H, dd, ArH, J = 8.8, 8.8 Hz), 7. 36 (2H, m, ArH), 7.34 (1H, d, ArH, J = 5.4 Hz), 8.56 (1H, d, ArH, J = 5.4 Hz), 9.36 (1H, s, OH), 9.64 (1H, s, NH). ESI-MS: m / z 299.3 [M + H] +; C15H14N4OS requires 298.09. Anal. RP-HPLC: t R 18.44 min (0-60% MeCN gradient for 20 min); purity > 95% [4- (4,5-Dimethyl-thiazol-2-yl) pyrimidin-2-yl] - (3-trifluoromethyl-phenyl) -amine (X) 1H-NMR (DMSO-d6) d: 2.36 (3H, s, CH3), 2.44 (3H, s, CH3), 7.31 (1H, d, ArH, J = 8.8 Hz), 7.42 (1H, d , ArH, J = 5.4 Hz), 7.54 (1H, d, ArH, J = 8.8, 8.8 Hz), 7.94 (1H, d, ArH, J = 8.8 Hz), 8.41 (1H, s, ArH), 8.62 ( 1H, d, ArH, J = 5.4 Hz), 10.16 (1H, s, NH). ESI-MS: m / z 351.4 [M + 1] +; C16H13F3N4S requires 350.08. Anal. RP-HPLC: tR 20.07 min (20-80% MeCN gradient for 20 min); purity > 95% (4-Chloro-3-trifluoromethyl-phenyl) - [4- (4,5-dimethyl-thiazol-2-yl) -pyrimidin-2-yl] -amine (XI) 1 H-NMR (DMSO-de) d: 2.36 (3H, s, CH3), 2.43 (3H, s, CH3), 7.46 (1H, d, ArH, J = 5.4 Hz), 7.65 (1H, d, ArH, J = 8.8 Hz), 7.98 (1H, dd, ArH, J = 8.8, 2.9 Hz), 8.52 (1H, d, ArH, J = 2.9 Hz), 8.65 (1H, d, ArH, J = 5.4 Hz), 10.38 (1H, s, NH). ESI-MS: m / z 385.3 [M + H] +; C16H12CIF3N4S requires 384.04. Anal. RP-HPLC: t R 24.67 min (20-80% MeCN gradient for 20 min); purity > 95% [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (3-nitro-phenyl) -amine (XII) 1 H-NMR (DMSO-de) d: 2.38 (3H, s, CH3), 2.45 (3H, s, CH3), 7.47 (1H, d, ArH, J = 5.4 Hz), 7.61 (1H, dd, ArH, J = 8.8, 8.8 Hz), 7.84 (1H, d, ArH, J = 8.8 Hz), 8.08 (1H, d, ArH, J = 8.8 Hz), 8.67 (1H, d, ArH, J = 5.4 Hz), 9.98 (1H, s, ArH), 10.34 (1H, s , NH). ESI-MS: m / z 328.4 [M + H] +; C15H13N5O2S requires 327.08. Anal. RP-HPLC: t R 23.70 min (10-70% MeCN gradient for 20 min); purity > 95% (6-Methoxy-pyridin-3-yl) -4- (thiazol-2-yl-pyrimidin-2-yl) -amine (Xlll) 1 H-NMR (DMSO-de) d: 3.72 (3H, s, OCH3) , 6.82 (1H, d, ArH, J = 8.8 Hz), 7.43 (1H, d, ArH, J = 4.9 Hz), 7.99 (1H, d, ArH, J = 3.4 Hz), 8.03 (1H, dd, ArH , J = 8.8, 2.9 Hz), 8.08 (1H, d, ArH, J = 3.4 Hz), 8.56 (1H, d, ArH, J = 2.9 Hz), 8.60 (1H, d, ArH, J = 4.9 Hz) 9.76 (1H, s, NH). ESI-MS: m / z 285 [M + H] +; C ^ H ^ NsOS requires 285.07. Anal. RP-HPLC: t R 16.49 min (0-60% MeCN gradient for 20 min); purity > 95% [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (6-methoxy-pyridin-3-yl) -amine (XVI) 1 H-NMR (DMSO-d 6) d: 2.36 (3H, s, CH3), 2.44 (3H, s, CH3), 3.83 (3H, s, OCH3), 6.83 (1H, d, ArH, J = 8.8 Hz), 7.34 (1H, d, ArH, J = 5.4 Hz), 8.02 (1H, dd, ArH, J = 2.9 Hz), 8.55 (1H, d, ArH, J = 5.4 Hz), 8.56 (1H, d, ArH, J = 2.9 Hz), 9.70 (1H , s, NH). ESI-MS: m / z 314.32 [M + H] +; C15H15N5OS requires 313.10. Anal. RP-HPLC: tR 20.26 min (0-60% MeCN gradient for 20 min); purity > 95% (6-Chloro-pyridin-3-yl) - [4- (4,5-dimethyl-thiazol-2-yl) -pyrimidin-2-yl] -amine (XVII) 1 H-NMR (DMSO-d 6) d: 2.36 (3H, s, CH3), 2.45 (3H, s, CH3), 7.44 (1H, d, ArH, J = 5.4 Hz), 7.48 (1H, d, ArH, J = 8.8 Hz), 8.21 (1H, dd, ArH, J = 8.8, 2.9 Hz), 8.62 (1H, d, ArH, J = 5.4 Hz), 8.67 (1H, d, ArH, J = 2.9 Hz), 10.13 (1H, s, NH). ESl-MS: m / z 318.24 [M + H] +; C14H12CIN5S requires 317.05. Anal. RP-HPLC: t R 21.72 min (10-70% MeCN gradient for 20 min); purity > 95% [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (4-morpholin-4-yl-phenyl) -amine (XVIII) 1 H-NMR (DMSO-d 6) d: 2.36 (3H, s, CH3), 2.44 (3H, s, CH3), 3.05 (4H, m, morpholine-H), 3.74 (4H, m, morpholine-H), 6.92 (1H, d, J = 8.5 Hz , ArH), 7.28 (1H, d, J = 5.0 Hz, pyrimidine-H), 7.65 (1H, d, J = 8.5 Hz, ArH), 8.51 (1H, d, J = 5.0 Hz, pyrimidine-H), 9.54 (1H, s, NH). ESI-MS: m / z 368.5 [M + H] +; C? GH21N5OS requires 367.15. Anal. RP-HPLC: t R 13.77 min (10-70% MeCN gradient for 20 min); purity > 95% [4- (4,5-D-methyl-thiazol-2-yl) -pyrimidin-2-yl] - (4-methyl-3-nitro-phenyl) -amine (XIX) 1 H-NMR (CDCl 3) d: 2.43 (3H, s, CH3), 2.47 (3H, s, CH3), 2.58 (3H, s, CH3), 7.29 (1H, d, J = 8.0 Hz, ArH), 7.35 (1H, s, NH), 7.52 (1H, d, J = 5.5 Hz, pyrimidine-H), 7.59 (1 H, dd, J = 8.0, 2.5 Hz, ArH), 8.52 (1H, d, J = 5.5 Hz, pyrimidine-H), 8.72. (1H, d, J = 2.5 Hz, ArH). ESI-MS; m / z 342.4 [M + H] +; C16H15N5O2S requires 341.09. Anal. RP-HPLC: t R 10.49 min (10-70% MeCN gradient for 20 min); purity > 95% 4- [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-ylamino] -phenol (XX) 1 H-NMR (CDCl 3) d: 2.40 (3H, s, CH 3), 2.43 (3H , s, CH3), 6.84 (1H, m, ArH), 7.37 (1H, d, J = 5.0 Hz, pyrimidine-H), 7.47 (1H, m, ArH), 8.40 (1H, d, J = 5.0 Hz , pyrimidine-H). ESI-MS: m / z 299.4 [M + H] +; C15H14N4OS requires 298.09. Anal. RP-HPLC: t R 13.42 min (10-70% MeCN gradient for 20 min); purity > 95% (6-Pyrrolidyryl-1-yl-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine (XXI II) 1 H-NMR (DMSO-de) d: 1.80 (2H , m, CH2), 1.94 (2H, m, CH2), 3.05 (2H, m, NCH2), 3.36 (2H, m, NCH2), 6.44 (1H, d, ArH, J = 8.8 Hz), 7.34 (1H , d, ArH, J = 5.4 Hz), 7.84 (1H, d, ArH, J = 8.8 Hz), 7.98 (1H, d, ArH, J = 3.4 Hz), 8.06 (1H, d, ArH, J = 3.4 Hz), 8.38 (1H, s, ArH), 8.54 (1H, d, ArH, J = 5.4 Hz), 9.45 (1H, s, NH). ESI-MS: m / z 325.41 [M + H] +; C16H16N6S requires 324.40. Anal. RP-HPLC: t R 14.80 min (0-60% MeCN gradient for 20 min); purity > 95% (6-Chloro-5-methyl-pyridin-3-yl) - (4-thiazol-2-if-pyrimidin-2-yl) -amine (XXVII) 1 H-NMR (DMSO-d 6) d: 2.36 (3 H, s, CH 3), 7.54 (1 H, d, Ar H, J = 4.9 Hz), 8.05 (1 H, d, Ar H, J = 2.9 Hz), 8.11 (1 H , d, ArH, J = 2.9 Hz), 8.29 (1H, d, ArH, J = 2.9 Hz), 8.65 (1H, d, ArH, J = 2.9 Hz), 8.71 (1H, d, ArH, J = 4.9 Hz), 10.16 (1H, s, NH). ESI-MS: m / z 304.37 [M + H] +; C13H10CIN5S requires 303.77. Anal. RP-HPLC: tR 23.1 9 min (0-60% MeCN gradient for 20 min); purity > 95% Example 4 2-Oxo-1,2-dihydro-pyrimidine-4-carbaldehyde oxime To a solution of 4-methyl-1 H-pyrimidin-2-one hydrochloride (14.7 g, 0.1 mol) in 50% aqueous acetic acid (1 00 mL) at 1 5 ° C, is added in a portion of sodium nitrite (10.4 g, 0. 15 molj with vigorous stirring.) After an exothermic reaction (~ 40 ° C) a yellow precipitate forms. filter, rinse with cold water, and dry in vacuo to provide the title compound (13.51 g, 97%). H-NMR (DMSO-de) d: 6.65 (1 H, d, ArH, J = 6.4 Hz) , 7.75 (1 H, s, CH), 7.91 (2H, d, ArH, J = 6.4 Hz), 1 1 .87 (1 H, s, NH), 12.41 (1 H, s, OH). MS: m / z 1 39.89 [M + H] +; C5H5N3O2 requires 139.1 1. Anal RP-HPLC: tR 5.35 min (0-60% MeCN gradient for 20 min), purity> 95%. pyrimidine-4-carbonitrile A mixture of 2-oxo-1,2-dihydro-pyrimidine-4-carbaldehyde oxime (5 g, 0.036 mol) in cold phosphorus oxychloride (20 mL) is heated slowly until a vigorous reaction begins , e At such a time the heating is discontinued. Once the complete dissolution has taken place, diethylphenylamine (2.5 mL) is added and the reaction mixture is refluxed for a further 30 min. After cooling the mixture is poured onto ~150 g of ice and extracted in dichloromethane (5 x 30 mL), then rinsed with saturated sodium bicarbonate solution (2 x 50 mL) and water (2 x 50 mL), before of drying over anhydrous magnesium sulfate. After removal of solvent, the residue is dried under vacuum and permanently molded. No further purification was necessary. 1 H-NMR (DMSO-d 6) d: 7.63 (1 H, d, Ar H, J = 4.9 Hz), 8.89 (1 H, d, Ar H, J = 4.9 Hz). Anal. RP-HPLC: t R 12.07 min (0-60% MeCN gradient for 20 min); purity > 95% min. 2- (4-chloro-phenylamino) -pyrimidine-4-carbonitrile 2-chloro-pyrimidine-4-carbonitrile (1.03 g, 7.38 mmol) and 4-chloroanillna (0.94 g, 7.3.8 mmol) are dissolved in ethanol (10 mL) and the solution is heated at 1 00 ° C for 90 min. On cooling the title product is crystallized from the reaction mixture and filtered (0.84 g, 42%). 1 H-NMR (DMSO-d6) d: 7.37 (2H, d, ArH, J = 8.8 Hz), 7.42 (1H, d, ArH, J = 4.9 Hz), 7.72 (2H, d, ArH, J = 8.8 Hz), 8.78 (1 H, d, Ar H, J = 4.9 Hz), 10.32 (1 H, s, NH). ESI-MS: m / z 231 .1 6 [M + H] +; CH H7CIN4 requires 230.65. Anal. RP-HPLC: t R 22.41 min (0-60% MeCN gradient for 20 min); purity > 95% 2- (4-Chloro-phenylamino) -pyrimidine-4-carbothioic acid amide A solution of 2- (4-chloro-phenylamino) -pyrimidine-4-carbonitrile (463 mg, 2.01 mmol) and ammonium sulfide (20%) p / p in H2O, 4 mL) in methanol (10 mL) is heated under reflux for 5 h. Upon cooling, water (1 mL) is added and the resulting precipitate is filtered to provide the title compound (369 mg, 69%). 1 H-NMR (DMSO-de) d: 7.44 (2H, d, ArH, J = 8.8 Hz), 7.53 (1H, d, ArH, J = 4.9 Hz), 7.78 (2H, d, ArH, J = 8.8 Hz), 8.64 (1 H, d, Ar H, J = 4.9 Hz), 9.61 & 10.39 (2H, s, S = CNH2), 9.92 (1 H, s, NH). ESI-MS: m / z 265.81 [M + H] +; CH H9CI 4S requires 264.73. Anal. RP-HPLC: t R 22.03 min (0-60% MeCN gradient for 20 min); purity > 95% 2- (6-Chloro-pyridin-3-ylamino) -pyrimidine-4-carbonitrile This compound is prepared from 2-chloro-pyrimidine-4-carbonitrile and 6-chloro-pyridin-3-ylamine. 1 H-NMR (DMSO-d6) d: 7.48 (1 H, d, ArH, J = 4.9 Hz), 7.51 (1 H, d, ArH, J = 8.8 Hz), 8.17 (1 H, dd, ArH, J = 8.8, 2.9 Hz), 8.70 (1 H, d, Ar H, J = 2: 9 Hz), 8.83 (1 H, d, Ar H, J = 4.9 Hz), 10.51 (1 H, s, NH). ESI-MS: m / z 231 [M] +; C10H6CIN5 requires 231 .03. Anal. RP-HPLC: t R 17.84 min (0-60% MeCN gradient for 20 min); purity > 95% 2- (6-Chloro-pyridin-3-yamino) -pyrimidine-4-carbothioic acid amide This compound is prepared from 2- (6-chloro-pyridin-3-ylamino) -pyrimidine-4-carbonitrile with ammonium sulfide in an analogous manner as described above for 2- (4-chloro-phenylamino) -pyrimidine-4-carbothioic acid amide. 1 H-NMR (DMSO-d6): 7.36 (1 H, d, Ar H, J = 4.9 Hz), 7.45 (1 H, d, Ar H, J = 8.8 Hz), 7.83 &; 7.94 (2H, s, S = CNH2), 8.28 (1 H, dd, ArH, J = 8.8, 2.9 Hz), 8.74 (2H, m, ArH), 10.16 (1 H, s, NH). ESI-MS: m / z 265 [M + H] + (~ 20%); C10H8CIN5S requires 265.02. Anal. RP-HPLC: t R 13.94 min (0-60% MeCN gradient for 20 min); purity > 95% Example 5 1-. { 2- [2- (4-Chloro-phenylamino) -pyrimidin-4-yl] -4-methyl-thiazol-5-yl} -etanone (II) A mixture of 2- (4-chloro-phenylamino) -pyrimidine-4-carbothioic acid amide (31 mg, 0.1 13 mmol), 3-chloro-pentane-2,4-dione (30 μL, 0.249 mmol ), and pyridine (14 μL, 0.17 mmol) in methanol (2 mL) is heated at 150 ° C in a Smith Creator microwave reactor (Personal Chemistry AB, Uppsala, Sweden) for 1 5 min. Upon cooling, the resulting precipitate of the title compound is collected by filtration and rinsed with cold methanol (21 mg, 54%). 1 H-NMR (DMSO-d 6): 2.63 (3 H, s, CH 3), 2.74 (3 H, s, C = OCH 3), 7.39 (2 H, d, Ar H, J = 8.8 Hz), 7.15 (1 H, d , ArH, J = 4.9 Hz), 7.82 (2H, d, ArH, J = 8.8 Hz), 8.71 (1 H, d, ArH, J = 4.9 Hz), 10.08 (1 H, s, NH). ESI-MS: m / z 345 [M + H] +; C16H13C1 N4OS requires 344.05. Anal. RP-HPLC: tR 24.34 min (1 0-70% MeCN gradient for 20 min); purity > 95% Exemplary compounds 11 I-VI I, XV, XXI I, and XXIV-XXVI listed in Table 1 are prepared in a similar manner by reaction of 2- (4-chloro-phenylamino) -pyrimidine-4-carbothioic acid amide or amide of 2- (6-chloro-pyridin-3-ylamino) -pyrimidine-4-carbothioic acid with the appropriate haloacyl compound (1-chloro-propan-2-one, 2-bromo-1-phenyl-ethanone, ethyl ester of 2-chloro-3-oxo-butyric acid, 4-cyclo-3-oxo-butyric acid methyl ester, 2-bromo-malonic acid methyl ester, 2-bromo-propionic acid ethyl ester, or ethyl ester of acid 2-bromo-4-hydroxy-butyric). (4-Chloro-phenyl) - [4- (4-methyl-thiazol-2-yl) -pyrimidin-2-yl] -amine (lll) 1 H-NMR (DMSO-d 6): 2.47 (3H, s, CH 3 ), 7.36 (2H, d, ArH, J = 8.8 Hz), 7.44 (1 H, d, ArH, J = 4.9 Hz), 7.59 (1 H, s, ArH), 7.84 (2H, d, ArH, J = 8.8 Hz), 8.64 (1 H, d, ArH, J = 4.9 Hz), 9.98 (1 H, s, NH). ESI-MS: m / z 303 [M + H] +; C14HnCIN4S requires 302.04. Anal. RP-HPLC: t R 20.74 min (20-80% MeCN gradient for 20 min); purity > 95% 2- [2- (4-Chloro-phenylamino) -pyrimidin-4-yl] -4-hydroxy-thiazole-5-carboxylic acid ethyl ester (Vi l) 1 H-NMR (DMSO-de): 1.28 ( 3H, t, CH3, J = 7.3 Hz), 4.24 (2H, q, CH2, J = 7.3 Hz), 7.31 (1 H, d, ArH, J = 5.4 Hz), 7.36 (1 H, d, ArH, J = 8.8 Hz), 7.78 (1 H, d, Ar H, J = 8.8 Hz), 8.70 (1 H, d, Ar H, J = 5.4 Hz), 9.94 (1 H, s, NH), 12.18 (1 H , s, OH). ESI-MS: m / z 377.25 [M + H] +; C16H13CIN4O3S requires 376.04. Anal. RP-HPLC: t R 20.90 min (20-80% or MeCN gradient for 20 min); purity > 95%, 1-. { 2- [2- (6-Chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -4-methyl-thiazol-5-yl} -etanone (XV) 1H-NMR (DMSO-d6): 2.63 (3H, s, CH3), 2.74 (3H, s, C = OCH3), 7.52 (1H, d, ArH, J = 8.8 Hz), 7.57 (1 H, d, ArH, J = 5.4 Hz), 8.22 (1 H, dd, ArH, J = 8.8, 2.9 Hz), 8.75 (1 H, d, ArH, J = 5.4 Hz), 8.86 (1 H , d, ArH, J = 2.9 Hz), 10.28 (1 H, s, NH). ESI-MS: m / z 346 [M + H] +; C15H12CIN5OS requires 345.05. Anal. RP-HPLC: t R 19.77 min (10-70% MeCN gradient over 20 min); purity > 95% 2- [2- (4-Chloro-phenylamino) -pyridin-4-yl] -5-methyl-thiazol-4-ol (XXI I) 1 H-NMR (DMSO-de): 2.28 (3H, s, CH 3 ), 7.26 (1 H, d, Ar H, J = 5.4 Hz), 7.37 (2 H, d, Ar H, J = 8.8 Hz), 7.36 (2 H, d, Ar H, J = 8.8 Hz), 7.82 (1 H, d, ArH, J = 5.4 Hz), 9.91 (1 H, s, NH), 1 0.61 (1 H, s, OH). ESI-MS: m / z 319.24 [M + H] +; C15H12CIN3OS requires 317.04. Anal. RP-HPLC: t R 16.76 min (20-80% MeCN gradient for 20 min); purity > 95% 2- [2- (6-Chloro-pyridin-3-ylamino) -pyrmidin-4-yl] -4-hydroxy-thiazole-5-carboxylic acid ethyl ester (XXIV) 1 H-NMR (DMSO-d6): 1.28 (3H, t, CH3, J = 6.8 Hz), 4.25 (2H, q, OCH2, J = 6.8 Hz), 7.43 (1H, d, ArH, J = 4.9 Hz), 7.50 (1H, d, ArH, J = 8.8 Hz), 8.18 (1H, dd, ArH, J = 8.8, 2.9 Hz), 8.75 (1H, d, ArH, J = 4.9 Hz), 8.88 (1H, d, ArH, J = 2.9 Hz), 10.25 (1H, s, NH). ESI-MS: m / z 378.42 [M + H] +; C15H12CIN5O3S requires 377.81. Anal. RP-HPLC: t R 14.67 min (10-70% MeCN gradient over 20 min); purity > 95% 2- [2- (6-Chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -5-methyl-thiazol-4-ol (XXV) 1 H-NMR (DMSO-de): 2.28 (3H, s , CH3), 7.32 (1H, d, ArH, J = 4.9 Hz), 7.47 (1H, d, ArH, J = 8.8 Hz), 8.22 (1H, dd, ArH, J = 8.8, 2.9 Hz), 8.62 ( 1H, d, ArH, J = 4.9 Hz), 8.86 (1H, d, ArH, J = 2.9 Hz), 10.10 (1H, s, NH), 10.64 (1H, s, OH). ESI-MS: m / z 320.22 [M + H] +; C13H10CIN5OS requires 319.77. Anal. RP-HPLC: t R 15.51 min (10-70% MeCN gradient for 20 min); purity > 95% 2 ~ [2- (6-Chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -5- (2-hydroxy-ethyl) -thiazole-4-oi (XXVI) 1 H-NMR (DMSO-d6) : 2.83 (2H, t, CH2, J = 6.7 Hz), 3.35 (CH2OH, J = 6.7 Hz), 4.93 (1H, s, OH), 7.33 (1H, d, ArH, J = 5.4 Hz), 7.47 ( 1H, d, ArH, J = 8.3 Hz), 8.22 (1H, dd, ArH, J = 8.3, 2.4 Hz), 8.61 (1H, d, ArH, J = 5.4 Hz), 8.88 (1H, d, ArH, J = 2.4 Hz), 10.10 (1H, s, NH), 10.66 (1H, s, OH). ESI-MS: m / z 348.34 [M + H] +; C14H12CIN5O2S requires 349.80. Anal. RP-HPLC: t R 9.41 min (20-80% MeCN gradient for 20 min); purity > 95% Example 6 2- (3-Hldroxy-phenylamino) -isonicotinonitrile 2-Chloro-isonicotinonitrile (1.0 eq) is dissolved in anhydrous toluene before the addition of 3-amino-phenol (1.1 eq), palladium II acetate (0.1 eq), and bis (diphenylphosphino) propane (0.12 eq). The reaction mixture is stirred at room temperature for 10 min before the addition of sodium tert-butoxide (1.3 eq). The resulting suspension is heated at 70 ° C for 20 h. The reaction mixture is cooled, diluted with diethyl ether, and rinsed with brine. The organic fraction is dried (MgSO 4) and concentrated in vacuo. The crude product is purified by silica gel column chromatography [heptane: ethyl acetate (12:? 1: 1)] to provide the desired title product, as well as 2-chloro -? / - (3-hydroxy) -phenyl) -isonicotinamidine as a secondary product [33]. 2- (3-Hydroxy-phenylamino) -thioisonicotin amide 2- (3-Hydroxy-phenylamino) -isonicotinonitrile is dissolved in methanol before the addition of ammonium sulphide (20% in water). The reaction mixture is heated at 75 ° C for 3 h. Water is added to the cooling solution and the desired title product is filtered, rinsed with cold water, and dried. 1-. { 2- [2- (4-Hydroxy-phenylamino) -pyridin-4-yl] -4-methyl-thiazol-5-yl} -etanone (XX1) 2- (3-Hydroxy-phenylamino) -thioisonicotinamide (1.0 eq) is dissolved in methanol before the addition of pyridine (1.4 eq) and 3-chloro-2,4-pentadione (1) .1 eq). The reaction mixture is heated (150 ° C) in a Smith Creator microwave reactor for 15 min. The resulting solution is cooled and concentrated in vacuo to obtain the crude product. The crude product is purified using silica gel column chromatography [heptane: ethyl acetate (12: 1 → 3: 1)] to provide the title compound. 1 H-NMR (DMSO-d6) d: 2.58 (3H, s, CH3), 2.71 (3H, s, CH3), 6.70 (2H, d, ArH, J = 8.5 Hz), 7.15 (1H, d, ArH, J = 5.5 Hz), 7.36 (3H, m, ArH,), 8.14 (1 H, d, Ar-H, J = 5.5 Hz), 9.21 (1 H, s, NH). ESI-MS: m / z 326 [M + H] +; C17H15N3O2S requires 325.08. Anal. RP-HPLC: t R 10.49 min (10-70% MeCN gradient for 20 min); purity > 95% Example 7 Production of recombinant proteins CDK4 / cyclin D1, CDK1 / cyclin B, CDK2 / cyclin E, CDK2 / cyclin A, CDK9 / cyclin T1 and CDK7 / cyclin H, all with a His6 tag at the N-terminus, are expressed in Sf9 insect cells using an appropriate baculovirus construct. Culture Sf9 (1.6 x 106 cells / mL) is infected (MOI of 3) for two days. The cells are harvested by low speed centrifugation and the protein is purified from the insect cell pellet by metal affinity chromatography. In summary, the insect cell pellet is smoothed on Regulator A (10 mM Tris-HCl pH 8.0, 150 mM NaCl, 0.02% NP-40.5 mM β-mercaptoethanol, 20 mM NaF, 1 mM Na3VO4, and Cocktail of Sigma Protease Inhibitor) by sonication. The soluble fraction is cleared by centrifugation and loading in Ni-NTA-Agarose (Qiagen). Unbound protein is rinsed with 300 mM NaCl, 5-15 mM imidazole in regulator A and the bound protein is eluted with regulator A supplemented with 250 mM imidazole. The purified proteins are dialyzed extensively against storage buffer (20 mM HEPES pH 7.4, 50 mM NaCl, 2 mM DTT, 1 mM EDTA, 1 mM EGTA, 0.02% NP-40, 10% v / v glycerol) and Store at -70 ° C. Example 8 Kinase activity GSK-33 GSK-3 is obtained from New England Biolabs (UK) Ltd.

Hitchin, Herts. The recombinant enzyme is isolated from a strain of £. coli carrying a clone expressing GSK-3β derived from a rabbit skeletal muscle cDNA library [34]. Inhibition of GSK-3 function is assessed by phosphorype phosphorylation measurement of CREB KRREl LSRRPpSYR in the presence of test compounds. Using a 96-well assay format, GSK3 (7.5 U) is incubated for 30 min at 30 ° C in a total volume of 25 μL in 20 mM MOPS pH 7.2, 25 mM ß-glycerophosphate, 5 mM EGTA, 1 mM DTT , 1 mM Na3VO3, 40 μM peptide CREB, 15 mM MgCl2 and 100 μM ATP (containing 0.25 μCi [y-32P] -ATP) in the presence of variable concentrations of test compound. Samples are transferred to 96-well p81 filter plates (Whatman Polyfiltronics, Kent, UK), and the plates are rinsed 4 times with 200 μL / well of 75 mM aqueous orthophosphoric acid. Sample liquid (50 μL) is added to each well, and incorporated radioactivity for each sample is determined using a scintillation counter (TopCount, Packard Instruments, Pangbourne, Berks, UK). Cyclin / CDK Kinase Assays The compounds are investigated for their inhibitory activity of CDK2 / cyclin E, CDK2 / cyclin A, CDK1 / cyclin B, and CDK4 / cyclin D1. Recombinant human cyclin-dependent kinases labeled with His6 CDK1 / cyclin B1, CDK2 / cyclin E, CDK2 / cyclin A, and CDK4 are expressed in sf9 insect cells using a baculovirus expression system. Recombinant cyclin D1 is expressed in E. coli. Proteins are purified by metal chelate affinity chromatography at more than 90% homogeneity. Kinase assays are performed in 96-well plates using CDK / recombinant cyclins. The assays are performed in assay buffer (25 mM ß-glycerophosphate, 20 mM MOPS, 5 mM EGTA, 1 mM DTT, 1 mM Na3VO3, pH 7.4), in which 2-4 μg of active enzyme is added with appropriate substrates (Histone purified H 1 for CDK1 and CDK2, recombinant GST retinoblastoma protein (residues 773-928) for CDK4). The reaction is initiated by the addition of Mg / ATP mixture (15 mM MgCl2 + 100 μM ATP with 30-50 kBq per [? -32P] -ATP cavity) and the mixtures are incubated for 10-45 min, as required , at 30 ° C. The reactions are stopped on ice, followed by filtration through p81 or GF / C filter plates (for CDK4) (Whatman Polyfiltronics, Kent, UK). After rinsing 3 times with 75 mM orthophosphoric acid ac, the plates are dried, scintillator is added and the measured radioactivity is incorporated in scintillation counter (TopCount, Packard Instruments, Pangbourne, Berks, UK). Compounds for kinase assays are made as reservoirs of 10 mM in DMSO and diluted in 10% DMSO in assay buffer. The data is analyzed using curve fitting software (GraphPad Prism version 3.00 for Windows, GraphPad Software, San Diego California USA) to determine IC50 values (concentration of compound test that inhibits kinase activity by 50%). Example 9 Differentiation of rat myocytes L6 and 3T3 mouse adipocytes Rat skeletal muscle myoblasts L6 / G8.C5 are seeded at 2.4 x 10 5 cells per 1 cm dish in DMEM 1 0% fetal bovine serum (FCS), containing penicillin / streptomycin. When 90% of confluence is reached, the medium is exchanged with MEM, supplemented with 2%. FCS and penicillin / streptomycin. The medium is cooled c 48 hours and 4-7 days later the myocytes are formed. The 3T3-F442A mouse pre-adipocytes are seeded in 9x105 cells per 1 cm dish in 10% FCS DMEM, containing penicillin / streptomycin. When 90% confluent, the same medium is supplemented with 1 μg / mL insulin. After 3-5 days (when most cells differentiate) the insulin is removed and 4 days later the cells were ready to be used. Glycogen synthase (GS) assay Cells in 10 cm dishes (293 Human Embryonic Kidney (HEK) cells, L6 rat myocytes, or 3T3 mouse adipocytes) are treated with different concentrations of GSK3 inhibitors or DMSO vehicle by 90 min. The incubation medium is removed and the cells are rinsed with cold phosphate buffered saline (PBS) before using on ice in 50 mM HEPES, pH 7.5, 10 mM EDTA, 100 mM NaF, 5 mM DTT, cocktail of protease inhibitor (Sigma).

After a freeze / thaw cycle the samples are sonicated for 10 sec and centrifuged at 1 5,000 g for 10 min at 4 ° C. The supernatants of lysate are rapidly frozen in liquid nitrogen and stored at -80 ° C. The lysates are assayed for glycogen synthase activity in regulator (50 mM Tris-HCl, pH 7.8, 20 mM EDTA, 25 mM NaF, 5 mM DTT, 1% glycogen, 0.3 mM UDP-glucose and 0.06 μCi of [14C] -UDP-glucose in the presence of 0.1 or 10 mm glucose-6-phosphate The reaction is carried out for 30 min at 30 ° C. 70 μL of the reaction mixture (total volume 90 μL) are transferred to a plate of 96-well GFC filter (bottom sealed with aluminum foil), containing 140 μL 96% ethanol.The GFC plate is incubated for 1 h on ice and then rinsed with 66% ethanol.To each cavity 100 μL of scintillating liquid is added and the radioactivity of the samples is measured using a scintillation counter (Topcount, HP) The data are expressed as -increment at times in glycogen synthase activity ratios over those of the control samples.Example 10 Table 2 summarizes the biological activity of the exemplified compounds Example 1 1 Intrinsic inhibition constants (Ki) for example, compound XIV against a number of Ser / Thr kinases are determined and summarized in Table 3. Example 12 Compound of Example XIV increased the activity of glycogen synthase in HEK293, rat myocyte, and mouse adipocyte cells, measured by the fractional velocity of the enzyme (the ratio between the activity at 0.1 and 10 mM glucose-6-phosphate). An example of activation in HEK293 and adipocyte cells is shown in Table 4. Exemplary compound XIV increased GS activity in HEK293 cells and 3T3 adipocytes. 5 μm XIV induced the activation of GS in HEK293 cells comparable to that induced by 40 mM Lie. In 3T3 adipocytes the activation induced by 5 μM was approximately 2 times higher than that induced by 40 mM LiCI. The EC50 values for XIV-induced activation of glycogen synthase in the three cell lines evaluated are calculated from dose response curves: EC50 (HEK293) = 1.5. 0.6 μM; EC50 (myocytes L6) = 4.0 ± 1.5 μM; EC50 (3T3 adipocytes) = 5.0 ± 2.3 μM. Example 13 Selection of selectivity of the protein guinasa panel of compound XIV The names of the 29 kinases comprising the selection of selectivity, as well as the concentrations of ATP used in each case of kinase, are given in Table 5. The test of Kinase is carried out as previously described [35,36].

Compound XIV at a concentration of 1 μM is selected from the panel of 29 kinases (Dundee University) and the results are shown below in Table 6. Compound XIV was highly selective for GSK3. At the concentration used only two other kinases were slightly inhibited (approximately 40%) - JNK and SAPK4. Example 14 Accumulation of β-catenin and transcriptional activation One of the possible toxicities related to the inhibition of GSK3 is the accumulation of β-catenin, which has been implicated in the development of colon cancer [37] and melanoma [38]. The effect of the exemplary compound XIV on the endogenous levels of β-catenin in HEK293 cells is studied in concentrations that are effective in the activation of cellular glycogen synthase. Compound XIV (up to 5 μM) does not significantly change the levels of cellular β-catenin, does not inhibit phosphorylation at specific sites GSK3 S33.37 / T41, as shown in Figure 1. In addition, the effect of compound XIV on β-catenin-dependent transcription activity, as measured in a luciferase-based reporter gene assay, was studied. No induction of transcriptional activity of β-catenin is observed in HEK293 cells treated with compound XIV (up to 10 μM). At the same time, LiCI induced the massive induction of β-catenin-dependent luciferase activity. These results suggest that, at concentrations required for the activation of glycogen synthase, compound XIV does not inhibit β-catenin phosphorylation and therefore does not induce the accumulation of the protein or its transcriptional activity. Reporter gene assay regulated by β-Catenin-LEF / TCF HEK293 cells are transfected with either reporter vector insensitive to LEF / TCF-β-catenin or sensitive to LEF / TCF-β-catenin (Upstate Biotechnology, Inc.) using Lipofectamine Plus reagent (GibcoBRL) according to the manufacturer's instructions. The next day, the cells are trypsinized, rinsed in serum-free medium, counted and plated in 40,000 cells per well in a 96-well plate. Subsequent to cell binding, the inhibitor compound LiCI or GSK-3 are added to the medium at the required concentrations. The control cells were treated by vehicle DMSO. 16 h after the addition of inhibitor, the cells are analyzed for luciferase activity using the Steady-Glo Luciferase assay system (Promega) according to the manufacturer's instructions. Example 15 Oral glucose tolerance test (OGTT) For ZDF fa / fa male OGTT rats (Charles River, USA), those of 10-1 1 weeks of age are used. After 15 h the feeding of the animals is dosed intravenously with 5 mg / kg compound test in dosing vehicle, or with dosing vehicle (10% DMSO, 90% PEG-400) only at -270 and -30 min. At 0 min, the rats are given 2 g / kg of glucose by oral forced feeding. Plasma samples are taken before and every 15 minutes after OGTT for the determination of blood glucose. Compound XIV improved glucose tolerance in ZDF rats significantly. Absolute and reactive AUC levels are reduced by 44 and 29%, respectively. Various modifications and variations of the described aspects of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention Although the invention has been described in connection with the specific preferred embodiments, it should be understood that the invention as claimed, it should not be unduly limited to such specific embodiments, however, various modifications of the modes described for carrying out the invention that are obvious to those skilled in the relevant fields are proposed to be within the scope of the following claims.

REFERENCES [1] Chen, Y. H.; Hansen, L.; Chen, M.X.; Bjorbaek, C; Vestergaard, H.; Hansen, T.; Cohen, P.T.; Pedersen, O. Diabetes, 1994, 43, 1234. t2] Nikoulina, S. E.; Ciaraldi, T. P.; Mudaliar, S.; Mohideen, P.; Cárter, L.; Henry, R. R. Diabetes, 2000, 49, 263. [3] Frame, S.; Cohen, P. Biochem. J., 2001, 359, 1. [4] Mattson, M. P. Nat Rev. Mol Cell Biol, 2000, 1, 120. [5] Goedert, M. Curr. Opin. Gen. Dev., 2001, 1 1, 343. [6] Zhu, A.J .; Watt, F.M. Development, 1999, 126, 2285. [7] DasGupta, R .; Fuchs, E. Development, 1999, 126, 4557. [8] Katritzky, A.R .; Ostercamp, D.L .; Yousaf, T.l. Tetrahedron, 1987, 43, 5171. [9] Baum, F. Chem. Ber., 1908, 41, 532. [10] Zimmermann, J .; Caravatti, G .; Mett, H .; Meyer, T .; Müller, M .; Lydon, N.B .; Fabbro, D. Arch. Pharm. Pharm. Med. Chem., 1996, 329, 371. [11] Feichtinger, K .; Zapf, C; Sings, H.L .; Goodman, M. J. Org. Chem., 1998, 63, 3804. [12] Katritzky, A.R .; Parris, R.L .; Allin, S.M .; Steel, P.J. Synth Commun., 1995, 25, 1173. [13] Bredereck, H .; Effenberger, FJ; Botsch, H. Chem. Ber., 1964, 97, 3397. [14] Davies, D.H .; Hall, J .; Smith, E.H. J. Chem. Soc. Perkin Trans. 1, 1991, 2691. [15] Jones, G .; Ollivierre, H .; Fuller, L.S .; Young, J.H. Tetrahedron, ' 1991, 47, 2861 [16] Metzger, J .; Koether, B. Bull. Soc. Chim. France, 1953, 702. [17] Kiss, J .; D'Souza, R .; Spiegelberg, H. Helv. Chim. Acta, 1968, 51, 825. [18] Riley, T.A .; Hennen, W.J .; Dalley, N.K .; Wilson, B.E .; Robins, R.K .; Larson, S.B. J. Heterocycl. Chem., 1987, 24, 955 [19] Dorigo, P .; Fraccarollo, D .; Santostasi, G .; Maragno, I .; Floreani, M .; Borea, P.A .; Mosti, L .; Sansebastiano, L .; Fossa, P .; et al. J. Med. Chem., 1996, 39, 3671 [20] Goel, O.P .; Krolls, U. Synthesis, 1987, 162. [21] Raucher, S .; Klein, P. J. Org. Chem., 1981, 46, 3558. [22] Yde, B .; Yousif, N. M .; Pedersen, U .; Thomsen, I .; Lawesson, S.O. Tetrahedron, 1984, 40, 2047. [23] Cava, M.P .; Levinson, M.l. Tetrahedron, 1985, 41, 5061. [24] Varma, R.S .; Kumar, D. Org. Lett., 1999, 1, 697. [25] Spychala, J. Tetrahedron, 2000, 56, 7981. [26] Chsontte, A.B .; Grenon, M. J. Org. Chem., 2003, 68, 5792. [27] Hurst, D.T .; Biggadike, K .; Tibble, J.J. Heterocycles, 1977, 6, 2005. [28] Schlieper, C.A .; Wemple, J. Nucleosides & Nucleotides, 1984, 3, 369. [29] Clark, J .; Pendergast, W. Journal of the Chemical Society [Section] C: Organic, 1969, 2780. [30] Daves, G.D., Jr .; O'Brien, D.E .; Lewis, L.R .; Cheng, C.C. J.

Heterocycl. Chem., 1964, 1, 130. [31] Lipinski, C.A .; Craig, R.H .; Wright, R.B. J. Heterocycl. Chem., 1985; 22, 1723. [32] Warczykowska, I .; Wojciechowski, J. Polish Journal of Chemistry, 1980, 54, 335. [33] Wagaw, S .; Buchwald, S.L. J. Org. Chem., 1996, 61, 7240. [34] Wang, Q.M .; Fiol, C.J .; DePaoli-Roach, A.A .; Roach, P.J. J.

Biol. Chem., 1994, 269, 14566. [35] Bain, J .; McLauchlan, H .; Elliott, M .; Cohen, P. Biochem. J., 2003, 371, 199. [36] Davies, S.P .; Reddy, H .; Caívano, M .; Cohen, P. Biochem. J., 2000, 351, 95. [37] Korinek, V .; Barker, N .; Morin, P.J .; van Wichen, D .; from Weger, R .; Kinzier, K.WJ; Vogelstein, B .; Clevers, H. Science, 1997, 275, 1784. [38] Rubinfeld, B .; Robbins, P .; El-Gamil, M .; Albert, I .; Porfiri, E .; Polakis, P. Science, 1997, 275, 1790. [39] Wang D, Source C, Deng L, Wang L, Zilberman I, Eadie C, Healey M, Stein D, Denny T, Harrison LE, Meijer L, Kashanchi F. Inhibition of human immunodeficiency virus type 1 transcription by chemical cyclin-dependent kinase inhibitors. J. Virol.2001; 75: 7266-7279. [40] Goedert, M. Curr. Opin. Gen. Dev., 2001, 11.343. [41] Sunkel et al., J. Cell Sci-, 1988, 89, 25. [42] Llamazsons et al., Genes Dev., 1991, 5, 2153. [43] Glover et al., Genes Dev., 1998, 12, 3777. [44] Lee et al., Proc. Nati Acad. Sci. USA, 1998, 95, 9301. [45] Leung et al., Nat. Struct. Biol., 2002, 9, 719. [46] Kauselmann et al., EMBO J., 1999, 18, 5528. [47] Nigg, Curr. Opin. Cell Biol., 1998, 10, 776. [48] Yuan et al., Cancer Res., 2002, 62, 4186. [49] Seong et al., J. Biol. Chem., 2002, 277, 32282. [ 50] Lane et al., J. Cell. Biol., 1996, 135, 1701. [51] Cogscavidad et al., Cell Growth Differ., 2000, 11, 615.

[52] Liu et al., Proc. Nati Acad. Sci. USA, 2002, 99, 8672.

[53] Toyoshima-Morimoto et al., Nature, 2001,410, 215. [54] Roshak et al., Cell. Signaling, 2000, 12, 405. [55] Smits et al., Nat. Cell Biol., 2000, 2, 672. [56] van Vugt et al., J. Biol. Chem., 2001, 276, 41656. [57] Sumara et al., Mol. Cell, 2002, 9, 515. [58] Golan et al., J. Biol. Chem., 2002, 277, 15552. [59] Kotani et al., Mol. Cell, 1998,1, 371. [60] Feng et al., Cell Growth Differ., 2001, 12, 29. [61] Dai et al., Oncogene, 2002, 21, 6195. [62] Nurse, Nature, 1990, 344, 503. [63] Nigg, Nat. Rev. Mol. Cell Biol., 2001, 2, 21. [64] Hagtlng et al., EMBO J., 1998, 17, 4127. [65] Hagting et al., Curr. Biol., 1999, 9, 680. [66] Yang et al., J. Biol. Chem., 2001, 276, 3604. [67] Takizawa et al., Curr. Opin. Cell Biol., 2000, 12, 658.

[68] Seki et al., Mol. Biol. Cell, 1992, 3, 1373. [69] Heald et al., Cell, 1993, 74, 463. [70] Dalal et al., Mol. Cell. Biol., 1999, 19, 4465. [71] Toyoshima-Morimoto et al., Nature, 2001,410, 215. [72] Toyoshima-Morimoto et al., EMBO Rep., 2002, 3, 341.

[73] Wang et al., Mol. Cell. Biol., 2002, 22, 3450.

Table 1. Exemplifying compounds Table 2: In vitro kinase activity and activation of cellular glycogen synthase by exemplary compounds aIC50 (CDK2 / E) / IC50 (GSK3β) 6 In HEK293 cells in [compound] = 5 μM CNA - not active in primary selection (inhibition <50% at 1 μM) d Not determined Table 3. GSK against CDK selectivity of the exemplary compound XIV Table 4. Activation of cellular glycogen synthase activity by exemplary compound XIV Table 5. Description of protein kinase panel Table 6. Selective kinase selectivity of exemplary compound XIV (1 μM).

Claims (6)

CLAIMS 1. A compound of formula I, a pharmaceutically acceptable salt thereof, wherein: Z1 is N or CH; Z2 and Z3 are each independently N or CR7; R1, R2, R3, R4, R5, R6, and R7 are each independently H, R8, or R9; each R8 is independently a hydrocarbyl group; and each R9 is independently halo, NO2, alkoxy, CN, CF3, SO3H, SO2NR10R1 1, SO2R12, NR13R14, (CH2) aCOOR15, (CH2) bCONR16R17, (CH2) cCOR18 or (CH2) dOH; a, b, c and d are each independently 0, 1 2 3 or 4; R 10-18 are each independently H or alkyl; provided that when R1 and R2 are both H, Z1 is CH; or Z2 is N; or Z1 is CH and Z2 is N; and wherein the compound is other than 4- (4,5-dimethylthiazol-2-yl) -N- (3,4,5-trimethoxyphenyl) -2-pyrimidineamine or 4- (5- (2-hydroxyethyl) -4 - methylthiazol-2-yl) -N- (3,4,5-trimethoxyphenyl) -2-pyrimidineamine. 2. A compound according to claim 1 wherein each R8 is independently a C?, Hydrocarbyl group, optionally containing up to twelve heteroatoms selected from N, S, and O, and optionally carrying up to six substituents each independently selected from halo, NO2, CN, CF3, SO3H, SO2NH2, SO2Me, OH, NH2, COOH, and CONH2. 3. A compound according to claim 1 or claim 2 wherein each R8 is independently an alkyl group, an aryl group or a cycloheteroalkyl group. 4. A compound according to claim 1 or claim 2 wherein each R9 is independently halo, NO2, alkoxy, CN, CF3, SO3H, SO2NH2, SO2Me, OH, NH2, (CH2) aCOOR15, (CH2) dOH, CONH2 or COR18. 5. A compound according to any preceding claim wherein: R1 is H, alkyl, aryl, (CH2) aCOOR1 or OH; R2 is H, (CH2) dOH, (CH2) aCOOR15, COR18 or alkyl; R3 is halo, H, alkoxy, cycloheteroalkyl, alkyl or OH; R4 is H, NH2, OH, alkyl, CF3 or NO2; and R5 and R6 are both H. 6. A compound according to any preceding claim wherein: R1 is H, Me, Ph, CH2COOMe or OH; R2 is H, (CH2) 2OH, COOEt, COMe or Me; R3 is Cl, H, OMe, N-morpholinyl, N-pyrrolidinyl, Me or OH; R4 is H, NH2, OH, Me, CF3 or NO2; and R5 and R6 are both H. 7. A compound according to claim 1 wherein Z1 is CH and Z2 and Z3 are each independently N or CR7. 8. A compound according to claim 7 wherein Z2 and Z3 are each independently CR7. 9. A compound according to claim 7 or claim 8 wherein; R1 is alkyl or OH; R2 is alkyl or COR1 8; R3 is OH or halo; and Z2 and Z3 are both CH. 10. A compound according to claim 9 wherein R1 is Me or OH, R2 is COMe or Me, and R3 is OH or Cl. 1 1. A compound according to claim 1 wherein Z1 is N and Z2 and Z3 are each independently N or CR7. 12. A compound according to claim 1 wherein Z2 and Z3 are each independently CR7. 13. A compound according to claim 12 wherein: R is alkyl, aryl, OH or (CH2) aCOOR15; R2 is COR18, H, COOR15 or alkyl; R3 is halo, H, OH, alkyl or morpholino; R4 is H, NH2, OH, CF3 or NO2; and Z2 and Z3 are both CH. 14. A compound according to claim 1 wherein: R1 is Me, Ph, OH or CH2COOMe; R2 is COMe, H, COOEt or Me; and R3 is halo, H, OH, alkyl or morpholino. 1 5. A compound according to claim 1 wherein Z2 is N and Z3 is CR7. 16. A compound according to claim 15 wherein: R1 is H, OH or alkyl; R2 is H, (CH2) dOH, alkyl, (CH2) aCOOR15, COR18; R3 is halo, alkoxy or heterocycloalkyl; R 4 is H or alkyl; and Z3 is CH. 17. A compound according to claim 16 wherein: R1 is H, OH or Me; R2 is H, (CH2) 2OH, Me, COOEt, COMe; R3 is halo, OMe or N-pyrrolidinyl; R4 is H or Me; and Z3 is CH. 18. A compound according to claim 1 which is selected from the following: 1 -. { 2- [2- (4-Chloro-phenylamino) -pyrimidin-4-yl] -4-methyl-thiazol-5-yl} -etanone (4-chloro-phenyl) - [4- (4-methyl-thiazol-2-yl) -pyrimidin-2-yl] -amine (4-chloro-phenyl) - [4- (4-phenyl-thiazole -2-yl) -pyrimidin-2-yl] -amine 2- [2- (4-Chloro-phenylamino) -pyrimidin-4-yl] -4-methyl-thiazole-5-carboxylic acid ethyl ester Methyl ester of acid. { 2- [2- (4-Chloro-phenylamino) -pyrimidin-4-yl] -thiazoI-4-yl} -acetic acid 2- [2- (4-Chloro-phenylamino) -pyrimidin-4-yl] -4-hydroxy-thiazole-5-carboxylic acid ethyl ester? / - [4- (4, 5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] -benzene-1,3-diamine 3- [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-ylamino ] -phenol [4 - '(4,5-Dimethyl-thiazol-2-yl) -pyrim id in-2-yl] - (3-trif luoromethyl-f en il) -am ina (4-Chloro-3-) trifluoromethyl-phenyl) - [4- (4,5-dimethyl-thiazol-2-yl) -pyrimidin-2-yl] -amine [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2 -yl] - (3-n-phenyl) -amine (6-methoxy-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine (6-chloro-pyridine -3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine 1 -. { 2- [2- (6-Chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -4-methyl-thiazole-5-yl} -etanone [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (6-methoxy-pyridin-3-yl) -amine (6-chloro-pyridin-3-yl) - [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] -amine [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (4-morpholin-4-yl-phenyl) -amine [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (4-methyl-3-nitro-phenyl) -amine 4- [4- (4,5-D-methyl-thiazol-2-yl) -pyrimidin-2-ylamino] -phenol 2- [2- (4-chloro-phenylamino) -pyridin-4-yl] -5-methyl-thiazol-4-ol (6-pyrrolidin-

1-yl-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine Ethyl ester of acid 2- [ 2- (6-Chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -4-hydroxy-thiazole-5-carboxylic acid 2- [2- (6-chloro-pyridin-3-ylamino) -pyrimidin-4 -yl] -5-methyl-thiazole-4-ol 2- [2- (6-Chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -5- (2-hydroxy-ethyl) -thiazole-4-ol (6-chloro-5-methyl-pyridine- 3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine. 19. A compound according to claim 1 which is selected from the following: 2- [2- (4-Chloro-phenylamino) -pyrimidin-4-yl] -4-hydroxy-thiazole-5-carboxylic acid ethyl ester; ? / - [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] -benzene-1,3-diamine 3- [4- (4,5-Dimethyl-thiazole-2- il) -pyrimidin-2-ylamino] -phenol [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (3-trifluoromethyl-phenyl) -amine (4-Chloro-3-trifluoromethyl-phenyl) - [4- (4,5-dimethyl-thiazol-2-yl) -pyrimidin-2-yl] -amine (6-methoxy-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amina (6-chloro-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) - amine [4- (4,5-Dimethyl-thiazol-2-yl) -pyrimidin-2-yl] - (6-methoxy-pyridin-3-yl) -amine

2- [2- (4-Chloro-phenylamino) -pyridin-4-ii] -5-methyl-thiazol-4-ol (6-pyrrolidin-1-yl-pyridin-

3-yl) - (

4-thiazole) 2-yl-pyrimidin-2-yl) -amine 2- [2- (6-Chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -4-hydroxy-thiazole-

5-carboxylic acid ethyl ester 2 - [2- (

6-Chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -5-methyl-thiazol-4-ol 2- [2- (6-chloro-pyridin-3-ylamino) -pyrimidine -4-yl] -5- (2-hydroxy-ethyl) -thiazole-4-ol (6-chloro-5-methyl-pyridin-3-yl) - (4-thiazol-2-yl-pyr) midin-2-yl) -amine. 20. A compound according to claim 1 which is selected from the following: 2- [2- (4-Chloro-phenylamino) -pyrimidin-4-yl] -4-hydroxy-thiazole-5-carboxylic acid ethyl ester; (6-Methoxy-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine; and (6-Chloro-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine 2- [2- (4-chloro-phenylamino) -pyridin-4-yl] - 5-methyl-thiazol-4-ol (6-pyrrolidin-1-yl-pyridin-3-yl) - (4-thiazol-2-yl-pyrimid-2-yl) -amine Ethyl ester of acid 2- [2- (6-Chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -4-hydroxy-thiazole-5-carboxylic acid 2- [2- (6-chloro-pyridin-3-ylamino) - pyrimidin-4-yl] -5-methyl-thiazol-4-ol 2- [2- (6-chloro-pyridin-3-ylamino) -pyrimidin-4-yl] -5- (2-hydroxy-ethyl) ) -thiazole-4-ol (6-chloro-5-methyl-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine 21. A compound according to claim 1 which is (6-chloro-pyridin-3-yl) - (4-thiazol-2-yl-pyrimidin-2-yl) -amine. 22. A pharmaceutical composition comprising a compound according to any preceding claim in admixture with a pharmaceutically acceptable carrier, excipient or diluent. 23. Use of a compound according to any of claims 1 to 21 in the preparation of a medicament for treating a proliferative disorder. 24. Use according to claim 23 wherein the proliferative disorder is cancer or leukemia. 25. Use according to claim 23 wherein the proliferative disorder is glomerulonephritis, rheumatoid arthritis, psoriasis or chronic obstructive pulmonary disorder. 26. Use of a compound according to any of claims 1 to 21 in the preparation of a medicament for treating a viral disorder. 27. Use according to claim 23 wherein the viral disorder is selected human cytomegalovirus (HCMV), herpes simplex virus type 1 (HSV-1), human immunodeficiency virus type 1 (VI H-1), and virus from varicella zoster (VZV). 28. Use of a compound according to any of claims 1 to 21 in the preparation of a medicament for treating a CNS disorder. 29. Use according to claim 28 wherein the CNS disorder is Alzheimer's disease or bipolar disorder. 30. Use of a compound according to any of claims 1 to 21 in the preparation of a medicament for treating alopecia. 31 Use of a compound according to any of claims 1 to 21 in the preparation of a medicament for treating a stroke. 32. Use according to any of claims 23 to 31 wherein the compound is administered in an amount sufficient to inhibit at least one PLK enzyme. 33. Use according to claim 32 wherein the PLK enzyme is PLK1. 34. Use according to any of the claims 23 to 31 wherein the compound is administered in an amount sufficient to inhibit at least one CDK enzyme. 35. Use according to claim 34 wherein the CDK enzyme is CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and / or CDK9. 36. Use according to any of claims 23 to 31 wherein the compound is administered in an amount sufficient to inhibit aurora kinase. 37. Use of a compound according to any of claims 1 to 21 in the preparation of a medicament for treating diabetes. 38. Use according to claim 37 wherein the diabetes is non-insulin dependent diabetes or II diabetes. 39. Use according to any of claims 37 or 38 wherein the compound is administered in an amount sufficient to inhibit GSK. 40. Use according to claim 39 wherein the compound is administered in an amount sufficient to inhibit GSK3β. 41 Use of a compound according to any of claims 1 to 21 in the preparation of a medicament for treating an inflammatory disease or an infectious disease. 42. Use of a compound according to any of claims 1 to 21 in an assay to identify additional candidate compounds capable of inhibiting one or more of a cyclin-dependent kinase, aurora kinase, GSK and a PLK-enzyme. 43. Use according to claim 38 wherein said assay is a competitive binding assay. 44. A process for preparing a compound of formula I as defined in claim 1, said process comprising reacting a compound of formula 9 with a compound of formula 10 to form a compound of formula I, wherein R1" 6 are as defined in claim 1 9 I 45. A process for preparing a compound of formula I as defined in claim 1, said process comprising reacting a compound of formula 15 with a compound of formula 3 to form a compound of formula I, wherein R 1"6 are as defined in claim 1