MXPA00004488A - Aminothiazole inhibitors of cyclin dependent kinases - Google Patents

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof. As used in formula (I), and throughout the specification, the symbols have the following meanings:R1 and R2 are independently hydrogen, fluorine or alkyl;R3 is aryl or heteroaryl. The compounds of formula (I) are protein kinase inhibitors and are useful in the treatment and prevention of proliferative diseases, for example cancer, inflammation and arthritis.

Description

AMINOTIAZOL HINIBIDORES OF CYCLIN DEPENDENT KINASES Brief description of the invention.

The present invention is directed to compounds of the formula and pharmaceutically acceptable salts thereof. As used in formula I, through the specifications, the symbols have the following meanings: Ri and 2 are independently hydrogen, fluorine or alkyl; , __ R3 is aryl or heteroaryl R4 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; or REF .: 119342 CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-hetrocicloalquilo, CONH-alkyl-heterocycloalkyl; or COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, C00-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl; or S02-alkyl, S02-cycloalkyl, S02-aryl, S 2-alkyl-cycloalkyl, S02-alkyl-aryl, S02-heteroaryl, S02-alkyl-heteroaryl, S02-heterocycloalkyl, S-alkyl-heterocycloalkyl 2?; or C (NCN) NH-alkyl, C (NCN) NH-cycloalkyl, C (NCN) NH-aryl, C (NCNNH) -alkyl-cycloalkyl, C (NCN) NH-alkyl-aryl, C (NCN) NH- heteroaryl, C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocycloalkyl; or C (NN02) NH-alkyl, C (NN02) NH-cycloalkyl, C (nn02) NH-aryl, C (nn02) NH-alkyl-cycloalkyl, C (nn02) NH-alkyl-aryl, C (nn02) NH-heteroaryl, C (nn02) NH-alkyl-heteroaryl, C (nn02) NH-heterocycloalkyl, C (NN02) NH-alkyl-heterocycloalkyl; or C (NH) NH-alkyl, C (NH) H-cycloalkyl, C (NH) NH-aryl, C (NH) NH-alkyl-cycloalkyl, C (NH) NH-alkyl-aryl, C (NH) NH -heteroaryl, C (NH) NH-alkyl-heteroaryl, C (NH) NH ~ heterocycloalkyl, C (NH) NH-alkyl-heterocycloalkyl; or C (NH) NHCO-alkyl, C (NH) NHCO-cycloalkyl, C (NH) NHCO-aryl, C (NH) NHCO-alkyl-cycloalkyl, C (NH) NHCO-alkyl-aryl, C (NH) NHCO-heteroaryl, C (NH) NHCO-alkyl-heteroaryl, C (NH) NHCO-heterocycloalkyl, C (NH) NHCO-alkyl-heterocycloalkyl; or C (NOR 5) NH-alkyl, C (NOR 5) NH-cycloalkyl, C (NOR6) NH-aryl, C (NOR6) NH-alkyl-cycloalkyl, C (NOR6) NH-alkyl-aryl, C (NOR6) NH-heteroaryl, C (NOR6) NH-alkyl-heteroaryl, C (NOR6) NH-heterocycloalkyl, C (NORβ) NH-alkyl-heterocycloalkyl; Rs is hydrogen or alkyl; Re is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; m is an integer from 0 to 2; and n is an integer from 1 to 3.

The compounds of formula I are inhibitors of the protein kinase and are useful in the treatment and prevention of proliferative diseases, for example, cancer, inflammation and arthritis. They are also useful in the treatment of neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, viral diseases and fungal diseases.

Description of the invention. The present invention is provided for compounds of formula I, pharmaceutical compositions employing such compounds and for methods using such compounds.

The list below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to terms as used throughout the specification (unless otherwise limited in specific instances), either individually or as part of a larger group.

It should be noted that any heteroatom with unsatisfied valences is assumed to have the hydrogen atom to satisfy the valences.

Carboxylate anion refers to a negatively charged -C00 ~ group.

The term "alkyl" or "alkyl" refers to a radical derived from monovalent alkane (hydrocarbon) containing from 1 to 12 carbon atoms, unless otherwise defined. An alkyl group is a linear, branched or cyclic optionally substituted hydrocarbon group. When substituted, the alkyl groups may be substituted with up to four substituent groups, at any available point of attachment. When it is said that the alkyl group is substituted with an alkyl group, it is used interchangeably with "branched alkyl group". Examples of such unsubstituted groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylphenyl, octyl, 2,2-trimethylpentyl, nonyl, decilo, undecilo, dodecilo, and their like. Examples of substituents may include but are not limited to one or more of the following groups: halo (such as F, Cl, Br, I), haloalkyl (such as CC13 or CF3j, alkoxy, alkylthio, hydroxyl, carboxyl (-C00H ), alkyloxycarbonyl (-C (O) R), alkylcarbonyloxy (-0C0R), amino (-NH2), carbamoyl (-NHC00R- or -0C0NHR-), urea (-NHC0NHR-) or thiol (-SH). alkyl as defined may also comprise one or more one or more carbon carbon double bonds or one or more triple carbon carbon bonds.

The term "alkenyl" refers to a linear, branched or cyclic hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon carbon double bond.

The term "alkynyl" refers to a linear, branched or cyclic hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon carbon triple bond.

Cycloalkyl is a kind of alkyl containing from 3 to 15 carbon atoms, without alternating double bonds 0 resonates between the carbon atoms. It can contain from 1 to 4 rings. Examples of such unsubstituted groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, etc. Examples of substituents include one or more of the following groups: halogen, alkyl, alkoxy, alkyl hydroxy, amino, nitro, cyano, thiol and / or alkylthio.

The terms "alkoxy" or "alkylthio", as used herein, denote an alkyl group as described above linked through an oxygen bond (-0-) or a sulfur bond (-S-) respectively.

The term "alkyloxycarbonyl", as used herein, denotes an allocoxyl group linked through a carbonyl group. An alkoxycarbonyl radical is represented by the formula: -C (0) 0R, wherein the R group is a linear or branched alkyl group of C-β.

The term "alkylcarbonyl" refers to an alkyl group attached through a carbonyl group.

The term "alkylcarbonyloxy", as used herein, denotes an alkylcarbonyl group that is attached through an oxygen bond.

The term "arylalkyl", as used herein, denotes an aromatic ring attached to an alkyl group as described above.

The term "aryl" refers to oncyclic or bicyclic aromatic rings, for example, phenyl, substituted phenyl and the like, as well as groups that are fused, for example, naphthyl, phenanthrenyl and the like. An aryl group in this manner contains at least one ring having at least 6 atoms, up to five such rings present, containing up to 22 atoms therein, with alternating double (resonant) bonds between adjacent carbon atoms or suitable heteroatoms . The aryl groups may be optionally substituted with one or more groups including but not limited to halogens, alkyl, alkoxy, hydroxyl, carboxyl, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amyl, cycloalkyl, cyano, alkyl S (0) m ( m = 0, 1, 2), or thiol.

The term "heteroaryl" refers to an aromatic monocyclic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in that a carbon or nitrogen atom is the point of attachment, and wherein one or two additional carbon atoms are optionally replaced by a heteroatom selected from O or S, and wherein from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of heteroaryl groups include the following: thienyl, furyl, pyrrolyl, pyridinyl, i idazolyl, pyrrolidinyl piperidinyl, thiazolyl, oxazolyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrimidinalo, triazinilazepinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, benzofuranyl, and tetrahydropyranyl. Examples of substituents include one or more of the following: halogen, alkyl, alkoxide, hydroxyl, carboxyl, carbamoyl, alkyloxycarbonyl, trifluoromethyl, cycloalkyl, nitro, cyano, amino, alkylS (0) m (m = 0, 1, 2), or thiol.

The term "heteroaryl" refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge.

The term "heterocycloalkyl" refers to a cycloalkyl (non-aromatic) group in which one of the carbon atoms in the ring is replaced by a heteroatom selected from 0, S or N, and in which up to three additional atoms of carbon can be replaced by said heteroatoms.

The term "quaternary nitrogen" refers to a positively charged tetravalent nitrogen which includes, for example, positively charged nitrogen in a tetraalkylammonium group (eg, tetramethylammonium, N-methylpyridinium), positively charged nitrogen in protonated ammonium species (eg. example trimethylhydroammonium, N-hydropyridinium), nitrogen positively charged to amine N-oxides (e.g., N-methyl-morpholin-N-oxide, pyridine-N-oxide) and nitrogen positively charged to an N-amino group. ammonium (for example, N-aminopyridinium).

The term "heteroatom" means 0, S or N selected on an independent basis.

The term "halogen" or "halo" refers to chlorine. Bromine, fluoride or iodine.

When a functional group is qualified as "protected", this means that the group is in a modified form to prevent undesirable collateral reactions in the protected site. Suitable protecting groups for the compounds of the present invention will be recognized from the present application by taking within exactly the skill level in the art, and with reference to standard textbooks, such as Greene, TW Et al., Protective Groups in Organic Synthesis, Wiley, NY (1991). Suitable examples of salts of the compounds according to the invention with organic and inorganic acids are hydrochlorides, bromohydrates, sulphate, phosphate. Salts which are not suitable for pharmaceutical uses but which can be used, for example, to isolate or purify the free compounds I or their pharmaceutically acceptable salts, are also included.

All steroids of the compounds of the instant invention are contemplated, either in a mixture or in the pure or substantially pure form. The definition of the compounds according to the invention covers all possible steroisomers and their mixtures. It particularly covers the racemic forms and the isolated optical isomers having the specific activity. The racemic forms can be resolved by physical methods such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.

It should be understood that the solvates (for example hydrates) of the compounds of formula I are also within the scope of the present invention. Solvation methods are generally known in the art. Accordingly, the compounds of the instant invention may be in the form of the free hydrate, and may be obtained by methods exemplified by the following schemes.

Scheme 1 R * -L EijN SCH B «N» - 8 SCM a »ap > av > < V > As illustrated in Scheme 1, the compounds of formula I where X is S are prepared by the reaction of 2-aminothiazole (II) with bromine in the presence of sodium thioacyanate or potassium to obtain a thiocyanate aminothiazole, especially 5- thiocyanatoaminothiazole (III).

Compound III is then treated with R 4 -L where L is a leaving group such as halogen, in the presence of such a base or triethylamine to provide an intermediate 5-thiocyanatothiazole (IV), where R 4 is as defined in the specifications. The intermediate (IV) is then reduced to a thiol (V) using reducing agents such as dithiothreitol (DTT), sodium borohydride, zinc or other known reducing agents. The compound (V) is then reacted with alkyl, aryl or heteroaryl halide, such as R3 (CR? R2) -L, where L is a leaving group such as halogen, in the presence of a base such as potassium carbonate for to obtain compounds of formula I. The steps of reducing thiocyanatothiazole intermediate (IV) to thiol (V), and the reaction of reduced thiol (V) to provide compounds of formula I where X is S, can be carried out sequentially without purification . Scheme 2 HaC > (IX) (D (XBS) In scheme 2, the 5-thioacetyl-2-acetylaminothiazole of structure VI is reacted with an alkoxide such as potassium t-butoxide in a solvent, alcohol or THF and the resulting thiol it reacts with a group of formula R3 (CR? R2) nL (where L is a leaving group, such as a halogen) such as 2-halomethyloxazole (VII) to provide a compound such as that of formula VIII, wherein Ri and R2 are hydrogen, and Re is acetyl The 2-halomethyloxazole compounds of formula VII can be prepared using some synthetic routes known in the art, Chem. Pharm. Bull., 30, 1965 (1982), Bull. Chem. Soc. Japan (52, 3597 (1979); JCS Chem. Comm. 322 (1981); Comprehensive Heterocyclic Chemistry, vol.6, 177, edited by A. Katritzky and CW Rees, Pergamon Press (1984).

The compounds of formula VIII (a compound of formula I wherein R 4 is acetyl and X is sulfur) can be hydrolyzed in the presence of a base such as sodium hydroxide to provide a compound of formula IX. A compound of formula IX can then be reacted with R-L, in the presence of a base such as triethylamine, where L is a leaving group such as a halogen, to give compounds of formula I wherein X is sulfur. In this manner, the compounds of formula IX, which are a compound of formula I where R_ is hydrogen, can be treated with agents such as isothiocyanates, halides, acyl halides, chloroformates, isocyanates or sulfonyl chlorides to provide thioureas, amines, amides, carbamates, ureas or sulfonamides. The procedures in Scheme 2 specifically illustrate a methyloxazole group, but are general for all of the R3 (CR? R2) n-specified groups by Formula I.

Alternatively, compounds of formula VII, where L is bromide, can be prepared by halogenation of 2-methyloxazole using N-bromosuccinimide in the presence of dibenzoylperoxide. Scheme 3 « 00 (XI) < xp) (xpi) (VII) Scheme 3 illustrates an alternative method of preparing compounds VII, which is a compound of formula R (CR R) nL where L is chloro and n is the integer 1. In this 3 12 scheme, compound VII is prepared by the reaction of a compound of formula X and formula XI in the presence of a base such as triethylamine to provide compounds of formula XII. Compounds XII can be oxidized by an oxidizing agent such as chloroxalyl / DMSO in the presence of a base such as triethylamine to provide a compound of formula XIII which can be cyclized by an agent such as phosphorus oxychloride to provide compounds of formula VII, where L is chloro Alternatively, compounds of formula XIII can be prepared by reacting the amino ketone corresponding to X with an acid chloride such as XI.

Scheme 4 (XIV) (XV) (VII) The compounds of formula VII, wherein L is chloro, can also be prepared by the reaction of diazo ketones as illustrated by formula XIV in scheme 4 with chloronitriles, as indicated by formula XV, in the presence of BF etherate to provide compounds of formula VII, wherein L is chloro.

-Scheme 5 • * (xm (XVII.). Step 1 Step 2 . { XIX Step 3 Step 4 In Scheme 5, the initial compound XVI denotes a bonding resin supported by a benzyl alcohol used for solid phase synthesis which is prepared from a Merrifield resin denoted as ^ ?. , and 2-methoxy-4-hydroxybenzaldehyde, followed by reduction with reducing agents such as NaBH. In step 1, the initiator compound XVI is treated with triphosgene and triphenylphosphine (PPh3) in dichloromethane to give the chlorobenzyl resin of formula XVII. In step 2, a trifluoroacetamide thiocinate (XVIII) is alkylated with the bound resin of benzyl chloride (XVII) in the presence of diisopropylethylamine (DIPEA) to form a thiocyanate linking resin (XIX) - The trifluoroacetic thiocyanate compound ida of formula XVII is prepared by the reaction of the 5-thiocyanatoaminothiazole of formula III (Scheme I) with trifluoroacetic anhydride using a base such as 2,6-lutidine.

The thiocyanate linking resin (XIX) is then reduced to a thiol linking resin (XX) in step 3 with a reducing agent such as dithiothreitol (DTT) in tetrahydrofuran (THF) and methanol. The thiol binding resin (XX) is reacted with R3 (CR? R2) nL, where L is a leaving group, in the presence of a base such as 1,8-diazabicyclo [5,, 0] undec-7-ene (DBU) at 80 ° C in dimethylformamide (DMF) to form compounds of formula XXI (step 4). Deprotection of the trifluoroacetyl group of compound XXI is carried out in step 5 using sodium borohydride to provide a compound of formula XXII. In step 6, the deprotected group XXII is reacted with R6X where X is a leaving group, in the presence of a base such as diisopropylethylamine to provide compounds of formula XXIII. The product is then cleaved from the solid phase resin in step 7 with trifluoroacetic acid (TFA) to give compounds of formula I wherein X is sulfur. The compounds of formula I wherein X is S (0) m and is 1 or 2 can be prepared from compounds of formula I wherein m is 0 by oxidation with an oxidant such as sodium periodate, eta-chloroperbenzoic acid, or oxane .

The starting compounds of schemes 1-5 are commercially available or can be prepared by methods known to a person ordinarily skilled in the art. All compounds of formula I can be prepared by modification of the methods described herein.

Preferred compounds of formula I are those wherein: Ri and R2 are independently hydrogen, fluorine or alkyl; where Y is oxygen, sulfur or NR9; R 4 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; or CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-hetrocycloalkyl, CONH-alkyl-heterocycloalkyl; or COO-alkyl, COO-cycloalkyl, COQ-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, __COO-alkyl-heterocycloalkyl; or S02-alkyl, S02-cycloalkyl, S02-aryl, S02-alkyl-cycloalkyl, S02-alkyl-aryl, S02-heteroaryl, SO2-alkyl-heteroaryl, SO2-heterocycloalkyl, SO2-alkyl-heterocycloalkyl; or ~ C (NCN) NH-alkyl, C (NCN) NH-cycloalkyl, C (NCN) NH-aryl, C (NCNJNI-alkyl-cycloalkyl, C (NCN) NH-alkyl-aryl, C (NCN) NH-heteroaryl, C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocycloalkyl, or C (NN02) NH-alkyl, C (NN02) NH-cycloalkyl, C (NN02) NH-aryl, C (NN02) NH-alkyl-cycloalkyl, C (NN0) NH-alkyl-aryl, C (NN02) NH-heteroaryl, C (NN02) NH-alkyl-heteroaryl, C (NN02) NH-heterocycloalkyl, C (NN02) NH-alkyl-heterocycloalkyl; or C (NH) NH-alkyl, C (NH) NH-cycloalkyl, C (NH) NH-aryl, C (NH) NH-alkyl-cycloalkyl, C (NH) NH-alkyl-aryl, C (NH) NH -heteroaryl, C (NH) NH-alkyl-heteroaryl, C (NH) NH-heterocycloalkyl, C (NH) NH-alkyl-heterocycloalkyl; or C (NH) NHCO-alkyl, C (NH) NHCO-cycloalkyl, C (NH) NHCO-aryl, C (NH) NHCO-alkyl-cycloalkyl, C (NH) NHCO-alkyl-aryl, C (NH) NHCO-heteroaryl, C (NH) NHCO-alky1-heteroaryl, C (NH) NHCO-heterocycloalkyl, C (NH) NHCO-alkyl-heterocycloalkyl; or C (NOR6) NH-alkyl, C (NOR6) NH-cycloalkyl, C (NOR6) NH-aryl, C (NOR6) NH-alkyl-cycloalkyl, C (NOR6) NH-alkyl-aryl, C (N0R6) NH-heteroaryl, C (N0R6) NH-alkyl-heteroaryl, C (NOR6) NH-heterocycloalkyl, C (N0R6) NH-alkyl-heterocycloalkyl; R5 is hydrogen or alkyl; . R6 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R7 and Rs are independently hydrogen, alkyl, cycloalkyl, aryl, alkylcycloalkyl, alkylaryl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkylheterocycloalkyl or halogen; R9 is H or alkyl; m is the integer 0; Y n is the integer 1.

The most preferred compounds of formula I are those where: Ri is hydrogen; R2 is hydrogen fluorine or alkyl: R3 is a substituted oxazole having the configuration: R 4 is CO-alkyl, CO-alkyl-aryl, CO-cycloalkyl, CO-alkyl-heteroaryl, CO-alkyl-heteroalkyl, CO-alkyl-heterocycloalkyl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl, or CONH-alkyl-heterocycloalkyl; Rs is hydrogen; R7 is hydrogen; R8 is an alkyl group, such as tert-butyl; m is the integer 0; and n is the integer 1.

The compounds according to the invention have pharmacological properties; in particular, the compounds of formula I are inhibitors of protein kinases such as the cyclin-dependent kinase (cdks), for example, cdc2 (cdkl), cdk2, and cdk4. The new compounds of formula I are expected to be useful in the therapy of proliferative diseases such as cancer, autoimmune diseases, viral diseases, FUNGAL diseases, neurodegenerative disorders and cardiovascular disease.

More specifically, the compounds of formula I are useful in the treatment of a variety of cancers, including (but not limited to) the following: Carcinoma, including that of bladder, breast, colon, kidney, liver, lung, including cancer of the small cells of the lung, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including carcinoma of cells squamous; -hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, and Burkett's lymphoma; - Itotogenic tumors of myeloid lineage, including chronic and acute myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; - tumors of mesenchymal origin, including ficrosarcoma and rhabdomyosarcoma; - tumors of the central and peripheral nervous system, including astrocyto a, neuroblastoma, glioma and scuanomas; Y -other tumors including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, ceratoctantoma, follicular cancer of the thyroid and Kaposi's sarcoma. . ~~ Due to the key role of cdks in the regulation of cell proliferation in general, the inhibitors could act as reversible cytostatic agents that may be useful in the treatment of any disease process characterized by abnormal cell proliferation, for example, benign hyperplasia of the prostate, polyposis familial adenomtosis, atherosclerosis neurofibromatosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis followed by angioplasty or vascular surgery, formation of hypertrophic scars, inflammatory bowel disease, rejection of transplants, endotoxic shock, and fungal infections.

The compounds of formula I may also be useful in the treatment of Alzheimer's disease, since recent discoveries suggest that cdk5 is involved in the phosphorylation of the tau protein (J.

Biochem, 117, 741-749 (1995)).

The compounds of formula I can induce or inhibit apoptosis. The apoptotic response is aberrant in a variety of human diseases. The compounds of formula I, as modulators of apoptosis will be useful in the treatment of cancer (included but not limited by those types mentioned above), viral infections (including but not limited to hyperviruses, poxviruses, Epstein-Barr, Sindbis virus and adenovirus), prevention of the development of AIDS in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, autoimmune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer's disease), dementia related to AIDS, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, muscular spinal atrophy and cerebral degeneration), myelodysplastic syndromes, aplastic anemia, ischemic damage associated with myocardial infarctions, attacks and reperfusion damage, arrhythmia, atherosclerosis, liver diseases induced by toxins or associated with alcohol, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis , multiple sclerosis, kidney disease and pain from cancer.

The compounds of formula I, as inhibitors of cdk5, can modulate the level of synthesis of RNA and cellular DNA. These agents should therefore be useful in the treatment of viral infections (including but not limited to HIV, human papilloma virus, herpes virus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus).

The compounds of formula I may also be useful in the chemoprevention of cancer. Chemoprevention is defined as the inhibition of the development of invasive cancer by either blocking the initial mutagenic event or by blocking the progression of premalignant cells that have already suffered a relapse of trauma or inhibition of a tumor.

The compounds of formula I may also be useful in the inhibition of angiogenesis and tumor metastasis. The compounds of formula I can also act as inhibitors of other protein kinases, eg protein C kinases, her2, raf 1, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, P13 kinase. , weel kinase, be, abl and also be effective in the treatment of diseases associated with other protein kinases.

The compounds of this invention may also be useful in combination (administration -some or sequentially) with known anti-cancer treatments such as radiation therapy or with cytostatic or cytotoxic agents, such as, for example, but not limited to DNA interactive agents, such as cisplatin or doxorubicin; Topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; interactive tubulin agents, such as paclitaxel, docetaxel or the efotilones; hormonal agents such as tamoxifen; inhibitors of thymidylate synthesis, such as methoxytrexate.

If formulated as a fixed dose, such a combination of products employs the compounds of this invention within the dosage range described below and the other pharmaceutically active agents or treatments within the approved dosage range. For example, oligoxin inhibitor of cdc2 has been found to act synergistically with known cytotoxic agents in the induction of apoptosis (J. Cell Sci., 108, 287 (1995)). The compounds of formula I can also be administered sequentially with known anti-cancer agents or cytotoxic agents when a combination formulation is inappropriate. The invention is not limited in the administration sequence; the compounds of formula I can be administered any before or after the administration of the anticancer or cytotoxic agents. For example, the cytotoxic activity of flavopiridol inhibitory cyclin-dependent kinase is affected by the sequence of administration with anticancer agents. Cancer research, 57.3375 (1997).

The pharmacological properties of the compounds of this invention can be confirmed by a number of pharmacological tests. The exemplified pharmacological tests that follow have been carried out with the compounds according to the invention and their salts. The compounds of Examples 1 to 8 exhibit cdc2 / cyclin Bl kinase activity with IC 50 values less than 50 μM. The compounds of Examples 1 to 8 exhibit cdk2 / cyclin E kinase activity with IC50 values less than 50 μM. The compounds of Examples 1 to 8 exhibit DI k4 kinase activity / cyclin with IC 50 values less than 50 μM.

Cdc2 / cyclin bl kinase assay The activity of the kinase Bl cdc2 / cyclin was determined by monitoring the incorporation of 32P into histone Hl. The reaction consisted of 50 ng of GST-cdc2 expressed by baculovirus, 75 ng of GST-cyclin Bl expressed by baculovirus, 1 μg of histone Hl (Boehringer Mannheim), 0.2 mCi of 32P g-ATP and 25 mM of ATP in buffer of kinase (50 nM Tris, pH 8.0, 10 mM MgCl2, lmM EGTA, 0.5 mM DTT). The reaction was incubated at 30 ° C for 30 minutes and then stopped by the addition of trichloroacetic acid (TCA) to a final concentration of 15% and incubated on ice for 20 minutes. The reaction was collected on non-filtering GF / C plates (Packard) using a Packard Filter ate Universal collector, and the filters were counted in a 96-well Topcount liquid scintillation counter (Marshak, D.R.

Vanderberg, M.T., Bae, Y.S., Yu, IJ. , J. De Cellular Biochemistry, 45, 391-400 (1991), incorporated by references herein).

E cdJc2 / cycline kinase assay The activity of the kinase E cdk2 / cyclin was determined by monitoring the incorporation of 32P into the retinoblastoma protein. The reaction consisted of 2.5 ng of GTS-cdk2 E expressed by baculovirus, 500 ng GTS-retinoblastoma protein produced bacterially (aa 776-928), 0.2 mCi 32P g-ATP and 25 mM of ATP in kinase buffer (50 mM Hepes , pH 8.0, 10 mM MgCl2, 5 mM EGTA, 2 mM DTT). The reaction was incubated at 30 ° C for 30 minutes and then stopped by the addition of cold trifluoroacetic acid (TCA) to a final concentration of 15% and incubated for 20 minutes on ice. The reaction was collected on unifilter GF / C plates (Packard) using a Packard Filtermate Universal harvester, and the filters were counted in a Packard TopCount 96-well liquid scintillation counter.

Di cdk4 / cyclin kinase activity The activity of the DI cdk / cyclin kinase was determined by monitoring the incorporation of 32P into the retinoblastoma protein. The reaction consisted of 165 ng of baculovirus expressed as GTS-cdk4, 282 ng bacterially expressed as S-tag of cyclin DI, 500 ng of bacterially produced GTS-retinoblastoma protein (aa 776-928), U.2μCi of 32P? -ATP and 25 μM of ATP in kinase buffer (50 mM Hepes, pH 8.0, 10 mM MgCl 2, 5 mM EGTA, 2 mM DTT). The reaction was incubated at 30 ° C for 1 hour and then stopped by the addition of cold trifluoroacetic acid (TCA) to a final concentration of 15% and incubated on ice for 20 minutes. The reaction was coacted on unifilter GF / C plates using a Packard Filtermate Universal cooker, and the filters were counted in a liquid scintillation counter of 96 TopCount tanks (Coleman, KG, Wautlet, BS, Morissey, D, Mulheron, JG, Sedman, S., Brinkley, P. Price, S., Wedster, KR (1997) Identification of CDK4 Sequences involved in cyclin D, and pl6 bibding J. Biol, Chem. 272, 30: 18869-18874, incorporated by reference here).

Other related matters of the invention include pharmaceuticals for use as described above including cancer control, inflammation and arthritis, containing at least one compound of the formula I as defined above or at least one of its pharmacologically acceptable acid addition salts. , and the use of a compound of formula I as defined above for the preparation of a pharmaceutical having activity against proliferative diseases as previously described, including against cancer, inflammation and / or arthritis.

The following examples and preparations describe the manner and process of making and using the invention and are illustrative rather than limiting. It should be understood that there may be other embodiments that fall within the spirit and scope of the invention as defined by the appended claims.

Example 1 N- [5- [[(5-ethyl-2-oxazolyl] thio] iol ] -2-thiazolyl] acetamide A. Preparation of l-beziloxycarbonylamino-2-butanol A mixture of l-amino-2-butanol (5.5 g, 61.8 mmol), benzyl chloroformate (11.5 g, 67.6 mmol) and sodium carbonate (7.16 g, 67.7 mmol) in water (50 mL) was stirred at 0 ° C. ° C per product was extracted with methylene chloride (3x20 mL) The methylene chloride extract was dried over Na 2 SO 4 and concentrated The residue was passed through a short column (SiO 2, hexane: ethyl acetate / 10: 1, then ethyl acetate) to give l-benzyloxycarbonylamino-2-butanol (13.9 G, 100%) as a liquid XH NRM (CDC13) d 7.30 (m, 5H), 5.45 (s, 1H), 5.06 (s) , 2H), 3.57 (s, 1H), 3.31 (m, 1H), 3.04 (, 1H), 2.91 (, 1H), 1.43 (m, 2H), 0.91 (t, J = 7.6 Hz, 3H).

B. Preparation of l-benzyloxycarbonylamino-2-butanone To oxylene chloride (6 mL) at -78 ° C under argon oxalyl chloride (37 mL of 2M solution in methylene chloride, 74 mol) was added, followed by DMSO (7.8 g, 100 mmol). The mixture was stirred at -78 ° C for 20 min. and to this mixture was added a solution of l-benzyloxycarbonylamino-2-butanol (13.9 g, 61.8 mmol) in methylene chloride (40 mL).

The mixture was stirred at -78 ° C for 1 h and triethylamine was added. (21 mL) to the mixture. Warmed to room temperature (rt) and washed successively with IN hydrochloric acid and aqueous sodium bicarbonate solution. The methylene chloride solution was dried over MgSO4 and concentrated to give l-benzyloxycarbonylamino-2-butanone (11.2 g, 82%) as a solid, which was sufficiently pure for the next reaction. aH NMR (CDCl 3) d 7.32 (m, 5H), 5.50 (s, 1H), 5.06 (s, 2H), 4.07 (s, 2H), 2.43 (q, J = 7.6 Hz, 2H), 1.06 (t, J = 7.6 Hz, 3H). c. Preparation of l-amino-2-butanone a solution of l-benzyloxycarbonylamino-2-butanone (9.30 mg, 42 mmol) in ethanol (50 mL) and hydrochloric acid IN (46 mL) was stirred under hydrogen atmosphere in the presence of Pd / C (1.5 g, 10%) to rt for 4 hours. The mixture was filtered through a celite bed and the filtered solution was concentrated. The residue was triturated with ethyl ether to give 1-amino-2-butanone (5.3 g, 102%) as a hydrochloride salt. 2H NRM (CD30D) d 3.97 (s, 2H), 2.60 (q, J = 7.6 Hz, 2H), 1. 08 (t, J = 7.6 Hz, 3H).

D .Preparation of 2-amino-5-thiocyanatothiazole 2-Aminothiazole (41 g, 410 mM) and sodium thiocyanate (60 g, 740 mM, dried in a vacuum oven at 130 ° C for one night) was dissolved in 450 mL of anhydrous methanol and the solution was cooled in a cold water bath. Here bromine (23 mL, 445 mM) was added dropwise with good agitation. After the addition, it was stirred for 4 h at rt. To the mixture, 500 mL of water was added and stirred for 5 minutes, filtered through a celite bed and the bed was washed with water. The pH of the filtered solution was about 1. More methanol was removed under reduced pressure and the pH of the solution was adjusted to about 7 by the addition of aq. Sodium carbonate. slowly with agitation. The precipitated solid was filtered and washed with water to obtain 37 g (57%) of the desired colored product of dark coffee after drying, mp 140-143 ° C.

XH NMR (CD30D) d 7.33 (s, 1 H); MS (CI / NHa m / e 179 (M + Na) +, 158 (M + H) +.

E .Preparation of 2-acetylamino-5-thiocyanatothiazole To a mixture of 2-amino-5-thiocyantothiazole (15.7 g, 0. 1 mol) and pyridine (12 g, 0.15 mol) in methylene chloride (100 mL) was added acetic anhydride (1.2 g, 0.12 mol) at room temperature. The mixture was stirred at room temperature for 6 h. The mixture was concentrated to dryness and MeOH (50 mL) was added to the residue. The precipitates were collected and washed with water. The solid was dried and recrystallized from MeOH to give 2-acetylamino-5-thiocyanatothiazole (15.2 g, 76%) as a solid, mp 212 ° C. aH NMR (CD3OD) d 7.79 (s, 1H), 2.23 (s, 3H).

.Preparation of [[2- (acetylamino) -5-thiazole) io] acetic acid 1-di-methylethyl ester To a mixture of 2-acetamino-5-thiocyanatothiazole (5.97 g, 30 mmol) in MeOH (360 mL) under argon was added dithiothreitol (9.26 g, 60 mmol) at room temperature. The mixture was stirred at room temperature for 2 h and concentrated to give a solid product. This solid product was dissolved in DMF (30 mL) and to this solution was added tert-butyl bromoacetate (5.85 g, 30 mmol) and potassium carbonate (5.0 g, 36 mmol). The mixture was stirred at room temperature for 2 h and water (200 mL) was added to the mixture. The precipitates were collected, washed with water and dried. The solid was dissolved in methylene chloride (100 mL) and MeOH (10 mL) and filtered through a pad of silica gel. The filtered solution was concentrated to give the desired product (7.5 g, 87%) as a solid, mp 162-163 ° C.

X H NMR (CDCl 3) d 12.2 (s, 1 H), 7.48 (3, 1 H), 3.37 (2, 2 H), 2.32 (3, 3 H), 1.45 (3, 9 H); MS m / e 289 (M + H) +, 287 (M-H). " HPLC (column: YMC S3 ODS 4.6x50mm; flow rate: 2.5 mL / min; solvent system: 0-100% B in 8 min Solvent A: 10% MeOH-90% water-0.2% H3P04; Solvent B: 90% MeOH-10% water-0.2% H3P04; UV: 220 nm): retention time 6.44 min.

G.Preparation of [[2- (acetylamino) -5-thiazolyl] thio] acetic acid 1,1-dimethyl ester A solution of 1, 1-dimethylethyl ester of acid [[2- (acetylamino) -5-thiazolyl] thio] acetic acid (4.32 g, 15 mmol) in methylene chloride (30 mL) and trifluoroacetic acid (20 mL) was stirred at room temperature overnight and concentrated in vacuo. empty. To the residue was added ethyl ether (50 mL). The precipitated solid was collected, washed with ethyl ether and dried to give the desired compound (3.38 g, 97%) as a solid mp 210 ° C. JH MR (CD3OD) d 7.48 (s, 1H), 3.47 (s, 2H), 2.20 (s, 3H) ppm; MS m / e 231 (MH) "; HPLC (column: Zorbax Rapid Resolution C-18; flow rate: 2.5 mL / min; solvent system: 0-100% B in 8 min. Solvent A: 10% MeOH -90% water-0.2% H3P04; Solvent B: 90% MeOH-10% Water-0.2% H3P0; UV: 254 nm): retention time 4.36 min.

H. repair of [[2- (acetylamino) -5-thiazolyl] thio] -N- (2-oxobutyl) cetamide A mixture of [[2-acetylamino) -5-thiazolyl-thioj acetic acid (9.0 g, 38.8 mmol), HOBT ( 5.94 g, 38.8 mmol) and hydrochloride salt of (Ethyldimethylaminopropylcarbodiimide (11.16 g, 58.2 mmol) in DMF (50 mL) was stirred at 0 ° C for 0.5 h. To this mixture was added l-amino-2-butanone hydrochloride (5.27 g, 42.7 mmol) followed by triethylamine ( 15 mL, 107.5 mmol) The mixture was stirred at 0 ° C for 0.5 h and at room temperature for 1 h Water was added (200 mL) to the mixture and the product was extracted with methylene chloride containing 10% MeOH ( 5x100 mL) The methylene chloride extract was dried over Na 2 SO 4 and co-concentrated, the residue was triturated with water and the precipitated solid product was collected by filtration, dried to obtain the desired product (10.5 g, 90%). 195-196 ° C. H NMR (CDC13) d 7.53 (s, 1H), 4.14 (s, 2H), 3.46 (s, 2H), 2.50 (q, J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.12 (t, J = 7.6 Hz, 3H); MS m / e 302 (M + H) +. HPLC (column: Zorbax rapid resolution C-18, flow rate: 2.5 mL / min, solvent system: 0-100% B in 8 min solvent A: 10% MeOH-90% water-0.2% H3P04; solvent B: 90% MeOH-10% Water-0.2% H3P0; UV: 254 nm): retention time 4.36 min.

I. Preparation of N-5 [5- [[(5-ethyl-2-oxazolyl) ethyl] thio] -2-thiazolyl] acetamide To a solution of [[2- (acetylamino) -5-thiazolyl] thio] -N- (-2-oxobutyl) acetamide (10.5 g, 3.48 mmol) in acetic anhydride (100 mL) was added concentrated sulfuric acid (10mL). The mixture was stirred at 55-60 ° C for 2 h and sodium acetate (15g, 0.18 mol) was added to the mixture. The mixture was concentrated in vacuo. To the residue was added cold water (100 mL). The solid precipitate was collected, washed with water and dried. Purified by a flash chromatography column (Si02, methylene chloride: MeOH / 100: 5) to give N- [5- [[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide ( 4.2 g, 43%) as a solid, mp 147-148 ° C. XH NMR (CDC13) d 12.47 (s, 1H), 6.61 (s, 1H), 3.91 (s, 2H), 2.64 (q, J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.21 (t, J = 7.6 Hz, 3H) ppm; MS m / e 284 (M + H) +. HPLC (column: Zorbax rapid resolution C-18, flow rate: 2.5 mL / min, solvent system: 0-100% B in 8 min Solvent A: 10% MeOH-90% water-0.2% H3PO4; Solvent B: 90% MeOH-10% Water-0.2% H3PO4; UV: 254 nm): retention time 6. 50 min Example 2 N- [5- [[5-ethyl-2-oxazolyl) ethyl] io] -2- thiazolyl] benzamide A. Preparation of 2-amino-5- [[(5-ethyl-2-oxazolyl) ethyl)] thio] -tlazole A solution of N- [5- [[(-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide (1.3 g, 4.0 mmol) in 1N hydrochloric acid (15 mL) was stirred at 80-90 ° C for 3 h.

It was cooled to room temperature and the pH of the solution was 'adjusted to 7 with sodium carbonate. The product was extracted with methylene chloride (3x10 L). The combined extracts were dried over Na 2 SO and concentrated. The residue was triturated with ethyl ether and the precipitated solid was collected to give 2-amino-5- [[(5-ethyl-2-oxazolyl) methyl] thio] -thiazole (610 mg, 55%) as a solid, mp 119-120 ° C.

X H NMR (CDCl 3) d 6.93 (s, 1 H), 6.61 (s, 1 H), 5.41 (s, 2H), 3.82 (s, 3H), 2.62 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H); MS m / e 242 (M + H) +. HPLC (column: Zorbax rapid resolution C-18, flow rate: 2.5 L / min, solvent system: 0-100% B in 8 min solvent A: 10% MeOH-90% water-0.2% H3P04; solvent B: 90% MeOH-10% Water-0.2% H3PO4; UV: 254 nm): retention time 3.96 min.

B. Preparation of N- [5- [[(5-ethyl-2-oxazolyl) methyl] thio] -2- iazolyl] benzamide A mixture of 2-amino-5- [[(5-ethyl-2-oxazolyl)] methyl] thio] -thiazole (48.2 mg, 0.2 mmol), benzoyl chloride (24.4 mg, 0.21 mmol) and triethylamine (35 mg, 0.35 mmol) in methylene chloride (0.5 mL) was stirred at room temperature for 10 min . the organic solution was washed with water and concentrated. The residue was purified by a flash column (Si02; hexane: ethyl acetate / 2: 1) to give N- [5- [[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] benzamide ( 41 mg, 59%) as a solid, mp 122-123 ° C. 1H NMR (CDC13) d 12.65 (s, 1H), 7.96 (, 2H), 7.61 (m, 1H), 7.49 (m, 2H), 6.88 (s, 1H), 6.56 (s, 1H), 3.93 (s) , 2H), 2.61 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H); MS m / e 346 (M + H) +; HPLC (column: Zorbax rapid resolution C-18, flow rate: 2.5 mL / min, solvent system: 0-100% B in 8 min solvent A: 10% MeOH-90% water-0.2% H3P04; solvent B: 90% MeOH-10% Water-0.2% H3P04; UV: 254 nm): retention time 7.94 min.

Example 3 N- [5- [[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] benzenesulfonamide a mixture of 2-amino-5- [5-ethyl-2-oxazolyl) methyl-thio] -thiazole (24.1 mg, 0.1 mmol), benzenesulfonyl chloride (19.4 mg, O.llmmol) and triethylamine (22 mg, 0.21 g) mmol) in methylene chloride (0.3mL) was stirred at room temperature for 10 h. The product of the reaction mixture was purified by preparative HPLC (column: YMC packed ODSA S3 20 x 100 mm, method: gradient from 0% B to 100% B in 20 min and flow rate 20 mL / min; UV: 254 nm; Solvent A: 10% MeOH-90% water-1.0% TFA; Solvent B: 90% -MeOH-10% water-0.1% TFA) to obtain N- [5- [[(5-ethyl- 2-oxazolyl) methyl] thio] -2-thiazolyl-J-benzenesulfonamide (2.5 mg) as a solid after drying via lyophilization. 2H NMR (CDC13) d 7.88 (d, J = 8.0 Hz, 1H), (s, 2H), 7.49 (m, 3H), 6.89 (s, 1H), 6.64 (s, 1H), 4.01 (s, 2H) ), 2.68 (q, J = 7.4 Hz, 2H), 1.27 (t, J = 7. Hz, 3H); MS m / e 382 (M + H) +. HPLC (column: Zorbax rapid resolution C-18, flow rate: 2.5 mL / min, solvent system: 0-100% B in 8 min solvent A: 10% MeOH-90% water-0.2% H3P04; solvent B: 90% MeOH-10% Water-0.2% H3P04; UV: 254 nm): retention time 6.84 min.

Example 4 N- [5- [[(4,5-dimethyl-2-oxazolyl) methyl) thio] -2-thiazolyl] acetamide A. Preparation of 2-bromomethyl) -4,5-d-methyloxazole A mixture of 2,4-trimethyloxazole (0.50 mL), 4.3 mmol), N-bromosuccinimide (0.77 g, 4.3 mmol) and benzoyl peroxide (0.21 g) g, 0.86 mmol) in carbon tetrachloride (4 mL) was heated at 76 ° C under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the solid was removed by filtration. The filtered solution was washed with saturated aqueous NaHCO3 (20 mL) and concentrated. The residue was purified by flash chromatography column (SiO2, hexane: ethyl acetate /: 1) to give 2- (bromomethyl) -4,5-dimethyloxazole (64 mg) as a yellow oil. 2H NMR (CDC13) d 4.4 (s, 2H), 2.25 (s, 3H), 2.05 (s, 3H). B. Preparation of N- [5- [(4,5-dimethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] cetamide N- [5- (acetylthio) -2-thiazolyl] acetamide (0.050 g, o.23 mmol) was dissolved in THF (10 mL) and here potassium tert-butoxide (1.0 solution in THF, 0.25 mL, 0.25 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 15 min., And 2- (bromomethyl) -4,5-dimethyloxazole (0.64 g, 0.34 mmol) was added to this mixture. The reaction mixture was stirred at room temperature for 3 h and saturated aqueous NaHCO 3 solution (20 mL) was added to this mixture. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3x20 mL). The combined organic phases were concentrated. The residue was purified by a flash chromatography column (Si02; methanol: dichloromethane / l: 20) to give N- [5- [[(4,5-dimethyl-2-oxazolyl) ethyl] thiol] -2-thiazolyl] acetamide (15 mg, 23%) as a yellow solid. X H NMR (CDCl 3) dll.78 (s, 1 H), 7.38 (s, 1 H), 3.90 (s, 2 H), 2.30 (s, 3 H), 2.22 < s, 3H), 2.05 (s, 3H); MS m / e 284 (M + H) +; HPLC (Column: Zorbax Rapid Resonance C-18; Flow Rate: 2.5 mL / min; Solvent System: 0-100% B in 8 min Solvent A: 10% CH3OH / 90% H2O / 0.2% H3P04; Solvent B: 90% CH3OH / 10% H2O / 0.2% H3P04; UV: 254 nm): retention time 5.87 min.

Example 5 N- [5- [[(5-t-Butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide A. Preparation of Diazomethane To a mixture of 15 mL of 40% KOH solution and 50 mL of diethyl ether at 0 ° C was added 5 g (68 mmol) of N-methyl-N'-nitro-N-nitrosoguanidine in portions with stirring. The resulting mixture was stirred at 0 ° C for 0.5 h. The organic phase was decanted into a dry flask and dried on solid KOH pellets to give 50 mL of diazomethane solution (ca 0.5 M, by triple treatment with acetic acid).

B. Preparation of l-diazo-3,3-dimethyl-2-butanone To the diazomethane solution at 0 ° C was added a solution of 1.23 mL (1.21 g, 10 mmol, Aldrich) of trimethylacetyl chloride in 1 mL of diethyl ether in the form of drops with stirring. The resulting mixture was kept at 0 ° C for 16 h. The solution was flushed with argon to remove excess diazomethane and the diethyl ether was removed under reduced pressure to give 1.33 g (10 mmol, 100%) of crude l-diazo-3,3-dimethyl-2-butanone as a solid. yellow.

C. Preparation of 2-Chloromethyl-5-t-butyloxazole To a solution of 2 mL (2.3 g, 16 mmol) of boron trifluoride etherate in 20 mL of chloroacetonitrile at 0 ° C was added a solution of 1.33 g (10 mmol) of l-diazo-3,3-dimethyl-2 -butanone in 5 mL of chloroacetonitrile in the form of drops. The resulting solution was stirred at 0 ° C for 0.5 h. The reaction mixture was added to saturated aqueous sodium bicarbonate solution to neutralize the acid and the product was extracted three times with dichloromethane. The combined extracts were dried (sodium sulfate), concentrated and purified by a flash chromatography column (Merck silica, 25x200 mm, dichloromethane) to give 1.1 g of 2- (chloromethyl) -5-t-butyloxazole as a liquid. yellow (6.4 mmol, 64% overall from the acid chloride).

E NMR d (CDC13): 1.30 (s, 9H), 4.58 (s, 2H), 6.68 (s, 1H); MS 174 (M + H) +; TLC: Rf (silica gel, dichloromethane) = 0.33; HPLC: fcR (YMC S-3 ODS 4.6x50mm fast resolution, 2.5ml / min, gradient 0-100% B for 8 min, solvent A: 10% CH3OH / 90% H2O / 0.2% H3P04; solvent B: 90% CH3OH / 10% H2O / 0.2% H3P04; UV: 254 nm) = 6.5 min.

D. Preparation of N- [5 - [[(5-t-butyl-2-oxazoilyl) methyl] thio] -2-thiazolyl] acetamide To a solution of 50 mg (0.23 mmol, Applied Chemical Laboratory) of N- [5 - (acetylthio) -2-thiazolyl] acetamide in 10 mL of THF were added 0.25 mL of potassium t-butoxide solution (1M solution, 0.25 mmol) at room temperature under argon. The resulting suspension was stirred for 15 minutes at room temperature, then a solution of 59 mg of 2- (chloromethyl) -5-t-butyloxazole (0.34 mmol) in 1 mL of THF was added. The resulting mixture was stirred at room temperature for 16 h, concentrated under reduced pressure and purified by flash chromatography column (silica gel, 25x200 mm, 1: 1 EtOAc / hexane followed by 100% EtOAc) to give the reaction medium. mg (0.14 mmol, 61%) of N- [5- [[(5-tbutyl-2-oxazolyl) methyl] thiol] -2-thiazolyl] acetamide as a white solid. 1R NMR d (CDC13) 1.27 (s, 9H), 2.27 (s, 3H), 3.95 (s, 2H), 6.59 (s, 1H), 7.31 (s, 1H), 11.03 (amplitude s, 1H); MS 312 (M + H) +; TLC: Rf (silica gel, ethyl acetate) = 0.53, UV; HPLC: retention time (YMC S-3 ODS 4.6x50 mm fast resolution, 2.5 ml / min, gradient 0-100% B for 8 min, Solvent A: 10% CH3OH / 90% H2O / 0.2% H3P04; Solvent B; 90% CH3OH / 10% H2O / 0.2% H3PO4; UV: 254 nm) = 6.8 min.

Example 6 N- [5- [[(5-t-Butyl-2-oxazilyl) methyl] thiol] -2-thiazolyl] trimethylacetamide A. Preparation of N - [(5-thiocyanato) -2-thiazolyl] trifluoroacetamide (XVIII) To a mixture of 5-thiocyanato-2-aminothiazole (30 mmol) and 2,6-lutidine (35 mmol) in tetrahydrofuran (25 mL ) and dichloromethane (50 mL) at -78 ° C under argon was slowly added trifluoroacetic anhydride (33 mmol). After the addition, the mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with dichloromethane (100mL), and the organic solution was washed with 5% aqueous citric acid followed by brine, dried over magnesium sulfate and passed through a pad of silica gel. The product containing eluent was concentrated to give 5.3 g of a slightly brown solid. 2H-MR (CDC13) d 12.4 (br, 1H), 7.83 (s, 1H).

B. Preparation of the resin Merrifiled 4-hydroxymethyl-3-methoxyphenyloxy (XVT) To a suspension of sodium hydride (11.7 g, 60% in mineral oil, 293 mmol) in dimethyl formamide (30 mL) at 0 ° C under argon a solution of 4-hydroxy-3-methoxybenzaldehyde (44.5 g, 295.5 mmol) in dimethylformamide (100 mL) was slowly added. To the resulting mixture was added Merrifield resin (1% DVB, from Chemtech Advanced, loading 1.24 mmmol / g, 50 g, 62 mmol) and a catalytic amount of tetra-n-butylammonium iodide, and heated to 65 ° C. one day. The resin was filtered, washed with water (2X), 50% dimethylformamide in water (3x), dimethylformamide (2x) and methanol (5x), and dried in vacuo. The dried resin (15 g) was treated with sodium borohydride (3.4 g, 90 mmol) in tetrahydrofuran (50 mL) and ethanol (50 L) overnight. The resin was filtered, washed with 50% dimethylformamide in water (3x), dimethylformamide (2x), methanol (2x) and dichloromethane (5x), and dried in vacuo.

C. Preparation of 4-chloromethyl-3-methoxyphenyloxy Merrifield resin (XVII) To a solution of triphenylphosphine (17 g, 65 mmol) in dichloromethane (200 mL) at 0 ° C was slowly added triphosgene (9.2 g, 31 mmol) in the form of portions for a period of 30 minutes. After the addition, the reaction mixture was stirred at 0 ° C for 10 minutes. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (200 mL). Merrifield resin of 4-hydroxymethyl-3-methoxyphenyloxy (12 g) was added to this mixture. The resulting mixture was stirred for 4 h. The resin was washed with dry dichloromethane (6x) and dried in vacuo.

D. Preparation of the Merrifield resin of 4- [N - [(5-thiocyanato) -2-thiazolyl-rifluoroacetamido] methyl] -3-methoxyphenyloxy (XIX) A mixture of the Merrifield resin of 4-chloromethyl-3-methoxyphenyloxy (15) g), N- [(5-thiocyanato) -2-thiazolyl] -trifluoroacetamide (14 g, 55.3 mmol) and diisopropylethylamine (7.8 mL, 45 mmol) 'in dimethylformamide (50 mL) and dichloromethane (100 mL) was stirred by a night. The resin was washed with dimethylformamide (2x), methanol (2x), dichloromethane (4x), and dried in vacuo. E. Preparation of the Merrifield Resin of - [[N - [(5-mercapto) -2-thiazolyl] -trifluoroacetamido] methyl] -3-methoxyphenyloxy (XX) A mixture of the Merrifield resin of 4- [N - [(5)] -thiocyanate) -2- thiazolyltrifluoroacetamido] methyl] -3-methoxyphenyloxy (XIX, 18.5 g) and dithiothreitol (12 g, 78 mmol) in tetrahydrofuran (100 mL) and methanol (100 mL) was stirred overnight. The resin was washed with dimethylformamide (2x), methanol (2x), dichloromethane (4x), and dried in vacuo and stored under an argon atmosphere at -20 ° C.

F. Preparation of the Merrifiel resin of 4-N- [5- [[[(5-t-butyl-2-oxazolyl) methyl) thio] -2-thiazolyl] trifluoroacetamido] methyl-3-methoxyphenyloxy (XXI) A stream of argon was pumped through a mixture of the Merrifield resin of 4- [[N- [(5-mercapto) -2-thiazolyl] trifluoroacetamido] methyl-3-methoxyphenyloxy (XX, 500 mg), halide (2.0 mmol) and 1, 8-diazabicyclo [5,, 0] undec-7-ene (DBU, 1.5 mmol) in dimethylformamide 3 mL) for 5 min, and the mixture was heated at 80 ° C for 2 hours. The resin was washed with dimethylformamide (2x), methanol (2x), cyclochloromethane (4x) and dried in vacuo. 6. Preparation of the Merrifield resin of 4-N- [5- [[(5-t-butyl-2-oxazolyl) ethyl] thio] -2- thiazolyl] methyl-3-methoxyphenyloxy (XXII) A mixture of the Merrifield resin of 4-N- [5- [[[(5-t-butyl-2-oxazolyl) methyl) thio] -2-thiazolyl] trifluoroacetamido] methyl-3-methoxyphenyloxy (XXI, 500 mg) and sodium borohydride 8 4 mmol ) in tetrahydrofuran (2 mL) and ethanol (2 mL) was stirred overnight. The resin was washed with 50% dimethylformamide in water (2x), dimethylformamide (2x), methanol, dichloromethane (4x), and dried in vacuo.

H.Preparation of Merrifield resin 4-N- [5- [[[(5- t -butyl-2-oxazolyl) methyl] thiol] -2- thiazolyl] trimethylacetamido] methyl-3-methoxy enyloxy (XXIII) A mixture of Merrifield resin 4-N- [5- [[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] methyl-3-methoxyphenyloxy (XXII, 100 mg), diisopropylethylamine (1.2 mmol) and trimethylacetyl chloride (1 mmol) in dichloromethane (2 mL) in a tube filled with a calcined polyethylene and a stopcock was stirred overnight. The resin was washed with dimethylformamide (2x), methanol (2x), dichloromethane (4x), and used in the next step without drying.

I .Preparation of N- [5- [[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] trimethylacetamide The Merrifield resin 4-N- [5- [[[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] trimethylacetamido] methyl-3-methoxyphenyloxy (XXIII) was treated with 60% acid trifluoroacetic acid in dichloromethane (2 mL) in a polyprolone tube filled with a calcined polyethylene and a stopcock for 4 hours. The solution was decanted into a tube and the resin was washed with dichloromethane. The combined organic solution was concentrated in a rapid vacuum. The residue was purified by preparative HPLC to give 11.3 mg of the desired product. MS m / e 354 (M + H) +.

Example 7 N- [5- [[(4-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide A. Preparation of 2- (2-chloroacetamido) -1-butanol To a mixture of 2-amino-1-butanol (5.0 mL, 53 mmol) and triethylamine (15.0 mL, 111 mmol) in dichloromethane (20 mL) a - At 70 ° C, chloroacetyl chloride (4.6 mL, 58 mmol) was added dropwise. The reaction mixture was stirred at -70 ° C for 15 minutes and then allowed to warm to room temperature. It was diluted with EtOAc (50 mL) and the reaction was cooled by the addition of water (50 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3x30 mL). The combined organic phases were concentrated to give 2- (2-chloroacetamido) -1-butanol (8.6 g, 98%) as a brown solid. 1H NMR (CDCL3) d 6.75 (bs, 1H), 4.10 (s, 2H), 4.08 (dd, 1H), 3.90 (m, 1H), 3.68 (m, 2H), 2.98 (bs, 1H), 1.60 ( m, 2H), 0.97 (t, 3H).

B. Preparation of 2- (2-chloroacetamido) -1-butyraldehyde To a solution of oxalyl chloride (14.5 mL, 29.0 mmol) in dichloromethane (30 mL) at -78 ° C was added DMSO (2.75 mL, 38.8 mmol) in the form of drops for 5 minutes. After stirring for 10 min. at -78 ° C, a solution of 2- (2-chloroacetamido) -1-butanol (4.0 g, 24 mmol) in 20 mL of dichloromethane was added dropwise for 15 minutes. The reaction mixture was stirred for 40 min. at -78 ° C and triethylamine (9.4 mL, 68 mmol) was added as drops for 5 minutes and the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The solid was removed by filtration and washed with EtOAc. The organic phase was washed with 1N HCl (2xl00mL); Saturated aqueous NaHC03 (lxlOmL) and concentrated to give 2- (2-chloroacetamido) -1-butyraldehyde (3.7 g, 95%) as a brown oil. XH NMR (CDC13) d 9.60 (s, 1H), 4.52 (q, 1H), 4.12 (s, 2H), 2.05 (m, 1H), 1.80 (, 1H), 0.97 (t, 3H).

C. Preparation of 2-chloromethyl-4-ethyloxazole To a solution of 2- (2-chloroacetamido) -1-butyraldehyde (3.7 g, 23 mmol) in toluene (10 mL) was added POCI3 (6.3 L. 68 mmol). The reaction mixture was heated at 90 ° C for 1 h under nitrogen. After the reaction mixture was cooled to room temperature it was poured into ice water (10 mL) and the pH of the solution was adjusted to 7 with 5N NaOH. The toluene layer was separated and the aqueous phase was washed with dichloromethane (3x20 L). The combined organic solution was concentrated and distilled to give 2-chloromethyl-4-ethyloxazole (1.1 g 31%) as a colorless liquid. XE NMR (CDCl 3) d 7.30 (s, 1H), 4.22 (s, 2H), 2.50 (q, 2H), 1.22 (t, 3H).

D. Preparation of N- £ 5- [£ (4-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide To a solution of 2-acetylamino-5-thiazolyl thiol (0.010 g, 0.050 mmol) in dry THF (5 mL) was added potassium tert-butoxide (1M solution in THF, 0.060 mL, 0.060 mmol). The reaction mixture was stirred at room temperature for 15 min and 2-chloromethyl-4-ethyloxazole (0.015 g, 0.10 mmol) was added. After 3 h, saturated aqueous solution of NaHCO 3 (5 mL) was added to the mixture. The organic phase was separated and the aqueous phase was washed with dichloromethane (3x 10 mL). The combined organic phases were concentrated. The residue was purified by flash chromatography (Si02; methanol: dichloromethane / l: 20) to give N- [5- [[(4-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide (5 mg, 36%) as a white solid.

XH NMR (CDC13) d 11.25 (s, 1H), 7.34 (s, 1H), 7.31 (sAlH), 3.95 (s, 2H), 2.50 (q, 2H), 2.27 (s, 3H), 1.19 (t, 3H); MS m / e 284 (M + H) +; HPLC (Column: Zorbax de -.Resolution C-18 rapid, flow rate: 2.5 ml / min, solvent system: 0-100% B in 8 min Solvent A: 10% CH3OH / 90% H2O / 0.2% H3PO4 Solvent B: 90% CH3OH / 10% H2O / 0.2% H3P04; UV: 254 nm); Retention time 6.14 min. using the methods described herein or by modification of the procedures described herein as known to one or ordinarily skilled in the art, the following additional compounds have been prepared and described in Table 1: TABLE 1 -fifty - - - - - - - - Example 636 Preparation of N- [5- [[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] -N'-cyano-N "- (2,6-d-fluoroTphenyl) guanidine A solution of 100 mg of N- [5- [[(5-t-Butyl-2-oxazolyl) methyl] thio] -2-aminithiazole and 68 mg of 2,6-difluoro-phenyl isothiocyanate was heated to 65 ° C. 16 ± ioras under argon. The solution was evaporated to dryness and the residue was purified by flash chromatography to give 91 mg of the thiourea intermediate.

To a solution of 30 mg of N- [5- [[(5-t-Butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] -N "- (2,6-difluorophenyl) thiourea, 52 mg of ethyl-3 (3-dimethylamino) propyl carbodiimide hydrochloride and 48 μL of diisopropylethylamine in 0.5 mL of methylene chloride was added a solution of 29 mg of cyanamide in 0.1 mL of tetrahydrofuran. After stirring for 1 hr, the solvent was removed and the crude material was purified by HPLC to give 8 mg of the compound of Example 636. MS: (M + H) + 449 +. 1 H NMR (400 MHz, CDC13): d 1.27 (9H, s), 4.19 (2H, s) ', 6.69 (1H, s), 7.03 (2H, m) 7.35 (1H, m), 8.47 (1H, s) ).

Example 637 Preparation of N- [5- [[(5-isopropyl-2-oxazolyl) fluoromethyl] -io] -2-thiazolyl acetamide.

To a stirred solution of 2-acetamido-5-thiazole thiol acetate. (141 mg) in 3 mL of dry THF under argon was added t-ButOK IN in THF (0.72 mL). This mixture was stirred at room temperature for 25 min, and a solution of 5-isopropyl- (2-chlorofluoromethyl)) oxazole (116 mg) in 2 mL of dry THF was added. The reaction mixture was stirred at 60 ° C for 18 hr, diluted with 150 L • of EtOAc and washed with saturated NH 4 Cl solution (2 x 25 mL), saturated NaHCO 3 solution (1 x 25 mL) and brine (1 x 25 mL). The organic phase was dried (MgSO), filtered and concentrated in vacuo to give the compound of Example 637. MS: (M + HJ + 316; HPLC retention time 3.52 min. (column: YMC ODS S05 4.6X 50 mm column, 0% to 100% B gradient in 4 min Solvent A: 10% CH3OH / 90% H2O / 0.2% H3P04; Solvent B: 90% CH3OH / 10% H2O / 0.2 % H3P04; UV 220 nM). DECLARATION THAT INCLUDES PROCESS It is stated that in relation to this date, the method known by the applicant to carry out the aforementioned invention, is that which is clear from the description of the invention.

Having described the invention as above, it is as property that contained in the following.

Claims (45)

1. A compound of formula and pharmaceutically acceptable salts thereof, characterized in that: Ri and R2 are independently hydrogen, fluorine or alkyl; R3 is aryl or heteroaryl R4 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkyl, arylalkyl, hepheroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; or CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-hetrocycloalkyl, CONH-alkyl-heterocycloalkyl; or COO-alkyl, COO-cycloalkyl, COO-aryl, C00-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl; or S0-cycloalkyl, S02-aryl, S02-alkyl-cycloalkyl, S02-alkyl-aryl, S02-heteroaryl, S02-alkyl-heteroaryl, S02-heterocycloalkyl, S0-alkyl-heterocycloalkyl-alkyl; or C (NCN) NH-alkyl, C (NCN) NH-cycloalkyl, C (NCN) NH-aryl, C (NCNNH) -alkyl-cycloalkyl, C (NCN) NH-alkyl-aryl, C (NCN) H- heteroaryl, C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocycloalkyl; or C (NN02) NH-alkyl, C (NN02) NH-cycloalkyl, C (NN02) NH-aryl, C (NN02) NH-alkyl-cycloalkyl, 'C (NN02) NH-alkyl-aryl, C (NN02) NH-heteroaryl, C (NN02) NH-alkyl-heteroaryl, C (NN02) NH-heterocycloalkyl, C (NN02) NH-alkyl-heterocycloalkyl; or C (NH) NH-alkyl, C (NH) NH-cycloalkyl, C (NH) NH-aryl, C (NH) NH-alkyl-cycloalkyl, C (NH) NH-alkyl-aryl, C (NH) NH -heteroaryl, C (NH) NH-alkyl-heteroaryl, C (NH) NH-heterocycloalkyl, C (NH) NH-alkyl-heterocycloalkyl; or C (NH) NHCO-alkyl, C (NH) NHCO-cycloalkyl, C (NH) NHCO-aryl, C (NH) NHCO-alkyl-cycloalkyl, C (NH) NHC0-alkyl-aryl, C (NH) NHCO-heteroaryl, C (NH) NHCO-alkyl-heteroaryl, C (NH) NHCO-heterocycloalkyl, C (NHJ NHCO-alkyl-heterocycloalkyl; or C (N0R6) NH-alkyl, C (NOR6) NH-cycloalkyl, C (NOR6) NH-aryl, C (NOR6) NH-alkyl-cycloalkyl, C (N0R6) NH-alkyl-aryl, C (N0R6) NH-heteroaryl, C (NOR6) NH-alkyl-heteroaryl, C (NOR6) NH-heterocycloalkyl, C (NOR6) NH-alkyl-heterocycloalkyl; Rs is hydrogen or alkyl; Re is hydrogen alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; m is an integer from 0 to 2; and n is an integer from 1 to 3.

2. the compounds as described in the claim 1 characterized in that: Ri and R2 are independently hydrogen, fluorine or alkyl; where Y is oxygen, sulfur or NR9; _3 is alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; or CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-hetrocycloalkyl, CONH-alkyl-heterocycloalkyl; or COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl; or S02-cycloalkyl, S02-aryl, S02-alkyl-cycloalkyl, S02-alkyl-aryl, SO2-heteroaryl, SO2-alkyl-heteroaryl, SO2-heterocycloalkyl, SO2-alkyl-heterocycloalkyl or -alkyl; or C (NCN) NH-alkyl, C (NCN) NH-cycloalkyl, C (NCN) NH-aryl, C (NCNNH) -alkyl-cycloalkyl, C (NCN) NH-alkyl-aryl, C (NCN) NH- heteroaryl, C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocycloalkyl; or C (NN02) NH-alkyl, C (NN02) NH-cycloalkyl, C (NN02) NH-aryl, C (NN02) NH-alkyl-cycloalkyl, C (NN02) NH-alkyl-aryl, C (NN02) NH-heteroaryl, C (NN02) NH-alkyl-heteroaryl, C (NN02) NH-heterocycloalkyl, C (NN0) NH-alkyl-heterocycloalkyl; or C (NH) NH-alkyl, C (NH) NH-cycloalkyl, C (NH) NH-aryl, C (NH) NH-alkyl-cycloalkyl, C (NH) NH-alkyl-aryl, C (NH) NH -heteroaryl, C (NH) NH-alkyl-heteroaryl, C (NH) NH-heterocycloalkyl, C (NH) NH-alkyl-heterocycloalkyl; or C (NH) NHCO-alkyl, C (NH) NHCO-cycloalkyl, C (NH) NHCO-aryl, C (NH) HCO-alkyl-cycloalkyl, C (NH) NHC0-alkyl-aryl, C (NH) NHCO-heteroaryl, C (NH) NHCO-alkyl-heteroaryl, C (NH) NHCO-heterocycloalkyl, C (NH) NHCO-alkyl-heteroclcloalkyl; or C (NOR6) NH-alkyl, C (N0R6) NH-cycloalkyl, C (NOR6) N-aryl, C (N0R6) NH-alkyl-cycloalkyl, C (NOR6) NH-alkyl-aryl, C (NOR6) NH-heteroaryl, C (NOR6) NH-alkyl-heteroaryl, C (NOR6) NH-heterocycloalkyl, C (NOR6) NH-alkyl-heterocycloalkyl; R5 is hydrogen or alkyl; Re is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R7 and R8 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, cycloalkylalkyl, arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; Rg is hydrogen, alkyl, cycloalkyl, aryl, alkylcycloalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; m is an integer from 0 to 2; Y n is an integer from 1 to 3.

3. The compounds as described in claim 1, characterized in that: Ri and R2 are independently hydrogen, fluorine or alkyl; where Y is oxygen; R 4 is alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; or CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-hetrocycloalkyl, CONH-alkyl-heterocycloalkyl; or COO-alkyl, COO-cycloalkyl, COO-aryl, C00-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl; or S02-cycloalkyl, S02-aryl, S02-alkyl-cycloalkyl, S02-alkyl-aryl, S02-heteroaryl, SO2-alkyl-heteroaryl, SO2-heterocycloalkyl, SO2-alkyl-heterocycloalkyl or -alkyl; or 2 C (NCN) NH-alkyl, C (NCN) NH-cycloalkyl, C (NCN) NH-aryl, C (NCNNH) -alkyl-cycloalkyl, C (NCN) H-alkyl-aryl, C (NCN) NH -heteroaryl, C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocycloalkyl; or C (NN02) NH-alkyl, C (NN02) NH-cycloalkyl, C (NN02) NH-aryl, C (NN02) NH-alkyl-cycloalkyl, C (NN02) NH-alkyl-aryl, C (NN02) NH-heteroaryl, C (NN02) NH-alkyl-heteroaryl, C (NN02) NH-heterocycloalkyl, C (NN02) NH-alkyl-heterocycloalkyl; or C (NH) NH-alkyl, C (NH) NH-cycloalkyl, C (NH) NH-aryl, C (NH) H-alkyl-cycloalkyl, C (NH) NH-alkyl-aryl, C (NH) NH -heteroaryl, C (NH) NH-alkyl-heteroaryl, C (NH) NH-heterocycloalkyl, C (NH) NH-alkyl-heterocycloalkyl; or C (NH) NHCO-alkyl, C (NH) NHCO-cycloalkyl, C (NH) NHCO-aryl, C (NH) NHCO-alkyl-cycloalkyl, C (NH) NHCO-alkyl-aryl, C (NH) HCO-heteroaryl, C (NH) NHCO-alkyl-heteroaryl, C (NH) HCO-heterocycloalkyl, C (NH) NHCO-alkyl-heterocycloalkyl; or C (NOR6) NH-alkyl, C (NOR6) NH-cycloalkyl, C (NOR6) NH-aryl, C (NOR6) NH-alkyl-cycloalkyl, C (NOR6) NH-alkyl-aryl, C (NOR6) NH-heteroaryl, C (NOR6) NH-alkyl-heteroaryl, C (NOR6) NH-heterocycloalkyl, C (NOR6) NH-alkyl-heterocycloalkyl; R5 is hydrogen; Re is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; R7 and Ra are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, cycloalkylalkyl, arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; m is an integer from 0 to 2; Y n is an integer from 1 to 34.

The compounds as described in claim 1, characterized in that: Ri and R2 are independently hydrogen, fluorine or alkyl; where Y sulfur; R 4 is alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; or CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-hetrocycloalkyl, CONH-alkyl-heterocycloalkyl; or COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl; or S02-cycloalkyl, S02-aryl, S02-alkyl-cycloalkyl, S02-alkyl-aryl, S02-heteroaryl, SO2-alkyl-heteroaryl, SO2-heterocycloalkyl, SO2-alkyl-heterocycloalkyl or -alkyl; or 2 C (NCN) NH-alkyl, C (NCN) NH-cycloalkyl, C (NCN) NH-aryl, C (NCNNH) -alkyl-cycloalkyl, C (NCN) H-alkyl-aryl, C (NCN) NH -heteroaryl, C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocycloalkyl; 'or C (NN02) NH-alkyl, C (NN02) NH-cycloalkyl, C (NN02) NH-aryl, C (NN02) NH-alkyl-cycloalkyl, C (NN02) NH-alkyl-aryl, C (NN02) NH-heteroaryl, C (NN02) NH-alkyl-heteroaryl, C (NN02) NH-heterocycloalkyl, C (NN02) NH-alkyl-heterocycloalkyl; or C (NH) NH-alkyl, C (NH) NH-cycloalkyl, C (NH) NH-aryl, C (NH) H-alkyl-cycloalkyl, C (NH) NH-alkyl-aryl, C (NH) NH -heteroaryl, C (NH) NH-alkyl-heteroaryl, C (NH) NH-heterocycloalkyl, C (NH) NH-alkyl-heterocycloalkyl; or C (NH) NHCO-alkyl, C (NH) NHCO-cycloalkyl, C (NH) NHCO-aryl, C (NH) NHCO-alkyl-cycloalkyl, C (NH) NHC0-alkyl-aryl, C (NH) HCO-heteroaryl, C (NH) NHCO-alkyl-heteroaryl, C (NH) NHCO-heterocycloalkyl, C (NH) NHCO-alkyl-heterocycloalkyl; or C (NOR6) NH-alkyl, C (NOR6) NH-cycloalkyl, C (NOR6) NH-aryl, C (NOR6) NH-alkyl-cycloalkyl, C (NOR6) NH-alkyl-aryl, C (N0R6) NH-heteroaryl, C (N0R6) NH-alkyl-heteroaryl, C (N0R6) NH-heterocycloalkyl, C (NORe) NH-alkyl-heterocycloalkyl; R5 is hydrogen; R6 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R7 and R8 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, cycloalkylalkyl, arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; m is an integer from 0 to 2; Y n is an integer from 1 to 3.

5. The compounds as described in claim 1, characterized in that: Ri and R2 are independently hydrogen, fluorine or alkyl; where Y is NR9; R is alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl; or CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-hetrocycloalkyl, CONH-alkyl-heterocycloalkyl; or COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl; or S02-cycloalkyl, S02-aryl, S02-alkyl-cycloalkyl, S02-alkyl-aryl, S02-heteroaryl, SO2-alkyl-heteroaryl, SO2-heterocycloalkyl, SO2-alkyl-heterocycloalkyl or -alkyl; or C (NCN) NH-alkyl ?, C (NCN) H-cycloalkyl, C (NCN) NH-aryl, C (NCNNH) -alkyl-cycloalkyl, C (NCN) NH-alkyl-aryl, C (NCN) NH -heteroaryl, C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocycloalkyl; or C (NN02) NH-alkyl, C (NN02) NH-cycloalkyl, C (NN02) NH-aryl, C (NN02) NH-alkyl-cycloalkyl, C (NN02) NH-alkyl-aryl, C (NN02) NH-heteroaryl, C (NN02) NH-alkyl-heteroaryl, C (NN02) NH-heterocycloalkyl, C (NN02) NH-alkyl-heterocycloalkyl; or C (NH) NH-alkyl, C (NH) NH-cycloalkyl, C (NH) NH-aryl, C (NH) NH-alkyl-cycloalkyl, C (NH) H-alkyl-aryl, C (NH) NH -heteroaryl, C (NH) NH-alkyl-heteroaryl, C (NH) NH-heterocycloalkyl, C (NH) NH-alkyl-heterocycloalkyl; or C (NH) NHCO-alkyl, C (NH) NHCO-cycloalkyl, C (NH) NHCO-aryl, C (NH) NHCO-alkyl-cycloalkyl, C (NH) NHCO-alkyl-aryl, C (NH) NHCO -heteroaryl, C (NH) NHCO-alkyl-heteroaryl, C (NH) NHCO-heterocycloalkyl, C (NH) NHCO-alkyl-heterocycloalkyl; or C (NOR6) NH-alkyl, C (N0R6) NH-cycloalkyl, C (NORs) NH-aryl, C (NOR6) NH-alkyl-cycloalkyl, C (NOR6) NH-alkyl-aryl, C (NOR6) NH -heteroaryl, C (NOR6) NH-alkyl-heteroaryl, C (NOR6) NH-heterocycloalkyl, C (NOR6) NH-alkyl-heterocycloalkyl; Rs is hydrogen; R6 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R7 and Re are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, cycloalkylalkyl, arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; Rg is hydrogen. Alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; _ m is an integer from 0 to 2; Y n is an integer from 1 to 3.

6. The compounds as described in claim 1, characterized in that: Ri and R2 are independently hydrogen, fluorine or alkyl; where Y is oxygen; R is CO-alkyl, CO-alkyl-aryl, CO-cycloalkyl, CO-alkyl-heteroaryl, CO-alkyl-heteroalkyl, CO-alkyl-heterocycloalkyl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl or CONH- alkyl-heterocycloalkyl; Rs is hydrogen; R7 and R8 are hydrogen, is the integer 0; Y n is the whole 1

7. The compounds as described in claim 1, characterized in that: Ri and R2 are independently hydrogen, fluorine or alkyl; where Y is oxygen; R 4 is CO-alkyl, CO-alkyl-aryl Co-alkyl-heteroalkyl, CO-cycloalkyl, CO-alkyl-hetercycloalkyl, CO-alkyl-heteroaryl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl or CONH-alkyl -heterocycloalkyl; Rs is hydrogen; R7 and Rs are alkyl, m is the integer 0; Y n is the integer 1.

8. The compounds as described in claim 1, characterized in that: Ri and R2 are independently hydrogen, fluorine or alkyl; where Y is oxygen; R 4 is CO-alkyl, CO-alkyl-aryl Co-alkyl-heteroalkyl, CO-cycloalkyl, CO-alkyl-hetercycloalkyl, CO-alkyl-heteroaryl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl or CONH-alkyl -heterocycloalkyl; Rs is hydrogen; . ~ R7 is hydrogen; Rs is alkyl; m is the integer 0; Y n is the integer 1.

9. The compounds as described in claim 1, characterized in that: Ri and R2 are independently hydrogen, fluorine or alkyl; where Y is oxygen; R 4 is CO-alkyl, CO-alkyl-aryl Co-alkyl-heteroalkyl, CO-cycloalkyl, CO-alkyl-hetercycloalkyl, CO-alkyl-heteroaryl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl or CONH-alkyl -heterocycloalkyl; R5 is hydrogen; R7 is alkyl; R8 is hydrogen; m is the integer 0; Y n is the whole 1

10. The compounds as described in claim 1, characterized in that: Ri and R2 are independently hydrogen, fluorine or alkyl; where Y is sulfur; R 4 is CO-alkyl, CO-alkyl-aryl Co-alkyl-heteroalkyl, CO-cycloalkyl, CO-alkyl-hetercycloalkyl, CO-alkyl-heteroaryl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl or CONH-alkyl -heterocycloalkyl; R5 is hydrogen; R7 is hydrogen; R8 is alkyl; m is the integer 0; Y n is the integer 1.

11. The compounds as described in claim 1, characterized in that: Ri and R2 are independently hydrogen, fluorine or alkyl; where Y is sulfur; R 4 is CO-alkyl, CO-alkyl-aryl Co-alkyl-heteroalkyl, CO-cycloalkyl, CO-alkyl-hetercycloalkyl, CO-alkyl-heteroaryl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl or CONH-alkyl -heterocycloalkyl; R5 is hydrogen; R7 is alkyl; R8 is hydrogen; m is the integer 0; Y n is the integer 1..

12. The compounds as described in claim 1, characterized in that: Ri and R2 are independently hydrogen, fluorine or alkyl; where Y is NR9; R 4 is CO-alkyl, CO-alkyl-aryl Co-alkyl-heteroalkyl, CO-cycloalkyl, CO-alkyl-hetericcioalkyl, CO-alkyl-heteroaryl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl or CONH-alkyl -heterocycloalkyl; R5 is hydrogen; R7 is hydrogen; R8 is alkyl; R9 is hydrogen, alkyl, cycloalkyl, aryl, alkyl-cycloalkyl, alkyl-aryl, heteroaryl, alkyl-heteroaryl, heterocycloalkyl, or alkyl-heterocycloalkyl; m is the integer 0; Y n is the integer 1.

13. The compounds as described in claim 1, characterized in that: Ri and R2 are independently hydrogen, fluorine or alkyl; where Y is NR9; R is CO-alkyl, CO-alkyl-aryl Co-alkyl-heteroalkyl, CO-cycloalkyl, CO-alkyl-hetercycloalkyl, CO-alkyl-heteroaryl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl or CONH-alkyl -heterocycloalkyl; Rs is hydrogen; . ~ R7 is alkyl; Rs is hydrogen; R9 is alkyl; m is the integer 0; Y n is the integer 1.

14. The compounds as described in claim 1, characterized in that: Ri and R2 are independently hydrogen, fluorine or alkyl; where X is N 3R 9; - R 4 is CO-alkyl, CO-alkyl-aryl Co-alkyl-heteroalkyl, CO-cycloalkyl, CO-alkyl-hetercycloalkyl, CO-alkyl-heteroaryl, CONH-alkyl, CONH-alkyl-aryl, CONH-cycloalkyl or CONH-alkyl-heterocycloalkyl; R5 is hydrogen; R7 is alkyl; R8 is hydrogen; R9 is hydrogen; m is the integer 0; Y n is the integer 1,

15. The compound as recited in Claim 1, characterized in that it is: N- [5- [[5-Ethyl-2-oxazolyl) methyl] thio] -2-thiazole-J-acetamide; N- [5- [[5-Ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] benzamide; , 5"N- [5- [[(Ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] benzansulfonamide N- [5- [[(4,5-Dimethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide; N- [5- [[(5-t-Butyl-2-Dxazolyl) methyl] thio] 2-thiazolyl] acetamide; N- [5- [[5-t-Butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] trimethylacetamide; N- [5- [[(4-Styyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide; or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition characterized in that it includes a compound of claim 1 and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition characterized in that it includes a compound of claim 1 in combination with a pharmaceutically acceptable carrier, and an anti-cancer agent formulated as a fixed dose.

18. A pharmaceutical composition according to claim 16 characterized in that it includes a compound of Claim 1 in combination with a pharmaceutically acceptable carrier, with an anti-cancer treatment or anti-cancer agent administered in sequence.

19. The pharmaceutical composition according to claim 18, characterized in that said combination includes said compounds of claim 1 and said pharmaceutically acceptable carrier is administered prior to the administration of said anticancer treatment or agent.

20. The pharmaceutical composition according to claim 18, characterized in that said combination includes said compound of Claim 1 and said pharmaceutically acceptable carrier, is administered after administration of said anticancer agent or agent. ~~

21. A method of inhibiting protein kinases characterized in that it comprises administering to a mammalian species in need thereof an effective chlidin-dependent kinase inhibitory amount of a compound of Claim 1.

22. A method for inhibiting cdk2 (cdkl) characterized in that it includes adminsitration to a mammalian species in need thereof of an effective inhibitory amount of the protein cyclin dependent kinase of a compound of Claim 1.

23. A cdk2 inhibition method (cdkl) characterized in that it comprises the administration to a mammalian species in need thereof of an effective cdc2 inhibitory amount of a compound of claim 1.

24. A cdk2 inhibition method characterized in that it comprises administering to a mammalian species in need thereof an effective cdk2 inhibitory amount of a compound of claim 1.

25. A cdk3 inhibition method characterized in that it comprises administering a mammalian species in need thereof with an effective cdk3 inhibitory amount of a compound of claim 1.

26. A cdk4 inhibition method characterized in that it comprises administering a mammalian species in need thereof with an effective cdk4 inhibitory amount of a compound of claim 1.

27. A cdk5 inhibition method characterized in that it comprises administering a mammalian species in need thereof with an effective cdk4 inhibitory amount of a compound of claim 1.

28. A cdk6 inhibition method characterized in that it comprises administering to a mammalian species in need thereof an effective cdk6 inhibitory amount of a compound of claim 1.

29. A method of cdk7 inhibition characterized in that it comprises the administration to a mammalian species in need thereof of an effective cdk7 inhibitory amount of a compound of Claim 1.

30. A cdkd inhibition method characterized in that it comprises administering to a mammalian species in need thereof an effective cdk8 inhibitory amount of a compound of claim 1.

31. A method for the treatment of proliferative diseases characterized in that it comprises administering to a mammalian species in need thereof an effective therapeutic amount of a compound of Claim 16.

32. A method for treating cancer characterized in that it comprises administering to a mammalian spice in need thereof a therapeutically effective amount of a composition of claim 16.

33. A method for the treatment of inflammation, inflammatory bowel disease or. rejection to transplante.s, characterized in that it comprises the administration to a mammalian species in need thereof of a therapeutically effective amount of a composition of Claim 16.

34. A method for the treatment of arthritis characterized in that it comprises administration to a mammalian species in need thereof of a therapeutically effective amount of a composition of Claim 16.

35. A method for the treatment of HIV infection and prevention of the development of AIDS, characterized in that it comprises administering to a mammalian species in need thereof a therapeutically effective amount of a composition of Claim 16.

36. A method for the treatment of viral infections, characterized in that it comprises the administration to a mammalian species in need thereof of a therapeutically effective amount of a composition of claim 16.

37. A method for the treatment of fungal infections, characterized in that it comprises the administration to a mammalian species in need thereof of a therapeutically effective amount of a Composition of Claim 16.

38. A method for preventing the development of cancer or tumor relapse, characterized in that it comprises the administration to a mammalian species in need thereof of a therapeutically effective amount of a composition of claim 16.

39. A method for the treatment of neurodegenerative diseases to a mammalian species in need thereof of a therapeutically effective amount of a composition of Claim 16.

40. A method for the treatment of proliferative diseases characterized in that it comprises administering to a mammalian species in need thereof a therapeutically effective amount of a composition of Claim 17.

41. A method for treating cancer characterized in that it comprises administering to a mammalian species in need thereof a therapeutically effective amount of a composition of claim 17

42. A method for preventing the development of cancer or relapse of tumors characterized in that it comprises administering to a mammalian species in need thereof a therapeutically effective amount of a composition of Claim 17.

43. A method for the treatment of proliferative diseases characterized in that it comprises administering to a mammalian species in need thereof a therapeutically effective amount of a composition of Claim 18.

44. A method for treating the cancer characterized in that it comprises administering to a mammalian species in need thereof a therapeutically effective amount of a composition of Claim 18.

45. A method for preventing the development of cancer or relapse of tumors characterized in that it comprises administering to a mammalian species in need thereof a therapeutically acceptable amount of a composition of Claim 18. HINOBETHYLOLS OF CYCLIN DEPENDENT KINASES SUMMARY OF THE INVENTION Compound of the formula (i; and pharmaceutically acceptable salts thereof. As used in the formula (I), and through the specifications, the symbols have the following meanings: Ri and R are independently hydrogen, fluoride or alkyl; R3 is aryl or heteroaryl. The compounds of the formula I are inhibitors of the protein kinase and are useful in the treatment and prevention of proliferative diseases, for example, cancer, inflammation and arthritis.