HRP20030116A2 - N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]carboxamide inhibitors of cyclin dependent kinases - Google Patents

Description

This invention relates to compounds of formula I

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and their enantiomers, diastereomers, solutions and pharmaceutically acceptable salts, wherein

R is alkyl;

R 1 is hydrogen or alkyl;

X is NR 2 or CHNR 2 R 3 ;

R 2 and R 3 are each independently hydrogen, alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl; n is 0, 1, 2 or 3.

The compounds of formula I are particularly useful as potent protein kinase inhibitors, and are useful in the treatment of proliferative diseases, for example cancer, inflammation and arthritis. They may also be useful in the treatment of Alzheimer's disease, chemotherapy-induced baldness, and cardiovascular disease.

This invention describes compounds of formula I, pharmaceutical preparations containing these compounds, as well as methods for using these compounds.

The following are definitions of various terms used in describing this invention. These definitions apply to terms used in the specification of the invention (unless in particular cases otherwise limited), either individually or as part of a larger group.

The term "alkyl" or "alk" refers to a monovalent alkane (hydrocarbon) radical containing from 1 to 12, preferably 1 to 6, more preferably 1 to 4, carbon atoms, unless otherwise specified. An alkyl group is an optionally substituted straight-chain, branched or cyclic saturated hydrocarbon group. When substituted, alkyl groups may be substituted with up to four substituting groups, defined as R4, at any available attachment site. When an alkyl group is said to be substituted with an alkyl group, an alternate term for this is "branched alkyl group". Examples of such unsubstituted groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl , undecyl, dodecyl and the like.

Examples of substituents include, without limitation, one or more of the following groups: halo (such as F, Cl, Br or I), haloalkyl (such as CCl3 or CF3), alkoxy, alkylthio, hydroxy, carboxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, amino, carbamoyl, urea, amidinyl or thiol.

Cycloalkyl is a type of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It can contain from 1 to 4 rings. Examples of such unsubstituted groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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, refer to an alkyl group as described above attached via an oxygen bond (-O-) or a sulfur bond (-S-).

The term "alkyloxycarbonyl", as used here, denotes an alkoxy group attached via a carbonyl group. The alkyloxycarbonyl radical is represented by the formula: -C(O)OR5, where the R5 group is a straight-chain or branched C1±6 alkyl group.

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

The term "alkylcarbonyloxy", as used herein, means an alkylcarbonyl group which is attached by an oxygen bond.

As used herein, the term "compounds of the invention" is common to compounds of formula I and pharmaceutically acceptable salts and solutions, including their hydrates. Procedures for obtaining, dissolving and forming the hydrates are well known in the art. The invention also encompasses mixtures of stereoisomers of the compounds of the invention. Stereoisomers include, without limitation, enantiomers, diastereoisomers, and racemates, wherein the compounds have one or more chiral centers. This includes all stereoisomers of the compounds of this invention, either as admixtures, or in pure or nearly pure form. The definition of compounds according to the invention includes all possible stereoisomers and their mixtures. In particular, racemic forms and isolated optical isomers that have specific activity are understood. Racemic forms can be separated by physical procedures, for example fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chromatography on a chiral column. Individual optical isomers can be obtained from racemates by usual procedures, for example by forming a salt with an optically active acid, and then by crystallization. All configurational isomers of the compounds of this invention, either as admixtures, or in pure or nearly pure form, are encompassed. The definition of the compounds of this invention particularly refers to cis (Z) and trans (E) alkene isomers, as well as to cis and trans isomers of cycloalkyl or heterocycloalkyl rings.

Furthermore, salts of compounds of formula I which are pharmaceutically unsuitable but may be useful in other ways, for example for the isolation or purification of compounds of formula I, are also encompassed by the invention.

The compounds of the invention are defined herein by their chemical structures and/or chemical names. When a compound is mentioned by both a chemical structure and a chemical name, and the chemical structure and chemical compound do not match, the chemical structure is the key to determining the compound.

The term "pharmaceutically acceptable salt(s)", as used herein, includes without limitation salts of acidic or basic groups that may be present in the compounds of the invention. Examples of such pharmaceutically acceptable salts include, without limitation, the hydrochloride, hydrobromide, dihydrochloride, sulfate, trifluoroacetate, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts, as well as mixtures thereof. Also included are salts formed with other organic and inorganic acids, such as hydroxymethane sulfonic acid, acetic acid, benzenesulfonic acid, toluenesulfonic acid and various others, e.g. nitrates, phosphates, borates, benzoates, ascorbates, salicylates and the like. In addition, pharmaceutically acceptable salts of the compounds of formula I can be formed with alkali metals, such as sodium, potassium and lithium; alkaline earth metals, such as calcium and magnesium; organic bases, such as dicyclohexylamine, tributylamine, pyridine and the like; amino acids, such as arginine, lysine and the like.

Salts of the compounds of the invention include solutions, racemates and all stereoisomeric forms thereof including enantiomers and diastereomers (for example, D-tartrate and L-tartrate salts).

As used herein, the term "solution" means a compound of the invention or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of one or more solvent molecules bound by non-covalent intermolecular forces. Recommended solutions are volatile, non-toxic and/or acceptable for administration to humans in amounts of the order trace sizes. When the solvent is water, the solution is called a "hydrate".

Compounds of formula I can be prepared by adapting the procedures set forth in WO 99/65884 and WO 99/24416, both of which are incorporated herein by reference. Alternatively, the generic procedure shown in Scheme A below, which depicts the synthesis of a broad group of compounds of formula XIV, can be used to synthesize compounds of formula I. The starting compounds are commercially available or can be prepared by methods known to those skilled in the art. The following terms are used in Scheme A:

R 7 , R 8 and R 10 are independently hydrogen or alkyl;

R is alkyl, aryl or heteroaryl;

R 9 is hydrogen, alkyl, aryl or heteroaryl;

R 1 and R 11 are independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy;

R 12 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, CONR 13 R 14 , COR 15 or COOR 16 ;

R 13 , R 14 , R 15 and R 16 are independently hydrogen, alkyl, or aryl;

r is an integer in the range from 0 to 5;

s is an integer in the range 0 to 5;

L a suitable leaving group, such as halogen or sulfonate (R 6 SO 2 O-, CF 3 SO 2 O-, etc., where R 6 is alkyl, cycloalkyl or aryl);

M is hydrogen, Li, Na, K, Cs or a quaternary ammonium ion, eg, (R 6 ) 4 N or quaternary ammonium ions representing cyclic alkenetetramines, such as hexamethylenetetramine;

Q is hydroxy, halogen or acyloxy (R6COO-, R6OCOO-, etc.);

Y is O, S, NH, N-alkyl, N-aryl or N-acyl;

Z is hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl, S-aryl, NH 2 , N-alkyl, N-aryl or N-acyl; And

P is a nitrogen-protecting group (Boc, Cbz, R3Si, etc.). When a functional group is called "protecting", it means that the group has been modified to prevent unwanted side reactions at the protected site. Suitable protecting groups for the compounds involved in this process will be recognized from the specification depending on the level of skill in the art, and from standard textbooks. such as Greene, T. W., Protective Groups in Organic Synthesis, 3rd ed., (1999), which is incorporated herein by reference.

The process generally involves the reaction of an α-halo ketone II (commercially available or previously synthesized by well-known procedures) with an azide to give α-azido ketones III. Reduction of III with a reducing reagent yields α-amino ketones IV.

In another, more convenient way, α-amino ketones IV are prepared by reacting α-halo ketone II with cyclic alkyltetramine such as hexamethylenetetramine and the like, and then by hydrolysis, the new quaternary ammonium salt III' is obtained. This reaction enables excellent yields of the desired intermediate IV, above 90%.

Then, by reaction of α-amino ketone IV with α-halo acyl halide V in the presence of alkali or, alternatively, by coupling of α-amino ketone IV with α-halo acid, the corresponding amides VI are formed. Then, ring closure of VI with a dehydrating reagent affords 2-oxazolylalkyl halides VII. With a common dehydrating reagent, such as trihalophosphorus oxide such as POC13 used, isolation of the product is difficult due to the formation of large amounts of hydrochloric and phosphoric acid. Therefore, the process of the present invention preferably uses Burgess's reagent which provides excellent yields and allows easy and safe isolation of the product from water.

Subsequent treatment of 2-oxazolylalkyl halides VII with sulfur-containing reagent VIII or VIII' gives new key intermediates, 2-oxazolylalkyl sulfides IX. Coupling IX with 5-halo-2-aminothiazole X gives 5-(2-oxazolylalkylthio)-2-aminothiazole XI. Coupling XI with an azacycloalkanoic acid derivative XII gives thiazolyl amides XIII, which can be deprotected (in case P is a protecting group, e.g. Boc) to give 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles XIV.

Scheme A

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As can be seen in Scheme A, the processes for the preparation of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazole and analogs include the following transformations:

Step (a) comprises reacting an α-substituted ketone II such as, for example, an α-halo ketone, with an azide in a suitable solvent or solvent mixture to give an α-azido ketone III; or, more preferably, (a') reacting an α-substituted ketone II such as an α-halo ketone with a cyclic alkyltetramine such as, for example, hexamethylenetetramine in a suitable solvent or solvent mixture to give a new quaternary ammonium salt III'.

α-halo ketone includes α-halo aliphatic and α-halo aromatic ketones. Recommended α-halo ketones are α-halo pinacolones, with α-bromo pinacolone being the most recommended. Sulfonate, for example RSO2O- (where R is alkyl, aryl or heteroaryl), CF3SO20O- and the like, can be substituted with halogen at the α-position. Azides include both metal azides and quaternary ammonium azides. Metal azides are recommended, with sodium azide being the most recommended. Suitable solvent(s) include solvents such as hydrocarbons, ethers, amides, for example, dimethylformamide, ketones, etc., or mixtures thereof, with ketones such as acetone being recommended for both reactions (a) and (a').

Step (b) comprises reacting the α-azido ketone III obtained in step (a) with a reducing reagent in a suitable solvent or solvent mixture, thereby obtaining the α-amino ketone IV, or better, (b') reacting the quaternary ammonium salt III' obtained in step (a') with an acid in a suitable solvent or solvent mixture to give the α-amino ketone IV.

The reducing reagent in reaction (b) involves hydrogen in the presence of a transition metal catalyst such as palladium, trialkyl, or triarylphosphone. Hydrogen in the presence of a transition metal catalyst is recommended, and palladium on activated carbon is the most recommended. Suitable solvent(s) include solvents such as hydrocarbons, ethers and the like, or mixtures thereof, with an alcohol such as methanol being preferred. Alternatively, the reduction reaction can be carried out in the presence of an acidic medium such as, for example, hydrochloric acid in ethanol, thereby obtaining an α-amino ketone acid salt, which can be isolated as an acid salt or in the form of a free amine.

The acid in reaction (b') includes, without limitation, protic acids such as HCl, HBr, HI, H 2 SO 4 , H 3 PO 4 , etc., with HCl being preferred. Suitable solvent(s) include solvents such as hydrocarbons, ethers, alcohols and the like, or mixtures thereof, with an alcohol such as ethanol being preferred. The α-amino ketone product can be isolated as a salt or free base.

Step (c) comprises reacting (acylating) the α-amino ketone IV or its acid salt obtained in Step (b) or (b') with an α-substituted acyl derivative V such as, for example, an α-halo acyl halide, in the presence base and in a suitable solvent or mixture of solvents, which gives amide VI.

α-Halo acyl halide V includes α-alkyl or aryl substituted or unsubstituted α-halo acyl halide, with the latter being preferred. The most recommended α-halo acyl halide is α-chloroacetyl chloride. The base used in the reaction includes, without limitation, aromatic and aliphatic organic amines, with the latter being preferred. The most recommended base is triethylamine. Suitable solvent(s) include aprotic solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane being preferred. Alternatively, the reaction can be carried out using an unsubstituted acid instead of an α-substituted acyl derivative and then using a coupling reagent such as a water-soluble diimide, such as carbodiimide, haloformate, thionyl halide, etc. In both reactions, a sulfonate, for example RSO2O- (where R alkyl, aryl or heteroaryl), CF3SO2O- and the like, may be substituted with a halogen at the α-position of the α-halo acyl halide or α-halo acidic reactant, as illustrated.

Step (d) comprises reacting the amide VI obtained in Step (c) with a dehydrating reagent in a suitable solvent or solvent mixture to give a cyclized 2-oxazolylalkyl derivative VII such as, for example, a 2-oxazolylalkyl halide.

It is advanced that the reaction is carried out using (methoxycarbonylsulfamoyl)-triethylammonium hydroxide (Burgess reagent) as the dehydrating reagent. Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers and the like, or mixtures thereof. The most recommended is the use of Burgess's reagent in tetrahydrofuran. Suitable dehydrating reagents also include, without limitation, other bases, acids, acid anhydrides and the like, such as, e.g. concentrated sulfuric acid, polyphosphoric acid, etc. Although less commonly, the dehydrating reagent may for example be a trihalophosphorus oxide such as tribromophosphorus oxide or trichlorophosphorus oxide, alone or in combination with a solvent such as toluene.

Step (e) is directed to reacting the 2-oxazolylalkyl derivative VII obtained in Step (d) with a sulfur-containing reagent VIII or VIII' in a suitable solvent or solvent mixture to give 2-oxazolylalkyl sulfide IX, a new key intermediate.

The sulfur-containing reagent includes N-substituted or unsubstituted thioureas, thio acids or salts such as thioacetic acid or salts thereof, xanthine acid or salts such as the potassium salt of ethylxanthine acid. Unsubstituted thiourea is recommended. Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, alcohols and the like, or mixtures thereof, with an alcohol such as methanol or ethanol being preferred.

Step (f) involves reacting the 2-oxazolylalkyl sulfide IX obtained in Step (e) with 5-halo-2-aminothiazole X in the presence of a base and in a suitable solvent or solvent mixture to give 5-(2-oxazolylalkylthio)-2-aminothiazole XI.

5-Halo-2-aminothiazole includes 4-N-substituted or unsubstituted 5-halo-2-aminothiazoles, with 5-bromo-2-aminothiazole being preferred. Suitable bases include, but are not limited to, metal hydroxide, metal alkoxides, metal carbonates, and aqueous amines such as ammonium hydroxide. Sodium hydroxide is recommended. Suitable solvent(s) include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, alcohols and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane being preferred.

Step (g) comprises reacting the 5-(2-oxazolylalkylthio)-2-aminothiazole XI obtained in Step (f) with the azacycloalkanoic acid derivative XII in the presence of a coupling reagent in a suitable solvent or solvent mixture to give the thiazolyl amide XIII.

An azacycloalkanoic acid derivative includes N-protected derivatives, for example N-protected isonipecotic acid or N-protected nipecotic acid. Recommended nitrogen protecting groups are Boc, Cbz, silicon derivatives and the like, with Boc being the most recommended. Coupling reagents include, but are not limited to, water-soluble carbodiimides, haloformates, and the like, with carbodiimides such as alkylcarbodiimides being preferred. Suitable solvent(s) include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, etc., or mixtures thereof, with halogenated hydrocarbons such as dichloromethane being preferred.

Step (h) is directed to reacting the thiazolyl amide XIII obtained in Step (g) with a deprotection reagent in a suitable solvent or solvent mixture to give the desired 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazole XIV (wherein R11 is hydrogen ).

The choice of deprotection reagent is based on the nature of the protecting group (P). For a Boc protecting group, the recommended deprotection reagent is an acid such as hydrochloric acid or trifluoroacetic acid and a suitable solvent(s) for such a deprotection reaction, including solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides and the like, or mixtures thereof, provided that recommend halogenated hydrocarbons such as dichloromethane.

A more comprehensive synthesis of compounds of formula I is shown in Schemes 1-5 below. The starting compounds are commercially available or can be prepared by methods known to one of ordinary skill in the art. In Schemes 1-5 below, the following terms are used:

L is a suitable leaving group, such as halogen or sulfonate (eg, Br, Cl, I, R 6 SO 2 O-, CF 3 SO 2 O-, wherein R 6 is alkyl, cycloalkyl, heteroaryl or aryl);

M is hydrogen, Li, Na, K, Cs or a quaternary ammonium ion, eg, (R 6 ) 4 N or quaternary ammonium ions forming cyclic alkenetetramines, such as hexamethylenetetramine;

Q is hydroxy, halogen or acyloxy (R6COO-, R6OCOO-, etc.);

Y is O, S, NH, N-alkyl, N-aryl or N-acyl; And

Z is hydrogen, alkyl, aryl, O-alkyl, O-aryl, S-alkyl, S-aryl, NH 2 , N-alkyl, N-aryl or N-acyl. Scheme 1 shows the synthesis of compounds of formula 11.

Scheme 1: Synthesis of compounds of Formula 11

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Initially, step (a) comprises reacting a suitable α-substituted ketone 2, such as an α-halo ketone, with an azide in a suitable solvent or solvent mixture to give the α-azido ketone 3; or, more preferably, (a') reacting the ketone 2 with a cyclic alkyltetramine, such as hexamethylenetetramine in a suitable solvent or solvent mixture, to give the quaternary ammonium salt 3'.

Suitable α-halo ketones 2 include α-halo aliphatic and α-halo aromatic ketones. Recommended α-halo ketones are α-halo pinacolones, with α-bromo pinacolone being the most recommended.

A sulfonate, for example, R 6 SO 2 O- (wherein, as defined above, R 6 is alkyl, cycloalkyl, heteroaryl or aryl), CF 3 SO 2 O- and the like, may be substituted with a halogen (as group L) at the α-position. Azides include both metal azides and quaternary ammonium azides. Metal azides are recommended, with sodium azide being the most recommended. Suitable solvent(s) include hydrocarbons, ethers, amides, such as dimethylformamide, ketones, etc., or mixtures thereof, with ketones such as acetone being preferred for both reactions (a) and (a').

Step (b) comprises reacting the α-azido ketone 3 obtained in Step (a) with a reducing reagent in a suitable solvent or solvent mixture to give the α-amino ketone 4, or, more preferably, (b') reacting the quaternary ammonium salt 3' obtained in Step (a') with an acid in a suitable solvent or solvent mixture to give the α-amino ketone 4.

The reducing reagent in reaction (b) includes hydrogen in the presence of a transition metal catalyst such as palladium, a trialkyl- or triarylphosphine, such as triphenylphosphine. Hydrogen in the presence of a transition metal catalyst with hydrogen is recommended, and palladium on activated carbon is most recommended. Suitable solvent(s) in reaction (b) include hydrocarbons, ethers, alcohols and the like, or mixtures thereof, with alcohols such as methanol being preferred.

Alternatively, the reduction reaction can be carried out in the presence of an acidic medium such as hydrochloric acid in ethanol to give the aminoketone acid salt, which can be isolated as the acid salt or as the free amine.

Suitable acids for use in reaction (b') include, without limitation, HCl, HBr, HI, H 2 SO 4 , H 3 PO 4 , etc., with HCl being preferred. Suitable solvent(s) in reaction (b') include hydrocarbons, ethers, alcohols and the like, or mixtures thereof, with alcohols such as ethanol being preferred. The α-amino ketone product can be isolated as a salt or as a free base.

Step (c) comprises reacting (acylating) the α-amino ketone 4 or its acid salt obtained in Step (b) or (b') with an α-substituted acyl derivative 5, such as an α-halo acyl halide (i.e., Q and L = halo), in the presence of a base and in a suitable solvent or solvent mixture, giving amide 6.

α-Halo acyl halide 5 includes alkyl or aryl-α-halo acyl halides (substituted or unsubstituted), with the latter being preferred. The most recommended α-halo acyl halide is chloroacetyl chloride. The base used in the reaction includes, without limitation, aromatic and aliphatic organic amines, with the latter being preferred. The most recommended base is triethylamine. Suitable solvent(s) include aprotic solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane being preferred. Alternatively, the reaction can be carried out using an α-substituted acid (Q = OH) instead of an α-substituted acyl derivative and then using a coupling reagent, such as a water-soluble diimide (eg, carbodiimide), haloformate, thionyl halide, etc. In both reactions, sulfonate, for example R6SO2O- (where R6 is alkyl, cycloalkyl, aryl or heteroaryl), CF3SO2O- and the like, can be substituted by halogen at the α-position (i.e. group L) of compounds 5.

Step (d) comprises reacting the amide 6 obtained in Step (c) with a dehydrating reagent in a suitable solvent or solvent mixture to give a cyclized 2-oxazolylalkyl derivative 7, for example, a 2-oxazolylalkyl halide (i.e., L is halo).

It is advanced that the reaction is carried out using (methoxycarbonylsulfamoyl)-triethylammonium hydroxide (Burgess reagent) as the dehydrating reagent. Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers and the like, or mixtures thereof. The most recommended is the use of Burgess's reagent in tetrahydrofuran. Suitable dehydrating reagents also include, without limitation, other bases, acids, acid anhydrides and the like, such as concentrated sulfuric acid, polyphosphoric acid, etc. Less commonly, the dehydrating reagent may be trihalophosphorus oxide, such as tribromophosphorus oxide or trichlorophosphorus oxide, alone or with a solvent like toluene.

Step (e) comprises reacting the 2-oxazolylalkyl derivative 7 obtained in Step (d) with a sulfur-containing reagent 8 or 8' in a suitable solvent or solvent mixture to give the 2-oxazolylalkyl sulfide 9.

The sulfur-containing reagent includes N-substituted or unsubstituted thioureas, thio acids or salts such as thioacetic acid or salts thereof, xanthine acid or salts such as the potassium salt of ethylxanthanic acid. Unsubstituted thiourea is recommended. Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, alcohols and the like, or mixtures thereof, with alcohols such as methanol or ethanol being preferred.

Step (f) shows the reaction of the 2-oxazolylalkyl sulfide 9 obtained in Step (e) with 2-aminothiazole 10 (L halo is preferred) in the presence of a base and in a suitable solvent or solvent mixture to give 5-(2-oxazolylalkylthio)-2 -aminothiazole 11.

2-Aminothiazole 10 includes 4-N-substituted or unsubstituted 5-halo-2 aminothiazoles, and 5-bromo-2-aminothiazole is preferred. Suitable bases include, but are not limited to, metal hydroxides, metal alkoxides, metal carbonates, and aqueous amines, such as ammonium hydroxide. Sodium hydroxide is recommended. Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, alcohols and the like, or mixtures thereof, with halogenated hydrocarbons such as dichloromethane being preferred.

Scheme 2 shows the general synthesis of compounds of formula I by reaction of amine 11 with a carboxylic acid of formula 12 in the presence of a coupling agent. Suitable coupling reagents include, without limitation, water-soluble carbodiimides, haloformates, and the like, with carbodiimides such as alkylcarbodiimides, for example, a combination of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and a base, being preferred.

Scheme 2

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Scheme 3 below shows the synthesis of compounds of formula I, where X is NR2 and R2 is H. First, an amine of formula 11 is reacted with an N-protected carboxylic acid of formula 13 in the presence of a coupling agent, thereby forming an N-protected compound of formula 14. Then compound 14 is deprotected to give compounds of formula I. Suitable coupling reagents include, but are not limited to, water-soluble carbodiimides, haloformates, and the like, with carbodiimides such as alkylcarbodiimides, for example 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, being preferred. and bases.

Scheme 3

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In the scheme above, P is a nitrogen-protecting group (for example, Boc, Cbz, R3Si, etc.). When a functional group is called "protecting", it means that the group has been modified to prevent unwanted side reactions at the protected site. Suitable protecting groups for the compounds involved in this process will be recognized from the specification depending on the level of skill in the art, and from standard textbooks. such as Greene, T. W., Protective Groups in Organic Synthesis, 3rd ed., (1999), which is incorporated herein by reference. Recommended nitrogen-protecting groups are Boc, Cbz, silicon derivatives, with Boc being the most preferred. Suitable solvent/ solvents include hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, etc., or mixtures thereof, with halogenated hydrocarbons such as dichloromethane being preferred.

The choice of deprotection reagent is based on the nature of the protecting group (P). For a Boc protecting group, the recommended deprotection reagent is an acid such as hydrochloric acid or trifluoroacetic acid and a suitable solvent(s) for such a deprotection reaction, including solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides and the like, or mixtures thereof, provided that recommend halogenated hydrocarbons such as dichloromethane.

Scheme 4 which follows shows the synthesis of compounds of formula I, wherein X is NR2 and R2 is 2,3-dihydroxypropyl, by reaction of a compound of formula I, wherein X is NR2 and R2 is hydrogen with glyceraldehyde in the presence of a reducing agent such as sodium triacetoxyborohydride and an alcohol like methanol.

Scheme 4

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Scheme 5 which follows shows the synthesis of compounds of formula I, wherein X is NR2 and R2 is 2-hydroxyethyl, by reaction of a compound of formula I, wherein X is NR2 and R2 is hydrogen with a 2-(bromoethoxy)trialkylsilane of formula 15, yielding junction 16, and by deprotecting junction 16 with an acid such as hydrofluoric acid.

Scheme 5

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Recommended compounds of formula I are those in which:

R is alkyl;

R 1 is hydrogen;

X is NR 2 or CHNR 2 R 3 ; And

R 2 and R 3 are independently hydrogen, alkyl, substituted alkyl or cycloalkyl; And

n is 2.

The first group of more recommended compounds of this invention are those whose formula is Ia:

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as well as their enantiomers, diastereoisomers, solutions and pharmaceutically acceptable salts, wherein R2 is hydrogen, alkyl, substituted alkyl or cycloalkyl.

Another group of more recommended compounds of this invention are those whose formula is Ib:

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as well as their enantiomers, diastereoisomers, solutions and pharmaceutically acceptable salts, wherein R2 is hydrogen, alkyl, substituted alkyl or cycloalkyl.

The third group of more recommended compounds of this invention are those whose formula is Ic:

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as well as enantiomers, diastereoisomers, solutions and pharmaceutically acceptable salts thereof, wherein R 2 and R 3 are each independently hydrogen, alkyl, substituted alkyl or cycloalkyl.

In the following embodiment, the compounds of formula I include, without limitation, those listed in Table 1 below, as well as their enantiomers, diastereoisomers, solutions and pharmaceutically acceptable salts.

Table 1: Compounds of the invention

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Recommended salts of the above compounds are hydrochloride, hydrobromide, dihydrochloride, sulfate, trifluoroacetate, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts, as well as their mixtures.

This invention also includes methods based on the pharmacological properties of the compounds of the invention. The compounds according to the invention have pharmacological properties; preferably, the compounds of formula I are inhibitors of protein kinases such as cyclin-dependent kinases (cdk), for example, cdc2 (cdk1), cdk2, cdk3, cdk4, cdk5, cdk6, cdk7 and cdk8. Accordingly, the invention encompasses the use of the compounds of the invention in the treatment, prevention and/or management of cancer, inflammation or inflammatory diseases, arthritis, Alzheimer's disease and cardiovascular diseases. The invention includes, in a more specific form, the use of the compounds of the invention for the treatment, prevention and/or management of proliferative diseases or their symptoms. The invention also encompasses the use of the compounds of the invention in the treatment or prevention of local and systemic fungal infections.

More specifically, the compounds of formula I are useful in the treatment of various types of cancer, including (without limitation) the following:

- cancer, including bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid, prostate and skin;

- hematopoietic tumors of the lymphatic lineage, including acute lymphatic lymphomas, B-cell lymphomas and Burkett's lymphoma;

- hematopoietic tumors of the myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia;

- tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma;

- other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, neuroblastoma and glioma.

Without being limited by any theory, and because of the key role of cdks in general in the regulation of cell proliferation, the inhibitors could act as reversible cytostatic agents that could be useful in the treatment of any disease event involving a disorder of cell proliferation, e.g. neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, re-stenosis after angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplant rejection, angiogenesis and endotoxic shock.

The invention also includes the use of the compounds of the invention in the treatment of Alzheimer's disease, as indicated by recent findings that cdk5 is involved in the phosphorylation of tau protein (J Biochem, 117, 741-749 (1995)).

The invention also encompasses the use of compounds of the invention as inhibitors of other protein kinases, e.g. protein kinase C, her2, rafl, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, wee1 kinase, Src, Abl, VEGF and lck, and is therefore effective in the treatment of diseases associated with other protein kinases.

The invention also encompasses the use of the compounds of the invention to induce or suppress apoptosis, a process of physiological cell death that is crucial for normal growth and homeostasis. Alterations of apoptosis pathways contribute to the pathogenesis of various diseases in humans. The compounds of formula I, as modulators of apoptosis, will be effective in the treatment of various human diseases with disorders of apoptosis including cancer (in particular, without limitation, follicular lymphomas, carcinomas with p53 mutations, hormone-dependent tumors of the breast, prostate and ovary, as well as precancerous lesions such as familial adenomatous polyposis), viral infections (including, without limitation, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus, and adenovirus), autoimmune diseases (including, without limitation, systemic lupus erythematosus, immune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory disease bowel and autoimmune diabetes mellitus), neurodegenerative disorders (including, without limitation, Alzheimer's disease, AIDS dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), AIDS, myelodysplastic syndromes, aplastic anemia , ischemic damage associated with myocardial infarction, stroke and reperfusion injury, arrhythmias, atherosclerosis, toxic or alcoholic liver damage, hematological diseases (including, without limitation, chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including, without limitation, osteoporosis and arthritis), aspirin rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease and pain in malignant diseases.

In another embodiment, the invention includes a method for inhibiting cdk in a cell. In particular, the invention encompasses the treatment or prevention of diseases associated with cdk modulation by administering one or more compounds of the invention to a mammal in need thereof.

The invention encompasses the treatment of mammals, primarily humans.

In addition, the compounds of the invention can be used to treat chemotherapy-induced alopecia, chemotherapy-induced thrombocytopenia, chemotherapy-induced leukopenia, or mucositis. In the treatment of baldness caused by chemotherapy, the compounds of the invention are preferably applied topically, in the form of a medicinal agent such as a gel, solution, dispersion or paste.

The compounds of this invention may be used in combination (before, during or after, including cyclic administration) with known cancer treatment modalities such as radiation or with cytostatic and cytotoxic agents including, without limitation, microtubule stabilizing agents, microtubule destabilizing agents, alkylating agents , prometabolites, epidophyllotoxin, antineoplastic enzyme, topoisomerase inhibitor, procarbazine, mitoxantrone, platinum coordination complexes, biological response modulators, growth inhibitors, hormonal/antihormonal therapeutic agents, hematopoietic growth factors and the like.

Classes of anticancer agents that may be used in combination with compounds of formula I of the present invention include, without limitation, the anthracycline family of drugs, vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, taxanes, epothilones, discodermolide, the pteridine family of drugs, diynes, aromatase inhibitors, and podophyllotoxins. Members of these families particularly include, for example, paclitaxel, docetaxel, 7-O-methylthiomethylpaclitaxel (described in US 5646176), 3'-tert-butyl-3'-N-tert-butyloxycarbonyl-4-deacetyl-3'-dephenyl- 3'-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel (described in USSN 60/179965) dated February 3, 2000, which is incorporated herein by reference), C-4 methyl carbonate paclitaxel (described in WO 94/14787 ), epothilone A, epothilone B, epothilone C, epothilone D, desoxyepothilone A, desoxyepothilone B, [1S-[lR*, 3R*(E), 7R*,10S*,11R*,12R*,16S*]]- 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0 ]heptadecane-5,9-dione (described in WO 99/02514), [1S-[1R*, 3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[ 2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5 ,9-dione (described in USSN 09/506481 dated February 17, 2000 which is incorporated herein by reference), doxorubicin, arminomycin, daunorubicin, aminopterin, methotrexate, metho pterin, dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine and the like. Other useful anticancer agents that can be used in combination with the compounds of this invention include, without limitation, estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepu, cytarabine, idatrexate, trimetrexate, dacarbazine, L- asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons, interleukins and the like. In addition, the compounds of this invention can be used in combination with farnesyl protein transferase inhibitors such as described in US 6011029; anti-angiogenic agents such as angiostatin and endostatin; kinase inhibitors such as her2 specific antibodies; and modulator of p53 transactivation.

If formulated as a fixed dose, such combination products utilize the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its permitted dosage range. The compounds of formula I may be used sequentially, in any order, with known anticancer agents or cytotoxic agents when a combination formulation is warranted.

This invention also describes pharmaceutical compositions containing a compound of this invention and a pharmaceutically acceptable carrier. It should be understood that, in the context of pharmaceutical preparations of this invention, compounds of the invention or compounds of formula I refer to free bases, enantiomers, diastereoisomers, solutions, as well as pharmaceutically acceptable salts. Examples of such pharmaceutically acceptable salts include, without limitation, the hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts.

Also included are salts formed with other organic and inorganic acids such as hydroxymethane sulfonic acid, acetic acid, benzenesulfonic acid, toluenesulfonic acid and various others, eg, nitrates, phosphates, borates, benzoates, ascorbates, salicylates and the like. These salts include racemic forms as well as enantiomers and diastereomers (such as, for example, the D-tartrate and L-tartrate salts). In addition, pharmaceutically acceptable salts of compounds of formula I can be formed with alkali metals such as sodium, potassium and lithium; alkaline earth metals such as calcium and magnesium; organic bases such as dicyclohexylamine, tributylamine, pyridine and the like; amino acids such as arginine, lysine and the like.

The pharmaceutical compositions of this invention may further contain one or more pharmaceutically acceptable additional carriers, excipients, or diluents, including, without limitation, ingredients such as alum, stabilizers, antimicrobials, buffers, colors, flavors, and the like. The compounds and compositions of this invention may be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

For oral administration, the compounds and preparations of the invention can be administered in the form of tablets or capsules, or as solutions and suspensions. In the case of tablets for oral use, carriers often used include lactose and corn starch, and lubricants such as magnesium stearate are often added. For oral administration in capsule form, useful carriers include lactose and corn starch. When aqueous suspensions are used for oral administration, emulsifying agents and/or suspending agents are often added. In addition, sweeteners and/or flavorings can be added to oral preparations. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile solutions of the active ingredient/active ingredients are usually used, and the pH of these solutions should be adjusted and buffered appropriately. For intravenous administration, it is necessary to control the total concentration of the solution in order to maintain the isotonicity of the preparation.

Daily doses for the administration of the compounds of this invention to humans are usually determined by the attending physician, with the fact that the doses generally vary depending on the age, body weight, route of administration and response of the individual patient, as well as the severity of his complaints. The Formula I compound of this invention is preferably administered to humans in an amount of about 0.001 mg/kg body weight to about 100 mg/kg body weight per day, more preferably from about 0.01 mg/kg body weight to about 50 mg/kg body weight per day, and the most recommended is from about 0.1 mg/kg of body weight to about 20 mg/kg of body weight per day.

cdc2/cyclin B1 kinase assay

cdc2/cyclin B1 kinase activity is determined by monitoring the incorporation of 32p into histone HI. The reaction consists of 50 ng baculovirus expressing GST-cdc2, 75 ng baculovirus expressing GST-cyclin B1, 1 μg histone HI (Boehringer Mannheim), 0.2 μCi 32 γ-ATP, and 25 μM ATP in kinase buffer (50 mM Tris, pH 8.0, 10 mM MgCl2, 1 mM EGTA, 0.5 mM DTT). The reaction is incubated at 30°C for 30 minutes, and then stopped by adding cold trichloroacetic acid (TCA) to a final concentration of 15% and incubated on ice for 20 minutes. The reaction is harvested on GF/C unifilter plates (Packard) using a Packard Filtermate Universal device and filters are counted on a Packard TopCount 96-well liquid scintillation counter (Marshak, D. R., Vanderberg, M. T., Bae, Y. S., Yu, I. J., J Cellular Biochemistry , 45, 391-400 (1991), incorporated herein by reference).

cdk2/cyclin E kinase assay

cdk2/cyclin E kinase activity is determined by monitoring the incorporation of 32P into the retinoblastoma protein. The reaction consists of 2.5 ng baculovirus expressing GST-cdk2/cyclin E, 500 ng bacterially produced GST-retinoblastoma protein (aa 776-928), 0.2 μCi 32P γ-ATP, and 25 μM ATP in kinase buffer (50 mM Hepes, pH 8.0, 10 mM MgCl2, 5 mM EGTA, 2 mM DTT). The reaction is incubated at 30°C for 30 minutes, then stopped by adding cold trichloroacetic acid (TCA) to a final concentration of 15% and incubated on ice for 20 minutes. The reaction is harvested on GF/C unifilter plates (Packard) using a Packard Filtermate Universal device and filters are counted on a Packard TopCount 96-well liquid scintillation counter.

cdk 4/cyclin D1 kinase assay

Activity of cdk4/cyclin D1 kinase is determined by monitoring the incorporation of 32P into the retinoblastoma protein. The reaction consists of 165 ng baculovirus expressed as GST-cdk4, 282 ng bacterially expressed as S-tag cyclin D1, 500 ng bacterially produced GST-retinoblastoma protein (aa 776-928), 0.2 μCi 32P γ-ATP and 25 μM ATP. in kinase buffer (50 mM Hepes, pH 8.0, 10 mM MgCl2, 5 mM EGTA, 2 mM DTT). The reaction is incubated at 30°C for 1 hour, then stopped by adding cold trichloroacetic acid (TCA) to a final concentration of 15% and incubated on ice for 20 minutes. Reaction The reaction is harvested on GF/C unifilter plates (Packard) using a Packard Filtermate Universal device and the filters are counted on a Packard TopCount 96-well liquid scintillation counter. (Coleman, K. G., Wautlet, B. S., Morissey, D., Mulheron, J. G., Sedman, S., Brinkley, P., Price, S., Webster, K. R. (1997)

Identification of CDK4 Sequences involved in cyclin D, and p16 binding. J. Biol. Chem. 272, 30: 18869-18874, incorporated herein by reference).

In order to facilitate further understanding of the invention, the following examples are presented, primarily to illustrate specific compounds of the invention. The scope of the invention is not limited by these examples, but on the contrary, it encompasses the entire scope of the subject matter of the patent application.

Examples

Example 1:

Preparation of 5-[5-(t-Butyl)-2-oxazolylmethylthio]-2-(azacycloalkanoyl)amino-thiazole hydrochloride

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A. Preparation of α-Azido-pinacolone

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α-Bromo-pinacolone (199.07 g, 1.1115 mol, 1 eq) was mixed in 1.785 L of acetone with sodium azide (93.9 g, 1.4444 mol, 1.3 eq). The reaction was stirred at room temperature for 27.5 hours. The resulting solution is filtered and washed with acetone (3 x 150 mL). The filtrate was concentrated in vacuo to give 154.3 g (98.4%) of the title compound. HPLC 83.85% at 2.57 minutes (Phenomenex Inc., Torrance, CA, 5 μm C18 column 4.6 x 50 mm, 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) .

B. Preparation of α-Hexamethylenetetramino-pinacolone bromide

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α-Bromo-pinacolone (179 g, 1 mol, 1 eq) was mixed in 2 L of acetone with hexamethylenetetramine (154.21 g, 1.1 mol, 1.1 eq) and the reaction was stirred under N2 at room temperature for 26 hours. The resulting solution is filtered, the filter cake is washed with ether (3 x 50 mL) and dried in vacuo at 50°C overnight, yielding 330 g (100%) of the title compound containing 7% hexamethylenetetramine. HPLC room temp. = 0.17 min. (Phenomenex Inc., 5 μm C18 column 4.6 x 50 mm, 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

C. Preparation of α-Amino-pinacolone hydrochloride

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α-Azido-pinacolone (128.5 g, 0.911 mol) was mixed in 4.2 L of methanol with 77.1 mL of concentrated HCl and 15.42 g of 10% Pd/C. The reaction mixture was stirred in hydrogen for 1.5 hours. The catalyst is removed by filtration. The solvent is distilled to give a wet solid. The remaining water is azeotropically removed with isopropanol (2 x 500 mL). Tert-butyl methyl ether (300 mL) was added and the resulting solution was stirred, filtered, washed with t-butyl methyl ether (3 x 100 mL) and dried to give 131.0 g (95.5%) of the title compound.

D. Preparation of α-Amino-pinacolone hydrochloride

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α-Hexamethylenetetramino-pinacolone bromide (400 g, 1.254 mol, 1 eq) was stirred in 2 L of ethanol with 12 N aqueous HCl (439 mL, 5.26 mol, 4.2 eq). The reaction is stirred at 75°C for 1 hour and then allowed to cool to room temperature, the resulting solution is filtered, the filtrate is concentrated in vacuo and isopropyl alcohol is added. The solution is filtered again. Addition of 1.2 L of ether causes precipitation of the desired substance from the solution. The substance is filtered, washed with ether (2 x 300 mL) and dried in vacuo at 50°C overnight, yielding 184.1 g (97%) of the title compound.

E. Preparation of α-N-(2-Chloroacetylamino)-pinacolone

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The title compound from part D (130.96 g, 0.8637 mol, 1 eq) was dissolved in 3.025 L of CH2Cl2 in N2 at –5°C. Triethylamine (301 mL, 2.16 mol, 2.5 eq) was added, followed by chloroacetyl chloride (75.7 mL, 0.450 mol, 1.1 eq) in 175 mL of CH2Cl2. The resulting solution is stirred at -5 to -10°C for 2 hours. Add water (1,575 L), then 175 mL of concentrated HCl. The organic phase is washed a second time with 1.75 L of 10% aqueous HCl, then with 500 mL of water. The organic phase is dried over Na2SO4 and concentrated in vacuo to give 155.26 g (93.8%) of the title compound. HPLC room temp. = 2.27 min. (Phenomenex Inc., 5 μm C18 column 4.6 x 50 mm, 10-90% aqueous methanol, for 4 minutes, containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

F. Preparation of 5-(t-Butyl)-2-Oxazolylmethyl chloride

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The title compound from part E (180.13 g, 0.9398 mol, 1 eq) was mixed with phosphorus oxychloride (262 mL, 2.8109 mol, 3 eq) under N 2 . The reaction is heated to 105°C for 1 hour, the mixture is cooled to room temperature and quenched with 1.3 kg of ice. The aqueous phase is extracted with ethyl acetate (1 L, then 2 x 500 mL). The organic extracts are washed with saturated aqueous NaHCO3 (4 x 1 L) which is back-extracted several times with ethyl acetate. The organic phases are combined, washed with saturated aqueous NaHCO3 (500 mL) and then with saturated aqueous NaCl (300 mL), dried over MgSO4 and concentrated in vacuo to give a brown oil. The crude substance is distilled in a high vacuum at 100°C, which gives 155.92 g (96%) of the title compound. HPLC room temp. = 3.62 min. (Phenomenex Inc., 5 μm C18 column 4.6 x 50 mm, 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

Alternatively, the title compound from Part E (10.0 g, 52.17 mmol, 1 eq.) in 50 mL tetrahydrofuran (THF) was mixed with (methoxycarbonylsulfamyl)-triethylammonium hydroxide (Burgess reagent, 105.70 mmol, 2.03 eq., formed in situ from 9.2 mL of chlorosulfonyl isocyanate, 4.4 mL of methanol and 14.8 mL of triethylamine in 100 mL of THF). The reaction is heated to 45°C for 1.5 hours. After cooling to room temperature, the reaction is quenched with water (50 mL). The organic layer is separated and washed with saturated NaHCO3 (2 x 50 mL) and water (50 mL), dried over MgSO4 and passed through a small pad of silica gel. The solvent is removed to give an oil which is taken up in a mixture of 15 mL of heptane and 90 mL of t-butyl methyl ether, then washed with 0.2 N HCl (2 x 25 mL), brine (25 mL) and dried (MgSO4 ). Filtration and removal of the solvent gave 10.9 g of the title compound.

G. Preparation of 5-(t-Butyl)-2-oxazolylmethyl thiouronium hydrochloride

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The title compound from Part F (1.77 g, 10.2 mmol, 1.02 eq) was mixed with thiourea (0.76 g, 9.98 mmol, 1 eq) under N 2 in 10 mL of absolute ethanol. The reaction is heated under reflux for 1.5 hours. The mixture is cooled to room temperature and concentrated in vacuo. Trituration of the obtained crude material with t-butyl methyl ether gives 2.32 g (93%) of the title compound. HPLC room temp. = 2.05 min. (Phenomenex Inc., 5 μm C18 column 4.6 x 50 mm, 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm); 1H NMR (d6-DMSO): δ 9.48 (s, 3H), 6.85 (s, 1H), 4.73 (s, 2H), 1.24 (s, 9H).

H. Preparation of 5-[5-(t-Butyl)-2-oxazolylmethylthio]-2-aminothiazole

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The title compound from Part G (1.25 g, 5 mmol, 1 eq) was added to a mixture of NaOH (3.0 g, 75 mmol, 15 eq), water (10 mL), toluene (10 mL), and tetrabutylammonium sulfate (50 mg, 0.086 mmol). , 0.017 eq). 5-Bromo-2-aminothiazole hydrobromide (1.70 g, 5 mmol, 1 eq) was added and the reaction was stirred at room temperature for 14.5 hours. The mixture was diluted with water and extracted twice with ethyl acetate, the organic extracts were washed with water (4 x 10 mL), dried over MgSO4 and concentrated in vacuo to give 1.1 g (82%) of the title compound. HPLC 86.3% at 2.75 min. (Phenomenex Inc., 5 μm C18 column 4.6 x 50 mm, 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm); 1H NMR (CDCl3): δ 6.97 (s, 1H), 6.59 (s, 1H), 5.40 (br s, 2H), 3.89 (s, 2H), 1.27 (s, 9H).

I. Preparation of 5-[5-(t-Butyl)-2-oxazolylmethylthio]-2-[(N-t-butoxycarbonyl)-azacycloalkanoyl]aminothiazole

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The title compound from Part H (9.6 g, 35.6 mmol) was dissolved in N,N-dimethylformamide (36 mL) and CH2Cl2 (100 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.8 g, 72 mmol, 2 eq), N-t-butoxycarbonyl-azacycloalkanoic acid (12.6 g, 55 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (2 g, 16 mmol, 0.45 eq). The clear reaction mixture became cloudy with stirring at room temperature for 3.5 hours. Water (300 mL) and ethyl acetate (200 mL) were added and the resulting precipitate was removed by filtration. The filtrate was extracted with ethyl acetate, the organic extracts were dried over MgSO4 and concentrated in vacuo to give a yellow solid which was mixed with the precipitate obtained by filtration. The solid was boiled in a mixture of ethanol, acetone and water for 20 minutes, filtered, washed with a mixture of ethanol/water and dried to give 16.6 g (97%) of the title compound.

J. Preparation of 5-[5-(t-Butyl)-2-oxazolylmethylthio]-2-(azacycloalkanoyl)aminothiazole hydrochloride

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The title compound from Part I (16.6 g) was dissolved in 150 mL of CH2Cl2, trifluoroacetic acid (30 mL) was added dropwise and the mixture was stirred at room temperature for 2 hours. The reaction is concentrated in vacuo, diluted with water (300 mL), cooled in ice, basified in sodium hydroxide, the resulting solid is filtered and recrystallized from ethanol, water and methanol, which gives 11.2 g (83%) of the title compound in the form of a yellow solid substances. The white solid hydrochloride can be obtained by adding 18 mL of 1N aqueous HCl to 7 g of this substance in methanol. MS: 381 [M+H] + ; HPLC: 100% at 3.12 min. (YMC S5 ODS column 4.6 x 50 mm, 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

Example 2:

Preparation of (±)-N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide

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A. (±)-N-t-butoxycarbonyl-nipecotic acid

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Nipecotic acid (1.3 g, 10 mmol, 1 eq) was mixed with 10 mL dioxane, 2 mL acetonitrile, 10 mL water, and 10 mL 1N aqueous NaOH (1 eq). Di-t-butyl dicarbonate (3.3 g, 15 mmol, 1.5 eq) was added and the reaction mixture was stirred at room temp. over night. The reaction mixture was concentrated in vacuo to remove the organic solvent and 10% aqueous citric acid was added. The mixture was extracted with ethyl acetate (3 x 100 mL). The organic extracts are dried over Na2SO4, filtered through silica gel and concentrated in vacuo. The crude material was recrystallized from ethyl acetate and hexane to give 2.2 g (96%) of (±)-N-t-butoxycarbonyl-nipecotic acid as a white solid.

B. (±)-N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-(N-t-butoxycarbonyl)-3-piperidinecarboxamide

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1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (383 mg, 2 mmol, 2 eq) was added to a mixture of 2-amino-5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl] thio]thiazole (270 mg, 1 mmol, 1 eq), N-t-butoxycarbonyl-nipecotic acid (344 mg, 1.5 mmol, 1.5 eq), 4-(dimethylamino)pyridine (61 mg, 0.5 mmol, 0.5 eq), N, N-dimethylformamide (1 mL) and CH2Cl2 (6 mL). The reaction mixture is stirred at room temperature. 1.3 h. Triethylamine (0.28 mL, 2 mmol, 2 eq) was added and the reaction mixture was stirred for 1 h. Additional amounts of N-t-butoxycarbonyl-nipecotic acid (340 mg), triethylamine (0.28 mL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (380 mg) were added. After 1 h, no further change was observed. Additional 4-(dimethylamino)pyridine, N,N-dimethylformamide, triethylamine and starting acid are added and the reaction is stirred overnight at room temperature. The resulting black solution is diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic extracts are dried, concentrated in vacuo and purified by flash chromatography on silica gel eluting with a gradient of 50-100% ethyl acetate in hexanes, yielding 397 mg (83 %) of (±)-N-[5-[[[5 -(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-(N-t-butoxycarbonyl)-3-piperidinecarboxamide as a yellow glassy substance.

C. (±)-N-[5-[[[5-1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide

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(±)-N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-(N-t-butoxycarbonyl)-3-piperidinecarboxamide (355 mg, 0.74 mmol, 1 eq) is dissolved in 3 mL of CH2Cl2. Trifluoroacetic acid (3 mL) was added and the mixture was stirred at room temperature. 20 min. The reaction mixture is concentrated in vacuo and neutralized with saturated aqueous NaHCO3. The resulting mixture is extracted with ethyl acetate. The organic extracts were dried over Na2SO4, concentrated in vacuo and recrystallized from ethyl acetate to give 142 mg (50%) of (±)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl ]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide as a white solid. MS: 381 [M+H] + ; HPLC: 100% at 3.15 min. (YMC S5 ODS column 4.6 x 50 mm, 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

Example 3:

Preparation of (±)-1-(2,3-Dihydroxypropyl)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide

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N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (66 mg, 0.17 mmol, 1 eq) was mixed with glyceraldehyde ( 69 mg, 0.77 mmol, 4.5 eq), sodium triacetoxyborohydride (163 mg, 0.77 mmol, 4.5 eq) and 1,2-dichloroethane (4 mL). The resulting suspension is stirred at room temperature. 4 h. Methanol (1 mL) was added and the reaction mixture was stirred at room temp. overnight, concentrated in vacuo and purified by preparative HPLC, yielding 69 mg (59 %) of (±)-1-(2,3-dihydroxypropyl)-N-[5-[[[5-(1,1-dimethylethyl )-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide as a white solid. MS: 455 [M+H] + ; HPLC: 100% at 3.06 min. (YMC S5 ODS column 4.6 x 50 mm, 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

Example 4:

Preparation of N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(1-methylethyl)-4-piperidinecarboxamide

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A. Ethyl 1-(1-methylethyl)-4-piperidine carboxylate

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Ethyl isonipecotate (3.2 g, 20 mmol, 1 eq) was mixed with acetone (5.8 g, 100 mmol, 5 eq), sodium triacetoxyborohydride (10.5 g, 50 mmol, 2.5 eq) and 1,2-dichloroethane (200 mL). The reaction mixture is stirred at room temperature. 72 h. Saturated aqueous NaHCO3 was added and the mixture was extracted with CH2Cl2. The organic extracts are dried, filtered through a pad of silica gel and concentrated in vacuo to give 3.72 g (93%) of ethyl 1-(1-methylethyl)-4-piperidinecarboxylate as a colorless liquid.

B. 1-(1-Methylethyl)-4-piperidine carboxylic acid

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Ethyl 1-(1-methylethyl)-4-piperidine carboxylate (3.6 g, 18 mmol, 1 eq) was mixed with barium hydroxide octahydrate (10.4 g, 33 mmol, 1.8 eq) in a mixture of 70 mL of water and 44 mL of ethanol. The mixture is heated to 60°C for 1.3 h. The reaction mixture is concentrated in vacuo and diluted with 70 mL of water. Ammonium carbonate (6.9 g, 87 mmol, 4.8 eq) was added portionwise and the reaction mixture was stirred at room temp. over night. The mixture is filtered through diatomaceous earth, concentrated and lyophilized to give 3.1 g (100%) of 1-(1-methylethyl)-4-piperidine carboxylic acid as a white solid.

C. N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(1-methylethyl)-4-piperidinecarboxamide

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1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g, 5.2 mmol, 2 eq) was added to a mixture of 2-amino-5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl] thio]thiazole (0.7 g, 2.6 mmol, 1 eq), 1-(1-methylethyl)-4-piperidine carboxylic acid (0.78 g, 3.9 mmol, 1.5 eq), 4-(dimethylamino)pyridine (0.16 g, 1.3 mmol) , 0.5 eq), N,N-dimethylformamide (2.6 mL) and CH2Cl2 (7.8 mL). The reaction mixture is stirred at room temperature. 1 h, dilute with 30 mL of water and extract with ethyl acetate (2 x 70 mL). The organic extracts are dried over Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel eluting with a gradient of 5-10% triethylamine in ethyl acetate. The substance is recrystallized from ethanol and water, resulting in 0.93 g (85%) of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1 -(1-methylethyl)-4-piperidinecarboxamide as a yellowish solid. MS: 423 [M+H] + ; HPLC: 100% at 3.15 min. (YMC S5 ODS column 4.6 x 50 mm, 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

Example 5:

Preparation of 1-Cyclopropyl-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide

[image]

A. 1-Cyclopropyl-4-piperidine carboxylic acid

[image]

Ethyl isonipecotate (1.57 g, 10 mmol, 1 eq) was mixed with ((1-ethoxycyclopropyl)oxy)trimethyl silane (8.7 g, 50 mmol, 5 eq) in 100 mL of methanol. Add acetic acid (5.7 mL, 100 mmol, 10 eq) and molecular sieves. After 30 min. at room temp., sodium triacetoxyborohydride (2.5 g, 40 mmol, 4 eq) was added and the reaction mixture was heated to 65°C overnight. The reaction mixture is cooled and NaCO3 (20 g) is added. The mixture is stirred at room temperature. 2 h and filtered through diatomaceous earth. Diatomaceous earth is washed with methanol. The filtrates were combined, concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic extracts were dried, filtered through a pad of silica gel and concentrated in vacuo to give 2.4 g of a colorless liquid. This substance was mixed with barium hydroxide octahydrate (5.7 g, 18 mmol, 1.8 eq) in a mixture of 38 mL of water and 24 mL of ethanol. The mixture is heated to 60°C for 1 h. The reaction mixture is concentrated in vacuo and diluted with 38 mL of water. Ammonium carbonate (3.8 g) was added portion by portion and the reaction was stirred at room temperature. 2 h. The mixture is filtered through diatomaceous earth, washed with water. The filtrate is washed with ethyl acetate. By concentrating the aqueous phase, 1.56 g (92%) of 1-cyclopropyl-4-piperidine carboxylic acid is obtained in the form of a hygroscopic white solid.

B. 1-Cyclopropyl-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]-methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide

[image]

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g, 5.2 mmol, 2 eq) was added to a mixture of 2-amino-5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl] thio]thiazole (0.7 g, 2.6 mmol, 1 eq), 1-cyclopropyl-4-piperidine carboxylic acid (0.77 g, 3.9 mmol, 1.5 eq), 4-(dimethylamino)pyridine (0.16 g, 1.3 mmol, 0.5 eq) , N,N-dimethylformamide (2.6 mL) and CH2Cl2 (7.8 mL). The reaction mixture is stirred at room temperature. 1 h, dilute with water (30 mL) and extract with ethyl acetate (2 x 70 mL). The mixed organic extracts are dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel eluting with a gradient of 0-10% triethylamine in ethyl acetate. The substance is crystallized from ethyl acetate and hexane, which gives 0.7 g (65 %) of 1-cyclopropyl-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2 -thiazolyl]-4-piperidinecarboxamide in the form of white crystals. MS: 421 [M+H] + ; HPLC: 100 % at 3.13 min. (YMC S5 ODS column 4.6 x 50 mm, 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

Example 6:

Preparation of N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(2-hydroxyethyl)-4-piperidinecarboxamide

[image]

A. N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(2-dimethyl-t butylsilyloxyethyl)-4-piperidinecarboxamide

[image]

N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (1.4 g, 3.68 mmol, 1 eq) was dissolved in 30 mL N,N-dimethylformamide and 100 mL of tetrahydrofuran. 2-(Bromoethoxy)-t-butyldimethylsilane (0.79 mL, 3.68 mmol, 1 eq) and NaHCO3 were added and the reaction mixture was stirred at 50°C for 23 h. More 2-(bromoethoxy)-t-butyldimethylsilane (0.9 mL) was added and the reaction mixture was stirred at 50°C for 22 h, cooled, concentrated in vacuo and diluted with water (25 mL). The resulting aqueous mixture was extracted with ethyl acetate (50 mL). The organic extract is dried over Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel eluting with a gradient of 0-5% triethylamine in ethyl acetate, which gives 1.7 g (84%) of N-[5-[[[5-( 1,1 dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(2-dimethyl-t-butylsilyloxyethyl)-4-piperidinecarboxamide as a yellow solid. MS: 539 [M+H] + ; HPLC: 98% at 4.01 min. (YMC S5 ODS column 4.6 x 50 mm, 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

B. N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(2 hydroxyethyl)-4-piperidinecarboxamide

[image]

N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(2-dimethyl-t-butylsilyloxyethyl)-4-piperidinecarboxamide (1.45 g , 2.7 mmol, 1 eq) was dissolved in 100 mL of acetonitrile and mixed with aqueous HF (48% aq., 2.5 mL). The reaction mixture was stirred for 4 h at room temperature. Another 2.5 mL of aqueous HF is added and the reaction mixture is stirred overnight. Ethyl acetate (100 mL) and saturated aqueous NaHCO3 (50 mL) were added. More solid NaHCO3 is added to make the mixture alkaline. The mixture was extracted with ethyl acetate (2 x 50 mL). The organic extracts are dried over Na2SO4, filtered through a pad of silica gel and concentrated in vacuo. The resulting white solid was crystallized from ethanol and water to give 1.6 g (59%) of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl ]-1-(2-hydroxyethyl)-4-piperidinecarboxamide as a white solid. MS: 425 [M+H] + ; HPLC: 100 % at 3.05 min. (YMC S5 ODS column 4.6 x 50 mm, 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

Example 7:

Preparation of (R)-N-[5-[[[5-(1,1-Dimethylethyl)-2 oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidine-carboxamide hydrochloride

[image]

A. (R) and (S)-N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl-(N-t-butoxycarbonyl)-3-piperidinecarboxamide

[image]

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.8 g, 20 mmol, 2 eq) was added to a mixture of 2-amino-5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl] thio]thiazole (2.7 g, 10 mmol, 1 eq), N-t-butoxycarbonyl-nipecotic acid (3.4 g, 1.5 mmol, 1.5 eq), N,N-dimethylformamide (10 mL) and CH2Cl2 (30 mL). The reaction mixture is stirred at room temperature. 4 h. The resulting black solution was concentrated in vacuo, diluted with water (90 mL) and extracted with ethyl acetate (100 mL, then 2 x 75 mL). The organic extracts are dried over Na2CO3, concentrated in vacuo and purified by flash chromatography on silica gel eluting with a gradient of 50-100% ethyl acetate in hexanes, yielding 3.8 g (79%) of a yellow solid. The enantiomers were separated by chiral HPLC (Chiral Pak AD 5 x 50 cm 20 μm: eluent 10 % (0.1 % triethylamine in isopropanol) in hexanes; 45 mL/min, detection at 254 nm, loading 300 mg in 5 mL isopropanol), giving obtain both optically pure isomers: 1.65 g of the R isomer and 1.65 g of the S isomer.

B. (R)-N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3 piperidinecarboxamide hydrochloride

[image]

Isomer (R) from part A (1.65 g, 3.43 mmol, 1 eq) was dissolved in 10 mL of CH2Cl2. Trifluoroacetic acid (6 mL) was added and the mixture was stirred at room temperature. a few hours. The reaction mixture is concentrated in vacuo and neutralized with saturated aqueous NaHCO3. The resulting mixture was mixed with ethyl acetate for 1 h. The organic extracts were dried over Na2SO4 and concentrated in vacuo to give a yellowish solid.

The solid is dissolved in methanol and 1 eq of 1N aqueous HCl is added. The resulting solution is lyophilized, resulting in 1 g (77 %) of (R)-N-[5-[[[5-(1,1-dimethylethyl)-2 oxazolyl]methyl]thio]-2-thiazolyl]-3 -piperidinecarboxamide hydrochloride as a yellow solid. MS: 381 [M+H] + ; HPLC: 100 % at 3.14 min. (YMC S5 ODS column 4.6 x 50 mm, 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

Example 8:

Preparation of (S)-N- [5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]-methyl]thio]-2-thiazolyl]-3-piperidine carboxamide hydrochloride

[image]

Isomer (S) from Example 7, Part A (1.65 g, 3.43 mmol, 1 eq) was dissolved in 10 mL of CH2Cl2. Trifluoroacetic acid (6 mL) was added and the mixture was stirred at room temp. a few hours. The reaction is concentrated in vacuo and neutralized with saturated aqueous NaHCO3. The resulting mixture was mixed with ethyl acetate for 1 h. The organic extracts were dried over Na2SO4 and concentrated in vacuo to give a yellowish solid.

The solid is dissolved in methanol and 1 eq of 1N aqueous HCl is added. The obtained solution is lyophilized, which gives 0.918 g (70 %) of (S)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]- 3-piperidinecarboxamide hydrochloride as a yellow solid. MS: 381 [M+H] + ; HPLC: 100% at 3.15 min. (YMC S5 ODS column 4.6 x 50 mm, 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

Example 9:

Preparation of cis-4-Amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide hydrochloride and trans-4-Amino-N-[ 5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-cyclohexylcarboxamide hydrochloride

[image]

A. 4-(t-Butoxycarbonylamino)cyclohexane carboxylic acid

[image]

A total of 6.5 g (30 mmol) of tBoc anhydride was added to a solution of 2.86 g (20 mmol) of 4-aminocyclohexane carboxylic acid in 40 mL of 0.5 M aqueous NaOH solution, 20 mL of dioxane and 4 mL of acetonitrile at room temperature. After 20 h, 100 mL of ethyl acetate and 100 mL of a 10% aqueous solution of citric acid are introduced. The resulting aqueous layer is separated and extracted three times with 50 mL of ethyl acetate. The organic phases are mixed, dried (sodium sulfate) and concentrated in vacuo to give 6.0 g (125%) of crude 4-(t-butoxycarbonylamino)cyclohexane carboxylic acid in the form of a colorless oil which solidifies on standing.

B. 4-(t-Butoxycarbonylamino)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]-methyl]thio]-2-thiazolyl]cyclohexylcarboxamide

[image]

Solutions of 5 g of crude 4-(t-butoxycarbonylamino)cyclohexane carboxylic acid and 3.50 g (13 mmol) of 2-amino-5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]thiazole in 13 mL of N,N-dimethylformamide and 36 mL of methylene chloride were added to 5.0 g (26 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at room temperature. The reaction mixture is stirred overnight and diluted with 100 mL of water. The aqueous layer is separated and extracted twice with 150 mL of ethyl acetate. The mixed organic phases are dried (sodium sulfate) and then filtered through a pad of silica gel. The filtrate was concentrated in vacuo to give an orange solid. The crude material is recrystallized (95% ethanol), which gives 4-(t-butoxycarbonylamino)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]- 2-thiazolyl]cyclohexylcarboxamide as a yellow solid. The mother liquors are also concentrated in vacuo to give additional 4-(t-butoxycarbonylamino)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl ]cyclohexylcarboxamide as a brown solid.

C. cis-4-Amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide hydrochloride and trans-4-amino-N- [5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-cyclohexylcarboxamide hydrochloride

[image]

In a suspension of 4-(t-butoxycarbonylamino)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide (from Part B mother liquors) suspended 5 mL of trifluoroacetic acid is added to 15 mL of methylene chloride at room temperature. The reaction mixture was stirred for 2 h, then concentrated in vacuo to remove vapors. The residue is diluted with water, made alkaline with an aqueous NaOH solution, then the obtained aqueous solution is extracted with ethyl acetate. The combined organic extracts are dried (sodium sulfate) to give the crude cis/trans product. The crude material is purified by flash chromatography (Merck silica, 25x3 cm, 1:9 isopropylamine/ethyl acetate, then 1:2:7 methanol/isopropylamine/ethyl acetate), which gives 0.74 g of the cis isomer as a yellow solid and 0.50 g trans isomer as a brown solid. The cis isomer is dissolved in methanol, then 0.34 mL of 5N aqueous HCl is added. The solution is concentrated in vacuo, washed with ether, diluted with water and lyophilized to give 0.80 g of cis-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl ]thio]-2-thiazolyl]cyclohexylcarboxamide hydrochloride as a yellow solid. MS: 395 [M+H] + ; HPLC-HI 98 % at 3.17 min. (YMC S5 ODS column 4.6 x 50 mm, 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). The trans isomer is dissolved in methanol, then 0.24 mL of 5N aqueous HCl is added. The solution is concentrated in vacuo, washed with ether, diluted with water and lyophilized to give 0.54 g of trans-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2oxazolyl]methyl]thio ]-2-thiazolyl]cyclohexylcarboxamide hydrochloride as an orange solid. MS: 395 [M+H] + ; HPLC-HI 96 % at 3.22 min. (YMC S5 ODS column 4.6 x 50 mm, 10-90 % aqueous

methanol for 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

Example 10:

N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, monohydrochloride

[image]

Acetyl chloride (0.28 mL, 3.9 mmol) was added dropwise to a solution of 40 mL of absolute EtOH cooled in an ice bath. The reaction mixture is allowed to warm to room temperature for 30 min., then N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]-thio]-2-thiazolyl]- 4-piperidinecarboxamide (1.50 g, 3.94 mmol, 1 eq) with stirring to give a thick solution. Water (~4 mL) was added until homogenized, then concentrated in vacuo to give a crude pale yellow solid. The crude material was recrystallized (aq EtOH) to give the title compound (70%) as a white solid, m.p. 256-258°C. Analysis of calc. for C17H24N4O2S2·HCl: C, 48.96; H, 6.04; N, 13.43; S, 15.38; Cl, 8.50. Found: C, 48.69; H, 5.99; N, 13.24; S, 15.27; Cl, 8.31.

Example 11:

N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, monohydrobromide

[image]

To a solution of 1M HBr in EtOH (0.5 mL) was added N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (190 mg, 0.5 mmol, 1 eq), then cooled to -40°C overnight. The resulting solid precipitate was collected on a Buchner funnel, washed with absolute EtOH, then dried in vacuo at 100°C to give the title compound (72%) as a fine white powder, m.p. 235-237°C. Analysis of calc. for C17H24N4O2S2·HBr: C, 44.24; H, 5.46; N, 12.14; S, 13.89; No, 17.31. Found: C, 44.16; H, 5.40; N, 12.12; S, 13.91; No. 17.70.

Example 12:

N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, 0.5-1-salt of tartaric acid

[image]

To a warm solution of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (1.75 g, 4.6 mmol) in absolute EtOH (70 mL ) was added to a solution of L-tartaric acid (345 mg, 2.3 mmol, 0.5 eq) in absolute EtOH (5 mL). After a few minutes, a precipitate begins to form. The mixture is allowed to stand for 4 h at room temperature, then the solid precipitate is collected on a Buchner funnel, washed with absolute EtOH and dried in vacuo at 85°C for 24 h, which gives the title compound (94%) in the form of pale yellow crystals, m.p. 234-236°C. Analysis of calc. for C17H24N4O2S2·0.5-1-tartaric acid: C, 50.09; H, 5.97; N, 12.29; S, 14.07. Found: C, 49.85; H, 5.90; N, 12.12; S, 13.75.

Example 13:

N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, 0.5-D-salt of tartaric acid

[image]

To a warm solution of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (1.00 g, 2.63 mmol) in absolute EtOH (40 mL) ) was added to a solution of D-tartaric acid (198 mg, 1.32 mmol, 0.5 eq) in absolute EtOH (4 mL). After a few minutes, a precipitate begins to form. The mixture was allowed to stand for 18 h at room temperature, then the solid precipitate was collected on a Buchner funnel, washed with absolute EtOH and dried in vacuo at 65°C for 6 h, which gave the title compound (73%) as a white solid, m.p. 232-233ºC. Analysis of calc. for C17H24N4O2S2·0.5-D-tartaric acid: C, 50.09; H, 5.97; N, 12.29; S, 14.07. Found: C, 49.75; H, 5.81; N, 12.04; S, 13.37.

Example 14:

N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, 0.5-salt of fumaric acid

[image]

To a warm solution of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (1.75 g, 4.6 mmol) in absolute EtOH (100 mL ) was added to a solution of fumaric acid (276 mg, 2.3 mmol, 0.5 eq) in absolute EtOH (5 mL). After 10 minutes, a precipitate begins to form. The mixture is left to stand for 2 hours at room temperature, then 16 hours at 5°C. The resulting solid precipitate was collected on a Buchner funnel, washed with absolute EtOH and dried in vacuo at 65°C for 24 h to give the title compound (84%) as a white solid, m.p. 206-207ºC. Analysis of calc. for C17H24N4O2S2·0.5-1-fumaric acid: C, 52.04; H, 5.98; N, 12.77; S, 14.62. Found: C, 51.74; H, 5.76; N, 12.57; S, 14.19. Recrystallization (95% aq EtOH) gave the title compound containing 1 mol EtOH (83%) in the form of large colorless crystals, m.p. 212-214ºC. Analysis of calc. for C17H24N4O2S2·0.5-fumaric acid·EtOH: C, 52.05; H, 6.66; N, 11.56; S, 13.23. Found: C, 52.03; H, 6.06; N, 11.50; S, 12.99.

Example 15:

N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, 0.5-salt of succinic acid

[image]

To a warm solution of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (50 mg, 0.13 mmol) in absolute EtOH (2 mL ) was added to a solution of succinic acid (7.7 mg, 0.065 mmol, 0.5 eq) in absolute EtOH (0.25 mL). After 10 minutes, a precipitate begins to form. The mixture was allowed to stand for 1 h at room temperature, then the precipitate was collected on a Buchner funnel, washed with absolute EtOH and dried in vacuo at 100°C for 24 h to give the title compound (70%) as a white solid, m.p. 190-192°C. Analysis of calc. for C17H24N4O2S2·0.5-succinic acid·0.46 H2O: C, 50.96; H, 6.28; N, 12.51; S, 14.32. Found: C, 50. 96; H, 6.20; N, 12.49; S, 14.23.

Example 16:

N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, 0.5-salt of sulfuric acid

[image]

To a warm solution of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (50 mg, 0.13 mmol) in absolute EtOH (2 mL ) is added to a 1M aq solution of sulfuric acid (0.065 mL, 0.065 mmol, 0.5 eq). A precipitate forms almost simultaneously. The mixture is cooled to 5ºC for 2 h, then the precipitate is collected on a Buchner funnel, washed with absolute EtOH and dried in vacuo at 100ºC for 24 h, giving the title compound (79%) as a white solid, m.p. 256-258ºC. Analysis of calc. for C17H24N4O2S2O·0.5H2SO4·0.68 H2O: C, 46.22; H, 6.01; N, 12.68; S, 18.14. Found: C, 46.21; H, 5.95; N, 12.71; S, 18.23.

Example 17:

N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, 0.5-salt of citric acid

[image]

To a warm solution of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (50 mg, 0.13 mmol) in absolute EtOH (2 mL ) citric acid solution (8.3 mg, 0.043 mmol, 0.33 eq) was added. The solution is cooled to 5ºC for 18 h, then the resulting precipitate is collected on a Buchner funnel, washed with absolute EtOH and dried under vacuum at 100ºC for 24 h, which gives the title compound (68%) as a white solid, m.p. 214-216ºC. Analysis of calc. for C17H24N4O2S2·0.5-citric acid·0.10 H2O: C, 50.21; H, 5.94; N, 11.71; S, 13.40. Found: C, 50.21; H, 6.01; N, 11.83; S, 13.44.

Example 18:

N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, methanesulfonic acid salt

[image]

To a thick solution of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (100 mg, 0.26 mmol) in isopropyl alcohol (0.75 mL ) methanesulfonic acid (0.017 mL, 0.26 mmol, 1 eq) was added. The thick solution is heated to 70ºC, which gives a clear solution, and then methyl t-butyl ether (1.5 mL) is added. A precipitate forms within 15 minutes. The resulting mixture is stirred at 55ºC for 2 h, then at room temperature for 14 h. The resulting precipitate is collected by filtration, then dried in a vacuum at 50ºC for 14 h, which gives the title compound (85%) in the form of a colorless powder, m.p. 105ºC. Analysis of calc. for C17H24N4O2S2·MSA·H2O: C, 43.70; H, 6.11; N, 11.32; S, 19.44. Found: C, 43.53; H, 6.14; N, 11.15; S, 19.15.

Example 19:

N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, 0.5-D,L-malic acid salt

[image]

Solutions of N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (100 mg, 0.26 mmol) in isopropyl alcohol (0.80 mL) at 70ºC, a solution of D,L-malic acid (35 mg, 0.13 mmol, 0.5 eq) in isopropyl alcohol (0.3 mL) is gradually added. A precipitate immediately forms. The resulting mixture is stirred at 55ºC for 2 h, then at room temperature for 14 h. The precipitate is collected by filtration, then dried in vacuum at 50ºC for 14 h, which gives the title compound (75%) in the form of a colorless powder, m.p. 216ºC. Analysis of calc. for C17H24N4O2S2·0.5-C4H6O5·H2O: C, 50.98; H, 6.08; N, 12.51; S, 14.32. Found: C, 50.55; H, 6.17; N, 12.29; S, 14.05.

Claims (59)

1. Compound of formula I [image] and its enantiomers, diastereomers, solutions and pharmaceutically acceptable salts, characterized in that: R is alkyl; R 1 is hydrogen or alkyl; X is NR 2 or CHNR 2 R 3 ; R 2 and R 3 are each independently hydrogen, alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl; n is 0, 1, 2 or 3. 2. Compound according to claim 1, characterized in that: R is alkyl; R 1 is hydrogen; X is NR 2 or CHNR 2 R 3 ; R 2 and R 3 are each independently hydrogen, alkyl, substituted alkyl or cycloalkyl; And n is 2. 3. Compound according to claim 1, formula Ia [image] and its enantiomers, diastereomers, solutions and pharmaceutically acceptable salts, characterized in that: R 2 is hydrogen, alkyl, substituted alkyl or cycloalkyl. 4. Compound according to claim 1, formula Ib [image] and its enantiomers, diastereomers, solutions and pharmaceutically acceptable salts, characterized in that: R 2 is hydrogen, alkyl, substituted alkyl or cycloalkyl. 5. Compound according to claim 1, formula Ic [image] and its enantiomers, diastereomers, solutions and pharmaceutically acceptable salts, characterized in that: R 2 and R 3 are each independently hydrogen, alkyl, substituted alkyl or cycloalkyl. 6. Compound according to claim 1, characterized in that it is selected from the group consisting of: N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide; (±)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide; (±)-1-(2,3-dihydroxypropyl)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide; N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(1-methylethyl)-4-piperidinecarboxamide; 1-cyclopropyl-N-[5-[[[-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide; N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-1-(2-hydroxyethyl)-4-piperidinecarboxamide; (R)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide; (S)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide; cis-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide; and trans-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide; and their enantiomers, diastereomers, solutions and pharmaceutically acceptable salts. 7. N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide and its enantiomers, diastereomers, solutions and pharmaceutically acceptable salts. 8. (±)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide and its enantiomers, diastereomers, solutions and pharmaceutical acceptable salts. 9. (R)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide and its enantiomers, diastereomers, solutions and pharmaceutical acceptable salts. 10. (S)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-3-piperidinecarboxamide and its enantiomers, diastereomers, solutions and pharmaceutical acceptable salts. 11. cis-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide and its enantiomers, diastereomers, solutions and pharmaceutically acceptable salts. 12. trans-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide and its enantiomers, diastereomers, solutions and pharmaceutically acceptable salts. 13. Pharmaceutical preparation, characterized in that it contains the compound of claim 1 and a pharmaceutically acceptable carrier. 14. Pharmaceutical preparation, characterized in that it contains the compound of claim 1 in combination with a pharmaceutically acceptable carrier and an anticancer agent formulated as a fixed dose. 15. Pharmaceutical preparation, characterized in that it contains the compound of claim 1 in combination with a pharmaceutically acceptable carrier and a p53 transactivation modulator formulated as a fixed dose. 16. A method for modulating apoptosis, characterized in that it comprises the administration to a mammal in need of the compound according to claim 1 in an amount effective for modulating apoptosis. 17. A method for inhibiting protein kinases, characterized in that it comprises administering to a mammal in need of it the compound according to claim 1 in an amount effective for inhibiting protein kinase. 18. A method for inhibiting cyclin-dependent kinases, characterized in that it comprises administering to a mammal in need thereof the compound according to claim 1 in an amount effective for inhibiting a cyclin-dependent kinase. 19. A method for inhibiting cdc2 (cdk1), characterized in that it comprises administering to a mammal in need of it the compound according to claim 1 in an amount effective for inhibiting cdc2. 20. A method for inhibiting cdk2, characterized in that it comprises administering to a mammal in need of it the compound according to claim 1 in an amount effective for inhibiting cdk2. 21. A method for inhibiting cdk3, characterized in that it comprises administering to a mammal in need thereof the compound according to claim 1 in an amount effective for inhibiting cdk3. 22. A method for inhibiting cdk4, characterized in that it comprises administering to a mammal in need of it the compound according to claim 1 in an amount effective for inhibiting cdk4. 23. A method for inhibiting cdk5, characterized in that it comprises administering to a mammal in need of it the compound according to claim 1 in an amount effective for inhibiting cdk5. 24. A method for inhibiting cdk6, characterized in that it comprises administering to a mammal in need of it the compound according to claim 1 in an amount effective for inhibiting cdk6. 25. A method for inhibiting cdk7, characterized in that it comprises administering to a mammal in need thereof the compound according to claim 1 in an amount effective for inhibiting cdk7. 26. A method for inhibiting cdk8, characterized in that it comprises administering to a mammal in need thereof the compound according to claim 1 in an amount effective for inhibiting cdk8. 27. A method for the treatment of proliferative diseases, indicated by the fact that it comprises the administration of a therapeutically effective amount of the preparation from claim 13 to a mammal in need thereof. 28. A method for treating cancer, characterized by the fact that it comprises the administration to a mammal in need of it of a therapeutically effective amount of the preparation from claim 13. 29. A method for treating inflammation, inflammatory bowel disease or post-transplantation rejection, characterized in that it comprises administering to a mammal in need of it a therapeutically effective amount of the composition of claim 13. 30. A method for the treatment of arthritis, characterized in that it comprises administering to a mammal in need of it a therapeutically effective amount of the preparation from claim 13. 31. A method for the treatment of proliferative diseases, characterized by the fact that it comprises the application to a mammal in need of it of a therapeutically effective amount of the preparation from claim 14. 32. A method for the treatment of cancer, indicated by the fact that it comprises the administration to a mammal in need of it of a therapeutically effective amount of the preparation from claim 14. 33. A method for the treatment of proliferative diseases, indicated by the fact that it comprises the application to a mammal in need of it of a therapeutically effective amount of the preparation from claim 15. 34. A method for the treatment of cancer, indicated by the fact that it comprises the administration to a mammal in need of it of a therapeutically effective amount of the preparation from claim 15. 35. A method for treating a disorder associated with cyclin-dependent kinase, comprising administering to a mammal in need thereof an effective amount of at least one compound of claim 1. 36. A method for the treatment of chemotherapy-induced baldness, chemotherapy-induced thrombocytopenia, chemotherapy-induced leukopenia, or mucositis, characterized in that it comprises administering to a mammal in need of it a therapeutically effective amount of the composition of claim 1. 37. The method of claim 1, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 38. The method of claim 2, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 39. The method of claim 3, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 40. The method of claim 4, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 41. The method of claim 5, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 42. The method of claim 6, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 43. The method of claim 7, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 44. The method of claim 8, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 45. The method of claim 9, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 46. The method of claim 10, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 47. The method of claim 11, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 48. The method of claim 12, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 49. The method of claim 13, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 50. The method of claim 14, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 51. The method of claim 15, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 52. The method of claim 17, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 53. The method of claim 18, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 54. The method of claim 20, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 55. The method of claim 27, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 56. The method of claim 28, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 57. The method of claim 31, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 58. The method of claim 32, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts . 59. The method of claim 36, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts .