BG65132B1 - N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]carboxamide derivatives, pharmaceutical composition and use thereof as inhibitors of cyclin dependent kinases - Google Patents

Abstract

The present invention describes compounds of the formula and enantiomers, diasteromers, solvates, and pharmaceutically acceptable salts thereof. The formula compounds are protein kinase inhibitors and are useful in the treatment of proliferative diseases, for example, cancer, inflammation and arthritis. They also may be useful in the treatment of Alzheimer's disease, chemotherapy-induced alopecia, and cardiovascular disease.

Description

(54) N- | 5- || [5-AL KIL-2-OXAZOLYL | METHYL] THIO] -2-THIAZOLYL] -CARBOXAMIDE DERIVATIVES, PHARMACEUTICAL COMPOSITION AND USE OF ITS AS INHIBITORS

Technical field

The present invention relates to N [5 - [[[5-alkyl-2-oxazolyl] methyl] thio] -2-thiazolyl] -carboxamide derivatives of formula I:

and to their enantiomers, diastereomers, solvates and pharmaceutically acceptable salts;

in which: R is lower alkyl;

R ¹ represents hydrogen;

X is NR ² or CHNR ² R ³ ;

R ² and R ³ each independently represent hydrogen, lower alkyl, which may be optionally substituted by one or more hydroxyl groups, or lower cycloalkyl;

η stands for 0,1,2 or 3.

The compounds of formula I are useful as potent inhibitors of protein kinase and in the treatment of proliferative diseases such as cancer, inflammation and arthritis. They may also be useful in the treatment of Alzheimer's disease, alopecia due to chemotherapy and cardiovascular disease.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I, pharmaceutical compositions comprising such compounds, and the use of compounds of formula I for the preparation of medicaments.

The definitions of the various expressions used to describe the compounds of the invention are listed below. These definitions refer to the expressions as they are used in the description (unless otherwise limited in a particular case) either individually or as part of a larger group.

The term "alkyl or alk" refers to a monovalent lower alkane (hydrocarbon) radical containing from 1 to 6 and most preferably 1 to 4 carbon atoms. The lower alkyl group may be optionally substituted by a straight, branched or cyclic saturated hydrocarbon group. The substituent groups are one or more hydroxyl groups.

When the lower alkyl group is said to be substituted by an alkyl group, this is equivalent to a "branched alkyl group".

The term "alkyloxycarbonyl" as used herein means an alkoxy group linked via a carbonyl group. The alkoxycarbonyl radical is represented by the formula -C (O) OR ⁵ , wherein the R ⁵ group is a straight or branched C ₁₆ alkyl group.

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

The term "alkylcarbonyloxy" as used herein means an alkylcarbonyl group which is bonded via an oxygen bond.

As used herein, the term "compounds of the invention" means generally compounds of formula I and their pharmaceutically acceptable salts and solvates, including hydrates. Methods for preparing salts, solvates and hydrates are well known. The invention also encompasses mixtures of stereoisomers of the compounds of the invention. Stereoisomers include, but are not limited to, enantiomers, diastereomers and racemates in which the compound has one or more chiral centers. All stereoisomers of the compound of this invention may be either in admixture or parts or in practically pure form. The definition of the compounds of the invention encompasses all possible stereoisomers and mixtures thereof. In particular, it encompasses racemic forms and isolated optical isomers having specific activity. The racemic forms may be redissolved by physical methods such as, for example, fractional crystallization, separation or crystallization of diastereoisomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by conventional methods, such as forming a salt with an optically active acid followed by crystallization. All configuration isomers of compounds of the present invention are designed either in mixtures or in pure or substantially pure form. The definition of compounds of the present invention encompasses in great detail both alkenic isomers of cis (Z) and trans (E), as well as the cis and trans isomers of cycloalkyl or heterocycloalkyl rings.

In addition, salts of compounds of formula I that are pharmaceutically unsuitable but useful in other respects, 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 structure and chemical name, if the chemical structure and chemical name differ, the chemical structure is determining to identify the compound.

The term "pharmaceutically acceptable salt (s)" as used herein is not limited to salts of acidic or basic groups that may be present in the compounds of the invention. Examples of such pharmaceutically acceptable salts include, but are not limited to, hydrochloride, hydrobromide, dihydrochloride, sulfate, trifluoroacetate, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and technetate, bromate and technetium. Also included are salts formed with other organic or inorganic acids, such as hydroxymethane sulfonic acid, acetic acid, benzenesulfonic acid, toluenesulfonic acid, and the like, such as nitrates, phosphates, borates, benzoates, ascorbates, silicates and the like. In addition, pharmaceutically acceptable salts of compounds of formula I may 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, and pyridines and the like; and amino acids such as arginine, lysine and the like.

Salts of the compounds of the invention encompass solvates, racemates and all their stereoisomeric forms, including enantiomers and diastereoisomers (e.g., D-tartrate and L-tartrate salts).

The term "solvate" as used herein means a compound of the invention or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of one or more bound molecules in a solvent by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic and / or acceptable for human administration in minor amounts. When the solvent is water, the solvate is called "hydrate".

The compounds of formula I can be prepared by adapting the methods set forth in WO1999 / 065884 and WO1999 / 024416, two of which are cited herein. Alternatively, the generic method shown in Scheme A below, which illustrates the synthesis of a large class of compounds of formula XIV, can be used to synthesize compounds of formula I. The starting compounds are commercially available or can be obtained by methods known in the art. of a specialist in the field of engineering. Scheme A uses the following expressions:

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 , COOR ¹⁶ ;

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

d is an integer in the range 0 to 5; s is an integer in the range 0 to 5;

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

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

Q is hydroxy, halogen or acyloxy (R ⁶ COO-, ROCOO-, 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 Nacyl; and

P is a nitrogen protecting group (Boc, Cbz, R ₃ Si, etc.). When a functional group is called "protected" it means that the group is in a modified form to prevent undesirable side effects at the protected site. Suitable protecting groups for saedinenietoshtklyucheni in the present invention will be recognized from the specification taking into account the level of knowledge in the art and in conjunction with guides, such as Greene, TW, Protective Groups in Organic Synyhesis, 3 ^th edition (1999), herein incorporated by literature .

The processes generally involve the reaction of alpha-halo ketones II (commercially available or readily synthesized by well-known methods) with azide to give alpha-azido ketones III. Reaction of III with a reducing reagent yields alphaamino ketones IV.

Alternatively and more preferably, alphaamino ketones IV are prepared by reacting alpha-halo ketones II with cyclic alkylenetetramine, such as hexamethylenetetramine and the like, followed by hydrolysis of the resulting new quaternary ammonium salt III '. This reaction provides excellent yields of the desired intermediate IV above 50%.

Therefore, reacting the alpha-amino ketones IV with alpha-halo acyl halide V in the presence of a base or, alternatively, coupling the alpha-amino ketones IV with alpha-halo acid yields the corresponding amides VI. Then, closing the ring of VI with a dehydrating reagent makes it possible to obtain 2-oxazolylalkyl halides VII. When using a conventional dehydrating reagent such as trichalophosphoric oxide such as POCl _{3 the} isolation of the product is difficult due to the formation of large amounts of hydrochloric and phosphoric acids. Thus, the method of the present invention preferably utilizes a Burgess reagent that yields excellent yields and allows easy isolation of a safe product from water.

Subsequent treatment of 2-oxazolyl halides VII with a sulfur VIII or VIII 'reagent enables new key intermediates, 2-oxazolylalkyl sulfides IX. Coupling of IX with 5-halo-2-aminothiazole X makes it possible to obtain 5- (2-oxazolylalkylthio) -2-aminothiazoles XI. Coupling of XI with an azacycloalkanoic acid derivative XII enables the preparation of thiazolyl amides XIII, which may be deprotected (the case where P is a protecting group, for example Boc), to give 5- (2-oxazolylalkylthio) - 2-Azacycloalkanoylaminothiazoles XIV.

Scheme A

As mentioned above in Scheme A, methods for preparing 5- (2-oxazolylalkylthio) -2-azacycloalkanoylaminothiazoles and analogs include the following transformations:

Step (a) involves reacting an alpha-substituted ketone II, for example, an alpha-halo ketone, with azide in a suitable solvent or solvent mixtures to obtain an alpha-azido ketone

III; or more preferably (a) 'reaction of alpha-substituted ketone II such as alpha-halo ketone with cyclic alkylenetetramine, for example, hexamethylenetetramine in a suitable solvent or solvent mixtures to form a quaternary ammonium salt III'.

The alpha-halo ketone includes alpha-halo aliphatic and alpha-halo aromatic ketones. Preferred alpha-halo ketones are alpha-halo pinacolines with the most preferred alpha-bromo pinacoline. A sulfonate, for example, R ₈ O ₂ O- (where R is alkyl, aryl or heteroaryl), CF ₃ SO ₂ O- and the like, may be substituted for the halogen at the alpha position. The azides include two metal azides and quaternary ammonium azides. Metal azides are preferred with sodium azide. Suitable solvent (s) include solvents such as hydrocarbons, ethers, amides, e.g., dimethylformamide, ketones, or mixtures thereof with ketones, preferably acetone for both reactions (a) and (a) '.

Step (b) consists of reacting alpha-azido ketone III obtained in step (a) with a reducing reagent in a suitable solvent or solvent mixtures to obtain alpha-amino ketone IV, or more preferably (b ' ) reacting quaternary ammonium salt III ', obtained in step (a') with an acid in a suitable solvent or solvent mixtures to give the alpha-amino ketone IV.

The reducing reagent in step (b) includes hydrogen in the presence of a transition metal valence catalyst such as palladium, trialkyl or triarylphosphines such as triphenylphosphine. Hydrogen in the presence of a transient valence metal catalyst is preferably hydrogen and most preferably palladium over activated carbon. Suitable solvent (s) in reaction (b) include solvents such as hydrocarbons, ethers, alcohols and the like, or mixtures thereof with alcohol such as methanol is preferred. Alternatively, the reduction reaction may be carried out in the presence of an acidic medium, such as hydrochloric acid in ethanol, to give an acidic salt of an alpha-amino ketone, which may be isolated as the acidic salt or free amine forms.

Acid in reaction (b ') includes, but is not limited to, hydrofluoric acids such as HCl, HBr, HI, H ₂ SO ₄ , H ₃ PO ₄ , etc., with HCl being preferred. Suitable solvent (s) in reaction (b ') include solvents such as hydrocarbons, ethers, alcohols and the like, or mixtures thereof with alcohol, with ethanol being preferred, the alpha-amino ketone may be isolated as a salt or free alkali form. .

Step (c) involves the interaction (acylation) of alpha-amino ketone IV or its acidic form obtained in step (b) or (b ') alpha-substituted acyl derivative V such as, for example, alpha-halo acyl halide in the presence of a base and in a suitable solvent or solvent mixtures to give amide VI.

Alpha-halo acyl halide V includes alphaalkyl or aryl substituted or unsubstituted alpha-halo acyl halide, the latter being preferred. The most preferred alpha-halo acyl halide is alpha-chloroacetyl chloride. The base used in the reaction includes, but is not limited to, aromatic and aliphatic organic amines, preferably the latter. The most preferred base is triethylamine. Suitable solution (s) include aprotic solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters and the like, or mixtures thereof, with halogenated hydrocarbons, as dichloromethane is recommended. Alternatively, the reaction may be carried out using alpha-substituted acid instead of an alpha-substituted acyl derivative and then using a coupling reagent such as a water-soluble diimide such as carbodiimide, haloformate, thionyl halide and the like. In each reaction, the sulfonate, for example, RSO ₂ O- (KbfleT0 R is alkyl, aryl or heteroaryl), CF ₃ SO ₂ O- and the like, may be substituted for the halogen at the alpha position of the alpha-halo acyl halide or alpha -halo acid reagents which are illustrated.

Step (d) refers to the reaction of the amide VI obtained in step (c) with a dehydrating reagent in a suitable solvent or solvent mixtures to give a cyclized derivative of 2-oxazolylalkyl VII, for example, 2oxazolylalkyl halide.

The reaction was carried out using (methoxycarbonylsulfamoyl) -triethylammonium hydroxide (Burgess reagent) as a dehydrating reagent. Suitable solvent (s) include hydrocarbons, halogenated hydrocarbons, ethers and the like, or mixtures thereof. Most preferred is the use of the Burgess reagent in tetrahydrofuran. Suitable dehydrating reagents also include, but are not limited to, other bases, acids, acidic anhydrides, and the like, such as, concentrated sulfuric acid, polyphosphoric acid, and the like. Although less suitable, the dehydrating reagent, for example, may be trichalophosphorus oxide, such as tribromophosphorus oxide or trichlorophosphorus oxide, alone or with a toluene-like solvent.

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

The sulfur-containing reagent includes N-substituted or unsubstituted thioureas, thioacids or salts such as thioacetic acid or a salt, xanthogenic acids or salts such as potassium salt of ethylxanthic acid. Unsubstituted thiourea is preferred. Suitable solution (s) include hydrocarbons, halogenated hydrocarbons, ethers, amides, alcohols and the like, or mixtures thereof, with an alcohol such as methanol or ethanol is preferred.

Step (f) refers to the reaction of 2oxazolylalkyl 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 mixtures to give 5- (2- oxazolylalkylthio) -2-aminothiazole XI.

5-halo-2-aminothiazole includes 4-N-3 substituted or unsubstituted 5-halo-2-aminothiazoles, preferably 5-bromo-2-aminothiazole. Suitable bases include, but are not limited to, metal hydroxide, metal alkoxides, metal carbonates, and aqueous amines such as ammonium hydroxide. Sodium hydroxide is preferred. 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) involves reacting 5- (2oxazolylalkylthio) -2-aminothiazole XI obtained in step (f) with an azacycloalkanoic acid XII in the presence of a coupling reagent in a suitable solvent or solvent mixtures to obtain thiazolyl amide XIII .

The azacycloalkanoic acid derivative includes N-protected derivatives, for example, N-protected isonepecotinic acid or N-protected niecotinic acid. Preferred nitrogen protecting groups are Boc, Cbz, silicone derivatives and the like, with Boc being the most preferred. The 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 deprotecting reagent in a suitable solvent or solvent mixtures to give 5- (2-oxazolylalkylthio) -2-azacycloalkanoylaminothiazole XIV (where R ¹¹ is hydrogen).

The choice of deprotecting reagent is based on the nature of the protecting group (P). For the Boc protecting group, the preferred deprotecting reagent is an acid, such as hydrochloric acid or trifluoroacetic acid, and suitable solvent (s) for such a deprotection reaction include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, amidors, amidors or mixtures thereof, with halogenated hydrocarbons, such as dichloromethane being preferred.

A more detailed 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. Schemes 1-5 use the following expressions:

L is a suitable leaving group such as halogen or sulfonate (e.g., Br, Cl, I, R ⁶ SO ₂ O ', CF ₃ SO ₂ O, where R ⁶ is alkyl, cycloalkyl or aryl).

M is hydrogen, Li, Na, K, Cs, or a quaternary ammonium ion, for example, (R ⁶ ) ₄ N or quaternary ammonium ions containing cyclic alkyntetramines such as hexamethyltetramine;

Q is hydroxy, halogen or acyloxy (R ⁶ COO-, R ⁶ OCOO-, etc.);

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

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

Oh

A. · 5

Oh

Scheme 1. Synthesis of a compound of formula 11

NH ₂

First, step (a) involves reacting a suitable alpha-substituted ketone 2, such as an alpha-halo ketone with azide in a suitable solvent or mixtures of solutions, to obtain alpha-azido ketone 3; or more preferably (a ') reacting ketone 2 with cyclic alkylenetetramine, such as hexamethylenetetramine in a suitable solvent or solvent mixtures, to form a quaternary ammonium salt 3'.

Suitable alpha-halo ketones 2 include alpha-halo aliphatic and alpha-halo aromatic ketones. Preferred alpha halo ketones are alpha-halo pinacolines with the most preferred alpha-bromo pinacoline. A sulfonate, for example, R ⁶ SO ² O '(where defined above, R ⁶ is alkyl, cycloalkyl, heteroaryl or aryl), CF ₃ SO ₂ O', and the like, may be substituted for halogen (such as group L) in alpha -position. Azides include both, metal azides and quaternary ammonium azides. Metal azides are preferred, preferably with sodium azide. Suitable solution (s) include hydrocarbons, ethers, amides, such as dimethylformamide, ketones, etc., or mixtures thereof with ketones such as acetone, are preferred for both reactions (a) and (a ').

Step (b) involves reacting the alpha-azido ketone 3 obtained in step (a) with a reducing reagent in a suitable solvent or solvent mixtures to give the alpha-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 mixtures to give the alphaamino ketone 4.

The reducing reagent in reaction (b) includes halogen in the presence of a transition metal valence catalyst such as palladium, trialkyl or triarylphosphines such as triphenylphosphine. Hydrogen in the presence of a transition metal valence catalyst is recommended with hydrogen and palladium over activated carbon best. Suitable solvent (s) in reaction (b) include hydrocarbons, ethers, alcohols and the like, or mixtures thereof, with alcohols such as methanol is recommended. Alternatively, the reduction reaction may be carried out in the presence of an acidic medium, such as hydrochloric acid in ethanol, to give an acidic salt of an alpha-amino ketone, which may be isolated as the acidic salt or free amine forms.

Suitable acids for use in reaction (b ') include, but are not limited to, HCl, HBr, HI, H ₂ SO ₄ , H ₃ PO ₄ , etc., with preferred HCl. Suitable solvent (s) in reaction (b ') include hydrocarbons, ethers, alcohols and the like, or mixtures thereof with alcohols such as ethanol, the alpha-amino ketone may be isolated as a salt or free alkali form.

Step (c) consists of reacting the alpha-amino ketone 4 or an acid salt thereof obtained in step (b) or (b ') with an alpha-substituted acyl derivative 5, such as alpha-halo acyl halide (i.e., Q and L = halo), in the presence of a base and in a suitable solvent or solvent mixtures to give amide 6.

The alpha-halo acyl halide 5 includes alkyl or aryl-alpha-halo acyl halides (substituted or unsubstituted), the latter being preferred. The most preferred alpha-halo acyl halide is alpha-chloroacetyl chloride. The base used in the reaction includes, but is not limited to, aromatic and aliphatic organic amines, the latter being preferred. The most preferred 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 may be carried out using alpha-substituted acid (Q-OH) instead of an alpha-substituted acyl derivative and then using a coupling reagent such as water-soluble diimide (e.g., carbodiimide, haloformate, thionyl halide, etc.). any reaction, sulfonate, for example, R ⁶ SO ² O '(where R ⁶ is alkyl, cycloalkyl, aryl or heteroaryl), CF ₃ SO ₂ O may be substituted for the halogen at the alpha position (i.e., at group L) of compounds 5.

Step (d) involves the reaction of ami 6 obtained in step (c) with a dehydrating reagent in a suitable solvent or solvent mixtures to give a cyclized 2-oxazolylalkyl derivative 7, for example, 2-oxazolylalkyl halide (i.e. , L is halo).

Advantageously, the reaction is carried out using (methoxycarbonylsulfamoyl) -triethylammonium hydroxide (Burgess reagent) as a dehydrating reagent. Suitable solvent (s) include hydrocarbons, halogenated hydrocarbons, ethers and the like, or mixtures thereof. Most preferred is the use of Burgee reagent in tetrahydrofuran. Suitable dehydrating reagents also include, but are not limited to, other bases, acids, acidic anhydrides, and the like, such as concentrated sulfuric acid, polyphosphoric acid, etc. More conveniently, the dehydrating reagent may be trichalophosphorus oxide, such as tribromophosphorus oxide or trichlorophosphorus oxide, alone or with a toluene-like solvent.

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

The sulfur-containing reagent includes N-substituted or unsubstituted thioureas, thio acids or salts, such as thioacetic acid or a salt thereof, xanthic acids or salts, such as potassium salt of ethylxanthogenic acid. Unsubstituted thiourea is preferred. 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 is preferred.

Step (f) illustrates the reaction of 2oxazolylalkyl sulfide 9 obtained in step (e) with 2-aminothiazole 10 (preferably L is halo) in the presence of a base in a suitable solvent or mixtures of solutions to give 5 (2-oxazolylalkylthio) ) -2-aminothiazole 11.

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

Scheme 2 clarifies the general synthesis of compounds of formula I by reacting amine 11 with a carboxylic acid of formula 12 in the presence of a coupling reagent. Suitable 5 coupling agents include, but are not limited to, water-soluble carbodiimides, haloformates and the like, with carbodiimide such as alkylcarbodiimide hydrochloride and base.

Scheme 3 below illustrates the synthesis of compounds of formula I in which X is NR ² and R ² is H. First, an amine of formula 11 is reacted with an N protected carboxylic acid of formula 13 in 40 in the presence of a coupling agent to form The N-protected compound of formula 14. Subsequently, the compound 14 is deprotected to obtain the compound of formula I. Suitable coupling reagents include, but are not limited to, water-soluble carbodiimide, haloformates and the like, with carbodiimides such as alkylcarbodiimides are preferred, for example, 1- (3-dimethylamino) opyl) -3-ethylcarbodiimide hydrochloride and base.

Scheme 3

R ¹ ι

In the no-rope scheme, P is a nitrogen protecting group (e.g., Boc, Cbz, R ₃ Si, etc.). When a functional group is called "protective" it means that the group is in a modified form to prevent undesirable side effects at the protected site. Suitable protecting groups for the compounds involved in the present methods will be recognized from the specification taking into account the level of skill in the art by reference to standard textbooks such as Greene.TW, Protective Groups in Organic Synthesis, 3 ^rd Edition (1999), given here by quote. Preferred protecting groups are Boc, Cbz, silicone derivatives, with Boc being preferred. Suitable solvent (s) include hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, etc., or mixtures thereof with halogenated hydrocarbons such as dichloromethane are recommended. The choice of deprotecting reagent is based on the nature of the protecting group (P). For the Boc protecting group, the preferred deprotecting reagent is an acid such as hydrochloric acid or trifluoroacetic acid, and suitable solvent (s) for such a deprotection reaction include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides and the like. mixtures thereof with halogenated hydrocarbons such as dichloromethane are preferred.

Scheme 4 below illustrates the synthesis of compounds of formula I in which X is NR ² and R ² is 2,3-dihydroxypropyl by reaction of a compound of formula I in which X is NR ² and R ² is

Scheme 4

R ¹

I hydrogen with glyceraldehyde in the presence of a reducing agent such as sodium triacetoxyborohydride and an alcohol such as methanol.

or

Scheme 5 below illustrates the synthesis of compounds of formula I wherein X is NR ² and R ² is 2-hydroxyethyl by reacting a compound of formula I wherein X is NR ² and R ² is hydrogen with 2- (bromoethoxy) trialkylsilane of formula 15 to give intermediate 16, and the intermediate deprotecting 16 with an acid such as hydrofluoric.

CH ₂ CH ₂ OH (D

Preferred compounds of formula I are those wherein R is alkyl;

R ¹ is hydrogen;

X is NR ² CHNR ² R ³ and R ² and R ³ each independently represent hydrogen, lower alkyl, which may optionally be substituted by one or more hydroxyl groups, or lower cycloalkyl and η is 2.

A first group of more preferred compounds of the present invention are those of formula Ia:

and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, wherein R ² is hydrogen, lower alkyl, which may be optionally substituted by one or more hydroxyl groups, or lower cycloalkyl.

A second group of more preferred compounds of the present invention are those of formula lb:

And their enantiomers, diastereomers, solvates and pharmaceutically acceptable salts, in which R ² represents hydrogen, lower alkyl, which may be optionally substituted by one or more hydroxyl groups, or lower cycloalkyl.

A third group of more preferred compounds of the present invention are those of formula Ic:

and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, wherein R ² and R ³ each independently represent hydrogen, lower alkyl, which may optionally be substituted by one or more hydroxyl groups, or lower cycloalkyl.

In another preferred embodiment of the invention, compounds of formula I include, but are not limited to, those listed in Table 1 below and their enantiomers, diastereomers, solvates and pharmaceutically acceptable salts.

Table 1. Compounds according to the invention

Name Structure N- [5 - [[[5- (1,1-dimethylethyl) -2oxazolyl] methyl] hyo] -2-thiazolyl] -4-piperidinecarboxamide (±) -N- [5 - [[[[5- (1,1-dimethylethyl) -2oxazolyl] methyl] thio] -2-thiazolyl] -3-piperidinecarboxamide s. (±) -1- (2,3-dihydroxypropyl) -N- [5 - [[[5- (1,1 -. Dimethylethyl) -2-oxazolyl] metil1tio] ^{-2-1-thiazolyl]} -4-pyperodynkarb0ksamid \ —O _ n I 1 Ai N- [5 - [[[5- (1,1-dimethyl ethyl) -2oxazolyl] methyl] thio] -2-thiazolyl] -1- (dimethylethyl) -4-piperidinecarboxamide 1-Cyclopropyl-N- [5-C [5- (1,1-dimethylethyl) -2oxazolyl] methyl) thio] -2-thiazolyl] -4-piperidinecarboxamide '.I. '·· * ~~~ N- (5 - [[[5- (1 L-dimethylethylEgoxazolyl) ethyl] -O-thiazolyl-N, N- ¹ hydroxyethyl) -4-piperidinecarboxamide - ΧΥΊ. (R) -N- [5 - [[(5- (1,1-dimethylethyl) -2oxazolyl] methyl] thio] -2-thiazolyl] -3-piperidinecarboxamide (S) -N- (5- [[[5- (1,1-dimethylethyl) -2oxazolyl] methyl] thio] -2-thiazolyl] -3-piperidinecarboxamide (HjChQ / X ZJi / c-4-aHHO-N- [5 - [[[5- (1,1-dimethylethyl) -2oxazolyl] methyl] thio] -2thiazolyl] cyclohexylcarboxamide 7rans-4-amino-N- [5 - [[[5- (1,1-dimethylethyl) -2oxazolyl] methyl] thio] -2-thiazolyl] cyclohexylcarboxamide OijOA

Preferred salts of the above compounds are hydrochloride, hydrobromide, dihydrochloride, sulfate, trifluoroacetate, tartrate, fumarate, succinate, maleate, nitrate, methanesulfonate, bromate or iodate salts.

The present invention also includes methods based on the pharmacological properties of the compounds of the invention. The compounds of the invention have pharmacological properties; in particular, the compounds of formula I are inhibitors of protein kinases, such as cyclin dependent kinases (cdks), for example cdc2 (cdkl), cdk2, cdk3, cdk4, cdk5, cdk6, cdk7 and cdk8. Thus, the invention encompasses the use of compounds of the invention in the treatment, prophylaxis and / or control of cancer, inflammation or inflammatory diseases, arthritis, Alzheimer's disease, and cardiovascular diseases. The invention also encompasses, in a more specific embodiment, the use of compounds of the invention for the treatment, prophylaxis and / or control of proliferative diseases or their symptoms. The invention also encompasses the use of the compounds of the invention in the treatment of common and organic fungicidal infections.

In particular, the compounds of formula I are useful in the treatment of various cancers, including, but not limited to, including the following:

- carcinomas, including those of the bladder, of the breast, of the colon, of the kidney, of the liver, of the lungs, of the ovaries, of the pancreas, of the stomach, of the cervix, of the thyroid, of the prostate and of the skin .

hematostatic tumors of lymphoid binding, including acute lymphocytic leukemia, B-cell lymphoma, Burkett lymphoma;

- hematostatic myelid-binding tumors, including acute and chronic myelogenous leukemia, and promyelocytic leukemia;

- tumors of mesenchymal nature, including fibrosarcoma and rhabdomyosarcoma; and

- other tumors, including melanoma, seminomas, teratosarcoma, osteosarcoma, neuroblastoma and glioma. Without being restricted by any theory due to the key role in regulating cell proliferation in general, inhibitors may act as reversible cytostatic agents that may be useful in the treatment of any disease process that characterizes abnormal cell proliferation, e.g. neurofibroblastoma, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis after angioplasty or vascular surgery, hypertrophic scar formation, inflammation of the thin they bowel, transplant rejection, angiogenesis, and endotoxic stroke.

The invention also encompasses the use of the compounds of the invention in the treatment of Alzheimer's disease, as suggested by the recent discovery 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 of other protein kinases, for example protein kinase C, her2, rail, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, weel kinase, Src, Ab 1, VEGF and Ick and thus be effective in treating diseases associated with other protein kinases.

The invention also encompasses the use of the compounds of the invention to introduce or inhibit apoptosis, a process of physiological cell death critical to normal development and homeostasis. Alterations in apoptotic pathways contribute to the pathogenesis of various human diseases. Compounds of formula I, as modulators of apoptosis, will be useful in the treatment of various human diseases with abnormalities in apoptosis, including tumor (especially, but not limited to, follicular lymphoma, carcinomas with p53 mutations, hormone-dependent breast tumors, prostate and ovarian and pre-tumor lesions, such as inherited adenomatous multiple polyps formation, viral infections (including, but not limited to, viral herpes, varicella, Epstein-Barr virus, Sindbis virus, adenovirus), autoimmune diseases (including but not limited to limited systemic lupus, erythematosus, immune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, infectious diseases of the small intestine and autoimmune diabetes mellitus), neurodegenerative disorders (including, but not limited to, Alzheimer's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, pigmented retinitis, spinal muscular atrophy and cerebral degeneration), AIDS, myelodysplastic syndromes, aplastic anemia, ischemic damage associated with myocardial infarction, stroke and stroke donation related to recurrent perfusion, arrhythmia, atherosclerosis, liver disease associated with toxicity or alcohol damage, haematological diseases (including, but not limited to, chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system , but not limited to, osteoporosis and arthritis), rhinosinusitis, aspirin sensitive, cystic fibrosis, multiple sclerosis, kidney disease and cancer related pain.

In another preferred embodiment, the invention relates to a method of inhibiting cdk in a cell. In particular, the invention encompasses a method of treating or preventing diseases associated with the modulation of cdk by administering one or more compounds of the invention to a mammal in need of treatment.

The invention encompasses the treatment of mammals, in particular humans.

In addition, the compounds of the invention may be useful for treating alopecia caused by chemotherapy, thrombocytopenia caused by chemotherapy, leukopenia caused by chemotherapy or mucocyte. In the treatment of alopecia caused by chemotherapy, the compounds of the invention are preferably administered topically in the form of a drug, such as a gel, solution, dispersion or paste.

The compounds of this invention may be used in combination (before, during, after, including cyclic administration) with known antitumor treatments, such as radiation therapy or with cytostatic and cytotoxic agents, including, but not limited to, microtubules, stabilizing agents, microtubule, destructive agents, alkylating agents, antimetabolites, epidophyllotoxin, antineoplastic enzyme, topoisomerase inhibitor, procarbazine, mitoxantrone, platinum coordinating complexes, biological response modifiers, growth inhibitors a, hormonal / antihormonal therapeutic agents, haematopoietic growth factors and the like.

Classes of antitumor agents that can be used in combination with the compounds of Formula I of the present invention include, but are not limited to, the anthracycline family of drugs, vinca drugs, mitomycin, bleomycin, cytotoxic nucleosides, taxanes, epothilodins, discodermolines a family of drugs, dienes, aromatase inhibitors and polyphyllotoxins. Specific members of these classes include, for example, paclitaxel, docetaxel, 7-O-methylthiomethylpaclitaxel (L8 5,646,176), 3 '-tert-butyl-3' -N-tert-butyloxycarbonyl-4-deacetyl-3'-L1-debenzoyl- 4-O-methoxycarbonyl-paclitaxel (USSN 60 / 179,965), C-4 methyl carbonate paclitaxel (WO1994 / 014787), epothilone A, epothilone B, epothilone C, epothilone D, deoxyepotilone A, deoxyepotilone B, [1 S-epitone R, [1 S- *, 3R * (E), 7R *, 1OS *, 11R *, 12R *, 16S * 2] -7, 11-dihydroxy-8,8,10,12,16pentamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4-aza-17-oxabicyclo [14.1.0] heptadecane-5-, 9-dione (disclosed in WO 1999/002514), [1S [1R *, 3R * ( E), 7R *, 10S *, llR *, 12R *, 16S * 2] -3- [2 [2- (aminometer l) -4-thiazolyl] -1-methylethenyl] -

7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17 dioxabicyclo [14.1.0] heptadecane-5,9-dione (disclosed in USSN 09 / 506,481), doxorubicin, carinomycin, daunorubicin, aminopterin, methotrexate, metopterin, dichloromethotrexate, mitomycin C, porphyromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin derivatives, such as etoposide, epotoside phosphatin, tenfenvirotin, Other useful antitumor agents that can be used in combination with the compounds of the present invention include, but are not limited to, estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thioterate, cytarabit, cytarabit trimethaxate, dacarbazine, L-asparaginase, camptothecin, CPT11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons, interleukins and the like. In addition, the compounds of this invention may be useful in combination with farnesyl protein transferase inhibitors, such as those described in US 6,011029; anti-angiogenic agents such as angiostatin and endostatin; kinase inhibitors such as her2 specific antibodies and modulators of p53 transactivation.

When formulated as a fixed dose, such combination products use the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range. The compounds of formula I can be used sequentially, in any order, with known antitumor or cytotoxic agents, when the composition of the combination is inappropriate.

The present invention also provides pharmaceutical compositions which consist of a compound of the invention and a pharmaceutically acceptable carrier. It should be noted that in the context of the pharmaceutical compounds of the present invention, the compounds of the present invention or compounds of formula I refer to the free base, enantiomers, diastereomers, solvates, as well as pharmaceutically acceptable salts. Examples of such pharmaceutically acceptable salts include, but are not limited to, hydrochloride, dihydrochloride, sulphate, trifluoroacetate, mixtures of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate and methanesulfate, methanesulfonate, methanesulfate, methanesulfate 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, for example, nitrates, phosphates, borates, benzoates, ascorbates, salicylates and the like. These salts include racemic forms as well as enantiomers and diastereomers (e.g., Dartartrate and L-tartrate salts). In addition, the pharmaceutically acceptable salts of the compounds of formula I may be formed with alkali metals such as sodium, potassium and lithium; alkaline earth metals such as calcium, magnesium, organic bases such as dicyclohexylamine, tributylamine, and pyridine and the like; and amino acids such as alginine, lysine and the like.

The pharmaceutical compounds of the present invention may further comprise one or more pharmaceutically acceptable carriers, excipients, or diluents, including, but not limited to, ingredient (s) such as aluminum, stabilizers, antimicrobials, buffers, coloring agents, flavoring agents and the like . The compounds and compositions of this invention may be administered orally or parenterally, including intravenously, intramuscularly, intraperitoneally, subcutaneously, rectally, and topical routes of administration.

For oral use, the compounds and compositions of this invention may be administered, for example, in the form of tablets or capsules, or as solutions or suspensions. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch and lubricants such as magnesium stearate are commonly added. For oral capsule administration, useful carriers include lactose and corn starch. When aqueous suspensions are used for oral administration, emulsifying and / or suspending agents are commonly used. In addition, sweetening and / or flavoring agents may be added to the oral compositions. For intramuscular, subcutaneous and intravenous use, sterile solutions of the active ingredient (s) are usually used, and the pH of the solutions should be appropriately adjusted and buffered. For intravenous use, the total concentration of the solute must be controlled to obtain an isotonic composition.

The daily doses for administering the compounds of this invention to a person are determined by the treating physician, with dosages varying according to the age, weight, mode of administration and response of the patient, as well as the severity of the symptoms. A compound of formula I of this invention is preferably administered to humans in an amount of from about 0.001 to about 100 mg / kg body weight per day, more preferably from about 0.01 to about 50 mg / kg body weight per day, and most preferably well from about 0.1 to about 20 mg / kg body weight per day.

Analysis of cbc2 / cyclin B1 kinase

The activity of c <1c2 / cyclin B1 kinase was determined by observing the introduction of ³² P in histone HI. The reaction consists of 50 ng bacul-5 virus expressed as GST-cdc2,75 ng baculovirus expressed as GST-cyclin B1, 1 mg histone HI (Boehringer Mannheim), 0.2 microCi ³² P gamma-ATP and 25 microM ATP in kinase buffer (50 mM Tris, pH 8.0, 10 mM MgCl ₂ , 1 mM EGTA, 0.5 mM 10 DTT). The reaction was incubated at 30 ° C for 30 min, then quenched by the addition of cold trichloroacetic acid (TCA) to a final concentration of 15% and incubated on ice for 20 min. Reaction 15 was plated in GF / C single-filter dishes (Packard) using a universal Packard Filtermate device and filters were counted on a 96-well Packard Top Count scintillation counter (Marshak, DR, Vanderberg, Μ. T, Bae, YS, Yu, 20 IJ, J. of Cellular Biochemistry, 45, 391-400 (1991), incorporated herein by reference.

Analysis of cbk2 / cyclin E kinase

The activity of cdk2 / uHKnHH E kinase was determined by observing the introduction of ³² P into 25 retinoblastoma protein. The reaction consists of 2.5 ng baculovirus expressed as GSTcbk2 / cyclin E, 500 ng baculovirus prepared as GST-retinoblastoma protein (aa 776-928), 0.2 microCi ³² P gamma-ATP, and 25 microM ATP in kinase-30 Zen buffer ( 50 mM Hepes, pH 8.0, 10 mM MgCl ₂ , 5 mM EGTA, 2 mM DTT). The reaction was incubated at 30 ° C for 30 min, then quenched by the addition of cold trichloroacetic acid (TCA) to a final concentration of 35 15% and incubated on ice for 20 min. The reaction was seeded in GF / C single-filter dishes (Packard) using a universal Packard Filtermate device and filters were counted on a 96-well 40 Packard Top Count scintillation counter.

Activity of cbk4 / cyclin D1 kinase

The activity of cbk4 / cyclin D1 kinase was determined by observing the incorporation of ³² P into the retinoblastoma protein. The reaction consists of 45 ng of 165 ng baculovirus expressed as GSTcdk4, 282 ng bacterially expressed as Stag cyclin D1, 500 ng bacterially derived GSTretinoblastoma protein (aa 776-928), 0.2 microCi ³² P gamma-ATP and 25 mocroM ATP. Zen buffer (50 mM Hepes, pH 8.0.10 mM MgCl ₂ , 5 mM EGTA, 2 mM DTT). The reaction was incubated at 30 ° C for 1 h, then quenched by the addition of cold trichloroacetic acid (TCA) to a final concentration of 15% and incubated on ice for 20 min. The reaction was seeded in GF / C single-filter dishes (Packard) using a universal Packard Filtermate device and filters were counted on a 96-well Packard Top Count scintillation counter (Coleman, K. G., Wautlet, B. S., Morrissey, D Mulheron, J. G., Sedman, S., Brinkley, P., Price, S., Webster, K.R., (1997) Identification of CDK4 Sequences involved in Cyclin D, and pl 6 binding, J. Biol. Chem., 272. 30: 18869-18874, incorporated herein by citation).

Examples of carrying out the invention

Example 1. Preparation of 5- [5- (4-butyl) 2-oxazolylmethylthio] -2- (azacycloalkanoyl) amino-thiazole hydrochloride

A. Preparation of alpha-azido-pinacoline

Oh

Alpha-bromo-pinacoline (199.07 g, 1.1115 mol, 1 eq) was collected in 1.785 l of acetone with sodium azide (93.9 g, 1.4444 mol, 1.3 eq). The reaction mixture was stirred at room temperature for 27.5 h. The resulting cake was 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 min (Phenomenex Inc. Jorrance, CA, 5 µm Cl8 column 4.6 x 50 mm, 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 ml / min, observation at 220 nm).

B. Preparation of alpha-hexamethylenetetramino-pinacoline bromide

Alpha-bromo pinacoline (179 g, 1 mmol leq) was collected in 21 acetone with hexamethylenetetramine (154.21 g, 1.1 mol, 1.1 eq) and the reaction mixture was stirred under nitrogen at room temperature for 26 h. The resulting cake was filtered, the filter cake was washed with ether (3 x 50 ml) and dried under vacuum at 50 ° C overnight to give 330 g (100%) of the title compound containing 7% hexamethylenetetramine. HPLC R.T. = 0.17 min (Phenomenex Inc., 5 µm C18 column 4.6 x 50 mm, 1090% aqueous methanol over 4 min, containing 0.2% phosphoric acid, 4 ml / min, observation at 220 nm).

C. Preparation of alpha-amino-pinacoline hydrochloride

About · HCI

Alpha-azido-pinacoline (128.5 g, 0.911 mol) was collected in 4.21 methanol with 77.1 ml concentrated HCl and 15.42 g 10% Pd / C. The reaction mixture was stirred under hydrogen for 1.5 h. The catalyst was removed by filtration. The solvent was distilled to give a wet solid. The remaining water was azeotropically removed with isopropanol (2 x 500 ml). Tert-butyl methyl ether (300 ml) was added and the resulting cake 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 alpha-amino-pinacoline hydrochloride

About · HCI

Alpha-hexamethylenetetramino-pinacoline bromide (400 g, 1.254 mol, 1 eq) was collected in 2 L of ethanol with 12 N aqueous HCl (439 ml, 5.26 mol, 4.2 eq). The reaction mixture was stirred at 75 ° C for 1 h, then allowed to cool to room temperature, the resulting cake filtered, the filtrate concentrated in vacuo and isopropyl alcohol added. The solution is filtered again. The material was filtered, washed with ether (2 x 300 ml), and dried in vacuo at 50 ° C overnight to give 184.1 g (97%) of the title compound.

E. Preparation of alpha 4 N- (2-chloroacetylamino) -pincols

The title compound of part D (130.96 g, 0.8637 mol, 1 eq) was distilled in 3.025 1 CH ₂ Cl ₂ under nitrogen 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 CH ₂ Cl ₂ . The resulting cake was stirred at -5 ° C to -10 ° C for 2 h. Water (1.575 l) was added, followed by 175 ml of concentrated hydrochloric acid. The organic phase was washed a second time with 1.75 1 10% aqueous hydrochloric acid and then with 500 ml of water. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo to give 155.26 g (93.8%) of the title compound. HPLC RT = 2.27 min (Phenomenex Inc., 5 µm Cl8 column 4.6 x 50 mm, 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 ml / min, observation at 220 nm).

F. Preparation of 5- (6-butyl) -2-oxazolyl-

The title compound of part E (180.13 g, 0.9398 mol, 1 eq) was combined with phosphorus oxychloride (262 ml, 2.8109 mol, 3 eq) under nitrogen. The reaction mixture was heated at 105 ° C for 1 h, the mixture cooled to room temperature and quenched with ice. The aqueous phase was extracted with ethyl acetate (11, then 3 x 500 ml). The organic extracts were washed with saturated aqueous NaHCO ₃ (4 x 11), which was back-extracted several times with ethyl acetate. The organic phases were combined, washed with saturated aqueous NaHCO ₃ (500 ml), then with saturated aqueous NaCl (300 ml), dried over MgSO ₄ and concentrated in vacuo to give a brown oil. The crude material was distilled under high vacuum at 100 ° C to afford 155.92 g (96%) of the title compound. HPLC RT = 3.62 min (Phenomenex Inc., 5 µm C18 column 4.6 χ 50 mm, 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 ml / min, observation at 220 µg).

Alternatively, the title compound of part E (10.0 g, 52.17 mmol, 1 eq) in 50 ml tetrahydrofuran (THF) was combined with (methoxycarbonylsulfamyl) -triethylammonium hydroxide (Burgess reagent, 105.70 mmol, 2.03 eq, obtained 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 mixture was heated to 45 ° C for 1.5 h. After cooling to room temperature, the reaction was rapidly cooled with water (50 ml). The organic layer was separated and washed with a saturated solution of NaHCO ₃ (2 x 50 ml) and water (50 ml), dried over MgSO ₄ and passed through a small silica gel pad. The solvent was removed to give an oil which was taken up in a mixture of 15 ml of heptane and 90 ml of t-butyl methyl ether and then washed with 0.2 N HCl (2 x 25 ml) saturated brine (25 ml) and dried (MgSO ₄ ). Filtration and removal of solvent gave 10.9 g of the title compound.

G. Preparation of 5- (1-butyl) -2-oxazolylmethyl thioron hydrochloride

The title compound of part F (1.77 g, 10.2 mmol, 1.02 eq) was combined with thiourea (0.76 g, 9.98 mmol, 1 eq) under nitrogen in 10 ml of absolute alcohol. The reaction mixture was refluxed for 1.5 h. The mixture was cooled to room temperature and concentrated in vacuo. Powder conversion of the resulting crude material with t-butylmethyl ether provided 2.32 g (93%) of the title compound. HPLC RT = 2.05 min (Phenomenex Inc., 5 µm C18 column 4.6 χ 50 mm, 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 ml / min, observation at 220 nm). NMR (d ₆ DMSOI): delta 9.48 (s, 3H), 6.85 (s, 1H), 4.73 (s, 2H), 1.24 (s, 9H).

H. Preparation of 5- [5- (1-Butyl) -2-oxazolylmethylthio] -2-aminothiazole

The title compound of 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-aminothiazolehydrobromide (1.70 g, 5 mmol, 1 eq) was added and the reaction mixture was stirred at room temperature for 14.5 h. The mixture was diluted with water and extracted twice with ethyl acetate, the organic extracts washed with water (4x10 ml), dried over MgSO ₄ 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 Cl8 column 4.6 χ 50 mm, 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 ml / min, observation at 220 nm). 1 H NMR (CDCl ₃ ): delta 6.97 (s, 1H), 6.59 (s, 1H), 5.40 (brs, 2H), 3.89 (s, 2H), 1.27 (s, 9H).

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

The title compound of part H (9.6 g, 35.6 mmol) was dissolved in N, N-dimethylformamide (36 ml) and CH ₂ Cl ₂ (100 ml), to which 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added. (13.8 g, 72 mmol, 2 eq), (N, N-butoxycarbonyl-azacycloalkanoic acid (12.6 g, 55 mmol, 1.5 eq) and 4- (dimethylamino) pyridine (2 g, 16 mmol, 0.45 eq). the mixture is turbid as it is stirred at room temperature for 3.5 h. Water (300 ml) and ethyl acetate (200 ml) are added and the resulting precipitate is removed by filtration. The filtrate is extracted with ethyl acetate, the organic extracts dried over MgSO4 and concentrated in vacuo to give a yellow solid which was recovered from the precipitate obtained by filtration The solid was boiled in a mixture of ethanol, acetone and water for 20 min, filtered, washed was combined with ethanol / water and dried to give 16.6 g (97%) of the title compound.

J. Preparation of 5- [5- (Tutyl) -2-oxazolylmethylthio] -2- (azacycloalkanoyl) amino-thiazole hydrochloride

The title compound of part I (16.6 g) was dissolved in 150 ml of CH ₂ Cl ₂ , trifluoroacetic acid (30 ml) was added dropwise and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo, diluted with water (300 ml), cooled with ice, made basic with sodium hydroxide and the resulting solid filtered and recrystallized from ethanol, water and methanol to give 11.2 g (83%) of the title compound as a yellow solid. 10 White solid hydrochloride can be obtained by adding 18 ml of 1N aqueous HCl to 7 g of this material in methanol. MS: 381 [M + H] +;

HPLC: 100% at 3.13 min (YMC S5 ODS column

4.6 x 50 mm, 10-90% aqueous methanol over 4 min, 15 containing 0.2% phosphoric acid, 4 ml / min, observation at 220 nm).

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

A. (±) -CM-butoxycarbonyl-nipecic acid

Nipecotinic acid (1.3 g, 10 mmol, eq) was collected with 10 ml of dioxane, 2 ml of acetone-40 nitrile, 10 ml of water and 10 ml of 1N aqueous sodium hydroxide (1 eq). Di-L-butyl dicarbonate (3.3 g, 15 mmol, 1.5 eq) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to remove the organic solvent and 10% aqueous citric acid solution was added. The mixture was extracted with ethyl acetate (3 x 100 ml). The organic extracts were dried over magnesium sulfate, filtered through silica gel, and concentrated in vacuo. The crude material was recrystallized from ethyl acetate and hexanes to give 2.2 g (96%) of (±) -N4-butoxycarbonylpecotinic acid as a white solid.

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

- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (383 g, 2 mmol, 2 eq) was added to a mixture of 2-amino- [5 - [[[5- (1,1-dimethylethyl) 2-oxazolyl] -methyl] ] thio] -2-thiazole (270 mg, 1 mmol, 1 eq). Nt-Butoxycarbonyl-nipecotinic acid 5 (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 CH ₂ C1 ₂ (6 ml). The reaction mixture was stirred at room temperature for 1.3 h. Triethylamine (0.28 ml, 2 mmol, 2 eq) was added and the reaction mixture was stirred for 1 h. In addition Nt-butoxycarbonyl-nicotinic acid (340 mg), triethylamine (0.28 ml) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added. No further change was observed after 1 h. Additionally 410 (dimethylamino) pyridine, N, N-dimethylformamide, triethylamine and starting acid were added and the reaction mixture was stirred overnight at room temperature. The resulting black solution was diluted with saturated aqueous NaHCO 3 solution and extracted with CH ₂ Cl ₂ . The organic extracts were dried, concentrated in vacuo and purified by flash chromatography on silica gel eluting with a gradient of 50100% ethyl acetate in hexanes to give 397 mg (83%) of (±) -N- [5 - [[[ 5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] - (b1-1-butoxycarbonyl) -3-piperidinecarboxamide as a yellow shiny solid.

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

(±) -N- [5 - [[[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] - (N-1-butoxycarbonyl) -3-piperidinecarboxamide (355 mg. 0.74 mmol, 1 eq) was dissolved in 3 ml of CH ₂ Cl ₂ . Trifluoroacetic acid (3 ml) was added and the mixture was stirred at room temperature for 20 min. The reaction mixture was concentrated in vacuo and neutralized with saturated aqueous HaNaHCO ₃ . The resulting mixture was extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, 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 over 4 min, containing 0.2% phosphoric acid, 4 ml / min, observation at 220 nm).

Example 3. Preparation of (±) -1- (2,3dihydroxypropyl-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] -4-piperidinecarboxamide (66 mg, 0.17 mmol, leq) was combined with glyceraldehyde ( 69 mg, 0.77 mmol, 4.5 eq), triacetoxyborohydride (163 mg, 0.77 mmol, 4.5 eq) 5 and 1,2-dichloroethane (4 ml). The resulting suspension was stirred at room temperature for 4 h. Methanol (1 ml) was added and the reaction mixture was stirred at room temperature overnight. Concentrated in vacuo and purified by preparative HPLC to give 69 mg (59%) (+) - 1- (2,3-dihydroxypropyl) -Ν- [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 over 4 min, containing 0.2% phosphoric acid, 4 ml / min, observation at 220 nm).

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

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

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

Ethyl isonepecotate (3.2 g, 20 mmol) was combined 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 was stirred at room temperature for 72 h. Saturated aqueous NaHCO ₃ solution was added and the mixture was extracted with CH ₂ Cl ₂ . The organic extracts were dried, extracted through a silica gel pad and concentrated in vacuo to give 3.72 g (93%) of ethyl 1- (1-methylethyl) -4-piperidine carboxylate as a colorless liquid.

Ethyl 1- (1-methylethyl) -4-piperidine carboxylate (3.6 g, 18 mmol, 1 eq) was combined with barium hydroxide octahydrate (10.4 g, 33 mmol, 1.8 eq) in a mixture of 70 ml water with 44 ml ethanol. The mixture was heated at 60 ° C for 1.3 h. The reaction mixture was concentrated in vacuo and diluted with 70 ml of water. Ammonium carbonate (6.9 g, 87 mmol, 4.8 eq) was added in portions and the reaction mixture was stirred at room temperature overnight. The mixture was filtered through a 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

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), Ν, Ν -dimethylformamide (2.6 ml) and CH ₂ Cl ₂ (7.8 ml). The reaction mixture was stirred at room temperature for 1 h, diluted with 30 ml water and extracted with ethyl acetate (2 x 70 ml). The organic extracts were dried over sodium sulfate, concentrated under pressure and purified by flash chromatography on silica gel, eluting with a gradient of 5-10% triethylamine in ethyl acetate. The material was recrystallized from ethanol and water to give 0.93 g (83%) 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, 1090% aqueous methanol over 4 min, containing 0.2% phosphoric acid, 4 ml / min, observation at 220 nm).

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

A. 1-Cyclopropyl-4-piperidine carboxylic acid sulphon A

Ethyl isonepecotate (1.57 g, 10 mmol, 5 eq) was combined with ((1-ethoxycyclopropyl) oxy) trimethyl silane (8.7 g, 50 mmol, 5 eq) in 100 ml of methanol. Acetic acid (5.7 m, 100 mmol, 10 eq) and molecular sieves were added. After 30 min at room temperature, sodium triacetoxyborohydride (2.5 g, 40 mmol, 4 eq) was added and the reaction mixture was heated at 65 ° C overnight. The reaction mixture was cooled and Na ₂ CO ₃ (20 g) was added. The mixture was stirred at room temperature for 2 hours and filtered through an infuser. The infusion finger was washed with methanol. The filtrates were collected, concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic extracts were dried, filtered through a silica gel pad and concentrated in vacuo to give 2.4 g of a colorless liquid. This material was combined with barium hydroxide octahydrate (5.7 g, 18 mmol, 1.8 eq) in a mixture of 5 in 38 ml of water with 24 ml of ethanol. The mixture was heated at 60 ° C for 1 h. The reaction mixture was concentrated in vacuo and diluted with 38 ml of water. Ammonium carbonate (3.8 g) was added portionwise and the reaction was stirred at room temperature for 2 h. The mixture was filtered through a diatomaceous earth, washed with water. The filtrate was washed with ethyl acetate. Concentration of the aqueous phase provided 1.56 g (92%) of 1-cyclopropyl-4-piperidine carboxylic acid as a hygroscopic white solid.

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

- (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] -2-thiazole (0.7 g, 2.6 mmol, 1 eq), 1-cyclopropyl-4-piperidine carboxylic acid (0.77 g, 1.5 eq), 4 (dimethylamino) pyridine (0.16 g, 1.3 mmol, 0.5 eq), N, N-dimethylformamide (2.6 ml) and CH 2 Cl 2 (7.8 ml). The reaction mixture was stirred at room temperature for 1 h, diluted with water (30 ml) and extracted with ethyl acetate (2 x 70 ml). The combined organic extracts were dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel, eluting with a 0-10% triethylamine gradient in ethyl acetate. The material was crystallized from ethyl acetate and hexanes to give 0.7 g (65%) of 1-cyclopropyl-N- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] - 2-Thiazolyl] -4-piperidinecarboxamide as 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 over 4 min, containing 0.2% phosphoric acid, 4 ml / min, observation at 220 nm).

Example 6. Preparation of N- [5 - [[[5 (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2thiazolyl] -1- (2-hydroxyethyl) -4-piperidinecarboxamide

A. N- [5 - [[[5- (1,1-dimethylethyl) -2-ox- ^1- butylsilyloxyethyl) -4-piperidinecarbox-

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 Ν, Ν-dimethylformamide and 100 ml tetrahydrofuran. 2- (boromoethoxy) -butyldimethylsilane (0.79 ml, 3.68 mmol, 1 eq) and NaHCO ₃ were added and the reaction mixture was stirred at 50 ° C for 23 h. 2- (Bromoethoxy) -1-butyldimethylsilane (0.9 ml) was further 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 was dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography on silica gel, eluting with a gradient of 05% triethylamine in ethyl acetate to give

1.7 g (84%) of N- [5 - [[[[5- (1,1-dimethylethyl) -2-ox5azolyl] -methyl] thio] -2-thiazolyl] -1- (2-dimethyl-butylsilyloxyethyl) - 4-sheridinecarboxamide as a yellow solid. MS: 539 [M + H] +: HPLC: 100% at 4.01 min (YMC S5 ODS column 4.6 x 50 mm. 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 ml / min, observation at 220 nm).

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

N- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] -1- (2-dimethyl-1: butylsilyloxyethyl) -4-piperidinecarboxamide (1.45 g, 2.7 mmol, 1 eq) was dissolved in 100 ml of acetonitrile and combined with aqueous HF (48% aqueous, 2.5 ml). The reaction mixture was stirred for 4 h at room temperature. An additional 2.5 ml of aqueous HF was added and the reaction mixture was stirred overnight. Ethyl acetate (100 ml) and saturated aqueous NaHCO ₃ (50 ml) were added. Additional solid NaHCO ₃ was added to make the mixture alkaline. The mixture was extracted with ethyl acetate (2 x 50 ml). The organic extracts were dried over sodium sulfate, filtered through a silica gel pad, 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 χ 50 mm, 10-90% aqueous methanol over 4 min, containing 0.2% phosphoric acid, 4 ml / min, observation at 220 nm).

Example 7. Preparation of (R) -N- [5 [([5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] -3-piperidine-carboxamide hydrochloride

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

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), Nt-butoxycarbonyl-nicotinic acid (3.4 g, 1.5 mmol, 1.5 eq), N, N-dimethylformamide (10 ml) and CH ₂ C1 ₂ (30 ml ). The reaction mixture was stirred at room temperature for 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 were dried over Na ₂ CO ₃ , concentrated in vacuo, and purified by flash chromatography on silica gel. eluting with a gradient of 50-100% ethyl acetate in hexanes to give 3.8 g (79%) of a yellow solid. The enantiomers were separated by chiral HPLC (Chiral Cancer AD 5 χ 50 cm 20 microns: eluent 10% (0.1% triethylamine in isopropanol) in hexanes; 45 ml / min, detection at 254 nm, loaded 300 mg in 5 ml isopropanol to give each of the two optically pure isomers was obtained: 1.65 g of the R isomer and 1.65 g of the S isomer.

B. (P) -> [5 - [[[[5- (1,1-dimethylethyl) -2oxazolyl] -methyl] thio] -2-thiazolyl] -3-piperidinecarboxamide hydrochloride

(R) The isomer of part A (1.65 g, 3.43 mmol, 1 eq) was dissolved in 10 ml of CH ₂ Cl ₂ . Trifluoroacetic acid (6 ml) was added and the mixture was stirred at room temperature for several hours. The reaction mixture was concentrated in vacuo and neutralized with saturated aqueous NaHCO ₃ . The resulting mixture was stirred with ethyl acetate for 1 h. The organic extracts were dried over sodium sulfate and concentrated in vacuo to give a yellowish solid. The product was dissolved in methanol and 1 eq of 1N aqueous hydrochloric acid was added. The resulting solution was lyophilized to give 1 g (77%) of (R) -N- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl ] -3-piperidinecarboxamide hydrochloride as a yellow solid. 5 MS: 381 [M + H] +; HPLC: 100% at 3.14 min (YMC S5 ODS column 4.6 x 50 mm, 10-90% aqueous methanol over 4 min. Containing 0.2% phosphoric acid, 4 ml / min, observation at 220 nm).

Example 8. Preparation of (S) -N- [5 - [[[5 (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] -3-piperidinecarboxamide hydrochloride

(S) The isomer of Example 7 part A (1.65 g, 15 (70%) (S) -N [5 - [[[5- (1,1-dimethylethyl) -2-oxa] 3.43 mmol, 1 eq) dissolved in 10 ml of CH ₂ Cl ₂ . Trifluoroacetic acid (6 ml) was added and the mixture was stirred at room temperature for several hours. The reaction mixture was concentrated in vacuo and neutralized with saturated aqueous NaHCO ₃ . The resulting mixture was stirred with ethyl acetate for 1 h. The organic extracts were dried over sodium sulfate and concentrated in vacuo to give a yellowish solid.

The product was dissolved in methanol and 1 eq of 1N aqueous hydrochloric acid was added. The resulting solution was lyophilized to give 0.918 g (CH3) 3C

Solyl] -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 over 4 min, containing 0.2% phosphoric acid, 4 ml / min, observation 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-aHHO -N- [5 - [[[5 (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] -cyclohexylcarboxamide hydrochlo-

(cf. ₃ ) ₃ p

A. 4- (1-Butoxycarbonylamino) cyclohexane carboxylic acid

NHffiOC

To a solution of 2.86 g (20 mmol) of 4-aminocyclohexane carboxylic acid in 40 ml of $ 0

0.5 M aqueous sodium hydroxide solution, 20 ml dioxane and 4 ml acetonitrile were added a total of 6.5 g (30 mmol) of tBoc anhydride at room temperature. After 20 h 100 ml of ethyl acetate and 100 ml of 10% aqueous citric acid solution were added. The aqueous layer formed was separated and extracted with three portions of 50 ml of ethyl acetate. The organic phases were combined, dried (sodium sulfate) and concentrated in vacuo to give 6.0 g (125%) of crude 4- (1-butoxycarbonylamino) cyclohexane carboxylic acid as a colorless oil which solidified upon standing.

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

NHffiOC

To a solution of 5 g of crude 4- (1-butoxycarbonylamino) -cyclohexane carboxylic acid and 3.50 g (13 mmol) of 2-amino- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] ] -2-Thiazole in 13 ml of N, N-dimethylformamide and 36 ml of methylene chloride was added 2.0 g (26 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride at room temperature. The reaction mixture was stirred overnight and diluted with 100 ml of water. The aqueous layer was separated and extracted with two 150 ml of ethyl acetate. The combined organic phases were 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 was recrystallized (95% ethanol) to give 4- (1-butoxycarbonylamino) N - [5 - [[[5 (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2thiazolyl] cyclohexylcarboxamide as a yellow solid. The mother liquors were also concentrated in vacuo to give additional 4- (1: -butoxycarbonylamino) -N- [5 [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] 2-thiazolyl ] cyclohexylcarboxamide as a brown solid.

C. C1-3-amino-L- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] cyclohexylcarboxamide hydrochloride and trans-4-amino-H - [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] methyl] thio] -2-thiazolyl] cyclohexylcarboxamide hydrochloride

To a suspension of 4- (1-butoxycarbonylamino) -N- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] cyclohexylcarboxamide (from Part B stock solutions ), suspended in 15 ml of methylene chloride, 5 ml of trifluoroacetic acid are added at room temperature. The reaction mixture was stirred for 2 h, then concentrated in vacuo to remove volatile products. The residue 50 was diluted with water, basified with aqueous sodium hydroxide solution and then the resulting aqueous solution was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate to give crude cis / trans product). The crude material was purified by flash chromatography (Merck silica, 25 x 3 cm, 1: 9 isopropylamine / ethyl acetate then 1: 2: 7 methanol / isopropylamine / ethyl acetate) to give 0.74 g of the cis isomer as a yellow solid and 0.50 g of the trans isomer as a brown solid. The cis isomer is dissolved in methanol, then 0.34 ml of 5N HCl 5 is added. The solution was 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 10 hydrochloride as a yellow solid. MS: 395 [M + H] +; HPLC-HI98%: at 3.17 min (YMC S5 ODS column 4.6 x 50 mm, 10-90% aqueous methanol over 4 min, containing 0.2% phosphoric acid, 4 ml / min, observation at 220 nm). The trans 15 isomer is dissolved in methanol, then 0.24 ml of 5N aqueous HCl is added. The solution was concentrated in vacuo, washed with ether, diluted with water and lyophilized to give trans-4-aHHO-N- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl]] -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 over 4 min, containing 0.2% phosphoric acid, 4 ml / min, observation at 220 nm).

Example 10. N- [5 - [[[5- (1,1-dimethylethyl) 2-oxazolyl] -methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide, monohydrochloride

Acetyl chloride (0.28 ml, 3.9 mmol) was added dropwise to a solution of 40 ml absolute ethyl alcohol cooled in an ice bath. The reaction mixture was allowed to warm to room temperature for more than 30 minutes, followed by 14- [5 - [[[5- (1,1-dimethylethyl) 2-oxazolyl] -methyl] thio] -2-thiazolyl ] -4-Piperidinecarboxamide (1.50 g, 3.94 mmol, 1 eq) was added in one portion to give a thick cake. Water (~ 4 ml) was added to homogenize and then concentrated in vacuo to give a pale yellow solid. The crude material was recrystallized (aqueous ethyl alcohol) to give the title compound (70%) as a white solid, mp 256-258.

Analysis calculated for C ₁₇ H ₂₄ N ₄ O ₂ S ₂ ·

HCl: C, 48.96; H, 6.04; N, 13.43; S, 15.38; C1.8.50 Found: C, 48.69; H, 5.99 N, 13.24;

S, 15.27; Cl, 8.31

Example 11. b1- [5 - [[[5- (1,1-dimethylethyl) 2-oxazolyl] -methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide, monohydrobromide

To a solution of 1 M 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 solid precipitate that formed was collected on a Buchner funnel, washed with absolute EtOH and dried in vacuo at 100 ° C to give the title compound (72%) as a fine white powder, mp 235-237.

Analysis calculated for _{C] 7} H ₂₄ N ₄ O ₂ S ₂ ·. HBr: C, 44.24; H, 5.46; N, 12.14; S, 13.89; Br, 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-piper dicarboxamide, 0.5-L-tartaric acid salt

To a warmed 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 a solution of L-tartaric acid (345 mg, 2.3 mmol, 0.5 eq) in absolute EtOH (5 ml). A precipitate begins to form in a few minutes. The mixture was allowed to stand for 4 h at room temperature, then the solid precipitate was collected on a funnel, washed with absolute EtOH and dried in vacuo at 85 ° C for 24 h to give the title compound ( 94%) as pale yellow crystals, mp 234236 ° C.

Analysis calculated for C ₁₇ H ₂₄ N ₄ O ₂ S ₂ * 0.5 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 13.14- [5 - [[[5- (1,1-dimethylethyl) 2-oxazolyl] -methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide, 0.5-D-tartaric acid

To a warmed 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 a solution of D-tartaric acid (198 mg, 1.32 mmol, 0.5 eq) in absolute EtOH (4 ml). A precipitate begins to form in a few minutes. 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 to give the title compound ( 73%) as a white solid, mp 232-233 ° C.

Analysis calculated for C _{) 7} H ₂₄ N ₄ O ₂ S ₂ · 0.5 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. T4- [5 - [[[5- (1,1-dimethylethyl) 2-oxazolyl] -methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide, 0.5-fumaric acid salt

To a warmed 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 a solution of fumaric acid (276 mg, 2.3 mmol, 0.5 eq) in 5 absolute EtOH (5 ml) was added. After 10 min, a precipitate begins to form. The mixture was allowed to stand for 2 h at room temperature, then at 5 ° C for 16 h. The solid precipitate which formed was collected on a 10-Buchner funnel, washed with absolute ethyl alcohol and dried in vacuo at 65 ° C for 24 h to form the title compound (84%) as a white solid. substance, mp 206-207 ° C. 15

Analysis calculated for C ₁₇ H ₂₄ N ₄ O ₂ S ₂ · 0.5 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% aqueous EtOH) gave the title compound containing 1 mol of EtOH (83%) as large colorless crystals, mp 21214 ° C.

Analysis calculated for _C] H _{24 7} N ₄ O ₂ S ₂ * 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. b1- [5 - [[[5- (1,1-dimethylethyl) 2-oxazolyl] -methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide, 0.5-succinic acid salt

To a warmed solution of N- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide (50 g, 0.13 mmol) in absolute EtOH (2 ml) was added a solution of succinic acid (7.7 mg, 0.065 mmol, 0.5 eq) in absolute EtOH (0.25 ml). After 10 min, a precipitate begins to form. The mixture was allowed to stand for 1 hour at room temperature, then collected on a Buchner funnel, washed with absolute ethyl alcohol and dried in vacuo at 100 ° C for h to form the title compound (70% ) as a white solid, mp 190192 ° C.

Analysis calculated for C ₁₇ H ₂₄ N ₄ O ₂ S ₂ · 0.5 succinic acid · 0.46 H ₂ O: 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. b1- [5 - [[[5- (1,1-dimethylethyl) 2-oxazolyl] -methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide, 0.5-sulfuric acid salt

To a warmed solution of N- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide (50 g, 0.13 mmol) in absolute EtOH (2 ml) was added 1M aqueous sulfuric acid solution (0.065 mg, 0.065 mmol, 0.5 eq). Almost immediately a precipitate forms. The mixture was cooled to 5 ° C for 2 h, then the precipitate was collected on a Buchner funnel, washed with absolute ethyl alcohol and dried in vacuo at 100 ° C for 24 h to form the title compound (79 %) as a white solid, mp

256-258 ° C.

Analysis calculated for _{C] 7} H ₂₄ N ₄ O ₂ S ₂ · 0.5

H ₂ SO ₄ · 0.68 H ₂ O: 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-piperidine dicarboxamide, 0.5-citric acid salt

To a warmed solution of N- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide (50 g, 0.13 mmol) in absolute EtOH (2 citric acid solution (8.3 mg, 0.043 mmol, 0.33 eq) was added. The solution was cooled to 5 ° C for 18 h, after which the precipitate formed was collected on a Buchner funnel, washed with absolute ethyl alcohol, and dried in vacuo at 100 ° C for 24 h. the title compound (68%) was formed as a white solid, mp 214-216 ° C.

Analysis calculated for C ₁₇ H ₂₄ N ₄ O ₂ S ₂ · 0.5 citric acid · 0.10 H ₂ O: 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 18.14- [5 - [[[5- (1,1-dimethylethyl) 2-oxazolyl] -methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide, methanesulfonic acid salt

To a suspension of N- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] -4- 40 piperidinecarboxamide (100 mg, 0.26 mmol) in isopropyl alcohol (0.75 ml) was added methane sulfonic acid (0.017 ml, 0.26 mmol, 1 eq). The suspension was heated to 70 ° C to give a clear solution, then methyl 45 t-butyl ether (1.5 ml) was added. A precipitate formed within 15 min. The resulting mixture was stirred at 55 ° C for 2 h, then at room temperature for 14 h. The precipitate which formed was collected by filtration, then dried in vacuo at 500C for 14 h to give the title compound (85%) as a colorless powder at 105 ° C.

Analysis calculated for C ₁₇ H ₂₄ N ₄ O ₂ S ₂ ·. MSA • H ₂ O: 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 19.1 N- [5 - [[[5- (1,1-dimethylethyl) 2-oxazolyl] -methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide, 0.5-D, L-con of malic acid

To a solution of b [- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide (100 mg, 0.26 mmol) in isopropyl alcohol (0.80 ml) was slowly added at 70 ° C a solution of O, L-malic acid (35 mg, 0.13 mmol, 0.5 eq) in isopropyl alcohol (0.3 ml). A precipitate immediately forms. The resulting mixture was stirred at 550C for 2 h, then at room temperature for 14 h. The precipitate was collected by filtration, then dried under vacuum at 50 ° C for 14 h to give the title compound (75%) as a colorless powder, mp 216 ° C.

Analysis calculated for C ₁₇ H ₂₄ N ₄ O ₂ S ₂ · C ₄ H ₆ O ₅ · H ₂ O: 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)

Claims 1-cyclopropyl-N- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] 4-piperidinecarboxamide; N- [5 - [[[5- (1,1-dimethyl ethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] -1- (2-hydroxyethyl) -4-piperidinecarboxamide; N-) - 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-aminoH-N- [5 - [[[5- (1,1-dimethylethyl) 2-oxazolyl] -methyl] thio] -2-thiazolyl] cyclohexylcarboxamide; and 1-5-5-amino-T4- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] cyclohexylcarboxamide; and their enantiomers, diastereomers, solvates and pharmaceutically acceptable salts. (±) -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; (1s) 1. L1- [5 - [[[5-alkyl-2-oxazolyl] methyl] thio] -2-thiazolyl] -carboxamide derivatives of formula I (I) and their enantiomers, diastereomers, solvates and pharmaceutically acceptable salts, in which : R is lower alkyl; R ¹ represents hydrogen; X is NR ² or CHNR ² R ³ ; R ² and R ³ each independently represent hydrogen, lower alkyl, which may be optionally substituted by one or more hydroxyl groups, or lower cycloalkyl; η stands for 0, 1, 2 or 3. Compounds according to claim 1, wherein R is lower alkyl; R ¹ represents hydrogen; X is NR ² or CHNR ² R 3; R ² and R ³ each independently represent hydrogen, lower alkyl, which may be optionally substituted by one or more hydroxyl groups, or lower cycloalkyl; η means 2. A compound according to claim 1 of formula Ia (Ia) and its enantiomers, diastereomers, solvates and pharmaceutically acceptable salts, in which R ² represents hydrogen, lower alkyl, which may optionally be substituted by one or more hydroxyl groups, or lower cycloalkyl . The compound of claim 1 of formula lb (CH ₃ ) ₃ C X, (1b) and its enantiomers, diastereomers, solvates and pharmaceutically acceptable salts, in which R ² represents hydrogen, lower alkyl, which may optionally be substituted by one or more hydroxyl groups, or lower cycloalkyl. The compound of claim 1 of formula Ic and its enantiomers, diastereomers, solvates and pharmaceutically acceptable salts, in which R ² and R ³ each independently represent hydrogen, lower alkyl, which may be optionally substituted by one or more hydroxyl groups, or lower cycloalkyl. A compound according to claim 1 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; A compound according to claim 6, which is N- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide and its enantiomers, diastereomers, solvates and pharmaceutically acceptable salts. A compound according to claim 6 which is (±) -1 '1- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] -3- piperidinecarboxamide and its enantiomers, diastereomers, solvates and pharmaceutically acceptable salts. A compound according to claim 6 which is (R) -L- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] -3-piperidinecarboxamide and pharmaceutically acceptable salts thereof. 10. (S) -L- [5 - [[[[5- (1,1-dimethylethyl) -2oxazolyl] -methyl] thio] -2-thiazolyl] -3-piperidinecarboxamide and its pharmaceutically acceptable salts. 11. Cis-4-aminoH-N- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] cyclohexylcarboxamide and its pharmaceutically acceptable salts. 12. Trans-4-aminoH-N- [5 - [[[5- (1,1-dimethylethyl) -2-oxazolyl] -methyl] thio] -2-thiazolyl] cyclohexylcarboxamide and its pharmaceutically acceptable salts. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier and an anti-tumor agent formulated as a fixed dose, A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier and a p53 transactivation modulator formulated as a fixed dose. The use of an effective amount of a compound of claim 1, its enantiomers, diastereomers and pharmaceutically acceptable salts, for the preparation of a medicament for modulating apoptosis. Use of an effective amount of a compound of claim 1, its enantiomers, diastereomers and pharmaceutically acceptable salts, for the preparation of a protein kinase inhibitory drug. The use of an effective amount of a compound of claim 1, its enantiomers, diastereomers and pharmaceutically acceptable salts, for the preparation of a medicament for inhibiting cyclin dependent kinase. The use of an effective amount of a compound of claim 1, its enantiomers, diastereomers and pharmaceutically acceptable salts, for the preparation of a medicament for inhibiting cdc2 (cdkl). Use of an effective amount of a compound according to claim 1, its enantiomers, diastereomers and pharmaceutically acceptable salts, for the preparation of a medicament for inhibiting cdk2. Use of an effective amount of a compound according to claim 1, its enantiomers, diastereomers and pharmaceutically acceptable salts, for the preparation of a medicament for inhibiting cdk3. Use of an effective amount of a compound according to claim 1, its enantiomers, diastereomers and pharmaceutically acceptable salts, for the preparation of a medicament for inhibiting cdk4. Use of an effective amount of a compound according to claim 1, its enantiomers, diastereomers and pharmaceutically acceptable salts, for the preparation of a medicament for inhibiting cdk5. Use of a compound according to claim 1, its enantiomers, diastereomers and pharmaceutically acceptable salts, for the preparation of a medicament for inhibiting cdk6. The use of a compound according to claim 1, its enantiomers, diastereomers and pharmaceutically acceptable salts, for the preparation of a medicament for inhibiting cdk7. The use of an effective amount of a compound of claim 1, its enantiomers, diastereomers and pharmaceutically acceptable salts, for the preparation of a medicament for inhibiting cdk8. Use of an effective amount of a composition according to claim 13, enantiomers, diastereomers and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier for the preparation of a medicament for the treatment of proliferative diseases. Use of an effective amount of a composition according to claim 13, its enantiomers, diastereomers and pharmaceutically acceptable salts and a pharmaceutically acceptable carrier for the preparation of a medicament for the treatment of tumors. The use of an effective amount of a composition according to claim 13, its enantiomers, diastereomers and pharmaceutically acceptable salts and a pharmaceutically acceptable carrier for the preparation of a medicament for the treatment of inflammation, inflammatory bowel disease or transplant rejection. Use of an effective amount of a composition according to claim 13, its enantiomers, diastereomers and pharmaceutically acceptable salts and a pharmaceutically acceptable carrier for the preparation of a medicament for the treatment of arthritis. Use of an effective amount of a composition according to claim 14 for the preparation of a medicament for the treatment of a proliferative disease. Use of an effective amount of a composition according to claim 14 for the preparation of a medicament for the treatment of cancer. Use of an effective amount of a composition according to claim 15 for the preparation of a medicament for the treatment of a proliferative disease. Use of an effective amount of a composition according to claim 15 for the preparation of a medicament for the treatment of cancer. Use of an effective amount of a compound according to claim 1, its enantiomers, diastereomers and pharmaceutically acceptable salts, for the preparation of a medicament for the treatment of a cyclin dependent kinase related disorder. Use of an effective amount of a compound of claim 1, its enantiomers, diastereomers and pharmaceutically acceptable salts, for the preparation of a medicament for the treatment of chemotherapy-induced alopecia, chemotherapy-induced thrombocytopenia, chemotherapy-induced leukopenia or mucocytosis. The compound of claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, methanate, maleate . The compound of claim 2, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, methanate, maleate . The compound of claim 3, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, methanate, maleate . The compound of claim 4, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, methanate, maleate . The compound of claim 5, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, methanate, maleate . The compound of claim 6, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, methanate, maleate . The compound of claim 7, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, maleate salts. The compound of claim 8, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, methanate, maleate . The compound of claim 9, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, methanate, maleate . The compound of claim 10, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, methanate, maleate . The compound of claim 11, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, methanate, maleate . The compound of claim 12, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, methanate, maleate . The compound of claim 13, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, methanate, maleate . The compound of claim 14, wherein the 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. The compound of claim 15, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, methanate, maleate . Use according to claim 17, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, maleate, maleate . Use according to claim 18, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, maleate, maleate . The use of claim 20, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, maleate, maleate . The use according to claim 27, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleic methanate salts. The use according to claim 28, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, maleate, maleate . Use according to claim 31, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, maleate, maleate . The use according to claim 32, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, 5 dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, malate salts. 1θ The use according to claim 36, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, dihydrochloride, sulfate, trifluoroacetate, a mixture of trifluoroacetate and hydrochloride, 15 tartrate, fumarate, succinate, maleate, maleate, malate salts.