EP1515953A2

EP1515953A2 - Novel hexahydro-pyridazine-3-carbocylic acid hydrazide or hydrazone derivatives, combinatorial libraries containing same, use thereof as medicines, pharmaceutical compositions containing same and methods for preparing same

Info

Publication number: EP1515953A2
Application number: EP03760021A
Authority: EP
Inventors: Neerja Bhatnagar; Pierre Broto; Jean-François Gourvest; Jacques Mauger
Original assignee: Aventis Pharma SA
Current assignee: Aventis Pharma SA
Priority date: 2002-06-14
Filing date: 2003-06-12
Publication date: 2005-03-23
Also published as: AU2003260582A1; CA2489447A1; JP2005530823A; US20050215553A1; IL165731A0; BR0312127A; WO2003106431A3; FR2840898A1; FR2840898B1; US7279480B2; MXPA04010747A; WO2003106431A2

Abstract

The invention concerns a compound of general formula (I). The invention also concerns combinatorial libraries containing same, use thereof as medicines, pharmaceutical compositions and methods for preparing same.

Description

NOVEL HYDRAZIDE OR HYDRAZONE DERIVATIVES OF ACID

HEXAHYDRO-PYRIDAZINE-3-CARBOXYLIQUE, CHEMOTOTHS

CONTAINING THEIR USE AS MEDICINES,

PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR

PREPARATION PROCESSES

The invention relates to new hydrazide or hydrazone derivatives of hexahydro-pyridazine-3-carboxylic acid, the chemical libraries (or bookshops) the containers, their preparation, their use as medicaments, in particular as inhibitors of cathépsine K., as well as the pharmaceutical compositions containing them.

Metabolic enzymes such as proteases or kinases are enzymes widely distributed in the animal kingdom. By way of non-exhaustive examples, reference may be made, as bibliographical references for the proteases, to the documents: "Methods in Enzymology XLII (1975)" and "Journal of Medicinal Chemistry" vol. 43 No. 3 (D. Leung, G. Abbenante and D.P. Fairlie) and for kinases, the document: "Methods in Enzymology", Vol 80 (1981) (Académie Press Inc.).

Among the proteases capable of selectively catalyzing the hydrolysis of polypeptide layers, the four main classes can be cited: aspartic protease, serine, cysteine and metallo-protease. As aspartic protease, mention may in particular be made of HIV-1 protease, renin, plasmepsins, cathépsine D. Mention may in particular be made, as serine protease, of thrombin, factor Xa, elastase, tryptase, "complement of convertases", protease NS3 and hepatitis C. Among the cysteine proteases, there are three structurally distinct groups, the papain group and cathepsins, the ICE group (the caspases) and the picorna-viral group (similar to the serine proteases in which the serine is replaced by a cystene). Thus, there may be mentioned in particular cathépsine K, cathépsine B, cathépsine L, cathépsine S, caspases, rhinovirus 3C protease and papains and calpains.

As metalloprotease, there may be mentioned in particular the angiotensin converting enzyme, the neutral endopeptidase and the mixture of the two, the metalloprotease matrix as well as the Tumor-necrosis Factor-α-Converting Enzyme.

These kinase or protease enzymes are involved in catabolization and inter and intracellular communication processes: they play an important role in a large number of diseases in different fields such as in particular the cardiovascular field, oncology, the central nervous system, 'inflammation, osteoporosis and also infectious, parasitic, fungal or viral diseases. This is why these proteins are targets of great interest for pharmaceutical research.

The subject of the present invention is therefore a compound of general formula (I):

(D in which: n is an integer from 0 to 6 inclusive;

R _x represents a group chosen from: C (0) - (CH ₂ ) _m -R

C (O) -NH- (CH ₂ ) _m -R or C (S) -NH- (CH ₂ ) _m -R S0 ₂ - (CH ₂ ) _m -R in which m is an integer from 0 to 6 inclusive ; a double bond which may possibly be present when n is greater than 2; R is one of the groups: hydrogen when m is different from 0; hydroxy or thiol; cyano; linear or branched alkoxy containing from 1 to 6 carbon atoms or aryloxy or aralkoxy; cycloalkyl having 3 to 6 carbon atoms; saturated or unsaturated monocyclic or bicyclic heterocyle group; the nucleus of the heterocyl radical being optionally substituted with one to three substituents chosen from: OH, SH, NH ₂ , NO ₂ , cyano, carboxy, 5 carbamoyl, halogen, trifluoromethyl, linear or branched alkyl containing from 1 to 6 carbon atoms, linear or branched alkoxy containing from 1 to 6 carbon atoms, acyl containing from 2 to 6 carbon atoms, aryl or aralkyl, a monocyclic or bicyclic heterocyle saturated or unsaturated, these alkyl or aryl radicals or aralkyl or heterocyls being themselves even optionally substituted with one to three substituents chosen from: OH, SH, NH ₂ , N0 ₂ , cyano, carboxy,

20 carbamoyl, halogen, trifluoromethyl, an aryl group containing from 6 to 10 carbon atoms or aralkyl containing from 7 to 11 carbon atoms, the ring of the aryl or aralkyl radical being optionally substituted with one to three substituents chosen from: OH, SH, NH ₂ , N0 ₂ , cyano, carboxy, carbamoyl, halogen,

30 trifluoromethyl, linear or branched alkyl containing 1 to 6 carbon atoms, linear or branched alkoxy containing from 1 to 6 carbon atoms, acyl containing from 2 to 6 carbon atoms, saturated or unsaturated monocyclic or bicyclic heterocyle, these alkyl radicals or heterocycles being themselves optionally substituted with one to three substituents chosen from: OH, SH, NH ₂ , NO ₂ , cyano, carboxy, carbamoyl, halogen, trifluoromethyl; a group NRR _{5 /} R ₄ being a hydrogen atom or a linear or branched alkyl group having from 1 to 6 carbon atoms R ₅ being a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 atoms carbon or an aryl group;

R ₂ identical or different has the same meaning as Ri, or may represent hydrogen;

the lateral group:

^,

represents NR ₃ or N = R ₃ , in which

R ₃ identical or different has the same meaning as Ri, when this side group represents NR ₃ ; and R ₃ identical or different has the same meaning as R, when this side group represents N = R ₃ ; said products of formula (I) being in all the isomeric, racemic, enantiomeric and diastereoisomeric forms; as well as addition salts with mineral and organic acids or with mineral and organic bases of these products.

According to one embodiment, n is 2. According to one embodiment, R ₂ represents hydrogen.

According to one embodiment, the lateral group

NL ^* ^• .

represents NR ₃ .

According to one embodiment, the lateral group

NOT-

R.

represents N = R ₃ .

According to one embodiment, the compound has the following stereochemistry:

The products of the present invention as defined above and below have inhibitory properties of metabolic enzymes as defined above in particular of kinases or of proteases such as in particular the cysteine proteases or serine proteases.

The products of the present invention can thus in particular be useful in the prevention or treatment of diseases in which such metabolic enzymes are involved such as certain cardiovascular diseases, diseases of the central nervous system, inflammatory diseases, bone diseases such as for example osteoporosis, infectious diseases requiring in particular for their therapy anti-infectives or certain cancers.

In the products of formula (I) and in the following:

the bivalent group represented by - (CH ₂ ) _n - can be linear or branched.

the term aryl containing 6 to 10 carbon atoms denotes an unsaturated radical, comprising one or two fused rings, optionally interrupted by one to three heteroato es chosen from nitrogen, oxygen and sulfur. Mention may be made of: phenyl, naphthyl.

the term aralkyl containing from 7 to 11 carbon atoms denotes an aryl radical as above, linked by a linear or branched alkyl radical, this alkyl radical having from 1 to 5 carbon atoms. Mention may in particular be made of benzyl.

the terms alkoxy, ayloxy and aralkyloxy indicate the presence of a terminal oxygen on the alkyl, aryl or aralkyl group.

the term monocyclic heterocyclic radical denotes a saturated or unsaturated radical consisting of 5 or 6 links such that one or more of the links represents an oxygen, sulfur or nitrogen atom: such a heterocyclic radical thus denotes a carbocyclic radical interrupted by one or more heteroatoms chosen from oxygen, nitrogen or sulfur atoms, it being understood that heterocyclic radicals can contain one or more heteroatoms chosen from oxygen, nitrogen or sulfur atoms and only when these heterocyclic radicals have more than one heteroatom, the heteroatoms of these heterocyclic radicals may be the same or different. Mention may in particular be made of the dioxolane, dioxane, dithiolane, thiooxolane, thiooxane, morpholinyl, piperazinyl, piperazinyl radical substituted by an alkyl radical, linear or branched, containing at most 4 carbon atoms, piperidyl, thienyl such as 2-thienyl and 3- thienyl, furyl such as 2-furyl, pyrimidinyl, pyridyl such as 2-pyridyl, 3-pyridyl and 4-pyridyl pyrimidyl, pyrrolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, triazolyl, free or salified tetrazolyl thiadiazolyl, thiazolyl, thiazolyl , 3- or 4-isoxazolyle. Mention may very particularly be made of the morpholinyl and thienyl radicals such as 2-thienyl and 3-thienyl and furyl radicals such as 2-furyl, tetrahydrofuryl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyridyl and pyrrolidinyl.

the term bicyclic heterocyclic radical denotes a saturated or unsaturated radical consisting of 8 to 12 members such that one or more of the members represents an oxygen, sulfur or nitrogen atom and in particular condensed heterocyclic groups containing at least one heteroatom chosen from sulfur, nitrogen and oxygen, for example benzothienyl such as 3-benzothienyl, benzothiazolyl, quinolyl, tetralone, benzofuryl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl or purinyl.

The compounds of formula (1) can be salified by various groups known to those skilled in the art, among which there may be mentioned, for example:

- among the exceptication compounds, mineral bases such as, for example, an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxy-methyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procalne, lysine, arginine, histidine, N-methyl-glucamine,

-The addition salts with mineral or organic acids of the products of formula (1) can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic acids , benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulfonic acids such as for example methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, alkylldisulfonic acids such as for example methanedisulfonic acid, alpha acid , beta-ethanedisulfonic, arylmonosulfonic acids such as benzenesulfonic acid and aryldisulfonic acids. It may be recalled that stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same developed formulas, but the different groups of which are arranged differently in space, such as in particular in monosubstituted cyclohexanes whose substituent can be in axial or equatorial position, and the different possible rotational conformations of ethane derivatives. However, there is another type of stereoisomerism, due to the different spatial arrangements of fixed substituents, either on double bonds or on rings, which is often called geometric isomerism or cis-trans isomerism. The term stereoisomers is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above.

Chemicals of compounds according to the invention

The present invention thus also relates to chemical libraries (or bookstores). These libraries are in particular in the form of matrices of variable rank, the rank being at least 2, at least 2 rows containing at least 2 compounds, each compound being individualized. It is understood that these matrices can be made available in a form which is not necessarily of the same rank; thus it is possible to obtain a row 3 matrix in the form of plates with test pieces, the plates being of order 2. It is also understood that the matrices, for example of row 3, when they are available in a order form 3 or lower, are not necessarily ordered.

The invention also covers the chemical libraries in the form of sets comprising a plurality of compounds according to the invention, each compound being individualized. This set of compounds notably comprises plates with wells each comprising a compound according to the invention. These sets comprise at least 4 individualized compounds according to the invention.

The chemical libraries according to the invention are in particular discreet.

The chemical libraries generally comprise a large number of compounds, typically of the order of a hundred or a thousand.

These libraries are used as a research tool for drug screening. The compounds forming the chemical library show the pharmacological properties mentioned below.

Method according to the invention

In the process according to the invention, the compounds are prepared in the form of chemical libraries, as indicated above. It is also possible to prepare them in a conventional manner by implementing the process, compound by compound. The method according to the invention thus comprises the following steps:

(i) coupling to an immobilized support of the compound of formula (II):

in which n has the value indicated above, in an immobilized reagent of formula (III):

in which the circle designates the support; (ii) reaction of the compound of formula III with a compound of formula R _x ', i' being a precursor of the group Ri, this precursor having the meaning corresponding to that of Ri as indicated above in a compound of formula ( IV):

(iii) optionally reacting the compound of formula IV with a compound of formula R ₂ ', R ₂ ' being a precursor of the group R ₂ , this precursor having the meaning corresponding to that of R ₂ as indicated above in a compound of formula (V):

(iv) hydrazynolysis of the compound of formula IV or V into the compound of formula (VI):

(v) reaction of the compound of formula VI with a compound of formula R ₃ ', R ₃ ' being a precursor of the group R ₃ , this precursor having the meaning corresponding to that of R ₃ as indicated above in a compound of formula (VII):

(vi) cleavage of the compound of formula VII into the desired compound of formula I.

In the above, the reagents used Ri ', R ₂ ' and R ₃ 'are precursors. They react with amino functions (secondary or primary) to lead to the desired groups. In particular, the precursors Ri 'and R ₂ ' are chosen from acids, anhydrides, chlorides (of acid, sulfonyl or carbamoyl), chloroformates, isocyanates and thioisocyanates. It is the same for the precursor R ₃ 'of R ₃ when the NR ₃ bond is simple. When the bond N = R ₃ is double; the precursor is an aldehyde. These reactions (ii), (iii) and (v) are carried out under conventional conditions, in relation to the reactions considered, known to those skilled in the art. For example, these reactions are conventionally carried out in an aprotic dipolar solvent in the presence of a base. When the bond N = R ₃ is double, the aldehyde is reacted with the hydrazides, for example in a THF / methyl orthoformate mixture.

The coupling reaction is carried out conventionally on a resin type support, for example by reductive amination (typically reaction of the primary amine on an aldehyde present on the base resin; the reaction is carried out by adding a suspension of the product II in a dichloromethane / DMF mixture with the resin followed by addition of sodium borohydride triacetate). The resin is a 4-formyl-3,5-dimethoxyphenoxy type resin (PL-FDMP, Polymer Laboratories Stratospheres). The hydrazynolysis reaction is carried out conventionally by adding hydrazine.

The cleavage reaction is carried out conventionally by the action of trifluoroacetic acid in dichloromethane (50/50).

The process according to the invention can also comprise one or more of the following optional reactions, in an appropriate order, to obtain the desired compound:

- protection of reactive functions,

- deprotection of reactive functions,

- esterification,

- saponification, - amidification,

- acylation,

- sulfonylation;

- alkylation;

- introduction of a double bond; - reduction of carboxylic acids;

- salification;

- ion exchange;

- splitting or separation of diastereoisomers. The optional steps are generally conventional reactions, well known to those skilled in the art.

Thus, the reactive functions which it is appropriate, if necessary, to protect are generally the carboxylic acid, amino, amide and hydroxy functions. The protection of the acid function is in particular carried out in the form of alkyl esters, allylic esters, benzyl, benzhydryl or p-nitrobenzyl.

Deprotection is carried out by saponification, acid hydrolysis, hydrogenolysis, or even cleavage using soluble complexes of Palladium O.

The protection of amines and amides is in particular carried out in the form of benzylated derivatives, in the form of carbamates, in particular of allyl, benzyl, phenyl or tertbutyl, or also in the form of silylated derivatives such as the tertbutyl dimethyl, trimethyl, triphenyl derivatives or else diphenyl tertbutyl-silyl.

Deprotection is carried out, depending on the nature of the protective group, by sodium or lithium in liquid ammonia, by hydrogenolysis or using soluble complexes of Palladium O, by the action of an acid, or by the action of fluoride. of tetrabutylammonium.

The protection of alcohols is carried out in a conventional manner, in the form of ethers, esters or carbonates. The ethers may be alkyl or alkoxyalkyl ethers, preferably methyl or methoxyethoxymethyl ethers, aryl or preferably aralkyl ethers, for example benzyl, or silylated ethers, for example derivatives silylates cited above. The esters can be any cleavable ester known to a person skilled in the art and preferably acetate, propionate or benzoate or p-nitrobenzoate. The carbonates can be, for example, methyl, tert-butyl, allyl, benzyl or p-nitrobenzyl carbonates.

Deprotection is carried out by means known to those skilled in the art, in particular saponification, 1 hydrogenolysis, cleavage by soluble complexes of Palladium O, hydrolysis in an acid medium or, for silylated derivatives, treatment with tetrabutylammmonium fluoride. The amidification reaction is carried out starting from the carboxylic acid using an activating agent such as an alkyl chloroformate or EDCI, by the action of ammonia or an appropriate amine. or their acid salts. Where appropriate, the acylation and sulfonylation reactions are carried out on the hydroxyureas by the action respectively of a suitable halide or anhydride of carboxylic acid or a suitable halide of sulfonic acid. The alkylation reaction is carried out by action on the hydroxylated derivatives of an alkyl halide or of substituted alkyl, in particular by a free or esterified carboxy radical.

If necessary, the possible final introduction of a double bond is carried out by the action of a halogen derivative of selenium then oxidation, according to methods known to those skilled in the art.

If necessary, the reduction of acids into alcohols can be carried out by the action of a borane or, via an intermediate mixed anhydride, by the action of an alkaline borohydride. The mixed anhydride is prepared for example using an alkyl chloroformate.

Salification with acids is optionally carried out by adding an acid in the soluble phase to the compound. Salification with bases can relate either to compounds comprising an acid function, in particular carboxy, or those comprising a function sulfooxy or those comprising an heterocycle of acidic nature. In the first case, the procedure is carried out by adding an appropriate base such as those mentioned above. In the second case, the pyridinium salt is obtained directly during the action of the SO ₃ -pyridine complex and the other salts are obtained from this pyridinium salt. In either case, one can still operate by ion exchange on resin. Examples of salifications appear below in the experimental part.

The separation of enantiomers and diastereoisomers can be carried out according to techniques known to those skilled in the art, in particular chromatography.

For the synthesis of chemical libraries, the classical techniques of combinatorial chemistry are used (with linear synthesis or not). The following documents may be cited, for example, without limitation: US-P-5324483, US-P-5143854, US-P-5010175, US-P-5288514, US-P- 5549974, WO-A-9209300 and WO-A-9502566.

Including IRORI ^® technology is used (including the "directed sorting"), steps (ii), (iii) and (v) being randomized with reagents R _x ', R _2' and R ₃ 'available. The individualized products are then then collected in flasks.

Salification with acids is optionally carried out by adding an acid in the soluble phase to the compound. Salification with bases can relate either to compounds comprising an acid function, in particular carboxy, or those comprising a function sulfoxy or those comprising an heterocycle of acidic nature. In the first case, the procedure is carried out by adding an appropriate base such as those mentioned above. In the second case, the pyridinium salt is obtained directly during the action of the SO ₃ -pyridine complex and the other salts are obtained from this pyridinium salt. In either case, it is still possible to operate by ion exchange on resin. Examples of salifications appear below in the experimental part.

Illustrations of such reactions defined above are given in the preparation of the examples described below.

Pharmacological properties.

The products of formula (I) as defined above as well as their addition salts with acids have interesting pharmacological properties.

The products of the present invention can thus be endowed with inhibitory properties of one or more metabolic enzymes as defined above, in particular kinases or proteases.

Certain products of formula (I) of the present invention as defined above, can therefore in particular have inhibitory properties of certain protein kinases or proteases. As proteases of interest, it is possible to target cathepsins B, H, J, L, N, S, T, C, V, K or O, 02; especially those involved in diseases of cartilage and bone metabolism and bone cancer, and especially cathépsine K.

The levels, regulation and activity of a certain number of protein kinases or proteases play a role in several human pathologies. The activity of a protein kinase or protease can in particular be associated with receptors having transmembrane domains or with intracellular proteins.

Certain kinases or proteases can play a role in the initiation, development and completion of cell cycle events and thus, inhibitory molecules of such kinases or proteases are capable of limiting unwanted cell proliferation such as those observed in cancers, psoriasis, growth of fungi, parasites (animals, protists): such molecules inhibiting these kinases or proteases are thus also likely to intervene in the regulation of neurodegenerative diseases such as Alzheimer's disease.

Certain products of formula (I) of the present invention can thus be endowed with antimitotic properties.

Certain products of formula (I) as defined above may, as kinase or protease inhibitors, have in particular the property of inhibiting bone resorption mediated by osteoclasts. They can therefore be useful for the therapeutic or prophylactic treatment of diseases which are caused at least in partly by an unwanted increase in bone resorption, for example osteoporosis.

Certain products of formula (I) of the present invention can thus for example inhibit the enzymatic digestion of the collagen of the bone matrix and thus the bone resorption by the osteoclasts.

Bone diseases the treatment or prevention of which requires the use of the compounds of formula

(I), are in particular osteoporosis, hypercalcemia, osteopenia, for example caused by bone metastases, dental disorders for example periodontitis, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, disease of Paget, osteopenia induced by immobilization. In addition, the compounds of formula (I) can be used to relieve, prevent or treat bone disorders which are caused by treatments, by glucocorticoids, therapies linked to the taking of steroids or corticosteroids or by deficiencies. male or female sex hormones.

All of these disorders are characterized by bone loss, which is based on a lack of balance between bone formation and bone destruction and which can be favorably influenced by the inhibition of bone resorption by osteoclasts.

Certain products of formula (I) of the present invention may have, in addition to their specific inhibitory properties of kinases or proteases, interesting cellular effects such as antiproliferative properties and in particular effects on apoptosis. It is known from the work described in the literature such as in WO 97/20842 that relationships exist between the cell cycle and apoptosis. Among the pathways leading to apoptosis, some are dependent on kinases or proteases.

The products of the present invention are particularly useful for the therapy of tumors.

The products of the invention can thus also increase the therapeutic effects of commonly used anti-tumor agents.

The products of formula (I) of the present invention also have antimitotic and anti-neurodegenerative properties.

Certain products of the present invention can be inhibitors of vasoconstrictor and hypertensive effects and thus produce an anti-ischemic effect, or even oppose stimulating effects at the level of certain cellular types in particular smooth muscle cells, fibroblasts, cells. neuronal and bone cells.

The products according to the present invention can thus be used in the treatment of diseases such as proliferative diseases, cancer, restenosis, inflammation; allergies, cardiovascular disease or certain infectious diseases.

The products of the present invention can also be used in the treatment of certain gastrointestinal, gynecological disorders and in particular for a relaxing effect on the uterus. The products of formula (I) of the present application can thus have interesting properties pharmacological justifying their application in therapy.

The invention therefore also relates to the compounds according to the invention for their use as medicaments, intended for the prevention or treatment of the diseases mentioned above.

The invention particularly relates to pharmaceutical compositions containing as active ingredient at least one of the compounds according to the invention in combination with a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention as defined above can be administered by the oral route, by parenteral route or by local route in topical application on the skin and the mucous membranes or by injection by intravenous or intramuscular route. These compositions can be solid or liquid and can be presented in all the pharmaceutical forms commonly used in human medicine such as, for example, simple or coated tablets, pills, tablets, capsules, drops, granules, injectable preparations, ointments, creams or gels; they are prepared according to the usual methods. The active ingredient can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.

The usual dosage, which varies according to the product used, the subject treated and the condition in question, can be, for example, from 0.05 to 5 g per day in adults, or preferably from 0.1 to 2 g per day.

Another subject of the invention is the use of the compounds according to the invention for the manufacture of medicaments intended for the prevention or treatment of the diseases mentioned above.

The following examples illustrate the invention without limiting it. In these, the following abbreviations are used:

DCM: dichloromethane

DMF: N, N-dimethylformamide

DIEA: Diisopropylethylamine DIC: Diisopropylcarbodiimide

TFA: Trifluoroacetic Acid

AcOEt: ethyl acetate

HOBt: 1-hydroxybenzotriazole hydrate

Example 1. Synthesis of the skeleton.

The backbone of formula II is prepared by synthesis from intermediate hexahydropyridazic-3-carboxylic acid (see also the description as an intermediate product in documents WO-A-9955724,

WO-A-9722619 and EP-A-25941). a) Esterification of the acid function. Hexahydropyridazic acid (40g; 0.151 mol) is dissolved in 200ml of methanol and cooled to 0 ° C. SOCl ₂ (36ml; 0.45mol) is added dropwise. The solution becomes clear; the temperature is allowed to slowly return to room temperature and then heated to reflux for one hour. The mixture is poured onto a DCM (200 ml) / ice (500 g) / NaHCO ₃ (60 g) mixture. The aqueous phase is extracted with DCM. The organic phase is washed with a saturated NaHCO ₃ solution and then dried over MgSO ₄ . A colorless oil is obtained (41 g; 99%) used as it is. b) Amidation of the amino function (coupling with alanine).

The N- [(phenylmethoxy) carbonyl] - β-Alanine (50g; 0.183 mol) in solution in DCM / DMF (200ml / 20ml) is cooled to 0 ° C; S0C1 ₂ (25ml; 0.32mol) is added dropwise. The mixture is left stirring for one hour at 0 ° C. The corresponding chloride is thus obtained. The product obtained in step a) is dissolved in 150 ml of DCM at 0 ° C; then we add DIEA

(33ml; 0.19mol) then the chloride obtained previously. The mixture is left for 3 hours with stirring; the temperature slowly rises to room temperature.

The mixture is washed successively with saturated solutions of NaHC0 ₃ , KHS0 ₄ and NaCl, then dried over MgS0 ₄ . A yellow oil purified by chromatography is obtained. (Column 1300g of silica; eluent DCM / AcOET 90/10). c) Deprotection of amino functions by hydrogenolysis. The compound obtained in step b) (26g; 0.054 mol) is dissolved in 250ml of DCM / 250ml of MeOH; the Pd / C (2.7 g) is then added. The mixture is left 12 hours under pressure between 1900 and 1950mbar. The palladium is changed during the reaction. The filtrate is evaporated to dryness. White crystals are obtained (8.5 g; 73%). LC-MS analysis confirms that it is indeed the compound of formula II sought after (n = 2).

The overall reaction scheme is represented above (Z representing the group C ₆ H ₅ CH ₂ OC (O) -).

Example 2. Coupling on resin.

A 4-formyl-3,5-dimethoxyphenoxy-methyl polystyrene resin is used. The resin (25g, 1.5 mmol / g) is put to swell in DCM (250ml) then filtered; it is then suspended in 200ml of DCM plus 100ml of DMF. Then add the substrate (compound to be grafted) (12g; 0.056mol) and NaBH (OAc) ₃ (20g; 0.094mol). A gas evolution is observed. The mixture is left stirring for 4 hours then the resin is filtered and washed successively with 2X200ml of DMF then 4X following the cycle of 200ml of DCM and 200ml of MeOH, one last washing being carried out with 200 ml of ether. 35 g of grafted resin are obtained. HR Mass analysis is consistent.

The product of formula (III) is then obtained, with the compound resin of the formula (PS meaning polystyrene):

Example 3. Synthesis of a chemical library (rank 3; NR ₃ single bond). Chemistry library of hydrazide derivatives.

This synthesis is carried out in Irori ^® minikans. Each minikan contains 35 mg of resin, with a load of 1.2 mmol / g. We predict 2; 5mL of solvent by MiniKan during the reaction and the various washes. The MiniKans are dried under vacuum at 40 ° C for 5 hours after washing.

a) first randomization (group Ri). This is implemented in a variable manner depending on the reagents used. Each reactor contains 90 MiniKans in 250 mL of the reaction solvent.

Isocyanates, isothiocyanate: the reagent is added

(5 eq) in the DCM, then the DIEA (10 eq). The mixture is stirred at ambient temperature for 4 h and then the resin is washed (DCM 2X250ml; methanol / DCM 5X250ml; ether 1X250ml). The The following reagents are used: trifluoromethylphenyl isocyanate, ethyl isocyanate and cyclopropyl isothiocyanate.

Acid anhydrides: the reagent (2 eq) is added to the DCM and then the DIEA (5 eq). The mixture is stirred at ambient temperature for 4 h and then the resin is washed (same cycle as above). The following reagents are used: acetic anhydride, isovaleric anhydride, 4-methoxybenzoic anhydride. Sulfonyl chlorides: the conditions are the same as for (thio) isocyanates. The following reagents are used: thiophene sulfonyl chloride, naphthalene sulfonyl chloride and mesitylene sulfonyl chloride.

b) second randomization (group R ₂ ). This is implemented under the following conditions (including a blank -case of hydrogen R ₂ ). Each reactor contains 90 MiniKans in 250 mL of the reaction solvent.

Add the acid chloride (10 eq) in DCM, then DIEA (16mL). The mixture is stirred at ambient temperature for 3 h and then the resin is washed (same protocol as above). The following reagents are used: acetyl chloride, butyryl chloride, furoyl chloride, methoxy acetyl chloride, methyl chloroformate, pentanoyl chloride.

Add the acid chloride (10 eq) in DCM, then pyridine (8mL). The mixture is stirred at ambient temperature for 5 h and then the resin is washed (same protocol as above). The following reagents are used: benzoyl chloride and anisoyl chloride. c) formation of hydrazide.

It is a common step. The 810 MiniKans are placed in 0.6L of DMF and 0.2L of hydrazine monohydrate. The mixture is stirred at ambient temperature for 15 h and then the resin is washed with 2XDMF (0.6L), then 5XDCM / MeOH

(IL), 1XDCM (IL) and lXether (IL). The minikans are then dried.

c) third randomization (group R ₃ ).

This step is implemented in the same way as the first randomization step. Each reactor contains 81 MiniKans in 160 mL of the reaction solvent. Acid chloride: Add the acid chloride (3 eq) in DCM, then pyridine (6 eq). The mixture is stirred at ambient temperature for 3 h and then the resin is washed

(same protocol as above). The following reagents are used: piperonoyl chloride, 4-morpholine carbonyl chloride and N-methyl chloride, N-phenyl carbamoyl.

Sulfonyl chlorides: Add the acid chloride (5 eq) in DCM, then pyridine (10 eq).

The mixture is stirred at room temperature for 3 h and then the resin is washed. The following reagents are used: propane sulfonyl chloride and 2-thiophene sulfonyl chloride.

Isocyanates, isothiocyanate: the reagent is added

(5 eq) in the DCM, without base. The mixture is stirred at ambient temperature for 3 h and then the resin is washed. The following reagents are used: phenylethyl isocyanate and 4-acetylphenyl thioisocyanate. Acids: add the reagent (4 eq) in the DMF then HOBt (4 eq). The mixture is stirred at ambient temperature for 12 h and then the resin is washed. The following reagents are used: 2-thiophene acetic acid and 2-pyridyl acryloic acid.

Acid anhydrides: the reagent (2 eq) is added to the DCM and then the DIEA (4 eq). The mixture is stirred at ambient temperature for 3 h and then the resin is washed. The following reagent is used: phenoxy acetic anhydride.

e) Cleavage.

The kans are sorted into IRORI ^® cleavage blocks with the help of the autosortor. The products are cleaved by adding 2 ml of TFA / DCM 50/50 solution. The cleavage solutions are filtered in pre-prepared test tubes and evaporated. Each product is redissolved in 1 ml of acetonitrile, 50 μl of aliquot of which is taken and transferred to a 96-well plate for LC / MS analysis. The aliquot is diluted in 1 ml of CH ₃ CN / H ₂ 0 solution and directly injected in LC / MS.

This gives a library of 810 (9x9x10) compounds, useful for screening these compounds as drugs.

Example 4. Synthesis of a chemical library (rank 2; N = R ₃ double bond). Chemistry library of hydrazide derivatives.

This synthesis is carried out in Irori ^® minikans. Each minikan contains 44 mg of resin, with a load of 1.12 mmol / g. 2mL of solvent is expected per MiniKan during of the reaction and the various washes. These are all performed on the following model:

2 times using the reaction solvent 5 methanol / DCM cycles - 1 time ether.

The MiniKans are then dried under vacuum at 40 ° C for 5h.

a) first randomization (group Ri). This is implemented in a variable manner depending on the reagents used. Each reactor contains 21 MiniKans in 50 mL of the reaction solvent.

Isocyanates, isothiocyanate: the reagent (5 eq) is added to the DCM. The mixture is stirred at ambient temperature for 2 h and then the resin is washed. The following reagents are used: Ethyl isocyanate; 4- (trifluoromethyl) phenyl isocyanate; Cyclopropyl isothiocyanate; Phenyl isocyanate.

Carboxylic acids: the reagent (3 eq) and 993 mg of HOBt (6 eq, 135.13 g / mol) are added to DMF then 1.15 mL of DIC (6 eq, 126.20 g / mol, 0.806). The mixture is stirred at ambient temperature for 1 night and then the resin is washed. The following reagents are used: 3- (1-cyanoethyl) benzoic acid; benzoic acid; 6-methylpicolinic acid; 3- (2-pyridyl) -acrylic acid; pyrazine carboxylic acid; benzofurazan-5-carboxylic acid; quinaldic acid; trans-2-hexenoic acid. acid hydrides: the reagent (5 eq) is added to DCM and then 2.5 mL of DIEA (12 eq, 129.26 g / mol, 0.755). The mixture is stirred at ambient temperature for 4 h and then the resin is washed. The following reagents are used: valeric anhydride; isovalenic anhydride; anhydride 4- methoxybenzoic; methacrylic anhydride; 2-phenylbutyric anhydride; acetic anhydride.

Sulfonyl chlorides: the reagent (5 eq) is added to the DCM and then 2.1 mL of DIEA (10 eq). The mixture is stirred at ambient temperature for 4 h and then the resin is washed. The following reagents are used: 2-naphthalenesulfonyl chloride; 2-mesitylenesulfonyl chloride; 2-thiophenesulfonyl chloride.

b) formation of hydrazide.

It is a common step. The 504 MiniKans are placed in 1.5 L of hydrazine monohydrate (1/3) / DMF

(2/3). The mixture is stirred at room temperature for 2 h and then the resin is washed with 2 XDMF (IL), then 2XMeOH (IL), 3XDCM (IL). The minikans are then dried.

c) second randomization (group R ₃ ). Each reactor contains 24 MiniKans in 50 mL of THF / HC (OMe) ₃ (l / l). Each aldehyde is added so as to obtain a concentration of 0.5M. The mixture is heated at 60 ° C. for 18 hours and then the resin is washed. The following reagents are used: 3-carboxybenzaldehyde; 3- methoxybenzaldehyde; 6-methoxy-2-naphthaldehyde; 4- nitrocinnamaldehyde; 4-cyanobenzaldehyde; 4- (ethylmercapto) benzaldehyde; 4-

(trifluoromethoxy) benzaldehyde; pyridine-3-carboxaldehyde; 4- (1-pyrrolidino) benzaldehyde; 4-formyl-2-phenylimidazole; l-methyl-2-imidazolecarboxaldehyde; 1- (phenylsulfonyl) -2-pyrrole-carboxaldehyde; 2-quinoline carboxaldehyde; 4- (3-dimethylamino) propoxy) -benzaldehyde; 2-butyl-4-formylimidazole; 6-fluoro-veratraldehyde; 3-dimethylamino-2, 2-dimethylpropionaldehyde; 2-furaldehyde; pyrazol-3 -carboxaldehyde; 2 - (4-Methoxy-phenyl) - benzofuran-7-carbaldehyde; 4- (5 -Formyl-furan-2-yl) - benzenesulfonamide; 1- (4-chlorophenyl) pyrrole-2-carboxaldehyde; 2 - [1-methyl-3 - (trifluoromethyl) pyrazol - 5 - yl] thiophene-5 -carboxaldehyde; pyridine-4 - carboxaldehyde.

d) Cleavage.

The kans are sorted into IRORI ^® cleavage blocks with the help of the autosortor. The products are cleaved by adding 2 ml of TFA / DCM 50/50 solution. The cleavage solutions are filtered in pre-prepared test tubes and evaporated. Each product is redissolved in 1 ml of acetonitrile, 50 μl of aliquot of which is removed and transferred to a 96-well plate for LC / MS analysis. The aliquot is diluted in 1 ml of CH ₃ CN / H ₂ 0 solution and directly injected in LC / MS.

This gives a library of 504 (21X24) compounds, useful for screening these compounds as drugs.

Pharmacological study of the products of the invention

Study of the inhibition of Cathépsine K

The products to be tested (10 mM) are diluted to 1 mM in DMSO and distributed in 96 well Nunc polystyrene plates at a rate of 2 μl per well. Column 12 of the plate is reserved for controls and therefore receives 1 μl of DMSO (without products) per well. The plates are stored at -80 ° C. and thawed on the day of the experiment.

The products are diluted to 50 μM by adding 38 μl of reaction buffer: 100 mM sodium acetate, EDTA 5 mM, 1 mM DTT, pH 5.5. The addition as well as all the following pipetting operations are carried out by a 96-cone CybiWell pipetting device. After mixing the solutions, each product is transferred to 2 wells (duplicates) of a 384-well black Greiner plate at the rate of 10 μl per well. We can therefore test 2 plates 96 in a plate 384.

A 50 μM substrate solution, Z-Val-arg-AMC (Calbiochem), is prepared in the reaction buffer. The substrate is then distributed in all the wells of the plate 384 (20 μl per well).

A solution of Cathépsine K at 12.5 ng / ml is prepared in the reaction buffer and distributed to all the wells of the plate 384 (20 μl per well) except the 16 wells serving as 100% inhibition controls (column 23 and 24, lines I to P) which will receive 20 μl of buffer without enzyme. The 100% inhibition controls are carried out in columns 23 and 24, lines A to H which do not contain products.

The plates are then incubated for 2 hours at ambient temperature, then read on Fluoroskan (Labsystems): excitation 390 nm; emission 460 nra

The final concentrations of each of the reagents are: Products 10 μM, Substrate 20 μM, enzyme 5 ng / ml.

The% inhibition for each of the products is calculated using the points at 0 and 100% inhibition of each plate as references. Products with significant inhibition are then retested over a concentration range from 50 to 0.5 μM to determine an IC50. The results show that the products according to the invention are active. Example 6

Pharmaceutical composition

Tablets corresponding to the following formula were prepared:

Compound according to the invention 500 mg

Excipient for one tablet finished at 1 g

(detail of excipient: lactose, talc, starch, magnesium stearate).

Claims

1. Compound of general formula (I)

(D in which: n is an integer from 0 to 6 inclusive;

Ri represents a group chosen from: C (0) - (CH ₂ ) _m -R

C (O) -NH- (CH ₂ ) _m -R or C (S) -NH- (CH ₂ ) _m -R S0 ₂ - (CH ₂ ) _m -R in which m is an integer from 0 to 6 inclusive ; a double bond which may possibly be present when n is greater than 2; R is one of the groups: hydrogen when m is different from 0; hydroxy or thiol; cyano; linear or branched alkoxy containing from 1 to 6 carbon atoms or aryloxy or aralkoxy; cycloalkyl having 3 to 6 carbon atoms; saturated or unsaturated monocyclic or bicyclic heterocyle group; the nucleus of the heterocyl radical being optionally substituted with one to

5 three substituents chosen from: OH,

SH, NH ₂ , N0 ₂ , cyano, carboxy, carbamoyl, halogen, trifluoromethyl, linear or branched alkyl containing from 1 to 6 carbon atoms, linear or branched alkoxy containing from 1 to 6 carbon atoms, acyl containing from 2 to 6 carbon atoms, aryl or aralkyl, a monocyclic or bicyclic heterocyle saturated or unsaturated, these alkyl or aryl or aralkyl or heterocyl radicals being themselves optionally substituted with one to three

20 substituents chosen from: OH,

SH, NH ₂ , N0 ₂ , cyano, carboxy, carbamoyl, halogen, trifluoromethyl, an aryl group containing from 6 to 10

25 carbon or aralkyl atoms containing from 7 to 11 carbon atoms, the nucleus of the aryl or aralkyl radical being optionally substituted with one to three substituents chosen from:

30 OH, SH, NH ₂ , N0 ₂ , cyano, carboxy, carbamoyl, halogen, trifluoromethyl, linear alkyl or branched containing from 1 to 6 carbon atoms, linear or branched alkoxy containing from 1 to 6 carbon atoms, acyl containing from 2 to 6 carbon atoms, monocyclic or bicyclic heterocyle saturated or unsaturated, these alkyl or heterocycles radicals being themselves optionally substituted with one to three substituents chosen from: OH, SH, NH ₂ , NO ₂ , cyano, carboxy, carbamoyl, halogen, trifluoromethyl; a group NR ₄ R ₅ , R ₄ being a hydrogen atom or a linear or branched alkyl group having from 1 to 6 carbon atoms R ₅ being a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms or an aryl group;

the lateral group:

NOT-

^• R.

represents NR ₃ or N = R ₃ , in which R ₃ identical or different has the same meaning as Ri, when this side group represents NR ₃ ; and

R ₃ identical or different has the same meaning as R, when this side group represents N = R ₃ ; said products of formula (I) being in all the isomeric, racemic, enantiomeric and diastereoisomeric forms; as well as addition salts with mineral and organic acids or with mineral and organic bases of these products.

2. Compound according to claim 1, characterized in that n is 2.

3. Compound according to claim 1 or 2, characterized in that R ₂ represents hydrogen.

4. Compound according to claim 1, 2 or 3, characterized in that the lateral group

NOT-

^• R.

represents NR ₃ .

5. Compound according to claim 1, 2 or 3, characterized in that the lateral group

^ R, represents N = R ₃ .

6. Compound according to any one of claims 1 to 5, having the following stereochemistry:

7. Compound according to any one of claims 1 to 6, for its use as a medicament.

8. Compound according to claim 7, for its use as a medicament intended for the prevention or treatment of diseases in which metabolic enzymes chosen from proteases and kinases are involved.

9. Compound according to claim 7 or 8, for its use as a medicament intended for the prevention or treatment of diseases in which cathépsine K is involved.

10. Compound according to claim 8 or 9, the diseases to be prevented or treated being chosen from the group of diseases consisting of cardiovascular diseases, cancers, diseases of the nervous system central, inflammatory diseases, infectious diseases and bone diseases.

11. A compound according to claim 8 or 9, the diseases to be prevented or treated are osteoporosis, hypercalcemia, osteopenia, gum disease, arthritis, Paget's disease, bone cancer.

12. Pharmaceutical composition containing, as active principle, at least one compound according to one of claims 1 to 11, in association with a pharmaceutically acceptable carrier.

13. Use of a compound according to one of claims 1 to 11, for the preparation of a medicament intended for the prevention or treatment of diseases in which metabolic enzymes chosen from proteases and kinases are involved.

14. compound library according to one of claims 1 to 6, in the form of a matrix of rank at least equal to 2, at least 2 rows each comprising at least two compounds, preferably at least five, the compounds being individualized .

15. A chemical library according to claim 14, in the form of a matrix of rank equal to 3, the first rank corresponding to the group R _x , the second rank corresponding to the group R ₂ and the third rank corresponding to the group R ₃ , each rank comprising each at least two compounds, the compounds being according to claim 4.

16. A chemical library according to claim 15, in which: the first rank corresponding to the group R _1f this group being chosen from the following residues: 4- (trifluoromethyl) -phenyl carbamoyl, Ethyl carbamoyl, Cyclopropyl thiocarbamoyl, Thiophene sulfonyl, Naphthalene sulfonyl,

Mesitylene sulfonyl, Acetyl, Isovaloyroyl, 4-methoxybenzoyl, the second rank corresponding to the group R ₂ , this group being chosen from the following residues: Acetyl, Benzoyl, Butyroyl, 2-Furoyle,

Anisoyl, Methoxyacetyl, Methoxycarbonyl, Pentanoyl, Hydrogen, the third rank corresponding to the group R ₃ , this group being chosen from the following residues:

Pipéronoyle,

4-morpholine carbonyl, N-methyl, -phenyl carbamoyl,

Propane sulfonyl,

2-thiophene sulfonyl, 43

Phenylethylcarbamoyl, 4-acetylphenyl thiocarbamoyl, 2-thiophene methyl carbonyl, 2-pyridyl ethenyl carbonyl, Phenoxy acetyl,

17. A chemical library according to claim 14, in the form of a matrix of rank equal to 2, the first rank corresponding to the group Ri, the second rank corresponding to the group R ₃ , each rank each comprising at least two compounds, the compounds being according to claim 5.

18. A chemical library according to claim 17, in which: the first rank corresponding to the group Ri, this group being chosen from the following residues: ethyl carbamoyl,

4- (trifluoromethyl) phenyl carbamoyl, cyclopropyl thiocarbamoyl, phenyl carbamoyl,

3- (l-cyanoethyl) benzoyl, benzoyl,

6-methylpicolinoyl, 3- (2-pyridyl) -acryloyl, pyrazine carbonyl, benzofurazan-5-carbonyl, quinaldoyl, trans-2-hexenoyl, valeroyl, isovaleryl, -methoxybenzoyl, methacryloyl, 2-phenylbutyroyl, acetyl,

2-naphthalenesulfonyl,

2-mesitylenesulfonyl, 2-thiophenesulfonyl, the second rank corresponding to the group R ₃ , this group being chosen from the following residues:

3 -carboxybenzaldehyde hydrazone;

3-methoxybenzaldehyde hydrazone; 6-methoxy-2-naphthaldehyde hydrazone;

4 -nitrocinnamaldehyde hydrazone;

4-cyanobenzaldehyde hydrazone;

4- (methylmercapto) benzaldehyde hydrazone;

4- (trifluoromethoxy) benzaldehyde hydrazone; pyridine-3 -carboxaldehyde hydrazone;

4- (1-pyrrolidino) benzaldehyde hydrazone;

4 -formyl-2-phenylimidazole hydrazone;

1-methyl-2-imidazolecarboxaldehyde hydrazone;

1- (phenylsuifonyl) -2 -pyrrole-carboxaldehyde hydrazone;

2-quinoline carboxaldehyde hydrazone;

4- (3-dimethylamino) propoxy) -benzaldehyde hydrazone;

2-butyl-4-formylimidazole hydrazone; 6-fluoro-veratraldehyde hydrazone;

3-dimethylamino-2, 2-dimethylpropionaldehyde hydrazone;

2 -furaldehyde hydrazone; pyrazol-3 -carboxaldehyde hydrazone; 2- (4-Methoxy-phenyl) -benzofuran-7-carbaldehyde hydrazone; 4- (5-Formyl-furan-2-yl) -benzenesulfonamide hydrazone;

1- (4-chlorophenyl) pyrrole-2-carboxaldehyde hydrazone; 2- [1-methyl-3- (trifluoromethyl) pyrazol-5-yl] thiophene-5-carboxaldehyde hydrazone; pyridine-4-carboxaldehyde hydrazone. the group R ₂ being hydrogen.

19. Chemical library of compounds according to one of claims 1 to 6, in the form of a set of compounds, these compounds being individualized, the set comprising at least 4 distinct compounds.

20. A chemical library according to claim 19, these compounds being individualized, the assembly comprising the compounds in which the groups Ri, R ₂ and R ₃ are as defined in claim 16.

21. A chemical library according to claim 19, these compounds being individualized, the assembly comprising the compounds in which the groups R _x and R ₃ are as defined in claim 18, the groups R ₂ being equal to 1 hydrogen.

22. Use of a chemical library according to one of claims 14 to 21 as a tool for screening drugs intended for the prevention or treatment of diseases in which metabolic enzymes chosen from proteases and kinases are involved. 03 1

46

23. Process for preparing the compound according to one of claims 1 to 6, comprising the following steps:

(i) coupling to an immobilized support of the compound of formula (II):

in which n has the value indicated in one of claims 1 to 6, in an immobilized reagent of formula (III):

in which the circle designates the support;

(ii) reaction of the compound of formula III with a compound of formula Ri ', Ri' being a precursor of the group

Ri, this precursor having the meaning corresponding to that of Ri as indicated in one of claims 1 to 6 in a compound of formula (IV): 47

(iii) optionally reaction of the compound of formula IV with a compound of formula R ₂ ', R ₂ ' being a precursor of the group R ₂ , this precursor having the meaning corresponding to that of R ₂ as indicated in one of the Claims 1 to 6 into a compound of formula (V):

(v) reaction of the compound of formula VI with a compound of formula R ₃ ', R ₃ ' being a precursor of the group R ₃ , this precursor having the meaning corresponding to that of R ₃ as indicated in one of the claims 1 to 6 in a compound of formula (VII):

24. The method of claim 23, wherein the reactants Ri 'and R ₂ ' are chosen from isocyanates and isothiocyanate, carboxylic acids, acid anhydrides, sulfonyl chlorides, carbamoyl chlorides, acid chlorides and chloroformates.

25. The method of claim 23 or 24, wherein the reagent R ₃ 'is selected from isocyanates and isothiocyanate, carboxylic acids, acid anhydrides, sulfonyl chlorides, carbamoyl chlorides, acid chlorides and chloroformates when the bond NR ₃ is a single bond and among aldehydes when the bond N = R ₃ is double.

26. Method for preparing a chemical library according to one of claims 14 to 21, by implementation simultaneous and / or sequential of the method according to one of claims 23 to 25 on a plurality of reagents.

27. The method of claim 26, wherein the reactants Ri 'are chosen from isocyanates and isothiocyanates, carboxylic acids, acid anhydrides, sulfonyl chlorides and the reagents R ₂ ' are chosen from acid chlorides and reactants R ₃ 'are chosen from isocyanates and isothiocyanates, carboxylic acids, acid anhydrides, sulfonyl chlorides and acid chlorides.

28. The method of claim 26, wherein the reagents Ri 'are chosen from isocyanates and isothiocyanates, carboxylic acids, acid anhydrides, sulfonyl chlorides, the reagent R ₂ ' is a white and the reagents R ₃ 'are chosen among aldehydes.