EP2129675A2

EP2129675A2 - Derivatives of imidazo, pyrimido and diazepine pyrimidine-dione, and use thereof as a drug

Info

Publication number: EP2129675A2
Application number: EP07872379A
Authority: EP
Inventors: Lydie Poitout; Valérie Brault
Original assignee: Ipsen Pharma SAS
Current assignee: Ipsen Pharma SAS
Priority date: 2006-12-18
Filing date: 2007-12-17
Publication date: 2009-12-09
Also published as: WO2008090286A3; WO2008090286A2; FR2910001B1; FR2910001A1; US20100144714A1

Abstract

The present invention relates to new derivatives of imidazo, pyrimido and diazepine-pyrimidine-dione of the general formula (I) in which R1, R2, L1, L2, Y, Z and A are various and varying groups. These products exhibit a good affinity for certain sub-types of cannabinoid receptors, in particular the CB2 receptors. They are particularly useful for treating pathological conditions and diseases in which one or more cannabinoid receptors are involved. The invention also relates to pharmaceutical compositions containing said products, and to the use thereof for preparing a drug.

Description

Derivatives of imidazo, pyrimido and diazepine pyrimidine-dione and their use as medicaments

The present application relates to new derivatives of imidazo, pyrimido and diazepine pyrimidine-dione. These products have good affinity for certain cannabinoid receptor subtypes, particularly CB2 receptors. They are particularly useful for treating disease states and diseases in which one or more cannabinoid receptors are involved. The invention also relates to pharmaceutical compositions containing said products and their use for the preparation of a medicament.

Cannabinoids are psychoactive components found in Indian cannabis (Cannabis sativa) including nearly 6 different molecules, the most represented being delta-9-tetrahydrocannabinol. The knowledge of the therapeutic activity of cannabis dates back to the ancient Chinese dynasties in which, 5000 years ago, cannabis was used for the treatment of asthma, migraines and gynecological disorders. It was in 1850 that cannabis extracts were recognized and included in the American pharmacopoeia.

Cannabinoids are known to have different effects on many functions and organs, the most important being the central nervous system and the cardiovascular system. These effects include impaired memory, euphoria, and sedation. Cannabinoids also increase the pulse rate and change the systemic blood pressure. Peripheral effects related to bronchial constriction, immunomodulation and inflammation were also observed. More recently, cannabinoids have been shown to modulate cellular and humoral immune responses and have anti-inflammatory properties. Despite all these properties, the therapeutic use of cannabinoids is controversial for its psychoactive effects (cause of dependence) but also for its multiple side effects not yet fully characterized. Although much work has been done in this area since the 1940s, there was little information on the characterization of cannabinoid receptors, the existence of endogenous ligands, and until recently on selective a particular receptor subtype. Two cannabinoid receptors have been identified and cloned, CB1 and CB2. CB1 is expressed predominantly in the central nervous system while CB2 is expressed in peripheral tissues, mainly in the immune system. These two receptors are members of the G-protein coupled receptor family and their inhibition is related to the activity of adenylate cyclase.

On the basis of all this information, there is a need for compounds capable of selectively modulating the cannabinoid receptors and thus the pathologies associated with such receptors. Thus, CB2 modulators offer a unique approach to pharmacotherapy against immune disorders, inflammation, osteoporosis, renal ischemia and other disease states. There is considerable interest in developing cannabinoid analogs having a high affinity for the CB2 receptor. Cannabinoid analogs that specifically modulate the CB2 receptor directly or indirectly can produce clinically useful effects without affecting the central nervous system thereby providing a rational therapeutic approach for a wide variety of disease states.

The novel compounds of this invention modulate CB2 activity and are therefore useful for the treatment and prevention of disease states and diseases associated with cannabinoid receptor activity such as, but not limited to, cell proliferative disorders such as cancer, immune disorders, inflammation, pain, osteoporosis, atherosclerosis, epilepsy, nausea associated with chemotherapy, fibrosis, gastrointestinal disorders, neurodegenerative diseases including multiple sclerosis, and dyskinesia, Parkinson's disease, Huntington's chorea, Alzheimer's disease but also to prevent or cure diseases associated with motor function such as Tourette's syndrome, to provide neuroprotection.

The subject of the invention is therefore compounds of general formula (I)

in racemic, enantiomeric form or any combination of these forms and in which

Li represents ^~ ^ - _D

K4; L ₂ represents ^{~ c} ^ pr ^ β

/

R 1, R ₂ , R ₃ , R ₄ , R ₅ and R ₆ represent, independently, a hydrogen atom or a hydroxy, halo, (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) haloalkyl, (C ₂ -C ₈ ) alkenyl,

(C ₂ -C ₈ ) alkynyl, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₇ ) heterocycloalkyl, (C ₁ -C ₆ ) alkoxy-

(C ₁ -C ₈ ) alkyl, (C ₁ -C ₆ ) alkylthio- (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, aralkyloxy, aralkylthio or a radical - (CH ₂ ) _P -R ₇ , all these radicals being optionally substituted with one or more identical or different substituents selected from: halo, nitro, hydroxy, oxo, amino, carboxamide, (C ₁ -C ₆ ) alkylcarbonyl, (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) haloalkyl,

(Ci-C ₈₎ alkoxy, _(Ci-C8) haloalkoxy, aryl or aryloxy;

or R 1 and R ₂ , R ₃ and R ₄ , or R ₅ and R ₆ together with the carbon atom to which they are attached form a (C ₃ -C ₈ ) cycloalkyl radical (C ₃ -C ₇ ) heterocycloalkyl, indanyl, tetrahydronaphthyl or decahydronaphthyl, these radicals being optionally substituted by one or more identical or different substituents chosen from: halo, hydroxy, (Ci-Cg) alkyl, (Ci-C ₈ ) haloalkyl, (Ci-C ₆ alkoxy;

or else finally the radicals R ₃ and R ₄ together with the neighboring radicals R 1 and R _{2 form,} on the one hand, or R ₅ and R _6, on the other hand, a cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl radical, these radicals being optionally substituted with one or more identical or different substituents selected from halo, nitro, hydroxy, amino, carboxamide, (C ₁ -C ₆ ) alkylcarbonyl, (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) haloalkyl, (C ₁ -C ₈ ) alkoxy, (C 1 -C ₈ ) haloalkoxy;

p represents 1, 2, 3 or 4;

R ₇ represents a radical -C (O) -O- (C, -C ₈ ) alkyl, -C (O) -NR _N R ¹ N, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₇ ) heterocycloalkyl, aryl or heteroaryl, all these radicals being optionally substituted by one or more identical or different substituents chosen from: halo, nitro, hydroxy, amino, (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) haloalkyl, (C ₁ -C ₈ ) C ₈ ) alkoxy, (C ₁ -C ₈ ) haloalkoxy or aralkyloxy;

RN and R'N independently represent a hydrogen atom or a (C 1 -C ₈ ) alkyl radical, (C 1 -C ₈ ) haloalkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl radical (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₇ ) heterocycloalkyl, aryl or heteroaryl;

or RN and R'N together form a (C ₃ -C ₇ ) heterocycloalkyl radical;

Z represents a nitrogen atom or a radical -CH-;

Y represents an oxygen atom, a radical -CHR ₈ or -NR ₈ ;

R ₈ represents a hydrogen atom, a (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) haloalkyl radical;

A represents a condensed, unsaturated, aromatic or nonaromatic mono- or bi-cyclic ring, optionally containing one or more identical or different heteroatoms chosen from O, S and N, and optionally substituted by one or more radicals, which may be identical or different, chosen from: halo, nitro, cyano, oxy, -XA-YA, and aryl optionally substituted with one or more substituents chosen from: halo, (dC ₆ ) alkyl and (C _r C ₆ ) haloalkyl;

XA represents a covalent bond, -O-, -S-, -C (O) -, -NR " _N -C (O) -, -C (O) -NR" _N -, -C (O) -O -, -SO ₂ - or -SO ₂ NH-;

YA represents the hydrogen atom or a (C ₁ -C ₆ ) alkyl or (C 1 -C ₆ ) haloalkyl radical;

R "N represents the hydrogen atom or a (C ₁ -C ₆ ) alkyl radical; m represents 0 or 1; n is 0 or 1;

or a pharmaceutically acceptable salt thereof.

In the definitions given above, the expression halo represents the fluoro, chloro, bromo or iodo radical, preferably chloro, fluoro or bromo. The expression (C ₁ -C ₈ ) alkyl represents an alkyl radical having from 1 to 8 carbon atoms, linear or branched, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and ter radicals. butyl, pentyl or amyl, isopentyl, neopentyl, hexyl or isohexyl, heptyl or octyl. The term (Ci-C ₆₎ alkyl is an alkyl radical having from 1 to 6 carbon atoms, linear or branched as defined above.

By (C ₂ -C 8) alkylenic is meant a linear or branched hydrocarbon radical containing from 2 to 8 carbon atoms and having at least one unsaturation (double bond), for example vinyl, allyl, propenyl, butenyl, pentenyl, hexenyl or heptenyl. (C ₂ -C ₈ ) alkynyl means a linear or branched alkyl radical having from 2 to 8 carbon atoms and having at least one double unsaturation (triple bond) such as for example an ethynyl, propargyl, butynyl or pentynyl radical.

By haloalkyl is meant an alkyl radical of which at least one of the hydrogen atoms (and possibly all) is replaced by a halogen atom (halo); in the case of several halo radicals, the latter may be identical, for example trifluoromethyl or different. The term alkylcarbonyl (or alkyl-C (O) -) refers to radicals in which the alkyl radical is as defined above, for example methylcarbonyl, ethylcarbonyl, butylcarbonyl.

The term alkoxy denotes radicals in which the alkyl radical is as defined above such as, for example, methoxy, ethoxy, propyloxy or isopropyloxy radicals, but also linear, secondary or tertiary butoxy, pentyloxy radicals. By haloalkoxy is meant an alkoxy radical at least one of the hydrogen atoms (and possibly all) is replaced by a halogen atom (halo); in the case of several halo radicals, the latter may be identical, for example trifluoromethoxy or different. Alkoxyalkyl is understood to mean a radical in which the alkoxy and alkyl radicals are as defined above, such as, for example, methoxyethyl, methoxymethyl or ethoxyethyl. The term alkylthio refers to radicals in wherein the alkyl radical is as defined above such as, for example, methylthio, ethylthio. By alkylthio-alkyl is meant a radical in which the alkylthio and alkyl radicals are as defined above such as for example methylthio-ethyl, methylthio-methyl, ethylthio-ethyl.

The term (C ₃ -C ₈ ) cycloalkyl designates a saturated carbon monocyclic system comprising from 3 to 8 carbon atoms, namely the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl rings. The expression (C ₃ -C ₇ ) heterocycloalkyl denotes a saturated monocyclic or fused bicyclic system containing from 3 to 7 carbon atoms and at least one heteroatom. This radical can contain several identical or different heteroatoms. Preferably, the heteroatoms are selected from oxygen, sulfur or nitrogen. As examples of heterocycloalkyl, mention may be made of the following rings: azetidine, pyrrolidine, imidazolidine, pyrrazolidine, isothiazolidine, thiazolidine, isoxazolidine, oxazolidine, piperidine, piperazine, morpholine, azepane (azacycloheptane), tetrahydrofuran (tetrahydrofuryl radical), tetrahydropyran, dioxane, dioxolane or tetrahydrothiophene (tetrahydrothienyl radical).

The term (C ₃ -C ₈ ) cycloalkenyl denotes an unsaturated carbon monocyclic system comprising from 3 to 8 carbon atoms and a double bond, for example cyclopentenyl or cyclohexenyl. The term (C ₃ -C ₇ ) heterocycloalkenyl denotes an unsaturated carbon monocyclic system comprising from 3 to 7 carbon atoms, a carbon-carbon double bond and one or more identical or different heteroatoms chosen from sulfur, nitrogen or oxygen such as, for example, tetrahydropyridine, tetrahydropyrimidine, dihydrofuran, dihydropyrrole, dihydrofuran or dihydrothiophene.

The term "aryl" represents an aromatic radical, consisting of a ring or condensed rings, such as, for example, the phenyl, naphthyl, fluorenyl or anthryl radical. The term heteroaryl refers to an aromatic radical, consisting of a ring or condensed rings, with at least one ring containing one or more identical or different heteroatoms selected from sulfur, nitrogen or oxygen. As an example of a heteroaryl radical, mention may be made of the following radicals: pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, quinolyl, isoquinolyl, quinoxalinyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxadiazoyl, carbazolyl, phenoxazinyl, thienopyridinyl (thieno [2,3-b] pyridine, thieno [3,2-b] pyridine, thieno [2,3-pyridyridine, thieno [3,2-c] pyridine, thieno [3,4-b] pyridine, thieno [3,4-c] pyridine), thieno-pyrazinyl (thieno [2,3] pyrazine, thieno [3,4-b] pyrazine), thienyl, benzothienyl, furyl, benzofuryl, dihydrobenzofuryl, thioxanthenyl, pyranyl, benzopyranyl, dibenzopyrazinyl, acridinyl.

The term aryloxy preferably denotes radicals in which the aryl radical is as defined above; an example of aryloxy is phenoxy or naphthyloxy.

The term aralkoxy (aralkyl-oxy or aryl-alkoxy) preferably denotes radicals in which the aryl and alkoxy radical are as defined above, such as, for example, benzyloxy or phenethyloxy. The term aralkylthio (or aryl-alkylthio) preferably denotes radicals in which the aryl and alkylthio radical are as defined above, such as for example benzylthio.

The term fused, unsaturated aromatic mono- or bi-cyclic radical can be illustrated either by the aryl radical as defined above when said aromatic radical does not contain a heteroatom, or by the heteroaryl radical as defined above. above when said aromatic radical contains at least one heteroatom.

The expression mono- or bi-cyclic radical condensed, unsaturated, non-aromatic, and containing no heteroatom, can be illustrated by cyclopentenyl or cyclohexenyl.

The expression condensed mono- or bi-cyclic radical, unsaturated, nonaromatic and containing at least one heteroatom, can be illustrated by the heteroaryl radicals as defined above and in which at least one double bond is hydrogenated. Examples which may be mentioned are the radicals associated with the following cycles: dihydroindolyl, dihydrothiophene (2,5-dihydrothiophene, 2,3-dihydrothiophene), tetrahydropyridine (2,3,4,5-tetrahydropyridine, 1,2,3,6 tetrahydropyridine

1, 2,3,4-tetrahydropyridine), tetrahydro-thieno-pyridine (4,5,6,7-tetrahydro-thieno [3,2-b] pyridine, 4,5,6,7-tetrahydro-thieno [2 , 3-c] pyridine, 4,5,6,7-tetrahydro-thieno [3,2-c] pyridine), tetrahydropyrimidine (2,3,4,5-tetrahydropyrimidine,

1,2,3,4-tetrahydropyrimidine, 1,4,5,6-tetrahydropyrimidine), tetrahydrobenzothiophene (4,5,6,7-tetrahydro-1-benzothiophene), dihydrocyclopentathiophene (5,6-dihydro-4H-cyclopenta [b] thiophene, benzodioxole, dihydro-benzodioxine.

The present invention more particularly relates to compounds of formula I as defined above characterized in that A represents a ring selected from: phenyl, naphthyl, thienyl, furyl, pyrrolyl, benzothienyl, benzofuryl, thienopyridinyl, indolyl and tetrahydrobenzo-thienyl; or a pharmaceutically acceptable salt thereof.

The present invention more particularly relates to compounds of formula I as defined above characterized in that A is optionally substituted by one or more radicals, identical or different, chosen from: halo, nitro, -X _A -Y _A and phenyl;

X _A represents a covalent bond, -O- or -C (O);

Y _A represents a hydrogen atom or a radical (Ci-C ₆₎ alkyl or (Ci-C ₆₎ haloalkyl; or a pharmaceutically acceptable salt thereof.

Very preferably, A represents a phenyl radical optionally substituted by one or more radicals (Ci-C ₆₎ alkyl or (Ci-C ₆₎ alkoxy same or different; or a pharmaceutically acceptable salt thereof.

The present invention more particularly relates to compounds of formula I as defined above, characterized in that Z represents a nitrogen atom; or a pharmaceutically acceptable salt thereof.

The present invention more particularly relates to compounds of formula I as defined above characterized in that Y represents the -NR ₈ radical and R ₈ represents a (C ₁ -C ₆ ) alkyl radical; or a pharmaceutically acceptable salt thereof.

The present invention more particularly relates to compounds of formula I as defined above characterized in that they correspond to the following formula:

or a pharmaceutically acceptable salt thereof.

The present invention more particularly relates to compounds of formula I as defined above characterized in that n represents 0; or a pharmaceutically acceptable salt thereof.

The present invention more particularly relates to compounds of formula I as defined above characterized in that m represents 0; or a pharmaceutically acceptable salt thereof.

The present invention more particularly relates to compounds of formula I as defined above characterized in that

m and n represent 0;

Ri represents the hydrogen atom;

R ₂ represents a hydrogen atom or a radical (C) -C ₈₎ alkyl, (C ₃ -C ₈₎ cycloalkyl, (C ₃ -C ₇₎ heterocycloalkyl, aryl optionally substituted with aryl, heteroaryl, or a radical - (CH ₂ ) _P -R ₇ ;

p represents 1 or 2;

R ₇ represents a (C ₃ -C ₈ ) cycloalkyl or aryl radical;

or R ₁ and R ₂ together with the carbon atom to which they are attached form a (C ₃ -C ₈ ) cycloalkyl or an indanyl radical; and preferentially

Ri represents the hydrogen atom;

R ₂ represents a (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, tetrahydropyranyl, naphthyl, phenyl optionally substituted with a phenyl, thienyl or a - (CH ₂ ) _p -R ₇ radical;

p represents 1 or 2;

R ₇ represents a cyclohexyl or phenyl radical;

or R 1 and R ₂ together with the carbon atom to which they are attached form a (C ₃ -C ₈ ) cycloalkyl or an indanyl radical; or a pharmaceutically acceptable salt thereof.

The present invention more particularly relates to compounds of formula I as defined above characterized in that m represents 1; or a pharmaceutically acceptable salt thereof.

n is 0 and m is 1;

- or R 1, R ₂ , R ₃ and R ₄ represent, independently, a hydrogen atom;

- or R ₃ and R ₄ represent, independently, a hydrogen atom; and

. Ri represents the hydrogen atom; R ₂ represents a (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, tetrahydropyranyl, phenyl radical, or a radical - (CH ₂ ) _P -R ₇ ; p represents 1 or 2 and R ₇ represents a cyclohexyl or phenyl radical; or

. R 1 and R ₂ represent, independently, a (C ₁ -C ₈ ) alkyl radical; or

. R 1 and R ₂ together with the carbon atom to which they are attached form a (C ₃ -C ₈ ) cycloalkyl. either R 1 and R ₂ represent, independently, a hydrogen atom;

. R ₃ represents the hydrogen atom; R ₄ represents a radical (C) -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, tetrahydropyranyl, phenyl, or a radical - (CH ₂ ) _P -R ₇ ; p represents 1 or 2 and R ₇ represents a cyclohexyl radical; or

. R ₃ and R ₄ represent, independently, a (C ₁ -C ₈ ) alkyl radical; or

. R ₃ and R ₄ together with the carbon atom to which they are attached form a (C ₃ -C 8) cycloalkyl.

or the radicals R ₃ and R ₄ together with the neighboring radicals R 1 and R _{2 form} a phenyl radical; or a pharmaceutically acceptable salt thereof.

The present invention more particularly relates to compounds of formula I as defined above characterized in that n and m represent 1; or a pharmaceutically acceptable salt thereof.

n and m represent 1;

R 1, R ₂ , R ₅ and R ₆ represent, independently, a hydrogen atom or a (C 1 -C ₈ ) alkyl radical;

R ₃ and R ₄ independently represent a hydrogen atom or together with the carbon atom to which they are attached form a (C ₃ -C ₈ ) cycloalkyl; or a pharmaceutically acceptable salt thereof.

In the present application, the symbol -> * corresponds to the point of attachment of the radical. When the site of attachment is not specified on the radical, it means that the attachment is made on one of the available sites of this radical for such attachment. According to the definitions of the variable groups A, Y, Z, Ri, R _2, R _3, R _4, R _5, R ₆ and R _7, the compounds of the invention may be prepared according to the procedures A to E described below below:

Preparation according to reaction scheme A (where m and n represent 0):

As described in Scheme A, the α-amino ester (2) can react with an ortho ester isothiocyanate (1) in a polar solvent such as methanol in the presence or absence of a tertiary amine such as triethylamine. a temperature of 18 to 50 ° C, for 3 to 24 hours to yield the thioxo-pyrimidinone derivative (3). The derivative (3) can be chlorinated by reaction with phosphorus oxychloride in the presence or absence of phosphorus pentachloride, at room temperature or heated in a microwave at a temperature of 100 to 150 ° C. The chlorinated derivative ( 4) can react with the amine (5) in an aprotic solvent such as tetrahydrofuran in the presence or absence of an inorganic base or a tertiary amine such as triethylamine, at room temperature or well heated under microwaves at a temperature of 80 to 120 ° C to yield the imidazo-pyrimidine-dione derivative (6). Example A1: 1 '- [4- (4-methylpiperazin-1-yl) benzyl] -2'H-spiro [cyclopentane-1,3'-imidazo [2,1-b] quinazoline] -2' hydrochloride 5 '(rH) -dione

Step 1: Methyl 1- (4-oxo-2-thioxo-1,4-dihydroquinazolin-3 (2H) -yl) cyclopentanecarboxylate

A mixture of methyl hydrochloride 1-aminocyclopentanecarboxylate (1 g), methyl 2-isothiocyanatobenzoate (1.18 g) and triethylamine (15 ml) in methanol (60 ml) is stirred at room temperature for 20 h and then concentrated under reduced pressure at 40 ° C. The solid obtained is supplemented with dichloromethane and water. After decantation and extractions, the combined organic phases are washed with brine, dried over Na ₂ SO ₄ and then concentrated under reduced pressure at 40 ° C. Purification by flash chromatography on silica gel (eluent: heptane / ethyl acetate 7: 3-6: 4) gives the expected compound as a powder (1.08 g, 64% yield).

MS / CL: calculated MM = 304.4; m / z = 305.2 (MH +)

NMR ^(1H, 400 MHz, _DMSO-6 Û?): S 1.76 to 1.95 (m, 6H), 2.07 (m, 2H), 3.73 (s, 3H), 7.42 (AB, 1H), 7.60 (m, 1H), 7.74 (m, 1H), 7.99 (AB, 1H), 10.8 (s, 1H).

Step 2: Methyl 1- (2-chloro-4-oxoquinazolin-3 (4H) -yl) cyclopentanecarboxylate

To a suspension of methyl 1- (4-oxo-2-thioxo-1,4-dihydroquinazolin-3 (2H) -yl) cyclopentanecarboxylate (500 mg) in phosphorus oxychloride (2 mL) is added phosphorus pentachloride. (375 mg). The mixture is stirred at ambient temperature for 18 hours and then concentrated under reduced pressure at 40 ° C. The residue is treated with dichloromethane and water. After decantation and extractions, the combined organic phases are washed with brine, dried over Na ₂ SO ₄ then concentrated under reduced pressure at 40 ° C to yield the expected product as a yellow oil, used in the next step without further purification.

Step 3: r- [4- (4-methylpiperazin-1-yl) benzyl] -2'H-spiro [cyclopentane-1,3'-imidazo [2,1-ό] quinazoline] -2 'hydrochloride (rH) -dione

To methyl l- (2-chloro-4-oxoquinazolin-3 (4H) -yl) cyclopentanecarboxylate (520 mg) in anhydrous THF (2 mL) was placed in a reaction tube "Biotage ^®", is added [4- ( 4-methylpiperazin-1-yl) benzyl] amine (950 mg). The reaction tube is sealed with a cap, stirred at room temperature for 1 hour and then placed in the microwave "Biotage ^®" and heated with magnetic stirring at 100 ° C for 1 hour. The mixture is concentrated under reduced pressure at 40 ° C. Purification by flash chromatography on silica gel (eluent: dichloromethane / methanol 95: 5) gives the expected compound in free base form. The corresponding hydrochloride salt is formed by adding 1N HCl solution in ethyl ether to the solution of the free base in ethyl acetate. The precipitate obtained is filtered and dried to give the expected hydrochloride compound (235 mg, 27% yield from step 2).

MS / CL: calculated MM = 443.5; m / z = 444.3 (MH +)

NMR ^(1H, 400 MHz, CDCl _3): δ 2.07 (s, 2H), 2.19 (s, 6H), 2.90 (s, 3H), 3.61 (m, 6H), 4 , 0.6 (m, 2H), 5.55 (s, 2H), 7.27 (m, 2H), 7.46 (m, 1H), 7.77 (m, 3H), 8.24 (AB, 1H), 8.68 (AB, 1H), 13.35 (s, 1H).

Example A2: 3-Isobutyl-1- [4- (4-methylpiperazin-1-yl) benzyl] imidazo [2,1- [6] quinazolin-2,5 (1H, 3H) -dione hydrochloride

Step 1: Methyl 4-methyl-2- (4-oxo-2-thioxo-1,4-dihydroquinazolin-3 (2H) -yl) pentanoate

A mixture of methyl leucinate hydrochloride (2 g), methyl

2-isothiocyanatobenzoate (2 g) and triethylamine (20 ml) in methanol (60 ml) is stirred at room temperature for 24 h and then concentrated under reduced pressure at 40 ° C.

The solid obtained is added with dichloromethane and water. After decantation and extractions, the combined organic phases are washed with brine, dried over Na ₂ SO ₄ and then concentrated under reduced pressure at 40 ° C. Purification by flash chromatography on silica gel (eluent: heptane 100% to heptane / ethyl acetate 4: 6) gives the expected compound as a white foam (3.4 g, 92% yield).

MS / CL: calculated MM = 306.4; m / z = 307.2 (M +)

NMR ^(1H, 400 MHz, DMSO- ^ _5): δ 0.85 (d, 3H), 0.95 (d, 3H), 1.67 (s, IH), 1.83 (s, IH) 2.18 (m, 1H), 3.59 (s, 3H), 6.54 (s, 1H), 7.35 (t, 1H), 7.41 (d, 1H), t, 1H), 7.93 (d, 1H).

Step 2: methyl 2- (2-chloro-4-oxoquinazolin-3 (4H) -yl) -4-methylpentanoate

To a solution of methyl 4-methyl-2- (4-oxo-2-thioxo-1,4-dihydroquinazolin-3 (2H) -yl) pentanoate (3.4 g) in phosphorus oxychloride (20 mL) ) is added phosphorus pentachloride (2.5 g). The mixture is stirred at ambient temperature for 20 hours and then concentrated under reduced pressure at 40 ° C. The residue is treated with dichloromethane and water. After decantation and extractions, the combined organic phases are washed with brine, dried over Na ₂ SO ₄ and then concentrated under reduced pressure at 40 ° C. to yield the expected product in the form of a yellow oil, used in the next step without further purification.

NMR ^(1H, 400 MHz, DMSO- ^ _6): δ 0.86 (d, 3H), 0.95 (d, 3H), 1.57 (m, IH), 1.99 (m, IH) , 2.20 (m, 1H), 3.65 (s, 3H), 7.62 (t, 1H), 7.67 (d, 1H), 7.91 (t, 1H), 8.12 ( d, 1H). Step 3: 3-Isobutyl-1- [4- (4-methylpiperazin-1-yl) benzyl] imidazo [2,1-b] quinazolin-2,5 (1H, 3H) -dione hydrochloride

To methyl 2- (2-chloro-4-oxoquinazolin-3 (4H) -yl) -4-methylpentanoate (150 mg) in anhydrous THF (2 mL) placed in a "Biotage ^® " reaction tube is added the [ 4- (4-methylpiperazin-1-yl) benzyl] amine (194 mg). The reaction tube is sealed with a cap, stirred at room temperature for 1 hour and then placed in the microwave "Biotage ^®" and heated with magnetic stirring at 150 ° C for 1 hour. The mixture is concentrated under reduced pressure at 40 ° C. Purification by flash chromatography on silica gel (eluent: dichloromethane / methanol 95: 5) gives the expected compound in free base form. The corresponding hydrochloride salt is formed by adding 1N HCl solution in ethyl ether to the solution of the free base in ethyl acetate. The precipitate obtained is filtered and dried to give the expected hydrochloride compound (145 mg, 60% yield from step 2).

MS / LC: MM calcd = 445.6; m / z = 446.3 (MH +)

NMR ^(1H, 400 MHz, DMSO-D _6): £ 0.81 (m, 6H), 1.80 (m, IH), 2.01 (m, 2H), 2.77 (s, 3H) , 3.06 (m, 4H), 3.40 (m, 2H), 3.77 (m, 2H), 4.79 (AB, 1H), 4.81 (AB, 1H), 4.93 (m.p. t, 1H), 6.96 (AB, 1H), 7.32 (AB, 1H), 7.42 (t, 1H), 7.57 (AB, 1H), 7.76 (t, 1H), 8.08 (AB, 1H), 10.96 (s, 1H).

In a similar manner to the procedure described for [4- (4-methylpiperazin-1-yl) benzyl] -2'H-spiro [cyclopentane-1,3'-imidazo [2,1-ejquinazoline] hydrochloride] 2 ', 5' (1H) -dione and 3-isobutyl-1- [4- (4-methylpiperazin-1-yl) benzyl] imidazo [2,1-b] quinazolin-2 hydrochloride , 5 (1H, 3H) -dione, the following compounds were prepared:

in which R ₂ represents the hydrogen atom and R 1 represents one of the radicals below:

or in which R 1 and R ₂ represent the same radical chosen from methyl, propyl and butyl;

or in which R 1 and R ₂ together form one of the following radicals:

and in which / z- # γ ~~~ _\ represents one of the following radicals

rΛA / Preparation according to reaction scheme B (where m and n represent 0):

As described in Scheme B, the methylglycinate (7) can react with an ortho ester isothiocyanate (1) in a polar solvent such as methanol in the presence or absence of a tertiary amine such as triethylamine at a temperature of 18 to 50 ° C, for 3 to 24 hours to yield the thioxo-pyrimidinone derivative (8). The derivative (8) can be chlorinated by reaction with phosphorus oxychloride in the presence or absence of phosphorus pentachloride, at room temperature or heated in a microwave at a temperature of 100 to 150 ° C. The chlorinated derivative (9 ) can react with the amine (5) in an aprotic solvent such as tetrahydrofuran in the presence or absence of an inorganic base or a tertiary amine such as triethylamine, at room temperature or heated under microwaves at a temperature of temperature of 80 to 120 ° C to yield the imidazo-pyrimidine-dione derivative (10). The derivative (10) can be treated with a strong base such as lithium diisopropylamine followed by alkylation with a halogen derivative. The reaction may be repeated with a second halogen derivative to yield derivative (11). Preparation according to Reaction Scheme C (where m is 1 and n is 0)

As described in Scheme C, the β-amino ester (12) can react with an ortho ester isothiocyanate (1) in a polar solvent such as methanol in the presence of a tertiary amine such as triethylamine at a temperature of 18 to 50 ° C, for 3 to 96 hours to yield the thioxo-pyrimidinone derivative (13). The derivative (13) can be chlorinated by reaction with phosphorus oxychloride in the presence or absence of phosphorus pentachloride, at room temperature or heated under microwave at a temperature of 100 to 150 ° C. The chlorinated derivative (14 ) can react with the amine (5) in an aprotic solvent such as tetrahydrofuran or dimethylformamide, in the presence of an inorganic base or a tertiary amine such as triethylamine, at a temperature of 80 to 120 ° C for to the pyrimido-pyrimidine-dione derivative (15).

Example C1: 4,4-dimethyl-1- [4- (4-methylpiperazin-1-yl) benzyl] -3,4-dihydro-2H-pyrimido [2,1- [6] quinazoline-2,6 hydrochloride ( lH) -dione

Step 1: Methyl 3-methyl-3- (4-oxo-2-thioxo-1,4-dihydroquinazolin-3 (2H) -yl) butanoate

To a solution cooled to 0 ° C, 3-amino-3-methylbutanoic acid (1 g) in methanol (8 mL) is added thionyl chloride (1.56 mL). The mixture is stirred for 10 min at 0 ° C. and then brought to room temperature and heated at reflux for

3 hours. The mixture is then concentrated under reduced pressure at 40 ° C. and the oily residue is then added with dichloromethane and concentrated again under reduced pressure at 40 ° C. This co-evaporation is repeated several times until the methyl-3-aminomethylamine is obtained. 3-methylbutanoate as a solid (1.83 g, quantitative yield). To a solution of methyl 3-amino-3-methylbutanoate (1.43 g) in methanol (4 mL) are added triethylamine (10 mL) and then a solution of methyl 2-isothiocyanatobenzoate (1.65 g) in methanol. (2 mL) The mixture is agitated

4 days at room temperature and filtered. The solid obtained is washed with a minimum of methanol and then with diethyl ether and then dried to give the expected compound in the form of a white powder (1.2 g, 48% yield).

MS / CL: calculated MM = 292.1; m / z = 293.1 (M +)

NMR ^(1H, 400 MHz, DMSCW ₆₎ - δ 1.36 (s, 3H), 1.40 (s, 3H), 2.76 (dd, 2H), 3.75 (s, 3H), 7 23 (AB, 1H), 7.48 (t, 1H), 7.63 (t, 1H), 7.94 (AB, 1H), 9.98 (s, 1H).

Step 2: Methyl 3- (2-chloro-4-oxoquinazolin-3 (4H) -yl) -3-methylbutanoate

To a suspension of methyl 3-methyl-3- (4-oxo-2-thioxo-1,4-dihydroquinazolin-3 (2H) -yl) butanoate (146 mg) in phosphorus oxychloride (2 mL) is added phosphorus pentachloride (200 mg). The mixture is stirred at ambient temperature for 18 hours and then concentrated under reduced pressure at 40 ° C. The residue is treated with dichloromethane and water. After decantation and extractions, the combined organic phases are washed with brine, dried over Na ₂ SO ₄ and then concentrated under reduced pressure at 40 ° C. to yield the expected product in the form of a colorless oil, used in the next step without further purification. Step 3: 4,4-dimethyl-1- [4- (4-methylpiperazin-1-yl) benzyl] -3,4-dihydro-2H-pyrimido [2,1-d] quinazolin-2,6-hydrochloride ( 1 H) -dione

Methyl 3- (2-chloro-4-oxoquinazolin-3 (4H) -yl) -3-methylbutanoate (146 mg) in anhydrous DMF (5 mL) is supplemented with [4- (4-methylpiperazin) -1- yl) benzyl] amine (205 mg) followed by potassium carbonate (170 mg). The mixture is heated at 120 ° C. for 6 hours and then concentrated under reduced pressure at 40 ° C. The residue is treated with dichloromethane and water. After decantation and extractions, the combined organic phases are washed with brine, dried over Na ₂ SO ₄ and then concentrated under reduced pressure at 40 ° C. Purification by flash chromatography on silica gel (eluent: dichloromethane / methanol 95: 5 ) gives the expected compound as a free base. The corresponding hydrochloride salt is formed by adding 1N HCl solution in ethyl ether to the solution of the free base in ethyl acetate. The precipitate obtained is filtered and dried to give the expected hydrochloride compound (50 mg, 20% yield from step 2).

MS / LC: M calculated = 431.2; m / z = 432.3 (M +)

NMR ^(1H, 400 MHz, DMSO-D _6): δ 1.63 (s, 6H), 2.77 (d, 3H), 2.98 (m, 4H), 3.11 (m, 2H) , 3.42 (d, 2H), 3.74 (d, 2H), 5.17 (s, 2H), 6.90 (AB, 1H), 7.25 (AB, 1H), 7.38 (b, 2H), t, 1H), 7.48 (AB, 1H), 7.74 (t, 1H), 8.0 (AB, 1H), 10.43 (s, 1H).

In a similar manner to the procedure described for 4,4-dimethyl-1- [4- (4-methylpiperazin-1-yl) benzyl] -3,4-dihydro-2H-pyrimido [2,1-o] hydrochloride 2,6-Quinazolin (1H) -dione, 5- [4- (4-methylpiperazin-1-yl) benzyl] -7,8-dihydro-6H-pyrimido [1,2-a] hydrochloride were prepared. ] thieno [3,2-c] pyrimidine-6,10 (5H) -dione and the following compounds:

in which R ₂ , R ₃ and R ₄ represent the hydrogen atom and R 1 represents one of the following radicals:

in which R 1, R ₂ and R ₃ represent the hydrogen atom and R ₄ represents the benzyl radical;

in which R 1, R ₂ , R ₃ and R ₄ represent the hydrogen atom;

in which R 1 and R ₂ represent the hydrogen atom and R ₃ and R ₄ represent the methyl radical.

Example C2: 6- [4- (4-methylpiperazin-1-yl) benzyl] -5H-quinazolino [3,2-α] quinazolin-5,12 (6H) -dione hydrochloride

Step 1: methyl 2- (4-oxo-2-thioxo-1,4-dihydroquinazolin-3 (2H) -yl) benzoate

A mixture of methyl 2-aminobenzoate (0.76 g) and methyl 2-isothiocyanatobenzoate (1.1 g) in methanol (2 mL) and triethylamine (2 mL) was stirred at room temperature for 24 hours. The precipitate formed is filtered and washed with methanol and then with ethyl ether and then dried to give the expected compound in the form of a white powder (0.6 g, 36% yield).

MS / CL: calculated MM = 312.3; m / z = 313.2 (M +)

NMR ^(1H, 400 MHz, DMSO-D _6): δ 3.65 (s, 3H), 7.31 to 8.07 (m, 8H), 13.05 (s, IH). Step 2: methyl 2- (2-chloro-4-oxoquinazolin-3 (4H) -yl) benzoate

To a suspension of methyl 2- (4-oxo-2-thioxo-1,4-dihydroquinazolin-3 (2H) -yl) benzoate (160 mg) in phosphorus oxychloride (2 mL) is added phosphorus pentachloride. (200 mg). The mixture is stirred at ambient temperature for 18 hours and then concentrated under reduced pressure at 40 ° C. The residue is treated with dichloromethane and water. After decantation and extractions, the combined organic phases are washed with brine, dried over Na ₂ SO ₄ and then concentrated under reduced pressure at 40 ° C. to yield the expected product in the form of a colorless oil, used in the next step without further purification.

MS / CL: calculated MM = 314.1; m / z = 315.2 (M +)

Step 3: 6- [4- (4-methylpiperazin-1-yl) benzyl] -5H-quinazolino [3,2-α] quinazolin-5,12 (6H) -dione hydrochloride

A solution of methyl 2- (2-chloro-4-oxoquinazolin-3 (4H) -yl) benzoate (170 mg) and [4- (4-methylpiperazin-1-yl) benzyl] amine (200 mg) in a THF / DCM / Et ₃ N mixture (1 mL / 1 mL / 1 mL) is stirred for 4 days at room temperature and then added with water and dichloromethane. After decantation and extractions, the combined organic phases are washed with brine, dried over Na ₂ SO ₄ and then concentrated under reduced pressure at 40 ° C. Purification by flash chromatography on silica gel (eluent: dichloromethane / methanol 100: 0 at 92: 8) gives the expected compound as a free base. The corresponding hydrochloride salt is formed by adding 1N HCl solution in ethyl ether to the solution of the free base in ethyl acetate. The precipitate obtained is filtered and dried to give the expected hydrochloride compound (85 mg, 36% yield from step 2).

MS / LC: MM calcd = 431.2; m / z = 432.3 (MH +)

NMR ^(1H, 400 MHz, DMSO- ^ _6): δ 2.83 (d, 3H), 3.12 (m, 4H), 3.48 (d, 2H), 3.81 (d, 2H) , 5.55 (s, 2H), 6.98 (AB, 2H), 7.55 (m, 3H), 7.66 (m, 2H), 7.90 (m, 2H), 8.25 (m, 2H), AB, 1H), 8.31 (AB, 1H), 9.11 (AB, 1H), 10.75 (s, 1H). Preparation according to reaction scheme D (where m and n represent 1)

16 17 18

As described in Scheme D, the γ-amino ester (16) can react with an isothiocyanate ortho ester (1) in a polar solvent such as methanol in the presence of a tertiary amine such as triethylamine at a temperature of 18 to 50 ° C, for 3 to 96 hours to yield the thioxo-pyrimidinone derivative (17). The derivative (17) can be chlorinated by reaction with phosphorus oxychloride in the presence or absence of phosphorus pentachloride, at room temperature or heated under microwave at a temperature of 100 to 150 ° C to yield the derivative (18). ). The chlorinated derivative 18 can react with the amine (5) in an aprotic solvent such as tetrahydrofuran, in the presence or absence of an organic base such as triethylamine, at room temperature or else heated under microwaves at a temperature of 80.degree. at 120 ° C to yield derivative (19). The ester (19) is then saponified in the presence of a base such as sodium hydroxide, potassium hydroxide, potassium tert-butoxide or lithium hydroxide in an aprotic solvent such as tetrahydrofuran or in a protic solvent such as methanol, at a temperature of 18 to 80 ° C, for 2 to 24 hours to yield the corresponding acid (20). The derivative (20) may be treated with a coupling agent such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) or carbonyldiimidazole (CDI) with or without 1-hydroxybenzotriazole (HOBt), or with Mukayiama reagent (2-chloro-1-methyl-pyridinium chloride) in the presence of an amine tertiary amine such as triethylamine or diisopropylethylamine, in an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide at room temperature for 3 to 24 hours or alternatively heated under microwave at a temperature of 80 to 120 ° C (equipment Biotage®), in a sealed tube, for 10 to 30 minutes, to give the derivative (21).

Example D1: 1- [4- (4-Methylpiperazin-1-yl) benzyl] -4,5-dihydro [1,3] diazepino [2,1- 6] quinazolin-2,7 (1H, 3H) hydrochloride -dione

Step 1: Methyl 4- (4-oxo-2-thioxo-1,4-dihydroquinazolin-3 (2H) -yl) butanoate

To a solution of methyl 4-aminobutanoate (2 g) in methanol (5 mL) are added triethylamine (5 mL) and then methyl 2-isothiocyanatobenzoate (1.65 g). The mixture is stirred for 24 hours at ambient temperature and then filtered. The solid obtained is washed with a minimum of methanol and then with diethyl ether and then dried to give the expected compound in the form of a white powder (3.1 g, 86% yield).

MS / LC: MM calcd = 278, 1; m / z = 279, 1 (M +)

NMR ^(1H, 400 MHz, DMSO-D _6): δ 1.96 (t, 2H), 2.38 (t, 2H), 3.54 (s, 3H), 4.43 (t, 2H) 7.31 (t, 1H), 7.36 (AB, 1H), 7.71 (t, 1H), 7.95 (AB, 1H), 12.88 (s, 1H).

Step 2: Methyl 4- (2-chloro-4-oxoquinazolin-3 (4H) -yl) butanoate

To a suspension of methyl 4- (4-oxo-2-thioxo-1,4-dihydroquinazolin-3 (2H) -yl) butanoate (139 mg) in phosphorus oxychloride (2 mL) is added phosphorous pentachloride. (200 mg). The mixture is stirred at ambient temperature for 18 hours and then concentrated under reduced pressure at 40 ° C. The residue is treated with dichloromethane and water. After settling and extractions, the organic phases combined were washed with brine, dried over Na ₂ SO ₄ and then concentrated under reduced pressure at 40 ° C to yield the expected product as a colorless oil, used in the next step without further purification.

MS / CL: MM calcd = 280.1; m / z = 281.1 (MH +)

Step 3: Methyl 4- [2 - {[4- (4-methylpiperazin-1-yl) benzyl] amino} -4-oxoquinazolin-3 (4H) -yl] butanoate

To a solution of methyl 4- (2-chloro-4-oxoquinazolin-3 (4H) -yl) butanoate (140 mg) in tetrahydrofuran (3 mL) are successively added triethylamine (0.4 mL) and [4 (4-methylpiperazin-1-yl) benzyl] amine (300 mg). The mixture is stirred at room temperature for 24 hours and then added with water and ethyl acetate. After decantation and extractions, the combined organic phases are washed with brine, dried over Na ₂ SO ₄ then concentrated under reduced pressure at 40 ° C. Purification by flash chromatography on silica gel (eluent: dichloromethane / methanol 95: 5 ) gives the expected compound as beige crystals (131 mg, 58% yield from step 1).

MS / CL: MM calculated = 449.2; m / z = 450.2 (M +)

NMR ^(1H, 400 MHz, DMSO-D _6): δ 1.85 (t, 2H), 2.21 (s, 3H), 2.40 (m, 6H), 3.08 (m, 4H) , 3.54 (s, 3H), 4.05 (t, 2H), 4.54 (d, 2H), 6.86 (AB, 2H), 7.08 (t, 2H), 7.18 ( AB, 1H), 7.25 (AB, 2H), 7.48 (t, 1H), 7.52 (t, 1H), 7.89 (AB, 1H).

Step 4: 4- [2 - {[4- (4-methylpiperazin-1-yl) benzyl] amino} -4-oxoquinazolin-3 (4H) -yl] butanoic acid

To a suspension of potassium tertbutylate (50 mg) in tetrahydrofuran (2 mL) is added a solution of 4- [2 - {[4- (4-methylpiperazin-1-yl) benzyl] amino} -4-oxoquinazolin Methyl 3- (4H) -yl] butanoate (100 mg) in tetrahydrofuran (2 mL). The mixture is stirred at room temperature for 2 hours and then concentrated under reduced pressure at 40 ° C. The residue is treated with water and dichloromethane. After decantation, the aqueous phase is acidified with acetic acid and then extracted several times with dichloromethane. The combined organic phases are washed with brine, dried over Na ₂ SO ₄ and then concentrated under reduced pressure at 40 ° C. The acid thus obtained is dried and used in the next step without further purification (77 mg, 81% yield).

MS / LC: MM calcd = 435.2; m / z = 436.3 (MH +)

Step 5: 1- [4- (4-methylpiperazin-1-yl) benzyl] -4,5-dihydro [1,3] diazepino [2,1-e] quinazoline-2,7 (1H, 3H) hydrochloride -dione

To a solution of 4- [2 - {[4- (4-methylpiperazin-1-yl) benzyl] amino} -4-oxoquinazolin-3 (4H) -yl] butanoic acid (70 mg) in dichloromethane (3mg). ml) are successively added the hydrochloride of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC) (62 mg), 1-hydroxybenzotriazole (ΗOBt) (44 mg) and diisopropylethylamine (115 μl). The mixture is stirred at ambient temperature for 24 hours and then water and dichloromethane are added. After decantation and extractions, the combined organic phases are washed with brine, dried over Na ₂ SO ₄ and then concentrated under reduced pressure at 40 ° C. Purification by flash chromatography on silica gel (eluent: dichloromethane / methanol 95: 5 ) gives the expected compound as a free base. The corresponding hydrochloride salt is formed by adding 1N HCl solution in ethyl ether to the solution of the free base in ethyl acetate. The precipitate obtained is filtered and dried to give the expected hydrochloride compound (21 mg, 30% yield).

MS / CL: calculated MM = 417.2; m / z = 418.3 (M +)

NMR ^(1H, 400 MHz, CDCl _3): δ 2.19 (t, 2H), 2.65 (m, 2H), 2.85 (d, 3H), 3.02 (m, 2H), 3 , 12 (m, 2H), 3.50 (d, 2H), 3.83 (d, 2H), 4.20 (m, 2H), 5.12 (s, 2H), 6.96 (AB, 2H), 7.31 (AB, 2H), 7.57 (m, 1H), 7.70 (AB, 1H), 7.89 (m, 1H), 8.16 (AB, 1H), 10, 5 (s, 1H).

In a similar manner to the procedure described for 1- [4- (4-methylpiperazin-1-yl) benzyl] -4,5-dihydro [1,3] diazepino [2,1- [6] quinazolin-2 hydrochloride, 7 (1H, 3H) -dione, [4- (4-methylpiperazin-1-yl) benzyl] spiro [cyclohexane-1,4 '- [1,3] diazepino [2,1-] hydrochloride; quinazoline] -2 ', 7' (H, 3'H) -dione was prepared. Preparation according to reaction scheme E (where Z represents a nitrogen atom and Y represents -NR ₈ ):

As described in Scheme E, the chlorinated derivative (22) may react with the amine (23) in an aprotic solvent such as tetrahydrofuran in the presence or absence of an inorganic base or a tertiary amine such as triethylamine, at room temperature or heated under microwave at a temperature of 80 to 120 ° C to yield derivative (24). The Λf-Boc derivative (24) can be deprotected by acid treatment such as hydrogen chloride or trifluoroacetic acid in an aprotic solvent such as dichloromethane or dioxane for 1 to 4 hours, at room temperature, to lead to derivative (25). The piperazine (25) can be alkylated by a halogenated reagent in the presence of an inorganic base or a tertiary amine such as triethylamine in an aprotic solvent such as tetrahydrofuran, at room temperature or alternatively can be treated with an aldehyde followed reducing the imine by a reducing agent such as sodium cyanoborohydride to yield the derivative (26). Example E1 1- [4- (4-ethylpiperazin-1-yl) benzyl] hydrochloride

3-isobutylimidazo [2, l-Z>] quinazoline-2,5 (lH, 3H) -dione

Step 1: tert-Bu [4- {4 - [(3-isobutyl-2,5-dioxo-2,3-dihydroimidazo [2,1-b] quinazolin-1 (5H) -yl) methyl] phenyl } piperazine-1-carboxylate

To a solution of methyl 1- (2-chloro-4-oxoquinazolin-3 (4H) -yl) cyclopentanecarboxylate (prepared according to example A2, 620 mg) in THF (5 mL) are added tert-butyl 4- [ 4- (aminomethyl) phenyl] piperazine-1-carboxylate (930 mg) and triethylamine (0.56 mL). The mixture is stirred for 48 hours at room temperature and the precipitate formed is filtered and washed with THF. The filtrate is concentrated under reduced pressure at 40 ° C. and then purified by flash chromatography on silica gel (eluent: heptane 100% to heptane / ethyl acetate 7: 3) gives the expected compound in the form of a white powder (880 mg, 83% yield).

MS / LC: MM calcd = 531.3; m / z = 532.3 (MH +)

NMR ^(1H, 400 MHz, DMSO- ^ _5): δ 0.80 (m, 6H), 1.40 (s, 9H), 1.79 (m, IH), 2.01 (m, 2H) , 3.05 (t, 4H), 3.41 (t, 4H), 4.77 (AB, 1H), 4.82 (AB, 1H), 4.93 (t, 1H), 6.90 (b.p. AB, 2H), 7.30 (AB, 2H), 7.41 (t, 1H), 7.57 (AB, 1H), 7.77 (t, 1H), 8.08 (AB, 1H).

Step 2: 3-Isobutyl-1- (4-piperazin-1-ylbenzyl) imidazo [2,1-d] quinazolin-2,5 (1H, 3H) -dione hydrochloride

4- {4 - [(3-Isobutyl-2,5-dioxo-2,3-dihydroimidazo [2,1- [6] quinazolin-1 (5H) -yl) methyl] phenyl} piperazine-1-tert-butyl -carboxylate (880 mg) is added a solution of hydrochloric acid in dioxane (4N, 4 mL). The solution is stirred at ambient temperature for 4 hours and then concentrated under reduced pressure at 40 ° C. The powder obtained is dried (720 mg, 90% yield). MS / LC: MM calcd = 431.2; m / z = 432.3 (MH +)

NMR ^(1H, 400 MHz, DMSO-D _6): δ 0.80 (m, 6H), 1.79 (m, IH), 2.01 (m, 2H), 3.16 (m, 4H) , 3.33 (m, 4H), 4.78 (AB, 1H), 4.83 (AB, 1H), 4.93 (t, 2H), 6.95 (AB, 2H), 7.33 (b.p. AB, 2H), 7.40 (t, 1H), 7.57 (AB, 1H), 7.76 (t, 1H), 8.08 (AB, 1H), 9.28 (s, 2H).

Step 3: 1- [4- (4-ethylpiperazin-1-yl) benzyl] -3-isobutyl] imidazo [2,1-e] quinazolin-2,5 (1H, 3H) -dione hydrochloride

To a suspension of 3-isobutyl-1- (4-piperazin-1-ylbenzyl) imidazo [2,1-e] quinazoline-2,5 (1H, 3H) -dione hydrochloride (56 mg) and sodium carbonate (40 mg) in anhydrous acetonitrile (1 mL) is placed in a reaction tube "Biotage ^® " is added iodoethane (19 mg). The reaction tube is sealed with a capsule, placed in the microwave "Biotage ^® " and heated with magnetic stirring at 100 ° C for 1 hour. The mixture is concentrated under reduced pressure at 40 ° C. and then added with water and dichloromethane. After decantation and extractions, the combined organic phases are washed with brine, dried over Na ₂ SO ₄ and then concentrated under reduced pressure at 40 ° C. Purification of the residue obtained by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane / ethyl methanol 95: 5) gives the expected compound as free base. The corresponding hydrochloride salt is formed by adding 1N HCl solution in ethyl ether to the solution of the free base in ethyl acetate. The precipitate obtained is filtered and dried to give the expected hydrochloride compound (64 mg, 65% yield).

MS / CL: calculated MM = 459.3; m / z = 460.3 (M +)

NMR ^(1H, 400 MHz, DMSO-D _6): δ 0.80 (m, 6H), 1.26 (t, 3H), 1.79 (m, IH), 2.00 (m, 2H) 3.10 (m, 6H), 3.50 (m, 2H), 3.78 (m, 2H), 4.80 (AB, 1H), 4.88 (AB, 1H), 4.94 (m.p. t, 2H), 6.96 (AB, 2H), 7.33 (AB, 2H), 7.41 (t, 1H), 7.57 (AB, 1H), 7.76 (t, 1H), 8.08 (AB, 1H), 10.92 (s, 1H).

In a similar manner to the procedure described for 1- [4- (4-ethylpiperazin-1-yl) benzyl] -3-isobutyl] imidazo [2,1-l] quinazolin-2,5 (1H, 3H) -dione hydrochloride. the following compounds have been prepared:

in which R ₈ represents one of the following radicals

The subject of the present invention is also a process for preparing a compound of formula (I) as defined above, characterized in that the chlorinated derivative (II) is reacted.

in which A, Ri and R ₂ are as defined above, with the amine (III)

in which Y and Z are as defined above, in an aprotic solvent in the presence or absence of an inorganic base or a tertiary amine, at a temperature of 18-80 ° C, to yield compound (I) in which n and m represent 0.

The subject of the present invention is also a process for preparing a compound of formula (I) as defined above, characterized in that the chlorinated derivative (IV) is reacted.

in which A, Ri, R ₂ , R ₃ and R ₄ are as defined above, with amine (III)

wherein Y and Z are as defined above, in an aprotic solvent in the presence of an inorganic base or a tertiary amine, at a temperature of 80 to 120 ° C, to yield compound (I) wherein n and m represent 1 and 0 respectively.

The subject of the present invention is also a process for preparing a compound of formula (I) as defined above, characterized in that the chlorinated derivative (V) is reacted.

in which A, R 1, R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as defined above, with the amine (III)

in which Y and Z are as defined above, in an aprotic solvent in the presence or absence of an organic base, to form the ester (VI)

the ester (VI) thus formed is saponified in the presence of a base in an aprotic or protic solvent, at a temperature of 18 to 80 ° C, for 2 to 24 hours, to give the corresponding acid (VII)

and the derivative (VII) is treated with a coupling agent or with the Mukayiama reagent in the presence of a tertiary amine, in an inert organic solvent, at room temperature for 3 to 24 hours to yield the compound (I) in which n and m represent 1.

The compounds of the present invention possess valuable pharmacological properties. Thus, it has been found that the compounds of the present invention have good affinity for certain cannabinoid receptor subtypes, particularly CB2 receptors. They are particularly useful for treating disease states and diseases in which one or more cannabinoid receptors are involved.

The compounds of the present invention can thus be used in various therapeutic applications. They can advantageously be used for the treatment and prevention of pathological conditions and diseases associated with the activity of cannabinoid receptors such as cell proliferation disorders such as cancer, immune disorders, inflammation, pain, osteoporosis, atherosclerosis, epilepsy, nausea associated with chemotherapy treatments, fibrosis, gastrointestinal disorders, neurodegenerative diseases including multiple sclerosis and dyskinesia, Parkinson's disease, Huntington's chorea, Alzheimer's disease. They can also be used to prevent or cure diseases associated with motor function such as Tourette's syndrome, or to provide neuroprotection. The compounds of the present invention may be administered alone or in combination with other agents related to the treatment of the symptoms or cause of the disease or condition as mentioned above. In the experimental section, an illustration of the pharmacological properties of the compounds of the invention is given below.

The present application also relates to pharmaceutical compositions containing, as active ingredient, at least one product of formula I as defined above, or an addition salt with pharmaceutically acceptable mineral or organic acids of said product of formula I, in combination with a pharmaceutically acceptable carrier.

The present application also relates to the use of the compounds according to the present invention, for the preparation of a medicament for the treatment of cell proliferation disorders and preferably for the treatment of cancer.

The present application also relates to the use of the compounds according to the present invention, for the preparation of a medicament for the treatment of immune disorders, inflammation, pain, osteoporosis, neurodegenerative diseases including multiple sclerosis and dyskinesia, Parkinson's disease.

The pharmaceutical composition may be in the form of a solid, for example, powders, granules, tablets, capsules or suppositories. Suitable solid carriers may be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidine and wax.

The pharmaceutical compositions containing a compound of the invention may also be in liquid form, for example, solutions, emulsions, suspensions or syrups. Suitable liquid carriers may be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in various proportions, in water, added to oils or fats pharmaceutically acceptable. Sterile liquid compositions may be used for intramuscular, intraperitoneal or subcutaneous injections and sterile compositions may also be administered intravenously.

All technical and scientific terms used in this text have the meaning known to those skilled in the art. In addition, all patents (or patent applications) as well as other bibliographic references are incorporated by reference.

Experimental part :

The compounds according to the invention obtained according to the procedures previously described are collated in the table below.

The compounds are characterized by their retention time (tr) and their molecular peak determined by mass spectrometry (MH +).

For mass spectrometry, a single quadrupole mass spectrometer (Micromass, Platform model) equipped with an electrospray source is used with a resolution of 0.8 Da at 50% valley. Calibration is carried out monthly between the masses 80 and 1000 Da using a calibrating mixture of sodium iodide and rubidium iodide dissolved in an isopropanol / water mixture (1/1 vol.).

For liquid chromatography, a Waters system including an in-line degasser, a Waters 600 quaternary pump, a Gilson 233 plate injector and a Waters PAD 996 UV detector is used.

The elution conditions used are as follows:

Eluent: A water + 0.02% trifluoroacetic acid; B acetonitrile

Flow rate: 1 ml / min; Injection: 10 μl; Column: Uptisphere ODS 3 μm 75 * 4.6 mm i.d.

These examples are presented to illustrate the above procedures and should in no way be construed as limiting the scope of the invention.

Pharmacological study

The affinity of the compounds of the present invention for the different cannabinoid receptor subtypes was measured according to procedures analogous to those described hereinafter for the human CB2 receptor.

Study of the affinity of the compounds for CB2 human cannabinoid receptors

The affinity of the compounds of the invention for CB2 human receptors is determined by measuring the inhibition of [ ³ H] -CP55940 binding to membrane preparations of transfected CHO-K1 cells.

CHO-K1 cells stably expressing human CB2 receptors are cultured in RPMI 1640 medium containing 10% fetal calf serum, 2 mM glutamine, 100 U / ml penicillin, 0.1 mg / ml streptomycin and 0.5 mg / ml G418. The cells are collected with 0.5 mM EDTA and centrifuged at 500 g for 5 min at 4 ° C. The pellet is resuspended in phosphate buffered saline (PBS) and centrifuged at 500 g for 5 min at 4 ° C. The pellet is resuspended in a 50 mM Tris buffer medium at pH 7.4 and centrifuged at 500 g for 5 min at 4 ° C. The cells are lysed by sonication and centrifuged at 39,000 g for 10 min at 4 ° C. The pellet is resuspended in 50 mM Tris buffer medium at pH 7.4 and centrifuged at 50,000 g for 10 min at 4 ° C. The membranes obtained in this latter pellet are stored at -80 ° C.

The measurement of competitive inhibition of [ ³ H] -CP55940 binding to CB2 receptors is performed in duplicate using 96-well polypropylene plates. The cell membranes (10 μg protein / well) are incubated with [ ³ H] -CP55940 (1 nM) for 60 min at 25 ° C. in a 50 mM Tris-HCl buffer medium, pH 7.4, comprising 0, 1% bovine serum albumin (BSA), 5 mM MgCl ₂ , and 50 μg / ml bacitracin.

The bound [ ³ H] -CP55940 is separated from free [ ³ H] -CP55940 by filtration through GF / C glass fiber filter plates (Unifilter, Packard) preimpregnated with 0.1% polyethylenimine (PEI). ), using a Filtermate 196 (Packard). The filters are washed with 50 mM Tris-HCl buffer, pH 7.4 at 0-4 ° C and the radioactivity present is determined using a counter (Packard Top Count).

The specific binding is obtained by subtracting the non-specific binding (determined in the presence of 0.1 μM of WIN55212-2 from the total binding). The data are analyzed by computer-assisted nonlinear regression (MDL). For each test, a Cheng-Prusoff correction is made to convert the IC50 to a constant of inhibition Ki.

So,

Ki = IC50

1 + [L] / Kd

where [L] is the concentration of radioligand used in the assay and Kd is the radioligand dissociation constant at equilibrium.

Table 1 below groups together the examples having an inhibition constant Ki of less than 5 × 10 ^-6 M and, among these examples, those which have an inhibition constant of less than 50 × 10 ^-9 M. The CB2 receptor agonist or antagonist activity of the compounds of the present invention was determined by measuring the cyclic AMP production by CHO-K1 cells transfected with the CB2 receptor.

Measurement of intracellular cyclic AMP production via CB 2 receptors:

CHO-K1 cells expressing cannabinoid CB2 receptors are cultured in 384-well plates in RPMI 1640 medium with 10% fetal calf serum and 0.5 mg / ml G418. The cells are washed twice with 50 μl of RPMI medium comprising 0.2% BSA and 0.5 mM of 3-isobutyl-1-methylxanthine (IBMX).

To measure the agonist effect of a compound, the cells are incubated for 5 min at 37 ° C. in the presence of 0.5 mM of IBMX, then the stimulation of cyclic AMP production is obtained by adding 5 μM of Forskolin and inhibition is measured by adding the compound at concentrations of between 1 μM and 10 μM in duplicate for 20 min at 37 ° C. The antagonistic effect of a compound is measured by inhibiting the inhibition of the production of Cyclic AMP induced by WIN55212-2 in the presence of 5 μM Forskolin, at concentrations of between 1 μM and 10 μM, in the presence of the test compound, at concentrations of between 1 nM and 10 μM, in duplicate for 20 min at 37 ° C.

The reaction medium is removed and 80 .mu.l of lysis buffer are added. The level of intracellular cyclic AMP is measured by a competition test with fluorescent cyclic AMP (CatchPoint, Molecular Devices).

Table 1:

Claims

1. Compounds of general formula (I)

in racemic, enantiomeric form or any combination of these forms and in which

Li represents - Q

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R 4 represent, independently, a hydrogen atom or a hydroxy, halo, (C ₁ -C ₈ ) alkyl, (C 1 -C 8) haloalkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₇ ) heterocycloalkyl, (C ₁ -C ₆ ) alkoxy- (C 1 -C 8) alkyl, ( C ₁ -C ₆ ) alkylthio- (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, aralkyloxy, aralkylthio or a radical - (CH ₂ ) _P -R ₇ , all of these radicals being optionally substituted with one or more identical or different substituents selected from: halo, nitro, hydroxy, oxo, amino, carboxamide, (C ₁ -C ₆ ) alkylcarbonyl, (C ₁ -C ₈ ) alkyl, (C 1 -C 6) haloalkyl, (C ₁ -C ₈ ) alkoxy, (C 1 -C) ₈ ) haloalkoxy, aryl or aryloxy;

or R 1 and R ₂ , R ₃ and R ₄ , or R ₅ and R ₆ together with the carbon atom to which they are attached form a (C ₃ -C ₈ ) cycloalkyl radical (C ₃ -C ₇ ) heterocycloalkyl, indanyl, tetrahydronaphthyl or decahydronaphthyl, these radicals being optionally substituted by one or more identical or different substituents chosen from: halo, hydroxy, (Ci-Cg) alkyl, (Ci-C ₈ ) haloalkyl, (Ci-C ₆ alkoxy; or else finally the radicals R ₃ and R ₄ together with the neighboring radicals R 1 and R _{2 form,} on the one hand, or R ₅ and R _6, on the other hand, a cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl radical, these radicals being optionally substituted by one or more identical or different substituents selected from halo, nitro, hydroxy, amino, carboxamide, (Ci-C ₆₎ alkylcarbonyl, (Ci-C ₈₎ alkyl, (Ci-C ₈₎ haloalkyl, (Ci-C ₈ ) alkoxy, (C ₁ -C ₈ ) haloalkoxy;

p represents 1, 2, 3 or 4;

R ₇ represents a radical -C (O) -O- (C, -C ₈ ) alkyl, -C (O) -NR _N R ¹ _N , (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₇ ) heterocycloalkyl, aryl or heteroaryl, all these radicals being optionally substituted by one or more identical or different substituents chosen from: halo, nitro, hydroxy, amino, (Ci-C ₈ ) alkyl, (Ci-Cg) haloalkyl, (Ci-C) ₈ ) alkoxy, (C ₁ -C ₈ ) haloalkoxy or aralkyloxy;

R _N and R _N independently represent a hydrogen atom or a (Ci-Cg) alkyl, (Ci-C ₈₎ haloalkyl, (C ₂ -C ₈₎ alkenyl, (C ₂ -C ₈₎ alkynyl, ( C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₇ ) heterocycloalkyl, aryl or heteroaryl;

or R _N and R ' _N together form a (C ₃ -C ₇ ) heterocycloalkyl radical;

Z represents a nitrogen atom or a radical -CH-;

Y represents an oxygen atom, a radical -CHR ₈ or -NR ₈ ;

A represents a condensed, unsaturated, aromatic or nonaromatic mono- or bi-cyclic ring, optionally containing one or more identical or different heteroatoms chosen from O, S and N, and optionally substituted by one or more radicals, which may be identical or different, chosen from: halo, nitro, cyano, oxy, -X _A -Y _A , and aryl optionally substituted by one or more substituents chosen from: halo, (C ₁ -C ₆ ) alkyl and (C 1 -C ₆ ) haloalkyl;

X _A represents a covalent bond, -O-, -S-, -C (O) -, -NR ¹ VC (O) -, -C (O) -NR ¹ V, -C (O) -O-, -SO ₂ - or -SO ₂ NH-; Y _A represents a hydrogen atom or a radical (Ci-C ₆₎ alkyl or (Ci-C ₆₎ haloalkyl;

R " _N represents the hydrogen atom or a (C ₁ -C ₆ ) alkyl radical;

n represents 0 or 1; m represents 0 or 1; or a pharmaceutically acceptable salt thereof.

2. Compounds according to claim 1, characterized in that A represents a ring selected from: phenyl, naphthyl, thienyl, furyl, pyrrolyl, benzothienyl, benzofuryl, thienopyridinyl, indolyl and tetrahydrobenzo-thienyl; or a pharmaceutically acceptable salt thereof.

3. Compounds according to one of the preceding claims, characterized in that A is optionally substituted by one or more radicals, identical or different, selected from: halo, nitro, -X _A -Y _A , and phenyl;

X _A represents a covalent bond, -O- or -C (O);

4. Compounds according to any of the preceding claims, characterized in that A represents a phenyl radical optionally substituted by one or more radicals (Ci-C ₆₎ alkyl or (Ci-C ₆₎ alkoxy same or different; or a pharmaceutically acceptable salt thereof.

5. Compounds according to one of the preceding claims, characterized in that Z represents a nitrogen atom; or a pharmaceutically acceptable salt thereof.

6. Compounds according to one of the preceding claims, characterized in that Y represents the -NR ₈ radical and R ₈ represents a (C ₁ -C ₆ ) alkyl radical; or a pharmaceutically acceptable salt thereof.

7. Compounds according to one of the preceding claims, characterized in that they correspond to the following formula:

or a pharmaceutically acceptable salt thereof

Compounds according to claim 1, characterized in that n represents 0; or a pharmaceutically acceptable salt thereof.

9. Compounds according to one of the preceding claims, characterized in that m represents 0; or a pharmaceutically acceptable salt thereof.

10. Compounds according to one of the preceding claims, characterized in that

n and m represent 0;

R ₁ represents the hydrogen atom;

R ₂ represents a hydrogen atom or a (C 1 -C 8) alkyl radical,

(C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₇ ) heterocycloalkyl, aryl optionally substituted with an aryl radical, heteroaryl, or a radical - (CH ₂ ) _P -R ₇ ;

p represents 1 or 2;

R ₇ represents a (C ₃ -C ₈ ) cycloalkyl or aryl radical;

11. Compounds according to claim 10, characterized in that m and n represent 0;

Ri represents the hydrogen atom;

p represents 1 or 2;

R ₇ represents a cyclohexyl or phenyl radical;

12. Compounds according to one of claims 1 to 8, characterized in that m represents 1; or a pharmaceutically acceptable salt thereof.

13. Compounds according to one of claims 1 to 8 or 12, characterized in that

n is 0 and m is 1; and

- or R 1, R ₂ , R ₃ and R ₄ represent, independently, a hydrogen atom;

- or R ₃ and R ₄ represent, independently, a hydrogen atom; and

. R 1 and R ₂ represent, independently, a (C ₁ -C ₈ ) alkyl radical; or

. R 1 and R ₂ together with the carbon atom to which they are attached form a (C ₃ -C ₈ ) cycloalkyl.

either R 1 and R ₂ represent, independently, a hydrogen atom;

. R ₃ represents the hydrogen atom; R ₄ represents a radical (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, tetrahydropyranyl, phenyl, or a radical - (CH ₂ ) _P -R ₇ ; p represents 1 or 2 and R ₇ represents a cyclohexyl radical; or

. R ₃ and R ₄ represent, independently, a (C ₁ -C ₈ ) alkyl radical; or

. R ₃ and R ₄ together with the carbon atom to which they are attached form a (C ₃ -C ₈ ) cycloalkyl;

or the radicals R ₃ and R ₄ together with the neighboring radicals R ₁ and R _{2 form} a phenyl radical; or a pharmaceutically acceptable salt thereof.

14. Compounds according to one of claims 1 to 6, characterized in that n and m represent 1; or a pharmaceutically acceptable salt thereof.

15. Compounds according to one of claims 1 to 7, 12 or 14, characterized in that

m and n are 1;

R 1, R ₂ , R ₅ and R ₆ represent, independently, a hydrogen atom or a (C ₁ -C ₈ ) alkyl radical;

16. Process for the preparation of a compound of formula (I) as defined in claim 1, characterized in that the chlorinated derivative (II) is reacted

in which A, R 1 and R ₂ are as defined in claim 1, with the amine (III)

in which Y and Z are as defined in claim 1, in an aprotic solvent in the presence or absence of an inorganic base or a tertiary amine, at a temperature of 18-80 ° C, to yield the compound (I ) in which n and m represent 0.

17. Process for the preparation of a compound of formula (I) as defined in claim 1, characterized in that the chlorinated derivative (IV) is reacted

in which A, R 1, R ₂ , R ₃ and R ₄ are as defined in claim 1, with the amine (III)

wherein Y and Z are as defined in claim 1, in an aprotic solvent in the presence of an inorganic base or a tertiary amine, at a temperature of 80 to 120 ° C, to yield compound (I) in which m and n represent 1 and 0 respectively.

18. Process for preparing a compound of formula (I) as defined in claim 1, characterized in that the chlorinated derivative (V) is reacted.

in which A, R 1, R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as defined in claim 1, with the amine (III)

in which Y and Z are as defined in claim 1, in an aprotic solvent in the presence or absence of an organic base, to form the ester (VI)

and finally the derivative (VII) is treated with a coupling agent, or with the Mukayiama reagent in the presence of a tertiary amine, in an inert organic solvent, at room temperature for 3 to 24 hours, to give the compound ( I) in which n and m represent 1.

19. Pharmaceutical compositions containing, as active ingredient, at least one product of formula I as defined in one of claims 1 to 15, or an addition salt with pharmaceutically acceptable mineral or organic acids of said product of formula I, in combination with a pharmaceutically acceptable carrier.

20. Use of a compound according to one of claims 1 to 15, for the preparation of a medicament for the treatment of cell proliferation disorders, and preferably cancer.

21. Use of a compound according to one of claims 1 to 15, for the preparation of a medicament for the treatment of immune disorders, inflammation, pain, osteoporosis, fibrosis, gastrointestinal disorders, diseases neurodegenerative diseases including multiple sclerosis and dyskinesia, Parkinson's disease.