EP1940823A2

EP1940823A2 - Substituted 1-amino-phthalzine derivatives, preparation and therapeutic use thereof

Info

Publication number: EP1940823A2
Application number: EP06820177A
Authority: EP
Inventors: Jean Michel Augereau; Gilles Courtemanche; Michel Geslin; Laurence Serva
Original assignee: Sanofi Aventis France
Current assignee: Sanofi SA
Priority date: 2005-10-12
Filing date: 2006-10-10
Publication date: 2008-07-09
Also published as: WO2007042660A2; FR2891828B1; FR2891828A1; JP2009511552A; US20090124624A1; TW200800208A; DOP2006000217A; GT200600455A; AR057980A1; WO2007042660A3; PE20070550A1

Abstract

The invention concerns 1-amino-phthalazine derivatives of general formula (I), wherein: A, B = optionally substituted C1-4 alkylene; L = single bond or C1-2 alkylene, -CH=CH- or -C C; the C1-2 alkylene and -CH=CH- groups being optionally substituted, or L = cycloprop-1,2-diyl; R = H or C1-5 alkyl, C1-3 fluoroalkyl, C3-6 cycloalkyl, -C(O)C1-3 alkyl, C1-3 alkylene-C3-6 cylcoalkyl, -CH2-C CH, C1-3 alkylene-NRaRb, C1-3 alkylene-X-C1-3 alkyl with X=O, SO2; R1 = aryl or a heteroaryl optionally substituted; R2, R3 = H, C1-3 alkyl or C1-3 fluoroalkyl, or R2 and R3 together form a cycloprop-1,1-diyl; R4 = H or a C1-5 alkyl, C1-3 fluoroalkyl, C3-6 cycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, C1-3 alkylene-C3-6 cycloalkyl, C1-3 alkylene-O-C1-3 alkyl, or R4 = C1-3 alkylene-(OH), C1-3 alkylene-X-C1-3 alkyl where X = S, SO or SO2, or R4 = heterocycle, a C1-3 alkylene-NraRb group, aryl, C1-3 alkylene-aryl, -O-aryl, C1-3 alkylene-O-aryl, C1-3 alkylene-O-C1-3 alkylene-aryl, heteroaryl or C1-3 alkylene-heteroaryl, optionally substituted. R5 = halogen or a C1-5 alkyl, C1-3 fluoroalkyl, C1-5 alkoxy, C1-3 fluoroalkoxy, C1-3 alkylene-(OH), -CN, -X-C1-3 alkyl where X = S, SO or SO2, or R5 = NraRb, C1 3 alkylene- NraRb, aryl, C1-3 alkylene-aryl, -O-aryl or heteroaryl, optionally substituted; R7 = H, halogen or a C1-5 alkyl, C1-3 fluoroalkyl, C1-5 alkoxy, -COOH, -C(O)OC1-5 alkyl, C1-3 fluoroalkoxy, C1-3 alkylene-(OH), -CN, -X-C1-3 alkyl where X represents S, SO or SO2, or R7 = -NraRb, C1-3 alkylene-NraRb,-C(O)-NraRb, -C(O)-C1-3 alkyl, aryl, -O-aryl or heteroaryl, optionally substituted; in base or acid addition salt form, as well as in hydrate or solvate form. The invention also concerns the preparation of said compounds and their therapeutic use.

Description

DERIVATIVES OF SUBSTITUTED 1-AMINO-PHTALAZINE, THEIR PREPARATION AND

THEIR APPLICATION IN THERAPEUTICS

The present invention relates to 1-amino-phthalazine derivatives, their preparation and their therapeutic application. The search for MCH receptor 1 antagonists (Melanin-Concentrating

Hormone), the MCH- receptor, arouses interest from many pharmaceutical companies. A certain number of patent applications have been filed, among which mention may be made of WO01 / 21577 (Takeda), WO02 / 06245 (Synaptic), WO03 / 106452

(Millennium). A number of publications have appeared including Ma V.V. et al (Amgen) 224th Nat. ACS Boston Meeting. Poster MEDI 343 (21.08.2002).

During the last decade, it has been shown that many neuropeptides are involved in the central regulation of dietary behavior and energy balance (Inui et al, TINS 1999; 22 (2): 62-67). MCH is one of these neuropeptides. Two MCH receptors have recently been cloned, the MCH ₁ receptor previously called the SLC-1 or GPR24 receptor (Chambers et al., Nature 1999; 400: 261-265), and the MCH ₂ receptor previously called SLT (Mori et al. Biochem Biophys Res Common

2001; 283: 1013-1018).

There is therefore a real interest in finding new compounds for modulating the activity of the MCH ₁ receptor, the MCH receptor 1.

WO2005 / 103033 discloses 1-amino-phthalazine derivatives capable of modulating

Pacíficated MCH 1 receptor.

It has now been found that compounds, derived from 1-amino-phthalazine, are very affine and selective towards the MCH ₁ receptor. These compounds have an activity in vitro but also in vivo with respect to the MCH1 receptor.

The subject of the present invention is compounds corresponding to the following general formula (I):

wherein: • A represents a C _1-4 -alkylene group optionally substituted with one or more R ₉ groups which are identical to or different from each other; B represents a C _1-4 -alkylene group optionally substituted with one or more groups R _{10 which are} identical to or different from one another;

• R ₉ and R ₁₀ are each, independently of one another, a hydrogen atom or a Ci _-5 alkyl group,. or R ₉ and R ₁₀ together form a single bond or a C _1-4 alkylene group;

L represents a single bond or a C _1-2 -alkylene group, -CH = CH- or -C≡C-; the C _1-2 -alkylene groups and -CH = CH- being optionally substituted by one or more C _1-2 -alkyl substituents, or L represents a cycloprop-1, 2-diyl group;

• R represents a hydrogen atom or a C ₅ alkyl group, C _1-3 fluoroalkyl, C _3-6 -. Cycloalkyl, -C (O) C _1-3 -alkyl, C _1-3 -alkylene- C _3-6 -cycloalkyl, -CH ₂ -C = CH, C _2-3 -alkylene-NR ₃ R _b , C _1-3 -alkylene-X-C _1-3 -alkyl wherein X is O or SO ₂ ;

R 1 represents aryl or heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other;

• R ₂ and R ₃ independently of one another, a hydrogen atom or a C _1-3 -alkyl or Ci. ₃ fluoroalkyl,

. or R ₂ and R ₃ together with the carbon atom carrying them, form a cycloprop-1, 1-diyl group;

R ₄ represents:

. a hydrogen atom or a C _1-5 -alkyl, C _1-3 -fluoroalkyl, C _3-6 -cycloalkyl, C _1-3 -alkylene-C _{3 group} . ₆ -cycloalkyl, C _1-3 -alkylene-O-C _1-3 -alkyl, C _1-3 -alkylene-OC ₄ .

6-cycloalkyl, a C _1-3 -alkylene- (OH), C _1-3 -alkylene-X-C _1-3 -alkyl group where X is S, SO or SO ₂ ,

. a heterocycle group; said heterocycle group being optionally substituted with a C _1-3 -alkyl, -C (O) C _1-3 -alkyl, -C (O) C _1-3 -fluoroalkyl, C _1-3 -alkylene-C _{3 group} . ₆ - cycloalkyl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-heteroaryl; the C _1-3 -alkylene-aryl and C _1-3 -alkylene-heteroaryl groups being optionally substituted by one or more radicals

Z identical or different from each other,

. or R ₄ represents a C _1-3 -alkylene-NRaRb, aryl, C _1-3 -alkylene-aryl group,

-O-aryl, C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-OC _1-3 -alkylene-aryl, heteroaryl or C _1-3 -alkylene-heteroaryl; aryl, C _1-3 -alkylene-aryl, -O-aryl, C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-OC _1-3 -alkylene-aryl, heteroaryl and C _{1- 3} -alkylene-heteroaryl being optionally substituted with one or more radicals Z which are identical to or different from each other; • R ₅ represents a hydrogen or halogen atom or a group CI_ ₅ -alkyl, C _1-3 -. Fluoroalkyl, C _1-5 alkoxy, C ₃ -fluoroalkoxy, Ci.s-alkylene-ζOH) -CN, -XC _1-3 -alkyl where X represents S, SO or SO ₂ ,

. or R ₅ is -NR _a R _b , C _1-3 -alkylene-NR _a R _b , aryl, C _1-3 - alkylene-aryl, -O-aryl or heteroaryl; the aryl, C _1-3 -alkylene-aryl, -O-aryl and heteroaryl groups being optionally substituted with one or more Z radicals which are identical to or different from each other;

R ₇ represents a hydrogen or halogen atom or a C _1-5 alkyl, C _1-3 fluoroalkyl, C _1-5 alkoxy, -COOH, -C (O) OC _{1-3 group} ; alkyl, C _1-3 -fluoroalkoxy, C _1-3 -alkylene- (OH), -CN, -XC _1-3 -alkyl wherein X is S, SO or SO ₂ ,

. or R ₇ represents a group -NR ₃ R _b , C _1-3 -alkylene-NR _a R _b , -C (O) -NR ₃ Rb, -C (O) -C _1-3 -alkyl, aryl, -O-aryl or heteroaryl; the aryl, -O-aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other; • Z represents a halogen atom or a Ci _-5 alkyl group, C _1-3 fluoroalkyl, C _3-6 - cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, Ci _-5 alkoxy , C _1-3 -fluoroalkoxy, C _1-3 -alkylene-O-C _1-3 -alkyl, C _1-3 -alkylene- (OH), NO ₂ , -CN, -SO ₂ NRaRb, -XC _{1- 3} -alkyl, C _1-3 -alkylene-X-Cl. ₃ -alkyl where X is S, SO or SO ₂ ,

. or Z is optionally substituted by a halogen atom phenyl, C _1-5 -alkyl, CI_ ₅ -alkoxy or C _1-3 fluoroalkyl,

. or Z represents an alkynyl radical of type -C = CR _C , in which R ₀ represents a hydrogen atom, a C _1-3 -alkyl, C _1-6 -alkylene-O-Rd or C _{1-6 group;} alkylene NR _a R _b ,

. or Z represents a -C _4-6 -alkylene-ORd group, or Z represents a tetrazole group substituted with a C _1-3 -alkyl group,

. or Z is -NR ₃ Rb, C _1-3 -alkylene-NR _a Rb, -C (O) -NR ₃ Rb, -C (O) -C _1-3 -alkyl, -CO ₂ -C _1-4 -alkyl, -C (O) -C ₃ . ₆ -cycloalkyl,

. or Z represents a -C ₄ group. ₆ -alkylene-NR _a R _b , or Z represents an oxo radical, or else Z represents a group

. or Z represents a -OC _0-3 -alkylene-heterocycle group, optionally substituted by one or more C _1-3 -alkyl, oxo or -C (O) -C _1-3 -alkyl groups, or Z is -O-C _1-5 -alkylene-O-Rd,

. or Z represents a group -OC _0-3 -alkylene-C _5-7 -cycloalkyl optionally substituted with a group -OR _d ,

. or Z represents a group -NR _e -C _0-3 -alkylene-heterocycle optionally substituted by one or more C _1-3 -alkyl, oxo or -C (O) -C _1-3 -alkyl groups, . or Z represents a group -NR _e -C ₂ . ₅ -alkylene-OR _d , or Z represents a -O-C1-3-alkylene-heteroaryl group optionally substituted with one or more C _1-3 -alkyl groups,

. or Z represents -CONH-C _1-5 -alkylene-NR _a R _b ,. or Z is -CONH-C _1-5 -alkylene-O-Rd,

. or else Z represents a group . or Z represents a fused bicyclic or fused bicyclic heterocyclic ring, or two adjacent Z radicals together form a C _1-3 - alkylenedioxy group; R _a and R _b each independently represent a hydrogen atom or a C _1-3 -alkyl or -C (O) -C _1-3 -alkyl group,

. or R _a and R _b together with the nitrogen atom to which they are attached form a heterocycle optionally substituted with one or more C _1-3 -alkyl, oxo, -NR _a R _b , hydroxy, C _{1 groups; -3-} alkoxy, or -C (O) -C _1-3 -alkyl; • R _d represents a hydrogen atom or a C _1-3 -alkyl group; • R _e represents a hydrogen atom or a C _1-3 -alkyl group;

it being understood that when R represents a hydrogen atom, then at least one of the conditions defined below is fulfilled: R ₄ represents a heterocycle group, said heterocycle being optionally substituted by a C _1-3 alkyl group , -C (O) C _1-3 -alkyl, -C (O) Cl. _3- fluoroalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-heteroaryl; the groups C _1-3 -alkylene-aryl and C _1-3 -alkylene-heteroaryl being optionally substituted with one or more radicals Z that are identical to or different from each other as defined above; or

- Z represents phenyl substituted by a halogen atom, a group C _1-5 - alkyl, Ci _-5 alkoxy or C _1-3 fluoroalkyl, or

Z represents an alkynyl radical of the type -C = CR ₀ in which R ₀ represents a hydrogen atom, a C _1-3 -alkyl, C _1-6 -alkylene-OR _d or C _1-6 -alkylene-group; NR _a R _b , or else

Z represents a -C _4-6 -alkylene-OR _{d group} , or

Z represents a tetrazole group substituted with a C _1-3 -alkyl group, or

Z represents a group -C ₄ . ₆ -alkylene-NR _a R _b , or else

Z represents a group -SO ₂ -NR ₃ R _b , or -Z represents a group -O-C 1 -C ₅ -alkylene-NR _a R _b , or

Z represents a group -OC ₀ . ₃ -alkylene heterocycle optionally substituted with one or more C _1-3 -alkyl, oxo or -C (O) -C _1-3 -alkyl groups, or Z represents a group -OC _1-5 -alkylene-O-Rci, or

- Z represents a group -0-C _{_0-3} -alkylene-C _5. ₇ -cycloalkyl optionally substituted with a group -OR _d , or

Z represents -NR _e -C _{_0-3} -alkylene-heterocycle optionally substituted by one or more C _1-3 alkyl, oxo or -C (O) -C _1. _3- alkyl, or

Z represents a group -NR _e -C _2- 5 -alkylene-OR _d , or

Z represents a group -OC-ι _-3 -alkylene-heteroaryl optionally substituted with one or more C _1-3 -alkyl groups, or

Z represents a -CONH-C _1-5 -alkylene-NR _a R _{b group} , or -Z represents a -CONH-C _1-5 -alkylene-OR _{d group} , or

Z represents a group -OC _1-3 -alkylene-C (O) -NR _a R _b , in the groups Z mentioned above, the groups R _a , R _b , R _d and R _e are as defined previously , to know :

R _a and R _b each independently represent a hydrogen atom or a C _1-3 -alkyl or -C (O) -C 1 _-3 -alkyl group,

. or R _a and R _b together with the nitrogen atom to which they are attached form a heterocycle optionally substituted with one or more C _1-3 -alkyl, oxo, -NR ₃ R _b , hydroxy, C _{1 groups; -3-} alkoxy, C _1-3 -alkylene- (OH) or -C (O) -C-ι- ₃ -alkyl;

• R _d represents a hydrogen atom or a C _1-3 -alkyl group; • R _e represents a hydrogen atom or a C _1-3 -alkyl group;

- or Z represents a fused bicyclic or fused bicyclic heterocycle,

- or Z represents a group -NR ₃ R _b in which R _a and R _b together with the nitrogen atom to which they are attached form a heterocycle substituted with one or more -NR _a R _b , hydroxy groups, C _1-3 -alkoxy, C _1-3 -alkylene- (OH) or -C (O) -C _1-3 -alkyl.

The compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention.

The compounds of formula (I) may comprise one or more rings. They can therefore exist in the form of axial / equatorial isomers, or endo / exo, or cis / trans. These isomers and their mixtures are part of the invention. The compounds of formula (I) may comprise one or more olefinic functions.

They can therefore exist as ZIE isomers. These isomers and their mixtures are part of the invention. The compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.

These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.

The compounds of formula (I) can also exist in the form of hydrates and / or solvates, namely in the form of combinations or combinations with water and / or solvent. Such hydrates and solvates are also part of the invention.

In the context of the present invention, the following terms mean:

C _t-2 where t and z can take the values from 0 to 6, a carbon chain or ring which can have from t to z carbon atoms, for example C _0-3 can characterize a single bond or a carbon chain having from 1 to 3 carbon atoms; a halogen atom: a fluorine, a chlorine, a bromine or an iodine; an alkyl group: a saturated monovalent aliphatic group, linear or branched. By way of examples, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and the like; an alkylene group: a divalent saturated, linear or branched aliphatic group. By way of example, a C _1-3 -alkylene group represents a divalent carbon chain of 1 to 3 carbon atoms, linear or branched, such as a methylenyl (-CH ₂ -), an ethylenyl (-CH ₂ CH ₂ - ), a 1-methylethylenyl (-CH (CH ₃ ) CH ₂ -), a propylenyl (-CH ₂ CH ₂ CH ₂ -), etc .; a cycloalkyl group: a saturated cyclic aliphatic group. By way of examples, mention may be made of cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, and the like; an alkoxy group: an O-alkyl radical where the alkyl group is as previously defined; an alkylenedioxy group: a -O-alkylene-O- group, where the alkylene group is as previously defined. As examples, mention may be made of methylenedioxy, ethylenedioxy or propylenedioxy groups; a fluoroalkyl group: an alkyl group of which one or more hydrogen atoms have been substituted by a fluorine atom. By way of examples, mention may be made of the groups -CF ₃ , -CH ₂ CF ₃ ; a fluoroalkoxy group: an alkoxy group of which one or more hydrogen atoms have been substituted by a fluorine atom. By way of examples, mention may be made of the groups -OCF ₃ , -OCHF ₂ ; a heterocycle group: a 5- to 7-membered saturated cyclic group having one to several heteroatoms such as nitrogen, oxygen or sulfur atoms. By way of examples, mention may be made of pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperidonyl, morpholinyl, piperazinyl and N-methyl-piperazinyl groups, and the like; . or a heterocycle group may represent a bridged heterocycle group comprising from 6 to 10 members, wherein at least 2 atoms of the bicyclic structure are connected by a single bond or a chain which may have from 1 to 4 members.

By way of examples, mention may be made of: the 1-azabicyclo [2.2.2] octyl group:

or the 8-azabicyclo [3.2.1] octyl group

an aryl group: monocyclic or polycyclic aromatic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms. When the system is polycyclic, at least one of the rings is aromatic. By way of examples, mention may be made of phenyl, naphthyl, tetrahydronaphthyl, indanyl, etc .; a heteroaryl group: monocyclic or polycyclic aromatic system comprising from 5 to 14 members, preferably from 5 to 10 members and comprising one to more heteroatoms such as nitrogen, oxygen or sulfur atoms. When the system is polycyclic, at least one of the rings is aromatic. Nitrogen atoms can be in the form of N-oxides. As examples of monocyclic heteroaryl groups, mention may be made of thiazolyl, thiadiazolyl, thienyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyrimidinyl and pyridazinyl groups. As examples of bicyclic heteroaryl groups, mention may be made of the indolyl, benzofuranyl, chromen-2-on-yl, benzimidazolyl, benzothienyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, indazolyl, indolizinyl, quinazolinyl, phthalazinyl and quinoxalinyl groups. , naphthyridinyl, 2,3-dihydro-1H-indolyl, 2,3-dihydro-benzofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl.

In the general formula (I), the cycle: can be, for example, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, 8-azabicyclo [3.2.1] octyl, 8-azabicyclo [3.3.1] nonanyl, decahydroisoquinolinyl, 3-azabicyclo [3.1.0] hexanyl.

Among the compounds of formula (I) which are subjects of the invention, there may be mentioned a first subgroup of compounds which are defined as follows:

A represents a C 1 -C 4 alkylene group, such as the ethylene group, optionally substituted with one or more R ₉ groups identical to or different from each other; B represents a C _1-4 -alkylene group, such as the ethylene group, optionally substituted by one or more groups R _{10 which are} identical to or different from each other;

R ₉ and R ₁₀ each independently represent a hydrogen atom;

• L represents a single bond;

R represents a hydrogen atom, a C _1-5 -alkyl group such as methyl or ethyl, or a -C (O) C _1-3 -alkyl group such as -C (O) -methyl;

R ₁ represents aryl such as phenyl or naphthyl, or R 1 represents a heteroaryl group such as benzo-1,3-dioxolyl or pyrrolyl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other; • R ₂ and R ₃ represent independently of each other a hydrogen atom;

R ₄ represents:

. a hydrogen atom or a C _1-5 alkyl group such as methyl or ethyl, C ₁ . _3- fluoroalkyl such as trifluoromethyl, C _1-3 -alkylene-OC _1-3 -alkyl such as methylene-O-methyl, a heterocycle group such as a piperidinyl or tetrahydropyranyl group; said heterocycle group being optionally substituted by a C _1-3 -alkylene-aryl group such as -methylene-phenyl,

. or R ₄ represents an aryl group such as a phenyl group; said aryl group being optionally substituted with one or more radicals Z which are identical to or different from each other;

R ₅ represents a hydrogen atom, C _1-5 alkoxy such as a methoxy group;

R ₇ represents a halogen atom such as a chlorine or a C _1-5 alkoxy group such as a methoxy group; Z represents a hydrogen atom, a halogen atom such as a fluorine, a C _1-5 alkoxy group such as a methoxy or a phenyl optionally substituted by a C _1-3 -fluoroalkyl group such as trifluoromethyl,

. or Z represents an alkynyl radical of the type -C = CR ₀ , in which R ₀ represents a hydrogen atom, C _1-6 -alkylene-OR _d or C _1-6 -alkylene-NR _a Rb in which the groups C _1-6 -alkylene are such as isopropylene or methylene,

. or Z represents a -C ₄ group. ₆ -alkylene-OR _d wherein the group C _4-6 - alkylene is such as butylene,

. or Z represents a tetrazole group substituted by a C _1-3 -alkyl group such as a methyl group,

. or Z represents a group -NR ₃ Rb,

. or Z represents a -C _4-6 -alkylene-NR _a Rb group in which the C _4-6 -alkylene group is such as butylene,

. or Z represents a -OC _1-5 -alkylene-NR _a R _{b group} in which the C _1-5 -alkylene group is such as ethylene or propylene,

. or Z represents a group -OC _0-3 -alkylene-heterocycle in which the alkylene group is absent or is such that a methylene, ethylene group, and the heterocycle is such that an azepanyl, pyrrolidinyl, piperidinyl group, tetrahydrofuranyl, the 1-azabicyclo [2.2.2] octyl group or the 8-azabicyclo [3.2.1] octyl group, the said -O-C _0-3 -alkylene-heterocycle group being optionally substituted by one or more C ₁ groups _-3 - alkyl such as methyl or an oxo group,

. or Z represents a -O-C _1-5 -alkylene-O-Rd group in which the C _1-5 -alkylene group is such that an ethylene or propylene group,

. or Z is -NR _e -C _2-5 -alkylene-OR _group wherein the _2- C 5 -alkylene is such that an ethylene group,

. or Z represents a -OC _1-3 -alkylene-heteroaryl group in which the C _1-3 -alkylene group is such as a methylene or ethylene group and the heteroaryl group is such that an imidazolyl or pyridinyl group,

. or Z represents a -CONH-C _1-5 -alkylene-NR _a R _{b group} in which the C _1-5 -alkylene group is such that an ethylene group,

or Z is -OC _1-3 -alkylene-C (O) -NR _a R _b wherein C _1-3 - alkylene is such as methylene,

. or Z represents a fused or spiric bicyclic diamino heterocycle chosen from: in which the dotted lines represent the point of attachment to the remainder of the molecule of formula (I) and the solid lines represent a methyl substituent;

R _a and R _b each independently represent a C _1-3 -alkyl group such as methyl,

. or else R ₃ and R _b together with the nitrogen atom to which they are attached form a heterocycle such as a morpholinyl, piperidinyl or pyrrolidinyl group, optionally substituted with one or more oxo groups, -NR ₃ R _b or hydroxy; • R _d represents a hydrogen atom or a C _1-3 -alkyl group such as methyl; R _e represents a C _1-3 -alkyl group such as methyl;

it being understood that when R represents a hydrogen atom, then at least one of the conditions defined below is fulfilled: R ₄ represents a heterocycle group such as a piperidinyl or tetrahydropyranyl group, said heterocycle being optionally substituted by a C _1-3 -alkylene-aryl group such as methylene-phenyl, or

Z represents a phenyl group substituted with a C _1-3 -fluoroalkyl group such as a trifluoromethyl, or Z represents an alkynyl radical of the type -C≡CR _C in which R ₀ represents a hydrogen atom, C _{1 -6} -alkylene-O-Rci or _-6 -alkylene-NR _a R b wherein Ci _-6 -alkylene is such as isopropyl or methyl, or

Z represents a -C _4-6 -alkylene-OR _{d group} in which C ₄ . ₆ -alkylene is such that a butylene or -Z represents a C _1-3 -alkyl-substituted tetrazole group such as methyl, or else

Z represents a -C _4-6 -alkylene-NR _a R _{b group} in which C _4-6 -alkylene is such that a butylene group, or

Z represents a group -OC _1-5 -alkylene-NR _a Rb, in which C ^ -alkylene is such as propylene or ethylene, or

Z represents a group -OC ₀ . ₃ -alkylene-heterocycle in which the alkylene group is absent or is such that a methylene, ethylene or propylene group and in wherein the heterocycle is such that azepanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, the 1-azabicyclo [2.2.2] octyl group or the 8-azabicyclo [3.2.1] octyl group, the group -OC ₀ - ₃ -alkylene-heterocycle being optionally substituted by one or more C _1-3 -alkyl groups such as methyl or an oxo group, or

Z represents a group -OC _1-5 -alkylene-OR _d in which C _1-5 -alkylene is such that an ethylene or propylene group, or

- Z is -NR ₈ -C _{_2-5} -alkylene-OR _d wherein C ₂ .5-alkylene is such that ethylene, or - Z represents a group -OC _1-3 -alkylene-heteroaryl wherein C _1-3 -alkylene is such as methylene or ethylene and wherein the heteroaryl group is such that an imidazolyl, pyridinyl group, or

Z represents a group -CONH-C-ι _-5 -alkylene-NR _a R _b in which C _1-5 -alkylene is such that an ethylene group, or -Z represents a -OCi group. ₃ -alkylene-C (O) -NR _a Rb in which C _1-3 -alkylene is such as methylene, or in the Z groups mentioned above, R ₃ , R _b , R _d and R _e are as defined previously, namely:

. or else R _a and R _b together with the nitrogen atom to which they are attached form a heterocycle such as a piperidinyl, morpholinyl or pyrrolidinyl group, said heterocycle group being optionally substituted by one or more oxo groups, - NR Rb ₃ or hydroxy; • R _d represents a hydrogen atom or a C _1-3 -alkyl group such as methyl;

R _e represents a C _1-3 -alkyl group such as methyl;

or Z represents a fused bicyclic or spiroic diamino heterocycle chosen from:

in which the dotted lines represent the point of attachment to the remainder of the molecule of formula (I) and the solid lines represent a methyl substituent; or else Z represents a group -NR ₃ R _b in which R _a and R _b together with the nitrogen atom to which they are attached form a heterocycle such as a pyrrolidinyl or piperidinyl group substituted with one or more groups; -NR ₃ R _b or hydroxy.

Among the compounds of formula (I) which are subjects of the invention, there may be mentioned a second subgroup of compounds which are defined as follows:

A represents an ethylene group;

B represents an ethylene group; • L represents a single bond;

R represents a hydrogen atom, a methyl group, ethyl group or a -C (O) -methyl group;

R ₁ represents a phenyl, naphthyl, benzo-1,3-dioxolyl or pyrrolyl group; said phenyl, naphthyl, benzo-1,3-dioxolyl and pyrrolyl groups being optionally substituted with one or more Z radicals which are identical to or different from each other;

• R ₂ and R ₃ represent, independently of one another a hydrogen atom;

R ₄ represents:

. a hydrogen atom or a methyl, ethyl, trifluoromethyl or methylene-O-methyl group, a piperidinyl or tetrahydropyranyl group; said piperidinyl or tetrahydropyranyl groups being optionally substituted by a methylene-phenyl group, or R ₄ represents a phenyl group; said phenyl group being optionally substituted with one or more radicals Z which are identical to or different from each other; R ₅ represents a hydrogen atom or a methoxy group;

• R ₇ represents a chlorine atom or a methoxy group;

Z represents a hydrogen atom or a fluorine atom, a methoxy group or a phenyl group optionally substituted by a trifluoromethyl group,

. or Z represents an alkynyl radical of the type -C = CR _C , in which R _c represents a hydrogen atom, C _1-6 -alkylene-OR _d or Ci. ₆ -alkylene-NR _a R _b in which the groups C ^ -alkylene _B are such as isopropylene or methylene,

. or Z represents a butylene-OR group _d ,

. or Z represents a tetrazole group substituted by a methyl group,

. or Z represents a group -NR ₃ R _b ,. or Z represents a butylene-NR _a R _{b group} ,

. or Z represents a group -OC ₁ . _5- propylene-NR _to R _b or -OC _1-5- ethylene

NR ₃ Rb, . or Z represents -O-heterocycle, -O-methylene-heterocycle, -O-ethylene-heterocycle, wherein heterocycle is such that azepanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, 1-azabicyclo [ 2.2.2] octyl or the 8-azabicyclo [3.2.1] octyl group, said -O-heterocycle, -O-methylene-heterocycle, -O-ethylene-heterocycle groups being optionally substituted by one or more methyl groups or a group oxo,

. or Z is -O-ethylene-OR _d or -O-propylene-OR _d,. or Z represents a group -NR _e -ethylene-OR _d ,

. or Z represents a -O-methylene-heteroaryl, -O-ethylene-heteroaryl group in which the heteroaryl group is such that an imidazolyl, pyridinyl group,

. or Z is -CONH-ethylene-NR _a R _b , or Z is -O-methylene-C (O) -NR _a Rb,. or Z represents a fused or spiric bicyclic diamino heterocycle chosen from:

in which the dotted lines represent the point of attachment to the remainder of the molecule of formula (I) and the solid lines represent a methyl substituent;

• R ₃ and R _b each represent, independently of each other, a methyl group, or R _a and R _b together with the nitrogen atom to which they are attached form a morpholinyl, piperidinyl or pyrrolidinyl group, optionally substituted with one or more oxo groups, -NR _a R _b or hydroxy;

• R _d represents a hydrogen atom or a methyl group; • R _β represents a methyl group;

it being understood that when R represents a hydrogen atom, then at least one of the conditions defined below is fulfilled:

R ₄ represents a piperidinyl or tetrahydropyranyl group, said piperidinyl or tetrahydropyranyl groups being optionally substituted with a methylene-phenyl group, or

Z represents a phenyl group substituted with a trifluoromethyl group, or

Z represents an alkynyl radical of type -C = CR ₀ in which R ₀ represents a hydrogen atom, isopropylen-O-Rd or methylene-NR _a Rb, or

Z represents a butylene-OR group _d , or

Z represents a tetrazole group substituted with a methyl group, or

Z represents a butylene-NR _a Rb group, or -Z represents a -O-propylene-NR _a R _{b group} , or

. Z represents -O-heterocycle, -O-methylene-heterocycle, -O-ethylene-heterocycle, wherein heterocycle is such that azepanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, 1-azabicyclo [2.2. 2] octyl or the 8-azabicyclo [3.2.1] octyl group, said -OC _0-3 -alkylene-heterocycle group being optionally substituted with one or more methyl groups or an oxo group, or

Z represents a group -O-ethylene-OR _d or -O-propylene-OR _d , or

Z represents a group -NR _e -ethylene-OR _d , or

Z represents a group -O-methylene-heteroaryl, -O-ethylene-heteroaryl wherein the heteroaryl group is such that an imidazolyl, pyridinyl group, or -Z represents a -CONH-ethylene-NR _a Rb group, or good

Z represents a group -OC _1-3 -methylene-C (O) -NR _a Rb, in the groups Z mentioned above, the groups R ₃ , R _b , R _d and R _e are as defined previously, to know :

• R ₃ and R _b each represent, independently of each other, a methyl group, or R _a and R _b together with the nitrogen atom to which they are attached form a piperidinyl, morphonlinyl or pyrrolidinyl group, said piperidinyl, morpholinyl and pyrrolidinyl groups being optionally substituted with one or more oxo groups, -NR _a R _b or hydroxy;

• R _d represents a hydrogen atom or a methyl group; • R _e represents a methyl;

or Z represents a fused bicyclic or spiroic diamino heterocycle chosen from:

or else Z represents a group -NR ₃ R _b in which R _a and R _b together with the nitrogen atom to which they are attached form a piperidinyl or pyrrolidinyl group optionally substituted with one or more -NR ₃ R groups; _b or hydroxy. Among the compounds of formula (I) which are subjects of the invention, there may be mentioned a third subgroup of compounds which are defined as follows:

A represents a C _1-4 -alkylenic group optionally substituted with one or more groups R _{9 which are} identical to or different from one another;

B represents a C _1-4 -alkylene group optionally substituted with one or more groups R _{10 which are} identical to or different from one another;

R ₉ and R ₁₀ each independently represent a hydrogen atom or a C _1-5 -alkyl group; or R ₉ and R ₁₀ together form a single bond or a C _1-4 alkylene group;

• R represents a hydrogen atom or a Ci _-5 alkyl group, C _1-3 fluoroalkyl, C _3-6 - cycloalkyl, -C (O) C _1-3 -alkyl, C _1-3 -alkylene- C _3-6 -cycloalkyl, -CH ₂ -C≡CH, C _2-4 -alkylene-NR _a R _b , C _1-3 -alkylene-XC _1-3 -alkyl wherein X is O or SO ₂ ;

R ₁ represents aryl or heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other;

• R ₂ and R ₃ independently of one another, a hydrogen atom or a C _1-3 alkyl or C _1-3 fluoroalkyl,

R ₄ represents:

. a hydrogen atom or a C _1-5 -alkyl, C _1-3 -fluoroalkyl, C _3-6 -cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, C _1-3 -alkylene- OC _1-3 -alkyl,

. a C _1-3 -alkylene- (OH), C _1-3 -alkylene-XC _1-3 -alkyl group where X is S, SO or SO ₂ ,

. a heterocycle group; said heterocycle group being optionally substituted by a C _1-3 -alkyl, -C (O) C _1-3 -alkyl, -C (O) C _1-3 -fluoroalkyl, C _1-3 -alkylene-C _{3- 6} - cycloalkyl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-heteroaryl; the C _1-3 -alkylene-aryl and C _1-3 -alkylene-heteroaryl groups being optionally substituted with one or more Z radicals that are identical to or different from one another,

. or R ₄ is C _1-3 -alkylene-NR _a R _b , aryl, C _1-3 -alkylene-aryl, -O-aryl, C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-OC _1-3 -alkylene-aryl, heteroaryl or C _1-3 - alkylene heteroaryl; aryl, C _1-3 -alkylene-aryl, -O-aryl, C-1. ₃ -alkylene-O- aryl, Ci. ₃ -alkylene-OC _1-3 -alkylene-aryl, heteroaryl and C _1-3 -alkylene-heteroaryl being optionally substituted by one or more identical or different radicals Z one of other; • R ₅ represents a hydrogen or halogen atom or a Ci _-5 alkyl group, C _1-3 - fluoroalkyl, C ^ -alkoxy, C _1-3 -fluoroalkoxy, C _1-3 -alkylene- (OH ), -CN, -XC _1-3 -alkyl where X is S, SO or SO ₂ ,

. 'Or R ₅ is -NR _a R _b, Cii ₃ -alkylene-NR _a R b, aryl, C _1-3 - alkylene-aryl, -O-aryl or heteroaryl; the aryl, C _1-3 -alkylene-aryl, -O-aryl and heteroaryl groups being optionally substituted with one or more Z radicals which are identical to or different from each other;

• R ₇ represents a hydrogen or halogen atom or a Ci _-5 alkyl group, C _1-3 - fluoroalkyl, C _1-5 alkoxy, -COOH, -C (O) OC, ₃ -alkyl, C _1-3 -fluoroalkoxy, C _1-3 -alkylene- (OH), -CN, -XC _1-3 -alkyl wherein X is S, SO or SO ₂ , or R ₇ represents a group -NR ₃ Rb, C _1-3 -alkylene-NR _a R _b , -C (O) -NR _a R _b ,

-C (O) -C ₁ . ₃ -alkyl, aryl, -O-aryl or heteroaryl; the aryl, -O-aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other;

• Z represents a halogen atom or a Ci _-5 alkyl group, C _1-3 fluoroalkyl, C _3. ₆ - cycloalkyl, C _1-3 -alkylene-C ₃ . ₆ cycloalkyl, phenyl, Ci, ₅ -alkoxy, C _1-3 -fluoroalkoxy, C _1-3 - alkylene-OC _1-3 -alkyl, C _1-3 -alkylene- (OH), NO _2, -CN , -SO ₂ NR _a R _b , -XC _1-3 -alkyl, C _1-3 - alkylene-XC _1-3 -alkyl where X is S, SO or SO ₂ ,

. or Z is -NR _a R _b, C _1-3 -alkylene-NR _a R _b, -C (O) -NR _a R _b, -C (O) -C. ₃ -alkyl, -C (O) OC _1-4 -alkyl, -C (O) -C ₃ . ₆ -cycloalkyl, or else Z represents an oxo radical,

. or Z represents a group -O-C _1-5 -alkylene-NR _a R _b ,

. or two adjacent Z radicals together form a C _1-3 - alkylenedioxy group;

R _a and R _b each independently represent a hydrogen atom or a C-ι _-3 -alkyl or -C (O) -C _1-3 -alkyl group,

. or R _a and R _b together with the nitrogen atom carrying them, form a heterocycle optionally substituted with one or more C _1-3 -alkyl or oxo groups; it being understood that when R represents a hydrogen atom, then at least one of the two following conditions is met: R ₄ represents a heterocycle group; said heterocycle being optionally substituted, - Z represents a group -SO ₂ -NR _a R _b or a group -O-C _1-5 -alkylene-NR _a R _b . Among the compounds of formula (I) which are subjects of the invention, there may be mentioned a fourth subgroup of compounds which are defined as follows:

A represents a C 1-4 alkylene group optionally substituted with one or more groups R _{9 which are} identical to or different from one another; • B represents a C-ι _-4 -alkylene group optionally substituted by one or more identical or Rio groups different from each other;

• R ₉ and R ₁₀ are each independently of one another, a hydrogen atom or a C ^ -alkyl group and in particular methyl,

. or R ₉ and R ₁₀ together form a C _1-4 -alkylene group; • L represents a single bond or -CH = CH-;

• R represents a hydrogen atom or a C _1-5 -alkyl, C _1-3 fluoroalkyl, C _3-6 - cycloalkyl, Ci _-3 -alkylene-C _3-6 -cycloalkyl;

R ₂ and R ₃ independently of one another represent a hydrogen atom or a C _1-3 -alkyl group;

R ₄ represents:

. a hydrogen atom or a C _1-5 -alkyl, C _3-6 -cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, C _1-3 -alkylene-OC _1-3 -alkyl group, . a C _1-3 -alkylene- (OH) group,

. a heterocycle group; said heterocycle group being optionally substituted with a C _1-3 -alkyl, -C (O) C _1-3 -alkyl, -C (O) C ₁ -C ₃ -fluoroalkyl, C _1-3 -alkylene- C ₃ . ₆ - cycloalkyl, C _1-3 -alkylene-aryl; the group C _1-3 -alkylene-aryl optionally substituted by one or more identical radicals Z or different from each other,

. or R ₄ is C _1-3 -alkylene-NR _a R _b , aryl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-OC _{1 -3} -alkylene-aryl, heteroaryl or C-ι _-3 -alkylene-heteroaryl; aryl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-O-

C ₁ . ₃ -alkylene-aryl, heteroaryl and C _1-3 -alkylene-heteroaryl being optionally substituted with one or more radicals Z which are identical to or different from each other;

R ₅ represents a hydrogen atom or a C _1-5 alkyl, C _1-5 alkoxy or aryl group; the aryl group being optionally substituted by one or more radicals Z which are identical or different from one another;

R ₇ represents a halogen atom or a C _1-5 -alkyl group and in particular a methyl, C _1-5 -alkoxy and in particular a methoxy, CN, COOH or -C (O) OC _1-3 - alkyl;

• Z represents a halogen atom or a Ci _-5 alkyl group, C _1-3 fluoroalkyl, C _3-6 - cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, phenyl, C _{1 -5} -alkoxy, C _1-3 -fluoroalkoxy, C _1-3 - Alkylene-OC _1-3 -alkyl, C _1-3 -alkylene- (OH), NO ₂ , -CN, -SO ₂ NR _a R _b , -XC _1-3 -alkyl, C _1-3 - alkylene-XC _1-3 -alkyl where X is S, SO or SO ₂ ,

. or Z represents a group -NR ₃ Rb, C _1-3 -alkylene-NR _a R _b , -C (O) -NR ₃ Rb, -CCCO-C-μs-alkyl, -C (O) OC _{1- 4} -alkyl, -C (O) -C ₃ . ₆ -cycloalkyl, or else Z represents an oxo radical,

. or Z represents a group -OC _1-5 -alkylene-NRaRb,

. or two adjacent Z radicals together form a C _1-3 - alkylenedioxy group;

R _a and R _b each independently represent a hydrogen atom or a C _1-3 -alkyl or -C (O) -C _1-3 -alkyl group,

. or R ₃ and R _b together with the nitrogen atom carrying them, form a heterocycle optionally substituted with one or more C _1-3 -alkyl or oxo groups; it being understood that at least one of the conditions previously stated is respected.

Among the compounds of formula (I) which are subjects of the invention, there may be mentioned a fifth subgroup of compounds which are defined as follows:

A represents a C _1-4 -alkylene group and in particular an ethylene, optionally substituted with one or more R ₉ groups;

B represents a C _1-4 -alkylene group and in particular an ethylene, optionally substituted with one or more R ₁₀ groups;

Rg and Rio each represent, independently of one another, a hydrogen atom or a methyl,

. or R ₉ and R ₁₀ together form a C _1-4 -alkylene group;

• L represents a single bond or -CH = CH-; R represents a hydrogen atom or a C _1-5 alkyl group and in particular an ethyl C ₁ . ₃ -alkylene-C ₃ . _6- cycloalkyl;

R ₁ represents aryl or heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other; R ₂ and R ₃ represent, independently of each other, a hydrogen atom or a C _1-3 -alkyl group and in particular a methyl;

R ₄ represents:

. a hydrogen atom or a C _1-5 -alkyl, C ₃ -s _- cycloalkyl, C _1-3 -alkylene-C _{3 group} . ₆ -cycloalkyl, C _1-3 -alkylene-OC _1-3 -alkyl and in particular methylene-O-methyl, a C _1-3 -alkylene- (OH) group,

. a heterocycle group optionally substituted by a C _1-3 alkyl-C (O) C _{1 group} . ₃ -alkyl, -C (O) C ₁ . ₃ fluoroalkyl, Ci. ₃ -alkylene-C _3. ₆ -cycloalkyl, C _1-3 -alkylene-aryl and in particular methylene-phenyl; the C _1-3 -alkylene-aryl group being optionally substituted by one or more radicals Z that are identical to or different from each other,

. or R ₄ represents a C _1-3 -alkylene-NR _a R _b , aryl and in particular a phenyl, C _1-3 -alkylene-aryl and in particular a C _1-3 -alkylene-phenyl, C _{1- 3} -alkylene-O-aryl and in particular a C _1-3 -alkylene-O-phenyl, C _1-3 -alkylene-OC _1-3 -alkylene-aryl and in particular a C _1-3 -alkylene-OC _{1 -3-} alkylene-phenyl, heteroaryl and especially thienyl or pyridinyl; aryl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-O-aryl, C _{1 groups} .

₃ -alkylene-OC _1-3 -alkylene-aryl and heteroaryl being optionally substituted with one or more radicals Z which are identical to or different from each other;

R ₅ represents a hydrogen atom;

R ₇ represents a halogen atom, a methyl, a methoxy, CN, COOH or -C (O) O-C _1-3 -alkyl;

Z represents a halogen atom or a C _1-5 alkyl group, a phenyl, C _1-5 alkoxy and in particular methoxy, C ₁ . _3- Alkylene-OC _1-3 -alkyl, C _1-3 -alkylene- (OH), -CN, -SO ₂ NR _a R _b ,

-XC _1-3 -alkyl, C _1-3 -alkylene-XC _1-3 -alkyl wherein X is S, SO or SO ₂ ;

. or Z represents a group -NR ₃ Rb, C _1-3 -alkylene-NR _a Rb, -C (O) -NR ₃ Rb, -C (O) -C _1-3 -alkyl,

. or Z represents an oxo radical, or Z represents a group -OC _1-5 -alkylene-NR _a R _b ,

. or two adjacent Z radicals together form a C _1-3 -alkylenedioxy group, and in particular a methylenedioxy;

R _a and R _b each independently represent a hydrogen atom or a C _1-3 -alkyl or -C (O) -C _1-3 -alkyl group; or R _a and R _b together with the nitrogen atom carrying them, form a heterocycle optionally substituted with one or more C _1-3 -alkyl or oxo groups; it being understood that at least one of the conditions previously stated is respected.

Among the compounds of formula (I) which are subjects of the invention, there may be mentioned a sixth subgroup of compounds which are defined as follows:

A represents an ethylene, optionally substituted with one or more groups R ₉ ;

B represents an ethylene, optionally substituted with one or more R ₁₀ groups;

R ₈ and R ₁₀ each independently represent a hydrogen atom or a methyl; L represents a single bond;

R represents a hydrogen atom, an ethyl group or C _1-3 -alkylene-C ₃ . ₆ - cycloalkyl; R ₁ represents aryl or heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other;

R ₂ and R ₃ represent, independently of one another, a hydrogen atom or a methyl group;

R ₄ represents:

. a hydrogen atom or a C _1-5 -alkyl, C _3-6 -cycloalkyl, C _1-3 -alkylene-C _{3 group} . ₆ -cycloalkyl, methylene-O-methyl,

. a C _1-3 -alkylene- (OH) group, a heterocycle group optionally substituted with a C _1-3 -alkyl group,

-C (O) C _1-3 -alkyl, -C (O) C _1-3 -fluoroalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, methylene-phenyl; the methylene-phenyl group being optionally substituted with one or more radicals Z that are identical to or different from one another,

. or R ₄ represents a C _1-3 -alkylene-NR _a Rb group, a phenyl, a C _1-3 -alkylene-phenyl, a C _1-3 -alkylene-O-phenyl, a C _1-3 -alkylene- OC _1-3 -alkylene-phenyl, thienyl or pyridinyl; the phenyl, C _1-3 -alkylene-phenyl, C _1-3 -alkylene-O-phenyl, C _1-3 -alkylene-OC _1-3 -alkylene-phenyl, thienyl and pyridinyl groups being optionally substituted by one or more radicals Z identical to or different from each other; R ₅ represents a hydrogen atom;

• R ₇ represents a halogen atom, a methyl, a methoxy, CN;

• Z represents a halogen atom or a Ci _-5 alkyl group, phenyl, methoxy, C _1-3 -alkylene-OC _1-3 -alkyl, C _1-3 -alkylene- (OH) -CN , -SO ₂ NR _a R _b , -XC _1-3 -alkyl, C _1-3 - alkylene-XC _1-3 -alkyl where X is S, SO or SO ₂ ,. or Z is -NR _a R _b , C _1-3 -alkylene-NR _a R _b , -C (O) -NR _a R _b ,

-C (O) -C _1-3 -alkyl,

. or else Z represents an oxo radical,

. or Z represents a group -OC _1-5 -alkylene-NR _a R _b ,

. or two adjacent Z radicals together form a methylenedioxy group;

. or R _a and R _b together with the nitrogen atom carrying them, form a heterocycle optionally substituted with one or more C ₁ -C ₃ -alkyl or oxo groups; it being understood that at least one of the conditions previously stated is respected.

Among the compounds of formula (I) which are subjects of the invention, mention may especially be made of compounds selected from:

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -4- (1-benzylpiperidin-4-yl) -7-methoxyphthalazin-1-amine hydrochloride (compound no. 1)

N- (1- {4- [3- (Dimethylamino) propoxy] benzyl} piperidin-4-yl) -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine hydrochloride (Compound No. 3) )

N- {1- [3-fluoro-4- (3-morpholin-4-ylpropoxy) benzyl] piperidin-4-yl} -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine hydrochloride (compound no. 4)

7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (2-piperidin-1-ylethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine hydrochloride (Compound No. 5) -N- (1- {4- [3- (dimethylamino) propoxy] -3-fluorobenzyl} piperidin-4-yl) -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine hydrochloride (compound no. 8)

7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (2-pyrrolidin-1-ylethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine hydrochloride (compound no. 9) -7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (2-morpholin-4-ylethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine hydrochloride (compound n ° 10)

7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (3-piperidin-1-ylpropoxy) benzyl] piperidin-4-yl} phhalazin-1-amine hydrochloride (compound no. 11)

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -N-ethyl-7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine dihydrochloride (compound no. ° 12)

4 - [(4 - {[7-Methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] -N- (2-piperidin-1-ylethyl) hydrochloride ) benzamide (compound 13)

N- [1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] -7-methoxy-4- (tetrahydro-2H-pyran-4-yl) phthalazin-1-amine dihydrochloride ( Compound No. 19) 7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (3-methoxypropoxy) benzyl] piperidin-4-yl} phthalazin-1-amine dihydrochloride (Compound No. ° 20)

N- (1- {4- [3- (dimethylamino) propoxy] -3-fluorobenzyl} piperidin-4-yl) -4-ethyl-7-methoxyphthalazin-1-amine hydrochloride (Compound No. 21)

N- (1- {4- [3- (dimethylamino) propoxy] -3-fluorobenzyl} piperidin-4-yl) -7-methoxy-4- (methoxymethyl) phthalazin-1-amine hydrochloride (compound no. 22)

N- {1- [3-fluoro-4- (3-pyrrolidin-1-ylpropoxy) benzyl] piperidin-4-yl} -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine hydrochloride (compound No. 23)

1- (3- {4 - [(4 - {[7-Methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propyl) pyrrolidine hydrochloride -2-one (compound No. 24)

N- (1- {4- [2- (Dimethylamino) ethoxy] benzyl} piperidin-4-yl) -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine hydrochloride (Compound No. 25) ) 7-Methoxy-4- (4-methoxyphenyl) -N- (1- {4 - [(1-methylazepan-4-yl) oxy] benzyl} piperidin-4-yl) phthalazin-1-amine hydrochloride ( compound no. 26)

7-Methoxy-4- (4-methoxyphenyl) -N- (1- {4- [2- (1-methylpyrrolidin-2-yl) ethoxy] benzyl} piperidin-4-yl) phthalazin-1 hydrochloride amine (Compound No. 27) 4-Ethyl-N- [1- (4-ethynylbenzyl) piperidin-4-yl] -7-methoxyphthalazin-1-amine dihydrochloride (Compound No. 28)

N- (1- {4- [3- (dimethylamino) prop-1-yn-1-yl] benzyl} piperidin-4-yl) -4-ethyl-7-methoxyphthalazin-1-amine hydrochloride (compound n ° 29)

3- {4 - [(4 - {[7-Methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol dihydrochloride (compound n ° 30)

4-Ethyl-7-methoxy-N- {1- [4- (4-pyrrolidin-1-ylpiperidin-1-yl) benzyl] piperidin-4-yl} phthalazin-1-amine hydrochloride (compound no. 31)

N- (1- {4- [3- (dimethylamino) propoxy] benzyl} piperidin-4-yl) -7-methoxy-4- (methoxymethyl) phthalazin-1-amine hydrochloride (Compound No. 32) N- (1- {4 - [(3S) -3- (dimethylamino) pyrrolidin-1-yl] benzyl} piperidin-4-yl) -7-methoxy-4- (methoxymethyl) phthalazin-1-amine trihydrochloride (compound no. 33)

N- (1- {4 - [(3R) -3- (dimethylamino) pyrrolidin-1-yl] benzyl} piperidin-4-yl) -7-methoxy-4- (methoxymethyl) phthalazin-1-hydrochloride amine (compound no. 34)

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -7-methoxy-4- [4- (2-methyl-2H-tetrazol-5-yl) phenyl) dihydrochloride ] Phthalazin-1-Amine (Compound No. 35)

7-Methoxy-4- (methoxymethyl) -N- (1- {4 - [(1-methylpyrrolidin-3-yl) methoxy] benzyl} piperidin-4-yl) phthalazin-1-amine hydrochloride (compound no. ° 36)

7-Methoxy-4- (methoxymethyl) -N- (1- {4 - [(8-methyl-8-azabicyclo [3.2.1] oct-3-yl) oxy] benzyl} piperidin-4- hydrochloride yl) phthalazin-1-amino (Compound No. 37) - 2 - [{4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalamino-1-yl] amino} piperidin-1 hydrochloride -yl) methyl] phenyl (methyl) amino] ethanol (compound 38)

7-Methoxy-4- (methoxymethyl) -N- {1- [4- (2-oxo-2-pyrrolidin-1-ylethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine dihydrochloride (compound n ° 39)

3- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol dihydrochloride (compound ° 40)

7-Methoxy-4- (methoxymethyl) -N- (1- {4 - [(1-methylazepan-4-yl) oxy] benzyl} piperidin-4-yl) phthalazin-1-amine hydrochloride (Compound No. ° 41)

7-Methoxy-4- (methoxymethyl) -N- (1- {4- [2- (1-methylpiperidin-2-yl) ethoxy] benzyl} piperidin-4-yl) phthalazin-1-amine hydrochloride ( Compound No. 42) 2- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} ethanol dihydrochloride (compound n ° 43)

7-Methoxy-4-methyl-N- (1- {4 - [(1-methylazepan-4-) hydrochloride yl) oxy] benzyl} piperidin-4-yl) phthalazin-1-amine (Compound No. 44)

3- {3 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol dihydrochloride (compound 45 )

3- [4 - ({4 - [(7-Methoxy-4-methylphthalazin-1-yl) amino] piperidin-1-yl} methyl) phenoxy] propan-1-ol dihydrochloride (Compound No. 46)

7-Chloro-4-methyl-N- (1 - {4 - [(1-methylazepan-4-yl) oxy] benzyl} piperidin-4-yl) phthalazin-1-amine hydrochloride (Compound No. 47) )

3- [4 - ({4 - [(7-Chloro-4-methylphthalazin-1-yl) amino] piperidin-1-yl} methyl) phenoxy] propan-1-ol dihydrochloride (Compound No. 48) (3S) -1- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenyl} pyrrolidin-3-ol trihydrochloride ( Compound No. 49)

(3R) -1- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenyl} pyπrolidin-3-ol hydrochloride (Compound No. 50)

7-Methoxy-4- (methoxymethyl) -N- {1- [4- (4-pyrrolidin-1-ylbutyl) benzyl] piperidin-4-yl} phthalazin-1-amine tri-trioxalate (Compound 53)

2- {3 - [(4 - {[7-Methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} ethanol dihydrochloride (Compound 54)

2- {3 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} ethanol dihydrochloride (Compound 55) - Dihydrochloride of 3 - {3 - [(4 - {[7-methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol (Compound 56)

3- {4 - [(4 - {[7-Methoxy-4- (trifluoromethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol dihydrochloride (Compound 57)

7-Methoxy-4- (methoxymethyl) -N- {1- [4- (octahydro-2H-pyrido [1,2-a] pyrazin-2-yl) benzyl] piperidin-4-yl} phthalazin hydrochloride -1-Amine (Compound 58)

3- [4 - ({4 - [(7-methoxyphthalazin-1-yl) amino] piperidin-1-yl} methyl) phenoxy] propan-1-ol dihydrochloride (Compound 63)

7-Methoxy-4- (methoxymethyl) -N- [1- [4- (6-methyloctahydro-1H-pyrrolo [3,4-b] pyridin-1-yl) benzyl] piperidine-4-trihydrochloride 1-Phthalazin-1-amine compound (Compound No. 64) -7-Methoxy-4- (4-methoxyphenyl) -N- [1- [4- (7-methyl-2) _] - diazaspiro hydrochloride [4.4] ] Non-2-yl) benzyl] piperidin-4-yl} phthalazin-1-amine (Compound No. 65)

4- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenyl} butan-1-ol dihydrochloride (compound no. 66)

7-Methoxy-4- (methoxymethyl) -1- [1 - ({1- [4- (trifluoromethyl) phenyl] -1H-pyrrol-3-yl} methyl) piperidin-4-yl] dihydrochloride phthalazin-1-amine (compound 67)

Λ- (1- {4- [2- (1H-imidazol-1-yl) ethoxy] benzyl} piperidin-4-yl) -hydrochloride Methoxy-4- (4-methoxyphenyl) phthalazin-1-amine (Compound No. 68)

7-Methoxy-4- (4-methoxyphenyl) -N- (1- [4- (pyridin-4-ylmethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine hydrochloride (Compound No. 69) )

7-Methoxy-4- (4-methoxyphenyl) -N- (1- [4- (tetrahydrofuran-2-ylmethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine dihydrochloride (Compound No. 70 )

According to the invention, the compounds of general formula (I) can be prepared according to the process illustrated by the following scheme 1.

In the following diagrams, the starting compounds and the reagents, when their method of preparation is not described, are commercially available or described in the literature, or they can be prepared according to the methods described therein or are known to those skilled in the art.

The compound of general formula (I) can be obtained according to Scheme 1 which follows.

Diagram 1

According to Scheme 1, the compound of general formula (I) is prepared from a compound of general formula (III), wherein R4, R5 and R7 are as defined in general formula (I), according to the A, by nucleophilic substitution of chlorine with the amine of the compound of general formula (II), wherein R, R 1, R 2, R 3, L, A and B are as defined in general formula (I). This reaction can be carried out by heating the compounds of general formulas (II) and (III) in an alcohol such as n-butanol or n-pentanol in the presence of ammonium chloride according to the method described by Contreras et al (J. Chem., 2001, 44, 2707-2718), or it may also be catalyzed by a transition metal such as palladium for example in the form tris (dibenzylidene-acetone) -palladium in the presence of a ligand such as BINAP (2,2'-bis (diphenylphosphino) -1,1'-binaphthyl) and a base such as sodium or potassium tert-butylate using toluene or dimethoxyethane as the solvent. optionally in the presence of lithium bromide according to the method described by Wolfe et al (JACS, 1996, 118, 7215-7216), which may be modified (Tet, Let 1997, 38 (12), 2073-2074, Angew Chem Int. Ed 2005, 44, 1371-1375).

In the case where R ₃ is a hydrogen atom, the compound of general formula (I) may also be prepared, according to route B, from the compound of general formula (Ib), in which A, B, R, R ₄ , R ₅ and R ₇ are as defined in the general formula (I) and in which the nitrogen of the nitrogenous ring is not substituted, in particular by a reductive amination reaction with an aldehyde or a ketone of general formula R ₁ -L-C (O) R ₂ , wherein L, R ₁ and R ₂ are as defined in general formula (I). This reaction may for example be carried out in the presence of sodium triacetoxy borohydride in a solvent such as dichloromethane or 1,2-dichloroethane according to one of the methods described in Abdel-Magid et al (J. Org Chem 1996, 61, 3849-3862). The compound of general formula (Ib) is obtained by deprotection of the compound of general formula (la) which has on the nitrogen of the nitrogen ring a protective group PG. This protecting group can be, for example, benzyl, ethoxycarbonyl or tert-butoxycarbonyl and deprotection can be carried out according to the methods cited in Protective Groups in Organic Synthesis 3 ^rd edition John Wiley & Sons, New York 1999. The compound of general formula (Ia) is synthesized by reacting a compound of general formula (III) as defined above with a compound of general formula (IIa) according to the methods already described above for compound (I).

The amine of general formula (IIa) wherein R represents a hydrogen atom, when it is not commercial, may be prepared by analogy to the methods described in the literature (Mach et al., J. Med Chem 1993 36, 3707-3720, Dostert et al., Eur J. Chem Chem Ther 1984, 19 (2), 105-110). The amine of formula (II) wherein R represents a hydrogen atom, when it is not commercial can be prepared by analogy with the methods previously mentioned for (IIa) and with the methods described in the following publications: Moragues et al (Farmaco, Sci., 1980, 35 (11), 951-964) and Shum et al (Nucleoside Nucleotides 2001, (4-7), 1067-1078).

The amines of formula (II) or (IIa) for which R represents a methyl may be prepared by reduction with lithium aluminum hydride (LiAlH ₄ ) of the tert-butoxycarbonyl group previously introduced on the primary amine according to the reduction method. employed by Gibson et al (Tetrahedron Asymmetry 1995, 6, 1553-1556). The amines of formula (II) or (IIa) for which R represents an alkyl other than methyl can be prepared by reducing an amide (previously introduced on the primary amine) with lithium aluminum hydride (LiAlH ₄ ). or borane-tetrahydrofuran complex (BH ₃ -THF). For example, when R represents an ethyl group, the primary amine is acylated with acetyl chloride and then the acetamide obtained is reduced by lithium aluminum hydride.

The 1-chlorophthalazine of general formula (III) can be obtained by heating 2H-phthalazin-1-one of general formula (IV) in phosphoryl chloride, for example.

2 / - / - phthalazin-1-one of general formula (IV) may be prepared from a 2-acyl-benzoic acid of general formula (V) by heating in an alcohol such as ethanol, in presence of hydrazine hydrate for example.

The 2-acyl-benzoic acid of general formula (V) can be synthesized from a 2-bromo-benzoic acid of general formula (VII) by halogen-metal exchange and then reaction with a chloride of acid of general formula (VI) or with a Weinreb amide, of type / -methoxy-Λ / -methylamide type of formula (Vl ¹ ):

(VI ') or an ester such as ethyl trifluoroacetate. Halogen-metal exchange can be carried out with n-butyllithium in tetrahydrofuran at -78 ° C. In the case where R ₄ represents a hydrogen atom, the acid chloride of general formula (VI) is replaced by dimethylformamide. The compounds of formula (VI ') can be obtained from the compound of formula (VI) and Λ-methoxy-β-methylamine, in particular according to the method described by Weinreb (Tetrahedron Letters, (1981), 22 (39)). ): 3815-3818).

The 2-acyl-benzoic acid of general formula (V) can also be obtained by other reactions such as, for example, the Friedel-Crafts reaction on a compound of general formula (VIII) in the presence of a compound of general formula (VI). This reaction is carried out in the presence of aluminum chloride in a solvent such as dichloromethane.

The compound of general formula (I) can also be obtained according to scheme 2 which follows.

Figure 2

According to Scheme 2, the compound of general formula (I) in which R is different from the hydrogen atom can also be prepared from the compound of general formula (Ic) in which R is a hydrogen atom, by alkylation with an alkyl halide (RX) in the presence of a base, for example sodium hydride in a solvent such as tetrahydrofuran. The compound of general formula (Ic) can also be acylated with an anhydride or an acid chloride of R ¹ C (O) Y type to form an amide of general formula (Id). This amide can be reduced by lithium aluminum hydride (LiAlH ₄ ) or by the borane-tetrahydrofuran complex (BH ₃ -THF) to obtain a compound of general formula (I) in which R represents an alkyl /

The compounds of formula (I) are very affine and selective with respect to the Melanin-Concentrating Hormone Receptor (MCH) 1, MCH-1.

In vitro tests have demonstrated the affinity of the compounds for MCH receptors and in particular MCH ₁ .

Since MCH is an important regulator of food intake, small nonpeptide molecules able to antagonize its stimulating action of the MCH ₁ receptor are a therapy of choice for treating metabolic problems related to obesity but also to bulimia nervosa. Indeed, the use of an MCH-1 receptor antagonist such as SNAP-7941 (described by Synaptic Laboratories) confirms the important role of MCH in the regulation of energy balance and the development of obesity ( Katsuura et al., Curr Med Chem 2003; 3: 217-227).

The compounds according to the invention therefore represent a therapy of choice for the treatment of diseases presenting disorders of the regulation of the energy balance as well as for the treatment of the development of obesity.

MCH is a functional antagonist of the melanocortin system, counteracting its effects on food intake and on the hypothalamic-pituitary-adrenal axis (Ludwig et al., Am J Physiol 1998; 274: E627-E633). It is also involved in regulation of the hypothalamic-pituitary-adrenal axis and in stress response via hypothalamic CRF release (Kennedy et al., J Neuroendocrinol 2003; 15 (3): 268-272). The use of an MCH ₁ receptor antagonist has recently confirmed the anxiogenic effect of MCH. Indeed, SNAP-7941 has an anxiolytic and / or antidepressant profile in different animal models such as social conflict and forced swimming in rats as well as maternal separation in guinea pigs (Katsuura et al, Curr Med Chem 2003; : 217-227). MHC ₁ receptor antagonist molecules are therefore of therapeutic interest in depression and / or anxiety. The MCH seems to be involved with other regulatory systems. By its testicular location (Hervieu et al., Biology of Reproduction 1996; 5: 1161-1172) and hypothalamic (dependent estrogen, Viale et al., Peptides 1999; 20: 553-559) and by its stimulating effects of the sexual activity of the male rats (Gonzales et al., Peptides 1996; 17: 171-177) and the secretion of luteinizing hormone (Chiocchio et al., Biology of Reproduction 2001; 64: 1466-1472), the MCH thus seems to play a role in the reproductive functions.

It was also observed that MCH is involved in behavior related to cognitive functions by increasing the extinction of Pévitement liability in rats, suggesting that MCH receptor antagonist may be useful when _one memory disorders (McBride et al Peptides 1994; 15 (4): 757-759). Thus, the compounds according to the invention may constitute a therapy of choice for the treatment of memory disorders.

Finally, it has also been shown that MCH plays a role in urinary disorders and in particular urinary incontinence (US2004 / 0038855A1).

Thus, the compounds of the invention find use in therapy, especially in the treatment of obesity, cellulitis, urinary incontinence, metabolic disorders and their associated pathologies such as diabetes, cardiovascular disorders, Syndrome X, in the treatment of stress-related pathologies such as anxiety and depression, as well as in the treatment of any other diseases involving dysfunction related to the MCHi receptor either centrally and / or peripherally.

Thus, according to another of its aspects, the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid, or a hydrate or a solvate.

According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active ingredient, at least one compound according to the invention. These pharmaceutical compositions comprise an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or solvate of said compound, as well as at least one pharmaceutically acceptable excipient. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its salt, solvate or hydrate, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.

Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.

By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg

Croscaramellose sodium 6.0 mg

Corn starch 15.0 mg

Hydroxypropyl methylcellulose 2.25 mg

Magnesium stearate 3.0 mg

Said unit forms are dosed to allow daily administration of 0.5 mg to 800 mg of active ingredient per individual, more particularly from 0.5 mg to 200 mg, depending on the dosage form.

There may be cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient. The present invention, according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or of one of its pharmaceutically acceptable salts or hydrates or solvates. The following examples describe the preparation of compounds according to the invention. These examples are not limiting and only illustrate the present invention. The numbers of the exemplified compounds refer to those given in Table I.

The abbreviations and symbols used for the description of the procedures of synthesis and for the description of the compounds are the following: DMF for dimethylformamide,

DMSO for dimethylsulfoxide, THF for tetrahydrofuran,

HCI for hydrochloric acid, HBr for hydrobromic acid, NaOH for sodium hydroxide,

- And for ethyl, - Me for methyl.

- TFA for trifluoroacetic acid NMP for N-methyl pyrrolidinone

Melting points (PF) are expressed in degrees Celsius. They were measured either with a Koffler apparatus (mention (K) in the following), or with a Mettler-Toledo FP62 apparatus (mention (M) in the following), or with a Bϋchi B540 apparatus (reference (B) ) in the following).

The conditions for analysis by liquid chromatography coupled with mass spectrometry (LC / UV / MS) are as follows:

For the liquid chromatography part 3 types of chromatographic systems with different pH are used:

- chromatographic system at pH 3.1 (+/- 0.1)

- Symmetry column C18 (2.1 x 50 mm) 3.5 μm No. WAT200650 - Eluent A = H ₂ O + 0.005% TFA

Eluent B = CH ₃ CN + 0.005% TFA.

Gradient from 100% A to 90% B in 10 minutes, then elution with 90% B for 5 minutes.

- Flow 0.4ml / minute - Injection of 2μL of 0.5 mg / ml solution in methanol

- chromatographic system at pH 2.2 (+/- 0.1)

- Xterra MS C18 column (2.1 x 50 mm) 3.5 μm No. 186000400 Eluent A = H ₂ O + 0.1% HFBA (heptafluorobutyric acid)

Eluent B = 90% CH ₃ CN + 10% H ₂ O TFA + 0.1% HFBA.

Gradient: 100% A for 2 minutes then 100% A to 100% B in 10 minutes, then elution with 100% B for 5 minutes. - Flow 0.4ml / minute

Injection of 2 μL of 0.5 mg / ml solution in methanol - chromatographic system at pH 7 (+/- 0.1)

- Xterra MS C18 column (2.1 x 50 mm) 3.5 μm No. 186000400

Eluent A = aqueous solution of ammonium acetate 0.01 M - Eluent B = CH ₃ CN

- Flow 0.4ml / minute; temperature 30 ^° C.

Injection of 2 μl of 0.5 mg / ml solution in methanol The products are detected in UV at 220 nm or at 210 nm. For the mass spectrometry part:

Ionization mode: positive electrospray (API-ES polarity +)

- Scanning from 120 to 1500 uma

The analytical characteristics of LC / MS of the products are the ratio m / z of the ion MH ⁺ and MNa ⁺ ion and retention time (tR) of the corresponding peak observed in UV and expressed in minutes. Some pluriazote products can be eluted on the HPLC column in two forms, a very large majority, depending on the degree of salification; in this case, the two retention times are noted.

Proton nuclear magnetic resonance spectra ( ¹ H NMR) were carried out at 250 MHz, 300 MHz, 400 MHz or 500 MHz on Brϋker instruments. The abbreviations used to characterize the signals are as follows: s = singlet, m = multiplet, d = doublet, t = triplet, q = quadruplet.

Quantification salts and solvates is determined using elemental analysis, the determination of water content by the Karl-Fischer and the integration of the signals characteristic of Solvent ¹ H NMR

The compounds of the invention as well as their analytical characteristics (PF, LC / MS, salts and solvates) are indicated in Table I. Example 1

(N - [1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] -4- (1-benzylpiperidin-4-yl) -7-methoxy-phthalazin-1-amine hydrochloride (Compound) n ° 1)

1.1 [1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] tert-butyl carbamate

To a solution of 9.36 g (46.8 mmol) of tert-butyl (piperidin-4-yl) carbamate in 170 ml of 1,2-dichloroethane is added piperonal 7.02 g (46.8 mmol). . The reaction mixture is placed under a nitrogen atmosphere and stirred for 30 min at room temperature. 13.9 g (63.5 mmol) of sodium triacetoxyborohydride are then introduced in small portions. After stirring at room temperature overnight, the reaction mixture is hydrolyzed with water and 2N sodium hydroxide solution and then extracted with dichloromethane. The combined organic phases are washed with water and with salt water, then dried over anhydrous sodium sulphate and evaporated under reduced pressure. 12.9 g of a white solid are obtained. MP = 96 ° C (M)

MH ⁺ = 335 (tR = 5.16 minutes pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.35-1.45 (m, 2H); 1.38 (s, 9H); 1.65-1.75 (m, 2H); 1.85-2.0 (m, 2H); 2.65-2.8 (m, 2H); 3.1-3.3 (m, 1H); 3.33 (s, 2H); 5.99 (s, 2H); 6.7-6.8 (m, 1H); 6.8-6.9 (m, 2H).

1.2. 1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl-amine

A suspension of 12.9 g (38.8 mmol) of tert-butyl [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] carbamate in 130 mL of ethyl acetate is added 130 mL of a solution of 2N HCl in diethyl ether. The reaction mixture is stirred at room temperature for 12 hours. The precipitate formed is filtered off, rinsed with ethyl acetate and then dried in an oven (40 ^° C.) under reduced pressure. 12.7 g of dihydrochloride are obtained in the form of a white solid. A portion is converted to the corresponding base: 312 mg are stirred with 1.17 g (4 equivalents) of (polystyrylmethyl) trimethylammonium bicarbonate resin (Novabiochem) in 10 ml of dichloromethane for 5 hours. After filtration and rinsing of the resin with dichloromethane, the organic phase is evaporated. 174 mg of a white solid are obtained. M.p. = 69 ° C (M)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1, 10-1, 30 (m, 2H); 1.60-1.75 (m, 2H); 1.85-2.0 (m, 2H); 2.45-2.55 (m, 1H); 2.65-2.75 (m, 2H); 2.7-3.4 (m, 2H, NH ₂ ); 3.33 (s, 2H); 5.99 (s, 2H); 6.7-6.8 (m, 1H); 6.8-6.9 (m, 2H).

1.3. Methyl (piperidin-4-yl) carboxylate hydrochloride

5.0 g (38.7 mmol) of isonipecotic acid is slowly added to a solution of 9.3 ml of thionyl chloride (129 mmol) in 50 ml of methanol, keeping the temperature below -10 ^° C. The mixture is stirred at ambient temperature for 22 hours. The reaction medium is evaporated under reduced pressure. 6.8 g of the expected derivative are obtained in the hydrochloride form.

¹ H NMR (DMSO-de, 250 MHz) δ ppm: 1, 7-1, 85 (m, 2H); 1.9-2.05 (m, 2H); 2.6-2.75 (m,

1H); 2.8-3.0 (m, 2H); 3.15-3.3 (m, 2H); 3.64 (s, 3H); 8.9-9.3 (m, 2H, NH ₂ ⁺ ).

1.4. Methyl (1-benzyl-piperidin-4-yl) carboxylate

4.80 mL of benzyl bromide (37.9 mmol) is slowly added to a solution of methyl (piperidin-4-yl) carboxylate hydrochloride (6.84 g, 37.9 mmol) in 40 mL of dichloromethane. Then, 10.7 ml (76.9 mmol) of triethylamine are slowly added while maintaining the temperature at 100 ^° C. After stirring overnight at room temperature, the reaction medium is hydrolyzed with water and a saturated solution of sodium hydrogencarbonate, then extracted with dichloromethane. The combined organic phases are washed with water and with salt water, then dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: dichloromethane / methanol 100/0 to 95/5 (v / v)). 7.03 g of product are obtained in the form of an orange oil. MH ⁺ = 234 (tR = 3.79 and 3.95 minutes, pH 3.1) ¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.5-1.7 (m, 2H); 1.75-1.9 (m, 2H); 1.9-2.05 (m, 2H); 2.25-2.4 (m, 1H); 2.7-2.8 (m, 2H); 3.45 (s, 2H); 3.61 (s, 3H); 7.2-7.4 (m, 5H).

1.5 (1-Benzyl-piperidin-4-yl) -Λ / ^{r-methoxy-yV-methyl-carboxamide:}

A solution of 4.17 g (42.8 mmol) of N, O-dimethylhydroxylamine hydrochloride in 195 ml of THF is cooled to -20 ^° C., and 6.51 g (28 mmol) of 1-Benzyl-piperidin-4-yl) methyl carboxylate. Then 85 ml of a 1 M solution of isopropylmagnesium bromide in THF are added for 20 minutes keeping the temperature close to 5 ° C. The mixture is stirred at -10 ^° C. for 20 minutes. The reaction medium is hydrolyzed with 40 ml of a 20% solution of ammonium chloride and is then extracted with ethyl acetate. The combined organic phases are washed with water and with salt water, then dried over anhydrous sodium sulphate and evaporated under reduced pressure. 6.9 g of oily product are obtained. ¹ H NMR (DMSO-d _6, 250 MHz) δ ppm: 1, 5-1, 75 (m, 4H); 1.9-2.05 (m, 2H); 2.55-2.7 (m, 1H); 2.8-2.9 (m, 2H); 3.09 (s, 3H); 3.46 (s, 2H); 3.67 (s, 3H); 7.2-7.4 (m, 5H).

1.6 2 - [(1-Benzylpiperidin-4-yl) carbonyl] -5-ethoxybenzoic acid

A solution of 2-bromo-5-methoxybenzoic acid (0.9 g (3.89 mmol) in 10 mL of THF is stirred under argon at -78 ° C., followed by the dropwise addition of 7.4 mL (11 mL). 84 mmol) of a 1.6 M solution of n-butyllithium in hexane. The reaction mixture is stirred for 1 hour at -78 ° C., then 0.97 g (3.7 mmol) of (1-benzyl-piperidin-4-yl) -Λ-methoxy- / is added dropwise. V-methyl carboxamide in 5 mL of THF. The reaction mixture is stirred for 1 hour at -78 ° C and 18 hours at room temperature. The mixture is hydrolyzed with 0.6 ml of water and then evaporated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (solvent: dichloromethane / methanol 100/0 to 85/15 (v / v)). 0.47 g of oily product is obtained. MH ⁺ = 354 (tR = 5.08 minutes, pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.3-1.5 (m, 2H); 1, 6-1, 75 (m, 2H); 1.85-2.0 (m, 2H); 2.3-2.5 (m, 1H); 2.75-2.9 (m, 2H); 3.45 (s, 2H); 3.85 (s, 3H); 7.15-7.45 (m, 8H).

1.7 4- (1-Benzylpiperidin-4-yl) -7-methoxy-2H-phthalazin-1-one

A solution of 2.49 g (9.05 mmol) of 2 - [(1-benzylpiperidin-4-yl) carbonyl] -5-methoxybenzoic acid in 45 ml of ethanol is added 4.9 ml ( 45 mmol) of hydrazine hydrate and then stirred at reflux for 2 hours. The reaction medium is cooled and then filtered. The precipitate obtained is washed with ethanol and then dried under reduced pressure at 40 ^° C. 2 g of product are obtained in the form of a white solid. Mp = 262 ⁰ C (M)

MH ⁺ = 350 (tR = 5.06 minutes, pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.7-1.9 (m, 4H); 2.1-2.25 (m, 2H); 2.9-3.0 (m, 2H); 3.1-3.25 (m, 1H); 3.53 (s, 2H); 3.94 (s, 3H); 7.2-7.4 (m, 5H); 7.5 (dd, J ₁ = 7.5 Hz, J ₂ = 2.5 Hz, 1H); 7.67 (d, J = 2.5 Hz, 1H); 8.02 (d, J = 7.5 Hz, 1H); 12.40 (s, 1H, NH).

1.8 4- (1-Benzylpiperidin-4-yl) -1-chloro-7-methoxy-phthalazine

4- (1-Benzylpiperidin-4-yl) -7-methoxy-2H-phthalazin-1-one (350 mg, 1 mmol) is dissolved in 5 ml of phosphoryl chloride. The solution is heated for 3 hours at 80 ^° C. The reaction medium is cooled to ambient temperature and then poured slowly into 200 ml of water with stirring. The mixture is then stirred at 5 ⁰ C and neutralized with a 35% sodium hydroxide solution. The precipitate formed is filtered, washed with water and dried in an oven. 370 mg of product are obtained in powder form. MH ⁺ = 368 (tR = 5.57 minutes) ¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 2.05-2.2 (m, 2H); 2.25-2.45 (m, 2H); 3.05-3.60 (m, 4H); 3.8-3.95 (m, 1H); 4.04 (s, 3H); 4.35 (s, 2H); 7.45-7.6 (m, 4H); 7.6-7.7 (m, 2H); 7.75 (dd, J ₁ = 8.5 Hz, J ₂ = 2.5 Hz, 1H); 8.45 (d, J = 8.5 Hz, 1H).

1.9. N- [1- (1,3-benzodioxol-5-ylmethyl) -piperidin-4-yl] -4- (1-benzylpiperidin-4-yl) -7-methoxy-phthalazin-1-amine trihydrochloride (compound n ° 1)

A suspension of 370 mg (1 mmol) of 4- (1-benzylpiperidin-4-yl) -1-chloro-7-methoxy- phthalazine, in 5 ml of n-butanol is added 234 mg (1 mmol) of 1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl-amine and 53 ml (1 mmol) of sodium chloride. 'ammonium. The mixture is heated at 140 ^° C. for 18 hours. The reaction medium is cooled to ambient temperature, hydrolysed with water and then basified to pH 10 with 1N sodium hydroxide. The mixture is then extracted with ethyl acetate. The organic phase is washed with salt water, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (solvent: dichloromethane / methanol 100/0 to 85/15 (v / v)). 150 mg of oily product are obtained. MH ⁺ = 566 (tR = 4.50 minutes, pH3.1)

¹ H NMR (DMSOd ₆ , 400 MHz) δ ppm: 1.6-1.7 (m, 2H); 1.75-1.85 (m, 2H); 1.85-2.15 (m, 6H); 2.15-2.3 (m, 2H); 2.85-3.0 (m, 2H); 3.2-3.45 (m, 3H); 3.45 (s, 2H); 3.55 (s, 2H); 3.94 (s, 3H); 4.1-4.2 (m, 1H); 6.00 (s, 2H); 6.75-6.9 (m, 4H); 7.2-7.3 (m, 1H); 7.3-7.4 (m, 4H); 7.45 (dd, J ₁ = 8.5 Hz, J ₂ = 2.5 Hz, 1H), 7.68 (d, J = 2.5 Hz, 1H); 8.0 (d, J = 8.5 Hz ₁ 1 H). The trihydrochloride is obtained after treatment of the product dissolved in dichloromethane with a solution of hydrochloric acid in diethyl ether. After concentration and addition of diisopropyl ether, a suspension is obtained which is filtered. The powder obtained is dried at 50 ^° C. under reduced pressure.

Example 2

7-Methoxy-4- (4-methoxyphenyl) -N-methyl-N- [1- (2-naphthylmethyl) piperidin-4-yl] phthalazin-1-amine dihydrochloride (Compound No. 2)

2.1. Fert -butyl [1- (2-Naphtylmethyl) piperidin-4-yl] carbamate

To a solution of 15 g (75 mmol) of tert-butyl (piperidin-4-yl) carbamate in 300 ml of 1,2-dichloroethane is added 11.7 g (75 mmol) of 2-naphthaldehyde. The reaction mixture is placed under a nitrogen atmosphere and stirred for 45 minutes at room temperature. Then 20.6 g (97 mmol) of sodium triacetoxyborohydride are introduced in portions. After stirring at room temperature overnight, the reaction mixture is hydrolyzed with water and basified with about 150 ml of a 1N aqueous sodium hydroxide solution. After extraction with dichloromethane, the phases The combined organic compounds are washed with water and with salt water, dried over anhydrous magnesium sulphate and then evaporated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: dichloromethane / methanol 100/0 to 90/10 (v / v)). 22 g of a white solid are obtained. LC / MS: MH ⁺ = 341 (tR = 5.90 minutes, pH 3.1)

¹ H NMR (DMSOd ₆ , 300 MHz) δ ppm: 1.39 (s, 9H); 1, 3-1, 45 (m, 2H); 1, 6-1, 7 (m, 2H); 1.9-2.05 (m, 2H); 2.75-2.85 (m, 2H); 3.15-3.3 (m, 1H); 3.58 (s, 2H); 6.70-6.75 (m, 1H ₁ NH); 7.45-7.55 (m, 3H); 7.75 (m, 1H); 7.85-7.95 (m, 3H).

2.2. / V-Wléthyl- / V- [1- (2-naphthylmethyl) piperidin-4-yl] -amine

A solution of 1 g (2.94 mmol) of tert-butyl [1- (2-naphthylmethyl) piperidin-4-yl] carbamate in 5 ml of THF is added slowly over a suspension of 223 mg (5.9 mmol). ) lithium aluminum hydride in 10 mL of THF at room temperature. The reaction medium is refluxed for 3 hours. It is then stirred at 0 ° C. and hydrolyzed with 0.2 ml of water, 0.2 ml of 1N sodium hydroxide and then 0.6 ml of water. The gel obtained is filtered and rinsed with dichloromethane. The filtrate is dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 0.7 g of oil are obtained. LC / MS: MH ⁺ = 255 (tR = 2.84 min, pH 3.1) ¹ H NMR (DMSO-d ₆ , 300 MHz) δ ppm: 1, 15-1, 3 (m, 2H); 1.7-1.8 (m, 2H); 1.9-2.05 (m, 2H); 2.15-2.3 (m, 1H); 2.24 (s, 3H); 2.7-2.8 (m, 2H); 3.3-3.4 (m, 1H); 3.58 (s, 2H); 7.4-7.55 (m, 3H); 7.75 (m, 1H); 7.85-7.95 (m, 3H).

2.3. yV, 4-Dimethoxy-yV-methylbenzamide

A solution of 25 g (147 mmol) of 4-methoxybenzoic acid chloride in 450 ml of dichloromethane, stirred at 0-5 ^° C. under nitrogen, is added in fractions of 14.7 g (151 mmol) of hydrochloride. Λ /, O-dimethylhydroxylamine. The mixture stirred at 0-5 ^° C. is then slowly added with 51 ml (370 mmol) of triethylamine. The reaction medium is stirred at room temperature for 3 hours. The mixture is hydrolyzed with 250 ml of water and then extracted with dichloromethane. The organic phase is washed with 100 mL of 1N HCl, 150 mL of 1N NaOH and then with water and salt water. It is dried over anhydrous sodium sulphate, filtered and evaporated to dryness. 26.9 g of orange oil are obtained which are purified on a silica column (eluent: dichloromethane / methanol from 100/0 to 95/5 (Wv)). 25.4 g of yellow oil are obtained. LC / MS: MH ⁺ = 196 (tR = 5.21 minutes, pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 3.26 (s, 3H); 3.56 (s, 3H); 3.82 (s, 3H); 7.00 (d, J = 8.5 Hz, 2H); 7.63 (d, J = 8.5 Hz, 2H).

2.4. 5-methoxy-2- (4-methyl) acid

A solution of 18.5 g (80 mmol) of 2-bromo-5-methoxybenzoic acid in 150 mL of THF is stirred under nitrogen at -78 ° C. 100 ml (160 mmol) of a 1.6M solution of n-butyllithium in hexane are added dropwise for about 1 hour, making sure that the temperature does not exceed -70 ^° C. After the addition the mixture is stirred at -78 ° C for 1 hour and then a solution of 15.9 g (80 mmol) of Λ, 4-dimethoxy-β-methylbenzamide in 20 mL of THF is added dropwise. The reaction medium is stirred at -78 ° C. for 1 hour and then at room temperature for 18 hours. The mixture is hydrolyzed with 100 mL of water, basified to pH = 12 with 2N NaOH solution and extracted with tert-butyl methyl ether. The aqueous phase containing the carboxylate is acidified with a solution of 5N HCl to pH = 1 and extracted with dichloromethane. The dichloromethane phase is washed with salt water, dried over anhydrous sodium sulphate, filtered and evaporated. The product is crystallized in isopropyl ether; after filtration and drying, 14.6 g of white crystals are obtained. Mp = 170 ^° C (M)

LC / MS: MH ⁺ = 287 (tR = 7.07 minutes, pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 3.85 (s, 3H); 3.90 (s, 3H); 7.03 (d, J = 8.5 Hz, 2H); 7.24 (dd, J ₁ = 8.5 Hz, J ₂ = 2.5 Hz, 1H); 7.35 (d, J = 8.5 Hz, 1H); 7.42 (d, J = 2.5 Hz, 1H); 7.61 (d, J = 8.5 Hz, 2H); 13.1 (s, 1H, COOH). 2.5. 7-Methoxy-4- (4-methoxyphenyl) -2H-phthalazin-1-one

A solution of 21.6 g (75 mmol) of 5-methoxy-2- (4-methoxybenzoyl) benzoic acid in 150 ml of ethanol is added with 18.5 ml (380 mmol) of hydrazine hydrate and is refluxed for 2 hours. The reaction medium is cooled and then filtered. The precipitate obtained is washed with ethanol and then dried under reduced pressure at 40 ^° C. 19 g of a white solid are obtained. MP = 245 ° C (M)

LC / MS: MH ⁺ = 283 (tR = 6.98 minutes, pH 3.1) ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 3.86 (s, 3H); 3.98 (s, 3H); 7.12 (d, J = 8.5 Hz, 2H); 7.48 (dd, J ₁ = 9 Hz, J ₂ = 2.7 Hz, 1H); 7.52 (d, J = 8.5 Hz, 2H); 7.67 (d, J = 9.0 Hz, 1H); 7.75 (d, J = 2.7 Hz, 1H); 12.72 (s, 1H, NH).

2.6. 1-Chloro-7-methoxy-4- (4-methoxyphenyl) phthalazine

19 g (67 mmol) of 7-methoxy-4- (4-methoxyphenyl) -2H-phthalazin-1-one are dissolved in

100 mL of phosphoryl chloride. The solution is heated for 2 hours at 80 ^° C.

The reaction medium is cooled to ambient temperature and then poured slowly into

500 mL of water at 40-50 ° C with stirring. The mixture is then stirred at 5 ° C., neutralized by addition of a 35% sodium hydroxide solution and then extracted with dichloromethane. The organic phase is washed with water and then with salt water and dried over anhydrous sodium sulphate.

After filtration and evaporation under reduced pressure, 19.3 g of a beige powder are obtained.

Mp = 173 ° C (M) LC / MS: MH ⁺ = 301 (tR = 8.52 minutes, pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 3.90 (s, 3H); 4.07 (s, 3H); 7.19 (d, J = 8.5Hz ₁ 2H);

7.60 (d, J = 2.5 Hz, 1H); 7.68 (d, J = 8.5 Hz, 2H); 7.72 (dd, Ji = 9.2 Hz, J ₂ = 2.5 Hz, 1H); 8.02 (d, J = 9.2 Hz, 1H).

2.7. 7-Methoxy-4- (4-methoxyphenyl) -N-methyl-N- [1- (2-naphthylmethyl) piperidin-4-yl] phthalazin-1-amine dihydrochloride (Compound No. 2)

A suspension of 830 mg (2.96 mmol) of 1-chloro-7-methoxy-4- (4-methoxyphenyl) phthalazine in 5 ml of 1-butanol is added with 700 mg (2.75 mmol) of Β-methyl-β- [1- (2-naphthylmethyl) piperidin-4-yl] -amine and 147 mg (2.8 mmol) of ammonium chloride. The mixture is heated under reflux (oil bath at 140 ^° C.) for 27 hours. The reaction mixture is hydrolyzed and then basified with a 1N sodium hydroxide solution and then extracted with dichloromethane. The combined organic phases are washed with salt water, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel (eluent: dichloromethane / methanol from 100/0 to 90/10 (Wv)). We obtain 220 mg of oily product. The dihydrochloride is obtained after treatment of the product dissolved in ethanol with a solution of hydrochloric acid in diethyl ether. After concentration and addition of ethyl acetate, a suspension is obtained which is filtered. The powder obtained is dried at 40 ^° C. under reduced pressure in the presence of diphosphorus pentoxide. ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 2.05-2.2 (m, 2H); 2.55-2.75 (m, 2H); 3.14 (s, 3H); 3.15-3.35 (m, 2H); 3.4-3.6 (m, 3H); 3.91 (s, 3H); 4.09 (s, 3H); 4.25-4.4 (m, 1H); 4.4-4.5 (m, 2H); 7.26 (d, J = 8.7 Hz, 2H); 7.5-7.8 (m, 5H); 7.85 (d, J = 7.5 Hz, 1H); 7.9-8.1 (m, 5H); 8.15 (m, 1H); 11.5 (m, 1 H)

Example 3 N- (1- {4- [3- (Dimethylamino) propoxy] benzyl} piperidin-4-yl) -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine trihydrochloride (Compound No. ° 3)

3.1. Λ- (1-Benzylpiperidin-4-yl) -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine

A suspension of 8 g (26.6 mmol) of 1-chloro-7-methoxy-4- (4-methoxyphenyl) phthalazine (preparation see paragraph 2.6.) In 50 ml of 1-butanol is added with 10.1 g ( 53 mmol) of 4-amino-1-benzylpiperidine and 1.44 g (27 mmol) of ammonium chloride. The mixture is refluxed for 7 hours. The reaction medium is cooled to ambient temperature, hydrolyzed with 50 ml of saturated aqueous sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic phase is washed with salt water, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel (eluent: dichloromethane / methanol 95/5 (v / v)). The yellow oil thus obtained forms a solid by trituration in isopropyl ether. After filtration and drying, 10.5 g of white powder are obtained. Mp = 150 ^° C. (M) LC / MS: MH ⁺ = 455 (tR = 4.71 min, pH 3.1) ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.7-1.8 (m.p. 2H); 2.0-2.2 (m, 4H); 2.90-3.0 (m, 2H); 3.54 (s, 2H); 3.86 (s, 3H); 4.0 (s, 3H); 4.2-4.3 (m, 1H); 7.0 (d, J = 7.5 Hz ₁ ₁ H NH); 7.10 (d, J = 8.5 Hz, 2H); 7.25-7.40 (m, 5H); 7.43 (dd, J ₁ = 9.0 Hz, J ₂ = 2.5 Hz, 1H); 7.53 (d, J = 8.5 Hz, 2H); 7.75-7.77 (m, 2H).

3.2. 7-Methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine

The manipulation is carried out under an inert atmosphere (nitrogen). In a three-necked 500 ml are introduced 1 g of 10% palladium on carbon and 100 ml of water. To this stirred mixture at 85 ° C is added dropwise, for 1 hour, a previously prepared solution of 13.3 g of N- (1-benzylpiperidin-4-yl) -7-methoxy-4- (4- methoxyphenyl) phthalazin-1-amine in 50 mL of ethanol and 4.4 mL of formic acid. The reaction mixture is stirred at reflux for 2 hours. After return to temperature Ethanol is evaporated under reduced pressure. The mixture is then basified to pH 12 with 2N sodium hydroxide and then extracted with dichloromethane. The organic phase is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The yellow oil obtained is triturated in diisopropyl ether to obtain a white solid. After filtration and drying under vacuum in the presence of phosphorus pentoxide, 10.29 g product is obtained. Mp = 143 ° C (M)

LC / MS: MH ⁺ = 365 (tR = 4.88min, pH 3.1)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.5-1.65 (m, 2H); 2.0-2.1 (m, 2H); 2.6-2.7 (m, 2H); 3.0-3.1 (m, 2H); 3.3 (s, 1H, NH); 3.85 (s, 3H); 3.98 (s, 3H); 4.2-4.3 (m, 1H); 7.0 (d, J = 7.5 Hz, 1H); 7.10 (d, J = 8.5 Hz, 2H); 7.42 (dd, J ₁ = 9.2 Hz, J ₂ = 2.5 Hz, 1H); 7.52 (d, J = 8.5 Hz, 2H); 7.75 (d, J = 9.2 Hz, 1H); 7.78 (d, J = 2.5 Hz, 1H).

3.3. N- (1- {4- [3- (dimethylamino) propoxy] benzyl} piperidin-4-yl) -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine trihydrochloride (Compound No. 3)

A solution of 500 mg (1.4 mmol) of 7-methoxy-4- (4-methoxyphenyl) -α- (piperidin-4-yl) phthalazin-1-amine in 10 ml of 1,2-dichloroethane is added 284 mg (1.4 mmol) of 4- [3- (dimethylamino) propoxy] benzaldehyde. The mixture is stirred for 30 minutes under nitrogen, then 380 mg (1.8 mmol) of sodium triacetoxyborohydride are added. The reaction medium is stirred for 24 hours at room temperature, hydrolyzed with water and 1N sodium hydroxide and then extracted with ethyl acetate. The organic extract is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue is purified on a column of neutral alumina (eluent: 100/0 to 98/2 (v / v) dichloromethane / methanol). 380 mg of brown product is obtained.

¹ H NMR (DMSO-ds, 250 MHz) δ ppm: 1.6-1.65 (m, 2H); 1.7-1.9 (m, 2H); 2.0-2.2 (m, 4H); 2.15 (s, 6H); 2.35 (t, J = 5Hz, 2H); 2.85-2.95 (m, 2H); 3.45 (s, 2H); 3.85 (s, 3H); 3.95-4.05 (m, 2H); 3.98 (s, 3H); 4.2-4.35 (m, 1H); 6.89 (d, J = 8 Hz, 2H); 6.97 (d, J = 7.5 Hz, 1H); 7.08 (d, J = 8 Hz, 2H); 7.23 (d, J = 8 Hz, 2H); 7.42 (dd, J ₁ = 7.5 Hz, J ₂ = 2.5 Hz, 1H); 7.52 (d, J = 8 Hz, 2H); 7.7-7.75 (m, 2H); The trihydrochloride is obtained after treatment of the product dissolved in dichloromethane with a solution of hydrochloric acid in diethyl ether. A suspension is obtained which is filtered. The powder obtained is dried at 40 ^° C. under reduced pressure in the presence of diphosphorus pentoxide.

Example 4

N- {1- [3-Fluoro-4- (3-morpholin-4-ylpropoxy) benzyl] piperidin-4-yl} -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine trihydrochloride ( compound no. 4)

4.1. 4- (3-chloropropyl) -morpholine

1 g (6.9 mmol) of 4- (3-hydroxypropyl) -morpholine is stirred at 0 ^° C. and 2.5 ml (34.4 mmol) of thionyl chloride are added. The mixture is stirred for 6 hours at room temperature, slowly poured into ice-cold 1N NaOH solution and then extracted with dichloromethane. The organic extract is dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 1.1 g of colorless oily product are obtained. ¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.8-1.95 (m, 2H); 2.3-2.4 (m, 6H); 3.5-3.6 (m, 4H); 3.65-3.70 (m, 2H).

4.2. 3-Fluoro-4- (3-morpholin-4-ylpropoxy) benzaldehyde

A solution of 396 mg (2.4 mmol) of 4- (3-chloropropyl) -morpholine and 339 mg (2.4 mmol) of 3-fluoro-4-hydroxybenzaldehyde in 10 mL of DMF is added with 334 mg ( 2.4 mmol) of potassium carbonate. The mixture is stirred at 80 ^° C. for 5 hours and then, after cooling, is added water and extracted with ethyl acetate. The organic extract is washed with water and then with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 400 mg of oily product is obtained. ¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.90-2.0 (m, 2H); 2.32-2.48 (m, 6H); 3.55-3.60 (m, 4H); 4.20-4.28 (m, 2H); 7.37-7.44 (m, 1H); 7.74 (d, J = 11Hz, 1H), 7.78 (d, J = 7.5Hz, 1H), 9.58 (s, 1H ₁ CHO). 4.3. N- {1- [3-Fluoro-4- (3-morpholin-4-ylpropoxy) benzyl] piperidin-4-yl} -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine trihydrochloride ( compound no. 4)

A solution of 500 mg (1.37 mmol) of 7-methoxy-4- (4-methoxyphenyl) -β- (piperidin-4-yl) phthalazin-1-amine in 10 mL of 1,2-dichloroethane is added 367 mg (1.37 mmol) of 3-fluoro-4- (3-morpholin-4-ylpropoxy) benzaldehyde. The mixture is stirred for 30 minutes under nitrogen, then 378 mg (1.78 mmol) of sodium triacetoxyborohydride are added. The reaction medium is stirred overnight at room temperature and then hydrolyzed with water and 1N sodium hydroxide and extracted with ethyl acetate. The organic extract is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue is purified on a silica column (eluent: 100/0 to 85/15 (v / v) dichloromethane / methanol). 380 mg of white solid are obtained. ¹ H NMR (DMSOd ₆ , 400 MHz) δ ppm: 1.62-1.75 (m, 2H); 1.87-1.94 (m, 2H); 2.05-2.16 (m, 4H); 2.32-2.45 (m, 6H); 2.87-2.93 (m, 2H); 3.46 (s, 2H); 3.55-3.60 (m, 4H); 3.84 (s, 3H); 3.97 (s, 3H); 4.05-4.10 (m, 2H); 4.20 - 4.30 (m, 1H); 6.97 (d, J = 7.5 Hz, 1H); 7.05- 7.18 (m, 5H); 7.42 (dd, J ₁ = 7.5 Hz, J ₂ = 2.5 Hz ₁ 1 H); 7.51 (d, J = 8 Hz, 2H); 7.72-7.77 (m, 2H); By treatment of the product dissolved in dichloromethane with a solution of hydrochloric acid in diethyl ether, a suspension is obtained which is filtered. The powder obtained is dried at 40 ^° C. under reduced pressure in the presence of diphosphorus pentoxide.

Example 5

7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (2-piperidin-1-ylethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine trihydrochloride (Compound No. 5) )

5.1. 4- (2-Piperidin-1-ylethoxy) benzaldehyde

A solution of 7.54 g (40.9 mmol) of Λ / - (2-chloroethyl) piperidine hydrochloride and 5 g (40.9 mmol) of 4-hydroxybenzaldehyde in 100 ml of DMF is added with 11.88 g (86 mmol) of sodium carbonate. potassium. The mixture is stirred at 80 ^° C. for 5 hours and then, after cooling, is poured into water and extracted with ethyl acetate. The organic extract is washed with water and then with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 10.5 g of oily orange product containing 0.3 equivalents of DMF are obtained. MH ^{4 "=} 234 (R = 3.89 min, pH 3.1).

¹ H NMR (DMSO-dβ, 250 MHz)? Ppm: 1, 32-1.45 (m, 2H); 1.45-1.55 (m, 4H); 2.40-2.48 (m, 4H); 2.65-2.72 (m, 2H); 4.17-4.22 (m, 2H); 7.14 (d, J = 8 Hz, 2H), 7.86 (d, J = 8 Hz, 2H), 9.9 (s, 1H ₁ CHO).

5.2. 7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (2-piperidin-1-ylethoxy) benzyl] -piperidin-4-yl} phthalazin-1-amine hydrochloride (Compound No. 5) )

This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine with 4- (2-piperidin-1-ylethoxy) benzaldehyde.

¹ H NMR (DMSO-d _6, 400 MHz) δ ppm: 1, 35-1.42 (m, 2H); 1.45-1.55 (m, 4H); 1.60-1.73 (m, 2H); 2.02-2.12 (s, 4H); 2.40-2.48 (m, 2H); 2.60-2.70 (m, 2H); 2.88-2.93 (m, 2H); 3.28-3.33 (m, 2H); 3.44 (s, 2H); 3.84 (s, 3H); 3.97 (s, 3H); 4.03-4.08 (m, 2H); 4.20 - 4.30 (m, 1H); 6.90 (d, J = 8 Hz, 2H); 6.97 (d, J = 7.5 Hz, 1H); 7.09 (d, J = 8 Hz, 2H); 7.23 (d, J = 8 Hz, 2H); 7.41 (dd, J ₁ = 7.5 Hz, J ₂ = 2.5 Hz, 1H), 7.51 (d, J = 8 Hz, 2H); 7.72-7.75 (m, 2H); The trihydrochloride is obtained by the treatment described in 4.3. Example 6

N- [1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] -4-ethyl-7-methoxy-N-methylphthalazin-1-amine dihydrochloride (Compound No. 6)

6.1. 5-Methoxy-2-propionylbenzoic acid

This compound is synthesized according to the method described in 2.4. by reacting 2-bromo-5-methoxybenzoic acid previously treated with n-butyl lithium with N-methoxy-N-methyl-propionamide. It is used raw in the next reaction.

6.2. 4-Ethyl-7-methoxy-2H-phthalazin-1-one

This compound is obtained according to the procedure described in 2.5. by reaction of the unpurified 5-methoxy-2-propionyl-benzoic acid with hydrazine hydrate. LC / MS: MH ⁺ = 205 (tR = 6.32 minutes pH 3.1)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.25 (t, J = 7.5 Hz, 3H); 2.92 (q, J = 7.5 Hz, 2H); 3.94 (s, 3H); 7.50 (dd, Ji = 9 Hz, J ₂ = 2.7 Hz, 1H); 7.60 (d, J = 2.7 Hz, 1H); 7.94 (d, J = 9 Hz, 1H); 12.38 (s, 1H, NH).

6.3. 1-Chloro-4-ethyl-7-methoxy-phthalazine

This compound is obtained according to the procedure described in 2.6. by reaction of 4-ethyl-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride. MP = 191 ° C (Mettler FP62) LC / MS: MH ⁺ = 223 (tR = 6.84 minutes pH 3.1)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.36 (t, J = 7.5 Hz, 3H); 3.30 (q, J = 7.5 Hz, 2H); 4.04 (s, 3H); 7.50 (d, J = 2.7 Hz ₁ 1H); 7.71 (dd, J ₁ = 9 Hz, J ₂ = 2.7 Hz, 1H); 8.30 (d, J = 9 Hz, 1H).

6.4 1 - (1,3-Benzodioxol-5-ylmethyl) -W-methylpiperidin-4-amine

A solution of 1.94 g (5.8 mmol) of tert-butyl [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] carbamate (synthesis described in 1.1) in 10 ml of THF is slowly added to a suspension of 0.45 g of LiAlH ₄ (11.8 mmol) in 10 mL of THF. The mixture is stirred at reflux for 2 hours and then after cooling is successively added 0.45 mL of water, 0.45 mL of 15% NaOH and 1.45 mL of water. The suspension obtained is filtered on celite and the celite is rinsed with dichloromethane. The filtrate is evaporated under reduced pressure. 1.35 g of oily product are obtained. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 1.10-1.37 (m, 2H); 1.70-1.80 (m, 2H); 1.88-1.98 (m, 2H); 2.18-2.22 (m, 1H); 2.24 (s, 3H); 2.67-2.72 (m, 2H); 3.33 (s, 2H); 5.98 (s, 2H); 6.72 (m, 1H); 6.81-6.85 (m, 2H).

6.5. N- [1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] -4-ethyl-7-methoxy-N-methylphthalazin-1-amine dihydrochloride (Compound No. 6)

This compound in the base form is obtained according to the procedure described in 1.9. by reaction of 1-chloro-4-ethyl-7-methoxy-phthalazine with 1- (1,3-benzodioxol-5-ylmethyl) -N-methylpiperidin-4-amine. ¹ H NMR (DMSO-ds, 400 MHz) δ ppm: 1.36 (t, J = 7.5 Hz, 3H); 1.70-1.80 (m, 2H); 1.88- 2.00 (m, 4H); 2.82-2.90 (m, 2H); 2.92 (s, 3H); 3.18 (q, J = 7.5 Hz, 2H); 3.35 (s, 2H); 3.48- 3.58 (m, 1H); 3.97 (s, 3H); 5.99 (s, 2H); 6.71-6.75 (m, 1H); 6.81-6.86 (m, 2H), 7.27 (d, J = 2.5 Hz, 1H); 7.53 (dd, J ₁ = S ₁ O Hz, J ₂ = 2.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H).

The dihydrochloride is obtained after treatment of the product dissolved in dichloromethane with a solution of hydrochloric acid in diethyl ether. After concentration and addition of diisopropyl ether, a suspension is obtained which is filtered. The powder obtained is dried at 40 ^° C. under reduced pressure in the presence of diphosphorus pentoxide. Example 7

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -7-methoxy-4- dihydrochloride

(Methoxymethyl) -N-methylphthalazin-1-amine (Compound No. 7)

7.1 5-Methoxy-2- (methoxyacetyl) -benzoic acid

This compound is synthesized according to the method described in 2.4. by reacting 2-bromo-5-methoxybenzoic acid previously treated with n-butyllithium with 2, N-dimethoxy-β-methyl-acetamide. It is used raw in the next reaction.

7.2. 7-Methoxy-4-methoxymethyl-2H-phthalazin-1-one

This compound is obtained according to the procedure described in 2.5. by reaction of unpurified 5-methoxy-2- (methoxyacetyl) benzoic acid with hydrazine hydrate.

Mp = 184 ° C (Mettler FP62)

LC / MS: MH ⁺ = 221 (tR = 5.33 minutes, pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 3.33 (s, 3H); 3.96 (s, 3H); 4.62 (s, 2H); 7.53 (dd,

J ₁ = 8.8 Hz, J ₂ = 2.7 Hz, 1H); 7.66 (d, J = 2.7 Hz, 1H); 8.0 (d, J = 8.8 Hz, 1H); 12.61 (s, 1H ₁ NH).

7.3. 1-Chloro-7-methoxy-4-methoxymethyl phthalazine

This compound is obtained according to the procedure described in 2.6. by reaction of 7-methoxy-4-methoxymethyl-2H-phthalazin-1-one with phosphoryl chloride. ¹ H NMR (DMSO-Cl ₆ , 250 MHz) δ ppm: 3.33 (s, 3H); 4.06 (s, 3H); 5.02 (s, 2H); 7.56 (d, J = 2.7 Hz, 1H); 7.77 (dd, J ₁ = 9.2 Hz, J ₂ = 2.7 Hz, 1H); 8.35 (d, J = 9.2 Hz, 1H).

7.4. N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -7-methoxy-4- (methoxymethyl) -N-methylphthalazin-1-amine dihydrochloride (Compound No. 7)

This compound in the base form is obtained according to the procedure described in 1.9. by reaction of 1-chloro-7-methoxy-4-methoxymethyl phthalazine with 1- (1,3-benzodioxol-5-ylmethyl) -4-methylamino-piperidine.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 1.72-1.82 (m, 2H); 1.88-2.02 (m, 4H); 2.82-2.90 (m, 2H); 2.96 (s, 3H); 3.32 (s, 3H); 3.35 (s, 2H); 3.60-3.70 (m, 1H); 3.98 (s, 3H); 4.87 (s, 2H); 5.98 (s, 2H); 6.71-6.75 (m, 1H); 6.81-6.86 (m, 2H), 7.27 (d, J = 2.5 Hz, 1H); 7.54 (dd, Ji = 8.5 Hz, J ₂ = 2.5 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H). The dihydrochloride salt is obtained by treatment of the product dissolved in dichloromethane with a solution of 2M hydrochloric acid in diethyl ether. After concentration and addition of ethyl ether, a suspension is obtained which is filtered. The powder obtained is dried at 40 ° C. under reduced pressure in the presence of diphosphorus pentoxide.

Example 8

N- (1- {4- [3- (dimethylamino) propoxy] -3-fluorobenzyl} piperidin trihydrochloride

4-yl) -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine (Compound No. 8)

8.1. 4- (3-Dimethylaminopropoxy) -3-fluoro-benzaIdehyde

Ge compound is obtained according to the procedure described in 4.2. by reaction of N, N-dimethyl-3-chloropropylamine with 3-fluoro-4-hydroxybenzaldehyde. ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.85-1.98 (m, 2H); 2.15 (s, 6H); 2.34-2.40 (m, 2H); 4.19-4.24 (m, 2H); 7.36-7.43 (m, 1H); 7.70 (d, J = 11Hz, 1H), 7.77 (d, J = 7.5Hz, 1H), 9.87 (s, 1H ₁ CHO).

8.2. N- (1- {4- [3- (Dimethylamino) propoxy] -3-fluorobenzyl} -piperidin-4-yl) -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine trihydrochloride (Compound No. ° 8)

A solution of 300 mg (0.82 mmol) of 7-methoxy-4- (4-methoxyphenyl) -α- (piperidin-4-yl) phthalazin-1-amine in 8 ml of 1,2-dichloroethane is added with 185 mg (0.82 mmol) of 4- (3-dimethylaminopropoxy) -3-fluoro-benzaldehyde. The mixture is stirred for 1 hour under nitrogen, then 226 mg (1. 07 mmol) of sodium triacetoxyborohydride are added. The reaction medium is stirred for 20 hours at room temperature, hydrolyzed with water and 1N sodium hydroxide and then extracted with dichloromethane. The organic extract is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue is purified on an alumina column (eluent: 100/0 to 98/2 (v / v) dichloromethane / methanol). 278 mg of oily orange product are obtained.

¹ H NMR (DMSO-d _6, 400 MHz) δ ppm: 1, 62-1, 73 (m, 2H); 1.80-1.88 (m, 2H); 2.04-2.14 (m, 4H); 2.14 (s, 6H), 2.30-2.38 (m, 2H); 2.87-2.90 (m, 2H); 3.46 (s, 2H); 3.84 (s, 3H); 3.97 (s, 3H); 4.02-4.08 (m, 2H); 4.20 - 4.30 (m, 1H); 6.97 (d, J = 7.5 Hz, 1H); 7.05-7.18 (m, 5H); 7.42 (dd, J ₁ = 7.5 Hz, J ₂ = 2.5 Hz, 1H); 7.51 (d, J = 8 Hz, 2H); 7.72-7.77 (m, 2H). The trihydrochloride is obtained by the treatment described in 7.4. .

Example 9

7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (2-pyrrolidin-1-ylethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine trihydrochloride (Compound No. 9) )

9.1 4- (2-Pyrrolidin-1-ylethoxy) benzaldehyde

This compound is obtained according to the procedure described in 5.1. by reaction of Λ / -2-chloroethyl-pyrrolidine hydrochloride with 4-hydroxybenzaldehyde. MH ⁺ = 220 (tR = 2.41 minutes, pH 3.1).

¹ H NMR (DMSOd ₆ , 400 MHz) δ ppm: 1.65-1.72 (m, 4H); 2.50-2.56 (m, 4H); 2.78-2.82 (m, 2H); 4.15-4.20 (m, 2H); 7.13 (d, J = 8Hz, 2H), 7.85 (d, J = 8Hz, 2H), 9.87 (s, 1H, CHO).

9.2. 7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (2-pyrrolidin-1-ylethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine trihydrochloride (Compound No. 9) )

This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) -β- (piperidin-4-yl) phthalazin-1-amine with 4- (2-pyrrolidin-1-ylethoxy) -benzaldehyde. ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.60-1.80 (m, 6H); 2.0-2.20 (m, 4H); 2.45-2.60 (m, 3H); 2.72-2.98 (m, 5H); 3.45 (s, 2H); 3.85 (s, 3H); 3.98 (s, 3H); 4.03-4.10 (m, 2H); 4.20 - 4.30 (m, 1H); 6.85-7.0 (m, 3H); 7.09 (d, J = 8 Hz, 2H); 7.23 (d, J = 8 Hz, 2H); 7.41 (dd, J ₁ = 7.5 Hz, J ₂ = 2.5 Hz, 1H), 7.51 (d, J = 8 Hz, 2H); 7.73-7.76 (m, 2H); The trihydrochloride is obtained by the treatment described in 7.4.

Example 10

7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (2-morpholin-4-ylethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine trihydrochloride (Compound No. 10) )

10.1. 4- (2-morpholin-4-yl-ethoxy) benzaldehyde

This compound is obtained according to the procedure described in 5.1. by reaction of 4- (2-chloroethyl) morpholine hydrochloride with 4-hydroxybenzaldehyde. MH ⁺ = 236 (tR = 3.30 minutes, pH 3.1).

¹ H NMR (DMSOd ₆ , 400 MHz) δ ppm: 2.45-2.52 (m, 4H); 2.70-2.75 (m, 2H); 3.55-3.60 (m, 4H); 4.18-4.25 (m, 2H); 7.14 (d, J = 8Hz, 2H), 7.86 (d, J = 8Hz, 2H), 9.87 (s, 1H, CHO).

10.2. 7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (2-morpholin-4-ylethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine trihydrochloride (Compound No. 10) )

This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) -β- (piperidin-4-yl) phthalazin-1-amine with the

4- (2-morpholin-4-yl-ethoxy) benzaldehyde. ¹ H NMR (DMSOd ₆ , 400 MHz) δ ppm: 1.60-1.75 (m, 2H); 2.0-2.15 (m, 4H); 2.45-2.60 (m,

4H); 2.68-2.72 (m, 2H); 2.88-2.98 (m, 2H); 3.45 (s, 2H); 3.58-3.62 (m, 4H); 3.84 (s, 3H);

3.97 (s, 3H); 4.02-4.10 (m, 2H); 4.20 - 4.30 (m, 1H); 6.88-7.04 (m, 3H); 7.09 (d, J = 8.8

Hz, 2H); 7.24 (d, J = 8 Hz, 2H); 7.42 (dd, J ₁ = 9 Hz, J ₂ = 2.5 Hz, 1H), 7.51 (d, J = 8.8 Hz,

2H); 7.73-7.76 (m, 2H); The trihydrochloride is obtained by the treatment described in 7.4.

Example 11

7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (3-piperidin-1-ylpropoxy) benzyl] piperidin-4-yl} phthalazin-1-amine hydrochloride (Compound No. 11) )

11.1 4- (3-Piperidin-1-ylpropoxy) benzaldehyde

This compound is obtained according to the procedure described in 5.1. by reaction of β- (3-chloropropyl) piperidine hydrochloride with 4-hydroxybenzaldehyde.

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.40-1.55 (m, 6H); 1.84-1.87 (m, 2H); 2.30- 2.45 (m, 6H); 4.10-4.18 (m, 2H); 7.13 (d, J = 8Hz, 2H), 7.86 (d, J = 8Hz, 2H), 9.87 (s, 1H, CHO).

MH ⁺ = 248 (tR = 4.43 minutes, pH 3.1).

11.2. 7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (3-piperidin-1-ylpropoxy) benzyl] piperidin-4-yl} phthalazin-1-amine trihydrochloride (Compound No. 11) )

This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine with 4- (2-piperidin-1-ylpropoxy) -benzaldehyde. ¹ H NMR (DMSOd ₆ , 400 MHz) δ ppm: 1, 35-1.42 (m, 2H); 1, 48-1.55 (m, 4H); 1, 62-1.75 (m, 2H); 1.82-1.92 (m, 2H); 2.03-2.14 (m, 4H); 2.30-2.40 (m, 6H); 2.88-2.95 (m, 2H); 3.44 (s, 2H); 3.84 (s, 3H); 3.96 (s, 3H); 3.96-4.01 (m, 2H); 4.20 - 4.30 (m, 1H); 6.88 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 7.6 Hz, 1H, NH); 7.08 (d, J = 8.8 Hz, 2H); 7.22 (d, J = 8.4 Hz, 2H); 7.41 (dd, J ₁ = 9 Hz, J ₂ = 2.5 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H); 7.72-7.75 (m, 2H); The trihydrochloride is obtained by the treatment described in 7.4. Example 12

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -N-ethyl-7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine dihydrochloride (compound no. 12)

12.1 N- [1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine

This compound is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) -β- (piperidin-4-yl) phthalazin-1-amine with piperonal. MH ⁺ = 499 (tR = 8.32 minutes, pH 7)

¹ H NMR (DMSO-ds, 250 MHz) δ ppm: 1.60-1.80 (m, 2H); 2.0-2.20 (m, 4H); 2.85-2.95 (m, 2H); 3.44 (s, 2H); 3.85 (s, 3H); 3.98 (s, 3H); 4.20-4.30 (m, 1H), 6.01 (s, 2H); 6.78-6.91 (m, 3H); 6.99 (d, J = 7.5Hz, 1H), 7.09 (d, J = 8Hz, 2H); 7.43 (dd, J ₁ = 8.5 Hz, J ₂ = 2.5 Hz, 1H), 7.51 (d, J = 8 Hz, 2H); 7.72-7.76 (m, 2H). 12.2 N- [1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] -N-ethyl-7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine dihydrochloride (compound no. ° 12)

A solution of 200 mg (0.39 mmol) of N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine in 15 mL of THF is stirred at 0 ^° C. under nitrogen and 155 mg of an oily suspension of 60% sodium hydride (0.39 mmol) are added. The mixture is stirred for 1 hour and then 0.062 ml (0.78 mmol) of iodoethane is added. The mixture is stirred for 24 hours at room temperature and is then cooled in an ice bath, water added and extracted with dichloromethane. The organic extract is washed with salt water, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is purified on a column of neutral alumina (eluent: 100/0 to 98/2 (v / v) dichloromethane / methanol) and then on silica gel column (solvent: dichloromethane / methanol 100/0 to 85/15 (v / v)). ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.02 (t, J = 6.7 Hz, 3H), 1.75-2.0 (m, 6H); 2.82- 2.90 (m, 2H); 3.34 (s, 2H); 3.42-3.60 (m, 3H), 3.85 (s, 3H); 3.96 (s, 3H); 5.99 (s, 2H); 6.73 (d, J = 7.7 Hz, 1H), 6.82-6.86 (m, 2H); 7.13 (d, J = 9 Hz, 2H); 7.37 (d, J = 2.5 Hz, 1H); 7.52 (dd, J ₁ = 9 Hz, J ₂ = 2.5 Hz, 1H), 7.64 (d, J = 9 Hz, 2H), 7.88 (d, J = 9 Hz, 1H). The dihydrochloride is obtained by the treatment described in 6.5.

Example 13

4 - [(4 - {[7-Methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] aminopiperidin-1-yl) methyl] -N- (2-piperidin-1-ylethyl) trihydrochloride Benzamide (Compound 13)

13.1 4-Chloromethyl-W- (2-piperidin-1-ylethyl) benzamide

A solution of 5 g (26.4 mmol) of 4-chloromethyl-benzoyl chloride in 100 ml of dichloromethane is stirred at 0 ^° C. and treated with a solution of 3.39 g (26.4 mmol) of 1- (2-aminoethyl) piperidine and 5.53 ml (39.7 mmol) of triethylamine in 10 ml of dichloromethane. The mixture is stirred for 5 hours at 0 ^° C. and then overnight at room temperature. The mixture is added with water and then extracted with dichloromethane. The organic extract is washed with salt water, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is purified on a column of silica gel (solvent: dichloromethane / methanol from 100/0 to 85/15 (v / v)). Obtain 1.3 g of solid product. MH ⁺ = 281 (tR = 4.72 minutes, pH 3.1) ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.34-1.44 (m, 2H); 1.44-1.58 (m, 4H); 2.35-2.48 (m, 6H); 3.30-3.42 (m, 2H); 4.83 (s, 2H); 7.53 (d, J = 8Hz, 2H), 7.83 (d, J = 8Hz, 2H), 8.40 (m, 1H ₁ NH). 13.2. 4 - [(4 - {[7-Methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] -N- (2-piperidin-1-ylethyl) trihydrochloride Benzamide (Compound 13)

A solution of 300 mg (0.82 mmol) of 7-methoxy-4- (4-methoxyphenyl) -β- (piperidin-4-yl) phthalazin-1-amine and 311 g (0.82 mmol) of 4-chloromethyl- Λ / - (2-piperidin-1-ylethyl) benzamide in 20 ml of DMF is treated with 114 mg (0.82 mmol) of potassium carbonate. The mixture is stirred at room temperature for 18 hours then is added with water and extracted with ethyl acetate. The organic extract is washed with water and then with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is purified on a column of neutral alumina (eluent: dichloromethane / methanol 100/0 to 95/5 (Wv)) and then on a column of basic alumina under the same conditions. 130 mg of yellow gummy product is obtained. ¹ H NMR (DMSOd ₆ , 400 MHz) δ ppm: 1, 32-1.42 (m, 2H); 1.45-1.55 (m, 4H); 1.63-1.75 (m, 2H); 2.05-2.20 (m, 4H); 2.32-2.44 (m, 6H); 2.90-2.95 (m, 2H); 3.33-3.40 (m, 2H); 3.57 (s, 2H); 3.84 (s, 3H); 3.97 (s, 3H); 4.20 - 4.30 (m, 1H); 6.98 (d, J = 7.2Hz, 1H, NH), 7.08 (d, J = 8.8Hz, 2H); 7.40-7.43 (m, 3H); 7.51 (d, J = 8.8 Hz, 2H); 7.73 (d, J = 8.8 Hz, 2H); 7.80 (d, J = 8.8 Hz, 2H); 8.30-8.35 (m, 1H, CONH) The trihydrochloride is obtained by the treatment described in 4.3.

Example 14

7-Methoxy-4- (4-methoxyphenyl) -N- (1- {4 - [(1-methylazepan-3-yl) oxy] benzyl} piperidin-4-yl) phthalazin-1-amine trihydrochloride (compound n ° 14)

14.1. 4 - [(1-Methylazepan-3-yl) oxy] benzaldehyde and

4 - [(1-methylpiperidin-2-yl) methoxy] benzaldehyde

A solution of 2.59 g (21.2 mmol) 2-chloromethyl-1Λ / methylpiperidine (obtained by reaction of 1α-methylpiperidin-2-yl-nnethanol with SOCl ₂ , hydrolysis with N NaOH and then extraction with dichloromethane) and 3.13 g (21.2 mmol) of 4-hydroxybenzaldehyde in 42 ml of DMF is added with 2.93 g ( 21.2 mmol) of potassium carbonate. The mixture is stirred at 80 ^° C. for 4 hours and then, after cooling, is poured into water and extracted with ethyl acetate. The organic extract is washed with water and then with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 900 mg of the residue obtained are purified on a column of silica gel (solvent: dichloromethane / methanol 100/0 to 95/5 (v / v)). 360 mg of 4 - [(1-methylazepan-3-yl) oxy] benzaldehyde and 192 mg of 4 - [(1-methylpiperidin-2-yl) methoxy] benzaldehyde are obtained. These products are oily. 4 - [(1-Méthylazépan-3-yl) oxy] benzaldehyde:

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 1.48-1.80 (m, 5H); 2.0-2.10 (m, 1H); 2.31 (s, 3H); 2.45-2.55 (m, 1H); 2.55-2.70 (m, 2H); 2.82-2.90 (m, 1H); 4.18-4.23 (m, 1H); 7.14 (d, J = 9Hz, 2H), 7.84 (d, J = 9Hz, 2H), 9.86 (s, 1H, CHO). 4 - [(1-methylpiperidin-2-yl) methoxy] benzaldehyde:

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 1.20-1.60 (m, 4H); 1.68-1.80 (m, 2H); 2.02-2.10 (m, 1H); 2.20-2.27 (m, 1H); 2.24 (s, 3H); 2.74-2.80 (m, 1H); 4.0-4.05 (m, 1H); 4.18-4.22 (m, 1H); 7.13 (d, J = 9Hz, 2H), 7.85 (d, J = 9Hz, 2H), 9.88 (s, 1H, CHO).

14.2. 7-Methoxy-4- (4-methoxyphenyl) -N- (1- {4- trihydrochloride

[(1-methylazepan-3-yl) oxy] benzyl} piperidin-4-yl) phthalazin-1-amine (Compound No. 14)

This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine with 4 - [(1-methylazepan-3-yl) oxy] benzaldehyde.

¹ H NMR (DMSO-d _6, 400 MHz) δ ppm: 1, 50-1.76 (m, 8H); 1, 96-2.10 (m, 5H); 2.30 (s, 3H); 2.55-2.65 (m, 2H); 2.80-2.95 (m, 3H); 3.43 (s, 2H); 3.84 (s, 3H); 3.97 (s, 3H); 4.20 - 4.30 (m, 1H); 4.45-4.55 (m, 1H); 6.85 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 7.6 Hz, 1H ₁ NH), 7.08 (d, J = 8.8 Hz, 2H); 7.21 (d, J = 8.4 Hz, 2H); 7.41 (dd, J ₁ = 8.8 Hz, J ₂ = 2.5 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H); 7.70-7.78 (m, 2H)

The trihydrochloride is obtained by the treatment described in 7.4. Example 15

7-Methoxy-4- (4-methoxyphenyl) -N- (1- {4 - [(1-methylpiperidin-2-yl) methoxy] benzyl} piperidin-4-yl) phthalazin-1-amine trihydrochloride (Compound n ° 15)

This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine with 4 - [(1-methylpiperidin-2-yl) methoxy] benzaldehyde.

¹ H NMR (DMSO-d _6, 400 MHz) δ ppm: 1, 20-1.80 (m, 8H); 2.0-2.12 (m, 5H); 2.15-2.23 (m, 1H); 2.23 (s, 3H); 2.72-2.80 (m, 1H); 2.88-2.93 (m, 2H); 3.44 (s, 2H); 3.84 (s, 3H); 3.84- 3.88 (m, 1H); 3.97 (s, 3H); 4.02-4.07 (m, 1H); 4.20 - 4.30 (m, 1H); 6.90 (d, J = 8.4 Hz, 2H); 6.96 (d, J = 7.6 Hz, 1H, NH), 7.08 (d, J = 8.8 Hz, 2H); 7.23 (d, J = 8.4 Hz, 2H); 7.41 (dd, J ₁ = 9 Hz, J ₂ = 2.5 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H); 7.70-7.76 (m, 2H) The trihydrochloride is obtained by the treatment described in 7.4.

Example 16

N- [7-Methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] -N- [1- (2-naphthylmethyl) piperidin-4-yl] acetamide dihydrochloride (Compound No. 16)

16.1. 7-Methoxy-4- (4-Methoxyphenyl) -N- [1- (naphthalen-2-ylmethyl) piperidin

4-yl] phthalazin-1-amine

A solution of 1.46 g (4 mmol) of 7-methoxy-4- (4-methoxyphenyl) -β- (piperidin-4-yl) -phthalazin-1-amine (synthesis see 3.2) in 20 ml of dichloromethane is 1,2-ethane is added 0.63 g (4 mmol) of naphthalen-2-aldehyde. The mixture is stirred for 30 minutes under nitrogen, then 1.1 g (5.2 mmol) of sodium triacetoxyborohydride are added. The reaction medium is stirred for 24 hours at room temperature then hydrolyzed with 20 ml of 1N N sodium hydroxide and extracted with dichloromethane. The organic extract is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue is purified on a silica column (eluent dichloromethane / methanol 100/0 to 90/10 (MN)). 1.74 g of solid product recrystallized from isopropyl ether (mp = 195 ^° C.) are obtained.

LC / MS: MH ⁺ = 505 (tR = 5.73 minutes pH 3.1)

¹ H NMR (DMSO-d6, 300 MHz) δ ppm: 1.65-1.80 (m, 2H); 2.03-2.28 (m, 4H); 2, 90-3.02 (m, 2H); 3.70 (s, 2H); 3.84 (s, 3H); 3.97 (s, 3H); 4.2-4.3 (m, 1H); 6.99 (d, J = 7.2 Hz ₁ ₁ H NH); 7.08 (d, J = 8.5 Hz, 2H); 7.42 (dd, J ₁ = 9.0 Hz, J ₂ = 2.5 Hz, 1H); 7.48-7.58 (m, 5H); 7.70-7.76 (m, 2H); 7.80-7.92 (m, 4H).

16.2. N- [7-methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] -N- [1- (2-naphthylmethyl) piperidin-4-yl] acetamide dihydrochloride (Compound No. 16)

A mixture of 625 mg (1.23 mmol) of 7-methoxy-4- (4-methoxyphenyl) -N- [1- (naphthalene)

2-ylmethyl) piperidin-4-yl] phthalazin-1-amine and 5 ml of acetic anhydride is stirred at ambient temperature for 22 hours and then at 80 ^° C. for 3 hours. The reaction medium is hydrolyzed by adding water and then basified with 2N NaOH. The mixture is extracted with dichloromethane and the organic extract is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is purified on a silica column (eluent: 100/0 to 85/15 (v / v) dichloromethane / methanol). 395 mg of solid product is obtained. ¹ H NMR (DMSO-d ₆ , 600 MHz) δ ppm: 1.0-1.08 (m, 1H); 1.63 (s, 3H); 1.72-1.98 (m, 2H); 2.0-2.15 (m, 3H); 2.72-2.78 (m, 1H); 2.85-3.92 (m, 1H); 3.52-3.57 (m, 2H); 3.89 (s, 3H); 3.99 (s, 3H); 4.52-4.62 (m, 1H); 7.18 (d, J = 9 Hz, 2H); 7.34 (d, J = 1.8 Hz ₁ H); 7.37 (d, J = 8.4 Hz ₁ H); 7.43-7.47 (m, 2H); 7.65 (dd, J ₁ = 9 Hz, J ₂ = 1.8 Hz, 1H); 7.69-7.80 (m, 6H); 8.04 (d, J = 9 Hz, 1H). The dihydrochloride salt is obtained by the treatment described in 4.3. Example 17

7-Methoxy-4- (4-methoxyphenyl) -N- (1- {4 - [(1-methylpiperidin-4-yl) oxy] benzyl} piperidin-4-yl) phthalazin-1-amine trihydrochloride (Compound n ° 17)

17.1. 4 - [(1-methylpiperidin-4-yl) oxy] benzaldehyde

A mixture of 1 g (8.19 mmol) of 4-hydroxybenzaldehyde, 2.79 g (10.65 mmol) of triphenylphosphine and 0.943 g (8.19 mmol) of 4-hydroxy-1-methylpiperidine in 15 ml of THF is stirred at 0 ^° C. and slowly adding a solution of 1.76 mL (9.0 mmol) of diisopropylazodicarboxylate in 5 mL of THF. The reaction mixture is stirred for 15 minutes at 0 ° C. and then overnight at room temperature. After evaporation under reduced pressure, the residue is purified on a column of silica gel (eluent dichloromethane / methanol from 100/0 to 85/15 (v / v)). 1.4 g of oily product are obtained.

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.60-1.76 (m, 2H); 1.90-2.05 (m, 2H); 2.21 (s, 3H); 2.20-2.30 (m, 2H); 2.60-2.70 (m, 2H); 4.50-4.60 (m, 1H); 7.14 (d, J = 9 Hz, 2H), 7.85 (d,

J = 9 Hz, 2H), 9.80 (s, 1H, CHO).

17.2. 7-Methoxy-4- (4-methoxyphenyl) -N- (1- {4 - [(1-methylpiperidin-4-yl) oxy] benzyl} piperidin-4-yl) phthalazin-1-amine trihydrochloride (Compound n ° 17)

This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine with 4 - [(1-methylpiperidin-4-yl) oxy] benzaldehyde.

The trihydrochloride is obtained by treatment of the product dissolved in ethanol with a 2M solution of hydrochloric acid in diethyl ether. After concentration and addition of ethyl ether, a suspension is obtained which is filtered. The powder obtained is dried at 40 ^° C. under reduced pressure in the presence of diphosphorus pentoxide. Example 18

N- {1- [4- (1-azabicyclo [2.2.2] oct-3-yloxy) benzyl] piperidin-4-yl} hydrochloride

7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine (Compound No. 18)

18.1. 4- (1-Aza-bicycloï2,2,2] oct-3yloxy) ben2aldéhyde

A mixture consisting of 2 g (10.98 mmol) of 3-chloroquinuclidine hydrochloride, 1.34 g (10.98 mmol) of 4-hydroxybenzaldehyde, 3.036 g (22 mmol) of potassium carbonate, 22 ml of NMP and 10 ml of DMF is stirred at 165 ° C for 8 hours. The cooled reaction medium is added with water and ethyl acetate. The organic phase is washed successively with 1N sodium hydroxide, with water and with water saturated with sodium chloride. It is dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The oily residue obtained (0.92 g) is heated in a ball oven at 50 ^° C. under a pressure of 1 mbar to distill the residual 3-chloroquinuclidine. 0.46 g of gummy aldehyde is obtained.

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.22-1.42 (m, 1H); 1.50-1.88 (m, 3H); 2.03-2.12 (m, 1H); 2.55-2.82 (m, 4H); 3.22-3.30 (m, 2H); 4.57-4.65 (m, 1H); 7.10 (d, J = 9Hz, 2H), 7.85 (d, J = 9Hz, 2H), 9.88 (s, 1H ₁ CHO).

18.2. N- {1- [4- (1-azabicyclo [2.2.2] oct-3-yloxy) benzyl] piperidin-4-yl} -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-hydrochloride amine (compound no. 18)

This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) -β- (piperidin-4-yl) phthalazin-1-amine with 4- (1-Aza-bicyclo [2,2,2] octahydrophosphoric acid 3yloxy) benzaldehyde. The hydrochloride is obtained by the treatment described in 7.4. Example 19

N- [1- (1,3-Benzodioxol-5-ylmethyl)] -Peridin-4-yl] -7-methoxy-4- dihydrochloride

(tetrahydro-2H-pyran-4-yl) phthalazin-1-amine (Compound No. 19)

19.1. / V-WIéthoxy- / V-methyl-tetrahydro-2H-pyran-4-carboxamide

This oily compound is obtained according to the procedure described in 2.3. by reaction of tetrahydro-2H-pyran-4-carbonyl chloride with N, O-dimethylhydroxylamine hydrochloride. ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.53-1.62 (m, 4H); 2.85-3.0 (m, 1H); 3.10 (s, 3H); 3.30-3.42 (m, 2H); 3.69 (s, 3H); 3.82-3.91 (m, 2H).

19.2. 5-Methoxy-2- (tetrahydro-2H-pyran-4-ylcarbonyl) benzoic acid

This compound is obtained according to the procedure described in 2.4. by reaction of 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide. It is used raw in the next reaction.

19.3. 7-Methoxy-4- (tetrahydro-2H-pyran-4-yl) phthalazin-1 (2H) -one

This compound is obtained according to the procedure described in 2.5. by reaction of unpurified 5-methoxy-2- (tetrahydro-2H-pyran-4-ylcarbonyl) benzoic acid with hydrazine hydrate, followed by purification on a column of silica gel (dichloromethane / methanol eluent). 100/0 to 90/10 (v / v)). PF = 276 ⁰ C (M)

LC / MS: MH ⁺ = 261 (tR = 6.23 minutes pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.72-1.82 (m, 4H); 3.40-3.62 (m, 3H); 3.90-4.0 (m, 3H); 3.97 (s, 3H); 7.49 (dd, J ₁ = 9 Hz, J ₂ = 2.7 Hz, 1H); 7.68 (d, J = 2.7 Hz, 1H); 8.08 (d, J = 9.0 Hz, 1H).

19.4. 4-Chloro-6-methoxy-1- (tetrahydro-2H-pyran-4-yl) phthalazine

This compound is obtained according to the procedure described in 2.6. by reaction of 7-methoxy-4- (tetrahydro-2H-pyran-4-yl) phthalazin-1 (2H) -one with phosphoryl chloride.

Mp = 146 ° C (M)

LC / MS: MH ⁺ = 279 (tR = 7.08 minutes pH 3.1) ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.78-1.88 (m, 2H); 1.90-2.10 (m, 2H); 3.58-3.68

(m, 2H); 3.82-4.02 (m, 3H); 4.04 (s, 3H); 7.53 (d, J = 2.5 Hz, 1H); 7.73 (dd, J ₁ = 9 Hz, J ₂

= 2.5 Hz, 1H); 8.46 (d, J = 9.0 Hz, 1H).

19.5. N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -7-methoxy-4- (tetrahydro-2H-pyran-4-yl) phthalazin-1-amine dihydrochloride (compound n ° 19)

This compound in the base form is obtained according to the procedure described in 2.7. by reaction of 4-chloro-6-methoxy-1- (tetrahydro-2H-pyran-4-yl) phthalazine with 1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl-amine. The dihydrochloride salt is obtained by the treatment described in 4.3. Example 20

7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (3-methoxypropoxy) benzyl] -piperidin-4-yl} phthalazin-1-amine dihydrochloride (Compound No. 20)

20.1. 4- (3-Wléthoxypropoxy) benzaldehyde

This compound is obtained by the Mitsunobu reaction according to the procedure described in 17.1 by reaction of 4-hydroxybenzaldehyde and 3-methoxy-propan-1-ol. ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.92-2.05 (m, 2H); 3.26 (s, 3H); 3.46-3.51 (m, 2H); 4.11-4.18 (m, 2H); 7.13 (d, J ≈ 9 Hz, 2H); 7.86 (d, J = 9 Hz, 2H); 9.87 (s, 1H, CHO).

20.2. 7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (3-methoxypropoxy) benzyl] piperidin-4-yl} phthalazin-1-amine dihydrochloride (Compound No. 20)

This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine with 4- (3-methoxypropoxy) benzaldehyde. The dihydrochloride salt is obtained by the treatment described in 4.3.

Example 21

N- (1- {4- [3- (Dimethylamino) propoxy] -3-fluorobenzyl} -piperidin-4-yl) -4-ethyl-7-methoxyphthalazin-1-amine trihydrochloride (Compound No. 21)

21.1. N- (1-Benzylpiperidin-4-yl) -4-ethyl-7-methoxy-phthalazin-1-amine

This compound is obtained according to the procedure described in 3.1. by reaction of 1-chloro-4-ethyl-7-methoxy-phthalazine (synthesis described in 6.3) with 4-amino-1-benzylpiperidine. LC / MS: MH ⁺ = 377 (tR = 4.82 minutes pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.28 (t, J = 7.5 Hz, 3H); 1.57-1.75 (m, 2H); 1.98-2.18 (m, 4H); 2.85-2.95 (m, 2H); 3.03 (q, J = 7.5 Hz, 2H); 3.52 (s, 2H); 3.99 (s, 3H); 4.10- 4.22 (m, 1H); 6.77 (d, J = 7.2 Hz ₁ 1H); 7.22-7.37 (m, 5H), 7.44 (dd, J ₁ = 9 Hz, J ₂ = 2.5 Hz, 1H) ₁ 7.69 (d, J = 2.5 Hz, 1H); 7.96 (d, J = 9 Hz, 1H).

21.2. 4-Ethyl-7-methoxy-Λ- (piperidin-4-yl) -phthalazin-1-amine

This compound is obtained by debenzylation of Λ- (1-benzylpiperidin-4-yl) -4-ethyl-7-methoxy-phthalazin-1-amine according to the procedure described in 3.2. Mp = 203 ^° C. (B) )

LC / MS: MH ⁺ = 287 (tR = 3.84 and 3.96 minutes, pH 3.1)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.28 (t, J = 7.5 Hz, 3H); 1.35-1.57 (m, 2H); 1.92- 2.04 (m, 2H); 2.10-2.25 (m, 1H); 2.55-2.65 (m, 2H); 2.96-3.10 (m, 4H); 3.96 (s, 3H); 4.12-4.25 (m, 1H); 6.76 (d, J = 7.2 Hz, 1H); 7.44 (dd, J ₁ = 9 Hz, J ₂ = 2.5 Hz, 1H), 7.71 (d, J = 2.5 Hz, 1H); 7.96 (d, J = 9 Hz, 1H).

21.3. N- (1- {4- [3- (dimethylamino) propoxy] -3-fluorobenzyl} piperidin-4-yl) -4-ethyl-7-methoxyphthalazin-1-amine trihydrochloride (Compound No. 21)

This compound in the base form is obtained according to the procedure described in 8.2. by reaction of 4-ethyl-7-methoxy-β- (piperidin-4-yl) -phthalazin-1-amine with 4- (3-dimethylaminopropoxy) -3-fluoro-benzaldehyde prepared in 8.1. The trihydrochloride is obtained by the treatment described in 6.5. Example 22

N- (1- {4- [3- (Dimethylamino) propoxy] -3-fluorobenzyl} -piperidin trihydrochloride

4-yl) -7-methoxy-4- (methoxymethyl) phthalazin-1-amine (Compound No. 22)

22.1. N- (1-Benzylpiperidin-4-yl) -7-methoxy-4-methoxymethyl-phthalazin-1-amine

This compound is obtained according to the procedure described in 3.1. by reaction of 1-chloro-7-methoxy-4-methoxymethyl phthalazine (synthesis described in 7.3) with 4-amino-1-benzylpiperidine.

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.57-1.77 (m, 2H); 1.98-2.20 (m, 4H); 2.85-2.98 (m, 2H); 3.28 (s, 3H); 3.52 (s, 2H); 3.96 (s, 3H); 4.12-4.30 (m, 1H); 4.77 (s, 2H); 6.99 (d, J = 7.2 Hz, 1H); 7.22-7.38 (m, 5H), 7.47 (dd, J ₁ = 9 Hz, J ₂ = 2.5 Hz, 1H), 7.71 (d, J = 2.5 Hz, 1H); 8.01 (d, J = 9 Hz, 1H).

22.2. 7-Methoxy-4-methoxymethyl-3- (piperidin-4-yl) -phthalazin-1-amine

This compound is obtained by debenzylation of Λ- (1-Benzylpiperidin-4-yl) -7-methoxy-4-methoxymethyl-phthalazin-1-amine according to the procedure described in 3.2. Mp = 195 ^° C. (B) )

LC / MS: MH ⁺ = 303 (tR = 3.82 minutes, pH 3.1)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.42-1.55 (m, 2H); 1.93-2.02 (m, 2H); 2.05-2.20 (m, 1H); 2.53-2.63 (m, 2H); 2.98-3.08 (m, 2H); 3.28 (s, 3H); 3.96 (s, 3H); 4.20-4.30 (m, 1H); 4.76 (s, 2H); 6.98 (d, J = 7.2 Hz, 1H); 7.45 (dd, J ₁ = 9 Hz, J ₂ = 2.5 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H); 8.00 (d, J = 9 Hz, 1H). 22.3. N- (1- {4- [3- (Dimethylamino) propoxy] -3-fluorobenzyl} piperidin-4-yl) -7-methoxy-4- (methoxymethyl) phthalazin-1-amine trihydrochloride (Compound No. 22 )

This compound in the base form is obtained according to the procedure described in 8.2. by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine with 4- (3-dimethylaminopropoxy) -3-fluoro-benzaldehyde prepared in 8.1. The trihydrochloride is obtained by the treatment described in 7.4.

Example 23

N- {1- [3-Fluoro-4- (3-pyrrolidin-1-ylpropoxy) benzyl] piperidin-4-yl} -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine trihydrochloride ( compound no. 23)

23.1 3-Fluoro-4- (3-pyrrolin-1-ylpropoxy) benzaldehyde

This compound is obtained according to the procedure described in 4.2. by reaction of β- (3-chloropropyl) pyrrolidine with 3-fluoro-4-hydroxybenzaldehyde.

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.60-1.80 (m, 4H); 1.86-2.02 (m, 2H); 2.34-2.58

(m, 6H); 4.18-4.28 (m, 2H); 7.36-7.45 (m, 1H); 7.70 (d, J = 11Hz, 1H), 7.77 (d, J = 9Hz, 1H), 9.88 (s, 1H ₁ CHO).

23.3. N- {1- [3-Fluoro-4- (3-pyrrolin-1-ylpropoxy) benzyl] piperidin-4-yl} -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine trihydrochloride

(compound No. 23)

3-fluoro-4- (3-pyrrolidin-1-ylpropoxy) benzaldehyde.

The trihydrochloride is obtained by the treatment described in 6.5.

Example 24:

1- (3- {4 - [(4 - {[7-Methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] aminopiperidin-1-yl) methyl] phenoxy} propyl) pyrrolidinic trihydrochloride; 2-one (compound no. 24)

24.1. 4- [3- (2-Oxopyrrolidin-1-yl) propoxy] benzaldehyde

This compound is obtained according to the procedure described in 4.2. by reaction of 4-hydroxybenzaldehyde with 1- (3-chloropropyl) -pyrrolidin-2-one which has previously been obtained by reaction of 1- (3-hydroxypropyl) -pyrrolidin-2-one with thionyl chloride. LC / MS: MH ⁺ = 248 (tR = 6.31 minutes, pH 3.1)

24.2 1- (3- {4 - [(4 - {[7-Methoxy-4 (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propyl) pyrrolidine trihydrochloride -2-one (compound No. 24)

This compound in the base form is obtained according to the procedure described in 8.2. by reaction of 7-methoxy-4- (4-methoxyphenyl) -β- (piperidin-4-yl) phthalazin-1-amine with the

4- [3- (2-oxopyrrolidin-1-yl) propoxy] benzaldehyde.

¹ H NMR (DMSO-d _6, 400 MHz) δ ppm: 1.62 to 1, 78 (m, 2H); 1, 88-1, 98 (m, 4H); 2.0-2.15 (m, 4H); 2.20-2.28 (m, 2H); 2.85-2.95 (m, 2H); 2.30-2.40 (m, 4H); 3.48 (s, 2H); 3.85 (s, 3H);

3.92-4.00 (m, 2H); 4.0 (s, 3H); 4.20 - 4.30 (m, 1H); 6.89 (d, J = 8 Hz, 2H); 6.98 (d, J = 7.5

Hz, 1H); 7.08 (d, J = 8 Hz, 2H); 7.23 (d, J = 8 Hz, 2H); 7.42 (dd, J ₁ = 7.5 Hz, J ₂ = 2.5 Hz ₁

1H); 7.50 (d, J = 8 Hz, 2H); 7.72-7.78 (m, 2H); The trihydrochloride is obtained by the treatment described in 6.5.

Example 25

N- (1- {4- [2- (Dimethylamino) ethoxy] benzyl} piperidin-4-yl) -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine trihydrochloride (Compound No. 25)

25.1. 4- [2- (Dimethylamino) ethoxy] benzaldehyde

This compound is obtained according to the procedure described in 5.1. by reaction of 2-chloro-Λ, Λ-dimethyl-ethylamine hydrochloride with 4-hydroxybenzaldehyde.

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 2.22 (s, 6H); 2.65 (t, J = 5.7 Hz, 2H); 4.17 (t, J

5.7 Hz, 2H); 7.14 (d, J = 6.8 Hz ₁ 2H), 7.86 (d, J = 6.8 Hz, 2H), 9.88 (s, 1H, CHO).

25.2. N- (1- {4- [2- trihydrochloride

(dimethylamino) ethoxy] benzyl) piperidin-4-yl) -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine (compound 25)

This compound in the base form is obtained according to the procedure described in 8.2. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine with 4- [2- (dimethylamino) ethoxy] benzaldehyde. The trihydrochloride is obtained by the treatment described in 17.2. Example 26:

7-Methoxy-4- (4-methoxyphenyl) -N- (1- {4- [2- (1-methylpyrrolidin-2-yl) ethoxy] benzyl} piperidin-4-yl) phthalazin-1-amine trihydrochloride (compound no

27)

26.1 4- [2- (1-Methylpyrrolidin-2-yl) ethoxy] benzaldehyde and 4 - [(1-methylazepan-4-yl) oxy] benzaldehyde

These compounds are obtained according to the procedure described in 14.1. by reaction of 2- (2-chloroethyl) -α-methyl-pyrrolidine hydrochloride with 4-hydroxybenzaldehyde.

The two compounds are separated by chromatography on silica gel (eluent toluene / methanol 50/50 (v / v)).

The first compound eluted is 4- [2- (1-methylpyrrolidin-2-yl) ethoxy] benzaldehyde:

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.15-1.25 (m, 1H); 1.40-1.75 (m, 4H); 1.85-2.20 (m, 4H); 2.23 (s, 3H); 2.92-3.0 (m, 1H); 4.10-4.18 (m, 1H); 7.13 (d, J = 9 Hz, 2H), 7.85 (d,

J = 9 Hz, 2H), 9.88 (s, 1H, CHO).

The second compound eluted is 4 - [(1-methylazepan-4-yl) oxy] benzaldehyde:

¹ H NMR (DMSO-ds, 250 MHz) δ ppm: 1.50-1.92 (m, 4H); 2.0-2.18 (m, 2H); 2.22 (s, 3H);

2.45-2.68 (m, 4H); 4.72-4.80 (m, 1H); 7.14 (d, J = 9Hz, 2H), 7.84 (d, J = 9Hz, 2H), 9.86 (s, 1H, CHO).

26.2 7-Methoxy-4- (4-methoxyphenyl) -N- (1- {4- [2- (1-methylpyrrolidin-2-yl) ethoxy] benzyl} piperidin-4-yl) phthalazin-1-trihydrochloride amine (compound no. 27)

A solution of 300 mg (0.82 mmol) of 7-methoxy-4- (4-methoxyphenyl) -β- (piperidin-4-yl) phthalazin-1-amine in 10 mL of 1,2-dichloroethane is added with 172 mg (0.74 mmol) 4- [2- (1-methylpyrrolidin-2-yl) ethoxy] benzaldehyde. The mixture is stirred for 1 hour 30 minutes under nitrogen, then 226 mg (1. 07 mmol) of sodium triacetoxyborohydride are added. The reaction medium is stirred for 48 hours at room temperature, added 20 mL of 1N sodium hydroxide and then extracted with dichloromethane. The organic phase is extracted with 40 ml of N hydrochloric acid. The acidic aqueous phase obtained is basified with 2N sodium hydroxide and then extracted with dichloromethane. The organic extract is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue is purified on a basic alumina column (eluent: dichloromethane / methanol 100/0 to 98/2 (v / v)). We obtain 220 mg of oily product. The trihydrochloride is obtained by the treatment described in 4.3.

Example 27:

7-Methoxy-4- (4-methoxyphenyl) -N- (1- {4 - [(1-methylazepan-4-yl) oxy] benzyl} piperidin-4-yl) phthalazin-1-amine trihydrochloride (Compound n ° 26)

This compound in the base form is obtained according to the procedure described in 26.2. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine with 4 - [(1-methylazepan-4-yl) oxy] benzaldehyde. The trihydrochloride is obtained by the treatment described in 4.3.

Example 28

4-ethyl-N- [1- (4-ethynylbenzyl) piperidin-4-yl] -7-methoxyphthalazin-1-amine dihydrochloride (Compound No. 28)

28.1. 4-Ethyl-7-methoxy-Λ- (1 - {4 - [(trimethylsilyl) ethynyl] benzyl} piperidin-4-yl) phthalazin-1-amine

-7 ^If - This compound is obtained according to the procedure described in 4.3. by reaction of 4-ethyl-7-methoxy-β- (piperidin-4-yl) -phthalazin-1-amine with 4- (trimethylsilyl) ethynylbenzaldehyde.

LC / MS: MH ⁺ = 473 (tR = 6.05 minutes pH 3.1)

5 ¹ H NMR (DMSO-d _6, 400 MHz) δ ppm: 0.29 (s, 9H); 1.26 (t, J = 7.5 Hz, 3H); 1.60-1.70 (m, 2H); 1.98-2.18 (m, 4H); 2.83-2.90 (m, 2H); 3.05 (q, J = 7.5 Hz, 2H); 3.53 (s, 2H); 3.95 (s, 3H); 4.10-4.20 (m, 1H); 6.75 (d, J = 7.2 Hz, 1H); 7.32-7.36 (m, 2H), 7.40-7.45 (m, 3H), 7.67 (d, J = 2.5 Hz, 1H); 7.95 (d, J = 9 Hz, 1H).

10 28.2. 4-Ethyl-N- [1- (4-ethynylbenzyl) piperidin-4-yl] -7-methoxyphthalazin-1-amine dihydrochloride (Compound No. 28)

A solution of 0.85 g (1.8 mmol) of 4-ethyl-7-methoxy-N - (1- {4- [(trimethylsilyl) ethynyl] benzyl} piperidin-4-yl) phthalazin-1-amine in 90 ml of methanol

0.55 g (4 mmol) of potassium carbonate is added thereto. The mixture is stirred for 24 hours at ambient temperature, then water and 1N hydrochloric acid are added until neutral pH and extracted with dichloromethane. The organic extract is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 0.75 g of gummy product is obtained. 0 LC / MS: MH ⁺ = 401 (tR ≈ 4.77 minutes pH 3.1)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.28 (t, J = 7.5 Hz, 3H); 1.58-1.72 (m, 2H); 1.98-2.18 (m, 4H); 2.83-2.92 (m, 2H); 3.05 (q, J = 7.5 Hz, 2H); 3.53 (s, 2H); 3.96 (s, 3H); 4.14 (s, 1H); 4.10-4.20 (m, 1H); 6.76 (d, J = 7.2 Hz, 1H); 7.33-7.38 (m, 2H), 7.42-7.50 (m, 3H), 7.69 (d, J = 2.5 Hz, 1H); 7.96 (d, J = 9 Hz, 1H). The dihydrochloride is obtained by the treatment described in 6.5.

Example 29

N- (1- {4- [3- (dimethylamino) prop-1-yn-1-yl] benzyl} piperidin-4-yl) -4-ethyl-7-methoxyphthalazin-1-amine hydrochloride salt (compound no. ° 29)

A mixture of 250 mg (0.62 mmol) of 4-ethyl-N- [1- (4-ethynylbenzyl) piperidin-4-yl] -7-methoxyphthalazin-1-amine, 120 mg (1.28 mmol) of Λ /, Λ-dimethyl-methylene-iminium chloride and 6 mg (0.06 mmol) copper (I) chloride in 6.3 mL of dioxane. The mixture is stirred for 12 hours at 70 ^° C. During this heating period, twice 60 mg of / V, Λ-dimethyl-methylene-iminium are added to the reaction medium. After cooling, the mixture is added with water and 1N sodium hydroxide and ethyl acetate and is filtered on celite. The organic phase is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is purified on a silica column (eluent: dichloromethane / methanol from 100/0 to 85/15 (Wv)). We obtain 220 mg of oily product. ¹ H NMR (DMSOd ₆ , 400 MHz) δ ppm: 1.25 (t, J = 7.5 Hz, 3H); 1.60-1.70 (m, 2H); 1.98- 2.15 (m, 4H); 2.24 (s, 6H); 2.85-2.90 (m, 2H); 3.05 (q, J = 7.5 Hz, 2H); 3.45 (s, 2H); 3.95 (s, 3H); 4.10-4.20 (m, 1H); 6.76 (d, J = 7.2 Hz, 1H); 7.33-7.38 (m, 2H), 7.40-7.48 (m, 3H), 7.68 (d, J = 2.5 Hz, 1H); 7.96 (d, J = 9 Hz, 1H). The trihydrochloride is obtained by the treatment described in 6.5.

Example 30

3- {4 - [(4 - {[7-Methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol dihydrochloride (compound no. ° 30)

30.1 4- [3- (Tetrahydro-2H-pyran-2-yloxy) propoxy] benzaldehyde

A solution of 1.31 g (5.9 mmol) of 2- (3-bromopropoxy) tetrahydro-2H-pyran and 0.94 g (7.7 mmol) of 4-hydroxybenzaldehyde in 23 mL of DMF is added with 1.63 g (11.8 mmol). ) of potassium carbonate. The mixture is stirred at room temperature for 20 hours then is added with water and extracted with ethyl acetate. The organic extract is washed with water and then with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 1.52 g of oily product are obtained. ¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.45-1.80 (m, 6H); 1.92-2.08 (m, 2H); 3.38-3.58 (m, 2H); 3.70-3.83 (m, 2H); 4.15-4.22 (m, 2H); 4.55-4.60 (m, 1H); 7.13 (d, J = 9Hz, 2H), 7.86 (d, J = 9Hz, 2H), 9.88 (s, 1H, CHO). 30.2 3- {4 - [(4 - {[7-Methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol dihydrochloride (compound n ° 30)

A solution of 528 mg (2 mmol) of 7-methoxy-4- (4-methoxyphenyl) -α- (piperidin-4-yl) phthalazin-1-amine in 20 ml of 1,2-dichloroethane is added with 875 g of mg (2.4 mmol) 4- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] benzaldehyde. The mixture is stirred for 30 minutes under nitrogen, then 550 mg (2.6 mmol) of sodium triacetoxyborohydride are added. The reaction medium is stirred for 24 hours at room temperature, hydrolyzed with water and 1N sodium hydroxide and then extracted with dichloromethane. The organic extract is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue is purified on a silica column (eluent: 100/0 to 90/10 (v / v) dichloromethane / methanol). 943 mg of oily product are obtained. 350 mg (0.57 mmol) of this product are dissolved in 7 mL of methanol and the solution is supplemented with 3.5 mL (2.45 mmol) of Dowex 50X2-200 resin previously washed with methanol. The mixture is stirred for 24 hours and then filtered. The resin is washed with methanol and then suspended in 4 mL of methanol and 3.5 mL of 7N ammonia methanol. The mixture is stirred for at least 4 hours and then filtered. The filtrate is evaporated under reduced pressure. The product obtained is sufficiently pure. The dihydrochloride is obtained by the treatment described in 6.5.

Example 31:

4-Ethyl-7-methoxy-N- {1- [4- (4-pyrrolidin-1-ylpiperidin-1-yl) benzyl] piperidin-4-yl} phthalazin-1-amine trihydrochloride (Compound No. 31 )

31.1 4- (4-Pyrrolidin-1-ylpiperidin-1-yl) benzaldehyde

A mixture consisting of 1 g (5.4 mmol) of 4-bromobenzaldehyde, 1 g (6.5 mmol) of A- (i-pyrrolidinyl) piperidine in 10 mL of anhydrous toluene is stirred at room temperature under an argon atmosphere and 2.46 (7.56 mmol) cesium carbonate, 50 mg tris (dibenzylideneacetone) dipalladium (0) and 50 mg 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (racemic). The mixture is stirred at 80 ^° C. for 40 hours, then, after cooling, is filtered on celite. The solid is rinsed with ethyl acetate and the filtrate is evaporated to dryness. The residue obtained is purified on a silica column (eluent: 100/0 to 85/15 (v / v) dichloromethane / methanol). 0.94 g of an orange oil is obtained in which the product crystallizes. ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.35-1.52 (m, 2H); 1.60-1.75 (m, 4H); 1.85-1.95 (m, 2H); 2.20-2.32 (m, 1H); 2.45-2.60 (m, 4H); 2.95-3.05 (m, 2H); 3.85-3.96 (m, 2H); 7.04 (d, J = 9Hz, 2H), 7.70 (d, J = 9Hz, 2H), 9.70 (s, 1H, CHO).

31.2 4-Ethyl-7-methoxy-N- {1- [4- (4-pyrrolidin-1-ylpiperidin-1-yl) benzyl] piperidin-4-yl} phthalazin-1-amine trihydrochloride (Compound no. 31)

This compound in the base form is obtained according to the procedure described in 26.2. by reaction of 4-ethyl-7-methoxy-N- (piperidin-4-yl) -phthalazin-1-amine with 4- (4-pyrrolidin-1-ylpiperidin-1-yl) benzaldehyde. The trihydrochloride is obtained by treatment of the product dissolved in ethyl acetate with a solution of 2N hydrochloric acid in diethyl ether. A suspension is formed which is filtered. The powder obtained is dried at 40 ^° C. under reduced pressure.

Example 32: N- (1- {4- [3- (Dimethylamino) propoxy] benzyl} piperidin-4-yl) -7-methoxy-4- (methoxymethyl) phthalazin-1-amine trihydrochloride (Compound No. 32) )

This compound in the base form is obtained according to the procedure described in 8.2. by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (prepared in 22.2.) with 4- (3-dimethylaminopropoxy) -benzaldehyde. The trihydrochloride is obtained by the treatment described in 7.4.

Example 33:

N- (1- {4 - [(3R) -3- (dimethylamino) pyrrolidin-1-yl] benzyl} piperidin-4-yl) -7-methoxy-4- (methoxymethyl) phthalamino-1-amine trihydrochloride (compound no. 34)

33.1 4 - [(3R) -3- (Dimethylamino) pyrrolidin-1-yl] benzaldehyde

This compound is obtained according to the procedure described in 31.1 by reaction of 4-bromobenzaldehyde with (3R) -3- (dimethylamino) pyrrolidine.

[α] _D ²² = - 3.1 (c = 0.49, methanol)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.75-1.95 (m, 1H); 2.10-2.21 (m, 1H); 2.22 (s, 6H);

2.72-2.88 (m, 1H); 3.09-3.18 (m, 1H); 3.29-3.40 (m, 1H); 3.47-3.62 (m, 2H); 6.66 (d, J = 9 Hz, 2H), 7.68 (d, J = 9 Hz, 2H), 9.66 (s, 1H ₁ CHO).

33.2. N- (1- {4 - [(3R) -3- (dimethylamino) pyrrolidin-1-yl] benzyl} -piperidin-4-yl) -7-methoxy-4- (methoxymethyl) phthalazin-1-amine trihydrochloride (compound no. 34)

This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl- (V- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4 - [(3f?) - 3- (dimethylamino) pyrrolidin-1-yl] benzaldehyde. The trihydrochloride is obtained by the treatment described in 6.5 .. Example 34

N- (1- {4 - [(3S) -3- (dimethylamino) pyrrolidin-1-yl] benzyl} piperidin-4-yl) -7-methoxy-4- (methoxymethyl) phthalazin-1-amine trihydrochloride (compound no. 33)

34.1 4 - [(3S) -3- (Dimethylamino) pyrrolidin-1-yl] benzaldehyde

This compound is obtained according to the procedure described in 31.1 by reaction of 4-bromobenzaldehyde with (3S) -3- (dimethylamino) pyrrolidine. [α] _D ²² = + 2.8 (c = 0.67, methanol).

34.2. N- (1- {4 - [(3S) -3- (dimethylamino) pyrrolidin-1-yl] benzyl} piperidin-4-yl) -7-methoxy-4- (methoxymethyl) phthalazin-1-amino trihydrochloride (compound no. 33)

This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4 - [(3S) -3- (dimethylamino) pyrrolidin-1-yl] benzaldehyde. The trihydrochloride is obtained by the treatment described in 6.5 ..

Example 35

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl) -7-methoxy-4- dihydrochloride

[4- (2-methyl-2H-tetrazol-5-yl) phenyl] phthalazin-1-amine (Compound No. 35)

35.1. N-Methoxy-N-methyl-4- (2H-tetrazol-5-yl) benzamide

A solution of 5 g (26.3 mmol) of 4-cyano-β-methoxy-β-methylbenzamide in 100 ml of THF is added with 13.96 ml (106 mmol) of trimethylsilylazide and 3.27 g.

(13.14 mmol) of dibutyltin oxide and then stirred for 6 hours under reflux. 10 ml of trimethylsilylazide are added and the mixture is heated for a further 8 hours under reflux.

After cooling, the mixture is evaporated under reduced pressure and the residue obtained is purified on a silica column (eluent: dichloromethane / methanol from 100/0 to 85/15 (v / v)). 5.1 g of white solid are obtained.

Mp = 173 ^° C (M)

LC / MS: MH ⁺ = 234 (tR = 5.26 minutes pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 3.30 (s, 3H); 3.58 (s, 3H); 7.81 (d, J = 8.5 Hz, 2H);

8.1 1 (d, J = 8.5 Hz, 2H).

35.2. / V-Methoxy-N-methyl-4- (2-methyl-2H-tetrazol-5-yl) benzamide

A solution of 5.1 g (21.8 mmol) of β-Methoxy-β-methyl-4- (2H-tetrazol-5-yl) benzamide in 100 ml of DMF is supplemented with 3.32 g (24 mmol) of potassium carbonate. then 2.72 mL (44 mmol) of iodomethane. The mixture is stirred at ambient temperature for 16 hours and is then added with water. A precipitate is formed which is filtered, washed with ethyl acetate and dried in an oven under reduced pressure.

2.7 g of white powder are obtained.

F = 173 ⁰ C (K) ¹ H NMR (DMSO-d _6, 250 MHz) δ ppm: 3.30 (s, 3H); 3.58 (s, 3H); 4.46 (s, 3H); 7.77 (d, J =

8.5 Hz, 2H); 8.12 (d, J = 8.5 Hz, 2H). 35.3. 5-Methoxy-2- [4- (2-methyl-2H-tetra-2-yl-5-yl) benzoyl] benzoic acid

This compound is synthesized according to the method described in 2.4. by reacting 2-bromo-5-methoxybenzoic acid previously treated with n-butyl lithium with N-methoxy-Λ-methyl-4- (2-methyl-2H-tetrazol-5-yl) benzamide . It is used raw in the next reaction.

35.4. 7-Methoxy-4- [4- (2-methyl-2H-tetrazol-5-yl) phenyl] phthalazin-1 (2H) -one

This compound is obtained according to the procedure described in 2.5. by reaction of unpurified 5-methoxy-2- [4- (2-methyl-2H-tetrazol-5-yl) benzoyl] benzoic acid with hydrazine hydrate. Mp = 289 ^° C (M) LC / MS: MH ⁺ = 335 (tR = 7.34 minutes pH 3.1)

^1H NMR δ in ppm (DMSO d 6): 3.98 (s, 3H); 4.48 (s, 3H); 7.50 (dd, J ₁ = 9 Hz, J ₂ = 2.7 Hz, 1H); 7.68-7.81 (m, 4H); 8.23 (d, J = 8.5 Hz, 2H); 12. 8 (s, 1H, NH).

35.5. 4-Chloro-6-methoxy-1- [4- (2-methyl-2H-tetrazol-5-yl) phenyl] PhtA [azine

This compound is obtained according to the procedure described in 2.6. by reaction of 7-methoxy-4- [4- (2-methyl-2H-tetrazol-5-yl) phenyl] phthalazin-1 (2H) -one with phosphoryl chloride. MP = 235 ° C (M)

LC / MS: MH ⁺ = 353 (tR = 8.29 minutes pH 3.1)

^{1 H} NMR δ in ppm (DMSO d 6): 4.08 (s, 3H); 4.49 (s, 3H); 7.64 (d, J = 2.5 Hz ₁ 1H); 7.73 (dd, J ₁ = 9 Hz, J ₂ = 2.7 Hz ₁ 1 H); 7.92 (d, J = 8.5 Hz, 2H); 8.03 (d, J = 9 Hz, 1H); ); 8.30 (d, J = 8.5 Hz, 2H).

35.6 N- [1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] -7-methoxy-4- [4- (2-methyl-2H-tetrazol-5-yl) phenyl] dihydrochloride ] Phthalazin-1-Amine (Compound No. 35)

This compound in the base form is obtained according to the procedure described in 1.9. by reaction of 4-chloro-6-methoxy-1- [4- (2-methyl-2H-tetrazol-5-yl) phenyl] phthalazine with 1 - (1,3-benzodioxol-5-ylmethyl) ) piperidin-4-yl-amine. The dihydrochloride is obtained by the treatment described in 4.3.

Example 36

7-Methoxy-4- (methoxymethyl) -N- (1- {4 - [(1-methylpyrrolidin-3-yl) methoxy] benzyl} piperidin-4-yl) phthalazin-1-amine trihydrochloride (Compound No. 36)

36.1. 4 - [(1-methylpyrrolidin-3-yl) methoxy] benzaldehyde

This compound is obtained by the Mitsunobu reaction according to the procedure described in 17.1. by reaction of 4-hydroxybenzaldehyde with (1-methylpyrrolidin-3-yl) methanol synthesized by the reaction described in J. Org. Chem. 1961 p.1519-1524. LC / MS: MH ⁺ = 220 (tR = 4.00 minutes pH 3.1) 36.2 7-Methoxy-4- (methoxymethyl) -N- (1- {4 - [(1-methylpyrrolidin-3-yl) methoxy] benzyl} piperidin-4-yl) phthalazin-1-amine trihydrochloride

(Compound No. 36)

This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4 - [(1-methylpyrrolidin-3-yl) methoxy] benzaldehyde. ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.43-1.55 (m, 1H); 1.58-1.70 (m, 2H); 1.90-2.10 (m, 5H); 2.23 (s, 3H); 2.32-2.42 (m, 2H); 2.45-2.60 (m, 3H); 2.85-2.91 (m, 2H); 3.28 (s, 3H); 3.43 (s, 3H); 3.80-3.85 (m, 2H); 3.95 (s, 3H); 4.15-4.25 (m, 1H); 4.76 (s, 2H); 6.88 (d, J = 8.8 Hz, 2H); 6.99 (d, J = 7.6 Hz, 1H); 7.22 (d, J = 8.8 Hz, 2H); 7.46 (dd, J ₁ = 8.8 Hz, J ₂ = 2 Hz, 1H); 7.70 (d, J = 2 Hz, 1H); 8.0 (d, J = 8.8 Hz, 1H). The trihydrochloride is obtained by the treatment described in 4.3.

Example 37

7-Methoxy-4- (methoxymethyl) -N- (1- {4 - [(8-methyl-8-azabicyclo [3.2.1] oct-3-yl) oxy] benzyl beta-anomeric trihydrochloride piperidin-4-yl) phthalazin-1-amine (compound No. 37)

37.1. 4 - [(8-Methyl-8-azabicyclo [3.2.1] oct-3-yl) oxy] benzaldehyde (beta anomer)

This compound is obtained according to the procedure described in 17.1. by reaction of 4-hydroxybenzaldehyde with 8-methyl-8-azabicyclo [3.2.1] octan-3-ol (alpha anomer) ¹ H NMR (DMSO-d, 250 MHz) δ ppm: 1.10-1.25 (m, 2H) ; 1.60-1.78 (m, 3H); 1.90-2.02 (m, 3H); 2.23 (s, 3H); 3.10-3.20 (m, 2H); 4.66-4.82 (m, 1H, CH-O axial); 7.14 (d, J = 9Hz, 2H), 8.83 (d, J = 9Hz, 2H), 9.86 (s, 1H, CHO). 37.2 7-Methoxy-4- (methoxymethyl) -N- (1- {4 - [(8-methyl-8-azabicyclo [3.2.1] oct-3-yl) oxy] benzyl beta-anomeric trihydrochloride piperidin-4-yl) phthalazin-1-amine (Compound No. 37)

This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4 - [(8-methyl-8-azabicyclo [3.2.1] oct-3-yl) oxy] benzaldehyde (beta-anomer).

The trihydrochloride is obtained by the treatment described in 4.3.

Example 38

2 - [{4 - [(4 - {[7-methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenyl} (methyl) amino] ethanol trihydrochloride (compound no. ° 38)

This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the Λ / -methyl-N- (2-hydroxyethyl) -4-aminobenzaldehyde. The trihydrochloride is obtained by the treatment described in 4.3.

Example 39

7-Methoxy-4- (methoxymethyl) -N- {1- [4- (2-oxo-2-pyrrolidin-1-ylethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine dihydrochloride (compound no. ° 39)

39.1. 4- (2-Oxo-2-pyrrolidin-1-yl-ethoxy) beπzaldéhyde

A mixture consisting of 1 g (5.55 mmol) of 4-formylphenoxyacetic acid and 0.435 g (6.11 mmol) of pyrrolidine in 50 ml of DMF is supplemented with 1.117 g (5.83 mmol) of chlor / - hydrochloride. dimethylaminopropyl) -N-ethylcarbodiimide (EDCl) and 0.71 g (5.83 mmol) of dimethylaminopyridine (DMAP). The mixture is stirred at room temperature for 20 hours then is added with water and extracted with ethyl acetate. The organic phase is washed with 1N hydrochloric acid, 1N sodium hydroxide to ₁ with water and then with water saturated with sodium chloride. It is dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 0.33 g of beige solid is obtained. ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.72-1.98 (m, 4H); 3.30-3.39 (m, 2H); 3.45-3.52 (m, 2H); 4.89 (s, 2H); 7.10 (d, J = 9Hz, 2H), 8.86 (d, J = 9Hz, 2H), 9.88 (s, 1H, CHO).

39.2. 7-Methoxy-4- (methoxymethyl) -N- {1- [4- (2-oxo-2-pyrrolidin-1-ylethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine dihydrochloride (compound no. ° 39)

This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4- (2-Oxo-2-pyrrolidin-1-yl-ethoxy) benzaldehyde. The dihydrochloride salt is obtained by the treatment described in 4.3.

Example 40

3- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] aminopiperidin-1-yl) methyl] phenoxy} propan-1-ol dihydrochloride (Compound No. 40 )

This compound in the base form is obtained according to the procedure described in 30.2 by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] benzaldehyde (preparation in 30.1) The dihydrochloride salt is obtained by the treatment described in 4.3.

Example 41:

7-Methoxy-4- (methoxymethyl) -N- (1- {4 - [(1-methylazepan-4-yl) oxy] benzyl} piperidin-4-yl) phthalazin-1-amine trihydrochloride (Compound No. 41)

This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4 - [(1-Methylazepan-4-yl) oxy] benzaldehyde (Preparation see 26.1.) -

The trihydrochloride is obtained by the treatment described in 4.3.

Example 42

7-Methoxy-4- (methoxymethyl) -N- (1- {4- [2- (1-methylpiperidin-2-yl) ethoxy] benzyl} piperidin-4-yl) phthalazin-1-amine trihydrochloride (compound n ° 42)

42.1. 4- [2- (1-W! Ethylpiperidin-2-yl) ethoxy] benzaldehyde

This compound is obtained according to the procedure described in 5.1. by reaction of 2- (2-chloroethyl) -1-methylpiperidine hydrochloride with 4-hydroxybenzaldehyde.

LC / MS: MH ⁺ = 248 (tR = 4.70 minutes pH 3.1)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.15-1.58 (m, 4H); 1.58-1.72 (m, 2H); 1.72-1.92

(m, 1H); 1.92-2.11 (m, 3H); 2.19 (s, 3H); 2.70-2.80 (m, 1H); 4.10-4.18 (m, 2H); 7.13 (d, J

= 9 Hz, 2H), 8.86 (d, J = 9 Hz, 2H), 9.86 (s, 1H, CHO). 42.2. 7-Methoxy-4- (methoxymethyl) -N- (1- {4- [2- (1-methylpiperidin-2-yl) ethoxy] benzyl} piperidin-4-yl) phthalazin-1-amine trihydrochloride (compound n ° 42)

This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4- [2- (1-methylpiperidin-2-yl) ethoxy] benzaldehyde The trihydrochloride is obtained by the treatment described in 4.3.

Example 43: 2- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} ethanol dihydrochloride (Compound No. 43)

43.1. 4- [2- (tetrahydro-2W-pyran-2-yloxy) ethoxy] benzaldehyde

This compound is obtained according to the procedure described in 30.1. by reaction of 4-hydroxybenzaldehyde with 2- (2-bromoethoxy) tetrahydro-2Al-pyran. ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.35-1.80 (m, 6H); 3.40-3.50 (m, 1H); 3.65-3.84 (m, 2H); 3.85-4.0 (m, 1H); 4.24-4.30 (m, 2H); 4.65-4.70 (m, 1H); 7.16 (d, J = 9 Hz, 2H), 7.86 (d, J = 9 Hz ₁ 2H), 9.90 (s, 1H, CHO).

43.2 2- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} ethanol dihydrochloride (Compound No. 43)

This compound in the base form is obtained according to the procedure described in 30.2 by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine

(Preparation in 22.2) with 4- [2- (tetrahydro-2H-7-pyran-2-yloxy) ethoxy] benzaldehyde. The dihydrochloride salt is obtained by the treatment described in 4.3. Example 44

7-Methoxy-4-methyl-N- (1- {4 - [(1-methylazepan-4-yl) oxy] benzyl} piperidin-4-yl) phthalazin-1-amine trihydrochloride (Compound No. 44)

44.1 2-Acetyl-5-methoxybenzoic acid

This compound is synthesized according to the method described in 2.4. by reacting 2-bromo-5-methoxybenzoic acid previously treated with n-butyllithium with N-methoxy-N-methylacetamide. It is used raw in the next reaction.

44.2. 7-Methoxy-4-methyl-2H-phthalazin-1-one

This compound is obtained according to the procedure described in 2.5. by reacting unpurified 2-acetyl-5-methoxy-benzoic acid with hydrazine hydrate. PF = 202 ⁰ C (Mettler FP62)

LC / MS: MH ⁺ = 191 (tR = 5.73 minutes)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 2.50 (s, 3H); 3.96 (s, 3H); 7.52 (dd, J ₁ = 8.8 Hz, J ₂

= 2.7 Hz, 1H); 7.66 (d, J ≈ 2.7 Hz, 1H); 7.90 (d, J = 8.8 Hz, 1H); 12.35 (s, 1H, NH).

44.3. 1-Chloro-7-methoxy-4-methyl-phthalazine

This compound is obtained according to the procedure described in 2.6. by reaction of 7-methoxy-4-methyl-2H-phthalazin-1-one with phosphoryl chloride. LC / MS: MH ⁺ = 209 (tR = 6.26 minutes) ¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 2.92 (s, 3H); 4.06 (s, 3H); 7.54 (d, J = 2.5 Hz, 1H); 7.77 (dd, J ₁ = 9.2 Hz, J ₂ = 2.5 Hz, 1H); 8.31 (d, J = 9.2 Hz, 1H). 44.4. N- (1-Benzylpiperidin-4-yl) -7-methoxy-4-methyl-phthalazin-1-amine

This compound is obtained according to the procedure described in 3.1. by reaction of 1-chloro-7-methoxy-4-methyl-phthalazine with 4-amino-1-benzyl-piperidine. LC / MS: MH ⁺ = 363 (tR = 3.84 minutes pH 3.1)

¹ H NMR (DMSOd ₆ , 400 MHz) δ ppm: 1.57-1.70 (m, 2H); 1.98-2.12 (m, 4H); 2.62 (s, 3H); 2.85-2.92 (m, 2H); 3.51 (s, 2H); 3.95 (s, 3H); 4.10-4.22 (m, 1H); 6.77 (d, J = 7.2 Hz, 1H); 7.22-7.30 (m, 1H); 7.30-7.38 (m, 4H); 7.44 (dd, J ₁ = 9 Hz, J ₂ = 2.5 Hz, 1H); 7.68 (d, J = 2.5 Hz, 1H); 7.99 (d, J = 9 Hz, 1H).

44.5. 7-Methoxy-4-methyl-N- (piperidin-4-yl) phthalazin-1-amine

This compound is obtained by debenzylation of Λ- (1-benzylpiperidin-4-yl) -7-methoxy-4-methyl-phthalazin-1-amine according to the procedure described in 3.2. Mp = 221 ^° C. (M. )

LC / MS: MH ⁺ = 273 (tR = 5.03 minutes, pH 7)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.38-1.57 (m, 2H); 1.92-2.04 (m, 3H); 2.55-2.62 (m, 2H); 2.63 (s, 3H); 2.98-3.08 (m, 2H); 3.96 (s, 3H); 4.12-4.28 (m, 1H); 6.74 (d, J = 7.2 Hz, 1H); 7.44 (dd, J ₁ = 9 Hz, J ₂ = 2.5 Hz, 1H), 7.71 (d, J = 2.5 Hz, 1H); 7.91 (d, J = 9 Hz, 1H).

44.6. 7-Methoxy-4-methyl-N- (1- {4 - [(1-methylazepan-4-yl) oxy] benzyl} piperidin-4-yl) phthalazin-1-amine hydrochloride (Compound No. 44)

This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methyl-β- (piperidin-4-yl) -phthalazin-1-amine with 4 - [(1 methylazepan-4-yl) oxy] benzaldehyde (synthesis see 26.1). The trihydrochloride is obtained by the treatment described in 4.3. Example 45

3- {3 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol hydrochloride (Compound No. 45 )

45.1 3- [3- (2-Tetrahydro-2-pyran-2-yloxy) propoxy] benzaldehyde

This compound is obtained according to the procedure described in 30.1. by reaction of 3-hydroxybenzaldehyde with 2- (3-bromopropoxy) tetrahydro-2H-pyran. LC / MS: MNa ⁺ = 287 (tR = 8.98 minutes, pH 3.1) ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.40-1.80 (m, 6H); 1.97-2.10 (m, 2H); 3.38-3.58 (m, 2H); 3.70-3.85 (m, 2H); 4.10-4.20 (m, 2H); 4.55-4.60 (m, 1H); 7.26-7.32 (m, 1H), 7.45-7.48 (m, 1H), 7.50-7.55 (m, 2H); 9.90 (s, 1H, CHO).

45.2. 3- {3 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol hydrochloride (Compound No. 45 )

This compound in the base form is obtained according to the procedure described in 30.2 by reaction of 7-methoxy-4-methoxymethyl- (V- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 3- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] benzaldehyde. The dihydrochloride salt is obtained by the treatment described in 4.3. Example 46

This compound in the base form is obtained according to the procedure described in 30.2 by reaction of 7-methoxy-4-methyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 44.5) with the 4- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] benzaldehyde (preparation in 30.1)

The dihydrochloride salt is obtained by the treatment described in 4.3.

Example 47

7-Chloro-4-methyl-N- (1 - {4 - [(1-methylazepan-4-yl) oxy] benzyl} -piperidin-4-yl) phthalazin-1-amine trihydrochloride (Compound No. 47)

47.1. 2-Acetyl-5-chlorobenzoic acid

This compound is synthesized according to the method described in 2.4. by reacting 2-bromo-5-chlorobenzoic acid previously treated with n-butyllithium with N-methoxy-N-methylacetamide. It is used raw in the next reaction.

47.2. 7-Chloro-1-hydroxy-4-methyl-phthalazine

This compound is obtained according to the procedure described in 2.5. by reaction of unpurified 2-acetyl-5-chloro-benzoic acid with hydrazine hydrate. Mp = 195 ⁰ C (M)

LC / MS: MH ⁺ = 195 (tR = 6.14 minutes pH 3.1) ^{1 H} NMR δ ppm (DMSO-d ₆ , 500 MHz): 2.53 (s, 3H); 7.97-8.01 (m, 2H); 8.15 (s, 1H); 12.55 (s, 1H ₁ OH).

47.3. 1,7-Dichloro-4-methyl-phthalazin

This compound is obtained according to the procedure described in 2.6. by reaction of 7-chloro-1-hydroxy-4-methyl-phthalazine with phosphoryl chloride. LC / MS: MH ⁺ = 213 (tR = 7.18 minutes pH 3.1)

^{1 H} NMR δ in ppm (DMSOd ₆ , 250 MHz): 2.93 (s, 3H); 8.20 (dd, J ₁ = 9 Hz, J ₂ = 2 Hz, 1H); 8.30 (d, J = 2 Hz, 1H); 8.37 (d, J = 9 Hz, 1H).

47.4. 7-Chloro-4-methyl-N- (piperidin-4-yl) phthalazin-1-amine

A suspension of 2.7 g (12.6 mmol) of 1,7-dichloro-4-methyl-phthalazine in 18 ml of n-butanol is admixed with 2.62 g (15.2 mmol) of 4-amino-piperidin-1-yl-carboxylate. ethyl and 0.68 g (12.7 mmol) of ammonium chloride. The mixture is heated at 140 ^° C. for 8 hours. The reaction medium is cooled to ambient temperature, saturated aqueous sodium hydrogencarbonate solution is added and the mixture is extracted with ethyl acetate. The organic phase is washed with salt water, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (solvent: dichloromethane / methanol 100/0 to 95/5 (v / v)). 3.2 g of gummy product is obtained in ethyl carbamate form. This compound is supplemented with 48 ml of a solution of hydrobromic acid at 33% in acetic acid and the mixture is stirred at 115 ° C. for 3 hours. After cooling, the precipitate is taken up in isopropanol and the suspension obtained is filtered. The partially dried precipitate is dissolved in 120 ml of water and the solution obtained is basified with 60 ml of 1N sodium hydroxide. A suspension is formed which is extracted with dichloromethane. The organic phase is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 2.29 g of beige product are obtained. M.p. 214 ° C (M)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.38-1.55 (m, 2H); 1.92-2.02 (m, 2H); 2.55-2.62 (m, 2H); 2.67 (s, 3H); 2.98-3.08 (m, 2H); 3.20-3.35 (m, 1H); 4.10-4.28 (m, 1H); 6.99 (d, J = 7.2 Hz, 1H); 7.89 (dd, J ₁ = 9 Hz ₁ J ₂ = 2 Hz ₁ 1 H), 8.01 (d, J = 9 Hz, 1H); 8.55 (d, J = 2 Hz, 1H).

47.5. 7-Chloro-4-methyl-N- (1- {4 - [(1-methylazepan-4-yl) oxy] benzyl} piperidin-4-yl) phthalazin-1-amine hydrochloride (Compound No. 47)

This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-chloro-4-methyl-β- (piperidin-4-yl) -phthalazin-1-amine with 4 - [(1 - methylazepan-4-yl) oxy] benzaldehyde (preparation in 26.1) The trihydrochloride is obtained by the treatment described in 4.3.

Example 48

3- [4 - ({4 - [(7-Chloro-4-methylphthalazin-1-yl) amino] piperidin-1-yl} methyl) phenoxy] propan-1-ol dihydrochloride (Compound No. 48)

This compound in the base form is obtained according to the procedure described in 30.2 by reaction of 7-chloro-4-methyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 47.4) with the 4- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] benzaldehyde (synthesis see 30.1.) Followed by purification on a column of silica (eluent: dichloromethane / methanol from 100/0 to 85 / (Wv)). The dihydrochloride salt is obtained by the treatment described in 4.3.

Example 49

(3S) -1 - {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] aminopiperidin-1-yl) methyl] phenyl} pyrrolidin-3-ol trihydrochloride ( Compound No. 49)

49.1 4 - [(3S) -3-Hydroxypyrrolidin-1-yl] benzaldehyde

This compound is obtained according to the procedure described in 31.1 by reaction of 4-bromobenzaldehyde with (S) -3-hydroxypyrrolidine. This compound is too colored to measure its rotational potency LCyMS: MH ⁺ = 192 (tR = 5.21 minutes pH 3.1)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.88-2.14 (m, 2H); 3.18-3.25 (m, 1H); 3.40-3.55 (m, 3H); 4.40-4.50 (m, 1H); 5.04 (d, J = 3.7 Hz, 1H), 6.64 (d, J = 9 Hz, 2H), 7.68 (d, J = 9 Hz, 2H), 9.66 (s, 1H, CHO).

49.2. (3S) -1- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenyl} pyrrolidin-3-ol trihydrochloride (Compound No. ° 49)

This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl- (V- (piperidin-4-yl) -phthalazin-1-amine 0 (preparation in 22.2) with 4 - [(3S) -3-hydroxypyrrolidin-1-yl] benzaldehyde. The dihydrochloride salt is obtained by the treatment described in 4.3. Example 50:

(3R) -1- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenyl} pyrrolidin-3-ol trihydrochloride ( compound no. 50)

50.1 4 - [(3 R) -3-Hydroxypyrrolidin-1-yl] benzaldehyde

This compound is obtained according to the procedure described in 31.1 by reaction of 4-bromobenzaldehyde with (R) -3-hydroxypyrrolidine. This compound is too colored to measure its rotary LC / MS: MH ⁺ = 192 (tR = 5.20 minutes pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.88-2.15 (m, 2H); 3.18-3.26 (m, 1H); 3.40-3.55 (m, 3H); 4.40-4.50 (m, 1H); 5.04 (d, J = 3.7 Hz, 1H), 6.64 (d, J = 9 Hz, 2H), 7.68 (d, J = 9 Hz, 2H), 9.66 (s, 1H ₁ CHO).

50.1 (3R) -1- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} -piperidin-1-yl) methyl] phenyl} pyrrolidin-3-ol trihydrochloride (Compound No. 50)

This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4 - ^[(; 3 /?) - 3-hydroxypyrrolidin-1-yl] benzaldehyde. The dihydrochloride salt is obtained by the treatment described in 4.3. Example 51

3- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalin-1-yl] amino} piperidin-1-yl) methyl] phenyl} prop-2-yn-1-ol (compound ° 51)

This compound is obtained according to the procedure described in 8.2. by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with 4- (3-hydroxyprop-1-yn-1-yl) benzaldehyde. It was purified on a silica column (eluent: dichloromethane / methanol from 100/0 to 90/10 (v / v)) and is concretized in isopropyl ether. ¹ H NMR (DMSOd ₆ , 400 MHz) δ ppm: 1.60-1.72 (m, 2H); 2.0-2.17 (m, 4H); 2.85-2.90 (m, 2H); 3.28 (s, 3H); 3.53 (s, 2H); 3.95 (s, 3H); 4.15-4.25 (m, 1H); 4.30 (d, J = 6 Hz, 2H); 4.76 (s, 2H); 5.30 (t, J = 6Hz, 1H, OH); 6.98 (d, J = 7.2 Hz ₁ ₁ H NH); 7.31-7.41 (m, 4H); 7.46 (dd, J ₁ = 8.8 Hz, J ₂ = 2 Hz, 1H); 7.71 (d, J = 2 Hz, 1H); 8.0 (d, J = 8.8 Hz, 1H).

Example 52

4- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} -piperidin-1-yl) methyl] phenyl} -2-methylbut-3-yn-2-ol (composed 52)

52.1. 4- (3-Hydroxy-3-methylbut-1-yn-1-yl) benzaldehyde

A mixture consisting of 3 g (16.2 mmol) of 4-bromobenzaldehyde, 0.15 g of copper iodide (I), 0.66 g of palladium on charcoal, 0.84 g of triphenylphosphine and 3 ml (49 mmol) of ethanolamine in 120 mL of water is stirred under nitrogen at room temperature for 30 minutes, then 2.4 ml (24.3 mmol) of 2-methyl-3-butyne-2-ol are added dropwise. The reaction mixture is stirred at 70 ^° C. for 7 hours and then overnight at room temperature. It is added with ethyl acetate and then filtered on celite. The organic phase is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. We obtain 4 g of oily product which is subsequently used without purification. LC / MS: MH ⁺ = 279 (tR = 7.03 minutes pH 3.1)

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 1.48 (s, 6H); 5.51 (s, 1H, OH); 7.47 (d, J = 8.4 Hz, 2H) ₁ 7.71 (d, J = 8.4 Hz, 2H), 8.31 (s, 1H, CHO).

52.2. 4- {4 - [(4 - {[7-H] -lethoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenyl} -2-methylbut-3-yn-2 -ol (compound 52)

This compound is obtained according to the procedure described in 8.2. by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with 4- (3-Hydroxy-3-methylbut-1-yn) 1-yl) benzaldehyde. It was purified on a silica column (eluent: 100/0 to 90/10 (v / v) dichloromethane / methanol) and is concretized in isopropyl ether.

¹ H NMR (DMSO-d _6, 400 MHz) δ ppm: 1.46 (s, 6H); 1.60-1.72 (m, 2H); 2.0-2.20 (m, 4H); 2.85-2.92 (m, 2H); 3.28 (s, 3H); 3.53 (s, 2H); 3.95 (s, 3H); 4.18-4.28 (m, 1H); 4.76 (s,

2H); 5.43 (s, 1H, OH); 6.98 (d, J = 7.2 Hz ₁ ₁ H NH); 7.30-7.38 (m, 4H); 7.46 (dd, J ₁ = 8.8

Hz; J ₂ = 2 Hz, 1H); 7.71 (d, J = 2 Hz, 1H); 8.0 (d, J = 8.8 Hz, 1H).

Example 53: 7-Methoxy-4- (methoxymethyl) -N- {1- [4- (4-pyrrolidin-1-ylbutyl) benzyl] piperidin-4-yl} phthalazin-1-amine trioxoxane (Compound 53)

53.1 Ethyl 4- {4 - [(Methoxysulfonyl) oxy] butyl} benzoate

A solution of ethyl 4- (4-hydroxybutyl) benzoate (0.79 g, 3.6 mmol) (Synthesis method described in J. Med Chem, 1983 26 (3) pp. 335-341) and 0.5 ml. 3.6 mmol) of triethylamine in 15 ml of dichloromethane is stirred at 0 ^° C. and 0.33 ml (4.32 mmol) of mesyl chloride are added. The mixture is stirred at ambient temperature for 2 hours and is then hydrolyzed and extracted with dichloromethane. The organic phase is washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. 1.073 g of oily product is obtained. ¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.32 (t, J = 7 Hz, 3H); 1.64-1.74 (m, 4H); 2.65-2.75 (m, 2H); 3.16 (s, 3H); 4.18-4.28 (m, 2H); 4.31 (q, J = 7 Hz, 2H); 7.37 (d, J = 8 Hz, 2H), 7.90 (d, J = 8 Hz, 2H).

53.2 Ethyl 4- (4-pyrrolidin-1-ylbutyl) benzoate

A solution of 0.96 g (3.2 mmol) of 4- {4 - [(méthoxysulfonyl) oxy] butyl} benzoate in 100 ethyl ¹ ml of isopropanol was added 8 mL (130 mmol) of pyrrolidine. The mixture is heated for 23 hours at reflux. After cooling, the isopropanol is evaporated under reduced pressure and the evaporation residue is added with water and extracted with ethyl acetate. The organic phase is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is purified on a silica column (eluent: dichloromethane / methanol from 100/0 to 90/10 (v / v)). The product is obtained quantitatively in oily form. ¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.32 (t, J = 7.2 Hz, 3H); 1.60-1.70 (m, 4H); 1.88- 1.98 (m, 4H); 2.68-2.75 (m, 2H); 3.03-3.30 (m, 6H); 4.31 (q, J = 7.2 Hz, 2H); 7.38 (d, J = 8.2 Hz, 2H); 7.90 (d, J = 8.2 Hz, 2H).

53.3 [4- (4-Pyrrolidin-1-ylbutyl) phenyl] methanol

A suspension of 154 mg (4 mmol) of lithium aluminum hydride in 20 ml of THF is added with a solution of 746 mg (2.7 mmol) of ethyl 4- (4-pyrrolidin-1-ylbutyl) benzoate in 10 mL of THF. The mixture is stirred at room temperature for 3 days then is added slowly and successively with 0.2 mL of water, 0.2 mL of 6N sodium hydroxide and 0.6 mL of water. A precipitate forms which is filtered on celite and rinsed with ethyl acetate. The filtrate is evaporated under reduced pressure. 597 mg of oily product are obtained. ¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.35-1.70 (m, 8H); 2.30-2.40 (m, 6H); 2.52-2.60 (m, 2H); 4.45 (d, J ≈ 5.5 Hz, 2H); 5.09 (t, J = 5.5 Hz, 1H, OH); 7.13 (d, J = 8 Hz, 2H); 7.22 (d, J = 8 Hz, 2H).

53.4 4- (4-Pyrrolidin-1-ylbutyl) benzaldehyde

A solution of 590 mg (2.5 mmol) of [4- (4-pyrrolidin-1-yl butyl) phenyl] methanol in 15 ml of dioxane is added with 1.1 g (12.6 mmol) of manganese dioxide. The mixture is stirred at 80 ^° C. for 4 hours. After cooling, it is filtered on celite by rinsing with dichloromethane. The filtrate is evaporated under reduced pressure. 545 mg of product are obtained. ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.38-1.52 (m, 2H); 1.52-1.70 (m, 6H); 2.30-2.40 (m, 6H); 2.67-2.72 (m, 2H); 7.44 (d, J = 8 Hz, 2H); 7.83 (d, J = 8 Hz, 2H); 9.97 (s, 1H, CHO).

53.5 7-Methoxy-4- (methoxymethyl) -N- {1- [4- (4-pyrrolidin-1-ylbutyl) benzyl] piperidin-4-yl} phthalazin-1-amine trioxalate (Compound 53)

This compound is obtained according to the procedure described in 26.2. by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with 4- (4-pyrrolidin-1-ylbutyl) benzaldehyde.

¹ H NMR (DMSO-d6 400 MHz) δ ppm: 1.40-1.48 (m, 2H); 1.55-1.70 (m, 8H); 2.0-2.12 (m, 4H); 2.32-2.40 (m, 4H); 2.52-2.60 (m, 2H); 2.85-2.92 (m, 2H); 3.28 (s, 3H); 3.47 (s, 3H); 3.96 (s, 3H); 4.15-4.27 (m, 1H); 4.76 (s, 2H); 6.98 (d, J = 7.2 Hz, 1H); 7.13 (d, J = 8 Hz, 2H); 7.22 (d, J = 8 Hz, 2H); 7.46 (dd, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz, 1H); 7.70 (d, J = 2.4 Hz, 1H); 8.0 (d, J = 8.8 Hz, 1H).

Trioxalate is obtained by treatment of the product dissolved in acetone with 3 equivalents of oxalic acid. A precipitate is formed which is filtered. The powder obtained is dried at 40 ^° C. under reduced pressure in the presence of diphosphorus pentoxide. Example 54

54.1 3- [2- (Tetrahydro-2H-pyran-2-yloxy) ethoxy] benzaldehyde

This compound is obtained according to the procedure described in 30.1. by reaction of 3-hydroxybenzaldehyde with 2- (2-bromoethoxy) tetrahydro-2H-pyran. ¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.40-1.80 (m, 6H); 3.40-3.50 (m, 1H); 3.68-3.40 (m, 3H); 4.20-4.25 (m, 2H); 4.65-4.70 (m, 1H); 7.30-7.35 (m, 1H), 7.45-7.48 (m, 1H), 7.50-7.55 (m, 2H); 9.99 (s, 1H, CHO).

54.2 2- {3 - [(4 - {[7-Methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} ethanol dihydrochloride (Compound 54)

This compound in the base form is obtained according to the procedure described in 30.2 by reaction of 7-methoxy-4- (4-methoxyphenyl) -β- (piperidin-4-yl) phthalazin-1-amine (preparation in 3.2 with 3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] benzaldehyde. The dihydrochloride salt is obtained by the treatment described in 4.3.

Example 55

2- {3 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} ethanol dihydrochloride (compound 55)

This compound in the base form is obtained according to the procedure described in 30.2 by reaction of 7-methoxy-4-methoxymethyl-A / - (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] benzaldehyde (Preparation 54.1.).

The dihydrochloride salt is obtained by the treatment described in 4.3.

Example 56

3- {3 - [(4 - {[7-Methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol dihydrochloride (Compound 56 )

This compound in the base form is obtained according to the procedure described in 30.2 by reaction of 7-methoxy-4- (4-methoxyphenyl) -β- (piperidin-4-yl) phthalazin-1-amine (preparation in 3.2 .) with 3- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] benzaldehyde (preparation in 45.1.). The dihydrochloride is obtained by the treatment described in 6.5.

Example 57:

3- {4 - [(4 - {[7-Methoxy-4- (trifluoromethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol dihydrochloride (57)

57.1. 5-Methoxy-2-trifluoroacetylbenzoic acid

A solution of 5 g (21.64 mmol) of 2-bromo-5-methoxybenzoic acid in 100 mL of THF is stirred under nitrogen at -78 ^° C. and 27 ml (43.28 mmol) of a 1.6 M solution of n-butyllithium in hexane are then added dropwise. The mixture is stirred at -78 ° C. for 1 hour and then 2.58 ml (21.64 mmol) of ethyl trifluoroacetate are added dropwise. The reaction medium is stirred at -78 ° C. for 1 hour and then at room temperature for 18 hours. The mixture is added with water and extracted with tert-butyl methyl ether. The aqueous phase is acidified with a 2N hydrochloric acid solution and extracted with dichloromethane. The dichloromethane phase is washed with salt water, dried over anhydrous sodium sulphate, filtered and evaporated. The crude product as a yellow oil is used in the next reaction without purification.

57.2. 7-Methoxy-4-trifluoromethyl-2H-phthalazin-1-one

This compound is obtained according to the procedure described in 2.5. by reaction of 5-methoxy-2-trifluoroacetylbenzoic acid with hydrazine hydrate. The product is purified on a silica column (eluent: 100/0 to 95/5 (v / v) dichloromethane / methanol).

Mp = 205 ⁰ C (M)

LC / MS: MH ⁺ = 245 (tR = 7.57 minutes pH 3.1)

¹ H NMR (DMSO-d ₆ , 300 MHz) δ ppm: 3.98 (s, 3H); 7.62 (dd, J ₁ = 9 Hz, J ₂ = 2.7 Hz, 1H);

7.74 (d, J = 2.7 Hz, 1H); 7.90 (d, J = 9 Hz, 1H); 13.25 (s, 1H, NH)

57.3. 1-Chloro-7-methoxy-4-trifluoromethyl-phthalazine

This compound is obtained according to the procedure described in 2.6. by reaction of 7-methoxy-4-trifluoromethyl-2H-phthalazin-1-one with phosphoryl chloride. The product is purified on a silica column (eluent: 100/0 to 95/5 (v / v) dichloromethane / methanol). LC / MS: MH ⁺ = 263 (tR = 8.53 minutes)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 4.10 (s, 3H); 7.72 (d, J = 2.5 Hz, 1H); 7.92 (dd, J ₁ = 9.2 Hz, J ₂ = 2.5 Hz, 1H); 8.27 (d, J = 9.2 Hz, 1H). 57.4. N- (1-Benzylpiperidin-4-yl) -7-methoxy-4-trifluoromethyl-phthalazin-1-amine

This compound is obtained according to the procedure described in 3.1. by reaction of 1-chloro-7-methoxy-4-trifluoromethyl phthalazine with 4-amino-1-benzylpiperidine. LC / MS: MH ⁺ = 417 (tR = 6.13 minutes pH 3.1)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.62-1.80 (m, 2H); 1.98-2.18 (m, 4H); 2.87-2.98 (m, 2H); 3.53 (s, 2H); 3.99 (s, 3H); 4.27-4.40 (m, 1H); 7.24-7.36 (m, 5H); 7.58-7.67 (m, 2H); 7.86-7.95 (m, 2H).

57.5. 7-Methoxy-N- (piperidin-4-yl) -4-trifluoromethyl-phthalazin-1-amine

This compound is obtained by debenzylation of β- (1-benzylpiperidin-4-yl) -7-methoxy-4-trifluoromethyl-phthalazin-1-amine according to the procedure described in 3.2. Mp = 203 ^° C. (M. ) 15 LC / MS: MH ⁺ = 327 (t R = 4.43 min, pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.48-1.63 (m, 2H); 1.93-2.06 (m, 3H); 2.56-2.68 (m, 2H); 3.02-3.10 (m, 2H); 4.0 (s, 3H); 4.30-4.45 (m, 1H); 7.58-7.70 (m, 2H); 7.88-7.94 (m, 2H).

0 57.6. 3- {4 - [(4 - {[7-Methoxy-4- (trifluoromethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol dihydrochloride (57)

This compound in the base form is obtained according to the procedure described in 30.2 by reaction of 7-methoxy-β- (piperidin-4-yl) -4-trifluoromethyl-phthalazin-1-amine with 4- [3 - (tetrahydro-2H- (2-pyran-2-yloxy) propoxy] benzaldehyde (synthesis see 30.1.). The dihydrochloride salt is obtained by the treatment described in 4.3. Example 58:

7-Methoxy-4- (methoxymethyl) -N- {1- [4- (octahydro-2H-pyrido [1,2-a] pyrazin-2-yl) benzyl] piperidin-4-yl} phthalazin trihydrochloride 1-amino (compound 58)

58.1 4- (Octahydro-2H-pyrido [1,2-a] pyrazin-2-yl) benzaIdehyde

This compound is obtained according to the procedure described in 31.1. by reaction of 4-bromobenzaldehyde with commercial (+/-) -1,4-diazabicyclo [4,4,0] decane. This aldehyde difficult to purify is used in impure form in the next reaction.

58.2. 7-Methoxy-4- (methoxymethyl) -N- {1- [4- (octahydro-2H-pyrido [1,2-a] pyrazin-2-yl) benzyl] piperidin-4-yl} phthalazin trihydrochloride; 1-amine (compound

58)

This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4- (octahydro-2H-pyrido [1,2-a] pyrazin-2-yl) benzaldehyde. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 1.13-1.32 (m, 2H); 1.42-1.75 (m, 6H); 1.90-2.09 (m, 6H); 2.18-2.24 (m, 1H); 2.29-2.35 (m, 1H); 2.66-2.82 (m, 3H); 2.85-2.90 (m, 2H); 3.28 (s, 3H); 3.39 (s, 2H); 3.47-3.59 (m, 2H); 3.95 (s, 3H); 4.13-4.23 (m, 1H); 4.76 (s, 2H); 6.89 (d, J = 8.8 Hz, 2H); 6.98 (d, J = 7.6 Hz ₁ H, NH); 7.15 (d, J = 8.8 Hz, 2H); 7.46 (dd, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz, 1H); 7.70 (d, J = 2.4 Hz, 1H); 8.0 (d, J = 8.8 Hz, 1H). The trihydrochloride is obtained by the treatment described in 6.5 .. Example 59:

4-Ethyl-N- [1- (4-ethynylbenzyl) piperidin-4-yl] -5,7-dimethoxyphthalazin-1-amine dihydrochloride (Compound 59)

59.1. N- (1-Benzylpiperidin-4-yl) -5,7-dimethoxy-4-ethyl-phthalazin-1-amine

This compound is obtained according to the procedure described in 3.1. by reaction of 1-chloro-5,7-dimethoxy-4-ethyl-phthalazine (described in WO05 / 103033) with 4-amino-1-benzyl-piperidine. LC / MS: MH ⁺ = 407 (tR = 4.34 minutes pH 3.1)

59.2. 5,7-Dimethoxy-4-ethyl-N- (piperidin-4-yl) phthalazin-1-amine

This compound is obtained by debenzylation of Λ- (1-Benzylpiperidin-4-yl) -5,7-dimethoxy-4-ethyl-phthalazin-1-amine according to the procedure described in 3.2. Mp = 211 ⁰ C (M)

LC / MS: MH ⁺ = 317 (tR = 4.30 min, pH 3.1) ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.19 (t, J = 7.5 Hz ₁ 3H); 1.40-1.58 (m, 2H); 1.92- 2.04 (m, 2H); 2.53-2.68 (m, 2H); 2.98-3.10 (m, 2H); 3.14 (q, J = 7.5 Hz, 2H); 3.3 (m, 1H ₁ NH); 3.95 (s, 6H); 4.12-4.30 (m, 1H); 6.61 (d, J = 7.5 Hz ₁ 1H, NH); 6.92 (s, 1H); 7.22 (s, 1H).

59.3. 4-ethyl-N- [1- (4-ethynylbenzyl) piperidin-4-yl] -5,7-dimethoxyphthalazin-1-amine dihydrochloride (Compound 59)

This compound in the base form is obtained according to the procedure described in 4.3. by reaction of 5,7-dimethoxy-4-ethyl-β- (piperidin-4-yl) -phthalazin-1-amine with 4- (trimethylsilyl) -ethynylbenzaldehyde followed by deprotection of the trimethylsilyl group by method described in 28.2. ¹ H NMR (DMSOd ₆ , 400 MHz) δ ppm: 1.18 (t, J = 7.6 Hz, 3H); 1.58-1.70 (m, 2H); 1.98- 2.08 (m, 2H); 2.08-2.25 (m, 2H); 2.83-2.90 (m, 2H); 3.15 (q, J = 7.6 Hz, 2H); 3.52 (s, 2H); 3.97 (s, 6H); 4.14 (s, 1H); 4.10-4.20 (m, 1H); 6.59 (d, J = 7.2 Hz, 1H); 6.91 (d, J = 1.8 Hz, 1H); 7.19 (d, J = 1.8 Hz, 1H); 7.35 (d, J = 8 Hz, 2H); 7.45 (d, J = 8 Hz, 2H). The dihydrochloride is obtained by the treatment described in 6.5.

Example 60:

3- {2-Methoxy-4 - [(4 - {[7-methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-dihydrochloride ol (60)

60.1. 4- [3- (Tetrahydro-2H-pyran-2-yloxy) propoxy]) - 3-methoxybenzaldehyde

This compound is obtained according to the procedure described in 30.1. by reaction of 4-hydroxy-3-methoxybenzaldehyde with 2- (3-bromopropoxy) tetrahydro-2H-pyran. LC / MS: MNa ⁺ = 317 (tR = 8.20 minutes, pH 3.1)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.35-1.80 (m, 6H); 1.95-2.08 (m, 2H); 3.37-3.58 (m, 2H); 3.68-3.83 (m, 2H); 3.84 (s, 3H); 4.12-4.20 (m, 2H); 4.55-4.60 (m, 1H); 7.20 (d, J = 8.2 Hz, 1H); 7.41 (d, J = 1.8 Hz, 1H); 7.55 (dd, J ₁ = 8.2 Hz, J ₂ = 1.8 Hz, 1H); 9.88 (s, 1H, CHO). 60.2. 3- {2-Methoxy-4 - [(4 - {[7-methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1 dihydrochloride ol (60)

This compound in the base form is obtained according to the procedure described in 30.2 by reaction of 7-methoxy-4- (4-methoxyphenyl) -β- (piperidin-4-yl) phthalazin-1-amine (preparation in 3.2 with 4- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] -3-methoxybenzaldehyde The dihydrochloride is obtained by the treatment described in 6.5.

Example 61

3- {2-Methoxy-4 - [(4 - {[7-methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol dihydrochloride ( compound 61)

This compound in the base form is obtained according to the procedure described in 30.2 by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] -3-methoxybenzaldehyde (Preparation 60.1.). The dihydrochloride is obtained by the treatment described in 7.4.

Example 62

1- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenyl} piperidin-4-ol trihydrochloride (Compound 62)

not 62.1 4- (4-Hydroxypiperidin-1-yl) benzaldehyde

This compound is obtained according to the procedure described in 31.1. by reaction of 4-bromobenzaldehyde with 4-hydroxypiperidine.

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.32-1.50 (m, 2H); 1.75-1.88 (m, 2H); 3.08-3.20 (m, 2H); 3.69-3.84 (m, 3H); 4.75 (d, J = 4.2 Hz, 1H); 7.04 (d, J = 9 Hz, 2H); 7.69 (d, J = 9 Hz, 2H); 9.69 (s, 1H ₁ CHO).

62.2 1- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenyl} piperidin-4-ol hydrochloride (Compound 62 )

H

This compound in the base form is obtained according to the procedure described in 26.2. by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with 4- (4-hydroxypiperidin-1-yl) benzaldehyde. The trihydrochloride is obtained by the treatment described in 4.3.

Example 63:

3- [4 - ({4 - [(7-Methoxyphthalazin-1-yl) amino] piperidin-1-yl} methyl) phenoxy] propan-1-ol hydrochloride (Compound 63)

63.1. / V- (1-Benzylpiperidin-4-yl) -7-methoxy-phthalazin-1-amine

A mixture of 500 mg (2.6 mmol) of 1-chloro-7-methoxy-phthalazine (synthesis described in WO05 / 103033) and 0.63 ml (3.1 mmol) of 4-amino-1-benzylpiperidine in 2.5 ml of dimethoxyethane is stirred at room temperature under an argon atmosphere and is added 346 mg (3.6 mmol) of sodium fumarate, 23 mg of tris (dibenzylideneacetone) dipalladium (0), 16 mg of 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (racemic) and 67 mg of lithium bromide. The mixture is stirred at 100 ^° C. for 18 hours and then, after cooling, is added 10 ml of 1N sodium hydroxide. The mixture is extracted with ethyl acetate. The organic phase is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is purified on a silica column (eluent: dichloromethane / methanol from 100/0 to 90/10 (v / v)). 620 mg of orange solid are obtained. ¹ H NMR (DMSOd ₆ , 400 MHz) δ ppm: 1.60-1.72 (m, 2H); 2.0-2.16 (m, 4H); 2.87-2.92 (m, 2H); 3.51 (s, 2H); 3.95 (s, 3H); 4.15-4.25 (m, 1H); 6.91 (d, J = 7.6 Hz, 1H, NH); 7.23-7.30 (m, 1H); 7.30-7.35 (m, 4H); 7.44 (dd, J ₁ = 8.8 Hz, J ₂ ≈ 2.4 Hz, 1H); 7.70 (d, J = 2.4 Hz, 1H); 7.83 (d, J = 8.8 Hz, 1H); 8.28 (s, 1H).

63.2. 7-Ethoxy-N- (p -peridin-4-yl) -4-trifluoromethyl-phthalamino-1-amine

This compound is obtained by debenzylation of Λ- (1-benzylpiperidin-4-yl) -7-methoxy-phthalazin-1-amine according to the procedure described in 3.2.

Mp = 252 ⁰ C (M)

LC / MS: MH ⁺ = 327 (tR = 4.43 minutes, pH 3.1)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.20-1.30 (m, 1H); 1.40-1.60 (m, 2H); 1.95-2.10 (m, 2H); 2.55-2.68 (m, 2H); 2.98-3.10 (m, 2H); 3.96 (s, 3H); 4.20-4.35 (m, 1H); 6.92 (d, J =

7.5 Hz, 1H, NH); 7.44 (dd, J ₁ = 8.8 Hz, J ₂ = 2.2 Hz, 1H); 7.73 (d, J = 2.2 Hz, 1H); 7.84 (d,

J ≈ 8.8 Hz, 1H); 8.76 (s, 1H).

63.3. 3- [4 - ({4 - [(7-methoxyphthalazin-1-yl) amino] piperidin-1-yl} methyl) phenoxy] propan-1-ol dihydrochloride (Compound 63)

This compound in the base form is obtained according to the procedure described in 30.2 by reaction of 7-methoxy-β- (piperidin-4-yl) -phthalazin-1-amine with 4- [3- (tetrahydro-2H) pyran-2-yloxy) propoxy] benzaldehyde (synthesis see 30.1.). The dihydrochloride salt is obtained by the treatment described in 4.3. Example 64

7-Methoxy-4- (methoxymethyl) -N- {1- [4- (6-methyloctahydro-1H-pyrrolo [3,4-b] pyridin-1-yl) benzyl] piperidin-4-yl hydrochloride } Phthalazin-1-Amine (Compound No. 64)

64.1. 4- (6-Méthyloctahydro-1H-pyrrolo [3,4-b] pyridin-1-yl) benzaldéhydeO

This compound is obtained according to the procedure described in 31.1. by reaction of 4-bromobenzaldehyde with commercial 6-methyl-octahydro-pyrrolo [3,4-b] pyridine. LC / MS: MH ⁺ = 245 (tR = 4.43 minutes, pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.50-1.92 (m, 4H); 2.29 (s, 3H); 2.30-2.55 (m, 3H); 2.70-2.85 (m, 2H); 2.90-3.02 (m, 1H); 3.60-3.70 (m, 1H); 4.45-4.57 (m, 1H); 6.98 (d, J = 8.8 Hz, 2H); 7.69 (d, J = 8.8 Hz, 2H); 9.69 (s, 1H, CHO).

64.2. 7-Methoxy-4- (methoxymethyl) -N- [1- [4- (6-methyloctahydro-1H-pyrrolo [3,4-b]] pyridin-1-yl) benzyl] piperidin-4-dihydrochloride; Phthalazin-1-amine (Compound No. 64)

This compound is obtained according to the procedure described in 26.2. by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with 4- (6-methyloctahydro-1 / - / - pyrrolo [ 3,4-ό] pyridin-1-yl) benzaldehyde.

LC / MS: MH ⁺ = 531 (tR = 4.60 minutes, pH 3.1)

¹ H NMR (DMSOd ₆ , 400 MHz) δ ppm: 1.48-1.85 (m, 6H); 1.98-2.10 (m, 2H); 2.24 (s, 3H);

2.22-2.30 (m, 1H); 2.41-2.48 (m, 2H); 2.60-2.68 (m, 2H); 2.80-2.92 (m, 3H); 3.28 (s, 3H); 3.38 (s, 2H); 3.84 (s, 3H); 3.96 (s, 3H); 4.13-4.26 (m, 1H); 4.28-4.36 (m, 1H); 4.33 (s,

2H); 6.83 (d, J = 8.8 Hz, 2H); 6.98 (d, J = 7.2 Hz ₁ ₁ H NH); ); 7.12 (d, J = 8.8 Hz, 2H);

7.46 (dd, J ₁ = 9.2 Hz; J ₂ = 2.4 Hz, 1H); 7.70 (d, J = 2.4 Hz, 1H); 8.0 (d, J = 9.2 Hz, 1H). The trihydrochloride is obtained by the treatment described in 4.3.

Example 65

7-Methoxy-4- (4-methoxyphenyl) -N- [1- [4- (7-methyl-2,7-dia2aspiro [4.4] non-yl) benzyl] piperidin-4-yl} phthalazinic acid; 1-Amine (Compound No. 65)

65.1. 7- (4-Formylphenyl) -2,7-diazaspiro [4.4] nonane-2-carboxylic acid tert-butyl ester

This compound is obtained according to the procedure described in 31.1. by reaction of 4-bromobenzaldehyde with commercial Fe / f-butyl 2,7-diazaspiro [4.4] nonane-2-carboxylate. LC / MS: MH ⁺ = 331 (tR = 9.18 minutes, pH 3.1)

65.2. [4- (7-Methyl-2,7-diazaspiro [4.4] non-2-yl) phenyl] methanol

XXX

A suspension of 512 mg (13.5 mmol) of lithium aluminum hydride in 5 ml of THF is added with a solution of 445 mg (1.35 mmol) 7- (4-formylphenyl) -2,7-diazaspiro [4.4] nonan-2-carboxylic acid ester in 5 ml of THF. The mixture is stirred at 60 ^° C. for 4 hours and overnight at ambient temperature, then is added slowly and successively with 0.5 ml of water, 0.5 ml of 6N sodium hydroxide and 1.5 ml of water. A precipitate forms which is filtered on celite and rinsed with ethyl acetate. The filtrate is evaporated under reduced pressure. 347 mg of oily product are obtained. LC / MS: MH ⁺ = 247 (tR = 4.08 minutes, pH 3.1)

65.3. 4- (7-Methyl-2,7-diazaspiro [4.4] non-2-yl) benzaldehyde

This compound is obtained by oxidation with manganese dioxide of [4- (7-methyl-2,7-diazaspiro [4.4] non-2-yl) phenyl] methanol according to the procedure described in 53.4. . LC / MS: MH ⁺ = 245 (tR = 4.38 minutes, pH 3.1) 65.4. 7-Isethoxy-4- (4-methoxyphenyl) -N- {1- [4- (7-methyl-2,7-diazaspiro [4.4] non-yl) benzyl] piperidin-4-yl} phthalazoline; 1-Amine (Compound No. 65)

This compound is obtained according to the procedure described in 26.2. by reaction of 7-methoxy-4- (4-methoxyphenyl) -β- (piperidin-4-yl) phthalazin-1-amine (preparation in 3.2.) with 4- (7-methyl-2,7- diazaspiro [4.4] non-2-yl) benzaldehyde. LC / MS: MH ⁺ = 593 (tR = 4.79 minutes, pH 3.1)

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 1.58-1.70 (m, 2H); 1.72-1.80 (m, 2H); 1.85-2.10 (m, 6H); 2.25 (s, 3H); 2.38-2.42 (m, 1H); 2.45-2.60 (m, 3H); 2.85-2.92 (m, 2H); 3.10-3.13 (m, 1H); 3.20-3.38 (m, 3H); 3.40 (s, 2H); 3.84 (s, 3H); 3.96 (s, 3H); 4.20-4.30 (m, 1H); 6.46 (d, J = 8.8 Hz, 2H); 6.98 (d, J = 7.6 Hz, 1H, NH); 7.05-7.13 (m, 4H); 7.42 (dd, Ji = 8.8 Hz, J ₂ = 2.4 Hz, 1H); 7.51 (d, J = 8.8 Hz, 2H); 7.70-7.77 (m, 2H).

Example 66: 4- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenyl} butan-1-ol hydrochloride (compound n ° 66)

66.1. Ethyl 4- [4- (tetrahydro-2H-pyran-2-yloxy) butyl] benzoate

A solution of 1.15 g (56 mmol) of ethyl 4- (4-hydroxybutyl) benzoate (synthesized according to the method described in J. Med Chem, 1983 26 (3) pp. 335-341) and 2.36 ml. mmol) of 3,4-dihydropyran in 20 ml of dichloromethane is stirred at 0 ^° C. and treated with 10 mg of p-toluenesulphonic acid monohydrate. The mixture is stirred at ambient temperature for 4 hours, then dichloromethane and a saturated aqueous solution of sodium hydrogencarbonate are added. The organic phase is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is purified on a silica column (eluent: heptane / dichloromethane from 100/0 to 0/100 (v / v)). 1.5 g of oily yellow product.

¹ H NMR (DMSO-Cl _6, 250 MHz) δ ppm: 1.32 (t, J = 7Hz, 3H); 1.40-1.85 (m, 10H); 2.63-2.73 (m, 2H); 3.30-3.48 (m, 2H); 3.60-3.78 (m, 2H); 4.30 (q, J = 7 Hz, 2H); 4.50- 4.55 (m, 1H); 7.36 (d, J = 8Hz ₁ 2H); 7.89 (d, J = 8Hz, 2H).

66.2. {4- [4- (Tetrahydro-2H-pyran-2-yloxy) butyl] phenyl} methanol

This compound is obtained according to the procedure described in 53.3. by reduction of ethyl 4- [4- (tetrahydro-2H-pyran-2-yloxy) butyl] benzoate. ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.40-1.80 (m, 10H); 2.55-2.62 (m, 2H);

3.30-3.48 (m, 2H); 3.58-3.78 (m, 2H); 4.45 (d, J = 5.5 Hz, 2H); 4.50-4.55 (m, 1H); 5.10 (t, J = 5.5 Hz, 1H, OH); 7.14 (d, J = 8 Hz, 2H); 7.22 (d, J = 8 Hz, 2H).

66.3. 4- [4- (tetrahydro-2A / -pyran-2-yloxy) butyl] benzaldehyde

This compound is obtained according to the procedure described in 53.4. by oxidation of {4- [4- (tetrahydro-2H-pyran-2-yloxy) butyl] phenyl} methanol.

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.40-1.80 (m, 10H); 2.65-2.78 (m, 2H); 3.35-3.48 (m, 2H); 3.60-3.78 (m, 2H); 4.51-4.56 (m, 1H); 7.45 (d, J = 8 Hz, 2H); 7.85 (d, J = 8 Hz, 2H); 10.0 (s, 1H ₁ CHO).

66.4. 4- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] aminopiperidin-1-yl) methyl] phenyl} butan-1-ol dihydrochloride (Compound No. 66 )

This compound in the base form is obtained according to the procedure described in

30.2. by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with 4- [4- (tetrahydro-2H-pyran-2-yloxy) ) butyl] benzaldehyde. The dihydrochloride salt is obtained by the treatment described in 4.3. Example 67

7-Methoxy-4- (methoxymethyl) -N- [1 - ({1- [4- (trifluoromethyl) phenyl] -1H-pyrrol-3-yl} methyl) piperidin-4-yl] phthalazin-1-dihydrochloride Amine (Compound 67)

26.2. by reaction of 7-methoxy-4-methoxymethyl-β- (piperidin-4-yl) -phthalazin-1-amine

(Preparation in 22.2) with 1- [4- (trifluoromethyl) phenyl] -1H-pyrrole-3-carbaldehyde synthesized according to the method described in Synthetic Communications 1994, 24 (13) 1855-0187.

The dihydrochloride salt is obtained by the treatment described in 4.3.

Example 68

W- (1- {4- [2- (1H-imidazol-1-yl) ethoxy] benzyl} piperidin-4-yl) -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-trichlorhydrate amine (compound no. 68)

68.1. 4- (2-chloroethoxy) benzaldehyde

A solution of 2.5 g (20.5 mmol) of 4-hydroxybenzaldehyde in 200 ml of butan-2-one is stirred at room temperature under nitrogen and added with 7.33 g (22.5 mmol) of cesium carbonate. The mixture is stirred for one hour at room temperature, then 11.7 g (61.4 mmol) of 2-chloro-1-iodoethane and 2.5 mg of potassium iodide are added. The mixture is stirred at 80 ^° C. for 8 hours and then at ambient temperature overnight. The reaction medium is added with water and ethyl acetate. The organic phase is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure.

The residue obtained is purified on a silica column (eluent: dichloromethane / methanol from

100/0 to 80/20 (v / v)). 1.3 g of gummy product is obtained.

LC / MS: MH ⁺ = 185 (tR = 7.78 minutes, pH 3.1) ¹ H NMR (DMSO-d ₆₁₂₅₀ MHz) δ ppm: 3.98-4.03 (m, 2H); 4.38-4.43 (m, 2H); 7.18

(d, J = 8 Hz, 2H); ); 7.89 (d, J = 8 Hz, 2H); 9.90 (s, 1H, CHO). 68.2. 4- [2- (1H-lmîdazol-1yl) ethoxy] benzaldehyde

A solution of 1.2 g (6.5 mmol) of 4- (2-chloroethoxy) benzaldehyde in 10 ml of DMF is stirred at 0 ^° C. under nitrogen and 374 mg of an oily suspension of sodium hydride 60% ( 9.35 mmol). The mixture is stirred at 0 ° C. for 1 hour and then a solution of 0.487 g (7.15 mmol) of imidazole in 10 ml of DMF is added. The mixture is stirred for 18 hours at room temperature and is then heated at 60 ^° C. for 4 hours 30 minutes. After returning to ambient temperature, and adding 50 ml of water, the mixture is extracted with ethyl acetate. The organic phase is washed with water and then with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is purified on a silica column (eluent: 100/0 to 95/5 (v / v) dichloromethane / methanol).

LC / MS: MH ⁺ = 217 (tR = 3.48 minutes, pH 3.1)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 4.33-4.43 (m, 4H); 6.90 (d, J = 1 Hz, 1H); 7.14 (d, J = 8.8 Hz, 2H); 7.27 (dd, J ₁ = J ₂ = 1 Hz, 1H); 7.70 (d, J = 1 Hz, 1H); 7.88 (d, J = 8.8 Hz, 2H); 9.88 (s, 1H, CHO).

68.3. (N- (1- {4- [2- (1H-imidazol-1-yl) ethoxy] benzyl} piperidin-4-yl) -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-dihydrochloride am [ne (Compound No. 68)

8.2. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine (Preparation 3.2) with 4- [2- (1W-imidazol-1) yl) ethoxy] benzaldehyde. The trihydrochloride is obtained by the treatment described in 4.3. Example 69: 7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (pyridin-4-ylmethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine trihydrochloride (Compound No. 69)

69.1. 4- (Pyridin-4-ylmethoxy) benzaldehyde

A mixture of 5 g (40.9 mmol) of 4-hydroxybenzaldehyde, 16.1 g (61.4 mmol) of triphenylphosphine and 0.943 g (8.19 mmol) of pyridin-4-yl-methanol in 170 mL of THF is stirred at 0 ^° C. and slowly added with 12.09 mL (61.4 mmol) of diisopropylazodicarboxylate. The reaction medium is stirred for 15 minutes at 0 ^° C. and then overnight at room temperature. The mixture is supplemented with 2N sodium hydroxide and extracted with tert-butyl methyl ether. The organic phase is extracted with a solution of 1N HCl. The acidic aqueous phase obtained is basified with 6N sodium hydroxide and then extracted with tert-butyl methyl ether. The organic phase is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is chromatographed on a silica column (eluent: dichloromethane / methanol 100/0 to 85/15 (v / v)). The oily brown product still impure is used as it is.

LC / MS: MH ⁺ = 214 (t R = 4.36 min, pH 3.1)

69.2. 7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (pyridin-4-ylmethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine trihydrochloride (Compound No. 69)

This compound in the base form is obtained according to the procedure described in 26.2. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine (Preparation 3.2) with 4- (pyridin-4-ylmethoxy) benzaldehyde. ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.60-1.78 (m, 2H); 2.0-2.18 (m, 4H); 2,88- 2.96 (m, 2H); 3.46 (s, 2H); 3.85 (s, 3H); 3.97 (s, 3H); 4.20 - 4.30 (m, 1H); 5.18 (s, 2H); 6.95-7.04 (m, 3H); 7.09 (d, J = 8.8 Hz, 2H); 7.26 (d, J = 8.8 Hz, 2H); 7.40-7.50 (m, 3H); 7.52 (d, J = 8.8 Hz, 2H); 7.72-7.79 (m, 2H); 8.59 (d, J = 6Hz, 2H). The trihydrochloride is obtained by the treatment described in 4.3.

Example 70

7-Methoxy-4- (4-methoxyphenyl) -N- [1- [4- (tetrahydrofuran-2-ylmethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine dihydrochloride (Compound No. 70)

70.1. 4- (tetrahydrofuran-2-ylmethoxy) benzaldehyde

This compound is obtained by the Mitsunobu reaction according to the procedure described in 17.1. by reaction of 4-hydroxybenzaldehyde with (R, S) - (tetrahydrofuran-2-yl) methanol. LC / MS: MH ⁺ = 207 (tR = 6.97 minutes, pH 3.1)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.64-1.72 (m, 1H); 1.80-1.93 (m, 2H); 1.98- 2.08 (m, 1H); 3.17-3.22 (m, 1H); 3.25-3.30 (m, 1H); 4.01-4.12 (m, 2H); 4.15-4.20 (m, 1H); 7.13 (d, J = 8.8 Hz, 2H); 7.85 (d, J = 8.8 Hz, 2H); 9.87 (s, 1H, CHO).

70.2. Ethyl 7-methoxy-4- (4-methoxyphenyl) -Λl ^f - {1- [4 ~

(Tetrahydrofuran-2-ylmethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine (Compound No. 70)

This compound in the base form is obtained according to the procedure described in 26.2. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine (Preparation 3.2) with 4- (tetrahydrofuran-2-yimethoxy) benzaldehyde. The dihydrochloride salt is obtained by the treatment described in 4.3. Table 1

The compounds according to the invention have been the subject of pharmacological tests. Their affinity towards the Melanin-Concentrating Hormone (MCH) receptor 1, MCH ₁ , was thus determined.

Attempts were to measure the in vitro activity of the compounds of the invention on MCH ₁ MCH receptors.

Liaison studies:

The affinity of the compounds of the invention for the MCH receptors was measured by studying the displacement of the binding of a radio-labeled MCH derivative to the MCH ₁ receptors. This study is carried out on membrane preparations of rat and / or mouse brain according to the protocol described below.

In preparation for binding studies, the brains were diluted in 25 mM HEPES buffer (pH 7.4) containing MgCl ₂ 5 mM of CaCl ₂ 1 mM, homogenized using a Polytron 3 times 20 seconds (speed 25), then undergo ultracentrifugation for 22 minutes at 22,000 RPM at +4 ^° C. The pellet is taken up with the same buffer and the membranes are aliquoted and stored frozen at -80 ^° C. until they are used. The membranes are brought back to ambient temperature and are then incubated in the presence of the test compounds, and 50 μM of a radiolabelled molecule derived from MCH, [ ¹²⁵ I] -Tyr-S36057 (8-amino-3,6-dioxyoctanoyl). 6-17 MCH marketed by Perkin-Elmer) in 25 mM HEPES buffer (pH 7.4) containing MgCl ₂ 5 mM of CaCl ₂ 1 mM, bacitracin 140 mg / L of the 1 mM phenanthroline, and 0.2% serum bovine albumin. The incubation is carried out at room temperature for 30 minutes, then stopped by rapid addition of ice-cold 25 mM HEPES buffer (pH 7.4), supplemented with 0.2% serum bovine albumin, and filtration on GF / fiberglass filters. B preincubated for 2 hours in an aqueous solution of polyethyleneimine 0.1%. The radioactivity retained on the filters is measured using a gamma scintillation counter. Nonspecific binding is determined in the presence of 1 μM of non-radiolabelled S36057. Specific binding is obtained by difference between total binding and non-specific binding. The inhibitory activity of the compounds of the invention is expressed by the concentration which inhibits 50% of the specific binding (Cl ₅₀ ).

In the context of the invention, the Cl ₅₀ compounds are generally less than 10 .mu.M. The compounds of formula (I) advantageously have Cl ₅₀ less than 1 μM, more advantageously less than or equal to 10 μM and even more advantageously less than or equal to 10 μM. For exemple :

the compound according to Example 1 has a Cl ₅₀ of 0.5 nM in the rat and 0.2 nM in the mouse;

the compound according to Example 3 has a Cl ₅₀ of 52 nM in the rat and 38 nM in the mouse.

Pharmacological model of food intake:

The activity of an MCH receptor 1 antagonist can be pharmacologically controlled using a rat test (young rats weighing 80-150 g).

This test consists in inducing a food intake behavior by an i.c.v injection.

(intra-cerebroventricular) MCH performed manually. The injection i.c.v. peptide solubilization buffer (without the MCH) in a first control group makes it possible to quantify the importance of the effect due to the MCH. A compound according to the invention is administered orally 1 or 2 hours before treatment i.c.v.

The effect of a compound according to the invention is measured by the reduction it can cause on food intake, previously induced by i.c.v injection. from MCH.

The specificity of action of the product can be evaluated using another orexigenic peptide such as NPY, also injected by i.c.v. Thus, a specific product of the MCH 1 receptor will have no effect on the intake of food induced by another orexigenic peptide such as NPY.

The compounds of the invention can be used for the preparation of drugs, particularly drugs antagonists of MCH receptor ₁ of the MCH.

Claims

1. Compound corresponding to the following general formula (I)

in which :

• A represents a C _1-4 -alkylene group optionally substituted by one or more groups R ₉ identical or different from each other;

R ₉ and R ₁₀ each represent, independently of one another, a hydrogen atom or a C _1-5 -alkyl group,

. or R ₉ and R ₁₀ together form a single bond or a C _1-4 alkylene group; L represents a single bond or a C _1-2 -alkylene group, -CH = CH- or -C≡C-; the C _1-2 -alkylene groups and -CH = CH- being optionally substituted by one or more C _1-2 -alkyl substituents,

. or L represents a cycloprop-1, 2-diyl group;

R represents a hydrogen atom or a C _1-5 -alkyl, C _1-3 -fluoroalkyl, C _3-6 -cycloalkyl, -C (O) C _1-3 -alkyl, C _1-3 -alkylene group; -C _3-6 -cycloalkyl, -CH ₂ -C = CH, C _2-3 -alkylene-

NR _a R _b , C _1-3 -alkylene-XC _1-3 -alkyl wherein X is O or SO ₂ ;

R ₁ represents aryl or heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other; • R ₂ and R ₃ independently of one another, a hydrogen atom or a C _1-3 -alkyl or Ci. ₃ fluoroalkyl,

• R ₄ represents:. a hydrogen atom or a C _1-5 -alkyl group, C-). ₃ -fluoroalkyl, C _3-6 - cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, C _1-3 -alkylene-OC _1-3 -alkyl, C _1-3 -alkylene-OC _4- ₆ -cycloalkyl,

. a C _1-3 -alkylene- (OH), C _1-3 -alkylene-XC _1-3 -alkyl group where X is S, SO or SO ₂ , a heterocycle group; said heterocycle group being optionally substituted by a C _1-3 -alkyl, -C (O) C _1-3 -alkyl, -C (O) C _1-3 -fluoroalkyl, C _1-3 -alkylene-C _{3- 6} - cycloalkyl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-heteroaryl; the C _1-3 -alkylene-aryl and C _1-3 -alkylene-heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other, or R ₄ represents a C _1-3 -alkylene-NR _a R _b , aryl, C _1-3 -alkylene-aryl group,

-O-aryl, C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-OC _1-3 -alkylene-aryl, heteroaryl or C _1-3 -alkylene-heteroaryl; aryl, C _1-3 -alkylene-aryl, -O-aryl, C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-OC _1-3 -alkylene-aryl, heteroaryl and C _{1- 3} -alkylene-heteroaryl being optionally substituted with one or more radicals Z which are identical to or different from each other;

R ₅ represents a hydrogen or halogen atom or a C _1-5 -alkyl, C _1-3 -fluoroalkyl, C _1-5 -alkoxy, C _1-3 -fluoroalkoxy, C _1-3 -alkylene group; - (OH), -CN, -XC _1-3 -alkyl where X represents S, SO or SO ₂ ,

. or R ₅ is -NR _a R _b , C _1-3 -alkylene-NR _a Rb, aryl, C _1-3 - alkylene-aryl, -O-aryl or heteroaryl; the aryl, C _1-3 -alkylene-aryl, -O-aryl and heteroaryl groups being optionally substituted with one or more Z radicals which are identical to or different from each other;

• R ₇ represents a hydrogen or halogen atom or a Ci _-5 alkyl group, C _1-3 - fluoroalkyl, C _1-5 alkoxy, -COOH, -C (O) OC _1-3 alkyl , C _1-3 -fluoroalkoxy, C _1-3 -alkylene- (OH), -CN, -XC 1 _-3 -alkyl wherein X is S, SO or SO ₂ ,

. or R ₇ represents a group -NR ₃ Rb, C _1-3 -alkylene-NR _a Rb, -C (O) -NR _a R _b , -C (O) -C _1-3 -alkyl, aryl, O-aryl or heteroaryl; the aryl, -O-aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other; • Z represents a halogen atom or a Ci _-5 alkyl group, C _1-3 fluoroalkyl, C _3-6 - cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, C _1-5 - alkoxy, C _1-3 -fluoroalkoxy, C _1-3 -alkylene-O-C _1-3 -alkyl, C _1-3 -alkylene- (OH), NO ₂ , -CN, -SO ₂ NRaRb, -XC _{1 -3-} alkyl, C _1-3 -alkylene-XC ^ ₃ -alkyl where X is S, SO or SO ₂ ,

. or Z represents a phenyl optionally substituted by a halogen atom, a C _1-5 -alkyl, C _1-5 -alkoxy or C _1-3 -fluoroalkyl group,

. or Z represents an alkynyl radical of the type -C≡CR _C , in which R ₀ represents a hydrogen atom, a C _1-3 -alkyl, C _1-6 -alkylene-OR _d or C _{1-6 group} ; alkylene-NR _a R _b ,

. or Z represents a -C _4-6 -alkylene-OR _{d group} ,

. or Z represents a tetrazole group substituted with a C _1-3 -alkyl group, or Z is -NR _a R _b , C _1-3 -alkylene-NR _a R _b -C (O) -NR _a R _b , -C (O) -C _1-3 -alkyl, -CO ₂ -C _1-4 -alkyl, -C (O) -C ₃ . ₆ -cycloalkyl,

. or Z represents a group -C _4-6 -alkylene-.NR _a R _b ,. or Z represents an oxo radical, or Z represents a group -OC _1-5 -alkylene-NR _a Rb,. or Z is -OC _0- 3-alkyfène-heterocycle, optionally substituted by one or more C _1-3 alkyl, oxo or -C (O) -C _1-3 -alkyl. or Z represents a group -OC _1-5 -alkylene-OR _d ,

. or Z represents a group -NR _e -C _0-3 -alkylene-heterocycle optionally substituted with one or more C _1-3 -alkyl, oxo or -C (O) -C _1-3 -alkyl groups. or Z represents a group -NR _e -C _2-5 -alkylene-OR _d ,. or Z is -OC _1-3 -alkylene-heteroaryl optionally substituted by one or more C _1-3 alkyl groups,

. or Z represents -CONH-C _1-5 -alkylene-NR _a R _b ,. or Z represents a group -CONH-C _1-5 -alkylene-OR _cl ,

. or Z represents a group -OC _1-3 -alkylene-C (O) -NR _a R _b ,. or Z represents a fused bicyclic or fused bicyclic heterocyclic ring, or two adjacent Z radicals together form a C _1-3 - alkylenedioxy group; R ₃ and R _b each independently of one another represent a hydrogen atom or a C _1-3 -alkyl or -C (O) -C _1-3 -alkyl group,

. or R ₃ and R _b together with the nitrogen atom to which they are attached form a heterocycle optionally substituted with one or more C _1-3 alkyl, oxo, -NR _a R _b , hydroxy, C _{1 groups; -3} -alkoxy, C _1-3 -alkylene- (OH) or -C (O) -C _1-3 -alkyl; • R _d represents a hydrogen atom or a C _1-3 -alkyl group; • R _e represents a hydrogen atom or a C _1-3 -alkyl group;

it being understood that when R represents a hydrogen atom, then at least one of the conditions defined below is fulfilled: R ₄ represents a heterocycle group, said heterocycle being optionally substituted by a C _1-3 alkyl group , -C (O) C _1-3 -alkyl, -C (O) C _1-3 -fluoroalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, C _1-3 -alkylene-aryl, C _{1 -3} -alkylene-heteroaryl; groups C _1-3 - alkylene-aryl and C _1-3 -alkylene-heteroaryl being optionally substituted with one or more radicals Z which are identical to or different from each other as defined above; or

Z represents a phenyl substituted with a halogen atom, a C ₁ -C ₅ alkyl, C _1-5 alkoxy or C _1-3 -fluoroalkyl group, or

Z represents an alkynyl radical of the type -C = CR ₀ in which R _c represents a hydrogen atom, a C _1-3 -alkyl, C _1-6 -alkylene-OR _d or C _1-6 -alkylene-group; NR ₃ R _b , or else

Z represents a -C _4-6 -alkylene-OR _{d group} , or -Z represents a C _1-3 -alkyl-substituted tetrazole group, or

- Z is -C _4- 6 alkylene-NR _a R _b, or

Z represents a group -SO ₂ -NR _a R _b , or

Z represents a group -OC _1-5 -alkylene-NR _a Rb, or

- Z is -OC _0-3 -alkylene-heterocycle optionally substituted with one or more groups CI_ ₃ -alkyl, oxo or -C (O) -C _1-3 -alkyl, or

Z represents a group -OC _1-5 -alkylene-O-Rd, or

- Z represents a group -0-Co _-3 -alkylene-C _5, ₇ -cycloalkyl optionally substituted by an -OR _group, or

Z represents a group -NR _e -C _0-3 -alkylene-heterocycle optionally substituted with one or more C _1-3 -alkyl, oxo or -C (O) -C _1-3 -alkyl groups, or

- Z represents an -NRe-C _2- 5-alkylene-O-Rd, or

Z represents a group -OC _1-3 -alkylene-heteroaryl optionally substituted by one or more C _1-3 -alkyl groups, or

Z represents a group -OC _1-3 -alkylene-C (O) -NR _a R _b , in the groups Z mentioned above, the groups R _a , Rb, R _d and R _e are as defined previously, to know :

. or R _a and R _b together with the nitrogen atom to which are they attached, a heterocycle optionally substituted by one or more groups CI_ ₃ -alkyl, oxo, -NR _a R _b, hydroxy, C _1-3 -alkoxy, C _1-3 -alkylene- (OH) or -C (O) -C _1-3 -alkyl;

• R _d represents a hydrogen atom or a C _1-3 -alkyl group; R _e represents a hydrogen atom or a C _1-3 -alkyl group;

- or Z represents a fused bicyclic or fused bicyclic heterocycle, or else Z represents a group -NR ₃ Rb in which R _a and R _b together with the nitrogen atom to which they are attached form a heterocycle substituted with one or more -NR ₃ R _b , hydroxy, C groups; _1-3 -alkoxy, C _1-3 -alkylene- (OH) or -C (O) -C _1-3 -alkyl; in the form of a base or an acid addition salt, as well as a hydrate or solvate state, as well as its enantiomers, diastereoisomers and mixtures thereof.

2. Compound of formula (I) according to claim 1, characterized in that:

A represents a C _1-4 -alkylene group, optionally substituted with one or more groups R ₉ identical to or different from each other;

B represents a C 1 -C 4 alkylene group, optionally substituted with one or more groups R _{10 which are} identical to or different from one another;

R ₉ and R ₁₀ each independently represent a hydrogen atom;

• L represents a single bond; R represents a hydrogen atom, a C _1-5 alkyl group or a -C (O) C _1-3 alkyl group;

R ₁ represents an aryl or R ₁ represents a heteroaryl group; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other; • R ₂ and R ₃ represent independently of each other a hydrogen atom;

R ₄ represents:

. a hydrogen atom or a C _1-5 -alkyl, C _1-3 -fluoroalkyl, C _1-3 -alkylene-OC _1-3 -alkyl group,

. a heterocycle group; said heterocycle group being optionally substituted by a C _1-3 -alkylene-aryl group,

. or R ₄ represents an aryl group; said aryl group being optionally substituted with one or more radicals Z which are identical to or different from each other;

R ₅ represents a hydrogen atom, C _1-5 alkoxy;

R ₇ represents a halogen atom or a C _1-5 alkoxy group; Z represents a halogen atom, a C _1-5 alkoxy or phenyl group optionally substituted with a C _1-3 -fluoroalkyl group,

. or Z represents an alkynyl radical of the type -C≡CR _C , in which R ₀ represents a hydrogen atom, C- | ₆ -alkylene-O-Rd or C _1-6 -alkylene-NR _a Rb,

. or Z represents a group -NR ₃ Rb,. or Z represents a -C _4-6 -alkylene-NR _a R _{b group} ,

. or Z represents a group -O-C _1-5 -alkylene-NR _a Rb,

. or Z is -OC _0- 3-alkylene-heterocycle, said -O- CO- ₃ -alkylene-heterocycle being optionally substituted with one or more C _1- ₃ alkyl or an oxo group,. or Z represents a group -O-C _1-5 -alkylene-OR _d ,

. or Z represents a group -NR _e -C ₂ -5-alkylene-OR _c i,. or Z is -OC _1-3 -alkylene-heteroaryl, or Z represents -CONH-C _1-5 -alkylene-NR _a R _b ,. or Z represents a group -OC _1-3 -alkylene-C (O) -NR _a R _b ,. or Z represents a fused or spiric bicyclic diamino heterocycle chosen from:

R _a and R _b each represent independently of the other a C _1-3 -alkyl group,

. or R ₃ and R _b together with the nitrogen atom to which they are attached form a heterocycle, optionally substituted with one or more oxo groups, - NR _a R _b or hydroxy; • R _d represents a hydrogen atom or a C _1-3 -alkyl group;

• R _e represents a C _1-3 -alkyl group;

it being understood that when R represents a hydrogen atom, then at least one of the conditions defined below is fulfilled: R ₄ represents a heterocycle group, said heterocycle being optionally substituted with a C _1-3 -alkylene group; -aryle, or

Z represents a phenyl group substituted by a C _1-3 -fluoroalkyl group, or

Z represents an alkynyl radical of type -C = CR ₀ in which R ₀ represents a hydrogen atom, C _1-6 -alkylene-OR _d or C _1-6 -alkylene-NR _a R _b , or

Z represents a -C _4-6 -alkylene-OR _{d group} , or

- Z is a tetrazole group substituted by a Ci _-3 alkyl group, or

Z represents a group -C ₄ . ₆ -alkylene-NR _a R _b , or else Z represents a group -O-C 1 -C ₅ -alkylene-NR _a R _b , or

Z represents a group -OC _0-3 -alkylene-heterocycle, the said -O-C _0-3 -alkylene-heterocycle group being optionally substituted by one or more C ₁ -C 3 alkyl groups or an oxo group, or Z represents a group -OC _1-5 -alkylene-OR _d , or

Z represents a group -NR _e -C _2- 5 -alkylene-OR _d , or

Z represents a group -OC _1-3 -alkylene-heteroaryl, or

Z represents a group -CONH-C _1-5 -alkylene-NR _a R _b , or

Z represents a group -OC _1-3 -alkylen-C (O) -NR _a Rb, in the groups Z mentioned above, the groups R _a , R _b , R _d and R _Θ are as defined previously, namely:

R _a and R _b each represent independently of the other a C _1-3 -alkyl group,

. or R _a and Rb together with the nitrogen atom to which they are attached form a heterocycle, said heterocycle group being optionally substituted with one or more oxo groups, -NR ₃ R _b , hydroxy;

• R _d represents a hydrogen atom or a C _1-3 -alkyl group;

• R _e represents a C _1-3 -alkyl group;

or Z represents a fused bicyclic or spiroic diamino heterocycle chosen from:

or Z represents a group -NR _a R _b in which R _a and R _b together with the nitrogen atom to which they are attached form a heterocycle substituted with one or more -NR _a R _b or hydroxy groups; in the form of a base or an acid addition salt, as well as a hydrate or solvate state, as well as its enantiomers, diastereoisomers and mixtures thereof.

3. Compound of formula (I) according to any one of claims 1 or 2, characterized in that: A represents an ethylene group;

B represents an ethylene group;

• L represents a single bond;

R 1 represents a phenyl, naphthyl, benzo-1,3-dioxolyl or pyrrolyl group; said phenyl, naphthyl, benzo-1,3-dioxolyl and pyrrolyl groups being optionally substituted with one or more Z radicals which are identical or different from each other;

• R ₂ and R ₃ represent independently of each other a hydrogen atom; R ₄ represents:

. a hydrogen atom or a methyl, ethyl, trifluoromethyl or methylene-O-methyl group,

. a piperidinyl or tetrahydropyranyl group; said piperidinyl or tetrahydropyranyl groups being optionally substituted by a methylene-phenyl group, or R ₄ represents a phenyl group; said phenyl group being optionally substituted with one or more radicals Z which are identical to or different from each other;

R ₅ represents a hydrogen atom or a methoxy group;

• R ₇ represents a chlorine atom or a methoxy group; Z represents a fluorine atom, a methoxy group or a phenyl group optionally substituted by a trifluoromethyl group,

. or Z represents a radical -C = CR ₀ , in which R ₀ represents a hydrogen atom, C _1-6 -alkylene-OR _d or C _1-6 -alkylene-NR _a R _b ,

. or Z is butylene-OR _d . or Z represents a tetrazole group substituted by a methyl group,

. or Z represents a group -NR _a R _b ,. or Z represents a butylene-NR _a R _{b group} ,

. or Z is -O-propylene-NR _a R _b or -O-ethylene-NR _a R _b , or Z represents a -O-heterocycle, -O-methylene-heterocycle, -O-ethylene-heterocycle group, said -O-heterocycle, -O-methylene-heterocycle, -O-ethylene-heterocycle groups being optionally substituted by a or more than one methyl group or one oxo group, or

. or Z is -O-ethylene-OR _d or -O-propylene-OR _d,. or Z represents a group -NR _e -ethylene-OR _d ,. or Z is -O-methylene-heteroaryl, -O-ethylene-heteroaryl,

. or Z represents a -CONH-ethylene-NR _a Rb group,

. or Z is -O-ethylene-C (O) -NR _a Rb,. or Z represents a fused or spiric bicyclic diamino heterocycle chosen from:

R _a and R _b each represent, independently of each other, a methyl group,

. or R _a and R _b together with the nitrogen atom to which they are attached form a morpholinyl, piperidinyl or pyrrolidinyl group, optionally substituted with one or more oxo groups, -NR ₃ R _b or hydroxy;

• R _d represents a hydrogen atom or a methyl group;

• R _e represents a methyl group;

- R ₄ represents a piperidinyl or tetrahydropyranyl group, said piperidinyl or tetrahydropyranyl groups being optionally substituted with a methylene-phenyl group, or - Z represents a phenyl group substituted with a trifluoromethyl group, or

Z represents an alkynyl radical of type -C = CR ₀ in which R _c represents a hydrogen atom, isopropylene-O-R _d or methylene-NR _a R _b , or

Z represents a butylene-OR group _d , or

Z represents a tetrazole group substituted with a methyl group, or Z represents a butylene-NR _a R _{b group} , or

Z represents a group -O-propylene-NR _a R _b , or

. Z represents a group -O-heterocycle, -O-methylene-heterocycle, -O-ethylene-heterocycle, said groups being optionally substituted by one or more methyl groups or an oxo group, or -Z represents a -O-ethylene group -OR _d or -O-propylene-O-R _dl or

Z represents a group -NR _e -ethylene-OR _d , or

Z represents a group -O-methylene-heteroaryl, -O-ethylene-heteroaryl, or

Z represents a -CONH-ethylene-NR _a Rb group, or Z represents a group -OC _1-3 -methylene-C (O) -NR _a Rb, in the groups Z mentioned above, the groups R _a , Rb, Rd and R _e are as defined above, namely :

• R _a and R _b each represent, independently of the other, a methyl group, or R _a and Rb together with the nitrogen atom to which they are attached form a piperidinyl, morpholinyl or pyrrolidinyl group, said piperidinyl, morphonlinyl and pyrrolidinyl groups being optionally substituted with one or more oxo groups, -NR _a R _b or hydroxy;

or Z represents a fused bicyclic or spiroic diamino heterocycle chosen from:

or else Z represents a group -NR ₃ R _b in which R _a and R _b together with the nitrogen atom to which they are attached form a piperidinyl or pyrrolidinyl group optionally substituted with one or more -NR ₃ R groups; _b , hydroxy; in the form of a base or an acid addition salt, as well as a hydrate or solvate state, as well as its enantiomers, diastereoisomers and mixtures thereof.

4. Compound of formula (I) according to claim 1, characterized in that: • A represents a C _1-4 -alkylene group optionally substituted with one or more groups R _g identical to or different from each other;

. or R ₉ and R ₁₀ together form a single bond or a C _1-4 alkylene group;

L represents a single bond or a C _1-2 -alkylene group, -CH = CH- or -C = C-; the C _1-2 -alkylene groups and -CH = CH- being optionally substituted by one or more C _1-2 alkyl substituents,

. or L represents a cycloprop-1, 2-diyl group;

R represents a hydrogen atom or a C _1-5 -alkyl, C _1-3 -fluoroalkyl, C _3-6 -cycloalkyl, -C (O) C _1-3 -alkyl, C _1-3 -alkylene group; -C ₃ - ₆ -cycloalkyl, -CH ₂ -C = CH, C _2-4 -alkylene-NR ₃ R _b , C _1-3 -alkylene-XC _1-3 -alkyl wherein X is O or SO ₂ ;

R ₄ represents:

. a C _1-3 -alkylene- (OH), C _1-3 -alkylene-XC-ι- ₃ -alkyl group where X is S, SO or SO ₂ ,

. a heterocycle group; said heterocycle group being optionally substituted with a C _1-3 -alkyl, -C (O) C _1-3 -alkyl, -C (O) C _1-3 -fluoroalkyl, C _1-3 -alkylene-C _{3- 6} - cycloalkyl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-heteroaryl; the C _1-3 -alkylene-aryl and C _1-3 -alkylene-heteroaryl groups being optionally substituted by one or more radicals

Z identical or different from each other,

. or R ₄ represents a C _1-3 -alkylene-NR _a Rb, aryl, C _1-3 -alkylene-aryl, -O-aryl, C _1-3 -alkylene-O-aryl, C _1-3 - alkylene-OC _1-3 -alkylene-aryl, heteroaryl or C _1-3 -alkylene-heteroaryl; aryl, C _1-3 -alkylene-aryl, -O-aryl, C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-OC _1-3 -alkylene-aryl, heteroaryl and C _{1- 3} -alkylene-heteroaryl being optionally substituted with one or more radicals Z which are identical to or different from each other;

• R ₅ represents a hydrogen or halogen atom or a Ci _-5 alkyl group, C _1-3 - fluoroalkyl, C _1-5 -alkoxy, C _1-3 -fluoroalkoxy, C _1-3 -alkylene- (OH), -CN, -XC-ι _-3 -alkyl where X is S, SO or SO ₂ ,

R ₇ represents a hydrogen or halogen atom or a C _1-5 alkyl, C _1-3 fluoroalkyl, C _1-5 alkoxy, -COOH, -C (O) OC _{1-3 group} ; alkyl, C _1-3 -fluoroalkoxy, C _1-3 -alkylene- (OH), -CN, -XC _1-3 -alkyl where X represents S, SO or SO ₂ ,

. or R ₇ represents a group -NR _a R _b , C _1-3 -alkylene-NR _a Rb, -C (O) -NR _a R _b , -C (O) -C _1-3 -alkyl, aryl, -O-aryl or heteroaryl; the aryl, -O-aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other;

Z represents a halogen atom or a C _1-5 -alkyl, C _1-3 -fluoroalkyl, C _3-6 -cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, a phenyl, Ci _-5- Alkoxy, C _1-3 -fluoroalkoxy, C _1-3 -alkylene-OC _1-3 -alkyl, C _1-3 -alkylene- (OH), NO ₂ , -CN, -SO ₂ NR _a R _b , -XC _1-3 -alkyl, C _1-3 -alkylene-XC _1-3 -alkyl wherein X is S, SO or SO ₂ , or Z is -NR _a R _b , C _1-3 -alkylene-NR _a R _b , -C (O) -NR _a R _b ,

-C (O) -C _1-3 -alkyl, -C (O) OC _1-4 -alkyl, -C (O) -C _3-6 -cycloalkyl,

. or else Z represents an oxo radical,

. or Z represents a group -O-C _1-5 -alkylene-NR _a R _b ,

. or two adjacent Z radicals together form a C _1-3 - alkylenedioxy group;

. or R _a and R _b together with the nitrogen atom carrying them, form a heterocycle optionally substituted with one or more C _1-3 -alkyl or oxo groups; it being understood that when R represents a hydrogen atom, then at least one of the two following conditions is met:

- R ₄ represents a heterocycle group; said heterocycle being optionally substituted,

Z represents a group -SO ₂ -NR _a R _b or a group -OC _1-5 -alkylene-NR _a R _b ; in the form of a base or an acid addition salt, as well as a hydrate or solvate state, as well as its enantiomers, diastereoisomers and mixtures thereof.

5. Compound of formula (I) according to claim 4, characterized in that:

• A represents a C _1-4 -alkylene group optionally substituted by one or more groups R ₉ identical or different from each other; B represents a C _1-4 -alkylene group optionally substituted with one or more groups R _{10 which are} identical to or different from one another;

R ₉ and R ₁₀ represent, independently of one another, a hydrogen atom or a C _1-5 alkyl group and in particular a methyl,

• R represents a hydrogen atom or a Ci _-5 alkyl group, C _1-3 fluoroalkyl, C _3-6 - cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl; R ₁ represents aryl or heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other;

R ₄ represents:

. a hydrogen atom or a C _1-5 -alkyl, C _3-6 -cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, C _1-3 -alkylene-OC _1-3 -alkyl group,

. a C _1-3 -alkylene- (OH) group, a heterocycle group; said heterocycle being optionally substituted with a group C- | .. ₃ -alkyl, -C (O) C _1-3 -alkyl, -C (0) C _1-3 fluoroalkyl, C _1-3 -alkylene- C ₃ . ₆ - cycloalkyl, C _1-3 -alkylene-aryl; the group C _1-3 -alkylene-aryl optionally substituted by one or more identical radicals Z or different from each other,

. or R ₄ is C _1-3 -alkylene-NR _a R _b , aryl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-OC _{1 -3} -alkylene-aryl, heteroaryl or C _1-3 -alkylene-heteroaryl; aryl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-O-

C _1-3 -alkylene-aryl, heteroaryl and C _1-3 -alkylene-heteroaryl being optionally substituted with one or more Z radicals the same or different from each other;

• R ₇ represents a halogen atom or a C _1-5 -alkyl and especially methyl, Ci _-5 alkoxy and in particular methoxy, CN, COOH or -C (O) OC _1-3 alkyl ;

• Z represents a halogen atom or a group CI_ ₅ -alkyl, C _1-3 fluoroalkyl, C _3-6 - cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, phenyl, C _{1- 5-} Alkoxy, C _1-3 -fluoroalkoxy, C _1-3 -alkylene-OC _1-3 -alkyl, C _1-3 -alkylene- (OH), NO ₂ , -CN, -SO ₂ NR _a R _b , -XC _1-3 -alkyl, C _1-3 - alkylene-XC _1-3 -alkyl wherein X is S, SO or SO ₂ ,

. or Z is -NR _a R _b , C- ^ - alkylene-NR _a R _b , -C (O) -NR _a R _b , -C (O) -C _1-3 -alkyl, -C ( O) OC _1-4 -alkyl, -C (O) -C _3-6 -cycloalkyl, or else Z represents an oxo radical,

. or Z represents a group -O-C _1-5 -alkylene-NR _a R _b ,

. or two adjacent Z radicals together form a C _1-3 - alkylenedioxy group;

6. Compound of formula (I) according to any one of claims 4 or 5, characterized in that: • A represents a C _1-4 -alkylene group and in particular an ethylene, optionally substituted with one or more groups R ₉ ;

B represents a C _1-4 -alkylene group and in particular an ethylene, optionally substituted by one or more Rio groups;

R ₉ and R ₁₀ each represent, independently of one another, a hydrogen atom or a methyl,

. or R ₉ and R ₁₀ together form a C _1-4 -alkylene group;

• L represents a single bond or -CH = CH-;

R represents a hydrogen atom or a C _1-5 alkyl group and in particular an ethyl, C _1-3 -alkylene-C _3-6 -cycloalkyl; R ₁ represents aryl or heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other;

R ₂ and R ₃ represent, independently of each other, a hydrogen atom or a C _1-3 -alkyl group and in particular a methyl; R ₄ represents:

. a hydrogen atom or a C _1-5 -alkyl, C _3-6 -cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, C _1-3 -alkylene-OC _1-3 -alkyl group and in particular methylene-O-methyl, a C _1-3 -alkylene-COH group,

. a heterocycle group optionally substituted with a C _1-3 -alkyl, -C (O) C _1-3 -alkyl, -C (O) C _1-3 -fluoroalkyl, C _1-3 -alkylene-C _{3-6 group} -cycloalkyl, C _1-3 -alkylene-aryl and in particular a methylene-phenyl; the group C _1-3 -alkylene-aryl optionally substituted by one or more identical radicals Z or different from each other,

. or R ₄ represents a C _1-3 -alkylene-NR _a Rb, aryl and in particular a phenyl, C _1-3 -alkylene-aryl and in particular a C _1-3 -alkylene-phenyl, C _1-3 -alkylene-O-aryl and in particular a C _1-3 -alkylene-O-phenyl, C _1-3 -alkylene-OC _1-3 -alkylene-aryl and in particular a C _1-3 -alkylene-OC- _{1- 3} -alkylene-phenyl, heteroaryl and in particular a thienyl or pyridinyl; aryl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-O-aryl, C-ι_ ₃ -alkylene-OC _1-3 -alkylene-aryl and heteroaryl being optionally substituted by one or more radicals Z identical or different from each other;

R ₅ represents a hydrogen atom; R ₇ represents a halogen atom, a methyl, a methoxy, CN, COOH or -C (O) O-C _1-3 -alkyl;

Z represents a halogen atom or a C1-s-alkyl group, a phenyl, C _1-5 alkoxy and in particular methoxy, C _1-3 -alkylene-OC _1-3 -alkyl, C _1-3 - alkylene- (OH), -CN, -SO ₂ NR _a R _b , -XC _1-3 -alkyl, C _1-3 -alkylene-X-C ₁ -C ₃ -alkyl wherein X is S, SO or SO ₂ ; . or Z is -NR _a R _b , C _1-3 -alkylene-NR _a R _b , -C (O) -NR _a R _b ,

-C (O) -C _1-3 -alkyl,

. or else Z represents an oxo radical,

. or Z represents a group -OC _1-5 -alkylene-NR _a R _bl

. or R ₃ and R _b together with the nitrogen atom carrying them, form a heterocycle optionally substituted with one or more C _1-3 -alkyl or oxo groups; it being understood that when R represents a hydrogen atom, then at least one of the two following conditions is met:

Z represents a group -SO ₂ -NR _a R _b or a group -O-C _1-5 -alkylene-NR _a R _b ; in the form of a base or an acid addition salt, as well as a hydrate or solvate state, as well as its enantiomers, diastereoisomers and mixtures thereof.

7. Compound of formula (I) according to any one of claims 4 to 6, characterized in that:

A represents an ethylene, optionally substituted by one or more groups Rg; B represents an ethylene, optionally substituted with one or more Rio groups;

R ₉ and R ₁₀ are each independently of one another a hydrogen atom or a methyl,

• L represents a single bond;

R represents a hydrogen atom, an ethyl or C _1-3 -alkylene-C _3-6 -cycloalkyl group;

Ri represents an aryl or a heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical or different, one of the other ;

• R ₄ represents:. a hydrogen atom or a C _1-5 -alkyl, C ₃ -6 cycloalkyl, C _1-3 -alkylene-

C _3-6 -cycloalkyl, methylene-O-methyl, a C _1-3 -alkylene- (OH) group,

. a heterocycle group optionally substituted with a C _1-3 -alkyl, -C (O) C _1-3 -alkyl, -C (O) C _1-3 -fluoroalkyl, C _1-3 -alkylene-C _{3 group} . _6- cycloalkyl, methylenephenyl; the methylene-phenyl group being optionally substituted with one or more radicals Z that are identical to or different from one another,

. or R ₄ represents a C _1-3 -alkylene-NR _a R _b, phenyl, C _1-3 - alkylene-phenyl, C _1-3 -alkylene-O-phenyl, ₃ -alkylene CI_ OC _1-3 -alkylene-phenyl, thienyl or pyridinyl; the phenyl, C _1-3 -alkylene-phenyl, C _1-3 -alkylene-O-phenyl, C _1-3 -alkylene-OC _1-3 -alkylene-phenyl, thienyl and pyridinyl groups being optionally substituted by one or more radicals Z identical to or different from each other;

R ₅ represents a hydrogen atom;

• R ₇ represents a halogen atom, a methyl, a methoxy, CN; Z represents a halogen atom or a C _1-5 alkyl group, a phenyl, a methoxy, C _1-3 -alkylene-OC _1-3 -alkyl, C _1-3 -alkylene- (OH) - CN, -SO ₂ NR _a R _b , -XC _1-3 -alkyl, C _1-3 - alkylene-XC _1-3 -alkyl where X is S, SO or SO ₂ ,

. or Z is -NR _a R _b , C _1-3 -alkylene-NR _a Rb, -C (O) -NR _a R _b , -C (O) -C _1-3 -alkyl,. or else Z represents an oxo radical,

. or Z represents a group -OC _1-5 -alkylene-NR _a R _b ,. or two adjacent Z radicals together form a methylenedioxy group;

. or R ₃ and R _b together with the nitrogen atom carrying them, form a heterocycle optionally substituted with one or more C _1-3 -alkyl or oxo groups; it being understood that when R represents a hydrogen atom, then at least one of the two following conditions is met: R ₄ represents a heterocycle group; said heterocycle being optionally substituted, - Z represents a group -SO ₂ -NR _a R _b or a group -OC _1-5 -alkylene-NR _a R _b ; in the form of a base or an acid addition salt, as well as in the state of hydrate or solvate, as well as its enantiomers, diastereoisomers and mixtures thereof.

8. Compounds of formula (I) according to any one of claims 1 to 3, selected from: N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] hydrochloride - (1-benzylpiperidin-4-yl) -7-methoxyphthalazin-1-amine;

N- (1- {4- [3- (dimethylamino) propoxy] benzyl} piperidin-4-yl) -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine hydrochloride;

N- {1- [3-fluoro-4- (3-morpholin-4-ylpropoxy) benzyl] piperidin-4-yl} -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine hydrochloride ;

7-methoxy-4- (4-methoxyphenyl) -N- {1- [4- (2-piperidin-1-ylethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine hydrochloride;

N- (1- {4- [3- (dimethylamino) propoxy] -3-fluorobenzyl} piperidin-4-yl) -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine hydrochloride; 7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (2-pyrrolidin-1-ylethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine hydrochloride;

7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (2-morpholin-4-ylethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine hydrochloride;

7-methoxy-4- (4-methoxyphenyl) -N- {1- [4- (3-piperidin-1-ylpropoxy) benzyl] piperidin-4-yl} phhalazin-1-amine hydrochloride;

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -N-ethyl-7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine hydrochloride;

4 - [(4 - {[7-Methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] -N- (2-piperidin-1-yl) hydrochloride ) benzamide; N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -7-methoxy-dihydrochloride

4- (tetrahydro-2H-pyran-4-yl) phthalazin-1-amine;

7-methoxy-4- (4-methoxyphenyl) -N- {1- [4- (3-methoxypropoxy) benzyl] piperidin-4-yl} phthalazin-1-amine dihydrochloride;

N- (1- {4- [3- (dimethylamino) propoxy] -3-fluorobenzyl} piperidin-4-yl) -4-ethyl-7-methoxyphthalazin-1-amine hydrochloride;

N- (1- {4- [3- (dimethylamino) propoxy] -3-fluorobenzyl} piperidin-4-yl) -7-methoxy-4- (methoxymethyl) phthalazin-1-amine hydrochloride;

N- {1- [3-fluoro-4- (3-pyrrolidin-1-ylpropoxy) benzyl] piperidin-4-yl} -7-methoxy-4- (4-methoxyphenyl) phthalazin-1-amine hydrochloride ; 1- (3- {4 - [(4 - {[7-Methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propyl) pyrrolidine hydrochloride -2-one;

N- (1- {4- [2- (Dimethylamino) ethoxy] benzyl} piperidin-4-yl) hydrochloride methoxy-4- (4-methoxyphenyl) phthalazin-1-amine;

7-methoxy-4- (4-methoxyphenyl) -N- (1- {4 - [(1-methylazepan-4-yl) oxy] benzyl} piperidin-4-yl) phthalazin-1-amine hydrochloride;

7-Methoxy-4- (4-methoxyphenyl) -N- (1- {4- [2- (1-methylpyrrolidin-2-yl) ethoxy] benzyl} piperidin-4-yl) phthalazin-1 hydrochloride amine;

4-ethyl-N- [1- (4-ethynylbenzyl) piperidin-4-yl] -7-methoxyphthalazin-1-amine dihydrochloride;

N- (1- {4- [3- (dimethylamino) prop-1-yn-1-yl] benzyl} piperidin-4-yl) -4-ethyl-7-methoxyphthalazin-1-amine hydrochloride; 3- {4 - [(4 - {[7-Methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol dihydrochloride;

4-Ethyl-7-methoxy-N- {1- [4- (4-pyrrolidin-1-ylpiperidin-1-yl) benzyl] piperidin-4-yl} phthalazin-1-amine hydrochloride;

N- (1- {4- [3- (dimethylamino) propoxy] benzyl} piperidin-4-yl) -7-methoxy-4- (methoxymethyl) phthalazin-1-amine hydrochloride;

N- (1- {4 - [(3S) -3- (dimethylamino) pyrrolidin-1-yl] benzyl} piperidin-4-yl) -7-methoxy-4- (methoxymethyl) phthalazin-1-hydrochloride amine;

N- (1- {4 - [(3R) -3- (dimethylamino) pyrrolidin-1-yl] benzyl} piperidin-4-yl) -7-methoxy-4- (methoxymethyl) phthalazin-1-hydrochloride amine; N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -7-methoxy-dihydrochloride

4- [4- (2-methyl-2H-tetrazol-5-yl) phenyl] phthalazin-1-amine;

7-Methoxy-4- (methoxymethyl) -N- (1- {4 - [(1-methylpyrrolidin-3-yl) methoxy] benzyl} piperidin-4-yl) phthalazin-1-amine hydrochloride;

7-Methoxy-4- (methoxymethyl) -N- (1- {4 - [(8-methyl-8-azabicyclo [3.2.1] oct-3-yl) oxy] benzyl} piperidin-4- hydrochloride yl) phthalazin-1-amine;

2 - [{4 - [(4 - {[7-methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenyl} (methyl) amino] ethanol hydrochloride;

7-methoxy-4- (methoxymethyl) -N- {1- [4- (2-oxo-2-pyrrolidin-1-ylethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine dihydrochloride; 3- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol dihydrochloride;

7-Methoxy-4- (methoxymethyl) -N- (1- {4 - [(1-methylazepan-4-yl) oxy] benzyl} piperidin-4-yl) phthalazin-1-amine hydrochloride;

7-methoxy-4- (methoxymethyl) -N- (1- {4- [2- (1-methylpiperidin-2-yl) ethoxy] benzyl} piperidin-4-yl) phthalazin-1-amine hydrochloride;

2- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} ethanol dihydrochloride; 7-methoxy-4-methyl-N- (1 - {4 - [(1-ethyl-4-yl) oxy] benzyl} piperidin-4-yl) phthalazin-1-amine hydrochloride;

3- {3 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol dihydrochloride; 3- [4 - ({4 - [(7-methoxy-4-methylphthalazin-1-yl) amino] piperidin-1-yl} methyl) phenoxy] propan-1-ol dihydrochloride;

7-Chloro-4-methyl-N- (1 - {4 - [(1-methylazepan-4-yl) oxy] benzyl} piperidin-4-yl) phthalazin-1-amine hydrochloride;

3- [4 - ({4 - [(7-chloro-4-methylphthalazin-1-yl) amino] piperidin-1-yl} methyl) phenoxy] propan-1-ol dihydrochloride;

(3S) -1- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenyl} pyrrolidin-3-ol hydrochloride ;

(3R) -1- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenyl} pyrrolidin-3-ol hydrochloride ; 7-methoxy-4- (methoxymethyl) -N- {1- [4- (4-pyrrolidin-1-ylbutyl) benzyl] piperidin-4-yl} phthalazin-1-amine trihaloaluminate;

2- {3 - [(4 - {[7-Methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} ethanol dihydrochloride;

2- {3 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} ethanol dihydrochloride;

3- {3 - [(4 - {[7-methoxy-4- (4-methoxyphenyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol dihydrochloride;

3- {4 - [(4 - {[7-methoxy-4- (trifluoromethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenoxy} propan-1-ol dihydrochloride; 7-Methoxy-4- (methoxymethyl) -N- {1- [4- (octahydro-2H-pyrido [1,2-a] pyrazin-2-yl) benzyl] piperidin-4-yl} phthalazin hydrochloride -1-amine;

3- [4 - ({4 - [(7-methoxyphthalazin-1-yl) amino] piperidin-1-yl} methyl) phenoxy] propan-1-ol dihydrochloride;

7-Methoxy-4- (methoxymethyl) -β- {1- [4- (6-methyloctahydro-1H-pyrrolo [3,4-b] pyridin-1-yl) benzyl] piperidin-4-trihydrochloride Phthalazin-1-amino;

7-Methoxy-4- (4-methoxyphenyl) -N- [1- [4- (7-methyl-2,7-diazaspiro [4.4] non-2-yl) benzyl] piperidin-4- hydrochloride phthalazin-1-amine;

4- {4 - [(4 - {[7-Methoxy-4- (methoxymethyl) phthalazin-1-yl] amino} piperidin-1-yl) methyl] phenyl} butan-1-ol dihydrochloride; 7-Methoxy-4- (methoxymethyl) -Λ / - [1 - ({1- [4-) dihydrochloride

(trifluoromethyl) phenyl] -1H-pyrrol-3-yl) methyl) piperidin-4-yl] phthalazin-1-amine;

Λ- (1- {4- [2- (1H-Imidazol-1-yl) ethoxy] benzyl} piperidin-4-yl) -hydrochloride methoxy-4- (4-methoxyphenyl) phthalazin-1-amine;

7-methoxy-4- (4-methoxyphenyl) -N- {1- [4- (pyridin-4-ylmethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine hydrochloride;

7-Methoxy-4- (4-methoxyphenyl) -N- {1- [4- (tetrahydrofuran-2-ylmethoxy) benzyl] piperidin-4-yl} phthalazin-1-amine dihydrochloride.

9. Process for preparing a compound of formula (I) according to any one of claims 1 to 8, characterized in that a compound of general formula (III) is reacted.

("I) wherein R ₄ , R ₅ and R ₇ are as defined in the general formula (I) according to claim 1, with a compound of the general formula (II)

in which R ₁ R ₁ , R ₂ , R 3, L ₁ A and B are as defined in the general formula (I) according to claim 1.

10. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 8, or a salt of addition of this compound to a pharmaceutically acceptable acid, or a hydrate or a solvate of the compound of formula (I).

11. Pharmaceutical composition, characterized in that it comprises at least one compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, as well as at least one pharmaceutically acceptable excipient.

12. Use of a compound of formula (I) according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of all diseases involving a dysfunction related to the MCH ₁ receptor.

13. Use of a compound of formula (I) according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of obesity, cellulitis, urinary incontinence, disorders metabolic diseases and their associated pathologies such as diabetes, cardiovascular disorders, syndrome X, in the treatment of stress-related conditions such as anxiety and depression.