EP1879887A2 - Antagonistes npy, preparation et utilisations - Google Patents

Antagonistes npy, preparation et utilisations

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Publication number
EP1879887A2
EP1879887A2 EP06743700A EP06743700A EP1879887A2 EP 1879887 A2 EP1879887 A2 EP 1879887A2 EP 06743700 A EP06743700 A EP 06743700A EP 06743700 A EP06743700 A EP 06743700A EP 1879887 A2 EP1879887 A2 EP 1879887A2
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EP
European Patent Office
Prior art keywords
ethyl
ureido
phenoxy
phenyl
propyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06743700A
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German (de)
English (en)
French (fr)
Inventor
Iuliana Botez
Christelle David-Basei
Nelly GOURLAOUËN
Eric NICOLAÏ
Fabrice Balavoine
Gérard Valette
Claudine Serradeil-Le Gal
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Cerep SA
Original Assignee
Cerep SA
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Publication date
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Publication of EP1879887A2 publication Critical patent/EP1879887A2/fr
Withdrawn legal-status Critical Current

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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • the present invention relates to novel compounds, their preparation and their uses, in particular therapeutic. It relates more particularly to compounds having at least two aromatic rings, their preparation and their uses, in particular in the field of human or animal health. These compounds have affinity for the neuropeptide Y, NPY receptors present in the central and peripheral nervous systems.
  • the compounds according to the invention are preferably NPY antagonists and more particularly antagonists of the NPY Yl subtype, and can therefore be used in the therapeutic or prophylactic treatment of disorders involving over expression of NPY.
  • the present invention also relates to pharmaceutical compositions comprising such compounds, their preparation and uses, and methods of treatment using said compounds.
  • Neuropeptide Y consists of 36 amino acids and was first isolated in 1982 from porcine brain. This neuropeptide is part of a family of peptides also including peptide YY (PYY) and pancreatic peptide (PP). It acts on several types of receptors bound to G proteins and called Y 1 , Y 2 ... Y 6 [Tatemoto et al Nature, 296, 1982, p. 659; Thorsell et al Neuropeptides, 36, 2002, p. 182; Redrobe et al Life Sd. , 11, 2002, p. 2921; Silva et al. Clin. CHm. Acta, 326, 2002, p. 3; Michel et al., Pharmacol. Rev.
  • NPY neuropeptide Y
  • the most notable effect of NPY is to regulate eating behavior, particularly by stimulating the appetite by hypothalamic effect. It also decreases the thermogenesis of adipocytes, inhibits lipolysis and promotes obesity.
  • NPY has an anxiolytic and sedative effect, an antinociceptive (analgesic) effect. It also seems to play a role in central regulation of blood pressure because, injected into certain areas of the animal's brain, it causes hypotension and bradycardia. It is also described that NPY inhibits the release of certain mediators, that of glutamate, for example. Its main peripheral effect described is vasoconstriction.
  • the Applicant has discovered a family of compounds which have an affinity for NPY receptors, and in particular the NPY Yl receptor. More particularly, the compounds described below exhibit an antagonist activity of NPY receptors and in particular Yl. They can, as such, be of great interest in the treatment of various diseases and disorders, particularly in the treatment and / or prevention of obesity or metabolic disorders.
  • a first subject of the invention relates to compounds of general formula (I) below:
  • X represents an N- (C1-C6) alkylamino group, optionally substituted by a (C1-C3) alkoxy (C1-C3) alkyl group; a N 5 N- (C 1 -C 6) dialkylamino (C 1 -C 3) alkyl group,
  • X is a hydrazino group, as shown below:
  • Rl 2 and Rl 3 which are identical or different, represent a hydrogen atom or a (Cl-C ⁇ ) alkyl radical, or else R12 and R13 may form, with the nitrogen atom to which they are bonded, a heterocycle nitrogen such as aziridine, azetidine, pyrrolidine, piperidine, homopiperidine,
  • Z represents the oxygen atom or an -NH- radical
  • ArI represents a phenyl
  • Y represents the oxygen or sulfur atom
  • Y represents the nitrogen atom and in this case it forms, with Z and the phenyl to which Z is attached, a heterocycle such as benzimidazole or benzoxazole, - Rl and R2, identical or different, represent an atom of hydrogen; an atom of ? halogen; a hydroxyl group; (C1-C6) alkyl, (C1-C6) alkoxy, hydroxy (C1-C3) alkyl, (C1-C6) alkoxy (C1-C3) alkyl, (C1-C3) alkoxy (C2-C3) alkoxy, hydroxy (C2-C3) alkoxy, amino (C2-C3) alkoxy, N-
  • C6 dialkylaminocarbonyl (C1-C3) alkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkoxycarbonyl (C1-C3) alkyl, - L1 represents the oxygen atom, the sulfur atom or a group (Cl -C3) alkylene,
  • Ar 2 represents an aryl, heteroaryl or heterocycle group such as phenyl, thiazole, indole, benzofuran, benzoxazole, benzimidazole, 2,3-dihydrobenzofuran, or 3H-quinazolin-4-one
  • R3 and R4 identical or different, represent a hydrogen atom; a halogen atom; a hydroxyl group; a radical (C1-C6) alkyl, (C1-C ⁇ ) alkoxy, hydroxy (C1-C3) alkyl, (C1-C6) alkoxy (C1-C3) alkyl, (C1-C3) alkoxy (C2-C3) alkoxy, hydroxy (C2-C3) alkoxy, (C2-C3) alkoxy, N- (C1-C3) alkylamino (C2-C3) alkoxy, N, N- (C1-C3) dialkylamino (C2-C3) alkoxy, trifluoromethyl, trifluoromethoxy, R1 and R3 may furthermore form together with ArI, Ar2 and Ll a tricycle and, in this case, R1 and R3 together represent a (C1-C3) alkylene group, with L1 representing in particular an oxygen atom When Ar 2 is phenyl or thio
  • RI1 represents the hydrogen atom; a (C1-C6) alkyl radical, optionally mono or polyfluorinated, optionally substituted by a heterocycle such as tetrahydrofuran or tetrahydropyran; a radical
  • Rl 1 can further form with Ar2, which in this case represents a phenyl group, and with the nitrogen to which it is attached a heterocycle such as indoline; isoindoline; tetrahydroisoquinoline; tetrahydroquinoline; 3,4-dihydro-2H-benzo [l, 4] oxazine; 6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene or 1,2,3,5-tetrahydro-benzo [e] [1,4] oxazepine;
  • RIl can further form with Ar3, which in this case represents a phenyl group, and with the nitrogen to which it is attached a heterocycle such as indoline; tetrahydroquinoline; 3,4-dihydro-2H-benzo [1,4] oxazine; 6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene or 1,2,3,5-tetrahydro-benzo [e] [1,4] oxazepine;
  • R 1 may form with Ar 3, which in this case represents a phenyl group, and with the nitrogen to which it is attached a heterocycle such as 1,3-dihydro-indol-2 one; 2,3-dihydroisoindol-1-one; 1,4-dihydro-2H-isoquinolin-3-one or 3,4-dihydro-2H-quinolin-1-one; or else for L 2b, R 1 may form with Ar 2, which in this case represents a phenyl group, and with the nitrogen to which it is attached a heterocycle such as 2,3-dihydro-isoindol-1-one or 3,4 dihydro-2H-isoquinolin-1-one; or L2 represents a methyleneoxy or oxymethylene radical, or L 2 represents a single bond with Ar 2 representing a phenyl, indole, benzofuran, benzoxazole, benzimidazole or
  • L 2 represents a single bond with Ar 2 representing a phenyl group and Ar 3 representing an indole, benzofuran, benzoxazole, benzimidazole, 2,3-dihydro-benzofuran or 3H-quinazolin-4-one group,
  • Ar 3 represents a heteroaryl, aryl or heterocycle group such as phenyl, indole, benzofuran, benzoxazole, benzimidazole, 2,3-dihydro-benzofuran, or piperidine, Ar 3 and Ar 2 can not simultaneously be heteroaryl or heterocycle groups when L 2 is a bond simple,
  • R5 and R6 identical or different, represent a hydrogen atom; a halogen atom; a hydroxyl or trifluoromethyl group; a radical (C1-C6) alkyl, (C1-C6) alkoxy, hydroxy (C1-C3) alkyl, (C1-C6) alkoxy (C1-C3) alkyl, (C1-C3) alkylcarbonyl, (C1-C3) alkoxy (C2-C3) alkoxy, hydroxy (C2-C3) alkoxy, amino (C2-C3) alkoxy, N- (Cl-C3) alkylamino (C2-C3) alkoxy or N 5 N- (Cl- C3) dialkylamino (C2 -C 3) alkoxy,
  • - A represents a single bond; an oxygen atom; a group (C1-C3) alkylene, (C2-C3) alkylidene, (C1-C3) alkylenoxy or oxy (C1-C3) alkylene,
  • R7 represents a hydrogen atom; a (Cl-C ⁇ ) alkyl or (C1-C ⁇ ) alkylcarbonyl group;
  • R 7 can form with L 3 and the nitrogen atom to which R 7 is bound a nitrogen heterocycle such as piperidine, pyrrolidine, homopiperidine, pyrrolidin-2-one, piperidin-2-one, azepan-2-one;
  • R 7 can optionally be formed with Ar 3, which in this case represents a phenyl group, and with the nitrogen to which it is attached, a heterocycle such as indoline, tetrahydroquinoline, 2,3-dihydroisoindol-1-one or 3,4-dihydroisoindol-1-one.
  • Ar 3 which in this case represents a phenyl group
  • a heterocycle such as indoline, tetrahydroquinoline, 2,3-dihydroisoindol-1-one or 3,4-dihydroisoindol-1-one.
  • L3 represents a (Cl-C6) alkylene, (C3-C8) cycloalkylene, N- (C2-C6) alkyleneamino, (C2-C6) alkylidene, (C3-C8) cycloalkylidene 5 bicyclo or polycyclo (C6- C12) alkylene, bicyclo or polycyclo (C 6 -C 12) alkylidene, L 3 can not be a methylene radical in the case where it is directly bonded to both an oxygen atom and a nitrogen atom or to two nitrogen atoms , the radicals mentioned above possibly being substituted by one or more fluorine atoms, by one or more (C 1 -C 3) alkyl, (C 1 -C 3) alkoxy, hydroxy, hydroxy (C 1 -C 3) alkyl or (Cl -C3) alkoxy,
  • L 3 may optionally form with A and Ar 3 an oxygenated heterocycle such as 2,3-dihydrobenzofuran, benzofuran or chroman;
  • alkylcarbonyloxy (C2-C6) alkyl 5 groups cited above may be substituted by one or more fluorine atoms,
  • R8 and R9 may form, together with the nitrogen atom to which they are bonded, a mono or polycyclic nitrogen heterocycle such as aziridine, azetidine, pyrrolidine, piperidine, piperazine, homopiperazine, [1,5] diazocane, homopiperidine, morpholine, 2,7-diaza-spiro [4.4] nonane, octahydro-pyrrolo [3,4-c] pyrrole, octahydro-pyrrolo [3,2-b] pyrrole, optionally substituted by one or more fluorine atoms, by one or more hydroxyl, hydroxy (C1-C6) alkyl, (C1-C6) alkyl, (C1-C4) alkoxy, amino (C1-C6) alkyl, N- (C1-C4) alkylamino (C1-C6) alkyl, N radicals, N- (C1-C4) dialkylamino (C1-C6) alky
  • R8 and / or R9 can form with L3 and with the nitrogen atom to which they are attached a mono or polycyclic nitrogenous heterocycle, saturated or unsaturated, such as pyrrolidine, piperidine, homopiperidine, 8-azabicyclo [3.2.1] octane, 2-aza-bicyclo [2.2.2] octane, 2-aza-bicyclo [2.2.1] heptane, 7-aza-bicyclo [2.2.1] heptane, 1, 2,3,6-tetrahydro pyridine, optionally substituted with one or more fluorine atoms, with one or more hydroxyl, hydroxy (C1-C6) alkyl, (C1-C6) alkyl, (C1-C6) alkoxy, amino radicals ( Cl-C6) alkyl, N- (Cl-C4) alkylamino (Cl-C6) alkyl, N 5 N- (C l-C4) dialkylamino (Cl-C6) alkyl
  • C4 alkoxy (C1-C6) alkyl, hydroxycarbonyl (C1-C3) alkyl, (C1-C6) alkoxycarbonyl (C1-C3) alkyl, (C1-C3) alkylcarbonyloxy (C1-C6) alkyl or mono or polyfluoro (C1- C6) alkyl; for the particular case where L3 forms with A and Ar3 an oxygenated heterocycle and at the same time R8 and / or R9 form with L3 and with the nitrogen atom to which they are bonded a nitrogenous heterocycle, the assembly constitutes a polycycle such that 1,2,3,4-tetrahydro-benzo [4,5] furo [3,2-c] pyridine or 1,2,3,4,4a, 9b-hexahydro-benzo [4,5] furo [3, 2-c] pyridine, or a polycycle as described below:
  • R8 and / or R9 may optionally form, with R7, L3 and the nitrogen atom to which R8 and R9 are bonded, a mono or polycyclic nitrogen heterocycle such as piperazine, homopiperazine, [1,5] diazocane, 2,7-diaza-spiro [4.4] nonane, octahydro-pyrrolo [3,4-c] pyrrole, octahydro-pyrrolo [3,2-b] pyrrole, piperazine-2 -one, [1,4] diazepan-5- or 2-one, [1,5] diazocan-2-one,
  • a mono or polycyclic nitrogen heterocycle such as piperazine, homopiperazine, [1,5] diazocane, 2,7-diaza-spiro [4.4] nonane, octahydro-pyrrolo [3,4-c] pyrrole, octahydro-pyrrolo [3,2-b] pyrrole, piperazine-2
  • the nitrogen atom bonded to R8 and R9 may be in the form of quaternary ammonium, it is then in the following form:
  • R8 and R9 being as defined above, in particular they represent a (C1-C6) alkyl group, and R10 represents a (C1-C6) alkyl group,
  • alkyl denotes a saturated monovalent hydrocarbon radical, linear or branched.
  • (C1-C3) alkyl; (C1-C4) alkyl; (C2-C6) alkyl and (C1-C6) alkyl is understood to mean an alkyl radical comprising from 1 to 3; from 1 to 4; from 2 to 6 and 1 to 6 carbon atoms, respectively. Mention may especially be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, pentyl, neopentyl or n-hexyl radicals.
  • Hydroxyalkyl means a hydroxyl group connected to the rest of the molecule by an alkyl radical as defined above.
  • Mono or polyfluoro (C1-C6) alkyl groups are alkyl radicals bearing one or more fluorine atoms. There may be mentioned especially perfluoroalkyl radicals, such as perfluororhethyl, or the 4-fluoro-butyl, 4,4,4-trifluorobutyl, 3,3,3-trifluoropropyl or 2,2,2-trifluoropropyl radicals. ethyl.
  • aminoalkyl is meant an NH 2 - group connected to the rest of the molecule by an alkyl radical as defined above.
  • tetrahydropyran-4-yl-aminoalkyl refers to a tetrahydropyran-4-yl group connected to the remainder of the molecule by an aminoalkyl radical as defined above.
  • cycloalkyl denotes an alkyl group of 3 to 10 carbon atoms forming a saturated monocyclic system.
  • cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or norbornyl.
  • C 3 -C 8 cycloalkyl is meant a cycloalkyl radical comprising from 3 to 8 carbon atoms.
  • cycloalkyl alkyl is meant a cycloalkyl group connected to the rest of the molecule by an alkyl radical as defined above.
  • alkylene groups within the meaning of the invention are divalent groups corresponding to the alkyl groups as defined above by removal of a hydrogen atom.
  • the (C1-C3) alkylene and (C2-C6) alkylene groups correspond to an alkylene radical comprising from 1 to 3 and respectively from 2 to 6 carbon atoms.
  • the term "cycloalkylene” denotes a divalent cycloalkyl group as defined above by removal of a hydrogen atom.
  • (C 3 -C 8) cycloalkylene is meant a cycloalkylene radical comprising from 3 to 8 carbon atoms.
  • Polycyclo (C6-C12) alkylene means an alkylene radical comprising from 6 to 12 carbon atoms forming a saturated polycyclic system.
  • alkylidene groups within the meaning of the invention are divalent groups corresponding to the alkylene groups as defined above and comprising at least one ethylenic unsaturation.
  • (C2-C3) alkylidene and (C2-C6) alkylidene is meant an alkylidene radical comprising from 2 to 3 and 2 to 6 carbon atoms, respectively.
  • polycyclo (C6-C12) alkylidene is meant a polycyclic alkylidene radical comprising from 6 to 12 carbon atoms.
  • Aryl groups are mono- or bi-cyclic aromatic hydrocarbon systems, generally 5 or 6-membered, having from 6 to 14 carbon atoms. Mention may in particular be made of the phenyl or naphthyl radical.
  • the "heteroaryl” groups are aromatic hydrocarbon systems as defined above having on the ring (s) at least one heteroatom, such as nitrogen, sulfur or oxygen. As heteroaryl, mention may be made especially of the pyrrole, pyrazole, imidazole, furan, oxazole, thiazole, thiadiazole, oxadiazole, indole, benzimidazole, benzoxazole, benzofuran, benzothiazole and pyridine groups.
  • heterocycle denotes mono-, bi- or polycyclic hydrocarbon systems, saturated or unsaturated, having on the ring (s) at least one heteroatom, such as nitrogen, sulfur or sulfur. oxygen. They can be aromatic or not. They are preferably non-aromatic.
  • heterocycle there may be mentioned the piperidine, pyran, dioxane, piperazine, pyrrolidine, morpholine, homopiperazine, homopiperidine, thiomorpholine, [1,5] diazocane, pyrrolidin-2-one, piperidin-2-one, azepan group.
  • Polycycle means a radical comprising at least two hydrocarbon rings, aromatic or unsaturated, saturated or unsaturated, optionally having one or more heteroatoms, such as O, N or S.
  • a polycycle there may be mentioned group 1, 2,3,4-tetrahydro-benzo [4,5] -cyclo [3,2-c] pyridine or 1,2,3,4,4a, 9b-hexahydro-benzo [4,5] furo [3,2- c] pyridine, or the groups described below:
  • alkoxy groups correspond to the alkyl groups defined above and connected to the rest of the molecule via an oxygen atom.
  • (C1-C4) alkoxy groups; (C1-C6) alkoxy and (C1-C3) alkoxy are an alkyl radical of 1 to 4; from 1 to 6 and 1 to 3 carbon atoms respectively connected to the rest of the molecule through an oxygen atom.
  • An alkoxyalkyl group corresponds to an alkyl radical interrupted by an oxygen atom.
  • alkyleneoxy or “oxyalkylene” groups correspond to the alkylene groups defined above and connected in particular to the remainder of the molecule via an oxygen atom.
  • (C1-C3) alkyleneoxy or oxy (C1-C3) alkylene is meant an alkylene radical comprising from 1 to 3 carbon atoms connected in particular to the rest of the molecule through an oxygen atom.
  • hydroxycarbonylalkyl is meant a hydroxycarbonyl (carboxyl) -COOH group attached to the remainder of the molecule through an alkyl as defined above.
  • alkoxycarbonyl alkyl is meant an alkoxycarbonyl group connected to the rest of the molecule by an alkyl radical as defined above.
  • alkylcarbonyloxyalkyl refers to an alkyl radical as defined above,
  • N-alkylamino or N, N-dialkylamino groups correspond to an alkyl group or to two alkyl groups as defined above, connected to the rest of the molecule by a nitrogen atom or an amino group.
  • An "alkylaminoalkyl” group corresponds to an alkyl radical interrupted by an amino group.
  • N-alkyleneamino groups within the meaning of the invention are divalent groups corresponding to N-alkylamino groups as defined above by removal of a hydrogen atom.
  • the N- (C2-C6) alkyleneamino groups correspond to an alkylene radical comprising from 2 to 6 carbon atoms connected to the rest of the molecule by a nitrogen atom or an amino group.
  • (C1-C6) dialkylhydrazino is meant an R12 type hydrazino group as defined in formula (I) above, for which R1 and R13 are alkyl radicals having from 1 to 6 carbon atoms.
  • alkylaminocarbonyl alkyl refers to an alkylaminocarbonyl group as defined above, connected to the remainder of the molecule through an alkyl.
  • aminocarbonyl alkyl refers to an aminocarbonyl group as defined above, connected to the remainder of the molecule through an alkyl.
  • An alkoxyalkoxy group is an alkoxy group connected to the rest of the molecule by another alkoxy group.
  • An aminoalkoxy group is an amino group connected to the remainder of the molecule by an alkoxy group.
  • N-alkylaminoalkoxy or N, N-dialkylaminoalkoxy groups correspond to the alkylamino or dialkylamino groups as defined above connected to the remainder of the molecule via an alkoxy radical.
  • halogen is meant a fluorine, chlorine, bromine or iodine atom.
  • heteroatom is meant an atom selected from O, N and S.
  • the 8-azabicyclo [3.2.1] octane group preferably has the following formula:
  • the 2-aza-bicyclo [2.2.2] octane group preferably has the following formula:
  • the 2-aza-bicyclo [2.2.1] heptane group preferably has the following formula:
  • the 7-aza-bicyclo [2.2.1] heptane group preferably has the following formula:
  • the 1,2,3,6-tetrahydropyridine group preferably has the following formula:
  • the [1,5] diazocane group preferably has the following formula:
  • the 2,7-diaza-s ⁇ iro [4.4] nonane group preferably has the following formula:
  • the octahydro-pyrrolo [3,4-c] pyrrole group preferably has the following formula:
  • the octahydro-pyrrolo [3,2-b] pyrrole group preferably has the following formula:
  • the azepan-2-one group preferably has the following formula:
  • the [1,4] diazepan-5-one group preferably has the following formula:
  • the [1,4] diazepan-2-one group preferably has the following formula:
  • the [1,5] diazocan-2-one group preferably has the following formula:
  • the tetrahydrofuran group preferably has one of the following formulas:
  • the tetrahydropyran group preferably has one of the following formulas:
  • the thiazole group preferably has the following formula:
  • the indoline group preferably has one of the following formulas:
  • the isoindoline group preferably has one of the following formulas:
  • the tetrahydroquinoline group preferably has one of the following formulas:
  • the tetrahydroisoquinoline group preferably has one of the following formulas:
  • the 3,4-dihydro-2H-benzo [1,4] oxazine group preferably has one of the following formulas:
  • the 6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene group preferably has one of the following formulas:
  • the 1,2,3,5-tetrahydro-benzo [e] [1,4] oxazepine group preferably has one of the following formulas:
  • the 1,3-dihydroindol-2-one group preferably has the following formula:
  • the 2,3-dihydroisoindol-1-one group preferably has one of the following formulas:
  • the 3,4-dihydro-2H-isoquinolin-1-one group preferably has one of the following formulas:
  • the 1,4-dihydro-2H-isoquinolin-3-one group preferably has the following formula:
  • the 3H-quinazolin-4-one group preferably has one of the following formulas:
  • the indole group preferably has one of the following formulas:
  • R14 is a hydrogen atom, a (C1-C ⁇ ) alkyl or (C1-C3) alkoxy (C2-C6) alkyl radical and R3 to R6 being as defined above.
  • the benzimidazole group preferably has one of the following formulas:
  • R 14 is a hydrogen atom, a (C 1 -C 6) alkyl or (C 1 -C 3) alkoxy (C 2 -C 6) alkyl radical, and R 1, R 4 and R 6 are as defined above.
  • the benzoxazole group preferably has one of the following formulas:
  • the benzofuran group preferably has one of the following formulas:
  • the 2,3-dihydro-benzofuran group preferably has one of the following formulas:
  • the chromane group preferably has the following formula:
  • the 1,2,3,4-tetrahydro-benzo [4,5] furo [3,2-c] pyridine group preferably has the following formula:
  • the 1,2,3,4,4a, 9b-hexahydro-benzo [4,5] furo [3,2-c] pyridine group preferably has the following formula:
  • the preferred compounds of the invention are compounds of formula (I) as defined above, in which at least one of the groups R8 and R9 is different from the hydrogen atom. .
  • a family of preferred compounds corresponds to compounds of formula (I) above, in which R 1 is as defined above and R 2 is a hydrogen atom.
  • R1 represents a hydrogen atom; a halogen atom; a radical (C1-C ⁇ ) alkyl, (C1-C6) alkoxy, hydroxy (C1-C3) alkyl, (C1-C6) alkoxy (C1-C3) alkyl, trifluoromethyl, N- (C1-C6) alkylaminocarbonyl, N- (C1-C6) alkylaminocarbonyl (C1-C3) alkyl, or (C1-C6) alkoxycarbonyl.
  • a family of preferred compounds corresponds to compounds of formula (I) above, in which R 1 and R 2, as defined above, are simultaneously different from the atom of hydrogen.
  • they may be a halogen atom, preferably fluorine; a radical (Cl-C ⁇ ) alkyl, (Cl- C6) alkoxy, hydroxy (Cl-C3) alkyl, (Cl-C6) alkoxy (Cl-C3) alkyl or N 5 N- (Cl- C3) dialkylamino (C2- C3) alkoxy.
  • a family of preferred compounds corresponds to compounds of formula (I) in which Y represents an oxygen atom, Z represents an -NH- radical and advantageously X represents an N- ( C1-C6) alkylamino, optionally substituted with a (C1-C3) alkoxy (C1-C3) alkyl group.
  • a family of preferred compounds corresponds to compounds of formula (I) above, in which L2 is an L2a type amide bond.
  • the compounds of the invention are compounds of formula (F) above, in which A is an oxygen atom, ArI and Ar3 are phenyl radicals, Ar2 is a thiazole or a phenyl, and X, Y, Z, L1, L3, R1-R9 and R11 are as defined in general formula (I) above.
  • This family of compounds is represented by the following formula (II):
  • L1 is oxygen
  • Ar1 and Ar3 are advantageously 3- or 4-phenyl radicals
  • Ar2 is a thiazole, according to the following formula (IIa):
  • the compounds of structure (IIa) advantageously have the following characteristics:
  • ArI and Ar3 are 4-phenyl radicals Or
  • ArI is the 4-phenyl radical and Ar3 is the 3-phenyl radical. Even more advantageously, in the formula (IIa):
  • X represents an N- (C 1 -C 6) alkylamino group, optionally substituted by a (C 1 -C 3) alkoxy (C 1 -C 3) alkyl group, preferentially isopropylamino and 1-ethylpropylamino, or a (C 1 -C 6) dialkylhydrazino group; as defined in the formula
  • R 1 represents a hydrogen atom or a (C 1 -C 6) alkyl radical, and / or L 3 is a (C 2 -C 6) alkylene group, and / or
  • R 8 and R 9, as defined in formula (I) above, form together with the nitrogen atom to which they are bonded a nitrogen heterocycle, preferably piperidine,
  • R9 forms with L3 and with the nitrogen atom to which it is attached a nitrogen heterocycle, preferably piperidine or pyrrolidine.
  • R1, R2, R5, R6 and R8 are as defined in formula (I) above.
  • ArI, Ar2 and Ar3 advantageously represent 3- or 4-phenyl radicals.
  • the formula (Ilb) can be represented as follows:
  • the compounds of subfamily (IIb) advantageously have the following characteristics:
  • Ar 1, Ar 2 and Ar 3 are 4-phenyl radicals or Ar 1 is the 4-phenyl radical and Ar 2 and Ar 3 are 3-phenyl radicals
  • ArI and Ar2 are 4-phenyl radicals and Ar3 is the 3-phenyl radical or
  • ArI and Ar3 are 3-phenyl radicals and Ar2 is the 4-phenyl radical or ArI is the 3-phenyl radical and Ar2 and Ar3 are 4-phenyl radicals or
  • ArI and Ar3 are 4-phenyl radicals and Ar2 is the 3-phenyl radical.
  • X represents an N- (C 1 -C 6) alkylamino group, optionally substituted by a (C 1 -C 3) alkoxy (C 1 -C 3) alkyl group, preferably isopropylamino, 1-ethylpropylamino and 1-methoxymethylpropylamino, or a group (C1-C6) dialkylhydrazino as defined in formula (I) above, preferably 2,2-dimethylhydrazino, and
  • Y, Z, L3, R1 to R11 are as defined in formula (I) above.
  • the compounds of subfamily (IIb) have the following characteristics: X represents an N- (Cl-C 6) alkylamino group, optionally substituted with a (C 1 -C 3) alkoxy (C 1 -C 3) alkyl group preferably isopropylamino, 1-ethylpropylamino and 1-methoxymethylpropylamino, or a (C 1 -C 6) dialkylhydrazino group as defined in formula (I) above, preferably 2,2-dimethylhydrazino, and / or Y is the oxygen atom, and / or
  • Z is a radical -NH-, and / or
  • RI1 represents the hydrogen atom; a (Cl-C ⁇ ) alkyl radical, optionally mono or polyfluorinated, optionally substituted with a heterocycle such as tetrahydrofuran or tetrahydropyran; a (C3-C10) cycloalkyl radical; a hydroxy (C2-C6) alkyl group; (C1-C6) alkoxy (C2-C6) alkyl; amino (C2-C6) alkyl; NOT-
  • C1-C6) alkylamino (C2-C6) alkyl N 5 N- (C 1 -C 6) dialkylamino (C 2 -C 6) alkyl; a heterocycle such as tetrahydrofuran or tetrahydropyran,
  • Rl 1 forms with Ar2 and with the nitrogen to which it is attached a heterocycle, preferably indoline, 3,4-dihydrp-2H-benzo [1,4] oxazine, 6,7,8,9-tetrahydro- 5-oxa-9-aza-benzocycloheptene or 1,2,3,5-tetrahydro-benzo [e] [1,4] oxazepine, and in this case the group in formula (IIb) above, preferably represents:
  • R9 forms with L3 and with the nitrogen atom to which it is attached a nitrogen heterocycle and in this case the group
  • R9 preferably represents a pyrrolidin-3-yl, piperidin-3 or 4-yl, homopiperidin-4-yl radical, optionally substituted by one or more fluorine atoms, by one or more hydroxyl, hydroxy (C1-C6) alkyl radicals; (C1-C6) alkyl, (C1-C6) alkoxy, amino (C1-C6) alkyl, N- (C1-C4) alkylamino (C1-C6) alkyl, N, N- (C1-C4) dialkylamino (Cl) -C6) alkyl, (C1-C4) alkoxy (C1-C6) alkyl, hydroxycarbonyl (C 1 -C 3) alkyl, (C 1 -C 6) alkoxycarbonyl (C 1 -C 3) alkyl, (Cl-C 6) alkoxycarbonyl (C 1 -C 3) alkyl, (Cl-
  • R9 ⁇ preferably represents
  • R1 to R6 and R8 are as defined in formula (I) above, According to another preferred variant, the compounds of subfamily (IIb) have the following characteristics:
  • X represents a (C 1 -C 6) alkylamino group, optionally substituted by a (C 1 -C 3) alkoxy (C 1 -C 3) alkyl group, preferably isopropylamino and 1-ethylpropylamino, or a (C 1 -C 4) dialkylhydrazino group such that defined in formula (I) above, preferably 2,2-dimethylhydrazino, and / or
  • Y is an oxygen, and / or
  • Z is a radical -NH-, and / or
  • R 1 represents the hydrogen atom or a (C 1 -C 6) alkyl radical, and / or
  • L3 is a (C2-C6) alkylene group, and / or
  • R8 and R9 form together with the nitrogen atom to which they are attached a nitrogenous heterocycle, preferably piperidine, optionally substituted with a hydroxyl radical, and / or
  • R 1 to R 6 are as defined in formula (I) above.
  • the compounds of type (II) correspond to the following formula (Ile):
  • X represents a (C1-C6) alkylamino group, optionally substituted by a (C1-C3) alkoxy (C1-C3) alkyl group, preferably isopropylamino and 1-ethylpropylamino, and / or
  • L3 is a (C2-C6) alkylene group, and / or
  • R 1 to R 6 are as defined in formula (I) above.
  • a subfamily of preferred compounds (III) corresponds to compounds of formula (F) above, in which A represents a single bond, an oxygen atom or a group ( Cl-C3) alkylene, (C2-C3) alkylidene, (Cl-C3) alkyleneoxy or oxy (Cl-C3) alkylene and X, Y, Z, Ll, L3, Ar2, Ar3 5 Rl FIR are as defined in formula (I) above.
  • the formula (III) can be represented as follows:
  • L1 is an oxygen atom
  • Ar1 and Ar3 are phenyl radicals, preferably 4-phenyl
  • Ar2 is a thiazole.
  • the formula (HIa) can be represented as follows:
  • X represents a (C 1 -C 6) alkylamino group, optionally substituted with a (C 1 -C 3) alkoxy (C 1 -C 3) alkyl group, preferably isopropylamino and 1-ethylpropylamino, or a (C 1 -C 6) dialkylhydrazino group such as defined in formula (I) above, preferably 2,2-dimethylhydrazino, and / or
  • Y is an oxygen, and / or
  • Z is the radical -NH-, and / or the group
  • R9 A - is as defined in formula (HIa) above,
  • R1, R2, R5, R6 and R11 are as defined in formula (I) above.
  • L1 is an oxygen
  • Ar2 and Ar3 are phenyl radicals, preferably 4-phenyl, and the group
  • R9 A is as defined in formula (HIa) above.
  • X represents a (C1-C6) alkylamino group, optionally substituted by a (C1-C3) alkoxy (C1-C3) alkyl group, preferably isopropylamino and 1-ethylpropylamino, or a (C1-C6) dialkylhydrazino group such as defined in formula (I) above, preferably 2,2-dimethylhydrazino, and / or
  • Y is an oxygen, and / or
  • Z is the radical -NH-, and / or
  • R 1 to R 6 and R 11 are as defined in formula (I) above.
  • the compounds of type (III) have the following characteristics:
  • A represents a single bond
  • Ar 2 is a phenyl radical, preferably 4-phenyl, or thiazole, and / or Ar 3 is an indole, benzimidazole or benzofuran group,
  • the compounds of subfamily (IIIc) have the following characteristics:
  • X represents a (C 1 -C 6) alkylamino group, optionally substituted by a (C 1 -C 3) alkoxy (C 1 -C 3) alkyl group, preferably isopropylamino and 1-ethylpropylamino, or a (C 1 -C 6) dialkylhydrazino group; as defined in formula (I) above, preferably 2,2-dimethylhydrazino, and / or - Y is the oxygen atom, and / or
  • Z is a radical -NH-, and / or
  • L1 is the oxygen atom, and / or
  • L3 is a (C1-C ⁇ ) alkylene group or a (C3-C8) cycloalkylene group, and / or
  • R8 and R9 as defined in formula (I) above, together with the nitrogen atom to which they are bonded form a nitrogen heterocycle, preferably piperidine,
  • R9 forms with L3 and with the nitrogen atom to which it is bonded a nitrogen heterocycle, preferably piperidine,
  • R 1 to R 6 and R 11 are as defined in formula (I) above and R 14 is a hydrogen atom, a (C 1 -C 6) alkyl or (C 1 -C 3) alkoxy radical (C 2 -C C6) alkyl.
  • R 14 is a hydrogen atom, a (C 1 -C 6) alkyl or (C 1 -C 3) alkoxy radical (C 2 -C C6) alkyl.
  • the compounds of type (III) have the following characteristics:
  • Ar 2 is a phenyl radical, preferably 4-phenyl, or thiazole,
  • - Ar3 is a piperidine, - the group
  • X, Y, Z, L1, L3, R1 to R4, R8, R9 and R11 are as defined in formula (I) above.
  • the compounds of the subfamily (HId) have the following characteristics:
  • X represents a (C 1 -C 6) alkylamino group, optionally substituted with a (C 1 -C 3) alkoxy (C 1 -C 3) alkyl group, preferably isopropylamino and 1-ethylpropylamino, or a (C 1 -C 6) dialkylhydrazino group as defined in formula (I) above, preferably 2,2-dimethylhydrazino, and / or - Y is the oxygen atom, and / or
  • Z is a radical -NH-, and / or
  • L1 is the oxygen atom, and / or
  • L3 is a (C1-C ⁇ ) alkylene group or a (C3-C8) cycloalkylene group, and / or
  • R8 and R9 as defined in formula (I) above, together with the nitrogen atom to which they are attached form a nitrogen heterocycle, preferably piperidine,
  • R 9 forms with L 3 and with the nitrogen atom to which it is bonded a nitrogen heterocycle, preferably piperidine, R 1 to R 4 and R 11 are as defined in formula (I) above.
  • the subfamily of preferred compounds (IV) corresponds to compounds of formula (F) above, in which ArI and Ar3 are phenyl radicals and A represents one of the groups below. below: Aa Ab Ac Ad
  • Y is an oxygen
  • / or Z is an NH group
  • / or L1 is an oxygen
  • ArI and Ar3 are 4-phenyl radicals
  • / or Ar2 is a thiazole and A is as defined in formula (IV) above.
  • the formula (IVa) can preferably be represented as follows:
  • X represents a (C 1 -C 6) alkylamino group, optionally substituted with a (C 1 -C 3) alkoxy (C 1 -C 3) alkyl group, preferably isopropylamino and 1-ethyl- propylamino, or a (C 1 -C 6) dialkylhydrazino group as defined in the formula (I) above, preferably 2,2-dimethylhydrazino, and / or - Rl 1 represents the hydrogen atom or a radical (Cl -C6) alkyl, and / or - L3 and R1 to R9 are as defined in formula (I) above.
  • Y is an oxygen
  • / or Z is an NH group
  • / or L1 is an oxygen
  • Ar1, Ar2 and Ar3 are phenyl radicals, preferably 4-phenyl radicals and A is such that defined in formula (IV) above.
  • the formula (IVb) can preferably be represented as follows:
  • X represents a (C1-C ⁇ ) alkylamino group, optionally substituted with a (C1-C3) alkoxy (C1-C3) alkyl group, preferably isopropylamino and 1-ethylpropylamino, or a (C1-C6) dialkylhydrazino group as defined in formula (I) above, preferably 2,2-dimethylhydrazino, and / or - RI 1 represents a hydrogen atom, a (Cl-C ⁇ ) alkyl radical or (Cl-
  • C3) (C2-C6) alkoxy alkyl, and / or - L3 and R1 to R9 are as defined in formula (I) above.
  • X represents a (C 1 -C 6) alkylamino group, optionally substituted by a (C 1 -C 3) alkoxy (C 1 -C 3) alkyl group, preferably isopropylamino and 1-ethyl- propylamino, or a (Cl-C ⁇ ) dialkylhydrazino group as defined in the formula
  • RI1 represents a hydrogen atom; a (C1-C6) alkyl radical optionally substituted by a heterocycle, preferably tetrahydrofuran; a radical (Cl-
  • - A is a group of type Ac or Ad, and / or
  • R7 is a (C1-C6) alkyl radical, and / or R7 forms with R8 and / or R9 and the nitrogen to which they are attached a heterocycle such as piperazine or homopiperazine, or
  • R7 forms with Ar3 a heterocycle, preferably indoline, and / or
  • L3 and R1 to R9 are as defined in formula (I) above.
  • a family of preferred compounds corresponds to compounds of formula (I) above, in which L 2 represents an amide bond of the L 2b type as defined for formula (I) above. and / or A is oxygen.
  • a sub-family of particular compounds according to the invention consists of the compounds of formula (V) represented below,
  • Va L1 is oxygen and / or Ar1, Ar2 and Ar3 are 4-phenyl radicals.
  • Variant (Va) can preferably be represented as follows:
  • X represents a (C1-C6) alkylamino group, optionally substituted by a (C1-C3) alkoxy (C1-C3) alkyl group, preferably isopropylamino and 1-ethylpropylamino, and / or
  • Y is an oxygen, and / or Z is a radical -NH-, and / or
  • RI1 represents a hydrogen atom; a (C1-C6) alkyl radical optionally substituted by a heterocycle preferentially.
  • tetrahydrofuran a (C1-C3) alkoxy (C2-C6) alkyl radical; a heterocycle such as tetrahydrofuran or tetrahydropyran, and / or - L3 is a (C2-C6) alkylene group, and / or
  • R9 forms with L3 and with the nitrogen atom to which it is bonded a nitrogenous heterocycle, preferably piperidine,
  • R 1 to R 6 and R 8 are as defined in formula (I) above.
  • a family of preferred compounds corresponds to compounds of formula (I) above, in which L2 represents a single bond and / or A is oxygen.
  • a sub-family of particular compounds according to the invention consists of the compounds of formula (VI) represented below,
  • X represents a (C1-C6) alkylamino group, optionally substituted by a (C1-C3) alkoxy (C1-C3) alkyl group, preferably isopropylamino and 1-ethylpropylamino, or a (C1-C6) dialkylhydrazino group such as defined in formula (I) above, preferably 2,2-dimethylhydrazino, and / or
  • Y is an oxygen, and / or
  • Z is a radical -NH-, and / or
  • Ar 2 is a heteroaryl or heterocycle group of indole, benzimidazole, benzoxazole, benzofuran or 2,3-dihydro-benzofuran type, in which case the group
  • L3 is a (C2-C6) alkylene group or a (C3-C8) cycloalkylene group, and / or
  • R.8 and R9 form together with the nitrogen atom to which they are bound a nitrogenous heterocycle, Alternatively, R 9 forms with L 3 and with the nitrogen atom to which it is bonded a nitrogen heterocycle, preferably pyrrolidine, piperidine or homopiperidine, R 1 to R 6 and R 14 are as defined in formula (I) above.
  • L1 is an oxygen and Ar1 and Ar2 are 4-phenyl radicals.
  • Variant (VIb) can preferably be represented as follows:
  • X represents a (C1-C6) alkylamino group, optionally substituted by a (C1-C3) alkoxy (C1-C3) alkyl group, preferably isopropylamino and 1-ethylpropylamino, or a (C1-C6) dialkylhydrazino group such as defined in formula (I) above, preferably 2,2-dimethylhydrazino, and / or
  • Y is an oxygen, and / or
  • Z is a radical -NH-, and / or
  • Ar 3 is a heteroaryl group of the benzoxazole, indole, benzimidazole, benzofuran or 2,3-dihydro-benzofuran type, in which case the group
  • L3 is a (C2-C6) alkylene group or a (C3-C8) cycloalkylene group, and / or R 8 and R 9, as defined in formula (I) above, form together with the nitrogen atom to which they are bonded a nitrogenous heterocycle,
  • R9 forms with L3 and with the nitrogen atom to which it is bonded a nitrogenous heterocycle, preferably pyrrolidine, piperidine or homopiperidine, - R1 to R9 and R14 are as defined in formula (I) ci- above.
  • the compounds of the invention may be in the form of salts, in particular acid addition salts or bases, preferably compatible with a pharmaceutical use.
  • pharmaceutically acceptable acids mention may be made, without limitation, of hydrochloric, sulfuric, phosphoric, acetic, lactic, tartaric, citric, maleic, methanesulphonic or ethanesulphonic acids.
  • pharmaceutically acceptable bases mention may be made, without limitation, of sodium hydroxide, potassium hydroxide, triethylamine and tert-butylamine.
  • the compounds according to the invention may be in the form of different optical isomers, separated or in a mixture, in particular in the form of racemic mixtures.
  • the racemic mixtures can be separated into individual isomers by well known techniques, such as the separation of diastereoisomeric salts formed with optically active acids, followed by conversion to optically active bases.
  • the prodrugs (or prodrugs) of the compounds of formula (I) are also understood in the context of the invention.
  • the prodrugs represent any structure having covalent bonds capable of releasing in vivo a compound of the general formula (I).
  • Different types of prodrugs are well known in the prior art and described in the literature. The following references can notably be cited: Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); Methods in Enzimology, Vol 42, p 309-396, edited by K. Widder et al (Academy Press, 1985); A Textbook ofDrug Design and Development, edited by Krosgaard-Larsen and H.
  • Bundgaard Chapter 5, "Design and Application of Prodrugs," p 113-191 (1991) and H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992).
  • Specific examples of preferred compounds according to the invention are in particular the compounds as described in Examples Nos. 1 to 335, as well as their pharmaceutically acceptable salts, solvates, hydrates, optical and geometrical isomers or their mixtures, more specifically those of Examples no.
  • Particularly preferred compounds according to the invention are: N- (5- ⁇ 4- [3- (1-ethyl- ⁇ ropyl) -ureido] -2-methoxymethyl- ⁇ -phenoxy ⁇ -thiazol-2-yl) -4- - isopropyl-piperidin-4-yloxy) -benzamide
  • the present invention also relates to the compounds of formula (1) chosen from:
  • the present invention describes various synthetic routes, which are illustrated in Schemes 1 to 29 and in the examples, and can be practiced by those skilled in the art, as shown in the examples.
  • the starting compounds can be obtained commercially or synthesized according to methods described in the literature. It is
  • AIBN azoisobutyronitrile
  • APCl + atmospheric positive pressure chemical ionization 0
  • BOC tert-butyloxycarbonyl
  • DIAD diisopropylazadicarboxylate
  • DIA diisopropylethylamine
  • DMSO dimethylsulfoxide 0
  • EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • NMP N-methylpyrollidinone NH 4 OH: ammonium hydroxide (aqueous solution of ammonia)
  • PPP polyphosphoric acid
  • TBAF tetra-n-butylammonium fluoride
  • TBME tertbutyl methyl ether
  • TOTUS O - [(ethoxycarbonyl) cyanomethylenamino] - N, N, N ', N'-tetramethyluronium tetrafluoroborate
  • the present invention also relates to a process for the preparation of the compounds of formula (F), characterized in that: a / amide coupling is carried out between a carboxylic acid (1) and an amine (2) of formulas described in SCHEME 1 above, either by in situ activation of the acid (1) according to procedures known to those skilled in the art, or by means of an activated species isolated from this acid such as the acid chloride or an activated ester such as HOBt ester; or using conventional N-alkylation reactions, an amine of formula (3) described in SCHEME 1 is reacted in the presence of a base with a halide of R8-Hal type, HaI being advantageously a chlorine atom.
  • bromine or iodine and R8 being in this case a group (Cl-C ⁇ ) alkyl; (C3-C8) cycloalkyl; (C3-C8) cycloalkyl (C1-C4) alkyl; N, N- (C1-C4) dialkylamino (C2-C6) alkyl; hydroxy (C2-C6) alkyl; (C1-C4) (C2-C6) alkoxyalkyl; (C1-C6) alkoxycarbonyl (C1-C3) alkyl; (C1-C3) alkylcarbonyloxy (C2-C6) alkyl; mono or polyfluoro (C1-C6) alkyl; or, in the presence of a reducing agent such as sodium borohydride or sodium triacetoxyborohydride, an amine of formula (3) described in SCHEME 1 is reacted with an appropriate aldehyde or ketone according to known procedures of US Pat.
  • a reducing agent such as sodium borohydr
  • an activating agent such as 1 R carbonyldiimidazole or 1,1-thiocarbonyldiimidazole.
  • Another subject of the present invention is a method of preparation for the compounds of formula (V) characterized in that: a compound of formula (5) in which Z 'is -NH 2 is reacted by reacting it with an isocyanate, an isothiocyanate or an amine in the presence of an activating agent, such as carbonyldiimidazole
  • Another subject of the present invention is a process for the preparation of the compounds of formula (VI), characterized in that: a compound of formula (6) in which Z 'is an -NH 2 group is reacted by reacting it with an isocyanate or with an amine in the presence of an activating agent such as 1,4-carbonyldiimidazole.
  • the invention relates to a process for preparing the carboxylic acids of formula (Ia) or (Ia '),
  • A is an oxygen or a methyleneoxy radical
  • L3 represents a (C2-C6) alkylene group; a (C3-C8) cycloalkylene group; bicyclo or polycyclo (C6-C12) alkylene,
  • R5, R6, R8 and R9 are as defined in formula (F).
  • the carboxylic acids of formula (Ia) are advantageously prepared by hydrolysis in an acidic or basic medium of the carboxylic acid precursor (IIa), which is preferably a nitrile or a lower alkyl ester, and which is obtained according to the different lanes indicated on SCHEMES 4a and 4b.
  • the aromatic halogen derivative (8a) for which HaI advantageously represents a fluorine or a chlorine undergoes a SNAr with an aminoalcohol (7a) in a solvent such as DMF, DMA, DMSO or acetone in the presence a base such as NaH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 at temperatures of between -65 ° C. and 150 ° C., from 2 hours to 72 hours.
  • the aminoalcohol (7a) is reacted with phenol (9) in the presence of DIAD and triphenylphosphine in an anhydrous solvent such as THF at temperatures of between -78 ° C.
  • the phenol (9) is reacted with a chlorohalogenated alkyl derivative (32) for which HaI advantageously represents an atom of chlorine, bromine or iodine, in a solvent such as DMF, DMA, DMSO or acetone in the presence of a base such as NaH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 at temperatures between -20 ° C. and 150 ° C., from 2 h to 72 h.
  • a chlorohalogenated alkyl derivative (32) for which HaI advantageously represents an atom of chlorine, bromine or iodine in a solvent such as DMF, DMA, DMSO or acetone in the presence of a base such as NaH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 at temperatures between -20 ° C. and 150 ° C., from 2 h to 72 h.
  • the chlorinated derivative (9 ') thus obtained is treated with a suitable amine in a solvent such as DMF, DMA, NMP, THF, ACN or acetone in the presence of a base such as TEA, DIEA or K 2 CO 3 at temperatures between 0 ° C and 100 ° C, from 1 h to 96 h to generate (1 la).
  • a suitable amine such as DMF, DMA, NMP, THF, ACN or acetone
  • a base such as TEA, DIEA or K 2 CO 3
  • (IIa) is obtained from the intermediate (Hb) by the deprotection of the protecting group GP according to procedures known to those skilled in the art, GP being preferably a BOC, a benzyl or a phthalimide followed by reductive amination or N-alkylation.
  • (1 Ib) is obtained according to the following routes:
  • the aromatic halogenated derivative (8a) undergoes a SNAr with an aminoalcohol (7b), for which GP represents a protective group preferably BOC, benzyl or phthalimide.
  • V amino alcohol (7b) is converted into methanesulphonate derivative following procedures known to those skilled in the art, followed by the reaction with phenol (9) in a solvent such as DMF, DMA, DMSO or acetone in the presence a base such as NaH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 at temperatures between -20 ° C and 15O 0 C, from 2h to 72h.
  • phenol 9
  • a solvent such as DMF, DMA, DMSO or acetone
  • a base such as NaH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 at temperatures between -20 ° C and 15O 0 C, from 2h to 72h.
  • (IIa) can also be obtained according to the route indicated on SCHEME 4c: the alcohol (7b) is reacted with the phenol (9 ') according to a Mitsunobu reaction.
  • the intermediate (Ile) thus obtained is treated with succinimide iodide in acid medium, resulting in the iodinated amine (Hd) which, after a reductive amination or N-alkylation, gives the derivative (Ile).
  • Treatment of (Ile) with copper cyanide in a solvent such as DMF at reflux leads to the intermediate (1 la).
  • the carboxylic acids of formula (Ia ') are advantageously prepared according to the route indicated on SCHEME 4d by hydrolysis in an acidic or basic medium of the carboxylic acid precursor (Ha'), which is preferably a nitrile or an alkyl ester.
  • Ha' carboxylic acid precursor
  • the protecting group GP of the intermediate (Hf) thus obtained is deprotected according to the procedures applied for (1 Ib), followed by a reducing animation or N-alkylation of the amine thus liberated, to generate (11 a ').
  • the invention relates to a process for the preparation of the carboxylic acids of formula (Ib) or (Ib '),
  • Ar 3 is a phenyl radical
  • R9 represents:
  • R5, R6 and R9 are as defined in formula (I)
  • the carboxylic acids of formula (Ib) are advantageously prepared according to the different routes indicated on SCHEMES 5 and 6, starting from the key intermediate.
  • oxazoline (16) The intermediate oxazoline (14) is obtained by a peptide coupling of 2-amino-2-methyl-1-propanol with a benzoic acid of type (12) according to procedures known to those skilled in the art to generate the amide (13) which is cyclized in the presence of an excess of thionyl chloride between 0 ° C and 100 ° C, from 1 hour to 72 hours, in the presence or absence of an inert organic solvent.
  • the oxazoline (16) is subsequently obtained by treatment of (14) with a magnesium derivative prepared, according to procedures known to those skilled in the art, from a commercially available type (15) ketone, in an inert solvent of THF type, between 0 ° C and 100 ° C, from 1 h to 24 h.
  • the amine function of the intermediate (16), protected by a benzyl group (BzI), is first released by catalytic hydrogenation, preferably in the presence of a Pd catalyst on carbon, in a inert solvent such as ethyl acetate, in the presence or absence of acetic acid, at ambient pressure or under high pressure, between 0 ° C. and 100 ° C., from 1 h to 24 h; in a second step, the released amine function reacts with:
  • a suitable aldehyde or ketone in the presence of a reducing agent such as sodium borohydride or sodium triacetoxyborohydride in an inert solvent of the DCM, chloroform, dichloroethane or acetonitrile type in the presence or absence of an acid such as acetic acid at temperatures between 0 ° C and 100 ° C, from 1 hour to 96 hours, according to a reducing animation reaction;
  • a reducing agent such as sodium borohydride or sodium triacetoxyborohydride in an inert solvent of the DCM, chloroform, dichloroethane or acetonitrile type in the presence or absence of an acid such as acetic acid at temperatures between 0 ° C and 100 ° C, from 1 hour to 96 hours, according to a reducing animation reaction
  • an alkyl halide preferably an iodide, bromide or alkyl chloride, in a solvent such as DMF 5 DMA, NMP, THF, ACN, or acetone in the presence of a base such as TEA, DIEA or K 2 CO 3 at temperatures between 0 0 C and 100 ° C, from 1 h to 96 h;
  • a base such as TEA, DIEA or K 2 CO 3
  • the unsaturated carboxylic acids (Ib) are obtained from (17) according to the 3 alternative routes described in SCHEME 5:
  • the carboxylic acids (Ib) and (Ib ') are prepared from a key intermediate ester (20), which is obtained by the hydrolysis of oxazoline (16) in medium acid, preferably with an excess of H 2 SO 4 in an alcohol-type solvent, preferably ethanol, at temperatures between 0 ° C. and 100 ° C., followed by deprotection of the benzyl function under the same conditions than that described for (16).
  • Intermediate (20) leads to acids (Ib) or (Ib ') according to the 3 ways described in SCHEME 6:
  • the intermediate (20) first undergoes dehydration followed by the introduction of the R9 function under the same conditions as those described for (17) and by the hydrolysis of the unsaturated ester (22);
  • the invention relates to a process for preparing the carboxylic acids of formula (Ic),
  • R9 A- represents:
  • R5, R6 and R9 are as defined in formula (I).
  • the carboxylic acids of formula (Ic) are advantageously prepared according to the route indicated on SCHEME 7, starting from the key oxazoline intermediate (16).
  • the dehydration and hydrolysis of (16) as well as the deprotection of the benzyl of the intermediate (23) by hydrogenation according to the conditions described for (16) lead to the saturated ester (24).
  • the introduction of the R9 function is by reductive amination, N-alkylation or acylation of the amine (24) according to the conditions described to obtain (17). This gives the ester (25), which is hydrolyzed leading to the acid (Ic). reduction
  • the invention relates to a process for the preparation of carboxylic acids of formula (Id) or (Id '),
  • Ar 3 is a phenyl radical
  • - A is a (C1-C3) alkylene or (C2-C3) alkylidene group
  • R9 represents:
  • R5, R6 and R9 are as defined in formula (I).
  • the carboxylic acids of formula (Id) and (Id ') are advantageously prepared according to the route indicated on SCHEME 8, from a key phosphite intermediate (27), obtained by treatment with triethylphosphite at 160 ° C. and without solvent a benzyl bromide (26). (27) is then reacted with an N-alkylpiperidone (28) in a basic medium at temperatures close to 0 ° C and under an inert atmosphere in the presence of an anhydrous solvent such as THF, to generate the unsaturated ester ( 29).
  • the acids (Id) are obtained by hydrolysis in an acidic or basic medium of the ester (29), whereas the acids (Id ') are obtained from the acids (Id) by a hydrogenation at atmospheric pressure in solvents such as methanol, ethyl acetate or THF, in the presence of a suitable catalyst, preferably palladium on carbon, at RT for 1 h to 24 h.
  • solvents such as methanol, ethyl acetate or THF
  • the invention relates to a process for preparing the carboxylic acids of formula (Ie), (Ie ') or (Ie "),
  • Ar 3 is an indolyl or indolynyl group
  • L 3 - A / R 6 represents:
  • L3 is a (C2-C6) alkylene radical
  • R5, R6, R8, R9 and R14 are as defined in formula (I).
  • the carboxylic acids of formula (Ic) are advantageously prepared according to the routes indicated in SCHEME 9a, from the key methyl ester intermediate of 1H-indole-5-carboxylic acid (30a).
  • the precursor ester (31a) is obtained by the deprotonation of the NH function of the indole (30a) by the action of a base such as NaH at room temperature for 30 minutes to 2 hours. in a solvent such as THF, DMF, DMA or DMSO, followed by alkylation with an aliphatic halogen derivative of formula (10) at temperatures between 50 0 C and 150 0 C, from 1 h to 24 h.
  • the NH function of the indole (30a) is firstly alkylated, under the conditions described above, with a chlorohalogenated alkyl derivative (32) in which HaI preferably represents a chlorine atom, bromine or iodine.
  • the 1-chloroalkylindole (33) thus obtained is reacted with an amine in the presence of a base such as pyridine, TEA or DIEA, in a solvent such as THF, DMF, DMA or DMSO, between 50 ° C and 150 ° C., from 3 hours to 72 hours to generate the ester (31), which after acid or basic hydrolysis leads to the carboxylic acid (the).
  • R9-N) R9 represents a piperidine of type - are advantageously prepared according to SCHEME 9b: the aniline (30b) is reacted with a piperidone (28) according to a reductive amination reaction to give the intermediate ( 30c), which is cycled to the indole (31b) in strongly acidic medium. The carboxylic acid (1c) is then obtained by the hydrolysis of the ester function of (31b). On the other hand, the indole (31b) is first reduced to indoline (31c) in the presence of a reducing agent such as sodium cyanoborohydride in acetic acid; the ester function of (31c) is then hydrolysed to generate the carboxylic acid (Ie ').
  • a reducing agent such as sodium cyanoborohydride in acetic acid
  • the carboxylic acids of formula (Ie ") are advantageously prepared according to the route indicated on SCHEME 10, from the key intermediate methyl ester of an 1H-Indole-6-carboxylic acid (34).
  • NH-indole is alkylated, according to the procedure described for (31a), with an alkyl halide (35) for which HaI advantageously represents the chlorine, bromine or iodine atom, the alkylated indole (36) thus obtained is reacted with a suitable amine in the presence of formaldehyde and acetic acid at temperatures between 0 0 C and 50 ° C, from 1 h to 24 h, to generate the precursor ester (37) which after hydrolysis acidic or basic leads to the carboxylic acid (Ie ").
  • the invention relates to a process for the preparation of carboxylic acids of formula (If),
  • Ar 3 is a benzofuranyl group
  • R5 and R6 are hydrogen atoms
  • L3 is a (C1-C ⁇ ) alkylene radical
  • R8 and R9 are as defined in formula (I).
  • the carboxylic acids of formula (If) are advantageously prepared according to the route indicated on SCHEME 11.
  • the invention relates to a process for preparing the carboxylic acids of formula (1 g),
  • Ar 3 is a benzimidazolyl group
  • R 5 and R 6 are hydrogen atoms
  • - L3 is a radical (C1 -C6) alkylene, i - R8, R9 and R14 are as defined in formula (I).
  • the carboxylic acids of formula (Ig) are advantageously prepared according to the route indicated on SCHEME 12: the nitrohalogenated benzoic acid (42) for which HaI preferably represents a chlorine or fluorine atom, is subjected to a SNAr by an amine in a solvent such as DMF, DMA, DMSO or acetone in the presence of a base such as Eta or DIEA at temperatures between 0 ° C and 150 ° C, from 2 h to 72 h, followed by the hydrogenation of the nitro function in the presence of a catalyst of Raney Ni or Pd type on carbon, in a solvent such as THF, MeOH, ethanol, methoxyethanol, DCM or DMF, at room temperature, from 2 h to 24 h, to generate orto phenylenediamine (43).
  • a solvent such as DMF, DMA, DMSO or acetone
  • a base such as Eta or DIEA
  • the primary amine function of (43) is acylated by an amino acid of type (44) according to procedures known to those skilled in the art.
  • the orto phenylenediamine monoacylated (43 ') thus obtained is cyclized to benzimidazole in aqueous hydrochloric acid medium in the presence of an alcohol, preferably ethanol, and diethyl ether at temperatures of between 0 ° C. and 100 ° C., of 2 h to 72 h. Under these conditions, the ester (45) is obtained which is hydrolyzed to generate the acid (1 g).
  • the invention relates to a process for preparing the carboxylic acids of formula (Ih-Aa), (Ih-Ab), (Ih-Ac) or (Ih-Ad)
  • - Ar3 is a phenyl, - A represents one of the groups below Aa Ab Ac Ad
  • L3 is a (C2-C6) alkylene radical
  • R5 to R9 are as defined in formula (I).
  • the carboxylic acids of formula (Ih-Aa) are advantageously prepared according to the routes indicated on SCHEME 13:
  • the amine function of the aminobenzoic acid ester (46) for which R is a lower alkyl is acylated by a halogenated aliphatic acid (47) for which HaI preferably represents a chlorine atom, bromine or iodine.
  • the halogen derivative (48) thus obtained is reacted with an appropriate amine in the presence of a base such as pyridine, TEA or DIEA, in a solvent such as THF, DMF, DMA or DMSO, between 50 ° C and 150 ° C, from 3 hours to 72 hours to generate the ester ( 50) which after hydrolysis leads to the acid (Ih-Aa) - according to route 13.11.
  • the ester (50) is directly obtained by acylation of the aniline (46) with an amino acid of the type (44)
  • the carboxylic acids of formula (Ih-Ab) are prepared . advantageously according to SCHEME 14, by coupling a mono-protected phthalic acid (51) with a suitable diamine (52), followed by the hydrolysis of the ester (53).
  • the carboxylic acids of formula (Ih-Ac) and (Ih-Ad) are advantageously prepared according to the routes indicated on SCHEMES 15. According to SCHEME 15a, they are obtained from a halogen derivative (54) for which HaI is preferably a chlorine or fluorine atom and P is a carboxylic acid precursor, preferably a nitrile or a lower alkyl ester:
  • R7 represents a hydrogen atom or a (C1-C6) alkyl group
  • the key intermediate (54) undergoes a SNAr with a diamine of type (52a) in a solvent such as DMF , DMA, DMSO or acetone in the presence of a base such as NaH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 at temperatures between -65
  • an amine of the type (55c), obtained according to procedures known to those skilled in the art, is initially treated with succinimide iodide in acid medium and then with copper cyanide in a solvent such as DMF at reflux to generate the nitrile (55d), which is hydrolyzed in acidic or basic medium leading to. the carboxylic acid (Ih-Ac).
  • a diamine of the type (52a) is reacted with the halogenated benzyl derivative (8c) for which HaI represents. preferably a chlorine or a bromine, in a solvent such as DMF, DMA, DMSO, acetone or ethanol in the presence of a base such as NaH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 at temperatures between -20 ° C. and 150 ° C., from 2 hours to 72 hours.
  • the function P of the derivative (55e) thus obtained is subsequently hydrolysed in an acidic or basic medium to generate the acid (Ih-Ad).
  • the invention relates to a process for the preparation of amines of formula (2a) or (2a '),
  • Ar2 is a thiazole
  • Y and L1 are oxygen atoms
  • Z is an NH radical
  • X represents an N- (C 1 -C 6) alkylamino group
  • - R 1 to R 4 and R 11 are as defined in formula (I)
  • the amines (2a) are advantageously prepared according to the routes indicated in SCHEME 16, starting from the key phenoxythiazole intermediate (60), obtained by reacting 2-amino-5-bromothiazole with a nitrophenol (59) in a solvent. such as DMF, DMA, DMSO or acetone in the presence of a base such as NaH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 at temperatures of between -20 ° C. and 150 ° C., 2 to 72 hours:
  • the nitro function of (60) is hydrogenated to the amine (61) under the conditions described to obtain (43).
  • the amino function of (60) is protected by a BOC group according to procedures known to those skilled in the art and then the nitro group is hydrogenated to generate (62).
  • the amine function of (62) is reacted with an isocyanate or with an appropriate amine or hydrazine in the presence of CDI under the same conditions as those described for (61).
  • the BOC group is then deprotected in an acid medium to generate (2a)
  • R12 and R13 are as defined for the general formula (I)
  • R20 represents a (C1-C6) alkyl group optionally substituted by a (C1-C3) alkoxy (C1-C3) alkyl group
  • R21 and R22 which may be identical or different, represent a hydrogen atom or a (C1-C6) alkyl group optionally substituted by a (C1-C3) alkoxy (C1-C3) alkyl group.
  • the amines (2a ') are advantageously prepared from the amines (2a), according to the route indicated on SCHEME 16: the amine function of (2a) is acylated by a suitable carboxylic acid RlT-CO 2 H, RH' being a (C1-C5) alkyl radical, and the amide function of the intermediate thus obtained is reduced in the presence of an excess of LAH in an anhydrous solvent such as THF, at temperatures of between 0 ° C. and 80 ° C., 12 to 72 hours.
  • an anhydrous solvent such as THF
  • the invention relates to a process for preparing the amines of formula (2b) or (2b ') 5
  • ArI and Ar2 are phenyl radicals
  • Y is an oxygen atom
  • L1 is an oxygen or sulfur atom
  • Z is an NH group
  • the amines (2b) and (2b ') are advantageously prepared according to the routes indicated in SCHEMES 17a-d and 18, from the key intermediates (65), (68a), (68a') and (66b):
  • (65) is treated with an R20-NCO isocyanate or an aminoacylimidazole under the conditions described for (61); or else (65) is acylated by a carboxylic acid R 23 -CO 2 H, R 23 being a N 5 N- (C 1 -C 6) dialkylamino (C 1 -C 3) alkyl radical.
  • the protecting group BOC is subsequently deprotected to generate (2b).
  • (68a) is reacted with an isocyanate or aminoacylimidazole under the conditions described for (61), or it is acylated with a carboxylic acid R23-CO 2 H, followed by hydrogenation to generate the aniline (2b).
  • (2b) is obtained from intermediate (68a), for which R2 is a phenol function protected by the protecting group GP, preferably a methyl.
  • the phenol is first deprotected under conditions known to those skilled in the art, followed by the protection with a BOC group of the aniline (68b) thus obtained, and by the alkylation of the phenol with a halogenated derivative R2 '-Hal, Hal is preferably a chlorine or bromine atom, and R2' is a radical (Cl-C6) alkyl, (Cl-C3) alkoxy (C2-C3) alkyl or N 5 N- (Cl- C3 ) dialkylamino (C2-C3) alkyl.
  • Two alternative routes are then used to generate (2b) from the intermediate (68c) thus obtained: according to the route 17c.L, the OO
  • protecting group BOC is first deprotected, followed by the reaction of the aniline function thus liberated with an isocyanate R20-NCO, with an aminoacylimidazole or with a carboxylic acid R23-CO 2 H, as described in Schemes 17a and 17b , and finally by the hydrogenation of the nitro function; according to the route 17c.IL, the nitro function is first hydrogenated, followed by the reaction of the aniline function thus released with an isocyanate R20-NCO, with an aminoacylimidazole or with a carboxylic acid R23-CO 2 H, as described in Schemes 17a and 17b, and finally by the deprotection of the protective group BOC.
  • urea is obtained by treating aniline (66b) with an R20-NCO isocyanate or an aminoacylimidazole under the conditions described for (61). (66c) then reacts with a halogen derivative (67) for which HaI is preferably a chlorine or fluorine atom, in a solvent such as DMF, DMA, DMSO or acetone in the presence of a base such as NaH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 at temperatures between -20 ° C and 15O 0 C, from 2 h to 72 h, followed by the hydrogenation of the nitro group under the conditions described to obtain ( 43).
  • a halogen derivative for which HaI is preferably a chlorine or fluorine atom
  • the secondary aniline (2b ') is obtained from (2b) according to two alternative ways: according to the route 18.L, (2b) is acylated by a carboxylic acid RH "- CO 2 H, Rl 1" being a (C1-C5) alkyl or (C1-C6) alkoxy (C2-C5) alkyl radical, and the amide linkage of (65 ') thus obtained is reduced in the presence of LAH, under the conditions described to obtain (2a'); according to 18.11.
  • (2b 5 ) is obtained directly by the N-alkylation of aniline (2b) with a halogen derivative Rl 1-Hal in a solvent such as DMF, DMA, DMSO or acetone in the presence of a base such as NaH , Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 at temperatures between -
  • the intermediate (68a) is obtained as described in Scheme 17b, route 17b.L, by the reaction of a phenol or a thiol (66a) and a halogen derivative (67) in a solvent such as DMF , DMA, DMSO or acetone in the presence of a base such as NaH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 at temperatures between -20 ° C and 150 ° C, from 2 hours to 72 hours. h, followed by deprotection of the BOC group.
  • (68a) is obtained from the derivative (66b), unprotected on the aniline function, and the halogen derivative (67), as described above for the reaction of ( 66a).
  • the invention relates to a process for the preparation of amines of formula (2c),
  • ArI and Ar2 are phenyl radicals
  • Y, Z and L1 are oxygen atoms
  • X is an N- (C 1 -C 6) alkylamino group
  • R1 to R4 are as defined in formula (I).
  • the amines (2c) are advantageously prepared according to the route indicated on SCHEME 19, from the key intermediate (70): the chloromethylenecarbonate derivative (71), obtained by treatment of (70) with chloromethyl chloroformate in a solvent such as THF or DCM, at temperatures between -20 ° C and 60 ° C, from 1 hour to 24 hours, is reacted with an appropriate amine to obtain a carbamate derivative which, after hydrogenation of the nitro function according to the conditions described to obtain (43), leads to aniline (2c).
  • a solvent such as THF or DCM
  • the key intermediate (70) is obtained as described in SCHEME 19 by reacting a phenol of the type (69) with a halogen derivative (67), in a solvent such as DMF, DMA, DMSO or acetone in the presence of a base such as NaH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 at temperatures of between -20 ° C. and 150 ° C., from 2 h to 72 h, followed by deprotection of the methoxy group in an acid medium, preferably concentrated HBr or pyridine hydrochloride at temperatures between 20 ° C and 190 ° C, 1 h to 15 h.
  • the radicals R21 and R22 are as defined for SCHEME 16.
  • the invention relates to a process for the preparation of amines of formula (2d),
  • ArI and Ar2 are phenyl radicals
  • X is an N- (Cl-C6) alkylamino group
  • Y is an oxygen atom
  • Z is an NH radical
  • R1 to R4 are as defined in formula (I).
  • the amines (2d) are advantageously prepared according to the route indicated on SCHEME 20: methylenedianiline (72), mono protected with a BOC group, commercially available or obtained according to methods known to those skilled in the art, is treated with an isocyanate R20-NCO or an aminoacylimidazole according to the conditions described for (61), followed by deprotection of the BOC group to generate (2d).
  • radicals R1 and R13 are as defined in general formula (I) and R20 to R22 are as defined for SCHEME 16.
  • the invention relates to a process for preparing the amines of formula (3a) or (3a ') 5
  • Ar 1, Ar 2 and Ar 3 are phenyl radicals, X is an N- (C 1 -C 6) alkylamino group optionally substituted with a group (Cl-
  • C3) alkoxy (C1-C3) alkyl Y is oxygen, Z is NH, L1 is oxygen, A is oxygen or NH,
  • L3 preferably represents a (C2-C6) alkylene group; a (C 3 -C 8) cycloalkylene group optionally substituted by one or more (C 1 -C 3) alkyl groups, a hydroxy group or a (C 1 -C 3) alkoxy group; bicyclo or ⁇ olycyclo (C 6 -C 12) alkylene - R 9, R 1 to R 6 and R 11 are as defined in formula (I).
  • the amines (3 a) and (3 a ') are advantageously prepared as indicated in SCHEMES 21 and 22:
  • amidic coupling of aniline of type (2b), for which L1 is preferably oxygen, is carried out with the key amino acid intermediate.
  • a protecting group GP which preferably represents a benzyl or a BOC.
  • the protecting group GP of the intermediate (78) thus obtained is deprotected according to procedures known to those skilled in the art to generate (3a) According to SCHEME 22, the key intermediate (77) is reacted according to an acylation reaction with a nitroaniline (82).
  • the amide (83) thus obtained is alkylated with a halogenated derivative RI l -HaI in which HaI advantageously represents a bromine or iodine atom, in a solvent such as DMF, DMA, DMSO or acetone in the presence of a base such as NaH, Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 at temperatures between -20 ° C and 15O 0 C, from 2 h to 120 h and then the nitro function is hydrogenated at amine under the conditions described to obtain (43).
  • Intermediate (84) is treated with an R20-NCO isocyanate or aminoacylimidazole under conditions as described for (61) and the protected amine (85) thus obtained is deprotected to generate compound (3 a ').
  • GP advantageously represents a group BOC and R20 to R22 are as defined for SCHEME 16.
  • a protective group GP preferably benzyl or BOC
  • the function P, P being a carboxylic acid precursor, preferably a nitrile or a lower alkyl ester
  • the intermediate (76) thus obtained is hydrolysed with the acid (77) - according to the route 21.IL, an amino acid of the type (la) , for which R 8 is methyl, is demethylated according to procedures described in the literature (see for example Boja et al J. Med Chem, 37, 1994, p 1220) and the amine (80) thus obtained, for which
  • A is oxygen, is protected by a GP group, preferably a BOC, under conditions known to those skilled in the art.
  • Nitroaniline (82) is advantageously prepared according to the route indicated on SCHEME 22, by reacting compounds (63) and (64) as described in SCHEME 17, followed by deprotection of the BOC protecting group of intermediate (81). thus obtained.
  • the invention relates to a process for the preparation of amines of formula (4a) or (4a '),
  • ArI, Ar2 and Ar3 are phenyl radicals, - Z 'is an NH 2 radical,
  • L1 and A are oxygen atoms
  • R8, R11 and R1 to R6 are as defined in formula (I)
  • the amines (4a) and (4a ') are advantageously prepared as shown in SCHEMES 23 and 24:
  • an acid (77) for which A is oxygen and GP is advantageously a BOC group reacts in an amidic coupling with an aniline (82) and the amide (87) thus obtained is alkylated by a derivative halogen Rl 1 -HaI, according to the procedure described in SCHEME 22, followed by deprotection of the protecting group GP.
  • the amino function of (88) is N-alkylated with an alkyl halide, preferably chloride, bromide or iodide, or reacted by reductive amination on an appropriate aldehyde or ketone, according to the procedures described in SCHEME 1, and the group nitro is subsequently hydrogenated to generate aniline (4a 5 ).
  • the invention relates to a process for preparing the amines of formula (5a),
  • ArI, Ar2 and Ar3 are phenyl radicals
  • L1 and A are oxygen atoms
  • Rl 1 is the hydrogen atom
  • R8 and R1 to R6 are as defined in formula (I)
  • the amines (5a) are advantageously prepared as shown in SCHEME 25:
  • aniline (90) is obtained from an aromatic nitrohalogen derivative (89), which undergoes an SNAr with aminoalcohol (7a), followed by a catalytic hydrogenation of the nitro group
  • the carboxylic acid (92) is obtained from an aromatic halogenated nitrile derivative (8 '), which undergoes a SNAr with nitrophenol (91), followed by the hydrolysis of the nitrile group
  • (89), (8 ') and (91) are commercially available or obtained according to procedures known to those skilled in the art; the various reactions involved in SCHEMA 25 are carried out according to protocols already described for the preceding schemes; for (89) and (91) HaI is preferably a chlorine or fluorine atom.
  • the invention relates to a process for the preparation of amines of formula (6a) or (6b),
  • ArI and Ar3 are phenyl radicals
  • Ar 2 is a benzimidazolyl or indolyl radical
  • L1 and A are oxygen atoms
  • R8, R14 and R1 to R6 are as defined in formula (I).
  • the amines (6a) are advantageously prepared as shown in SCHEME 26 from the key nitroaniline intermediate (96): the catalytic hydrogenation of the nitro group of (96) is followed by the acylation of the aniline thus obtained by an acid (1a) and the cyclization of the intermediate (97) in an acidic medium, preferably aqueous HCl, at temperatures between 20 ° C and 100 ° C, for 1 h to 24 h, to generate benzimidazole (98).
  • an acidic medium preferably aqueous HCl
  • the methoxy function of (98) is deprotected in an acid medium and preferably concentrated HBr at temperatures between 20 ° C and 135 ° C for 1 h to 6 h, followed by the reaction, according to a SNAr, with a nitrohalogenated aromatic derivative (89 ') for which HaI represents a chlorine or fluorine atom.
  • the catalytic hydrogenation of the nitro function of (99) generates aniline (6a).
  • the key intermediate (96) is prepared by the N-alkylation of a nitroaniline (94) with an aliphatic halogenated MR-Hall halogen derivative, with Hall being preferably chlorine, bromine or iodine in an anhydrous solvent such as DMF.
  • the amines (6b) are advantageously prepared as shown in SCHEME 27: an (100) type aniline is acylated by an acid (1a).
  • the intermediate (101) thus obtained is cyclized to the indole in the presence of butyl lithium in an anhydrous solvent such as THF, temperatures between 0 ° C. and 30 ° C. for 24 h, followed by alkylation of the indole NH function with an aliphatic R14-Hall halogen derivative according to the conditions described for the alkylation of the intermediate (30a), Scheme 9a.
  • the methoxy function of the intermediate (102) thus obtained is deprotected in an acidic medium, preferably concentrated HBr, at temperatures of between 20 ° C. and 135 ° C. for 1 hour to 6 hours, followed by the reaction according to a SNAr. with a nitrohalogenated aromatic derivative (89 ').
  • the catalytic hydrogenation of the nitro function of (103) generates aniline (6b).
  • the invention relates to a process for the preparation of amines of formula (6c) or (6d),
  • ArI and Ar2 are phenyl radicals
  • Ar 3 is a benzoxazolyl or benzofuranyl radical
  • L1 and A are oxygen atoms
  • R8 and R1 to R6 are as defined in formula (I).
  • the amines (6c) are advantageously prepared as indicated in SCHEME 28: Faminophenol (104) is reacted with the acid chloride (105), which is also used as a solvent for the reaction medium, at temperatures of between 100 ° C. C and 20 ° C, for 2 h to 24 h, to generate benzoxazole benzoic ester (106).
  • the ester (106) is saponified and the phenol thus liberated reacts according to a Mitsunobu reaction with an aminoalcohol (7a), in the presence of triphenylphosphine and DIAD in an anhydrous solvent such as THF, at temperatures of between -20 ° C. C and 30 ° C, for 24 h to 48 h.
  • the methoxy group of the derivative (107) thus obtained is deprotected by pyridine hydrochloride at temperatures of 160 ° C to 190 ° C for 1 h to 15 h, followed by the reaction according to a SNAr with a nitrohalogenated aromatic derivative (89 ') .
  • the catalytic hydrogenation of the nitro function of (108) generates aniline (6c).
  • the amines (6d) are advantageously prepared as indicated in SCHEME 29 from the key benzofuran (109) intermediate, commercially available or prepared according to procedures described in the literature (see René et al Bull, Soc., Chim. 1973, p 2355-2356).
  • the methoxy group of (109) is deprotected by pyridine hydrochloride at temperatures of 160 ° C. to 190 ° C. for 1 hour to 15 hours and the phenol thus liberated is protected in the form of silylated ether by the reaction of chloride. of tertbutyldimethyl silyl in the presence of imidazole and DMAP in a catalytic amount in a solvent such as DMF at AT for 15 h to 24 h.
  • a phenylmethoxy group is subsequently introduced at the 2-position of benzofuran by the reaction of the silylated derivative (110) with the iodinated aromatic compound (III) in the presence of butyl lithium, zinc bromide and palladium tetrakis triphenylphosphine in an anhydrous solvent.
  • anhydrous solvent such as THF at temperatures between -10 ° C and 30 ° C for 15 h to 24 h.
  • the silylated ether of (112) is deprotected with TBAF in a solvent such as THF, at RT for 3 h to 24 h and the phenol thus liberated reacts according to a Mitsunobu reaction with an amino alcohol (7a).
  • the methoxy group of the derivative (113) is deprotected with pyridine hydrochloride as described for (109), followed by the reaction according to a SNAr with a nitrohalogenated aromatic derivative (89 ') to obtain the nitrated intermediate (114). Catalytic hydrogenation of the nitro function of (114) gives aniline (6d).

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