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  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
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  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

• indole derivatives as activators of NURR-1, for their application as a medicine for the treatment of Parkinson's disease.
• the present invention relates to novel indole compounds. preferentially indole benzoic derivatives, as well as their method of preparation and their use as active principle of drugs, in particular for the treatment and / or prevention of diseases involving nuclear NURR-1 receptors. More specifically, this invention relates to the use of these compounds for the manufacture of a medicament for the treatment and / or prevention of neurodegenerative diseases and in particular Parkinson's disease.
• Neurodegenerative diseases are defined as diseases characterized by progressive dysfunction of the nervous system. They are often associated with atrophy of the structures of the affected central or peripheral nervous system. These include, among others, diseases such as Alzheimer's disease, Creutzfeldt-Jakob disease, Huntington's disease, Parkinson's disease. lysosomal diseases. progressive supranuclear palsy, multiple sclerosis and amyotrophic lateral sclerosis.
• Parkinson's disease is a condition that affects approximately four million people worldwide. Although it affects individuals of all ages, it is more common in older people (with 2% of the population of people over 65 living with cancer). It is characterized by a degeneration of dopaminergic neurons of substantia nigra. These types of neurons synthesize dopaminc and use it as neurotransmitters.
• Dopamine plays a central role in the control of voluntary movements, cognitive functions and the development of behaviors associated with emotions.
• the current therapeutic strategy for the treatment of Parkinson's disease is based on the alleviation of symptoms by replacing dopamine deficiency with the administration of a metabolic precursor such as L-OD A.
• a metabolic precursor such as L-OD A.
• the increase in the frequency of this pathology has made it necessary to develop new therapeutic agents, exerting a beneficial role in neuronal survival and differentiation.
• NURR-1 a member of the orphan nuclear receptor superfamily
• the nuclear receptor NURR-1 is involved in the maintenance of the dopaminergic phenotype via the regulation of specific genes of dopaminergic neurons (DA). It also promotes the survival of DA neurons by protecting them from toxic attacks.
• the NURR-1 nuclear receptor thus serves as a specific transcription factor for dopaminergic neurons for which activities could be regulated by modulating dopaminergic neurotransmission in Parkinson's disease.
• RXR Retinoid X Receptor
• RXRa is ubiquitously expressed whereas the expression of RXRy is mainly concentrated in the brain and especially in the striatum. hypothalamus and pituitary gland.
• the complexes formed NURR-1 / RXRa and NURR-1 / RXR "/ are able to regulate transcription in response to an RXR ligand, thus RXR positively modulates the transcriptional activation potential of NURR-1.
• WO2003 / 015780 discloses active heterocyte compounds for the treatment of Parkinson's disease. Furthermore, the documents WO2004 / 072050, FR 2 903 105, FR 2 903 106 and
• FR 2,903,107 disclose activating compounds of the NURR-1 receptor, while the use of heterocyclic compounds modulating the activity of G1B family receptors (of which NURR-1 is a member) is described in WO2005. / 047268.
• WO 00/46196 and WO 99/07678 disclose compounds derived from indole-2-carboxylic acid for their anti-inflammatory activity
• WO 98/41092 discloses indole-2-carboxamide derivatives active against pain
• the present invention relates to Findole-derived compounds which are NURR-1 / RXRcx and URR-1 / RXRy agonists. capable of inhibiting neuronal degeneration observed in Parkinson's disease for their use as a drug and are selected from:
• Cy represents a phenyl group or a 5- or 6-membered heteroaromatic group
• R 1 and R 2 each represent, independently of one another, a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 4 carbon atoms, optionally totally or partially halogenated, a group alkoxy having 1 to 4 carbon atoms, heterocyclic group having 4 to 6 atoms, -SCH 3 , -OC F, -NH 2 , -NHR or -NR 2 ;
• R3 and R4 are each, independently of each other, a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy group or an alkoxy group having 1 to 4 atoms of carbon ;
• R5 and R6 are each, independently of each other, a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy group;
• R7 represents a -COOR group, a carboxylic acid bioisostere group or a -CN group;
• R8 represents:
• an aryl, heteroaryl, cyclic or heterocyclic group unsubstituted or substituted by one, two or three identical or different substituents, chosen from halogen atoms, alkyl groups having 1 to 6 carbon atoms, which may be totally or partially halogenated; , or possibly hydroxylated. alkoxy groups having 1 to 6 carbon atoms, optionally totally or partially halogenated, phenoxy group.
• R9 represents a hydrogen atom, a halogen atom or an alkyl group having
• R represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
• the invention relates to the abovementioned compounds for their use as therapeutically active substances, in the treatment and / or prevention of non-germicidal diseases, in particular Parkinson's disease, as well as than the pharmaceutical compositions containing them.
• the invention relates to the use of at least one compound of formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient for the preparation of a medicament for the treatment of diseases in which the NURR-1 receptor is involved, including neurodegenerations, such as in particular Parkinson's disease.
• the present invention relates to novel indole-derived compounds which are URR-1 / RXRa and NURR-1 / RXRy agonists, capable of inhibiting neuronal degeneration observed in Parkinson's disease, which are chosen from compounds of formula (I) as defined above, excluding the following compounds:
• the present application aims to cover a method of preventing and / or treating diseases in which the URR-1 receptor is involved, especially neurodegenerative diseases, especially Parkinson's disease, comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition containing such a compound.
• alkyl group means a saturated hydrocarbon chain which may be linear and having at least 1 carbon atom or branched or cyclic and having at least 3 carbon atoms (also referred to as " cycloalkyl”).
• an alkyl group having 1 to 6 carbon atoms may be methyl, ethyl, propyl, butyl, pentyl, hexyl. 1-methylethyl. 1-methylpropyl, 2-methylpropyl. 1,1-dimethylethyl. 1-methylbutyl, 1,1-dimethylpropyl. 1-methylpentyl, 1,1-dimethylbutyl. cyclopropyl. cyclobutyl, cyclopentyl, cyclohexyl or c yc 1 open ty 1 met thy 1 e.
• halogen means an atom of bromine, fluorine or chlorine.
• halogenated alkyl group means an alkyl group as defined above in which one (or more) hydrogen atom (s) is (are) replaced by an atom (s) halogen. Examples of such groups include difluoromethyl or trifluoromethyl groups.
• hydroxylated alkyl group means an alkyl group as defined above in which a hydrogen atom is replaced by a hydroxyl group.
• alkoxy group means an OR group in which R is an alkyl group as defined above.
• R is an alkyl group as defined above.
• methoxy groups there may be mentioned methoxy groups. ethoxy, propoxy, butoxy, 1-methylethoxy, 1,1-dimethylethoxy, 1-methylpropoxy. 2-methylpropoxy or cyclopropylethoxy.
• aryl group means a monocyclic or bicyclic aromatic hydrocarbon group having from 6 to 12 carbon atoms.
• ryle group mention may be made of phenyl and naphthyl groups.
• heteroaryl group means a monocyclic, bicyclic or tricyclic aromatic hydrocarbon group comprising at least one heteroatom in one of the rings, said heteroatom being chosen from nitrogen, oxygen and sulfur (and also their oxidized form such as N-oxide, sulfoxide or sulfone).
• a heteroaryl group may be a 5- or 6-membered monocyclic group, a 7 to 11-membered bicyclic group or a 10 to 16 membered tricyclic group, said group containing 1 to 3 heteroatoms, preferably 1 or 2 heteroatoms. selected from nitrogen, oxygen and sulfur.
• heteroaryl group As an example of a 5- or 6-membered monocyclic heteroaryl group (also referred to as "heteroaromatic group"). mention may be made of pyrrolyl, pyrazolyl and imidazolyl groups. oxazolyl, isoxazolyl, triazolyl, furanyl, thienyl, thiazolyl, isothiazolyl. thiadiazolyl, pyridyl, pyridazinyl. pyrimidinyl. pyrazinyl and triazinyl.
• bicyclic heteroaryl group mention may be made of benzothiazolyl, benzoxazolyl, benzoxazinone and benzoxadia / olvle groups. 1,3-benzodioxolyl, benzofuryl. benzopyrazinyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzopyranyl. pyrrolopyridyl, furopyridinyl, isoquinolinyl, quinolinyl and imidazothiazolyl.
• cyclic group means a saturated or partially unsaturated hydrocarbon group containing 1 to 3 rings having 3 to 8 carbon atoms per ring.
• a monocyclic group mention may be made of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl and cyclohexenyl groups.
• heterocyclic group means a cyclic group as defined above, one (or more) carbon atom (s) (optionally associated with one or more hydrogen atoms) is (are) replaced by a (or more) heteroatom (s) selected in particular from oxygen and nitrogen.
• heterocyclic group mention may be made of monocyclic groups such as tetrahydrofuryl, piperidinyl, pyrrolidinyl, tetrahydropyranyl or morpholinyl groups. thiamorpholinyl.
• bicyclic groups such as dihydroquinazolinyl, dihydrobenzofuryl, especially 2,3-dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzoxazinyl, especially 3,4-dihydro-1,4-benzoxazinyl and 3-oxo-3,4-dihydro-1,4 benzoxazinyl, dihydrobenzodioxinyl, especially 2,3-dihydrobenzodioxinyl, dihydrobenzopyranyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydroindolyl, dihydrobenzodioxepinyl, especially 3,4-dihydro-2H-1,5-benzodioxepinyl.
• carboxylic acid bioisosteric group means a group having chemical and physical similarities and producing biological properties substantially similar to a carboxylic group as described in Lipinski, Animal Reports in Medicinal Chemistry. 1986, 21, p. 283 "Bioisosterism In Drug Design”; Oraham, Theochem. 1995,343, p.105-109 "Thcorctical Studies Applied To Drug Design: Ab initio Electronic Distributions In Bioisosteres”.
• acyl hydrazine groups optionally substituted acyl hydrazine carboxylates, optionally substituted alkyl and aryl sulfonyl carbamoyl, optionally substituted sulfonamides, oxadiazolones, optionally substituted phosphonates, optionally isothiazoles. substituted, optionally substituted isoxazoles, optionally substituted isoxazolones, tetrazoles, optionally substituted thiazolidine-diones, optionally substituted thioxothiazolidinones.
• the compounds of formula (1) in which the substituents R5 and R6 are different have an asymmetric center. For these compounds, the invention covers both the racemic compound and each optical isomer considered separately.
• the compounds of formula (I) in which R7 represents a COOH group are carboxylic acids which can be used in the form of free acids or in the form of salts, said salts being obtained by combining the acid with a mineral base or non-toxic organic, preferably pharmaceutically acceptable.
• a mineral base it is possible to use, for example, hydroxides of sodium, potassium, magnesium or calcium.
• organic bases it is possible to use, for example, amines, amino alcohols, basic amino acids such as lysine or arginine or compounds carrying a quaternary ammonium function such as, for example, betaine or choline.
• a first family of compounds according to the invention corresponds to formula I in which:
• Cy represents a group of formula
• A represents a carbon atom monosubstituted by a hydrogen atom or a nitrogen atom
• R 1 and R 2 each independently represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms. optionally totally or partially halogen, an alkoxy group having 1 to 4 carbon atoms, a heterocyclic group having 4 to 6 atoms or an OC group F -,;
• R3 and R4 are each, independently of each other, a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy group or an alkoxy group having 1 to 4 atoms of carbon ;
• R5 and R6 are each, independently of each other, a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy group;
• R7 represents a COOR group, a carboxylic acid bioisosteric group or a -CN group
• R8 represents:
• an aryl, heteroaryl, cyclic or heterocyclic group unsubstituted or substituted with one, two or three identical or different substituents, chosen from halogen atoms, alkyl groups having 1 to 6 carbon atoms, optionally totally or partially halogenated; or optionally hydroxylated, alkoxy groups having 1 to 6 carbon atoms, optionally totally or partially halogenated, phenoxy group, cyclic groups having 3 to 6 carbon atoms, aryl and heteroaryl groups, in particular phenyl and pyrazolyl, not substituted or substituted with one or two substituents, identical or different, selected from halogen atoms and alkyl groups having 1 to 4 carbon atoms, SCHF 2 and acyl-morpholine groups;
• R9 represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 4 carbon atoms,
• R represents a hydrogen atom or an alkyl group (linear or branched) having 1 to 4 carbon atoms.
• a preferred family of compounds according to the invention consists of the compounds of formula I above, in which:
• R8 represents:
• a naphthyl group a thienyl group which is unsubstituted or substituted with a phenyl group; a pyridinyl group which is unsubstituted or substituted with a substituent chosen from alkoxy groups having 1 to 4 carbon atoms, phenoxy group, 6-membered heterocyclic groups, in particular the morpholinyl group; a benzofuranyl group; a group of methyl-substituted hydrobenzonitrile;
• a tetrahydronaphthyl group unsubstituted or substituted with one to four alkyl groups having 1 to 4 carbon atoms, an unsubstituted or alkyl-substituted dihydrobenzodioxinyl group having 1 to 4 carbon atoms, an unsubstituted or substituted dihydrobenzodioxazinyl group; an alkyl group having 1 to 4 carbon atoms, a dihydrobenzodioxepinyl group, a piperidinyl group, a dihydrobenzofuranyl group unsubstituted or substituted by one or two alkyl groups having 1 to 4 carbon atoms, a dihydrobenzopyranyl group which is unsubstituted or substituted by one or two alkyl groups having 1 to 4 carbon atoms.
• the compounds of formula I in which at least one of the following conditions is carried out are more particularly preferred:
• Cy represents a phenyl, pyridyl, furanyl ring. thienyl. pyrrolyl or thiazolyl;
• RI represents a hydrogen atom, a chlorine atom, a bromine atom, a -CF 3 , OCH 3 , -OCF 3 , -C (CH 3 ) 3 or pyrrolidinyl group;
• R2 represents a hydrogen atom
• R3 represents hydrogen atom *, chlorine atom, fluorine atom, hydroxy, methyl or methoxy
• R4 represents a hydrogen atom or the fluorine atom
• R5 and R6 each independently represent a hydrogen atom, a methyl group or hydroxy group or together with the carbon atom to which they are attached an ethylene or anortho group;
• R8 represents a phenyl group substituted with a branched C3-C4 alkyl group; and R9 represents a hydrogen atom, a fluorine atom or a methyl group, preferably a hydrogen atom.
• R 7 group represents a carboxylic acid bioisosteric group and more particularly the optionally substituted isoxazolone groups, oxadiazolones. optionally substituted alkyl and aryl radicals.
• R 5 and R 6 represent a hydrogen atom
• R 5 and R 6 represent a hydrogen atom
• R 1 and R 2 each represent, independently of one another, a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 4 carbon atoms, optionally totally or partially halogenated, a stern alkoxides having 1 to 4 carbon atoms, -SC3 ⁇ 4, - ( ⁇ 3 ⁇ 4, a heterocyclic group having 4 to 6 atoms, -N3 ⁇ 4 » -NHR or -NR 2 ;
• R represents a hydrogen atonia or an alkyl group having 1 to 4 carbon atoms
• R9 represents a hydrogen atom " a halogen atom, an alkyl group having 1 to
• R8 represents an alkyl group having 1 to 6 carbon atoms, an aryl or heteroaryl group, substituted or unsubstituted, a cyclic or heterocyclic group, substituted or unsubstituted; in the presence of a solvent, such as, for example, tetrahydrofuran. and a base, such as sodium hydride, at room temperature for about 2 to 24 hours to obtain the compound of formula IV:
• R8 and R9 retain the same meaning as in the starting compounds; b) reacting the compound of formula IV with a borate of formula B (OAlk) in which Alk represents an alkyl group having 1 to 4 carbon atoms, such as in particular B (OiPr); base, such as butyl lithium (BuLi) or lithium diisopropyl amide (LDA), and a solvent such as tetrahydrofuran or ether, at a temperature of about -100 ° C at room temperature, preferably at -78 ° C for a period of about 1 to 24 hours, preferably 18 hours, to obtain the compound of formula V:
• R3 and R4 each independently of one another represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms;
• R7 represents a -COOR group wherein R represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, a carboxylic acid bioisosteric group or a -CN group, and
• Cy represents a phenyl group or a 5- or 6-membered heteroaromatic group
• R1, R2, R3, R4, R7, R8, R9 and Cy retain the same meaning as in the starting compounds;
• R 1 and R 2 each independently represent a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 4 carbon atoms, optionally totally or partially halogenated, an alkoxy group having 1 to 4 carbon atoms, a group -SCH 3 , -OC F ", a heterocycle group having 4 to 6 atoms, -N3 ⁇ 4, -HR or -NR 2 ;
• LG represents an iodine, bromine, tosylate or trifluoromethanesulfonate group and R represents a hydrogen atom or a linear or branched alkyl group having 1 to 14 carbon atoms;
• R 1, R 2, R 8 and LG retain the same meaning as in the starting compounds
• R3 and R4 each independently of one another represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms;
• R5 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms
• R7 represents a group -COOR, wherein R represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, a carboxylic acid bioisosteric group or a -CN group;
• Cy represents a phenyl group or a 5- or 6-membered heteroaromatic group
• a palladium catalyst such as, for example, bis (triphenyl phosphine) palladium chloride. and an organic base such as diethylamine or triethylamine, in a solvent such as dimethylformamide, under reflux, for 30 minutes to 8 hours, to obtain the compound of formula Ia: wherein R1, R2, R3, R4, R5, R7, R8 and Cy retain the same meaning as in the starting compounds;
• R1, R2, R3, R4, R7, R8 and Cy retain the same meaning as in the starting compound;
• R5 and R6 are each, independently of each other, a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy group;
• the compound of formula VIII above can be obtained from the compound of formula VII above by a sulfonylation process comprising the passage through a disulfonyl compound of formula X:
• R1, R2, R8 and LG have the same meaning as previously indicated.
• a mixture is formed in variable proportions of the monosulphonylated product of formula VIII and of the disulfonylated product of formula X by a treatment identical to that described in step a) of the second process, the reaction being however carried out for a much longer period of up to 3 weeks; then
• the crude reaction product thus obtained is treated directly with potassium hydroxide in a solvent such as in particular dioxane for a period of about 2 to 24 hours.
• R3, R4, R5, R7 and Cy have the same meaning as in product IX, with ethynylmagnesium bromide at a temperature of 0 ° C for a period of 10 minutes to 18 hours.
• R 9 represents a hydrogen atom or a halogen atom and R 7 is a carboxylic group -COOH
• R 9 represents a hydrogen atom or a halogen atom
• R 7 is a carboxylic group -COOH
• R3 and R4 are each independently of one another, a hydrogen atom, "a halogen atom, an alkyl group having 1 to 4 carbon atoms, hydroxy or alkoxy group having 1 to 4 carbon atoms;
• R5 and R6 each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy group;
• R represents an alkyl group having 1 to 4 carbon atoms
• Cy represents a phenyl group or a 5- or 6-membered heteroaromatic group
• a palladium-based catalyst such as, for example, bis (triphenylphosphine) palladium chloride, and an organic base such as diethylamine or triethylamine, in a solvent such as, for example the mixture is refluxed for 30 minutes to 8 hours to give the compound of formula XII:
• R1, R2, R3, R4, R5, R6, R and Cy retain the same meaning as in the starting compounds
• R1, R2, R3, R4, R5, R6, R and Cy retain the same meaning as in the starting compounds
• H al represents a halogen atom
• R1, R2, R3, R4, R5, R6, R8 and Cy retain the same meaning as in the starting compounds
• R9 represents a hydrogen atom or a halogen atom
• R1, R2, R3, R4, R5, R6, R8, R and Cy retain the same meaning as in the starting compounds;
• Certain compounds according to the invention can also be prepared according to a fifth method consisting of:
• R3 and R4 are each, independently of each other, a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 atoms of carbon ;
• R7 represents a -COOR group wherein R represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, a carboxylic acid bioisosteric group or a -CN group;
• Cy represents a phenyl group or a 5- or 6-membered heteroaromatic group
• R1, R2, R3, R4, R7, R8, R9 and Cy retain the same meaning as in the starting compound
• R5 and R6 are each, independently of each other, a hydrogen atom, a halogen atom, a hydroxy group;
• R1, R2, R3, R4, R5, R6, R8, R9 and Cy retain the same meaning as in the starting compound.
• Certain compounds according to the invention may also be prepared according to a sixth process consisting of:
• R3 and R4 are each, independently of each other, a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy group or an alkoxy group having 1 to 4 atoms of carbon ;
• Cy represents a phenyl group or a 5- or 6-membered heteroaromatic group
• LG represents an iodine, bromine atom or a tosylate or trifluoromethanesulfonate group
• a base such as in particular butyl lithium (BuLi) or lithium diisopropyl amide (LDA)
• a solvent such as tetrahydrofuran or ether.
• R5 and R6 are each, independently of each other, a hydrogen atom, a halogen atom, a hydroxy group;
• R1, R2. R3, R4, R5, R6, R8, R9 and Cy retain the same meaning as the starting compound.
• R 5, R 6 and R 9 represent a hydrogen atom
• a seventh process consisting of:
• step a) of the above-mentioned second process reacting the compound of formula VIII prepared according to step a) of the above-mentioned second process with prop-2-yn-1-ol in the presence of cuprous iodide and a palladium-based catalyst, for example bis (triphenyl phosphine) palladium (II) chloride, and an organic base such as for example dimethylamine or triethylamine, in a suitable solvent such as for example N, N-dimethyltormamide. at a temperature between room temperature and the reflux temperature of the solvent, for a period of between 30 minutes and 6 hours, to obtain the compound of formula XVII:
• a palladium-based catalyst for example bis (triphenyl phosphine) palladium (II) chloride
• organic base such as for example dimethylamine or triethylamine
• R1, R2 and R8 retain the same meaning as in the starting compounds: b) reacting the compound of formula XVII above with a source of bromine, such as, for example, phosphorus tribromide, in a suitable solvent, for example dichloromethane, at room temperature for a period of about 1 to 6 hours, to obtain the compound of formula XVIII;
• a source of bromine such as, for example, phosphorus tribromide
• R1, R2 and R8 retain the same meaning as in the starting compounds
• Cy represents a phenylc group or a heteroaromatic group having five or six members
• R3 and R4 are each, independently of each other, a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy group. an alkoxy group having 1 to 4 carbon atoms;
• R7 represents a -COOR group, a carboxylic acid bioisostere group such as the sulfonamide group or a -CN group;
• a suitable solvent such as, for example, a mixture of ethanol and dioxane
• a palladium-based catalyst for example the complex Pd (dppf) Cl 2 , CH 2 Cl 2
• a suitable base such as potassium carbonate
• R1, R2, R3, R4, R7, R8 and Cy retain the same meaning as in the starting compounds.
• R1, R2 and R8 retain the same meanings as in the starting compounds
• R1, R2 and R8 retain the same meaning as in the starting compounds
• R1, R2 and R8 retain the same meaning as in the starting compounds
• R I. R2 and R8 retain the same meaning as in the starting compounds.
• carboxylic acid function of the compounds of formula Ib, Id and Ik may advantageously be replaced by a carboxylic acid bioisosteric group according to methods well known to those skilled in the art, such as the methods described below.
• R 7 represents a bioisosteric group acylhydrazine, acyl hydrazine carboxylate or oxadiazolone
• R 7 represents a bioisosteric group acylhydrazine, acyl hydrazine carboxylate or oxadiazolone
• a coupling agent such as, in particular, the pair of reagents 1- (3-diethylaminopropyl) -3-ethyl-carbodiimide (EDCI ) / 1-hydroxy-7-azabenzotriazole (HOAT).
• an organic solvent such as in particular toluene at room temperature and for 2 to 24 hours to give acylhydrazine carboxylate of formula Im:
• R1, R2, R3, R4, R5, R6, R8, R9 and Cy retain the same meaning as in the starting compounds; and R represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms;
• the compounds of formula I according to the invention, wherein R7 is a bioisostere sulfonylcarbamoyl group or a derivative group may be prepared by a method comprising coupling the compound of formula Ib, Id. Ii or Ik with a sulfonamide in the presence of a coupling agent such as in particular the pair of reagents 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride / 4-dimethylaminopyridine (EDCI / D AP) in an organic solvent such as dichloromethane at room temperature for 12 to 24 hours; hours.
• a coupling agent such as in particular the pair of reagents 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride / 4-dimethylaminopyridine (EDCI / D AP) in an organic solvent such as dichloromethane at room temperature for 12 to 24
• R 7 represents an isoxazole bioisostere group or a derivative group such as an isoxazolone group
• R 7 represents an isoxazole bioisostere group or a derivative group such as an isoxazolone group
• R1, R2, R3, R4, R5, R6, R8, R9 and Cy retain the same meaning as in the starting compounds.
• the cyano function represented by R7 in the compounds of formula I or II can be advantageously replaced by a carboxylic acid bioisosteric group according to methods well known to those skilled in the art, such as the methods described below.
• the compounds of formula I according to the invention wherein R7 represents a tetrazole bioisostere group, may be prepared by a process of coupling the compound of formula I or formula II, wherein R7 represents a cyano group, with azidotrimethyltin. in a solvent such as ortho-xylene, to form, after 10 to 24 hours, at the reflux of the solvent, the tetrazole of formula Ip:
• R1, R2, R3, R4, R5, R6, R8, R9 and Cy retain the same meaning as in the starting compounds.
• the compounds of formula I according to the invention, wherein R7 represents an oxadiazole bioisostere group or a derivative group such as an oxadiazolone group can be prepared according to a process consisting of:
• R1, R2, R3, R4, R5, R6, R8, R9 and Cy retain the same meaning as in the starting compounds.
• R 7 represents a thiazolidine bioisostere group or a derived group such as the thia / olidinedione group or the thioxothiazolidinone group which may be prepared according to a process consisting in carrying out a condensation of Knövenagel a thiazolidine on the compound of formula XXIII in the presence of an inert solvent such as toluene, a catalyst such as piperidine and in the presence of acetic acid.
• R 7 represents a thiazolidine bioisostere group or a derived group such as the thia / olidinedione group or the thioxothiazolidinone group which may be prepared according to a process consisting in carrying out a condensation of Knövenagel a thiazolidine on the compound of formula XXIII in the presence of an inert solvent such as toluene, a catalyst such as piperidine and in the presence of acetic acid.
• the compound of formula XXIII may be obtained according to a process of identical embodiment in step c) of the seventh process, by reacting the compound of formula XVIII above with the compound of formula XXIV:
• the compounds of the invention in the form of salts of the acids of formula Ib, Id, Ik, Ii with a mineral or organic base can be obtained in a conventional manner, using the methods well known to those skilled in the art, for example by mixing stoichiometric quantities of the acid of formula Ib, Id, Ik, Ig, and the base in a solvent, such as, for example, water or a hydroalcoholic mixture, and then freeze-drying the resulting solution.
• a solvent such as, for example, water or a hydroalcoholic mixture
• LiOH lithium hydroxide
• MgS0 magnesium sulphate
• NMP N-methylpyrrolidone
• the melting points (F) were measured using an automatic apparatus (Optimelt) and the Nuclear Magnetic Resonance spectral values were characterized by the chemical shift ( ⁇ ) calculated with respect to the TMS (tetramethylsilane), by the number of protons associated with the signal and by the form of the signal (s for singlet, d for doublet, t for triplet, q for quadruplet, m for multiplet, seven for septet, dd for doublet of doublet).
• the working frequency (in MegaHerz) and the solvent used are indicated for each compound.
• ⁇ 1.15 (d, 6H), 2.92 (sep, 1H), 3.73 (s, 3H). 4.48 (s, 2H), 6.57 (s, 1H), 6.82 (dd, 1H), 7.00 (d, 1H), 7.41 (d, 2H), 7.58; (d, 1H), 7.64 (dd, 1H), 7.73 (d, 2H). 7.96 (s, 1H), 8.27 (d, 1H), 12.51 (brs, 1H).
• ⁇ 1.16 (s, 911). 3.85 (s, 3H), 4.53 (s, 2H), 6.67 (s, 1H), 7, 18 (m, 2H), 7.47 (t, 1H), 7.68 (s, 1H), m, 4H), 7.83 (m-1H), 7.97 (s, 1H), 8.27 (d, 1H).
• a stock solution was prepared by mixing 2.9 g of the ester obtained according to Preparation VII in solution in 14.5 ml of NMP and 696 mgd sodium hydride (60% suspension in oil for 20 minutes) 500 ⁇ l of this solution was added to a solution of 148 mg of 4- (1,1-dimethylpropyl) benzenesulphonyl chloride in 700 ⁇ l of NMP, and The reaction mixture was stirred for 18 hours at room temperature, the solvent was then evaporated under reduced pressure, and 500 ul of a saturated aqueous ammonium chloride solution was added to the residue thus obtained and the reaction mixture was stirred.
• ⁇ 0.52 (t, 3H), 1, 18 (s, 6H). 1.55 (q, 2H), 4.51 (s, 2H), 6.60 (s, 1H), 7.29 (d, 2H). 7.45 (d.2H), 7.65 (d, 1H), 7.69 (d, 2H), 7.85 (d, 2H), 7.98 (s, 1H). 8.27 (d, 1H), 12.92 (brs, 1H).
• ⁇ 2.10 (q, 2H), 4.14 (t, 2H), 4.21 (t, 2H), 4.50 (s, 2H), 6.65 (s, 1H), 7.01 (d, 1H), 7.10 (d, 1H), 7.31 (d, 2H), 7.40 (dd, 1H), 7.65 (dd, 1H), 7.87 (d, 2H); , 7.98 (s, 1H), 8.23 (d, 1H), 12.88 (brs, 1H).
• ⁇ 3.90 (s, 3H), 4.55 (s, 2H), 6.58 (s, 1H), 6.77 (d, 1H), 7.37 (d, 2H), 7.56 (t, 1H), 7.67 (m, 2H), 7.77 (d, 1H), 7.88 (d, 2H), 7.96 (s, 1H), 8.05 (m, 1H) , 8.17 (m, 1H), 8.26 (d, 1H), 12.87 (brs, 1H).
• ⁇ 1.10 (s, 6H), 1.17 (s, 6H), 1.58 (s, 4H), 4.50 (s, 2H), 6.57 (s, 1H), 7.29 (d, 2H), 7.47 (m, 2H), 7.64 (s, 1H), 7.66 (d, 1H), 7.86 (d, 2H), 7.97 (s, 1H); , 8.31 (d, 1H), 12.91 (brs, 1H).
• ⁇ 1.22 (s, 9H), 4.52 (s, 2H), 6.60 (s, 1H), 7.29 (d, 2H), 7.51 (d, 2H), 7.65 (d, 1H), 7.70 (d, 2H), 7.85 (d, 2H), 7.98 (s, 1H), 8.27 (d, 1H), 12.88 (brs, 1H). ).
• ⁇ 1.02 (d, 6H). 2.35 (s, 3H), 2.82 (sep, 1H), 4.36 (s, 2H), 6.67 (s, 1H), 7.09 (d, 1H), 7.22 (d, 1H), , 2H), 7.31 (d, 1H), 7.44 (dd, 1H), 7.60 (dd, 1H), 7.82 (d, 2H), 8.02 (d, 1H), 8 , 06 (s, 1H), 12.86 (broad, 1H).
• ⁇ 1.19 (s, 9H), 3.85 (s, 3H), 4.55 (s, 2H), 6.60 (s, 1H), 7.39 (d, 2H), 7.50 (d, 1H), 7.59 (m, 2H), 7.73 (m, 3H), 7.92 (d, 2H), 8.29 (s, 1H).
• the reaction mixture was stirred for 15 minutes at 0 ° C., then hydrolysed with 100 ml of a 10% aqueous solution of NH 4 Cl, and then extracted 3 times with 50 ml of ethyl acetate.
• the combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure.
• the residue obtained was purified by chromatography on silica gel eluting with a cyclohexane / ethyl acetate mixture (90/10, v / v).
• the reaction mixture was heated for 1 hour at 100 ° C in a microwave apparatus, then diluted in water and extracted twice with ethyl acetate.
• the combined organic phases were dried over magnesium sulphate and evaporated under reduced pressure.
• the reaction was then restarted under the same conditions as before (same amount of reagent).
• the reaction mixture was heated for 1 hour at 100 ° C in a microwave apparatus and then diluted in water and extracted twice with ethyl acetate.
• the combined organic phases were dried over magnesium sulphate and evaporated under reduced pressure.
• the residue was purified by silica gel chromatography eluting with cyclohexane / ethyl acetate (90:10 v / v).
• ⁇ 0.60 (m, 2H). 0.96 (m, 2H), 1.92 (m, 1H), 3.85 (s, 3H), 4.55 (s, 211). 6.64 (s, 1H), 7.3 (d, 1H), 7.38 (m, 4H), 7.54 (d, 1H), 7.65 (d, 111). 7.90 (d, 2H), 7.97 (s, 1H), 8.23 (d, 1H).
• ⁇ 1.34 (m, 611). 3, 11 (m, 4H). 3.84 (s, 3H). 6.28 (bs, 111), 6.32 (bs, 1H), 6.72 (s, 1H), 7.31 (dd, 1H), 7.47 (d 2H), 7, 71 (d, M), 7.87 (d, 1H), 7.93 fd, 2H).
• the reaction mixture was stirred for 2 hours at -70 ° C, then diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and then evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a cyclohexane / ethyl acetate mixture (90/10, v / v), then with a dichloromethane / ethyl acetate mixture (80/20; v).
• ⁇ 1.22 (s, 9H), 3.90 (s, H). 6.54 (s, 1H), 6.60 (d, 1H), 6.74 fd, 1H), 7.51 (t, 1H), 7.66 (dd, 1H), 7.73 (m.p. , 1H), 7.80 (d, 1H). 7.81 (m, I II). 7.97 (m, 2H), 8.25 (d, 1H), 8.39 (dd, 1H), 8.98 (dd, 1H).
• the reaction medium was diluted with ethyl acetate and washed successively with water and then with a saturated aqueous solution of NaCl.
• the organic phase was dried over magnesium sulfate and concentrated under reduced pressure to give 14.7 g of [1 -
• [3- (1,1-Dimethylethyl) phenyl Isulfonyl] -5-trinuoromethyl-1H-indol-2-yl] methanol as a brown oil (yield 96%).
• ⁇ 8.26 (d, 1H), 8.00 (s, 1H). 7.93 (m, 1H), 7.80 (d, 1H), 7.75 (d, 1H), 7.64 (m, 1H), 7.54 (t, 1H), 6.91 (s). , 1H), 5.68 (t, 1H), 4.88 (d, 2H), 1.20 (s, 9H).
• the reaction medium was heated for 20 minutes in the microwaves at 120 ° C., then diluted with ethyl acetate and washed successively with water and then with a saturated aqueous solution of NaCl.
• the organic phase was dried over magnesium sulfate and concentrated under reduced pressure.
• the residue obtained was purified by preparative LC-UV (sunfire Cl 8) eluting with a mixture of H2O / CH 3 CN / 0.1% TFA.
• the fractions containing the expected product were combined and concentrated to dryness under reduced pressure to give 15 mg of 5- [1- (3- (1,1-dimethylethyl) benzenesulfonyl) -5-trifluoromethyl-1H-indol-2-acid.
• ⁇ 12.60 (s, 1H), 8.29 (d, 1H), 8.19 (s, 1H), 7.96 (s, 1H), 7.65 (dd, 1H), 7, 05 (dd, 1H), 6.91 (d, 1H), 6.75 (d, 1H), 6.61 (s, 1H), 6.44 (s, 1H), 4.51 (s, 2H); ), 4.23 (t, 2H), 3.24 (t, 2H), 2.78 (s, 3H).
• ⁇ 8.53 (s, 1H), 8.25 (d, 1H), 8.03 (d, 1H), 7.91 (s, 2H), 7.70 (m, 2H), 7.48 (m, 2H), 6.98 (m, 1H), 4.28 (m, 2H), 2.04 (s, 3H), 1.31 (t, 3H), 1.25 (s, 9H); .
• thiophene-2-carboxylic acid methyl ester (Example 80) in 10.2 ml of dichloromethane was added successively and dropwise 1.05 g (9.02 mM) of triethylsilane, 0.02 g of trifluoroacetic acid and 1, 28 g (9.02 mM) boron trifluoride diethyl ether.
• the reaction was instantaneous and the reaction medium was evaporated and then purified by chromatography on silica gel, eluting with a cyclohexane / ethyl acetate mixture (95/5 v / v).
• ⁇ 8.29 (d, 1H), 7.97 (s, 1H), 7.72 (d, 1H), 7.68 (d, 1H), 7.60 (d, 1H), 7, 56 (m, 1H), 7.52 (m, 1H), 7.40 (t, 1H), 6.95 (d, 1H), 4.72 (s, 2H), 3.75 (s, 3H). ), 2.80 (s, 3H), 1, 12 (s, 9H).
• ⁇ 8.35 (s, II), 8.30 (d 1H), 8.00 (s, 1H), 7.64 (m, 3H), 7.58 (d, 1H), 7.43 (t, III). 4.88 (s, 2H), 4.28 (q, 2H), 2.29 (s, 3H), 1.29 (t, 3H), 1, 15 (s, 9H).
• thiophene-2-carboxylic acid obtained according to Example 90 in 2.00 ml of dichloromethane was added 136.4 mg (0.36 mM) of pyridinium dichromate, then the reaction medium was stirred overnight at room temperature.
• the reaction medium was filtered through a nylon membrane and the solid was rinsed with dichloromethane.
• the solvent of the filtrate was concentrated under reduced pressure and the evaporation residue was purified by chromatography on silica gel using a cyclohexane / ethyl acetate eluent (90/10, v / v). The fractions containing the expected product were combined and concentrated to dryness under reduced pressure.
• ⁇ 1.13 (d, 6H), 2.91 (sep, 1H), 3.73 (s, 3H), 3.78 (s, 3H), 4.45 (s, 2H), 6.41 (s, 1H), 6.82 (dd, 1H), 7.02 (d, 1H), 7.33 (dd, 1H), 7.38 (d, 2H), 7.59 (dd, 1H), 7.62 (d, 1H), 7.70 (d, 211), 8.06 (d, 1H).

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