Novel acetylcholin esterase inhibitors and their use for prevention and treatment of obsessive-compulsive disorder and neurodegenerative diseases

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof. The invention also relates to the use of the compounds of formula (I) as a medicament, in particular for the prevention or treatment of obsessive-compulsive disorder and related behaviors, including addiction, obsessive-compulsive disorder and dietary disorder, and neurodegenerative diseases, such as Parkinson's disease or Alzheimer's disease.

Description

TECHNICAL FIELD

[0001] The present application relates to new acetylcholinesterase inhibitors, in particular for the prevention and / or treatment of acetylcholine-related disorders, such as compulsive disorders, including eating disorders, addiction, obsessive compulsive disorder and neurodegenerative diseases. BACKGROUND

[0002] Acetylcholine (ACh) is the main neuromodulator of the striatal network and a key transmitter at neuromuscular junctions. Upon ACh exocytotic release, its action is rapidly terminated by hydrolysis catalyzed by an enzyme called acetylcholinesterase (AChE). AChE inhibitors (AChEI) inhibit this reaction and prevent the breakdown of ACh into choline and acetate. Thus, AChEI can increase the extracellular level of ACh at the central nervous system and at neuromuscular junctions and prolong its action time.

[0003] Applicants recently discovered that striatal ACh also plays a major role in compulsive disorders, in particular eating disorders (Favier et al., The Journal of Clinical Investigation, 2020, 130, 12, p. 6616-6630). Eating disorders (e.g. anorexia nervosa and bulimia nervosa) affect up to 10% of the population in full-blown and subthreshold forms. Anorexia nervosa is the psychiatric disorder with the highest mortality rate (~ 5% per decade). Eating disorders result from abnormal processing of habitual behaviors. The understanding of the neural basis of anorexia nervosa is very limited and, as a result, there is no specific biological and pharmacological treatment for this severe disorder.

[0004] Cholinergic interneurons are key regulators of the striatum and habit formation. To study the role of ACh in habitual behavior, Applicants silenced ACh signaling in the striatum in a mouse model of vesicular acetylcholine transporter deletion (VAChTcKO mice). Applicants subsequently demonstrated that VAChTcKO mice reduced ACh transmission and mice were more prone to develop excessive habits. To understand whether these excessive habits could lead to eating disorders, Applicants subsequently used a pathological eating model of VAChTcKO mice: the activity-based anorexia model (ABA, a model of anorexia nervosa (Klenotich and Dulawa, 2012)). In the ABA model, mutant mice lacking ACh in the striatum were more prone to self-starve than control mice.

[0005] Based on these unexpected findings, the present inventors surmised that acetylcholinesterase inhibitors could be used for the prevention and / or treatment of compulsive disorders.

[0006] Despite the variety of acetylcholinesterase inhibitors on the market, especially for Alzheimer's disease, they often cause severe side effects (dizziness, nausea and vomiting, heart problems, etc.).

[0007] Therefore, there is a constant need for new acetylcholinesterase inhibitors with higher affinity for AChE and limited peripheral effects. SUMMARY

[0008] In this context, the inventors have surprisingly designed and developed new acetylcholinesterase inhibitors (AChEI) that act only in the brain (and not in the body). This mode of action therefore limits the neuromuscular effects of the AChEI and the undesirable peripheral side effects. These new compounds have been shown to be useful for preventing and / or treating obsessive-compulsive disorders, in particular eating disorders such as anorexia.

[0009] According to a first aspect, the present application relates to a compound of formula (I):

[0010]

[0011] or a pharmaceutically acceptable salt and / or solvate thereof,

[0012] wherein

[0013] represents a single or double bond,

[0014] X is an oxygen atom or a N-OH group,

[0015] R 1 and R 2 each independently is H, an optionally substituted nitrogen-containing heterocyclyl group, an optionally substituted C1-C6 aliphatic chain or an optionally substituted aryl group, wherein up to 4 methylene units of the aliphatic chain are optionally replaced by O, C(O), NH or N-C1-C6 alkyl, provided that at least one of R 1 and R 2 is an optionally substituted nitrogen-containing heterocyclyl group,

[0016] L1and L2each independently is a divalent group derived from a C1-C 12 aliphatic chain, wherein one or more, preferably one to four methylene units are optionally replaced by arylene, -O-, -S-, -C(=O)-, -SO2- or -N(C1-C6 alkyl)-, wherein the aliphatic chain is optionally substituted,

[0017] p and n each independently is 0 or 1, provided that when R 1 is an optionally substituted nitrogen-containing heterocyclyl group, p is 1, when R2 n is 1 when R is an optionally substituted nitrogen-containing heterocyclyl group, and

[0018] R' is H, halogen, optionally substituted C1-C6aliphatic chain, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted C1-C6alkyl-aryl, wherein up to 4 methylene units of the aliphatic chain are optionally replaced by O, C(O), NH, or N-C1-C6alkyl.

[0019] According to a second aspect, the present application relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined above, a pharmaceutically acceptable salt and / or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0020] According to a third aspect, the present application also relates to a compound of formula (I) according to the present application, a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to the present application, for use as a medicament.

[0021] The present application also relates to the use of a compound of formula (I) according to the present application, a pharmaceutically acceptable salt and / or solvate thereof, or of a pharmaceutical composition according to the present application, as a medicament or for the manufacture of a medicament.

[0022] The present application also relates to a method for the prevention and / or treatment of obsessive-compulsive disorders, including addiction, eating disorders and obsessive-compulsive disorders, and Alzheimer's disease, comprising administering to a person in need thereof an effective dose of a compound of formula (I) according to the present application, a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to the present application.

[0023] DETAILED DESCRIPTION

[0024] DEFINITIONS

[0025] The term "stereoisomer" as used in the present application refers to stereoisomers in terms of configuration, more particularly to optical isomers. Thus, optical isomers which are not mirror images of one another are referred to as "diastereomers" and optical isomers which are mirror images of one another are referred to as "enantiomers". An equimolar mixture of two enantiomers of a chiral compound is referred to as a racemic mixture or racemate.

[0026] For the purposes of the present application, the term "pharmaceutically acceptable" is intended to mean useful for the manufacture of a pharmaceutical composition and generally safe and non-toxic for pharmaceutical use.

[0027] Within the framework of the present application, the term "pharmaceutically acceptable salt and / or solvate" is intended to mean a salt and / or solvate of a pharmaceutically acceptable compound as defined above, which has the pharmacological activity of the corresponding compound.

[0028] Pharmaceutically acceptable salts include:

[0029] (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, fumaric acid, glucoheptonic acid, glycolic acid, glutamic acid, glyceric acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, succinic acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, and the like, and

[0030] (2) base addition salts formed when ionic groups present in the compounds are replaced by a metal ion (such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion), or complexed with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0031] Acceptable solvates for therapeutic use with the compounds of the application include conventional solvates, e.g., those formed from the presence of a solvent, during the final step of the preparation of the compounds of the application. By way of example, mention can be made of solvates formed from the presence of water (these solvates are also known as hydrates) or from the presence of ethanol.

[0032] As used in the present application, the term "halogen" means a fluorine, bromine, chlorine, or iodine atom.

[0033] The term "C x -C y An "aliphatic chain" refers to a straight-chained or branched hydrocarbon chain which is completely saturated or contains one or more degrees of unsaturation, but which is not aromatic, comprising x to y carbon atoms, especially 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. According to the present application, the term "aliphatic chain" includes substituted or unsubstituted, straight-chained or branched, alkyl, alkenyl, or alkynyl groups.

[0034] As used in the present application, the term "C1-C6alkyl" refers to a straight-chained or branched, monovalent saturated hydrocarbon chain containing 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0035] As used in the present application, the term "C2-C6alkenyl" refers to a straight-chained or branched, monovalent unsaturated hydrocarbon chain containing 2 to 6 carbon atoms and containing at least one double bond, including but not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

[0036] As used in the present application, the term "C2-C6alkynyl" refers to a straight-chain or branched-chain monovalent unsaturated hydrocarbon chain containing from 2 to 6 carbon atoms and containing at least one triple bond, including but not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.

[0037] As used in the present application, the term "C1-C 12 alkanediyl" refers to a straight-chain or branched-chain divalent saturated hydrocarbon chain containing from 1 to 12 carbon atoms, including but not limited to methanediyl (methylene), ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl and the like.

[0038] As used in the present application, the term "C1-C 12 alkenediyl" refers to a straight-chain or branched-chain divalent unsaturated hydrocarbon chain containing from 1 to 12 carbon atoms and containing at least one double bond, including but not limited to ethenediyl, propenediyl, butenediyl, pentenediyl, hexenediyl and the like.

[0039] As used in the present application, the term "aryl" refers to an aromatic hydrocarbon group preferably comprising from 6 to 12 carbon atoms and comprising one or more fused rings, such as but not limited to a phenyl or naphthyl group. Advantageously, it is a phenyl group.

[0040] As used in the present application, the term "heterocyclyl" refers to an aromatic or non-aromatic, saturated or unsaturated, monocyclic or polycyclic group (including fused, bridged or spirocyclic rings) comprising preferably from 5 to 10, in particular 5, 6, 9 or 10 atoms in the ring, wherein one or more, in particular one to four, advantageously one or two, of the ring carbon atoms are each replaced by a heteroatom selected from a sulfur atom, an oxygen atom and a nitrogen atom. When the heterocyclyl is a "nitrogen-containing heterocyclyl", it means that at least one of the heteroatoms in the ring is a nitrogen atom. It is not excluded that a "nitrogen-containing heterocyclyl" according to the application comprises, in addition to the at least one nitrogen atom, also an oxygen atom and / or a sulfur atom in the ring. When a nitrogen-containing heterocyclyl according to the application is attached to the rest of the molecule via a nitrogen atom, it can be in the form of a cation, whereby the valence is 4.

[0041] When the heterocyclyl is aromatic, it can be referred to in the present disclosure as a "heteroaryl". Examples of "nitrogen-containing heteroaryl" include but are not limited to pyrrolyl, pyridyl, thiazinyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridazinyl, purinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, isoindolyl or indolyl. Preferably, in the context of the present application, the nitrogen-containing heteroaryl is not a pyridyl group.

[0042] When the heterocyclyl group is a non-aromatic compound, it can be referred to as "heterocycloalkyl" in the present disclosure. Examples of "nitrogen-containing heterocycloalkyl" include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, indolinyl and isoindolinyl.

[0043] As used in the present application, the term "Ci-C6alkyl aryl" refers to an alkyl group as defined above substituted with an aryl group as defined above. Advantageously, the "Ci-C6alkyl aryl" is a benzyl group.

[0044] In the context of the present application, "optionally substituted" groups means that said group is optionally substituted with one or more, preferably one or two, substituents which can be in particular selected from the group consisting of halogen, Ci-C6alkyl, Ci-C6haloalkyl, C2-C6alkene, C2-C6alkyne, aryl, N3, oxo, NR a R b , COR c , CO2R d , CONR e R f , OR g , N + R h R i R j , CN and NO2, wherein R a to R j are each independently H, Ci-C6alkyl or aryl, preferably H or Ci-C6alkyl. Advantageously, the "optionally substituted" groups are substituted with one or two substituents selected from the group consisting of Ci-C6alkyl and OR g , wherein R g is H or Ci-C6alkyl.

[0045] The term "Ci-C6haloalkyl" refers to a Ci-C6alkyl chain as defined above wherein one or more hydrogen atoms are replaced by a halogen atom selected from fluorine, chlorine, bromine or iodine, preferably a fluorine atom. For example, it is a CF3group.

[0046] In the context of the present application, "unsaturated" means that the hydrocarbon chain can contain one or more degrees of unsaturation, i.e. a double bond C=C or a triple bond C≡C, advantageously one degree of unsaturation.

[0047] The term "leaving group" refers to an atom or group of atoms capable of readily departing from a molecule with a lone pair of electrons, breaking the bond between it and the molecule.

[0048] Within the framework of the present application, the term "pharmaceutical composition" is understood as a composition having prophylactic and therapeutic properties.

[0049] The term "prodrug" refers to a typically pharmacologically inactive or less active derivative of an active drug, which is bio-transformed by chemical or enzymatic reactions within the cell or in the body to release the active drug. In the context of the present invention, "a typically pharmacologically inactive or less active derivative" is to be understood in the sense that the prodrug has no relevant activity in vitro in terms of inhibiting the acetylcholinesterase active site. However, the oxidized form is active in in vitro and in vivo experiments, as such conditions allow the transformation needed to provide the active drug. Prodrugs can offer a number of advantages over the parent drug, for example, greater brain penetration and thus higher activity in the brain, greater stability, higher bioavailability.

[0050] In the context of the present invention, the prodrug compounds defined by the present disclosure have an enhanced activity in the brain. Upon penetration into the brain, the prodrug compounds are oxidized to give the corresponding active drug, i.e. a potent acetylcholinesterase inhibitor.

[0051] Compounds of formula (I)

[0052] The compounds of formula (I) for use according to the present invention can be in the form of a stereoisomer or a mixture of stereoisomers, for example a mixture of enantiomers, diastereomers or tautomers, in particular a racemic mixture.

[0053] In the context of the present invention, the nitrogen atom of the compounds of formula (I) can be trivalent or tetravalent. When they are tetravalent, for example when they are protonated, the nitrogen atom is in the cationic form.

[0054] In particular, the nitrogen of the piperidine moiety bearing the benzyl group in the compounds of formula (I) can be trivalent or tetravalent. When the nitrogen atom is tetravalent, it is in the cationic form, i.e. ammonium. 1 and / or R 2 The nitrogen atom of the nitrogen-containing heterocyclyl group can be trivalent or tetravalent. When it is tetravalent, it is in the cationic form, i.e. ammonium. This is especially true when the heterocyclyl group is a heteroaryl group.

[0055] In particular, the nitrogen of the piperidine moiety bearing the benzyl group in the compounds of formula (I) can be trivalent or tetravalent. When the nitrogen atom is tetravalent, it is in the cationic form, i.e. ammonium.

[0056] In the context of the present invention, the nitrogen-containing heterocyclyl group (for R 1 and / or R 2 ) generally does not contain any heteroatom other than a nitrogen atom.

[0057] In the context of the present invention, the nitrogen-containing heterocyclyl group (for R 1 and / or R 2The group is selected from pyrrole, pyridinyl, thiazinyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridazinyl, purine, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, isoindolyl, indolyl, piperidinyl, piperazinyl, pyrroleyl, pyrazolylyl, imidazolyl, thiazolyl, isothiazolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indololinyl, and isoindololinyl.

[0058] According to some implementation plans, R 1 and R 2 Each is independently a nitrogen-containing heterocyclic group or a C1-C6 aliphatic chain with optional substituted components, wherein up to four methylene units of the aliphatic chain are optionally substituted with O, C(O), NH or N-C1-C6 alkyl groups, provided that R 1 and R 2 At least one of them is an optionally substituted nitrogen-containing heterocyclic group.

[0059] According to some implementation plans, R 1 and R 2 Each is independently a nitrogen-containing heterocyclic group that is either the same or different as defined below and can be optionally substituted.

[0060] According to the preferred implementation scheme, R 1 and R 2 Different, R 1 and R 2 One of them is an optional substituted nitrogen-containing heterocyclic group as defined below, and the other is H, an optional substituted C1-C6 aliphatic chain or an optional substituted aryl group, preferably H, an optional substituted C1-C6 aliphatic chain (e.g., C1-C6 alkyl) or an optional substituted aryl group (e.g., phenyl), more preferably H, C1-C6 alkyl or aryl (e.g., phenyl), and even more preferably C1-C6 alkyl, including methyl, ethyl, propyl, tert-butyl, n-butyl, especially methyl.

[0061] According to a preferred embodiment, R 1 and / or R 2 R is preferred 1 and R 2 One of them is an optionally substituted nitrogen-containing heterocyclic group, which has 1 to 4 nitrogen atoms substituting carbon atoms in the ring, preferably 1 or 2, more preferably 1.

[0062] According to a preferred embodiment, R 1 and / or R 2 R is preferred 1 and R 2One of them is an optionally substituted nitrogen-containing heterocyclic group, wherein the optionally substituted nitrogen-containing heterocyclic group is selected from the optionally substituted pyrrole, pyridinyl, thiazinyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridazinyl, purine, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, isoindolyl, indolyl, piperidinyl, piperazinyl, pyrroleyl, pyrazolylyl, imidazolyl, thiazolyl, isothiazolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indololinyl, and isoindololinyl.

[0063] In one particular implementation scheme, R 1 and / or R 2 R is preferred 1 and R 2 One of them is an optionally substituted nitrogen-containing heteroaryl group, wherein the optionally substituted nitrogen-containing heteroaryl group is particularly selected from pyrrole, thiazinyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridazinyl, purine, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, isoindolyl, or indolyl.

[0064] In another specific implementation, R 1 and / or R 2 R is preferred 1 and R 2 One of them is an optionally substituted nitrogen-containing heterocyclic alkyl group, wherein the optionally substituted nitrogen-containing heterocyclic alkyl group is particularly selected from piperidinyl, piperazinyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, thiazoalkyl, isothiazolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indololinyl and isoindololinyl.

[0065] Preferably, when R 1 and / or R 2 When the substituent is a nitrogen-containing heterocyclic group, it is either unsubstituted or substituted by one or more, preferably one or two, more preferably one substituent, wherein the substituent is selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C2-C6 alkenes, C2-C6 alkynes, aryl groups, N3, oxo, NH2, NH-C1-C6 alkyl groups, N(C1-C6 alkyl)2, C(O)H, CO2-C1-C6 alkyl groups, CO2H, CN, and NO2, preferably halogens (e.g., Cl), OH, NH2, C1-C6 alkyl groups (e.g., methyl), and O-C1-C6 alkyl groups (e.g., methoxy).

[0066] Preferably, R 1 and / or R 2 R is preferred 1 and R 2 One of them is a group corresponding to one of the following formulas:

[0067]

[0068] wherein

[0069] R 3 to R 8 are each independently selected from H, halogen, OH, NH2, NH-Ci-C6alkyl, Ci-C6aliphatic chain, aryl, heteroaryl, and Ci-C6alkyl-aryl, wherein up to 4 methylene units of the aliphatic chain are optionally replaced by O, C(O), NH, or N-Ci-C6alkyl, the aliphatic chain, aryl, heteroaryl, or alkyl-aryl being optionally substituted, or

[0070] R 3 -R 4 , R 4 -R 5 , R 5 -R 6 , and R 6 -R 7 one or more of the pair together with the carbon atom to which they are attached form a 5- or 6-membered aromatic or non-aromatic, optionally substituted ring,

[0071] R 9 and R 10 are each independently one or more substituents selected from H, Ci-C6aliphatic chain, aryl, heteroaryl, and Ci-C6alkyl-aryl, wherein up to 4 methylene units of the aliphatic chain are optionally replaced by O, C(O), NH, or N-Ci-C6alkyl, the aliphatic chain, aryl, heteroaryl, or alkyl-aryl being optionally substituted,

[0072] represents a single or double bond, and

[0073] represents R 1 and the remainder of the molecule.

[0074] It is understood that in formula (C), R 9 is one or more substituents borne by the carbon atom of the nitrogen-containing ring, and R 10 is one or more substituents borne by the carbon atom of the phenyl moiety attached to the remainder of the molecule.

[0075] More preferably, R 3 to R 8 are each independently selected from H, halogen, OH, NH2, NH-Ci-C6alkyl, Ci-C6alkyl, and aryl (e.g., phenyl), or

[0076] R 3 -R 4 , R 4 -R 5 , R5 -R 6 and R 6 -R 7 one or more, preferably one, of the substituents selected from the group consisting of halogen, OH, NH2, NH-Ci-C6-alkyl, Ci-C6-alkyl and O-Ci-C6-alkyl, form together with the carbon atom to which they are attached a 5- or 6-membered aromatic or non-aromatic ring, which is unsubstituted or substituted by one or more, preferably one, of the substituents selected from the group consisting of halogen, OH, NH2, NH-Ci-C6-alkyl, Ci-C6-alkyl and O-Ci-C6-alkyl.

[0077] According to a preferred embodiment, R 8 is H or Ci-C6-alkyl, for example methyl, ethyl or isopropyl, in particular methyl.

[0078] According to a preferred embodiment, R 3 -R 4 , R 4 -R 5 , R 5 -R 6 and R 6 -R 7 one of the pairs forms together with the carbon atom to which they are attached a 6-membered aromatic ring, for example phenyl, which is unsubstituted or substituted by one or more, preferably one, of the substituents selected from the group consisting of halogen, OH, NH2, NH-Ci-C6-alkyl, Ci-C6-alkyl and O-Ci-C6-alkyl, for example methoxy, R 3 to R 7 are H.

[0079] According to a preferred embodiment, R 9 and R 10 are each independently one or more, preferably one, of the substituents selected from the group consisting of H, Ci-C6-alkyl, halogen, OH, NH2and NH-Ci-C6-alkyl. More preferably, R 9 is one substituent selected from the group consisting of OH and halogen, for example Cl, R 10 is H.

[0080] When R 1 or R 2 is of formula (B) as defined above, the nitrogen attached to the rest of the molecule can be in a neutral or cationic state, depending on the bond the bond is a single or a double bond, provided that the valency of the nitrogen is not exceeded by 4.

[0081] In a particular embodiment, R 1 and / or R 2 , preferably R 1 and R 2one of R and R is an optionally substituted 8- to 10-membered bicyclic nitrogen-containing heterocyclyl, especially selected from quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, which is unsubstituted or substituted by one or more, preferably one, substituent selected from halogen, OH, NH2, NH-Ci-C6-alkyl, Ci-C6-alkyl or 0-Ci-C6-alkyl (e.g. methoxy).

[0082] The compounds of formula (I) as defined herein encompass active compounds, i.e. drugs, and prodrugs thereof.

[0083] According to one particular embodiment, when the compound of formula (I) is a prodrug, R 1 and / or R 2 , preferably R 1 and R 2 are each independently selected from hydrogen, halogen, OH, NH2, NH-Ci-C6-alkyl, Ci-C6-alkyl or 0-Ci-C6-alkyl (e.g. methoxy). 1 one of R and R is an optionally substituted 8- to 10-membered bicyclic nitrogen-containing heterocyclyl, especially selected from quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, which is unsubstituted or substituted by one or more, preferably one, substituent selected from halogen, OH, NH2, NH-Ci-C6-alkyl, Ci-C6-alkyl or 0-Ci-C6-alkyl (e.g. methoxy). 2 According to this embodiment, the heterocycloalkyl group can undergo an oxidation reaction after the prodrug has penetrated into the brain, thereby generating the active drug.

[0084] According to one particular embodiment, when the compound of formula (I) is a prodrug, R 1 or R 2 is a nitrogen-containing heterocyclyl, it is an optionally substituted nitrogen-containing heteroaryl, i.e. the ring is aromatic. In this embodiment, if the other of R 1 or R 2 is also a nitrogen-containing heterocyclyl, it is preferably the same or a different nitrogen-containing heteroaryl.

[0085] According to one particular embodiment, when the compound of formula (I) is a prodrug, R 1 and / or R 2 is an optionally substituted nitrogen-containing heterocycloalkyl, it is preferably selected from pyrrolyl, thiazinyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridazinyl, purinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, isoindolyl and indolyl, preferably quinolinyl and isoquinolinyl.

[0086] According to one particular embodiment, when the compound of formula (I) is a prodrug, R 1 and / or R 2 is an optionally substituted nitrogen-containing heteroaryl, it is preferably selected from piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl and isoindolinyl, preferably dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0087] In the context of this invention, the pharmaceutical compound is an oxidized form of the corresponding prodrug compound. For example, if the prodrug contains a heterocyclic alkyl group, it is oxidized and thus aromatized in the corresponding pharmaceutical compound to obtain the corresponding heteroaryl group.

[0088] X is preferably an oxygen atom.

[0089] L1 and L2 are each independently derived from C1-C 12 The linker of the divalent group of the aliphatic chain, wherein one or more, preferably one to four, more preferably one or two methylene units are optionally substituted with aryl, -O-, -S-, -C(=O)-, -SO2- or -N(C1-C6 alkyl)-, wherein the aliphatic chain is optionally substituted with one or more, preferably one, substituents selected from OH, halogen, C1-C6 alkyl or aryl, preferably OH or C1-C6 alkyl.

[0090] According to a preferred embodiment, L1 and L2 are each independently derived from unsubstituted C1-C 12 The divalent groups of the aliphatic chain are preferably C1-C. 12 Alkyl, C2-C 12 The linker is an alkyl group or a linker of the formula -CH=, especially a C1-C6 alkyl group or a linker of the formula -CH=. More preferably, L1 and L2 are each independently a linker of a methylene group or a linker of the formula -CH=. It should be understood that when the linker is of the formula -CH=, it directly binds to R via a double bond. 1 It is connected, and linked to an oxygen atom via a single bond.

[0091] In the compound of formula (I), n and p are each independently 0 or 1, provided that R 1 When R is an optionally substituted nitrogen-containing heterocyclic group, p is 1, and when R 2 When R is an optionally substituted nitrogen-containing heterocyclic group, n is 1. Therefore, when R 1 When the nitrogen-containing heterocyclic group is not optionally substituted, p can be 0 or 1, and when R 2 When the nitrogen-containing heterocyclic group is not optionally substituted, n can be 0 or 1. Preferably, when R 1 When the nitrogen-containing heterocyclic group is not optionally substituted, p is 0, and when R 2 When R is not an optionally substituted nitrogen-containing heterocyclic group, n is 0. In other words, when R... 1 or R 2 When the R is not an optionally substituted nitrogen-containing heterocyclic group, 1 or R 2 It is preferable to connect directly to the oxygen atom of the indanone group, rather than connecting via connector L1 or L2.

[0092] According to a preferred embodiment, R' is H, halogen, Ci-C6alkyl, aryl, heteroaryl or Ci-C6alkyl-aryl, said alkyl, aryl, heteroaryl or alkyl-aryl being unsubstituted or substituted by one or more, preferably one, substituent selected from OH, halogen, Ci-C6alkyl or aryl, in particular OH or Ci-C6alkyl. Preferably, R' is H, halogen or Ci-C6alkyl, such as methyl or ethyl. More preferably, R' is H.

[0093] In a particular embodiment, R 1 is an optionally substituted nitrogen-containing heterocyclyl group as defined in the present disclosure, R' is H or Ci-C6alkyl, such as methyl or ethyl, p is 1, n is 0, R 2 is Ci-C6alkyl, including methyl, ethyl, propyl, t-butyl, n-butyl. Preferably, R 1 is an optionally substituted nitrogen-containing heterocyclyl group as defined in the present disclosure, p is 1, L1 is a divalent radical derived from a Ci-C 12 aliphatic chain, preferably a methylene or a linker of formula -CH=, R 2 is methyl, n is 0, R' is H.

[0094] According to a particular embodiment, in the compound of formula (I), R 1 is selected from quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, which are unsubstituted or substituted by one or more, preferably one, substituent selected from halogen, OH, NH2, NH-Ci-C6alkyl, Ci-C6alkyl or O-Ci-C6alkyl (e.g. methoxy), R 2 is methyl, n is 0, p is 1, L1 is a divalent radical derived from a Ci-C 12 aliphatic chain, preferably a methylene or a linker of formula -CH=, R' is H.

[0095] In other embodiments, R 2 is an optionally substituted nitrogen-containing heterocyclyl group as defined in the present disclosure, R' is H or Ci-C6alkyl, such as methyl or ethyl, p is 0, n is 1, R 1 is Ci-C6alkyl, including methyl, ethyl, propyl, t-butyl, n-butyl. Preferably, R 2 is an optionally substituted nitrogen-containing heterocyclyl group as defined in the present disclosure, p is 0, L2 is a divalent radical derived from a Ci-C 12 aliphatic chain, preferably a methylene or a linker of formula -CH=, R 1 is methyl, n is 1, R' is H.

[0096] In other embodiments, in the compound of formula (I), R 2selected from quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, which is unsubstituted or substituted by one or more, preferably one, substituent selected from halogen, OH, NH2, NH-Ci-C6-alkyl, Ci-C6-alkyl or 0-Ci-C6-alkyl (e.g. methoxy), R 1 is methyl, n is 1, p is 0, L2is a divalent radical derived from a Ci-C6-alkanediol, preferably methylene or a linker of the formula -CH=, R' is H. 12 is methyl, n is 1, p is 0, L2is a divalent radical derived from a Ci-C6-alkanediol, preferably methylene or a linker of the formula -CH=, R' is H.

[0097] According to one preferred embodiment, the compound of formula (I) is selected from the group consisting of:

[0098]

[0099]

[0100]

[0101]

[0102]

[0103] In some embodiments, the compound of formula (I) is selected from compounds 1' to 76', wherein X is N-OH and the remaining substituents are defined as in compounds 1 to 76, respectively. For example, in compound 1', X is N-OH and the remaining substituents are defined as in compound 1, i.e. R' is H, R 2 is CH3, L1is -CH2-, p is 1, n is 0, R 1 is dihydroquinolinyl.

[0104] In one particular embodiment, the compound of formula (I) according to the application is a prodrug as defined above, in particular selected from the group consisting of:

[0105]

[0106]

[0107] In one particular embodiment, the compound of formula (I) according to the application is a drug as defined above, in particular selected from the group consisting of:

[0108]

[0109]

[0110]

[0111]

[0112] In a particular and preferred embodiment, the compound of formula (I) according to the application is selected from:

[0113]

[0114]

[0115] and the hydrochloride salt thereof.

[0116] In a more preferred embodiment, the compound of formula (I) according to the application is:

[0117]

[0118] or the hydrochloride salt thereof.

[0119] Processes for preparing compounds of formula (I)

[0120] The compound of formula (I) as described above, or a pharmaceutically acceptable salt and / or solvate thereof, can be obtained by conventional methods well known in the art. In particular, the compound of formula (I) as described above, or a pharmaceutically acceptable salt and / or solvate thereof, can be obtained by a process comprising the following steps:

[0121] (a) reacting a compound of formula (II):

[0122]

[0123] wherein

[0124] is a single or double bond,

[0125] R x is an optionally substituted nitrogen-containing heterocyclyl group as defined above,

[0126] L x is a divalent radical derived from a C1-C 12 aliphatic chain as defined above,

[0127] v is 0 or 1, and

[0128] LV is a leaving group,

[0129] with a compound of formula (III) or (III’):

[0130]

[0131] wherein

[0132] X is an oxygen atom or a N-OH group,

[0133] R i is R 2 -(L2)n provided that R 2 is not an optionally substituted nitrogen-containing heterocyclyl group, in particular R i is methyl,

[0134] R ii is R 1 -(L1) p provided that R 1 is not an optionally substituted nitrogen-containing heterocyclyl group, in particular R ii is methyl,

[0135] and

[0136] R' is as defined above,

[0137] (b) optionally, reacting the compound of formula (III) or (III') with a compound of formula (IV)

[0138]

[0139] wherein

[0140] is a single or double bond,

[0141] R y is an optionally substituted nitrogen-containing heterocyclyl group as defined above,

[0142] L y is a divalent group derived from a C1-C 12 aliphatic chain as defined above,

[0143] w is 0 or 1, and

[0144] LV is a leaving group.

[0145] The compounds of formula (II), (III), (III') and (IV) can be obtained according to methods well known to the person skilled in the art. It will be appreciated that the preferred embodiments described in the present disclosure for the compounds of formula (I) also apply to the compounds of formula (II), (III), (III') and (IV).

[0146] It will be appreciated that when the compound of formula (II) is reacted with the compound of formula (III), Rx is typically as defined above for R 1 , L x is typically as defined above for L1, v is typically as defined above for p, and in the compound of formula (IV), R y is typically as defined above for R 2 , L y is typically as defined above for L2, and n is typically as defined above for n.

[0147] It is also understood that when the compound of formula (II) is reacted with a compound of formula (III') Rx is typically as defined above for R 2 L1 is typically as defined above for L2, v is typically as defined above for n, and when applicable in the compound of formula (IV), R x L1 is typically as defined above for L2, v is typically as defined above for n, and when applicable in the compound of formula (IV), R y L1 is typically as defined above for L2, v is typically as defined above for n, and when applicable in the compound of formula (IV), R 1 L1 is typically as defined above for L2, v is typically as defined above for n, and when applicable in the compound of formula (IV), R y L1 is typically as defined above for L2, v is typically as defined above for n, and when applicable in the compound of formula (IV), R

[0148] LV is especially selected from halogen (preferably CI) and a sulfonate group (e.g. a methanesulfonate or toluenesulfonate group).

[0149] In a preferred embodiment, in the compound of formula (III), R i is methyl and R' is H. The synthesis of said preferred compound of formula (III) is especially described in Wang, Wei; Guangdong Huagong, 2015, Vol. 42(17), p. 73-74 and EP296560A2.

[0150] Optionally, additional protection / deprotection and / or functionalization steps well known to the person skilled in the art can be performed before or after the reaction of the compound of formula (II) with the compound of formula (III) or (III') to obtain a compound of formula (I) having suitable substituents as described above.

[0151] In particular, after step (a) and before step (b), the compound of formula (III) or (III') can be deprotected at the position bearing the substituent R i or R ii , i.e. the group R i or R ii is removed to obtain an OH group at the corresponding position, whereby said -OH can react with the compound (IV) to obtain a compound of formula (I) wherein R 1 and R 2 are both a nitrogen-containing heterocyclyl group.

[0152] According to a preferred embodiment, only one of R 1 and R 2 is a nitrogen-containing heterocyclyl group. According to this embodiment, step (b) is not performed and the group R i in the compound (III) corresponds to the group R 2 -(L2) n - in the final compound of formula (I), or the group R ii in the compound (III') corresponds to the group R 1 -(L1) p-.

[0153] According to a preferred embodiment, the compound of formula (III) or (III') is obtained from donepezil by selective removal of one of the two methoxy groups borne by the indanone moiety, for example by using strong basic conditions. In this embodiment, R i or R ii are each a methyl group.

[0154] In the process for the preparation of a compound of formula (I), the intermediate compound obtained at the end of a reaction step or the final compound obtained at the end of a reaction can be separated from the reaction medium by methods well known to those skilled in the art, such as extraction, evaporation of the solvent or by precipitation or crystallization followed by filtration.

[0155] If necessary, the compounds can also be purified by methods well known in the art, such as by recrystallization, by distillation, by column chromatography (for example on silica gel) or by high-performance liquid chromatography (HPLC).

[0156] Pharmaceutical compositions

[0157] The present application also relates to a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and at least one compound of formula (I) as described above or a pharmaceutically acceptable salt and / or solvate thereof.

[0158] According to some embodiments, the pharmaceutical composition of the application comprises from 0.1 mg to 5 mg, preferably from 0.1 mg to 2.5 mg of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0159] The pharmaceutical composition of the application can be administered orally, parenterally (including, but not limited to, subcutaneous, intramuscular, intravenous), intraperitoneally, intraocularly, intravitreally, topically, sublingually, preferably intraperitoneally, orally or intravenously. The active ingredient can be mixed with conventional pharmaceutical carriers in unit dosage form for administration to animals, preferably mammals, including humans.

[0160] For oral administration, the pharmaceutical composition can be in solid or liquid (solution or suspension) form.

[0161] The solid compositions can take the form of tablets, gelatin capsules, powders, granules, and the like. In such tablets the active ingredient can be mixed with a pharmaceutical carrier in the form of a solid diluent, e.g., lactose, dicalcium phosphate, starch, magnesium stearate, talc, and the like; or as a liquid diluent, e.g., water, oil, syrup, elixir, and the like; or as an active ingredient with a combination of both. The tablets can optionally be coated and formulated so as to provide a sustained or delayed release of the active ingredient. In the case of granules and powders, the active ingredient can be mixed with a diluent or with any other pharmaceutical carrier. In gelatin capsules, the active ingredient can be present in the form of a powder or granular material, mixed with a pharmaceutical carrier such as a mannitol, lactose, starch, magnesium stearate, talc, and the like.

[0162] The liquid compositions can contain the active ingredient in a solvent (e.g., water) and can also contain a sweetening agent, a flavoring agent, or a suitable coloring agent. The liquid compositions can also be obtained by suspending or dissolving the above-mentioned powders or granules in a liquid such as water, fruit juice, milk, and the like. For example, it can be a syrup or an elixir.

[0163] For parenteral administration, the composition can be in the form of a sterile suspension or solution in a vegetable oil such as arachis oil, or in a nontoxic, parenterally acceptable diluent or solvent such as water, or saline, or the like. The composition advantageously is sterile. It can be in the form of an isotonic solution (comparable to blood).

[0164] Therapeutic uses

[0165] The compounds of formula (I) according to the application, their pharmaceutically acceptable salts and / or solvates or the pharmaceutical compositions according to the application are acetylcholinesterase inhibitors, meaning that they are capable of inhibiting the hydrolysis of acetylcholine to choline and acetate, thereby prolonging the duration of action of acetylcholine in the central nervous system.

[0166] The present application relates to a compound of formula (I) according to the application or a pharmaceutically acceptable salt and / or solvate thereof or a pharmaceutical composition according to the application for use as a medicament, in particular for use in the prevention and / or treatment of acetylcholinesterase-related diseases.

[0167] In other words, the present application relates to the use of a compound of formula (I) according to the application or a pharmaceutically acceptable salt and / or solvate thereof or a pharmaceutical composition according to the application for the manufacture of a medicament, in particular for the prevention and / or treatment of acetylcholinesterase-related diseases.

[0168] In other words, the present application relates to the use of a compound of formula (I) according to the application or a pharmaceutically acceptable salt and / or solvate thereof or a pharmaceutical composition according to the application for the prevention and / or treatment of acetylcholinesterase-related diseases.

[0169] In other words, the present application relates to a method for preventing and / or treating an acetylcholinesterase-related disease, comprising administering to a human in need thereof an effective dose of a compound of formula (I) according to the application or a pharmaceutically acceptable salt and / or solvate thereof or a pharmaceutical composition according to the application.

[0170] According to some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in the prevention and / or treatment of an acetylcholinesterase-related disease is administered to a subject in need thereof at a daily dose of 0.005 mg / kg to 0.5 mg / kg, preferably 0.01 mg / kg to 0.1 mg / kg, more preferably 0.01 mg / kg to 0.05 mg / kg, even more preferably 0.01 mg / kg to 0.03 mg / kg.

[0171] The acetylcholine-related disease is preferably selected from obsessive-compulsive disorders and related behaviors, including addiction, obsessive-compulsive disorders and eating disorders, and neurodegenerative diseases, such as Parkinson's disease or Alzheimer's disease. In the context of the present application, the term "eating disorder" includes anorexia (in particular anorexia nervosa), bulimia (in particular bulimia nervosa) and compulsive obesity. Within the framework of the present application, "compulsive obesity" is understood to mean that overweight obese patients generally exhibit compulsive eating behavior (see Houben et al., Journal of Health Psychology, Vol. 24, 2019, p. 1145-1152).

[0172] In particular, the compound of formula (I) according to the application or a pharmaceutically acceptable salt and / or solvate thereof can be used for preventing or treating obsessive-compulsive disorders and related behaviors, including addiction, obsessive-compulsive disorders and eating disorders, in particular eating disorders, such as anorexia nervosa and bulimia nervosa. BRIEF DESCRIPTION OF DRAWINGS

[0173] Figure 1 : Experiment #1: Effect of donquine (i.e. compound 56) and donepezil at 0.03 mg / kg daily dose on VGLUT3 expression in the ABA model T8I / T8I Effect of saline control on VGLUT3 expression in the ABA model T8I / T8I Effect of saline control on VGLUT3 expression in the ABA model. Wild-type (WT) groups treated with saline were used as controls. (A) WT mice (n = 8, circles), VGLUT3 T8I / T8I Effect of saline control on VGLUT3 expression in the ABA model. Wild-type (WT) groups treated with saline were used as controls. (A) WT mice (n = 8, circles), VGLUT3 T8I / T8IMeasure of food intake (% of baseline) in mice (n=8, squares). (B) Body weight was monitored daily, and mice with body weight less than 75% of their baseline were considered to have anorexia. During the food restriction period of the ABA test: in WT mice (n=8, solid line), VGLUT3 T8I / T8I mice (n=7, dotted line) and VGLUT3 T8I / T8I mice (n=8, short-dashed line) in which the percentage of mice with body weight equal to or greater than 75% of their baseline body weight. Experiment #2: 0.01 mg / kg daily dose of donepezil (i.e., compound 56) versus T8I / T8I mice (n=8, short-dashed line) in which the percentage of mice with body weight equal to or greater than 75% of their baseline body weight. Experiment #2: 0.01 mg / kg daily dose of donepezil (i.e., compound 56) versus T8I / T8I mice (n=7, triangles), VGLUT3 T8I / T8I mice (n=8, squares) and VGLUT3 T8I / T8I Measure of food intake (% of baseline) in mice (n=8, squares). (D) During the food restriction period of the ABA test: in VGLUT3 T8I / T8I mice (n=8, solid line), VGLUT3 T8I / T8I mice (n=7, dotted line) and VGLUT3 T8I / T8I mice (n=8, short-dashed line) in which the percentage of mice with body weight equal to or greater than 75% of their baseline body weight. DETAILED DESCRIPTION

[0174] Examples

[0175] 1) Synthesis

[0176] 1.1) MATERIALS

[0177] Air and moisture sensitive operations were performed under nitrogen or vacuum using standard Schlenk techniques. Anhydrous solvents (Et20, EtOH, DCM, MeOH, CH3CN, THF, toluene and hexane) were purchased from Sigma-Aldrich (Merck KGaA, Darmstadt, Germany). All other chemicals were purchased from Alfa Aesar (Karlsruhe, Germany), Sigma Aldrich and TCIEurope (Boerenveldseweg, Belgium) and used without further purification unless otherwise stated. Analytical thin layer chromatography (TLC) was performed using Merck SIL G / UV254 plates. Compounds were visualized by exposure to UV light or by dipping the plates into phosphomolybdic acid, ninhydrin or potassium permanganate solutions followed by heating. Flash column chromatography was performed using silica gel 60 (Sigma-Aldrich, St. Louis, USA). NMR spectra were recorded by Brucker Avance III nanobay 300 MHz or 400 MHz spectrometers. 1 H- and 13 C-NMR chemical shifts (d) are expressed in parts per million (ppm) relative to TMS scale. Coupling constants J are expressed in Hz. The following abbreviations are used to designate proton spectrum multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; qt, quintet; sp, septet; m, multiplet; br., broad; dd, doublet of doublets; dt, doublet of triplets. Coupling constants (J) are expressed in Hertz (Hz). Mass spectrometry analysis was performed at the Mass Spectrometry Center of Paris-Saclay University, in infusion mode or using a Shimadzu Nexera X2 HPLC system (Kyoto, Japan) and a high resolution Orbitrap Exactive mass spectrometer (Thermo Fisher, San Jose, USA). HPLC purification was performed with a Gilson analyser (Villiers le Bel, France).

[0178] 1.2) Synthesis and characterization

[0179] General procedure A

[0180] · Step 1 : Synthesis of iodo-1-alkyl quinolinium derivatives

[0181] Refiux the optionally substituted quinoline (5 g, 31.40 mmol) with the appropriate iodoalkane (15.6 mL, 157 mmol) for 48 hours. Cool the reaction mixture to room temperature and add Et20. Triturate the mixture and then wash the residue with Et20 to give the corresponding 1-alkyl-quinolinium iodide as a solid. The compound is used without further purification. Then, the optionally substituted 1-alkyl-quinolinium iodide is added to a MeMgBr solution (3 M in DCM, 19.43 mL, 58.3 mmol) at 0 °C over 5 minutes. Stir the reaction mixture at this temperature for 1 hour and then at room temperature for 2 hours. Slowly add water and then concentrated HCl solution until two layers form, then add ammonium chloride and adjust the solution to basic with aqueous ammonia. Wash the organic layer with water, dry over MgS04, and concentrate in vacuo to give the corresponding dihydroquinoline, which is used directly in the next step without purification. Reflux the dihydroquinoline with iodine (9.6 g) in EtOH (40 mL) for 15 minutes and then cool to room temperature. Filter the resulting residue and wash with EtOH and Et20 to give the corresponding 1-alkyl-methylquinolin-1-ium iodide. Dissolve 100 mg (0.29 mmol, 1 eq) of the optionally substituted 1-alkyl-methylquinolin-1-ium iodide in 15 mL of dichloromethane (DCM) and the color is a yellowish brown. After dissolution, add about 90 μL (0.64 mmol, 2.2 eq) of triethylamine (TEA). The red-brown solution darkens to a brownish black. After five minutes, add iodine (0.29 mmol, 1 eq). After 3 hours, add iodine again (0.29 mmol, 1 eq). Stir the reaction at room temperature for 60 hours. Purify the mixture as follows: remove the solvent in vacuo (blackish brown oily liquid). Add 5 mL of cyclohexane, which turns pink. After 1 hour, remove the cyclohexane and remove the remainder in vacuo. Dilute the reaction mixture with DCM (30 mL) and wash with saturated NaCl (2 x 20 mL). Remove the solvent in vacuo. TLC and ninhydrin tests show triethylammonium in water. The NMR spectrum still shows excess TEA. Dilute the reaction mixture with DCM (3 mL) and filter through 1 cm of silica gel DCM / MeOH (1 :0→ 95:5). Usually no purification is needed and the crude product is used for the addition of abacavir or formed in situ.

[0182] Specific example: synthesis of intermediate H2-QUIN

[0183]

[0184] Scheme 1. Synthesis scheme for the synthesis of H2-QUIN

[0185] 6-methoxy-1-isopropylquinolin-1-ium iodide

[0186] 6-methoxyquinoline (5 g, 31.40 mmol) with iodopropane (15.6 mL, 157 mmol) was refluxed for 48 hours. The reaction mixture was cooled to room temperature, Et20 was added. The mixture was triturated and the residue was washed with Et20 to give the title compound (9.4 g, 91%) as a yellow solid; 1 H-NMR (400 MHz, DMSO-d6) δ 9.44 (dd, 1 H, J = 1.5, 6.0 Hz, ArH), 9.11 (d, 1 H, J = 8.4 Hz, ArH), 8.67 (d, 1 H, J = 9.9 Hz, ArH), 8.14 (dd, 1 H, J = 6.0, 8.3 Hz, ArH), 7.94 (d, 1 H, J = 3.0 Hz, ArH), 7.90 (dd, 1 H, J = 7.3, 9.0 Hz, ArH), 5.86 (h, 1 H, J = 6.5 Hz, CHCH3), 4 (s, 3H, OCH3), 1.70 (d, 6H, J = 6.5 Hz, CHCH3).

[0187] 1 -isopropyl-6-methoxy-2-methylquinolin-1 -ium iodide P1

[0188] 1 -isopropyl-6-methoxyquinolin-1 -ium iodide (10 g, 29.15 mmol) was added to a MeMgBr solution (3 M in DCM, 19.43 mL, 58.3 mmol) at 0 °C over 5 minutes. The reaction mixture was stirred at this temperature for 1 hour and then at room temperature for 2 hours. Water was added slowly, followed by a concentrated HC1 solution until two layers were formed, then ammonium chloride was added and the solution was made basic with aqueous ammonia. The organic layer was washed with water, dried over MgS04, concentrated in vacuo to give the dihydroquinoline (6.02 g) which was used directly in the next step without purification. The dihydroquinoline was refluxed with iodine (9.6 g) in EtOH (40 mL) for 15 minutes and cooled to room temperature. The resulting residue was filtered and washed with EtOH and Et20 to give 1 -isopropyl-6-methoxy-2-methylquinolin-1 -ium iodide (9.2 g) in 88% yield; 1 H-NMR (400 MHz, DMSO-d6) δ 9.44 (dd, 1 H, J = 1.5, 6.0 Hz, ArH), 9.11 (d, 1 H, J = 8.4 Hz, ArH), 8.67 (d, 1 H, J = 9.9 Hz, ArH), 8.14 (dd, 1 H, J = 6.0, 8.3 Hz, ArH), 7.94 (d, 1 H, J = 3.0 Hz, ArH), 7.90 (dd, 1 H, J = 7.3, 9.0 Hz, ArH), 5.86 (h, 1 H, J = 6.5 Hz, CHCH3), 4 (s, 3H, OCH3), 1.70 (d, 6H, J = 6.5 Hz, CHCH3).

[0189] Synthesis of 2-(iodomethyl)-l-isopropyl-6-methoxyquinolin-l-ium iodide (H2-QUIN).

[0190] Dissolve 100 mg (0.29 mmol, 1 eq) of l-isopropyl-6-methoxy-2-methylquinolin-l-ium iodide in 15 mL of dichloromethane (DCM) and the color is a yellowish brown. After dissolution, add about 90 μL (0.64 mmol, 2.2 eq) of triethylamine (TEA). The reddish brown solution turns dark to blackish brown. After five minutes, add 74 mg (0.29 mmol, 1 eq) of iodine. After 3 hours, add 74 mg (0.29 mmol, 1 eq) of iodine. Stir the reaction at room temperature for 60 hours. Purify the mixture by removing the solvent under vacuum (blackish brown oily liquid). Add 5 mL of cyclohexane and it turns pink. After 1 hour, remove the cyclohexane and remove the remainder under vacuum. Dilute the reaction mixture with DCM (30 mL) and wash with saturated NaCl (2 x 20 mL). Remove the solvent under vacuum. TLC and ninhydrin test show triethylamine in water. NMR spectrum still shows excess TEA. Dilute the reaction mixture with DCM (3 mL) and filter through 1 cm of silica gel DCM / MeOH (1 :0→ 95:5). Usually no purification is needed and the crude product is used for the addition of abacavir or formed in situ.

[0191] · Step 2: Coupling with donepezil

[0192] Demethylate by reacting donepezil (1 g, 2.6 mmol) with NaCN (1.25 g, 26 mmol) in DMSO (10 mL) at the 5 position. Stir the reaction at 100 °C for two days, cool, dilute with water, and extract with dichloromethane. Acidify the aqueous solution with concentrated HCl and extract with dichloromethane. Dry the organic layer over MgSO4and evaporate to give the corresponding intermediate (500 mg).

[0193] In an argon-purged flask with magnetic stirring, add the intermediate (61 mg, 0.164 mmol), silver acetate (AgOAc) (2.13 mg, 12.8 μmol), and 1,2-bis(diphenylphosphino)ethane (dppe) (5.1 mg, 12.8 μmol). Then add 0.64 mL of DMF. Stir the mixture at room temperature for 10 minutes and then at -10 °C. Then, add the product of Step 1 in 0.64 mL of DMF. Stir the reaction at -10 °C for 2 hours. Dilute the reaction with water and extract with dichloromethane. Dry the organic layer over MgSO4and evaporate to give the product (60 mg, 0.164 mmol, 100% yield). Iodo-1- alkyl quinolinium derivatives(0.1 g, 0.213 mmol) and LiHMDS (2.8 mg, 17 pmol). The reaction medium was left under these conditions for 8 hours until the reagent was consumed. Finally, we performed a fractionation separation by column chromatography (cyclohexane / EtOAc 7:3) according to thin layer chromatography. Compound was obtained with a yield of 3-10%.

[0194] Specific example: synthesis of compound 56

[0195]

[0196] Intermediate A7:

[0197] 1 H-NMR (400 MHz, CDC13) δ 7.30 - 7.20 (m, 3H, aromatic), 7.19 - 7.15 (m, 2H, aromatic), 7.10 (s, 1H, aromatic), 6.85 (s, 1H, aromatic), 3.85 (s, 3H, OCH3), 3.43 (s, 2H, NCH2Ph), 3.15 (dd, 1H), 2.90-2.80 (m, 2H), 2.66 (m, 2H), 1.93 - 1.83 (m, 3H), 1.69 - 1.55 (m, 2H), 1.40 (m, 1H), 1.35 - 1.15 (m, 3H).

[0198] Compound 56: (yield = 10%)

[0199] 1 H-NMR (400 MHz, CDC13) δ 9.34 (d, 1H, NH), 8.80 (d, 1H, aromatic), 8.47 (d, 1H, aromatic), 8.41 (d, 1H, aromatic), 8.56 (s, 1H, aromatic), 8.26 (s, 1H, aromatic), 7.94 (d, 1H, aromatic), 7.50 - 7.45 (m, 2H, aromatic), 7.40 - 7.35 (m, 2H, aromatic), 7.15 (s, 1H, aromatic), 6.92 (s, 1H, aromatic), 4.05 (s, 3H, OCH3); 3.96 (s, 3H, OCH3), 3.13 (s, 2H, NCH2Ph), 3.05 (s, 1H); 3.01 (m, 1H), 2.90-2.80 (m, 2H), 2.67 (m, 2H), 2.05 - 1.80 (m, 3H), 1.69 - 1.55 (m, 2H), 1.40 (m, 1H), 1.35 - 1.20 (m, 3H).

[0200] Characterization of the compounds of the invention

[0201] Compound 62: (Yield = 3.5%)

[0202]

[0203] 1 H-NMR (400 MHz, CDC13) δ 9.77 (d, 1H, NH), 8.91 (d, 1H, aromatic), 8.23-8.09 (m, 1H, aromatic), 7.86 (d, 2H, aromatic), 7.70 (m, 2H, aromatic), 7.40-7.35 (m, 2H, aromatic), 7.17 (s, 1H, aromatic), 6.89 (s, 2H, aromatic), 5.92 (s, 2H, CH2); 4.68 (s, 3H, OCH3), 3.13 (s, 2H, NCH2Ph), 3.05 (s, 1H); 3.01 (m, 1H), 2.90-2.80 (m, 2H), 2.67 (m, 2H), 2.05-1.80 (m, 3H), 1.69-1.55 (m, 2H), 1.45 (m, 3H).

[0204] Compound 64: (Yield = 4.20%)

[0205]

[0206] 1 H-NMR (400 MHz, CDC13) δ 8.95 (d, 1H), 8.41-8.16 (m, 3H, aromatic), 8.08 (m, 1H) 7.85 (m, 1H), 7.75 (m, 1H), 7.62 (m, 1H); -7.30 (m, 5H), 7.13 (d, 1H), 6.94 (s, 1H); 5.00 (s, 2H); 3.86 (s, 3H); 3.75 (s, 3H); 3.16 (s, 2H); 3.22 (3H); 2.84-2.51 (m, 4H); 2.05-1.85 (m, 2H); 1.59-1.25 (m, 5H).

[0207] Compound 63: (Yield = 3.26%)

[0208]

[0209] 1H-NMR (400 MHz, CDC13) δ 8.30 (d, 2H), 8.00 (m, 2H), 7.82 (s, 1H), 7.48 (m, 2H), 7.35-7.15 (m, 6H), 6.93 (s, 1H); 6.31 (s, 2H); 3.94 (m, 6H); 3.53 (s, 2H); 3.35 (1H); 2.92-2.85 (m, 2H); 2.15-1.90 (m, 4H); 1.57 (m, 2H), 1.37-1.20 (m, 5H).

[0210] Compound 75 (Yield = 9.15%)

[0211]

[0212] 1 H-NMR (400 MHz, CDC13) δ 8.30 (d, 2H), 8.00 (m, 2H), 7.82 (s, 1H), 7.48 (m, 2H), 7.35-7.15 (m, 6H), 6.93 (s, 1H); 6.31 (s, 2H); 3.94 (m, 6H); 3.53 (s, 2H); 3.35 (1H); 2.92-2.85 (m, 2H); 2.15-1.90 (m, 4H); 1.57 (m, 2H), 1.37-1.20 (m, 5H).

[0213] Compound 76 (Yield = 6.48%)

[0214]

[0215] 1 H-NMR (400 MHz, CDC13) δ 8.30 (d, 2H), 8.00 (m, 2H), 7.82 (s, 1H), 7.48 (m, 2H), 7.35-7.15 (m, 6H), 6.93 (s, 1H); 6.31 (s, 2H); 3.94 (m, 6H); 3.53 (s, 2H); 3.35 (1H); 2.92-2.85 (m, 2H); 2.15-1.90 (m, 4H); 1.57 (m, 2H), 1.37-1.20 (m, 5H).

[0216] General procedure B

[0217] Demehtylation in position 5 was performed by reacting donepezil (1 g, 2.6 mmol) with NaCN (1.25 g, 26 mmol) in DMSO (10 mL). The reaction was stirred at 100 °C for two days, cooled, diluted with water, extracted with dichloromethane. The aqueous solution was acidified with concentrated HC1 and extracted with dichloromethane. The organic layer was dried over MgS04and evaporated to give the corresponding intermediate (500 mg).

[0218] In an argon protected flask, equipped with magnetic stirring, the intermediate (61 mg, 0.164 mmol) was stirred with K2C03(25 mg, 0.25 mmol, 1.5 eq), iodo methyl bromide (4 eq) and DMF (2 mL) at room temperature for 3 hours. Then, the mixture was extracted with dichloromethane and, after evaporation, the crude compound was used without further purification with the quinoline derivative. The quinoline derivative (3.14 mmol, 2 eq) was refluxed with the crude iodo donepezil derivative (15.7 mmol, 5 eq) in anhydrous THF for 48 hours. The reaction mixture was cooled to room temperature and Et20 was added. The mixture was triturated and the residue was washed with Et20 to give the title compound as a brown solid in 2.45-10.3% yield.

[0219] Compound 59: (yield = 5.43%)

[0220]

[0221] 1 H-NMR (400 MHz, CDC13): δ 7.65 (m, 3H), 7.49 (m, 5H), 7.21-7.09 (m, 2H), 6.92 (s, 1H), 5.38 (s, 2H), 5.31 (s, 1H), 4.19 (s, 3H), 3.49 (s, 2H), 3.22 (m, 1H), 2.90-2.40 (m, 4H), 2.60-2.45 (m, 4H), 2.05-1.80 (m, 2H), 1.57-1.35 (m, 2H), 1.30-1.10 (m, 3H).

[0222] Compound 58: (yield = 2.45%)

[0223]

[0224] 1H-NMR (400 MHz, CDC13) δ 8.94 (d, 1H), 8.78 (d, 1H, aromatic), 8.18 (m, 2H, aromatic), 7.75 (d, 1H, aromatic), 7.65 - 7.35 (m, 6H, aromatic), 7.19 (s, 1H, aromatic), 7.13 (s, 1H, aromatic), 5.65 (s, 2H, CH2); 3.91 (s, 3H); 3.71 (s, 2H), 3.55 (m, 1H); 2.95 (s, 2H); 2.60 - 2.22 (m, 6H), 1.80 - 1.54 (m, 5H).

[0225] Compound 57: (Yield = 10.3%)

[0226]

[0227] 1 H-NMR (400 MHz, CDC13) δ 8.94 (d, 1H), 8.78 (d, 1H, aromatic), 8.18 (m, 2H, aromatic), 7.75 (d, 1H, aromatic), 7.65 - 7.35 (m, 6H, aromatic), 7.19 (s, 1H, aromatic), 7.13 (s, 1H, aromatic), 5.65 (s, 2H, CH2); 3.91 (s, 3H); 3.71 (s, 2H), 3.55 (m, 1H); 2.95 (s, 2H); 2.60 - 2.22 (m, 6H), 1.80 - 1.54 (m, 5H).

[0228] 2) Efficacy of donequinine (i.e. compound 56) in mutant mice lacking Ach in the ABA model

[0229] The activity-based anorexia (ABA) test models self-starvation behavior (Klenotich, S.J., Dulawa, 2012 Methods Mol Biol 829, 377-93). In this test, animals are housed in an environment with a running wheel. Their food is progressively restricted over an 8-day period. For these animal experiments, a low cholinergic mouse model was used. The vesicular glutamate transporter type 3 (VGLUT3) is expressed in all cholinergic striatal interneurons (El Mestikawy et al. 2011, Nat Rev Neurosci 12(4), 204-16).

[0230] In 2015, the El Mestikawy team discovered a p.T8I variant of VGLUT3, which is expressed in patients with substance use disorders and eating disorders (Sakae et al. Mol Psychiatry, 2015, 20(11), 1448-59). Mice expressing this variant (VGLUT3T8I / T8I Striatal cholinergic tone is reduced in mice, and anhedonia is more readily self-induced in the ABA model. In other words, VGLUT3 T8I / T8I Mice exhibit the same major symptoms as anorexia patients and are considered the preferred model of anorexia.

[0231] Activity-based anhedonia (ABA) model

[0232] The ABA model was implemented as described by Klenotich and Dulawa (Klenotich, S. J., Dulawa, 2012 Methods Mol Biol 829, 377-93) and previously reported (Favier, M. et al. J Clin Invest 130, 6616-6630 (2020)). To acclimate the mice to the environment, all mice were individually housed in cages with a running wheel for 7 days and allowed unlimited access to food, water, and the running wheel. After the acclimation period, all mice were continued to be housed in the same running wheel cages for an additional 8 days. Mice were progressively restricted from accessing food, from 8 hours per day (day 1) to 2 hours per day (day 8). Body weight and food intake were measured daily, before and after food access, respectively. Mice that lost more than 25% of their initial (baseline) body weight were considered to have “anhedonia”. The number of days it took for the mice to lose 75% or less of their baseline body weight was used as a survival indicator. For drug treatment experiments, mice were injected intraperitoneally daily with donepezil (i.e., compound 56, 0.03 or 0.01 mg / kg, diluted in 0.9% NaCl), donepezil (reference compound, 0.03 mg.kg -1 , diluted in 0.9% NaCl), or 0.9 wt% control saline (NaCl) solution. Mice were treated daily 30 minutes before the start of food access during the baseline and food restriction periods.

[0233] Figure 1 (A) shows that VGLUT3 T8I / T8I mice administered donepezil (i.e., compound 56) at a dose of 0.03 mg / kg daily for 7 days resulted in food intake levels similar to wild-type mice treated with saline. In contrast, VGLUT3 T8I / T8I mice treated with saline ate less and exhibited anhedonic behavior similar to self-starvation.

[0234] Figure 1 (B) shows that all (100%) VGLUT3 T8I / T8I mice treated with saline had a body weight less than 75% of their baseline body weight after 8 days. In contrast, administration of donepezil at a daily dose of 0.03 mg / kg prevented VGLUT3 T8I / T8IThe mice lost weight, as 60% of them still had a body weight of at least 75% of their baseline body weight after 8 days, similar to the control wild-type group treated with saline. Similarly, Figure 1 Figure 1 C shows that a daily dose of 0.01 mg / kg of donepezil also prevented the mice from starving themselves, as about 90% of the mice had a body weight of at least 75% of their baseline body weight after 8 days. Taken together, these data demonstrate that donepezil is suitable and effective for treating anorectic behavior.

[0235] In contrast, the same experiment was performed with the known acetylcholinesterase inhibitor, donepezil (see Figure 1 Figure 1 C and Figure 1 Figure 1 D). Figure 1 Figure 1 C shows that a lower dose (0.01 mg / kg) of donepezil was more effective than 0.03 mg / kg of donepezil in reducing the number of VGLUT3 T8I / T8I mice that lost weight to 75% or less of their baseline body weight. Figure 1 Figure 1 D shows that a daily dose of 0.03 mg / kg of donepezil was less effective than a daily dose of 0.01 mg / kg of donepezil in reducing the number of VGLUT3 T8I / T8I mice that lost weight to 75% or less of their baseline body weight.

[0236] 3) Inhibition of acetylcholinesterase (AChE)

[0237] 3.1) Procedure

[0238] Solutions of each test compound were prepared by dissolving the compound in DMSO to make a 1 mM stock solution, then diluting with water to the following concentrations: 100 nM, 10 nM and 1 nM.

[0239] The procedure for the Sigma Aldrich MAK119 kit assay (colorimetric test) is described below:

[0240] The working reagent of the kit (MAK119C) is freshly prepared and used within 30 minutes. Solution A is prepared by dissolving the working reagent (192 mg) in 19.2 ml of the assay buffer of the kit (MAK119A).

[0241] Solution B, prepared with 200 mL of water and 200 mL of calibrant (MAK119B in the kit), is dispensed into individual wells of a 96-well plate. 10 mL of the test compound solution is added to the wells, then 190 mL of solution A is added to all sample wells. Negative control wells are prepared by adding solution A and solution B but no test compound solution, and positive control wells are prepared by adding solution A, solution B and 1 mM donepezil.

[0242] The plate is incubated for 2 minutes at room temperature and the initial absorbance (A 412 ) ini After 10 minutes of incubation at room temperature, the final absorbance (A 412 ) 最终 .

[0243] Then, the following calculation is made: the inhibition is calculated by comparing the absorbance at 412 nm (A 412 ) of the sample containing the test compound after 12 minutes of incubation with the absorbance at 412 nm of the negative and positive controls (A 412 ) 空白 inhibition.

[0244] 3.2) Results

[0245] Test compound % inhibition (100 nM) % inhibition (10 nM) % inhibition (1 nM) 56 100 75 50 62 100 100 59 100 100 57 100 100 76 100 100 63 75 75 75 64 100 100 25 75 100 100 Donepezil 100 75 25

[0246] These results show that the compounds of the application are at least as effective as donepezil in inhibiting acetylcholinesterase and that some of them are more effective than donepezil.

Claims

1. A compound of formula (I): ###0001### or a pharmaceutically acceptable salt and / or solvate thereof, wherein X is an oxygen atom or a N-OH group, R is H, halogen, optionally substituted C1-C6 aliphatic chain, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted C1-C6 alkyl-aryl, wherein up to 4 methylene units of the aliphatic chain are optionally replaced by O, C(O), NH or N-C1-C6 alkyl.

2. The compound according to claim 1, wherein the optionally substituted nitrogen-containing heterocyclic group is selected from the group consisting of pyrrolyl, pyridinyl, thiazinyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridazinyl, purinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, isoindolyl, indolyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl and isoindolinyl. wherein represents a single or double bond, and 10. The compound according to any one of claims 1 to 9, wherein R' is H. R 1 and R 2 each independently is H, optionally substituted nitrogen-containing heterocyclyl, optionally substituted C1-C6 aliphatic chain, or optionally substituted aryl, wherein up to four methylene units of the aliphatic chain are optionally replaced by O, C(O), NH, or N-C1-C6 alkyl, provided that at least one of R 1 and R 2 is optionally substituted nitrogen-containing heterocyclyl, L1and L2are each independently a divalent radical derived from a C1-C 12 a divalent radical of an aliphatic chain, wherein one or more, preferably one to four, methylene units are optionally replaced by arylene, -0-, -S-, -C(=0)-, -SO2-, or -N(C1-C6alkyl)-, wherein said aliphatic chain is optionally substituted, each p and n is independently 0 or 1, provided that when R 1 is optionally substituted nitrogen-containing heterocyclyl, p is 1, when R 2 is optionally substituted nitrogen-containing heterocyclyl, n is 1, and 11. The compound according to any one of claims 1 to 10, wherein X is an oxygen atom.

12. The compound according to any one of claims 1 to 11, selected from the group consisting of: ###0002### ###0003### ###0004### ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ###0059### ###0060### ###0061### ###0062### ###0063### ###0064### ###0065### ###0066### ###0067### ###0068### ###0069### ###0070### ###0071### ###0072### ###0073### ###0074### ###0075### ###0076### ###0077### ###0078### ###0079### ###0080### ###0081### ###0082### ###0083### ###0084### ###0085### ###0086### ###0087### ###0088### ###0089### ###0090### ###0091### ###0092### ###0093### ###0094### ###0095### ###0096### ###0097### ###0098### ###0099### ###0100### ###0101### ###0102### ###0103### ###0104### ###0105### ###0106### ###0107### ###0108### ###0109### ###0110### ###0111### ###0112### ###0113### ###0114### ###0115### ###0116### ###0117### ###0118### ###0119### ###0120### ###0121### ###0122### ###0123### ###0124### ###0125### ###0126### ###0127### ###0128### ###0129### ###0130### ###0131### ###0132### ###0133### ###0134### ###0135### ###0136### ###0137### ###0138### ###0139### ###0140### ###0141### ###0142### ###0143### ###0144### ###0145### ###0146### ###0147### ###0148### ###0149### ###0150### ###0151### ###0152### ###0153### ###0154### ###0155### ###0156### ###0157### ###0158### ###0159### ###0160### ###0161### ###0162### ###0163### ###0164### ###0165### ###0166### ###0167### ###0168### ###0169### ###0170### ###0171### ###0172### ###0173### ###0174### ###0175### ###0176### ###0177### ###0178### ###0179### ###0180### ###0181### ###0182### ###0183### ###0184### ###0185### ###0186### ###0187### ###0188### ###0189### ###0190### ###0191### ###0192### ###0193### ###0194### ###0195### ###0196### ###0197### ###0198### ###0199### ###0200### ###0201### ###0202### ###0203### ###0204### ###0205### ###0206### ###0207### ###0208### ###0209### ###0210### ###0211### ###0212### ###0213### ###0214### ###0215### ###0216### ###0217### ###0218### ###0219### ###0220### ###0221### ###0222### ###0223### ###0224### ###0225### ###0226### ###0227### ###0228### ###0229### ###0230### ###0231### ###0232### ###0233### ###0234### ###0235### ###0236### ###0237### ###0238### ###0239### ###0240### ###0241### ###0242### ###0243### ###0244### ###0245### ###0246### ###0247### ###0248### ###0249### ###0250### ###0251### ###0252### ###0253### ###0254### ###0255### ###0256### ###0257### ###0258### ###0259### ###0260### ###0261### ###0262### ###0263### ###0264### ###0265### ###0266### ###0267### ###0268### ###0269### ###0270### ###0271### ###0272### ###0273### ###0274### ###0275### ###0276### ###0277### ###0278### ###0279### ###0280### ###0281### ###0282### ###0283### ###0284### ###0285### ###0286### ###0287### ###0288### ###0289### ###0290### ###0291### ###0292### ###0293### ###0294### ###0295### ###0296### ###0297### ###0298### ###0299### ###0300### ###0301### ###0302### ###0303### ###0304### ###0305### ###0306### ###0307### ###0308### ###0309### ###0310### ###0311### ###0312### ###0313### ###0314### ###0315### ###0316### ###0317### ###0318### ###0319### ###0320### ###0321### ###0322### ###0323### ###0324### ###0325### ###0326### ###0327### ###0328### ###0329### ###0330### ###0331### ###0332### ###0333### ###0334### ###0335### ###0336### ###0337### ###0338### ###0339### ###0340### ###0341### ###0342### ###0343### ###0344### ###0345### ###0346### ###0347### ###0348### ###0349### ###0350### ###0351### ###0352### ###0353### ###0354### ###0355### ###0356### ###0357### ###0358### ###0359### ###0360### ###0361### ###0362### ###0363### ###0364### ###0365### ###0366### ###0367### ###0368### ###0369### ###0370### ###0371### ###0372### ###0373### ###0374### ###0375### ###0376### ###0377### ###0378### ###0379### ###0380### ###0381### ###0382### ###0383### ###0384### ###0385### ###0386### ###0387### ###0388### ###0389### ###0390### ###0391### ###0392### ###0393### ###0394### ###0395### ###0396### ###0397### ###0398### ###0399### ###0400### ###0401### ###0402### ###0403### ###0404### ###0405### ###0406### ###0407### ###0408### ###0409### ###0410### ###0411### ###0412### ###0413### 3. A compound according to claim 1 or 2, R 1 and / or R 2 , preferably R 1 and R 2 are one of the groups corresponding to one of the following formulae: ​ R 3 to R 8 each independently is selected from the group consisting of H, halogen, OH, NH2, NH-Ci-C6alkyl, Ci-C6aliphatic chain, aryl, heteroaryl, and Ci-C6alkyl-aryl, wherein up to 4 methylene units of the aliphatic chain are optionally replaced by O, C(O), NH, or N-Ci-C6alkyl, the aliphatic chain, aryl, heteroaryl, or alkyl-aryl being optionally substituted, or R 3 -R 4 , R 4 -R 5 , R 5 -R 6 and R 6 -R 7 one or more of the pairs together with the carbon atom to which they are attached form a 5 or 6 membered aromatic or non-aromatic optionally substituted ring, R 9 and R 10 each independently is one or more substituents selected from the group consisting of H, C1-C6 aliphatic chain, aryl, heteroaryl, and C1-C6 alkyl-aryl, wherein up to 4 methylene units of the aliphatic chain are optionally replaced by O, C(O), NH, or N-C1-C6 alkyl, the aliphatic chain, aryl, heteroaryl, or alkyl-aryl being optionally substituted, Indicates a single bond or a double bond, and represents R 1 a bond to the remainder of the molecule.

4. The compound of claim 3, wherein R 8 is H or Ci-C6alkyl, e.g., methyl.

5. The compound according to claim 3 or 4, wherein R 3 -R 4 R 4 -R 5 R 5 -R 6 and R 6 -R 7 One of the atoms in the pair, together with the carbon atoms they are attached to, forms a 6-membered aromatic ring, which is either unsubstituted or substituted by one or more substituents selected from halogens, OH, NH2, NH-C1-C6 alkyl, C1-C6 alkyl, and O-C1-C6 alkyl. 3 To R 7 The other groups in it are H.

6. The compound according to claim 3 or 4, wherein R 9 is one substituent selected from OH and halogen, R 10 is H.

7. The compound according to any one of claims 1 to 6, wherein R 1 and / or R 2 , preferably R 1 and R 2 are selected from quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, which are unsubstituted or substituted by one or more substituents selected from OH, C1-C6-alkyl or O-C1-C6-alkyl.

8. The compound according to any one of claims 1 to 7, wherein R 1 and one of R 2 is an optionally substituted nitrogen-containing heterocyclyl group as defined in claims 1 to 7, the other is H, optionally substituted C1-C6 aliphatic chain or optionally substituted aryl, preferably H, C1-C6 alkyl or phenyl, more preferably C1-C6 alkyl, including methyl, ethyl, propyl, t-butyl, n-butyl, especially methyl.

9. The compound of any one of claims 1 to 8, wherein L 1 and L 2 each independently is methylene or a linker of the formula -CH=. ​ ​ ​ ​ ​ ​

Images