Carbazole derivatives used as neuroprotectants and in the treatment of disorders with reduced NAD metabolism

Abstract

The invention concerns a compound of formula (I) wherein R, R1 and R2 are independently selected form the group consisting of: a hydrogen atom, a halogen atom, an alkyl group, linear, cyclic or branched, saturated or unsaturated, possibly substituted, comprising from 1 to 10 carbon atoms, an acyl group comprising from 1 to 10 carbon atoms, a carboxyl group, an amido group comprising from 1 to 10 carbon atoms, and an imino group, possibly substituted by an alkyl group, linear, cyclic or branched, saturated or unsaturated, and wherein R3, R4, R5 and R6 are independently selected form the group consisting of: a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, linear, cyclic or branched, saturated or unsaturated, possibly substituted, comprising from 1 to 10 carbon atoms, an alkoxy group comprising from 1 to 10 carbon atoms, an acyl group comprising from 1 to 10 carbon atoms, a carbonate group from 1 to 10 carbon atoms, a carboxyl group, and a cyano group, for use as neuroprotectants, or in the treatment of disorders with reduced NAD metabolism.

Description

[0001] 1

[0002] CARBAZOLE DERIVATIVES USED AS NEUROPROTECTANTS AND IN THE TREATMENT OF DISORDERS WITH REDUCED NAD METABOLISM The present invention belongs to the fields of human and animal health and notably 5 cancerology and neurology. The present invention concerns carbazole derivatives of formula (I) for use as neuroprotectants, or in the treatment of disorders with reduced NAD metabolism. The present invention also concerns pharmaceutical compositions comprising such compounds of formula (I) for use as neuroprotectants, or in the treatment of disorders with 10 reduced NAD metabolism. TECHNOLOGICAL BACKGROUND Patent application WO2021069736 discloses a family of compounds providing improved treatments against cancers and in particular, providing a solution to the technical 15 problem of reducing the toxicity of compounds stabilizing cell microtubules, and in particular of paclitaxel. This family of compounds provides a solution to reducing the resistance to compounds stabilizing the microtubules, in particular of the resistance to paclitaxel. This family also provided new treatments targeting LKB1-deficient cells. One aim of the family of compounds was to provide compounds for use in a 20 pharmaceutical treatment, notably against a cancer, that could alleviate the above technical limitations, to reduce the resistance to compounds stabilizing the microtubules, in particular the resistance to paclitaxel and to provide compounds being selectively cytotoxic against LKB1-deficient cells. Chemotherapy agents are still widely used as 1st and 2nd line therapies, although 25 new effective therapeutic approaches against cancer (kinase inhibitors, immune checkpoint inhibitors, etc.) have emerged in recent years. Paclitaxel (PTX) or Taxol®belongs to the taxanes family. This microtubule-targeting agent is considered the world's leading chemotherapeutic agent. However, its side effects may limit its use to the maximum effective therapeutic dose. 30 Chemotherapy-induced peripheral neuropathy (CIPN) is a common and frequent adverse effect. Physicians are faced with the problem and have no treatment to prevent CIPN. CIPN often persist after chemotherapy and can have a long-term impact on the patient's quality of life. CIPN is an adverse effect of not only taxanes but also of many chemotherapy agents 35 such as vinca alkaloids, platinum salts, etc., affecting several million patients worldwide every year. CIPN is characterized by altered sensations in the hands and feet, with tingling 2 and burning, or numbness and decreased sensation to touch. Pain symptoms generally appear at the beginning of treatment cycles, while numbness and tingling develop later and can last for years after treatment has stopped. CIPN has a major impact on several levels. On cancer treatment, as their occurrence 5 leads practitioners to reduce doses of therapeutic agents, thus compromising patients' chances of recovery. On patients' quality of life, not only during treatment but also afterwards, as symptoms persist chronically in half of all patients, and may even prevent them from returning to work. The economic consequences of CIPN are also considerable for the healthcare system. 10 With the increasing number of cancer survivors due to improved patient’s management, CIPN is a growing concern as it negatively and often permanently affects the quality of life of many patients. There are a few symptomatic treatments for neuropathic pain, all of them of questionable efficacy. Duloxetine, a serotonin and norepinephrine reuptake inhibitor approved for the treatment of major depressive disorders, is the only drug 15 recommended by ASCO; however, not all patients benefit from duloxetine (for example, its analgesic efficacy is better against platinum derivatives than against taxanes). Moreover, several undesirable side-effects have been reported for duloxetine such as sleeping difficulties, headaches, etc. Regarding prevention and treatment of CIPN, there is currently no FDA, nor EMA -approved drugs. One of the main obstacles to the development of such 20 neuroprotective drugs is the heterogeneity of the mechanisms - changes in ion channels (sodium, potassium, and calcium), transient receptor potential channels, mitochondrial dysfunction, and immune cell interactions - by which chemotherapeutic agents produce toxicity. Several products are currently undergoing clinical trials- such as those developed by AlgoTx (a topical analgesic hydrogel that inhibits nociceptive sodium channels), by 25 Osmol Therapeutics (intracellular calcium modulation), Sonnet biotherapeutics (recombinant human Interleukin-6), Egetis-Pledpharma (Pledox, an agent acting on oxidative stress, which clinical development has been arrested)- demonstrating the attractiveness of the indication. 30 There is therefore a need for a compound, or a family of compound that could act as neuroprotectant, alone or in combination with chemotherapeutic treatment. DETAILLED DESCRIPTION OF THE INVENTION In a first aspect, the invention relates to a compound of formula (I) for use as a 35 neuroprotectant, preferably by preventing peripheral neurons from degenerating after chemotherapeutic treatment. 3

[0003] In addition to potentiating the effect of PTX and other taxanes, the inventors have observed that the compounds of formula (I) also exert a neuroprotective effect, preventing peripheral neurons from degenerating after chemotherapy. This neuroprotective action has been validated in vitro, on cultured neurons from dorsal root ganglia (DRG) (Figures 1 and 5 2) and in vivo on a rat model of neuropathy (Figure 4). Moreover, an impairment of myelinated fiber function could be responsible for the sensory disturbances in CIPN. The inventors have observed that the compounds of formula (I) also exert a protective effect on Schwann cells, which produce the myelin sheath, significantly sparing them from the toxicity of chemotherapeutic agents (such as PTX or Cisplatin). These results support a general 10 mechanism of neuroprotective action of compounds of formula (I), which might be effective not only in toxicity-induced, but also in related types of familial neuropathies. This opens a wide range of application since neuroprotection does not only concern neuropathies resulting from treatment with PTX and taxanes, but also those resulting from 15 treatment with platinum salts such as cisplatin. Surprisingly, it was discovered by present inventors that a compound of formula (I) ofthe invention not only potentiates the effect of a compound stabilizing cell microtubules, in particular the effect of paclitaxel, without significantly increasing its toxicity as described in WO2021069736, but also act as neuroprotectants. 20 It has thus now been observed that the compounds of formula (I) disclosed in WO2021069736 have a dual activity: a synergistic anti-tumor effect with taxanes, reducing doses of these toxic compounds, and a neuroprotective effect. The inventors have also demonstrated that this neuroprotective effect is independent of its synergistic effect with taxanes on microtubules, observed in tumors, and results not 25 from tubulin targeting but from activation of a metabolic enzyme: nicotinamide phosphoribosyl transferase (NAMPT), most probably. NAMPT is a key enzyme in the nicotinamide adenine dinucleotide (NAD) salvage pathway, playing a central role in maintaining the cellular NAD pool. Numerous studies indicate that NAD is a central modulator controlling the health of damaged or diseased neurons (Verdin, Science, 2015, 30 doi:10.1126 / science.aac4854). The neuroprotective action, independent of its effect on microtubules, would represent the therapeutic solution to CIPN and would therefore be an important differentiating factor answering an important unmet medical need. Moreover, to our knowledge, there are no drug with such a double mechanism: 35 synergizing with taxanes, enabling dosing regimens reduction, and preventing one of their most incapacitating side effects. 4

[0004] This opens the compounds of formula (I) to a great variety of application, and they can thus be used alone or in combination with a great variety of chemotherapeutic drugs and therapeutic drugs for their neuroprotective effect, preferably by preventing peripheral neurons from degenerating after chemotherapy. 5 On another aspect, the present invention is the compound of formula (I) for use in the NAD production in patients. The compound for use according to the invention may find applications in the treatment of disorders with reduced NAD metabolism such as: - central and peripheral neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's, Amyotrophic Lateral Sclerosis (ALS), Charcot Marie Tooth (CMT), Guillain- 10 Barré syndrome); - neuronal trauma, including noise-induced hearing loss (Brown KD, et al. Activation of SIRT3 by the NAD⁺ precursor nicotinamide riboside protects from noise-induced hearing loss. Cell Metab.2014 Dec 2;20(6):1059-68. doi: 10.1016 / j.cmet.2014.11.003); - metabolic diseases such as diabetes or obesity; 15 - organ damage / failure (liver, kidney, heart); - certain muscular diseases (Duchene disease); - ageing; - metabolic defects affecting sperm mobility; - the oxidative damage during virus infection. 20 Another object of the present invention is thus the compound of formula (I) for use in the treatment of disorders with reduced NAD metabolism. The disorders with reduced NAD metabolism may be chosen from the following: - central and peripheral neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis disease, Charcot 25 Marie Tooth disease; - neuronal trauma, including noise-induced hearing loss; - metabolic diseases such as diabetes or obesity; - organ damage / failure such as liver damage / failure, kidney damage / failure or heart damage / failure; 30 - certain muscular diseases such as Duchene disease; - ageing (the effects of ageing resulting from a fall in NAD); - metabolic defects affecting sperm mobility; - the oxidative damage during virus infection. 35 The present invention thus concerns a compound of formula (I): 5 1 4 R R3R CH 5 R wherein R, R1and R2are i onsisting of: - a hydrogen atom, - a halogen atom, 5 - an alkyl group, linear, cyclic or branched, saturated or unsaturated, possibly substituted, comprising from 1 to 10 carbon atoms, - an acyl group comprising from 1 to 10 carbon atoms, - a carboxyl group, - an amido group comprising from 1 to 10 carbon atoms, and 10 - an imino group, possibly substituted by an alkyl group, linear, cyclic or branched, saturated or unsaturated, and wherein R3, R4, R5and R6are independently selected form the group consisting of: - a hydrogen atom, - a halogen atom, 15 - a hydroxyl group, - an alkyl group, linear, cyclic or branched, saturated or unsaturated, possibly substituted, comprising from 1 to 10 carbon atoms, - an alkoxy group comprising from 1 to 10 carbon atoms, - an acyl group comprising from 1 to 10 carbon atoms, 20 - a carbonate group from 1 to 10 carbon atoms, - a carboxyl group, and - a cyano group, for use as a neuroprotectant, preferably by preventing peripheral neurons from degenerating after chemotherapy. 25 The present invention thus concerns a compound of formula (I): 6 134 R R R CH 5 R wherein R, R1and R2are i onsisting of: - a hydrogen atom, - a halogen atom, 5 - an alkyl group, linear, cyclic or branched, saturated or unsaturated, possibly substituted, comprising from 1 to 10 carbon atoms, - an acyl group comprising from 1 to 10 carbon atoms, - a carboxyl group, - an amido group comprising from 1 to 10 carbon atoms, and 10 - an imino group, possibly substituted by an alkyl group, linear, cyclic or branched, saturated or unsaturated, and wherein R3, R4, R5and R6are independently selected form the group consisting of: - a hydrogen atom, - a halogen atom, 15 - a hydroxyl group, - an alkyl group, linear, cyclic or branched, saturated or unsaturated, possibly substituted, comprising from 1 to 10 carbon atoms, - an alkoxy group comprising from 1 to 10 carbon atoms, - an acyl group comprising from 1 to 10 carbon atoms, 20 - a carbonate group from 1 to 10 carbon atoms, - a carboxyl group, and - a cyano group, for use in the treatment of defects observed in disorders with a reduced NAD metabolism. The disorders with reduced NAD metabolism may be chosen from the 25 following: - central and peripheral neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis disease, Charcot Marie Tooth disease; - neuronal trauma, including noise-induced hearing loss; 30 - metabolic diseases such as diabetes or obesity; 7

[0005] - organ damage / failure such as liver damage / failure, kidney damage / failure or heart damage / failure; - certain muscular diseases such as Duchene disease; - ageing (the ageing resulting from a fall in NAD); 5 - metabolic defects affecting sperm mobility; - the oxidative damage during virus infection. It is meant by neuroprotectant an agent that protects against neuronal degeneration secondary to chemotherapeutic treatment, trauma, metabolic damage, neurological damage (ALS, Alzheimer's, etc.). It may be preventing peripheral neurons from 10 degenerating after chemotherapy. It may also be preventing Schwann cells from degenerating after chemotherapy. The compound of formula (I) for use according to the invention may also be in the form of its tautomeric, racemic, enantiomeric or polymorphic forms or pharmaceutically- 15 acceptable salts. The compound of formula (I) for use according to the invention may also be in the form of co-crystal, said co-crystal comprising the compound of formula (I) and a co-former. The co-former may be chosen from nicotinamide, isonicotinamide, nicotinamide riboside, nicotinamide mononucleotide, ascorbic acid, syringic acid, gallic acid and caffeine. 20 The invention refers to a “substituted” group or moiety, which is known to mean that at least one hydrogen radical of said group or moiety is replaced with an atom or a group ofatoms called substituent. Examples of preferred substituents are halogen (chloro, iodo, bromo, or fluoro); alkyl; 25 alkenyl; alkynyl; hydroxy; alkoxy; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (-O); haloalkyl (e.g., trifluoromethyl); cycloalkyl, which may be monocyclic or fused or non- fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g.,30 pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl), monocyclic or fused or non- fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); CO2CH3; 35 CONH2; OCH2CONH2; NH2; SO2NH2; OCHF2; CF3; OCF3; and such moieties may also be optionally substituted by a fused-ring structure or bridge, for example -OCH2O-. These 8 substituents may optionally be further substituted with a substituent selected from such groups. The invention refers to an “acyl” group, which is known as a moiety derived by theremoval of the hydroxyl group from a carboxylic acid. Examples of acyl groups are 5 aldehydes, ketones, esters, amides or acyl chlorides. Preferably, in the compound of formula (I) for use according to the invention, R, R1and R2are independently selected from the group consisting of: - a hydrogen atom, 10 - a halogen atom, - an alkyl group of formula –CnH2n+1-xXx, X being selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, and n being an integer between 1 and 10 and x being the number of X present in the alkyl group, and preferably x being 1 and X being in terminal position in the alkyl group, 15 - an alkyl group bearing an amino (primary, secondary, or tertiary), - an alkyl group bearing an ester, the ester being preferably an ester of a protected (e.g. Boc, Fmoc or Cbz protected) amino acid such as lysine, valine, tyrosine, cysteine, glutamic acid, an ester of a diacid, such as succinic acid or an ester of acid bearing a polyethylene glycol, having from 4 to 50 repeating units, 20 - an alkyl group bearing piperidine or a dipiperidine linked via a carbamate, - an acyl group of formula –C(O)ORa, Rabeing a linear and saturated alkyl group comprising from 1 to 9 carbon atoms, - an acyl group of formula –C(O)H, - a carboxyl group (-COOH),25- an amido group of formula –C(O)NRb, Rbbeing a linear and saturated alkyl group comprising from 1 to 9 carbon atoms, and - an imino group of formula –C=N-Rc, Rcbeing selected from the group consisting of a hydrogen atom or an alkyl group, linear, saturated and comprising from 1 to 10 carbon atoms, or a phenyl group, and 30 R3, R4, R5and R6are independently selected from the group consisting of: - a hydrogen atom, - a halogen atom, - a hydroxyl group, - an alkyl group of formula –CnH2n+1, linear, saturated and n being an integer between 35 1 and 10, 9

[0006] - an alkoxy group of formula –ORd, Rdbeing a linear and saturated alkyl group comprising from 1 to 9 carbon atoms, - an acyl group of formula –C(O)ORa, Rabeing a linear and saturated alkyl group comprising from 1 to 9 carbon atoms, 5 - an acyl group of formula –C(O)Re, Re being a hydrogen atom or an alkyl group, linear, cyclic or branched, saturated or unsaturated, possibly substituted, comprising from 1 to 10 carbon atoms, - a carbonate group of formula –OC(O)ORf, Rfbeing a linear and saturated alkyl group comprising from 1 to 9 carbon atoms, 10 - a carboxyl group (-COOH), and - a cyano group (-CN). More preferably, in the compound of formula (I) for use according to the invention, R and R1are independently selected from the group consisting of: 15 - a hydrogen atom, - a halogen atom, - an alkyl group, linear, saturated and comprising from 1 to 10 carbon atoms, R2is selected from the group consisting of: - a hydrogen atom, 20 - a halogen atom, - an alkyl group of formula –CnH2n+1-xXx, X being selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, and n being an integer between 1 and 10 and x being the number of X present in the alkyl group, and preferably x being 1 and X being in terminal position in the alkyl group, 25 - an alkyl group bearing an amino (primary, secondary, or tertiary), - an alkyl group bearing an ester, the ester being preferably an ester of a protected (e.g. Boc, Fmoc or Cbz protected) amino acid such as lysine, valine, tyrosine, cysteine, glutamic acid, an ester of a diacid, such as succinic acid or an ester of acid bearing a polyethylene glycol, having from 4 to 50 repeating units, 30 - an alkyl group bearing piperidine or a dipiperidine linked via a carbamate, - an acyl group of formula –C(O)ORa, Ra being a linear and saturated alkyl group comprising from 1 to 9 carbon atoms, - an acyl group of formula –C(O)H, - a carboxyl group (-COOH), 35 - an amido group of formula –C(O)NRb, Rb being a linear and saturated alkyl group comprising from 1 to 9 carbon atoms, and 10 - an imino group of formula –C=N-Rc, Rcbeing selected from the group consisting of a hydrogen atom or an alkyl group, linear, saturated and comprising from 1 to 10 carbon atoms, or a phenyl group, R3, R5and R6are independently selected from the group consisting of: 5 - a hydrogen atom, - a halogen atom, - an alkyl group of formula –CnH2n+1, linear, saturated and n being an integer between 1 and 10, and R4is selected from the group consisting of: 10 - a hydrogen atom, - a halogen atom, - a hydroxyl group, - an alkyl group of formula –CnH2n+1, linear, saturated and n being an integer between 1 and 10, 15 - an alkoxy group of formula –ORd, Rdbeing a linear and saturated alkyl group comprising from 1 to 9 carbon atoms, - an acyl group of formula –C(O)ORa, Ra being a linear and saturated alkyl group comprising from 1 to 9 carbon atoms, - an acyl group of formula –C(O)Re, Re being a hydrogen atom or an alkyl group, 20 linear, cyclic or branched, saturated or unsaturated, possibly substituted, comprising from 1 to 10 carbon atoms, - a carbonate group of formula –OC(O)ORf, Rf being a linear and saturated alkyl group comprising from 1 to 9 carbon atoms, - a carboxyl group (-COOH), and 25 - a cyano group (-CN). Even more preferably, in the compound of formula (I) for use according to the invention, R and R1are independently selected from the group consisting of a hydrogen atom, a chloride atom and a methyl group, 30 R2is selected from the group consisting of a hydrogen atom, a methyl group, a –COH group, an alkyl group of formula –CH2X, X being selected from the group consisting of a chloride atom, a bromide atom, a iodine atom and a hydroxyl group, an acyl group of formula –C(O)ORa, Rabeing a methyl group or an ethyl group, an acyl group of formula –C(O)H, a carboxyl group (-COOH), an amido group of formula –C(O)NRb,35 Rb being a methyl group or an ethyl group, an imino group of formula –C=N-Rc, Rc being a phenyl group, –CH2Y, Y being selected from the group consisting of an amino 11 group of formula -NRzRz, Rzindependently representing H or a C1 to C3 alkyl group, an ester, the ester being preferably an ester of a protected (e.g. Boc, Fmoc or Cbz protected) amino acid such as lysine, valine, tyrosine, cysteine, glutamic acid, an ester of a diacid, such as succinic acid or an ester of acid bearing a polyethylene glycol, 5 having from 4 to 50 repeating units, or a piperidine or a dipiperidine linked via a carbamate, R3, R5and R6are independently selected from the group consisting of a hydrogen atom, a chloride atom, a methyl group and an ethyl group, and R4is selected from the group consisting of a hydrogen atom, a methyl group, a 10 hydroxyle group, a chloride atom, a bromide atom, a fluoride atom, a iodine atom, an alkoxy group of formula –ORd, Rd being a methyl group or an ethyl group, an acyl group of formula –C(O)ORa, Ra being a methyl group or an ethyl group, an acyl group of formula –C(O)Re, Re being a methyl group, an ethyl group, a linear propyl group, a linear pentyl group, - CH2CH2-cyclopentyl group and a (para-methyl)phenyl group, a carbonate group of formula 15 –OC(O)ORf, Rfbeing a methyl group or an ethyl group, a carboxyl group (-COOH), and a cyano group (–CN). Advantageously, in the compound of formula (I) for use according to the invention, R and R1are independently selected from the group consisting of a hydrogen atom and a 20 methyl group, R2is selected from the group consisting of a hydrogen atom, a –COH group, a – CH2OH group, a –CH2NHC2H5 group, a –CH2N(C2H5)2 group, a -CH2O-ValBoc group, a - CH2O—(Boc)LysBoc group, a -CH2OOC(CH2)2COOH group, a -CH2OCO(PEG)-OCH3 group and a -CH2OCO(NC5H9)NC5H10 group,25R3, R5and R6are independently selected from the group consisting of a hydrogen atom, a chloride atom and an ethyl group, and R4is selected from the group consisting of a hydrogen atom, a hydroxyl group, a chloride atom, a bromide atom, a fluoride atom, a carbonate group of formula –OC(O)ORf, Rf being an ethyl group and an acyl group of formula –C(O)ORa, Ra being a methyl group. 30 According to an embodiment, the compound of formula (I) for use according to the invention is characterized in that at least three of the substituents selected from the group consisting of R3, R4, R5and R6are a hydrogen atom. 35 According to an embodiment, the compound of formula (I) comprises at least one of the substituents selected from the group consisting of R, R1and R2is a hydrogen atom. 12 According to an embodiment, the compound of formula (I) comprises at least two of the substituents selected from the group consisting of R, R1and R2are a hydrogen atom. According to an embodiment, R = R1= R2= H. 5 In a preferred embodiment, the compound of formula (I) is selected from the group consisting of Cl Cl CH3CH3,l , r , 10 , 13 CH3O 3, 15 . n a preerre em o men, e compoun o ormua () s seece rom e group consisting of Cl Cl CH3CH35 , l , 16 Br Br CH3CH33, 17 Cl CH3HOCH3N N , , 18 nd . Preferably, a compound of formula (I) is selected from the group consisting of a compound of formula (I-a), a compound of formula (I-f), a compound of formula (I-h), a 5 compound of formula (I-e), a compound of formula (I-m), a compound of formula (I-n), a compound of formula (I-r), a compound of formula (I-s), a compound of formula (I-t), a compound of formula (I-u), a compound of formula (I-w), a compound of formula (I-x), a compound of formula (I-y), a compound of formula (I-z), and any combination thereof Preferably, a compound of formula (I) is selected from the group consisting of a 10 compound of formula (I-a), a compound of formula (I-f), a compound of formula (I-t), a compound of formula (I-u), and any combination thereof. 19 Preferably, a compound of formula (I) is selected from the group consisting of a compound of formula (I-a), a compound of formula (I-f), a compound of formula (I-t), a compound of formula (I-u), and any combination thereof. Preferably, a compound of formula (I) is selected from the group consisting of a 5 compound of formula (I-a), a compound of formula (I-f), a compound of formula (I-r), a compound of formula (I-s), a compound of formula (I-t), a compound of formula (I-u), and any combination thereof. More preferably, a compound of formula (I) is selected from the group consisting of a compound of formula (I-a), a compound of formula (I-r), a compound of formula (I-s), a 10 compound of formula (I-f), a compound of formula (I-t), a compound of formula (I-u), and any combination thereof. Advantageously, the compound of formula (I) is a compound of formula (I-a). Advantageously, the compound of formula (I) is a compound of formula (I-r), a compound of formula (I-s), a compound of formula (I-f), a compound of formula (I-w), a 15 compound of formula (I-x), a compound of formula (I-y), a compound of formula (I-z), and any combination thereof. The present invention also concerns a pharmaceutical composition for use as neuroprotectant, comprising at least one compound of formula (I) according to the invention 20 and at least one pharmaceutically acceptable excipient. In the pharmaceutical composition for use according to the invention, the compound of formula (I) may also be in the form of co-crystal, said co-crystal comprising the compound of formula (I) and a co-former. The co- former may be chosen from nicotinamide, isonicotinamide, nicotinamide riboside, nicotinamide mononucleotide, ascorbic acid, syringic acid, gallic acid and caffeine. 25 The present invention also concerns a pharmaceutical composition for use in the treatment of defects observed in disorders with a reduced NAD metabolism, comprising at least one compound of formula (I) according to the invention and at least one pharmaceutically acceptable excipient. In the pharmaceutical composition for use according to the invention, the compound of formula (I) may also be in the form of co-crystal, said co- 30 crystal comprising the compound of formula (I) and a co-former. The co-former may be chosen from nicotinamide, isonicotinamide, nicotinamide riboside, nicotinamide mononucleotide, ascorbic acid, syringic acid, gallic acid and caffeine. The expression "pharmaceutically acceptable excipient" refers to any diluents, 35 adjuvants or vehicles, such as preserving agents, fillers, disintegrating agents, wetting 20 agents, emulsifying agents, suspending agents, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The expression “patient” may refer either to a human patient or to an animal patient. The pharmaceutical composition of the present invention may be administered by any 5 suitable route, for example, by oral, buccal, inhalation, sublingual, nasal, percutaneous, i.e. transdermal or parenteral (including intravenous, intramuscular, subcutaneous and intracoronary) administration. Therefore, the pharmaceutical composition of the invention can be provided in various forms, such as in the form of hard gelatin capsules, of capsules, of compressed tablets, of suspensions to be taken orally, of lozenges or of injectable 10 solutions, ointments, cream or in any other form appropriate to the method of administration. The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's conditions. Dosage amount and interval of administration can be adjusted individually to provide plasma levels of compound of formula (I) which are sufficient to maintain the preventive or therapeutic effects. The amount of 15 pharmaceutical composition administered therefore depends on the subject being treated, on the subject's weight, the severity of the affliction and the manner of administration. The invention also relates to a co-crystal comprising one compound of formula (I) as defined in any one of claims 1 to 7 and a co-former, the co-former being preferably chosen from nicotinamide, isonicotinamide, nicotinamide riboside, nicotinamide mononucleotide, 20 ascorbic acid, syringic acid, gallic acid, caffeine. The invention will be better understood from reading the following non-limiting examples. 25 FIGURES Figure 1 represents the quantitative analysis of the neuroprotective effect of compound I-a and I-s on isolated mouse adult DRG . Figure 2 represents the kinetics of NADH autofluorescence in HeLa cells after treatment with I-a (5 µM) or I-s (0.5 µM). 30 As shown on Figure 2, in comparison with controls (dots) a dose-dependent increase in NADH production after I-a (lozenges) and I-s (triangles) treatment was measured duringthe 25-minute analysis. This clearly indicates an activation of the pathways leading to NADH production. Figure 3 represents the effect of compounds I-a, I-f, I-m, I-n, I-q and the comparative 35 example on the cytotoxicity mediated by NAMPT inhibitor FK866. 21 HeLa cells were seeded in microplates and incubated with 3.5 nM FK866 without (black) or in the presence of 6 µM of I-a and different analogues (grey), as indicated, for 72 hours. A viability assay (prestoblue assay) was then conducted. While FK866 induced cell death of over 80% of cells, leaving only 20% alive cells (Y-axis), co-incubation of this 5 inhibitor with compounds I-a, I-n and I-q significantly reduced cell death. Compound I-m had no detectable protective effect. These results show that compounds I-a, I-f, I-m, I-n and I-q can relieve the cytotoxicity of the NAMPT inhibitor FK866, strongly suggesting that activation of NAMPT is involved in the protective activity of these compounds. Of note, the comparative example does not reduce FK866-induced cell death. 10 Figure 4 represents the effect of compound I-a on tactile sensitivity in a rat model of paclitaxel-induced neuropathy. Behavioral assessments were performed on 5-week-old male Sprague-Dawley rats before (basal values) and at days 4, 7, 11 and 14 after the beginning of the drug injections (Compound I-a 50 mg / kg, paclitaxel (PTX) 4 mg / kg, Compound I-a 50 mg / kg + PTX 4 mg / kg). Control animals (Vehicle) received vehicle 15 injections. The results are presented by mean ± standard deviation (n = 6 per group). Tactile nociceptive thresholds were assessed using an electronic von Frey test (J. Ferrier, F. Marchand, D. Balayssac, Assessment of mechanical allodynia in rats using the electronic von frey test, BIO-Protoc., 6 (2016), 10.21769 / BioProtoc.1933). Rats were placed individually in plastic compartments on an elevated wire floor and left for habituation for 20 15 min before each experiment. The von Frey apparatus, consisting of a plastic tip fitted in a hand-held force transducer, was applied perpendicularly to the animal’s right hind paw from below and the force applied was gradually increased until paw withdrawal. The maximum force applied (expressed in grams) to induce paw withdrawal was recorded automatically. 25 As shown on the figure, while rats treated with PTX (white triangle) developed progressively tactile hypersensitivity with a decrease of thresholds in comparison to basal value at day 0, rats treated with compound I-a, alone (black dots) or in combination with PTX (black triangles), presented tactile thresholds not different from those of the vehicle (white dots), clearly demonstrating that compound I-a has no effect in itself and prevents the 30 hypersensitivity induced by PTX. Figure 5 shows representative images of neurofilament staining in axons of adult mouse Dorsal Root Ganglia neurons (DIV 12) treated for 72 h with DMSO (Control), 12 µM of compound I-a, 10 µM of Cisplatin (Cis), 100 nM of Bortezomib (Bort), or a combination of the drugs with compound I-a as indicated. Scale bar, 50 μm. 35 22 EXAMPLES Example 1: Synthesis of compounds of formula (I) 5 The following compounds of formula (I) were synthesized according to the procedures described in WO2021069736. The following compounds were prepared: Références composés Structures 27 yn ess o compoun s (-), (-u), Dichloro[1,3-dihydro-1,3-bis(1-methylethyl)-2H-imidazol-2-ylidene][(1,2,3,4,5-η)- 1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iridium (0.5-1.0 mol %), K2CO3 (5 mol %), 5 compound (I-s) (1.0 mmol) and a 50% aqueous solution of dimethylamine or ethylamine (6.0 mmol) are mixed in a stainless tube. The latter is sealed and the mixture is stirred for 20 hours at 120-130°C. The reaction mixture is then cooled to room temperature and the product is extracted with dichloromethane. The solvent is evaporated to dryness and the crude product is purified through silica gel chromatography. 10 Synthesis of compounds (I-v), (I-w), (I-x), (I-y), (I-z) To one equivalent of (I-s)in pyridine at RT was added 1.1 equivalent of acid chloride and one crystal of 4-(dimethylamino)pyridine. After 12h, the reaction was quenched with saturated NH4Cl, extracted with EtOAc and dried with Na2SO4 to give the crude esters. The 15 latter were purified through silica gel chromatography. 28 Tfus IR (KBr) Compound ion1H NMR and MS (ESI) (°C) (cm-1) , , 29 J = 2.7, 1.8 Hz, 1H), 5.13 (s, 2H), 2.71 – 2.68 (m, 4H), 2.57 (s, 3H), 2.54 (s, 3H). , , y p -y To absolute EtOH (10 ml) was added [1-(6-chloro-1,4-dimethyl-9H-carbazol-3- yl)pyrrol-3-yl]methyl 4-(1-piperidyl)piperidine-1-carboxylate (0.020 g, 0.038 mmol). The 5 suspension was heated up to 70°C to dissolve the molecule and then allowed to cool down to room temperature. Hydrogen chloride was bubbled through the solution for a short period then the reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was then degassed with nitrogen for 10 minutes and filtered. The precipitate was washed with Et2O affording the desired compound in 70% yield. 10 1H NMR (600 MHz, MeOD) δ 8.12 (s, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 8.6Hz, 1H), 7.15 (s, 1H), 6.91 (s, 1H), 6.80 (s, 1H), 6.33 (s, 1H), 5.11 (s, 2H), 4.37 (d, J = 13.6 Hz, 2H), 3.59 (d, J = 13.3 Hz, 1H), 3.50 (s, 1H), 3.39 (m, 1H), 3.12 (t, J = 13.2 Hz, 1H), 3.04 (s, 2H), 2.58 (s, 3H), 2.54 (s, 3H), 2.38 (d, J = 13.7 Hz, 1H), 2.12 (d, J = 12.1 Hz, 2H), 2.05 – 1.83 (m, 6H), 1.72 – 1.61 (m, 2H). 15 MS [M+H]+ for C30H3635ClN4O2 = 519.25 IR (KBr, cm-1): 3196, 2949,1686, 1448 30 Synthesis of compound Comparative example: Synthesis of 6-chloro-1,4-dimethyl-9-(oxiran-2-ylmethyl)-3-pyrrol-1-yl-carbazole : 5 A solution of 6-chloro-1,4-diméthyl-3-pyrrol-1-yl-9H-carbazole (I-a) (0.50 g, 1.69 mmol) and crushed potassium hydroxide pellets (0.11 g, 2.03 mmol) in DMF (3 ml) was 10 stirred for an hour before the addition of epichlorohydrin (0.33 ml, 4.24 mmol). The reaction was stirred overnight at room temperature. The mixture was worked up by dilution with EtOAc (20 ml), and washed two times with water (10 ml) and then brine. The organic layer was dried over MgSO4, filtered and evaporated in vacuo. The crude product is purified on silica gel with gradient of elution cyclohexane to cyclohexane / DCM 8 / 2. The compound 15 expected was obtained as a yellow solid in 73% yield. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 1.9 Hz, 1H), 7.39 (dd, J = 8.8, 1.9 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.11 (s, 1H), 6.75 (t, J = 2.1 Hz, 2H), 6.27 (t, J = 2.1 Hz, 2H), 4.95 (dd, J = 16.4, 2.3 Hz, 1H), 4.59 (dd, J = 16.5, 4.2 Hz, 1H), 3.32 (tt, J = 4.2, 2.4 Hz, 1H), 2.77 – 2.70 (m, 4H), 2.50 (s, 3H), 2.35 (dd, J = 4.7, 2.6 Hz, 1H). 2013C NMR (101 MHz, CDCl3) δ 140.5, 138.8, 133.0, 128.8, 127.5, 125.7, 125.3, 124.8, 123.1 (2C), 122.3, 121.9, 117.8, 110.2, 108.5 (2C), 51.3, 45.3, 44.7, 20.2, 15.1. Synthesis of N-[3-(6-chloro-1,4-dimethyl-3-pyrrol-1-yl-carbazol-9-yl)-2-hydroxy- propyl]-1,1,1-trifluoro-N-(3-methoxyphenyl)methanesulfonamide: 25 31 N-BuLi (2.5 M in hexanes, 0.21 ml) was added dropwise to an ice-cooled solution of 1,1,1-trifluoro-N-(3-methoxyphenyl)methanesulfonamide (0.09g, 0.37 mmol) in dry dioxane 5 (3 ml). The solution was then stirred at room temperature for 15 minutes before addition of 6-chloro-1,4-dimethyl-9-(oxiran-2-ylmethyl)-3-pyrrol-1-yl-carbazole (0.10 g, 28.5 mmol), followed by heating at 90°C for two hours. The reaction was allowed to cool to room temperature then diluted with EtOAc (20 ml) and washed two times with water and finally brine. The organic layer was dried over MgSO4, filtered and evaporated in vacuo. The crude 10 product is purified on silica gel with gradient of elution cyclohexane to cyclohexane / EtOAc 8 / 2. The desired compound was obtained as a yellow oil in 72% yield. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 2.0 Hz, 1H), 7.33 (dd, J = 8.7, 2.0 Hz, 1H), 7.22 (dd, J = 8.4, 3.6 Hz, 2H), 7.07 (s, 1H), 6.86 (dd, J = 8.6, 2.4 Hz, 2H), 6.79 (t, J = 2.3 Hz, 1H), 6.73 (t, J = 2.1 Hz, 2H), 6.27 (t, J = 2.1 Hz, 2H), 4.60 – 4.46 (m, 2H), 4.18 – 4.14 15 (m, 1H), 4.01 – 3.85 (m, 2H), 3.72 (s, 3H), 2.63 (s, 3H), 2.48 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.4, 139.9, 138.4, 137.8, 133.4, 130.5, 129.0, 127.6, 125.8, 125.6, 125.2, 123.1 (2C), 122.5, 122.2, 121.9, 120.4, 117.5, 115.2, 114.9, 114.1 (q, J= 245.1 Hz),109.9, 108.6 (2C), 55.6, 54.7 (d, J= 22.4 Hz), 46.4 (d, J= 22.7 Hz), 20.4, 15.1. 20 Synthesis of N-[3-(6-chloro-1,4-dimethyl-3-pyrrol-1-yl-carbazol-9-yl)-2-fluoro-propyl]- 1,1,1-trifluoro-N-(3-methoxyphenyl)methanesulfonamide

[0007] 32 Morpho-Dast (0.35 ml, 0.03 mmol) was added to a solution of N-[3-(6-chloro-1,4- dimethyl-3-pyrrol-1-yl-carbazol-9-yl)-2-hydroxy-propyl]-1,1,1-trifluoro-N-(3- 5 methoxyphenyl)methanesulfonamide (0.50 g, 0.82 mmol) in anhydrous DCM (8 ml) and stirred overnight at room temperature. The solution, in a water bath at ambient temperature, was neutralized by dropwise addition of 3.75 ml saturated bicarbonate solution. The biphasic mixture was extracted with DCM twice. The combined organics were dried over MgSO4, filtered and condensed. The crude product is purified on silica gel with gradient of 10 elution cyclohexane to cyclohexane / EtOAc 8 / 2. The desired compound was obtained as a yellow solid in 74% yield. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 8.8, 2.1 Hz, 1H), 7.37 – 7.31 (m, 1H), 7.29 (m, 1H), 7.17 (s, 1H), 6.99 – 6.92 (m, 2H), 6.89 (t, J = 2.3 Hz, 1H), 6.83 (t, J = 2.1 Hz, 2H), 6.36 (t, J = 2.1 Hz, 2H), 4.94 – 4.79 (m, 2H), 4.79 – 4.67 (m, 1H), 15 4.26 – 4.03 (m, 2H), 3.81 (s, 3H), 2.70 (s, 3H), 2.58 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.6, 139.9, 138.5, 138.0, 133.2, 130.4, 128.2, 127.4, 125.6, 125.3, 125.0,123.0 (2C), 122.4, 122.0, 120.2, 117.9, 114.8, 114,7, 114.1 (q, J= 245.1 Hz) 110.3, 108.5 (2C), 90.5 (d, J= 182 Hz), 69.8, 56.3 (d, J= 21.7 Hz), 48.2 (d, J= 21.7 Hz), 20.4, 15.1. 20 Synthesis of N-[3-(6-chloro-1,4-dimethyl-3-pyrrol-1-yl-carbazol-9-yl)-2-fluoro-propyl]- 3-methoxy-aniline 33 A two neck flask containing N-[3-(6-chloro-1,4-dimethyl-3-pyrrol-1-yl-carbazol-9-yl)-2- fluoro-propyl]-1,1,1-trifluoro-N-(3-methoxyphenyl)methanesulfonamide (0.20 g, 0.328 5 mmol) was purged with N2 before addition of degassed xylene (3 ml). The solution was cooled in a dry-ice acetone bath before the dropwise addition of Red-Al®(sodium bis(2- methoxyethoxy)aluminium hydride solution, 65% wt in toluene, 0.44 ml, 1.53 mmol) during which the internal temperature was maintained between -50 to -40°C. The cold bath was removed immediately upon completion of Red-Al addition. The reaction was allowed to 10 warm slowly to about -20°C at which time, the reaction flask was heated until the internal temperature was 60°C. Heating was continued for an hour, and then the mixture was allowed to cool to ambient temperature over 30 minutes. The reaction mixture was diluted with EtOAc and washed with water twice. The organic layer was dried over MgSO4, filtered and condensed. The crude product is purified on silica gel with gradient of elution 15 cyclohexane to cyclohexane / EtOAc 8 / 2. The desired compound was obtained as a yellow solid in 50% yield. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 2.0 Hz, 1H), 7.34 (dd, J = 8.7, 2.0 Hz, 1H), 7.29 (d, J = 8.9 Hz, 1H), 7.09 (s, 1H), 7.02 (t, J = 8.1 Hz, 1H), 6.74 (t, J = 2.3 Hz, 2H), 6.27 (p, J = 3.0 Hz, 2H), 6.14 (dd, J = 8.2, 2.2 Hz, 1H), 6.06 (t, J = 2.4 Hz, 1H), 4.98 (m, 1H), 20 4.87 (dd, J = 15.9, 7.5 Hz, 1H), 4.73 (dd, J = 15.9, 4.1 Hz, 1H), 3.90 (t, J = 6.4 Hz, 1H), 3.42 – 3.24 (m, 2H), 2.68 (s, 3H), 2.50 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.9, 148.5, 140.1, 138.5, 133.2, 130.3, 129.0, 127.6, 125.7, 125.4, 125.1, 123.1(2C), 122.5, 122.2, 117.8, 110.2, 108.5 (2C), 106.3, 103.7, 99.5, 91.5 (d, J= 180 Hz), 55.1, 46.4 (d, J=22.3Hz), 45.7 (d, J=22.3Hz), 20.3, 15.1. 25 34 Example 2: Quantitative analysis of the neuroprotective effect of compound I-a and I-s Isolation of adult DRG neurons Dorsal root ganglia (DRG) were dissected from 8- to 10-wk-old C57BL / 6J mice in cold 5 Hank's balanced salt solution (HBSS) (Life Technologies) or Dulbecco's Modified Eagle's medium (Life Technologies) and dissociated in 1 mg / mL Collagenase A for 1 h at 37°C, followed by 0.05% trypsin (Life Technologies) digestion for 3 to 5 min at 37°C and washed with Neurobasal medium (Invitrogen) supplemented with 2% B-27 (Invitrogen), 0.5 mM glutamine (Invitrogen), fetal bovine serum (FBS), and 100 U / mL penicillin-streptomycin. 10 DRG neurons were then triturated by repeated gentle pipetting until no clump was visible, and neuronal bodies were resuspended in Neurobasal medium with FBS prior to plating onto 12 well plates (over 18 mm coverslips) that had been coated overnight with 100 μg / mL poly-D-lysine at 37°C and for 1 h at 37°C with 10 μg / mL laminin (Life Technologies). After 30 min, Neurobasal medium, without FBS, was added to the plate. At15 4 days in vitro (DIV), at least 30% of media was changed and 10 μM Cytosine β-D- arabinofuranoside hydrochloride (Sigma) was added to media every 4 days. Treatments of dissociated DRG neurons Dissociated adult DRG neurons prepared as described above were treated for 72h by 50 nM paclitaxel (PTX), 12 µM compound I-a, 1µM compound I-s or their combination, as 20 indicated, fixed and immunostained with mouse antineurofilament antibodies before measurement of the degeneration index. Degeneration Index Measurements in DRG Neurons. Images of random fields of dissociated adult DRG neurons fixed and immunostained with mouse antineurofilament antibodies were acquired using a 20Å~ objective lens (Olympus 25 IX81) coupled to a monochrome charge-coupled device camera (Sensicam QE; Cooke Corporation). To quantify axonal degeneration, the areas occupied by the axons (total axonal area) and degenerating axons (fragmented axonal area) were measured in the same field from images of DRG neurons. Images were automatically thresholded (global threshold) using a default autothreshold method, binarized, and the fragmented axonal 30 area measured by using the particle analyzer module of ImageJ (size of small fragments = 20 to 10,000 pixels). Degeneration index was calculated as the ratio between the fragmented axonal area and the total axonal area. Images of random fields of dissociated adult DRG neurons, treated for 72h by PTX (50 nM), compound I-a (12 µM), compound I-s (1 µM) or their combination, as indicated, 35 fixed and immunostained with mouse anti-neurofilament antibodies, were acquired using a 35 20Å~ objective lens (Olympus IX81) coupled to a monochrome charge-coupled device camera (Sensicam QE; Cooke Corporation). To quantify axonal degeneration, the areas occupied by the axons (total axonal area) and degenerating axons (fragmented axonal area) were measured in the same field from 5 images of DRG neurons. Degeneration index was calculated as the ratio between the fragmented axonal area and the total axonal area. Example 3: Mechanism behind the neuroprotective effect of the compounds of formula I 10 T as been identified. It has been demonstrated their neuroprotective effect results from activation of a metabolic enzyme: nicotinamide phosphoribosyl transferase (NAMPT), most probably. NAMPT is a key enzyme in the nicotinamide adenine dinucleotide (NAD) salvage pathway, playing a central role in maintaining the cellular NAD pool. Recent studies indicate that NAD 15 is a central modulator controlling the health of damaged or diseased neurons. The inventors have shown that I-a activates NAMPT in vitro, in a biochemical assay, but also in cells, in two different assays. The first measures the kinetics of endogenous NADH production by confocal microscopy after UV excitation (351-364 nm) and measurement of NADH autofluorescence at 390-486 nm. A dose-dependent increase in20 NADH production after I-a and I-s treatment was measured (see figure 2). In another assay, it was demonstrated that the series of compounds can counteract NAMPT inhibition by FK866. The compound FK866 is known to be a potent selective inhibitor of the NAMPT enzyme. Administration of FK866 in cultured cells results in depletion of intracellular NAD levels and subsequent cell death. The effect of compound I- 25 a and other compounds of the series on FK866-induced cytotoxicity in HeLa cells was assayed. HeLa cells were seeded in microplates and incubated with 3.5 nM FK866 without (black) or in the presence of 6 µM of I-a and different analogues (grey), as indicated, for 72 hours. A viability assay (prestoblue assay) was then conducted. 30 While FK866 induced cell death of over 90% of cells, leaving only 8% alive cells (Y- axis), co-incubation of this inhibitor with compounds I-a, I-f, I-m, I-n and I-q reduced cell death. Compound I-m had no detectable protective effect. These results show that compounds I-a, I-f, I-m, I-n and I-q can relieve the cytotoxicity of the NAMPT inhibitor FK866, strongly suggesting that activation of NAMPT is involved in the protective activity of these 35 compounds. Of note, the comparative example does not reduce FK866-induced cell death. 36 Example 4: prevention of paclitaxel-induced neuropathy by compound I-a in the rat The neuroprotection evidenced in vitro in the example 2 also occurs in-vivo, in a rat model of neuropathy. 5 In this model, injections of 4 mg / mL of PTX (white triangle) progressively induce a tactile hypersensitivity, assessed by results from the electronic von Frey assay, which measures the maximum force applied (expressed in grams, Y-axis) to induce paw withdrawal. Such a hypersensitivity does not occur on rats treated with the vehicle, with compound I-a (50mg / kg), alone (black dots) or in combination with PTX (black triangles). 10 This example demonstrates that compound I-a has no hypersensitive effect in itself and prevents the hypersensitivity induced by PTX. Example 5: Synergy with paclitaxel (PTX) of different compounds according to the invention 15 The effect of each compound and of PTX on cell viability was first analyzed. Cell viability was analyzed using the colorimetric Prestoblue assay. Cells were seeded in 96- well microplates at a density of 7,500 cells per well, allowed to adhere for 24 h and treated for 72 h with either DMSO or drugs at different concentrations. Prestoblue (10 µL) was then added to each well, followed by a 30-minute incubation. Fluorescence was measured using 20 a FLUOstar Optima microplate reader (Excitation, 544 nm; Emission, 580 nm, BMG Labtech). The GI50 (50% of growth inhibition) for PTX was calculated. Then, using the highest non-cytotoxic dose of each compound, we quantified the potential for synergy with PTX by the ratio GI50 PTX / GI50 (compound + PTX). The last column of Table 1 indicates qualitatively this potential for synergy. 25 Table 1: Comparative analysis of the potential of synergy with paclitaxel (PTX) of different compounds according to the invention, assessed by their effect on HeLa cell viability alone or in combination with PTX. Compound R R1 R2 R3 R4 R5 R6Synergy with Paclitaxel 30 37 Example 6: Analysis of the potential of activating NAMPT of different compounds The effect of each compound and of FK866, a selective inhibitor of NAMPT, on cell viability was first analyzed. Cell viability was analyzed using the colorimetric Prestoblue 5 assay. Cells were seeded in 96-well microplates at a density of 7,500 cells per well, allowed to adhere for 24 h and treated for 72 h with either DMSO or drugs at different concentrations. Prestoblue (10 µL) was then added to each well, followed by a 30-minute incubation. Fluorescence was measured using a FLUOstar Optima microplate reader (Excitation, 544 nm; Emission, 580 nm, BMG Labtech). The GI50 (50% of growth inhibition) for FK866 was 10 calculated. Then, using the highest non-cytotoxic dose of each compound, we quantified the potential the potential for activation of NAMPT by the ratio GI50 (compound + FK866) / GI50 FK866. The last column of Table 2 indicates qualitatively this potential for NAMPT activation. Table 2: Comparative analysis of the potential of activating NAMPT of different 15 compounds, assessed the HeLa cell resistance to FK866 (a specific NAMPT inhibitor) cytotoxic activity. In cellulo Compound R R1 R2 R3 R4 R5 R6target f 20 PTX, Cisplatin and Bortezomib Compound I-a has a neuroprotective action against not only PTX-, but also Cisplatin- and Bortezomib- neurotoxicity. Primary cultures of dissociated adult dorsal root ganglia (DRG) neurons were isolated from 8- to 10-week-old male and female C57Bl / 6J mice. DRGs were dissected from in cold 25 Hank’s balanced salt solution (HBSS) or Dulbecco’s Modified Eagle’s medium (DMEM) and dissociated in 1 mg / mL Collagenase P for 1 h at 37 °C, followed by 0.05% trypsin for 3 min at 37 °C. Dissociated cells were washed with Neurobasal medium supplemented with 2% B-27 Plus Supplement, 0.5 mM glutamine, 10% FBS, and 100 µg / mL penicillin- streptomycin. Neurons were then triturated by repeated gentle pipetting until there were no 30 more visible clumps, resuspended in Neurobasal medium with 10% FBS and plated onto 12-well plates (over Ø18 mm coverslips) that have previously been coated overnight with 100 μg / mL poly-D-lysine at 37 °C and for 1 h at 37 °C with 10 μg / mL laminin. After 4 days in vitro (DIV), at least 30% of media was changed and 10 μM AraC (Cytosine β-D-arabino 38 furanoside) was added to suppress non-neuronal growth. At DIV 12, neurons were treated for 72 h with 12 µM Carba1, alone or in combination with 50 nM PTX, 10 µM Cis, or 100 nM Bort. Neurons were fixed with 4% paraformaldehyde, washed with PBS, permeabilized with PBS-0.01% Triton X-100 for 15 min, and blocked with PBS-10% FBS for 1 h before being 5 stained overnight at 4°C with neurofilament antibody. Following PBS washes, secondary antibody (Goat anti-Chicken AlexaFluor 488) was applied for 2 h at room temperature (R.T.). Following additional PBS washes, coverslips were mounted with Fluormount-G.

Claims

39 CLAIMS 1. A compound of formula (I) 1 4 R R3R CH 5 R 5 rein R, R1whe and R2are independently selected form the group consisting of: - a hydrogen atom, - a halogen atom, - an alkyl group, linear, cyclic or branched, saturated or unsaturated, possibly 10 substituted, comprising from 1 to 10 carbon atoms, - an acyl group comprising from 1 to 10 carbon atoms, - a carboxyl group, - an amido group comprising from 1 to 10 carbon atoms, and - an imino group, possibly substituted by an alkyl group, linear, cyclic or 15 branched, saturated or unsaturated, and wherein R3, R4, R5and R6are independently selected form the group consisting of: - a hydrogen atom, - a halogen atom, 20 - a hydroxyl group, - an alkyl group, linear, cyclic or branched, saturated or unsaturated, possibly substituted, comprising from 1 to 10 carbon atoms, - an alkoxy group comprising from 1 to 10 carbon atoms, - an acyl group comprising from 1 to 10 carbon atoms, 25 - a carbonate group from 1 to 10 carbon atoms, - a carboxyl group, and - a cyano group for use as neuroprotectants, preferably by preventing peripheral neurons from degenerating after chemotherapy, or in the treatment of defects observed in disorders with 30 a reduced NAD metabolism, preferably chosen from the following:40 - central and peripheral neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis disease, Charcot Marie Tooth disease, Guillain-Barré syndrome; - neuronal trauma, including noise-induced hearing loss; 5 - metabolic diseases such as diabetes or obesity; - organ damage / failure such as liver damage / failure, kidney damage / failure or heart damage / failure; - certain muscular diseases such as Duchene disease; - ageing; 10 - metabolic defects affecting sperm mobility; - the oxidative damage during virus infection.

2. The compound of formula (I) for use according to claim 1, wherein R, R1and R2are independently selected from the group consisting of: 15 - a hydrogen atom, - a halogen atom, - an alkyl group of formula –CnH2n+1-xXx, X being selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, and n being an integer between 1 and 10 and x being the number of X present in the alkyl group, 20 and preferably x being 1 and X being in terminal position in the alkyl group, - an alkyl group bearing an amino (primary, secondary, or tertiary), - an alkyl group bearing an ester, the ester being preferably an ester of a protected (e.g. Boc, Fmoc or Cbz protected) amino acid such as lysine, valine, tyrosine, cysteine, glutamic acid, an ester of a diacid, such as succinic acid or an 25 ester of acid bearing a polyethylene glycol, having from 4 to 50 repeating units, - an alkyl group bearing piperidine or a dipiperidine linked via a carbamate, - an acyl group of formula –C(O)ORa, Rabeing a linear and saturated alkyl group comprising from 1 to 9 carbon atoms, - an acyl group of formula –C(O)H, 30 - a carboxyl group (-COOH), - an amido group of formula –C(O)NRb, Rb being a linear and saturated alkyl group comprising from 1 to 9 carbon atoms, and - an imino group of formula –C=N-Rc, Rcbeing selected from the group consisting of a hydrogen atom or an alkyl group, linear, saturated and comprising 35 from 1 to 10 carbon atoms, or a phenyl group, and41 wherein R3, R4, R5and R6are independently selected from the group consisting of: - a hydrogen atom, - a halogen atom, 5 - a hydroxyl group, - an alkyl group of formula –CnH2n+1, linear, saturated and n being an integer between 1 and 10, - an alkoxy group of formula –ORd, Rdbeing a linear and saturated alkyl group comprising from 1 to 9 carbon atoms, 10 - an acyl group of formula –C(O)ORa, Ra being a linear and saturated alkyl group comprising from 1 to 9 carbon atoms, - an acyl group of formula –C(O)Re, Re being a hydrogen atom or an alkyl group, linear, cyclic or branched, saturated or unsaturated, possibly substituted, comprising from 1 to 10 carbon atoms, 15 - a carbonate group from 1 to 10 carbon atoms, - a carboxyl group (-COOH), and - a cyano group (-CN).

3. The compound of formula (I) for use according to claim 1 or 2, wherein R and R120 are independently selected from the group consisting of: - a hydrogen atom, - a halogen atom, - an alkyl group, linear, saturated and comprising from 1 to 10 carbon atoms, wherein R2is selected from the group consisting of: 25 - a hydrogen atom, - a halogen atom, - an alkyl group of formula –CnH2n+1-xXx, X being selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, and n being an integer between 1 and 10 and x being the number of X present in the alkyl group, 30 and preferably x being 1 and X being in terminal position in the alkyl group, - an alkyl group bearing an amino (primary, secondary, or tertiary), - an alkyl group bearing an ester, the ester being preferably an ester of a protected (e.g. Boc, Fmoc or Cbz protected) amino acid such as lysine, valine, tyrosine, cysteine, glutamic acid, an ester of a diacid, such as succinic acid or an 35 ester of acid bearing a polyethylene glycol, having from 4 to 50 repeating units,42 - an alkyl group bearing piperidine or a dipiperidine linked via a carbamate,- an acyl group of formula –C(O)ORa, Rabeing a linear and saturated alkyl group comprising from 1 to 9 carbon atoms, - an acyl group of formula –C(O)H, 5 - a carboxyl group (-COOH), - an amido group of formula –C(O)NRb, Rb being a linear and saturated alkyl group comprising from 1 to 9 carbon atoms, and - an imino group of formula –C=N-Rc, Rcbeing selected from the group consisting of a hydrogen atom or an alkyl group, linear, saturated and comprising 10 from 1 to 10 carbon atoms, or a phenyl group, wherein R3, R5and R6are independently selected from the group consisting of: - a hydrogen atom, - a halogen atom, - an alkyl group of formula –CnH2n+1, linear, saturated and n being an integer 15 between 1 and 10, and wherein R4is selected from the group consisting of: - a hydrogen atom, - a halogen atom, - a hydroxyl group, 20 - an alkyl group of formula –CnH2n+1, linear, saturated and n being an integer between 1 and 10, - an alkoxy group of formula –ORd, Rd being a linear and saturated alkyl group comprising from 1 to 9 carbon atoms, - an acyl group of formula –C(O)ORa, Ra being a linear and saturated alkyl 25 group comprising from 1 to 9 carbon atoms, - an acyl group of formula –C(O)Re, Rebeing a hydrogen atom or an alkyl group, linear, cyclic or branched, saturated or unsaturated, possibly substituted, comprising from 1 to 10 carbon atoms, - a carbonate group of formula –OC(O)ORf, Rf being a linear and saturated 30 alkyl group comprising from 1 to 9 carbon atoms, - a carboxyl group (-COOH), and - a cyano group (-CN).

4. The compound of formula (I) for use according to any one of claims 1 to 3, 35 wherein R and R1are independently selected from the group consisting of a hydrogen atom, a chloride atom and a methyl group,43 wherein R2is selected from the group consisting of a hydrogen atom, a methyl group, a –COH group, an alkyl group of formula –CH2X, X being selected from the group consisting of a chloride atom, a bromide atom, a iodine atom and a hydroxyl group, an acyl group of formula –C(O)ORa, Ra being a methyl group or an ethyl 5 group, an acyl group of formula –C(O)H, a carboxyl group (-COOH), an amido group of formula –C(O)NRb, Rb being a methyl group or an ethyl group, and an imino group of formula –C=N-Rc, Rcbeing a phenyl group, –CH2Y, Y being selected from the group consisting of an amino group of formula -NRzRz, Rzindependtly representing H or a C1 to C3 alkyl group, an ester, the ester being 10 preferably an ester of a protected (e.g. Boc protected) amino acid such as lysine, valine, tyrosine, cysteine, glutamic acid, an ester of a diacid, such as succinic acid or an ester of acid bearing a polyethylene glycol, having from 4 to 50 repeating units, or a piperidine or a dipiperidine linked via a carbamate, wherein R3, R5and R6are independently selected from the group consisting of a 15 hydrogen atom, a chloride atom, a methyl group and an ethyl group, and wherein R4is selected from the group consisting of a hydrogen atom, a methyl group, a hydroxyl group, a chloride atom, a bromide atom, a fluoride atom, a iodine atom, an alkoxy group of formula –ORd, Rd being a methyl group or an ethyl group, an acyl group of formula –C(O)ORa, Ra being a methyl group or an ethyl group, an 20 acyl group of formula –C(O)Re, Rebeing a methyl group, an ethyl group, a linear propyl group, a linear pentyl group, -CH2CH2-cyclopentyl group and a (para- methyl)phenyl group, a carbonate group of formula –OC(O)ORf, Rf being a methyl group or an ethyl group, a carboxyl group (-COOH), and a cyano group (–CN). 25 5. The compound of formula (I) for use according to any one of claims 1 to 4, wherein R and R1are independently selected from the group consisting of a hydrogen atom and a methyl group, wherein R2is selected from the group consisting of a hydrogen atom, a –COH group, a –CH2OH group, a –CH2NHC2H5 group, a –CH2N(C2H5)2 group, a -CH2O-30 ValBoc group, a -CH2O—(Boc)LysBoc group, a -CH2OOC(CH2)2COOH group, a - CH2OCO(PEG)-OCH3 group and a -CH2OCO(NC5H9)NC5H10 group ,wherein R3, R5and R6are independently selected from the group consisting of a hydrogen atom, a chloride atom and an ethyl group, and wherein R4is selected from the group consisting of a hydrogen atom, a hydroxyl 35 group, a chloride atom, a bromide atom, a fluoride atom, a carbonate group of44 formula –OC(O)ORf, Rfbeing an ethyl group and an acyl group of formula – C(O)ORa, Rabeing a methyl group.

6. The compound of formula (I) for use according to any one of claims 1 to 5, 5 characterized in that at least three of the substituents selected from the group consisting of R3, R4, R5and R6are a hydrogen atom.

7. The compound of formula (I) for use according to any one of claims 1 to 6, characterized in that said compound is selected from the group consisting of Cl Cl CH3CH310 , l , r ,,45 CH3O 3,47 .. p armaceu ca compos on comprsng a eas one compoun o ormula (I) according to any one of claims 1 to 7 and at least one pharmaceutically acceptable 5 excipient, for use as neuroprotectants.

9. A pharmaceutical composition comprising at least one compound of formula (I) according to any one of claims 1 to 7 and at least one pharmaceutically acceptable excipient, for use in the treatment of defects observed in disorders with a reduced 10 NAD metabolism.

10. The pharmaceutical composition for use according to any of claims 8 to 9, said composition being in the form of hard gelatin capsules, of capsules, of compressed tablets, of suspensions, of lozenges or of injectable solutions, ointments, creams. 15 11. The compound of formula (I) for use according to any of claims 1 to 7 or the pharmaceutical composition for use according to any of claims 8 to 10, said compound or composition being administered to a patient, the patient being human or animal, preferably by oral, buccal, inhalation, sublingual, nasal, 20 percutaneous, i.e. transdermal or parenteral, including intravenous, intramuscular, subcutaneous and intracoronary, administration.48 12. The compound of formula (I) for use according to any of claims 1 to 7 or the pharmaceutical composition for use according to claims 8 to 11, wherein the compound is in the form of its tautomeric, racemic, enantiomeric or polymorphic forms or pharmaceutically- acceptable salts. 5 13. The compound of formula (I) for use according to any of claims 1 to 7 or the pharmaceutical composition for use according to claims 8 to 12, wherein the compound is in the form of a co-crystal, said co-crystal comprising the compound of formula (I) and a co-former, the co-former being preferably chosen from 10 nicotinamide, isonicotinamide, nicotinamide riboside, nicotinamide mononucleotide, ascorbic acid, syringic acid, gallic acid and caffeine.

14. A co-crystal comprising one compound of formula (I) as defined in any one of claims 1 to 7 and a co-former, the co-former being preferably chosen from 15 nicotinamide, isonicotinamide, nicotinamide riboside, nicotinamide mononucleotide, ascorbic acid, syringic acid, gallic acid, caffeine.