Sphingosine-1-phosphate lyase inhibitors for use in the treament of neurodegenerative diseases

Abstract

The present invention relates to a sphingosine-1-phosphate lyase (S1PL) inhibitor compound of Formula (I), as described herein, for use in the treatment of a neurodegenerative disease. Formula (I), (I).

Description

SPHINGOSINE-1-PHOSPHATE LYASE INHIBITORS FOR USE IN THE TREAMENT OF NEURODEGENERATIVE DISEASES FIELD OF INVENTION

[0001] The present invention relates to small molecule Sphingosine-1-Phosphate Lyase (S1PL) inhibitors and their use in the treatment of neurogenerative diseases. BACKGROUND OF INVENTION

[0002] Neurodegenerative disorders (ND) are marked by extensive neuronal apoptosis and gliosis. Several apoptosis-inducing agents have been described, which improved the understanding of the regulatory mechanisms underlying modes of cell death and their relations with the occurrence of neurodegenerative disorders. A major breakthrough in delineation of the mechanism of cell death came from elucidation of the sphingomyelin (SM)-ceramide pathway that has received increasing attention in recent years. The SM pathway induces apoptosis, differentiation, proliferation, and growth arrest depending upon cell and receptor types, and on downstream targets. Sphingomyelin, a plasma membrane constituent, is abundant in mammalian nervous system, and ceramide, its primary catabolic product released by activation of either neutral or acidic sphingomyelinase, serves as a potential lipid second messenger. The unregulated apoptosis leading the loss of specific populations of neurons is generally recognized as a trigger to the development of several adult neurological disorders including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and cerebral ischemia. Furthermore, neurogenerative diseases can also be accompanied by central or peripheral inflammation. Consequently, there is a substantial need to supply an effective and pleiotropic treatment for the treatment of neurogenerative disorders.

[0003] Sphingosine-1-Phosphate (S1P) is a lipid metabolite that is produced from ceramide and other higher order sphingolipids by sphingosine kinase (SphK1 and SphK2). S1PL is a vitamin B6-dependent enzyme localized in the membrane of the endoplasmic reticulum.S1P levels are tightly controlled through production via SphKs,recycling back into sphingosine-by-sphingosine phosphatases (SGPP1 and 2) or lipid phosphate phosphatases (LPP1 and 2) and irreversible degradation through sphingosine- 1-phosphate lyase (S1PL; also known as SGPL1 in mammals) into phospho-ethanolamine (pEtN) and 2-hexadecanal. S1PL inhibitors, such as LX2931 or LX2932 have been reported for their use in the treatment of autoimmune diseases (BAGDANOFF, J. T. et al.: “Inhibition of Sphingosine-1-Phosphate Lyase for the Treatment of Autoimmune Disorders”, Journal of Medicinal Chemistry 2009, Vol.52, pp.3941-3953). Furthermore, the international application WO 2019 / 034768 (AC BIOSCIENCE) discloses the use of S1PL inhibitors as an adjuvant treatment that enhances the anticancer chemotherapy efficacy. The function of S1P pathway and in particular of the S1PL implication in the pathophysiology of the nervous system, and in the development and course of neurogenerative disorders has not been clearly elucidated.

[0004] The present invention aims at supplying S1PL inhibitor compounds for their use in an efficient treatment of neurogenerative diseases.

[0005] According to an advantageous aspect of the invention, the S1PL inhibitors disclosed herein present an enhanced pharmacodynamic and / or pharmacokinetic profile. In particular, the S1P inhibitors disclosed herein present an enhanced S1PL inhibitory effect, thereby being capable of fine tuning the S1P pathway that can treat and / or attenuate the symptoms of neurogenerative diseases in a pleiotropic manner. For instance, the effective S1PL inhibition provided by the compounds disclosed herein may not only inhibit the peripheral S1PL, thereby affecting the peripheral manifestations of the neurogenerative diseases, but also the S1PL present in the central nervous system. Furthermore, the S1PL inhibitor compounds disclosed herein may reduce the neuronal inflammation of the neurodegenerative disease and / or the apoptosis of neuronal cells.

[0006] According to a further advantageous aspect, the S1PL inhibitors compounds disclosed herein can readily act on the S1PL, without necessitating multiple bioconversion steps, thereby showing an improved pharmacokinetic profile, further improving the therapeutic potential of the medical uses and methods disclosed herein.SUMMARY

[0007] The invention relates to a sphingosine-1-phosphate lyase (S1PL) inhibitor compound for use in the treatment of a neurodegenerative disease, wherein the S1PL inhibitor compound is a compound of formula (I)or a tautomer thereof, or a pharmaceutically acceptable salt thereof; wherein Z is selected from the group consisting of O, S, and NH; Q is selected from the group consistingX is selected from the group consisting of O and NR3; W, Y, and V are each independently selected from the group consisting of CH2, CH, N, NH, O, and S; A is selected from the group consisting of N and N+R5; R1 is selected from the group consisting of ORA, NHOH, hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted arylalkyl, optionally substituted heteroalkyl, optionally substituted heterocycle, optionally substituted alkylheterocycle, and optionally substituted heterocyclealkyl; R2 is selected from the group consisting of ORB, C(O)ORB, hydrogen, halogen, nitrile, optionally substituted hydroxyalkyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted arylalkyl, optionally substituted heteroalkyl, optionally substituted heterocycle, optionally substituted alkylheterocycle, andoptionally substituted heterocyclealkyl; R3 is selected from the group consisting of ORC, N(RC)2, NHC(O)RC, NHSO2RC, and hydrogen; R4is selected from the group consisting of ORD, OC(O)RD, N(RE)2, hydrogen, halogen, optionally substituted hydroxyalkyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted arylalkyl, optionally substituted heteroalkyl, optionally substituted heterocycle, optionally substituted alkylheterocycle, and optionally substituted heterocyclealkyl; R5 is selected from the group consisting of alkyl and alkyl-oxy-alkyl; RA, RB, RC, RD, and RE are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted arylalkyl, optionally substituted heteroalkyl, optionally substituted heterocycle, optionally substituted alkylheterocycle, and optionally substituted heterocyclealkyl; provided that the compound of Formula (I) is not selected from 2-acetyl-4-tetrahydroxybutylimidazole (THI), tautomers thereof, and pharmaceutically acceptable salts thereof; and wherein the neurogenerative disease is selected from the group consisting of Alzheimer’s disease, Huntington’s disease, motor neuron disease such as amyotrophic lateral sclerosis (ALS), ataxia, Parkinson’s disease, and multiple system atrophy.

[0008] In some embodiments,, X is O or N-OH, R1 is methyl, R2is hydrogen, and R4is an hydroxylated C1-C4 alkyl.

[0009] In some embodiments, the S1PL inhibitor compound for use according to the invention is a compound of formulae (II), (III) or (IV), preferably the compound is of formula (II) or formula (III)

[0010] According to some particular embodiments, R4is an hydroxylated C1-C4 alkyl selected from the group consisting of hydroxymethyl, 1-hydroxy-ethyl, 1,2-dihydroxyethyl, 1-hydroxypropyl, 1,2-dihydorxypropyl, 1,3-dihydroxypropyl, 1,2,3-trihydroxypropyl, 1-hydroxybutyl, 1,2-dihydroxybutyl, 1,2,3-trihydroxybutyl, and 1,2,3,4-tetrahydroxybutyl; preferably the hydroxylated C1-C4 alkyl is hydroxymethyl or 1,2,3,4-tetrahydroxybutyl.

[0011] According to a series of embodiments, A in the above formulae (I) to (IV) is N.

[0012] According to one embodiment, the S1PL inhibitor compound is selected from (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime (Compound 1), tautomers thereof, and pharmaceutically acceptable salts thereofCompound 1

[0013] According to another embodiment, the S1PL inhibitor compound for use according to the invention is selected from (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (Compound 2), tautomers thereof, and pharmaceutically acceptable salts thereof

[0014] According to another embodiment, the S1PL inhibitor compound for use according to the invention is selected from (E)-1-(4-(hydroxymethyl)-1H-imidazol-2- yl)ethan-1-one oxime (Compound 3), tautomers thereof, and pharmaceutically acceptable salts thereofCompound 3

[0015] According to another embodiment, the compound is selected from (2-(isoxazol- 3-yl)-1H-imidazol-4-yl)methanol (Compound 4), tautomers thereof, and pharmaceutically acceptable salts thereofCompound 4

[0016] According to another series of embodiments, A is N+R5.

[0017] In some embodiments, R5 is a C1-C4 alkyl or C1-C4 alkyl-oxy-C1-C4 alkyl, preferably wherein R5 is selected from the group consisting of methyl, ethyl, n-propyl, and methoxy-ethyl.

[0018] In some embodiments, A is N+R5 and Q is acetyl, preferably wherein R5 is selected from the group consisting of methyl, ethyl, n-propyl, and methoxy-ethyl.

[0019] Thus, in some specific embodiments, the S1PL inhibitor compound can be selected from Compounds 5-8 and pharmaceutically acceptable salts thereofCompound 7 Compound 8

[0020] In some further embodiments, the S1PL inhibitor compound is selected from Compounds 9-22, tautomers thereof, and pharmaceutically acceptable salts thereofCompound 11 Compound 12Compound 21Compound 22

[0021] In some embodiments, the neurogenerative disease is selected from the group consisting of Alzheimer’s disease, Huntington’s disease, motor neuron disease such as amyotrophic lateral sclerosis (ALS), and Parkinson’s disease. In some particular embodiments, the neurogenerative disease is Alzheimer’s disease. In some particular embodiments, the neurogenerative disease is Huntington’s disease. In some particular embodiments, the neurogenerative disease is a motor neuron disease, preferably amyotrophic lateral sclerosis (ALS). In some particular embodiments, the neurogenerative disease is Parkinson’s disease.

[0022] In some embodiments, the S1PL inhibitor compound, as defined hereinabove, reduces the neuronal inflammation of the neurodegenerative disease and / or reduces the apoptosis of oligodendrocytes and astrocytes. DEFINITIONS

[0023] In the present invention, the following terms have the following meanings:

[0024] “Alkyl” refers to a straight chain, branched and / or cyclic (“cycloalkyl”) hydrocarbon having from 1 to 20 or 1 to 10 or 1 to 4 carbon atoms. Alkyl moieties having from 1 to 4 carbons are referred to as “lower alkyl” or “C1-C4 alkyl”. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl. Cycloalkyl moieties may be monocyclic or multicyclic, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Additional examples of alkyl moieties have linear, branched and / or cyclic portions (e.g., l-ethyl-4-methyl-cyclohexyl).

[0025] “Alkenyl” refers to a straight chain, branched and / or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 10 or 2 to 6) carbon atoms, and including at least one carbon-carbon double bond. Representative alkenyl moieties include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl and 3-decenyl.

[0026] “Alkylaryl” or “alkyl-aryl” refers to an alkyl moiety bound to an aryl moiety.

[0027] “Alkylheteroaryl” or “alkyl-heteroaryl” refers to an alkyl moiety bound to a heteroaryl moiety.

[0028] “Alkylheterocycle” or “alkyl-heterocycle” refers to an alkyl moiety bound to a heterocycle moiety.

[0029] “Alkynyl” refers to a straight chain, branched or cyclic hydrocarbon having from 2 to 20 or 2 to 20 or 2 to 6 carbon atoms, and including at least one carbon-carbon triple bond. Representative alkynyl moieties include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3 -methyl- 1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7- octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl and 9-decynyl.

[0030] “Alkoxy” or “alkyl-oxy” refers to an -O-alkyl group. Examples of alkoxy groups include, but are not limited to, -OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, and -O(CH2)5CH3.

[0031] “Aryl” refers to an aromatic ring or an aromatic or partially aromatic ring system composed of carbon and hydrogen atoms. An aryl moiety may comprise multiple rings bound or fused together. Examples of aryl moieties include, but are not limited to, anthracenyl, azulenyl, biphenyl, fluorenyl, indanyl, indenyl, naphthyl, phenanthrenyl, phenyl, 1,2,3,4-tetrahydro-naphthalene, and tolyl.

[0032] “Arylalkyl” or “aryl-alkyl” refers to an aryl moiety bound to an alkyl moiety.

[0033] “Halogen” and “halo” encompass fluorine, chlorine, bromine, and iodine.

[0034] “Heteroalkyl” refers to an alkyl moiety (linear, branched or cyclic) in which at least one of its carbon atoms has been replaced with a heteroatom (such as N, O or S).

[0035] “Heteroaryl” refers to an aryl moiety wherein at least one of its carbon atoms has been replaced with a heteroatom (such as N, O or S). Examples include, but are not limited to, acridinyl, benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoquinazolinyl, benzothiazolyl, benzoxazolyl, furyl, imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, thiazolyl, and triazinyl.

[0036] “Heteroarylalkyl” or “heteroaryl-alkyl” refers to a heteroaryl moiety bound to an alkyl moiety.

[0037] “Heterocycle” refers to an aromatic, partially aromatic or non-aromatic monocyclic or polycyclic ring or ring system comprised of carbon, hydrogen and at least one heteroatom (e.g., N, O or S). A heterocycle may comprise multiple (i.e., two or more) rings fused or bound together. Heterocycles include heteroaryls. Examples include, but are not limited to, benzo[l,3]dioxolyl, 2,3-dihydro-benzo[l,4]dioxinyl, cinnolinyl, furanyl, hydantoinyl, morpholinyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl and valerolactamyl.

[0038] “Heterocycloalkyl” or “heterocycle-alkyl” refers to a heterocycle moiety bound to an alkyl moiety.

[0039] “Heterocycloalkyl” refers to a non-aromatic heterocycle.

[0040] “Heterocycloalkylalkyl” or “heterocycloalkyl-alkyl” refers to a heterocycloalkyl moiety bound to an alkyl moiety.

[0041] The term “substituted” when used to describe a chemical structure or moiety, refers to a derivative of that structure or moiety wherein one or more of its hydrogen atoms is substituted with a chemical moiety or functional group such as, but not limited to, alcohol, aldehyde, alkoxy, alkanoyloxy, alkoxy carbonyl, alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl), alkynyl, alkylcarbonyloxy (-OC(O)alkyl), amide (-C(O)NH-alkyl- or -alkylNHC(O)alkyl), amidinyl (-C(NH)NH-alkyl or -C(NR)NH2), amine (primary, secondary and tertiary such as alkylamino, arylamino, arylalkylamino), aroyl, aryl, aryloxy, azo, carbamoyl (-NHC(O)O-alkyl- or -OC(O)NH-alkyl), carbamyl (for example CONH2, as well as CONH-alkyl, CONH-aryl, and CONH-arylalkyl), carbonyl, carboxyl, carboxylic acid, carboxylic acid anhydride, carboxylic acid chloride, cyano, ester, epoxide, ether (e.g., methoxy, ethoxy), guanidino, halo, haloalkyl (for example -CCI3, -CF3, -C(CF3)3), heteroalkyl, hemiacetal, imine (primary and secondary), isocyanate, isothiocyanate, ketone, nitrile, nitro, oxo, phosphodiester, sulfide, sulfonamido (e.g., SO2NH2), sulfone, sulfonyl (including alkylsulfonyl, arylsulfonyl and arylalkylsulfonyl), sulfoxide, thiol (e.g., sulfhydryl, thioether) and urea (-NHCONH- alkyl-).

[0042] “Tautomers” refer to compounds whose structures differ markedly in the arrangement of atoms, but which exist in easy and rapid equilibrium. Indeed, some compounds of the present invention can exist in a tautomeric form which is also intended to be encompassed within the scope of the present invention. It is to be understood that compounds of present invention may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the present invention, and the naming of the compounds does not exclude any tautomeric form. For instance, compounds of formula (I) wherein Z is NH and A is N, may presented tautomeric forms that can be illustrated as formula (I’). The same visual representation can be also applied for formulae (II)-(IV) wherein Z is NH and A is N. In a solution, tautomers exist as mixtures of a tautomeric set. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the compounds disclosed herein. A tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This reaction results in the formal migration of a hydrogen atom accompanied by a shift of adjacent conjugated double bonds. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers can be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerizations is called tautomerism. Tautomerizations are catalyzed by: Base: 1. deprotonation; 2. formation of a delocalized anion (e.g., an enolate); 3. protonation at a different position of the anion; Acid: 1. protonation; 2. formation of a delocalized cation; 3. deprotonation at a different position adjacent to the cation.

[0043] “Administration” or “administering” to a subject refers to any means of introducing at least one compound of the invention or the pharmaceutical composition of the invention onto and / or into the subject (patient) body or a portion thereof.

[0044] “Pharmaceutically acceptable excipients and / or carriers” means that the compositions or components thereof so described are suitable for suitable for administration to subject (patient) body without undue toxicity, incompatibility, instability, irritability, allergic response, and the like.

[0045] “Subject” and “patient” are well-recognized in the art, and, are used herein to refer to a mammal, including, for example, humans, animals, domestic pets, livestock and other farm animals; the most preferably a mammal is a human. In some embodiments, the subject is a subject in need of treatment or a subject being affected by a neurogenerative disease. The term does not denote a particular sex. Thus, male or female subjects, affected by or prone to be affected by neurogenerative diseases or neurogenerative manifestation are intended to be covered by this term.

[0046] “Therapeutically effective amount”, as used herein, refers to any amount of a compound of the invention that will cause inhibition of a disease or a manifestation thereof in a subject and thus reduction of symptoms, disappearance of the symptoms or relief from symptoms related to a disease or a disorder, when applied, either once, or repeatedly over time. Therapeutically effective amounts can be readily determined by persons skilled in the art using routine experimentation and using tests and measures commonly employed in the art, or can be based upon the subjective response of patients undergoing treatment. The therapeutically effective amount may also encompass a "prophylactically effective amount," intended to include the amount of a compound of the invention that, when administered to a subject who does not yet experience or display symptoms of a disease or a disorder, but who may be predisposed to the disease or the disorder, is sufficient to prevent or ameliorate the disease or the disorder or one or more symptoms of the disease or the disorder. Ameliorating the disease or the disorder includes slowing the course of the disease or the disorder or reducing the severity of later- developing disease or disorder. The "prophylactically effective amount" can be readily determined by persons skilled in the art using routine experimentation and using tests and measures commonly employed in the art, or can be based upon the subjective response of patients undergoing treatment.

[0047] “Treat” and its grammatical variants (for example “to treat”, “treating”, and “treatment”) refer to administration of an active pharmaceutical ingredient to a subject (patient), such as the compound of the invention, with the purpose of inhibiting a disease or a disorder (in particular a neurogenerative disorder) in a subject (patient). Treating the disease or the disorder includes ameliorating at least one symptom, reducing severity,impeding progress, and / or curing the subject (patient) of the disease or the disorder. In the present context, treatment entails oral, parenteral, mucosal and / or topical administration of the compounds of the invention or the pharmaceutical composition of the invention to a subject (patient). In a specific embodiment of the invention, treating a neurogenerative disease refers to impeding, or slowing down its progression. In the context of the invention the treatment also refers to prophylactic steps taken to reduce the likelihood of a subject from suffering from a particular manifestation of a neurogenerative disease or disorder. The likelihood of the disease or the disorder occurring in the subject need not be reduced to zero for the preventing to occur; rather, if the steps reduce the risk of a deleterious manifestation across a population, then the steps to impede a deleterious manifestation of the disease or the disorder is within the scope and meaning herein. DETAILED DESCRIPTION

[0048] This invention thus relates to sphingosine-1-phosphate lyase (S1PL) inhibitor compounds as detailed hereinbelow, and in particular the use of the S1PL inhibitors in the treatment of a neurogenerative disease.

[0049] According to a first aspect, the compound according to the invention is a compound of formula (I)or a tautomer thereof, or a pharmaceutically acceptable salt thereof; wherein Z, A ,Q, R2and R4are as defined hereinbelow.

[0050] Z is selected from selected from the group consisting of O, S, and NH. According to some preferred embodiments, Z is NH.

[0051] Q is selected from the group consisting ofwherein W, Y, and V are each independently selected from CH2, CH, N, NH, O, and S, preferably each of W, Y, and V are each independently selected from the group consisting of CH2, CH, N, and NH. According to some preferred embodiments, Q is selected from the group consisting of oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, acetyl, and ethanone oxime, more preferably Q is selected from the group consisting of isoxazolyl (preferably isoxazol-3-yl), acetyl, and ethanone oxime.

[0052] X is selected from the group consisting of O and NR3, wherein R3is as described hereinbelow.

[0053] A is selected from the group consisting of N and N+R5, wherein R5is as described hereinbelow.

[0054] R1 is selected from the group consisting of ORA (wherein RA is as described hereinbelow), NHOH, hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted arylalkyl, optionally substituted heteroalkyl, optionally substituted heterocycle, optionally substituted alkylheterocycle, and optionally substituted heterocyclealkyl. Preferably, R1 is a C1-C4 alkyl, more preferably R1is methyl.

[0055] R2is selected from the group consisting of ORB, C(O)ORB (wherein RBis as described hereinbelow), hydrogen, halogen, nitrile, optionally substituted hydroxyalkyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted arylalkyl, optionally substituted heteroalkyl, optionally substituted heterocycle, optionally substituted alkylheterocycle, and optionally substituted heterocyclealkyl. Preferably, R2 is hydrogen.

[0056] R3is selected from the group consisting of OH, ORC, N(RC)2, NHC(O)RC, NHSO2RC, and hydrogen, wherein Rc is as described hereinbelow.

[0057] R4 is selected from the group consisting of ORD, OC(O)RD, N(RE)2 (wherein RD and REare as described hereinbelow), hydrogen, halogen, optionally substituted hydroxyalkyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted arylalkyl, optionally substituted heteroalkyl, optionally substituted heterocycle, optionally substituted alkylheterocycle, and optionally substituted heterocyclealkyl. Preferably R4is an hydroxyalkyl, more preferably an hydroxylated C1-C4 alkyl selected from the group consisting of hydroxymethyl; 1-hydroxy-ethyl, 1,2-dihydroxyethyl, 1-hydroxypropyl, 1,2-dihydorxypropyl, 1,3-dihydroxypropyl, 1,2,3-trihydroxypropyl, 1-hydroxybutyl, 1,2-dihydroxybutyl, 1,2,3-trihydroxybutyl, 1,2,3,4-tetrahydroxybutyl, even more preferably R4 is hydroxymethyl or 1,2,3,4-tetrahydroxybutyl.

[0058] R5is selected from the group consisting of alkyl and alkyl-oxy-alkyl, preferably R5is a C1-C4 alkyl or C1-C4 alkyl-oxy-C1-C4 alkyl, more preferably R5is selected from the group consisting of methyl, ethyl, n-propyl and methoxy-ethyl.

[0059] RA, RB, RC, RD, and REare each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted arylalkyl, optionally substituted heteroalkyl, optionally substituted heterocycle, optionally substituted alkylheterocycle, and optionally substituted heterocyclealkyl.

[0060] In some embodiments, A is selected from the group consisting of N, N-C1-C4 alkyl or N-C1-C4 alkyl-oxy-C1-C4 alkyl, more preferably A is selected from the group consisting of N, NH, N-methyl, N-ethyl, N-(n-propyl), and N-methoxy-ethyl. According to a first embodiment A is N. According to a second embodiment, A is N-(C1-C4 alkyl) or N-(C1-C4 alkyl-oxy-C1-C4 alkyl), preferably A is selected from the group consisting of N-methyl, N-ethyl, N-(n-propyl), and N-methoxy-ethyl.

[0061] In some embodiments, in the S1PL inhibitor compound of formula (I), Q ismethyl, R2is hydrogen, and R4is an hydroxylated C1-C4 alkyl.

[0062] The compounds of formulae disclosed herein or tautomers thereof, or pharmaceutically acceptable salts of said compounds or tautomers disclosed herein can have asymmetric centers. The compounds of the disclosed Formulae or tautomers thereof, or pharmaceutically acceptable salts of said compounds or tautomers of the present invention containing an asymmetrically substituted atom can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Cis and trans geometric isomers of the compounds can be isolated as a mixture of isomers or as separate isomeric forms. All chiral, diastereomeric, racemic, and geometric isomeric forms of a structure are intended, unless specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present Formulae or tautomers thereof, or pharmaceutically acceptable salts of said compounds or tautomers of the present invention and intermediates made herein are considered to be part of the present invention. All tautomers of shown or described compounds are also considered to be part of the present invention. Specifically, the compounds of the present formulae can contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Unless otherwise specified, the present invention is meant to comprehend all such isomeric forms of the compounds of the disclosed formulae. If necessary, the compounds of the disclosed formulae may be separated into their individual diastereoisomers such as for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof, or via chiral chromatography using an optically active stationary phase. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystallineintermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. Alternatively, any stereoisomer of a compound of the general structural formula (I) may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base.

[0063] It is of note that when Z is NH and A is N, tautomerism may be observed between the nitrogen atoms of the imidazole ring. Accordingly, in some embodiments, the S1PL inhibitor compound is of formula (I’)(I’) wherein R2, R4 and Q are as defined hereinabove.

[0064] The same applies for the formulae (II-IV), formulae (Ia-Iva) and compounds described herein wherein Z is NH and A is N.

[0065] The compounds of formula (I) or tautomers thereof, or pharmaceutically acceptable salts of said compounds or tautomers disclosed herein have at least one side chain that is typically an aliphatic primary alcohol such as -(CH2)n-OH, wherein n ranges from 1 to 5, preferably n is 1. Without willing to be bound by a theory, such compounds can be phosphorylated by kinases during metabolization of the compounds of theinvention in the human body, thereby providing phosphorylated derivatives of the compounds of the invention.

[0066] Accordingly, in some embodiments, the S1PL inhibitor is of formula (Ia), wherein A, Z and Q are as defined hereinabove

[0067] According to a first variant, the S1PL inhibitor is a compound of formula (I) wherein Q is ethanone oxime, i.e., whereinmethyl, and X is NR3, wherein R3 is OH.

[0068] Accordingly, the S1PL inhibitor compound can be of formula (II), tautomers thereof (in particular when A is N), and pharmaceutically acceptable salts thereofwherein R4and A are as defined hereinabove.

[0069] In some embodiments, R4 in formula (II) is an optionally substituted hydroxyalkyl, preferably R4 is an hydroxyalkyl, more preferably an hydroxylatedC1-C4 alkyl selected from the group consisting of hydroxymethyl, 1-hydroxy-ethyl, 1,2-dihydroxyethyl, 1-hydroxypropyl, 1,2-dihydorxypropyl, 1,3-dihydroxypropyl, 1,2,3-trihydroxypropyl, 1-hydroxybutyl, 1,2-dihydroxybutyl, 1,2,3-trihydroxybutyl, 1,2,3,4-tetrahydroxybutyl, even more preferably R4 is hydroxymethyl or 1,2,3,4-tetrahydroxybutyl, still more preferably R4is hydroxymethyl.

[0070] In formula (II), A can be selected from of N and N+R5, R5being alkyl, or alkyl- oxy-alkyl, preferably R5 is a C1-C4 alkyl or C1-C4 alkyl-oxy- C1-C4 alkyl, more preferably R5 is selected from the group consisting of methyl, ethyl, n-propyl and methoxy-ethyl. According to a first embodiment A is N. According to a second embodiment, A is N-(C1-C4 alkyl) or N-(C1-C4 alkyl-oxy-C1-C4 alkyl), preferably A is selected from the group consisting of N-methyl, N-ethyl, N-(n-propyl), and N-methoxy-ethyl.

[0071] When A is N and R4is 1,2,3,4-tetrahydroxybutyl,s more specifically (1R,2S,3R)-1,2,3,4-tetrahydroxybutyl, the S1PL inhibitor compound is LX2931 (CAS N°948840-25-3) referenced herein as Compound 1. One of its tautomers is referenced herein as Compound 1’. Compound 1 (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H- imidazol-2-yl)ethanone oxime Compound 1’ (E)-1-(5-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H- imidazol-2-yl)ethanone oxime

[0072] In some embodiments, the S1PL inhibitor is of formula (IIa), wherein A is as defined above.

[0073] In one embodiment, the S1PL inhibitor is of formula (IIa) wherein A is N, the S1PL inhibitor is preferably Compound 3. One of its tautomers is referenced herein as Compound 3’. Compound 3 (E)-1-(4-(hydroxymethyl)-1H-imidazol-2-yl)ethan-1-one oxime Compound 3’ (E)-1-(5-(hydroxymethyl)-1H-imidazol-2-yl)ethan-1-one oxime

[0074] According to a second variant, the S1PL inhibitor is a compound of formula (I) wherein Q is isoxazol-3-yl or isoxazol-5-yl, preferably(isoxazol-3-yl).

[0075] Accordingly, the S1PL inhibitor compound can be of formula (III), tautomers thereof (in particular when A is N), and pharmaceutically acceptable salts thereof:wherein R4and A are as defined hereinabove.

[0076] In some embodiments, R4 in formula (III) is an optionally substituted hydroxyalkyl, preferably R4is an hydroxyalkyl, more preferably an hydroxylated C1-C4 alkyl selected from the group consisting of hydroxymethyl, 1-hydroxy-ethyl, 1,2-dihydroxyethyl, 1-hydroxypropyl, 1,2-dihydorxypropyl, 1,3-dihydroxypropyl, 1,2,3-trihydroxypropyl, 1-hydroxybutyl, 1,2-dihydroxybutyl, 1,2,3-trihydroxybutyl, 1,2,3,4-tetrahydroxybutyl, even more preferably R4is hydroxymethyl or 1,2,3,4-tetrahydroxybutyl, still more preferably R4 is hydroxymethyl.

[0077] In formula (III), A can be selected from the group consisting of N and N+R5, R5 being alkyl, or alkyl-oxy-alkyl, preferably R5is a C1-C4 alkyl or C1-C4 alkyl-oxy- C1-C4 alkyl, more preferably R5is selected from the group consisting of methyl, ethyl, n-propyl and methoxy-ethyl. According to a first embodiment A is N. According to a second embodiment, A is N-(C1-C4 alkyl) or N-(C1-C4 alkyl-oxy-C1-C4 alkyl), preferably A is selected from the group consisting of N-methyl, N-ethyl, N-(n-propyl), and N-methoxy-ethyl.

[0078] When A is N and R4 is 1,2,3,4-tetrahydroxybutyl, more specifically (1R,2S,3R)-1,2,3,4-tetrahydroxybutyl, the S1PL inhibitor compound is LX2932 (CAS N°1055027-48-9) referenced herein as Compound 2. One of its tautomers is referenced herein as Compound 2’.Compound 2 (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4- yl)butane-1,2,3,4-tetraol Compound 2’ (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-5- yl)butane-1,2,3,4-tetraol

[0079] In some embodiments, the S1PL inhibitor is of formula (IIIa), wherein A is as defined hereinabove.

[0080] In one embodiment, the S1PL inhibitor is of formula (IIIa) wherein A is N, the S1PL inhibitor is preferably Compound 4. One of its tautomers is referenced herein as Compound 4’.Compound 4 (2-(isoxazol-3-yl)-1H-imidazol-4-yl)methanol Compound 4’ (2-(isoxazol-3-yl)-1H-imidazol-5-yl)methanol

[0081] According to a third variant, the S1PL inhibitor compound is of formula (I) wherein R2 is hydrogen, Q is acetyl, i.e., whereinmethyl and X is O. Thus, the S1PL inhibitor compound is of formula (IV)wherein R4 and A are as defined hereinabove.

[0082] When R4is 1,2,3,4-tetrahydroxybutyl and A is N, the compound of formula (IV) is 1-[4-(1(R),2(S),3(R),4-tetrahydroxybutyl)-1H-imidazol-2-yl]-ethanone or 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole, also known as THI (CAS N° 94944-70-4). In some embodiments, the S1PL inhibitor for use according to the invention is not 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI).

[0083] When R4 is hydroxymethyl and A is N, the compound of formula (II) is 2-acetyl-4-hydroxymethyl-imidazole, also known as A6770 (CAS N° 1331754-16-5). In some embodiments, the S1PL inhibitor for use according to the invention is not A6770.

[0084] According to some preferred embodiments, the S1PL inhibitor compound is a compound of formula (IV) wherein R4is hydroxymethyl, i.e., a compound of formula (IVa), wherein A is as defined above:

[0085] In formulae (IV) and (IVa), A can be selected from of N and N+R5, R5being alkyl, or alkyl-oxy-alkyl, preferably R5is a C1-C4 alkyl or C1-C4 alkyl-oxy-C1-C4 alkyl, more preferably R5 is selected from the group consisting of methyl, ethyl, n-propyl and methoxy-ethyl. According to a first embodiment A is N. According to a preferred embodiment, A is N-(C1-C4 alkyl) or N-(C1-C4 alkyl-oxy-C1-C4 alkyl), preferably A is selected from the group consisting of N-methyl, N-ethyl, N-(n-propyl), and N-methoxy- ethyl.

[0086] In some embodiments, the S1PL inhibitor compound is a compound of formula (IVa) selected from the group consisting of the following Compounds 5 to 8. Compound 5 Compound 61-[3-(methyl)-4-(hydroxymethyl)-1H- 1-[3-(ethyl)-4-(hydroxymethyl)-1H- imidazol-3-ium-2-yl]ethanone imidazol-3-ium-2-yl]ethanone Compound 7 Compound 8 1-[3-(n-propyl)-4-(hydroxymethyl)-1H- 1-[3-(methoxyethyl)-4-(hydroxymethyl)- imidazol-3-ium-2-yl]ethanone 1H-imidazol-3-ium-2-yl]ethanone

[0087] According to some exemplary embodiments, the S1PL inhibitor compound is selected from the group consisting of the following Compounds 1 to 24. Compound 1’ (tautomer 1) Compound 1 (tautomer 2) Compound 2’ (tautomer 1) Compound 2 (tautomer 2) Compound 3’ (tautomer 1) Compound 3 (tautomer 2)Compound 4 (tautomer 2) Compound 4’ (tautomer 1) Compound 5 Compound 6 Compound 7 Compound 8 Compound 9 Compound 10 Compound 11 Compound 12Compound 13 Compound 14 Compound 15 Compound 16 Compound 18 Compound 17 Compound 20 Compound 19 Compound 21 Compound 22

[0088] In some embodiments, R4 in formula (I) or formula (I’) is hydroxymethyl and the S1PL inhibitor is selected from any one of Compounds 3 to 22, typically from any one of Compounds 3 to 8, in particular from any one of Compounds 3 to 5.

[0089] The S1PL inhibitor compounds disclosed herein, that are not commercially available, such as Compounds 1 and 2, can be prepared by any means known in the art. For instance, compounds of formula (Ia) can be produced by the cleavage ofcommercially available compounds of formula (I), by a catalytic cleavage of the R2 chain into hydroxymethyl with a two-step reaction with NaIO4 and NaBH4.

[0090] In some embodiments, when A is N and X is NR3, then R3is not hydrogen. In some particular embodiments, when A is N, then X is not NR3. In some embodiments, R1 is not optionally substituted alkyl.

[0091] In some embodiments, the S1PL inhibitor for use according to the invention is not Compound 1 ((E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2- yl)ethanone oxime), as defined hereinabove. In some embodiments, the S1PL inhibitor for use according to the invention is not Compound 1’ ((E)-1-(5-((1R,2S,3R)-1,2,3,4- tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime) as defined hereinabove. In some embodiments, the S1PL inhibitor for use according to the invention is not Compound 2 ((1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol), as defined hereinabove. In some embodiments, the S1PL inhibitor for use according to the invention is not Compound 2’ ((1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-5-yl)butane-1,2,3,4- tetraol), as defined hereinabove. In some embodiments, the S1PL inhibitor for use according to the invention is not Compound 3 ((E)-1-(4-(hydroxymethyl)-1H-imidazol- 2-yl)ethan-1-one oxime), as defined hereinabove. In some embodiments, the S1PL inhibitor for use according to the invention is not Compound 3’ ((E)-1-(5-(hydroxymethyl)-1H-imidazol-2-yl)ethan-1-one oxime), as defined hereinabove. In some embodiments, the S1PL inhibitor for use according to the invention is not Compound 4 ((2-(isoxazol-3-yl)-1H-imidazol-4-yl)methanol), as defined hereinabove. In some embodiments, the S1PL inhibitor for use according to the invention is not Compound 4’ ((2-(isoxazol-3-yl)-1H-imidazol-5-yl)methanol), as defined hereinabove.

[0092] The invention also relates to a method for treating a neurogenerative disease comprising administering to a subject in need thereof a therapeutically effective amount of at least one S1PL inhibitor as described herein. Furthermore, the invention also relates to the use of at least one S1PL inhibitor compound, as described in any one of the disclosed embodiments, for the manufacture of a medicament suitable for the treatment of a neurogenerative disease.

[0093] Neurogenerative diseases to be treated according to the present compound for use or method include Alzheimer’s disease, Multiple Sclerosis, Huntington’s disease, motor neuron disease such as Amyotrophic Lateral sclerosis, ataxia, Parkinson’s disease and multiple system atrophy. In some embodiments, the neurogenerative disease to be treated according to the present compound for use or method is selected from the group consisting of Alzheimer’s disease, Multiple Sclerosis, Amyotrophic Lateral sclerosis and Huntington’s disease. In some embodiments, the neurogenerative disease to be treated according to the present compound for use or method is selected from Amyotrophic Lateral sclerosis and Huntington’s disease. According to some embodiments, the neurogenerative disease to be treated according to the present compound for use or method is selected from the group consisting of Alzheimer’s disease, Huntington’s disease, motor neuron disease such as Amyotrophic lateral sclerosis (ALS), ataxia, Parkinson’s disease, and multiple system atrophy. In some preferred embodiments, the neurogenerative disease is selected from the group consisting of Alzheimer’s disease, Huntington’s disease, motor neuron disease such as amyotrophic lateral sclerosis (ALS), and Parkinson’s disease. In some further preferred embodiments, the neurogenerative disease is Alzheimer’s disease. In some further preferred embodiments, the neurogenerative disease is Huntington’s disease. In some further preferred embodiments, the neurogenerative disease is a motor neuron disease, preferably amyotrophic lateral sclerosis (ALS). In some further preferred embodiments, the neurogenerative disease is Parkinson’s disease.

[0094] In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 1 ((E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H- imidazol-2-yl)ethanone oxime) as defined hereinabove and the neurogenerative disease is Alzheimer’s disease. In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 1 as defined hereinabove and the neurogenerative disease is Huntington’s disease. In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 1 as defined hereinabove and the neurogenerative disease is motor neuron disease (preferably, amyotrophic lateral sclerosis (ALS)). In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 1 as defined hereinabove and the neurogenerative disease isataxia. In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 1 as defined hereinabove and the neurogenerative disease is Parkinson’s disease. In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 1 as defined hereinabove and the neurogenerative disease is multiple system atrophy. The embodiments in this paragraph are also disclosed herein with Compound 1’ ((E)-1-(5-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H- imidazol-2-yl)ethanone oxime) replacing any reference to Compound 1.

[0095] In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 2 ((1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane- 1,2,3,4-tetraol) as defined hereinabove and the neurogenerative disease is Alzheimer’s disease. In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 2 as defined hereinabove and the neurogenerative disease is Huntington’s disease. In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 2 as defined hereinabove and the neurogenerative disease is motor neuron disease (preferably, amyotrophic lateral sclerosis (ALS)). In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 2 as defined hereinabove and the neurogenerative disease is ataxia. In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 2 as defined hereinabove and the neurogenerative disease is Parkinson’s disease. In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 2 as defined hereinabove and the neurogenerative disease is multiple system atrophy. The embodiments in this paragraph are also disclosed herein with Compound 2’ ((1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-5-yl)butane-1,2,3,4- tetraol) replacing any reference to Compound 2.

[0096] In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 3 ((E)-1-(4-(hydroxymethyl)-1H-imidazol-2-yl)ethan-1-one oxime) as defined hereinabove and the neurogenerative disease is Alzheimer’s disease. In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 3 as defined hereinabove and the neurogenerative disease is Huntington’s disease. In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitorcompound is Compound 3 as defined hereinabove and the neurogenerative disease is motor neuron disease (preferably, amyotrophic lateral sclerosis (ALS)). In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 3 as defined hereinabove and the neurogenerative disease is ataxia. In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 3 as defined hereinabove and the neurogenerative disease is Parkinson’s disease. In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 3 as defined hereinabove and the neurogenerative disease is multiple system atrophy. The embodiments in this paragraph are also disclosed herein with Compound 3’ ((E)-1-(5-(hydroxymethyl)-1H-imidazol-2-yl)ethan-1-one oxime) replacing any reference to Compound 3.

[0097] In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 4 ((2-(isoxazol-3-yl)-1H-imidazol-4-yl)methanol) as defined hereinabove and the neurogenerative disease is Alzheimer’s disease. In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 4 as defined hereinabove and the neurogenerative disease is Huntington’s disease. In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 4 as defined hereinabove and the neurogenerative disease is motor neuron disease (preferably, amyotrophic lateral sclerosis (ALS)). In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 4 as defined hereinabove and the neurogenerative disease is ataxia. In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 4 as defined hereinabove and the neurogenerative disease is Parkinson’s disease. In some embodiments, the sphingosine-1-phosphate lyase (S1PL) inhibitor compound is Compound 4 as defined hereinabove and the neurogenerative disease is multiple system atrophy. The embodiments in this paragraph are also disclosed herein with Compound 4’ ((2-(isoxazol-3-yl)-1H-imidazol-5-yl)methanol) replacing any reference to Compound 4.

[0098] Without willing to be bound by a theory, the administration of the S1PL inhibitor according to the invention, raises the levels of the S1P that counterbalances thedetrimental effects of ceramide accumulation in the context of neurodegenerative disorders. Indeed, several studies have implicated ceramide in the apoptosis of neuronal and oligodendroglia cells, i.e., oligodendrocytes and astrocytes, in the neuroinflammatory and neurodegenerative disorders. For instance, several studies have shown that increased levels of ceramide are implicated in the induction of neural cell death, oxidative stress, and proinflammatory gene expression. Therefore, maintaining a strict sphingolipid balance is of key importance for cellular survival. Accordingly, in some embodiments, the S1PL inhibitor compound reduces the neuronal inflammation of the neurodegenerative disease and / or reduces the apoptosis of oligodendrocytes and astrocytes.

[0099] According to some advantageous embodiments, the S1PL inhibitor compound increases the production of Brain-derived neurotrophic factor (BDNF) acting so as neuronal protecting molecule, thereby exerting a neuroprotective effect. According to some embodiments, and in particular when the neurogenerative disease to be treated is Amyotrophic Lateral sclerosis (ALS), the S1PL inhibitor compound regulates the cell proliferation and tissue repair and / or suppresses dystrophic muscle degeneration.

[0100] Another aspect of the present invention provides a pharmaceutical composition comprising at least one S1PL inhibitor compound as described herein in association with at least one pharmaceutically acceptable excipient and / or carrier. Thus, the invention further relates to a pharmaceutical composition comprising at least one S1PL inhibitor as described herein, for its use in the treatment of neurodegenerative diseases, as described above. The invention further relates to a method for treating neurodegenerative diseases, as described herein, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of at least one S1PL inhibitor as described herein in association with at least one pharmaceutically acceptable excipient and / or carrier.

[0101] Certain pharmaceutical compositions of the invention are single unit dosage forms suitable for oral or mucosal (such as nasal, sublingual, or buccal) administration to a patient. Examples of dosage forms include, but are not limited to, tablets, caplets, capsules, such as soft elastic gelatine capsules, cachets, troches, lozenges, dispersions, powders, solutions, aerosols (such as nasal sprays or inhalers), liquid dosage formssuitable for oral or mucosal administration to a patient, including suspensions (such as aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs. The formulation of the pharmaceutical composition of the invention should suit the mode of administration. For example, oral administration requires enteric coatings to protect the compounds of this invention from degradation within the gastrointestinal tract. Similarly, a formulation may contain ingredients that facilitate delivery of the active ingredient(s) to the site of action. The pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (such as chewable tablets), caplets, capsules, and liquids (such as flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art.

[0102] Typical oral dosage forms are prepared by combining the compound of the invention in an intimate admixture with at least one excipient and / or carrier according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by conventional methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the compound of the invention with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary. Disintegrants may be incorporated in solid dosage forms to facility rapid dissolution. Lubricants may also be incorporated to facilitate the manufacture of dosage forms (such as tablets). For example, pharmaceutically acceptable excipients particularly suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. The pH of a pharmaceutical composition or dosage form, may also be adjusted to improve delivery of one or more compounds of theinvention. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates may also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent.

[0103] Other pharmaceutical compositions of the invention are parenteral dosage forms administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are specifically sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to a person skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.EXAMPLES

[0104] The present invention is further illustrated by the following examples in a non-limitative manner. Example 1: Synthesis of the compounds

[0105] Synthesis of the following compounds is herein provided.

[0106] Tetrahydroxylated imidazole (referred to as THI) was synthesized by the reaction of fructosamine and the imidate formed by the action of sodium methoxide on 2-ethoxyacrylonitrile.

[0107] Compound 1 (LX2931) was produced in a straightforward manner from THI by condensation with hydroxylamine.

[0108] Compound 2 (LX2932) was obtained analogously to THI by using isoxazole-3-carbonitrile as the imidate source.

[0109] Compound 3 was constructed based on commercially available hydroxymethylimidazole that was sequentially protected with chlorotriethylsilane and chloromethyl ethyl ether to furnish imidazole “13” as an inconsequential mixture of regioisomers. This regioisomeric mixture then underwent C2-lithiation and acetylation at -78 °C to afford methyl ketone “14” (also as a mixture of regioisomers) in acceptable yields. Removal of the O-silyl group was carried out with K2CO3 in MeOH. The finaldeprotection step in the synthesis of Compound 3 was achieved by heating hydroxymethylimidazole “15” in aqueous HCI that was transformed to oxime (Compound 3) by condensation with hydroxylamine.N-regioisomers Compound 3

[0110] Compound 4 was obtained in a 2-step reaction of LX2932 (Compound 2) with NaIO4 and NaBH4.

[0111] Compound 12 was obtained in 4 steps from known thioamide “17” whose alkylation with bromopyruvate, followed by treatment with triflic anhydride and base furnished thiazole “18” in high yield. In a straightforward manner, reduction of the ester and release of the ketone with aqueous hydrochloric acid provided Compound 12.12Example 2: Thermodynamic parameters describing the binding of human sphingosine-1- phosphate Lyase (S1PL) inhibitors to the catalytic site of the Lyase enzyme

[0112] The evaluation of the thermodynamic binding parameters of different sphingosine-1 -phosphate inhibitors has been carried out. The assay has been done with the phosphorylated compounds which are the actual S1PL inhibitors in-vivo. Crystal structure of S1PL in the PDB (4Q6R) was used to perform the docking experiments. Docking was made with GOLD (Protein-Ligand docking using Genetic Algorithm) using the CHEMPLP scoring function (Protein-Ligand ANT System). Poses were optimized and rescored with ChemScore to obtain AG binding energies. CHARMM force field was used to estimate the total binding and interaction energies of the rescored poses.

[0113] The results are presented in Table 1. Compounds Total Total VDW Total ∆G Total Interaction Interaction Electrostatic Binging Binging Energy energy Interaction Energy Energy Kcal / mol Kcal / mol Energy Kcal / mol Kcal / mol Kcal / mol CHARMM* S1P -276.01532 9.39604 -285.41136 -31.254 -504.836 THI -43.42677 -18.12644 -27.34425 -18.02 -61.88 A6770 -14.40720 -5.47068 -8.93652 -19.19 -55.22 A6770-P T1 -284.26823 -5.66954 -278.59869 -28.13 -188.55 A6770-P T2 -291.67197 -2.81322 -288.85875 -28.05 -186.28 Table 1: Thermodynamic parameters describing the binding of S1P lyase inhibitors to the catalytic site of the enzyme. S1P: Sphingosine-1-phosphate. VDW: Van Der Walls. *Absolute binding free energy. THI : 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)- imidazole, A6770 : 2-acetyl-4-hydroxymethyl-imidazole, A6770-P: phosphorylated 2-acetyl-4-hydroxymethyl)-imidazole, T1: tautomer 1, T2: tautomer 2.

[0114] Accordingly, the A6770-P as actual S1P lyase inhibitor is clearly assessed by docking experiments of THI and metabolites in the catalytic site of the human S1PL (Table 1). Compared to S1P, THI and A6770 display low binding values in terms of interaction energy and total binding energy. This due for a large part to the low electrostatic interaction energy. In contrast, the phosphorylated forms of the THImetabolite display a strong binding energy mainly due to electrostatic interaction provided by the phosphate group. The position of the basic nitrogen of the imidazole ring has a marginal impact on the binding.

[0115] For phosphorylated tautomers of A6770, namely, T1 and T2, the total interaction energy is close to the one of S1P. However, the total binding energy as calculated with all thermodynamics parameters provided by the force field CHARMM is much lower than the one of S1P (188 vs 504 Kcal / mol).

[0116] In view of the above, without willing to be bound by a theory, both THI and A6770 could be considered as prodrugs, the A6770-P being the pharmacologically active molecule.

[0117] Based on the above, the S1PL inhibitors of the present disclosure can readily act on the S1PL, without necessitating any bioconversion steps, thereby showing an improved pharmacokinetic profile, further improving the therapeutic potential for their use and method that enables them as disclosed herein.

Claims

CLAIMS 1. A sphingosine-1-phosphate lyase (S1PL) inhibitor compound for use in the treatment of a neurodegenerative disease, wherein the S1PL inhibitor is a compound of formula (I)or a tautomer thereof, or a pharmaceutically acceptable salt thereof; wherein Z is selected from the group consisting of O, S, and NH; Q is selected from the group consistingX is selected from the group consisting of O and NR3; W, Y, and V are each independently selected from the group consisting of CH2, CH, N, NH, O, and S; A is selected from the group consisting of N and N+R5; R1is selected from the group consisting of ORA, NHOH, hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted arylalkyl, optionally substituted heteroalkyl, optionally substituted heterocycle, optionally substituted alkylheterocycle, and optionally substituted heterocyclealkyl;R2 is selected from the group consisting of ORB, C(O)ORB, hydrogen, halogen, nitrile, optionally substituted hydroxyalkyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted arylalkyl, optionally substituted heteroalkyl, optionally substituted heterocycle, optionally substituted alkylheterocycle, and optionally substituted heterocyclealkyl; R3 is selected from the group consisting of ORC, N(RC)2, NHC(O)RC, NHSO2RC, and hydrogen; R4is selected from the group consisting of ORD, OC(O)RD, N(RE)2, hydrogen, halogen, optionally substituted hydroxyalkyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted arylalkyl, optionally substituted heteroalkyl, optionally substituted heterocycle, optionally substituted alkylheterocycle, and optionally substituted heterocyclealkyl; R5is selected from the group consisting of alkyl and alkyl-oxy-alkyl; RA, RB, RC, RD, and REare each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted arylalkyl, optionally substituted heteroalkyl, optionally substituted heterocycle, optionally substituted alkylheterocycle, and optionally substituted heterocyclealkyl; provided that the compound of formula (I) is not selected from 2-acetyl-4-tetrahydroxybutylimidazole (THI), tautomers thereof, and pharmaceutically acceptable salts thereof; and wherein the neurogenerative disease is selected from the group consisting of Alzheimer’s disease, Huntington’s disease, motor neuron disease such as amyotrophic lateral sclerosis (ALS), ataxia, Parkinson’s disease, and multiple system atrophy.

2. The S1PL inhibitor compound for use according to claim 1, whereinX is O or N-OH, R1 is methyl, R2 is hydrogen, and R4is an hydroxylated C1-C4 alkyl.

3. The S1PL inhibitor compound for use according to claim 1 or claim 2, wherein the S1PL inhibitor compound is of formulae (II), (III) or (IV), preferably the compound is of formula (II) or formula (III)4. The S1PL inhibitor compound for use according to any one of claims 1 to 3, wherein R4 is an hydroxylated C1-C4 alkyl selected from the group consisting of hydroxymethyl, 1-hydroxy-ethyl, 1,2-dihydroxyethyl, 1-hydroxypropyl, 1,2-dihydorxypropyl, 1,3-dihydroxypropyl, 1,2,3-trihydroxypropyl, 1-hydroxybutyl, 1,2-dihydroxybutyl, 1,2,3-trihydroxybutyl, and 1,2,3,4-tetrahydroxybutyl; preferably the hydroxylated C1-C4 alkyl is hydroxymethyl or 1,2,3,4-tetrahydroxybutyl.

5. The S1PL inhibitor compound for use according to any one of claims 1 to 4, wherein A is N.

6. The S1PL inhibitor compound for use according to claim 1, wherein the compound is selected from (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2- yl)ethanone oxime (Compound 1), tautomers thereof, and pharmaceutically acceptable salts thereofCompound 1 7. The S1PL inhibitor compound for use according to claim 1, wherein the compound is selected from (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4- tetraol (Compound 2), tautomers thereof, and pharmaceutically acceptable salts thereof8. The S1PL inhibitor compound for use according to claim 1, wherein the compound is selected from (E)-1-(4-(hydroxymethyl)-1H-imidazol-2-yl)ethan-1-one oxime (Compound 3), tautomers thereof, and pharmaceutically acceptable salts thereofCompound 39. The S1PL inhibitor compound for use according to claim 1, wherein the compound is selected from (2-(isoxazol-3-yl)-1H-imidazol-4-yl)methanol (Compound 4), tautomers thereof, and pharmaceutically acceptable salts thereof10. The S1PL inhibitor compound for use according to any one of claims 1 to 4, wherein A is N+R5.

11. The S1PL inhibitor compound for use according to claim 10, wherein R5is a C1-C4 alkyl or C1-C4 alkyl-oxy-C1-C4 alkyl, preferably wherein R5is selected from the group consisting of methyl, ethyl, n-propyl, and methoxy-ethyl.

12. The S1PL inhibitor compound for use according to claim 9 or claim 10, wherein Q is acetyl.

13. The S1PL inhibitor compound for use according to any one of claims 9 to 11, wherein the compound is selected from Compounds 5-8 and pharmaceutically acceptable salts thereofCompound 5 Compound 6Compound 7 Compound 8 14. The S1PL inhibitor compound for use according to any one of claims 1 to 4, wherein the compound is selected from Compounds 9-22, tautomers thereof, and pharmaceutically acceptable salts thereofCompound 11 Compound 12Compound 15Compound 16Compound 20 Compound 19Compound 21Compound 2215. The S1PL inhibitor compound for use according to any one of claims 1 to 14, wherein the neurogenerative disease is selected from the group consisting of Alzheimer’s disease, Huntington’s disease, motor neuron disease such as amyotrophic lateral sclerosis (ALS), and Parkinson’s disease.

16. The S1PL inhibitor compound for use according to claim 15, wherein the neurogenerative disease is Alzheimer’s disease.

17. The S1PL inhibitor compound for use according to claim 15, wherein the neurogenerative disease is Huntington’s disease.

18. The S1PL inhibitor compound for use according to claim 15, wherein the neurogenerative disease is a motor neuron disease, preferably amyotrophic lateral sclerosis (ALS).

19. The S1PL inhibitor compound for use according to claim 15, wherein the neurogenerative disease is Parkinson’s disease.

20. The S1PL inhibitor compound for use according to any one of claims 1 to 19, wherein the S1PL inhibitor compound reduces the neuronal inflammation of the neurodegenerative disease and / or wherein the S1PL inhibitor compound reduces the apoptosis of oligodendrocytes and astrocytes.

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