Triazole derivatives and their use in the treatment of neurodegenerative disorders

Abstract

The present invention provides a compound of formula (C1A) or a salt, a solvate, a hydrate, a polymorph, a tautomer, a racemate or a stereoisomer thereof, or a prodrug thereof; wherein A1, L1, R4, L3, and A2 have the same meaning as that defined in the claims. The present invention also relates to a pharmaceutical composition comprising a compound of the invention, and at least one pharmaceutical acceptable carrier. The present invention also relates to a compound of the invention for use as a medicine. The present invention also relates to a compound of the invention of formula (C1) for use for treating and / or preventing certain neurodegenerative disorders, wherein A1, L1, R3, U, V, R4, L3, and A2 have the same meaning as that defined in the claims.

Description

[0001] TRIAZOLE DERIVATIVES AND THEIR USE IN THE TREATMENT OF NEURODEGENERATIVE DISORDERS

[0002] Field of the invention

[0003] The present invention relates to compounds useful in the treatment of certain neurodegenerative disorders, such as neurodegenerative disorders characterized by cytotoxic TAU misfolding and / or aggregation and / or aggregation of amyloid beta.

[0004] Background of the invention

[0005] TAU is a protein with the ability to bind -and consequently stabilize and define- microtubule structure and function in neurons. The binding of TAU to microtubules is regulated by phosphorylation of TAU; several TAU phosphorylation sites and their corresponding kinases have been identified which control phosphorylation status of TAU and consequently modulate the affinity of TAU-binding to microtubules.

[0006] Tauopathies are characterized by insoluble aggregates or polymers of hyperphosphorylated TAU which are formed by self-polymerization of TAU monomers.

[0007] An important aspect of the TAU aggregation is its associated cytotoxicity, which reduces neuronal integrity and functionality and ultimately resulting in disease symptoms. A direct role of TAU in disease onset has been established unequivocally by the elucidation of familial mutations in TAU, which appear to be responsible for a very early and sometimes aggressive form of tauopathy. Such mutations comprise changes in the amino acid sequence of TAU that -directly or indirectly promote neurotoxic aggregation.

[0008] Alzheimer’s disease is the best known of these, where TAU protein is deposited within neurons in the form of neurofibrillary tangles (NFTs). They were first described by the eponymous Alois Alzheimer in one of his patients suffering from the disorder.

[0009] The term “Alzheimer’s disease” as used herein, refers to a chronic progressive nervous disease characterized by neurodegeneration with as most important (early) symptom being memory loss. As the disease advances, symptoms may include confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as their senses decline. Tangles are formed by hyperphosphorylation of a microtubule-associated protein known as tau, causing it to aggregate in an insoluble form. (These aggregations of hyperphosphorylated tau protein are also referred to as PHF, or "paired helical filaments"). The precise mechanism of tangle formation is not completely understood, and it is still controversial whether tangles are a primary causative factor in the disease or play a more peripheral role. AD is also classified as an amyloidosis because of the presence of senile plaques. Other conditions in which neurofibrillary tangles are commonly observed include: Progressive supranuclear palsy, dementia pugilistica (chronic traumatic encephalopathy), frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease (Parkinson-dementia complex of Guam), tangle-predominant dementia with NFTs, similar to AD, but without plaques, ganglioglioma and gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, tuberous sclerosis, Hallervorden-Spatz disease, and lipofuscinosis.

[0010] The non-Alzheimer's tauopathies are sometimes grouped together as "Pick's complex". In Pick's disease and corticobasal degeneration tau proteins are deposited in the form of inclusion bodies within swollen or "ballooned" neurons. Argyrophilic grain disease (AGD), another type of dementia, is marked by the presence of abundant argyrophilic grains and coiled bodies on microscopic examination of brain tissue.

[0011] Currently used treatments for tauopathies, including Alzheimer’s disease, offer only symptomatic benefit without impacting the underlying neurodegeneration. Treatments aimed to suppress cytotoxic TAU misfolding and / or aggregation in order to delay or halt the progression of disease are presently not available.

[0012] Thus, there is a need for new treatments that target the underlying molecular mechanism of noxious TAU misfolding and / or aggregation in order to reduce neuronal cell death and / or degeneration in patients suffering from tauopathies such as Alzheimer’s disease (AD).

[0013] Summary of the invention

[0014] To at least partially overcome the problems stated above, the present invention provides new compounds as defined herein.

[0015] Objects of the present invention are compounds of formula (C1), their use for the treatment of diseases related to the biological function of dysfunction of TAU protein, which diseases comprise Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia and parkinsonism (linked to chromosome 17, FTDP-17), their manufacture and medicaments based on a compound in accordance with the invention in the control or prevention of illnesses.

[0016] In a first aspect, the present invention provides a compound of formula (01) or a salt, a solvate, a hydrate, a polymorph, a tautomer, a racemate or a stereoisomer thereof, or a prodrug thereof; wherein

[0017] II is N or C;

[0018] V is selected from CH, N, or NH; with the proviso that when II is N, V is CH; when V is N, or NH, II is C;

[0019] R3is absent or R3is hydrogen, or Ci-ealkyl;

[0020] R4independently selected from the group comprising hydrogen, hydroxyl, halo, Ciwalkoxy, and Ci-ealkyl;

[0021] L1is a single bond or -C(R5)2-; each R5is independently selected from hydrogen, or Ci-ealkyl;

[0022] L3is -(C(R7)2)n-; wherein n is an integer selected from 1 or 2; each R7is independently selected from hydrogen, hydroxyl, halo, or Ci-ealkyl;

[0023] A1is selected from the group comprising Cs-ecycloalkyl, Ce-waryl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, C2-ealkenyl, C2-ealkynyl, hydrogen, Ci^alkoxy, haloCi-ealkoxy, cyano, hydroxy, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, Cs-ecycloalkyl, oxo, Ci- ealkylcarbonylamino, (R8)2N-, and (R8)2N-carbonyl; and / or two R1together with the atom(s) to which they are attached can form a 5-10 membered saturated or partially saturated heterocyclyl, or a Ce- aryl, a 5-10 membered heteroaryl;

[0024] A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, 5-6 membered saturated or partially saturated heterocyclyl, and C3- ecycloalkyl; wherein each of said group can be unsubstituted or substituted with one or more R2, wherein each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, (R8)2N-carbonyl, and C1- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl;

[0025] R8is selected from hydrogen, or Ci-ealkyl; with the proviso that said compound is not 1-(phenylmethyl)-4-[3-(phenylmethyl)-1 H-1 ,2,4-triazol- 5-yl]-piperidine.

[0026] Preferably the invention provides a compound of formula (C1A), or a salt, a solvate, a hydrate, a polymorph, a tautomer, a racemate or a stereoisomer thereof; or a prodrug thereof, wherein

[0027] R4independently selected from the group comprising hydrogen, hydroxyl, halo, Ci-ealkoxy, and Ci-ealkyl;

[0028] L1is a single bond or -C(R5)2-; each R5is independently selected from hydrogen, or Ci-ealkyl;

[0029] L3is -(C(R7)2)n-; wherein n is an integer selected from 1 or 2; each R7is independently selected from hydrogen, halo, or Ci-ealkyl;

[0030] A1is selected from the group comprising Cs-ecycloalkyl, Ce-waryl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, C2-ealkenyl, C2-ealkynyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, Cs-ecycloalkyl, oxo, C1- ealkylcarbonylamino, (R8)2N-, and (R8)2N-carbonyl; and / or two R1together with the atom(s) to which they are attached can form a 5-10 membered saturated or partially saturated heterocyclyl, or a Ce- aryl, a 5-10 membered heteroaryl;

[0031] A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, 5-6 membered saturated or partially saturated heterocyclyl, and C3- ecycloalkyl; wherein each of said group can be unsubstituted or substituted with one or more R2, wherein each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, (R8)2N-carbonyl, and Ci- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl;

[0032] R8is selected from hydrogen, or Ci-ealkyl; with the proviso that said compound is not

[0033] The present invention also relates, in a second aspect, to a pharmaceutical composition comprising a compound according to the first aspect of the invention, and at least one pharmaceutical acceptable carrier.

[0034] The present invention also relates to a compound according to the first aspect of the invention, or a pharmaceutical composition according to the second aspect for use as a medicine.

[0035] The present compounds and compositions are useful for treating certain neurodegenerative disorders, such as neurodegenerative disorders characterized by suppress cytotoxic TAU misfolding and / or aggregation in order to delay or halt the progression of such diseases. Preferably, the neurodegenerative disorder is selected from the group consisting of Parkinson's disease, Alzheimer’s disease, diffuse Lewy body disease, amyotrophic lateral sclerosis, Niemann Pick disease, Hallervorden Spatz syndrome, Down syndrome, Pick’s disease, progressive supranuclear palsy, vascular dementia, neuroaxonal dystrophy, Huntington’s disease, frontotemporal lobar degeneration (FTLD), multiple system atrophy and Creutzfeldt-Jacob’s disease, preferably said neurodegenerative disorder is Alzheimer’s disease.

[0036] The above and other characteristics, features, and advantages of the present invention will become apparent from the following detailed description, which illustrate, by way of example, the principles of the invention.

[0037] Detailed description of the invention

[0038] When describing the invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise.

[0039] Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, definitions for the terms used in the description are included to better appreciate the teaching of the present invention. When describing the compounds, processes, articles, and uses of the invention, the terms used are to be construed in accordance with the following definitions, unless the context dictates otherwise.

[0040] As used herein, the singular forms "a", "an", and "the" include both singular and plural referents unless the context clearly dictates otherwise. By way of example, "a compound" means one compound or more than one compound.

[0041] The terms "comprising", "comprises" and "comprised of" as used herein are synonymous with "including", "includes" or "containing", "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. The terms "comprising", "comprises" and "comprised of" also include the term “consisting of”.

[0042] The recitation of numerical ranges by endpoints includes all integer numbers and, where appropriate, fractions subsumed within that range (e.g., 1 to 5 can include 1 , 2, 3, 4 when referring to, for example, a number of elements, and can also include 1.5, 2, 2.75 and 3.80, when referring to, for example, measurements). The recitation of end points also includes the end point values themselves (e.g., from 1.0 to 5.0 includes both 1.0 and 5.0). Any numerical range recited herein is intended to include all sub-ranges subsumed therein.

[0043] The term "and / or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0044] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the following claims and statements, any of the embodiments can be used in any combination.

[0045] The term “leaving group” or “LG” as used herein means a chemical group which is susceptible to be displaced by a nucleophile or cleaved off or hydrolyzed in basic or acidic conditions. In a particular embodiment, a leaving group is selected from a halogen atom (e.g., Cl, Br, I) or a sulfonate (e.g., mesylate, tosylate, triflate).

[0046] The term “protecting group” or “PG” refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. The chemical substructure of a protecting group varies widely. One function of a protecting group is to serve as intermediates in the synthesis of the parental drug substance. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See: “Protective Groups in Organic Chemistry”, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.

[0047] Whenever the term “substituted” is used herein, it is meant to indicate that one or more hydrogen atoms on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group, provided that the indicated atom’s normal valence is not exceeded, and that the substitution results in a chemically stable compound, i.e. , a compound that is sufficiently robust to survive isolation from a reaction mixture.

[0048] The term “halo” or “halogen” as a group or part of a group is generic for fluoro, chloro, bromo, iodo.

[0049] The term “cyano” as used herein refers to the group -CN.

[0050] The term “hydroxyl” or “hydroxy” as used herein refers to the group -OH.

[0051] The term "oxo" as used herein refers to the group =0.

[0052] The term "alkyl" as a group or part of a group, refers to a hydrocarbyl group of formula CnH2n+i wherein n is a number greater than or equal to 1 , with no site of unsaturation. Alkyl groups may be linear or branched and may be substituted as indicated herein. Generally, alkyl groups of this invention comprise from 1 to 18 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, the term "Ci-ealkyl", as a group or part of a group, refers to a hydrocarbyl group of formula CnH2n+i wherein n is a number ranging from 1 to 6. Thus, for example, “Ci-ealkyl” includes all linear or branched alkyl groups with between 1 and 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, / -propyl, butyl, and its isomers (e.g., n-butyl, / - butyl, and f-butyl); pentyl and its isomers, hexyl, and its isomers, etc. For example, Ci-4alkyl includes all linear or branched alkyl groups having 1 to 4 carbon atoms, and thus includes for example methyl, ethyl, n-propyl, / -propyl, 2-methyl-ethyl, butyl, and its isomers (e.g., n-butyl, / - butyl, and f-butyl), and the like. In particular embodiments, the term alkyl refers to Ci-i2alkyl (C1-12 hydrocarbons), yet more in particular to Ci-galkyl (C1-9 hydrocarbons), yet more in particular to C1- ealkyl (C1-6 hydrocarbons) as further defined herein above. Non-limiting examples of alkyl include methyl, ethyl, 1 -propyl (n-propyl), 2-propyl ( / Pr), 1 -butyl, 2-methyl-1-propyl(j-Bu), 2-butyl (s-Bu), 2- dimethyl-2-propyl (t-Bu), 1 -pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2- butyl, 3-methyl-1 -butyl, 2-methyl-1 -butyl, 1 -hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3- dimethyl-2-butyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, and n-icosyl.

[0053] When the suffix "ene" is used in conjunction with an alkyl group, i.e., “alkylene”, this is intended to mean the alkyl group as defined herein having two single bonds as points of attachment to other groups. As used herein, the term “alkylene” also referred as “alkanediyl”, by itself or as part of another substituent, refers to alkyl groups that are divalent, i.e., having two monovalent group centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane, i.e., with two single bonds for attachment to two other groups. Alkylene groups may be linear or branched and may be substituted as indicated herein. Non-limiting examples of alkylene groups include methylene (-CH2-), ethylene (-CH2-CH2-), methylmethylene (-CH(CH3)-), 1-methyl-ethylene (-CH(CH3)-CH2-), n-propylene (-CH2-CH2-CH2-), 2- methylpropylene (-CH2-CH(CH3)-CH2-), 3-methylpropylene (-CH2-CH2-CH(CH3)-), n-butylene (- CH2-CH2-CH2-CH2-), 2-methylbutylene (-CH2-CH(CH3)-CH2-CH2-), 4-methylbutylene (-CH2-CH2- CH2-CH(CH3)-), pentylene and its chain isomers, hexylene and its chain isomers.

[0054] The term “hydrocarbyl” group is used herein in accordance with the definition specified by IIIPAC as follows: a univalent group formed by removing a hydrogen atom from a hydrocarbon (that is, a group containing only carbon and hydrogen).

[0055] The term “alkenyl” as a group or part of a group, refers to an unsaturated hydrocarbyl group which may be linear, or branched, comprising one or more with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely at least one sp2carbon-sp2carbon double bond. Generally, alkenyl groups of this invention comprise from 2 to 20 carbon atoms, preferably from 2 to 10 carbon atoms, preferably from 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Examples of 02-ealkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl, and the like. The double bond may be in the cis or trans configuration. When the suffix "ene" is used in conjunction with an alkenyl group, i.e., “alkenylene”, this is intended to mean the alkenyl group as defined herein having two single bonds as points of attachment to other groups. As used herein, the term “alkenylene” by itself or as part of another substituent, refers to alkenyl groups that are divalent, i.e., having two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene, i.e., with two single bonds for attachment to two other groups. Alkenylene groups may be linear or branched and may be substituted as indicated herein. Non-limiting examples of alkenylene groups include -CH=CH-, -C(CH3)=CH-, -C(CH3)=C(CH3)-, -CH=CH-CH2-, -CH2- C(CH3)=CH-, -CH2-CH=C(CH3)-, -CH2-CH2-CH=CH-, and the like.

[0056] The term “alkynyl” as a group or part of a group, refers to a branched or straight chain hydrocarbon comprising at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a sp1carbon-sp1carbon triple bond. In particular embodiments, the term alkynyl refers to C2-i2alkynyl (C2-i2hydrocarbons), preferably to C2-9 alkynyl (C2-9 hydrocarbons) yet more preferably to C2-6 alkynyl (C2-6 hydrocarbons) as further defined herein above with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely at least one sp1carbon-sp1carbon triple bond. Examples of alkynyl include but are not limited to: ethynyl (-OCH), 3-ethyl-cyclohept-1-ynylene, and 1-propynyl (propargyl, -CH2OCH).

[0057] When the suffix "ene" is used in conjunction with an alkynyl group, i.e., “alkynylene”, this is intended to mean the alkynyl group as defined herein having two single bonds as points of attachment to other groups. As used herein, the term “alkynylene” by itself or as part of another substituent, refers to alkynyl groups that are divalent, i.e., with two single bonds for attachment to two other groups. Alkynylene groups may be linear or branched and may be substituted as indicated herein. Non-limiting examples of alkynylene groups include -C=C-, -CH2-C=C-, -C=C- CH2-, -CH2-CH2-OC-, and the like.

[0058] The term “cycloalkyl”, as a group or part of a group, refers to a cyclic alkyl group, that is a monovalent, saturated, hydrocarbyl group having 1 or more cyclic structure, and comprising from 3 to 20 carbon atoms, more preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms; more preferably from 3 to 6 carbon atoms. Cycloalkyl includes all saturated hydrocarbon groups containing 1 or more rings, including monocyclic, bicyclic groups or tricyclic. For example, cycloalkyl comprises a C3-io monocyclic or C7-18 polycyclic saturated hydrocarbon, such as for instance cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylethylene, methylcyclopropylene, cyclohexyl, cycloheptyl, cyclooctyl, cyclooctylmethylene, norbornyl, fenchyl, trimethyltricycloheptyl, decalinyl, adamantyl and the like. The further rings of multi-ring cycloalkyls may be either fused, bridged and / or joined through one or more spiro atoms. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, the term “Cs-iocycloalkyl”, refers to a cyclic alkyl group comprising from 3 to 10 carbon atoms. For example, the term “Cs-scycloalkyl”, refers to a cyclic alkyl group comprising from 3 to 8 carbon atoms. For example, the term “C3- ecycloalkyl”, refers to a cyclic alkyl group comprising from 3 to 6 carbon atoms. For the avoidance of doubt, fused systems of a cycloalkyl ring with a heterocyclic ring are considered as heterocycle irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkyl ring with an aryl ring are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of a cycloalkyl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.

[0059] The term “alkoxy" or “alkyloxy”, as a group or part of a group, refers to a group of formula -ORbwherein Rbis alkyl as defined herein. Non-limiting examples of suitable Ci-ealkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0060] The term “aryl”, as a group or part of a group, refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e., phenyl) or multiple aromatic rings fused together (e.g., naphthyl), or linked covalently, typically containing 6 to 20 atoms; preferably 6 to 10, wherein at least one ring is aromatic. Typical aryl groups include, but are not limited to 1 ring, or 2 or 3 rings fused together, derived from benzene, naphthalene, anthracene, biphenyl, and the like. The aromatic ring may optionally include one to two additional rings. Fused systems of an aryl ring with a cycloalkyl ring, or a cycloalkenyl ring, or a cycloalkynyl ring, are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of an aryl ring with a heterocycle are considered as heterocycle irrespective of the ring that is bound to the core structure. Fused systems of an aryl ring with a heteroaryl are considered as heteroaryl irrespective of the ring that is bound to the core structure. Examples of suitable aryl include Ce-2oaryl, preferably Ce- aryl, more preferably Ce-garyl. Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, or 1-or 2-naphthanelyl; 1-, 2-, 3-, 4-, 5- or 6-tetralinyl (also known as “1 , 2,3,4- tetrahydronaphtalene); 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-azulenyl, 4-, 5-, 6 or 7-indenyl; 4- or 5-indanyl; 5-, 6-, 7- or 8-tetrahydronaphthyl; 1 ,2,3,4-tetrahydronaphthyl; and 1 ,4-dihydronaphthyl; 1-, 2-, 3-, 4- or 5-pyrenyl. Preferred aryl is phenyl.

[0061] When the suffix "ene" is used in conjunction with an aryl group, i.e., “arylene”, this is intended to mean the aryl group as defined herein having two single bonds as points of attachment to other groups. As used herein, the term “arylene” by itself or as part of another substituent, refers to aryl groups that are divalent, i.e., having two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent aryl, i.e., with two single bonds for attachment to two other groups. Arylene groups may be substituted as indicated herein. The term "arylalkyl", as a group or part of a group, refers to an alkyl as defined herein, wherein at least one hydrogen atom is replaced by at least one aryl as defined herein. Non-limiting examples of arylalkyl group include benzyl, phenethyl, dibenzylmethyl, benzyl, 2-phenylethan-1-yl, 2- phenylethen-1-yl, naphthylmethyl, 2-naphthylethyl, and the like. The term “Ce- arylCi-ealkyl” means that the alkyl moiety of the arylalkyl group can comprises 1 to 6 carbon atoms and the aryl moiety is 6 to 10 carbon atoms.

[0062] The term “aryloxy”, as a group or part of a group, refers to a group of formula -O-Rfwherein Rfis aryl as defined herein.

[0063] The term "haloalkyl", as a group or part of a group, refers to an alkyl group having the meaning as defined herein, wherein one or more hydrogen atoms are each replaced with a halogen as defined herein. Non-limiting examples of such haloalkyl groups include chloromethyl, 1- bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 ,1 ,1 -trifluoroethyl and the like.

[0064] The term “haloalkoxy”, as a group or part of a group, refers to a group of formula -O-Re, wherein Reis haloalkyl as defined herein. Non-limiting examples of suitable haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1 ,1 ,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trichloroethoxy, trichloromethoxy, 2- bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy, 4,4,4-trichlorobutoxy.

[0065] The term “heterocyclyl” as used herein refer to non-aromatic, fully saturated or partially unsaturated ring system comprising from 3 to 18 atoms including at least one N, O, S, or P, preferably 3 to 14 atoms (3-14 membered heterocyclyl) (for example, 3 to 7 member monocyclic, 7 to 14 member bicyclic, preferably comprising a total of 3 to 10 ring atoms (3-10 membered heterocyclyl), more preferably 4 to 10 atoms (4-10 membered heterocyclyl), yet more preferably 5 to 10 atoms (5-10 membered heterocyclyl). Each ring of the heterocycle or heterocyclyl may have 1 , 2, 3 or 4 heteroatoms selected from N, O, P and / or S, where the N and S heteroatoms may optionally be oxidized, and the N heteroatoms may optionally be quaternized; and wherein at least one carbon atom of heterocyclyl can be oxidized to form at least one C=O. The heterocyclyl may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocyclyls or heterocycles may be fused, bridged and / or joined through one or more spiro atoms. Fused systems of a heterocycle or heterocyclyl with an aryl ring are considered as heterocycle or heterocyclyl irrespective of the ring that is bound to the core structure. Fused systems of a heterocycle or heterocyclyl with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.

[0066] Non limiting exemplary heterocycles or heterocyclic groups include piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl (tetra hydro-2 H- thiopyranyl), tetrahydrofuranyl, pyrrolidinyl, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, imidazolinyl, pyrazolidinyl imidazolidinyl, oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, succinimidyl, indolinyl, isoindolinyl, chromanyl (also known as 3,4-dihydrobenzo[b]pyranyl), 2H-pyrrolyl, pyrrolinyl (such as 1 -pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl), 4H-quinolizinyl, 2-oxopiperazinyl, pyrazolinyl (such as 2-pyrazolinyl, 3-pyrazolinyl), tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl-1 -oxide, tetrahydro-2H-thiopyranyl-1 ,1 -dioxide, 2H-pyranyl, 4H-pyranyl, dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2- oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-ylsulfoxide, thiomorpholin-4- ylsulfone, 1 , 3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl, 1 ,3,5-trioxanyl, 1 H-pyrrolizinyl, tetrahydro- 1 ,1 -dioxothiophenyl, N- formyl-piperazinyl, thiomorpholinyl, dihydrofuranyl, dihydrothienyl, tetrahydrothienyl, dihydropyrazolyl, dihydroimidazolyl, isothiazolinyl, thiazolinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazol idinyl, dihydro-pyridinyl, tetrahydro-pyridinyl, 1 ,2,3,6-tetrahydropyridinyl, hexahydro- pyridinyl, dihydro-pyrimidinyl, tetrahydro-pyrimidinyl, 1 ,4,5,6-tetrahydropyrimidinyl, dihydro- pyrazinyl, tetrahydro-pyrazinyl, dihydro-pyridazinyl, tetrahydro-pyridazinyl, dihydro-triazinyl, tetrahydro-triazinyl, hexahydro-triazinyl, 1 ,4-diazepanyl, dihydro-indolyl, indolinyl, tetrahydro- indolyl, dihydro-indazolyl, tetrahydro-indazolyl, dihydro-isoindolyl, dihydro-benzofuranyl, tetrahydro-benzofuranyl, dihydro-benzothienyl, tetrahydro-benzothienyl, dihydro-benzimidazolyl, tetrahydro-benzimidazolyl, dihydro-benzooxazolyl, 2,3-dihydrobenzo[d]oxazolyl, tetrahydro- benzooxazolyl, dihydro-benzooxazinyl, 3,4-dihydro-2H-benzo[b][1 ,4]oxazinyl, tetrahydrobenzooxazinyl, benzo[1 ,3]dioxolyl, benzo[1 ,4]dioxanyl, dihydro-purinyl, tetrahydro-purinyl, dihydro-quinolinyl, 1 ,2,3,4-tetrahydroquinolinyl, dihydro-isoquinolinyl, 3,4-dihydroisoquinolin-

[0067] (1 H)-yl, tetrahydro-isoquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, dihydro-quinazolinyl, tetrahydro- quinazolinyl, dihydro-quinoxalinyl, tetrahydro-quinoxalinyl, 1 ,2,3,4-tetrahydroquinoxalinyl, 2,5- dihydro-1 H-pyrrolyl, 4,5-dihydro-1 H-imidazolyl, hexahydropyrrolo[3,4-b][1 ,4]oxazin-(2H)-yl, 3,4- dihydro-2H-pyrido[3,2-b][1 ,4]oxazinyl, (cis)-octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4-b]pyrrol-(1 H)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7-dihydro-6H- pyrrolo[3,4-b]pyridinyl , tetrahydro-1 H-pyrrolo[3,4-b]pyridin-(2H,7H,7aH)-yl, hexahydro-1 H- pyrrolo[3,4-b]pyridin-(2 H)-yl , (octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1 ,2- a]pyrazin-(1 H)-yl, 3,4,6,7,8,8a-hexahydro-1 H-pyrrolo[1 ,2-a]pyrazinyl, 2,3,4,9-tetrahydro-1 H- carbazolyl, 1 ,2,3,4-tetrahydropyrazino[1 ,2-a]indolyl , 2,3-dihydro-1 H-pyrrolo[1 ,2-a]indolyl , 1 ,3- dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2- azabicyclo[2.2.1]heptenyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1 ,0]hexanyl, 5- azaspiro[2.4]heptanyl, 4,7-diazaspiro[2.5]octanyl, 2.6-diazaspiro[3.3]heptanyl 2.5- diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2.7-diazaspiro[3.5]nonanyl 2,7- diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl, 2.8-diazaspiro[4.5]decanyl, 3.6- diazabicyclo[3.2.1]octyl, 1 ,4-dihydroindeno[1 ,2-c]pyrazolyl, dihydropyranyl, dihydropyridinyl, dihydroquinolinyl, 8H-indeno[1 ,2-d]thiazolyl , tetrahydroimidazo[1 ,2-a]pyridinyl , pyridin-2( 1 H)-one, 8-azabicyclo[3.2.1]oct-2-enyl. The term “aziridinyl” as used herein includes aziridin-1-yl and aziridin-2-yl. The term “oxyranyl” as used herein includes oxyranyl-2-yl. The term “thiiranyl” as used herein includes thiiran-2-yl. The term “azetidinyl” as used herein includes azetidin-1-yl, azetidin-2-yl and azetidin-3-yl. The term “oxetanyl” as used herein includes oxetan-2-yl and oxetan-3-yl. The term “thietanyl” as used herein includes thietan-2-yl and thietan-3-yl. The term “pyrrolidinyl” as used herein includes pyrrolidin-1 -yl, pyrrolidin-2-yl and pyrrolidin-3-yl. The term “tetrahydrofuranyl” as used herein includes tetrahydrofuran-2-yl and tetrahydrofuran-3-yl. The term “tetrahydrothiophenyl” as used herein includes tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl. The term “succinimidyl” as used herein includes succinimid-1-yl and succininmid-3-yl. The term “dihydropyrrolyl” as used herein includes 2,3-dihydropyrrol-1 -yl, 2,3- dihydro-1 H-pyrrol-2-yl, 2,3-dihydro-1 H-pyrrol-3-yl, 2, 5-dihydropyrrol- 1 -yl, 2,5-dihydro-1 H-pyrrol- 3-yl and 2,5-dihydropyrrol-5-yl. The term “2H-pyrrolyl” as used herein includes 2H-pyrrol-2-yl, 2H- pyrrol-3-yl, 2H-pyrrol-4-yl and 2H-pyrrol-5-yl. The term “3H-pyrrolyl” as used herein includes 3H- pyrrol-2-yl, 3H-pyrrol-3-yl, 3H-pyrrol-4-yl and 3H-pyrrol-5-yl. The term “di hydrofuranyl” as used herein includes 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,3-dihydrofuran-4-yl, 2,3- dihydrofuran-5-yl, 2,5-dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl, 2,5-dihydrofuran-4-yl and 2,5- dihydrofuran-5-yl. The term “dihydrothiophenyl” as used herein includes 2,3-dihydrothiophen-2- yl, 2,3-dihydrothiophen-3-yl, 2,3-dihydrothiophen-4-yl, 2,3-dihydrothiophen-5-yl, 2,5- dihydrothiophen-2-yl, 2,5-dihydrothiophen-3-yl, 2,5-dihydrothiophen-4-yl and 2,5- dihydrothiophen-5-yl. The term “imidazolidinyl” as used herein includes imidazolidin-1 -yl, imidazolidin-2-yl and imidazolidin-4-yl. The term “pyrazolidinyl” as used herein includes pyrazolidin-1 -yl, pyrazolidin-3-yl and pyrazolidin-4-yl. The term “imidazolinyl” as used herein includes imidazolin-1 -yl, imidazolin-2-yl, imidazolin-4-yl and imidazolin-5-yl. The term “pyrazolinyl” as used herein includes 1-pyrazolin-3-yl, 1-pyrazolin-4-yl, 2-pyrazolin-1-yl, 2-pyrazolin-3-yl, 2- pyrazolin-4-yl, 2-pyrazolin-5-yl, 3-pyrazolin-1-yl, 3-pyrazolin-2-yl, 3-pyrazolin-3-yl, 3-pyrazolin-4- yl and 3-pyrazolin-5-yl. The term “dioxolanyl” also known as “1 ,3-dioxolanyl” as used herein includes dioxolan-2-yl, dioxolan-4-yl and dioxolan-5-yl. The term “dioxolyl” also known as “1 ,3- dioxolyl” as used herein includes dioxol-2-yl, dioxol-4-yl and dioxol-5-yl. The term “oxazolidinyl” as used herein includes oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl and oxazolidin-5-yl. The term “isoxazolidinyl” as used herein includes isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl and isoxazolidin-5-yl. The term “oxazolinyl” as used herein includes 2-oxazolinyl-2-yl, 2- oxazolinyl-4-yl, 2-oxazolinyl-5-yl, 3-oxazolinyl-2-yl, 3-oxazolinyl-4-yl, 3-oxazolinyl-5-yl, 4- oxazolinyl-2-yl, 4-oxazolinyl-3-yl, 4-oxazolinyl-4-yl and 4-oxazolinyl-5-yl. The term “isoxazolinyl” as used herein includes 2-isoxazolinyl-3-yl, 2-isoxazolinyl-4-yl, 2-isoxazolinyl-5-yl, 3-isoxazolinyl- 3-yl, 3-isoxazolinyl-4-yl, 3-isoxazolinyl-5-yl, 4-isoxazolinyl-2-yl, 4-isoxazolinyl-3-yl, 4-isoxazolinyl- 4-yl and 4-isoxazolinyl-5-yl. The term “thiazolidinyl” as used herein includes thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl and thiazolidin-5-yl. The term “isothiazolidinyl” as used herein includes isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl and isothiazolidin-5-yl. The term “thiazolinyl” as used herein includes 2-thiazolinyl-2-yl, 2-thiazolinyl-4-yl, 2-thiazolinyl-5-yl, 3- thiazolinyl-2-yl, 3-thiazolinyl-4-yl, 3-thiazolinyl-5-yl, 4-thiazolinyl-2-yl, 4-thiazolinyl-3-yl, 4- thiazolinyl-4-yl and 4-thiazolinyl-5-yl. The term “isothiazolinyl” as used herein includes 2- isothiazolinyl-3-yl, 2-isothiazolinyl-4-yl, 2-isothiazolinyl-5-yl, 3-isothiazolinyl-3-yl, 3-isothiazolinyl- 4-yl, 3-isothiazolinyl-5-yl, 4-isothiazolinyl-2-yl, 4-isothiazolinyl-3-yl, 4-isothiazolinyl-4-yl and 4- isothiazolinyl-5-yl. The term “piperidyl” also known as “piperidinyl” as used herein includes piperid- 1-yl, piperid-2-yl, piperid-3-yl and piperid-4-yl. The term “dihydropyridinyl” as used herein includes

[0068] 1 .2-dihydropyridin- 1 -yl, 1 ,2-di hydropyridin-2-yl , 1.2-dihydropyridin-3-yl, 1.2-dihydropyridin-4-yl,

[0069] 1 .2-dihydropyridin-5-yl, 1.2-di hydropyridin-6-yl , 1.4-dihydropyridin-1 -yl, 1.4-dihydropyridin-2-yl,

[0070] 1 .4-dihydropyridin-3-yl, 1.4-di hydropyridin-4-yl , 2.3-dihydropyridin-2-yl, 2.3-dihydropyridin-3-yl,

[0071] 2.3-dihydropyridin-4-yl, 2.3-dihydropyridin-5-yl, 2.3-dihydropyridin-6-yl, 2.5-dihydropyridin-2-yl,

[0072] 2.5-dihydropyridin-3-yl, 2.5-dihydropyridin-4-yl, 2.5-dihydropyridin-5-yl, 2.5-dihydropyridin-6-yl,

[0073] 3.4-dihydropyridin-2-yl, 3.4-dihydropyridin-3-yl, 3.4-dihydropyridin-4-yl, 3.4-dihydropyridin-5-yl and 3,4-dihydropyridin-6-yl. The term “tetrahydropyridinyl” as used herein includes 1 ,2,3,4- tetrahydropyridin-1-yl, 1.2.3.4-tetrahydropyridin-2-yl, 1 .2.3.4-tetrahydropyridin-3-yl, 1.2.3.4- tetrahydropyridin-4-yl, 1.2.3.4-tetrahydropyridin-5-yl, 1 .2.3.4-tetrahydropyridin-6-yl, 1 ,2,3,6- tetrahydropyridin-1-yl, 1.2.3.6-tetrahydropyridin-2-yl, 1 .2.3.6-tetrahydropyridin-3-yl, 1 ,2,3,6- tetrahydropyridin-4-yl, 1.2.3.6-tetrahydropyridin-5-yl, 1 .2.3.6-tetrahydropyridin-6-yl, 2.3.4.5- tetrahydropyridin-2-yl, 2.3.4.5-tetrahydropyridin-3-yl, 2.3.4.5-tetrahydropyridin-3-yl, 2, 3,4,5- tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl and 2,3,4,5-tetrahydropyridin-6-yl. The term “tetrahydropyranyl” also known as “oxanyl” or “tetrahydro-2H-pyranyl”, as used herein includes tetrahydropyran-2-yl, tetrahydropyran-3-yl and tetrahydropyran-4-yl. The term “tetrahydrothiopyranyl” also known as “thianyl” or “tetrahydro-2H-thiopyranyl”, as used herein includes tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl and tetrahydrothiopyran-4-yl. The term “2H-pyranyl” as used herein includes 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran- 5-yl and 2H-pyran-6-yl. The term “4H-pyranyl” as used herein includes 4H-pyran-2-yl, 4H-pyran-

[0074] 3-yl and 4H-pyran-4-yl. The term “3,4-dihydro-2H-pyranyl” as used herein includes 3,4-dihydro- 2H-pyran-2-yl, 3,4-dihydro-2H-pyran-3-yl, 3,4-dihydro-2H-pyran-4-yl, 3,4-dihydro-2H-pyran-5-yl and 3,4-dihydro-2H-pyran-6-yl. The term “3,6-dihydro-2H-pyranyl” as used herein includes 3,6- dihydro-2H-pyran-2-yl, 3,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 3,6-dihydro-2H- pyran-5-yl and 3,6-dihydro-2H-pyran-6-yl. The term “tetrahydrothiophenyl”, as used herein includes tetrahydrothiophen-2-yl, tetrahydrothiophenyl -3-yl and tetrahydrothiophenyl -4-yl. The term “2H-thiopyranyl” as used herein includes 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-

[0075] 4-yl, 2H-thiopyran-5-yl and 2H-thiopyran-6-yl. The term “4H-thiopyranyl” as used herein includes 4H-thiopyran-2-yl, 4H-thiopyran-3-yl and 4H-thiopyran-4-yl. The term “3,4-dihydro-2H- thiopyranyl” as used herein includes 3,4-dihydro-2H-thiopyran-2-yl, 3,4-dihydro-2H-thiopyran-3- yl, 3,4-dihydro-2H-thiopyran-4-yl, 3,4-dihydro-2H-thiopyran-5-yl and 3,4-dihydro-2H-thiopyran-6- yl. The term “3,6-dihydro-2H-thiopyranyl” as used herein includes 3,6-dihydro-2H-thiopyran-2-yl,

[0076] 3.6-dihydro-2H-thiopyran-3-yl, 3,6-dihydro-2H-thiopyran-4-yl, 3,6-dihydro-2H-thiopyran-5-yl and

[0077] 3.6-dihydro-2H-thiopyran-6-yl. The term “piperazinyl” also known as “piperazidinyl” as used herein includes piperazin-1 -yl and piperazin-2-yl. The term “morpholinyl” as used herein includes morpholin-2-yl, morpholin-3-yl and morpholin-4-yl. The term “thiomorpholinyl” as used herein includes thiomorpholin-2-yl, thiomorpholin-3-yl and thiomorpholin-4-yl. The term “dioxanyl” as used herein includes 1 ,2-dioxan-3-yl, 1 ,2-dioxan-4-yl, 1 ,3-dioxan-2-yl, 1 ,3-dioxan-4-yl, 1 ,3- dioxan-5-yl and 1 ,4-dioxan-2-yl. The term “dithianyl” as used herein includes 1 ,2-dithian-3-yl, 1 ,2- dithian-4-yl, 1 ,3-dithian-2-yl, 1 ,3-dithian-4-yl, 1 ,3-dithian-5-yl and 1 ,4-dithian-2-yl. The term “oxathianyl” as used herein includes oxathian-2-yl and oxathian-3-yl. The term “trioxanyl” as used herein includes 1 ,2,3-trioxan-4-yl, 1 ,2,3-trioxan-5-yl, 1 ,2,4-trioxan-3-yl, 1 ,2,4-trioxan-5-yl, 1 ,2,4- trioxan-6-yl and 1 ,3,4-trioxan-2-yl. The term “azepanyl” as used herein includes azepan-1-yl, azepan-2-yl, azepan-3-yl and azepan-4-yl. The term “homopiperazinyl” as used herein includes homopiperazin-1 -yl, homopiperazin-2-yl, homopiperazin-3-yl and homopiperazin-4-yl. The term “indolinyl” as used herein includes indolin-1 -yl, indolin-2-yl, indolin-3-yl, indolin-4-yl, indolin-5-yl, indolin-6-yl, and indolin-7-yl. The term “quinolizinyl” as used herein includes quinolizidin-1 -yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “isoindolinyl” as used herein includes isoindolin-1 -yl, isoindolin-2-yl, isoindolin-3-yl, isoindolin-4-yl, isoindolin-5-yl, isoindolin-6- yl, and isoindolin-7-yl. The term “3H-indolyl” as used herein includes 3H-indol-2-yl, 3H-indol-3-yl, 3H-indol-4-yl, 3H-indol-5-yl, 3H-indol-6-yl, and 3H-indol-7-yl. The term “quinolizinyl” as used herein includes quinolizidin-1 -yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “quinolizinyl” as used herein includes quinolizidin-1 -yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “tetrahydroquinolinyl” as used herein includes tetrahydroquinolin-1-yl, tetrahydroquinolin-2-yl, tetrahydroquinolin-3-yl, tetrahydroquinolin-4-yl, tetrahydroquinolin-5-yl, tetrahydroquinolin-6-yl, tetrahydroquinolin-7-yl and tetrahydroquinolin-8-yl. The term “tetrahydroisoquinolinyl” as used herein includes tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl and tetrahydroisoquinolin-8-yl. The term “chromanyl” as used herein includes chroman-2-yl, chroman- 3-yl, chroman-4-yl, chroman-5-yl, chroman-6-yl, chroman-7-yl and chroman-8-yl. The term “1 H- pyrrolizine” as used herein includes 1 H-pyrrolizin-1 -yl, 1 H-pyrrolizin-2-yl, 1 H-pyrrolizin-3-yl, 1 H- pyrrolizin-5-yl, 1 H-pyrrolizin-6-yl and 1 H-pyrrolizin-7-yl. The term “3H-pyrrolizine” as used herein includes 3H-pyrrolizin-1 -yl, 3H-pyrrolizin-2-yl, 3H-pyrrolizin-3-yl, 3H-pyrrolizin-5-yl, 3H-pyrrolizin- 6-yl and 3H-pyrrolizin-7-yl. When the suffix "ene" is used in conjunction with a heterocyclyl group, i.e. , “heterocyclylene”, this is intended to mean the heterocyclyl group as defined herein having two single bonds as points of attachment to other groups. As used herein, the term “heterocyclylene” by itself or as part of another substituent, refers to heterocyclyl groups that are divalent, i.e., having two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent heterocyclyl, i.e., with two single bonds for attachment to two other groups. Heterocyclylene groups may be substituted as indicated herein.

[0078] The term “heteroaryl” refers to an aromatic ring system comprising from 5 to 18 atoms including at least one N, O, S, or P, containing 1 or 2 rings which can be fused together or linked covalently, preferably 5 to 14 atoms (5-14 membered heteroaryl), yet more preferably 5 to 10 atoms (5-10 membered heteroaryl), each ring typically containing 5 to 6 atoms; at least one of said rings is aromatic, where the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized, and wherein at least one carbon atom of said heteroaryl can be oxidized to form at least one C=O. Fused systems of a heteroaryl ring with a cycloalkyl ring, or a cycloalkenyl ring, or a cycloalkynyl ring, are considered as heteroaryl irrespective of the ring that is bound to the core structure. Fused systems of a heteroaryl ring with a heterocycle are considered as heteroaryl irrespective of the ring that is bound to the core structure. Fused systems of a hetero aryl ring with an aryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure. Non-limiting examples of such heteroaryl, include: pyridinyl, pyrrolyl, thiophenyl (also referred as thienyl), furanyl, thiazolyl, isothiazolyl, thiadiazolyl, triazol-2-yl, 1 H- pyrazol-5-yl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, pyranyl, thiopyranyl, imidazo[2, 1 -b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1 ,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1 ,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl,1 ,3-benzoxazolyl, 1 ,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1 ,3- benzothiazolyl, 1 ,2-benzoisothiazolyl, 2,1 -benzoisothiazolyl, benzotriazolyl, 1 ,2,3- benzoxadiazolyl, 2,1 ,3-benzoxadiazolyl, benzo[c][1 ,2,5]oxadiazolyl, 1 ,2,3-benzothiadiazolyl, 2,1 ,3-benzothiadiazolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydro-benzofuranyl, thienopyridinyl, purinyl, 9H-purinyl, imidazo[1 ,2-a]pyridinyl, imidazo[1 ,2-a]pyrazinyl, imidazo[5,1-a]isoquinolinyl, imidazo[1 ,5-a]pyridinyl, 6-oxo-pyridazin-1 (6H)-yl, 2-oxopyridin-1 (2H)-yl, 1 ,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl; acridinyl, phthalazinyl, 1 ,4- dihydroindeno[1 ,2-c]-1 H-pyrazolyl, 2,3-dihydro-1 H-inden-1-one, 2,3-dihydro-1 H-indenyl, 3,4- dihydroquinolin-2(1 H)-one, 5,6-dihydroimidazo[5, 1 -a]isoqu i nol i ny 1 , 8H-indeno[1 , 2-d]th iazoly I , benzo[d]oxazol-2(3H)-one, quinolin-2(1 H)-one, quinazolin-4(1 H)-one, quinazoline-2,4(1 H,3H)- dione, benzo-[d]oxazolyl, and pyrazolo[1 ,5-a]pyridinyl. In some preferred embodiments, the term “5 or 6-membered heteroaryl” denotes an aromatic ring system, containing one or more heteroatoms, selected from N, S or O, wherein in some embodiment, the heteroaryl can be for example selected from the group comprising pyrazolyl, thienyl, pyridinyl, thiadiazolyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrrolyl, pyrazinyl, or furanyl.

[0079] The term “pyrrolyl” (also called azolyl) as used herein includes pyrrol-1 -yl, pyrrol-2-yl and pyrrol-

[0080] 3-yl. The term “furanyl” (also called "furyl") as used herein includes furan-2-yl and furan-3-yl (also called furan-2-yl and furan-3-yl). The term “thiophenyl” (also called "thienyl") as used herein includes thiophen-2-yl and thiophen-3-yl (also called thien-2-yl and thien-3-yl). The term “pyrazolyl” (also called 1 H-pyrazolyl and 1 ,2-diazolyl) as used herein includes pyrazol-1-yl, pyrazol-3-yl or 1 H-pyrazol-5-yl, pyrazol-4-yl and pyrazol-5-yl. The term “imidazolyl” as used herein includes imidazol-1-yl, imidazol-2-yl, imidazol-4-yl and imidazol-5-yl. The term “oxazolyl” (also called 1 ,3-oxazolyl) as used herein includes oxazol-2-yl, oxazol-4-yl and oxazol-5-yl. The term “isoxazolyl” (also called 1 ,2-oxazolyl), as used herein includes isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl. The term “thiazolyl” (also called 1 ,3-thiazolyl),as used herein includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl (also called 2-thiazolyl, 4-thiazolyl and 5-thiazolyl). The term “isothiazolyl” (also called 1 , 2-thiazolyl) as used herein includes isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl. The term “triazolyl” as used herein includes triazol-2-yl, 1 H-triazolyl and 41-1-1 ,2,4- triazolyl, “1 H-triazolyl” includes 1 H-1 ,2,3-triazol-1-yl, 1 H-1 ,2,3-triazol-4-yl, 1 H-1 ,2,3-triazol-5-yl, 1 H-1 ,2,4-triazol-1-yl, 1 H-1 ,2,4-triazol-3-yl and 1 H-1 ,2,4-triazol-5-yl. “4H-1,2,4-triazolyl” includes 4H-1 ,2,4-triazol-4-yl, and 4H-1 ,2,4-triazol-3-yl. The term “oxadiazolyl” as used herein includes 1 ,2,3-oxadiazol-4-yl, 1 ,2,3-oxadiazol-5-yl, 1 ,2,4-oxadiazol-3-yl, 1 ,2,4-oxadiazol-5-yl, 1 ,2,5- oxadiazol-3-yl and 1 ,3,4-oxadiazol-2-yl. The term “thiadiazolyl” as used herein includes 1 ,2,3- thiadiazol-4-yl, 1 ,2,3-thiadiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl, 1 ,2,5-thiadiazol-3- yl (also called furazan-3-yl) and 1 ,3,4-thiadiazol-2-yl. The term “tetrazolyl” as used herein includes 1 H-tetrazol-1-yl, 1 H-tetrazol-5-yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5-yl. The term “oxatriazolyl” as used herein includes 1 ,2,3,4-oxatriazol-5-yl and 1 ,2,3,5-oxatriazol-4-yl. The term “thiatriazolyl” as used herein includes 1 ,2,3,4-thiatriazol-5-yl and 1 ,2,3,5-thiatriazol-4-yl. The term “pyridinyl” (also called "pyridyl") as used herein includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl (also called 2- pyridyl, 3-pyridyl and 4-pyridyl). The term “pyrimidyl” as used herein includes pyrimid-2-yl, pyrimid-

[0081] 4-yl, pyrimid-5-yl and pyrimid-6-yl. The term “pyrazinyl” as used herein includes pyrazin-2-yl and pyrazin-3-yl. The term “pyridazinyl as used herein includes pyridazin-3-yl and pyridazin-4-yl. The term “oxazinyl” (also called "1 ,4-oxazinyl") as used herein includes 1 ,4-oxazin-4-yl and 1 ,4- oxazin-5-yl. The term “dioxinyl” (also called "1 ,4-dioxinyl”) as used herein includes 1 ,4-dioxin-2-yl and 1 ,4-dioxin-3-yl. The term “thiazinyl” (also called "1 ,4-thiazinyl”) as used herein includes 1 ,4- thiazin-2-yl, 1 ,4-thiazin-3-yl, 1 ,4-thiazin-4-yl, 1 ,4-thiazin-5-yl and 1 ,4-thiazin-6-yl. The term “triazinyl” as used herein includes 1 ,3,5-triazin-2-yl, 1 ,2,4-triazin-3-yl, 1 ,2,4-triazin-5-yl, 1 ,2,4- triazin-6-yl, 1 ,2,3-triazin-4-yl and 1 ,2,3-triazin-5-yl. The term “imidazo[2,1-b][1 ,3]thiazolyl” as used herein includes imidazo[2, 1 -b][1 ,3]thiazoi-2-yl, imidazo[2, 1 -b][1 ,3]thiazol-3-yl, imidazo[2,1- b][1 ,3]thiazol-5-yl and imidazo[2,1-b][1 ,3]thiazol-6-yl. The term “thieno[3,2-b]furanyl” as used herein includes thieno[3,2-b]furan-2-yl, thieno[3,2-b]furan-3-yl, thieno[3,2-b]furan-4-yl, and thieno[3,2-b]furan-5-yl. The term “thieno[3,2-b]thiophenyl” as used herein includes thieno[3,2- b]thien-2-yl, thieno[3,2-b]thien-3-yl, thieno[3,2-b]thien-5-yl and thieno[3,2-b]thien-6-yl. The term “thieno[2,3-d][1 ,3]thiazolyl” as used herein includes thieno[2,3-d][1 ,3]thiazol-2-yl, thieno[2,3- d][1 ,3]thiazol-5-yl and thieno[2,3-d][1 ,3]thiazol-6-yl. The term “thieno[2,3-d]imidazolyl” as used herein includes thieno[2,3-d]imidazol-2-yl, thieno[2,3-d]imidazol-4-yl and thieno[2,3-d]imidazol-5- yl. The term “tetrazolo[1 ,5-a]pyridinyl” as used herein includes tetrazolo[1 ,5-a]pyridine-5-yl, tetrazolo[1 ,5-a]pyridine-6-yl, tetrazolo[1 ,5-a]pyridine-7-yl, and tetrazolo[1 ,5-a]pyridine-8-yl. The term “indolyl” as used herein includes indol-1 -yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol- 6-yl and indol-7-yl. The term “indolizinyl” as used herein includes indolizin-1 -yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl, indolizin-7-yl, and indolizin-8-yl. The term “isoindolyl” as used herein includes isoindol-1 -yl, isoindol-2-yl, isoindol-3-yl, isoindol-4-yl, isoindol-5-yl, isoindol-

[0082] 6-yl and isoindol-7-yl. The term “benzofuranyl” (also called benzo[b]furanyl) as used herein includes benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl and benzofuran-7-yl. The term “isobenzofuranyl” (also called benzo[c]furanyl) as used herein includes isobenzofuran-1-yl, isobenzofuran-3-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6- yl and isobenzofuran-7-yl. The term “benzothiophenyl” (also called benzo[b]thienyl) as used herein includes 2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5- benzo[b]thiophenyl, 6-benzo[b]thiophenyl and -7-benzo[b]thiophenyl (also called benzothien-2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl and benzothien-7-yl). The term “isobenzothiophenyl” (also called benzo[c]thienyl) as used herein includes isobenzothien-1-yl, isobenzothien-3-yl, isobenzothien-4-yl, isobenzothien-5-yl, isobenzothien-6-yl and isobenzothien-

[0083] 7-yl. The term “indazolyl” (also called 1 H-indazolyl or 2-azaindolyl) as used herein includes 1 H- indazol-1-yl, 1 H-indazol-3-yl, 1 H-indazol-4-yl, 1 H-indazol-5-yl, 1 H-indazol-6-yl, 1 H-indazol-7-yl, 2H-indazol-2-yl, 2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, and 2H- indazol-7-yl. The term “benzimidazolyl” as used herein includes benzimidazol-1-yl, benzimidazol- 2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl and benzimidazol-7-yl. The term “1 ,3-benzoxazolyl” as used herein includes 1 ,3-benzoxazol-2-yl, 1 ,3-benzoxazol-4-yl, 1 ,3- benzoxazol-5-yl, 1 ,3-benzoxazol-6-yl and 1 ,3-benzoxazol-7-yl. The term “1 ,2-benzisoxazolyl” as used herein includes 1 ,2-benzisoxazol-3-yl, 1 ,2-benzisoxazol-4-yl, 1 ,2-benzisoxazol-5-yl, 1 ,2- benzisoxazol-6-yl and 1 ,2-benzisoxazol-7-yl. The term “2,1-benzisoxazolyl” as used herein includes 2,1-benzisoxazol-3-yl, 2,1-benzisoxazol-4-yl, 2,1-benzisoxazol-5-yl, 2,1-benzisoxazol-6- yl and 2,1-benzisoxazol-7-yl. The term “1 ,3-benzothiazolyl” as used herein includes 1 ,3- benzothiazol-2-yl, 1 ,3-benzothiazol-4-yl, 1 ,3-benzothiazol-5-yl, 1 ,3-benzothiazol-6-yl and 1 ,3- benzothiazol-7-yl. The term “1 ,2-benzoisothiazolyl” as used herein includes 1 ,2-benzisothiazol-3- yl, 1 ,2-benzisothiazol-4-yl, 1 ,2-benzisothiazol-5-yl, 1 ,2-benzisothiazol-6-yl and 1 ,2- benzisothiazol-7-yl. The term “2,1 -benzoisothiazolyl” as used herein includes 2,1-benzisothiazol-

[0084] 3-yl, 2,1-benzisothiazol-4-yl, 2,1-benzisothiazol-5-yl, 2,1-benzisothiazol-6-yl and 2,1- benzisothiazol-7-yl. The term “benzotriazolyl” as used herein includes benzotriazol- 1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl and benzotriazol-7-yl. The term “1 ,2,3- benzoxadiazolyl” as used herein includes 1 ,2,3-benzoxadiazol-4-yl, 1 ,2,3-benzoxadiazol-5-yl,

[0085] 1.2.3-benzoxadiazol-6-yl and 1 ,2,3-benzoxadiazol-7-yl. The term “2,1 ,3-benzoxadiazolyl” as used herein includes 2, 1 ,3-benzoxadiazol-4-yl, 2,1 ,3-benzoxadiazol-5-yl, 2,1 ,3-benzoxadiazol-6-yl and

[0086] 2.1.3-benzoxadiazol-7-yl. The term “1 ,2,3-benzothiadiazolyl” as used herein includes 1 ,2,3- benzothiadiazol-4-yl, 1 ,2,3-benzothiadiazol-5-yl, 1 ,2,3-benzothiadiazol-6-yl and 1 ,2,3- benzothiadiazol-7-yl. The term “2,1 ,3-benzothiadiazolyl” as used herein includes 2,1 ,3- benzothiadiazol-4-yl, 2,1 ,3-benzothiadiazol-5-yl, 2,1 ,3-benzothiadiazol-6-yl and 2,1 ,3- benzothiadiazol-7-yl. The term “thienopyridinyl” as used herein includes thieno[2,3-b]pyridinyl, thieno[2, 3-c]pyridinyl, thieno[3,2-c]pyridinyl and thieno[3,2-b]pyridinyl . The term “purinyl” as used herein includes purin-2-yl, purin-6-yl, purin-7-yl and purin-8-yl. The term “imidazo[1 ,2-a]pyridinyl”, as used herein includes imidazo[1 ,2-a]pyridin-2-yl, imidazo[1 ,2-a]pyridin-3-yl, imidazo[1 ,2- a]pyridin-4-yl, imidazo[1 ,2-a]pyridin-5-yl, imidazo[1 ,2-a]pyridin-6-yl and imidazo[1 ,2-a]pyridin-7- yl. The term “1 ,3-benzodioxolyl”, as used herein includes 1 ,3-benzodioxol-4-yl, 1 ,3-benzodioxol- 5-yl, 1 ,3-benzodioxol-6-yl, and 1 ,3-benzodioxol-7-yl. The term “quinolinyl” as used herein includes quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl and quinolin-8- yl. The term “isoquinolinyl” as used herein includes isoquinolin-1 -yl, isoquinolin-3-yl, isoquinolin-

[0087] 4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl. The term “cinnolinyl” as used herein includes cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl and cinnolin-8-yl. The term “quinazolinyl” as used herein includes quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl and quinazolin-8-yl. The term “quinoxalinyl” as used herein includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl.

[0088] When the suffix "ene" is used in conjunction with a heteroaryl group, i.e. , “heteroarylene”, this is intended to mean the heteroaryl group as defined herein having two single bonds as points of attachment to other groups. As used herein, the term “heteroarylene” by itself or as part of another substituent, refers to heteroaryl groups that are divalent, i.e., having two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent heteroaryl, i.e., with two single bonds for attachment to two other groups. Heteroarylene groups may be substituted as indicated herein. Heteroaryl and heterocycle or heterocyclyl as used herein includes by way of example and not limitation these groups described in Paquette, Leo A. “Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly Chapters 1 , 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, C.W. and Scriven, E. “Comprehensive Heterocyclic Chemistry” (Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566.

[0089] The term “carbonyl” as a group or part of a group, refers to the group -C(=O)-, also written as - CO-.

[0090] The term “carboxy", “carboxyl” or “hydroxycarbonyl”, as a group or part of a group, refers to the group -C(=O)-OH.

[0091] The term “alkoxycarbonyl” or “alkyloxycarbonyl”, as a group or part of a group, refers to a group of formula -C(=O)-O-Rb, wherein Rbis alkyl as defined herein.

[0092] The term “amino” as a group or part of a group, refers to the -NH2 group.

[0093] The term “mono- or di-alkylamino”, as a group or part of a group, refers to a group of formula -N(R')(Rb), wherein R1is hydrogen or alkyl, Rbis alkyl as defined herein. Thus, such term includes mono-alkyl amino group (e.g., mono-alkylamino group such as methylamino and ethylamino), and di-alkylamino group (e.g., di-alkylamino group such as dimethylamino and diethylamino). Non-limiting examples of suitable mono- or di-alkylamino groups include n- propylamino, isopropylamino, n-butylamino, / -butylamino, sec-butylamino, f-butylamino, pentylamino, n-hexylamino, di-n-propylamino, di- / -propylamino, ethylmethylamino, methyl-n- propylamino, methyl- / -propylamino, n-butylmethylamino, / -butylmethylamino, f-butylmethylamino, ethyl-n-propylamino, ethyl- / -propylamino, n-butylethylamino, i-butylethylamino, f-butylethylamino, di-n-butylamino, di- / -butylamino, methylpentylamino, methylhexylamino, ethylpentylamino, ethylhexylamino, propylpentylamino, propylhexylamino, and the like.

[0094] The term “alkylcarbonylamino", as a group or part of a group, refers to a group of formula -N(R')- C(=O)-Rb, wherein R1is hydrogen or alkyl, Rbis alkyl as defined herein.

[0095] The term “single bond” as used herein for a linking group i.e. , in a way that a certain linking group is selected from a single bond, etc. in the formulas herein, refers to a molecule wherein the linking group is not present and therefore refers to compounds with a direct linkage via a single bond between the two moieties being linked by the linking group.

[0096] Any substituent designation that is found in more than one site in a compound of this invention shall be independently selected. Substituents optionally are designated with or without bonds. Regardless of bond indications, if a substituent is polyvalent (based on its position in the structure referred to), then any and all possible orientations of the substituent are intended.

[0097] Any reference to a "compound according to the invention", or "compound of formula (I)" also includes isomers such as stereoisomers and tautomers, salts such as pharmaceutically and / or physiologically acceptable salts, hydrates, solvates, polymorphs of such compounds unless expressly indicated otherwise.

[0098] As used herein and unless otherwise stated, the term “solvate” includes any combination which may be formed by a derivative of this invention with a suitable inorganic solvent (e.g., hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters, ethers, nitriles, and the like.

[0099] Preferred statements (features) and embodiments of the methods, compositions, and uses of this invention are set herein below. Each statement and embodiment of the invention so defined may be combined with any other statement and / or embodiment, unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other features or statements indicated as being preferred or advantageous. Hereto, the present invention is in particular captured by any one or any combination of one or more of the below numbered statements and embodiments, with any other aspect and / or embodiment.

[0100] 1. A compound of formula (C1), or a salt, a solvate, a hydrate, a polymorph, a tautomer, a racemate or a stereoisomer thereof; or a prodrug thereof, wherein

[0101] II is N or C;

[0102] V is selected from CH, N, or NH; with the proviso that when II is N, V is CH; when V is N, or NH, II is C;

[0103] R3is absent or R3is hydrogen, or Ci-ealkyl;

[0104] R4independently selected from the group comprising hydrogen, hydroxyl, halo, Ci-ealkoxy, and Ci-ealkyl;

[0105] L1is a single bond or -C(R5)2-; each R5is independently selected from hydrogen, or Ci-ealkyl;

[0106] L3is -(C(R7)2)n-; wherein n is an integer selected from 1 or 2; each R7is independently selected from hydrogen, hydroxyl, halo, or Ci-ealkyl;

[0107] A1is selected from the group comprising Cs-ecycloalkyl, Ce-waryl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, C2-ealkenyl, C2-ealkynyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, Cs-ecycloalkyl, oxo, Ci- ealkylcarbonylamino, (R8)2N-, and (R8)2N-carbonyl; and / or two R1together with the atom(s) to which they are attached can form a 5-10 membered saturated or partially saturated heterocyclyl, or a Ce- aryl, a 5-10 membered heteroaryl;

[0108] A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, 5-6 membered saturated or partially saturated heterocyclyl, and Cs-ecycloalkyl; wherein each of said group can be unsubstituted or substituted with one or more R2, wherein each R2is independently selected from the group comprising halo, haloCiwalkyl, hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, (R8)2N-carbonyl, and C1- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen; halo, or Ci-ealkyl;

[0109] R8is selected from hydrogen, or Ci-ealkyl; with the proviso that said compound is not 1-(phenylmethyl)-4-[3-(phenylmethyl)-1 H-1 ,2,4- triazol-5-yl]-piperidine.

[0110] 2. The compound according to statement 1 , having structural formula (C1A), (C1C), or (C1 E), wherein A1, L1, L3, R3, R4, and A2have the same meaning as that defined in statement 1. A compound of formula (C1A), or a salt, a solvate, a hydrate, a polymorph, a tautomer, a racemate or a stereoisomer thereof; or a prodrug thereof, wherein

[0111] R4independently selected from the group comprising hydrogen, hydroxyl, halo, Ci-ealkoxy, and Ci-ealkyl;

[0112] L1is a single bond or -C(R5)2-; each R5is independently selected from hydrogen, or Ci-ealkyl;

[0113] L3is -(C(R7)2)n-; wherein n is an integer selected from 1 or 2; each R7is independently selected from hydrogen, halo, or Ci-ealkyl;

[0114] A1is selected from the group comprising Cs-ecycloalkyl, Ce-waryl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, C2-ealkenyl, C2-ealkynyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, Cs-ecycloalkyl, oxo, Ci- ealkylcarbonylamino, (R8)2N-, and (R8)2N-carbonyl; and / or two R1together with the atom(s) to which they are attached can form a 5-10 membered saturated or partially saturated heterocyclyl, or a Ce- aryl, a 5-10 membered heteroaryl;

[0115] A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, 5-6 membered saturated or partially saturated heterocyclyl, and Cs-ecycloalkyl; wherein each of said group can be unsubstituted or substituted with one or more R2, wherein each R2is independently selected from the group comprising halo, haloCiwalkyl, hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci -ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, (R8)2N-carbonyl, and C1- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl;

[0116] R8is selected from hydrogen, or Ci-ealkyl; with the proviso that said compound is not The compound according to any one of statements 1-3, wherein

[0117] R4is independently selected from the group comprising hydrogen, hydroxyl, halo, and Ci- ealkoxy; preferably R4is independently selected from hydrogen, hydroxyl, or halo;

[0118] L1is a single bond or -C(R5)2-; each R5is independently selected from hydrogen, or Ci-ealkyl; preferably each R5is independently selected from hydrogen, or Ci-4alkyl; preferably each R5is independently selected from hydrogen, or Ci-2alkyl; preferably each R5is hydrogen;

[0119] L3is -(C(R7)2)n-; preferably L3is -(CHR7)n-; wherein n is an integer selected from 1 or 2; each R7is independently selected from hydrogen, hydroxyl, halo, or Ciwalkyl; preferably each R7is independently selected from hydrogen, halo, or Ci-ealkyl; preferably each R7is independently selected from hydrogen, or halo ; preferably L3is -CH2- or -CH2CH2-;

[0120] A1is selected from the group comprising Cs-ecycloalkyl, Ce-waryl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising Cs-ecycloalkyl, Ce- aryl, 5-9 membered heteroaryl containing at least one N, O and / or S, and 5-9 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising Cs-ecycloalkyl, Ce-waryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and 5-6 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising Cs-ecycloalkyl, Ce-waryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and 5-6 membered saturated heterocyclyl containing at least one O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising Cs-ecycloalkyl, phenyl, 5-6 membered heteroaryl containing at least one N, and / or S, and 5-6 membered saturated heterocyclyl containing at least one O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising Cs- ecycloalkyl, phenyl, 5-6 membered heteroaryl containing one N, or one S, and 6 membered saturated heterocyclyl containing one O or one S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising cyclohexyl, phenyl, thienyl, pyridyl, thianyl, oxanyl, and cyclopentyl, wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising cyclohexyl, phenyl, wherein each of said cyclohexyl or phenyl can be unsubstituted or substituted with one or more R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, C2-ealkenyl, C2-ealkynyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, Cs-ecycloalkyl, oxo, Ci- ealkylcarbonylamino, (R8)2N-, and (R8)2N-carbonyl; preferably wherein each of said cyclohexyl or phenyl can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, Cs-ecycloalkyl, oxo, Ci- ealkylcarbonylamino, (R8)2N-, and (R8)2N-carbonyl; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci- ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, Ci- ealkoxycarbonyl, Cs-ecycloalkyl, oxo, Ci-ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, oxo, Ci-ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci- ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, oxo, Ci- ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, or three R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, oxo, and Ci- ealkylcarbonylamino; A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, 5-6 membered saturated or partially saturated heterocyclyl, and Cs-ecycloalkyl; wherein each of said group can be unsubstituted or substituted with one or more R2, preferably A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, 5-6 membered saturated or partially saturated heterocyclyl, and Cs-ecycloalkyl; wherein each of said group can be unsubstituted or substituted with one or more R2, preferably A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, and 5-6 membered saturated or partially saturated heterocyclyl; wherein each of said group can be unsubstituted or substituted with one or more R2; preferably A2is selected from a 5-6 membered heteroaryl containing at least one N, O and / or S, and phenyl; wherein each of said heteroaryl and phenyl can be unsubstituted or substituted with one or more R2; preferably A2is selected from the group comprising pyrazyl, phenyl, pyridyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrrolyl, oxazolyl, benzo[1.3]dioxol, or 2,2-difluoro-benzo[1.3]dioxol; pyrimidinyl, cyclohexyl, oxanyl, and pyrazinyl; wherein each of said group can be unsubstituted or substituted with one or more R2, wherein each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, (R8)2N-carbonyl, and Ci- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen; halo, or Ci-ealkyl; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi- ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, (R8)2N-carbonyl, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen; halo, or Ci-ealkyl; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, Ci-ealkoxycarbonyl, (R8)2N-carbonyl, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O- CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci- ealkyl; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, Ci-ealkoxycarbonyl, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci- ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, and C1- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, and C1- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, and -SO2-R8; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo; and

[0121] R8is selected from hydrogen, or Ci-ealkyl.

[0122] 5. The compound according to any one of statements 1-4, wherein

[0123] R4is independently selected from the group comprising hydrogen, hydroxyl, halo, and C1- 4alkoxy; preferably R4is independently selected from hydrogen, hydroxyl, or halo;

[0124] L1is a single bond or -C(R5)2-; each R5is independently selected from hydrogen, or Ci-4alkyl; preferably each R5is independently selected from hydrogen, or Ci-4alkyl; preferably each R5is independently selected from hydrogen, or Ci-2alkyl; preferably each R5is hydrogen;

[0125] L3is -(C(R7)2)n-; preferably L3is -(CHR7)n-; wherein n is an integer selected from 1 or 2; each R7is independently selected from hydrogen, hydroxyl, halo, or Ci-4alkyl; preferably each R7is independently selected from hydrogen, halo, or Ci-4alkyl; preferably each R7is independently selected from hydrogen, halo, or Ci-2alkyl; preferably each R7is independently selected from hydrogen, or halo ; preferably L3is -CH2- or -CH2CH2-.

[0126] 6. The compound according to any one of statements 1-5, wherein

[0127] R4is independently selected from the group comprising hydrogen, hydroxyl, halo, and C1- 2alkoxy; preferably R4is independently selected from hydrogen, hydroxyl, or halo; L1is a single bond or -C(R5)2-; each R5is independently selected from hydrogen, or Ci-2alkyl; preferably each R5is independently selected from hydrogen, or methyl; preferably each R5is hydrogen;

[0128] L3is -(C(R7)2)n-; preferably L3is -(CHR7)n-; wherein n is an integer selected from 1 or 2; each R7is independently selected from hydrogen, hydroxyl, halo, or Ci-2alkyl; preferably each R7is independently selected from hydrogen, halo, or Ci-2alkyl; preferably each R7is independently selected from hydrogen, or halo; preferably L3is -CH2- or -CH2CH2-. The compound according to any one of statements 1-6, having structural formula (C1A3),

[0129] (C1C3), or (C1 E3), wherein A1, L1, R3, R4, R7and A2have the same meaning as that defined in any one of statements 1-6. The compound according to any one of statements 1-7, having structural formula (C1A4), (C1C4), or (C1 E4), wherein A1, L1, R3, R4, and A2have the same meaning as that defined in any one of statements 1-7. The compound according to any one of statements 1-8, having structural formula (C1A5), (C1C5), or (C1 E5), wherein A1, L1, R3, and A2have the same meaning as that defined in any one of statements 1-8. The compound according to any one of statements 1-9, wherein

[0130] A1is selected from the group comprising Cs-ecycloalkyl, Ce-waryl, 5-9 membered heteroaryl containing at least one N, O and / or S, and 5-9 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising Cs-ecycloalkyl, Ce- aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and 5-6 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising Cs-ecycloalkyl, Ce-waryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and 5-6 membered saturated heterocyclyl containing at least one O, and / or one S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising Cs-ecycloalkyl, phenyl, 5-6 membered heteroaryl containing at least one N, and / or S, and 5-6 membered saturated heterocyclyl containing at least one O, and / or one S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising Cs-ecycloalkyl, phenyl, 5-6 membered heteroaryl containing one N, or one S, and 6 membered saturated heterocyclyl containing one O or one S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising cyclohexyl, phenyl, thienyl, pyridyl, thianyl, oxanyl, and cyclopentyl, wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising cyclohexyl, phenyl, wherein each of said cyclohexyl or phenyl can be unsubstituted or substituted with one or more R1; wherein each R1is independently selected from the group comprising halo, Ciwalkyl, haloCiwalkyl, C2-ealkenyl, C2-ealkynyl, hydrogen, Ciwalkoxy, haloCiwalkoxy, cyano, hydroxy, carboxyl, Ciwalkoxycarbonyl, Cs-ecycloalkyl, Cs-ecycloalkyl, oxo, Ci- ealkylcarbonylamino, (R8)2N-, and (R8)2N-carbonyl; preferably wherein each of said cyclohexyl or phenyl can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, Cs-ecycloalkyl, oxo, Ci- ealkylcarbonylamino, (R8)2N-, and (R8)2N-carbonyl; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci- ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, Ci- ealkoxycarbonyl, Cs-ecycloalkyl, oxo, Ci-ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, oxo, Ci-ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci- ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, oxo, Ci- ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, or three R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, oxo, and Ci- ealkylcarbonylamino;

[0131] R8is selected from hydrogen, or Ci-ealkyl. The compound according to any one of statements 1-10, wherein

[0132] A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, 5-6 membered saturated or partially saturated heterocyclyl, and C4-ecycloalkyl; wherein each of said group can be unsubstituted or substituted with one or more R2; preferably A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, 5-6 membered saturated or partially saturated heterocyclyl, and Cs-ecycloalkyl; wherein each of said group can be unsubstituted or substituted with one or more R2, preferably A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, and 5-6 membered saturated or partially saturated heterocyclyl; wherein each of said group can be unsubstituted or substituted with one or more R2; preferably A2is selected from a 5-6 membered heteroaryl containing at least one N, O and / or S, and phenyl; wherein each of said heteroaryl and phenyl can be unsubstituted or substituted with one or more R2; preferably A2 is selected from the group comprising pyrazyl, phenyl, pyridyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrrolyl, oxazolyl, benzo[1.3]dioxol, or 2,2-difluoro-benzo[1.3]dioxol; pyrimidinyl, cyclohexyl, oxanyl, and pyrazinyl; wherein each of said group can be unsubstituted or substituted with one or more R2, wherein each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, (R8)2N-carbonyl, and Ci- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi- ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, (R8)2N-carbonyl, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, Ci-ealkoxycarbonyl, (R8)2N-carbonyl, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O- CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci- ealkyl; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, Ci-ealkoxycarbonyl, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, and Ci- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, and -SO2-R8; and / or two R2together can form a - O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; and

[0133] R8is selected from hydrogen, or Ci-ealkyl. The compound according to any one of statements 1-11 , wherein

[0134] A1is selected from the group comprising Cs-ecycloalkyl, Ce- aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and 5-6 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising Cs-ecycloalkyl, Ce- aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and 5-6 membered saturated heterocyclyl containing at least one O, and / or one S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising Cs-ecycloalkyl, phenyl, 5-6 membered heteroaryl containing at least one N, and / or S; 6 membered saturated heterocyclyl containing at least one O, and / or one S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising Cs-ecycloalkyl, phenyl, 5-6 membered heteroaryl containing one N, or one S, and 5-6 membered saturated heterocyclyl containing one O, or one S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising cyclohexyl, phenyl, thienyl, pyridyl, thianyl, oxanyl, and cyclopentyl, wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising cyclohexyl, phenyl, wherein each of said cyclohexyl or phenyl can be unsubstituted or substituted with one or more R1; wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, carboxyl, Ciwalkoxycarbonyl, Cs-ecycloalkyl, Cs-ecycloalkyl, oxo, C1- ealkylcarbonylamino, (R8)2N-, and (R8)2N-carbonyl; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci- ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, C1- ealkoxycarbonyl, Cs-ecycloalkyl, oxo, Ci-ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, oxo, Ci-ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci- ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, oxo, Ci- ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, or three R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, oxo, and Ci- ealkylcarbonylamino;

[0135] R8is selected from hydrogen, or Ci-ealkyl. The compound according to any one of statements 1-12, wherein

[0136] A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, 5-6 membered saturated or partially saturated heterocyclyl, and Cs-ecycloalkyl; wherein each of said group can be unsubstituted or substituted with one or more R2, preferably A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, and 5-6 membered saturated or partially saturated heterocyclyl; wherein each of said group can be unsubstituted or substituted with one or more R2; preferably A2is selected from a 5-6 membered heteroaryl containing at least one N, O and / or S, and phenyl; wherein each of said heteroaryl and phenyl can be unsubstituted or substituted with one or more R2; preferably A2is selected from the group comprising pyrazyl, phenyl, pyridyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrrolyl, oxazolyl, benzo[1.3]dioxol, or 2,2-difluoro-benzo[1.3]dioxol; pyrimidinyl, cyclohexyl, oxanyl, and pyrazinyl; wherein each of said group can be unsubstituted or substituted with one or more R2, wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, (R8)2N-carbonyl, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, Ci-ealkoxycarbonyl, (R8)2N-carbonyl, and Ci- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi- ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, Ci-ealkoxycarbonyl, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O- CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci- ealkyl; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, and -SO2-R8; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; and

[0137] R8is selected from hydrogen, or Ci-ealkyl. The compound according to any one of statements 1-13, wherein

[0138] A1is selected from the group comprising Cs-ecycloalkyl, Ce- aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and 5-6 membered saturated heterocyclyl containing at least one O, and / or one S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising Cs-ecycloalkyl, phenyl, 5-6 membered heteroaryl containing at least one N, and / or S; 5-6 membered saturated heterocyclyl containing one O, or one S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising C5- ecycloalkyl, phenyl, 5-6 membered heteroaryl containing one N, or one S, and 6 membered saturated heterocyclyl containing one O, or one S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising cyclohexyl, phenyl, thienyl, pyridyl, thianyl, oxanyl, and cyclopentyl, wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising cyclohexyl, phenyl, wherein each of said cyclohexyl or phenyl can be unsubstituted or substituted with one or more R1; wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, oxo, Ci-ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, oxo, Ci-ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, oxo, Ci-ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, or three R1; wherein each R1is independently selected from the group comprising halo, Ci- ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, oxo, and Ci- ealkylcarbonylamino;

[0139] R8is selected from hydrogen, or Ci-ealkyl. The compound according to any one of statements 1-14, wherein

[0140] A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, and 5-6 membered saturated or partially saturated heterocyclyl; wherein each of said group can be unsubstituted or substituted with one or more R2; preferably A2is selected from a 5-6 membered heteroaryl containing at least one N, O and / or S, and phenyl; wherein each of said heteroaryl and phenyl can be unsubstituted or substituted with one or more R2; preferably A2is selected from the group comprising pyrazyl, phenyl, pyridyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrrolyl, oxazolyl, benzo[1.3]dioxol, or 2,2-difluoro- benzo[1.3]dioxol; pyrimidinyl, cyclohexyl, oxanyl, and pyrazinyl; wherein each of said group can be unsubstituted or substituted with one or more R2, wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, Ci-ealkoxycarbonyl, (R8)2N-carbonyl, and Ci- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-6alkyl;preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi- ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, Ci-ealkoxycarbonyl, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O- CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or C1- 6alkyl;preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-6alkyl;preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, and -SO2-R8; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; and

[0141] R8is selected from hydrogen, or Ci-ealkyl. The compound according to any one of statement 1-15, wherein

[0142] A1is selected from the group comprising Cs-ecycloalkyl, Ce- aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and 5-6 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, oxo, Ci-ealkylcarbonylamino, (R8)2N-, and (R8)2N-carbonyl; A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, 5-6 membered saturated or partially saturated heterocyclyl, and Cs-ecycloalkyl; wherein each of said group can be unsubstituted or substituted with one or more R2, wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, (R8)2N-carbonyl, and Ci-6alkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl;

[0143] R8is selected from hydrogen, or Ci-ealkyl. The compound according to any one of statements 1-16, wherein

[0144] A1is selected from the group comprising Cs-ecycloalkyl, Ce- aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and 5-6 membered saturated heterocyclyl containing at least one O, and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising Cs-ecycloalkyl, phenyl, 5- 6 membered heteroaryl containing at least one N, and / or S, and 5-6 membered saturated heterocyclyl containing one O, or one S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising C5- ecycloalkyl, phenyl, 5-6 membered heteroaryl containing one N, or one S, and 6 membered saturated heterocyclyl containing one O, or one S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising cyclohexyl, phenyl, thienyl, pyridyl, thianyl, oxanyl, and cyclopentyl, wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising cyclohexyl, phenyl, wherein each of said cyclohexyl or phenyl can be unsubstituted or substituted with one or more R1; wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, oxo, Ci-ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, oxo, Ci-ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, oxo, Ci-ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, or three R1; wherein each R1is independently selected from the group comprising halo, Ci- ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, oxo, and Ci- ealkylcarbonylamino;

[0145] A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, and 5-6 membered saturated or partially saturated heterocyclyl; wherein each of said group can be unsubstituted or substituted with one or more R2; preferably A2is selected from a 5-6 membered heteroaryl containing at least one N, O and / or S, and phenyl; wherein each of said heteroaryl and phenyl can be unsubstituted or substituted with one or more R2; preferably A2is selected from the group comprising pyrazyl, phenyl, pyridyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrrolyl, oxazolyl, benzo[1.3]dioxol, or 2,2-difluoro- benzo[1.3]dioxol; pyrimidinyl, cyclohexyl, oxanyl, and pyrazinyl; wherein each of said group can be unsubstituted or substituted with one or more R2, wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, Ci-ealkoxycarbonyl, (R8)2N-carbonyl, and C1- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl;preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi- ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, Ci-ealkoxycarbonyl, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O- CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or C1- 4alkyl;and / or two R2together with the atom(s) to which they are attached can form a 5-6 membered saturated or partially saturated heterocyclyl; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, and Ci- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-2alkyl;preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi- ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, and -SO2-R8; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; and

[0146] R8is selected from hydrogen, or Ci-ealkyl. The compound according to any one of statements 1-17, wherein

[0147] A1is selected from the group comprising Cs-ecycloalkyl, phenyl, 5-6 membered heteroaryl containing at least one N, and / or S; and 5-6 membered saturated heterocyclyl containing at least one O, and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising Cs-ecycloalkyl, phenyl, 5- 6 membered heteroaryl containing one N, or one S, and 5-6 membered saturated heterocyclyl containing one O, or one S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising cyclohexyl, phenyl, thienyl, pyridyl, thianyl, oxanyl, and cyclopentyl, wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising cyclohexyl, phenyl, wherein each of said cyclohexyl or phenyl can be unsubstituted or substituted with one or more R1; wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, oxo, Ci-ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci- ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, oxo, Ci- ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, or three R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, oxo, and Ci- ealkylcarbonylamino; A2is selected from a 5-6 membered heteroaryl containing at least one N, O and / or S, and phenyl; wherein each of said heteroaryl and phenyl can be unsubstituted or substituted with one or more R2; preferably A2is selected from the group comprising pyrazyl, phenyl, pyridyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrrolyl, oxazolyl, benzo[1.3]dioxol, or 2,2-difluoro- benzo[1.3]dioxol; pyrimidinyl, cyclohexyl, oxanyl, and pyrazinyl; wherein each of said group can be unsubstituted or substituted with one or more R2, wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, Ci-ealkoxycarbonyl, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-6alkyl;preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, and Ci- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, and -SO2-R8; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; and

[0148] R8is selected from hydrogen, or Ci-ealkyl. The compound according to any one of statements 1-18, wherein

[0149] A1is selected from the group comprising Cs-ecycloalkyl, phenyl, 5-6 membered heteroaryl containing one N, or one S, and 5-6 membered saturated heterocyclyl containing one O, or one S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising cyclohexyl, phenyl, thienyl, pyridyl; thianyl, oxanyl, and cyclopentyl, wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising cyclohexyl, phenyl, wherein each of said cyclohexyl or phenyl can be unsubstituted or substituted with one or more R1; wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, oxo, Ci-ealkylcarbonylamino, and (R8)2N-; preferably wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, or three R1; wherein each R1is independently selected from the group comprising halo, Ci- ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, oxo, and Ci- ealkylcarbonylamino;

[0150] A2is selected from a 5-6 membered heteroaryl containing at least one N, O and / or S, and phenyl; wherein each of said heteroaryl and phenyl can be unsubstituted or substituted with one or more R2; preferably A2is selected from the group comprising pyrazyl, phenyl, pyridyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrrolyl, oxazolyl, benzo[1.3]dioxol, or 2,2-difluoro- benzo[1.3]dioxol; pyrimidinyl, cyclohexyl, oxanyl, and pyrazinyl; wherein each of said group can be unsubstituted or substituted with one or more R2, wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, and -SO2-R8; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; and

[0151] R8is selected from hydrogen, or Ci-ealkyl.

[0152] 20. The compound according to any one of statements 1-19, wherein A1is selected from the group comprising Cs-ecycloalkyl, phenyl, 5-6 membered heteroaryl containing one N, or one S, 5-6 membered saturated heterocyclyl containing one O, or one S; wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising cyclohexyl, phenyl, thienyl, pyridyl, thianyl, oxanyl, and cyclopentyl, wherein each of said group can be unsubstituted or substituted with one or more R1; preferably A1is selected from the group comprising cyclohexyl, phenyl, wherein each of said cyclohexyl or phenyl can be unsubstituted or substituted with one or more R1; wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, or three R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, oxo, and Ci-6alkylcarbonylamino;

[0153] A2is selected from a 5-6 membered heteroaryl containing at least one N, O and / or S, and phenyl; wherein each of said heteroaryl and phenyl can be unsubstituted or substituted with one or more R2; preferably A2is selected from the group comprising pyrazyl, phenyl, pyridyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrrolyl, oxazolyl, benzo[1.3]dioxol, or 2,2-difluoro- benzo[1.3]dioxol; pyrimidinyl, cyclohexyl, oxanyl, and pyrazinyl; wherein each of said group can be unsubstituted or substituted with one or more R2, wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, and -SO2-R8; and / or two R2together can form a - O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; and

[0154] R8is selected from hydrogen, or Ci-ealkyl.

[0155] 21. The compound according to any one of statements 1-20, having structural formula (C1A6), (C1C6), (C1 E6), (C1A7), (C1C7), or (C1 E7), wherein L1, R1, R3and A2have the same meaning as that defined in any one of statements 1-20, and s is an integer selected from 1, 2, 3 or 4, q is an integer selected from 0 or 1 , Y1is selected from CH2, O, S, or NH, and Z1is selected from CH, N, O or S, preferably Y1is selected from CH2, O, or S; and Z1is selected from CH, N, or S. The compound according to any one of statements 1-21 , having structural formula (C1A8), (C1C8), (C1E8), (C1A9), (C1C9), or (C1 E9),

[0156] wherein L1, R1, R3and A2have the same meaning as that defined in any one of statements 1-21 , and s is an integer selected from 1 , 2, 3 or 4.

[0157] 23. The compound according to any one of statements 1-22, wherein

[0158] A2is selected from a 5-6 membered heteroaryl containing at least one N, O and / or S, and phenyl; wherein each of said heteroaryl and phenyl can be unsubstituted or substituted with one or more R2; preferably A2is selected from the group comprising pyrazyl, phenyl, pyridyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrrolyl, oxazolyl, benzo[1.3]dioxol, or 2,2-difluoro- benzo[1.3]dioxol; pyrimidinyl, cyclohexyl, oxanyl, and pyrazinyl; wherein each of said group can be unsubstituted or substituted with one or more R2, wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; preferably wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, and -SO2-R8; and / or two R2together can form a - O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen or halo such as fluoro or chloro; and

[0159] R8is selected from hydrogen, or Ci-ealkyl. A compound according to any one of statements 1-23, wherein said compound is selected from the group comprising the compounds listed in Table 1C. A pharmaceutical composition comprising a compound according to any one of statements 1- 24, and at least one pharmaceutical acceptable carrier. A compound according to any one of statements 1-24, or a pharmaceutical composition according to statement 25 for use as a medicine. A compound according to any one of statements 1-24 for use as therapeutically active substance. A compound according to any one of statements 1-24, or a pharmaceutical composition according to statement 25, for use in the prevention and / or treatment of neurodegenerative disorders, such as neurodegenerative disorders characterized by cytotoxic TAU misfolding and / or aggregation, in order to delay or halt the progression of such diseases. The compound or the pharmaceutical composition for use according to statement 28, wherein said disease is selected from the group consisting of Parkinson's disease, Alzheimer’s disease, diffuse Lewy body disease, amyotrophic lateral sclerosis, Niemann Pick disease, Hallervorden Spatz syndrome, Down syndrome, Pick’s disease, progressive supranuclear palsy, vascular dementia, neuroaxonal dystrophy, Huntington’s disease, frontotemporal lobar degeneration (FTLD), multiple system atrophy and Creutzfeldt-Jacob’s disease, preferably said neurodegenerative disorder is Alzheimer’s disease. A compound according to any one of statements 1-24, or a pharmaceutical composition according to statement 25, in the prevention and / or treatment of a disease selected from the group consisting of Parkinson's disease, Alzheimer’s disease, diffuse Lewy body disease, amyotrophic lateral sclerosis, Niemann Pick disease, Hallervorden Spatz syndrome, Down syndrome, Pick’s disease, progressive supranuclear palsy, vascular dementia, neuroaxonal dystrophy, Huntington’s disease, frontotemporal lobar degeneration (FTLD), multiple system atrophy and Creutzfeldt-Jacob’s disease, preferably said neurodegenerative disorder is Alzheimer’s disease. A method for the prevention and / or treatment of neurodegenerative disorders, such as neurodegenerative disorders characterized by cytotoxic TAU misfolding and / or aggregation, in order to delay or halt the progression of such diseases, which method comprises administering an effective amount of a compound according to any one of statements 1-24, to a subject in need thereof.

[0160] 32. The method according to statement 31 , wherein the disease is selected from the group consisting of Parkinson's disease, Alzheimer’s disease, diffuse Lewy body disease, amyotrophic lateral sclerosis, Niemann Pick disease, Hallervorden Spatz syndrome, Down syndrome, Pick’s disease, progressive supranuclear palsy, vascular dementia, neuroaxonal dystrophy, Huntington’s disease, frontotemporal lobar degeneration (FTLD), multiple system atrophy and Creutzfeldt-Jacob’s disease, preferably said neurodegenerative disorder is Alzheimer’s disease.

[0161] The invention provides a compound of formula (C1), and preferably a compound of formula (C1A), as defined herein (including all embodiments thereof as described herein).

[0162] In some embodiments of compound of formula (C1), and of compound of formula (C1A), as defined herein (including all embodiments thereof as described herein),

[0163] R4is independently selected from the group comprising hydrogen, hydroxyl, halo, and Ci-ealkoxy;

[0164] L1is a single bond or -C(R5)2-; each R5is independently selected from hydrogen, or Ci-4alkyl;

[0165] L3is -(C(R7)2)n-; preferably L3is -(CHR7)n-; wherein n is an integer selected from 1 or 2; each R7is independently selected from hydrogen, hydroxyl, halo, or Ci-ealkyl; preferably each R7is independently selected from hydrogen, halo, or Ci-ealkyl;

[0166] A1is selected from the group comprising Cs-ecycloalkyl, Ce- aryl, 5-9 membered heteroaryl containing at least one N, O and / or S, and 5-9 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; wherein each of said cyclohexyl or phenyl can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, Cs-ecycloalkyl, oxo, Ci- ealkylcarbonylamino, (R8)2N-, and (R8)2N-carbonyl;

[0167] A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, 5-6 membered saturated or partially saturated heterocyclyl, and C4- ecycloalkyl; wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, (R8)2N-carbonyl, and Ci- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl; and

[0168] R8is selected from hydrogen, or Ci-ealkyl.

[0169] In some embodiments of compound of formula (C1), and of compound of formula (C1A), as defined herein (including all embodiments thereof as described herein),

[0170] R4is independently selected from the group comprising hydrogen, hydroxyl, halo, and Ci-ealkoxy;

[0171] L1is a single bond or -C(R5)2-; each R5is independently selected from hydrogen, or Ci-4alkyl;

[0172] L3is -(C(R7)2)n-; preferably L3is -(CHR7)n-; wherein n is an integer selected from 1 or 2; each R7is independently selected from hydrogen, hydroxyl, or halo; preferably each R7is hydrogen or halo; preferably L3is -CH2- or -CH2CH2-;

[0173] A1is selected from the group comprising Cs-ecycloalkyl, Ce- aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and 5-6 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, oxo, Ci-ealkylcarbonylamino, and (R8)2N-;

[0174] A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, 5-6 membered saturated or partially saturated heterocyclyl, and Cs- ecycloalkyl; wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, Ci-ealkoxycarbonyl, (R8)2N-carbonyl, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl;and

[0175] R8is selected from hydrogen, or Ci-ealkyl.

[0176] In some embodiments of compound of formula (C1), and of compound of formula (C1A), as defined herein (including all embodiments thereof as described herein),

[0177] R4is independently selected from the group comprising hydrogen, hydroxyl, halo, and Ci-ealkoxy;

[0178] L1is a single bond or -C(R5)2-; each R5is independently selected from hydrogen, or Ci-4alkyl; L3is -(C(R7)2)n-; preferably L3is -(CHR7)n-; wherein n is an integer selected from 1 or 2; preferably each R7is independently selected from hydrogen, hydroxyl, or halo; preferably each R7is hydrogen or halo; preferably L3is -CH2- or -CH2CH2-;

[0179] A1is selected from the group comprising Cs-ecycloalkyl, Ce- aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and 5-6 membered saturated heterocyclyl containing at least one O and / or S; preferably A1is selected from the group comprising Cs-ecycloalkyl, phenyl, 5-6 membered heteroaryl containing at least one N, and / or S, and 6 membered saturated heterocyclyl containing one O or one S; preferably A1is selected from the group comprising Cs- ecycloalkyl, phenyl, 5-6 membered heteroaryl containing one N, or one S; wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, oxo, Ci-ealkylcarbonylamino, and (R8)2N-;

[0180] A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, and 5-6 membered saturated or partially saturated heterocyclyl; preferably A2is selected from a 5-6 membered heteroaryl containing at least one N, O and / or S, and phenyl; preferably A2is selected from the group comprising pyrazyl, phenyl, pyridyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrrolyl, oxazolyl, benzo[1.3]dioxol, or 2,2-difluoro-benzo[1.3]dioxol; pyrimidinyl, cyclohexyl, oxanyl and pyrazinyl; wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, Ci-ealkoxycarbonyl, and Ci-ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl;and

[0181] R8is selected from hydrogen, or Ci-ealkyl.

[0182] In some embodiments of compound of formula (C1), and of compound of formula (C1A), as defined herein (including all embodiments thereof as described herein),

[0183] R4is independently selected from the group comprising hydrogen, hydroxyl, halo, and Ci-ealkoxy;

[0184] L1is a single bond or -C(R5)2-; each R5is independently selected from hydrogen, or Ci-2alkyl;

[0185] L3is -(C(R7)2)n-; preferably L3is -(CHR7)n-; wherein n is an integer selected from 1 or 2; each R7is independently selected from hydrogen, hydroxyl, or halo; preferably each R7is hydrogen or halo; preferably L3is -CH2- or -CH2CH2-; A1is selected from the group comprising Cs-ecycloalkyl, phenyl, 5-6 membered heteroaryl containing at least one N, and / or S, and 6 membered saturated heterocyclyl containing one O or one S; wherein each of said group can be unsubstituted or substituted with one or more R1; wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, oxo, Ci-6alkylcarbonylamino, and (R8)2N-;

[0186] A2is selected from a 5-6 membered heteroaryl containing at least one N, O and / or S, and phenyl; wherein each of said heteroaryl and phenyl can be unsubstituted or substituted with one or more R2; wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, - SO2-R8, and Ci-6alkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl;and

[0187] R8is selected from hydrogen, or Ci-ealkyl.

[0188] In some embodiments of compound of formula (C1), and of compound of formula (C1A), as defined herein (including all embodiments thereof as described herein),

[0189] R4is independently selected from the group comprising hydrogen, hydroxyl, halo, and Ci-ealkoxy;

[0190] L1is a single bond or -C(R5)2-; each R5is independently selected from hydrogen, or Ci-2alkyl;

[0191] L3is -CH2- or -CH2CH2-;

[0192] A1is selected from the group comprising Cs-ecycloalkyl, phenyl, 5-6 membered heteroaryl containing one N, or one S, and 6 membered saturated heterocyclyl containing one O or one S; preferably A1is selected from the group comprising cyclohexyl, phenyl, thienyl, pyridyl, thianyl, oxanyl, and cyclopentyl, preferably A1is selected from the group comprising cyclohexyl, phenyl, wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, oxo, Ci-ealkylcarbonylamino, and (R8)2N-;

[0193] A2is selected from a 5-6 membered heteroaryl containing at least one N, O and / or S, and phenyl; preferably A2is selected from the group comprising pyrazyl, phenyl, pyridyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrrolyl, oxazolyl, benzo[1.3]dioxol, or 2,2-difluoro-benzo[1.3]dioxol; pyrimidinyl, cyclohexyl, oxanyl, and pyrazinyl; wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, or three R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, and -SO2-R8; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, or halo; and

[0194] R8is selected from hydrogen, or Ci-ealkyl.

[0195] In a preferred embodiment of the invention, the compound is selected from the group of compounds listed in Table 1C below, or a salt, a solvate, a hydrate, a polymorph, a tautomer, a racemate, a stereoisomer, or a prodrug thereof.

[0196] Any reference to a compound of formula (C1) as defined herein (including all embodiments thereof as described herein) also includes isomers such as stereoisomers and tautomers, salts such as pharmaceutically and / or physiologically acceptable salts, hydrates, solvates, polymorphs, and prodrugs of such compounds unless expressly indicated otherwise.

[0197] The term "isomers" as used herein means all possible isomeric forms, including tautomeric and stereochemical forms, which the compounds of formulae herein may possess, but not including position isomers. Typically, the structures shown herein exemplify one tautomeric or resonance form of the compounds, but the corresponding alternative configurations are contemplated as well.

[0198] Depending on its substitution pattern, the compounds of the present invention as defined herein (including all embodiments thereof as described herein) may or may not have one or more optical stereocenters and may or may not exist as different enantiomers or diastereomers. Any such enantiomers, diastereomers or other optical isomers are encompassed by the scope of the invention. Unless otherwise stated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers (since the compounds of formulae herein may have at least one chiral center) of the basic molecular structure, as well as the stereochemically pure or enriched compounds. More particularly, stereogenic centers may have either the R- or S-configuration, and multiple bonds may have either cis- or trans-configuration. The terms R- or S-configuration are used herein in accordance with Chemical Abstracts nomenclature. The terms cis and trans are used herein in accordance with Chemical Abstracts nomenclature and include reference to the position of the substituents on a ring moiety. The absolute stereochemical configuration of the compounds of the formulae described herein may easily be determined by those skilled in the art while using well- known methods such as, for example, X-ray diffraction.

[0199] The term “pharmaceutically acceptable salts” relates to any salts that the compounds may form, and which are suitable for administration to subjects, in particular human subjects, according to the present invention. Therefore, the compounds of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na+, Li+, K+, Ca2+and Mg2+. Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid. The compounds of the invention may bear multiple positive or negative charges. The net charge of the compounds of the invention may be either positive or negative. Any associated counter ions are typically dictated by the synthesis and / or isolation methods by which the compounds are obtained. Typical counter ions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, and the like. It will be understood that the identity of any associated counter ion is not a critical feature of the invention, and that the invention encompasses the compounds in association with any type of counter ion. Moreover, as the compounds can exist in a variety of different forms, the invention is intended to encompass not only forms of the compounds that are in association with counter ions (e.g., dry salts), but also forms that are not in association with counter ions (e.g., aqueous or organic solutions). Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound. In addition, salts may be formed from acid addition of certain organic and inorganic acids to basic centers, typically amines, or to acidic groups. Examples of such appropriate acids include, for instance, inorganic acids such as hydrohalogen acids, e.g., hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e., ethanedioic), malonic, succinic (i.e., butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic (i.e., 2-hydroxybenzoic), p-aminosalicylic and the like. Furthermore, this term also includes the solvates which the compounds of formulae herein as well as their salts are able to form, such as for example hydrates, alcoholates and the like. Finally, it is to be understood that the compositions herein comprise compounds of the invention in their unionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.

[0200] Also included within the scope of this invention are the salts of the parental compounds with one or more amino acids, especially the naturally-occurring amino acids found as protein components. The amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.

[0201] The compounds of the invention as defined herein (including all embodiments thereof as described herein) also include physiologically acceptable salts thereof. Examples of physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX4+(wherein X is C1-C4 alkyl). Physiologically acceptable salts of a hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic, and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p- toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound containing a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+and NX4+(wherein X typically is independently selected from H or a C1-C4 alkyl group). However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.

[0202] Non-limiting examples of suitable such salts include but are not limited to acid addition salts, formed either with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1 -carboxylic acid, glucoheptonic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. Other salts include 2,2-dichloroacetate, adipate, alginate, ascorbate, aspartate, 2-acetamidobenzoate, caproate, caprate, camphorate, cyclamate, laurylsulfate, edisilate, esylate, isethionate, formate, galactarate, gentisate, gluceptate, glucuronate, oxoglutarate, hippurate, lactobionate, napadisilate, xinafoate, nicotinate, oleate, orotate, oxalate, palmitate, embonate, pidolate, p- aminosalicylate, sebacate, tannate, rhodanide, undecylenate, and the like; or salts formed when an acidic proton present in the parent compound is replaced, such as with ammonia, arginine, benethamine, benzathine, calcium, choline, deanol, diethanolamine, diethylamine, ethanolamine, ethylendiamine, meglumine, glycine, hydrabamine, imidazole, lysine, magnesium, hydroxyethylmorpholine, piperazine, potassium, epolamine, sodium, trolamine, tromethamine, or zinc.

[0203] The present invention includes within its scope solvates of the compounds as defined herein (including all embodiments thereof as described herein). The term “solvates” refers to crystals formed by an active compound and a second component (solvent) which, in isolated form, is liquid at room temperature. Such solvates may be formed with common organic solvents, e.g., hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol, or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate. Alternatively, the solvates of the compounds herein may be formed with water, in which case they will be hydrates.

[0204] Another embodiment of this invention relates to various precursor or “prodrug” forms of the compounds of the present invention. It may be desirable to formulate the compounds of the present invention in the form of a chemical species which itself is not significantly biologically- active, but which when delivered to the animal, mammal or human will undergo a chemical reaction catalyzed by the normal function of the body of the fish, inter alia, enzymes present in the stomach or in blood serum, said chemical reaction having the effect of releasing a compound as defined herein. In general, such prodrugs will be functional derivatives of the compounds described herein which are readily convertible in vivo, e.g., by endogenous enzymes in the gut or the blood, into the required GPR17 modulating compounds described herein. The term “prodrug” thus relates to these species which are converted in vivo into the active pharmaceutical ingredient.

[0205] The prodrugs of the compounds of the present invention as defined herein (including all embodiments thereof as described herein) can have any form suitable to the formulator, for example, esters are non-limiting common prodrug forms. In the present case, however, the prodrug may necessarily exist in a form wherein a covalent bond is cleaved by the action of an enzyme present at the target locus. For example, a C-C covalent bond may be selectively cleaved by one or more enzymes at said target locus and, therefore, a prodrug in a form other than an easily hydrolysable precursor, inter alia an ester, an amide, and the like, may be used. The counterpart of the active pharmaceutical ingredient in the prodrug can have different structures such as an amino acid or peptide structure, alkyl chains, sugar moieties and others as known in the art.

[0206] For the purpose of the present invention the term “therapeutically suitable prodrug” can be defined herein as a compound modified in such a way as to be transformed in vivo to the therapeutically active form, whether by way of a single or by multiple biological transformations, when in contact with the tissues of the animal, mammal, or human to which the prodrug has been administered, and without undue toxicity, irritation, or allergic response, and achieving the intended therapeutic outcome.

[0207] More specifically the term “prodrug”, as used herein, relates to an inactive or significantly less active derivative of a compound such as represented by the structural formulae herein described, which undergoes spontaneous or enzymatic transformation within the body in order to release the pharmacologically active form of the compound. For a comprehensive review, reference is made to Rautio J. et al. (“Prodrugs: design and clinical applications” Nature Reviews Drug Discovery, 2008, doi: 10.1038 / nrd2468).

[0208] The compound of the present invention as defined herein (including all embodiments thereof as described herein) may also exist in different crystal forms, i.e., as polymorphs and mixtures thereof, all of which are encompassed by the present invention.

[0209] The term “polymorph” refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and / or conformations of the molecules in the crystal lattice. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Although polymorphs can have the same chemical composition, they can also differ in composition due to the presence or absence of co-crystallized water or other molecules, which can be weakly or strongly bound in the lattice. Polymorphs can differ in such chemical, physical and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability. One skilled in the art will appreciate that a polymorph of a compound described herein can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved biological performance) relative to another polymorph or a mixture of polymorphs of the same compound. Preparation and isolation of a particular polymorph of a compound can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions. For a comprehensive discussion of polymorphism see Rolf Hilfiker, Ed., Polymorphism in the Pharmaceutical Industry, Wiley-VCH, Weinheim, 2006.

[0210] The present invention also compasses pharmaceutical compositions comprising at least one compound according to the invention as defined herein (including all embodiments thereof as described herein), and at least one pharmaceutically acceptable carrier.

[0211] The term "pharmaceutically acceptable carrier1' refers to a diluent, adjuvant, excipient, or carrier, or other ingredient with which a compound of the invention is administered and which a person of skilled in the art would understand to be pharmaceutically acceptable.

[0212] Tablets will contain excipients, glidants, fillers, binders, and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Formulations optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like.

[0213] Subsequently, the term "pharmaceutically acceptable carrier" as used herein means any material or substance with which the active ingredient is formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing, or diffusing the said composition, and / or to facilitate its storage, transport, or handling without impairing its effectiveness. The pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, e.g., the compositions of this invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets, or powders.

[0214] Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art, and there is no particular restriction to their selection within the present invention. They may also include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, e.g., carriers and additives which do not create permanent damage to mammals. The pharmaceutical compositions of the present invention may be prepared in any known manner, for instance by homogeneously mixing, coating and / or grinding the active ingredients, in a one-step or multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents, may also be prepared by micronization, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 pm, namely for the manufacture of microcapsules for controlled or sustained release of the active ingredients.

[0215] Suitable surface-active agents, also known as emulgent or emulsifier, to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and / or anionic materials having good emulsifying, dispersing and / or wetting properties. Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface-active agents. Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C10-C22), e.g., the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable from coconut oil or tallow oil. Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulfonates and sulfates; sulfonated benzimidazole derivatives and alkylarylsulfonates. Fatty sulfonates or sulfates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl group having from 8 to 22 carbon atoms, e.g., the sodium or calcium salt of lignosulfonic acid or dodecylsulfonic acid or a mixture of fatty alcohol sulfates obtained from natural fatty acids, alkaline or alkaline-earth metal salts of sulfuric or sulfonic acid esters (such as sodium lauryl sulfate) and sulfonic acids of fatty alcohol / ethylene oxide adducts. Suitable sulfonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylarylsulfonates are the sodium, calcium or alcoholamine salts of dodecylbenzene sulfonic acid or dibutyl-naphthalenesulfonic acid or a naphthalene-sulfonic acid / formaldehyde condensation product. Also suitable are the corresponding phosphates, e.g., salts of phosphoric acid ester and an adduct of p-nonylphenol with ethylene and / or propylene oxide, or phospholipids. Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as e.g., phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidyl- choline, dipalmitoylphoshatidyl-choline and their mixtures.

[0216] Suitable non-ionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulfonates and dialkylsulfosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol. Further suitable non-ionic surfactants are water-soluble adducts of polyethylene oxide with polypropylene glycol, ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups and / or 10 to 100 propyleneglycol ether groups. Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit. Representative examples of non-ionic surfactants are nonylphenol -polyethoxyethanol, castor oil polyglycolic ethers, polypropylene / polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethyleneglycol, and octylphenoxypolyethoxyethanol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose and pentaerythritol are also suitable non-ionic surfactants.

[0217] Suitable cationic surfactants include quaternary ammonium salts, particularly halides, having 4 hydrocarbon groups optionally substituted with halogen, phenyl, substituted phenyl or hydroxy; for instance, quaternary ammonium salts containing as N-substituent at least one Cs^alkyl (e.g., cetyl, lauryl, palmityl, myristyl, oleyl, and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and / or hydroxy-lower alkyl.

[0218] A more detailed description of surface-active agents suitable for this purpose may be found for instance in "McCutcheon's Detergents and Emulsifiers Annual" (MC Publishing Crop., Ridgewood, New Jersey, 1981), "Tensid-Taschenbucw1, 2 d ed. (Hanser Verlag, Vienna, 1981) and "Encyclopaedia of Surfactants, (Chemical Publishing Co., New York, 1981).

[0219] Compounds of the invention as defined herein (including all embodiments thereof as described herein) and their pharmaceutically acceptable salts (hereafter collectively referred to as the active ingredients) may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal, and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). The preferred route of administration may vary with, for example, the condition of the recipient.

[0220] While it is possible for the active ingredients to be administered alone it is preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the present invention comprise at least one active ingredient, as above described, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic ingredients. The carrier(s) optimally are "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0221] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

[0222] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in- water cream base. If desired, the aqueous phase of the cream base may include, for example, a polyhydric alcohol, e.g., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1 ,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.

[0223] The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Optionally, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

[0224] The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should optionally be a non- greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0225] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0226] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 pm (including particle sizes in a range between 20 and 500 pm in increments of 5 pm such as 30 pm, 35 pm, etc.), which is administered in the manner in which snuff is taken, e.g., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.

[0227] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foam, or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0228] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0229] Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

[0230] It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0231] Compounds of the invention as defined herein (including all embodiments thereof as described herein) can be used to provide controlled release pharmaceutical formulations containing as active ingredient one or more compounds of the invention ("controlled release formulations") in which the release of the active ingredient can be controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given invention compound. Controlled release formulations adapted for oral administration in which discrete units comprising one or more compounds of the invention can be prepared according to conventional methods.

[0232] Additional ingredients may be included in order to control the duration of action of the active ingredient in the composition. Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino acids, polyvinyl pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulfate and the like. The rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g., microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethyl methacrylate and the other above-described polymers. Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on. Depending on the route of administration, the pharmaceutical composition may require protective coatings. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol and the like and mixtures thereof.

[0233] In view of the fact that, when several active ingredients are used in combination, they do not necessarily bring out their joint therapeutic effect directly at the same time in the mammal to be treated, the corresponding composition may also be in the form of a medical kit or package containing the two ingredients in separate but adjacent repositories or compartments. In the latter context, each active ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g., one of them may be in the form of an oral or parenteral formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.

[0234] The compounds of the present invention as defined herein (including all embodiments thereof as described herein) are useful in the prevention and / or treatment of neurodegenerative diseases or disorders, such as neurodegenerative diseases or disorders characterized by cytotoxic TAU misfolding and / or aggregation and / or aggregation of amyloid beta, but not limited thereto, in order to delay or halt the progression of such diseases or disorders in subjects such as animals, in particular in humans, as described herein.

[0235] The term "preventing” or "prevention" as used herein refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject, in particular a human subject, that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).

[0236] The term "treating" or "treatment1of any disease or disorder includes, in one embodiment, to improve the disease or disorder (i.e., arresting or reducing the development of the disease or at least reducing one of the clinical symptoms of the disease). In another embodiment "treating" or "treatment" refers to improve at least one physical parameter, which may or may not be discernible by the subject, in particular a human subject, but which is based on or associated with the disease or disorder to be treated. In yet another embodiment, "treating" or "treatment" refers to modulating or alleviating the disease or disorder, either physically (e. g. stabilization of a discernible on non-discernible symptom), physiologically (e. g. stabilization of a physiological parameter), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset or progression of the disease or disorder. Accordingly, “treating" or “treatment’ includes any causal treatment of the underlying disease or disorder (i.e., disease modification), as well as any treatment of signs and symptoms of the disease or disorder (whether with or without disease modification), as well as any alleviation or amelioration of the disease or disorder, or its signs and symptoms. The terms “disease(s)" and “disorders)” are used largely interchangeably herein.

[0237] The term “diagnosis”, “diagnoses” or “diagnosing” of a disease or disorder, as used herein, include, in one embodiment, the identification and measurement of signs and symptoms which are associated with said disease.

[0238] The term “subject” refers to an animal preferably a mammalian patient in need of such treatment, such as a human. The term also refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation, or experiment. The terms "human”, "patient" and “human subject” are typically used interchangeably herein, unless clearly indicated.

[0239] The invention also relates to methods of treating an animal disease or disorder, as described in more detail herein, in particular a human disease or disorder, which includes the administration of the compounds of the present invention as defined herein (including all embodiments thereof as described herein) in therapeutically effective amounts.

[0240] The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that, when administered to a subject, elicits the biological or medicinal response in a tissue system, or a subject that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes alleviation or partial alleviation of the symptoms of the disease or disorder being treated. The therapeutically effective amount can vary depending on the compound, the disease and its severity, and the condition, age, weight, gender etc. of the subject, in particular a human subject, to be treated.

[0241] The compounds of the invention as defined herein (including all embodiments thereof as described herein) are useful for treating or preventing a neurodegenerative disorder.

[0242] The term “neurodegenerative disorders” as used herein, unless otherwise stated, refers to diseases, disorders or conditions characterized by a degeneration (e.g. including loss of function and eventually cell death) of neurons in either the brain and / or the nervous system of an individual. The progressive damage that occurs to the nerve cells and nervous system connections may have a great impact on mobility, coordination, strength, sensation, and / or cognition.

[0243] In particular embodiments, the neurodegenerative disorder may include or may be characterized by the occurrence of cognitive dysfunction in the subject.

[0244] In particular embodiments, the neurodegenerative disorder may include or may be characterized by dementia or the symptoms of dementia. Dementia may be diagnosed by any methods known in the art, such as by cognitive and neuropsychological tests (e.g. memory, language skills). Neurodegenerative dementias are progressive and irreversible due to deterioration of nerve cells and their interconnections. Neurodegenerative dementias include Alzheimer’s dementia, Lewy body dementia, vascular dementia and frontotemporal lobar dementia, but are not limited thereto. Accordingly, the neurodegenerative disorder may be, may include or may be characterized by Alzheimer’s dementia, Lewy body dementia, vascular dementia and / or frontotemporal lobar dementia (FTD).

[0245] In particular embodiments, the neurodegenerative disorder, such as the neurodegenerative disorder which includes or is characterized by dementia as one of its main symptoms, may include or be characterized by protein aggregation. In particular embodiments, the neurodegenerative disorder may include or be characterized by aggregation of tau or amyloid p (Ap). In further particular embodiments, the neurodegenerative disorder may include or be characterized by tau aggregation and / or beta-amyloid aggregation (i.e. formation of beta-amyloid plaques). In other words, in particular embodiments, the neurodegenerative disorder may be an amyloid p (Ap)- and / or tau-driven neurodegenerative disorder. In further particular embodiments, the neurodegenerative disorder may include or be characterized by Tau- and / or Ap-driven neurotoxicity. In further particular embodiments, the neurodegenerative disorder may be a tauopathy (e.g. Alzheimer’s disease, Pick’s disease, frontotemporal lobar degeneration (FTLD)) or a beta-amyloidopathy (e.g. Alzheimer’s disease, Down syndrome).

[0246] In particular embodiments, the neurodegenerative disorder may be a tauopathy and / or a- synucleopathy, and thereby includes, but is not limited to Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, parkinsonism (linked to chromosome 17, FTDP-17), Parkinson’s disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis (ALS), Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, and multiple system atrophy.

[0247] In further particular embodiments, the neurodegenerative disorder may be a tauopathy, a beta- amyloidopathy and / or a-synucleopathy. The term “Tauopathy" as used herein, unless otherwise stated, refers to a disease characterized by dysfunctioning of the TAU protein, for instance manifested by insoluble aggregates or polymers of said protein. The precise molecular mechanisms involved in TAU aggregation are not precisely known, but may involve a partial denaturation or misfolding of TAU in conformations which have a high propensity to self-organize into higher order structures. The misfolding and aggregation may be triggered by hyperphosphorylation of TAU, although at present, it cannot be excluded that such aberrant phosphorylation is a consequence rather than the cause of aggregation.

[0248] The compounds of the invention (including all embodiments thereof as described herein) are particularly useful for treating certain neurodegenerative disorders including or being characterized by cytotoxic TAU misfolding and / or aggregation in order to delay or halt the progression of such diseases. Such diseases may be summarized under the term tauopathy, as described elsewhere in the present specification.

[0249] TAU is a protein with the ability to bind -and consequently stabilize and define- microtubule structure and function in neurons. The binding of TAU to microtubules is regulated by phosphorylation of TAU; several TAU phosphorylation sites and their corresponding kinases have been identified which control phosphorylation status of TAU and consequently modulate the affinity of TAU-binding to microtubules.

[0250] An important aspect of the TAU aggregation is its associated cytotoxicity, which reduces neuronal integrity and functionality and ultimately resulting in disease symptoms. A direct role of TAU in disease onset has been established unequivocally by the elucidation of familial mutations in TAU, which appear to be responsible for a very early and sometimes aggressive form of tauopathy. Such mutations comprise changes in the amino acid sequence of TAU that -directly or indirectly promote neurotoxic aggregation.

[0251] Alzheimer’s disease is the best known of these, where TAU protein is deposited within neurons in the form of neurofibrillary tangles (NFTs). They were first described by the eponymous Alois Alzheimer in one of his patients suffering from the disorder. The term “Alzheimer’s disease” as used herein, refers to a chronic progressive nervous disease characterized by neurodegeneration with as most important (early) symptom being memory loss. As the disease advances, symptoms may include confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as their senses decline.

[0252] Tangles are formed by hyperphosphorylation of a microtubule-associated protein known as TAU, causing it to aggregate in an insoluble form. (These aggregations of hyperphosphorylated TAU protein are also referred to as PHF, or "paired helical filaments"). The precise mechanism of tangle formation is not completely understood, and it is still controversial whether tangles are a primary causative factor in the disease or play a more peripheral role. AD is also classified as an amyloidosis because of the presence of senile plaques.

[0253] Other conditions in which neurofibrillary tangles are commonly observed include: Progressive supranuclear palsy, dementia pugilistica (chronic traumatic encephalopathy), frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease (Parkinson-dementia complex of Guam), tangle-predominant dementia with NFTs, similar to AD, but without plaques, ganglioglioma and gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, tuberous sclerosis, Hallervorden-Spatz disease, and lipofuscinosis.

[0254] The non-Alzheimer's tauopathies are sometimes grouped together as "Pick's complex". In Pick's disease and corticobasal degeneration TAU proteins are deposited in the form of inclusion bodies within swollen or "ballooned" neurons. Argyrophilic grain disease (AGD), another type of dementia, is marked by the presence of abundant argyrophilic grains and coiled bodies on microscopic examination of brain tissue.

[0255] The compounds of the invention (including all embodiments thereof as described herein) are particularly useful for the prevention and / or treatment of diseases related to the biological function of dysfunction of TAU protein, which diseases can comprise Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia and parkinsonism (linked to chromosome 17, FTDP-17). The preferred indication is Alzheimer’s disease.

[0256] The present invention also encompasses a compound of the invention (including all embodiments thereof as described herein) for use in a method for the prevention and / or treatment the prevention and / or treatment of diseases related to the biological function of dysfunction of TAU protein, which diseases can comprise Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia and parkinsonism (linked to chromosome 17, FTDP-17), which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the invention.

[0257] The present invention also encompasses a method for the prevention and / or treatment the prevention and / or treatment of diseases related to the biological function of dysfunction of TAU protein, which diseases can comprise Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia and parkinsonism (linked to chromosome 17, FTDP-17), which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the invention (including all embodiments thereof as described herein).

[0258] The term “amyloidosis” as used herein, unless otherwise stated, refers to both systemic and localized amyloid-related diseases, and prion-related encephalopathies, and thereby includes, but is not limited to type II diabetes mellitus, Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, parkinsonism (linked to chromosome 17, FTDP-17), Parkinson’s disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, cataract, Creutzfeldt-Jakob’s disease, cystic fibrosis, phenylketonuria, Huntington’s disease, Marfan syndrome, osteogenesis imperfect, sickle cell anemia, Tay-Sachs disease, a-antitrypsin deficiency, cerebral amyloid angiopathy, retinitis pigmentosa, amyloid A amyloidosis, AL amyloidosis, familial transthyretin amyloidosis, familial Mediterranean fever, amyloidosis associated with long term hemodialysis, amyloidosis associated with medullary carcinoma of the thyroid and multiple system atrophy. For example, the amyloidosis, may be a beta-amyloidopathy.

[0259] The term “a-synucleopathy” as used herein, unless otherwise stated, refers to a disease characterized by the presence of pathological deposition of insoluble a-synuclein polymers or aggregates intracellularly and / or extracellularly. Such diseases include, but are not limited to, Parkinson’s disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, and multiple system atrophy.

[0260] The present invention further also encompasses a compound of the invention for use in the prevention and / or treatment of a brain disease or disorder.

[0261] In particular embodiments, the brain disease or disorder may include or be characterized by dementia, such as by Alzheimer’s disease-related dementia, vascular dementia, Lewy Body dementia, Frontotemporal dementia, Alcohol related dementia, Down syndrome-related dementia, HIV associated dementia and Chronic Traumatic Encephalopathy (CTE) dementia, but not being limited thereto.

[0262] In particular embodiments, the brain disease or disorder may include or be characterized by protein aggregation, such as aggregation of tau and / or amyloid p (Ap), but not being limited thereto.

[0263] In particular embodiments, the brain disease or disorder may be a neurodegenerative condition and / or a vascular condition (e.g. neurovascular condition). For example, the brain disease or disorder may be a neurovascular condition including or being characterized by aggregation of amyloid p (Ap), such as cerebral amyloid angiopathy.

[0264] In particular embodiments, the brain disease or disorder may be a tauopathy. For example, the brain disease or disorder may be Primary age-related tauopathy (PART) dementia, Chronic traumatic encephalopathy (CTE), Progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD), Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Vacuolar tauopathy, Lytico-bodig disease (Parkinson-dementia complex of Guam), Ganglioglioma and gangliocytoma, Meningioangiomatosis, or Postencephalitic parkinsonism.

[0265] In particular embodiments, the neurodegenerative disorder is selected from the group consisting of Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, vascular dementia, frontotemporal dementia, parkinsonism (linked to chromosome 17, FTDP-17), Parkinson’s disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis (ALS), Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, multiple system atrophy, Huntington’s disease, frontotemporal lobar degeneration (FTLD), cystic fibrosis and Creutzfeldt-Jacob’s disease.

[0266] In further particular embodiments, the neurodegenerative disorder is selected from Parkinson's disease, Alzheimer’s disease, diffuse Lewy body disease, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, Pick’s disease, progressive supranuclear palsy, vascular dementia, neuroaxonal dystrophy, Huntington’s disease, frontotemporal lobar degeneration (FTLD), multiple system atrophy and Creutzfeldt- Jacob’s disease.

[0267] In particular embodiments, the neurodegenerative disorder is characterized by Ca2+dyshomeostasis.

[0268] In particular embodiments, the neurodegenerative disorder is Alzheimer’s disease.

[0269] The compounds of the invention as described herein (including all embodiments thereof as described herein) can be prepared while using a series of chemical reactions well known to those skilled in the art, altogether making up the process for preparing said compounds and exemplified further. The processes described further are only meant as examples and by no means are meant to limit the scope of the present invention.

[0270] Abbreviations used in the description, particularly in the Schemes and Examples, are as follows: Boc - ter-Butoxycarbonyl, BuOH - butanol, CHCh - chloroform, Cui - Copper iodide, DAST - Diethylaminosulfur trifluoride, DCE - 1 ,2-dichloroethane, DCM - Dichloromethane, DIPEA - Diisopropyl-ethyl amine, DMAc - Dimethylacetamide, DMAP - dimethylaminopyridine, DMF - N,N-Dimethylformamide, DMSO - Dimethylsulfoxide, EDC = 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride; Et3N - Triethyl amine, Et20 - Diethyl ether, EtOAc - Ethyl acetate, EtOH - Ethanol, Eq. - Equivalent, Fmoc - Fluorenylmethyloxycarbonyl chloride, GCMS - Gas chromatography-mass spectrometry, h - Hour, HCI - hydrogen chloride, HOBt - 1-hydroxy- benzotriazol hydrat; H - hexane, HPLC - High performance liquid chromatography, iPrOH - isopropyl alcohol, iP^NEt - Ethyl-diisopropyl-amine, K2CO3- potassium carbonate, LCMS - Liquid chromatography-mass spectrometry, MeCN (CH3CN) - ACN - Acetonitrile, mCPBA - metachloroperoxybenzoic acid, Mel - methyl iodide, MeOH - Methanol, MgSO4 - Magnesium sulfate, min. - Minute, mL - ml - milliliter, MPLC - medium pressure liquid chromatography, MsCI - methanesulfonyl chloride, NaBH4 - sodium borohydride, Na2COs - sodium carbonate, NaH - sodium hydride, NaHCCh - sodium bicarbonate, Na2SC>4 - Sodium sulfate, Na2S20s - sodium thiosulfate , NH3 - ammonia, NH4CI - ammonium chloride, NMR - Nuclear Magnetic Resonance, RP - Reverse phase, RT - Room temperature, rt time- retention time, sat. - Saturated, SFC - Supercritical fluid chromatography, STAB - sodium triacetoxyborohydride, TFA - Trifluoroacetic acid, THF - Tetrahydrofuran, TsCI - p-toluenesulfonyl chloride.

[0271] The preparation of compounds of the present invention as defined herein (including all embodiments thereof as described herein) may be carried out in sequential or convergent synthetic routes.

[0272] Embodiments for the syntheses of the compounds of the invention as defined herein (including all embodiments thereof as described herein) are shown in the following schemes.

[0273] The skills required for carrying out the reactions and purifications of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before unless indicated to the contrary.

[0274] In more detail, the compounds as defined herein (including all embodiments thereof as described herein) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. It can be convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.

[0275] In some embodiments, compounds of formula C1A can be prepared according to the general procedure outlined in Scheme 1.

[0276] Scheme 1: wherein A1, L1, R4, L3and A2have the same meaning as that defined herein, and PG is a protecting group which can be Boc, Fmoc, Ts and the like

[0277] Step a) Acetylene derivatives II can be either commercially available or can be synthesized according to methods known in the art. These acetylene derivatives II can be conveniently reacted with azides III (commercially available, or known in the art), for example in the presence of copper salts to afford triazole derivatives IV.

[0278] Step b) The protecting group (PG) can be cleaved under suitable conditions and Br-L3-A2can be introduced through reaction with a suitable electrophile or with a reductive amination to yield compounds C1A.

[0279] In some embodiments, compounds of formula C1C can be prepared according to the general procedure outlined in Scheme 2.

[0280] Scheme 2: wherein A1, L1, L3, R3, R4, and A2have the same meaning as that defined herein, and PG is a protecting group which can be Boc, Fmoc, Ts and the like

[0281] Step a) Hydrazide derivatives VIII are either commercially available or can be synthesized according to methods known in the art. These hydrazide derivatives VIII can be conveniently reacted with nitrile derivatives XI (commercially available, or known in the art), for example in the presence of copper salts to afford triazole derivatives X.

[0282] Step b) The protecting group (PG) can be cleaved under suitable conditions and an alkylation with Br-L3-A2or a reductive amination can yield compounds C1C. These might be the final compounds, or they can be further derivatized with suitable electrophiles (l-Ci-ealkyl, such as Mel and the like) to yield substituted compound C1C wherein R3is Ci-ealkyL

[0283] In some embodiments, compounds of formula C1A4 can be prepared according to the general procedure outlined in Scheme 3.

[0284] Scheme 3: wherein A1, L1, R4, and A2have the same meaning as that defined herein

[0285] Compound 1 , commercially available or synthesized by procedures known to the skilled in the art, can be coupled with an azide 2 (commercially available or synthesized by procedures known to the person skilled in the art or as set forth examples below), for example in the presence of copper salts, preferably in a suitable solvent or mixture of solvents (e.g., THF, DMF, DCM, CHCh, MeCN, toluene, dioxane, water, and the like), for example at a temperature in the range of RT to 60°C to provide intermediates of formula 3. Other suitable protecting groups can be used instead of Boc, such as Fmoc, Ts and the like. After removal of the Boc-protecting group under standard conditions, the intermediate 4 can be obtained. Compound C1A4 can be obtained upon reductive amination of intermediate 4 with aldehyde 5, for example in the presence of a suitable reductive reagent (e.g. STAB, NaBF , Pd / C H2, and the like), or by alkylation with halogen 6 (commercially available or synthesized by procedures known to the person skilled in the art), for example in a suitable solvent or mixture of solvents (e.g., MeOH, DMF, DCM, DCE, DMAc, CHCI3, MeCN, EtOAc, EtOH, iPrOH, and the like), for example at a temperature in the range of RT to 60°C.

[0286] The general schemes depicted above should be considered as non-limiting examples. It will be understood that compounds of the invention may be obtained through other methods, which are known to people skilled in the art.

[0287] The following examples are provided for the purpose of illustrating the present invention and by no means should be interpreted to limit the scope of the present invention.

[0288] EXAMPLES

[0289] Table 1C: Structures of the compounds of the invention and their respective codes

[0290] Part A represents the preparation of the compounds (intermediates and final compounds) whereas Part B represents the pharmacological examples.

[0291] Part A

[0292] All starting materials which are not explicitly described were either commercially available (the details of suppliers such as for example Aldrich, Combi-Blocks, Enamine, FluoroChem, MatrixScientific, Merck, TCI, etc. can be found in the SciFinder® Database for example) or the synthesis thereof has already been described precisely in the specialist literature (experimental guidelines can be found in the Reaxys® Database or the SciFinder® Database respectively, for example) or can be prepared using the conventional methods known to the person skilled in the art. The reactions were, if necessary, carried out under an inert atmosphere (mostly argon and N2). The number of equivalents of reagents and the amounts of solvents employed as well as the reaction temperatures and times can vary slightly between different reactions carried out by analogous methods. The work-up and purification methods were adapted according to the characteristic properties of each compound and can vary slightly for analogous methods. The yields of the compounds prepared are not optimized.

[0293] The indication “equivalents" ("eq." or “eq” or “equiv.”) means molar equivalents, “RT“ or “rt” means room temperature T (23 ± 7 °C), “M“ are indications of concentration in mol / l, “sol.“ means solution, "cone." means concentrated. The mixing ratios of solvents are usually stated in the volume I volume ratio.

[0294] Key analytical characterization was carried out by means of1H-NMR spectroscopy and / or mass spectrometry (MS, m / z for [M+H]+and / or for [M-H]-) for all the exemplary compounds and selected intermediate products.

[0295] Analytical instruments employed were e.g., for NMR analysis a BRLIKER 400MHz (Software Topspin). For LC / MS analysis e.g., an Agilent 1260, Mass:6130 (ESI) (Software Open lab Chemstation) was employed. Analytical UPLCs were measured e.g., on Waters ICIass (Software MassLynx). For GCMS analysis e.g., an Agilent 6890N was employed.

[0296] Preparative HPLC were performed e.g., on an Agilent G6120 or Waters and reversed phase MPLC were performed e.g., on Reveleris.

[0297] Some structures of compounds that contain stereocenters are drawn and named with absolute stereochemistry, if known. In case of unknown absolute stereochemistry, the compounds can be either racemic, a mixture of diastereomers, a pure diastereomer of unknown stereochemistry, or a pure enantiomer of unknown stereochemistry.

[0298] The MS analyses mentioned in the experimental part were performed on a Waters system. In acidic conditions: Waters ICIass; Bin. Pump: IIPIBSM, SM: UPISMFTN with SO; LIPCMA, PDA: UPPDATC, 210-320 nm, MS: QDa ESI, pos / neg 100-800; column: Waters XSelect CSH C18, 50x2.1 mm, 2.5p, Temp: 40 °C, Flow: 0.6 mL / min, Gradient: to = 5% A, t2.omin = 98% A, t2.7min = 98% A, Posttime: 0.3 min, Eluent A: 0.1 % formic acid in acetonitrile, Eluent B: 0.1 % formic acid in water. In basic conditions: Apparatus: Waters ICIass; Bin. Pump: IIPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210-320 nm, MS: QDa ESI, pos / neg 100-800; column: Waters XSelect CSH C18, 50x2.1mm, 2.5p, Temp: 25 °C, Flow: 0.6 mL / min, Gradient: to = 5% A, t2.omin = 98% A, t2.7min = 98% A, Posttime: 0.3 min, Eluent A: acetonitrile, Eluent B: 10mM ammonium bicarbonate in water (pH=9.5)

[0299] The GCMS analyses mentioned in the experimental part were performed on an Agilent 6890N G1530 gas chromatography system coupled with G2577A 5973 MSD detector (El-positive, Det. temp.: 280°C) Mass range 50-550, Column: Restek RXi-5MS (20 m ID 180 pm, df 0.18 pm), Average velocity: 50 cm / s, Injection vol: 1 pl, Injector temp: 250°C, Split ratio: 100 / 1 , Carrier gas: He; Initial temp: 100°C, Initial time: 1.5 min, Solvent delay: 1.0 min, Rate 75°C / min, Final temp 250°C, Hold time 4.3 min.

[0300] Preparative HPLC purifications mentioned in this experimental part have been carried out with a Waters system in basic conditions: MS instrument type: ACQ-SQD2; HPLC instrument type: Waters Modular Preparative HPLC System; column: Waters XSelect (C18, 100x30mm, 10pm); flow: 55 ml / min prep pump; column temp: RT; eluent A: 10mM ammonium bicarbonate in water pH=9.5, eluent B: 100% acetonitrile; Gradient: t = 0 min 5% B, t = 17 min 100% B; detection: DAD (220-320 nm); detection: MSD (ESI pos / neg) mass range: 100 - 800; fraction collection based on MS and DAD.

[0301] Preparative HPLC purifications mentioned in this experimental part in acidic conditions have been carried out with an Agilent system: MS instrument type: Agilent Technologies G6120AA Quadrupole; HPLC instrument type: Agilent Technologies 1200 preparative LC; Column: Waters XSelect CSH (C18, 100x30mm, 10p); Flow: 55 ml / min; Column temp: RT; Eluent A: 0.1 % formic acid in water; Eluent B: 100% acetonitrile; Gradient: t = 0 min 5% B, t = 17 min 100% B Detection: DAD (220-320 nm); Detection: MSD (ESI pos / neg) mass range: 100 - 1000; fraction collection based on MS and DAD.

[0302] Reversed phase MPLC purifications mentioned in this experimental part in acidic conditions have been carried out with Reveleris: Instrument type: Reveleris™ prep MPLC; Column: Phenomenex LUNA C18(3) (150x25 mm, 10p); Flow: 40 mL / min; Column temp: rt.; Eluent A: 0.1 % (v / v) Formic acid in water, Eluent B: 0.1% (v / v) Formic acid in acetonitrile; Gradient: t = 0 min 5% B, t = 20 min 100% B.; Detection UV: 220, 254, 280 nm.

[0303] In basic conditions, reversed phase MPLC purifications mentioned in this experimental part in have been carried out with Reveleris: Instrument type: Reveleris™ prep MPLC; column: Waters XSelect CSH C18 (145 x 25 mm, 10 ); Flow: 40 mL / min; Column temp: rt.; Eluent A: 10 mM ammoniumbicarbonate in water pH = 9.0); Eluent B: 99% acetonitrile + 1 % 10 mM ammoniumbicarbonate in water; Gradient: t = 0 min 5% B, t = 20 min 100% B. Detection UV: 220, 254, 280 nm.

[0304] EXAMPLES OF THE PREPARATION OF INTERMEDIATES

[0305] Synthesis of tert-butyl 4-ethynyl-4-hydroxypiperidine-1-carboxylate (CI1-2)

[0306] Step 1: Ethynylmagnesium bromide solution (0.5 M in THF) (23 mL, 11.50 mmol) was placed under argon and cooled to 0°C. Then, a solution of tert-butyl 4-oxopiperidine-1 -carboxylate (2.1 g, 10.54 mmol) in THF (dry) (21.08 mL) was added dropwise. The reaction mixture was stirred at 0 °C and allowed to warm up to rt in 3 hours. The reaction was quenched with aq. sat. NH4CI (25 mL) which was stirred for 20 minutes. The mixture was extracted with Et20 (3x 40 mL). The combined organics were dried with Na2SO4 and concentrated in vacuo (2.53 g). The crude compound was purified by flash chromatography (24 g silica, 0-25% EtOAc in heptane). The product fractions were then pooled and concentrated to obtain the product as a clear oil that solidified to a white solid overnight. (2.18 g, 9.68 mmol, yield: 92%)

[0307] 1H NMR (400 MHz, DMSO): 5 ppm 5.62 (s, 1 H), 3.50-3.60 (m, 2H), 3.39 (s, 1 H), 3.17 (m, 2H), 1.66-1.72 (m, 2H), 1.49-1.55 (m, 2H), 1.39 (s, 9H).

[0308] Synthesis of 4-azido-1 ,1-difluorocyclohexane (Cl 2-1)

[0309] Step 1: 4,4-difluorocyclohexan-1-one (2.56 g, 19.09 mmol) was dissolved in MeOH (95 mL) and cooled to 0°C. NaBH4 (0.62 g, 16.39 mmol) was added in portions while stirring and the reaction was allowed to warm to rt in 30 min. The reaction was concentrated, redissolved in DCM (70 mL) and washed with sat. aq. NH4CI (50 mL). The water layer was extracted with DCM (70 mL), the combined organic layers were dried over Na2SO4 and concentrated to afford 4,4- difluorocyclohexan-1-ol. No further purification was performed.

[0310] Step 2: 4,4-difluorocyclohexan-1-ol (2.66 g, 19.54 mmol) was dissolved in DCM (35 mL), cooled on ice, pyridine (2.5 mL, 30.9 mmol) and mesyl chloride (1.75 mL, 22.46 mmol) were added. The reaction was allowed to warm to rt and stirred overnight. The reaction was quenched with sat. aq. NaHCOs (40 mL), the water layer was extracted with DCM (40 mL), the combined organic layers were extracted with brine, dried over Na2SC>4 and concentrated to yield a thin orange liquid. This was diluted with DCM (40 mL) and washed with 0.5M aq. HCI (50 mL, 20 mL). The water layer was extracted with DCM (30 mL), the combined organic layers were dried over Na2SC>4 and concentrated to yield 4,4-difluorocyclohexyl methanesulfonate (5.5 g; orange oil). The crude compound was further purified by flash chromatography (0-60% EtOAc in heptane). Product fractions were combined and concentrated to yield 4,4-difluorocyclohexyl methanesulfonate as a clear oil that crystalizes over time (3.54g, 16.5 mmol, yield : 85%).

[0311] 1H NMR (400 MHz, CDCI3): 5 ppm 4.91 (dg, 1 H), 3.05 (s, 3H), 2.25-1.87 (m, 8H).

[0312] Step 3: 4,4-difluorocyclohexyl methanesulfonate (2 g, 9.34 mmol) was dissolved in DMF (dry) (15 mL), placed behind a blast shield, sodium azide (0.910 g, 14.00 mmol) was added and the reaction was stirred at 70°C overnight. The reaction mixture was diluted with aq. sat. Na2COs (60 mL) and brine (60 mL) and extracted with EtC>2 (3x 100 mL), the combined organic layers were dried with Na2SO4, partially concentrated (max -600 mbar vacuum) until ca. 30 mL remained and the obtained 4-azido-1 ,1 -difluorocyclohexane was used directly. (GCMS (m / e): 161.1 (rt = 2.00 min)

[0313] The following intermediates were prepared in a similar manner (use of appropriate reagents and purification methods known to the person skilled in the art) as described for CI2-1 : CI2-2, CI2-11, CI2-12 and CI2-13. The two diastereoisomers CI2-12 and CI2-13 were synthesized starting from a mixture of c / s / trans isomers of 4-(trifluoromethyl)cyclohexan-1-ol.

[0314] Synthesis of 4-(1-(4,4-difluorocyclohexyl)-1 H-1 ,2,3-triazol-4-yl)piperidine hydrochloride (CI4-1)

[0315] Step 1: 4-azido-1 ,1 -difluorocyclohexane (in -30 mL Et20) (1.505 g, 9.34 mmol) was mixed with THF (170 mL). Tert-butyl 4-ethynylpiperidine-1-carboxylate (2.346 g, 11.21 mmol), DIPEA (1.958 mL, 11.21 mmol), 2,2'-bipyridyl (0.146 g, 0.934 mmol) and Cui (0.089 g, 0.467 mmol) were added and the mixture was stirred overnight at RT. After 2h, additional tert-butyl 4-ethynylpiperidine-1- carboxylate (0.586 g, 2.80 mmol) was added. The reaction was mostly concentrated, diluted with DCM (200 mL) and sat. aq. NH4CI (150 mL), the layers were separated, the organic layer was dried over Na2SC>4, filtered and concentrated. The crude mixture was purified by flash chromatography (0-80% EtOAc in heptane). Product fractions were pooled to yield tert-butyl 4- (1 -(4, 4-difluorocyclohexyl)-1 H-1 , 2, 3-triazol-4-yl)piperidine-1 -carboxylate as white solid (2.5g, 6.75 mmol, yield: 72.3%). MS (m / e): 371 .2 (MIT).

[0316] 1H NMR (400 MHz, DMSO): 5 ppm 8.03 (s, 1 H), 4.75-4.59 (m, 1 H), 3.95 (d, 2H), 3.02-2.71 (m, 3H), 2.21-1.83 (m, 10H), 1.52-1.34 (m, 11 H).

[0317] Step 2: To a solution of tert-butyl 4-(1-(4,4-difluorocyclohexyl)-1 H-1 ,2,3-triazol-4-yl)piperidine-1- carboxylate (2.50 g, 6.75 mmol) in DCM (34 ml) was added HCI (4M in dioxane) (25 mL) and the reaction was mixed and then left to stand for 2h at RT, swirling occasionally. The reaction was concentrated, co-evaporated twice with DCM to yield 4-(1-(4,4-difluorocyclohexyl)-1 H-1 ,2,3- triazol-4-yl)piperidine hydrochloride CI4-1 as a white powder (2.27 g). No further purification was performed. MS (m / e): 271.2 (MH+).

[0318] The following intermediates were prepared in a similar manner (use of appropriate reagents and purification methods known to the person skilled in the art) as described for CI4-1 : CI4-2, CI4-3,

[0319] CI4-4, CI4-5, CI4-6, CI4-7, CI4-8, CI4-9, CI4-10, CI4-12, CI4-13, CI4-14, CI4-15, CI4-16, CI4-17 (with use of CI1 -2) and CI4-19 (with use of CI1 -2).

[0320] Synthesis of 4-(4-(piperidin-4-yl)-1 H-1 ,2,3-triazol-1-yl)tetrahvdro-2H-thiopyran 1 ,1 -dioxide hydrochloride (CI4-11)

[0321] Step 1: 4-azidotetrahydro-2H-thiopyran (536 mg, 3.74 mmol) was mixed with THF (75 mL). Tert- butyl 4-ethynylpiperidine-1-carboxylate (900 mg, 4.30 mmol), DIPEA (0.784 mL, 4.49 mmol), 2,2'- bipyridyl (61 mg, 0.391 mmol) and Cui (35.6 mg, 0.187 mmol) were added and the mixture was stirred overnight at RT. The reaction was mostly concentrated, diluted with DCM (120 mL) and sat. aq. NH4CI (75 mL), the layers were separated, the organic layer was dried over Na2SO4, filtered and concentrated. The crude mixture was purified by flash chromatography (0-80% EtOAc in heptane). Product fractions were pooled to yield tert-butyl 4-(1-(tetrahydro-2H-thiopyran-4-yl)- 1 H-1 , 2, 3-triazol-4-yl)piperidine-1 -carboxylate as white solid (0.55 g, 1.56 mmol, yield: 41.7%). MS (m / e): 353.2 (MIT).

[0322] 1H NMR (400 MHz, DMSO): 5 ppm 8.00 (s, 1 H), 4.58-4.42 (m, 1 H), 3.95 (d, 2H), 2.92-2.78 (m, 5H), 2.73 (d, 2H), 2.29 (d, 2H), 2.03 (m, 2H), 1.89 (d, 2H), 1.51-1.41 (m, 2H), 1.40 (s, 9H). Step 2: To a solution of tert-butyl 4-(1-(tetrahydro-2H-thiopyran-4-yl)-1 H-1 ,2,3-triazol-4- yl)piperidine-1 -carboxylate (0.3 g, 0.851 mmol) in DCM (6 mL) was added mCPBA (0.506 g, 2.128 mmol) and the reaction was stirred overnight at RT. The mixture was diluted with DCM (6 mL), washed with sat. Aq. Na2S20s (6 mL) and sat.aq. NaHCCh solution (2x 6 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated under vacuum to yield tert-butyl 4-(1-(1 ,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1 H-1 ,2,3-triazol-4-yl)piperidine- 1 -carboxylate as a white solid (0.29 g, 0.754 mmol, yield: 89%).

[0323] 1H NMR (400 MHz, DMSO): 5 ppm 8.10 (s, 1 H), 4.86-4.92 (m, 1 H), 3.93-3.97 (d, 2H), 3.40-3.47 (m, 2H), 3.18-3.22 (m, 2H), 2.83-2.87 (m, 3H), 2.38-2.46 (m, 4H), 1.88 (d, 2H), 1.42-1.52 (m, 11 H).

[0324] Step 3: To a solution of tert-butyl 4-(1-(1 ,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1 H-1 ,2,3-triazol- 4-yl)piperidine-1 -carboxylate (0.3 g, 0.78 mmol) in DCM (8ml) was added HCI (4M in dioxane) (3 ml, 12 mmol) and the reaction was mixed and then left to stand for2h at RT, swirling occasionally. The reaction was concentrated, co-evaporated twice with DCM to yield 4-(4-(piperidin-4-yl)-1 H- 1 ,2,3-triazol-1-yl)tetrahydro-2H-thiopyran 1 ,1 -dioxide hydrochloride as a white powder. No further purification was performed. MS (m / e): 285.1 (MH+).

[0325] Synthesis of 4-(1-(3-chlorophenyl)-1 H-1 ,2,3-triazol-4-yl)-4-methoxypiperidine dihydrochloride (CI4-18)

[0326] Step 1: tert-butyl 4-(1-(3-chlorophenyl)-1 H-1 , 2, 3-triazol-4-yl)-4-hydroxypiperidine-1 -carboxylate (227 mg, 0.599 mmol) was dissolved in DMF (dry) (6 mL) and cooled to 0 °C. Sodium hydride (28.8 mg, 0.719 mmol) was added, and the mixture was stirred for 15 min at 0 °C. Then, Mel (0.045 mL, 0.719 mmol) (as a stock solution in anhydrous DMF) was added and the mixture was stirred overnight at RT. The reaction mixture was quenched with sat. Aq. NH4CI and EtOAc was added. The layers were separated, and the organic layer was extracted with 80% sat. Aq. NaCI (3x). The organic fractions were concentrated under reduced pressure. The crude product was purified by flash column chromatography (12 g silica, wet loading from DCM, heptane / EtOAc = 95:5 -> 1 :1) to obtain tert-butyl 4-(1-(3-chlorophenyl)-1 H-1 ,2,3- triazol-4-yl)-4-methoxypiperidine- 1 -carboxylate (200 mg, 0.509 mmol, 85 % yield) as a yellow oil.

[0327] 1H NMR (400 MHz, CDCI3): 5 ppm 7.91 (s, 1 H), 7.80 (s, 1 H), 7.65-7.68 (m, 1 H), 7.27-7.50 (m, 2H), 3.76 (s, 1 H), 3.34-3.70 (m, 2H), 3.15 (s, 3H), 2.05-2.18 (m, 4H), 1.47 (s, 9H), 1.26-1.28 (m, 1 H), 0.86-0.90 (m, 1 H).

[0328] Step 3: To a solution of obtain tert-butyl 4-(1-(3-chlorophenyl)-1 H-1 ,2,3- triazol-4-yl)-4- methoxypiperidine-1 -carboxylate (165 mg, 0.42 mmol) in DCM (7 mL) was added HCI (4M in dioxane) (1.05 ml, 4.20 mmol) and the reaction was mixed and then left to stand for 2h at RT, swirling occasionally. The reaction was concentrated, co-evaporated twice with DCM to yield 4- (1-(3-chlorophenyl)-1 H-1 ,2,3-triazol-4-yl)-4-methoxypiperidine dihydrochloride as a white powder. No further purification was performed. MS (m / e): 293.0 (MH+).

[0329] SYNTHESIS OF EXAMPLES

[0330] Synthesis of 4-n-(3-Fluoro-benzyl)-1 H-n ,2,31triazol-4-yl1-1-f2-(3-methoxy-phenyl) -ethyll- piperidine (Cpd C001) a) 4-H-(3-Fluoro-benzyl)-1 H-f1 , 2, 31triazol-4-yl1-piperidine-1 -carboxylic acid tert-butyl ester

[0331] A mixture of tert-butyl 4-ethynylpiperidine-1 -carboxylate (400 mg, 1.91 mmol), 1-(azidomethyl)-3- fluorobenzene (289 mg, 1.91 mmol), copper (I) iodide (364 mg, 1.91 mmol), DI PEA (371 mg, 501 pl, 2.87 mmol) and DMSO (400 pL) in THF (10 mL) was stirred at room temperature. The resulting brownish fine suspension was filtered over a dicalit-plug and washed with ethyl acetate. The filtrate was washed with brine (2 x 75 mL) and the aqueous layers were back-extracted with ethyl acetate (1 x 75 mL). The combined organic layers were dried over Na2SO4, filtered off and concentrated in vacuo. The residue was purified by silica chromatography over silica eluting with a gradient formed from ethyl acetate and heptane. The product containing fractions were evaporated to yield 410 mg (54 % ) as viscous colorless oil. MS(m / e): 361.3 (MH+). b) 4-n-(3-Fluoro-benzyl)-1 H-n ,2,31triazol-4-yl1-piperidine, dihydrochloride A mixture of tert-butyl 4-(1-(3-fluorobenzyl)-1 H-1 , 2, 3-triazol-4-yl)piperidine-1 -carboxylate (410 mg, 1.14 mmol) and 4 N HCI / dioxane (2.84 mL, 11.4 mmol) in dioxane (10 mL) was stirred over night at ambient temperature. The mixture was diluted with Et20 (30 mL), filtered off and washed with Et20 (3 x 10 mL). The wet filter cake was dried in vacuo at 50 °C to yield 349 mg (87 %) of the title compound as white solid. MS(m / e): 261.2 (MIT). c) 4-n-(3-Fluoro-benzyl)-1 H-n ,2,31triazol-4-yl1-1-f2-(3-methoxy-phenyl)-ethyl1-piperidine

[0332] A mixture of 4-(1-(3-fluorobenzyl)-1 H-1 ,2,3-triazol-4-yl)piperidine dihydrochloride (25 mg, 75.0 pmol), 1-(2-bromoethyl)-3-methoxybenzene (24.2 mg, 113 pmol) and DIPEA (48.5 mg, 65.5 pL, 375 pmol) in N-Methyl-2-pyrrolidinone (800 pL) was heated for 2 x 20 min at 165 °C under microwave irradiation. The resulting amber reaction solution was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3to yield after evaporation of the product containing fractions 6 mg (20 %) of the title compound as light brown amorphous solid. MS(m / e): 395.3 (MIT).

[0333] Synthesis of 1-Benzon ,31dioxol-5-ylmethyl-4-H-(3-fluoro-benzyl)-1 H-n ,2,31triazol-4-yl1- piperidine (Cpd C002)

[0334] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 / 7-[1 ,2,3]triazol- 4-yl]-1-[2-(3-methoxy-phenyl)-ethyl]-piperidine (Cpd C001 , step c) the title compound was prepared from 4-[1-(3-Fluoro-benzyl)-1 H-[1 ,2,3]triazol-4-yl]-piperidine, dihydrochloride and 5- (chloromethyl)benzo[d][1 ,3]dioxole as off-white solid. MS(m / e): 395.2 (MIT).

[0335] Synthesis of 4-H-(3-Fluoro-benzyl)-1 H-n ,2,31triazol-4-yl1-1-(2-methyl-benzyl)-piperidine (Cpd C003)

[0336] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 / 7-[1 ,2,3]triazol- 4-yl]-1-[2-(3-methoxy-phenyl)-ethyl]-piperidine (Cpd C001 , step c) the title compound was prepared from 4-[1-(3-Fluoro-benzyl)-1 H-[1 ,2,3]triazol-4-yl]-piperidine, dihydrochloride and 1- (chloromethyl)-2-methylbenzene as off-white solid. MS(m / e): 365.4 (MIT).

[0337] Synthesis of 1-f2-(3-Methoxy-phenyl)-ethyl1-4-(1-p-tolyl-1 H-n ,2,31triazol-4-yl)-piperidine (Cpd C004) a) 4-(1-p-Tolyl-1 H-n ,2,31triazol-4-yl)-piperidine; dihydrochloride

[0338] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 H-[1 ,2,3]triazol- 4-yl]-piperidine, dihydrochloride (Cpd C001 , step b) the title compound was prepared from tert- butyl 4-ethynylpiperidine-1 -carboxylate and 1-azido-4-methylbenzene with subsequent removal of the protecting group with HCI in dioxane. MS(m / e): 243.4 (MIT). b) 1-f2-(3-Methoxy-phenyl)-ethyl1-4-(1-p-tolyl-1 / - / -n ,2,31triazol-4-yl)-piperidine

[0339] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 / 7-[1 ,2,3]triazol- 4-yl]-1-[2-(3-methoxy-phenyl)-ethyl]-piperidine (Cpd C001 , step c) the title compound was prepared from 4-(1 -p-Tolyl-1 H-[1 ,2,3]triazol-4-yl)-piperidine; dihydrochloride and 1-(2- bromoethyl)-3-methoxybenzene as amorphous light brown solid. MS(m / e): 377.4 (MT).

[0340] Synthesis of 1-Benzon ,31dioxol-5-ylmethyl-4-(1-p-tolyl-1 H-n ,2,31triazol-4-yl)-piperidine (Cpd C005)

[0341] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 / 7-[1 ,2,3]triazol- 4-yl]-1-[2-(3-methoxy-phenyl)-ethyl]-piperidine (Cpd C001 , step c) the title compound was prepared from 4-(1 -p-Tolyl-1 H-[1 ,2,3]triazol-4-yl)-piperidine; dihydrochloride and 5- (chloromethyl)benzo[d][1 ,3]dioxole as amorphous light brown solid. MS(m / e): 377.4 (MH+).

[0342] Synthesis of 1-(2-Methyl-benzyl)-4-(1-p-tolyl-1 H-n ,2,31triazol-4-yl)-piperidine (Cpd C006)

[0343] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 / 7-[1 ,2,3]triazol- 4-yl]-1-[2-(3-methoxy-phenyl)-ethyl]-piperidine (Cpd C001 , step c) the title compound was prepared from 4-(1 -p-Tolyl-1 H-[1 , 2, 3]triazol-4-yl)-piperidine; dihydrochloride and 1- (chloromethyl)-2-methylbenzene as off-white solid. MS(m / e): 347.3 (MH+).

[0344] Synthesis of 4-n-(4-Fluoro-phenyl)-1 H-n ,2,31triazol-4-yl1-1-f2-(4-methoxy-phenyl)-ethyl1- piperidine (Cpd C007) a) 4-H-(4-Fluoro-phenyl)-1 H-n ,2,31triazol-4-yl1-piperidine, dihydrochloride

[0345] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 H-[1 ,2,3]triazol- 4-yl]-piperidine, dihydrochloride (Cpd C001 , step b) the title compound was prepared from tertbutyl 4-ethynylpiperidine-1 -carboxylate and 1-azido-4-fluorobenzene 0.5 M in tert, butylmethylether with subsequent removal of the protecting group with HCI in dioxane. MS(m / e): 247.3 (MH+). b) 1-f2-(3-Methoxy-phenyl)-ethyl1-4-(1-p-tolyl-1 / - / -n ,2,31triazol-4-yl)-piperidine

[0346] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 / 7-[1 ,2,3]triazol- 4-yl]-1-[2-(3-methoxy-phenyl)-ethyl]-piperidine (Cpd C001 , step c) the title compound was prepared from 4-[1-(4-Fluoro-phenyl)-1 H-[1 ,2,3]triazol-4-yl]-piperidine, dihydrochloride and 1-(2- bromoethyl)-3-methoxybenzene as white solid. MS(m / e): 381.3 (MIT).

[0347] Synthesis of 4-n-(4-Chloro-phenyl)-1 H-n ,2,31triazol-4-yl1-1-f2-(4-methoxy-phenyl)-ethyl1- piperidine (Cpd C008) a) 4-H-(4-Chloro-phenyl)-1 H-n ,2,31triazol-4-yl1-piperidine

[0348] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 H-[1 ,2,3]triazol- 4-yl]-piperidine, dihydrochloride (Cpd C001 , step b) the title compound was prepared from tertbutyl 4-ethynylpiperidine-1 -carboxylate and 1-azido-4-chlorobenzene 0.5 M in tert. butylmethylether with subsequent removal of the protecting group with HCI in dioxane. MS(m / e): 263.2 (MH+). b) 1-f2-(3-Methoxy-phenyl)-ethyl1-4-(1-p-tolyl-1 / - / -n ,2,31triazol-4-yl)-piperidine

[0349] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 / 7-[1 ,2,3]triazol- 4-yl]-1-[2-(3-methoxy-phenyl)-ethyl]-piperidine (Cpd C001 , step c) the title compound was prepared from 4-[1-(4-Chloro-phenyl)-1 H-[1 ,2,3]triazol-4-yl]-piperidine and 1-(2-bromoethyl)-3- methoxybenzene as white solid. MS(m / e): 397.2 (MH+).

[0350] Synthesis of 4-n-(4-Chloro-benzyl)-1 H-n ,2,31triazol-4-yl1-1-f2-(4-methoxy-phenyl)-ethyl1- piperidine (Cpd C009) a) 4-H-(4-Chloro-benzyl)-1 H-n ,2,31triazol-4-yl1-piperidine, dihydrochloride

[0351] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 H-[1 ,2,3]triazol- 4-yl]-piperidine, dihydrochloride (Cpd C001 , step b) the title compound was prepared from tertbutyl 4-ethynylpiperidine-1 -carboxylate and 1-(azidomethyl)-4-chlorobenzene with subsequent removal of the protecting group with HCI in dioxane. MS(m / e): 277.2 (MH+). b) 1-f2-(3-Methoxy-phenyl)-ethyl1-4-(1-p-tolyl-1 / - / -n ,2,31triazol-4-yl)-piperidine

[0352] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 / 7-[1 ,2,3]triazol- 4-yl]-1-[2-(3-methoxy-phenyl)-ethyl]-piperidine (Cpd C001 , step c) the title compound was prepared from 4-[1-(4-Chloro-benzyl)-1 H-[1 ,2,3]triazol-4-yl]-piperidine, dihydrochloride and 1-(2- bromoethyl)-3-methoxybenzene as off-white solid. MS(m / e): 411.3 (MIT).

[0353] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 H-[1 ,2,3]triazol- 4-yl]-piperidine, dihydrochloride (Cpd C001 , step b) the title compound was prepared from tertbutyl 4-ethynylpiperidine-1 -carboxylate and 1-(azidomethyl)-4-fluorobenzene with subsequent removal of the protecting group with HCI in dioxane. MS(m / e): 261.2 (MH+). b) 1-[2-(3-Methoxy-phenyl)-ethyll-4-(1-p-tolyl-1 / 7-[1 ,2,3]triazol-4-yl)-piperidine

[0354] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 / 7-[1 ,2,3]triazol- 4-yl]-1-[2-(3-methoxy-phenyl)-ethyl]-piperidine (Cpd C001 , step c) the title compound was prepared from 4-[1-(4-Fluoro-benzyl)-1 H-[1 ,2,3]triazol-4-yl]-piperidine dihydrochloride and 1-(2- bromoethyl)-3-methoxybenzene as off-white solid. MS(m / e): 395.2 (MH+).

[0355] Synthesis of 1-[2-(4-Chloro-phenyl)-ethyll-4-[1-(4-fluoro-phenyl)-1 H-[1 ,2,3]triazol-4-yll-piperidine (Cpd C011)

[0356] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 / 7-[1 ,2,3]triazol- 4-yl]-1-[2-(3-methoxy-phenyl)-ethyl]-piperidine (Cpd C001 , step c) the title compound was prepared from 4-(1-(4-fluorophenyl)-1 H-1 ,2,3-triazol-4-yl)piperidine dihydrochloride and 1-(2- bromoethyl)-4-chlorobenzene as off-white solid. MS(m / e): 385.2 (MH+).

[0357] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 / 7-[1 ,2,3]triazol- 4-yl]-1-[2-(3-methoxy-phenyl)-ethyl]-piperidine (Cpd C001 , step c) the title compound was prepared from 4-(1-(4-chlorophenyl)-1 H-1 ,2,3-triazol-4-yl)piperidine dihydrochloride and 1-(2- bromoethyl)-4-chlorobenzene as off-white solid. MS(m / e): 401.2 (MH+). In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 / 7-[1 ,2,3]triazol- 4-yl]-1-[2-(3-methoxy-phenyl)-ethyl]-piperidine (Cpd C001 , step c) the title compound was prepared from 4-(1-(4-fluorobenzyl)-1 H-1 ,2,3-triazol-4-yl)piperidine dihydrochloride and 1-(2- bromoethyl)-4-chlorobenzene as off-white solid. MS(m / e): 399.2 (MIT).

[0358] Synthesis of 4-n-(3,4-Difluoro-phenyl)-1 H-n ,2,31triazol-4-yl1-1-f2-(4-trifluoromethyl-phenyl)- ethyll-piperidine (Cpd C017) a) 4-H-(3,4-Difluoro-phenyl)-1 H-n ,2,31triazol-4-yl1-piperidine, dihydrochloride

[0359] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 H-[1 ,2,3]triazol- 4-yl]-piperidine, dihydrochloride (Cpd C01 , step b) the title compound was prepared from tertbutyl 4-ethynylpiperidine-1 -carboxylate and 4-azido-1 ,2-difluorobenzene with subsequent removal of the protecting group with HCI in dioxane. b) 4-n-(3,4-Difluoro-phenyl)-1H-n ,2,31triazol-4-yl1-1-f2-(4-trifluoromethyl-phenyl)-ethyl1- piperidine

[0360] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0361] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-[1-(3,4-Difluoro-phenyl)-1 H-[1 ,2,3]triazol-4-yl]-piperidine, dihydrochloride and 1-(2- bromoethyl)-4-(trifluoromethyl)benzene. MS(m / e): 437.2 (MIT).

[0362] Synthesis of 1-r2-(3,4-Difluoro-phenyl)-ethyl1-4-n-(3,4-difluoro-phenyl)-1 H-n ,2,31triazol-4-yl1- piperidine (Cpd C018)

[0363] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0364] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-[1-(3,4-Difluoro-phenyl)-1 H-[1 ,2,3]triazol-4-yl]-piperidine, dihydrochloride and 4-(2- bromoethyl)-1 ,2-difluorobenzene. MS(m / e): 405.3 (MIT).

[0365] Synthesis of 4-n-(3,4-Difluoro-phenyl)-1 H-n ,2,31triazol-4-yl1-1-f2-(3-trifluoromethyl-phenyl)- ethyll-piperidine (Cpd C019)

[0366] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0367] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-[1-(3,4-Difluoro-phenyl)-1 H-[1 ,2,3]triazol-4-yl]-piperidine, dihydrochloride and 1-(2- bromoethyl)-3-(trifluoromethyl)benzene. MS(m / e): 437.2 (MIT).

[0368] Synthesis of 2-Methoxy-4-{2-f4-(1-phenyl-1 H-n ,2,31triazol-4-yl)-piperidin-1-yl1-ethyl}-pyridine

[0369] (Cpd C020) a) 4-(1-Phenyl-1 H-f1 ,2,31triazol-4-yl)-piperidine, dihydrochloride

[0370] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 H-[1 ,2,3]triazol- 4-yl]-piperidine, dihydrochloride (Cpd C01 , step b) the title compound was prepared from tertbutyl 4-ethynylpiperidine-1 -carboxylate and azidobenzene with subsequent removal of the protecting group under acidic conditions with HCI. MS(m / e): 229.3 (MT). b) 2-Methoxy-4-{2-r4-(1-phenyl-1 / - / -n ,2,31triazol-4-yl)-piperidin-1-yl1-ethyl}-pyridine

[0371] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H- [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-(1 -Phenyl-1 H-[1 ,2,3]triazol-4-yl)-piperidine, dihydrochloride and 4-(2-bromoethyl)-2- methoxypyridine. MS(m / e): 364.2 (MH+).

[0372] Synthesis of 4-{2-r4-(1-Benzyl-1 H-n ,2,31triazol-4-yl)-piperidin-1-yl1-ethyl}-2-methoxy-pyridine (Cpd C021) a) 4-(1-Benzyl-1 H-n ,2,31triazol-4-yl)-piperidine, dihydrochloride

[0373] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 H-[1 ,2,3]triazol- 4-yl]-piperidine, dihydrochloride (Cpd C01 , step b) the title compound was prepared from tertbutyl 4-ethynylpiperidine-1 -carboxylate and (azidomethyl)benzene with subsequent removal of the protecting group under acidic conditions with HCI. MS(m / e): 243.3 (MH+). b) 4-{2-r4-(1-Benzyl-1 / - / -n ,2,31triazol-4-yl)-piperidin-1-yl1-ethyl}-2-methoxy-pyridine

[0374] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0375] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-(1-Benzyl-1 H-[1 ,2,3]triazol-4-yl)-piperidine, dihydrochloride and 4-(2-bromoethyl)-2- methoxypyridine. MS(m / e): 378.4 (MIT).

[0376] Synthesis of 4-(2-{4-[1-(3,4-Difluoro-benzyl)-1 H-[1 ,2,3]triazol-4-yl]-piperidin-1-yl}-ethyl)-2-

[0377] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 H-[1 ,2,3]triazol- 4-yl]-piperidine, dihydrochloride (Cpd C01 , step b) the title compound was prepared from tertbutyl 4-ethynylpiperidine-1 -carboxylate and 4-(azidomethyl)-1 ,2-difluorobenzene with subsequent removal of the protecting group under acidic conditions with HCI. MS(m / e): 279.1 (MH+). b) 4-(2-{4-[1-(3,4-Difluoro-benzyl)-1 / 7-[1 ,2,3ltriazol-4-'

[0378] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0379] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-[1-(3,4-Difluoro-benzyl)-1 H-[1 ,2,3]triazol-4-yl]-piperidine, dihydrochloride and 4-(2- bromoethyl)-2-methoxypyridine. MS(m / e): 414.4 (MH+).

[0380] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0381] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-(1 -Phenyl-1 H-[1 ,2,3]triazol-4-yl)-piperidine, dihydrochloride and 4-(2-bromoethyl)-1 ,2- difluorobenzene. MS(m / e): 369.2 (MH+).

[0382] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0383] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-(1-Benzyl-1 H-[1 ,2,3]triazol-4-yl)-piperidine, dihydrochloride and 4-(2-bromoethyl)-1 ,2- difluorobenzene. MS(m / e): 383.2 (MH+). > In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0384] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-[1-(3,4-Difluoro-benzyl)-1 H-[1 ,2,3]triazol-4-yl]-piperidine, dihydrochloride and 4-(2- bromoethyl)-1 ,2-difluorobenzene. MS(m / e): 419.2 (MIT).

[0385] Synthesis of 1-Phenethyl-4-(1-phenyl-1 H-[1 ,2,3]triazol-4-yl)-piperidine (Cpd C026)

[0386] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0387] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-(1 -Phenyl-1 H-[1 ,2,3]triazol-4-yl)-piperidine, dihydrochloride and (2-bromoethyl)benzene. MS(m / e): 333.3 (MT).

[0388] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0389] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-(1-Benzyl-1 H-[1 ,2,3]triazol-4-yl)-piperidine, dihydrochloride and (2-bromoethyl)benzene. MS(m / e): 347.2 (MH+). C028)

[0390] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0391] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-[1-(3,4-Difluoro-benzyl)-1 H-[1 ,2,3]triazol-4-yl]-piperidine, dihydrochloride and (2- bromoethyl)benzene. MS(m / e): 347.2 (MH+).

[0392] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0393] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-[1-(3,4-Difluoro-phenyl)-1 H-[1 ,2,3]triazol-4-yl]-piperidine, dihydrochloride and (2- bromoethyl)benzene. MS(m / e): 369.2 (MH+).

[0394] |-4-[1-(3,4-difluoro-phenyl)-1 H-[1 ,2,3ltriazol-4-yll-

[0395] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0396] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-[1-(3,4-Difluoro-phenyl)-1 H-[1 ,2,3]triazol-4-yl]-piperidine, dihydrochloride and 1-(2- bromoethyl)-4-chlorobenzene. MS(m / e): 403.4 (MH+).

[0397] Synthesis of 4-(2-{4-[1-(3,4-Difluoro-phenyl)-1 H-[1 ,2,3ltriazol-4-yll-piperidin-1-yl}-ethyl)-2-

[0398] C031 In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0399] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-[1-(3,4-Difluoro-phenyl)-1 H-[1 ,2,3]triazol-4-yl]-piperidine, dihydrochloride and 4-(2- bromoethyl)-2-methoxypyridine. MS(m / e): 400.2 (MIT).

[0400] Synthesis of 4-H-(3-Chloro-phenyl)-1 H-n ,2,31triazol-4-yl1-1-(2-methyl-benzyl)-piperidine (Cpd C037) a) 4-H-(3-Chloro-phenyl)-1 H-n ,2,31triazol-4-yl1-piperidine, dihydrochloride

[0401] In analogy to the procedure described for the synthesis of 4-[1-(3-Fluoro-benzyl)-1 H-[1 ,2,3]triazol- 4-yl]-piperidine, dihydrochloride (Cpd C01 , step b) the title compound was prepared from tertbutyl 4-ethynylpiperidine-1 -carboxylate and 1-azido-3-chlorobenzene with subsequent removal of the protecting group with HCI in dioxane. MS(m / e): 263.1 (MH+). b) 4-H-(3-Chloro-phenyl)-1 H-n ,2,31triazol-4-yl1-1-(2-methyl-benzyl)-piperidine

[0402] A mixture of 4-(1-(3-chlorophenyl)-1 H-1 ,2,3-triazol-4-yl)piperidine dihydrochloride (50 mg, 149 pmol), K2CO3 (103 mg, 745 pmol) and O-methylbenzyl chloride in acetonitrile (3 mL) I ethanol (1 .5 mL) was stirred for 4 h at 80 °C. The reaction mixture was absorbed on Isolute HM-N (10 g) and concentrated in vacuo. The crude product was purified by silica column chromatography eluting with a gradient formed from DCM, methanol and NH3. The product containing fractions were evaporated to yield 53 mg (97%) of the title compound. MS(m / e): 367.2 (MH+).

[0403] Synthesis of 4-H-(3-Chloro-phenyl)-1 H-n ,2,31triazol-4-yl1-1-(3-methyl-benzyl)-piperidine (Cpd C038)

[0404] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0405] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-(1-(3-chlorophenyl)-1 H-1 ,2,3-triazol-4-yl)piperidine dihydrochloride and l-(bromomethyl)-

[0406] 3-methylbenzene at room temperature. MS(m / e): 367.2 (MH+).

[0407] Synthesis of 4-H-(3-Chloro-phenyl)-1 H-n ,2,31triazol-4-yl1-1-(4-methyl-benzyl)-piperidine (Cpd C039)

[0408] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0409] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-(1-(3-chlorophenyl)-1 H-1 ,2,3-triazol-4-yl)piperidine dihydrochloride and l-(bromomethyl)-

[0410] 4-methylbenzene at room temperature with DIPEA as base. MS(m / e): 367.2 (MH+).

[0411] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0412] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-(1-(3-chlorophenyl)-1 H-1 ,2,3-triazol-4-yl)piperidine dihydrochloride and 4-(2-bromoethyl)- 1 ,2-difluorobenzene. MS(m / e): 403.3 (MIT).

[0413] Synthesis of 1-[2-(4-Chloro-phenyl)-ethyl]-4-[1-(3-chloro-phenyl)-1 H-[1 ,2,3]triazol-4-yll-piperidine (Cpd C041)

[0414] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0415] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-(1-(3-chlorophenyl)-1 H-1 ,2,3-triazol-4-yl)piperidine dihydrochloride and 1-(2-bromoethyl)- 4-chlorobenzene. MS(m / e): 401.2 (MT). C042)

[0416] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0417] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-(1-(3-chlorophenyl)-1 H-1 ,2,3-triazol-4-yl)piperidine dihydrochloride and (2- bromoethyl)benzene. MS(m / e): 367.2 (MH+).

[0418] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0419] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-(1-(3-chlorophenyl)-1 H-1 ,2,3-triazol-4-yl)piperidine dihydrochloride and 4-(2-bromoethyl)- 2-methoxypyridine. MS(m / e): 398.2 (MH+).

[0420] Synthesis of 1-Benzo[1 ,3]dioxol-5-ylmethyl-4-[5-(3-fluoro-benzyl)-2H-[1 ,2,4]triazol-3-yll- > a) 4-[5-(3-Fluoro-benzyl)-2H-[1 , 2, 4]triazol-3-yl]-piperidine-1 -carboxylic acid tert-butyl ester

[0421] In a microwave- Teflon-vessel, tert-butyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate (1 g, 4.11 mmol), 2-(3-fluorophenyl)acetonitrile (1.67 g, 12.3 mmol) and K2CO3 (568 mg, 4.11 mmol) in butan-1-ol (25 mL) was heated for 4 h at 150 °C under microwave irradiation. The resulting amber reaction suspension was filtered off and concentrated in vacuo. The residue was purified by silica chromatography to yield 0.76 g (51 %) of the title compound as light yellow viscous oil. MS(m / e): 361.3 (MT). b) 4-f5-(3-Fluoro-benzyl)-2H-n ,2,41triazol-3-yl1-piperidine, hydrochloride

[0422] A mixture of tert-butyl 4-(3-(3-fluorobenzyl)-1 H-1 , 2, 4-triazol-5-yl)piperidine-1 -carboxylate (0.76 g, 2.11 mmol) and 4 N HCI / dioxane (5.27 mL, 21.1 mmol) in dioxane (15 mL) and methanol (15 mL) was stirred at room temperature and concentrated in vacuo after consumption of the starting material. The residue was suspended in diethyl ether, the precipitate filtered off and washed with diethyl ether and dried in vacuo at 50 °C to yield 618 mg (99 %) of the title compound as off-white solid. MS(m / e): 261.2 (MIT). c) 1-Benzon ,31dioxol-5-ylmethyl-4-f5-(3-fluoro-benzyl)-2 / - / -n ,2,41triazol-3-yl1-piperidine

[0423] A mixture of 4-(3-(3-fluorobenzyl)-1 H-1 ,2,4-triazol-5-yl)piperidine hydrochloride (60 mg, 202 pmol), DIPEA (78.4 mg, 607 pmol), AcOH (54.6 mg, 910 pmol), piperonal (33.4 mg, 222 pmol) and sodium triacetoxyborohydride (64.3 mg, 303 pmol) in CH2CI2 (10 mL) was stirred at room temperature overnight. Water (1 mL) was added and 10% Na2CO3-solution aq. (5 mL) and stirred for 10min. The organic layer was separated and extracted with brine (5 mL). The aqueous layer were extracted with CH2CI2 (2 x 10mL). The combined organic layer were dried over Na2SO4, filtered off and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with a gradient formed from CH2CI2, methanol and 2 N NH3 to yield after evaporation of the product containing fractions 32 mg (40 %) of the title compound as colorless viscous oil. MS(m / e): 395.2 (MIT).

[0424] Synthesis of 4-f5-(3-Fluoro-benzyl)-2H-n ,2,41triazol-3-yl1-1-(2-methyl-benzyl)-piperidine (Cpd C047)

[0425] In analogy to the procedure described for the synthesis of 1-Benzo[1 ,3]dioxol-5-ylmethyl-4-[5-(3- fluoro-benzyl)-2 / 7-[1 ,2,4]triazol-3-yl]-piperidine (Cpd C046) the title compound was prepared from 4-(3-(3-fluorobenzyl)-1 H-1 ,2,4-triazol-5-yl)piperidine hydrochloride and o-tolualdehyde as colorless viscous oil. MS(m / e): 365.4 (MIT).

[0426] Synthesis of 1-(2,2-Difluoro-benzon ,31dioxol-5-ylmethyl)-4-f5-(3-fluoro-benzyl)-2H-n ,2,41triazol- 3-yll-piperidine (Cpd C048)

[0427] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H- [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 1-[1-(4-Chloro-phenyl)-1 H-[1 ,2,3]triazol-4-ylmethyl]-piperazine, dihydrochloride and 5- (bromomethyl)-2,2-difluorobenzo[d][1 ,3]dioxole as light yellow viscous oil. MS(m / e): 431.1 (MH+).

[0428] Synthesis of 4-r5-(4-Chloro-phenyl)-4H-n ,2,41triazol-3-yl1-1-f2-(4-fluoro-phenyl)-ethyl1-piperidine

[0429] (Cpd C049) a) 4-r5-(4-Chloro-phenyl)-4H-f1 ,2,41triazol-3-yl1-piperidine, dihydrochloride

[0430] In analogy to the procedure described for the synthesis of 4-[5-(3-Fluoro-benzyl)-2H-[1 ,2,4]triazol- 3-yl]-piperidine-1 -carboxylic acid tert-butyl ester (Cpd C046, step a) the title compound was prepared from tert-butyl 4-(hydrazinecarbonyl)piperidine-1 -carboxylate and 4-chlorobenzonitrile with subsequent removal of the protecting group with HCI. MS(m / e): 263.1 (MH+). b) 4-r5-(4-Chloro-phenyl)-4H-n ,2,41triazol-3-yl1-1-f2-(4-fluoro-phenyl)-ethyl1-piperidine

[0431] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H- [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-[5-(4-Chloro-phenyl)-4H-[1 ,2,4]triazol-3-yl]-piperidine, dihydrochloride and 1-(2- bromoethyl)-4-fluorobenzene as white solid. MS(m / e): 385.1 (MH+).

[0432] Synthesis of 4-r5-(4-Chloro-phenyl)-4H-n ,2,41triazol-3-yl1-1-f2-(4-methoxy-phenyl)-ethyl1- piperidine (Cpd C050)

[0433] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H- [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-[5-(4-Chloro-phenyl)-4H-[1 ,2,4]triazol-3-yl]-piperidine, dihydrochloride and 1-(2- bromoethyl)-4-methoxybenzene as white solid. MS(m / e): 397.1 (MH+).

[0434] Synthesis of 4-r5-(4-Chloro-benzyl)-4H-n ,2,41triazol-3-yl1-1-f2-(4-methoxy-phenyl)-ethyl1- piperidine (Cpd C051) a) 4-f5-(4-Chloro-benzyl)-4H-n ,2,41triazol-3-yl1-piperidine, dihydrochloride

[0435] In analogy to the procedure described for the synthesis of 4-[5-(3-Fluoro-benzyl)-2H-[1 ,2,4]triazol- 3-yl]-piperidine-1 -carboxylic acid tert-butyl ester (Cpd C046, step a) the title compound was prepared from tert-butyl 4-(hydrazinecarbonyl)piperidine-1 -carboxylate and 2-(4- chlorophenyl)acetonitrile with subsequent removal of the protecting group with HCI. MS(m / e): 277.2 (MIT). b) 4-r5-(4-Chloro-phenyl)-4H-n ,2,41triazol-3-yl1-1-f2-(4-fluoro-phenyl)-ethyl1-piperidine

[0436] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0437] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-[5-(4-Chloro-benzyl)-4H-[1 ,2 ,4]triazol-3-yl]-piperidine, dihydrochloride and 1-(2-bromoethyl)-4-methoxybenzene as white solid. MS(m / e): 411.1 (MT).

[0438] Synthesis of 4-r5-(4-Chloro-phenyl)-4H-n ,2,41triazol-3-yl1-1-(2,2-difluoro-benzon ,31dioxol-5- ylmethyD-piperidine (Cpd C052)

[0439] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0440] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-[5-(4-Chloro-phenyl)-4H-[1 ,2 ,4]triazol-3-yl]-piperidine, dihydrochloride and 5-(bromomethyl)-2,2-difluorobenzo[d][1 ,3]dioxole as white solid. MS(m / e): 433.1 (MH+).

[0441] Synthesis of 4-r5-(4-Chloro-benzyl)-4H-n ,2,41triazol-3-yl1-1-(2,2-difluoro-benzon ,31dioxol-5- ylmethyD-piperidine (Cpd C053)

[0442] In analogy to the procedure described for the synthesis of 4-[1-(3-Chloro-phenyl)-1 H-

[0443] [1 ,2,3]triazol-4-yl]-1-(2-methyl-benzyl)-piperidine (Cpd C037) the title compound was prepared from 4-[5-(4-Chloro-benzyl)-4H-[1 ,2 ,4]triazol-3-yl]-piperidine, dihydrochloride and 5-(bromomethyl)-2,2-difluorobenzo[d][1 ,3]dioxole. MS(m / e): 447.1 (MH+).

[0444] Synthesis of 1-r2-(4-Chloro-phenyl)-ethyl1-4-f5-(3-chloro-phenyl)-2H-n ,2,41triazol-3-yl1-piperidine (Cpd C054) a) 1-f2-(4-Chloro-phenyl)-ethyl1-piperidine-4-carboxylic acid hydrazide

[0445] A mixture of ethyl 1-(4-chlorophenethyl)piperidine-4-carboxylate (5.16 g, 17.4 mmol) and hydrazine monohydrate (8.74 g, 175 mmol) in EtOH (50 mL) was heated to reflux for 38 h. Stirred for totally 38 hours at reflux. The mixture was evaporated and suspended in diethyl ether (50 mL). the precipitate was filtered off and washed with diethyl ether (3 x 20 mL), dried in vacuo at 40°C to yield 4.65 g, (95 %) of the title compound as white needles. MS(m / e): 284.4 (MIT). b) 1-r2-(4-Chloro-phenyl)-ethyl1-4-f5-(3-chloro-phenyl)-2H-n ,2,41triazol-3-yl1-piperidine

[0446] In analogy to the procedure described for the synthesis of 4-[5-(3-Fluoro-benzyl)-2H-[1 ,2,4]triazol- 3-yl]-piperidine-1 -carboxylic acid tert-butyl ester (Cpd C046, step a) the title compound was prepared from 1-[2-(4-Chloro-phenyl)-ethyl]-piperidine-4-carboxylic acid hydrazide and 3- chlorobenzonitrile as white solid. MS(m / e): 401.1 (MT).

[0447] Synthesis of 4-f5-(3-Chloro-phenyl)-2H-n ,2,41triazol-3-yl1-1-phenethyl-piperidine (Cpd C055) a) 1-Phenethyl-piperidine-4-carboxylic acid hydrazide

[0448] In analogy to the procedure described for the synthesis of 1-[2-(4-Chloro-phenyl)-ethyl]- piperidine-4-carboxylic acid hydrazide (Cpd C054, step a) the title compound was prepared from ethyl 1-phenethylpiperidine-4-carboxylate and hydrazine monohydrate as white needles. MS(m / e): 248.3 (MH+). b) 4-f5-(3-Chloro-phenyl)-2H-n ,2,41triazol-3-yl1-1-phenethyl-piperidine

[0449] In analogy to the procedure described for the synthesis of 4-[5-(3-Fluoro-benzyl)-2H-[1 ,2,4]triazol- 3-yl]-piperidine-1 -carboxylic acid tert-butyl ester (Cpd C046, step a) the title compound was prepared from 1-Phenethyl-piperidine-4-carboxylic acid hydrazide and 3-chlorobenzonitrile as white solid. MS(m / e): 367.1 (MH+).

[0450] Synthesis of 4-r5-(4-Chloro-benzyl)-2H-n ,2,41triazol-3-yl1-1-f2-(4-chloro-phenyl)-ethyl1-piperidine (Cpd C056)

[0451] In analogy to the procedure described for the synthesis of 4-[5-(3-Fluoro-benzyl)-2H-[1 ,2,4]triazol- 3-yl]-piperidine-1 -carboxylic acid tert-butyl ester (Cpd C046, step a) the title compound was prepared from 1-[2-(4-Chloro-phenyl)-ethyl]-piperidine-4-carboxylic acid hydrazide and 2-(4- chlorophenyl)acetonitrile as white solid. MS(m / e): 415.1 (MH+).

[0452] Synthesis of 4-f5-(4-Chloro-benzyl)-2H-n ,2,41triazol-3-yl1-1-phenethyl-piperidine (Cpd C057)

[0453] In analogy to the procedure described for the synthesis of 4-[5-(3-Fluoro-benzyl)-2H-[1 ,2,4]triazol- 3-yl]-piperidine-1 -carboxylic acid tert-butyl ester (Cpd C046, step a) the title compound was prepared from 1-phenethyl-piperidine-4-carboxylic acid hydrazide and 2-(4- chlorophenyl)acetonitrile as white solid. MS(m / e): 381.1 (MIT).

[0454] Synthesis of 4-r5-(4-Chloro-benzyl)-2H-f1 ,2,41triazol-3-yl1-1-(2-methyl-benzyl)-piperidine (Cpd C058)

[0455] In analogy to the procedure described for the synthesis of 1-Benzo[1 ,3]dioxol-5-ylmethyl-4-[5-(3- fluoro-benzyl)-2 / 7-[1 ,2,4]triazol-3-yl]-piperidine (Cpd C046) the title compound was prepared from 4-[5-(4-Chloro-benzyl)-4H-[1 ,2,4]triazol-3-yl]-piperidine, dihydrochloride and o-tolualdehyde as off-white foam. MS(m / e): 381.1 (MT).

[0456] Synthesis of 1-(4-Chloro-benzyl)-4-f5-(4-chloro-benzyl)-2H-n ,2,41triazol-3-yl1-piperidine (Cpd C059)

[0457] In analogy to the procedure described for the synthesis of 1-Benzo[1 ,3]dioxol-5-ylmethyl-4-[5-(3- fluoro-benzyl)-2 / 7-[1 ,2,4]triazol-3-yl]-piperidine (Cpd C046) the title compound was prepared from 4-[5-(4-Chloro-benzyl)-4H-[1 ,2,4]triazol-3-yl]-piperidine, dihydrochloride and 4- chlorobenzaldehyde as off-white foam. MS(m / e): 401.1 (MH+).

[0458] Synthesis of 4-f5-(3-Chloro-phenyl)-2H-n ,2,41triazol-3-yl1-1-(2-methyl-benzyl)-piperidine (Cpd C060) a) 4-f5-(3-Chloro-phenyl)-2H-n ,2,41triazol-3-yl1-piperidine, dihydrochloride

[0459] In analogy to the procedure described for the synthesis of 4-[5-(3-Fluoro-benzyl)-2H-[1 ,2,4]triazol-

[0460] 3-yl]-piperidine-1 -carboxylic acid tert-butyl ester (Cpd C046, step a) the title compound was prepared from tert-butyl 4-(hydrazinecarbonyl)piperidine-1 -carboxylate and 3-chlorobenzonitrile with subsequent removal of the protecting group with HCI. MS(m / e): 263.2 (MH+). b) 4-f5-(3-Chloro-phenyl)-2H-n ,2,41triazol-3-yl1-1-(2-methyl-benzyl)-piperidine

[0461] In analogy to the procedure described for the synthesis of 1-Benzo[1 ,3]dioxol-5-ylmethyl-4-[5-(3- fluoro-benzyl)-2 / 7-[1 ,2,4]triazol-3-yl]-piperidine (Cpd C046) the title compound was prepared from

[0462] 4-[5-(3-Chloro-phenyl)-2H-[1 ,2,4]triazol-3-yl]-piperidine, dihydrochloride and o-tolualdehyde as off-white foam. MS(m / e): 367.1 (MH+).

[0463] Synthesis of 1-(4-Chloro-benzyl)-4-f5-(3-chloro-phenyl)-2H-n ,2,41triazol-3-yl1-piperidine (Cpd

[0464] C061) In analogy to the procedure described for the synthesis of 1-Benzo[1 ,3]dioxol-5-ylmethyl-4-[5-(3- fluoro-benzyl)-2 / 7-[1 ,2,4]triazol-3-yl]-piperidine (Cpd C046) the title compound was prepared from 4-[5-(3-Chloro-phenyl)-2H-[1 ,2,4]triazol-3-yl]-piperidine, dihydrochloride and 4- chlorobenzaldehyde as white foam. MS(m / e): 387.1 (MIT).

[0465] In analogy to the procedure described for the synthesis of 1-[2-(4-Chloro-phenyl)-ethyl]- piperidine-4-carboxylic acid hydrazide (Cpd C054, step a) the title compound was prepared from ethyl 1-(2-(2-methoxypyridin-4-yl)ethyl)piperidine-4-carboxylate and hydrazine monohydrate as off-white solid. MS(m / e): 279.3 (MT). b) 4-(2-{4-[5-(3-Chloro-phenyl)-2 / 7-[1 ,2,4]triazol-3-yl]-piperidin-1-yl}-ethyl)-2-methoxy-pyridine

[0466] In analogy to the procedure described for the synthesis of 4-[5-(3-Fluoro-benzyl)-2H-[1 ,2,4]triazol- 3-yl]-piperidine-1 -carboxylic acid tert-butyl ester (Cpd C046, step a) the title compound was prepared from 1-[2-(2-Methoxy-pyridin-4-yl)-ethyl]-piperidine-4-carboxylic acid hydrazide and 3- chlorobenzonitrile as white solid. MS(m / e): 398.1 (MH+).

[0467] In analogy to the procedure described for the synthesis of 4-[5-(3-Fluoro-benzyl)-2H-[1 ,2,4]triazol- 3-yl]-piperidine-1 -carboxylic acid tert-butyl ester (Cpd C046, step a) the title compound was prepared from 1-[2-(2-Methoxy-pyridin-4-yl)-ethyl]-piperidine-4-carboxylic acid hydrazide and 4- chlorobenzyl cyanide as white solid. MS(m / e): 412.1 (MH+). a) 4-[5-(4-Chloro-benzyl)-2H-[1 , 2, 4]triazol-3-yl]-piperidine-1 -carboxylic acid tert-butyl ester In analogy to the procedure described for the synthesis of 4-[5-(3-Fluoro-benzyl)-2H-[1 ,2,4]triazol-

[0468] 3-yl]-piperidine-1 -carboxylic acid tert-butyl ester (Cpd C046, step a) the title compound was prepared from tert-butyl 4-(hydrazinecarbonyl)piperidine-1 -carboxylate and 4-chlorobenzyl cyanide as light yellow foam. MS(m / e): 377.1 (MIT). b) 4-r5-(4-Chloro-benzyl)-1-methyl-1 H-n ,2,41triazol-3-yl1-1-f2-(4-chloro-phenyl)-ethyl1-piperidine

[0469] A mixture of tert-butyl 4-(3-(4-chlorobenzyl)-1 H-1 , 2, 4-triazol-5-yl)piperidine-1 -carboxylate (1345 mg, 3.57 mmol), potassium tert-butoxide (420 mg, 3.75 mmol) and methyl-p-toluenesulfonate (698 mg, 566 pL, 3.75 mmol) in THF (40 mL) was stirred for 1 h at room temperature. 10 % Na2CC>3-solution aq. (50 mL) was added, the aqueous layer was separated and extracted with AcOEt (1 x 50 mL). The organic layers were washed with brine (1 x 50 mL), dried over Na2SO4, filtered off and concentrated in vacuo. The residue was dissolved in dioxane (30 mL) I MeOH (20 mL) and HCL 4M in dioxane (8.9 mL, 35.7 mmol) was added. The mixture was stirred over night at room temperature, concentrated in vacuo and dried at 45 °C . The residue was dissolved in acetonitrile (5 mL) and ethanol (3 mL) and K2CO3 (315 mg, 2.28 mmol) was added and stirred for 15 min at room temperature. 1-(2-bromoethyl)-4-chlorobenzene (301 mg, 1.37 mmol) was added and stirred for 24 h at reflux. The suspension was filtered off and the filtrate was concentrated in vacuo and the residue was purified by silica column chromatography eluting with a gradient formed from DCM, methanol and NH 3 to yield after evaporation of the product containing fractions 75 mg of the title compound as white solid. MS(m / e): 429.1 (MIT).

[0470] Synthesis of 4-r5-(4-Chloro-benzyl)-1-methyl-1 H-n ,2,41triazol-3-yl1-1-phenethyl-piperidine (Cpd C065)

[0471] In analogy to the procedure described for the synthesis of 4-[5-(4-Chloro-benzyl)-1-methyl-1 H- [1 ,2,4]triazol-3-yl]-1-[2-(4-chloro-phenyl)-ethyl]-piperidine the title compound was prepared from

[0472] 4-[5-(4-Chloro-benzyl)-2H-[1 , 2, 4]triazol-3-yl]-piperidine-1 -carboxylic acid tert-butyl ester through the same sequence of reactions (methylation, deprotection) and subsequent reaction with (2- bromomethyl)benzene as light green viscous oil. MS(m / e): 395.1 (MIT).

[0473] Synthesis of 4-(1-(4,4-difluorocyclohexyl)-1 H-1 ,2,3-triazol-4-yl)-1-(2-chloro-4-fluorobenzyl) piperidine (Cpd C066)

[0474] 4-(1-(4,4-difluorocyclohexyl)-1 H-1 ,2,3-tnazol-4-yl)piperidine hydrochloride (27.0 mg, 0.1 mmol) and 2-chloro-4-fluorobenzaldehyde (23.8 mg, 0.15 mmol) in DMAc (0.5 mL) were mixed and the reaction was shaken for 5h at RT. Sodium triacetoxyborohydride (0.053 g, 0.250 mmol) (stock suspension in DMAc (0.8 mL)) was added and the reaction was shaken overnight at rt. 35% aq. NH3 (0.2 mL, -1.75 mmol) was added, the reactions were filtered (0.45pm) and purified by basic preparative HPLC-MS. Product fractions were concentrated, combined with ACN, water was added and the product was lyophilized to afford 4-(1-(4,4-difluorocyclohexyl)-1 H-1 ,2,3-triazol-4- yl)-1-(2-chloro-4-fluoro benzyl)piperidine (Cpd C066) (30.9 mg, 32.0 % yield). MS (m / e): 413.2 (MH+) rt = 1.80 min.

[0475] The following compounds were prepared in a similar manner (use of appropriate starting material, intermediates, reagents and purification methods (including chiral HPLC or chiral SFC) known to the person skilled in the art or as described herein) as described for Cpd C066: Cpd C067, Cpd

[0476] C068, Cpd C069, Cpd C070, Cpd C071, Cpd C072, Cpd C073, Cpd C074, Cpd C075, Cpd C076, Cpd C077, Cpd C078, Cpd C079, Cpd C080, Cpd C081, Cpd C082, Cpd C083, Cpd C084, Cpd C085, Cpd C086, Cpd C087, Cpd C088, Cpd C089, Cpd C090, Cpd C091, Cpd C092, Cpd C093, Cpd C094, Cpd C095, Cpd C096, Cpd C097, Cpd C098, Cpd C099, Cpd C100, Cpd C101, Cpd C102, Cpd C103, Cpd C104, Cpd C105, Cpd C106, Cpd C107, Cpd C108, Cpd C109, Cpd C110, Cpd C111, Cpd C112, Cpd C113, Cpd C114, Cpd C115, Cpd C116, Cpd C117, Cpd C118, Cpd C119, Cpd C120, Cpd C121, Cpd C122, Cpd C123, Cpd C124, Cpd C125, Cpd C126, Cpd C127, Cpd C128, Cpd C129, Cpd C130, Cpd C131, Cpd C132, Cpd C133, Cpd C134, Cpd C135, Cpd C136, Cpd C137, Cpd C138, Cpd C139, Cpd C140, Cpd C141, Cpd C142, Cpd C143, Cpd C144, Cpd C145, Cpd C146, Cpd C147, Cpd C148, Cpd C149, Cpd C150, Cpd C151, Cpd C152, Cpd C153, Cpd C154, Cpd C155, Cpd C156, Cpd C157, Cpd C158, Cpd C159, Cpd C160, Cpd C161, Cpd C162, Cpd C163, Cpd C164, Cpd C166, Cpd C167, Cpd C168, Cpd C169, Cpd C170, Cpd C171, Cpd C172, Cpd C173, Cpd C174, Cpd C175, Cpd C176, Cpd C177, Cpd C178, Cpd C179, Cpd C180, Cpd C181, Cpd C182, Cpd C183, Cpd C184, Cpd C185 , Cpd C186, Cpd C187, Cpd C188, Cpd C189, Cpd C190, Cpd C191, Cpd C192, Cpd C193, Cpd C194, Cpd C195, Cpd C196, Cpd C197, Cpd C198, Cpd C199, Cpd C200, Cpd C201 and Cpd C202.

[0477]

[0478] Synthesis of 1-(2-(2-fluorophenyl)ethyl)-4-(1-(4-(trifluoromethyl)phenyl)-1 H-1 ,2,3-triazol-4- vDpiperidine (Cpd C203)

[0479] To 4-(1-(4-(trifluoromethyl)phenyl)-1 H-1 ,2,3-triazol-4-yl)piperidine dihydrochloride 14-16 (0.032 g, 0.1 mmol) (stock solution / suspension in DMAc (0.5 mL)) was added K2CO3 (0.055 g, 0.400 mmol) and DMAc (1 mL in total) and the reaction was shaken for 5 min. Then, 2-fluorophenethyl bromide (42.1 pl, 0.300 mmol) was added and the reaction was shaken overnight at rt. The reaction was filtered (0.45pm) and purified by basic preparative HPLC-MS. Product fractions were concentrated, combined with ACN; water was added and the product was lyophilized to afford 1- (2-(2-fluorophenyl)ethyl)-4-(1-(4-(trifluoromethyl)phenyl)-1 H-1 ,2,3-triazol-4-yl)piperidine (Cpd C203) (34.5 mg, 36.1 % yield). MS (m / e): 419.2 (MIT) rt = 1.89 min.

[0480] The following compounds were prepared in a similar manner (use of appropriate starting material, intermediates, reagents and purification methods known to the person skilled in the art or as described herein) as described for Cpd C203: Cpd C204, Cpd C205 and Cpd C206.

[0481] Synthesis of 2-(4-(1-(m-tolyl)-1 H-1 ,2,3-triazol-4-yl)piperidin-1-yl)-1-(4-(trifluoromethoxy)phenyl) ethan-1-ol (Cpd C209)

[0482] Step 1 : 4-(1 -(m-tolyl)-l H-1 ,2,3-triazol-4-yl)piperidine dihydrochloride (100 mg, 0.317 mmol) was dissolved in DMF (dry) (2 ml) and Et3N (0.221 ml, 1.586 mmol) was added. After 3 min, 2-bromo- 1-(4-(trifluoromethoxy)phenyl)ethan-1-one (99 mg, 0.349 mmol) was added and the resulting solution was stirred for 1 hour at rt. Water and ACN were added and the mixture was purified by basic preparative HPLC-MS. The desired fractions were collected and freeze-dried to obtain 2- (4-(1-(m-tolyl)-1 H-1 ,2,3-triazol-4-yl)piperidin-1-yl)-1-(4-(trifluoromethoxy)phenyl) ethan-1-one (74.7 mg, 0.168 mmol, 53.0 % yield) as a white solid. MS (m / e): 445.4 (MT) rt = 1.94 min.

[0483] Step 2:

[0484] 2-(4-(1 -(m-tolyl)-l H-1 ,2,3-triazol-4-yl)piperidin-1 -yl)-1 -(4-(trifluoromethoxy)phenyl)ethan-1 -one (50 mg, 0.112 mmol) was dissolved in MeOH (1 mL) and NaBH4 (8.51 mg, 0.225 mmol) was added in 1 portion. The reaction mixture was stirred for 1 hour at rt. First, water and DMSO were added followed by the addition of a few drops of aqueous HCI (2M) to fully dissolve the target. The mixture was purified by basic preparative HPLC-MS. The desired fractions were collected and freeze-dried to obtain 2-(4-(1 -(m-tolyl)-l H-1 ,2,3-triazol-4-yl)piperidin-1 -yl)-1 -(4- (trifluoromethoxy) phenyl)ethan-1-ol (28.6 mg, 0.064 mmol, 56.9 % yield) as a white solid. MS (m / e): 447.4 (MH+) rt = 1.95 min. Cpd C210 was prepared in a similar manner (use of appropriate starting material, intermediates, reagents and purification methods known to the person skilled in the art or as described herein) as described for Cpd C209.

[0485] Synthesis of 1-phenyl-2-(4-(1-(m-tolyl)-1 H-1 ,2,3-triazol-4-yl)piperidin-1-yl)ethan-1-ol (Cpd C211)

[0486]

[0487] 4-(1 -(m-tolyl)-l H-1 ,2,3-triazol-4-yl)piperidine dihydrochloride (50 mg, 0.159 mmol) was dissolved in DMF (dry) (1.5 mL) and Et3N (0.111 mL, 0.793 mmol) was added. After 3 min, 2-bromo-1- phenylethan-1-one (34.7 mg, 0.174 mmol) was added and the resulting solution was stirred for 1 hours at rt. NaBH4 (24.00 mg, 0.634 mmol) was added and the mixture was stirred overnight at rt. ACN and aqueous HCI (1 M) were added and the resulting solution was purified by basic preparative HPLC-MS. The desired fractions were collected and freeze-dried to obtain 1-phenyl- 2-(4-(1-(m-tolyl)-1 H-1 ,2,3-triazol-4-yl)piperidin-1-yl)ethan-1-ol (20.9 mg, 0.058 mmol, 36.4% yield) as a white solid. MS (m / e): 363.2 (MIT) rt = 0.96 min. The following compounds were prepared in a similar manner (use of appropriate starting material, intermediates, reagents and purification methods known to the person skilled in the art or as described herein) as described for Cpd C211 : Cpd C212, Cpd C213, Cpd C214 and Cpd C215.

[0488] Synthesis of 1-(2-fluoro-2-(4-(trifluoromethoxy)phenyl)ethyl)-4-(1-(m-tolyl)-1 H-1 ,2,3-triazol-4- vDpiperidine (Cpd C219)

[0489] 2-(4-(1-(m-tolyl)-1 H-1 ,2,3-triazol-4-yl)piperidin-1-yl)-1-(4-(trifluoromethoxy)phenyl)ethan-1-ol (Cpd C209) (44 mg, 0.099 mmol) was dissolved in DCM and the solution was cooled to 0 °C. Then, DAST (26.0 pl, 0.197 mmol) was carefully added and the reaction mixture was stirred for 3 hours slowly warming up to RT. The reaction mixture was quenched with water and the DCM was carefully evaporated. The residue was dissolved in water / ACN and purified by basic preparative HPLC-MS. The desired fractions were collected and freeze-dried to obtain 1-(2-fluoro-2-(4- (trifluoromethoxy)phenyl)ethyl)-4-(1-(m-tolyl)-1 H-1 ,2,3-triazol-4-yl)piperidine (7.5 mg, 0.017 mmol, 16.97 % yield) as a white solid. MS (m / e): 449.4 (MIT) rt = 1.19 min. The following compounds were prepared in a similar manner (use of appropriate starting material, intermediates, reagents and purification methods known to the person skilled in the art or as described herein) as described for Cpd C219: Cpd C216 (from Cpd C191), Cpd C217 (from Cpd C194) and Cpd C218 (from Cpd C192).

[0490] Table 2C: Analytical data (1H-NMR, 400MHz) of example compounds

[0491] Compounds Cpd C301 to Compound Cpd C424

[0492] These compounds were prepared following the procedures as indicated in the below Table

[0493] Part B

[0494] The compounds were investigated in accordance with the test given hereinafter.

[0495] Construction of a TAU gene over-expressing cell line A TAU expression plasmid was constructed by sub-cloning the cDNA encoding for human TAU- P301 L protein, wherein proline at position 301 is substituted by a leucine residue, into mammalian expression vector pcDNA3.1 resulting in the plasmid pcDNA3.1-TAUP301 L. Plasmids pcDNA3.1 and pcDNA3.1-TAU P301 L were transfected into human neuroblastoma cells (BE-M17; ATCC No. CRL-2267™) using lipofectamine reagent and subsequently, independent clonal cell lines with the plasmids stably integrated into the genome were selected by antibiotic resistance selection (Geneticin (G418)), resulting in cell lines M17.pcDNA3 and M17_3TAUP301 L. Expression of the TAUP301 L gene in the M17_3TAUP301 L cells was confirmed by Western blot analysis.

[0496] Use of TAU expressing cells as a model of neuronal degeneration

[0497] The expression of TAU P301 L in M17_3TAU(P301 L) cells was found to confer increased toxicity relative to control cells expressing no TAU after 7 days of cell differentiation using retinoic acid (RA). Differentiation of the cells with RA leads to phosphorylation and subsequent aggregation of TAU, inducing a tauopathy in these cells. Cytotoxicity of cells was measured by quantification of lactate dehydrogenase (LDH) levels. In dead cells LDH is leaked out of the cells into the medium due to a loss of plasma-membrane integrity.

[0498] Briefly, 3 days preceding the experiment pre-cultures of M17.pcDNA3 and M17_3TAU(P301 L) cells were prepared, starting from a stock culture, at a density of 50.000-100.000 cells / cm2 in detection medium (Optimem Reduced Serum without phenol red (Gibco, Cat. 31985-047) supplemented with 1% fetal calf serum (FCS), 1 mM sodium pyruvate, 1 x non-essential amino acids (NEAA), 500 pg / ml G418 and 0,5 x antibiotic / antimycotic (ABAM)). At the day of the experiment these precultures were diluted to ~10A5 cells / ml in detection medium without FCS and 60 pL of this suspension is dispensed per well into a 96-well microtiter plate. After 3 hours of incubation at 37°C / 5% CO2 an equal volume of detection medium containing 2.5 pM RA was added and subsequently incubated for 7 days at 37°C / 5% CO2. After 7 days, LDH activity was determined using the Promega Cytotox 96 Non-Radioactive cytotoxicity assay (Cat. G1780), according to the manufacturer’s instructions. Cytotoxicity is measured as the ratio of LDH increase in the supernatant divided by the LDH increase in the total cell suspension (sum of the LDH measured in cells and supernatant). Toxicity was determined after 7 days of differentiation with retinoic acid in M17_3TAU(P301 L) cells compared to M17.pcDNA3 cells. Toxicity is clearly higher in the M17_3TAU(P301 L) cells demonstrating that it is specifically provoked by the presence of the mutant TAU P301 protein.

[0499] Use of the neuroblastoma tauopathy model to screen compounds

[0500] The M17_3TAU(P301 L) cell line makes it possible to assess the ability of novel compounds to inhibit TAU-induced cytotoxicity. Active inhibitors of Tauopathy in these cells were found to inhibit cytotoxicity or LDH increase in the medium of M17_3TAU(P301 L) cells treated as described in Example above. Compounds were tested for their ability to hamper TAU-induced toxicity at different concentrations, ranging from low non-effective concentrations to high potent concentrations. Afterwards, the dose-dependent inhibition curve was used to calculate their ECso (Table 3C).

[0501] Although the pharmacological properties of the compounds disclosed in this invention vary with structural change, active compounds most particularly possess ECso in a cell-based assay in a range from about <0.00007 to 4.00 pM.

[0502] The tested compounds show a ECso value (pM) as shown in Table 3C below. Table 3C: ECso values (pM)

[0503] The compounds as defined herein (including all embodiments thereof as described herein) can be used as medicaments, e.g., in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g., in the form of suppositories, or parenterally, e.g., in the form of injection solutions.

[0504] The compounds as defined herein (including all embodiments thereof as described herein) can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

[0505] The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

[0506] Medicaments containing a compound as defined herein (including all embodiments thereof as described herein) and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds as defined herein (including all embodiments thereof as described herein) and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

[0507] The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia and parkinsonism (linked to chromosome 17, FTDP-17).

[0508] The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration, the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.

Claims

Claims1. A compound of formula (C1A), or a salt, a solvate, a hydrate, a polymorph, a tautomer, a racemate or a stereoisomer thereof; or a prodrug thereof, whereinR4independently selected from the group comprising hydrogen, hydroxyl, halo, Ci-ealkoxy, and Ci-ealkyl;L1is a single bond or -C(R5)2-; each R5is independently selected from hydrogen, or Ci-ealkyl;L3is -(C(R7)2)n-; wherein n is an integer selected from 1 or 2; each R7is independently selected from hydrogen, halo, or Ci-ealkyl;A1is selected from the group comprising Cs-ecycloalkyl, Ce-waryl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, C2-ealkenyl, C2-ealkynyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, Cs-ecycloalkyl, oxo, Ci- ealkylcarbonylamino, (R8)2N-, and (R8)2N-carbonyl; and / or two R1together with the atom(s) to which they are attached can form a 5-10 membered saturated or partially saturated heterocyclyl, or a Ce- aryl, a 5-10 membered heteroaryl;A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, 5-6 membered saturated or partially saturated heterocyclyl, and Cs-ecycloalkyl; wherein each of said group can be unsubstituted or substituted with one or more R2, wherein each R2is independently selected from the group comprising halo, haloCiwalkyl, hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, (R8)2N-carbonyl, and C1- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl;R8is selected from hydrogen, or Ci-ealkyl;with the proviso that said compound is not2. The compound according to claim 1 , whereinR4is independently selected from the group comprising hydrogen, hydroxyl, halo, and Ci- 4alkoxy;L1is a single bond or -C(R5)2-; each R5is independently selected from hydrogen, or Ci-4alkyl;L3is -(C(R7)2)n-; wherein n is an integer selected from 1 or 2; each R7is independently selected from hydrogen, halo, or Ci-4alkyl.

3. The compound according to any one of claims 1-2, whereinR4is independently selected from the group comprising hydrogen, hydroxyl, halo, and Ci- 2alkoxy;L1is a single bond or -C(R5)2-; each R5is independently selected from hydrogen, or Ci-2alkyl;L3is -(C(R7)2)n-; wherein n is an integer selected from 1 or 2; each R7is independently selected from hydrogen, halo, or Ci-2alkyl.

4. The compound according to any one of claims 1-3, having structural formula (C1A3),wherein A1, L1, R4, R7and A2have the same meaning as that defined in any one of claims 1- 3.

5. The compound according to any one of claims 1-4, whereinA1is selected from the group comprising Cs-ecycloalkyl, Ce- aryl, 5-9 membered heteroaryl containing at least one N, O and / or S, and 5-9 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1;wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, C2-ealkenyl, C2-ealkynyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, Cs-ecycloalkyl, oxo, Ci- ealkylcarbonylamino, (R8)2N-, and (R8)2N-carbonyl;R8is selected from hydrogen, or Ci-ealkyl.

6. The compound according to any one of claims 1-5, whereinA2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, 5-6 membered saturated or partially saturated heterocyclyl, and C^cycloalkyl; wherein each of said group can be unsubstituted or substituted with one or more R2; wherein each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, (R8)2N-carbonyl, and C1- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl;R8is selected from hydrogen, or Ci-ealkyl.

7. The compound according to any one of claims 1-6, whereinA1is selected from the group comprising Cs-ecycloalkyl, Ce- aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and 5-6 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; wherein each of said group can be unsubstituted or substituted with one or more R1, for example one, two, three or four R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, oxo, Ci-ealkylcarbonylamino, (R8)2N-, and (R8)2N-carbonyl;A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, 5-6 membered saturated or partially saturated heterocyclyl, and Cs-ecycloalkyl; wherein each of said group can be unsubstituted or substituted with one or more R2, wherein each of said group can be unsubstituted or substituted with one or more R2, for example one, two, three or four R2, each R2is independently selected from the group comprising halo, haloCi-ealkyl, hydrogen, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, cyano,hydroxy, (R8)2N-, -SO2-R8, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, (R8)2N-carbonyl, and Ci-6alkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkylR8is selected from hydrogen, or Ci-ealkyl.

8. The compound according to any one of claims 1-7, wherein L3is -(CHR7)n-; wherein n is an integer selected from 1 or 2; each R7is independently selected from hydrogen, halo, or C1- 2alkyl.

9. The compound according to any one of claims 1-8, having structural formula (C1A4)wherein A1, L1, R4, and A2have the same meaning as that defined in any one of claims 1-8.

10. The compound according to any one of claims 1-9, having structural formula (C1A5),wherein A1, L1, and A2have the same meaning as that defined in any one of claims 1-9.

11. A compound selected from the group comprising the compounds Cpd C001 to Cpd C013, Cpd C017 to Cpd C031 , Cpd C037 to Cpd C043, Cpd C066 to Cpd C206, Cpd C209 to Cpd C219, Cpd C301 , Cpd C303, Cpd C306, Cpd C308 to Cpd C314, Cpd C316 to Cpd C318, Cpd C321 , Cpd C323 to Cpd C327, Cpd C334 to Cpd C336, Cpd C338, Cpd C339, Cpd C341 , Cpd C343 to Cpd C352, Cpd C354 to Cpd C390, Cpd C393 to Cpd C397, Cpd C401 to Cpd C406, Cpd C414 to Cpd C416, Cpd C419 to Cpd C424 as listed in Table 1C.

12. A pharmaceutical composition comprising a compound according to any one of claims 1-11 , and at least one pharmaceutical acceptable carrier.

13. A compound according to any one of claims 1-11 , or a pharmaceutical composition according to claim 12 for use as a medicine.

14. A compound according to any one of claims 1-11 , or a pharmaceutical composition according to claim 12, for use in the prevention and / or treatment of a neurodegenerative disorder.

15. A compound according to any one of claims 1-11 , or a pharmaceutical composition according to claim 12, for use in the prevention and / or treatment of a neurodegenerative disorder selected from the group consisting of Parkinson's disease, Alzheimer’s disease, diffuse Lewy body disease, amyotrophic lateral sclerosis, Niemann Pick disease, Hallervorden Spatz syndrome, Down syndrome, Pick’s disease, progressive supranuclear palsy, vascular dementia, neuroaxonal dystrophy, Huntington’s disease, frontotemporal lobar degeneration (FTLD), multiple system atrophy and Creutzfeldt-Jacob’s disease, preferably said neurodegenerative disorder is Alzheimer’s disease.

16. A compound of formula (C1), or a salt, a solvate, a hydrate, a polymorph, a tautomer, a racemate or a stereoisomer thereof; or a prodrug thereof, for use in the prevention and / or treatment of a neurodegenerative disorder, whereinII is N or C;V is selected from CH, N or NH; with the proviso that when II is N, V is CH; when V is N or NH, II is C;R3is absent or R3is hydrogen, or Ci-ealkyl;R4independently selected from the group comprising hydrogen, hydroxyl, halo, Ci-ealkoxy, and Ci-ealkyl;L1is a single bond or -C(R5)2-; each R5is independently selected from hydrogen, or Ci-ealkyl;L3is -(C(R7)2)n-; wherein n is an integer selected from 1 or 2; each R7is independently selected from hydrogen, hydroxyl, halo, or Ci-ealkyl;A1is selected from the group comprising Cs-ecycloalkyl, Ce-waryl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; wherein each of said group can be unsubstituted or substituted with one or more R1; wherein each R1is independently selected from the group comprising halo, Ci-ealkyl, haloCi-ealkyl, C2-ealkenyl, C2-ealkynyl, hydrogen, Ci-ealkoxy, haloCi-ealkoxy, cyano, hydroxy, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, Cs-ecycloalkyl, oxo, Ci- ealkylcarbonylamino, (R8)2N-, and (R8)2N-carbonyl; and / or two R1together with the atom(s) to which they are attached can form a 5-10 membered saturated or partially saturated heterocyclyl, or a Ce- aryl, a 5-10 membered heteroaryl;A2is selected from the group comprising 5-6 membered heteroaryl containing at least one N, O and / or S, phenyl, naphthyl, 5-6 membered saturated or partially saturated heterocyclyl, and Cs-ecycloalkyl; wherein each of said group can be unsubstituted or substituted with one or more R2, wherein each R2is independently selected from the group comprising halo, haloCiwalkyl, hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci -ealkoxy, haloCi-ealkoxy, cyano, hydroxy, (R8)2N-, -SO2-R8, carboxyl, Ci-ealkoxycarbonyl, Cs-ecycloalkyl, (R8)2N-carbonyl, and C1- ealkylcarbonylamino; and / or two R2together can form a -O-CR2aR2b-O-, wherein each R2a, R2bis independently selected from hydrogen, halo, or Ci-ealkyl; andR8is selected from hydrogen, or Ci-ealkyl.

17. The compound for use according to claim 16, for use in the prevention and / or treatment of a neurodegenerative disorder selected from the group consisting of Parkinson's disease, Alzheimer’s disease, diffuse Lewy body disease, amyotrophic lateral sclerosis, Niemann Pick disease, Hallervorden Spatz syndrome, Down syndrome, Pick’s disease, progressive supranuclear palsy, vascular dementia, neuroaxonal dystrophy, Huntington’s disease, frontotemporal lobar degeneration (FTLD), multiple system atrophy and Creutzfeldt-Jacob’s disease, preferably said neurodegenerative disorder is Alzheimer’s disease.

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