Novel inhibitors

Abstract

The present invention relates to compounds of formula (I), including all tautomers and stereoisomers thereof: ABDE(I) or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein: A is selected from monocyclic and bicyclic heteroaryl, which are independently optionally substituted by alkyl or amino; B is selected from alkyl, heteroalkyl, alkyl-amino, aryl, heteroaryl, cycloalkyl, heterocyclyl, and alkylene, which are independently optionally substituted by alkyl; D is selected from aryl-amino, heteroaryl-amino, cycloalkyl-amino, heterocyclyl, heterocyclyl-amino, urea, thioamide, thiourea, sulfonamide, sulfoximine, and sulfamoyl, where the aryl, heteroaryl, cycloalkyl, and heterocyclyl groups are independently optionally substituted; and E is selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl, where the aryl, heteroaryl, cycloalkyl, and heterocyclyl groups are independently optionally substituted. The compounds of formula (I) are inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC converts the N-terminal glutamine residue to pyroglutamic acid (5-oxo-prolyl, pGlu) with the release of ammonia. * ) and the intramolecular cyclization of the N-terminal glutamic acid residue to pyroglutamic acid with the release of water. [Selection diagram] None

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to novel heterocyclic derivatives as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC converts the N-terminal glutamine residue to pyroglutamic acid (5-oxo-prolyl, pGlu * ) and the intramolecular cyclization of the N-terminal glutamic acid residue to pyroglutamic acid with the release of water. [Background technology]

[0002] BACKGROUND OF THEINVENTION Glutaminyl cyclase (QC, EC 2.3.2.5) converts N-terminal glutamine residues to pyroglutamic acid (pGlu *QC was first isolated in 1963 by Messer from the latex of the tropical plant Carica papaya (Messer, M. 1963 Nature 4874, 1299). Twenty-four years later, the corresponding enzymatic activity was found in animal pituitaries (Busby, WHJ et al. 1987 J Biol Chem 262, 8532-8536; Fischer, WH and Spiess, J. 1987 Proc Natl Acad Sci USA 84, 3628-3632). Concerning mammalian QC, the conversion of Gln to pGlu by QC could be demonstrated for the precursors of TRH and GnRH (Busby, WHJ et al. 1987 J Biol Chem 262, 8532-8536; Fischer, WH and Spiess, J. 1987 Proc Natl Acad Sci USA 84, 3628-3632). Furthermore, early QC localization experiments revealed colocalization with putative catalytic products in bovine pituitary gland, further enhancing the suggested function in peptide hormone synthesis (Bockers, TM et al. 1995 J Neuroendocrinol 7, 445-453). In contrast, the physiological function of QC in plants is less clear. In the case of the enzyme from papaya, a role in plant defense against pathogenic microorganisms was suggested (El Moussaoui, A. et al. 2001 Cell Mol Life Sci 58, 556-570). Putative QCs from other plants have recently been identified by sequence comparison (Dahl, SW et al. 2000 Protein Expr Purif 20, 27-36). However, the physiological functions of these enzymes remain obscure.

[0003] Known QCs from plants and animals showed strict specificity for L-glutamine at the N-terminal position of the substrate, and their kinetic behavior was found to follow the Michaelis-Menten equation (Pohl, T. et al., 1991 Proc Natl Acad Sci USA 88, 10059-10063; Consalvo, AP et al., 1988 Anal Biochem 175, 131-138; Gololobov, MY et al., 1996 Biol Chem Hoppe Seyler 377, 395-398). However, comparison of the primary structure of QC from papaya with that of highly conserved QCs from mammals did not reveal any sequence homology (Dahl, SW et al., 2000 Protein Expr Purif 20, 27-36). Whereas plant QC appears to belong to a new enzyme family (Dahl, SW et al. 2000 Protein Expr Purif 20, 27-36), mammalian QC was found to have significant sequence homology with bacterial aminopeptidases (Bateman, RC et al. 2001 Biochemistry 40, 11246-11250), leading to the conclusion that plant and animal QC have different evolutionary origins.

[0004] Recently, recombinant human QC, as well as QC activity from brain extracts, have been shown to catalyze both N-terminal glutaminyl and glutamic acid cyclizations. Most striking is the finding that cyclase-catalyzed Glu1-conversion is favored around pH 6.0, whereas Gln1-conversion to pGlu-derivatives occurs with an optimum pH of around 8.0. Since the formation of pGlu-Aβ-related peptides can be suppressed by inhibition of recombinant human QC and QC activity from porcine pituitary extracts, the enzyme QC is a target for drug development for the treatment of Alzheimer's disease.

[0005] Inhibitors of QC are described, for example, in WO 2004 / 098625, WO 2004 / 098591, WO 2005 / 039548, WO 2005 / 075436, WO 2008 / 055945, WO 2008 / 055947, WO 2008 / 055950, WO2008 / 065141, WO 2008 / 110523, WO 2008 / 128981, WO 2008 / 128982, WO 2008 / 128983, WO 2008 / 128984, WO 2008 / 128985, WO Nos. 2008 / 128986, 2008 / 128987, WO 2010 / 026212, WO 2011 / 029920, WO 2011 / 107530, WO 2011 / 110613, WO 2011 / 131748, and WO 2012 / 123563.

[0006] EP 02 011 349.4 discloses polynucleotides encoding insect glutaminyl cyclases, and the polypeptides encoded thereby, and their use in screening methods for agents that reduce glutaminyl cyclase activity. Such agents are useful as insecticides.

[0007] (definition) "k i " or "K I " and "K D The term "binding constant" refers to the binding of an inhibitor to an enzyme and its subsequent release from the enzyme. Another measure is the "IC 50 " value, which reflects the inhibitor concentration that results in 50% enzyme activity at a given substrate concentration.

[0008] The term "DP IV inhibitor" or "dipeptidyl peptidase IV inhibitor" is well known to those skilled in the art and refers to an enzyme inhibitor that inhibits the catalytic activity of DP IV or a DP IV-like enzyme.

[0009] "DP IV activity" is defined as the catalytic activity of dipeptidyl peptidase IV (DP IV) and DP IV-like enzymes, which are post-proline (and to a lesser extent, post-alanine, post-serine, or post-glycine) cleaving serine proteases found in various tissues of the mammalian body, including kidney, liver, and intestine, where they remove dipeptides with high specificity from the N-terminus of bioactive peptides when a proline or alanine forms the residue adjacent to the N-terminal amino acid of the peptide sequence.

[0010] The term "PEP inhibitor" or "prolyl endopeptidase inhibitor" is well known to those skilled in the art and refers to an enzyme inhibitor that inhibits the catalytic activity of prolyl endopeptidase (PEP, prolyl oligopeptidase, POP).

[0011] "PEP activity" is defined as the catalytic activity of an endoprotease capable of hydrolyzing a post-proline bond in a peptide or protein where a proline is located 3 or more amino acid positions from the N-terminus of the peptide or protein substrate.

[0012] The term "QC" as used herein includes glutaminyl cyclase (QC) and QC-like enzymes. QC and QC-like enzymes have the same or similar enzymatic activity, which is further defined as QC activity. In this regard, QC-like enzymes may differ fundamentally from QC in their molecular structure. Examples of QC-like enzymes are glutaminyl-peptide cyclotransferase-like proteins (QPCTLs) from human (GenBank NM_017659), mouse (GenBank BC058181), cynomolgus monkey (Macaca fascicularis) (GenBank AB168255), rhesus monkey (Macaca mulatta) (GenBank XM_001110995), dog (Canis familiaris) (GenBank XM_541552), brown rat (Rattus norvegicus) (GenBank XM_001066591), house mouse (Mus musculus) (GenBank BC058181), and bovine (Bos taurus) (GenBank BT026254).

[0013] As used herein, the term "QC activity" refers to the conversion of N-terminal glutamine residues to pyroglutamic acid (pGlu * ) or the intramolecular cyclization of N-terminal L-homoglutamine or L-β-homoglutamine to cyclic pyro-homoglutamine derivatives. See therefore Schemes 1 and 2. (Scheme 1: Cyclization of glutamine by QC) [ka] (Scheme 2: Cyclization of L-homoglutamine by QC) [ka]

[0014] The term "EC" as used herein includes the activity of QC and QC-like enzymes as glutamate cyclase (EC), further defined as EC activity.

[0015] As used herein, the term "EC activity" refers to the conversion of N-terminal glutamic acid residues to pyroglutamic acid (pGlu * ) is defined as the intramolecular cyclization to the corresponding aryl group. See therefore Scheme 3. (Scheme 3: N-Terminal Cyclization of Uncharged Glutamyl Peptides with QC (EC)) [ka]

[0016] The terms "QC inhibitors" and "glutaminyl cyclase inhibitors" are well known to those skilled in the art and refer to enzyme inhibitors which inhibit the catalytic activity of glutaminyl cyclase (QC) or its glutamyl cyclase (EC) activity.

[0017] (Efficacy of QC inhibition) In a preferred embodiment, taking into account the correlation with QC inhibition, the subject methods and medical uses include the IC 50 More preferably, the K is 10 μM or less, more preferably, 1 μM or less, even more preferably, 0.1 μM or less or 0.01 μM or less, or most preferably, 0.001 μM or less. i Inhibitors with values ​​in the lower μM, preferably nM, and even more preferably pM ranges are envisaged. Thus, for convenience, the active agents are described herein as "QC inhibitors", although it will be understood that such terminology is not intended to limit the subject matter of the present invention to a particular mechanism of action.

[0018] (Molecular weight of QC inhibitor) In general, the QC inhibitors of the subject methods or medical uses will be small molecules, e.g. with a molecular weight of 500 g / mol or less, 400 g / mol or less, preferably 350 g / mol or less, even more preferably 300 g / mol or less and even 250 g / mol or less.

[0019] The term "subject" as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0020] As used herein, the term "therapeutically effective amount" means an amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue system, animal, or human that is being sought by a researcher, veterinarian, physician, or other clinician, including alleviation of the symptoms of the disease or disorder being treated.

[0021] As used herein, the term "pharmaceutical acceptable" encompasses both human and veterinary use: for example, the term "pharmaceutical acceptable" encompasses a compound that is veterinarily acceptable or a compound that is acceptable in human medicine and medical practice.

[0022] Throughout this specification and claims, the term "alkyl" is used in the following sense unless otherwise specified. 1-12 Alkyl groups, preferably C 1-8 Alkyl groups, e.g., C 1-6 Alkyl groups, e.g., C 1-4The alkyl group is shown. The alkyl group may be linear or branched. Suitable alkyl groups include, for example, methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, iso-butyl, sec-butyl, and tert-butyl), pentyl (e.g., n-pentyl), hexyl (e.g., n-hexyl), heptyl (e.g., n-heptyl), and octyl (e.g., n-octyl). The term "alk" in, for example, "alkoxy", "haloalkyl", and "thioalkyl" should be interpreted according to the definition of "alkyl". Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy), butoxy (e.g., n-butoxy), pentoxy (e.g., n-pentoxy), hexoxy (e.g., n-hexoxy), heptoxy (e.g., n-heptoxy), and octoxy (e.g., n-octoxy). Exemplary thioalkyl groups include methylthio-. Exemplary haloalkyl groups include fluoroalkyl, such as CF3.

[0023] The term "alkylene" means a group of the formula -(CH2) n In the formula, n is an integer, for example, 1 to 5, unless otherwise specified.

[0024] The term "cycloalkyl" means, unless otherwise specified, C 3-10 Cycloalkyl groups (i.e., 3 to 10 ring carbon atoms), more preferably C 3-8 Cycloalkyl groups, such as C 3-6 The cycloalkyl group is shown. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The most preferred number of ring carbon atoms is 3 to 6.

[0025] The term "heterocyclyl", unless otherwise limited, refers to a carbocyclyl group in which one or more (e.g., 1, 2 or 3) ring atoms are replaced by a heteroatom selected from N, S, and O. Specific examples of heterocyclyl groups are cycloalkyl groups in which one or more (e.g., 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by a heteroatom selected from N, S, or O (e.g., cyclopentyl, or more particularly, cyclohexyl). Exemplary heterocyclyl groups containing one heteroatom include pyrrolidine, tetrahydrofuran, and piperidine, and exemplary heterocyclyl groups containing two heteroatoms include morpholine, piperazine, dioxolane, and dioxane. Further particular examples of heterocyclyl groups are cycloalkenyl groups (e.g. cyclohexenyl groups) in which one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by a heteroatom selected from N, S, and O. An example of such a group is dihydropyranyl (e.g. 3,4-dihydro-2H-pyran-2-yl-).

[0026] The term "aryl" means, unless otherwise specified, C 6-12 Aryl groups, preferably C 6-10 Aryl groups, more preferably C 6-8 The aryl group is shown. The aryl group contains at least one aromatic ring (e.g., 1, 2, or 3 rings). A typical example of an aryl group having one aromatic ring is phenyl. A typical example of an aryl group having two aromatic rings is naphthyl.

[0027] The term "heteroaryl", unless otherwise limited, refers to an aryl residue in which one or more (e.g., 1, 2, 3, or 4, preferably 1, 2, or 3) ring atoms are replaced by a heteroatom selected from N, S, and O, or a 5-membered aromatic ring containing one or more (e.g., 1, 2, 3, or 4, preferably 1, 2, or 3) ring atoms selected from N, S, and O. Exemplary monocyclic heteroaryl groups having one heteroatom include: 5-membered rings (e.g., pyrrole, furan, thiophene); and 6-membered rings (e.g., pyridine, such as pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl). Exemplary monocyclic heteroaryl groups having two heteroatoms include: 5-membered rings (e.g., pyrazole, oxazole, isoxazole, thiazole, isothiazole, imidazole, e.g., imidazol-1-yl, imidazol-2-yl, imidazol-4-yl); 6-membered rings (e.g., pyridazine, pyrimidine, pyrazine). Exemplary monocyclic heteroaryl groups having three heteroatoms include: 1,2,3-triazole and 1,2,4-triazole. Exemplary monocyclic heteroaryl groups having four heteroatoms include tetrazole. Exemplary bicyclic heteroaryl groups include: indole (e.g., indol-6-yl), benzofuran, benzthiophene, quinoline, isoquinoline, indazole, benzimidazole, benzthiazole, quinazoline, and purine.

[0028] The term "-alkylaryl" refers to an alkylene moiety, e.g., C 1-4 The aryl residues are connected via an alkylene moiety.

[0029] The term "-alkylheteroaryl" refers to an alkylene moiety, e.g., C 1-4 Represents a heteroaryl residue attached via an alkylene moiety.

[0030] The term "halogen" or "halo" includes fluorine (F), chlorine (Cl), and bromine (Br).

[0031] The term "amino" refers to the group --NH.

[0032] Benzimidazolyl: [ka] When the compound is shown as benzimidazol-5-yl, which is represented as: [ka] It will be recognized that benzimidazol-6-yl, represented as: is an equivalent structure. As used herein, the two forms of benzimidazolyl are encompassed by the term "benzimidazol-5-yl."

[0033] (stereoisomer:) All possible stereoisomers of the claimed compounds are included in the present invention.

[0034] When the compound according to the present invention has at least one chiral center, the compound can exist accordingly as enantiomers.When the compound has two or more chiral centers, the compound can also exist as diastereomers.It should be understood that all such isomers and their mixtures are included within the scope of the present invention.

[0035] Preparation and isolation of stereoisomers: When the preparation process of the compounds according to the invention gives rise to a mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. The compounds can be prepared in racemic form, or the individual enantiomers can be prepared either by enantiospecific synthesis or by resolution. The compounds can be resolved into their component enantiomers by standard techniques, such as, for example, salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and / or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base to form diastereomeric pairs. The compounds can also be resolved by the formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using a chiral HPLC column.

[0036] (Pharmaceutically acceptable salts: In view of the close relationship between a free compound and a compound in the form of its salt or solvate, whenever a compound is mentioned in this context, the corresponding salt, solvate or polymorph is also intended, provided that such are possible or appropriate under the circumstances.

[0037] Salts and solvates of the compounds of formula (I) and their physiologically functional derivatives which are suitable for use in medicine are those in which the counterion or associated solvent is pharma- ceutically acceptable. However, salts and solvates having pharma-ceutically unacceptable counterions or associated solvents are also within the scope of the invention, for example for use as intermediates in the preparation of other compounds and their pharma-ceutically acceptable salts and solvates.

[0038] Suitable salts according to the invention include those formed with both organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, triphenylacetic acid, sulfamic acid, sulfanilic acid, succinic acid, oxalic acid, fumaric acid, maleic acid, malic acid, mandelic acid, glutamic acid, aspartic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, arylsulfonic acids (e.g., p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, or naphthalenedisulfonic acid), salicylic acid, glutaric acid, gluconic acid, tricarballylic acid, cinnamic acid, substituted cinnamic acids (e.g., phenyl, including 4-methyl and 4-methoxycinnamic acid), and the like. 1,4-benzenediacrylic acid), ascorbic acid, oleic acid, naphthoic acid, hydroxynaphthoic acid (e.g., 1- or 3-hydroxy-2-naphthoic acid), naphthaleneacrylic acid (e.g., naphthalene-2-acrylic acid), benzoic acid, 4-methoxybenzoic acid, 2- or 4-hydroxybenzoic acid, 4-chlorobenzoic acid, 4-phenylbenzoic acid, benzeneacrylic acid (e.g., 1,4-benzenediacrylic acid), isethionic acid, perchloric acid, propionic acid, glycolic acid, hydroxyethanesulfonic acid, pamoic acid, cyclohexanesulfamic acid, salicylic acid, saccharic acid, and trifluoroacetic acid. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, e.g., alkali metal salts of sodium and potassium, alkaline earth metal salts, e.g., alkaline earth metal salts of calcium and magnesium, and salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine.

[0039] All pharma- ceutically acceptable acid addition salt forms of the compounds of the present invention are intended to be embraced by the scope of this invention.

[0040] (Polymorphic crystal form:) In addition, some of the crystalline forms of the compounds may exist as polymorphs, and as such are intended to be included in the present invention.In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be included within the scope of the present invention.The compounds, including their salts, may also be obtained in the form of their hydrates, or may include other solvents used in their crystallization.

[0041] (Prodrug:) The present invention further includes within its scope prodrugs of the compounds of the present invention. In general, such prodrugs are functional derivatives of the compounds that are easily convertible in vivo into the desired therapeutically active compound. Thus, in these cases, the term "administering" in the treatment method of the present invention is intended to encompass the treatment of the various disorders described with one or more of the claimed compounds, but in a prodrug form that is converted in vivo into the above-identified compound after administration to a subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs" edited by H. Bundgaard (Elsevier, 1985).

[0042] (Protecting group:) During any of the processes for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be achieved by conventional protecting groups, such as those described in "Protective Groups in Organic Chemistry" edited by JFW McOmie (Plenum Press, 1973); and "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts (John Wiley & Sons, 1991), which are incorporated herein by reference in their entirety. The protecting groups can be removed at a later convenient stage using methods known in the art.

[0043] As used herein, the term "composition" is intended to encompass products containing a therapeutically effective amount of the claimed compounds, as well as any product resulting directly or indirectly from the combination of the claimed compounds.

[0044] (Carriers and additives for herbal medicines:) Thus, for example, for liquid oral preparations such as suspensions, elixirs, and solutions, suitable carriers and additives may advantageously include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like; for example, for solid oral preparations such as powders, capsules, gelcaps, and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like.

[0045] Carriers that may be added to the mixture include necessary and inert pharmaceutical excipients, including, but not limited to, suitable binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, coatings, disintegrants, dyes, and colorants.

[0046] Soluble polymers as targetable drug carriers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamide-phenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. In addition, the compounds of the present invention can be coupled to classes of biodegradable polymers useful for achieving controlled release of drugs, such as polyactic acid, polyepsiloncaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0047] Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.

[0048] The disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like. Summary of the Invention

[0049] Description of the Invention According to the present invention there is provided a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers thereof: [ka] (In the formula: A is selected from monocyclic and bicyclic heteroaryl, which are optionally substituted independently by alkyl or amino; B is selected from alkyl, heteroalkyl, alkyl-amino, aryl, heteroaryl, cycloalkyl, heterocyclyl, and alkylene, wherein said groups are optionally and independently substituted with alkyl; D is selected from aryl-amino, heteroaryl-amino, cycloalkyl-amino, heterocyclyl, heterocyclyl-amino, urea, thioamide, thiourea, sulfonamide, and sulfoximine, wherein the aryl, heteroaryl, cycloalkyl, and heterocyclyl groups are optionally independently substituted with one or more substituents.

[0050] In another embodiment, D is sulfamoyl; E is selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl, where the aryl, heteroaryl, cycloalkyl, and heterocyclyl groups are optionally independently substituted with one or more substituents.

[0051] In a preferred embodiment, there is provided a compound of formula (I) wherein i) when B is alkyl or heteroalkyl, D may not be a sulfonamide; and ii) The compound of formula (I) is [ka] The compound is not selected from the group consisting of

[0052] Compounds of condition i) are known from the CAS Registry database without a functional definition and are selected from: [Table 1] TIFF0007674811000009.tif221170

[0053] In a preferred embodiment according to proviso i), the compound of formula (I) is not a compound selected from compounds AU.

[0054] Compound V under condition ii) is known from the CAS registry of CAS number 2117405-13-5 without functional definition. Compound W under condition ii) is known from the CAS registry of CAS number 1090606-68-0 without functional definition. Compound W under condition ii) is known from the CAS registry of CAS number 2093539-54-7 without functional definition.

[0055] When A is monocyclic heteroaryl, A is preferably selected from thiadiazolyl, for example 1,3,4-thiadiazolyl, thiazolyl, and triazolyl, for example 1,2,4-triazolyl.In one embodiment of the present invention, the monocyclic heteroaryl is substituted by amino or methyl.In another embodiment, the monocyclic heteroaryl is unsubstituted.

[0056] When cycloalkyl and heterocyclyl are substituted, they are typically substituted by one or two substituents (e.g., one substituent). Typically, the substituent is C 1-6 It is preferably alkyl (i.e. methyl) or halogen (i.e. chlorine or fluorine).More typically, the cycloalkyl and heterocyclyl groups are unsubstituted.

[0057] When aryl and heteroaryl are substituted, they are typically substituted with 1, 2, or 3 (e.g., 1 or 2) substituents. The substituents of aryl and heteroaryl are C 1-6 Alkyl (e.g., methyl), C 2-6 Alkenyl (e.g. buten-3-yl), C 2-6 Alkynyl (e.g., butyn-3-yl), C 1-6 Haloalkyl (e.g., fluoromethyl, trifluoromethyl), -C 1-6 Thioalkyl (e.g., -S-methyl), -SOC 1-4 Alkyl (e.g., -SOmethyl), -SOC 1-4 Alkyl (e.g., -SO2 methyl), C 1-6 Alkoxy- (e.g., methoxy, ethoxy), -OC 3-8Cycloalkyl (e.g., -O-cyclopentyl or -O-cyclohexyl), C 3-8 Cycloalkyl (e.g., cyclopropyl, cyclohexyl), -SO2C 3-8 Cycloalkyl (e.g., -SO2 cyclohexyl), -SOC 3-6 Cycloalkyl (e.g., -SOcyclopropyl), -O-aryl (e.g., -O-phenyl)C 3-6 alkenyloxy- (e.g., -O-buten-2-yl), C 3-6 Alkynyloxy- (e.g., -O-buten-2-yl), -C(O)C 1-6 Alkyl (e.g., -C(O)ethyl), -C(O)OC 1-6 Alkyl (e.g., -C(O)O-methyl), C 1-6 Alkoxy-C 1-6 Alkyl- (e.g., methoxy-ethyl-), nitro, halogen (e.g., fluoro, chloro, bromo), cyano, hydroxyl, -C(O)OH, -NH2, -NHC 1-4 Alkyl (e.g., -NHmethyl), -N(C 1-4 Alkyl)(C 1-4 alkyl) (e.g., -N(methyl)2), -C(O)N(C 1-4 Alkyl)(C 1-4 alkyl) (e.g., -C(O)N(methyl)2), -C(O)NH2, -C(O)NH(C 1-4 alkyl) (e.g., -C(O)NHmethyl), -C(O)NH(C 3-10 cycloalkyl) (e.g., —C(O)NHcyclopropyl). More typically, the substituents are selected from 1-6 Alkyl (e.g., methyl), C 1-6 Haloalkyl (e.g., C 1-6 Fluoroalkyl, e.g., CF3), C 1-6 selected from alkoxy (e.g., OMe), halogen, and hydroxy

[0058] When E represents aryl, it preferably represents optionally substituted phenyl. Exemplary substituted phenyl groups for E include 2-bromophenyl, 2-bromo-4-fluorophenyl-, 2-bromo-5-fluorophenyl-, 2-fluoro-5-bromophenyl, 2-chlorophenyl-, 2-fluorophenyl-, 3-chlorophenyl-, 3-bromophenyl-, 3-fluorophenyl-, 4-chlorophenyl-, 4-fluorophenyl-, 4-bromophenyl-, 4-bromo-2-fluorophenyl, 2-chloro-3,6-difluorophenyl), 2,3-dichlorophenyl-, 2,3-difluorophenyl. nyl-, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,4-dichlorophenyl-, 2,4-difluororophenyl-, 2,4,6-trifluorophenyl-, 2,5-dichlorophenyl-, 2,6-dichlorophenyl-, 2,6-difluorophenyl-, 3,4-dichlorophenyl-, 3,4-difluorophenyl-, 3,5-difluorophenyl-, 2,4,5-trifluorophenyl-, 3,4,5-trifluorophenyl-, 2,4-dimethyl phenyl, 3-methylphenyl, 3,4-dimethylphenyl, 4-methylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 2,4,6-trimethylphenyl, 2-isopropyl-6-methylphenyl, 2-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2,4-bis(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 2-methoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl E may represent unsubstituted phenyl-, 3-methoxyphenyl-, 4-methoxyphenyl-, 4-ethoxyphenyl-, 4-propoxyphenyl-, 4-butoxyphenyl-, 4-pentoxyphenyl-, 4-isopropyloxyphenyl-, 3-(cyclopentyloxy)-4-methoxyphenyl-, 3,4,5-trimethoxyphenyl-, 3,4-dimethoxyphenyl-, 3,5-dimethoxyphenyl-, 4-tetrafluoroethyloxyphenyl, 4-cyanophenyl-, 4-thiomethylphenyl-, and 4-dimethylaminophenyl. Alternatively, E may represent unsubstituted phenyl-.Further exemplary substituted phenyl groups include 2,3-difluoro-4-methylphenyl, 2-fluoro-5-(trifluoromethyl)phenyl-, 2-hydroxy-3-methoxyphenyl-, 2-hydroxy-5-methylphenyl-, 3-fluoro-4-(trifluoromethyl)phenyl-, 3-fluoro-5-(trifluoromethyl)phenyl-, 2-fluoro-4-(trifluoromethyl)phenyl-, 2-fluoro-3-(methyl)phenyl-, 3-fluoro-4-(methoxy)phenyl-, 3-hydroxy-4-methoxyphenyl-, 4-chloro-3-(trifluoromethyl)phenyl-, 4-chloro-3-methylphenyl, 4-bromo-4-ethylphenyl, 2,3,5,6-tetrafluoro-4-(methyl)phenyl-, 2,6-difluoro-4-(methoxy)phenyl-, and 2-fluoro-4,5-(dimethoxy)phenyl-.

[0059] When E represents an optionally substituted heteroaryl, examples include pyridinyl (e.g., pyridin-2-yl and pyridin-4-yl) and pyrimidinyl. Particular substituents that may be mentioned are one or more, for example 1, 2 or 3, groups selected from halogen, hydroxyl, alkyl (e.g., methyl), and alkoxy- (e.g., methoxy-). An exemplary substituted ring is 1-oxy-pyridin-4-yl-.

[0060] In a more preferred embodiment, when A is a monocyclic heteroaryl, A is [ka] is selected from.

[0061] In the most preferred embodiment, when A is a monocyclic heteroaryl, A is [ka] It is.

[0062] In a further most preferred embodiment, when A is a monocyclic heteroaryl, A is [ka] It is.

[0063] In a further most preferred embodiment, when A is a monocyclic heteroaryl, A is [ka] It is.

[0064] When A is a bicyclic heteroaryl it is suitably selected from benzimidazole and imidazopyridine, for example imidazo[1,2-a]pyridine.

[0065] In a more preferred embodiment, when A is a bicyclic heteroaryl, A is [ka] is selected from.

[0066] In a most preferred embodiment, when A is a bicyclic heteroaryl, A is [ka] It is.

[0067] In a further most preferred embodiment, when A is a bicyclic heteroaryl, A is [ka] It is.

[0068] In a further most preferred embodiment, when A is a bicyclic heteroaryl, A is [ka] It is.

[0069] In a preferred embodiment, B is C 3-5-heteroalkyl, phenyl, C5-C6-heterocyclyl, and C 1-5 alkylene, wherein the C 1-5 The alkylene groups may be independently substituted with alkyl.

[0070] More preferably, B is [ka] (wherein X1 is alkyl, N, O, or S, preferably methyl or S; and n is an integer selected from 1 and 2); [ka] (wherein o is 0 or 1; and p is 0 or 1); and [ka] (wherein R1 is hydrogen or alkyl, and q is 0, 1, or 2). is selected from.

[0071] In the most preferred embodiment, B is [ka] where X1 and n are as defined above.

[0072] In a further most preferred embodiment, B is [ka] where o is as defined above.

[0073] In a further most preferred embodiment, B is [ka] where R1 and p are as defined above.

[0074] In a preferred embodiment, D is [ka] is a group selected from Where: R is absent or hydrogen; or R together with the nitrogen atom form a heterocyclic ring of group B; R2 is hydrogen, alkyl, or cycloalkyl; Y1, Y2, Y3, and Y4 are independently selected from CH, N, S, and O.

[0075] D, [ka] When R is preferably absent, R2 is preferably hydrogen or alkyl.

[0076] D, [ka] When R is preferably hydrogen.

[0077] In a further embodiment, D is [ka] where R is hydrogen or alkyl.

[0078] In a further preferred embodiment, when D is one of the above groups, R together with the nitrogen to which it is attached forms a heterocyclic ring of the group B. More preferably, the heterocyclic ring formed by the NR group is selected from piperidine, pyrrolidine, tetrahydrofuran, morpholine, piperazine, dioxolane, and dioxane. Most preferably, when D is one of the above groups, R together with the nitrogen to which it is attached forms the structure [ka] A piperidine ring having the formula:

[0079] D, [ka] In this case, Y1 to Y4 are preferably CH or N.

[0080] In a more preferred embodiment, Y1 to Y4 are all CH. Even more preferably, one of Y1 to Y4 is N and the other three are CH. In further more preferred embodiments, two of Y1-Y4 are N and the other two are CH. Even more preferably, three of Y1 to Y4 are N and the other one is CH. Even more preferably, Y1 to Y4 are all N. When Y4 is CH, it may be substituted or unsubstituted. In a preferred embodiment, Y4 is CH and is unsubstituted. In another preferred embodiment, Y4 is CH and is substituted. When Y4 is CH and is substituted, Y4 is preferably substituted with halogen or alkyl, most preferably with fluorine or methyl.

[0081] E is preferably [ka] and Where: Y5 is C; Y6~Y 10 is independently selected from CH, N, or O; and R3, R4, R5, R6, and R7 are independently selected from hydrogen, halogen, alkyl, and O-alkyl.

[0082] In a preferred embodiment, Y 10is independently selected from CH and N.

[0083] In a preferred embodiment, R3, R4, R5, R6, and R7 are independently selected from hydrogen, halogen, and O-alkyl.

[0084] In a further preferred embodiment, R3, R4, R5, R6, and R7 are independently selected from O-phenyl and O-cycloalkyl.

[0085] When R3, R4, R5, R6, and R7 are independently halogen, R3, R4, R5, R6, and R7 are preferably fluorine or chlorine, most preferably fluorine.

[0086] When R3, R4, R5, R6, and R7 are independently O-alkyl, R3, R4, R5, R6, and R7 are independently O-alkyl. 1-4 Alkyl is preferably methoxy, ethoxy, propoxy, or butoxy, more preferably methoxy or propoxy.

[0087] When R3, R4, R5, R6, and R7 are independently O-alkyl, R3, R4, R5, R6, and R7 are more most preferably methoxy.

[0088] R3, R4, R5, R6, and R7 may be independently substituted or unsubstituted. Preferably, up to three of R3 to R7 are substituted, and the other one is hydrogen.

[0089] In a most preferred embodiment, E represents a pyridine ring, where Y6 to Y 10 One of them is N and the other is CH.

[0090] In another most preferred embodiment, E represents a pyridine ring, where Y6 to Y 10 Two of them are N and the other one is CH.

[0091] The pyrimidine ring may be optionally substituted with halo or alkyl, preferably fluorine and methoxy.

[0092] In a particularly preferred embodiment, there is provided a compound of formula (I), which is a compound of formula (IIa) or formula (IIb), or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers thereof: [ka] (In the formula, Z is selected from CH and N; X1 is selected from alkyl, N, O, S, preferably CH2 and S; n is 1 or 2; Y1 to Y4 and Y6 to Y 10 is independently selected from CH, N, S, and O, preferably CH and N; Y5 is C; R5 is selected from halogen, alkyl, and O-alkyl, preferably from fluorine and methoxy; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy.

[0093] In a preferred embodiment, Z is CH. In another preferred embodiment, Z is N. Most preferably, X1 is CH2. Even most preferably, X1 is S. Most preferably, n is 1.

[0094] Preferably, one, two, three, or all four of Y1, Y2, Y3, and Y4 are N. In a more preferred embodiment, Y1, Y2, Y3, and Y4 are CH; or Y1 is N and Y2, Y3 and Y4 are CH; or Y1 and Y2 are N and Y3 and Y4 are CH; or Y1 is CH, Y2 is N and Y3 and Y4 are CH; or Y1 and Y3 are N and Y2 and Y4 are CH; or Y1 and Y3 are CH and Y2 and Y4 are N; or Y1 and Y2 are CH and Y3 and Y4 are N; or Y1, Y2, and Y3 are CH and Y4 is N.

[0095] Preferably, Y6 to Y 10 One or two of the above are N, and Y6 to Y 10 The other one is CH. In a more preferred embodiment, Y6, Y7, Y8, Y9, and Y 10 is CH; or Y6 is N, and Y7, Y8, Y9, and Y 10 is CH; or Y6 is CH, Y7 is N, and Y8, Y9, and Y 10 is CH; or Y6 is N, Y7, Y8, and Y9 are CH, and Y 10 is N; or Y6 and Y7 are N, and Y8, Y9, and Y 10 is CH; or Y6 is CH, Y7 is N, Y8 is CH, Y9 is N, and Y 10 is CH; or Y6 and Y7 are CH, Y8 is N, Y9 is CH, and Y 10 is N; or Y6 and Y7 are CH, Y8 is N, and Y9 and Y 10 is CH; or Y6 is N, Y7 and Y8 are CH, Y9 is N, and Y 10 is CH.

[0096] R5 is preferably hydrogen, fluorine or methoxy. R6 is preferably hydrogen or methoxy. More preferably, R5 and R6 are both hydrogen; or R5 is fluorine and R6 is hydrogen; or · R5 and R6 are both methoxy.

[0097] In a further particularly preferred embodiment, there is provided a compound of formula (I), which is a compound of formula (IIIa) or formula (IIIb), or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers thereof: [ka] (In the formula, X1 is selected from alkyl, N, O, S; n is 1 or 2; Y1 to Y4 and Y6 to Y 10 is independently selected from CH, N, S, and O, preferably CH and N; Y5 is C; R5 is selected from halogen, alkyl, and O-alkyl, preferably from fluorine and methoxy; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy.

[0098] Most preferably, X1 is CH2. Even most preferably, X1 is S. Most preferably, n is 1. Preferably, one, two, three, or all four of Y1, Y2, Y3, and Y4 are N. In a more preferred embodiment, Y1, Y2, Y3, and Y4 are CH; or Y1 is N and Y2, Y3 and Y4 are CH; or Y1 and Y2 are N and Y3 and Y4 are CH; or Y1 is CH, Y2 is N and Y3 and Y4 are CH; or Y1 and Y3 are N and Y2 and Y4 are CH; or Y1 and Y3 are CH and Y2 and Y4 are N; or Y1 and Y2 are CH and Y3 and Y4 are N; or Y1, Y2, and Y3 are CH and Y4 is N.

[0099] Preferably, Y6 to Y 10 One or two of the above are N, and Y6 to Y 10 The other one is CH. In a more preferred embodiment, Y6, Y7, Y8, Y9, and Y 10 is CH; or Y6 is N, and Y7, Y8, Y9, and Y 10 is CH; or Y6 is CH, Y7 is N, and Y8, Y9, and Y 10 is CH; or Y6 is N, Y7, Y8, and Y9 are CH, and Y 10 is N; or Y6 and Y7 are N, and Y8, Y9, and Y 10 is CH; or Y6 is CH, Y7 is N, Y8 is CH, Y9 is N, and Y 10 is CH; or Y6 and Y7 are CH, Y8 is N, Y9 is CH, and Y 10 is N; or Y6 and Y7 are CH, Y8 is N, and Y9 and Y 10 is CH; or Y6 is N, Y7 and Y8 are CH, Y9 is N, and Y 10 is CH.

[0100] R5 is preferably hydrogen, fluorine or methoxy. R6 is preferably hydrogen or methoxy. More preferably, R5 and R6 are both hydrogen; or R5 is fluorine and R6 is hydrogen; or · R5 and R6 are both methoxy.

[0101] In a further particularly preferred embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers thereof, which is a compound of formula (IVa) or formula (IVb): [ka] (In the formula, Z is selected from CH and N; o is 0 or 1; p is 0 or 1; Y1 to Y4 and Y6 to Y 10 is independently selected from CH, N, S, and O, preferably CH and N; Y5 is C; R5 is selected from halogen, alkyl, and O-alkyl, preferably from fluorine and methoxy; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy.

[0102] In a further embodiment, R5 is O-phenyl; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy. In a preferred embodiment, Z is CH. In another preferred embodiment, Z is N. Most preferably, o is 0. Most preferably, p is 0. In a further most preferred embodiment, p is 1.

[0103] Preferably, one, two, three, or all four of Y1, Y2, Y3, and Y4 are N. In a more preferred embodiment, Y1, Y2, Y3, and Y4 are CH; or Y1 is N and Y2, Y3 and Y4 are CH; or Y1 and Y2 are N and Y3 and Y4 are CH; or Y1 is CH, Y2 is N and Y3 and Y4 are CH; or Y1 and Y3 are N and Y2 and Y4 are CH; or Y1 and Y3 are CH and Y2 and Y4 are N; or Y1 and Y2 are CH and Y3 and Y4 are N; or Y1, Y2, and Y3 are CH and Y4 is N.

[0104] Preferably, Y6 to Y 10 One or two of the above are N, and Y6 to Y 10 The other one is CH. In a more preferred embodiment, Y6, Y7, Y8, Y9, and Y 10 is CH; or Y6 is N, and Y7, Y8, Y9, and Y 10 is CH; or Y6 is CH, Y7 is N, and Y8, Y9, and Y 10 is CH; or Y6 is N, Y7, Y8, and Y9 are CH, and Y 10 is N; or Y6 and Y7 are N, and Y8, Y9, and Y 10 is CH; or Y6 is CH, Y7 is N, Y8 is CH, Y9 is N, and Y 10 is CH; or Y6 and Y7 are CH, Y8 is N, Y9 is CH, and Y 10 is N; or Y6 and Y7 are CH, Y8 is N, and Y9 and Y 10 is CH; or Y6 is N, Y7 and Y8 are CH, Y9 is N, and Y 10 is CH.

[0105] R5 is preferably hydrogen, fluorine or methoxy. More preferably, R5 is propoxy or O-phenyl. R6 is preferably hydrogen or methoxy. More preferably, R5 and R6 are both hydrogen; or R5 is fluorine and R6 is hydrogen; or R5 is methoxy and R6 is hydrogen; or R5 and R6 are both methoxy; or R5 is propoxy and R6 is hydrogen; or ·R5 is O-phenyl and R6 is hydrogen.

[0106] In a further particularly preferred embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers thereof, which is a compound of formula (Va) or formula (Vb): [ka] (In the formula, o is 0 or 1; p is 0 or 1; Y1 to Y4 and Y6 to Y 10 is independently selected from CH, N, S, and O, preferably CH and N; Y5 is C; R5 is selected from halogen, alkyl, and O-alkyl, preferably from fluorine and methoxy; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy.

[0107] In a further embodiment, R5 is O-phenyl; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy. In a preferred embodiment, Z is CH. In another preferred embodiment, Z is N. Most preferably, o is 0. Most preferably, p is 0. In a further most preferred embodiment, p is 1.

[0108] Preferably, one, two, three, or all four of Y1, Y2, Y3, and Y4 are N. In a more preferred embodiment, Y1, Y2, Y3, and Y4 are CH; or Y1 is N and Y2, Y3 and Y4 are CH; or Y1 and Y2 are N and Y3 and Y4 are CH; or Y1 is CH, Y2 is N and Y3 and Y4 are CH; or Y1 and Y3 are N and Y2 and Y4 are CH; or Y1 and Y3 are CH and Y2 and Y4 are N; or Y1 and Y2 are CH and Y3 and Y4 are N; or Y1 and Y2 are CH; Y3 is N and Y4 is CH, or Y1, Y2, and Y3 are CH and Y4 is N.

[0109] Preferably, Y6 to Y 10 One or two of the above are N, and Y6 to Y 10 The other one is CH. In a more preferred embodiment, Y6, Y7, Y8, Y9, and Y 10 is CH; or Y6 is N, and Y7, Y8, Y9, and Y 10 is CH; or Y6 is CH, Y7 is N, and Y8, Y9, and Y 10is CH; or Y6 is N, Y7, Y8, and Y9 are CH, and Y 10 is N; or Y6 and Y7 are N, and Y8, Y9, and Y 10 is CH; or Y6 is CH, Y7 is N, Y8 is CH, Y9 is N, and Y 10 is CH; or Y6 and Y7 are CH, Y8 is N, Y9 is CH, and Y 10 is N; or Y6 and Y7 are CH, Y8 is N, and Y9 and Y 10 is CH; or Y6 is N, Y7 and Y8 are CH, Y9 is N, and Y 10 is CH.

[0110] R5 is preferably hydrogen, fluorine or methoxy. R6 is preferably hydrogen or methoxy. More preferably, R5 and R6 are both hydrogen; or R5 is fluorine and R6 is hydrogen; or · R5 and R6 are both methoxy.

[0111] In a further particularly preferred embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers thereof, which is a compound of formula (VI): [ka] (In the formula, Z is selected from CH and N; X1 is selected from alkyl, N, O, S, preferably CH2 or S; n is 1 or 2; R5 is selected from halogen, alkyl, and O-alkyl, preferably from fluorine and methoxy; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy.

[0112] In a preferred embodiment, Z is CH. In another preferred embodiment, Z is N. Most preferably, X1 is CH2. Even most preferably, X1 is S. Most preferably, n is 1.

[0113] R5 is preferably hydrogen, fluorine or methoxy. R6 is preferably hydrogen or methoxy. More preferably, R5 is fluorine and R6 is hydrogen; or · R5 and R6 are both methoxy.

[0114] In a further particularly preferred embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers thereof, which is a compound of formula (VII): [ka] (In the formula, Z is selected from CH and N; X1 is selected from alkyl, N, O, S, preferably CH2 or S; n is 1 or 2; R2 is selected from alkyl and cycloalkyl, preferably from methyl and cyclopropyl; R5 is selected from halogen, alkyl, and O-alkyl, preferably from fluorine and methoxy; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy.

[0115] In a preferred embodiment, Z is CH. In another preferred embodiment, Z is N. Most preferably, X1 is CH2. Even most preferably, X1 is S. Most preferably, n is 1. In a preferred embodiment, R2 is methyl. In a further preferred embodiment, R2 is cyclopropyl.

[0116] R5 is preferably hydrogen, fluorine or methoxy. R6 is preferably hydrogen or methoxy. More preferably, R5 is fluorine and R6 is hydrogen; or · R5 and R6 are both methoxy.

[0117] In a further particularly preferred embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers thereof, which is a compound of formula (VIII): [ka] (In the formula, X1 is selected from alkyl, N, O, S, preferably CH2 or S; n is 1 or 2; R5 is selected from halogen, alkyl, and O-alkyl, preferably from fluorine and methoxy; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy.

[0118] Most preferably, X1 is CH2. Even most preferably, X1 is S. Most preferably, n is 1. R5 is preferably hydrogen, fluorine or methoxy. R6 is preferably hydrogen or methoxy. More preferably, R5 is fluorine and R6 is hydrogen; or · R5 and R6 are both methoxy.

[0119] In a further particularly preferred embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers thereof, which is a compound of formula (IX): [ka] (In the formula, X1 is selected from alkyl, N, O, S, preferably CH2 or S; n is 1 or 2; R2 is selected from alkyl and cycloalkyl, preferably from methyl and cyclopropyl; R5 is selected from halogen, alkyl, and O-alkyl, preferably from fluorine and methoxy; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy.

[0120] Most preferably, X1 is CH2. Even most preferably, X1 is S. Most preferably, n is 1. In a preferred embodiment, R2 is methyl. In a further preferred embodiment, R2 is cyclopropyl. R5 is preferably hydrogen, fluorine or methoxy. R6 is preferably hydrogen or methoxy. More preferably, R5 is fluorine and R6 is hydrogen; or · R5 and R6 are both methoxy.

[0121] In a further particularly preferred embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, which is a compound of formula (X), including all tautomers and stereoisomers thereof: [ka] (In the formula, o is 0 or 1; R5 is selected from halogen, alkyl, and O-alkyl, preferably from fluorine and methoxy; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy.

[0122] Most preferably, o is 0. Most preferably, p is 0. Even more preferably, p is 1. R5 is preferably hydrogen, fluorine or methoxy. R6 is preferably hydrogen or methoxy. More preferably, R5 is fluorine and R6 is hydrogen; or · R5 and R6 are both methoxy.

[0123] In a further particularly preferred embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, which is a compound of formula (XI), including all tautomers and stereoisomers thereof: [ka] (In the formula, o is 0 or 1; R2 is selected from alkyl and cycloalkyl, preferably from methyl and cyclopropyl; R5 is selected from halogen, alkyl, and O-alkyl, preferably from fluorine and methoxy; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy.

[0124] Most preferably, o is 0. Most preferably, p is 0. Even more preferably, p is 1. In a preferred embodiment, R2 is methyl. In a further preferred embodiment, R2 is cyclopropyl. R5 is preferably hydrogen, fluorine or methoxy. R6 is preferably hydrogen or methoxy. More preferably, R5 is fluorine and R6 is hydrogen; or · R5 and R6 are both methoxy.

[0125] In a further particularly preferred embodiment, there is provided a compound of formula (I), which is a compound of formula (XIIa) or formula (XIIb), or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers thereof: [ka] (In the formula, Z is selected from CH and N; Y1 to Y4 and Y6 to Y 10 is independently selected from CH, N, S, and O, preferably CH and N; Y5 is C; R5 is selected from halogen, alkyl, and O-alkyl, preferably from fluorine and methoxy; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy.

[0126] In a preferred embodiment, Z is CH. In another preferred embodiment, Z is N.

[0127] Preferably, one, two, three, or all four of Y1, Y2, Y3, and Y4 are N. In a more preferred embodiment, Y1, Y2, Y3, and Y4 are CH; or Y1 is N and Y2, Y3 and Y4 are CH; or Y1 and Y2 are N and Y3 and Y4 are CH; or Y1 is CH, Y2 is N and Y3 and Y4 are CH; or Y1 and Y3 are N and Y2 and Y4 are CH; or Y1 and Y3 are CH and Y2 and Y4 are N; or Y1 and Y2 are CH and Y3 and Y4 are N; or Y1, Y2, and Y3 are CH and Y4 is N.

[0128] Preferably, Y6 to Y 10 One or two of the above are N, and Y6 to Y 10 The other one is CH. In a more preferred embodiment, Y6, Y7, Y8, Y9, and Y 10 is CH; or Y6 is N, and Y7, Y8, Y9, and Y 10 is CH; or Y6 is CH, Y7 is N, and Y8, Y9, and Y 10 is CH; or Y6 is N, Y7, Y8, and Y9 are CH, and Y 10 is N; or Y6 and Y7 are N, and Y8, Y9, and Y 10 is CH; or Y6 is CH, Y7 is N, Y8 is CH, Y9 is N, and Y 10 is CH; or Y6 and Y7 are CH, Y8 is N, Y9 is CH, and Y 10 is N; or Y6 and Y7 are CH, Y8 is N, and Y9 and Y 10 is CH; or Y6 is N, Y7 and Y8 are CH, Y9 is N, and Y 10 is CH.

[0129] R5 is preferably hydrogen, fluorine or methoxy. R6 is preferably hydrogen or methoxy. More preferably, R5 and R6 are both hydrogen; or R5 is fluorine and R6 is hydrogen; or · R5 and R6 are both methoxy.

[0130] In a further particularly preferred embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers thereof, which is a compound of formula (XIII): [ka] (In the formula, Z is selected from CH and N; R5 is selected from halogen, alkyl, and O-alkyl, preferably from fluorine and methoxy; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy.

[0131] In a preferred embodiment, Z is CH. In another preferred embodiment, Z is H. R5 is preferably hydrogen, fluorine or methoxy. R6 is preferably hydrogen or methoxy. More preferably, R5 is fluorine and R6 is hydrogen; or · R5 and R6 are both methoxy.

[0132] In a further particularly preferred embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, which is a compound of formula (XIV), including all tautomers and stereoisomers thereof: [ka] (In the formula, R5 is selected from halogen, alkyl, and O-alkyl, preferably from fluorine and methoxy; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy.

[0133] R5 is preferably hydrogen, fluorine or methoxy. R6 is preferably hydrogen or methoxy. More preferably, R5 is fluorine and R6 is hydrogen; or · R5 and R6 are both methoxy.

[0134] In a further particularly preferred embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers thereof, which is a compound of formula (XVa) or formula (XVb): [ka] (In the formula, Y1 to Y4 and Y6 to Y 10 is independently selected from CH, N, S, and O, preferably CH and N; Y5 is C; R5 is selected from halogen, alkyl, O-alkyl, O-phenyl, and O-cycloalkyl, preferably halogen, OC 1-4 O-alkyl, O-phenyl, and O-cycloalkyl.

[0135] In a more preferred embodiment, R5 is fluorine or chlorine, most preferably fluorine. In another more preferred embodiment, R5 is OC 1-4 Alkyl, for example, methoxy, ethoxy, propoxy, or butoxy, most preferably methoxy, propoxy, or propan-2-yloxy. In another more preferred embodiment, R5 is O-phenyl. In another more preferred embodiment, R5 is O-cycloalkyl, most preferably O-cyclohexyl. R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy.

[0136] Preferably, one, two, three, or all four of Y1, Y2, Y3, and Y4 are N. In a more preferred embodiment, Y1, Y2, Y3, and Y4 are CH; or Y1 is N and Y2, Y3 and Y4 are CH; or Y1 and Y2 are N and Y3 and Y4 are CH; or Y1 is CH, Y2 is N and Y3 and Y4 are CH; or Y1 and Y3 are N and Y2 and Y4 are CH; or Y1 and Y3 are CH and Y2 and Y4 are N; or Y1 and Y2 are CH and Y3 and Y4 are N; or Y1 is N, Y2 and Y3 are CH and Y4 is N; or Y1, Y2, and Y3 are CH and Y4 is N.

[0137] When Y4 is CH, it may be substituted or unsubstituted. In a preferred embodiment, Y4 is CH and is unsubstituted. In another preferred embodiment, Y4 is CH and is substituted. When Y4 is CH and is substituted, Y4 is preferably substituted with halogen or alkyl, most preferably with fluorine or methyl.

[0138] Preferably, Y6 to Y 10 One or two of the above are N, and Y6 to Y 10 The other one is CH. In a more preferred embodiment, Y6, Y7, Y8, Y9, and Y 10 is CH; or Y6 is N, and Y7, Y8, Y9, and Y 10 is CH; or Y6 is CH, Y7 is N, and Y8, Y9, and Y 10 is CH; or Y6 is N, Y7, Y8, and Y9 are CH, and Y 10 is N; or Y6 and Y7 are N, and Y8, Y9, and Y 10 is CH; or Y6 is CH, Y7 is N, Y8 is CH, Y9 is N, and Y 10 is CH; or Y6 and Y7 are CH, Y8 is N, Y9 is CH, and Y 10 is N; or Y6 and Y7 are CH, Y8 is N, and Y9 and Y 10 is CH; or Y6 is N, Y7 and Y8 are CH, Y9 is N, and Y 10 is CH.

[0139] R5 is preferably hydrogen, fluorine or methoxy. R6 is preferably hydrogen or methoxy. More preferably, R5 and R6 are both hydrogen; or R5 is fluorine and R6 is hydrogen; or · R5 and R6 are both methoxy.

[0140] In a further particularly preferred embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, which is a compound of formula (XVI), including all tautomers and stereoisomers thereof: [ka] (In the formula, R5 is selected from halogen, alkyl, and O-alkyl, preferably from fluorine and methoxy; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy.

[0141] R5 is preferably hydrogen, fluorine or methoxy. R6 is preferably hydrogen or methoxy. More preferably, R5 is fluorine and R6 is hydrogen; or · R5 and R6 are both methoxy.

[0142] In a further particularly preferred embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, which is a compound of formula (XVII), including all tautomers and stereoisomers thereof: [ka] (In the formula, R2 is selected from alkyl and cycloalkyl, preferably from methyl and cyclopropyl; R5 is selected from halogen, alkyl, and O-alkyl, preferably from fluorine and methoxy; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy.

[0143] In a preferred embodiment, R2 is methyl. In a further preferred embodiment, R2 is cyclopropyl. R5 is preferably hydrogen, fluorine or methoxy. R6 is preferably hydrogen or methoxy. More preferably, R5 is fluorine and R6 is hydrogen; or · R5 and R6 are both methoxy.

[0144] In a further particularly preferred embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, which is a compound of formula (XVIII), including all tautomers and stereoisomers thereof: [ka] (In the formula, X1 is selected from alkyl, N, O, S, preferably CH2 or S; n is 1 or 2; R5 is selected from halogen, alkyl, and O-alkyl, preferably from fluorine and methoxy; and R6 is selected from hydrogen, alkyl and O-alkyl, preferably from hydrogen and methoxy.

[0145] Most preferably, X1 is CH2. Even most preferably, X1 is S. Most preferably, n is 1. R5 is preferably hydrogen, fluorine or methoxy. R6 is preferably hydrogen or methoxy. More preferably, R5 is fluorine and R6 is hydrogen; or · R5 and R6 are both methoxy.

[0146] In one embodiment, the compound of formula (I) is a compound according to any one of Examples 1-1323, including all tautomers and stereoisomers, or a pharma- ceutically acceptable salt, solvate, or polymorph thereof.

[0147] In a preferred embodiment, the compounds of formula (I) include all tautomers and stereoisomers: 5-[3-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)propyl]-1,3,4-thiadiazol-2-amine; 5-{[2-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine; 5-{[2-({3',4'-dimethoxy-[1,1'-biphenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine; 4'-Fluoro-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]-[1,1'-biphenyl]-2-amine; 3',4'-Dimethoxy-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]-[1,1'-biphenyl]-2-amine; 5-[4-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)phenyl]-1,3,4-thiadiazol-2-amine; 5-(4-{[2-(3,4-dimethoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine; 5-(4-{[2-(4-methoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-2-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-4-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(3,4-dimethoxyphenyl)pyridin-4-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyridin-2-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyrazin-2-amine; 5-(4-{[2-(4-phenoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine; 5-(4-{[2-(4-propoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine; 5-[4-({2-[4-(propan-2-yloxy)phenyl]phenyl}amino)phenyl]-1,3,4-thiadiazol-2-amine; 4'-Fluoro-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[1,1'-biphenyl]-2-amine; 3',4'-Dimethoxy-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[1,1'-biphenyl]-2-amine; N-[2-(4-methoxyphenyl)phenyl]-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline; 2-(4-Methoxyphenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine; 2-(4-fluorophenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine; 4-(4-methyl-4H-1,2,4-triazol-3-yl)-N-[2-(4-phenoxyphenyl)phenyl]aniline; 3-(3,4-dimethoxyphenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-4-amine; N-[3-(5-amino-1,3,4-thiadiazol-2-yl)propyl]-4-fluorobenzene-1-sulfonamide; N-{2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]ethyl}-4-fluorobenzene-1-sulfonamide; 5-(3-{[(4-fluorophenyl)(methyl)oxo-λω-sulfanylidene]amino}propyl)-1,3,4-thiadiazol-2-amine; 4-Fluoro-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]benzene-1-sulfonamide; 4-Fluoro-N-{2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]ethyl}benzene-1-sulfonamide; [(3,4-dimethoxyphenyl)sulfamoyl]({2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]ethyl})amine; N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-4-fluorobenzene-1-sulfonamide; N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-3,4-dimethoxybenzene-1-sulfonamide; 5-(1-{4'-fluoro-[1,1'-biphenyl]-2-yl}piperidin-4-yl)-1,3,4-thiadiazol-2-amine; 5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3-thiazol-2-amine; 5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3,4-thiadiazol-2-amine; 1-(4-fluorobenzenesulfonyl)-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine; N-[(1H-1,3-benzodiazol-5-yl)methyl]-4'-fluoro-[1,1'-biphenyl]-2-amine; N-[(1H-1,3-benzodiazol-5-yl)methyl]-3',4'-dimethoxy-[1,1'-biphenyl]-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)pyridin-3-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-4-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-4-(4-methoxyphenyl)pyridin-3-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-5-(4-methoxyphenyl)pyrimidin-4-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyrazin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-4-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyrazin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-fluorophenyl)pyridin-3-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyridin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyrazin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-phenoxyphenyl)aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(cyclohexyloxy)phenyl]aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-propoxyphenyl)aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(propan-2-yloxy)phenyl]aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)-3-methylaniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-methylaniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-chlorophenyl)-3-fluoroaniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-fluoro-2-(4-fluorophenyl)aniline; N-[(1H-1,3-benzodiazol-5-yl)methyl]-4-fluorobenzene-1-sulfonamide; and [(1H-1,3-benzodiazol-5-yl)methyl][(4-fluorophenyl)(methyl)oxo-λω-sulfanylidene]amine; or a pharma- ceutically acceptable salt, solvate, or polymorph thereof.

[0148] In a more preferred embodiment, the compound of formula (I) includes all tautomers and stereoisomers: 5-(1-{4'-fluoro-[1,1'-biphenyl]-2-yl}piperidin-4-yl)-1,3,4-thiadiazol-2-amine; N-[(1H-1,3-benzodiazol-5-yl)methyl]-4'-fluoro-[1,1'-biphenyl]-2-amine; N-[(1H-1,3-benzodiazol-5-yl)methyl]-3',4'-dimethoxy-[1,1'-biphenyl]-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)pyridin-3-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-4-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-4-(4-methoxyphenyl)pyridin-3-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-5-(4-methoxyphenyl)pyrimidin-4-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyrazin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-4-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyrazin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-fluorophenyl)pyridin-3-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyridin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyrazin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-phenoxyphenyl)aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(cyclohexyloxy)phenyl]aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-propoxyphenyl)aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(propan-2-yloxy)phenyl]aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)-3-methylaniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-methylaniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-chlorophenyl)-3-fluoroaniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-fluoro-2-(4-fluorophenyl)aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)-3-methylaniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-methylaniline; and N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline; or a pharma- ceutically acceptable salt, solvate, or polymorph thereof.

[0149] In a uniformly preferred embodiment, compounds of formula (I) include all tautomers and stereoisomers: 5-(1-{4'-fluoro-[1,1'-biphenyl]-2-yl}piperidin-4-yl)-1,3,4-thiadiazol-2-amine; N-[(1H-1,3-benzodiazol-5-yl)methyl]-4'-fluoro-[1,1'-biphenyl]-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyrazin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-4-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyrazin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-phenoxyphenyl)aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(cyclohexyloxy)phenyl]aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(propan-2-yloxy)phenyl]aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)-3-methylaniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-methylaniline; and N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline; or a pharma- ceutically acceptable salt, solvate, or polymorph thereof.

[0150] In the most preferred embodiment, the compounds of formula (I) include all tautomers and stereoisomers: N-[(1H-1,3-benzodiazol-5-yl)methyl]-4'-fluoro-[1,1'-biphenyl]-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyrazin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)-3-methylaniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-methylaniline; and N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline; or a pharma- ceutically acceptable salt, solvate, or polymorph thereof.

[0151] In a further most preferred embodiment, the compound of formula (I) includes all tautomers and stereoisomers: 5-(1-{4'-fluoro-[1,1'-biphenyl]-2-yl}piperidin-4-yl)-1,3,4-thiadiazol-2-amine; or a pharma- ceutically acceptable salt, solvate, or polymorph thereof.

[0152] In a further most preferred embodiment, the compound of formula (I) includes all tautomers and stereoisomers: N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline; or a pharma- ceutically acceptable salt, solvate, or polymorph thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0153] (Synthesis method) The compounds of formula (I) of the present invention can be prepared by a method selected from synthetic methods A to R described in the Examples section below. Accordingly, the present invention further relates to synthetic methods A, B, C, D, E, F, G, H, I, K, L, M, N, O, P, Q, and R.

[0154] In a preferred embodiment, the compounds of formula (I) of the present invention are prepared according to synthetic method A. In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to synthetic method B. In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to synthetic method C. In a further preferred embodiment, the compounds of formula (I) according to the present invention are prepared according to synthetic method D. In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to synthetic method E. In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to synthetic method F.

[0155] In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to synthetic method G. In a further preferred embodiment, the compounds of formula (I) according to the invention are prepared according to synthetic method H. In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to synthetic method I. In a further preferred embodiment, the compounds of formula (I) according to the invention are prepared according to synthetic method K. In a further preferred embodiment, the compounds of formula (I) according to the invention are prepared according to synthetic method L. In a further preferred embodiment, the compounds of formula (I) according to the invention are prepared according to synthetic method M.

[0156] In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to synthetic method N. In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to synthetic method O. In a further preferred embodiment, the compounds of formula (I) according to the invention are prepared according to synthetic method P. In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to synthetic method Q. In a further preferred embodiment, the compounds of formula (I) according to the invention are prepared according to synthetic method R.

[0157] (therapeutic use) Physiological substrates of QC (EC) in mammals include, for example, amyloid β-peptides (3-40), (3-42), (11-40), and (11-42), ABri, ADan, gastrin, neurotensin, FPP, CCL2, CCL7, CCL8, CCL16, CCL18, fractalkine, orexin A, [Gln 3 ]-Glucagon (3-29), [Gln 5 ]-Substance P(5-11), and peptide QYNAD. For further details, see Table 1. The compounds and / or combinations according to the invention and pharmaceutical compositions comprising at least one QC (EC) inhibitor are useful for the treatment of conditions that can be treated by modulation of QC activity. Table 1: Amino acid sequences of bioactive peptides with an N-terminal glutamine residue that are susceptible to cyclization to the final pGlu. [Table 2] TIFF0007674811000049.tif205170TIFF0007674811000050.tif211170TIFF0007674811000051.tif179170 TIFF0007674811000052.tif204170TIFF0007674811000053.tif192170TIFF0007674811000054.tif185170

[0158] Glutamic acid is found in the amyloid β-peptide at positions 3, 11, and 22. Among them, a glutamic acid (E) to glutamine (Q) mutation at position 22 (corresponding to the amyloid precursor protein APP 693, Swissprot P05067) has been described as the so-called Dutch-type cerebral arterial amyloidosis mutation.

[0159] β-amyloid peptides with pyroglutamic acid residues at positions 3, 11, and / or 22 have been described as more cytotoxic and hydrophobic than amyloid β-peptide 1-40 (42 / 43) (Saido TC, 2000 Medical Hypotheses 54(3): 427-429).

[0160] Several N-terminal variations, such as Aβ(3-40), Aβ(3-42), Aβ(11-40), and Aβ(11-42), can be generated from the full-length peptides Aβ(1-40) and Aβ(1-42) by the β-secretase enzyme β-site amyloid precursor protein-cleaving enzyme (BACE) at various sites (Huse JT et al., 2002 J. Biol. Chem. 277(18): 16278-16284) and / or by aminopeptidase or dipeptidyl aminopeptidase treatment. In each case, cyclization of the glutamic acid residue then occurring at the N-terminus is catalyzed by QC.

[0161] Transepithelial transducing cells, particularly gastrin (G) cells, coordinate gastric acid secretion with the arrival of food in the stomach. Recent studies have shown that multiple active products are generated from gastrin precursors and that there are multiple control points in gastrin biosynthesis. The biosynthetic precursors and intermediates (progastrin and Gly-gastrin) are putative growth factors; their products, amidated gastrins, not only potently stimulate acid secretion but also regulate the expression of genes related to epithelial cell proliferation, differentiation of acid-producing parietal cells and histamine-secreting enterochromaffin-like (ECL) cells, and histamine synthesis and storage in ECL cells. Gastrin also stimulates the production of members of the epidermal growth factor (EGF) family, which then inhibit parietal cell function but stimulate proliferation of surface epithelial cells. Plasma gastrin concentrations are elevated in subjects with Helicobacter pylori, who are known to be at increased risk for duodenal ulcer disease and gastric cancer (Dockray, GJ 1999 J Physiol 15 315-324).

[0162] Gastrin, a peptide hormone released from antral G cells, is known to stimulate the synthesis and release of histamine from ECL cells in the oxyntic mucosa via the CCK-2 receptor. The mobilized histamine induces acid secretion by binding to H(2) receptors located on parietal cells. Recent studies suggest that gastrin, both in its fully amidated form and in its less processed form (progastrin and glycine-extended gastrin), is also a growth factor for the gastrointestinal tract. The main trophic effect of amidated gastrin is on the gastric oxyntic mucosa, where it has been shown to cause increased proliferation of gastric stem cells and ECL cells, leading to an increase in parietal and ECL cell mass. On the other hand, the main trophic target of less processed gastrin (e.g., glycine-extended gastrin) appears to be the colonic mucosa (Koh, TJ and Chen, D., 2000 Regul Pept 9337-44).

[0163] Neurotensin (NT) is a neuropeptide implicated in the pathophysiology of schizophrenia, where it specifically regulates neurotransmitter systems previously demonstrated to be misregulated in this disorder. Clinical trials measuring cerebrospinal fluid (CSF) NT concentrations have revealed a subset of schizophrenia patients with reduced CSF NT concentrations that are reversed by effective antipsychotic treatment. There is also considerable evidence consistent with the involvement of the NT system in the mechanism of action of antipsychotics. The behavioral and biochemical effects of centrally administered NT are remarkably similar to those of systemically administered antipsychotics, and antipsychotics increase NT neurotransmission. This body of knowledge has led to the hypothesis that NT functions as an endogenous antipsychotic. Furthermore, typical and atypical antipsychotics differentially alter NT neurotransmission in nigrostriatal and mesolimbic dopamine terminal regions, and these effects predict side effect liability and efficacy, respectively (Binder, EB et al. 2001 Biol Psychiatry 50 856-872).

[0164] Fertilization-promoting peptide (FPP), a tripeptide related to thyrotropin-releasing hormone (TRH), is found in seminal plasma. Recent evidence obtained in vitro and in vivo indicates that FPP plays an important role in regulating sperm capacitation. Specifically, FPP initially stimulates non-fertilized (uncapacitated) sperm to "switch on" and become more rapidly fertilizable, but then stops capacitation so that sperm do not undergo spontaneous acrosome loss and therefore do not lose capacitation. These responses are mimicked and indeed enhanced by adenosine, which is known to regulate the adenylyl cyclase (AC) / cAMP signaling pathway. Both FPP and adenosine have been shown to stimulate cAMP production in uncapacitated cells but inhibit it in capacitated cells, and the FPP receptor somehow interacts with adenosine receptors and G proteins to achieve regulation of AC. These events affect the tyrosine phosphorylation state of various proteins, some of which are important in initially "switching on" and others that may be involved in the acrosome reaction itself. Calcitonin and angiotensin II, also found in seminal plasma, have a similar effect in vitro on uncapacitated spermatozoa and can enhance the response to FPP. These molecules have a similar effect in vivo, influencing fertility by stimulating and then maintaining capacitation. Either reduced availability of FPP, adenosine, calcitonin, and angiotensin II or defects in their receptors contribute to male infertility (Fraser, LR and Adeoya-Osiguwa, SA, 2001 Vitam Horm 63, 1-28).

[0165] CCL2 (MCP-1), CCL7, CCL8, CCL16, CCL18, and fractalkine play important roles in pathophysiological conditions such as inhibition of proliferation of bone marrow progenitor cells, neoplasia, inflammatory host responses, cancer, psoriasis, rheumatoid arthritis, atherosclerosis, vasculitis, humoral and cellular immune responses, leukocyte adhesion and migration processes at the endothelium, inflammatory bowel disease, restenosis, pulmonary fibrosis, pulmonary hypertension, hepatic fibrosis, liver cirrhosis, nephrosclerosis, ventricular remodeling, heart failure, arterial disease after organ transplantation, and vein graft failure.

[0166] Several studies have demonstrated that it is especially effective in treating atherosclerosis (Gu, L et al. (1998) Mol. Cell 2, 275-281; ​​Gosling, J et al. (1999) J Clin. Invest 103, 773-778); rheumatoid arthritis (Gong, J. H et al. (1997) J Exp. Med 186, 131-137; Ogata, H et al. (1997) J Pathol. 182, 106-114); pancreatitis (Bhatia, M et al. (2005) Am. J Physiol Gastrointest. Liver Physiol 288, G1259-G1265); Alzheimer's disease (Yamamoto, M et al. (2005) Am. J Pathol. 166, 1475-1485); pulmonary fibrosis (Inoshima, I et al. (2004) Am. J Physiol Lung Cell Mol. Physiol 286, L1038-L1044); renal fibrosis (Wada, T et al. (2004) J Am. Soc. Nephrol. 15, 940-948), and transplant rejection (Saiura, A et al. (2004) Arterioscler. Thromb. Vasc. Biol. 24, 1886-1890). Furthermore, MCP-1 may play a role as a paracrine factor in preeclampsia (Katabuchi, H. et al. (2003) Med Electron Microsc. 36, 253-262), tumor development (Ohta, M. et al. (2003) Int.J Oncol. 22, 773-778; Li, S. et al. (2005) J Exp.Med 202, 617-624), neuropathic pain (White, FA et al. (2005) Proc. Natl. Acad.Sci.USA), and AIDS (Park, IW, Wang, JF, and Groopman, JE (2001) Blood 97, 352-358; Coll, B. et al. (2006) Cytokine 34, 51-55).

[0167] MCP-1 levels are increased in the CSF of AD patients and patients exhibiting mild cognitive impairment (MCI) (Galimberti, D et al. (2006) Arch. Neurol. 63, 538-543). Furthermore, MCP-1 shows increased levels in the serum of patients with MCI and early AD (Clerici, F et al. (2006) Neurobiol. Aging 27, 1763-1768).

[0168] Recently, several cytotoxic T-lymphocyte peptide-based vaccines against hepatitis B, human immunodeficiency virus, and melanoma have been investigated in clinical trials. One interesting melanoma vaccine candidate, alone or in combination with other tumor antigens, is the decapeptide ELA. This peptide is an immunodominant peptide analog of the Melan-A / MART-1 antigen with an N-terminal glutamic acid. It has been reported that the amino and gamma-carboxyl groups of glutamic acid, and the amino and gamma-carboxamide groups of glutamine, readily condense to form pyroglutamic acid derivatives. To overcome this stability issue, several medicamentously interesting peptides have been developed that have pyroglutamic acid instead of N-terminal glutamine or glutamic acid without losing their pharmacological properties. Unfortunately, in comparison with ELA, the pyroglutamic acid derivative (PyrELA) and also the N-terminal acetyl-capped derivative (AcELA) did not induce cytotoxic T-lymphocyte (CTL) activity. Despite the obvious minor modifications introduced into PyrELA and AcELA, these two derivatives probably have lower affinity than ELA for the specific class I major histocompatibility complex. As a result, to preserve the full activity of ELA, the formation of PyrELA must be avoided (Beck A. et al., 2001, J Pept Res 57(6):528-38).

[0169] Orexin A is a neuropeptide that plays an important role in the regulation of food intake and sleep-insomnia, possibly by coordinating the complex behavioral and physiological responses of these complementary homeostatic functions. It also plays a role in the homeostatic regulation of energy metabolism, autonomic function, hormone balance, and fluid regulation.

[0170] Recently, elevated levels of the pentapeptide QYNAD have been identified in the cerebrospinal fluid (CSF) of patients with multiple sclerosis or Guillain-Barre syndrome compared to healthy individuals (Brinkmeier H. et al., 2000, Nature Medicine 6, 808-811). There is considerable controversy in the literature regarding the mechanism of action of the pentapeptide Gln-Tyr-Asn-Ala-Asp (QYNAD), in particular its effect of interacting with and blocking sodium channels involved in inflammatory autoimmune diseases of the central nervous system, resulting in the promotion of axonal dysfunction. However, it has recently been shown that not QYNAD, but its cyclized pyroglutamic acid form, pEYNAD, is the active form, which blocks sodium channels, resulting in the promotion of axonal dysfunction. Sodium channels are densely expressed in myelinated axons and play an essential role in conducting action potentials along axons in the mammalian brain and spinal cord. They are therefore speculated to be involved in some aspects of the pathophysiology of inflammatory autoimmune diseases, in particular multiple sclerosis, Guillain-Barré syndrome, and chronic inflammatory demyelinating polyneuropathy.

[0171] Furthermore, QYNAD is a substrate for the enzyme glutaminyl cyclase (QC, EC 2.3.2.5), which is also present in mammalian brain, particularly in humans, and which efficiently catalyzes the formation of pEYNAD from its precursor QYNAD.

[0172] Thus, the present invention relates to a method for treating mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, Down's Syndrome neurodegeneration, Huntington's disease, Kennedy's disease, ulcer disease, duodenal cancer with or without Helicobacter pylori infection, colorectal cancer, Zolliger-Ellison syndrome, gastric cancer with or without Helicobacter pylori infection, pathological psychiatric conditions, schizophrenia, infertility, neoplasia, inflammatory host response, cancer, malignant metastasis, melanoma, psoriasis, arthritis, osteoporosis ... The present invention provides a use of a compound of formula (I) for the preparation of a medicament for the prevention or alleviation or treatment of a disease selected from the group consisting of rheumatism, atherosclerosis, pancreatitis, restenosis, disorders of humoral and cellular immune responses, leukocyte adhesion and migration processes in the endothelium, eating disorders, sleep-insomnia disorders, disorders of homeostatic regulation of energy metabolism, disorders of autonomic function, disorders of hormone balance or disorders of fluid regulation, multiple sclerosis, Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy.

[0173] Furthermore, administration of the compounds according to the invention to a mammal may make it possible to stimulate the proliferation of bone marrow progenitor cells.

[0174] Furthermore, the administration of QC inhibitors according to the invention can result in the suppression of male fertility.

[0175] In a preferred embodiment, the present invention provides the use of inhibitors of QC (EC) activity in combination with other drugs, in particular for the treatment of neuronal diseases, atherosclerosis and multiple sclerosis.

[0176] The present invention also provides a method for the treatment of the aforementioned diseases comprising the administration to a mammal, preferably a human, of a therapeutically active amount of at least one compound of formula (I).

[0177] Most preferably, the methods and corresponding uses are for the treatment of a disease selected from the group consisting of Mild Cognitive Impairment, Alzheimer's Disease, Familial British Dementia, Familial Danish Dementia, Down's Syndrome neurodegeneration, Parkinson's Disease, and Huntington's Chorea, comprising the administration to a mammal, preferably a human, of a therapeutically active amount of at least one compound of formula (I).

[0178] More preferably, the present invention provides therapeutic methods and corresponding uses for the treatment of rheumatoid arthritis, atherosclerosis, pancreatitis, and restenosis.

[0179] (Drug combination) In a preferred embodiment, the present invention provides a composition, preferably a pharmaceutical composition, comprising at least one QC inhibitor, optionally in combination with at least one other drug selected from the group consisting of nootropics, neuroprotectants, anti-Parkinson's drugs, amyloid protein deposition inhibitors, beta-amyloid synthesis inhibitors, antidepressants, anxiolytics, antipsychotics, and anti-multiple sclerosis drugs.

[0180] Most preferably, said QC inhibitor is a compound of formula (I) according to the present invention.

[0181] More specifically, the other agent is selected from the group consisting of β-amyloid antibodies, vaccines, cysteine ​​protease inhibitors, PEP inhibitors, LiCl, acetylcholinesterase (AChE) inhibitors, PIMT enhancers, inhibitors of β-secretase, inhibitors of γ-secretase, inhibitors of aminopeptidases, preferably inhibitors of dipeptidyl peptidases, most preferably DP IV inhibitors; inhibitors of neutral endopeptidases, inhibitors of phosphodiesterase-4 (PDE-4), TNFα inhibitors, muscarinic M1 receptor antagonists, NMDA receptor antagonists, σ-1 receptor inhibitors, histamine H3 antagonists, immunomodulators, immunosuppressants, MCP-1 antagonists, or anticancer drugs such as Antegren (natalizumab), Neurelan (fampridine-SR), Campath (alemtuzumab), IR 208, NBI 5788 / MSP 771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD271, adapalene), BAY 361677 (interleukin-4), matrix metalloproteinase inhibitors (e.g., BB 76163), interferon-tau (trophoblastin), and SAIK-MS.

[0182] In addition, other drugs may be used, e.g. (a) Benzodiazepines, such as alprazolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, fludiazepam, loflazepate, lorazepam, methaqualone, oxazepam, prazepam, tranzene, (b) Selective serotonin reuptake inhibitors (SSRIs), e.g., citalopram, fluoxetine, fluvoxamine, escitalopram, sertraline, paroxetine, (c) Tricyclic antidepressants, e.g., amitriptyline, clomipramine, desipramine, doxepin, imipramine (d) monoamine oxidase (MAO) inhibitors; (e) Azapirones, e.g., buspirone, tandopsilon, (f) Serotonin-norepinephrine reuptake inhibitors (SNRIs), e.g., venlafaxine, duloxetine, (g) mirtazapine, (h) Norepinephrine reuptake inhibitors (NRIs), e.g. reboxetine, (i) bupropion, (j) nefazodone, (k) beta-blockers, (l) NPY-receptor ligand: NPY agonist or antagonist The therapeutic agent may be an anti-anxiety or anti-depressant selected from the group consisting of:

[0183] In further embodiments, the other agent is, for example, a) dihydroorotate dehydrogenase inhibitors, such as SC-12267, teriflunomide, MNA-715, HMR-1279 (synonymous with HMR-1715, MNA-279); b) Autoimmune suppressants, e.g. laquinimod, c) paclitaxel, d) antibodies, such as AGT-1, anti-granulocyte macrophage colony-stimulating factor (GM-CSF) monoclonal antibodies, Nogo receptor modulators, ABT-874, alemtuzumab (CAMPATH), anti-OX40 antibodies, CNTO-1275, DN-1921, natalizumab (synonymous with AN-100226, Antegren, VLA-4 Mab), daclizumab (synonymous with Zenepax, Ro-34-7375, SMART anti-Tac), J-695, priliximab (synonymous with Centara, CEN-000029, cM-T412), MRA, Dantes, anti-IL-12 antibodies, e) peptide nucleic acid (PNA) preparations, such as reticulose; f) interferon alpha, e.g. alpha interferon, human alpha interferon (synonymous with omniferon, alpha leucoferon); g) Interferon beta, e.g. interferon beta-1a such as Frone, Avonex, recombinant interferon beta-1b such as Betron (Rebif), interferon beta analogues, interferon beta-transferrin fusion protein, Betaseron; h) interferon tau, i) peptides, e.g., cyclic peptides such as AT-008, AnaergiX.MS, immunokines (α-immunokine-NNSO3), ZD-7349; j) therapeutic enzymes, such as soluble CD8 (sCD8); k) plasmids encoding multiple sclerosis-specific autoantigens and plasmids encoding cytokines, e.g., BHT-3009; l) TNF-α inhibitors, such as BLX-1002, thalidomide, SH-636, m) TNF antagonists, such as solimatat, Lenercept (RO-45-2081, synonymous with Tenefuse), Onercept (sTNFR1), CC-1069, n) TNFα, e.g., etanercept (Enbrel, synonymous with TNR-001) o) CD28 antagonists, such as abatacept, p) Lck tyrosine kinase inhibitors, q) cathepsin K inhibitors, r) Analogues of the neuron-targeted membrane transporter protein taurine and the plant-derived calpain inhibitor leupeptin, e.g., Neurodur s) chemokine receptor-1 (CCR1) antagonists, such as BX-471; t) CCR2 antagonists; u) AMPA receptor antagonists, such as ER-167288-01 and ER-099487, E-2007, talampanel, v) potassium channel blockers, e.g. fampridine, w) tosyl-proline-phenylalanine small molecule antagonists of the VLA-4 / VCAM interaction, e.g., TBC-3342; x) cell adhesion molecule inhibitors, such as TBC-772; y) antisense oligonucleotides, such as EN-101; z) antagonists of free immunoglobulin light chain (IgLC) binding to mast cell receptors, such as F-991; aa) apoptosis-inducing antigens, such as Apogen MS; bb) alpha-2 adrenergic receptor agonists, for example tizanidine (synonymous with Zanaflex, Ternelin, Sirdalvo, Sirdalude, Mionidine); cc) Copolymers of L-tyrosine, L-lysine, L-glutamic acid, and L-alanine, such as glatiramer acetate (synonymous with Copaxone, COP-1, Copolymer-1); dd) topoisomerase II modulators, for example mitoxantrone hydrochloride, ee) adenosine deaminase inhibitors, e.g., cladribine (synonymous with Leustatin, Mylinax, RWJ-26251); ff) interleukin-10, e.g. ilodecakin (synonymous with tenovir, Sch-52000, CSIF), gg) Interleukin-12 antagonists, such as lisofylline (CT-1501R, LSF, synonymous with lisofylline), hh) ethanaminium, for example, SRI-62-834 (synonymous with CRC-8605, NSC-614383); ii) Immunomodulators, such as SAIK-MS, PNU-156804, alpha-fetoprotein peptide (AFP), IPDS, jj) retinoid receptor agonists, e.g. adapalene (synonymous with Differin, CD-271); kk) TGF-β, e.g., GDF-1 (growth differentiation factor 1); ii) TGF-β-2, e.g., betakine; mm) MMP inhibitors, for example Glycomed, nn) phosphodiesterase 4 (PDE4) inhibitors, for example RPR-122818, oo) purine nucleoside phosphorylase inhibitors, for example 9-(3-pyridylmethyl)-9-deazaguanine, perdecine (synonymous with BCX-34, TO-200); mm) alpha-4 / beta-1 integrin antagonists, for example ISIS-104278, qq) antisense α4 integrin (CD49d), e.g., ISIS-17044, ISIS-27104, rr) cytokine inducers, e.g., nucleosides, ICN-17261, ss) cytokine inhibitors, tt) heat shock protein vaccines, e.g., HSPPC-96; uu) Neuregulin growth factors, e.g. GGF-2 (neuregulin, synonymous with glial growth factor 2); vv) cathepsin S inhibitors, ww) Bropirimine analogues, e.g., PNU-56169, PNU-63693, xx) Monocyte chemotactic protein-1 inhibitors, such as benzimidazole-like MCP-1 inhibitors, LKS-1456, PD-064036, PD-064126, PD-084486, PD-172084, PD-172386 The anti-multiple sclerosis agent may be selected from the group consisting of:

[0184] Furthermore, the present invention provides pharmaceutical compositions for parenteral, enteral or oral administration, comprising, for example, at least one QC inhibitor, optionally in combination with at least one other aforementioned agent.

[0185] These combinations provide particularly beneficial effects. Thus, such combinations have been shown to be effective and useful in the treatment of the aforementioned diseases. Accordingly, the present invention provides methods for the treatment of these conditions.

[0186] The method comprises either the simultaneous administration or the sequential administration of at least one QC inhibitor and at least one other drug.

[0187] Simultaneous administration includes administration of a formulation containing at least one QC inhibitor and at least one other drug or essentially simultaneous administration of separate formulations of each drug.

[0188] β-amyloid antibodies and compositions containing the same are disclosed in, for example, WO / 2009 / 065054, WO / 2009 / 056490, WO / 2009 / 053696, WO / 2009 / 033743, WO / 2007 / 113172, WO / 2007 / 022416, WO 2006 / 137354, WO 2006 / 118959, WO 2006 / 103116, WO 2006 / 095041, WO 2006 / 081171, WO 2006 / 066233, WO 2006 / 066171, WO 2006 / 066089, WO 2006 / 066049, WO 2006 / 055178, WO 2006 / 046644, WO 2006 / 039470, WO 2006 / 036291, WO 2006 / 026408, WO 2006 / 016644, WO 2006 / 014638, WO 2006 / 014478, WO 2006 / 008661, WO 2005 / 123775, WO 2005 / 120571, WO 2005 / 105998, WO 2005 / 081872, WO 2005 / 080435, WO 2005 / 028511, WO 2005 / 025616, WO 2005 / 025516, WO 2005 / 023858, WO 2005 / 018424, WO 2005 / 011599, WO 2005 / 000193, WO 2004 / 108895, WO 2004 / 098631, WO 2004 / 080419, WO 2004 / 071408, WO 2004 / 069182, WO 2004 / 067561, WO 2004 / 044204, WO 2004 / 032868, WO 2004 / 031400, WO 2004 / 029630, WO 2004 / 029629, WO 2004 / 024770, WO 2004 / 024090, WO 2003 / 104437, WO 2003 / 089460, WO 2003 / 086310, WO 2003 / 077858, WO 2003 / 074081, WO 2003 / 070760, WO 2003 / 063760, WO 2003 / 055514, WO 2003 / 051374, WO 2003 / 048204, WO No. 2003 / 045128, WO2003 / 040183, WO 2003 / 039467, WO 2003 / 016466, WO 2003 / 015691, WO 2003 / 014162, WO 2003 / 012141, WO 2002 / 088307, WO 2002 / 088306, WO 2002 / 074240, WO 2002 / 046237, WO 2002 / 046222, WO 2002 / 041842, WO 2001 / 062801, WO 2001 / 012598, WO 2000 / 077178, WO Nos. 2000 / 072880, 2000 / 063250, WO 1999 / 060024, WO 1999 / 027944, WO 1998 / 044955, WO 1996 / 025435, WO 1994 / 017197, WO 1990 / 014840, WO 1990 / 012871, WO 1990 / 012870 and WO 1989 / 006242.

[0189] The β-amyloid antibody can be selected from, for example, a polyclonal antibody, a monoclonal antibody, a chimeric antibody, or a humanized antibody. Furthermore, the antibody can be useful for developing active and passive immunotherapy, i.e., vaccines and monoclonal antibodies.

[0190] Suitable examples of β-amyloid antibodies include ACU-5A5, huC091 (Acumen / Merck); PF-4360365, RI-1014, RI-1219, RI-409, RN-1219 (Rinat Neuroscience (Pfizer)); nanobody therapeutics from Ablynx / Boehringer Ingelheim; β-amyloid specific humanized monoclonal antibodies from Intellect Neurosciences / IBL; m266, m266.2 (Eli Lilly); AAB-02 (Elan); bapineuzumab (Elan); BAN-2401 (Bioarctic Neuroscience AB); ABP-102 (Abiogen Pharma); BA-27, BC-05 (Takeda Pharmaceutical); R-1450 (Roche); ESBA-212 (ESBATech); AZD-3102 (AstraZeneca), and Mindset BioPharmaceuticals' beta-amyloid antibody.

[0191] Particularly preferred is an antibody that recognizes the N-terminus of Aβ peptide. A suitable antibody that recognizes the Aβ-N-terminus is, for example, Acl-24 (AC Immune).

[0192] Monoclonal antibodies against β-amyloid peptide are disclosed in WO 2007 / 068412, WO / 2008 / 156621 and WO / 2010 / 012004, respectively chimeric and humanized antibodies are disclosed in WO 2008 / 011348 and WO / 2008 / 060364. Vaccine compositions for treating amyloid-related diseases are disclosed in WO / 2002 / 096937, WO / 2005 / 014041, WO 2007 / 068411, WO / 2007 / 097251, WO / 2009 / 029272, WO / 2009 / 054537, WO / 2009 / 090650 WO / 2009 / 095857, WO / 2010 / 016912, WO / 2010 / 011947, WO / 2010 / 011999, WO / 2010 / 044464.

[0193] Suitable vaccines for treating amyloid-related diseases are, for example, Afitope AD-01 and AD-02 (GlaxoSmithKline), ACC-01 and ACC-02 (Elan / Wyeth), CAD-106 (Novartis / Cytos Biotechnology).

[0194] Suitable cysteine ​​protease inhibitors are inhibitors of cathepsin B. Inhibitors of cathepsin B and compositions containing such inhibitors are described, for example, in WO / 2008 / 077109, WO / 2007 / 038772, WO 2006 / 060473, WO 2006 / 042103, WO 2006 / 039807, WO 2006 / 021413, WO 2006 / 021409, WO 2005 / 097103, WO 2005 / 007199, WO2004 / 084830, WO 2004 / 078908, WO 2004 / 026851, WO 2002 / 094881, WO 2002 / 027418, WO This is described in WO 2002 / 021509, WO 1998 / 046559 and WO 1996 / 021655.

[0195] An example of a suitable PIMT enhancer is 10-aminoaliphatyl-dibenzo[b,f]oxepines, as described in WO 98 / 15647 and WO 03 / 057204, respectively.Further useful according to the invention are modulators of PIMT activity, as described in WO 2004 / 039773.

[0196] Inhibitors of β-secretase and compositions containing such inhibitors are described, for example, in WO / 2010 / 094242, WO / 2010 / 058333, WO / 2010 / 021680, WO / 2009 / 108550, WO / 2009 / 042694, WO / 2008 / 054698, WO / 2007 / 051333, WO / 2007 / 021793, WO / 2007 / 019080, WO / 2007 / 019078, WO / 2007 / 011810, WO / 2003 / 05 No. 9346, No. WO2006 / 099352, No. WO2006 / 078576, No. WO2006 / 060109, No. WO2006 / 057983, No. WO2006 / 057945, No. WO2006 / 055434, No. WO2006 / 044497 No., WO2006 / 034296, WO2006 / 034277, WO2006 / 029850, WO2006 / 026204, WO2006 / 014944, WO2006 / 014762, WO2006 / 002004, US No. 7,109,217, No. WO2005 / 113484, No. WO2005 / 103043, No. WO2005 / 103020, No. WO2005 / 065195, No. WO2005 / 051914, No. WO2005 / 044830, No. WO2005 / 032471, No. WO2005 / No. 6,562,783, WO02 / 098849, and WO02 / 096897.

[0197] Suitable examples of beta-secretase inhibitors for the purposes of the present invention include WY-25105 (Wyeth); Posiphen, (+)-phenserine (TorreyPines / NIH); LSN-2434074, LY-2070275, LY-2070273, LY-2070102 (Eli Lilly); PNU-159775A, PNU-178025A, PNU-17820A, PNU-33312, PNU-38773, PNU-90530 (Elan / Pfizer); KMI-370, KMI-358, kmi-008 (Kyoto University); OM-99-2, OM-003 (Athenagen); AZ-12304146 (AstraZeneca / Astex); GW-840736X (GlaxoSmithKline), DNP-004089 (De Novo Pharmaceuticals), and CT-21166 (CoMentis).

[0198] Gamma secretase inhibitors and compositions containing such inhibitors are described, for example, in WO / 2010 / 090954, WO / 2009 / 011851, WO / 2009 / 008980, WO / 2008 / 147800, WO / 2007 / 084595, WO2005 / 008250, WO2006 / 004880, US 7,122,675, US 7,030,239, US 6,992,081, US 6,982,264, WO2005 / 097768, WO2005 / 028440, WO2004 / 101562, US 6,756,511, US 6,683,091, WO03 / 066592, WO03 / 014075, WO03 / 013527, WO02 / 36555, WO01 / 53255, US 7,109,217, US 7,101,895, US 7,049,296, US 7,034,182, US 6,984,626, WO2005 / 040126, WO2005 / 030731, WO2005 / 014553, US 6,890,956, EP 1334085, EP Nos. 1263774, WO2004 / 101538, WO2004 / 00958, WO2004 / 089911, WO2004 / 073630, WO2004 / 069826, WO2004 / 039370, WO2004 / 031139, WO2004 / 031137, US 6,713,276, US 6,686,449, WO03 / 091278, US 6,649,196, US 6,448,229, WO01 / 77144, and WO01 / 66564.

[0199] Suitable gamma secretase inhibitors for the purposes of the present invention are GSI-953, WAY-GSI-A, WAY-GSI-B (Wyeth); MK-0752, MRK-560, L-852505, L-685-458, L-852631, L-852646 (Merck); LY-450139, LY-411575, AN-37124 (Eli Lilly); BMS-299897, BMS-433796 (Bristol-Myers Squibb); E-2012 (Eisai); EHT-0206, EHT-206 (ExonHit Therapeutics); NGX-555 (TorreyPines Therapeutics), and semagacestat (Eli Lilly).

[0200] DPIV-inhibitors and compositions containing such inhibitors are described, for example, in US 6,011,155; US 6,107,317; US 6,110,949; US 6,124,305; US 6,172,081; WO99 / 61431, WO99 / 67278, WO99 / 67279, DE19834591, WO97 / 40832, WO95 / 15309, WO98 / 19998, WO00 / 07617, WO99 / 38501, WO99 / 46272, WO99 / 38501, WO01 / 68603, WO01 / 401 No. 80, No. WO01 / 81337, No. WO01 / 81304, No. WO01 / 55105, No. WO02 / 02560, No. WO01 / 34594, No. WO02 / 38541, WO02 / 083128, WO03 / 072556, WO03 / 002593, WO03 / 000250, WO03 / 000180, WO03 / 000181, EP1258476, WO03 / 002553, WO03 / 002531, WO03 / 002530, WO03 / 004496, WO03 / 0044 No. 98, No. WO03 / 024942, No. WO03 / 024965, No. WO03 / 033524, No. WO03 / 035057, No. WO03 / 035067, No. WO0 No. 3 / 037327, No. WO03 / 040174, No. WO03 / 045977, No. WO03 / 055881, No. WO03 / 057144, No. WO03 / 05766 No. 6, WO03 / 068748, WO03 / 068757, WO03 / 082817, WO03 / 101449, WO03 / 101958, WO03 / No. 104229, No. WO03 / 74500, No. WO2004 / 007446, No. WO2004 / 007468, No. WO2004 / 018467, No. WO2004 / No. 018468, No. WO2004 / 018469, No. WO2004 / 026822, No. WO2004 / 032836, No. WO2004 / 033455, No. WO200 4 / 037169, WO2004 / 041795, WO2004 / 043940, WO2004 / 048352, WO2004 / 050022, WO 2004 / 052850, WO2004 / 058266, WO2004 / 064778, WO2004 / 069162, WO2004 / 071454,WO2004 / 076433, WO2004 / 076434, WO2004 / 087053, WO2004 / 089362, WO2004 / 099185, WO2004 / 10 No. 3276, No. WO2004 / 103993, No. WO2004 / 108730, No. WO2004 / 110436, No. WO2004 / 111041, No. WO2004 / 112701, No. WO2 No. 005 / 000846, No. WO2005 / 000848, No. WO2005 / 011581, No. WO2005 / 016911, No. WO2005 / 023762, No. WO2005 / 02555 No. 4, WO2005 / 026148, WO2005 / 030751, WO2005 / 033106, WO2005 / 037828, WO2005 / 040095, WO2005 / No. 044195, No. WO2005 / 047297, No. WO2005 / 051950, No. WO2005 / 056003, No. WO2005 / 056013, No. WO2005 / 058849, W No. O2005 / 075426, No. WO2005 / 082348, No. WO2005 / 085246, No. WO2005 / 087235, No. WO2005 / 095339, No. WO2005 / 0953 No. 43, WO2005 / 095381, WO2005 / 108382, WO2005 / 113510, WO2005 / 116014, WO2005 / 116029, WO200 No. 5 / 118555, No. WO2005 / 120494, No. WO2005 / 121089, No. WO2005 / 121131, No. WO2005 / 123685, No. WO2006 / 995613; Nos. WO2006 / 009886; WO2006 / 013104; WO2006 / 017292; WO2006 / 019965; WO2006 / 020017; WO2006 / 023750; WO2006 / 039325; WO2006 / 041976; WO2006 / 047248; WO2006 / 058064; WO2006 / 058628; WO2006 / 066747; WO2006 / 066770, and WO2006 / 068978.

[0201] Suitable DP IV inhibitors for the purposes of the present invention are, for example, sitagliptin, des-fluoro-sitagliptin (Merck); vildagliptin, DPP-728, SDZ-272-070 (Novartis); ABT-279, ABT-341 (Abbott Laboratories); denagliptin, TA-6666 (GlaxoSmithKline); SYR-322 (Takeda San Diego); talabostat (Point Therapeutics); Ro-0730699, R-1499, R-1438 (Roche Holdings); FE-999011 (Ferring Pharmaceuticals); TS-021 (Taisho Pharmaceuticals); GRC-8200 (Glenmark Pharmaceuticals); ALS-2-0426 (Alantos Pharmaceuticals Holding); ARI-2243 (Arisaph Pharmaceuticals); SSR-162369 (Sanofi-Synthelabo); MP-513 (Mitsubishi Pharma); DP-893, CP-867534-01 (Pfizer); TSL-225, TMC-2A (Tanabe Pharmaceuticals); PHX-1149 (Phenomenix); saxagliptin (Bristol-Myers Squibb); PSN-9301 ((OSI) Prosidion), S-40755 (Servier); KRP-104 (ActivX Biosciences); sulphostin (Zaidan Hojin); KR-62436 (Korea Chemical Technology Research Institute); P32 / 98 (Probiodrug); BI-A, BI-B (Boehringer Ingelheim); SK-0403 (Sanhwa Chemical Research Institute); and NNC-72-2138 (Novo Nordisk).

[0202] Other preferred DP IV inhibitors are (i) dipeptide-like compounds disclosed in WO 99 / 61431, such as N-valylprolyl, O-benzoylhydroxylamine, alanylpyrrolidine, isoleucylthiazolidine such as L-allo-isoleucylthiazolidine, L-threo-isoleucylpyrrolidine and its salts, in particular the fumarate salt, and L-allo-isoleucylpyrrolidine and its salts; (ii) peptide structures disclosed in WO 03 / 002593, e.g., tripeptides; (iii) peptidyl ketones as disclosed in WO 03 / 033524; (vi) substituted aminoketones as disclosed in WO 03 / 040174; (v) locally active DP IV inhibitors as disclosed in WO 01 / 14318; (vi) prodrugs of the DP IV inhibitors disclosed in WO 99 / 67278 and WO 99 / 67279; and (v) Glutaminyl-based DP IV inhibitors disclosed in WO 03 / 072556 and WO 2004 / 099134 It is.

[0203] Suitable beta amyloid synthesis inhibitors for the purposes of the present invention are, for example, Bisnorcymserine (Axonyx); (R)-flurbiprofen (MCP-7869; Flurisan) (Myriad Genetics); Nitroflurbiprofen (NicOx); BGC-20-0406 (Sankyo Pharmaceuticals), and BGC-20-0466 (BTG), RQ-00000009 (RaQualia Pharma).

[0204] Suitable amyloid protein deposition inhibitors for the purposes of the present invention are, for example, SP-233 (Samaritan Pharmaceuticals); AZD-103 (Ellipsis Neurotherapeutics); AAB-001 (bapineuzumab), AAB-002, ACC-001 (Elan); colostrinin (ReGen Therapeutics); tramiprosate (Neurochem); AdPEDI-(amyloid-β1-6)11) (Vaxin); MPI-127585, MPI-423948 (Mayo Foundation); SP-08 (Georgetown University); ACU-5A5 (Acumen / Merck); transthyretin (State University of New York); PTI-777, DP-74, DP 68, Exebril (ProteoTech); m266 (Eli Lilly); EGb-761 (Dr. Willmar Schwabe); SPI-014 (Satori Pharmaceuticals); ALS-633, ALS-499 (Advanced Life Sciences); AGT-160 (ArmaGen Technologies); TAK-070 (Takeda Pharmaceuticals); CHF-5022, CHF-5074, CHF-5096, and CHF-5105 (Chiesi Farmaceutici), SEN-1176 and SEN-1329 (Senexis), AGT-160 (ArmaGen Technologies), davunetide (Allon Therapeutics), ELND-005 (Elan / Transition Therapeutics), and nilvadipine (Archer Pharmaceuticals).

[0205] Suitable PDE-4 inhibitors for the purposes of the present invention are, for example, doxofylline (Instituto Biologico Chemioterapica ABC); izudilast eye drops, tipelukast, ibudilast (Kyorin Pharmaceuticals); theophylline (Elan); cilomilast (GlaxoSmithKline); Atopik (Barrier Therapeutics); tofimilast, CI-1044, PD-189659, CP-220629, PDE 4d inhibitor BHN (Pfizer); allofylline, LAS-37779 (Almirall Prodesfarma); roflumilast, hydroxypumafentrine (Altana), tetomilast (Otsuka Pharmaceuticals); tipelukast, ibudilast (Kyorin Pharmaceuticals), CC-10004 (Celgene); HT-0712, IPL-4088 (Inflazyme Pharmaceuticals); MEM-1414, MEM-1917 (Memory Pharmaceuticals); oglemilast, GRC-4039 (Glenmark Pharmaceuticals); AWD-12-281, ELB-353, ELB-526 (Elbion); EHT-0202 (ExonHit Therapeutics); ND-1251 (Neuro3d); 4AZA-PDE4 (4 AZA Bioscience NV); AVE-8112 (Sanofi Aventis); CR-3465 (Rottapharm); GP-0203, NCS-613 (French National Center for Scientific Research); KF-19514 (Kyowa Hakko Kogyo); ONO-6126 (Ono Pharmaceutical); OS-0217 (Dainippon Pharmaceutical); IBFB-130011, IBFB-150007, IBFB-130020, IBFB-140301 (IBFB Pharma); IC-485 (ICOS); RBx-14016, and RBx-11082 (Ranbaxy Laboratories). A preferred PDE-4-inhibitor is rolipram.

[0206] MAO inhibitors and compositions containing such inhibitors are described, for example, in WO2006 / 091988, WO2005 / 007614, WO2004 / 089351, WO01 / 26656, WO01 / 12176, WO99 / 57120, WO99 / 57119, WO99 / 13878, WO98 / 40102, WO98 / 01157, WO96 / 20946, WO94 / 07890, and WO92 / 21333.

[0207] Suitable MAO inhibitors for the purposes of the present invention are, for example, linezolid (Pharmacia); RWJ-416457 (RW Johnson Pharmaceutical Laboratories); budipine (Altana); GPX-325 (BioResearch Ireland); isocarboxazid; phenelzine; tranylcypromine; indantadol (Chiesi Farmaceutici); moclobemide (Roche Holdings); SL-25.1131 (Sanofi-Synthelabo); CX-1370 (Burroughs Wellcome); CX-157 (Krenitsky Pharmaceuticals); desoxypeganine (HF Arzneimittelforschung); bifemelane (Mitsubishi Tokyo Pharma); RS-1636 (Sankyo Pharmaceuticals); Esprone (BASF); rasagiline (Teva Pharmaceutical Industries); radstigil (Hebrew University of Jerusalem); safinamide (Pfizer), NW-1048 (Newron Pharmaceuticals), and EVT-302 (Evotec).

[0208] Suitable histamine H3 antagonists for the purposes of the present invention are, for example, ABT-239, ABT-834 (Abbott Laboratories); 3874-H1 (Aventis Pharma); UCL-2173 (Free University Berlin), UCL-1470 (BioProjet, Societe Civile de Recherche); DWP-302 (Daewoong Pharmaceutical); GSK-189254A, GSK-207040A (GlaxoSmithKline); Cipralisant, GT-2203 (Gliatech); Ciproxifan (INSERM), 1S,2S-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (Hokkaido University); JNJ-17216498, JNJ-5207852 (Johnson & Johnson); NNC-0038-0000-1049 (Novo Nordisk); and Sch-79687 (Schering-Plough).

[0209] PEP inhibitors and びそのような Inhibitors contain する compositions は, example えば, JP No. 01042465, JP 03031298, JP 04208299, WO 00 / 71144, US No. 5,847,155; JP 09040693, JP 10077300, JP 05331072, JP 05015314, WO 95 / 15310, WO 93 / 00361, EP 0556482, JP 06234693, JP No. 01068396, EP No. 0709373, US No. 5,965,556, US No. 5,756,763, US No. 6,121,311, JP No. 63264454, JP No. 64000069, JP No. 63162672, EP No. 0268190, EP No. 0277588, EP No. 0275482, US No. 4,977,180, US No. 5,091,406, US No. 4,983,624, US No. 5,112,847, US No. 5,100,904, US No. 5,254,550, US No. 5,262,431, US No. 5,340,832, US No. 4,956,380, EP No. 0303434, JP 03056486, JP 01143897, JP 1226880, EP 0280956, US 4,857,537, EP 0461677, EP 0345428, JP 02275858, US 5,506,256, JP 06192298, EP 0618193, JP 03255080, EP 0468469, US 5,118,811, JP 05025125, WO 9313065, JP 05201970, WO 9412474, EP 0670309, EP 0451547, JP 06339390, US 5,073,549, US 4,999,349, EP 0268281, US 4,743,616, EP 0232849, EP 0224272, JP 62114978, JP 62114957, US 4,757,083, US 4,810,721, US 5,198,458, US 4,826,870, EP 0201742, EP 0201741, US 4,873,342, EP 0172458, JP 61037764, EP 0201743, US 4,772,587, EP 0372484, US 5,028,604, WO 91 / 18877, JP 04009367, JP 04235162, US 5,407,950, WO 95 / 01352, JP 01250370, JP 02207070, US 5,221,752, EP 0468339, JP 04211648, WO 99 / 46272, WO 2006 / 058720, and PCT / EP2006 / 061428.

[0210] Suitable prolyl endopeptidase inhibitors for the purposes of the present invention are, for example, Fmoc-Ala-Pyrr-CN, Z-Phe-Pro-benzothiazole (Probiodrug), Z-321 (Zeria Pharmaceutical Co., Ltd.); ONO-1603 (Ono Pharmaceutical Co., Ltd.); JTP-4819 (Japan Tobacco Inc.), and S-17092 (Servier).

[0211] Other suitable compounds which can be used in combination with QC inhibitors according to the invention are NPY, NPY mimetics, or NPY agonists or antagonists, or ligands of the NPY receptor.

[0212] Preferred according to the invention are antagonists of the NPY receptor.

[0213] Suitable ligands or antagonists for NPY receptors are the compounds derived from 3a,4,5,9b-tetrahydro-1h-benzo[e]indol-2-ylamine, which are disclosed in WO 00 / 68197.

[0214] NPY receptor antagonists which may be mentioned include those described in European Patent Applications EP 0 614 911, EP 0 747 357, EP 0 747 356 and EP 0 747 378; International Patent Applications WO 94 / 17035, WO 97 / 19911, WO 97 / 19913, WO 96 / 12489, WO 97 / 19914, WO 96 / 22305, WO 96 / 40660, WO 96 / 12490, WO 97 / 09308, WO 97 / 20820, WO 97 / 20821, WO 97 / 20822, WO 97 / 20823, WO Nos. 5,552,411, 5,663,192, and 5,567,714; 6,114,336, Japanese Patent Application JP 09157253; International Patent Applications WO 94 / 00486, WO 93 / 12139, WO 95 / 00161, and WO 98 / 07420; WO 00 / 30674, U.S. Patent Nos. 5,552,411, 5,663,192, and 5,567,714; 99 / 15498; U.S. Patent No. 5,328,899; German Patent Application DE 393 97 97; European Patent Applications EP 355 794 and EP 355 793; and Japanese Patent Applications JP 06116284 and JP 07267988. Preferred NPY antagonists include those specifically disclosed in these patent documents. More preferred compounds include amino acid and non-peptide based NPY antagonists.Amino acid and non-peptide based NPY antagonists which may be mentioned include those described in European Patent Applications EP 0 614 911, EP 0 747 357, EP 0 747 356, and EP 0 747 378; International Patent Applications WO 94 / 17035, WO 97 / 19911, WO 97 / 19913, WO 96 / 12489, WO 97 / 19914, WO 96 / 22305, WO 96 / 40660, WO 96 / 12490, WO 97 / 09308, WO 97 / 20820, WO 97 / 20821, WO 97 / 20822, WO Nos. 5,552,411, 5,663,192, and 5,567,714; and Japanese Patent Application JP 09157253. Preferred amino acid and non-peptide based NPY antagonists include those disclosed specifically in these patent documents.

[0215] Particularly preferred compounds include amino acid-based NPY antagonists.The amino acid-based compounds that may be mentioned include those disclosed in International Patent Application WO 94 / 17035, WO 97 / 19911, WO 97 / 19913, WO 97 / 19914, or preferably WO 99 / 15498.Preferred amino acid-based NPY antagonists include those specifically disclosed in these patent documents, such as BIBP3226, in particular (R)-N2-(diphenylacetyl)-(R)-N-[1-(4-hydroxy-phenyl)ethyl]argininamide (Example 4 of International Patent Application WO 99 / 15498).

[0216] M1 receptor agonists and compositions containing such inhibitors are described, for example, in WO2004 / 087158 and WO91 / 10664.

[0217] Suitable M1 receptor antagonists for the purposes of the present invention are, for example, CDD-0102 (Cognitive Pharmaceuticals); cevimeline (Evoxac) (Snow Brand Milk Products); NGX-267 (TorreyPines Therapeutics); sabcomeline (GlaxoSmithKline); albamelin (H Lundbeck); LY-593093 (Eli Lilly); VRTX-3 (Vertex Pharmaceuticals); WAY-132983 (Wyeth), CI-1017 / (PD-151832) (Pfizer), and MCD-386 (Mitridion).

[0218] Acetylcholinesterase inhibitors and compositions containing such inhibitors are described, for example, in WO2006 / 071274, WO2006 / 070394, WO2006 / 040688, WO2005 / 092009, WO2005 / 079789, WO2005 / 039580, WO2005 / 0 No. 27975, No. WO2004 / 084884, No. WO2004 / 037234, No. WO2004 / 032929, No. WO03 / 101458, No. WO03 / 091220, WO03 / 082820, WO03 / 020289, WO02 / 32412, WO01 / 85145, WO01 / 78728 No., WO01 / 66096, WO00 / 02549, WO01 / 00215, WO00 / 15205, WO00 / 23057, WO00 / 33 No. 840, No. WO00 / 30446, No. WO00 / 23057, No. WO00 / 15205, No. WO00 / 09483, No. WO00 / 07600, No. WO00 / 02549, WO99 / 47131, WO99 / 07359, WO98 / 30243, WO97 / 38993, WO97 / 13754, WO94 / 29255, WO94 / 20476, WO94 / 19356, WO93 / 03034, and WO92 / 19238.

[0219] Suitable acetylcholinesterase inhibitors for the purposes of the present invention are, for example, donepezil (Eisai); rivastigmine (Novartis); (-)-phenserine (TorreyPines Therapeutics); ladostigil (Hebrew University of Jerusalem); Huperzine A (Mayo Foundation); galantamine (Johnson & Johnson); Memoquin (University of Bologna); SP-004 (Samaritan Pharmaceuticals); BGC-20-1259 (Sankyo Pharmaceutical); physostigmine (Forest Laboratories); NP-0361 (Neuropharma); ZT-1 (Debiopharm); tacrine (Warner-Lambert); metrifonate (Bayer), INM-176 (WhanIn), Huperzine A (Neuro-Hitech / Xel Pharmaceutical), mimopezil (Debiopharm), and dimebon (MediVation / Pfizer).

[0220] NMDA receptor antagonists and compositions containing such inhibitors are described, for example, in WO2006 / 094674, WO2006 / 058236, WO2006 / 058059, WO2006 / 010965, WO2005 / 000216, WO2005 / 102390, WO2005 / 079779, WO2005 / 079756, WO2005 / 072705, WO2005 / 070429, WO2005 / 055996, , WO2005 / 035522, WO2005 / 009421, WO2005 / 000216, WO2004 / 092189, WO2004 / 039371, WO2004 / 028522, WO2004 / 009 No. 062, No. WO03 / 010159, No. WO02 / 072542, No. WO02 / 34718, No. WO01 / 98262, No. WO01 / 94321, No. WO01 / 92204, No. WO01 / 81295, No. WO01 / 32640 , WO01 / 10833, WO01 / 10831, WO00 / 56711, WO00 / 29023, WO00 / 00197, WO99 / 53922, WO99 / 48891, WO99 / 45963, WO99 / 01416, WO99 / 07413, WO99 / 01416, WO98 / 50075, WO98 / 50044, WO98 / 10757, WO98 / 05337, WO97 / 32873, WO97 / 23216 No. 6,393,621, WO97 / 23215, WO97 / 23214, WO96 / 14318, WO96 / 08485, WO95 / 31986, WO95 / 26352, WO95 / 26350, WO95 / 26349, WO95 / 26342, WO95 / 12594, WO95 / 02602, WO95 / 02601, WO94 / 20109, WO94 / 13641, WO94 / 09016, and WO93 / 25534.

[0221] Suitable NMDA receptor antagonists for the purposes of the present invention include, for example, memantine (Merz); topiramate (Johnson & Johnson); AVP-923 (Neurodex) (Neurological Research Center); EN-3231 (Endo Pharmaceuticals Holdings); neramexane (MRZ-2 / 579) (Merz and Forest); CNS-5161 (CeNeS Pharmaceuticals); dexanabinol (HU-211; cinnabidol; PA-50211) (Pharmos); EpiCept NP-1 (Dalhousie University); indantadol (V-3381; CNP-3381) (Vernalis); perzinfotel (EAA-090, WAY-126090, EAA-129) (Wyeth); RGH-896 (Gedeon Richter's; Traxoprodil (CP-101606), Besonprodil (PD-196860, CI-1041) (Pfizer); CGX-1007 (Cognetix); Delcemin (NPS-1506) (NPS Pharmaceuticals); EVT-101 (Roche Holdings); Acamprosate (Synchroneuron); CR-3991, CR-2249, CR-3394 (Rottapharm); AV-101 (4-Cl-kynurenine (4-Cl-KYN)), 7-chloro-kynurenic acid (7-Cl-KYNA) (VistaGen); NPS-1407 (NPS Pharmaceuticals); YT-1006 (Yaupon Therapeutics); ED-1812 (Sosei R&D; himantane (N-2-(adamantly)-hexamethylene-imine hydrochloride) (RAMS); lancisamine (AR-R-15896) (AstraZeneca); EVT-102, Ro-25-6981, and Ro-63-1908 (Hoffmann-La Roche / Evotec), neramexane (Merz).

[0222] Furthermore, the present invention relates to combination therapies useful for the treatment of atherosclerosis, restenosis or arthritis, in which a QC inhibitor is administered in combination with another therapeutic agent selected from the group consisting of inhibitors of angiotensin converting enzyme (ACE); angiotensin II receptor blockers; diuretics; calcium channel blockers (CCBs); β-blockers; platelet aggregation inhibitors; cholesterol absorption modulators; HMG-Co-A reductase inhibitors; high density lipoprotein (HDL) increasing compounds; renin inhibitors; IL-6 inhibitors; anti-inflammatory corticosteroids; antiproliferative agents; nitric oxide donors; inhibitors of extracellular matrix synthesis; growth factor or cytokine signaling inhibitors; MCP-1 antagonists, and tyrosine kinase inhibitors, resulting in a beneficial or synergistic therapeutic effect over each monotherapy component alone.

[0223] Angiotensin II receptor blockers are understood to be active agents that bind to the AT1 receptor subtype of angiotensin II receptors but do not cause activation of said receptor. As a result of blocking the AT1 receptor, these antagonists can be used, for example, as antihypertensive agents.

[0224] Suitable angiotensin II receptor blockers that may be used in the combination of the present invention include AT1 receptor antagonists with various structural features, preferably those with non-peptidic structures, such as valsartan (EP 443983), losartan (EP 253310), candesartan (EP 459136), eprosartan (EP 403159), irbesartan (EP 454511), olmesartan (EP 503785), tasosartan (EP 539086), telmisartan (EP 522314), the compound having the symbol E-4177 and the formula: [ka] A compound of the formula: [ka] and the compound of the following formula having the symbol ZD-8731: [ka] or, in each case, a pharma- ceutically acceptable salt thereof.

[0225] Preferred AT1-receptor antagonists are approved and marketed drugs, most preferred is valsartan or a pharma- ceutically acceptable salt thereof.

[0226] Blocking the enzymatic degradation of angiotensin to angiotensin II by ACE inhibitors is a successful transformation in blood pressure regulation and therefore also makes available a therapeutic approach for the treatment of hypertension.

[0227] Suitable ACE inhibitors for use in the combination of the present invention are, for example, a compound selected from the group consisting of alacepril, benazepril, benazeprilat; captopril, ceronapril, cilazapril, delapril, enalapril, enaprilat, fosinopril, imidapril, lisinopril, movertpril, perindopril, quinapril, ramipril, spirapril, temocapril, and trandolapril, or, in each case, a pharma- ceutically acceptable salt thereof.

[0228] Preferred ACE inhibitors are those agents which have been marketed, most preferred are benazepril and enalapril.

[0229] The diuretic is, for example, a thiazide derivative selected from the group consisting of chlorothiazide, hydrochlorothiazide, methylclothiazide, and chlorothalidon. The most preferred diuretic is hydrochlorothiazide. The diuretic further includes a potassium-sparing diuretic, for example, amiloride or triamterine, or a pharma- ceutically acceptable salt thereof.

[0230] The class of CCBs essentially includes dihydropyridines (DHPs), as well as non-DHPs, such as diltiazem-type and verapamil-type CCBs.

[0231] The CCBs useful in the combination are preferably representative DHPs selected from the group consisting of amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, and nivaldipine, and preferably representative non-DHPs selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil, and verapamil, and in each case, pharma- ceutically acceptable salts thereof. All of these CCBs are used therapeutically, for example as antihypertensives, antianginals, or antiarrhythmics.

[0232] Preferred CCBs include amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil, or, depending on the particular CCB, for example, a pharma- ceutically acceptable salt thereof. Particularly preferred as a DHP is amlodipine or a pharma- ceutically acceptable salt thereof, in particular the besylate salt. A particularly preferred representative of a non-DHP is verapamil or a pharma- ceutically acceptable salt thereof, in particular the hydrochloride salt thereof.

[0233] Suitable β-blockers for use in the present invention include β-adrenergic blocking agents (β-blockers), which compete with epinephrine for β-adrenergic receptors and block the action of epinephrine. Preferably, the β-blockers are selective for β-adrenergic receptors compared to α-adrenergic receptors and therefore do not have significant α-blocking effects. Suitable β-blockers include compounds selected from acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, and timolol. Where the β-blocker is an acid or base, or is otherwise capable of forming a pharma- ceutically acceptable salt or prodrug, these forms are considered to be encompassed herein, with the understanding that the compound may be administered in free form or in the form of a pharma- ceutically acceptable salt or prodrug, such as a physiologically hydrolyzable and acceptable ester. For example, metoprolol is suitably administered as its tartrate salt, propranolol is suitably administered as the hydrochloride salt, and so forth.

[0234] Platelet aggregation inhibitors include PLAVIX® (clopidogrel bisulfate), PLETAL® (cilostazol), and aspirin.

[0235] Cholesterol absorption modulators include ZETIA® (ezetimibe) and KT6-971 (Kotobuki Pharmaceutical, Japan).

[0236] HMG-Co-A reductase inhibitors (also called β-hydroxy-β-methylglutaryl-coenzyme A reductase inhibitors or statins) are understood to be active agents that can be used to lower lipid levels, including cholesterol, in the blood.

[0237] The class of HMG-Co-A reductase inhibitors includes compounds with various structural features. For example, mention may be made of the compounds selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, or in each case, their pharma- ceutically acceptable salts.

[0238] Preferred HMG-Co-A reductase inhibitors are those agents which have been marketed, most preferred being atorvastatin, pitavastatin or simvastatin, or a pharma- ceutically acceptable salt thereof.

[0239] HDL-increasing compounds include, but are not limited to, cholesterol ester transfer protein (CETP) inhibitors. Examples of CETP inhibitors include JTT7O5 and its pharma- ceutical acceptable salts, which are disclosed in Example 26 of U.S. Patent No. 6,426,365, issued July 30, 2002.

[0240] Inhibition of interleukin-6 mediated inflammation can be achieved indirectly by modulation of endogenous cholesterol synthesis and isoprenoid depletion, or by direct inhibition of signal transduction pathways utilizing interleukin-6 inhibitors / antibodies, interleukin-6 receptor inhibitors / antibodies, interleukin-6 antisense oligonucleotides (ASON), gp130 protein inhibitors / antibodies, tyrosine kinase inhibitors / antibodies, serine / threonine kinase inhibitors / antibodies, mitogen-activated protein (MAP) kinase inhibitors / antibodies, phosphatidylinositol 3-kinase (PI3K) inhibitors / antibodies, nuclear factor kappa B (NF-kappa B) inhibitors / antibodies, Ikappa B kinase (IKK) inhibitors / antibodies, activator protein-1 (AP-1) inhibitors / antibodies, STAT transcription factor inhibitors / antibodies, modified IL-6, partial peptides of IL-6 or IL-6 receptor, or SOCS (suppressors of cytokine signaling) proteins, PPAR gamma and / or PPAR beta / delta activators / ligands or functional fragments thereof.

[0241] A preferred anti-inflammatory corticosteroid is dexamethasone. Preferred antiproliferative agents are cladribine, rapamycin, vincristine, and taxol. A preferred extracellular matrix synthesis inhibitor is Halofuginone. A suitable growth factor or cytokine signaling inhibitor is, for example, the ras inhibitor R115777. A preferred tyrosine kinase inhibitor is a tyrphostin. Suitable renin inhibitors are described, for example, in WO 2006 / 116435. A preferred renin inhibitor is aliskiren, preferably in the form of its hemifumarate salt.

[0242] The MCP-1 antagonist may be selected, for example, from an anti-MCP-1 antibody, preferably a monoclonal antibody or a humanized monoclonal antibody, an MCP-1 expression inhibitor, a CCR2-antagonist, a TNF-α inhibitor, a VCAM-1 gene expression inhibitor, and an anti-C5a monoclonal antibody.

[0243] MCP-1 antagonists and compositions containing such inhibitors are described, for example, in WO02 / 070509, WO02 / 081463, WO02 / 060900, US2006 / 670364, US2006 / 677365, WO2006 / 097624, US2006 / 316449, WO2004 / 056727, WO03 / 053368, WO00 / 198289, WO00 / 157226, WO00 / 046195, , WO00 / 046196, WO00 / 046199, WO00 / 046198, WO00 / 046197, WO99 / 046991, WO99 / 007351, WO98 / 006703, WO97 / 012615, WO2005 / 105133, WO03 / 037376, WO2006 / 125202, WO2006 / 085961, WO2004 / 024921, WO2006 / 074265.

[0244] Suitable MCP-1 antagonists include, for example, C-243 (Telik); NOX-E36 (Noxxon Pharma); AP-761 (Actimis Pharmaceuticals); ABN-912, NIBR-177 (Novartis); CC-11006 (Celgene); SSR-150106 (Sanofi Aventis); MLN-1202 (Millenium Pharmaceuticals); AGI-1067, AGIX-4207, AGI-1096 (Atherio Genics); PRS-211095, PRS-211092 (Pharmos); anti-C5a monoclonal antibodies, for example neutrazumab (G2 Therapies); AZD-6942 (AstraZeneca); 2-mercaptoimidazole (Johnson & Johnson); TEI-E00526, TEI-6122 (Deltagen); RS-504393 (Roche Holdings); SB-282241, SB-380732, ADR-7 (GlaxoSmithKline); and anti-MCP-1 monoclonal antibody (Johnson & Johnson).

[0245] The combination of a QC inhibitor with an MCP-1 antagonist may be useful for the treatment of inflammatory diseases in general, including neurodegenerative diseases.

[0246] The combination of a QC inhibitor with an MCP-1 antagonist is preferred for the treatment of Alzheimer's disease.

[0247] Most preferably, the QC inhibitor is combined with one or more compounds selected from the following group: PF-4360365, m266, bapineuzumab, R-1450, Posiphen, (+)-phenserine, MK-0752, LY-450139, E-2012, (R)-flurbiprofen, AZD-103, AAB-001 (bapineuzumab), tramiprosate, EGb-761, TAK-070, doxofylline, theophylline, cilomilast, tofimilast, roflumilast, tetomilast, tipelukast, ibudilast, HT-0712, MEM-1414, oglemilast, linezolid, budilast , isocarboxazid, phenelzine, tranylcypromine, indantadol, moclobemide, rasagiline, ladostigil, safinamide, ABT-239, ABT-834, GSK-189254A, ciproxifan, JNJ-17216498, Fmoc-Ala-Pyrr-CN, Z-Phe-Pro-benzothiazole, Z-321, ONO-1603, JTP-4819, S-17092, BIBP3226; (R)-N2-(diphenylacetyl)-(R)-N-[1-(4-hydroxyphenyl) (ethyl)argininamide, cevimeline, sabcomeline, (PD-151832), donepezil, rivastigmine, (-)-phenserine, ladostigil, galantamine, tacrine, metrifonate, memantine, topiramate, AVP-923, EN-3231, neramexane, valsartan, benazepril, enalapril, hydrochlorothiazide, amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, verapamil, amlodipine, acebuphenone, tolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol, PLAVIX® (clopidogrel bisulfate), PLETAL® (cilostazol), aspirin, ZETIA® (ezetimibe) and KT6-971, the statins, atorvastatin, pitavastatin, or simvastatin;Dexamethasone, Cladribine, Rapamycin, Vincristine, Taxol, Aliskiren, C-243, ABN-912, SSR-150106, MLN-1202, and Betaferon.

[0248] In particular, the following combinations are considered: - a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with atorvastatin, for the treatment and / or prevention of atherosclerosis, a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with an immunosuppressant, preferably rapamycin, for the prevention and / or treatment of restenosis, a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with an immunosuppressant, preferably paclitaxel, for the prevention and / or treatment of restenosis, - a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with an AChE inhibitor, preferably donepezil, for the prevention and / or treatment of Alzheimer's disease, a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with an interferon, preferably Aronex, for the prevention and / or treatment of multiple sclerosis, - a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with an interferon, preferably betaferon, for the prevention and / or treatment of multiple sclerosis, a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with an interferon, preferably Rebif, for the prevention and / or treatment of multiple sclerosis, a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with copaxone, for the prevention and / or treatment of multiple sclerosis, a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with dexamethasone, for the prevention and / or treatment of restenosis, a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with dexamethasone, for the prevention and / or treatment of atherosclerosis, A combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with dexamethasone for the prevention and / or treatment of rheumatoid arthritis. - a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with an HMG-Co-A-reductase inhibitor, where the HMG-Co-A-reductase inhibitor is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, for the prevention and / or treatment of restenosis. - a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with an HMG-Co-A-reductase inhibitor, where the HMG-Co-A-reductase inhibitor is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, for the prevention and / or treatment of atherosclerosis. - a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with an HMG-Co-A-reductase inhibitor, where the HMG-Co-A-reductase inhibitor is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, for the prevention and / or treatment of rheumatoid arthritis. - a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with an amyloid-β antibody, for the prevention and / or treatment of mild cognitive impairment, wherein the amyloid-β antibody is Acl-24 - a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with an amyloid-β antibody, for the prevention and / or treatment of Alzheimer's disease, wherein the amyloid-β antibody is Acl-24. - a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with an amyloid-β antibody, for the prevention and / or treatment of neurodegeneration in Down's syndrome, wherein the amyloid-β antibody is Acl-24 - a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with a beta-secretase inhibitor, for the prevention and / or treatment of mild cognitive impairment, wherein the beta-secretase inhibitor is selected from WY-25105, GW-840736X, and CTS-21166 - a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with a β-secretase inhibitor, for the prevention and / or treatment of Alzheimer's disease, where the β-secretase inhibitor is selected from WY-25105, GW-840736X and CTS-21166 - a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, in combination with a beta-secretase inhibitor, for the prevention and / or treatment of neurodegeneration in Down's syndrome, wherein the beta-secretase inhibitor is selected from WY-25105, GW-840736X and CTS-21166 - a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with a γ-secretase inhibitor, for the prevention and / or treatment of mild cognitive impairment, wherein the γ-secretase inhibitor is selected from LY-450139, LY-411575 and AN-37124. - a combination of a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323, with a γ-secretase inhibitor, for the prevention and / or treatment of Alzheimer's disease, where the γ-secretase inhibitor is selected from LY-450139, LY-411575 and AN-37124. - a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of Examples 1 to 1323 in combination with a γ-secretase inhibitor, wherein the γ-secretase inhibitor is selected from LY-450139, LY-411575, and AN-37124, for the prevention and / or treatment of neurodegeneration in Down's syndrome.

[0249] Such combination therapy is particularly useful in the neurodegeneration of AD, FAD, FDD, and Down's syndrome, as well as atherosclerosis, rheumatoid arthritis, restenosis, and pancreatitis.

[0250] Such combination therapy may result in better therapeutic effects (reduced proliferation as well as reduced inflammation, which is a stimulus to proliferation) than either agent alone.

[0251] With regard to specific combinations of QC inhibitors with further compounds, particular reference is made to WO 2004 / 098625 in this regard, which is incorporated herein by reference.

[0252] Pharmaceutical Composition To prepare the pharmaceutical composition of the present invention, at least one compound of formula (I) can be used as an active ingredient, optionally in combination with at least one of the other aforementioned agents. The active ingredient is intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, and the carrier can take a wide variety of forms, depending on the form of preparation desired for parenteral administration, such as oral or intramuscular administration. When preparing the composition in oral dosage form, any of the usual pharmaceutical media can be utilized. Thus, for liquid oral preparations, such as suspensions, elixirs, and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like; for solid oral preparations, such as powders, capsules, gelcaps, and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. Tablets and capsules are the most advantageous oral dosage unit forms due to their ease of administration, in which case solid pharmaceutical carriers are obviously used. If desired, tablets can be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.

[0253] Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents, and the like may be utilized. The pharmaceutical compositions herein contain the amount of active ingredient necessary to deliver an effective amount as described above per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful, etc. The pharmaceutical compositions herein contain about 0.03 mg to 100 mg / kg (preferably 0.1 to 30 mg / kg) per dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful, etc., and may be administered at a dosage of about 0.1 to 300 mg / kg / day (preferably 1 to 50 mg / kg / day) of each active ingredient or combination thereof. However, the dosage may vary depending on the needs of the patient, the severity of the condition being treated, and the compound being utilized. The use of either daily or post-periodic administration may be utilized.

[0254] Preferably, these compositions are in unit dosage form, such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosols or liquid sprays, drops, ampoules, auto-injector devices, or suppositories, for oral, parenteral, intranasal, sublingual, or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be provided in a form suitable for weekly or monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. To prepare solid compositions, such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, such as conventional tableting ingredients, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dibasic calcium phosphate, or gums, and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a homogeneous mixture of the compound of the present invention or a pharma-ceutically acceptable salt thereof. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is uniformly dispersed throughout the composition such that the composition can be readily subdivided into equally effective dosage forms such as tablets, pills, and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of each active ingredient or combinations thereof of the present invention.

[0255] The tablet or pill of the composition of the present invention can be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action.For example, the tablet or pill can comprise an inner dosage component and an outer dosage component, the outer dosage component being in the form of an envelope covering the inner dosage component.These two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allows the inner component to pass intact into the duodenum or be delayed in release.Various materials can be used for such enteric layers or coatings, including some polymeric acids, including materials such as shellac, cetyl alcohol, and cellulose acetate.

[0256] The liquid forms into which the compositions of the present invention may be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions including edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums, such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, or gelatin.

[0257] The pharmaceutical composition may contain about 0.01 mg to 100 mg, preferably about 5 to 50 mg, of each compound and may be configured into any form suitable for the selected mode of administration. Carriers include necessary and inert pharmaceutical excipients, including but not limited to binders, suspending agents, lubricants, flavorings, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid dosage forms such as pills, tablets, caplets, capsules (each including immediate release, sustained release, and extended release formulations), granules, and powders, as well as liquid dosage forms such as solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.

[0258] Advantageously, the compound of the present invention can be administered in a single dose per day, or the total daily dosage can be administered in divided doses of 2, 3 or 4 times per day.Furthermore, the compound of the present invention can be administered in intranasal form by topical use of suitable intranasal vehicles, or by transdermal skin patches well known to those skilled in the art.To be administered in the form of a transdermal delivery system, the administration of this dosage will naturally be continuous, not intermittent, throughout the entire dosage regimen.

[0259] For example, for oral administration in the form of tablet or capsule, the active drug component can be combined with an oral non-toxic pharma- ceutically acceptable inert carrier, such as ethanol, glycerol, water, etc. Furthermore, if desired or necessary, suitable binders; lubricants, disintegrants, and colorants can also be incorporated into this mixture. Suitable binders include, but are not limited to, starch, gelatin, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums, such as gum arabic, tragacanth, or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0260] Liquid forms in suitable flavored suspending or dispersing agents, such as natural and synthetic gums, for example, tragacanth, acacia, methyl-cellulose, etc. For parenteral administration, sterile suspensions and solutions are desired. When intravenous administration is desired, isotonic preparations, which generally contain suitable preservatives, are employed.

[0261] The compounds or combinations of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0262] The compounds or combinations of the present invention can also be delivered by using monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamid-ephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. In addition, the compounds of the present invention can be coupled with crosslinked or amphiphilic block copolymers of biodegradable polymer classes useful for achieving controlled release of drugs, such as polyactic acid, polyepsiloncaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels.

[0263] The compounds or combinations of the present invention can be administered in any of the compositions described above and according to dosing regimens established in the art whenever necessary to treat the disorder addressed.

[0264] The daily dosage of the product may vary over a wide range from 0.01 to 1.000 mg per mammal per day. For oral administration, the composition is preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, and 500 mg of each active ingredient or combination thereof, for symptomatic adjustment of the dosage to the patient being treated. An effective amount of the drug is usually supplied at a dosage level of about 0.1 mg / kg to about 300 mg / kg body weight per day. Preferably, the range is about 1 to about 50 mg / kg body weight per day. The compound or combination may be administered on a regimen of 1 to 4 times per day.

[0265] Optimal dosages to be administered can be readily determined by one of skill in the art and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additionally, it will be necessary to adjust the dosage depending on factors related to the particular patient being treated, including the patient's age, weight, diet, and time of administration.

[0266] In a further aspect, the present invention also provides a method for preparing a pharmaceutical composition comprising at least one compound of formula (I) optionally in combination with at least one other aforementioned agent and a pharma- ceutical acceptable carrier.

[0267] The composition is preferably in unit dosage form in an amount appropriate for the relevant daily dosage.

[0268] Suitable dosages, particularly including unit dosages, of the compounds of the invention include the known dosages, including unit doses, of these compounds described or referenced in the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (see, e.g., page 341 of the 31st Edition and pages cited therein), or in other references such as the publications mentioned above. EXAMPLES

[0269] (Example) In a further embodiment, the present invention provides compounds of formula (IIa) and (IIb), wherein X1, n, Z, Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y 10 , R5, and R6 are as defined in Examples 1-265: [ka] [Table 3] TIFF0007674811000060.tif234170TIFF0007674811000061.tif234170TIFF0007674811000062.tif235170TIFF00076748110 00063.tif235170TIFF0007674811000064.tif234170TIFF0007674811000065.tif234170TIFF0007674811000066.tif150170

[0270] In a further embodiment, the present invention provides compounds of formula (IIIa) and (IIIb), wherein X1, n, Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y 10 , R5, and R6 are as defined in Examples 266-443: [ka] [Table 4] TIFF0007674811000069.tif232170TIFF0007674811000070.tif233170TIFF0007674811000071.tif233170TIFF0007674811000072.tif227170

[0271] In a further embodiment, the present invention provides compounds of formula (IVa) and (IVb), wherein X1, o, Z, Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y 10 , R5, and R6 are as defined in Examples 444-795: [ka]

[0272] In both formulas (IVa) and (IVb), o is 0. [Table 5] TIFF0007674811000075.tif234170TIFF0007674811000076.tif233170TIFF000 7674811000077.tif234170TIFF0007674811000078.tif234170TIFF00076748110 00079.tif234170TIFF0007674811000080.tif234170TIFF0007674811000081.t if233170TIFF0007674811000082.tif234170TIFF0007674811000083.tif115170

[0273] In a further embodiment, the present invention provides compounds of formula (IVa) and (IVb), wherein X1, o, Z, Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y 10 , R5, and R6 are as defined in Examples 1289-1296: [ka]

[0274] In both formulas (IVa) and (IVb), o is 0. [Table 6]

[0275] In a further embodiment, the present invention provides compounds of formula (Va) and (Vb), wherein o, Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y 10 , R5, and R6 are as defined in Examples 796-971: [ka]

[0276] In both formulas (Va) and (Vb), o is 0. [Table 7] TIFF0007674811000088.tif237170TIFF0007674811000089.tif234170TIFF0007674811 000090.tif237170TIFF0007674811000091.tif233170TIFF0007674811000092.tif39170

[0277] In a further embodiment, the present invention provides compounds of formula (Va) and (Vb), wherein o, Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y 10 , R5, and R6 are as defined in Examples 1297-1300: [ka]

[0278] In both formulas (Va) and (Vb), o is 0. [Table 8]

[0279] In a further embodiment, the present invention provides a compound of formula (VI), wherein X1, n, Z, R5, and R6 are as defined in Examples 972-977: [ka] [Table 9]

[0280] In a further embodiment, the present invention provides a compound of formula (VII), wherein X1, n, Z, R2, R5, and R6 are as defined in Examples 978-54: [ka] [Table 10]

[0281] In a further embodiment, the present invention provides a compound of formula (VIII), wherein X1, n, R5, and R6 are as defined in Examples 990-993: [ka] [Table 11]

[0282] In a further embodiment, the present invention provides a compound of formula (IX), wherein X1, n, R2, R5, and R6 are as defined in Examples 994-1001: [ka] [Table 12]

[0283] In further embodiments, the present invention provides a compound of formula (X), wherein o, R5, and R6 are as defined in Examples 1002-1005: [ka]

[0284] o is 0. [Table 13]

[0285] In a further embodiment, the present invention provides a compound of formula (XI), wherein o, R2, R5, and R6 are as defined in Examples 1006-1013: [ka]

[0286] o is 0. [Table 14]

[0287] In a further embodiment, the present invention provides compounds of formula (XIIa) and (XIIb), wherein Z, Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y 10 , R5, and R6 are as defined in Examples 1014-1189: [ka] [Table 15] TIFF0007674811000109.tif234170TIFF0007674811000110.tif233170TIFF0007674811000111.tif234170TIFF0007674811000112.tif186170

[0288] In a further embodiment, the present invention provides a compound of formula (XIII), wherein Z, R5, and R6 are as defined in Examples 1190-1193: [ka] [Table 16]

[0289] In a further embodiment, the present invention provides a compound of formula (XIV), wherein R5 and R6 are as defined in Examples 1194-1195: [ka] [Table 17]

[0290] In a further embodiment, the present invention provides compounds of formula (XVa) and (XVb), wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y 10 , R5, and R6 are as defined in Examples 1196-1282: [ka] [Table 18] TIFF0007674811000119.tif234170TIFF0007674811000120.tif122170

[0291] In a further embodiment, the present invention provides compounds of formula (XVa) and (XVb), wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y 10 , R5, and R6 are as defined in Examples 1310-1319: [ka] [Table 19]

[0292] In a further embodiment, the present invention provides a compound of formula (XVI), wherein R5 and R6 are as defined in Examples 1283-1284: [ka] [Table 20]

[0293] In a further embodiment, the present invention provides a compound of formula (XVII), wherein R2, R5, and R6 are as defined in Examples 1285-1288: [ka] [Table 21]

[0294] In a further embodiment, the present invention provides a compound of formula (XVIII), wherein X1, n, R5, and R6 are as defined in Examples 1320-1323: [ka] [Table 22]

[0295] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers thereof, wherein the compound of formula (I) is selected from: [Table 23] TIFF0007674811000130.tif248170TIFF0007674811000131.tif249170TIFF0007674811000132.tif248170TIFF0007674811000133.t if247170TIFF0007674811000134.tif247170TIFF0007674811000135.tif249170TIFF0007674811000136.tif249170TIFF00076748110 00137.tif248170TIFF0007674811000138.tif248170TIFF0007674811000139.tif248170TIFF0007674811000140.tif248170TIFF000 7674811000141.tif248170TIFF0007674811000142.tif247170TIFF0007674811000143.tif248170TIFF0007674811000144.tif247170

[0296] Synthesis of Examples (Synthesis method A) [ka] (4-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)butanenitrile) 4'-Fluoro-[1,1'-biphenyl]-2-amine (0.5 g, 2.7 mmol), sodium cyanoborohydride (.25 g, 4.0 mmol), and 4-oxobutanenitrile (0.44 g, 5.3 mmol) were dissolved in anhydrous MeOH (15 mL) and acetic acid was added (0.5 mL). The reaction was stirred for 2 h until complete consumption of the amine was observed by UPLC analysis. After this time, the reaction mixture was diluted with saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, evaporated, and purified by column chromatography using 10-20% ethyl acetate in hexane as eluent to give the pure title compound (0.17 g, 12%).

[0297] (5-[3-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)propyl]-1,3,4-thiadiazol-2-amine (A2)) 4-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)butanenitrile (0.16 g, 0.6 mmol) and thiosemicarbazide (0.06 g, 0.7 mmol) were dissolved in trifluoroacetic acid (1.3 mL). The reaction was monitored by UPLC analysis. After completion of the reaction, the solvent was removed in vacuum and the crude material was purified by column chromatography using 0-2% MeOH in DCM as eluent to give the pure title compound (70 mg, 33%). LCMS-Method 10 (200 nm): RT=5.81 min, 95.2% purity, [M+1]=329.2. [ka]

[0298] (Synthesis method B) [ka] (Process 1) [ka] The 2-substituted aniline (1.0 equiv), sodium cyanoborohydride (1.5 equiv), and t-butyldimethylsilyloxyacetaldehyde (2.0 equiv) were dissolved in anhydrous MeOH (30.0 vol) and acetic acid was added (1.0 vol). The reaction was stirred for 1-2 h until complete consumption of the amine was observed by UPLC analysis. After this time, the reaction mixture was diluted with saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, evaporated, and used in the next step without further purification.

[0299] (Process 2) [ka] The product from step 1 (1.0 equiv.) and tetrabutylammonium fluoride trihydrate (1.05 equiv.) were dissolved in THF (40.0 vol.). The reaction was monitored by UPLC analysis. After completion of the reaction, the solvent was removed in vacuo and the crude material was carried on to step 3.

[0300] (5-{[2-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine (A3)) To a solution of 2-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)ethan-1-ol (0.58 g, 2.5 mmol), 2-amino-5-mercapto-thiadiazole (0.50 g, 3.8 mmol), and triphenylphosphine (1.18 g, 4.5 mmol) in anhydrous THF (16.0 mL) was added diethylene azodicarboxylate (0.66 g, 3.8 mmol). The reaction mixture was stirred at room temperature overnight. After this time, the solvent was removed in vacuo. The crude product was purified by column chromatography using 0-3% MeOH in DCM and further repurified by preparative TLC method using MeOH in DCM as eluent. Final repurification was performed by preparative HPLC method to give the pure product (40 mg, 7%). LCMS-Method 7 (200nm): RT=5.81 min, 98.7% purity, [M]=346.0. [ka]

[0301] (5-{[2-({3',4'-dimethoxy-[1,1'-biphenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine (A4)) To a solution of 2-({3',4'-dimethoxy-[1,1'-biphenyl]-2-yl}amino)ethan-1-ol (0.9 g, 8.3 mmol), 2-amino-5-mercapto-thiadiazole (1.0 g, 7.5 mmol), and triphenylphosphine (2.17 g, 8.3 mmol) in anhydrous THF (10.0 mL) was added dropwise diethylene azadicarboxylate (2.25 g, 9.8 mmol) in 5 mL of anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature overnight. After this time, the solvent was removed in vacuo. The crude product was purified by column chromatography using 0-3% MeOH in DCM and repurified by a preparative HPLC method to give the pure product (80 mg, 7%). LCMS-Method 7 (205 nm): RT=5.27 min, 98.1% purity, [M]=386.9. [ka]

[0302] (Synthesis method C) [ka] (Process 1) [ka] To a solution of the amine (4.27 mmol) in MeOH (25.0 mL) was added methyl 4-oxobutanoate (0.99 g, 8.54 mmol) and acetic acid (0.8 mL). The reaction mixture was stirred at ambient temperature for 1.5 h. Then NaBH3CN (0.40 mg, 6.41 mmol) was added and the mixture was stirred for 1 h. The reaction was quenched with a saturated solution of NaHCO3. The aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give the product.

[0303] (Methyl 4-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)butanoate (0.875g, 71%) 4'-Fluoro-[1,1'-biphenyl]-2-amine was used. The crude (1.47 g) was purified by column chromatography using 100% DCM as eluent. UPLC (254 nm): RT=4.14 min, 76% purity, [M+H]=288.20.

[0304] (Methyl 4-({3',4'-dimethoxy-[1,1'-biphenyl]-2-yl}amino)butanoate (1.00g, 71%) 3',4'-Dimethoxy-[1,1'-biphenyl]-2-amine was used. The crude product was purified by column chromatography using 0-20% EA in hexane as eluent.

[0305] (Process 2) [ka] To a solution of the corresponding starting material (3.04 mmol) in EtOH (30 mL) was added 50% hydrazine (5.0 equiv.) in H2O. The reaction mixture was stirred at 80° C. for 18 h. The solvent was then evaporated to give the pure compound.

[0306] (4-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)butanehydrazide (0.85 g, 96%)) Methyl 4-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)butanoate (0.875 g, 3.04 mmol) was used as starting material. UPLC (254 nm): RT = 3.06 min, [M+H] = 288.35.

[0307] (4-({3',4'-dimethoxy-[1,1'-biphenyl]-2-yl}amino)butanehydrazide (0.97g, 97%)) Methyl 4-({3',4'-dimethoxy-[1,1'-biphenyl]-2-yl}amino)butanoate (1.0 g, 3.04 mmol) was used as starting material. UPLC (254 nm): RT = 2.82 min, [M+H] = 330.30.

[0308] (Step 3) [ka] To a solution of the corresponding starting material (2.6 mmol) in MeOH (8 mL) was added N,N-dimethylforamide dimethyl acetal (311 mg, 2.6 mmol). The reaction mixture was stirred at 80° C. for 1 h. The solvent was then evaporated to give the desired product.

[0309] (N'-[(1E)-(dimethylamino)methylidene]-4-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)butane-hydrazide (0.894 g, 100%)) 4-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)butanehydrazide (0.75 g, 2.61 mmol) was used as the starting material. UPLC (254 nm): RT = 3.40 min, [M+H] = 343.15.

[0310] (4-({3',4'-dimethoxy-[1,1'-biphenyl]-2-yl}amino)-N'-[(1E)-(dimethylamino)methylidene]-butanehydrazide (1.014g, 100%)) 4-({3',4'-dimethoxy-[1,1'-biphenyl]-2-yl}amino)butane-hydrazide (0.869 g, 2.64 mmol) was used as starting material. UPLC (254 nm): RT = 3.40 min, [M+H] = 385.30.

[0311] (Step 4) [ka] 2M MeNH2 in THF (20 equiv.) was added to a solution of the corresponding starting material in anhydrous THF (10.0 mL) under argon atmosphere. The reaction mixture was cooled to 0° C. and acetic acid (2 mL) was carefully added. The reaction mixture was stirred at 100° C. for 18 h. Then the reaction was cooled to room temperature and water (5 mL) was added. The layers were separated and the aqueous layer was extracted three times with EA (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography using 0-4% MeOH in DCM as eluent and then repurified by preparative HPLC. The fractions containing the title compound in pure form were concentrated to give the product.

[0312] (4'-Fluoro-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]-[1,1'-biphenyl]-2-amine (B1) (101 mg, 11%)) N'-[(1E)-(dimethylamino)methylidene]-4-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)butane-hydrazide (1.00 g, 2.92 mmol) was used as starting material. LCMS-Method 2 (220 nm): RT=4.78 min, 98.89% purity. [ka]

[0313] (3',4'-Dimethoxy-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]-[1,1'-biphenyl]-2-amine (B3) (5 mg, 0.4%)) 4-({3',4'-dimethoxy-[1,1'-biphenyl]-2-yl}amino)-N'-[(1E)-(dimethylamino)-methylidene]-butanehydrazide (1.10 g, 2.86 mmol) was used as starting material. LCMS-Method 8 (210 nm): RT=12.12 min, 99.45% purity. [ka]

[0314] (Synthesis method D) [ka] (Process 1) [ka] (N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide) 5-(4-Bromophenyl)-1,3,4-thiadiazol-2-amine (0.5 g, 2.0 mmol), triethylamine (0.54 mL, 4.0 mmol) were dissolved in DCM (5 mL), acetyl chloride (0.17 g, 2.15 mmol) was added dropwise at 5° C., and the reaction was stirred at room temperature for 1 h, after which another portion of triethylamine and acetyl chloride was added at 5° C., and the reaction mixture was stirred for an additional 30 min. The mixture was diluted with DCM (15.0 mL) and washed with a saturated solution of sodium bicarbonate (20 mL), water (20 mL). The title compound was obtained (0.40 g, 60%) as a 1:1 mixture of the acetylated amine (UPLC (254 nm): RT = 3.13 min [M + H] = 297.9) and the diacetylated amine (UPLC (254 nm): RT = 3.58 min [M + H] = 338.9). It was used in the next step without purification.

[0315] (Process 2) [ka] (N-{5-[4-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)phenyl]-1,3,4-thiadiazol-2-yl}acetamide) N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (0.2 g, 0.67 mmol), 4'-fluoro-[1,1'-biphenyl]-2-amine (0.12 g, 0.56 mmol), sodium tert-butanolate (0.15 mg, 1.56 mmol), and Xantphos (40 mg, 0.07 mmol) were suspended in 1,4-dioxane (6 ml), the reaction mixture was degassed with a stream of argon for 20 min, and tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (35 mg, 0.035 mmol) was added. The reaction was stirred at 100° C. overnight. The reaction mixture was then cooled to room temperature, filtered through Celite, evaporated and purified by column chromatography using 0-3% MeOH in DCM as eluent to give the pure product (0.24 g, 88%). UPLC (254 nm): RT=3.78 min, 85% purity, [M+H]=404.8.

[0316] [ka] (5-[4-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)phenyl]-1,3,4-thiadiazol-2-amine (C2)) To a solution of N-{5-[4-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)phenyl]-1,3,4-thiadiazol-2-yl}acetamide (0.17 g, 0.42 mmol) in methanol (2.5 mL) was added concentrated hydrochloric acid (2.5 mL) dropwise. The reaction mixture was refluxed overnight. After this time, the reaction was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with DCM (6 x 15 mL), the organic layers were combined, dried over sodium sulfate, filtered and evaporated. The crude product was purified by a preparative HPLC method to give the pure product (40 mg, 25%). LCMS-Method 6 (200 nm): RT = 20.57 min, 91.6% purity, [M+H] = 363.14, LCMS (340 nm): RT = 20.57 min, 99.2% purity, [M+H] = 363.14. [ka]

[0317] [ka] (N-{5-(4-{[2-(3,4-dimethoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl}acetamide) N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34 mmol), 2-(3,4-dimethoxyphenyl)aniline (60 mg, 0.28 mmol), sodium tert-butanolate (75 mg, 1.56 mmol), and Xantphos (40 mg, 0.035 mmol) were suspended in 1,4-dioxane (3 ml), the reaction mixture was degassed with a stream of argon for 20 min, and tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (17 mg, 0.017 mmol) was added. The reaction was stirred at 100 °C overnight. The reaction mixture was then cooled to room temperature, filtered through Celite, evaporated, and purified by column chromatography using 0-3% MeOH in DCM as eluent to give the pure product (0.2 g, 80%). UPLC (254nm): RT=3.64 min, 85% purity, [M+H]=447.15.

[0318] [ka] (5-(4-{[2-(3,4-dimethoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine (C3)) To a solution of N-{5-(4-{[2-(3,4-dimethoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl}acetamide (0.20 g, 0.42 mmol) in methanol (3.0 mL) was added concentrated hydrochloric acid (3.0 mL) dropwise. The reaction mixture was refluxed overnight. After this time, the reaction was diluted with saturated sodium bicarbonate solution (20 mL), extracted with DCM (6×15 mL), the organic layers were combined, dried over sodium sulfate, filtered and evaporated. The crude product was purified by a preparative HPLC method to give the pure product (44 mg, 25%). LCMS (LCMS-Method 10, 200 nm), RT=5.22 min, 96.1% purity, [M+H]=405.11. [ka]

[0319] [ka] (N-[5-(4-{[2-(4-methoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide) N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (128 mg, 0.43 mmol), 2-(4-methoxyphenyl)aniline (102 mg, 0.51 mmol), cesium carbonate (279 mg, 0.86 mmol), and Xantphos (50 mg, 0.09 mmol) were suspended in 1,4-dioxane (3.8 mL). The reaction mixture was degassed with a stream of argon for 20 min and tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.04 mmol) was added. The reaction was stirred at 100° C. for 96 h. The reaction mixture was then cooled to room temperature, filtered through Celite, evaporated, and purified by column chromatography using 1:0→98:2 DCM / MeOH as eluent to give the product as a yellow solid (62.5 mg, 35.01%). UPLC (254nm): RT=7.14 min, 80.9% purity, [M+H]=417.10.

[0320] [ka] (5-(4-{[2-(4-methoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine C4) To a solution of N-[5-(4-{[2-(4-methoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide (63 mg, 0.15 mmol) in methanol (1.0 mL) was added concentrated hydrochloric acid (1.0 mL) dropwise. The reaction mixture was refluxed overnight. After this time, the reaction was diluted with saturated sodium bicarbonate solution (20 mL), methanol was evaporated and extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC eluting with 70:25:5 Hex / EtOAc / MeOH to give the desired product as a yellow solid (19.6 mg, 35%). LCMS (LCMS-Method 11, 200 nm): RT=2.75 min, 98.9% purity, [M+H]=375.21. [ka]

[0321] [ka] (N-[5-(4-{[3-(4-methoxyphenyl)pyridin-2-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide) N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (87 mg, 0.29 mmol), 3-(4-methoxyphenyl)pyridin-2-amine (70 mg, 0.35 mmol), cesium carbonate (190 mg, 0.58 mmol), and Xantphos (34 mg, 0.06 mmol) were suspended in 1,4-dioxane (2.6 mL). The reaction mixture was degassed with a stream of argon for 20 min and tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.03 mmol) was added. The reaction was stirred at 100° C. for 72 h. The reaction mixture was then cooled to room temperature, filtered through Celite, evaporated, and purified by column chromatography using 1:0→95:5 DCM / MeOH as eluent to give the product as a pale yellow solid (114 mg, 93.6%). UPLC (254nm): RT=5.35 min, 65% purity, [M+H]=418.70.

[0322] [ka] (N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-2-amine (C5)) To a solution of N-[5-(4-{[3-(4-methoxyphenyl)pyridin-2-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide (114 mg, 0.27 mmol) in methanol (1.7 mL) was added concentrated hydrochloric acid (1.7 mL) dropwise. The reaction mixture was refluxed overnight. After this time, the reaction was diluted with saturated sodium bicarbonate solution (20 mL), methanol was evaporated and extraction was carried out with ethyl acetate (2×15 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC eluting with 9:1 DCM / MeOH to give the desired product as a yellowish solid (16.4 mg, 16%). LCMS-Method 5 (200 nm): RT=1.75 min, 99.3% purity, [M+H]=376.19. [ka]

[0323] [ka] (N-[5-(4-{[3-(4-methoxyphenyl)pyridin-4-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide) N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34 mmol), 3-(4-methoxyphenyl)pyridin-4-amine (81 mg, 0.40 mmol), cesium carbonate (219 mg, 0.67 mmol), and Xantphos (39 mg, 0.07 mmol) were suspended in 1,4-dioxane (3 mL). The reaction mixture was degassed with a stream of argon for 20 min and tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol) was added. The reaction was stirred at 100° C. for 72 h. The reaction mixture was then cooled to room temperature, filtered through Celite, evaporated, and purified by column chromatography using 1:0→95:5 DCM / MeOH as eluent to give the product as a yellow solid (75 mg, 53.6%). UPLC (310nm): RT=3.96 min, 93% purity, [M+H]=418.95.

[0324] [ka] (N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-4-amine (C6)) To a solution of N-[5-(4-{[3-(4-methoxyphenyl)pyridin-4-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide (75 mg, 0.18 mmol) in methanol (1.12 mL) was added concentrated hydrochloric acid (1.12 mL) dropwise. The reaction mixture was refluxed overnight. After this time, the reaction was diluted with saturated sodium bicarbonate solution (20 mL), methanol was evaporated and extracted with ethyl acetate (2×15 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC eluting with 9:1 DCM / MeOH. Repurification by preparative TLC eluting with 9:1 DCM / MeOH gave the desired product as an off-white solid (32.0 mg, 47%). LCMS-Method 3 (200nm): RT=3.01 min, 99.8% purity, [M+H]=376.18. [ka]

[0325] [ka] (N-[5-(4-{[3-(3,4-dimethoxyphenyl)pyridin-4-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide) N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34 mmol), 3-(3,4-dimethoxyphenyl)pyridin-4-amine (93 mg, 0.40 mmol), cesium carbonate (219 mg, 0.67 mmol), and Xantphos (39 mg, 0.07 mmol) were suspended in 1,4-dioxane (3 mL). The reaction mixture was degassed with a stream of argon for 20 min and tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol) was added. The reaction was stirred at 100° C. for 72 h. The reaction mixture was then cooled to room temperature, filtered through Celite, evaporated, and purified by column chromatography using 1:0→95:5 DCM / MeOH as eluent to give the product as a pale yellow solid (49 mg, 32.7%). UPLC (310nm): RT=4.72 min, 100% purity, [M+H]=448.15.

[0326] [ka] (N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(3,4-dimethoxyphenyl)pyridin-4-amine (C7)) To a solution of N-[5-(4-{[3-(3,4-dimethoxyphenyl)pyridin-4-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide (49 mg, 0.11 mmol) in methanol (0.75 mL) was added concentrated hydrochloric acid (0.75 mL) dropwise. The reaction mixture was refluxed overnight. After this time, the reaction was diluted with saturated sodium bicarbonate solution (10 mL), methanol was evaporated and extraction was performed with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC eluting with 95:5 DCM / MeOH to give the desired product as a pale yellow solid (11 mg, 24.8%). LCMS-Method 3 (200 nm): RT=2.90 min, 99.6% purity, [M+H]=406.17. [ka]

[0327] [ka] (N-[5-(4-{[3-(4-fluorophenyl)pyridin-2-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide) N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34 mmol), 3-(4-fluorophenyl)pyridin-2-amine (52 mg, 0.28 mmol), cesium carbonate (219 mg, 0.67 mmol), and Xantphos (39 mg, 0.07 mmol) were suspended in 1,4-dioxane (3 mL). The reaction mixture was degassed with a stream of argon for 20 min and tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol) was added. The reaction was stirred at 100° C. for 72 h. The reaction mixture was then cooled to room temperature, filtered through Celite, evaporated, and purified by column chromatography using 1:0→99:1 DCM / MeOH as eluent to give the product as a yellowish solid (75 mg, 55.6%). UPLC (254nm): RT=5.92 min, 96.8% purity, [M+H]=406.95.

[0328] [ka] (N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyridin-2-amine (C8)) To a solution of N-[5-(4-{[3-(4-fluorophenyl)pyridin-2-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide (75 mg, 0.18 mmol) in methanol (1.2 mL) was added concentrated hydrochloric acid (1.2 mL) dropwise. The reaction mixture was refluxed overnight. After this time, the reaction was diluted with saturated sodium bicarbonate solution (20 mL), methanol was evaporated and extracted with ethyl acetate (2×15 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC eluting with 95:5 DCM / MeOH. Repurification by preparative TLC eluting with 95:5 DCM / MeOH gave the desired product as a yellowish solid (4.3 mg, 6.4%). LCMS-Method 2 (200nm): RT=4.69 min, 98.9% purity, [M+H]=364.18. [ka]

[0329] [ka] (N-[5-(4-{[3-(4-fluorophenyl)pyrazin-2-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide) N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34 mmol), 3-(4-fluorophenyl)pyrazin-2-amine (76 mg, 0.40 mmol), cesium carbonate (219 mg, 0.67 mmol), and Xantphos (39 mg, 0.07 mmol) were suspended in 1,4-dioxane (3 mL). The reaction mixture was degassed with a stream of argon for 20 min and tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol) was added. The reaction was stirred at 100° C. for 72 h. The reaction mixture was then cooled to room temperature, filtered through Celite, evaporated, and purified by column chromatography using 1:0→97:3 DCM / MeOH as eluent to give the product as a yellowish solid (68 mg, 49.8%). UPLC (254nm): RT=5.88 min, 95.5% purity, [M+H]=407.05.

[0330] [ka] (N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyrazin-2-amine (C9)) To a solution of N-[5-(4-{[3-(4-fluorophenyl)pyrazin-2-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide (68 mg, 0.17 mmol) in methanol (1 mL) was added concentrated hydrochloric acid (1 mL) dropwise. The reaction mixture was refluxed overnight. After this time, the reaction was diluted with saturated sodium bicarbonate solution (20 mL), methanol was evaporated and extraction was performed with ethyl acetate (2×15 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC eluting with 9:1 DCM / MeOH. Repurification was performed by preparative TLC eluting with 95:5 DCM / MeOH to give the desired product as a yellow solid (20.2 mg, 33.2%). LCMS-Method 4 (328 nm): RT=2.44 min, 97.0% purity, [M+H]=365.15. [ka]

[0331] [ka] (N-[5-(4-{[2-(4-phenoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide) N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34 mmol), 2-(4-phenoxyphenyl)aniline (105 mg, 0.40 mmol), cesium carbonate (219 mg, 0.67 mmol), and Xantphos (39 mg, 0.07 mmol) were suspended in 1,4-dioxane (3 mL). The reaction mixture was degassed with a stream of argon for 20 min and tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol) was added. The reaction was stirred at 100° C. for 72 h. The reaction mixture was then cooled to room temperature, filtered through Celite, evaporated, and purified by column chromatography using 1:0→98:2 DCM / MeOH as eluent to give the product as a yellow solid (115 mg, 71.7%). UPLC (254nm): RT=7.96 min, 88.6% purity, [M+H]=479.15.

[0332] [ka] (5-(4-{[2-(4-phenoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine (C10)) To a solution of N-[5-(4-{[2-(4-phenoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide (95 mg, 0.20 mmol) in methanol (1.4 mL) was added concentrated hydrochloric acid (1.4 mL) dropwise. The reaction mixture was refluxed overnight. After this time, the reaction was diluted with saturated sodium bicarbonate solution (20 mL), methanol was evaporated, and extracted with ethyl acetate (2×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The crude product was purified by preparative TLC eluting with 8:2 DCM / MeOH. Repurification was performed by preparative TLC eluting with 70:25:5 Hex / EtOAc / MeOH to give the desired product as a yellowish solid (17.2 mg, 19.9%). LCMS-Method 11 (200nm): RT=3.57 min, 97.5% purity, [M+H]=437.16. [ka]

[0333] [ka] (N-[5-(4-{[2-(4-propoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide) N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (120 mg, 0.40 mmol), 2-(4-propoxyphenyl)aniline (110 mg, 0.48 mmol), cesium carbonate (262 mg, 0.80 mmol), and Xantphos (47 mg, 0.08 mmol) were suspended in 1,4-dioxane (3.6 mL). The reaction mixture was degassed with a stream of argon for 20 min and tris(dibenzylideneacetone)dipalladium(0) (33 mg, 0.04 mmol) was added. The reaction was stirred at 100° C. for 72 h. The reaction mixture was then cooled to room temperature, filtered through Celite, evaporated, and purified by column chromatography using 1:0→97:3 DCM / MeOH as eluent to give the product as a yellowish solid (55.7 mg, 31.1%). UPLC (254nm): RT=8.07 min, 86.8% purity, [M+H]=445.30.

[0334] [ka] (5-(4-{[2-(4-propoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine (C11)) To a solution of N-[5-(4-{[2-(4-propoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide (56 mg, 0.13 mmol) in methanol (0.84 mL) was added concentrated hydrochloric acid (0.84 mL) dropwise. The reaction mixture was refluxed overnight. After this time, the reaction was diluted with saturated sodium bicarbonate solution (10 mL), methanol was evaporated and extraction was performed with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC eluting with 70:25:5 Hex / EtOAc / MeOH. Repurification was performed by cold maceration with diethyl ether to give the desired product as a light brown solid (11 mg, 22%). LCMS-Method 4 (200 nm): RT=3.67 min, 98.9% purity, [M+H]=403.19. [ka]

[0335] [ka] (N-{5-[4-({2-[4-(propan-2-yloxy)phenyl]phenyl}amino)phenyl]-1,3,4-thiadiazol-2-yl}acetamide) N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34 mmol), 2-[4-(propan-2-yloxy)phenyl]aniline (91 mg, 0.40 mmol), cesium carbonate (219 mg, 0.67 mmol), and Xantphos (39 mg, 0.07 mmol) were suspended in 1,4-dioxane (3 mL). The reaction mixture was degassed with a stream of argon for 20 min and tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol) was added. The reaction was stirred at 100° C. for 72 h. The reaction mixture was then cooled to room temperature, filtered through Celite, evaporated, and purified by column chromatography using 1:0→97:3 DCM / MeOH as eluent to give the product as a yellowish solid (87.4 mg, 58.6%). UPLC (254nm): RT=7.59 min, 87.6% purity, [M+H]=445.15.

[0336] [ka] (5-[4-({2-[4-(propan-2-yloxy)phenyl]phenyl}amino)phenyl]-1,3,4-thiadiazol-2-amine (C12)) To a solution of N-{5-[4-({2-[4-(propan-2-yloxy)phenyl]phenyl}amino)phenyl]-1,3,4-thiadiazol-2-yl}acetamide (87 mg, 0.20 mmol) in methanol (1.3 mL) was added concentrated hydrochloric acid (1.3 mL) dropwise. The reaction mixture was refluxed overnight. After this time, the reaction was diluted with saturated sodium bicarbonate solution (15 mL), methanol was evaporated and extraction was performed with ethyl acetate (2×15 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC eluting with 70:25:5 Hex / EtOAc / MeOH. Repurification was performed by cold maceration with methanol to give the desired product as a yellow solid (7 mg, 8.8%). LCMS-Method 4 (200 nm): RT=3.54 min, 97.4% purity, [M+H]=403.20. [ka]

[0337] (Synthesis method E) [ka] To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (100 mg, 0.52 mmol) and the corresponding base (1.20 mmol, 2.3 equiv.) in 1,4-dioxane (3.0 mL) was added the amine (1.0 equiv.). The reaction mixture was degassed for 30 min. Then, Xantphos (30 mg, 0.05 mmol) and the corresponding catalyst were added and the mixture was stirred at 100° C. for 5 days. The reaction mixture was filtered through Celite, the filtrate was concentrated and purified by column chromatography using 0-10% MeOH in DCM as eluent. The fractions containing the title compound were combined and concentrated. The product was repurified by P-TLC using 4% MeOH in DCM as eluent.

[0338] (4'-Fluoro-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[1,1'-biphenyl]-2-amine (D1) (34 mg, 19%)) 4'-Fluoro-[1,1'-biphenyl]-2-amine (97 mg, 0.52 mmol), t-BuONa (115 mg, 1.2 mmol), tris(dibenzylideneacetone)dipalladium(0) in chloroform (26 mg, 0.05 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.05 mmol) were used. LCMS-Method 2 (200 nm): RT=5.54 min, 97.6% purity, [M+H]=345.15. [ka]

[0339] (3',4'-Dimethoxy-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[1,1'-biphenyl]-2-amine (D2) (45 mg, 28%)) 3',4'-Dimethoxy-[1,1'-biphenyl]-4-amine (120 mg, 0.52 mmol), Cs2CO3 (396 mg, 1.2 mmol), tris(dibenzylideneacetone)dipalladium(0) in chloroform (26 mg, 0.05 mmol) were used. LCMS-Method 2 (200 nm) RT = 4.8 min, 98.7% purity, [M+H] = 387.14. [ka]

[0340] [ka] (N-[2-(4-methoxyphenyl)phenyl]-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (D3)) To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (73 mg, 0.38 mmol) and Cs2CO3 (285 mg, 0.87 mmol) in 1,4-dioxane (2.25 mL) was added 2-(4-methoxyphenyl)aniline (75 mg, 0.38 mmol). The reaction mixture was degassed for 30 min. Then, Xantphos (22 mg, 0.04 mmol) and tris(dibenzylideneacetone)dipalladium(0) in chloroform adduct (19 mg, 0.02 mmol) were added and the mixture was stirred at 100 °C overnight. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated and purified by column chromatography using 0-10% MeOH in DCM as eluent. The fractions containing the title compound were combined and concentrated. The product was repurified by P-TLC using 4% MeOH in DCM as eluent to give the desired product as an orange solid (13 mg, 10%). LCMS-Method 2 (200 nm): RT=5.38 min, 94.03% purity, [M+H]=357.21. [ka]

[0341] [ka] (2-(4-Methoxyphenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine (D4)) To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (68 mg, 0.35 mmol) and Cs2CO3 (264 mg, 0.81 mmol) in 1,4-dioxane (2.10 mL) was added 2-(4-methoxyphenyl)pyridin-3-amine (70 mg, 0.35 mmol). The reaction mixture was degassed for 30 min. Then, Xantphos (20 mg, 0.03 mmol) and tris(dibenzylideneacetone)dipalladium(0) in chloroform adduct (18 mg, 0.02 mmol) were added and the mixture was stirred at 100 °C overnight. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated and purified by column chromatography using 0-10% MeOH in DCM as eluent. The fractions containing the title compound were combined and concentrated. The product was repurified by P-TLC using 4% MeOH in DCM as eluent to give the desired product as a white solid (35 mg, 28%). LCMS-Method 1 (200 nm): RT=5.58 min, 96.3% purity, [M+H]=358.22. [ka]

[0342] [ka] (2-(4-fluorophenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine (D5)) To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (77 mg, 0.40 mmol) and Cs2CO3 (301 mg, 0.92 mmol) in 1,4-dioxane (2.25 mL) was added 2-(4-fluorophenyl)pyridin-3-amine (75 mg, 0.40 mmol). The reaction mixture was degassed for 30 min. Then, Xantphos (23 mg, 0.04 mmol) and tris(dibenzylideneacetone)dipalladium(0) in chloroform adduct (20 mg, 0.02 mmol) were added and the mixture was stirred at 100 °C overnight. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated and purified by column chromatography using 0-10% MeOH in DCM as eluent. The fractions containing the title compound were combined and concentrated. The product was repurified by P-TLC using 4% MeOH in DCM as eluent to give the desired product as a pale orange solid (5 mg, 4%). LCMS-Method 1 (205 nm): RT=5.82 min, 99.46% purity, [M+H]=346.22. [ka]

[0343] [ka] (4-(4-methyl-4H-1,2,4-triazol-3-yl)-N-[2-(4-phenoxyphenyl)phenyl]aniline (D6)) To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (74 mg, 0.38 mmol) and Cs2CO3 (289 mg, 0.89 mmol) in 1,4-dioxane (3.00 mL) was added 2-(4-phenoxyphenyl)aniline (100 mg, 0.38 mmol). The reaction mixture was degassed for 30 min. Then, Xantphos (22 mg, 0.04 mmol) and tris(dibenzylideneacetone)dipalladium(0) in chloroform adduct (20 mg, 0.02 mmol) were added and the mixture was stirred at 100 °C overnight. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated and purified by column chromatography using 0-5% MeOH in DCM as eluent. The fractions containing the title compound were combined and concentrated. The product was repurified by P-TLC using 4% MeOH in DCM as eluent to give the desired product as a white solid (25 mg, 16%). LCMS-Method 5 (200 nm): RT=2.25 min, 99.51% purity, [M+H]=419.20. [ka]

[0344] [ka] (3-(3,4-dimethoxyphenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-4-amine (D7)) To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (59 mg, 0.30 mmol) and Cs2CO3 (230 mg, 0.71 mmol) in 1,4-dioxane (2.10 mL) was added 3-(3,4-dimethoxyphenyl)pyridin-4-amine (70 mg, 0.30 mmol). The reaction mixture was degassed for 30 min. Then, Xantphos (18 mg, 0.03 mmol) and tris(dibenzylideneacetone)dipalladium(0) in chloroform adduct (16 mg, 0.02 mmol) were added and the mixture was stirred at 100 °C overnight. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated and purified by column chromatography using 0-10% MeOH in DCM as eluent. The fractions containing the title compound were combined and concentrated. The product was repurified by P-TLC using 4% MeOH in DCM as eluent to give the desired product as a white solid (20 mg, 16%). LCMS-Method 3 (305 nm): RT=2.69 min, 98.21% purity, [M+H]=388.24. [ka]

[0345] (Synthesis method F) [ka] [ka] (5-(3-bromopropyl)-1,3,4-thiadiazol-2-amine) Phosphoryl chloride (7.37 mL, 79.0 mmol) was added to aminothiourea (2.185 g, 24.0 mmol) and 4-bromobutanoic acid. The mixture was stirred at 85° C. overnight, cooled and poured into ice. A solution of saturated sodium biscarboxylate was added to the solution and the aqueous layer was extracted three times with EA (3×80 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography using 0-10% DCM in MeOH as eluent. The fractions containing the title compound were combined and concentrated (3.301 g, 62%). UPLC (254 nm): RT=1.91 min, 68% purity, [MH]=223.7.

[0346] [ka] (N-[5-(3-bromopropyl)-1,3,4-thiadiazol-2-yl]acetamide) To a solution of 5-(3-bromopropyl)-1,3,4-thiadiazol-2-amine (3.3 g, 14.8 mmol) in anhydrous DCM (35 mL) was added triethylamine (4.14 mL, 29.7 mmol) and acetyl chloride (1.16 mL, 16.3 mmol) under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 6 h. Then 1 M HCl (50 mL) was added and the aqueous layer was extracted three times with DCM (3×80 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give the pure product (3.144 g, 80%). UPLC (254 nm): RT=2.43 min, 89% purity, [M+H]=265.65.

[0347] [ka] (N-[5-(3-azidopropyl)-1,3,4-thiadiazol-2-yl]acetamide) To a solution of N-[5-(3-bromopropyl)-1,3,4-thiadiazol-2-yl]acetamide (1.0 g, 3.8 mmol) in anhydrous DMF (20.0 mL) was added sodium azide (0.37 g, 5.7 mmol) under argon atmosphere. The reaction mixture was stirred for 2 h. Then water (10 mL) was added and the aqueous layer was extracted with DCM (3×80 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give the pure product (0.6 g, 71%). UPLC (254 nm): RT=2.29 min, 98% purity, [M+H]=227.0.

[0348] [ka] (N-[5-(3-aminopropyl)-1,3,4-thiadiazol-2-yl]acetamide) A solution of methyl N-[5-(3-azidopropyl)-1,3,4-thiadiazol-2-yl]acetamide (0.6 g, 2.7 mmol) in anhydrous tetrahydrofuran (7 mL) was added dropwise to a suspension of LAH pellets (0.1 g, 2.8 mmol) in anhydrous THF (5 mL) under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 1 h. LAH (0.1 g, 2.8 mmol) was then added. Stirring was continued for 2 h. Then 0.2 mL of water was added, followed by 0.4 mL of 20% NaOH and 0.6 mL of water. The suspension was filtered through Celite and washed with 9:1 DCM / MeOH. Evaporation of the solvent afforded the title compound (0.22 g, 41%). UPLC (254 nm): RT=1.17 min, 57% purity, [MH]=201.2.

[0349] [ka] (N-{5-[3-(4-fluorobenzenesulfonamido)propyl]-1,3,4-thiadiazol-2-yl}acetamide) To a solution of 3,4-dichlorobenzenosulfonyl chloride (165 mg, 0.85 mmol) in a mixture of the solvents DCM (1.0 mL) and pyridine (1.0 mL) was added N-[5-(3-aminopropyl)-1,3,4-thiadiazol-2-yl]acetamide (170 mg, 0.85 mmol). The reaction mixture was stirred at ambient temperature for 18 h. Then the solvent was evaporated, to the residue was added 1 M HCl and the aqueous layer was extracted with DCM (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give the product (0.02 g, 7%). UPLC (254 nm): RT=2.56 min, 98% purity, [M+H]=358.85.

[0350] [ka] (N-[3-(5-amino-1,3,4-thiadiazol-2-yl)propyl]-4-fluorobenzene-1-sulfonamide (E2)) N-{5-[3-(4-fluorobenzenesulfonamido)propyl]-1,3,4-thiadiazol-2-yl}acetamide (20 mg, 0.06 mmol) was dissolved in a solution of HCl (2 mL) and MeOH (2 mL). The reaction mixture was stirred at 80° C. for 18 h. Then a solution of sodium biscarboxylate was added and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. Purification of the crude product by P-TLC using 4% methanol in dichloromethane as eluent afforded the desired product (3 mg, 17%). LCMS-Method 1 (200 nm): RT=2.56 min, 96.0% purity. [M+H]=317.15. [ka]

[0351] (Synthesis method G) [ka] [ka] (N-(2-chloroethyl)-4-fluorobenzene-1-sulfonamide) 2-Chloroethylamine hydrochloride (0.25 g, 2.2 mmol), 4-fluorobenzenesulfonyl chloride (0.42 g, 2.2 mmol) were dissolved in DCM (2.5 mL) and pyridine (2.5 mL). The reaction was stirred at room temperature overnight. The mixture was diluted with DCM (15.0 mL) and washed with 1 M hydrochloric acid solution (20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The title compound was obtained as a yellow oil (0.5 g, 86% yield). [ka]

[0352] [ka] (N-{2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]ethyl}-4-fluorobenzene-1-sulfonamide (E3)) N-(2-chloroethyl)-4-fluorobenzene-1-sulfonamide (0.18 g, 0.75 mmol), 2-amino-5-mercapto-1,3,4-thiadiazole (0.10 g, 0.75 mmol), potassium carbonate (0.31 g, 2.25 mmol) were dissolved in acetonitrile (2.0 mL) and stirred at 80 °C overnight. The reaction mixture was then cooled to room temperature, filtered through Celite, evaporated and purified by column chromatography using 0-5% MeOH in DCM as eluent to give the pure product (120 mg, 48%). LCMS-Method 2 (200 nm): RT = 4.24 min, 99.71% purity, [M+H] = 334.97. [ka]

[0353] [ka] (4-Fluoro-N-{2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]ethyl}benzene-1-sulfonamide (G2)) N-(2-chloroethyl)-4-fluorobenzene-1-sulfonamide (0.21 g, 0.87 mmol), 3-mercapto-4-methyl-4H-1,2,4-triazole (0.10 g, 0.87 mmol), potassium carbonate (0.36 g, 2.61 mmol) were dissolved in acetonitrile (2.0 mL) and stirred at 80 °C overnight. The reaction mixture was then cooled to room temperature, filtered through Celite, evaporated and purified by column chromatography using 0-5% MeOH in DCM as eluent to give the pure product (200 mg, 73%). LCMS-Method 2 (200 nm): RT = 3.79 min, 97.39% purity, [M+H] = 317.05. [ka]

[0354] (Synthesis method H) [ka] [ka] N-[5-(3-bromopropyl)-1,3,4-thiadiazol-2-yl]acetamide was synthesized following the procedure described for E2.

[0355] [ka] (N-[5-(3-{[(4-fluorophenyl)(methyl)oxo-λ 6 -sulfanylidene]amino}propyl)-1,3,4-thiadiazol-2-yl]acetamide (4-Fluorophenyl)(imino)methyl-λ 6To a solution of -sulfanone (0.1 g, 0.58 mmol) in anhydrous DMSO (4 mL) was added KOH (0.065 g, 1.15 mmol) under an argon atmosphere. The suspension was stirred at ambient temperature for 1.5 h. Then, a solution of N-[5-(3-bromopropyl)-1,3,4-thiadiazol-2-yl]acetamide (0.229 g, 0.87 mmol) in anhydrous DMSO (4 mL) was added dropwise slowly (1.5 h). Immediately after the addition was complete, the reaction was quenched with water (5 mL). The aqueous layer was extracted with DCM (10 mL) and then five times with a 3:1 mixture of chloroform / isopropyl alcohol (5 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated to give the pure product (0.06 g, 29%). UPLC (254nm): RT=2.2 min, 61% purity, [M+H]=357.2

[0356] [ka] (5-(3-{[(4-fluorophenyl)(methyl)oxo-λ 6 -sulfanylidene]amino}propyl)-1,3,4-thiadiazol-2-amine (F2) N-[5-(3-{[(4-fluorophenyl)(methyl)oxo-λ 6 [-sulfanylidene]amino}propyl)-1,3,4-thiadiazol-2-yl]acetamide (20 mg, 0.06 mmol) was dissolved in a solution of HCl (2 mL) and MeOH (2 mL). The reaction mixture was stirred at 80° C. for 3 h. Then a solution of sodium biscarboxylate was added and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. Purification of the crude product by P-TLC using 4% methanol in dichloromethane as eluent afforded the desired product (5 mg, 9%). LCMS (245 nm): RT=5.91 min, 98.88% purity. [M+H]=315.17 [ka]

[0357] (Synthesis method I) [ka] [ka] (Methyl-4-(4-fluorobenzenesulfonamido)butanoate) To a solution of 3,4-dichlorobenzenosulfonyl chloride (633 mg, 3.25 mmol) in DCM (3.0 mL) was added triethylamine (1.3 mL, 9.76 mmol) and methyl-4-aminobutanoate hydrochloride (500 mg, 3.25 mmol). The reaction mixture was stirred at ambient temperature for 18 h. Then 1 M HCl (5 mL) was added and the aqueous layer was extracted with DCM (3×5 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give the product (0.605 g, 68%). UPLC (254 nm): RT=2.89 min, [M+H]=275.85.

[0358] [ka] (4-Fluoro-N-[3-(hydrazinecarbonyl)propyl]benzene-1-sulfonamide) To a solution of methyl-4-(4-fluorobenzenesulfonamido)butanoate (605 mg, 2.09 mmol) in EtOH (10 mL) was added 50% hydrazine in HO (0.65 mL, 10.4 mmol). The reaction mixture was stirred at 80° C. for 1 h. After that, the reaction mixture was cooled, water (20 mL) was added and the aqueous layer was extracted three times with EA (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give the pure product (180 mg, 31%). UPLC (254 nm): RT=1.88 min, 65% purity, [M+H]=276.2.

[0359] [ka] (N-(3-{N'-[(1-dimethylamino)methylidene]hydrazinecarbonyl}propyl)-4-fluorobenzene-1-sulfonamide) To a solution of 4-fluoro-N-[3-(hydrazinecarbonyl)propyl]benzene-1-sulfonamide (180 mg, 0.65 mmol) in MeOH (2 mL) was added N,N-dimethylforamide dimethyl acetal (78 mg, 0.65 mmol). The reaction mixture was stirred at 80° C. for 1 h. The solvent was then evaporated to give the desired product (216 mg, 100%). UPLC (254 nm): RT=1.78 min, 60% purity, [M+H]=331.3.

[0360] [ka] (4-Fluoro-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]benzene-1-sulfonamide (G1)) MeNH2 2M in THF (32 mL, 3.3 mmol) was added to a solution of N-(3-{N'-[(1-dimethylamino)methylidene]hydrazinecarbonyl}propyl)-4-fluorobenzene-1-sulfonamide (216 mg, 0.63 mmol) in anhydrous THF (5.0 mL) under argon atmosphere. The reaction mixture was cooled to 0 °C and acetic acid (2 mL) was carefully added. The reaction mixture was stirred at 100 °C for 1 h. Then the reaction was cooled to room temperature, water (5 mL) was added and the aqueous layer was extracted three times with EA (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography using 0-4% MeOH in DCM as eluent. 40 mg of the product obtained was repurified by P-TLC using 4% MeOH in DCM as eluent and then by preparative HPLC. The fractions containing the title compound in pure form were concentrated (3 mg, 2%). LCMS-Method 1 (200 nm): RT=6.17 min, 99.5% purity, [M+H]=299.2. [ka]

[0361] (Synthesis method K) [ka] [ka] (N-(2-chloroethyl)sulfamoyl chloride) 2-Chloroethylamine hydrochloride (0.50 g, 4.3 mmol), sulfuryl chloride (3.49 g, 2.10 mL, 25.8 mmol) were dissolved in acetonitrile (5.0 mL) and the reaction was stirred at 80° C. overnight. The mixture was concentrated and used directly in the next step. The title compound was obtained as a yellow oil (0.5 g, 86% yield). [ka]

[0362] [ka] ((2-Chloroethyl)[(3,4-dimethoxyphenyl)sulfamoyl]amine) N-(2-Chloroethyl)sulfamoyl chloride (0.14 g, 0.78 mmol) and 3,4-dimethoxyaniline (0.12 g, 0.78 mmol) were dissolved in DCM (1.2 mL) and pyridine (1.2 mL). The reaction was stirred at room temperature overnight. The reaction mixture was then cooled to room temperature. The mixture was diluted with DCM (15.0 mL) and washed with 1 M hydrochloric acid solution (20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The title compound was obtained as a yellow oil (0.23 g, 100% yield). The compound was used in the next step without further purification. UPLC (280 nm): RT=3.14 min, 11% purity, [M+H]=294.95

[0363] [ka] ([(3,4-dimethoxyphenyl)sulfamoyl]({2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]ethyl})amine (G5)) (2-Chloroethyl)[(3,4-dimethoxyphenyl)sulfamoyl]amine (0.085 g, 0.74 mmol), 3-mercapto-4-methyl-4H-1,2,4-triazole (0.22 g, 0.74 mmol), potassium carbonate (0.31 g, 2.21 mmol) were dissolved in acetonitrile (1.7 mL) and stirred at 80 °C for 3 h. The reaction mixture was then cooled to room temperature, filtered through Celite, evaporated and purified by column chromatography using 0-5% MeOH in DCM as eluent to give the pure product (8 mg, 3%). LCMS-Method 2 (200 nm): RT = 3.08 min, 99.1% purity, [M+H] = 374.03. [ka]

[0364] (Synthesis method L) [ka] [ka] ([4-(4-fluorobenzenesulfonamido)phenyl]boronic acid) 4-Aminophenylboronic acid (1.5 g, 8.7 mmol) and 4-fluorophenylsulfonyl chloride (1.53 g, 7.9 mmol) were dissolved in pyridine (43 mL). The mixture was stirred at 50° C. overnight, cooled to room temperature and the solvent was removed in vacuo. The crude product was used in the next step without further purification (5.4 g, 200%). UPLC (254 nm): RT=2.88 min, 50% purity, [M-2H]=293.5.

[0365] [ka] ([4-(3,4-dimethoxybenzenesulfonamido)phenyl]boronic acid) 4-Aminophenylboronic acid (2.35 g, 11.6 mmol) and 3,4-dimethoxyphenylsulfonyl chloride (1.53 g, 7.9 mmol) were dissolved in pyridine (80 mL). The mixture was stirred at 50° C. overnight, cooled to room temperature and the solvent was removed in vacuo. The crude product was used in the next step without further purification (8.1 g, 200%). UPLC (254 nm): RT=2.77 min, 50% purity, [M-2H]=335.6.

[0366] [ka] (N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-4-fluorobenzene-1-sulfonamide (I1)) A solution of [4-(4-fluorobenzenesulfonamido)phenyl]boronic acid (2.75 g, 9.2 mmol), 2-amino-5-bromo-thiazole hydrobromide (2.00 g, 7.7 mmol), and potassium carbonate (3.21 g, 23.1 mmol) in 1,4-dioxane (40.0 mL) and water (4.0 mL) was degassed with a stream of argon for 20 min and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.84 g, 1.2 mmol) was added in one portion. The reaction mixture was stirred at 130° C. overnight. After this time, the reaction was filtered through Celite, which was washed with DCM, water (40 mL) was added, the layers were separated, the aqueous layer was extracted three times with DCM (3×25 mL), the organic layers were combined, dried over sodium sulfate, filtered, and evaporated. The crude product was purified by column chromatography using methanol (0-3%) in DCM as eluent and the fractions containing the product were further re-purified by preparative HPLC method to give the pure product as a red solid (48 mg, 2%). LCMS-Method 1 (254 nm): RT=6.73 min, 99.6% purity, [M+H]=349.7. [ka]

[0367] [ka] (N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-3,4-dimethoxybenzene-1-sulfonamide (I2)) A solution of [4-(3,4-dimethoxybenzenesulfonamido)phenyl]boronic acid (1.64 g, 5.5 mmol), 2-amino-5-bromo-thiazole hydrobromide (1.20 g, 4.6 mmol), and potassium carbonate (3.21 g, 23.1 mmol) in 1,4-dioxane (40.0 mL) and water (4.0 mL) was degassed with a stream of argon for 20 min and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.51 g, 0.7 mmol) was added in one portion. The reaction mixture was stirred at 130° C. overnight. After this time, the reaction was filtered through Celite, which was washed with DCM, water (40 mL) was added, the layers were separated, the aqueous layer was extracted three times with DCM (3×25 mL), the organic layers were combined, dried over sodium sulfate, filtered, and evaporated. The crude product was purified by column chromatography using methanol (0-3%) in DCM as eluent and the fractions containing the product were further re-purified by preparative HPLC method to give the pure product as an orange solid (45 mg, 3%). LCMS-Method 2 (200 nm): RT=2.99 min, 99.9% purity, [M+H]=392.0. [ka]

[0368] (Synthesis method M) [ka] [ka] (2-Bromo-4'-fluoro-1,1'-biphenyl) A solution of 1,2-dibromobenzene (8.26 g, 35.0 mmol), 4-flurophenylboronic acid (2.5 g, 17.9 mmol), and sodium carbonate (3.79 g, 35.0 mmol) in ethanol (35.0 mL), toluene (35.0 mL), and water (35.0 mL) was degassed with a stream of argon for 20 min and tetrakis(triphenylphosphine)palladium(0) (1.00 g, 0.9 mmol) was added in one portion. The reaction mixture was stirred at 100° C. overnight. After this time, the reaction was filtered through Celite, the layers were separated, the aqueous layer was extracted twice with ethyl acetate (2×15 mL), and the organic layers were combined, dried over sodium sulfate, filtered, and evaporated. The crude product was purified by column chromatography using hexane as eluent to give the title product (5.50 g, 122%). UPLC (254 nm): RT=4.33 min, 91% purity, [M+H]=none observed.

[0369] [ka] (1-{4'-fluoro-[1,1'-biphenyl]-2-yl}piperidine-4-carbonitrile) A solution of 2-bromo-4'-fluoro-1,1'-biphenyl (0.3 g, 1.2 mmol), piperidine-4-carbonitrile (0.2 g, 1.8 mmol), xantphos (0.14 g, 0.24 mmol), and cesium carbonate (0.78 g, 2.4 mmol) in anhydrous 1,4-dioxane (3.0 mL) was degassed with a stream of argon for 20 min and tris(dibenzylideneacetone)dipalladium(0) (0.11 g, 0.12 mmol) was added in one portion. The reaction mixture was stirred at 100° C. overnight. After this time, the reaction was filtered through Celite, washed with ethyl acetate, and evaporated. The crude product was purified by column chromatography using ethyl acetate (0-4%) in hexane as eluent to give the title product (0.18 g, 54%). UPLC (254nm): RT=4.25 min, 90% purity, [M+H]=281.4.

[0370] [ka] (5-(1-{4'-fluoro-[1,1'-biphenyl]-2-yl}piperidin-4-yl)-1,3,4-thiadiazol-2-amine (L2)) A solution of 1-{4'-fluoro-[1,1'-biphenyl]-2-yl}piperidine-4-carbonitrile (0.18 g, 0.7 mmol) and thiosemicarbazide (0.09 g, 1.05 mmol) in trifluoroacetic acid (1.5 mL) was stirred at 65° C. for 2 h. After this time, the reaction was cooled to room temperature, diluted with saturated sodium bicarbonate solution (15 mL), extracted with DCM (3×15 mL), the organic layers combined, dried over sodium sulfate, filtered, and evaporated. The crude product was triturated with ethyl acetate (1 mL), filtered off, and dried under vacuum to give the pure product (100 mg, 45%). LCMS (LCMS method: LCMS-002-20-80-95-12-05-25(Gemini-BCM)-UV, 200nm): RT=4.97 min, 96.7% purity, [M+H]=355.2. [ka]

[0371] (Synthesis method N) [ka] [ka] tert-Butyl-4-(2-amino-1,3-thiazol-5-yl)piperidine-1-carboxylate was synthesized in two steps according to the literature (total yield: 60%).

[0372] [ka] (tert-Butyl-4-(2-acetamido-1,3-thiazol-5-yl)piperidine-1-carboxylate) To a solution of tert-butyl-4-(2-amino-1,3-thiazol-5-yl)piperidine-1-carboxylate (3.75 g, 13.23 mmol) in anhydrous DCM (35 mL) was added triethylamine (3.69 mL, 26.4 mmol) and acetyl chloride (1.00 mL, 14.6 mmol) under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. Then water (50 mL) was added and the aqueous layer was extracted five times with DCM (5×80 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give the pure product (4.175 g, 97%). UPLC (254 nm): RT=4.27 min, [M+H]=326.25.

[0373] [ka] (N-[5-(piperidin-4-yl)-1,3-thiazol-2-yl]acetamide) To a solution of tert-butyl 4-(2-acetamido-1,3-thiazol-5-yl)piperidine-1-carboxylate (4.175 g, 12.83 mmol) in THF (90.0 mL) was added 4M HCl in dioxane (10 mL). The reaction mixture was stirred for 18 h. Afterwards, the reaction mixture was filtered and the precipitate was washed with EA (2×40 mL) and dried under reduced pressure to give the pure product (2.752 g, 82%). UPLC (254 nm): RT=2.1 min, [M+H]=226.25.

[0374] [ka] (N-{5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3-thiazol-2-yl}acetamide) To a solution of 3,4-dichlorobenzenosulfonyl chloride (182 mg, 0.94 mmol) in a mixture of solvents DCM (3.0 mL) and pyridine (3.0 mL) was added N-[5-(piperidin-4-yl)-1,3-thiazol-2-yl]acetamide (211 mg, 0.94 mmol). The reaction mixture was stirred at ambient temperature for 48 h. Afterwards, the solvent was evaporated and the crude product was carried on to the next step.

[0375] [ka] (5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3-thiazol-2-amine (M1)) N-{5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3-thiazol-2-yl}acetamide (300 mg, 0.78 mmol) was dissolved in a solution of HCl (12 mL) and MeOH (12 mL). The reaction mixture was stirred at 80° C. for 18 h. Then a solution of saturated sodium biscarboxylate was added and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, evaporated and purified by column chromatography using 0-10% MeOH in DCM as eluent. The fractions containing the title compound were combined and concentrated. The product was repurified by P-TLC using 4% MeOH in DCM as eluent (16 mg, 6%). LCMS-Method 1 (220 nm): RT=6.37 min, 95.99% purity, [M+H]=342.07. [ka]

[0376] [ka] (1-(4-fluorobenzenesulfonyl)piperidine-4-carbonitrile) To a solution of piperidine-4-carbonitrile (500 mg, 4.54 mmol) in a mixture of solvent DCM (5.0 mL) and pyridine was added 4-4luorobenzenesulfonyl chloride (880 mg, 4.54 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with 1M HCl (50 ml) and DCM (50 ml) and the layers were separated. The organic layer was washed twice with 1M HCl (2×50 ml) and concentrated to give the desired product as a beige solid. [ka]

[0377] [ka] (5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3,4-thiadiazol-2-amine (M2)) 1-(4-Fluorobenzenesulfonyl)piperidine-4-carbonitrile (500 mg, 1.86 mmol) and thisemicarbazide (190 mg, 2.05 mmol) were dissolved in TFA (4.0 mL) and the reaction mixture was stirred at 60° C. for 2 h. Then the solvent was concentrated and the residue was suspended in DCM:MeOH (4.0 ml, 95:5; vol:vol) solution and the precipitate was filtered to give the desired compound as a white solid (610 mg, 96.0%). LCMS-Method 2 (Method: LCMS Method 2 (Gemini BCM)-UV, 200 nm): RT=4.29 min, 97.59% purity, [M+H]=343.13. [ka]

[0378] (Synthesis method O) [ka] [ka] (tert-Butyl 4-{N'-[(1E)-(dimethylamino)methylidene]hydrazinecarbonyl}piperidine-1-carboxylate) To a solution of tert-butyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate (500 mg, 2.05 mmol) in DMF (5 mL) was added N,N-dimethylforamide dimethyl acetal (245 mg, 2.05 mmol). The reaction mixture was stirred at 100° C. for 18 h. The solvent was then evaporated to give the desired product (601 mg, 98%).

[0379] [ka] (tert-Butyl 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate) MeNH2 2M in THF (15 mL, 40.2 mmol) was added to a solution of tert-butyl 4-{N'-[(1E)-(dimethylamino)methylidene]hydrazinecarbonyl}piperidine-1-carboxylate (600 mg, 2.01 mmol) in anhydrous THF (6.0 mL) under argon atmosphere. The reaction mixture was cooled to 0 °C and acetic acid (2 mL) was carefully added. The reaction mixture was stirred at 100 °C for 18 h. After that, the reaction was cooled to room temperature, water (20 mL) was added and the aqueous layer was extracted three times with EA (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give the crude compound (511 mg, 95%).

[0380] [ka] (4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine) To a solution of tert-butyl 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (511 mg, 1.71 mmol) in THF (5.0 mL) was added 4M HCl in dioxane (6.0 mL). The reaction mixture was stirred for 18 h. Afterwards, the reaction mixture was filtered and the precipitate was washed with EA (2×40 mL) and dried under reduced pressure to give the product (347 mg, 100%).

[0381] [ka] (1-(4-fluorobenzenesulfonyl)-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine (N1)) To a solution of 4-fluorobenzenosulfonyl chloride (117 mg, 0.60 mmol) in pyridine (1.0 mL) was added 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine (100 mg, 0.60 mmol). The reaction mixture was stirred at ambient temperature for 18 h. Then the solvent was evaporated, 1 M HCl (5 mL) was added and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The product was purified by P-TLC using 5% MeOH in DCM as eluent (6 mg, 3%). LCMS-Method 2 (220 nm): RT=3.63 min, 96.34% purity, [M+H]=325.11 [ka]

[0382] (Synthesis method P) [ka] [ka] (tert-Butyl 5-methyl-1H-1,3-benzodiazole-1-carboxylate) 5-Methyl-1H-1,3-benzodiazole (0.5 g, 7.6 mmol), Boc anhydride (2.44 g, 11.4 mmol), DMAP (92 mg, 0.76 mmol), and triethylamine (2.11 mL, 15 mmol) were dissolved in acetonitrile (10 mL). The mixture was stirred at 80° C. overnight, cooled, and the solvent was removed in vacuo. The crude product was purified by column chromatography using DCM as eluent. Fractions containing the title compound were combined and concentrated (0.80 g, 46%). UPLC (254 nm): RT=3.75 min, 93.2% purity, [M+H]=233.2.

[0383] [ka] (tert-Butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate) tert-Butyl 5-methyl-1H-1,3-benzodiazole-1-carboxylate (0.8 g, 3.44 mmol), N-bromosuccimide (0.64 g, 3.62 mmol), dibenzoyl peroxide (22 mg, 0.1 mmol) were suspended in tetrachloromethane (16 ml) and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to 0° C., the precipitate was filtered off, and the filtrate was concentrated in vacuo to give the desired product as a pale yellow oil (0.95 g, 89%). UPLC (254 nm): RT=3.75 min, 80% purity, [M+H]=312.75.

[0384] [ka] (4'-Fluoro-[1,1'-biphenyl]-2-amine) A solution of 2-bromoaniline (1.5 g, 8.7 mmol), 4-flurophenylboronic acid (1.46 g, 10.5 mmol), and potassium carbonate (4.16 g, 30.1 mmol) in 1,4-dioxane (15.0 mL) and water (15.0 mL) was degassed with a stream of argon for 20 min and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.43 g, 0.5 mmol) was added in one portion. The reaction mixture was stirred at 100 °C overnight. After this time, the reaction was filtered through Celite, the layers were separated, the aqueous layer was extracted twice with ethyl acetate (2 x 15 mL), and the organic layers were combined, dried over sodium sulfate, filtered, and evaporated. The crude product was purified by column chromatography using 10% ethyl acetate in hexane as eluent to give the pure product (1.65 g, 100%). UPLC (254 nm): RT=3.31 min, 99% purity, [M+H]=187.9.

[0385] [ka] (N-[(1H-1,3-benzodiazol-5-yl)methyl]-4'-fluoro-[1,1'-biphenyl]-2-amine (O1)) To a solution of 4'-fluoro-[1,1'-biphenyl]-2-amine (100 mg, 0.53 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (244 mg, 0.59 mmol) in DMF (1.0 mL) was added sodium carbonate (170 mg, 1.6 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then diluted with ethyl acetate (15.0 mL) and washed with half-saturated brine (3×20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give the crude product, which was purified by column chromatography using 0-2% MeOH in DCM as eluent to give the desired product as an off-white solid (48 mg, 22%). LCMS-Method 2 (200 nm): RT=4.13 min, 97.2% purity, [M+H]=318.25. [ka]

[0386] [ka] (3',4'-Dimethoxy-[1,1'-biphenyl]-2-amine) A solution of 2-bromoaniline (3.0 g, 17.4 mmol), 3,4-dimethoxyphenylboronic acid (3.81 g, 20.9 mmol), and potassium carbonate (8.32 g, 30.1 mmol) in 1,4-dioxane (30.0 mL) and water (30.0 mL) was degassed with a stream of argon for 20 min and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.85 g, 1.1 mmol) was added in one portion. The reaction mixture was stirred at 100° C. overnight. After this time, the reaction was filtered through Celite, the layers were separated, the aqueous layer was extracted twice with ethyl acetate (2×15 mL), and the organic layers were combined, dried over sodium sulfate, filtered, and evaporated. The crude product was purified by column chromatography using 2-10% ethyl acetate in hexane as eluent to give the pure product (3.2 g, 80%). UPLC (254 nm): RT=3.25 min, 90% purity, [M+H]=229.9.

[0387] [ka] (N-[(1H-1,3-benzodiazol-5-yl)methyl]-3',4'-dimethoxy-[1,1'-biphenyl]-2-amine (O2)) To a solution of 3',4'-dimethoxy-[1,1'-biphenyl]-2-amine (200 mg, 0.87 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (0.398 g, 0.96 mmol) in DMF (1.0 mL) was added sodium carbonate (277 mg, 2.62 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then diluted with ethyl acetate (15.0 mL) and washed with half-saturated brine (3×20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give the crude product, which was purified by column chromatography using 0-2% MeOH in DCM as eluent to give the desired product as an off-white solid (70 mg, 17%). LCMS-Method 2 (205 nm): RT=3.66 min, 96.5% purity, [M+H]=360.1. [ka]

[0388] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)aniline (O3)) To a solution of 2-(4-methoxyphenyl)aniline (90 mg, 0.45 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (156 mg, 0.50 mmol) in DMF (1.0 mL) was added sodium carbonate (144 mg, 1.36 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 100:0→98:2 DCM / MeOH. Repurification was performed by preparative TLC eluting with 95:5 DCM / MeOH to give the desired product as an off-white solid (35 mg, 23%). LCMS-Method 2 (230nm): RT=3.90 min, 96.6% purity, [M+H]=330.24. [ka]

[0389] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)pyridin-3-amine (O4)) To a solution of 2-(4-methoxyphenyl)pyridin-3-amine (90 mg, 0.45 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (155 mg, 0.50 mmol) in DMF (1.0 mL) was added sodium carbonate (143 mg, 1.36 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 100:0:0→9:1:0.1 DCM / MeOH / NH3. Repurification was performed by preparative TLC eluting with 95:5:0.1 DCM / MeOH / NH3 to give the desired product as an off-white solid (10 mg, 7%). LCMS-Method 1 (205nm): RT=4.66 min, 97.8% purity, [M+H]=331.27. [ka]

[0390] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-2-amine (O5)) To a solution of 3-(4-methoxyphenyl)pyridin-2-amine (100 mg, 0.50 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (202 mg, 0.65 mmol) in DMF (1.0 mL) was added sodium carbonate (159 mg, 1.50 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 95:5:0→9:1:0.1 DCM / MeOH / NH3. Repurification was performed by preparative TLC eluting with 95:5:0→9:1:0.1 DCM / MeOH / NH3 to give the desired product as a white solid (4 mg, 2.5%). LCMS-Method 3 (200nm): RT=2.66 min, 96.3% purity, [M+H]=331.11. [ka]

[0391] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-4-amine (O6)) To a solution of 3-(4-methoxyphenyl)pyridin-4-amine (100 mg, 0.50 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (172 mg, 0.55 mmol) in DMF (1.0 mL) was added sodium carbonate (159 mg, 1.50 mmol). The reaction mixture was stirred at 80° C. overnight. After that, the reaction mixture was cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 95:5:0→9:1:0.1 DCM / MeOH / NH3. Repurification was performed by preparative TLC eluting with 95:5:0→9:1:0.1 DCM / MeOH / NH3 to give the desired product as a white solid (12 mg, 7%). LCMS-Method 3 (245nm): RT=2.36 min, 97.4% purity, [M+H]=331.25. [ka]

[0392] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-4-(4-methoxyphenyl)pyridin-3-amine O7) To a solution of 4-(4-methoxyphenyl)pyridin-3-amine (100 mg, 0.50 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (172 mg, 0.55 mmol) in DMF (1.0 mL) was added sodium carbonate (159 mg, 1.50 mmol). The reaction mixture was stirred at 80° C. overnight. Afterwards, the reaction mixture was cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 95:5:0→9:1:0.1 DCM / MeOH / NH3. Repurification was carried out by preparative HPLC to give the desired product as a white solid (5 mg, 4%). LCMS (LCMS-Method 3, 245 nm): RT=2.43 min, 73.7% purity, [M+H]=331.25. [ka]

[0393] [ka] (N-(1H-1,3-Benzodiazol-5-ylmethyl)-5-(4-methoxyphenyl)pyrimidin-4-amine (O8)) To a solution of 5-(4-methoxyphenyl)pyrimidin-4-amine (50 mg, 0.25 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (86 mg, 0.28 mmol) in DMF (0.5 mL) was added sodium carbonate (79 mg, 0.75 mmol). The reaction mixture was stirred at 80° C. overnight. Afterwards, the reaction mixture was cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by preparative HPLC to give the desired product as a yellowish solid (1.96 mg, 1.8%). LCMS-Method 12 (200 nm): RT=4.5 min, 100.0% purity, [M+H]=332.20. [ka]

[0394] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyrazin-2-amine (O9)) To a solution of 3-(4-methoxyphenyl)pyrazin-2-amine (140 mg, 0.70 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (240 mg, 0.77 mmol) in DMF (1.0 mL) was added sodium carbonate (221 mg, 2.09 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 95:5:0→9:1:0.1 DCM / MeOH / NH3. Repurification was performed by preparative TLC eluting with 95:5:0→9:1:0.1 DCM / MeOH / NH3 to give the desired product as an off-white solid (5 mg, 2%). LCMS-Method 3 (270nm): RT=3.04 min, 87.4% purity, [M+H]=332.24. [ka]

[0395] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-4-amine (O10)) To a solution of 3-(3,4-dimethoxyphenyl)pyridin-4-amine (100 mg, 0.43 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (214 mg, 0.69 mmol) in DMF (1.0 mL) was added sodium carbonate (137 mg, 1.30 mmol). The reaction mixture was stirred at 80° C. overnight. Afterwards, the reaction mixture was cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 95:5→9:1 DCM / MeOH. The fractions containing the product were collected and evaporated. The residue was suspended in MeOH and filtered to give the desired product as a white solid (11 mg, 7%). LCMS-Method 9 (200nm): RT=2.8 min, 95.2% purity, [M+H]=361.16. [ka]

[0396] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-2-amine (O11)) To a solution of 3-(3,4-dimethoxyphenyl)pyridin-2-amine (100 mg, 0.43 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (150 mg, 0.48 mmol) in DMF (1.0 mL) was added sodium carbonate (138 mg, 1.30 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 95:5:0→9:1:0.1 DCM / MeOH / NH3. Repurification was performed by preparative TLC eluting with 95:5:0→9:1:0.1 DCM / MeOH / NH3 to give the desired product as an off-white solid (11 mg, 7%). LCMS-Method 1 (200nm): RT=4.98 min, 93.2% purity, [M+H]=361.25. [ka]

[0397] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyrazin-2-amine (O12)) To a solution of 3-(3,4-dimethoxyphenyl)pyrazin-2-amine (100 mg, 0.43 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (175 mg, 0.56 mmol) in DMF (1.0 mL) was added sodium carbonate (137 mg, 1.30 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 95:5:0→9:1:0.1 DCM / MeOH / NH3. Repurification was performed by preparative TLC eluting with 95:5:0→9:1:0.1 DCM / MeOH / NH3 to give the desired product as an off-white solid (8 mg, 5%). LCMS-Method 3 (200nm): RT=2.97 min, 87.7% purity, [M+H]=362.21. [ka]

[0398] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-fluorophenyl)pyridin-3-amine (O13)) To a solution of 2-(4-fluorophenyl)pyridin-3-amine (110 mg, 0.58 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (202 mg, 0.65 mmol) in DMF (1.0 mL) was added sodium carbonate (186 mg, 1.75 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 95:5:0→9:1:0.1 DCM / MeOH / NH3. Repurification was performed by preparative TLC eluting with 95:5:0→9:1:0.1 DCM / MeOH / NH3 to give the desired product as an off-white solid (8 mg, 4%). LCMS-Method 1 (200nm): RT=3.04 min, 96.1% purity, [M+H]=319.23. [ka]

[0399] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyridin-2-amine (O14)) To a solution of 3-(4-fluorophenyl)pyridin-2-amine (70 mg, 0.37 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (128 mg, 0.41 mmol) in DMF (0.7 mL) was added sodium carbonate (118 mg, 1.12 mmol). The reaction mixture was stirred at 80° C. overnight. Afterwards, the reaction mixture was cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by preparative HPLC. Repurification was performed by preparative TLC eluting with 95:5:0.1 DCM / MeOH / NH3 to give the desired product as a white solid (7.7 mg, 4.95%). LCMS-Method 1 (200 nm): RT=5.04 min, 97.1% purity, [M+H]=319.23. [ka]

[0400] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyrazin-2-amine (O15)) To a solution of 3-(4-fluorophenyl)pyrazin-2-amine (100 mg, 0.53 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (214 mg, 0.69 mmol) in DMF (1.0 mL) was added sodium carbonate (137 mg, 1.30 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 95:5:0→9:1:0.1 DCM / MeOH / NH3. Repurification was performed by preparative TLC eluting with 95:5:0→9:1:0.1 DCM / MeOH / NH3 to give the desired product as an off-white solid (3 mg, 2%). LCMS-Method 1 (202nm): RT=3.08 min, 95.4% purity, [M+H]=320.22. [ka]

[0401] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-phenoxyphenyl)aniline (O16)) To a solution of 2-(4-phenoxyphenyl)aniline (100 mg, 0.38 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (132 mg, 0.42 mmol) in DMF (1.0 mL) was added sodium carbonate (122 mg, 1.15 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 1:0→96:4 DCM / MeOH. Repurification was performed by preparative TLC eluting with 95:5:0.1 DCM / MeOH / NH3 to give the desired product as a white solid (25 mg, 16.7%). LCMS-Method 2 (205nm): RT=4.99 min, 99.6% purity, [M+H]=392.26. [ka]

[0402] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(cyclohexyloxy)phenyl]aniline (O17)) To a solution of 2-[4-(cyclohexyloxy)phenyl]aniline (100 mg, 0.37 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (129 mg, 0.42 mmol) in DMF (1.0 mL) was added sodium carbonate (119 mg, 1.12 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by preparative TLC eluting with 95:5 DCM / MeOH. Repurification by preparative TLC eluting with 95:5 DCM / MeOH gave the desired product as a white solid (4.9 mg, 3.3%). LCMS-Method 2 (200nm): RT=5.17 min, 100% purity, [M+H]=398.26. [ka]

[0403] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-propoxyphenyl)aniline (O18)) To a solution of 2-(4-propoxyphenyl)aniline (100 mg, 0.44 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (152 mg, 0.49 mmol) in DMF (1.0 mL) was added sodium carbonate (140 mg, 1.32 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 1:0→98:2 DCM / MeOH. Repurification was performed by preparative TLC eluting with 95:5 DCM / MeOH to give the desired product as a white solid (34.4 mg, 21.9%). LCMS-Method 2 (200nm): RT=4.58 min, 100% purity, [M+H]=358.25. [ka]

[0404] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(propan-2-yloxy)phenyl]aniline (O19)) To a solution of 2-[4-(propan-2-yloxy)phenyl]aniline (100 mg, 0.44 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (152 mg, 0.49 mmol) in DMF (1.0 mL) was added sodium carbonate (140 mg, 1.32 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 1:0→99:1 DCM / MeOH. Repurification was performed by preparative TLC eluting with 95:5 DCM / MeOH to give the desired product as a white solid (24.3 mg, 15.5%). LCMS-Method 4 (200nm): RT=2.42 min, 97.3% purity, [M+H]=358.26. [ka]

[0405] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)-3-methylaniline (O20)) To a solution of 2-(4-methoxyphenyl)-3-methylaniline (100 mg, 0.47 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (162 mg, 0.52 mmol) in DMF (1.0 mL) was added sodium carbonate (149 mg, 1.41 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 1:0→97:3 DCM / MeOH. Repurification was performed by preparative TLC eluting with 9:1 DCM / MeOH to give the desired product as a white solid (40.7 mg, 25.3%). LCMS (LCMS-Method 4, 205nm): RT=2.14 min, 98.9% purity, [M+H]=344.27. [ka]

[0406] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-methylaniline (O21)) To a solution of 2-(3,4-dimethoxyphenyl)-3-methylaniline (100 mg, 0.41 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (142 mg, 0.46 mmol) in DMF (1.0 mL) was added sodium carbonate (131 mg, 1.23 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 1:0→97:3 DCM / MeOH. Repurification was performed by preparative TLC eluting with 95:5 DCM / MeOH to give the desired product as a white solid (47.5 mg, 31%). LCMS (LCMS-Method 4, 205nm): RT=1.99 min, 97.3% purity, [M+H]=374.27. [ka]

[0407] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-chlorophenyl)-3-fluoroaniline (O22)) To a solution of 2-(4-chlorophenyl)-3-fluoroaniline (100 mg, 0.45 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (156 mg, 0.50 mmol) in DMF (1.0 mL) was added sodium carbonate (143 mg, 1.35 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 1:0→97:3 DCM / MeOH. Repurification was performed by preparative TLC eluting with 95:5 DCM / MeOH to give the desired product as a white solid (40.6 mg, 25.6%). LCMS (LCMS-Method 4, 200nm): RT=2.29 min, 94.2% purity, [M+H]=344.27. [ka]

[0408] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline (O23)) To a solution of 2-(3,4-dimethoxyphenyl)-3-fluoroaniline (100 mg, 0.40 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (140 mg, 0.45 mmol) in DMF (1.0 mL) was added sodium carbonate (129 mg, 1.21 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 1:0→97:3 DCM / MeOH. Repurification was performed by preparative TLC eluting with 9:1 DCM / MeOH to give the desired product as a white solid (29.3 mg, 19.2%). LCMS (LCMS-Method 4, 200nm): RT=1.92 min, 90.1% purity, [M+H]=378.23. [ka]

[0409] [ka] (N-(1H-1,3-benzodiazol-5-ylmethyl)-3-fluoro-2-(4-fluorophenyl)aniline (O24)) To a solution of 3-fluoro-2-(4-fluorophenyl)aniline (100 mg, 0.49 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (168 mg, 0.54 mmol) in DMF (1.0 mL) was added sodium carbonate (155 mg, 1.46 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to RT and filtered through Celite. The Celite pad was washed with MeOH. The filtrate was evaporated to give the crude product, which was purified by column chromatography using 1:0→97:3 DCM / MeOH. Repurification was performed by preparative TLC eluting with 9:1 DCM / MeOH to give the desired product as a white solid (29.3 mg, 19.2%). LCMS (LCMS-Method 4, 205nm): RT=2.12 min, 96.6% purity, [M+H]=336.23. [ka]

[0410] (Synthesis method Q) [ka] (N-[(1H-1,3-benzodiazol-5-yl)methyl]-4-fluorobenzene-1-sulfonamide (P1)) (1H-1,3-Benzodiazol-5-yl)methanamine dihydrochloride (0.25 g, 1.15 mmol) was dissolved in pyridine (7 mL) and stirred at room temperature for 30 min. Then 4-fluorophenylsulfonyl chloride (0.21 g, 1.08 mmol) was added and the reaction mixture was heated to 70° C. and stirred overnight. The mixture was quenched with 10 mL of 20% aqueous sodium hydroxide solution and stirred at 70° C. for another night. The layers were separated and pyridine was evaporated in vacuo. The crude product was purified by column chromatography using MeOH (0-3%) in DCM as eluent. The fractions containing the title compound were combined and concentrated (55 mg, 19%). LCMS-Method 1 (200 nm): RT=5.81 min, 93.2% purity, [M+ACN]=347.27. [ka]

[0411] (Synthesis method R) [ka] [ka] ([(1H-1,3-benzodiazol-5-yl)methyl][(4-fluorophenyl)(methyl)oxo-λ 6 -sulfanilidene]amine (Q1) (4-Fluorophenyl)(imino)methyl-λ in DMSO (13.0 mL) 6 -sulfanone (250 mg, 1.5 mmol) and potassium hydroxide (234 mg, 2.18 mmol) were stirred at 50° C. for 1 h. After this time, the reaction was cooled to room temperature and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (650 mg, 2.10 mmol) was added. The reaction was stirred overnight, after which water (50 mL) was added and extracted with DCM (5×30 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a DMSO solution of the crude product which was purified by a preparative HPLC method to give the title compound as a colorless oil (26 mg, 5%). LCMS-Method 1 (200 nm): RT=5.72 min, 96.3% purity, [M+H]=304.15. [ka]

[0412] (Analysis method) (NMR) 1H NMR-spectra (300 MHz) were recorded on a BRUKER FOURIER 300. The solvent was DMSO-D6 unless otherwise stated. Chemical shifts are expressed as parts per million (ppm) downfield from tetramethylsilane. Splitting patterns are designated as follows: s (singlet), d (doublet), dd (double doublet), t (triplet), m (multiplet), and br (broad signal).

[0413] (HPLC-MS) (LCMS-Method 1) (Instrument:) Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus (Column:) Gemini-NX 3μ C18 (4.6×50mm), 110A, column number OOB-4453-EO, internal column number 002 (Reagents:) - Formic acid ≥98%, Sigma-Aldrich -Acetonitrile / Gradient Grade for HPLC UV, Baker -μQ-Water for LCMS (HPLC conditions:)-Wavelength range: (190~340)nm±4nm -Flow rate: 0.5ml / min -Column temperature: 25℃ -Autosampler temperature: 20℃ -Injection volume: 2.0μl -Analysis time: 14 minutes -Elution: Gradient [Table 24] (Mobile phase A:) 0.1% v / v solution of formic acid in water (Mobile phase B:) 0.1% v / v solution of formic acid in acetonitrile (Syringe cleaning solution:) 20% MeOH (MS conditions:)-Mass range: 100~1000m / z -Ionization: Alternating -Scanning speed: 12000amu / sec

[0414] (LCMS-Method 2) (Instrument:) Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus (Column:) Gemini-NX 3μ C18 (4.6×50mm), 110A, column number OOB-4453-EO, internal column number 002 (Reagents:) - Formic acid ≥98%, Sigma-Aldrich -Acetonitrile / Gradient Grade for HPLC UV, Baker -μQ-Water for LCMS (HPLC conditions:)-Wavelength range: (190~340)nm±4nm -Flow rate: 0.5ml / min -Column temperature: 25℃ -Autosampler temperature: 20℃ -Injection volume: 2.0μl -Analysis time: 12 minutes -Elution: Gradient [Table 25] (Mobile phase A:) 0.1% v / v solution of formic acid in water (Mobile phase B:) 0.1% v / v solution of formic acid in acetonitrile (Syringe cleaning solution:) 20% MeOH (MS conditions:)-Mass range: 100~1000m / z -Ionization: Alternating -Scanning speed: 12000amu / sec

[0415] (LCMS-Method 3) (Instrument:) Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus (Column:) Kinetex® 2.6 μm XB-C18 (4.6 × 50 mm), 110A, column number OOB-4496-E0, internal column number 019 (Reagents:) - Formic acid ≥98%, Sigma-Aldrich -Acetonitrile / Gradient Grade for HPLC UV, Baker -μQ-Water for LCMS (HPLC conditions:)-Wavelength range: (190~340)nm±4nm -Flow rate: 1.0ml / min -Column temperature: 25℃ -Autosampler temperature: 20℃ -Injection volume: 2.0μl -Analysis time: 7 minutes -Elution: Gradient [Table 26] (Mobile phase A:) 0.1% v / v solution of formic acid in water (Mobile phase B:) 0.1% v / v solution of formic acid in acetonitrile (Syringe cleaning solution:) 20% MeOH (MS conditions:)-Mass range: 100~1000m / z -Ionization: Alternating -Scanning speed: 12000amu / sec

[0416] (LCMS-Method 4) (Instrument:) Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus (Column:) Kinetex® 2.6 μm XB-C18 (4.6 × 50 mm), 110A, column number 00B-4496-E0, internal column number 019 (Reagents:) - Formic acid ≥98%, Sigma-Aldrich -Acetonitrile / Gradient Grade for HPLC UV, Baker -μQ-Water for LCMS (HPLC conditions:)-Wavelength range: (190~340)nm±4nm -Flow rate: 1.0ml / min -Column temperature: 25℃ -Autosampler temperature: 20℃ -Injection volume: 2.0μl -Analysis time: 6 minutes -Elution: Gradient [Table 27] (Mobile phase A:) 0.1% v / v solution of formic acid in water (Mobile phase B:) 0.1% v / v solution of formic acid in acetonitrile (Syringe cleaning solution:) 20% MeOH (MS conditions:)-Mass range: 100~1000m / z -Ionization: Alternating -Scanning speed: 12000amu / sec

[0417] (LCMS-Method 5) (Instrument:) Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus (Column:) Kinetex® 2.6 μm XB-C18 (4.6 × 50 mm), 110A, column number OOB-4496-E0, internal column number 019 (Reagents:) - Formic acid ≥98%, Sigma-Aldrich -Acetonitrile / Gradient Grade for HPLC UV, Baker --μQ-Water for LCMS (HPLC conditions:)-Wavelength range: (190~340)nm±4nm -Flow rate: 1.0ml / min -Column temperature: 25℃ -Autosampler temperature: 20℃ -Injection volume: 2.0μl -Analysis time: 7 minutes -Elution: Gradient [Table 28] (Mobile phase A:) 0.1% v / v solution of formic acid in water (Mobile phase B:) 0.1% v / v solution of formic acid in acetonitrile (Syringe cleaning solution:) 20% MeOH (MS conditions:)-Mass range: 100~1000m / z -Ionization: Alternating -Scanning speed: 12000amu / sec

[0418] (HPLC-Method 6) (Apparatus:) HPLC-Merck Chromester equipped with gradient pump and DAD detector (Column:) XBridge C18 3.5μ (4.6×150mm), column number 186003034, internal column number 009 (reagent:) -Methanol for HPLC Ultra Gradient HPLC Grade, Baker -Boric acid ≥99.5%, Sigma-Aldrich -Sodium hydroxide analytical grade, Eurochem BGD - HPLC grade purified water (HPLC conditions:) -Wavelength: 210.0nm±4.0nm -Flow rate: 0.5mL / min -Column temperature: 25℃ -Autosampler temperature: 20℃ -Injection volume: 5μL -Analysis time: 30 minutes -Elution: Gradient [Table 29] (Mobile phase A:) Borate buffer c=5mM, pH=9.6 Preparation: 0.618 g of boric acid in a 2 L volumetric flask was dissolved in 1.5 L of purified water. The pH value was adjusted to 9.6 with 1 M NaOH solution (6 mL). Finally, the solution was diluted to standard with purified water. (Mobile phase B:) 1L MeOH (3 mL) containing a similar amount of 1M NaOH as in Phase A. (Syringe cleaning solution:) Acetonitrile

[0419] (LCMS-Method 7) (Instrument:) Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus (Column:) Gemini-NX 3μ C18 (4.6×50mm), 110A, column number OOB-4453-EO, internal column number 002 (Reagents:) - Formic acid ≥98%, Sigma-Aldrich -Acetonitrile / Gradient Grade for HPLC UV, Baker -μQ-Water for LCMS (HPLC conditions:)-Wavelength range: (190~340)nm±4nm -Flow rate: 0.5ml / min -Column temperature: 25℃ -Autosampler temperature: 20℃ -Injection volume: 2.0μl -Analysis time: 12 minutes -Elution: Gradient [Table 30] (Mobile phase A:) 0.1% v / v solution of formic acid in water (Mobile phase B:) 0.1% v / v solution of formic acid in acetonitrile (Syringe cleaning solution:) 20% MeOH (MS conditions:)-Mass range: 100~1000m / z -Ionization: Alternating -Scanning speed: 12000amu / sec

[0420] (LCMS-Method 8) (Instrument:) Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus (Column:) Gemini-NX 3μ C18 (4.6×50mm), 110A, column number OOB-4453-EO, internal column number 002 (Reagents:) - Formic acid ≥98%, Sigma-Aldrich -Acetonitrile / Gradient Grade for HPLC UV, Baker -μQ-Water for LCMS (HPLC conditions:)-Wavelength range: (190~340)nm±4nm -Flow rate: 0.5ml / min -Column temperature: 25℃ -Autosampler temperature: 20℃ -Injection volume: 2.0μl -Analysis time: 28 minutes -Elution: Gradient [Table 31] (Mobile phase A:) 0.1% v / v solution of formic acid in water (Mobile phase B:) 0.1% v / v solution of formic acid in acetonitrile (Syringe cleaning solution:) 20% MeOH (MS conditions:)-Mass range: 100~1000m / z -Ionization: Alternating -Scanning speed: 12000amu / sec

[0421] (LCMS-Method 9) (Instrument:) Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus (Column:) Kinetex XB-C18 2.6μm (4.6×50mm), 100A, column number 00B-4496-E0, internal column number 019 (Reagents:) - Formic acid ≥98%, Sigma-Aldrich -Acetonitrile / Gradient Grade for HPLC UV, Baker -μQ-Water for LCMS (HPLC conditions:)-Wavelength range: (190~340)nm±4nm -Flow rate: 1.0ml / min -Column temperature: 25℃ -Autosampler temperature: 20℃ -Injection volume: 2.0μl -Analysis time: 7 minutes -Elution: Gradient [Table 32] (Mobile phase A:) 0.1% v / v solution of formic acid in water (Mobile phase B:) 0.1% v / v solution of formic acid in acetonitrile (Syringe cleaning solution:) 20% MeOH (MS conditions:)-Mass range: 100~1000m / z -Ionization: Alternating -Scanning speed: 12000amu / sec

[0422] (LCMS-Method 10) (Instrument:) Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus (Column:) Gemini-NX 3μ C18 (4.6×50mm), 110A, column number OOB-4453-EO, internal column number 002 (Reagents:) - Formic acid ≥98%, Sigma-Aldrich -Acetonitrile / Gradient Grade for HPLC UV, Baker -μQ-Water for LCMS (HPLC conditions:)-Wavelength range: (190~340)nm±4nm -Flow rate: 0.5ml / min -Column temperature: 25℃ -Autosampler temperature: 20℃ -Injection volume: 2.0μl -Analysis time: 12 minutes -Elution: Gradient [Table 33] (Mobile phase A:) 0.1% v / v solution of formic acid in water (Mobile phase B:) 0.1% v / v solution of formic acid in acetonitrile (Syringe cleaning solution:) 20% MeOH (MS conditions:)-Mass range: 100~1000m / z -Ionization: Alternating -Scanning speed: 12000amu / sec

[0423] (LCMS-Method 11) (Instrument:) Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus (Column:) Kinetex® 2.6 μm XB-C18 (4.6 × 50 mm), 110A, column number 00B-4496-E0, internal column number 019 (Reagents:) - Formic acid ≥98%, Sigma-Aldrich -Acetonitrile / Gradient Grade for HPLC UV, Baker -μQ-Water for LCMS (HPLC conditions:)-Wavelength range: (190~340)nm±4nm -Flow rate: 1.0ml / min -Column temperature: 25℃ -Autosampler temperature: 20℃ -Injection volume: 2.0μl -Analysis time: 6 minutes -Elution: Gradient [Table 34] (Mobile phase A:) 0.1% v / v solution of formic acid in water (Mobile phase B:) 0.1% v / v solution of formic acid in acetonitrile (Syringe cleaning solution:) 20% MeOH (MS conditions:)-Mass range: 100~1000m / z -Ionization: Alternating -Scanning speed: 12000amu / sec

[0424] (LCMS-Method 12) (Instrument:) Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus (Column:) Gemini-NX 3μ C18 (4.6×50mm), 110A, column number OOB-4453-EO, internal column number 002 (Reagents:) - Formic acid ≥98%, Sigma-Aldrich -Acetonitrile / Gradient Grade for HPLC UV, Baker -μQ-Water for LCMS (HPLC conditions:)-Wavelength range: (190~340)nm±4nm -Flow rate: 0.5ml / min -Column temperature: 25℃ -Autosampler temperature: 20℃ -Injection volume: 2.0μl -Analysis time: 14 minutes -Elution: Gradient [Table 35] (Mobile phase A:) 0.1% v / v solution of formic acid in water (Mobile phase B:) 0.1% v / v solution of formic acid in acetonitrile (Syringe cleaning solution:) 20% MeOH (MS conditions:)-Mass range: 100~1000m / z -Ionization: Alternating -Scanning speed: 12000amu / sec

[0425] (UPLC-MS) (Apparatus:) Shimadzu LCMS-2020 single quadrupole liquid chromatograph mass spectrometer (Column:) Acquity UPLC 1.8μm C18(2.1×50mm), 100Å, column number 186003532, internal column number Pur CC - MS001 (reagent:) -Formic acid ≥ 98%, Sigma-Aldrich, -Acetonitrile / Gradient Grade for HPLC UV, Baker - HPLC grade purified water (UPLC conditions:) -Wavelength: 254nm and 280nm -Flow rate: 0.5ml / min -Column temperature: 25℃ -Autosampler temperature: 20℃ -Injection volume: 3μl -Analysis time: 6,0 minutes -Elution: Gradient [Table 36] (Mobile phase A:) Formic acid 0.1% v / v solution (Mobile phase B:) 0.1% v / v formic acid in acetonitrile (Syringe cleaning solution:) 100% acetonitrile (MS conditions:) -Mass range: 50~1000m / z -Ionization: Alternating -Scanning speed: 7500u / sec

[0426] (Activity Screening) (Glutaminyl cyclase, determination of IC50 value by assay, and calculation of Ki value) 10 mM compound stock solutions were prepared in DMSO. For IC50 determinations, compound stocks were serially diluted (1:3) in DMSO.

[0427] All measurements were performed on an EnSpire Perkin Elmer multimode reader using glutaminyl-7-amino-4-methylcoumarin (H-Gln-AMC) as substrate and recombinant pyroglutamyl aminopeptidase (pGAP) as co-enzyme. Reactions were performed in black 96-well half-area microplates at ambient temperature. Each sample consisted of 1 μl of test compound solution or solvent (DMSO) and 49 μl of QC appropriately diluted in assay buffer (50 mM Tris / HCl, pH 8.0 or 50 mM MES buffer, pH=6.0). After a 10 min preincubation at ambient temperature, the enzymatic reaction was started by adding 50 μl of Gln-AMC-substrate / pGAP mixture in assay buffer. The final substrate concentrations were 50 and 200 μM for measurements at pH 8.0 or 6.0, respectively. The emission of fluorescent AMC was recorded at excitation / emission wavelengths of 380 / 460 nm. The initial rate of the enzymatic reaction was calculated by linear regression of the first 10 data points using Enspire Manager software. Final evaluation and calculation of IC50 was performed using GraphPad Prism software. IC50 values ​​were calculated from normalized data (QC activity without inhibitor = 100%) by nonlinear regression with a 4-parameter logistic equation.

[0428] Ki values ​​were calculated according to the following formula: Ki = IC50 / (1 + [S] / Km), where [S] denotes the concentration of substrate in the assay (200 μM for pH 6.0 and 50 μM for pH 8.0), and Km is the respective Michaelis-Menten constant (390 μM at pH 6.0 and 62 μM at pH 8.0).

[0429] (MALDI-TOF mass spectrometry) Matrix-assisted laser desorption / ionization mass spectrometry was performed using a Hewlett-Packard G2025 LD-TOF system with a linear time-of-flight analyzer. The instrument was equipped with a 337 nm nitrogen laser, a potential acceleration source (5 kV), and a 1.0 m flight tube. The detector was operated in positive ion mode. Signals were recorded and filtered using a LeCroy 9350M digital storage oscilloscope connected to a personal computer. Samples (5 μl) were mixed with an equal volume of matrix solution. For the matrix solution, DHAP / DAHC was used, which was prepared by dissolving 30 mg of 2',6'-dihydroxyacetophenone (Aldrich) and 44 mg of diammonium hydrogen citrate (Fluka) in 1 ml acetonitrile / 0.1% TFA (1:1 (v / v)) in water. A small amount (approximately 1 μl) of the matrix-analyte mixture was transferred to the probe tip and immediately evaporated in a vacuum chamber (Hewlett-Packard G2024A Sample Preparation Accessory) to ensure rapid and homogenous sample crystallization.

[0430] Long-term Glu 1 -For cyclization studies, Aβ-derived peptides were incubated at 30 °C in 100 μl of 0.1 M sodium acetate buffer (pH 5.2) or 0.1 M Bis-Tris buffer (pH 6.5). Peptides were applied at a concentration of 0.5 mM [Aβ(3-11)a] or 0.15 mM [Aβ(3-21)a] and 0.2 U of QC was added for a total of 24 h. In the case of Aβ(3-21)a, the assay contained 1% DMSO. At various time points, samples were removed from the assay tubes and peptides were extracted using ZipTips (Millipore) according to the manufacturer's recommendations and mixed with matrix solution (1:1 (v / v)), after which mass spectra were recorded. Negative controls contained either no QC or heat-inactivated enzyme. For inhibitor testing, the sample composition was the same as above, except for the addition of inhibitor compound (5 mM or 2 mM of the test compound of the invention).

[0431] The compounds and combinations of the present invention may have advantages over other compounds of the prior art, for example, being more potent, selective, having fewer side effects, having better formulation and stability properties, having better pharmacokinetic properties, having greater bioavailability, being able to cross the blood-brain barrier and being effective in the mammalian brain, being compatible or effective in combination with other drugs, or being easily synthesized.

[0432] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be understood to imply the inclusion of a stated integer, step, group of integers, or group of steps, but not the exclusion of any other integer, step, group of integers, or group of steps.

[0433] All patents and patent applications mentioned throughout this specification are hereby incorporated by reference in their entirety.

[0434] The present invention includes all combinations of the preferred and more preferred groups and embodiments of the groups listed above. The present application provides the following aspects of the invention. (Aspect 1) A compound of Formula I, or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers thereof: (chemical 1) TIFF0007674811000339.tif9170 (In the formula: A is, (chemical 2) TIFF0007674811000340.tif67170 monocyclic and bicyclic heteroaryl selected from B is selected from alkyl, heteroalkyl, alkyl-amino, aryl, heteroaryl, cycloalkyl, heterocyclyl, and alkylene, wherein said groups are optionally and independently substituted with alkyl; D is selected from aryl-amino, heteroaryl-amino, cycloalkyl-amino, heterocyclyl, heterocyclyl-amino, sulfonamido, sulfoximine, and sulfamoyl, where the aryl, heteroaryl, cycloalkyl, and heterocyclyl groups are optionally independently substituted with one or more substituents; E is selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl, where the aryl, heteroaryl, cycloalkyl, and heterocyclyl groups are optionally independently substituted with one or more substituents; The heteroaryl, cycloalkyl, and heterocyclyl groups are optionally independently substituted with one or more substituents; however, i) when B is alkyl or heteroalkyl, D may not be a sulfonamide; and ii) The compound of formula (I) is (3) TIFF0007674811000341.tif122170 (not a compound selected from the group consisting of (Aspect 2) The compound according to embodiment 1, wherein A is a monocyclic heteroaryl selected from thiadiazolyl, thiazolyl, and triazolyl, and said monocyclic heteroaryl is substituted with amino or methyl; or A is a bicyclic heteroaryl selected from benzimidazole and imidazopyridine. (Aspect 3) A, (C4) TIFF0007674811000342.tif69170 3. The compound according to embodiment 1 or 2, selected from: (Aspect 4) B is C 3-5 -heteroalkyl, phenyl, C 5 -C 6 -heterocyclyl, and C 1-5 alkylene, wherein the C 1-5 The compound according to any one of embodiments 1 to 3, wherein the alkylene groups are optionally and independently substituted with alkyl. (Aspect 5) B, (C5) TIFF0007674811000343.tif17170 (where X 1 is alkyl, N, O, or S, preferably methyl or S; and n is 1 or 2; (6) TIFF0007674811000344.tif24170 (wherein o is 0 or 1; and p is 0 or 1); and (C7) TIFF0007674811000345.tif24170 (where R 1 is hydrogen or alkyl, and q is 0, 1, or 2. The compound according to any one of embodiments 1 to 4, selected from: (Aspect 6) D, (8) TIFF0007674811000346.tif140170 is a group selected from Where: R is absent or is hydrogen; or R together with the nitrogen atom to which it is attached forms a heterocyclic ring of group B; R 2 is hydrogen, alkyl, or cycloalkyl; Y 1 、Y 2 、Y 3 , and Y 4 is independently selected from CH, N, S, and O; Y 4 is optionally substituted with alkyl or halogen; A compound according to any one of embodiments 1 to 5. (Aspect 7) E, (9) TIFF0007674811000347.tif51170 and Where: Y 5 is C and Y 6 ~Y 10 is independently selected from CH, N, or O; and R 3 、R 4 、R 5 、R 6 , and R 7 is independently selected from hydrogen, halogen, alkyl, O-alkyl, O-phenyl, and O-cycloalkyl; The compound according to any one of embodiments 1 to 6. (Aspect 8) The compound according to any one of embodiments 1 to 7, which is a compound of formula (IIa) or (IIb): (C10) TIFF0007674811000348.tif143170 (In the formula, Z is selected from CH and N; X 1 is selected from alkyl, N, O, S; n is 1 or 2; Y 1 ~Y 4 and Y 6 ~Y 10 is independently selected from CH, N, S, and O; Y 5 is C; R 5 is selected from halogen, alkyl, and O-alkyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl. (Aspect 9) The compound according to any one of embodiments 1 to 7, which is a compound of formula (IIIa) or (IIIb): (Chem.11) TIFF0007674811000349.tif142170 (In the formula, X 1 is selected from alkyl, N, O, S; n is 1 or 2; Y 1 ~Y 4 and Y 6 ~Y 10 is independently selected from CH, N, S, and O; Y 5 is C; R 5 is selected from halogen, alkyl, and O-alkyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl. (Aspect 10) The compound according to any one of embodiments 1 to 7, which is a compound of formula (IVa) or (IVb): (C12) TIFF0007674811000350.tif156170 (In the formula, Z is selected from CH and N; o is 0 or 1; p is 0 or 1; Y 1 ~Y 4 and Y 6 ~Y 10 is independently selected from CH, N, S, and O; Y 5 is C; R 5 is selected from halogen, alkyl, O-alkyl, and O-phenyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl. (Aspect 11) The compound according to any one of embodiments 1 to 7, which is a compound of formula (Va) or formula (Vb): (C13) TIFF0007674811000351.tif179170 (In the formula, o is 0 or 1; p is 0 or 1; Y 1 ~Y 4 and Y 6 ~Y 10 is independently selected from CH, N, S, and O; Y 5 is C; R 5 is selected from halogen, alkyl, O-alkyl, and O-phenyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl. (Aspect 12) The compound according to any one of embodiments 1 to 7, which is a compound of formula (VI): (C14) TIFF0007674811000352.tif63170 (In the formula, Z is selected from CH and N; X 1 is selected from alkyl, N, O, S; n is 1 or 2; R 5 is selected from halogen, alkyl, and O-alkyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl. (Aspect 13) The compound according to any one of embodiments 1 to 7, which is a compound of formula (VII): (C15) TIFF0007674811000353.tif64170 (In the formula, Z is selected from CH and N; X 1 is selected from alkyl, N, O, S; n is 1 or 2; R 2 is selected from alkyl and cycloalkyl; R 5 is selected from halogen, alkyl, and O-alkyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl. (Aspect 14) The compound according to any one of embodiments 1 to 7, which is a compound of formula (VIII): (C16) TIFF0007674811000354.tif64170 (In the formula, X 1 is selected from alkyl, N, O, S; n is 1 or 2; R 5 is selected from halogen, alkyl, and O-alkyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl. (Aspect 15) The compound according to any one of embodiments 1 to 7, which is a compound of formula (IX): (C17) TIFF0007674811000355.tif63170 (In the formula, X 1 is selected from alkyl, N, O, S; n is 1 or 2; R 2 is selected from alkyl and cycloalkyl; R 5 is selected from halogen, alkyl, and O-alkyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl. (Aspect 16) The compound according to any one of embodiments 1 to 7, which is a compound of formula (X): (C18) TIFF0007674811000356.tif77170 (In the formula, o is 0 or 1; p is 0 or 1; R 5 is selected from halogen, alkyl, and O-alkyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl. (Aspect 17) The compound according to any one of embodiments 1 to 7, which is a compound of formula (XI): (C19) TIFF0007674811000357.tif85170 (In the formula, o is 0 or 1; p is 0 or 1; R 2 is selected from alkyl and cycloalkyl; R 5 is selected from halogen, alkyl, and O-alkyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl. (Aspect 18) NR, (20) TIFF0007674811000358.tif34170 The compound of embodiment 6, wherein the compound is represented by: (Aspect 19) The compound according to any one of embodiments 1 to 7 and 18, which is a compound of formula (XIIa) or (XIIb): (21) TIFF0007674811000359.tif155170 (In the formula, Z is selected from CH and N; Y 1 ~Y 4 and Y 6 ~Y 10 is independently selected from CH, N, S, and O; Y 5 is C; R 5 is selected from halogen, alkyl, and O-alkyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl. (Aspect 20) The compound according to any one of embodiments 1 to 7 and 18, which is a compound of formula (XIII): (22) TIFF0007674811000360.tif37170 (In the formula, Z is selected from CH and N; R 5 is selected from halogen, alkyl, and O-alkyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl. (Aspect 21) The compound according to any one of embodiments 1 to 7 and 18, which is a compound of formula (XIV): (23) TIFF0007674811000361.tif39170 (In the formula, R 5 is selected from halogen, alkyl, and O-alkyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl. (Aspect 22) The compound according to any one of embodiments 1 to 7, which is a compound of formula (XVa) or (XVb): (24) TIFF0007674811000362.tif153170 (In the formula, Y 1 ~Y 4 and Y 6 ~Y 10 is independently selected from CH, N, S, and O; Y 5 is C; Y 4 is optionally substituted with alkyl or halogen; R 5 is selected from halogen, alkyl, O-alkyl, O-phenyl, and O-cycloalkyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl. (Aspect 23) The compound according to any one of embodiments 1 to 7, which is a compound of formula (XVI): (25) TIFF0007674811000363.tif58170 (In the formula, R 5 is selected from halogen, alkyl, and O-alkyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl. (Aspect 24) The compound according to any one of embodiments 1 to 7, which is a compound of formula (XVII): (26) TIFF0007674811000364.tif53170 (In the formula, R 2 is selected from alkyl and cycloalkyl; R 5 is selected from halogen, alkyl, and O-alkyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl. (Aspect 25) The compound according to any one of embodiments 1 to 7, which is a compound of formula (XVIII): (27) TIFF0007674811000365.tif43170 (In the formula, X 1 is selected from alkyl, N, O, S; n is 1 or 2; R 5 is selected from halogen, alkyl, and O-alkyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl. (Aspect 26) The compound according to embodiment 1 or 2, which is a compound of Examples 1-1323 or a pharma- ceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers. (Aspect 27) Includes all tautomers and stereoisomers: 5-[3-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)propyl]-1,3,4-thiadiazol-2-amine; 5-{[2-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine; 5-{[2-({3',4'-dimethoxy-[1,1'-biphenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine; 4'-Fluoro-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]-[1,1'-biphenyl]-2-amine; 3',4'-Dimethoxy-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]-[1,1'-biphenyl]-2-amine; 5-[4-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)phenyl]-1,3,4-thiadiazol-2-amine; 5-(4-{[2-(3,4-dimethoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine; 5-(4-{[2-(4-methoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-2-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-4-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(3,4-dimethoxyphenyl)pyridin-4-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyridin-2-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyrazin-2-amine; 5-(4-{[2-(4-phenoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine; 5-(4-{[2-(4-propoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine; 5-[4-({2-[4-(propan-2-yloxy)phenyl]phenyl}amino)phenyl]-1,3,4-thiadiazol-2-amine; 4'-Fluoro-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[1,1'-biphenyl]-2-amine; 3',4'-Dimethoxy-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[1,1'-biphenyl]-2-amine; N-[2-(4-methoxyphenyl)phenyl]-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline; 2-(4-Methoxyphenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine; 2-(4-fluorophenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine; 4-(4-methyl-4H-1,2,4-triazol-3-yl)-N-[2-(4-phenoxyphenyl)phenyl]aniline; 3-(3,4-dimethoxyphenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-4-amine; N-[3-(5-amino-1,3,4-thiadiazol-2-yl)propyl]-4-fluorobenzene-1-sulfonamide; N-{2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]ethyl}-4-fluorobenzene-1-sulfonamide; 5-(3-{[(4-fluorophenyl)(methyl)oxo-λω-sulfanylidene]amino}propyl)-1,3,4-thiadiazol-2-amine; 4-Fluoro-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]benzene-1-sulfonamide; 4-Fluoro-N-{2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]ethyl}benzene-1-sulfonamide; [(3,4-dimethoxyphenyl)sulfamoyl]({2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]ethyl})amine; N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-4-fluorobenzene-1-sulfonamide; N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-3,4-dimethoxybenzene-1-sulfonamide; 5-(1-{4'-fluoro-[1,1'-biphenyl]-2-yl}piperidin-4-yl)-1,3,4-thiadiazol-2-amine; 5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3-thiazol-2-amine; 5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3,4-thiadiazol-2-amine; 1-(4-fluorobenzenesulfonyl)-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine; N-[(1H-1,3-benzodiazol-5-yl)methyl]-4'-fluoro-[1,1'-biphenyl]-2-amine; N-[(1H-1,3-benzodiazol-5-yl)methyl]-3',4'-dimethoxy-[1,1'-biphenyl]-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)pyridin-3-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-4-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-4-(4-methoxyphenyl)pyridin-3-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-5-(4-methoxyphenyl)pyrimidin-4-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyrazin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-4-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyrazin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-fluorophenyl)pyridin-3-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyridin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyrazin-2-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-phenoxyphenyl)aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(cyclohexyloxy)phenyl]aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-propoxyphenyl)aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(propan-2-yloxy)phenyl]aniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)-3-methylaniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-methylaniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-chlorophenyl)-3-fluoroaniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-fluoro-2-(4-fluorophenyl)aniline; N-[(1H-1,3-benzodiazol-5-yl)methyl]-4-fluorobenzene-1-sulfonamide; and [(1H-1,3-benzodiazol-5-yl)methyl][(4-fluorophenyl)(methyl)oxo-λω-sulfanylidene]amine; or a pharma- ceutically acceptable salt, solvate, or polymorph thereof. (Aspect 28) A compound of formula I according to any one of embodiments 1 to 27 for use as a medicament. (Aspect 29) A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 27, optionally in combination with one or more therapeutically acceptable diluents or carriers. (Aspect 30) 30. The pharmaceutical composition of embodiment 29, further comprising at least one compound selected from the group consisting of neuroprotectants, anti-Parkinson's agents, amyloid protein deposition inhibitors, beta-amyloid synthesis inhibitors, antidepressants, anti-anxiety agents, antipsychotic agents, and anti-multiple sclerosis agents. (Aspect 31) PEP-inhibitors, LiCl, inhibitors of DP IV or inhibitors of DP IV-like enzymes, acetylcholinesterase (ACE) inhibitors, PIMT enhancers, inhibitors of beta-secretase, inhibitors of gamma-secretase, inhibitors of neutral endopeptidase, inhibitors of phosphodiesterase-4 (PDE-4), TNFα inhibitors, muscarinic M1 receptor antagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulators, immunosuppressants, or Antegren (natalizumab), Neurelan (fampridine-SR), Campath (alemtuzumab), IR 208, NBI 5788 / MSP 771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD271, adapalene), BAY 31. The pharmaceutical composition of embodiment 29 or 30, further comprising at least one compound selected from the group consisting of agents selected from the group consisting of 361677 (interleukin-4), matrix metalloproteinase inhibitors, interferon-tau (trophoblastin), and SAIK-MS. (Aspect 32) 32. A compound according to any one of embodiments 1 to 27 or a pharmaceutical composition according to any one of embodiments 28 to 31 for use in the treatment of a disease selected from the group consisting of Kennedy's disease, duodenal cancer with or without Helicobacter pylori infection, colorectal cancer, Zolliger-Ellison syndrome, gastric cancer with or without Helicobacter pylori infection, pathological psychotic states, schizophrenia, infertility, neoplasia, inflammatory host response, cancer, malignant metastasis, melanoma, psoriasis, disorders of humoral and cellular immune responses, leukocyte adhesion and migration processes in the endothelium, eating disorders, sleep disorders - insomnia, disorders of homeostatic regulation of energy metabolism, disorders of autonomic function, disorders of hormonal balance or disorders of fluid regulation, multiple sclerosis, Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy. (Aspect 33) A compound according to any one of embodiments 1 to 27 or a pharmaceutical composition according to any one of embodiments 28 to 31 for use in the treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, Down's Syndrome neurodegeneration, and Huntington's Disease. (Aspect 34) A compound according to any one of embodiments 1 to 27 or a pharmaceutical composition according to any one of embodiments 28 to 31 for use in the treatment of a disease selected from the group consisting of rheumatoid arthritis, atherosclerosis, pancreatitis, and restenosis. (Aspect 35) 32. A method for the treatment or prevention of a disease selected from the group consisting of Kennedy's disease, ulcer disease, duodenal cancer with or without Helicobacter pylori infection, colorectal cancer, Zolliger-Ellison syndrome, gastric cancer with or without Helicobacter pylori infection, pathological psychotic states, schizophrenia, infertility, neoplasia, inflammatory host response, cancer, malignant metastasis, melanoma, psoriasis, disorders of humoral and cellular immune responses, leukocyte adhesion and migration processes in the endothelium, eating disorders, sleep disorders - insomnia, disorders of homeostatic regulation of energy metabolism, disorders of autonomic function, disorders of hormone balance or disorders of fluid regulation, multiple sclerosis, Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy, said method comprising administering to a subject an effective amount of a compound according to any one of embodiments 1 to 27 or a pharmaceutical composition according to any one of embodiments 28 to 31. (Aspect 36) 32. A method for treating or preventing a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, Down's Syndrome neurodegeneration, and Huntington's disease, comprising administering to a subject an effective amount of a compound according to any one of Aspects 1 to 27 or a pharmaceutical composition according to any one of Aspects 28 to 31. (Aspect 37) A method for treating or preventing a disease selected from the group consisting of rheumatoid arthritis, atherosclerosis, pancreatitis, and restenosis, the method comprising administering to a subject an effective amount of a compound according to any one of Aspects 1 to 27 or a pharmaceutical composition according to any one of Aspects 28 to 31.

Claims

1. A compound of formula I, or a pharma- ceutically acceptable salt, or solvate thereof, including all tautomers and stereoisomers thereof: 【Chemistry 1】 (In the formula: A is, 【Chemistry 2】 Selected from; B is, 【Chemistry 3】 where X is 1 is CH 2 or S, and n is 1 or 2 (provided that B is 【Chemistry 4】 then D is not a sulfonamide); D is a compound of the formula: 【Chemistry 5】 wherein R is hydrogen or NR is B. 【Chemistry 6】 Together with the formula: 【Chemistry 7】 forming a heterocyclic ring of the formula: 【Chemistry 8】 where R is hydrogen; or NR is B. 【Chemistry 9】 Together with the formula: 【Chemistry 10】 forming a heterocyclic ring of the formula: Y 1 , Y 2 , Y 3 , and Y 4 is independently selected from CH and N; and Y 4 If CH, then Y 4 is selected from the group consisting of alkyl, halogen, and E is selected from aryl and heteroaryl, where the aryl and heteroaryl groups are optionally substituted with one or more substituents independently selected from halogen, alkyl, O-alkyl, O-phenyl, and O-cycloalkyl.

2. B, 【Chemistry 11】 (where X 1 is CH 2 or S; and n is 1 or 2.

3. D, 【Chemistry 12】 and Where: R is hydrogen; Y 1 , Y 2 , Y 3 , and Y 4 is independently selected from CH and N; and Y 4 If CH, then Y 4 is optionally substituted with alkyl; 3. A compound according to claim 1 or 2.

4. E, 【Chemistry 13】 and Where: Y 5 is C; Y 6 ~Y 10 is independently selected from C or N; Y 6 ~Y 10 If C, then R 3 , R 4 , R 5 , R 6 , and R 7 is independently selected from hydrogen, halogen, alkyl, O-alkyl, O-phenyl, and O-cycloalkyl; and Y 6 ~Y 10 If N, then R 3 , R 4 , R 5 , R 6 , and R 7 does not exist, A compound according to any one of claims 1 to 3.

5. The compound according to any one of claims 1 to 4, which is a compound of formula (IIa): 【Chemistry 14】 (In the formula, Z is selected from CH and N; X 1 is CH 2 and S; n is 1 or 2; Y 1 ~Y 4 and Y 6 , Y 7 and Y 10 is independently selected from CH and N; Y 5 is C; Y 8 and Y 9 is independently selected from C and N; Y 8 If C, then R 5 is selected from halogen, alkyl, and O-alkyl, and Y 8 If N, then R 5 does not exist; Y 9 If C, then R 6 is selected from hydrogen, alkyl, and O-alkyl, and Y 9 If N, then R 6 does not exist).

6. Compound of formula (IVa): 【Chemistry 15】 (In the formula, Z is selected from CH and N; o is 0 or 1; p is 0 or 1; Y 1 ~Y 4 and Y 6 , Y 7 and Y 10 is independently selected from CH and N; Y 5 is C; Y 8 and Y 9 is independently selected from C and N; Y 8 If C, then R 5 is selected from halogen, alkyl, and O-alkyl, and Y 8 If N, then R 5 does not exist; Y 9 If C, then R 6 is selected from hydrogen, alkyl, and O-alkyl, and Y 9 If N, then R 6 does not exist).

7. Compounds of formula (X): 【Chemistry 16】 (In the formula, o is 0 or 1; p is 0 or 1; R 5 is selected from halogen, alkyl, and O-alkyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl.

8. NR, 【Chemistry 17】 4. The compound of claim 3, represented by:

9. The compound according to any one of claims 1 to 4 and 8, which is a compound of formula (XIIa): 【Chemistry 18】 (In the formula, Z is selected from CH and N; Y 1 ~Y 4 and Y 6 , Y 7 and Y 10 is independently selected from CH and N; Y 5 is C; Y 8 and Y 9 is independently selected from C and N; Y 8 If C, then R 5 is selected from halogen, alkyl, and O-alkyl, and Y 8 If N, then R 5 does not exist; Y 9 If C, then R 6 is selected from hydrogen, alkyl, and O-alkyl, and Y 9 If N, then R 6 does not exist).

10. The compound according to any one of claims 1 to 4 and 8, which is a compound of formula (XIII): 【Chemistry 19】 (In the formula, Z is selected from CH and N; R 5 is selected from halogen, alkyl, and O-alkyl; and R 6 is selected from hydrogen, alkyl, and O-alkyl.

11. Including all tautomers and stereoisomers thereof: 5-[3-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)propyl]-1,3,4-thiadiazol-2-amine; 5-{[2-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine; 5-{[2-({3',4'-dimethoxy-[1,1'-biphenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine; 5-[4-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)phenyl]-1,3,4-thiadiazol-2-amine; 5-(4-{[2-(3,4-dimethoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine; 5-(4-{[2-(4-methoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-2-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-4-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(3,4-dimethoxyphenyl)pyridin-4-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyridin-2-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyrazin-2-amine; 5-(4-{[2-(4-phenoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine; 5-(4-{[2-(4-propoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine; 5-[4-({2-[4-(propan-2-yloxy)phenyl]phenyl}amino)phenyl]-1,3,4-thiadiazol-2-amine; N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-4-fluorobenzene-1-sulfonamide; N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-3,4-dimethoxybenzene-1-sulfonamide; 5-(1-{4'-fluoro-[1,1'-biphenyl]-2-yl}piperidin-4-yl)-1,3,4-thiadiazol-2-amine; 5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3-thiazol-2-amine; 5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3,4-thiadiazol-2-amine; 2. The compound of claim 1, which is selected from the group consisting of:

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, optionally in combination with one or more therapeutically acceptable diluents or carriers.

14. 14. The pharmaceutical composition of claim 12 or 13, further comprising at least one compound selected from the group consisting of neuroprotectants, anti-Parkinson's agents, amyloid protein deposition inhibitors, beta-amyloid synthesis inhibitors, antidepressants, anti-anxiety agents, antipsychotic agents, and anti-multiple sclerosis agents.

15. PEP-inhibitors, LiCl, inhibitors of DP IV or DP IV-like enzymes, acetylcholinesterase (ACE) inhibitors, PIMT enhancers, inhibitors of beta-secretase, inhibitors of gamma-secretase, inhibitors of neutral endopeptidase, inhibitors of phosphodiesterase-4 (PDE-4), TNFα inhibitors, muscarinic M1 receptor antagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulators, immunosuppressants, or Antegren (natalizumab), Neurelan (fampridine-SR), Campath (alemtuzumab), IR 208, NBI 5788 / MSP 771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD271, adapalene), BAY 15. The pharmaceutical composition of any one of claims 12 to 14, further comprising at least one compound selected from the group consisting of agents selected from the group consisting of 361677 (interleukin-4), matrix metalloproteinase inhibitors, interferon-tau (trophoblastin), and SAIK-MS.

16. 16. The pharmaceutical composition according to any one of claims 12 to 15, for use in the treatment of a disease selected from the group consisting of Kennedy's disease, duodenal cancer with or without Helicobacter pylori infection, colorectal cancer, Zolliger-Ellison syndrome, gastric cancer with or without Helicobacter pylori infection, pathological psychotic states, schizophrenia, infertility, neoplasia, inflammatory host response, cancer, malignant metastasis, melanoma, psoriasis, disorders of humoral and cellular immune responses, leukocyte adhesion and migration processes in the endothelium, eating disorders, sleep disorders - insomnia, disorders of homeostatic regulation of energy metabolism, disorders of autonomic function, disorders of hormone balance or disorders of fluid regulation, multiple sclerosis, Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy.

17. 16. The pharmaceutical composition of any one of claims 12 to 15, for use in the treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, Down's Syndrome neurodegeneration, and Huntington's disease.

18. 16. The pharmaceutical composition according to any one of claims 12 to 15, for use in the treatment of a disease selected from the group consisting of rheumatoid arthritis, atherosclerosis, pancreatitis, and restenosis.

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